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Introduction to leukemia

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INTRODUCTION TO LEUKEMIA Acute leukemias T CELL MATURATION ACUTE LEUKEMIAS Incidence ALL is primarily a disease of young children (2-5 years), but it can also ... – PowerPoint PPT presentation

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Title: Introduction to leukemia


1
Introduction to leukemia
  • Acute leukemias

2
Introduction to leukemia
  • Leukemia is a malignant disease characterized by
    unregulated proliferation of one cell type.
  • It may involve any of the cell lines or a stem
    cell common to several cell lines.
  • Leukemias are classified into 2 major groups
  • Chronic in which the onset is insidious, the
    disease is usually less aggressive, and the cells
    involved are usually more mature cells
  • Acute in which the onset is usually rapid, the
    disease is very aggressive, and the cells
    involved are usually poorly differentiated with
    many blasts.

3
Introduction to leukemia
  • Both acute and chronic leukemias are further
    classified according to the prominent cell line
    involved in the expansion
  • If the prominent cell line is of the myeloid
    series it is a myelocytic leukemia (sometimes
    also called granulocytic)
  • If the prominent cell line is of the lymphoid
    series it is a lymphocytic leukemia
  • Therefore, there are four basic types of leukemia
  • Acute myelocytic leukemia AML- (includes
    myeloblastic, promyelocytic, monocytic,
    myelomonocytic, erythrocytic, and megakaryocytic)
  • Acute lymphocytic leukemia ALL- (includes T
    cell, B cell, and Null cell)
  • Chronic myelocytic leukemia CML - (includes
    myelocytic and myelomonocytic)

4
Introduction to leukemia
  • Chronic lymphocytic leukemia CLL - (includes
    plasmocytic multiple myeloma, Hairy cell,
    prolymphocytic, large granular cell lymphocytic,
    Sezarys syndrome, and circulating lymphoma)
  • Etiology the exact cause is frequently not
    known, but predisposing factors are known
  • Host factors
  • Some individuals have an inherited increased
    predisposition to develop leukemia
  • There is an increased incidence in those with an
    inherited tendency for chromosome fragility or
    abnormality or those with increased numbers of
    chromosomes (such as Downs syndrome).
  • Many of these diseases are characterized by
    chromosomal translocations.

5
Introduction to leukemia
  • There is an increased incidence in those with
    hereditary immunodeficiencies.
  • There is an increased incidence in those with
    chronic marrow dysfunction such as those with
    myeloproliferative diseases, myelodysplastic
    syndromes, aplastic anemia, or paroxsymal
    nocturnal hemoglobinuria.
  • Environmental factors
  • Exposure to ionizing radiation
  • Exposure to mutagenic chemicals and drugs
  • Viral infections

6
Introduction to leukemia
  • Incidence
  • Acute leukemias can occur in all age groups
  • ALL is more common in children
  • AML is more common in adults
  • Chronic leukemias are usually a disease of adults
  • CLL is extremely rare in children and unusual
    before the age of 40
  • CML has a peak age of 30-50

7
Introduction to leukemia
  • Comparison of acute and chronic leukemias
  • Acute
    Chronic
  • Age all ages
    usually adults
  • Clinical onset sudden
    insidious
  • Course (untreated) 6 mo. or less
    2-6 years
  • Leukemic cells immature gt30 blasts
    more mature cells
  • Anemia prominent mild
  • Thrombocytopenia prominent
    mild
  • WBC count variable
    increased
  • Lymphadenopathy mild
    presentoften prominent
  • Splenomegaly mild
    presentoften prominent

8
Introduction to leukemia
  • Acute leukemia
  • Is a result of
  • Malignant transformation of a stem cell leading
    to unregulated proliferation and
  • Arrest in maturation at the primitive blast
    stage. Remember that a blast is the most immature
    cell that can be recognized as committed to a
    particular cell line.
  • Clinical features
  • Leukemic proliferation, accumulation, and
    invasion of normal tissues, including the liver,
    spleen, lymph nodes, central nervous system, and
    skin, cause lesions ranging from rashes to
    tumors.
  • A humoral mediator from the leukemic cells may
    inhibit proliferation of normal cells.

9
Introduction to leukemia
  • Failure of the bone marrow and normal
    hematopoiesis may result in pancytopenia with
    death from hemorrhaging and infections.
  • Lab evaluation
  • The lab diagnosis is based on two things
  • Finding a significant increase in the number of
    immature cells in the bone marrow including
    blasts, promyelocytes, promonocytes (gt30 blasts
    is diagnostic)
  • Identification of the cell lineage of the
    leukemic cells

10
Introduction to leukemia
  • Peripheral blood
  • Anemia (normochromic, normocytic)
  • Decreased platlets
  • Variable WBC count
  • The degree of peripheral blood involvement
    determines classification
  • Leukemic increased WBCs due to blasts
  • Subleukemic blasts without increased WBCs
  • Aleukemic decreased WBCs with no blasts
  • Classification of the immature cells involved may
    be done by

11
Introduction to leukemia
  • Morphology an experienced morphologist can look
    at the size of the blast, the amount of
    cytoplasm, the nuclear chromatin pattern, the
    presence of nucleoli and the presence of auer
    rods (are a pink staining, splinter shaped
    inclusion due to a rod shaped alignment of
    primary granules found only in myeloproliferative
    processes) to identify the blast type
  • AML the myeloblast is a large blast with a
    moderate amount of cytoplasm, fine lacey
    chromatin, and prominent nucleoli. 10-40 of
    myeloblasts contain auer rods.

12
Myeloblasts with auer rods
13
Introduction to leukemia
  • ALL in contrast to the myeloblast, the
    lymphoblast is a small blast with scant
    cytoplasm, dense chromatin, indistinct nucleoli,
    and no auer rods

14
Introduction to leukemia
  • Cytochemistry help to classify the lineage of a
    leukemic cell (myeloid versus lymphoid)
  • Myeloperoxidase is found in the primary
    granules of granulocytic cells starting at the
    late blast stage. Monocytes may be weakly
    positive.

15
Sudan black
  • Sudan black stains phospholipids, neutral fats
    and sterols found in primary and secondary
    granules of granulocytic cells and to a lesser
    extent in monocytic lysosomes. Rare positives
    occur in lymphoid cells

16
Nonspecific Esterase
  • Nonspecific esterase is used to identify
    monocytic cells which are diffusely positive. T
    lymphocytes may have focal staining

17
Acid phosphatase
  • Acid phosphatase may be found in myeloblasts and
    lymphoblasts. T lymphocytes have a high level of
    acid phosphatase and this can be used to help
    make a diagnosis of acute T-lymphocytic leukemia.

18
Leukocyte Alkaline phosphatase
  • Leukocyte alkaline phosphatase is located in
    the secondary granules of segmented neutrophils,
    bands and metamyelocytes. The LAP score is
    determined by counting 100 mature neutrophils and
    bands. Each cell is graded from 0 to 5. The
    total LAP score is calculated by adding up the
    scores for each cell.

19
Leukocyte alkaline phosphatase
20
Introduction to leukemia
  • Immunologic markers (immunophenotyping) these
    are used mainly for lymphocytes, i.e., for
    determining B cell or T cell lineage. These
    tests rely on antibodies made against specific
    surface markers.
  • They constitute what we would call the primary
    antibody and in an indirect assay they are
    allowed to react with the cells and unbound
    antibody is then washed away.
  • Fluorescently labeled antibody (secondary
    antibody) against the primary antibody is added
    and allowed to react and then unbound secondary
    antibody is washed away.
  • The cells are then sent through a flow cytometer
    that will determine the number of cells that have
    a fluorescent tag and which are thus positive for
    the presence of the surface marker to which the
    primary antibody was made.
  • In a direct assay, the primary antibody is
    fluorescently labeled.

21
Direct versus indirect labeling of antigens
B or T cell specific Ab
B or T cell specific Ab
B or T Cell marker
B or T Cell marker
22
Flow cytometer
23
Terminal deoyxtidyl transferase
  • This is a unique DNA polymerase present in stem
    cells and in precursor B and T lymphoid cells.
  • High levels are found in 90 of lymphoblastic
    leukemias.
  • It can also be detected using appropriate
    antibodies and flow cytometry.

24
Introduction to leukemia
  • Cytogenetics cytogenetics studies can now be
    used for diagnosis and for prognosis of
    hematologic malignancies.
  • Many leukemias (and lymphomas) are characterized
    by specific chromosomal abnormalities, including
    specific translocations and aneuploidy. The
    specific type of malignancy can be identified
    based on the specific abnormality or
    translocation. These may be identified by
  • Looking at the karyotypes of the chromsomes from
    the abnormal cells
  • DNA based tests these tests are very useful for
    following the course of the disease
  • RT-PCR
  • Southern blotting
  • A normal karyotype is usually associated with a
    better prognosis.

25
Chromosomal translocation
26
Chromosome karyotyping
27
Acute leukemias
  • Acute lymphoblastic leukemia
  • They may be classified on the basis of the
    cytological features of the lymphoblasts into
  • L1 - This is the most common form found in
    children and it has the best prognosis.
  • The cell size is small with fine or clumped
    homogenous nuclear chromatin and absent or
    indistinct nucleoli.
  • The nuclear shape is regular, occasionally
    clefting or indented.
  • The cytoplasm is scant, with slight to moderate
    basophilia and variable vacuoles.
  • L2 This is the most frequent ALL found in
    adults.
  • The cell size is large and heterogenous with
    variable nuclear chromatin and prominent
    nucleoli.
  • The nucleus is irregular, clefting and indented.
  • The cytoplasm is variable and often moderate to
    abundant with variable basophilia and variable
    vacuoles.

28
ALL-L1
29
ALL-L2
30
Acute leukemias
  • L3 This is the rarest form of ALL.
  • The cell size is large, with fine, homogenous
    nuclear chromatin containing prominent nucleoli.
  • The nucleus is regular oval to round.
  • The cytoplasm is moderately abundant and is
    deeply basophilic and vacuolated.

31
ALL-L3
32
Acute leukemias
  • ALL may also be classified on the basis of
    immunologic markers into
  • Early pre-B ALL
  • Pre-B ALL
  • B ALL
  • T ALL
  • Null or unclassified ALL (U ALL) - lack B or T
    markers and may be the committed lymphoid stem
    cell)

33
B cell maturation
34
T cell maturation
35
Acute leukemias
  • Incidence ALL is primarily a disease of young
    children (2-5 years), but it can also occur in
    adults
  • Clinical findings pancytopenia with resulting
    fatigue, pallor, fever, weight loss,
    irritability, anorexia, infection, bleeding, and
    bone pain.
  • L1 occurs in children, L2 in adults, and L3 is
    called Burkitts leukemia

36
Acute leukemias
  • Prognosis age, WBC count, and cell type are the
    most important prognostic indicators
  • Patients younger then 1 and greater than 13 have
    a poor prognosis
  • If the WBC count is lt 10 x 109/L at presentation,
    the prognosis is good If the WBC count is gt 20 x
    109/L at presentation the prognosis is poor
  • T cell ALL (more common in males) has a poorer
    prognosis than any of the B cell ALLs which have
    a cure rate of 70

37
Acute leukemias
  • Acute leukemias with mixed lineage occasionally
    there are acute leukemias that are biphenotypic
    and display phenotypes for two different lineages
  • B lymphoid/myeloid
  • T lymphoid/myeloid
  • B/T lymphoid
  • Myeloid/Natural killer
  • A rare trilineage leukemia has also been seen
    (was B/T lymphoid/myeloid!)

38
Acute leukemias
  • Acute myeloid leukemia (also called acute
    granulocytic leukemia) classification depends
    upon
  • Bone marrow blast morphology
  • Degree of cell maturation
  • Cytochemical stains
  • Immunophenotyping
  • AML is divided into 7 different classifications
  • M1 myeloblastic without maturation
  • The bone marrow shows ? 90 blasts and lt 10
    promyelocytes
  • The disease occurs in older adults

39
AML M1
  • Note the myeloblasts and the auer rod

40
Acute leukemias
  • M2 myeloblastic with maturation
  • The bone marrow shows 30-89 blasts and gt 10
    promyelocytes
  • This is characterized by an 8,21 chromosomal
    translocation
  • This occurs in older adults
  • M3 hypergranular promyelocytic
  • This form of AML has a bone marrow with gt30
    blasts
  • Is more virulent than other forms
  • Occurs with a medium age of 39
  • The WBC count is decreased
  • Treatment causes a release of the granules and
    may send the patient into disseminated
    intravascular coagulation and subsequent bleeding
  • It is characterized by a 15,17 chromosomal
    translocation

41
AML M2
  • Note myeloblasts and hypogranulated PMNs

42
AML M3
  • Note hypergranular promyelocytes

43
Acute leukemias
  • M3m hypogranular promyelocytic
  • The bone marrow has gt 30 blasts
  • The WBC count is increased.
  • Like the M3 type, treatment causes a release of
    the granules and may send the patient into
    disseminated intravascular coagulation and
    subsequent bleeding and
  • It is characterized by a 15,17 translocation
  • M4 acute myelomonoblastic leukemia
  • Both myeloblasts and monoblasts are seen in the
    bone marrow and peripheral blood
  • Infiltration of extramedullary sites is more
    common than with the pure granulocytic variants

44
AML M3M
  • Note hypogranular promyelocytes

45
AML M4
  • Note monoblasts and promonocytes

46
Acute leukemias
  • M5 acute monoblastic leukemia
  • gt80 of the nonerythroid cells in the bone
    marrow are monocytic
  • There is extensive infiltration of the gums, CNS,
    lymph nodes and extramedullary sites
  • This form is further divided into
  • M5A - Poorly differentiated (gt80 monoblasts)
  • M5B - Well differentiated (lt80 monoblasts)
  • M6 erythroleukemia
  • This is rare and is characterized by a bone
    marrow having a predominance of erythroblasts
  • It has 3 sequentially morphologically defined
    phases
  • Preponderance of abnormal erythroblasts
  • Erythroleukemia there is an increase in both
    erythroblasts and myeloblasts
  • Myeloblastic leukemia M1, M2, or M4
  • Anemia is common

47
AML M5A
  • Note monoblasts

48
AML-M5B
  • Note monoblasts, promonocytes, and monocytes

49
AML M6
  • Note M1 type monoblasts

50
Acute leukemias
  • M7 - Acute megkaryoblastic leukemia
  • This is a rare disorder characterized by
    extensive proliferation of megakaryoblasts,
    atypical megakaryocytes and thrombocytopenia
  • Treatment of leukemias
  • There are 2 goals
  • Eradicate the leukemic cell mass
  • Give supportive care
  • Except for ALL in children, cures are not common
    but complete remission (absence of any leukemia
    related signs and symptoms and return of bone
    marrow and peripheral blood values to within
    normal values) is

51
Acute leukemias
  • There are four general types of therapy
  • Chemotherapy usually a combination of drugs is
    used
  • Bone marrow transplant
  • Radiotherapy
  • Immunotherapy stimulate the patients own immune
    system to mount a response against the malignant
    cells
  • Monoclonal antibodies examples include Rituxin
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