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MKSAP17
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Chapter13:CutaneousManifestationsofInternalDisease
RelatedQuestions
Previous:AutoimmuneBlisteringDiseases

CutaneousManifestationsofInternalDisease

Rheumatology
LupusErythematosus
RelatedQuestions
Question26
Question72
Thecutaneousmanifestationsoflupuserythematosus(LE)areessentialforclinicianstorecognizebecauseskinfindingsarekey
diagnosticcriteria.Becausethesubtypesoflupusareimportanttodistinguish,thedermatologicexaminationiscrucial.Skinlesions
maybeeitherspecificornonspecific.Lupusspecificskinlesionsarecutaneoussignsoflupusthatarecharacteristicofthedisease
andwhenbiopsiedshowdiagnostichistologicfindings(interfacereactionoflymphocytesatthedermalepidermaljunction
causingdamagetothebaseoftheepidermis).Inaddition,patientswithlupuscanalsoexperiencelupusnonspecificskinlesions
representingcutaneoussequelaeofthedisease(Table21).
Table21.OpeninNewWindowTypesofLupusLesions
LupusSpecificSkinLesions
Malarbutterflyrash(acutelupus)

NonspecificCutaneousManifestationsofLupus
Livedoreticularis

Annularscalypatches(subacutelupus) Vasculitis

Psoriasiformpatches(subacutelupus)

Urticaria(generallyatypicalurticariallesionslastingmorethan24hoursandleaving
bruising)

Discoidlesions(chroniccutaneous
lupus)

Lobularpanniculitis

Oralulcers
Alopecia
Themalarrashofacutecutaneouslupusconsistsofbrighterythematouspatchesoverbothcheeksandthenasalbridge,almost
alwayssparingthenasolabialfolds(incontrasttothemoreviolaceousfacialerythemaofdermatomyositis,whichofteninvolves
thatcrease)(Figure94).Othercommonlymistakenentitiesincluderosacea,whichoftenhasinflammatorypapulesandsmall
pustules,aswellastelangiectasias,bothofwhichareraretoabsentinlupus,andseborrheicdermatitis,whichisoftencharacterized
byagreasyscaleandtendstoinvolvethenasolabialfolds,eyebrows,andoftenthescalpaswell.
Figure94.OpeninNewWindow

Erythematousplaquesinvolvingthebridgeofthenoseandmalarareaswithsparingofthenasolabialfoldscharacteristicofacute
cutaneouslupuserythematosus.

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Theclassicdiscoidlupuslesionisadyspigmentedpatchorplaquethatmaybeeitheratrophicorhyperkeratotic,withassociated
scarringwithinlesions.Theseoccurinsunexposedareassuchasthefaceandscalporwithintheconchalbowloftheear
(Figure95).
Figure95.OpeninNewWindow

Discoidlupuserythematosuswithactivelesionscharacterizedbyerythematoustoviolaceousinflammatorypatchesandplaques
withraisedbordersandscaling,andchronicareasofdamageconsistingofhyperorhypopigmentedtodyspigmented,scarred,
atrophic,depressedplaques.

AlesswidelyknownsubtypeofcutaneouslupusissubacutecutaneousLE(SCLE).Thetypicalclinicaleruptionconsistsofcircular
orpolycyclicscalyerythematouspatchesandpapulosquamousplaquesovertheforearms,chest,orespeciallytheupperback,inaV
shapedconfiguration.
Lesscommonvariantsofcutaneouslupusarelupuspanniculitis,withinflammationconfinedtothefattyareas,whichoftenpresents
withdelllike(shallow,smooth)depressionsoftheproximalextremitiesbullouslupuserythematosus,whichmaypresentwith
blisterswithinoraroundthemoreclassiclupuslesionsandtumidlupus,whichpresentswithdeeplyinduratedsubcutaneous
plaques.
PatientswiththemalarrashofacuteLEshouldreceiveathoroughevaluationforsystemicinvolvement.Thesepatientsareathigh
riskforlupusnephritisandsevereinternaldisease.DiagnosisofSCLEshouldpromptevaluationofpatients'medications,asthis
eruptionisassociatedwithalonglistofpotentialcausativemedications,includinghydrochlorothiazide,calciumchannelblockers,
ACEinhibitors,terbinafine,andtheTNFinhibitors.PatientswithSCLEareoftenphotosensitiveandfrequentlywillbe
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seropositiveforantinuclearantibody(ANA),antiRo/SSA,orantiLa/SSBantibodies.Antihistoneantibodypositivityisnonspecific
butmaybeacluethatthereactionisassociatedwithamedication,althoughthisisonlypresentinaboutonethirdofpatients(even
ifamedicationmaybethecause).AsubsetofpatientswithSCLEwillhavekidneyinvolvement,andathoroughevaluationis
warranted.Recognitionofthisentityisessentialaspatientsmaybeinappropriatelytreatedforsystemiclupuserythematosus(SLE)
whentheyhavedruginducedSCLE,anddiscontinuationoftheincitingcausativemedicationisparamount.Patientswithdiscoid
lesionsofchroniccutaneouslupusfrequentlydevelopirreversiblescarringandmayrequireearlyaggressivetherapyeveninthe
absenceofsignificantsystemicinvolvement.
Lupus,likemanyautoimmuneskindiseases,isexacerbatedbyultraviolet(UV)light.Patientswithstablediseasemayexperience
severediseaseflareswhenontripstosunnylocationsorastheseasonsshifttowardspringandsummer.Photoprotectionisan
essentialpartoftherapy.Patientsshouldbecounseledtoavoidsunexposure,wearUVblockingclothing,andapplyandreapply
broadspectrumsunblock(includingextendedspectrumUVAblockingchemicalsunscreens,ofteninconjunctionwithphysical
blockingagentssuchaszincoxideandtitaniumoxide).Mostmedicationsforcutaneouslupusareusedofflabel.Topical
glucocorticoids,topicaltacrolimus,topicalretinoids,andinjectionsofglucocorticoidsmayhelpimproveindividuallesionsor
limitedskindisease.Firstlinesystemictherapyiswithantimalarialagents,usuallyhydroxychloroquine.Patientswithrefractory
diseasewillsometimesrespondtothalidomideadditionaloptionsincludealternateorcombinationantimalarialdrugs,methotrexate,
mycophenolatemofetil,cyclosporine,dapsone,andcombinationimmunosuppressanttherapy.Patientswhofailtorespondto
antimalarialagents,orthosewithextensiveskininvolvementorsignsofscarring,shouldbereferredtoaspecialist.

KeyPoints
Patientswiththemalarrashofacutelupuserythematosusshouldreceiveathoroughevaluationforsystemicinvolvement
theyareathighriskforlupusnephritisandsevereinternaldisease.
Subacutecutaneouslupuserythematosusisadruginduced,photosensitiveeruptionofcircular,scaly,erythematouspatches
overtheforearms,chest,orupperbackpotentialcausessuchashydrochlorothiazide,calciumchannelblockers,ACE
inhibitors,terbinafine,andtheTNFinhibitorsshouldbeidentifiedanddiscontinuedimmediately.
Sunprotection,topicalglucocorticoids,andhydroxychloroquineareusedtotreatcutaneouslupuserythematosus.
Firstlinesystemictherapyforcutaneouslupuserythematosusiswithantimalarialagents,usuallyhydroxychloroquine.

Dermatomyositis
RelatedQuestion
Question18
Dermatomyositiscanoccurastheclassicform,withskininvolvementandmuscleinflammation,orasamyopathicor
hypomyopathicdermatomyositis,witheithercutaneousdiseaseonlyorwithminimalmuscleinflammation,respectively.
Amyopathicdermatomyositisisalmostascommonasclassicdermatomyositis,andrecognitionofthecutaneousfeaturesisessential
(seeMKSAP17Rheumatology).
ThepathognomoniccutaneousfeaturesofdermatomyositisaretheheliotroperashandGottronpapules.Theheliotroperashis
namedafterapurpleflower,heliotrope,whichmovestofacethesun,anaptnamethatcapturesboththecharacteristiccolorofthe
cutaneousinflammationindermatomyositisandtheimportantrolethatultravioletlightmayplayinexacerbatingthisdisease.The
heliotroperashisadistinctivepurpleorlilacerythemaoftheeyelidsthatmaybeaccompaniedbyedema(Figure96).
Figure96.OpeninNewWindow

Theheliotroperashofdermatomyositisisadistinctivepurpleorlilac,symmetricerythemaoftheeyelidsthatmaybeaccompanied
byslightedema,generallyfocusedaroundtheorbits.

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Gottronpapulesareerythematoustoslightlyviolaceous,flat,atrophicappearingpapulesconcentratedovertaut,stretchedextensor
surfaces,particularlytheinterphalangealjointsorelbows(Figure97).Patientsfrequentlyexhibitinflammationoftheproximalnail
fold,whichmaybeflat,atrophic,andpink,andoftenshowsperiungualtelangiectasiasorfrayedcuticles.
Figure97.OpeninNewWindow

Gottronpapulesareviolaceousslightlyscalyplaquesoverthebonyprominencesonthehands.

Patientswithdermatomyositisoftenexhibitcutaneousinflammationdirectlyoverlyingthejointsofthehands(namely,theproximal
interphalangeal,distalinterphalangeal,andmetacarpophalangealjoints),whereaspatientswithlupusoftenexhibitcutaneous
inflammationintheoverlyingspacebetweenthejoints.Patientswithdermatomyositiswillfrequentlyhaveareasofpoikiloderma
withilldefinedpatchyerythemaandsaltandpepperdyspigmentationaccompaniedbytelangiectasiasonthechestorupperback.
TheremaybeslightlyviolaceouserythemaovertheVoftheneck,chest,andtheupperback(theShawlsign)(Figure98)oron
thelateralhips(theholstersign).Patientsmayhaveviolaceouserythemaoftheface,frequentlyinvolvingthenasolabialfold,
upperextremities,andtrunk.Scalperythemaisverycommonindermatomyositis.Patientswithdermatomyositisfrequentlyreport
lesionalpruritus.Thesepatientstypicallyhavenormalserumcreatinekinaseandaldolaselevels,butmayhaveevidenceof
subclinicalmuscleinflammationonMRIorelectromyogram.Notably,patientsmayhaveamyopathicdermatomyositiswithno
evidenceofmuscleinvolvementrecognitionofthisentityisabsolutelyessentialaspatientswithamyopathicdermatomyositisareat
thesameriskofinternaldiseaseaspatientswiththeclassicform.
Figure98.OpeninNewWindow

Dermatomyositis:erythemaoftheVoftheneckandchest.Therearephotodistributederythematousmaculesandpatcheswith
areasofpoikilodermaonthesunexposedpartoftheupperchest.

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Mechanic'shands,orthickened,scaly,hyperkeratoticskinonthetipsofthefingers,isassociatedwithinterstitiallungdisease,and
physiciansshouldconsiderbaselineimagingandpulmonaryfunctiontesting,includingDLCOmeasurementinthesepatients.
Dermatomyositisisoftendifficulttotreat.SimilartothosewithLE,patientswithdermatomyositisshouldpracticestrictsun
avoidance,wearprotectiveclothing,andfrequentlyapplybroadspectrumsunscreen.Topicalglucocorticoidsmaybeeffectivein
somepatients.Systemictherapyislimitedtoofflabeltreatmentandusuallyconsistsofantimalarialagents(suchas
hydroxychloroquine,chloroquine,quinacrine),ormethotrexateormycophenolatemofetilthereareanecdotalreportsdescribingthe
useofintravenousimmuneglobulin,dapsone,andsomeofthenewerbiologicagents.

KeyPoints
ThepathognomoniccutaneousfeaturesofdermatomyositisaretheheliotroperashandGottronpapules.
Dermatomyositismayoftenbetreatedeffectivelywithsunprotectionandtopicalglucocorticoidssystemictherapyusually
consistsofantimalarialagents.

VasculitisandVasculopathy
Vasculitis,aninflammationofthebloodvessels,canbecausedbydifferenttypesofinflammatorycells,andtheinflammationmay
occurindifferentsizedbloodvessels.Theclinicalmanifestations,histology,serologies,organsaffected,andtreatmentdependon
thesizeofthebloodvesselaffected.Vasculopathyisaninjurytothebloodvesselfromintravascularorluminalprocesses.Thiscan
beadepositionalprocess,suchascalciphylaxis,inwhichthevesselwallisinfiltratedwithcalciumandsubsequentthromboses,ora
thromboembolicprocess,whereinclotsformorembolizetodamagethevasculature,suchasincryoglobulinemiaor
antiphospholipidantibodysyndrome.
LivedoReticularis
RelatedQuestion
Question44
Livedoreticularisisasubtle,lacynetworkoffaintlypinkorbluishredvessels,usuallyseenonthelowerlegs(Figure99).Itisdue
tosluggishbloodflowthroughthevessels,butextravasationofblooddoesnotoccur,differentiatingitfrompurpuraorecchymoses.
Livedoreticulariscansometimesbeelicitedbykeepingaleginthedependentpositionifthisresolveswhenthelegisstraightened
horizontally,itislikelytobeanormalorphysiologicprocessratherthanapathologicprocess.Livedoreticularisisanonspecific
findingandmaybeseeninanyconditioninwhichthereisalteredbloodflowthroughthesuperficialvasculature(Table22).
Althoughtypicallytransient,livedoreticularismaysometimespersist,andifadvancedorlongstanding,ulcerationmayrarely
occur.
Figure99.OpeninNewWindow

Livedoreticularisisacutaneousreactionpatternthatproducesapinkorbluishred,mottled,netlikepatternontheskin.Itiscaused
byslowbloodflowthroughthesuperficialcutaneousvasculature.Itmostcommonlyaffectsthelowerextremities.

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Table22.OpeninNewWindowSelectedDiseasesandConditionsAssociatedwithLivedoReticularis
Disease/Condition

Example

Neurohumoral
diseases

Pheochromocytoma,carcinoidsyndrome

Hematologic
diseases

Polycythemiavera,leukemia,thrombocytosis

Hypercoagulable
states

Antiphospholipidantibodysyndrome

Paraproteinemias

Multiplemyelomaandassociatedtype1cryoglobulinemia

Autoimmune
diseases

Systemiclupuserythematosus,dermatomyositis,scleroderma,Sjgrensyndrome,Stilldisease,rheumatoid
arthritis,Feltysyndrome

Infections

ParvovirusB19,hepatitisC,syphilis,meningococcemia,pneumococcalsepsis,tuberculosis

Drugreactions

Amantadine,quinidine,warfarin,minocycline

Vasculitides

Polyarteritisnodosa,granulomatosiswithpolyangiitis,microscopicpolyarteritis,eosinophilicgranulomatosis
withpolyangiitis(formerlyknownasChurgStrausssyndrome),Takayasudisease,temporalarteritis

Calciphylaxis

Endstagekidneydiseasewithabnormalcalciumphosphorusproduct

Cholesterolemboli Oftenfollowinganintravascularproceduresuchasangiography
Endocarditis

Microvascular
occlusion
syndromes

Hemolyticuremicsyndrome,thromboticthrombocytopenicpurpura,disseminatedintravascularcoagulation,
heparinnecrosis,paroxysmalnocturnalhemoglobinuria

Cryoglobulinemia
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Purpura
RelatedQuestion
Question66
Purpuraistheresultofvascularcompromise,eitherfromvesselinflammationorplugging,causingsubcutaneousmicrohemorrhage.
Thenonblanchingredorpurpleskinlesionsresultfromthepresenceofextravascularerythrocyteswithinthedermis.Purpuric
lesionsshouldbedistinguishedfromecchymoses,asecchymoticlesionsaretypicallysmall,superficial,nonpalpable,anddisplay
multiplecolorsrangingfromredandpurpletoyellowandgreenfromthebreakdownofheme.Thesmallestpurpuricmaculesare
petechiae,whicharepinpointnonblanchingredmaculesusuallyseeninthesettingofloworabnormalplateletcounts.Purpuric
maculesandflatpatchesmayoccuronsunexposedareas(actinicorsolarpurpura)orinpatientsonchronicglucocorticoidtherapy
(duetothin,fragileskinandvasculature).
SmallVesselVasculitis
RelatedQuestion
Question61
Apalpableareaofthepurpura,usuallyasmallpinpointbarelyperceptiblepapulewithinthepurpuricmacule,maybeacluetoan
activesuperficialskinorsmallvesselvasculitis.Smallvesselvasculitis(alsocalledleukocytoclasticvasculitisorcutaneous
leukocytoclasticangiitis)isinflammationofthesmallestbloodvessels.Thisinflammationmayaffecttheskin,butthorough
evaluationofallothersmallvesselsisessential.Thepalpablepurpuriclesionstendtooccurrapidlyandsimultaneously,often
initiallyormoreprominentlyindependentareasandareasofpressure(includingelasticwaistbandsandsocklines).Smallvessel
vasculitissymptomsmayrangefromasymptomatictomilditchtoburningandtenderness(Figure100).Rapiddiagnosisis
important,assmallvesselvasculitismayaffectinternalorgans.Diagnosisismadebyskinbiopsy.Anypurpuriclesionswitha
palpablecomponentrequirethoroughinvestigationandmaywarrantadermatologyconsultation.
Figure100.OpeninNewWindow

Palpablepurpuraonthelowerleganddorsalfoot.Thenonblanchingredmaculesandsmallpapulesindicateareasofsmallvessel
vasculitisandextravasatedbloodduetovesselinjury.

Anotherformofsmallvesselinflammationisurticarialvasculitis,whichpresentswitheitherpersistenturticarialplaqueslasting
longerthan24hoursorurticariathatpresentswithtinglingpainratherthanpruritusandresolveswithbruiselike
hyperpigmentation.Biopsyisimportant,asurticarialvasculitisisassociatedwithunderlyingautoimmunedisease,mostcommonly
SLE,in50%ofpatients.
Smallvesselvasculitisisfrequentlyidiopathicbutmayoccurinthesettingofinfectionorsepsis,underlyingautoimmunedisease,
medicationreactions,or,rarely,malignancy.Patientsshouldbeevaluatedforextracutaneousmanifestations,withparticularattention
tokidneyinvolvement,andthelaboratoryevaluationmayincludeaurinalysis,comprehensivemetabolicpanel,completeblood
count,serumcomplementlevels,antinuclearantibodytiter,andevaluationforintravascularinfectionwhenappropriate.Athorough
historyandreviewofsystemsarenecessarytoassessforinternalmanifestationsandtoidentifyanypotentialtriggers.Druginduced
vasculitisisnotcommon,butthereisawiderangeofpotentialculpritmedicationstoconsider(antibiotics,particularlypenicillins
NSAIDshydralazineantiTNFagentsandsometargetedchemotherapeuticagents).Intheinpatientsetting,smallvessel
vasculitisisfrequentlyseeninpatientswithinfectivebacterialendocarditisorantibioticuse.Ifendocarditisorantibioticsisa
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potentialculprit,consultationwithanexperienceddermatologistisessential.Formildcases,itmaybeappropriatetocontinue
antibioticsandmonitorforprogressionifthevasculitisimproves,itmayhavebeenduetotheendocarditis.Ifthevasculitisworsens
oraffectsorgansbeyondtheskin(thatis,ifthereiskidneyinvolvement),changingtheantibioticregimenshouldbeconsidered.
Dependingontheseverityoftheeruption,skinlimitedcutaneoussmallvesselvasculitiscanbemanagedwithrestandelevation,
topicalglucocorticoids,NSAIDs(unlessimplicatedasapotentialcausativeagent),orantihistamines.Asthepathologicprocessis
neutrophilmediated,colchicineordapsonemaybeeffectiveinselectpatients.Patientswithsevereeruptions,includingrarebullous
eruptionsorulcerativelesions,orthosewithwidespreaddiseasemayrequiresystemicglucocorticoids.Mostpatientswithsmall
vesselvasculitishaveresolutionafterasingleepisodeorwhenthetriggerisidentifiedapproximately10%ofpatientswillhavea
chronic,intermittentcourse.

KeyPoints
Palpablepurpuraisamanifestationofsmallvesselvasculitis,andrapiddiagnosiswithskinbiopsyisessentialasthevasculitis
mayprogressivelyaffectinternalorgans(kidneys)andrequiresystemictreatment.
Skinlimitedcutaneoussmallvesselvasculitiscanbemanagedwithrestandelevation,topicalglucocorticoids,NSAIDs,or
antihistamines.
Cryoglobulinemia
Cryoglobulinsarecoldprecipitatingimmunoglobulinsthattypicallyremainsolubleatbodytemperaturebutmayprecipitateinthe
peripheralvasculatureawayfromthewarmerbodycore.Thisintravascularprecipitationleadstosmallvesselfibrinthrombiand
clotting,vascularinjurythatmayincludeanactiveinflammatoryvasculitis,anddownstreamtissueischemia(Figure101).
Clinically,thispresentsaseitherpalpablepurpura(ifthereisaninflammatorysmallvesselvasculitisduetospecifictypesof
cryoglobulinsthatleadtocomplementfixation)orretiform,angulatedpurpura(seeMKSAP17Rheumatology).
Figure101.OpeninNewWindow

Largeareaofjaggedlybranching,angulatedretiformpurpuraconsistentwithavascularinjuryprocess.Inthispatient,type1
cryoglobulinsprecipitatedinthesmallvesselsoftheskin,leadingtointravascularclotformationandvesselinjury,withoverlying
skinnecrosis.

RheumatoidArthritis
Theskinisinvolvedinasubsetofpatientswithrheumatoidarthritis(RA),eitherfromcutaneousmanifestationsofthediseaseor
complicationsoftreatment.RheumatoidnodulesarethemostcommoncutaneousmanifestationofRA,occurringinuptoonethird
ofpatients.Thesearetypicallyfirmsubcutaneousnodulesfoundoverextensorjointsortendons(Figure102).Theymaycomeand
goinparallelwiththeunderlyingjointinflammationduringtreatment.Thephenomenonofacceleratednodulosis,orskinnodules
developingrapidlywhilethearthritisisbeingtreatedandresponding,hasbeennotedasasideeffectofmanyRAmedications,
particularlymethotrexate.OtherformsofgranulomatousdermatitisseeninRAarepalisadedneutrophilicandgranulomatous
dermatitis,characterizedbysymmetric,crusted,umbilicated,pinkpapulesaroundtheelbows,andinterstitialgranulomatous
dermatitis,whichclassicallymanifestsasalinearerythematouscordonthetrunk.ArareskinmanifestationofRAisrheumatoid
vasculitis,whichisgenerallyseeninpatientswithchronic,severeRA.Itmaypresentasulceratedpurpuraorseverelivedo
reticularis.PatientswithRAwhoaretreatedwithTNFinhibitorsmaydevelopasecondarypsoriasiformeruption,including
severepalmoplantarpustulardermatitis.
Figure102.OpeninNewWindow

Firm,fleshcoloredpapulesovertheextensorelbowjointconsistentwithmultiplerheumatoidnodulesinapatientwithrheumatoid
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arthritis.

SclerosingDisorders
SclerosingdisordersarediscussedcomprehensivelyintheMKSAP17Rheumatologysection.Patientswithallformsofsclerosing
disordersmayexhibitskinfindingsrangingfrompuffyhandsofearlydiffusesystemicsclerosis(scleroderma),todiffuseskin
tighteningofadvanceddiffusesystemicsclerosis,tothecharacteristiccalcinosis,Raynaudphenomenon,esophagealdysfunction
syndrome,sclerodactyly,andtelangiectasiasoflimiteddiffusesystemicsclerosis(CREST).
Morphea,orlocalizedscleroderma,usuallypresentsasafocalpatchofskinthickeningwithoutinternalmanifestations.Morphea
mayoccurasoneorafewpatches(circumscribed),widespreadpatches(generalized),linearordiffusepatches(pansclerotic).When
morpheaextendsoverjointspaces,itcanimpactthemuscles,bones,andjointmobility.Recognitionisimportant,aspatientsareat
riskofbeingmisclassifiedashavingsystemicsclerosisandthusareinappropriatelytreated.Itisimportanttoexcludescleroderma
andCRESTsyndrome,andthenmanagementshouldbefocusedonsymptomcontrol,rangeofmotionpreservation(ifajointis
affected),andpreventionofnewlesionswithimmunomodulatoryorimmunosuppressiveagents.Whilethereislimitedevidenceof
efficacy,patientsmaybetreatedwithglucocorticoids,hydroxychloroquine,methotrexate,phototherapy,andsometimesantiTNF
agents,orotherimmunomodulatoryorimmunosuppressiveagents,dependingontheseverityandextentofthedisease.

Nephrology
Bothchronickidneydiseaseandadvancedliverdiseasearecommonlyassociatedwithintense,severepruritus,attributedtothe
accumulationoftoxins.Patientswithendstagekidneydiseaseoftenexhibitdry,xeroticskinandcommonlyhavesecondaryskin
changesfromchronicitchingandscratching,includingexcoriations,prurigonodules,andlichenifiedpatches.Somepatientsmay
develophyperpigmentedumbilicatedpapuleswithacentralkeratincore,orKyrledisease,inwhichcollagenfibersareextruded
throughtheepidermis.Pruritusfromkidneydiseaseshouldbemanagedwithlukewarmbaths,gentlesoaps,andthick,bland
emollientsseverepruritusmayrequiretopicalglucocorticoidsorphototherapy.Twoentitiesencounteredinchronickidneydisease
warrantparticularmention,calciphylaxisandnephrogenicsystemicfibrosis.

Calciphylaxis
RelatedQuestion
Question29
Calciphylaxistypicallyoccursinpatientswithadvancedkidneydysfunctionandelevatedcalciumphosphorusproducts(6070
mg2/dL2).Calciphylaxisoccursasaresultofabnormaldepositionofcalciumwithinthelumenofarterialvasculature,whichthen
compromisesflowandleadstoanincreasedriskofluminalthrombosisanddownstreamischemia,resultinginsubsequentpainful
tissuenecrosis.Notably,asinglemeasurementofnormalcalciumandphosphoruslevelsdoesnotexcludethediagnosis.Patients
receivingdialysismayhavemarkedfluctuationsinserumminerallevels,andthecalciumphosphoruslevelsmaybenormalatthe
timeofcalciphylaxisdiagnosisbutmayhavebeenmarkedlyabnormalattheonsetofdiseasethatdevelopedweeksbeforepatient
presentation.Calciphylaxisisrare,occurringinlessthan5%ofpatientsondialysis,butisassociatedwitha60%to80%1year
mortalityrate.Generally,patientshavenonhealingskinulcersthatdevelopanescharandsecondarybacterialcolonizationand
eventualinfectionandsepsis.Clinically,lesionsofcalciphylaxisareexquisitelypainfulsubcutaneousnodulesorplaqueswith
overlyingredbrowndiscolorationandoftensuperimposedangulatedpurpuricpatches,oftenwithcentralnecrosis.Patientswith
advancedcalciphylaxismayhaveulcerationorlarge,thick,blackescharformation.Lesionsusuallyoccurinhighfatareasandare
commonlyseenonthelowerextremities(especiallythethighs)(Figure103).Sodiumthiosulfatemaybehelpfulintreatingthe
disease,possiblypartiallybycausingthedepositedcalciumwithinthevesselstoremineralize,mobilize,andberemovedthrough
dialysis.Othertreatmentsaretheuseofalowcalciumdialysateandeffortstoreduceoverallserumcalciumandphosphorouslevels,
maintaininganormalparathyroidhormonelevel(byeitherchemicalorsurgicalparathyroidectomy),cautioususeof
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bisphosphonatesinselectpatients,andavoidingpotentialtriggers(suchassystemicglucocorticoidsandwarfarin).Meticulous
woundcareandsurgicalevaluationwithlimiteddebridementarealsoimportanthyperbaricoxygenmayalsobebeneficial.Theuse
ofthrombolyticagentsmayaidreperfusionbutcarriesahighriskofseverebleedingcomplications.
Figure103.OpeninNewWindow

Calciphylaxismanifestsaspainfulsubcutaneousnodulesorplaqueswithoverlyingredbrowndiscolorationandoftensuperimposed
angulatedpurpuricpatches,oftenwithcentralnecrosis.

KeyPoints
Calciphylaxistypicallyoccursinpatientswithadvancedkidneydysfunctionandelevatedcalciumphosphorusproducts.
Calciphylaxislesionsarepainfulsubcutaneousnodulesorplaqueswithoverlyingredbrowndiscolorationandangulated
purpuricpatches,oftenwithcentralnecrosispatientswithadvanceddiseasemayhaveulcerationorblackescharformation.

NephrogenicSystemicFibrosis
Nephrogenicsystemicfibrosis(NSF)isarelativelyrecentlydescribedentityfirstrecognizedintheearly2000s.Thefirstpatients
weredescribedinthelate1990saspresentingwithwhatwastermedascleromyxedemalikeillnessofkidneydisease,withdistal
skinpainandthickeningandlossofmobility(Figure104).EpidemiologicstudiesimplicatedtheuseofgadoliniumbasedMRI
contrastagentsadministeredinthesettingofacidemiafromkidneydiseaseasakeytriggerhowever,thelimitednumbersof
affectedpatientscomparedwiththenumberofcontrastMRIstudiesperformedinpatientswithendstagekidneydiseasesuggest
thatotherimportantetiologicfactorsarerequiredforNSFtooccur.Sincetherecognitionoftheroleofgadoliniumandavoidanceof
thiscontrastagentinpatientswithkidneyinsufficiency,therehasbeenamarkedreductioninthenumberofnewcasesofNSF.NSF
isgraduallyprogressive,andwhereassomecasereportssuggestpossiblebenefitwithanumberofdifferenttherapeuticmodalities,
includingphototherapy(UVAtherapyinparticular),photopheresis,andantifibroticagents,kidneytransplantationseemstobethe
mosteffectivetreatment.
Figure104.OpeninNewWindow

Nephrogenicsystemicfibrosispresentswithtighteningandthickeningoftheskin,sometimeswithclinicallyapparentfleshyor
yellowpapulesandplaques,predominantlyontheextremities.

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Kidneytransplantationisassociatedwithspecificdermatologicrisks.Patientswhoundergosolidorgantransplantationareat
increasedriskforthedevelopmentofcutaneousmalignancies,particularlynonmelanomaskincancer.Kidneytransplantrecipients
areupto30timesmorelikelytodevelopsquamouscellcarcinomathanhealthyhosts,possiblydueinparttotheoncogenic
propertiesofhumanpapillomavirus,whichmaybefoundwithinsomesquamouscellcarcinomasinthispatientpopulation.The
immunosuppressiveregimenisakeyfactoraswell,withspecificmedicationshavinghigherrisksandsomeofferingpotential
preventivebenefits(OKT3andtacrolimuscarryanincreasedriskandrapamycinoffersamildprotectiveeffect).Allpatients
receivinganorgantransplantshouldbecounseledaboutsunprotectivemeasuresandreceiveanannualskincheck.

KeyPoints
Theuseofgadoliniumbasedcontrastagentshasbeenidentifiedasakeytriggerofnephrogenicsystemicfibrosis.
Patientswhoundergosolidorgantransplantationareatincreasedriskforthedevelopmentofcutaneousmalignancies,
particularlynonmelanomaskincancer.

Pulmonology
Sarcoidosis
RelatedQuestion
Question71
Sarcoidosisisaninflammatorydiseasecharacterizedbygranulomaformationinmultipleorgansapproximately30%ofpatients
willhavecutaneousinvolvement.Recognitionofskindiseaseisessential,asitismucheasiertoobtainatissuediagnosisbyskin
biopsythanbyaninternalsurgicalsampling.Sarcoidosishasbeencalledthegreatimitator,andamultitudeofskinlesionshave
beendescribed.Classiccutaneoussarcoidosisappearsasviolaceouspapulesaroundthenoseincludingtheala,orperiorbitallyand
periorificially(aroundtheoropharynxandnasalopenings)(Figure105).Sarcoidlesionsmayalsopreferentiallydevelopinsitesof
trauma,suchasscarsortattoos.Thetermlupuspernioisasourceofpotentialconfusion.Lupusgenerallyreferstosystemiclupus
erythematosus.Perniogenerallyreferstoaconditionofpurplepapulesonthedistaldigitsinsomepatientswholiveincold,wet
climatesandlupusvulgarisisaformoftuberculosisoftheskin.Lupusperniohaslittletodowiththese,however.Lupusperniois
sarcoidosisofthenoseandcentralface,withviolaceoussubcutaneousplaquesornodules,oftenwithsomeoverlyingscaling.Thisis
morecommoninblackpersonsandisimportanttorecognize,aspersonswithlupusperniofrequentlyhaveachronic,refractory
course.Limitedcutaneoussarcoidosismaybetreatedwithtopicalglucocorticoidsmoreextensivediseasewarrantssystemic
therapy,withhydroxychloroquinethemostappropriatefirstlineagent.Patientswhofailtorespondmaybetreatedwith
thalidomide,methotrexate,oroccasionallyTNFinhibitors.Additionaltherapeuticoptionsforsomepatientsincludetetracycline
classantibiotics,retinoids,phosphodiesteraseinhibitors,andotherimmunosuppressiveagents.Treatmentdependsonwhichorgans
areaffected,withthemoreimportantorseverelyaffectedorgansystemsdeterminingtherapeuticconsideration.
Figure105.OpeninNewWindow

Thispatienthaslupuspernio,withsarcoidlesionsthroughoutthenoseandcheeks,alongwithdiscretesarcoidpapulesonthenasal
tipandoverthenasalala.

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KeyPoint
Classiccutaneoussarcoidosisappearsasviolaceouspapulesaroundthenoseorperiorbitallyandperiorificiallyitmayalso
developinsitesoftrauma,suchasscarsortattoos.

ErythemaNodosum
Erythemanodosum(EN)isthemostcommonformofpanniculitis,orinflammationofthefat,withmostinflammationconcentrated
ontheintralobularseptae.Becausetheinflammationisdeepundertheskin,theclinicalmanifestationseenonthesurfaceisoften
illdefinederythemawithsomesubstanceonpalpation,whichmayfadefromanactiveinflammatoryredpinktoamoredullbrown
overtime.Thelesionsarefrequentlytenderwhenactivelyinflamed.Mostcommonly,ENoccursbilaterallyandsymmetricallyon
theanteriorshinshowever,itmayalsoappearinanyfattyareas(Figure106).Althoughlesionswilloftencomeandgo,most
resolveover4to6weeks.ENisanonspecificreactionpattern,withinflammationinthefatoccurringinresponsetosomesystemic
process.MultiplecauseshavebeenassociatedwithEN,includingsystemicinflammatorydiseases,reactionstomedicationsor
hormones,andoccultorsymptomaticinfections.ENcanalsobeidiopathic(Table23).
Figure106.OpeninNewWindow

Erythemanodosummanifestsasred,illdefined,tendernodulesofvaryingsizetypicallyontheanteriorshins.

Table23.OpeninNewWindowSelectedCausesofErythemaNodosum
Infections
Streptococcalpharyngitis
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Tuberculosis
Pulmonaryfungalinfections(coccidioidomycosis,blastomycosis,histoplasmosis)
Gastrointestinalbacterialinfections(Yersiniaenterocolitis,Salmonellagastroenteritis)
Psittacosis
Catscratchfever
Leprosy
Drugs
Antibiotics(penicillin,sulfonamides)
Estrogencontainingmedications(oralcontraceptives,hormonereplacementtherapy)
SystemicConditions
Inflammatoryboweldisease
Pregnancy
Sarcoidosis
Connectivetissuedisorders(dermatomyositis,lupuserythematosus,scleroderma)
Malignancy(rare)
Sweetsyndrome
Behetsyndrome
Themostcommonassociationsarestreptococcalinfection,hormones(includingoralcontraceptives,hormonereplacementtherapy,
orpregnancy),inflammatoryboweldisease,sarcoidosis,andmedicationreactions.TheappearanceofENinpatientswith
sarcoidosisgenerallyportendsanacutepresentationwithagoodlongtermprognosiswithlowerrisksofchronicdisease.EN,
arthritis,hilarlymphadenopathy,andfeversconstituteLfgrensyndrome,whichismorecommoninpatientsofNorthernEuropean
descent(seeSarcoidosis).
AlthoughENitselfisfrequentlyselflimited,patientsmaybemanagedwithNSAIDs,rest,elevation,andsometimesgentle
compression.Patientswithrecalcitrantdiseasemayrequiretreatmentwithsystemicimmunomodulatorydrugssomepatientsmay
respondtosaturatedsolutionofpotassiumiodide,colchicine,ordapsone.

KeyPoints
Erythemanodosumischaracterizedbytendersubcutaneousnoduleswithilldefinedoverlyingerythema.
Themostcommonassociationsoferythemanodosumarestreptococcalinfection,hormones,inflammatoryboweldisease,
sarcoidosis,andmedicationreactions.

Gastroenterology
Inflammatoryboweldisease(IBD)maypresentwithcutaneousmanifestations.Erythemanodosum(EN)isoneofthemore
commonskinfindingsinpatientswithIBD,occurringineitherCrohndiseaseorulcerativecolitisinupto20%ofpatients.Crohn
diseasemayalsopresentwithdistinctivelinearpustulesanderosionsoftheoralmucosaandgingiva,termedpyostomatitis
vegetans,withcutaneousCrohndisease(typicallygranulatingulcersperiorificially)orperianalskintags.Patientswithboth
ulcerativecolitisandCrohndiseasemaydevelopinflammatoryneutrophilicdermatitis,particularlypyodermagangrenosum.
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PyodermaGangrenosum
RelatedQuestion
Question33
Pyodermagangrenosum(PG)isanautoimmuneneutrophilicdermatosisinwhichneutrophilsinvadeandfillthedermis,leadingto
markedtissueedemaandpossibleulceration(Figure107).PGmayalsopresentwithbullouslesions,pustulonodules,and
vegetativeplaques.Thetypicalhistoryisasmallpustuleorrednodulethatmaydevelopaftertraumaandrapidlyexpandscausing
anedematous,infiltrated,activelyinflamedborderandapainful,exudativewetulcer.Classicallytheborderisdescribedas
violaceousand,becauseofthenatureoftheinflammation,theepidermisoftenoverliestheulcer,withahangingborderorresidual
thinanastomosingstrandsofepidermisremainingovertheexpandingulcer(seeFootandLegUlcers).
Figure107.OpeninNewWindow

Pyodermagangrenosum,presentingasapainful,exudativeulcerwithapurulentbaseandragged,edematous,violaceous,
overhangingborder.

AsPGresolves,ittendstohealwithatrophicscarringinacrosslikeorcribriformpattern.Onehelpfulclinicalfeaturefor
diagnosingactivePGmaybethepresenceofpathergy,ortheoccurrenceoflesionsatsitesoftrauma.Pathergyisseeninmany
neutrophilicdermatoses(PG,Sweetsyndrome,andBehetsyndromeinparticular),butonly20%to30%ofpatientswithPGwill
exhibitpathergy.PeristomalPGoccursaroundostomysitesandmaybeaparticularformofpathergy.Theconstantexposureof
bowelcontentstotheskinandneedforadhesivestobindtheostomybagstotheareacancreateaclinicalchallengewhenulcers
develop.
DiagnosingPGischallenging,andallpatientswithsuspectedPGshouldbeevaluatedforpotentialunderlyingcauses(Table24).
Therearenodefinitivetests,andPGisadiagnosisofexclusionexcludingothercausesalmostalwaysrequiresaskinbiopsyand
tissueculture.ItisessentialtoruleoutotherdiseasesbeforemakingadiagnosisofPGandtoreevaluatethediagnosisduring
treatment.PGisusuallyglucocorticoidresponsive,andfailuretorespondtotherapyshouldpromptevaluationforanalternative
diagnosis.PGmaybeidiopathic,butitisassociatedwithanunderlyingdiseasein50%ofpatients.
Table24.OpeninNewWindowPyodermaGangrenosumEvaluation
DiagnosticCriteria(2major,4minor)
Major:
Historyofrapidlyprogressing,painfululcerwithirregular,violaceous,underminedborder
Exclusionofothercausesofulcerations(typicallyvasculitis,neoplasm,infection)
Minor:
Skinbiopsyshowingsterileneutrophilicinflammation
Presenceofpathergyorhealingwithcribriformscarring
Presenceofsystemicdiseasesassociatedwithpyodermagangrenosum(inflammatoryboweldisease,IgAparaproteinemia,
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internalmalignancy,systemiclupuserythematosus,orotherautoimmunedisease)
Responsetosystemicglucocorticoidtherapy(12mg/kg/d,anticipate50%sizedecreasewithin4weeks)
SystemicEvaluation
Allpatients:
Completebloodcount,comprehensivemetabolicprofile
Biopsy,oftenincludingaseparatedeeptissueculture
Dictatedbyhistory,presentation,reviewofsystems:
Ageandsexappropriatecancerevaluation
Evaluationforinflammatoryboweldiseasewithupperendoscopyandcolonoscopy(almostalwaysindicated)
Chestradiographyforlungpathologyormalignancy
Serumandurineproteinelectrophoresisforparaproteinemia(especiallyIgA)
Hematologicstudiesforcoagulationabnormalities(includingantiphospholipidantibodies)
Bonemarrowaspirationandbiopsy
Extendedserologictestingforalternativeexplanationsorassociatedautoimmunediseases(RF/CCP,ANA,ANCA,
cryoglobulins)
Vascularflowstudies(ifontheleg)toexcludecomponentofvascularinsufficiencymimickingpyodermagangrenosumor
impactingwoundhealing
RF/CCP=rheumatoidfactor/anticycliccitrullinatedpeptideANA=antinuclearantibodyANCA=antineutrophil
cytoplasmicantibody.
Managementisthreefold:evaluateforunderlyingdisease,treatthePGinflammation,andmanagetheresultingwound.TreatingPG
canbeachallenge,andifthereisanassociatedunderlyingdisease,therapyshouldbedirectedatcontrollingthatprocess.PGis
oftenresponsivetotopicalorintralesionalglucocorticoids.Cyclosporineandinfliximabmayalsobeeffective,withinfliximab
havingthehighestqualityevidence,althoughmostcliniciansusesystemicglucocorticoidsasfirstlinetherapy.Secondline
treatmentincludesotherimmunomodulatorydrugssuchasthalidomide,mycophenolatemofetil,azathioprine,methotrexate,
intravenousimmuneglobulin,andotherbiologicagents.Becausethepathologicprocessisneutrophildependent,dapsoneor
colchicinetherapysometimesprovidesbenefit,includingpotentialdualbenefitfordapsoneasPneumocystispneumoniaprophylaxis
forpatientsrequiringlongtermglucocorticoidsfordiseasecontrol.Localsupportivecareisalsoessentialtoachieveulcer
resolution.ManypatientswillhavePGinflammationcontrolled,andthatiswhensystemicimmunosuppressantsshouldbetapered.
Woundhealingmaytakelongerandrequireintensivelocalwoundcare.Importantmeasuresincludeachievingadequatepain
controlmaintainingaclean,noninfectedulcerbase(potentiallywithantimicrobialsoaks,topicalantimicrobialagents,and
absorptivedressings)andminimizingedemaintheaffectedlimbwithcompressionastolerated.

KeyPoints
Pyodermagangrenosumpresentsasapainful,exudativeulcerwithapurulentbaseandragged,edematous,violaceous,
overhangingborderitmaybeidiopathicbutisassociatedwithanunderlyingdiseaseinsomepatients.
Pyodermagangrenosumisresponsivetoglucocorticoids,andcyclosporineandinfliximabmayalsobeeffective.

DermatitisHerpetiformis
Dermatitisherpetiformis(DH)isaneruptioncharacterizedbypruriticpapulesandtransient,almostimmediatelyexcoriatedblisters
ontheelbows,knees,andbuttocks(Figure108).Histologically,neutrophilsarefoundinthepapillarydermis,anddirect
immunofluorescencemayrevealgranularIgAdepositions.PatientswithDHhaveintensepruritusandalmostimmediatelyrespond
totreatmentwithdapsone.DHisstronglyassociatedwithglutensensitivityandceliacdisease,andpatientsshouldbeevaluatedfor
celiacdiseaseandmaintainaglutenfreediet,ortheyareatincreasedriskforsmallbowellymphoma(seeAutoimmuneBlistering
Diseases).
Figure108.OpeninNewWindow

Groupcrusted,excoriatedpapulesinapatientwithdermatitisherpetiformis.Thevesiclesaresosuperficialandfragileandpatients
havesuchintensepruritusthatthevesiclesarerarelyseenintact.

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Patientswithcirrhosisalsofrequentlyhaveskininvolvement.Thesepatientsoftenhavexerosisanddevelopdiffuse,intense
pruritus,potentiallypartiallyduetoaccumulationofbilesaltsintheskin.Chronicscratchingleadstothickened,lichenifiedplaques
andindividualhypertrophichyperpigmented,excoriatedprurigonodules.Thisformofpruritusisbestmanagedwithaggressive
topicalemollients,andpatientswithrefractorydiseasemaybenefitfromphototherapy.Patientswithadvancedliverdiseasemay
alsodevelopspidertelangiectasias(redpapuleswithtinynetworksofcapillariesextendingoutward),jaundice,erythemaofthe
thenarorhypothenareminences,andchangestothenailplatesuchasTerrynails,inwhichthenailbedturnsopaque.

PorphyriaCutaneaTarda
RelatedQuestion
Question60
Porphyriacutaneatarda(PCT)isarareskindiseaseassociatedwithliverdisease.Itmaydevelopfromextensivealcoholuse,
hemochromatosis,orhepatitisCvirus(HCV)infection.OnlyrarelyisPCTageneticdiseasecausedbyreducedactivityofthe
enzymeuroporphyrinogendecarboxylasehowever,80%ofcasesareacquired,mostofwhicharefromchronicHCVinfection.PCT
presentswithskinfragilityandsmall,transient,easilyrupturedvesiclesinsunexposedareas,mainlyonthehands(Figure109).
Whenthelesionsrupture,thereisusuallyscarring,shallowerosions,andoccasionalwhitepapulesfrompinpointepidermal
inclusioncystsfromabnormalhealing(milia).Excesshairgrowth,orhypertrichosis,maybeseenonthetopsofthehandsor
cheeks.Laboratorytestingmayshowelevateduroporphyrinlevels.Askinbiopsyshowingapauciinflammatorysubepidermal
bullaecanconfirmthediagnosis.Treatmentisaimedatlimitingironoverloadbyphlebotomyantimalarialagentssuchas
hydroxychloroquinemayalsobebeneficial.PCTthatdevelopsinthesettingofHCVmaywarranttreatingtheinfection.
Figure109.OpeninNewWindow

Achronic,blisteringskindisease,withmultiplescarsandlesionsofvaryingstages,onsunexposedskin,especiallyonthebackof
thehands,consistentwithporphyriacutaneatarda.

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TreatmentofHCVinfectionmayresultinsecondaryskinsideeffectsthatareimportanttoconsider.Interferonalfatreatmentis
associatedwiththedevelopmentofgranulomatousdermatitisandinsomepatients,sarcoidosis.Arelativelynewagentfortreating
HCVinfection,telaprevir,hasbeenassociatedwithskineruptionsinasignificantpercentageoftreatedpatients,withsomereports
indicatingasmanyas35%to50%ofthesepatientsdevelopingacutaneouseruption.Someofthereportederuptionshavebeen
severe,withpotentiallylifethreateningskinreactionsdevelopinginafewpatients.PatientsreceivingtelaprevirforHCVinfection
shouldbefollowedclosely,andanyskineruptionwarrantsathoroughevaluation.

Hematology/Oncology
Recognizingparaneoplasticdermatosesmayleadtoearlierdiagnoses,andmanagementofparaneoplasticeruptionsiscriticalinthe
careofpatientswithinternalmalignancies.Cutaneoussignsofmalignancyincludebothfeaturesofhereditarysyndromeswith
cutaneousmanifestationsandanassociatedincreasedlifetimeriskofinternalmalignancy,andcutaneousinflammatoryreaction
patternsthatdevelopinthesettingofmalignancy(Table25).Paraneoplasticeruptionsmayprecede,parallel,orfollowadiagnosis
ofcancer.Potentialparaneoplasticskineruptionswarrantageandsexappropriatescreeningstudies,withadditionaldiagnostic
testingdependingonthespecificskinreactionpattern(Table26).
Table25.OpeninNewWindowGeneticDiseaseswithCancerAssociationsandSkinFindingsa
Condition

ClinicalFindings

AssociatedMalignancy/Comments

MuirTorre
syndrome
(Lynch
syndrome)

Sebaceousneoplasmsandkeratoacanthomas(squamouscell
carcinomasubtype)

Adenocarcinomasofthegastrointestinaltractor
othertumorsofthegenitourinarytract.Lung,
breast,andhematologicmalignanciesmayoccur.

Cowden
syndrome

Tanfacialpapules(tricholemmomas)andoralpapillomasor
cobblestoning

Adenocarcinomasofthebreastorthyroidand/or
polypsofthegastrointestinaltract

BirtHogg
Dube
syndrome

Finewhitescleroticfacialpapules(fibrofolliculomasor
trichodiscomas)spontaneouspneumothoraces

Kidneycancer

Reed
syndrome

Tendercutaneouspapules(leiomyomas)uterinefibroids

Kidneycancer

Tuberous
sclerosis
complex

Multiplecutaneouslesions(facialangiofibromas,ashleafspots,
hypopigmentedmacules,subungualpapules)corticaltubersand
Kidneycancer
seizuresfemalepatientsmaydeveloplymphangioleiomyomatosis

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aThistableisabriefreviewfocusedongeneticdiseasesthatcanpresentinadulthoodthisisnotacomprehensivelistof

geneticskindiseaseswithcancerassociations.
Table26.OpeninNewWindowParaneoplasticDisorders:ConditionsThatAreStronglyLinkedtoInternalMalignancy
Condition

ClinicalFindings

AssociatedMalignancy/Comments

Acanthosis
nigricans

Velvetyorverrucoushyperpigmentationof
intertriginousareas,weightloss,glossitis

Adenocarcinoma,usuallyGIorGU,mostcommonly
ofstomachoccursalsoinpatientswith
endocrinopathy

LeserTrlatsign

Rapidappearanceorinflammationofmultiple
seborrheickeratosesoftenoccursinconjunctionwith
acanthosisnigricans

Samecancerassociationasacanthosisnigricans
seborrheickeratosesarecommonlesionsLeser
Trlatsignisveryrare

Tripepalms

Ifoccurringwithacanthosisnigricans,samecancer
Rugosefoldsonthepalmsandsolesmayoccurwithor associationifoccurringwithoutacanthosisnigricans,
withoutacanthosisnigricans
squamouscellcarcinomaoftheheadandneckor
lungs

Bazexsyndrome
(alsoknownas
acrokeratosis
paraneoplastica)

Squamouscellcarcinomaoftheupperrespiratory
Psoriasiform,violaceousscalingontheacralsurfaces
tractorupperGItracteffectivetherapyofan
(fingers,toes,nose,andears)keratodermamayalsobe
associatedcancerisfollowedbyresolutionofthe
present
dermatosis

Carcinoid
syndrome

Episodicflushing,oftenaccompaniedbydiarrheaand Pulmonarycarcinoidtumorsorcarcinoidtumors
bronchospasmcaneventuallyresultintelangiectasiaor metastatictothelivertumorremovalisfollowedby
permanentruddiness
resolutionoftheskinandsystemicfindings

EctopicACTH
syndrome

Generalizedhyperpigmentation

Smallcelllungcancertumorremovalcanresultin
improvementofthepigmentation

Necrolytic
migratory
erythema

Intertriginouserythema,scales,anderosionsglossitis
andangularcheilitisarecommon

Glucagonsecretingtumorofthepancreas

Neutrophilic
dermatoses

Sweetsyndromeatypicalpyodermagangrenosum
(bullouslesionswithabluegrayborder,oftenonthe
hands,arms,orface)

Myeloidleukemia,myelofibrosis,andrefractory
anemiasthesedisordersalsooccurwithout
malignancyin80%to90%ofpatients

Pagetdiseaseof
thebreast

Erythematous,irregularlyborderedplaqueonthenipple

Representsanextensionofaductaladenocarcinoma
ofthebreast

Extramammary
Pagetdisease

CanceroftheGIorGUtractispresentin25%of
Erythematousscalypatchorplaqueontheperinealskin, patientsitisnotcontiguouswiththedermatosisthe
scrotum,orperianalarea
dermatosisisamalignancyandneedsappropriate
excisionorablation

Paraneoplastic
pemphigus

Severemucosalerosions,tenseandflaccidbullaethat
maybewidespread

NonHodgkinBcelllymphoma,Castlemandisease,
chroniclymphocyticleukemia

Dermatomyositis

Heliotroperash,Gottronpapulesandsign,
photodistributedviolaceouserythemascalyerythemaof
thescalpwithdiffusealopeciaperiungual
telangiectasiasandcuticularovergrowth

20%to25%ofpatientswithdermatomyositishad,
have,orwillhaveamalignancyovariancanceris
overrepresentedparaneoplasticcourseispossiblebut
unusual

Necrobiotic
xanthogranuloma

Purpleorangenodulesandplaques,oftenontheupper
eyelids,whichfrequentlyulcerate

90%ofpatientshaveanassociatedparaproteinemia
(generallyIgG)andmaydevelopmultiplemyeloma

Amyloidosis

Pinchpurpurainsitesofthinskinsuchasthe

Seeninmultiplemyelomaorsystemicamyloidosis

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periorbitalarea,usuallyaccompaniedbymacroglossia
andsmoothingofthetongue

Scleromyxedema

Waxyfinepapulesovertheface,neck,anduppertrunk

Mostpatientshaveanassociatedparaproteinemia
(generallyIgG)andmaydevelopovertmultiple
myeloma

ACTH=adrenocorticotropinhormoneGI=gastrointestinalGU=genitourinary.

SweetSyndrome
RelatedQuestion
Question41
Sweetsyndrome,oracutefebrileneutrophilicdermatosis,isoneoftheclassicneutrophilicdermatoses,drivenbyneutrophilic
infiltrationandcytokineinflammation.Otherneutrophilicdermatosesincludepyodermagangrenosumerythemaelevatumdiutinum
(avasculitisthatpredominantlyaffectstheskinoverlyingextensorjointspaces)neutrophiliceccrinehidradenitis(typicallyseen
followingchemotherapyexposures)andsubcornealpustulardermatosis(whichusuallycausesrelapsingpustularplaquesofthe
foldsofskininmiddleagedandolderwomen).Neutrophilicinflammationcanpredominateinothermultipleskineruptions,
includingBehetsyndrome,erythemanodosum,linearIgAbullousdermatosis,dermatitisherpetiformis,andmore.Sweetsyndrome
maybeidiopathicoroccurinassociationwithanunderlyingdiseasethesyndrometypicallydevelopsafteranupperrespiratoryor
gastrointestinalinfectionorinthesettingofhematologicabnormalities,particularlymyelodysplasticsyndromeandmyelodysplastic
syndromeevolvingintoacutemyeloidleukemia.Sweetsyndromehasalsobeenassociatedwithsolidmalignanciesandmedications
(particularlyneutrophilstimulatingmedicationssuchasgranulocytecolonystimulatingfactor(GCSF)andalltransretinoicacid).
Patientswillhavehighfevers,leukocytosiswithaleftshift,elevatedinflammatorymarkers,andoftenmuscleorjointpain,along
withtheskineruption.Theskinlesionsaredescribedasjuicyinduratededematousredpurpleplaquesandnodules,sharply
demarcatedfromtheadjacentskin.Biopsywillshowaneutrophilicinfiltratewithprominentsuperficialpapillarydermaledema.
Thisintenseedemahighupintheskiniswhatcausesthecharacteristicswollen,juicyappearanceclinically.Intenselyinflamed
lesionsmayulcerateandresemblePG(Figure110).
Figure110.OpeninNewWindow

RedpurplejuicynodulecharacteristicofSweetsyndromelesions.Themarkededemaistypical,leadingtoapseudovesicular
appearance.

AswithPG,pathergymayoccurandofferacluetothediagnosis.UnlikePG,lesionsofSweetsyndromeresolvewithoutscarring.
AllpatientswithSweetsyndromeshouldhaveacompletebloodcountandshouldbeevaluatedforpotentialunderlyingmalignancy,
particularlyacutemyeloidleukemia.FlaresofSweetsyndromecansometimesparalleltheunderlyingdisease,butSweetsyndrome
mayalsodevelopaspatientsarebeingtreatedfortheleukemia.Flaresmaybeduetoendogenouscytokinesignaling,suchas
elevatedlevelsofGCSFinresponsetocytotoxicbonemarrowablativechemotherapyforleukemia.Sweetsyndromeis
dramaticallyglucocorticoidresponsive,andpatientsoftenhaveimmediatereliefafterjustonedose,withresolutionoffeversand
dramaticreductioninskinlesions.Alternativestoglucocorticoidsinpatientswhoareunabletosuccessfullytaperoffinclude
saturatedsolutionofpotassiumiodide,dapsone,colchicine,andNSAIDs.Selectpatientsmayrequirecyclosporine,mycophenolate
mofetil,andTNFinhibitorsorpossiblytargetedantineutrophilicbiologicagentssuchasantiinterleukin1anakinra.
Skinfindingsinpatientsundergoingtreatmentforcancerareimportatntaswell.Cutaneouseruptionscanhavesevereimpactson
patientsundergoingchemotherapy,andfailuretorecognizeormanagethesesideeffectscanleadtotreatmentinterruptionsor
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suboptimaldosereduction(Table27).Almostallchemotherapeuticagentshavebeenreportedtocausetheentirespectrumof
classiccutaneousadversedrugreactions,suchasmorbilliformexanthemsandurticarialeruptions.Multipleagentshavealsobeen
associatedwithdevelopmentoferythemamultiforme,StevensJohnsonsyndrome,andtoxicepidermalnecrolysis.
Table27.OpeninNewWindowSelectDermatologicChemotherapyReactions
Reaction

ChemotherapeuticAgents

Dermatomyositislikeeruption

Hydroxyurea

Neutrophilicdermatoses(PG,Sweet
syndrome)

GCSF,GMCSF,ATRA,thalidomide,lenalidomide,bortezomib

Acneiformeruption

EGFRinhibitors

Paronychia

EGFRinhibitors

Pseudoporphyria

5Fluorouracil

Cutaneouslupus

5Fluorouracil,capecitabine

Handfootsyndrome/acralerythema

Cytarabine,5fluorouracil,capecitabine,methotrexate,docetaxel,paclitaxel,
anthracyclines

Neutrophiliceccrinehidradenitis

Cytarabine,multipleotheragents

Handfootskinreaction

Sorafenib,sunitinib

Serpentinesupravenoushyperpigmentation 5Fluorouracil
Flagellatehyperpigmentation

Bleomycin

Alopecia

Multipleagents

Morbilliform

Multipleagents

Urticarial

Multipleagents

SJSTEN

Multipleagents

Erythemamultiforme

Multipleagents

Vasculitis

Multipleagents

ATRA=alltransretinoicacidEGFR=epidermalgrowthfactorGCSF=granulocytecolonystimulatingfactorGMCSF=
granulocytemacrophagecolonystimulatingfactorSJS=StevensJohnsonsyndromeTEN=toxicepidermalnecrolysis.
Patientswhoareundergoingchemotherapyareoftenseverelyimmunocompromised,andcarefulevaluationandmanagementofthe
skinisessentialtopreventandrecognizeinfections.Violaceousnodulesorareasofpurpura,particularlyifwithnecrosis,shouldbe
evaluatedimmediatelytoexcluderapidlyprogressiveinvasiveinfections.Carefulskinexaminationforsitesofbreakdownor
trauma,suchasintheskinfoldsorwebspaces,canhelppreventsuperficialskininfectionsfromservingasaportalofentryfor
systemicinfection.
Patientswhoundergobonemarrowtransplantshaveadditionalskinspecificissues.Graftversushostdiseaseisoneofthemost
commoncomplicationsofbonemarrowtransplantationandmaypresentinitiallyorsolelyintheskin.Patientswillclassically
developerythemaoftheears,upperbackandneck,outershouldersorouterarms,anddorsalfeetorhands,andtheerythemamaybe
folliculocentricinitially.Patientsshouldbeevaluatedforsignsofengraftmentinthemarrow(cellcountrecovery)andforliveror
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gastrointestinalinvolvement.Acutegraftversushostdiseaserarelydevelopswithinthefirst2weeksfollowingtransplantation,but
oncecountrecoveryhasstarted,itisacommoncauseofsignificantmorbidityandtreatmentrelatedmortality.Patientsmayhavea
morbilliformeruption,whichcanbeclinicallychallengingtodistinguishfromcutaneousadversedrugreactions.Thetiming,
morphology,distribution,andassociatedsymptoms(suchasdiarrheaorliverchemistryabnormalities)canhelpdifferentiatethese
twoentitiesskinbiopsymaybeofusealthoughtherearenotdefinitivefeatures.
Chronicgraftversushostdiseasegenerallyoccursintheskinaseitherlichenplanuslikelesionsorsclerodermalikechanges.
Patientsmaydevelopchronicinflamederythematoustoviolaceouspapulesorplaqueswithoverlyingscale,whichmaybe
accompaniedbyinflammationoftheeyes,mouth,orgenitals.

KeyPoints
LesionsofSweetsyndromecanappearasjuicyinduratededematousredpurpleplaquesandnodules,sharplydemarcated
fromtheadjacentskin.
Sweetsyndromehasbeenassociatedwithacutemyeloidleukemia,solidtumors,chemotherapy,andinfections.

Endocrinology
Theskinisaffectedbyahostofendocrinologicconditions,rangingfromtheassociationbetweenautoimmuneskindiseasessuchas
vitiligoandalopeciaareatawiththyroiddisease,togynecomastiafromhormonalimbalances,orthediffusehyperpigmentationof
Addisondisease.Thissectionwillfocusondiabetesmellitusandthyroiddisease.

DiabetesMellitus
Patientswithdiabetesmellituscandevelopawiderangeofskinfindingssuchasthevelvetyhyperpigmentationofacanthosis
nigricans,whichtendstopresentintheintertriginousareas,particularlyintheaxillae,inobesepersonswithdiabetes(Figure111).
Thismaybeaccompaniedbyskintags,whicharecommoninobesepersons.
Figure111.OpeninNewWindow

Acanthosisnigricans,characterizedbyavelvetybrownplaqueinanobesepatient.

Somefindingsareconnectedtotheunderlyingetiopathogenesisofthedisease.Forexample,patientswithtype1diabetesareat
increasedriskfordevelopmentofvitiligo(asymptomaticdepigmentedpatchesperiorificiallyorinsitesoftraumacausedby
autoimmunityagainstmelanocytes).Patientswithdiabetesmaydeveloporange,atrophicplaquesontheiranteriorshins(necrobiosis
lipoidica).Patientswithnecrobiosislipoidicaoftenhaveretinalorkidneydamageaswell.Othercutaneousfindingsassociatedwith
diabetesarebullousdiabeticorum(large,asymptomatic,noninflammatorybullaeonthelowerextremities)andscleredema(an
uncommonskinfindingcharacterizedbyedematousindurationoftheupperback).Diabeticdermopathy(multiplehyperpigmented
maculesontheanteriorshins)isoneofthemostcommoncutaneousfindings.
Patientswithdiabetesareatanincreasedriskofskininfection,suchasinterdigitalandintertriginousinfectionwithCandidaand
dermatophytes.Earlyrecognitionisessential,asuntreatedcutaneousfungalinfectionsmayserveasaportalofentryforbacteria,
resultingincellulitis.Intertriginouserythematouseruptionswithscaleshouldbeevaluated,andifduetotinea,thelesionsshouldbe
treatedwithtopicalantifungalagents(suchasketoconazole),whichoftenrequiresrepeatedusetoclearandmaintainnormalskin.

KeyPoints
Acanthosisnigricanspresentsasskinthickeninganddarkeningoftheintertriginousareas,particularlytheaxillae.
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Necrobiosislipoidicareferstoorange,atrophicplaquesontheanteriorshinsofpatientswithdiabetesmellitusthatareoften
associatedwithretinalorkidneydamage.

ThyroidDisease
RelatedQuestion
Question34
Hyperthyroidismcanleadtowarm,moist,smooth,thinskin,oftenwithhyperhidrosis.Thehairwillgrowthinandfeelsoft,andnail
fragilitymaydevelop.Cutaneousmyxedemacanoccuranywherebuttypicallyisconcentratedontheanteriorshins,withtheskin
appearinginduratedwithcompressibleplaquesthatmayhaveapeaudorangeappearancefromintradermalmucindeposition.
ThyroidacropachyisararefindinginsomepatientswithGravesdisease,characterizedbyswellingofthesofttissuesofthehands
andfeetwithassociateddigitalclubbingduetoperiostealboneformation(Figure112).Patientswithhypothyroidismdevelopcool,
dry,paleskin,whichmayprogresstoichthyosisorplatelikescalingresemblingfishscales.Thehairbecomesdryandbrittleand
mayfallout.Lossofthelateralthirdoftheeyebrowsiscommon.Generalizedmyxedemacanleadtoawaxy,swollenappearance
withpuffylipsandedematousanddroopyeyelids.
Figure112.OpeninNewWindow

ClubbingisseenspecificallyinpatientswithGravesdisease.

InfectiousDisease
HIVInfection
RelatedQuestion
Question42
PatientswithHIVinfection(generallywithCD4cellcounts200/L)mayhaveamarkedphotosensitivityanddevelopastriking
photodermatitiswiththickeningandlichenificationofsunexposedareas.Patientspresentingwithneworworseningpsoriasis
shouldbeevaluatedforHIVriskfactors,andHIVtestingshouldbeoffered.Severeoutbreaksofseborrheicdermatitis(erythema
withgreasyscaleinthescalporTzoneofthecentralface)mayoccurinpatientswithHIVinfectionaswell,andpatientswith
refractoryorextensiveseborrhearequirepromptevaluation.Patientswithothersexuallytransmittedinfections,includinggenital
warts,warrantevaluationforHIVinfectionaswell.
TherashofacuteHIVseroconversionisnonspecific,characterizedbyasymptomaticerythematousmaculesandsmallpapulesover
theuppertrunk,face,andproximalextremities,sometimesincludingthepalms,andoftenaccompaniedbystrikingoralaphthous
ulcers.HIVantibodytestingmaybenegativeinacuteseroconversion,andviralloadtestingordelayedantibodytestingisessential.
PatientswithHIVinfectionfrequentlyhavepruritus.Chronicpruritusandsubsequentlichenificationandareasofthickenedplaques
oflichensimplexchronicusorpapulesofprurigonodularisarecommon.Pruritusmaybefromskinsuperinfectionandchronic
bacterialfolliculitis,HIVrelatedxerosis,orasaresultofmedications.Twospecificpruriticeruptionsarepruriticpapulareruption
ofHIV(acommonchronicpapularrashseenin10%to45%ofpatients,whichischaracterizedbysymmetricskincoloredor
hyperpigmentedpapulesonthetrunkandextremities)andeosinophilicpustularfolliculitis(characterizedbyrecurrent,extremely
pruriticredorhyperpigmentedpapulesonthefaceandupperchest)(Figure113).PatientswithHIVinfectionareatriskfor
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secondaryskininfectionwithmolluscum,superficialbacterialinfections,andsuperficialfungalinfectionsandhaveahighrateof
herpessimplexandherpeszostervirusinfectionsandreactivation.Theseinfectionsmaypresentwithmorewidespreaddiseaseand
atypicalclinicalfeaturesinpatientswithadvancedHIVinfection.PatientswithverylowCD4cellcountsarealsoatriskfor
secondarycutaneousmalignanciesincludingcutaneouslymphomaandKaposisarcoma(causedbyhumanherpesvirus8)
(Figure114).Thesepatientsoftenhaveanincreasedriskofsquamouscellcarcinoma(frequentlyHPVassociated),including
squamouscellcarcinomasofthedigitaltipsandunderthenailsandofthepenis,perineum,andperianalregion.
Figure113.OpeninNewWindow

PruriticpapulareruptionofHIV.Thefolliculocentricpapulesandexcoriated,hyperpigmentedremnantsofpreviouslesionsare
clusteredonthechestandtrunk.PhotocourtesyofRobertMicheletti,MD.

Figure114.OpeninNewWindow

Kaposisarcomaischaracterizedbyviolaceoustohyperpigmentedplaques.Thecentralplaqueshownherehasavascularappearing,
violaceouspapulewithinit.

KeyPoint
TherashofacuteHIVseroconversionischaracterizedbyasymptomaticerythematousmaculesandsmallpapulesoverthe
uppertrunk,face,andproximalextremities,oftenaccompaniedbystrikingoralaphthousulcers.

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Chapter13
0Notes
CutaneousManifestationsofInternalDisease
ViewNotesIndex
Questions
ReferenceRanges

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