Introduction to Leukemia

Introduction to LeukemiaThe Acute LeukemiasLeukemias typically fill up the marrow with abnormal cells, displacing normal hematopoiesis. The marrow here is essentially 100% cellular, but composed almost exclusively of leukemic cells. Normal hematopoiesis is reduced via replacement (a "myelophthisic" process) or by suppressed stem cell division.

Leukemias - DefinitionLeukemic cells are frequently present in the:peripheral bloodinvade the reticulendothelial tissuesspleen, liver, and lymph nodesmay also invade other tissuesuntreated, eventually causes deathClassificationClassified according to cell type with regard to both:cell maturity used to distinguish between acute and chronic leukemiaif malignant cells are immature acuterapidly aggressiveif predominantly mature - chronicslow or indolent coursecell lineageMyeloid (granulocytic, monocytic, megakaryotic, and erythrocytic )LymphoidCategories of LeukemiasAcute lymphoid leukemia (ALL)Acute myeloid leukemia (AML) or acute nonlymphoblastic leukemia (ANLL)Chronic lymphocytic leukemiaAcute lymphocytic leukemiaEtiology/Risk FactorsHeredityCongenital chromosomal abnormalitieshereditary immunodeficiency statesChronic marrow dysfunctionDrugs anticancer drugsIonizing radiationChemicalsVirusesHTLV-1 causative agent of adult T-cell leukemia/lymphomaComparison of Acute and Chronic LeukemiaAcuteChronicAgeAll agesAdultsClinical onsetSuddenInsidiousCourse (untreated)< 6 mo2 6 yearsLeukemic cellsImmatureMatureAnemiaMild to severeMild ThrombocytopeniaMild to severeMildWhite cell countVariableIncreasedOrganomegalyMildProminentAcute LeukemiaClassification and DifferentiationClinical Features of Acute LeukemiaPathogenesisClinical ManifestationsBone Marrow Failure AnemiaFatigue, malaise, pallor ThrombocytopeniaBruising, bleeding GranulocytopeniaFever, infectionsOrgan Infiltration Marrow expansionBone or joint pain SpleenSplenomegaly LiverHepatomegaly Lymph nodesLymphadenopathy Central nervous systemNeurologic symptoms Gums, mouthGingival hypertrophy,oral lesionsLaboratory Evaluation of Acute LeukemiaPurpose: Confirm the diagnosis and distinguish AML from ALLPreliminary evaluation:complete blood count and peripheral blood examinationbone marrow studiesmorphologic examinationcytochemical staining immunologic markerscytogenetic studiesmolecular genetic studieselectron microscopy ?Morphologic Approach to ClassificationCytologic Features of Blasts in Acute ANLL and Acute Lymphocytic LeukemiaFeatureAMLALLBlast sizeLarger, usually uniformVariable, small to medium sizeNuclear chromatinUsually finely dispersedCoarse to fineNucleoli1-4, often prominentAbsent or 1-2, often indistinctCytoplasmModerately, abundant, fine granules often presentUsually scant, coarse granules sometimes present (~7%)Auer rodsPresent in 60-70% of casesNot presentOthersOften dysplastic changes in maturing myeloid cellsMyeloid cells not dysplastic

Copyright 2003 American Society of Hematology. Copyright restrictions may apply.Maslak, P. ASH Image Bank 2003;2003:100726Figure 1. A type I myeloblast has a large nuclus with prominent nucleoli12

Copyright 2003 American Society of Hematology. Copyright restrictions may apply.Maslak, P. ASH Image Bank 2003;2003:100739Figure 3. Small number of granules are clustered in the cytoplasm of this myeloblast13

Copyright 2004 American Society of Hematology. Copyright restrictions may apply.Maslak, P. ASH Image Bank 2004;2004:100953Figure 2. Type III blasts have greater than 20 granules but no centrosome14

Copyright 2005 American Society of Hematology. Copyright restrictions may apply.Maslak, P. ASH Image Bank 2005;2005:101341Figure 1. Auer rods are distinctive cytoplasmic inclusion bodies which are found in MDS and AML15

Copyright 2004 American Society of Hematology. Copyright restrictions may apply.Maslak, P. ASH Image Bank 2004;2004:101139Figure 1. This lymphoid blast has a rounded, "regular" appearance without cytoplasmic granules16Cytochemical Reactions Useful in the Diagnosis of Acute LeukemiaSpecial StainSite of ActionCells StainedCommentMyeloperoxidaseMainly primary granules; Auer rodsLate myeloblasts, granulocytes; monocytes less intenselySeparates AML (+) from ALL (-)Sudan black BPhospholipids; sterols, neutral fatsLate myeloblast, granulocytes; monocytes less intenselyParallels peroxidase, but smears do not need to freshSpecific esterase (Naphthol AS-D chloroacetateCytoplasmNeutrophilic granulocytes; mast cellsParallels peroxidase, but less sensitive; Non-specific esterase (alpha-napththyl acetate and butyrate)CytoplasmMonocytes; focal staining in T cellsUseful for determining degree of monocytic differentiation; separates mono (+) from myelo (-) blastsPeriodic acid-SchiffGlycogen and related substancesLymphocytes, granulocytes, megakaryocytesHelpful in supporting diagnosis of erythroleukemiaImmunologic Markers Used in the Classification of Acute LeukemiaLineageAntigenB cellCD19, CD20, CD21, CD22, CD23, D24T cellCD1, CD2, CD3, CD4, CD5, CD7, CD8LymphoidTdTMyeloid (granulocytic)CD13, CD33, CD11b, CD15MonocyticCD14, CD11bErythroidGlycophorin AMegakaryocyticCD41, CD42b, CD61Lineage Independent AntigensHLA-DRHLA class IICD45Leukocyte common antigenCD34Stem cell antigenCD10Common ALL antigen (CALLA)Acute Myeloid Leukemia(AML)Acute Nonlymphoid Leukemia(ANLL)DefinitionAML are clonal malignancies that are characterized by the appearance of increased numbers of immature myeloid cells in the marrow and blood.DefinitionAML is a clonal, malignant disease of the hematopoietic tissue that is characterized byaccumulation of abnormal (leukemic) blast cells, principally in the marrowimpaired production of normal blood cells.EtiopathogenesisRisk factorsEnvironmentalradiationbenzenesalkylating agents and other cytotoxic drugs therapy-related AMLEvolution from a chronic clonal hemopathyInherited syndromesEpidemiologyAML is the predominant form of leukemia during the neonatal period and accounts for 15 to 20 percent of acute leukemia in children and80 percent of acute leukemia in adults.

Revised Criteria for the Classification of AML (FAB)M0 with minimal differentiationLarge, agranular blasts (resemble ALL L2, rarely L1). Myeloperoxidase negative or90 percent of non erythroid cells. At least 3 percent of these are myeloperoxidase or Sudan black positive.Remaining 10 percent (or less) of cells are maturing granulocytes or monocytesRevised Criteria for the Classification of AML (FAB)M2 with maturationSum of agranular and granular blasts (types I and II) is from 30 to 89 percent of non-erythroid cells.Monocytic cells, 10 percent.M3 PromyelocyticMajority of cells are abnormal promyelocytes with heavy granulation.Characteristic cells containing bundles of Auer rods (faggots) invariably present. Note: Microgranular variant (M3v) also occurs. Promyelocytes have marked nuclear irregularity that includes reniform, lobulated and monocyte-like indented nuclei. The cytoplasm contains fine or indistinct granules in contrast to the coarse azurophilic granules in typical M3.Revised Criteria for the Classification of AML (FAB)M4 MyelomonocyticIn the marrow, blasts >30 percent of non-erythroid cells.Sum of myeloblasts, promyelocytes, myelocytes and later granulocytes is between 30 and 80 percent of non-erythroid cells.> 20 percent of non-erythroid cells are monocyte lineage.If monocytic cells exceed 80 percent, diagnosis is M5 Note: (a) If marrow findings as above and peripheral blood monocytes (all types) are > 5.0 x 109/L, diagnosis is M4 (b) If monocyte count < 5 x 109/L, M4 can be confirmed on basis of serum lysozyme, combined esterase, etc. (c) Diagnosis of M4 confirmed if > 20 percent of marrow precursors are monocytes (confirmed by special stains).Revised Criteria for the Classification of AML (FAB)M4 with eosinophiliaEosinophils > 5 percent of non-erythroid cells in marrow.Eosinophils are abnormal.Eosinophilis are chloroacetate and PAS positive.M5 Monocytic80 percent of marrow non-erythroid cells are monoblasts, promonocytes or monocytes.M5a, 80 percent of monocytic cells are monoblasts.M5b, < 80 percent of monocytic cells are monoblasts, remainder are predominantly promonocytes and monocytes.Revised Criteria for the Classification of AML (FAB)M6 ErythroleukemiaThe erythroid component of the marrow exceeds 50 percent of all nucleated cells.30 of the remaining non-erythroid cells are agranular or granular blasts ( types I and II). Note: If > 50 percent erythroid cells but < 30 percent blasts, diagnosis becomes myelodysplastic syndromes. A rare form of erythoird neoplasia, erythremic myelosis, involves only the red blood cell precursors. The erythroblasts, primarily pronormoblasts and basophilic normoblasts, constitute 90% or more of the marrow cells.M7 Megakaryocytic30 percent at least of nucleated cells are blasts.Blasts identified by platelet peroxidase on electron microscopy, or by monoclonal antibodies.Increased reticulin is common.

Copyright 2003 American Society of Hematology. Copyright restrictions may apply.Maslak, P. ASH Image Bank 2003;2003:100838Figure 1. Blasts are the predominant population in the bone marrowAML (M1)29

Copyright 2003 American Society of Hematology. Copyright restrictions may apply.Maslak, P. ASH Image Bank 2003;2003:100722Figure 2. Aspirate has a large number of blastsAML (M2)30

Copyright 2002 American Society of Hematology. Copyright restrictions may apply.Maslak, P. et al. ASH Image Bank 2002;2002:100532Figure 1. The most common form of APL is easily recognized by the heavy granulation of the abnormal promyelocytes (AML M3)31

Copyright 2002 American Society of Hematology. Copyright restrictions may apply.Maslak, P. et al. ASH Image Bank 2002;2002:100598Figure 1. The granules in this morphologic variant of APL are less prominent than those seen in the most common form of this disease32

Copyright 2004 American Society of Hematology. Copyright restrictions may apply.Lazarchick, J. ASH Image Bank 2004;2004:101148Figure 4. The increased number of blasts are noted with a prominent background of eosinophils and abnormal eosinophilic myelocytes33

Copyright 2002 American Society of Hematology. Copyright restrictions may apply.Maslak, P. et al. ASH Image Bank 2002;2002:100537Figure 1. Monoblasts are large cells with ample cytoplasm34

Copyright 2003 American Society of Hematology. Copyright restrictions may apply.Maslak, P. ASH Image Bank 2003;2003:100635Figure 3. Erythroid elements comprise greater than or equal to 50% of the nucleated cellular elements while the myeloblasts make up greater than or equal to 20% of the nonerythroid population35

Copyright 2002 American Society of Hematology. Copyright restrictions may apply.Maslak, P. ASH Image Bank 2002;2002:100478Figure 1. Blasts in acute megakaryoblastic leukemia may show cytoplasmic budding reminiscent of the process where platelets are shed from normal megakaryocytes (MacNeal Tetrachrome 400x)36Common Cytogenetic Abnormalities Associated with AMLChromosomeAbnormalityAssociated Disordert(8;21)AML (M2)t(15;17)Unique to APL (M3)16q abnormalities:inv (16) and del (16)AML with abnormal eosinophilia (M4E)t9;22) t(9;11)TreatmentRemission-induction therapyPost-remission maintenance therapyStem cell transplantAcute Lymphoid Leukemiaacute lymphoblastic leukemiaacute lymphocytic leukemiaDefinitionALL is a neoplastic disease that results from multistep somatic mutations in a single lymphoid progenitor at one of several discrete stages of development.The immunophenotype of leukemic cells at diagnosis reflects the level of differentiation achieved by the dominant clones.

EtiopathogenesisRisk FactorsGenetic syndromesEnvironmental factorsHost pharmocogeneticsIn utero development of ALLEvent-free and Overall Survival in ALL

FAB Classification of ALLMorphologicFeaturesL1L2L3Cell sizeSmallLargeLargeNuclear chromatinFine or clumpedFineFineNuclear shapeRegular, may have cleft of indentationIrregular, may have cleft or indentationRegular, oval to roundNucleoliIndistinct or not visible1 or more per cell; large prominent1 or more per cell; large prominentAmount of cytoplasmScantyModerately abundantModerately abundandCytoplasmic basophiliaSlightSlightProminentCytoplasmic vacuolesVariableVariablevariableALL (L1)

ALL (L2)

ALL (L3)

Acute LeukemiaA heterogeneous group of neoplasms affecting uncommitted or partially committed hematopoietic stem cells.The retained capacity of some differentiation is the basis for the phenotypic classification.Broadly divided into (based on cell origin)Non-lymphoid (Myeloid) leukemiaLymphoid leukemia Classification of LeukemiaAcute Myeloid (FAB classification)Acute myeloblastic leukemiawithout differentiation (M0)without maturation (M1)with maturation (M2)Acute promyelocytic leukemia (M3) APLAcute myelomonocytic leukemia (M4) AMMLAcute monocytic leukemia (M5) AMoLErythroleukemia (M6) Di Guglielmos syndromeAcute megakaryoblastic leukemia (M7)Classification of LeukemiaAcute LymphoblasticPrecursor B-cell ALLEarly-Pre-B-cell ALLPre-B-cell ALLB-cell ALLT-cell ALLChronic MyeloidChronic myelogenous leukemia (CML)Chronic eosinophilic leukemia (CEL)Chronic basophilic leukemia (CBL)Classification of LeukemiaChronic LymphoidChronic lymphocytic leukemia (CLL)B-cell CLLT-cell CLLProlymphocytic leukemiaHairy cell leukemiaPlasma cell leukemiaSzary syndromeEtiology and Risk FactorsHost FactorsHeredityCongenital chromosomal abnormalitiesImmunodeficiencyChronic marrow dysfunctionEnvironmental FactorsIonizing radiationChemicals and drugsViruses