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Week 10: Leukemia AML ALL FAB classification WHO classification

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1 Week 10: Leukemia AML ALL FAB classification WHO classification
Cytochemistries MPO SBB PAS ORO CD markers Flowcytometry CML CLL Karyotype Ph chromosome LAP

2 Signs and Symptoms of AML
Insidious nonspecific onset Pallor due to anemia Febrile due to ineffective WBC Petechiae due to thrombocytopenia Mucus membrane and gum bleed in M4 and M5 Bone pain

3 Typical Labs of AML Leukocytosis Blastemia Leukemic hiatus
Auer rods in M2, M3, M4 Thrombocytopenia Anemia >20% blasts in BM

4 Other Findings CD 13 and CD 33 in flowcytometry Cytochemistries
Myeloperoxidase Sudan black B Choloroacetate esterase (specific) Nonspecific esterase

5 FAB (1976) Classification M0 -- Undifferentiated AML
M1 -- AML without maturation M2 -- AML with maturation M3 -- Acute Promyelocytic Leukemia M4 -- Acute Meylomonocytic Leukemia M5 -- Acute Monocytic Leukemia M6 -- Erythroleukemia (DiGuglielmo’s) M7 -- Megakaryoblastic Leukemia


7 M1 and M2



10 Myeloperoxidase (MPO) p-Phenylene diamine + Catecol + H2O2 MPO > Brown black deposits

11 M3 M4 M5

12 Chloracetate (Specific) Esterase
Myeloid Cell Line Naphthol-ASD-chloracetate CAE > Free naphthol compounds + Stable diazonium salt (eg, Fast Corinth) > Red deposit

13 Non-Specific Esterase
Monocytic Line  Naphthyl acetate ANAE > Free naphthyl compounds +Stable diazonium salt (eg, Fast blue RR) > Brown deposits

14 NSE with Fl inhibition Histiocyte Double Esterase in M4

15 FAB vs WHO Classifications of Hematologic Neoplasm
FAB criteria Morphology Cytochemistry WHO criteria Morphology Immunophenotyping Genetic features Karyotyping Molecular testing Clinical features

16 WHO Classification of AML
AML with recurrent cytogenic translocations AML with multi-lineage dysplasia AML and myelodysplasia, therapy related AML, not otherwise categorized

17 AML with Recurrent Cytogenetic Translocations (WHO 1995)
t(8;21) -- some maturation of neutrophilic line; rare in older patients; AML1/ETO fusion protein; >90% FAB M2 t(15;17) -- APL (granular and microgranular variants); retinoic acid receptor (RAR) leukemias; middle aged adults; DIC inv(16) or t(16;16) -- monocytic and granulocytic; abnormal eosinophilic component 11q23 -- monocytic; children; most common is t(9;11)




21 FAB Classification of ALL
L1: Small homogeneous blasts; mostly in children L2: Large heterogeneous blasts; mostly in adults L3: “Burkitt” large basophilic B-cell blasts with vacuoles

22 L2 L3

23 Periodic Acid Schiff Periodic acid + Glycogen oxidation > Aldehyde + Schiff reagent (para-rosaniline, Na metabisulfite) > Red deposit

24 ALL Cytochemistries Oil Red O: stains L3 vacuoles
Terminal deoxynucleotidyl transferase (Tdt): DNA polymerase in early lymphoblasts Cell surface markers (CD’s) Cytoplasmic and surface immunoglobulins: B-cell line T-cell receptor (TCR)

25 WHO Classification of Lymphoproliferative Syndromes
Precursor B Lymphoblastic Leukemia/Lymphoma (ALL/LBL) -- ALL in children (80-85% of childhood ALL); LBL in young adults and rare; FAB L1 or L2 blast morphology Precursor T ALL/LBL -- 15% of childhood ALL and 25% of adult ALL Burkitt Leukemia/Lymphoma (FAB L3)

26 Antigens B-Lineage T-Lineage HLA Dr Tdt CD34 + 0 to + CD19 C 22 CD10 CD20 Cyt- SIg cALL and older Pre-B and older B-ALL Pre-T CD7 CD3 CD5 CD2 CD1 T-ALL

27 Prognosis Indicators Favorable Poor WBC < 50,000/L  50,000/L Age
1 - 10 < 1 or 10 Gender Female Male Blast B-cell T-cell and mixed Karyotype Hyperploidy Trisomy 4, 10, 17 t(12;21) (TEL/AML1) Hypoploidy Trisomy 5 t(1;19 (E2A/PBX1) Mixed lineage leukemia T(9;22) (Ph) BM blast count during induction Mkd reduction at day 7 Mild reduction at day 7

28 Typical Labs in CML Leukocytosis with blastemia Thrombocytosis
Basophilia Micro-megakaryocytes Low LAP score (intermediate if infected) About 10% blasts in BM Philadelphia chromosome

29 CML

30 Bone marrow aspirate and biopsy

31 Pseudo-Gaucher’s cells in BM

32 Leukocyte Alkaline Phosphatase (LAP)
Naphthol AS-MX phosphate LAP at pH8.6 > Naphthol AS-MX + Diazonium salt (eg, Fast blue RR) > Insoluble pigment

33 LAP Score Count 100 consecutive segs and bands Score: 0 = no granules
1+ = occasional diffuse granules 2+ = moderate number of granules 3+ = many strongly positive granules 4+ = confluent strongly positive granules

34 1+ 2+ 3+ 4+

35 LAP Score Example: 0 x 35 cells = 0 1+ x 30 cells = 30

36 Philadelphia Chromosome
9 and 22 translocation almost specific to CML Karyotype to visualize Ph chromosome Produces BCR/c-abl fusion oncogene Gene product p190 is a hyperactive tyrosine kinase Ph chromosome seen in ALL produces p210 and chronic neutrophilic leukemia produces p230

37 Karyotype 46,XX,t(9;22)(q34;q11.2) -- Ph chromosome


39 FISH showing the BCR (green), ABL (orange), and BCR-ABL fusion signals (arrow): A=positive (contains a residual ABL signal), B=normal

40 FAB (1982) Classification of Myeloproliferative Disease (MPD)
Chronic Myelocytic Leukemia (CML) Polycythemia Vera (PV) Essential Thrombocythemia (ET) Agnogenic Myeloid Metaplasia with or without Myelofibrosis (AMM) Benign Leukemoid Reaction

41 WHO Classification of MPS (1997)
CML becomes CML, Ph + t(9;22) BCR/ABL Chronic Neutrophilic Leukemia (CNL) Chronic Eosinophilic Leukemia and Hyper-eosinophilic Syndrome (CEL/HES) PV remains PV ET remains ET AMM becomes Chronic Idiopathic Myelofibrosis

42 Myelofibrosis

43 Myelofibrosis


45 Chronic Lymphocytic Leukemia
Exclusive in elderly Lyphocytosis unrelated to viral infection Hyper-mature lymphocytes with highly condensed nuclei Smudge cells: preventable with a drop of bovine albumin

46 CLL PB and BM



49 Bone Marrow


51 WHO Lymphoid Neoplasms
B cell neoplasms T/NK cell neoplasms Hodgkin lymphoma (disease)

52 Mature B Cell Neoplasms
B cell CLL/SLL B prolymphocytic leukemia Burkitt’s lymphoma / leukemia Splenic marginal zone B lymphoma Extranodal marginal B lymphoma Hairy cell leukemia Lymphoplasmocytic leukemia Mantle cell lymphoma Plasma cell myeloma / plasmacytoma Follicular lymphoma Diffuse large B lymphoma

53 T/NK Cell Neoplasms T prolymphocytic leukemia
T granular lymphocytic leukemia Aggressive NK cell leukemia Adult T lymphoma / leukemia Mycosis fungoides (Sezary syndrome) Anaplastic large cell lymphoma Hepatosplenic T lymphoma Peripheral T lymphoma Immunoblastic T lymphoma

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