Lymphoma: Diagnosis and Treatment - AAFP

Open lymph node biopsy should be used to definitively diagnose lymphoma. ... Positron emission tomography/computed tomography should be used to ... Advertisement search close Lymphomarepresentsaheterogeneousgroupofmalignantneoplasmsoflymphocytes,whichcaninvolvelymphatictissue,bonemarrow,orextranodalsites.TheWorldHealthOrganization’sclassificationsystemidentifiesmorethan90differentsubtypes(Table1).1,2TheinitialstratificationisderivedfromB-cell,T-cell,ornaturalkillercellorigin.Furtherclassificationofdistinctlymphomasubtypesisbeyondthescopeofthisarticle;however,theyareultimatelyeachdefinedbymorphology,immunopheno-type,genetic,molecular,andclinicalfeatures.1,3Thisarticlewillfocusonthetypesoflymphomatraditionallyclassifiedasnon-HodgkinorHodgkin. ClinicalrecommendationEvidenceratingCommentsOpenlymphnodebiopsyshouldbeusedtodefinitivelydiagnoselymphoma.14,15CExpertopinionandclinicalreviewarticlesPositronemissiontomography/computedtomographyshouldbeusedtodeterminethestagingofthelymphoma.19CExpertopinionandclinicalreviewarticlePatientswithlymphomashouldhaveintensivefollow-upsurveillanceforthefirsttwoyearsfollowingremission.40CExpertopinionandclinicalreviewarticleA13-valentpneumococcalconjugatevaccine(Prevnar13),followedbya23-valentpneumococcalpolysaccharidevaccine(Pneumovax23)atleasteightweekslaterandthenagainatleastfiveyearslater,shouldbeadministeredfollowinglymphomatreatment.44,45CExpertopinionandguidelines LymphomasubtypeIncidenceper100,000Five-yearsurvivalHodgkin2.885.7%Non-HodgkinB-celllymphomas Burkitt0.464.1% DiffuselargeBcell7.263.2% Follicular3.588.4% Marginalzone2.290.3% PrecursorBcell1.568.9%Non-HodgkinT-cellandnaturalkillercelllymphomas Mycosisfungoides0.690.9% PeripheralT-cell1.258.4% Epidemiology Morethan82,000newpatientsareprojectedtobediagnosedwithlymphomain2019,representing4.7%ofallnewcancercasesintheUnitedStates.Thecurrentfive-yearsurvivalratefornon-Hodgkinlymphomais72.0%,andforHodgkinlymphomaitis86.6%.Almost21,000peopleareprojectedtodiefromlymphomain2019,representing3.5%ofallcancerdeaths.Incidenceofnon-Hodgkinlymphomaishigherinmenandwhites,anditincreaseswithage.Themedianageofpatientsatdiagnosisofnon-Hodgkinlymphomais67years,andthemedianageatdeathis76.Hodgkinlymphomaismostcommonlydiagnosedat20to34yearsofage;however,themedianageatdeathis68becauseofthehighersurvivalrateamongyoungerpatients.2,4 RiskFactors Genetic,infectious,andinflammatoryetiologiesincreasetheriskoflymphoma.First-degreerelativesofpatientswithnon-HodgkinlymphomaandHodgkinlymphomahavearespective1.7-foldand3.1-foldincreasedriskofdevelopinglymphoma.Afamilyhistoryofaspecificsubtypeoflymphomaisassociatedwithdevelopingthatsamesubtype.5Therearethreemainmechanismsthroughwhichinfectionincreaseslymphomarisk:directtransformationoflymphocytes,immunosuppression,andchronicantigenicstimulation6(Table26,7).Rheumatoidarthritis,systemiclupuserythematosus,Sjögrensyndrome,dermatomyositis,andceliacdiseaseareinflammatoryconditionsthatincreasetheriskoflymphomathroughdisease-specificcausesandthechronicuseofimmunosuppressivemedications.8 MechanismInfectionLymphomatypeDirectlymphocytetransformationEpstein-BarrvirusBurkitt,non-Hodgkin,HodgkinHumanT-lymphotropicvirustype1T-cellleukemiaImmunosuppressionHIVHodgkin,non-HodgkinChronicantigenicstimulationHelicobacterpyloriChlamydiapsittaciCampylobacterjejuniCampylobactercoliBorreliaburgdorferiNon-Hodgkin(mucosa-associatedlymphoidtissue)HepatitisCSplenicmarginalzone Modifiableriskfactorsincludecurrentorformertobaccouse9andobesity(bodymassindexof30kgperm2orhigher).10Breastimplantsandlong-termpesticideexposurehavealsobeenassociatedwithnon-Hodgkinlymphoma.11–13 ClinicalPresentation Lymphomacommonlypresentsaspainlessadenopathy.Adenopathycanwaxandwaneoveryearsinindolentpresentationsorinvolverapidlyprogressiveadenopathyinmoreaggressivesubtypes.Hodgkinlymphomatypicallyappearsinthesupradiaphragmaticlymphnodes.Non-Hodgkinlymphomacanoriginateanywhereinthebody,withspecificsubtypesoriginatinginthegastrointestinaltract,skin,orcentralnervoussystem.Systemicsymptomsoffever,unexplainedweightloss,andnightsweatsoccurinasubsetofpatientswithmoreadvanceddisease.Lymphomaspreadstoextranodalsitesbydirectinvasionorbyhematogenousspreadtothespleen,liver,lungs,orbonemarrow.14,15High-gradelymphomascanpresentasoncologicemergenciesbecauseofthestructuralcompressionfromtheenlargingtumor,includingsuperiorvenacavasyndrome,malignantepiduralspinalcordcompression,ormalignantpericardialeffusion.16Paraneoplasticsyndromesarerarewithlymphoma,occurringasparaneoplasticcerebellardegenerationinHodgkinlymphomaandasdermatomyositisandpolymyositisinHodgkinandnon-Hodgkinlymphomas.17 Diagnosis Thediagnosisoflymphomaismadeusinganopenlymphnodebiopsy,basedoffmorphology,immunohistochemistry,andflowcytometry.3Althoughfine-needleaspirationandcoreneedlebiopsyareoftenpartoftheinitialevaluationofanyadenopathy,neitherwillprovideadequatetissueforthediagnosisoflymphomabecauseoftheneedtoverifyHodgkinlymphomaviathepresenceofReed-Sternbergcells.15,18 Staging TheAnnArborstagingsystemwasinitiallydevelopedin1971forHodgkinlymphoma,andwaslateradaptedfornon-Hodgkinlymphoma.TheLuganoclassificationsystemfurthermodifiedstagingbyincorporatingpositronemissiontomography/computedtomography(PET-CT)resultstodeterminethestagingofthelymphoma(Table319).PET-CTisusedforfluorodeoxyglucose-avidlymphomasubtypes,withsymptomsalonebeingusedforstagingtheremainingsubtypes.Thenewstagingsystemincorporatestwosymptom-basedclassifications:A(absenceofsymptoms)andB(presenceoffever,weightloss,andnightsweats)forHodgkinlymphoma.AbonemarrowbiopsyisnowrecommendedonlyfordiffuselargeB-celllymphomawithanegativePET-CTresult.19 Stage*Descriptionofdiseasefrompositronemissiontomography/computedtomographyresultsISinglenodalgrouporsingleextralymphaticlesionII†MultiplenodalgroupsonsamesideofdiaphragmorwithlimitedcontiguousextralymphaticinvolvementIIIMultiplenodalgroupsonbothsidesofthediaphragm;mayinvolvethespleenIVNoncontiguousextralymphaticinvolvement Prognosis TheInternationalPrognosticIndexisusedbroadlyforallsubtypesofnon-Hodgkinlymphoma,andtheInternationalPrognosticScoreisusedforHodgkinlymphoma20,21(Table422,23). Non-HodgkinHodgkinInternationalPrognosticIndexInternationalPrognosticScoreCriteriaCriteriaAge>60Age>45ElevatedserumlactatedehydrogenaseMalesexEasternCooperativeOncologySerumalbuminconcentration<4.0gperdL(40gperL)Groupperformancestatus≥2*Hemoglobinconcentration<10.5gperdL(105gperL)AnnArborstageIIIorIVdisease†Extranodalsites>1AnnArborstageIVdisease†Leukocytosis(≥15,000μL[15×109whitebloodcellsperL])Lymphopenia(<600lymphocytesperμL[0.6×109perL],or<8%oftotalwhitebloodcellcount)Totalscore____Totalscore____Five-yearoverallsurvivalratebasedonnumberofcriteriafromInternationalPrognosticIndex/ScoreScore0or1=73%Score0=89%Score2=51%Score1=90%Score3=43%Score2=81%Score4or5=26%Score3=78%Score4=61%Score≥5=56% Treatment Treatmentoflymphomaconsistsofchemotherapyaloneorincombinationwithradiotherapy.24Radiotherapyaloneisnotrecommended.25Toxicityfromradiotherapycanleadtoseriouslong-termcomplicationssuchassecondarycancersintheirradiatedarea,includingbreastorlungcancers.25Additionally,patientsreceivingchemotherapycansubsequentlydevelopbreastorlungcancers,melanoma,oracutemyeloidleukemia.26,27Patientswhoareolderthan60yearsatdiagnosishaveworseoutcomes,regardlessofthestaging.TheNationalComprehensiveCancerNetwork(NCCN)recommendsavoidingcertainchemotherapeuticagentsinpatientsolderthan60years.Thephysicianshouldfocusonshareddecision-makingwhendiscussingtreatmentoptionswithallpatients,butparticularlyforthoseolderthan60years,includingwhetherthepatientshouldpursuetreatment.25 ThestandardtreatmentforHodgkinlymphomaisABVD(doxorubicin[Adriamycin],bleomycin,vinblastine[Velban],anddacarbazine),butotherregimenssuchastheStanfordV(doxorubicin,vinblastine,mechlorethamine,etoposide[Toposar],vincristine,bleomycin,andprednisone)andescalated-BEACOPP(bleomycin,etoposide,doxorubicin,cyclophosphamide,vincristine,procarbazine[Matulane],andprednisone)canbeused.24–28Treatmentfornon-Hodgkinlymphomavariesdependingonthehistology,butoftenusestreatmentssuchasCHOP(cyclophosphamide,doxorubicin,vincristine,andprednisone)withorwithoutrituximab(Rituxan;R-CHOP),amonoclonalantibodyspecificforCD20-positiveBlymphocytes.29Othermedicationssuchasbendamustine(Bendeka),analkylatingagent,andlenalidomide(Revlimid)arealsousedinmanynon-Hodgkinlymphomatreatments.30,31CommoncomplicationsofthesetherapiesarelistedinTable5.25–27,29–36 TherapyRegimenShort-termcomplicationsLong-termcomplicationsHodgkinlymphomaABVDDoxorubicin(Adriamycin)Nausea/vomitingAlopeciaNeutropeniaNeuropathyBleomycin-inducedpulmonarytoxicityCardiotoxicity(heartfailure)NeuropathyPulmonaryfibrosisIncreasedriskofmyocardialinfarctionBleomycinVinblastine(Velban)DacarbazineStanfordVDoxorubicinNausea/vomitingFatiguePulmonarytoxicityNeuropathyNeuropathyPulmonaryfibrosisCardiotoxicityRarelysolidsecondarymalignanciesofbreast,lung,andskinVinblastineMechlorethamineEtoposide(Toposar)VincristineBleomycinPrednisoneEscalated-BEACOPPBleomycinAnemiaLeukopeniaThrombocytopeniaNausea/vomitingInfectionDisulfiramreactionbetweenethanolandprocarbazineAcutemyeloidleukemiaSterility/infertilityEtoposideDoxorubicin(Adriamycin)CyclophosphamideVincristine(Oncovin)Procarbazine(Matulane)PrednisoneNon-HodgkinlymphomaCHOPCyclophosphamideHeartfailureConstipationHyperglycemiaNeuropathyCardiomyopathyMyelosuppressionNeuropathyDoxorubicin(Hydroxydaunorubicin)Vincristine(Oncovin)PrednisoneR-CHOPRituximab(Rituxan)+CHOPReactivatehepatitisBinfectionProgressivemultifocalleukoencephalopathy ACochranereviewthatexaminedseventrialsconsistingofmorethan2,500adultpatientswithearlyHodgkinlymphomaconcludedthattheuseofcombinedtherapycouldincreaseprogression-freesurvivalwithlittledifferencebetweentheoverallsurvivalrates.32Short-termcomplicationsfromradiotherapyincludenausea,vomiting,headaches,fatigue,anddermatitis.Radiotherapycanalsoleadtolong-termcomplications,includingcardiacandpulmonarytoxicity,hypothyroidism,orbreastorlungcancers.24–32RadiotherapycanbeavoidedinpatientswithstageIAorIIAlymphomawithoutbulkydisease25(Table319). InterimReassessment PET-CTscans,andsubsequentDeauvillescoring(Table621),shouldbeusedtoassesstheresponsetochemotherapyinnon-HodgkinandHodgkinlymphoma.25,30,31,33Ascoreof3orlessisconsideredcompleteremissioninnon-Hodgkinlymphomaandshouldconcludethecurrenttreatmentcourse.Ascoreof4or5isanindicatortoconsiderescalatingtherapy.25PatientswithHodgkinlymphomawithaDeauvillescoreof1or2havebeenshowntohavesimilarprogressionandmortalityoutcomesbetweenradiotherapyandnofurthertreatment.32Patientswhoreceiveascoreof3or4shouldreceiveadditionalchemotherapyand/orradiotherapy,andascoreof5indicatestheneedforabiopsy(excisionalorcoreneedle)inadditiontochemotherapyandradiotherapy.25Apositivebiopsyshouldbeconsideredrefractorydisease.25 PET-CTfindingScoreNoFDGuptakerelatedtolymphoma1FDGuptakeatlymphomasiteis≤mediastinumFDGuptake2FDGuptakeatlymphomasiteis>mediastinumFDGuptakebutliverFDGuptakeatanysite4FDGuptakeatlymphomasiteissubstantially>liverFDGuptakeornewFDGuptakesitesfound5 Relapse Relapseratesfornon-Hodgkinlymphomaarevariableandbasedonthespecificsubtype.Themostcommonsubtype,diffuselargeB-celllymphoma,hasa40%lifetimerelapserate.37LifetimerelapseinHodgkinlymphomaoccursin10%to15%ofpatientswithearlystagediseaseand40%ofpatientswithadvancedstagedisease.38 Surveillance Patientswhohaveachievedremissionneedroutinesurveillancetomonitorforcomplicationsandrelapse,aswellasage-appropriatescreeningsrecommendedbytheU.S.PreventiveServicesTaskForce.39Complicationsoflymphomatreatmentincludesecondarymalignancies(e.g.,breast,lung,skin,colon),cardiacdisease,infertility,andendocrine,neurologic,andpsychiatricdysfunctions.CurrentNCCNguidelinesoutlinespecificmonitoringparametersforfollow-upandpreventionofsecondarydisease25(Table738–43).Theextentandfrequencyoffollow-upspecificallydependonthehistologicsubtypeoflymphoma.Patientsshouldfollowupwithanoncologisteverythreetosixmonthsforthefirsttwoyears,everysixto12monthsuntilyear3,thenannuallythereafter.Afterfiveyearsofbeingcancerfree,thepatientcanbetransitionedtoaprimarycarephysician.40 CancerscreeningLaboratoryscreeningCardiacscreeningCounselingImmunizationsBreast:annualscreeningmammographystartingatage40;historyofchestoraxillaradiation:starteightto10yearsaftertreatmentoratage40,whichevercomesfirst;considerannualbreastmagneticresonanceimagingifchestradiationwasreceivedbetweenages10and30;considerreferraltobreastsubspecialisttodiscusspossiblechemopreventionCompletebloodcount,fastingbloodglucose,andcomprehensivemetabolicpanelannuallyAnnualbloodpressurescreening,lifestylemodification,andtreatmentofobesity,hypertension,andtobaccouseAnnualdepressionscreeningAge-appropriateimmunizationspertheCentersforDiseaseControlandPreventionschedule,includingannualinfluenzavaccine;resumelivevaccinesatleastthreemonthsaftercompletionofchemotherapyRoutinesurveillancetestsforcervical,colorectal,lung,andprostatecancerspertheUSPSTFguidelinesLipidprofilepertheUSPSTFguidelinesConsiderstresstestand/orechocardiographyat10-yearintervals(frequencyoftestingbasedonfindingsandotherassociatedriskfactors)Neurocognitiveimpairmentscreeningforanypatientwhoishighrisk(e.g.,historyofbrainradiationorintrathecaltreatment)PCV13(Prevnar13),followedbyPPSV23(Pneumovax23)atleasteightweekslaterandagainatleastfiveyearslaterThyroid-stimulatinghormoneannuallyifneckirradiationCarotidultrasonographyevery10yearsifneckirradiationInfertility:considerreproductiveendocrinologistreferralHaemophilusinfluenzaetypeb:threedosesfollowinghematopoieticstemcelltransplantation Ifapatientisasymptomatic,routinesurveillanceimagingdoesnotimproveoutcomesorprovideaclinicalbenefit.40,41Surveillanceimagingshouldbeusedinpatientswhohavereportedsymptomsorwhoareathighriskofrelapseinaplacethatwouldnotbeeasilyexamined,andwhowouldbecandidatesfortreatment.However,NCCNimagingguidelinesforlymphomasurveillancestatethatitisacceptabletoperformchestradiographyorCTofthechesteverysixto12monthsforthefirsttwoyearsandthenyearlyforthenextthreetofiveyearsposttreatment.41SurveillanceimagingwithPET-CTscansfollowingcompleteremissionisnotrecommended.40,41Diseasemarkerresearchisongoing,examiningminimalresidualdiseasemeasurements,apolymerasechainreaction–basedmethodthatlooksatidentifyingtumor-specificDNAsequences.41 Immunizations Allpatientswithlymphomashouldreceivepneumococcalvaccinationinitiallywitha13-valentpneumococcalconjugatevaccine(Prevnar13),followedatleasteightweekslaterbya23-valentpneumococcalpolysaccharidevaccine(PPSV23;Pneumovax23)andthenanotherPPSV23atleastfiveyearslater.44Patientsreceivinganti–B-cellantibodiesshouldnotreceiveannualinfluenzavaccination,andadministrationoflivevaccinesiscontraindicatedduringchemotherapy.RoutinevaccinationsrecommendedbytheCentersforDiseaseControlandPrevention(CDC)shouldresume,includinganyrecommendedinactivatedorlivevaccinesthreemonthsafterchemotherapyorsixmonthsafteranti–B-cellantibodytherapy.43,45PatientsreceivingahematopoieticstemcelltransplantshouldreceiveaseriesofthreedosesofHaemophilusinfluenzaetypebvaccinestartingsixto12monthsafterasuccessfultransplant.HouseholdcontactsshouldreceiveappropriateCDC-recommendedimmunizations.43 ThisarticleupdatesapreviousarticleonthistopicbyGlass.46 DataSources:APubMedsearchwascompletedusingcombinationsofthekeytermslymphoma,non-Hodgkin,Hodgkin,presentation,diagnosis,staging,treatment,andfollowup.Thesearchincludedmeta-analyses,randomizedcontrolledtrials,clinicaltrials,andreviews.Searchdates:April18,May17,andMay31,2018,andAugust30,2019.WealsosearchedtheAgencyforHealthcareResearchandQualityevidencereports,UpToDate,theCochranedatabase,EssentialEvidencePlus,theNationalComprehensiveCancerNetwork,andtheSurveillance,Epidemiology,andEndResultsdatabase.Searchdates:April18,2018,andAugust30,2019.ResearchreportedinthisarticlewassupportedbytheNationalInstituteofGeneralMedicalSciencesoftheNationalInstitutesofHealthunderawardnumber5U54GM104942-03.ThecontentissolelytheresponsibilityoftheauthorsanddoesnotnecessarilyrepresenttheofficialviewsoftheNationalInstitutesofHealth. ContinueReading Advertisement MoreinAFP MoreinPubmed ArticleSections Copyright©2020bytheAmericanAcademyofFamilyPhysicians. ThiscontentisownedbytheAAFP.Apersonviewingitonlinemaymakeoneprintoutofthematerialandmayusethatprintoutonlyforhisorherpersonal,non-commercialreference.Thismaterialmaynototherwisebedownloaded,copied,printed,stored,transmittedorreproducedinanymedium,whethernowknownorlaterinvented,exceptasauthorizedinwritingbytheAAFP.  Seepermissions for copyright questionsand/orpermissionrequests. Copyright ©2022AmericanAcademyofFamilyPhysicians.AllRightsReserved.