Plasma Cell Neoplasms (2021)

Hematopathology Lecture Series

1. Plasma Cell Neoplasms
By:Ahmed MakboulAhmed
M.B.B.Ch, M.Sc
Assistant Lecturer, Clinical Pathology Department, South Egypt Cancer Institute

2. •Plasmacellsareshort-livedantibody-producingcellsderived
fromB-lymphocytes.
•B-lymphocytesdifferentiateintoplasmacells.
•Oncereleasedintothebloodandlymph,theantibodiesbindto
thetargetantigen(foreignsubstance)andinitiateits
neutralizationordestruction.Antibodyproductioncontinuesfor
severaldaysormonths,untiltheantigenhasbeenovercome.
•Eachplasmacellcansecreteseveralthousandmoleculesof
antibody,thusreleasingalargeamountofantibodyinto
thecirculation.
PLASMACELLS

3. •Humoralimmunitybeginswhenanantibody
onB-cellbindstoanantigen.TheB-cellthen
internalizestheantigenandpresentsittoa
specializedhelperT-cell,whichinturn
activatestheB-cell.
•ActivatedB-cellsgrowrapidly,
producingplasmacells,whichrelease
antibodiesintothebloodstream,andmemory
B-cells,whichstoreinformationaboutthe
pathogeninordertoprovidefutureimmunity.

4. Plasmacellmorphology
•Size:8to20µm.
•Nucleus:Roundoroval;eccentric.
oNucleoli:None.
oChromatin:Coarse.
•Cytoplasm:Deeplybasophilic,oftenwith
perinuclearclearzone(hof).
•Granules:None.
•Vacuoles:Nonetoseveral.
•N:Cratio:2:1to1:1

7. IMMUNOGLOBULINS
•ImmunoglobulinsaresynthesizedbyB-cellsandarebothsynthesizedand
secretedbyplasmacells.
•Antibodiesnoncovalentlybindtoantigenstoimmobilizethem,renderthem
harmless,or"tag"theantigenfordestructionandremovalbyother
componentsoftheimmunesystem.Indoingso,antibodiesfacilitatetheability
ofothercellsandmoleculesintheimmunesystemtoidentifyandinteractwith
antigens.

8. Structureofimmunoglobulin

9. PLASMACELLNEOPLASMS
-Plasmacellneoplasmsareclonalproliferationsofplasmacellsorlymphocytesthat
makeandsecreteasingleclassofIgorapolypeptidesubunitofasingleIgthatis
usuallydetectableasamonoclonalprotein(M-protein)onserumorurineprotein
electrophoresis.
-MostofthesehavetheiroriginasBMtumorsbutoccasionallypresentin
extramedullarysites

10. CLASSIFICATION
The 2016 WHO classification of Plasma Cell Neoplasms
1.Plasmacellmyeloma(PCM).
2.Monoclonalgammopathyofundeterminedsignificance(MGUS).
3.Plasmacytoma.
4.Monoclonalimmunoglobulindepositiondiseases:
oPrimaryamyloidosis.
oSystemiclightchainandheavychaindepositiondiseases.
5.Plasmacellneoplasmswithassociatedparaneoplasticsyndrome:
oPOEMSsyndrome.
oTEMPIsyndrome.

11. 1. PLASMA CELL MYELOMA (PCM)
DEFINITION
-Plasmacellmyeloma(PCM)isaBMbased,multifocalplasmacellneoplasmusually
associatedwithanM-proteininserumorurine.
-TheBMisthesiteoforiginofnearlyallmyelomasandinmostcasesthereisdisseminated
BMinvolvement.Otherorgansmaybesecondarilyinvolved.
-Thediagnosisofmyelomaismadebyacombinationofclinical,morphologic,immunologic
andradiographicinformation.Thediseasespansaclinicalspectrumfromasymptomaticto
highlyaggressive.

12. PATHOGENESIS
•Myelomacellsoriginatefromantigen-exposedpost-germinal
centerBcellswithsomatichypermutation,IgHgene
rearrangement,andclassswitching.Theprogenyofthiscell
migratestoBMwherematurationtoterminallydifferentiated
plasmacellsoccurs.
•AnearlyeventischromosomaltranslocationinvolvingIGHon
chromosome14q32thatpreventnormalcelldifferentiation
andapoptosis;causingimmortalizationofplasmacell
clone.
•Furthergeneticchangesleadtotransformationtoabnormal
plasmacellclone(monoclonalgammopathyofundetermined
significanceorMGUS).Itisnowrecognizedthatinalmostall
cases,PCMisprecededbyasymptomaticMGUS.

13. CLINICALISSUES
Incidence
•10-15%ofhematopoieticmalignancies.
•1%ofmalignanttumors.
Age
•Incidenceisincreasingaspopulationages.
•90%ofcasesare>50yearsold.
•Rarelyobservedinpeople<35yearsold.
•Myelomaisnotfoundinchildren.
Sex
-Itismorecommoninmenthanwomen(M:Fratio=3:2).

14. DIAGNOSTICWORKUP
RecommendeddiagnosticstudiesforPCMpatientsaccordingtoInternationalMyelomaWorkingGroup(IMWG):
I.Historyandphysicalexamination
•UniquetriadoBMplasmacytosis.
oOsteolyticbonelesions.oMonoclonalgammopathy
•Clinical&laboratoryfindingsreflectoraresecondarytotheseabnormalities:oBonepain,fatigue,weightloss(mostcommonpresentingsymptoms).
oPallor:dueto:§Anemiaofchronicdisease.§BMreplacement.
§Bleeding.§Decreasederythropoietinduetokidneyfailure.

15. oRenalfailure:dueto:
§Amyloiddeposits.
§Excesslightchain(LC).
§MonoclonalLCproteinuriafromtubulardamage.
oRecurrentbacterialinfections:dueto
§Hypogammopathy&immunodeficiency.
§NeutropeniafromBMinfiltration.
oBleeding:dueto:
§Thrombocytopenia(fromBMinfiltration).
§Plateletdysfunction(duetocoatingoftheplateletswithimmunoglobulins).
oOccasionalneurologicmanifestations:
§Spinalcordcompression,peripheralneuropathy.

16. II.Routinetesting
1.CBCwithdifferentialandperipheralblood
smearreview
RBCs
•Anemiadevelopswithprogressionofdiseaseinall
patientsandisnormocyticandnormochromic.
•Rouleauxformation:causedbyincreased
immunoglobulin.
WBCs
•WBCcountmaybenormalorlow.
Platelets
•Plateletcountisusuallynormal.
•Thrombocytopenia,whenpresent,isusuallymild.

17. 2.Chemistrypanel&otherlabinvestigations
a).Liverfunctiontests
•Totalprotein:increased.
•Albumin:decreasedwithinvertedA/Gratio.
•Serumalkalinephosphatase(ALP):isnormalorslightlyincreased.
•ALPishelpfulindifferentiatingMMfromskeletalinvolvementduetohyperparathyroidismormetastaticcarcinomainwhichalkalinephosphataseismarkedlyraised.
b).Kidneyfunctiontests
•Serumcreatinine:increasedinthepresenceofrenalinsufficiency.
•Uricacid:increased(>50%).
c).LDH.

18. d).SerumCalcium
•Hypercalcemiaisoftenpresent.
e).β2microglobulin
•Increased(75%atdiagnosis).
•Surrogatemarkerfortumorburden.
•Usefulforprognostication.
f).C-reactiveprotein(CRP)
•Asurrogatemarkerofinterleukin(IL)-6activity.
oIL-6isoftenreferredtoastheplasmacellgrowthfactor.
•CRPisusefulforprognostication.
g).ESR
•Amarkedlyincreased(orrapid)ESRisatypicalfeature.Itisduetoincreasedimmunoglobulins.

19. 3.Serumproteinelectrophoresis(SPEP)and24-hoururineproteinelectrophoresis
(UPEP)
•Proteinelectrophoresisisanelectrophoreticmethodofseparatingproteinspresentin
serumorurinetovariousfractionsbasedontheirmolecularweightandelectric
charges.

20. Direction of electric current
Migration of proteins

21. Principleofproteinelectrophoresis
•Theprocedurestartsbyapplyinganaliquotoftheserumtoagel.
•Thegelcontainsanalkalinebuffer,andinthisenvironment,alltheproteinshaveanegativechargeofdifferentmagnitude(i.e.anions).
•Astrongelectricalcurrentthenispassedthroughthemediumforasettimeperiod.
•Duringthistimetheproteinsmigratefromtheapplicationpointtowardthepositivelychargedanodeforvaryingdistancesrelatedtotheircharge,size,andshape.
•Albuminhasthestrongestnegativechargeinthealkalinegelenvironmentandisoneofthesmallestproteinsinserum.Duetothechargeandsmallsize,albuminmigratesthefurthest.
•Largeandmoreweaklychargedproteins,suchastheimmunoglobulins,maymigrateverylittlewithintheelectricalcurrent.

22. •Albuminzone:showstheonlyalbumin.
•Alpha1-zone:
oAlpha1-antitrypsin.
•Alpha2zone:
oAlpha2macroglobulins.
oHaptoglobin.
oHDL.
•Betazone:
oTransferrin.
oLDL
oC3.
•Gammazone:
oImmunoglobulins:IgA,IgM,IgG.
oCRP.
oFibrinogen.

23. RoleofSPEPinPCM
•SPEPistheinitialstepintheidentificationofabnormalproteins.
•Mband:Alocalizeddensebandwithsharpmarginsinthegammaregiontoalpha-2region.
oFeatures:narrow-based,tall,sharplydefinedspike.
•Thepositionofthebandmaysuggestthetypeofimmunoglobulin,e.g.IgGislocatedingammaregionwhileIgAmigratestobetaregion.
•Mbandinserumisnotobservedin:
oNon-secretorymyeloma.
oLightchaindisease(duetorapidexcretionoflightchaininurine).
oPrimaryamyloidosis.

24. Roleof24-hourUPEPinPCM
•Usefulinplasmacellneoplasmsinwhichonly
lightchainsaresynthesizedinwhichMbandmay
notbedetectedonSPE.
oThisisbecause,duetotheirlowmolecular
weight,lightchainsareexcretedinurine.
•BenceJonesproteininurinereferstoeitherκor
λlightchainssynthesizedbyaneoplasticcloneof
plasmacells.

25. 4.Immunofixationelectrophoresis(IFX)
•Thistechniqueisthegoldstandardforidentificationof
natureofMproteinandisparticularlyhelpfulforthe
identificationofasmallamountofMprotein.
•PrincipleofIFX
oInthistechnique,serumproteinsareseparatedby
electrophoresisinagelandmonospecificantiserum
(IgG,IgM,IgA,κorλlightchains)isapplieddirectly
overthesurfaceofthegel.
oIdentificationoflightchaintype(κorλ)isdoneby
immunoelectrophoresisorimmunofixation.
oImmunoprecipitationbanddevelopsinthegel
betweencorrespondingproteinantigenandthe
monospecificantiserum.

26. •DistributionofMcomponentinPCMpatients
oIgG(50%).
oIgA(20%).
oLightchain(20%).
oIgD(2%).
oBiclonal(2%).
oIgE/IgM(<1%).
oNon-secretory(3%).
•Forlightchain,kappaismorecommonthanlambda.

27. 5.Nephelometricquantitationofimmunoglobulins
•Thequantitationofmonoclonalandotherimmunoglobulinsisnecessarytoassessthe
diseaseseverityandfollowresponsetotreatment.
•TheheightofthepeakonSPEPisdirectlyproportionaltotheamountofMprotein.
•Normalresultsforthe3immunoglobulinsare:
oIgG:560to1800mg/dL.
oIgM:45to250mg/dL.
oIgA:100to400mg/dL.

28. 6.SerumFreeLightChain(SFLC)assay
Indications
1.Forthemorethan3%ofmyelomapatientsinwhichMbandisnotdetected:
oNon-secretory.
oOligosecretorydisease
oLightchainonlydisease.
2.ForthemajorityofpatientswithALamyloidosis(AL).
ØInthesepatients,thetraditionalmethodsofmeasuringcirculatingmonoclonal
immunoglobulinsarenotadequate.
3.SFLCtestingisalsousefulforprognosisandmonitoring,andmaynegatetheneedfor
24-hoururinecollections.

29. •SFLCassaymeasurestheconcentrationoffreekappaandlambdalightchainsand
canincreasethesensitivityofdiagnostictesting.
•Notallmonoclonalgammopathiessecreteexcessfreelightchains,soSFLCtesting
aloneisinsufficientfordiagnosisandshouldbepairedwithSPEPandIFX.
•Someconditions,suchasrenalinsufficiencyandsomeautoimmuneconditions,may
causeabnormalitiesinSFLCmeasurements

30. III.Bonemarrowstudies
1.Bonemarrowaspiration(BMA)
-Thisrevealsplasmacytosis(>10%plasmacells).
-BMinvolvementisoftenfocalandpercentageofplasmacellsaspiratedfromdifferent
sitesisvariable.
-Onthebasisoftheircytologicfeatures,myelomashavebeenclassifiedintomature,
intermediate,immature,andplasmablasticcytologictypes(Greippsystem):

31. The mature-type myeloma
•Cytoplasm:abundant,deeplybasophilic
cytoplasmwithaperinuclearclearareaor‘hof’
representingGolgizone.
•Nucleus:eccentrically-placednucleuswith
coarsechromatinandnonucleoli.
The immature-type myeloma
•Size:Largerthantypicalplasmacells.
•Nucleus:
oLargernucleus,whichmaybecentrallyor
eccentricallylocated.
oFinelydispersednuclearchromatin.
oOneortwoprominentnucleoli.
oTheymaybebiormultinucleated.
•Cytoplasm:Lightbluecytoplasm.
•Pleomorphismmaybeseen.

32. The intermediate-type myeloma
•Theplasmacellsexhibitfeaturesintermediate
betweenmatureandimmaturetypesof
myeloma.
•Theyhavemoderatelydispersedchromatinand
occasionalsmallnucleoli;severalhavelobated
nuclei,andtwoarebinucleate.
The plasmablastic myeloma
•Plasmacellsareatypicalwithahighnuclear-to-
cytoplasmicratio.
•Thenucleihavedispersedchromatinand
containsmallnucleoli.

33. Morphologicvariants:(duetoaccumulationof
immunoglobulinsinplasmacells)
•Mottcellswithpale,bluish-white,grape-like
accumulations.
•Russellbodieswithcherry-redrefractiveround
bodies.
•FlamecellswithglycogenrichIgA.
•Crystal-likeinclusions.
•Crystallinerods.

34. 2.Bonemarrowtrephinebiopsy
•LargeclustersorsheetsofplasmacellsonBMbiopsy
arehighlysuggestiveofaneoplasticratherthana
reactivedisorder.
•Astagingsystemhasbeenproposedbasedon
percentageofmarrowspacereplacedbymyelomainBM
trephinebiopsies:
oStageI:<20%ofBMisreplacedbyplasmacells.
oStageII:20to50%ofBMisreplacedbyplasma
cells.
oStageIII:>50%ofBMisreplacedbyplasmacells.
•TheextentofinvolvementinBMbiopsysectionsusually
reflectstheoveralltumorburden.

35. 3.Ancillarystudies
a).Immunohistochemistry
•IndicationsofimmunohistochemistryinPCM
1.AssessmentofquantityofplasmacellsinBMbiopsies.
2.Identificationofamonoclonal(vs.polyclonal)plasmacellproliferation
3.Identificationofunusualmorphologicvariantsofmyeloma.
4.Distinctionofmyelomafromotherneoplasms.
•Markersused:CD138,kappa(κ)&lambda(λ)lightchains:
oQuantifyclonalPCpopulationintissue.
oNormalplasmacells:kappa>lambda(2-3:1)
CD138
Kappa
Lambda

36. b). Flow cytometric immunophenotyping
Benignplasmacells:
•PositiveforCD19,CD38,CD138andCD45.
•NegativeforCD20,CD28,CD117,andCD56.
•Expresspolytypiccytoplasmicimmunoglobulinlightchain.
Malignantplasmacells:
•TheyshowbrightCD138expression,dimCD38expression.
•DecreasedorabsentCD19orCD45.
•IncreasedCD56andCD117.
•Expressmonotypiccytoplasmicimmunoglobulinlightchain.

37. c).Genetictesting
•Myelomaisdividedatthehighestgeneticlevelintotwosubtypes:
oHyperdiploid(h-MM):
§48–75chromosomes.
§RepresentsabouthalfofcasesofPCM.
oNon-hyperdiploid(nh-MM):
§<48or>75chromosomes.
§Thenon-hyperdiploidtypeischaracterizedbyimmunoglobulinheavy-chain(IgH)
translocationsandisgenerallyassociatedwithmoreaggressivediseaseandshorter
survival.

38. The International Myeloma Working Group (IMWG) Cytogenetic Classification
(%) of patients
I.Hyperdiploid(h-MM) 45
II.Non-hyperdiploid(nh-MM): 40
1.CyclinDtranslocation: 18
ot(11;14)(q13;q32) 16
ot(6;14)(p21;q32) 2
ot(12;14)(p16;q32) <1
2. FGFR3 translocation:15
ot(4;14)(p16;q32)(FGFR3-IGH)15
3. MAF translocation:8
ot(14;16)(q32;q23)(IGH-MAF)5
ot(14;20)(q32;q11) 2
ot(8;14)(q24;q32) 1
III.Unclassified(other)15

39. MayoStratificationofMyelomaandRisk-AdaptedTherapy(m-SMART)
Standard Risk (60%)Intermediate Risk (20%)High Risk (20%)
t(11;14)t(4;14)del (17p)
t(6;14)del (13)t(14;16)
HyperdiploidHypodiploidt(14;20)
All othersPC labelling index ≥ 3High risk signature GEP
OS= 8 –10 yearsOS= 4 –5 yearsOS= 3 years

40. Methodsoftesting
1.ConventionalCytogeneticAnalysis
(Karyotyping)
•PerformedonBMspecimenatclinical
presentation.
oMayuseIL-6orIL-4tostimulategrowth
duetotypicallylowplasmacellproliferative
activity.
oInformativein30-40%ofPCM.

41. 2.FluorescenceinSituHybridization(FISH)
Interphasefluorescentinsituhybridization(I-FISH)
•FISHdetectschromosomalabnormalitiesin>90%ofPCM.
•54%ofbonemarrowswithnormalcytogeneticsshowabnormalitiesbyI-FISH.
•Considered”goldstandard”.
RecommendedFISHprobesbyIMWGforriskstratification
1.del(13q).
2.TP53deletion[del(17p)].
3.t(4;14)(p16;q32)andt(14;16)(q32;q23)are2highrisktranslocationsnotclearlyseenincytogenetics.
4.Hyperdiploidytestingandt(11;14)(q13;q32).
FGFR3-IGH
Del(17p)

42. IV. Imaging
Bonesurvey
•Osteolyticlesionsin70%ofcases.
oVertebrae>ribs>skull>shoulder>pelvis>longbones.
•Ifnolesionsidentified,mayrequireMR,CT,orPETscans.
•MRrecommendedininitialassessmentofsmolderingPCM.
•Osteoporosis(10-15%).
Radiographiclesions
•MayrequiredirectedbiopsiestoestablishdiagnosisofPCMinsomepatients.

43. DIAGNOSTICCRITERIA
The revised IMWG diagnostic criteria of Plasma cell myeloma
ClonalBMplasmacells≥10%orbiopsy-provenplasmacytomaPLUSanyoneormoreofthefollowingmyelomadefiningevents(MDEs):
1.End-organdamageattributabletotheplasmacellproliferativedisorder(CRAB):
•Hypercalcemia:serumcalcium>1mg/dLhigherthantheupperlimitofnormalor>11mg/dL.
•Renalinsufficiency:creatinineclearance<40mLperminorserumcreatinine>2mg/dL.
•Anemia:Hemoglobinvalueof>2g/dLbelowthelowerlimitofnormalorahemoglobinvalue<10g/dL.
•Bonelesions:oneormoreosteolyticlesionsonskeletalradiography,CT,orPET-CT.
2.Oneormoreofthebiomarkersofmalignancy:
oClonalBMplasmacellpercentage≥60%.oInvolved:uninvolvedserumfreelightchainratio(kappa:lambdaorlambdatokapparatio)≥100(providedthattheabsolutelevelofinvolvedFLCisatleast100mg/L).oMorethanonefocallesionsonMRIstudies.

44. PROGNOSIS:
Revisedinternationalstagingsystemformyeloma(IMWG2015)
I.ISSstage:
StageI:oSerumβ2microglobulin<3.5mg/L.
oSerumalbumin≥3.5g/L.
StageII:Not ISS stage I or stage III.
StageIII:Serum β2 microglobulin≥ 5.5 mg/L.
II.ChromosomalabnormalitiesbyiFISH:
Highrisk:Presence of: t(4;14) and/or t(14;16) and/or del(17p).
Standardrisk:No high risk-chromosomal abnormalities.
III.LDH:
Normal:SerumLDH<theupperlimitofnormal.
High:SerumLDH>theupperlimitofnormal.

45. Revised international staging system for myeloma (IMWG 2015)
Stage 5-yearsurvivalrates
R-ISSstageI:oISSstageI.
oStandardriskCA.
oNormalLDH.
82%
R-ISSstageII:NotR-ISSstageIorstageIII.62%
R-ISSstageIII:oISSstageIII.
oHighriskCA.
oHighLDH.
10%

46. LABORATORYTESTINGFORFOLLOWUPOFPCM:
Laboratory testing for follow-up of myeloma patients
Every treatment cycleAt suspected complete
response
At suspected
progression
SerumproteinelectrophoresisYesYesYes
SerumimmunofixationOnly if not measurable
at electrophoresis
YesYes
UrineproteinelectrophoresisYesYesYes
UrineimmunofixationOnly if not measurable
at electrophoresis
YesNo
SerumfreelightchainOnly if not measurable
at electrophoresis
YesYes
Bonemarrowaspirate/biopsyNoYesYes
Haemoglobin,serumcreatinine,
calcium
YesYesYes

47. PLASMACELLMYELOMAVARIANTS
1.SmolderingPlasmaCellMyeloma(Asymptomaticmyeloma)
Incidence
-About8%to14%ofpatientswithPCMareasymptomaticatthetimeofdiagnosis.
Features
•Absenceofend-organdamage,biomarkersofmalignancy,oramyloidosis.
•Thesepatientshave10%ormoreBMplasmacellsandanM-proteinatmyeloma
levels.
•PlasmacellsarecytologicallyatypicalinBMaspiratesmears,andfocalaggregatesof
plasmacells,interstitialinfiltration,orbotharefoundinBMbiopsysections.
•Theimmunophenotypeandgeneticsappeartobesimilartoothermyelomas.

48. Diagnosticcriteria
The revised IMWG diagnostic criteria of Smoldering Myeloma
•SerumM-protein(IgGorIgA)≥30g/LorurinaryM-protein≥500mgper24hr.
AND/OR
oClonalBMplasmacells10%to60%.
oAbsenceofmyelomadefiningeventsoramyloidosis.
Bothcriteriamustbemet.

49. 2.Non-SecretoryPlasmaCellMyeloma
Incidence
•About 3% of PCMs.
Features
•Neoplasticplasmacellslackthecapacitytosecreteimmunoglobulin.
oAsaresult,thereisnoM-proteinineithertheserumorurinebyimmunofixationanalysis.
•Inabouttwothirdsofthesepatients,however,elevatedserumfreelightchainsoranabnormalfreelightchainratioisdetectable.
•Monoclonallightchainsaredemonstratedinthecytoplasmofthemyelomacellsinabout85%ofcasesbyimmunohistochemicalstaining(producermyeloma).In15%ofcases,nostainingisdetected,suggestingthatIgisnotproduced(non-producermyeloma).
•Theclinicalfeaturesofnon-secretorymyelomaarealsogenerallysimilartootherPCMs,exceptforlowerincidenceofrenalinsufficiencyandhypercalcemia.
•Thecytologicandhistologicfeatures,immunophenotype,andgeneticsofnon-secretorymyelomaappeartobesimilartoothermyelomas.

50. 3.PlasmaCellLeukemia(PCL)
Definition
•Plasmacellleukemia(PCL)isanaggressivediseasedefinedasanabsoluteplasma
cellcountofmorethan2x109/Lorplasmacellsconstitutingmorethan20%ofthetotal
leukocytecountintheperipheralblood.
•PrimaryPCL
oRepresents5%ofthenewlydiagnosedcasesofmyelomabut60%ofallPCL
cases.
oItisfrequentlyassociatedwithhepatosplenomegaly,extramedullarydissemination,
andapooroutcome.
•SecondaryPCL
oItresultsfromexcessivetumorgrowthandrepresents1%ofallmyelomacases.

51. CBC
RBCs
•Anemiaispresentin80%ofcasesofPCL.
Platelets
•Thrombocytopeniain50%.
WBCs
•ThetotalWBCcountmaybeinthenormalrangebutisusuallyelevatedandmaybeashighas100x109/L.
•Plasmacellsare>20%oftotalWBCsorabsolutePCcountexceeds2x109/L.oOften,manyofPCsaresmallerthanusualwithrelativelylittlecytoplasmandmayresembleplasmacytoidlymphocytes.
oLargeandpleomorphicplasmacellsareuncommon.
oCaseswiththesefeaturesmaybedifficulttodistinguishfromalymphoplasmacyticlymphomaonPBsmearexamination.

52. Immunophenotyping
•Malignant plasma cells in PCL show bright CD138 expression, dim CD38 expression(as PCM).
•PrimaryPCLtendstobepositiveforCD20(50%)butnegativeforCD117andCD56comparedtomyeloma.
•TheplasmacellsusuallyexpresscytoplasmicbutnotsurfaceIglightchainwithrareexception.
Cytogenetics
•AnabnormalkaryotypeismorefrequentlyfoundinPCLthaninothermyelomas.
oThereisahigherincidenceofhigh-riskgeneticsinbothprimaryandsecondaryPCL.Theseincludehypodiploidy,del(13q),del(17p)t(14;16),1qamplification,and1plosses.
oThet(11;14),usuallyassociatedwithafavorableprognosisinPCM,isalsomorefrequentinprimaryPCL.

53. 2. MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS)
DEFINITION
•MGUSisanasymptomaticdisorderinwhichamonoclonalimmunoglobulinissecretedbylowproliferatingplasmacellsinthebonemarrow.
•ThediagnosisofMGUSrequires:
oSerumMprotein<30g/L.
oBMplasmacells<10%.
oAbsenceofmyeloma-definingeventssuchasCRAB.
•PatientswithMGUSmayeventuallyprogresstoPCM.

54. ThreetypesofMGUSrecognized:
i.Non-IgMMGUS(plasmacell)
•85%ofMGUS;IgGparaprotein.
•Hasmyeloma-typegenetics.
•Progressestoplasmacellmyeloma(PCM),solitaryplasmacytoma,plasmacellleukemia.
ii.IgMMGUS(lymphoidorlymphoplasmacytoid)
•15-20%ofMGUS;IgMparaprotein.
•Lacksmyeloma-typegenetics.
•NoevidenceofotherB-cellproliferativedisorder.
•ProgressestoWaldenströmmacroglobulinemia(WM).
iii.LightchainMGUS
•Newentity.
•ProgressestolightchainPCM.

55. DiagnosticCriteria
The revised IMWG diagnostic criteria of MGUS
1.SerumM-protein(IgAorIgG)<30g/L.
2.ClonalBMplasmacells<10%.
3.Absenceofend-organdamage(CRAB:hypercalcemia,renalinsufficiency,anemia,bonelesions)oramyloidosisattributabletotheplasmacellproliferativedisorder.
4.ForlightchainMGUS:
oAbnormalfreelightchainratio(<0.26or>1.65).
oIncreasedleveloftheinvolvedfreelightchain.
oNoimmunoglobulinheavychainexpressiononIFE.
oUrinaryM-protein<500mg/24hr.
oClonalplasmacells<10%.
oAbsenceofend-organdamage(CRAB)oramyloidosis.

56. 3. PLASMACYTOMA
SOLITARYPLASMACYTOMAOFTHEBONE
•Localizedtumorcomposedofclonalplasmacellsthatarecytologically,immunophenotypically,andgeneticallysimilartothoseofPCM.
•IMWGdiagnosticcriteria:oBiopsy-provensolitarylesionofboneorsofttissueconsistingofclonalplasmacells.oNormalrandomBMbiopsywithnoevidenceofclonalplasmacells.oNormalskeletalsurveyandMRIorCTexceptforthesolitarylesion.
oAbsenceofCRABfeatures.
EXTRAOSSEOUSPLASMACYTOMA
•Localizedplasmacelltumorsthatariseintissuesotherthanbonemarrow.
•AppeartobebiologicallydistinctfromsolitaryplasmacytomaofboneandPCM.

57. 4. AMYLOIDOSIS
•Amyloidosisiscausedbyaccumulationofinsolubleproteinswithaβ-pleatedsheetconfiguration.
•Primaryamyloidosis,amyloidlightchain(AL)type,isassociatedwithplasmacellneoplasm.
•Theamyloidcontainsapartofthevariableregionofthelightchain,mostoftenλ(75%)andsometimesκ(25%).
•Allofthefollowingcriterianeedtobefulfilled:
1.Thepresenceofamyloid-relatedsystemicsyndrome(suchasrenal,liver,heart,gastrointestinaltract,orperipheralnerveinvolvement).2.PositiveamyloidstainingbyCongoredorEMinanytissue,confirmingthattheamyloidiscomposedofIgchainbyimmunostainingormassspectrometry.3.DetectionofmonoclonalplasmacellproliferationsuchasserumorurineMprotein,abnormalFLCratio,ormonotypicplasmacellsinBM.

58. 5. SYSTEMIC LIGHT CHAIN AND HEAVY CHAIN DEPOSITION DISEASES
•Monoclonallightchainandheavychaindepositiondiseasesareplasmacellorrarelylymphoplasmacyticneoplasmsthatsecreteanabnormallightchainorheavychain(orboth)thatdepositintissuescausingorgandysfunction.
•Theabnormallightchaindepositsdonotformamyloidβ-pleatedsheetsorbindCongored,andtheylackamyloidP-component.
•Bonemarrowisinvolvedin50%ofcases.
•Thisgroupofdisordersincludeslightchaindepositiondisease(LCDD),heavychaindepositiondisease(HCDD),andlightandheavychaindepositiondisease(LHCDD);LCDDisthemostfrequent.

59. 6. Plasma cell neoplasms associated with paraneoplastic syndrome
POEMSSyndrome(OsteoscleroticMyeloma)
•POEMSisaparaneoplasticsyndromeusuallyassociatedwithanosteoscleroticplasmacellneoplasmandaccompaniedbyasyndromethatincludes:•Polyneuropathy
•Organomegaly•Endocrinopathy.•Monoclonalgammopathy.•Skinlesions.
TEMPI syndrome
•TEMPIsyndromeisarecentlydescribedplasmacellneoplasmwithparaneoplasticfeatures.
•Theacronymdenotesto:•Telangiectasias.
•ElevatedErythropoietin/Erythrocytosis.
•Monoclonalgammopathy.•Perinephricfluidcollection.•Intrapulmonaryshunting.

60. BONEMARROWPLASMACYTOSIS:APRACTICALALGORITHM