The Leukemias

Definition
Leukemias (Cancer of blood)
Are a group of disorders characterized by the
accumulation of malignant white cells in the bone
marrow and blood.
Classification
1. Acute 2. Chronic

A. Myeloid A . Myeloid

B. Lymphoid B. Lymphoid
 Etiology( Unknown !!!!)
 There are many predisposing factors which increase
the incidence of leukemia ,these includes the following :
1. Radiation(exposure or therapy).
2. Genetic factors (Down's syndrome).
3. Chemical agents (e.g, Benzene and Cytotoxic drugs)
4. Viruses(Human T.lymphotrophic virus I )
5. Prior hematological abnormalities(MDS,PNH)
Mechanism
1. Proto- oncogen /Oncogenes:
arise because of gain-of-function mutation in normal
cellular genes called proto-oncogene.
2. Tumour–suppressor genes:
Tumour-suppressor genes may acquire loss-of-function
mutations, usually by point mutation.
Incidence
 Acute leukemias
o Can occur in all age groups
o ALL is more common in children
o AML is more common in adults
 Chronic leukemias
o Are usually a disease of adults
o CLL is extremely rare in children and unusual before the age of
40.
o CML has a peak age of 30-50
Acute Leukemias
Definition
 Malignant clonal disorders characterized by
uncontrolled proliferation of hemopoietic
precursor cells, with loss of maturation and
differentiation.
Types of acute leukemias
1. Acute Lymphoblastic leukemia(ALL)
- Derived from (CFU-L)
2. Acute myeloid leukemia(AML)
- Derived from (CFU-GEMM)
 The peak incidence of ALL is 3 – 5 years
 falling off by 10 years , with secondary rise after the
age of 40 years.
 The median age for patients with AML is
approximately 65 years.
o AML form only a minor fraction of the leukemia in
children (10-15 %).
o Both AML and ALL have a slight male predominance.
Symptoms and Signs
 The clinical features are secondary to:
 Bone marrow failure:
Anemia, leucopenia, and thrombocytopenia.
 Organ infiltration by leukemic cells (blasts):
Splenomegaly, hepatomegaly, meningeal syndrome, and
lymphadenopathy.
 Coagulopathy:
DIC is common in patient (M3),Gum hypertrophy with monocytic
Leukemias (M4 & M5).
 Rarely patient with AML develop Chloroma (solid tumors of
leukemic myeloblasts).
Classification
Most widely used are :
 WHO classification :
Depends on information obtained from:
1. Morphology (Blasts ≥ 20 % )
2. Immunophenotyping.
3. Cytogenetic (Karyotyping).
4. Molecular genetic analysis.
 French American British classification(FAB)
Represent the old way for the classification of acute
Leukemias .
 Either the classical FAB classification (depends
largely only on morphology and the number of blasts
present in BM and/or blood) or modified FAB (on
morphology and cytochemistry stain, in addition to
number of blasts ≥ 30 %).
FAB Classification of AML
 M0 : undifferentiated
 M1: without maturation(rare -Auer rod )
 M2: with maturation(Auer rod may seen)
 M3: promyelocytic hyper/ with hypo variant
 M4: Myelomonocytic/Eos variant
 M5: monoblastic(M5a) /cytic (M5b)
 M6: erythroleukemia
 M7: megakaryoleukemia
AML (M0)
AML ( M5)
AML. Leukemic myeloblast with an
Auer rod.
FAB Classification of ALL
 L1:
Small, uniform, ↑ N:C (scanty cytoplasm)
 L2:
Heterogeneous, variable amount of
cytoplasm, irregular nuclei with large nucleoli
 L3:
Large homogeneous blasts, basophilic
cytoplasm, round nuclei with prominent
nucleoli,cytoplasmic vaculation.
ALL (L1)
ALL (L2)
ALL (L3)
Laboratory Findings
 Full blood count:
With careful examination of a well prepared
blood smear. Blasts should be ≥30 % (FAB),
WHO Blasts ≥ 20 %
 WBCs commonly increased, but may be normal
or even reduced.
 Thrombocytopenia is common, with N.N anemia
 Bone marrow aspirate :
(Trephine biopsy is necessary in case
of Hypocellular or fibrotic marrow) for
morphology and special tests.
(same findings as peripheral blood)
 Cytochemical stains:
1. Myeloperoxidase (MPO):
Positive for most cases of AML.
2. Sudan black B (SBB):
Positive in most cases of AML.
3. Specific esterase:
Positive in some cases of AML (Granulocytic)
4. Non specific esterase:
Positive in some cases of AML indicate monocytic
lineage
5. Periodic acid- Schiff:
Positive in ALL
 Immunophenotyping(CD markers):
Is essential in diagnosis of acute
Leukemias especially lymphoblastic
one, and is now performed largely by
using anticoagulated blood or bone
marrow samples, either by :
- Flow cytometry or
- Immunocytochemistry
 Myeloid markers:
CD13.CD33.CD117.MPO, glycophorin A
(M6) , CD14 and CD64(M4&M5), CD41 &
CD61(M7).
 Lymphoid markers:
o B-lymph: CD10,CD19,CD20,CD22,CD79a,
and surface immunoglobulin(sIg) .
o T-lymph:
CD2,CD3, CD5, and CD7
 Cytogenetic (Chromosomal) analysis:
Is essential for both prognostic reason
and treatment, it is best to performed in
bone marrow.
 Examples:
The t(9;22)(q34;q11) translocation and the
corresponding BCR-ABL fusion gene are
associated with unfavorable treatment
response in both children (3%) and in
Adult(25 %)
 Molecular genetic analysis :
Essential for the selection of suitable
treatment & for Prognosis, carried by
different techniques such as :
1. PCR
2. Florescence insitu hyperdization (FISH)
Chronic leukemias
Chronic Myeloid Leukemia
CML
Definition
 A clonal malignant hemopoietic stem cell disorder
characterized be predominant proliferation of
granulocytic cells.
 Occurs at all ages , but predominantly in older adults.
 a slight male predominance ( ~1.5 : 1.0)
 CML has been linked to exposure to ionizing radiation;
no other predisposing factors are known.
Clinical Features
 Weight loss
 Night sweats
 Features of anemia
 Common sign is splenomegaly
 Occasionally :Symptoms of hyperviscosity due
to very high WBCs.(i.e. Spontaneous bleeding,
visual disturbance and neurologic symptoms)
 In up to 50 % of cases the diagnosis is made
incidentally by a routine blood count
Phases of CML
 Chronic phase:
Most cases are presented in chronic phase, and usually show an
excellent response to chemotherapy, Blasts in Bone
marrow(and blood) in most cases are usually < 5.0 %
 Accelerated phase:
Anemia, thrombocytopenia (Not related to therapy) or
thrombocytosis ( Not respond to therapy), basophilia,
eosinophilia, and blasts in bone marrow and blood (6.0 – 19.0 %)
 Blast phase (Acute transformation):
Blasts marrow (> 20.0 %) ,In the majority , the
transformation is into AML (> 75.0 %) , in
about 25 % of cases acute transformation is
lymphoblastic ( into ALL ).
Laboratory Diagnosis
 Raised leucocytes count(usually > 50.000/ul)
 Basophilia & eosinophilia
 Normocytic, normochromic anemia
 Platelets count may be increased (most
frequently),normal or decreased
 Leukocyte alkaline phosphatase score is
reduced(LAP score)
 Bone marrow : Hypercellular with
marked proliferation of all granulocytic
elements.
 Cytogenetic analysis:
> 95 % show Philadelphia chromosome
t(9;22)
Philadelphia chromosome
Differential Diagnosis
Both CML and Leukemoid reactions
cause leucocytosis with a left shift.
 Leukemoid reaction
A benign bone marrow response to a
systemic inflammation (e.g. Abscess
and metastatic carcinoma)
Parameter CML Leukemoid reaction
1.Clinical features Splenomegaly as per underlying disease

2. Blood :
Leucocyte count Usually > 100.000 /ul Usually < 50.000 /ul
Immature WBCs(Blasts) Often present Usually absent
Basophilia & Eosinophilia Present Absent
Toxic granulation Absent Commonly present
3.N.RBCs Usually present Sometimes present
4.LAP Score Usually low Increased

5.Cytogenetic analysis Philadelphia chromosome (Ph1) Normal

6.Bone marrow Trilineage hyperplasia Granulocytic hyperplasia

Chronic Lymphocytic
Leukemia (CLL)
 CLL is a malignant disorder characterized by
an increased number of small mature
appearing lymphocytes in the blood.
 It is a disease of older subject (rarely occurs
before 40 years of age).
 Male being more affected than female
( male to female ratio 2:1)
 It is virtually never seen in children.
 Cells of CLL is generally clonal population of
mature appearing B.lymphocytes (T-cell CLL
are rare).Exhibiting monoclonal surface
immunoglobulin (SIg), and unusual feature is
expression of the CD5 membrane marker
occurs in mature T.lymphocytes.
Clinical Features
 Bilateral cervical lymphadenopathy
 features of anemia may be present.
 Splenomegaly
 Hepatomegaly
 Bacterial or fungal infection are common in later
stages of the disease.
 The diagnosis is often made incidentally from a
persistent lymphocytosis
Laboratory Diagnosis
 Lymphocytosis, there must be > 5.000/ul
lymphocytes in the blood.
 Relative neutropenia (absolute neutrophils may be
normal, decrease, or increased).
 Characteristic feature in blood smear is the
presence of smudge cell, or basket cell (ruptured
cells).
 Hypogammaglobulinemia may present in about two
third of patient.
 There may be prolymphcytes ( < 10 %).
 Anemia and thrombocytopenia may be caused by
lymphocyte infiltration of bone marrow, autoimmune
or hypersplenism .
 Direct coomb,s positive (worm antibody hemolytic
anemia occurs in about 10 % of patients ,and immune
thrombocytopenia in about 5 %)
 Bone marrow: Contains > 30 % lymphocytes.
 Immunophenotyping
o Shows cells to be B.lymphocytes (surface
CD 19 positive), weakly express surface
immuno- globulin (IgM or IgD).
o The cells are also surface CD5 and CD23
positive.
‫‪Thank you for attention‬‬
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