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AIDSrelatedlymphomas:Epidemiology,riskfactors,andpathobiology
Authors
LawrenceDKaplan,MD
WeiAi,MD,PhD

SectionEditor
ArnoldSFreedman,MD

DeputyEditor
RebeccaFConnor,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Feb2015.|Thistopiclastupdated:Jun20,2014.
INTRODUCTIONHumanimmunodeficiencyvirus(HIV)infectionresultsinimpairedcellularimmunity,a
conditionknowntopredisposepersonstodevelopneoplasms[14].AsthelifespanofHIVinfectedpatientshas
increased,malignancieshavebecomeaknowncauseofmorbidityandmortalityinthispopulation.Beforethe
adventofantiretroviraltherapy(ART),malignanciesaccountedforapproximately10percentofHIVrelateddeaths.
SincetheroutineimplementationofARTtherapy,acancerdiagnosisismadeinover40percentofHIVinfected
patientsduringthecourseoftheHIVinfection[5],andover28percentofHIVrelateddeathsareattributableto
malignancy[6,7].
Therearethreeacquiredimmunedeficiencysyndrome(AIDS)definingmalignancies:Kaposi'ssarcoma,non
Hodgkinlymphoma(NHL)ofhighgradepathologictypeandofBcellorunknownimmunologicphenotype[8],and
invasivecervicalcarcinoma.Inaddition,nonAIDSdefiningmalignanciescontributetomortalityinHIVinfected
persons.(See"HIVinfectionandmalignancy:Epidemiologyandpathogenesis"and"HIVinfectionand
malignancy:Managementconsiderations".)
Theepidemiology,riskfactors,andpathobiologyofAIDSrelatedNHLwillbereviewedhere.Issuesrelatedtothe
treatmentofNHLinthispopulationarediscussedseparately.(See"AIDSrelatedlymphomas:Treatmentof
systemiclymphoma"and"AIDSrelatedlymphomas:Primarycentralnervoussystemlymphoma",sectionon
'Treatment'and"AIDSrelatedlymphomas:Primaryeffusionlymphoma",sectionon'Treatment'.)
EPIDEMIOLOGY
GeneralissuesTwentyfiveto40percentofhumanimmunodeficiencyvirus(HIV)positivepatientswilldevelop
amalignancy,withapproximately10percentdevelopingnonHodgkinlymphoma(NHL)[1,3,5,7,917].Asan
example,aseriesof1073HIVpositivepatientsreportedatotalcancerincidenceof4percentperyeartherateof
NHLwas1.2percentperyear[12].AlthoughtherateoflymphomaintheHIVinfectedpopulationpriortothe
introductionofeffectiveantiviraltherapyappearedtobehigherinnonBlacksthanBlacks[12,18],thishasnot
beenborneoutinmorerecentstudies[19]Theselymphomasappeartobemorecommoninmalesthanin
females,regardlessofantiretroviraluse[1921].
ComparedwithnonHIVinfectedpatients,patientswhoareseropositiveforHIVhaveasubstantiallyincreased
riskofdevelopinglymphoma.Afterthewidespreadimplementationofantiretroviraltherapy(ART),theriskofNHL
decreasedinitiallyandhasremainedstablesince[22,23].Thisdeclineinincidenceappearstoreflect
improvementsinCD4counts[24].
Ametaanalysisthatincludeddataon444,172patientsfromsevencancerregistriesdemonstratedariskof
lymphomadevelopmentintheHIVpositivepopulationbetween23and353foldrelativetothenon
immunocompromisedpopulation[25].Althoughthesestudiespredominantlyincludedpersonswhowerenot
receivingART,theydidincludesignificantnumbersofpatientswhowerereceivingART,therebypotentially
loweringtheincidence.Oneanalysisof2566HIVpatientsfromanurbanHIVclinicinwhich26percentofpatients
werereceivingARTdemonstratedthattheratiosofobservedtoexpectednewcasesoflymphoma(standard
incidenceratios)were31forsystemicdiffuselargeBcelllymphoma,2100forcentralnervoussystemlymphoma,
and26forBurkittlymphoma[26].

SpecificNHLsubtypesAcquiredimmunedeficiencysyndrome(AIDS)relatednonHodgkinlymphoma(NHL)
canbedividedintothreegeneralcategoriesbasedonlocation:
SystemicNHL
Primarycentralnervoussystem(CNS)lymphoma
Primaryeffusion(orbodycavity)lymphoma
SystemicNHLaccountsforthegreatmajorityofAIDSrelatedlymphomas,whileprimaryCNSlymphoma
accountsforapproximately15percent,andprimaryeffusionlymphomaforlessthan1percent[2730].Systemic
NHLcanbefurtherdividedintocommonsubtypesdescribedintheWorldHealthOrganization(WHO)
classificationsystem(table1)[31].(See"Classificationofthehematopoieticneoplasms".)
ThemostcommonsystemicNHLsubtypesseeninHIVpositivepersonsare:[2730,32]

Burkittlymphoma(approximately25percent)
DiffuselargeBcelllymphoma(DLBCL,approximately75percent)
Plasmablasticlymphoma(lessthan5percent)
Tcelllymphoma(1to3percent)
IndolentBcelllymphoma(lessthan10percent)

TheWHOclassificationdoesnotorderlymphoidneoplasmaccordingtotheiraggressiveness,inpartdueto
recognitionthatthenaturalhistoryofthesetumorsshowssignificantpatienttopatientvariability.However,some
studieshaveseparatedhistologicsubtypesintothreegeneralcategories(highlyaggressive,aggressive,and
indolent)accordingtotheusualclinicalbehaviorofeachofthelymphoidneoplasms(table2)[27,3337]:
Approximately70to90percentofAIDSrelatedlymphomasarehighlyaggressiveandarealmostexclusively
theimmunoblasticvariantofDLBCLandBurkittlymphoma.Comparedwiththegeneralpopulation,the
relativeriskforhighlyaggressivelymphomasisincreasedmorethan400foldoverall[38],and650foldand
260foldforDLBCLandBurkittlymphoma,respectivelyamongpatientswithHIV[27].(See"Classificationof
thehematopoieticneoplasms",sectionon'Lymphoidneoplasms'.)
Theaggressivelymphomas,predominatelyothervariantsofDLBCL,compriseapproximately20percentof
AIDSrelatedlymphomas.Comparedwiththegeneralpopulation,therelativeriskisincreasedmorethan
110foldforaggressivelymphomas[27,38]
TcelllymphomasareuncommoninHIVdisease.However,linkageofAIDSandCancerregistrydata
indicatesanapproximately15foldincreaseintheselymphomasintheHIVpositivepopulationcompared
withthegeneralpopulation[39].Theyrepresented2.6percentofallHIVassociatedNHLdiagnosedata
largeurbanmedicalcenterbetween1982and2001[36].Multiplepathologicsubtypeswereseen.Thereare
norecentepidemiologicdataindicatingtheeffectofARTontheincidenceofthisgroupoflymphomas.They
donotconstituteanAIDSdefiningmalignancy.
Theindolentlymphomasarealsouncommon,comprisinglessthan10percentofAIDSrelatedlymphomas.
TheydonotconstituteanAIDSdefiningmalignancy.Comparedwiththegeneralpopulation,therelativerisk
isincreasedmore15foldforindolentlymphomas[27,38].
WhilemanyNHLsubtypesarealsoseeninpatientswithoutimmunocompromise,primaryeffusionlymphomaand
plasmablasticlymphomaoccurpredominantlyinimmunocompromisedpatients,particularlythoseinfectedwith
HIV.
Plasmablasticlymphomaisestimatedtoaccountforapproximately2.6percentofallHIVrelatedlymphomas
[40],althoughthetrueincidenceisnotknown.
PrimaryeffusionlymphomaisoneoftheleastcommonoftheAIDSrelatedlymphomas,accountingforless
than5percentofcases.(See"AIDSrelatedlymphomas:Primaryeffusionlymphoma",sectionon

'Epidemiology'.)
AmongpatientswithHIV,theincidenceofprimaryCNSlymphomais2to6percent,buthasbeenashigh
as10percentinanautopsyseriesinthepreARTera[4143].Thisincidenceisatleast1000timeshigher
thanthatofthegeneralpopulation[41].PrimaryCNSlymphomaaccountsforupto15percentofNHLsin
HIVinfectedpatientscomparedwith1percentofNHLsinthegeneralpopulation[27].Therehasbeena
cleardecreaseintheincidenceofAIDSrelatedprimaryCNSlymphomasincetheadventofART[44].(See
"AIDSrelatedlymphomas:Primarycentralnervoussystemlymphoma".)
HodgkinlymphomaHodgkinlymphoma(HL)isamongthemostcommonnonAIDSdefiningmalignancies,
withanincidence15to30foldhigherthaninthenonHIVinfectedpopulation[45].HLappearstobesignificantly
morecommoninmenwhohavesexwithmencomparedwiththosewhowereintravenousdrugusers[46].
FeaturesofHLinpatientswithHIVinfectionincludethefollowing:
UnfavorablehistologyissubstantiallymorecommoninpatientswithHIVinfection.MixedcellularityHL
accountedforapproximately60percentofcasesintwolargeseries[47,48].(See"Epidemiology,pathologic
features,anddiagnosisofclassicalHodgkinlymphoma".)
MostpatientswithHIVassociatedHLareEpsteinBarrvirus(EBV)positive,witha75to100percentrateof
EBVcoinfection.HLtendstodevelopearlyinHIVinfection.(See"TheroleofEpsteinBarrvirusinHodgkin
lymphoma".)
TherelationshipbetweenHLandCD4cellcountisunclear,withsomestudiesindicatingthatHLis
associatedwithadvancedHIVrelatedimmunosuppression[49].IntheSwisscohortstudy,theincreased
incidencewithalowerCD4countwasnotstatisticallysignificant[46].
ThereisconflictingevidenceabouttheimpactofpotentARTontheincidenceofHL.Somestudiessuggest
thattheincidencehasincreasedintheARTera[5052],butatleastonestudydidnotobserveasignificant
change[46,53].TheriskofdevelopingHLmaybeparticularlyincreasedinthefirstmonthsaftertheinitiation
ofART[54,55].
Itisclear,however,thatuseofantiretroviraltherapyhasnotreducedtheincidenceofHLinthispopulation,
ashasbeenobservedforaggressiveBcellNHL.
RISKFACTORSRiskfactorsforacquiredimmunedeficiencysyndrome(AIDS)relatedlymphomaincludeboth
humanimmunodeficiencyvirus(HIV)specificriskfactors,suchastheCD4countandHIVviralload,andmore
generalriskfactorsknowntoincreasetheriskofnonHodgkinlymphoma(NHL)inpatientswithoutHIV.Thelatter
groupofriskfactorsispresentedseparately.(See"ClinicalpresentationanddiagnosisofnonHodgkinlymphoma",
sectionon'Patienthistory'.)
TheriskofdevelopingNHLinthesettingofHIVincreasesdirectlywiththelevelofimmunesystemdysfunction.
Theincidence,pathology,clinicalpresentationandcourseofAIDSrelatedlymphomasdonotseemtoberelated
totheriskfactorfortheHIVinfectionitself[15,34].EpsteinBarrvirus(EBV)coinfectionisariskfactorforand
involvedinthepathogenesisofsubtypesofNHL.(See'EBVcoinfection'below.)
CD4countNHLisprimarilyencounteredinpatientswithmoreadvancedHIVinfection[14,56],andaCD4
countthatisusuallybelow100cells/microL[33,57,58].AhistoryofalowCD4countnadirmayalsobea
significantriskfactorforthedevelopmentofNHL[59].Retrospectiveandprospectivestudieshavedemonstrated
anassociationbetweenalowermostrecentCD4countandahigherriskofsystemicNHLinpatientswhohador
hadnotreceivedpriorantiretroviraltherapy(ART)[19,58,60].Incomparison,anassociationbetweenthenadir
CD4countandNHLdevelopmentwasnotasstrong[19].
InaFrenchprospectivecohortstudyinvolving52,278HIVinfectedpatients,personswithCD4countsless
than50cells/microLwereapproximately15foldmorelikelytodevelopNHLwhencomparedwiththose
havingCD4countover500cells/microL[60].TheriskratioforNHLdevelopmentgraduallydeclinedwith

increasingCD4countsuchthatpatientswithaCD4countof350to499cells/microLwereapproximately
twotimesaslikelytodevelopNHLthansomeonewithaCD4countover500cells/microL[60].
MatchingAIDSandCancerRegistrydatawerecomparedfor325,516personswithAIDSrelated
malignanciestolookforassociationsbetweenCD4countandcancerincidence[24].Foreach50cell/microL
declineinCD4lymphocytecount,increasedriskswereidentifiedforprimarycentralnervoussystem(CNS)
lymphomaandfornonCNSdiffuselargeBcelllymphoma,butnotforsystemicBurkittlymphoma[32].The
effectofCD4countwasobservedregardlessofARTuse.
HIVrelatedBurkittlymphomafrequentlydevelopsinrelativelyyoungerpatientsand/orwhentheCD4countis
relativelyhigh,typicallyover200cells/microL[32,35,61,62].PrimaryCNSlymphomarequiresamoresevere
degreeofimmunosuppressionthanmostotherAIDSrelatedcomplications,astheCD4countsinaffectedpatients
aregenerallylessthan50cells/microL[63,64].
HIVviralloadAhighHIVviralloadisalsoariskfactorforNHL[11,65].TheriskofNHLrisessignificantlyfor
thosewithplasmaHIVRNAlevels>100,000copies/mLcomparedwiththosewithcontrolledviralloads[60].Two
largecohortstudieshavedemonstratedanincreasedriskforNHLinindividualswithextendedperiodsof
uncontrolledHIVviremiawhilereceivingART[58,66].ThiseffectwasmostpronouncedforBurkittlymphomaand
wasnotobservedforprimaryCNSlymphoma[66].Approximately75percentoftheselymphomasdevelopin
individualswithpoorlycontrolledHIVinfection[67]onequarter,however,developevenwhentheHIVviralloadis
undetectable.(See"TechniquesandinterpretationofHIV1RNAquantitation".)
EffectofARTThewidespreaduseofantiretroviraltherapy(ART)haschangedthedemographics,incidence
rate,andproportionsofsubtypesofHIVassociatedlymphomas.Thiswasillustratedinastudythatexamineda
cohortofmorethan23,000HIVpositivepatientsdiagnosedfrom1996to2010obtainedfromtheCenterforAIDS
ResearchNetworkofIntegratedClinicalSystems(CNICS)[68].Astheyearofdiagnosisincreased,theageat
diagnosisofHIVassociatedlymphomasteadilyincreased,andtheproportionofpatientswithnonwhite,nonblack
ethnicityrose,reflectingtheshiftofdemographicsofHIVepidemic.
Althoughvariableaccordingtohistologicsubtype,theoverallincidenceofNHLhasdeclinedwiththewidespread
useofART[22,67].Nevertheless,theincidenceofNHLinHIVseropositivepatientsremainsabovethatofthe
nonHIVinfectedpopulation[69,70].Furthermore,whiletheincidenceofAIDSdefiningcancersdecreasedinthe
ARTera,theincidenceofcertaintypesofnonAIDSdefiningcancers,suchasanal,lung,liver,andprostate
cancers,aswellasHodgkinlymphoma,hasincreased[59,71,72],mostlikelyreflectingagingandprolonged
survivalofHIVinfectedindividualsintheARTera[73,74].
InaSwissHIVCohortStudy,whichincluded12,959HIVseropositivepatients,theincidenceofNHL
peakedat13.6per100,000personyearsin1993to1995,andthendeclinedto1.8in2002to2006.ARTuse
wasassociatedwithadeclineinincidenceandthisdeclinewasgreatestforthosewithprimaryCNS
lymphoma[21].AftertheinitiationofART,theriskofNHLwashalvedbyfivemonthsandcontinuedtofall.
ThereductioninNHLriskpersistedunchangeduptonineyearsafterARTinitiation[75].Inpatientsreceiving
ARTtherewasamarkeddeclineinthenumberoflymphomacasesandashifttowardincreasedCD4count
atdiagnosis(figure1).
Similarly,anItalianAIDSandCancerregistrystudydemonstratedan86percentfallintheincidenceof
primaryCNSlymphomaanda79percentreductionintheincidenceofsystemicNHLfromtheperiod1986to
1996and1997to2004[76].
IntheUnitedStates,theestimatednumberofAIDSdefiningcancersdecreasedbygreaterthanthreefold
fromthefouryearspriortoARTintroduction(1991to1995)toafouryearspanafterARTwasemployed
(2001to2005)[72].
AlthoughdecreasingHIVviralloadmaybeatleastpartlyresponsible[58],themostlikelyeffectofARTisa
reductionintheproportionofpatientswiththelowCD4levelsorhistoriesoflowCD4countnadirs[59],thegroup

mostlikelytodevelophighgradeNHL[59,77,78].Burkittlymphomas,whichcanoccurinthosewithrelativelyhigh
CD4counts,arebeingencounteredwithincreasingfrequency[79].ThepresentingclinicalfeaturesofAIDS
relatedlymphomasarethesameinthepreandpostARTeras[80].(See"HIVinfectionandmalignancy:
Epidemiologyandpathogenesis",sectionon'Epidemiology'.)
TherapyfortheunderlyingHIVinfectionthatincludesnonnucleosidereversetranscriptaseinhibitors(NNRTIs)
and/orproteaseinhibitors(PIs)maydecreasetheriskofdevelopingalymphoma[81].Themagnitudeofthis
curtailmentinriskseemstobeequivalentbetweenPIsandNNRTIs,whiletheprotectiveeffectfornucleoside
analoguesaloneisinferior[81].
IntheARTerabetween1996and2010dividedbythreetimeperiods(1996to2000versus2010to2005versus
2006to2010),therehasbeenashiftofincidenceratesoflymphomasubtypes[68].Nosignificanttrendwas
observedinproportionaldistributionofHodgkinlymphoma(HL)versusNHL.However,amongNHLcategories,
therewasasignificantproportionalincreaseinBurkittlymphoma.(See"HIVinfectionandmalignancy:
Managementconsiderations",sectionon'Hodgkinlymphoma'.)
BcellabnormalitiesThehallmarkofHIVinfectionisprogressivelossofCD4lymphocytes,butBcell
dysfunctionisalsopresentasevidencedbyabnormallylowlevelsofantibodiestospecificpathogensandapoor
immuneresponsetovaccines[82].Paradoxically,totalserumlevelsofimmunoglobulinsareelevated,reflecting
nonspecificpolyclonalBcellactivation.
MarkersofBcellactivation(suchastotalserumimmunoglobulins,serumfreelightchains,andserumsoluble
CD30)maybepredictiveforthedevelopmentofNHLinHIVinfectedindividuals,particularlyinthosewith
relativelypreservedCD4cellcounts[22,58,59,6164,67,69,77,78,8083].
GeneticfactorsHIVinfectedpatientswhohavetheCCR532deletiontendtohaveamorefavorableprognosis
withrespecttotheHIVinfectionthesepatientsalsoarelesslikely,byafactorofthreefold,todevelopanAIDS
relatedlymphoma[84,85].Thisprotection,however,doesnotseemtoapplytootherAIDSrelatedneoplasms.It
hasbeenspeculatedthatthereducedactivityofCCR5inthosepatientswiththe32basepairdeletionresultsina
decreaseinthemitogenicresponsetoRANTESand,therefore,alowerriskofmalignanttransformation[84,85].
(See"ImmunologyofHIV1infection".)
OthergeneticmutationsmayadverselyaffecttheriskofdevelopinganAIDSrelatedlymphoma[85].Onegroup
hasshownthatapolymorphisminthegenethatencodesfortheCXCR4chemokinereceptorwasassociated
withatwotofourfoldincreaseintheriskofdevelopinganAIDSrelatedNHL[86].
FamilyhistoryIntheHIVseronegativepopulation,thereisanelevatedriskoflymphoproliferativedisordersin
thosewithafamilyhistoryofsuch,particularlyinafirstdegreerelative[87].Thisriskispresumedtoapplytothe
HIVpositivepopulationaswell,althoughnotyetdemonstratedwithclinicaldata.
PATHOBIOLOGY
GeneralThepathogenesisofnonHodgkinlymphoma(NHL)inthesettingofhumanimmunodeficiencyvirus
(HIV)infectionispoorlyunderstood,butimmunederegulationleadingtolossofcontrolofviruses,suchas
EpsteinBarrvirus(EBV)isthoughttoplayanimportantrole.
Acquiredimmunedeficiencysyndrome(AIDS)relatedNHLsaremostcommonlyderivedfromBcells[88].There
isanunregulatedexpansionofcellsthatarearrestedindevelopmentandunabletoundergoterminaldifferentiation
[65].Geneticalterationsmaybeinvolved,notonlyinthepathogenesisofAIDSrelatedlymphomas,butalsoin
determiningthehistologyoftheresultingclonalproliferation(s).
FurtherdescriptionofthemolecularpathogenesisofdiffuselargeBcelllymphomaandBurkittlymphomain
immunocompetenthostsispresentedseparately.(See"PathobiologyofdiffuselargeBcelllymphomaandprimary
mediastinallargeBcelllymphoma"and"PathobiologyofBurkittlymphoma".)
ImmunedysregulationThedevelopmentofAIDSrelatedlymphoidneoplasmsisatleastpartiallyrelatedto

theprogressiveimpairmentofdendriticcellfunctionandtheresultingfunctionaldisorganizationoflymphnodes
thatoccurswithHIVinfection[89,90].Thisprogressionlikelyresultsfromtheincreasedproductionofcytokines
(eg,interleukin6andinterleukin10)fromthedamageddendriticcellsthatareknowntodrivelymphoidcells[89
91].
Anotherfactorthatplaysaroleinthegenesis,progression,andspreadofAIDSrelatedlymphomasisthe
enhancedadhesionofneoplasticlymphocytestoendothelialcellsthatresultsfromtheinfectionofthelatterby
HIVitself.Thisbringstheneoplasticcellsintocloseproximitytogrowthfactorsproducedbytheendothelialcells
andacceleratesextravasationofthemalignantcellsintothetissues[92,93].
Viralinfection
HIVinfectionHIVdoesnotinfecttheneoplasticcellsofAIDSrelatedlymphomas[94].Onestudy,
however,hasindicatedthattheTatproteinofHIVmaybetakenupbyBlymphocytes,leadingtoderegulationof
theoncosuppressorproteinproductsofthepRb2/p130gene[95].TheTatproteinmayalsobeactiveinthe
pathogenesisoftumorsintheHIVinfectedpopulationbyaugmentingtheangiogenicactivitiesofbFGFandVEGF
[96].
EBVcoinfectionManyAIDSrelatedsystemiclymphomasdemonstratedirectinfectionofthemalignant
cellswithEpsteinBarrvirus(EBV)[9799].ThehighfrequencyofEBVinfectedBcellsinpatientswithAIDS,
independentofthedevelopmentoflymphoma,maybedueinparttoadefectinTcellimmunitytoEBV[100103].
TheriskofdevelopinganAIDSrelatedlymphomacorrelateswiththedecreaseinEBVspecificcytotoxic
lymphocytes[100,104,105].Unlikethesituationinthepostorgantransplantsetting,intheHIVseropositive
populationtheriskoflymphomadoesnotcorrelatewellwiththeEBVviralloadinperipheralbloodmononuclear
cells[106,107].
OnestudyfoundthatthenumbersofEBVspecificCD8cellsdidnotfall,butratherproductionofinterferongamma
decreasedfollowingEBVpeptidestimulationinassociationwithanincreaseinEBVviralload[108].
IthasbeenproposedthatimmunosuppressionandEBVinfectionfavortheexpansionofBcellclones,thereby
allowingclonesofcellsthathaveundergonealterationsinoncogenesortumorsuppressorgenestoproliferate.
SomeofthesegenesincludecMYC[99]andtheTCL1oncogeneinthecaseofimmunoblasticlymphomas[109].
ConsistentwiththishypothesisistheobservationthatserumlevelsofsolubleCD23,aBcellstimulatoryfactor,
aremarkedlyelevatedinAIDSpatientswithlymphoma,ascomparedwiththosewithoutlymphoma[110].This
findingsuggeststhatchronicBcellstimulationisasignificantfactorintheinductionoflymphomainthissetting,
andraisesthepossibilitythatsolubleCD23maybeanearlymarkerforthedevelopmentofNHL.
ThefrequencyofEBVpositivityvariesbylymphomasubtype[111113]:
Inoneseries,forexample,only30to40percentofBurkittlymphomaswereEBVpositivecomparedwith79
percentofimmunoblasticorlargecelllymphomas[98,114,115].Intheformertypeoflymphoma,cellular
immunityisrelativelypreservedwhencomparedwithAIDSrelatedlymphomasofthelatterhistologies
[61,100].
EBVisseeninthemajorityofprimaryeffusionlymphomacases[116118],butinfectionwithhuman
herpesvirus8(alsocalledKaposi'ssarcomaassociatedherpesvirusorKSHV)isthoughttobeofprimary
importance.
EBVhasbeendetectedin74percentofAIDSrelatedplasmablasticlymphoma[119,120].Inoneseries,all
caseswerepositiveforEpsteinBarrvirusencodedRNA(EBER)butlackedEBVlatemembraneproteins
(LMP)[121].
EBVinfectionhasbeendetectedinvirtuallyallpatientswithAIDSrelatedprimarycentralnervoussystem
(CNS)lymphoma[42,43,122].
ThepathogenesisofAIDSrelatedprimaryCNSlymphomaisstronglyrelatedtoEBV[41,43].Inonereport,for

example,EBVtranscriptsandexpressionofaviralproteinwereseeninall21casesofAIDSrelatedprimaryCNS
lymphoma[43].EBVDNAsequencescanalsobedetectedinthecerebrospinalfluid(CSF)ofthesepatients,
whichmayassistinmakingthediagnosis.InoneseriesofHIVinfectedpatientswithfocalbrainlesions,EBV
DNAsequencesweredetectedintheCSFin24of30patients(80percent)withprimaryCNSlymphoma
comparedwithnoneof61patientswithoutprimaryCNSlymphoma[123].(See"Clinicalmanifestationsand
treatmentofEpsteinBarrvirusinfection",sectionon'Malignancy'.)
AsmallnumberofcirculatingBcellsentertheCNS,andmaydosoinincreasednumbersasHIVinfection
advances[124].EBVestablisheslatent,lifelonginfectioninover95percentofadults[102].Duringthecourseof
HIVinfection,EBVspecificTcellsprogressivelylosethecapacitytoproduceinterferongammainresponseto
EBVpeptides[108].Inaddition,EBVpositiveBlymphocytesoccurmorefrequentlyintheCNSofHIVinfected
individualsthaninnormalbrains[124].
HHV8Themalignantcellsofprimaryeffusionlymphoma(PEL)aremonoclonalBcellsthatcontain
genomicmaterialfromhumanherpesvirus8(HHV8,alsocalledKaposi'ssarcomaassociatedherpesvirusor
KSHV)[116,117].DetailsonthepathobiologyofthisNHLsubtypearepresentedseparately.(See"AIDSrelated
lymphomas:Primaryeffusionlymphoma",sectionon'Pathogenesis'.)
EvidenceofHHV8infectionhasalsobeenreportedinplasmablasticlymphoma,withaprevalencerangingfrom
17to100percentinseveralcaseseries[120,125,126].HHV8+,CD138+/CD20negativelymphomasoccurring
outsideoftheoralcavityhavealsodescribedasasolidvariantofPEL[127].
MulticentricCastleman'sdisease,whilenottypicallyaclonaldisorder,isanHIVassociatelymphoproliferative
diseaseassociatedwithlowCD4countandotherHHV8positivemalignancies[128,129].HHV8ispresentin
almostallcases[129,130].(See"MulticentricCastleman'sdisease".)
GenedysregulationAIDSrelateddiffuselargeBcelllymphoma(DLBCL)displaysseveralgenotypic
differencescomparedwithDLBCLoftheimmunocompetenthost,althoughanexplanationforthegenetic
peculiaritiesofAIDSrelatedDLBCLremainsobscure[114].Asexamples:
IncontrasttoDLBCLarisinginimmunocompetenthosts,BCL2activationisgenerallynotseeninAIDS
relatedDLBCL.
MutationsresultinginderegulationoftheBCL6protooncogeneareseeninonly20percentofAIDSrelated
DLBCL[114,131].
cMYCtranslocationsoccurinapproximately20percentofAIDSrelatedDLBCLtheseoccurless
commonlyinDLBCLintheHIVseronegativepopulation[114].
FurtherdescriptionofthemolecularpathogenesisofDLBCLandBurkittlymphomainimmunocompetenthostsis
presentedseparately.(See"PathobiologyofdiffuselargeBcelllymphomaandprimarymediastinallargeBcell
lymphoma"and"PathobiologyofBurkittlymphoma".)
BCL6expressionMutationsresultinginderegulationoftheBCL6protooncogenearepresentinover70
percentofAIDSrelatedlymphomasofallhistologies[132],butonly20percentofAIDSrelatedDLBCL[114,131].
ThesemayresultfromtranslocationsofpromotersnotintrinsictothenormalBCL6geneleadingtoincreased
BCL6expression,ortomutationsinthe5'noncodingregionoftheBCL6gene[133,134].Innormalphysiology,
BCL6expressionisrestrictedtogerminalcentercells,andisrequiredfornormalgerminalcenterformation[135
137].(See"PathobiologyofdiffuselargeBcelllymphomaandprimarymediastinallargeBcelllymphoma",section
on'AberrantBCL6expression'.)
Innormallymphnodephysiology,BCL6maypreventdevelopinglymphocytesfromundergoingapoptosisin
responsetothenormalDNAbreaksrequiredforlymphocytedevelopment[89,135].AIDSrelatedlymphomaswith
BCL6activationwithoutothergeneticlesions(denotinggerminalcenteretiology)tendtohaveabetterprognosis
comparedwiththosewithapostgerminalcenter(BCL6negative)origin[138].

Undernormalcircumstances,germinalcenter(GC)cellsstopexpressingtheproductoftheBCL6geneandgoon
toexpresstheCD138antigen(syndecan1),markingtheirdifferentiationintoplasmacells[139].Malignant
transformationofGCcellsthatexpressBCL6andhavenotyetexpressedtheCD138antigen
(BCL6+/syndecan1)developalongthehistologicpathwayofBurkittlikeorlargenoncleavedcelllymphoma
[132,140].UponcessationofexpressionoftheproductoftheBCL6geneandexpressionoftheCD138
(syndecan1)antigen,cellsthatundergomalignanttransformationmayexpresstheLMP1antigencharacteristicof
infectionbyEBV(BCL6/syndecan1+/LMP1+),producinglymphomasofimmunoblasticplasmacytoidhistology
[140142].IftheydonotexpressLMP1(BCL6/syndecan1+/LMP1),theytendtodevelopintoprimaryeffusion
lymphomas[141,143].
cMYCoverexpressionThemolecularpathogenesisofAIDSrelatedBurkittlymphoma(BL)inWestern
countriesinvolvescMYCactivationandEBVinfectionin100percentand30percentofthecases,respectively
[88,144].ThelocationofcMYCbreakpointsinAIDSrelatedBL,aswellasthefrequencyofEBVinfection,
indicatesthatthemolecularpathogenesisofAIDSrelatedBLinWesterncountriescloselymimicsthatofsporadic
BLoftheimmunocompetenthostratherthanendemicBL[88].However,AIDSrelatedBLoccurringinAfricais
stronglyassociatedwithEBVinfection,suggestingagreaterrelationtoendemicBL.(See"PathobiologyofBurkitt
lymphoma".)
ThebreakpointswithinthecMYCgenedifferbetweenendemicandHIVrelatedBurkittlymphoma[35].Virtually
allofthecellsofAIDSrelatedBLcontainareciprocalchromosomaltranslocationthatplacesthecMYCgene
adjacenttotheimmunoglobulinloci,resultinginthelossofregulationandconstitutiveexpressionofthisproto
oncogenethatencodesforanuclearphosphoproteinthatpermitstheaberrantlymphocytestobeinaperpetually
proliferativestate[35,114,144].
cMYCtranslocationsoccurinapproximately20percentofAIDSrelatedDLBCLtheseoccurlesscommonlyin
DLBCLintheHIVseronegativepopulation[114].Therearenodataavailableregardingtheincidenceofsocalled
"doublehit"lymphomas(cMYCwithBCL2and/orBCL6)inthesettingofHIVinfection.
p53mutationApproximately60percentofcasesofAIDSrelatedBurkittlikelymphomasharbormutations
inthep53tumorsuppressorgenethatresultinderegulationofapoptosis[145148].Onepathologyreviewof66
casesofDLBCLshowedthatofthe11of13caseswithplasmablastic/plasmacytoidfeatureshadamonoallelic
p53deletionbyfluorescenceinsituhybridization[149].
AberrantsomatichypermutationTheaberrantsomatichypermutationactivitydescribedinDLBCLof
immunocompetenthostshasalsobeenreportedinalargeproportionofAIDSrelatedNHL,includingBurkitt
lymphoma,primaryeffusionlymphomaandprimaryCNSlymphoma[150,151].
SUMMARYPatientswhoareseropositiveforhumanimmunodeficiencyvirus(HIV)haveasubstantially
increasedriskofcancer.Twentyfiveto40percentofHIVpositivepatientswilldevelopamalignancy,with
approximately10percentdevelopinganonHodgkinlymphoma(NHL).Althoughvariableaccordingtohistologic
subtype,theoverallincidenceofNHLhasdeclinedwiththewidespreaduseofantiretroviraltherapy(ART).
Nevertheless,theincidenceofNHLinHIVseropositivepatientsremainsabovethatofthenonHIVinfected
population.(See'Generalissues'aboveand'EffectofART'above.)
Acquiredimmunedeficiencysyndrome(AIDS)relatedNHLcanbedividedintothreegeneralcategories:
SystemicNHL(>80percent)
Primarycentralnervoussystem(CNS)lymphoma(15percent)
Primaryeffusion(orbodycavity)lymphoma(<5percent)
ThemostcommonsystemicNHLsubtypesseeninHIVpositivepersonsare:
Burkittlymphoma(approximately25percent)
DiffuselargeBcelllymphoma(DLBCL,approximately75percent)

 Plasmablasticlymphoma(lessthan1percent)
Tcelllymphoma(1to3percent)
IndolentBcelllymphoma(<10percent)
WhilemanyNHLsubtypesarealsoseeninpatientswithoutimmunocompromise,primaryeffusionlymphomaand
plasmablasticlymphomaoccurpredominantlyinimmunocompromisedpatients,particularlythoseinfectedwith
HIV.(See'SpecificNHLsubtypes'above.)
RiskfactorsforAIDSrelatedlymphomaincludebothHIVspecificriskfactors,suchasalowCD4countandhigh
HIVviralload,andmoregeneralriskfactorsknowntoincreasetheriskofNHLinpatientswithoutHIV.(See'Risk
factors'aboveand"ClinicalpresentationanddiagnosisofnonHodgkinlymphoma",sectionon'Pasthistory'.)
ThepathogenesisofNHLinthesettingofHIVinfectionispoorlyunderstood,butimmunederegulationleadingto
lossofcontrolofviruses,suchasEpsteinBarrvirusisthoughttoplayanimportantrole.AIDSrelatedNHLsare
mostcommonlyderivedfromBcells.ThereisanunregulatedexpansionoftheseBcellsthatarearrestedin
developmentandunabletoundergoterminaldifferentiation.Geneticalterationsmaybeinvolved,notonlyinthe
pathogenesisofAIDSrelatedlymphomas,butalsoindeterminingthehistologyoftheresultingclonal
proliferation(s).(See'Pathobiology'above.)
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Topic4726Version14.0

GRAPHICS
WHOclassificationoflymphoidmalignanciesassociatedwithHIV
infection(2008)
Lymphomasalsooccurringinimmunocompetentpatients
BurkittandBurkittlikelymphomas
DiffuselargeBcelllymphomas
Centroblastic
Immunoblastic(includingprimaryCNSlymphoma)
ExtranodalMALTlymphoma(rare)
PeripheralTcelllymphoma(rare)
ClassicalHodgkinlymphoma

LymphomaoccurringmorespecificallyinHIVpositivepatients
Primaryeffusionlymphoma
Plasmablasticlymphomaoftheoralcavity

Lymphomaalsooccurringinotherimmunodeficiencystates
PolymorphicBcelllymphoma(PTLDlike)(rare)
MALT:marginalzonelymphomaofmucosaassociatedlymphoidtissuePTLD:posttransplant
lymphoproliferativedisorderCNS:centralnervoussystem.
Source:Swerdlow,SH,Campo,E,Harris,NL,etal.(Eds).WorldHealthOrganizationClassificationof
TumoursofHaematopoieticandLymphoidTissues.IARCPress:Lyon2008.
Graphic79517Version1.0

WHOclassificationofthenonHodgkinlymphomas(subclassified
accordingtoclinicalaggressiveness*)
Theindolentlymphomas
Bcellneoplasms
Smalllymphocyticlymphoma/Bcellchroniclymphocyticleukemia
Lymphoplasmacyticlymphoma(Waldenstrom'smacroglobulinemia)
Plasmacellmyeloma/plasmacytoma
Hairycellleukemia
Follicularlymphoma(gradeIandII)
MarginalzoneBcelllymphoma
Mantlecelllymphoma
Tcellneoplasms
Tcelllargegranularlymphocyteleukemia
Mycosisfungoides
Tcellprolymphocyticleukemia
Naturalkillercellneoplasms
Naturalkillercelllargegranularlymphocyteleukemia

Theaggressivelymphomas
Bcellneoplasms
Follicularlymphoma(gradeIII)
DiffuselargeBcelllymphoma
Mantlecelllymphoma
Tcellneoplasms
PeripheralTcelllymphoma
Anaplasticlargecelllymphoma,T/nullcell

Thehighlyaggressivelymphomas
Bcellneoplasms
Burkitt'slymphoma
PrecursorBlymphoblasticleukemia/lymphoma
Tcellneoplasms
AdultTcelllymphoma/leukemia
PrecursorTlymphoblasticleukemia/lymphoma
*Editor'snote:TheWHOclassificationsystemofnonHodgkinlymphoma(NHL)ispresentedhere,
subclassifiedaccordingtothedegreeofclinicalaggressiveness(ie,indolent,aggressive,highlyaggressive)

shownbyeachvariant.
Mantlecelllymphomacanbehaveclinicallyaseitheranindolentoranaggressivedisorder.
AdaptedfromHarris,NL,Jaffe,ES,Diebold,J,etal.WorldHealthOrganizationclassificationofneoplastic
diseasesofthehematopoieticandlymphoidtissues:ReportoftheClinicalAdvisoryCommitteemeeting
AirlieHouse,Virginia,November1997.JClinOncol199917:3835.
Graphic59978Version2.0

DistributionofnonHodgkinlymphomas(NHLs)byuseof
HAARTandCD4cellcountatdiagnosis

Distributionof347NHLsbyuseofHAARTandCD4cellcountatNHLdiagnosis.
CD4cellcountatdiagnosiswasnotavailablefor82NHLs.
HAART:highlyactiveantiretroviraltherapy.
Reproducedwithpermissionfrom:PoleselJ,CliffordGM,RickenbachM,etal.NonHodgkin
lymphomaincidenceintheSwissHIVCohortStudybeforeandafterhighlyactive
antiretroviraltherapy.AIDS200822:301.Copyright2008LippincottWilliams&
Wilkins.
Graphic59898Version8.0