WHO新分類與胃腸胰神經(jīng)內(nèi)分泌腫瘤

ThenewWHOclassificationandgastroenteropancreaticneuroendocrineneoplasms

WHO-classification2010ofneuroendocrineneoplasmofthedigestivesystemPremises-AllneuroendocrineneoplasmshaveamalignantpotentialThemalignantpotentialhastobestratified low…….high-Themalignantpotentialdependsontumorlocalization differentiation extensionWHO1980WHO2000WHO2010I.CarcinoidWell-differentiatedendocrinetumour(WDET)*Well-differentiatedendocrinecarcinoma(WDEC)*Poorlydifferentiatedendocrinecarinoma/smallcellcarcinoma(PDEC)NETG1(carcinoid)

2.NETG2*

3.NECG3largecellorsmallcelltypeII.MucocarcinoidIII.Mixedformscarcinoid-adenocarcinoma4.Mixedexocrine-endocrinecarcinoma(MEEC)4.Mixedadenoneuroendocrinecarcinoma(MANEC)IV.Pseudotumourlesions5.Tumour-likelesions(TLL)5.Hyperplasticandpreneoplasticlesions

NET,neuroendocrinetumor–welldiff.;NEC,neuroendocrinecarcinoma–poorlydiff.;G,Grade

*IncasethattheKi67indexexceeds20%,thisNETmaybelabelledG3NeuroendocrineNeoplasms–NENsofthegastroenteropancreaticsystemStandardizedapproachtowardsthediagnosisofNENEuropeanNeuroendocrineTumorSociety(ENETS)-must

-H&Ehistopathology:wellorpoorlydifferentiated-must -IHneuroendocrinemarkers -synaptophysinandchromograninA-must

-IHproliferation -Ki67/Mib1

welldifferentiated-NETpoorlydifferentiated-NECNECsmallcelltypeNEClargecelltypeNE-cellSynaptophysin+++diffuseChromograninA+++polarizedMarkersofneuroendocrinecellsCGSynMarkersofneuroendocrinecellsCGChromograninA:+++SynSynaptophysin

:+++NE-cellSynaptophysin +++ChromograninA ----CD56:nogeneralNEmarkerNSE:unspecificreactionsLargegastrictumorNEC(poorlydifferentiatedneuroendocrinecarcinoma)?CgASYNGradingofGEP-NETs G1 G2

G3

Ki-67index <2% 2-20% >20%

Mitoticindex

Rindi,Kl?ppel,Ahlman,.....Wiedenmann:TNMstagingofforgutneuroendocrinetumors:aconsensusproposalincludingagradingsystem VirchowsArchiv:2006,449,395Ki67/MIB16%3%EuropeanNeuroendocrineTumorSociety(ENETS):StandardizedapproachtowardsthediagnosisofNET2009

-mandatory

-expressionoftheneuroendocrinemarkers synaptophysinandchromograninA(bothoronlysyn) -histopathology(H&E):wellorpoorlydifferentiated -proliferativeactivity(Ki67/MIB1):G1–G3 -stage:pTNMENETS2007andUICC2009angioinvasionTNMclassificationofGEP-NENsSite-specificTNMstagingofNETsofthegastroenteropancreaticsystem (stomach,duodenum,ileum,appendix,colo-rectum,pancreas)ENETS:2006/2007Rindi,Kl?ppel,Ahlman,.....Wiedenmann:TNMstagingofforgut,midgutandhindgutneuroendocrinetumors:aconsensusproposalincludingagradingsystem.VirchowsArchiv:2006,449,395und2007,451,757UICC:2009

TNMclassificationofmalignanttumours.Sobin,Gospdarowicz,Wittekind.7thEdition.EuropeanNeuroendocrineTumorSociety(ENETS):StandardizedapproachtowardsthediagnosisofNET2009

-mandatory

-expressionoftheneuroendocrinemarkers synaptophysinandchromograninA(bothoronlysyn) -histopathology(H&E):wellorpoorlydifferentiated -proliferativeactivity(Ki67/MIB1):G1–G3 -stage:pTNMENETS2007andUICC2009-optional

-immunostainingforhormonesandtranscriptionfactors(CDX2,Isl-1)

becauseofCUP(livermeta)orhormonalsymptoms

-somatostatinreceptorSSTR2

becauseofdiagnosisandtherapyangioinvasionHormonesandprimarytumorsiteintheGI-tract

Histamin(ECL-cell)–VMAT2 Stomach Gastrin(G-cell) Duodenum

Serotonin(EC-cell) Ileum CDX1!Somatostatin(D-cell) Duodenum(Pancreas) Calcitonin(C-cell) TTF1!

Thyroid

LiverbiopsyBiopsytissuepositiveforSYNandCGWhereistheprimary?SEROMetastasisofanilealwelldiff.neuroendocrinecarcinoma?Midgutcarcinoid“IlealserotoninproducingNEcarcinoma(?Carcinoid“)xLnmetaExpressionofsomatostatin-receptors(SSTR1-5)

SSTR2

welldiff.NEN - 95% insulinoma-50%

ClosecorrelationbetweenimmunohistochemicalSSTR2expressionandoctreotid-scan-positivityandproteinradioreceptortherapy(PRRT)response

JansonetalCancerRes58,2375,1998SSTR2Expressionofsomatostatin-receptors(SSTR1-5)

SSTR2

NEC-poorlydiff.NEN-smallcelltype-0%largecelltype-?%SSTR2SYN

CGMIB15–10%SOMSSTR2D2-40forangioinvasion

91-97%ofGEP-NENsareNETs

-organoidarchitectureandwelldiff.cytology -absenceofnonneuroendocrinecomponents -componentsofG1orG2(exceptional:G3) -usuallystrongimmunoexpressionofNEmarkers -usuallyhormonalimmunoexpression -mayshowahormonalsyndrome -maybeassociatedwithotherdiseases(CAG,MEN1)

Featuresofwelldiff.neuroendocrineneoplasms

3-9%ofGEP-NENsareNECs

-lessorganoidarchitectureanddistinctlyatypicalcytology -absenceofcomponentsofG1orG2 -mayhavenonneuroendocrinecomponents -lessintenseimmunoexpressionofNEmarkers -usuallynohormonalimmunoexpression -usuallynohormonalsyndrome -noassociationwithotherdiseases

Featuresofpoorlydiff.neuroendocrineneoplasmsNEC:poorlydifferentiatedNEN-smallcelltypeNEC:poorlydifferentiatedNEN-largecelltypeSYNSmallcelltypeCGSYNpositiveCGnegative(+)CD56positiveCKdot-likepos.SYNLargecelltypeSYNpositiveCGpositiveCD56negative/(+)CKnon-dot-likepos.SYNNEC:poorlydifferentiatedNEN-largecelltypewithadeno-cacomponentStemcellPDX1PancreasstemcellIntestinalstemcellCDX2MATH1SomatostatincellGastrincellNGN3Isl1?endocrine-precursorcellduodenumNGN3StemcelloriginofGEP-NENsendocrine-precursorcellpancreasGastrincellSomatostatincellPPcellGlucagoncellInsulincellIsl1Isl1Isl1Isl1Isl1,PDX1Isl1NGN3p53,rb,othermut.MEN1LOH11qPoorlydifferentiated-NECWelldifferentiated-NEThistopathology:welldifferentiatedhistopathology:poorlydifferentiatedType1(2)GastricNETwithCAG(MEN1)Type3GastricNETwithoutCAG/MEN1

<1cm/mucosa,submucosa–nometas

>1cm/andormuscularwallinfiltration–ln-metas:5%-20%:AntrumType1Type1gastricNETSynaptophysinNEcellhyperplasiapositiveforENETSTNMstagingforgastricneuroendocrinetumorsT–primarytumorTisinsitutumor/dysplasia(<0.5mm)T1tumorinvadeslaminapropriaorsubmucosaand<1cmT2tumorinvadesmuscularispropriaorsubserosaor>1cmT3tumorpenetratesserosaT4tumorinvadesadjacentstructuresanyTadd(m)formultipletumors.N-regionallymphnodesN1regionallymphnodemetastasisM-distantmetastasisM1presenceofdistantmetastasisRindi,Kl?ppel,Ahlman,.....Wiedenmann:TNMstagingofforgutneuroendocrinetumors:aconsensusproposalincludingagradingsystem VirchowsArchiv:2006,449,395SporadicandMEN1-GAS-NETsSporadicSERO-NETsSporadicandNF1-SOM-NETsGangliocyticPGsPoorlydiffNECNeuroendocrinetumorsoftheduodenum56-year-oldmanwithsmall(0.8cm)polypoidtumorintheduodenalbulb,accidentalfinding.DuodenalNET,G1(<2%),gastrinproducing,withoutZES

GastrinGangliocyticparagangliomaNeuroendocrineneoplasmsoftheduodenumbenigncoursedespite>2cmIlealserotoninproducingNET(?ilealcarcinoid“)Lnmeta

invasionofthe musclelayerand subserosaltissue

NETG1serotoninproducingserotoninAppendicealNETAppendicealNETwithinfiltrationofmesoappendixRegionallymphnodemetastasesarerarelyfoundbelowasizeof2cmAppendicealNETwithoutinfiltrationofmesoappendixRectalNETG1RectalNETG1<1cmLnmetriskalmostzeroresectionmarginPanNEN:ClinicalclassificationNon-functioning

(withouthormonalsyndrome)

70%ofallPanNENsFunctioning

(withhormonalsyndrome)30%ofallPanNENsInsulinoma HypoglycemiaGastrinoma Zollinger-EllisonsyndromeGlucagonoma diabetes,dermatitisetc.VIPoma Verner-Morrisonsyndrome: watery diarrheaSomatostatinoma diabetes,steatorrhea,gallstonessyndrome???othersNon-functioningPanNENs

nohormonalsyndrome,butmayshowhormoneexpressionandsecretionintotheserum

WelldifferentiatedPanNENs–NETs >0.5cm

glucagon-,PP(pancreaticpolypeptide)-, somatostatin-,calcitonin-producing,others

<0.5cmPanNETs-Microadenoma

Non-functioningpancreaticNENs-welldifferentiated(NETs)0.5cmGLUNon-functioningPanNENs

WelldifferentiatedPanNENs–NETs

Microadenomas

PoorlydifferentiatedPanNENs–NECs-large,focalnecrosis,metastases

PanNEN:ClinicalclassificationNon-functioning

(withouthormonalsyndrome)Functioning

(withhormonalsyndrome)Insulinoma HypoglycemiaGastrinoma Zollinger-EllisonsyndromeGlucagonoma diabetes,dermatitisetc.VIPoma WDHHA-orVerner-MorrisonsyndromeSomatostatinoma diabetes,steatorrhea,gallstonessyndrome???othersInsulinproducingNETsFunctioning: insulinomaNon-functioning: noneIntrapancreatic: 99%Benign: 90%Specialfeatures: small(<2cm);amyloidAssociatedwithMEN1 yesInsulinproducingNETs insulinomaBenignbehavior: 90%Malignant: 10%AmyloidGlucagonproducingNETsFunctioning: glucagonomaNon-functioning: glucagon-positiveNETIntrapancreatic: 99%Behavior: >2cmmetastaticSpecialfeatures: commonlycystic,trabecularAssociatedwithMEN1:commonCysticpanNETsarefrequently(65%) glucagonpositive

KonukiewitzetalVirchowsArchiv458,47-53,2011Glucagon-pos.NETSomatostatinproducingNETsFunctioning: somatostatinoma?Non-functioning: somatostatin-positiveNETIntrapancreatic: 70%(duodenal30%)Behavior: >2cmmetastaticSpecialfeatures: paraganglioma-like,psammomasAssociatedwithMEN1,VHLorNF1:yesGarbrechtetalEndocrRelatCancer15:229-241(2008)SomatostatinproducingPanNETsfrequentlyshowaparaganglioma- likepattern genetics?SOMGastrinproducingNETsFunctioning: gastrinomaNon-functioning: gastrin-positiveNET(rare)Intrapancreatic: 20%(duodenal80%)