LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS

DrDr AdelAdel MM AbuzenadahAbuzenadah

LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS

„ QuantitativeQuantitative „ Change in number „ TerminologyTerminology „ Cytosis / philia „ Increase in number „ Cytopenia „ Decrease in number „ QualitativeQualitative „ Morphologic changes „ Functional changes LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS Quantitative changes

RelativeRelative vsvs AbsoluteAbsolute valuesvalues „ TotalTotal whitewhite bloodblood cellcell countcount „ DifferentialDifferential countcount „ AbsoluteAbsolute countcount „ DifferentialDifferential givesgives thethe relativerelative percentagepercentage ofof eacheach WBCWBC „ AbsoluteAbsolute valuevalue givesgives thethe actualactual numbernumber ofof eacheach WBC/mmWBC/mm3 ofof bloodblood „ Calculation:Calculation: absoluteabsolute count=count= TotalTotal WBCWBC xx percentpercent LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS Quantitative changes

„ RegulationRegulation ofof cellcell productionproduction „ RegulatoryRegulatory mechanismsmechanisms mustmust operateoperate inin closeclose controlledcontrolled wayway „ HaemopoieticHaemopoietic growthgrowth factorsfactors „ TheThe controlcontrol ofof cellcell deathdeath „ InhibitorsInhibitors ofof cellcell proliferationproliferation „ StromalStromal cellcell factorsfactors (cell(cell--cellcell andand cellcell--matrixmatrix interaction)interaction) LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS Quantitative changes (LEUCOCYTOSIS)

„ LeucocytesLeucocytes „ PhagocytesPhagocytes „ Granulocytes „ Neutrophils „ Eosinophils „ Basophils „ Mononuclear phagocytic cells „ Monocytes „ Macrophage and denderetic cells „ LymphocytesLymphocytes „ B-cells „ T-cells LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS Quantitative changes (LEUCOCYTOSIS)

„ DefinitionDefinition RaisedRaised TWBCTWBC duedue toto elevationelevation ofof anyany ofof aa singlesingle lineage.lineage. „ Note: elevation of the minor cell populations can occur without a rise in the total white cell count. „ NormalNormal referencereference rangerange (adult(adult 2121 years)years) „ 4.5 -- 11.0 x 109/L LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS QuantitativeQuantitative changeschanges (LEUCOPENIA)(LEUCOPENIA)

„ DefinitionDefinition TWBCTWBC lowerlower thanthan thethe referencereference rangerange forfor thethe ageage isis defineddefined asas leucopenialeucopenia „ LeucopeniaLeucopenia maymay affectaffect oneone oror moremore lineageslineages andand itit isis possiblepossible toto bebe severelyseverely neutropenicneutropenic oror lymphopeniclymphopenic withoutwithout aa reductionreduction inin totaltotal whitewhite cellcell count.count. LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS QuantitativeQuantitative changeschanges (contd.)(contd.)

„ GranulocytosisGranulocytosis IncreaseIncrease inin thethe countcount ofof allall oror oneone ofof thethe granulocyticgranulocytic componentcomponent „ Neutrophils „ Basophils „ Eosinophils „ AgranulocytosisAgranulocytosis DecreaseDecrease inin thethe countcount ofof allall oror oneone granulocyticgranulocytic componentcomponent WBCWBC Histogram:Histogram: NeutrophilsNeutrophils

„ CountCount 2.52.5 -- 7.57.5 xx 10109/l/l „ GranularGranular cytoplasmcytoplasm „ TransientTransient staystay inin bloodblood „ MajorMajor phagocyticphagocytic rolerole „ BacterialBacterial killingkilling „ 33--55 lobeslobes ofof nucleusnucleus LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS QuantitativeQuantitative changeschanges (NEUTROPHILIA)(NEUTROPHILIA)

„ DefinitionDefinition „ Increase in the number of neutrophils and / or its precursors „ In adults count >7.5 x 109/L but the counts are age dependent „ Increase may results from alteration in the normal steady state of „ Production „ Increased progenitor cell proliferation „ Increased frequency of cell division of committed neutrophil precursors „ Transit „ Impaired transit to tissutissuee „ Migration „ Destruction LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS QuantitativeQuantitative changeschanges (NEUTROPHILIA)(NEUTROPHILIA) contd.contd.

„ CausesCauses ofof NeutrophiliaNeutrophilia „ Infection „ Bacterial „ Inflammatory conditions „ Autoimmune disorders „ Gout „ Neoplasia „ Metabolic conditions „ Uraemia „ Acidosis „ Haemorhage „ Corticosteroids „ Marrow infiltration/fibrosis „ Myeloproliferative disorders LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS QuantitativeQuantitative changeschanges (NEUTROPHILIA)(NEUTROPHILIA) contd.contd.

„ AcuteAcute NeutrophiliaNeutrophilia „ MobilizedMobilized rapidlyrapidly byby stress,stress, suggestedsuggested byby adrenalineadrenaline stressstress test;test; duedue toto reducedreduced neutrophilneutrophil adhesionadhesion „ Bacterial infection „ Stress „ Exercise „ SlowerSlower riserise whenwhen cellscells areare releasedreleased fromfrom thethe bonebone marrowmarrow storagestorage poolpool „ Steroid „ Infections (reactive changes; left shift, toxic granulation, high NAP score and Dohle bodies. „ SteroidsSteroids alsoalso reducesreduces thethe passagepassage toto thethe tissuestissues LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS QuantitativeQuantitative changeschanges (NEUTROPHILIA)(NEUTROPHILIA) contd.contd.

„ ChronicChronic neutrophilianeutrophilia „ Long term corticosteroid therapy „ Chronic inflammatory reactions „ Infections or chronic blood loss „ Infections „ Less common organisms e.g poliomyelitis „ Leukemoid reactions „ Applied to chronic neutrophilia with marked leucocytosis (>20 x 109/L) „ The usual feature is the shift to the left of myeloid cells „ Causes include „ Infections „ Marrow infiltration „ Systemic disease (Acute liver failure) LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS QuantitativeQuantitative changeschanges (NEUTROPENIA)(NEUTROPENIA) contd.contd.

„ NeutropeniaNeutropenia isis anan absoluteabsolute reductionreduction inin thethe numbernumber ofof circulatingcirculating neutrophilsneutrophils „ Mild (1- 1.5 x 109/L) „ Moderate (0.5 – 1 x 109/L) „ Severe (<0.5 x 109/L) „ Symptoms are rare with the neutrophil count above 1 x 109/L „ Bacterial infections are the commonest „ Fungal, viral and parasitic infection are relatively uncommon LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS QuantitativeQuantitative changeschanges (NEUTROPENIA)(NEUTROPENIA) contd.contd.

„ Causes of Neutropenia „ Racial „ Congenital „ Cyclical neutropenia „ Marrow aplasia „ MarMarrowrow infiltration „ Megaloblastic anemia „ Acute infections „ Typhoid, Miliary TB, viral hepatitis „ Drugs „ Irradiation exposure „ Immune disorders „ HIV „ SLE „ Felty’s syndrome „ Neonatal isoimmune and autoimmune neutropenia „ Hyperslplenism LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS QuantitativeQuantitative changeschanges (NEUTROPENIA)(NEUTROPENIA) contd.contd.

„ ManagementManagement ofof NeutropeniaNeutropenia „ Remove the cause if possible „ Treat any infection aggressively „ Role of „ Growth factors „ Splenectomy „ CyclicalCyclical neutropenianeutropenia „ Regular recurring episodes ofof severesevere neutropenianeutropenia (<0.2(<0.2 xx 10109/L) usually lasting for 3-6 days „ Can be familial & inherited with maturation arrest „ Three suggested mechanisms for cyclical neutropenia „ Stem cell defect & altered response to growth factors „ Defect in humoral or cellular stem cell control „ Periodic accumulation of an inhibitor EosinophilsEosinophils

„ CountCount 0.20.2 –– 0.80.8 xx 10109/l/l „ BilobedBilobed nucleusnucleus „ PhagocyticPhagocytic activityactivity isis lowlow „ ModulationModulation ofof hypersensitivityhypersensitivity andand allergicallergic reactionsreactions LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS QuantitativeQuantitative changeschanges (EOSINOPHILIA)(EOSINOPHILIA)

„ IncreaseIncrease inin thethe eosinophileosinophil countcount mustmust promptprompt forfor furtherfurther investigationinvestigation (>0.6(>0.6 xx 10109/L)/L) „ TheThe causescauses ofof eosinophiliaeosinophilia cancan bebe consideredconsidered underunder followingfollowing headingsheadings „ Allergy „ Atopic, drug sensitivity and pulmonary eosinophilia „ Infection „ ParasitesParasites,, recovery from infections „ Malignancy „ Hodgkin’s disease, NHL and myeloprolifmyeloproliferativeerative disorders „ Drugs „ Skin disorders „ Gastrointestinal disorders „ Hypereosinophilic syndrome LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS QuantitativeQuantitative changeschanges (EOSINOPHILIA)(EOSINOPHILIA) Contd.Contd.

„ HypereosinophilicHypereosinophilic syndromesyndrome „ CriteriaCriteria ofof diagnosisdiagnosis „ Peripheral blood eosinophil >1.5 x 109/L „ Persistence of counts more than 6 months „ End organ damage „ Absence of any obvious cause for eosinophilia „ OrganOrgan mostmost commonlycommonly involvedinvolved „ Heart „ Lung „ Skin „ Neurological MonocytesMonocytes

„ CountCount isis 0.20.2--0.80.8 xx 10109/l/l „ FunctionsFunctions „ Antigen presentation „ Cytokine production „ Phagocytosis LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS QuantitativeQuantitative changeschanges (MONOCYTOSIS)(MONOCYTOSIS)

„ AbsoluteAbsolute monocytemonocyte countcount isis ageage dependentdependent „ CountCount rarelyrarely exceedsexceeds >1.0>1.0 xx 10109/L/L „ HaveHave nono marrowmarrow reservesreserves „ UsefulUseful harbingerharbinger ofof engraftmentengraftment „ CausesCauses ofof monocytosismonocytosis cancan bebe groupedgrouped asas „ Infections „ Chronic infection (TB, typhoid fever, infective endocarditis) „ Recovery ffromrom acute infection „ Malignant disease „ MDS, AML, HD, NHL „ Connective tissue disorders „ Ulcerative colitis, Sarcoidosis, Crohn’s disease „ Post splenectomy BasophilsBasophils

„ CountCount 0.10.1 –– 0.20.2 xx 10109/l/l „ BilobedBilobed nucleusnucleus „ NucleusNucleus isis hidedhided behindbehind thethe granulesgranules „ InflammatoryInflammatory responseresponse „ BasophiliaBasophilia isis seenseen inin MyeloproliferativeMyeloproliferative disordersdisorders (CML)(CML) LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS QuantitativeQuantitative changeschanges (BASOPHILIA)(BASOPHILIA)

„ BasophilsBasophils areare leastleast commoncommon ofof thethe granulocytesgranulocytes „ ReferenceReference rangerange forfor adultadult isis 00 –– 0.20.2 xx 10109/L/L „ MostMost commonlycommonly associatedassociated withwith hypersensitivityhypersensitivity reactionsreactions toto drugsdrugs oror foodfood „ InflammatoryInflammatory conditionsconditions e.ge.g RA,RA, ulcerativeulcerative colitiscolitis areare alsoalso sometimesometime associatedassociated withwith basophiliabasophilia „ MyeloproliferativeMyeloproliferative disordersdisorders „ ChronicChronic myeloidmyeloid leukemialeukemia LymphocytesLymphocytes

„ CountCount variesvaries withwith ageage 1.51.5 –– 3.53.5 x10x109/l/l „ TheThe subsetsubset cellscells areare „ B-cells „ Antibody mediated immunity „ T-cells „ Cell mediated immunity „ NK cells LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS QuantitativeQuantitative changeschanges (LYMPHOCYTOSIS)(LYMPHOCYTOSIS)

„ TheThe bloodblood containcontain onlyonly fewfew percentpercent ofof totaltotal bodybody lymphocyteslymphocytes „ TheThe mostmost consistentconsistent variationvariation isis seenseen withwith ageage „ AlterationAlteration ofof lymphocytelymphocyte countscounts cancan resultresult fromfrom „ The redistribution of lymphocytes „ Results in variation in count in serial measurements „ Absolute increase of lymphocyte number „ Loss of lymphocytes „ Combination of these LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS QuantitativeQuantitative changeschanges (LYMPHOCYTOSIS)(LYMPHOCYTOSIS)

„ NonNon--malignantmalignant causescauses ofof lymphocytosislymphocytosis „ Infections „ Viral infections „ Infectious mononucleosis „ CMV „ Rubella, hepatitis, adenoviruses, chicken poxpox,dengue,dengue „ Bacterial infections „ Pertussis „ Healing TB, typhoid fever „ Protozoal infections „ ToxoplasmosiToxoplasmosiss „ Allergic drug reactions „ Hyperthyroidism „ Splenectomy „ Serum sickness LEUCOCYTESLEUCOCYTES BENIGNBENIGN DISORDERSDISORDERS QuantitativeQuantitative changeschanges (LYMPHOCYTOSIS)(LYMPHOCYTOSIS)

„ InfectiousInfectious MononucleosisMononucleosis „ Epstein-Barr virus „ Saliva from infected personperson isis thethe mainmain contagioncontagion „ Virus infect epithelial cells and B cells „ Autocrine growth stimulation „ Infection in children under the age of 10 does not cause illness and result in life long immunity „ Clinical features „ Fever, mmalaise,alaise, fatfatigue,igue, sore throat, diagnostic red spots at the junction of soft and hard palate, splenomegaly „ Blood picture shows leucocytosis ( 10 – 20 x 109/L) due to absolute increase in the number of lymphocytes „ DiagnDiagnosisosis is by serologicserologicalal tests „ There is no specific treatment NonmalignantNonmalignant LeukocyteLeukocyte DisordersDisorders

„ Leukemoid reaction – this is an extreme neutrophilia with a WBC count > 30 x 109/L „ Many bands, metamyelocytes, and myelocytes are seen „ Occasional promyelocytes and myeloblasts may be seen. „ This condition resembles a chronic myelocytic leukemia (CML), but can be differentiated from CML based on the fact that in leukemoid reactions: „ There is no Philadelphia chromosome „ The condition is transient „ There is an increased leukocyte alkaline phosphatase score (more on this later) „ Leukemoid reactions may be seen in tuberculosis, chronic infections, malignant tumors, etc. LeukemoidLeukemoid reactionreaction LeukemoidLeukemoid reactionreaction NonmalignantNonmalignant LeukocyteLeukocyte DisordersDisorders

„ MorphologicMorphologic andand functionalfunctional abnormalitiesabnormalities ofof neutrophilsneutrophils „ Acquired, morphologic – these are reactive, transient changes accompanying infectious states. They include „ Toxic granulation „ Dohle bodies „ Cytoplasmic vacuoles DohleDohle bodiesbodies MorphologicMorphologic neutrophilneutrophil changeschanges

Vacuolated cell MorphologicMorphologic neutrophilneutrophil changeschanges

Toxic granulation NonmalignantNonmalignant LeukocyteLeukocyte DisordersDisorders

„ Inherited functional and/or morphological abnormalities „ Pelger- Huet Anomaly – this is a benign, inherited, autosomal dominant abnormality in which the neutrophil nucleus does not segment beyond the bilobular stage (“Prince-nez cells”). „ The cells may sometimes resemble bands, but the chromatin is more condensed (mature). „ The cells function normally. „ Acquired or pseudo Pelger-Huet Anomaly is seen in myeloproliferative and myelodysplastic states PelgerPelger--HuetHuet AnomalyAnomaly PseudoPseudo PelgerPelger--HuetHuet AnomalyAnomaly

Note nuclear maturity NonmalignantNonmalignant LeukocyteLeukocyte DisordersDisorders

„ Alder-Reilly Anomaly – in this disorder all leukocytes contain large, purplish granules (due to partially degraded protein- carbohydrates) in the cytoplasm, but the cells function normally. „ This is seen in Hurler’s and HHunterunter’s syndromes in which there is an incomplete breakdown of mucopolysaccharides HurlerHurler’’ss SyndromeSyndrome

Note the granules NonmalignantNonmalignant LeukocyteLeukocyte DisordersDisorders

„ Chediak-Higashi Anomaly – „ This is a rare autosomal recessive ddisorderisorder in which abnormal lysosomes are formed by the fusion of primary granules. These are seen as grayish-green inclusions „ The cells are ineffective in killing microorganisms and affected individuals often die early in life ffromrom pyogenic infections. ChediakChediak--HigashiHigashi AnomalyAnomaly

Note abnormal lysosomes NonmalignantNonmalignant LeukocyteLeukocyte DisordersDisorders

„ May-Hegglin Anomaly „ This is a rare, autosomal dominant ddisorderisorder in which the leukocytes contain large basophilic inclusions containing RNA that look similar to Dohle bodies. „ It can be differentiated from an infection because toxic granulation is not seen. „ The patients also have giant platlets that have a shortened survival time. Because of this, patients may have bleeding problems, but they usually have no other clinical symptoms MayMay--HegglinHegglin AnomalyAnomaly

Basophilic inclusions NonmalignantNonmalignant LeukocyteLeukocyte DisordersDisorders

„ Chronic granulomatous disease „ This is a lethal, sex-linked disorder affecting the function of the neutrophil „ The neutrophil can function in phagocytosis, but it cannot kill microorganisms because the cells have a defect in the respiratory burst oxidase system. „ Affected individuals have chronic infections with organisms that do not normally cause infections in normal individuals „ Myeloperoxidase deficiency „ This is a benign, autosomal recessive disorder characterized by a lack of myeloperoxidase in the neutrophils NonmalignantNonmalignant LeukocyteLeukocyte DisordersDisorders

„ Affected individuals may have occasional problems with CandiCandidada infections, but usually they have no problems with infections because they have other mechanisms to kill microorganisms „ Leukocyte adhesion deficiency „ This is a rare, autosomal recessirecessiveve disorder characterized by the absence of leukocyte cell surface adhesion proteins „ Because of the lack of the adhesion molecules, the leukocytes have functional defects in: „ ChemotaxiChemotaxiss „ Phagocytosis „ Respiratory burst activactivationation „ Degranulation „ Affected individuals have frequent bacterial and fungal infections and mortality in childhood is highigh.h. NonmalignantNonmalignant LeukocyteLeukocyte DisordersDisorders

„ InheritedInherited abnormalitiesabnormalities ofof neutrophilsneutrophils areare alsoalso seenseen inin monocytesmonocytes becausebecause theythey originateoriginate fromfrom aa commoncommon stemstem cellcell:: „ Chronic granulomatous disease (defective respiratory burst) „ Chediak Higashi (abnormal lysosomes caused by fusion of primary granules) „ Alder Reilly Anomaly (large purple-blue granules)