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Part I Neoplastic Proliferation Of Wbc
 

Part I Neoplastic Proliferation Of Wbc

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    Part I Neoplastic Proliferation Of Wbc Part I Neoplastic Proliferation Of Wbc Presentation Transcript

    • NEOPLASTIC PROLIFERATION OF WBC
      1
    • LYMPHOID NEOPLASM
      MYELOID NEOPLASM - Hematopoietic stem cells
      MYELOID LINEAGE
      1. ERYTHROID
      2. GRANULOCYTIC
      AML
      MYELODYSPLASTIC
      CHRONIC MYELOPROLIFERATIVE D/O
      3. THROMBOCYTIC
      HISTIOCYTOSES
      2
      CATEGORIES:
    • Acute Myelogenous
      Immature progenitor cells accumulate in BM
      Myelodysplastic Syndromes
      Ineffective Hematopoiesis
      Peripheral Cytopenias
      Chronic Myeloproliferative D/O
      Increased production
      1 or more terminally differentiated myeloid elements
      GRANULOCYTES
      Leads to elevated peripheral blood counts
      3
      Granulocytic Lineage
    • 4
      Pathogenetic factors
    • Mutated genes  Produce Negative protein
      Interfere with its normal function/ or Inapropriate increase in some normal activity ( MALTomas )
      Translocation of either MALT1 or BCL10 protein  Upregulation of NF-kB
      Normally Bind to form complex  regulate NF-kB
      NF-kB has important pro-survival function in normal lymphocytes
      Oncoprotein created by genomic abberations
      Often Block normal maturation  Affect rapidly proliferating cells
      Acute Leukemias
      Proto-Oncogenes
      Often activated in lymphocytes by errors that occur during attempted antibody diversification
      5
      Chromosomal Translocation & Other Acquired Mutations
    • 6
      Pathogenetic factors
    • 7
      Pathogenetic factors
    • 8
      Pathogenetic factors
    • 9
      Pathogenetic factors
    • 10
      Smoking
    • LYMPHOID NEOPLASMS
      11
    • CLASSIFICATION:
      Lymphocytic Leukemia
      Lymphoma
      Plasma cell Neoplasm
      12
    • Lymphoid neoplasm
      Widespread Bone Marrow Involvement
      Usually (+) Large Numbers of Tumor cells in Peripheral smear
      13
      Lymphocytic leukemia
    • Proliferations arising as Discrete tissue masses
      2 Types
      1. Non-HodgkinsLmphoma
      2. HodgkinsLymhoma
      Many types present with Leukemia
      Term used – Tissue distribution of the disease at time of clinical presentation
      14
      lymphoma
    • Most commonly arise in Bone Marrow
      Rarely present as Leukemia
      R/T Secretion of Antibodies by tumor cells
      15
      Plasma cell Neoplasm
    • Vast majority are B cell in origin
      Markers recognized by Antibodies help in characterization into 5 categories
      Often disrupt normal architecture & function of Immune system
      Susceptibility to infection
      Autoimmune
      16
      FEATURES- Lymphoid Neoplasm
    • Inherited or acquired Immunedeficiency High risk certain lymphoid neoplasm
      Particularly caused by oncogenic virus eg. EBV
      17
      FEATURES- Lymphoid Neoplasm
    • Tend to home to a particular tissue sites
      Follicular Lymphoma – Germinal center
      T-cell Lymphomas – Skin
      Some recirculate through the lymphatics & peripheral blood  Distant sites
      Except Hodgkins, Marginal zone lymphoma ( MALToma )
      18
      FEATURES- Lymphoid Neoplasm
    • Determined by Anatomic distribuation of disease
      2/3 NHL and 100% of Hodgkin Lymphomas
      Enlarged Nontender LN
      Often > 2 cm
      Remaining 1/3 NHL
      Symptoms r/t to involvement of Extranodal sites
      Skin, Stomach, Brain
      19
      Clinical PresentationLymphoma
    • Abrupt stormy onset
      Present w/in days to few weeks
      S/S related to Suppression of normal Hematopoiesis by tumor cells in BM
      Characteristic is Infiltrate in Spleen & Liver
      20
      LYMPHOCYTICLEUKEMIA
    • Involve the skeleton
      Local bone destruction
      Pain
      Pathologic Fractures
      Addendum
      Secretion of whole Ab or Ig fragments
      21
      PLASMA CELL NEOPLASM
    • Precursor B cell Neoplasm
      Immature B cells
      Peripheral B cell Neoplasms
      Mature B cells
      Percursor T-cell Neoplasm
      Immature T cells
      Peripheral T-cell & NK cell Neoplasm
      Mature T cell & NK cells
      Hodgkin Lymphoma
      22
      WHO 5 CATEGORIES
    • Precursor B and T –Cell Neoplasms
      - Neoplasm of Immature B cells
      Acute Lymphoblastic Leukemia/Lymphoma
      23
    • Group of Neoplasm composed of Immature pre-B or Pre-T LYMPHOBLASTS
      Most common cancer of Children
      Slightly higher in boys
      2 Types:
      1. Pre-B cell
      2. Pre-T cell
      Both tumors types are morphologically indistinguishable
      Features :
      24
    • 85% are B-ALLs
      Manifest as Childhood Acute Leukemia
      Peak age is 3 y/o
      Extensive BM involvement
      Variable Peripheral involvement
      Uncommonly present as Lymphoma
      Less common is T-ALLs
      Adolescent males
      As Thymic Lymphoma
      Many evolve to Leukemia
      Features :
      25
    • B-ALL
      Leukemic Presentation
      Marrow Hyperplasia and packed with Lymphoblast
      T-ALL
      Mediastinalthymic mass
      Often with LNadenopathy & Splenomegaly
      26
      Morphology
    • Lymphoblast in PBS
      DefinitveDx based on Lymphocyte –specific markers with Antibodies
      Histochemical stain
      Negative for myeloperoxidase
      Often (+) PAS in cytoplasmic aggregates
      Immunophenotype
      (+) TdT in > 95% of cases
      DNA polymerase
      Expressed only in pre-B and pre-T lymphoblast
      Morphology :
      27
    • 28
      Acute Lymphoblastic Leukemia
    • B-ALL lymphoblast (+)
      CD19, CD10, CD19, CD20
      T-ALL lymphoblast (+)
      CD1, CD2, CD5, CD7
      Arrest in normal Maturation of Lymphoblast
      Dysregulation in epxression and function of transcription factors
      29
    • About 90% ALL have numerical or structural chromosomal changes
      Most commonly – Hyperploidy
      > 50 chromosomes
      Hypoploidy
      Translocation
      Hyperploidy & Hypoploidy are seen only in B-ALL
      B & T ALL are associated wuth completely different sets of translocation
      30
      Molecular Pathogenesis
    • 70% of T-ALL
      Have gain-of-function mutations in NOTCH1
      NOTCH1 is essential for T-cell development
      High Fraction of B-ALL
      Have loss-of-function mutations in genes for B cell development
      NET EFFECT:
      1. Disturb differentiation of Lymphoid precursor
      2. Promote Maturation arrest
      Single mutations are not sufficient to produce ALL  Must Acquire additional mutation before ALL develop
      31
      Molecular Pathogenesis
    • Abrupt stormy onset
      Present w/in days to few weeks
      Symptoms r/t bone marrow suppression
      Anemia , Infection, Bleeding episodes
      Clinical Features :
      32
    • Mass Effects
      Bone pain & tenderness
      Generalized Lymphadenopathy, Splenomegaly, Hepatomegaly
      T-ALL
      Complications R/T complression of large vessels and Airways in mediastinum
      Both may have CNS manifestation
      Due to meningeal spread
      Headache, Vomiting, Nerve palsies
      Clinical Features :
      33
    • 34
    • Aggressive ChemoTx often w/ prophylactic CNS treatment
      > 95% of children achieve complete remission
      75-85% of choldren are Cured
      Still the leading cause of cancer death in children
      Treatment & Prognosis :
      35
    • Unfavorable Prognostic Factors
      < 2y/o
      Presentation in adolescence or childhood
      Peripheral blast count > 100,000
      Presence of Ph’ chromosome
      T(9;22)
      Commonly seen in adult patients
      ALLOGENIC BM TRANSPLANT – POOR PROGNOSTIC CATEGORIES
      36
    • Age 2-10 y/o
      Low WBC count
      Early pre-B phenotype
      Hyperploidy or t(12;21)
      Favorable Prognostic Factor
      37
    • Peripheral B cell Neoplasm- Neoplasm of Mature B cells
      38
      Chronic Lymphocytic Leukemia & Small Lymphocytic Lymphoma
      2. Follicular Lymphoma
      3. Diffuse Large Cell Lymphoma
      4. Extranodal marginal zone Lymphoma
      5. Burkitts Lymphoma
    • CHRONIC LYMPHOCYTIC LEUKEMIA –CLLand SMALL LYMPHOCYTIC LYMPHOMA- SLL
      39
    • Features
      Similar - Morphological, Phenotype, Genotype
      Differ only in degree of peripheral blood Lymphocytosis
      40
    • Features
      CLL – Chronic Lymphocytic Leukemia
      Most common leukemia of Adults in Western countries
      Median age 60 y/o
      2:1 male preponderance
      Diagnostic Criteria
      Absolute Lymphocytosis > 4000 per mm3
      PERIPHERAL BLOOD
      WBC counts is High
      Increased numbers of Small Lymphocytes
      Smudge cell
      41
    • Chronic Lymphocytic Leukemia
      42
    • Features
      SLL – Small Lymphocytic Lymphoma.
      Represent 4% of Non-Hodgkin Lymphoma
      Total WBC count is Variable
      If w/ Bone Marrow Involvement can present as Leukopenia
      LYMPH NODE
      Diffusely Effaced , Predominant Small Lymphocytes
      Variable large Prolymphocytes
      CREATE PROLIFERATION CENTERS
      PATHOGNOMONIC FOR CLL/SLL
      43
    • Small Cell Lymphoma
      44
    • Immunophenotype/ Molecular Genetics
      CD5 – present in tumor cells
      T-cell marker
      Expressed by small subset of normal B lymphos
      Chromosomal translocation is rare
      Most are Deletions
      13q14
      11q
      17p
      45
    • Clinical Features
      Mostly over 50 y/o
      Male > Female 2:1
      Often Asymptomatic
      Nonspecific symptoms when manifest
      BONE MARROW INVOLVEMENT
      All cases of CLL
      Most cases of SLL
      46
    • Clinical Features
      50-60% show
      Generalized Lymphadenopathy
      Hepatosplenomegaly
      VARIABLE INVOLVEMENT OF SPLEEN & HEPATIC PORTAL TRATS
      47
    • Clinical Features
      Disrupts Immune function
      Hypogammaglobulinemia – Susceptible to INFXN
      Autoimmune
      Auto-Antibodies produced by non-neoplastic B cells
      10-15% develop Hemolytic anemia /Thrombocytopenia
      48
    • Prognosis
      Extremely Variable
      Depend mostly on Stage
      Overall Median is 4-6 years
      Minimal Tumor burden  10 years
      49
    • Poor Prognostic Factors
      Presence of Deletions 11q & 17p
      Usually higher stage
      Transformation to higher grades
      Prolymphocytic 15%-30%
      Worsening cytopenias
      Increasing Splenomegaly
      Diffuse Large cell 5%-10%
      Rapidly enlarging mass w/in LN or spleen
      Richter syndrome
      Survival < 1 year
      50