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NON-NEOPLASTIC DISORDERS OF GRANULOCYTIC WBCS. Qualitative Disorders:Defective chemotaxis or random migration is associated with clinical syndromes generally characterized by deficient resistance to infection and specifically by deficient cellular defenses. These abnormalities are classified as ab


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1. NON-NEOPLASTIC DISORDERS OF GRANULOCYTIC WBCS Non-neoplastic white blood cell disorders can be generally classified as either qualitative or quantitative.

2. NON-NEOPLASTIC DISORDERS OF GRANULOCYTIC WBCS Qualitative Disorders: Defective chemotaxis or random migration is associated with clinical syndromes generally characterized by deficient resistance to infection and specifically by deficient cellular defenses. These abnormalities are classified as abnormalities of chemotactic factors or abnormalities of cell response.

3. Qualitative Defects rare but: Requirements for normal granulocyte release All of the granules must be intact

4. Qualitative Defects Examples of abnormalities of cell response Chediak-Higashi syndrome: The basic abnormality is unknown. It is postulated that there is a microtubular defect accounting for fusion of the granules. Consequently, granulocytes have huge, nonfunctional granules. Lazy Leukocyte Syndrome: When subjected to an infection, patients fail to show an adequate chemotactic response, but are still able to kill the microorganisms. Protracted bacterial infections are common in these patients. Abnormal Chemotactic Migration: Observed in patients with (congenital or acquired) hypogammaglobulinemia, diabetes mellitus, rheumatoid arthritis and neoplasms Abnormal Phagocytosis: Common in any viral infection, and in patients with sickle cell disease or chronic granulomatous disease (CGD)

5. Qualitative Defects Abnormalities of Chemotaxis Substrate deficiencies Complement component deficiencies, esp. C3, C5a and C567 Kinin-generating system: Factors XII & XIII Inhibition of complement activation: Patients with liver cirrhosis, autoimmune disorders (SLE) Inhibition of chemotactic factors (not complement related): Prototype is Hodgkin's disease; Sezary syndrome, Wiskott-Aldrich syndrome

6. QUANTITATIVE DISORDERS OF GRANULOCYTIC WBCS Marrow responses to increased need Increased activity in stem cell compartment (circulating and in marrow) Increased mitotic activity in proliferative compartment (bone marrow) Shortened generation time, it results in increased numbers of band neutrophils (to 10-15% of total leukocytes); this change in the differential count is referred to as a "shift to the left" meaning an increase in less mature cells in the periphery. Accelerated bone marrow transit time Accelerated release from bone marrow

7. QUANTITATIVE DISORDERS OF GRANULOCYTIC WBCS Note: When the bone marrow is stimulated because of a decrease in a blood cell, it usually responds by all five mechanisms at once.

8. Absolute vs. relative increases in the number of WBCs (granulocytosis) Relative increase in cells: The proportion of cells is increased but the actual total number of cells is normal. Absolute increase: The total number of cells is increased; the percentage of the cell line may be normal or increased, depending on the total WBC count

9. Non-Neoplastic Causes of Granulocytopenia or Neutropenia Infections can also decrease the number of WBCs. The important ones: influenza, measles, hepatitis, infectious mononucleosis, miliary TB, septicemia Hemopoietic disorders: pernicious anemia, aplastic anemia, aleukemic leukemia, hypersplenism, Gaucher's disease

10. Non-Neoplastic Causes of Granulocytopenia or Neutropenia Chemical agents: sulfonamides, antibiotics, antihistaminics, analgesics, anticonvulsants (esp. dilantin), antithyroid drugs, quinine, pronestyl, barbiturates, chlorpromazine, colchicine Miscellaneous: ionizing radiation, SLE, cyclic neutropenia

11. Leukemia A bone marrow based disease, which involves the peripheral blood secondarily. The pathogenetic hallmark of acute leukemia is the morphologic and functional arrest of a cell at the earliest state of differentiation-----the blast stage.

12. Leukemia It will proliferate, fill up the morrow, obliterate normal hematopoiesis, but it won't mature. Because the leukemic blasts fill the marrow space and suppress normal hematopoiesis, the presence of normal cells in the peripheral blood (red blood cells, granulocytes, and platelets) is decreased.

13. Leukemia In chronic leukemia, the leukemic cells are not arrested morphologically at an early stage. They are able to proliferate and mature morphologically, and yet they are clonal, do not function as normal cells, have escaped normal negative feedback inhibitory growth controls, and are, therefore, malignant.

14. Leukemia Myelogenous: acute & chronic myeloid leukemia Lymphocytic: acute & chonic lymphocytic leukemia

15. Acute myeloid leukemia precursor lesion: myelodysplasia --acquired stem cell abnormality which produces abnormal myeloid maturation and peripheral blood cytopenias. Over time, frequent progression to AML as genetic lesions accumulate

16. Acute myeloid leukemia bone marrow damage: benzene, irradiation, chemotherapeutic agents ,often unknown acquired chromosomal abnormalities which occur in myeloid progenitor cells that arrest maturation and promote proliferation; associated with most forms of AML, e.g. t(8;21), t(15;17), inv(16); often involve translocation of oncogenes. occurs any age, peaks in adults

17. Acute myeloid leukemia laboratory findings peripheral blood normochromic normocytic anemia low reticulocyte count thrombocytopenia total white cell count can be low, normal or elevated; blasts are detected in peripheral blood; frequent neutropenia

18. Acute myeloid leukemia (AML) Bone marrow findings: hypercellular (typically) due to proliferation of leukemic blasts; little normal hematopoiesis greater than 20% blasts (some with Auer rods) cytochemistry: Sudan Black B positivity in blasts flow cytometry: blasts express myeloid antigens (CD13, CD33, etc.)

19. Bone marrow: normal vs AML

20. Acute myeloid leukemia MO - AML without maturation M1 - AML with minimal maturation M2 - AML with maturation M3 - Acute Progranulocytic Leukemia M4 - Acute Myelomonocytic Leukemia M5 - Acute Monocytic Leukemia M6 - Erythroleukemia M7 - Acute Megakaryocytic Leukemia

21. Chronic myeloid leukemia(CML) A form of chronic myeloproliferative disease(CMD) A group of disorders in which a common hematopoietic stem cell gives rise to clonal populations of granulocytes, erythrocytes, megakaryocytes and occasionally lymphocytes.

22. Chronic myeloid leukemia(CML) The cell type that predominates gives rise to the specific clinicopathologic syndrome. The marrows become variably fibrotic in these diseases, but the fibroblasts are not part of the malignant clone.

23. Chronic myeloid leukemia(CML) The long term outcome of these syndromes is either 1) bone marrow failure secondary to progressive marrow fibrosis 2) transformation to acute leukemia.

24. Chronic myeloid leukemia(CML) It is important to emphasize that although these syndromes are stem cell disorders, in these diseases the abnormality does not arrest maturation (as it does in acute leukemia). In chronic MPD, the abnormality allows the cells to proliferate and mature while escaping normal feedback inhibitory growth signals.

25. Chronic myeloid leukemia(CML) Types: chronic myelogenous leukemia polycythemia rubra vera essential or primary thrombocythemia chronic idiopathic myelofibrosis

26. Chronic myeloid leukemia(CML) CML: clinical disease of middle age (40 - 50) weakness and fatigue, slow onset splenomegaly, often massive bleeding may be asymptomatic at diagnosis

27. Chronic myeloid leukemia(CML) CML: pathogenesis Philadelphia chromosome (Ph1) - t(9;22); in this translocation, the c-abl oncogene is moved to a very specific location on chromosome 22. Other factors: irradiation, toxic agents (benzene)

28. Ph chromosome

29. CML Lab. findings leukocytosis, usually over 50,000; neutrophils, granulocyte precursors (especially myelocytes), basophils and eosinophils; may be difficult to distinguish from reactive leukocytosis thrombocytosis early, thrombocytopenia late in disease normochromic, normocytic anemia with nucleated erythrocytes and Howell-Jolly bodies (nuclear remnants) leukocyte alkaline phosphatase: low

30. CML Lab. findings bone marrow (may be nondiagnostic because of overlap with reactive granulocytic hyperplasia): hypercellular increased myeloid: erythroid ratio (e.g., 10:1; normal 3-4:1) clusters of megakaryocytes

31. CML: course of disease chronic phase: median of three years with treatment, usually no new cytogenetic abnormalities. accelerated phase: 5 to 20% blasts in the marrow; marked by increasing basophilia, thrombocytosis, leukocytosis, anemia, splenomegaly and marrow fibrosis; new cytogenetic abnormalities appear blastic phase: greater than 20% blasts in marrow. 2/3 of blast phase - myeloid blasts 1/3 of blast phase - lymphoid blasts

32. Lymphocytic Leukemia Acute (ALL) mainly a disease of children survival rate greatly improved: about 90% achieve first remission, about 50% to 75% are long-term survivors occurs in adults, but survival is much worse in that patient population

33. Clinical of ALL pallor and fever lethargy purpura and petechiae mild lymphadenopathy and splenomegaly central nervous system involvement can occur some subtypes of ALL associated with a clinicopathologic syndrome, i.e., T-ALL: mediastinal mass; high white count B-ALL: abdominal mass (in U.S.)

34. ALL pathogenesis-- unknown; many cases and subtypes associated with cytogenetic abnormalities; some familial cases; irradiation

35. ALL laboratory features peripheral blood normochromic, normocytic anemia thrombocytopenia leukocyte count can be low, normal or high; 50% of cases present with low or normal counts blasts appear in peripheral blood

36. ALL bone marrow hypercellular greater than 20% blasts, often greater than 90% cytochemistry: Sudan Black B negative in blasts little maturing hematopoiesis blasts contain an enzyme, terminal deoxynucleotidyl transferase (TDT), which is very specific for lymphoblasts three morphologic subtypes: L1, L2, L3

37. Bone marrow:Normal vs ALL

38. ALL course of disease after diagnosis, patients are treated with chemotherapeutic agents (distinct from those used in AML); many children achieve long lasting remissions and are cured; adults frequently relapse and bone marrow transplantation is a possible treatment option.

39. CLL Chronic (CLL) Clinical findings disease of the elderly (greater than 60 years of age) M:F ratio is 2:1 occasionally asymptomatic and discovered incidentally symptoms may occur relating to anemia: weakness and fatigue Lymphadenopathy:usually mild hepatomegaly prolonged course

40. CLL pathogenesis unknown; some cytogenetic abnormalities noted: Trisomy 12 T CLL t(8;14) c-myc oncogene not associated with irradiation exposure

41. CLL laboratory features mild to severe anemia mild to severe thrombocytopenia lymphocytosis , at least greater than 5000/cumm (5 x 109/L), but usually much higher, up to 200,000/cumm (200 x 109/L) morphologically, lymphocytes are small, round, mature-appearing cells (but are malignant)

42. CLL bone marrow heavy infiltration by lymphocytes variable amount of remaining hematopoiesis hemolytic anemia may occur, in which case, erythroid hyperplasia can be seen in the marrow Hypogammaglobulinemia immunophenotyping B CLL 95-98% T CLL 2-5%

43. CLL course of disease many long-term survivors (six years or longer); may terminate in Richter's syndrome (large cell lymphoma, resulting from morphologic dedifferentiation of the small lymphocytes of CLL) prolymphocytic transformation (leukemic process in which CLL cells transform into large lymphocytes with prominent nucleoli); both Richter's syndrome and prolymphocytic transformation are aggressive events and imply short survival

44. Malignant Lymphoma Solid tumors of the hematopoietic system nonHodgkin's lymphoma Hodgkin's disease

45. NON-HODGKIN'S LYMPHOMA Pathologic Diagnosis -- Malignancy of lymphocytes, either B or T cell type. (most, however, are of B lymphocytes) destruction or distortion of normal lymph node architecture morphologically, predominance of one lymphocyte cell type pattern of involvement: nodular or diffuse

46. NON-HODGKIN'S LYMPHOMA Clinical wide range of ages; although most occur in late middle age (50's - 60's); from childhood to elderly; nodular lymphoma rare in those less than 30 years localized or generalized painless lymphadenopathy; 1/3 of cases extranodal may have toxic symptomatology; fever, night sweats, weight loss may see hepatosplenomegaly when nonHodgkin's lymphomas disseminate, they primarily spread to other hematologic sites, i.e., other lymph nodes, bone marrow, spleen

47. NON-HODGKIN'S LYMPHOMA Pathogenesis viral associated:   Burkitt's lymphoma  Epstein Barr  adult T cell lymphoma/leukemia  HTLV I cytogenetic abnormalities follicular lymphomas t(14;18)  bcl-2 oncogene

48. NON-HODGKIN'S LYMPHOMA more common in immunosuppressed (AIDS, exogenous immunosuppression, etc.): When the T cell arm (CMI) is impaired, the lack of control and downregulation of the B cell response to antigen allows exuberant B cell proliferation. At first this is polyclonal, but as mutations begin to occur in the proliferating cells, small clones (oligoclones) are created. With further unchecked proliferation and additional mutations, a monoclonal population of B lymphocytes is produced

51. Hodgkin’s disease Characterized by neoplastic giant cell called Reed-Sternberg (RS) cell Etiology: Unknown Monoclonal but diverse origin ( can B or T cell) Not of monocyte-macrophage Dysregulation rather than transformation EBV in 40-50% of cases and also EBV genome RS cell ? IL-5 ? eosinophils

52. RS cell

53. Hodgkin’s disease Clinical course: Painless enlargement of L.N. Stage I / II ,usually young paients without systemic manifestations Stage III/IV :fever, Wt. loss, pruritus, anemia

54. Treatment of lymphoma chemotherapy Radiation Steroids Stem cell transplantation

55. Plasma cell dyscrasia Multiple myeloma(MM) Solitary myeloma Waldenstrom macroglobulinemia Heavy-chain disease Primary amyloidosis Monoclonal gammopathy

56. MM Most common malignant Clonal proliferation of neoplastic plasma cell (myeloma cell)in B.M. + multifocal lytic lesions throughout the skeletal system Triggered by IL-6 from fibroblasts & macrophages in B.M. High serum IL-6 Bence Jones protein in urine

57. Punch out lesion in MM

58. Gross pathology of MM

59. B.M. biopsy in MM

60. Clinical of MM Peak 50-60 years Bone pain Pathological fracture Hypercalcemia Recurrent infections Hyperviscosity syndrome Renal insufficiency Amyloidosis

61. Histiocytoses Proliferative disorders of histiocytes or macrophages Langerhans’ cell histiocytosis: clonal proliferation of dendritic antigen-presenting cells Acute disseminated Langerhans’ cell histiocytosis Unifocal Langerhans’ cell histiocytosis Multifocal Langerhans’ cell histiocytosis

62. Langerhans’ cell histiocytosis Acute : < 2 years of age, cutaneous lesion, hepatosplenomegaly, pulmonary lesions osteolytic bone lesions, anemia, thrombocytopenia, recurrent infections Unifocal: skeletal lesions, asymptomatic to pain and tenderness, fracture Multifocal: children, fever, diffuse eruption, URI, lymphadenopathy, hepatosplenomegaly, DI, exophthalmos

63. Treatment Acute: rapidly fatal if untreated, chemoRx ?50% 5 yr. survival Unifocal : spontaneous remission or local excision or irradiation Multifocal:Spontaneous remission or chemotherapy

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