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I. Benign Qualitative WBC Disordersa. Pathogenesis

i. Defects in leukocyte structure, i.e. membrane fusion defect in Chediak-Higashi syndromeii. Effects in leukocyte fn

1. Leukocyte adhesion defect, i.e. deficient selectin or CD11a/CD182. Phagocytosis defect, i.e. decreased opsonins in Brutons agammaglobulinemia 3. Microbicidal defect, i.e. deficiency of MPO

b. Clinical findingsi. Unual pathogens, i.e. coag Staphii. Frequent infections & growth failure in kids

iii. Lack of inflamm response, i.e. production of cold abscessesiv. Severe gingivitis

c. Jobs syndrome: AR disorder of PMNsi. Abnormal chemotaxis leads to cold soft tissue abscesses due to S. aureusii. Pts have red hair, leonine face, chronic eczema & increased IgE (hyperimmune E syndrome)

d. Unusual benign leukocyte rxnsi. 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 infectionii. Leukoerythroblastic rxn

1. Immature BM cells enter peripheral blood2. Pathogenesis: BM infiltrative disease, i.e. fibrosis, metastatic breast CA3. PBS findings

1. Myeloblasts, progranulocytes, nucleated & teardrop RBCs (if fibrosis present)II. Benign Quantitative WBC Disorders

a. Disorders involving neutrophilsi. Neutrophilic luekocytosis

1. Absolute neutrophil count > 70002. Etiology

1. Infection, i.e. acute appendicitis2. Sterile inflamm w/necrosis, i.e. acute MI3. Drugs, i.e. corticosteroids

3. Pathogenesis1. Increased BM production or release of PMNs2. Decreased activation of PMN adhesion molecules

a. Fewer PMNs adhere to endothelial cellsb. Ex: corticosteroids, catecholamines, Li

ii. Neutropenia1. Absolute neutrophil count < 15002. Etiology

1. Aplastic anemia2. Immune destruction, i.e. SLE3. Septic shock

3. Pathogenesis1. Decreased production2. Increased destruction by complement, macrophages3. Activation of neutrophil adhesion molecules

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a. Increase # PMNs adhering to endotheliumb. Ex: endotoxins

b. Disorders involving eosinophilsi. Eosinophilia

1. Absolute eosinophil count > 7002. Etiology

1. Type I HSR, i.e. bronchial asthma, penicillin rxn, hay fever2. 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. Pathogenesis1. Release of eosinophil chemotact factor from mast cells (type I HSR)2. No sequestering of eosinophils in LNs, i.e. hypocortisolism

ii. Eosinopenia1. Etiology

1. Hypercortisolism, i.e. Cushing syndrome, corticosteroids2. Corticosteroids sequester eosinophils in LNs

c. Disorders involving basophilsi. Basophilia

1. Absolute basophil count > 1102. Etiology: chronic myeloproliferative disorders, i.e. polycythemia vera (PV)

d. Disorders involving lymphocytesi. Lymphocytosis

1. Absolute lymphocyte count > 4000 in adults or > 8000 in kids2. Etiology

1. Viral, i.e. mononucleosis, CMV2. Bacterial, i.e. whooping cough3. Drugs, i.e. phenytoin

3. Pathogenesis1. Increased production2. Decreased entry into LN, i.e. due to lymphocytosis-promoting factor made by

B. pertussis

ii. Atypical lymphocytosis1. Etiology

1. Infection, i.e. mononucleosis, viral hepatitis, CMV infection, toxoplasmosis2. Drugs, i.e. phenytoin

2. Pathogenesis1. Agically-stimulated lymphocytes2. Prominent nucleoli & abundant blue cytoplasm

iii. Infectious mononucleosis1. Caused by EBV2. Pathogenesis1. Transmitted by kissing: EBV initially replicates epithelial cells in oropharynx

2. Infection spreads to B cells in LNa. Attaches to CD21 receptors on B cellsb. Causes B cell proliferation & increased synthesis of IgM Absc. Virus remains dormant in B cells, recurrences may occur

3. Clinical findings1. Severe fatigue, exudative tonsillitis2. Hepatosplenomegaly: danger of splenic rupture in contact sports

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3. Generalized painful lymphadenopathy, rash develops if tx w/ampicillin4. Lab findings

1. Atypical lymphocytosisa. > 20% total WBC countb. Agically-stimulated T cells

2. + heterophil Ab testa. Initial screening testb. Detects IgM Abs against horse, sheep & bovine RBCsc. Sensitivity 87%, specificity 91%

3. Antiviral capsid Ag (VCA) Absa. High sensitivity & specificity, early in infection, persists for life

4. Anti-early Ag (EA) Abs: increased w/chronic infections5. Anti-EB nuclear Ag (EBNA) Abs

a. High sensitivity & specificity, late in infection, persists for life6. Increased serum transaminases from hepatitis: jaundice is rare

iv. Lymphopenia1. Absolute lymphocyte count < 1500 in adults or < 3000 in kids2. Etiology

1. HIV: lysis of CD4 Th cells2. Immunodeficiency

a. DiGeorge syndrome (T-cell def), SCID (B & T-cell def)3. Immune destruction, i.e. SLE4. Corticosteroids, i.e. apoptosis5. Radiation: lymphocytes most sensitive cells

3. Pathogenesis1. Increased destruction (see etiology for examples)2. Decreased production, i.e. Brutons agammaglobulinemia

e. Disorders involving monocytesi. Monocytosis

1. Absolute monocyte count > 8002. Etiology

1. Chronic infection, i.e. TB, subacute infective endocarditis2. Autoimmune disease, i.e. RA, cirrhosis3. Malignancy, i.e. carcinoma, malignant lymphoma

3. Pathogenesis: response to chronic inflamm or malignancyIII. Leukemias (Acute & Chronic)

a. Epidemiologyi. Malignant diseases of BM stem cells, may involve all cell lines; more common in malesii. Risk factors

1. Chr abnormalities, i.e. Down syndrome, chr instability syndromes2. Ionizing radiation, i.e. nuclear plant explosion3. Chemicals, i.e. benzene (myeloid leukemia)4. Alkylating agents, i.e. busulfan5. Chronic myeloproliferative diseases, i.e. PV6. Paroxysmal nocturnal Hburia7. Cigarette smoking8. Immunodeficiency disease, i.e. Wiskott-Aldrich syndrome (WAS)

iii. Age ranges for common leukemias1. More common in adults2. Newborn to 14 yo: acute leukoblastic leukemia (ALL)

1. Most common leukemia in kids, most common CA in kids

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3. 15-39 yo: acute myeloblastic leukemia (AML)4. 40-60 yo

1. AML in > 60%2. Chronic myelogenous leukemia (CML) in 40%: may occur in pts > 60 yo

5. > 60 yo: chronic lymphocytic leukemia (CLL), most common overall type of leukemiab. Pathogenesis

i. Block in stem cell differentiation1. Monoclonal proliferation of neoplastic leukocytes behind block2. Acute leukemia: block occurs at early stage3. Chronic leukemia: block at later stage, some evidence of maturation

ii. Leukemic cells1. Replace most of BM, replace normal hematopoietic cells2. Enter peripheral blood, metastasize throughout body

c. Clinical findings in acute leukemiai. Abrupt onset of S & Sii. Clinical findings: fever (infection), bleeding (thrombocytopenia), fatigue (anemia)

iii. Metastatic disease: hepatosplenomegaly, generalized painless lymphadenopathy, CNSinvolvement (esp in ALL), skin involvement (esp in T-cell leukemias), testicles (esp in ALL)

iv. Bone pain & tenderness: due to BM expansion by leukemic cellsd. Lab findings in acute leukemia

i. Peripheral WBC count1. < 10,000 to > 100,0002. Blast cells present, i.e. myeloblasts, lymphoblasts, monoblasts

ii. Normocytic anemia or macrocytic (if folate is depleted in production of leukemic cells)iii. Thrombocytopenia: < 100,000iv. BM: hypercellular w/>20% blasts, often completely replaced by blasts

e. Clinical findings in chronic leukemiai. Insidious onset, slightly more common than acuteii. Hepatosplenomegaly, generalized painless lymphadenopathy

f. Lab findings in chronic leukemiai. 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%)IV. Neoplastic Myeloid Disorders

a. Overviewi. Myeloid disorders are neoplastic stem cell disorders, may involve 1 or more stem cell linesii. Classification

1. Chronic myeloproliferative disorders2. Myelodysplastic syndrome (MDS)3. Acute myeloblastic leukemia (AML)

b. Chronic myeloproliferative disordersi. Classification

1. Polycythemia vera (PV)2. Chronic myelogenous leukemia (CML)3. Myeloid metaplasia w/myelofibrosis4. Essential thrombocythemia

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ii. General characteristics: splenomegaly, reactive BM fibrosis (spent phase), transformation toacute leukemia

iii. Polycythemia1. Increased Hb, Hct & RBC count2. Plasma V varies w/type of polycythemia3. RBC count vs RBC mass

1. RBC count = # RBCs/uL blood; RBC mass : plasma V2. RBC mass = total # RBCs in body in mL/kg

4. Relative polycythemia: most common type1. Increased RBC count due to decrease in plasma V2. RBC mass is normal, no increase in BM production of RBCs3. EPO & SaO2 are normal4. Fluid replacement will correct

5. Absolute polycythemia1. Increase in BM production of RBCs: increase in RBC count & mass2. Appropriate absolute polycythemia

a. Hypoxic stimulus for EPO releaseb. Ex: primary lung disease, cyanotic congenital heart disease, high

altitudec. Decreased O2 sat (SaO2)d. Increased RBC count & mass, EPOe. Normal plasma V

3. Inappropriate absolute polycythemia: ectopic EPO productiona. No hypoxic stimulus for EPO release but ectopic release of EPO from

renal cell carcinoma

b. Increased RBC count & mass, EPOc. Normal plasma V & SaO2

iv. Polycythemia vera1. Inappropriate absolute polycythemia2. Pathogenesis

1. Clonal expansion of myeloid stem cell2. Most due to mut of JAK2 gene on short arm of chr 9

a. Same mut may manifest as myelofibrosis & myeloid metaplasia oressential thrombocythemia

3. Increased production of RBCs, granulocytes (PMNs, eosinophils, basophils),mast cells & platelets

3. Clinical findings1. Hepatosplenomegaly2. Ruddy (plethoric) face: due to vessel congestion3. Thrombotic events

a. Due to hyperviscosity from increased RBC countb. Ex: hepatic vein thrombosis, dural sinus thrombosis, retinal vein

thrombosis4. Impaired sinus circulation: headache, blurred vision, retinal vein engorgement,

vertigo, transient ischemic attack, stroke

5. Signs of increased histamine released from mast cellsa. Pruritis after bathing: common initial complaint, mast cells

degranulate w/change in skin temp

b. Peptic ulcer disease: histamine stimulates production of gastric acid6. Gout: increased breakdown of nucleated cells w/release of purines which are

converted to uric acid

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4. Lab findings1. Increased RBC count & mass, plasma V2. Decreased EPO: best initial test for PV3. Normal SaO2

5. Major & minor criteria for dx PV: 3 major or 1 st 2 major + 2 minor1. Major criteria

a. Increased RBC mass > 36 or > 32 in womenb. Normal SaO2 (> 92%)c. Splenomegaly

2. Minora. Absolute leukocytosis > 12,000b. Thrombocytosis > 400,000c. Increased serum LAP > 100d. Increased serum vit B12 > 900 or vit B12 binding protein > 2200

3. Hypercellular BM w/fibrosis in later stages6. Tx

1. Nonpharmacologic: phlebotomy to reduce hyperviscosity2. Pharmacologic: hydroxyurea + phlebotomy, IFN-a

7. Prognosis: median survival 6-18 monthsv. CML

1. Epidemiology1. 40-60 yo, 15% adult leukemias2. Risk factors: exposure to ionizing radiation & benzene

2. Pathogenesis1. 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-oncogenea. Proto-oncogene fuses w/break cluster region (BCR) on chr 22; chr22

w/translocation = Philadelphia chr

3. Clinical findings1. Hepatosplenomegaly & generalized painless lymphadenopathy (due to

metastatsis)

2. Blast crisis: occurs in 5 yrsa. Increase # myeloblasts or lymphoblastsb. Myeloblasts do NOT contain Auer rods

4. Lab findings1. Peripheral WBC count 50,000-200,000

a. Myeloid series in all stages of development, basophilia2. Normocytic anemia or macrocytic (if folate is depleted in production of

leukemic cells)

3. Platelet counta. Thrombocytosis in 40-50% cases (uncommon in leukemia)b. Thrombocytopenia in rest4. BM: myeloblasts < 10%, hypercellular

5. + Philadelphia chr (95% cases)a. Not specific for CML & is in other leukemias, i.e. ALLb. Not lost during therapy unless IFN-a is used

6. BCR-ABL fusion gene in 100% casesa. This is the most sensitive & specific test for CML

7. Decreased LAP score

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a. LAP is absent in neoplastic granulocytes & present in benigngranulocytes

5. Tx1. Imatinib: oral tyrosine kinase inhibitor, < 35% Philadelphia chr + cells after tx2. Allogenic stem cell transplantation

6. Prognosis: 90% 5-yr survival ratevi. Myelofibrosis & myeloid metaplasia

1. Epidemiology: in > 50 yo, most common cause of splenomegaly2. Pathogenesis

1. Clonal myeloproliferative disease2. Most due to mut of JAK2 gene on short arm of chr 9

a. Same mut may manifest as PV or thrombocythemia3. Ineffective erythropoiesis, dysplastic megakaryocytes, immature granulocytes,

reactive myelofibrosis

a. Marrow fibrosis occurs earlier here4. Hematopoiesis moves to spleen, liver & other sites (extramedullary

hematopoiesis)

3. Clinical findings1. Massive splenomegaly w/portal HTN2. Splenic infarcts w/L-sided pleural effusion

4. Lab findings1. BM fibrosis2. Peripheral WBC count 10,000 to 50,0003. Normocytic anemia: teardrop cells (damaged RBCs) & leukoerythroblastic rxn4. Platelet count is variable, platelets have abnormal morphology5. Serum LAP is normal to increased

a. Decreased in CML, increased in PV5. Tx: hydroxyurea, IFN-a

vii. Essential thrombocythemia1. Pathogenesis

1. Clonal myeloproliferative disease w/excess formation of dysplastic & defectiveplatelets

2. Most due to mut of JAK2 gene on short arm of chr 9a. Same mut may manifest as PV or myelofibrosis & myeloid

metaplasia

2. Clinical findings: bleeding: GI w/concomitant Fe def, platelets nonfnal; splenomegaly3. Lab findings

1. Thrombocytosis: platelets > 600,000, often > 1 million, abnormal morphology2. Mild neutrophilic leukocytosis3. Basophilia4. Hypercellular BM w/abnormal megakaryocytes

4. Tx: hydroxyureac. Myelodysplastic syndromes (MDSs)i. Epidemiology: in men btwn 50-80 yo

ii. Pathogenesis1. Group of acquired clonal disorders affecting stem cells2. Cytopenias & hypercellular marrow3. Classification

1. Refractory anemia2. Refractory anemia w/ringed sideroblasts3. Chronic myelomonocytic leukemia

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4. Refractory anemia w/excess blasts in transformation4. Frequently progresses to AML (30%)

iii. Lab findings1. Severe pancytopenia

1. Normocytic to macrocytic anemia: dimorphic RBC pop (microcytic &macrocytic)

2. Leukoerythroblastic rxn2. 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 classificationii. Cytogenetic abnormalities are common, i.e. t(15;17) in acute promyelocytic leukemia (M3)

iii. Clinical findings1. DIC is common (invariable in acute promyelocytic leukemia)2. Gum infiltration is common in acute monocytic leukemia (M5)

iv. Auer rods1. Splinter-shaped to rod-shaped structures in cytosol of myeloblasts2. Fused azurophilic granules3. Only present in AML (M2 & M3), not present in myeloblasts in CML

v. Treatment1. Induction therapy: cytarabine + daunorubicin2. Consolidation therapy: aggressive chemo w/or w/out radiation3. 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 Leukemiasa. Acute lymphoblastic leukemia (ALL)

i. Epidemiology1. 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 diseaseiii. Early pre-B-cell ALL

1. + for common ALL Ag (CALLA, CD10) & for TdT2. Favorable prognosis w/t(12;21) translocation3. >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 AML2. B-cell types: mets to CNS & testicles3. 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% lymphoblasts2. Normocytic anemia w/thrombocytopenia3. BM: totally replaced by lymphoblasts

vii. Treatment1. Induction therapy: vincristine, prednisone, L-asparagine2. Consolidation therapy: aggressive chemo w/or w/out radiation3. Maintenance therapy: methotrexate + 6-mercaptopurine4. BM transplantation is an option

b. Adult T-cell leukemiai. Epidemiology

1. Malignant leukemia assoc. w/human T-cell leukemia virus (HTLV-1)2. May present as malignant lymphoma

ii. Pathogenesis1. Activation of TAX gene which inhibits TP53 suppressor gene2. Leads to monoclonal proliferation of neoplastic CD4 Th cells

iii. Clinical findings1. Hepatosplenomegaly & generalized lymphadenopathy2. 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 findings1. Peripheral WBC count 10,000-50,000, > 20% lymphoblasts2. CD4+ & TdT-3. Normocytic anemia & thrombocytopenia4. BM: replaced by CD4 lymphoblasts

c. Chronic lymphocytic leukemia (CLL)i. Epidemiology

1. In pts > 60 yo, most common overall leukemia2. 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 AML2. Increased incidence of immune hemolytic anemia: warm (IgG) & cold (IgM)

iv. Lab findings1. Peripheral WBC count 15,000-200,000, lymphoblasts < 10%, neutropenia2. 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: chlorambucild. Hairy cell leukemia: type of B-cell leukemia, most common in middle-aged men

i. Clinical findings1. Splenomegaly (90%): primary site of proliferation of neoplastic cells2. Absence of lymphadenopathy: only leukemia to do so3. Hepatomegaly (20%), autoimmune vasculitis & arthritis

ii. Lab findings1. Pancytopenia, leukemic cells have hair-like projections2. BM: packed w/neoplastic cells, increased reticulin fibers; + (TRAP) stain

iii. Tx: purine analogs, i.e. 2-chloro-2-deoxyadenosine