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MYELOPROLIFERATIVE SYNDROMES & LEUKEMIA

MYELOPROLIFERATIVE SYNDROMES & LEUKEMIA. Doç. Dr. Işın Doğan Ekici. Myeloproliferative syndromes ( MPS ; blast crisis ). Excess proliferation of marrow cells (m yelopoiesis ) with dysplasia Progress to Leukemia Ineffective Myelopoiesis m arrow hyperplasia with pancytopenia .

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MYELOPROLIFERATIVE SYNDROMES & LEUKEMIA

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  1. MYELOPROLIFERATIVE SYNDROMES &LEUKEMIA Doç. Dr. Işın Doğan Ekici

  2. Myeloproliferative syndromes (MPS; blastcrisis) • Excess proliferation of marrow cells (myelopoiesis) with dysplasia • Progress to Leukemia • Ineffective Myelopoiesis • marrow hyperplasia with pancytopenia. Primary or Secondary

  3. Bone Marrow Cellularity Normal Hypercellular Hypocellular

  4. Primary MPS • Agnogenic myeloid metaplasia • Polycythemia rubra vera • Chronic myeloid leukemia • Essential hemorrhagicthrombocythemia • Myelofibrosis

  5. The following "myeloproliferative diseases" are all "tumors of the multipotent myeloid stem cell", and can transform into one another (usually from a mild one to a bad one): • polycythemia rubra vera (PV) • essential (hemorrhagic) thrombocythemia (ET) • agnogenic myeloid metaplasia (AMM) • idiopathic "aplastic anemia" (AA) • chronic myeloid leukemia. (CML)

  6. Myeloproliferative syndromes: Pathogenesis

  7. Agnogenic (idiopathic) myeloid metaplasia • Proliferation of neoplastic stem cells in the • bone marrow (becomes hypercellular) • red pulp of the spleen (enlarges greatly; splenomegaly). • the cells that enter the blood are fully functional • neutrophilia/neutropenia/normal neutrophil counts • no tendency to over-produce red cells. • Peripheral smear shows a leukoerythroblastic pattern: • red cells made in the spleen tend to be teardrop-shaped (poikilocyte), • nucleated red-cell precursors from the spleen.

  8. Bone marrow dense fibrosis (several years) Cytopenia or transformation to acute leukemia. • Differential diagnosis(if there is an unexplained myelofibrosis without splenomegaly): • Chronic myeloid leukemia, • Polycythemia vera, • Metastatic carcinoma.

  9. Polycythemia rubra vera (PV) • Syn.:Osler's polycythemia; erythrocytosis. • An abnormally high hemoglobin.

  10. Classification • Relative polycythemia • Dehydration • Absolute polycythemia(increased circulating red cell mass): • Primary polycythemia • Polycythemia vera rubra • Secondary polycythemia • Effective renal arterial hypoxia • Emphysema • Tetralogy of Fallot • Hemoglobins with too much oxygen affinity • Erythropoietin-producing tumors • Renal cell carcinoma • Hepatocellular carcinoma • Cerebellar hemangioblastoma (?!) • Anabolic steroid users • Sleep apnea • After kidney transplant • Altitude

  11. Polycythemia vera is a proliferation of stem cells: • they are very erythropoietin-sensitive • mostly mature into red cells • in addition to a high red cell count, white cells and platelets are likely to be high. • Older middle-age. • Increased volume of hyperviscous blood. • On biopsy: • a very hypercellular marrow, • with all cell lineages increased. • In the late stages: • marrow fibrosis • replacement by blasts • transformation to acute myelogenous leukemia.

  12. Complications: • Congestion (widespread; red face) • Venous stasis • Rupture of dilated veins • hemorrhage • GI bleedings • Hemorrhagic stroke.

  13. Myelofibrosis • The marrow is replaced by fibrous (scar) tissue. • Causes blood formation to take place in sites other than the bone marrow, such as the liver and spleen, causing enlargement of these organs. • Primary • Idiopathic myeloid metaplasia • Secondary • Autoimmune SLE • Polycytemia vera • Carcinoma infiltration • Leukemias • Complications: • Sever anemia with low platelet & splenomegaly • Hepatomegaly & Liver failure • Acute myelogenous leukemia.

  14. Myelofibrosis teardrop cells

  15. Myelodysplastic syndromes (Preleukemias ; Carl Sagan's disease) • Ineffective Myelopoiesis • marrow hyperplasia with pancytopenia. • Excess proliferation with dysplasia. • This is a family of disorders in which there are problems in producing • red cells, • granulocytes, • platelets.

  16. FAB classification • 1. Refractory anemia (poor hemoglobinization, too few red cells): (Blasts <1%) • 2. Refractory anemia with ringed sideroblasts (>15% of nucleated red cells) • 3. Refractory anemia with excess blasts (5-20% myeloblasts) • 4. Refractory anemia with excess blasts in transformation (20-30% myeloblasts) • 5. Chronic myelocytic leukemia.

  17. WHO 2008 MDS CLASSIFICATION • ● Refractory anemia (RA): <5% blasts, <15% ringed sideroblasts; variable marrow cellularity, unicytopenia or bicytopenia, unilineage dysplasia >10% in one myeloid lineage● RA with Ringed Sideroblasts (RARS): 15% or more sideroblasts, less than 5% blasts, erythroid dysplasia only● Refractory cytopenia with multilineage dysplasia (RCMD): cytopenia, <5% blasts, dysplasia in >10% of cells in two or more lineages, no Auer rods● RA with Excess Blasts (RAEB): type 1 has 5-9% blasts in blood/marrow, peripheral cytopenia, unilineage or multilineage dysplasia, no Auer rods; type 2 has 10-19% blasts in blood/marrow, unilineage or multilineage dysplasia, Auer rods may be present, peripheral cytopenia ● MDS with isolated 5q- syndrome: anemia, <5% blasts, del(5q), no Auer rods, normal/increased hypolobated megakarycoytes ● MDS, unclassified: cytopenia(s), dysplasia in <10% of cells in one or more myeloid cell lines, accompanied by cytogenetic abnormalities with presumptive evidence of MDS, <5% blasts ● Therapy related MDS

  18. Dysplastic Erythroblasts

  19. Clinical findings • Most patients are older adults, • often asymptomatic (detected on routine screening) • in the more aggressive forms, death follows in a few years. • Propensity to transform into acute myeloid leukemia.

  20. LEUKEMIAS ACUTE & CHRONIC

  21. WBC Neoplastic disorders • Leukemias Bone marrow, blood, blast cells • Acute/Chronic & Myeloid/Lymphoid • AML / ALL & CML / CLL • Lymphomas – Lymph nodes, tumor • Hodgkins - • Non-Hodgkins. Myeloma • Premalignantconditions: • Myeloproliferative syndromes (MPS) • Myelodysplastic syndromes (MDS)

  22. Introduction: • No Benign Neoplasms – All are considered malignant or premalignant. • Neoplastic Cells flood blood stream – Leukemia. • Commonly arise in marrow (myelo/ly) or Lymphnode (lymphoid), • Spread to blood & other RES tissues rarely to other organs • Symptoms are due to deficient normal hemopoiesis. RBC, WBC & Plt.

  23. Leukemia - Clinical Features • Anemia (low RBC) • Fever - Infections (low WBC) • Bleeding tendency (low PLT) • Tender bones, lymphadenopathy, spleenomegaly etc. (Leukemic infiltration)

  24. Leukemia Classification • Acute Leukemias: • Acute Myeloid Leukemia - AML • AML M0, M1, M2, M3, M4, M5, M6 & M7 • Acute Lymphoid Leukemia - ALL • ALL - L1, L2 & L3 - maturity • Chronic Leukemias: • Chronic Myeloid Leukemia- CML • Chronic Lymphoid Leukemia - CLL

  25. ACUTE LEUKEMIA Genetic disorder characterized by uncontrolled clonal proliferation of expansion of hematopoietic cells that do not retain the capacity to differentiate normally to mature cells

  26. Triggers of Differentiation Mishap Not really known Virus Clusters of leukemia Ionizing radiation Survivors of Hiroshima and Nagasaki Genetics Higher incidence in siblings and twins of affected pt Higher incidence in children with fragile chromosomes and impaired DNA repair mechanisms Down syndrome, Fanconi syndrome, Bloom Syndrome Ataxia-telangiectasia, congenital hypogammaglobulinemia

  27. ACUTE LEUKEMIA Systemic Findings • Cytopenias • anemia, • neutropenia, • thrombocytopenia. • Bone pain • expansion of the marrow • infiltration of the periosteum. • Involvement of all other organs • brain involvement is especially troublesome. • T-cell leukemias often produce a mass in the anterior mediastinum. • Death • hemorrhage (cerebral, GI, other), • infection (neutropenia, chemotherapy), • complications of bone marrow transplantation.

  28. ALL-Acute Lymphocytic Leukemia • Common in Children. • FAB classification L1, L2 & L3 • CD10 + and, Pre B cell type common. • Growth failure, Fever, Anemia Lymphadenopathy, bleeding. • Moderate Hepatosplenomegaly

  29. The Cause Clonal expansion of lymphoid progenitor cells is altered Progenitor cells get stuck at a particular stage of differentiation and do not progress

  30. AcuteLymphocyticLeukemia (ALL) • Acute lymphoid / lymphocytic leukemia • “Childhood leukemia", with peak age in four year old kids. • Risk Factors: • Radiation exposure • Down's syndrome kids are at 15x the normal risk, • Viruses (as-yet-unidentified) an unusual response to.

  31. L1 (85%): Cells <= 2x the diameter of a normal lymphocyte; smooth nuclei; common in kids. L2(14%): Bigger cells, lots of clefts, often nucleoli; more common in adults. L3 (1%): Even bigger cells;leukemic form of Burkitt's lymphoma. Subclassification ofAcute lymphoblastic leukemia by blast morphology “FAB classification”

  32. ALL-L1

  33. ALL-L2

  34. ALL-L3

  35. The immunologic classification: • B-cell (80%) leukemia • “pre-B” cell leukemia (Burkitt's) • T-cell (15%) leukemia

  36. ALL:Cervical Lymphadenopathy

  37. Mediastinal Lymphadenopathy - ALL

  38. AML-Acute Myeloid Leukemia • Adults common • FAB classification - M0 to M7. • Anemia, Fever, Bleeding • Hepatosplenomegaly moderate • No significant lymphadenopathy

  39. Organomegaly

  40. Platelet Coagulation Petechiae, Purpura Hematoma, Joint bl.

  41. Acute MyeloblasticLeukemia (AML) • “Poorly differentiated granulocytic leukemia", • “Acute non-lymphocytic leukemia", • This is the common acute leukemia of adults (seldom over age 40, occasionally children are affected) • Bleeding tendency: • DIC • Gum bleeding common

  42. AML-M5 - Gum Hypertrophy:

  43. Down's syndrome Fragile chromosome syndromes Bloom's ataxia telangiectasia Fanconi's anemia Benzene exposure Ethylene oxide exposure Radiation exposure Previous cancer chemotherapy Myelodysplastic syndromes (preleukemia) Any "chronic myeloproliferative syndrome" ("blast crisis") agnogenic myeloid metaplasia polycythemia vera rubra "essential" hemorrhagic thrombocythemia chronic myelogenous leukemia idiopathic aplastic anemia. Risk factors

  44. M0: undifferentiated myeloblasts without myeloperoxidase M1: undifferentiated myeloblasts with myeloperoxidase M2: some promyelocytic differentiation, maybe a few Auer rods; M3: very granular promyelocytes, often many Auer rods, DIC (from annexin II on the surfaces which activates plasmin). M4: myeloid and monocytic differentiation M5: monocytic differentiation only M6: features of red cell precursors predominate; "erythroleukemia" M7: platelet markers; acute marrow fibrosis. The FAB classification of AML

  45. Promyelocytic M3 Monocytic leukemia M5

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