A ccumulation of abnormal blasts I mmature precursors of WBC in bone marrow and blood leading to 1 Bone marrow failure anemia neutropenia amp thrombocytopenia 2 Organ infiltration ID: 1048058
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1. Aggressive malignant hematopoietic disorders Accumulation of abnormal blasts (Immature precursors of WBC) in bone marrow and blood leading to: 1- Bone marrow failure (anemia ,neutropenia & thrombocytopenia) 2- Organ infiltration ( hepatosplenomegy ,lymphadenopathy )Acute leukemia
2. Means “white blood” in Greek. Named by pathologist Virchow in 1845. Classified by FAB classification systems in 1976. Reclassified by World Health Organization in 2001 & 2008.HISTORY
3. PATHOGENESIS
4. Genetic alteration in the immature precursors Block of differentiation ,Enhanced proliferation & Decreased apoptosis Genetic predisposition Environmental factorsInfection Previous therapy Other hematological disordersUnknown Mechanism Acute lymphoblastic leukemiaAcute myeloid leukemia Acute mixed lineage leukemia
5. No differentiation Proliferation AMLALLPATHOGENESIS
6. AL represent about 8% of neoplastic diseases & cause about 4% of malignancy related deaths ! AML has an incidence of 2 – 3 per 100 000 per year in children, rising to 15 per 100 000 in adults.ALL has an incidence of 30 per million & represent about 76% of childhood leukemia . Epidemiology
7. Acute leukemia Acute Lymphoid Leukemia Acute Myeloid Leukemia Acute Leukemia of Ambiguous Lineage General Classification
8. Clinical history (Previous therapy)Morphology Flow cytometry Chromosomal Karyotyping Molecular study Basis of Classification
9. Myeloblast:-Size: medium-Large -Nucleous: round, oval or irregular-Nucleolus: prominent-Cytoplasm: abundant, granular Auer rods is characteristic Lymphoblast:Size: small- medium Nucleous: roundNucleolus: not prominentCytoplasm: scanty ,agranular may be vacuolated1- Light microscopy (blood smear, bone marrow aspirate & biopsy ) Blast count : it should be >20% out of the total cells Blast morphology :
10. 2-Flow cytometry: Laser based technology allows for cells counting & detection of their surface &cytoplasmic markers by suspending them in a stream of fluid followed by analysis through electronic system.
11. Basis of ClassificationStem Cell Markers: (CD34& TDT)MPOCD13CD33CD14CD64CD41CD235aCD10CD19CD22CD79aCD3CD4CD5CD7CD8MyeloidB-LymphoidT-Lymphoid
12. 3-Chromosomal KaryotypeSet of the chromosomes from one cell during metaphase to study the numerical(deletion &trisomy) and structural ( translation &inversion ) abnormality
13. 4- Molecular studies: Several techniques used to detect and localize the presence or absence of specific DNA sequences on chromosomes Fluorescent In-Situ Hybridization (FISH) Polymerase Chain Reaction(PCR)
14. Recurrent genetic abnormalitiesAMLALLMolecularKaryotypeBCR-ABL1t (9;22)AF4-MLLt (4;11)ETV6-RUNX1t (12;21)IL3-IGHt (5;14)Molecular KaryotypeAML1-ETOt (8;21)CBFB-MYH11t (16;16) or inv(16)PML-RARAt (15;17)MLLT1-MLLt (9;11)
15. Acute Myeloid Leukemia
16. Group of hematopoietic neoplasms caused by proliferation of malignant myeloid blasts in bone marrow and blood. The blast ≥20% or t(8;21) t (16;16) or t(15;17).More in Adults (do occur in infants!)Worse than ALLAcute Myeloid Leukemia
17. ErythroblastMegakaryoblastHSC
18. ErythroblastMegakaryoblastHSCMixed M0 ,M1M7M6M4M2M5M3B-ALLT-ALL
19. FAB Classification Based on morphology& flow cytometryCD235aCD41
20. AML Classification (WHO)AML with recurrent genetic abnormalities Myelodysplasia related AMLTherapy related AMLAML, not otherwise specified(FAB) 1- t(8;21)2- t(16;16)3- t(15;17)Prognosis:GoodBlasts≥ 20%Significant dysplasia Prognosis:poorBlasts≥ 20%Previous chemotherapy Prognosis:poorBlasts≥ 20%Genetic: NNo dysplasia Prognosis:Standard
21. M0M1M2M3
22. M4M6M7M5
23. 1-Pancytopenia:WBC infection (fever ,septic shock)Hb anemia (fatigue , headache , pallor ,SOB….) platelets bleeding (bruises , epistaxis ,menorrhagia…) 2-Organ infiltration:Hepatosplenomegally. Lymphadenopathy (rare)Myeloid sarcomaGum hypertrophyCNS diseaseMore with Acute Monoblastic Leukemia Clinical Features of AML Acute onset
24. 4-Disseminated Intravascular Coagulation (DIC):Widespread activation of coagulation system leading to intravascular fibrin deposition &consumption of platelet and coagulation factors which can be manifested as bleeding (85%) or thrombosis (15%)More with Acute Promyelocytic leukemia (M3) 3-Leucostasis (increased blood viscosity) Clinical Features of AML
25. Myeloid sarcomaGum hypertrophy Clinical Features of AML
26. Case Study56 years old female presented to ER with fatigue ,fever and nose bleeding for 2 weeks. O/E : moderate hepatosplenomegaly & multiple bruises. CBC : WBC :40 x109/L HB: 7g/dL PLT: 51 x109/L
27. Blood smear & bone marrow:?Flow cytometry :There are 2 population of blasts :1- (40%): CD34 ,CD13,CD33,CD117 and MPO2- (20%): CD 34, CD14, CD 64
28. Acute myelomoncytic leukemia (M4)(FAB)
29. Karyotype :The final diagnosis: AML t(16;16) (WHO)
30. Better prognosis:Genetics: t(8;21), inv(16;16) or t(15;17)Age: < 60 yearsPrimary better than secondaryTreatmentChemotherapy:AML: M0-M8 but not M3 ( same protocol)AML: M3 (ATRA or arsenic) Stem cell transplantationPrognosis and treatment
31. ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
32. Acute leukemia characterized by proliferation of malignant lymphoid blasts in bone marrow and blood.B and T cellsMore common in ChildrenBetter than AMLAcute Lymphoblastic Leukemia (ALL)
33. 1-Pancytopenia:WBC infection (fever ,septic shock)Hb anemia (fatigue , headache , pallor ,SOB….) platelets bleeding (bruises , epistaxis ,menorrhagia…) 2-Organ infiltration:Lymphadenopathy (very common)Hepatosplenomegally. testicles involvement CNS diseaseMediastinal mass Clinical Features of ALL Acute onset Characteristic for T-ALL
34. Morphological subtypes (FAB)L3 Burkitt’sL2L1HomogenousHeterogeneousHomogenousMorphologySmallVariableSmallSizeVaculatedMoreLittleCytoplasmProminentProminentNot prominentNucleolit(8;14) cmycVariableVariableGenetics
35. Immunophenotypic Subtypes (WHO)
36. L3 (Burkitt’s) represents mature lymphoid neoplasmso it is a type of lymphoma not Acute lymphoblastic leukaemia
37. Precursor B cellMature B cellCD34& TDTSurface ImmunoglobulinCD10CD19,CD20 &CD79aB- ALLBurkitt’sCommon B-ALLB-ALL
38. 3838sCD3cCD3(CD4&CD8)(CD4&CD8)- VE+VECD4 onlyCD8 onlyCD2,CD5&CD7T-ALLPrecursor T- cellMature T- cellT-ALLT- Cell Lymphoma
39. Treatment:Chemotherapy (high cure rate) Stem cell transplantationPrognosis &treatmentWorseBetter<2 - >10 yrs2 - 10 yrsAgeMFGenderHighLowWBC countT cellB cellCell typeOthersCommonB-ALL phenotypeHypodiploidyt(9;22)Hyperdiploidyt(12;21)B-ALL geneticsYesNoCNS involvement
40. Acute leukaemia is a fatal neoplastic condition20% or more blasts = Acute leukaemiaDiagnosis requires special investigationsAuer rods = AMLAML M3 = DIC &target therapyGum hypertrophy = mostly M4 or M5, Mediastinal = T-ALLRemember !
41. Subtypes of AML (M0-M8) + cytogenetic abnormalitiesSubtypes of ALL (T or B cell)Main lineages markers are MPO, CD19 and CD3Stem cell markers are CD34,TDTFAB classification based mainly on morphologyWHO classification focused more on genetics Remember !
42. ??