Carcinoma of Unknown Primary (CUP)€¦ · Metasta c Carcinoma of Unknown Primary: Diagnos c Approach Using Immunohistochemistry James R. Conner, MD, PhD Mount Sinai Hospital Toronto,

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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