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Components of the Hematopoietic System

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1 Chapter 13 Diseases 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 = 1:1

5 Leukopenia Neutropenia (granulocytopenia) more common
agranulocytosis – clinically significant reduction, severe infecitons when neutrophil count <500/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 >100,000 Presence of particular cytogenic aberrations (Ph chromosome) “2 Adolescents in Philadelphia stole > $100,000” Favorable prognosis 2-10 years of age low WBC count hyperploidy Trisomy of 4,7,10 Presence of t (12:21)

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 -> 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(14;18) 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(14:18) 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 < 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 > 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(11:14) 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- CD4+cells, HTLV-1 (cloverlef, flow cells) Mycosis fungoides/Sezary Syndrome CD4+helper 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- L&H 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 > 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(15;17) 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 (9;22) (q34;q11)
Adults, 4500 new cases per year Hypercellular marrow WBC >100,000 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 Rupture (trauma, malaria, mono, typhoid fever, lymphoid neoplasms)

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

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