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ACUTE LEUKEMIAHematologic Malignancies
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DefinitionLeuko = white
Emia = blood
Acute Leukemia: is a stem cell malignant disorder characterized by abnormal proliferation of malignant clone in uncontrolled fashion. It is a bone marrow based malignancy where expansion of the malignant clone interfere with normal BM function
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Types
Acute leukemia: runs a rapid and explosive course.
Chronic Leukemia: runs a more protracted and less severe course.
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EtiologyExact cause: Still unknown?
Possible etiologic associations:
1- Radiation-
Ionizing radiation exposure increases incidence of AL. Evidence from atomic bomb survivors in Japan & ankylosing spondylitis patients were treated with radiotherapy.
No risk from diagnostic radiation in patients & medical personnel.
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2- V iruses: Oncogenic viruses
HTLV-I associated with ATLL
HTLV-II causes in experimental animals a syndrome similar to Hairy cell Leukemia
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3- Genetics:
Increased AL in hereditary diseases with chromosomal instability
AR- Ataxia-telangiectasia
- Bloom syndrome
- Fanconi Anemia
X-linked infantile agammaglobulinemia
Others- Down’s synd, Turner, Kleinfelter
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Inv 16 – AML M4
t( 9;22) Ph + ALL, AML, CML
t(15;17) – AML M3
t(10;14)(q24;q11) – ALL
t(8;14)(q24;q32)
Hyperdiploidy
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4- Chemicals:
Benzene, insecticides, pesticides, herbicides
Drugs:
Alkylating agents- CTx, chlorambucil, melphalan
Nitrosoureas, etoposide
Bimolane – used for psoriasis
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5- Chronic BM stem cell disease e.g. PNH,AA,MDS ....etc
Others- Potent EM fields - smoking
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Epidemiology
More in developed countriesMale > femaleALL in children > adults
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classification
FAB (Frech-American-British)
1- Acute lymphoblastic Leukemia (ALL) L1 in children L2 in adults L3 Burkitt-lymphoma-like 2- Acute myeloblastic Leukemia (AML)
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AML
M0 – acute undifferentiated leukemia
M1 - AML with minimal differentiation
M2- AML with differentiation
M3- Acute promyelocytic Leukemia
M4 – Acute myelomonoblastic leuk
M4E – with peripheral eosinophilia
M5- Acute monoblastic leukemia
M6- Acute erythroleukemia
M7- Acute megakaryoblastic leukemia
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Clinical Manifestations
Dx suspected in presence of Triad ( Anemia, fever & bleeding) due to BM occupation blasts
Anemia- pallor, palpitation, easy fatigue, anorexia, SOB, Chest pain, dizziness
Fever- due to neutropenia & infection ( G-ve bacilli, coagulase –ve staph, viruses, fungi...)
Bleeding- hemorrhage into skin (petechiae, purpura, ecchymoses, bruises), gum, mucosae
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Bone pain may be so severe that mimic JCAHepatosplenomegaly – ALL > AML Lymphadenopathy – ALL > AML Peculiar features- Soft tissues myeloblastoma (Chloroma) –
AML Cutaneous infiltration – M4,M5 Meningeal infiltration- ALL< M4,M5 Testicular infiltration- ALL Gum hypertrophy- M4,M5 Lactic acidosis- L3 Prolonged prodromal phase- M6BM fibrosis- M7 Leukostasis- AML
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Lab DxCBC- Anemia- Hb low, platelets low - WBC may be increased (if
>50000 risk of hyperleukocytosis), may be normal, may be decreased.
- blasts are seen. If scanty (subleukemic).
If absent ( Aleukemic leukemia) Schistocytes- DIC (M3)
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BMA&B- Hypercellular hyperplastic active
Blasts > 30% of nucleated cellsDecreased megakaryocytesBM fibrosis (M7) reticulin stain
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ChemistryS uric acid increased SLDH increasedSerum lysozyme increased
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TypingLight microscope – using conventional
stains detect blasts shape, nucleus size & shape
Blasts in AML look larger with large nucleus, open chromatin with cytoplasmic inclusion bodies (Auer’s rods)
Blasts in L1 look homogeneous, small size, high N/C ratio
L2 larger, heterogeneous, low N/c ratioL3 large, homogeneous, pale
vacuolated cytoplasm, similar to Burkitt NHL cells
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Special StainsSudan Black (SB-B) +ve AMLMPO stain +ve AMLPAS stain +ve M4,M5, M6, L3tdT +ve ALL L1&L2Electron microscopy – detect minimal
MPO positivity in perinuclear space, Golgi, endoplasmic reticulum
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ImmunophenotypingUtilizing Cluster differentiation (CD) Flow cytometry or slide agglutinationCD10 – L1CD3 – T cell ALLCD19- B lineage ALL CD33- myeloid markerCD13- = = = CD41,42 – platelet
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Karyotyping & CytogeneticsChromosomal number & abnormalitiesHyperdiploidy , hypodiploidyDletion, inversion, mutation,
translocation Philadelphia chromosome t(9;22)
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Molecular BiologyUsing PCR & FISHBCR/ABL hybrid geneC-myc mutationPML mutationMLL mutationRARA gene over expression FLT3 gene mutation
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DDxALL- Acute Myelogenous Leukemia
Lymphoma, B-CellLymphoma, High-Grade Malignant ImmunoblasticLymphoma, Mantle CellLymphoma, Non-HodgkinAcute biphenotypic leukemiaNK-cell leukemia
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DDxAML- Acute Lymphoblastic Leukemia
Lymphoma, B-CellAgnogenic Myeloid Metaplasia With MyelofibrosisLymphoma, LymphoblasticAgranulocytosisMyelodysplastic SyndromeMyelophthisic AnemiaAplastic AnemiaChronic Myelogenous Leukemia
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ALL- L2
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ALL- Flow cytometry