Follicular lymphoma - Wikipedia

Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled ... Follicularlymphoma FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch MedicalconditionFollicularlymphomaMicrographofafollicularlymphoma,showingthecharacteristicallyabnormallymphoidfolliclesthatgavetheconditionitsname.H&Estain.SpecialtyHematologyandoncology Follicularlymphoma(FL)isacancerthatinvolvescertaintypesofwhitebloodcellsknownaslymphocytes.ThecanceroriginatesfromtheuncontrolleddivisionofspecifictypesofB-cellsknownascentrocytesandcentroblasts.Thesecellsnormallyoccupythefollicles(nodularswirlsofvarioustypesoflymphocytes)inthegerminalcentersoflymphoidtissuessuchaslymphnodes.ThecancerouscellsinFLtypicallyformfollicularorfollicle-likestructures(seeadjacentFigure)inthetissuestheyinvade.Thesestructuresareusuallythedominanthistologicalfeatureofthiscancer.[1] ThereareseveralsynonymousandobsoletetermsforFLsuchasCB/CClymphoma(centroblasticandcentrocyticlymphoma),nodularlymphoma,[2]Brill-SymmersDisease,andthesubtypedesignation,follicularlarge-celllymphoma.[3]IntheUSandEurope,thisdiseaseisthesecondmostcommonformofnon-Hodgkin'slymphomas,exceededonlybydiffuselargeB-celllymphoma.[4]FLaccountsfor10-20%ofnon-Hodgkin'slymphomaswith~15,000newcasesofitbeingnewlydiagnosedeachyearintheUSandEurope.[5]RecentstudiesindicatethatFLissimilarlyprevalentinJapan.[6] FLisabroadandextremelycomplexclinicalentitywithawiderangeofmanifestations[7]whichhavenotyetbeenfullysystematized.[8]Itiscommonlyprecededbyabenignprecancerousdisorderinwhichabnormalcentrocytesand/orcentroblastsaccumulateinlymphoidtissue.Theymaythencirculateinthebloodtocauseanasymptomaticconditiontermedinsitulymphoidneoplasiaofthefollicularlymphomatype(i.e.ISFL).AsmallpercentageofthesecasesprogresstoFL.[9]Mostcommonly,however,FLpresentsasaswellingoflymphnodesintheneck,armpits,and/orgroin.Lessoften,itpresentsasagastrointestinaltractcancer,acancerinchildreninvolvinglymphoidtissuesoftheheadandneckarea(e.g.tonsils),[10]oroneormoremassesinnon-lymphoidtissuessuchasthetestes.[11] FLtypicallyhasaslowdiseasecoursewhichpersistsessentiallyunchangedforyears.[7]However,eachyear2-3%[12]ofFLcasesprogresstoahighlyaggressiveformoftentermedstage3BFL,toanaggressivediffuselargeB-celllymphoma,ortoanothertypeofaggressiveB-cellcancer.Thesetransformedfollicularlymphomas(t-FL)areessentiallyincurable.[5]However,recentadvancementsinthetreatmentoft-FL(e.g.theadditiontostandardchemotherapyofagentssuchasrituximab)haveimprovedoverallsurvivaltimes.ThesenewerregimensmayalsodelaythetransformationofFLtot-FL.[5]AdditionaladvancesinunderstandingFLmayleadtofurtherimprovementsintreatingthedisease.[12][13] Contents 1Pathophysiology 1.1Genomicalterations 1.1.1Insitufollicularlymphoma 1.1.2Follicularlymphoma 1.1.3Transformedfollicularlymphoma 1.2Tumorenvironment 2Presentationandcourse 2.1Insitufollicularlymphoma 2.2Follicularlymphoma 2.2.1Duodenal-typefollicularlymphoma 2.2.2Primarygastrointestinaltractfollicularlymphoma 2.2.3Predominantlydiffusefollicularlymphomawith1p36deletion 2.2.4Pediatric-typefollicularlymphoma 2.2.5Primaryfollicularlymphomaofthetestis 2.3Transformedfollicularlymphoma 3Diagnosis 3.1Differentialdiagnosis 4Treatmentandprognosis 4.1Insitufollicularlymphoma 4.2Localizedfollicularlymphoma 4.3Asymptomaticfollicularlymphoma 4.4Symptomaticfollicularlymphoma 4.5Transformedfollicularlymphoma 4.5.1Prevention 4.6Relapsedfollicularlymphoma 5Seealso 6References 7Externallinks Pathophysiology[edit] Genomicalterations[edit] TheserialprogressionsofinsituFLtoFLandFLtot-FLappeartoinvolvetheaccumulationofincreasingnumbersofgenomicalterations(i.e.chromosomeabnormalitiesandgenemutations)intheformativeB-cellprecursorstothesedisorders.Atleastsomeofthesealterationsappeartocausetheover-expressionorunder-expressionoftheproductsofgenesthatregulatethesecells'susceptibilitytodevelopfurthergenomicalterations,tosurvive,toproliferate,and/ortospreadtoothertissues.Inconsequence,multipleB-cellclonesthatexhibitincreasinggenomicalterationsandmalignantbehaviorspopulatethedisorder.NosinglegenomicalterationseemsresponsibleforthedevelopmentofeachofthespectrumofFLdisorders.Rather,interactionsbetweenmultiplegenomicalterationsappeartounderliethisserialprogression.[5][12] Insitufollicularlymphoma[edit] InsitufollicularlymphomaisanaccumulationofmonoclonalBcells(i.e.cellsdescendentfromasingleancestralcell)inthegerminalcentersoflymphoidtissue.Thesecellscommonlybearapathologicalgenomicabnormality,i.e.atranslocationbetweenposition32onthelong(i.e."q")armofchromosome14andposition21onchromosome18'sqarm.ThistranslocationjuxtaposestheB-celllymphoma2(BCL2)geneonchromosome18atpositionq21.33neartotheimmunoglobulinheavychainlocus(IGH@)onchromosome14atpositionq21.Inconsequence,BCL2overexpressesitsproduct,BCL2apoptosisregulator(i.e.Bcl2).Bcl2functionstoinhibitprogrammedcelldeaththerebyprolongingcellsurvival.[14]TheoverexpressionofBcl2intheB-cellsofISFListhoughttobeacriticalfactorintheirpathologicalaccumulationandsubsequentmalignantprogression.[9]Smallnumbers(e.g.1in100,000)ofcirculatingnucleatedbloodcellsbearingthist(14:18)q32:q21)translocationarefoundin50-67%ofotherwisehealthyindividuals.Theprevalenceofthisfindingincreaseswithageandyearsoftobaccosmoking.SincemostindividualswiththistranslocationintheirbloodcellsdonotdevelopISFL,thet(14:18)(q32:q21)translocation,whileprolongingcellsurvival,mustbejustonestepinthedevelopmentofISFN.ThistranslocationisproposedtooccurduringtheearlydevelopmentofimmaturebonemarrowB-cells(i.e.pre-B-cells/pro-B-cells)afterwhichthesecellscirculatefreelyandinrarecasesaccumulateandmaturetocentrocytesand/orcentroblastsinthegerminalcentersoflymphoidfolliclestoformISFL.Themechanismfavoringthislocalizationandfurtheraccumulationisunclear.[15] IndividualswithISFLprogresstoFLatarateof2-3%/yearforatleastthefirst10yearsfollowingdiagnosis.[12]Thisprogressionlikelyinvolvestheacquisitionofgenomicaberrationsbesidesthet(14:18)q32:q21)translocationintheISFLB-cells.Suspectmutationsincludethoseinthefollowinggenes:1)EZH2(encodespolycombrepressivecomplex2familyproteinwhichisinvolvedinmaintainingthetranscriptionalrepressivestateofvariousgenes[16]andisfoundinupto27%ofFLcases);[9]2)CREBBP(encodesCREB-bindingproteinwhichcontributestotheactivationofvariousgenes[17]);3)TNFSF14(encodestumornecrosisfactorsuperfamilymember14,amemberofthetumornecrosisfactorsuperfamilywhichmayfunctionasaco-stimulatoryfactorfortheactivationoflymphoidcells[1][18]);and4)KMT2D(encodeshistone-lysineN-methyltransferase2D,ahistonemethyltransferasewhichregulatestheexpressionofvariousgenes[19]).[20]ISFLmayalsoacquirenumerouscopy-numbervariations(i.e.duplicationsanddeletionsofaportionofachromosomealongwithanyofthegenescontainedtherein)thatmaycontributetoFL.Inallcases,thenumberofgeneticabnormalitiesacquiredintheB-cellsofISFLaremuchlessthanthoseinFL.[9] Follicularlymphoma[edit] ThegenomicalterationsfoundinFLinclude1)thet(14:18)(q32:q21.3)translocation(85-90%ofcases);2)1p36deletions(i.e.deletionsintheqarmofchromosome1atposition36,[60-70%ofcases])thatleadtoloseofTNFAIP3(encodestumornecrosisfactor,alpha-inducedprotein3whichinhibitstheactivationofNF-κB,blockscelldeathduetoapoptosis,andregulateslymphocyte-basedimmuneresponsesthroughitsubiquitinligaseactivity[21]);3)mutationsinPRDM1(encodesthePRdomainzincfingerproteinwhichpromotesthematurationandproliferationofB-cells);[22]and4)thesamemutationsseeninISFLincludingKMT2D(85-90%ofcases),CREEBP(40-65%ofcases),BCL2(40-65%ofcases),andEZH2(20-30%ofcases)aswellasothermutationssuchasthoseinthehistone-modifyinggeneHIST1H1E(20-30%ofcases),theRRAGCgene(~17%ofcases)whichregulatescellgrowth,survival,death,andproliferation,[23]and,in≤15%ofcasesseveralothergenesincludingMEF2B,STAT6,EP300,ARID1A,SLC22A2,CARD11,FOXO1,GNA12,B2M(i.e.thegeneforbeta-2microglobulin),andSGK1.Exceptforthet(14:18)(q32:q21.3)translocationandEZH2mutationswhichleadtogainsintheexpressionandfunction,respectively,oftheirproducts,thegeneticalterationsgenerallyleadtoalossintheproductionorfunctionofthecitedgenesproducts.However,theexactroles,ifany,ofthesegenomicabnormalitiesinpromotingtheprogressionofISFLtoFLareunclear.[24] Transformedfollicularlymphoma[edit] ThetransformationofFLtoamoreaggressivestateorothertypeofaggressivelymphomaisassociatedwith:1)primarilygene-activatingmutationsinCREEBP,KMT2D,STAT6,CARD11(encodingaguanylatekinasewhichinteractswithBCL10andactivatesNF-κBtoregulatecellsurvival);2)changesintheexpressionofdiversegenes;3)theoverproductionofvariouscell-activatingcytokines[25]andCD79B(encodingtheIg-betaproteincomponentoftheB-cellreceptor[26]);4)gene-inactivatingmutationsinTNFAIP3,CD58(encodingthecelladhesionmolecule,lymphocytefunction-associatedantigen3,thatisinvolvedinactivatingT-cells[27]),CDKN2A(encodingp16INK4aandp14arftumorsuppressorproteins[28])orCDKN2B(encodingcyclindependentkinaseinhibitor2Bmultipletumorsuppressor2[29])(inactivationofeitherCDKN2genecausesgenomeinstability,i.e.increasedfrequencyofothergenemutations),andTNFRSF4(encodingonetypeoftumornecrosisfactorreceptor[30]);and5)gene-activatingor-inactivatingmutationsin,orothercausesfortheunder-orover-expressionof,c-MYC((encodingthec-Mycproto-oncogenetranscriptionfactorthatregulatestheexpressionofdiversegenesmanyofwhichpromotecellproliferation[31]).[24] Tumorenvironment[edit] Thenon-neoplasticimmuneandstromalcellsaswellastheextracellularmatrixintissuesmayenableneoplasticfollicularcellstosurvive,proliferate,andavoidsurveillancebytheimmunesystem.Forexample,laboratorystudiesshowthat:1)folliculardendriticcells,fibroblasticreticularcells,andThelpercellsprovidegrowthandsurvivalsignalstoneoplasticfollicularB-cells;2)neoplasticfollicularB-cellsrecruitregulatoryTcellsthatacttosuppressimmuneresponsestothem;3)thecytotoxicT-cellswhichnormallykillneoplasticcellsbecomedysfunctionalinthepresenceofneoplasticfollicularcellsthatareembeddedinthismulticellularenvironment;and4)bonemarrowstromalcellsdirectlysupportthegrowthofneoplasticfollicularcells.[24]Reducedlevelsofimmune-infiltrationhasbeenshowntobestronglyassociatedwithearlyprogressionofdisease.[32] Presentationandcourse[edit] Insitufollicularlymphoma[edit] FLiscommonlyprecededbybutuncommonlyprogressestoISFL,anasymptomaticdisorderthatusuallyisdiscoveredintissueswhicharebiopsiedforotherreasons.FLlymphomamaybediagnosedintheuncommoncasesinwhichindividualswithISFLarefoundtohaveFLonfollow-upexaminations.[9]Similarly,individualswith>1in10,000circulatinglymphocytescontainingthet(14:18)q32:q21)translocationareatincreasedbutstillsmallriskofdevelopingFLandbeingdiagnosedashavingFLonfollowupexaminations.[10] Follicularlymphoma[edit] FLcommonlypresentsasanotherwiseasymptomaticenlargementoflymphnodesintheneck,armpit,groin,[13]femoralcanal,[33]orothersitesinindividuals(medianage65)withoutaknownhistoryofISFLorabnormalnumbersofcirculatingt(14:18)q32:q21-conatianinglymphocytes.[13]Theseenlargementsmayhavebeenpresentformonthstoyearsandduringthistimewaxedandwanedinsize.[8]Lesscommonly,FLpresentsasextra-nodalmassesintheskin,thyroidgland,salivarygland,breast,testicles.[11]spleen,liver,[33]and/orlung.[4]Regardlessofthetypeofpresentation,FLisusually(~80%ofcases[8])atanadvancedstageatdiagnosisasindicatedbyinvolvementofthebonemarrow(50%[13]to70%[8]ofcases),multiplelymphnodesindifferentpartsofthebody,[9]and/orothertissues.[11]Aminority(<33%)[8]ofFLpatientspresentwithBsymptoms,i.e.recurrentunexplainedfevers,recurrentnightsweats,and/orweightloss≥10%inthepast6months.[5]Generally,thediseasehasanindolentandprolongedcoursewithamedianlifeexpectancyof15–20years:alargepercentageofpatientsdiefromothercausesthantheirFLdisease.[5]However,eachyear,includingtheearlyyearsafterdiagnosis,some2-3%ofFLcasestransformtot-FL;[12]Mediansurvivalhasbeen~4.5yearsaftertheonsetofthistransformation.[5] TherearelesscommonsubtypesofFLthatdiffernotonlyintheirpresentationbutalsointheirhistopathology,geneticabnormalities,andcourse.Thesesubtypes,whicharenow(i.e.primarygastrointestinaltractFL)ormayinthefuture(pediatric-typeFL)beconsidereddistinctivediseases,are: Duodenal-typefollicularlymphoma[edit] Mainarticle:Duodenal-typefollicularlymphoma Duodenal-typefollicularlymphoma(DFL)wasinitiallyconsideredtobeatypeofPrimarygastrointestinaltract(GItract)follicularlymphoma(PGTFL),i.e.afollicularlymphomainwhichGItractlesionswereprominentpartsofthedisease.[34]However,asubsetofPGTFLcaseshadlesionsthatwerelocalizedtotheduodenumandotherpartsofthesmallintestineusuallywithoutinvolvingotherpartsoftheGItractortissuesoutsideoftheGItract.ThiscontrastswiththeothercasesofPGTFLwhichweresystemicdiseasesinvolvingawiderangeofGItractandnon-GItracttissues.Consequently,theWorldHealthOrganization(2017)removedthelocalizeddiseasefromtheprimarygastrointestinaltractfollicularlymphomacategory,reclassifieditasadistinctdiseaseentity,andtermeditduodenal-typefollicularlymphoma.[6]DFLismostoftenanasymptomaticdiseasethatisdiagnosedonendoscopicexaminationoftheGItractconductedforotherreasons.Lesscommonly,itpresentswithvagueabdominalsymptoms.[35][36]Inonereviewofformerstudies,thelesionsin85%ofprimaryduodenalfollicularlymphomawerelocatednotonlyintheduodenumbutalsoothersitesintheintestine(i.e.jejunumand/orileum),[11]withrarecaseshavinglesionsintherectum[37]orcecum[38]PDFisanindolentdiseasethatmayspontaneouslyremitandrelapsebutonlyrarelyprogressestoamoreaggressiveform.Awatch-and-waitstrategyhasbeenagenerallyrecommendedmethodfortheinitialtreatmentofthedisease.[39] Primarygastrointestinaltractfollicularlymphoma[edit] PGTFLisafollicularlymphoma(whichascurrentlydefinedexcludescasesofduodenal-typefollicularlymphoma)thathasaprominentcomponentofGItractinvolvement.Thediseasemaypresentwithsignsandsymptomstypicalofthecommontypeoffollicularlymphoma.Forexample,enlargementoflymphnodesintheneck,armpit,groin,[13]femoralcanal,and/orotherareas,[33]and/orsignsandsymptomsofGItractdisease[34]duetolesionsinthestomach,smallintestine,largeintestine[11]orrectummaybeseen.[37]Thesesignsandsymptomsmayincludeabdominalpain,bowelobstruction,[11]persistentnauseaandvomiting,hematochezia(i.e.passageoffreshbloodusuallyonfecesthroughtherectum),ormelena(i.e.passageoftarryfecescontainingbloodthathasbeendigestedinthestomachorupperintestine).[40]PGTFLisgenerallytreatedlikecasesofcommonfollicularlymphoma:dependingontheseverityofthediseaseanditssymptoms,patientsaretreatedwithwatchfulwaiting,surgery,chemotherapy,radiation,immunotherapyplusradiotherapy,orcombinationsofthesemodalities.[40] Predominantlydiffusefollicularlymphomawith1p36deletion[edit] Predominantlydiffusefollicularlymphomawith1p36deletionisararesubtypeofFL[7]inwhichinvolvedlymphnodesshowinfiltrationsofcentrocytesandcentoblaststhatgenerallydonotformthenodular,swirlingpatternscharacteristicofmosttypesofFL.[1]Inaddition,thesecellslackthet(14:18)(q32:q21.3)translocationcommonlyfoundinotherFLtypesbut,similartomanyFLcases,haveadeletionintheterminalpartoftheshort(i.e."p")armofchromosome1thatencodestheTNFRSF14gene(seepathophysiologysection).[13]Predominantlydiffusefollicularlymphomawith1p36deletionusuallypresentswithbulkyenlargementsofinguinal(i.e.groin)lymphnodesbutmaypresentwithenlargementsoftheaxillary(i.e.armpit)orcervical(i.e.,neck)lymphnodes.Inrarecases,theremaybeinvolvementofthebonemarrow.Inspiteoftheevidenceofbulkyanddisseminateddisease,predominantlydiffusefollicularlymphomawith1p36deletionappearstobeanindolentdisorderthatmayrequirelong-termobservationratherthanovertreatment.[7] Pediatric-typefollicularlymphoma[edit] Mainarticle:Pediatric-typefollicularlymphoma Pediatric-typefollicularlymphoma(PTFL)wasinitiallyreportedtooccurinchildrenages1–17yearsold(medianage~13-14)butmorerecentlyhasbeenreportedtooccurinadults.[41]ThedisorderwasrecentlydefinedbytheWorldHealthOrganization(2016)asadistinctentitythatoccursmostlyinmales[7]andinvolvesswollenlymphnodesinthehead(includingtonsilsandadenoids),neck,[41]or,rarely,axillary,oringuinalareas,ornon-lymphoidtissues.[42]Currently,however,patientswhohadexhibitedorareexhibitinginvolvementofareasortissuesoutsideofthehead,neck,armpit,orgroinareasarenowregardedasfarmorelikelytohaveanewlyandprovisionallydefineddisease,largeB-celllymphomawithIRF4rearrangement.[41] ThelesionsinPTFLconsistsofinfiltratescontainingrapidlyproliferatingcentrocytesandcentroblaststhatlackthet(14:18)(q32:q21.3)translocationbutnonethelessoftenoverexpresstheBCL2gene.[7]Thesecellsmayshowalossofheterozygosityat1p36(20-50%ofcases)thatresultsindecreasedexpressionoftheTNFRSF14gene(seePathophysiologysection)aswellasmutationsintheIRF8(10-50%ofcases),whichcontributestothedevelopmentandfunctionofBcells,[43][44]andtheMAP2K1gene(10-40%ofcases),whichregulatesactivationoftheERKcellsignalingpathway.[45]Morethan2dozenothergeneshavebeenreportedtobemutatedinrarecasesofPTFLbutingeneralthegeneticabnormalitiesfoundinthisdisorderarefewerandlesscomplexthanthoseinothertypesofFL.[42]PTFLhasanindolent,relapsingandremittingcoursewitha5-yearsurvivalrateof>95%.[42]PatientsdiagnosedwithPTFLhavebeentreatedwithchemotherapy,surgery,andcombinationsofthesetreatments.Ingeneral,thesepatientsdidwell(100%survivalwith<5%ofcasesrelapsingregardlessoftreatmentmodality).Morerecently,36patientshavebeentreatedwithsurgicalresectionalonefollowedbyobservation;allthesepatientssurvivedwithonlyonehavingarelapse.Thus,PTFLappearstobeahighlyindolenttypeofFLinwhichmultiplestudieshavereportedoverallandprogression-freesurvivalratesof100%and>90%,respectively,for>2yearsandanestimatedprobabilityof5-yearevent-freesurvivalrateof~96%.Thetherapeuticregimensversusfollow-upobservationsthatbesttreatthisdisorderinchildren,adolescents,andadults(adultsmayrequiredifferenttreatmentsthanchildrenandadolescents)requiresfurtherstudy.[41] Primaryfollicularlymphomaofthetestis[edit] Primaryfollicularlymphomaofthetestis(PFLT),alsotermedtesticularfollicularlymphoma,wasclassifiedasadistinctformofFLbytheWorldHealthOrganizationin2016.[33]Itisanextremelyrarediseasethathasbeenrecognizedasoccurringprimarilyinchildrenandadolescents[46]butalsohasbeenreportedin5adults.[47]PFLTdiffersfromcasesoftypicalfollicularlymphomathatinvolvethetestisinthatitmoreoftenoccursinchildrenandadolescents;involvesmalignantB-cellsthatdohavethet(14:18)q32:q21)translocation;andpresentswithdiseasethatisstrictlylimitedtothetestis.Whilesimilartopediatric-typefollicularlymphomainnotinvolvingcellsthatbearthet(14:18)q32:q21)translocation,PFLTdiffersfromtheformerdiseaseinthatitislimitedtothetestisandinvolvesmalignantcellsthatdonotexpressBcl2.[48]PFTLisanextremelyindolentdiseasewhichismanifestedbylesionsthatexhibitatypicalFLhistologyor,morecommonly,amixedFL-diffuselargecelllymphomahistology.Itusuallyinvolvesa2-4centimeterlesioninasingletesticle.Patientshavebeentreatedwithremovaloftheinvolvedtestesfollowedbyvariousstandardanti-lymphomachemotherapyregimenstoattainexcellentresults,i.e.100%completedremissionswithnorecurrenceofdiseasein15childandadolescentpatientsobservedfor4–96months.Nocasesofprimaryfollicularlymphomaofthetestishavebeenreportedtoprogresstot-FL.Surgeryfollowedbylessstrenuousorevennochemotherapymayprovetobetheoptimaltreatmentforthisdisease.[46] Transformedfollicularlymphoma[edit] FLprogressesatarateof2-3%peryearforatleastthefirst10yearsafterdiagnosistoamoreaggressiveform,principallydiffuselargeB-celllymphoma(~93%ofcases)orBurkitt-likelymphoma(~7%ofcases)orinrarecasesexhibitthehistologyresemblingprecursorB-celllymphoblasticleukemia,plasmablasticlymphoma,thehighgradesubtypeofB-celllymphoma,HodgkinlymphomaoftheB-celltype,chroniclymphocyticleukemia/smallcelllymphcyticlymphoma,[5]orhistiocyticsarcoma.[1]t-FLisalmostalwaysdiagnosedinpatientsbeingfollowedforFL.TheseFLpatientspresentwiththe:fastgrowthoflymphnodes;formationofextra-nodallesionsinextra-nodalsitessuchasthecentralnervoussystem,liverorbone;theonsetofB-symptoms(i.e.fever,nightsweats,weightloss);developmentofhypercalcemia(i.e.highserumlevelsofcalcium);and/orsuddenrisesinserumlevelsoftheenzymelactatedehydrogenase.[5]Aminorityoft-FLpatientspresentwithoutahistoryofFL.Thesepatientsgenerallypresentwithadvanced,bulkydiseasethatmaybeaccompaniedbyextra-nodallesionsandB-symptoms.[1]Typically,allthevariousformsoft-FLareaggressive,rapidlyprogressivediseaseswithoverallmediasurvivaltimesintreatedpatientsof~4.5years.[1][5]ThetransformationofFLtoDLBCLisinover70%ofcasesassociatedwiththegainofMYCactivitybygeneticornon-geneticmechanisms.[49] Diagnosis[edit] Follicularlymphomareplacingalymphnode;thebubble-likeoutgrowthsareenlargedfollicles. ThediagnosisofFLdependsonexamininginvolvedtissuesforhistological,immunological,andchromosomalabnormalitiesthatareindicativeofthedisease.FLusuallyinvolvesenlargedlymphnodespopulatedbyabnormalfollicles(seeadjacentpicture)thatwhenexaminedhistologicallycontainamixtureofcentrocytesorcentroblastsurroundedbynon-malignantcells,mostlyT-cells.Thecentrocytes,whichtypicallyoutnumbercentroblasts,aresmalltomedium-sizedB-celllymphocytesthatcharacteristicallyexhibitcleavednuclei;thecentropblastsarelargerB-celllymphocyteswithoutcleavednuclei.[11]RarecasesofFLmayshowlesionsthatcontaintissueinfiltrationsdominatedbyB-cellswithfeaturesofprecursor(i.e."blast")cells,monocytes,ormalignantmantlecellssuchasthosefoundinmantlecelllymphoma.[1]ImmunochemicalanalysesrevealthatthesecellsgenerallyexpressB-cellsurfacemarkersincludingtheCD10(60%ofcases),CD20,CD19,CD22,andCD79butnotCD5,CD11c,orCD23cellsurfaceproteins;[4]genomicanalysesrevealthatthesecellscontaint(14:18)(q32:q21.3)translocation(85-90%ofcases),1p36deletions(60-70%ofcases),andwithfarlessfrequencytheothergenomicabnormalitieslistedintheabovesectionsonPathophysiologyandPresentationandcourse.NoneoftheseproteinmarkersorgenomicabnormalitiesarediagnosticforFL,e.g.thet(14:18)(q32:q21.3)translocationisfoundin30%ofdiffuselargeB-celllymphomaandinasmallnumberofreactivebenignlymphnodes.Rather,thediagnosisismadebyacombinationofhistological,immunological,andgenomicabnormalities.[4]AccordingtoWorldHealthOrganization(WHO)criteria,differencesinthemicroscopicallydeterminedmorphologyofthesetissuescanbeusedtodiagnoseandcategorizedFLintothefollowing3Gradeswithgrade3havingAandBsubtypes:[50] Histologiccomparisonofcelltypesinagerminalcenter,H&Estain:-Centrocytesaresmalltomediumsizewithangulated,elongated,cleaved,ortwistednuclei.-Centroblastsarelargercellscontainingvesicularnucleiwithonetothreebasophilicnucleoliapposingthenuclearmembrane.-Folliculardendriticcellshaveroundnuclei,centrallylocatednucleoli,blandanddispersedchromatin,andflatteningofadjacentnuclearmembrane. Grade1:follicleshave<5centroblastsperhigh-powerfield(hpf). Grade2:follicleshave6to15centroblastsperhpf. Grade3:follicleshave>15centroblastsperhpf. Grade3A:Grade3inwhichthefolliclescontainpredominantlycentrocytes. Grade3B:Grade3inwhichthefolliclesconsistalmostentirelyofcentroblasts. Grades1and2areregardedaslowgradeFL;Grade3AisusuallyalsoregardedaslowgradeFLalthoughsomestudieshaveregardeditashighgradeFL;andGrade3BisregardedasahighlyaggressiveFLinthet-FLcategory.[8] Inadditiontograde3Bdisease,histologicexaminationsmayrevealotherevidenceoft-FLsuchashistologicfindingsconsistentwithFLanddiffuselargecelllymphomainthesametissue(referredtoascompositelymphomas)orinseparatetissues(referredtoas(discordantlymphomas)orhistologicfindingssimilartothosefoundinBurkittlymphoma,precursorB-celllymphoblasticleukemia,plasmablasticlymphoma,thehighgradesubtypeofB-celllymphoma,HodgkinlymphomaoftheB-celltype,chroniclymphocyticleukemia/smallcelllymphocyticlymphoma,[5]orhistiocyticsarcoma.[1]Otherfindingsindicatingthepresenceofthistransformationincluderapidgrowthinsizeoflymphnodes,recentlyacquiredornewBsymptoms,recentdevelopmentofFLlesionsinnon-nodaltissue,rapidrisesinserumlactatedehydrogenaselevels,andthepresenceofhighlevelsofserumcalcium.[12] Differentialdiagnosis[edit] FLmaybeconfusedwithmarginalzoneB-celllymphoma,mantlecelllymphoma,andthesmalllymphocyticlymphomavariantofchroniclymphocyticleukemia.ThemalignantcellsinmarginalzoneB-celllymphomamayformfollicularstructuresbutcommonlyproliferateinthemarginalzoneratherthangerminalcenteroflymphoidtissues.Thesemalignantcellsoftenshowfeaturesofmonocytesorplasmacells.Mantlecelllymphomasshowmonotonous,medium-sizedlymphocytes,monocytes,andatrophiedgerminalcenters;unlikeFL,themalignantlymphocytesinthisdiseasearepositiveforCyclinD1byimmunohistochemistrystaining.Smalllymphocyticlymphomasarecomposedofnodularstructureswithsmall-tomedium-sizedmalignantcellssurroundingimmaturelymphocytesandimmunoblasts.Themalignantcellsinthisdisease,unlikeFL,stainpositiveforCD5andCD23.[11] Treatmentandprognosis[edit] FListypicallyaslowlygrowinglymphomawithanoverallmedianlifeexpectancyfortreatedpatientsof10–15years[34]withmanycasesofitwaxingandwaninginthesizeoftheirlesionsandrarecasesofitremittingspontaneously.[4]TheseconsiderationsfavortheuseofobservationoverinterventioninpatientswhoseparticularformofFLhasafavorableprognosisorwhoareintoleranttoaggressivetreatments.[4]However,mostcasesofFLhavealessfavorableprognosisatsomestageoftheirdiseaseandwillthereforerequireintervention.ThereislittleconsensusregardingtheguidelinestobeusedtodefinetheprognosisandtreatmentforFLatitspresentationorduringitscourse..Currentlyusedindicatorsforthisincludethedisease's:1)histology;2)subtype;3)predictedindolenceandpotentialfortransformation;and4)extentofdiseaseasmeasuredbyclinicalexaminations,bonemarrowbiopsytodeterminebonemarrowinvolvement,andPET/CTimagingofthechest,abdomen,pelvis,andanyareasoutsideoftheseregionsifphysicalexaminationsuggestsinvolvement.[51]SomesuggestedguidelinesusingtheseparameterstoindicatetheprognosisandneedfortreatmentinFLinclude:[8] TheWHOcriteriausinghistologicalgrade(seeprevioussection):PatientswithGrades1,2,and3AdiseasearepredictedtohavethesamelowriskprognosisthatisseenincasesoftypicalFLwhilepatientswithgrade3Bdiseasearepredictedtohavethehighriskprognosistypicaloft-FL. TheFollicularLymphomaInternationalPrognosticIndex(FLIPI):FLIPIusesthefollowingcriteria:age≥60years;AnnArbordiseasestageIII(i.e.lesionslocatedbothaboveandbelowthethoracicdiaphragm)orIV(i.e.disseminatedlesionsinvolvingoneormorenon-lymphaticorgans);bloodhemoglobin<12gram/deciliter;serumlactosedehydrogenaselevelabovenormal;andinvolvementof>4lymphnodes.Patientspositivefor0–1,2,or≥3ofthesefactorsareclassifiedasinlow,intermediate,andhighriskgroup,respectively,andaftertreatmentwithregimensthatincluderituximabhave2yearpredictedprogressionfreesurvivalsof84,72,and65%,respectively,andoverallsurvivalsof98,94,and87%,respectively.[4] TheFLIP2index.ThismodificationofFLIP1usesage≥60;bloodhemoglobin<12gram/deciliter;serumlactosedehydrogenaselevelabovenormal;serumbeta-2microglobulinlevelabovenormal;≥1lymphnodewithadiameter>6centimeters;andbonemarrowinvolvement.Thepredictedpercentageoftherapy-treatedpatientswithprogressionfreesurvivalat5yearsforindividualspositivefor0,1–2,and≥3ofthesefactorsare80,51,and19%,respectively.[8] CT/PETimaging:Thismethodmeasurestotalbodytumorvolumeasdetectedbytissueuptakeofradioactivefludeoxyglucose(F18).Progressionfreeandoverallsurvivalat5yearsforpatientswithestimatedtumorvolumesaboveversusbelow510cubiccentimetersarereportedtobe32.7and84.8%versus65.1and94.7%,respectively.[8] Luganostaging:thismethodclassifiesStageIdiseaseasinvolvingasinglelymphaticregionorextra-lymphaticsite;StageIIdiseaseasinvolving≥2lymphaticsitesor1lymphaticsiteplus1extralympaticsitewithalllesionsbeingonthesamesideofthediaphragm;StageIIIdiseaseasinvolving≥2lymphaticregionsthatareonoppositesidesofthediaphragm;andStageIVdiseaseasdisseminatedlesionsthatarefoundtobein≥1non-lymphaticorgans.[4] Response-basedprognosis:FLpatientswhosediseaseprogresseswithin24monthsofinitiatingtreatmentwithchemotherapyandimmunotherapyversuspatientswhosediseasedoesnotprogresswithin24monthsarepredictedtohave5yearsurvivalratesof50-74%versus~90%,respectively.[8] TheprognosisandtreatmentforthespecificpresentationsoftypicalFLcases(seeabovesectionsfortheprognosesandtreatmentrecommendationsforprimarygastrointestinaltractFL,predominantlydiffuseFLwith1p36deletion,pediatric-typeFL,andprimaryFLofthetestis)thatareincommonuseareasfollows: Insitufollicularlymphoma[edit] ISFLisabenignconditionthatmaybereevaluatedperiodicallytodetecttherarecasesofitwhichprogresstoFL;otherwiseISFLisnottreated.[9] Localizedfollicularlymphoma[edit] In10-20%ofcases,FLappearslimitedtosingleradiationfield,doesnotinvolvethebonemarrow,andisthereforeregardedaslocalizedearly-stageFL.Inthesecases,whicharesometimesclassifiedasAnnArborstageI(i.e.diseaselimitedtoasinglerestrictedregion)orstageII(i.e.diseaserestrictedtotwositesthatareonthesamesideofthediaphragm),[4]radiationtherapyachieves10yearoverallsurvivalratesof60-80%andmedianoverallsurvivaltimesof19years.[8]Itseemslikelythatmanyoftherelapsesinthesecasesareduetoundetecteddiseaseoutsideoftheradiationfieldatthetimeofradiationtreatment.TheuseofPET/CTimagingisstronglyrecommendedtoinsurethattheFLislocalized.Inanycase,theexcellentresultsachievedwithradiationtherapystronglysupportitsuseinlocalizeddisease.TheuseofanimmunotherapeuticagentsuchasRituximabaloneorincombinationwithachemotherapeuticregimensuchasCVP(i.e.cyclophosphamide,vincristine,prednisoneandrituximab)incasesoflocalized,early-stagediseasemaybeappropriatechoicesforsomeoftheseearly-stagepatients.[4]However,thelatterapproachisrecommendedforcasesoflocalizeddiseaseinwhichthediseaseextendsbeyondasinglefield:56%ofpatientstreatedinthismannerhadprogression-freesurvivalat10yearswhilepatientstreatedwithotherregimenshadprogressionfreesurvivalsof41%.Nonetheless,overallsurvivaldidnotdifferbetweenthetwogroups.[13] Asymptomaticfollicularlymphoma[edit] PatientswithasymptomaticbutnotlocalizedlowgradeFL,[8][52][53]gastrointestinaltractFL,[34]andpediatric-typefollicularlymphoma[41]havebeenservedbycarefulfollow-upwithouttherapeuticintervention.Evenhighgrade,aggressive,relapsed,ortransformedFLmayalsobeservedwithobservationinpatientswhoareasymptomatic.Findingsinasymptomaticpatientswhohavebeenrecommendedastriggersforstartingtreatmentincludeoneormoreofthefollowing:tumorsize≥7 cmindiameter;involvementof≥3nodesin3distinctareas,eachofwhichis≥3 cmindiameter;organcompression;presenceofascitesorpleuraleffusion(i.e.build-upoffluidintheabdominalorpleuralcavities);poorperformancestatusduetothedisease;elevatedlevelsofserumlactosedehydrogenaseorbeta-2microglobulin;[4]presenceoflocalizedbonelesions;kidneyinvolvement;reducedlevelsofcirculatingbloodplateletsoranyofthevarioustypesofwhitebloodcells;onsetofsignificantpruritus(i.e.itchingsensation)orotherBsymptoms;andenlargement(i.e.≥50%increaseinsizeoveraperiodofatleast6months)oflymphnodes,spleen,orotherfollicularlymphoma-infiltratedorgansortissues.[33] Symptomaticfollicularlymphoma[edit] SymptomaticFLrequirestreatmentsdirectedatrelievingsymptomsbyreducingtheloadoftumorcells.Variouschemotherapeuticregimenshavebeenusedforthisincludingcombinationsofalkylatingantineoplasticagents,nucleosideanalogues,and/oranthracyclines.TwocommonlyusedchemotherapeuticregimensareCVP(seeLocalizedFLsection)andCHOP(i.e.CVPplustheanthracyclineadriamycin).NeweragentsusedtotreatFLincludemonoclonalantibodiessuchasrituximab,obinutuzumab,galiximab,inotuzumabozogamicin,orepratuzumabandimmunomodulatorssuchaslenalidomideandinterferon.ThelattermedicationshavebeenusedincombinationoralonetotreatsymptomaticFL.[13]Mostsuchregimensaddrituximab(amonoclonalantibodywhichbindsandtherebykillstheCD20cellsurfaceproteinonBcells)withCVPorCHOPregimens(termedR-CVPandR-CHOPregimens). TheR-CHOPregimenappearssuperiortotheR-CVPregimenwith,forexample,onestudyfinding8-yearprogression-freesurvivalratesof57%versus46%forthetworespectiveregimens.[33]Morerecently,FLpatientshavebeentreatedwithotherregimensincluding:1)rituximabcombinedwiththechemotherapeuticalkylatingagentbendamustine;2)rituximabcombinedwiththechemotherapeuticagentfludarabineandtheinhibitorofTypeIItopoisomerase,mitoxantrone;[33]and3)rituximabcombinedwithanotherimmunotherapeuticagentsuchasgaliximab,epratuzumab(monoclonalantibodiesdirectedrespectivelyagainsttheCD80orCD22cellsurfaceproteinsonimmunecellsincludingBcells),ortheimmunomodulatingmedication,lenalidomide.[13]Whileitistoosoontojudgethelong-termresultsofthelatterregimens,theregimenshaveshownsimilarresultswhenanalyzedbasedonpoortreatmentresponses(~10-20%poorresponses).BendamustinewithrituximabmaybepreferabletoR-CHOPorR-CVPfortreatinglow-grade(i.e.Grades1,2,andpossibly3A)FL;R-CHOPmaybepreferredinFLthathashigh-riskcharacteristics(e.g.highlevelsofBeta-2macroglobulinorbonemarrowinvolvement).ThecombinationoflenalidomidewithrituximabhasshowngoodpotentialintreatingindolentcasesofFL.[13] Studiesindicatethatmaintenancetherapywithrituximabfollowingsuccessfulinductiontherapyprolongsprogression-freesurvival;forexampleonestudyfoundprogression-freesurvivalafter6yearsoftreatmentwas59.2%inpatientstreatedwithrituximabmaintenanceand42.7%withoutthismaintenance;however,overallsurvivalat6yearswassimilarinthetwogroups,87.4%and88.7%,respectively.Anotherstudyfoundthatprolongedmaintenancewithrituximabdidnothaveanybenefitsoveraneight-monthmaintenanceperiod.[13]Finally,surgery[54][55]andradiation[4][13][33]areadditionaltherapiesthatcanbeusedtorelievesymptomscausedbybulkyt-FLdiseaseortotreatlesionsinpatientswhocannotwithstandothertypesoftreatment. Transformedfollicularlymphoma[edit] Earlystudiesontreatingt-FLwithvariouspurelychemotherapyregimensgavepoorresultswithmedianoverallsurvivaltimesof1–2years.However,theadditionofrituximabtotheregimenssuchasCVPandCHOPaspartofinductionandmaintenancetherapies(i.e.R-CVPandR-CHOP)greatlyimprovedoverall5yearsurvivaltoratesof73%.TheR-CHOPregimenisagoodoptionfortreatingsuchcases.[5]However,theseregimensneednotbestartedinpeoplewithFLwhoareasymptomaticandhavelowtumorburdens:theoutcomesinsuchpatientsshownodifferencebetweenearlyversusdelayedtreatment.Somerecentstudiesfoundthattheuseofrituximabincombinationwithbendamustine(i.e.theRBregimen)providedbetterresultsthanR-CHOP:progression-freesurvivaltimesinonestudywere69.5monthsforRBand31.2monthsforR-CHOP.SimilarresultswereobtainedwhenRBwascomparedtoR-CVP.ThesestudiesalsofoundnooverallsurvivaltimebenefitbetweentheRBandR-CHOPregimens.Otherrecentlyexaminedregimensinclude1)theuseofobinutuzumabinsteadofrituximabintheR-CHOPandR-CVPregimentstoattainprogression-freesurvivalratesat3yearsof80%fortheobinutuzumab-chemotherapyregimenversus73%fortherituximab-chemotherapyregimenand2)thecombinationofrituximabwithlenalidomide(nochemotherapyagent)versusvariouschemotherapyplusimmunotherapy(principallyrituximab)toachievesimilarcompleteremissionand3yearprogression-freesurvivalratesbutwithrituximabpluslenalidomidecausinglesstoxicity(i.e.severeneutropenia).Manyofthesestudiesdiduserituximabmaintenancetherapyafterinductiontherapy.[4] Prevention[edit] Severalstudies,whilenotconclusive,suggestthattheearlytreatmentoflowriskFLreducestheincidenceofthediseaseprogressingtot-FL.Thetreatmentsusedinthesestudiesincludechemotherapy,radiationtherapy,andimmunotherapycombinationsplusrituximabmaintenancetherapy.[12] Relapsedfollicularlymphoma[edit] PatientswhorelapseafterinitialtherapyforFLmaybefollowedcloselywithouttherapyifasymptomatic.Whentreatmentisrequired,patientsmaybetreatedwiththeinitialtreatmentregimenwhensuchtreatmentledtoaremissionthatlastedforatleastoneyear;otherwiseanalternativeregimenisused.[13]TheregimenscommonlyusedinrelapsedlymphomaincludeR-CHOP,R-CVP,RFM(i.e.rituximab,fludarabine,andmitoxantrone),andRB(Bendamustineplusrituximab).[4]Patientswhohaveearlytreatmentfailure(e.g.within1–2yearsofinitialtreatment)ormultiplerelapseshavealsobeentreatedwitheitherautologous(i.e.stemcellstakenfrompatient)orallogeneic(i.e.stemcellstakenfromadonor)stemcellbonemarrowtransplantation.Whilestudiesareinconclusive,autologousstemcellbonemarrowtransplantationappearstoprolongsurvivalinearlytreatmentfailurepatientswhoarehealthyenoughtowithstandthistherapy.Unfitpatientsmaybenefitfrominitialtreatmentwithobinutuzumabplusbendamustinefollowedbymaintenancetreatmentwithobinutuzumab(iftheyhavenotbeentreatedpreviouslywithobinutuzumab).[13] Othermostlyexperimentaltreatmentscurrentlyunderstudyinpatientswithmultipletreatmentfailuresinclude:1)Phosphoinositide3-kinaseinhibitorssuchascopanlisib,duvelisib,andidelalisibwhichblockthephosphoinositide3-kinasesignalingpathwaythatpromotesthesurvival,proliferation,andotherpotentiallymalignantbehaviorsofcells;2)infusionoftisagenlecleucelchimericantigenreceptorTcells(i.e.CARTcells)(i.e.Tcellsthathavebeenisolatedfrompatients,engineeredtoexpressareceptorfortheCD19proteinon,andtherebykill,Tcells,andtheninfusedbackintothedonorpatient);[51]3)Bruon'styrosinekinaseinhibitor,ibrutinib,toblocktheB-cellmaturatingactionsofthiskianase;4)BCLinhibitorvenetoclaxtoblockBcl2'sactioninpromotingB-cellsurvivalandproliferation;5)histonedeacetylaseinhibitorsabexinostatandtazemetostattomodifytheexpressionofvariousgenes;and6)Checkpointinhibitorsnivolumab,pidilizumab,andpembrolizumabtopromotetheimmunesystem'sabilitytosuppresscancercellgrowth.[4]InpreliminarystudiesonFLpatientswhowereknownorthoughttoberefractortomoreconventionaltherapiesthesedrugs,whencombinedwithmoreconventionaldrugs,particularlyrituximab,producedpromisingresults.Phosphoionsitide3-kinaseinhibitorsproducedoverallresponseratesof10–12.5monthsin42-59%;tisagenlecleucecellsproducedanoverallprogression-freeresponserateof70%afterafollow-upof28months;[51]phosphoinositide3-kinaseinhibitorsproducedoverallresponseratesof~40%andcompleteresponseratesof1-20%;Bruton'styrosinekinaseinhibitorproducedoverallandcompleteresponseratesof38%and18%,respectively;theBclinhibitorproduceoverallandcompleteresponseratesof33%and14%,respectively;histonedeacetylaseinhibitorsproduceoverallresponseratesof35%-71%;andcheckpointinhibitorsproduceoverallresponseratesof40%-80%andcompleteresponseratesof10-60%.[4] 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^KarubeK,ScarfòL,CampoE,GhiaP(February2014)."MonoclonalBcelllymphocytosisand"insitu"lymphoma".SeminarsinCancerBiology.24:3–14.doi:10.1016/j.semcancer.2013.08.003.PMID 23999128. ^EntrezGene2146 ^EntrezGene1387 ^EntrezGene8740 ^EntrezGene8085 ^CarboneA,GloghiniA(March2014)."Emergingissuesaftertherecognitionofinsitufollicularlymphoma".Leukemia&Lymphoma.55(3):482–90.doi:10.3109/10428194.2013.807926.PMID 23713483.S2CID 39451928. ^EntrezGene7128 ^EntrezGene639 ^EntrezGene64121 ^abcGascoyneRD,NadelB,PasqualucciL,FitzgibbonJ,PaytonJE,MelnickA,et al.(December2017)."Follicularlymphoma:State-of-the-artICMLworkshopinLugano2015".HematologicalOncology.35(4):397–407.doi:10.1002/hon.2411.hdl:11343/292747.PMID 28378425.S2CID 23980925. ^EntrezGene84433 ^EntrezGene974 ^EntrezGene965 ^EntrezGene1029 ^EntrezGene1030 ^EntrezGene8764 ^EntrezGene4609 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Externallinks[edit] ClassificationDICD-10:C82ICD-9-CM:202.0ICD-O:M9690/3OMIM:151430MeSH:D008224ExternalresourceseMedicine:med/1362 FollicularlargecelllymphomaentryinthepublicdomainNCIDictionaryofCancerTerms vteLeukaemias,lymphomasandrelateddiseaseBcell(lymphoma,leukemia)(mostCD19 CD20)Bydevelopment/markerTdT+ ALL(PrecursorBacutelymphoblasticleukemia/lymphoma) CD5+ naiveBcell(CLL/SLL) mantlezone(Mantlecell) CD22+ Prolymphocytic CD11c+(Hairycellleukemia) CD79a+ germinalcenter/follicularBcell(Follicular Burkitt's GCBDLBCL Primarycutaneousfolliclecenterlymphoma) marginalzone/marginalzoneB-cell(Splenicmarginalzone MALT Nodalmarginalzone Primarycutaneousmarginalzonelymphoma) RS(CD15+,CD30+) ClassicHodgkinlymphoma(Nodularsclerosis) CD20+(NodularlymphocytepredominantHodgkinlymphoma) PCDs/PP(CD38+/CD138+) seeimmunoproliferativeimmunoglobulindisorders Byinfection KSHV(Primaryeffusion) EBV Lymphomatoidgranulomatosis Post-transplantlymphoproliferativedisorder ClassicHodgkinlymphoma Burkitt'slymphoma HCV Splenicmarginalzonelymphoma HIV(AIDS-relatedlymphoma) Helicobacterpylori(MALTlymphoma) Cutaneous DiffuselargeB-celllymphoma IntravascularlargeB-celllymphoma Primarycutaneousmarginalzonelymphoma Primarycutaneousimmunocytoma Plasmacytoma Plasmacytosis Primarycutaneousfolliclecenterlymphoma T/NKTcell(lymphoma,leukemia)(mostCD3 CD4 CD8)Bydevelopment/marker TdT+:ALL(PrecursorTacutelymphoblasticleukemia/lymphoma) prolymphocyte(Prolymphocytic) CD30+(Anaplasticlarge-celllymphoma LymphomatoidpapulosistypeA) CutaneousMF+variants indolent:Mycosisfungoides Pagetoidreticulosis Granulomatousslackskin aggressive:Sézarydisease AdultT-cellleukemia/lymphoma Non-MF CD30-:Non-mycosisfungoidesCD30−cutaneouslargeT-celllymphoma PleomorphicT-celllymphoma LymphomatoidpapulosistypeB CD30+:CD30+cutaneousT-celllymphoma SecondarycutaneousCD30+large-celllymphoma LymphomatoidpapulosistypeA Otherperipheral Hepatosplenic Angioimmunoblastic Enteropathy-associatedT-celllymphoma PeripheralT-celllymphomanototherwisespecified(Lennertlymphoma) SubcutaneousT-celllymphoma Byinfection HTLV-1(AdultT-cellleukemia/lymphoma) NKcell/(mostCD56) AggressiveNK-cellleukemia BlasticNKcelllymphoma TorNK EBV(ExtranodalNK-T-celllymphoma/Angiocentriclymphoma) Largegranularlymphocyticleukemia Lymphoid+myeloid Acutebiphenotypicleukaemia Lymphocytosis Lymphoproliferativedisorders(X-linkedlymphoproliferativedisease Autoimmunelymphoproliferativesyndrome) Leukemoidreaction Diffuseinfiltrativelymphocytosissyndrome Cutaneouslymphoidhyperplasia Cutaneouslymphoidhyperplasia withbandlikeandperivascularpatterns withnodularpattern Jessnerlymphocyticinfiltrateoftheskin General Hematologicalmalignancy leukemia Lymphoproliferativedisorders Lymphoidleukemias vteChromosomeabnormalitiesAutosomalTrisomies/Tetrasomies Patausyndrome 13 Edwardssyndrome 18 Downsyndrome 21 Warkanysyndrome2 8 Trisomy9 Tetrasomy9p Trisomy16 Cateyesyndrome/Trisomy22 22 Monosomies/deletions (1q21.1copynumbervariations/1q21.1deletionsyndrome/1q21.1duplicationsyndrome/TARsyndrome/1p36deletionsyndrome) 1 Wolf–Hirschhornsyndrome 4 Criduchatsyndrome/Chromosome5qdeletionsyndrome 5 Williamssyndrome 7 Jacobsensyndrome 11 Miller–Diekersyndrome/Smith–Magenissyndrome/17q12microdeletionsyndrome 17 DiGeorgesyndrome 22 22q11.2distaldeletionsyndrome 22 22q13deletionsyndrome 22 genomicimprinting Angelmansyndrome/Prader–Willisyndrome(15) Distal18q-/Proximal18q- X/YlinkedMonosomy Turnersyndrome(45,X) Trisomy/tetrasomy,otherkaryotypes/mosaics Klinefeltersyndrome(47,XXY) XXYYsyndrome(48,XXYY) XXXYsyndrome(48,XXXY) XXXXYsyndrome(49,XXXXY) TrisomyX(47,XXX) TetrasomyX(48,XXXX) PentasomyX(49,XXXXX) XYYsyndrome(47,XYY) XYYYsyndrome(48,XYYY) XYYYYsyndrome(49,XYYYY) 45,X/46,XY 46,XX/46,XY TranslocationsLeukemia/lymphomaLymphoid Burkittlymphomat(8MYC;14IGH) Follicularlymphomat(14IGH;18BCL2) Mantlecelllymphoma/Multiplemyelomat(11CCND1:14IGH) Anaplasticlarge-celllymphomat(2ALK;5NPM1) Acutelymphoblasticleukemia Myeloid Philadelphiachromosomet(9ABL;22BCR) Acutemyeloblasticleukemiawithmaturationt(8RUNX1T1;21RUNX1) Acutepromyelocyticleukemiat(15PML,17RARA) Acutemegakaryoblasticleukemiat(1RBM15;22MKL1) Other Ewingsarcomat(11FLI1;22EWS) Synovialsarcomat(xSYT;18SSX) Dermatofibrosarcomaprotuberanst(17COL1A1;22PDGFB) Myxoidliposarcomat(12DDIT3;16FUS) Desmoplasticsmall-round-celltumort(11WT1;22EWS) Alveolarrhabdomyosarcomat(2PAX3;13FOXO1)t(1PAX7;13FOXO1) Other FragileXsyndrome Uniparentaldisomy XXmalesyndrome/46,XXtesticulardisordersofsexdevelopment Markerchromosome Ringchromosome 6;9;14;15;18;20;21,22 Retrievedfrom"https://en.wikipedia.org/w/index.php?title=Follicular_lymphoma&oldid=1102922376" Categories:Non-HodgkinlymphomaHiddencategories:CS1:longvolumevalueArticleswithshortdescriptionShortdescriptionisdifferentfromWikidata Navigationmenu Personaltools NotloggedinTalkContributionsCreateaccountLogin Namespaces ArticleTalk English Views ReadEditViewhistory More Search 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