hematology and oncology
Hematology and Oncology
Medical Knowledge Self-Assessment Program
Hematology and Oncology All New Content, Including 144 Multiple-Choice Questions
150591010
20 AMA PRA Category 1 Credits™ available until July 31, 2015.
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Table of Contents
Hematopoietic Stem Cells and Their Disorders Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Bone Marrow Failure Syndromes. . . . . . . . . . . . . . . . . . . . 1 Aplastic Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Pure Red Cell Aplasia . . . . . . . . . . . . . . . . . . . . . . . . . 3 Neutropenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Thrombocytopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 The Myelodysplastic Syndromes. . . . . . . . . . . . . . . . . . . . . 5 Myeloproliferative Disorders . . . . . . . . . . . . . . . . . . . . . . . 6 Polycythemia Vera. . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Essential Thrombocythemia . . . . . . . . . . . . . . . . . . . . 8 Chronic Myeloid Leukemia . . . . . . . . . . . . . . . . . . . . 8 Primary Myelofibrosis . . . . . . . . . . . . . . . . . . . . . . . . . 9 Acute Myeloid Leukemia . . . . . . . . . . . . . . . . . . . . . 10 Acute Lymphoblastic Leukemia . . . . . . . . . . . . . . . . 11 Hematopoietic Growth Factors. . . . . . . . . . . . . . . . . 12 Hematopoietic Stem Cell Transplantation. . . . . . . . . 12
Multiple Myeloma and Related Disorders Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Multiple Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Clinical Manifestations and Findings . . . . . . . . . . . . . 13 Diagnosis and Prognosis . . . . . . . . . . . . . . . . . . . . . . 14 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Monoclonal Gammopathy of Undetermined Significance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Immunoglobulin Light-Chain Amyloidosis . . . . . . . . . . . 16 Waldenstrรถm Macroglobulinemia . . . . . . . . . . . . . . . . . . 17
Approach to Anemia Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Anemia Due to Erythrocyte Underproduction or Maturation Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Iron Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Cobalamin (Vitamin B12) Deficiency. . . . . . . . . . . . . 21 Folate Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Inflammatory Anemia. . . . . . . . . . . . . . . . . . . . . . . . 24 Anemia of Kidney Disease. . . . . . . . . . . . . . . . . . . . . 24 Hemolytic Anemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Congenital Hemolytic Anemias . . . . . . . . . . . . . . . . . . . . 26 Hereditary Spherocytosis . . . . . . . . . . . . . . . . . . . . . 26 Glucose-6-Phosphate Dehydrogenase Deficiency . . . 26 Thalassemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Sickle Cell Syndromes. . . . . . . . . . . . . . . . . . . . . . . . 28 Other Hemoglobinopathies . . . . . . . . . . . . . . . . . . . 31 Acquired Hemolytic Anemias. . . . . . . . . . . . . . . . . . . . . . 32 Autoimmune Hemolytic Anemia . . . . . . . . . . . . . . . 32 Warm Autoimmune Hemolytic Anemia . . . . . . . . . . 32 Cold Agglutinin Disease . . . . . . . . . . . . . . . . . . . . . . 32 Drug-induced Autoimmune Hemolytic Anemia . . . . 33 Microangiopathic Hemolytic Anemia . . . . . . . . . . . . 33 Paroxysmal Nocturnal Hemoglobinuria . . . . . . . . . . 34 Other Causes of Hemolysis. . . . . . . . . . . . . . . . . . . . 35 Iron Overload Syndromes . . . . . . . . . . . . . . . . . . . . . . . . 35 Hemochromatosis . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Secondary Iron Overload . . . . . . . . . . . . . . . . . . . . . 36
Transfusion Cellular Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Erythrocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Platelets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Plasma Products. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 Fresh Frozen Plasma. . . . . . . . . . . . . . . . . . . . . . . . . 39 Cryoprecipitate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 Other Plasma-derived Transfusion Products . . . . . . . 39 Transfusion Complications. . . . . . . . . . . . . . . . . . . . . . . . 39 Hemolytic Reactions. . . . . . . . . . . . . . . . . . . . . . . . . 39 Nonhemolytic Reactions. . . . . . . . . . . . . . . . . . . . . . 40 Allergic Reactions and Anaphylaxis . . . . . . . . . . . . . . 40 Transfusion-associated Graft-Versus-Host Disease . . . 40 Infectious Complications . . . . . . . . . . . . . . . . . . . . . 40 Therapeutic Apheresis . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Bleeding Disorders Overview of Normal Hemostasis . . . . . . . . . . . . . . . . . . . 42 Evaluation of Patients with Suspected Bleeding Disorders . . 42 History and Physical Examination. . . . . . . . . . . . . . . 42 Laboratory Evaluation . . . . . . . . . . . . . . . . . . . . . . . 43 Congenital Bleeding Disorders. . . . . . . . . . . . . . . . . . . . . 43 Hemophilia A and B . . . . . . . . . . . . . . . . . . . . . . . . . 43 von Willebrand Disease. . . . . . . . . . . . . . . . . . . . . . . 45 Acquired Bleeding Disorders . . . . . . . . . . . . . . . . . . . . . . 46 Acquired Hemophilia . . . . . . . . . . . . . . . . . . . . . . . . 46 Coagulopathy of Liver Disease . . . . . . . . . . . . . . . . . 46 Disseminated Intravascular Coagulation . . . . . . . . . . 46 Vitamin K Deficiency . . . . . . . . . . . . . . . . . . . . . . . . 46 ix
Platelets
Issues in Oncology
Normal Platelet Physiology . . . . . . . . . . . . . . . . . . . . . . . 47 Approach to the Patient with Thrombocytopenia. . . . . . . 47 Immune (Idiopathic) Thrombocytopenic Purpura . . . . . . 49 Heparin-induced Thrombocytopenia . . . . . . . . . . . . . . . . 50 Thrombotic Thrombocytopenic Purpura–Hemolytic Uremic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Other Thrombocytopenias Due to Underproduction. . . . 52 Qualitative Platelet Disorders . . . . . . . . . . . . . . . . . . . . . . 52 Platelet Function Testing . . . . . . . . . . . . . . . . . . . . . 52 Acquired Platelet Dysfunction. . . . . . . . . . . . . . . . . . 52
Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Surgical Resection. . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Adjuvant Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Defining Treatment Goals . . . . . . . . . . . . . . . . . . . . 67 Era of Personalized Cancer Treatment . . . . . . . . . . . 68
Thrombotic Disorders Pathophysiology of Thrombosis and Thrombophilia . . . . 53 Inherited Thrombophilic Conditions . . . . . . . . . . . . . . . . 53 Factor V Leiden . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Prothrombin G20210A Gene Mutation . . . . . . . . . . 53 Antithrombin Deficiency . . . . . . . . . . . . . . . . . . . . . 53 Protein C Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . 53 Protein S Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . 53 Dysfibrinogenemia . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Acquired Thrombophilic Conditions . . . . . . . . . . . . . . . . 54 Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Trauma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Antiphospholipid Syndrome . . . . . . . . . . . . . . . . . . . 54 Catastrophic Antiphospholipid Syndrome . . . . . . . . . 55 Other Acquired Thrombophilic Disorders. . . . . . . . . 55 Management and Prevention . . . . . . . . . . . . . . . . . . . . . . 55 Thrombophilia Testing . . . . . . . . . . . . . . . . . . . . . . . 55 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Use of Anticoagulants. . . . . . . . . . . . . . . . . . . . . . . . 56 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Hematologic Issues in Pregnancy Gestational Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 Iron Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 Folate Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 Sickle Cell Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Thrombocytopenia in Pregnancy . . . . . . . . . . . . . . . . . . . 63 Gestational Thrombocytopenia . . . . . . . . . . . . . . . . . 63 Immune Thrombocytopenic Purpura . . . . . . . . . . . . 63 Microangiopathy of Pregnancy . . . . . . . . . . . . . . . . . 64 Thrombophilia and Venous Thromboembolism in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Epidemiology, Pathophysiology, and Risk Factors . . . 65 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 x
Breast Cancer Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Epidemiology and Risk Factors . . . . . . . . . . . . . . . . . . . . 69 Chemoprevention and Other Risk Reduction Strategies . . 70 Primary Breast Cancer Therapy . . . . . . . . . . . . . . . . . . . . 71 Ductal Carcinoma in Situ . . . . . . . . . . . . . . . . . . . . . 71 Invasive Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . 71 Adjuvant Systemic Therapy for Early-Stage Breast Cancer . . 72 Adjuvant Endocrine Therapy . . . . . . . . . . . . . . . . . . 72 Adjuvant Chemotherapy . . . . . . . . . . . . . . . . . . . . . . 73 Locally Advanced and Inflammatory Breast Cancer Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Breast Cancer Follow-up and Survivorship . . . . . . . . . . . . 74 Metastatic Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . 74
Ovarian and Cervical Cancer Ovarian Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Epidemiology and Risk Factors . . . . . . . . . . . . . . . . . 75 Screening and Risk Reduction Strategies . . . . . . . . . . 75 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Management of Recurrent Ovarian Cancer . . . . . . . . 77 Monitoring and Follow-Up . . . . . . . . . . . . . . . . . . . 77 Supportive Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 Epidemiology and Risk Factors . . . . . . . . . . . . . . . . . 78 Diagnosis and Staging. . . . . . . . . . . . . . . . . . . . . . . . 78 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Gastrointestinal Malignancies Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 Postoperative Colorectal Cancer Surveillance . . . . . . 81 Anal Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Esophageal Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 Gastric Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Gastrointestinal Neuroendocrine Tumors. . . . . . . . . . . . . 83
Lung Cancer Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Screening. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Non–Small Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . 85 Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 Small Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Diagnosis and Staging. . . . . . . . . . . . . . . . . . . . . . . . 87 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Head and Neck Cancer Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 Diagnosis and Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Genitourinary Cancer Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 Epidemiology and Risk Factors . . . . . . . . . . . . . . . . . 89 Diagnosis and Staging. . . . . . . . . . . . . . . . . . . . . . . . 90 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Prostate Cancer Follow-up and Posttreatment Recurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 Testicular Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 Diagnosis and Staging. . . . . . . . . . . . . . . . . . . . . . . . 93 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 Bladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 Diagnosis and Staging. . . . . . . . . . . . . . . . . . . . . . . . 94 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Renal Cell Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Diagnosis and Staging. . . . . . . . . . . . . . . . . . . . . . . . 96 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Lymphadenopathy and Lymphoid Malignancies Epidemiology and Risk Factors of Malignant Lymphomas . . 97 Diagnosis of Malignant Lymphomas . . . . . . . . . . . . . . . . 98 Classification, Staging, and Prognosis of Malignant Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 Overview and Treatment of Indolent Lymphomas. . . . . 100 Follicular Lymphoma . . . . . . . . . . . . . . . . . . . . . . . 100 Mucosa-associated Lymphoid Tissue (MALT) Lymphoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Chronic Lymphocytic Leukemia. . . . . . . . . . . . . . . 101 Hairy Cell Leukemia. . . . . . . . . . . . . . . . . . . . . . . . 102 Overview and Treatment of Aggressive Lymphomas . . . 102 Diffuse Large Cell Lymphoma . . . . . . . . . . . . . . . . 102
Mantle Cell Lymphoma . . . . . . . . . . . . . . . . . . . . . 103 Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . 103 Cutaneous T-cell Non-Hodgkin Lymphoma . . . . . 104
Cancer of Unknown Primary Site Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 Favorable Prognostic Subgroups . . . . . . . . . . . . . . . . . . 105 Poorly Differentiated Carcinoma . . . . . . . . . . . . . . 105 Isolated Regional Lymphadenopathy . . . . . . . . . . . 105 Peritoneal Carcinomatosis in Women . . . . . . . . . . . 105 Management of Patients Not in Favorable Prognosis Subgroups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Melanoma Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 Risk Factors and Prognosis. . . . . . . . . . . . . . . . . . . . . . . 106 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Primary Central Nervous System Tumors . . . . . . . 107 Oncologic Urgencies and Emergencies Structural Urgencies and Emergencies . . . . . . . . . . . . . . 107 Superior Vena Cava Syndrome . . . . . . . . . . . . . . . . 107 Brain Metastases Causing Increased Intracranial Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 Spinal Cord Compression . . . . . . . . . . . . . . . . . . . . 108 Malignant Pleural and Pericardial Effusions. . . . . . . 108 Metabolic Urgencies and Emergencies . . . . . . . . . . . . . . 109 Tumor Lysis Syndrome. . . . . . . . . . . . . . . . . . . . . . 109 Hypercalcemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Effects of Cancer and Cancer Therapy . . . . . . . . . . . . . . 109 Hematopoietic Disorders . . . . . . . . . . . . . . . . . . . . 109 Disorders of Cardiac Function . . . . . . . . . . . . . . . . 110 Disorders of Pulmonary Function . . . . . . . . . . . . . . 110 Disorders of Genitourinary and Renal Function . . . 110 Sexual Function . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 Secondary Malignancies . . . . . . . . . . . . . . . . . . . . . 110 Other Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 Self-Assessment Test . . . . . . . . . . . . . . . . . . . . . . . . 117 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
xi
Hematology and Oncology
Hematopoietic Stem Cells and Their Disorders
microenvironment, stroma, and growth factors are essential to the production of mature blood cells. Failure of the stem cell itself or any of its developmental regulators may lead to bone marrow failure or abnormal maturation.
Overview Hematopoiesis refers to the orderly formation and differentiation of circulating blood cells. Hematopoietic stem cells are the earliest cellular precursors, have the unique capacity for self-renewal and differentiation, and can develop into cells of other lineages such as brain cells. Stem cells are recognized by their unique surface markers such as CD34. The development of mature blood cells follows an orderly progression from committed progenitor cells (Figure 1) to the well-recognized cellular elements of the peripheral blood. The bone marrow
Bone Marrow Failure Syndromes Aplastic Anemia Aplastic anemia refers to conditions in which the bone marrow fails to produce blood cells, resulting in a hypocellular bone marrow and pancytopenia. The disease can be acquired or congenital and may be classified as moderate, severe, or very severe (Table 1). Most cases are idiopathic, but drugs, infection, toxins, and radiation exposure must first be excluded as
F I G U R E 1 . Regulation of hematopoiesis. The process of hematopoiesis is regulated by lineage-specific cytokines. These cytokines stimulate the proliferation and/or differentiation of pluripotent stem cells to committed mature peripheral blood cells. CFU GEMM = colony-forming unit–granulocyte, erythrocyte, megakaryocyte, monocyte; CFU GM = colony-forming unit–granulocyte, monocyte; BFU-E = burst-forming unit–erythrocyte; CFU MEG = colony-forming unit–megakaryocyte; CFU-G = colony-forming unit–granulocyte; CFU-M = colony-forming unit–monocyte; CFU-Baso = colony-forming unit–basophil; CFU-Eo = colony-forming unit–eosinophil; G-CSF = granulocyte colony-stimulating factor; M-CSF = macrophage colony-stimulating factor; CFU-E = colony-forming unit–erythrocyte.
1
Hematopoietic Stem Cells and Their Disorders
TA B L E 1 .
Classification of Aplastic Anemia
Classification
Characteristics
Very severe aplastic anemia
ANC <200/µL (0.2 × 109/L)
Severe aplastic anemia
Two or more of the following: ANC 200-500/µL (0.2-0.5 × 109/L) Platelet count <20,000/µL (20 × 109/L) Absolute reticulocyte count <40,000/µL (40 × 109/L)
Moderate aplastic anemia
ANC 500-1000/µL (0.5-1.0 × 109/L)
ANC = absolute neutrophil count.
potential causes. Aplastic anemia is inherited in approximately 15% to 20% of patients. The most common form of congenital aplastic anemia, Fanconi anemia, is an autosomal recessive, or X-linked, disorder, often accompanied by skin defects, short stature, hypogonadism, microcephaly, and urogenital abnormalities. In most patients with acquired aplastic anemia, immune dysfunction is thought to be central to the pathophysiology, and abnormal expression of suppressor T cells is often present. Patients with aplastic anemia may have the typical symptoms of anemia, including fatigue, exertional dyspnea, or worsening angina. Alternative presentations include bleeding due to thrombocytopenia or infection due to neutropenia. The complete blood count usually shows pancytopenia but, less commonly, may reveal more isolated anemia, neutropenia, or thrombocytopenia. The peripheral blood smear may demonstrate morphologic changes suggestive of other disorders, such as myelodysplasia. The bone marrow aspirate and biopsy is essential to the diagnosis and typically shows a hypocellular marrow with increased fat space and a decrease in hematopoietic elements (Figure 2). Cytogenetic analysis should be performed to exclude the characteristic chromosome mutations seen in hypocellular myelodysplastic syndrome and other bone marrow disorders. Additional laboratory studies to evaluate other conditions associated with pancytopenia include serum cobalamin (vitamin B12) and folate measurement, liver chemistry tests, HIV testing, hepatitis serologies, paroxysmal nocturnal hemoglobinuria (PNH) screening (see Hemolytic Anemia in Approach to Anemia), and, in patients younger than 50 years of age, chromosomal breakpoint analysis to exclude Fanconi anemia. Small PNH clones identified by the absence of CD55 and CD59, but without overt hemolysis, can be identified by flow cytometry in approximately 50% of patients with aplastic anemia, whereas patients with classic PNH may later develop aplastic anemia. In patients with aplastic anemia who have not undergone hematopoietic stem cell transplantation (HSCT), annual screening for a PNH clone is recommended because an increase may predate a more classic hemolytic 2
F I G U R E 2 . Aplastic anemia. Hypocellular bone marrow with increased fat content in a patient with pancytopenia. Almost no identifiable hematopoiesis can be seen.
presentation or an evolving bone marrow failure syndrome. In the absence of hemolysis, treatment of asymptomatic PNH is generally not initiated. Patients with severe aplastic anemia who are younger than 40 years with minimal comorbidities and a human leukocyte antigen (HLA)–compatible sibling should be offered allogeneic HSCT as initial therapy, which is associated with a cure rate ranging from 75% to 90% in some studies. For patients who are not HSCT candidates, who have less severe disease, or who have no matched donors, immunosuppressive therapy consisting of antithymocyte globulin and cyclosporine has resulted in long-term survival in 60% to 85% of patients. Relapses occur in up to one third of patients, especially as cyclosporine is tapered. The 10-year cumulative rate of myelodysplasia or acute myeloid leukemia is 5% to 10% in surviving patients. Appropriate supportive care is essential for long-term survival. Prophylactic antibiotic, antiviral, and antifungal agents are appropriate to avoid life-threatening infections that can complicate treatment. Proper transfusion management is also essential for minimizing bleeding risk. Leukodepletion of erythrocytes and platelets minimizes the risk for alloimmunization. Cytomegalovirus–negative products should be transfused until the patient’s cytomegalovirus status is determined. Irradiation of blood products to prevent transfusionacquired graft-versus-host disease (GVHD) can be considered before transplantation; irradiation is generally performed after transplantation. Prophylactic platelet transfusions may be appropriate in patients at high risk or in those with a platelet count of less than 10,000/µL (10 × 109/L). The use of growth factors such as granulocyte colony-stimulating factor (G-CSF) has been shown to be ineffective as primary therapy and is a controversial adjunctive treatment.
This self-assessment test contains one-best-answer multiple-choice questions. Please read these directions carefully before answering the questions. Answers, critiques, and bibliographies immediately follow these multiple-choice questions. The American College of Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The American College of Physicians designates MKSAP 16 Hematology and Oncology for a maximum of 20 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Earn “Same-Day” CME Credits Online For the first time, print subscribers can enter their answers online to earn CME credits in 24 hours or less. You can submit your answers using online answer sheets that are provided at mksap.acponline.org, where a record of your MKSAP 16 credits will be available. To earn CME credits, you need to answer all of the questions in a test and earn a score of at least 50% correct (number of correct answers divided by the total number of questions). Take any of the following approaches: ➢ Use the printed answer sheet at the back of this book to record your answers. Go to mksap.acponline.org, access the appropriate online answer sheet, transcribe your answers, and submit your test for same-day CME credits. There is no additional fee for this service. ➢ Go to mksap.acponline.org, access the appropriate online answer sheet, directly enter your answers, and submit your test for same-day CME credits. There is no additional fee for this service. ➢ Pay a $10 processing fee per answer sheet and submit the printed answer sheet at the back of this book by mail or fax, as instructed on the answer sheet. Make sure you calculate your score and fax the answer sheet to 215-351-2799 or mail the answer sheet to Member and Customer Service, American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106-1572, using the courtesy envelope provided in your MKSAP 16 slipcase. You will need your 10-digit order number and 8-digit ACP ID number, which are printed on your packing slip. Please allow 4 to 6 weeks for your score report to be emailed back to you. Be sure to include your email address for a response. If you do not have a 10-digit order number and 8-digit ACP ID number or if you need help creating a username and password to access the MKSAP 16 online answer sheets, go to mksap.acponline.org or email custserv@ acponline.org. CME credit is available from the publication date of July 31, 2012, until July 31, 2015. You may submit your answer sheets at any time during this period.
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Self-Assessment Test
Hematology and Oncology Self-Assessment Test
Each of the numbered items is followed by lettered answers. Select the ONE lettered answer that is BEST in each case.
Hematology Questions
Laboratory studies: Hemoglobin
Item 1 A 62-year-old man undergoes a routine examination. He notes increasing fatigue of 8 months’ duration but states he can perform his usual daily activities. He has no fever, night sweats, anorexia, or weight loss. The medical history is noncontributory, and he takes no medications. On physical examination, vital signs are normal. The spleen is palpable three finger breadths below the left midcostal margin. There is no lymphadenopathy or hepatomegaly. Laboratory studies indicate a hemoglobin level of 12.5 g/dL (125 g/L), a leukocyte count of 14,400/µL (14.4 × 109/L), and a platelet count of 148,000/µL (148 × 109/L). A peripheral blood smear is shown.
Leukocyte count
Platelet count Reticulocyte count
8.3 g/dL (83 g/L) (following transfusion of 1 unit of irradiated packed erythrocytes last week) 500/µL (0.5 × 109/L) with 23% neutrophils, 3% band forms, and 71% lymphocytes 26,000/µL (26 × 109/L) 0.2%
Review of the bone marrow biopsy done 2 weeks ago confirms the diagnosis of aplastic anemia, demonstrating an aplastic bone marrow with normal cytogenetics. Which of the following is the most appropriate treatment? (A) Allogeneic hematopoietic stem cell transplantation (B) Antithymocyte globulin, corticosteroids, and cyclosporine (C) Autologous hematopoietic stem cell transplantation (D) Corticosteroids (E) Granulocyte colony-stimulating factor
Item 3
The bone marrow cannot be aspirated, but the bone marrow biopsy reveals a hypercellular marrow with extensive fibrosis and abnormal-appearing megakaryocytes. Results of conventional cytogenetic testing are normal. The JAK2 mutation assay is positive. Fluorescence in situ hybridization of the bone marrow for the (9;22) translocation is negative. Which of the following is the most appropriate management of this patient now? (A) (B) (C) (D) (E)
Allogeneic hematopoietic stem cell transplantation Danazol Hydroxyurea Imatinib Observation
A 32-year-old woman undergoes preoperative evaluation prior to a complex spinal surgery for repair of severe scoliosis. Her expected blood loss is 2.5 liters. She had a severe anaphylactic reaction during a prior erythrocyte transfusion she received for postpartum hemorrhage at age 25 years. On physical examination, temperature is 36.8 °C (98.4 °F), blood pressure is 132/76 mm Hg, and pulse rate is 78/min. Laboratory studies indicate a hemoglobin level of 13.6 g/dL (136 g/L), a leukocyte count of 7800/µL (7.8 × 109/L), and a platelet count of 186,000/µL (186 × 109/L). Previous laboratory studies indicate an IgG level of 868 mg/dL (8.68 g/L), an IgA level <5 mg/dL (0.05 g/L), and an IgM level of 64 mg/dL (0.64 g/L). No monoclonal spike is found on serum protein electrophoresis. Which of the following is the most appropriate erythrocyte product for this patient? (A) (B) (C) (D) (E)
Cytomegalovirus negative γ-Irradiated Leukoreduced Phenotypically matched Washed
Item 4 Item 2 A 24-year-old man undergoes follow-up evaluation for treatment of aplastic anemia. Two of his siblings are HLAidentical matches.
A 75-year-old man is evaluated in the hospital for community-acquired pneumonia. He is bedbound. He has heart failure and hypertension for which he takes lisinopril and carvedilol. 119
Self-Assessment Test
Directions
Answers and Critiques Hematology Answers Item 1
Answer:
E
Bibliography Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895-2901. [PMID: 18988864]
The most appropriate management of this patient now is observation. This patient has primary myelofibrosis, which is a chronic myeloproliferative disorder characterized by overproduction of megakaryocytes and bone marrow stromal cell-mediated collagen deposition. The peripheral blood smear shows marked leukoerythroblastic findings with tear drop–shaped erythrocytes and megathrombocytes. The bone marrow aspirate is often “dry” (unsuccessful aspirate), and bone marrow biopsy shows marked fibrosis. This patient has low-risk primary myelofibrosis (PMF) given the absence of high-risk features such as age older than 65 years; fever, night sweats, and a weight loss of 10% or more; a hemoglobin concentration of less than 10 g/dL (100 g/L); a leukocyte count greater than 25,000/µL (25 × 109/L); and circulating blasts of 1% or more. As such, his median overall survival is 135 months or approximately 11 years. Given his favorable prognosis, he requires only observation for now. Allogeneic hematopoietic stem cell transplantation is potentially curative in patients with PMF but is associated with significant morbidity and mortality and would not be a good choice for a patient with low-risk disease, but it could be considered if the disease progresses. Transplantation is the preferred treatment for younger patients with two or more adverse prognostic features. Danazol is used to treat PMF-related anemia and leads to responses in 37% of patients with transfusion-dependent anemia or a hemoglobin level less than 10 g/dL (100 g/L). This treatment is not indicated in this patient considering his hemoglobin level of 12.5 g/dL (125 g/L). Hydroxyurea would be a reasonable therapy if the patient had constitutional symptoms such as fever, weight loss, night sweats, symptomatic splenomegaly, or problematic thrombocytosis; however, this treatment is not required now. Imatinib is appropriate therapy in patients with chronic myeloid leukemia, but it is not effective in treating PMF. KEY POINT
• Close observation, with palliative care as needed, is appropriate for patients with lowrisk primary myelofibrosis.
Item 2
Answer:
A
Educational Objective: Treat aplastic anemia in a young patient. The most appropriate treatment is allogeneic hematopoietic stem cell transplantation (HSCT). Aplastic anemia is classified by the severity of the neutropenia. Moderate aplastic anemia is diagnosed when the absolute neutrophil count (ANC) is 500 to 1000/µL (0.5-1.0 × 109/L). Severe aplastic anemia occurs when two or more of the following are present: ANC 200 to 500/µL (0.2-0.5 × 109/L), platelet count less than 20,000/µL (20 × 109/L), and reticulocyte count less than 0.2%. Very severe aplastic anemia is diagnosed when the ANC is less than 200/µL (0.2 × 109/L). ANC is calculated as leukocyte count × percentage of polymorphonuclear cells + band forms. This patient has very severe aplastic anemia. Patients with severe aplastic anemia who have an HLA-identical sibling and are younger than 40 years should be offered allogeneic HSCT as initial therapy. Because of the high mortality rate associated with this procedure, HSCT is generally not recommended as initial therapy for patients older than 40 years or those who are not medically fit to undergo transplantation or who have no HLA-identical sibling; these patients are typically treated with antithymocyte globulin and cyclosporine as initial therapy. Because this patient is young, healthy, and has two siblings who are an HLA-identical match, he should be offered allogeneic transplantation as initial therapy. In some clinical trials of patients who are not transplant candidates, intravenous antithymocyte globulin plus corticosteroids and cyclosporine can result in partial and complete responses in 60% to 80% of patients. Many of these patients become transfusion independent, although response is often delayed for 3 to 6 months, and relapses can occur when the cyclosporine is tapered. Autologous HSCT would not be an appropriate treatment choice because this patient has an essentially acellular bone marrow. Prednisone as a single agent produces a very low response rate in patients with aplastic anemia. Growth factors such as granulocyte colony-stimulating factor should not be given as primary therapy for aplastic anemia, and the use of growth factors as concomitant therapy is controversial. These agents are expensive, and some 159
Answers and Critiques
Educational Objective: Manage a patient with low-risk primary myelofibrosis.