MKSAP 17 - Hematology and Oncology by American College of Physicians

Medical Knowledge Self-Assessment ProgramÂŽ

Hematology and Oncology

22 AMA PRA Category 1 Creditsâ&#x201E;˘ available until July 31, 2018.

Table of Contents Hematopoietic Stem Cells and Their Disorders Overview. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Bone Marrow Failure Syndromes . . . . . . . . . . . . . . . . . . . . 2 Aplastic Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Pure Red Cell Aplasia . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Neutropenia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 The Myelodysplastic Syndromes. . . . . . . . . . . . . . . . . . . . . 3 Myeloproliferative Neoplasms. . . . . . . . . . . . . . . . . . . . . . . 4 Chronic Myeloid Leukemia . . . . . . . . . . . . . . . . . . . . . 5 Polycythemia Vera. . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Essential Thrombocythemia . . . . . . . . . . . . . . . . . . . . 7 Primary Myelofibrosis. . . . . . . . . . . . . . . . . . . . . . . . . . 8 Eosinophilia and Hypereosinophilic Syndromes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Acute Leukemias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Acute Myeloid Leukemia . . . . . . . . . . . . . . . . . . . . . . 9 Acute Lymphoblastic Leukemia. . . . . . . . . . . . . . . . . 10 Hematopoietic Growth Factors. . . . . . . . . . . . . . . . . . . . . 10 Hematopoietic Stem Cell Transplantation. . . . . . . . . . . . 11

Iron Overload Syndromes Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Primary/Hereditary Hemochromatosis. . . . . . . . . . . . . 36 Secondary Iron Overload. . . . . . . . . . . . . . . . . . . . . . . . . . 37

Platelet Disorders Normal Platelet Physiology . . . . . . . . . . . . . . . . . . . . . . . . 37 Approach to the Patient with Thrombocytopenia. . . . . . . . . . . . . . . . . . . . . . . . . . 37 Thrombocytopenic Disorders . . . . . . . . . . . . . . . . . . . . . . 37 Non窶的mmune-Mediated Thrombocytopenia. . . . . . 38 Immune-Mediated Thrombocytopenia . . . . . . . . . 39 Qualitative Platelet Disorders . . . . . . . . . . . . . . . . . . . . . 40 Acquired Platelet Dysfunction. . . . . . . . . . . . . . . . . 40 Platelet Function Testing . . . . . . . . . . . . . . . . . . . . . 40

Bleeding Disorders

Multiple Myeloma and Related Disorders Overview. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evaluation for Monoclonal Gammopathies . . . . . . . . . . . Monoclonal Gammopathy of Undetermined Significance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Multiple Myeloma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Manifestations and Findings . . . . . . . . . . . . Diagnosis and Prognosis. . . . . . . . . . . . . . . . . . . . . . . Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunoglobulin Light-Chain Amyloidosis. . . . . . . . . . . Waldenstrﾃｶm Macroglobulinemia. . . . . . . . . . . . . . . . . . . Cryoglobulinemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Congenital Hemolytic Anemias. . . . . . . . . . . . . . . . . 27 Acquired Hemolytic Anemias . . . . . . . . . . . . . . . . . . 33 Other Causes of Hemolysis. . . . . . . . . . . . . . . . . . . . 35

11 11 14 15 15 16 16 17 19 19

Normal Hemostasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Evaluation of Patients with Suspected Bleeding Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Congenital Bleeding Disorders . . . . . . . . . . . . . . . . . . . . . 43 Hemophilia A and B. . . . . . . . . . . . . . . . . . . . . . . . . . 43 von Willebrand Disease . . . . . . . . . . . . . . . . . . . . . . 44 Acquired Bleeding Disorders. . . . . . . . . . . . . . . . . . . . . . 44 Coagulopathy of Liver Disease. . . . . . . . . . . . . . . . . 44 Acquired Hemophilia. . . . . . . . . . . . . . . . . . . . . . . . . 45 Disseminated Intravascular Coagulation . . . . . . . . . 45

Transfusion Erythrocyte Disorders Approach to Anemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Anemia Due to Erythrocyte Underproduction or Maturation Defects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Iron Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Inflammatory Anemia . . . . . . . . . . . . . . . . . . . . . . . . 24 Anemia of Kidney Disease. . . . . . . . . . . . . . . . . . . . . 24 Cobalamin (Vitamin B12) Deficiency. . . . . . . . . . . . . 25 Folate Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Hemolytic Anemias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Cellular Products. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Erythrocytes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Platelets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 Plasma Products. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Fresh Frozen Plasma. . . . . . . . . . . . . . . . . . . . . . . . . 48 Cryoprecipitate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Other Plasma-Derived Transfusion Products . . . . 49 Transfusion Complications . . . . . . . . . . . . . . . . . . . . . . . 50 Hemolytic Reactions. . . . . . . . . . . . . . . . . . . . . . . . . 50 Nonhemolytic Transfusion Reactions. . . . . . . . . . . 50 Allergic Reactions and Anaphylaxis . . . . . . . . . . . . . 51 ix

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Transfusion-associated Graft-versus-Host Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Infectious Complications. . . . . . . . . . . . . . . . . . . . . . 51 Therapeutic Apheresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Thrombotic Disorders Pathophysiology of Thrombosis and Thrombophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Thrombophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Inherited Thrombophilic Conditions . . . . . . . . . . . . 53 Acquired Thrombophilic Conditions . . . . . . . . . . . . 55 Deep Venous Thrombosis and Pulmonary Embolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Long-term Complications . . . . . . . . . . . . . . . . . . . . 60 Other Sites of Thrombosis. . . . . . . . . . . . . . . . . . . . . . . . . 61 Superficial Venous Thrombophlebitis. . . . . . . . . . . . 61 Upper Extremity DVT. . . . . . . . . . . . . . . . . . . . . . . . . 61 Budd-Chiari Syndrome. . . . . . . . . . . . . . . . . . . . . . . . 61 Portal and Mesenteric Vein Thrombosis. . . . . . . . . . 62 Splenic Vein Thrombosis . . . . . . . . . . . . . . . . . . . . . . 62 Cerebral and Sinus Vein Thrombosis . . . . . . . . . . . . 62 Retinal Vein Thrombosis. . . . . . . . . . . . . . . . . . . . . . . 62 Unexplained Arterial Thrombosis. . . . . . . . . . . . . . 63 Anticoagulants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Unfractionated Heparin. . . . . . . . . . . . . . . . . . . . . . 63 Low-Molecular-Weight Heparin . . . . . . . . . . . . . . . 63 Fondaparinux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Warfarin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 New Oral Anticoagulants. . . . . . . . . . . . . . . . . . . . . 66

Hematologic Issues in Pregnancy Gestational Anemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Sickle Cell Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Thrombocytopenia in Pregnancy . . . . . . . . . . . . . . . . . . 68 Gestational Thrombocytopenia. . . . . . . . . . . . . . . . 68 Immune Thrombocytopenic Purpura. . . . . . . . . . . 68 Microangiopathy of Pregnancy . . . . . . . . . . . . . . . . 68 Thrombophilia and Venous Thromboembolism in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Epidemiology, Pathophysiology, and Risk Factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

Issues in Oncology Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Staging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

Performance Status. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Goals of Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Understanding Cancer Terminology. . . . . . . . . . . . . . . . . 72 Treatment Approaches. . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 Traditional Cancer Therapies. . . . . . . . . . . . . . . . . . . 72 Personalized Medicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

Breast Cancer Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Epidemiology and Risk Factors. . . . . . . . . . . . . . . . . . . . . 74 Chemoprevention and Other Risk Reduction Strategies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Staging and Prognosis of Early-Stage Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . 76 Primary Breast Cancer Therapy. . . . . . . . . . . . . . . . . . . . . 78 Ductal Carcinoma in Situ. . . . . . . . . . . . . . . . . . . . . . 78 Invasive Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . 78 Adjuvant Systemic Therapy for Nonmetastatic Breast Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 Adjuvant Endocrine Therapy. . . . . . . . . . . . . . . . . . . 79 Adjuvant Chemotherapy. . . . . . . . . . . . . . . . . . . . . . 80 Locally Advanced and Inflammatory Breast Cancer. . . 80 Breast Cancer Follow-up and Survivorship. . . . . . . . . . . 81 Metastatic Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 82

Ovarian Cancer Epidemiology and Risk Factors. . . . . . . . . . . . . . . . . . . . . 83 Screening and Risk-Reduction Strategies. . . . . . . . . . . . 84 Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 Monitoring and Follow-up. . . . . . . . . . . . . . . . . . . . . . . . . 85 Management of Recurrent Ovarian Cancer. . . . . . . . . . 86

Cervical Cancer Epidemiology and Risk Factors. . . . . . . . . . . . . . . . . . . . 86 Diagnosis, Staging, and Treatment. . . . . . . . . . . . . . . . . 86 Prognosis and Surveillance . . . . . . . . . . . . . . . . . . . . . . . . 87

Gastroenterological Malignancies Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 Surgical Management. . . . . . . . . . . . . . . . . . . . . . . . 88 Adjuvant Treatment of Colorectal Cancer. . . . . . . . 89 Metastatic Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . 89 Postoperative Surveillance. . . . . . . . . . . . . . . . . . . . 90 Anal Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Pancreatic Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Gastroesophageal Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . 91 Neuroendocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . 92 Gastrointestinal Stromal Tumors. . . . . . . . . . . . . . . . . . . . 92

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Lung Cancer

Prognostic Subgroups of CUP . . . . . . . . . . . . . . . . . . . . . 112 Favorable Subgroups. . . . . . . . . . . . . . . . . . . . . . . . . 112 Nonfavorable Subgroups. . . . . . . . . . . . . . . . . . . . . . 113

Nonâ&#x20AC;&#x201C;Small Cell Lung Cancer. . . . . . . . . . . . . . . . . . . . . . 93 Diagnosis and Staging. . . . . . . . . . . . . . . . . . . . . . . . 93 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 Small Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Diagnosis and Staging. . . . . . . . . . . . . . . . . . . . . . . . 95 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Prognosis and Follow-up. . . . . . . . . . . . . . . . . . . . . . . . . 114

Head and Neck Cancer

Oncologic Urgencies and Emergencies

Risk Factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 Clinical Manifestations. . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Evaluation and Staging. . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Posttreatment Surveillance . . . . . . . . . . . . . . . . . . . . . . . 100

Structural Urgencies and Emergencies. . . . . . . . . . . . . . 115 Superior Vena Cava Syndrome. . . . . . . . . . . . . . . . . 115 Neoplastic Diseaseâ&#x20AC;&#x201C;Induced Acute Central Nervous System Emergencies . . . . . . . . . . . . . . . . . 115 Malignant Pleural and Pericardial Effusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 Metabolic Urgencies and Emergencies. . . . . . . . . . . . . . 117 Tumor Lysis Syndrome. . . . . . . . . . . . . . . . . . . . . . . 117 Hypercalcemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

Genitourinary Cancer Prostate Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Epidemiology and Risk Factors. . . . . . . . . . . . . . . . 101 Diagnosis and Staging. . . . . . . . . . . . . . . . . . . . . . . . 101 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Metastatic Prostate Cancer. . . . . . . . . . . . . . . . . . . . 103 Testicular Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Renal Cell Carcinoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 Bladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

Lymphoid Malignancies Epidemiology and Risk Factors. . . . . . . . . . . . . . . . . . . . 105 Evaluation and Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . 106 Classification, Staging, and Prognosis of Malignant Lymphoma. . . . . . . . . . . . . . . . . . . . . . . . . . . 106 Overview and Treatment of Indolent Lymphomas. . . . . . . . . . . . . . . . . . . . . . . . . . 107 Follicular Lymphoma. . . . . . . . . . . . . . . . . . . . . . . . 107 Mucosa-associated Lymphoid Tissue Lymphoma. . . . . . . . . . . . . . . . . . . . . . . . . . . 108 Chronic Lymphocytic Leukemia. . . . . . . . . . . . . . . 109 Hairy Cell Leukemia. . . . . . . . . . . . . . . . . . . . . . . . . 109 Overview and Treatment of Aggressive Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . 110 Diffuse Large B-Cell Lymphoma. . . . . . . . . . . . . . . 110 Mantle Cell Lymphoma. . . . . . . . . . . . . . . . . . . . . . . 110 Hodgkin Lymphoma. . . . . . . . . . . . . . . . . . . . . . . . . 111 Cutaneous T-Cell Non-Hodgkin Lymphoma . . . . . 111

Melanoma

Effects of Cancer Therapy and Survivorship Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 Acute Effects of Cancer Therapy. . . . . . . . . . . . . . . . . . . 118 Hematopoietic Toxicity. . . . . . . . . . . . . . . . . . . . . . . 118 Neutropenia and Fever. . . . . . . . . . . . . . . . . . . . . . . 119 Thrombocytopenia and Anemia. . . . . . . . . . . . . . . 119 Disorders of Pulmonary Function. . . . . . . . . . . . . . 119 Disorders of Genitourinary and Kidney Function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 Immune-Related Toxicities . . . . . . . . . . . . . . . . . . . 120 Effects on Bone Health. . . . . . . . . . . . . . . . . . . . . . . 120 Late Effects of Cancer Therapy . . . . . . . . . . . . . . . . . . . . 120 Secondary Malignancies. . . . . . . . . . . . . . . . . . . . . . 120 Disorders of Cardiac Function. . . . . . . . . . . . . . . . . 120 Sexual Function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Survivorship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 General Principles. . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Survivorship Care Plan. . . . . . . . . . . . . . . . . . . . . . . 121 Screening for Second Cancers and Lifestyle Modifications . . . . . . . . . . . . . . . . . . . . . . . 121 Cognitive Function after Cancer Therapy. . . . . . . . 121 Other Issues for Survivors . . . . . . . . . . . . . . . . . . . . 122

Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Cancer of Unknown Primary Site

Self-Assessment Test. . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .112 Diagnosis and Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . 112

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

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Hematology and Oncology Hematopoietic Stem Cells and Their Disorders Overview Hematopoiesis is the orderly formation of all recognizable blood elements from a pluripotent stem cell in the bone marrow. Hematopoietic stem cells (HSCs) can self-renew and differentiate (Figure 1) but can also transdifferentiate into mesenchymal tissues. Hematopoietic growth factors, bone marrow stroma, and adequate nutrients are all key ingredients in normal blood production. Disorders of the blood may occur at the HSC level or with any of the more differentiated descendants such as the myeloid, lymphoid, or erythroid progenitors.

Pure red cell aplasia (PRCA) and isolated neutropenia often reflect the response of the blood to autoimmunity or viral infection. Similarly, isolated thrombocytopenia is rarely caused by bone marrow failure. Its mechanism usually involves peripheral consumption and immune-mediated causes. Pancytopenia, in contrast, indicates failure of the bone marrow or severe peripheral sequestration, most often associated with cirrhosis and hypersplenism. Aplastic anemia and myelodysplastic syndrome (MDS) are contrasting marrow-failure disorders presenting with pancytopenia and very different findings within the bone marrow. The myeloproliferative neoplasms (MPNs) are clonal myeloid conditions in which blood production is deregulated and independent of hematopoietic growth factors.

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. The pluripotent HPC is also known as an HSC. BFU-E = burst-forming unit–erythrocyte; CFU-Baso = colony-forming unit–basophil; CFU-E = colony-forming unit–erythrocyte; CFU-Eo = colony-forming unit–eosinophil; CFU-G = colony-forming unit–granulocyte; CFU GEMM = colonyforming unit–granulocyte, erythrocyte, megakaryocyte, monocyte; CFU GM = colony-forming unit–granulocyte, monocyte; CFU-M = colony-forming unit–monocyte; CFU-MEG = colony-forming unit–megakaryocyte; G-CSF = granulocyte colony-stimulating factor; HPC = hematopoietic progenitor cell; M-CSF = macrophage colony-stimulating factor. Cell images courtesy of Deepty Bhansali, MD; Baylor Scott & White Health.

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Hematopoietic Stem Cells and Their Disorders

Acute leukemias of myeloblastic (AML) or lymphoblastic (ALL) origin can arise de novo or from a pre-existing MDS or MPN. They are often initially managed emergently. The clinical use of hematopoietic growth factors and HSC transplantation (HSCT) can be very helpful in the management of these diseases.

Bone Marrow Failure Syndromes Aplastic Anemia The normal adult bone marrow contains blood-making elements and fat in a ratio inversely related to age. Aplastic (without formation) anemia (AA) is a condition characterized by pancytopenia, with associated neutropenia, anemia, and thrombocytopenia, and a severely hypocellular bone marrow (<10%). Isolated cytopenias are uncommon despite the designation of anemia. The severity of the condition is defined by the degree of neutropenia, thrombocytopenia, or reticulocytopenia and has important implications for treatment and prognosis (Table 1). AA is usually acquired and is caused by toxic, viral, or autoimmune mechanisms. Although many medications may cause dose-related suppression of the bone marrow, true AA is rare. Marrow suppression caused by NSAIDs, β-lactam antibiotics, antiepileptic drugs, and psychotropic medications will usually resolve with discontinuation of the medication. Finding a definitive medication or viral association with AA, however, is uncommon. Autoimmunity is the dominant cause of adult AA. Autoreactive T cells attack pluripotent HSCs and cause aplasia. Therefore, immunosuppression with cyclosporine and antithymocyte globulin is first-line therapy and leads to disease control in 70% of adult patients. Allogeneic HSCT is a potentially curative therapy and should be considered for those younger than 50 years who have compatible donors. Treatment with hematopoietic growth factors is ineffective. AA, paroxysmal nocturnal hemoglobinuria (PNH), and MDS are all acquired defects of the HSC, so clinical overlap is considerable. PNH is an acquired disorder in which erythrocytes lack membrane proteins CD55 and CD59 required to stabilize complement, leading to episodic intravascular hemolysis (see Erythrocyte Disorders). Screening patients with AA

reveals that up to 50% have erythrocytes lacking CD55 and CD59; however, this is usually without evidence of overt hemolysis or thrombosis. A hypoplastic variant of MDS exists that can be difficult to distinguish from AA. Clues indicating the former can include cytogenetic abnormalities or dysplastic hematopoietic cells in the marrow. Up to 10% of patients with AA will develop typical MDS or AML within 10 years. Key Points

• Immunosuppression with cyclosporine and antithymocyte globulin leads to disease control in 70% of adult patients with aplastic anemia. • Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for aplastic anemia and should be considered for patients younger than 50 years who have compatible donors. • Management of aplastic anemia with hematopoietic growth factors is ineffective.

HVC

Pure Red Cell Aplasia The cardinal clinical feature in PRCA is isolated, severe anemia without an adequate reticulocyte response. Examination of the bone marrow shows an absence of erythrocyte precursors. Known causes and associations of PRCA are listed in Table 2. Similar to AA, the mechanism of action is predominantly T cell autoimmunity (pregnancy, thymoma, malignancy) or direct toxicity to erythrocyte precursors (viral, medications). In patients with chronic, compensated hemolytic anemia such as sickle cell anemia, parvovirus B19 infection can cause PRCA and a severe anemic crisis. Such patients rely on high levels of reticulocytosis and can lose all reserve with infection. Intravenous immune globulin (IVIG) may hasten viral clearance by providing adopted immunity to parvovirus and can be helpful in immunocompromised patients. Immunocompetent patients and those without chronic hemolytic anemia are less vulnerable to PRCA from this infection and may recover without IVIG. Bone marrow examination is required to diagnose PRCA and is useful for excluding secondary causes such as chronic lymphocytic leukemia or other indolent non-Hodgkin

Table 2. Causes of Acquired Pure Red Cell Aplasia Table 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)

ANC = absolute neutrophil count.

Parvovirus B19 infection Thymoma Autoimmune disease Lymphoid leukemias and lymphomas Solid tumors Drugs (phenytoin, isoniazid) Pregnancy Anti-EPO antibodies in patients receiving EPO EPO = erythropoietin.

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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.

Self-Assessment Test

Hematology and Oncology Self-Assessment Test

The American College of Physicians designates MKSAP 17 Hematology and Oncology for a maximum of 22 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Earn “Instantaneous” CME Credits Online Print subscribers can enter their answers online to earn Continuing Medical Education (CME) credits instantaneously. You can submit your answers using online answer sheets that are provided at mksap.acponline.org, where a record of your MKSAP 17 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 instantaneous 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 instantaneous CME credits. There is no additional fee for this service. ➢ Pay a $15 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 17 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 user name and password to access the MKSAP 17 online answer sheets, go to mksap.acponline.org or email custserv@acponline.org. CME credit is available from the publication date of July 31, 2015, until July 31, 2018. You may submit your answer sheets at any time during this period.

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Each of the numbered items is followed by lettered answers. Select the ONE lettered answer that is BEST in each case.

Hematology Questions Item 1 A 45-year-old woman is evaluated in the emergency department for a 1-day history of abdominal pain and fever. She also reports unexpected, heavy menstrual bleeding of 1 day’s duration and easy bruising of 2 days’ duration. Medical and family histories are unremarkable, and she takes no medications. On physical examination, the patient is oriented to person and place, but not time. Temperature is 38.1 °C (100.6 °F), blood pressure is 170/98 mm Hg, pulse rate is 110/min, and respiration rate is 20/min. Other than confusion, neurologic examination is normal. Subconjunctival hemorrhages are present. Cardiopulmonary examination is normal. Abdominal examination reveals tenderness to palpation without guarding or rebound. Pelvic examination shows blood in the vaginal vault with no cervical motion tenderness or adnexal masses. Laboratory studies: Hematocrit Leukocyte count Platelet count Reticulocyte count Bilirubin, total Creatinine Lactate dehydrogenase

26% 10,300/µL (10.3 × 109/L) 24,000/µL (24 × 109/L) 8.3% of erythrocytes 2.3 mg/dL (39.3 µmol/L) 3.2 mg/dL (283 µmol/L) 1500 U/L

Which of the following is the most appropriate diagnostic test to perform next? (A) (B) (C) (D)

ADAMTS-13 activity level Osmotic fragility test Peripheral blood smear Stool Shiga toxin assay

Item 2 A 75-year-old man arrives at the emergency department after passing three large-volume, melenic stools over a 2-hour period. Medical history is significant for atrial fibrillation and hypertension. Medications are warfarin, metoprolol, and lisinopril. On physical examination, he is diaphoretic and the skin is cool to the touch. Temperature is 36.8 °C (98.2 °F), blood pressure is 82/64 mm Hg, pulse rate is 142/min and irregular, and respiration rate is 20/min. Oxygen saturation is 95% breathing ambient air. Cardiac examination reveals tachycardia. Pulmonary examination is normal. Peripheral pulses are thready. Rectal examination reveals melenic stool that is guaiac positive. Laboratory studies: Hemoglobin Leukocyte count Platelet count INR

8.2 g/dL (82 g/L); 12.8 g/dL (128 g/L) 3 months ago 8600/µL (8.6 × 109/L) 183,000/µL (183 × 109/L) 7.4

In addition to intravenous vitamin K and fluid resuscitation, which of the following is the most appropriate treatment? (A) 4-Factor prothrombin complex concentrate (B) Activated factor VII

Item 3

Self-Assessment Test

Directions

A 37-year-old woman is evaluated for a 6-month history of progressive shortness of breath. Although she remains physically active, she becomes dyspneic when walking up multiple flights of stairs or running to catch a bus. Medical history is significant for a diagnosis of a pulmonary embolism 2 years ago, which was associated with oral contraceptive use. She was initially treated with low-molecular-weight heparin followed by therapeutic warfarin for 3 months. She is a nonsmoker. Medical history is otherwise unremarkable, and she takes no medications. On physical examination, she is afebrile, blood pressure is 128/76 mm Hg at rest, pulse rate is 72/min, and respiration rate is 15/min. Oxygen saturation is 98% breathing ambient air. Pulmonary examination reveals clear lungs. Cardiac examination is significant for a fixed, split S2, a holosystolic murmur at the left sternal border that increases on inspiration, and a heave. Trace lower extremity bilateral edema is present. The remainder of the examination is noncontributory. Walking up stairs at the office at a moderate pace, she becomes short of breath after two flights of stairs, oxygen saturation decreases to 92%, and pulse rate increases to 145/min. A chest radiograph is normal, showing no parenchymal abnormalities. Transthoracic echocardiography shows right atrial and ventricular dilation and moderate tricuspid regurgitation but no other valvular abnormalities. Which of the following is the most appropriate diagnostic test to perform next? (A) (B) (C) (D)

Pulmonary CT angiography Serum D-dimer test Venous Doppler ultrasonography of the legs Ventilation-perfusion (V/Q) lung scan

Item 4 A 48-year-old woman is evaluated for fatigue and intermittent abdominal discomfort of 2 months’ duration and occasional dark urine. Medical and family histories are unremarkable. Her only medication is an oral contraceptive pill. On physical examination, temperature is 37.2 °C (99.0 °F), blood pressure is 125/74 mm Hg, pulse rate is 68/min, and respiration rate is 13/min. Pallor is observed, and abdominal tenderness is present on palpation. No icterus, bruising, or splenomegaly is noted. Laboratory studies: Hemoglobin Leukocyte count Platelet count Reticulocyte count Bilirubin, total Direct antiglobulin (Coombs) test

7.2 g/dL (72 g/L) 3000/µL (3 × 109/L) with a normal differential 125,000/µL (125 × 109/L) 8% of erythrocytes Normal Negative 129

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Answers and Critiques

Item 1

Answer:

Educational Objective: Diagnose thrombotic thrombocytopenic purpura. The most appropriate diagnostic test to perform at this time is a peripheral blood smear. This patient likely has thrombotic thrombocytopenic purpura (TTP). TTP should be suspected in patients who have microangiopathic hemolytic anemia, characterized by schistocytes on the peripheral blood smear and increased serum lactate dehydrogenase levels, and thrombocytopenia. A peripheral blood smear is essential to determine whether the anemia is caused by a microangiopathic hemolytic process as indicated by the presence of schistocytes. Patients may also have fever; kidney manifestations such as hematuria, elevated creatinine level, and proteinuria; and fluctuating neurologic manifestations, but the absence of these symptoms does not exclude the diagnosis. Assays for ADAMTS-13 activity and inhibitor titer are available but are best used for prognosis rather than to guide therapy, because TTP requires immediate treatment that cannot be delayed until laboratory test results are available. Low activity levels and a positive inhibitor titer confer a higher risk for relapse. An osmotic fragility test is used to evaluate for hereditary spherocytosis, which can produce hemolysis in the setting of an acute infection. However, hereditary spherocytosis does not cause thrombocytopenia, kidney injury, or mental status changes. TTP can overlap with hemolytic uremic syndrome (HUS), which usually occurs in children. HUS may be precipitated by an infectious diarrheal illness, especially Escherichia coli O157:H7 or Shigella species. These bacteria elaborate a toxin that resembles antigens on renal endothelial cells and bind and cause renal cell death. It is not clinically helpful to attempt to distinguish between TTP and HUS, because many patients with HUS respond to plasma exchange, the treatment for TTP. Key Point

• Thrombotic thrombocytopenic purpura is a clinical diagnosis that requires the presence of thrombocytopenia and microangiopathic hemolytic anemia, which is confirmed by schistocytes on the peripheral blood smear.

Bibliography Crawley JT, Scully MA. Thrombotic thrombocytopenic purpura: basic pathophysiology and therapeutic strategies. Hematology Am Soc Hematol Educ Program. 2013;2013:292-9. [PMID: 24319194]

Item 2

Answer:

Educational Objective: Treat a patient for major bleeding who is taking warfarin. The patient should be given 4-factor prothrombin complex concentrate (4f-PCC) in addition to intravenous vitamin K and fluids. He is experiencing major bleeding complicated by warfarin therapy and requires immediate anticoagulation reversal. 4f-PCC is a plasma-derived product that contains all four vitamin K–dependent coagulation factors (factors II, VII, IX, and X). Unlike fresh frozen plasma (FFP), 4f-PCC is stored at room temperature, does not require ABO typing, and can be infused quickly because of its small volume, thus reducing the time to delivery of therapy. Compared with FFP, 4f-PCC has been shown to more rapidly achieve hemostasis in patients with visible or musculoskeletal bleeding with less risk of fluid overload and no difference in thromboembolic events. This agent has therefore been approved by the FDA for urgent reversal of coagulation factor deficiencies related to vitamin K antagonist therapy for adult patients with acute major bleeding, as well as for adult patients in need of urgent surgery or an invasive procedure. Activated factor VII (factor VIIa) has been evaluated in case series for the treatment of vitamin K antagonist– related bleeding. Although factor VIIa can correct the INR quickly in most instances, it is unclear if this is associated with achievement of optimal hemostasis considering factors II, IX, and X are not replaced with this agent. A low dose of factor VIIa may be used in conjunction with 3-factor PCCs (which contain very little factor VII) for treatment of major vitamin K antagonist–associated bleeding in situations when 4f-PCCs are not available and the patient has a contraindication to the use of FFP (for example, uncompensated heart failure). Cryoprecipitate is rich in fibrinogen and is used to treat inherited or acquired fibrinogen deficiency or dysfibrinogenemia. It has no role in the management of vitamin K antagonist–related bleeding. FFP can be used when 4f-PCC is not readily available. However, 4f-PCC is also less likely than FFP to induce transfusion-associated circulatory overload, an important consideration in patients with heart failure or transfusion-related acute lung injury. Furthermore, 4f-PCC goes through viral inactivation, which reduces the incidence of transfusion-transmitted infectious diseases.

Answers and Critiques

Hematology Answers

Key Point

• Major bleeding associated with vitamin K antagonists should be treated by reversing anticoagulation with 4-factor prothrombin complex concentrate in addition to intravenous vitamin K.

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