WBC disorders

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WBC disorders
2013-04-03 02:15:55

WBC disorders
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  1. Hematopoiesis
    • Myeloid stem cells
    • → AML
    • Lymphoid stem cells
    • → ALL, CL
  2. Leukopenia
    WBC count <5,000

    • Usually due to one cell type:
    • 1. Neutropenia
    • -Cuase:drug toxicity - chemotherapy; severe infection
    • -Tx: GM-CSF or G-CSF (to boost granulocyte production)

    • 2. Lymphopenia
    • -Cause: immunodeficiency (DeGeorge, HIV); corticosteroids/cushing syndrome; autoimmune destruction (SLE); whole body radiation
  3. Leukocytosis
    • WBC > 10,000
    • Also usually due to one cell type:
    • 1. Neutrophilic leukocytosis:
    • -bacterial infection, tissue necrosis; high cortisol state

    • 2. Monocytosis
    • -chronic inflammatory states, malignancy

    • 3. Eosinophilia:
    • -allergic reactions (type I hypersensitivity), parasitic infections, Hodgkin lymphoma

    • 4. Basophilia
    • -chronic myeloid leukemia

    • 5. Lymphocytic leukemia
    • -viral infection; Bordetella pertussis infection
  4. Infectious mononucleosis
    • Cause:
    • -EBV infection → lymphocytic leukocytosis (reactive CD8+ T cells)
    • -CMV is less common cause

    • Effects of EBV:
    • -Oropharynx → pharyngitis
    • -liver → hepatitis, hepatomegaly, ↑ liver enzymes
    • -B cells

    • T cell response:
    • -Generalized lymphadenopathy
    • -Splenomegaly
    • -↑ WBC count with atypical lymphocytes

    • Complications:
    • -splenic rupture
    • -rash if exposed to ampicillin
    • -Recurrence, possibly B-cell lymphoma (especially if immunodeficient)
  5. Infectious mono
    • Monospot test:
    • -Detects IgM antibodies
    • -Usually turns positive after 1 week
    • -Negative monospot → possible CMV
  6. Acute leukemia
    • Proliferation of blasts - > 20% blast in bone marrow defines acute leukemia

    • Presentation:
    • -anemia (fatigue)
    • -thrombocytopenia (bleeding)
    • -neutropenia (infection)

    • Types:
    • -Acute lymphoblastic leukemia (ALL)
    • -Acute myelogenous leukemia (AML)
  7. Acute Lymphoblastic Leukemia (ALL)
    • Lymphoblasts (>20%) in the bone marrow
    • Positive nuclear staining for TdT (DNA polymerase)
    • Childhood neoplasia (after age 5)
    • Associated with Down syndrome
    • Subclass: B-ALL and T-ALL
  8. B-ALL
    • Most common type
    • Lymphoblasts (TdT+) that express CD10, CD19,CD20
    • Prognosis based on cytogenetics:
    • -t(12:21) has good prognosis - more common in children
    • -t(9:22) has poor prognosis - more common in adults ("Philadelphia+ ALL)
    • Tx: Excellent response to chemotherapy
  9. T-ALL
    • Lymphoblasts (TdT+) that express CD2-CD8 (no CD10)
    • Presentation: Teenagers, mediastinal (thymic) mass
    • aka acute lymphoblastic lymphoma bc cells form a mass
    • *T-ALL, Teenagers, Thymic mass
  10. Acute Myeloid Leukemia
    • Accumulation of myeloblasts (>20%)
    • Positive cytoplasmic staining for myeloperoxidase (MPO) - seen as Auer rods
    • Presentation: Adults (50-60yrs)
    • Subclass: cytogenetic abnormalities, lineage of myeloblasts, surface markers
    •      -Acute Promyelocytic Leukemia (APL)
    •      -Acute Monocytic Leukemia
    •      -Acute Megakaryoblastic Leukemia
    • Pre-existing dysplasia: myelodysplastic syndrome
  11. Myelodysplastic syndrome
    Can progress to AML, especially with exposure to alkylating agents or radiotherapy

    • Presentation:
    • -cytopenias
    • -hypercellular bone marrow
    • -abnormal maturation of cells
    • -increased blasts (<20%)

    *Most die from infection or bleeding; some progress to acute leukemia
  12. Acute promyelocytic leukemia (APL)
    • -t(15:17) - retinoic acid receptor (RAR) on chrom 17 → chrom 15
    • -Increase risk for DIC
    • Tx:
    • -all-trans-retinoic acid (ATRA) - a vitamin A derivative (causes blasts to mature)
  13. Acute monocytic leukemia
    • Proliferation of monoblasts
    • usually lack MPO
    • Blasts infiltrate gums
  14. Acute megakaryoblastic leukemia
    • Proliferation of megakaryoblasts
    • Lack MPO
    • Associated with Down syndrome (arises before the age of 5)
  15. Chronic leukemia
    • Proliferation of mature circulating lymphocytes
    • High WBC count
    • Insideous in onset
    • Older adults
    • Types:
    •      -Chronic Lymphocytic Leukemia (ALL)
    •      -Hairy Cell Leukemia
    •      -Adult T-Cell Leukemia/Lymphoma (ATLL)
    •      -Mycosis Fungoides
  16. Chronic Lymphocytic Leukemia (CLL)
    • Proliferation of naïve B cells that co-express CD5 and CD20
    • Most common leukemia overall

    • Blood smear: lymphoctes, smudge cells

    Can involve lymph nodes → generalized lymphadenopathy ("small lymphocytic lymphoma")

    • Complications:
    • -Hypogammaglobulinemia
    • -Autoimmune hemolytic anemia
    • -Transform to diffuse large B-cell lymphoma (Richter transformation)
  17. Hairy Cell Leukemia
    • Proliferation of mature B cells - hairy cytoplasmic processes
    • Positive for tartrate-resistant acid phosphatase (TRAP)
    • Features: splenomegaly; "dry tap" on bone marrow aspiration
    • Tx: 2-CDA (cladribine) (an adenosine deaminase inhibitor)
  18. Adult T-Cell Leukemia/Lymphoma (ATLL)
    • -Proliferation of mature CD4+ T cells
    • -Associated with HTLV-1 (Japan, Caribbean)

    • Features:
    • -rash
    • -generalized lymphadenopathy
    • -hepatosplenomegaly
    • -lytic (punched-out) bone lesions with hypercalcemia
  19. Mycosis Fungoides
    • Proliferation of mature CD4+ T cells that infiltrate the skin → localized rash, plaques, nodules
    • "Pautrier microabscesses"

    • *Cells can spread to involve the blood → Sezary syndrome
    • -Sezary cells: cerebriform nuclei on blood smear (lobes)
  20. Myeloproliferative disorders
    • Mature cells of myeloid lineage
    • Epidemiology: late adulthood (50-60yrs)
    • Presentation: high WBC count; hypercellular bone marrow; ↑ granuclocytes
    • Complications: hyperuricemia, gout; progression to marrow fibrosis or transform to acute leukemia
    • Types:
    • -Chronic myeloid leukemia
    • -Polycythemia vera
    • -Essential thrombocythemia
    • -Myelofibrosis
  21. Chronic Myeloid Leukemia (CML)
    • Proliferation of myeloid cells, especially granulocytes and their precursors
    • Basophils are characteristically increased
    • t(9:22) (Philadelphia chromosome) → BCR-ABL fusion protein (↑ tyrosine kinase activity)
    • Splenomegaly is common → suggests accelerated phase of disease
    • Tx: imatinib (blocks tyrosine kinase)
    • Complications: transform to AML (2/3 of cases) or ALL (1/3 of cases)
  22. CML vs leukemoid reaction (reactive neutrophilic leukocytosis)
    • CML:
    • -Negative leukocyte alkaline phosphatease (LAP) stain
    • -Increased basophils
    • -t(9:22)
  23. Polycythemia vera (PV)
    • Proliferation of mature myeloid cells, especially RBCs (↑ granulocytes, ↑ platelets)
    • JAK2 kinase mutation

    • Clinical presentationhyperviscosity of blood...
    • -Blurry vision and headache
    • -Increased risk of venous thrombosis (hepatic vein, portal vein, dural sinus)
    • -Flushed face due to congestion
    • -Itching

    Tx: phlebotomy; hydroxyurea

    • Distinguish from reactive polycythemia:
    • -PV → EPO levels are decreased, SaO2 is normal
    • -Reactive polycythemia (high altitude, lung disease) → SaO2 is decreased, EPO is high
    • -Reactive polycythemia (ectopic EPO production from RCC) → both EPO and SaO2 are high
  24. Essential Thrombocythemia (ET)
    • Proliferation of mature myeloid cells, especially platelets (↑ RBCs, ↑ granulocytes)
    • *JAK2 kinase mutation

    • Sxincreased risk of bleeding and/or thrombosis
    • -rarely progresses to marrow fibrosis or acute leukemia
    • -No significant risk for hyperuricemia or gout
  25. Myelofibrosis
    • Proliferation of mature myeloid cells, especially megakaryocytes
    • *JAK2 kinase mutation (50% of cases)
    • Megakaryocytes → excess platelet-derived growth factor (PDGF) causing marrow fibrosis
    • Clinical feature:
    • -Splenomegaly (extramedullary hematopoiesis)
    • -Leukoerythroblastic smear
    • -Increased risk of infection, thrombosis, bleeding
  26. Lymphadenopathy (LAD)
    • Painful LAD: acute infection (acute lymphadenitis)
    • Painless LAD: chronic inflammation, metastatic carcinoma, lymphoma
    •       → hyperplasia of particular regions:
    • 1. Follicular hyperplasia (B-cell region) seen in RA, early HIV infections
    • 2. Paracortex hyperplasia (T-cell region) seen in viral infections (mono)
    • 3. Hyperplasia of sinus histiocytes seen in LN that are draining cancer
  27. Lymphoma
    • Proliferation of lymphoid cells that form a mass; within LN or extranodul tissue
    • non-Hodgkin (NHL, 60%) vs Hodgkin lymphoma (HL, 40%)

    • NHL subclasses:
    • -Small B cells: follicular, mantle, marginal, small lymphocytic lymphoma (CLL cells that involve tissue)
    • -Intermediate-sized B cells: Burkitt lymphoma
    • -Large B cells: diffuse large B-cell lymphoma
  28. Non-Hodgkin Lymphoma
    • Malignant cells: Lymphoid cells
    • Composition of mass: lymphoid cells
    • Clinical presentation: Painless LAD, usually arises in late adulthood
    • Spread: diffuse; often extranodal
    • Staging: limited importance
    • Leukemic phase: occurs
  29. Hodgkin lymphoma
    • Malignant cells: Reed-Sternberg cells
    • Composition of mass: Predominantly reactive cells (inflammatory cells and fibrosis)
    • Clinical presentation: Painless LAD occasionally with 'B' symptoms; young adults
    • Spread: Contiguous; rarely extranodal
    • Staging: guides therapy; radiation is mainstay of tx
    • Leukemic phase: Does NOT occur
  30. Follicular lymphoma
    • Neoplastic proliferation of small B cells (CD20+)
    • Presentation: late adulthood, painless LAD

    • t(14:18) - BCL2 on chromosome 18 translocates to the Ig heavy chain on chromosome 14
    • → overexpression of Bcl2, which inhibits apoptosis

    • Treatment: only when symptomatic, low dose chemo or rituximab (anti-CD20 antibody)
    • Complication: preogression to diffuse large B-cell lymphoma

    • Follicular lymphoma vs reactive follicular hyperplasia:
    • -disruption of normal LN architecture
    • -lack of tingible body macrophages in germinal centers
    • -Bcl2 expression in follicles
    • -Monoclonality
  31. Mantle cell lymphoma
    Neoplasatic proliferation of small B cells (CD20+) that expands the mantle zone

    Presentation: late adulthood, painless LAD

    • t(11:14)
    • -Cyclin D1 gene on chromosome 11 translocates to Ig heavy chain locus on chromosome 14
    • -Overexpression of cyclin D1 promotes G1/S transition in cell cycle
  32. Marginal zone lymphoma
    Neoplasatic proliferation of small B cells (CD20+) that expands the marginal zone

    • Associated with chronic inflammatory states:
    • -Hashimoto thyroiditis
    • -Sjögren syndrome
    • -H pylori gastritis

    MALToma is marginal zone lymphoma in mucosal sites
  33. Burkitt lymphoma
    • Neoplastic proliferation of intermediate-size B cells (CD20+)
    • Associated with EBV
    • Presentation: extranodal mass in child or young adult (African → jaw; sporadic → abdomen)
    • t(8:14) → c-myc on chromosome 8 to the Ig heavy chain locus on chromosome 14
    • →overexpression of c-myc oncogene promotes cell growth
    • "Starry-sky" appearance
  34. Diffuse Large B-Cell Lymphoma
    • Neoplastic proliferation of large B cells (CD20+) that grow diffusely in sheets
    • Most common form of NHL
    • Clinically aggressive (high-grade)
    • Sporadically or from transformation of a low-grade lymphoma (follicular lymphoma)
    • Presentation: late adulthood as an enlarging lymph node or extranodal mass
  35. Hodgkin lymphoma
    • Neoplastic proliferation of Reed-Sternberg (RS) cells; large B cells with multilobed nuclei
    • Prominant nucleoli ('owl-eyed nuclei')
    • CD15 and CD30 positive

    • RS cells: secrete cytokines
    • -"B" symptoms (fever, chills, night sweats)
    • -Attract reactive lymphocytes, plasma cells, macrophages, eosinophils
    • -May lead to fibrosis

    • HL subtypesbased on reactive inflammatory cells (make up bulk of the tumor)
    • -Nodular sclerosis (most common)
    • -Lymphocyte-rich (best prognosis)
    • -Mixed cellularity (abundant eosinophils)
    • -Lymphocyte-depleted (most aggressive; seen in elderly and HIV-positive)
  36. Plasma cell disorders
    • Myltiple myeloma
    • Monoclonal gammopathy of undetermined significance (MGUS)
    • Waldenström macroglobulinemia
  37. Multiple myeloma
    • Malignant proliferation of plasma cells in the bone marrow
    • -Most common primary malignancy of bone
    • -High serum IL-6 is sometimes present (stimulates plasma cell growth and Ig production)

    • Clinical features:
    • -Bone pain with hypercalcemia (punched-out lesions, especially skull)
    • -Elevated serum protein (M spike; IgG or IgA most commonly)
    • -Increased risk of infection (antibodies lack antigenic diversity)
    • -Rouleaux formation of RBCs on smear
    • -Primary AL amyloidosis
    • -Proteinuria
  38. Monoclonal gammopathy of undetermined significance (MGUS)
    • Increased serum protein with M spike
    • other features of multiple myeloma are absent
    • Common in elderly (5% of 70 year olds)
    • 1% of pts with MGUS develop multiple myeloma each year
  39. Waldenström macroglobulinemia
    B-cell lymphoma with monoclonal IgM production

    • Clinical features:
    • -Generalized LAD (lytic bone lesions are absent)
    • -Increased serum protein with M spike
    • -Visual and neurologic deficits - IgM causes serum hyperviscosity
    • -Bleeding

    Tx: acute complications are treated with plasmapheresis, which removes IgM from the serum
  40. Langerhans cell histiocytosis
    • Langerhans cells are specialized dendritic cells, found predominantly in the skin
    • -from bone marrow monocytes
    • -Present antigen to naive T cells

    • Neoplastic proliferation of langerhans cells:
    • -Birbeck (tennis racket) granules are seen on em
    • -CD1a+ and S100+ by immunohistochemistry

    • Types:
    • -Letterer-Siwe disease
    • -Eosinophilic granuloma
    • -Hand-Schuller-Christian disease
  41. Letterer-Siwe disease
    • Malignant proliferation of Langerhans cells
    • Presentation: skin rash, cystic skeletal defects in an infant (<2 years old)
    • Multiple organs may be involved
    • rapidly fatal
  42. Eosinophilic granuloma
    • Benign proliferation of Langerhans cells in bones
    • Presentation: pathologic fracture in an adolescent
    • Skin is not involved
    • Bx: Langerhans cells with mixed inflammatory cells, eosinophils
  43. Hand-Schüller-Christian disease
    • Malignant proliferation of Langerhans cells
    • Presentation: scalp rash, lytic skull defects, diabetes insipidus, exopthalmos
    • Children (>3 years old)