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MLAB Hematology Keri Brophy-Martinez

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1 MLAB 1415- Hematology Keri Brophy-Martinez
Chapter 21: Introduction to Hematopoietic Neoplasms

2 Terms Neoplasm or tumor: “New growth”
Results from a dysregular prolieferation of a single transformed cell Can be malignant or benign Malignant “Deadly” Clone of abnormal , proliferating cells, without function or differentiation Have the potential to metastasize or get bigger “Cancer” Benign Premalignant Originate from highly organized, differentiated cells Do not spread or invade surrounding tissues

3 Classification of Neoplasms in Bone Marrow
Lymphoid Only lymphocytic cells affected Myeloid Granulocytes, monocytes, megakaryocytes, erythrocytes affected Both Lymphoid and Myeloid lines can include benign and malignant neoplasms

4 Further Classifications
Premalignant myeloid neoplasm Myeloproliferative disorders (MPD) Myelodysplastic syndromes (MDS) Premalignant lymphoid disorders Chronic lymphoproliferative disorders Plasma cell disorders Lymphoid and myeloid malignant bone marrow neoplasms Leukemia

5 More Terms Leukemia A malignant disease of hematopoietic tissue characterized by replacement of normal bone marrow elements with abnormal (neoplastic) blood cells. Abnormal cells are also seen in peripheral blood Lymphoma Abnormal proliferation of lymphoid cells within the lymphatic tissue or lymph nodes, results in a solid tumor

6 Leukemias

7 General Classification
Acute Chronic Age All ages Adults Clinical onset Sudden Gradual Course of disease Weeks to months Months to years Predominant cell Blasts Some mature forms Mature forms Anemia Mild-severe Mild Thrombocytopenia WBC Variable Increased Organomegaly Prominent

8 Blood Picture Acute Chronic

9 How Do Leukemias Arise? Somatic mutation of a single hematopoietic stem or progenitor cell Unlimited self-renewal of the cancer-initiating cell As the mutant cell line predominates, normal hematopoiesis is inhibited causing leukemic cells to spill into peripheral blood

10 Proto-oncogenes and Oncogenes
Proto-Oncogene—normal unaltered gene that has the potential to become an oncogene Oncogene–Altered cell genes that cause tumors Located at breakpoints of chromosomal aberrations, such as translocations

11 Oncogene Activation Factors Genetic susceptibility Fanconi’s anemia
Down’s syndrome (18-20 fold increased incidence) Somatic mutation Ionizing radiation, nuclear weapons Chemicals and drugs Benzene,Chloramphenicol, phenylbutazone Certain chemotherapy drugs that are cytotoxic, especially when used in conjuction with therapeutic radiation Viral infection Retrovirus-HIV-1, HTLVI, II Immunologic dysfunction Ataxia-telangiectasia - lymphoid leukemia or lymphoma Sex-linked agammaglobulinemia From studies on laboratory animals, several factors have been proposed as playing roles in the activation of oncogenes including Genetic susceptibility, somatic mutation, viral infection, and immunologic dysfunction. Strong evidence suggests that hereditary factors and abnormal genetic material have significant impact on oncogene activation. A number of individuals who have congenital abnormalities associated with karyotypic abnormalities have a markedly increased risk of developing acute leukemia. Down syndrome is the best known of the genetic abnormalities associated with leukemia, but Fanconi’s is another. A somatic cell mutation is an ACQUIRED change in the genetic matierial of cells OTHER THAN those involved in reproduction. Mutations in the chromosome NEAR the proto-oncogenes likely play a role in the development of neoplasms. More than 50% of patients with leukemia show acquired abnormal karyotypes. Radiation, some chemicals, and drugs can cause chromosome mutations. Ionizing radiation has long been recognized as capable of inducing leukemia, which is evident from observations of human exposure to radiation from nuclear reactions, therapeutic radiation, and occupational exposure. An increase in leukemia has be observed after treatmetn with alkylating agents and other chemotherapies. Benzene, Chloramphenicol, and phenlybutazone can cause somatic mutations as well. Retroviruses contain a reverse transcriptase that allows them to produce a DNA copy of the viral RNA core. The DNA can then be copied to produce more viral cores or can be incorporated INTO the HOST’s cells nuclear DNA. The strongest support for the existence of a leukemia causing virus in humans come fro the isolation of several retroviruses known as HUMAN T CELL LEUKEMIA/LYMPHOMA virus ONE , TWO and FIVE. The Acronym is HTLV 1, two or five. The other retrovirus that causes leukemia is the human immunodeficiency virus or HIV-one. Hereditary immunologic disorders such as Wiskott-Aldrich syndrome or Bruton’s type x-linked agammaglobulinemia, and ataxia-telangietasia can lead to leukemia due to the bodies inability to recognize and destroy neoplastic cells.

12 Epidemiology Most new cases found in older adults ( > 67 yrs old)
50% of leukemias are acute More common in whites Age groups ALL: children 2-5 years old: lymphoid CLL: Adults> 50: lymphoid AML: adults: myeloid CML: adults: myeloid

13 Clinical Findings Anemia Due to erythropenia Infection
Due to neutropenia Bleeding Episodes Due to thrombocytopenia Bone pain Due to marrow expansion Weight loss

14 Evaluation of Leukemia
Note onset of symptoms Analyzing CBC Thrombocytopenia? RBC level/ anemia? Observe cell lineage Lymphoid or Myeloid? Assess maturity of predominating cells

15 Lab Features Normochromic,normocytic anemia Thrombocytopenia
Platelet morphology and function can be abnormal Leukocyte count can be increased, decreased or normal Immature leukocyte precursors seen Bone marrow hypercellular Maturation abnormalities in all cell lines Uric acid increased

16 Official Hematopoietic Neoplasm Classification
Two systems French-American British(FAB) Historical World Health Organization (WHO)** Widely accepted Important because.. Allows clinicians a way to compare therapeutic regimens System for ID and comparison of clinical features & lab findings Permit associations of cytogenetic abnormalities with disease

17 Consists of three groups
FAB classification Consists of three groups Myeloproliferative Disorders(MPD) Myelodysplastic Syndromes(MDS) Acute leukemia (AL) Based on morphological characteristic of Wright-stained cells in peripheral blood or bone marrow with supplementary cytochemical stains

18 WHO Classification Classification system uses morphology, cytochemistry and immunophenotyping to determine cell lineage and degree of maturation(similar to FAB) Additionally uses genetic and clinical features prior to therapy and history of MDS to define subgroups Consists of four groups Myeloid Further classified as MPD, MDS/MPD, MDS, AML Lymphoid Further classified as B cell, T/NK cell, Hodgkin’s Disease Mast cell Histiocytic

19 Lab Techniques for Diagnosis and classification of neoplasms
Cytochemical analysis In vitro staining of cells to look at cells’ chemical composition Evaluation of positivity in these stains must be determined on the leukemic blast stage of the cell Usually performed on bone marrow slides Helpful in differentiating lymphoid or myeloid lineage of blasts in AL Reactions are either enzymatic or nonenzymatic

20 Cytochemical stains Types Myeloperoxidase (MPO)
Activity is present in the primary granules and Auer rods of myeloid cells Separates myeloid and lymphoid blasts Stains late myeloblasts, granulocytes, monocytes less intensely Differentiates AML from ALL Granules stain reddish-brown Smears must be fresh

21 Cytochemical stains: con’t
Sudan Black B Activity is present in phospholipids in the membrane of 1̊ (nonspecific) and 2̊ granules (specific) Parallels myeloperoxidase but smears do not have to be fresh Granules stain black Periodic Acid Schiff (PAS) Activity is in glycogen and related substances Stains lymphocytes, granulocytes, megakaryocytes Helpful in diagnosing erythroleukemia where there is strong reactivity in normoblasts Stains red-purple in blocks in cytoplasm

22 Cytochemical stains: con’t
Esterases Specific Esterase (Naphthol AS-D Chloroacetate) Activity is in cytoplasm Stains neutrophilic granulocytes, differentiates monoblasts and myeloblasts Granules of myeloblasts stain blue-black Nonspecific Esterase (Alpha-Naphthyl Acetate) Stains monocytes and also megakaryocytes Differentiates myeloblasts from monoblasts (can use a double staining technique to view both specific and nonspecific stains on one smear) Addition of Na fluoride to this stain inhibits activity in monocytes Granules stain orange red

23 Cytochemical stains: con’t
Leukocyte Alkaline Phosphatase (LAP) Enzyme within the 2O or specific granules of maturing granulocytes Distinguishes leukemoid reactions ( ) from chronic myelogenous leukemia ( ) Acid Phosphatase Present in lysosomes in normal leukocytes Helpful in diagnosing hairy cell leukemia because they are NOT inhibited by TRAP

24 Cytochemical stains: con’t
Terminal Deoxynucleotidy transferase (TdT) Primitive cell marker found in cell nuclei Distinguishes ALL from malignant lymphoma Toluidine Blue Positive marker for basophils and mast cells

25 Lab Techniques for Diagnosis and classification of neoplasms
Immunologic marker studies Cell surface markers Monoclonal or polyclonal antisera is added to cell suspensions of fresh peripheral blood or bone marrow and an immunofluorescent method is used in a flow cytometry instrument to analyze the markers which are expressed as cluster designations (CD). CD’s identify antibodies that are specific for certain cells and allow for a positive identification.

26 Lab Techniques for Diagnosis and classification of neoplasms
Molecular Genetics This newer method of diagnosing leukemia consists of DNA probes and polymerase chain reaction (PCR)-based studies. They are rapid and precise and are used to confirm chromosomal abnormalities that are not detected by conventional studies. They are also used to monitor residual disease following therapy. FISH (Fluorescence in situ hybridization) Cytogenetics (Chromosome studies) Identifies chromosome translocations which are specific for certain leukemias Philadelphia chromosome (t[9:22]) is associated with CML t[15:17] is associated with acute promyelocytic leukemia

27 Treatment Cures are not common except in childhood leukemia. The best hope for a cure in adults lies in bone marrow transplantation. Cytoreductive chemotherapy Reduces the leukemic cell mass Block DNA synthesis Block RNA synthesis Complications arise from marrow hypoplasia and resulting cytopenia

28 Treatment Radiotherapy (radiation) Bone marrow transplantation
Kills focalized leukemic cells Usually used in addition to chemotherapy and for CNS prophylaxis Bone marrow transplantation Bone marrow is eradicated with chemo and radiation. Compatible donor cells are transfused and they travel to the empty marrow where they engraft and repopulate the marrow with healthy cells. Complications include graft vs host (GVH) disease which can be fatal. READ FROM SLIDE

29 References McKenzie, Shirlyn B., and J. Lynne. Williams. "Chapter 21." Introduction. Clinical Laboratory Hematology. Boston: Pearson, Print.

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