不明原发灶肿瘤诊断

不明原发灶肿瘤诊断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

◆

一群异源发生的肿瘤◆除外淋巴瘤、转移性黑色素瘤和转移性肉瘤◆集中于上皮细胞组织，包括腺癌、鳞状上皮细胞癌、分化不良上皮癌和神经内分泌癌CUP

CUP的诊断标准◆组织活检证实为恶性肿瘤(活检部位不能检出原发灶)◆经过彻底地收集病史或物理检查(包括女性盆腔检查和男性睾丸及前列腺触诊)未发现原发性肿瘤CUP

◆

CUP实验室检查结果正常，包括完整的血细胞计数、血液生化、胸部X线、腹部和盆腔CT、乳房影像学检查或前列腺特异性抗原(PSA)检查等等CUPCLINICAL◆完整的病史和彻底的体格检查是诊断CUP的基本前提，尤其是既往组织活检结果◆家族史很可能提示遗传性非息肉病性结肠癌或乳腺癌易感性CUP◆彻底的体检可能会发现特异性原发肿瘤◆左侧锁骨上淋巴结肿大(Virehow’S结节)(胃Ca)◆脐周淋巴结肿大或包块(SisterMaryJosph’S结节-由恶性腹水造成的腹胀以及脐周肿块{脐孔肿大变硬,产生冰山样脐部肿块})(低分化癌-胃肠道)◆腹股沟淋巴结肿大、肛周包块(肛门肿瘤)

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-脱氧葡萄糖(18F-FDG)-PET可辅助指导活组织检查，确定疾病程度和辅助选择恰当的治疗CUPWORKUP(ImagingStudies)◆Althoughpromising,highcostandfalsepositiveratesof20%limititsutilityincasesofCUP◆ThecombinationofPET/CTmayreducethefalse-positiverateCUPOtherTests◆TheroleoftumormarkerslikeAFP,beta-HCG,CA125,CA27.29,CA19.9,andCEAtoestablishaspecificprimarysiteCUPOtherTests◆Mosttumormarkersarenonspecific◆ItmaynotbeusedtoestablishdefinitivediagnosesCUPOtherTests◆男性腺癌和骨转移，常规检查血清PSA◆男性未分化癌和低分化癌，检测B-HCG和AFP,AFP也用于诊断HCC◆B-HCG和AFP水平并不能预测化疗效果或生存期CUPOtherTests◆CEA、CA125、CA19-9和CA15-3对于确定原发灶没有帮助◆大多数血清肿瘤标记物是非特异性的，可判断预后CUPProcedures◆Abiopsyofthemetastaticsite◆AcarefulevaluationofthepathologyCUPHistologicFindings◆ThepathologisthasanindispensableroleintheevaluationofCUPCUPHistologicFindings◆Needlebiopsyspecimensmayprovideinsufficienttissuefordiagnosisorprovidetissuethathasbeentoo

damaged

ordistortedbythebiopsyprocedureforaccuratediagnosis

CUPHistologicFindings◆Variousimmunoperoxidase(免疫过氧化物酶)stainsareavailableforprovidingadifferentialdiagnosis

forCUPCUPHistologicFindings◆

AppropriateDNAmicroarray(微阵列)techniquesandproteonomic(蛋白质组学)studiestoestablishadefinitivediagnosisCUPHistologicFindings◆

如果查不到原发肿瘤，要想确定各种CUP患者的治疗策略和判断预后是非常困难的CUPHistologicFindings◆免疫组化和影像学联合检查的诊断率约为20％-30％◆目前认为,最有前途的可提高诊断率的方法是肿瘤的分子诊断。现有的基因表达数据库对于CUP的诊断极有帮助CUPHistologicFindings◆预警基因分为两类，一类是在某些起源组织中特异性表达的基因，另一类是在各种肿瘤中均有异常表达的基因CUPHistologicFindings◆

一批源于l0种普通肿瘤的100个原发癌样品，用110个在这些肿瘤中表达最低的基因开发了一个预警芯片。对另外75个盲样(包括l2个转移癌样品)进行检验，预测肿瘤原发灶的正确率大于90％，12个转移癌中有l1个被正确分类CUPHistologicFindin◆对218个肿瘤(14个普通类型)组织和90个正常组织样品的寡核苷酸微阵列基因表达进行分析，用16063个基因表达的相对水平和表达基因的序列标签开发了一个基因预警芯片CUPHistologicFindin◆

对54个肿瘤样品(其中8例转移性肿瘤)检测，总的预测正确率是78％，转移性肿瘤中有6例被正确识别出原发部位◆提示肿瘤保留其组织起源标记物是贯穿于转移过程的始终CUPHistologicFindings◆引用一系列基因表达库的分析数据和相关肿瘤标记物的文献资料确定了61个基因为候选肿瘤基因，以其表达模式预测起源位置。用反转录PCR对原发性腺癌样品(包括乳腺、卵巢、胃、胰腺和肺)检测了其中11个基因，7个(64％)基因存在组织特异性◆这些组织限制性肿瘤标志物能够用于CUP原发性肿瘤可能位点的预测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在胃肠道上皮、泌尿道上皮和Merkel细胞中表达◆CK7在肺癌、卵巢癌、子宫内膜癌和乳腺癌中有表达；而在低位胃肠道肿瘤未发现表达◆CK20阳性和CK7阴性强烈支持结肠原发肿瘤。75％～95％的结肠肿瘤呈现此染色模式◆肺癌仅有9％～15％CK20呈阳性，这有助于肺内转移性腺癌原发灶的鉴别CUPHistologicFindings

◆CK20阴性和CK7阳性将鉴别诊断缩小至肺癌、乳腺癌、胆管癌、胰腺癌、卵巢癌和子宫内膜癌◆应用TTF-1和表面活性物质脱辅基蛋白(surfactantapoprotein)可将原发性肺癌从其他CK7阳性肿瘤中区分出来CUPHistologicFindings◆

TTF-1是一种38kD的含有同源结构域的核蛋白，在甲状腺、中脑和呼吸道上皮胚胎发生过程的转录活化中起作用◆TTF-1在肺癌和甲状腺癌呈典型阳性染色◆有利于对转移性颈部淋巴结肿大和转移性胸腔积液的原发肿瘤的诊断CUPHistologicFindings

◆Electronmicroscopy:ThisstudyhaslimitedutilityinidentificationoftheprimarysiteofcancerofunknownprimaryoriginbutmayrarelybeusedinpoorlydifferentiatedtumorsCUPHistologicFindings◆Chromosomalstudies:IncasesofCUPwithsuspectedoccultNPC,DNAamplificationofEpsteinBarrvirus(EBV)intissuemayclinchthediagnosisCUPHistologicFindings◆Thepresenceofiso-chromosome12p,i(12p),aspecificchromosomalmarkercharacteristicofgermcelltumorscanhelpdiagnoseextragonadalgermcelltumorsinpatientswithCUPCUPHistologicFindings◆生殖细胞肿瘤有特征性的细胞遗传学改变(等臂染色体12p-i[12p]◆拷贝数增加或12号染色体长臂缺如◆与无染色体异常的患者相比，生殖细胞肿瘤有染色体异常的患者对顺铂为主的化疗有更好的反应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表现为转移性疾病但未找到原发灶CUP◆原发灶隐匿的原因可能与以下因素有关机体的免疫机制控制了原发灶，于转移后消失原发灶太小，不能被目前的检查方法所发现CUPNaresh[19]假设认为◆原发灶血供改变使其生长受抑◆在内脏，转移灶可能处于静止期，直到有生成血管表型的亚克隆出现，才导致转移性肿瘤迅速生长◆在肿瘤发生过程中，转移灶发生于晚期的传统理论正受到质疑◆新的数据提示，肿瘤发生早期即有转移倾向CUP◆CUP的原发性肿瘤极有可能从一开始就有“预后不良”的特征◆分子靶点和DNA微阵列在CUP诊断中的应用正在开展◆揭示转移癌的发病机制◆促进新的治疗药物的开发CUP◆代表肿瘤类型的、已知的原发性肿瘤基因引入诊断CUP◆无足够的源于原发性肿瘤转移灶样品的基因表达数据，尤其是低分化肿瘤CUP◆DNA微阵列与更大规模的免疫组化标记物和转移模式相结合◆提高预测CUP起源位置的正确率◆原发灶与其转移灶的基因转录谱的对比性研究

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(间变性肿瘤)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(嗜铬铁蛋白)orNSE◆OftenpresentwithextensiveliverorbonemetastasesCUPTREATMENT◆29patients,19weretreatedwithintensivecisplatin-basedCT◆6othersreceiveddoxorubicin-basedcombinations◆CRin6patients◆4ofthesepatientswerealive19-100monthsafterdiagnosisCUPTREATMENT(Inguinalnodemetastasis)◆1-3.5%◆Squamouscellhistologyinthisareaisusuallymetastaticfromthegenital/anorectalarea◆TheanorectalareashouldbecarefullyinspectedinbothsexesCUPTREATMENT◆Inguinalnodemetastasis

Vulvar,vaginal,andcervicalexaminationinwomenandpenileexaminationinmeniswarrantedCUPTREATMENT◆Treatme