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

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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


1
Chapter 13Diseases of White Blood Cells, Lymph
Nodes, Spleen, and Thymus
2
Components of the Hematopoietic System
  • Myeloid Tissues
  • Bone marrow and cells derived from it
  • Lymphoid Tissues
  • Thymus, Lymph nodes, Spleen

3
Development and Maintenance of the Hemapoietic
Tissues
  • 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
    skeleton

4
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
    dependence
  • 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

5
Leukopenia
  • 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
    Syndrome)
  • Accelerated removal or destruction of
    neutrophils
  • 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

6
Leukocytosis
  • 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
    necrosis
  • 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

7
Lymphadenitis
  • The activation of resident immune cells leads to
    morphologic changes in lymph nodes
  • Acute Nonspecific lymphadenitis painful, red,
    absecesses
  • 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

8
Neoplastic Proliferation of WBCs
  • Lymphoid neoplasms- B-cells, T-cells, NK cells
    origin
  • Myeloid neoplasms Acute myeloid leukemias,
    myelodysplastic, myeloproliferative
  • Histiocytosis macrophages, dendritic cells,
    Langerhans cells

9
Overview of Etiologic and Pathogenetic Factors
  • Chromosome translocations and other acquired
    mutations
  • 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,
    HIV)
  • Iatrogenic factors (radiation therapy)
  • Smoking (AML)

10
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

11
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)

12
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

13
ALL
  • 85 0f B-ALLs childhood acute leukemias
  • T-Alls less common, present as thymic lymphomas
    in adolescent males (lymphadenopathy and
    splenomegaly)
  • 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

14
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,
    E2A
  • Single mutations are not sufficient to produce ALL

15
ALL Clinical Features
  • Abrupt stormy onset
  • Symptoms related to bone marrow suppression
  • Mass effect caused by neoplastic infiltration
    (testicular enlargement)
  • CNS manifestations

16
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
    chromosome)
  • 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)

17
CLL/SLL
  • Most common leukemia of adults in the Western
    world
  • Proliferation centers are pathognomic
  • Smudge cells
  • Distinctive immunophenotype (CD19/20 and low
    IgM/D translocations rare, deletions common)

18
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

19
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
    Centroblasts
  • t(1418) overexpression of BCL2 (no apoptosis)
  • Clinical presentation
  • Painless, generalized lymphadenopathy
  • Histologic transformation to diffuse large B-cell
    lymphoma

20
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

21
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
    t(8,14)
  • Essentially all endemic tumors are infected with
    EBV
  • Clinical features
  • most present as tumor at extranodal site
  • - Endemic mandible, ab viscera
  • - Sporadic ileocecum, peritoneum

22
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

23
Monoclonal gammaopathies
  • Multiple myeloma
  • Waldenstrom macroglobulinemia (high Igm,
    hyperviscosity)
  • Heavy-chain disease
  • Primary or immunocyte-associated amyloidosis
  • Monoclonal gamopathy of undetermined significance
    (most common pasma cell dyscrasia asymptomatic,
    M protein lt 3)

24
Multiple myeloma
  • Multifocal involvement of the skeleton
  • The Ig genes in myeloma cells show evidence of
    hypermutation
  • The proliferation and survival of myeloma cells
    are dependent are several cytokines, particularly
    IL-6
  • 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)

25
Lympoplasmacytic Lymphoma
  • Plasma cell component secretes monoclonal IgM
    leading to hyperviscosity syndrome _ Waldenstrom
    macroglobulinemia
  • Clinical features
  • weakness, fatigue, weight loss
  • lymphadenopathy, hepatosplenomegaly
  • Anemia, auto-immune hemolysis caused by cold
    agglutinins
  • hyperviscosity syndrome
  • Visual impairment
  • neurologic problems
  • Bleeding
  • Cryoglobulinemia
  • Incurable, plasmapheresis

26
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

27
Marginal Zone Lymphomas
  • Maltomas
  • Often arise in areas of chronic inflammation (h.
    pylori)
  • 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

28
Hairy Cell Leukemia
  • Dry tap
  • Spenomegaly, pancytopenia, infections
  • Indolent course, excellent prognosis
  • Pale blue cytoplasm

29
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
    erythroderma
  • Large granular lymphocytic leukemia
  • neutropenia and anemia, Increased rheumatologic
    disorders large lymphocytes with abundant blue
    cytoplasm
  • 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

30
Hodgkin Lymphoma
  • HL arises in a single node or chain of nodes and
    spreads first to anatomically contiguous lymphoid
    tissues
  • 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

31
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
    cell)

32
Hodgkin Lymphoma
  • Clinical features
  • Painless lymphadenopathy
  • Constitutional symptoms fever, night sweats,
    weight loss
  • Cutaneous anergy
  • Staging Table 13-9
  • Secondary Cancers

33
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
    differentiation

34
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

35
AML
  • 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
    AML
  • t(1517) respond to all-trans retinoic acid)
  • Most patients present with anemia, neutropenia,
    thrombocytopenia
  • Fever, fatigue, mucosal and cutaneous bleeding

36
Myelodysplastic Syndromes
  • Group of clonal stem cell disorders characterized
    by
  • 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

37
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

38
Myeloproliferative Disorders
  • CML
  • Polycythemia vera
  • Essential thrombocythemia
  • Primary myelofibrosis
  • Systemic mastocytosis
  • Chronic eosinophilic leukemia
  • Stem cell leukemia

39
CML
  • 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

40
Polycythemia Vera
  • Increased RBCs cause the most symptoms
  • Low erthropoietin
  • Increased blood viscosity
  • Bleeding and thrombosis
  • Point mutations in JAK2

41
Essential thrombocytosis
  • Abnormally large platelets in peripheral smear
  • Dysfunctional platelets (thrombosis and
    hemorrhage)
  • Erthromelalgia (throbbing and burning of hands
    and feet)
  • Mutations in JAK2 or MPL

42
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
    biopsy

43
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

44
Spleen
  • Filter for the blood
  • Site of immune responses to blood borne
  • pathogens
  • Functions
  • Phagocytosis of blood cells and particulate
    matter
  • 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
    necrosiis)
  • Accessory spleens

45
Thymus
  • Third, sometimes fourth pharyngeal pouch
  • Hassall corpuscles
  • Tcells
  • Thymic hypopasia (DiGeorge syndrome 22q11, cysts)
  • Thymic hyperplasia (myasthenia gravis -gt myoid
    cells)
  • Thymomas- MG, other autoimmune
  • 40 present because of impingement on other
    mediastinal structures
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