Myeloproliferative

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Myeloproliferative

  1. 1. MYELOPROLIFERATIVE DISORDERS www.freelivedoctor.com
  2. 2. Hematopoietic Neoplasms overview <ul><li>The majority of hematopoietic neoplasms can be classified and characterized according to three characteristics: </li></ul><ul><li>1. Lineage: Lymphoid vs. Myelogenous </li></ul><ul><li>2. Survival: Acute vs. Chronic </li></ul><ul><li>3. Blood/Bone Marrow vs. Tissue </li></ul><ul><li>Virtually any combination of these characteristics can occur. </li></ul>www.freelivedoctor.com
  3. 3. Lymphoid vs Myelogenous <ul><li>Lymphoid neoplasms : </li></ul><ul><ul><li>derived from the CFU-L or one of its more differentiated derivatives </li></ul></ul><ul><ul><li>can exhibit B-cell lineage or T-cell lineage </li></ul></ul><ul><li>Myelogenous neoplasms : </li></ul><ul><ul><li>derived from the CFU-GEMM or one of the differentiated derivatives of the CFU-GEMM </li></ul></ul><ul><ul><li>can exhibit features of multiple lineages </li></ul></ul>www.freelivedoctor.com
  4. 4. Acute vs Chronic <ul><li>Acute : </li></ul><ul><ul><li>primarily of immature cells, with little of no differentiation </li></ul></ul><ul><ul><li>aggressive course with survival of only weeks to few months if untreated </li></ul></ul><ul><ul><li>primarily involving blood and bone marrow </li></ul></ul><ul><ul><li>examples: </li></ul></ul><ul><ul><ul><li>acute lymphoblastic leukemia/lymphoma (ALL) </li></ul></ul></ul><ul><ul><ul><li>acute myelogenous leukemia (AML) </li></ul></ul></ul><ul><ul><ul><li>various subtypes of ALL and AML exist, depending on the specific lineage or differentiation exhibited by the neoplastic cells </li></ul></ul></ul>www.freelivedoctor.com
  5. 5. Acute vs Chronic <ul><li>Chronic : </li></ul><ul><ul><li>primarily of mature cells </li></ul></ul><ul><ul><li>tends to be indolent, with survival in years </li></ul></ul><ul><ul><li>examples: </li></ul></ul><ul><ul><ul><li>chronic lymphocytic leukemia (CLL) </li></ul></ul></ul><ul><ul><ul><li>chronic myeloproliferative disorders </li></ul></ul></ul><ul><ul><ul><ul><ul><li>chronic myelogenous leukemia (CML) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>polycythemia rubra vera </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>essential thrombocythemia </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>agnogenic myeloid metaplasia </li></ul></ul></ul></ul></ul>www.freelivedoctor.com
  6. 6. Blood/BM vs Tissue <ul><li>Blood/BM  leukemia </li></ul><ul><li>Tissue  “lymphoma” </li></ul><ul><li>myeloid : granulocytic sarcoma </li></ul><ul><li>lymphoid : lymphoma (non-Hodgkin’s) </li></ul><ul><li>Hodgkin’s disease </li></ul><ul><li>plasma cell : multiple myeloma </li></ul><ul><li>plasmacytoma </li></ul>www.freelivedoctor.com
  7. 7. “ leukoproliferative disorders” <ul><li>lymphoid lymphoid neoplasms acute </li></ul><ul><li>chronic </li></ul><ul><li>myeloid myeloid neoplasms acute </li></ul><ul><li>chronic </li></ul>www.freelivedoctor.com
  8. 8. “ leukoproliferative disorders” <ul><li>lymphoid lymphoid neoplasms acute </li></ul><ul><li>chronic </li></ul><ul><li>myeloid myeloid neoplasms acute </li></ul><ul><li>chronic </li></ul>www.freelivedoctor.com
  9. 9. myeloid neoplasms <ul><li>acute myeloid leukemia >30% blasts in BM </li></ul><ul><li> (1985 FAB classification) </li></ul><ul><li> trilineage morphologic dysplasia </li></ul><ul><li>myelodysplastic syndrome + </li></ul><ul><li>chronic myeloproliferative disorders - </li></ul>www.freelivedoctor.com
  10. 10. “ leukoproliferative disorders” <ul><li>lymphoid lymphoid neoplasms acute </li></ul><ul><li>chronic </li></ul><ul><li>myeloid myeloid neoplasms acute </li></ul><ul><li>chronic </li></ul>www.freelivedoctor.com
  11. 11. Myeloproliferative Disorders (old classification) <ul><li>a group of disease characterized by overgrowth of one or more hematologic cell lines in BM </li></ul><ul><ul><ul><li>1. chronic myelogenous leukemia (CML) </li></ul></ul></ul><ul><ul><ul><li>2. polycythemia vera (PV) </li></ul></ul></ul><ul><ul><ul><li>3. essential thrombocythemia </li></ul></ul></ul><ul><ul><ul><li>4. agnogenic myeloid metaplasia/myelofibrosis </li></ul></ul></ul>www.freelivedoctor.com
  12. 12. Chronic Myeloproliferative Disorders (new WHO classification) <ul><ul><ul><li>1. polycythemia vera </li></ul></ul></ul><ul><ul><ul><li>2. chronic idiopathic myelofibrosis </li></ul></ul></ul><ul><ul><ul><li>3. essential thrombocytosis </li></ul></ul></ul><ul><ul><ul><li>4. chronic myeloid leukemia (CML) </li></ul></ul></ul><ul><ul><ul><li>5. [chronic neutrophilic leukemia] </li></ul></ul></ul><ul><ul><ul><li>6. [chronic eosinophilic leukemia] </li></ul></ul></ul><ul><ul><ul><li>7. [hypereosinophilic syndrome] </li></ul></ul></ul><ul><ul><ul><li>“ myelodysplastic/myeloproliferative diseases” </li></ul></ul></ul><ul><ul><ul><li>juvenile myelomonocytic leukemia </li></ul></ul></ul><ul><ul><ul><li>atypical chronic myeloid leukemia (lacking t(9;22)) </li></ul></ul></ul><ul><ul><ul><li>chronic myelomocytic leukemia </li></ul></ul></ul>www.freelivedoctor.com
  13. 13. Chronic Myelogenous Leukemia (CML) <ul><li>second most common leukemia </li></ul><ul><li>middle aged </li></ul><ul><li>excess number of “mature” and immature granulocytes </li></ul><ul><li>all stages of maturation in bone marrow </li></ul><ul><li>chromosomal abnormality </li></ul>Philadelphia chromosome t(9;22) www.freelivedoctor.com
  14. 14. Chronic Myelogenous Leukemia (CML) laboratory <ul><li>WBC : >100,000 </li></ul><ul><li>thrombocytosis </li></ul><ul><li>numerically increased, but functionally impaired granulocytes </li></ul>www.freelivedoctor.com
  15. 15. Chronic Myelogenous Leukemia (CML) clinical <ul><li>non-specific constitutional symptoms </li></ul><ul><ul><li>weakness </li></ul></ul><ul><ul><li>wt. Loss </li></ul></ul><ul><ul><li>fatigue </li></ul></ul><ul><li>excessive bleeding or bruising </li></ul><ul><li>two-phase disease </li></ul><ul><ul><li>slowly progressive disease </li></ul></ul><ul><ul><li>(chronic phase) </li></ul></ul><ul><ul><li>terminal “blast crisis” </li></ul></ul><ul><ul><li>(acute/blast phase) </li></ul></ul>www.freelivedoctor.com
  16. 16. Polycythemia Vera (PV) <ul><li>increased red blood mass </li></ul><ul><li>increased blood volume and viscosity (hyperviscosity syndrome) </li></ul><ul><li>BM: hypercellular erythroid, megakaryocytic & granulocytic hyperplasia may eventually become fibrotic </li></ul><ul><li>Tx: repeated phlebotomy </li></ul>www.freelivedoctor.com
  17. 17. Polycythemia Vera (PV) <ul><li>Incidence: 0.5 to 3.5 per 100,000 </li></ul><ul><li>Age at Dx: ~60 y/o </li></ul><ul><li>F to M ratio: male dominance (1:1.6 to 2.2) </li></ul><ul><li>Social risk factor: participants in nuclear weapons test </li></ul><ul><li>Clinical features: hyperviscosity, thrombosis </li></ul><ul><li>headache </li></ul><ul><li>dizziness </li></ul><ul><li>visual symptoms </li></ul><ul><li>Median survival: 12 to 13 years </li></ul>www.freelivedoctor.com
  18. 18. Polycythemia Vera (PV) diagnostic criteria <ul><li>by polycythemia vera study group (1975) </li></ul><ul><li>Major Criteria </li></ul><ul><li>1. increased RBC male >= 36 mL/kg </li></ul><ul><li>female >= 32 mL/kg </li></ul><ul><li>2. normal arterial oxygen saturation >= 92% </li></ul><ul><li>3. splenomegaly </li></ul><ul><li>Minor Criteria </li></ul><ul><li>1. platelet > 400,000/  L </li></ul><ul><li>2. leukocytes >13,000/  L </li></ul><ul><li>3. leukocyte alkaline phosphatase >100 </li></ul><ul><li>or </li></ul><ul><li> vit B12 >900 pg/mL </li></ul><ul><li>or </li></ul><ul><li> unbound B12 binding capacity >2200 pg/mL </li></ul>www.freelivedoctor.com
  19. 19. Essential Thrombocythemia <ul><li>Rare disorder (1.5 per 100,000) </li></ul><ul><li>proliferation of megakaryocytes causing marked increase in circulating platelets (>1 million) </li></ul><ul><li>morphologically abnormal platelets </li></ul><ul><li>splenomegaly, mucosal hemorrhage, thromboses </li></ul>arrow: macrothrombocyte www.freelivedoctor.com
  20. 20. Essential Thrombocythemia <ul><li>Incidence: 1.5 per 100,000 </li></ul><ul><li>Age at Dx: 60 y/o (~20% <40 y/o) </li></ul><ul><li>F to M ratio: 1.6 : 1 </li></ul><ul><li>Social risk factor: 1. long-term use of dark hair dyes </li></ul><ul><li>2. living in tuff house </li></ul><ul><li>3. electrician </li></ul><ul><li>Clinical features: - near normal life expectancy </li></ul><ul><li>- frequent vasomotor and thrombo- hemorrhagic episodes </li></ul><ul><li>Treatment: low-dose acetylsalicylic acid </li></ul>www.freelivedoctor.com
  21. 21. Myelofibrosis <ul><li>bone marrow fibrosis </li></ul><ul><ul><li>fibroblasts may be “innocent bystanders” </li></ul></ul><ul><ul><li>fibrosis probably driven by neoplastic megakaryocytes </li></ul></ul><ul><li>middle aged adults (50-60 y/o) </li></ul><ul><li>extramedullary hematopoiesis (spleen, liver) </li></ul><ul><li>may occur as an extension of CML or PV </li></ul><ul><li>abnormal peripheral RBCs (“tear-drop” & nucleated RBCs) </li></ul><ul><li>immature WBC and abnormal platelets </li></ul><ul><li>infection, thrombosis and hemorrhage as a major complication </li></ul>www.freelivedoctor.com
  22. 22. Myelofibrosis Aniso-poikilocytosis leukemoid reaction “ naked” nuclear fragments www.freelivedoctor.com
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  24. 24. Acute Myelogenous Leukemia (AML) <ul><li>60% of acute leukemias </li></ul><ul><li>arises from myeloid stem cell line </li></ul><ul><li>young to middle aged adults </li></ul><ul><li>pallor & petechiae may be initial presentation </li></ul><ul><li>lymphadenopathy/splenomegaly may or may not be present </li></ul><ul><li>no fever unless secondary infection </li></ul>www.freelivedoctor.com
  25. 25. Acute Myelogenous Leukemia <ul><li>Incidence: ~3.6 per 100,000 people per year </li></ul><ul><li>M:F = 4.4:3.0 (M>F) </li></ul><ul><li>incidence increases with age </li></ul><ul><li> 1.7 in <65 yrs age group </li></ul><ul><li>16.2 in >65 yrs age group </li></ul><ul><li>Etiology: heredity, radiation, chemical and other occupational exposures and drugs have been implicated </li></ul><ul><li>increased incidence in trisomy 21, XXY, trisomy 13, Fanconi anemia, Bloom syndrome, ataxia telangiectasia, Kostmann syndrome </li></ul>www.freelivedoctor.com
  26. 26. AML clinical symptoms <ul><li>non-specific symptoms that are consequence of </li></ul><ul><li>anemia </li></ul><ul><li>leukocytosis </li></ul><ul><li>leukopenia or leukocyte dysfunction </li></ul><ul><li>thrombocytopenia </li></ul><ul><li>fatigue (most common) </li></ul><ul><li>anorexia and wt. loss </li></ul><ul><li>fever with or without infection (~10%) </li></ul><ul><li>bleeding, easy bruising (~5%) </li></ul>www.freelivedoctor.com
  27. 27. AML physical findings <ul><li>hepatosplenomegaly, lymphadenopathy, sternal tenderness, evidence of infection and hemorrhage </li></ul><ul><li>acute promyelocytic leukemia (APL) </li></ul><ul><li>gastrointestinal bleeding </li></ul><ul><li>intrapulmonary hemorrhage </li></ul><ul><li>intracranial hemorrhage </li></ul><ul><li>monocytic AML </li></ul><ul><li>coagulopathy </li></ul>www.freelivedoctor.com
  28. 28. Acute Myelogenous Leukemia (AML) peripheral blood smear <ul><li>normocytic, normochromic anemia </li></ul><ul><li>decreased reticulocyte count </li></ul><ul><li>normal or depressed WBC count </li></ul><ul><li>myeloblast (may be with Auer rods) </li></ul><ul><li>low platelet </li></ul>www.freelivedoctor.com
  29. 29. AML hematologic findings <ul><li>anemia: can be severe usually normocytic normochromic </li></ul><ul><li>reduced reticulocyte count  low erythropoiesis </li></ul><ul><li>short erythrocyte survival  accelerated destruction </li></ul><ul><li>median WBC count: 15,000/ μ L </li></ul><ul><li>platelet count: <100,000/ μ L (~75% of patients) <25,000/ μ L (~25% of patients) </li></ul><ul><li>morphologic and functional platelet abnormalities </li></ul>www.freelivedoctor.com
  30. 30. Acute Myelogenous Leukemia (AML) special stains <ul><li>myeloperoxidase (MP) </li></ul><ul><li>Sudan black B (SBB) </li></ul><ul><li>nonspecific esterase (NSE) </li></ul><ul><li>chloroacetate esterase (CLE) </li></ul><ul><li>periodic acid Schiff (PAS) </li></ul>www.freelivedoctor.com
  31. 31. AML classification <ul><li>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. </li></ul><ul><li>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. </li></ul>www.freelivedoctor.com
  32. 32. Acute Myelogenous Leukemia (AML) WHO classification (2001) <ul><li>I. AML with rucurrent genetic abnormalities </li></ul><ul><li>AML with t(8;21)(q22;q22);AML1(CBF α )/ETO </li></ul><ul><li>AML with abnormal bone marrow eosinophils [inv(16)(p13q22) or t(16;16)(p13;q22);CBF β /MYH11] </li></ul><ul><li>Acute promyelocytic leukemia [AML with t(15;17)(q22;q12) (PML/RAR α and variants] </li></ul><ul><li>AML with 11q23 (MLL) abnormalities </li></ul><ul><li>II. AML with multilineage dysplasia </li></ul><ul><li>Following a myelodysplastic syndrome or myelodysplastic syndrome/myeloproliferative disorder </li></ul><ul><li>Without antecedent myelodysplastic syndrome </li></ul><ul><li>III. AML and myelodysplastic syndromes, therapy-related </li></ul><ul><li>Alkylating agent-related </li></ul><ul><li>Topoisomerase type II inhibitor-related </li></ul><ul><li>Other types </li></ul><ul><li>IV. AML not otherwise categorized </li></ul><ul><li>AML minimally differentiated </li></ul><ul><li>AML without maturation </li></ul><ul><li>AML with maturation </li></ul><ul><li>Acute myelomonocytic leukemia </li></ul><ul><li>Acute monoblastic and monocytic leukemia </li></ul><ul><li>Acute erythroid leukemia </li></ul><ul><li>Acute megakaryoblastic leukemia </li></ul><ul><li>Acute basophilic leukemia </li></ul><ul><li>Acute panmyelosis with myelofibrosis </li></ul><ul><li>Myeloid sarcoma </li></ul>≥ 20% myeloblasts in blood and/or bone marrow = AML positive myeloperoxidase reaction in >3% of blasts = AML (↔ ALL) www.freelivedoctor.com
  33. 33. Acute Myelogenous Leukemia (AML) FAB classification (1985) <ul><li>M0 : minimally differentiated acute myeloblastic leukemia </li></ul><ul><li>M1 : acute myeloblastic leukemia without maturation </li></ul><ul><li>M2 : acute myeloblastic leukemia with maturation </li></ul><ul><li>M3 : acute promyelocytic leukemia </li></ul><ul><li>M4 : acute myelomonocytic leukemia </li></ul><ul><li>M5 : acute monocytic leukemia </li></ul><ul><li>M6 : erythroleukemia </li></ul><ul><li>M7 : acute megakaryoblastic leukemia </li></ul>www.freelivedoctor.com
  34. 34. M0 : Minimally Differentiated Acute Myelogenous Leukemia <ul><li>no conclusive morphologic evidence of cellular differentiation </li></ul>www.freelivedoctor.com peroxidase negative
  35. 35. M1 : Acute Myeloblastic Leukemia without Maturation <ul><li>MP (+), SBB (+), NSE (neg), CLE (+) </li></ul><ul><li>90% or more of BM non-erythroid cells are blasts </li></ul>www.freelivedoctor.com
  36. 36. M2 : Acute Myeloblastic Leukemia with Maturation <ul><li>MP (+), SBB (+), NSE (neg), CLE (neg) </li></ul><ul><li>blasts in 30-9% of BM non-erythroid cells </li></ul><ul><li>t(8;21) --- seen in 40-50% of case favorable prognosis </li></ul>www.freelivedoctor.com
  37. 37. M3 : Acute Promyelocytic Leukemia <ul><li>MP (+), SBB (+), NSE (neg), CLE (+) </li></ul><ul><li>abnormal promyelocytes </li></ul><ul><li>heavy primary granulation </li></ul><ul><li>frequently associated with DIC </li></ul><ul><li>t(15;17) --- favorable prognosis </li></ul>www.freelivedoctor.com
  38. 38. M4 : Acute Myelomonocytic Leukemia <ul><li>MP (+), SBB (+), NSE (+) , CLE (+) </li></ul><ul><li>monocytic lineage cells in 20-80% of BM non-erythroid cells </li></ul><ul><li>abnormal 11q </li></ul>www.freelivedoctor.com
  39. 39. M5 : Acute Monocytic Leukemia <ul><li>MP (+), SBB (+), NSE (+) , CLE (neg) </li></ul><ul><li>monocytic lineage cells in 80% or more of BM non-erythroid cells </li></ul><ul><li>erythrophagocytosis may be present </li></ul><ul><li>hypertrophied gum , oral and anorectal ulcers </li></ul><ul><li>“ chloroma ” (green tumor) </li></ul><ul><li>lymphadenopathy and splenomegaly </li></ul><ul><li>t(9;11) --- unfavorable prognosis </li></ul>www.freelivedoctor.com
  40. 40. M6 : Erythroleukemia <ul><li>>50% of all nucleated cells in BM are erythroblasts </li></ul><ul><li>>30% of non-erythroid cells are blasts </li></ul><ul><li>dyserythropoiesis </li></ul><ul><li>unfavorable prognosis </li></ul>www.freelivedoctor.com
  41. 41. M7 : Acute Megakaryoblastic Leukemia <ul><li>MP (neg), SBB (neg) </li></ul><ul><li>associated with trisomy 21 </li></ul><ul><li>unfavorable prognosis </li></ul>www.freelivedoctor.com
  42. 42. Acute Myelogenous Leukemia (AML) prognostic factors <ul><li>good bad </li></ul><ul><li>age <40 y/o >60 y/o </li></ul><ul><li>WBC <10,000 >100,000 </li></ul><ul><li>DIC absent present </li></ul><ul><li>LDH normal high </li></ul><ul><li>type M3, M4Eo M0, M5, M6, M7 </li></ul><ul><li>cytogenetics t(15;17) complex karyotype </li></ul><ul><li>t(8;21) -7 </li></ul><ul><li>inv(16) inv(3) </li></ul><ul><li>molecular markers PTD of MLL </li></ul><ul><li>ITD of FLT3 </li></ul><ul><li>history primary lesion post-therapy </li></ul>www.freelivedoctor.com
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