PathologyofB-CellLymphomas:DiagnosisandBiomarkerDiscoverySarahL.Ondrej - PDF document

PathologyofB-CellLymphomas:DiagnosisandBiomarkerDiscoverySarahL.OndrejkaandEricD.HsiThediagnosisofB-cellnon-Hodgkinlymphomashaschangedsignicantlyoverthepastfewdecadesasnewimmunophenotypicmarkers,molecularsubtypecationschemes,andnovelbiomarkershaveemerged.Meanwhile,therehasbeenanincreasingemphasisonindividualizingtreatmentapproachesinaccordancewithabiologicheterogeneitythathasbeenuncoveredwithinmanyoftheindividualB-celllymphomaentities.Theapplicationofhigh-throughputgenomicsequencingtoB-celllymphomashasyieldedlargeamountsofvaluableinformation.Thedataencompassdiscoveriesessentialtoanunderstandingofpathogenesis,clonalortumoralevolution,andidenticationofbiomarkersthatmaybeusefulforprognosticortherapeuticconsiderations.Thefollowingreviewdiscussesseveralofthemorecommon,primarilytissuebasedB-celllymphomas,withafocusonpathologicclassicationandcertainphenotypiccharacteristicsorgeneticlesionsthatapplytorenementofdiagnosisandtherapy.B-celllymphomaBiomarker S.L.OndrejkaE.D.Hsi(ClevelandClinicRobertJ.TomsichPathologyandLaboratoryMedicineInstitute,9500EuclidAve,L3,Cleveland,OH44195,USAe-mail:hsie@ccf.orgSpringerInternationalPublishingSwitzerland2015A.M.EvensandK.A.Blum(eds.),Non-HodgkinLymphomaCancerTreatmentandResearch165,DOI10.1007/978-3-319-13150-4_2 1Introduction....................................................................................................................282PracticalPoints.................................................................................................................293FollicularLymphoma.............................................................................................................314LymphoplasmacyticLymphoma...........................................................................................335MantleCellLymphoma.........................................................................................................346DiffuseLargeB-CellLymphoma,NotOtherwiseSpecified...............................................377PrimaryMediastinalLargeB-CellLymphoma.....................................................................398BurkittLymphoma.................................................................................................................409B-CellLymphoma,Unclassifiable,withFeaturesIntermediateBetweenDiffuseLargeB-CellLymphomaandBurkittLymphoma...............................................................4110Next-GenerationSequencingforMinimalResidualDiseaseMonitoringandMutationDetection.......................................................................................................42References.......................................................................................................................421IntroductionB-celllymphomadiagnosishasconventionallyincorporatedmorphologic,immu-nophenotypic,andgeneticndingsforclassicationintospecicdiseasecatego-ries.Despitethis,theclinicalbehaviorwithineachB-celllymphomasubtypeisvariableandreectsabiologicheterogeneitythatisincreasinglyrecognizedwiththeapplicationofunbiasedmolecularcharacterization.RecentdiscoveryofnewbiomarkershasledtoimprovementsindiagnosisandprognosisinB-celllym-phomas.Massivelyparallelsequencingtechnologieshaveidentiedrecurrentmutationsthattargetimportantcellularpathways,andthishasdeepenedourunderstandingoftheoncogenicmechanismsofmanyoftheseneoplasms.Asidefromprovidinginsightsintopathogenesis,identicationofbiomarkersthatmightprovidecluestonewtherapeuticoptionsortargetedtherapieswithlowertoxicitywouldbeofgreatbenettopatientswithB-celllymphomas.Anadditionalbeneofusefulbiomarkersisthattheymightservetopredictdiseasecourse,inordertoinformindividualizedtreatmentdecisions.Thisreviewwillcoversomeofthemorecommon,primarilytissue-basedB-celllymphomas,progressingfromsmallB-cellentitiestothediffuseaggressiveB-celllymphomas.Pertinentpathologicfeaturesandcurrentclassicationissueswillbeaddressedalongtheway,includingphe-notypic(Table)andgeneticconsiderationsfordiagnosisanddiseasemanagement.Potentialbiomarkersthathavesurfacedoverthelastfewyearswillbeconsideredalongwitheachentity,inlightofthefeasibilityofapplicationinroutineclinicalsettings(Table).Finally,adiscussionofperhapsthemostpromisingdiscoveriesoutofnext-generationsequencingstudieswillprovideaframeworkforongoingliteraturereviewastheeldadvances. 28S.L.OndrejkaandE.D.Hsi 2PracticalPointsDiagnosisofB-celllymphomaisbestachievedwithexcisionalorincisionallymphnodeorextranodaltissuebiopsy.Examinationofthefreshbiopsytissue(bytouchimprintorfrozensection)clinicallysuspectedoflymphomatousinvolvementatthetimeoftheprocedureallowsproperallocationoffreshtissueforowcytometryandcytogeneticstudies.Whilene-needleaspirationcanresultinprocurementoffreshcellsforancillaryowcytometrytesting,itisnotidealfordenitivelymphomacationsincethisrequiresassessmentofspatialandarchitecturalpatternrecognitionthatislostinFNAsamples.Similarly,needlecorebiopsiesmaynotshowimportantarchitecturalfeaturesandmayresultinanon-denitivediagnosis,misclassication,orevenmisdiagnosis.Formalinxationisthestandard,andthroughtechnicaladvancesoverthepast20years,formalin-xedparafn-embed-dedtissuescannowbeusedfordetailedimmunophenotypingbyimmunohisto-chemistry(essentialinmodernpractice),uorescenceinsituhybridizationfor Table1ExpectedimmunophenotypeofselectedBcellnon-HodgkinlymphomasExpectedimmunophenotypeFollicularlymphomaCD19+,CD20+,IgMIgD,monotypicsIg+,CD10+,bcl-6+,bcl-2,HGAL,LMO2;associatedwithCD21+/CD23+folliculardendriticcellmeshworksLymphoplasmacyticlymphomaCD19+,CD20+,monotypicsIg+,IgM,CD22+,CD79a+,;plasmacellshavemonotypiccytoplasmicIgMantlecelllymphomaCD19+,CD20+,monotypicsIg+,IgMIgD,CD5+,orweakly+,cyclinD1+,SOX11,LEF1DiffuselargeBcelllymphoma,CD19+,CD20+,monotypicsIg+orabsentsIg,BCL2MYC+insomecasesoftypicalDLBCL,nos,andinBCL-UGerminalcenterBlikeHans:(CD10+)or(CD10Choi:(GCET+/MUM1)or(GCET/CD10+)orTally:ScoringsystemfavorsCD10,GCET,andLMO2�30%Non-germinalcenterBlikeHans:(CD10)or(CD10Choi:(GCET+/MUM1+)or(GCETFOXP1+)or(GCETTally:ScoringsystemfavorsMUM1,FOXP1,andLMO2%Primarymediastinal(thymic)largeB-celllymphomaCD19+,CD20+,CD22+,CD79a+,MAL+,cREL+,CD200,MUM1,CD23,BCL2,BCL6,CD30heterogeneous),surfaceIgweaktoabsentBurkittlymphomaCD19+,CD20+,CD10+,BCL6+,BCL2-,monotypicsIg+,MUM1,MYC+,Ki670-3;9.2;馘砀95%.CasesassociatedwithEBV:EBV-encodedRNA+/EBNA-1+and PathologyofB-CellLymphomas:Diagnosis Table2RecentlyinvestigatedmolecularbiomarkersinselectedB-cellnon-HodgkinlymphomasMolecularbiomarkerUsefulmethodfordetectionSigniL265PmutationAllele-specicPCRFairlysensitiveandspecicforLPL/WMandIgMMGUSdiagnosis.MaybepredictiveofdiseaseburdenandindicateriskofprogressioninIgMMGUSMantlecellSOX11transcriptionfactorImmunohistochemistry(especiallymonoclonalanti-SOX11,CellMarque,Rocklin,CA)GoodbiomarkerforMCLdiagnosis,includingcyclinD1-negativevariant.Maybeausefulprognosticparameter,butstudiesareicting.MaybeapromisingprospectforMRDanalysis.SuppressesterminalB-celldifferentiationanddrivesangiogenesisinMCL[DiffuseaggressiveB-celllymphomagenotype(dualtranslocationsaremostFluorescenceinsituhybridization(FISH)detectsgenetictranslocationPrognosticbiomarker(worseprogression-freeandoverallsurvival).Double-protein-positive(MYCandBCL2proteinbyimmunohistochemistry)independentlypredictsaworsesurvivalinrituximabpatientswithDLBCLDiffuselargeB-cellGerminalcenterBcell-like(GCB)versusactivatedBcell-like(ABC)geneexpressionproSeveralimmunohistochemistryalgorithms,ornewmultiplexgeneexpressionassay(ICEPlexPrimeraDx,Manseld,MA)Prognosticandbiologicallysignicant.TheABCsubtypehasaworseoutcomeandindicatesactivationoftheB-cellreceptorandBpathways.Thismayalsopredictresponsetotargetedtherapiesandsupportclinicaltrials 30S.L.OndrejkaandE.D.Hsi cchromosomalrearrangementsornumericalabnormalities,andDNA-orRNA-basedtesting(suchasgenerearrangement,otheramplication-based,expression,orsequencingstudies).Tosummarize,excisionallymphnodebiopsywithasmallportionsentforowcytometricanalysisprovidesthebestguaranteeofarrivingataspecicdiagnosis,particularlyifanadequatelymphoidsamplecanbermedatthetimeofsurgery.3FollicularLymphomaFollicularlymphoma(FL)isacommonB-celllymphomathataccountsfor20%ofnon-HodgkinlymphomasintheUSAandWesternEurope.Ithasamedianageof60yearsandfemalepredominance.Patientsusuallypresentwithpainless,slowlyprogressivelymphadenopathyandhigherstage(AnnArborIIIIV)withfewexhibitingBsymptoms.Despiteitsprototypicclinicalcourse,ithasbeenknownforsometimethatthediseaseisvariablewithsomepatientsexperiencingwaxingandwaningsymptoms,whileothersmightsuccumbfollowingearlytransformationtoahigh-gradelymphoma[Histopathologically,thislymphomasubtypeeffacesthenodalarchitecturewithatleastapartiallyfollicularpattern.Thecytologiccompositionisamixtureofcentrocytesandcentroblastsinvaryingproportions,andgradingisbasedonthenumberofcentroblastsper400microscopiceld(grades13B).ThephenotypeisthatofagerminalcenterBcell(GCB)withexpressionofBCL6,CD10,LMO2,andHGALinmostcases[].Thegeneticfeaturesincludeclonallyrear-rangedimmunoglobulingenesandt(14;18)(q32;q21)thatleadstoaberrantexpression.Alternatively,canbeduplicated/ampliedortranslocatedtooneoftheimmunoglobulinlight-chaingenes,buttheproportionofcasesthathaverearrangementsdecreaseswithincreasingcytologicgrade.Thelargestpro-portionofFLinNorthAmericaandWesternEuropehaslow-gradecytology,t(14;18)(q32;q21),andCD10andBCL2proteincoexpression[].FISHseemstobethemostsensitivemethodfordetectionoftranslocation[FLisincurablebutrelativelyindolent.TheoutcomecanbepredictedbytheFL-cInternationalPrognosticIndex(i.e.,FLIPI),whichwasdevelopedforallFLhistologies,andincludesapointsystembasedon5factors(age�60,stageIII/IV,LDH�upperlimitofnormal,nodalgroups�4,andHgb12[].ThiswasrevisedtotheFLIPI-2whichwasdesignedintherituximaberaandtookintoaccountthemassdiametersize,aswellasusingprogression-freesurvivalasanendpointinsteadofoverallsurvival[TheclinicalheterogeneityinFLwasinvestigatedbygeneexpressionproling.Thisledtothediscoveryoftheimportanceofthemicroenvironmentinpredictingsurvival.WithinalargecohortofFL,asurvivalpredictorwasgeneratedbasedongenesthatwerefoundtoreectthenonmalignantimmunecells(suchasTcells,macrophages,anddendriticcells)thatwereowsortedfromthetumor[].Aseparategeneexpressionstudyusingdifferentselectioncriteriaandendpointsfound PathologyofB-CellLymphomas:Diagnosis differencesbetweentransformedandnon-transformedFL,notablypossessionofanactivatedfollicularhyperplasiaversusadownregulatedimmuneresponsesignature,respectively.Theyalsofoundthatcharacterizationoftheimmunestatebyimmu-nohistochemistrywasasensitivewaytoassessthemicroenvironmentalfeaturesfeatures31].However,therewaslittleoverlapintermsofaclinicallyusefulgenesetthatcouldbeexploited.Additionalimmunohistochemistry-basedstudiesasasurrogateforGEP,inanattempttocharacterizetheimmunecellcomposition(lymphoma-associatedmacrophages,polarizedmacrophages,andT-cellhelperorregulatorysubsets)forprognosticbenet,yieldedconictingresults,especiallywhenthiswasextendedtoprospectivestudiesofpatientsonmonoclonalantibodytherapy.Somewereabletostratifygroupsbasedonoutcome[],whileothersshowednoassociationwithimmunemakeupandoverallsurvival[].Differencesinresultsmaybeexplainedbydifferencesinpatientselection,treatmentregimens,ortechnicalissues.Regardless,thereisevidencethatthemicroenvironmentalcompositioninFLshiftsduringdiseaseprogressionandislikelyimportantfortumorsurvival[FL,alongwithotherB-cellmalignancies,possessesmanygeneticalterationsthatarebeingdenedandcharacterizedastobiologicandclinicalsigniRecently,mutationsingenesassociatedwithchromatinmodication(,20%ofFL)andhistonemethytransferases(MLL2,89%ofFL;CREBBP,32%ofFL)werediscoveredusinghigh-throughputsequencingtechnologies[hasahighmutationalfrequencyandwasthushypothesizedtocooperatewithothermutationstoincreasegeneticinstability.CREBBPmutationattenuatesacetylation,resultinginanincreaseinactivityofthatoncogeneandalteredexpressiontargetgenes[].Importantlythough,tounderstandthesignicanceofeachmutationinlymphomagenesis,apursuitoftheclonal/subclonalarchitectureofFLdemonstratedthatfrequentlyunderliesthedisease(assumedtobetheprimaryevent),whileCREBBPisacandidatedrivermutationandanimportantsecondaryevent.MLL2wereconsideredtertiaryacceleratormutations[Tosummarize,theFLIPIremainsthemostwidelyusedprognosticatorforFLatdiagnosis.Cytologicgradeisnotprognosticinmanystudies,butFLgrade3B(comprisedalmostentirelyoflargecentroblasts)sharesbiologicfeaturesmoreakintodiffuselargeB-celllymphoma[],andarecentlargeretrospectivereviewfoundthatFLgrade3Bhasahighermortalityandadistinctlydifferentclinicalcourse(moreaggressive,butcurable)incomparisonwithgrades12and3a[].StudiesusingarraycomparativegenomichybridizationtodetectDNAcopynumberalterationsorusinggeneexpressionprolingrevealinglesionsofCKND2A,orincreasedexpressionlevels,haveapproximatedriskoftrans-formation.However,thisisnotroutinelydone,andriskisnotconsistentlypre-dictableforallsamples,precludingitsclinicalutility[].Atpresent,thereisnoprospectivelyvalidatedclinicaltoolwithwhichtousegeneexpressionproinFLtoevaluatethemicroenvironmentforpredictionofprognosis.High-throughputsequencingisanavenuethatwilllikelybeutilizedasapartofroutinediagnosticsinthenearfuture,nowthatitisfeasibleonformalin-xedparafembeddedtissues.Uncoveringtheclonalarchitectureofneoplasmscanhelpto 32S.L.OndrejkaandE.D.Hsi identifytherapeutictargetsbyhelpingtofocusonwhatmutationsmightbesub-clonal(andlesseffectiveforatargetedtherapy)asopposedtoafounder,driver,oracceleratormutation[].Theseshedlightonnewtargetsfortherapiessuchasdemethylatingagents,histone-orchromatin-modifyingtherapies,andsmall-mol-eculeinhibitorsbutalsomightbepowerfultopredictwhetherapatientsindividualtumormightberesponsivetothesetherapiesbasedonitsstageofclonalevolution.4LymphoplasmacyticLymphomaLymphoplasmacyticlymphoma(LPL)isasmallB-cellneoplasmofolderadultsthatusuallyaffectsthebonemarrow,andlessofteninvolvesspleenorlymphnodesnodes101].ItischaracteristicallyaccompaniedbyaserumIgMmonoclonalparaprotein.Clinically,itisassociatedwithhyperviscosityandWaldenstrmmacroglobuline-mia(WM),denedasbonemarrowinvolvementwithmonoclonalBcellsofLPLtypeandserumIgMparaproteinemiaatanylevel[].Whilethepathologicfea-turescanbedistinctive,itsharesfeatureswithothertypesofsmallB-celllym-phomas,andgeneticabnormalitiessuchasdeletionof6qoccurringmostcommonlyinLPLareneithersensitivenorspecicinassistingthediagnosis[Recently,whole-genomesequencingidentiedarecurrentsomaticmutationinthemyeloiddifferentiationresponsegene88(MYD88L265P)presentinapproxi-mately91%ofpatientswithWM,whichisabsentinmultiplemyelomaandrarelypresentinsplenicmarginalzonelymphoma(approximately6%)[].ThemutationitselfwasinitiallydiscoveredinDLBCL(29%ofactivatedB-cell-likeDLBCLvs.1.4%germinalcenter-like,and9%ofgastricMALTlymphomas),whereitwasshowntopromotecellsurvivalviaanIRAKkinaseproteincomplexleadingtoJAK-STAT3activation,NF-KBsignaling,andinterleukin/interferonsecretion[].ItisprevalentamongothertypesofaggressiveB-celllymphomaswithanactivatedB-cell-likeimmunophenotype,suchasprimarycentralnervoussystemlymphoma[]andprimarycutaneousDLBCL,legtype[MYD88L265PisnotentirelyspecicforLPLinsmallB-celllymphomas.Itcanbeidentiedusinghigh-sensitivityallele-specicPCRinasmallpercentageofsplenicmarginalzonelymphomaandaverysmallminorityofchroniclymphocyticleukemia,aswellasonereportedcaseofhairycellleukemia.[].Itisalsopresentin5087%ofIgMMGUS[].AsidefromitsuseindiagnosisofLPL/WM,recurrentsomaticmutationsinWMsuchasand,toalesserdegree,inthemorerecentlydiscoveredchemokinereceptor(27%)maydetermineclinicalpresentation,progression,and/oroverallsurvival.ForpatientswithIgMMGUS,presenceofMYD88L265Pwasassociatedwithgreaterdiseaseburdenandanincreasedriskofdiseaseprogression,suchthatitmightprovetobeausefulbiomarkerinevaluationofthisdisease[].TheBrutontyrosinekinase(BTK)inhibitoribrutinibwasshowntoinhibitMYD88-BTKcomplexesandthussupportlymphoplasmacyticcellsurvivalinpatientswithWM[].PresenceoftheCXCR4mutationwasshowntobeassociatedwithresistancetoibrutinibby PathologyofB-CellLymphomas:Diagnosis mediatingsignalingpathwaysresistanttogrowthsuppressioninthepresenceofCXCR4ligand[].Nonetheless,inaphaseIstudy,ibrutinibtherapyshowedpromisingresultsinpatientswithWM[].DetectionofMYD88L265PintheperipheralbloodofpatientswithWMandIgMMGUSbyquantitativeallele-cPCRisanareaofrecentinterest,asthedeltaCtmightpredictdiseaseburdeninthebonemarrowandmightobviatetheneedforbonemarrowaspiration/biopsy-basedmonitoringofpatientswithWM/IgMMGUS[].Itmayalsohaveutilityinminimalresidualdisease(MRD)assessment.Thus,MYD88L265Phasprovenitsutilitynotonlyasadiagnosticmarker,butasabiomarkerfordiseaseburdenand/orprogression,anditisafairlysimpleassaytoimplementinaclinicallaboratorysetting.5MantleCellLymphomaMantlecelllymphomarepresents28%ofnon-HodgkinlymphomasintheUnitedStates.Itpresentsintheseventhdecade(medianage63years)andischaracterizedbyawidespreadnodalpresentation(AnnArborstageIII/IV)accompaniedbyBsymptoms,withahighfrequencyofWaldeyerstonsillarringinvolvement,andoftenwithsplenicinvolvement.Somepatientshavegastrointestinalmanifestationsintheformofmultipleintestinallymphomatouspolyposis.Stagingbonemarrowexaminationsarefrequentlypositive,andoccasionally,circulatinglymphomacellsareidentiablebymorphologyandowcytometricanalysis[].Themediansurvivalhasincreasedoverthepast30yearsandisnowestimatedtobe45years.MCListypiedbyahighresponsetofrontlinetherapieswithdevelopmentofchemoresistanceatthetimeofrelapse[Varioushistopathologicgrowthpatternsoflymphnodeinvolvementincludemantlezone,nodular,anddiffuse,inadditiontoarelativelyrecentlydescribed,extremelyrareinsitupatternoflocalization[];Weisenburgeretal.[Theneoplasticcellsaremonomorphoussmalllymphocyteswithnuclearirregu-laritiesandscantcytoplasm,withadistinctiveB-cellimmunophenotype(CD19+,CD20+,sIg+,CD5+,CD10,CD23orsubset+,IgMIgD,cyclinD1+).Lesscommonly,blastoidorpleomorphicvariantswithlymphoblast-likeorcentroblast-likecytologicfeaturesandnumerousmitosescanoccur,eitherdenovoorashistologicprogressionofusualmantlecelllymphoma[].MCLswithahigherproliferativeindexasestimatedbyKi-67immunohistochemistryorbymitoticindexhaveaworseoverallsurvival,regardlessofthecytologicvariant[Thegenetichallmarkofmantlecelllymphomaist(11;14)(q13;q32).Asaresultofthistranslocation,thecyclinD1gene(CCND1)onchromosomalregion11q13istranslocatedintothelocus,whereitcomesunderregulatorycontroloftheenhancersequences,resultinginoverexpressionofcyclinD1protein[Thisleadstoconstitutivecellcycledysregulation,whichtogetherwithsecondaryalterationsinDNAdamageresponseandwithactivationofcellsurvivalsignalsunderliesthepathogenesisofMCL.Lessoften,otherpartnerlocisuchaseitherof 34S.L.OndrejkaandE.D.Hsi theimmunoglobulinlight-chaingenes(,2p11;,22q11)arejoinedtoCCND1151].Whileanin-depthdiscussionofcyclinD1-negativemantlecelllymphomaisbeyondthescopeofthischapter,itisanincreasinglystudiedvariantthatcanberecognizedbytypicalmorphologicandphenotypicfeaturesofMCLandasharedglobalgenomicprole,withtheexceptionofcyclinD1[].ArecentstudyfoundthatinoverhalfofthecyclinD1-negativeMCLvariants,aCCND2rearrangementwasdetectedpredominantlyinvolvingoneoftheIglight-chaingenes.Still,themolecularmechanismforcyclinD1-negativemantlecelllymphomasisonlypar-tiallyrevealed.TheclinicalandbiologicbehaviorofthecyclinD1-negativemantlecelllymphomaswassimilartothatofconventionalMCL,indicatingthatCCND2rearrangementcanbeabiomarkerthatindicatesaneedforintensivechemotherapyy88].InadditiontocyclinD1translocation,therearenumeroussecondarygeneticalterationsinmantlecelllymphomathatcontributetoitspathogenesisincludingdeletionofthe9p21locus(therebyandaffectingcellcyclecontrolviaINK4a/CDK4/RB1),pointmutationordeletionof,othergenecation,ordeletioncontributingtogenomicinstability[].Finally,somaticmutationaldatageneratedbywhole-genomeorexomesequencingtech-nologieshaveidentiedsignicantlymutatedgenesinMCLincludingknowndriversofpathogenesisandothersthatplayaroleinanti-apoptosisorchromatinNOTCH2mutationswerediscoveredandcorrelatedwithapoorprognosis.Additionalstudiesareneededtofurtherunderstandmutationalprolesinthesettingofdiseaseprogressionandsignicanceforbiologictherapies[TheMantleCellLymphomaInternationalPrognosticIndex(MIPI)canaccu-ratelystratifypatientsintolow-,intermediate-,andhigh-riskgroups.AssessmentofthetumorcellproliferativeindexbyKi67yieldedvaluableprognosticinformationindependentoftheMIPI,butcombinedwiththeprognosticindex,acanserveasaprognosticguideforrisk-adaptedtherapy[].Sofar,TP53appearstobetheonlysignicantindependentmolecularmarkertoaddadditionalprognosticvaluetotheMIPIinmultivariateanalysis[Whilemantlecelllymphomaistypiedbyoverallshortsurvivalandrelativelyaggressivediseasecourse,itisnowrecognizedthatanindolentformofmantlecelllymphomaexists.Itcanbeidentiedclinicallyasasubgroupofpatientswithnon-nodaldiseasewhomaypresentwithsplenomegalyandleukemicinvolvement.ThishasbeenassociatedwithmutatedIGVHgenesandlackofCD38expression[Thesepatientshavebeenshowntohaveafavorableprognosiswithamediansurvivalof79monthscomparedtoagroupofnodal-basedlymphomawithmedianOSof30months[].Indeed,patientswithwhatcouldbeconsideredamonoclonalB-celllymphocytosiswitht(11;14)havebeenidentied[].Furthermore,wenowrealizethatpatientsdonotneedtobetreatedatdiagnosisandmaydowellwithawaitandwatchstrategy[].Severalindependentstudieshaveidentirecurrentbiologicandclinicalfeaturesthatmayidentifythisindolentsubtype,includingnon-nodalleukemicpresentation,hypermutatedimmunoglobulinheavy-chainvariablegenes(IGVH,indicatingderivationfrompost-GCBs),simplekaryotype,andstablediseasewithlongersurvival[].Thesefeatureswerereinforcedbygeneexpressionprolinginastudythatidentiedamolecular PathologyofB-CellLymphomas:Diagnosis signatureof13genesthatwashighlyexpressedinconventionalmantlecelllym-phomaascomparedtoindolentMCL.Withinthegeneset,thetranscriptionfactorSOX11wasparticularlyoverexpressedinconventionalmantlecelllymphomaandrmedbyproteinexpression[].Aseparateoutcomes-basedstudydividedpatientsintogroupsbasedondegreeofIGHVmutationsfromgermline.Therewasasignicantdifferenceinoverallsurvivalbetweenthosewithhighandlowmutationalload.Thehighlymutatedcaseshadabettersurvival,werepreferentiallySOX11negative,hadlowergenomiccomplexity,andweremoreoftennon-nodalindiseasedistribution[].Furthermore,studiesofpatientswithamonoclonalB-lymphocytosis-likepresentationofcyclinD1-positiveMCLweremoreoftenSOX11negativeascomparedwithsymptomatic,nodalcases[WhilemostcohortsofindolentpatientsshowedapredilectionforSOX11negativity,apopulation-basedcohortstudypublishedconictingresultswithashorteroverallsurvivalinSOX11-cases,butthesignicancewaslostonmulti-variateanalysis[].Anotherstudyamongpatientstreatedwithdose-intensive(i.e.,hyper-CVADbased)regimensfoundthathighSOX11expressionwasassociatedwithimprovedsurvival[].Lackofuniformityamongstudiesanddifferenceinselectioncriteriaofindolentpopulationsaddtothedifcultyindrawinganoverallconclusionfromthesedata.SOX11hasbeenrecognizedinthelastseveralyearsasareliablebiomarkerincationofmantlecelllymphomaaswellasthecyclinD1-negativeconven-tionalorblastoidvariants[].Severalnewmonoclonalantibodiesarecommerciallyavailabletoincorporateintoroutinediagnosticpractice[].IthasbeensuggestedthatSOX11byitselfshouldnotbeconsideredtobeaprognosticparameterbutratherusedasabiomarkerthatmayhelptorecognizeeithercyclinD1-negativeMCLorasubtypeofMCLwithdifferentbiologicandclinicalfeatures.Nonetheless,studyofSOX11targetgenesisanactiveareaofinterestanditremainstobedeterminedwhetherSOX11couldbeausefulprognosticmarker.WithabroadrangeoftreatmentoptionsforpatientswithsmallB-celllym-phomas,somepatientsachievealong-lastingremission.However,themajoritysufferarelapsethatmightbeheraldedbyverylowlevelsofresiduallymphomacells.DetectionofMRDhasbeenexpandedfromacutelymphoblasticleukemiatoB-celllymphomas,includingMCL,inanincreasinglyimportanttoolforriskprediction[].Thiscanbeachievedviavariousmodalitiesincludingowcyto-metricanalysis,reportingsensitivitiesofapproximately10108].PCR-basedmethodshavemadegreatstridesinachievingoptimalsensitivity.Real-timequantitativePCRusingallele-specicprimerdesignhasstandardizationguidelinesguidelines108]andahighsensitivity(10),superiortothesensitivityofimmunoglobulinheavy-chainPCRanalysisusingconsensusprimersandovercominginherentlim-itationssuchasongoingsomaticmutation[].Anideal,MCL-specictargetisthet(11;14)translocation,whichcanbehighlysensitive(10)bynestedPCR,butthetranslocationisPCRdetectableinonly2540%ofcases[].Apromisingprospect,SOX11,asaMRDmarkerforMCLwasstudiedusingmRNA-speciquantitativePCR(qPCR)technologyinlongitudinalperipheralbloodsamplesofMCLpatients.TheresearcherswereabletocorrelatequantiablelevelofSOX11 36S.L.OndrejkaandE.D.Hsi expressionwithclinicalstatusandwithleveloft(11;14)byqPCR.Still,patientselectionandvalidationoverlargercohortsofpatientgroupswillberequiredbeforethiscouldbeconsideredforclinicaluse[Insummary,cyclinD1andSOX11remaingoodbiomarkersforthediagnosisofMCL,includingcyclinD1-negativeMCL.TheMIPIisagoodclinicalriskstrat-cationtool,andassessmentofproliferationandTP53provideaddedprognosticinformation.Furtherworkondeningadditionalusefulprognosticbiomarkerswillrequirevalidationinuniformlytreatedpatientpopulations.6DiffuseLargeB-CellLymphoma,NotOtherwiseThissectioncoversdiffuselargeB-celllymphoma(DLBCL),whichrepresentsthemostcommontypeofnon-Hodgkinlymphoma(3040%ofadultnon-Hodgkinlymphomas)andcanarisedenovoorfromtransformationofapreexistinglow-gradelymphoma.PatientsusuallypresentwitharapidlyenlargingmassthatisFDGavidonpositronemissiontomographyimaging.Occurrenceatlymphnodesitesismostcommon,butitcanariseinvirtuallyanylocationinthebodyandiscommonatextranodalsitessuchasthegastrointestinaltractorskin.Patientsaremostoftentreatedwithanthracyclin-containingmultiple-agentchemotherapyregimensthatincluderituximab,andthereisanapproximately55%5-yearsurvival[],butthereismuchvariabilityinthatpercentagedependingonotherprognosticfactors.TheInternationalPrognosticIndex(IPI)isavaluabletoolthatcanseparatepatientsindistinctprognosticriskgroups[],andithasbeenrevisedandvalidatedintherituximabera[Fromamorphologicstandpoint,therecognizedvariantsofDLBCL,notother-wisespecied(NOS),includecentroblastic,immunoblastic,andanaplastic.Rarervariantsalsoexistandareimportantforrecognitionbythepathologist.Theim-munoblasticvariant(beingcomposedofatleast90%immunoblasts)hasbeenassociatedwithpoorerevent-freeandoverallsurvival[].OtherspecialcategoriesoflargeB-celllymphoma(withoutplasmablasticfeatures)thatarebeyondthescopeofthisdiscussionincludeTcell/histiocyte-richlargeB-celllymphoma,pri-maryDLBCLofthecentralnervoussystem,primarycutaneousDLBCL,legtype,EBV-positiveDLBCLoftheelderly,DLBCLassociatedwithchronicintion,lymphomatoidgranulomatosis,andintravascularlargeB-celllymphoma,alongwithothercategoriesoflargeB-celllymphomainassociationwithimmunodeTobetterunderstandtheheterogeneityofthislymphoma,geneexpressionlinghasidenticell-of-originmolecularsubgroupsofDLBCLthataresimilartotheprolesofdifferentnormalB-cellcounterparts.OnesubgroupretainedthegeneexpressionprogramoftheGCBandwasthustermedGCBlike,whiletheothergroupexpressedgenesthatwereinducedduringactivationofperipheralbloodBcells(activatedBcelllike,ABC)[].Asidefromproviding PathologyofB-CellLymphomas:Diagnosis insightintoadditionalmolecularalterationsandactivatedpathwayswithinthesubgroups,distinctdifferencesinoverallsurvivalbetweenpatientswithGCBversusABCsubgroupswereobserved.TheABCtypewasshowntohaveaninferioroutcomecomparedwiththeGCBtype,evenintherituximabera.Thesubgroupoccursinanolderproportionofpatients�(70years)andhasbiologiccanceforsustainedactivationoftheNF-Bpathway[].Sincethen,sub-sequentstudieshavevalidatedthisclassicationapproachwithlargenumbersofpatientsandhaveselectedsmallergenesetstoidentifygroups[].Tomoreeasilyidentifyamolecularsubtype,immunohistochemicalstainingalgorithmsweredevelopedbasedontheresultsofgeneexpressionproling[].Whenperformedinqualiedlaboratories,thesealgorithmscanshowverygoodconcor-dancewiththeGEPclassier[].TheCOOconceptasaprognosticbiomarkerisrelevantwithmodernimmunochemotherapy[].However,inaddition,itmaygainaddedrelevanceasapredictivemarker.GiventhattheABC-likeDLBCLsdemonstratemutationsthatactivatetheB-cellreceptorsignalingpathwayandultimatelyNFkB,developmentoftargetedtherapieswithpreferentialactivityintheABCsubtypemaycallforknowledgeofCOOsubtypeinordertoassistintherapyselection.Preliminarydatasupportthisapproach,andtrialsareunderwayandintheplanningphasesthatrequireCOOdeterminationaspartofeligibilityrequirements[Recentattentionhasbeendrawntotheimportanceoftranslocationsinvolving,and.ApartfromidentifyingsomecasesofB-celllymphoma,unclassiable,withfeaturesintermediatebetweenDLBCLandBurkittlymphoma(BL,seebelow),thesetranslocationsmayhaveprognosticsignicanceinDLBCL,NOS.ThemostfrequentgeneticndinginDLBCL,NOS,isarearrangementof(3q27,3040%),whichoccursmoreoftenintheABCsubgroup,whereastranslocationsareusuallyassociatedwithGCBDLBCL.Inpar-MYCtranslocationsoccurinapproximately10%ofDLBCLandportendadismalprognosis,eitherasasinglegeneticinsultorasadditionalhitsinvolvingdouble-hitlymphomas),ortherarerearrangedlymphomas[].ThisincludescaseswithIGH@BCL2(14;18)(q32;q21)plusextrasignalsoramplication,aswellascaseswithrearrangementswithextracopies[].However,thereisstillcontro-versyastowhetherrearrangementsinDLBCLaretrulyanindependentpredictorofprognosis.Studiesofriskstraticationinpatientstreatedwithritux-CHOPfoundcontranslocationaspredictiveofprogression-freesurvivalandoverallsurvivalonmultivariateanalysis[]andalsoshowedasig-cantassociationwithtreatmentresistance[].Similarly,aSouthwestOncologyGroupStudyofhigh-grademorphologicfeaturesandMYCproteinexpressionbyimmunohistochemistry[]foundMYCtobeapoorprognosticfactoronmultivariateanalysisandindependentofmorphology,highlightingtheimportanceofstainingforthisproteininroutineclinicalpractice.However,otherstudieshavequestionedtheprognosticpowerofMYCasasingleabnormality.InonestudyexaminingBCL2andMYCproteinexpression,theprognosticimpactofwasduetotheconfoundingeffectofBCL2/MYCdouble-protein-positive 38S.L.OndrejkaandE.D.Hsi cases,andpositivityalonedidnotimpactoverallsurvival[].Anotherstudyshowedthatisolatedrearrangementshaveweakerprognosticrelevancethantranslocations[].Inanattempttoclarifythisissue,arecentsystematicreviewandmeta-analysisthatincluded24enrollingclinicaltrialscon-rmedtheprognosticrelevanceofisolatedaberrations(includingamplitions)intermsofbothproteinandmRNAexpression;however,interpretationofthedataischallengedbytheheterogeneityoftheincludedstudies[Morerecently,itwasfoundthatMYCandBCL2proteincoexpressionpredictssurvivalinpatientswithDLBCLthataretreatedwithrituximab(R)CHOPche-motherapy(cyclophosphamide,doxorubicin,vincristine,andprednisone).WhilehighMYCproteinexpressionbyIHCisoften(butnotinvariably)associatedwithatranslocation(andthusanadverserisk),thenegativeimpactofMYCproteinexpressiononprogression-freeandoverallsurvivalwasshownonlywhenBCL2proteinwascoexpressed.Thiswassignicantevenafteradjustingforhigh-riskfeaturesintheIPIscore[].Thepracticaluseofanimmunohistochemicaldouble-hitscorewasdemonstratedinastudythatvalidatedshorteroverallandprogression-freesurvivalinpatientswithhighBCL2/MYCproteincoexpressionindependentofothervariablesandwasabletoidentifypatientswithhigh-riskdouble-hitbiologyfromwithinanindependentcohortofDLBCL[].WhenexaminingthesebiomarkersinDLBCLpatientsaccordingtothecelloforigin,thelevelofpositiveproteinexpressionwasastrongindependentpredictorofoverallsurvivalinpatientswithGCB,butnotthenon-GCBsubtypeDLBCL,withhighBCL2�(30%)andMYC�(50%)coexpressioncorrelatingwiththeworstoutcomeutcome75].Becauseofitswideavailability,assessmentofBCL2andMYCexpressionbyimmunohistochemistryisbecomingaroutinepartofthepathologyreporttoprovideadditionalprognosticinformationtoclinicians.7PrimaryMediastinalLargeB-CellLymphomaPrimarymediastinallargeB-celllymphoma(PMBL)ariseswithinthemediastinumfromBcellsofprobablethymicorigin.Patientsareyoungadultswithamedianageof35andafemalepredominance.Theymaypresentwithabulkyanterosuperiormediastinalmassthatcansecondarilyinvadenearbyorganssuchaslungsordirectlyextendtolocallymphnodes,butitrarelydisseminates.Itisimportanttoexcludeprimarylymphnodeinvolvementatothersites,aswellasbonemarrowinvolvement,toavoidmisdiagnosisofasystemicDLBCLthatmightsecondarilyinvolvethemediastinum[Themicroscopicfeaturesofthislymphomatypevaryfromcasebutcantaketheformofadiffuseproliferationofintermediatetolargecellswithamoderateamountofclearcytoplasmandeitherovoidorsometimesslightlymorepleomorphicnuclei.Compartmentalizingalveolarsclerosisisaprominentfeatureinmanycases.ThephenotypeincludesmostB-cellantigensincludingIRF4/MUM1,positiveforCD23,withlowtoabsentimmunoglobulinandCD10expression,sometimes PathologyofB-CellLymphomas:Diagnosis heterogeneous/weakCD30expression,andMALantigen.Frequentkaryotypicabnormalitiesincludechromosomalaberrationsfor2p16.1,9p24.1,and8q24[AlargestudyofB-celllymphomasdemonstratedrearrangementoftheMHCclassIItransactivator(16p13.13)inPMBL(29/77,38%)[].Theimplicationofsuchanaberrationmightbethatthetumorcanthenescapefromimmunesur-veillancebydownregulationofHLAclassIIassociatedproteins,amongothermechanisms.Anassociationwasfoundbetweengenefusions,andreducedHLA-DRproteinexpressionwasdemonstrated[].AdditionalresearchisneededtoidentifybiomarkersforprognosisinPMBL,thoughonerecentstudyfoundMUM1proteinexpressiontocorrelateindependentlywithadecreasedoverallsurvival[ItrecognizedthatsomelymphomashavecombinedfeaturesofbothclassicalHodgkinlymphomaandDLBCL,particularlynodularsclerosisclassicalHodgkinlymphomaandPMBL[].Furthermore,somepatientswerereportedtodeveloplargeB-celllymphomaaftertreatmentforHodgkinlymphoma,whileothersreportedcompositeHodgkin/largeB-celllymphoma,andthusthedesignationmediastinalgray-zonelymphomaphoma32,119].WhilePMBLlackstrulydistinctivemorphologicfeaturesthatmightotherwisedistinguishitfromconventionalDLBCL,identicationofgeneexpressionsignatureuniquetothisentitywaspivotalinthemolecularclassicationoflargeB-celllymphoma.Infact,whengeneexpressionprolingwasusedtoestablishamoreprecisemoleculardiagnosisofPMBL,itemergedasanentitythatprimarilyaffectedyoungerpatientsandiden-edasubgroupwithabetterprognosiscomparedtootherDLBCLs.Genepro-lingsupportedthesuspectedrelationshipbetweenPMBLandHodgkinlymphomainthatoverone-thirdofthegenesthatwerepartofthePMBLsignaturewerecharacteristicofHodgkinlymphomacells[].Furthermore,theepigeneticproofPMBLwasfoundtobedistinctandseparatefromDLBCL,andanalysisofmethylationpatternssupportedanintermediatepositionbetweenDLBCLandclassicalHodgkinlymphoma[8BurkittLymphomaBLisahighlyaggressivematureB-cellneoplasmthatmakesup40%ofnon-Hodgkinlymphomasinyouthunderage20.Itpresentsasarapidlyenlargingmass,commonlyinvolvingextranodalsites,andexistsinthreedifferentclinicalvariants.TheendemicformpredominantlyaffectsyoungchildreninequatorialAfricaandisusuallyassociatedwithEpstein-Barrviralinfection,andthetumorsareoftenlocalizedtothejaworfacialbones,kidneys,orabdominalregion.ThesporadictypeoccursinabroadgeographicdistributionthatincludesNorthAmericaandEuropeancountries,andoftenaffectstheabdomenorterminalileumofimmuno-competentchildren.Thethirdtypeisimmunodeciencyrelated,anditisknownforitsassociationwithHIV.Rarely,aleukemicphaseexists,eitherinpatientswith 40S.L.OndrejkaandE.D.Hsi bulkydiseaseorveryuncommonlyasadenovoperipheralblood/bonemarrowleukemiaphenomenon[Theneoplasticinltrateiscomposedofintermediatelysized,monotonousBcellswithnumerousmitosesandtingiblebodymacrophagesimpartingaappearance.BLcellsresemblegerminalcentercentroblastsbycytomorpho-logicgroundsandexpresspanB-cellantigensandsurfaceimmunoglobulin,plusCD10andBCL6.BCL2ischaracteristicallynegativeoronlyweaklypositive[Thevastmajorityofcaseshaveadetectabletranslocation(8q24)totheimmunoglobulinheavy-chainregion(14q32),ortothekappalight-chaingene(2p11)orlambda-chaingene(22q11).Insomecases,aMYCcannotbedemon-stratedbyFISH,butinthesecases,differencesinthebreakpointorsubde-tectableinsertions/deletionsinthegenemayeludedetection.Thus,anegativetestresultdoesnotexcludethediagnosis.Similarly,itisimportanttorememberthatothertypesoflymphomascanharborarearrangement,suchasDLBCLdiscussedpreviously,aswellasmantlecelllymphomaandFLcanacquireatranslocationasittransformstoamoreaggressivetumor[GeneexpressionprolinghasrevealedadistinctmolecularphenotypeforBLBL17]andthatBLcanbeidentiedwithcertaintyonthebasisofanumberofMYCtargetgenes,involvedingerminalcenterdifferentiation,NF-KBactivation,andMHCclassImolecules[].ThegeneticmakeupofBLwasfurtherelucidatedbyusingdeepsequencingtechnologieswhichidentiasanimportanttumorsuppressorgeneinBLthatappearstoserveasanegativeregulatorofof80,90].9B-CellLymphoma,Unclassifiable,withFeaturesIntermediateBetweenDiffuseLargeB-CellLymphomaandBurkittLymphomaTheWHO2008categoryofB-celllymphoma,unclassiable,incorporatescaseswithmorphologic,immunophenotypicandgeneticfeaturesthatareintermediatebetweenDLBCLandBL(WHO2008classication).Theexistenceofthiscategoryissupportedbygeneexpressionandkaryotypic/genomicproling,whichcanidentifyamolecularBurkittsignature[].Classicationofthesecasesatthepracticelevelisproblematic,sincethetoolsusedtodenethemarenotreadilyavailableinclinicallaboratories.Thesetypesofcasewerelikelyincludedinformerdesignationssuchassmallnon-cleaved,non-Burkitt(WorkingFormulation),atypicalBurkittlymphoma,high-gradeB-celllymphoma,Burkitt-like(RevisedEuropeanandAmericanLymphomaClassication)orwerelooselyreferredtoasDLBCLwithhigh-gradefeatures,gray-zonelymphoma,diffuseaggressiveB-celllymphoma.Geneticallydedouble-hitmasareincludedinthiscategoryofB-celllymphoma,unclassiable(BCL-U)[ThesecanberecognizedwithcurrentlyavailableclinicallaboratorytestssuchasFISHtesting.Thus,assessmentofMYC,BCL2,andtranslocationshouldbeperformedinalldiffuseaggressiveB-celllymphomassuspectedofbeingadouble- PathologyofB-CellLymphomas:Diagnosis hitlymphoma.OnepracticalwaytoscreenistoperformMYCIHCgivenitsabilitytopredictpresenceofMYCtranslocationandtoperformFISHconrmation(forallthreetargets)incaseswithhighnuclearMYC�(4050%)expression.Thisstillleavesadifcultgroupofcasesthatbelongtothiscategoryforwhichwecannotyetdenitivelyrecognizebycurrentlaboratorytests.Thecategoryshouldthenbeusedonlyforcasesinwhichtheclinical,morphologic,phenotypic,and/orgeneticevidencecauseatrulyinscrutablediagnosticconundrumbetweenDLBCLandBL[].Anexamplemaybecaseswithmorphologicfeaturessug-gestivebutinsufcientforBLinwhichaBL-like(CD10+/BCL2weak-negative)phenotypeisseen,inthesettingofademonstratedimmunoglobulingene/MYCtranslocationwithcomplexkaryotype.10Next-GenerationSequencingforMinimalResidualDiseaseMonitoringandMutationDetectionManyadvanceshavebeenmadeinthetreatmentofB-celllymphoma,andaneedexistsforpost-treatmentassessmentandmonitoringoftreatedpatientsasameanstoidentifyanearlyrelapseorpredictthepotentialforrelapse.MRDcanbedetectedbycytogenetics,owcytometry,orPCR-basedmethods.PCR-basedMRDdetectionbydetectionofimmunoglobulinheavy-chainand/orT-cellreceptorgenerearrangementsusingtumor-specicprimershaspotentialtobeasensitivemeansofassessment[].Next-generationsequencingwasshowntobeafeasibletoolinMRDdetectioninMCL,withcomparableresultstoreal-timequantitativePCRPCR53].IdenticationofanidealMRDmarker/targetisofutmostimportanceinestablishingausefulassay,anddifcultiesmightariseduetoongoingsomatichypermutationorclonalevolution.Certainly,next-generationsequencingonrou-tinepatientsampleswillbefeasibleinthenextseveralyears,anditmayprovidevaluablediagnosticinformationandprognosticinformationandhelpguideindi-vidualizedtherapiesbyidentifyingbiologicpathwaysthatcanbetargetedwithnewtherapies.Thechallengewillbetorenethemforuseinroutinelyprocessedtissuesandapplythesetechniquestohighlyannotatedclinicaldatasetsinordertobegintorationallyusethiscomplexdataforprognosisandprediction.1.AdamP,SchieferAI,PrillS,HenoppT,Quintanilla-MartinezL,BosmullerHC,ChottA,FendF(2012)Incidenceofpreclinicalmanifestationsofmantlecelllymphomaandmantlecelllymphomainsituinreactivelymphoidtissues.ModPathol25(12):16292.AdvaniRH,BuggyJJ,SharmanJP,SmithSM,BoydTE,GrantB,KolibabaKS,FurmanRR,RodriguezS,ChangBYetal(2013)Brutontyrosinekinaseinhibitoribrutinib(PCI-32765)hassignicantactivityinpatientswithrelapsed/refractoryB-cellmalignancies.JClinOncol31(1):88 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3.AlizadehAA,EisenMB,DavisRE,MaC,LossosIS,RosenwaldA,BoldrickJC,SabetH,TranT,YuXetal(2000)DistincttypesofdiffuselargeB-celllymphomaidentiedbygeneexpressionproling.Nature403(6769):5034.AndersenNS,DonovanJW,BorusJS,PoorCM,NeubergD,AsterJC,NadlerLM,FreedmanAS,GribbenJG(1997)Failureofimmunologicpurginginmantlecelllymphomaassessedbypolymerasechainreactiondetectionofminimalresidualdisease.Blood905.BarransS,CrouchS,SmithA,TurnerK,OwenR,PatmoreR,RomanE,JackA(2010)RearrangementofMYCisassociatedwithpoorprognosisinpatientswithdiffuselargeB-celllymphomatreatedintheeraofrituximab.JClinOncol28(20):33606.BeaS,Valdes-MasR,NavarroA,SalaverriaI,Martin-GarciaD,JaresP,GineE,PinyolM,RoyoC,NadeuFetal(2013)Landscapeofsomaticmutationsandclonalevolutioninmantlecelllymphoma.ProcNatlAcadSciUSA110(45):182507.BerndHW,ZiepertM,ThornsC,KlapperW,WackerHH,HummelM,SteinH,HansmannML,OttG,RosenwaldAetal(2009)LossofHLA-DRexpressionandimmunoblasticmorphologypredictadverseoutcomeindiffuselargeB-celllymphomaanalysesofcasesfromtwoprospectiverandomizedclinicaltrials.Haematologica94(11):15698.BottcherS,RitgenM,BuskeS,GeskS,KlapperW,HosterE,HiddemannW,UnterhaltM,DreylingM,SiebertRetal(2008)Minimalresidualdiseasedetectioninmantlecelllymphoma:Methodsandsignicanceoffour-colorowcytometrycomparedtoconsensusIGH-polymerasechainreactionatinitialstagingandforfollow-upexaminations.Haematologica93(4):5519.BraggioE,DoganA,KeatsJJ,ChngWJ,HuangG,MatthewsJM,MaurerMJ,LawME,BoslerDS,BarrettMetal(2012)Genomicanalysisofmarginalzoneandlymphoplasmacyticlymphomasidentiedcommonanddisease-specicabnormalities.ModPathol25(5):65110.BruggemannM,DroeseJ,BolzI,LuthP,PottC,vonNeuhoffN,ScheueringU,KnebaM(2000)ImprovedassessmentofminimalresidualdiseaseinBcellmalignanciesusinguorogenicconsensusprobesforreal-timequantitativePCR.Leukemia14(8):141911.CaoY,HunterZR,LiuX,XuL,YangG,ChenJ,PattersonCJ,TsakmaklisN,KananS,RodigS,etal(2014)TheWHIM-likeCXCR4somaticmutationactivatesAKTandERK,andpromotesresistancetoibrutinibandotheragentsusedinthetreatmentofwaldenstrommacroglobulinemia.LeukemiaJun10.[Epubaheadofprint]12.Carvajal-CuencaA,SuaLF,SilvaNM,PittalugaS,RoyoC,SongJY,SargentRL,EspinetB,ClimentF,JacobsSAetal(2012)Insitumantlecelllymphoma:Clinicalimplicationsofanincidentalndingwithindolentclinicalbehavior.Haematologica97(2):27013.ChoiWW,WeisenburgerDD,GreinerTC,PirisMA,BanhamAH,DelabieJ,BrazielRM,GengH,IqbalJ,LenzGetal(2009)AnewimmunostainalgorithmclassiesdiffuselargeB-celllymphomaintomolecularsubtypeswithhighaccuracy.ClinCancerRes1514.CollieAM,NollingJ,DivakarKM,LinJJ,CarverP,DurkinLM,HillBT,SmithMR,RadivoyevitchT,KongLIetal(2014)Molecularsubtypeclassicationofformalin-n-embeddeddiffuselargeB-celllymphomasamplesontheICEPlexsystem.BrJHaematol167(2):28115.CookJR,GoldmanB,TubbsRR,RimszaL,LeblancM,StiffP,FisherR(2014)ClinicalcanceofMYCexpressionand/ormorphologyinnon-Burkitt,diffuseaggressiveB-celllymphomas:ASWOGS9704correlativestudy.AmJSurgPathol3816.DaveSS,WrightG,TanB,RosenwaldA,GascoyneRD,ChanWC,FisherRI,BrazielRM,RimszaLM,GroganTMetal(2004)Predictionofsurvivalinfollicularlymphomabasedonmolecularfeaturesoftumor-inltratingimmunecells.NEnglJMed351(21):2159 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