Evaluacion de La Leucocitosis PDF

EvaluationofLeukocytosis
TracyI.George,MD
AssociateProfessorofPathology
Albuquerque,NM,UnitedStates
September24,2014
NoConflictsofInteresttoDisclose
Outline
Definitionofleukocytosis
Automateddifferentials
Examiningthebloodsmear
Diagnosticalgorithm
Blasts
Lymphoidleukocytosis
Myeloidleukocytosis(granulocyticleukocytosis,
monocytosis)
1
Leukocytosis
ElevationofWBCforthatpatientsage
Knowyourlabsreferenceranges
40
35
30
25
WBC
20 Max
(x109/L) Min
15
10
0
Birth 13d 1wk 2wk 1mo 2mo 324mo 212yr >12yr
Age
AutomatedDifferential
andFlagging
Analyzersdesignedtoproduceaccurate&
precisebloodcountsonnormalspecimens,and
toalerttheoperatortounusualcharacteristics
whichleadtoinaccuratemeasurementsor
requirereviewofabloodsmear.
1.Blasts,immaturegranulocytes,NRBC,variant/
atypicallymphocytes
2.PLTclumps,GPLTorRBC/PLToverlap
3.Abnormalitieslikelytobeassociatedwith
spurious results
GeorgeTI.Automatedhematologyinstrumentation.http://www.uptodate.com
2
FlaggedResultsRequireReview
Aslidereviewisappropriateinallpatients
withanunexplainedleukocytosis
Properslidepreparationandstaining
Confirmautomatedcellcountsorperforma
manualdifferential/automatedimage
analysisforleukocyteclassification
BarnesPWetal.LabHematol 2005;11(2):8390.
Kratz Aetal.AmJClin Pathol 2005;124(5):770781. http://blog.cellavision.com/
DiagnosticAlgorithmforLeukocytosis
*Mustinterpretallfindings Leukocytosis
inproperclinicalcontext
ConfirmCBCanddifferential
Examinebloodsmear
Gran/mono
Lymphocytosis
Increasedblasts
3
Acute
Lymphoblastic
Leukemia
AcuteLymphoblastic
Leukemia
4
AcutePromyelocytic Leukemia
AcuteMonoblastic Leukemia
RiskforDIC,intracranialhemorrhage
Immediatediagnosisnecessary
FISH/PCRforPMLRARA
Rapidcytochemical MPO
Flowcytometry:CD34/+,HLADR not
pathognomonic
Bonemarrow,cytogenetics
5
Dualfusionprobe
Red=PML
Green=RARA
Yellow=PMLRARA
TransientAbnormalMyelopoiesis
AssociatedwithDownSyndrome
AcuteMyeloidLeukemia
ArisingfromMyelodysplastic
Syndrome
AcuteMyeloid
Leukemiawith
t(8;21)(q22;q22)
6
Examinebloodsmear
Gran/mono
Lymphocytosis
Increasedblasts
Evaluateforacute
leukemia/
precursor
Bonemarrow neoplasms
examination
withflow
cytometry,
cytogenetic
studies;
molecular
geneticstudies
asappropriate
Examinebloodsmear
Gran/mono
Lymphocytosis
Increasedblasts
Monomorphic Pleomorphic
Suspect Reactive
lympho lymphocytosis
proliferative
disorder
7
Lymphocytosis
Monomorphic Pleomorphic
Suspectneoplastic Suspectreactive
Infectious
Mononucleosis
Pleomorphic
lymphocytosis
Youngerage
WBC<50x
109/L
Heterophile ab
test
Serology
8
Causes of a Reactive Lymphocytosis
Viral infections
(EBV, CMV, HSV, influenza, adenovirus, hepatitis, coxsackie, HIV,
dengue)
Bacterial infections
(tuberculosis, syphilis, brucellosis, typhus, Bordetella pertussis*)
Toxoplasma
Malaria
Babesiosis
Drug hypersensitivity
Autoimmune disease
Cytokines
Vaccination
Smoking
Stress (trauma, cardiac, extreme exercise)
Endocrine disorders (Addison disease, hyperthryroidism,
hypopituitarism)
Secondary to malignancy
Pereira I, George TI, Arber DA. Atlas of Peripheral Blood. The Primary Diagnostic Tool. Philadelphia, PA:
Wolters Kluwer, Lippincott Williams and Wilkins, Inc.; 2012:128.
Bordetella Pertussis
9
LargeGranularLymphocytosis
IncreasedLGLsseenwith:
Viralinfections
Malignancy
Afterbonemarrow
transplantation
Followingchemotherapy
PersistenceofLGLs+
neutropenia+
variableanemia
Tcelllargegranular
lymphocyticleukemia
(TLGL)
Dhodapkar MVetal.Blood1994;84:16201627.
Monomorphic Lymphocytosis
ChronicLymphocyticLeukemia Prolymphocytoid TransformationofCLL SplenicMarginalZoneLymphoma
Blastic MantleCellLymphoma Lymphoplasmacytic Lymphoma FollicularLymphoma
10
CLL
Small,roundnuclei MCL Flowcytometry
MBL TPLL FISH
Foldedor FL Flowcytometry
Tcell
cleavednuclei MCL FISHCCND1,BCL2
AtypicalCLL Pertussis* Tissuebiopsy
Convoluted Sezary syndrome Flowcytometry

nuclei AdultTcellleukemia Tcellclonality
HCL
TPLL
Villouscytoplasm SMZL Flowcytometry
LPL
HCLV
LPL
Flowcytometry
Plasmacytoid Plasmacellmyeloma SPEP/UPEP
Plasmacellleukemia
Flowcytometry
Granules TLGL
Tcellclonality
NKcellleukemia
KIRprofile
TPLL
Prominent BPLL Flowcytometry
nucleoli HCLV Cytogenetics
MCL
Burkitt Leukemia
DLBCL Flowcytometry
Largecells
MCL FISHMYC
ALCL
FrequencyofPeripheralBloodInvolvementby
BoneMarrowLymphoma
Arber DA, George TI. Am J Surg Pathol. 2005;29:1549-1557.
11
Whentoperformflowonperipheral
bloodinadults?
Reviewedflowcytometry ofpatients50yr+
withABSLYMPH4x109/Lthathadbeen
calledsuspiciousforalymphoproliferative
disorderaftersmearreviewbypathologist
ABSLYMPH>6.7x109/L
Age67yr
Sensitivity95%,specificity76%inpredictingan
abnormalphenotypebyflowcytometry
AndrewsJMetal.Leuk Lymph2008;49:1731
Lymphocytosis
Lymphocytosis
Examinebloodsmear Pleomorphic
Monomorphic
Suspect Reactive
Gran/mono lymphocytosis
lympho
Increasedblasts proliferative
disorder
Flowcytometry,select
moleculargenetic
tests
CCND1IGH@ FISH MCL

IGH@BCL2FISH/PCR FL
TCRrearrangements TLGL,Tcelllymphomas
HTLV1 ATLL
TissueorBMbiopsynecessaryforsome
patients
12
Granulocytic/monocytic Leukocytosis
Examinebloodsmear
Gran/mono
Lymphocytosis
Increasedblasts
Neutrophilia
Basophilia
Monocytosis
Eosinophilia
Examinebloodsmear
Gran/mono
Lymphocytosis
Increasedblasts
Neutrophilia
Basophilia
Monocytosis
Eosinophilia
13
ReactiveNeutrophilia =
Neutrophilic Leukemoid Reaction
Mechanisms Causes
Increasedproductionof Infections!
Bacterial,viral,mycobacterial,
neutrophils treponemal
Demargination of Malignancy
neutrophils Inflammation
Drugs
Decreasedegressof
Myeloidgrowthfactors
neutrophilsfromthe Hemorrhage
peripheralcirculationto Splenectomy
tissues Smoking
Anystrongstimulustothe
bonemarrow
Neutrophilia
Favorsreactive Favorsmalignant
WBC<50x109/L WBC>50x109/L
Predominantlymature Pronouncedleftshift
Toxicgranulationandvacuoles Basophilia orEosinophilia
Dhle bodies Dacrocytes
Thrombocytosis Dysplasia
14
Infection/sepsisMarkers
Culture
Creactiveprotein
Sedimentationrate(ESR)
Lacticacid
Procalcitonin
NeutrophilsCD64(flowcytometry)
Cellpopulationdataonneutrophilsinsome
hematologyanalyzers
Reactive Neutrophilia
15
YersiniaPestis Infection
GCSFEffect
Chronic myelogenous leukemia,

BCR-ABL1 Positive, chronic phase
16
Leukoerythroblastic Smear
Marrowinfiltrative
process
o Metastatictumor
withorwithout
fibrosis
o Myeloproliferative
neoplasm(e.g.PMF)
o Acuteleukemia
Growthfactors
Regeneratingmarrows
Examinebloodsmear
Gran/mono
Lymphocytosis
Increasedblasts
Neutrophilia
Basophilia
Monocytosis
Eosinophilia
17
Monocytosis,>1x109/L
ReactiveMonocytosis NeoplasticMonocytosis
Malignancy Chronicmyelomonocytic
Carcinoma leukemia
Multiplemyeloma Chronicmyeloidleukemia
Lymphomas Juvenilemyelomonocytic
Chronicinfections leukemia
Autoimmunedisorders AtypicalCML
MDS/MPN,unclassifiable
Splenectomy
Acutemyeloidleukemia,
Regeneratingmarrows especiallyacute
Bonemarrowtransplant monoblastic/monocytic
Chemotherapy leukemia
Monocytosis
Favorneoplastic Favorreactive
Persistent Transient
Promonocytes andblasts Predominantlymature
Dysplasia Reactivechanges
18
AtypicalMonocytosis
Differential
diagnosis:
AML
CMML
MDS/MPN
Alloftheabove
requirebone
marrow
examinationwith
flowcytometry,
cytogenetic
studies,molecular
geneticstudiesas
appropriate
LRShier,TIGeorge.PathologyoftheMyeloproliferative Neoplasms.In:GreerJP,RodgersGM,Glader B,ArberDA,Means

RT,ListA(editors).WintrobesClinicalHematology,ThirteenthEdition.LippincottWilliamsandWilkins,Inc.(2013). 37
Examinebloodsmear
Gran/mono
Lymphocytosis
Increasedblasts
Neutrophilia
Basophilia
Monocytosis
Eosinophilia
19
Eosinophilia
Prolongedeosinophilia>1.5x109/Lfor6months
Reactive +
Screenforsecondarycausesofeosinophilia
eosinophilia

+
AbnormalTcell EvaluatePB&bonemarrow
clone
Othermalignancy
AssessforTKmutation
witheosinophilia
(HD,Tcell
lymphoma,ALL) +
Clonaleosinophilia MPNwith Clonality or>1%blastsin
duetoCML,AML eosinophilia+ PB,>5%blastsinBM
PDGFRA,
PDGFRB,or +
FGFR1
CEL HES
Gotlib J.Curr Opin Hematol 2010;17;117.
JohnsonR,GeorgeTI.SurgicalPathology2013;6(4):767.
Eosinophilia
Favorneoplastic Favorreactive
Persistent Transient
Immaturecellspresent Clinicalpresenceofdrugs,
Cytopenias anddysplasiain allergyorinfection
otherlineages
20
Examinebloodsmear
Gran/mono
Lymphocytosis
Increasedblasts
Neutrophilia
Basophilia
Monocytosis
Eosinophilia
Basophilia
Favorneoplastic Reactive=rare
>0.3x109/L
Unusual
Strongassociation
withCMLandother
MPNs
Bonemarrow,
cytogenetics
BCRABL1
JAK2 V617F
OtherMPNmutations
Chronicmyelogenous leukemia
21
TIGeorge.Am Soc Hematol Educ *Mustinterpretallfindings
Program.2012;47584. Leukocytosis inproperclinicalcontext
DChabotRichards,TIGeorge.Int J
LabHematol 2014;36(3):27988. ConfirmCBCanddifferential
Manualbloodsmear
Myeloid
Lymphocytosis
Increasedblasts
Evaluateforacute Neutrophilia Monomorphic Pleomorphic
leukemia/ Monocytosis Basophilia
precursor
neoplasms SuspectMPN
Favor Reactive
Suspect
Reactive malignant
Favor BCRABL1 CML lympho lymphocytosis
Persistence,
reactive JAK2V617F
dysplasia, proliferative
otherMPN
blasts disorder
Bonemarrowand
Leftshift karyotyping
WBC>50 Neutrophils:
Chronic Toxic Flowcytometry,select
infection Markedleft Eosinophilia
Bonemarrow shift granulation moleculargenetic
Malignancy reactive
examination Basophilia Dohle bodies tests
Splenectomy
withflow Autoimmune Dysplasia Vacuoles
cytometry, Regenerating WBC<50 Allergies
bonemarrow BCRABL1 neg Ruleout Parasites CCND1IGH@ FISH MCL
cytogenetic
Bonemarrow MPNeos Drug IGH@BCL2FISH/PCR FL
studies; TCRrearrangements TLGL,Tcelllymphomas
examination
molecular HTLV1 ATLL
withancillary Bonemarrow,
geneticstudies Infectionwork TissueorBMbiopsynecessaryforsome
testsas cytogenetics,FISH/PCR
asappropriate up,etc.. patients
appropriate forPDGFRA
Conclusions
Pleomorphiclymphocytosisfavorsareactivelymphocytosis
Monomorphiclymphocytosisshouldtriggerancillarystudies
(flowcytometry,molecular)
Myeloidleukemoid reactions>>myeloidmalignancies
Cluestomyeloidleukemoid reactionsincludeactivated
neutrophilsandWBC<50
Suspicionformyeloidmalignanciesshouldtriggeraworkup
includingbonemarrowexamination,moleculartesting,and
flowcytometry (ifblastsareelevated)
22
Questions?
Questions?
23

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EvaluationofLeukocytosis

ChronicLymphocyticLeukemia Prolymphocytoid TransformationofCLL SplenicMarginalZoneLymphoma

Blastic MantleCellLymphoma Lymphoplasmacytic Lymphoma FollicularLymphoma

Convoluted Sezary syndrome Flowcytometry

Arber DA, George TI. Am J Surg Pathol. 2005;29:1549-1557.

CCND1IGH@ FISH MCL

Chronic myelogenous leukemia,

LRShier,TIGeorge.PathologyoftheMyeloproliferative Neoplasms.In:GreerJP,RodgersGM,Glader B,ArberDA,Means

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