Post on 25-May-2019
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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