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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
and rate of extravasation of cells from blood to tissues o Leukocyte homeostasis is maintained by cytokines. but histological examination of lymph nodes or other involved tissues is required for diagnosis. pertussis. HIV). H. cancer-draining nodes). nontender lymph nodes.Reactive (Inflammatory) Proliferations of White Cells and Lymph nodes – expansion of leukocytes in response to underlying primary. neoplastic . bands) Table 13. CLL Lymphadenitis – activation of resident immune cells leads to morphological changes in lymph nodes (primary follicles changed to germinal centers). Down syndrome. rate of release from pools. vascular disorders Myeloproliferative disease (CML) Chronic infections (TB). abscesses. often microbial. ataxia telangiectasia o Viruses – “lymphotropic viruses” HTLV-1 (adult T cell leukemia/lymphoma). toxoplasmosis. simulating myeloid leukemia. focal or systemic. painful. 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. parasitic. when caused by pyogenic bacteria can cause node to undergo necrosis o Chronic nonspecific lymphadenitis: nontender. 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. 85-90% are B-cell origin (remainder T-cell. inherited or acquired immunodeficiency). 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. certain malignancies (lymphomas). and cytoplasmic vaculoes) o Leukemoid reaction: severe infection (like viral infection in children) causes many immature granulocytes to appear in the blood. antigen-receptor gene rearrangement preceeds transformation (all daughter cells have same gene configuration). growth. 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. RA. brain) Hodgkin lymphoma Non-Hodgkin lymphoma Plasma cell neoplasms: arise in bone marrow and only infrequently involve lymph nodes or peripheral blood.3 Causes of Leukocytosis Type of Leukocytosis Neutrophil Eosinophil Basophil Monocye Lymphocyte Causes Acute bacterial infections (esp pyogenic).g. pylori (B-cell lymphoma). 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. draining sinuses. red. occur in the majority of white cell neoplasms Mutated or altered genes often play critical roles in the development. 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. present with signs and symptoms of suppression of normal hematopoiesis by tumor cells in bone marro Lymphoma: discrete tissue masses. burns) Allergic. NK cell rare). organized collections in non-immune tissues (H. most present as enlarged. large reactive germinal centers. Celiac disease (intestinal T-cell lymphomas). stomach. left shift (more immature cells. paracortical hyperplasia (T-cell responses. most commonly translocations. viral infections. or survival of the normal counterparts of the malignant cells ( e. Fanconi anemia. viral infections). IBD (Crohns) Chronic infections (TB). proportion of cells adherent to blood vessel walls (marginal pool). growth factors. disease Leukocytosis – increased number of white cells in the blood. Hodgkin.g. 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. Döhle bodies. reticular hyperplasia/sinus histiocytosis (increased number and size of cells lining lymphatic sinusoids. NF1. infections and inflammatory stimuli elicit regional or systemic immune reactions in lymph nodes o Acute nonspecific lymphadenitis: enlarged. if not then present as extranodal symptoms (skin. tissue necrosis (MI. and adhesion molecules o Most important cause of neutrophilic leukocytosis is infection – release of IL-1. EBV (Burkitt. degree and pattern of the changes are dependent on the inciting stimulus and intensity of the response. 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. pylori stimulate Peyer’s patches. increased risk for leukemia Bloom syndrome. follicular hyperplasia (B-cell responses. often associated with immune abnormalities (loss of protective immunity (susceptibility to infection) and breakdown of tolerance (autoimmunity). drugs.
EBV). testicular enlargement. Generalized lymphadenopathy. middle age. vomiting) Prognostic factors: 95% obtain complete remission. chromosomal translocations are rare. CD5. Most common leukemia of adults in the western world. arises from germinal center B cells. presentation in adolescence or adulthood. 5% of CLBCLs have c-MYC translocations. distinctive immunophenotype (CD19. usually treated with low-dose chemotherapy or immunotherapy. bleeding. CNS manifestations (headache. anorexia. endemic Burkitt presents as mass involving the mandible. 10-20% t(14. increasing splenomegaly. also seen in abdominal viscera (kidneys. strongly associated with chromosomal translocations involving BCL2. hyperploidy. Disrupts normal immune function through uncertain mechanisms (hypogammaglobulinemia common. typically manifest as childhood acute leukemias. increased number of prolymphocytes. median survival <1yr after transformation Diffuse Large B-cell Lymphoma Pathogenesis: most common form of NHL. Sporadic (nonendemic). presence of particular cytogenic aberrations (Ph chromosome) Favorable prognosis: 2-10 YOA. smudge cells. aggressive and rapidly fatal without treatment (anti-CD20 antibody). undergo somatic hypermutation (like normal germinal B-cells) leading to point mutations Prognosis: indolent waxing and waning course. CD20. presence of t(12. Principle cell types: centrocytes and centroblasts. fatigue.and B-cell antigens). T-ALL peaks in adolescence (largest thymus). Subtypes: 1) immunodeficiency-associated large B-cell lymphoma in the setting of T-cell immunodeficiency = EBV. Waldeyer ring in oral cavity common involved. weight loss. large cell size and diffusion pattern of growth. must be distinguished from Burkitt lymphoma (chemo) Burkitt Lymphoma Pathogenesis: Types: African (endemic. “starry sky” appearance. generalized lymphadenopathy. ALL remains leading cause of cancer deaths in children Worse prognosis: <2YOA (MLL gene translocations). males=females. CD19. Symptoms related to bone marrow suppression (fever. surface Ig. lymphadenopathy. 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. growth of CLL/SLL cells is confined to proliferation centers.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. nerve palsies from meningeal spread. hispanics > whites > blacks. 2) Primary effusion lymphoma = KSV/HHV-8 Clinical Features: typically presents as rapidly enlarging mass at nodal or extranodal site.o B and T cells tend to behave like their normal counterparts (home to certain tissue sites by using same adhesion molecules and receptors). 30% of childhood NHL. marrow is hypercellular and packed with lymphoblasts. most present as tumor in extranodal site. subset in HIV pts (aggressive) – they are histologically identical. petichieae). “starry sky pattern” = high mitotic index and numerous apoptotic cells. Hallmark t(14. 90% have numerical or structural chromosomal changes. sporadic involves ileocecum and peritoneum . slightly male>female. most tumors are widely disseminated at time of diagnosis (except Hodgkin). hemolytic anemia or thrombocytopenia due to autoantibodies against non-neoplastic B-cells) Prognosis: Variable course and prognosis depending on stage. B-ALL peaks at age 3 (greatest # of pre-B cells). histologic transformation to diffuse large Bcell lymphoma (30-50%) from chromosomal translocations involving c-MYC. hepatosplenomegaly. CD20. Single mutations are not sufficient to produce ALL Clinical features: Abrupt stormy onset. 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. stimulate NF-kB (promotes cell growth and survival) Clinical Features: Often asymptomatic at diagnosis. Mass effect caused by neoplastic infiltration (bone pain. hepatomegaly. proliferation centers are pathognomic. surface Ig). anywhere in the body. peripheral blast counts >100. median age 60. cell of origin may be a postgerminal center memory B cell or a naïve B cell. compression of large vessels in mediastinum). Immunostaining for terminal deoxynucleotidyltransferase (TdT) positive in >95%. Hepatosplenomegaly. adrenals. splenomegaly. Trisomy of 4. CLL= absolute lymphocyte count >4000/m^3. less common T-ALLs present in adolescent males as thymic lymphomas. cells resemble Reed-Sternberg cells.18) translocation which leads to overexpression of BCL2 Clinical Features: painless.18). primary and secondary involvement of liver and spleen. most common cancer in children. CD23.7. Tendency to transform to more aggressive tumors Prolymphocytic and large-cell transformations (Richter syndrome) – poor prognosis. translocations of c-MYC gene on chromosome 8.10. generalized lymphadenopathy.000. worsening cytopenias. 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. median age 60yrs. increases c-MYC expression and inactivation p53 (increases frequency of c-MYC translocations) Clinical Features: children or young adults. Nonspecific –fatigue. dysregulation of BCL6 leading to overexpression which silences p53. males>females. definitive dx by antibodies for T. must be distinguised from AML (for chemo reasons. low WBC count. 75-85% are cured with chemotherapy. ovaries).
multifocal tumorous masses scattered throughout the skeletal system. indolent course. many relapse but respond to retreatment Peripheral T-cell and NK-cell neoplasms (mature cells) Peripheral T-cell Lymphoma. punched out defects 1-4cm in diameter. spleen. proliferation and survival of myeloma cells are dependent on several cytokines (esp IL6). amyloidosis. Hashimoto thyroiditis. rearrangements involving the Ig heavy chain gene of Chromosome 14q32. fatigue. dutcher bodies. liver. autoimmune hemolysis. most die of organ infiltration of tumor. leukemic cells have fine hair-like projections seen under phase contrast microscopy Clinical features: white males. recurrent bacterial infections (decreased normal Igs). lymphadenopathy is rare. median 55YOA. continuum between reactive lymphoid hyperplasia and fullblown lymphoma. Bence-Jones proteins excreted in urine Multiple myeloma: most common and deadly. tumor cells contain clonal HTLV-1 provirus. definitive diagnosis required bone marrow examination Prognosis: variable. t(11. anti-CD20 chemotherapy. unspecified: pleimorphic mixture of variably sized malignant T-cells often with prominent infiltrate of reactive cells (eosinophils and macrophages). hyperviscosity. high incidence of somatic hypermutation (possible post-germinal center memory B-cell origin). late disease charachterized by extracutaneous spread (lymph nodes and bone marrow). some patients have multiple myeloma Monoclonal gammopathy of uncertain significance (MGUS): moderately large M components in their blood. sometimes eosinophilia. begins as polyclonal immune reaction. axial skeleton. diagnosis requires immunophenotyping with DNA confirmation Clinical features: generalized lymphadenopathy. hyperviscosity syndrome (visual impairment. extranodal involvement (bone marrow. express high levels of cyclin D1. hepatosplenomegaly. weight loss. remain localized for prolonged periods. pylori gastritis). factors produced by the neoplastic plasma cells mediate bone destruction. HTLV-1 encodes Tax protein that activates NF-kB Clinical features: skin lesions. most children and young adults can be cured Plasma Cell Neoplasms and related disorders (monoclonal gammaopathies)– secrete a monoclonal Ig or Ig fragment. Rouleaux formation (RBCs look like stacks of coins). bleeding. splenomegaly). cryoglobulinemia) Prognosis: incurable. anemia. excellent prognosis with response to gentle chemotherapy. Russell bodies and Dutcher bodies Clinical features: weakness. fatal within months to one year. infections (atypical mycobacterial infections). pancytopenia. gut). painless generalized lymphadenopathy. HTLV-1 endemic areas. involve soft tissues. mott cells. poor prognosis (3-4 years). bone marrow transplant Waldenstrom macroglobulinemia: high levels of IgM leads to hyperviscosity syndrome. progresses in three distinct phases (premycotic. neurological problems. elderly. spleen and liver usually involved (hepatomegaly. poor prognosis Anaplastic Large-cell Lymphoma (ALK positive): ALK gene on chromosome 2p23 (activates tyrosine kinases and JAK/STAT pathway). dry tap on bone marrow because infiltrated cells are enmeshed in ECM of bone marrow. renal insufficiency (trails only infection as cause of death). and tumor). resembles CLL/SLL (except cells are terminally differentiated). common in the elderly Lymphoplasmacytic lymphoma: plasma cell component secretes monoclonal IgM leading to hyperviscosity syndrome (Waldenstrom macroglobulinemia). CD20 markers. bone marrow transplant and proteasome inhibitors may be helpful Marginal Zone Lymphomas: “Maltomas”. good prognosis. median survival 8-9yrs.14) Clinical features: Male 50-60yoa. plasmablasts. in addition HTLV-1 infection sometimes causes demyelinating disease of CNS and spinal cord Mycosis Fungiodes/Sézary Syndrome: CD4+ helper T-cell tumor. may regress if inciting agent is eradicated. plaque. large anaplastic cells containing horseshoe-shaped nuclei and voluminous cytoplasm (hallmark cells) Clinical features: children or young adults. occasionally lymphomatoid polyposis. fever. tumors may acquire mutations and translocations that upregulate BCL10 or MALT1 which activate NF-kB (promotes growth and survival of cells). flame cells. chronic pain and hypercalcemia. weight loss. tumors can spread to distant sites and become diffuse large B-cell lymphomas Hairy Cell Leukemia: CD19. lymphadenopathy. Prognosis: very aggressive but responds well to intensive chemo. bisphosphonates. tumor cells have multilobed nuclei (“cloverleaf” or “flower” cells). tumor cells express adhesion molecule CLA and chemokine receptors CCR4 and CCR10 (contribute to homing of normal CD4+ T-cells to the skin. cure rate 70-80% Adult T-cell Leukemia/Lymphoma: CD4+ cells. generalized lymphadenopathy. russell bodies. SPE M protein. pruritis. H. often synthesize excess light or heavy chains along with complete Igs. median survival is 4 years Mantle Cell Lymphoma: tumor cells closely resemble the normal mantle zone B cells that surround the germinal centers. myeloma kidney Clinical Features: bone resorption leading to pathologic fractures. homes to skin (epidermis and dermis). 99% Bence-Jones proteinuria and Igs in blood and/or light chains. Ig genes in myeloma cells always show evidence of hypermutation. seen in lymphoplasmacytic lymphoma and Mediterranean lymphoma Primary or immunocyte-associated amyloidosis: secrete light chains and are deposited as amyloid. B-cell neoplasm of older adults (60-70s). men>women. hepatosplenomegaly. peripheral blood lymphocytosis and hypercalcemia. often arise in areas of chronic inflammation (Sjögren syndrome. plasmapheresis alleviates hyperviscosity. occurs in older adults in association with lymphoplasmacytic lymphoma Heavy chain disease: synthesis and secretion of free heavy-chain fragments. can transform to aggressive T-cell lymphoma . but generally poor Treatment: thalidomide.
gastric cancer. cytogenetic analysis is helpful. 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. fatigue. median survival 9-29 months. increased rheumatologic disorders. can be primary (idiopathic) or secondary (genotoxic drug or radiation). young adults. RS cells. large lymphocytes with abundent blue cytoplasm seen on peripheral smears. males>females. WBCs. night sweats. reactive lymphocytes most of cellular infiltrate. nuclear budding abnormalities. macrophages. non-classical RS cells. developing countries. weight loss. staging important in treatment (involves PE. usually found incidentally on blood test. young males with cervical or axillary lymphadenopathy. AML not otherwise specified) o Myelodysplastic Syndromes – associated with ineffective hematopoeisis and resultant peripheral blood cytopenias. spread is stereotyped: node. when symptomatic presents as weakness. occasionally presents as a localized soft-tissue mass (myeloblastoma. >55YOA. painless lymphadenopathy. Sézary syndrome variant has generalized exfoliative erythroderma. pawn ball megakaryocytes. AML. associated with EBV (rare in US). AML with MDS-like features. evidence that mutated tyrosine kinases collaborate with transcription factors to produce AML. mediastinal. neoplastic multipotent stem cell retains the capacity to differentiate but does so ineffectively and in disordered fashion. t(15. older males. and platelets. megaloblastic maturation. infections are frequent. drenching night sweats. thrombocytopenia). both myelodysplastic syndrome and myeloproliferative disorders can “transform” into AML. NHL. cutaneous anergy. paucity of lymphocytes. treatment is limited (bone marrow transplant in younger patients. associated leukemia with cerebriform nuclei Large Granular Lymphocytic Leukemia: mainly adults. infection and hemorrhages (pancytopenia). AML therapy-related. pts often die of complications of thrombocytopenia (bleeding) and neutropenia (infection). progression to AML in 10-40% (associated with additional cytogenetic abnormalities). and megakaryocyte lineages to varying degrees (ringed sideroblasts. neutropenia. mucosal and cutaneous bleeding (petichiae.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. autoimmunity may be cause. Pseudo-Pelger-Huet cells. males=females. Auer rods. neoplastic giant cells (Reed-Sternberg cells derived from germinal center or post-germinal B-cells) release factors that induce accumulation of reactive lymphocytes. T-cells. splenomegaly. T-cell variants are CD3+. granulocytic sarcoma. other tissue Prognosis: curable in most cases. myeloid blasts usually <10%) Clinical Features: elderly. EBV Lymphocyte-rich – uncommon. EBV Lymphocyte depletion – uncommon. group of clonal stem cell disorders characterized by: maturation defects. biphasic incidence (young adults and >55YOA). monocytic. collagen bands divide lymph nodes into circumscribed nodules Mixed cellularity – males>females. HIV-infected pts. primarily involve the bone marrow. surrounds and invades blood vessels leading to ischemic necrosis. many recurrent genetic aberrations seen in AML disrupt genes encoding transcription factors required for normal differentiation. 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. one of the most common cancers of young adults and adolescents. high risk forms treated with bone marrow transplants Classification: 4 Major Subtypes (AML with genetic aberrations. myeloid neoplasm manifestations influenced by the position of the transformed cell within the hierarchy of progenitors. lymphocyte predominance type Reed-Sternberg cells have B-cell immunophenotype Nodular sclerosis – most common. most patients present with anemia. fever. or chloroma) Prognosis: difficult to treat. neutropenia and anemia. >20% myeloid blasts in bone marrow. may develop secondary cancers from chemo and radiation (myelodysplastic syndromes. have this disorder as underlying cause Extranodal NK/T-cell Lymphoma: destructive nasopharyngeal mass. older pts treated with antibiotics and blood product transfusions. plasma cells. spleen. thalidomide and DNA methylase inhibitors improve effectiveness of hematopoiesis in some . EBV Lymphocyte predominance – uncommon.17) important pathologically and guides treatment Clinical Features: incidence after 60YOA. all forms of MDS can transform to AML. sarcoma. effect of transporting events on differentiation. cytogenetics have central role in classification. immunophenotype helps distinguish myeloblasts from lymphoblasts (stain for myeloid-specific antigens). highly aggressive but respond well to radiation (resistant to chemo). marrow. lung cancer. usually present with altered hematopoiesis. normal hematopoiesis has homeostatic feedback mechanisms involving cytokines and growth factors that modulate production of RBCs. NK-cell LGLL are CD3-. eosinophils. course is variable Felty Syndrome: Triad of RA. high risk of transformation to AML. L&H (popcorn cell) variants Table 13. imaging and bone marrow biopsy). eccymoses). thrombocytopenia. most characteristic finding is disordered (dysplastic) differentiation affecting erythroid. ineffective hematopoiesis ( hallmark is bone marrow progenitors that undergo apoptotic death at an increased rate). fever. mild to moderate lymphocytosis and splenomegaly. breast cancer. macrophages and granulocytes (make up 90% of tumor cellularity). anema. granulocytic. liver. melanoma) Classification (five subtypes): first 4 are classic types and Reed-Sternberg cells have similar immunophenotype. neutropenia. CD56+. lacunar variant RS cells. and/or unexplained weight loss >10% of normal body weight Myeloid Neoplasms – common feature of this group is origin from hematopoietic progenitor cells. activation of NF-kB Clinical Features: average age at diagnosis is 32 years.
MI. serum EPO levels in PVC are very low.000. increase in metabolism. CCK19 and 21 ligands for CCR7 in lymphoid organs) o Langerhans cell histiocytosis: immature dendritic cell. multiple erosive bony masses. leukoerythroblastosis (premature release of nucleated erythroud and early granulocyte progenitors) and immature cells from EMH. weight loss. progressive anemia and splenomegaly. hyperuricemia and secondary gout due to high cell turnover. dizziness. bone marrow transplant (curative in 75% in stable phase) Polycythemia Vera: increased marrow production of red cells. characteristic feature is sea-blue histiocytes. unifocal indolent. constitutively activated tyrosine kinases (circumvent normal controls and lead to growth factor-independent proliferation and survival of marrow progenitors). multifocal unisystem disease affects young children. CD1a Clinicopathologic entities: Multifocal multisystem Langerhans cell histiocytosis (Letterer-Siwe disease): <2YOA. but increas in red cells (polycythemia) is responsible for symptoms. Hct >60%. bleeding gums). insidious. bone marrow cellularity mildly increased. Tx: bone marrow transplant and kinase inhibitors Others: Systemic mastocytosis. death by incurrent infections. middle-aged adults. typically arises from medullary cavities of bones (calvarium. transformation in 1-2% of patients to AML Clinical Features: uncommon. leading to cytopenias and extensive neoplastic dysordered extramedullary hematopoiesis. monoclonal proliferation. less common unisystem lesions (skin. peripheral blood contains increased basophils and abnormally large platelets. most originate in multipotent myeloid progenitors. hypercellular marrow. WBCs 12. pts are plethoric and cyanotic (stagnation and deoxygenation of blood). tenderness. tumor cells express HLA-DR. peptic ulceration. headache. there is extensive marrow fibrosis. megakaryocytes markedly increased. does not respond to cortisone. marrow is hypercellular. 50% 5YSR with aggressive chemo Unifocal and multifocal unisystem langerhans cell histiocytosis (eosinophili granuloma): proliferations of langerhans cells mixed with eosinophils. strongly associated with activating point mutations in tyrosine kinase JAK2. without treatment death occurs from bleeding or thrombosis (within months of dx). pulmonary lesions. after 3 years 50% develop accelerated phase with increasing anemia and thrombocytopenia. posterior pituitary stalk leads to diabetes insipidus. splenomegaly (causes dragging sensation in abdomen or acute LUQ pain from splenic infarct). WBC>100. and platelets (panmyelosis). Myeloproliferative Disorders – increased production of one or more terminally differentiated myeloid elements leads to elevated peripheral blood counts. DVT. Dx: chromosomal analysis or PCR. eventually osteolytic bone lesions.q11). “blast crisis”. granulocytes. minor hemorrhages (epistaxis. absent polycythemia and marrow fibrosis. insidious onset (mild-moderate anemia and hypermetabolism due to increased cell turnover leading to fatigue. 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). cell of origin is pluripotent hematopoietic stem cell. variable transformation to spent phase. increased extramedullary hematopoiesis (spleen and liver) later in disease causing organomegaly (early organomegaly caused by congestion). Complications: DVT. elevated hematocrit leads to increased blood viscosity and sludging. teardrop cells (dacrocytes) (damaged by escape from fibrotic marrow) Clinical features: older than 60YOA. stroke. lab studies show moderate to severe normochromic normocytic anemia with leukoerythroblastosis.000 /mm^3. indolent disorder. and anorexia). extramedullary hematopoiesis is seen. night sweats. can transform to AML. spontaneous remission or chemo treatment Hand-Schuller-Christian Triad: calvarial bone defects. chronic bleeding leads to iron deficiency which can suppress EPO and lower Hct into normal range. plasma cells. mild organomegaly (extramedullary hematopoiesis). Stem cell leukemia Histiocytosis: proliferative disorders of dendritic cells or macrophages. intense pruritis. slow progression. 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. untreated is rapidly fatal. BCR-ABL drives proliferation of progenitors and causes abnormal release of immature cells from the marrow to the blood. bleeding related to platelet abnormalities. pathologic fx. adults 4500 new cases/yr. transformation to AML (5-20%). patients are prone to thrombosis and bleeding. S-100. development of cutaneous lesions resembling seborrheic eruption (caused by infiltrates of langerhans cells on trunk and scalp). most have hepatosplenomegaly. have abundant vaculolated cytoplasm and vesicular nuclei containing linear grooves or folds. lungs. MI. Hgb (14-28gm/dL). bone lesions can be asymptomatic or cause pain. replacement of bone marrow by fibrosis suppresses bone marrow hematopoiesis. thrombocytopenia. progenitor cells have decreased requirement for EPO and other growth factors. originates from pluirpotent stem cell with both myeloid and lymphoid potential Clinical Features: adults >50YOA. and neutrophils. hypertension. 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. weakness. lymphocytes. median survival 12-15 years. MPL mutations in 1-5%. Chronic eosinophilic leukemia.22) (q34. median survival 3 yrs. Hyperuricemia (increased cell breakdown -> pruritis and GOUT) Treatment/Prognosis: phlebotomy (extends like 10 years). portal and hepatic vein thrombosis. 50-60% have activating JAK2 mutations. erythromelalgia (throbbing. GI symptoms. fibrosis probably caused by release of fibrogenic factors from the neoplastic megakaryocytes (PDGF and TNF-). common features: mutated. some cases may be PVC disguised by iron deficiency Clinical features: elevated platelet counts (but they don’t funtion properly leading to thrombosis and hemorrhage). weight loss. femur). therapy is “gentle chemo” Primary myelofibrosis: hallmark is development of obliterative marrow fibrosis.000-50. burning of hands and feet caused by occlusion of small arterioles by platelet aggregates. bowel infarction. extensive infiltration of marrow leads to anemia. cured by local excision or radiation. lymphadenopathy. bone marrow biopsy essential for diagnosis Treatment/prognosis: 3-5 year survival. platelets are usually large and ineffective 4 H’s of PCV: Hyperviscosity (-> thrombosis). presence of Birbeck granules in cytoplasm is characteristic (“tennis racket cells”) contain protein langerin. predisposition to recurrent infections (otitis media and mastoiditis). Hypervolemia (increased plasma volume). fatigue. peripheral smears show abnormally large platelets with mild leukocytosis. Histaminemia (from mast cells -> generalized pruritis). thrombotic episodes. diabetes insipidus and exophthalmos o . Budd-Chiari syndrome. ribs. stomach) unifocal lesions (skeleton). variable transformation to acute leukemia Chronic Myeloid Leukemia (CML): chimeric BCR-ABL gene created by Philadelphia chromosome t(9.
pylephlebitis. also spontaneous portal vein thrombosis. incidental). benign fibromas. 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. Grave’s disease. treated with splenectomy. 40% present because of impingement on other mediastinal structures. carcinomas of stomach or pancreas). chronically enlarged spleens are less likely to rupture because of extensive reactive fibrosis Thymus – 3rd. spleen is enlarged and soft. anterior mediatinum. hypoplasia is more common. thyroid. neck. 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. lymphangiomas (cavernous). often precipitates intraperitoneal hemorrhage. leukopenia. may be mistaken for thymoma Neoplasms o Thymomas – tumor of thymic epithelial cells and typically contains benign immature T-cells (thymocytes). ie situs inversus). H. look for thymoma or lymphoma) Thymic hyperplasia – appearance of B-cell germinal centers within the thymus (thymic follicular hyperplasia). Grave’s disease. and lymphoid neoplasms). two routes for blood through red pulp to splenic veins Functions: Phagocytosis of blood cells and particulate matter – also responsible for “pitting”of red cells (excision of inclusions like Heinz bodies and Howell-Jolly bodies) Antibody production – dendritic cells trap antigens and present to T-cells. frequent site of lodged emboli (usually from heart). benign but invasive or metastatic. sometimes 4th pharyngeal pouches. give rise to long-lived CD4+ and CD8+ T-cells. neoplastic-related cysts (caused by compression of the normal thymus. Hassall corpuscles. “spontaneous ruptures” spleens are never normal (usually fragile due to mono. and thrombocytopenia (alone or in combination). RA. also associated with hypogammaglobulinemia. can cause hypersplenism characterized by anemia. usually adults >40YOA. 3 histological types (benign and noninvasive. seen in chronic inflammatory and immunological states. influenza). disorders that directly impinge on portal or splenic veins leading to portal or splenic hypertension (liver cirrhosis is main cause. if seen. hyposplenism caused by autoinfarction or splenectomy have increased susceptibility to sepsis caused by encapsulated bacteria (pneumococcus. accessory spleens are common (can be important in hereditary spherocytosis and immune thrombocytopenia purpura) Rupture – precipitated by blunt trauma. platelets can be sequestered causing thrombocytopenia. lymphoma. or pulmonary hilus. pure red cell aplasia.spleen is rarely site of primary disease. carcinoid) o . may regress when smoking is stopped. site of immune responses to blood-borne pathogens. single or multiple. white pulp may undergo necrosis (esp in hemolytic strep) Congestive splenomegaly – chronic venous outflow obstruction causing splenic enlargement. associated with hypoparathyroidism) Thymic cysts: isolated (uncommon. abnormalities in the selection of maturing T-cells in the neoplasm may contribute to development of autoimmune disorders Other neoplasms (germ cell tumor. may be reactive hyperplasia (not neoplasia) Spleen: filter for the blood. also scleroderma. other autoimmune disorde rs. osteomas. usually bland (b/c of end organ. 30-45% from evaluation of MG. and Cushing syndrome. infiltrating tumors. typhoid fever. or white cells and produce leukopenia Splenic insufficiency . hemangiomas (cavernous) Congenital anomalies – complete absence (rare. meningococcus. chrondromas. 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. infarcts can be small or large. and malignant carcinoma). probably cause is increased sequestration and increased phagocytosis by splenic macrophages o Nonspecific acute splenitis – blood-borne infection. usually pale and wedge-shaped) or can be septic in pts with infectious endocarditis Neoplasms – rare. systemic or central venous congestion is caused by cardiac decompensation. or involve entire organ. T-cell maturation. acute red pulp congestion. discomfort after eating. most frequently myasthenia gravis. caused by pathogens and cytokines. rest are incidentally discovered. asplenic pts should be vaccinated Splenomegaly – dragging sensation in LUQ. dermatomyo sitis-polymyositis. SLE. Pulmonary Langerhans cell histiocytosis: adult smokers. usually associated with other abnormalities. pernicious anemia. malaria.
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