HENATOLYMPHOIDSYSTEM

THIRDYEARMEDICALSTUDENTS-UNIVERSITYOFJORDAN

AHMADT.MANSOUR,MD

NONNEOPLASTICDISEASESOFTHEWHITEBLOODCELLS

• TherearefivemajortypesofWBCsintheblood:neutrophils,lymphocytes,eosinophils,basophilsandmonocytes.

• Thenormalfunctionofthewhitebloodcellsdependsonatightregulationoftheircountandtheirfunction.Therefore,diseasedevelopsifthereisaderangementofthecellscountorfunction,ittakesoneofthefollowingforms:

o Cytosis:increaseinthenumberofcirculatingcellsabovereferencerange.(Note:leukocytosismeansanincreaseintheWBCcount,neutrophiliameansincreaseintheneutrophiliccount,lymphocytosismeansincreaseinthelymphocyticcount,monocytosismeansincreaseinthemonocyticcount,basophiliameansincreaseinthebasophiliccountandeosinophiliameansincreaseintheeosinophiliccount).

o Cytopenia:decreaseinthenumberofcirculatingcellsbelowreferencerange.(Note:neutropeniameansdecreasedneutrophils,lymphocytopenia,orsimplylymphopenia,meansdecreaseinlymphocytes,monocytopeniameansdecreaseinmonocytes,eosinopeniameansdecreaseineosinophils,andbasopeniameansdecreaseinbasophils).

o Abnormalorabsentfunction

• Cytosis:o Neutrophilia:definedasanincreaseintheneutrophiliccountinthe

peripheralbloodabovereferencerangeforage.o Causes:bacterialinfectionisthemostcommonandmostimportant

etiology.Tissuenecrosisincasesofburnsortraumaandmedicationssuchasepinephrineandcorticosteroidsarealsoadditionalcausesforneutrophilia.

§ Somephysiologicconditionscanleadtoneutrophiliasuchasstress,smokingandpregnancy.

o Pathophysiology:neutrophilsarepresentinthebloodintwopopulations:circulatingandmarginal(meaningneutrophilsstuckto

thevesselwall).ThenormalneutrophilcountreflectsonlythecirculatingpopulationandNOTthemarginalone.

§ Normally,thereisabalancebetweenneutrophilsproducedinthebonemarrowandtheonesremovedfromtheblood;therefore,thecountisnormallykeptinanormalrange.

§ Ifthisbalanceisbroken;duetoinfection,necrosis…etc.,therewillbeanincreaseinthenumberintheperipheralblood.Therearetwomechanismsforthisincrease:

• Demarginalization:thecellsmovefromthevesselwalltothecirculationwithoutanactualincreaseinthebonemarrowproduction:thisisseeninthesettingofstress,exerciseandepinephrineinjection.Alltheseconditionshaveincommonanincreaseinepinephrineinthebody,whichincreasestheproductionofcAMPthat,inturn,mobilizesthecellsfromthevesselwalltothecirculation.Thisconditionistermedpseudoneutrohiliaasthereisnoactualincreaseinbonemarrowproduction.

• Anincreaseinthebonemarrowproduction:thisisseenintissuenecrosis,bacterialinfectionandsteroidadministration.Severalmediators(interleukinsandcytokines)affectthebonemarrowdirectlyandincreasetheproliferationandreleaseofneutrophilsintotheblood.

Morphology:• Thereisanincreaseinthenumberofneutrophilsintheperipheralblood• Thereisa“leftshift”,whichmeansinincreaseinthenumberofmore

immaturegranulocyticcellssuchasbandsandmetamyelocytes.• Toxicchanges:thisismostnotablewithseverebacterialsepsisandis

composedofo Coarsecytoplasmicgranuleswhichareabnormalprimarygranuleso Döhlebodies:sky-bluepatchesofexpandedendoplasmicreticulumo Cytoplasmicvacuoles

Differentiationbetweenreactiveandneoplasticgranulocytosisisusuallystraightforward,howeverconfusioncanariseinonesetting,theso-calledLEUKEMOIDREACTION.Leukemoidreactionisareactivegranulocyticproliferationsecondarytobacterialinfectionthatresultsinextremeelevationintheneutrophiliccountandextremeleftshift.Pleaseremember,intypicalbacterialinfectionstheWBCcountrisesupto15000-20000cell/microliter.However,inleukemoidreactiontherisemayreachupto40,000-100,000cell/microliter,whichoverlapswiththenumbersseeninthemoreominousneoplasmChronicMyeloidLeukemia(CML).Thepathogenesisofleukemoidreactioninvolvesoutpouringofhighquantitiesofinterleukinsandcytokines(suchasIL1andTNFa)thatinducesproliferationofgranulocytesinthebonemarrowandsubsequentlyintheperipheralblood.TherearedifferentmethodstodifferentiatebetweentheleukemoidreactionandCML:

1- HistoryofbacterialinfectionfavorsleukemoidreactionoverCML2- Leukocytealkalinephosphatase(theamountofalkalinephosphatasein

theWBCs)islowinCMLwhilenormalorhighinleukemoidreaction3- ThepresenceofBCR/ABLgenefusionisonlypresentinCMLandabsent

inleukemoidreaction4- Leukemoidreactionusuallysubsideswithtreatmentoftheunderlying

infection,whileCMLhaspersistentelevationintheWBCcounts.

o Lymphocytosis:anincreaseinthenumberoflymphocytesintheperipheralbloodabovethereferencerangeforage.

o Causes:viralinfection,chronicbacterialinfectionsuchastuberculosis,brucellosisand,inchildren,pertussis

o Pathophysiology:activationofcellularimmuneresponseinresponsetovirallyinfectedcellsandthesurgeinantibodiesthataccompanythatinfection.Inpertussis:changesinthesurfaceproteinsinthelymphocytesfavortheirmobilizationintothebloodandpreventingtheirgoingbacktothelymphoidtissue.

Morphology:Dependsontheetiology-Inlymphocytosiscausedbycertainvirusessuchascoxacki,adenovirusandechovirustherewillbelymphocytosisinwhichlymphocyteshavenormal,maturemorphology(similartonormallymphocytesbutincreasedinnumber)-InEBVinfectiousmononucleosis:reactivelymphocytesarenoted:thesearelymphocyteswithabundantcytoplasmthathavecytoplasmicextensionsthatwraparoundRBCs(pleaserememberthatEBVinfectsBlymphocytesbutthereactivelymphocytesareTcell)-Inpertussis:thelymphocyteshavecleavednucleisimilartotheonesyouseeincasesoffollicularlymphoma***Herearethemajordifferencesbetweenfollicularlymphomaandpertussis -Ageofpresentation:FLisadiseaseofpeopleabovetheageof50,pertussischieflyaffectschildren -Clinicalpresentation:WhoopingcoughinpertussisandlymphadenopathyinFL -ThecellsinFLaremonoclonal(expresseitherkappaorlambdalightchainsbutnotboth,cellsinpertussisarepolyclonal) -BCL2ispositiveinFLandnegativeinreactivefollicularhyperplasia

Figure:peripheralbloodfromapatientwithpertussis,noticelymphocyteswithcleavednuclei(similarfindingcanbeseeninfollicularlymphoma)

Figure:peripheralbloodfromapatientwithinfectiousmononucleosis(EBV),noticereactivelymphocyteswithabundantcytoplasmandcytoplasmicextensionswrappingaroundRBCs

o Eosinophilia:anincreaseinthenumberofeosinophilsintheperipheralbloodabovereferencerange

o Causes:o Allergicdisorders:asthma,hayfever,urticariao Parasiticinfections:trichinosis,filarial...etc.o Nonparasiticinfections:systemicfungalinfection,scarletfever,

chlamydiao Certainmedicationssuchaspilocarpine,physostigmine,digitalis,p-

aminosalicylicacid,sulfonamides,chlorpromazine,andphenytoin

o Pathophysiology:thecommonfeaturetoallconditionscausingeosinophiliaisthereleaseofIL-5,whichrecruitseosinophilsandincreasestheirproliferationandreleaseformbonemarrow.

o Morphology:normalmorphologybutincreaseinnumber

o Basophilia:anincreaseinthenumberofbasophilsintheperipheralbloodabovereferencerange

o Causes:o Rarelyasareactiveconditionincasesofallergy,postsplenectomyand

inflammatoryboweldiseaseo Associationwithunderlyinghematolymphoidmalignancy,most

commonlychronicmyeloidleukemia.o Morphology:normalinmorphology,justincreaseinnumber

o Monocytosis:anincreaseinthenumberofmonocytesintheperipheralbloodabovereferencerange

o Causes:o Infections:tuberculosis,protozoalinfections,subacutebacterial

endocarditis,syphiliso Recoveryfromneutropeniao Collagenvasculardisorderssuchasmyositis,temporalarteritis,and

polyarteritis.o Certainleukemias

o Morphology:inreactiveconditions,monocyteshavenormalmorphologywithincreaseinnumbers,however,inmalignantconditionssuchasleukemia,thechromatinisfinewithprominentnucleoli.

**Thefirstimagerepresentsreactivemonocytosisandthesecondrepresentsacuteleukemiawithmonocyticdifferentiation(malignantmonocytes).Noteinthefirstimagethatthemonocyteshavenormalmorphologywithfoldednucleiandcoarsechromatinandinthesecondimagethenucleiareroundwithfinechromatinandprominentnucleoli.

• Cytopenia:o Neutropenia:adecreaseinthenumberofneutrophilsinthe

peripheralbloodbelowreferencerange.o Causes

§ Decreaseproduction• Marrowhypoplasiainpatientswhoreceive

chemotherapyorradiationtherapy• Leukemiaorothertumorsreplacingthemarrow• Medications• Certaintypesofneoplasticlymphocyticproliferations

suchaslargegranularleukemia(LGL)§ Increasedperipheraluse

• Autoimmunedestruction• Overwhelmingbacterial,fungalorrickettsiainfection• Splenomegaly

o Labfindings:decreaseneutrophiliccountwithotherfindingsdependingontheunderlyingcause.

o Complications:increaseriskofinfection,especiallybacterialinfections.

o Lymphocytopenia,orsimply,lymphopenia,isadecreaseinthelymphocyticcountintheperipheralbloodbelowthereferencerange.

o Causes:§ ThemostimportantfactorisHIVinfection§ Mediationssuchassteroids,chemotherapyandmedications

forHIVinfection§ Debilitativeconditionssuchasadvancedcancer,renalfailure,

aplasticanemia,autoimmunedisordersandstarvation§ Infections:suchasTB,influenza,typhoidfever§ Abnormallymphaticcirculation:intestinallymphangectasia,

thoracicductobstructiono Labfindings:decreaselymphocyticcountwithotherfindings

dependingontheunderlyingcause.o Complications:increasedriskofinfectionbyawidevarietyof

organismsincludingcandida,virusesandbacteria.§ Opportunisticinfections:aninfectionthatiscausedbya

pathogenthatwouldnotcauseinfectioninnormalconditions,andtakestheopportunityofdisruptedimmunesystemtocausesevere,andsometimes,fataldisease.

o Monocytopenia:adecreaseinthemonocyticcountintheperipheralbloodbelowreferencerange.

o Rareasanisolatedfinding.

o Causes:§ Steroids,monocytesdropinthefirstfewhoursofreceiving

steroids.§ Hairycellleukemia:aformofBcellneoplasm.

o Basopeniaandeosinopeniaarenotacauseofclinicalconcernandwillnotbecoveredinthismanuscript.

• Functionaldisorders:o Neutrophilicfunctionaldisorders:fourdisorderswillbediscussed

§ Chédiak-Higashisyndrome§ Chronicgranulomatousdisease§ Myeloperoxidasedeficiency§ Leukocyteadhesiondeficiency

o Chédiak-Higashisyndrome:autosomalrecessiveaffectingtheLYSTgene(lysosomaltraffickingregulator).Thisgeneisinvolvedinregulationofvesicularsize,trafficking,andintracellularmovement,suchthatvesicularmigrationandreleaseareabnormal.

o Clinically:recurrentpyogenicinfection,albinism(affectsvesiclesthatcontainmelaninpigment,neurologicmanifestationsandphotophobia).Earlydeathduetoinfections.

o Morphology:largecytoplasmicgranulesintheneutrophils,monocytesandlymphocytes.

Noteinthisimagethelargebasophiliccytoplasmicgranulesintheneutrophil,similargranulescanbeseeninlymphocytesandmonocytes.

o Chronicgranulomatousdisease:autosomalrecessive(66%)orX-linked(33%)resultingingeneticdefectaffectingNADPHoxidase,thisenzymecatalyzestheproductionofoxygenradicalspeciesthatplaysavitalroleinkillingmicroorganisms.This,inturn,resultsininabilityofthecellstokillphagocytizedbacteria.

o Clinically:chronic,recurrentbacterialinfectionswithfrequentgranulomatouslesions

o Morphology:thereisnomorphologicchangeinthebloodcells(normalappearance).

o Myeloperoxidasedeficiency:autosomalrecessivedisorder,resultinginqualitativeorquantitativedeficiencyofMPO.

o Mostpeoplewiththisdeficiencyarecompletelyasymptomaticwithincreasedriskofinfection

o Inlessthan5%ofpatientsfungalinfectionsbycandidaspeciescandevelop.

o Theneutrophilslookabsolutelynormal.o Leukocyteadhesionmoleculesdeficiency(LAD):rare

disordercharacterizedbydefectiveexpressionoftheadhesionmoleculesontheneutrophils

o Clinically,thereisanincreaseriskofinfection,neutrophiliaanddelayedseparationoftheumbilicalcord.

o Therearenomorphologicchanges,theneutrophilslookabsolutelynormal.

***Functionaldiseasesofthelymphocyteswillbecoveredintheimmunologycourseandwon’tbediscussedinthismanuscript.

NONEOPLASTICLYMPHNODEDISEASES

Lymphoidtissue(lymphnodes,mucosaassociatedlymphoidtissue,Peyerpatches...etc.)aredynamicorgansthatundergochangesinresponsetoantigenicstimulation.Lymphadenopathyreferstoenlargementofthelymphnodes,readilynotableinthesuperficialgroupssuchascervical,axillaryandinguinallymphnodes.

Thefollowingwillbediscussed1. Acutelymphadenitis2. Follicularandparafollicularhyperplasia.3. Sarcoidosis.

Acutenonspecificlymphadenitis:Occursinthesettingofinfectioninthevicinityofthelymphnodes.Forexample,infectionofthetonsilsorteethabscesscanresultincervicalacutelymphadenitis.Infectionofthebreastcanresultinaxillarylymphadenitis,andinfectionoftheskinofthelowerextremitycausesinguinallymphnodeenlargement.Somebacterialorviralinfectionscanresultingeneralizedlymphadenopathy.Acutemesentericlymphadenitiscanresultasacomplicationtocertainviralinfections,andcanmimicacuteappendicitisclinically.Morphology:

o Enlarged,sometimestender,lymphnodes.o Large,variablysizedfollicleswithnecroticgerminalcentersandneutrophilic

infiltration.

o

Noteintheimagethatthecentercontainsalargenecroticfocusfilledwithdeadtissueandneutrophilicinfiltration.FollicularandparafollicularhyperplasiaRememberthatthelymphnodecontainsareasforB-lymphocytescalledthefolliclesorthecortexandareasforT-lymphocytestypicallyresidebetweenthefolliclesintheparafollicularorparacorticalarea.Thelocationoftheofthehyperplasia(corticalorparacortical)dependsthenatureofthestimulatingantigen,rememberthatBlymphocytesareinvolvedinhumoral(antibodyproducing)immuneresponsewhileTlymphocytesareactivatedbystimulithatneedT-cellmediatedimmuneresponse.FollicularhyperplasiaisdefinedasanincreaseinthenumberandsizeoffolliclessecondarytostimulithatneedBcellresponse

o Causeso Bacterialinfectiono Rheumatoidarthritiso Lupuso EarlystagesofHIVinfectiono Sometimesnoknowncauseisfound

o Morphologyo Numerous,variablysizedsecondaryfollicles(follicleswithgerminal

centers)o Abundanttangible-bodymacrophagesinthegerminalcenterso Frequentmitosiso Smallmantlezones

o

Noteintheimagesthepresenceoffollicleswithdifferentsized.Inthesecondimagenotethepresenceoftigible-bodymacrophagesthatcontaindebrisofapoptoticcells.

o Differentialdiagnosis:themostimportantdifferentialdiagnosisisfollicularlymphoma

o Incontrasttofollicularlymphoma,follicularhyperplasiaischaracterizedby

§ Tingible-bodymacrophages(FLdoesnothavemacrophagesasitiscomposedonlyofneoplasticBcells)

§ Ageofpresentation,follicularhyperplasiatypicallyaffectsyoungpatientswhileFLisaisadiseaseofthepeopleolderthat50yearsofage

§ BCL2(anantiapoptoticprotein)istypicallynegativeinhyperplasiawhilepositiveinFL(seelaterdiscussionoffollicularlymphoma)

ParacorticalhyperplasiaisdefinedasanexpansionoftheparacorticalareasbyTlymphocytesinvariousstagesofstimulationandmaturation.

o Causedusuallybyviralinfection,medicationsandaftervaccinationso Morphology:

o Expansionoftheparacorticalareaswithresultingatrophyofthefollicles

o Theparacorticalareasshowthepresenceofimmunoblasts(activatedTlymphocytesthatarethreetimeslargerthanthenormalTlymphocyteswithfinechromatinandprominentnucleoli.

o

Noteinthefirstimagethepresenceofatrophicfollicleintheupperhalfandanexpandedparacortexinthelowerhalf.Inthesecondimage,notethepresenceoflargecells(immunoblasts,thickarrow),comparethemtothematurelymphocyte(thinarrow).Sarcoidosis:Sarcoidosisisasystemicgranulomatousdiseaseofunknowncausethatmayinvolvemanydifferenttissuesandorgans.Inthevastmajorityofcasesthelungandhilarlymphnodesareinvolved.

o Morphology:thelymphnodesareeffacedbyalargenumberofnonnecrotizinggranulomas

o

Noteinthefirstimagethepresenceofnumerousgranulomas.Inthesecondimage,noticethatthesegranulomasdonotcontainnecrosisandarecomposedofepithelioidhistiocyteswitharimoflymphocytes.