女性生殖道的癌前病变：从宫颈到输卵管（英文版）

PrecursorsoftheGynecologicTract:fromtheCervixtotheFallopianTube"Pathogenesis1.HPV-relatedneoplasms:MonoclonalselectionandatypiaareconcurrentwithHPVinfectionClonalselectionandatypiaoccurintandemwithgeneticmutations.Clonalselectionthateventuallyleadstomalignancypredatesmorphologicatypia.ThreeModelsofPrecursorDiseaseCervixHPVoncogenictransformationEndometriumpTENmutationsTubo-OvarianP53+BRCATheCervicalTransformationZoneAnarrowcircumferentialzoneofsquamo-columnartransition.IsthesiteoforiginforHPVrelatedcervicalneoplasiaEctocervixT-ZoneEndocervixTheCervicalTransformationZoneEcto Endo ReserveCellsp63Nl CIN1CIN2CIN3 LSIL HSIL HSILRisk1%5%12%20%HPV1610%45%68%SquamousIntraepithelialLesions“Easy”LSILsExophyticcondylomaFlatcondyloma(CIN1)ExophyticCondyloma(CINI)ExophyticarchitectureParabasalexpansionMildbasalatypiaPreservedpolarityViralcytopathiceffectLowmitoticindexLowriskHPVtypesFlatCondyloma(CINI)FlatarchitectureTypicallyassociatedwith“intermediate”orhighriskHPVtypes“Easy”HSILsClassicCIN2-CIN3KoilocyticHSILKeratinizingHSILKoilocyticHSIL

(CIN2)ProminentkoilocyteswithconspicuousatypiaParabasalcellnuclearenlargement,molding,lossofpolarity,hyperchromasiaorabnormalmitosesCINIIIFullthicknessatypiaImmatureKeratinizingHSILProminentsuperficialparakeratosiswithconspicuousatypia,anisokaryosisandhyperchromasiaParabasalcellatypiamaybesubtleThe“Metaplastic”SILsImmaturemetaplasticLSILsassociatedwithLRHPVs(immaturecondyloma)Semi-maturemetaplasticSILs(Eosinophilicdysplasia)ImmaturemetaplasticSILs(HSIL)StratifiedvariantsofAIS(SMILEs)HPVCellTropismsandLesionsTransformationZone Ectocervix

IndifferentSquamousColumnarSquamous

HPV16/18

HPV6

HPV16

HPV6HPV16/18

HSIL ImmatureMetapl SMILEACIS LSILACISLSILHSILImmatureCondyloma

(PapillaryImmatureMetaplasia)SlenderpapillaelinedbyimmaturemetaplasticepitheliumLowmitoticindexRegularnuclearspacingwithnucleoliLowtomoderateKi-67indexLowriskHPVtypesImmatureCondyloma(LSIL)PapillaeMinimalatypiaImmatureCondyoma(LSIL)EosinophilicDysplasia(CIN1-2)Zhengetal,2004Immature“metaplastic”HSIL(CIN3)SMILE(StratifiedAIS)StratifiedEndocervicalCellsImplicationsImmaturecondyloma–benign,butexcludeco-existingHSILEosinophilicdysplasia–CIN1-2Metaplastichighgrade–CIN3SMILE–AdenocarcinomainsituNormalLSILHSILMolecularDiagnosisofCervicalNeoplasiaHPVnucleicacidtestingtodetermineriskHostbiomarkersassurrogatesofHPVCellcycleandHPVcyclinsandotherbiomarkersAtrophy+HSILMiB1 p16MiB1 p16HSIL(immaturemetphenotype)MiB1 p16ReactiveProspectiveRiskof≥CIN3(1)Follow-uptime(years)

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10

11Cumulativeincidencerate(%)05101520HPV16+HPV18+HC2+HRHPV-PortlandKhanetal.,JNCIIntheVaccineEraThemostimportantHPVswouldbeneutralizedParadigmsofscreeningandmanagementwouldbemoreconservative?RoleofHPVtestingvsotherparameters.ClassificationSystemsandManagementofPre-invasiveSquamousCellLesionsoftheCervix1960s1970-80s1990sMild ModerateSevereCISCondyloma/CIN1 CIN2CIN3

LSIL HSIL HSILFollow Cone/HysterectomyCryotherapyLaser/ConeFollowLEEPFuture?

LSIL(-)HPV16 greyzone HSIL+HPV16

FollowLEEPHPVInfectionHSILACISSquamousCellCaAdenocarcinomaEndometrialCarcinoma30,000cases,10,000deathsperyearNotreadilydiagnosedbyPapsmearTargetsendometrialliningepitheliumPersistentestrogenstimulationAbnormalbleedingPrecursorlesion(EndometrialintraepithelialneoplasiaorEIN)AnovulatoryPremalignantMalignantEstrogenMutation→ClonalAggressiveCarcinomaEINBenignGeometryof

Benign,Premalignant,andMalignantlesionsSurfaceRepairRepair“RegularlyIrregular”G.L.MutterG.L.MutterEIN

ArchitectureAreaofGlands>Stroma(VPS<55%)

CytologyCytologydiffersbetweenarchitecturallycrowdedfocusandbackground.

Size>1mmMaximumlineardimensionexceeds1mm.

ExcludemimicsBenignconditionswithoverlappingcriteria:ExcludeCancerCarcinomaifmazelikeglands,solidareas,orsignificantcribriforming

EIN(AtypicalHyperplasia)EINCytologicDemarcationEINVariant(intraglandularcomplexity)VolumePercentageStromaInEIN,AreaofGlands>Stroma0102030405060708090100Baak,Mutter,andJanssen2000-2002CancerNoCancern=297MonoclonalPolyclonaln=940500100015002000FollowupInterval,DaysCHWACHWOASHWOAHyperperplasiaDx0500100015002000NoCancerCancerOutcomeFollowupInterval,DaysBenign,

Non-EINEINEINDxHechtetal,2005Clinicaloutcomesof97endometrial“hyperplasias”byWHOandEINsubjectiveDiagnosisPTENandEndometrialCancerAlsoknownasMMAC-1orTEP-1ActsviaAkt-dependentpathwaytosuppresscelldivisionHighfrequencyofmutationinEIN(60%)Notadiagnosticmarker,buthashelpedtodefineEINEINProliferativeG.L.MutterPTENG.L.MutterProliferative EINDifferentialDiagnosisofEINArtifactsofcrowdinginproliferativeandsecretoryendometriumMildglandcrowdinginpolypsMixedpatternsduetoclonaldiversityPolypClonalMixedPatternClonalMixedPatternClonalMixedPatternSecretoryEINSecretoryEINLossofPTENExpressionpriortoNeoplasia(LatentPrecursor)Proliferative EIN AnovulatoryG.L.MutterEndometrioidPrecursorsLossofpTENisacommonmarkerforprecursors(EIN)ThesamemutationmaypredateEIN(LatentPrecursors)Aremutationscommonintheadultendometrium?YesPersistentestrogenstimulationselectsforpTENandsubsequentmutations.G.L.MutterTreatmentofLatentPrecancersOrboetal(CancerResearch2006)Frequencyoflatent(pTENnullglands)wascomputedbeforeandaftertherapywithprogestin-coatedIUDTherapyreducedrateofpersistentlatentprecursorsfrom62and5percentrelativetountreatedwomen.SummaryDiagnosisofEINbasedonreproduciblecriteriaLatentprecursorexistswhichmaybepreventablePrecursorstoserouscarcinomaarestillunderinvestigationThePathogenesisofOvarianCancer25,000cases/12,000deathsperyearMostdifficulttoidentifyearlybecauseoflocationTraditionallyassumedtooccurincorticalepithelialcystswithintheovaryDirecttransformationofthesurfacemesothelium/epitheliumoftheovaryTransportfromthefallopiantubeTransportfromtheuterus(endometriosis)CorticalInclusionCystsOvarianCarcinomasPathogenesisSometumorsappeartoarisefrominclusioncysts,suchasendometrioidcarcinomas(fromendometriosis)ormucinouscystadenocarcinomas.Theoriginofthemostlethalcarcinomas(serous)hasbeenlessclear.HighGradeSerousCarcinomaBRCAasaModelforEarlyOvarianCancerUpto50%ofwomenwithBRCAmutations(BRCA+)willdevelopepithelialovariancancerOpportunitytoevaluatethetubesandovariesinwomenwhoundergoprophyacticsalpingo-oophorectomyanddetecttumorsearlyintheircourseColgan2001,Leeper2002,Powell2005,Finch2005,Cass2005,Medeiros2006

DistributionofEarlySerousCarcinomainBRCA+WomenAuthor

No.

Tumor(%)

Tubal

(%tumors)Leeper’02305(17)3(60)Powell’05 677(10) 4(57)Finch’061597(4) 6(86)BWH’05-071407(5)7(100)SEE-FIMProtocolSectioningandextensivelyexaminingthefimbriatedendBasedonthehypothesisthatthefimbriatedendisuniqueandsusceptibletotubalneoplasiaMedeirosetal2006p53SerousTubalIntraepithelialCarcinoma(STIC)Acommonearlyserouscarcinomadetectedin~5%ofBSOsfromBRCA+WomenPathogenesisinBRCA+Women85+%ofcarcinomasdetectedearlyinBRCA+womenoriginateinthedistalfallopiantube.Thedistalfallopiantubeisthepreferredsiteforalltubalcarcinomas,irrespectiveofBRCAstatusMedeirosetal2006,Cassetal2005,Finchetal2006Do“Ovarian”SerousCarcinomasActuallyAriseintheDistalTube?Findings~70ConsecutiveserouscarcinomasOnehalfoftumorsclassifiedasovarianorperitonealcarcinomaswereassociatedwithanearlycarcinoma(STIC)inthefimbria.10of10casesanalyzedcontainedidenticalp53mutationsintubalandovarian/peritonealneoplasmsKindelbergeretal2007,Carlsonetal,submittedOvarianserouscarcinomaandseroustubalintraepithelialcarcinoma(STIC)“Ovarian”CarcinomaCoexistingovarianserouscarcinomaandseroustubalintraepithelialcarcinoma(STIC)thatsharedidenticalp53mutationsTubalintraepithelialcarcinomaassociatedwith“primaryperitonealserouscarcinoma”TwopathwaysforthedevelopmentofovarianserouscarcinomaPelvicCarcinomainBRCA+WomenSymptomaticvsAsymptomatic

Piek’03 Medeiros’06K’berger’07Carlson(unpub)APecursortoPelvicSerousCarcinomaShouldbecommonShouldbeinthesamelocationasthecancerShouldarisefromthesamecelltypeShouldfulfillsomebutnotallofthebiologicattributesofmalignancyShouldsharesomeofthesameriskfactorsascarcinomaShouldbeseenincontinuitywithmalignancyp53Signatures(latentprecursors)STIC BenignMucosaH&E p53 H&E p53Immuno-localizationofp53protein(associatedwithmutation)canbefoundinbothearlyserouscarcinomasandbenigntubalmucosa(p53signatures)“p53Signature”Intensep53nuclearaccumulationinnon-neoplastictubalmucosaLeeetal2006P53SignaturesTheTubal“p53Signature”isaPrecursortoPelvicSerousCarcinomaInthismodel,theproposedprecursor(p53signature)sharesthefollowingwithserouscarcinoma:Involvessecretorycells(BCL-2+,HMFG2+)Predominatesinthedistalfallopiantube(fimbria)ExhibitsevidenceofDNAdamage(γ-H2AX)Frequentp53mutationsbyLCManddirectsequencingEvidenceoftransitionlesions(TILTs)SeenincontinuitywithSTIC.SimilarepidemiologicprofileasovariancancerLee,Miron,etal2007SecretorycellP53SignatureTILTSTICInvasionTubeOvarySerous(surface)CarcinomaOvulationPeritonealCarcinomaOxidativestressInitiatorDNADamageP53mutationPromotor(BRCA+)GrowthdisregulationStratificationExfoliation?SerousCarcinogenicSequenceintheFimbriaH&Ep53MiB1H&Ep53MiB1H&EMiB1ClonalP53mutationClonalP53mutation+expansionClonalP53mutation+expansion+proliferationClonalP53mutation+expansion+proliferation+lossofpolarity+exfoliationLatentprecursor(p53signature)LesionintransitionIntraepithelialCAStepI StepII StepIIIJarboeetal,2007(IntJGynecolPatholinpress)BRCA+WomenApproximately5%ofmutation-positivewomenwillharboranearlymalignancyintheirprophylacticspecimen.Mostwillbelocatedinthedistaltube.Mostwillbenon-invasive(STIC)ExaminationofovariansurfacesessentialMustbedistinguishedfromnormalmucosa.SpectrumofSTICCommonvariablesLossofepithelialcellpolarity,fractures,exfoliationNuclearenlargement,nucleoliHomogeneouscelltype,absenceofciliaP53+(80-90%)HighMIB1indexVariantsNon-stratifiedDegenerativeFallopianTube(STIC)STICTIC TICTIC NormalTICSTICfromPatientPreviouslyTreatedforBreastCAObserverReproducibilityforSTICFor12reviewers=0.333Forpathologyresidents=0.253Forexperiencedgynecologicpathologists=0.453ItishighlyadvisabletocorroboratethisdiagnosiswithanotherobserverCarlsonetal2008BenignSalpingealEpitheliumHeterogeneous,normalnuclearmorphologySerousTubalIntraepithelialCarcinomaHomogeneous,abnormalnuclearmorphologyProblematicLesionsTubalintraepitheliallesionsintransition(TILT).Maintenanceofpseudo-stratifiedepitheliumMixtureofciliatedandsecretorycellsModerateMIB1immunoreactivityShouldbereviewedbymorethanoneobserverifnecessarytoexcludeSTICThereportshouldstateclearlythatthelesionisorisnotdiagnosticofSTIC