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LEUKAEMIA

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LEUKAEMIA DIAGNOSIS Chronic lymphocytic leukaemia (CLL) is a chronic B-lineage lymphoproliferative disorder defined by characteristic morphology and immunophenotype. – PowerPoint PPT presentation

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Title: LEUKAEMIA


1
  • LEUKAEMIA
  • DIAGNOSIS

2
  • 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.

3
  • 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.

4
  • Diagnosis of leukaemia.
  • The diagnosis of leukaemia and categorization
  • required the following parameters.
  • 1- Morphology.
  • 2-Cytochimestry
  • 3-Immunophenotyping.
  • 4-Cytogenetic.
  • 5- Molecular study.

5
  • Acute Lymphoblastic Leukaemia

6
  • Background
  • 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. 

7
  • Pathophysiology
  • 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

8
  • 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.

9
  • The classification of ALL
  • FAB classification.
  • L1
    ALL L2 ALL
    L3 ALL
  • 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

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14
  • 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.

15
  • 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(1221)(p12,q22) TEL/AML-1
  • t(119)(q23p13) PBX/E2A
  • t(922)(q34q11) ABL/BCR
  • T(V,11)(Vq23) V/MLL
  • ii. Precursor T acute lymphoblastic
    leukemia/lymphoma
  • 2- Burkett's leukemia/lymphoma Synonyms Former
    FAB L3
  • 3- Biphenotypic acute leukemia

16
  • Immunophenotyping

17
  • 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).

18
  • 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

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20
  • Cytogenetic study.
  • With techniques now available, 7090 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
  • significance.

21
  • B-lineage ALL
  • L1 high/ hyperdiploidy.
  • L1 or L2/t(922)/BCR-ABL fusion
  • L1 or L2/t(411)(q21q23)
  • L1 or L2/t(1221)(p12q22)/early precursor or
    common ALL
  • L1 or L2/t(119)(q23p13)/pre-B ALL

22
  • T-lineage ALL.
  • L1 or L2/t(1014)(q24q11)
  • Burkett's-lineage
  • L3/t(814)(q24q32) or t(822)(q24q11) or
  • t(28)(p12q24).

23
  • Acute Myeloblastic Leukaemia

24
  • 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)
  • stains.
  • If Cytochemical reactions for myeloid cells are
  • negative, presumptive diagnosis of ALL must
  • be confirmed Immunophenotyping.

25
  • Background.
  • 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.

26
  • Pathophysiology.
  • 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.

27
  • 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

28
  • 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.

29
  • 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
    lt3
  • 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.

30
  • AML M0 without differentiation

31
  • 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

32
  • AMLM1 with minimal maturation.

33
  • Criteria for the diagnosis of acute myeloid
    leukaemia of M2.
  • Blasts 30 of bone marrow cells. Blasts 3089 of
    bone marrow
  • non-erythroid cells
  • Bone marrow maturing granulocytic component
    (promyelocytes to
  • polymorphonuclear leucocytes) gt10 of
    non-erythroid cells
  • Bone marrow monocytic component (monoblasts to
    monocytes)
  • lt20 of non-erythroid cells and other criteria
    for M4 not met

34
  • AML M2 shows Auer Rod and maturation

35
  • 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

36
  • 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.

37
  • AML M3 leukaemic promyelocytes

38
  • AML M3

39
  • 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.

40
  • AML M4 myeloblast and leukaemic monocyte

41
  • 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 lt80 bone marrow monocytic component

42
  • AML M5 monoblasts

43
  • Criteria for the diagnosis of acute myeloid
    leukaemia of M6
  • Erythroblasts .50 of bone marrow
  • nucleated cells
  • Blasts 30 of bone marrow non-erythroid
  • cells

44
  • AML M6 erythroblasts

45
  • 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

46
  • AML M7 megakaryoblast

47
  • AML M7 many megakaryocytes

48
  • 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(821)(q22q22)
  • AML with abnormal bone marrow eosinophils
    with
  • inv(16)(p13q22) or
    t(1616)(p13q22)
  • Acute promyelocytic leukemia with
  • t(1517)(q22q12)
  • 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

49
  • CHRONIC MYELOID
  • LEUKAEMIAS

50
  • 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
  • category

51
  • Classification of the chronic myeloid
    leukaemias, based on the WHO classification.
  • Myeloproliferative disorders
  • Chronic myelogenous leukaemia Chronic
    neutrophilic
  • leukaemia
  • Chronic eosinophilic leukaemia
  • Basophilic leukaemia
  • Mast cell leukaemia
  • Myelodysplastic/myeloproliferative disorders
  • Chronic myelomonocytic leukaemia
  • Chronic myelomonocytic leukaemia with
    eosinophilia
  • Myelodysplastic/myeloproliferative disorder
    associated with
  • t(512)(q33p13)
  • Atypical chronic myeloid leukaemia
  • Juvenile myelomonocytic leukaemia

52
  • 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.

53
  • CGL is a disease of
  • bi- or triphasic with a chronic and an acute
  • phase and, sometimes, an intervening
  • accelerated phase

54
  • 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.

55
  • 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 .

56
  • Almost all patients have an absolute
  • basophilia and more than 90 have
  • eosinophilia.
  • The platelet count is most often normal or
  • somewhat elevated but is low in about 5
  • of cases.

57
  • BM film of a patient with CGL showing neutrophil
    leucocytosis with left shift.

58
  • The bone marrow is intensely hypercellular
  • with marked granulocytic hyperplasia and
  • with the myeloid/erythroid (ME) ratio
  • being greater than 101.
  • There is hyperplasia of neutrophil,
  • eosinophil and basophil lineages.

59
  • Bone marrow shows myeloid hyperplasia.

60
  • 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.

61
  • The WHO group have suggested the following
    criteria for accelerated phase
  • (i) Myeloblasts constitute 1019 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.

62
  • 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

63
  • 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.

64
  • Karyotype of a patient with CGL showing t(922)

65
  • Chronic lymphocytic leukaemia

66
  • 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

67
  • 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

68
  • 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

69
  • 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.

70
A scoring system for the immunophenotypicdiagnosi
s 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

71
  • Peripheral blood chronic lymphocytic leukaemia
    showing
  • two mature lymphocytes and one smear cell

72
  • 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

73
  • 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.

74
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)

75
  • CLL Transformation.
  • Chronic lymphocytic leukaemia may undergo
  • two types of transformation.
  • 1-Prolymphocytoid transformation.
  • 2-large cell transformation, referred to as
  • Richters syndrome.

76
  • CLL with transformation to PLL
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