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Chapter 13 Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus


Chapter 13 Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus Acute Myeloid Leukemia Tumor of hematopoietic progenitors Caused by acquired oncogenic ... – PowerPoint PPT presentation

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Title: Chapter 13 Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus

Chapter 13Diseases of White Blood Cells, Lymph
Nodes, Spleen, and Thymus
Components of the Hematopoietic System
  • Myeloid Tissues
  • Bone marrow and cells derived from it
  • Lymphoid Tissues
  • Thymus, Lymph nodes, Spleen

Development and Maintenance of the Hemapoietic
  • Hemapoietic Stem Cells
  • Mesoderm
  • Migrate to the liver Chief site of blood cell
    formation until shortly before birth
  • At birth bone marrow throughout the skeleton is
    active and then liver shuts down
  • At puberty activity restricted to the axial

Figure 13-1 Differentiation of Blood Cells
  • The formed elements of blood have a common origin
    from HSCs
  • HSCs Essential properties
  • Pluripotency
  • Capacity for self-renewal
  • Can appear in peripheral blood during times of
    stress ( e.g. severe anemia)
  • Niches in other tissues unveiled
    extramedullary hematopoiesis
  • The marrow response to short-term physiologic
    needs regulated by hematopoietic growth factors
    through effects on committed progenitors
  • Many diseases alter the production of blood cells
  • Tumors of hematopoietic origin are often
    associated with mutations that block progenitor
    cell maturation or abrogate their growth factor
  • Leukoerythroblastosis abnormal release of
    immature precursors into the peripheral blood
  • Table 13-1 Adult reference ranges for blood cells
  • Nurse cells macrophages that supply iron to
    RBCs in BM
  • Normal fat to hempatopoeitic elements ratio 11

  • Neutropenia (granulocytopenia)
  • more common
  • agranulocytosis clinically significant
    reduction, severe infecitons when neutrophil
    count lt500/mm3
  • Inadequate or ineffective granulopoiesis
  • Suppression of HSCs
  • Suppression of committed granulocytic
    precursors by drugs most common cause
  • Disease states with ineffective hematopoiesis
  • Rare congenital conditions impairment of
    granulocytic differentiation (Kostmann
  • Accelerated removal or destruction of
  • Immunologically mediated injury
  • Splenomegaly
  • Increased peripheral utilization
  • Clinical features infection, malaise, chills,
    fever, weakness, fatigue
  • Lymphopenia
  • immunodeficiency diseases
  • Treatment with steroids, cytotoxic drugs
  • autoimmune disorders
  • Acute viral infections

  • Mechanisms of leukocytosis -Table 13-2
  • Increased production
  • Increased release from marrow stores
  • Decreased margination
  • Decreased extravasation into tissues
  • Types of leukocytosis Table 13-3
  • Neutrophils acute bacterial infections, tissue
  • Eosinophils allergic, parasitic, drugs,
    certain malignancies, collagen vascular
  • Basophils myeloproliferative
  • Monocytosis chronic infections, IBD
  • Lymphocytosis chronic infections, viral
    infections, pertussis
  • Reactive changes in sepsis or severe
    inflammatory disorders
  • Dohle bodies
  • Toxic granules
  • cytoplamic vacuoles
  • Leukomoid reaction

  • The activation of resident immune cells leads to
    morphologic changes in lymph nodes
  • Acute Nonspecific lymphadenitis painful, red,
  • Chronic Nonspecific lymphadenitis-nontender
  • Follicular hyperplasia (tingible-body
    macrophages B-cells, centroblasts/cytes)
  • Paracortical hyperplasia (T-cells)
  • Reticular hyperplasia ( sinus histiocytosis
    macrophage and dendritic cells)
  • Organized collections in non-immune tissues

Neoplastic Proliferation of WBCs
  • Lymphoid neoplasms- B-cells, T-cells, NK cells
  • Myeloid neoplasms Acute myeloid leukemias,
    myelodysplastic, myeloproliferative
  • Histiocytosis macrophages, dendritic cells,
    Langerhans cells

Overview of Etiologic and Pathogenetic Factors
  • Chromosome translocations and other acquired
  • Nonrandom chromosomal abnormalities, most
    commonly translocations, occur in the majority of
    white cell neoplasms
  • Mutated or altered genes often play critical
    roles in the development, growth, or survival of
    the normal counterparts of the malignant cells (
    e.g. MALTomas B-cell lymphoma of MALT1/BCL10
    constitutively activating NF-kB)
  • Oncoproteins created by genomic aberrations
    often block normal maturation (BCL6 need for
    germinal centers but turn off for maturation)
  • Proto-oncogenes are often activated in lymphoid
    cells by errors that occur during antigen
    receptor gene rearrangement and diverification (
    e.g. in germinal center B cells during antobody
    diversificaiton AID inducing translocations and
    lesions in DNA)
  • Inherited genetic factors
  • Bloom, Fanconi, Down, ataxia teleangectasia and
    type I NF
  • Viruses
  • HTLV-1, EBV, HHV-8
  • Chronic Immune stimulation (H. pylori, celiacs,
  • Iatrogenic factors (radiation therapy)
  • Smoking (AML)

Lymphoid Neoplasms
  • Lymphocytic leukemia vs lymphoma
  • Widespread involvement of the bone marrow and
    peripheral blood vs
  • Discrete tissue masses
  • Clinical presentations
  • Enlarged lymph nodes
  • Involvement of extranodal sites
  • Suppression of normal hematopoiesis
  • Secretion of circulating factors
  • Pain due to bone destruction

Lymphoid Neoplasms
  • Precursor B cell (immature B cells)
  • Peripheral B cell (mature B cells)
  • Precursor T cell (immature T cells)
  • Peripheral T cell amd NK cell ( mature cells)
  • Hodgkin lymphoma ( Reed-Sternberg cells)

Lymphoid Neoplasms
  • Histologic examination is required for diagnosis
  • Most of the time, antigen receptor gene
    rearrangement preceded transformation hence all
    of daughter cells share the same antigen receptor
    gene configuration
  • Vast majority are of B cell origin ( 85-90)
  • Often associated with immune abnormalities
  • Neoplastic B and T cells tend to behave like
    their normal counterparts (T-cells to skin and
    B-cells to germinal centers)
  • Hodgkin lymphoma spreads in an orderly fashion

  • 85 0f B-ALLs childhood acute leukemias
  • T-Alls less common, present as thymic lymphomas
    in adolescent males (lymphadenopathy and
  • ALL is the most common cancer of childhood
  • Must be distinguished from AML because of
    differing responses to chemotherapy (ALL
    myeloperoxidase negative)
  • TdT , starry sky, hypercellular

ALL Molecular Pathogenesis
  • 90 have numerical or structural chromosomal
    changes (hyperploidy)
  • Many of the chromosomal aberrations seen in ALL
    dysregulate the expression and function of
    transcription factors that are required for
    normal b and t cells development.
  • - T-cell GOF in NOTCH1, B-cell LOF in PAX5, EBF,
  • Single mutations are not sufficient to produce ALL

ALL Clinical Features
  • Abrupt stormy onset
  • Symptoms related to bone marrow suppression
  • Mass effect caused by neoplastic infiltration
    (testicular enlargement)
  • CNS manifestations

ALL Prognostic Factors
  • Worse prognosis
  • Age under 2 (MLL gene translocations)
  • Presentation in adolescence or adulthood
  • Peripheral blast counts gt100,000
  • Presence of particular cytogenic aberrations (Ph
  • 2 Adolescents in Philadelphia stole gt 100,000
  • Favorable prognosis
  • 2-10 years of age
  • low WBC count
  • hyperploidy
  • Trisomy of 4,7,10
  • Presence of t (1221)

  • Most common leukemia of adults in the Western
  • Proliferation centers are pathognomic
  • Smudge cells
  • Distinctive immunophenotype (CD19/20 and low
    IgM/D translocations rare, deletions common)

CLL/SLL Clinical features
  • Often asymptomatic at diagnosis
  • Nonspecific fatigue, weight loss, anorexia
  • Generalized lymphadenopathy
  • Hepatosplenomegaly
  • Disrupts normal immune function through uncertain
    mechanisms (hypogammaglobinemia, autoantibodes -gt
    anemia, thrombocytopenia)
  • Variable course and prognosis
  • Tendency to transform to more aggressive tumors
    Prolymphocytic and large-cell transformations
    (latter Richter syndrome) poor prognosis

Follicular lymphoma
  • Most common form of indolent NHL
  • Arises from germinal center B cells
  • Strongly associated with chromosomal
    translocations involving BCL2
  • Centrocytes (small cleaved cells) and
  • t(1418) overexpression of BCL2 (no apoptosis)
  • Clinical presentation
  • Painless, generalized lymphadenopathy
  • Histologic transformation to diffuse large B-cell

Diffuse large B-cell lymphoma
  • Most common form of NHL
  • Large cell size and diffuse pattern of growth
  • Dysregulation of BCL6
  • t(1418)
  • Immunodeficiency-associated large b-cell lymphoma
    in setting of T-cell immundeficiency EBV
  • Primary effusion lymphoma KSHV/HHV-8
  • Clinical features
  • Typically presents as a rapidly enlarging mass
    at a nodal or extranodal site (waldeyer ring
    commonly affected)
  • Aggressive

Burkitt Lymphoma
  • African (endemic)
  • Sporadic (nonendemic)
  • Aggressive subset in HIV
  • Starry sky pattern high mitotic index and
    numerous apoptotic cells
  • Translocations of the c-MYC gene on Chromosome 8
  • Essentially all endemic tumors are infected with
  • Clinical features
  • most present as tumor at extranodal site
  • - Endemic mandible, ab viscera
  • - Sporadic ileocecum, peritoneum

Plasma cell neoplasms and related disorders
  • Secrete a monoclonal Ig or Ig fragment
  • Most common and deadly is multiple myeloma
  • Often synthesize excess light or heavy chains
    along with complete Igs (M component)
  • Bence-Jones proteins

Monoclonal gammaopathies
  • Multiple myeloma
  • Waldenstrom macroglobulinemia (high Igm,
  • Heavy-chain disease
  • Primary or immunocyte-associated amyloidosis
  • Monoclonal gamopathy of undetermined significance
    (most common pasma cell dyscrasia asymptomatic,
    M protein lt 3)

Multiple myeloma
  • Multifocal involvement of the skeleton
  • The Ig genes in myeloma cells show evidence of
  • The proliferation and survival of myeloma cells
    are dependent are several cytokines, particularly
  • Factors produced by the neoplasti plasma cells
    mediate boney destruction
  • Rearrangements involving the Ig heavy chain gene
    of Chromosome 14q32
  • Axial skeleton
  • Punched-out defects 1-4 cm in diameter
  • Plasmablasts, Flame cells, Mott cells, Russell
    bodies (cytoplasmic), Dutcher bodies (nuclear)
  • Rouleaux formation, Myeloma kidney
  • Clinical features
  • Bone resorption leading to pathologic fractures
    and hroni pain
  • Hypercalcemia
  • Recurrent bacterial infections
  • Renal insufficiency
  • SPE M protein
  • Anemia (CRAB)
  • Solitary Myeloma (Plasmacytoma) Smoldering
    Myeloma (asymptomatic, M protein gt 3)

Lympoplasmacytic Lymphoma
  • Plasma cell component secretes monoclonal IgM
    leading to hyperviscosity syndrome _ Waldenstrom
  • Clinical features
  • weakness, fatigue, weight loss
  • lymphadenopathy, hepatosplenomegaly
  • Anemia, auto-immune hemolysis caused by cold
  • hyperviscosity syndrome
  • Visual impairment
  • neurologic problems
  • Bleeding
  • Cryoglobulinemia
  • Incurable, plasmapheresis

Mantle Cell Lymphoma
  • Tumor cells closely resemble the normal mantle
    zone B cells that surround germinal centers
  • Express high levels of cyclin D1
  • t(1114)
  • Small lmphocytes with cleaved contours
  • Painless adenopathy

Marginal Zone Lymphomas
  • Maltomas
  • Often arise in areas of chronic inflammation (h.
  • Remain localized for prolonged periods
  • May regress if inciting agent is eradicated
  • Continuum between reactive lymphoid hyperplasia
    and full-blown lymphoma
  • Up regulations of BCL10/MALT1

Hairy Cell Leukemia
  • Dry tap
  • Spenomegaly, pancytopenia, infections
  • Indolent course, excellent prognosis
  • Pale blue cytoplasm

Peripheral T-cells and NK-Cell Neoplasms
  • Peripheral T-cell lymphoma, unspecified
    (malignant T cells infiltrate of reactive cells)
  • Anaplastic Large-cell lymphoma ALK gene,
    hallmark cell (horse-shoe shaped nuclei involve
    soft tissues, good prognosis)
  • Adult T-cell leukemia/lymphoma- CD4cells, HTLV-1
    (cloverlef, flow cells)
  • Mycosis fungoides/Sezary Syndrome
  • CD4helper Tell tumor, homes to the skin (CLA
    and CCR4/10)
  • Sezary syndrome generalized exfolaitive
  • Large granular lymphocytic leukemia
  • neutropenia and anemia, Increased rheumatologic
    disorders large lymphocytes with abundant blue
  • Felty syndrome rheumatoid arthritis,
    neutropenia, splenomegaly
  • Extranodal NK/Tcell Lymphoma
  • Destructive nasopharyngeal mass, surrounds and
    invades blood vessels leading to ischemic necrois
  • associated with EBV

Hodgkin Lymphoma
  • HL arises in a single node or chain of nodes and
    spreads first to anatomically contiguous lymphoid
  • Staging is very important in guiding therapy
  • Reed-Sternberg cells
  • WHO classification
  • Nodular sclerosis-
  • Mixed cellularity- -Classical forms RS CD30/15
  • Lymphocyte-rich-
  • Lymphocyte depletion-
  • Lymphocyte predominance

Hodgkin Lymphoma
  • Nodular Sclerosis
  • Lacunar variant RS cells
  • Collagen bands that divide lymph nodes into
    circumscribed nodules
  • Mixed-cellularity
  • T cells, eosinophils, plasma cells, macrophages,
    RS cells, EBV
  • Lymphocyte-rich
  • Reactive lymphocytes most of cellular
    infiltrate, EBV
  • Lymphocyte depletion
  • Paucity of lymphocytes, EBV
  • Lymphocyte predominance
  • Non-classical RS cells- LH variants (popcorn

Hodgkin Lymphoma
  • Clinical features
  • Painless lymphadenopathy
  • Constitutional symptoms fever, night sweats,
    weight loss
  • Cutaneous anergy
  • Staging Table 13-9
  • Secondary Cancers

Myeloid Neoplasms
  • The common feature of this group is origin from
    hematopoietic progenitor cells
  • Primarily involve the bone marrow
  • Usually present with altered hematopoiesis
  • Acute myeloid leukemia
  • Myelodysplastic syndromes
  • Myeloproliferative disorders
  • Manifestations due to
  • The position of the transformed cell within the
    hierarchy of progenitors
  • The effect of the transporting events on

Acute Myeloid Leukemia
  • Tumor of hematopoietic progenitors
  • Caused by acquired oncogenic mutations that
    impede differentiation
  • Leading to accumulation of immature myeloid
    blasts in the marrow
  • Leading to marrow failure
  • Neutropenia,anemia, thrombocytopenia
  • Incidence peaks after 60 years

  • Diagnosis
  • gt 20 myeloid blasts in bone marrow
  • Auer rods
  • Immunophenotype helps distinguish myeloblasts
    from lymphoblasts myeloperoxidase positive
  • Cytogenetics central role in classification
  • Many recurrent genetic aberrations seen in AML
    disrupt genes encoding transcription factors that
    are required for normal differentiation
  • Evidence that mutated tyrosine kinases
    collaborate with transcription factors to produce
  • t(1517) respond to all-trans retinoic acid)
  • Most patients present with anemia, neutropenia,
  • Fever, fatigue, mucosal and cutaneous bleeding

Myelodysplastic Syndromes
  • Group of clonal stem cell disorders characterized
  • maturation defects
  • ineffective hematopoiesis
  • high risk of transformation to AML
  • Disordered differentiation
  • ringed sideroblasts RBCs, megaloblastic
    maturation platelets, nuclear budding
    abnormalities, Pseudo-Pelger-Huet cells
    neutrophils, pawn ball megakarocytes, myeloid
    blasts usually less than 10

Myeloproliferative Disorders
  • Common features
  • mutated tyrosine kinase
  • increased proliferative drive in the bm
  • Extra medullary hematopoiesis
  • Variable transformation to spent phase
  • Variable transformation to acute leukemia

Myeloproliferative Disorders
  • CML
  • Polycythemia vera
  • Essential thrombocythemia
  • Primary myelofibrosis
  • Systemic mastocytosis
  • Chronic eosinophilic leukemia
  • Stem cell leukemia

  • Chimeric BCR-ABL gene
  • Ph chromosome t (922) (q34q11)
  • Adults, 4500 new cases per year
  • Hypercellular marrow
  • WBC gt100,000
  • Splenomegaly (extramedullary hematopoeisis)
  • Insidious onset, slow progression
  • Blast crisis
  • Mutations in Ikaros

Polycythemia Vera
  • Increased RBCs cause the most symptoms
  • Low erthropoietin
  • Increased blood viscosity
  • Bleeding and thrombosis
  • Point mutations in JAK2

Essential thrombocytosis
  • Abnormally large platelets in peripheral smear
  • Dysfunctional platelets (thrombosis and
  • Erthromelalgia (throbbing and burning of hands
    and feet)
  • Mutations in JAK2 or MPL

Primary myelofibrosis
  • Development of obliterative marrow fibrosis
  • Extramedullary hematopoiesis
  • Leukoerthroblastosis
  • Teardrop-shaped red cells
  • Increased uric acid ? gout
  • Nonspecific symptoms due to increased metabolism
  • Jak2 and MPL mutations must have bone marrow

Langerhans cell histiocytosis
  • Birbeck granules in the cytoplasm
  • Letterer-Siwe Disease (multifocal)
  • seborrheic like skin eruption
  • Eosinophilic granuloma
  • Unifocal bone
  • Multifocal
  • Hand-Schuller-Christian Triad
  • DI, exophthalmos, calvarial boney defects
  • Pulmonary Langerhans cell histiocytosis
  • Adult smokers
  • Regresses when smoking is stopped

  • Filter for the blood
  • Site of immune responses to blood borne
  • pathogens
  • Functions
  • Phagocytosis of blood cells and particulate
  • Antibody production
  • Hematopoiesis
  • Sequestration of formed blood elements
  • No spleen
  • Hib, pneumococcus, meningococcus
  • Spenomegaly
  • Infections
  • Congestive states (cirrhosis is the main cause,
    also portal vein thrombosis
  • Lymphohematogeneous disorders
  • Immunological
  • Storage diseases
  • Misc
  • Infarcts- bland or septic (bland are subcapsular,
    wedge-shaped septic infarcts have suppurative
  • Accessory spleens

  • Third, sometimes fourth pharyngeal pouch
  • Hassall corpuscles
  • Tcells
  • Thymic hypopasia (DiGeorge syndrome 22q11, cysts)
  • Thymic hyperplasia (myasthenia gravis -gt myoid
  • Thymomas- MG, other autoimmune
  • 40 present because of impingement on other
    mediastinal structures