CasesfromtheCornfields!Nkanyezi Ferguson,MDJohnSelby,MD,PhDBrianSwick,MD

KarolynWanat,MDDepartmentsofDermatologyandPathology

UniversityofIowaHospitalsandClinicsIowaCityVAHealthCareSystem

Cases#2and#3• DermatitisHerpetiformis– New diagnosis?• CheckG6PD• GastroenterologyConsultifnoknowndiagnosisofCeliac• Startdapsone• DietitianConsultforinstitutionofagluten-freediet

dapsone

monoacetyldapsone

glucuronides

N-acetyltransferase acrylacetamidedeacetylase

renalexcretion

dapsone

dapsonehydroxylamine

N-hydroxylase

hemolyticanemiamethemoglobinemia

G6PD

reducedmetabolites

hepaticglucuronidation

enterohepatic circulation

Cases#2and#3

J Am Acad Dermatol 2001;45:420-34Arch Dermatol Res2014;306:103-24

• Dapsone- MechanismofAction– Anti-inflammatoryeffects• Interferencewithneutrophilchemotaxis• Scavengingofextracellularreactiveoxygenspecies• Inhibitionofmyeloperoxidase-mediatedcytotoxicity• Inhibitionofeosinophilperoxidase• SuppressionofleukotrieneB4-stimulatedinflammation

Cases#2and#3

J Am Acad Dermatol 2001;45:420-34Arch Dermatol Res2014;306:103-24

• Dapsone- AdverseEffects– Hemolyticanemia–Methemoglobinemia– Agranulocytosis– Hypersensitivitysyndrome– Gastrointestinaleffects– Photosensitivity– Carcinogenesis

Edhegard,k.,andR.P.HallIII.“Dapsone.”ComprehensiveDermatologicDrugTherapy,ThirdEdition.Ed.Wolverton,S.E.Edinburgh:ElsevierSaunders,2013.228-240.Print.

Cases#2and#3

HemoglobinA1Clevelsfalselylow

Labmonitoringforweeks1-12

• Dapsone- AdverseEffects– Psychiatriceffects?

• JAmAcad Dermatol 1983;9(2):274-5– Irritability– Insomnia

– Psychiatriceffectsappeartobe...• Dose-independent• Occurearlyorlateinthetreatmentcourse• Independentofapre-existingmoodorpsychoticdisorder

Cases#2and#3

– Irrationalspeech– Psychosis

• Dapsone- AdverseEffects– Peripheralneuropathy• Primarilydistalmotor,butsensoryinvolvementcanoccur• Reportedforvariabledoses/exposures

– highdose/shortterm– lowdose/longterm

• Recoverycanbeobservedupto2yearsafterdiscontinuationofdapsone• Mechanismuncertain

Cases#2and#3

• Stopdapsone?– Yes;neuropathyisthoughttobereversible

• Dietitianconsult?– Important,but...– Youcan’tteachanolddognewtricks

Cases#2and#3

• Sulfapyridine?– CasereportsofDHpatientssuccessfullytreatedwithsulfapyridine after developmentofdapsoneneuropathy• Int JDermatol 1986;25:314-6• ArchDermatol 1984;120:356-9

– Jacobus Pharmaceuticalshaltedproductionanddistributionofsulfapyridine circa1/2011

– NolongeravailableintheU.S.

Cases#2and#3

• Topicaldapsone?– CasereportsofDHpatientssuccessfullytreatedwithtopicaldapsone• JCutan MedSurg 2016;20(6):600-1• JDermatol CaseRep2012;6(4):132-3

– Systemicabsorption?• Acutemethemoglobinemia reportedinanacnepatientNEnglJMed 2015;372(5):491-2• No reports of neuropathy

Cases#2and#3

-Yes!

• Cimetidine?– 400mgTIDdecreases methemoglobinemia byinhibiting formation of hydroxylaxmine metabolites

– Effect(s)onneuropathy prevention/treatment uncertain

Cases#2and#3

• Sulfasalazine(SS)?– NumerouscasereportssuggestingefficacyofsulfasalazineforthetreatmentofDH• JAmAcad Dermatol1990;22(4):697• Australas JDermatol 2005;46:101-3• Dermatol Clin 2011;29:631-5• Int JDermatol 2017;56:e89-e105

Cases#2and#3

• Sulfasalazine(SS)- Pharmacokinetics– Enteric-coatedSSpoorlyabsorbedinsmallintestine

– Gutflorainlargeintestineconvertenteric-coatedSSinto5-aminosalicylicacid(5ASA)andsulfapyridine

Cases#2and#3

• Sulfasalazine(SS)- Pharmacokinetics– Sulfapyridine isvariablyabsorbed,dependentonguttransittime

– 5ASAconcentrateslocallyinthelargebowel;excretedinfeces

– Metabolismofsulfapyridine similartodapsone(acetylation,hydroxylation,glucuronidation)

Cases#2and#3

• Sulfasalazine(SS)- Mechanismofaction

– Sulfapyridine effectslikelysimilartodapsone• Inhibitionofneutrophilchemotaxis• Modulationofpolymorphonuclear leukocytefunction• Inhibitionofhistaminereleasefrommastcells

Cases#2and#3

• Sulfasalazine(SS)- AdverseEffects– Common• Nausea,anorexia,dyspepsia,vomiting

– Minimizedbyenteric-coatedformulation• Headache

– Rare• Hepatitis• Pneumonitis• Hypersensitivity

Cases#2and#3

• Aplasticanemia• Agranulocytosis

• Sulfasalazine(SS)- AdverseEffects

–Veryrareassociations• Granulomatosiswithpolyangiitis• Encephalopathy• EBVhypersensitivitysyndrome• Hemophagocyticsyndrome

Cases#2and#3

• Sulfasalazine(SS)- AdverseEffects– DoesSScauseorexacerbateaperipheralneuropathy?• ReportsofSS-associatedneuropathyarescarce

– Practitioner 1970;204:850-1– Postgrad MedJ1985;61:147-8– RevueNeurologique1992;148:154-6– ClinExp Rheumatol 2008;26:671-2

Cases#2and#3

• CaseOutcomes– Bothpatientsstartedonenteric-coatedsulfasalazine1gtwicedaily(G6PDnormal)

–MonitoredCBCwithdifferential,ALT,ASTeveryotherweekfor2months,thenevery3-4months

–Markedimprovementinflaresofpruritusandrashwithin1-3months

– Nochangesinneuropathy-relatedsymptoms>2years

Cases#2and#3

PharmacologyPearls#1• HbA1Clevelsarefalselylow inpatientstakingdapsone

• Dapsonecanhavepsychiatriceffects

• SulfapyridineisnolongeravailableintheU.S.

• Topicaldapsonecanhavesystemicabsorption

PharmacologyPearls#1• Consider enteric-coatedsulfasalazineforthetreatmentofDHinpatientswhoareintolerantofdapsoneorwhenthereisconcernforevolvingneuropathy

• Dapsoneorsulfasalazine– Continuevigilantmonitoringforsigns/symptomsofneworworseningneuropathy

• Methemoglobinemiainpatientstakingdapsone?– Asymptomatic(3-15%)– Cyanosis(>15%)• Slate-bluecolorofskinandmucousmembranes

Cases#2and#3

• Methemoglobinemiainpatientstakingdapsone?– Asymptomatic(3%<MetHb<15%)– Cyanosis(MetHb>15%)

• Slate-bluecolorofskinandmucousmembranes• Differentialdiagnosis

– Methemoglobin >1.5g/dL or8to12%oftotalhemoglobin– Deoxygenatedhemoglobin>4to5g/dL– Sulfhemoglobin >0.5g/dL

– Signs&symptomsofhypoxia• Lightheadedness,headache,tachycardia(15%<MetHb<30%)• Fatigue,confusion,lethargy,tachypnea(30%<MetHb<50%)• Coma,seizures,death(MetHb>50%)

Cases#2and#3

ClevClinJMed2015;82(3):156-60

Cases#2and#3

• Whenmethemoglobinpresent...• Leftshiftinoxygendissociationcurve• Decreasedoxygenunloading• Increasedtissuehypoxia

Clin Chem 2005;51(2):434-44

• Methemoglobinemiainpatientstakingdapsone?– Whataboutanasymptomatic patienttakingdapsonewhohasno cyanosisandno signs&symptomsofhypoxia?

• Methemoglobinemia (3-15%)shouldbeexpected

• Bereadytoexplain abnormalpulseoximetry readingsanddiscrepancieswitharterialbloodgasmeasurements!

Cases#2and#3

Cases#2and#3

• SaO2 (%)=percentageofhemoglobinthatissaturatedwithoxygen

• IndirectlymeasuredwithaninvasiveABG

• SpO2 (%)=estimateofSaO2measuredbynon-invasivepulseoximetry

• Standardtwo-wavelengthpulseoximetry• 660nm– deoxyhemoglobin• 940nm– oxyhemoglobin• SpO2 =SaO2 +/- 3%

Cases#2and#3• Standardtwo-wavelengthpulseoximetry

doesnotyieldaccuratereadingsinthepresenceofmethemoglobinemia

• SpO2 underestimates SaO2formethemoglobin <20%

• SpO2 overestimates SaO2formethemoglobin>20%

• “Saturationgap”SaO2 - SpO2 >5%>10%clinicallysignificant

Anesthesiology 1989;70(1):112-7

• Methemoglobinemiainpatientstakingdapsone?– Normalvaluesforarterialoxygensaturation(SaO2,SpO2)arenotdefined

– Manypractitionersunfamiliarwithdapsonepharmacologywillgetnervousfor90%<SpO2 <95%

– YoushouldbenervousforSpO2 <89%

– SignificanceofabnormalpulseoximetryandABGmeasurementsdependsontheclinicalcontext• Cyanosisandsigns&symptomsofhypoxia?• Totalhemoglobin?• Functionalcardiopulmonarystatus?

Cases#2and#3

• Methemoglobinemiainpatientstakingdapsone?– Considertwoasymptomatic patientstakingdapsone

• PulseoximetryshowsSpO2 =92%• OrderHbandMetHb

– PatientA(Healthy):• Hb12.0g/dL;MetHb15%

– PatientB(CADstatuspoststentplacement):• Hb10.0g/dL;MetHb15%

Cases#2and#3

Edhegard,k.,andR.P.HallIII.“Dapsone.”ComprehensiveDermatologicDrugTherapy,ThirdEdition.Ed.Wolverton,S.E.Edinburgh:ElsevierSaunders,2013.228-240.Print.

EffectiveHb10.2g/dL

EffectiveHb8.5g/dL

PharmacologyPearls#2• Methemoglobinemiawilloccurinallpatientsondapsone

• Standardpulseoximetrymeasurementsareinaccurate forpatientstakingdapsone

• SpO2 >90%may ormaynotbeacauseforconcern– Dependsontheclinicalcontext

• SpO2 <89%arecauseforconcern,eveninanasymptomaticpatient(MetHb~20%)

Case#4• OralCandidiasis– Pseudomembranous(whitenon-adherent plaques)• Thrush

– Erythematous(redwithout plaques)• Medianrhomboidglossitis• Antibioticsoremouth• Angularcheilitis

– Hyperplastic(white/yellowadherent plaques)• Chronichyperplasticcandidiasis

Case#4• Chronichyperplasticcandidiasis– Adherent keratotic plaques– Buccal mucosa,dorsaltongue,palate– Riskfactors• Immunosuppression• Diabetes• Tobaccouse• Reducedsalivaryglandfunction• Steroiduse

Case#4• Chronichyperplasticcandidiasis– Treatment

• Minimizationofriskfactors• Systemics

– Azoles» fluconazole,itraconazole

• Topicals– Azoles

» clotrimazole troche,miconazole solution– Nystatin suspension

– Questionableroleinpromotingdysplasia&malignancy

PharmacologyPearls#3

• Shouldyoueverworryaboutmedicationinteractionswithclotrimazoletroches?– Yes!

PharmacologyPearls#3• Clotrimazole trochescommonlyadministeredasroutineprophylaxisoforalthrushinpost-transplantpatients

– Multiplecasereportsandcaseseriesinliverandkidneytransplantpopulationsdemonstratingincreasedtacrolimuslevelsinpatientsusingclotrimazole troches

• Transplantation 1991;56(6):1086-1087• ClinicalTransplantation2001;15(2):95–99• Therapeutic DrugMonitoring2005;27:587–591• Pharmacy and Therapeutics 2010;35(10):568-569

PharmacologyPearls#3

Clin Transplant 2001;15(2):95–99

PharmacologyPearls#3• Recommendclosemonitoringoftacrolimuslevelswhenstarting orstopping clotrimazoletrochesinatransplantpatient

• Nystatin swish/swallowandswish/spitareprobablysaferalternatives

Blastomycosis-likecandidiasis• “Moniliasisaspossibleetiologicfactorforpseudoepitheliomatoushyperplasia”– Verruciformlesionsinthemouthunderorthodontics

– ArchDerm1967;96:598

• “InductionofepithelialhyperplasiabyCandidaalbicans”– Comparisonofhumanmucousmembranelesionstoinoculatedchorio-allantoicmembraneofembryonatedchickeneggs

– BrJDermatol1973;89:497

Blastomycosis-likepyoderma• Singleormultipleverrucousplaquesonfaceordistalextremities– Pseudoepitheliomatoushyperplasiawithabscessesand/orgranulomatousinflammation• Resemblingblastomycosisortubeculosisverrucosacutis

• Usuallybacterial– S.aureus>ß-streptococcus,Pseudomonas,Proteus,E.coli

• RarelyCandida– ArchDerm 1979;115:170

Blastomycosis-likepyoderma.ArchDerm 1979;115:170

Blastomycosis-likepyoderma• Exaggeratedtissuereactionpatientsw/lowresistancetoinfection

– ArchDerm 1979;115:170– IndianJDermatol Venereol Leprol 1985;51:226– PedDermatol 2017;34:201

– Iatrogenicimmunosuppression– Diabetesmellitus– Leukemia– Alcoholism– Genodermatosesw/cutaneousinfx(KIDsyndrome)

VegetatingCandidiasis:AMimickerofSquamousCellCarcinomainKeratitisIchthyosisDeafnessSyndrome

PediatricDermatologyVolume34,Issue2,pages201-203,23JAN2017

VegetatingCandidiasis:AMimickerofSquamousCellCarcinomainKeratitisIchthyosisDeafnessSyndrome

PediatricDermatologyVolume34,Issue2,pages201-203,23JAN2017

Fusionofmyogeniccellstonewmyofibersindamagedskeletalmuscle• Skeletalmuscleregenerationafterinjury(undergraftinthiscase)– Inflammation,phagocytosis,&– Activation,proliferation,fusionmuscleprecursors• Sarcoplasmicextensionscontainingmultipleclumpednucleicalled“buds”or”stumps”atendsofmyofibers– Neuropathology&appliedneurobiology1993;19:350– Diagnosticcytopathology1985;2:91

Reactivechangesinskeletalmuscle• Canmimicrhabdomyosarcoma

• Histopathology1998;33:136• Recognitionasskeletalmuscle

(notcarcinomaormyofibroblastic)– Occurringunderflap/graft– Striations– Desminexpression

PTAH

Hypertrophiclupuserythematosus• Discoidlupuserythematosusvariant

– Extensorextremities&face(earlyonfewlesionspresent)– Difficulttotreat

• Clinicalresemblance– Hypertrophicactinickeratosis– Squamouscellcarcinoma– Keratoacanthoma– Hypertrophiclichenplanus– Prurigo nodularis– Verrucavulgaris

• BothcutaneousLE&atypicalsquamouslesionsonsunexposedskin

• FrederickMohsinadvertentlyperformedsurgeryonDLEmasqueradingasSCC

DermatolSurg 1995;21:255

Hypertrophiclupuserythematosus• HyperLP-likeorSCC(KA)-like

– Squamousatypia(reactive)– Pseudo-invasivegrowth– Lichenoidtissuerxn

• Follicularplugging• Superficial&deepperivascular

infiltrate• BMZthickening• Dermalmucin

Clinicalinformation&Adequatetissueveryhelpful!

JCutan Pathol 2003;30:443JCutan Pathol 2011;38:889

Plasmacytoid dendriticcellsinhypertrophicdiscoidlupuserythematosus:anobjectiveevaluationoftheir

diagnosticvalue

JournalofCutaneousPathologyVolume42,Issue1,pages32-38,15DEC2014

• IncreasedCD123expressingplasmayctoiddendriticcells(pDCs) inlupusinfiltrate

• LackinginSCC/HAK• Nothelpfulindistinguishing

hypertrophicLPvshypertrophicLE• pDCs secretetypeIIFN&playamajor

roleinpathogenesisoflichenoid/interfacedermatoses

JInvestDermatol2009;129:1088

Squamouscellcarcinomaarisinginhypertrophiclupus

JournalofCutaneousPathologyVolume42,Issue1,pages32-38,15DEC2014

• LesionsofdiscoidLEmaydevelopSCC(3.3%longstandingcases)

• Mostcommoninfacialdiscoidlesions• Heavilyscarredareas• Activelesionsonthelip!

• MeandelayfromLEtoSCC30.8yrs(range26-41yrs)

• Clin Exp Derm 1978;3:161

Surgicalpearl• Importanttolookattheentireclinicalpicture

• Avoidsurgicalblinders• Delaysurgeryiffurtherwork-upisneeded– Importantasmorepatientsareseenassame-dayMohsevaluationandsurgery

Surgicalpearl• Haveahighindexofsuspicion• DonotperformMohssurgeryorexcisiononhypertrophiclupus

Reviewingexternalpathologyslides• ConsideredstandardofcaretoreviewoutsidebiopsyslidespriortoMohs

• Ratesofdiscrepancybetweenpathologyreportsintheliteraturerangewidely (0.5%to43%)

• StudywithinMohs– Diagnosisof74(2.2%)outof3,345tumorswaschangedonreviewofpathology

– 45(61%)resultedinachangeinmanagement

ButlerST,etal.DermatolSurg.2009Mar;35(3):407-12

Desmoplasticmelanoma• Desmoplasticmelanomasmayhaveanoverlyinglentigomalignaoratypicalintraepidermalmelanocyticproliferation

• ?progressionfromthelentiginouscomponentorarises"denovo“

EgbertB,etal.Cancer.1988Nov1;62(9):2033-41DeSouzaBastos,etal.AnBrasDermatol.2013May-Jun;88(3):408–412

Desmoplasticmelanoma• Desmoplasticmelanomarepresentsaminority(4%)ofcutaneousmelanomas

• “UnrecognizedDesmoplasticMelanoma”areresponsibleformalpracticeclaimsrelatedtomelanoma– Shavebiopsiesorsuperficialpunchbiopsiesmayonlycapturetheatypicallentiginousproliferation

Troxel DB,Etal.AmJSurg Pathol.2003Sep;27(9):1278-83

MohsPathologyPearl• Importanttolookfordesmoplasticmelanomainallbiopsiesoflentigomaligna

• ForthelayMohssurgeon/dermatologist:– “Actinicdamagedskin+scarordesmoplasia=ruleoutdesmoplasticmelanoma”

Troxel DB,Etal.AmJSurg Pathol.2003Sep;27(9):1278-83

Mohsdebulkspecimen• CriticaltosubmitMohsdebulkforLM,MISormelanoma

forpermanenthistology– LM/MISmaybeupstagedonreviewofMohsresectionmargins

(range5– 8%)• Importanceofverticalpermanenthistology

– Necessaryforaccuratetumorstaging– Mohsmicrographicsurgeryexaminesonlytheperipheryand

baseofthecentralportionofthetumortodeterminewhetherthemarginisclear

– HorizontalsectionsprecludemeasurementofBreslow

Iorizzo L,etal.DermatolSurg 2013;39:365–371

Mohsdebulkspecimen• Detectionofhigh-riskhistologicfeaturesandtumor

upstagingofnon-melanomaskincancers– Aggressivehistologicsubtypemaydirectlyaffectstaging,

treatment,andoutcomes– Potentialforsamplingerrorininitialbiopsy– MMScentraltumorisoftencurettedorscalpeldebulked– SinghB,etal:

• BCC:30%reclassifiedfromlow-risktohigh-riskhistology• SCC:9.1%perAJCC-7and11.1%perBWHwereupstaged• Biopsyspecimensfailedtodetect89%ofcasesofPNI

SinghB,etal.DermatolSurg.2017Aug;43(8):1003-1011

Surgerypearl• BillingforMMS(17311-17315)

– Reservedforthesurgeonwhoremovesthelesionandpreparesandinterpretsthepathologyslides

• Medicarerecoveryauditcontractors– MayassertthatMMSwasnotbeingperformedifpermanent-

sectionpathologycodesareusedonthesamedayasMohs• Documentationmustbeexplicitregardingreasonsfor

sendingdebulkforpermanentsections– Tumorstaging

Iorizzo L,etal.DermatolSurg 2013;39:365–371

Epidermalnevus– syndromes?• Heterogeneousgroupofsyndromes• EpidermalandadnexalhamartomasPLUSotherorganinvolvement– CNS– clinicalorstructural– Ocular– Skeletal– includingfacialdysmorphism

• SomaticmutationsincludeFGFR3,RAS,PIK3CABMCMedGenet.2011Jun5;12:79AmJMedGenetA.2008Sep1;146A(17):2275-9 .BrJDermatol.2007Jun;156(6):1353-6.Epub 2007Apr17.

Orallinearepidermalnevus?• Fewcasereportswithbothassociatedcutaneousepidermalneviandasisolatedfinding

Reportsofepidermalneviandmucosalneuromas?

• Onecasereportfrom2009• TeenagegirlinItaly– Leftsidedepidermalnevus– Leftsidedfacialhypertrophyandtonguepapules

Castelli,etal.Kosmetiche Medizin.Dec2009.31(6):298-305

PIK3CAMutations

AmJMedGenetA.2015Feb;0(2):287–295.

AmJMedGenetA.2015Feb;0(2):287–295.

PIK3CAPearls• PIK3CAsomaticmutationscanresultinovergrowthinanynormalunderlyingtissue

Managementofepidermalnevus• Cryotherapy• Shave• Excisionaldebulking• AblativeCO2laser

Managementofmucosalneuroma• Shaveorexcisionaldebulking• AblativeCO2laser– Goodlocalhemostasis– Reducededema– Reducedpostoperativediscomfort–Minimaltonowoundcontractionandscarring

GamaSKC,etal.LasersMedSci 2008;23:459-465

Oralsofttissuebiopsypearls• Stabilizetissue– Gauze,chalazionclamp

• Anesthesia– Localinfiltration

• Hemostasis– Pressure,silvernitrate,electrocautery

– Suture*AvonS,etal.JCanDentAssoc 2012;78:c75Davari P,etal.ClinicsinDermatology(2016)34,440–448

Oralsofttissuebiopsypearls• Suture– Silk:Soft,goodtensilestrengthandlesslikelytocutthroughmucosaltissue

– Chromicgut:Eliminatesneedforsutureremoval

– Suturemaybecomelooseonthetongueinthishighlymobileregionwithriskforaspiration

AvonS,etal.JCanDentAssoc 2012;78:c75Davari P,etal.ClinicsinDermatology(2016)34,440–448

LaserLightEffectsonTissue• SelectivePhotothermolysis–Wavelengthmustpenetratetheskintoreachitsdepth

–Wavelengthoflightisabsorbedbythetargetchromophore

– Lightisabsorbedandconvertedintothermalenergy

NouriK.HandbookofLasersinDermatology

AblativeCO2Laser• Wavelengthsthatarehighlyabsorbedbywateraretermed‘ablative’

• Variouswater-containingstructuresatdifferingdepths:– Epidermalkeratinocytes,collagen,bloodvessels

• Fullfieldablativelaserresurfacingremovestheentireepidermalskin/mucosalsurface

Hruza G,etal.LasersandLightsNouriK.HandbookofLasersinDermatology

AblativeCO2Laser• Vaporization– Watervaporizesandgasifiesandvolumeexpands

– Targetisremovedbyfragmentation,vaporization,andablation

• Coagulation– Residualthermaldamageoccursinsurroundingzoneviathermocoagulation

Omi,T,etal.LaserTher.2014Mar27;23(1):49–60