Tuesday, November 21 (ellen)

Lymphoid and Hematopoetic System Pathology – November 21, 2006 White Cell Disorders A) Neoplastic Proliferations of White Cells ~ 3 general categories: ~ 1) Lymphoid neoplasms ~ 2) Myeloid neoplasms – from stem cells ~ 3) Histiocytic neoplasms – proliferative lesions of histiocytes (aka macrophages) Lymphoid Neoplasms ~ spread in lymph tissues ~ can be Hodgkin or Non-Hodgkin ~ will see Reed-Sternberg giant cells in Hodgkin lymphoma ~ 3 major categories: ~ 1) tumours of b cells (mainly see this type) ~ 2) T cells and NK cells ~ 3) Hodgkin lymphoma ~ all lymphoid neoplasms are from a single transformed cell and therefore monoclonal (all from 1 clone) Precursor B and T cell Lymphoblastic Leukemia/Lymphoma ~ aggressive ~ usually in young children and adults ~ usually have clinical appearance of acute lymphoblastic leukemia (ALL) Pathophysiology of ALL ~ Pre B and T cells differentiation blocked ~ therefore, get accumulation of pre B and T cell ~ get suppression of other normal hematopoietic cells (ie: WBC, RBC, and platelets) Small Lymphocytic Lymphoma and Chronic Lymphocytic Leukemia ~ these lymphomas are almost identical ~ if there is increase of circulating cells it’s CLL ~ if there is NOT an increase of circulating cells it’s SLL Pathophysiology of SLL/CLL ~ B cells doesn’t respond to antigenic stimulation ~ see suppressed B cells function ~ usually decrease in IgG (hypogammaglobulinemia) ~ see karyotypic abnormalities, usually trisomy 12 and deletion of chromosome 11 & 12 ~ CLL/SLL – accumulation of long-lived, nonfunctional B lymphocytes that infiltrate bone marrow, blood, lymph nodes, and other tissues Diffuse Large B-Cell Lymphoma ~ all share B-cell phenotype, a diffuse growth pattern, and an aggressive clinical hx

~ most important type of adult lymphoma – 50% of all non-Hodgkin lymphoma ~ 3 distinct subtypes ~ 1) EBV ~ 2) Herpes virus – cause many chronic ds ~ 3) mediastinal large B-cell lymphoma – in young females and spreads to CNS and abdomen Burkitt Lymphoma (Non-Hodgkin) ~ endemic ~ involves translocations of MYC gene in chromosome 8 ~ see mandibular enlargement Multiple Myeloma and Related Plasma Cell Dyscrasias ~ dyscrasias = improper cellular growth ~ B cell neoplasm ~ single clone of Ig secreting cells ~ monoclonal growth of Ig producing plasma cells ~ plasma cell ends up producing large amounts of a specific type of Ig ~ will crowd out development of all other Ig cells ~ homogeneous immunoglobulin in blood is called M component ~ aka monoclonal gammopathies Multiple Myeloma ~ m/c malignant plasma cell dyscrasias ~ clonal proliferation of neoplastic cells in bone marrow consequently crowding out other bone marrow cellular growth ~ see multifocal lytic lesions throughout the skeletal system ~ involved with translocation of IgG locus on chromosome 14 ~ most common M component of IgG ~ up to 80% of px will show both Bence-Jones proteins and serum M components Hodgkin Lymphoma ~ involves lymphoid tissue ~ single node or chain of nodes that spread to other nodes ~ characterized morphologically by presence of distinctive neoplastic giant cells called Reed-Sternberg cells ~ 4 subtypes: ~ 1) nodular sclerosis ~ 2) mixed cellularity ~ 3) lymphocyte predominance ~ 4) lymphocyte depletion (very rare) ~ basically the B cells in germinal centre have “gone crazy” ~suspect EBV as the etiologic agent ~ EBV genome can be see in RS cells up to 70% of cases Myeloid Neoplasms

~ myeloid cells – precursor cells of WBC, RBC, platelets ~ in hematopoetic stem cells ~ give rise to monoclonal proliferations that diffusely replace normal bone marrow cells ~ 3 general categories: ~ 1) acute myeloblastic leukemias – blocked early differentiation in myeloid cells ~ 2) chronic myeloproliferative disorder – go to last differentiation but have increase or messed up growth ~ 3) myelodysplastic syndromes – cells produced but don’t function properly Acute Myeloblastic Leukemia ~ increases steadily with age ~ marrow failure caused by replacement of normal marrow elements by leukemic blasts ~ diverse in terms of their predominant line of differentiation and the maturity of cells ~ number of recurrent cytogenetic abnormalities correlate well with outcome ~ greater chance of living if AML due to translocation between chromosome 8 and 21 or inversion of chromosome 16 Myelodysplastic Syndromes ~ cells differentiate but as they mature they become defective and do not give rise to right number of cells or the correctly functioning cells ~ they take over bone marrow and reduce ability of normal differentiation ~ bone marrow is hypercellular or normocellular but peripheral blood shows pancytopenia Chronic Myeloproliferative Disorders ~ increased proliferation of neoplastic bone marrow progenitors (stem cells) ~ these seed secondary hematopoietic organs (SP, LV, lymph nodes) and retain ability to terminal differentiate ~ 4 diagnostic entities: ~ 1) chronic myelogenous leukemia ~ 2) polycythemia vera ~ 3) myeloid metaplasia w/ myelofibrosis (self study) ~ 4) essential thrombocythemia (self study) Chronic Myelogenous Leukemia ~ unique chromosomal abnormality – Ph (Philadelphia) chromosome ~ Ph chromosome is a reciprocal translocation from long arm of chromosome 22 to long arm of chromosome 9 ~ Ph is highly characteristic, not diagnostic Polycythemia Vera ~ excess proliferation of everything from single neoplastic stem cell ~ 1) relative polycythemia – lost fluid, same number cells but less fluid to dilute it (hemoconcentration) ~ 2) absolute polycythemia – more cells in set amount of fluid (like a thick protein shake) ~ increase EPO

Histiocytic Neoplasms A) Langerhans Cell Histiocytosis ~ histiocytosis = proliferative disorders of histiocytes (aka macrophages) ~ 3 categories: ~ 1) Lettere-Siwe syndrome ~ 2) Hand-Schuller-Christian disease ~ 3) Eosinophilic granuloma ~ these three are basically different expressions of same basic disorder ~ Proliferating Langerhans cells are HLA-DR positive and express CD1 Ag ~ they also show characteristic HX bodies (Birbeck granules) in cytoplasm Bleeding Disorders ~ abnormal bleeding ~ causes of abnormal bleeding: ~ 1) defect in vessel wall ~ 2) platelet deficiency or dysfunction ~ 3) derangement of coagulation factors ~ 3 categories of bleeding disorders: ~ 1) increased fragility of vessels ~ 2) deficiencies of platelets ~ 3) derangement of blood clotting A) Disseminated Intravascular Coagulation ~ secondary complication in variety of disease ~ activation of coagulation sequence  formation of thrombi throughout microcirculation ~ consequence: widespread thromboses, consumption of platelet and coagulation factors, and activation of fibrinolysis ~ clotting is initiated with 1 of 2 pathways: ~ 1) extrinsic – involves thromboplastin ~ 2) intrinsice – involves factor XII ~ 2 major mechanisms can trigger DIC ~ 1) release of thromboplastin ~ 2) widespread injury to endothelial cells ~ most likely follows sepsis, obstetric complications, malignancy, and major trauma ~ shock, hypoxia, and acidosis often coexist ~ 2 consequences: ~ 1) too much fibrin deposition  ischemia ~ 2) bleeding diathesis B) Thrombocytopenia ~ thrombocyte = platelet ~ spontaneous bleeding, prolong bleeding time, and normal PT and PTT ~ see petechiae or large ecchymoses in skin and GI mucous membranes

~ decreased platelet production with forms of marrow failure or injury ~ one of m/c hematologic manifestations of AIDS ~ 4 causes: ~ 1) decreased production of platelets ~ 2) decreased platelet survival ~ 3) sequestration ~ 4) dilutional Coagulation Disorders ~ acquired: usually with deficiencies of multiple clotting factors (vit K def  needed for synthesis of prothrombin and clotting factors VII, IX, X) ~ also see parenchymal diseases of liver since liver is site of synthesis ~ hereditary: hemophilia A (Factor VIII), hemophilia B (Christmas disease), and von Willebrand Disease A) Deficiencies of Factor VII/von Willebrand Factor Complex ~ Factor VIII/vWF – made from 2 proteins ~ factor VII procoagulant protein – activates factor X in intrinsic pathway ~ vWF – helps platelet adhesion to damaged blood vessel walls ~ the complex together circulates in plasma and helps clot and helps platelet-blood vessel wall interactions to ensure hemostasis B) vON Willebrand Disease ~ decreased circulating vWF and since vWF stabilizes factor VIII, factor VIII decreases as well ~ see spontaneous bleeding, excessive bleeding, or prolonged bleeding ~ autosomal dominant disorder C) Factor VIII Deficiency – Hemophilia A, Classic Hemophilia ~ decreased Factor VIII ~ x-linked recessive trait ~ 30% of cases are new mutations and hence do not have a family history ~ spontaneous hemorrhages frequently seen in body regions normally subject to trauma – esp joints (aka hemarthroses) ~ petechiae are characteristically absent ~ treatment - infusion of Factor VIII D) Factor IX Deficiency – Hemophilia B, Christmas Disease ~ decreased factor IX ~ clinically indistinguishable from hemophilia A ~ X linked recessive trait ~ less common than Factor VIII Splenomegaly ~ usually secondary to changes elsewhere ~ massive, moderate, or mild

Thymus ~ central lymphoid organ ~ plays critical role in T-cell differentiation ~ two m/c disorders: thymic hyperplasias and thymomas A) Thymic hyperplasia ~ hyperplasia of thymus with lymphoid follicles in medulla ~ found in most px with myasthenia gravis and other autoimmune disorders ~ produce autoantibodies to Ach membrane receptors at neuromuscular junction leading to decreased muscular strength B) Thymoma ~ thymoma – tumours in which epithelial cells constitute the neoplastic element ~ lymphomas arising in lymphoid elements are NOT thymomas ~ benign or malignant ~ malignant type 1: cytologically benign but biologically aggressive – local invasion, but rarely spread ~ malignant type 2: thymic carcinoma: cytologically malignant with all features of CA