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LEUKAEMIA DIAGNOSIS. Leukaemia is a disease resulting from the neoplastic proliferation of haemopoietic or lymphoid cells. Leukaemias are broadly divided into: Acute leukaemias, which, if untreated, lead to death in weeks or months.

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Leukaemia is a disease resulting from the neoplastic proliferation of haemopoietic

or lymphoid cells.

Leukaemias are broadly divided into:

  • Acute leukaemias, which, if untreated, lead to death in weeks or months.
  • chronic leukaemias, which, if untreated, lead to death in months or years.
They are further divided into lymphoid, myeloid and biphenotypic leukaemias, the latter showing both lymphoid and myeloid differentiation.

Acute leukaemias are characterized by a defect in maturation, leading to an imbalance between proliferation and maturation; since cells of the leukaemic clone continue to proliferate without maturing to end cells.

Diagnosis of leukaemia.

The diagnosis of leukaemia and categorization

required the following parameters.

1- Morphology.




5- Molecular study.


Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children, representing nearly one third of all pediatric cancers.

The annual incidence rate for acute lymphoblastic leukemia is 30.9 cases per million population. The peak incidence occurs in children aged 2-5 years. 


In acute lymphoblastic leukemia, a lymphoid

progenitor cell becomes genetically altered

and subsequently undergoes dysregulated

proliferation, survival, and clonal expansion.

In most cases, the pathophysiology of transformed

lymphoid cells reflects the altered expression of

genes whose products contribute to the normal

development of B cells and T cells

Clinical feature.

Children with acute lymphoblastic leukemia (ALL) generally

Present with signs and symptoms that reflect bone marrow

infiltration and extramedullary disease.

Because leukemic blasts replace the bone marrow, patients

Present with signs of bone marrow failure, including anemia,

thrombocytopenia, and neutropenia.

Clinical manifestations include fatigue and pallor, petechiae and

bleeding, and fever.

In addition, leukemic spread may manifest as lymphadenopathy

And hepatosplenomegaly. Other signs and symptoms of leukemia

including weight loss, bone pain, and dyspnea.

The classification of ALL

FAB classification.


Cell size Mainly small Large, heterogeneous Large, homogeneous

Nuclear chromatin Fairly homogeneous Heterogeneous Finely stippled,

Nuclear shape Mainly regular Irregular; clefting Regular

Nucleolus Not visible Usually visible Usually prominent

Amount of cytoplasm Scanty Variable abundant Moderately abundant

Cytoplasmic basophilia Slight to moderate Variable Strong

Cytoplasmic vacuolation Variable Variable Often prominent

Clinical correlates of FAB categories of ALL

Many cases of L3 ALL represent a distinct entity that

requires specific management. However, the categorization

of a case as L1 or L2 ALL is of little importance.

The FAB L1 category includes more childhood

cases with a relatively good prognosis.

The incidence of ALL L1 falls with increasing age whereas

the incidence of ALL L2 does not vary much with age.

ALL L2 has generally been found to have a worse

prognosis, although the difference is not major.

WHO proposed classification of acute lymphoblastic leukemia

The recent WHO International panel on ALL recommends that

the FAB classification be abandoned, since the morphological

classification has no clinical or prognostic relevance.

1- Acute lymphoblastic leukemia/lymphoma Synonyms:

Former Fab L1/L2

i. Precursor B acute lymphoblastic leukemia/lymphoma.

Cytogenetic subtypes:

  • t(12;21)(p12,q22) TEL/AML-1
  • t(1;19)(q23;p13) PBX/E2A
  • t(9;22)(q34;q11) ABL/BCR
  • T(V,11)(V;q23) V/MLL

ii. Precursor T acute lymphoblastic leukemia/lymphoma

2- Burkett's leukemia/lymphoma Synonyms: Former FAB L3

3- Biphenotypic acute leukemia

Characterization of the Immunophenotyping is referred to as Immunophenotyping and is achieved by means of labeled antibodies that recognize specific epitopes of cellular antigens.

In general, the most useful antibodies are monoclonal antibodies (McAb) produced by hybridoma technology but, for some antigens, polyclonal antibodies (PcAb) (antisera) are better.

The technique employed for Immunophenotyping may be immunocytochemistry or, much more often, flow cytometry.

Immunophenotyping is essential for the diagnosis of B- or T-lineage acute lymphoblastic leukaemia (ALL).

First panel

B lymphoid CD19, CD22, CD79a, CD10

T lymphoid CD3, CD2, CD7

Second panel

If B lineage cm, k, l, CD20, CD24

If T lineage CD1a, SmCD3, CD4, CD5, CD8, anti-TCR ab, anti-TCR gd

Cytogenetic study.

With techniques now available, 70–90% of cases of ALL

have a demonstrable cytogenetic abnormality.

In ALL, chromosomal abnormalities correlate

with other clinical and hematological factors

of prognostic importance but they also have

a considerable independent prognostic


B-lineage ALL

L1 high/ hyperdiploidy.

L1 or L2/t(9;22)/BCR-ABL fusion

L1 or L2/t(4;11)(q21;q23)

L1 or L2/t(12;21)(p12;q22)/early precursor or common ALL

L1 or L2/t(1;19)(q23;p13)/pre-B ALL

T-lineage ALL.

L1 or L2/t(10;14)(q24;q11)


L3/t(8;14)(q24;q32) or t(8;22)(q24;q11) or


Distinguishing between AML and ALL

Correct assignment of patients to the categorize

AML and ALL is very important for prognosis

and choice of therapy.

The FAB group recommended the use of

MPO,SBB and non-specific esterase (NSE)


If Cytochemical reactions for myeloid cells are

negative, presumptive diagnosis of ALL must

be confirmed Immunophenotyping.


AML is the most common acute leukaemia affecting adults, and its incidence increases with age.

Although AML is a relatively rare disease, accounting for approximately 1.2% of cancer deaths in the United States, its incidence is expected to increase as the population ages.


The malignant cell in AML is the myeloblast.

In normal haematopoiesis, the myeloblast is an immature precursor of myeloid white blood cells; a normal myeloblast will gradually mature into a mature white blood cell.

However, in AML, a single myeloblast accumulates genetic changes which "freeze" the cell in its immature state and prevent differentiation Such a mutation alone does not cause leukemia; however, when such a "different combined with other maturation which disrupt genes controlling proliferation, the result is the uncontrolled growth of an immature clone of cells, leading to the clinical entity of AML.

Clinical feature.

The symptoms of AML are caused by replacement of normal bone marrow with leukemic cells, which causes a drop in red blood cells, platelets, and normal white blood cells.

These symptoms include fatigue, shortness of breath, easy bruising and bleeding, and increased risk of infection

The classification of AML

FAB classification.

M0 Undifferentiated acute myeloblastic leukemia.

M1 Acute myeloblastic leukemia with minimal maturation.

M2 Acute myeloblastic leukemia with maturation.

M3 Acute promyelocytic leukemia.

M4 Acute myelomonocytic leukemia.

M4 eosAcute myelomonocytic leukemia with eosinophilia.

Acute monocytic leukemia.

M6 Acute erythroid leukemia.

M7 Acute megakaryoblastic leukemia.

Criteria for the diagnosis of acute myeloid leukaemia of M0

Blasts .30% of bone marrow nucleated cells

Blasts .30% of bone marrow non-erythroid cells <3%

of blasts positive for Sudan black B or for myeloperoxidase

by light microscopy.

Blasts demonstrated to be myeloblasts by immunological

markers or by ultrastructural cytochemistry.

Criteria for the diagnosis of acute myeloid leukaemia of M1.

Blasts 30% of bone marrow cells .Blasts .90% of bone marrow

non-erythroid cells .3% of blasts positive for peroxidase or

Sudan black B

Bone marrow maturing monocytic component (promonocytes to

monocytes) .10% of non-erythroid cells

Bone marrow maturing granulocytic component (promyelocytes to

polymorphonuclear leucocytes) .10% of non-erythroid cells

Criteria for the diagnosis of acute myeloid leukaemia of M2.

Blasts 30% of bone marrow cells. Blasts 30–89% of bone marrow

non-erythroid cells

Bone marrow maturing granulocytic component (promyelocytes to

polymorphonuclear leucocytes) >10% of non-erythroid cells

Bone marrow monocytic component (monoblasts to monocytes)

<20% of non-erythroid cells and other criteria for M4 not met

Acute hypergranular promyelocytic

Leukaemia M3 AML

In acute hypergranular promyelocytic

leukaemia the predominant cell is a highly

abnormal promyelocyte.

In the majority of cases, blasts are fewer than

30% of bone marrow nucleated cells. The

distinctive cytological features are sufficient to permit a diagnosis and

In some cases there are giant granules or

multiple Auer rods, which are often present

in sheaves or ‘faggots’. Most cases have a minority of cells that are agranular.

M3 AML has been found to be very sensitive

to the differentiating capacity of all-trans-

retinoic acid (ATRA). Following such therapy

an increasing proportion of cells beyond the

promyelocyte stage are apparent.

Criteria for the diagnosis of acute myeloid leukaemia of M4.

Blasts .30% of bone marrow cells

Blasts .30% of bone marrow non-erythroid cells

Bone marrow granulocytic component 20% of non-erythroid cells

Significant monocytic component as shown by one of the following:

Bone marrow monocytic component 20% of non-erythroid cells and peripheral blood monocytic.

Bone marrow resembling M2 but peripheral blood monocytic component .5000/cumm.

Criteria for the diagnosis of acute myeloid leukaemia of M5

Blasts .30% of bone marrow cells

Blasts .30% of bone marrow non-erythroid cells

Bone marrow monocytic component .80% of non-erythroid cells

Acute monoblastic leukaemia (M5a)

Monoblasts .80% of bone marrow monocytic component

Acute monocytic leukaemia (M5b)

Monoblasts <80% bone marrow monocytic component

Criteria for the diagnosis of acute myeloid leukaemia of M6

Erythroblasts .50% of bone marrow

nucleated cells

Blasts 30% of bone marrow non-erythroid


Criteria for the diagnosis of acute myeloid leukaemia of M7

Blasts 30% of bone marrow nucleated cells.

Blasts demonstrated to be megakaryoblasts by

immunological markers, ultrastructural examination

or ultrastructural cytochemistry

The WHO classification of AML.

Therapy-related AML and MDS. Alkylating agent-related Topoisomerase II-inhibitor-related Other types

AML with recurrent cytogenetic abnormalities*

AML with t(8;21)(q22;q22)

AML with abnormal bone marrow eosinophils with

inv(16)(p13q22) or t(16;16)(p13;q22)

Acute promyelocytic leukemia with


AML with 11q23 (MLL) abnormalities.

AML with multilineage dysplasia following MDS.

AML not otherwise categorized. This group is nearly similar to FAB group, but blast cells are 20% in stead of 30%



The World Health Organization (WHO)

classification assigns some chronic myeloid

leukaemias to a myeloproliferative category and

others, in which there are also dysplastic

features, to a myeloproliferative/myelodysplastic


Classification of the chronic myeloid leukaemias, based on the WHO classification.

Myeloproliferative disorders

Chronic myelogenous leukaemia Chronic neutrophilic


Chronic eosinophilic leukaemia

Basophilic leukaemia

Mast cell leukaemia

Myelodysplastic/myeloproliferative disorders

Chronic myelomonocytic leukaemia

Chronic myelomonocytic leukaemia with eosinophilia

Myelodysplastic/myeloproliferative disorder associated with


Atypical chronic myeloid leukaemia

Juvenile myelomonocytic leukaemia

Chronic granulocytic leukaemia

Chronic granulocytic leukaemia (CGL) is a disease

entity with specific haematological, cytogenetic

and molecular genetic features.

Alternative designations are chronic myelogenous

leukaemia, chronic myeloid leukaemia and chronic

myelocytic leukaemia.

CGL is a disease of

bi- or triphasic with a chronic and an acute

phase and, sometimes, an intervening

accelerated phase

The chronic phase of chronic granulocytic leukaemia

Clinical and haematological features.

CGL is predominantly a disease of adults. The usual clinical

presentation is with splenomegaly, hepatomegaly, symptoms

of anaemia, and systemic symptoms such as sweating and

weight loss.

Occasionally this is an incidental diagnosis when a blood

count is performed for another reason.

The peripheral blood usually shows anemia

and leucocytosis with a very characteristic

differential count.

The two predominant cell types are the myelocyte and the mature neutrophil .

Almost all patients have an absolute

basophilia and more than 90% have


The platelet count is most often normal or

somewhat elevated but is low in about 5%

of cases.

The bone marrow is intensely hypercellular

with marked granulocytic hyperplasia and

with the myeloid/erythroid (M:E) ratio

being greater than 10:1.

There is hyperplasia of neutrophil,

eosinophil and basophil lineages.

CGL in accelerated phase and blast Transformation

After a variable period in chronic phase, usually

several years, CGL undergoes further evolution.

There may be an abrupt transformation to an

Acute leukaemia, designated blast transformation,

or there may be an intervening phase of

accelerated disease.

The WHO group have suggested the following criteria for accelerated phase:

(i) Myeloblasts constitute 10–19% of peripheral blood

white cells or bone marrow nucleated cells.

(ii) peripheral blood basophiles are 20% or more of

nucleated cells.

(iii) there is persistent thrombocytopenia or persistent

thrombocytosis that does not respond to treatment.

(iv) there is an increasing white cell count and increasing

spleen size that does not respond to treatment.

(v) cytogenetic evolution .

(vi) there is marked granulocyte dysplasia or prominent

proliferation of small dysplastic megakaryocytes in

large clusters or sheets.

Blast transformation phase.

Transformation may be myeloid or lymphoid.

It is important to make the distinction since

there lymphoblastic transformation. Lymphoid

blast crisis is more likely to emerge suddenly

without a preceding accelerated phase

Cytogenetic and molecular genetic features

CGL was the first malignant disease for which a

consistent association with an acquired non-

random cytogenetic abnormality was recognized.

In 1960 Nowell and Hungerford reported its

Association with an abnormal chromosome designated the Philadelphia (Ph) chromosome after the city of its discovery.

Chronic lymphocytic leukaemia (CLL) is a chronic

B-lineage lymphoproliferative disorder defined by characteristic morphology and immunophenotype.

Small lymphocytic lymphoma is an equivalent lymphoma without circulating neoplastic cells

CLL is the most common leukaemia in western

Europe and North America with an incidence in

different surveys varying between 1 and more

than 10/100 000/year.

The incidence is lower in Chinese, Japanese and

South American Indians.

It is typically a disease of the elderly with a

higher incidence in males

Clinical feature.

In the later stages, CLL is characterized

by lymphadenopathy, hepatomegaly,

splenomegaly and eventually by impairment

of bone marrow function.

In the early stages of the disease there are

no symptoms or abnormal physical findings

and the diagnosis is made incidentally

Various arbitrary levels of absolute lymphocyte

count have been suggested for the diagnosis of

CLL (for example greater than 10 000/cumm).

But the demonstration of a monoclonal population

of B lymphocytes with a characteristic

immunophenotype permits diagnosis at an earlier

stage when the lymphocyte count is less elevated.

a scoring system for the immunophenotypic diagnosis of chronic lymphocytic leukaemia cll
A scoring system for the immunophenotypicdiagnosis of chronic lymphocytic leukaemia (CLL)

Score 1 for each of the following:

• Weak expression of SmIg

• Expression of CD5

• Expression of CD23

• No expression of FMC7

• No expression of CD22

A score of ≥4 points is confirmatory of CLL

Peripheral blood chronic lymphocytic leukaemia showing

two mature lymphocytes and one smear cell

Peripheral blood findings

In the early stages of the disease the Peripheral

blood abnormality is confined to the lymphocytes.

Later in the disease course there is a normocytic,

normochromic anaemia and thrombocytopenia.

Neutropenia is uncommon unless cytotoxic therapy

has been administered

Bone marrow findings.

The bone marrow aspirate is hypercellular

as a consequence of infiltration by

lymphocytes with similar features to those

in the peripheral blood.

Lymphocytes percentage in the bone

marrow is 40% of all nucleated marrow cells total.

rai staging system for chronic lymphocytic leukaemia
Rai staging system for chronic lymphocytic leukaemia

0 Peripheral blood and bone marrow lymphocytosis only.

I Intermediate Lymphocytosis and lymphadenopathy.

II Intermediate Lymphocytosis plus hepatomegaly,

splenomegaly or both.

III Lymphocytosis and anaemia (haemoglobin

concentration less than 11 g/dl).

IV Lymphocytosis and thrombocytopenia (platelet count

less than 100 000/cmm)

CLL Transformation.

Chronic lymphocytic leukaemia may undergo

two types of transformation.

1-Prolymphocytoid transformation.

2-large cell transformation, referred to as

Richter’s syndrome.