不明原發(fā)灶腫瘤診斷

不明原發(fā)灶腫瘤診斷MetastaticCancer

UnknownPrimarySite

Synonymsandrelatedkeywords◆tumorofunknownprimary◆cancerofunknownorigin◆carcinomaofunknownorigin◆unknownprimarycancer

MetastaticCancer

UnknownPrimarySite

◆unknownprimarycarcinoma◆carcinomaofunknownprimaryorigin

MetastaticCancer

UnknownPrimarySite

◆cancerofunknownprimarysite(cups)◆carcinomaofunknownprimaryorigin(CUP)MetastaticCancer

UnknownPrimarySite

◆metastaticcancer◆metastaticcarcinoma◆metastatictumor◆metastases◆occultprimarymalignancyCUP

Background(intheUnitedStates)

◆32,100patswithCUPSin2007(15,720males;16,380females)◆About2%ofallcancersCUP

◆DeathsduetoCUPS:45,230(24,440males;20,790females)

CUP◆Thisdiscrepancybetweenincidenceandmortalityisbelievedtobeduetoalackofspecificityinthelistingof

causeofdeathondeathcertificatesCUP

◆Itstrueincidenceismostprobablybetween2%and6%◆In15-25%ofcases,theprimarysitecannotbeidentifiedevenonpostmortemCUP

Pathophysiology

◆Cancersarethoughttoarisefromasinglecellthatescapesthecontrolsofnormalcellreplication◆Formsatumoratthesiteoforigin◆UltimatelymetastasizestootherorgansCUP

Pathophysiology◆Insomecasestheoriginaltumormayremainsmallorundetectableatthetimeofmetastasis◆LeadingtotheclinicalpresentationofCUPCUPFrequency◆UnitedStates:2-6%

◆International:2-9%CUPMortality/Morbidity◆Mediansurvival

rangesfrom11weeksto11months◆The5-yearoverallsurvivalrateisabout11%CUPSex◆AnapproximateequalincidenceformenandwomenCUP

Age◆Themedianageonpresentationforbothmenandwomenrangesfrom59-66yearsCUP

CLINICAL(History)◆Becausemostpatientswithcuphavefairlyadvanced-stagedcancers◆Theconstitutionalsymptomsofmalaise,weakness,fatigue,andweightlossarepresentinnearlyallpatients

CUPCLINICAL(Physical)◆Theclinicalpresentationofcupisextremelyvariable◆DependsontheextentandtypeoforganinvolvementCUP

◆

一群異源發(fā)生的腫瘤◆除外淋巴瘤、轉(zhuǎn)移性黑色素瘤和轉(zhuǎn)移性肉瘤◆集中于上皮細(xì)胞組織，包括腺癌、鱗狀上皮細(xì)胞癌、分化不良上皮癌和神經(jīng)內(nèi)分泌癌CUP

CUP的診斷標(biāo)準(zhǔn)◆組織活檢證實(shí)為惡性腫瘤(活檢部位不能檢出原發(fā)灶)◆經(jīng)過徹底地收集病史或物理檢查(包括女性盆腔檢查和男性睪丸及前列腺觸診)未發(fā)現(xiàn)原發(fā)性腫瘤CUP

◆

CUP實(shí)驗(yàn)室檢查結(jié)果正常，包括完整的血細(xì)胞計(jì)數(shù)、血液生化、胸部X線、腹部和盆腔CT、乳房影像學(xué)檢查或前列腺特異性抗原(PSA)檢查等等CUPCLINICAL◆完整的病史和徹底的體格檢查是診斷CUP的基本前提，尤其是既往組織活檢結(jié)果◆家族史很可能提示遺傳性非息肉病性結(jié)腸癌或乳腺癌易感性CUP◆徹底的體檢可能會(huì)發(fā)現(xiàn)特異性原發(fā)腫瘤◆左側(cè)鎖骨上淋巴結(jié)腫大(Virehow’S結(jié)節(jié))(胃Ca)◆臍周淋巴結(jié)腫大或包塊(SisterMaryJosph’S結(jié)節(jié)-由惡性腹水造成的腹脹以及臍周腫塊{臍孔腫大變硬,產(chǎn)生冰山樣臍部腫塊})(低分化癌-胃腸道)◆腹股溝淋巴結(jié)腫大、肛周包塊(肛門腫瘤)

CUPCLINICAL(Physical)◆Themostcommonsitesofinvolvementbeinglung,bone,lymphnodes,andliverCUPCLINICAL(Physical)◆Includingheadandneck,rectal,testicular,pelvic,andbreastexaminationsCUPCLINICAL(Physical,Labandradiologicalstudies

)◆Acompletebloodcellcount(irondeficiencymaypointtowardanoccultgastrointestinalmalignancyleadingtochronicbloodloss)CUPCLINICAL(Physical,Labandradiologicalstudies

)◆urinalysis(microscopichematuriamaybeasignofoccultgenitourinarymalignancy)CUPCLINICAL(Physical,Labandradiologicalstudies

)◆liverandrenalfunctiontests◆stoolforoccultblood◆chestradiographCUPCLINICAL(Physical,Labandradiologicalstudies

)◆abdomenandpelvisCT◆mammographyinwomen◆measurementofPSAinmenCUPPhysicalAscitesshouldleadonetoevaluateforaGIoranovarianprimaryAnaxillarymassinafemaleshouldmakethecliniciancheckforbreastcancerAcervicalnodeshouldleadtoathoroughENTexaminationCUPPhysicalAbrainmetastasisshouldleadtoasearchforalung,breast,orkidneyprimaryBonemetastasisshouldleadtoevaluationforprostate,breast,lung,renal,orthyroidprimaryCUPPhysicalAtesticularmassshouldleadtomeasurementoftumormarkerssuchasbeta-HCGandAFPCUPPhysicalDependingontheclinicalsituation,thesemayincludechestCT,breastMRI,upperorlowerendoscopyCUPCLINICAL(Physical)◆Insuspectedheadandneckmalignancies,panendoscopyoftheupperaerodigestivepathwaysshouldbeperformedwithevenasindicatedblindbiopsiesofthelymphoidtissueintheseareasCUPCLINICAL(Physical)◆DiagnostictonsillectomymaybewarrantedCUPCLINICAL(Physical)◆IntensivetestingalsoaddstothemorbidityfortheweakandfrailpatientCUPCLINICAL(Physical)◆Alargenegativecost-to-benefitratioexistsforanextensiveunguidedclinicalevaluationCUPCLINICAL(Physical)◆Onestudyquotinga9.5%increasein1-yearsurvivalatacostof2-8milliondollarsCUPCLINICAL(Physical)◆Whentheseinvestigationsfailtorevealapotentialprimarylesion,acancerofunknownprimaryoriginisassumedCUPWORKUP(ImagingStudies)◆18F-FDG-PETisincreasinglybeingusedintheevaluationofmetastaticmalignanciesCUPWORKUP(ImagingStudies)◆Thismaybeespecially

thecaseinsuspectedheadandneckmalignanciesCUPWORKUP(ImagingStudies)◆ThistestinglacksspecificityandmayonlybeusefultoidentifypromisingsitesforbiopsyCUPWORKUP(ImagingStudies)◆18氟-脫氧葡萄糖(18F-FDG)-PET可輔助指導(dǎo)活組織檢查，確定疾病程度和輔助選擇恰當(dāng)?shù)闹委烠UPWORKUP(ImagingStudies)◆Althoughpromising,highcostandfalsepositiveratesof20%limititsutilityincasesofCUP◆ThecombinationofPET/CTmayreducethefalse-positiverateCUPOtherTests◆TheroleoftumormarkerslikeAFP,beta-HCG,CA125,CA27.29,CA19.9,andCEAtoestablishaspecificprimarysiteCUPOtherTests◆Mosttumormarkersarenonspecific◆ItmaynotbeusedtoestablishdefinitivediagnosesCUPOtherTests◆男性腺癌和骨轉(zhuǎn)移，常規(guī)檢查血清PSA◆男性未分化癌和低分化癌，檢測B-HCG和AFP,AFP也用于診斷HCC◆B-HCG和AFP水平并不能預(yù)測化療效果或生存期CUPOtherTests◆CEA、CA125、CA19-9和CA15-3對于確定原發(fā)灶沒有幫助◆大多數(shù)血清腫瘤標(biāo)記物是非特異性的，可判斷預(yù)后CUPProcedures◆Abiopsyofthemetastaticsite◆AcarefulevaluationofthepathologyCUPHistologicFindings◆ThepathologisthasanindispensableroleintheevaluationofCUPCUPHistologicFindings◆Needlebiopsyspecimensmayprovideinsufficienttissuefordiagnosisorprovidetissuethathasbeentoo

damaged

ordistortedbythebiopsyprocedureforaccuratediagnosis

CUPHistologicFindings◆Variousimmunoperoxidase(免疫過氧化物酶)stainsareavailableforprovidingadifferentialdiagnosis

forCUPCUPHistologicFindings◆

AppropriateDNAmicroarray(微陣列)techniquesandproteonomic(蛋白質(zhì)組學(xué))studiestoestablishadefinitivediagnosisCUPHistologicFindings◆

如果查不到原發(fā)腫瘤，要想確定各種CUP患者的治療策略和判斷預(yù)后是非常困難的CUPHistologicFindings◆免疫組化和影像學(xué)聯(lián)合檢查的診斷率約為20％-30％◆目前認(rèn)為,最有前途的可提高診斷率的方法是腫瘤的分子診斷?，F(xiàn)有的基因表達(dá)數(shù)據(jù)庫對于CUP的診斷極有幫助CUPHistologicFindings◆預(yù)警基因分為兩類，一類是在某些起源組織中特異性表達(dá)的基因，另一類是在各種腫瘤中均有異常表達(dá)的基因CUPHistologicFindings◆

一批源于l0種普通腫瘤的100個(gè)原發(fā)癌樣品，用110個(gè)在這些腫瘤中表達(dá)最低的基因開發(fā)了一個(gè)預(yù)警芯片。對另外75個(gè)盲樣(包括l2個(gè)轉(zhuǎn)移癌樣品)進(jìn)行檢驗(yàn)，預(yù)測腫瘤原發(fā)灶的正確率大于90％，12個(gè)轉(zhuǎn)移癌中有l(wèi)1個(gè)被正確分類CUPHistologicFindin◆對218個(gè)腫瘤(14個(gè)普通類型)組織和90個(gè)正常組織樣品的寡核苷酸微陣列基因表達(dá)進(jìn)行分析，用16063個(gè)基因表達(dá)的相對水平和表達(dá)基因的序列標(biāo)簽開發(fā)了一個(gè)基因預(yù)警芯片CUPHistologicFindin◆

對54個(gè)腫瘤樣品(其中8例轉(zhuǎn)移性腫瘤)檢測，總的預(yù)測正確率是78％，轉(zhuǎn)移性腫瘤中有6例被正確識別出原發(fā)部位◆提示腫瘤保留其組織起源標(biāo)記物是貫穿于轉(zhuǎn)移過程的始終CUPHistologicFindings◆引用一系列基因表達(dá)庫的分析數(shù)據(jù)和相關(guān)腫瘤標(biāo)記物的文獻(xiàn)資料確定了61個(gè)基因?yàn)楹蜻x腫瘤基因，以其表達(dá)模式預(yù)測起源位置。用反轉(zhuǎn)錄PCR對原發(fā)性腺癌樣品(包括乳腺、卵巢、胃、胰腺和肺)檢測了其中11個(gè)基因，7個(gè)(64％)基因存在組織特異性◆這些組織限制性腫瘤標(biāo)志物能夠用于CUP原發(fā)性腫瘤可能位點(diǎn)的預(yù)測CUPHistologicFindings◆Putsthetissuespecimenthrough1-4steps,dependingontheneedCUPHistologicFindings◆lightmicroscopy◆Immunohistochemicalstains◆Electronmicroscopy◆ChromosomalanalysisincludingcytogeneticsCUPHistologicFindings

◆Lightmicroscopy:epithelialcancers,lymphomas,sarcomas,melanomas,orgermcelltumorsCUPHistologicFindings◆Whencytologicdistinguishingfeaturesarelimited,thetumormaybeclassifiedasundifferentiatedorpoorlydifferentiatedcarcinomaCUPHistologicFindings

◆Immunohistochemistry:Thesetestshelpdefinetumorlineagebyusingperoxidase-labeledantibodyagainstspecifictumorantigensCUPHistologicFindings

◆Theseincludestainsforkeratin,LCAandS-100(expressedinmelanomas),TTF-1(forlungandthyroidcancer),PSA,HCG(forgermcelltumors),AFP(forgerm-celltumorsandhepatomas),ER,PR,andHer-2(forbreastcancer)CUPHistologicFindings

◆CK20在胃腸道上皮、泌尿道上皮和Merkel細(xì)胞中表達(dá)◆CK7在肺癌、卵巢癌、子宮內(nèi)膜癌和乳腺癌中有表達(dá)；而在低位胃腸道腫瘤未發(fā)現(xiàn)表達(dá)◆CK20陽性和CK7陰性強(qiáng)烈支持結(jié)腸原發(fā)腫瘤。75％～95％的結(jié)腸腫瘤呈現(xiàn)此染色模式◆肺癌僅有9％～15％CK20呈陽性，這有助于肺內(nèi)轉(zhuǎn)移性腺癌原發(fā)灶的鑒別CUPHistologicFindings

◆CK20陰性和CK7陽性將鑒別診斷縮小至肺癌、乳腺癌、膽管癌、胰腺癌、卵巢癌和子宮內(nèi)膜癌◆應(yīng)用TTF-1和表面活性物質(zhì)脫輔基蛋白(surfactantapoprotein)可將原發(fā)性肺癌從其他CK7陽性腫瘤中區(qū)分出來CUPHistologicFindings◆

TTF-1是一種38kD的含有同源結(jié)構(gòu)域的核蛋白，在甲狀腺、中腦和呼吸道上皮胚胎發(fā)生過程的轉(zhuǎn)錄活化中起作用◆TTF-1在肺癌和甲狀腺癌呈典型陽性染色◆有利于對轉(zhuǎn)移性頸部淋巴結(jié)腫大和轉(zhuǎn)移性胸腔積液的原發(fā)腫瘤的診斷CUPHistologicFindings

◆Electronmicroscopy:ThisstudyhaslimitedutilityinidentificationoftheprimarysiteofcancerofunknownprimaryoriginbutmayrarelybeusedinpoorlydifferentiatedtumorsCUPHistologicFindings◆Chromosomalstudies:IncasesofCUPwithsuspectedoccultNPC,DNAamplificationofEpsteinBarrvirus(EBV)intissuemayclinchthediagnosisCUPHistologicFindings◆Thepresenceofiso-chromosome12p,i(12p),aspecificchromosomalmarkercharacteristicofgermcelltumorscanhelpdiagnoseextragonadalgermcelltumorsinpatientswithCUPCUPHistologicFindings◆生殖細(xì)胞腫瘤有特征性的細(xì)胞遺傳學(xué)改變(等臂染色體12p-i[12p]◆拷貝數(shù)增加或12號染色體長臂缺如◆與無染色體異常的患者相比，生殖細(xì)胞腫瘤有染色體異常的患者對順鉑為主的化療有更好的反應(yīng)CUP◆

ThemajorityofCUPareadenocarcinomasorundifferentiatedtumors(upto58%insomestudies)CUP◆Lesscommonly,squamouscellcarcinoma,melanoma,sarcoma,andneuroendocrinetumorscanalsopresentasmetastasiswithanunknownprimarysiteoforiginCUP◆Moststudiesexcludesarcomasandmelanomasfromtheiranalysis

CUP◆Intheapproximately30%ofCUP,themostcommonepithelialmalignanciesarelung(15%),pancreas(13%),colon/rectum(6%),kidney(5%),andbreast(4%)CUP◆Sarcomas,melanomas,andlymphomaseachcontribute6-8%CUP◆Theremainingprimarytumorsarethoseofstomach(4%),ovary(3%),liver(3%),esophagus(3%),prostate(2%),andavarietyofothermalignancies(22%)CUP◆StagingPatientswithcancerofunknownprimaryoriginarepresumedtoallhavestageIVdiseaseatthetimeofinitialpresentationCUP◆CUP表現(xiàn)為轉(zhuǎn)移性疾病但未找到原發(fā)灶CUP◆原發(fā)灶隱匿的原因可能與以下因素有關(guān)機(jī)體的免疫機(jī)制控制了原發(fā)灶，于轉(zhuǎn)移后消失原發(fā)灶太小，不能被目前的檢查方法所發(fā)現(xiàn)CUPNaresh[19]假設(shè)認(rèn)為◆原發(fā)灶血供改變使其生長受抑◆在內(nèi)臟，轉(zhuǎn)移灶可能處于靜止期，直到有生成血管表型的亞克隆出現(xiàn)，才導(dǎo)致轉(zhuǎn)移性腫瘤迅速生長◆在腫瘤發(fā)生過程中，轉(zhuǎn)移灶發(fā)生于晚期的傳統(tǒng)理論正受到質(zhì)疑◆新的數(shù)據(jù)提示，腫瘤發(fā)生早期即有轉(zhuǎn)移傾向CUP◆CUP的原發(fā)性腫瘤極有可能從一開始就有“預(yù)后不良”的特征◆分子靶點(diǎn)和DNA微陣列在CUP診斷中的應(yīng)用正在開展◆揭示轉(zhuǎn)移癌的發(fā)病機(jī)制◆促進(jìn)新的治療藥物的開發(fā)CUP◆代表腫瘤類型的、已知的原發(fā)性腫瘤基因引入診斷CUP◆無足夠的源于原發(fā)性腫瘤轉(zhuǎn)移灶樣品的基因表達(dá)數(shù)據(jù)，尤其是低分化腫瘤CUP◆DNA微陣列與更大規(guī)模的免疫組化標(biāo)記物和轉(zhuǎn)移模式相結(jié)合◆提高預(yù)測CUP起源位置的正確率◆原發(fā)灶與其轉(zhuǎn)移灶的基因轉(zhuǎn)錄譜的對比性研究

Thanksforyourattention!CUPTREATMENT(MedicalCare)

◆Multipleorganinvolvementandpoorperformancestatus

isgrave

CUPTREATMENT(MedicalCare)◆Themediansurvivalisonly3-4months◆The1-yearsurvivalrateislessthan

15%◆The5-yearsurvivalof

5-10%CUPPoorprognosticmarkers

◆malesex◆multiplebrainmetastases◆pleural/lunginvolvement◆liverinvolvement◆adrenalinvolvement◆adenocarcinomahistologyCUPFavorableprognosticmarkers

◆lymphnodeinvolvement

◆neuroendocrinehistology

CUPTREATMENT(cervicallymphnodes)◆Upperaerodigestivetract,includingdirectvisualizationofthehypopharynx,nasopharynx,larynx,andupperesophagusCUPTREATMENT◆Squamous◆Adenocarcinoma◆Melanoma◆Anaplastictumors(間變性腫瘤)CUPTREATMENT◆Squamousorundifferentiatedcarcinoma,tonsillectomiesshouldbeconsideredCUPTREATMENT◆Cervicaladenopathycanbetheprimarydiseasemanifestationin2-5%ofpatientswithprimarysquamouscellcarcinomaoftheheadandneckregionCUPTREATMENT◆Intheabsenceoflocalizationofaprimarysite,aggressivelocaltherapyisindicated.Thismayinvolveanyofthefollowing:

CUPTREATMENT◆Radicalradiationtherapywithcurativeintenttotheneckandpossiblesiteoforigin

CUPTREATMENT◆Preoperativeradiationtherapyfollowedbyradicalneckdissection◆Radicalneckdissection◆RadicalneckdissectionfollowedbyradiationtopossiblesitesoforiginCUPTREATMENT◆Five-yearsurvivalratesashighas30-50%havebeenachievedwiththisapproachCUPTREATMENT◆RoleofchemotherapyisdebatedCUPTREATMENT◆Onerandomizedstudyshowedimprovedresponserateandmediansurvivalwithcisplatinand5-fluorouracil—basedchemotherapywhencomparedtoradiationaloneCUPTREATMENT◆Asingleadenocarcinoma-involved

lymphnodeineitherthecervicaloringuinalareaswithnoevidenceofdiseaseelsewheremaybemanagedwithsurgicalexcisionaloneandwatchful

expectationCUPTREATMENT◆RadiationtherapytotheinvolvedandlocalfieldsmaybeprovidedaswellCUPTREATMENT◆Combinationtherapymaybesuperiortomonotherapywith5-yearsurvivalratesof35%reportedCUPTREATMENT◆MetastaticadenocarcinomapresentingasisolatedaxillarylymphadenopathyinwomenisusuallyamanifestationofanoccultbreastprimarycancerCUPTREATMENT◆Mastectomyspecimensinthissubsetofpatientshaveshownapreviouslyundiagnosedbreastprimarytumorin40-70%cases

CUPTREATMENT◆ImmunohistochemicalstainswithERandPRshouldbeperformedinthissetting,astheymayaidindiagnosis

CUPTREATMENT◆ModifiedradicalmastectomywithaxillarynodedissectionhasbeenadvocatedCUPTREATMENT◆Astudywith42patients,however,showedimprovedsurvivalwithsystemicchemotherapyandimprovedlocalcontrolwithbreastandaxillaryradiationCUPTREATMENT◆Localexcision◆Ashavingprimarybreastcancer◆50%ofpatientsachieve2-10yearsurvival◆Currently,managementisbasedontheguidelinesforstageIIbreastcancer

CUPTREATMENT◆Womenwithperitonealcarcinomatosiswithadenocarcinoma

havesimilaritieswithpatientswithovariancancer

CUPTREATMENT◆Papillaryhistology◆ElevationofCA125◆Agoodresponsetoplatinum-basedchemotherapy◆Butaprimarytumorisnotrevealedonexploratorylaparotomy

CUPTREATMENT◆Metastaticmelanomatoasinglenodalsite◆5%ofpatientswithmalignantmelanomamaypresentwithnodalmetastasisintheabsenceofadocumentedprimarysiteCUPTREATMENT◆Theyshouldbetreatedwithradicallymphnodedissection◆Survival,surprisingly,isslightlybetterthanthatforstageIImelanomainpatientswithaknownprimarysiteCUPTREATMENT◆Poorlydifferentiatedandundifferentiatedcarcinoma◆1/3CUP◆Canbepotentiallycurable◆Includeslymphomas,germcelltumors,orneuroendocrinetumorsCUPTREATMENT◆Thefeaturesthatpointtowardatreatment-responsivetumorincludethefollowing:◆Patientyoungerthan50years

◆Midlinedistribution,withelevatedlevelsofbeta-HCGorAFPCUPTREATMENT◆Beta-HCG/AFPpositiveonimmunohistochemistry◆Neuroendocrinegranules◆Rapidtumorgrowth◆Iso-chromosome12pinmidlinetumorsCUPTREATMENT◆Platinum-basedcombinationCTregimensspecificforgermcelltumors◆RR63%,CR26%◆10-yearsurvivalrates16%CUPTREATMENT(Poorlydifferentiatedneuroendocrinecarcinomas)◆Positivehistochemicalstainsforchromogranin(嗜鉻鐵蛋白)orNSE◆OftenpresentwithextensiveliverorbonemetastasesCUPTREATMENT◆29patients,19weretreatedwithintensivecisplatin-basedCT◆6othersreceiveddoxorubicin-basedcombinations◆CRin6patients◆4ofthesepatientswerealive19-100monthsafterdiagnosisCUPTREATMENT(Inguinalnodemetastasis)◆1-3.5%◆Squamouscellhistologyinthisareaisusuallymetastaticfromthegenital/anorectalarea◆TheanorectalareashouldbecarefullyinspectedinbothsexesCUPTREATMENT◆Inguinalnodemetastasis

Vulvar,vaginal,andcervicalexaminationinwomenandpenileexaminationinmeniswarrantedCUPTREATMENT◆Treatme