Introduction to Hematopoietic Neoplasms - PowerPoint Presentation

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Introduction to Hematopoietic Neoplasms

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Learning Objectives—Level IAt the end of this unit of study, the student should be able to:Define and differentiate the terms neoplasm and malignant and identify hematopoietic disorders that can be included in each category.Compare and contrast the general characteristics of the myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), and acute and chronic leukemias.

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Learning Objectives—Level IAt the end of this unit of study, the student should be able to:Describe the World Health Organization (WHO) classification system used for MDSs, MPNs, the leukemias, and lymphoid neoplasms.List the various laboratory methods used to classify the hematopoietic neoplasms.

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Learning Objectives—Level IAt the end of this unit of study, the student should be able to:Compare and contrast the laboratory findings of the acute and chronic leukemias and myeloid and lymphoid leukemias.Differentiate proto-oncogenes and oncogenes and summarize their relationship to neoplastic processes.

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Learning Objectives—Level IAt the end of this unit of study, the student should be able to:Correlate patient age to the overall incidence of the hematopoietic neoplasms.Explain the usefulness of immunological techniques, chromosome analysis, molecular genetic analysis, and cytochemistry in the diagnosis and prognosis of hematopoietic neoplasms.

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Learning Objectives—Level IAt the end of this unit of study, the student should be able to:State the prognosis and survival rates of the hematopoietic neoplasms.Define and differentiate proto-oncogenes and oncogenes.

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Learning Objectives—Level IIAt the end of this unit of study, the student should be able to:Explain how proto-oncogenes are activated, and the role that oncogenes and tumor suppressor genes and their protein products play in the etiology of hematopoietic neoplasms.Describe the effects of radiation on the incidence of leukemia.

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Learning Objectives—Level IIAt the end of this unit of study, the student should be able to:Differentiate between the acute and chronic myeloid and lymphoid leukemias based on their clinical and hematologic findings.Reconcile the use of chemotherapy for treatment of leukemia.

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Learning Objectives—Level IIAt the end of this unit of study, the student should be able to:Compare and contrast treatment options for the hematopoietic neoplasms, including possible complications.Name the leukemogenic factors of leukemia and propose how each contributes to the development of leukemia.

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Learning Objectives—Level IIAt the end of this unit of study, the student should be able to:Compare and contrast laboratory features of MDS, MPN, acute myeloid and lymphoid leukemia (AML, ALL), and mature lymphoid neoplasms, and justify a patient diagnosis based on these features.

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Learning Objectives—Level IIAt the end of this unit of study, the student should be able to:Define the principles of, explain the applications of, and select appropriate cytochemical stains for bone marrow evaluation of hematopoietic neoplasms.Select laboratory procedures appropriate for confirming cell lineage and diagnosis in hematopoietic neoplasms.

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Learning Objectives—Level IIAt the end of this unit of study, the student should be able to:Define epigenetics and define its role in cancer.Define cancer stem cell and explain its similarities to the hematopoietic stem cell (HSC).

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IntroductionNeoplasm"New growth"Dysregulated proliferationGenetic mutations Benign or malignant ("cancer")Neoplasms of hematopoietic cells Lymphoid or myeloidPremalignant and malignant neoplasms

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Figure 23-1 The spectrum of hematopoietic proliferation ranges from benign to malignant outcomes. Benign myeloid and lymphoid proliferation is usually a reactive process (reactive leukocytosis; leukemoid reaction). Mature myeloid and lymphoid neoplasms include myeloproliferative neoplasms (MPNs), and myelodysplastic syndromes (MDSs), chronic lymphocytic leukemia (CLL), and plasma cell neoplasms. These neoplasms are derived from a mutated precursor cell that divides incessantly but has some capacity to mature. Acute leukemia (AL) is a malignant precursor neoplasm characterized by unregulated cell proliferation and a block in maturation. Mature neoplasms can progress with additional genetic mutations and terminate in AL.

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IntroductionLeukemiaMalignant neoplasm of bone marrowLymphoid, myeloid, histiocytic/dendriticMyeloid and lymphoid subgrouped as: Precursor (acute) neoplasmMature (chronic) neoplasm

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Table 23-1 Comparison of Precursor and Mature Hematopoietic Neoplasms

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Acute LeukemiasPrecursor neoplasmsCharacterized by genetic mutations that promote proliferation and survival and/or block differentiation into mature cells

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Acute LeukemiasAcute leukemia has leukemic hiatus.Gap in the normal maturation of cells with many blasts, some mature formsArise from residual normal HSCs in the BM, but ↓ in intermediate maturational stages

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Figure 23-2 Acute myeloid leukemia. Note the large number of myeloblasts with no mature granulocytes present (Wright stain, 1000× magnification, peripheral blood).

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IntroductionMature neoplasms↑ in proliferation and survival of neoplastic cellsMaturation progenitor cells nearly normalLeukocytosisPredominant leukemic cells amitotic, mature, normal functionMay exhibit dysplastic features

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Figure 23-3 Chronic myelogenous leukemia. Note the large number of granulocytic cells in various stages of maturation including blasts, metamyelocyte, bands, and segmented neutrophils (Wright stain, 1000 magnification, peripheral blood).

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IntroductionLymphoma—abnormal proliferation lymphoid cells in lymphatic tissue or lymph nodesSolid tumorsWhen affects BM, lymphoma cells found in peripheral blood, considered the leukemic phase of lymphoma

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Figure 23-4 Clonal expansion of neoplastic cells in the bone marrow over a period of time leads to a decrease in the concentration of normal cells in both the bone marrow and peripheral blood.

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Etiology/PathophysiologyCancer initiating cellGenetic mutationHSC or differentiated progenitor cellCapacity for unlimited self-renewalGives rise to cancer stem cell

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Etiology/PathophysiologyCancer stem cellGenerate identical clones and sustain malignant growthHeterogeneous cell populationsChromosomal alterations (+/− abnormal karyotype)DNA alterations at the molecular level

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Figure 23-5 A hematopoietic neoplasm (left) is derived from a single cancer-initiating cell. The leukemic mutation(s) (black arrows) that transform a normal hematopoietic precursor cell to a cancer-initiating cell can occur at the hematopoietic stem cell (HSC) or more committed progenitor. If the cancer-initiating cell is a committed progenitor, then the mutations must include the capacity for self-renewal (blue arrows). If the mutation also can result in a block to terminal differentiation ( ) the resulting malignancy will be an acute leukemia (AL). Residual "normal" HSCs and committed progenitors in the marrow will still be capable of producing mature cells (right).

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OncogenesOncogeneAltered cellular gene that can cause cancer/tumors; plays role in cell cycleProto-oncogeneNormal, unaltered cellular counterpart of oncogeneRegulates initiation of DNA replication, cell division, commitment to cellular differentiation and/or apoptosis

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OncogenesOncogene activationStructural mutationsResult in continuous activity of protein or production of protein at wrong time or place

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OncogenesProto-oncogenes serve functions in normal cell growth:Growth factors Growth factor receptors Signal transducer molecules Transcription factors (nuclear)

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OncogenesProto-oncogene activationGene mutation, gene rearrangement, or gene amplificationResults in: Enhanced activity of geneProtein product no longer under normal regulatory control Cell proliferates without normal controls (↑ production for quantitative change)

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Tumor Suppressor GenesFunction is to inhibit cell growth in normal cells.Tumor suppressor mutations are loss of function mutations.

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Table 23-2 Properties of Oncogenes and Tumor Suppressor Genes

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EpigeneticsStable, heritable changes in gene expression, NOT due to changes in DNA sequenceChanges important in normal development and differentiationAssociated with "silencing genes" and chromatin condensation into heterochromatin

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EpigeneticsPassed from one cell generation to next during mitosis

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EpigeneticsMajor epigenetic changesDNA methylation of CpG dinucleotidesHistone acetylation/deacetylation reactions

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Cell-Cycle Checkpoints and CancerCommon features of cancer cellsLoss of regulation of cell-cycle checkpointsThrough overexpression of positive regulators (cyclins, Cdks)Loss of function of negative regulators (p53, Rb, Cdk inhibitors)

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Figure 23-6 Alterations of the G1 checkpoint that can lead to malignancy. Loss-of-function alterations in cell cycle negative regulators (i.e., the tumor suppressor gene products p16 or Rb) can contribute to uncontrolled proliferation. Similarly, gain-of-function mutations of positive regulators of proliferation can contribute to uncontrolled proliferation (i.e., the proto-oncogene gene products Cyclin D, Cdk4). = inhibition of the pathway; + = an alteration that increases activity of the indicated proteins; −=an alteration that decreases activity of the indicated proteins

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Apoptosis and CancerMutation of genes important in regulating apoptosis have been identified as oncogenes and tumor suppressor genes.Includes loss of function mutations initiate apoptosis (p53, Bax, Bcl-2 family members)

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Apoptosis and CancerMutation of genes important in regulating apoptosis have been identified as oncogenes and tumor suppressor genes.Results in production of cells with extended life span, ↑ proliferation capacity, diminished cell death

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LeukemogenesisSeveral factors play role:Genetic susceptibilitySomatic mutationViral infectionImmunologic dysfunctionMiscellaneous factors

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Table 23-3 Factors that May Play a Role in Leukemogenesis

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LeukemogenesisGenetic susceptibilityHereditary factors and abnormal genetic material have leukemogenic effects.Increase risk of developing acute leukemiaPotential to activate proto-oncogenes or eliminate function of tumor suppressor genes (TSGs)Example: Down syndrome

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LeukemogenesisSomatic mutationAcquired change in the genetic material of cells other than those involved in reproductionRadiation, chemicals, drugs cause mutations

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LeukemogenesisSomatic mutationChromosome breaks and translocations lead to oncogene activation to aberrant expression of protein product.Can produce hybrid genes with new protein products

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LeukemogenesisViral infectionUnclear how viruses cause leukemiaSuspected that viral genome incorporated into host DNA through retrovirusesActivates proto-oncogenes

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LeukemogenesisImmunologic dysfunctionCongenital and acquired immunologic disordersCould be due to breakdown in cellMediated immunologic self-surveillance systemProduction of antibodies against foreign Ags leading to neoplastic cells

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LeukemogenesisMiscellaneous factorsHematologic diseasesNo single factor, includes genetic factors and environmental exposures

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EpidemiologyMost cases occur in older adults> ½ occur after age of 67 ~ 50% are diagnosed as acute

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EpidemiologyVariations in leukemia among age groupsAcute leukemia occurs at all ages.Peak incidence in the first decade Decrease incidence in second and third decadeBegins to rise, rises steeply after age 50

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Table 23-4 Age Groups Typically Found in Acute (Precursor) and Chronic (Mature) Leukemias

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Clinical FindingsFailure of normal hematopoiesis Anemia, thrombocytopenia, neutropeniaOther signsBone pain (from BM expansion), weight loss, hepatosplenomegaly (+/−), lymphadenopathy (+/−)Neoplastic cells infiltrate body tissues.Spleen, liver, lymph nodes, skin, CNS

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Hematologic FindingsVariable cell counts and morphologyNormocytic/normochromic anemiaThrombocytopenia–acute leukemiaThrombocytosis–mature neoplasmsPlatelet morphology and function can be abnormal.

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Hematologic FindingsVariable cell counts and morphologyWBC countsNormal, decreased, increased↑ in immature formsBlasts are prominent in acute leukemia.

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Hematologic FindingsBone marrowHypercellular↑ reticulum↑ blasts (> 20% = acute leukemia)Maturation abnormalities in all three cell lines

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Hematologic FindingsOther tests↑ uric acid↑ LD↑ muramidase (lysozyme)Present in monocytes and granulocytes

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Table 23-5 Characteristic Hematologic Findings in Hematopoietic Neoplasms

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ClassificationImportant to classify neoplasmsCan compare various therapeutic regimensSystem for diagnosis using clearly defined clinical features and laboratory findingsPermits meaningful associations of genetic abnormalities with pathogenesis of disease

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ClassificationTwo major classification systemsBefore 2001, FAB (French-American-British)Morphology, cytochemistry, immunophenotyping

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ClassificationTwo major classification systemsWHO (2001) (World Health Organization)Morphology, cytochemistry, immunophenotyping, genetic features, prior therapy, history of myelodysplasia

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ClassificationWHO—based on neoplastic cell lineageThree major groupsMyeloidLymphoidHistiocytic/dendriticEach group subgrouped as precursor (acute) or mature (chronic) by morphology, genetic abnormalities, immunophenotyping, clinical features

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Table 23-6 2008 WHO Classification of Hematopoietic, Lymphopoietic, and Histiocytic/Dendritic Neoplasmsa

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Myeloid NeoplasmsPrecursor myeloid neoplasmsIncludes acute leukemias, myeloid sarcoma, blastic plasmacytoid dendritic cell neoplasms

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Myeloid NeoplasmsPrecursor myeloid neoplasmsAML subgrouped according toPrimary involved cell lineGenetic featuresPresence/absence myelodysplasiaPrevious therapyDon not meet inclusion criteriaAML not otherwise specified (NOS)

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Myeloid NeoplasmsMature myeloid neoplasmsGrouped based on genetic and biologic featuresMyeloproliferative neoplasms (MPNs)Myelodysplastic/myeloproliferative neoplasms

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Myeloid NeoplasmsMature myeloid neoplasmsGrouped based on genetic and biologic featuresMyelodysplastic syndromes (MDSs)Myeloid/lymphoid neoplasms with eosinophilia and abnormalities of platelet derived growth factor receptors (PDGFRA or PDGFRB) or fibroblast growth factor receptors (FGFR1)

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Myeloid NeoplasmsAccurate blast count essential for diagnosis% blasts = # blasts in all nucleated marrow cellsCounting blasts also includes:Monoblasts, promonocytesMegakaryoblasts Abnormal promyelocytesErythroblasts in pure erythroleukemia

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Lymphoid NeoplasmsClassified using Revised European-American Lymphoma (REAL)Utilizes immunophenotype, genetics, morphology, clinical featuresThree groups: B-cellT-/NK- cellHodgkin lymphoma

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Lymphoid NeoplasmsThree groups:Precursor (lymphoblastic)—no # blasts required for diagnosisB-cell and T-cell ALLLymphoblastic lymphoma

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Lymphoid NeoplasmsThree groups:Mature neoplasmsPlasma cell leukemiaAggressive, rapid progressionCLLIndolent progression

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Lymphoid NeoplasmsThree groups:Hodgkin lymphomaYoung adultsArise in lymph nodesReed-Sternberg cellsTwo types:Nodular lymphocyte predominantClassical

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Histiocytic and Dendritic Cell NeoplasmsHistiocytic neoplasms develop from myeloid-derived macrophages.Dendritic cell tumors develop from myeloid-derived macrophages and stromal-derived dendritic cells.Myeloid stem cell is precursor for histiocytes and dendritic cells.No unique phenotypic markers

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Diagnosing and Classifying NeoplasmsInitial evaluationPeripheral blood and BM samplesMorphology and blast countDifferentiation into cell lineageCytogenetic analysisMDS and MPNMorphology, genetic studies

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Table 23-7 Comparison of Acute Lymphoblastic Leukemia (ALL) and Acute Myeloid Leukemia (AML)a

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Diagnosing and Classifying NeoplasmsCytochemistryIn vitro staining of cellsMicroscopic examinationCytochemical markers Organelle-associated enzymes and proteinsCells incubated with substratesReact with specific cellular constituentsColored end product

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Diagnosing and Classifying NeoplasmsCytochemistryMPO (Myeloperoxidase)Positive in myeloblastsNegative in lymphoblasts, monoblasts, erythroblastsSBB (Sudan Black B)—stains lipids of cytoplasmic granulesSame staining patterns as MPO

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Diagnosing and Classifying NeoplasmsCytochemistryEsterase stain differentiates monoblasts and myeloblastsSpecific esterase—chloracetate esterase Positive in myeloblastsNonspecific esterase—α-naphthyl-acetate esterase (ANAE)Positive in monoblasts

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Diagnosing and Classifying NeoplasmsCytochemistryPAS (periodic acid-Schiff)—stains glycogen

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Diagnosing and Classifying NeoplasmsCytochemistryDiagnosis of ALL, acute erythroid, and megakaryoblastic leukemiaCan be negative or diffusely positive in myeloblastsPositive in lymphoblasts with block patternPositive in erythroblasts of erythroid leukemiaNormal erythroblasts do not stain with PAS

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Diagnosing and Classifying NeoplasmsCytochemistryLeukocyte alkaline phosphatase (LAP)Enzyme present in specific neutrophil granulesNot present in eosinophils and basophils Can distinguish leukemoid reaction (↑) from CML (↓).

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Diagnosing and Classifying NeoplasmsCytochemistryAcid phosphataseConstituent of lysosomes (present in most cells)T-cell ALL: focal polarized activityHairy cell leukemia: not inhibited by tartrate (TRAP)

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Diagnosing and Classifying NeoplasmsCytochemistryTerminal deoxynucleotidyl transferase (TdT)Nuclear DNA polymeraseUseful in distinguishing ALL from lymphomasPresent 90–95% of ALL (T- and B-cell)May be present in up to 20% of AML

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Diagnosing and Classifying NeoplasmsCytochemistryToluidine blueSpecifically (+) for basophils and mast cellsUseful for diagnosis of mast cell disease and basophilic leukemias

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Diagnosing and Classifying NeoplasmsImmunologic analysisIdentifies specific membrane antigens (surface markers) Characteristically found on particular cell lineagesUse monoclonal antibodies to identify "CD" antigens

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Diagnosing and Classifying NeoplasmsGenetic analysisCytogenetics—identify cell karyotypesMolecular analysis—identify specific mutations

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Diagnosing and Classifying NeoplasmsCytogeneticsIdentify characteristic nonrandom abnormal karyotypesSome specific chromosome changes associated with particular subgroupCan be used to identify: RemissionRelapseMinimal residual diseaseGenetic evolution (disease progression)

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Diagnosing and Classifying NeoplasmsMolecular analysisDNA technology Identifies genetic defects at the molecular levelSome cases have normal chromosome karyotype but molecular evidence of a genetic mutationProvide clues to pathogenesis of hematopoietic neoplasms

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Diagnosing and Classifying NeoplasmsMolecular analysisLimitations:Specific gene aberration must be identified, so probes to detect it can be made.Only single gene mutation identified using given probeQuantitative molecular methodsMonitor treatment, minimal residual disease in variety of disorders

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PrognosisHematologic remissionAbsence of neoplastic cells in PB and BMReturn to normal levels of hematologic parametersCytogenetic remissionAbsence of recognized cytogenetic abnormalities associated with a given neoplastic disease

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PrognosisMolecular remissionAbsence of detectable molecular abnormalities using PCR or related molecular technologies

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PrognosisMinimal residual diseaseNegative "traditional" tests (PB and BM cell counts, cytogenetics)Positive molecular tests (PCR/FISH)

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PrognosisTherapeutic success ratesDiffer by disease and the patient's condition at time of diagnosisOften obtain remission and then relapseMost treatment regimensTarget actively proliferating cells and not the LSC

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PrognosisSurvival in acute leukemias varies with age and group—ALL or AML80% children with ALL survive indefinitely.10–25% adults with ALL survive five years.55–65% adults achieve remission AML50% survive three years.

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PrognosisSurvival in chronic leukemias longer89% CML patients survive 5 years.CLL patients vary 30–120 months survival.

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TreatmentChemotherapyGoal is to eradicate all malignant cells.Allows for repopulation by residual normal precursorsProblemNot specific for leukemic cellsKills many normal cells

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TreatmentChemotherapyComplicationsBleeding, infections, anemiaThree groups of drugsAntimetabolites, alkylating agents, antibiotics

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TreatmentChemotherapyAntimetabolitesInhibits synthesis of DNAAffects rapidly dividing cellsAlso kills cellsLining the gutGerminal epithelium of the hair folliclesNormal hematopoietic cells

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TreatmentChemotherapyAlkylating agentsKills both resting and proliferating cellsInterferes with DNA synthesis

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TreatmentChemotherapyAntibioticsBinds both DNA and RNAInterferes with cell replication

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TreatmentPhases of therapyInduction therapy Induce complete remissionMaintenance therapy (consolidation therapy)Eradicate remaining leukemic cells

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TreatmentMolecular-targeted therapyTarget genetic mutationSilence the gene's expression or mutated proteinReactivate silenced geneTargeted therapies in useImatinib for CMLAll transretinoic acid (ATRA) for APL

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TreatmentMolecular-targeted therapyTherapies tolerated better than traditional chemotherapy

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TreatmentEpigenetic therapiesIn clinical trialsBone marrow transplantHighest rate of successPatients < 40 years old, in first remission with closely related donorAutologous transplants used when compatible donor can not be found

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TreatmentStem cell transplantsAutologous or allogeneicHematopoietic growth factorsSupportive care of AL patientsErythropoietin, G-CSF, GM-CSF, Interleukin-11

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Complications of TreatmentAggravate patient's clinical situation↑ uric acid from cell turnoverPrecipitates in renal tubulesLeads to renal failureLysed cellsRelease procoagulantsDIC and hemorrhage

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Complications of TreatmentChemo destroys normal and leukemic cells causing infection, bleeding, anemia

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Table 23-8 Chemotherapeutic Agents Usually Used in Acute Leukemia (AL) Treatment

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Chapter 23—Case Study72-year-old female, Agnes Persistent cough and fatigueHad always been in good healthUpon examination—pale, slight splenomegalyCBC WBC: 83.9 × 109/L

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Chapter 23—Case StudyConsider possible explanations for this test result and which reflex tests should be performed.

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Chapter 23—Case StudyQuestion 1:Given Agnes's laboratory results, would this most likely be considered an acute or chronic leukemia? Explain.

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Chapter 23—Case Study

CBC Results

WBC

83.9 × 10

9

/L

Differential:

RBC

3.15 × 10

12

/L

Segs 12%

Hb

9.5 g/dL (95 g/L)

Lymphs 88%

Hct

29% (0.29 L/L)

Platelets

130 × 10

9

/L

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Chapter 23—Case StudyQuestion 2:What group of leukemia (cell lineage) is suggested by the patient's blood cell differential results?Question 3:What would you expect the blast count in the bone marrow to be?

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Chapter 23—Case StudyQuestion 4:Would you expect Agnes to survive more than three years, or succumb fairly quickly after treatment?Question 5:Is Agnes a suitable candidate for a bone marrow transplant? Why or why not?

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Chapter 23—Case StudyQuestion 6:What types of treatment are available for Agnes?