2- Myeloid Neoplasms hematopathology(2).pptx

Myeloid neoplasm

1. Myeloid Neoplasms

2. arise from Myeloid hematopoietic progenitors clonal proliferations three types: acute myeloid leukemia ( AML), myeloproliferative disorders myelodysplastic syndromes, Both myelodysplastic syndromes and myeloproliferative disorders often transform to AML,

3. Acute Myeloid Leukemia the neoplastic cells are blocked at an early stage of myeloid cell development . Immature myeloid cells (blasts) accumulate in the marrow and replace it frequently circulate in the peripheral blood primarily affects older adults; the median age is 50 years. clinical :Fatigue, pallor , abnormal bleeding, and infections Splenomegaly and lymphadenopathy (less prominent than in ALL)

4. PATHOGENESIS mutations in genes encoding transcription factors that are required for normal myeloid cell differentiation. These mutations interfere with the differentiation of early myeloid cells, leading to the accumulation of blasts in the marrow. ( 15;17) translocation :results in the fusion of the retinoic acid receptor α ( RARA ) gene on chromosome 17 and the PML gene on chromosome 15. This produces a PML/RARα fusion protein that blocks myeloid differentiation at the promyelocytic stage, FLT3 , a receptor tyrosine kinase that is activated by mutations

5. MORPHOLOGY in AML myeloid blasts make up more than 20% of the bone marrow cellular component . Myeloblasts Auer rods, distinctive red-staining rodlike structures, monoblasts , erythroblasts, or megakaryoblasts

6. The diagnosis and classification of AML are based on: morphologic , histochemical, immunophenotypic , karyotypic findings. Most tumors express some combination of myeloid-associated antigens, such as CD13, CD14, CD15, CD64, or CD117 ( cKIT ).

7. The FAB classification eight subtypes (M - M 7 ). In M and M 1 there is no or minor evidence of maturation. In M 3 there is maturation to promyelocytes ; in M 4 and M 5 there is monocytic maturation ; in M 6 there is erythroid maturation; and in M 7 there is megakaryocytic maturation.

8. Prognosis & treatment Good prognostic markers: t[8;21] associated with a 50% chance of long-term disease-free survival, ATRA and arsenic salts. allogeneic hematopoietic stem cell transplantation .

9. Gum hypertrophy and haemorrhage in acute monocytic leukaemia

10. Gum hyperplasia

11. AML AML

12. Auer rod

13. Here are very large, immature myeloblasts with many nucleoli. A distincitve feature of these blasts is a linear red "Auer rod" composed of crystallized granules. These findings are typical for acute myelogenous leukemia (AML) that is most prevalent in young adults

14. Auer rod

15. Myelodysplastic Syndromes the bone marrow is replaced by transformed stem cell that retains the capacity to differentiate into red cells, granulocytes, and platelets, but in a manner that is both ineffective and disordered. the marrow is hypercellular or normocellular , the peripheral blood shows one or more cytopenias . The abnormal stem cell clone in the bone marrow is genetically unstable and prone to the acquisition of additional mutations the eventual transformation to AML .

16. Most cases are idiopathic, after chemotherapy with alkylating agents exposure to ionizing radiation therapy. As a result of cytopenias , pt suffer from infections, anemia , and hemorrhages . Transformation to AML occurs in 10% to 40%.

17. PATHOGENESIS poorly understood . Translocations are lacking, losses or gains of whole chromosomes or parts are frequent . common karyotypic abnormalities include: monosomy 5 or 7; deletions of 5q, 7q, and 20q; more often in women, associated with severe anemia and preserved or elevated platelet counts, Most persons are between 50 and 70 years of age responds to treatment with analogs of thalidomide,

18. MORPHOLOGY the marrow contain: megaloblastoid erythroid precursors ringed sideroblasts granulocyte precursors with abnormal granules small megakaryocytes

19. Chronic Myeloproliferative Disorders hyperproliferation of neoplastic myeloid progenitors that retain the capacity for terminal differentiation ; as a result, there is an increase in one or more formed elements of the peripheral blood. The neoplastic progenitors tend to seed secondary hematopoietic organs (the spleen, liver, and lymph nodes), resulting in hepatosplenomegaly A common theme is the association with activating mutations in tyrosine kinases,

20. Myeloproliferative Disorders : Chronic myelogenous leukemia (CML ), ( BCR-ABL fusion gene, ) polycythemia vera , (BCR-ABL–negative) Primary myelofirosis , (BCR-ABL–negative) essential thrombocythemia (BCR-ABL–negative ) The most common genetic abnormalities in the “ BCR-ABL– negative ” myeloproliferative disorders are activating mutations in the tyrosine kinase JAK2, which occur in virtually all cases of polycythemia vera and about 50% of cases of primary myelofirosis and essential thrombocythemia . All myeloproliferative disorders can transform to a “spent phase” resembling primary myelofbrosis or to a “blast crisis” identical to acute leukemia, by the acquisition of other somatic mutations.

21. Chronic Myelogenous Leukemia affects adults between 25 and 60 (The peak incidence is in the fourth and fifth decades always associated with the presence of a BCR-ABL fusion gene . the BCRABL gene is the product of a balanced (9;22) translocation(Ph chromosome ) that moves ABL from chromosome 9 to a position on chromosome 22 adjacent to BCR . Ph chromosome is highly characteristic of CML , it also is present in 25% of adult B cell–ALLs and a small subset of AMLs.

22. MORPHOLOGY leukocyte count is elevated, exceeding 100,000 cells/ µL . The circulating cells are predominantly neutrophils, metamyelocytes , and myelocytes basophils and eosinophils Platelets are usually increased. The bone marrow is hypercellular owing to increased numbers of granulocytic and megakaryocytic precursors . extensive extramedullary hematopoiesis.

23. CGL

24. CHRONIC MYELOGENOUS LEUKEMIA

25. Philadelphia chromosome Myeloid cells of CML are also characterized by the Philadelphia chromosome (Ph1) on karyotyping. This is a translocation of a portion of the q arm of chromosome 22 to the q arm of chromosome 9, designated t(9:22).

26. Clinical Features insidious , easy fatigability, weakness, weight loss dragging sensation in the abdomen caused by splenomegaly. Slow progression. Even without treatment, the median survival is 3 years.

27. accelerated phase marked by increasing anemia and new thrombocytopenia, the appearance of additional cytogenetic abnormalities, and finally transformation into a picture resembling acute leukemia (blast crisis). 30 % of cases the blast crisis resembles precursor-B cell ALL, further attesting to the origin of CML from hematopoietic stem cells. In the remaining 70% of cases, the blast crisis resembles AML.

28. it is necessary to distinguish CML from a leukemoid reaction a dramatic elevation of the granulocyte count in response to infection, stress, chronic inflammation, and certain neoplasms. This distinction can be achieved definitively by testing for the presence of the BCR-ABL fusion gene, which can be done by karyotyping, florescence in situ hybridization, or PCR assay.

29. Polycythemia Vera Polycythemia vera is characterized by an excessive proliferation of erythroid, granulocytic, and megakaryocytic elements ( panmyelosis ), most clinical signs and symptoms are related to an absolute increase in red cell mass. associated with low levels of serum erythropoietin, presence of activating mutations in JAK2, a tyrosine kinase JAK2 mutation, lowers the dependence of hematopoietic cells on growth factors for growth and survival,

30. increases in blood volume and viscosity Plethoric congestion of many tissues is characteristic. The liver & spleen are slightly enlarged As a result of the increased viscosity and vascular stasis, thromboses and infarctions are common, particularly in the heart, spleen, and kidneys. Hemorrhages also occur as a result of excessive distention of blood vessels and abnormal platelet function . The peripheral blood often shows basophilia . The bone marrow is hypercellular

31. Clinical Course middle age. Patients are plethoric and often cyanotic. Histamine released from the neoplastic basophils cause pruritus increased incidence of peptic ulceration . thrombotic and hemorrhagic tendencies and to hypertension . Headache, dizziness, gastrointestinal symptoms , hematemesis, and melena are common. , symptomatic gout asymptomatic hyperuricemia

32. The diagnosis Red cell counts range from 6 to 10 million/µl and the hematocrit is often 60 % or greater . The granulocyte count can be as high as 50,000 cells/ µL, and the platelet count is often over 400,000 / µL. Basophilia is common . The platelets are functionally abnormal giant platelets and megakaryocyte fragments are often seen in the blood.

33. 30 % of patients develop thrombotic complications , usually affecting the brain or heart . Hepatic vein thrombosis giving rise to the Budd-Chiari syndrome (grave complication). Minor hemorrhages (e.g., epistaxis and bleeding from gums) are common median survival is increased to about 10 years by lowering the red cell count to near normal through repeated phlebotomy. polycythemia vera to evolve to a “spent phase resembling primary myelofirosis . After an average interval of 10 years, 15% to 20% of cases Owing to the extensive marrow fibrosis, hematopoiesis shifts to the spleen, which enlarges markedly . Transformation to a “blast crisis” identical to AML also occurs but much less frequently than in CML.

34. Primary Myelofibrosis a “spent phase” of marrow fibrosis supervenes early in the disease course, often after a brief period of granulocytosis and thrombocytosis. Hematopoiesis shifts from the fibrotic marrow to the spleen, liver, and lymph nodes, extreme splenomegaly and hepatomegaly develop . anemia , thrombocytopenia & Neutropenia

35. PATHOGENESIS The fibroblasts that lay down the collagen in the marrow are not neoplastic . the firoblast proliferation is stimulated by plateletderived growth factor and transforming growth factor β released from neoplastic megakaryocytes . marrow fibrosis and marked extramedullary hematopoiesis

36. MORPHOLOGY Red cells often exhibit bizarre shapes ( poikilocytes , teardrop cells ), nucleated erythroid precursors immature white cells ( myelocytes and metamyelocytes ), a combination of findings referred to as “ leukoerythroblastosis .” The spleen usually is markedly enlarged Subcapsular splenic infarcts, often multiple, Moderate hepatomegaly bone marrow in advanced cases is hypocellular and diffusely fibrotic, marrow megakaryocytes usually are increased in number and dysplastic

37. Clinical Course Early stage disease may have features suggestive of CML, but the Ph chromosome is absent. Most patients have moderate to severe anemia The white blood cell count may be normal, reduced, or markedly elevated. thrombocytopenia . Hyperuricemia and gout Median survival time is 4 to 5 years. thrombotic and hemorrhagic episodes stemming from platelet abnormalities . From 5% to 15% of affected persons develop a blast crisis resembling AML