ACUTE LEUKEMIAHematologic Malignancies

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

Types

Acute leukemia: runs a rapid and explosive course.

Chronic Leukemia: runs a more protracted and less severe course.

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.

2- V iruses: Oncogenic viruses

HTLV-I associated with ATLL

HTLV-II causes in experimental animals a syndrome similar to Hairy cell Leukemia

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

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

4- Chemicals:

Benzene, insecticides, pesticides, herbicides

Drugs:

Alkylating agents- CTx, chlorambucil, melphalan

Nitrosoureas, etoposide

Bimolane – used for psoriasis

5- Chronic BM stem cell disease e.g. PNH,AA,MDS ....etc

Others- Potent EM fields - smoking

Epidemiology

More in developed countriesMale > femaleALL in children > adults

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)

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

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

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

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)

BMA&B- Hypercellular hyperplastic active

Blasts > 30% of nucleated cellsDecreased megakaryocytesBM fibrosis (M7) reticulin stain

ChemistryS uric acid increased SLDH increasedSerum lysozyme increased

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

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

ImmunophenotypingUtilizing Cluster differentiation (CD) Flow cytometry or slide agglutinationCD10 – L1CD3 – T cell ALLCD19- B lineage ALL CD33- myeloid markerCD13- = = = CD41,42 – platelet

Karyotyping & CytogeneticsChromosomal number & abnormalitiesHyperdiploidy , hypodiploidyDletion, inversion, mutation,

translocation Philadelphia chromosome t(9;22)

Molecular BiologyUsing PCR & FISHBCR/ABL hybrid geneC-myc mutationPML mutationMLL mutationRARA gene over expression FLT3 gene mutation

DDxALL- Acute Myelogenous Leukemia

Lymphoma, B-CellLymphoma, High-Grade Malignant ImmunoblasticLymphoma, Mantle CellLymphoma, Non-HodgkinAcute biphenotypic leukemiaNK-cell leukemia

DDxAML- Acute Lymphoblastic Leukemia

Lymphoma, B-CellAgnogenic Myeloid Metaplasia With MyelofibrosisLymphoma, LymphoblasticAgranulocytosisMyelodysplastic SyndromeMyelophthisic AnemiaAplastic AnemiaChronic Myelogenous Leukemia

ALL- L2

ALL- Flow cytometry