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MYELOPROLIFERATIVE DISORDERS

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Title: MYELOPROLIFERATIVE DISORDERS


1
MYELOPROLIFERATIVE DISORDERS
  • Masatoshi Kida, M.D.
  • Dept. of Pathology
  • University of Vermont

2
Hematopoietic Neoplasmsoverview
  • The majority of hematopoietic neoplasms can be
    classified and characterized according to three
    characteristics
  • 1. Lineage Lymphoid vs. Myelogenous
  • 2. Survival Acute vs. Chronic
  • 3. Blood/Bone Marrow vs. Tissue
  • Virtually any combination of these
    characteristics can occur.

3
Lymphoid vs Myelogenous
  • Lymphoid neoplasms
  • derived from the CFU-L or one of its more
    differentiated derivatives
  • can exhibit B-cell lineage or T-cell lineage
  • Myelogenous neoplasms
  • derived from the CFU-GEMM or one of the
    differentiated derivatives of the CFU-GEMM
  • can exhibit features of multiple lineages

4
Acute vs Chronic
  • Acute
  • primarily of immature cells, with little of no
    differentiation
  • aggressive course with survival of only weeks to
    few months if untreated
  • primarily involving blood and bone marrow
  • examples
  • acute lymphoblastic leukemia/lymphoma (ALL)
  • acute myelogenous leukemia (AML)
  • various subtypes of ALL and AML exist, depending
    on the specific lineage or differentiation
    exhibited by the neoplastic cells

5
Acute vs Chronic
  • Chronic
  • primarily of mature cells
  • tends to be indolent, with survival in years
  • examples
  • chronic lymphocytic leukemia (CLL)
  • chronic myeloproliferative disorders
  • chronic myelogenous leukemia (CML)
  • polycythemia rubra vera
  • essential thrombocythemia
  • agnogenic myeloid metaplasia

6
Blood/BM vs Tissue
  • Blood/BM ? leukemia
  • Tissue ? lymphoma
  • myeloid granulocytic sarcoma
  • lymphoid lymphoma (non-Hodgkins)
  • Hodgkins disease
  • plasma cell multiple myeloma
  • plasmacytoma

7
leukoproliferative disorders
  • lymphoid lymphoid neoplasms acute
  • chronic
  • myeloid myeloid neoplasms acute
  • chronic

8
leukoproliferative disorders
  • lymphoid lymphoid neoplasms acute
  • chronic
  • myeloid myeloid neoplasms acute
  • chronic

9
myeloid neoplasms
  • acute myeloid leukemia gt30 blasts in BM
  • (1985 FAB classification)
  • trilineage morphologic
    dysplasia
  • myelodysplastic syndrome
  • chronic myeloproliferative disorders -

10
leukoproliferative disorders
  • lymphoid lymphoid neoplasms acute
  • chronic
  • myeloid myeloid neoplasms acute
  • chronic

11
Myeloproliferative Disorders(old classification)
  • a group of disease characterized by
    overgrowth of one or more hematologic cell lines
    in BM
  • 1. chronic myelogenous leukemia (CML)
  • 2. polycythemia vera (PV)
  • 3. essential thrombocythemia
  • 4. agnogenic myeloid metaplasia/myelofibrosis

12
Chronic Myeloproliferative Disorders(new WHO
classification)
  • 1. polycythemia vera
  • 2. chronic idiopathic myelofibrosis
  • 3. essential thrombocytosis
  • 4. chronic myeloid leukemia (CML)
  • 5. chronic neutrophilic leukemia
  • 6. chronic eosinophilic leukemia
  • 7. hypereosinophilic syndrome
  • myelodysplastic/myeloproliferative diseases
  • juvenile myelomonocytic leukemia
  • atypical chronic myeloid leukemia (lacking
    t(922))
  • chronic myelomocytic leukemia

13
Chronic Myelogenous Leukemia (CML)
  • second most common leukemia
  • middle aged
  • excess number of mature and immature
    granulocytes
  • all stages of maturation in bone marrow
  • chromosomal abnormality

Philadelphia chromosome t(922)
14
Chronic Myelogenous Leukemia (CML) laboratory
  • WBC gt100,000
  • thrombocytosis
  • numerically increased, but functionally impaired
    granulocytes

15
Chronic Myelogenous Leukemia (CML) clinical
  • non-specific constitutional symptoms
  • weakness
  • wt. Loss
  • fatigue
  • excessive bleeding or bruising
  • two-phase disease
  • slowly progressive disease
  • (chronic phase)
  • terminal blast crisis
  • (acute/blast phase)

16
Polycythemia Vera (PV)
  • increased red blood mass
  • increased blood volume and viscosity
    (hyperviscosity syndrome)
  • BM hypercellular erythroid,
    megakaryocytic granulocytic hyperplasia may
    eventually become fibrotic
  • Tx repeated phlebotomy

17
Polycythemia Vera (PV)
  • Incidence 0.5 to 3.5 per 100,000
  • Age at Dx 60 y/o
  • F to M ratio male dominance (11.6 to 2.2)
  • Social risk factor participants in nuclear
    weapons test
  • Clinical features hyperviscosity, thrombosis
  • headache
  • dizziness
  • visual symptoms
  • Median survival 12 to 13 years

18
Polycythemia Vera (PV)diagnostic criteria
  • by polycythemia vera study group (1975)
  • Major Criteria
  • 1. increased RBC male gt 36 mL/kg
  • female gt 32 mL/kg
  • 2. normal arterial oxygen saturation gt 92
  • 3. splenomegaly
  • Minor Criteria
  • 1. platelet gt 400,000/mL
  • 2. leukocytes gt13,000/mL
  • 3. leukocyte alkaline phosphatase gt100
  • or
  • vit B12 gt900 pg/mL
  • or
  • unbound B12 binding capacity gt2200 pg/mL

19
Essential Thrombocythemia
  • Rare disorder (1.5 per 100,000)
  • proliferation of megakaryocytes causing marked
    increase in circulating platelets (gt1 million)
  • morphologically abnormal platelets
  • splenomegaly, mucosal hemorrhage, thromboses

arrow macrothrombocyte
20
Essential Thrombocythemia
  • Incidence 1.5 per 100,000
  • Age at Dx 60 y/o (20 lt40 y/o)
  • F to M ratio 1.6 1
  • Social risk factor 1. long-term use of dark hair
    dyes
  • 2. living in tuff house
  • 3. electrician
  • Clinical features - near normal life expectancy
  • - frequent vasomotor and thrombo-
    hemorrhagic episodes
  • Treatment low-dose acetylsalicylic acid

21
Myelofibrosis
  • bone marrow fibrosis
  • fibroblasts may be innocent bystanders
  • fibrosis probably driven by neoplastic
    megakaryocytes
  • middle aged adults (50-60 y/o)
  • extramedullary hematopoiesis (spleen, liver)
  • may occur as an extension of CML or PV
  • abnormal peripheral RBCs (tear-drop nucleated
    RBCs)
  • immature WBC and abnormal platelets
  • infection, thrombosis and hemorrhage as a major
    complication

22
Myelofibrosis
Aniso-poikilocytosis leukemoid reaction
naked nuclear fragments
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24
Acute Myelogenous Leukemia (AML)
  • 60 of acute leukemias
  • arises from myeloid stem cell line
  • young to middle aged adults
  • pallor petechiae may be initial presentation
  • lymphadenopathy/splenomegaly may or may not be
    present
  • no fever unless secondary infection

25
Acute Myelogenous Leukemia
  • Incidence 3.6 per 100,000 people per year
  • MF 4.43.0 (MgtF)
  • incidence increases with age
  • 1.7 in lt65 yrs age group
  • 16.2 in gt65 yrs age group
  • Etiology heredity, radiation, chemical and other
    occupational exposures and drugs have been
    implicated
  • increased incidence in trisomy 21, XXY, trisomy
    13, Fanconi anemia, Bloom syndrome, ataxia
    telangiectasia, Kostmann syndrome

26
AMLclinical symptoms
  • non-specific symptoms that are consequence of
  • anemia
  • leukocytosis
  • leukopenia or leukocyte dysfunction
  • thrombocytopenia
  • fatigue (most common)
  • anorexia and wt. loss
  • fever with or without infection (10)
  • bleeding, easy bruising (5)

27
AMLphysical findings
  • hepatosplenomegaly, lymphadenopathy, sternal
    tenderness, evidence of infection and hemorrhage
  • acute promyelocytic leukemia (APL)
  • gastrointestinal bleeding
  • intrapulmonary hemorrhage
  • intracranial hemorrhage
  • monocytic AML
  • coagulopathy

28
Acute Myelogenous Leukemia (AML) peripheral blood
smear
  • normocytic, normochromic anemia
  • decreased reticulocyte count
  • normal or depressed WBC count
  • myeloblast (may be with Auer rods)
  • low platelet

29
AMLhematologic findings
  • anemia can be severe usually normocytic
    normochromic
  • reduced reticulocyte count ? low erythropoiesis
  • short erythrocyte survival ? accelerated
    destruction
  • median WBC count 15,000/µL
  • platelet count lt100,000/µL (75 of
    patients) lt25,000/µL (25 of patients)
  • morphologic and functional platelet abnormalities

30
Acute Myelogenous Leukemia (AML) special stains
  • myeloperoxidase (MP)
  • Sudan black B (SBB)
  • nonspecific esterase (NSE)
  • chloroacetate esterase (CLE)
  • periodic acid Schiff (PAS)

31
AML classification
  • Until 2000, the diagnosis of AML was established
    by the presence of 30 myeloblasts in the marrow
    and further classified based on morphology and
    cytochemistry according to the French-American-Bri
    tish (FAB) schema, which includes eight major
    subtypes, M0 to M7.
  • The 2001 WHO classification modified the FAB
    schema by reducing the number of blasts required
    for a diagnosis and incorporating molecular
    (including cytogenetic), morphologic
    (multilineage dysplasia), and clinical features
    (such as prior hematologic disorder) in defining
    disease entities.

32
Acute Myelogenous Leukemia (AML) WHO
classification (2001)
  • I. AML with rucurrent genetic abnormalities
  • AML with t(821)(q22q22)AML1(CBFa)/ETO
  • AML with abnormal bone marrow eosinophils
    inv(16)(p13q22) or t(1616)(p13q22)CBFß/MYH11
  • Acute promyelocytic leukemia AML with
    t(1517)(q22q12) (PML/RARa and variants
  • AML with 11q23 (MLL) abnormalities
  • II. AML with multilineage dysplasia
  • Following a myelodysplastic syndrome or
    myelodysplastic syndrome/myeloproliferative
    disorder
  • Without antecedent myelodysplastic syndrome
  • III. AML and myelodysplastic syndromes,
    therapy-related
  • Alkylating agent-related
  • Topoisomerase type II inhibitor-related
  • Other types
  • IV. AML not otherwise categorized
  • AML minimally differentiated
  • AML without maturation
  • AML with maturation
  • Acute myelomonocytic leukemia
  • Acute monoblastic and monocytic leukemia
  • Acute erythroid leukemia
  • Acute megakaryoblastic leukemia
  • Acute basophilic leukemia
  • Acute panmyelosis with myelofibrosis
  • Myeloid sarcoma

20 myeloblasts in blood and/or bone marrow AML
positive myeloperoxidase reaction in gt3 of
blasts AML (? ALL)
33
Acute Myelogenous Leukemia (AML) FAB
classification (1985)
  • M0 minimally differentiated acute myeloblastic
    leukemia
  • M1 acute myeloblastic leukemia without
    maturation
  • M2 acute myeloblastic leukemia with maturation
  • M3 acute promyelocytic leukemia
  • M4 acute myelomonocytic leukemia
  • M5 acute monocytic leukemia
  • M6 erythroleukemia
  • M7 acute megakaryoblastic leukemia

34
M0 Minimally Differentiated Acute Myelogenous
Leukemia
  • no conclusive morphologic evidence of cellular
    differentiation

35
M1 Acute Myeloblastic Leukemia without
Maturation
  • MP (), SBB (), NSE (neg), CLE ()
  • 90 or more of BM non-erythroid cells are blasts

36
M2 Acute Myeloblastic Leukemia with Maturation
  • MP (), SBB (), NSE (neg), CLE (neg)
  • blasts in 30-9 of BM non-erythroid cells
  • t(821) --- seen in 40-50 of case favorable
    prognosis

37
M3 Acute Promyelocytic Leukemia
  • MP (), SBB (), NSE (neg), CLE ()
  • abnormal promyelocytes
  • heavy primary granulation
  • frequently associated with DIC
  • t(1517) --- favorable prognosis

38
M4 Acute Myelomonocytic Leukemia
  • MP (), SBB (), NSE (), CLE ()
  • monocytic lineage cells in 20-80 of BM
    non-erythroid cells
  • abnormal 11q

39
M5 Acute Monocytic Leukemia
  • MP (), SBB (), NSE (), CLE (neg)
  • monocytic lineage cells in 80 or more of BM
    non-erythroid cells
  • erythrophagocytosis may be present
  • hypertrophied gum, oral and anorectal ulcers
  • chloroma (green tumor)
  • lymphadenopathy and splenomegaly
  • t(911) --- unfavorable prognosis

40
M6 Erythroleukemia
  • gt50 of all nucleated cells in BM are
    erythroblasts
  • gt30 of non-erythroid cells are blasts
  • dyserythropoiesis
  • unfavorable prognosis

41
M7 Acute Megakaryoblastic Leukemia
  • MP (neg), SBB (neg)
  • associated with trisomy 21
  • unfavorable prognosis

42
Acute Myelogenous Leukemia (AML) prognostic
factors
  • good bad
  • age lt40 y/o gt60 y/o
  • WBC lt10,000 gt100,000
  • DIC absent present
  • LDH normal high
  • type M3, M4Eo M0, M5, M6, M7
  • cytogenetics t(1517) complex karyotype
  • t(821) -7
  • inv(16) inv(3)
  • molecular markers PTD of MLL
  • ITD of FLT3
  • history primary lesion post-therapy

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