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