Done By : WESSEN ADNAN BUTHAINAH AL-MASAEED

Done By : WESSEN ADNAN BUTHAINAH AL-MASAEED

Acute Myeloid Leukemia

Firstly we ll start with this introduction then enter the title of the lecture, so be ready and let s begin by the name of Allah : We have 2 terms: leukemia & lymphoma, both are malignant especially in the precursor cells (blasts); but what are the differences between them?! Lymphoma: malignant proliferation of a cell in lymphoid lineage that causes mass or tumor and mainly occurs in lymph nodes. Also it can occur in: Secondary lymphoid tissues ; like :spleen & mucosa of *organs [ the lymphoid cells under the epithelium ] *organs; such as: GI, colon & small intestine. MALT: mucosal associated lymphoid tissue Lymphoid tissue of lungs Every tissue has a small portion of lymphoid. Leukemia: malignant proliferation of a cell in the lymphoid or myeloid lineage that occurs primary in bone marrow. The abnormal cells inside the bone marrow will cause deficiencies in the other cells (pancytopenia) and make the patients suffering from several complications like

1. RBCs deficiency Anemia 2. Platelets deficiency (thrombocytopenia) Bleeding 3. Leukocytes deficiency (**leukocytopenia) Immune deficiency **leukocytopenia of the functional leukocytes especially Neutrophils. *Leukemia affects the bone marrow & peripheral blood. *Lymphoma affects the lymph nodes. *Lymphoma sometimes can affect the bone marrow; in this case it will be followed by leukemia. Now let s start talking about our lecture s topic the <Acute Myeloid Leukemia> Generally we have: 1. Acute Myeloid Leukemia (AML); that is the worst. 2. Chronic Myeloid Leukemia (CML) 3. Acute Lymphoid Leukemia (ALL)

4. Chronic Lymphoid Leukemia (CLL)

*CFU Colony Forming Unit. They are the committed precursors from myeloid that the malignant proliferation in the myeloid leukemia happens to them; which leads to stopping the differentiation and accumulation in premature precursor cells. *The most affected cells are the precursors of neutrophils. Overview Originate from transformed hematopoietic (myeloid) progenitors due to acquired oncogenic mutations that impede differentiation leading to: Accumulation of immature myeloid forms (blasts) in the bone marrow suppresses normal hematopoiesis The replacement of the marrow with blasts produces marrow failure and complications related to anemia, thrombocytopenia, and neutropenia

Overview, cont d Occurs at all ages, but the incidence rises throughout life, peaking after 60 years of age. The current WHO classification subdivides AML into four categories see next slide The doctor s notes on the

previous table: *The oncogene mutation is a cause of leukemia and like any cancer it happens because of either stimulation of oncogene or inhibition of tumor suppressor gene. *inv inversion *t translocation *favorable good prognosis *poor bad prognosis *There are 4 categories of AML: First one: -Chromosomal translocation leads to leukemia. -2 chromosomes make translocation for one of their genes that cause an ONCOGENE. Second one: -myelodysplasia is different from the leukemia but it can become a leukemia (AML). -with previous myeloplastic leukemia above the myelodysplasia (myeloplastic syndrome happened before the leukemia comes) -without previous myeloplastic leukemia & myeloplastic syndrome happen at the same Time. Third one: -the chemotherapy (especially the Alkylating agent) may cause leukemia. Fourth one: -non defined. -after exclusion of all the previous categories we think of this category. -classified according to the cell types inside it. -the myeloid is not only occurring in myeloblasts & promyelocytes; it can occur also in (for example Monoblast)

Pathogenesis Most AMLs harbor mutations in genes encoding transcription factors that are required for normal myeloid cell differentiation defective maturation of early myeloid cells resulting in the accumulation of myeloid precursors (blasts) in the marrow Of particular interest is the (15;17) translocation in acute promyelocytic leukemia (malignant proliferation of promyelocytes) results in the fusion of the retinoic acid receptor α (RARA) gene on chromosome 17 and the PML gene on chromosome 15 the chimeric gene produces a PML/RARα fusion(the oncogene) that stops the myeloid proliferation at the promyelocytic stage; so abnormal formation and accumulation of immature promyelocytes protein that blocks myeloid differentiation at the promyelocytic stage probably in part by inhibiting the function of normal retinoic acid receptors

Pharmacologic doses of all-trans retinoic acid (ATRA) substance works same as the RARA that leads to normal differentiation, an analogue of vitamin A can be used also its combination with arsenic trioxide (a salt that induces the degradation of the PML/RARA fusion protein) can cure 80% of patients Pathogenesis, cont d Some of the other mutations implicated in AML have no effect on differentiation but instead enhance cellular proliferation and survival examples: - FLT3, a receptor tyrosine kinase - RAS

Morphology By definition, in AML myeloid blasts or promyelocytes make up more than 20% of the bone marrow cellular component Myeloblasts ( precursors of granulocytes ) -delicate nuclear chromatin -three to five nucleoli -fine azurophilic cytoplasmic granules -Auer rods, distinctive red-staining rod-like structures may be present in myeloblasts or more differentiated cells they are particularly numerous in acute promyelocytic leukemia

Auer rods are specific for neoplastic myeloblasts and thus a helpful diagnostic clue when present In other subtypes of AML, monoblasts, erythroblasts, or megakaryoblasts predominate *So the diagnosis occurs via morphology & nowadays via genetics (detection the translocation) *Firstly via morphology: -of blood film (peripheral blood) to diagnose the blood cells -of bone marrow (biopsy, histology & cytology)

*This is t(15;17) *Granules inside the cytoplasm azurophilic granules. الخيوط ال ي ل زي الدبابيسrods *Auer They are characteristic for abnormal neoplastic.

Clinical notes Splenomegaly and lymphadenopathy generally are less prominent than in ALL(because ALL occur in lymph node not only in the bone marrow). On rare occasions AML mimics a lymphoma by manifesting as a discrete tissue mass (a so-called granulocytic sarcoma <myeloid sarcoma>) AML can make metastasis under skin, in mouth, etc Clinical notes, cont d The overall survival in all patients is only 15% to 30% with conventional chemotherapy t(8,21) and inv16 are good. Hematopoietic stem cell transplantation sometimes used.

Diagnosis The diagnosis and classification of AML are based on: -morphologic -histochemical -immunophenotypic -karyotypic findings Of these, the karyotype (to detect translocations) is most predictive of outcome Immunohistochemistry (Immunophenotype of tumor cells) myeloid-associated antigens: CD13, CD14, CD15, CD64, CD117 (ckit), or CD33