dr a. mousavi.  15 % of all malignant white cell diseases  1% of all cancer deaths  group...

Download Dr A. Mousavi.  15 % of all malignant white cell diseases  1% of all cancer deaths  Group of lymphoid neoplasms of terminally differentiated B-cells

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  • Dr A. Mousavi
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  • 15 % of all malignant white cell diseases 1% of all cancer deaths Group of lymphoid neoplasms of terminally differentiated B-cells that have in common the expansion of a single clone of immunoglobulin(Ig)-secreting plasma cells and a resultant increase in serum levels of a single homogeneous(monoclonal) Ig or its fragments.
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  • Caused by malignant changes to plasma cells or the B lymphocyte cell line. Exhibit either: Excessive amounts of normal immunoglobulin proteins (Igs) Accumulation of Igs in an abnormal location Structurally abnormal Igs
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  • Terminally differentiated B-cells Not normally found in peripheral blood. Account for less than 3.5% of nucleated cells in the bone marrow Oval cells with low N:C ratio. Cytoplasm is basophilic blue. Nucleus (30-40% of the cell) is oval or round and typically placed eccentrically (to one side)of the cell. A clear, colorless area adjacent to the nucleus contains Golgi apparatus Russell bodies: Globules(2-3m) of accumulated immunoglobulins in the cytoplasm of plasma cells. Usually round. Russell bodies may be found in normal bone marrow.
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  • Develop from stem cells in bone marrow Stem cells develop into B cells (B lymphocytes) Antigens enter body then B cells develop into plasma cells Produce antibodies
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  • Which of these are the heavy chains? Name the 5 classes of heavy chain. Gamma, mu, alpha, delta and epsilon Which of these are the light chains? Name the 2 classes of light chain. Kappa and lambda NH3+ COO-
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  • Where is the constant region of the molecule? Where is the variable region? Which region defines the specificity of the antibody? Variable Which region is responsible for the physical properties of the antibody, such as ability to activate complement and binding to macrophages? Constant NH3+ COO-
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  • Normally, plasma cells produce immunoglobulins to fight infection However, in MM and MGUS a single cloned plasma cell proliferate and overproduce the same Ig ("M-protein" or Paraprotein") The M-protein is usually an IgG MM cells can also just produce the light chain component (Instead of the entire Ig)
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  • Consequence of producing lots of monoclonal Ig: o Hyperviscosity o Kidney Damage (from light chains only) o Bone pain, hypercalcemia and pathologic fractures from bone lesions. o Anemia/Pancytopenia from bone marrow invasion
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  • Y B Cell Normal Plasma Cell Malignant Plasma Cell Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
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  • Accumulation of a single protein that arises from proliferation of a single plasma cell clone. Since each B cell can respond to only one antigenic epitope, a plasma cell derived from that B cell produces antibody that is reactive against that unique epitope (monoclonal antibody). Malignant changes to that plasma cell result in uncontrolled production of its specific antibody. The specificity of the monoclonal antibody (M protein) varies between patients, but each affected patient has only one M protein specificity.
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  • Adhesion molecules Stromal cells Interactions: Cytokines (IL-6) Growth factors that promote angiogenesis (IGF-1, VEGF, SDF-1) Inactivated immune system
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  • Gammopathy Monoclonal gammopathy Dysproteinemia Paraproteinemia
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  • MGUS (62%) Malignant Monoclonal gammopathies: MM (18%) variants: smoldering myeloma (3%), non-secretory MM, light chain myeloma Plasmacytoma Plasma cell leukemia IgD myeloma POEMS syndromes (Osteosclerotic myeloma) Waldenstroms Macroglobulinemia (Lymphoplasmacytic lymphoma)
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  • Malignant lymphoproliferative disorders Heavy chain diseases (Gamma HCD, Mu HCD, Alpha HCD) Immunoglobulin deposition diseases (Primary Amyloidosis, Systemic light chain and heavy chain deposition diseases)
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  • In any suspected Monoclonal Gammopathy should include to accurately classify the disorder: Complete Blood Count (look for anemia) Comprehensive Metabolic panel Look for renal insufficiency, hypercalcemia and subtle clues like decreased anion gap
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  • Total protein and albumin level. Determine Globulin component.Too low globulin( 3.5gm%) is concerning:Determine if Polyclonal vs.Monoclonal. Evaluate further with: Quantitative Immunoglobulins: Increase in all components usually, polyclonal. Increase in single component with reciprocal decrease of uninvolved globulin usually, may suggest monoclonal.
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  • Serum Protein Electrophoresis with immunofixation if monoclonal gammopathy is suspected. 24HR-Urine protein electrophoresis with urine immunofixation (Serum Free Light Chain assay(/ratio) may be used in place of UPEP}
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  • Bone marrow biopsy to evaluate% plasma cells if there is monoclonal protein or abnormal UPEP or Light chain assay or if strong clinical picture of myeloma. Skeletal survey if monoclonal gammopathy has been established(Bone scans are usually negative in MM) Beta-2 microglobulin and Albumin for staging and prognosis in MM (once diagnosis is made).
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  • Denotes presence of an M-protein in a patient without a plasma cell or lymphoproliferative disorder (i.e; Undetermined Significance) M- protein < 3 gr/dl < 10% plasma cell in bone marrow No or small amounts of M- protein in urine Absence of lytic bone lesions, anemia, hypercalcemia, renal insufficiency No evidence of B- cell lymphoproliferative disorder Stability of M- protein over time
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  • Incidence increases with age Significance: can progress to monoclonal disease IgA or IgG MGUS IgM MGUS MM Primary Amyloidosis Related Plasma cell disorder NHL CLL Waldenstroms Macroglobulinemia
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  • Smoldering Myeloma: Serum monoclonal protein 3 g/dl and/or bone marrow plasma cells 10% No end organ damage related to plasma cell dyscrasia
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  • Rare variant: About 1% of Myelomas May present with Bone lesions (most common presenting symptom bone pain) No serum or urine monoclonal protein(diagnosis can be missed if one is not aware of this entity, NSMM). Renal failure and hypercalcemia are generally lacking Anemia may be present Bone marrow biopsy must be performed in suspected cases: Immunostaining for a monoclonal protein on bone marrow sections may establish the diagnosis Clonal plasma cell population in marrow. Must rule out IgD and IgE myeloma
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  • Localized plasma cell tumor Absence of a plasma cell infiltrate in random marrow biopsies No evidence of other bone lesions by radiographic examination Absence of renal failure, hypercalcemia or anemia Younger median age at presentation (55 y) Treatment: Radiation to site (5000 cGy) 50-60% will convert MM within 10 years Possible bone marrow collection/ storage
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  • Arise outside the bone marrow with no features of MM Most common: Head and Neck region Less common: Lymph nodes, Salivary glands, spleen, liver, 25% have small monoclonal spike Rare dissemination, rare revolution to myeloma Management: If completely resected during biopsy,no further therapy If incompletely resected,radiation therapy locally
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  • Three criteria: 1.Presence of a serum or urinary monoclonal protein 2.Presence of 10 percent or more clonal plasma cells in the bone marrow or a plasmacytoma 3.Presence of end organ damage felt related to the plasma cell dyscrasia, such as: M- CRAB: Monoclonal protein HyperCalcemia (calcium >11.5 gm/dl) Renal Insufficiency Anemia (Hb < 10gm/dl) Lytic Bone lesions
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  • Bone lesions: Conventional Radiographs (Skeletal Survey) is abnormal in 80% of MM Focal lytic bone: 57% Osteopenia or Osteoporosis: 20% Pathologic fractures: 20% Vertebral body compression fractures: 20%
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  • Anemia: Normochrome nomocyter in 75% of MM Hb < 10 mg/dl Renal insufficiency: Serum creatinine increased in >50% at diagnosis Creatinine >2g/dL in 20% of patients Renal failure may be presenting manifestation
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  • Cytogenetic: 14 q 32 1 q 5, 8, 12,. Deletion 17 p and Abnormalities associated with chromosome13 carry a particularly unfavorable prognosis and respond poorly to therapy
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  • Staging: International staging system: Stage I B2M
  • >2 X 10 9 /L plasma cells in blood(seen on peripheral smear) Younger age Higher incidence of organomegaly and lymphadenopathy More extensive bone marrow infiltration Renal failure more common Less bone pain, fewer lytic lesions Poor response to therapy
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  • Monoclonal gammopathy: IgM type Plasmacytoid lymphoma Median age at diagnosis: 60 yrs Presentation: Hyperviscosity syndrome(15%): visual impairment, neurologic manifestations Bleeding(Acqui