Acute Leukemia Presentation PDF

# Acute Leukemia Ahlam Elsir ## Introduction - The leukemia’s are a group of disorders characterized by the accumulation of malignant white cells in the bone marrow and blood. - These abnormal cells cause symptoms because of: - Bone marrow failure (e.g., anemia, neutropenia, thrombocytopenia)...

# Acute Leukemia Ahlam Elsir ## Introduction - The leukemia’s are a group of disorders characterized by the accumulation of malignant white cells in the bone marrow and blood. - These abnormal cells cause symptoms because of: - Bone marrow failure (e.g., anemia, neutropenia, thrombocytopenia) - Infiltration of organs (e.g., liver, spleen, lymph nodes). ## Classification of Leukemia - The main classification is into four types: acute and chronic leukemias, which are further subdivided into lymphoid or myeloid. ### Acute Leukemia - **Acute lymphoblastic leukemia (ALL)** - **Acute myeloid leukemia (AML)** or Acute Non Lymphoblastic leukemia (ANLL) ### Chronic Leukemia - **Chronic lymphoid leukemia (CLL)** - **Chronic myeloid leukemia** ## Classification of Acute Leukemia - Acute leukemia's are usually aggressive diseases in which malignant transformation occurs in the haemopoietic stem cell or early progenitors. - Genetic damage is believed to involve several key biochemical steps resulting in : - An increased rate of proliferation, - Reduced apoptosis and - A block in cellular differentiation. - Together these events cause accumulation in the bone marrow of early haemopoietic cells known as Blast Cells. ## Acute Myeloid Leukemia - Acute myeloid leukemia (AML) is the most common form of acute leukaemia in adults. ## Clinical Features - The clinical features of AML are dominated by the pattern of bone marrow failure caused by the accumulation of malignant cells within marrow infections are frequent and anemia and thrombocytopenia are often profound. - Bleeding tendency caused by thrombocytopenia and disseminated intravascular coagulation (DIC) is characteristic of the promyelocytic variant of AML. ## Diagnosis of Acute Leukemia - Acute leukemia is normally defined as the presence of over 20% of blast cells in the blood or bone marrow. - However, it can be diagnosed with less than 20% blasts if specific leukemia-associated cytogenetic or molecular genetic abnormalities are present. ### The Lineage of Blast Cells is Defined By: - Microscopic examination (morphology), - Immunophenotypic (flow cytometry) - This will define whether the blasts are of myeloid or lymphoid lineage. - The typical ‘myeloid immunophenotype’ is CD13+,CD33+, CD117 + - Cytogenetic and molecular analysis. ## Cytochemistry - Cytochemistry can be useful in determining the blast cell lineage. - Cytogenetic and molecular analysis is essential and is usually performed on marrow cells although blood may be used if the blast cell count is particularly high. ## French-American-British Classification of the Acute Myeloid Leukemias | Type | Description | |---|---| | M0 | Acute myeloid leukemia, minimally differentiated | | M1 | Acute myeloid leukemia without maturation | | M2 | Acute myeloid leukemia with maturation | | M3 | Acute promyelocytic leukemia | | M4 | Acute myelomonocytic leukemia | | M4eo | Acute myelomonocytic leukemia with eosinophilia | | M5a | Acute monocytic leukemia, poorly differentiated | | M5b | Acute monocytic leukemia, well differentiated | | M6 | Acute erythroleukemia | | M7 | Acute megakaryocytic leukemia | ### M0 - Acute myeloid leukemia, minimally differentiated (French-American-British classification M0). - Blasts lack myeloid morphologic features and yield negative results with myeloperoxidase and Sudan black B staining. - Auer rods are not seen. ### M1 - Acute myeloid leukemia without maturation (French-American-British classification M1). ### M2 - Acute myeloid leukemia with maturation. - Blasts constitute 20% or more of the nucleated cells of the bone marrow, and there is maturation beyond the promyelocyte. ### M3 - Acute myelomonocytic leukemia. - Both myeloid and monocytic cells are present. - Monocytic cells comprise at least 20% of all marrow cells, with monoblasts and promonocytes present (peripheral blood). ### M4 - Acute monoblastic leukemia. - More than 80% of the bone marrow cells are of monocytic origin. ### M5 - Acutemonocytic leukemia with promonocytes. - Promonocytes are considered blast equivalents. ### M6 - Acute erythroid leukemia. - Erythroid precursors showing dysplastic features, including multi-nucleation and megaloblastic. ### M7 - Acute megakaryocytic leukemia. ## Acute Myeloid Leukemia with Recurrent Genetic Abnormalities (2008 World Health OrganizationClassification) - AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 - AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 - APL with t(15;17)(q22;q12); PML-RARA - AML with t(9;11)(p22;q23); MLLT3-MLL - AML with t(6;9)(p23;q34); DEK-NUP214 - AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 - AML with t(1;22)(p13;q13) RBM15-MKL1 - Provisional entity: AML with mutated NPM1 - Provisional entity: AML with mutated CEBPA ## Cytochemical Stains and Interpretations - Techniques such as flow cytometry, cytogenetic analysis, and molecular testing are now commonly used in the diagnosis of acute leukemias. ## Myeloperoxidase - Myeloperoxidase (MPO) an enzyme found in the primary granules of granulocytic cells (neutrophil eosinophils, and, to a certain extent, monocytes). - Lymphocytes do not exhibit MPO activity - This stain is useful for differentiating the blasts of acute myeloid leukemia (AML) from those of acute lymphoblastic leukemia (ALL). ### Interpretation - MPO is present in the primary granules of most granulocytic cells, beginning at the promyelocyte stage and continuing throughout maturation. - Leukemic myeloblasts are usually positive for MPO. - In many cases of the AMLs (without maturation with maturation, and promyelocytic leukemia), it has been found that more than 80% of the blasts show MPO activity. - Auer rods found in leukemic blasts and promyelocytes test strongly MPO positive. ## Esterases - Esterase stains can be used to distinguish acute leukemias that are granulocytic from leukemias that are primarily of monocytic origin. - When naphthol AS-D chloroacetate is used as a substrate, the reaction is positive in the granulocytic cells and negative to weak in the monocytic cells. ## Sudan Black B - SBB staining is another useful technique for the differentiation of AML from ALL. - SBB stains cellular lipids. - The staining pattern is quite similar to that of MPO; SBB staining is possibly a little more sensitive for the early myeloid cells ### Interpretation - Granulocytes (neutrophils) show a positive reaction to SBB from the myeloblast through the maturation series. - The staining becomes more intense as the cell matures as a result of the increase in the numbers of primary and secondary granules. ## Immunological Markers (Flow Cytometry) | Marker | Result | Description | |---|---|---| | Myeloperoxidase | + | (including Auer)| | Sudan black | + | (including Auer)| | Non-specific esterase | + | in M4, M5| | CD13, CD33, CD117 | + | | | Glycophorin | + | (erythroid)| | Platelet antigens (e.g. CD41) | + | (megakaryoblasts) | | Myeloperoxidase | + | (undifferentiated) | ## Chromosome and Genetic Analysis | Type | Description | |---|---| | t(8;21)(q22;q22) | RUNX1-RUNX1T1 | | inv(16)(p13.1q22) or t(16;16)(p13.1;q22) | CBFB-MYH11 | | t(15;17)(q22;q12) | PML-RARA | | t(9;11)(p22;q23) | MLLT3-MLL | | t(6;9)(p23;q34) | DEK-NUP214 | | inv(3)(q21q26.2) or t(3;3)(q21;q26.2) | RPN1-EVI1 | | t(1;22)(p13;q13) | RBM15-MKL1 | | Provisional entity | AML with mutated NPM1 | | Provisional entity | AML with mutated CEBPA | ## Acute Lymphoblastic Leukemia (ALL) - Acute lymphoblastic leukaemia (ALL) is caused byan accumulation of lymphoblasts in the bone marrow and is the most common malignancy of childhood - Acute lymphoblastic leukemia (ALL) is primarily a disease of childhood, accounting for 25% of childhood cancers and up to 75% of childhood leukemia. - The peak incidence of ALL in children is between 2 and 7 years of age. There is a secondary rise after the age of 40 years. ## Classification - Acute lymphoblastic leukaemia, B cell or T cell, is subclassified by WHO (2008) according to the underlying genetic defect. ### Morphologic Classification - The morphologic classification is done by using the French-American-British (FAB) system. | Type | Description | |---|---| | L1 | Most common type in childhood. Monomorphic, small to intermediate-sized blasts that have round nuclei, scant cytoplasm (high nucleus to cytoplasm ratio), homogeneous nuclear chromatin, and inconspicuous nucleoli | | L2 | Most common type in adults. Larger, more variable cells with more abundant cytoplasm (lower n-c ratio), irregular nuclear contours, and more prominent nucleoli | | L3 | Rare (~1-3% of ALL). The cells are characterized by deeply basophilic (blue) cytoplasm with prominent clear cytoplasmic vacuoles containing lipid | - Burkitt-cell leukemia (FAB ALL-L3). Basophilic cytoplasm and prominent clear cytoplasmic vacuoles are present. ## WHO Classification of ALL - **Precursor B-cell ALL:** - t(9;22)(q34;q11); BCR/ABL (the Philadelphia chromosome) - t(v;11q23); MLL rearranged (MLL = myeloid-lymphoid leukemia gene) - t(1;19)(q23;p13); E2A/PBX1 - t(12;21)(p12;q22); TEL/AML1 - **Precursor T-cell ALL** - **Burkitt-cell leukemia** ## Clinical Features - Clinical features are a result of the following: - **Bone marrow failure** - Anemia pallor - Neutropenia (fever, malaise, features of mouth, throat, skin, respiratory or other infections); - Thrombocytopenia (spontaneous bruises, purpura, bleeding gums and menorrhagia). - **Organ infiltration** - Tender bones, lymphadenopathy a moderate splenomegaly, hepatomegaly ### B Cell ALL - Patient typically present with fatigue (caused by anemia), fever (caused by neutropenia and infection)and mucocutaneous bleeding (caused by thrombocytopenia). - Lymphadenopathy, including enlargement, is often a symptom. - Enlargement of the spleen (splenomegaly) and of the liver (hepatomegaly) may be seen. - Bone pain often results from intramedullary growth of leukemic cells. ### T-ALL - May present with anemia, thrombocytopenia, organomegaly, and bone pain, although the degree of leukopenia is often less severe ## Haematological Investigations - Normochromic normocytic anaemia with thrombocytopenia inmost cases. - The total white cell count may be decreased, normal or increased to 200 x 10^9/L or more. - The blood film typically shows a variable number of blast cells. - The bone marrow is hypercellular with >20% leukaemic blasts. The blast cell are characterized by morphology cytochemisty immunological tests and cytogenetic analysis. ## Immunophenotyping - Although morphology is the first tool used to distinguish ALL from AML, immunophenotyping and genetic analysis are the most reliable indicators of a cell's origin. - Because both B and T cells are derived from lymphoid progenitors, both usually express CD34, terminal deoxynucleotidyl transferase (TdT). ## Immunophenotypic Characteristics of Acute Lymphoblastic Leukemia | ALL Subtype | Immunophenotype | |---|---| | Early (pro/pre-pre) B-ALL | CD34, CD19, cytoplasmic CD22, TdT | | Intermediate (common) | CD34, CD19, CD10, cytoplasmic CD22, TdT | | B-ALL | CD34, CD19, cytoplasmic CD22, cytoplasmic µ, TdT (variable) | | T-ALL | CD2, CD3, CD4, CD5, CD7, CD8, TdT | ## Immunological Markers for Classification of Acute Lymphoblastic (ALL) Leukemia | Marker | ALL | |---|---| | B lineage | + | | CD19 | + | | CCD22 | + | | CCD79a | + | | CD10 | + or - | | clg | + | | slg | + (pre-B) | | TdT | + | | T lineage | + | | CD7 | - | | CCD3 | - | | CD2 | - | | TdT | + | ## Cytogentic Studies - Chromosomal translocations have been seen in 50% of ALL cases. - Certain translocations are associated with specific immunologic subtype of ALL.