Leukemias
CFU-Lymphocyte T
T lymphocyte
T lymphoblast
T lymphocyte
CFU-Lymphocyte B
B lymphocyte
B lymphoblast
B lymphocyte
CFS-Monocyte
Myeloblast
Promonocyte
Monocyte
CFS-G
Myeloblast
Promyelocyte
Neutromyelocyte
Stab Cell
Neutrophil
CFU-Eosinophil
CFU-Eosinophil
Myeloblast
Promyelocyte
Eosinophil Myelocyte
Eosinophil
Metamylocyte
Stab Cell
Eosinophil
CFU-Basophils
CFS-Basophil
Myeloblast
Promyelocyte
Basophil Myelocyte
Basophil
Metamylocyte
Stab Cell
Basophil
BFU-Erythrocyte
CFU-Erythrocyte
Basophilic
Erythroblast
Polychromatophilic
Erythroblast
Orthochromatophilic
Erythroblast
Reticulocyte
Erythrocyte
CFU-Megakaryoblast
Megakaryoblast
Promegakaryocyte
Megakaryocyte
Platelet
Lymphoid Stem Cells
CFU-GM
Haemopoetic
Pluripotent Stem Cell
Myeloid Stem Cells
L1 - Medium-sized
homogenous blasts
Acute Lymphoblastic
Leukemia
L2 - Heterogenous
blasts cells
Chronic Lymphocytic
Leukemia
L3 - Homogenous
basophilic Burkitt-type
blast cells
Lymphoid Lineage
M1 - Myeloblast
without differentiation
M2 - Myeloblast with
evidence of maturation
Leukemias
M3 - Acute
Promyelocytic
Leukemia
Acute Myeloid
Leukemia
M4 - Acute Myelocytic
Leukemia
Myeloid Lineage
M5a - Monoblast
Chronic Myeloid
Leukemia
M5 - Acute
Monocytic/Monoblastic
Leukemia
M5b - Monocyte
M6 - Erythroleukemia /
Di Guglielmo's
Syndrome
M7 - Megakaryoblastic
Leukemia
FAB Classifications

Morphology
Etiology
Clinical course
Leukaemogenesis
Clinical Manifestations




Acute Lymphoblastic Leukemias (ALL)
L1
L2
Medium-sized homogenous  Heterogenous lymphoblasts
lymphoblasts
 Some a marked, some a
Immunologically
nonmarking
nonmarking
 Mostly marked as T cells
Common in children
 Common in adult
85% cases of ALL
 14% cases of ALL
The best prognosis
 Bad prognosis
As a result of genetic alterations within single cell in the marrow
1. Epidemiological evidence
a. Hereditary’s Factors
i. Fanconi’s anemia
ii. Down’s syndrome
iii. Ataxia telangiectasia
b. Chemical agents
i. Benzene
ii. Phenylbutazone
iii. Arsenic
iv. Drug
1. Alkylating agent
2. Chloramphenicol
3. Antimetabolite
c. Viral related
i. HTLV1
ii. EBV
1. Acute clinical course with rapid development
2. ↓in one of more normal heamopoetic elements as bone
marrow is overrun by leukemic cells
a. Anemia
i. Pallor
ii. Hypoxic symptoms
iii. Normochromic-normocytic RBC
b. Thrombocytopenia
i. Heamorrhage
ii. Purpura
c. Neutropenia
i. Persistent infection
3. Metabolic imbalances
a. Hyperuriceamia due to high cellular turnover
4. Generalized lymphadenopathy
5. Bone pain and tenderness
6. Gum hypertrophy
2.
7.
8.
9.

L3
Homogenous basophilic
Burkitt-type blast cells
Mark as B cells



Children
I% cases of ALL (children)
Worse prognosis

Molecular Evidence
a. Alteration in Oncogene
i. Oncogene codes for protein involved in cellular
1. Proliferation
2. Differentiation
ii. It is altered through
1. Chromosomal translocation
2. Point mutation
3. Inactivation
Invasion of other organs
a. Hyperluekocytosis leads to ↑in blood viscosity;
predispose to
i. Microthrombi
ii. Acute bleeding
b. Involved
i. Brain
ii. Lung
iii. Eyes
c. Injudicious use of packed cells transfusion worsen the
blood viscosity
Leukostatic tumour
a. Lodging of blast cells in vessels forming a macroscopic
pseudotumour; may erode the vessels
b. Rare
Hidden relapse sites
a. Meninges
b. Testes
Acute Myeloblastic Leukemia (AML)
FAB
Classifications
M0


o
o
o

o
Characteristics
o
o

o
o
o

Epedimiology
M1
Minimally
differentiated
myeloblast
Blasts are stained
with
Myeloperoxida
se (MPO)
PAS
NSE
Negative for all
T & B cells
antigens
Platelets
glycoproteins
Erythroid
glycophorin A
Positive for all
myeloid antigens
CD13
CD33
CD11b

2-3% of
incidence




>90% are
myeloblasts
Myeloblast
without
differentiation
3% are stained
with MPO
CD8+ often seen
M2


M3

30-90% are
myeloblasts
Myeloblasts
with evidence
of maturation
15-20% of
incidence

10-15% of
incidence

T(15:17)(q22;q21
)

Fusion between
o
17q21
transcribing
for RARa
gene
o
15q22
transcribing
for PML gene

M4-Eo (with
eosinophil)
o
Del/inv16q

MYH1116p13

CBFbeta –
16q22
o
Marrow
eosinophil at
about 6-35%



Del (11q)
t(9;11)
t(11;19)
Unrecorded
o

o
30-40% of
incidence

15 % with
t(8:21)


CD13

Cytogenetic
Aberration
Clinical
Manifestations

o

Unrecorded
Markers
5-10% of
incidence
<35 years
old



CD34
CD33
Gum hypertrophy in M5
Mass effect on the eyes
o Leukemic infiltration on the lower chamber
of the eye obsecures the iris

Chloroma in the eye in M2

Raised lesions on the tongue


Acute
Myelomonocytic
Leukemia

20-80% are
o
Monocytes
o
Promonocytes

Is believed to arise
from CFU-GM

↑incidence of CNS
involvement
o
o


Divided into
subtypes
o
M5a –
monoblasts
without
maturation
o
M5b –
monoblasts
with
differentiation
(<5%)



M7
Erythroleukemia/
Di Guglielmo
>50% of all
nucleated
marrow elements
are of erythroid
precursors
30-50% more are
of myeloblasts
o
<30% are
myelodyspl
asia

<5% of AML
cases (rare)

<5% of AML
cases (rare)

t(1;22)


Associated with
1. Gums
a.
Gum
hypertrophy
2. Skin
a.
Eryhematou
s skin rash
b. Weakness
c.
Diffused
bleeding




M6

o

M5
Acute
Promyelocytic
leukemia
Promyelocytes
characterized with
Numerous darkly
stained
azurophilic
granules
Auer rod/faggot
cells may be
seen
Classical
hypergranular –
80% leukopenic
Variant
hypogranular –
leukocytosis
Granules contained
procoagulant
Leads to DIC
o
20% of
incidence
M4
Acute
Megakaryoblastic
leukemia
Associated with
fibrosis
Confirm origin
with
o
Platelet
peroxidase
with

Electron
microscopy

Methyleneblue/basic
fuchsin/Azu
re II (MAb)

vWF

glycoprotein
CD33
CD13
Marked
Petechiae
Ecchymoses
Pathologic fracture
Periorbital bacterial skin infection
Necrotic erythematous skin ulcer
Brain infection
o Aspergillosis

Oral candidiasis


Types of Leukemias
Epidemiology



Definition
Precursors cells
involved
FAB classifications
Morphology
Clinical Features


Acute Leukemias
Acute Lymphoblastic Leukemia
Less common
Predominantly occurs in young children
o Peak incidence at 3-4 years old
Presence in the bone marrow an peripheral blood
of uniform large cell
That resembles the proliferating lymphoblasts in
fetal development
Lymphoblasts of lymphoid lineage
L1,L2,L3
 Fewer nucleoli
 Condensed nuclear chromatin
 Scanty rim of cytoplasm
 Cytoplasmic granules are absent
 Absence of Auer rod/faggot cells


Presence of lymphadenopathy
Absence of chloroma or granulocytic sarcoma





Acute Myeloblastic Leukemia
More common
Predominantly occurs in young adults
o Peak incidence at 15-20 years old
Proliferation of cells of the granulocytes series
usually Neutrophils
Concomitant proliferation of basophils and
eosinophils are uncommon
Myeloblasts of myeloid lineage
M0, M1, M2, M3, M4, M5, M6, M7
 More prominent nucleoli
 Delicate/dispersed nuclear chromatin
 Fairly significant rim of cytoplasm
 Presence of azurophilc cytoplasmic granules
 Presence of Auer rod/faggot cells – a cytoplasmic
inclusion
 Lymphadenopathy is usually absent
 Presence of chloroma or granulocytic sarcoma
Chronic Leukemias
Types of Chronic
Leukemia
Definition
Morphology
Staging/Phasing
Epidemiology
Chronic Lymphocytic Leukemia






Proliferation of small mature lymphocytes
Resemble that of resting lymphocytes in the peripheral blood
95% are of B cells lineage
5% are of T cells lineage
Peripheral blood
o
Small round lymphocytes
o
Rim of cytoplasm
o
Smudged cells
Bone marrow
o
Mature small lymphocytes infiltrating between residual
normal heamopoetic elements
Rai Staging*
1. Stage 0
a. Lymphocytosis only (>15,000/mm3)
2. Stage 1
a. Lymphocytosis
b. Lymphadenopathy
3. Stage 2
a. Lymphocytosis
b. Splenomegaly w/o hepatomegaly
4. Stage 3
a. Lymphocytosis
b. Anemia (Hg <11g/dL)
c. With or without
i. Lymphadenopathy
ii. Hepatosplenomegaly
5. Stage 4
a. Lymphocytosis
b. Thrombocytopenia (Plt<100,000/UL)
c. With or without
i. Anemia
ii. Lymphadenopathy
iii. Hepatosplenomegaly
*There’s another staging called The Binet Staging System

Median age
o
65-70 years old


Sexual predeletion
o
Male to Female = 2 : 1
More common compared to CML
Chronic Myelocytic Leukemia


Proliferation of cells of the granulocyte series
That have matured beyond the myeloblast stage
Peripheral blood
o
Cells in all stages of granulocytic development
o
Myeloblast
o
Promyelocytes
o
Metamyelocytes
o
Myelocytes
o
Stab cells

Bone marrow
o
↑granulocytes and precursor blast cells
o
Small megakaryocytes
Present with 3 phases according to occurrence
1. Chronic phase
a. 1-5% of myeloblasts present
2. Accelerated phase
a. 5-19% of myeloblasts present
b. >20% basophils in the blood or bone marrow
c. Platelet count <100,000, unrelated to therapy
d. Platelet count >1,000,000, unresponsive to therapy
e. Increasing splenomegaly or white blood cell count, unresponsive to therapy
3. Blast phase
a. 20-30%* of myeloblast present
i. *more than 30% of myeloblasts will fall into AML category
b. Large clusters of blasts in the bone marrow on biopsy
c. Development of a chloroma (solid focus of leukemia outside the bone marrow)

Median age
o
SEA – 25-45 years old
o
Western world – 45-55 years old
Incidence increase by age; 30% more than 65 y/o

Sexual predeletion
o
Male to Female = 1.3 : 1

85% diagnosed during chronic phase

Less common compared to CLL

Types of Chronic
Leukemia
Chronic Lymphocytic Leukemia

Aetiology






Clinical features




Diagnostic tools


Chronic Myelocytic Leukemia
Family history
o
2-7 folds of risk
No documented environmental factors
No viral aetilogical evidence
Genetic mutations
o
Del 3q14
o
Del 11q22/ del 11q23
o
Trisomy 12 (20-25%)

Intermediate prognosis
o
Del in chrom 17 and 6 (less common)

20% are assymptomatic
Herpes zoster viral infection
o
Infecting the 5th cranial nerve of V1 opthalmic nerve
Herpes simplex eruptions on
o
Lips
o
Skin
Extensive oral candidiasis
Generalized lymphadenopathy
Hepatosplenomegaly – splenomegaly tends to be extensively
huge; due to
o
↑sequestration of leukemic cells
o
Infiltration of leukemic cells

Flow cytometry
o
CD19 w/o CD20 w

Coexpressed with CD5
o
Weak expression of surface Ig

sIgM

sIgD
o
May be expressed

CD21

CD23

CD24
Bone marrow aspirates
o
Not require for diagnosis
o
For determining the extent of disease for prognostic
implications

Diffuse infiltration shows poor prognosis
Other lab’s findings
o
Hypogammaglobulinaemia (>50%)
o
Small monoclonal peak (5-10%)
o
Positive Coomb’s test (30%)
o
Autoimmune hemolytic anemia (<10%)
o
Thrombocytopenia (<10%)








Due to exposures of
o
Radioactive ray
o
Chemicals

Benzene

Found in byproducts of laser printers and copy machine
Genetic mutations
o
Philadelphia Chromosome

T(9:22), fusion of

Moving ABL gene from 9p34

Fuse with BCR gene on 22q11
70% present with symptoms like
o
Fatigue
o
Abdominal discomfort
o
Weight loss
o
Sweating
Hepatosplenomegaly – splenomegaly tends to be extensively huge; due to
o
↑sequestration of leukemic cells
o
Infiltration of leukemic cells
Left abdominal discomfort is due to spleen infarction caused by
o
Aggregations of granulocytes
Retinal heamorrhage
Hyperuriceamia
↑buffy coat in blood tube
Flow cytometry
Karyotyping
**Pathogenesis in BCR-ABL translocation
Translocation of BCR-ABL gene leads to
1.
Encodes of protein
a. BCR gene encodes for fusion protein
b. ABL gene encodes for Tyrosine Kinase
2. In normal myeloid progenitor cell, it needs signal generation from GH in order to
a. Proliferate
b. Differentiate
3. But BCR-ABL gene tends to reduce the requirement of GH activation through
a. Tyrosine kinase in which it generates constitutive signals
b. These signals mimic in that of GH-factor receptor activation