Thenewenglandjournalofmedicinenengljmed389 5nejm. orgAugust3 2023406FromtheCentersforRegenerativeMedi- cine K. A. K. D. B. S. K. G. D. T. S. andSystemsBiology B. H. F. MassachusettsGeneralHospital theHarvardStemCellInstitute K. A. K. K. G. D. T. S. theDe- partmentofStemCellandRegenerativeBiology HarvardUniversity K. A. K. K. G. D. T. S. andHarvardMedicalSchool K. A. K. B. H. F. D. B. S. K. G. D. T. S. allinBoston. Dr. Scaddencanbecontactedatdscaddenmgh. harvard . eduorattheCenterforRegenerativeMedicine MassachusettsGeneralHos- pital 185CambridgeSt. Boston MA02114-2696. Drs. GustafssonandScaddencontributedequallytothisarticle. NEnglJMed2023 389 406-17. DOI 10. 1056NEJMoa2302892Copyright 2023MassachusettsMedicalSociety. BACKGROUNDThefunctionofthethymusinhumanadultsisunclear androutineremovalofthethymusisperformedinavarietyofsurgicalprocedures. Wehypothesizedthattheadultthymusisneededtosustainimmunecompetenceandoverallhealth. METHODSWeevaluatedtheriskofdeath cancer andautoimmunediseaseamongadultpa- tientswhohadundergonethymectomyascomparedwithdemographicallymatchedcontrolswhohadundergonesimilarcardiothoracicsurgerywithoutthymectomy. T-cellproductionandplasmacytokinelevelswerealsocomparedinasubgroupofpatients. RESULTSAfterexclusions 1420patientswhohadundergonethymectomyand6021controlswereincludedinthestudy 1146ofthepatientswhohadundergonethymectomyhadamatchedcontrolandwereincludedintheprimarycohort. At5yearsaftersurgery all-causemortalitywashigherinthethymectomygroupthaninthecon- trolgroup 8. 1 vs. 2. 8 relativerisk 2. 9 95 confidenceinterval CI 1. 7to4. 8 aswastheriskofcancer 7. 4 vs. 3. 7 relativerisk 2. 0 95 CI 1. 3to3. 2. Althoughtheriskofautoimmunediseasedidnotdiffersubstantiallybetweenthegroupsintheoverallprimarycohort relativerisk 1. 1 95 CI 0. 8to1. 4 adif- ferencewasfoundwhenpatientswithpreoperativeinfection cancer orautoim- munediseasewereexcludedfromtheanalysis 12. 3 vs. 7. 9 relativerisk 1. 5 95 CI 1. 02to2. 2. Inananalysisinvolvingallpatientswithmorethan5yearsoffollow-up withorwithoutamatchedcontrol all-causemortalitywashigherinthethymectomygroupthaninthegeneralU. S. population 9. 0 vs. 5. 2 aswasmortalityduetocancer 2. 3 vs. 1. 5. InthesubgroupofpatientsinwhomT-cellproductionandplasmacytokinelevelsweremeasured 22inthethymecto- mygroupand19inthecontrolgroup meanfollow-up 14. 2postoperativeyears thosewhohadundergonethymectomyhadlessnewproductionofCD4 andCD8 lymphocytesthancontrols meanCD4 signaljointT-cellreceptorexcisioncircle sjTREC count 1451vs. 526permicrogramofDNA P 0. 009 meanCD8 sjTRECcount 1466vs. 447permicrogramofDNA P0. 001 andhigherlevelsofproinflammatorycytokinesintheblood. CONCLUSIONSInthisstudy all-causemortalityandtheriskofcancerwerehigheramongpatientswhohadundergonethymectomythanamongcontrols. Thymectomyalsoappearedbeassociatedwithanincreasedriskofautoimmunediseasewhenpatientswithpreoperativeinfection cancer orautoimmunediseasewereexcludedfromtheanalysis. FundedbytheTraceyandCraigA. HuffHarvardStemCellInstituteRe- searchSupportFundandothers. ABSTRACTHealthConsequencesofThymusRemovalinAdultsKameronA. Kooshesh M. D. BrodyH. Foy D. Phil. DavidB. Sykes M. D. Ph. D. KarinGustafsson Ph. D. andDavidT. Scadden M. D. OriginalArticleTheNewEnglandJournalofMedicineisproducedbyNEJMGroup adivisionoftheMassachusettsMedicalSociety. Downloadedfromnejm. orgonJune17 2026. nengljmed389 5nejm. orgAugust3 2023407HealthConsequencesofThymusRemovalThethymusiscriticalfornormaldevelopmentoftheimmunesystem. InfantswhoundergothymectomyhavereducedT-cellcountsthatdonotrecovertonormallevels evenafterseveralyearsoffollow-up 1-3andhaveimpairedimmuneresponsestochildhoodvac- cines. 4 5ChildrenwithcongenitalheartdefectswhoundergothymectomyduringsurgeryhaveareductioninnaiveT-cellcountsthatpersistsintoyoungadulthood. 6 7Whetherthethymusiscriticalforadulthealthislessclear particularlysincethethymusnatu- rallyinvoluteswithage. Thymusatrophybeginsininfancyandismarkedlyacceleratedinpuberty anditresultsinanexponentialdeclineinnewT-cellgeneration. 8 9WithdecliningcentralT-cellproduction thebodymaintainsthenumberofTcellsthroughperipheralclonalproliferationofT-cellpopulations10thathaveanincreasinglylim- itedT-cellreceptor TCR repertoire11asaresultoflong-termstimulationofonlyafractionofTCRs. 12Age-relatedcontractionoftheTCRrep- ertoiremayhinderimmunesurveillance increas- ingtheriskofinfectionandcancer 13andmaybeariskfactorinthedevelopmentofautoimmunedisease. 14Previousstudieshaveshownthat althoughthethymuscontinuestoproduceTcellsintoadult- hood thymicactivitydecreasesgraduallywithage. 15 16Howimportant then istheadultthymus Weaddressedthisquestionbyevaluatinghealthoutcomesamongadultswhohadundergonethy- mectomy. Thymectomyisperformedbymeansofamediansternotomy video- orrobot-assistedthoracoscopicsurgery ortranscervicaldissection. Therefore patientswhohadundergonecardio- thoracicsurgerywithoutthymectomywerecho- sentocontrolfortheeffectofthesurgicalpro- cedure. Throughepidemiologic clinical andimmunologicanalyses weinvestigatedtheinflu- enceofthymectomyonmortalityandontheriskofinfection cancer andautoimmunedisease. MethodsStudiesinHumansUsingtheMassGeneralBrigham MGB ResearchPatientDataRegistry weidentifiedalladultpa- tientswhohadundergoneathymectomyproce- dureatMassachusettsGeneralHospital MGH betweenJanuary1 1993 andMarch1 2020. Patientswhodiedwithin90daysafterthepro- cedureorwhohadnonlaparoscopiccardiacsurgerywithin5yearsaftertheprocedurewereexcluded. Usingthesamedatabase weidentifiedalladultpatientsatMGHwhohadundergonenon- laparoscopiccardiacsurgerybetweenJanuary1 2000 andDecember31 2019 andhadnohis- toryofthymectomyforinclusioninthecontrolgroup. Patientswhodiedwithin90daysaftertheprocedure whohadpreoperativeheartfail- ure orwhohadasecondcardiacsurgerywithin5yearsaftertheprocedurewereexcluded be- causepreservationofthethymusisunlikelyinrepeatthoracicoperations. Forallpatients dataondemographiccharacteristics diagnostichis- tory andmortalitystatuswereobtainedfromtheResearchPatientDataRegistry thedataarevaliduptoMarch1 2022. Theincidenceofinfection cancer andauto- immunedisease alistisprovidedinthestatisti- calanalysisplan seetheSupplementaryAppen- dix availablewiththefulltextofthisarticleatNEJM. org wasinferredwiththeuseofcodesfromtheInternationalClassificationofDiseases ICD 9thand10threvisions. Postoperativeinfections cancers andautoimmunediseaseweredefinedasthosethatappearedsolelyaftersurgery withnosimilardiagnosisoccurringbeforetheproce- dure. Toreducebiasfromdelayedreporting anyinfection cancer orautoimmunediseasethatoc- curredwithin90daysaftersurgerywasassumedtobepreoperative. ThymomaswereassumedtobemalignantunlessexplicitlystatedasbenignintheICDcode. Giventhehighprevalenceofbe- nignthymomas keyresultswerealsogeneratedafterexclusionofallpatientswithpreoperativethymoma whethermalignantorbenign. Forsurvivalanalysis patientswhohadunder- gonethymectomywerematchedtocontrolswithrespecttosex race age 5-yeargap andtheoccurrenceofpreoperativeinfections cancers orautoimmunedisease separatelyforthethreecategories withoutreplacementofmatchedcontrols. Ifmultiplematcheswereavailable thepatientclosestinagewaschosen. Greaterthan1-to-1matchingwasnotperformedinordertolimittheexclusionofpatientswhohadunder- gonethymectomybutdidnothavemultiplematches. SurvivalanalysiswasperformedinthematchedgroupswiththeuseofKaplanMeiercurves withthelastdateofdatacollection March1 2022 usedasacensor. MortalitydataTheNewEnglandJournalofMedicineisproducedbyNEJMGroup adivisionoftheMassachusettsMedicalSociety. Downloadedfromnejm. orgonJune17 2026. nengljmed389 5nejm. orgAugust3 2023408Thenewenglandjournalofmedicinearenationallylinkedandaccuratelymaintained butdiagnosisdatamaynotbeforpatientswhohavemovedoutofstate. Giventhislimitation wereplicatedkeyresultswithdatacensoredonthebasisofeachpatientslastMGBsystemin- teraction mostrecentlaboratorytest procedure hospitalvisit orprescription. Thesignificanceofbetween-groupdifferencesinincidencewascalculatedwiththeuseofalog-ranktest. Toanalyzethecharacteristicsofcancersandautoimmunedisease chartreviewwasperformedfor75patientswhohadundergonethymectomyand75controlpatientswithpostoperativecancer aswellasfor75patientsineachgroupwhohadapostoperativeautoimmunedisease chart-reviewcohorts. Asamplesizeof75patientspergroupwascalculatedtopowerthedetectionofanef- fectsizeof0. 2diagnoses whichwasreasonedtobeclinicallymeaningful. Patientswereran- domlyselectedandtheirchartsassessedtoquan- tifyrelevantfeaturesofpostoperativediagnoses e. g. type severity andrecurrence. Wesoughttoinvestigatedifferencesindemographicprofilesbetweenpatientswhohadundergonethymec- tomyandcontrolswhosubsequentlyhadapost- operativeinfection cancer orautoimmunedis- ease aswellasdifferencesinthenatureofthesediagnoses. Consequently theseresultsdidnotin- volvematchingaccordingtodemographiccharac- teristics. Tocontrastmortalitywiththatinthegeneralpopulation mortalityinthethymectomygroupandmortalityinthecontrolgroupwerecomparedwithvaluesreportedforthegeneralpopulationbytheCentersforDiseaseControlandPrevention CDC. 17Thisanalysisincludeddatafromallpa- tientswithmorethan5yearsoffollow-upinourstudy regardlessofwhethertheyhadamatchedcontrolwithmorethan5yearsoffollow-updata. Age- andyear-stratifiedmortalitydatafromtheCDCwerepooledandweightedtomatchthedis- tributionofsurgicalyearandageatsurgeryinthethymectomygroup. ToaccountfordifferencesbetweenmortalityinMassachusettsandtheUnitedStatesasawhole thevaluesfromtheCDCwerereducedby17 thatis thedifferencebetweenMassachusettsandtheoverallUnitedStates 18weightedproportionallytothedistribu- tionofagesatthymectomyandyearsinwhichsurgerywasperformed. Mortalitywasconvertedfrom1yearto5yearsbyassumingindependence with5-yearmortalitycalculatedas 1 1 1-yearmortality 5 . Allthepatientsinthethymectomyandcon- trolgroupswereconsideredforfollow-upstudy. Atotalof96healthcareproviderswerenotifiedabouttheirpatients eligibility sincemanypa- tientshadchangedprovidersfromMGB. Studystaffobtainedconsentforphlebotomyfrompa- tientswhogavepermissiontotheirhealthcareproviders. AllconsentandphlebotomyprocedureswereconductedinaccordancewithnationalandinstitutionalguidelinesandwiththeapprovaloftheinstitutionalreviewboardofMGH. AssessingtheSeverityofCancerAcrossthechart-reviewcohorts weevaluatedpathologyreportsofbreastcancerinpatientsineachgroup andBloomRichardsonscoreswereaveragedandcomparedbetweenthethymectomygroupandthecontrolgroup. Becausethecan- cersthatdevelopedinthetwogroups andthereforetheirAmericanJointCommitteeonCancer AJCC tumornodemetastasis TNM stagingcriteria differed TNMstagingcriteriawerenormalizedbyclassifyingcancersaseitherlocoregionalorwidespreaddiseaseonthebasisofNationalComprehensiveCancerNetwork NCCN guidelines. NCCNguidelineswerere- viewedforeachgastrointestinal genitourinary andhematologiccancerthatwasfoundinordertostratifythemaccordingtowhetheritwouldbetreatedwithaconservativecourseoranin- tensiveregimeninvolvingmultimodaltreatmentstrategies. ProcessingofSamplesfromPatientsA20-mlsampleofbloodwasobtainedbymeansofperipheralbloodphlebotomyatMGBfacilities. BloodwasseparatedwithFicollandcentrifuga- tionat500gfor30minutesatroomtempera- ture. Themononuclearlayerwascollectedandresuspendedin90 fetalbovineserum FBS Gibco and10 dimethylsulfoxide SigmaAl- drich forcryopreservationinliquidnitrogen. Foranalysis theperipheral-bloodmononuclearcellswerethawedandallowedtorestinculturefor24hoursinRPMI-1640supplementedwith10 FBS 10-mmol-per-literHEPES Gibco 1 peni- cillinstreptomycin Gibco and1 nonessentialaminoacids Gibco. After24hours separationofCD4 andCD8 lymphocyteswasperformedTheNewEnglandJournalofMedicineisproducedbyNEJMGroup adivisionoftheMassachusettsMedicalSociety. Downloadedfromnejm. orgonJune17 2026. nengljmed389 5nejm. orgAugust3 2023409HealthConsequencesofThymusRemovalwiththeuseofmagneticbeads STEMCELLTechnologies andpuritywasdeterminedtobeabove90. CytokineandsjTRECAnalysisForcytokineanalysis bloodplasmawasisolatedatthetimeofFicollseparationandcryopreservedbeforecytokineprofilingwiththeuseoftheHu- manCytokineChemokine71-PlexDiscoveryAssayArray HD71 EveTechnologies. Fortheanaly- sisofsignaljointT-cellreceptorexcisioncircles sjTRECs genomicDNAwasisolatedfromatleast200 000magneticallyseparatedCD4 andCD8 lymphocytesperpatientwiththeDNeasyBloodandTissuekit Qiagen. ThenumberofsjTRECswassubsequentlydeterminedwithasingleplexMyTRECreal-timequantitativepoly- merase-chain-reactionkit GenenPlus. TCRSequencingGenomicDNAwasisolatedfromatleast100 000CD4 andCD8 Tcells inmostcases genomicDNAwassubmittedfrommorethan200 000cells DNeasyBloodandTissueKit Qiagen andsenttoAdaptiveBiotechnologiesforbulkT-cellreceptorsequencingoftheVJ variableandjoin- ing orVDJ variable diversity andjoining regionsofTRB thegeneencodingTCR withtheuseoftheImmunoSEQHumanTCRBsequencingkit AdaptiveBiotechnologies. Productiverearrange- mentswerethenmeasuredwiththeImmuno- SEQAnalyzerplatformforanalysis. ClonalityofCD4 andCD8 TcellswasassessedwithadownsampledproductiveSimpsonsclonalityin- dex andrichnesswasmeasuredwiththeSimp- sonsevennessindex. StatisticalAnalysisStatisticalanalysiswasperformedwithRStudiosoftware version1. 2. 5042 Posit andMATLABsoftware version2021b MathWorks. Samplesizeswerechosenonthebasisofpreviousexperiments andnostatisticalmethodswereusedtoprede- terminesamplesize. Thesignificanceofdistri- butionswascalculatedwithanunpairedtwo-tailedStudentst-test normaldistributions orWilcoxonrank-sumtest nonnormaldistributions. Unlessotherwisespecified alldataareexpressedaseffectsizesand95 confidenceintervals andaPvalueoflessthan0. 05wasconsideredtoindi- catestatisticalsignificance. Epidemiologicandclinicalfindingswerenotadjustedformultiplecomparisons andthereforeinferencesdrawnfromconfidenceintervalsmaynotbereproducible. ResultsIdentificationofPatientsWhoHadUndergoneThymectomyOursearchoftheregistryidentified1470adultpatientswhohadundergonethymectomyand16 679patientswhohadundergonecardiothoracicsurgerywithoutthymectomy afterexclusions thenumbersthatremainedinthestudywere1420and6021 respectively. Ofthe1420patientsinthethymectomygroup 1146 81 hadatleastonevalidmatchtoacontrol andthereforetheprimarycohortconsistedof1146patientswhohadundergonethymectomyand1146age- race- andsex-matchedcontrols. Nopatientswith22q11. 2deletionsyndrome DiGeorgessyndrome werefoundamongthepatientsinthethymec- tomygroup. Theprimaryindicationsforsurgery obtainedthroughmanualchartreview aresum- marizedinTableS1intheSupplementaryAp- pendix. Halfthepatientsinthecohorthadhadtheirthymusremovedwithoutamalignantorotherdefinitivethymuscondition. DemographiccharacteristicsofthepatientsareshowninTa- bleS2. RiskofDeathTodeterminetheeffectofthymectomyonlifeexpectancy all-causemortalityat5yearsaftersurgerywasassessedinthethymectomygroupandthecontrolgroup. Patientswhohadunder- gonethymectomyweremorethantwiceaslikelyascontrolstodiewithin5years 8. 1 vs. 2. 8 relativerisk 2. 9 95 confidenceinterval CI 1. 7to4. 8 P0. 001 Fig. 1A. Thiseffectwaspre- servedaftertheexclusionofpatientswithpreop- erativemyastheniagravis patientswithpreopera- tivethymoma orpatientswithpreoperativecancer aswellasaftertheexclusionofallpatientswithanypreoperativeinfection cancer orautoimmunediseasetakentogether19-24 Fig. 1A. KaplanMeieranalysisoveraperiodof20yearsaftersurgeryalsoshowedsignificantlyhighermortalityamongpatientswhohadundergonethymectomy haz- ardratio 1. 5 95 CI 1. 3to1. 7 P 0. 001 Fig. 1B. ThissignalwasconsistentaftertheexclusionofpatientswithpreoperativemyastheniaTheNewEnglandJournalofMedicineisproducedbyNEJMGroup adivisionoftheMassachusettsMedicalSociety. Downloadedfromnejm. orgonJune17 2026. nengljmed389 5nejm. orgAugust3 2023410Thenewenglandjournalofmedicinegravis Fig. S1A thymoma Fig. S1B orcancer Fig. S1C aftertheexclusionofallpatientswithapreoperativehistoryofinfection cancer orautoimmunedisease Fig. 1C whencontrollingfortheincidenceofpostoperativeinfection can- cer andautoimmunedisease Fig. S2 andwhenonlypatientswhohadundergoneatotalthymec- tomywereincluded Fig. S5 asupersetanalysisexcludingallpatientswithpreoperativeinfections cancers orautoimmunediseaseorwithbenignormalignantthymomaisshowninFig. S6. Wealsoperformedananalysistocomparemortalityoverthe5yearsaftersurgery reflectingdatafromallpatientswith 5yearsoffollow-up withmortalityreportedfortheUnitedStatesbytheCDC 17afteradjustmentforage year andU. S. state. 18All-causemortalityat5yearsinthisanaly- siswashigheramongpatientswhohadunder- gonethymectomythaninthegeneralpopulationforeachagegroupandinaggregate 9. 0 vs. 5. 2 relativerisk 1. 7 95 CI 1. 4to2. 1 Fig. S3. RiskofCancerTodeterminetheeffectofthymectomyontheriskofcancer weassessedtherelativeriskofcancerat5yearsaftersurgeryinthecontrolgroupascomparedwiththethymectomygroup. Patientswhohadundergonethymectomyweremorelikelythancontrolstohavecancerwithin5yearsaftersurgery 7. 4 vs. 3. 7 relativerisk 2. 0 95 CI 1. 3to3. 2 theresultswererobusttotheexclusionofpatientswithpreoperativemyas- theniagravis patientswithpreoperativethymoma orpatientswithpreoperativecancer aswellastotheexclusionofallpatientswithpreoperativein- fection cancer orautoimmunedisease Fig. 2A. Inananalysiscomparingourdata fromallpatientswith 5yearsoffollow-up withdatafromtheNationalCancerInstitute the5-yearincidenceofcanceramongcontrols 3. 9 wassimilartothatamongsimilarlyagedmembersofthegen- eralU. S. population 0. 8 peryearforpersons55to59yearsofage or3. 9 cumulativelyoverFigure1. EffectofThymectomyonLong-TermMortality. PanelAshowstherelativeriskofdeathfromanycauseamongpatientswhohadundergonethymectomyascomparedwithage- race- andsex-matchedcontrolsinthefirst5yearsaftersurgery bothintheoverallstudypopulationandinsubgroups. Therelativeriskofdeathfromanycausewithin5yearswasincreasedinpatientswhohadundergonethymectomy regardlessofwhethertheyhadapreop- erativehistoryofinfection cancer orautoimmunedisease. PanelsBandCshowthepercentagesofpatientswhosurvivedoveraperiodof20yearsaftersurgeryinthegroupwithnoexclusions PanelB andinthesubgroupinwhichpatientswithapreoperativehistoryofinfection cancer orautoimmunediseasewereexcludedfromtheanalysis. Theinsetsshowthesamedataonanexpandedyaxis. 2. 04. 06. 0AllpatientsExcludingpatientswithpreviousinfection cancer orautoimmunediseaseExcludingpatientswithpreviousmyastheniagravisExcludingpatientswithpreviousthymomaExcludingpatientswithpreviouscancerNo. ofPatientsinEachGroupRelativeRiskofDeath 95 CISubgroup2. 5 1. 44. 3 3. 2 1. 66. 7 2. 7 1. 64. 5 0. 02. 4 1. 34. 3 2. 9 1. 74. 8 PValue11466491016518962 0. 001 0. 001 0. 001 0. 001 0. 001ADeathfromAnyCauseamongPatientsWhoHadUndergoneThymectomyBAllPatients N1146 CExcludingPatientswithPreviousInfection Cancer orAutoimmuneDisease N649 PercentageSurviving100809070604030105020005101520YearssinceSurgeryHazardratio 1. 5 95 CI 1. 31. 7 PercentageSurviving100809070604030105020005101520YearssinceSurgery100807090005101520Hazardratio 1. 5 95 CI 1. 31. 8 1008085759095005101520ControlControlThymectomyThymectomyTheNewEnglandJournalofMedicineisproducedbyNEJMGroup adivisionoftheMassachusettsMedicalSociety. Downloadedfromnejm. orgonJune17 2026. nengljmed389 5nejm. orgAugust3 2023411HealthConsequencesofThymusRemoval5years25 whereastheincidenceinthethymec- tomygroupwashigherthanthatinthegeneralpopulation 7. 0 relativerisk 1. 8 95 CI 1. 2to2. 7. InaKaplanMeieranalysisoverthe20yearsaftersurgery theriskofcanceramongpatientswhohadundergonethymectomywasalsohigh- erthanthatamongcontrols hazardratio 1. 6 95 CI 1. 4to1. 8 Fig. 2B evenaftertheexclu- sionofpatientswithpreoperativemyastheniagravis Fig. S1D thymoma Fig. S1E orcancer Fig. S1F andaftertheexclusionofallpatientswithpreoperativeinfection cancer orautoim- munedisease Fig. 2C aswellaswhentheanaly- siswaslimitedtopatientswhohadundergonetotalthymectomy Fig. S5 asupersetanalysisex- cludingpatientswithanyinfection cancer orautoimmunediseaseorwithbenignormalignantthymomaisshowninFig. S6. InananalysisofdatacensoredonthebasisofeachpatientslastMGBsysteminteraction mostrecentlaboratorytest procedure hospitalvisit orprescription thefindingsweresimilartothoseinthemainanalysis Fig. S7. CharacteristicsofPost-ThymectomyCancerDetailedmedicalrecordreviewswereperformedfor75patientswhohadundergonethymectomyand75controlsrandomlychosenfromthesub- groupofpatientswithpostoperativecancer Ta- bleS6. Thepatientswhohadundergonethymec- tomyhadmorecancersperpatient 1. 7vs. 1. 2 difference 0. 43 95 CI 0. 21to0. 65 Fig. 3A regardlessofpreoperativecancerhistory numberofpostoperativecancersperpatientamongthosewithapreoperativehistoryofcancer 1. 9vs. 1. 2 difference 0. 68 95 CI 0. 34to1. 02 Fig. 3B. Cancersamongpatientswhohadundergonethy- mectomyweremorediversethanthoseamongcontrols. Skincancers themostfrequentcan- cersintheUnitedStates26 27andthosemostcom- monlyassociatedwithimmunesuppression28 29Figure2. EffectofThymectomyontheLong-TermRiskofCancer. PanelAshowstherelativeriskofcanceramongpatientswhohadundergonethymectomyascomparedwithage- race- andsex- matchedcontrolsinthefirst5yearsaftersurgery bothintheoverallstudypopulationandinsubgroups. Therelativeriskofcancerwithin5yearswasincreasedinpatientswhohadundergonethymectomy regardlessofwhethertheyhadapreoperativehistoryofinfec- tion cancer orautoimmunedisease. PanelsBandCshowthepercentagesofpatientswhosurvivedwithoutcanceroveraperiodof20yearsaftersurgeryinthegroupwithnoexclusions PanelB andinthesubgroupinwhichpatientswithapreoperativehistoryofinfection cancer orautoimmunediseasewereexcludedfromtheanalysis. Theinsetsshowthesamedataonanexpandedyaxis. 1. 02. 03. 05. 04. 0AllpatientsExcludingpatientswithpreviousinfection cancer orautoimmunediseaseExcludingpatientswithpreviousmyastheniagravisExcludingpatientswithpreviousthymomaExcludingpatientswithpreviouscancerNo. ofPatientsinEachGroupRelativeRiskofCancer 95 CISubgroup2. 2 1. 24. 1 1. 6 0. 92. 9 1. 9 1. 23. 1 2. 2 1. 14. 4 0. 02. 0 1. 33. 211466491016518962AIncidenceofCanceramongPatientsWhoHadUndergoneThymectomyBAllPatients N1146 CExcludingPatientswithPreviousInfection Cancer orAutoimmuneDisease N649 PercentagewithoutCancer100809070604030105020005101520YearssinceSurgeryHazardratio 1. 6 95 CI 1. 41. 8 PercentagewithoutCancer100809070604030105020005101520YearssinceSurgery10085958090005101520Hazardratio 2. 0 95 CI 1. 62. 3 1008085759095005101520ControlControlThymectomyThymectomyTheNewEnglandJournalofMedicineisproducedbyNEJMGroup adivisionoftheMassachusettsMedicalSociety. Downloadedfromnejm. orgonJune17 2026. nengljmed389 5nejm. orgAugust3 2023412ThenewenglandjournalofmedicineNo. ofCancersperPatient42310ControlGroup N75 ThymectomyGroup N75 CDiversityofCancersAAllPatientsNo. ofCancersperPatient42310ControlGroup N45 ThymectomyGroup N25 BExcludingPatientswithPreviousCancerPercentageofCancersthatRecurredControlGroup N152instancesofrecurrence ThymectomyGroup N187instancesofrecurrence FTypesofRecurrentCancersDRecurrentCancerafterTherapyPercentageofCancers75255007525500ControlGroup N16cancers ThymectomyGroup N23cancers EMultimodalTreatmentforCancerControlGroup N75 ThymectomyGroup N75 ControlGroup N152instancesofrecurrence ThymectomyGroup N187instancesofrecurrence 1. 21. 96. 343. 5Melanoma 4. 4 BreastBrainProstatePeripheralT-celllymphomaBladderLungLiver1. 21. 7Lymphoma12. 5 Bladder12. 5 BreastLungProstateDLBCLRectalEmbryonalRenalFollicularlymphomaPancreaticBladder4. 617. 1BreastProstateLungRenalPancreaticCLLThyroidFollicularlymphomaCNSColorectalBladderPituitaryBasal-cellcarcinoma 26. 7 Basal-cellcarcinoma 22. 7 Basal-cellcarcinoma 36. 3 Basal-cellcarcinoma 37. 5 Squamous-cellcarcinoma 8. 6 Squamous-cellcarcinoma 37. 5 Squamous-cellcarcinoma 9. 1 Squamous-cellcarcinoma 24. 2 Melanoma 11. 2 Melanoma 4. 5 Difference 0. 43 95 CI 0. 210. 65 Difference 0. 68 95 CI 0. 341. 02 Relativerisk 3. 7 95 CI 1. 78. 2 Relativerisk 7. 0 95 CI 0. 9949. 1 TheNewEnglandJournalofMedicineisproducedbyNEJMGroup adivisionoftheMassachusettsMedicalSociety. Downloadedfromnejm. orgonJune17 2026. nengljmed389 5nejm. orgAugust3 2023413HealthConsequencesofThymusRemoval wereunexpectedlylessfrequentinthethymec- tomygroupthaninthecontrolgroup 46. 5 vs. 64. 9 ofcancers relativerisk 1. 40 95 CI 1. 1to1. 8 Fig. 3C. Nonskincancerswerefoundinalmosteverymajororgansysteminthebody withsomelesscommoncancers kidney thyroid pa- rotid andembryonal occurringinthethymec- tomygroup. Controlswithpostoperativecancerswerealsoolderatthetimeofsurgerythancor- respondingpatientswhohadundergonethymec- tomy 70yearsvs. 56yearsofage TableS6 whichsuggeststhatcancersinpatientswhohadundergonethymectomymayhavebeenlessage- driventhanthoseincontrols. Breastcancersamongpatientswhohadunder- gonethymectomyhadhormonalstatusandmutationrates TablesS7andS8 similartothoseamongcontrolsbuthadahighermeanhisto- logicgrade30 Fig. S8A. Gastrointestinal genito- urinary andhematologiccancersinpatientswhohadundergonethymectomyweremorefrequent- lywidespreadinthebodythanthoseincontrols percentageofcancerswithdistanttissueornodalmetastasis 52. 2 vs. 18. 8 relativerisk 2. 8 95 CI 0. 9to8. 3 Fig. S8B. Aftertreat- ment cancerrecurrencewasmorecommonamongpatientswhohadundergonethymectomythanamongcontrols percentageofcancersthatrecurred 17. 1 vs. 4. 6 relativerisk 3. 7 95 CI 1. 7to8. 2 Fig. 3D andpostoperativecan- cersinthethymectomygroupweremorelikelytoreceivemultimodaltreatmentthanthoseinthecontrolgroup 43. 5 vs. 6. 3 ofcancers relativerisk 7. 0 95 CI 0. 99to49. 1 Fig. 3E. DetailsofthecancersthatrecurredareshowninFigure3F. Mortalityfromcancerwashigherinthethymectomygroupthaninthecontrolgroup 2. 3 vs. 1. 0 relativerisk 2. 3 95 CI 1. 02to5. 1 andhigherinthethymectomygroupthaninanage- year- andstate-adjustedgeneralU. S. population 2. 3 vs. 1. 5 analysisbasedon951patientsinthethymectomygroupand786inthecontrolgroup. ThymectomywasassociatedFigure3 facingpage. CharacteristicsofPost-Thymec- tomyCancer Chart-ReviewCohort. Amongthepatientswithatleastonecanceraftersur- gery thenumberofcancersperpatientwaslarger onaverage amongthosewhohadundergonethymecto- mythanamongcontrols regardlessofthepreopera- tivehistoryofcancer. Detailedmedicalrecordreviewswereperformedfor75patientswhohadundergonethymectomyand75controlsrandomlychosenfromthesubgroupwhohadpostoperativecancer chart- reviewcohort. PanelAshowsdataforallpatientsinthecohort andPanelBshowsdataforthecohortmi- nuspatientswithapreoperativehistoryofcancer. PanelCshowsthetypesofcancerthatdevelopedaftersurgery 64. 9 ofthecancersinthecontrolgroupwereskincancers whereasonly46. 5 ofthecancersinthethymectomygroupwereskincancers. There- mainderofthecancersinthethymectomygrouprep- resentedmostmajortissuetypesinthebody thosefoundinmorethan1 ofthepatientsinthegrouparelistednexttothepiechart. Thetotalnumbersoftypesofpostoperativecancerinthechart-reviewcohortwere116inthethymectomygroupand91inthecontrolgroup. CLLdenoteschroniclymphocyticleukemia andCNScentralnervoussystem. PanelDshowscan- cerrecurrenceaftertherapy whichwasmorecommoninthethymectomygroupthaninthecontrolgroup. PanelEshowsthepercentagesofpostoperativecan- cersthatwouldbetreatedwithanintensiveregimeninvolvingmultimodaltherapy i. e. surgery chemother- apy radiation andmonoclonalantibodies accordingtoNationalComprehensiveCancerNetworkguide- lines. PanelFshowsthetypesofcancersthatrecurredineachgroup nonskincancersthatrecurredinthethymectomygrouparelistednexttothepiechart. DLBCLdenotesdiffuselargeB-celllymphoma. Figure4. EffectofThymectomyontheRiskofAutoimmuneDisease. Theriskofautoimmunediseaseinthethymectomygroupwascomparedwiththatamongage- race- andsex-matchedcontrolsinthefirst5yearsaftersurgery. Therelativeriskofautoimmunediseasewasincreasedamongpatientswhohadundergonethymectomywhodidnothaveahistoryofpreoperativeinfections cancers orautoimmunedisease. 1. 02. 03. 0AllpatientsExcludingpatientswithpreviousinfection cancer orautoimmunediseaseExcludingpatientswithpreviousmyastheniagravisExcludingpatientswithpreviousthymomaExcludingpatientswithpreviouscancerNo. ofPatientsinEachGroupRelativeRiskofAutoimmuneDisease 95 CISubgroup1. 3 0. 91. 7 1. 03 0. 71. 6 1. 1 0. 81. 5 1. 5 1. 022. 2 0. 01. 1 0. 81. 411466491016518962TheNewEnglandJournalofMedicineisproducedbyNEJMGroup adivisionoftheMassachusettsMedicalSociety. Downloadedfromnejm. orgonJune17 2026. nengljmed389 5nejm. orgAugust3 2023414Thenewenglandjournalofmedicinewithmorefrequent varied andaggressivecan- cersthathadahigherincidenceofrecurrenceandresultedinincreasedmortalityfromcancer. RiskofAutoimmuneDiseaseT-cellmediatedimmunityiscriticalforhealth soweassessedwhetherthymectomyisassoci- atedwithuncontrolledinflammationorautoim- munity. Althoughtheriskofautoimmunedis- easewasnothigherinthethymectomygroupthaninthecontrolgroupasawhole5yearsaftersurgery ananalysisinwhichpatientswithpreoperativeinfection cancer orautoimmunediseasewereexcludedrevealedahigherriskofsjTRECCountper gDNA800070006000400030001000500020000ControlGroupThymectomyGroupCConcentrationsofCytokinesinPlasmaACD4 LymphocytessjTRECCountper gDNA40003000100020000ControlGroupThymectomyGroupBCD8 LymphocytesP0. 009P0. 001ColorKeyandHistogramzScoreCountTMx10TMx8TMx18TMx5TMx13TMx15TMx1TMx17TMx20TMx6TMx2TMx14TMx12TMx3TMx11TMx7TMx9CCL5PDGF-ABBBMIGCXCL9CCL15CXCL12CCL22IL-27TPOIL-23IL-4IL-2IL-7IL-10IL-3IFN IL-17AIL-15IL-5CCL1IL-6IL-21LIFIL-9TSLPIL-28AIL-20IL-33TGFIL-17FSCFIL-1 1L-12p70EGFFLT-3LTNFCCL7IL-16CCL21IL-12p40CX3CL1FGF-2CXCL10IL-17EIL-25CXCL5CCL24CCL27CCL2IL-18GM-CSFIL-1RAVEGF-AM-CSFIL-8CXCL1IL-13IL-22IFN-2G-CSFCCL13CCL26PDGF-AACCL11CXCL13CCL17IL-1CCL8CCL3TRAILCCL4TNF TMx4TMx21TMx16TMx19Control4Control9Control2Control1Control11Control5Control6Control10Control15Control16Control3Control13Control14Control7Control17Control18Control8Control12ControlTMx2TMx1 2 100500400300200100123TheNewEnglandJournalofMedicineisproducedbyNEJMGroup adivisionoftheMassachusettsMedicalSociety. Downloadedfromnejm. orgonJune17 2026. nengljmed389 5nejm. orgAugust3 2023415HealthConsequencesofThymusRemovalpostoperativeautoimmunediseaseinthethy- mectomygroup 12. 3 vs. 7. 9 relativerisk 1. 5 95 CI 1. 02to2. 2 Fig. 4. Becausethisdifferencedissipatedwhenriskwasevaluatedovera20-yearperiod thymectomyappearedtohavetransientlyandmodestlyincreasedtheriskofautoimmunedisease. AnanalysisofdatacensoredonthebasisofeachpatientslastMGBsystemin- teractionshowedsimilarresults. Similartothewayinwhichweanalyzedcan- cers weanalyzedthemedicalrecordsof75pa- tientsinthethymectomygroupand75controlswhowererandomlychosenfromthecohortwithapostoperativeautoimmunedisease TableS9. Asintheanalysisofcancer controlswithapostoperativeautoimmunediseasewereolderatthetimeofsurgery 65yearsvs. 50years whichsuggeststhatautoimmunediseaseamongthepatientswhohadundergonethymectomymayhavebeenlessagedriventhanthatamongcon- trols. Amongthepatientswithanautoimmunedisease thosewhohadundergonethymectomyhadmoreautoimmunediseasesperpatientthancontrols 1. 7vs. 1. 1 difference 0. 60 95 CI 0. 31to0. 89 Fig. S9A. Whenpatientswithapreoperativehistoryofautoimmunedisease e. g. myastheniagravis wereexcluded thenumberofpostoperativeautoimmunediseasesperpatientwasstillhigherinthethymectomygroupthaninthecontrolgroup 1. 7vs. 1. 2 difference 0. 54 95 CI 0. 24to0. 83 Fig. S9B. ThetypesofpostoperativeautoimmunediseasefoundinthepatientsareshowninFigureS9C. AdultT-CellProductionStudystaffobtainedconsentforthecollectionoftheplasmaandperipheral-bloodTcellsfrom22patientswhohadundergonethymectomyand20controlsintotal thebloodsamplefrom1con- trolwasofinsufficientqualitytouseforstudy whichleft19controlsintheseanalyses. Thepatientsinthethymectomygroupdidnotdifferfromthoseinthecontrolgroupwithrespecttoage race orsex. NewT-cellproductioncanbemeasuredbyquantifyingsjTRECs theby-productsofVDJre- combinationineachnewlydevelopingTcellinthethymus. Inourcohort demographiccharac- teristicsareshowninTablesS10andS11 themeansjTRECcountsinCD4 andCD8 lym- phocyteswerehigheramongcontrolsthanamongpatientswhohadundergonethymectomy CD4 1451vs. 526permicrogramofDNA dif- ference 925 95 CI 82to1768 P 0. 009 CD8 1466vs. 447permicrogramofDNA dif- ference 1019 95 CI 330to1707 P0. 001 Fig. 5Aand5B. ThisresultindicatesthatthethymuscontinuedtocontributetonewT-cellFigure5 facingpage. T-CellProductionandInflamma- toryResponses. PanelsAandBshowananalysisofsignaljointT-cellreceptorexcisioncircles sjTRECs inCD4 PanelA andCD8 PanelB lymphocytes withresultsex- pressedasthesjTRECcountpermicrogramofDNA. CD4 andCD8 lymphocytesisolatedfrompatientsinthecontrolgrouphadlargermeansjTRECcountsthanthoseisolatedfrompatientsinthethymectomygroup CD4 1451vs. 526permicrogramofDNA difference 925 95 CI 82to1768 P 0. 009 andCD8 1466vs. 447permicrogramofDNA difference 1019 95 CI 330to1707. TheCD4 experimentincluded15pa- tientsinthethymectomygroupand17inthecontrolgroup theCD8 experimentincluded11patientsineachgroup. Intheviolinplots dotsindicateindividualsamplesandthewidthoftheshadedareaindicatestheprobabilitydensity. Ineachbox-and-whiskerplotwithinaviolinplot thehorizontallineindicatesthemedian thetopandbottomoftheboxindicatetheinterquartilerange andthewhiskersindicate1. 5timestheinter- quartilerange. PanelCshowsaheatmapofcytokinesmeasuredinbloodplasmaobtainedfrom21patientswhohadundergonethymectomy labeledTMx and19controls. Apanelof71cytokineswasused 15ofwhichdifferedsignificantlybetweenthegroups P0. 05withBonferronicorrection. Onecontrol of19 wasexclud- edfromthisanalysisbecauseanomalous out-of-rangereadingswereobtainedwithrepeatedtesting. Bonfer- ronicorrectionwasusedforallstatisticaltesting. Thefigureisbasedonlog10 -transformedcytokineconcen- trationsinordertoadjustfordifferencesinscalesofexpression. Unsupervisedclusteringshowedthatthepatientswhohadundergonethymectomyhadsimilarcytokine-expressionprofiles thesepatientsdominatedtwoclusters labeledTMx1andTMx2 thatdifferedfromthecontrolclusterintheirstrongexpressionoftype2andtype17helperT-cellcytokinesandacute- phasereactants especiallyinclusterTMx1 somepa- tientsinclusterTMx2sharedthisphenotype. Thezscoreishighlightedinthetopleftwithahistogramshowingthefrequencyofcytokineexpressionatdiffer- entz-scorevalues. EGFdenotesepidermalgrowthfactor FGFfibroblastgrowthfactor FLT-3LFMS-liketyrosinekinase3ligand G-CSFgranulocytecolony- stimulatingfactor GM-CSFgranulocytemacrophagecolony-stimulatingfactor IFNinterferon ILinterleukin LIFleukemiainhibitoryfactor M-CSFmacrophagecol- ony-stimulatingfactor MIGmonokineinducedbyinterferon- PDGFplatelet-derivedgrowthfactor SCFstem-cellfactor TNFtumornecrosisfactor TPOthrombopoietin TRAILtumornecrosisfactorrelatedapoptosis-inducingligand TSLPthymicstromallym- phopoietin andVEGFvascularendothelialgrowthfactor. TheNewEnglandJournalofMedicineisproducedbyNEJMGroup adivisionoftheMassachusettsMedicalSociety. Downloadedfromnejm. orgonJune17 2026. nengljmed389 5nejm. orgAugust3 2023416Thenewenglandjournalofmedicineproductioninadulthoodandthatprematureces- sationofthymopoiesismighthaveaffectedT-cell mediatedimmunity. T-cellclonality i. e. thedegreeofsamenessoftheTCRrepertoire hasbeenimplicatedinautoimmunityandtheriskofcancer. 31-33Toin- vestigatetheeffectofthymectomyonthecom- plexityoftheTCRrepertoire CD4 andCD8 lymphocyteswerepurifiedinbloodsamplesobtainedfrompatientswhohadundergonethy- mectomyandfromcontrolsandwereanalyzedbyTCRsequencing. Amongthepatientsinthethymectomygroupwhohadpostoperativecan- cer characteristicsofthepatientsareshowninTablesS12throughS15 TCRclonalitywasmoreevidentandtherichnessoftheTCRreper- toirewasdecreasedinCD4 andCD8 lympho- cytepopulations Fig. S10. ThesedatasuggestthattheincreasedriskofcancerseeninpatientswhohadundergonethymectomymayhavebeenrelatedtodecreasedTCRcomplexity. InflammatoryResponsesBloodplasmacytokineconcentrationswereas- sessedbyenzyme-linkedimmunosorbentassayin21patientsinthethymectomygroupand19patientsinthecontrolgroup Fig. 5C. Unsuper- visedclusteringofcytokineprofilesgroupedthepatientsintothreeclusters twodominatedbypatientswhohadundergonethymectomyandonelargelymadeupofcontrols Fig. 5C. Thymec- tomyclusters1and2hadasharedproinflam- matorypattern. Thispatternincludedinterleu- kin-33 thymicstromallymphopoietin andinterleukin-23 aswellasacute-phasereactants thrombopoietinandgranulocytecolony-stimu- latingfactor. Inaddition bothinterleukin-10andinterleukin-1Ra whichareknownsuppressorsofinflammation 34 35weresubstantiallydown-regu- latedinpatientswhohadundergonethymecto- my TableS16. Thecontrolgroupdidnotshowaconsistentproinflammatoryprofile. Takento- gether thesedatasuggestthatthymectomyisassociatedwithasharedcytokinesignatureofimmunedysregulation. DiscussionInthisstudy wefoundthatthymectomyinadulthoodwasassociatedwithanincreasedriskofdeathfromanycauseandanincreasedriskofcancer. Theseobservationsheldtrueeveninsepa- rateanalysesinwhichpatientswithapreoperativehistoryofpotentiallyconfoundingconditionssuchascancer autoimmunedisease infection myas- theniagravis orthymomawereexcluded. Inaddition inthesubgroupofpatientswithoutahistoryofconfoundingconditions anassociationbetweenthymectomyandpostoperativeautoim- munediseasewasnoted. PatientsacrossagegroupswhohadundergonethymectomyweremorelikelytodiefromanycauseandmorelikelytodiefromcancerthancontrolsandtheU. S. generalpopulation. Amongpatientswithpostop- erativecancer thymectomywasassociatedwithmoreaggressive recurrentdisease. Inaddition thymectomywasassociatedwithautoimmunedis- easeinconjunctionwithaproinflammatorymodificationofplasmacytokinelevels includ- ingsubstantiallyelevatedlevelsoftype2helperTcellpromotingfactors interleukin-33andthy- micstromallymphopoietin andtype17helperTcellpromotingfactors interleukin-23 thathavebeenexperimentallyassociatedwithcancerandautoimmunedisease. 36-39ThymectomywasassociatedwithreducedproductionofnewlyformedTcells asreflectedbypersistentlyde- pressedsjTRECcountsextendingtoameanfol- low-upof14. 2postoperativeyears range 8to26. ThisfindingisconsistentwiththatofanotherstudyinwhichdecreasedsjTRECcountswerefoundduringshorterfollow-up 500days ofpatientswhohadundergonethymectomyinadulthoodformyastheniagravis. 40Finally pa- tientswhohadundergonethymectomyandhadpostoperativecancerwerefoundtohavemoreoligoclonal lessdiverseTCRrepertoires whichcouldconceivablycontributetothedevelopmentofcancerandautoimmunedisease. 31-33Together thesefindingssupportaroleforthethymuscontributingtonewT-cellproduc- tioninadulthoodandtothemaintenanceofadulthumanhealth. Thedisruptionofhomeo- stasiscausedbythymectomyissufficienttoad- verselyaffectcriticalhealthoutcomes whicharguesstronglythattheadultthymusremainsfunctionallyimportant. Thisstudyisretrospectiveandobservational andthereforethedatacannotbeusedtoiden- tifycausation. However theyprovideevidenceofanassociationbetweenthymectomyandadverseoutcomesinpatients. Theseresultsstronglysug- gestthatwhenpossible preservationofthethy- musshouldbeaclinicalpriority. SupportedbytheTraceyandCraigA. HuffHarvardStemCellInstituteResearchSupportFund theGeraldandDarleneTheNewEnglandJournalofMedicineisproducedbyNEJMGroup adivisionoftheMassachusettsMedicalSociety. Downloadedfromnejm. orgonJune17 2026. nengljmed389 5nejm. orgAugust3 2023417HealthConsequencesofThymusRemovalJordanProfessorshipofMedicine andagrant U19AI149676 toDr. Scadden fromtheNationalInstitutesofHealth. Dr. KoosheshreceivedsupportfromtheAmericanSocietyofHe- matology. Dr. GustafssonreceivedsupportfromtheSwedishResearchCouncilandtheJohnS. MacdougallJr. andOliveR. MacdougallFund. DisclosureformsprovidedbytheauthorsareavailablewiththefulltextofthisarticleatNEJM. org. WethankJagSingh M. D. Ph. D. LaurenMaranian N. P. Lau- raAseltine N. P. andalltheproviderswhogavepermissionforourstudystafftoobtainconsentfromtheirpatientsfortheirparticipationinthisstudy JohnHiggins M. 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