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Myeloproliferative

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  • 1. MYELOPROLIFERATIVE DISORDERS www.freelivedoctor.com
  • 2. Hematopoietic Neoplasms overview
    • 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.
    www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 6. Blood/BM vs Tissue
    • Blood/BM  leukemia
    • Tissue  “lymphoma”
    • myeloid : granulocytic sarcoma
    • lymphoid : lymphoma (non-Hodgkin’s)
    • Hodgkin’s disease
    • plasma cell : multiple myeloma
    • plasmacytoma
    www.freelivedoctor.com
  • 7. “ leukoproliferative disorders”
    • lymphoid lymphoid neoplasms acute
    • chronic
    • myeloid myeloid neoplasms acute
    • chronic
    www.freelivedoctor.com
  • 8. “ leukoproliferative disorders”
    • lymphoid lymphoid neoplasms acute
    • chronic
    • myeloid myeloid neoplasms acute
    • chronic
    www.freelivedoctor.com
  • 9. myeloid neoplasms
    • acute myeloid leukemia >30% blasts in BM
    • (1985 FAB classification)
    • trilineage morphologic dysplasia
    • myelodysplastic syndrome +
    • chronic myeloproliferative disorders -
    www.freelivedoctor.com
  • 10. “ leukoproliferative disorders”
    • lymphoid lymphoid neoplasms acute
    • chronic
    • myeloid myeloid neoplasms acute
    • chronic
    www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 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(9;22))
        • chronic myelomocytic leukemia
    www.freelivedoctor.com
  • 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(9;22) www.freelivedoctor.com
  • 14. Chronic Myelogenous Leukemia (CML) laboratory
    • WBC : >100,000
    • thrombocytosis
    • numerically increased, but functionally impaired granulocytes
    www.freelivedoctor.com
  • 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)
    www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 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 (1:1.6 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
    www.freelivedoctor.com
  • 18. Polycythemia Vera (PV) diagnostic criteria
    • by polycythemia vera study group (1975)
    • Major Criteria
    • 1. increased RBC male >= 36 mL/kg
    • female >= 32 mL/kg
    • 2. normal arterial oxygen saturation >= 92%
    • 3. splenomegaly
    • Minor Criteria
    • 1. platelet > 400,000/  L
    • 2. leukocytes >13,000/  L
    • 3. leukocyte alkaline phosphatase >100
    • or
    • vit B12 >900 pg/mL
    • or
    • unbound B12 binding capacity >2200 pg/mL
    www.freelivedoctor.com
  • 19. Essential Thrombocythemia
    • Rare disorder (1.5 per 100,000)
    • proliferation of megakaryocytes causing marked increase in circulating platelets (>1 million)
    • morphologically abnormal platelets
    • splenomegaly, mucosal hemorrhage, thromboses
    arrow: macrothrombocyte www.freelivedoctor.com
  • 20. Essential Thrombocythemia
    • Incidence: 1.5 per 100,000
    • Age at Dx: 60 y/o (~20% <40 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
    www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 22. Myelofibrosis Aniso-poikilocytosis leukemoid reaction “ naked” nuclear fragments www.freelivedoctor.com
  • 23. www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 25. Acute Myelogenous Leukemia
    • Incidence: ~3.6 per 100,000 people per year
    • M:F = 4.4:3.0 (M>F)
    • incidence increases with age
    • 1.7 in <65 yrs age group
    • 16.2 in >65 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
    www.freelivedoctor.com
  • 26. AML clinical 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%)
    www.freelivedoctor.com
  • 27. AML physical findings
    • hepatosplenomegaly, lymphadenopathy, sternal tenderness, evidence of infection and hemorrhage
    • acute promyelocytic leukemia (APL)
    • gastrointestinal bleeding
    • intrapulmonary hemorrhage
    • intracranial hemorrhage
    • monocytic AML
    • coagulopathy
    www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 29. AML hematologic findings
    • anemia: can be severe usually normocytic normochromic
    • reduced reticulocyte count  low erythropoiesis
    • short erythrocyte survival  accelerated destruction
    • median WBC count: 15,000/ μ L
    • platelet count: <100,000/ μ L (~75% of patients) <25,000/ μ L (~25% of patients)
    • morphologic and functional platelet abnormalities
    www.freelivedoctor.com
  • 30. Acute Myelogenous Leukemia (AML) special stains
    • myeloperoxidase (MP)
    • Sudan black B (SBB)
    • nonspecific esterase (NSE)
    • chloroacetate esterase (CLE)
    • periodic acid Schiff (PAS)
    www.freelivedoctor.com
  • 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-British (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.
    www.freelivedoctor.com
  • 32. Acute Myelogenous Leukemia (AML) WHO classification (2001)
    • I. AML with rucurrent genetic abnormalities
    • AML with t(8;21)(q22;q22);AML1(CBF α )/ETO
    • AML with abnormal bone marrow eosinophils [inv(16)(p13q22) or t(16;16)(p13;q22);CBF β /MYH11]
    • Acute promyelocytic leukemia [AML with t(15;17)(q22;q12) (PML/RAR α 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 >3% of blasts = AML (↔ ALL) www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 34. M0 : Minimally Differentiated Acute Myelogenous Leukemia
    • no conclusive morphologic evidence of cellular differentiation
    www.freelivedoctor.com peroxidase negative
  • 35. M1 : Acute Myeloblastic Leukemia without Maturation
    • MP (+), SBB (+), NSE (neg), CLE (+)
    • 90% or more of BM non-erythroid cells are blasts
    www.freelivedoctor.com
  • 36. M2 : Acute Myeloblastic Leukemia with Maturation
    • MP (+), SBB (+), NSE (neg), CLE (neg)
    • blasts in 30-9% of BM non-erythroid cells
    • t(8;21) --- seen in 40-50% of case favorable prognosis
    www.freelivedoctor.com
  • 37. M3 : Acute Promyelocytic Leukemia
    • MP (+), SBB (+), NSE (neg), CLE (+)
    • abnormal promyelocytes
    • heavy primary granulation
    • frequently associated with DIC
    • t(15;17) --- favorable prognosis
    www.freelivedoctor.com
  • 38. M4 : Acute Myelomonocytic Leukemia
    • MP (+), SBB (+), NSE (+) , CLE (+)
    • monocytic lineage cells in 20-80% of BM non-erythroid cells
    • abnormal 11q
    www.freelivedoctor.com
  • 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(9;11) --- unfavorable prognosis
    www.freelivedoctor.com
  • 40. M6 : Erythroleukemia
    • >50% of all nucleated cells in BM are erythroblasts
    • >30% of non-erythroid cells are blasts
    • dyserythropoiesis
    • unfavorable prognosis
    www.freelivedoctor.com
  • 41. M7 : Acute Megakaryoblastic Leukemia
    • MP (neg), SBB (neg)
    • associated with trisomy 21
    • unfavorable prognosis
    www.freelivedoctor.com
  • 42. Acute Myelogenous Leukemia (AML) prognostic factors
    • good bad
    • age <40 y/o >60 y/o
    • WBC <10,000 >100,000
    • DIC absent present
    • LDH normal high
    • type M3, M4Eo M0, M5, M6, M7
    • cytogenetics t(15;17) complex karyotype
    • t(8;21) -7
    • inv(16) inv(3)
    • molecular markers PTD of MLL
    • ITD of FLT3
    • history primary lesion post-therapy
    www.freelivedoctor.com
  • 43. www.freelivedoctor.com
  • 44. www.freelivedoctor.com
  • 45. www.freelivedoctor.com
  • 46. www.freelivedoctor.com
  • 47. www.freelivedoctor.com
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