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Metasta�cCarcinomaofUnknownPrimary:Diagnos�cApproachUsingImmunohistochemistry
JamesR.Conner,MD,PhDMountSinaiHospital
Toronto,ON
CarcinomaofUnknownPrimary(CUP)
3-5%ofallnewmalignantdiagnoses
7thor8thmostcommonmalignanttumor
4thmostcommoncauseoftumordeath
Slowlydecliningincidence– Improveddiagnos�cimaging– Expandingrepertoireofimmunohistochemicalmarkers
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RolesofthePathologistinCUP
1. Dis�nguishcarcinomafrommelanoma,sarcoma,lymphoma
2. Definecarcinomasubtype(adenocarcinoma,squamouscellcarcinoma,hepatocellularcarcinoma,etc)
3. Iden�fysiteoforigin
ImmunohistochemistryinWorkupofCUP
Kera�nsandtheirdistribu�onincarcinomas
Lineagespecificmarkers:– Cytoplasmicproteins– Lineagerestrictedtranscrip�onfactors
Iden�fica�onofprimarylivertumors
Squamouscellcarcinomas
Neuroendocrinetumors
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HighandLowMolecularWeightKera�ns
LMWKs(CK8,CK18,CAM5.2)expressedby“simple”epithelium:– Glandularepithelium– Hepatocytes
HMWKs(CK5,CK14,34βE12)expressedby“complex”epithelium:– Stra�fied(squamous,transi�onal)epithelium– Someductalepithelium– Basalcells
CK7(KRT7)andCK20(KRT20)
Profile MostFrequentPrimarySites
CK7+/CK20- Breast,Mullerian,Lung,Thyroid
CK7+/CK20+ UpperGI,Pancreas,Urothelial
CK7-/CK20+ Colorectal,MerkelCell
CK7-/CK20- Prostate,Hepatocellular,Renal,Adrenal
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LineageRestrictedMarkers
Cytoplasmic(andMembranous)MarkersPrimarySite Markers(%Sensi�vity)
Breast Mammaglobin(60-80),GCDFP-15(60-80)
Lung NapsinA(60-80)
Thyroid Thyroglobulin(80-90)
Renal RCC(80-90primary,50-70metasta�c)
Hepatocellular HepPar1(70-90),Arginase-1(80-90)
Prostate PSA(85-95),PSAP(85-95)
Colorectal Villin(80-90)
AdrenalCortex MelanA/MART-1(85-95),Inhibin(85-95)
Bladder UroplakinIII(15-50),UroplakinII(50-80)
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Ingeneral,sensi�vityishighinwell-differen�atedtumorsbutdecreasessubstan�allyinpoorlydifferen�atedtumors
Cytoplasmic(andMembranous)Markers
GCDFP-15inBreastCarcinoma
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MammaglobininBreastCarcinoma
NapsinAinPulmonaryAdenocarcinoma
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RememberLimita�onsonSpecificity
NapsinA– Ovarianclearcellcarcinoma(80-100%)– Papillaryrenalcellcarcinoma(70-90%)
Mammaglobin– Endometrialcarcinoma(10-30%)
Inhibin,MelanA/MART-1– Sexcordstromaltumors(>80%)
PSA– Mammarycarcinomas(20-40%)– Salivaryglandcarcinomas(20-40%)
LineageRestrictedTranscrip�onFactors
Expandingrepertoire– 15yearsago:TTF-1,CDX-2– Now:>50markersforawidespectrumofmalignancies(NOTlimitedtocarcinoma)
Novelinsightsfromdevelopmentalbiology Essen�alfororganspecificdevelopment– Implica�on:Expressiono�enretainedeveninpoorlydifferen�atedtumors
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CommonlyEmployedMarkersinCUP
Marker PrimarySites
TTF-1 Lung,Thyroid
CDX-2 Colorectal,Appendix,UpperGI
PAX8 Mullerian,Kidney,Thyroid
GATA3 Breast,Bladder
SATB2 Colorectal
OCT3/4 GermCell
NKX3.1 Prostate
SF1 AdrenalCor�cal,SexCordStromal
PoorlyDifferen�ated(Insular)ThyroidCarcinoma
TTF-1 PAX8
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PoorlyDifferen�atedLungAdenocarcinoma
TTF-1 PAX8
PAX8inOvarianCarcinoma
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CDX-2inGastricAdenocarcinoma
*Par�cularlyusefultoexcludemetasta�clobularbreastcarcinoma
SATB2inColorectalCarcinoma
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SATB2andOsteoblas�cDifferen�a�on
DobrevaGetal.Cell2006
SATB2inOsteosarcoma
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GATA3inBreastCarcinoma
Mammaglobin GATA3
NKX3.1inProsta�cAdenocarcinoma
PSA NKX3.1
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SF1inAdrenalCor�calCarcinoma
RememberPrimaryLiverTumorsintheDifferen�alwithCUP
HepatocellularCarcinoma– Renalcellcarcinoma– Adrenalcor�calcarcinoma– Poorlydifferen�atedcarcinomafromanysite
Cholangiocarcinoma– Pancrea�cductaladenocarcinoma– Mostotheradenocarcinomas
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HepPar-1inHepatocellularCarcinoma
Cau�on:HepPar-1mayreactwithgastric,esophageal,andlungadenocarcinomas,especiallyhepatoidvariants
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Arginase-1inHepatocellularCarcinoma
PolyclonalCEAinHepatocellularCarcinoma
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Intrahepa�cCholangiocarcinoma
Noreliablyspecificmarker
O�enCK7+,CK20+/-,CDX-2weak,focal
Approximately50%withlossofSMAD4
Iden�calprofilecanbeseeninmetasta�cpancrea�cadenocarcinoma
Dis�nc�veRadiographicFeaturesofIntrahape�cCholangiocarcinoma
Heterogeneousanddelayedenhancement
Dilata�onofintrahepa�cbileducts
Capsularretrac�on
Satellitenodules
Lobaratrophy
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Intrahepa�cCholangiocarcinoma
Bahe�ADetal.2014
SquamousCellCarcinoma Confirma�on– p63(canbefocallyposi�veinupto30%oflungadenocarcinomas)
– p40(similarsensi�vity,greaterspecificity)– HMWKs(secondline)
Determina�onofprimarysiterarelypossible
Excep�on:virusassociatedtumors:– EBVandnasopharyngealcarcinoma– HPVandoropharyngealcarcinomas(tonsil/baseoftongue)
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WellDifferen�atedNeuroendocrineTumors
Increasinglyimportanttodetermineprimarysite
Pancrea�c(butnotmidgut)NETeffec�velytreatedwithStreptozocin,Temozolomide,Everolimus,Suni�nib
Metasta�cWDNETs
Midgut(mostcommon):CDX-2
Pancreas:PAX8(polyclonal)Islet-1
Lung:TTF-1
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pPAX8inPancrea�cWDNET
PoorlyDifferen�atedNEC
Key:dis�nguishvisceralfromcutaneoustumors– LocalizedMerkelcellcarcinomawillbetreatedsurgically– Allotherpa�entswillreceivepla�num-basedchemotherapy
CK20– 70-100%ofMerkelcellcarcinomas– RareinotherPDNECs
TTF-1– RareinMerkelcellcarcinoma– CommoninPDNECfrommostothersites
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Whatisthesiteoforigin?
TTF-1
KeyPoints
AssigningprimarysiteinCUPimprovesoutcomes
Expectlowersensi�vityinpoorlydifferen�atedtumors
Lineagespecifictranscrip�onfactorsincreasesensi�vityinmostcases
Knowledgeofcrossreac�vityiscri�caltoavoidmisdiagnosis
Remembertoconsiderprimarylivertumors
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SelectReferences
Kandala�PandGownA.ArchPatholLabMed(2015)Epubaheadofprint
ConnerJandHornickJ.AdvAnatPathol(2015)22(3):149-67
BellizziA.AdvAnatPathol(2013)20(5):285-314
