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Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
Hematology Rivas2008 Lecture4&5
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Hematology Rivas2008 Lecture4&5

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    • 1. Clonal Disorders of hematopoietic stem cells Antonio Rivas PA-C
    • 2. Objectives
      • Become familiar with pathogenesis, epidemiology, diagnosis and treatment of :
        • Thrombosis-DVT
        • Myelodisplastic Syndromes
        • Myeloproliferative disorders
        • Chronic Myeloid Leukemia
        • Acute Leukemias : AML , ALL
        • Neutropenia
    • 3. Arterial-thrombosis
      • Commonly related to coronary artery disease (ruptured atherosclerotic plaque)
      • Atherombolic disorder (ischemic stroke)
    • 4. Thrombosis
      • Virchow’s triad-defines mechanism underlying thrombosis
        • Diminished blood flow
        • Damage to the vascular wall
        • Imbalance favoring procoagulants over anticoagulants
    • 5. Thrombosis
      • Data shows unique regulation of hemostasis in different vascular beds:
      • Cong.deficiency of ATIII, protein C or protein S lead to:
          • DVT of lower extremities, but not upper
      • Inherited hypercoagulable disorders associated with factor V Leiden and the prothrombin G20210A mutation
          • produce DVT of the lower extremities and venous thrombosis of the brain
    • 6. Atherothrombosis- Endothelial Damage
      • Associated with increased levels of Homocysteine(HCY) in congenitals syndromes, with damage to the vascular endothelium and downregulation of the Ecs anticoagulant functions
      • Increased HCY levels in people with deficiency in the cofactors for HCY metabolism: B6,B12,and Folates
    • 7. Atherothrombosis - Platelets
      • Platelet activation and adherence critical to the development of the thrombus
      • Anti-platelet therapy :
        • Aspirin-inhibits COX - blocks TXA2 release
        • Clopidogrel(Plavix) - block ADP receptors in Plts, used with ASA to prevent ischemic stroke
        • Abciximab/Integrilin/Aggrastat - block plts receptors from binding with Fibrinogen and vWF
    • 8. Thrombosis-DVT
      • Inherited: recurrent thrombosis at early age, unusual sites, or family history
      • Adquired : systemic disorders ( auto- immune hemolytic anemia), collagen vascular disease(vasculitis), malignant disease
    • 9. Risk Factors for Venous Thrombosis
      • Inherited
        • Factor V Leiden
        • Prothrombin G20210A
        • Deficiency of natural anticoagulant proteins
    • 10. Inherited risk factors for DVT
      • Factor V Leiden mutation -most common inherited disorder causing DVT
      • Activated protein C unable to inactivate factor V mutation with increased formation of thrombin
    • 11.
      • Heterozygous in 5% of the population with five fold increased risk for DVT-PE
      • Homozygous less frequent, with 90% increased risk for DVT
      • Weak hypercoagulable risk
      • DVT-PE usually Associated to concomitant acquired factors: pregnancy, immobilization and oral contraceptives
    • 12. Prothrombin G20210A Mutation
      • Mutation leads to increased prothrombin levels
      • Two-fold increased risk for DVT
      • 3% European-derived population
      • Diagnosis examining DNA for mutation
    • 13. Inherited deficiency of natural anticoagulant proteins
      • ATIII, protein C, protein S
      • Less common than previous ones
      • More likely to produce symptomatic venous thrombosis at early age
      • Accounts for fewer than 5-10% of all patients with DVT/PE
      • Functional and Antigenic Assays (quant/qualt-deficiencies)
    • 14. Acquired risk factors for DVT Surgery-Trauma
      • Surgery-orthopaedic-trauma: associated with immobilization and stasis of lower extremities blood flow
      • Also associated with fat embolism and tissue damage(massive TF release)
      • More than 50% incidence of DVT
      • Prophylactic-temporary IVC filters used
      • to protect from PE in these cases
    • 15. Other Acquired risk factors for DVT
      • Pregnancy increases risk of DVT 5 fold(venous stasis and altered coagulation factors)
      • Oral Contraceptives /hormonal changes, increased risk for smokers
      • Prothrombotic states
        • Nephrotic syndromes-loss of ATIII through the kidneys
        • Blood cell destruction-exposure of procoagulant membrane phospholipids (artificial heart valves, hemolytic anemias, sickle cell disease)
        • HIT, TTP-increased Plt activation and clearance
        • Myeloproliferative disorders-increased aggregability of the Plts
    • 16. Antiphospholipid Antibody Syndrome
      • APA Syndrome acquired prothrombic disorder
      • Primary or Secondary to autoimmune Dis.SLE
      • Recurrent venous or arterial thrombosis, thrombocytopenia, fetal loss
      • Anticardiolipin Abs / Lupus anticoagulant present in serum
      • Antibodies directed against phospholipid - binding proteins such as:
              • Beta 2 glycoprotein I
              • Prothrombin
    • 17. DVT general considerations
      • More frequent - Deep veins of the lower extremities and pelvis
      • 80% arise in the deep calf veins
      • Development up to 2 weeks post - operatively
      • Higher incidence in Total Hip replacement surgery
      • Half patients has no symptoms in early stage
    • 18. DVT-Symptoms / Signs
      • Dull ache - tight feeling - frank pain in the calf or whole leg, worse with walking (leg claudication)
      • Slight swelling calf muscle
      • Distention superficial veins
      • Slight fever and tachycardia
      • Occlusion of femoral and iliac veins more symptomatic
      • Severe obstruction: cyanosis skin, and marked swelling
    • 19. DVT-Diagnosis
      • Doppler Ultrasonography-test of choice
      • Respiratory/cardiac symptoms -V/Q scan, spiral CT scan chest - to exclude PE
      • On Physical Exam patients may have pain in the affected calf muscle with Dorsi-flexion of the foot (Homan’s sign)
    • 20. DVT-Laboratory Test
      • Evaluate for hereditary and acquired hyper-coagulable state specially young patients W/O predisposing event
      • Coagulation Profile, protein S, protein C, DNA-testing for factor V Leiden and prothrombin mutations
      • Anti-phospholipids Abs, Lupus Anticoagulant, ANA
    • 21. DVT-Diff.Dx.
      • Calf muscle strain or contusion, difficult
      • Cellulitis where you might find a wound and inflammation is more striking
      • Lymphatic obstruction by tumor is usually painless and chronic
      • Acute arterial obstruction is more painful, absent peripheral pulses, no swelling present
      • Heart, Kidney, or liver disease edema is bilateral
      • Ruptured Baker’s cyst, history of arthritis in the same side knee
    • 22. DVT-Prophylactic
      • Elevation of the legs 15-20 degrees intra and post-operatively with knees slightly flexed
      • Intermittent pneumatic compression of the legs(sequential compressions devices)
      • Elastic anti-phlebitic stockings
      • Walking briefly but regularly after surgery, or during long airplane and automobile trips
      • Anticoagulants-low dose Heparin 5000 units every 8-12 hrs subcutaneously
    • 23. DVT-Treatment
      • Mandatory anticoagulant therapy in most cases to decrease the risk of PE
        • UHT- bolus titrated to achieve a PTT 1.5-2.0 times baseline-requires hospitalization, 4 days or more
        • LMWH-subcutaneous
        • Warfarin started within 24hrs to achieve INR 2.0-2.5 for at least 2 consecutive days before stopping heparin
        • 1rst episode - treat for 6 months
        • 2nd episode - variable
        • 3rd episode - lifelong, also if the trigger factor for the thrombosis is chronic (CHF,inherited disorder)
    • 24. Thrombolytic Therapy
      • Streptokinase, Urokinase and TPA
      • Risk of therapy :local and generalized bleeding, intracraneal hemorrhage
      • Patients without complications return to their routine in 3-6 weeks after appropriate treatment
    • 25. Myelodysplastic Syndrome
      • heterogeneous
      • ineffective and disordered hematopoiesis
      • affects myeloid cell lines
      • one or more cytopenias
      • Disordered maturation and increased intramedullary apoptosis (programmed cell death)
      • decreased mature cells into the periphery
      • normal or increased hematopoietic cells in the bone marrow
    • 26. Myelodysplastic Syndrome
      • 1 in 500 patients between the ages of 60 and 75 years
      • Most idiopathic , 25 % overall risk of transformation to acute myelogenous or myeloid leukemia
      • Exposure to radiation, chemotherapy, and organic chemicals (benzene) increase risk of MDS.
      • Secondary MDS, after treatment for other cancers, may occur at any age ,comprises 10% to 15% of all MDS cases.
    • 27. Myelodysplastic Syndrome
      • Pat. referred for evaluation of incidental cytopenias
      • If Symptomatic ,bleeding and bruising, infection, or fatigue and dyspnea related to anemia
      • PExam occasional splenomegaly, development of skin lesions with fever (acute febrile neutrophilic dermatosis, or Sweet's syndrome) may herald transformation of MDS into acute leukemia.
    • 28. Myelodysplastic Syndrome-Lab.Studies
      • Erythroid cells macrocytic, often with basophilic stippling.
      • Neutrophils hypogranular and hypolobulated, bilobed nucleus, pseudo-Pelger-Hu et abnormality.
      • Bone marrow : normo-hypercellular, dysplastic changes in all three cell lines
        • Shift to the left
        • Micro-megakariocytes / hypogranular
        • blasts
    • 29. World Health Organization Classification of Myelodysplastic Syndromes
      • Refractory Anemia (RA)
      • Ra with Ringed Sideroblasts (RARS)
      • Ref.Cytopenia with Multilineage Dysplasia (RCMD)
      • RC with MD and RS (RCMD-RS)
      • RA with excess Blasts 1 (RAEB-1)
      • RA with excess Blasts 2 (RAEB-2)
      • Myelodysplastic Syndrome Unclassified (MDS-U)
      • MDS associated with isolated del(5q)
    • 30. Myelodysplastic Syndrome
      • Median survival is usually less than 2 years
      • 15 - 20% of patients die of AML
      • Treatment is limited and dictated by age, performance status, quality of life, severity of disease, and prognostic category
      • Most managed supportively
    • 31. Myelodysplastic Syndrome treatment
      • Chronic RBC / Plt transfusion- iron overload-secondary hemochromatosis
      • EPO, G-CSF reduce transfusion needs
      • In patients with high risk transformation to AML- Chemotherapy
      • Only curative therapy- allogeneic stem cell transplant(<40 years of age)
      • Immune-suppresive therapy has been used (cyclosporin,thalidomide)
    • 32. Chronic Myeloproliferative Disorders
      • Clonal stem cell disorders
      • Leukocytosis, thrombocytosis, erythrocytosis, splenomegaly, and bone marrow hypercellularity
      • Failure to respond to normal feedback mechanisms regulating cell mass
      • Stem cells demonstrate clonal colony growth in vitro in the presence of serum without the addition of exogenous cytokines
    • 33. Chronic Myeloproliferative Disorders Polycythemia Vera (PV)
      • Absolute erythrocytosis
      • Half of the patients have leukocytosis and/or thrombocytosis
      • Clonal genetic abnormalities in marrow cells
      • No causes of secondary erythrocytosis
      • Low serum EPO levels
      • Palpable splenomegaly
    • 34. Polycythemia Vera (PV). Clinical features
      • Median age of onset 65 yo
      • Most common cause of death is thrombosis cerebral, coronary or mesenteric
      • Headaches, visual problems, mental clouding, pruritus after bathing
      • Stroke, TIAs , Myocardial ischemia, paresthesias, digital pain, and gangrene
      • Pulmonary, hepatic and portal venous thrombosis
      • Hemorrhagic events, GI bleeding
    • 35. Polycythemia Vera (PV).Labs
      • P.exam : retinal - vein occlusion , cyanosis, splenomegaly
      • Microcytic cells
      • Hypercellular marrow
    • 36. Polycythemia Vera (PV).Treatment
      • W/O treatment 50% mortality at 18 months of Dx
      • With therapy-chronic progressive disease
      • 5-20% risk of Myelofibrosis/Myeloid leukemia over 20 years
      • Excellent long term survival/effective therapy
      • Goal of therapy:
        • Hematocrit <45% in men
        • Hematocrit <42% in women
    • 37. Polycythemia Vera (PV).treatment
      • Intermittent phlebotomy
      • Cytoreductive therapy/allopurinol if hyperuricemia
      • Hydroxyurea -low cytotoxic agent
      • Interferon alpha
      • Anagrelide megakaryotoxic agent
      • ASA or NSAIDS
    • 38. Essential Thrombocythemia
      • Increased Plts and WBCs
      • Plt count >600,000 with normal RBC mass
      • Iron studies are normal
      • Predominant proliferation in mature Megakariocytes
      • No “factor independent”colony growth
    • 39. Essential Thrombocythemia. Clinical Features
      • 60-65yo, 10-25% younger than 40yo
      • Headaches , dizziness, visual changes, and erythromelalgia(burning pain and erythema in the hands and feet)
      • TIAs, strokes, seizure, angina, MI may occur
      • Great long term survival rate
    • 40. Essential Thrombocythemia
      • Low risk of leukemic transformation
      • High morbidity from hemorrhagic and thrombotic events
      • Aggressive management Cardio- vascular risk factors recommended
      • Therapy: ASA, 1rts line-Hydroxyurea, 2nd line-Anagrelide, interferon alpha
    • 41. Myelofibrosis
      • Excessive marrow fibrosis leading to marrow failure
      • Dysplastic megakaryocytes producing increased levels of fibroblast growth factors
      • Abnormal proliferation and collagen deposition which displaces precursors cells to the periphery: extramedullary hematopoiesis
    • 42. Myelofibrosis
      • Early- asymptomatic, occasional low blood counts
      • Rare, chronic disease of the elderly
      • Median survival poor, 2-5 years
      • Diagnosis :
        • Fibrosis in BM
        • Normal RBC mass
        • Lack of Philadelphia chromosome
    • 43. Myelofibrosis
      • Leukoerythroblastic changes in smear:
        • Tear-drop cells
        • Giant platelets
        • Immature RBCS and WBCs
    • 44. Myelofibrosis
      • Progressive fatigue and dypsnea
      • Early satiety and LUQ pain
      • Massive hepatosplenomegaly
      • With progressive BM failure, DIC may be present
      • Constitutional symptoms:
        • Fevers, weight loss, night sweats
    • 45. Myelofibrosis
      • Treatment, not shown to prolong survival:
          • Palliative transfusions
          • EPO
          • Hydroxyurea (to manage leukocytosis/thrombocytosis)
          • Splenectomy(extra medullary hematopoiesis)
          • Palliative splenic irradiation
          • Allogeneic stem cell transplantation
    • 46. Chronic Myeloid Leukemia CML
      • Overproduction myeloid cells
      • Normal differentiation during early phases
      • Transform into more malignant disease: accelerated acute blast phase
      • Philadelphia chromosome : reciprocal translocation between the long arms of chromosomes 9 and 22 - producing the oncogene-fusion gene bcr/abl
    • 47. Chronic Myeloid Leukemia CML
      • Median age at presentation 55 yo
      • Hypermetabolic state signs
        • Chronic fatigue
        • Night sweats
        • Low grade fever
      • Abdominal fullness - splenomegaly
      • Leukostasis(WBCs >500,000/mcl) - blurred vision, repiratory distress, or priapism
    • 48. Chronic Myeloid Leukemia CML
      • On P.Exam
        • Enlarged spleen
        • Sternal tenderness (marrow overexpansion)
        • Acceleration of disease associated to:
          • High fever in the absence of infection
          • Bone pain
          • splenomegaly
    • 49. Chronic Myeloid Leukemia CML
      • Laboratory findings:
        • Elevated WBC counts - Hallmark (150,000/mcl)
        • Peripheral blood-left shifted
        • Mature cells predominate
        • Basophilia and Eosinophilia
        • Blasts <5%
        • Philadelphia chromosome present
    • 50. Chronic Myeloid Leukemia
      • Bone Marrow changes:
        • Initial - hypercellular / left shifted
          • Myeloblasts comprise 5% marrow cells
        • Blast phase
          • Blasts constitute >20% of the BM cells
    • 51. Chronic Myeloid Leukemia CML
      • Differential Diagnosis
        • From Reactive leukocytosis
          • WBC <50,000/mcl
          • Splenomegaly absent
          • Philadelphia chromosome not present
        • From other myeloproliferative disorders. On CML you find:
          • Hct is normal
          • RBC morphology normal
          • Nucleated RBCs rare or absent
    • 52. CML-Treatment
      • Chronic phase
        • Imatinib mesylate :inhibits the activity of the oncogene
        • 400mg daily , oral
      • 98% control of chronic phase
        • Complete hematologic remission(3months)
          • Normal blood counts and resolution of splenomegaly
        • Cytogenetic response (6-12months)
          • Major cytogenetic response <35%cont. Phil. Chromosome
          • Complete cytogenetic response - absence of Phil.Chromosome
    • 53. CML-Treatment
      • Quantitative asesment Philadelphia Chromosome by Polymerase Chain Reaction (PCR)
      • Only curative therapy is allogeneic stem cell transplantation
      • Original therapy with Imatimib, if not optimum response-BM transplant is done
    • 54. CML-prognosis
      • Past - 3 to 4years median survival
      • Now - Imatinib - more than 80% of patients alive and in remission at 4years
    • 55.  
    • 56.  
    • 57. Chronic Lymphocytic Leukemias CLL
      • Malignant disorder of B-lymphocytes
      • Most common leukemia in US
      • More common in men
      • Incidence increases with age
      • 90% cases adults >50 yo
      • Cause unknown
      • Clonal proliferation of mature B cells
    • 58. Chronic Lymphocytic Leukemia CLL
      • 30-50% patients show cytogenetics abnormalities (trisomy 12) poor prognostic
      • Indolent course
      • Cells are immuno-incompetent
      • Immunosuppression, BM failure , and organ infiltration
      • Inadequate antibody production
      • Tissue damage by direct organ infiltration
    • 59. Chronic Lymphocytic Leukemias CLL
      • Clinical symptoms
        • Lymphadenopathy
        • Fatigue
        • Enlarged liver or spleen
        • May complicate with autoimmune hemolytic anemia, or thrombocytopenia
        • Isolated lymph node transforms into large cell lymphoma(Richter’s syndrome)
    • 60. Chronic Lymphocytic Leukemias CLL
      • Laboratory findings
        • Hallmark - isolated lymphocytosis >20k or several hundred thousand
        • Main cell - small mature looking lymphocytes
        • Hct and Plt count normal at presentation
        • BM infiltration by small mature looking lymphocytes
        • hypogammaglobulinemia
    • 61. Chronic Lymphocytic Leukemias CLL
      • Classification - Rai system
        • Stage 0 - lymphocytosis only
        • Stage I - lymphocytosis + lymph-adenopathy
        • Stage II- organomegaly
        • Stage III-anemia
        • Stage IV- thrombocytopenia
    • 62. Chronic Lymphocytic Leukemias CLL
      • Indications for therapy include:
      • Fatigue, lymphadenopathy, anemia or thrombocytopenia
      • Combination therapy with fludarabine + rituxan given for 6 months
      • Chlorambucil for the elderly
      • Alemtuzumab- monoc.ab for refractory cases
    • 63.  
    • 64. Acute Leukemias
      • Classification by:
        • Cell lineage
        • Morphology
        • Cytogenetics
        • Cell surface and Cytoplasmic markers
        • Molecular studies
    • 65. Acute Leukemias
      • Classification by cell lineage:
        • Acute Myeloblastic Leukemia (AML)
        • 90% adult Leukemias
        • Acute Lymphoblastic Leukemia (ALL)
        • 90% of childhood Leukemias
    • 66. Acute Leukemias
      • Unregulated proliferation of immature cells that are incapable of further differentiation ( blasts )>20% in BM
      • Not clear cause
      • Risk factors: radiations, toxins, chemotherapeutic agents
    • 67. Acute Leukemias
      • Results in marrow replacement
      • Hematopoietic failure
      • Organ infiltration(GI, Skin, Meninges)
      • AML - affects adults – 60 yo
      • ALL – affects children 3-7 yo
    • 68. Acute Lymphoblastic Leukemia (ALL)
      • Affects immature lymphoblasts
      • FAB class. L1, L2, L3(cell morphology)
      • More recent, WHO classification.
      • Precursor B ALL
      • Precursor T ALL
      • Based on cell surface Ags present on these cells during maturation
    • 69. Acute Leukemias
      • Cure rates 80% in children, 20-40% in adults
      • Patient not feeling well for days or weeks
      • Anemia, infection, and bleeding from peripheral cytopenias
      • Bone pain f.marrow infiltration
    • 70. Acute Leukemias
      • Risk of infection increases with neutrophils counts below 500/mcl
      • Common pathogens: gram neg.bact. and Fungi
      • Cellulitis, pneumonia, and perirectal infections
      • Gum hyperthrophy and bone and joint pain is possible
    • 71. Acute Leukemia PE
      • Pallor, purpura or petechiae
      • Stomatitis , gum hyperthrophy
      • Lymphadenopathy, hepato-splenomegaly
      • Bone tenderness sternum ,tibia, and femur
    • 72. Laboratory Findings
      • Hallmark-pancytopenias with circulating blasts
      • BM- hypercellular with more than 20% blasts (required for Dx)
      • Hyperuricemia may be present
      • If DIC present-decreased fibrinogen level, Pt is prolonged and FDP present
    • 73. Laboratory Findings
      • Patients with ALL may have a mediastinal mass present on chest Xray
      • Auer rods-eosinophilic needle like in the Cytoplasm-pathognomonic for AML
      • Histochemical stains-
        • Myeloid lineage - Myeloperoxidase
        • Monocytic lineage – butyrate esterase
    • 74. ALL
    • 75.  
    • 76.  
    • 77.  
    • 78. Laboratory Findings
      • ALL. considered if no morphological or histochemical stains demonstrate Myeloid precursors
      • Surface markers for lymphoid precursors are demonstrate by flow cytometry –TdT terminal present in 95% of ALL
    • 79.
      • Monoclonal antibodies to Lymphocytes antigens:
        • Primitive B lymphocytes-CD19/CD10
        • Primitive T cell-CD2/CD5/CD7
      • Cytogenetics studies are used to determine prognosis
      Laboratory Findings
    • 80. Acute Leukemias Treatment
      • ALL
        • Lengthy /multiple chemotherapy given over a period of 2-3 years
      • Induction chemotherapy : reduce blasts to undetectable levels, and restores normal hematopoiesis
        • Vincristine
        • Corticosteroids
        • L-asparaginase
        • Cytabarine
    • 81. Acute Leukemias Treatment
      • Consolidation therapy : continuing chemotherapy same agents to induce elimination of further leukemic cells
      • Intensification therapy : to treat cells resistant to the induction regimen
      • Maintenance therapy : low-dose intermittent chemotherapy to prevent relapse
    • 82. Acute Leukemias Treatment
      • Remission : presence of less than 5 % blasts in the BM with restoration of normal peripheral blood counts
      • Intratechal chemotherapy and brain irradiation to destroy cells in the CNS and testes ( leukemia Sanctuaries )
      • The worse the prognosis the early the transplant of BM should be offered
    • 83. Acute Myeloid Leukemia
      • See Classification for AML in the Book
      • Leukostasis / hyperleukocytosis syndrome
        • High levels of circulating blasts
        • Diffuse pulmonary infiltrates
        • Acute respiratory distress
    • 84. Acute Myeloid Leukemia AML
      • Blast cells may also injure vasculature causing CNS bleeding
      • Hyperkalemia , acidosis and hyperuricemia caused by increased cell breakdown can precipitate renal failure
      • Leukophoresis , Hydroxyurea, and hydration to avoid more damage
    • 85. Acute Myeloid Leukemia AML
      • Stem cell transplant only hope for cure in some patients with AML and poor prognosis, or after relapse
    • 86.  
    • 87.  
    • 88. Lymphocytes Disorders
      • Neoplasia of Lymphoid origin
        • Non Hodgkin’s Lymphoma
        • Hodgkin’s Lymphoma
        • Lymphoid Leukemia
        • Plasma cells Dyscrasias
    • 89. Lymphadenopathy
      • Painless enlargement of the lymph nodes is the most common presentation of lymphoid malignancy in adults
      • Cervical lymphadenopathy:
        • URI
        • IM
        • Bacterial pharyngitis
        • Other viral syndromes
    • 90. Lymphadenopathy
      • Unilateral axillary, inguinal, or femoral adenopathy
        • may be caused by local skin infections involving the affected area
      • Generalized lymphadenopathy caused by
        • systemic infections such as HIV, drug reactions, autoimmune Ds, lymphoma, or others
    • 91. Lymphadenopathy
      • Excisional lymph node biopsy is done if no apparent cause
      • Histological examination and immunophenotyping for classification
    • 92. Non Hodgkin’s Lymphoma
      • Heterogeneous group of cancers of the lymphocytes
      • From indolent course to rapidly progressing
      • Cause not known
      • Frequently associated with chromosomal translocations
    • 93. Non Hodgkin’s Lymphoma
    • 94. Non Hodgkin’s Lymphoma
      • Different classifications through the years
      • Most updated one REAL/WHO
      • REAL: Revised European-American Lymphoma Classification updated by WHO: World Health Organization in 2001
    • 95. Non Hodgkin’s Lymphoma
      • Most common types in the US:
        • Follicular lymphomas
        • Chronic Lymphocytic Leukemia(CLL) or small lymphocytic lymphoma
        • Mantel cell lymphomas
        • Diffuse large B-cell Lymphomas
    • 96. Non Hodgkin’s Lymphoma
      • Associated with oncogenic viruses:
      • EBV-AIDS related lymphomas
      • EBV-related to the Burkitt’s lymphoma that is endemic in Africa
      • HTLV-1 causally linked to T-cell leukemia endemic in Japan and the Caribbean
    • 97. Non Hodgkin’s Lymphoma
      • Extra nodal site involvement in the GI , BM, liver, and Waldeyer’s ring or any part of the body
      • More aggressive types have more extra nodal or diffuse involvement including CNS (Burkitt’s and Lymphoblastics)
    • 98. Non Hodgkin’s Lymphoma
      • After diagnosis of Lymphoma
      • Staging: determines the extent of involvement , prognosis, and may influence the choice of therapy
      • Modified Ann Arbor staging classification is used for both non H. and Hodgkin’s Lymphoma
    • 99.
      • Stage l: single lymph node region or structure, or extra lymphatic site
      • Stage ll: two or more lymph node regions on the same side of the Diaphragm or contiguous extra lymphatic site and lymph node region
      • Stage lll: involvement of lymph nodes regions on both sides of the Diaphragm , accompanied by extra lymphatic site or spleen or both
      • Stage lV diffuse or disseminated involvement of one or more extra lymphatic organs with or without associated lymph node involvement
      • Page 520
    • 100. Staging evaluation
      • History-constitutional symptoms (fever, nights sweats, and weight loss-B symptoms)
      • Complete PE – Lymph Nodes size and distribution
      • Blood work
      • CT scan ABD.CHEST.PELVIS
      • BM aspirate and Biopsy
      • PET scan
      • Lumbar puncture
    • 101. Non Hodgkin’s Lymphoma
      • Low grade/indolent includes :
        • Follicular lymphomas
        • Small lymphocytic lymphomas(CLL)
      • Are mature clonal B cell neoplasm
      • Advanced stage or disseminated at presentation (80-90%)
      • Non curable, and long natural Hx, watch and wait strategy
      • Advanced stage – systemic chemotherapy
    • 102. Non Hodgkin’s Lymphoma
      • Patients with diffuse aggressive lymphoma are treated immediately because these are potentially curable
      • Multidrug chemotherapy including anthracycline
      • CHOP: most common regimen, includes cyclophosphamide, doxorubicin, vincristine, and prednisone
      • 30-40% cure rate
    • 103. Non Hodgkin’s Lymphoma
      • Burkitt’s Lymphoma:
      • High grade B cell Lymphoma, rare in adults ,endemic in children in Africa (EBV), curable
      • Involve BM , and CNS
      • Urgent inpatient treatment, highly aggressive/rapid growth
      • Frequent abdominal pain and fullness /abdomen predilection
      • Tumor Lysis Syndrome common
    • 104. Non Hodgkin’s Lymphoma
      • Lymphoblastic lymphoma (ALL) T-cell lymphoma
      • + tdt (terminal deoxynucleotide tranferase)
      • Young male adults
      • Involves mediastinum and BM
    • 105.
      • Both require intensive treatment with multiple therapy
      • intrathecal therapy to prevent relapse
      • Prophylaxis for “tumor lysis syndrome” with hydration, alkalinization of the urine and allopurinol
      • BM autologous transplant used
      • MALT(mucosal associated lymp.tumors) of the stomach treated with antibiotics-H.pilory
      Non Hodgkin’s Lymphoma
    • 106. Prognosis
      • Adverse prognosis factors:
      • Age over 60 yo
      • Elevated serum LDH
      • Stage lll or IV
      • Poor performance state
      • Durable complete response 80%-no risk patients
      • Early treatment with high dose therapy and autologous stem cell transplant improves the outcome
    • 107. Hodgkin’s disease
      • Painless lymphadenopathy
      • Constitutional symptoms may or may not be present
      • Diagnosis by lymph node biopsy
      • Reed-sternberg(RS) cells present in lymphoid tissue involved
    • 108. Hodgkin’s disease
      • Reed-Sternberg cell: bi-nucleated cell with nucleoli - owl’s eyes, B cell in nature, present in only half the HD patients
    • 109. Hodgkin’s disease
      • Bimodal age distribution 20yo and >50yo
      • Presents as painless mass(neck) and spreads to contiguous lymph nodes
      • Some have constitutional symptoms only, and generalized pruritus
      • Pain in in lymph node after alcohol ingestion
      • Late in course - Vascular invasion and hematogenous spread
    • 110. Hodgkin’s disease
      • Four Pathological Variants:
        • Nodular Sclerosing(80%)
          • Young adults/mediastinum/above Diaph
        • Mixed cellularity (15%)
          • Any age group/subdiaphragmatic common
        • Lymphocyte depleted (1%)
          • Older adults/HIV patients
        • Lymphocyte predominant (5%)
          • Peripheral nodes involvement
          • Polylobated nuclei RS cells(popcorn cells)
    • 111. HL Mixed Cellularity
    • 112. Hodgkin’s disease
      • Advanced disease: BM failure and malaise , cachexia , infections
      • Staging the same as for NHL with the addition of A or B for the absence or presence of B symptoms respectively
    • 113. Staging Workup
      • Similar to NHL
      • Thorough H & P
      • Blood work including ESR
      • Chest Xray
      • CT chest, abdomen, pelvis
      • BM aspirate /Biopsy
      • PETscan/gallium scan
      • Bone scan, spinal magnetic resonance if needed
    • 114. HL Treatment
      • Radiation therapy- initial for low risk IA and IIA disease
      • Trial limited chemotherapy for some patients-
      • IIIB, IV - combination chemotherapy
        • Adriamycin(doxorubicin)
        • Bleomycin
        • Vincristine
        • dacarbazine
    • 115. HL prognosis
      • IA, IIA- excellent >80% surv.rate after 10 years
      • IIIB, IV- 50-60% at 5 years
      • Better prognosis - the Lymphocyte Predominant subtype
      • Treatment after relapse is high dose chemotherapy and autologous stem cell transplant
    • 116.  
    • 117. Plasma cells Disorders
      • B cells neoplasm with production and secretion of monoclonal(M) immunoglobulin or part of an immunoglobulin molecule
      • Mature plasma cells which produce large amount of immunoglobulins
      • Protein can be detected in serum or urine by Protein Electrophoresis test
    • 118. Plasma cells Disorders
      • Clinically characterized by:
      • Systemic effect of the M protein
      • direct effect of bone and BM infiltration by the M protein
      • Classification by the immunoglobulin produced(G,A,D,M,E,) or component produced(heavy or light chain)
    • 119. Plasma cells Disorders
      • M proteins found also in benign and malignant conditions
      • Autoreactive and infectious disorders
      • MGUS
        • Low level M protein on serum
        • No associated abnormalities
        • More common than Multiple Myeloma
        • Considered pre-malignant
        • Monitor patient annual PE
    • 120. Plasma cells Disorders
      • Multiple Myeloma (MM)
        • Neoplastic infiltration of bone and BM
        • M Immunoglobulin or light chains in the serum or urine
      • Dx >30% plasma cells in BM
        • Serum M protein other than IgM
          • IgG >3g/dl
          • IgA >2g/dl
        • Urine M protein
          • 1g/24 hrs
    • 121. Plasma cells Disorders
      • 20% of patients lack the M protein in serum but show light chains protein in urine
      • Diagnosis made in this cases by presence of hypogammaglobulinemia, lytic bone lesions, or plasmacytoma
    • 122. Plasma cells Disorders
      • Clinical Manifestations MM
      • Results from
        • Bone or BM infiltration of Plasma Cells
        • Systemic effects of the M protein
        • And humoral immune deficiency
    • 123. Plasma cells Disorders MM
      • Bone Pain- Bone Xray-osteolytic -punched out lesions- low back and ribs
      • Osteopenia-pathologic fractures-spinal cord compression
      • Hypercalcemia - bony involvement
      • Anemia - BM infiltration
      • Decreased WBC and Plts less common
      • Increased infections
      • Renal insufficiency - hypercalcemia/uricemia
    • 124. Plasma cells Disorders
      • Hyperviscocity ,cryoglobulinemia- vertigo, nausea, visual disturbances, alter mental status
      • Clotting abnormalities
      • Enlarged tongue - amyloidosis
    • 125. Plasma cells Disorders
      • Lab Findings
      • RBC morphology WNL - Rouleau formation
      • Hallmark - paraprotein in SPEP
      • Immunofixation to determine if monoclonal
      • BM plasma cells 20-100% abnormal
    • 126. Plasma cells Disorders MM
      • Diff Diagnosis
      • MGUS
      • Waldestrom’s macroglobulinemia
      • Reactive polyclonal hypergammaglobulinemia
      • Lymphomas
      • Primary amyloidosis
    • 127. Plasma cells Disorders MM
      • Treatment
      • Thalidomide + dexamethasone
      • Stem cell transplant
      • Treat hypercalcemia
      • Biphosphonates
    • 128. Waldestrom’s Macroglobulinemia
      • Hybrid cell between B lymphocyte and plasma cell
      • Secrete IgM paraprotein
      • Symptoms related to the macroglobulin
      • Insidious course in the elderly
      • Hyperviscocity in serum- GI bleeding
      • Lethargy , stupor , or comma
      • Peripheral neuropathy
    • 129. Waldestrom’s Macroglobulinemia
      • PE
        • Retinal vein engorgement
        • Lymphadenopathy
        • Hepatosplenomegaly
        • Purpura
    • 130. Waldestrom’s Macroglobulinemia
      • Laboratory Findings
      • Anemia- expansion of plasma (protein)
      • Rouleau formation
      • Other blood counts normal
      • BM infiltrated by plasmacytic lymphocytes
      • Hallmark- IgM spike on SPEP
      • No renal failure
      • No bone lesions
    • 131. Waldestrom’s Macroglobulinemia
      • Treatment
        • Emergency plasmapheresis - hyperviscocity
        • Fludarabine and Rituxan
        • Autologous cell transplant
    • 132. WBC disorders
      • Leukocytosis : non specific term, denotes increased in either neutrophils or lymphocytes
      • Neutrophilia : increase in netrophils
      • Leukemoid reaction :
        • Extreme elevation of WBCs >50,000/mcl and early myeloid precursors
    • 133. WBC disorders
      • Leukemoid reaction:
        • Associated with inflammatory reactions and infections
      • Leukopenia : decrease in lymphocytes or neutrophils
      • Neutropenia : neutrophil count <1500/mcl
    • 134. WBC disorders
      • Neutropenia
        • Decreased production (congenital/acquired)
        • Increased sequestration (splenomegaly)
        • Peripheral destruction (overwhelming infections, drug related, Collagen vascular disease
    • 135. WBC disorders
      • Cyclic neutropenia : asymptomatic patients, evaluate with serial CBCs
        • Neutrophil count varies by ethnic group, lower in African-Americans
        • Relative benign condition
        • If neutrophil count is very low can develop infections
    • 136. WBC disorders
      • Congenital Agranulocytosis (Kostmann’s syndrome)
        • Profound neutropenia
        • Infections perinatal period
        • Associate with development of acute leukemias
        • Better prognosis with cytokines therapy
    • 137. WBC disorders
      • Post viral neutropenia
        • Common in children
        • Increased neutrophil consumption and viral suppression of BM
        • When associated to overwhelming sepsis-poor prognosis
    • 138. WBC disorders
      • Drug induced Neutropenia
        • Dose dependent or idiosyncratic reaction
        • Chemotherapy, Bactrin, Chloramphenicol
        • Most respond to discontinuation of the drug and G-CSF therapy
    • 139. WBC disorders
      • Autoimmune neutropenia
        • Associated to Systemic autoimmune disorders
        • SLE, RA
        • Not usually severe, indicator of disease activity
    • 140. Neutropenia. Laboratory Eval.
      • Serologic studies to rule out CVD
      • BM examination indicated early – frequently diagnostic
      • Most often reflects hematological conditions
    • 141. Neutropenia management
      • 1000-1500/mcl no significant impairment, no treatment needed, find the cause and treat condition as needed
      • 500-1000/mcl alert patient to increase risk of infection
      • <500/mcl significant risk of infection , should notify MD at any signs of infections-fever, aggressive antibiotic management
      • Patients with immune mediated neutropenia are managed with steroids and IVIG
    • 142.  
    • 143.
      • the end

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