“DOUBLEHIT”DIFFUSELARGEB-CELLLYMPHOMA
Diagnosisof‘doublehit’diffuselargeB-celllymphomaandB-celllymphoma,unclassifiable,withfeaturesintermediatebetweenDLBCLandBurkittlymphoma:whenandhow,FISHversusIHC
StevenH.Swerdlow1
1University
ofPittsburghSchoolofMedicine,Pittsburgh,PA
IdentificationoflargeB-celllymphomasthatare“extra-aggressive”andmayrequiretherapyotherthanthatusedfordiffuselargeB-celllymphoma,nototherwisespecified(DLBCL,NOS),isofgreatinterest.LargeB-celllymphomaswithMYCplusBCL2and/orBCL6rearrangements,so-called‘doublehit’(DHL)or‘triplehit’(THL)lymphomas,areonesuchgroupofcasesoftenrecognizedusingcytogeneticFISHstudies.Whetherfeaturessuchasmorphologicclassification,BCL2expression,ortypeofMYCtranslocationpartnermaymitigatetheveryadverseprognosisofDHL/THLiscontroversial.ClassificationoftheDHL/THLisalsocontroversial,withmosteitherdividingthemupbetweentheDLBCL,NOSandB-celllymphoma,unclassifiable,withfeaturesintermediatebetweenDLBCLandBurkittlymphoma(BCLU)categoriesorclassifyingatleastthemajorityasBCLU.TheBCLUcategoryitselfhasmanyfeaturesthatoverlapthoseofDHL/THL.Currently,thereisgrowinginterestintheuseofMYCandotherimmunohistochemistryeithertohelpscreenforDHL/THLortoidentify“double-expressor”(DE)largeB-celllymphomas,definedinmoststudiesashaving?40%MYC?and?50%-70%BCL2?cells.DElargeB-celllymphomasaregenerallyaggressive,althoughnotasaggressiveasDHL/THL,aremorecommonthanDHL/THL,andaremorelikelytohaveanongerminalcenterphenotype.WhethersingleMYCrearrangementsorMYCexpressionaloneisofclinicalimportanceiscontroversial.ThefieldoftheDHL/THLandDElargeB-celllymphomasisbecomingmorecomplex,withmanhowever,greatinterestremainsinidentifyingthesecaseswhilemoreislearnedaboutthem.
Introduction
TheinspirationforthissessioncomesfromagreatdesireonthepartofpathologistsandclinicianstoidentifylargeB-celllymphomasthatcannotbecategorizedasoneofthespecificsubtypesrecognizedinthe2008WorldHealthOrganization(WHO)classification,butwhichare“extra-aggressive”andmayrequiretherapydifferentfromthatusedformostotherdiffuselargeB-celllymphomas,nototherwisespecified(DLBCL,NOS).ManyofthesecasesendupbeingcategorizedeitherinthebroadandheterogeneouscategoryofDLBCL,NOSor,aswillbediscussed,inthenewercategoryofB-celllymphoma,unclassifiable,withfeaturesintermediatebe-tweenDLBCLandBurkittlymphoma(BCLU).1Animportantsubsetofthesecasesarethe“double-hit”lymphomas(DHLs),withMYCandBCL2and/orBCL6rearrangementsidentifiedbasedoncytogenetictesting.Thereisgrowinginterestnowinthemorecommon“double-expressor”(DE)lymphomasdefinedbasedonimmunohistochemical(IHC)stainswithMYCandBCL2stainingonmorethanaspecifiedproportionoftumorcells.MajorissuesthatremainahottopicofdiscussionaretheprecisedefinitionfortheDHandDElargeB-celllymphomas,whetherthereareimportantsubsetsofthesecasesthatneedtodistinguishedforclinicalorbiologicalpurposes,whetherMYCabnormalitiesintheabsenceof
abnormalitiesinvolvingBCL2orBCL6arejustasominous,whattypeoftestingshouldbeperformed,howtheDHLarebestcategorizedonceidentified,andfinally,ofcourse,howtheyshouldbetreated.Manyofthesefrequentlycontroversialquestionsaredifficulttoresolvebecause,inadditiontotheobviousissuesofsubjectivity(eg,withhistopathologicclassification),theliteratureisveryinconsistentintermsofentrycriteriaforclinicalstudies,diagnosticcriteria,phenotypicandcytogeneticcriteria,andtherapeu-ticstrategies—animportantissuethatIwillnotkeepremindingthereaderabout,butwhichmayaffectmanyofthereporteddiscrepan-ciesthatIhighlight.
WhatisaDHL?
DHLisdefinedonthebasisoffindingaMYCrearrangementtogetherwithspecifiedotherchromosomalrearrangements.2,3Atthepresenttime,mostusethetermtorefertolymphomaswithMYCplusBCL2and/or,in?30%ofthecasesintherecentliterature,BCL6rearrangements(R)withtheevenlesscommonlymphomasbearingall3rearrangementsconsidered“triple-hit”lymphomas(THLs).4-7TheTHLsarefelttobemostsimilartotheBCL2DHLcases.8SomehaveincludedcasesthathaveMYCwithotherchromosomaltranslocations,suchasBCL3at9p13,orevenCCND1.2Conversely,manystudiesofDHLhavenotlookedforBCL6-R,thusmissingBCL6DHLandTHL.
Leavingthemorecontroversialissuestothediscussioninthefollowingsections,DHLsarecurrentlyprobablybestrestrictedtoeitherDLBCL,NOSorBCLUthatcannotbebetterclassifiedasamorespecifictypeoflymphoma.Forexample,amantlecell
90AmericanSocietyofHematology
lymphomawithaMYCandCCND1translocationshouldstillbediagnosedasamantlecelllymphomaeveniftheMYC-Rhasadditionalclinicopathologicimplications.9MYCandBCL2rearrange-mentsarealsofoundinaverysmallproportionoffollicularlymphomas(FL)andsomeB-lymphoblasticleukemias/lymphomas,particularly,casesrepresentingtransformationfromFL,butstillneedtobediagnosedasaFLorB-lymphoblasticleukemias/lymphomas.8,10,11-13WhetherdiffuseDHlargeB-celllymphomasthatrepresenttransformationofaFLshouldbegroupedwithotherDHLiscontroversial.Whereasoneseriesshowedatrendforaworseprognosisforthecasesrepresentingtransformation,anotherfoundthepresenceofaprecedingMYC-negativelymphomanottomakeadifference(although,inthatseries,theoverallsurvivalwas?6monthsandmostpatientsdidnotgetRituxan)andanothershowednoprognosticdifferencesbetweenpatientswithorwithoutapriorhistoryoflymphoma.10,14,15
ItisalsoimportanttorecognizethatDHLisnotadiagnosisrecognizedintheWHOclassification,butratheraslangtermforalargeB-celllymphomawiththetranslocationsnotedabove.Asdefinedinthisway,2%–12%ofDLBCL(moststudies?6%)and32%–78%ofBCLUareDHL,withthelatterproportionbeingbiasedinsomestudieseitherbecausetestingwasperformedonselectedcasesorbecauseDHwasusedasacriterionforBCLU.4-7,15-25TheincidenceofDH/THLincreaseswithpatientage.26
HowareDHLsdetected?
DHLsaredetectedusingcytogenetictechniques.Manyhavebeenidentifiedinthepastusingclassicalcytogenetictechniques(Figure1A);however,theserequirefreshtissue,arelaborintensive,andtherealityisthat,inmanylymphomas,theywillnothavebeenperformed.Althoughofgreatutilityforvariedreasons,specificgenesinvolvedintranslocationsareinferredbutnotproven[eg,t(14;18)(q32;q21)canrepresenteitheraBCL2orMALT1transloca-tion]andcryptictranslocationscanalsobemissed.Inonereport,classicalCGstudiesmissedMYC-Rinabouthalfofthecases.27Therefore,inmostcasestoday,DHLsaredetectedusingcytoge-neticFISHstudieswithlabeledprobestargetingspecificgenesofinterest(Figure1B,1C).FISHstudiescanbesuccessfullyper-formedinalmostallcasesusingformalin-fixedparaffin-embeddedtissuesections,althoughsmears,touchimprints,andfreshinter-phaseormetaphasecellscanalsobeused.4Reproducibilityisreportedtobeveryhigh,withconcordanceamong2observers?98%and,inanotherstudy,completeagreementforbreaks(kappa?1)andexcellentagreementforgains(kappa?0.89).5,7Determinationoftheproportionofabnormalcellsrequiredforapositiveresultdoesvarysomewhatbetweenstudiesandcaninfluencetheoverallresults.“Break-apart”FISHprobesareconsid-eredtobethemostsensitiveforpickingupchromosomalrearrange-however,theycanbefalselynegativedependingonthesiteoftheprecisebreakpoints.AminimalworkuptofindDHLincludesuseofaMYCbreak-apartprobeand,ifpositive,BCL2and,ifnegative,BCL6break-apartprobes.UseofaMYC/IGHdualfusionprobeisusefulinpickingupoccasionalcasesmissedbytheMYCbreak-apartprobeandalsoinidentifyingtheMYCpartnerinasubsetofthecases(seediscussioninthenextsectionregardingpotentialimportanceoftheMYCpartner).Inonestudy,MYCrearrangementsweredetectedonlywiththedualfusionprobein10%oftherearrangedcases,in38%onlyusingthebreak-apartprobe,andin51%withbothtypesofprobes.7UseofanIGHbreak-apartprobemayalsohavesomeutilityinidentifyingwhethertheremightbeatranslocationinvolvinganimmunoglobulin(IG)gene.
Hematology2014Figure1.CytogeneticdocumentationofDHL.(A)Classical
cytogeneticsshowsacomplexkaryotypewithpresumptiveMYC/IGHandBCL2/IGHtranslocations.(B)TheMYCtranslocationisconfirmedwithinterphaseFISHstudiesusingabreak-apartprobethatshowsonenormalfusedsignalandonesetofseparatedredandgreensignals.(C)TheBCL2translocationisconfirmedwithinterphaseFISHstudiesusingabreak-apartprobe.Thereisonenormalcellontherightwith2fusedsignalsandanabnormalcellwith1fusedand1setofseparatedredandgreensignals.(FigurecontributedbyU.SurtiandM.Sherer.)
Whataretheimplications,associatedcontroversies,andongoingquestionsrelatedtotheDHLs?
TheconventionalwisdomisthatDHLsareveryaggressiveneoplasmsthatdonotrespondwelltotherapy,withdescriptionssuchas“extremelydismal”or“grim”prognosesbeingused(Table1).28,29Asdefinedinthisdiscussion,thereisamorphologicspectrumfrommanythatbearsomeresemblanceto
nenecertain
Ampactonsurvivalofsingle-hitMYC-R
lyadverseinGCDLBCL(impactofanyMYC-RforGCDLBCLinmultivariateanalysislostwhenDHLwereexcluded)verse(nodifferencesdocumentedbetweenSHLandD/THL)Averse(can’tevaluateSHLvsDHL)
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verse(similartoDHL)
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Table1.Frequency,pathologiccharacterization,andimpactofDHL/THL
看过本文章的还看过。。。
classification on diffuse large b-cell lymphom ...the current clinic diagnosis methods have been ...of lymphoma: hodgkins and non-hodgkins .........
rituximab maintenance therapy in diffuse large b-cell lymphoma: is xy the most important variable? matthew a lunning and james o armitage university of .........
and non-gcb subgroups of diffuse large b-cell lymphoma.j clin oncol,..cell lymphoma:a study by the groupe detude des lymphomes de ladulte..........
and non-gcb subgroups of diffuse large b-cell lymphoma.jclin oncol,2007,...b-cell lymphoma:a study by the groupedetude des lymphomes de ladulte..........
snapshot: diffuse large b cell lymphoma 1 laura pasqualucci1,2,5 and riccardo dalla-favera1,2,3,4,5 institute for cancer genetics, 2department of .........
lymphoma of diffuse large b-cell type according to this scheme, and ...overall survival (os) was calculated from the time of diagnosis to the .........
annexin a5 inhibits diffuse large b-cell lymphoma cell invasion and chemoresistance through_电子电路_工程科技_专业资料。oncology reports 32: , .........
review urrent c opinion maintenance therapy in diffuse large b-cell lymphoma anne-sophie michallet, laure lebras, and bertrand coiffier purpose of review .........
in patients with diffuse large b-cell lymphoma and grey zone lymphoma. both...[key words] double- prognosis 约 40% .........
the final diagnosis of the patient was discordant lymphoma simultaneously comprised of diffuse large bcell lymphoma and peripheral tcell lymphoma. conclusions .........
and superiority of rituximab to aggressive b-cell lymphoma.methods: 78 cases...diffuselarge b-cell lymphoma:a study by the groupe detude deslymphomes .........
double hit myc genetic vs protein double hit do they have the same ...b-cell lymphoma, unclassified, intermediate between bl and dlbcl large cell .........
and trewatment of diffuse large b -cell lymphoma from american national ...尽管目前已经有一定数量的研究认为双重打击 淋巴瘤 (double hit lymphoma) 的.........
?629? [22]kobayashit,tsutsumiy,sakamoton,etadouble—hitlymphomascons6tu...indiffuselargeb— highlyera aggressiveof subgroup in diffuse large b—cell .........
当前淋巴瘤诊断中的几个问题_临床医学_医药卫生_专业资料。肺癌 ...impactofmycrearrangementsand“doublehit”abnormalitiesindiffuselargeb-celllymphoma.........
diffuse large b-cell lymphoma (including ...both t and b cells positive except follicle center...positive staining supports diagnosis of lymphoma reactive.........
21 9例弥漫性大b细胞淋巴瘤免疫表型及 遗传学特征分析immunophenotypesandcytogeneticalterationsin219casesofdiffuselargeb--celllymphoma 合作 导 师 201 2年05月 .........
introduction in recent years, due to improvements in cancer diagnosis and ...(3). here we report a case of primary diffuse large b?cell lymphoma (.........
fl3ab, a separate diagnosis of dlbcl is made...genetics: – myc, bcl2, both (double hit), ...(chl) and diffuse large b-cell lymphoma (dlbcl.........
位最常见,占所有 dhl的62%左右 等[1] 重打击淋巴瘤 (double-hitlymphomas,...presentationandprognosisofdiffuselargeb-celllymphomawitht(14;18)and8q24c-.........
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hit the screen 有哪几种意思?在这个句子中The workers should go through the films again and again before they hit the screen.film分别作电影和胶片讲时句子各是什么意思?
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hit the screen 在这里指“搬上荧幕”的意思 film 做影片讲,整句话意思是：工作人员应该在电影被搬上荧幕前一次又一次的浏览.film 做胶片将,整句话意思是：工作人员应该在电影上映前一次又一次的浏览胶片.谢谢您的支持!
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Vincent Roche discusses the acquisition of Hittite Inc.
The combination of Analog Devices and Hittite Microwave is compelling for our customers and strengthens ADI's position as a leader in high performance signal processing. The combination of ADI's 10,000 device RF/IF to baseband signal chain and complementary system components and Hittite's 1,100 RF, microwave and millimeter wave signal chain components gives our customers the expertise and solutions for high performance design. We are able to serve their needs better by providing a complete portfolio capable of converting the frequency spectrum including RF, microwave and millimeter wave. We believe this will significantly benefit our customers by creating an integrated supplier for all of their RF needs. This acquisition opens expansion opportunities into microwave and millimeter wave frequencies - technologies where Hittite Microwave specializes. ADI offers Hittite Microwave customers access to our complementary portfolio of products, a far-reaching distribution network, and access to an established set of world-class supply chain systems, partners, and practices.
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Visit PartnerZone, our new Design Partner Network community on EngineerZone! Easily connect with electronic design service companies and access their expertise with applying ADI technology across a wide range of markets and industries.
EngineerZone contains over 80 support forums to assist with your engineering project.
Use Analog Devices' education section to view the online library of technical resources, courses and tutorials, and to learn about our regional university programs.
Analog Devices has over fifty years of analog circuit design experience to share with you.
Did you know that there are over 20,000 registered members of EngineerZone?
Did you know that hundreds of ADI engineers regularly provide technical support to EngineerZone members?
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