金域大数据引发的宫颈癌筛查思考

从金域大样本检测数据引发的宫颈癌筛查思考金域宫颈病变检测中心孙宜M.D.&Ph.D

16,115,000金域检验宫颈癌筛查至今例次宫颈细胞学：1260万高危型HPV病毒检测：351.5万CAP质控体系和方法、分析和统计金域数据-论文发表：10篇分别在：2016年5月刚被“

JournalofCancer”接收2016年3月在“AmJClinPathol”《美国临床病理杂志》2015年7月在“CancerCytopathology”《癌症细胞病理》2015年3月在”JournaloftheAmericanSocietyofCytopathology”《美国细胞病理学》2015年3月在”ArchivesofPathologyandLaboratoryMedicine”《病理学与实验室医学档案》

《国际细胞学杂志》、《实用肿瘤学杂志》、《中国癌症防治杂志》、《BMC传染病学杂志》….金域数据-墙报展示：9篇分别在：2016年4月在ASCCP年会、2016年3月在USCAP年会2014年和2015年USCAP年会PrevalenceandgenotypedistributionofHPVInfectioninChina:analysisof51,345HPVgenotypingresultsfromChina’slargestCAPcertifiedlaboratoryZhengyuZeng,HuaitaoYang,ZaiboLi,XuekuiHe,ChristopherC.Griffith,XiamenChen,XiaoleiGuo,BaowenZheng,ShangweiWu,ChengquanZhao中国人群HPV感染率和基因型的研究：来自中国最大CAP认可实验室的51345例HPV送检标本结果分析曾征宇；杨怀涛；李再波；何学魁；ChristopherC.Griffith；陈显梅；郭晓磊；郑宝文；吴尚为；赵澄泉2016年5月，刚被“

JournalofCancer”接收2016年2月发表在AmJClinPathol《美国临床病理杂志》PrevalenceofHigh-RiskHumanPapillomavirusInfectioninChina，Analysisof671,163HumanPapillomavirusTestResultsFromChina’sLargestCollegeofAmericanPathologists-CertifiedLaboratoryZhengyuZeng,MD；R.MarshallAustin,MD,PhD；XuekuiHe；XianmeiChen,MD；XiaoleiGuo；BaowenZheng,MD；ShangweiWu,MD,PhD；HuaitaoYang,MD,PhD；ChengquanZhao,MD中国人群高危型HPV感染率的研究--来自CAP认可的中国最大实验室的671,163例HPV检测结果曾征宇；AustinM;何学奎；陈显梅；郭晓磊；郑宝文；吴尚为；杨怀涛；赵澄泉AmericanJournalofClinicalPathologyAdvanceAccesspublishedMarch2,2016GovernmentsupportedCPScervicalscreeningisbeingintroducedinruralareasofChinasuchasHainanProvince.TheinternationalCAPLAPhasprovidedlaboratoryqualitycontrolstandardsnototherwisereadilyavailableinmanyunderservedinternationalsettings.ReportingrateswerewithinCAPbenchmarkrangesfordifferentTBScategories,exceptforlowreportingratesforunsatisfactorysmearsandforAGC;educationaltrainingprogramshavebeeninstitutedtoaddresstheseissues.ResultsConclusionDesignBackground70%oftheChinesepopulationresidesinruralareas,where90%ofincidentcervicalcancercasesareestimatedtooccurandwherecervicalcancerscreeningisstilluncommonduetothefinancialrestraints.TheChinesegovernmenthasintroducedcervicalscreeningprograminruralareas.Thiswasaretrospectivestudytosummarizecervicalscreeningresultsin11ruralcountiesinHainanProvidence.Thewomenvolunteeredtoattendscreening.Mostofthewomenwerepreviouslyunscreened.TheconventionalPapspecimens(CPS)werecollectedsenttotheCAPcertifiedGuangzhouCytologyLaboratoryforslidepreparationandreview.TheTBSreportratesamongthedifferentyearswereshowninTable1.Thereportedabnormalratewas4.4%ofallwomen,withHSILreportedin0.5%.Abnormalcytologyratesvariedamongcounties.Intermsofagegroups,theLSILreportingratewassignificantlyhigherinwomen<50yearsthanyoungerwomen(1.04%vs0.64%).TheHSILreportingratewassignificantlyhigherinwomen≥40yearsthanyoungers(5.3%vs0.38%)(Table2).2286womenwithabnormalPapsmearshadcolposcopicandhistopathologicfollowupwithin3monthsaftertheabnormalPaptests.Cervicalcancer,CIN2/3,andCIN1wereidentifiedin1.0%,22%,and56%women,respectively(table3).2016ASCCPANNUALMEETING,NewOrleansConventionalPapSmearCervicalScreeningin11RuralCountiesinHainanProvidence,China:AnalysisofTBSReportingRatesFor218,195ScreenedWomen

BaowenZheng1,MarshallAustin2,XiaomanLiang1,HuanWan1,GuijianWei1,YaomingLiang1,ChengquanZhao21.GuangzhouKingmedDiagnosticsguangzhou,China2.DepartmentofPathology,Magee-Women'sHospitalofUPMC,Pittsburgh,PATable2TBSreportingrateindifferentagegroups(11counties)CategoryAge2011201220132014TotalASC-US(%)44.9941（2.88）1318（2.47）1866（2.73）1519（2.37）5644（2.6）ASC-H(%)48.191（0.28）164（0.31）219（0.32）234（0.37）708（0.3）LSIL(%)43.3299（0.92）380（0.71）743（1.09）563（0.88）1985（0.9）HSIL(%)46.3199（0.61）223（0.42）341（0.50）316（0.49）1079（0.5）SCC(%)51.410（0.03）002（0.003）12（0.01）AGC(%)44.709（0.02）6（0.01）14（0.02）29（0.01）NILM(%)45.331116（95.28）51168（96.07）64972（95.18）60891（95.12）208147（95.7）Unsat(%)44.401（0）114（0.17）476（0.74）591（0.3）Total45.932656532636826164015218195Table1.TBSreportingratebyyearsin11CountiesTable2TBSreportingrateindifferentagegroups(11counties)AgesASC-US(%)ASC-H(%)LSIL(%)HSIL(%)SCC(%)AGC(%)NILM(%)Unsatisfactory(%)Total20-2954（1.75）10（0.32）34（1.10）4（0.13）002971（96.06）20（0.65）309330-391399（2.49）119（0.21）595（1.06）221（0.39）1（0.002）5（0.009）53670（95.53）171（0.30）5618140-492504（2.86）247（0.28）902（1.03）462（0.53）4（0.005）20（0.022）83315（95.05）198（0.23）8765250-591296（2.40）259（0.48）348（0.64）287（0.63）6（0.011）4（0.007）51611（95.63）158（0.29）53969>=60260（2.34）58（0.52）66（0.59）68（0.61）1（0.009）010626（95.58）38（0.34）11117Unknown131（2.12）15（0.24）40（0.65）37（0.60）005954（96.30）6（0.10）6183Total5644（2.59）708（0.32）1985（0.91）1079（0.49）12（0.006）29（0.01）208147（95.39）591（0.27）218195CPSCategoryNegative%CIN1%CIN2/3%SCC%ADC%TotalASC-US342(29.8)700(60.9)103(9.0)4(0.35)01149LSIL69(11.2)479(77.9)67(10.9)00615ASC-H43(20.3)66(31.1)96(45.3)4(1.9)3(1.4)212HSIL9(3.0)43(14.2)243(79.9)7(2.3)2(0.66)304AGC01(16.7)2(33.3)03(50)6Total463(20.3)1289(56.4)511(22.4)15(0.66)8(0.35)2286Table3.SurgicalFollow-upresults.(Cancer23/2286=1.01%)Reportsofhighriskhumanpapillomavirus(hrHPV)testingpatternsandpositiveratesindifferentcytologicalcategoriesfromChinaarerare.WeevaluatedtestingpatternsandpositiveratesindifferentcytologicalcategoriesinChina'slargestCAP-accreditedlaboratory.MethodsConclusionsHighRiskHPVTestingandReportRate:ResultfromtheLargestCAPCertifiedIndependentLaboratoryinChinaBaowenZheng1,ZaiboLi2,ZhenyuZeng1,CongdeChen1,JaYou1,LingyunTan1,ChengquanZhao31.GuangzhouKingmedDiagnostics,Guangzhou,China,2.DepartmentofPathology,OhioStateUniversityMedicalCenter,Columbus,OH,3.DepartmentofPathology,Magee-Women'sHospitalofUPMC,Pittsburgh,PALogoThehrHPV-positiveratewas35%inpatientswithASC-US,with40%inpatientsyoungerthan30yearsand34.1%inpatientswithanageof30yearsorolder.ThehrHPV-positiveratewas12.1%inpatientswithNILM,with14.6%inpatientsyoungerthan30yearsand11.5%inpatientswithanageof30yearsorolder.TheoverallhrHPV-positiverateswere77.7%inLSIL,90.5%inHSILand80.8%inASC-Hand47%inAGC.ThehrHPV-positiveratewassimilarinvariousliquid-basedcytologymethodsincludingThinPrep,SurePath,LITOUliquid-basedpreparation,buthigherinconventionalandLIPUpreparations.ThisisthefirstroutineclinicalpracticereportofhrHPVpositiveratesinvariablePapcytologycategoriesinChina.ThehrHPV-positiveratereportedfromChina‘slargestCAP-accreditedlaboratorywascomparabletothatreportedamongUSlaboratories(HumanPapillomavirusTestingandReportingRatesin2012,ResultsofaCollegeofAmericanPathologistsNationalSurvey,ArchPatholLabMed2015;139:757–761).Therefore,participationintheinternationalCAPLaboratoryAccreditationProgramprovideslaboratoryqualitystandardsnototherwiseavailableinmanyinternationalsettings.HPVpositiverateis12%inwomenwithnegativePaptest,muchhigherthanthatinmostreportsintheWesterncountries

(??),indicatinghigherprevalenceofhrHPVinfectioninGuangdong,China.BackgroundResultsLogoResultsfrom128,195PapanicolaoutestswithhrHPVtestingbyHybridCapture2(HC2),renderedbetweenJanuary2011andDecember2014bytheGuangzhouKingMedDiagnosticsCytologyLaboratory,wereanalyzed.ThesamplesforPaptestandHPVtestweresavedintwodifferentvials.Categories<30years>=30yearsTotalCase#Positive(%)Case#Positive(%)Case#Positive(%)AgesASC-US2,425970(40.0)11,239

3,827(34.1)13,6644,797(35.1)37.8（16-80）LSIL1,3251,032(77.9)4,339

3,367(77.6)5,6644,399(77.7)35.8（15-93）ASC-H6343(69.3)671550(82.0)734593(80.8)43.7（23-80）HSIL7864(82.1)11571,054(91.1)12351,118(90.5)42.5（16-80）AGC126(50.0)12257(46.7)13463(47.0)41.5（28-64）NILM19,2372807(14.6)87,52710,065(11.5)106,76412,872(12.1)xxTotal23,1404922(21.3)105,05518,920(18.0)128,19523,842(18.6)xxTable1.HRHPVPositiveRatesinWomenwithVariousPapTestResults.PreparationThinPrepSurePathCPTLITUOLIPUCase#92,45818,0304,2188,7394,609HPVPositive#17,1673,1911,0701,5871,098Positiverate18.6%17.7%26.4%18.2%23.8%Table2.HRHPVPositiveRatesinVariousPreparationMethods.2016AnnualMeetingofUnitedStates&CanadaAcademyofPathology(USCAP),Seattle,WAOf8446patientswithhistologicallydiagnosedCIN2/3overa48-monthperiod,3342patients(averageage39.0,19-77years)hadpriorHC2hrHPVtestingand/orPaptestresultsincluding1657withpriorhrHPVtesting(average1.3months;0.5-9months)and2369withpriorPapcytology(average1.5months;0.5-11months)beforehistologicaldiagnosis.ThehrHPV-negativeratewas8.8%(145of1657patients)andthePap-negativeratewas6.6%(158/2396)(p=0.01).ThenegativePapratewassignificantlydifferentdependingonthepreparation,highestinLiqui-PrepandlowestinLituo.AbnormalPaptestresultsarelistedintable1.Of711patientswithbothHPVandPaptestingresults,62(8.7%)

hadnegativePapcytologyand50(7.0%)hadnegativeHPVtesting(p=0.23).Only16(2.3%)haddoublenegativeresults.Table1.PriorPapcytologyresultsin2396womenwithCIN2/3onhistologyKruskal-WallisP<0.0001PriorPaptestand/orHPVtestingresultsin3342womenwithhistologicallydiagnosedcervicalintraepithelialneoplasia2/3:datafromChina’slargestCAPcertifiedclinicallaboratoryTaoWu1,ChristopherC.Griffith2,BaowenZheng1,XiangdongDing1,YaomingLiang1,ChengquanZhao31.DepartmentofPathology,KingMedDiagnostics,Guangzhou,China,2.DepartmentofPathology,EmoryUniversity,Atlanta,GA3.DepartmentofPathology,Magee-Women'sHospitalofUPMC,Pittsburgh,PA2016AnnualMeetingofUnitedStates&CanadaAcademyofPathology(USCAP),Seattle,WAHighgradesquamouslesionscausedbypersistenthrHPVinfectionareregardedasprecursortocervicalcancer.ThisstudyweexaminePapcytologyandhrHPVtestingresultsprecedinghistologicdiagnosesofCIN2/3inChina.BackgroundDesignThisstudydemonstratesrelativelyhighpriornegativetestingresultswithbothhrHPVandPapcytologyinapopulationofwomenwithCIN2/3inChinawherethereisnonationalcancerscreeningprogramorcervicalcytologyqualitycontrolstandards.hrHPVtestingwasnotmoresensitivethanPapcytologyindetectionofhighgradesquamouslesion.PatientshavingbothpriorHPVandcytologyhadlowerratesofdoublenegativeresults,supportingthevalueofcontestingtoenhancedetectionofcervicalcancerprecursors.ConclusionsCasesofCIN2/3diagnosedfrom2011to2014byhistologywereretrievedfromPathologydepartment.PriorhrHPVandPapcytologyresultsintheyearbeforeCIN2/3diagnoseswererecorded.ResultsCategoryThinPrepSurePathLiqui-PrepLituoConventionalTotalHSIL514(42.1)108(48.6)31(36.5)244(51.7)173(43.7)1070(44.7)LSIL231(18.9)61(27.5)16(18.8)109(23.1)83(21.0)500(20.9)ASC-H192(15.7)17(7.7)14(16.5)64(13.6)67(16.9)354(14.8)ASC-US176(14.4)20(9.0)11(12.9)42(8.9)54(13.6)303(12.6)AGC8(0.7)1(0.5)01(0.2)1(0.3)11(0.5)Negative100(8.2)15(6.8)13(15.3)12(2.5)18(4.5)158(6.6)Total1221222854723962396CategoryHPVPositiveHPVNegativeTotalN%N%N%HSIL27241.191828139.5LSIL14622.161215221.4ASC-H8412.76129012.7ASC-US11016.6132612317.3AGC30.50030.4Negative467.01632628.7Total66110050100711100Table2.PriorPapandHPVtestresultsin711womenhavingbothtests2014USCAPANNUALMEETINGSan

Diego,CA数据分析细胞学检测&组织学结果比对高危型HPV检测&组织学结果比对细胞学联合病毒学检测&组织学结果比对细胞学检测结果数据分析

阳性检出率HSIL检出率HSIL阳性预测值金域集团2015年3,738,962例宫颈细胞学检测结果TBS分类液基涂片传统涂片合计（例）例%例%不满意305541.1275320.7438086ASCUS1044533.83218332.15126286ASC-H68190.2522740.229093LSIL412011.5168150.6748016HSIL151000.5530410.3018141SCC3980.01360.00434AGC11910.041840.021375总检测例数2,725,6501001,013,3121003,738,962阳性检出169,1626.21%41,7154.12%210,877阳性检出率：液基细胞学--6.21%传统涂片--4.12%HSIL检出率：液基细胞学--0.55%传统涂片--0.30%广东省2014年12县市99,573人农村两癌筛查

阳性检出率:7.98%

HSIL检出率1.01%液基细胞学海南省11县市农村218,195人宫颈癌筛查（2011~2014）

阳性检出率4.35%HSIL检出率0.5%

传统涂片癌前病变HSIL检出率传统涂片液基细胞学CAP中位数（2012）CAP中位数（2012）金域2,725,650例（2015）广东省99,573人农村筛查（2014）金域1,013,312例（2015）海南省218,195例农村筛查（2011-2014）细胞学检出HSIL的比例，明显高于CAP中位数

广州金域HSIL的阳性预测值PPV>80%

HSIL中检出癌比例3.5~4.8~10.1%

资料检测例数HSIL活检例数CIN2~3例数（%）癌例数（%）PPV（%）2007~2013*180410824141750（72.5）244（10.1）82.62014广东农村筛查99573312238（76.3）15（4.8）81.12012~2013海南农村筛查155082171141（82.5）6（3.5）86HSIL中检出癌前病变和癌的比例高细胞学检查的阳性检出率较高HSIL检出率较高（CAP)HSIL结果中，活检证实癌前病变和癌的比例较高细胞学检查阳性预测值（PPV）高宫颈癌的细胞学检查，检出率高宫颈细胞学的质量控制好（PPV>80%)宫颈细胞学在宫颈癌筛查中的作用不可替代结果：金域的数据结论：高危型HPV病毒学检测结果数据分析广州金域（2007-2014）671,163例高危型HPV检测结果分析

高危型HPV阳性检出率：21.4%PrevalenceandgenotypedistributionofHPVInfectioninChina:analysisof51,345HPVgenotypingresultsfromChina’slargestCAPcertifiedlaboratory

高危型HPV感染率前三的型别：52、16、58Categories<30years>=30yearsTotalCase#Positive(%)Case#Positive(%)Case#Positive(%)AgesASC-US2,425970(40.0)11,239

3,827(34.1)13,6644,797(35.1)37.8（16-80）LSIL1,3251,032(77.9)4,339

3,367(77.6)5,6644,399(77.7)35.8（15-93）ASC-H6343(69.3)671550(82.0)734593(80.8)43.7（23-80）HSIL7864(82.1)11571,054(91.1)12351,118(90.5)42.5（16-80）AGC126(50.0)12257(46.7)13463(47.0)41.5（28-64）NILM19,2372807(14.6)87,52710,065(11.5)106,76412,872(12.1)xxTotal23,1404922(21.3)105,05518,920(19.0)128,19523,842(18.6)xx广州金域128,195例不同细胞学结果中高危型HPV阳性率细胞学结果，并未见上皮病变（NILM）中，高危型HPV阳性率12.1%HSIL的高危型HPV阳性率最高，而在腺细胞病变中HPV阳性率较低广州金域427例宫颈癌病例的HPV检测结果（2011-2014.10)检测例数平均年龄（范围）HPV（+）（%）HPV-（%）42745.6(23-81)395（92.5）32（7.5）427例浸润性子宫颈癌诊断前高危型HPV检测与宫颈细胞学检查结果分析，《癌症细胞病理》杂志，2015-7思考：1、如何处理

12%hr-HPV+,（NILM）的病人？复检／阴道镜（病人管理)2、如何发现10%HSIL,20%ASC-H,而

hr-HPV(-)的病人？(donothing?->

SCC,undertreatment)3、如何发现>50%AGC,而hr-HPV(-)的病人？(donothing?–>AIS,Adenocarcinoma?undertreatment)3、如何早期发现7.5%

已经是宫颈癌,而hr-HPV依然(-)的病人？宫颈癌中HPV的阴性率：7.5%高危型HPV阳性检出率较高宫颈癌和癌前病变中存在不少hr-HPV阴性的病例(upto20%)结果：结论：高危型HPV检测

很好，检出较多阳性人群它也可会漏掉不少癌症和癌前病变hr-HPVtest不等于PapTest;不可替代Paptest二者互相补充，应该进行联合筛查若在经济落后的地区，PapTest更便宜细胞学联合病毒学检测结果分析宫颈癌病例中的阴性率CIN2、CIN3中的阴性率

细胞学HPV检测细胞学+HPV联合检测阳性152140154阴性（%）3（1.9%）15（9.7%）1（0.6%）在115例宫颈癌病例中，细胞学检查，阴性率为1.9%HPV检测，阴性率为9.7%细胞学+HPV检测,

阴性率

0.6%结论：联合检测是最好的筛查方法155例宫颈癌病例中细胞学和HPV检测的结果CategoryHPVPositiveHPVNegativeTotalN%N%N%HSIL27241.191828139.5LS