Pathology Chapter 13 White Blood Cells, Lymph Nodes, Spleen and Thymus

Components of the Hematopoietic System Myeloid tissues: bone marrow and cells derived from it (RBCs, platelets, granulocytes, monocytes) o Bone marrow is the source of all lymphoid progenitor cells o Neoplastic disorders of myeloid progenitor cells (myeloid leukemias) originate in bone marrow but secondarily involve the spleen and (lesser degree) lymph nodes Lymphoid tissues: thymus, lymph nodes, spleen

Development and Maintenance of the Hematopoietic Tissues Hematopoietic Stem Cells (HSCs) o Formation Initial site of blood cell progenitor production is yolk sac (3rd week) (not HSCs) Mesoderm: source of HSCs 3rd month: HSCs migrate to liver chief site of blood cell formation until shortly before birth 4th month: HSCs shift to bone marrow At birth bone marrow throughout the skeleton is active and liver shuts down blood cell production At puberty, activity is restricted to the axial skeleton o Properties Pluripotency: ability of one HSC to generate all mature hematopoietic cells Capacity for self-renewal: when an HSC divides, at least one daughter cell must be capable of self-renewal (may occur in in niches in stromal cells under influence of secreted factors) NOT sessile: can be mobilized to blood in stress (severe anemia), or extramedullary hematopoiesis o Marrow response to short-term physiologic needs is regulated by hematopoietic growth factorss through effects on committed progenitors As progenitors differentiate they express receptros for lineage-specific growth factors that stimulate their short-term growth and survival (stem cell factor (c-KIT), FLT3-ligand, EPO, GM-CSF, thrombopoietin); operate on feedback loops Tumors of hematopoietic origin are often associated with mutations that block progenitor cell maturation or abrogate their growth factor dependence (unregulated clonal expansion of hematopoietic elements) Can originate from transformed HSCs that can differentiate or more differentiated progenitors that have capacity for self-renewal Leukoerythroblastosis: abnormal release of immature precursors into the peripheral blood Nurse cells: red cell precursors that surround macrophages and provide some of the iron needed for synthesis of hemoglobin Formed elements of blood: RBCs, granulocytes, monocytes, platelets, lymphocytes have common origin in HSCs (pluripotent cells that sit at the apex of hierarchy of bone marrow progenitors) o HSCs give rise to 2 multipotent types of cells: Common lymphoid progenitors: source of T-cell, B-cell and NK cell precursors Common myeloid progenitors : give rise to Colony Forming Units, CFUs- committed progenitors restricted to differentiation along particular lineages Precursors (myeloblasts, proerythroblasts, megakaryocytes) give rise to mature granulocytes, RBCs and platelets

Table 13.1 Adult reference ranges for Blood Cells Cell Type White cells Granulocytes Neutrophils Lymphocytes Monocytes Eosinophils Basophils Red Cells Platelets

4.8-10.8 (x10^3/uL) 40-70% 1.4-6.5 (x10^3/uL) 1.2-3.4 (x10^3/uL) 0.1-0.6 (x10^3/uL) 0-0.5 (x10^3/uL) 0-0.2 (x10^3/uL) 4.3-5 (men); 3.5-5.0 (women (x10^3/uL) 150-450 (x10^3/uL)

Disorders of White Cells Leukopenia deficiency of leukocytes, usually results from reduced numbers of neutrophils (neutropenia, granulocytopenia), Lymphopenia decreased number of lymphocytes; less common o Causes: congenital immunodeficiency, AIDS, steroids, cytotoxic drugs, autoimmune disorders, malnutrition, acute viral disorders In acute viral disorder stems from activation not decreased number Neutropenia reduction in the number of neutrophils Agranulocytosis clinically significant reduction, o Causes: Inadequate or ineffective granulopoiesis (hypoplastic marrow): suppression of HSCs, suppression of committed granulocytic precursors by drugs (most common cause), disease states with ineffective hematopoiesis, rare congenital conditions (Kostmann syndrome,impairment of granulocytic differentiation) Drugs responsible: aminopyrine, chloramphenicol, sulfonamides, chlorpromazine, thiouracil, phenylbutazone o Antibody mediated destruction of mature neutrophils Accelerated removal of the neutrophils from the blood (hyperplastic marrow): immunologically mediated injury to neutrophils (lupus, drug exposure (antibiotics)), splenomegaly (sequesteration and hypersplenism), increased peripheral utilization (overwhelming bacterial, fungal and rickettsial infections) o Clinical features: infection (severe bacterial and fungal infections when neutrophil count <500/mm^3), malaise, chills, fever, weakness, fatigue, ulcerating necrotizing lesion of oral cavity o Treatment: if caused by myelosuppressive chemotherapy, can be treated with G-CSF

Reactive (Inflammatory) Proliferations of White Cells and Lymph nodes expansion of leukocytes in response to underlying primary, often microbial, disease Leukocytosis increased number of white cells in the blood, common reaction to variety of inflammatory states, usually a shift from the splenic pool to blood o Pathogenesis: blood count is influenced by size of storage pools, rate of release from pools, proportion of cells adherent to blood vessel walls (marginal pool), and rate of extravasation of cells from blood to tissues o Leukocyte homeostasis is maintained by cytokines, growth factors, and adhesion molecules o Most important cause of neutrophilic leukocytosis is infection release of IL-1, TNF and other cytokines stimulates production of hematopoietic growth factors G-CSF induces neutrophilia IL-5 stimulates eosinophilia o In sepsis or severe inflammatory disorders leukocytosis is accompanied by morphologic changes in neutrophils (toxic granulation, Dhle bodies, and cytoplasmic vaculoes) o Leukemoid reaction: severe infection (like viral infection in children) causes many immature granulocytes to appear in the blood, simulating myeloid leukemia; left shift (more immature cells, bands)

Table 13.3 Causes of Leukocytosis Type of Leukocytosis Neutrophil Eosinophil Basophil Monocye Lymphocyte

Causes Acute bacterial infections (esp pyogenic), tissue necrosis (MI, burns) Allergic, parasitic, drugs, certain malignancies (lymphomas), vascular disorders Myeloproliferative disease (CML) Chronic infections (TB), IBD (Crohns) Chronic infections (TB), viral infections, pertussis, CLL

Lymphadenitis activation of resident immune cells leads to morphological changes in lymph nodes (primary follicles changed to germinal centers); degree and pattern of the changes are dependent on the inciting stimulus and intensity of the response; infections and inflammatory stimuli elicit regional or systemic immune reactions in lymph nodes o Acute nonspecific lymphadenitis: enlarged, painful, red, abscesses, draining sinuses; focal or systemic; large reactive germinal centers, when caused by pyogenic bacteria can cause node to undergo necrosis o Chronic nonspecific lymphadenitis: nontender; follicular hyperplasia (B-cell responses; RA, toxoplasmosis, HIV), paracortical hyperplasia (T-cell responses; viral infections), reticular hyperplasia/sinus histiocytosis (increased number and size of cells lining lymphatic sinusoids; cancer-draining nodes), organized collections in non-immune tissues (H. pylori stimulate Peyers patches; lymphotoxin)

Neoplastic Proliferations of White Cells expansion of leukocytes due to primary neoplasm Etiologic and Pathogenic Factors in White Cell Neoplasia o 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) Oncoproteins created by genomic aberrations often block normal maturation often at stages when they are proliferating rapidly (activating mutations in tyrosine kinases that increase cell survival and proliferation) Proto-oncogenes are often activated in lymphoid cells by errors that occur during antigen receptor gene rearrangement and diversification (e.g. in germinal center B cells during antibody diversification) Upregulation of activation-induced cytosine deaminase (AID) (for class switching and somatic hypermutation): causes c-MYC and BCL6 activation Sometimes V(D)J recombinase mechanism goes awry causing tumors of T-cell precursors o Inherited genetic factors promote genetic instability; increased risk for leukemia Bloom syndrome, Fanconi anemia, Down syndrome, NF1, ataxia telangiectasia o Viruses lymphotropic viruses HTLV-1 (adult T cell leukemia/lymphoma), EBV (Burkitt, Hodgkin, B-cell and NK-cell lymphomas), HHV-8 (B-cell lymphoma that presents as malignant effusion in pleural cavity) o Chronic Immune stimulation environmental agents, H. pylori (B-cell lymphoma), Celiac disease (intestinal T-cell lymphomas), HIV (Bcell lymphomas) o Iatrogenic factors radiation and chemotherapy (increase risk of myeloid and lymphoid neoplasms o Smoking increased incidence of acute myeloid leukemia Lymphoid neoplasms o Definitions and classification Leukemia: widespread involvement of the bone marrow and peripheral blood; present with signs and symptoms of suppression of normal hematopoiesis by tumor cells in bone marro Lymphoma: discrete tissue masses; most present as enlarged, nontender lymph nodes; if not then present as extranodal symptoms (skin, stomach, brain) Hodgkin lymphoma Non-Hodgkin lymphoma Plasma cell neoplasms: arise in bone marrow and only infrequently involve lymph nodes or peripheral blood; some cause symptoms through secretion of circulating factors Multiple myeloma: causes bony destruction of skeleton and presents with pain due to pathologic fractures o Important principles: Diagnosis can be suspected from clinical features, but histological examination of lymph nodes or other involved tissues is required for diagnosis; antigen-receptor gene rearrangement preceeds transformation (all daughter cells have same gene configuration); 85-90% are B-cell origin (remainder T-cell; NK cell rare); often associated with immune abnormalities (loss of protective immunity (susceptibility to infection) and breakdown of tolerance (autoimmunity), inherited or acquired immunodeficiency); neoplastic

B and T cells tend to behave like their normal counterparts (home to certain tissue sites by using same adhesion molecules and receptors); most tumors are widely disseminated at time of diagnosis (except Hodgkin); Hodgkin lymphoma spreads in orderly fashion (staging is important in guiding therapy) Types: Precursor B-cell or T-cell neoplasms (immature cells = lymphoblasts) Acute Lymphoblastic Leukemia/Lymphoma (ALL): Pathogenesis: 85% are B-ALLs, typically manifest as childhood acute leukemias, less common T-ALLs present in adolescent males as thymic lymphomas; most common cancer in children, hispanics > whites > blacks, B-ALL peaks at age 3 (greatest # of pre-B cells), T-ALL peaks in adolescence (largest thymus); marrow is hypercellular and packed with lymphoblasts; lymphadenopathy, hepatosplenomegaly, starry sky appearance; must be distinguised from AML (for chemo reasons; definitive dx by antibodies for T- and B-cell antigens); Immunostaining for terminal deoxynucleotidyltransferase (TdT) positive in >95%; 90% have numerical or structural chromosomal changes; 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; Single mutations are not sufficient to produce ALL Clinical features: Abrupt stormy onset, Symptoms related to bone marrow suppression (fever, fatigue, bleeding, petichieae), Mass effect caused by neoplastic infiltration (bone pain, generalized lymphadenopathy, splenomegaly, hepatomegaly, testicular enlargement, compression of large vessels in mediastinum), CNS manifestations (headache, nerve palsies from meningeal spread, vomiting) Prognostic factors: 95% obtain complete remission, 75-85% are cured with chemotherapy; ALL remains leading cause of cancer deaths in children Worse prognosis: <2YOA (MLL gene translocations), presentation in adolescence or adulthood, peripheral blast counts >100,000, presence of particular cytogenic aberrations (Ph chromosome) Favorable prognosis: 2-10 YOA, low WBC count, hyperploidy, Trisomy of 4,7,10, presence of t(12;22) Peripheral B-cell neoplasms (mature B cells) Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) Pathogenesis: Two disorders differ only in degree of peripheral lymphocytosis; CLL= absolute lymphocyte count >4000/m^3; Most common leukemia of adults in the western world, median age 60, males>females; proliferation centers are pathognomic, smudge cells, distinctive immunophenotype (CD19, CD20, CD23, CD5, surface Ig), chromosomal translocations are rare, cell of origin may be a postgerminal center memory B cell or a nave B cell; growth of CLL/SLL cells is confined to proliferation centers, stimulate NF-kB (promotes cell growth and survival) Clinical Features: Often asymptomatic at diagnosis; Nonspecific fatigue, weight loss, anorexia; Generalized lymphadenopathy; Hepatosplenomegaly, Disrupts normal immune function through uncertain mechanisms (hypogammaglobulinemia common, hemolytic anemia or thrombocytopenia due to autoantibodies against non-neoplastic B-cells) Prognosis: Variable course and prognosis depending on stage; Tendency to transform to more aggressive tumors Prolymphocytic and large-cell transformations (Richter syndrome) poor prognosis, worsening cytopenias, increasing splenomegaly, increased number of prolymphocytes, rapidly enlarging mass in lymph node or spleen Treatment: Patients treated with gentle chemotherapy to control symptoms Follicular Lymphoma Pathogenesis: Most common form of indolent NHL in the US, middle age, males=females; arises from germinal center B cells; strongly associated with chromosomal translocations involving BCL2; Principle cell types: centrocytes and centroblasts; Hallmark t(14;18) translocation which leads to overexpression of BCL2 Clinical Features: painless, generalized lymphadenopathy, histologic transformation to diffuse large Bcell lymphoma (30-50%) from chromosomal translocations involving c-MYC; undergo somatic hypermutation (like normal germinal B-cells) leading to point mutations Prognosis: indolent waxing and waning course, usually treated with low-dose chemotherapy or immunotherapy; median survival <1yr after transformation Diffuse Large B-cell Lymphoma Pathogenesis: most common form of NHL, slightly male>female, median age 60yrs; large cell size and diffusion pattern of growth; cells resemble Reed-Sternberg cells; CD19, CD20, surface Ig; dysregulation of BCL6 leading to overexpression which silences p53; 10-20% t(14;18); Subtypes: 1) immunodeficiency-associated large B-cell lymphoma in the setting of T-cell immunodeficiency = EBV; 2) Primary effusion lymphoma = KSV/HHV-8 Clinical Features: typically presents as rapidly enlarging mass at nodal or extranodal site, anywhere in the body, Waldeyer ring in oral cavity common involved; primary and secondary involvement of liver and spleen; aggressive and rapidly fatal without treatment (anti-CD20 antibody); 5% of CLBCLs have c-MYC translocations, must be distinguished from Burkitt lymphoma (chemo) Burkitt Lymphoma Pathogenesis: Types: African (endemic, EBV), Sporadic (nonendemic), subset in HIV pts (aggressive) they are histologically identical; starry sky pattern = high mitotic index and numerous apoptotic cells; translocations of c-MYC gene on chromosome 8, increases c-MYC expression and inactivation p53 (increases frequency of c-MYC translocations) Clinical Features: children or young adults, 30% of childhood NHL; most present as tumor in extranodal site, endemic Burkitt presents as mass involving the mandible, also seen in abdominal viscera (kidneys, adrenals, ovaries), sporadic involves ileocecum and peritoneum

Prognosis: very aggressive but responds well to intensive chemo; most children and young adults can be cured Plasma Cell Neoplasms and related disorders (monoclonal gammaopathies) secrete a monoclonal Ig or Ig fragment, often synthesize excess light or heavy chains along with complete Igs; Bence-Jones proteins excreted in urine Multiple myeloma: most common and deadly, men>women, elderly; multifocal tumorous masses scattered throughout the skeletal system; Ig genes in myeloma cells always show evidence of hypermutation; proliferation and survival of myeloma cells are dependent on several cytokines (esp IL6); factors produced by the neoplastic plasma cells mediate bone destruction; rearrangements involving the Ig heavy chain gene of Chromosome 14q32; axial skeleton; punched out defects 1-4cm in diameter; plasmablasts, flame cells, mott cells, russell bodies, dutcher bodies, Rouleaux formation (RBCs look like stacks of coins); myeloma kidney Clinical Features: bone resorption leading to pathologic fractures, chronic pain and hypercalcemia, recurrent bacterial infections (decreased normal Igs), renal insufficiency (trails only infection as cause of death), SPE M protein; 99% Bence-Jones proteinuria and Igs in blood and/or light chains, amyloidosis, hyperviscosity; definitive diagnosis required bone marrow examination Prognosis: variable, but generally poor Treatment: thalidomide, bisphosphonates, bone marrow transplant Waldenstrom macroglobulinemia: high levels of IgM leads to hyperviscosity syndrome, occurs in older adults in association with lymphoplasmacytic lymphoma Heavy chain disease: synthesis and secretion of free heavy-chain fragments; seen in lymphoplasmacytic lymphoma and Mediterranean lymphoma Primary or immunocyte-associated amyloidosis: secrete light chains and are deposited as amyloid, some patients have multiple myeloma Monoclonal gammopathy of uncertain significance (MGUS): moderately large M components in their blood, common in the elderly Lymphoplasmacytic lymphoma: plasma cell component secretes monoclonal IgM leading to hyperviscosity syndrome (Waldenstrom macroglobulinemia); B-cell neoplasm of older adults (60-70s), resembles CLL/SLL (except cells are terminally differentiated); Russell bodies and Dutcher bodies Clinical features: weakness, fatigue, weight loss, lymphadenopathy, hepatosplenomegaly, anemia, autoimmune hemolysis, hyperviscosity syndrome (visual impairment, neurological problems, bleeding, cryoglobulinemia) Prognosis: incurable, plasmapheresis alleviates hyperviscosity, anti-CD20 chemotherapy; median survival is 4 years Mantle Cell Lymphoma: tumor cells closely resemble the normal mantle zone B cells that surround the germinal centers; express high levels of cyclin D1, t(11;14) Clinical features: Male 50-60yoa, painless generalized lymphadenopathy, extranodal involvement (bone marrow, spleen, liver, gut), occasionally lymphomatoid polyposis; poor prognosis (3-4 years), most die of organ infiltration of tumor, bone marrow transplant and proteasome inhibitors may be helpful Marginal Zone Lymphomas: Maltomas, often arise in areas of chronic inflammation (Sjgren syndrome, Hashimoto thyroiditis, H. pylori gastritis), remain localized for prolonged periods, may regress if inciting agent is eradicated; begins as polyclonal immune reaction; continuum between reactive lymphoid hyperplasia and fullblown lymphoma; tumors may acquire mutations and translocations that upregulate BCL10 or MALT1 which activate NF-kB (promotes growth and survival of cells); tumors can spread to distant sites and become diffuse large B-cell lymphomas Hairy Cell Leukemia: CD19, CD20 markers, high incidence of somatic hypermutation (possible post-germinal center memory B-cell origin); leukemic cells have fine hair-like projections seen under phase contrast microscopy Clinical features: white males, median 55YOA; dry tap on bone marrow because infiltrated cells are enmeshed in ECM of bone marrow; lymphadenopathy is rare; spleen and liver usually involved (hepatomegaly, splenomegaly), pancytopenia, infections (atypical mycobacterial infections); indolent course, excellent prognosis with response to gentle chemotherapy, many relapse but respond to retreatment Peripheral T-cell and NK-cell neoplasms (mature cells) Peripheral T-cell Lymphoma, unspecified: pleimorphic mixture of variably sized malignant T-cells often with prominent infiltrate of reactive cells (eosinophils and macrophages); diagnosis requires immunophenotyping with DNA confirmation Clinical features: generalized lymphadenopathy, sometimes eosinophilia, pruritis, fever, weight loss; poor prognosis Anaplastic Large-cell Lymphoma (ALK positive): ALK gene on chromosome 2p23 (activates tyrosine kinases and JAK/STAT pathway); large anaplastic cells containing horseshoe-shaped nuclei and voluminous cytoplasm (hallmark cells) Clinical features: children or young adults, involve soft tissues, good prognosis, cure rate 70-80% Adult T-cell Leukemia/Lymphoma: CD4+ cells, HTLV-1 endemic areas; tumor cells have multilobed nuclei (cloverleaf or flower cells); tumor cells contain clonal HTLV-1 provirus; HTLV-1 encodes Tax protein that activates NF-kB Clinical features: skin lesions, generalized lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis and hypercalcemia; fatal within months to one year; in addition HTLV-1 infection sometimes causes demyelinating disease of CNS and spinal cord Mycosis Fungiodes/Szary Syndrome: CD4+ helper T-cell tumor, homes to skin (epidermis and dermis); progresses in three distinct phases (premycotic, plaque, and tumor); late disease charachterized by extracutaneous spread (lymph nodes and bone marrow); tumor cells express adhesion molecule CLA and chemokine receptors CCR4 and CCR10 (contribute to homing of normal CD4+ T-cells to the skin; median survival 8-9yrs, can transform to aggressive T-cell lymphoma

Szary syndrome variant has generalized exfoliative erythroderma, associated leukemia with cerebriform nuclei Large Granular Lymphocytic Leukemia: mainly adults; mild to moderate lymphocytosis and splenomegaly; large lymphocytes with abundent blue cytoplasm seen on peripheral smears; T-cell variants are CD3+, NK-cell LGLL are CD3-, CD56+; neutropenia and anemia, increased rheumatologic disorders; autoimmunity may be cause; course is variable Felty Syndrome: Triad of RA, splenomegaly, neutropenia; have this disorder as underlying cause Extranodal NK/T-cell Lymphoma: destructive nasopharyngeal mass, surrounds and invades blood vessels leading to ischemic necrosis; associated with EBV (rare in US); highly aggressive but respond well to radiation (resistant to chemo), prognosis is poor in pts with advanced disease Hodgkin Lymphoma: arises in a single node or chain of nodes and spreads first to anatomically contiguous lymphoid tissue; staging important in treatment (involves PE, imaging and bone marrow biopsy); neoplastic giant cells (Reed-Sternberg cells derived from germinal center or post-germinal B-cells) release factors that induce accumulation of reactive lymphocytes, macrophages and granulocytes (make up 90% of tumor cellularity); activation of NF-kB Clinical Features: average age at diagnosis is 32 years, one of the most common cancers of young adults and adolescents; painless lymphadenopathy, fever, night sweats, weight loss, cutaneous anergy, spread is stereotyped: node, spleen, liver, marrow, other tissue Prognosis: curable in most cases, may develop secondary cancers from chemo and radiation (myelodysplastic syndromes, AML, lung cancer, NHL, breast cancer, gastric cancer, sarcoma, melanoma) Classification (five subtypes): first 4 are classic types and Reed-Sternberg cells have similar immunophenotype; lymphocyte predominance type Reed-Sternberg cells have B-cell immunophenotype Nodular sclerosis most common, males=females, young adults; lacunar variant RS cells; collagen bands divide lymph nodes into circumscribed nodules Mixed cellularity males>females, biphasic incidence (young adults and >55YOA); T-cells, eosinophils, plasma cells, macrophages, RS cells, EBV Lymphocyte-rich uncommon, males>females, >55YOA; reactive lymphocytes most of cellular infiltrate, EBV Lymphocyte depletion uncommon, older males, HIV-infected pts, developing countries; paucity of lymphocytes, EBV Lymphocyte predominance uncommon, young males with cervical or axillary lymphadenopathy, mediastinal; non-classical RS cells, L&H (popcorn cell) variants

Table 13.9 Clinical Staging of NHL and HL Stage I II

Distribution of Disease Single node region (I) or single extra-lymphatic site (E) 2+ node regions on same side of diaphragm (II) with localized involvement of extranodal site (IIE) III Node regions on both sides of diaphragm (II) with localized involvement of extranodal site (IIIE) IV Diffuse involvement of one or more extra-lymphatic organs or sites with/without lymphatic involvement All stages are further subdivided with (A) absence or (B) presence of: unexplained fever, drenching night sweats, and/or unexplained weight loss >10% of normal body weight

Myeloid Neoplasms common feature of this group is origin from hematopoietic progenitor cells; primarily involve the bone marrow; usually present with altered hematopoiesis; normal hematopoiesis has homeostatic feedback mechanisms involving cytokines and growth factors that modulate production of RBCs, WBCs, and platelets; myeloid neoplasm manifestations influenced by the position of the transformed cell within the hierarchy of progenitors, effect of transporting events on differentiation; both myelodysplastic syndrome and myeloproliferative disorders can transform into AML, also CML can transform into ALL o Acute Myeloid Leukemia (AML) caused by acquired oncogenic mutations that impede differentiation leading to accumulation of immature myeloid blasts (progenitor cells) in the marrow leading to marrow failure (neutropenia, anema, thrombocytopenia); many recurrent genetic aberrations seen in AML disrupt genes encoding transcription factors required for normal differentiation; evidence that mutated tyrosine kinases collaborate with transcription factors to produce AML; t(15;17) important pathologically and guides treatment Clinical Features: incidence after 60YOA, >20% myeloid blasts in bone marrow, Auer rods, immunophenotype helps distinguish myeloblasts from lymphoblasts (stain for myeloid-specific antigens); cytogenetics have central role in classification; most patients present with anemia, neutropenia, thrombocytopenia, fever, fatigue, mucosal and cutaneous bleeding (petichiae, eccymoses), infections are frequent; occasionally presents as a localized soft-tissue mass (myeloblastoma, granulocytic sarcoma, or chloroma) Prognosis: difficult to treat; high risk forms treated with bone marrow transplants Classification: 4 Major Subtypes (AML with genetic aberrations, AML with MDS-like features, AML therapy-related, AML not otherwise specified) o Myelodysplastic Syndromes associated with ineffective hematopoeisis and resultant peripheral blood cytopenias; group of clonal stem cell disorders characterized by: maturation defects, ineffective hematopoiesis ( hallmark is bone marrow progenitors that undergo apoptotic death at an increased rate), high risk of transformation to AML; neoplastic multipotent stem cell retains the capacity to differentiate but does so ineffectively and in disordered fashion; can be primary (idiopathic) or secondary (genotoxic drug or radiation), all forms of MDS can transform to AML; cytogenetic analysis is helpful; most characteristic finding is disordered (dysplastic) differentiation affecting erythroid, granulocytic, monocytic, and megakaryocyte lineages to varying degrees (ringed sideroblasts, megaloblastic maturation, nuclear budding abnormalities, Pseudo-Pelger-Huet cells, pawn ball megakaryocytes, myeloid blasts usually <10%) Clinical Features: elderly, usually found incidentally on blood test; when symptomatic presents as weakness, infection and hemorrhages (pancytopenia); median survival 9-29 months; progression to AML in 10-40% (associated with additional cytogenetic abnormalities); pts often die of complications of thrombocytopenia (bleeding) and neutropenia (infection); treatment is limited (bone marrow transplant in younger patients, older pts treated with antibiotics and blood product transfusions, thalidomide and DNA methylase inhibitors improve effectiveness of hematopoiesis in some

Myeloproliferative Disorders increased production of one or more terminally differentiated myeloid elements leads to elevated peripheral blood counts; common features: mutated, constitutively activated tyrosine kinases (circumvent normal controls and lead to growth factor-independent proliferation and survival of marrow progenitors); most originate in multipotent myeloid progenitors; extramedullary hematopoiesis is seen, variable transformation to spent phase, variable transformation to acute leukemia Chronic Myeloid Leukemia (CML): chimeric BCR-ABL gene created by Philadelphia chromosome t(9;22) (q34;q11); adults 4500 new cases/yr; hypercellular marrow, WBC>100,000; blast crisis; cell of origin is pluripotent hematopoietic stem cell; BCR-ABL drives proliferation of progenitors and causes abnormal release of immature cells from the marrow to the blood; characteristic feature is sea-blue histiocytes; originates from pluirpotent stem cell with both myeloid and lymphoid potential Clinical Features: adults >50YOA; insidious onset (mild-moderate anemia and hypermetabolism due to increased cell turnover leading to fatigue, weakness, weight loss, and anorexia), slow progression, splenomegaly (causes dragging sensation in abdomen or acute LUQ pain from splenic infarct); Dx: chromosomal analysis or PCR; median survival 3 yrs, after 3 years 50% develop accelerated phase with increasing anemia and thrombocytopenia, sometimes with increased basophils in blood within 6-12 months this phase terminates in blast crisis resembling acute leukemia Treatment: drugs that target BCR-ABL (imatinib), bone marrow transplant (curative in 75% in stable phase) Polycythemia Vera: increased marrow production of red cells, granulocytes, and platelets (panmyelosis), but increas in red cells (polycythemia) is responsible for symptoms; strongly associated with activating point mutations in tyrosine kinase JAK2; progenitor cells have decreased requirement for EPO and other growth factors; serum EPO levels in PVC are very low; elevated hematocrit leads to increased blood viscosity and sludging; patients are prone to thrombosis and bleeding; marrow is hypercellular, peripheral blood contains increased basophils and abnormally large platelets; there is extensive marrow fibrosis, increased extramedullary hematopoiesis (spleen and liver) later in disease causing organomegaly (early organomegaly caused by congestion); transformation in 1-2% of patients to AML Clinical Features: uncommon, insidious, middle-aged adults; pts are plethoric and cyanotic (stagnation and deoxygenation of blood); headache, dizziness, hypertension, GI symptoms, intense pruritis, peptic ulceration; Complications: DVT, Budd-Chiari syndrome, MI, stroke, bowel infarction; minor hemorrhages (epistaxis, bleeding gums); Hgb (14-28gm/dL), Hct >60%, chronic bleeding leads to iron deficiency which can suppress EPO and lower Hct into normal range; WBCs 12,000-50,000 /mm^3; platelets are usually large and ineffective 4 Hs of PCV: Hyperviscosity (-> thrombosis), Hypervolemia (increased plasma volume), Histaminemia (from mast cells -> generalized pruritis), Hyperuricemia (increased cell breakdown -> pruritis and GOUT) Treatment/Prognosis: phlebotomy (extends like 10 years); without treatment death occurs from bleeding or thrombosis (within months of dx); may evolve to spent phase (with prolonged treatment) with myelofibrosis and extramedullary hematopoiesis Essential thrombocytosis: activating point mutations in JAK2 (50%) or MPL (5-10%) makes progenitors thrombopoietinindependent and leads to hyperproliferation; bone marrow cellularity mildly increased, megakaryocytes markedly increased; peripheral smears show abnormally large platelets with mild leukocytosis; absent polycythemia and marrow fibrosis; some cases may be PVC disguised by iron deficiency Clinical features: elevated platelet counts (but they dont funtion properly leading to thrombosis and hemorrhage), mild organomegaly (extramedullary hematopoiesis); can transform to AML; DVT, portal and hepatic vein thrombosis, MI; erythromelalgia (throbbing, burning of hands and feet caused by occlusion of small arterioles by platelet aggregates; indolent disorder; median survival 12-15 years; therapy is gentle chemo Primary myelofibrosis: hallmark is development of obliterative marrow fibrosis; replacement of bone marrow by fibrosis suppresses bone marrow hematopoiesis, leading to cytopenias and extensive neoplastic dysordered extramedullary hematopoiesis; 50-60% have activating JAK2 mutations, MPL mutations in 1-5%; fibrosis probably caused by release of fibrogenic factors from the neoplastic megakaryocytes (PDGF and TNF-); leukoerythroblastosis (premature release of nucleated erythroud and early granulocyte progenitors) and immature cells from EMH; teardrop cells (dacrocytes) (damaged by escape from fibrotic marrow) Clinical features: older than 60YOA, progressive anemia and splenomegaly, fatigue, weight loss, night sweats, increase in metabolism, hyperuricemia and secondary gout due to high cell turnover; lab studies show moderate to severe normochromic normocytic anemia with leukoerythroblastosis; bone marrow biopsy essential for diagnosis Treatment/prognosis: 3-5 year survival, death by incurrent infections, thrombotic episodes, bleeding related to platelet abnormalities, transformation to AML (5-20%); Tx: bone marrow transplant and kinase inhibitors Others: Systemic mastocytosis, Chronic eosinophilic leukemia, Stem cell leukemia Histiocytosis: proliferative disorders of dendritic cells or macrophages; homing of neoplastic Langerhans cells is caused by aberrant expression of chemokine receptors that allow the cells to migrate to tissues that express relevant chemokines (CCL20 ligand for CCR6 in skin and bone; CCK19 and 21 ligands for CCR7 in lymphoid organs) o Langerhans cell histiocytosis: immature dendritic cell, monoclonal proliferation; have abundant vaculolated cytoplasm and vesicular nuclei containing linear grooves or folds; presence of Birbeck granules in cytoplasm is characteristic (tennis racket cells) contain protein langerin; tumor cells express HLA-DR, S-100, CD1a Clinicopathologic entities: Multifocal multisystem Langerhans cell histiocytosis (Letterer-Siwe disease): <2YOA; development of cutaneous lesions resembling seborrheic eruption (caused by infiltrates of langerhans cells on trunk and scalp), does not respond to cortisone; most have hepatosplenomegaly, lymphadenopathy, pulmonary lesions, eventually osteolytic bone lesions; extensive infiltration of marrow leads to anemia, thrombocytopenia, predisposition to recurrent infections (otitis media and mastoiditis); untreated is rapidly fatal, 50% 5YSR with aggressive chemo Unifocal and multifocal unisystem langerhans cell histiocytosis (eosinophili granuloma): proliferations of langerhans cells mixed with eosinophils, lymphocytes, plasma cells, and neutrophils; typically arises from medullary cavities of bones (calvarium, ribs, femur); less common unisystem lesions (skin, lungs, stomach) unifocal lesions (skeleton); bone lesions can be asymptomatic or cause pain, tenderness, pathologic fx; unifocal indolent, cured by local excision or radiation; multifocal unisystem disease affects young children, multiple erosive bony masses, posterior pituitary stalk leads to diabetes insipidus; spontaneous remission or chemo treatment Hand-Schuller-Christian Triad: calvarial bone defects, diabetes insipidus and exophthalmos o

Pulmonary Langerhans cell histiocytosis: adult smokers, may regress when smoking is stopped, may be reactive hyperplasia (not neoplasia)

Spleen: filter for the blood, site of immune responses to blood-borne pathogens; two routes for blood through red pulp to splenic veins Functions: Phagocytosis of blood cells and particulate matter also responsible for pittingof red cells (excision of inclusions like Heinz bodies and Howell-Jolly bodies) Antibody production dendritic cells trap antigens and present to T-cells; important source of antibodies against platelets and RBCs in immune thrombocytopenia purpura and immunohemolytic anemias Hematopoiesis can be reactivated in severe anemia and extramedullary hematopoiesis in myeloproliferative disorders Sequestration of formed blood elements red cell volume can increase with splenomegaly, platelets can be sequestered causing thrombocytopenia, or white cells and produce leukopenia Splenic insufficiency - spleen is rarely site of primary disease, hyposplenism caused by autoinfarction or splenectomy have increased susceptibility to sepsis caused by encapsulated bacteria (pneumococcus, meningococcus, H. influenza); asplenic pts should be vaccinated Splenomegaly dragging sensation in LUQ, discomfort after eating; can cause hypersplenism characterized by anemia, leukopenia, and thrombocytopenia (alone or in combination), probably cause is increased sequestration and increased phagocytosis by splenic macrophages o Nonspecific acute splenitis blood-borne infection, caused by pathogens and cytokines; spleen is enlarged and soft, acute red pulp congestion, white pulp may undergo necrosis (esp in hemolytic strep) Congestive splenomegaly chronic venous outflow obstruction causing splenic enlargement; disorders that directly impinge on portal or splenic veins leading to portal or splenic hypertension (liver cirrhosis is main cause, also spontaneous portal vein thrombosis, pylephlebitis, infiltrating tumors, carcinomas of stomach or pancreas); systemic or central venous congestion is caused by cardiac decompensation; spleen is firm and there is collagen deposition in basement membrane of sinusoids resulting in slowing of blood and increased destruction by macrophages (hypersplenism) Splenic infarcts caused by occlusion of major splenic artery or branches; frequent site of lodged emboli (usually from heart); infarcts can be small or large, single or multiple, or involve entire organ, usually bland (b/c of end organ, usually pale and wedge-shaped) or can be septic in pts with infectious endocarditis Neoplasms rare; benign fibromas, osteomas, chrondromas, lymphangiomas (cavernous), hemangiomas (cavernous) Congenital anomalies complete absence (rare, usually associated with other abnormalities, ie situs inversus), hypoplasia is more common; accessory spleens are common (can be important in hereditary spherocytosis and immune thrombocytopenia purpura) Rupture precipitated by blunt trauma, spontaneous ruptures spleens are never normal (usually fragile due to mono, malaria, typhoid fever, and lymphoid neoplasms); often precipitates intraperitoneal hemorrhage, treated with splenectomy; chronically enlarged spleens are less likely to rupture because of extensive reactive fibrosis Thymus 3rd, sometimes 4th pharyngeal pouches; Hassall corpuscles, T-cell maturation; involute in children and young adults in response to severe illness and HIV infection Developmental Disorders o o Thymic hypoplasia or aplasia: seen in DiGeorge syndrome (22q11 deletion syndrome) (severe defects in cell-mediated immunity and variable abnormalities in parathyroid development, associated with hypoparathyroidism) Thymic cysts: isolated (uncommon, incidental); neoplastic-related cysts (caused by compression of the normal thymus, if seen, look for thymoma or lymphoma)

Thymic hyperplasia appearance of B-cell germinal centers within the thymus (thymic follicular hyperplasia), seen in chronic inflammatory and immunological states, most frequently myasthenia gravis, also scleroderma, Graves disease, SLE, RA, other autoimmune disorde rs; may be mistaken for thymoma Neoplasms o Thymomas tumor of thymic epithelial cells and typically contains benign immature T-cells (thymocytes); 3 histological types (benign and noninvasive, benign but invasive or metastatic, and malignant carcinoma); usually adults >40YOA, anterior mediatinum, neck, thyroid, or pulmonary hilus; 40% present because of impingement on other mediastinal structures, 30-45% from evaluation of MG, rest are incidentally discovered; also associated with hypogammaglobulinemia, pure red cell aplasia, Graves disease, pernicious anemia, dermatomyo sitis-polymyositis, and Cushing syndrome; give rise to long-lived CD4+ and CD8+ T-cells; abnormalities in the selection of maturing T-cells in the neoplasm may contribute to development of autoimmune disorders Other neoplasms (germ cell tumor, lymphoma, carcinoid)