Jane L. Messina, MD September 16, 2017 MELANOMA VERSUS ... · Jane L. Messina, MD September 16,...
Transcript of Jane L. Messina, MD September 16, 2017 MELANOMA VERSUS ... · Jane L. Messina, MD September 16,...
Jane L. Messina, MD September 16, 2017
Jane L., Messina, MD September 16, 2017
MELANOMAVERSUSNEVUS:STRATEGIESFORTHEDIFFICULT
DECISION
Conflicts
• IserveasaconsultanttoCastleBiosciences
Objec.ves
• Reviewclassicfeaturesofmelanoma• AJCCupdate• Discusscommonlyencountereddiagnos<cdilemmas
Thereal thing
Asymmetry
Poorcircumscrip<on
Confluence,epidermaleffacement
Sheet-likegrowth,atypia,mitoses
AJCC8 th edi.onupdate (effec.ve
1/1/2018)
• Primarytumorstaging:– Breslowdepthtonearest0.1mm– Ulcera<on(widthmeasured!!)– Microsatellites:“microscopictumorfociwithindermisorsubQadjacenttobutdiscon<nuousfromprimary”;nominimumsizeordistance
– Repor<ngofmitoses“recommended”
AJCC8 th edi.onstagingchanges
TX Primarytumorthicknesscannotbeassessed(i.e.cureIagespecimen)
T0 Regressedmelanomaormelanomaofunknownprimary
T1a
T1b
0-0.8mm
>0.8mm-1.0mmorulcera.on
T2a/b 1.1-2.0mmw/orw/oulcera.on
T3a/b 2.1-4.0mmw/orw/oulcera.on
T4a/b >4.0mmw/orw/oulcera.on
N1 N2 N3
A-occult 1 2-3 >4
B-clinical 1 2-3,atleast1clinical+ >4,atleast1clinical+
C-microsatellites 0nodes+
microsatellite
Atleast1node+
microsatellite
Atleast2nodes+
microsatellite
Commonlyencounteredscenarios
• Lackofcompunc<onatthejunc<on• Specialsites• Nevoidmelanoma,dysplas<cnevus,orboth??• Downanddirtyinthedermis:spindled,pigmented,andugly
• Spitzoidlesions
Lackofcompunc.onatthe
junc.on
Melan-A
MITF
Melanoma in s i tu!
Immunohistochemistry in sun-damaged
skin
• S-100– Polyclonal:crossreactswithpigmentedAK
– Monoclonal:diminished
sensi.vityinLMandALM
• HMB-45:patchy/par.alstaining
• Melan-AandMart-1:overstainingaproblem
• Sox-10orMITF:ideal
Mart-1
MITF
Quan.fica.onof melanocytes insun-
damagedskin(CSD)-what is normal?
• Confluence>3melanocytesfoundin16%ofSDSspecimensonH&E,4%onMart-1
• Deepfollicularmelanocytesin6%,nestedmelanocytesin1BCCspecimen
• Melanocytedensity:LM>NMSCpa<ents
Barlow,Maize,andLang.DermatolSurg2007;33:199–207Madden,Forman,andElston.JAmAcadDermatol2011;64:548-52.)
*MANOVA
200µ
• Density:numberofmelanocytes/200µm• Diameter:modeofnucleardiameterofshortestaxisof3melanocytes• Densityxdiameter>80is85%sensi<veand100%specificforMIS
AmJDermatopathol2011;33:573–578
Minimaldiagnos.ccriteriaforMIS
(len.gomalignatype)
• H&EandSox-10/MITFstaining• Highnumberofmelanocytes:>10per200µm,especiallyif
presentoverabroadfront• Nuclearenlargement>9µmdiameter/pleomorphism• Inabsenceofnes<ng,confluenceof>3melanocytes• Irregulardistribu<onofmelanocytes• Descentofmelanocytesfardownadnexalstructures• Irregulardistribu<onofpigment• Melanocytespresentabovebasallayerinsignificantnumbers
AmJDermatopathology;18(6),December1996,pp560-566
Residual melanomavs melanocy.c
hyperplas ia?
Lookatrequisi<on!“r/oresidualBCC”
Diagnosis:NoresidualBCC(melanocy<chyperplasiaatpriorbiopsysite)
Previouslybiopsiedlesionwasdiscarded
MarkedcytologicatypiaMyriadresult:3.1
Diagnosis:melanomainsitu,recurrent
Lesiondiameter=2mmPa<entage:8
Diagnosis:PagetoidSpitznevus
PagetoidSpitz nevus
• 5-10%ofallSpitznevi• Largestseries(12):allfemale,extremitypredominant,medianage34years
• <5mmdiameter• Nests<1/3overallcellularity;singlecellsconfinedtolower½ofepidermisin75%
• Molecular/IHCanalysisnotextremelyhelpful
FernandezAP,BillingsSD,BergfeldWF,KoJS,PiliangM.PagetoidSpitznevi:clinicopathologiccharacteriza<onofaseriesof12cases.JCutanPathol2016;43:932–939
Junc.onal melanocy.cneoplasmonthe
leg of a woman
Diagnosis:Junc<onalmelanocy<cnevus(“len<ginous”type)
“Leg-type”nevi
• Describedonthigh,belowknee,andankle• “Epithelioidcellmelanocy<cnevus”,“melanocy<cneviofanklewithatypicalfeatures”,“dysplas<cnevioflegofwomen”
• Small(4-5mm)• Singlecells=nests• Lowpagetoidspread
Dona<P,MuscardinL,CotaC,PaneraC,PaolinoG.Themelanocy<cepithelioidcellnevusofthethighofwoman:asimulatorofmelanoma.AmJDermatopathol.2012Dec;34(8):853-5.doi:10.1097/DAD.0b013e31824d4f86.PubMedPMID:22481498.CorasB,LandthalerM,StolzW,VogtT.Dysplas<cmelanocy<cneviofthelowerleg:sex-andsite-specifichistopathology.AmJDermatopathol.2010Aug;32(6):599-602.doi:10.1097/DAD.0b013e3181ce910b.PubMedPMID:20534984.KhalifehI,TaraifS,ReedJA,LazarAF,DiwanAH,PrietoVG.Asubgroupofmelanocy<cnevionthedistallowerextremity(ankle)sharesfeaturesofacralnevi,dysplas<cnevi,andmelanomainsitu:apoten<almisdiagnosisofmelanomainsitu.AmJSurgPathol.2007Jul;31(7):1130-6.PubMedPMID:17592281.
©2012LippincorWilliams&Wilkins,Inc.PublishedbyLippincorWilliams&Wilkins,Inc. 2
FIGURE2
TheMelanocy.cEpithelioidCellNevusoftheThighof
Woman:ASimulatorofMelanoma.
Dona<,Pietro;Muscardin,Luca;Cota,Carlo;Panera,Chiara;Paolino,GiovanniAmericanJournalofDermatopathology.34(8):853-855,December2012.DOI:10.1097/DAD.0b013e31824d4f86
FIGURE2.Intraepidermalmelanocy<cprolifera<onwithepithelioidappearance(hematoxylinandeosinstain,originalmagnifica<onx10).
EverysiteisSPECIALinitsownway
Ahn,C.,Guerra,A.,andSangueza,OP.AmJDermatopathol2016;38:867-881
Acral sk in
• Len<ginous>nestedgrowth• Pagetoidspreadin36%(MANIAClesion!)• Banal,patchydermalcomponent
Genital ia
• Large(upto1cm)andwellcircumscribed• Highcellularityofjunc<onalnests• Bridgingandfibroplasia• Dermalmito<cac<vityin7%• LsEtAbackground:epidermaleffacementandsinglecellconfluencepossible
fromSanguezaetal.
GenitalnevuswithLSetA
Ear
• Poorcircumscrip<on• Irregularnes<ng,bridging,fibroplasia
• Cytologicatypialesscommon
fromSanguezaetal.
Scalp
• Featuresoverlapwithdysplas<cnevi– Asymmetry,poorcircumscrip<on,irregularnes<ng,bridging,fibrosis,inflamma<on
• Mostcommonly,butnotexclusively,foundinadolescentsFisherK,MaizeJC,andMaizeJC.JAmAcadDermatol2013;68:466-72.)
F lexura l s i tes
-m i l k l i ne
- an tecub i ta l /pop l i tea l fo s sae
- b reas t
• Nestsatsides/betweenrete• Dyscohesivenestsandsinglecells,len<ginousgrowth,pagetoidspread,andadnexalepithelialinvolvement
• Atypiamildtoabsent• Umbilicus:fibroplasia• Breast:atypia,highcellularitymorecommon
Breast nevi
fromSanguezaetal.
Nevoidmelanoma,dysplas.c
nevus,orboth?
Useful immunohistochemicaltools
OR ?
• Prolifera<onmarkers:Ki-67,phosphohistoneH3
• Matura<onmarker:HMB-45• P16
Ki-67:thegood,thebad,andthe
ugly
Melan-A/Ki-67(MelPro) innevoid
melanoma
Nevi:<5%Melanoma:>10%
MelPro in a nevus
PhosphohistoneH3formitoses
• Compoundnevus:MR0.06/sqmm• Spitznevus:meanMR0.5mitoses/10HPF(range0-2)orMR0.325/sqmm
• Melanoma:meanMR24.7(range2-75)
NasrMR,El-ZammarO.AmJDermatopathol.Apr2008;30(2):117-122Phadkeetal.AmJSurgPathol2011;35:656-699Glatzetal.AmJDermatopathol2010Oct;32(7)643-649.
HMB-45staininginnevusversus
nevoidmelanoma
NevusMelanoma
Pixalls• Bluenevus,DPN,trauma<zednevusexpressHMB-45
• 10%ofmelanomasshowgradientexpression
p16andmal ignant poten.al
AlDhaybiRetalJAmAcadDermatol.Aug2011;65(2):357-363Ohsieetal.JCutanPathol2008;35:433-444
Retainedexpression:favorsbenign
Expressionlostin50-98%ofmelanomas
p16caveats
• Manymelanomass<llexpressp16,andbenignnevimaynotexpressit
• Lossofp16stainingdoesnotequatetohomozygousdele<onof9p21– Itcanbeposi<veevenin9p21deletedlesions(15%)– Itcanbenega<veinlesionswithheterozygousloss,epigene<csilencing,orevennormal9p21
Gray-SchopferVCetal.BrJCancer2006;95:496-505Yazdanetal.AmJSurgPathol2014;38:638-645.
Nevoidmelanoma
• a/k/a/minimaldevia<onorsmallcellmelanoma,~3%ofmelanomas
• Non-uniformcriteria(Spitzoidlesions?)– 55%plaque-like:paralleltheques– 45%polypoid:resemblecompoundnevi– “pseudomatura<on”:cellsizeshrinks,butnucleusremainssame
– DEjunc<onmosthelpful– Deepmitoses
“Amelanocy<cneoplasmcalledanevus,butwith
subsequentdiagnos<cregret”DiwanandLazar,SurgPathClin
2009
DiwanAH,LazarAJ.SurgPatholClin2009Sep;2(3):521-33Idrissetal.JAAD2015Nov;73(5):836-42
Confluenceatjunc<onParallelthequesPseudomatura<onHopefullyamitosisortwo
Dermal melanomavs. pre-exis.ngnevus
Melanoma!
Pre-exis<ngnevus!
37y/omale,backlesion,“r/oatypia”
HMB-45
Sox10
Pagetoid melanocytes in dysplas.cnevi
• 43dysplas<cnevi• Pagetoidmelanocytesseenin63%ofcasesonIHC,11%onH&E
AmJDermatopathol2014;36:340–343)
Downanddirtyinthe
dermis
63
S-100
P75-NGFR
Sox-10
MiTF negative (usually)
HMB-45 negative
Melan-A negative
Desmoplas.cmelanoma
• Purevmixed:>or<90%paucicellulardermalgrowth– Hypercellularcomponentmaybespindleorepithelioid
64Busam et al. Am J Surg Pathol 2004; 28:1518-1525. Pure Mixed
Differen.al diagnosis
• Scar:Sox-10nega<ve• DesmoplasIc(Spitz)nevus:p16NOThelpful(strongin75%pureDM)
• Neurofibroma:“fingerprint”parernCD34posi<vity• MPNST:S-100andSox-10usuallyweak/patchy,BRAFusuallynega<ve,lossofH3K27me3
65
Neurofibroma DM Desmoplastic nevus
H3K27me3express ion can d is.nguish
betweenMPNSTand desmoplas.c melanoma
• LossofstainingusingC36B11an<body(CellSignalingTechnology)seenin69%ofMPNST
• However,insporadicandradia<on-relatedMPNST,absentstainingseenin95%and91%
• TMAcontaining55desmoplas<cmelanomasallshowedretainedstaining
66Prieto-Granada C et al., Am J Surg Pathol 2016; 49(4): 479-489
Reta ined express ion
of H3K27me3 in
desmoplas.c/
sp ind le ce l l
melanoma
67
Loss of H3K27me3 in MPNSTar is ing in
neurofibroma
68
Feel ingblue
Epithelioidbluenevus
Pigmentedepithelioidmelanocytoma
Animal-typemelanoma
Epithelioidbluenevus• Carneytriad
• LossofPRKAR1α
Pigmentedepithelioidmelanocytoma• Epidermalhyperplasia
• Perinuclearpigmentclearing• <<5%prolifera<onrate
• 40%SLN+• Allcasesnega<vef/uthusfar
Epithel ioid andfus i formbluenevus
• CSDskin,noCarneytriad,PRKAR1αretained
Yazdan,P.,Haghighat,Z.,Guitart,J.,andGermai,P.AmJSurgPathol2013;37:81–88)
Clonal nevus
Clonal(“invertedtypeA”)nevus
MBAIT(Melanocy<cBAP-1lossassociatedintradermaltumor)
• LossofnuclearstainingbyBAP1• Screenforuveal>cutaneousmelanoma,
mesothelioma
Whataboutme????
Incidence(%)
BAP-1lossHRASNTRKALKROS-1BRAFRETUnknown
34%unknown
Van-Engen-vanGrunsvenetal.AmJSurgPathol2010;34:1436-41Wiesneretal.NatCommun2014;5:3116
• FoundinlesionsacrossSpitzoidspectrum• Canbeiden<fiedbyimmunohistochemistry• AssociatedAST’smayhavedis<nc<vehistology• Conferpossiblesensi<vitytotargetedtherapy
• Crizo<nib,cabozantanib,vande<nibusedtotreatALKandROS-1+lungtumorsoflungandRET+thyroidtumors
Significanceofkinasefusions
Moffitt 5-tiered nomenclature for melanocytic neoplasms RISKOFMALIGNANCY
1 2 3 4 5
BENIGN ATYPICAL,FAVORBENIGN
UNCERTAINMALIGNANTPOTENTIAL
ATYPICAL,FAVOR
MALIGNANT
MALIGNANT
CATEGORY
B-BLUENEVUSLIKE
C-CONGENITAL
D-DYSPLASTIC
S-SPITZOID
• CLINICALHISTORYANDAPPEARANCE• HISTOLOGICANDIMMUNOHISTOCHEMICALFINDINGS
• MOLECULARTESTINGIFNECESSARY
Putting it all together
S1
BenignSpitz
nevus
S2
Atypical,
favorbenign
S3
Atypical,
uncertain
biologic
poten.al
S4
Atypical,
favor
malignant
S5
Spitzoid
melanoma
HRAS
amplifica.on
11por7pgain
6p25gain
11q13gain
9p21dele.on
orabn.CGH
6q23gain
Customizing treatment
S1
BenignSpitz
nevus
S2
Atypical,
favorbenign
S3
Atypical,
uncertain
biologic
poten.al
S4
Atypical,
favor
malignant
S5
Spitzoid
melanoma
Re-
excision
0.5-1cm
Re-excision1cmwithSLNB
541pa<entswithAST
SLNB303(56%)
+SLN119(39%)
CLND97(82%)
+CLND18(19%)
NoCLND22(18%)
-SLN184(61%)
NoSLNB238(44%)
5(4%)REGIONAL
RECURRENCE11(5%)REGIONAL
RECURRENCE
1DEATH 5(1%)DEATHS
Lallasetal.LancetOncol2014;15:e178–83
• 24studies,2002-2013• Averageage:24years• Medianf/u:59.3months
Let’s do the numbers….
Molecular tests for accurate
iden.fica.onof melanoma
• Fluorescenceinsituhybridiza<on– Frequentlyusedintheevalua<onofdiagnos<callychallengingmelanocy<cprolifera<ons
• AtypicalSpitzoidprolifera<ons(AST),atypicalbluenevus-likeprolifera<ons
• Compara<vegenomichybridiza<on• MyriadmyPATH
Oldassay6q23CEP66p25,11q13
Fluorescence in s i tu hybr idiza.on-
NeoSITE®melanoma
• NeogenomicsLaboratories(Ft.Myers,FL):$1500• Whataboutborderlinelesionssuchasthis?
Sensi<vity:87%Specificity:95%
Newassay8q249p21
94%98%
Unequivocalmelanoma
FISH in histological ly ambiguousSpitzoid
les ions (AST)
Probeset ASTw/o
recurrence
“AST”withpoor
outcome
(melanoma)
TypicalSpitz
OLDsensi<vity 50-100%6,1,4
OLDspecificity 57-91%4,1 75-100%5,1
NEWsensi<vity 50-100%3,2
NEWspecificity 74-87%2,3
1DemarchisEHetal,PediatrDermatol.2014;31(5)561-92Geramietal,AmJSurgPatholFeb20133Tetzlaffetal,AmJSurgPathol.Dec20134Massietal.JAmAcadDermatol2011;64:919-355DikaetalMelResearch2015;25(4):295-3016Vergieretal.ModernPathology2011;24:613-623
Spec ific F ISHabnormal i.es assoc iatedwith
outcome in border l ine les ions (AST)
• Homozygousdele.onof9p21:predictslocalrecurrenceandonlyfeaturepredic<veofdeath
• Gainof6p25and/or11q13:predictsSLNinvolvementbutnotrecurrenceordeath
• Heterozygous9p21loss:significantsen<nelnodeinvolvementbutnospreadbeyondtheregionalnodes
• 6q23(MYB)loss:associatedwithgoodlongtermoutcome
Geramietal,AmJSurgPathol,Feb2013Northetal.AmJSurgPathol2014;38:824-31Raskinetal.AmJSurgPathol2011;35:243-52
Compara.vegenomic hybridiza.on
• Assesseschromosomalcopynumberchangesacross<ssue,butmissesindividualcellabnormali<es
• 95%ofmelanomasharbornumerouschromosomalgainsandlosses
• Nevirarelyshowaberra<ons• ExcepIons:
– 12-26%ofSpitznevi(esp.recurrent)have11por7qgain– SomeASThaveabnormalCGH(45%,mostcommongainof1p)
• DoesnotpredictSLNinvolvement• Prolifera<venodulesincongenitalnevimayhavewholechromosomalgains
Bas<anBCetal.JInvestDermatol.1999;113:1065–1069.Bas<anBCetal.AmJPathol.2003;163:1765–1770Raskinetal.AmJSurgPathol2011;35:243–252
Compara.vegenomic hybridiza.on
• Mostcommonlyusedtodis<nguishpediatricatypicalSpitztumorfrommelanoma
• Notwidelyavailable,insurancecoveragevaries• Typicalout-of-pocketcost$2500
MyriadMyPath-diagnos.caid for
equivocal les ions
• 23-geneexpressionsignaturethatcanhelpdifferen<atenevifrommelanoma-u<lizes5recutslidesfromparaffinblock
• Trainingandvalida<oncohortsof900+unequivocalmelanomaandnevi:sensi<vity90%specificity91%
• Currentlyundergoinglarge-scaletes<ngofclinicalu<litywithmelEvalPRO
Clarkeetal.JCutanPathol2015;42:244-252
Superficial
spreading>nodular>len.go
maligna
Compound
anddermal
nevi
Independent val ida.onof myPath
• 1400lesionsindependentlyreviewedby3experts– Tripleconcordance:993lesions(70.9%)– Excludedindeterminatescores:860lesions(24%malignant,76%benign)
– Excludedlesionswith<10%tumorvolume:763lesions
• Sensi<vity91.5%--Specificity92.5%– Falsenega<ves-len<gomalignaanddesmoplas<cmelanomavariants
– Falseposi<ves-dysplas<cnevi
Clarkeetal.,Cancer,October2016Clarke,ASDPOctober2016
29yearoldpregnantfemalewithchanginglesiononback
Junc<onaldysplas<cnevuswithmoderatetosevereatypia
MyPathanddiagnos.cal ly chal lenging
les ions
• 39unequivocallesions:62%sensi<vity,95%specificity
• 78challenginglesionswithexpertconsensus(27favormalignant,30favorbenign,21ambiguous)
• myPathscoreagreedwithhistologyin64%,agreedwithFISH70%of<me– Limitedbylackofclinicaloutcome
SUMMARY:myPathscorecanincreasediagnos<ccertaintyandinfluencetreatmentrecommenda<ons,BUTperformancenotproveninambiguouslesions
Mincaetal,ModernPathology,August2016,29:832-843.
Molecular tests for melanomadiagnosis
Summary
• FISHandmyPathsensi<vityandspecificity~90%inunequivocalmelanomasandnevi
• FISHsensi<vitydropsto50-100%andspecificityto74-87%inAST
• CGHcanaidinatypicalcaseswithnega<veFISH,buthamperedbylimitedavailabilityandreimbursement