Leukemia & Multiple Myeloma

Roger S. Riley, M.D., Ph.D. Department of Pathology Medical College of Virginia

rsriley@hsc.vcu.edu http://www.labmedweb.com (804) 828-0338

Oct. 6, 1999

Goals & Objectives

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Understand nature and etiology Understand classification Understand clinical manifestations Understand principles of diagnosis Understand prognostic factors Understand principles of treatment

Lecture Contents

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Basic features Acute leukemias Chronic leukemias Multiple myeloma Summary

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Basic features
Definition Classification Clinical features Etiology Diagnosis

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Acute leukemias Chronic leukemias

What is leukemia ?

Malignant neoplasm of the white blood cell, characterized by involvement of the blood and bone marrow !

Leukemia Features
Acute Onset Cell type Survival Treatment
Rapid Immature (Blast) Fatal if no Rx Amenable to chemotherapy

Chronic
Gradual More Mature Long survival May be resistant

Clinical Features of Leukemia

Replacement of normal marrow elements

Production of physiologically active substances

Anemia Bleeding Infection

Leukostasis and tissue infiltration

Normal Hematopoiesis
Pluripotential Stem Cell Lymphoid Stem Cell Myeloid Stem Cell

Differentiation & Maturation

Leukemia Classification

Acute Lymphoid ALL

Chronic CLL

Myeloid

AML

CML

Leukemia Diagnosis
Light Microscopy (Morphology) Electron Microscopy (Ultrastructure) Immunophenotypic Analysis (Antigens)

1900

1950

2000

Cytochemical Stains (Enzymes)

Cytogenetic Analysis (Chromosomes)

Molecular Techniques (Genes)

Lecture Contents
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Basic features Acute leukemias

Etiology Acute lymphoblastic leukemia Acute myeloblastic leukemia

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Chronic leukemias Multiple myeloma Summary

Pluripotential Stem Cell

Lymphoid Stem Cell

Myeloid Stem Cell

Acute Leukemia and Age

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% % Patients Patients

ALL is primarily a pediatric disease AML is primarily an adult disease

100

Myeloblastic

80

60

40

20 Lymphoblastic 0 0 20 40 Age Age 60 > 70

Lecture Contents
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Basic features Acute leukemias

Etiology Acute lymphoblastic leukemia Acute myeloblastic leukemia

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Chronic leukemias Multiple myeloma Summary

Acute Lymphoblastic Leukemia

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Abrupt stormy onset Symptoms related to suppressed BM

Fatigue (anemia) Fever/infection (leukopenia) Bleeding/bruising (thrombocytopenia)

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Bone pain/tenderness Lymphadenopathy, hepatosplenomegaly CNS involvement

Acute Lymphoblastic Leukemia

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Proliferation of lymphoblasts Small cells with indistinct nucleoli High nuclear/ cytoplasmic ratio Fine chromatin

Peripheral Blood in ALL

Bone Marrow in ALL

FAB FAB Classification Classification

Standard morphologic classification system I French-American-British Cooperative Group I Features considered
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Cell size Amount of cytoplasm Nuclear vacuolarion Nuclear size and shape Cytoplasmic vacuolations Other features

FAB Classification
Acute Lymphoblastic Leukemia Three Subtypes L1, L2, L3 I Acute Myelogenous Leukemia Eight Subtypes M0, M1, M2, M3, M4, M5, M6, M7
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Cytochemistry of ALL
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Positive for TdT (terminal deoxytransferase) Negative for myeloperoxidase

Immunology of ALL
Pre-B ALL (FAB-L1 or L2)(85%) CD10 (CALLA) CD19 Children and adults I T-ALL (FAB-L1 or L2)(15%) Adolescent males Thymic mass I B-ALL (ALL-L3)(< 1%) Related to Burkitts lymphoma Poorer prognosis
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Immunology of ALL

Lymphoblastic Lymphoma

ALL, FAB-L3
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Leukemic counterpart of Burkitts lymphoma Endemic in parts of Africa Large cells with blue vacuolated cytoplasm Express monoclonal immunoglobulin light chain (usually ) t(8;14), concogene Associated with EBV infection

Cytogenetics in ALL
I 90% have chromosomal

abnormality

Hyperdiploidy (>50 chromosomes) Translocations (e.g. t(9;22))

I Prognostic significance

Treatment of ALL
Three treatment phases Remission induction Consolidation (intensification) Maintenance I Allopurinol to counter hyperuricemia from tumor cell breakdown I CNS prophylaxis I 70-85% cure rate in children, worse prognosis in adults
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Post-Chemotherapy Marrow

Lecture Contents
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Basic features Acute leukemias

Etiology Acute lymphoblastic leukemia Acute myeloblastic leukemia

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Chronic leukemias Multiple myeloma Summary

Pluripotential Stem Cell

Lymphoid Stem Cell

Myeloid Stem Cell

FAB Classification of AML

M0, M1, M2 M3 M4 M5 M6 M7 Myeloblastic Promyelocytic Myelomonocytic Monoblastic Erythroblastic Megakaryoblastic

Acute Myelogenous Leukemia

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Proliferation of immature myeloid cells Primarily occurs in adults Develops in some patients with chemotherapy, radiotherapy, etc. Abrupt presentation with anemia, infection, and/or bleeding Myeloblasts may have Extramedullary involvement in FAB M4 and M5 (gums, skin, internal organs) DIC in acute promyelocytic leukemia (FAB M3)

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Causes of AML
Idiopathic (vast majority) I Prior chemotherapy I Prior radiotherapy I Chemical exposure (benzene) I Myelodysplastic syndromes I Myeloproliferative diseases I Downs syndrome I Fragile chromosome syndromes I Aplastic anemia and PNH
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Morphology of AML

Cytochemistry of AML
Myeloperoxidase positive I TdT negative
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Immunology of AML
I Positive for myelo/monocytic Ags

CD13, CD33 I Negative for B-lineage antigens CD10, CD19 I Negative for T-lineage antigens CD3, CD7

Immunology of ALL

Cytogenetics of AML
I 90% have chromosomal

abnormalities I t(15;17)- APL I t(8;21) I -5 I -7 I +8

Acute Promyelocytic Leukemia

Neoplastic Neoplastic promyelocytes promyelocytes I I Many Many Auer Auer rods rods I I DIC DIC I I t(15;17) t(15;17) RAR RAR gene gene on on 17 17 I I Treated Treated with with retinoic retinoic acid acid
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Treatment of AML
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AML M0-M2, M4-M7 Induction chemotherapy Intensification (consolidation) Initial remission in 65% of patients Overall survival not as good as ALL Bone marrow transplantation used when possible AML FAB-M3 Trans-retinoic acid Relatively good prognosis