WBC PATH

I. Benign Qualitative WBC Disorders a. Pathogenesis i. Defects in leukocyte structure, i.e. membrane fusion defect in Chediak-Higashi syndrome ii. Effects in leukocyte fn 1. Leukocyte adhesion defect, i.e. deficient selectin or CD11a/CD18 2. Phagocytosis defect, i.e. decreased opsonins in Brutons agammaglobulinemia 3. Microbicidal defect, i.e. deficiency of MPO b. Clinical findings i. Unual pathogens, i.e. coag Staph ii. Frequent infections & growth failure in kids iii. Lack of inflamm response, i.e. production of cold abscesses iv. Severe gingivitis c. Jobs syndrome: AR disorder of PMNs i. Abnormal chemotaxis leads to cold soft tissue abscesses due to S. aureus ii. Pts have red hair, leonine face, chronic eczema & increased IgE (hyperimmune E syndrome) d. Unusual benign leukocyte rxns i. Leukemoid rxn 1. Absolute leukocyte count > 50,000 (may involve PMNs, lymphocytes or eosinophils) 2. Etiology 1. Perforated appendicitis (neutrophils) 2. Whooping cough (lymphocytes) 3. Cutaneous larva migrans (eosinophils) 3. Pathogenesis: exaggerated response to infection ii. Leukoerythroblastic rxn 1. Immature BM cells enter peripheral blood 2. Pathogenesis: BM infiltrative disease, i.e. fibrosis, metastatic breast CA 3. PBS findings 1. Myeloblasts, progranulocytes, nucleated & teardrop RBCs (if fibrosis present) Benign Quantitative WBC Disorders a. Disorders involving neutrophils i. Neutrophilic luekocytosis 1. Absolute neutrophil count > 7000 2. Etiology 1. Infection, i.e. acute appendicitis 2. Sterile inflamm w/necrosis, i.e. acute MI 3. Drugs, i.e. corticosteroids 3. Pathogenesis 1. Increased BM production or release of PMNs 2. Decreased activation of PMN adhesion molecules a. Fewer PMNs adhere to endothelial cells b. Ex: corticosteroids, catecholamines, Li ii. Neutropenia 1. Absolute neutrophil count < 1500 2. Etiology 1. Aplastic anemia 2. Immune destruction, i.e. SLE 3. Septic shock 3. Pathogenesis 1. Decreased production 2. Increased destruction by complement, macrophages 3. Activation of neutrophil adhesion molecules

II.

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a. b. b. Increase # PMNs adhering to endothelium Ex: endotoxins

c.

d.

Disorders involving eosinophils i. Eosinophilia 1. Absolute eosinophil count > 700 2. Etiology 1. Type I HSR, i.e. bronchial asthma, penicillin rxn, hay fever 2. Invasive helminthic infection, i.e. strongyloidiasis, hookworm infection a. Pinworms & adult ascariasis do NOT have eosinophilia (non-invasive) 3. Polyarteritis nodosa (PAN) 4. Addisons disease (cortical deficiency) 3. Pathogenesis 1. Release of eosinophil chemotact factor from mast cells (type I HSR) 2. No sequestering of eosinophils in LNs, i.e. hypocortisolism ii. Eosinopenia 1. Etiology 1. Hypercortisolism, i.e. Cushing syndrome, corticosteroids 2. Corticosteroids sequester eosinophils in LNs Disorders involving basophils i. Basophilia 1. Absolute basophil count > 110 2. Etiology: chronic myeloproliferative disorders, i.e. polycythemia vera (PV) Disorders involving lymphocytes i. Lymphocytosis 1. Absolute lymphocyte count > 4000 in adults or > 8000 in kids 2. Etiology 1. Viral, i.e. mononucleosis, CMV 2. Bacterial, i.e. whooping cough 3. Drugs, i.e. phenytoin 3. Pathogenesis 1. Increased production 2. Decreased entry into LN, i.e. due to lymphocytosis-promoting factor made by B. pertussis ii. Atypical lymphocytosis 1. Etiology 1. Infection, i.e. mononucleosis, viral hepatitis, CMV infection, toxoplasmosis 2. Drugs, i.e. phenytoin 2. Pathogenesis 1. Agically-stimulated lymphocytes 2. Prominent nucleoli & abundant blue cytoplasm iii. Infectious mononucleosis 1. Caused by EBV 2. Pathogenesis 1. Transmitted by kissing: EBV initially replicates epithelial cells in oropharynx 2. Infection spreads to B cells in LN a. Attaches to CD21 receptors on B cells b. Causes B cell proliferation & increased synthesis of IgM Abs c. Virus remains dormant in B cells, recurrences may occur 3. Clinical findings 1. Severe fatigue, exudative tonsillitis 2. Hepatosplenomegaly: danger of splenic rupture in contact sports

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3. Generalized painful lymphadenopathy, rash develops if tx w/ampicillin Lab findings 1. Atypical lymphocytosis a. > 20% total WBC count b. Agically-stimulated T cells 2. + heterophil Ab test a. Initial screening test b. Detects IgM Abs against horse, sheep & bovine RBCs c. Sensitivity 87%, specificity 91% 3. Antiviral capsid Ag (VCA) Abs a. High sensitivity & specificity, early in infection, persists for life 4. Anti-early Ag (EA) Abs: increased w/chronic infections 5. Anti-EB nuclear Ag (EBNA) Abs a. High sensitivity & specificity, late in infection, persists for life 6. Increased serum transaminases from hepatitis: jaundice is rare iv. Lymphopenia 1. Absolute lymphocyte count < 1500 in adults or < 3000 in kids 2. Etiology 1. HIV: lysis of CD4 Th cells 2. Immunodeficiency a. DiGeorge syndrome (T-cell def), SCID (B & T-cell def) 3. Immune destruction, i.e. SLE 4. Corticosteroids, i.e. apoptosis 5. Radiation: lymphocytes most sensitive cells 3. Pathogenesis 1. Increased destruction (see etiology for examples) 2. Decreased production, i.e. Brutons agammaglobulinemia e. Disorders involving monocytes i. Monocytosis 1. Absolute monocyte count > 800 2. Etiology 1. Chronic infection, i.e. TB, subacute infective endocarditis 2. Autoimmune disease, i.e. RA, cirrhosis 3. Malignancy, i.e. carcinoma, malignant lymphoma 3. Pathogenesis: response to chronic inflamm or malignancy Leukemias (Acute & Chronic) a. Epidemiology i. Malignant diseases of BM stem cells, may involve all cell lines; more common in males ii. Risk factors 1. Chr abnormalities, i.e. Down syndrome, chr instability syndromes 2. Ionizing radiation, i.e. nuclear plant explosion 3. Chemicals, i.e. benzene (myeloid leukemia) 4. Alkylating agents, i.e. busulfan 5. Chronic myeloproliferative diseases, i.e. PV 6. Paroxysmal nocturnal Hburia 7. Cigarette smoking 8. Immunodeficiency disease, i.e. Wiskott-Aldrich syndrome (WAS) iii. Age ranges for common leukemias 1. More common in adults 2. Newborn to 14 yo: acute leukoblastic leukemia (ALL) 1. Most common leukemia in kids, most common CA in kids 4.

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3. 4. 15-39 yo: acute myeloblastic leukemia (AML) 40-60 yo 1. AML in > 60% 2. Chronic myelogenous leukemia (CML) in 40%: may occur in pts > 60 yo > 60 yo: chronic lymphocytic leukemia (CLL), most common overall type of leukemia

IV.

5. Pathogenesis i. Block in stem cell differentiation 1. Monoclonal proliferation of neoplastic leukocytes behind block 2. Acute leukemia: block occurs at early stage 3. Chronic leukemia: block at later stage, some evidence of maturation ii. Leukemic cells 1. Replace most of BM, replace normal hematopoietic cells 2. Enter peripheral blood, metastasize throughout body c. Clinical findings in acute leukemia i. Abrupt onset of S & S ii. Clinical findings: fever (infection), bleeding (thrombocytopenia), fatigue (anemia) iii. Metastatic disease: hepatosplenomegaly, generalized painless lymphadenopathy, CNS involvement (esp in ALL), skin involvement (esp in T-cell leukemias), testicles (esp in ALL) iv. Bone pain & tenderness: due to BM expansion by leukemic cells d. Lab findings in acute leukemia i. Peripheral WBC count 1. < 10,000 to > 100,000 2. Blast cells present, i.e. myeloblasts, lymphoblasts, monoblasts ii. Normocytic anemia or macrocytic (if folate is depleted in production of leukemic cells) iii. Thrombocytopenia: < 100,000 iv. BM: hypercellular w/>20% blasts, often completely replaced by blasts e. Clinical findings in chronic leukemia i. Insidious onset, slightly more common than acute ii. Hepatosplenomegaly, generalized painless lymphadenopathy f. Lab findings in chronic leukemia i. Peripheral WBC count 1. Similar to acute, blast cells < 10% 2. Evidence of maturation of cells ii. Normocytic anemia or macrocytic (if folate is depleted in production of leukemic cells) iii. Thrombocytopenia (< 100,000): exception in CML (thrombocytosis in 40%) iv. BM: hypercellular < 10% blasts g. Survival rates (5-yr): ALL (87%), AML (21%), CLL (75%), CML (89%) Neoplastic Myeloid Disorders a. Overview i. Myeloid disorders are neoplastic stem cell disorders, may involve 1 or more stem cell lines ii. Classification 1. Chronic myeloproliferative disorders 2. Myelodysplastic syndrome (MDS) 3. Acute myeloblastic leukemia (AML) b. Chronic myeloproliferative disorders i. Classification 1. Polycythemia vera (PV) 2. Chronic myelogenous leukemia (CML) 3. Myeloid metaplasia w/myelofibrosis 4. Essential thrombocythemia b.

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ii. iii. General characteristics: splenomegaly, reactive BM fibrosis (spent phase), transformation to acute leukemia Polycythemia 1. Increased Hb, Hct & RBC count 2. Plasma V varies w/type of polycythemia 3. RBC count vs RBC mass 1. RBC count = # RBCs/uL blood; RBC mass : plasma V 2. RBC mass = total # RBCs in body in mL/kg 4. Relative polycythemia: most common type 1. Increased RBC count due to decrease in plasma V 2. RBC mass is normal, no increase in BM production of RBCs 3. EPO & SaO2 are normal 4. Fluid replacement will correct 5. Absolute polycythemia 1. Increase in BM production of RBCs: increase in RBC count & mass 2. Appropriate absolute polycythemia a. Hypoxic stimulus for EPO release b. Ex: primary lung disease, cyanotic congenital heart disease, high altitude c. Decreased O2 sat (SaO2) d. Increased RBC count & mass, EPO e. Normal plasma V 3. Inappropriate absolute polycythemia: ectopic EPO production a. No hypoxic stimulus for EPO release but ectopic release of EPO from renal cell carcinoma b. Increased RBC count & mass, EPO c. Normal plasma V & SaO2 Polycythemia vera 1. Inappropriate absolute polycythemia 2. Pathogenesis 1. Clonal expansion of myeloid stem cell 2. Most due to mut of JAK2 gene on short arm of chr 9 a. Same mut may manifest as myelofibrosis & myeloid metaplasia or essential thrombocythemia 3. Increased production of RBCs, granulocytes (PMNs, eosinophils, basophils), mast cells & platelets 3. Clinical findings 1. Hepatosplenomegaly 2. Ruddy (plethoric) face: due to vessel congestion 3. Thrombotic events a. Due to hyperviscosity from increased RBC count b. Ex: hepatic vein thrombosis, dural sinus thrombosis, retinal vein thrombosis 4. Impaired sinus circulation: headache, blurred vision, retinal vein engorgement, vertigo, transient ischemic attack, stroke 5. Signs of increased histamine released from mast cells a. Pruritis after bathing: common initial complaint, mast cells degranulate w/change in skin temp b. Peptic ulcer disease: histamine stimulates production of gastric acid 6. Gout: increased breakdown of nucleated cells w/release of purines which are converted to uric acid

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4. Lab findings 1. Increased RBC count & mass, plasma V 2. Decreased EPO: best initial test for PV 3. Normal SaO2 st Major & minor criteria for dx PV: 3 major or 1 2 major + 2 minor 1. Major criteria a. Increased RBC mass > 36 or > 32 in women b. Normal SaO2 (> 92%) c. Splenomegaly 2. Minor a. Absolute leukocytosis > 12,000 b. Thrombocytosis > 400,000 c. Increased serum LAP > 100 d. Increased serum vit B12 > 900 or vit B12 binding protein > 2200 3. Hypercellular BM w/fibrosis in later stages Tx 1. Nonpharmacologic: phlebotomy to reduce hyperviscosity 2. Pharmacologic: hydroxyurea + phlebotomy, IFN-a Prognosis: median survival 6-18 months Epidemiology 1. 40-60 yo, 15% adult leukemias 2. Risk factors: exposure to ionizing radiation & benzene Pathogenesis 1. Neoplastic clonal expansion of pluripotential stem cell (has capacity to differentiate into lymphoid or myeloid stem cell) 2. t(9;22) translocation of ABL proto-oncogene a. Proto-oncogene fuses w/break cluster region (BCR) on chr 22; chr22 w/translocation = Philadelphia chr Clinical findings 1. Hepatosplenomegaly & generalized painless lymphadenopathy (due to metastatsis) 2. Blast crisis: occurs in 5 yrs a. Increase # myeloblasts or lymphoblasts b. Myeloblasts do NOT contain Auer rods Lab findings 1. Peripheral WBC count 50,000-200,000 a. Myeloid series in all stages of development, basophilia 2. Normocytic anemia or macrocytic (if folate is depleted in production of leukemic cells) 3. Platelet count a. Thrombocytosis in 40-50% cases (uncommon in leukemia) b. Thrombocytopenia in rest 4. BM: myeloblasts < 10%, hypercellular 5. + Philadelphia chr (95% cases) a. Not specific for CML & is in other leukemias, i.e. ALL b. Not lost during therapy unless IFN-a is used 6. BCR-ABL fusion gene in 100% cases a. This is the most sensitive & specific test for CML 7. Decreased LAP score

5.

6.

7. v. CML 1.

2.

3.

4.

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a. 5. Tx LAP is absent in neoplastic granulocytes & present in benign granulocytes

c.

1. Imatinib: oral tyrosine kinase inhibitor, < 35% Philadelphia chr + cells after tx 2. Allogenic stem cell transplantation 6. Prognosis: 90% 5-yr survival rate vi. Myelofibrosis & myeloid metaplasia 1. Epidemiology: in > 50 yo, most common cause of splenomegaly 2. Pathogenesis 1. Clonal myeloproliferative disease 2. Most due to mut of JAK2 gene on short arm of chr 9 a. Same mut may manifest as PV or thrombocythemia 3. Ineffective erythropoiesis, dysplastic megakaryocytes, immature granulocytes, reactive myelofibrosis a. Marrow fibrosis occurs earlier here 4. Hematopoiesis moves to spleen, liver & other sites (extramedullary hematopoiesis) 3. Clinical findings 1. Massive splenomegaly w/portal HTN 2. Splenic infarcts w/L-sided pleural effusion 4. Lab findings 1. BM fibrosis 2. Peripheral WBC count 10,000 to 50,000 3. Normocytic anemia: teardrop cells (damaged RBCs) & leukoerythroblastic rxn 4. Platelet count is variable, platelets have abnormal morphology 5. Serum LAP is normal to increased a. Decreased in CML, increased in PV 5. Tx: hydroxyurea, IFN-a vii. Essential thrombocythemia 1. Pathogenesis 1. Clonal myeloproliferative disease w/excess formation of dysplastic & defective platelets 2. Most due to mut of JAK2 gene on short arm of chr 9 a. Same mut may manifest as PV or myelofibrosis & myeloid metaplasia 2. Clinical findings: bleeding: GI w/concomitant Fe def, platelets nonfnal; splenomegaly 3. Lab findings 1. Thrombocytosis: platelets > 600,000, often > 1 million, abnormal morphology 2. Mild neutrophilic leukocytosis 3. Basophilia 4. Hypercellular BM w/abnormal megakaryocytes 4. Tx: hydroxyurea Myelodysplastic syndromes (MDSs) i. Epidemiology: in men btwn 50-80 yo ii. Pathogenesis 1. Group of acquired clonal disorders affecting stem cells 2. Cytopenias & hypercellular marrow 3. Classification 1. Refractory anemia 2. Refractory anemia w/ringed sideroblasts 3. Chronic myelomonocytic leukemia

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4. Refractory anemia w/excess blasts in transformation 4. Frequently progresses to AML (30%) iii. Lab findings 1. Severe pancytopenia 1. Normocytic to macrocytic anemia: dimorphic RBC pop (microcytic & macrocytic) 2. Leukoerythroblastic rxn 2. BM findings 1. Ringed sideroblasts (nucleated RBCs w/excess Fe) 2. Myeloblasts < 20% (if > 20%, disease progressed to AML) d. Acute myeloblastic leukemia (AML) i. Epidemiology: btwn 15-59 yo, use FAB classification ii. Cytogenetic abnormalities are common, i.e. t(15;17) in acute promyelocytic leukemia (M3) iii. Clinical findings 1. DIC is common (invariable in acute promyelocytic leukemia) 2. Gum infiltration is common in acute monocytic leukemia (M5) iv. Auer rods 1. Splinter-shaped to rod-shaped structures in cytosol of myeloblasts 2. Fused azurophilic granules 3. Only present in AML (M2 & M3), not present in myeloblasts in CML v. Treatment 1. Induction therapy: cytarabine + daunorubicin 2. Consolidation therapy: aggressive chemo w/or w/out radiation 3. Maintenance therapy: cytarabine Class Comments M0 = minimally differentiated AML No Auer rods M1: AML w/out differentiation (20%) Rare Auer rods M2: AML w/maturation Most common type (30-40%), Auer rods, 15-59 yo M3: acute promyelocytic Many Auer rods, DIC, t(15;17) translocation, abnormal retinoic acid metabolism (high doses of all-trans-retinoic acid may induce remission by maturing cells) M4: acute myelomonocytic Auer rods uncommon M5: acute monocytic No Auer rods, gum infiltration M6: acute erythroleukemia Bizarre, multinucleated erythroblasts; myeloblasts present M7: acute megakaryocytic Myelofibrosis in BM, increased incidence in Down syndrome in kids < 3 yo V. Lymphoid Leukemias a. Acute lymphoblastic leukemia (ALL) i. Epidemiology 1. Most common leukemia & cancer in kids (0-14 yo) 2. Subtypes 1. Early pre-B-cell ALL (80%) 2. Pre-B, B & T-cell ALL ii. Pathogenesis: clonal lymphoid stem cell disease iii. Early pre-B-cell ALL 1. + for common ALL Ag (CALLA, CD10) & for TdT 2. Favorable prognosis w/t(12;21) translocation 3. >90% complete remission, at least 2/3 pts considered cured iv. T-cell ALL: CD10 and TdT + v. Clinical findings 1. Metastatic sites similar to those of AML 2. B-cell types: mets to CNS & testicles 3. T-cell type: presents as ant mediastinal mass or acute leukemia vi. Lab findings

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1. Peripheral WBC count 10,000-100,000, > 20% lymphoblasts 2. Normocytic anemia w/thrombocytopenia 3. BM: totally replaced by lymphoblasts vii. Treatment 1. Induction therapy: vincristine, prednisone, L-asparagine 2. Consolidation therapy: aggressive chemo w/or w/out radiation 3. Maintenance therapy: methotrexate + 6-mercaptopurine 4. BM transplantation is an option Adult T-cell leukemia i. Epidemiology 1. Malignant leukemia assoc. w/human T-cell leukemia virus (HTLV-1) 2. May present as malignant lymphoma ii. Pathogenesis 1. Activation of TAX gene which inhibits TP53 suppressor gene 2. Leads to monoclonal proliferation of neoplastic CD4 Th cells iii. Clinical findings 1. Hepatosplenomegaly & generalized lymphadenopathy 2. Skin infiltration (common finding in all T-cell malignancies) 3. Lytic bone lesions 1. Due to lymphoblast release of osteoclast-activating factor, assoc. w/hypercalcemia iv. Lab findings 1. Peripheral WBC count 10,000-50,000, > 20% lymphoblasts 2. CD4+ & TdT3. Normocytic anemia & thrombocytopenia 4. BM: replaced by CD4 lymphoblasts Chronic lymphocytic leukemia (CLL) i. Epidemiology 1. In pts > 60 yo, most common overall leukemia 2. Most common cause of generalized lymphadenopathy in this age grp ii. Pathogenesis: neoplastic disorder of virgin B cells (those that cant differentiate into plasma cells) iii. Clinical findings 1. Generalized lymphadenopathy, mets to same places as AML 2. Increased incidence of immune hemolytic anemia: warm (IgG) & cold (IgM) iv. Lab findings 1. Peripheral WBC count 15,000-200,000, lymphoblasts < 10%, neutropenia 2. Many smudge cells (fragile leukemic cells) 3. Normocytic anemia (50% cases) & thrombocytopenia (40% cases) 4. BM: completely replaced by neoplastic B cells, lymphoblasts < 10% 5. Hypogammaglobulinemia common: neoplastic B cells dont form plasma cells v. Tx: chlorambucil Hairy cell leukemia: type of B-cell leukemia, most common in middle-aged men i. Clinical findings 1. Splenomegaly (90%): primary site of proliferation of neoplastic cells 2. Absence of lymphadenopathy: only leukemia to do so 3. Hepatomegaly (20%), autoimmune vasculitis & arthritis ii. Lab findings 1. Pancytopenia, leukemic cells have hair-like projections 2. BM: packed w/neoplastic cells, increased reticulin fibers; + (TRAP) stain iii. Tx: purine analogs, i.e. 2-chloro-2-deoxyadenosine

b.

c.

d.