Robbins and Cotran Pathology Flash Cards SECOND EDITION Edward C. Klatt MD Professor of Pathology, Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia Director, Biomedical Education Program, Mercer University School of Medicine, Savannah, Georgia Richard N. Mitchell MD, PhD Professor of Pathology, Harvard Medical School and Health Sciences and Technology, Brigham and Women's Hospital, Boston, Massachusetts Director, Human Pathology, Harvard–MIT Division of Health Sciences and Technology, Boston, Massachusetts Staff Pathologist, Brigham and Women's Hospital, Boston, Massachusetts ERRNVPHGLFRVRUJ Table of Contents Cover image Title page Copyright Acknowledgments Answers Preface Unit I General Pathology 1 Cellular Responses to Stress and Toxic Insult 1.1 Side A Questions Answers: Side B 1.1 Side B Questions Answers: Side A 1.2 Side A Questions Answers: Side B 1.2 Side B Questions Answers: Side A 1.3 Side A Questions Answers: Side B 1.3 Side B Questions Answers: Side A 1.4 Side A Questions Answers: Side B 1.4 Side B Questions Answers: Side A 1.5 Side A Questions Answers: Side B 1.5 Side B Questions Answers: Side A 1.6 Side A Questions Answers: Side B 1.6 Side B Questions Answers: Side A 1.7 Side A Questions Answers: Side B 1.7 Side B Questions Answers: Side A 1.8 Side A Questions Answers: Side B 1.8 Side B Questions Answers: Side A 1.9 Side A Questions Answers: Side B 1.9 Side B Questions Answers: Side A 1.10 Side A Questions Answers: Side B 1.10 Side B Questions Answers: Side A 1.11 Side A Questions Answers: Side B 1.11 Side B Questions Answers: Side A 2 Acute and Chronic Inflammation 2.1 Side A Questions Answers: Side B 2.1 Side B Questions Answers: Side A 2.2 Side A Questions Answers: Side B 2.2 Side B Questions Answers: Side A 2.3 Side A Questions Answers: Side B 2.3 Side B Questions Answers: Side A 2.4 Side A Questions Answers: Side B 2.4 Side B Questions Answers: Side A 2.5 Side A Questions Answers: Side B 2.5 Side B Questions Answers: Side A 2.6 Side A Questions Answers: Side B 2.6 Side B Questions Answers: Side A 2.7 Side A Questions Answers: Side B 2.7 Side B Questions Answers: Side A 2.8 Side A Questions Answers: Side B 2.8 Side B Questions Answers: Side A 2.9 Side A Questions Answers: Side B 2.9 Side B Questions Answers: Side A 3 Tissue Renewal, Repair, and Regeneration 3.1 Side A Questions Answers: Side B 3.1 Side B Questions Answers: Side A 3.2 Side A Questions Answers: Side B 3.2 Side B Questions Answers: Side A 3.3 Side A Questions Answers: Side B 3.3 Side B Questions Answers: Side A 3.4 Side A Questions Answers: Side B 3.4 Side B Questions Answers: Side A 3.5 Side A Questions Answers: Side B 3.5 Side B Questions Answers: Side A 3.6 Side A Questions Answers: Side B 3.6 Side B Questions Answers: Side A 3.7 Side A Questions Answers: Side B 3.7 Side B Questions Answers: Side A 3.8 Side A Questions Answers: Side B 3.8 Side B Questions Answers: Side A 4 Hemodynamic Disorders, Thromboembolic Disease, and Shock 4.1 Side A Questions Answers: Side B 4.1 Side B Questions Answers: Side A 4.2 Side A Questions Answers: Side B 4.2 Side B Questions Answers: Side A 4.3 Side A Questions Answers: Side B 4.3 Side B Questions Answers: Side A 4.4 Side A Questions Answers: Side B 4.4 Side B Questions Answers: Side A 4.5 Side A Questions Answers: Side B 4.5 Side B Questions Answers: Side A 4.6 Side A Questions Answers: Side B 4.6 Side B Questions Answers: Side A 4.7 Side A Questions Answers: Side B 4.7 Side B Questions Answers: Side A 4.8 Side A Questions Answers: Side B 4.8 Side B Questions Answers: Side A 5 Genetic Disorders 5.1 Side A Questions Answers: Side B 5.1 Side B Questions Answers: Side A 5.2 Side A Questions Answers: Side B 5.2 Side B Questions Answers: Side A 5.3 Side A Questions Answers: Side B 5.3 Side B Questions Answers: Side A 5.4 Side A Questions Answers: Side B 5.4 Side B Questions Answers: Side A 5.5 Side A Questions Answers: Side B 5.5 Side B Questions Answers: Side A 5.6 Side A Questions Answers: Side B 5.6 Side B Questions Answers: Side A 5.7 Side A Questions Answers: Side B 5.7 Side B Questions Answers: Side A 5.8 Side A Questions Answers Side B 5.8 Side B Questions Answers Side A 5.9 Side A Questions Answers: Side B 5.9 Side B Questions Answers: Side A 5.10 Side A Questions Answers: Side B 5.10 Side B Questions Answers: Side A 6 Diseases of the Immune System 6.1 Side A Questions Answers: Side B 6.1 Side B Questions Answers: Side A 6.2 Side A Questions Answers: Side B 6.2 Side B Questions Answers: Side A 6.3 Side A Questions Answers: Side B 6.3 Side B Questions Answers: Side A 6.4 Side A Questions Answers: Side B 6.4 Side B Questions Answers: Side A 6.5 Side A Questions Answers: Side B 6.5 Side B Questions Answers: Side A 6.6 Side A Questions Answers: Side B 6.6 Side B Questions Answers: Side A 6.7 Side A Questions Answers: Side B 6.7 Side B Questions Answers: Side A 6.8 Side A Questions Answers: Side B 6.8 Side B Questions Answers: Side A 6.9 Side A Questions Answers: Side B 6.9 Side B Questions Answers: Side A 6.10 Side A Questions Answers: Side B 6.10 Side B Questions Answers: Side A 6.11 Side A Questions Answers: Side B 6.11 Side B Questions Answers: Side A 6.12 Side A Questions Answers: Side B 6.12 Side B Questions Answers: Side A 6.13 Side A Questions Answers: Side B 6.13 Side B Questions Answers: Side A 6.14 Side A Questions Answers: Side B 6.14 Side B Questions Answers: Side A 7 Neoplasia 7.1 Side A Questions Answers: Side B 7.1 Side B Questions Answers: Side A 7.2 Side A Questions Answers: Side B 7.2 Side B Questions Answers: Side A 7.3 Side A Questions Answers: Side B 7.3 Side B Questions Answers: Side A 7.4 Side A Questions Answers: Side B 7.4 Side B Questions Answers: Side A 7.5 Side A Questions Answers: Side B 7.5 Side B Questions Answers: Side A 7.6 Side A Questions Answers: Side B 7.6 Side B Questions Answers: Side A 7.7 Side A Questions Answers: Side B 7.7 Side B Questions Answers: Side A 7.8 Side A Questions Answers: Side B 7.8 Side B Questions Answers: Side A 7.9 Side A Questions Answers: Side B 7.9 Side B Questions Answers: Side A 7.10 Side A Questions Answers: Side B 7.10 Side B Questions Answers: Side A 7.11 Side A Questions Answers: Side B 7.11 Side B Questions Answers: Side A 7.12 Side A Questions Answers: Side B 7.12 Side B Questions Answers: Side A 8 Infectious Diseases 8.1 Side A Questions Answers: Side B 8.1 Side B Questions Answers: Side A 8.2 Side A Questions Answers: Side B 8.2 Side B Questions Answers: Side A 8.3 Side A Questions Answers: Side B 8.3 Side B Questions Answers: Side A 8.4 Side A Questions Answers: Side B 8.4 Side B Questions Answers: Side A 8.5 Side A Questions Answers: Side B 8.5 Side B Questions Answers: Side A 8.6 Side A Questions Answers: Side B 8.6 Side B Questions Answers: Side A 8.7 Side A Questions Answers: Side B 8.7 Side B Questions Answers: Side A 8.8 Side A Questions Answers: Side B 8.8 Side B Questions Answers: Side A 8.9 Side A Questions Answers: Side B 8.9 Side B Questions Answers: Side A 8.10 Side A Questions Answers: Side B 8.10 Side B Questions Answers: Side A 8.11 Side A Questions Answers: Side B 8.11 Side B Questions Answers: Side A 9 Environmental and Nutritional Diseases 9.1 Side A Questions Answers: Side B 9.1 Side B Questions Answers: Side A 9.2 Side A Questions Answers: Side B 9.2 Side B Questions Answers: Side A 9.3 Side A Questions Answers: Side B 9.3 Side B Questions Answers: Side A 9.4 Side A Questions Answers: Side B 9.4 Side B Questions Answers: Side A 9.5 Side A Questions Answers: Side B 9.5 Side B Questions Answers: Side A 9.6 Side A Questions Answers: Side B 9.6 Side B Questions Answers: Side A 9.7 Side A Questions Answers: Side B 9.7 Side B Questions Answers: Side A 9.8 Side A Questions Answers: Side B 9.8 Side B Questions Answers: Side A 9.9 Side A Questions Answers: Side B 9.9 Side B Questions Answers: Side A 9.10 Side A Questions Answers: Side B 9.10 Side B Questions Answers: Side A 10 Diseases of Infancy and Childhood 10.1 Side A Questions Answers: Side B 10.1 Side B Questions Answers: Side A 10.2 Side A Questions Answers: Side B 10.2 Side B Questions Answers: Side A 10.3 Side A Questions Answers: Side B 10.3 Side B Questions Answers: Side A 10.4 Side A Questions Answers: Side B 10.4 Side B Questions Answers: Side A 10.5 Side A Questions Answers: Side B 10.5 Side B Questions Answers: Side A 10.6 Side A Questions Answers: Side B 10.6 Side B Questions Answers: Side A 10.7 Side A Questions Answers: Side B 10.7 Side B Questions Answers: Side A 10.8 Side A Questions Answers: Side B 10.8 Side B Questions Answers: Side A 10.9 Side A Questions Answers: Side B 10.9 Side B Questions Answers: Side A 10.10 Side A Questions Answers: Side B 10.10 Side B Questions Answers: Side A 10.11 Side A Questions Answers: Side B 10.11 Side B Questions Answers: Side A Unit II Systemic Pathology: Diseases of Organ Systems 11 Blood Vessels 11.1 Side A Questions Answers: Side B 11.1 Side B Questions Answers: Side A 11.2 Side A Questions Answers: Side B 11.2 Side B Questions Answers: Side A 11.3 Side A Questions Answers: Side B 11.3 Side B Questions Answers: Side A 11.4 Side A Questions Answers: Side B 11.4 Side B Questions Answers: Side A 11.5 Side A Questions Answers: Side B 11.5 Side B Questions Answers: Side A 11.6 Side A Questions Answers: Side B 11.6 Side B Questions Answers: Side A 11.7 Side A Questions Answers: Side B 11.7 Side B Questions Answers: Side A 11.8 Side A Questions Answers: Side B 11.8 Side B Questions Answers: Side A 11.9 Side A Questions Answers: Side B 11.9 Side B Questions Answers: Side A 12 The Heart 12.1 Side A Questions Answers: Side B 12.1 Side B Questions Answers: Side A 12.2 Side A Questions Answers: Side B 12.2 Side B Questions Answers: Side A 12.3 Side A Questions Answers: Side B 12.3 Side B Questions Answers: Side A 12.4 Side A Questions Answers: Side B 12.4 Side B Questions Answers: Side A 12.5 Side A Questions Answers: Side B 12.5 Side B Questions Answers: Side A 12.6 Side A Questions Answers: Side B 12.6 Side B Questions Answers: Side A 12.7 Side A Questions Answers: Side B 12.7 Side B Questions Answers: Side A 12.8 Side A Questions Answers: Side B 12.8 Side B Questions Answers: Side A 12.9 Side A Questions Answers: Side B 12.9 Side B Questions Answers: Side A 12.10 Side A Questions Answers: Side B 12.10 Side B Questions Answers: Side A 12.11 Side A Questions Answers: Side B 12.11 Side B Questions Answers: Side A 12.12 Side A Questions Answers: Side B 12.12 Side B Questions Answers: Side A 12.13 Side A Questions Answers: Side B 12.13 Side B Questions Answers: Side A 13 Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus 13.1 Side A Questions Answers: Side B 13.1 Side B Questions Answers: Side A 13.2 Side A Questions Answers: Side B 13.2 Side B Questions Answers: Side A 13.3 Side A Questions Answers: Side B 13.3 Side B Questions Answers: Side A 13.4 Side A Questions Answers: Side B 13.4 Side B Questions Answers: Side A 13.5 Side A Questions Answers: Side B 13.5 Side B Questions Answers: Side A 13.6 Side A Questions Answers: Side B 13.6 Side B Questions Answers: Side A 13.7 Side A Questions Answers: Side B 13.7 Side B Questions Answers: Side A 13.8 Side A Questions Answers: Side B 13.8 Side B Questions Answers: Side A 13.9 Side A Questions Answers: Side B 13.9 Side B Questions Answers: Side A 13.10 Side A Questions Answers: Side B 13.10 Side B Questions Answers: Side A 13.11 Side A Questions Answers: Side B 13.11 Side B Questions Answers: Side A 13.12 Side A Questions Answers: Side B 13.12 Side B Questions Answers: Side A 14 Red Blood Cell and Bleeding Disorders 14.1 Side A Questions Answers: Side B 14.1 Side B Questions Answers: Side A 14.2 Side A Questions Answers: Side B 14.2 Side B Questions Answers: Side A 14.3 Side A Questions Answers: Side B 14.3 Side B Questions Answers: Side A 14.4 Side A Questions Answers: Side B 14.4 Side B Questions Answers: Side A 14.5 Side A Questions Answers: Side B 14.5 Side B Questions Answers: Side A 14.6 Side A Questions Answers: Side B 14.6 Side B Questions Answers: Side A 14.7 Side A Questions Answers: Side B 14.7 Side B Questions Answers: Side A 14.8 Side A Questions Answers: Side B 14.8 Side B Questions Answers: Side A 15 The Lung 15.1 Side A Questions Answers: Side B 15.1 Side B Questions Answers: Side A 15.2 Side A Questions Answers: Side B 15.2 Side B Questions Answers: Side A 15.3 Side A Questions Answers: Side B 15.3 Side B Questions Answers: Side A 15.4 Side A Questions Answers: Side B 15.4 Side B Questions Answers: Side A 15.5 Side A Questions Answers: Side B 15.5 Side B Questions Answers: Side A 15.6 Side A Questions Answers: Side B 15.6 Side B Questions Answers: Side A 15.7 Side A Questions Answers: Side B 15.7 Side B Questions Answers: Side A 15.8 Side A Questions Answers: Side B 15.8 Side B Questions Answers: Side A 15.9 Side A Questions Answers: Side B 15.9 Side B Questions Answers: Side A 15.10 Side A Questions Answers: Side B 15.10 Side B Questions Answers: Side A 15.11 Side A Questions Answers: Side B 15.11 Side B Questions Answers: Side A 15.12 Side A Questions Answers: Side B 15.12 Side B Questions Answers: Side A 15.13 Side A Questions Answers: Side B 15.13 Side B Questions Answers: Side A 15.14 Side A Questions Answers: Side B 15.14 Side B Questions Answers: Side A 15.15 Side A Questions Answers: Side B 15.15 Side B Questions Answers: Side A 15.16 Side A Questions Answers: Side B 15.16 Side B Questions Answers: Side A 15.17 Side A Questions Answers: Side B 15.17 Side B Questions Answers: Side A 15.18 Side A Questions Answers: Side B 15.18 Side B Questions Answers: Side A 16 Head and Neck 16.1 Side A Questions Answers: Side B 16.1 Side B Questions Answers: Side A 16.2 Side A Questions Answers: Side B 16.2 Side B Questions Answers: Side A 16.3 Side A Questions Answers: Side B 16.3 Side B Questions Answers: Side A 16.4 Side A Questions Answers: Side B 16.4 Side B Questions Answers: Side A 16.5 Side A Questions Answers: Side B 16.5 Side B Questions Answers: Side A 16.6 Side A Questions Answers: Side B 16.6 Side B Questions Answers: Side A 16.7 Side A Questions Answers: Side B 16.7 Side B Questions Answers: Side A 16.8 Side A Questions Answers: Side B 16.8 Side B Questions Answers: Side A 16.9 Side A Questions Answers: Side B 16.9 Side B Questions Answers: Side A 16.10 Side A Questions Answers: Side B 16.10 Side B Questions Answers: Side A 16.11 Side A Questions Answers: Side B 16.11 Side B Questions Answers: Side A 17 The Gastrointestinal Tract 17.1 Side A Questions Answers: Side B 17.1 Side B Questions Answers: Side A 17.2 Side A Questions Answers: Side B 17.2 Side B Questions Answers: Side A 17.3 Side A Questions Answers: Side B 17.3 Side B Questions Answers: Side A 17.4 Side A Questions Answers: Side B 17.4 Side B Questions Answers: Side A 17.5 Side A Questions Answers: Side B 17.5 Side B Questions Answers: Side A 17.6 Side A Questions Answers: Side B 17.6 Side B Questions Answers: Side A 17.7 Side A Questions Answers: Side B 17.7 Side B Questions Answers: Side A 17.8 Side A Questions Answers: Side B 17.8 Side B Questions Answers: Side A 17.9 Side A Questions Answers: Side B 17.9 Side B Questions Answers: Side A 17.10 Side A Questions Answers: Side B 17.10 Side B Questions Answers: Side A 17.11 Side A Questions Answers: Side B 17.11 Side B Questions Answers: Side A 17.12 Side A Questions Answers: Side B 17.12 Side B Questions Answers: Side A 17.13 Side A Questions Answers: Side B 17.13 Side B Questions Answers: Side A 17.14 Side A Questions Answers: Side B 17.14 Side B Questions Answers: Side A 17.15 Side A Questions Answers: Side B 17.15 Side B Questions Answers: Side A 17.16 Side A Questions Answers: Side B 17.16 Side B Questions Answers: Side A 17.17 Side A Questions Answers: Side B 17.17 Side B Questions Answers: Side A 17.18 Side A Questions Answers: Side B 17.18 Side B Questions Answers: Side A 17.19 Side A Questions Answers: Side B 17.19 Side B Questions Answers: Side A 17.20 Side A Questions Answers: Side B 17.20 Side B Questions Answers: Side A 17.21 Side A Questions Answers: Side B 17.21 Side B Questions Answers: Side A 17.22 Side A Questions Answers: Side B 17.22 Side B Questions Answers: Side A 17.23 Side A Questions Answers: Side B 17.23 Side B Questions Answers: Side A 17.24 Side A Questions Answers: Side B 17.24 Side B Questions Answers: Side A 17.25 Side A Questions Answers: Side B 17.25 Side B Questions Answers: Side A 17.26 Side A Questions Answers: Side B 17.26 Side B Questions Answers: Side A 18 Liver and Biliary Tract 18.1 Side A Questions Answers: Side B 18.1 Side B Questions Answers: Side A 18.2 Side A Questions Answers: Side B 18.2 Side B Questions Answers: Side A 18.3 Side A Questions Answers: Side B 18.3 Side B Questions Answers: Side A 18.4 Side A Questions Answers: Side B 18.4 Side B Questions Answers: Side A 18.5 Side A Questions Answers: Side B 18.5 Side B Questions Answers: Side A 18.6 Side A Questions Answers: Side B 18.6 Side B Questions Answers: Side A 18.7 Side A Questions Answers: Side B 18.7 Side B Questions Answers: Side A 18.8 Side A Questions Answers: Side B 18.8 Side B Questions Answers: Side A 18.9 Side A Questions Answers: Side B 18.9 Side B Questions Answers: Side A 18.10 Side A Questions Answers: Side B 18.10 Side B Questions Answers: Side A 18.11 Side A Questions Answers: Side B 18.11 Side B Questions Answers: Side A 18.12 Side A Questions Answers: Side B 18.12 Side B Questions Answers: Side A 18.13 Side A Questions Answers: Side B 18.13 Side B Questions Answers: Side A 18.14 Side A Questions Answers: Side B 18.14 Side B Questions Answers: Side A 19 The Pancreas 19.1 Side A Questions Answers: Side B 19.1 Side B Questions Answers: Side A 19.2 Side A Questions Answers: Side B 19.2 Side B Questions Answers: Side A 19.3 Side A Questions Answers: Side B 19.3 Side B Questions Answers: Side A 19.4 Side A Questions Answers: Side B 19.4 Side B Questions Answers: Side A 20 The Kidney 20.1 Side A Questions Answers: Side B 20.1 Side B Questions Answers: Side A 20.2 Side A Questions Answers: Side B 20.2 Side B Questions Answers: Side A 20.3 Side A Questions Answers: Side B 20.3 Side B Questions Answers: Side A 20.4 Side A Questions Answers: Side B 20.4 Side B Questions Answers: Side A 20.5 Side A Questions Answers: Side B 20.5 Side B Questions Answers: Side A 20.6 Side A Questions Answers: Side B 20.6 Side B Questions Answers: Side A 20.7 Side A Questions Answers: Side B 20.7 Side B Questions Answers: Side A 20.8 Side A Questions Answers: Side B 20.8 Side B Questions Answers: Side A 20.9 Side A Questions Answers: Side B 20.9 Side B Questions Answers: Side A 20.10 Side A Questions Answers: Side B 20.10 Side B Questions Answers: Side A 20.11 Side A Questions Answers: Side B 20.11 Side B Questions Answers: Side A 20.12 Side A Questions Answers: Side B 20.12 Side B Questions Answers: Side A 20.13 Side A Questions Answers: Side B 20.13 Side B Questions Answers: Side A 20.14 Side A Questions Answers: Side B 20.14 Side B Questions Answers: Side A 20.15 Side A Questions Answers: Side B 20.15 Side B Questions Answers: Side A 20.16 Side A Questions Answers: Side B 20.16 Side B Questions Answers: Side A 20.17 Side A Questions Answers: Side B 20.17 Side B Questions Answers: Side A 20.18 Side A Questions Answers: Side B 20.18 Side B Questions Answers: Side A 21 The Lower Urinary Tract and Male Genital System 21.1 Side A Questions Answers: Side B 21.1 Side B Questions Answers: Side A 21.2 Side A Questions Answers: Side B 21.2 Side B Questions Answers: Side A 21.3 Side A Questions Answers: Side B 21.3 Side B Questions Answers: Side A 21.4 Side A Questions Answers: Side B 21.4 Side B Questions Answers: Side A 21.5 Side A Questions Answers: Side B 21.5 Side B Questions Answers: Side A 21.6 Side A Questions Answers: Side B 21.6 Side B Questions Answers: Side A 21.7 Side A Questions Answers: Side B 21.7 Side B Questions Answers: Side A 21.8 Side A Questions Answers: Side B 21.8 Side B Questions Answers: Side A 21.9 Side A Questions Answers: Side B 21.9 Side B Questions Answers: Side A 21.10 Side A Questions Answers: Side B 21.10 Side B Questions Answers: Side A 22 The Female Genital Tract 22.1 Side A Questions Answers: Side B 22.1 Side B Questions Answers: Side A 22.2 Side A Questions Answers: Side B 22.2 Side B Questions Answers: Side A 22.3 Side A Questions Answers: Side B 22.3 Side B Questions Answers: Side A 22.4 Side A Questions Answers: Side B 22.4 Side B Questions Answers: Side A 22.5 Side A Questions Answers: Side B 22.5 Side B Questions Answers: Side A 22.6 Side A Questions Answers: Side B 22.6 Side B Questions Answers: Side A 22.7 Side A Questions Answers: Side B 22.7 Side B Questions Answers: Side A 22.8 Side A Questions Answers: Side B 22.8 Side B Questions Answers: Side A 22.9 Side A Questions Answers: Side B 22.9 Side B Questions Answers: Side A 22.10 Side A Questions Answers: Side B 22.10 Side B Questions Answers: Side A 22.11 Side A Questions Answers: Side B 22.11 Side B Questions Answers: Side A 22.12 Side A Questions Answers: Side B 22.12 Side B Questions Answers: Side A 22.13 Side A Questions Answers: Side B 22.13 Side B Questions Answers: Side A 22.14 Side A Questions Answers: Side B 22.14 Side B Questions Answers: Side A 23 The Breast 23.1 Side A Questions Answers: Side B 23.1 Side B Questions Answers: Side A 23.2 Side A Questions Answers: Side B 23.2 Side B Questions Answers: Side A 23.3 Side A Questions Answers: Side B 23.3 Side B Questions Answers: Side A 23.4 Side A Questions Answers: Side B 23.4 Side B Questions Answers: Side A 23.5 Side A Questions Answers: Side B 23.5 Side B Questions Answers: Side A 23.6 Side A Questions Answers: Side B 23.6 Side B Questions Answers: Side A 23.7 Side A Questions Answers: Side B 23.7 Side B Questions Answers: Side A 23.8 Side A Questions Answers: Side B 23.8 Side B Questions Answers: Side A 23.9 Side A Questions Answers: Side B 23.9 Side B Questions Answers: Side A 24 The Endocrine System 24.1 Side A Questions Answers: Side B 24.1 Side B Questions Answers: Side A 24.2 Side A Questions Answers: Side B 24.2 Side B Questions Answers: Side A 24.3 Side A Questions Answers: Side B 24.3 Side B Questions Answers: Side A 24.4 Side A Questions Answers: Side B 24.4 Side B Questions Answers: Side A 24.5 Side A Questions Answers: Side B 24.5 Side B Questions Answers: Side A 24.6 Side A Questions Answers: Side B 24.6 Side B Questions Answers: Side A 24.7 Side A Questions Answers: Side B 24.7 Side B Questions Answers: Side A 24.8 Side A Questions Answers: Side B 24.8 Side B Questions Answers: Side A 24.9 Side A Questions Answers: Side B 24.9 Side B Questions Answers: Side A 24.10 Side A Questions Answers: Side B 24.10 Side B Questions Answers: Side A 24.11 Side A Questions Answers: Side B 24.11 Side B Questions Answers: Side A 24.12 Side A Questions Answers: Side B 24.12 Side B Questions Answers: Side A 24.13 Side A Questions Answers: Side B 24.13 Side B Questions Answers: Side A 24.14 Side A Questions Answers: Side B 24.14 Side B Questions Answers: Side A 24.15 Side A Questions Answers: Side B 24.15 Side B Questions Answers: Side A 25 The Skin 25.1 Side A Questions Answers: Side B 25.1 Side B Questions Answers: Side A 25.2 Side A Questions Answers: Side B 25.2 Side B Questions Answers: Side A 25.3 Side A Questions Answers: Side B 25.3 Side B Questions Answers: Side A 25.4 Side A Questions Answers: Side B 25.4 Side B Questions Answers: Side A 25.5 Side A Questions Answers: Side B 25.5 Side B Questions Answers: Side A 25.6 Side A Questions Answers: Side B 25.6 Side B Questions Answers: Side A 25.7 Side A Questions Answers: Side B 25.7 Side B Questions Answers: Side A 25.8 Side A Questions Answers: Side B 25.8 Side B Questions Answers: Side A 25.9 Side A Questions Answers: Side B 25.9 Side B Questions Answers: Side A 25.10 Side A Questions Answers: Side B 25.10 Side B Questions Answers: Side A 26 Bones, Joints, and Soft-Tissue Tumors 26.1 Side A Questions Answers: Side B 26.1 Side B Questions Answers: Side A 26.2 Side A Questions Answers: Side B 26.2 Side B Questions Answers: Side A 26.3 Side A Questions Answers: Side B 26.3 Side B Questions Answers: Side A 26.4 Side A Questions Answers: Side B 26.4 Side B Questions Answers: Side A 26.5 Side A Questions Answers: Side B 26.5 Side B Questions Answers: Side A 26.6 Side A Questions Answers: Side B 26.6 Side B Questions Answers: Side A 26.7 Side A Questions Answers: Side B 26.7 Side B Questions Answers: Side A 26.8 Side A Questions Answers: Side B 26.8 Side B Questions Answers: Side A 26.9 Side A Questions Answers: Side B 26.9 Side B Questions Answers: Side A 26.10 Side A Questions Answers: Side B 26.10 Side B Questions Answers: Side A 26.11 Side A Questions Answers: Side B 26.11 Side B Questions Answers: Side A 26.12 Side A Questions Answers: Side B 26.12 Side B Questions Answers: Side A 26.13 Side A Questions Answers: Side B 26.13 Side B Questions Answers: Side A 26.14 Side A Questions Answers: Side B 26.14 Side B Questions Answers: Side A 26.15 Side A Questions Answers: Side B 26.15 Side B Questions Answers: Side A 26.16 Side A Questions Answers: Side B 26.16 Side B Questions Answers: Side A 26.17 Side A Questions Answers: Side B 26.17 Side B Questions Answers: Side A 26.18 Side A Questions Answers: Side B 26.18 Side B Questions Answers: Side A 27 Peripheral Nerve and Skeletal Muscle 27.1 Side A Questions Answers: Side B 27.1 Side B Questions Answers: Side A 27.2 Side A Questions Answers: Side B 27.2 Side B Questions Answers: Side A 27.3 Side A Questions Answers: Side B 27.3 Side B Questions Answers: Side A 27.4 Side A Questions Answers: Side B 27.4 Side B Questions Answers: Side A 27.5 Side A Questions Answers: Side B 27.5 Side B Questions Answers: Side A 28 The Central Nervous System 28.1 Side A Questions Answers: Side B 28.1 Side B Questions Answers: Side A 28.2 Side A Questions Answers: Side B 28.2 Side B Questions Answers: Side A 28.3 Side A Questions Answers: Side B 28.3 Side B Questions Answers: Side A 28.4 Side A Questions Answers: Side B 28.4 Side B Questions Answers: Side A 28.5 Side A Questions Answers: Side B 28.5 Side B Questions Answers: Side A 28.6 Side A Questions Answers: Side B 28.6 Side B Questions 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Kennedy Blvd. Ste. 1800 Philadelphia, PA 19103-2899 ROBBINS AND COTRAN PATHOLOGY FLASH CARDS SECOND EDITION ISBN: 978-0-323-35222-2 Copyright © 2016, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier's Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865 843830 (UK); fax: (+44) 1865 853333; e-mail: [email protected] . You may also complete your request online via the Elsevier website at http://www.elsevier.com/permissions . Notice Neither the publisher nor the authors assume any responsibility for any loss or injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. It is the responsibility of the treating practitioner, relying on independent expertise and knowledge of the patient, to determine the best treatment and method of application for the patient. The Publisher Executive Content Strategist: William Schmitt Content Development Specialist: Amy Meros Publishing Services Manager: Anne Altepeter Project Manager: Louise King Design Manager: Xiaopei Chen Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1 Acknowledgments The Flash Cards represent the work of many people. Here are two of them. 1. Who are these guys? 2. How will I use these cards? 3. Can I learn everything I need to know from these cards? 4. Who should I thank for putting all this together (besides the authors)? 5. What is the ultimate answer? Name the source. Answers 1. At left is Edward C. Klatt, MD, professor of Pathology, Department of Biomedical Sciences, Mercer University School of Medicine; the other guy is Rick Mitchell, MD, PhD, professor of Pathology and Health Sciences and Technology, Harvard Medical School. 2. Each card has two sides. Each side includes a vignette with text, image, and questions. Flip the card for the answers to questions on the opposite side. Both card sides illustrate the same or related disease process. This style effectively doubles your learning opportunities. 3. No, of course not. By design these flash cards only hit the highlights and scratch the surface. Use them to refresh concepts, but be curious and not content to let your knowledge end there. There's so much out there to learn. Repeat after us: I will enthusiastically seek knowledge in dedicating myself to the care of others at the highest level. 4. Thank the authors of Robbins and Cotran Pathologic Basis of Disease and Basic Pathology, the texts that serve as the primary source authority of information for the flash cards. Also, thank the people at Elsevier, Inc., including William Schmitt, executive content strategist, who had the inspiration for this project and guided it to completion. Finally, thank Amy Meros, content development specialist, who provided invaluable service (and infinite patience) to move the project from concept to reality. In addition, we are indebted to our designer, XiaoPei Chen, and the project manager, Louise King, for their assistance. 5. Love is the healer for all our ills (Rumi of Balkh, 1207–1273)—from his many sources of inspiration and enlightenment—not on your exams, but essential to good medicine. Preface The second edition of Robbins and Cotran Pathology Flash Cards is designed to reinforce the learning that begins with the study of other works in the Robbins family of textbooks, as well as in other clinical and basic science disciplines. The learning styles of our user base of students are continually evolving, and we now incorporate a variety of resources to support them. The Robbins list of titles continues to expand to support such a diversity of learning modalities. These flash cards are designed to stimulate recall and reinforce concepts in pathophysiology. Use the cards to consolidate your learning and inspire further study. UNIT I General Pathology OUTLINE 1 Cellular Responses to Stress and Toxic Insult 2 Acute and Chronic Inflammation 3 Tissue Renewal, Repair, and Regeneration 4 Hemodynamic Disorders, Thromboembolic Disease, and Shock 5 Genetic Disorders 6 Diseases of the Immune System 7 Neoplasia 8 Infectious Diseases 9 Environmental and Nutritional Diseases 10 Diseases of Infancy and Childhood ERRNVPHGLFRVRUJ 1 ERRNVPHGLFRVRUJ Cellular Responses to Stress and Toxic Insult Adaptation, Injury, and Death ERRNVPHGLFRVRUJ 1.1 Side A (PBD9: 36; BP9: 4) ERRNVPHGLFRVRUJ Questions A 70-year-old woman has had a blood pressure of 160/105 mm Hg for many years. Abdominal ultrasound shows the decreased size of one kidney. 1. What gross morphologic description applies to the abnormal kidney? 2. What is the likely cause of this finding? 3. How could this affect the patient's renal function? 4. What cellular organelle plays a major role in this process? 5. What cellular protein processing pathway is involved? ERRNVPHGLFRVRUJ Answers: Side B 1. Myocyte cellular atrophy is present as a result of lysosomal autophagy and increased proteasomal degradation. 2. Small angulated fibers with occasional central nuclei are grouped together. 3. Skeletal muscle fibers in a motor unit are randomly enervated; nerve injury initially leads to scattered myocyte atrophy within any given motor unit. After one nerve is injured, however, an adjacent neuron can branch and reinnervate denervated myocytes. If that neuron is now injured, the result is group atrophy of myocytes. ERRNVPHGLFRVRUJ 1.1 Side B (PBD9: 36; BP9: 4) ERRNVPHGLFRVRUJ Questions A 55-year-old man has repeated trauma to his upper arms from operating a jackhammer. He now has hand and forearm weakness. A skeletal muscle biopsy specimen reveals the pattern shown at the right. 1. What is the microscopic description of these myocytes? 2. What features support the diagnosis? 3. Why are smaller angulated fibers grouped together? ERRNVPHGLFRVRUJ Answers: Side A 1. The smaller kidney is atrophic . 2. Diminished blood supply (renal artery stenosis as a result of atherosclerosis) with chronic ischemia likely caused this. Although remaining individual cells in the parenchyma are smaller ( cellular atrophy ), most of the organ shrinkage is attributable to cell dropout because of ischemic injury. 3. Diminished blood supply leads to increased renin secretion by the hypoperfused kidney, which causes hypertension. 4. Lysosomes play a major role in cellular atrophy through autophagy. 5. Cellular atrophy is mediated through increased protein degradation by the ubiquitinproteasome pathway . ERRNVPHGLFRVRUJ 1.2 Side A (PBD9: 36; BP9: 4) ERRNVPHGLFRVRUJ Questions At 40 weeks' gestation, a 20-year-old woman delivers a healthy infant and begins nursing postpartum. Her breasts show bilateral enlargement. The microscopic appearance of her breast tissue is shown. 1. What is the morphologic description? 2. What is the substance represented by the pink-staining material within the lobules? 3. What hormonal stimuli account for these findings? ERRNVPHGLFRVRUJ Answers: Side B 1. As opposed to physiologic lobular hyperplasia in the female breast, the male breast lacks lobules, and elevated estrogen levels lead primarily to ductular hyperplasia with associated increases in extracellular matrix. This leads to hyperplastic male breast tissue, which is called gynecomastia . 2. Gynecomastia can suggest estrogen-secreting tumors (e.g., adrenal, testicular), exogenous estrogen administration, drug effects (e.g., mimicking estrogen, causing increased endogenous production), or abnormal estrogen metabolism (e.g., as a result of cirrhosis). ERRNVPHGLFRVRUJ 1.2 Side B (PBD9: 36; BP9: 4) ERRNVPHGLFRVRUJ Questions A 22-year-old man has had bilateral breast enlargement for the past 5 years. The microscopic appearance of his breast tissue is shown. 1. This lesion and the tissue shown on Side A represent estrogen effects on breast epithelium. What is the difference between the effects seen in male breasts versus female breasts? 2. Why might this man have elevated estrogen levels? ERRNVPHGLFRVRUJ Answers: Side A 1. The female breast lobules have increased cellularity. This is consistent with physiologic hyperplasia from elevated estrogen and progesterone levels during pregnancy. 2. The pink secretions within the lobules are milk. The breast is a modified apocrine gland; lipid-rich secretions are formed through the budding of apical portions of epithelial cytoplasm. 3. Estrogen and progesterone bind to breast epithelium steroid hormone receptors to cause specific nuclear mRNA transcription. This results in protein translation that promotes cellular proliferation and gain of function. ERRNVPHGLFRVRUJ 1.3 Side A (PBD9: 43; BP9: 10) ERRNVPHGLFRVRUJ Questions A 36-year-old man has sudden onset of a high fever. On examination, his temperature is 37.7° C, and a shrill holosystolic murmur is auscultated. A blood culture grows grampositive cocci in chains that are catalase-negative, that show alpha hemolysis when grown on blood agar, and that are optochin-resistant. Urine microscopic examination reveals RBCs but no WBCs. 1. What is suggested by the history along with the blood culture results? 2. What complication is shown on this image of the kidney? ERRNVPHGLFRVRUJ Answers: Side B 1. The pale pink region ( ▪) in the adrenal cortex results from a loss of nuclei but preserved cell outlines, which is typical of coagulative necrosis as a consequence of tissue hypoxia and cell death. 2. The necrotic cells undergo autolysis and proteolytic degradation by successive waves of neutrophils and then macrophages. The debris is phagocytized by the infiltrating leukocytes, and this is followed by the ingrowth of capillaries with fibroblasts and the eventual replacement of the necrotic zone by a fibrous scar. ERRNVPHGLFRVRUJ 1.3 Side B (PBD9: 43; BP9: 10) ERRNVPHGLFRVRUJ Questions A section of adrenal cortex shows the microscopic appearance in the 36-year-old man with infective endocarditis from Side A. 1. Name this process. 2. How does this lesion resolve? ERRNVPHGLFRVRUJ Answers: Side A 1. Blood culture findings are diagnostic of infection with viridans streptococci, and the history is consistent with an infective endocarditis involving a previously damaged or otherwise abnormal heart valve. Optochin resistance distinguishes viridans streptococci from other alpha-hemolytic streptococci (e.g., Streptococcus pneumoniae), which would be sensitive to the optochin compound and thus not grow around the drug-impregnated disk. 2. The cut kidney surface shows a wedge-shaped pale area ( ▪) of infarction ( coagulative necrosis ) with a red thromboembolus ( ▴) in a renal artery branch beneath the lesion. The vascular occlusion likely resulted from the embolization of a fragment of the valvular vegetation. Damage to small vessels near the infarct caused bleeding into calyces that manifested as hematuria. ERRNVPHGLFRVRUJ 1.4 Side A (PBD9: 34; BP9: 3) ERRNVPHGLFRVRUJ Questions A 64-year-old man has had increasing dyspnea for the last 12 months. On examination, his blood pressure is 170/105 mm Hg. Heart catheterization reveals elevated rightsided pressures, with a right atrial pressure of 12 mm Hg (nl 3 mm Hg) and a pulmonary capillary wedge pressure of 28 mm Hg (nl 9 mm Hg); the cardiac output is 3.4 L/min (nl 4 to 8 L/min). 1. Describe the appearance of this heart. 2. What is a likely explanation for the cardiac findings? 3. Explain the hemodynamic data. ERRNVPHGLFRVRUJ Answers: Side B 1. Myocyte hypertrophy is reflected by enlarged, boxy, and hyperchromatic nuclei with markedly expanded cytoplasm. 2. Congestive heart failure occurs when cardiac compensation fails. Left-sided heart failure leads to pulmonary edema with fluid filling the interstitial and alveolar spaces. Right-sided failure leads to body cavity effusions, visceral organ congestion (hepatomegaly), and peripheral edema (this is most marked in dependent areas, such as the feet when upright). ERRNVPHGLFRVRUJ 1.4 Side B (PBD9: 34; BP9: 3) ERRNVPHGLFRVRUJ Questions The ventricular myocardium of the 64-year-old patient from Side A is shown. There are crackles (rales) in both lungs, bilateral pedal edema, and an enlarged liver span. 1. Describe the microscopic findings. 2. Explain the physical examination findings. ERRNVPHGLFRVRUJ Answers: Side A 1. This heart shows cardiomegaly with severe biventricular hypertrophy and severe biatrial dilation (the latter reflecting stiff, noncompliant ventricles). 2. The left ventricular hypertrophy is attributable to chronic pressure overload caused by hypertension . The left ventricle compensates for the increased pressure load through the hypertrophy of myocardial fibers and the thickening of the ventricular wall. 3. Left ventricular diastolic dysfunction results in higher left atrial volume and pressure as measured by the pulmonary arterial wedge pressure. The pulmonary arterial and right atrial pressures subsequently increase as well, thereby inducing compensatory right ventricular hypertrophy and subsequent right atrial dilation. The left ventricular cardiac output is reduced because of the poor diastolic filling from decreased compliance with hypertrophy. ERRNVPHGLFRVRUJ 1.5 Side A (PBD9: 52; BP9: 18) ERRNVPHGLFRVRUJ Questions The maturation and education of T lymphocytes occurs within the thymus, with more than 97% of proliferating T lymphocytes being eliminated because they either respond to self or express T-cell receptors that interact too weakly or strongly with their relevant antigens. The microscopic appearance of a second-trimester fetal thymus is shown. 1. What process is shown? 2. What genes play a role in this process? 3. How could cell damage by free radicals, toxins, or radiation induce a similar response? ERRNVPHGLFRVRUJ Answers: Side B 1. This is graft-versus-host disease . Cytotoxic donor T lymphocytes kill host cells via an apoptotic pathway that involves the release of granzymes into a cellular target; granzyme proteins directly activate caspases and induce apoptosis (an apoptotic body is seen at the arrow). 2. The withdrawal of growth hormones (e.g., estrogen, progesterone) or growth factors may induce the increased synthesis of pro-apoptotic proteins. ERRNVPHGLFRVRUJ 1.5 Side B (PBD9: 53; BP9: 22) ERRNVPHGLFRVRUJ Questions After allogeneic bone marrow transplantation with engraftment, a desquamative skin rash occurs. The microscopic findings are shown. 1. Name this process, and give the mechanism by which the keratinocytes are eliminated (arrow ). 2. How might this form of cell death be involved in the cyclic sloughing of the endometrium (menses)? ERRNVPHGLFRVRUJ Answers: Side A 1. This is apoptosis . Thymocytes targeted for deletion undergo tightly regulated cellular fragmentation. Apoptotic bodies are consumed by phagocytes (e.g., macrophages), which gives the appearance of clear spaces filled with granular debris ( arrow). 2. Regulatory anti-apoptotic proteins such as Bcl-2 are lost or degraded, whereas proapoptotic proteins such as Bax are transcribed. Relative amounts of pro-apoptotic and anti-apoptotic proteins regulate mitochondrial cytochrome c release, which controls the activation of intracellular caspases that degrade cellular elements via a proteolytic cascade. 3. DNA damage halts the cell cycle for repair via the accumulation of p53 protein. If DNA is not successfully repaired, p53 triggers apoptosis. Absent or mutated p53 (e.g., as in certain cancers) does not trigger apoptosis, and the defective cell can survive and proliferate. ERRNVPHGLFRVRUJ 1.6 Side A (PBD9: 37; BP9: 5) ERRNVPHGLFRVRUJ Questions A 25-year-old man is a cigarette smoker with a chronic cough and frequent severe respiratory infections. The microscopic appearance of his bronchial epithelium is shown. 1. What cellular change has occurred? 2. Is this change reversible? 3. What additional epithelial change can arise? ERRNVPHGLFRVRUJ Answers: Side B 1. Normal squamous epithelium ( ◂) transitions to dysplasia ( ▸) with the loss of the normal maturation sequence from basal cells to the surface, hyperchromatic (darker) nuclei, and less cytoplasm (higher N/C ratio). 2. Dysplasia is disordered growth with a loss of normal cellular morphology, maturation, and polarity. The appearance reflects increased cell proliferation and decreased differentiation. This can occur with persistent insults in an epithelium, with or without prior metaplastic change. 3. Cervical squamous dysplastic lesions are driven by human papillomavirus (HPV) infection. HPV induces cellular proliferation with the concurrent acquisition of increasing numbers of mutations. The greater the number of sexual partners, the greater the risk for acquiring a high-risk strain of HPV. ERRNVPHGLFRVRUJ 1.6 Side B (PBD9: 271; BP9: 165) ERRNVPHGLFRVRUJ Questions A 29-year-old woman became sexually active at the age of 14 years, and she has since had 18 male sexual partners. A routine Pap smear showed abnormal cells, which prompted a cervical biopsy. The microscopic appearance of the biopsy specimen is shown. 1. Describe the abnormal change in this epithelium. 2. Explain the pathophysiology of this disease. 3. Why might this patient have developed this disease? ERRNVPHGLFRVRUJ Answers: Side A 1. The pseudostratified ciliated columnar epithelium ( ▸) is transformed into stratified squamous epithelium ( ◂). This is squamous metaplasia . 2. Yes. If the injury that produced the change in epithelium is removed, the normal epithelial cell appearance will return. 3. If the same injury that caused the metaplasia persists, it can induce malignant transformation. The next step along this pathway is dysplasia , which is also potentially reversible. However, it is further along in the pathogenesis of uncontrolled cell growth (cancer). ERRNVPHGLFRVRUJ 1.7 Side A (PBD9: 43; BP9: 10) ERRNVPHGLFRVRUJ Questions A 40-year-old homeless man presents with a 2-month history of fever, purulent productive cough with occasional hemoptysis, soaking night sweats, and weight loss. Physical examination reveals apical rales. His chest radiograph is shown. 1. What is present in the right upper lobe? 2. What would a sputum sample show? 3. Why does this patient have the systemic symptoms of fever, sweats, and weight loss? ERRNVPHGLFRVRUJ Answers: Side B 1. There is central caseation surrounded by enlarged, activated macrophages (so-called “epithelioid” macrophages). A Langhans multinucleated giant cell ( ▾) is derived from the fusion of multiple activated macrophages. 2. This is granulomatous inflammation with central caseous necrosis . Caseation is essentially liquefaction with coagulative necrosis, which in this case is associated with mycobacterial infection. 3. The immunosuppression caused by HIV leads to the anergy of cell-mediated immunity and a negative tuberculosis skin test, despite active mycobacterial infection as a result of the reactivation of a previous latent focus or of reinfection caused by a new exposure from the environment. ERRNVPHGLFRVRUJ 1.7 Side B (PBD9: 43; BP9: 10) ERRNVPHGLFRVRUJ Questions A 69-year-old man has had increasing dyspnea upon exertion for 3 months. He is known to be HIV-positive. A chest radiograph shows reticulonodular infiltrates in the upper lobes and prominent hilar lymphadenopathy. A skin test with purified protein derivative (PPD) is negative. A lung biopsy is performed. 1. What microscopic features are shown? 2. What is this pattern of inflammation and tissue necrosis called? 3. Why is this patient's skin test negative to PPD? ERRNVPHGLFRVRUJ Answers: Side A 1. There is upper lobe cavitation ( ▸) that is typical of secondary tuberculosis. 2. His sputum is likely to contain acid-fast bacilli from mycobacterial infection. The cavitation with erosion into the airways of this secondary lesion increases the likelihood of a positive sputum sample and infectivity. 3. The systemic symptoms are the consequences of cytokines such as tumor necrosis factor and interleukin-1 being released from activated macrophages. ERRNVPHGLFRVRUJ 1.8 Side A (PBD9: 43; BP9: 10) ERRNVPHGLFRVRUJ Questions A 70-year-old woman with a history of rheumatic mitral stenosis has an acute onset of right-sided hemiplegia. Three weeks later, she dies from complications of an aspiration pneumonia. 1. What three features are shown here? 2. What would have happened during the next 3 months if the patient had lived? 3. How could this lesion relate to the patient's heart disease? ERRNVPHGLFRVRUJ Answers: Side B 1. This cerebral abscess ( ▴) has highly vascularized granulation tissue around its margin that allows for the bright-appearing concentration of the injected radiocontrast material. With surrounding associated edema ( ▾), it is causing a massive ventricular shift to the right ( ◂). 2. An abscess is a localized collection of degenerating neutrophils; the release of their reactive oxygen species and proteolytic enzymes leads to liquefactive necrosis. Even without abscess formation, central nervous system injury of any form also results in liquefactive necrosis. 3. Abscesses are most often caused by bacterial organisms such as staphylococci and streptococci. ERRNVPHGLFRVRUJ 1.8 Side B (PBD9: 43; BP9: 10) ERRNVPHGLFRVRUJ Questions A 62-year-old man with a history of rheumatic valvular disease has fever and worsening headaches for 4 days. Physical examination reveals papilledema. A contrastenhanced MRI of his brain is shown. 1. What accounts for the ring enhancement? 2. What inflammatory cells are present in the center of the lesion? 3. What type of organism is most likely present? ERRNVPHGLFRVRUJ Answers: Side A 1. This is a cerebrovascular accident or “stroke” with cerebral hemispheric softening ( ▸) caused by liquefactive necrosis secondary to infarction. 2. Microglial cells (central nervous system macrophages) and circulating monocytes would have removed much of the necrotic debris, leaving a cavity ( ▴) or cortical depression; there also would be peripheral gliosis because of astrocyte enlargement and proliferation. 3. Mitral stenosis can lead to left atrial enlargement with subsequent mural thrombosis followed by embolization with infarction. Alternatively, a scarred rheumatic valve is more susceptible to endocarditis; the subsequent embolization of infected vegetation would produce a septic infarct. ERRNVPHGLFRVRUJ 1.9 Side A (PBD9: 64; BP9: 24) ERRNVPHGLFRVRUJ Questions A 58-year-old nonsmoker with normal lung function is killed in a hit-and-run accident. The gross appearance of the surface of his lungs is shown. 1. What is this pigment? 2. How does pigment get to this location? 3. What are the risk factors for increased amounts of this pigment? ERRNVPHGLFRVRUJ Answers: Side B 1. This is coal workers' pneumoconiosis causing restrictive lung disease. The massive amount of carbon pigment leads to the coal macules ( ▾) shown and their associated fibrosis. 2. Restrictive lung diseases lead to cor pulmonale with right heart failure. 3. Right heart failure leads to chronic liver passive congestion followed by fibrosis that bridges central veins (this is the opposite of portal cirrhosis). This is not a true cirrhosis, because nodular regeneration is lacking. ERRNVPHGLFRVRUJ 1.9 Side B (PBD9: 64; BP9: 24) ERRNVPHGLFRVRUJ Questions A 62-year-old coal miner with a 10-year history of progressive dyspnea develops peripheral edema, pleural effusions, and hepatic “cardiac cirrhosis.” Pulmonary function testing shows decreased FEV and decreased FVC. A lung biopsy reveals the findings shown here. 1 1. What is this patient's diagnosis? 2. What cardiac complication has developed? 3. Describe the pathogenesis of this patient's liver disease. ERRNVPHGLFRVRUJ Answers: Side A 1. Anthracotic pigment ( ▸) within the pleural lymphatics is responsible for the linear (reticular) black appearance of the pleural surface. This amount of pigment has no pathologic consequence. 2. Inhaled microscopic carbon particles are ingested by pulmonary macrophages and carried via the lymphatics through interlobular septa to the pleural surfaces and eventually to the hilar lymph nodes. 3. Increased amounts of this pigment come from smoking and polluted air. ERRNVPHGLFRVRUJ 1.10 Side A (PBD9: 64; BP9: 24) ERRNVPHGLFRVRUJ Questions A 92-year-old man dies of bronchopneumonia after a fall during which he fractured his femoral head. At autopsy, his myocardium has the microscopic appearance shown. 1. What is the brown-gold pigment? 2. What cellular mechanism produces this pigment? 3. Where in the cell does the pigment accumulate? 4. What effect does this pigment have on myocardial function? ERRNVPHGLFRVRUJ Answers: Side B 1. This is brown atrophy of the heart. 2. There is extensive lipochrome (lipofuscin) pigment within the myocardial fibers. 3. The liver and heart are the two organs most likely to contain significant amounts of lipochrome, although this “wear and tear” pigment can be found in many cells. 4. The myocytes have atrophied (reduced their size in response to diminished trophic stimulation, diminished nutritional status, or both). ERRNVPHGLFRVRUJ 1.10 Side B (PBD9: 64; BP9: 24) ERRNVPHGLFRVRUJ Questions A 78-year-old man with progressive dementia has become severely malnourished. At autopsy, his heart is small, with the gross appearance shown. 1. What is the name for this appearance? 2. What pigment within the myocardial fibers accounts for this appearance? 3. In what other organ is this pigment most likely to be found? 4. What is the cellular process that accounts for the decreased cardiac size? ERRNVPHGLFRVRUJ Answers: Side A 1. This is lipochrome (lipofuscin) pigment, which is characteristically found in a perinuclear location ( ▸). 2. Long-term recurrent free radical damage leads to lipid peroxidation and the crosslinking of polyunsaturated lipids of various cellular membranes, which cannot be catabolized further. 3. Lysosomes fuse with autophagic vacuoles to create autophagolysosomes, which are responsible for normal intracellular organellar turnover. Nondigestible debris from abnormally cross-linked cellular molecules persists as residual bodies in lysosomes and manifests as pigmented lipofuscin. 4. Some amount of lipofuscin can be found in all individuals with aging. Although it is indicative of past wear and tear, even large amounts have no deleterious effect on cellular function. ERRNVPHGLFRVRUJ 1.11 Side A (PBD9: 65; BP9: 25) ERRNVPHGLFRVRUJ Questions A 44-year-old man who has had increasing dyspnea on exertion for 6 years has a loud crescendo-decrescendo systolic ejection murmur and S . His carotids have pulsus parvus et tardus, and chest radiography shows pulmonary edema. His native aortic valve at replacement surgery is shown. 4 1. What is your diagnosis? 2. Why is this valve thickened with nodular densities? 3. Although more common during the eighth and ninth decades, this man's disease became symptomatic when he was 44 years old. Why? 4. Where else can this mineral be deposited? ERRNVPHGLFRVRUJ Answers: Side B 1. The dark blue deposits that thicken the interstitium are calcium deposits resulting from metastatic calcification. Elastic tissue, sites of necrosis, and cells with an intracellular alkaline environment (e.g., gastric parietal cells) favor calcium phosphate deposition. 2. She has primary hyperparathyroidism ; the neck mass is likely a parathyroid adenoma . 3. The serum ionized calcium and parathyroid hormone levels would be increased. ERRNVPHGLFRVRUJ 1.11 Side B (PBD9: 65; BP9: 26) ERRNVPHGLFRVRUJ Questions A 45-year-old woman had urolithiasis, bone pain, peptic ulcers, constipation, cardiac dysrhythmia, weakness, and depression over the past 4 months. A forearm radiograph showed osteitis fibrosa cystica, and a sestamibi scan showed a solitary neck mass. She died of a sudden cardiac arrhythmia. The microscopic appearance of her lungs is shown. 1. What is deposited in her alveolar walls and why? 2. What is her underlying disease? 3. What other laboratory findings would you expect? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has calcific degeneration of the aortic valve that leads to aortic stenosis. 2. The abnormal valve is subject to more wear and undergoes dystrophic calcification. 3. Congenital bicuspid aortic valve affects about 1% of the population and makes degenerative calcification accrue at a much earlier age. 4. Crystalline calcium phosphate deposition can occur in damaged or necrotic tissues, as part of atherogenesis, or during the healing of inflammatory processes (e.g., granulomas). ERRNVPHGLFRVRUJ 2 ERRNVPHGLFRVRUJ Acute and Chronic Inflammation ERRNVPHGLFRVRUJ 2.1 Side A (PBD9: 91; BP9: 43) ERRNVPHGLFRVRUJ Questions A 27-year-old man presents with fever and general malaise. In his left antecubital fossa are needle tracks, and pus is draining from a 2-cm erythematous, fluctuant, and tender subcutaneous nodule. There is jugular venous distention with an S gallop and a pansystolic murmur that is best heard along the lower left sternal border and is accentuated during inspiration. The patient's chest radiograph is shown. 3 1. Explain the appearance of nodules on the radiograph. 2. Suggest a pathophysiologic mechanism for the clinical findings. ERRNVPHGLFRVRUJ Answers: Side B 1. There is multifocal pneumonic consolidation , which is reflected grossly by white-tan areas ( ◂) of firmness. Microscopically, exudative airspace filling composed of neutrophils, blood, fibrin, and bacteria would be seen. 2. Acute bacterial infections lead to peripheral neutrophilia with “left shift” (i.e., the presence of band forms) as a result of the early bone marrow release of immature granulocytes. ERRNVPHGLFRVRUJ 2.1 Side B (PBD9: 91; BP9: 43) ERRNVPHGLFRVRUJ Questions The same patient described on Side A has a WBC count of 17,400/mm (nl 4000/mm to 11,000/mm ) with 72% neutrophils, 8% bands, 16% lymphocytes, and 4% monocytes. Despite the use of appropriate antibiotics, the patient dies of sepsis and pulmonary failure. His lung is shown. 3 3 1. In addition to cavitating abscesses (▸), what else is present? 2. Explain the peripheral blood findings. ERRNVPHGLFRVRUJ 3 Answers: Side A 1. The four nodular lesions have an air-fluid level ( ▸) that is typical for abscess . Neutrophil enzymes and reactive oxygen species destroy surrounding tissues, which causes liquefactive necrosis; the abscess contents layer out in an upright patient. 2. Intravenous drug abuse led to an antecubital fossa injection site abscess caused by bacterial skin contaminants. Subsequent hematogenous spread and endocarditis led to tricuspid valve destruction with regurgitation (hence the JVD, heart murmur, and S , reflecting a volume overload). Septic emboli from right-sided valvular vegetations traveled to the lungs to produce abscesses. 3 ERRNVPHGLFRVRUJ 2.2 Side A (PBD9: 98; BP9: 56) ERRNVPHGLFRVRUJ Questions A 45-year-old woman has had a nonproductive cough, intermittent fevers, and night sweats for 4 months; also, she has lost 3 kg without dieting. A transbronchial biopsy specimen shows the findings here. 1. Describe this pathologic lesion. 2. What are possible noninfectious causes? ERRNVPHGLFRVRUJ Answers: Side B 1. There is central pink caseation (■) surrounded by enlarged activated (“epithelioid”) macrophages driven into a frenzy under the influence predominantly of interferon-γ produced by a surrounding rim of T lymphocytes. The scattered nodules produce the radiographic reticulonodular appearance. 2. The upper lobe distribution and the caseation suggest an infectious cause. This is most often Mycobacterium tuberculosis, but it may also potentially be other mycobacteria (e.g., Mycobacterium kansasii) or fungi such as Cryptococcus or Histoplasma. ERRNVPHGLFRVRUJ 2.2 Side B (PBD9: 98; BP9: 56) ERRNVPHGLFRVRUJ Questions A 51-year-old woman presents with dyspnea, rales in the upper lung fields, and faint inspiratory wheezes. A chest radiograph shows a reticulonodular pattern of infiltrates, mainly in the upper lobes, with prominent hilar lymphadenopathy. A lymph node biopsy is performed, and the results are shown. 1. Explain the pathogenesis of this lesion. 2. What are possible infectious causes? ERRNVPHGLFRVRUJ Answers: Side A 1. This is granulomatous inflammation . There are prominent Langhans multinucleated giant cells ( ▸) but no caseation. The absence of caseation does not preclude an infectious etiology. 2. Granulomas can be infectious or noninfectious. Noninfectious granulomas result from innate or adaptive immune responses to large or persistent antigens that can include foreign material (dusts), self (rheumatoid nodules), and unknown agents ( sarcoidosis ). ERRNVPHGLFRVRUJ 2.3 Side A (PBD9: 68; BP9: 44) ERRNVPHGLFRVRUJ Questions A 15-year-old girl had streptococcal pharyngitis 3 weeks ago; she now has a low-grade fever, pleuritic chest pain, waxing and waning arthritis, and painful subcutaneous nodules. A friction rub is audible with chest auscultation. She suddenly dies of an apparent arrhythmia. The heart and pericardial sac are shown. 1. Describe the epicardial finding. 2. Explain the pathophysiology of this disease. ERRNVPHGLFRVRUJ Answers: Side B 1. There is a fibrinous exudate with pink fibrin strands that enmesh the leukocytes. 2. Rheumatic fever is caused by an immunologic response to a group A beta-hemolytic Streptococcus infection. In particular, antibodies against streptococcal M-proteins and other bacterial antigens (as reflected in the antistreptolysin O and anti–DNAse B titers) cross-react with heart valve glycoproteins. The antibodies cause injury by activating complement and by recruiting and activating neutrophils and macrophages. ERRNVPHGLFRVRUJ 2.3 Side B (PBD9: 566; BP9: 34) ERRNVPHGLFRVRUJ Questions A 13-year-old boy with recent “strep throat” develops a new heart murmur. Echocardiography shows small mitral valve vegetations. His WBC count is 12,130/mm (nl 4000/mm to 11,000/mm ), and his erythrocyte sedimentation rate is 30 mm/hr (nl 20 mm/hr). His antistreptolysin O titer is 1 : 512, and his anti–DNAse B titer is 1 : 240; both of these values are elevated. Two weeks later, these titers are increased fourfold. The microscopic appearance of the patient's epicardial and mitral valve vegetations is shown. 3 3 3 1. Describe the findings. 2. How does streptococcal infection induce rheumatic fever? ERRNVPHGLFRVRUJ Answers: Side A 1. The epicardium shows a dull, shaggy fibrinous exudate as well as serous fluid pooling in the pericardial cavity. 2. She had acute rheumatic fever caused by development of antibodies against certain streptococcal bacterial antigens; these antibacterial antibodies also cross-react with binding to self endocardial, myocardial, and pericardial antigens to cause inflammation (pericarditis) with fluid and blood protein exudation. Extravasated fibrinogen polymerizes to form fibrin strands that produce the shaggy exudate. Similar inflammation in the myocardium can cause myocyte damage and arrhythmia. ERRNVPHGLFRVRUJ 2.4 Side A (PBD9: 91; BP9: 44) ERRNVPHGLFRVRUJ Questions A 37-year-old man has a year-long history of worsening epigastric pain that is relieved by eating. Upper gastrointestinal endoscopy reveals the gross appearance shown. 1. What is the diagnosis? 2. Explain the pathophysiology of this disease. ERRNVPHGLFRVRUJ Answers: Side B 1. Ulceration is the loss of epithelium ( ▸). In its place are mucus, hemorrhage, fibrin thrombus, inflammatory cells, and necrotic debris. The surrounding submucosal tissue is showing classic signs of acute inflammation with vascular dilation, perivascular edema, and an infiltrate made predominantly of neutrophils. 2. In a broad sense, peptic ulcers result from an imbalance of mucosal defense mechanisms and injurious insults (e.g., hydrochloric acid, pepsin). Helicobacter pylori is a major cause of peptic ulcers as a result of its induction of intense inflammatory responses. It breaks down urea into toxic metabolites and reduces duodenal bicarbonate production while increasing gastric acid production and inducing capillary thrombosis. Alcohol and cigarettes may cause ulcers by direct toxic effects, and nonsteroidal antiinflammatory drugs (NSAIDs) can affect gastric arteriolar tone and reduce blood flow. ERRNVPHGLFRVRUJ 2.4 Side B (PBD9: 91; BP9: 44) ERRNVPHGLFRVRUJ Questions A biopsy specimen of the interface between the central erosion and the rolled edge of the gross lesion shown on Side A has the histologic appearance shown. 1. What is going on here? 2. What can cause this lesion? ERRNVPHGLFRVRUJ Answers: Side A 1. The endoscopic view shows a large gastric ulcer with raised, rolled edges ( ▸). 2. Marked inflammation of the mucosal epithelium has led to necrosis with sloughing of the epithelial cells forming the central bed of the ulcer. Surrounding vascular dilation and edema are responsible for the raised, rolled edge. Neutrophils are recruited by mediators such as complement C5a and leukotrienes; they adhere to vascular endothelium and move via diapedesis between endothelial cells. Extravasated neutrophils release proteases, arachidonic acid metabolites, and oxygen-free radicals that damage the epithelium. ERRNVPHGLFRVRUJ 2.5 Side A (PBD9: 94; BP9: 53) ERRNVPHGLFRVRUJ Questions A 37-year-old man has a 2-week history of increasing dyspnea and a nonproductive cough. Rales are heard in all lung fields. His WBC count is 11,130/mm (nl 4000/mm to 11,000/mm ), with a differential count of 50% neutrophils, 4% bands, 35% lymphocytes, and 11% monocytes. If a lung biopsy specimen were obtained, it would have the microscopic appearance shown. The patient improves over the next 2 weeks without therapy. 3 3 1. What is the pattern of inflammation? 2. What infectious agents are most likely to cause this? ERRNVPHGLFRVRUJ 3 Answers: Side B 1. The radiograph shows an interstitial pattern of infiltrates, with fine bright lines ( ▸) extending outward from the hila. 2. The inflammatory infiltrates are composed of mononuclear cells, including lymphocytes, macrophages, and plasma cells. There may be a few neutrophils; inflammatory processes do not involve only one cell type, and various immune responses occur simultaneously. ERRNVPHGLFRVRUJ 2.5 Side B (PBD9: 91; BP9: 53) ERRNVPHGLFRVRUJ Questions A 33-year-old man has a 1-week history of fever, malaise, and dyspnea, with a nonproductive cough. Sputum Gram staining shows normal flora; serologies show increasing titers of IgM against the influenza B virus. The patient's chest radiograph is shown. 1. What is the pattern of the chest radiograph? 2. What kind of inflammatory infiltrates are likely to be present? ERRNVPHGLFRVRUJ Answers: Side A 1. The patient has interstitial pneumonitis . Most of the cells present are mononuclear, and they are mainly lymphocytes; this correlates with his peripheral blood lymphocytosis. The mononuclear cells are within the interstitium ( ▸) and not filling the alveolar spaces, which explains his nonproductive cough. 2. Viral infections, including the respiratory pathogens influenza A and B, parainfluenza, adenovirus, and respiratory syncytial virus, are most likely in this setting . Pneumocystis jiroveci and cytomegalovirus can be seen in immunocompromised hosts. ERRNVPHGLFRVRUJ 2.6 Side A (PBD9: 91; BP9: 43) ERRNVPHGLFRVRUJ Questions A 42-year-old man with a 2-day history of fever and a cough productive of yellow sputum has coarse rales along with dullness to percussion in his right lower lung. His WBC count is 14,720/mm (nl 4000/mm to 11,000/mm ), with a differential count of 76% neutrophils, 9% band forms, 11% lymphocytes, and 4% monocytes. His chest radiograph is shown. 3 3 3 1. What is the pattern of the chest radiograph? 2. Describe the inflammatory infiltrates. 3. Explain this patient's WBC count and differential values. ERRNVPHGLFRVRUJ Answers: Side B 1. This is acute inflammation with exudation of neutrophils ( ▸) into alveolar spaces. 2. Bacterial organisms are the likely infectious agents. 3. Causes of death may include the use of the wrong antibiotic, a resistant organism, a significant comorbidity (e.g., congestive heart failure, coronary artery disease), or a pulmonary embolism caused by prolonged bed rest. ERRNVPHGLFRVRUJ 2.6 Side B (PBD9: 91; BP9: 43) ERRNVPHGLFRVRUJ Questions A 73-year-old woman has a 3-day history of fever, dyspnea, and a productive cough. Markers of an acute-phase response (e.g., erythrocyte sedimentation rate, serum fibrinogen levels, C-reactive protein) are all increased. Despite the use of antibiotics, the patient dies. The microscopic appearance of the lung at autopsy is shown. 1. What is the pattern of inflammation? 2. What are the most likely infectious agents? 3. Why might the patient have died despite the use of antibiotics? ERRNVPHGLFRVRUJ Answers: Side A 1. The patient has patchy infiltrates involving the right lower lobe that are consistent with bronchopneumonia . 2. The infiltrates likely contain neutrophils and protein exudates that fill alveolar spaces, thereby causing the opacification seen in the chest radiograph. 3. He has a neutrophilic leukocytosis; the “ left shift ” from increased bands is due to premature bone marrow release of immature forms, presumably to fight the infection. ERRNVPHGLFRVRUJ 2.7 Side A (PBD9: 73; BP9: 33) ERRNVPHGLFRVRUJ Questions During an aggressive game of croquet, a 24-year-old man sustained multiple blows to his knee. The next day, he had swelling, pain, and tenderness upon palpation. An MRI of the knee is shown. The fluid is aspirated, and it has a low protein and cell count. 1. What is the diagnosis? 2. What is the mechanism of fluid collection? 3. What would this collection of fluid be called if the fluid were blood? ERRNVPHGLFRVRUJ Answers: Side B 1. Posterior to the medial condyle is a popliteal cyst ( Baker cyst ). This is a fluid collection (▴) that extends between the semitendinosus and gastrocnemius tendons into a potential bursal space. 2. Arthritis (particularly osteoarthritis) produced this inflammation, which caused increased vascular permeability and the resulting fluid collection. 3. This is likely to be a transudate with very little protein and few inflammatory cells. An exudate would have many cells and higher protein content. ERRNVPHGLFRVRUJ 2.7 Side B (PBD9: 73; BP9: 33) ERRNVPHGLFRVRUJ Questions A 59-year-old man with chronic knee pain that is worsened by increased walking and bending now has new pain with localized swelling behind the knee. His MRI is shown. 1. Where is this lesion located? 2. What caused this lesion? 3. What are the cell count and protein content of this fluid? ERRNVPHGLFRVRUJ Answers: Side A 1. This effusion ( ▸) in the suprapatellar bursa followed an acute soft-tissue injury. The onset of this moderate effusion 1 day after injury is more consistent with a meniscal injury or a ligamentous sprain than with a rapidly forming large effusion (in ≤2 hours), which suggests the rupture of the anterior cruciate ligament or the fracture of the tibial plateau. 2. The injury produced local inflammation that was mediated by histamine, bradykinin, and leukotrienes; these substances caused vasodilation, stasis, increased hydrostatic pressure, increased permeability through endothelial gaps, and, ultimately, fluid leakage (protein-poor and mostly composed of water and electrolytes) into the extravascular spaces. 3. A hematoma is a localized collection of blood in the soft tissue. ERRNVPHGLFRVRUJ 2.8 Side A (PBD9: 94; BP9: 54) ERRNVPHGLFRVRUJ Questions One week after a deep puncture wound to his forearm, a 48-year-old man develops local pain, erythema, swelling, and warmth at the site. The microscopic appearance of a biopsy specimen is shown. 1. What phagocytic cells are present? 2. What cell surface components are needed for microbe binding and phagocytosis? 3. What opsonins aid in this phagocytic process? ERRNVPHGLFRVRUJ Answers: Side B 1. The iron is stored as hemosiderin granules (aggregates of ferritin micelles) that are mainly contained within Kupffer cells (▾), which are the macrophages of the liver. 2. The patient has hemochromatosis , a hereditary condition characterized by excessive iron absorption, retention, or both. Her skin changes reflect increased cutaneous iron stores, and her diabetes is due to iron-driven free radical injury to beta cells in the islets of Langerhans. 3. The body contains 2 to 4 g of iron. Most is stored as hemoglobin; some is stored as myoglobin, and some is stored as hemosiderin iron. Hemosiderin iron is found mostly in the bone marrow, but it may also appear in the spleen and the liver. ERRNVPHGLFRVRUJ 2.8 Side B (PBD9: 94; BP9: 54) ERRNVPHGLFRVRUJ Questions A 67-year-old woman has skin “bronzing” along with arthritis and nocturnal dyspnea that have been present for the past year. She has an elevated blood glucose level and an abnormal glucose tolerance test. The microscopic appearance of her liver biopsy specimen stained with Prussian blue iron stain is shown. 1. In what form is this iron stored, and in what cells is it contained? 2. What underlying disease does this patient have? 3. Where does iron in the body normally reside? ERRNVPHGLFRVRUJ Answers: Side A 1. Neutrophils and macrophages are present. The macrophage cytoplasm contains phagocytized and vacuolated debris. The history and findings strongly suggest a bacterial infection at the site. 2. Integrins such as CD11, CD18, scavenger receptors, mannose receptors, and Tolllike receptors ( pattern recognition receptors ) aid in binding to microbes as part of innate immunity . 3. The major opsonins that bind to microbes and aid in their phagocytosis include IgG (phagocytes bind via Fc receptors) and the C3b complement fragment. ERRNVPHGLFRVRUJ 2.9 Side A (PBD9: 76; BP9: 35) ERRNVPHGLFRVRUJ Questions A 62-year-old woman with a 4-day history of productive cough and fever has a WBC count of 14,260/mm (nl 3800/mm to 10,800/mm ), with 70% neutrophils and 10% band forms. A chest radiograph shows focal consolidation. Serum C-reactive protein and fibrinogen levels are increased. Her lungs would have the microscopic appearance shown. 3 3 3 1. How do neutrophils attach to endothelium? 2. What promotes neutrophil diapedesis? 3. Explain the laboratory findings. ERRNVPHGLFRVRUJ Answers: Side B 1. Note the shaggy fibrin ( ◂) with fibrinous pericarditis , causing a fatal pericardial tamponade . 2. Histamine, serotonin, interleukin-1, and tumor necrosis factor, among others, activate signaling pathways that phosphorylate cytoskeletal and other intracellular proteins to cause a loss of cell-cell adhesions and to induce endothelial cells to retract (separate) from each other. 3. Vasodilation is induced by various factors, including nitric oxide; histamine; serotonin; bradykinin; prostacyclin; and prostaglandins E , E , and D . Arterioles and venules may be differentially susceptible to the various mediators. 1 ERRNVPHGLFRVRUJ 2 2 2.9 Side B (PBD9: 90; BP9: 43) ERRNVPHGLFRVRUJ Questions A 56-year-old woman with rheumatic valvular disease develops endocarditis after a dental procedure. Despite the use of antibiotics, she develops chest pain followed by hypotension, and she dies. The gross appearance of her heart and pericardial sac is shown at autopsy after the removal of 350 mL of fibrinohemorrhagic and purulent fluid. 1. What is the diagnosis? 2. What mediators influence endothelial permeability? 3. What cytokines promote vasodilation? ERRNVPHGLFRVRUJ Answers: Side A 1. Endothelial cells ( ◂) express E-selectin, intercellular adhesion molecule-1 (ICAM1), and GlyCam-1; the corresponding neutrophil (▴) ligands are sialyl-Lewis X, CD11 and CD18 integrins, and L-selectin. 2. Chemotactic factors that promote neutrophil diapedesis include complement fragment C5a, interleukin-8, lipoxins, and leukotriene B . 4 3. Neutrophilic leukocytosis with a “left shift” and increased acute-phase reactants (e.g., fibrinogen, CRP) are features of acute inflammation. These are driven by inflammatory cytokines, particularly interleukin-1 and tumor necrosis factor. ERRNVPHGLFRVRUJ 3 ERRNVPHGLFRVRUJ Tissue Renewal, Repair, and Regeneration ERRNVPHGLFRVRUJ 3.1 Side A (PBD9: 101; BP9: 59) ERRNVPHGLFRVRUJ Questions A 42-year-old man with Hodgkin lymphoma receives a multidrug regimen and radiation therapy, with a good radiographic response (the tumor mass shrinks). A cell cycle schematic is shown. 1. At what point is the p53 protein going to arrest the cell cycle? 2. At what point is cell cycle arrest most likely to occur in response to radiation? ERRNVPHGLFRVRUJ Answers: Side B 1. This is granulation tissue , which is marked by angiogenesis (new capillaries, ▾), macrophages ( ▸), and fibroblasts ( ◂), with loose, edematous connective tissue. 2. Connective tissue cells (fibroblasts) and endothelial cells can re-enter the cell cycle after being stimulated by tissue injury, with ensuing inflammation and growth factor release. 3. Fibroblast migration and proliferation are stimulated by epithelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor. Angiogenesis is stimulated by vascular endothelial growth factor and basic fibroblast growth factor. ERRNVPHGLFRVRUJ 3.1 Side B (PBD9: 103; BP9: 66) ERRNVPHGLFRVRUJ Questions A 15-year-old boy incurs a laceration to his right calf after falling off of his skateboard onto a pile of bricks. Ten days later, the histologic appearance of the dermis is shown. 1. Name the histologic change shown. 2. What dermal cells have transitioned from G to G ? 0 1 3. What growth factors are responsible for this transition? ERRNVPHGLFRVRUJ Answers: Side A 1. This will occur at the G -S transition . Cells want to ensure DNA fidelity before they commit to a round of replication. Existing DNA damage (e.g., as a result of chemotherapy) increases levels of p53; p53 induces transcription of the cyclindependent kinase (CDK) inhibitor p21; and p21 blocks Rb phosphorylation, which prevents new DNA synthesis. If DNA damage is irreparable at this point, cells may undergo apoptosis. 1 2. This will likely occur at the G -M transition . Ionizing radiation leads to acquired mutations, largely in newly synthesized DNA. To prevent the transmission of chromosomal abnormalities to daughter cells, p53-dependent and p53-independent pathways arrest the cell cycle by inducing CDK inhibitors. 2 ERRNVPHGLFRVRUJ 3.2 Side A (PBD9: 100; BP9: 61) ERRNVPHGLFRVRUJ Questions Depending on the tissue environment, certain cells can re-enter the cell cycle and differentiate. This is shown in the diagram. 1. What is the quiescent cell marked “A”? 2. Where in the cell cycle is “A”? 3. Is cell “A” an embryonic stem cell? ERRNVPHGLFRVRUJ Answers: Side B 1. Asymmetric replication is the critical feature. When this occurs, one cell of every division retains the capacity for self-renewal; this is the functional definition of “stemness.” 2. Rather than directly inducing differentiation, each of the factors indicated in the boxes acts on specific surface receptors in a given population subset to provide signals that promote survival . In the absence of the appropriate cytokine or factor, the committed precursor cell dies. 3. No. They are already differentiated into specific lineages. ERRNVPHGLFRVRUJ 3.2 Side B (PBD9: 100; BP9: 60) ERRNVPHGLFRVRUJ Questions A multipotent common stem cell (top) is derived from a pleuripotent stem cell in the embryonic mesoderm; it can reconstitute bone marrow and generate all circulating blood cells after lethal irradiation. Stem cells have a high capacity for self-renewal, but they are largely quiescent (i.e., in the G state). With successive commitment to differentiation, the ability for self-renewal wanes, but the cells more actively proliferate. 0 1. What is the critical feature of pleuripotent stem cells? 2. Do the factors shown in the boxes induce differentiation? 3. Can cells in colony-forming units give rise to stem cells? ERRNVPHGLFRVRUJ Answers: Side A 1. This is a pleuripotent bone marrow stromal stem cell. 2. This cell is in G . Growth factors activate intracellular signal pathways that control gene expression through transcription factor binding to nuclear DNA. 0 3. No, it is a pleuripotent adult stem cell capable of differentiating into several different mesenchymal lineages. Embryonic stem cells capable of forming all tissues in the human body (totipotential) are largely confined to the blastocyst stage. ERRNVPHGLFRVRUJ 3.3 Side A (PBD9: 104; BP9: 67) ERRNVPHGLFRVRUJ Questions A 43-year-old woman with a 5-month history of recurrent headaches undergoes an MRI, which reveals a well-circumscribed superficial parasagittal mass compressing but not invading the cerebral cortex. Her cerebral angiogram is shown here. 1. What is the likely diagnosis? 2. Explain the angiographic appearance. 3. What growth factor is responsible, and what is the cell of origin? ERRNVPHGLFRVRUJ Answers: Side B 1. This is an epicardial metastasis of carcinoma. Note the extensive vascularity ( ◂) surrounding the tumor. 2. Epicardial and pericardial metastases tend to hemorrhage, and the collection of blood in the pericardial cavity produces cardiac tamponade. This leads to decreases in systolic blood pressure on inspiration of more than 10 mm Hg less than the systolic pressure on expiration—hence pulsus paradoxus. ERRNVPHGLFRVRUJ 3.3 Side B (PBD9: 104; BP9: 67) ERRNVPHGLFRVRUJ Questions A 71-year-old man has had chest pain for the past week. On examination, he is found to have pulsus paradoxus. Pericardiocentesis yields 300 mL of bloody fluid. The appearance of tissue from a pericardial biopsy specimen is shown. 1. What is shown here? 2. How does this lesion account for pulsus paradoxus? ERRNVPHGLFRVRUJ Answers: Side A 1. This is almost certainly a meningioma. This diagnosis is based on the lack of invasion and the circumscribed nature of the tumor. 2. This neoplasm is highly vascular, which accounts for the “blush” of vessels ( ▸) within the tumor mass. 3. Neoplasms (in this case, the meningioma cells) secrete growth factors, such as vascular endothelial growth factor (VEGF), which promote angiogenesis. As tumors grow, they exceed the capacity of the existing blood supply to provide adequate oxygenation and nutrition. Relative tissue hypoxia typically drives the VEGF expression that induces new vessel growth. ERRNVPHGLFRVRUJ 3.4 Side A (PBD9: 104; BP9: 67) ERRNVPHGLFRVRUJ Questions A surgical incision healing by primary intention contains a smorgasbord of growth factors that orchestrate orderly cellular proliferation and matrix synthesis. Some mediators made during this process—represented as “A” in the figure—act through cell surface receptors with intrinsic kinase activity (i.e., with the ability to phosphorylate select protein substrates). 1. What substance leads to endothelial cell mitogenesis with capillary proliferation and increased vascular permeability? 2. What substances can increase keratinocyte and fibroblast mitogenesis? 3. How do these extracellular molecules induce their intracellular effects? ERRNVPHGLFRVRUJ Answers: Side B 1. Catecholamines (epinephrine and norepinephrine). 2. GDP in the inactive protein is exchanged for GTP, which leads to G protein activation. Increased cAMP production is one associated downstream effect. 3. Inositol 1,4,5-triphosphate (IP ) induces the release of calcium from endoplasmic reticulum stores. 3 ERRNVPHGLFRVRUJ 3.4 Side B (PBD9: 105; BP9: 68) ERRNVPHGLFRVRUJ Questions A substance acts via the receptor mechanism diagrammed. Subsequently, there is tachycardia, perspiration, decreased bowel peristalsis, and mydriasis. 1. What hormone action is described? 2. What inactive protein is exchanged for the active form in this pathway? 3. In addition to cAMP, what second messenger ion can be released through the action of activated G proteins? ERRNVPHGLFRVRUJ Answers: Side A 1. Vascular endothelial growth factor (VEGF) 2. Fibroblast growth factor and epidermal growth factor 3. Growth factors activate signal transduction pathways that modulate gene transcription. This occurs through the modification of transcription factors, thereby preventing their degradation or allowing their nuclear localization so that they can bind to nuclear DNA and enable the transcription of relevant effector genes. ERRNVPHGLFRVRUJ 3.5 Side A (PBD9: 108; BP9: 72) ERRNVPHGLFRVRUJ Questions One week after an uncomplicated laparoscopic hernia repair, a 37-year-old pathologist elects to have the healing incision site biopsied for educational purposes. The microscopic appearance is shown. 1. What is wound strength at 1 week? What is wound strength at 2 to 3 months? 2. What enzymes are responsible for wound remodeling? 3. What vitamin deficiency delays this process? 4. What hormone delays this process? 5. What matrix components are poorly regenerated? ERRNVPHGLFRVRUJ Answers: Side B 1. This pleural adhesion ( ▴) is a form of fibrous scar; it divides the pleural cavity into separate regions so that fluid cannot freely move between them. 2. Fibroblast proliferation and activation are driven largely by tumor necrosis factor and interleukin-1. Collagen synthesis is driven by transforming growth factor-β . 3. Macrophages are key cellular elements that create the cytokine environment that directs healing. Proliferating endothelial cells allow for the leakage of plasma proteins (e.g., fibrinogen) that create a provisional stroma in which fibroblasts can proliferate. ERRNVPHGLFRVRUJ 3.5 Side B (PBD9: 104; BP9: 68) ERRNVPHGLFRVRUJ Questions A 36-year-old man with a history of a severe pneumonia is found on follow-up chest radiography to have developed loculated pleural effusions. Had we looked, his pleura would have appeared as shown. 1. What is your diagnosis? 2. What cytokines promote this process? 3. What cells play a key role in this outcome? ERRNVPHGLFRVRUJ Answers: Side A 1. With suture removal at 1 week, wound strength is 10%; 70% to 80% of pretrauma strength is achieved after 2 to 3 months. 2. Metalloproteinases (collagenases, gelatinases, stromelysins, and membrane-bound forms). 3. Vitamin C (ascorbic acid) promotes the hydroxylation of procollagen. Deficiency of this vitamin (scurvy) leads to poorly healing wounds. 4. Glucocorticoids such as cortisol impede wound healing, largely by attenuating the activation of macrophages. 5. Basement membrane scaffolding may not be perfectly regenerated, which can lead to imperfect epithelialization. Elastic fibers are also lost, so the scar is less distensible. ERRNVPHGLFRVRUJ 3.6 Side A (PBD9: 105; BP9: 63) ERRNVPHGLFRVRUJ Questions A 35-year-old woman has an abrupt loss of consciousness with a weak pulse, distant heart sounds, and hypotension. Her electrocardiogram shows reduced voltages. An emergency department physician astutely notices the patient's lens subluxation, arachnodactyly, and tall stature. Despite aggressive resuscitative efforts, the patient dies. Her aorta is shown. 1. What has happened? Why did the patient die? 2. What extracellular matrix component is abnormal? 3. What genetic diseases cause similar aortic changes? ERRNVPHGLFRVRUJ Answers: Side B 1. The “double lumen” ( ◂) in the ascending and descending aorta represents an aortic dissection. 2. The fluid density ( ▪) in the mediastinum is blood that has dissected through the aorta. Blood from aortic rupture may also (fatally) accumulate in the pericardial sac (hemopericardium) and the pleural cavity (hemothorax). 3. The aorta likely shows “cystic” medial degeneration, with a loss of smooth muscle cells and elastic fibers and an accumulation of excess glycosaminoglycans. A tear into this weakened mediastinum can produce a false channel (the so-called “double-barrel aorta”). ERRNVPHGLFRVRUJ 3.6 Side B (PBD9: 105; BP9: 63) ERRNVPHGLFRVRUJ Questions A 70-year-old man with uncontrolled hypertension and diabetes mellitus has a sudden onset of severe stabbing anterior chest pain that radiates to his back. His chest CT scan with contrast enhancement is shown. 1. What has happened to his aorta? 2. What is in his mediastinum? 3. Describe the microscopic changes that would occur in the aorta under these circumstances. ERRNVPHGLFRVRUJ Answers: Side A 1. This is an acute aortic dissection with a transverse tear ( ▾) and clinical findings of terminal cardiac tamponade . 2. This patient most likely has Marfan syndrome , which is one of several typically autosomal-dominant fibrillin-1 (FBN-1) gene mutations that lead to the defective assembly of microfibrils and consequently abnormal elastin fibers. Elastin is an important vessel matrix component, particularly for maintaining aortic integrity during repeated cycles of pulsatile high-pressure flow. 3. Any defect in extracellular matrix synthesis or turnover can potentially cause this condition. Ehlers-Danlos syndrome, defects in collagen synthesis, vitamin C deficiency (ascorbate is a necessary cofactor in collagen cross-linking), and transforming growth factor receptor mutations ( Loeys-Dietz syndrome ) are all causes of aortic aneurysms and dissections. ERRNVPHGLFRVRUJ 3.7 Side A (PBD9: 145; BP9: 221) ERRNVPHGLFRVRUJ Questions A 20-year-old woman had a diaphragmatic hernia repaired during infancy. Throughout her life, even minor trauma has resulted in poor wound healing, and joint dislocations occur frequently. Some of her physical examination findings are shown. 1. What extracellular matrix component is abnormal? 2. What is the genetic basis for her disease? 3. What similar gene mutation leads to vascular rupture? ERRNVPHGLFRVRUJ Answers: Side B 1. This is the perinatal lethal form of osteogenesis imperfecta (OI) or “brittle bone” disease. The markedly osteopenic bones fracture easily in utero (and during delivery), which results in bone deformity and shortening. 2. This type II variant of OI is sometimes an autosomal-recessive condition, and it results from mutations in the genes that encode the type I collagen α and α chains. 1 2 3. Type I OI is an autosomal-dominant condition caused by defective type I collagen synthesis; it allows for greater longevity than type II OI, albeit with multiple recurrent bone fractures. Dental abnormalities, deafness, joint laxity, and blue sclerae are also features of type I OI. ERRNVPHGLFRVRUJ 3.7 Side B (PBD9: 1185; BP9: 767) ERRNVPHGLFRVRUJ Questions A term infant has the appearance shown at birth. Decreased movement was noted during pregnancy, and ultrasound showed limb shortening and deformity. The child died shortly after birth from respiratory failure (pulmonary hypoplasia). 1. Explain the marked limb deformities. 2. What is the underlying genetic defect, and what extracellular matrix component is affected? 3. If the patient were to survive to the age of 20 years, what form of the disease would she have? ERRNVPHGLFRVRUJ Answers: Side A 1. This is most likely the classic form of Ehlers-Danlos syndrome (EDS). A defect in type V fibrillar collagen formation leads to fragile, stretchable skin and joint laxity. 2. This autosomal-dominant condition involves mutations in the COL5A1 and COL5A2 genes. 3. The EDS type associated with vascular abnormalities (including spontaneous rupture) involves abnormalities in type III collagen (the COL3A1 gene). ERRNVPHGLFRVRUJ 3.8 Side A (PBD9: 110; BP9: 69) ERRNVPHGLFRVRUJ Questions A year after the laceration of his ear, a 24-year-old African American man develops the lesion shown. 1. What is your diagnosis? 2. A similar lesion characteristically does not extend beyond the original scar and can regress. What is it called? 3. What therapies have been used for these lesions? ERRNVPHGLFRVRUJ Answers: Side B 1. There is a proliferation of fibroblasts ( ◂) forming dense bundles ( ▸) of pink collagen. This is consistent with keloid formation . 2. A normal healing reaction involves the formation of granulation tissue with capillaries and fibroblasts that fill the void, followed by re-epithelialization over the surface. The scar normally contracts over time as a result of matrix remodeling and the action of myofibroblasts, thereby minimizing the residual collagenous fibrosis. 3. Matrix metalloproteinases (MMPs) degrade collagen and other extracellular matrix proteins. The MMPs depend on zinc for their activity. ERRNVPHGLFRVRUJ 3.8 Side B (PBD9: 109; BP9: 69) ERRNVPHGLFRVRUJ Questions A 15-year-old Chinese girl had her earlobes pierced. Over the course of the next 4 months, she notes the growth of nodular scar tissue to 1 cm in size. The lesions are excised, and their microscopic appearance is shown. 1. What is your diagnosis? 2. What should normally occur in response to injury? 3. What family of enzymes is important in wound remodeling? ERRNVPHGLFRVRUJ Answers: Side A 1. This keloid is an overgrowth of dense fibrous tissue that develops during the healing of an injury. The exuberant fibrous proliferation extends beyond the borders of the original wound, does not regress spontaneously, and often recurs after excision. 2. Hypertrophic scar . 3. Treatment includes excision, occlusive dressings, compression therapy, and corticosteroid injections into the lesions, the last-mentioned of which is used to reduce cellular (particularly macrophage) activation. Anti–transforming growth factor-β therapy has also been used. ERRNVPHGLFRVRUJ 4 ERRNVPHGLFRVRUJ Hemodynamic Disorders, Thromboembolic Disease, and Shock ERRNVPHGLFRVRUJ 4.1 Side A (PBD9: 116; BP9: 76) ERRNVPHGLFRVRUJ Questions Two siblings with familial primary pulmonary hypertension have severe peripheral edema. Chest radiographs show bilateral pleural effusions, a prominent right heart border, and prominent pulmonary arteries. Heart catheterization shows elevated rightsided pressures (pulmonary arterial pressure, 60/32 mm Hg [nl 25/9 mm Hg]) but pulmonary arterial wedge pressure of only 10 mm Hg (nl 9 mm Hg). 1. Why does the liver have the gross appearance shown? 2. Explain the pathophysiology of the radiography and heart catheterization findings. 3. Name the gene mutation, and explain its action. ERRNVPHGLFRVRUJ Answers: Side B 1. Severe chronic passive congestion leads to central hepatocellular necrosis with elevated transaminases and diminished albumin synthesis. Biliary excretory function (normal alkaline phosphatase and bile levels) indicates that the portal triads of the liver lobules are relatively intact. 2. There is fibrosis ( ▾) that extends between the central veins that reflects past pericentral hepatocyte necrosis; conversely, the portal tracts ( ◂) are relatively spared (so-called “ cardiac cirrhosis ”). ERRNVPHGLFRVRUJ 4.1 Side B (PBD9: 116; BP9: 76) ERRNVPHGLFRVRUJ Questions In the patients described on side A, laboratory findings include the following values: serum total protein, 5 g/dL (nl 6 to 8.5 g/dL); albumin, 2.5 g/dL (nl 3.5 to 5 g/dL); aspartate aminotransferase, 186 U/L (nl 42 U/L); alanine aminotransferase, 200 U/L (nl 48 U/L); alkaline phosphatase, 102 U/L (nl 20 to 125 U/L); and total bilirubin, 1 mg/dL (nl 1.3 mg/dL). 1. Explain these laboratory data. 2. How does the wedge liver biopsy specimen shown explain the results of the “liver function tests”? ERRNVPHGLFRVRUJ Answers: Side A 1. The liver has a “nutmeg” appearance as a result of chronic passive congestion caused by right heart failure . 2. These data represent cor pulmonale: elevated pulmonary arterial pressures but lower pulmonary arterial wedge pressure that approximates the left atrial pressure. On the chest radiograph, the enlarged pulmonary arteries reflect pulmonary hypertension, whereas the prominent right heart border indicates right ventricular hypertrophy. 3. Bone morphogenetic protein receptor type 2 ( BMPR2 gene) signaling in smooth muscle cells inhibits cell proliferation and favors apoptosis. Deficient signaling leads to pulmonary vascular thickening and occlusion. ERRNVPHGLFRVRUJ 4.2 Side A (PBD9: 130; BP9: 93) ERRNVPHGLFRVRUJ Questions A 51-year-old man with rheumatic valvular disease with a 10-day history of fever now has a severe headache and a dilated (“blown”) left pupil. Lumbar puncture shows elevated opening pressure and copious neutrophils in his cerebrospinal fluid. His brain MRI is shown. 1. Give a gross morphologic description of this lesion. 2. How can we explain the history and findings? 3. What additional complications may occur? ERRNVPHGLFRVRUJ Answers: Side B 1. The left medial temporal lobe herniates beneath the tentorium and presses on the midbrain. 2. Inflammation leads to vasodilation followed by increased vascular (mostly venular) permeability, with leakage of fluid into the interstitium. 3. Vasodilation can be mediated by histamine and nitric oxide. Vascular permeability can be mediated by histamine, bradykinin, and leukotrienes that induce endothelial gaps. Interleukin-1, tumor necrosis factor, and interferon-γ promote this endothelial cell retraction. ERRNVPHGLFRVRUJ 4.2 Side B (PBD9: 113; BP9: 76) ERRNVPHGLFRVRUJ Questions The patient shown on Side A eventually dies, despite the use of antibiotics and supportive care. The gross appearance of the base of his brain is shown. 1. What part of the brain is involved? 2. How did the abscess cause edema? 3. Name the mediators of increased vascular permeability. ERRNVPHGLFRVRUJ Answers: Side A 1. He has a cerebral abscess with ring enhancement caused by the increased vascularity surrounding the region of liquefactive necrosis. Adjacent to the abscess is marked cerebral edema ( ▪), which causes effacement of the ventricles on the right with left shift of the midline. 2. He had a bacterial endocarditis that led to a septic embolus to the central nervous system. 3. Edema may lead to transtentorial cerebral herniation ( arrow on Side B) with compression of the right third cranial nerve (hence the “blown” pupil) and of the posterior cerebral artery that feeds the visual cortex. The patient may also develop ipsilateral hemiparesis, and damage to the perforating vessels of the midbrain and the pons may lead to Duret hemorrhages. ERRNVPHGLFRVRUJ 4.3 Side A (PBD9: 130; BP9: 90) ERRNVPHGLFRVRUJ Questions A 65-year-old woman has an intermittent 1-year history of sudden-onset dyspnea and chest pain with tachycardia. Three days before admission, her laboratory studies showed increased D-dimer with normal platelet count, prothrombin time, and partial thromboplastin time. She suddenly dies, and an autopsy is performed. Her left lung is shown. 1. What is the gross morphologic description? 2. What is the likely cause? 3. Explain the premortem laboratory findings. 4. Why did she abruptly die? ERRNVPHGLFRVRUJ Answers: Side B 1. This is a mixed thrombus with alternating bands of RBCs ( ◂) and fibrin-enmeshed platelets ( ▸, lines of Zahn ), which indicates that the thrombus formed with flow over the surface. 2. Her iliac vein thrombus dislodged and became an embolus that traveled up the vena cava and through the right heart. It lodged in her lung as a pulmonary embolus . 3. She has antiphospholipid syndrome , likely secondary to systemic lupus erythematosus. ERRNVPHGLFRVRUJ 4.3 Side B (PBD9: 125; BP9: 88) ERRNVPHGLFRVRUJ Questions Additional laboratory testing was performed for the patient on Side A, and her anticardiolipin, antinuclear antibody, and anti–double-stranded DNA tests were positive. She had a false-positive serologic test for syphilis. The microscopic appearance of a lesion from her right iliac vein is shown. 1. Describe the microscopic findings. 2. Relate her iliac vein lesion to her pulmonary lesion. 3. What underlying disease does she have? ERRNVPHGLFRVRUJ Answers: Side A 1. This image shows a wedge-shaped, pleural-based, hemorrhagic (red) infarct . 2. This pulmonary infarct ( ▴) is the result of a pulmonary embolus occluding a pulmonary arterial branch. Blood supplied via bronchial arteries was insufficient to prevent necrosis with cell death but did lead to extensive hemorrhage. 3. Fibrinolysis initiated with thrombus formation leads to the production of fibrin degradation products (i.e., a positive D-dimer test). 4. A large saddle embolus likely blocked all pulmonary artery outflow. The intermittent symptoms seen during the previous year were due to numerous smaller emboli. ERRNVPHGLFRVRUJ 4.4 Side A (PBD9: 130; BP9: 92) ERRNVPHGLFRVRUJ Questions A 71-year-old man with widely metastatic pancreatic cancer presents with flank pain and hematuria. His work-up reveals a new heart murmur. Before any further evaluation can occur, he dies of a massive and apparently embolic stroke. His kidney at autopsy is shown. 1. What is your diagnosis? 2. What cardiac valve and lesion do you suspect? 3. Suppose there is only lower-extremity deep venous thrombosis without valve pathology. How could you explain the systemic embolization? ERRNVPHGLFRVRUJ Answers: Side B 1. The aortic valve cusps have bland vegetations ( ◂) known as nonbacterial thrombotic endocarditis (NBTE) . 2. NBTE frequently occurs in the setting of severe underlying debilitating disease. In particular, with certain malignancies (e.g., adenocarcinoma), a paraneoplastic syndrome ( Trousseau syndrome , which is also called migratory thrombophlebitis ) leads to a hypercoagulable state as a result of the tumor's release of tissue factor (and other mediators). This leads to the formation of venous and arterial thrombi. ERRNVPHGLFRVRUJ 4.4 Side B (PBD9: 130; BP9: 88) ERRNVPHGLFRVRUJ Questions A 71-year-old man with inoperable cerebral glioblastoma develops lower-extremity deep vein thrombosis and dies suddenly of pulmonary thromboembolism. At autopsy, there are also splenic and renal infarctions with the aortic valve lesions shown; there are no other cardiac findings. 1. What is your diagnosis? 2. Explain the pathogenesis. ERRNVPHGLFRVRUJ Answers: Side A 1. A renal cortical pale, wedge-shaped embolic infarct ( •). 2. Because of their bileaflet nature and the large pressure differential between the left atrium and ventricle, mitral valves are more commonly affected by vegetations (e.g., infected, marantic, inflammatory) than the other valves are. In this case, the mitral valve likely has a bland thrombotic vegetation that embolized to the kidney to cause the infarction. 3. A “paradoxical embolus” occurs when an embolus in the venous circulation enters the arterial blood flow through a defect in the heart, thereby allowing direct right-to-left passage. Right heart pressures are typically increased to allow a right-to-left shunt, and Eisenmenger physiology may be present. ERRNVPHGLFRVRUJ 4.5 Side A (PBD9: 130; BP9: 93) ERRNVPHGLFRVRUJ Questions A 57-year-old man presents with a 4-hour history of chest pain radiating to his neck, with associated diaphoresis and dyspnea. His CK-MB and troponin I levels are mildly elevated, and his electrocardiogram shows anterior wall ST elevations. He dies suddenly after a ventricular tachycardia/ventricular fibrillation arrest. The gross appearance of his heart is shown. 1. What is your diagnosis? 2. What endothelial mechanisms modulate the vascular event that precipitated this? ERRNVPHGLFRVRUJ Answers: Side B 1. There is vasculitis with luminal thrombosis ( ♦). 2. Antiphospholipid antibodies as part of the spectrum of autoantibodies in patients with SLE can activate platelets and endothelium and cause endothelial dysfunction that leads to increased procoagulant activity. 3. Tissue factor (thromboplastin) release stimulates the extrinsic coagulation cascade, initially via the activation of factor VII. ERRNVPHGLFRVRUJ 4.5 Side B (PBD9: 125; BP9: 88) ERRNVPHGLFRVRUJ Questions A 20-year-old woman with systemic lupus erythematosus (SLE) develops chest wall and abdominal pain focally, with ischemia of the muscle and overlying skin. Her coagulation times and platelet count are normal. A biopsy specimen of the affected tissue with a medium-sized artery is shown microscopically. 1. What is your diagnosis? 2. What antibodies can promote this process? 3. How does the release of tissue factor affect coagulation? ERRNVPHGLFRVRUJ Answers: Side A 1. The left anterior descending artery shows an acute occlusive thrombus ( ▸); the distal myocardium perfused by that vessel is also mottled and dusky, which reflects a large area of myocardial necrosis. This is a myocardial infarction. 2. Endothelial anticoagulants include thrombomodulin, prostacyclin, adenosine diphosphatase, and activated proteins C and S that inhibit various aspects of platelet aggregation, the coagulation cascade, or both. Conversely, endothelial cells can promote thrombosis via the elaboration of procoagulants such as von Willebrand factor, tissue factor, and plasminogen activator inhibitor-1. ERRNVPHGLFRVRUJ 4.6 Side A (PBD9: 128; BP9: 91) ERRNVPHGLFRVRUJ Questions A 25-year-old man incurs multiple fractures in a motor vehicle accident. He is in stable condition until 3 days later, when he develops tachycardia, tachypnea, and dyspnea, followed by loss of consciousness and death. The gross appearance of his brain is shown. 1. What is your diagnosis? 2. What other organ is typically involved? 3. What is the pathogenesis? ERRNVPHGLFRVRUJ Answers: Side B 1. This is air embolism. Decreased attenuation with a layering effect ( ▴) is consistent with air in the right atrium. 2. The laceration involved a vein. Negative pressure drew air into the wound and into the vein. The air progressed through the vena cava and into the right atrium, where it produced an occlusion. At least 100 cc of air is required for this to occur. Surgical procedures and vascular lines can also introduce air emboli. 3. Air embolism can occur after rapid decompression in individuals such as divers, who have experienced the diffusion of nitrogen into tissues under increased pressure. Bubbles then form in the circulation when the pressure is reduced. ERRNVPHGLFRVRUJ 4.6 Side B (PBD9: 128; BP9: 91) ERRNVPHGLFRVRUJ Questions A 29-year-old man incurs a deep laceration to his lower chest and within minutes develops hypotension, tachycardia, dyspnea, and then cyanosis. A loud, churning, machinery-like murmur is auscultated over his precordium. His chest CT scan is shown. 1. What is your diagnosis? 2. What is the mechanism for this event? 3. How could this event occur within small arteries? ERRNVPHGLFRVRUJ Answers: Side A 1. The extensive petechial hemorrhages, mostly in the white matter, are characteristic of fat embolism syndrome . 2. Fat emboli often involve the pulmonary capillary bed, reducing pulmonary blood flow and leading to microvascular inflammation and thrombosis. 3. Fat globules may be released from marrow with injury, and then these globules release free fatty acids that activate platelets and injure endothelium. Thrombocytopenia can develop rapidly. ERRNVPHGLFRVRUJ 4.7 Side A (PBD9: 121; BP9: 78) ERRNVPHGLFRVRUJ Questions After eating potato salad, a 71-year-old man has diarrhea, followed in short order by acute renal failure, thrombocytopenia, and hemolytic anemia. His prothrombin time and partial thromboplastin time are normal. In the setting of low hematocrit and microvascular thrombosis, he has a myocardial infarction and dies. The gross appearance of his epicardium is shown. 1. What is your diagnosis? 2. Explain the pathogenesis. 3. What may occur in the pericardial cavity? ERRNVPHGLFRVRUJ Answers: Side B 1. Hemorrhages 3 mm to 1 cm are called purpura ; those larger than 1 cm are called ecchymoses . This patient has both. 2. Diminished platelet function, capillary fragility caused by vitamin C deficiency or Cushing syndrome, or vasculitis. 3. Erythrocytes are phagocytized by macrophages when hemoglobin is metabolized. The typical colors of these hemorrhages will change from blue-red (deoxygenated hemoglobin) to yellow-green (bilirubin) to blue-green (biliverdin) to rust brown (hemosiderin). 4. Bleeding into body cavities or tissues results in recycled heme; the iron is not lost, so the MCV will not decrease. ERRNVPHGLFRVRUJ 4.7 Side B (PBD9: 122; BP9: 78) ERRNVPHGLFRVRUJ Questions A 77-year-old woman has the appearance shown on all body surfaces in the absence of gross trauma. Her prothrombin time, partial thromboplastin time, and platelet counts are normal. 1. What are these lesions called? 2. What may have caused this? 3. What color changes may be seen over the next week? 4. With all this tissue bleeding, do you expect the mean corpuscular volume (MCV) to decrease? ERRNVPHGLFRVRUJ Answers: Side A 1. The small, pinpoint hemorrhages (<3 mm) over the epicardial surface are petechiae . Such hemorrhages often result from small vessel leakage in the setting of thrombocytopenia or defective platelets (decreased function). This is likely hemolyticuremic syndrome (HUS) caused by a toxin from Escherichia coli strain 0157:H7. 2. The causal toxin of HUS is absorbed from the gastrointestinal tract; it binds to endothelium throughout the body (especially glomerular endothelium), leading to complement activation and injury with subsequent platelet activation and aggregation. 3. Blood collecting in the pericardial cavity from the myriad petechiae can produce hemopericardium and tamponade . ERRNVPHGLFRVRUJ 4.8 Side A (PBD9: 123; BP9: 86) ERRNVPHGLFRVRUJ Questions A 64-year-old man with intermittent claudication and diminished lower-extremity pulses develops mid-abdominal pain and a palpable pulsatile mass deep to his umbilicus. In a coronal section, his aorta would appear as shown. 1. What is your diagnosis? 2. What complications can occur? ERRNVPHGLFRVRUJ Answers: Side B 1. Pale, wedge-shaped embolic infarcts in the spleen are likely caused by mural thrombi from a left ventricular aneurysm after myocardial infarction. The patient's bowel is likely infarcted. 2. Diabetes promotes accelerated atherosclerosis. This leads to chronic arterial stenosis, often with an acutely superimposed thrombus, which leads to infarction. 3. Dual circulation (e.g., lung) or collateral circulation (e.g., bowel) can allow continued perfusion despite local vascular blockage; this will be insufficient to prevent infarction, but it can be a source of bleeding into the necrotic tissue. The bowel may exhibit hemorrhagic (red) infarction . Infarcts caused by venous occlusion followed by reperfusion can also lead to a hemorrhagic appearance. ERRNVPHGLFRVRUJ 4.8 Side B (PBD9: 125; BP9: 89) ERRNVPHGLFRVRUJ Questions A 44-year-old woman with diabetes mellitus and prior myocardial infarction develops left upper quadrant abdominal pain and frankly bloody stools (hematochezia). She rapidly becomes septic and dies. Her spleen at autopsy is shown. 1. What is your diagnosis for the spleen? What is your diagnosis for the bowel? 2. How could this happen? 3. Why might the bowel appear grossly dark red? ERRNVPHGLFRVRUJ Answers: Side A 1. This is an abdominal aortic aneurysm . The aorta bulges in response to wall destruction and thinning. Because of the resulting abnormal flow and endothelial injury, there is also mural thrombus within the lumen. 2. Although the aortic lumen is rarely occluded completely, this thrombus can propagate, and aortic branches can become occluded. Portions of mural thrombus can also break off and embolize peripherally. Finally, the aneurysm can rupture, and the patient can experience exsanguination. When aneurysms are 5 cm or larger in diameter, there is a roughly 10% risk of rupture per year. ERRNVPHGLFRVRUJ 5 ERRNVPHGLFRVRUJ Genetic Disorders ERRNVPHGLFRVRUJ 5.1 Side A (PBD9: 147; BP9: 222) ERRNVPHGLFRVRUJ Questions A 31-year-old woman had a myocardial infarction last year and now undergoes carotid endarterectomy for transient ischemic attacks. Her total serum cholesterol level is 375 mg/dL (desirable, <200 mg/dL). One of her numerous similar facial lesions is shown. 1. What is your diagnosis of the lesion and her underlying genetic disorder? 2. What therapy is available? ERRNVPHGLFRVRUJ Answers: Side B 1. Familial hypercholesterolemia displays dosage sensitivity . Individuals with the normal allele have normal numbers of low-density lipoprotein (LDL) receptors and normal cholesterol levels. Heterozygotes have 50% fewer LDL receptors, with cholesterol levels of 300 to 400 mg/dL. Homozygotes have virtually no LDL receptors, and cholesterol levels can exceed 600 mg/dL. 2. The carrier rate is 1 : 500 in the United States; homozygotes are only roughly 1 of every 1 million people. 3. Defective or diminished LDL receptors lead to increased circulating LDL cholesterol that can be oxidized and that is available for monocyte-macrophage and smooth muscle cell binding and ingestion in arterial walls. Uptake by these cells leads to activation, proliferation, and matrix synthesis and culminates in atherosclerotic plaque. ERRNVPHGLFRVRUJ 5.1 Side B (PBD9: 147; BP9: 233) ERRNVPHGLFRVRUJ Questions A 22-year-old homozygous man in generation 2 of this pedigree for familial hypercholesterolemia had a cholesterol level of 710 mg/dL (desirable, <200 mg/dL). He died of a myocardial infarction. The cholesterol values of affected kindred are shown. 1. What inheritance pattern is shown? 2. What is the carrier rate for mutant alleles, and what is the frequency of homozygotes? 3. Why did this patient have such an early myocardial infarction? ERRNVPHGLFRVRUJ Answers: Side A 1. This eyelid xanthelasma (▾) contains lipid-laden macrophages. Xanthomas — dermal accumulations of lipid-laden macrophages—can appear at many sites, but they are most commonly found on the buttocks, the thighs, and the extensor surfaces of the extremities. This could be familial hypercholesterolemia . Mutations involved in lowdensity lipoprotein (LDL) receptor synthesis or trafficking result in marked serum cholesterol elevations, with increased risk for the complications of early and accelerated atherosclerosis. 2. HMG-CoA reductase inhibitors (statins) reduce serum cholesterol by blocking de novo cholesterol synthesis, which increases the synthesis of LDL receptors. Small inhibitory RNAs to block hepatic apoprotein B synthesis may also be helpful. ERRNVPHGLFRVRUJ 5.2 Side A (PBD9: 169; BP9: 241) ERRNVPHGLFRVRUJ Questions A 14-year-old boy with mental retardation has an elongated face with a prominent mandible, large everted ears, hyperextensible joints, a high-arched palate, and mitral valve prolapse. The representative appearance of his testis (right ) is considerably larger (macro-orchidism ) than an age-matched normal testis (left ). 1. What gene is mutated? 2. What is the mechanism for this gene mutation? 3. What would a karyotype show? ERRNVPHGLFRVRUJ Answers: Side B 1. This is an X-linked dominant disorder. 2. Random X inactivation is a major reason for reduced penetrance and expression in females. 3. Oogenesis—but not spermatogenesis—leads to the expansion of the normal number of triplet repeats; male carriers tend to pass roughly the same number of repeats to all of their daughters. Those daughters then pass expanded repeats to their offspring. The more repeats that are already present, the more likely it is that the subsequent expansion during female transmission will exceed 200 repeats. The number of affected males increases in successive generations. 4. More severe disease or increased frequency of disease in succeeding generations is called anticipation . ERRNVPHGLFRVRUJ 5.2 Side B (PBD9: 169; BP9: 241) ERRNVPHGLFRVRUJ Questions This pedigree shows a family with fragile X syndrome; affected individuals exhibit mental retardation. The triplet repeat numbers are shown for carriers and for affected individuals. 1. What inheritance pattern is shown? 2. Why are males affected more than females? 3. How do repeats expand? 4. Why are recent generations more affected? ERRNVPHGLFRVRUJ Answers: Side A 1. This is fragile X syndrome . The causal mutation involves the FMR-1 gene on the X chromosome that encodes familial mental retardation protein (FMRP), a cytoplasmic protein that is most abundant in the brain and testis and that has a putative role in the regulation of mRNA translation. 2. This is a triple repeat mechanism of gene silencing that results from the expansion of CGG nucleotide tandem repeats in the 5'-untranslated region of the FMR-1 gene. Normally, there are 10 to 55 repeats (average, 29), and even expansions of up to 200 repeats (called “premutations”) are not phenotypically evident. Affected individuals have more than 230 repeats, at which point hypermethylation leads to transcriptional suppression. 3. A karyotype performed from cells cultured in a folate-deficient medium shows discontinuity of staining on the X chromosome long arm; the chromosome appears “broken” and so is called fragile. ERRNVPHGLFRVRUJ 5.3 Side A (PBD9: 151; BP9: 229) ERRNVPHGLFRVRUJ Questions A 2-year-old girl appeared normal at birth, but she had motor weakness and incoordination at 6 months and is now nearly flaccid. She does not respond to verbal or visual stimuli. Funduscopic examination reveals the appearance shown. 1. What is the diagnosis and gene defect? 2. Explain the appearance of this retina. 3. What is the inheritance pattern? ERRNVPHGLFRVRUJ Answers: Side B 1. Large pale neurons (▪) in the cerebral cortex are typical for the accumulation of an intermediate metabolite in a lysosomal storage disease. The history and population suggest Tay-Sachs disease . 2. With a carrier rate of 1 : 30, the likelihood of a zygote getting a mutated gene (gene frequency) is 1 : 60, and the likelihood of a homozygote with Tay-Sachs disease is 1 : 3600. 3. Multiple alleles of the hexosaminidase A gene from different mutations result in a variable loss of enzyme activity. This accounts for differences in clinical findings, but, in most cases, death occurs by the age of 2 or 3 years. ERRNVPHGLFRVRUJ 5.3 Side B (PBD9: 151; BP9: 229) ERRNVPHGLFRVRUJ Questions An infant Jewish boy of Eastern European descent has not reached developmental milestones; he also has minimal neurologic function and blindness. The microscopic appearance of his neocortex is shown. 1. What is the diagnosis? 2. The carrier rate for this genetic disease is 1 : 30 in a population of Ashkenazi Jews. What is the likelihood that an infant in this population would have the disease? 3. What may account for different clinical expressions from the same gene? ERRNVPHGLFRVRUJ Answers: Side A 1. This is Tay-Sachs disease secondary to defective or decreased hexosaminidase A in the lysosomal ceramide degradation pathway. Although GM gangliosides accumulate in most tissues, the nervous system is most sensitive to the effects. 2 2. The retinal ganglion cells filled with GM ganglioside impart a pale appearance; the normal color of the macula appears “cherry red” (▸) by comparison. 2 3. This disease displays an autosomal-recessive inheritance pattern. ERRNVPHGLFRVRUJ 5.4 Side A (PBD9: 157; BP9: 233) ERRNVPHGLFRVRUJ Questions Three months after an uncomplicated pregnancy and delivery, a term infant develops intractable congestive heart failure, muscle hypotonia, macroglossia, and hepatomegaly. A skeletal muscle biopsy specimen shows markedly increased glycogen content. The infant's radiograph is shown. 1. What is the most likely storage disease? 2. What enzyme is deficient? ERRNVPHGLFRVRUJ Answers: Side B 1. This is Niemann-Pick disease type A; this is the severe neuropathic form of the disease, and it is caused by the almost complete absence of lysosomal sphingomyelinase. The large cells here are neurons filled with lipid, which imparts a foamy appearance. 2. The brain, liver, spleen, lymph nodes, marrow, gastrointestinal tract, and lungs are most affected. 3. Different mutations of the same gene can result in different levels of enzyme activity as well as greater or lesser disease severity. Severe deficiencies cause “infantile” forms, which manifest shortly after birth and result in short survival times; less severe enzyme deficiencies (i.e., greater enzyme synthesis or less defective enzyme activities) cause “juvenile” or “adult” forms, which involve longer survival times. ERRNVPHGLFRVRUJ 5.4 Side B (PBD9: 152; BP9: 230) ERRNVPHGLFRVRUJ Questions After a term gestation marked by diminished fetal movement but a normal karyotype, an infant develops marked hepatosplenomegaly and lymphadenopathy, with severe progressive psychomotor deterioration by 3 months. The child dies at 7 months of age. The microscopic appearance of the infant's neocortex is shown. 1. What inherited metabolic disease is present? 2. What organs are affected? 3. What explains the variable clinical severity of this disease in different patients? ERRNVPHGLFRVRUJ Answers: Side A 1. The clinical findings and the massive cardiomegaly in particular are most consistent with the infantile form of Pompe disease (glycogen storage disease type II). 2. This is an autosomal-recessive lysosomal storage disease caused by a deficiency of α-1,4-glucosidase (lysosomal glucosidase), which results in excessive intracellular glycogen accumulation in multiple cell types. Massive cardiac involvement is the major cause of death. ERRNVPHGLFRVRUJ 5.5 Side A (PBD9: 141; BP9: 808) ERRNVPHGLFRVRUJ Questions A 44-year-old man with scoliosis and numerous soft, sessile, pedunculated cutaneous lesions (shown) now presents with multifocal bone pain in his extremities. Radiographs show long bone erosive lesions and intraosseous cystic lesions, and the patient is noted to have iris hamartomas that the ophthalmologist calls Lisch nodules . 1. What gene mutation is probably present? 2. What inheritance patterns can occur? 3. What neoplasms can develop? ERRNVPHGLFRVRUJ Answers: Side B 1. This is neurofibromatosis type 2 (NF-2) , which is caused by mutation of the NF-2 gene. This gene codes for the tumor suppressor protein merlin , a membrane-tocytoskeletal linker protein involved in the regulation of Schwann cell proliferation and contact inhibition. 2. Yes. Inheritance is autosomal dominant. It is less than one tenth as common as NF-1. 3. NF-2 is associated with multiple meningiomas. Malignant transformation of the neoplasms associated with NF-2 is rare. ERRNVPHGLFRVRUJ 5.5 Side B (PBD9: 1317; BP9: 808) ERRNVPHGLFRVRUJ Questions A 28-year-old man with hearing loss secondary to bilateral acoustic schwannomas develops paraplegia from a lumbar spinal cord ependymoma. One of his many skin lesions is shown. 1. What underlying disease does he have? 2. Can other family members be affected? 3. What other brain tumor could he have? ERRNVPHGLFRVRUJ Answers: Side A 1. The history and skin tumors are consistent with neurofibromas with neurofibromatosis type 1 (NF-1) . The NF-1 gene encodes for the tumor suppressor neurofibromin , which downregulates p21 oncoprotein function. NF-1 mutations lead to diminished neurofibromin and increased p21 activity. 2. NF-1 has an autosomal-dominant pattern of expression. Spontaneous new mutations account for roughly half of cases. 3. NF-1 is also associated with Wilms tumor, rhabdomyosarcoma, meningioma, optic glioma, and pheochromocytoma. Malignant transformation into malignant peripheral nerve sheath tumor can occur in larger plexiform neurofibromas. ERRNVPHGLFRVRUJ 5.6 Side A (PBD9: 157; BP9: 233) ERRNVPHGLFRVRUJ Questions A 7-month-old infant with failure to thrive (height and weight at the 7th percentile) has recurring seizures, hepatomegaly, and renomegaly. Blood work shows hyperlipidemia, hyperuricemia, and elevated lactate. Her serum blood glucose level is chronically at the low end of the normal range (nl 70 to 125 mg/dL), with seizures being precipitated by levels of 24 mg/dL. A liver biopsy reveals a specific enzyme deficiency. The specific exon 2 missense mutation is shown diagrammatically; it substitutes an arginine for a cysteine. 1. What is your diagnosis? 2. Explain the clinical manifestations. 3. What is the likely inheritance pattern? ERRNVPHGLFRVRUJ Answers: Side B 1. This is DiGeorge syndrome , a developmental defect of the third and fourth pharyngeal pouches, which are normally involved in forming the thymus, the parathyroids, and significant portions of the heart base and the great vessels; facial deformities are also common. Thymic hypoplasia leads to defective T-cell maturation and to deficient cell-mediated immunity. 2. Defective parathyroid formation results in deficient parathyroid hormone and hypocalcemia. 3. A 22q11.2 deletion can be associated with psychoses (i.e., schizophrenia or bipolar disorder). ERRNVPHGLFRVRUJ 5.6 Side B (PBD9: 163; BP9: 237) ERRNVPHGLFRVRUJ Questions A term infant has a heart murmur, a cleft palate, and a prominent nose; her early life is marked by recurrent fungal and viral infections. Flow cytometry shows decreased CD4 and CD8 lymphocyte counts, and a fluorescence in situ hybridization assay with probes for the tip of chromosome 22 and a locus at 22q11 (D22S75 for the cognoscenti) shows a microdeletion in the 22q11 region. 1. What is your diagnosis? 2. Why would hypocalcemia occur? 3. What psychiatric illness can occur? ERRNVPHGLFRVRUJ Answers: Side A 1. This is von Gierke disease , a hepatic form of a glycogen storage disorder (type Ia) caused by defective hepatic glucose-6-phosphatase activity. 2. Hypoglycemia is due to defective hepatic glycogenolysis; lactic acidosis and hyperlipidemia are putatively compensatory responses. Hyperuricemia is a combination of increased production and diminished renal excretion. Organomegaly is due to accumulated glycogen. 3. Most mutations that involve enzymes in biochemical pathways are autosomalrecessive conditions; even just 25% of normal activity is often sufficient to prevent disease. ERRNVPHGLFRVRUJ 5.7 Side A (PBD9: 161; BP9: 237) ERRNVPHGLFRVRUJ Questions At 18 weeks' gestation, a 45-year-old, G3, P2 woman who is large for her dates notes minimal fetal movement. An ultrasound shows polyhydramnios. She gives birth at 32 weeks' gestation to a male infant with the profile shown. Other anomalies include an umbilical hernia and a stenotic small bowel. 1. What is the most likely karyotype? 2. How is this condition related to maternal age? 3. What is the cause of the polyhydramnios? ERRNVPHGLFRVRUJ Answers: Side B 1. The bilateral transverse (“simian”) creases (▾) are most suggestive of trisomy 21 ( Down syndrome ). 2. The “triple screen” likely would have shown low values for maternal serum αfetoprotein, unconjugated estriol, and β-human chorionic gonadotropin. 3. Inhibin A, which is secreted by the placenta and the corpus luteum, is increased with trisomy 21. 4. Adolescents with Down syndrome are at increased risk for acute leukemia and congenital heart disease. Survival to adulthood is associated with early Alzheimer disease . ERRNVPHGLFRVRUJ 5.7 Side B (PBD9: 161; BP9: 237) ERRNVPHGLFRVRUJ Questions A 23-year-old woman delivers a stillborn male fetus at 26 weeks' gestation. A large diaphragmatic hernia is present. The fetal hands are shown. 1. What chromosomal abnormality is likely present? 2. What would prenatal screening for maternal serum α-fetoprotein, unconjugated estriol, and increased amounts of β-human chorionic gonadotropin likely have shown? 3. What is the value of measuring inhibin A? 4. Describe the complications that occur with survival. ERRNVPHGLFRVRUJ Answers: Side A 1. Brachycephaly with a prominent occiput, abundant nuchal skin, low-set ears (i.e., the top of the helix is below the eye), epicanthal folds with a flattened facial profile, umbilical hernia, and bowel stenosis suggest trisomy 21 ( Down syndrome ). 2. There is a greater likelihood of nondisjunctional events with advancing maternal age. More than 90% of trisomy 21 cases are due to an extra maternal copy of the chromosome caused by meiotic nondisjunction . The risk for these events occurring in a 45-year-old mother is 1 : 20. 3. Polyhydramnios has been attributed to the diminished fetal ingestion of amniotic fluid as a result of of altered sucking or swallowing reflexes. In this case, it may be related to the intestinal stenosis. ERRNVPHGLFRVRUJ 5.8 Side A (PBD9: 162; BP9: 238) ERRNVPHGLFRVRUJ Questions A 20-year-old primigravida gives birth at term to a boy who survives only 1 hour. His hand is shown. Other anomalies included a large omphalocele, rocker-bottom feet, cyclopia, holoprosencephaly, and endocardial cushion defect. 1. What is the most likely karyotype? 2. What karyotype would explain survival to childhood? 3. What is contained within the omphalocele? ERRNVPHGLFRVRUJ Answers Side B 1. The bilateral cleft lip and palate are most suggestive of trisomy 13 ( Patau syndrome ), which involves midline defects. 2. The patient may be the carrier of a balanced translocation. In many cases, chromosome 13 is stuck onto chromosome 14 to yield a 46,XX,+13,der(13;14) fetal karyotype. 3. Chorionic villus sampling can be done at 9 to 12 weeks' gestation. Amniotic fluid sampling is generally performed between 14 and 20 weeks' gestation. Ultrasound reveals morphologic defects most easily from 16 to 20 weeks' gestation. ERRNVPHGLFRVRUJ 5.8 Side B (PBD9: 162; BP9: 238) ERRNVPHGLFRVRUJ Questions A 24-year-old woman has had three prior pregnancies end in second-trimester stillbirth. The fetus shown is a stillborn girl at 30 weeks' gestation. 1. What chromosomal abnormality is likely present? 2. What may explain this patient's multiple stillbirths? 3. Name methods for the prenatal diagnosis of this condition. ERRNVPHGLFRVRUJ Answers Side A 1. This is postaxial polydactyly ( ◂). The constellation of findings suggests a 47,XY,+13 karyotype (trisomy 13), which is also known as Patau syndrome. 2. An increased or decreased number of autosomes greatly diminishes survival. Somatic mosaicism with a 46,XY/47,XY,+13 karyotype means that some cells are normal, so survival is more likely. 3. A midline omphalocele involves the umbilicus and is covered by a membrane. A large one allows abdominal contents, particularly bowel, to herniate. ERRNVPHGLFRVRUJ 5.9 Side A (PBD9: 162; BP9: 237) ERRNVPHGLFRVRUJ Questions A 27-year-old primigravida gives birth to a boy who survives for a month. His face is shown. Other anomalies include a horseshoe kidney, a ventricular septal defect, rockerbottom feet, and limited hip abduction. 1. What is the most likely karyotype? 2. What is the value of measuring pregnancy-associated plasma protein A (PAPP-A)? 3. Why was his survival so short? ERRNVPHGLFRVRUJ Answers: Side B 1. The overlapping fingers are strongly suggestive of trisomy 18 ( Edwards syndrome ). 2. A large diaphragmatic hernia allows abdominal contents, most often bowel and liver, to ascend into the chest, thereby restricting lung development. Resultant pulmonary hypoplasia is generally incompatible with postnatal survival. 3. Most chromosomal abnormalities occur de novo, with low recurrence risk; one exception is a parental balanced (Robertsonian) translocation. ERRNVPHGLFRVRUJ 5.9 Side B (PBD9: 162; BP9: 237) ERRNVPHGLFRVRUJ Questions A 23-year-old woman delivers a stillborn boy at 26 weeks' gestation. His hand is shown. There is also a large diaphragmatic hernia. 1. What chromosomal abnormality is likely present? 2. How would a diaphragmatic hernia affect postnatal survival? 3. What is the recurrence risk? ERRNVPHGLFRVRUJ Answers: Side A 1. The micrognathia (small jaw) with the narrow face and short neck suggest trisomy 18 ( Edwards syndrome ); the karyotype is likely 47,XY,+1 8. 2. Low maternal serum PAPP-A may be associated with trisomies of chromosomes 13, 18, or 21. Independent of a trisomy, a low first-trimester PAPP-A level can also predict adverse pregnancy outcomes, including a small-for-gestational-age infant or stillbirth. Conversely, a high PAPP-A level can indicate a large-for-gestational-age infant. 3. The loss or gain of chromosomal material, particularly autosomes, is deleterious to survival. ERRNVPHGLFRVRUJ 5.10 Side A (PBD9: 166; BP9: 240) ERRNVPHGLFRVRUJ Questions A 27-year-old woman with two previous uneventful pregnancies and without a significant medical history experiences the loss of a female fetus at 20 weeks' gestation. The fetus is shown. 1. What is the most likely karyotype? 2. How could the placenta accompanying this fetus have a normal karyotype? 3. What karyotypic alteration would account for less severe manifestations and longer survival? ERRNVPHGLFRVRUJ Answers: Side B 1. This is a 45,X karyotype, which is consistent with Turner syndrome (monosomy X) . 2. Anomalies may include cystic hygroma from abnormal ectatic lymphatics in the posterior neck. Among surviving offspring, this becomes the “web neck” commonly seen in these patients. Aortic coarctation, “streak ovaries” and infertility, cubitus valgus, pigmented skin nevi, and peripheral edema are also often present. 3. Homeobox genes that affect stature ( SHOX) are located on the X chromosome. ERRNVPHGLFRVRUJ 5.10 Side B (PBD9: 166; BP9: 240) ERRNVPHGLFRVRUJ Questions A 21-year-old primigravida notes minimal fetal movement at 18 weeks' gestation. Fetal ultrasound shows multiple anomalies. The fetal karyotype is shown. 1. What chromosomal abnormality is present? 2. What anomalies may have been present? 3. What accounts for the short stature among surviving offspring with this abnormality? ERRNVPHGLFRVRUJ Answers: Side A 1. The large posterior cystic hygroma ( ▴) is characteristic of monosomy X (Turner syndrome) . 2. Confined placental mosaicism defines a difference in karyotype between the fetus and the placenta that arises in the developing zygote, the trophoblastic tissue, or both at different times after fertilization. If the placental karyotype is normal, the abnormal fetus may be sustained longer, possibly to term. If the fetus has a normal karyotype but the placenta is abnormal, then even a normal fetus may not be sustained to term; this may be the cause of 2% of cases of fetal growth retardation. 3. Somatic mosaicism occurs when a mutation takes place after fertilization. Depending on the timing, the fetus has variable combinations of normal and abnormal karyotype cells. ERRNVPHGLFRVRUJ 6 ERRNVPHGLFRVRUJ Diseases of the Immune System ERRNVPHGLFRVRUJ 6.1 Side A (PBD9: 202; BP9: 112) ERRNVPHGLFRVRUJ Questions A 27-year-old man has a 20-year history of severe “hay fever” and difficulty breathing through his nose. For the past 8 months, he has had complete nasal blockage. His head CT scan is shown. 1. Explain this radiologic appearance. 2. What type of hypersensitivity response is this? 3. What is the underlying immunologic lesion that leads to such hypersensitivity responses? ERRNVPHGLFRVRUJ Answers: Side B 1. The “allergic” polyps covered by pseudostratified ciliated columnar epithelium (not shown) are filled with markedly edematous loose connective tissue that contains inflammatory infiltrates, including eosinophils and plasma cells. 2. Allergen cross-linking of IgE bound to mast cell Fc receptors causes degranulation with the release of stored biogenic amines (e.g., histamine), thereby leading to vasodilation, increased vascular permeability, bronchial smooth muscle contraction, and mucous gland secretion. Leukotrienes, platelet-activating factor, and cytokines produced by mast cells have similar effects and lead to eosinophil recruitment. ERRNVPHGLFRVRUJ 6.1 Side B (PBD9: 201; BP9: 111) ERRNVPHGLFRVRUJ Questions A 30-year-old woman has seasonal and cat-related asthma and urticaria. A work-up for recurrent sinus infections revealed multiple nasal mucosal polyps, which were resected. The histology of these is shown. 1. Describe the findings. 2. How do mast cells contribute to this lesion? ERRNVPHGLFRVRUJ Answers: Side A 1. There is soft-tissue density (▪) in the nasal cavities instead of dark air density; this is consistent with inflammatory nasal polyps. 2. These are likely to be caused by type I hypersensitivity or allergy . 3. Individuals with type I hypersensitivity develop IgE isotype antibodies to certain antigens (called allergens). Their immune systems are tipped toward the generation of T 2-type helper lymphocytes, which are characterized by their production of cytokines such as interleukin-4 (IL-4); these in turn induce B cells to shift to IgE production. H ERRNVPHGLFRVRUJ 6.2 Side A (PBD9: 206; BP9: 114) ERRNVPHGLFRVRUJ Questions A 33-year-old woman has increasing weakness for 1 year. On examination, she has 5/5 muscle strength in all extremities that diminishes to 4/5 after repetitive movement. She also notices increasing ptosis and occasional diplopia, which is worse at the end of the day. On chest CT scan, a mediastinal mass is found and resected, with the histology shown. 1. What is the tissue, and what is the pathology? 2. What is the immunologic mechanism underlying her symptoms? 3. How is this disease treated? ERRNVPHGLFRVRUJ Answers: Side B 1. Coronal chest MRI shows a large anterior mediastinal mass (▪) that likely represents a thymoma , which is seen in about 15% of patients with myasthenia gravis. 2. Emergent plasmapheresis removes the acetylcholine receptor antibodies and improves the function of the neuromuscular junction. 3. Lambert-Eaton myasthenic syndrome, typically with small cell lung cancer ERRNVPHGLFRVRUJ 6.2 Side B (PBD9: 206; BP9: 115) ERRNVPHGLFRVRUJ Questions A 29-year-old man with diffuse muscle weakness improves symptomatically with edrophonium administration. He later develops acute respiratory distress that requires intubation and emergent plasmapheresis. An MRI of the patient's chest at that time reveals the lesion shown. 1. What is the lesion in his chest? 2. Why is plasmapheresis effective? 3. What paraneoplastic syndrome with muscular weakness involves autoantibodies that target motor end plate calcium channels? ERRNVPHGLFRVRUJ Answers: Side A 1. The thymus shows prominent thymic hyperplasia with lymphoid follicles (▴). Of patients with myasthenia gravis, 65% have thymic hyperplasia; another 15% have a thymoma. In either case, thymic resection generally yields improvement. 2. Type II hypersensitivity ( antibody against a fixed tissue antigen ) is the underlying immunologic mechanism. In this case, acetylcholine receptor antibodies block or down-modulate neuromuscular junction acetylcholine receptors. Consequently, nervous impulses are not translated into muscle contractions. 3. Besides thymectomy, patients can receive oral therapies such as corticosteroids to suppress the immune response and cholinesterase inhibitors to increase the local effective levels of acetylcholine. ERRNVPHGLFRVRUJ 6.3 Side A (PBD9: 207; BP9: 116) ERRNVPHGLFRVRUJ Questions With any prolonged time outdoors, a 23-year-old woman develops a skin rash with raised scaly erythema that is apparent only in sun-exposed areas. She is otherwise healthy. A biopsy specimen of lesion skin reveals the microscopic appearance shown. 1. Describe the appearance. 2. Explain the immunologic mechanism. ERRNVPHGLFRVRUJ Answers: Side B 1. There is immune complex deposition along the dermal–epidermal junction basement membrane (▸); this is a so-called positive “lupus band test.” In patients with systemic lupus erythematosus ( SLE )—as opposed to discoid lupus erythematosus ( DLE )— grossly normal-appearing skin also has such immune complex deposition. 2. About one third of patients with DLE have a positive ANA. Anti-Smith and anti–dsDNA antibodies are seen more often with SLE. Antihistone antibodies are typical for drug-induced lupus. 3. About 5% to 10% of patients with DLE eventually develop systemic manifestations. ERRNVPHGLFRVRUJ 6.3 Side B (PBD9: 207; BP9: 116) ERRNVPHGLFRVRUJ Questions Laboratory testing shows that the patient from Side A has a positive antinuclear antibody (ANA) titer. Anti-Smith and anti–double-stranded DNA (ds-DNA) antibodies are negative, and antihistone antibody titer is negative as well. 1. Explain the immunofluorescence pattern shown from the patient's skin biopsy specimen (adjacent normal-appearing skin shows no such changes). 2. Explain the laboratory findings. 3. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side A 1. A photosensitive rash with no other organ findings is highly suggestive of discoid lupus erythematosus . 2. This is a type III hypersensitivity reaction ; antibody-antigen complexes can accumulate at basement membrane interfaces, such as skin (rash), glomerular capillaries (glomerulonephritis), or mesothelial surfaces lining body cavities (serositis) or within any arterial wall (vasculitis). Symptoms are referable to the site of immune complex deposition, with subsequent complement activation and the recruitment of Fc receptor– bearing cells. ERRNVPHGLFRVRUJ 6.4 Side A (PBD9: 209; BP9: 1118) ERRNVPHGLFRVRUJ Questions A 39-year-old man applied a deodorant, and 30 hours later he noted the appearance shown. 1. What is a likely explanation for these lesions? 2. Explain the immunologic mechanism. 3. Name other diseases with similar basic immune pathogenesis. ERRNVPHGLFRVRUJ Answers: Side B 1. Circulating memory T cells recognize processed fragments of the BCG vaccine, which is made from a bile-attenuated strain of tuberculosis. As a result of this patient's prior vaccination, the tuberculin skin test cannot distinguish a prior “authentic” tuberculosis exposure. 2. The CD4+ cells elaborate interferon-γ that activates macrophages, which elaborate IL-12; this in turn induces more interferon-γ production by the CD4+ cells ( paracrine effect ). Activated T cells also produce IL-2, which promotes T-cell proliferation. The production of T cells and macrophage tumor necrosis factor increases endothelial adhesion molecule expression to attract more leukocytes. ERRNVPHGLFRVRUJ 6.4 Side B (PBD9: 210; BP9: 119) ERRNVPHGLFRVRUJ Questions A 28-year-old man from India has a tuberculin skin test placed (upper panel ), despite his objections that he was previously immunized with BCG. Two days later, the reaction with induration shown here is noted (lower panel ). 1. Why did this reaction occur? 2. What cells and cytokines are most important? ERRNVPHGLFRVRUJ Answers: Side A 1. Contact dermatitis resulted from exposure to substances in the antiperspirant that complex with host proteins to elicit a type IV (delayed-type) hypersensitivity response . Similar responses occur to compounds such as urushiol in poison ivy. 2. Cutaneous macrophages and dendritic cells take up and process conjugated proteins, thereby presenting modified peptides to circulating memory CD4+ T lymphocytes that recognize antigens from prior exposures. T-cell activation produces a T 1 response that is dominated by interferon-γ. H 3. Type IV hypersensitivity underlies the pathogenesis of type I diabetes mellitus , scleroderma , and inflammatory bowel disease , among others; it has also been implicated in multiple sclerosis and rheumatoid arthritis. ERRNVPHGLFRVRUJ 6.5 Side A (PBD9: 236; BP9: 139) ERRNVPHGLFRVRUJ Questions A 52-year-old woman with acute myelogenous leukemia undergoes an allogeneic bone marrow stem cell transplantation with a five of six HLA antigen match. A month after engraftment, she develops jaundice, watery diarrhea, and a scaling rash. Her skin biopsy specimen is shown. 1. What complication has occurred? 2. Explain the immunologic mechanism. ERRNVPHGLFRVRUJ Answers: Side B 1. This is Pneumocystis jiroveci. The cup-shaped or boat-shaped organisms (▸) frequently elicit little inflammation; these forms can persist long after an active infection has been cleared. BAL has high sensitivity for the detection of active infection. 2. Immunodeficiency can occur secondary to myeloablative therapy before transplant or as a result of GVHD through the donor cell destruction of host lymphocytes in tissues such as lymph node and spleen. 3. The antigen mismatch had the one advantage of producing a “ graft-versus-leukemia ” response. ERRNVPHGLFRVRUJ 6.5 Side B (PBD9: 236; BP9: 134) ERRNVPHGLFRVRUJ Questions Over the next 6 months, the patient described on Side A develops recurrent respiratory and urinary tract infections. Cytomegalovirus and adenovirus are cultured from her lungs, and bronchoalveolar lavage (BAL) reveals the organisms shown by silver staining. The patient's leukemia does not recur. 1. What is the organism shown? 2. Why does the patient have recurrent infections? 3. What helped to prevent the recurrence of leukemia? ERRNVPHGLFRVRUJ Answers: Side A 1. The patient has graft-versus-host disease (GVHD); the donor lymphocytes recognize the host major histocompatibility complex (MHC) as being foreign. Biliary, cutaneous, and bowel epithelium seem to be most susceptible to this reaction, so the development of jaundice, rash, and diarrhea is typical for acute GVHD. Note a modest number of chronic inflammatory cells with dyskeratosis and prominent keratinocyte apoptosis (▾); chronic GVHD of the skin eventually leads to significant dermal fibrosis. 2. Donor lymphocytes cause direct cytotoxicity (cytotoxic T lymphocytes), cytokinemediated injury, and heightened host natural killer cell damage. ERRNVPHGLFRVRUJ 6.6 Side A (PBD9: 224; BP9: 128) ERRNVPHGLFRVRUJ Questions A 33-year-old woman has had increasing fatigue, pleuritic chest pain, and a malar rash for 7 months, and she now has dark urine. Her serum creatinine level is 3.7 mg/dL (nl ≤ 1.2 mg/dL). A urinalysis shows RBC casts. Her renal biopsy specimen is shown; for comparison, a similar magnification of a normal glomerulus is also shown. 1. Explain this patient's renal disease. 2. What is the likely diagnosis? 3. What antibody studies would be confirmatory for the diagnosis? ERRNVPHGLFRVRUJ Answers: Side B 1. Note the necrotizing vasculitis (transmural leukocyte invasion) and fibrinoid necrosis (hyaline protein deposition in the vessel wall), which are characteristic of immune complex–induced vasculitis . The patient's history is strongly suggestive of SLE. 2. Such severe vessel inflammation leads to increased vascular permeability, with protein and cellular exudation; there is probably also a component of thrombosis and infarction. Recurrent bouts lead to fibrinopurulent pericardial effusions, organization of the exudates, and pericardial thickening and scarring. ERRNVPHGLFRVRUJ 6.6 Side B (PBD9: 224; BP9: 128) ERRNVPHGLFRVRUJ Questions A 55-year-old woman has a 2-year history of joint pain, Raynaud syndrome, and a skin rash in a sun-exposed distribution. She develops recurrent pericardial effusions and tamponade, which prompts a pericardiectomy. An artery from her pericardial specimen is shown. 1. What is the pathology shown here? 2. How does this explain the patient's pericardial disease? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has membranous glomerulonephritis with “wire loop” thickening of the glomerular capillaries caused by immune complex deposition . Antigen–antibody deposition activates complement and recruits Fc-receptor–bearing leukocytes, thereby causing decreased filtration (elevated creatinine) and hematuria (dark urine caused by the presence of RBC casts). 2. Systemic lupus erythematosus (SLE) 3. Anti-Smith and anti-ds-DNA antibodies are most specific for SLE, but these are not highly sensitive. There is overlap among autoimmune diseases, and so the SS-A antibodies most typical of Sjögren syndrome are also present in 50% of patients with SLE. ERRNVPHGLFRVRUJ 6.7 Side A (PBD9: 228; BP9: 133) ERRNVPHGLFRVRUJ Questions A 42-year-old woman has difficulty swallowing. She also notes that her fingers are cyanotic and painful with cold exposure. Her skin is diffusely thickened, with diminished hair. Her skin biopsy specimen is shown. 1. What is shown in her skin biopsy specimen? 2. Explain the immunologic mechanism. 3. Explain her cold sensitivity. ERRNVPHGLFRVRUJ Answers: Side B 1. She has extensive interstitial fibrosis (“honeycomb” lung [♦]) with restrictive lung disease. 2. Renal hyperplastic arteriolosclerotic narrowing leads to diminished perfusion with activation of the renin–angiotensin system. A vicious cycle ensues that can culminate in malignant hypertension. 3. Autoantibodies that are classically associated with scleroderma will likely be found. These include generic antinuclear antibody, anti–DNA topoisomerase I (in diffuse scleroderma), and anticentromeric antibody (most specific for CREST syndrome [calcinosis, Raynaud phenomenon, esophageal dysmotility, syndactyly, and telangiectasias]). ERRNVPHGLFRVRUJ 6.7 Side B (PBD9: 228; BP9: 133) ERRNVPHGLFRVRUJ Questions Over the next 3 years, the patient from Side A develops a nonproductive cough with increasing dyspnea. On examination, her blood pressure is 260/150 mm Hg. A lung biopsy is performed, and the specimen is shown with trichrome stain. 1. Describe the pulmonary findings from the patient's biopsy specimen. 2. What renal findings do you expect? 3. What laboratory findings would be expected? ERRNVPHGLFRVRUJ Answers: Side A 1. Note the extensive dermal fibrosis (♦). Similar esophageal collagen deposition explains the patient's dysphagia. 2. A CD4+ lymphocyte-mediated delayed-type hypersensitivity response is directed against vascular wall antigens. Chronic vascular inflammation with cytokine production (e.g., transforming growth factor-β) and superimposed thrombotic and ischemic injury have led to chronic fibrosis in multiple tissues. 3. Raynaud phenomenon is due to increased vasomotor tone (vasospasm) that is frequently triggered by cold exposure. ERRNVPHGLFRVRUJ 6.8 Side A (PBD9: 240; BP9: 140) ERRNVPHGLFRVRUJ Questions Although he is well developed and well nourished, a 9-month-old boy has a 3-month history of recurrent bouts of otitis media, sinusitis, bronchopneumonia, and gastroenteritis. His serum protein electrophoresis (SPEP) is shown and compared with a normal SPEP at the top. 1. What is the likely diagnosis? 2. What is the genetic deficit? What are the molecular and cellular consequences? 3. What organisms will likely be found in this infant's respiratory tract? What organisms will likely be found in his gastrointestinal tract? 4. Why did the infections begin only 3 months ago? ERRNVPHGLFRVRUJ Answers: Side B 1. Intravenous immunoglobulin therapy provides needed antibodies; presumably, the arthritis has an infectious etiology (e.g., Mycoplasma) that clears with therapeutic antibodies. 2. This is an X-linked recessive pattern. Females are typically carriers of the disease, but they are not affected. 3. Females can manifest an X-linked disease if both parents carry the abnormal gene. Alternatively, “random X inactivation” in a female carrier can lead to most of the X chromosomes with a functional gene being inactivated. ERRNVPHGLFRVRUJ 6.8 Side B (PBD9: 240; BP9: 140) ERRNVPHGLFRVRUJ Questions Over the next 2 years, the boy described on Side A develops arthritis; treatment with replacement immunoglobulins relieves the symptoms. The family pedigree is shown. 1. Why is intravenous immunoglobulin therapy helpful? 2. What is the inheritance pattern? 3. Under what circumstances could females be affected? ERRNVPHGLFRVRUJ Answers: Side A 1. The SPEP confirms agammaglobulinemia of Bruton as a result of the depressed levels of all serum immunoglobulins. 2. The BTK gene on the X chromosome encodes Bruton tyrosine kinase, which is required for B-cell antigen receptor signaling that drives pre–B cell maturation into immunoglobulin-producing cells. Although there is a normal number of T cells, mature B cells are absent. 3. The lack of circulating antibody leads to recurrent respiratory bacterial infections with Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus. In the gastrointestinal tract, Giardia lamblia and enteroviruses are common pathogens. 4. Maternally acquired antibody protection is depleted after about 6 months. ERRNVPHGLFRVRUJ 6.9 Side A (PBD9: 239; BP9: 142) ERRNVPHGLFRVRUJ Questions A 3-week-old boy has failure to thrive, severe diaper rash, and oral thrush. He subsequently develops Pneumocystis pneumonia and a bout of severe diarrhea with Pseudomonas aeruginosa . A brother died of overwhelming infections at the age of 4 months; two sisters are alive and well at the ages of 5 and 7 years. The microscopic appearance of the boy's kidney is shown. 1. What is wrong with the kidney? 2. What is the likely overarching diagnosis of this infant? 3. What is the most common cause of this disease? ERRNVPHGLFRVRUJ Answers: Side B 1. The patient's thymus was sampled. Hassall corpuscles are present, but virtually no thymocytes are found. 2. The patient likely has severe combined immunodeficiency syndrome (SCID) . The most common form of autosomal-recessive SCID results from adenine deaminase deficiency with the accumulation of intracellular metabolites that are toxic to lymphocytes. 3. The total peripheral lymphocyte count is reduced, mainly from a lack of T cells. Secondary B-cell impairment leads to markedly diminished immunoglobulin levels. ERRNVPHGLFRVRUJ 6.9 Side B (PBD9: 239; BP9: 142) ERRNVPHGLFRVRUJ Questions An infant girl has a history of multiple fungal, viral, and bacterial infections. Despite the recurrent infections, her lymph nodes are poorly developed. Her laboratory findings are shown. She dies after a severe viral pneumonitis. At autopsy, a small anterior mediastinal structure was sampled. 1. What was the small mediastinal structure? 2. What is the likely diagnosis of this patient? What is this disease's most common autosomal-recessive form? 3. Interpret these laboratory findings. Hemoglobin 13.4 g/dL Hematocrit 40.6% Platelet count 236,000/mm 3 WBC count 4550/mm 3 IgG 83 mg/dL IgA 5 mg/dL IgM 22 mg/dL CD4+ cells 91/mm 3 CD8+ cells 22/mm 3 NK cells 350/mm 3 ERRNVPHGLFRVRUJ Answers: Side A 1. This is cytomegalovirus (CMV). Note the prominent large intranuclear inclusions and the minimal inflammatory response. 2. Severe combined immunodeficiency (SCID) results from severe T-cell depletion; B cells are also affected because helper T cells are involved in their maturation. 3. The most common form of SCID (50% to 60% of patients) is X-linked, which results from a mutation of the common gc chain used by multiple cytokine receptors. ERRNVPHGLFRVRUJ 6.10 Side A (PBD9: 248; BP9: 146) ERRNVPHGLFRVRUJ Questions The 25-year-old sexual partner of an intravenous drug abuser has a 2-week history of fever, pharyngitis, arthralgia, myalgia, and headache. Examination reveals generalized tender lymphadenopathy and a diffuse erythematous rash. Her lymph node biopsy specimen is shown. 1. What is happening at this stage in this node? 2. What cells are targeted by this infection? Is the CD4+ count at this point high, low, or normal? 3. How could the infection be diagnosed? ERRNVPHGLFRVRUJ Answers: Side B 1. The HIV1-RNA viral load test gives an indication of the effectiveness of antiretroviral therapy (ART) . 2. Enfuvirtide works at point A to block the fusion of HIV to cell-surface receptors. Reverse transcriptase inhibitors work at point B. Protease inhibitors work at point E. Integrase (point C) inhibitors are in development. 3. ART suppresses viral replication for years, thereby converting HIV infection into a chronic disease. ERRNVPHGLFRVRUJ 6.10 Side B (PBD9: 255; BP9: 159) ERRNVPHGLFRVRUJ Questions A 41-year-old man has a CD4+ lymphocyte count of 138/mm (normal, 490 to 1740/mm ). The schematic shows potential therapeutic targets (A–E ). 3 3 1. What laboratory test best assesses anti-HIV drug efficacy? 2. Which labeled HIV targets currently have drug therapy? 3. How long is therapy expected to be effective? ERRNVPHGLFRVRUJ Answers: Side A 1. At this early stage of HIV infection, a host polyclonal B-cell response leads to marked follicular hyperplasia and lymphadenopathy. With time and CD4 “exhaustion,” the lymph node architecture involutes ( folliculolysis ). 2. The major target is the CD4+ lymphocyte, although antigen-presenting cells (e.g., dendritic cells, macrophages) are persistent viral reservoirs. During the early stages, CD4+ counts are relatively normal. However, as HIV infection progresses toward clinical AIDS, CD4+ counts decrease. 3. HIV infection is screened for with the use of an enzyme immunoassay test (EIA) and confirmed by Western blot. ERRNVPHGLFRVRUJ 6.11 Side A (PBD9: 253; BP9: 152) ERRNVPHGLFRVRUJ Questions Over the last 6 months, a 31-year-old man with a 10-year history of HIV infection has experienced chronic watery diarrhea, the loss of 10% of his body mass, and oral thrush. He has the skin lesions shown. 1. What is your diagnosis? 2. What has likely happened to his HIV1-RNA and CD4+ cell counts? 3. What would be the significance of similar lesions in an HIV-negative geriatric man from Eastern Europe? ERRNVPHGLFRVRUJ Answers: Side B 1. Kaposi sarcoma 2. This patient could have AIDS. He is likely to engage in sex with other men, because HHV-8 is much more prevalent among HIV-positive homosexuals than other populations that are at risk for HIV. 3. HHV-8, which is also called Kaposi sarcoma–associated herpesvirus (KSHV), infects endothelial cells, which results in the increased expression of p53 inhibitors and cyclin D. This drives cellular proliferation while reducing apoptosis. 4. This aggressive form of Kaposi sarcoma involves the lymph nodes. ERRNVPHGLFRVRUJ 6.11 Side B (PBD9: 253; BP9: 152) ERRNVPHGLFRVRUJ Questions A 42-year-old man with history of Pneumocystis pneumonia has recently developed multiple lower-extremity pink-red macules that are up to 1 cm in size. The microscopic appearance of one lesion is shown; note the irregular slitlike vascular channels (▴) and hemorrhage (◂). Human herpesvirus-8 (HHV-8) can be shown in the lesions by polymerase chain reaction. 1. What is your diagnosis? 2. What underlying disease and risk factor could he have? 3. How does HHV-8 contribute to these lesions? 4. What noncutaneous sites are most affected by the African endemic form of this disease? ERRNVPHGLFRVRUJ Answers: Side A 1. These are nodules of Kaposi sarcoma . 2. The HIV1-RNA viral load is increased, and the CD4+ cell count decreases as HIV infection progresses to clinical AIDS. 3. This would most likely represent the classic, endemic form of Kaposi sarcoma; it is less aggressive than AIDS-associated Kaposi sarcoma (only 10% of patients have visceral involvement). ERRNVPHGLFRVRUJ 6.12 Side A (PBD9: 257; BP9: 1153) ERRNVPHGLFRVRUJ Questions A 58-year-old man has increasing fatigue, back pain, and bilateral carpal tunnel syndrome. His work-up reveals the following: serum creatinine, 3 mg/dL (normal, ≤ 1.2 mg/dL); urea nitrogen, 28 mg/dL (normal, 7 to 30 mg/dL); total protein, 9.4 g/dL (normal, 6 to 8.5 g/dL); and albumin, 4.4 g/dL (normal, 3.5 to 5 g/dL). A radiograph of the spine shows multiple lytic lesions. After this patient's sudden arrhythmic death, autopsy shows that his adrenal gland contains the amorphous hyaline material seen here with a Congo red stain. 1. What is a bone marrow biopsy specimen likely to show? 2. What would serum protein electrophoresis show? 3. What is shown by the Congo red stain? ERRNVPHGLFRVRUJ Answers: Side B 1. About 3% of patients with rheumatoid arthritis patients have reactive systemic amyloidosis , with deposition of AA-type amyloid . This occurs mainly in the heart but also in other organs. 2. Localized cardiac amyloidosis involves mutated transthyretin (TTR) protein forming amyloid (although normal transthyretin or atrial natriuretic peptide can also deposit as isolated cardiac amyloid). ERRNVPHGLFRVRUJ 6.12 Side B (PBD9: 257; BP9: 154) ERRNVPHGLFRVRUJ Questions A 60-year-old woman who has had severe rheumatoid arthritis for 30 years has worsening congestive heart failure. Echocardiography shows restrictive changes with diminished ventricular wall motion and ejection fraction. Her endomyocardial biopsy specimen is shown with Congo red stain viewed with polarized light. 1. What is her diagnosis, and why did she develop it? 2. What protein would likely form these deposits in an elderly patient with isolated cardiac arrhythmia? ERRNVPHGLFRVRUJ Answers: Side A 1. Multiple myeloma is a clonal proliferation of plasma cells secreting a single immunoglobulin, with hypergammaglobulinemia. The patient's back pain relates to osteolysis from plasma cell accumulation and the production of osteoclast activating factors. 2. Protein electrophoresis shows a gamma globulin M-spike . 3. Excessive myeloma light chains form AL-type amyloid that is deposited in many organs, including the adrenals. Renal light-chain deposition accounts for renal failure. ERRNVPHGLFRVRUJ 6.13 Side A (PBD9: 226; BP9: 132) ERRNVPHGLFRVRUJ Questions A 55-year-old woman presents with blurred vision and ocular burning and itching. Review of systems uncovers that she also has difficulty swallowing solid foods because of a dry mouth. Physical examination reveals keratoconjunctivitis. Her submandibular sialogram is shown. 1. What is your diagnosis? 2. What autoantibodies are likely to be present? 3. What microscopic findings would you expect from a biopsy specimen of her submandibular gland? ERRNVPHGLFRVRUJ Answers: Side B 1. There is chronic inflammation with a lymphoid follicle (▾) that has a prominent germinal center. The lack of salivary and nasal secretions is typical for Sjögren syndrome . More than half of such patients also have rheumatoid arthritis, which accounts for this patient's hand and foot symptoms. 2. An initial polyclonal lymphoid proliferation in patients with Sjögren syndrome may give rise to an oligoclonal/monoclonal population that eventually becomes a full-blown non-Hodgkin lymphoma . ERRNVPHGLFRVRUJ 6.13 Side B (PBD9: 226; BP9: 132) ERRNVPHGLFRVRUJ Questions A 59-year-old woman with a 9-year history of hand and foot arthritis now has parotid gland enlargement with xerostomia, frequent epistaxis (as a result of mucosal dryness), and bronchitis. Her salivary gland biopsy specimen is shown. 1. Describe the findings and the likely diagnosis. 2. What malignancy is this patient at increased risk of developing? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has sicca syndrome (reduced lacrimal and salivary secretions), most likely secondary to Sjögren syndrome . Note the dilation (▴) and irregular filling of the submandibular gland ducts scarred by this inflammatory process. 2. The most specific serologic assays involve autoantibodies directed against ribonucleoproteins designated SS-A (Ro) and SS-B (La) ; more generic antinuclear antibodies (ANAs) and rheumatoid factor (RF, which is an IgG against IgM) are also often present. 3. The sialogram shows ectatic (dilated) ducts. Inflammation directed against the salivary gland has caused fibrosis and atrophy with more proximal duct dilation. ERRNVPHGLFRVRUJ 6.14 Side A (PBD9: 241; BP9: 141) ERRNVPHGLFRVRUJ Questions A 12-year-old boy has a 2-year history of multiple respiratory tract infections and watery diarrhea. He just recovered from a Streptococcus pneumoniae pneumonia, and he now has Giardia lamblia cysts in his stool. His hematocrit, platelet, and white blood counts are all normal, and he has normal levels of circulating T and B cells. His serum immunoelectrophoresis is shown. 1. What is your diagnosis? 2. What are the underlying immune abnormalities? 3. What future complications could this patient have? ERRNVPHGLFRVRUJ Answers: Side B 1. Normal neutrophils at the right exhibit multiple dark granules (azurophilic granules), whereas the patient's neutrophils do not. 2. The patient has chronic granulomatous disease (CGD) . This is a disorder of leukocyte function that results from the mutations of genes of the NADPH oxidase system, thereby leading to defective bactericidal activity. Two thirds of cases are Xlinked, and one third are autosomal recessive. ERRNVPHGLFRVRUJ 6.14 Side B (PBD9: 238; BP9: 38) ERRNVPHGLFRVRUJ Questions A 7-month-old boy presents with failure to thrive and diffuse lymphadenopathy. Stool cultures grow Serratia; a lymph node biopsy specimen shows macrophage hyperplasia, and cultures grow Aspergillus. A neck abscess exhibits granulomatous inflammation and Staphylococcus aureus. A nitroblue tetrazolium test of the patient's neutrophils (▴) is compared with control neutrophils (▾). 1. What does this test show? 2. What is your diagnosis? ERRNVPHGLFRVRUJ Answers: Side A 1. This is likely isolated IgA deficiency, but it could also represent common variable immunodeficiency (CVID). 2. There can be failure of B-cell maturation into plasma cells, excessive T-cell suppression, T-cell or B-cell autoantibodies, or defective T helper cell function. 3. The same deficient mucosal IgA-mediated immunity that leads to recurrent respiratory and gastrointestinal infections may also fail to neutralize extrinsic antigens, which promotes allergic disorders and autoimmune diseases. Lymphomas and gastric carcinoma are more likely to occur. ERRNVPHGLFRVRUJ 7 ERRNVPHGLFRVRUJ Neoplasia ERRNVPHGLFRVRUJ 7.1 Side A (PBD9: 326; BP9: 202) ERRNVPHGLFRVRUJ Questions A 26-year-old healthy woman who has been sexually active with multiple partners since the age of 16 years has a screening Pap smear that shows numerous dysplastic cells with increased nuclear-to-cytoplasmic ratios, nuclear atypia with angulation, and hyperchromasia. 1. What infection is she likely to have? 2. What do you expect a cervical biopsy specimen to show? 3. How does this agent cause epithelial proliferation? ERRNVPHGLFRVRUJ Answers: Side B 1. This is vulvar intraepithelial neoplasia (VIN) , which is also caused by a human papillomavirus (HPV) infection. The squamous epithelium is thickened (hyperkeratotic), and, even at this low power, several enlarged dysplastic cells with large hyperchromatic nuclei are evident. Abnormal cells are confined to the epithelium above the basement membrane (▸), so this is still an in situ lesion, and it can be cured by local excision or ablation. 2. Vaccination against several of the high-risk and condyloma-associated HPV strains (6, 11, 16, and 18) is now available. ERRNVPHGLFRVRUJ 7.1 Side B (PBD9: 271; BP9: 166) ERRNVPHGLFRVRUJ Questions A 34-year-old woman has a 1-year history of a 1-cm rough, white patch on her left labia. The biopsy specimen of this lesion is shown. 1. What is the diagnosis? Is this invasive? 2. How could this disease be prevented? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient likely has human papillomavirus (HPV) , a sexually transmitted infection that drives squamous epithelial proliferations. HPV types 16 and 18 are more oncogenic (i.e., “high risk”) than others. 2. A cervical biopsy specimen could show foci of abnormal differentiation with proliferation and dysplastic cells extending to various levels within the epithelial layer; this is so-called “cervical intraepithelial neoplasia” (which has also more recently been called “squamous intraepithelial lesion”). Invasion beyond the basement membrane constitutes invasive cervical carcinoma. 3. HPV produces E6 and E7 proteins, which inhibit p53 protein degradation and prevent p21 inhibition of cyclin/CDK4 activity with increased cell proliferation that ultimately drives the dysplasia-to-carcinoma sequence. ERRNVPHGLFRVRUJ 7.2 Side A (PBD9: 272; BP9: 168) ERRNVPHGLFRVRUJ Questions A 25-year-old woman has felt a painless lump in the upper, outer quadrant of her left breast for the last 8 months. Her mother, sister, and maternal aunt all had breast cancer. On examination, the lesion is ill-defined, firm, and 3 cm in its largest dimension; an enlarged and nontender axillary lymph node is also palpable. Her mammogram is shown. 1. What is this lesion most likely to be? Why is it ill-defined? 2. What does the palpable axillary node portend? 3. What gene mutation can be associated with familial breast cancer? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has breast carcinoma . There is an ill-defined, pale tan, scirrhous mass ( ▪) invading the yellow adipose tissue. Fixation to the chest wall also indicates invasion that would not occur with a benign lesion. 2. Paraneoplastic syndromes related to malignancy can include hypercalcemia as a result of the tumor's production of PTHrP. An elevated serum alkaline phosphatase level is also suggestive of either bony or hepatic metastases, depending on the alkaline phosphatase isoform that is elevated. ERRNVPHGLFRVRUJ 7.2 Side B (PBD9: 331; BP9: 209) ERRNVPHGLFRVRUJ Questions A 63-year-old woman notes that she has had a lump in her right breast for the last 6 months. On examination, there is an irregular, non-movable, 6-cm mass. Her serum parathyroid hormone–related peptide (PTHrP) and serum alkaline phosphatase levels are both elevated. A portion of the resected breast is shown. 1. What is your diagnosis? 2. Explain the elevated PTHrP and alkaline phosphatase. ERRNVPHGLFRVRUJ Answers: Side A 1. This lesion is most likely breast carcinoma . Malignant neoplasms invade surrounding tissues with irregular borders (▴) as a result of focal tumor necrosis, inflammation, or desmoplastic host stromal responses. 2. This node is indicative of metastatic disease . Depending on the type of malignancy, tumors often disseminate first to draining regional lymph nodes. This is especially true for breast cancer. 3. BRCA-1 or BRCA-2 mutations should be considered. Approximately 10% of breast cancers are familial, and approximately 80% of these are attributable to BRCA-1 or BRCA-2 mutations. ERRNVPHGLFRVRUJ 7.3 Side A (PBD9: 272; BP9: 168) ERRNVPHGLFRVRUJ Questions A 66-year-old man has a 7-month history of worsening back pain. On a complete examination, there are no obvious external lesions found, but he does have an irregular firm prostate. His bone scan is shown. 1. What is indicated by this bone scan? 2. What lesion is likely present in the prostate? 3. What abnormal serum values might this patient have? ERRNVPHGLFRVRUJ Answers: Side B 1. The marrow space has been replaced by metastatic carcinoma (▸); there is also reactive new bone formation ( ◂). This myelophthisic process results in immature WBCs and RBCs being released into the peripheral blood. 2. Tumor cell chemokine receptors can direct circulating metastatic cells into specific vascular beds, where high concentrations of the cognate ligand are expressed. 3. MMPs include collagenases, gelatinases, and stromelysins that can proteolytically degrade basement membranes to allow tumor cell invasion; these MMPs also mobilize growth factors in the stroma (e.g., basic fibroblast growth factor) that contribute to tumor angiogenesis. ERRNVPHGLFRVRUJ 7.3 Side B (PBD9: 306; BP9: 192) ERRNVPHGLFRVRUJ Questions A 74-year-old woman has a 5-month history of increasing fatigue and cutaneous petechial hemorrhages. She has anemia, thrombocytopenia, and leukopenia; her WBC differential shows 45% PMNs, 6% bands, 2% metamyelocytes, 35% lymphocytes, and 14% monocytes, with 2 nucleated RBCs/100 WBCs. Her bone marrow biopsy specimen is shown. 1. What is an explanation for the pancytopenia? 2. What role do CXCR4 and CCR7 chemokine receptors play in this process? 3. How do matrix metalloproteinases (MMPs) contribute? ERRNVPHGLFRVRUJ Answers: Side A 1. “Hot spots” ( dark areas) are areas of increased osteoclast or osteoblast activity secondary to fractures, infections, or tumor. The multiplicity of the “hot spots” shown here is indicative of metastatic tumor. 2. The abnormal prostate and the predilection of prostate cancer for bone suggest prostatic adenocarcinoma. 3. Metastases to bone can cause hypercalcemia and increase the serum alkaline phosphatase level; an elevated prostate-specific antigen level is also likely. ERRNVPHGLFRVRUJ 7.4 Side A (PBD9: 274; BP9: 168) ERRNVPHGLFRVRUJ Questions A 62-year-old man has an unexpected 5-kg weight loss over 3 months. His liver span is 17 cm (5 cm below the right costal margin), and he has occult blood in his stool. Before further work-up can be done, he dies in a motor vehicle accident. At autopsy, the medical examiner finds the massively enlarged liver shown. 1. What is the cause of the hepatomegaly? 2. What does the stool guaiac test likely indicate? 3. Why did this patient lose weight? ERRNVPHGLFRVRUJ Answers: Side B 1. Focal hepatic metastases ( ▪) cause elevated alkaline phosphatase, but they do not typically increase bilirubin and transaminase levels. 2. Cell proliferation in the setting of the chronic inflammation that occurs with UC leads to the accumulation of genomic mutations that culminate in colonic dysplasia and eventually carcinoma. Colon carcinoma typically metastasizes first to the liver. 3. Decreased attenuation ( darker appearance) in these focal metastases is the result of central necrosis when the tumor's vascular supply is unable to perfuse the lesion adequately. The necrosis leads to the grossly apparent collapse seen as a central umbilication in many of the lesions on Side A. ERRNVPHGLFRVRUJ 7.4 Side B (PBD9: 283; BP9: 178) ERRNVPHGLFRVRUJ Questions A 48-year-old man with ulcerative colitis (UC) that was diagnosed 25 years ago now has increasing fatigue and right upper quadrant discomfort. His abdominal CT scan is shown. 1. What liver-related laboratory findings are likely? 2. What is the relationship of these findings to UC? 3. Why is there decreased attenuation of these lesions? ERRNVPHGLFRVRUJ Answers: Side A 1. The patient's liver shows extensive metastatic disease. Note that, until approximately 90% of the liver was replaced by cancer, the patient would not have had liver failure. 2. The colon is the likely site of the primary tumor; angiogenesis and necrosis of a colonic lesion are responsible for the occult bleeding. Colon cancers tend to metastasize to the liver, because the liver is the first vascular bed that the cancer encounters after leaving the primary site. 3. Weight loss with cancer can result from the elaboration of cytokines such as tumor necrosis factor by tumor cells or by responding host inflammatory cells. ERRNVPHGLFRVRUJ 7.5 Side A (PBD9: 274; BP9: 168) ERRNVPHGLFRVRUJ Questions A 73-year-old man presents with 4-month history of unexplained weight loss and dyspnea. His work-up reveals deep venous thrombosis and pulmonary embolism. A firm and painless left supraclavicular node (Virchow node ) was biopsied and is shown here. 1. What is your diagnosis? 2. Why might the patient have a thromboembolism? 3. From where did this neoplasm likely arise? ERRNVPHGLFRVRUJ Answers: Side B 1. Invasive adenocarcinoma 2. Perineural invasion indicates the ability of the disease to degrade extracellular matrix and grow into other tissue spaces, potentially including blood vessels and lymphatics. This may also account for the patient's persistent and intractable pain. 3. Neoplastic cells develop a capacity to proliferate in the absence of physiologic growth signals and to frustrate normal apoptotic pathways. They often reactivate telomerase, which prevents the shortening of chromosomal telomeres with each division (as with normal somatic cell senescence) and allows for virtually unlimited replicative capacity. ERRNVPHGLFRVRUJ 7.5 Side B (PBD9: 303; BP9: 190) ERRNVPHGLFRVRUJ Questions A 56-year-old woman has a 7-month history of persistent and intractable abdominal pain. An abdominal CT shows a mass in the head of the pancreas; the biopsy specimen is shown. Note the microscopic appearance of peripheral nerves (♦) adjacent to the mass. 1. What is your diagnosis? 2. What is the significance of the perineural invasion? 3. Why are tumor cells “immortal”? ERRNVPHGLFRVRUJ Answers: Side A 1. The neoplastic cells are in a glandular configuration (▾), which is consistent with metastatic adenocarcinoma . 2. One paraneoplastic effect of malignancies is the production of procoagulant substances (e.g., mucin, tissue factor) that result in migratory thrombophlebitis ( Trousseau syndrome ). 3. Adenocarcinomas can arise in many locations: the lung, prostate, colon, and pancreas are the top possibilities for men; the breast, lung, colon, ovary, and pancreas are most likely for women. The involvement of a Virchow node classically suggests a gastric primary location. ERRNVPHGLFRVRUJ 7.6 Side A (PBD9: 269; BP9: 165) ERRNVPHGLFRVRUJ Questions A 65-year-old woman with no prior gynecologic evaluation now presents with vaginal bleeding, pain on defecation, and difficult urination. A large fungating mass is present in the proximal vagina; the biopsy specimen is shown. 1. Describe the cellular features. What is the degree of differentiation? 2. What is the probable primary site of this neoplasm? 3. What is the probable stage of this neoplasm? ERRNVPHGLFRVRUJ Answers: Side B 1. This neoplasm is composed of cells that closely resemble the cell of origin: an adipocyte. This is a benign lipoma . 2. Benign tumors are almost uniformly well differentiated, although there are occasional exceptions (e.g., Spitz nevi). 3. Benign neoplasms are unlikely to transform into malignant neoplasms unless there is ongoing cellular proliferation and the potential for acquiring transforming mutations (e.g., chronic inflammation). ERRNVPHGLFRVRUJ 7.6 Side B (PBD9: 266; BP9: 162) ERRNVPHGLFRVRUJ Questions A 40-year-old woman with a multiyear history of a painless subcutaneous “lump” in her right leg that has not increased in size finally has the lump excised. It has a thin connective tissue capsule, and it is uniformly yellow and soft throughout, without hemorrhage. The microscopic appearance is shown. 1. What is the name of this neoplastic process? 2. What is the degree of differentiation? 3. What would happen if this lesion were not excised? ERRNVPHGLFRVRUJ Answers: Side A 1. There is cellular pleomorphism (variation in shape and size) and nuclear hyperchromasia (dark staining from increased DNA), with a high nuclear-tocytoplasmic ratio . This is a poorly differentiated lesion, but the pink cytoplasm suggests keratinization and thus squamous cell carcinoma . 2. The cervix is the most likely primary site, with the tumor arising at the squamocolumnar junction. 3. The stage is high. This disease is probably stage IV because of the rectal and bladder involvement, which likely resulted from contiguous spread. ERRNVPHGLFRVRUJ 7.7 Side A (PBD9: 302; BP9: 189) ERRNVPHGLFRVRUJ Questions Autonomous cell growth in neoplasms can be promoted via the actions of mutated genes and their altered gene products (proteins), as shown diagrammatically. 1. Name a gene product that affects (A ). 2. Name a gene product that affects (B ). 3. Name a gene product that affects (C ). 4. Name a gene product that affects (D ). ERRNVPHGLFRVRUJ Answers: Side B 1. Single copy adenomatous polyposis coli (APC ) gene mutations can be inherited; a subsequent second “hit” on the remaining normal gene creates a homozygous mutant state with a loss of tumor suppression and increased cell proliferation. 2. Multiple mutations are typically required to induce sporadic (nonhereditary) malignancies; these are accumulated over a longer time span than familial (hereditary) malignancies. 3. β-Catenin binding to E-cadherin forms a cell surface protein complex that is important for intercellular adhesion independent of β-catenin's role as a transcription factor. Abnormalities of the cadherin–catenin pathway in certain cancers may disrupt this adhesion function mechanism. ERRNVPHGLFRVRUJ 7.7 Side B (PBD9: 296; BP9: 188) ERRNVPHGLFRVRUJ Questions Patients with colonic adenocarcinoma often have mutations that affect the pathway shown. Although most patients with colon cancer are older adults, a subset of affected individuals have an inherited disorder that causes colon cancer to occur during the second decade of life. 1. What gene is often mutated in patients with the inherited disorder? 2. Why do most cancers occur in older individuals? 3. Why are epithelial cancer cells typically less adhesive? ERRNVPHGLFRVRUJ Answers: Side A 1. Bcl-2 protein overexpression reduces apoptotic cell death, thereby allowing for the accumulation of neoplastic cells. 2. Myc mutations, which often lead to protein overexpression, are common in human cancers. They result in the sustained transcription of downstream target genes. 3. p53 normally halts the cell cycle when DNA is damaged, thereby permitting repair or inducing apoptosis. However, this may not occur with mutated p53, so neoplastic cells proliferate. 4. Mutated alleles of p16/INK4a cannot block cyclin D-cdk4 activity or prevent RB phosphorylation . These alleles thus lead to sustained cellular proliferation. ERRNVPHGLFRVRUJ 7.8 Side A (PBD9: 287; BP9: 174) ERRNVPHGLFRVRUJ Questions A 37-year-old woman with a 3-month history of increasing malaise has the following laboratory findings: hemoglobin, 8 g/dL (nl 12 to 15.6 g/dL); platelet count, 474,000/µL (nl 130,000 to 400,000/µL); and WBC count, 239,000/µL (nl 3800 to 10,800/µL). A bone marrow biopsy specimen shows 100% cellularity with the karyotypic abnormality diagrammed here. 1. What is this chromosomal alteration? 2. What is the resulting protein product? 3. What drug therapy could target the aberrant protein product? ERRNVPHGLFRVRUJ Answers: Side B 1. The RAS gene is mutated most commonly as an acquired point mutation; it is unlikely to be inherited as part of a cancer syndrome. RAS mutations are common in sporadic cancers and rare in familial cancers. 2. Mutated RAS protein lacks GTPase activity and remains constitutively activated. 3. Transcription factors typically drive cell proliferation ( mitogenesis ). ERRNVPHGLFRVRUJ 7.8 Side B (PBD9: 286; BP9: 179) ERRNVPHGLFRVRUJ Questions A 70-year-old man presents with recent unexplained weight loss, nausea, and abdominal pain. His CT shows a pancreatic mass; the neoplastic cells have a mutated RAS protein that affects the diagrammed pathways. 1. What kind of mutation probably occurred? Are these mutations commonly inherited? 2. Why does mutated RAS continuously stimulate the MAP kinase pathway? 3. What do transcription factors promote? ERRNVPHGLFRVRUJ Answers: Side A 1. This is a balanced translocation . 2. The ABL proto-oncogene product has tyrosine kinase activity. When the portion of the gene coding for the kinase activity fuses with the BCR gene, the normal transcriptional regulation of c- ABL is lost, and there is a resulting functional overexpression that drives cellular proliferation. 3. Imatinib mesylate targets the BCR-ABL tyrosine kinase (and some related kinases). ERRNVPHGLFRVRUJ 7.9 Side A (PBD9: 331; BP9: 209) ERRNVPHGLFRVRUJ Questions A 35-year-old woman has a 5-month history of hirsutism, acne, clitoromegaly, deepening voice, and amenorrhea. Her abdominal CT scan is shown. 1. What is your diagnosis? 2. What is the neoplasm likely producing? 3. What is this syndrome called? ERRNVPHGLFRVRUJ Answers: Side B 1. The peripheral mass (▴) is almost certainly a lung carcinoma. 2. The carcinoma is probably producing ectopic ACTH that is causing Cushing syndrome . 3. Cancers either erode adjacent normal tissues, including vascular structures, or undergo necrosis and bleed from within; the latter occurs because, although cancers can induce robust angiogenesis, the resulting vasculature is not well formed. 4. Laboratory findings would include elevated ACTH (and the inability to suppress it with dexamethasone); hyperglycemia, glucosuria, and lymphopenia would also result from the increased production of glucocorticoids. ERRNVPHGLFRVRUJ 7.9 Side B (PBD9: 331; BP9: 209) ERRNVPHGLFRVRUJ Questions A 66-year-old man with a 4-month history of centripetal fat redistribution, plethoric facies, diffuse muscle weakness, easy bruising, back pain (attributed to osteoporosis and vertebral body fractures), and hypertension develops hemoptysis. His chest radiograph is shown. 1. What is your diagnosis? 2. What substance is this lesion likely producing? 3. Why does he have hemoptysis? 4. What laboratory findings do you expect? ERRNVPHGLFRVRUJ Answers: Side A 1. The large mass (▾) in the left adrenal has variable attenuation, which is consistent with an adrenal neoplasm. This is most likely a cortical carcinoma . 2. The masculinization results from the increased production of male sex steroid hormones (principally testosterone) by the neoplasm. 3. This is a paraneoplastic syndrome . About 10% of malignancies produce a hormone with a systemic effect that may be the first clue to the presence of an occult neoplasm. ERRNVPHGLFRVRUJ 7.10 Side A (PBD9: 269; BP9: 165) ERRNVPHGLFRVRUJ Questions A 42-year-old woman with subacute hearing loss on the right side undergoes MRI that shows a 2-cm mass at the cerebellopontine angle. Cells from the resection of her mass (top ) are shown with S-100 immunohistochemical staining; the bottom panel shows the same staining of a different higher-grade lesion. 1. What is your diagnosis? 2. What is the degree of differentiation? 3. Why does the higher-grade lesion stain less intensely? 4. What gene mutation is likely present? ERRNVPHGLFRVRUJ Answers: Side B 1. The CD45 (“common leukocyte antigen”) positivity indicates that this is a hematopoietic malignancy. These malignancies include leukemias, lymphomas, and myeloproliferative disorders. 2. The degree of differentiation is poor; the cells do not show a clear morphologic pattern. 3. CD3 would indicate a T-cell origin, whereas CD20 indicates a B-cell origin. CD33 is present on myeloid precursors. ERRNVPHGLFRVRUJ 7.10 Side B (PBD9: 334; BP9: 210) ERRNVPHGLFRVRUJ Questions A 44-year-old man with a 5-month history of abdominal pain has a 9-cm mesenteric mass found with CT scanning. The biopsy specimen shows the microscopic appearance with H&E and CD45 immunohistochemical staining. 1. What is the name for this neoplastic process? 2. What is the degree of differentiation? 3. What would be gained by additional staining for CD3, CD20, and CD33? ERRNVPHGLFRVRUJ Answers: Side A 1. This is a schwannoma of the eighth cranial nerve. It is derived from the Schwann cells that form the nerve sheath. 2. It is well differentiated, with monotonous-appearing cells that demonstrate intense cytoplasmic staining with S-100. This is similar to what is seen with normal Schwann cells. 3. Higher-grade malignant neoplasms have lesser differentiation and do not recapitulate the cell of origin as well as lower-grade malignancies or benign tumors do; consequently, there is typically less cytoplasmic S-100 expressed. 4. Schwannomas have NF2 gene mutations. ERRNVPHGLFRVRUJ 7.11 Side A (PBD9: 334; BP9: 211) ERRNVPHGLFRVRUJ Questions A 64-year-old woman has a firm, irregular, fixed 4-cm invasive ductal carcinoma in her right breast. Special immunohistochemical staining is shown; the brown staining highlights virtually all of the tumor cell nuclei (the residual unstained nuclei are mostly endothelial cells). On the basis of the staining pattern shown, the patient is given tamoxifen therapy. 1. What is being identified with positive staining? 2. What does tamoxifen do? ERRNVPHGLFRVRUJ Answers: Side B 1. This is invasive lobular breast carcinoma. Tumor cells invade the stroma and do not form glands. 2. This carcinoma is positive for HER2/neu (c-erb B2), a transmembrane glycoprotein receptor for human epidermal growth factor; it is overexpressed in about 20% to 30% of breast cancers, primarily as a result of gene amplification. Her2/neu overexpression indicates a more aggressive tumor and generally a worse prognosis. 3. Trastuzumab blocks receptor–ligand interactions and removes a major growth stimulus. ERRNVPHGLFRVRUJ 7.11 Side B (PBD9: 285; BP9: 175) ERRNVPHGLFRVRUJ Questions A 71-year-old woman has a 3-cm mass in her left breast that is fixed to her chest wall; she also has axillary lymphadenopathy. The mass is excised, and it has the appearance shown with immunohistochemical staining. On the basis of the staining, the patient is given trastuzumab (a monoclonal antibody directed against the HER2/neu epidermal growth factor receptor). 1. What is the diagnosis? 2. What is being stained here? 3. How does trastuzumab work? ERRNVPHGLFRVRUJ Answers: Side A 1. The nuclear staining is characteristic for hormone receptors, such as receptors for estrogen and progesterone. The fact that the patient is given tamoxifen suggests that the stain is for the estrogen receptor and that the tumor would be responsive to estrogen receptor antagonists. 2. Tamoxifen is an estrogen receptor antagonist. Tumors that bear such receptors typically use estrogen as a proliferative signal; blockade would reduce cell division. ERRNVPHGLFRVRUJ 7.12 Side A (PBD9: 305; BP9: 191) ERRNVPHGLFRVRUJ Questions A 49-year-old woman with a 2-cm lump in her left breast and pleuritic chest pain undergoes a left-sided thoracentesis that yields 200 mL of serosanguineous fluid. A biopsy specimen of the visceral pleura has the microscopic appearance shown. 1. What likely caused the hemorrhage? 2. Explain the vascular proliferation pictured. 3. Why do such lesions bleed? ERRNVPHGLFRVRUJ Answers: Side B 1. This is an infiltrating ductal carcinoma of the breast . 2. There is extensive stromal collagen production ( ♦)—also called desmoplasia—that accounts for the firm or gritty characteristics (or both) of many cancers and for their fixation to adjacent structures. 3. Cancer cells can elaborate growth factors such as platelet-derived growth factor and transforming growth factor-β that promote normal adjacent fibroblasts to produce extracellular matrix. Normal fibroblasts can influence the proliferation and behavior of neighboring tumor cells. ERRNVPHGLFRVRUJ 7.12 Side B (PBD9: 298; BP9: 187) ERRNVPHGLFRVRUJ Questions A 59-year-old woman with a hard, non-movable mass in her right breast has a mammogram that reveals a spiculated mass attached to the chest wall with microcalcifications. A biopsy is performed, and the microscopic appearance of the specimen is shown. 1. What is this neoplasm? 2. What is the dense pink material present? 3. How do stromal fibroblasts and cancer cells interact? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient probably has metastatic breast carcinoma . The pleural metastases either have increased vascular leakiness or are partially necrotic as a result of aberrant blood vessel formation. 2. There is increased vascularity and prominent vascular ectasia ( ◂). These characteristics reflect angiogenesis driven by growth factors such as vascular endothelial growth factor and basic fibroblast growth factor , which are derived from the neoplastic cells. 3. Tumor vessels are disorganized, poorly formed, unstable, and leaky. ERRNVPHGLFRVRUJ 8 ERRNVPHGLFRVRUJ Infectious Diseases ERRNVPHGLFRVRUJ 8.1 Side A (PBD9: 359; BP9: 310) ERRNVPHGLFRVRUJ Questions After a recent allogeneic bone marrow transplant, a 30-year-old woman develops fever, cough, and dyspnea; she is pancytopenic with markedly reduced numbers of granulocytes and lymphocytes. A bronchoscopic biopsy specimen has the microscopic appearance shown. 1. What is your diagnosis? 2. When did this infection start? 3. How does the causal agent avoid detection and destruction by the cell-mediated immune system? ERRNVPHGLFRVRUJ Answers: Side B 1. These fungal organisms have a large capsule ( ▸) and display narrow-based budding ( ◂); these are typical characteristics of Cryptococcus neoformans . 2. Cryptococcal infections commonly cause meningitis, although the portal of entry is the lung; pneumonitis also is frequent. Wide dissemination is common in immunocompromised individuals, whereas infection is typically more limited in immunocompetent hosts. 3. The low CD4+ cell count suggests HIV/AIDS. ERRNVPHGLFRVRUJ 8.1 Side B (PBD9: 387; BP9: 829) ERRNVPHGLFRVRUJ Questions A 36-year-old man with a 3-day history of headache and fever has nuchal rigidity. His CD4+ lymphocyte count is 82/µL (nl 490 to 1740/µL). A lumbar puncture reveals the causal organisms as shown. 1. What is your diagnosis? 2. What other tissue sites does this organism commonly infect? 3. What underlying disease does this patient likely have? ERRNVPHGLFRVRUJ Answers: Side A 1. The large epithelial cells with large intranuclear inclusions ( ▴) are infected with cytomegalovirus ( CMV ). 2. The immunosuppression likely led to the reactivation of latent infection, which is present in more than half of adults. An infection that was newly acquired via saliva or respiratory secretions, venereal transmission, or blood and tissue transplantation is also possible. 3. CMV down-regulates surface MHC class I expression; this is important for displaying viral peptides to cytotoxic T cells. CMV also up-regulates ligands for inhibitory receptors on NK cells. ERRNVPHGLFRVRUJ 8.2 Side A (PBD9: 389; BP9: 313) ERRNVPHGLFRVRUJ Questions A 15-year-old girl has a 2-day history of pain and swelling of the left side of her face. Laboratory studies show a fasting glucose level of 447 mg/dL (nl ≤ 110 mg/dL), slightly elevated sodium and potassium levels, and a CO value of 9 mmol/L (nl 20 to 32 mmol/L). Urinalysis shows 4+ glucose and 4+ ketones. The girl's head MRI is shown. 2 1. What infection is she likely to have? 2. Where is this infection spreading? 3. What underlying diseases does she have? ERRNVPHGLFRVRUJ Answers: Side B 1. Broad, nonseptate, irregular hyphae ( ◂) of Mucor circinelloides are seen. 2. This patient has acute myelogenous leukemia. 3. Zygomycetes organisms are found in the environment and spread by the inhalation of asexual spores. The disease is not spread from person to person. ERRNVPHGLFRVRUJ 8.2 Side B (PBD9: 389; BP9: 313) ERRNVPHGLFRVRUJ Questions A 37-year-old man has had a fever and a nonproductive cough for 2 weeks. His hemoglobin level is 9.9 g/dL (nl 13.8 to 17.2 g/dL); his platelets are 82,000/mm (nl 130,000 to 400,000/mm ); and his WBC count is 76,500/mm (nl 3800 to 10,800/mm ), with a differential of 5% PMNs, 5% bands, 75% myeloblasts with Auer rods, 8% lymphocytes, and 7% monocytes. A chest radiograph shows nodular densities. His lung biopsy specimen is shown. 3 3 3 1. What opportunistic infection does he have? 2. What is his underlying disease? 3. How is this disease spread? ERRNVPHGLFRVRUJ 3 Answers: Side A 1. The soft-tissue swelling ( ▪) in the sinuses in concert with fasting hyperglycemia (and likely diabetes mellitus) is most suggestive of mucormycosis . 2. The infection is spreading into the ethmoid, maxillary, and sphenoid sinuses as well as the cavernous sinus on its way to becoming intracranial (rhinocerebral mucormycosis). 3. This patient has type 1 diabetes mellitus with ketoacidosis; diabetes favors the growth of Mucor circinelloides, which is a form of zygomycosis (a true fungus with a sexual phase). ERRNVPHGLFRVRUJ 8.3 Side A (PBD9: 390; BP9: 418) ERRNVPHGLFRVRUJ Questions A 19-year-old man recently emigrated from Ghana to the United States. He presents with a 1-month history of recurrent fever, rigors, and dark urine. His hemoglobin level is 6.9 g/dL (nl 13.8 to 17.2 g/dL), and his serum haptoglobin level is reduced. His peripheral blood smear is shown. 1. What parasitic infection does he have? 2. What is the intermediate host? 3. What is the life cycle of this organism? ERRNVPHGLFRVRUJ Answers: Side B 1. RBCs infected with Plasmodium clump and stick to endothelium, thereby resulting in vascular obstruction and ischemia. Central nervous system ischemia leads to cerebral malaria , which is the major cause of malarial death in children. The dark dots ( ▾) are the malarial hemazoin pigment that is formed during hemoglobin catabolism by the parasite. 2. The patient has malaria secondary to Plasmodium falciparum; less virulent species include P. vivax, P. ovale, and P. malariae. 3. Hemoglobin S imparts resistance after Plasmodium entry into RBCs; these changes promote better splenic sequestration and removal of infected RBCs. ERRNVPHGLFRVRUJ 8.3 Side B (PBD9: 390; BP9: 418) ERRNVPHGLFRVRUJ Questions A 7-year-old Nigerian girl with a 2-week history of fever and chills is found obtunded. A head CT scan shows diffuse cerebral edema, and she dies shortly thereafter. The microscopic appearance of her cerebral cortex is shown. 1. What is causing her cerebral edema? 2. What are the less virulent species of this parasite? 3. What imparts resistance to this organism? ERRNVPHGLFRVRUJ Answers: Side A 1. He has Plasmodium falciparum infection with parasite “ring forms” ( ◂) in many RBCs; occasional RBCs exhibit multiple parasites. Hemolysis is the cause of his low hemoglobin and haptoglobin levels as well as the dark urine. 2. The female Anopheles mosquito is the intermediate host. The females need a blood meal for egg development; the males just consume nectar and other forms of sugar. 3. The female mosquito bites an infected human and obtains gametocytes that begin a complex cycle to form sporozoites in the salivary gland. These are introduced with the next blood meal and invade human hepatocytes. These develop into circulating merozoites that infect RBCs and gametocytes that continue the cycle. ERRNVPHGLFRVRUJ 8.4 Side A (PBD9: 396; BP9: 313) ERRNVPHGLFRVRUJ Questions A 26-year-old man from a farm in the Caucasus Mountains has a 2-year history of right upper quadrant pain. His abdominal CT scan is shown. 1. What parasitic infection does he likely have? 2. What is the definitive host, and what is the usual intermediate host? 3. What is the life cycle of this organism? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has an echinococcal infection . The fluid from the cyst contains “hydatid sand” with daughter scolices that contain hooklets (*). The laminated cyst wall in the lower panel isolates the growing organism from a host immune response. 2. Liver, lung, bone, and brain are the most common sites of involvement. 3. Hepatomegaly, jaundice, and right upper quadrant pain may occur with this condition. ERRNVPHGLFRVRUJ 8.4 Side B (PBD9: 396; BP9: 313) ERRNVPHGLFRVRUJ Questions A 43-year-old man shoots a fox that has been preying on his sheep herd. He skins it for the pelt but cuts himself in the process. Over the next 4 months, he develops discrete right arm pain at the site of his original injury; 3 years later, he develops seizures. His work-up reveals obstructive hydrocephalus, and a cystic lesion in the aqueduct of Sylvius is subsequently excised. The cyst wall (lower panel ) and the cyst fluid (upper panel ) are shown. 1. What parasitic infection does this patient likely have, and what is shown in the upper panel of the image? 2. What tissue sites are most often involved? 3. Name the presenting signs and symptoms. ERRNVPHGLFRVRUJ Answers: Side A 1. He likely has Echinococcus granulosus infection with a large hepatic cyst ( ▪). 2. Dogs are the definitive host, and sheep are the usual intermediate host. 3. Ingested eggs hatch in the intestine; larvae then migrate to tissue sites such as the liver and develop into mature cysts. The subsequent ingestion of contaminated tissues releases scolices that become adult cestodes that release eggs. ERRNVPHGLFRVRUJ 8.5 Side A (PBD9: 360; BP9: 426) ERRNVPHGLFRVRUJ Questions A 21-year-old man with a 1-week history of fever, sore throat, and malaise has a WBC count of 14,000/mm (nl 3800 to 10,800/mm ), with 35% PMNs, 50% lymphocytes (10% atypical), and 15% monocytes. He has a positive heterophile antibody titer; this antibody can bind sheep, cow, and horse RBCs, and it is produced by infected B cells undergoing transformation to a plasmacytoid state. His peripheral blood smear is shown. 3 3 1. What does the peripheral smear show? 2. What infectious disease does he have, and how is it spread? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has infectious mononucleosis with splenomegaly ( ♦). Liver function is often mildly and only transiently impaired. 2. When infected, B cells represent a persistent reservoir of infection. More importantly, if T-cell immunity wanes (e.g., with HIV infection or immunosuppression), immortalized B cells can expand and develop into a B-cell lymphoma . ERRNVPHGLFRVRUJ 8.5 Side B (PBD9: 360; BP9: 426) ERRNVPHGLFRVRUJ Questions A 17-year-old boy has left upper quadrant discomfort and fever. He has a fine petechial rash, mild pharyngeal erythema with no exudate, and diffuse tender lymphadenopathy. His liver enzymes and bilirubin are modestly elevated. A Monospot assay for heterophile antibody is positive. His abdominal CT scan is shown. 1. What is the explanation for the left upper quadrant pain? 2. What is the possible long-term complication of an EBV infection? ERRNVPHGLFRVRUJ Answers: Side A 1. There are three large “atypical lymphocytes” ( ▸). These activated CD8+ T cells are specific for (and kill) virally infected B cells. 2. This is infectious mononucleosis , 90% of which is caused by Epstein-Barr virus (EBV) infection; the remainder is caused by cytomegalovirus and adenovirus. EBV is spread via close personal contact, typically through saliva. Although epithelial cells such as those in the pharynx may be initially targeted, the infection establishes itself in B lymphocytes. ERRNVPHGLFRVRUJ 8.6 Side A (PBD9: 367; BP9: 312) ERRNVPHGLFRVRUJ Questions A 41-year-old man has a 2-week history of fever and cough that has progressed to a severe headache with mental status changes. Three years ago, this patient underwent a cardiac transplant. His cerebrospinal fluid shows an increased protein level, a normal glucose level, and long filamentous gram-positive organisms. His brain MRI is shown. 1. What infection does he have? 2. What immune defect is likely present? 3. Where did this infection start? ERRNVPHGLFRVRUJ Answers: Side B 1. This is Nocardia asteroides, which often infects the lung and brain; Nocardia brasiliensis often infects the skin. These aerobic gram-positive organisms grow in long branched chains ( ▾). 2. An elevated hemoglobin A level suggests diabetes mellitus , which is often a risk factor for bacterial infection. A CD4+ count of less than 200/mm (e.g., in a patient with AIDS) would be another reason that nocardial infection may develop. 1c 3 ERRNVPHGLFRVRUJ 8.6 Side B (PBD9: 367; BP9: 488) ERRNVPHGLFRVRUJ Questions A 63-year-old man has a 1-month history of fever, 4-kg weight loss, and nonproductive cough. A chest radiograph shows extensive lingular infiltrates. A lung biopsy specimen shows suppurative necrosis along with the gram-positive (and weakly acid-fast) organisms shown. 1. What infection is this, and what other tissue sites does this organism commonly infect? 2. The patient's hemoglobin A level is 10% (normal, 6%). Why did he develop this infection? 1c ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has Nocardia infection. The MRI shows ring-enhancing lesions ( ▸) that represent cavitation with a peripheral rim of inflammation. 2. Nocardia infections are most common among patients who have defective T cell– mediated immunity , which in this case resulted from immunosuppressive therapy used to prevent transplant rejection. 3. The portal of infection is the lung. Primary pulmonary nocardial infection can lead to chronic abscessing pneumonia. ERRNVPHGLFRVRUJ 8.7 Side A (PBD9: 368; BP9: 317) ERRNVPHGLFRVRUJ Questions A 19-year-old woman develops a sore throat that is followed in short order by a dramatically worsening headache over 12 hours. On examination, she has nuchal rigidity and a temperature of 39°C. A lumbar puncture yields cloudy fluid with a protein level of 80 mg/dL (nl 20 to 45 mg/dL), a glucose level of 20 mg/dL (nl 50 to 100 mg/dL), and a cell count of 539/µL (nl ≤ 3/µL), with the appearance shown on the Gram stain. 1. What inflammatory cells are shown here? 2. What organism is pictured? 3. Explain the cerebrospinal fluid (CSF) findings. ERRNVPHGLFRVRUJ Answers: Side B 1. A thick yellow-tan exudate ( ▪) covers the surface of the base of the brain, which is consistent with acute bacterial meningitis . 2. Immunization has reduced the risk for Haemophilus influenzae in infants, and Streptococcus pneumoniae is now more common. Escherichia coli and group B streptococci are more common in neonates. 3. Inflammation leads to edema with brain swelling that is transmitted via the optic nerve to the eye. 4. Brain swelling can lead to herniation that involves the brainstem. Patients can also die of sepsis, with disseminated intravascular coagulation and hypotension. ERRNVPHGLFRVRUJ 8.7 Side B (PBD9: 364; BP9: 825) ERRNVPHGLFRVRUJ Questions A 3-month-old infant has been irritable and feeding poorly for 2 days. On examination, there is fever and papilledema. Within hours and despite the appropriate use of antibiotics, the infant dies. The gross appearance of the brain at autopsy is shown. 1. What is present? 2. What organisms are likely to cause this? 3. Explain the papilledema. 4. How could death occur? ERRNVPHGLFRVRUJ Answers: Side A 1. Neutrophils 2. Gram-negative diplococci ( ▾) are present, and this is consistent with Neisseria meningitidis. In older adults, Streptococcus pneumoniae and Listeria monocytogenes are more common pathogens in cases of meningitis. 3. The growth of microorganisms increases the CSF protein level and can reduce the CSF glucose level. Inflammatory cells indicate infection, or they may occur with tumors and thrombosis. The predominance of neutrophils and the markedly diminished glucose level suggest acute bacterial meningitis . ERRNVPHGLFRVRUJ 8.8 Side A (PBD9: 371; BP9: 493) ERRNVPHGLFRVRUJ Questions A 53-year-old homeless man has a 2-month history of fever, night sweats, and a cough that is productive of thin white sputum. His living companion was recently diagnosed with “an infection” and is half-heartedly taking isoniazid but does not like having to abstain from alcohol to do so. The patient's WBC count is normal, and his chest radiograph is shown. 1. What infection does he likely have? 2. What is the immune mechanism? 3. What test would you order on his sputum sample? ERRNVPHGLFRVRUJ Answers: Side B 1. The bright yellow rods ( ▸) are tubercle bacilli. 2. The patient's tuberculin skin test should show more than 10 mm of induration within 1 to 3 days of PPD challenge. Severe infections (e.g., systemic miliary tuberculosis ) can result in anergy and a false-negative PPD. 3. Granulomas with or without caseous necrosis and with scattered giant cells would likely be found. ERRNVPHGLFRVRUJ 8.8 Side B (PBD9: 371; BP9: 493) ERRNVPHGLFRVRUJ Questions A 53-year-old man with fever and cough has a miliary pattern of small nodules and hilar adenopathy on his chest radiograph. Miliary nodules also are seen in his liver and spleen on CT scan. A liver biopsy specimen with auramine fluorescent stain is shown. 1. What is shown here? 2. What skin testing is useful for diagnosis? 3. What histologic appearance would you expect in the biopsied miliary lesions? ERRNVPHGLFRVRUJ Answers: Side A 1. The man's story makes tuberculosis likely. Upper lobe cavitation ( ▴) from either reactivation or reinfection and resulting in a florid granulomatous response is most often caused by Mycobacterium tuberculosis; some “atypical” mycobacteria (e.g., Mycobacterium kansasii) can cause a similar response. 2. This is due to a type IV (“delayed type”) hypersensitivity reaction . 3. One should get an acid-fast stain (also known as an auramine stain ) to look for the tubercle bacilli. Culture and sensitivity testing will help to determine appropriate drug therapy. ERRNVPHGLFRVRUJ 8.9 Side A (PBD9: 386; BP9: 502) ERRNVPHGLFRVRUJ Questions A 29-year-old man with acute myelogenous leukemia receives multiple courses of chemotherapy. Within 1 week of his last cycle, he develops a nonproductive cough. A chest radiograph shows nodular infiltrates, and bronchoalveolar lavage is performed. A periodic–acid Schiff (PAS)–stained preparation is shown. 1. What infection does this patient have? 2. What is missing from his WBC population? 3. What are some of the virulence factors of this organism? 4. Could this be a false-positive result? ERRNVPHGLFRVRUJ Answers: Side B 1. These budding cells are typical for Candida species. 2. The previous antibiotic treatment eliminated protective commensal organisms such as Lactobacillus, which maintain an acidic environment that is inhospitable to yeast. 3. Cell-mediated immunity, particularly the T 1 response, is needed for protective antifungal immunity. T 1 cells activate the innate immune elements (e.g., macrophages) that are primarily responsible for containing mucosal and cutaneous candidiasis. Patients with AIDS, who lack CD4+ T cells, often develop thrush. H H ERRNVPHGLFRVRUJ 8.9 Side B (PBD9: 386; BP9: 502) ERRNVPHGLFRVRUJ Questions A 22-year-old woman has just finished a course of antibiotics for a bacterial urinary infection when she develops a curdlike vaginal discharge associated with intense itching. A Gram stain of the exudate is shown. 1. What fungal organism is present? 2. What role did the antibiotics play in this infection? 3. What parts of the immune system play a key role in defense against this organism? ERRNVPHGLFRVRUJ Answers: Side A 1. The budding cells with pseudohyphae are Candida organisms. 2. Systemic Candida infections are most likely to occur with neutropenia . Note the insignificant amount of inflammatory cell infiltrate in this biopsy specimen. 3. Candida organisms can secrete aspartyl proteinases, which promote invasion; catalases, which resist oxidative killing by phagocytes such as macrophages; and adenosine, which blocks neutrophil degranulation and oxygen free radical production. 4. Yes. Although the specimen was collected via the oropharynx, which is normally colonized with Candida, the clinical setting suggests a true positive. ERRNVPHGLFRVRUJ 8.10 Side A (PBD9: 387; BP9: 503) ERRNVPHGLFRVRUJ Questions A 42-year-old man has a 3-week history of fever, nonproductive cough, and increasing dyspnea. His chest CT scan is shown. 1. What radiographic pattern is present? 2. What fungal organisms are most likely to cause this pattern? 3. What underlying diseases could this man have? ERRNVPHGLFRVRUJ Answers: Side B 1. Budding yeasts with a thick gelatinous capsule ( ▪) highlighted with India ink (the clear zone around the refractile nucleus in the image) in an immunocompromised host with meningitis suggest Cryptococcus neoformans . 2. Clinical AIDS is reached when the CD4+ cell count is less than 200/mm . 3 3. The thick polysaccharide capsule interferes with phagocyte ingestion. ERRNVPHGLFRVRUJ 8.10 Side B (PBD9: 387; BP9: 829) ERRNVPHGLFRVRUJ Questions A 37-year-old woman has been HIV positive for 10 years and cannot afford medical care. She has a 1-week history of fever with nonproductive cough, followed by a worsening headache. On examination, she has nuchal rigidity. Lumbar puncture yields cerebrospinal fluid with the appearance shown after adding India ink. 1. What opportunistic infection does she have? 2. What is her CD4+ lymphocyte count likely to be? 3. What virulence factor prevents phagocytosis? ERRNVPHGLFRVRUJ Answers: Side A 1. This is a reticulonodular pattern (“tree in bud”); it is suggestive of disseminated granulomatous inflammation . 2. Cryptococcosis , histoplasmosis, and coccidioidomycosis are the most likely fungal organisms to be associated with this pattern. Miliary tuberculosis is also a likely bacterial agent. 3. Immunocompetent individuals can get these types of fungal infections, but typically not so diffusely. Disseminated infection occurs in immunocompromised hosts with AIDS, patients with leukemia or lymphoma, those undergoing chemotherapy for cancer treatment, and those who are immunosuppressed for transplantation procedures or as a result of autoimmune disease. ERRNVPHGLFRVRUJ 8.11 Side A (PBD9: 388; BP9: 829) ERRNVPHGLFRVRUJ Questions A 32-year-old man undergoes induction chemotherapy for acute myelogenous leukemia and develops fever and cough followed by headache and partial paralysis. His CBC shows anemia, thrombocytopenia, and leukopenia, with 13% segments, 4% bands, 62% lymphocytes, and 21% monocytes. A CT scan of his brain shows focal infarction with hemorrhage. A tissue section of a cerebral vessel with GMS (silver) stain is shown. 1. What infection does he have? 2. What immune defect is likely present? 3. Where did this infection start? ERRNVPHGLFRVRUJ Answers: Side B 1. This is Aspergillus flavus, which is commonly seen in immunocompromised individuals. 2. Aspergillus hyphae invade blood vessels and cause hemorrhage, thrombosis, or both. In this case, note the cavitary abscesses ( ▴) with enhanced rims of engorged blood vessels. 3. Aspergillus colonization of the airways can produce allergic bronchopulmonary aspergillosis as a result of the host's T 2-driven immune reaction. H ERRNVPHGLFRVRUJ 8.11 Side B (PBD9: 388; BP9: 504) ERRNVPHGLFRVRUJ Questions A 31-year-old woman has lupus nephritis that requires long-term high-dose corticosteroid therapy. She develops fever and cough. Her chest CT scan is shown. 1. What fungal infection might this be, given the cavitary lesions and the patient's immunocompromised state? 2. Why does the CT scan show bright enhancement around the circular lesions? 3. What disease does this organism cause in asthmatic patients? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has Aspergillus infection. These fungal organisms grow as acutely branching septate hyphae ( ◂). 2. Aspergillus infections are most common in immunocompromised patients, particularly when neutropenia is present as it is in this case, with an absolute neutrophil count of only 330/mm . 3 3. The portal of infection is the lung. ERRNVPHGLFRVRUJ 9 ERRNVPHGLFRVRUJ Environmental and Nutritional Diseases ERRNVPHGLFRVRUJ 9.1 Side A (PBD9: 409; BP9: 273) ERRNVPHGLFRVRUJ Questions A 25-year-old woman is found dead in her home. There is no evidence of trauma, and postmortem toxicology is negative for drugs of abuse and ethanol. There is an unvented kerosene heater in her bedroom. Her hand is shown. 1. What is the most likely cause of death? 2. Under what circumstances is this toxin produced? 3. What would routine pulse oximetry reveal had it been done during the last moments of her life? ERRNVPHGLFRVRUJ Answers: Side B 1. The markedly elevated transaminases are consistent with hepatotoxicity from acetaminophen ingestion; this is also consistent with the pattern of central liver necrosis. Although high levels of acetaminophen are not directly toxic, an intermediate metabolite generated by the liver cytochrome P-450 system (NAPQ1) is a toxic free radical. 2. This type of poisoning can be treated with hemodialysis and N-acetyl cysteine to conjugate the toxic free radical intermediary metabolite. ERRNVPHGLFRVRUJ 9.1 Side B (PBD9: 422; BP9: 284) ERRNVPHGLFRVRUJ Questions A 19-year-old woman is found comatose. She has a history of depression and had previously mentioned committing suicide by pill ingestion. No drugs of abuse are found, although aspirin, acetaminophen, and multivitamins are in her medicine cabinet. Initial laboratory studies show an aspartate aminotransferase level of 1092 U/L (nl ≤42 U/L), an alanine aminotransferase level of 1137 U/L (nl ≤48 U/L), and normal bilirubin and creatinine levels. She develops florid liver failure and dies. Her liver at autopsy shows marked necrosis (▪). 1. What drug did she most likely ingest? 2. How can this poisoning be treated? ERRNVPHGLFRVRUJ Answers: Side A 1. The cherry red color ( ◂) is due to carbon monoxide (CO) poisoning. CO binds hemoglobin 200 times more avidly than O . 2 2. Incomplete combustion can produce CO; sources include vehicle exhaust, cigarette smoke, and heating appliances. 3. Typical pulse oximetry does not discriminate the small absorption wavelength differences between oxyhemoglobin and carboxyhemoglobin; it would indicate “good” O saturation in this patient. 2 ERRNVPHGLFRVRUJ 9.2 Side A (PBD9: 426; BP9: 287) ERRNVPHGLFRVRUJ Questions A 19-year-old woman comes to the emergency department with her 18-year-old husband; he does all the talking, asserting that the lesion shown was caused by the accidental closing of a car door on his wife's wrist. On examination, there are also contusions of varying ages on her thighs, arms, and abdomen. The clinical record reveals multiple other previous emergency department visits for “accidents,” including a broken wrist and a broken nose. 1. Describe the injury shown here. 2. What is the likely circumstance for this injury? 3. What behavioral disorder is suggested by the husband's actions? ERRNVPHGLFRVRUJ Answers: Side B 1. These are lacerations produced by irregular tearing of the skin. 2. Granulation tissue would form at the base of the laceration, and this would be followed by re-epithelialization from the edges. ERRNVPHGLFRVRUJ 9.2 Side B (PBD9: 426; BP9: 287) ERRNVPHGLFRVRUJ Questions A 59-year-old man is working with a pipe wrench in a narrow space, and he sustains the injury shown here (with a few choice words uttered in the process). 1. Describe this injury. 2. How would this injury heal? ERRNVPHGLFRVRUJ Answers: Side A 1. A blunt force injury (e.g., a car door) would cause a laceration with irregular tearing and tissue bridging as a result of overstretching. By comparison, an incision made by a sharp instrument (e.g., a knife) has relatively clean edges and no bridging by tissue strands. 2. The appearance of this injury suggests a knife wound; the location suggests a defensive wound from fending off an attacker. Contusions of varying ages in locations not likely to occur from normal activities, falls, or sports raise further suspicion of domestic violence. 3. The husband's behavior is suggestive of a conduct disorder in adolescence . This is a repetitive and persistent pattern of aggressive behavior that includes threats, intimidation, and causing serious physical harm to others with a weapon. ERRNVPHGLFRVRUJ 9.3 Side A (PBD9: 1147; BP9: 862) ERRNVPHGLFRVRUJ Questions A 45-year-old white teacher in Australia has worked as a lifeguard each winter for the past 20 years. She always appears deeply tanned. Her skin biopsy specimen is shown. 1. What is her environmental exposure risk? 2. What has happened to her skin? 3. What future complications may develop? ERRNVPHGLFRVRUJ Answers: Side B 1. Note the prominent vascular fibrosis and narrowing ( ▴), which cause tissue ischemia, extensive interstitial fibrosis, skeletal muscle fiber atrophy, and some large hyperchromatic and atypical fibroblasts ( ◂). 2. Adjacent tissues in the path of the radiation beam are always affected to some degree. Vascular injury causes intimal hyperplasia and medial scarring, with secondary ischemic changes. 3. Radiation produces free radicals that damage DNA. Neoplastic cells are theoretically more sensitive because they proliferate more than adjacent normal tissues, and they must go through cell cycle checkpoints . If DNA damage is too great to correct, p53 activation and checkpoint editing trigger apoptosis . ERRNVPHGLFRVRUJ 9.3 Side B (PBD9: 429; BP9: 290) ERRNVPHGLFRVRUJ Questions A 62-year-old woman receives radiation treatment for pharyngeal squamous cell carcinoma. Two years later, she has a firm, slightly painful, mobile nodule in the soft tissues of her neck; this is excised to rule out recurrent malignancy, and it shows a blood vessel (▸) and skeletal muscle (▾). 1. What are the changes shown? 2. Why did this happen? 3. Why are tumor cells treated with radiation? ERRNVPHGLFRVRUJ Answers: Side A 1. Sun exposure damages skin with ionizing energy from ultraviolet light and subsequent free radical generation; UVB rays have a shorter wavelength and drop their energy in the more superficial layers of the skin. 2. Actinic damage manifests as abnormal collagen fibers in the upper dermis and results in a pale bluish zone ( ▪) called basophilic degeneration or solar elastosis . 3. A loss of skin elasticity with increased wrinkling may occur. There is also an increased risk for skin cancer, including basal cell carcinoma , squamous cell carcinoma , and melanoma . ERRNVPHGLFRVRUJ 9.4 Side A (PBD9: 410; BP9: 274) ERRNVPHGLFRVRUJ Questions A 38-year-old painter has a 2-month history of worsening headaches, fatigue, and abdominal pain. On examination, he has gray discoloration at the gingival margin of his teeth. His hemoglobin level is 9 g/dL (nl 13.7 to 17.2 g/dL), and his serum creatinine level is 3 mg/dL (nl ≤1.2 mg/dL). The appearance of his peripheral blood smear is shown. 1. To what environmental toxin has he been exposed? 2. What accounts for his increased serum creatinine level? 3. What findings might appear in a similarly exposed child? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient ingested methanol, which led to metabolic acidosis as a result of oxidation to formic acid in the liver. Respiratory depression resulted in the acidosis being uncompensated. 2. There is edema of the optic disks and optic nerves as well as optic radiation. 3. Methanol is metabolized by hepatic alcohol dehydrogenase to yield toxic formaldehyde and formic acid. Fomepizole (an inhibitor of alcohol dehydrogenase) and ethanol as a competitive enzyme substrate are treatments for methanol poisoning (methanol is metabolized at only one fifth the rate of ethanol). ERRNVPHGLFRVRUJ 9.4 Side B (PBD9: 1329; BP9: 281) ERRNVPHGLFRVRUJ Questions A 30-year-old man ingests a clear liquid. Within an hour, he develops dizziness, blurry vision, vomiting, and hyperkalemic acidosis without respiratory compensation. An MRI of his brain is shown. 1. What did he ingest, and what was the effect? 2. What are the changes shown? 3. What is the pathogenesis? What is the treatment? ERRNVPHGLFRVRUJ Answers: Side A 1. Note the basophilic stippling (as a result of ribosome clumping in precursor cells) in a nucleated RBC ( ◂), which suggests ineffective erythropoiesis. The differential diagnosis includes hemoglobinopathies such as thalassemia and toxic exposures. Overall, the findings suggest lead poisoning . 2. Chronic lead exposure produces tubulointerstitial nephritis . 3. The developing nervous system of children puts them at risk for encephalopathy and mental deterioration. Lead lines appear at the epiphyses of growing bones, but this condition does not significantly affect growth. ERRNVPHGLFRVRUJ 9.5 Side A (PBD9: 442; BP9: 302) ERRNVPHGLFRVRUJ Questions A 21-year-old primigravida has profound fatigue throughout her pregnancy. At her first obstetric visit during her second trimester, she has a marked macrocytic anemia. A screening ultrasound at 18 weeks' gestation reveals a defect, which is shown here at birth. 1. What is this defect? 2. What are potential consequences with survival? 3. What vitamin deficiency increases the risk for this condition? 4. What do the laboratory findings indicate? ERRNVPHGLFRVRUJ Answers: Side B 1. There is enhancement ( ◂) of the posterior columns that is attributable to myelin degeneration. 2. She has a megaloblastic anemia as a result of vitamin B deficiency. 12 3. In an older woman, pernicious anemia with chronic atrophic gastritis is likely. In patients with this disorder, the autoimmune destruction of parietal cells leads to diminished intrinsic factor (IF) production and fewer IF–cobalamin complexes for uptake in the ileum. Patients with pernicious anemia also have auto-antibodies that block IF–B binding or that block the ileal receptor. Alternatively, this patient might have intestinal malabsorption (e.g., from inflammatory bowel disease), which affects the terminal ileum where the IF–B complex is absorbed. 12 12 ERRNVPHGLFRVRUJ 9.5 Side B (PBD9: 442; BP9: 302) ERRNVPHGLFRVRUJ Questions A 68-year-old woman has had nausea with fatigue and lower leg paresthesias for 1 year. Her hemoglobin level is 8.4 g/dL (nl 12 to 15.6 g/dL), her hematocrit level is 25.6% (nl 35% to 46%), and her mean corpuscular volume is 120 fL (nl 78 to 102 fL). An axial MRI of her cervical spinal cord is shown. 1. What is shown? 2. On the basis of her laboratory findings, what condition does she have? 3. What gastrointestinal lesions might she have? ERRNVPHGLFRVRUJ Answers: Side A 1. This is a meningomyelocele , which is a large, open, neural tube defect in the lower thoracic region. 2. The defect carries an immediate risk for meningitis; such lesions can also cause paraplegia. 3. Folic acid participates in single carbon transfers, and it is an essential cofactor in nucleic acid synthesis and DNA methylation. Folate deficiency increases the risk for neural tube defects through mechanisms that may involve the generation of anti–folate receptor antibodies. 4. The mother has a macrocytic anemia that is consistent with folate deficiency; nevertheless, such megaloblastic anemias can also be due to vitamin B deficiency, because folate metabolism (i.e., converting 5-methyltetrahydrofolate to tetrahydrofolate) also requires vitamin B . 12 12 ERRNVPHGLFRVRUJ 9.6 Side A (PBD9: 438; BP9: 299) ERRNVPHGLFRVRUJ Questions A 70-year-old woman with a 1-year history of back pain recently sustained a broken wrist in a fall, which is healing poorly. Her hip radiograph is shown. 1. What morphologic change in her bone is present? 2. What dietary deficiencies can account for this? 3. What would such deficiencies cause in a child? 4. What would a radiologic DEXA scan show? ERRNVPHGLFRVRUJ Answers: Side B 1. The kinking of the vertebral column— kyphosis —is most pronounced in the thoracic portion. 2. The bone is osteopenic , with reduced strength from the loss of three-dimensional complexity and the thinning of the bone spicules. This leads to collapse of the vertebral bodies ( compression fracture ). 3. The number of vitamin D receptors on cell surfaces helps to create the set point for the action of vitamin D in bone development and maintenance. The presence of fewer receptors predisposes the affected individual to diminished peak bone mass and an increased risk for osteoporosis (or a greater need for vitamin D). ERRNVPHGLFRVRUJ 9.6 Side B (PBD9: 438; BP9: 299) ERRNVPHGLFRVRUJ Questions A 75-year-old woman with a 10-year history of back pain and increasing dyspnea has the chest MRI shown. 1. Describe her deformity. 2. What morphologic change is present in the vertebral bodies? 3. What cellular receptor plays a role in determining peak bone mass? ERRNVPHGLFRVRUJ Answers: Side A 1. There is increased lucency of cortical bone as a result of decreased bone mineral density; this is indicative of osteopenia (either osteomalacia or osteoporosis ). Normal bone with greater density should appear brighter or more opaque on a radiograph. 2. A deficiency of vitamin D, calcium, or both can lead to osteomalacia. 3. Children with this deficiency develop rickets . The manifestations are different, because the growing bones develop ancillary deformities, including epiphyseal widening and long bone curvature. 4. Dual-energy x-ray absorptiometry will show markedly decreased bone mineral density, with a T score of more than 2.5 standard deviations from the young adult mean. ERRNVPHGLFRVRUJ 9.7 Side A (PBD9: 427; BP9: 289) ERRNVPHGLFRVRUJ Questions A 33-year-old man accidentally grabbed an electrical line, which produced the entrance wound injury shown. The current exited on the dorsum of the same hand. 1. Is the injury that occurs during electrocution greater with direct current (DC) or alternating current (AC)? 2. Is this injury from high-voltage or low-voltage current? 3. What would be the significance of the exit wound on the opposite extremity? 4. How would a lightning strike differ? ERRNVPHGLFRVRUJ Answers: Side B 1. The thick cellulose walls of plant material ( ◂) that was inhaled while the boy was submerged are present. 2. The hypotonic fresh water osmotically injures alveoli and causes them to burst; absorbed free water dilutes blood electrolyte concentrations. 3. Generally, 3 to 5 minutes of hypoxemia leads to significant central nervous system damage in adults; children may be able to tolerate longer hypoxic episodes, especially if the body is cooled (i.e., hypothermic). ERRNVPHGLFRVRUJ 9.7 Side B (PBD9: 671; BP9: 461) ERRNVPHGLFRVRUJ Questions A child playing at the riverbank is not seen for 10 minutes. His father finds him immersed under a log beneath the surface but is unable to resuscitate him. The microscopy of his lung at autopsy is shown. 1. What is present in this bronchus? 2. What is the pattern of injury to the lung? 3. What are the consequences of prolonged submersion? ERRNVPHGLFRVRUJ Answers: Side A 1. This injury was caused by alternating current . Although AC potentially allows release from the electrocuting current, it is far more deadly, because it induces electrical disturbances such as cardiac arrhythmias and brain wave disruptions. Tissue resistance converts the current passing through the body into heat energy. 2. The depth of the burn indicates a high-voltage injury. 3. When current crosses the body (e.g., across the chest and heart), cardiac arrhythmias and death are more likely. 4. Lightning involves direct current at low amperage, but it also involves millions of volts. It often follows a superficial path across the body that includes the subcutaneous veins to produce an arborizing pattern ( Lichtenberg figures ). ERRNVPHGLFRVRUJ 9.8 Side A (PBD9: 426; BP9: 288) ERRNVPHGLFRVRUJ Questions A 45-year-old man is deep-frying a whole turkey, which he suspends over an open vat of oil that has been heated to 180° F (82° C). This precarious procedure goes well until a spill occurs, with the result shown. 1. Describe the injury. 2. What are the factors that affect the prognosis in this case? 3. How would this injury be treated? ERRNVPHGLFRVRUJ Answers: Side B 1. The hot gases generated in the fire can conduct heat to the body. 2. Although viable epidermis is present at the top of the image, the bottom of the image shows a full-thickness burn , because there is no viable epidermis or epidermal appendages. Skin grafting would be required. With partial-thickness burns, some epidermis or appendages remain. 3. The inhalation of hot gases can cause injury to respiratory tract epithelium. In addition, burning materials can generate carbon monoxide, cyanide, and other toxic substances that cause hypoxia or damage to the respiratory tract. ERRNVPHGLFRVRUJ 9.8 Side B (PBD9: 426; BP9: 288) ERRNVPHGLFRVRUJ Questions A child who is trapped during a house fire is rescued from a room with no open flames. He nevertheless develops pulmonary edema and bronchopneumonia. The microscopic appearance of a portion of his skin is shown. 1. Why did injury occur in the absence of flames? 2. What is the thickness of the burn injury? 3. Why did injury to the lung occur? ERRNVPHGLFRVRUJ Answers: Side A 1. This is a thermal burn that resulted from scalding. Liquids conduct heat better than air and deliver more energy with greater injury. Note the epidermal slippage and the deep fissure into the soft tissue. 2. The prognosis of burn injuries depends on the total body surface area involved, the depth of the burn, and the adequacy of the therapy. 3. Skin grafting may be required if there is no remaining viable epithelium. However, elastic fibers are lost, and scarring with contracture can occur after this type of burn, which in this case may compromise normal hand motion. ERRNVPHGLFRVRUJ 9.9 Side A (PBD9: 426; BP9: 287) ERRNVPHGLFRVRUJ Questions A 28-year-old man is found dead in his home with the lesion shown on his right temple. 1. Describe the injury. 2. What could be the manner (mode) of death? 3. What would be the significance of gunshot residue or blood on the victim's hand? ERRNVPHGLFRVRUJ Answers: Side B 1. Although this looks like a stab wound, it is an exit gunshot wound. A bullet passing through the body may be deformed or fragmented by striking bone; deformed bullets can tumble, and they push a wave front of energy ahead of them. The result with most gunshots is a larger, irregular, and lacerated-appearing exit wound. 2. Because the entrance wound would most likely be on the victim's back, accident and suicide are improbable; homicide is much more likely. 3. It is unlikely to have been a shotgun. Nothing can be said about the caliber of the weapon, because exit wounds are highly variable, and the size of the wound track is often larger than the caliber of the bullet. ERRNVPHGLFRVRUJ 9.9 Side B (PBD9: 426; BP9: 287) ERRNVPHGLFRVRUJ Questions It was a dark and stormy night. Suddenly, a shot rang out. Police arriving at the scene find the body of a deceased 70-year-old man with the wound on the anterior torso shown. 1. Explain how this could be consistent with a gunshot wound (it is a gunshot wound). 2. What is the probable manner (mode) of death? 3. What can be said about the weapon used? ERRNVPHGLFRVRUJ Answers: Side A 1. This is a round contact-range gunshot entrance wound, with grayish black discoloration caused by burned gunpowder being tattooed into the skin. 2. This cannot be a natural (disease-related) death, and accident is unlikely. Homicide and suicide are possible. 3. Residue on the victim's hand suggests that he fired the weapon; the location of the wound is also compatible with the deceased holding the gun to his forehead, thus making this a suicide. Any blood can undergo DNA fingerprinting to determine if it matches that of the victim or if it has come from someone else. ERRNVPHGLFRVRUJ 9.10 Side A (PBD9: 442; BP9: 302) ERRNVPHGLFRVRUJ Questions A 54-year-old man with a history of increasing ataxia, global confusion, and disorientation has ophthalmoplegia and nystagmus. He subsequently dies of alcoholic cirrhosis. A coronal section of his brain at autopsy is shown. 1. What vitamin deficiency did this patient likely have, how did he get it, and what is the name for his condition? 2. If he had retrograde amnesia, what syndromic name could be applied? 3. What other abnormalities can this vitamin deficiency cause? ERRNVPHGLFRVRUJ Answers: Side B 1. This is anencephaly with absence of the fetal cranial vault, so the brain is exposed in utero and does not develop normally. It is a form of neural tube defect. 2. Maternal folic acid supplementation can decrease the risk for fetal neural tube defects. 3. Folic acid deficiency can lead to megaloblastic anemia . ERRNVPHGLFRVRUJ 9.10 Side B (PBD9: 442; BP9: 302) ERRNVPHGLFRVRUJ Questions A 22-year-old primigravida notes minimal fetal movement at 19 weeks' gestation. Termination of the pregnancy occurs after a fetal ultrasound detects the abnormality shown. 1. What is your diagnosis? 2. What dietary supplementation could reduce the risk? 3. What problem can occur in adults with this deficiency? ERRNVPHGLFRVRUJ Answers: Side A 1. The clinical story and central nervous system findings are consistent with Wernicke disease as a result of thiamine (vitamin B ) deficiency ; note the mammillary body hemorrhages ( ▾). Chronic alcohol abuse is a common antecedent, because a diet that predominantly consists of alcohol provides only “empty” calories without significant nutritive value. 1 2. Korsakoff syndrome can occur with the chronic form of the disease. 3. Thiamine deficiency can cause beriberi ; clinical findings include polyneuropathy (“dry” beriberi) or cardiac dilation and peripheral vasodilation with edema (“wet” beriberi). ERRNVPHGLFRVRUJ 10 ERRNVPHGLFRVRUJ Diseases of Infancy and Childhood ERRNVPHGLFRVRUJ 10.1 Side A (PBD9: 457; BP9: 250) ERRNVPHGLFRVRUJ Questions A 2300-g infant delivered at 30 weeks' gestation has an Apgar score of 3 (out of 10) at 1 minute, with pallor, bradycardia (75 beats/min), slow respiratory effort, poor muscle tone with minimal motion, and absent responses to catheter stimulation. His Apgar score is 5 at 5 minutes, but he is in respiratory distress, with grunting and retractions. His radiograph is shown. 1. What is the likely diagnosis? 2. Explain the pathophysiology. 3. Why are premature infants prone to this complication? ERRNVPHGLFRVRUJ Answers: Side B 1. Pink hyaline membranes ( ◂) and thick interstitium are consistent with hyaline membrane disease . 2. Maternal diabetes retards fetal lung maturity as a result of compensatory fetal hyperinsulinemia . Type II pneumocyte production of surfactant is reduced. Premature birth is more likely with diabetic mothers. Fetal hyperinsulinemia postpartum becomes neonatal hypoglycemia. The infant is likely to be larger than normal, because insulin acts as a fetal growth factor. ERRNVPHGLFRVRUJ 10.1 Side B (PBD9: 457; BP9: 250) ERRNVPHGLFRVRUJ Questions A 20-year-old primigravida has a hemoglobin A level of 9% (nl ≤ 6%); amniotic fluid studies show reduced lamellar body count. Shortly after delivery, the infant has a PaO level of 60 mm Hg (nl 90 mm Hg) and a blood glucose level of 31 mg/dL (nl 70 to 125 mg/dL). The infant's pulmonary pathology is shown. 1c 2 1. What is the diagnosis? 2. What maternal condition is present? ERRNVPHGLFRVRUJ Answers: Side A 1. Diffuse opacification ( ▪) of all lung fields is likely, which is consistent with newborn respiratory distress syndrome (RDS) . 2. Insufficient surfactant production leads to increased alveolar surface tension, with early expiratory collapse, hypoxemia, CO retention, and acidosis. These lead to reflex pulmonary vasoconstriction, hypoperfusion that causes endothelial and epithelial damage, and plasma protein leakage into airspaces. 2 3. Immature lungs have insufficient type II pneumocyte surfactant production . ERRNVPHGLFRVRUJ 10.2 Side A (PBD9: 462; BP9: 255) ERRNVPHGLFRVRUJ Questions A 19-year-old primigravida notes decreased fetal movement at 19 weeks' gestation. Fetal ultrasound examination shows cardiomegaly. The fetus is stillborn at 22 weeks' gestation, with the appearance shown. 1. What is the name for this appearance? 2. Is an immune mechanism for this likely? 3. If no anomalies are present, what could cause this? ERRNVPHGLFRVRUJ Answers: Side B 1. The yellow staining in the basal ganglia is kernicterus . The infant was jaundiced as a result of hyperbilirubinemia . 2. This is immune hydrops with erythroblastosis fetalis . 3. Maternal exposure to fetal RBC antigens during prior pregnancies results in maternal immunization and the generation of circulating antibodies against fetal RBC antigens. Rh antigen incompatibility is the most common cause of this condition; anti-D antibody crosses the placenta and causes fetal RBC hemolysis, with subsequent anemia and heart failure. 4. The administration of anti-Rh immunoglobulin to at-risk mothers (i.e., Rh-negative mothers carrying Rh-positive fetuses) can often prevent the original immunization. ERRNVPHGLFRVRUJ 10.2 Side B (PBD9: 461; BP9: 254) ERRNVPHGLFRVRUJ Questions A 25-year-old woman (G3, P2) notes minimal fetal movement during pregnancy. Fetal ultrasound shows hydrops fetalis with hepatosplenomegaly and cardiomegaly. The infant is stillborn at 34 weeks' gestation. The appearance of the fetal brain is shown. 1. What is this finding in the brain? 2. What is the likely cause of fetal hydrops? 3. What is the pathogenesis? 4. How could this have been prevented? ERRNVPHGLFRVRUJ Answers: Side A 1. There is extensive fluid collection, particularly in the soft tissues, which is characteristic of hydrops fetalis . 2. An immune mechanism involved with this condition is not likely. Because this is the patient's first pregnancy, prior immune exposure to fetal RBC antigens has not occurred. 3. Causes of nonimmune hydrops without anomalies include fetal anemia (e.g., αthalassemia, parvovirus infection) and congenital infections (e.g., TORCH [toxoplasmosis, other microbes such as Treponema pallidum, rubella, cytomegalovirus, herpesvirus]). ERRNVPHGLFRVRUJ 10.3 Side A (PBD9: 463; BP9: 256) ERRNVPHGLFRVRUJ Questions A 20-year-old Cambodian primigravida delivers a markedly hydropic infant at 30 weeks' gestation. The infant dies from severe anemia and high-output congestive heart failure. At autopsy, there is hepatosplenomegaly with the microscopic findings shown. 1. What are the clusters of small, darkly staining cells? 2. What do these cells normally produce? 3. What could be the underlying abnormality? ERRNVPHGLFRVRUJ Answers: Side B 1. These identical twins should be similar in size, but a twin-twin transfusion syndrome has occurred. The recipient twin ( ◂)becomes hydropic from volume overload and congestive heart failure; the donor twin ( ▾)receives too little blood and is growth retarded. 2. An abnormal vascular connection across the monochorionic placenta allows blood from the donor (anemic) twin to overload the circulation of the recipient (plethoric) twin. ERRNVPHGLFRVRUJ 10.3 Side B (PBD9: 462; BP9: 250) ERRNVPHGLFRVRUJ Questions A 24-year-old woman (G2, P1) at 18 weeks' gestation has an ultrasound that shows oligohydramnios in one amniotic cavity and polyhydramnios in the other. The appearance of the monozygous infants is shown. 1. What accounts for the size and color differences? 2. Explain the pathogenesis of this condition. ERRNVPHGLFRVRUJ Answers: Side A 1. This is extramedullary hematopoiesis (EMH) . Clusters of hematopoietic cells, principally erythroid precursors ( ▴), are shown. The liver is the major hematopoietic organ of the second and early third trimester, but the persistence or expansion of EMH indicates defective RBC production or survival. 2. Fetal RBCs mainly produce hemoglobin F, with hemoglobin A production beginning during the late third trimester and postpartum. 1 3. α-Globin chains are needed for hemoglobin F and hemoglobin A production. Reduced or absent synthesis of all four α-globin chains results in α-thalassemia major . β-Thalassemia major (i.e., the lack of both β-globin chains) is a possibility, but it does not typically result in hydrops. ERRNVPHGLFRVRUJ 10.4 Side A (PBD9: 452; BP9: 246) ERRNVPHGLFRVRUJ Questions A 4300-g infant is delivered vaginally at term, although the labor is extremely difficult. A complication of this process is shown. 1. What is your diagnosis? 2. What is the name for a grossly similar process in which just interstitial fluid is present? 3. What more ominous finding would suggest brain injury? 4. What is an explanation for a 4300-g infant? ERRNVPHGLFRVRUJ Answers: Side B 1. Vaginal group B streptococcal infection led to ascending infection with inflammation, the release of prostaglandins, and premature labor. 2. Fetal distress led to the release of meconium into the amniotic fluid, where it stained the skin and placental surfaces. 3. Gasping respirations in utero led to meconium aspiration , with flattened squames ( ◂) and balls of meconium ( ▸) seen within the alveoli. 4. Lung lavage ERRNVPHGLFRVRUJ 10.4 Side B (PBD9: 460; BP9: 249) ERRNVPHGLFRVRUJ Questions A 20-year-old primigravida develops a fever, and a vaginal culture grows group B streptococcus. Premature rupture of the membranes occurs, and monitoring reveals fetal distress. At delivery, the skin and placenta have a green appearance. Had a biopsy specimen of the lung been obtained, it would appear as shown. 1. What is the pathogenesis of this premature birth? 2. Why were the skin and the placenta stained green? 3. What is present in the lung? 4. What emergent procedure must be performed? ERRNVPHGLFRVRUJ Answers: Side A 1. Hemorrhage beneath the scalp is a cephalhematoma ( ◂), which is caused by the rupture of small veins that perfuse the periosteum. Uncomplicated cephalhematomas are typically nonfatal. 2. Caput succedaneum is a common finding with little significance, because the fluid is quickly resorbed. 3. A skull fracture would suggest intracranial injury, such as subdural hematoma or contusion. 4. Large-for-gestational age infants commonly occur when their mothers are diabetic as a result of the growth-promoting effects of insulin produced by fetal islets of Langerhans. ERRNVPHGLFRVRUJ 10.5 Side A (PBD9: 469; BP9: 226) ERRNVPHGLFRVRUJ Questions A term infant fails to pass meconium by his second day of life, and he ultimately requires surgical resection of a portion of the ileum for bowel obstruction (shown). He subsequently has failure to thrive as a result of malabsorption, and he experiences recurrent episodes of Pseudomonas aeruginosa pneumonia. 1. Describe the findings shown. 2. What genetic disease is likely to be present? ERRNVPHGLFRVRUJ Answers: Side B 1. The inheritance pattern is autosomal recessive . Note the consanguinity in generation 3, which brought two recessive alleles together. 2. The findings suggest cystic fibrosis . 3. The most common gene mutation among individuals with cystic fibrosis is ΔF508, which leads to abnormal folding, endoplasmic reticulum retention, and subsequent degradation of the cystic fibrosis transmembrane conductance regulator ( CFTR ) protein, a cAMP-regulated chloride transporter. 4. The sweat chloride level is elevated, as are the sodium (to maintain electroneutrality) and water (as a result of the osmotic load) levels. ERRNVPHGLFRVRUJ 10.5 Side B (PBD9: 466; BP9: 223) ERRNVPHGLFRVRUJ Questions An 11-year-old boy has had recurrent lung infections since early childhood, along with steatorrhea, focal biliary cirrhosis, and agenesis of the ductus deferens. He is the affected male in the fourth generation shown. 1. Name the inheritance pattern. 2. What is the disease? 3. What gene mutation is present? 4. What laboratory finding is indicated by iontophoresis? ERRNVPHGLFRVRUJ Answers: Side A 1. Abnormal pancreatic secretions led to inspissated meconium with intestinal obstruction caused by meconium ileus during the first few days of life. This opened ileum shows inspissated green meconium; the unopened colon at the upper left and the appendix at the lower left beyond the ileocecal valve are not dilated, and little or no meconium has passed via the rectum. 2. This infant likely has cystic fibrosis . ERRNVPHGLFRVRUJ 10.6 Side A (PBD9: 476; BP9: 259) ERRNVPHGLFRVRUJ Questions An 18-month-old girl with a 1-month history of fever and weight loss has a palpable abdominal mass. Homovanillic acid and vanillylmandelic acid are detected in her urine. Her abdominal MRI is shown. 1. What is your diagnosis? 2. What histologic features imply a better prognosis? 3. Do infants with this neoplasm have a better prognosis than older children? ERRNVPHGLFRVRUJ Answers: Side B 1. This is a small round blue cell tumor, so-called because it is a monotonous, uniform collection of cells with round nuclei and little cytoplasm. Such tumors look histologically alike. However, depending on the primary site, they have different cells of origin, cytogenetic alterations, and marker expression. 2. Typical childhood small round blue cell tumors: (A) Neuroblastoma (B) Retinoblastoma (C) Ewing sarcoma/primitive neuroectodermal tumor (D) Leukemia/lymphoma (E) Wilms tumor (F) Medulloblastoma ERRNVPHGLFRVRUJ 10.6 Side B (PBD9: 475; BP9: 258) ERRNVPHGLFRVRUJ Questions A biopsy specimen of a large tumor mass in a 1-year-old boy reveals the histology shown. 1. What is a general description for this appearance? 2. What would your diagnosis be if the primary site for the neoplasm is: (A) Adrenal? (B) Eye? (C) Bone? (D) Bone marrow/lymph node? (E) Kidney? (F) Cerebellum? ERRNVPHGLFRVRUJ ERRNVPHGLFRVRUJ Answers: Side A 1. The history and the large mass ( ▴) in the left adrenal gland are most consistent with a neuroblastoma . These arise from primitive neuroblasts derived from neural crest cells. During childhood, approximately 40% of neuroblastomas arise in the adrenals; the remainder can occur anywhere along the sympathetic chain. 2. Schwannian stroma, gangliocytic differentiation, and microcalcifications 3. Yes. Individuals with neuroblastomas detected during infancy (≤1 year old) tend to do well even if these tumors are metastatic, and many spontaneously regress. ERRNVPHGLFRVRUJ 10.7 Side A (PBD9: 479; BP9: 261) ERRNVPHGLFRVRUJ Questions A 4-year-old boy with abdominal pain has a palpable mass, and his urinalysis reveals hematuria. His kidney is excised and shown here. 1. What is the likely diagnosis for this neoplasm? 2. What gene mutation is associated with this tumor plus (a) a niridia, g enital anomalies, and mental retardation ; (b) adrenal cytomegaly, hemihypertrophy, macroglossia, and omphalocele? ERRNVPHGLFRVRUJ Answers: Side B 1. This Wilms tumor has a blastema component of small blue cells and a stromal component of spindle cells. 2. Wilms tumor microscopically resembles the primitive nephrogenic zone of the fetal kidney and likely arises from nephrogenic rests. The WT1 gene can act as a transcription activator and repressor, and it is crucial for normal renal and gonadal development. Only 15% of sporadic (as opposed to syndromic) Wilms tumors have WT1 mutations, which suggests that there may be other causal genes. 3. The prognosis is excellent in most cases. ERRNVPHGLFRVRUJ 10.7 Side B (PBD9: 481; BP9: 262) ERRNVPHGLFRVRUJ Questions A 3-year-old boy with abdominal pain has a palpable abdominal mass and hypertension. The histology of his right renal mass is shown (▪), with adjacent compressed normal kidney (♦). 1. What is this neoplasm? 2. What is the precursor lesion? 3. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side A 1. This Wilms tumor ( ▪) arising in the kidney ( ♦) is the most common childhood primary renal tumor and the fourth most common pediatric malignancy in the United States. 2. (a) The WAGR syndrome arises from a deleted WT1 tumor suppressor gene and a contiguously deleted PAX6 gene (associated with aniridia) on chromosome 11p13. (b) The Beckwith-Wiedemann syndrome arises as a consequence of abnormal genetic imprinting . Genes in the WT2 locus, including the gene coding for insulin-like growth factor-2 (IGF-2), are normally expressed only from the paternal allele. In BeckwithWiedemann syndrome, maternal alleles are also expressed, thereby leading to IGF-2 overexpression. This may explain the “overgrowth” features of the syndrome. ERRNVPHGLFRVRUJ 10.8 Side A (PBD9: 43; BP9: 246) ERRNVPHGLFRVRUJ Questions An infant born at term has the findings shown. 1. What is present? What type of error in morphogenesis is this? 2. What is the hereditability risk of such an abnormality? ERRNVPHGLFRVRUJ Answers: Side B 1. The left leaf ( ▪) of the diaphragm did not completely form posteriorly, thereby allowing abdominal contents to herniate into the chest cavity. The liver is abnormally rotated toward the left and superiorly into the defect. Bowel and stomach ( ♦) are seen in the chest cavity. 2. This defect reduces the amount of space that the lungs have for development, so they are too small (hypoplastic), with inadequate oxygenation after birth. 3. The constellation of abnormalities in this case strongly suggests Edwards syndrome , which is caused by trisomy 18. ERRNVPHGLFRVRUJ 10.8 Side B (PBD9: 162; BP9: 238) ERRNVPHGLFRVRUJ Questions A boy delivered at term has severe respiratory distress and cannot be resuscitated. The major findings at autopsy are shown. Additional anomalies include a small face with micrognathia, overlapping fingers, and a horseshoe kidney. 1. Describe the abnormality shown in the image. 2. What is the immediate cause of death? 3. What syndrome is likely present in this case? ERRNVPHGLFRVRUJ Answers: Side A 1. This bilateral cleft lip is one of the most common birth defects with or without an associated cleft palate (approximately 1 in 1000 births). The failure of midline facial fusion has multiple potential causes; these include the teratogen retinoic acid as well as alterations in the expression of transforming growth factor or fibroblast growth factor or mutations in their receptors (or downstream targets). 2. Although environmental factors contribute, there is a genetic component; if either parent has a cleft lip, the chance of a child being born with such a deformity is approximately 5%. If neither parent has a cleft lip, the chance of such a deformity in a second child is also approximately 5%. ERRNVPHGLFRVRUJ 10.9 Side A (PBD9: 453; BP9: 246) ERRNVPHGLFRVRUJ Questions Fetal ultrasound at 20 weeks' gestation showed polyhydramnios. The premature infant was born at 34 weeks' gestation with the defect shown. 1. What is your diagnosis? 2. What is the consequence of this lesion in terms of bowel development? 3. Is there an underlying chromosomal or gene defect? 4. Explain the polyhydramnios. ERRNVPHGLFRVRUJ Answers: Side B 1. This gastroschisis is a large lateral abdominal wall defect that does not involve the umbilical cord and that is not covered by a membrane. Bowel ( ▴), stomach ( ▾), and liver ( ▸) are herniated outside of the abdominal cavity. 2. These findings, including the amnionic bands, are part of the limb–body wall complex . 3. A disruption is an extrinsic disturbance that destroys the morphogenesis of otherwise normal body parts. Amniotic bands (caused by the rupture of the amnion) are a common cause of disruptions. 4. No, such a defect is not likely. ERRNVPHGLFRVRUJ 10.9 Side B (PBD9: 453; BP9: 246) ERRNVPHGLFRVRUJ Questions A premature infant born at 32 weeks' gestation has a short umbilical cord, fingers that have been amputated by fibrous bands (amniotic bands) that extend to the placental fetal surface, and the defect shown. 1. What is this abdominal wall defect? 2. What is the infant's condition called? 3. What is the pathogenesis? 4. Is there likely to be a chromosomal or gene defect? ERRNVPHGLFRVRUJ Answers: Side A 1. This omphalocele is a large midline ventral abdominal wall defect that involves the umbilical cord and that is covered by a thin membrane. Note the herniated abdominal contents within. 2. Bowel developing outside of the abdominal cavity is malrotated, and the cavity is too small. 3. Some cases occur with chromosomal abnormalities such as trisomy 18; others are part of syndromes, and some are sporadic. 4. Polyhydramnios , or increased amniotic fluid, often occurs when a gastrointestinal tract abnormality prevents fetal swallowing and resorption of this fluid. ERRNVPHGLFRVRUJ 10.10 Side A (PBD9: 456; BP9: 824) ERRNVPHGLFRVRUJ Questions An infant born at 25 weeks' gestation weighs only 508 g (nl 660 g) and has only 60% oxygen saturation. Despite supportive treatment, the infant develops intractable seizures and dies. A coronal section of the brain at autopsy is shown. 1. What is your diagnosis? 2. Where was the initial hemorrhage located? 3. Why are premature, low-birth-weight infants at increased risk for this hemorrhage? 4. What complication can occur with survival? ERRNVPHGLFRVRUJ Answers: Side B 1. This is necrotizing enterocolitis (NEC). The villi show ischemic coagulative necrosis. 2. Gut ischemia can result from systemic hypotension or the selective reduction of blood flow to the intestines to preserve central nervous system perfusion. Local inflammation (potentially in response to feeding) can increase mucosal permeability and allow transluminal migration of gastrointestinal flora that eventually culminates in sepsis. 3. Pneumatosis intestinalis ERRNVPHGLFRVRUJ 10.10 Side B (PBD9: 459; BP9: 252) ERRNVPHGLFRVRUJ Questions A boy born at 32 weeks' gestation weighs 1480 g (nl 1700 g). At 1 week of age, he develops abdominal distention, bloody stool, and hypotension, and a radiograph shows bowel wall gas. He dies of sepsis. The microscopic appearance of the affected infant's small bowel is shown in the upper panel for comparison with normal bowel as shown in the lower panel . 1. What happened to this infant? 2. What is the pathogenesis? 3. What is the name for gas in the bowel wall? ERRNVPHGLFRVRUJ Answers: Side A 1. This is intraventricular hemorrhage (IVH). Blood fills the ventricular system and extends to the subarachnoid space. 2. Bleeding starts in the highly cellular and vascular region called the germinal matrix . 3. The germinal matrix is extremely sensitive to hypoxia and changes in intracranial pressure. 4. Organization of the hemorrhage can lead to obstructive hydrocephalus . ERRNVPHGLFRVRUJ 10.11 Side A (PBD9: 472; BP9: 253) ERRNVPHGLFRVRUJ Questions An infant born at term is developing normally but is subsequently found dead in his crib at the age of 6 months. Autopsy reveals no abnormalities. The family history includes first-degree relatives who died suddenly and unexpectedly. An ECG that illustrates a potential underlying abnormality is shown. 1. What is the name of this abnormality? 2. Is this sudden infant death syndrome (SIDS)? 3. What are risk factors for SIDS? 4. What should be suspected if retinal hemorrhages and subdural hematoma are found? ERRNVPHGLFRVRUJ Answers: Side B 1. This is stillbirth with intrauterine fetal demise. 2. The skin slippage indicates maceration, which is a postmortem finding that indicates that death occurred in utero. 3. No. SIDS occurs, by definition, in live-born infants who are between 1 month and 1 year old. The peak incidence for SIDS occurs at 3 to 4 months of age. ERRNVPHGLFRVRUJ 10.11 Side B (PBD9: 452; BP9: 245) ERRNVPHGLFRVRUJ Questions After an uncomplicated pregnancy, an infant is delivered at 36 weeks' gestation with Apgar scores of 0/0. The external appearance is shown. 1. What is the term for this product of conception? 2. What does the external appearance indicate? 3. Could this be sudden infant death syndrome (SIDS)? ERRNVPHGLFRVRUJ Answers: Side A 1. This is long QT syndrome . Note the life-threatening torsades de pointes (lower panel). The most common manifestations of this condition are syncope and episodic arrhythmia. A family history of the disorder or sudden death can suggest the diagnosis, although definitive diagnosis would require genetic sequencing. The most common causes are mutations in the genes that encode sodium or potassium channels. 2. No, SIDS is an exclusionary diagnosis. 3. Risk factors for SIDS include maternal smoking or drug abuse, young maternal age, short intergestational intervals, a lack of prenatal care, and low socioeconomic status. 4. Shaken infant syndrome should be considered if these are found. The mode of death is ruled to be either accident or homicide based on the investigation of the circumstances. ERRNVPHGLFRVRUJ UNIT II Systemic Pathology: Diseases of Organ Systems OUTLINE 11 Blood Vessels 12 The Heart 13 Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus 14 Red Blood Cell and Bleeding Disorders 15 The Lung 16 Head and Neck 17 The Gastrointestinal Tract 18 Liver and Biliary Tract 19 The Pancreas 20 The Kidney 21 The Lower Urinary Tract and Male Genital System 22 The Female Genital Tract 23 The Breast 24 The Endocrine System 25 The Skin 26 Bones, Joints, and Soft-Tissue Tumors 27 Peripheral Nerve and Skeletal Muscle ERRNVPHGLFRVRUJ 28 The Central Nervous System 29 The Eye ERRNVPHGLFRVRUJ 11 ERRNVPHGLFRVRUJ Blood Vessels ERRNVPHGLFRVRUJ 11.1 Side A (PBD9: 502; BP9: 345) ERRNVPHGLFRVRUJ Questions A 25-year-old man has a 2-year history of worsening right leg pain that is exacerbated by walking even short distances. On examination, his right femoral, popliteal, and posterior tibial arterial pulses are absent. His total cholesterol is 430 mg/dL (desirable ≤200 mg/dL), and his HDL cholesterol is 22 mg/dL (nl ≥35 mg/dL). His CT angiogram is shown. 1. Describe the key finding. 2. What is the likely underlying disease in this man? 3. How does this explain his examination findings? ERRNVPHGLFRVRUJ Answers: Side B 1. Small bright calcifications ( ▾) and mural thrombus are seen in the right iliac artery, with bright contrast enhancement of blood in the lumen and the branch vessel. 2. Atherosclerotic aneurysms are most frequent in the abdominal aorta, but aortic branches can also be involved. 3. Atherosclerosis weakens the arterial wall by increasing the diffusion distance of oxygen and nutrient supply to the smooth muscle cells of the inner media. Local inflammatory infiltrates elaborate matrix metalloproteinases, which degrade extracellular matrix, particularly collagen and elastin. ERRNVPHGLFRVRUJ 11.1 Side B (PBD9: 502; BP9: 345) ERRNVPHGLFRVRUJ Questions A 74-year-old man has diminished right femoral, popliteal, and dorsalis pedis pulses. A CT image of his pelvis below the aortic bifurcation is shown. 1. Describe the findings. 2. Where are such lesions most likely to occur? 3. What is the pathogenesis of his disease? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has a right iliac arterial aneurysm ( ▸). 2. The markedly elevated total cholesterol with diminished HDL cholesterol suggests familial hypercholesterolemia with defective or reduced numbers of LDL receptors coded by a mutated gene. This condition accounts for this patient's aneurysm complication of atherosclerosis at his young age. He is likely a heterozygote, because homozygotes have total cholesterol values that are routinely greater than 600 mg/dL. 3. The claudication of the right lower extremity is likely a consequence of mural thrombosis within the aneurysm occluding the vascular lumen and compromising blood flow. ERRNVPHGLFRVRUJ 11.2 Side A (PBD9: 509; BP9: 352) ERRNVPHGLFRVRUJ Questions A 29-year-old man with a 2-month history of intermittent abdominal pain and fever also has elevated creatinine and urea nitrogen levels. Serology for ANA and ANCA are negative. His superior mesenteric artery angiogram is shown. 1. What form of vasculitis does he have? 2. What histology do you expect to see in the affected vessels? 3. What infectious disease might he have? ERRNVPHGLFRVRUJ Answers: Side B 1. He has giant cell arteritis (temporal arteritis) , which typically involves the external carotid arterial branches, but it can also involve the aorta. Note the granulomatous inflammation with giant cells ( ■). 2. The ANA and ANCA titers are negative. 3. Involvement of the ophthalmic artery can lead to permanent blindness. Treatment involves corticosteroids. ERRNVPHGLFRVRUJ 11.2 Side B (PBD9: 507; BP9: 350) ERRNVPHGLFRVRUJ Questions A 67-year-old man has a 1-month history of fever, malaise, myalgias, 2-kg weight loss, and headaches. On examination, there is temporal tenderness on palpation and a bruit, and he has an erythrocyte sedimentation rate of 86 mm/hr (nl ≤20 mm/hr). His temporal artery biopsy specimen is shown. 1. What is the diagnosis? 2. What do you expect his ANA and ANCA titers to be? 3. What serious complication can occur? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has classic polyarteritis nodosa (PAN) , an immune complex vasculitis that involves small to medium-sized arteries. The angiogram shows focal arterial occlusions ( ■) caused by inflammation as well as arterial dilations that represent microaneurysms ( ♦). Symptoms are related to ischemia and infarction of the tissues perfused by the affected vasculature. 2. One third of patients with PAN have hepatitis B virus infection. In other cases, the antigen is unknown. 3. This patient may have transmural necrotizing arteritis with fibrinoid necrosis . ERRNVPHGLFRVRUJ 11.3 Side A (PBD9: 516; BP9: 358) ERRNVPHGLFRVRUJ Questions At birth, a newborn has the scalp lesion shown. It rapidly enlarges for 3 months, at which point it stabilizes. After the age of 3 years, it regresses, and it is 0.5 cm by age 7. 1. What is your diagnosis? 2. What would a similar lesion be called if (a) it extensively involved an extremity or an internal organ, or (b) it occurred after trauma to the gingiva or oral mucosa? ERRNVPHGLFRVRUJ Answers: Side B 1. A proliferation of small capillary channels ( ▸) forms this capillary hemangioma . 2. Cavernous hemangiomas are circumscribed lesions that are often larger than capillary hemangiomas; they are benign and usually incidental findings. 3. The von Hippel–Lindau ( VHL ) gene encodes a tumor suppressor protein in a complex that regulates hypoxia-inducible factor-1 degradation, which affects vascular endothelial growth factor expression in association with vascular tumors. VHL mutations can be associated with central nervous system and eye hemangiomas, hemangioblastomas, renal cell carcinomas, and pheochromocytomas. ERRNVPHGLFRVRUJ 11.3 Side B (PBD9: 516; BP9: 358) ERRNVPHGLFRVRUJ Questions A 29-year-old man has a red cutaneous nodule on the chest that has very slowly increased in size for many years. It is excised, and the microscopic appearance is shown. 1. Describe the lesion. 2. What is the significance of such a solitary lesion with larger, dilated vascular spaces in an internal organ? 3. What gene mutation can be associated with similar lesions in the central nervous system? ERRNVPHGLFRVRUJ Answers: Side A 1. This hemangioma has an exophytic growth pattern. One in 200 newborns has one of these “strawberry” hemangiomas, which can be multiple. 2. (a) Angiomatosis . Malignant transformation is rare. (b) Pyogenic granuloma . Some are also associated with pregnancy. ERRNVPHGLFRVRUJ 11.4 Side A (PBD9: 492; BP9: 336) ERRNVPHGLFRVRUJ Questions A 65-year-old man has a 5-year history of postprandial pain and intermittent claudication. His BMI is 35 (nl 18.5 to 25), his fasting glucose level is 209 mg/dL (nl <110 mg/dL), and creatinine level is 2.3 mg/dL (nl = 1.2 mg/dL). His abdominal CT scan is shown. 1. What does his aorta show? 2. What is the likely underlying condition? 3. What organ is missing? ERRNVPHGLFRVRUJ Answers: Side B 1. The extensive dark and mottled small intestine is infarcted. At least two of the three major arteries that supply blood to the bowel must be compromised for ischemia to occur. 2. Extensive atherosclerosis of the aortic branches (celiac, superior mesenteric, and inferior mesenteric) can lead to abdominal angina and infarction. Given the acute onset, atheroembolic disease (i.e., thrombus or friable atherosclerotic plaque) is likely. Alternatively, volvulus, intussusception, or adhesions caused by a previous surgery can literally “tie the bowel in knots” and compromise blood flow. ERRNVPHGLFRVRUJ 11.4 Side B (PBD9: 499; BP9: 342) ERRNVPHGLFRVRUJ Questions A 69-year-old man has sudden severe abdominal pain. On examination, his abdomen is distended, and no bowel sounds are auscultated. Doppler ultrasonography shows absent superior mesenteric artery flow; an exploratory laparotomy is performed. 1. What has happened here? 2. What are potential causes of this condition? ERRNVPHGLFRVRUJ Answers: Side A 1. An enlarged abdominal aorta ( ▾) shows extensive aortic mural thrombus, with softtissue attenuation, a dilated lumen that contains bright contrast, and bright calcifications in the media that are consistent with severe atherosclerosis. 2. The presence of obesity and an elevated serum glucose level suggest type 2 diabetes mellitus. The patient's leg pains suggest peripheral vascular disease. Smoking, hypercholesterolemia, hypertension, and any familial component will exacerbate the development of atherosclerosis. 3. The patient's left kidney is absent, and this is potentially attributable to atheroembolic renal artery occlusion with renal infarction. Diabetic nephropathy could reduce the function of the remaining kidney, which results in an elevated serum creatinine level. ERRNVPHGLFRVRUJ 11.5 Side A (PBD9: 490; BP9: 334) ERRNVPHGLFRVRUJ Questions A 64-year-old woman has moderate hypertension (blood pressure 170/115 mm Hg) and a hemoglobin A level of 9% (nl ≤6%). Ultrasound reveals reduced renal size bilaterally. Urinalysis shows 1+ proteinuria without hematuria. The microscopic appearance of her kidney biopsy specimen is shown. 1c 1. What is your diagnosis? 2. What diseases are associated with this? 3. What other component of the kidney is likely affected? ERRNVPHGLFRVRUJ Answers: Side B 1. This is hyperplastic arteriolosclerosis . Concentric thickening of the arteriolar media ( ♦) is due to intimal and smooth muscle hyperplasia along with the accumulation of plasma proteins and collagen. 2. Most cases arise with long-standing hypertension; others can arise de novo, and some are associated with progressive systemic sclerosis ( scleroderma ). 3. The plasma renin level is likely markedly elevated as a result of diminished renal perfusion pressures; this increases the angiotensin II level, which promotes further renal arterial and arteriolar vasoconstriction, thereby exacerbating the kidney insult. ERRNVPHGLFRVRUJ 11.5 Side B (PBD9: 490; BP9: 334) ERRNVPHGLFRVRUJ Questions A 53-year-old man has had essential hypertension for 10 years, but he is now severely hypertensive (blood pressure 275/160 mm Hg), with headache, nausea, vomiting, and blurry vision. The microscopic appearance of his kidney biopsy specimen is shown. 1. What is your diagnosis? 2. What is the pathogenesis? 3. What is his plasma renin level likely to be? ERRNVPHGLFRVRUJ Answers: Side A 1. The homogeneous pink hyaline thickening of the arteriolar wall ( ♦) with luminal narrowing is characteristic for hyaline arteriolosclerosis . Endothelial injury leads to plasma protein extravasation and increased basement membrane matrix. 2. Diabetes mellitus (elevated hemoglobin A ) and hypertension are associated with hyaline arteriolosclerosis. 1c 3. This patient has nephrosclerosis ; chronically impaired blood supply leads to gradual glomerular atrophy, often with associated mild proteinuria. ERRNVPHGLFRVRUJ 11.6 Side A (PBD9: 511; BP9: 353) ERRNVPHGLFRVRUJ Questions A 41-year-old man with a 5-month history of cough, sinusitis, and fever is found to have nasopharyngeal ulcerations. A chest radiograph shows nodular and cavity lesions. He has antineutrophil cytoplasmic antibodies against a cytosolic component (cANCA; also called antiproteinase 3–ANCA); his antinuclear antibody (ANA) test is negative. The microscopic appearance of a lung biopsy specimen is shown. 1. What is your diagnosis? 2. Why could his serum creatinine be elevated? 3. What is the course of this disease? ERRNVPHGLFRVRUJ Answers: Side B 1. This is vasculitis with a mixed inflammatory infiltrate and focal fibrinoid necrosis ( ◂). 2. These serologies suggest systemic lupus erythematosus as a cause of the vasculitis. 3. These findings suggest classic polyarteritis nodosa . 4. Rheumatoid arthritis can be accompanied by vasculitis and aortitis. ERRNVPHGLFRVRUJ 11.6 Side B (PBD9: 506; BP9: 349) ERRNVPHGLFRVRUJ Questions A 39-year-old woman with a 1-month history of fever, malaise, skin rash, and pleuritic chest pain has a BUN level of 36 mg/dL (nl 7 to 30 mg/dL). The microscopic appearance of her renal biopsy specimen is shown. 1. What is your diagnosis? 2. If she has positive ANA and anti–double-stranded DNA antibodies, what do you suspect? 3. If she has lesions of differing ages and negative serologies for ANA and ANCA, what do you suspect? 4. If she has a positive rheumatoid factor and bilateral symmetric small joint disease of the hands and feet, what do you suspect? ERRNVPHGLFRVRUJ Answers: Side A 1. The constellation of findings, the necrotizing ( ▾) granulomatous vasculitis, and the cANCA antibodies suggest ANCA-associated vasculitis (AAV) or granulomatosis with polyangiitis . 2. Renal involvement with AAV is common, with associated vasculitis and glomerulitis. 3. Eighty percent of untreated patients die within a year. Corticosteroid therapy markedly reduces morbidity and mortality. ERRNVPHGLFRVRUJ 11.7 Side A (PBD9: 495; BP9: 338) ERRNVPHGLFRVRUJ Questions A 65-year-old man reliably gets chest pain after climbing a single flight of stairs; the pain is promptly relieved by nitroglycerin. If we sampled his left anterior descending artery at this point, it would have the appearance shown. 1. Describe the microscopic findings. 2. What term describes his symptoms? 3. What are the possible risk factors? ERRNVPHGLFRVRUJ Answers: Side B 1. The chest pain and ECG changes are features of acute myocardial infarction . 2. The previously nonocclusive atheromatous plaque in this artery has ruptured, and this led abruptly to a virtually occlusive thrombus ( ♦). 3. Dysfunctional endothelium (secondary to hypertension, diabetes, smoking, or hyperlipidemia) promotes platelet and monocyte/macrophage adhesion as well as recruitment with subsequent cytokine release. Dysfunctional endothelium also leads to increased permeability and the accumulation of subendothelial oxidized lipids, which further activate accumulated macrophages. Released cytokines drive smooth muscle cell recruitment and activation in addition to the synthesis of extracellular matrix by smooth muscle cells and fibroblasts. ERRNVPHGLFRVRUJ 11.7 Side B (PBD9: 499; BP9: 342) ERRNVPHGLFRVRUJ Questions A 47-year-old woman has sudden chest pain that is radiating to her neck. An ECG shows Q waves and ST-segment elevation in two anatomically contiguous leads. She has a sudden arrhythmic event, and, despite intervention, she dies. The microscopic appearance of her left circumflex artery is shown. 1. What is your initial diagnosis? 2. What complication has occurred in this artery? 3. What cells contribute to this lesion? ERRNVPHGLFRVRUJ Answers: Side A 1. Atheromatous plaque with fibrointimal proliferation has narrowed the arterial lumen by at least 70%. 2. This patient has stable exercise-induced angina . This is a supply-and-demand mismatch that results from chronic luminal stenosis. 3. Nonmodifiable risk factors include the patient's age; his male sex; and his polygenic familial tendency toward hyperlipidemia, hypertension, and diabetes mellitus. Modifiable factors include reducing caloric intake (particularly of lipids, saturated fats, and trans fats) and increasing exercise. Hypertension, diabetes, and hypercholesterolemia can be treated, and the patient can avoid smoking. ERRNVPHGLFRVRUJ 11.8 Side A (PBD9: 497; BP9: 340) ERRNVPHGLFRVRUJ Questions The coronary artery of a 22-year-old man who died in a motor vehicle accident is shown. 1. Describe the lesions present. 2. Can these progress or regress? 3. What laboratory test findings indicate an increased risk of progression to myocardial infarction or cardiac-related death? ERRNVPHGLFRVRUJ Answers: Side B 1. The aorta shows severe ulcerating atherosclerosis with overlying mural thrombus ( ▸). Aortic branches can be narrowed by this, thereby leading to claudication or angina symptoms, or this can cause renal artery stenosis that leads to elevated renin and hypertension. Complete occlusion as a result of atheroembolism or acute thrombosis can cause organ or extremity infarction. 2. Thrombolysis can be used for acutely thrombosed vessels, and endovascular stents can be used to treat severely stenotic vessels. Plaques can also undergo a degree of regression if modifiable risk factors are addressed. 3. Vessel wall destruction with aneurysmal dilation may also occur. Such aneurysms have a risk of rupture as they enlarge (approximately 10% risk per year for an aneurysm ≥5 cm and 25% annual risk for an aneurysm ≥6 cm). ERRNVPHGLFRVRUJ 11.8 Side B (PBD9: 498; BP9: 341) ERRNVPHGLFRVRUJ Questions A 61-year-old woman with lower extremity claudication, abdominal angina, and hypertension dies as a result of bowel infarction and resulting sepsis. The gross appearance of her aorta at autopsy is shown. 1. Explain the clinical findings. 2. How can these problems be treated? 3. What additional complications may occur? ERRNVPHGLFRVRUJ Answers: Side A 1. These are yellow fatty streaks . Although such subintimal lipid accumulation ( ▸) has little hemodynamic significance, it can be the precursor of more severe atherosclerotic plaque . 2. Progression depends on the continuing of conditions that favor atheroma formation: endothelial injury from increased blood lipid levels in concert with hemodynamic alterations. Atheromas can regress when modifiable risk factors (e.g., smoking, hypertension, diabetes, hypercholesterolemia) are addressed. 3. Laboratory markers of atherogenic risk include serum total cholesterol, HDL cholesterol, lipoprotein(a), homocysteine, and glucose (or hemoglobin A ) as a measure of diabetic control. C-reactive protein , which is one marker of systemic inflammatory status, is an independent and highly predictive measure of risk. 1c ERRNVPHGLFRVRUJ 11.9 Side A (PBD9: 519; BP9: 361) ERRNVPHGLFRVRUJ Questions A 46-year-old man who was treated for stage IV Hodgkin lymphoma 10 years ago now has left upper quadrant pain. His angiography study is shown. The cell of origin marks with vWF and appears to be endothelial. 1. What is your diagnosis? 2. Explain the angiographic appearance. 3. What carcinogen is linked to this neoplasm in liver? 4. What related neoplasm complicates radical mastectomy? ERRNVPHGLFRVRUJ Answers: Side B 1. This is angiosarcoma . The plump, pleomorphic cells resemble endothelium and form irregular vascular channels filled with blood that spills into adjacent stroma. 2. Chemicals that come in contact with skin, especially arsenicals , are common causes of this condition. Foreign bodies (e.g., metals, plastics, wax) have also been implicated, including foreign bodies from surgical procedures, although these are exceedingly rare. 3. The prognosis is poor as a result of local extension, recurrence after resection, and the presence of distant metastases (e.g., to the lungs, as suggested by pulmonary nodules in this case). ERRNVPHGLFRVRUJ 11.9 Side B (PBD9: 519; BP9: 361) ERRNVPHGLFRVRUJ Questions A 66-year-old man has a 2-year history of a slowly enlarging mass on the back of his neck. It is 7 × 4 cm in size, with a nodular, bluish-black surface. On excision, the fleshy mass is gray-white, with foci of necrosis and hemorrhage. The microscopic appearance is shown. A chest radiograph shows pulmonary nodules. 1. What is your diagnosis? 2. What chemical exposure can cause this? 3. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side A 1. This is an angiosarcoma , which is a malignant endothelial neoplasm. 2. The angiogram shows a mass with a “blush” of contrast ( ▾) filling the small, irregular vascular channels of this vascular neoplasm. 3. Hepatic angiosarcomas are associated with polyvinyl chloride (PVC) exposure. 4. The disruption of lymphatics leads to chronic lymphedema and the development of lymphangiosarcoma . ERRNVPHGLFRVRUJ 12 ERRNVPHGLFRVRUJ The Heart ERRNVPHGLFRVRUJ 12.1 Side A (PBD9: 544; BP9: 380) ERRNVPHGLFRVRUJ Questions A 63-year-old man has severe substernal chest pain that radiates to his left jaw. He is hypotensive and tachycardic. He has elevated creatine phosphokinase and troponin I levels, and he is admitted to the cardiac intensive care unit. He dies 24 hours later of intractable ventricular tachycardia. His myocardium at autopsy is shown. 1. Describe the findings shown. 2. What are the risk factors for his disease? ERRNVPHGLFRVRUJ Answers: Side B 1. There is myocardial coagulative necrosis and dropout, now with increasing mononuclear inflammatory cells (macrophages) interspersed with a sparser neutrophil infiltrate. This suggests a myocardial infarction of 3 to 7 days' duration. 2. Transmural necrosis could lead to papillary muscle rupture with acute valvular incompetence or to ventricular wall rupture with hemopericardium and cardiac tamponade . Previous foci of infarcted myocardium and surrounding zones of ischemic (albeit still alive) myocardium can also be more prone to sudden arrhythmias . ERRNVPHGLFRVRUJ 12.1 Side B (PBD9: 548; BP9: 383) ERRNVPHGLFRVRUJ Questions A 56-year-old male smoker with hypertension and type 2 diabetes has a 3-hour episode of chest discomfort that he attributes to heartburn caused by shoveling snow too soon after a large beer and pizza repast. The discomfort abates, but he dies suddenly 5 days later while watching television. His myocardium at autopsy is shown. 1. Describe the microscopic findings. 2. What life-threatening complication of this disease may now have happened? ERRNVPHGLFRVRUJ Answers: Side A 1. Neutrophils infiltrate myocardial fibers that are undergoing coagulative necrosis , including nuclear karyolysis (▸). The appearance is consistent with that of an acute myocardial infarction of roughly 1 day's duration. 2. Abnormal blood lipids (i.e., increased LDL cholesterol, decreased HDL cholesterol, and hypertriglyceridemia), diabetes mellitus, hypertension, cigarette smoking, and a family history are associated risk factors. More recently, the long-term inflammatory status of the patient as reflected in his C-reactive protein levels is also likely to have contributed to his risk. ERRNVPHGLFRVRUJ 12.2 Side A (PBD9: 545; BP9: 381) ERRNVPHGLFRVRUJ Questions A 54-year-old man with hypertension and a 60 pack-year smoking history has prolonged chest pain that radiates to his neck. He abruptly develops severe dyspnea 3 days later. Examination reveals hypotension and tachycardia, with diffuse rales and a high-pitched holosystolic murmur that radiates to the axilla. He dies in florid pulmonary edema. His heart at autopsy is shown. 1. How does this finding explain the terminal events? 2. Why did this event happen at this time relative to his myocardial infarction (MI)? 3. Would his troponin I level be elevated at the time of his death? ERRNVPHGLFRVRUJ Answers: Side B 1. Most acute myocardial infarctions are due to atherosclerotic plaque rupture or erosion, with the development of a superimposed acute thrombus that blocks the coronary perfusion in that vessel. t-PA is administered to activate anticoagulant pathways and lyse the thrombus. 2. Yes. Note the numerous contraction bands (▾), which are caused when restoring blood flow floods ischemic myocytes with calcium and causes tetanic contraction. ERRNVPHGLFRVRUJ 12.2 Side B (PBD9: 539; BP9: 375) ERRNVPHGLFRVRUJ Questions A 65-year-old man has a 4-hour history of substernal chest pain; ECG and an elevated troponin I level confirm an evolving myocardial infarction. Tissue plasminogen activator (t-PA) is given, and the patient's chest pain resolves. However, 24 hours later, he dies suddenly of an arrhythmia. His myocardium at autopsy is shown. 1. Why was the patient given t-PA? 2. Did the t-PA restore blood flow to the myocardium? ERRNVPHGLFRVRUJ Answers: Side A 1. Note left ventricular papillary muscle rupture (▾) from the presumed infarction 3 days ago; this causes mitral valve insufficiency and pulmonary edema. 2. As successive waves of neutrophils and macrophages are recruited into infarcted myocardium, they degrade dead cells and extracellular matrix. At this point, only early granulation tissue (and not scar) is present, thereby increasing the risk of myocardial rupture from 1 day to 2 weeks after MI; the risk peaks at about 5 to 7 days. 3. After MI, troponins are elevated for 7 to 10 days, whereas CK-MB peaks at 1 day and returns to normal in 72 hours. ERRNVPHGLFRVRUJ 12.3 Side A (PBD9: 559; BP9: 393) ERRNVPHGLFRVRUJ Questions A 30-year-old intravenous drug user with a 2-day history of fever is found to have coarse systolic and diastolic murmurs, splenomegaly, and nail bed splinter hemorrhages. His CK-MB level is elevated. He experiences sudden cardiac arrest. His aortic valve at autopsy is shown. 1. Explain the murmurs. 2. What blood culture results do you expect? 3. Explain the splinter hemorrhages. 4. Why did this patient die? ERRNVPHGLFRVRUJ Answers: Side B 1. The valve cusps are still pliable, but they are infected with a large vegetation (▾) that is filling the valve orifice. 2. The subacute course suggests a low-virulence organism, such as viridans group streptococci; during this relatively late period after prosthetic valve surgery, bloodborne staphylococcal, streptococcal, or fungal infections are most likely. The lesions may be bulky and friable, as they are in this case. 3. Mechanical prosthetic valves require anticoagulation to prevent thrombosis; individuals who are at risk for hemorrhage, such as menstruating women or elderly individuals with osteoporosis, may elect to receive a bioprosthetic valve. ERRNVPHGLFRVRUJ 12.3 Side B (PBD9: 560; BP9: 394) ERRNVPHGLFRVRUJ Questions A 40-year-old woman with a congenital bicuspid valve receives an aortic valve bioprosthesis. Four months later, she develops a 3-week history of low-grade fever and malaise. She dies of an embolic cerebrovascular infarct. The bioprosthetic valve at autopsy is shown. 1. What is your diagnosis? 2. What organism do you expect on blood cultures? 3. Why select a bioprosthesis over a mechanical valve? ERRNVPHGLFRVRUJ Answers: Side A 1. These large vegetations (◂) have cuspal destruction that is consistent with infective endocarditis . The vegetations cause systolic murmurs, whereas cuspal destruction causes insufficiency that leads to diastolic (regurgitant) murmurs. 2. Intravenous drug use and the aggressive course suggest a virulent organism, such as Staphylococcus aureus. 3. Friable left-sided vegetations can cause systemic septic microemboli that lead to small vessel occlusion and possible secondary infection. 4. An elevated CK-MB level can come either from the destructive process extending into adjacent myocardium or from septic emboli entering the coronary circulation and causing an infarct, with myocardial necrosis and possible arrhythmias. ERRNVPHGLFRVRUJ 12.4 Side A (PBD9: 547; BP9: 382) ERRNVPHGLFRVRUJ Questions A 49-year-old woman with diabetes mellitus had an episode of palpitations and severe dyspnea 3 to 4 weeks ago, but there was no associated chest pain. Persistent shortness of breath prompted an echocardiogram that now shows decreased left ventricular wall motion and mitral regurgitation. If we looked histologically at this point, much of this patient's heart would appear as shown. 1. Describe the microscopic findings. 2. Explain the echocardiographic findings. 3. Would her troponin and CK-MB levels be elevated now? 4. Why didn't she feel chest pain with her infarct? ERRNVPHGLFRVRUJ Answers: Side B 1. A large left ventricular aneurysm is marked by the region of white fibrosis (■) on the endocardial surface. 2. The aneurysm (♦) is noncontractile, and total left ventricular contraction is diminished despite compensatory hypertrophy of the remaining viable myocardium (*). 3. Mural thrombi can form in areas of abnormal blood flow. Portions of this thrombus could have embolized to this patient's cerebral vasculature. ERRNVPHGLFRVRUJ 12.4 Side B (PBD9: 549; BP9: 384) ERRNVPHGLFRVRUJ Questions One year after a myocardial infarction, a 65-year-old woman has congestive heart failure with an ejection fraction of 25% (nl 50% to 75%). She has a sudden embolic stroke and dies; her heart is shown at autopsy. 1. Describe the gross appearance. 2. Explain the diminished cardiac output. 3. What complication might have led to her death? ERRNVPHGLFRVRUJ Answers: Side A 1. After the myocardial infarction that occurred 3 to 4 weeks ago, scattered residual cardiac myocytes (■) and pale brown, hemosiderin-laden macrophages (♦) were interspersed among vascularized connective tissue (*) that was on its way to becoming dense scar. 2. Scar tissue and a lack of myocardial contraction lead to left ventricular dilation. With ventricular chamber dilation, papillary muscles are pulled apart, and mitral valve leaflets do not coapt, thereby leading to regurgitation. 3. No. Troponin I levels return to normal after 2 weeks, and CK-MB levels normalize after approximately 3 days. 4. Long-standing diabetes mellitus can lead to a sensory neuropathy and so-called “silent” myocardial infarction. ERRNVPHGLFRVRUJ 12.5 Side A (PBD9: 534; BP9: 370) ERRNVPHGLFRVRUJ Questions A 42-year-old woman with progressive lower extremity edema is also found to have a prominent mid-systolic flow murmur over the pulmonary area, jugular venous distention, and an increased hepatic span. Her chest radiograph shows a prominent right heart border. An example of her cardiac lesion is shown. 1. What is your diagnosis? 2. Explain this patient's findings. 3. What complications could occur? 4. Why is this lesion less common in adults? ERRNVPHGLFRVRUJ Answers: Side B 1. This child has a large membranous ventricular septal defect (VSD) with secondary right ventricular hypertrophy. 2. The large size of this VSD leads to pronounced left-to-right shunting and volume overload. If uncorrected, this can produce irreversible pulmonary hypertension , which can eventually result in right-to-left shunting and cyanosis ( Eisenmenger complex ). ERRNVPHGLFRVRUJ 12.5 Side B (PBD9: 535; BP9: 371) ERRNVPHGLFRVRUJ Questions A 2-year-old girl with failure to thrive has a 3-month history of cyanosis and congestive heart failure. A diagrammatic representation of her heart is shown. 1. What is your diagnosis? 2. Explain the findings. ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has a secundum-type (▸) atrial septal defect . 2. The pressure difference between the atria is not great, so years can pass with left-toright shunting and modest volume overload. Eventually, pulmonary hypertension can develop with cor pulmonale . The ensuing right heart failure causes ascites, hepatic congestion, and peripheral edema. 3. Complications may include heart failure, pulmonary vascular disease , infective endocarditis , “ cardiac cirrhosis ,” and paradoxical embolization . 4. Many VSDs close spontaneously, but accompanying cardiac malformations may persist. ERRNVPHGLFRVRUJ 12.6 Side A (PBD9: 536; BP9: 373) ERRNVPHGLFRVRUJ Questions A neonate develops cyanosis within the first day of life. Angiography and echocardiographic evaluation reveal the congenital lesion that is shown here diagrammatically. 1. What is your diagnosis? 2. Why is cyanosis present? 3. How is survival possible? 4. What other shunts could allow survival? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has tetralogy of Fallot with (1) pulmonic stenosis (▸), (2) right ventricular hypertrophy (◂), and (3) an aorta that overrides (▾) a (4) large ventricular septal defect (▴). 2. The pulmonic stenosis produces right heart outflow obstruction; the ventricular septal defect and the overriding aorta permit a right-to-left shunt. 3. The pulmonic stenosis is “protective” of the pulmonary vasculature. ERRNVPHGLFRVRUJ 12.6 Side B (PBD9: 535; BP9: 372) ERRNVPHGLFRVRUJ Questions A 13-year-old boy has been cyanotic since birth, and he has a complex set of cardiac murmurs. Despite being treated with surgical shunts, he eventually requires cardiac transplantation; his explanted heart is shown. 1. What congenital heart disease is present? 2. Why was there cyanosis? 3. Why didn't this patient develop pulmonary hypertension (which might have precluded the transplant)? ERRNVPHGLFRVRUJ Answers: Side A 1. There is transposition of the great arteries (TGA); the aorta arises from the right ventricle, and the pulmonary trunk arises from the left ventricle. 2. TGA leads to two independent “closed circuit” venous and systemic arterial circulations. The systemic output is predominantly from the deoxygenated right ventricle. 3. The only oxygenated blood here is derived from mixing via the patent ductus arteriosus (PDA). Without correction or additional shunts, systemic oxygenation is tenuous at best. 4. Ventricular or atrial septal defects would also allow mixing. ERRNVPHGLFRVRUJ 12.7 Side A (PBD9: 554; BP9: 389) ERRNVPHGLFRVRUJ Questions A 77-year-old woman has had exertional dyspnea and syncope for 6 months. On examination, she has weak carotid pulses, a prominent S4, and a systolic crescendodecrescendo murmur that is heard best at the right second interspace. Her chest radiograph shows pulmonary edema. She declines surgical therapy and dies 6 months later; her heart is shown at autopsy. 1. What is the diagnosis? 2. What are the causes of this disease? 3. What changes occur in the left ventricle? ERRNVPHGLFRVRUJ Answers: Side B 1. She has postductal aortic coarctation ( arrow). 2. The findings strongly suggest monosomy X or Turner syndrome (45,X). 3. This patient would likely have rib notching. The obstruction of the distal aortic blood flow leads to development of collateral circulation through the intercostal arteries. 4. Nothing. This patient will have primary amenorrhea as a result of the accelerated loss of oocytes, which will effectively be complete when she reaches 2 years of age. ERRNVPHGLFRVRUJ 12.7 Side B (PBD9: 537; BP9: 373) ERRNVPHGLFRVRUJ Questions An infant girl with a late systolic murmur has upper extremity pulses and blood pressures that are greater than those found in her lower extremities. She also has a webbed neck and short fourth metacarpals. If an autopsy were performed at this point, we might see a heart and great vessels that look like the image shown. 1. What is the cardiovascular lesion? 2. What chromosomal abnormality does this patient have? 3. What rib abnormality might be seen on a chest radiograph? 4. What might happen at the time of this patient's menarche? ERRNVPHGLFRVRUJ Answers: Side A 1. This is calcific aortic valve stenosis in a normal valve with three cusps. Note the dense nodular calcifications (■). 2. At this woman's age, most patients with this condition developed it idiopathically as a result of gradual degenerative changes, although some cases are the result of rheumatic valvular disease. Degenerative calcific aortic stenosis during the fifth to sixth decades is most likely associated with a bicuspid aortic valve . 3. There is left ventricular hypertrophy as a result of outflow obstruction, and this eventually results in left-sided congestive heart failure and pulmonary edema. ERRNVPHGLFRVRUJ 12.8 Side A (PBD9: 570; BP9: 401) ERRNVPHGLFRVRUJ Questions A 39-year-old man with chest pain and dyspnea is found on examination to have atrial fibrillation and congestive heart failure as well as lower extremity edema and pleural effusions. A cardiac biopsy specimen has the lesion shown. 1. What is your diagnosis? 2. Explain this patient's clinical findings. 3. What are common infectious causes of this finding? 4. How might you prove a particular agent to be causal? ERRNVPHGLFRVRUJ Answers: Side B 1. The patient has a pseudocyst (◂) that contains bradyzoites of Toxoplasma gondii. Free tachyzoites are also present. This is Toxoplasma myocarditis . 2. Oocyst-shedding kittens 3. Toxoplasmosis can be a congenital infection . ERRNVPHGLFRVRUJ 12.8 Side B (PBD9: 571; BP9: 402) ERRNVPHGLFRVRUJ Questions A 42-year-old woman who had a cardiac transplant 10 years ago and who has been taking immunosuppressant drugs develops fever and congestive heart failure. The microscopic appearance of an endomyocardial biopsy specimen is shown. 1. What is your diagnosis? 2. What is a common vector for this infection? 3. What is the risk to the fetus if this patient becomes pregnant? ERRNVPHGLFRVRUJ Answers: Side A 1. The patient has myocarditis ; there is a dense lymphocytic infiltrate (▸) with associated myocyte damage. 2. He has right-sided and left-sided congestive heart failure. Myocarditis also commonly leads to arrhythmias. 3. Common infectious causes include viral myocarditis as a result of coxsackie B, ECHO, cytomegalovirus, HIV, adenovirus, and influenza viruses; one should also consider Lyme myocarditis (due to Borrelia), Rickettsia, Chlamydia, and, in more exotic locales, trypanosome myocarditis ( Chagas disease ). 4. Increasing antibody titers; showing the organisms by special stains; polymerase chain reaction for specific pathogen sequences ERRNVPHGLFRVRUJ 12.9 Side A (PBD9: 557; BP9: 391) ERRNVPHGLFRVRUJ Questions A 13-year-old girl develops malaise and fever, an irregular circular rash, and subcutaneous nodules on her forearms 3 weeks after a painful pharyngitis. A new heart murmur and friction rub are heard. Her mitral valve anterior leaflet would appear as shown. 1. What is your diagnosis? 2. What serologic findings are expected? 3. What is the pathogenesis? ERRNVPHGLFRVRUJ Answers: Side B 1. The mitral valve is stenotic (◂), with a “fish-mouth” shape; the left atrium (♦) above is severely dilated. 2. Mitral stenosis in adults is usually due to rheumatic valvular disease . Group A streptococcal infection leads to valve scarring; the mitral valve is most commonly affected. In addition to the thickening and fusion of the valve leaflets, there are shortened and thickened chordae. The functional result is mitral valve stenosis and insufficiency . 3. Mitral stenosis leads to left-sided congestive failure with pulmonary congestion and edema. The enlarged left atrium often leads to fibrillation, and it can also be a site of mural thrombosis. ERRNVPHGLFRVRUJ 12.9 Side B (PBD9: 558; BP9: 392) ERRNVPHGLFRVRUJ Questions A 48-year-old woman with a 5-year history of worsening orthopnea is found on examination to have atrial fibrillation and a rumbling diastolic murmur with an opening snap. The gross appearance of her heart during her surgical valve replacement is shown. 1. What valve is involved? 2. What is the cause and pathogenesis? 3. What are the possible complications? ERRNVPHGLFRVRUJ Answers: Side A 1. Small verrucous vegetations (▸) near the mitral valve closure line are typical for acute rheumatic endocarditis . 2. Elevated titers to streptolysin O, DNase B, and hyaluronidase would be likely. 3. Classically, infection with group A streptococci (i.e., the pharyngitis) elicits an antibody response that is directed against bacterial capsular M proteins ; these antibodies can be cross-reactive to cardiac antigens, thereby causing immune-mediated endocarditis (heart murmur), myocarditis (arrhythmia), and pericarditis (friction rub). ERRNVPHGLFRVRUJ 12.10 Side A (PBD9: 564; BP9: 397) ERRNVPHGLFRVRUJ Questions A 45-year-old man with a 6-year history of progressive exertional dyspnea is found by echocardiography to have an ejection fraction of 28% (nl 50% to 65%) with systolic dysfunction and mitral regurgitation. His native heart after cardiac transplantation is shown. 1. What is your diagnosis? 2. What might be seen microscopically? 3. What are the possible causes? ERRNVPHGLFRVRUJ Answers: Side B 1. This is myofiber disarray in a blue collagenous stroma (highlighted by the trichrome stain), which is typical for hypertrophic cardiomyopathy . 2. Sarcomeric protein genes that are likely mutated include β-myosin heavy chain, myosin-binding protein C, and troponin T (among many others). Most of these cases involve a single point missense mutation and are autosomal dominant. 3. Arrhythmia with sudden death is possible. Atrial fibrillation and dilated chambers promote mural thrombosis, and embolization can result. Patients often develop congestive heart failure. ERRNVPHGLFRVRUJ 12.10 Side B (PBD9: 569; BP9: 400) ERRNVPHGLFRVRUJ Questions A 14-year-old boy with episodic exertional dyspnea has a harsh systolic ejection murmur. Echocardiography shows left ventricular outflow obstruction and impaired diastolic filling. His interventricular septum would probably have the histologic appearance shown (trichrome stain with blue collagenous extracellular matrix). 1. What is your diagnosis? 2. What genetic mutations may be present? 3. What complications can develop? ERRNVPHGLFRVRUJ Answers: Side A 1. The marked dilation of this left ventricle is typical of dilated cardiomyopathy . 2. Myocyte hypertrophy and interstitial fibrosis 3. Approximately one third of patients with this condition have a genetic basis that typically involves nonsarcomeric proteins (some involve mitochondrial mutations). Other cases may be caused by toxic exposures (e.g., alcohol abuse, chemotherapy), associated with pregnancy, attributable to iron overload (hemochromatosis), or the result of past viral myocarditis. ERRNVPHGLFRVRUJ 12.11 Side A (PBD9: 573; BP9: 404) ERRNVPHGLFRVRUJ Questions A 63-year-old man with a history that is significant for hypertension and diabetes mellitus has a sudden onset of severe chest pain and hypotension. Pericardiocentesis yields sanguineous fluid. His chest CT scan is shown. 1. What is your diagnosis? 2. How do his risk factors influence the pathogenesis? 3. What genetic mutations may lead to this event? ERRNVPHGLFRVRUJ Answers: Side B 1. The patient had an acute myocardial infarction (MI). Although the CK-MB level peaks within 1 day of such an event and diminishes by 3 days after it, troponin I can persist for 7 to 10 days without tissue reperfusion. 2. This patient has ventricular rupture and cardiac tamponade . 3. The period that occurs 3 to 7 days after MI is when the myocardium is at the greatest risk for rupture; this is the time of maximal myocardial necrosis, with only early granulation tissue in its place. Ventricular rupture with hemopericardium or papillary muscle rupture with valvular incompetence is most likely to occur during this time. ERRNVPHGLFRVRUJ 12.11 Side B (PBD9: 574; BP9: 404) ERRNVPHGLFRVRUJ Questions A 54-year-old woman had 3 hours of chest pain 5 days ago. Now, after an abrupt loss of consciousness, her heart sounds are faint, and her ECG shows diminished voltages. Her serum CK-MB level is not elevated, but her troponin I level is modestly increased. Before any intervention can be done, she has a pulseless electrical activity arrest and dies. Her heart and pericardial contents are shown. 1. What happened 5 days ago? 2. What is your diagnosis now? 3. Why did this happen when it did? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has aortic dissection in the ascending aorta (▴) that extends distally (▾), with a false lumen and complicated by hemopericardium (♦). 2. Diabetes mellitus and hypertension contribute to medial ischemia via (1) atherosclerosis that increases the intimal diffusion distance, and (2) vascular stenosis in the vasa vasorum. The resulting medial degeneration is fertile ground for the propagation of a tear from an intimal defect. 3. Fibrillin mutations (Marfan syndrome) or mutated transforming growth factor-β receptors (Loeys-Dietz syndrome) cause defective elastic tissue synthesis. ERRNVPHGLFRVRUJ 12.12 Side A (PBD9: 530; BP9: 368) ERRNVPHGLFRVRUJ Questions A 72-year-old woman with long-standing severe emphysema has jugular venous distention and an increased liver span. The microscopic appearance of a liver biopsy specimen is shown. 1. Describe this appearance. 2. Why did this occur? ERRNVPHGLFRVRUJ Answers: Side B 1. The amorphous pink material (■) within the alveoli represents edema fluid. Note that the capillaries are prominently distended with red blood cells (♦). 2. Congestive heart failure is the underlying cause. Inadequate left ventricular function results in dilation and subsequent mitral incompetence. Valvular regurgitation and the inability of the left ventricle to pump against systemic pressures leads to increased pulmonary pressures, with pulmonary edema caused by vascular leak. 3. Left ventricular failure results in higher left atrial pressure as measured by the pulmonary arterial wedge pressure. The pulmonary arterial and right atrial pressures subsequently increase. ERRNVPHGLFRVRUJ 12.12 Side B (PBD9: 529; BP9: 367) ERRNVPHGLFRVRUJ Questions A 77-year-old man with increasingly intractable dyspnea has resting tachypnea (30 beats/min). He has bilateral diffuse rales, and his chest radiograph shows pulmonary edema. His cardiac output is 3.4 L/min (nl 4 to 8 L/min), with right atrial pressure of 12 mm Hg (nl 3 mm Hg), pulmonary arterial pressure of 36/28 mm Hg (nl 25/9 mm Hg), and pulmonary artery wedge pressure of 28 mm Hg (nl 9 mm Hg). He dies with progressively worsening hypoxia. His microscopic pulmonary findings at autopsy are shown. 1. Describe the findings. 2. What is the underlying cause of these problems? 3. Explain the hemodynamic data. ERRNVPHGLFRVRUJ Answers: Side A 1. The centrilobular sinusoids around the central vein (■) are engorged with red blood cells ( central passive congestion ). 2. Through the destruction of lung parenchyma, emphysema reduces the pulmonary vascular bed, thereby increasing pulmonary arterial resistance and pressure. This results in cor pulmonale and right heart failure with subsequent hepatic passive congestion. ERRNVPHGLFRVRUJ 12.13 Side A (PBD9: 575; BP9: 404) ERRNVPHGLFRVRUJ Questions A 53-year-old man has a 6-month history of a sudden loss of consciousness that lasts for 5 minutes. His physical examination is unremarkable. His chest CT scan and echocardiography reveal the lesion shown. 1. What is the diagnosis? 2. Why did this patient have fainting episodes? 3. How is this lesion treated? ERRNVPHGLFRVRUJ Answers: Side B 1. This myxoma has abundant pale extracellular matrix (■) composed of acid mucopolysaccharide in which there are small stellate multinuclear cells (♦) with hyperchromatic nuclei. 2. Portions of this myxoma can break off and embolize. Because it is in the left atrium, the emboli would go to the systemic circulation, including the cerebral arteries. 3. Carney syndrome would be suggested. About 10% of cardiac myxomas occur in patients with this condition, roughly half of whom have a mutation of the PRKAR1 gene, which encodes a regulatory subunit of cAMP-dependent protein kinase A. ERRNVPHGLFRVRUJ 12.13 Side B (PBD9: 575; BP9: 404) ERRNVPHGLFRVRUJ Questions A 51-year-old woman has a year-long history of fever, and she has had multiple transient ischemic attacks. She now has a hemorrhagic embolic “stroke.” Echocardiography reveals a lesion in the left atrium. It is excised, and its microscopic appearance is shown. 1. What is this lesion? 2. Explain the patient's vascular events. 3. If multiple family members had similar cardiac and extracardiac lesions and endocrinopathy, what syndrome is suggested? ERRNVPHGLFRVRUJ Answers: Side A 1. The small, circumscribed round mass (■) in the left atrium is a cardiac myxoma . This is the most common location for this type of mass, and this is the most common primary cardiac tumor of adults. 2. Large myxomas can produce a swinging “ball valve” effect in which they temporarily occlude the mitral orifice, thereby reducing cardiac output and cerebral perfusion. 3. This lesion is benign and can be readily excised surgically. ERRNVPHGLFRVRUJ 13 ERRNVPHGLFRVRUJ Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus ERRNVPHGLFRVRUJ 13.1 Side A (PBD9: 583; BP9: 426) ERRNVPHGLFRVRUJ Questions A 61-year-old woman with fever, rigors, and tachycardia has a blood culture that is positive for Enterobacter cloacae. Her peripheral blood smear is shown. 1. What leukocytes are present in this smear? 2. What is her total WBC count likely to be? 3. What precursor population in her marrow is increased? 4. What cytokines drive this process? ERRNVPHGLFRVRUJ Answers: Side B 1. These are bilobed neutrophils (not band neutrophils), which are characteristic for Pelger-Huet anomaly , an autosomal-dominant disorder caused by mutations in the lamin B receptor. Homozygotes lack any nuclear lobation and can have mild to moderate neutrophil dysfunction. Pseudo-pelgeroid changes are seen with myeloid leukemia and myelodysplastic syndromes . 2. The hypersegmented neutrophil is characteristic for megaloblastic change. This is probably a result of vitamin B deficiency given the patient's likely lack of intrinsic factor as a result of the loss of gastric parietal cells. 12 ERRNVPHGLFRVRUJ 13.1 Side B (PBD9: 615; BP9: 445) ERRNVPHGLFRVRUJ Questions A 25-year-old man has a normal total WBC count, but the “band count” is reportedly increased. His peripheral blood smear is shown in the upper frame. 1. What is the diagnosis for this man? A 50-year-old woman has anemia and atrophic gastritis. Her peripheral blood smear is shown in the lower frame. 2. What is the diagnosis for this woman? ERRNVPHGLFRVRUJ Answers: Side A 1. Segmented neutrophils and a band neutrophil can be seen. 2. The WBC count is increased, with leukocytosis and specifically neutrophilia as a consequence of her sepsis. 3. The myeloid population undergoes hyperplasia in response to the infection. 4. Inflammatory cytokines such as tumor necrosis factor and interleukin-1 stimulate bone marrow stromal cells to produce growth factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) , which drive myeloid proliferation. ERRNVPHGLFRVRUJ 13.2 Side A (PBD9: 584; BP9: 428) ERRNVPHGLFRVRUJ Questions A 24-year-old man with a 4-day history of abdominal pain, fever, diarrhea, and anorexia has the abdominal CT scan shown. His stool cultures are positive for Yersinia enterocolitica. 1. What structures are enlarged (▴)? 2. What would you expect on a biopsy specimen? 3. What would this patient's WBC count show? 4. What happens in the enlarged structures? 5. What is the route of infection? ERRNVPHGLFRVRUJ Answers: Side B 1. The large follicle has a pale germinal center ( ◂) with enlarged, activated lymphoid cells of all shapes and sizes ( polyclonal response ). There are also numerous macrophages ( ▾) that contain apoptotic bodies. 2. This is a benign, reactive lymphadenitis . Malignant lymphoid proliferations are typically painless and monoclonal, with effacement of their architecture. 3. Antigen-presenting cells include macrophages and dendritic cells (and, to a lesser extent, B cells); they can arrive via lymphatics from peripheral sites, or they can reach the node hematogenously. ERRNVPHGLFRVRUJ 13.2 Side B (PBD9: 584; BP9: 428) ERRNVPHGLFRVRUJ Questions A 10-year-old boy with a week-long history of right groin pain is found to have enlarged tender lymph nodes. A biopsy specimen of one of these is obtained and shown here. The pain and enlargement spontaneously subside over the next few weeks. 1. Describe the appearance. 2. Is this benign or malignant? 3. How is antigen delivered to this node? ERRNVPHGLFRVRUJ Answers: Side A 1. The enlarged mesenteric lymph nodes represent a reactive lymphadenitis . 2. The nodes exhibit large, expanded follicles with prominent germinal centers . 3. The patient likely has lymphocytosis (i.e., an increased lymphocyte count). 4. Affinity maturation occurs within germinal centers; B cells that produce more specific antibody are progressively selected and expanded. 5. Y. enterocolitica is spread by the fecal-oral route. ERRNVPHGLFRVRUJ 13.3 Side A (PBD9: 590; BP9: 430) ERRNVPHGLFRVRUJ Questions A 9-year-old boy with fatigue, epistaxis, and easy bruisability develops pneumonia. On examination, he also has extremity bone pain, mild splenomegaly, and generalized nontender lymphadenopathy. His peripheral blood smear is shown. 1. What form of leukemia does he have? 2. Explain his clinical findings. 3. What enzyme is expressed in these cells? ERRNVPHGLFRVRUJ Answers: Side B 1. The red population of WBCs marks for CD19 (a B-cell marker) and CD10 (a pre–B cell marker), which is consistent with acute pre–B cell lymphoblastic leukemia . There is a smaller green population of normal B cells with remaining normal marrow cells, which are highlighted here in gray. 2. This patient's prognosis is good. Worse prognostic factors include an age of onset of less than 2 years or onset during adolescence or adulthood, a higher WBC count, and presence of the t(9;22) “Philadelphia chromosome” translocation . ERRNVPHGLFRVRUJ 13.3 Side B (PBD9: 592; BP9: 433) ERRNVPHGLFRVRUJ Questions A 6-year-old girl has a 1-month history of fatigue, headache, and vomiting. Her hemoglobin level is 8 g/dL (nl 12 to 15.6 g/dL), her platelet count is 56,400/µL (nl 130,000 to 400,000/µL), and her total WBC count is 18,270/µL (nl 3800 to 10,800/µL). Flow cytometry of a marrow aspirate exhibits the pattern shown. 1. What is the diagnosis? 2. What is the prognosis with chemotherapy? ERRNVPHGLFRVRUJ Answers: Side A 1. These cells ( ▾) are blasts that have minimal agranular cytoplasm with enlarged nuclei that have small nucleoli; this is consistent with acute lymphoblastic leukemia (ALL) . Blasts comprise more than 25% of the marrow cellularity in ALL. Blasts typically appear in large numbers in the peripheral blood; in the rarer cases of “aleukemic” leukemia, they do not. 2. Leukemic cells fill the marrow and displace and suppress the normal hematopoietic elements, thereby leading to pancytopenia; the result is anemia with fatigue, thrombocytopenia with bleeding, and decreased myelopoiesis leading to bacterial infections. 3. Terminal deoxynucleotidyl transferase (TdT) is expressed only in pre-B and pre-T lymphoblasts. ERRNVPHGLFRVRUJ 13.4 Side A (PBD9: 593; BP9: 434) ERRNVPHGLFRVRUJ Questions A 68-year-old man with a 1-year history of progressive fatigue has an enlarged spleen and nontender cervical adenopathy. His hematocrit level is 26.8% (nl 41% to 50%) with normal indices, his platelet count is within normal limits, and his WBC count is 36,500/µL (nl 3800 to 10,800/µL). His peripheral smear is shown. 1. What is the predominant cell type shown here? 2. What are complications of his disease? ERRNVPHGLFRVRUJ Answers: Side B 1. Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma is suggested. The large population in red marks for CD20 (a pan B-cell marker) and CD5 (normally a T-cell marker, but it is present on a small population of B cells); a few normal CD20positive B cells ( green) are LAO present. The abnormal leukemic cells also express CD19 and CD23 as well as low levels of surface immunoglobulin. 2. Approximately 10% to 15% of patients with CLL develop autoimmune hemolytic anemia with a positive Coombs test. Serum haptoglobin is depleted as erythrocytes hemolyze and release their hemoglobin. ERRNVPHGLFRVRUJ 13.4 Side B (PBD9: 594; BP9: 434) ERRNVPHGLFRVRUJ Questions A 66-year-old man has anemia, hepatomegaly, and splenomegaly. His serum haptoglobin level is decreased, and his direct Coombs test is positive. Flow cytometry of his peripheral blood lymphocytes is shown. 1. What diagnosis is suggested by flow cytometry? 2. What complication is suggested by the positive Coombs test? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has chronic lymphocytic leukemia (CLL) with many small mature lymphocytes. CLL is often accompanied by a tissue phase known as small lymphocytic lymphoma, which involves the same abnormal lymphocytes infiltrating the spleen, liver, and lymph nodes. 2. Tumor progression is heralded by a prolymphocytic transformation with worsening cytopenias (15% to 30% of patients) or a Richter transformation to a diffuse large Bcell lymphoma (10% of patients). ERRNVPHGLFRVRUJ 13.5 Side A (PBD9: 595; BP9: 435) ERRNVPHGLFRVRUJ Questions A 51-year-old woman has diffuse nontender lymphadenopathy. The microscopic appearance of a lymph node biopsy specimen is shown. 1. What is the diagnosis? 2. Transformation to what disease may occur? 3. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side B 1. There is right posterior cervical lymphadenopathy (■). 2. Hodgkin lymphoma 3. Follicular lymphoma . Ninety percent of patients with this condition have a t(14;18) translocation that juxtaposes the IgH locus on chromosome 14 with the BCL2 locus on chromosome 18. This results in the overexpression of BCL-2 , which is an antiapoptotic protein that promotes follicular lymphoma cell survival. 4. Small lymphocytic lymphoma/chronic lymphocytic leukemia ERRNVPHGLFRVRUJ 13.5 Side B (PBD9: 595; BP9: 435) ERRNVPHGLFRVRUJ Questions A 44-year-old man has had painless lumps in his upper posterior neck for the past year. His head CT scan is shown. 1. What is enlarged in this CT scan? 2. What is the diagnosis if a biopsy specimen shows Reed-Sternberg cells? 3. What is the diagnosis if cells mark with CD10, CD19, and CD20? How does a t(14;18) translocation affect cellular proliferation? 4. What is the diagnosis if cells mark with CD5, CD19, CD20, and CD23? ERRNVPHGLFRVRUJ Answers: Side A 1. This is a follicular lymphoma , which is the most common form of non-Hodgkin lymphoma (about 45% of cases). Note the nodular expansion of the relatively monomorphous tumor cells. 2. Approximately 30% to 50% of these cases transform into diffuse large B-cell lymphoma. 3. Low-grade lymphomas tend to be indolent, but they cannot be cured. The median length of survival is 7 to 9 years. ERRNVPHGLFRVRUJ 13.6 Side A (PBD9: 597; BP9: 437) ERRNVPHGLFRVRUJ Questions A 38-year-old man with severe abdominal distention and air-fluid levels on a KUB radiograph undergoes emergent partial bowel resection to relieve the obstruction. There are three bulky lesions (◄) in this section of bowel; cells from these masses mark with CD19, CD20, CD10, EBV, and BCL6. A karyotype shows t(8;14). His CD4+ lymphocyte count is 100/mm3 (nl 490 to 1740/mm ). 3 1. What is your diagnosis? 2. Where do similar lesions in the African endemic form of this disease typically occur? 3. Is the peripheral blood usually involved? ERRNVPHGLFRVRUJ Answers: Side B 1. The large B cells and immunophenotype are consistent with diffuse large B-cell lymphoma (DLBCL) . 2. BCL-6 is a transcription factor required for normal germinal center formation; it is normally downregulated when B cells exit the germinal center. BCL-6 overexpression occurs in patients with DLBCL as a result of either promoter sequence mutations or BCL6 translocations; both may occur via the normal events involved in somatic B-cell hypermutation . ERRNVPHGLFRVRUJ 13.6 Side B (PBD9: 596; BP9: 436) ERRNVPHGLFRVRUJ Questions A 59-year-old man with a 3-month history of dysphagia has a head CT scan that reveals enlargement of the lymphoid tissues in the Waldeyer ring. The biopsy specimen shown yields cells that immunostain for CD20 and BCL6. He is treated with intensive chemotherapy, and he remains in remission after 5 years. 1. What form of non-Hodgkin lymphoma is present? 2. What is the genetic mechanism underlying the transformation of many of these tumors? ERRNVPHGLFRVRUJ Answers: Side A 1. The cells mark as Burkitt lymphoma , which is likely driven by an underlying Epstein-Barr virus (EBV) infection and immortalization. The low CD4+ count suggests HIV infection with AIDS as a predisposing event that facilitates the EBV-mediated Bcell expansion. 2. The mandible is usually involved. 3. No. Most Burkitt lymphomas occur at extranodal sites (witness the bowel involvement here), and the cells do not usually circulate or involve the bone marrow. ERRNVPHGLFRVRUJ 13.7 Side A (PBD9: 599; BP9: 438) ERRNVPHGLFRVRUJ Questions A 66-year-old woman with polyuria and fatigue has had two bouts of pneumococcal pneumonia during the past year. A pathologic femoral fracture prompts a workup that reveals multiple bony lytic lesions, an elevated creatinine level, and nephrotic-range proteinuria. Her bone marrow biopsy specimen is shown. 1. What is the diagnosis? 2. What is the cause of her fracture? 3. Why does she have proteinuria? ERRNVPHGLFRVRUJ Answers: Side B 1. There is a large “M” spike of immunoglobulin, which is typical for multiple myeloma . 2. The immunoglobulin light chains ( Bence Jones proteins ) can deposit as AL chain amyloidosis , which causes carpal tunnel syndrome . 3. Bisphosphonates inhibit osteoclast activity. Bortezomib , a proteasome inhibitor, blocks pro-apoptotic factor degradation. Thalidomide inhibits angiogenesis and stromal cell growth while modulating the production of cytokines such as tumor necrosis factor and interleukin-6, which contribute to myeloma cell survival. ERRNVPHGLFRVRUJ 13.7 Side B (PBD9: 600; BP9: 439) ERRNVPHGLFRVRUJ Questions A 71-year-old woman has lower back pain, and a radiograph shows a T12 compression fracture. There is a bilateral loss of sensation over the medial palmar aspect of her hands that involves the fifth and fourth fingers. Her serum calcium level is 12.8 mg/dL (nl 8.5 to 10.3 mg/dL), her total protein level is 9.6 g/dL (nl 6 to 8.5 g/dL), and her albumin level is 4.2 g/dL (nl 3.5 to 5 g/dL). Her serum protein electrophoresis (SPEP) is shown. 1. What does this SPEP show? 2. Explain this patient's signs and symptoms. 3. How can this malignancy be treated? ERRNVPHGLFRVRUJ Answers: Side A 1. This specimen contains more than 30% plasma cells, which is consistent with multiple myeloma . The defective production of normal immunoglobulins results in recurrent bacterial infections. Hypercalcemia from bone resorption and anemia from marrow replacement may be responsible for this patient's fatigue. 2. Multiple myeloma cells secrete factors such as the receptor activator of the NF-κβ ligand (RANKL), which acts as an osteoclast activating factor and leads to bone resorption. This in turn leads to hypercalcemia and the bony lytic lesions that cause pathologic fractures. 3. Excess light chains produced by the myeloma cells (also called Bence Jones proteins ) are toxic to the renal tubular epithelium; more than 6 g/dL may be present in the urine. ERRNVPHGLFRVRUJ 13.8 Side A (PBD9: 624; BP9: 456) ERRNVPHGLFRVRUJ Questions A 40-year-old man with a 6-month history of left upper quadrant abdominal discomfort has mild pancytopenia. His abdominal CT scan is shown. 1. Why does he have pancytopenia? 2. What are the causes of splenomegaly? 3. What would you suspect if this patient's marrow is fibrotic? 4. Could the splenomegaly be due to cirrhosis? ERRNVPHGLFRVRUJ Answers: Side B 1. The hairlike projections from these leukocytes are typical for hairy cell leukemia (HCL) . 2. B cells expressing CD19, CD20, and surface immunoglobulin as well as typical monocyte antigens CD11c and CD25 are present. These also classically have tartrateresistant acid phosphatase activity , as shown. 3. The reduction in normal leukocytes (particularly monocytes) with HCL predisposes affected individuals to infection, particularly atypical mycobacterial infections . 4. With chemotherapy, most patients develop long-lasting remission. ERRNVPHGLFRVRUJ 13.8 Side B (PBD9: 604; BP9: 442) ERRNVPHGLFRVRUJ Questions A 41-year-old man with a 5-month history of fatigue develops a persistent fever. He has marked splenomegaly but no lymphadenopathy, and he is pancytopenic. His peripheral blood smear is shown (bottom: tartrate-resistant acid phosphatase stain). 1. What is your diagnosis? 2. What is the immunophenotype of these cells? 3. What could this patient's fever represent? 4. What is his prognosis? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has splenomegaly ( ◂). Hypersplenism as a result of the sequestration of circulating cells causes pancytopenia. 2. Causes include cirrhosis of any cause, including primary hepatic and cardiogenic; obstruction of the portal or splenic veins (e.g., thrombosis in the setting of local inflammation) or extrinsic compression (e.g., by tumor); various infections; myeloproliferative disorders; storage diseases; and amyloidosis. 3. Myelofibrosis as part of a myeloproliferative disorder would be suspected. The resulting extramedullary hematopoiesis would cause splenomegaly. 4. No. This patient's liver is uniform and does not show cirrhosis. ERRNVPHGLFRVRUJ 13.9 Side A (PBD9: 607; BP9: 440) ERRNVPHGLFRVRUJ Questions A 30-year-old man with a 2-month history of dyspnea describes intermittent chest pain with alcohol consumption. Biopsy of the lesion shown on the chest CT scan reveals bands of fibrosis and lacunar cells marking for CD15 and CD30. 1. What is your diagnosis? 2. What is the stage of this patient's disease? 3. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side B 1. There are numerous Reed-Sternberg (R-S) cells ( ▸), which are diagnostic for Hodgkin lymphoma (HL) . Also present is a background of lymphocytes and macrophages, with several mononuclear variants that are typical for the mixed cellularity type of HL. 2. The R-S cells and their variants mark for Epstein-Barr virus. 3. Marrow involvement makes this stage IV disease; the patient's other symptoms indicate stage IV-B disease. 4. The patient has cutaneous anergy as a result of depressed cell-mediated immunity. ERRNVPHGLFRVRUJ 13.9 Side B (PBD9: 611; BP9: 442) ERRNVPHGLFRVRUJ Questions A 57-year-old man with a 3-month history of night sweats and weight loss has palpable nontender cervical and axillary lymph nodes with splenomegaly. Although a PPD test was positive in the past, it is now negative. His bone marrow biopsy specimen is shown. 1. What is your diagnosis? 2. What viral genome is present in these cells? 3. What is the stage of this disease? 4. What immunologic phenomenon explains the negative PPD test? ERRNVPHGLFRVRUJ Answers: Side A 1. In the subcarinal region between the right and left main bronchi is a mass ( ▸) of enlarged lymph nodes. The chest pain symptoms are a curious paraneoplastic finding of Hodgkin lymphoma (HL). The pathology description suggests HL, nodular sclerosis type . 2. If this is the only region involved, then the patient has stage I disease. If another lymph node region or contiguous spread to adjacent tissue is involved, then the patient has stage II disease. 3. The prognosis of patients with HL, nodular sclerosis type, is excellent. ERRNVPHGLFRVRUJ 13.10 Side A (PBD9: 612; BP9: 44) ERRNVPHGLFRVRUJ Questions A 41-year-old man with fatigue and fevers develops cutaneous petechiae and epistaxis. His hemoglobin level is 6.7 g/dL (nl 13.8 to 17.2 g/dL), his platelet count is 9800/mm (nl 130,000 to 400,000/mm ), and his WBC count is 168,400/mm (nl 3800 to 10,800/mm ). His peripheral smear is shown. 3 3 3 3 1. What form of leukemia does he have? 2. Explain his clinical findings. 3. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side B 1. The large immature myeloblasts with nucleoli and many cytoplasmic red granules ( ◂) are typical for promyelocytic leukemia , which is the M3 variant of acute myelogenous leukemia. The release of granules' procoagulant tissue factor leads to disseminated intravascular coagulation, with schistocytes ( ▾) and elevated D-dimer. 2. A t(15:17) translocation produces a fusion protein that stops differentiation at the promyelocyte stage. 3. All-transretinoic acid (ATRA) induces a transient remission in most cases by overcoming the differentiation blockade. ERRNVPHGLFRVRUJ 13.10 Side B (PBD9: 613; BP9: 445) ERRNVPHGLFRVRUJ Questions A 37-year-old woman has fatigue, purpura, and prolonged menstrual periods. Her hemoglobin level is 7 g/dL (nl 12 to 15.6 g/dL), her platelet count is 11,100/mm (nl 130,000 to 400,000/mm ), and her WBC count is 77,910/mm (nl 3800 to 10,800/mm ). Her prothrombin time, partial thromboplastin time, and D-dimer all are markedly increased. Her peripheral blood smear is shown. 3 3 3 1. What type of leukemia does she have? 2. What cytogenetic alteration is present? 3. What therapy is effective for the induction of remission? ERRNVPHGLFRVRUJ 3 Answers: Side A 1. The WBCs have enlarged nuclei, multiple nucleoli, and elongated condensations of abnormal azurophilic granules known as Auer rods ( ◂), which are consistent with the M2 form of acute myelogenous leukemia (AML). 2. The replacement of this patient's marrow with immature myeloid forms leads to pancytopenia; anemia explains the fatigue, and thrombocytopenia accounts for the bleeding problems. The abnormal WBCs do not function properly for the fighting of infections. 3. Although remission may be achieved, relapses are common, and few patients with AML are cured. ERRNVPHGLFRVRUJ 13.11 Side A (PBD9: 620; BP9: 448) ERRNVPHGLFRVRUJ Questions A 40-year-old woman who has had worsening fatigue for 1 year now presents with pneumonia. She has cutaneous petechiae and splenomegaly. Her hemoglobin level is 6 g/dL (nl 12 to 15.6 g/dL), her platelet count is 15,000/mm (nl 130,000 to 400,000/mm ), and her WBC count is 1000/mm (nl 3800 to 10,800/mm ). Her peripheral blood smear is shown. 3 3 3 1. What abnormal RBC form is present? 2. Why is her spleen enlarged? 3. What is the pathophysiology of this disorder? ERRNVPHGLFRVRUJ 3 Answers: Side B 1. This is secondary myelofibrosis ( ♦) resulting from neoplastic megakaryocytes arising in the context of the patient's CML. 2. Leukoerythroblastosis is the presence of immature RBC and WBC forms in the peripheral blood; it occurs with marrow-ablative processes, such as fibrosis or tumor. 3. Although myelofibrosis leads to extramedullary hematopoiesis , it tends to be ineffective, with high cell turnover that results in increased purines that get metabolized into uric acid. ERRNVPHGLFRVRUJ 13.11 Side B (PBD9: 620; BP9: 448) ERRNVPHGLFRVRUJ Questions A 60-year-old man who previously underwent chemotherapy for chronic myelogenous leukemia (CML) now has pancytopenia, splenomegaly, and uric acid renal calculi. His blood smear shows leukoerythroblastosis. His bone marrow biopsy specimen is shown. 1. What is the diagnosis? 2. What is leukoerythroblastosis? 3. Explain his uric acid calculi. ERRNVPHGLFRVRUJ Answers: Side A 1. Teardrop-shaped RBCs (dacryocytes) ( ▾) are seen in myelofibrosis , which in this case represents a primary chronic myeloproliferative disorder. 2. When the marrow space is filled with tumor or fibrosis, hematopoietic stem cells go elsewhere ( extramedullary hematopoiesis )—particularly the spleen—and cause prominent splenomegaly. 3. Neoplastic megakaryocytes release fibrosing cytokines, such as platelet-derived growth factor and transforming growth factor-β, which induce non-neoplastic fibroblasts in the marrow. In 5% to 20% of cases, transformation into acute myelogenous leukemia occurs. ERRNVPHGLFRVRUJ 13.12 Side A (PBD9: 617; BP9: 446) ERRNVPHGLFRVRUJ Questions A 45-year-old man with an 8-month history of fatigue and weight loss has marked splenomegaly. His hemoglobin level is 9 g/dL (nl 13.8 to 17.2 g/dL), his platelet count is 550,000/mm (nl 130,000 to 400,000/mm ), and his WBC count is 250,000/mm (nl 3800 to 10,800/mm ). His peripheral blood smear is shown. 3 3 3 1. What form of leukemia does he likely have? 2. What cytogenetic alteration is typically present? 3. What therapy is useful for treatment? ERRNVPHGLFRVRUJ 3 Answers: Side B 1. This patient has a chronic myeloproliferative disorder, most likely polycythemia vera . Treatment typically involves long-term phlebotomy, with a median survival of 10 years. 2. The neoplastic pleuripotent stem cells infiltrate many organs, particularly the spleen, which results in splenomegaly ( ■). 3. The markedly elevated peripheral counts can lead to abnormal blood flow; with platelet dysfunction, there is a significant risk of either thrombotic or hemorrhagic complications. Polycythemia vera tends to evolve to a burnt-out phase with myelofibrosis , but it can also proceed to acute myelogenous leukemia . ERRNVPHGLFRVRUJ 13.12 Side B (PBD9: 618; BP9: 447) ERRNVPHGLFRVRUJ Questions A 50-year-old woman has purpura, headaches, and abdominal fullness. Her hemoglobin level is 20 g/dL (nl 12 to 15.6 g/dL), her platelet count is 800,000/mm (nl 130,000 to 400,000/mm ), and her WBC count is 31,000/mm (nl 3800 to 10,800/mm ). Her abdominal CT scan is shown. 3 3 3 1. What is the diagnosis? 2. Explain the CT finding. 3. What complications may occur? ERRNVPHGLFRVRUJ 3 Answers: Side A 1. This patient has chronic myelogenous leukemia (CML) , which is one form of chronic myeloproliferative disorder. The WBC count is markedly elevated but with few blasts, and there are many immature myeloid cells ( ◂), basophils, and eosinophils ( ▾). 2. More than 90% of CML has the distinctive t(9;22) “Philadelphia chromosome” translocation . This forms a BCR-ABL fusion gene that results in a constitutively active tyrosine kinase that inhibits apoptosis and drives stem cell proliferation. 3. Imatinib (a selective tyrosine kinase inhibitor) induces remission in more than 90% of patients. The tumor cells frequently develop kinase mutations that no longer bind the drug. ERRNVPHGLFRVRUJ 14 ERRNVPHGLFRVRUJ Red Blood Cell and Bleeding Disorders ERRNVPHGLFRVRUJ 14.1 Side A (PBD9: 643; BP9: 409) ERRNVPHGLFRVRUJ Questions A 33-year-old woman with a 4-month history of worsening fatigue has a hemoglobin level of 7 g/dL (nl 12 to 15.6 g/dL) and a hematocrit level of 22% (nl 35% to 46%); her MCV is 98 fL (nl 78 to 102 fL), and her WBC and platelet counts are normal. Her serum haptoglobin level is 0.3 mg/dL (nl 43 to 212 mg/dL), and her antinuclear antibody (ANA) test is positive. Her peripheral blood smear is shown. 1. What is the diagnosis? 2. What are the direct and indirect Coombs tests? 3. What does the positive ANA result mean? ERRNVPHGLFRVRUJ Answers: Side B 1. β-Thalassemia minor results from deficient β-chain synthesis caused by gene point mutations and unimpaired α-chain production, with ineffective erythropoiesis and hypochromic microcytic RBCs. 2. Hemoglobin A and fetal hemoglobin increase in the absence of an adequate number of β chains to complex with the α chains. 2 3. No. Ineffective erythropoiesis leads to increased iron absorption and increased iron stores, which are reflected by the markedly increased serum ferritin level. ERRNVPHGLFRVRUJ 14.1 Side B (PBD9: 639; BP9: 414) ERRNVPHGLFRVRUJ Questions A 27-year-old man has had fatigue with exertion for years. His hemoglobin level is 9 g/dL (nl 13.8 to 17.2 g/dL), his hematocrit level is 26% (nl 41% to 50%), and his MCV is 68 fL (nl 78 to 102 fL); his WBC and platelet counts are normal. His serum ferritin level is 720 ng/mL (nl 18 to 350 ng/mL). His hemoglobin electrophoresis is shown; the hemoglobin A (α δ ) value is about 5% of the total hemoglobin (nl ≤2.5%), and the hemoglobin F value is also increased. A 2 2 2 1. What disease explains this presentation? 2. Explain the hemoglobin electrophoretic pattern. 3. Is this patient iron deficient? ERRNVPHGLFRVRUJ Answers: Side A 1. Nucleated RBCs ( ▸), polychromasia ( ◂), and microspherocytes ( ▾) are features of hemolytic anemia that are consistent with the markedly low haptoglobin level. Antibody bound to RBCs can lead to intravascular hemolysis as a result of complement-mediated rupture; splenic macrophages in the cords of Billroth also take “bites” out of antibodycoated RBCs, thus reducing their size. 2. The direct Coombs test detects antibody bound to RBCs; the indirect Coombs test detects anti-RBC antibody in a patient's serum. 3. A positive ANA test suggests an underlying autoimmune disease, such as systemic lupus erythematosus . ERRNVPHGLFRVRUJ 14.2 Side A (PBD9: 635; BP9: 411) ERRNVPHGLFRVRUJ Questions After developing mild dehydration after a diarrheal illness, a 9-year-old Bengalese girl develops sudden and severe extremity pain. She has a moderately enlarged spleen. Her hemoglobin level is 6.6 g/dL (nl 12 to 15.6 g/dL). Her peripheral blood smear is shown. 1. What is the diagnosis? What would hemoglobin electrophoresis show? 2. Why did she develop extremity pain? 3. What biliary tract complication can occur? ERRNVPHGLFRVRUJ Answers: Side B 1. There is microcytosis (many RBCs are smaller [ ▾] than the lymphocyte nucleus) and spherocytosis, including a loss of RBC central pallor ( ▸). Mild hemolytic anemia leads to compensatory reticulocytosis ( ◂). 2. Hereditary spherocytosis results from RBC membrane or cytoskeletal protein defects (e.g., ankyrin and spectrin mutations). 3. Autosomal dominant 4. Parvovirus infection could lead to temporary erythropoietic shutdown. ERRNVPHGLFRVRUJ 14.2 Side B (PBD9: 632; BP9: 410) ERRNVPHGLFRVRUJ Questions A 30-year-old man from Stockholm had neonatal jaundice, and he has had a lifelong history of fatigue. His spleen is enlarged. His hemoglobin level is 11 g/dL (nl 13.8 to 17.2 g/dL), his hematocrit level is 31% (nl 41% to 50%), and his MCV is 74 fL (nl 78 to 102 fL). His peripheral blood smear is shown. 1. What hemoglobinopathy is likely present? 2. What gene mutations could this patient have? 3. What is the inheritance pattern? 4. What infection could precipitate an aplastic crisis? ERRNVPHGLFRVRUJ Answers: Side A 1. Sickled RBCs ( ▸) with sickle cell anemia contain more than 90% hemoglobin S (α β ), some hemoglobin F (α γ ) and hemoglobin A (α δ ), but no hemoglobin A (α β ). 2 s A 2 2 A 2 2 2 A 2 1 2 A 2 2. Sickle cell crises can occur with reduced oxygen tension, infection, dehydration, or temperature change, but often no precipitating event can be found. Vaso-occlusive crises result when “sticky” sickled cells clog capillaries and cause tissue ischemia. 3. Chronic hemolysis leads to pigmented biliary stones. ERRNVPHGLFRVRUJ 14.3 Side A (PBD9: 638; BP9: 413) ERRNVPHGLFRVRUJ Questions A 13-year-old boy with sickle cell anemia and a lifelong history of sickle crises develops a high fever with hypotension. A positive blood culture grows the organisms that are shown here with Gram staining. 1. What are these organisms? 2. Why did the patient become septic? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has sickle cell anemia . The hemoglobin electrophoresis shows a large hemoglobin S peak, with smaller hemoglobin A and hemoglobin F fractions. 2 2. A single nucleotide mutation results in a valine-for-glutamic acid substitution at the sixth position in the hemoglobin β chain. When an individual is homozygous for this mutation, the resulting hemoglobin tetramers are more hydrophobic when they are deoxygenated, which results in aggregation and polymerization into long needle-like fibers that distort (“sickle”) the RBC. 3. Sickling makes the affected RBCs prone to plugging small capillaries, which leads to tissue hypoxia and the painful crises. Chest, abdominal, and back pain are common, and there is also risk for cerebrovascular accident (“stroke”) involving the brain. ERRNVPHGLFRVRUJ 14.3 Side B (PBD9: 635; BP9: 411) ERRNVPHGLFRVRUJ Questions A 24-year-old African-American man has a lifelong history of fatigue. His abdominal CT scan shows no apparent spleen. His hemoglobin level is 8 g/dL (nl 13.8 to 17.2 g/dL), his hematocrit level is 22.4% (nl 41% to 50%), and his MCV is 72 fL (nl 78 to 102 fL). A urinalysis shows hematuria. His hemoglobin electrophoresis is shown. 1. What is the diagnosis? 2. Explain the pathophysiology of this disease. 3. Why is pain so common? ERRNVPHGLFRVRUJ Answers: Side A 1. The Gram stain shows short, slightly curved gram-negative rods that are consistent with Haemophilus influenzae . Sepsis with H. influenzae and sepsis with Streptococcus pneumoniae are the most common causes of death in children with sickle cell disease. For unclear reasons, patients with sickle cell disease are also prone to Salmonella infections, typically either osteomyelitis or cholecystitis. 2. By late childhood, multiple autoinfarctions of the spleen have led to markedly reduced spleen size ( autosplenectomy ) so that the splenic immune function, which is particularly useful for encapsulated bacteria , is diminished. ERRNVPHGLFRVRUJ 14.4 Side A (PBD9: 649; BP9: 420) ERRNVPHGLFRVRUJ Questions A 54-year-old woman with an 8-month history of fatigue and exercise intolerance develops a painful, inflamed tongue and difficulty swallowing. Her hemoglobin level is 8.2 g/dL (nl 12 to 15.6 g/dL), her hematocrit level is 23.8% (nl 35% to 46%), and her MCV is 73 fL (nl 78 to 102 fL). Her peripheral blood smear is shown. 1. What nutritional deficiency does she likely have? 2. What other laboratory test findings do you expect? 3. Why does she have difficulty swallowing? ERRNVPHGLFRVRUJ Answers: Side B 1. Anemia of chronic disease has a low serum iron level and abundant stored iron, typically in phagocytes. Note the ringed sideroblast ( ▾); bone marrow macrophages should also be substantially iron replete. 2. The serum ferritin level reflects intracellular stores of iron, which are elevated. Free iron is ineffectively released from these intracellular stores. 3. Chronic inflammatory states lead to increased liver synthesis of hepcidin , which reduces the expression of ferroportin necessary for the release of intracellular iron stores. ERRNVPHGLFRVRUJ 14.4 Side B (PBD9: 652; BP9: 421) ERRNVPHGLFRVRUJ Questions A 56-year-old woman with a long history of rheumatoid arthritis has a chronic, lowgrade, microcytic, hypochromic anemia. Her serum iron and transferrin levels are low, but her serum ferritin level is elevated. A bone marrow biopsy specimen stained with Prussian blue for iron is shown. 1. What is the likely diagnosis? 2. Why is this patient's serum ferritin level high but her serum iron level low? 3. What is the mechanism for the anemia? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has iron deficiency anemia . Note the hypochromic (large central pallor) microcytic RBCs ( ▾). In an adult with iron deficiency, one should always suspect blood loss. 2. This patient's serum iron and serum ferritin levels should be low: her total iron binding capacity is increased, mainly because her transferrin saturation (normal ≥33%) is also low. 3. Glossitis, esophageal webs (which can impede swallowing), and microcytic hypochromic anemia constitute the triad of Plummer-Vinson syndrome . ERRNVPHGLFRVRUJ 14.5 Side A (PBD9: 662; BP9: 455) ERRNVPHGLFRVRUJ Questions A 17-year-old girl has had heavy menstrual periods since menarche; she also has gingival bleeding and cutaneous purpura with minimal trauma. She has abnormal platelet aggregation in the presence of ristocetin (her curve is shown in red as compared with the black control), although her platelets aggregate normally to ADP, collagen, and epinephrine. 1. What is your diagnosis? 2. What is the mechanism for her abnormal bleeding? 3. What is the inheritance pattern? 4. Name a (rare) disorder with the same assay but that involves abnormally large platelets. ERRNVPHGLFRVRUJ Answers: Side B 1. This patient had thrombotic thrombocytopenic purpura (TTP) . The arteriole contains a hyaline thrombus that is composed of aggregated platelets. 2. A deficiency of metalloproteinase ADAMTS13 prevents the processing of large von Willebrand factor multimers into smaller subunits, which leads to abnormal platelet aggregation and thromboses. 3. Hemolytic-uremic syndrome caused by Shiga-like toxin that damages endothelium is classically associated with infection caused by Escherichia coli strain O157:H7. ERRNVPHGLFRVRUJ 14.5 Side B (PBD9: 659; BP9: 453) ERRNVPHGLFRVRUJ Questions A 44-year-old woman develops fever, headaches, and confusion. She is anemic and thrombocytopenic, with a serum creatinine level of 5 mg/dL (nl ≤1.2 mg/dL) elevated D-dimer and schistocytes on a peripheral blood smear. She develops ventricular fibrillation and dies. A myocardial arteriole from her autopsy is shown. 1. What is your diagnosis? 2. What is the mechanism for this disorder? 3. What related disorder can accompany gastroenteritis? ERRNVPHGLFRVRUJ Answers: Side A 1. Ristocetin causes von Willebrand factor (vWF) to bind to platelet glycoprotein Ib receptors, and it induces platelet aggregation. A defective ristocetin aggregation assay most commonly indicates von Willebrand disease (vWD) . vWD has variable severity, depending on the mutation present, and it affects 1% of the population. 2. vWD is caused by decreased or mutated vWF. Bleeding occurs because there is abnormal platelet adhesion via the glycoprotein Ib receptors, and a primary hemostatic plug fails to form. Because factor VIII also binds to vWF, defective synthesis—if severe—can also prolong the partial thromboplastin time (PTT). 3. vWD is most commonly an autosomal-dominant disorder. 4. Autosomal-recessive Bernard-Soulier syndrome results from defective or deficient glycoprotein Ib receptors. ERRNVPHGLFRVRUJ 14.6 Side A (PBD9: 653; BP9: 424) ERRNVPHGLFRVRUJ Questions A 29-year-old woman with a 3-month history of easy bruising and fatigue develops pneumonia with septicemia. Her work-up involves an iliac crest bone marrow biopsy; the specimen is shown. 1. What appearance should her marrow have? 2. What is your diagnosis? 3. Explain her symptoms. ERRNVPHGLFRVRUJ Answers: Side B 1. Pancytopenia is caused by a marked reduction in erythroid, myeloid, and megakaryocytic cell lines. Aplastic anemia can result from a stem cell defect in the marrow, from a toxin, or from immunologically mediated marrow suppression (e.g., after infection). 2. Chemotherapeutic agents (e.g., vincristine, mercaptopurine) can cause this condition, and it may also result from idiosyncratic responses to small doses of antibiotics or other drugs (e.g., streptomycin, trimethoprim-sulfamethoxazole, chlorpromazine). 3. Infections that can cause this condition include viral hepatitis (i.e., non-A, non-B, non-C, and non-G), Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, and parvovirus. ERRNVPHGLFRVRUJ 14.6 Side B (PBD9: 653; BP9: 424) ERRNVPHGLFRVRUJ Questions A 48-year-old man with malaise, fever, and chills is found to have tachycardia and occult blood in his stools. He is also profoundly anemic, neutropenic, and thrombocytopenic, although his absolute lymphocyte count is roughly normal. A bone marrow biopsy specimen shows only fat and lymphocyte aggregates. A diagram of the possible pathogenic pathways is shown. 1. Aside from an acquired intrinsic mutation of the stem cell, what could be the pathogenesis of these findings? 2. What drugs can cause this? 3. What infections might cause this? ERRNVPHGLFRVRUJ Answers: Side A 1. At this age, the bone marrow should contain at least 50% hematopoietic cells; in this case, it is composed mainly of adipocytes. However, the bone is normal. 2. This patient has aplastic anemia . Despite the name of this condition, all major hematopoietic cell lines are reduced. 3. Thrombocytopenia results in easy bruising; reduced myelopoiesis leads to neutropenia with a risk for infection, and reduced erythropoiesis causes anemia with fatigue. ERRNVPHGLFRVRUJ 14.7 Side A (PBD9: 664; BP9: 452) ERRNVPHGLFRVRUJ Questions A 30-year-old woman presents with a 2-day history of dysuria, fever, and flank pain; she is hypotensive and tachycardic. A blood culture grows the organisms shown with Gram staining. 1. What is suggested by the history and the Gram stain? 2. What is the mechanism of this patient's fever and tachycardia? ERRNVPHGLFRVRUJ Answers: Side B 1. The lungs show microvascular thrombosis ( ■). This patient has disseminated intravascular coagulation (DIC) as a result of gram-negative sepsis. In patients with DIC, small fibrin thrombi can form in the microcirculation; this leads to tissue ischemia and RBC fragmentation ( schistocytes ). Components of gram-positive bacteria and fungi can elicit similar effects. 2. Lipopolysaccharide-mediated cytokine production induces monocytes and endothelial cells to release tissue factor , which initiates the widespread activation of the coagulation cascade. This consumption coagulopathy leads to these findings. ERRNVPHGLFRVRUJ 14.7 Side B (PBD9: 664; BP9: 452) ERRNVPHGLFRVRUJ Questions A 79-year-old man with Klebsiella pneumoniae sepsis has a hematocrit level of 35.5% (nl 41% to 50%), a platelet count of 87,600/mm (nl 130,000 to 400,000/mm ), and a WBC count of 15,130/mm (nl 3800 to 10,800/mm ). His prothrombin time is 23 seconds (nl 10 to 12.5 seconds), his partial thromboplastin time is 57 seconds (nl 20 to 36 seconds), and D-dimer value is 8 µg/mL (nl ≤0.25 µg/mL). His peripheral blood smear shows schistocytes. His lung is shown. 3 3 3 3 1. What is the diagnosis? 2. What is suggested by the laboratory data? ERRNVPHGLFRVRUJ Answers: Side A 1. The large gram-negative bacilli are typical of Enterobacteriaceae such as Escherichia coli with urinary tract infection. The fever and flank pain with hypotension and positive blood culture suggest acute pyelonephritis with septicemia. 2. Gram-negative bacterial cell walls contain lipopolysaccharide with a lipid A moiety that interacts with CD14 and Toll-like receptor 4 on leukocytes and macrophages to release tumor necrosis factor . ERRNVPHGLFRVRUJ 14.8 Side A (PBD9: 643; BP9: 417) ERRNVPHGLFRVRUJ Questions A week after intravenous cephalosporin treatment for pneumonia, a 93-year-old man has a hemoglobin level of 7.3 g/dL (nl 13.8 to 17.2 g/dL), a hematocrit level of 22.4% (nl 41% to 50%), normal RBC indices, and normal platelet and WBC counts. His Coombs test is positive at 37° C. His peripheral blood smear with methylene blue supravital stain is shown. 1. What are the RBCs with irregular bluish strands? 2. What does a positive Coombs test mean? 3. What caused this problem? ERRNVPHGLFRVRUJ Answers: Side B 1. The Heinz bodies ( ▾) are denatured globin chains from oxidant injury caused by reduced glucose-6-phosphate dehydrogenase (G6PD) activity in the RBCs. G6PD deficiency is an X-linked recessive disorder. 2. In the setting of G6PD deficiency, drugs with oxidant activity (e.g., nitrofurantoin, sulfa drugs, antimalarials, aspirin, phenacetin) can cause erythrocyte hemolysis. ERRNVPHGLFRVRUJ 14.8 Side B (PBD9: 634; BP9: 416) ERRNVPHGLFRVRUJ Questions A 24-year-old man takes a nitrofurantoin drug for a urinary tract infection. Three days later, he develops dark brown urine. His hemoglobin level is 8.6 g/dL (nl 13.8 to 17.2 g/dL), with normal platelet and WBC counts. His Coombs test is negative. His peripheral blood smear with Heinz body stain is abnormal, as shown. 1. What inherited enzyme deficiency does this patient have? 2. Why did he develop hemoglobinuria after drug therapy? ERRNVPHGLFRVRUJ Answers: Side A 1. These reticulocytes ( ◂) are immature forms of RBCs that can be prematurely released into the peripheral blood in certain settings. Reticulocytosis is a bone marrow response to anemia; it is prominent after blood loss in a healthy person and in those with hemolytic anemias. 2. A positive Coombs test is consistent with immunohemolytic anemia , and it indicates the presence of antibodies directed at the patient's own RBCs. These can be antibodies against either intrinsic RBC antigens or bound molecules ( haptens ). 3. This is a drug-induced warm antibody hemolytic anemia. Cephalosporins and penicillins can bind to RBC surface proteins and act as hapten targets to host antibodies. ERRNVPHGLFRVRUJ 15 ERRNVPHGLFRVRUJ The Lung ERRNVPHGLFRVRUJ 15.1 Side A (PBD9: 722; BP9: 511) ERRNVPHGLFRVRUJ Questions A 19-year-old man in a crowded hospital elevator develops a sudden feeling of unease that progresses to palpitations, trembling, dizziness, and numbness in his hands; he begins to hyperventilate. A similar episode 6 months ago resolved after a few minutes. His arterial blood gas values are as follows: pH 7.55 (nl 7.37 to 7.43), Pa 80 mm Hg (nl 90 mm Hg), Pa 25 mm Hg (nl 35 to 45 mm Hg), and HCO 21 mEq/L (nl 20 to 32 mEq/L). His chest radiograph is shown. o 2 co 2 3 1. What behavioral condition does he have? 2. What is the diagnosis based on the chest radiograph? 3. What may have caused this event? 4. Explain the blood gas findings. ERRNVPHGLFRVRUJ Answers: Side B 1. A chest tube (▾) has been placed to treat the pneumothorax. 2. Spontaneous pneumothorax in a young adult suggests the rupture of a bulla caused by distal acinar (paraseptal) emphysema. ERRNVPHGLFRVRUJ 15.1 Side B (PBD9: 722; BP9: 511) ERRNVPHGLFRVRUJ Questions A 17-year-old boy falls during a football game and suddenly becomes dyspneic. He has had two similar episodes during the past year. On examination, no breath sounds are heard on the right. The chest radiograph obtained after intervention is shown. 1. What was the intervention? 2. What form of emphysema could he have? ERRNVPHGLFRVRUJ Answers: Side A 1. A panic attack is a discrete period of intense fear or discomfort with multiple central nervous system, respiratory, cardiac, or gastrointestinal symptoms that peak after 10 minutes. The occurrence in the crowded, confined space suggests agoraphobia . 2. There is increased lucency on the right, with a shift of the mediastinum to the left (▸). This is consistent with tension pneumothorax . 3. Trauma is the most likely cause of the pneumothorax. Air trapping with long-standing emphysema or acute asthma can predispose an individual to pneumothorax. 4. This patient has uncompensated respiratory alkalosis from the hyperventilation and mild hypoxemia from the collapsed right lung. ERRNVPHGLFRVRUJ 15.2 Side A (PBD9: 702; BP9: 486) ERRNVPHGLFRVRUJ Questions An 83-year-old man with a 3-day history of productive cough and fever has crackles auscultated over the right upper lobe. His WBC count is 14,860/mm (nl 3800 to 10,800/mm ). His chest radiograph is shown. 3 3 1. Describe the radiographic findings. 2. What organisms are most likely in the setting of such a community-acquired infection? 3. What is the nature of this inflammatory process? ERRNVPHGLFRVRUJ Answers: Side B 1. The lower lobe is consolidated and tan (▾), with a lobar pneumonia . 2. Haemophilus influenzae is a common cause of community-acquired lobar pneumonia. 3. H. influenzae organisms produce pili and polyribose phosphate capsules as virulence factors that help them (1) adhere to respiratory epithelium and (2) avoid opsonization and phagocytosis. ERRNVPHGLFRVRUJ 15.2 Side B (PBD9: 702; BP9: 486) ERRNVPHGLFRVRUJ Questions A 40-year-old female smoker with a 4-day history of increasing dyspnea and fever has no breath sounds over her left lower lung field. A sputum Gram stain shows gramnegative coccobacilli; these organisms grow on chocolate and nutrient agars with X and V factors. The gross appearance of what her lung might look like is shown. 1. Why does the lung have this appearance? 2. What is the likely causal organism? 3. What are the characteristic virulence factors of this microorganism? ERRNVPHGLFRVRUJ Answers: Side A 1. Extensive, right upper lobe consolidation (▸) is seen, which is consistent with lobar pneumonia . 2. Streptococcus pneumoniae is the most common causal organism in this setting, followed by Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Legionella pneumophila, and the Enterobacteriaceae. 3. The consolidation represents acute inflammatory cells (neutrophils) exuding into and filling the alveoli, along with transudated fluid and proteins. Such an exudate in the lung can be reflected by viscous yellow-green sputum. ERRNVPHGLFRVRUJ 15.3 Side A (PBD9: 672; BP9: 461) ERRNVPHGLFRVRUJ Questions A 34-year-old man has a motor vehicle accident that results in blunt trauma injury to the chest, abdomen, and extremities. He is hypotensive, with a hematocrit level of 17% (nl 41% to 50%). Over the next week, his oxygen saturation deteriorates. He requires intubation and mechanical ventilation with increasing positive end-expiratory pressures and Fi . His chest CT scan is shown. o 2 1. What is this condition? 2. What is the pathophysiology? ERRNVPHGLFRVRUJ Answers: Side B 1. Diffuse alveolar damage results in a diffusion block that leads to hypoxia and CO retention, which causes pulmonary vasoconstriction and hypoperfusion. Hyaline membranes ( ▪) and thickened alveolar walls (♦) diminish compliance and require increased positive end-expiratory pressures. High levels of inspired oxygen are required to maintain arterial oxygen saturations; these high levels are themselves toxic, and they promote alveolar injury. The end result is a vicious cycle of ongoing injury and worsening ventilation and perfusion. 2 2. Infection can stimulate Toll-like receptors of the innate immune system that upregulate nuclear factor κβ expression, which results in locally increased proinflammatory cytokine production. ERRNVPHGLFRVRUJ 15.3 Side B (PBD9: 672; BP9: 461) ERRNVPHGLFRVRUJ Questions A 28-year-old woman in prolonged septic shock develops progressive pulmonary hypertension in the setting of systemic hypotension. The microscopic appearance of her lungs is shown. 1. What caused the pulmonary hypertension? 2. What role does sepsis play? ERRNVPHGLFRVRUJ Answers: Side A 1. This condition is clinically known as adult respiratory distress syndrome , diffuse alveolar damage (DAD) . It is the final common pathway for many acute lung injuries (e.g., “shock lung,” in this case, as a result of crush tissue injury and extensive thrombosis from tissue factor release). Although the initial chest radiograph is frequently unremarkable, accumulating alveolar fibrin-rich edema fluid eventually manifests as the diffuse, ground-glass infiltrates (▸) seen on this chest CT scan. 2. DAD results from injury to alveolar capillary endothelium and epithelial type I and type II cells; this leads to the exudation of plasma proteins with fluid filling the alveoli and coalescing to form characteristic hyaline membranes . ERRNVPHGLFRVRUJ 15.4 Side A (PBD9: 679; BP9: 468) ERRNVPHGLFRVRUJ Questions A 12-year-old girl with severe dyspnea has reduced breath sounds and expiratory wheezes. Her WBC count is 9220/mm (nl 3800 to 10,800/mm ), with 10% eosinophils. If a biopsy specimen of her bronchi were obtained, it would appear as shown. 3 1. What is your diagnosis? 2. What could trigger such an episode? 3. How is bronchoconstriction mediated? ERRNVPHGLFRVRUJ 3 Answers: Side B 1. A is a CD4+ T 2 lymphocyte producing interleukin-4 (IL-4); B is a B lymphocyte producing IgE. IgE attaches to Fc receptors (FcR) on mast cells (C). When bound IgE is cross-linked by allergen, mast cells release vasoactive substances (e.g., histamine), arachidonic acid mediators (prostaglandins and leukotrienes), and cytokines that recruit and activate eosinophils (D). H 2. Nonatopic forms of asthma occur with hyperreactive airways that are triggered by respiratory pathogens such as viruses, inhaled air pollutants, chemical exposure, or aspirin. 3. Charcot-Leyden crystals are whorls of sloughed epithelium, and Curschmann spirals are crystalloids of eosinophil membrane proteins. ERRNVPHGLFRVRUJ 15.4 Side B (PBD9: 679; BP9: 468) ERRNVPHGLFRVRUJ Questions A 14-year-old boy with acute wheezing and dyspnea coughs up copious mucus that contains Charcot-Leyden crystals and Curschmann spirals. A diagram of his inflammatory process is shown. 1. How do the cells labeled A, B, C, and D function in this reaction? 2. How can similar airway responses occur in the absence of this immune pathway? 3. What are Charcot-Leyden crystals and Curschmann spirals? ERRNVPHGLFRVRUJ Answers: Side A 1. Atopic asthma is a type I hypersensitivity response. Note an expanded edematous submucosa (▾) that has been infiltrated with inflammatory cells, mainly eosinophils (▴); the lumen is filled with mucus (◂). 2. Environmental allergens (e.g., animal dander, plant pollen, dust) could trigger this. 3. Histamine leads to vascular edema and bronchoconstriction. The lipoxygenase pathway produces leukotrienes, and the cyclooxygenase pathway produces prostaglandin D , thereby causing bronchoconstriction. Vagal stimulation also promotes smooth muscle constriction. 2 ERRNVPHGLFRVRUJ 15.5 Side A (PBD9: 683; BP9: 470) ERRNVPHGLFRVRUJ Questions A 20-year-old man has a lifelong history of sinus and respiratory tract infections. A routine chest radiograph shows a right-sided heart and aorta. The gross appearance of what his lung could look like is shown. 1. What obstructive disease does he have? 2. What syndrome does he have? 3. What epithelial structure does not function? ERRNVPHGLFRVRUJ Answers: Side B 1. Peripheral bronchial dilation and extensive consolidation are consistent with bronchiectasis complicated by pneumonia . 2. This patient has cystic fibrosis (CF) as a result of a mutation in the CF transmembrane conductance regulator gene ( CFTR, which is a chloride transporter). 3. Abnormal chloride ion transport results in pancreatic exocrine duct malfunction with pancreatic exocrine atrophy and a loss of enzyme output. Viscous pulmonary secretions are not readily cleared, and they support growth of select bacteria. Sweat gland salt production tends to be high. Men with CF often have agenesis of the vas deferens, which causes infertility. ERRNVPHGLFRVRUJ 15.5 Side B (PBD9: 683; BP9: 470) ERRNVPHGLFRVRUJ Questions A 25-year-old man has a lifelong history of severe recurrent pulmonary infections, most often Pseudomonas aeruginosa and Burkholderia cepacia. He also has malabsorption and steatorrhea. He dies of a severe pneumonia; his lung at autopsy is shown. 1. Describe the features shown. 2. What is his underlying disease? 3. Explain the extrapulmonary findings in this disease. ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has bronchiectasis . Note the dilation of the bronchi (▾) in the periphery, with areas of white consolidation (◂) that indicate superimposed infection as well as interlobar adhesions (▴) that result from postinflammatory scarring. 2. Situs inversus with bronchiectasis and sinusitis are seen with this patient's Kartagener syndrome ; this is an autosomal-recessive condition. 3. The cilia on the patient's respiratory epithelium have an absence or shortening of microtubular dynein arms. Ciliary immotility predisposes an affected individual to infection. ERRNVPHGLFRVRUJ 15.6 Side A (PBD9: 684; BP9: 472) ERRNVPHGLFRVRUJ Questions A 68-year-old man with no occupational or environmental exposures has a 3-year history of worsening dyspnea. His chest CT scan is shown. 1. What does the CT scan show? 2. What drives this process? 3. Explain his pulmonary function studies: Predicted Observed FVC (L) 5 3 FEV 1 3.75 2.7 FEV 1 /FVC (%) 75 90 MVV (L/min) 100 80 TLC 6 4 DL co 20 9 ERRNVPHGLFRVRUJ ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has diffuse pulmonary fibrosis . Grossly, the most affected areas are in lower lung fields, in subpleural locations, and around the lung lobules. The end stage is honeycomb (▴) fibrosis, with distal dilated residual airways. 2. Pruning of the pulmonary vascular bed leads to pulmonary hypertension and cor pulmonale . ERRNVPHGLFRVRUJ 15.6 Side B (PBD9: 684; BP9: 472) ERRNVPHGLFRVRUJ Questions A 50-year-old woman with a 10-year history of scleroderma notes worsening dyspnea. Her pulmonary compliance is reduced. The gross appearance of her lungs is shown. 1. What is your diagnosis? 2. What is the effect on her heart? ERRNVPHGLFRVRUJ Answers: Side A 1. Extensive bright interstitial fibrosis (◂) is present, with honeycomb change from distal airway dilation. Because there is no apparent cause, this is likely idiopathic pulmonary fibrosis (IPF) . 2. IPF may result from repeated lung injury caused by an unknown agent, with healing by fibrogenesis driven by the Wnt/β-catenin signaling pathway and mediated through transforming growth factor-β. 3. This restrictive lung disease has reduced residual volume and diminished total lung capacity. The FVC is reduced, and the FEV is reduced even more, so the FVC/FEV ratio is decreased. The fibrosis has impaired diffusing capacity (DL ). 1 1 co ERRNVPHGLFRVRUJ 15.7 Side A (PBD9: 690; BP9: 477) ERRNVPHGLFRVRUJ Questions A 52-year-old man with a 10-year history of progressive dyspnea has a chest radiograph that shows interstitial fibrosis and calcified pleural plaques. He is an independent contractor who remodels old houses. Images from his sputum are shown. 1. What are these objects? 2. For which lung diseases is he at risk? ERRNVPHGLFRVRUJ Answers: Side B 1. The bright, needle-shaped objects are silica crystals that are causing silicosis , with progressive pulmonary fibrosis and silicotic nodules. 2. Macrophages ingest the crystals and release cytokines such as tumor necrosis factor and interleukin-1, which drive inflammation and fibrosis. Because the crystals cannot be destroyed, the process continues indefinitely. 3. With extensive exposure, progressive massive fibrosis and restrictive lung disease can occur. There is a slight increased risk for lung cancer. ERRNVPHGLFRVRUJ 15.7 Side B (PBD9: 690; BP9: 476) ERRNVPHGLFRVRUJ Questions A 50-year-old man has worked his own mining claim for 30 years, boring tunnels into quartz rock. He has had increasing dyspnea for the last decade. The microscopic appearance of his lung biopsy specimen is shown under polarized light. 1. What crystalline material is present? 2. What is the pathogenesis of his pulmonary disease? 3. What lung diseases is he at risk for? ERRNVPHGLFRVRUJ Answers: Side A 1. The long, thin crystalline objects encrusted with iron and calcium in shish-kebab fashion are asbestos fibers (▾). The encrustation (▴) of these ferruginous bodies (through the action of macrophages) is best seen with Prussian blue iron stain. 2. Asbestosis leads to restrictive interstitial lung disease in proportion to the amount of exposure. Fibrous pleural plaques (particularly diaphragmatic) are common. This patient is at greatest risk for bronchogenic carcinoma , even more so if he is a smoker. There is a risk for mesothelioma that is not connected to the amount of exposure or smoking. ERRNVPHGLFRVRUJ 15.8 Side A (PBD9: 693; BP9: 478) ERRNVPHGLFRVRUJ Questions A 44-year-old woman has a 1-year history of increasing dyspnea and night sweats. A chest radiograph shows hilar lymphadenopathy. Her CT scan is shown. 1. Describe this CT scan. 2. What pattern of inflammation is likely to be present? ERRNVPHGLFRVRUJ Answers: Side B 1. Sarcoidosis typically produces noncaseating granulomas (▪). It is a diagnosis of exclusion that occurs after excluding infectious granulomas through special histologic stains, cultures, or serologies. 2. The lack of response to a control Candida antigen challenge is indicative of defective T-cell immunity or anergy . Dysregulated CD4 T-lymphocyte activity can also stimulate increased B-cell immunoglobulin production. 3. Eye involvement in the form of iritis, iridocyclitis, or lacrimal gland inflammation occurs in 20% to 50% of patients with sarcoidosis; corneal opacities, glaucoma, and complete visual loss can result. ERRNVPHGLFRVRUJ 15.8 Side B (PBD9: 693; BP9: 478) ERRNVPHGLFRVRUJ Questions A 39-year-old woman has a 5-year history of worsening dyspnea with visual impairment, fatigue, and a 10-kg weight loss. She has no reaction to a skin test with Candida antigen, although her serum gamma globulins are elevated. Cultures from a transbronchial biopsy show no growth. A biopsy specimen of an enlarged hilar lymph node is shown. 1. What is the diagnosis? 2. What immune deficit might she have? 3. Why does she have visual impairment? ERRNVPHGLFRVRUJ Answers: Side A 1. The CT scan shows a reticulonodular pattern of interstitial lung disease that is typical for granulomatous disease . 2. Granulomatous inflammation is composed of nodules of activated (epithelioid) macrophages; there may or may not be fusion of these activated macrophages to form giant cells . Macrophage activation occurs through the associated CD4+ helper T cells, which produce interferon-γ and other T 1 cytokines. H ERRNVPHGLFRVRUJ 15.9 Side A (PBD9: 697; BP9: 482) ERRNVPHGLFRVRUJ Questions A 20-year-old woman has a 6-year history of intermittent pleuritic chest pain and dyspnea. Examination reveals tachycardia, a right ventricular gallop, a palpable “lift” over the right heart, and a loud pulmonic valve closure sound. Her chest CT scan is shown. 1. What is shown in this CT scan? 2. What would explain this patient's multiple episodes of dyspnea and chest pain? ERRNVPHGLFRVRUJ Answers: Side B 1. There are large pulmonary embolus (PE) laminations (lines of Zahn) (▪), which indicate that this condition formed with flow over the surface. Statistically, the most likely site of origin in this case would be the deep leg veins. 2. The elevated D-dimer is consistent with PE. The blood gas values indicate hyperventilation without perfusion and anatomic dead space, so the Pa is low, and the pH is high; the Pa remains low even after the patient is given 100% O . co 2 o 2 2 ERRNVPHGLFRVRUJ 15.9 Side B (PBD9: 697; BP9: 482) ERRNVPHGLFRVRUJ Questions After a long period of immobilization, a 70-year-old man has sudden severe dyspnea on ambulation. His room air arterial blood gas values are as follows: pH 7.5 (nl 7.37 to 7.43), Pa 70 mm Hg (nl 90 mm Hg), Pa 30 mm Hg (nl 35 to 45 mm Hg), and normal HCO . Despite 100% F , his Pa increases to only 75 mm Hg. His D-dimer is 8 µg/mL (nl ≤0.25 µg/mL). The cause of these pulmonary findings is shown. o 2 3 co 2 io 2 o 2 1. What is this pathologic finding? 2. Explain the laboratory findings. ERRNVPHGLFRVRUJ Answers: Side A 1. Decreased attenuation (♦) within the main pulmonary artery is consistent with pulmonary embolism (PE). 2. Recurrent small PEs may explain her symptoms. PE at a young age suggests a heritable hypercoagulable state , such as factor V Leiden mutation; prothrombin gene mutation; antiphospholipid syndrome; deficiency in protein C, protein S, or antithrombin III; or hyperhomocysteinemia. A malignant neoplasm with a hypercoagulable state ( Trousseau syndrome or migratory thrombophlebitis ) is unlikely at this patient's age. ERRNVPHGLFRVRUJ 15.10 Side A (PBD9: 723; BP9: 512) ERRNVPHGLFRVRUJ Questions A 69-year-old former shipyard pipe fitter has a 1-year history of pleuritic chest pain. His chest CT scan is shown. 1. What is this neoplasm likely to be? 2. What caused it? ERRNVPHGLFRVRUJ Answers: Side B 1. The asbestos body (◂), which is also called the ferruginous body , has iron that coats the asbestos fiber. This encrustation occurs during frustrated phagocytic attempts by macrophages and leads to their activation with the production of fibrogenic cytokines and injurious oxygen free radicals. 2. Asbestosis carries with it an increased risk for bronchogenic carcinomas, gastrointestinal adenocarcinomas, and mesothelioma . 3. If enough asbestos fibers are inhaled, interstitial lung disease (as a result of diffuse macrophage activation) ensues, with restrictive physiology, reduced diffusing capacity, and hypoxia. Pleural plaques are also common, but they are not typically a source of significant dyspnea. ERRNVPHGLFRVRUJ 15.10 Side B (PBD9: 723; BP9: 512) ERRNVPHGLFRVRUJ Questions A 76-year-old man with progressive dyspnea and new hemoptysis has a right hilar lung mass seen on a chest CT scan. A biopsy specimen of the lesion shows non–small cell carcinoma; adjacent lung parenchyma also exhibits interstitial fibrosis and the additional microscopic findings shown (left, H&E; right, iron stain). 1. What was inhaled to produce these findings? 2. What is the relationship of these findings with the lung cancer? 3. Why might the patient be dyspneic? ERRNVPHGLFRVRUJ Answers: Side A 1. The chest CT scan shows nodular thickening (◂) caused by a mesothelioma arising in the right parietal pleura. This lesion will continue to grow and eventually compromise lung function. 2. Individuals who are exposed to short, brittle crocidolite asbestos fibers (e.g., pipe fitters; home contractors working on old structures; individuals who worked with brake linings during the 1940s, 1950s, and 1960s) are at risk for developing mesothelioma in the pleura, peritoneum, pericardium, and tunica vaginalis. ERRNVPHGLFRVRUJ 15.11 Side A (PBD9: 721; BP9: 511) ERRNVPHGLFRVRUJ Questions A 37-year-old woman involved in a high-speed motor vehicle accident in a tunnel under the Place de l'Alma has extreme dyspnea, and her breath sounds cannot be auscultated. Despite resuscitative measures, she dies. Her chest cavity is shown. 1. What term is applied to this appearance? 2. What nontraumatic conditions can produce this appearance? 3. What is the manner (mode) and likely mechanism of death? ERRNVPHGLFRVRUJ Answers: Side B 1. Bilateral pleural effusions (▪) have resulted in pulmonary atelectasis (♦). Note the increased tissue density of the collapsed lungs (atelectasis) and the contrasting dark air density of the bronchial tree. 2. Serous effusions with clear fluid often accompany congestive heart failure or possibly serositis with inflammation. ERRNVPHGLFRVRUJ 15.11 Side B (PBD9: 721; BP9: 511) ERRNVPHGLFRVRUJ Questions A 51-year-old man has increasing dyspnea for 2 months. His chest CT scan is shown. 1. What two diagnoses can you make from the CT scan? 2. What would clear yellow (serous) fluid on thoracentesis indicate? ERRNVPHGLFRVRUJ Answers: Side A 1. The chest cavity is filled with blood (▪). This condition is known as hemothorax , and it is most often the result of trauma to the chest, with rupture of the vasculature in the chest wall or lungs. Laceration of the aorta results in the fastest accumulation of blood. 2. Nontraumatic effusions typically collect more slowly. Bloody effusions can represent pleural involvement that results from metastatic disease or tuberculosis. Chylothorax (milky fluid with high lipid content) is rare and likely the result of lymphatic obstruction by a neoplasm. 3. The manner of death is accident ; the mechanism is potentially exsanguination and hypotensive shock , or it could be profound hypoxia if the pleural hemorrhage compromised lung expansion. ERRNVPHGLFRVRUJ 15.12 Side A (PBD9: 708; BP9: 492) ERRNVPHGLFRVRUJ Questions A 77-year-old woman progressed from a nonproductive cough 1 month ago to severe respiratory compromise with purulent yellow sputum, fever, and hypotension. A gramnegative bacillus is isolated from her blood culture. Her chest CT scan is shown. 1. What is present on the chest CT scan? 2. What was her most likely original problem, and what complications did she develop? ERRNVPHGLFRVRUJ Answers: Side B 1. Diffuse consolidation (▪), hemorrhage, and necrotizing pneumonia with abscess (♦) formation are present. 2. Virtually any organism can do this, especially in the context of defective immunity; Staphylococcus aureus, Klebsiella, and pneumococcal species are common, and so are typical oral flora anaerobes (e.g., Bacteroides). This probably began as pneumonia, but it rapidly progressed to destructive overgrowth and liquefactive necrosis. In the absence of intact innate immunity, antibiotics alone would be ineffective for the clearing of infection. 3. Aspergillus invades the vascular walls; it causes thrombosis and ischemic necrosis with cavitation. ERRNVPHGLFRVRUJ 15.12 Side B (PBD9: 708; BP9: 492) ERRNVPHGLFRVRUJ Questions A 24-year-old man undergoes myeloablative therapy for acute myelogenous leukemia, and this is followed by stem cell transplant. At the trough of his neutropenia, he develops fever as well as progressive and intractable dyspnea. Despite the use of broad-spectrum antibiotics, he dies. His lung at autopsy is shown. 1. Describe the lung findings. 2. What bacterial organisms can be implicated? 3. Why is Aspergillus particularly likely to cause abscess formation? ERRNVPHGLFRVRUJ Answers: Side A 1. The chest CT scan shows extensive bilateral infiltrates (♦) that are consistent with pneumonia . Liquefactive necrosis in several areas has resulted in an air-fluid level (▸) that indicates abscess formation. 2. This patient likely had a viral pneumonia such as influenza that became complicated by a bacterial pneumonia. Progression of the bacterial process led to abscess formation. ERRNVPHGLFRVRUJ 15.13 Side A (PBD9: 675; BP9: 463) ERRNVPHGLFRVRUJ Questions A 63-year-old man who has had worsening dyspnea for 5 years is using his accessory respiratory muscles. He has hyperresonance by percussion, and he also has expiratory wheezes. The gross appearance of his lungs would be as shown. 1. What is the diagnosis? 2. How does this happen? 3. Explain his pulmonary function studies: Predicted Observed FVC (L) 5 4 FEV 1 (L) 4 2 FEV 1 /FVC (%) 80 50 TLC (L) 6 7 DL co (mL/min/mm Hg) 20 8 ERRNVPHGLFRVRUJ ERRNVPHGLFRVRUJ Answers: Side B 1. It shows increased chest diameter, lucency of the upper lung fields, flattened diaphragms (▴), and a prominent right heart border (right ventricular hypertrophy). 2. This patient's findings are consistent with fully compensated respiratory acidosis , because his HCO value is increased. 3 ERRNVPHGLFRVRUJ 15.13 Side B (PBD9: 675; BP9: 463) ERRNVPHGLFRVRUJ Questions The arterial blood gas values of a 55-year-old male smoker on room air are as follows: pH 7.35 (nl 7.37 to 7.43), P 65 mm Hg (nl 90 mm Hg), P 60 mm Hg (nl 35 to 45 mm Hg), and HCO 32 mEq/L (nl 20 to 32 mEq/L). His chest radiograph is shown. o 2 co 2 3 1. What is shown in the chest radiograph? 2. What do the blood gas values indicate? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has centrilobular emphysema with a pronounced loss of respiratory bronchioles . 2. Most individuals with emphysema are cigarette smokers . Disease severity relates to the amount and duration of smoking (pack-years); it can also be attributed to increased protease activity (e.g., matrix metalloproteinases and particularly neutrophil elastase) with diminished antiprotease activity . Lung parenchymal destruction is irreversible. 3. TLC is increased because of increased residual volume . Emphysema yields reduced FEV along with FEV /FVC ratios of less than 70% . As emphysema worsens, diffusing capacity is lost. 1 1 ERRNVPHGLFRVRUJ 15.14 Side A (PBD9: 721; BP9: 505) ERRNVPHGLFRVRUJ Questions A 79-year-old woman has a 1-year history of worsening dyspnea and weight loss. Her chest radiograph is shown. 1. Describe what is shown in the chest radiograph. 2. What is the likely underlying cause of these problems? ERRNVPHGLFRVRUJ Answers: Side B 1. There are multiple light-tan masses (▪) that are consistent with metastases ; the lung shows no emphysema or significant anthracosis, thereby suggesting that she is a nonsmoker. 2. Malignant adenocarcinoma cells (forming glandlike structures or expressing mucin) are likely to be present. 3. The timing of the occurrence of the metastatic lesions after the resection of a breast mass is most suggestive of primary breast cancer . 4. Metastases to the pleura can cause impaired lymphatic drainage and increased capillary permeability from tumors that elaborate angiogenic factors. ERRNVPHGLFRVRUJ 15.14 Side B (PBD9: 721; BP9: 505) ERRNVPHGLFRVRUJ Questions A 55-year-old woman had a breast mass removed 1 year ago. She now has increasing dyspnea, and her chest radiograph shows pleural effusions and bilateral nodules. Her lungs would appear as shown in this image. 1. Describe these findings. 2. What would pleural fluid cytology show? 3. What was her breast lesion? 4. Explain the pleural effusions. ERRNVPHGLFRVRUJ Answers: Side A 1. There are multiple subtle bright mass lesions (▸) in all lung fields that are consistent with metastases . 2. A primary lung cancer typically occurs as a dominant mass, even if there is spread within the lungs. Multiple masses suggest hematogenous metastases from another primary site. Carcinomas that arise in the ovary, breast, kidney, or gastrointestinal tract are all possible, and so are melanoma and sarcoma. The lungs are the most common sites of the metastatic spread of many tumors. Metastases can occur as discrete masses or as subtler lymphangitic spread . ERRNVPHGLFRVRUJ 15.15 Side A (PBD9: 720; BP9: 505) ERRNVPHGLFRVRUJ Questions A 49-year-old man with a smoking history of 30 pack-years has had a persistent unproductive cough for 1 year. His CT scan is shown. 1. Describe the lesion. 2. What is the differential diagnosis? ERRNVPHGLFRVRUJ Answers: Side B 1. The small 2- to 4-µ yeasts within macrophages (▪) represent Histoplasma capsulatum , in this case presumably as a result of inhaling spores aerosolized from bat feces. 2. H. capsulatum organisms express heat shock protein 60 (HSP60), which binds to macrophage β -integrins and permits phagocytosis. The organisms survive, however, and they proliferate within the phagolysosomes of nonactivated macrophages, eventually rupturing the host cell. 2 3. Fungal and mycobacterial infections require activated macrophages for adequate containment and killing. Such activation is provided primarily by intact T cell–mediated immunity and specifically CD4 helper T 1 lymphocyte production of interferon-γ. H ERRNVPHGLFRVRUJ 15.15 Side B (PBD9: 709; BP9: 499) ERRNVPHGLFRVRUJ Questions A 46-year-old spelunker develops a persistent cough and fever. His chest radiograph shows nodular infiltrates and hilar lymphadenopathy. His bone marrow biopsy specimen is shown. 1. What organism is causing his disease? 2. How does the organism evade killing? 3. What problem with the immune system could lead to the dissemination of this infection? ERRNVPHGLFRVRUJ Answers: Side A 1. The peripheral, small, circumscribed lesion (◂) in the right mid lung with areas of brighter attenuation is a so-called coin lesion . 2. This could be a carcinoma , a granuloma (e.g., as a result of fungus or tuberculosis), or a hamartoma . The patient's history of smoking raises the concern for carcinoma. The lesion is at the limit of reach for either bronchoscopic biopsy or fine-needle aspiration biopsy. One could do a follow-up imaging study to determine if the size of the mass had changed. Neither an “old” quiescent granuloma nor a hamartoma would likely increase in size very rapidly. ERRNVPHGLFRVRUJ 15.16 Side A (PBD9: 713; BP9: 505) ERRNVPHGLFRVRUJ Questions A 58-year-old woman with a smoking history of 80 pack-years has had a cough for many years. It has worsened during the last few months, and she has had an associated weight loss. Sputum cytology shows squamous cells with hyperchromatic angulated nuclei and an increased N : C ratio. Her CT scan is shown. 1. Describe the CT findings. 2. What genetic changes are commonly seen in such lesions? ERRNVPHGLFRVRUJ Answers: Side B 1. The neoplastic cells are arranged in nests, with focal areas of squamous differentiation including a squamous pearl (▪), all of which are features of squamous cell carcinoma . 2. Tumor cell paraneoplastic production of parathyroid hormone–related peptide (PTHrP) can cause increased osteoclast activity with lytic bone lesions and hypercalcemia. Bone metastases are also possible; the bone, brain, and adrenals are all favored sites for metastatic squamous cell carcinoma of the lung. ERRNVPHGLFRVRUJ 15.16 Side B (PBD9: 713; BP9: 505) ERRNVPHGLFRVRUJ Questions A 67-year-old smoker who has had multifocal bony pain for 5 months has a firm and nontender left cervical lymph node (Virchow node). A chest radiograph shows a 7-cm left lung mass invading the mediastinum. His serum calcium level is 12.8 mg/dL (nl 8.5 to 10.3 mg/dL), and his phosphorus level is 2.2 mg/dL (nl 2.4 to 4.5 mg/dL); his serum albumin level is normal. A biopsy specimen from the cervical lymph node is shown. 1. What is the diagnosis? 2. Correlate his laboratory findings and bone pain. ERRNVPHGLFRVRUJ Answers: Side A 1. The large irregular mass (▴) impinges on the hilum. Posterior to the mass are infiltrates that represent postobstructive pneumonia . Cytologically, this is a squamous cell carcinoma ( non–small cell carcinoma ). 2. The tumor suppressor gene p53 is likely mutated; CDK inhibitor p16 and RAS mutations are also frequent. Nonmutated epidermal growth factor receptor is often overexpressed (approximately 80%); HER-2/neu is overexpressed in approximately 30% of cases. ERRNVPHGLFRVRUJ 15.17 Side A (PBD9: 714; BP9: 505) ERRNVPHGLFRVRUJ Questions A 63-year-old woman with a smoking history of 100 pack-years develops hemoptysis. On examination, she has generalized edema. Her serum sodium level is 109 mmol/L (nl 135 to 146 mmol/L). Her chest radiograph is shown. 1. What are the two major diagnoses? 2. Explain the profound hyponatremia. ERRNVPHGLFRVRUJ Answers: Side B 1. These small cells with scant cytoplasm and hyperchromatic nuclei represent smallcell carcinoma . RB and p53 mutations are extremely common in these tumors, and the anti-apoptotic gene BCL-2 is highly expressed in more than 90% of them. 2. Neurosecretory granules would likely be found. These tumors likely originate from the neuroendocrine progenitor cells that are normally interspersed along the bronchial epithelium. 3. This patient has Cushing syndrome as a result of the production of ectopic adrenocorticotropic hormone by his cancer; this is a paraneoplastic syndrome. 4. Virtually all small-cell carcinomas of the lung occur among cigarette smokers. ERRNVPHGLFRVRUJ 15.17 Side B (PBD9: 714; BP9: 505) ERRNVPHGLFRVRUJ Questions A 60-year-old man with a 6-month history of worsening cough has a hilar mass and hilar adenopathy on his chest radiograph. His serum cortisol level is also increased. His sputum cytology is shown. 1. What is the diagnosis? 2. What electron microscopic feature would likely be present in these cells? 3. Why does he have an increased cortisol level? 4. What is the most likely risk factor for this mass? ERRNVPHGLFRVRUJ Answers: Side A 1. There is a large right lung mass (▪) that has caused bronchial obstruction; this has led to extensive left lung infiltrates (♦) that represent either bronchopneumonia or lipid pneumonia. 2. This patient's cancer is probably secreting antidiuretic hormone (ADH), which is producing the syndrome of inappropriate antidiuretic hormone (SIADH) . Small-cell carcinomas of the lung are most likely to cause this particular paraneoplastic syndrome . ERRNVPHGLFRVRUJ 15.18 Side A (PBD9: 714; BP9: 505) ERRNVPHGLFRVRUJ Questions A 68-year-old male nonsmoker develops hemoptysis. He has deep vein thrombosis (DVT) that recurs after he completes a course of warfarin. His prothrombin time, his partial thromboplastin time, and his D-dimer all are normal. His chest CT scan is shown. 1. What is the lesion? 2. Correlate this mass to recurrent DVTs. ERRNVPHGLFRVRUJ Answers: Side B 1. The malignant cells express cytokeratin (which suggests carcinoma) and are arrayed in glands (▪), which makes this adenocarcinoma . Lung cancers are often so poorly differentiated that the broader term non–small cell carcinoma has to be used. 2. This cancer is likely T1 N0 M0 (stage Ia) because of the small size and apparent lack of nodal or distant metastases. 3. Most adenocarcinomas occur in smokers, but adenocarcinoma is also the most common lung cancer among nonsmokers. Adenocarcinomas tend to arise peripherally in areas of prior scarring. 4. Common mutations found in adenocarcinomas include p53, RB, and p16; K-RAS mutation is more likely to occur in adenocarcinomas found in smokers. ERRNVPHGLFRVRUJ 15.18 Side B (PBD9: 714; BP9: 505) ERRNVPHGLFRVRUJ Questions A 55-year-old smoker has had pleuritic chest pain for 5 months. A chest CT scan shows a peripheral 3-cm mass but no hilar lymphadenopathy, and a total body CT scan reveals no other lesions. A lung wedge resection yields the microscopic appearance shown with immunohistochemical staining for cytokeratin. 1. What is the diagnosis? 2. What is the stage of this neoplasm? 3. What is its relationship to smoking? 4. What gene mutations may be present in these cells? ERRNVPHGLFRVRUJ Answers: Side A 1. This small, circumscribed, peripheral lung mass (▾) could be a carcinoma, a granuloma, or a hamartoma. The history of recurrent DVTs is most worrisome for non– small cell carcinoma, particularly adenocarcinoma . 2. Trousseau syndrome (migratory thrombophlebitis) is a hypercoagulable state caused by the release of procoagulants from a malignant neoplasm. This is often caused by an adenocarcinoma (particularly of the lung or pancreas), but virtually any malignant neoplasm can do it. ERRNVPHGLFRVRUJ 16 ERRNVPHGLFRVRUJ Head and Neck ERRNVPHGLFRVRUJ 16.1 Side A (PBD9: 744; BP9: 555) ERRNVPHGLFRVRUJ Questions A 44-year-old man with an 8-year history of a painless, mobile, stable right jaw mass has the MR image shown. 1. Where is the lesion located? 2. Is this lesion benign or malignant? 3. What could it be? 4. What are the potential outcomes if this lesion is not completely excised or not excised at all? ERRNVPHGLFRVRUJ Answers: Side B 1. Warthin tumors (papillary cystadenoma lymphomatosum) have papillary structures with double layers of granular eosinophilic cells (▴) (oncocytes), cystic changes, and collections of mature lymphocytes (▸). 2. There is less than 5% recurrence and no risk for malignant transformation. However, these tumors are bilateral and multifocal in 10% of cases. 3. The facial nerve must be spared. ERRNVPHGLFRVRUJ 16.1 Side B (PBD9: 745; BP9: 555) ERRNVPHGLFRVRUJ Questions A 60-year-old man with a 5-year history of a painless, movable mass anterior to his left ear has the mass excised. The microscopic appearance is shown. 1. What is your diagnosis? 2. Is this lesion likely to recur after surgery? 3. What nerve must be localized to avoid injury during the surgical removal of this lesion? ERRNVPHGLFRVRUJ Answers: Side A 1. There is a well-circumscribed cystic and solid mass (▾) in the left superficial parotid gland. 2. The localized nature of this mass and its history of no progression over the course of many years are characteristic of a benign neoplasm. 3. Benign neoplasms of the salivary glands are most often pleomorphic adenomas and Warthin tumors . Other benign neoplasms, including adenomas, oncocytomas, and papillomas, are less frequent. 4. Pleomorphic adenomas can recur with incomplete excision, and there is an increasing risk for malignant transformation the longer they remain in the body. ERRNVPHGLFRVRUJ 16.2 Side A (PBD9: 737; BP9: 513) ERRNVPHGLFRVRUJ Questions A 53-year-old Cantonese man with a 3-month history of right facial pain, nasal obstruction, blood-tinged sputum, and headache has an enlarged, firm, nontender cervical lymph node. His head CT scan is shown. 1. Where is the lesion located? 2. Is this lesion benign or malignant? 3. What could it be? 4. With what viral infection is this lesion often associated? ERRNVPHGLFRVRUJ Answers: Side B 1. This nasopharyngeal carcinoma (NPC) has keratinizing ( pink) and nonkeratinizing squamoid cells in a syncytium that is admixed with lymphocytes. 2. The mass has occluded the opening of the eustachian tube to the middle ear (i.e., torus tubarius). 3. Because most NPCs are diagnosed at a late stage, complete surgical resection is difficult. Many of these cancers are radiosensitive, however. ERRNVPHGLFRVRUJ 16.2 Side B (PBD9: 737; BP9: 513) ERRNVPHGLFRVRUJ Questions A 48-year-old Algerian man has an 8-month history of increasing facial swelling, recurrent otitis media, unilateral conductive hearing loss, and tinnitus. A biopsy specimen is obtained from a mass that involves the lateral nasopharyngeal wall; its microscopic appearance is shown. 1. What is your diagnosis? 2. Why does this patient have recurrent otitis media? 3. How could this lesion be treated? ERRNVPHGLFRVRUJ Answers: Side A 1. There is an irregular mass (▾) that involves the right lateral nasopharynx. 2. The invasive nature of the lesion, the facial pain, and the enlarged node, which is suggestive of metastasis, all point to malignancy. 3. This is likely to be a nasopharyngeal carcinoma (NPC). 4. About 80% to 90% of patients with NPC have serologic evidence of Epstein-Barr virus infection. There is also a characteristic geographic distribution that affects African children and Southern Chinese adults. ERRNVPHGLFRVRUJ 16.3 Side A (PBD9: 731; BP9: 554) ERRNVPHGLFRVRUJ Questions A 51-year-old man has a 4-month history of increasing oral pain and dysphagia for solid food. His head CT scan is shown. 1. Where is the lesion located? 2. What is a biopsy specimen likely to show? 3. What are the major risk factors? 4. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side B 1. Nests of cells (▴) with pink cytoplasm and adjacent inflammation are seen below the normal squamous mucosa (▾). This is squamous cell carcinoma . 2. Mutations in p16, a CDK inhibitor, and p53, a tumor suppressor, are often present. The overexpression of cyclin D1 and EGFR are also common. 3. This type of lesion usually involves contiguous spread to the adjacent soft tissues and metastases via lymphatics to local and distant nodes. Hematogenous metastases occur to the lung, liver, and bone. ERRNVPHGLFRVRUJ 16.3 Side B (PBD9: 731; BP9: 554) ERRNVPHGLFRVRUJ Questions A 62-year-old man has a several-month history of increasing pain below his tongue when chewing food. On examination, he has a 3 × 4 cm ulcerated mass at the base of the tongue. His father had a similar lesion. A biopsy specimen has the microscopic appearance shown. 1. What is your diagnosis? 2. What molecular alterations are likely present? 3. How is this lesion most likely to spread? ERRNVPHGLFRVRUJ Answers: Side A 1. There is a mass (▾) that involves the left posterior base of the tongue and that extends into the soft tissues with darker central necrosis. 2. Squamous cell carcinoma is the most likely diagnosis because of the location and infiltrative nature of the lesion. 3. The use of tobacco products (e.g., cigarettes, pipes, chewing tobacco) and alcohol are the major risk factors. Chewing betel nuts also increases the risk. Half of these lesions involve associated human papillomavirus infections. 4. If this type of cancer is caught at an early stage, 5-year survival is 80% or more. However, most are found at an advanced stage, which involves less than 20% 5-year survival. The risk for a second primary cancer is 5% per year. ERRNVPHGLFRVRUJ 16.4 Side A (PBD9: 731; BP9: 553) ERRNVPHGLFRVRUJ Questions A 41-year-old man presents to his dentist for his first checkup in years. The oral lesion shown cannot be scraped off. A biopsy specimen reveals epithelial hyperkeratosis, acanthosis, and superficial dysplasia with submucosal lymphocytic infiltrates. 1. Define the histologic terms. 2. What is the diagnosis? 3. What is the significance of this lesion? ERRNVPHGLFRVRUJ Answers: Side B 1. Much less common—although far more ominous—than leukoplakia is the red patch shown here, which is erythroplakia . 2. Such a lesion almost always progresses at least to severe dysplasia or carcinoma in situ . 3. The most common risk factor for leukoplakia and erythroplakia is the use of tobacco products . Other risk factors include chronic irritation from malaligned or damaged teeth, focal oral infections such as Candida, and alcohol use . ERRNVPHGLFRVRUJ 16.4 Side B (PBD9: 731; BP9: 553) ERRNVPHGLFRVRUJ Questions A 44-year-old man has the red gingival lesion shown, and he has found that tooth brushing irritates it. A biopsy specimen reveals squamous epithelial erosion with fullthickness dysplasia and submucosal inflammation with severe vascular dilation, hence the intense erythema. 1. What is the diagnosis? 2. Why should this lesion be excised? 3. What are risk factors? ERRNVPHGLFRVRUJ Answers: Side A 1. Hyperkeratosis is thickening of the stratum corneum, which is usually absent in the oral mucosa. Acanthosis is epidermal hyperplasia; dysplasia reflects disordered maturation and cytologic changes, including an increased N : C ratio, nuclear hyperchromasia, and atypia. 2. The white patch, which is a diffuse and slightly raised lesion with the noted histologic changes, is called leukoplakia . 3. Leukoplakia occurs in 3% of middle-aged adults (40 to 70 years old) worldwide and in 1% of American adults. Men are affected twice as often as women, and 5% to 25% of these lesions are premalignant . ERRNVPHGLFRVRUJ 16.5 Side A (PBD9: 741) ERRNVPHGLFRVRUJ Questions A 9-year-old boy has a 5-year history of a slowly enlarging, mobile, nontender neck mass just slightly lateral of the midline. His CT scan is shown. 1. What is your diagnosis? 2. From what embryologic remnant is this derived? 3. What bone can be involved with this lesion? 4. If a similar cystic mass lesion were found in the lateral neck on the CT scan, what would your diagnosis be? ERRNVPHGLFRVRUJ Answers: Side B 1. There is pseudostratified columnar epithelium (◂), a lymphoid aggregate (▸), and thyroid follicles (▴). Sometimes squamous epithelium can be seen in these thyroglossal duct cysts , particularly when they occur in a more cephalad location nearer the mouth. 2. Malignant transformation is highly unlikely. There is a small recurrence risk with incomplete resection. ERRNVPHGLFRVRUJ 16.5 Side B (PBD9: 741) ERRNVPHGLFRVRUJ Questions An 11-year-old girl with difficulty swallowing has a head CT scan that shows a 4-cm midline cystic mass compressing the trachea just below the hyoid bone. The mass is excised, and it has the microscopic appearance shown. 1. What is your diagnosis? 2. Can this lesion become malignant? ERRNVPHGLFRVRUJ Answers: Side A 1. There is a cystic mass (▾) in the anterior neck, just to the left of midline; the history and location strongly suggest a thyroglossal tract cyst . 2. The route of the thyroglossal tract extends from the foramen cecum in the mouth to the eventual location of the thyroid gland anterior to the thyroid cartilage. The remnant of this tract can give rise to a cyst anywhere along its course. 3. The hyoid bone can sometimes be involved in this lesion. 4. Branchial (cervical lymphoepithelial) cysts are thought to arise from remnants of the second branchial arch. ERRNVPHGLFRVRUJ 16.6 Side A (PBD9: 740) ERRNVPHGLFRVRUJ Questions A 12-year-old boy with a 6-year history of recurrent otitis media and progressive unilateral hearing loss has the CT image shown. 1. What is your diagnosis? 2. What organisms likely caused his otitis? 3. What would Weber and Rinne tests reveal? ERRNVPHGLFRVRUJ Answers: Side B 1. A cholesteatoma is a cystic lesion lined with keratinizing squamous epithelium (▴) and filled with desquamation debris (▾). 2. Chronic otitis media leads either to perforation of the tympanic membrane with the implantation of squamous epithelium or to metaplasia of the lining of the middle ear. The squamous epithelium proliferates and forms a cystic mass that displaces or destroys the ossicular chain and eventually erodes the surrounding bone. 3. Deafness, dizziness, and changes in the ipsilateral taste sensation result from the involvement of the chorda tympani. ERRNVPHGLFRVRUJ 16.6 Side B (PBD9: 740) ERRNVPHGLFRVRUJ Questions A 13-year-old girl has a 2-year history of intermittent left head pain. On examination, there is left tympanic membrane perforation with protruding granulation tissue and draining exudate. A CT scan of the head reveals a 2-cm cystic mass of the middle ear, which is excised and shown here. 1. What is your diagnosis? 2. What is the pathogenesis? 3. What complications can occur? ERRNVPHGLFRVRUJ Answers: Side A 1. There is a soft-tissue mass that involves the middle ear and the ossicular chain, with erosion (▸) of adjacent bone. This is a complication of chronic otitis media known as cholesteatoma . 2. The most common organisms involved are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. 3. The Weber and Rinne tests would most likely suggest a conductive hearing loss as a result of middle ear involvement by the mass. ERRNVPHGLFRVRUJ 16.7 Side A (PBD9: 744; BP9: 556) ERRNVPHGLFRVRUJ Questions A 44-year-old man has a slow-growing, painless, freely mobile mass anterior to his left ear. The MR image of the lesion is shown. The lesion is excised and does not recur. 1. What is this neoplasm? 2. What cranial nerve is close to the resection margin? 3. If this neoplasm had rapidly increased in size after 15 years, what would you suspect? ERRNVPHGLFRVRUJ Answers: Side B 1. This pleomorphic adenoma (mixed tumor) in the right parotid gland (♦) has epithelial elements interspersed in a mesenchymal myxoid- to chondroid-like stroma (▪). 2. Although this type of tumor is slow growing and normally cured by complete excision, it is not encapsulated, and small tongues of neoplastic cells that extend into the surrounding salivary gland may not be completely removed without sufficiently broad margins. 3. Less common locations include the submandibular glands, the sublingual glands, and the minor salivary glands. ERRNVPHGLFRVRUJ 16.7 Side B (PBD9: 744; BP9: 556) ERRNVPHGLFRVRUJ Questions A 61-year-old woman is bothered by a slowly enlarging mass superior to the angle of her right jaw and anterior to her right ear. This mass is excised, but it recurs within a year. The microscopic appearance is shown. 1. What is this neoplasm? 2. On the basis of this appearance, why did it recur? 3. Where else may this neoplasm occur? ERRNVPHGLFRVRUJ Answers: Side A 1. The bright, round mass is a pleomorphic adenoma (mixed tumor) arising in the left parotid gland. This is the most common salivary gland tumor; most arise in the parotid. 2. The facial nerve (cranial nerve VII) must be carefully preserved during resection. If the tumor is infiltrative, a portion of the excised nerve can be grafted. 3. There can be malignant transformation to a malignant mixed tumor that either resembles adenocarcinoma or that is relatively undifferentiated. The risk for malignant transformation is almost 10% after 15 years. ERRNVPHGLFRVRUJ 16.8 Side A (PBD9: 746) ERRNVPHGLFRVRUJ Questions A 63-year-old man has a 2-year history of a slowly enlarging painful mass beneath his right mandible. His head CT scan is shown. The lesion is excised, but it continues to recur for the next 10 years. 1. On the basis of the clinical scenario, what is this neoplasm likely to be? 2. Where are metastases most likely to occur? ERRNVPHGLFRVRUJ Answers: Side B 1. The location and the cystic and solid appearance of this tumor make it an adenoid cystic carcinoma . 2. The tumor tends to be infiltrative, and perineural invasion is common. This leads to “neoplastic” pain that can be dull but constant. It is difficult to manage, even with analgesics such as opiate narcotics, to which tolerance can increase over time with increasing dosages. 3. This tumor has arisen in a minor salivary gland. Interestingly, the risk for malignancy is inversely proportional to the size of the salivary gland. ERRNVPHGLFRVRUJ 16.8 Side B (PBD9: 746) ERRNVPHGLFRVRUJ Questions A 66-year-old woman has a 2-cm left buccal submucosal mass excised; it diffusely infiltrates adjacent tissues, and clean margins are difficult to achieve. The microscopic appearance is shown. 1. What is this neoplasm? 2. Why is this lesion likely to be painful? 3. Explain the location of this mass. ERRNVPHGLFRVRUJ Answers: Side A 1. This mass (▸) is likely to be an adenoid cystic carcinoma ; it is occurring—as is typical for this type of tumor—in a submandibular gland. Histologically, it exhibits cystic and solid elements, and it is deeply infiltrative (hence its propensity for recurrence). These tumors behave aggressively, with 50% destined to metastasize. 2. Adenoid cystic carcinomas tend to recur locally, and they can eventually metastasize to the bone, the liver, and the brain. Five-year survival rates can be 60% to 70%, but they dwindle to 15% at 15 years. ERRNVPHGLFRVRUJ 16.9 Side A (PBD9: 741) ERRNVPHGLFRVRUJ Questions A 58-year-old man has had neck discomfort for 2 years. A family history of pheochromocytomas and medullary thyroid carcinomas suggests multiple endocrine neoplasia (MEN) type II. A mass is palpated near this patient's carotid, below the angle of the left mandible. His MR image is shown. 1. What might this mass represent? 2. What is the normal function of cells at this site? 3. What is the relationship to MEN type II? ERRNVPHGLFRVRUJ Answers: Side B 1. This paraganglioma at the carotid bifurcation has a tumor “blush” (▪) as a result of increased vascularity. Tumor cells form small nests ( zellballen) that are surrounded by a vascularized delicate fibrous stroma. 2. Paraganglia are clusters of neuroendocrine cells that are distributed throughout the body, including in the adrenal medulla, the carotid bodies, and the organ of Zuckerkandl. Related tumors in the adrenals are pheochromocytomas ; at other sites, they are paragangliomas . 3. Extra-adrenal paraganglion tissue may secrete catecholamines like pheochromocytomas. ERRNVPHGLFRVRUJ 16.9 Side B (PBD9: 741) ERRNVPHGLFRVRUJ Questions A 49-year-old woman with a history of labile hypertension has a right neck lump. The 3-cm mass has infiltrative margins, and it is difficult to excise. The microscopic appearance is shown along with the angiogram. 1. What is the likely diagnosis? 2. Where else can such tumors occur? 3. Why did this patient have hypertension? ERRNVPHGLFRVRUJ Answers: Side A 1. A circumscribed mass (▪) is in the region of the carotid bifurcation. This is a paraganglioma or a carotid body tumor. 2. Carotid body cells serve as chemoreceptors, primarily of dissolved oxygen in the blood. 3. Gain-of-function mutations in the RET gene lead to a constitutively active receptor tyrosine kinase that causes a characteristic pattern of tumors in numerous endocrine tissues (i.e., thyroid tissue, adrenal tissue, and occasionally in the carotid body); these are the so-called MEN type II syndromes . ERRNVPHGLFRVRUJ 16.10 Side A (PBD9: 735) ERRNVPHGLFRVRUJ Questions A 17-year-old boy has a 1-year history of left facial pain. His MR image is shown. The excised lesion is composed of tall columnar palisading epithelium with central areas of stellate cells (some with squamous metaplasia) and dysplastic calcification. 1. What is this neoplasm? 2. From what preexisting cystic lesion can it arise? 3. What other tumors can show similar histology? ERRNVPHGLFRVRUJ Answers: Side B 1. The dark, round, right mandibular lesion (▾) is an odontogenic keratocyst . These occur most often in the posterior mandible, and they manifest as loculated radiolucencies. The lining histology shows stratified squamous epithelium. These lesions have a tendency to recur, so resection needs to be aggressive. 2. The nevoid basal cell carcinoma syndrome (Gorlin syndrome) occurs as a result of mutations in the PTCH tumor-suppressor gene. ERRNVPHGLFRVRUJ 16.10 Side B (PBD9: 734; BP9: 557) ERRNVPHGLFRVRUJ Questions A 25-year-old man has a 1-year history of right jaw pain. His head CT scan is shown. The excised cystic lesion has a thin parakeratinized squamous lining, and it recurs. 1. What is the likely diagnosis? 2. What syndrome is associated with several such lesions? ERRNVPHGLFRVRUJ Answers: Side A 1. This bright mass (▸) is a maxillary ameloblastoma arising from odontogenic epithelium in the normal enamel organ. 2. Dentigerous cysts arise from the follicular epithelium near the crown of an unerupted tooth, and they are thought to occur as a result of the separation of the dental follicle. They have a potential for growth and neoplastic transformation into ameloblastomas. 3. Similar histologic appearances are seen in the craniopharyngiomas of the sella turcica and the adamantinomas of long bone, although these do not all have the same cells of origin. ERRNVPHGLFRVRUJ 16.11 Side A (PBD9: 739; BP9: 514) ERRNVPHGLFRVRUJ Questions A 61-year-old male smoker has a 5-month history of worsening nonproductive cough and hoarseness with recent hemoptysis. His CT scan is shown. 1. What is the likely diagnosis? 2. What lesions precede this end point? ERRNVPHGLFRVRUJ Answers: Side B 1. Adjacent to normal squamous epithelium ( ) is invasive squamous cell carcinoma (▪), which is characterized by pink cytoplasm that represents keratinization, and the occasional keratin pearl (♦). Nuclei are irregularly shaped and hyperchromatic. 2. The neck mass could be metastasis to a cervical lymph node. 3. Laryngeal carcinoma can be excised; extensive lesions require more radical surgery to obtain clean margins and to remove lymph nodes involved by overt (or potentially occult) metastases. Squamous cell carcinomas are also amenable to radiation therapy. 4. Although most of these cancers arise in the setting of smoking, alcohol also can be contributory, potentially because it solubilizes carcinogens and facilitates their entry into cells. Asbestos exposure, irradiation, and nutritional factors can also contribute to increased risk. ERRNVPHGLFRVRUJ 16.11 Side B (PBD9: 739; BP9: 514) ERRNVPHGLFRVRUJ Questions A 69-year-old woman with a smoking history of 50 pack-years and a history of alcohol abuse has recently developed throat pain and dysphagia. Endoscopy reveals a left supraglottic exophytic eroded mass, the biopsy specimen of which is shown. On examination, she has a firm, painless mass anterior to the left sternocleidomastoid. 1. Describe the histologic features. 2. What could the anterolateral neck mass be? 3. How is this lesion treated? 4. What are the risk factors for laryngeal carcinoma? ERRNVPHGLFRVRUJ Answers: Side A 1. The history and the irregularly thickened right vocal fold (◂) are worrisome for laryngeal squamous cell carcinoma . 2. Squamous metaplasia occurs in response to the chronic irritation of cigarette smoke, and it can progress to dysplasia . Metaplasia and dysplasia are potentially reversible, but dysplasia can progress to frank malignancy, which is irreversible. ERRNVPHGLFRVRUJ 17 ERRNVPHGLFRVRUJ The Gastrointestinal Tract ERRNVPHGLFRVRUJ 17.1 Side A (PBD9: 753; BP9: 558) ERRNVPHGLFRVRUJ Questions A 56-year-old man with a 3-month history of increasing dysphagia undergoes a barium swallow. The results are shown. 1. What abnormality is shown? 2. What is the diagnosis if the underlying problem involves the absence of myenteric ganglia? 3. What is the likely diagnosis if a biopsy specimen of the lesion shows esophageal columnar metaplasia? 4. What is a possible diagnosis if the patient had ingested food that contained nitrosamine? ERRNVPHGLFRVRUJ Answers: Side B 1. There is enlargement ( ▸) of the lower esophagus that is consistent with hiatal hernia, which leads to gastroesophageal reflux disease (GERD) . 2. Barrett esophagus with columnar metaplasia and goblet cells arises in the esophagus with GERD. 3. There is a long-term risk for adenocarcinoma . 4. Obesity with high body mass index is a risk factor; weight loss helps to alleviate GERD. ERRNVPHGLFRVRUJ 17.1 Side B (PBD9: 755; BP9: 560) ERRNVPHGLFRVRUJ Questions A 43-year-old man with a 20-year history of substernal burning pain that is worse after large meals or recumbency has the chest CT scan shown. 1. What is wrong with this picture? 2. What might a biopsy specimen of the lower esophagus show? 3. What cancer could arise in this setting? 4. Name an increasingly prevalent risk factor for this entity (hint: fast food). ERRNVPHGLFRVRUJ Answers: Side A 1. There is an esophageal stricture ( ▸) above the lower esophageal sphincter. 2. He would have achalasia . 3. He would have gastroesophageal reflux disease with inflammation leading to scarring and stricture. In the setting of columnar metaplasia ( Barrett esophagus ), there is an increased possibility of adenocarcinoma. 4. Risks for esophageal squamous carcinoma include nitrosamines, alcohol, and tobacco. ERRNVPHGLFRVRUJ 17.2 Side A (PBD9: 756; BP9: 559) ERRNVPHGLFRVRUJ Questions A 42-year-old man with a long history of alcohol abuse develops intractable hematemesis and ultimately exsanguination. At autopsy, the everted esophagus shows the causal lesion (▾); in another patient, the same area is shown after treatment (▴). 1. What is your diagnosis? 2. What is the pathogenesis? 3. What liver disease does this patient have? 4. What therapies can be employed to treat this condition? ERRNVPHGLFRVRUJ Answers: Side B 1. These dilated and ruptured esophageal veins ( ▾) are varices caused by portal hypertension. 2. The irregularly shaped liver ( ▸) has cirrhosis , which is the cause of the portal hypertension . 3. Note the fluid ( ▴) in the peritoneal cavity. This is also known as ascites , and it probably results from portal hypertension and deficient albumin synthesis. 4. Infection with Schistosoma mansoni or Schistosoma japonicum can lead to fibrosis and subsequent hepatic vascular remodeling that leads to portal hypertension. ERRNVPHGLFRVRUJ 17.2 Side B (PBD9: 756; BP9: 559) ERRNVPHGLFRVRUJ Questions A 51-year-old Vietnamese man who was a lifelong rice grower develops sudden and severe hematemesis. His CT scan is shown. 1. What is your diagnosis for the cause of his bleeding? 2. What is wrong with his liver? 3. What else is present in the peritoneal cavity? 4. Name a parasitic disease with these findings. ERRNVPHGLFRVRUJ Answers: Side A 1. In both images, large bleeding varices (dilated submucosal veins) are present. 2. Esophageal varices result from portal hypertension caused by hepatic cirrhosis. With portal hypertension, portosystemic shunts (e.g., esophageal varices, caput medusae, hemorrhoids) open and expand, which potentially results in bleeding complications. 3. This patient has micronodular cirrhosis as a result of alcohol abuse. 4. Note the varices ( ▴), which have been treated with sclerotherapy. Emergency tamponade may be attempted to stop the bleeding. A hepatic portosystemic vascular shunt may be placed to relieve the portal hypertension. ERRNVPHGLFRVRUJ 17.3 Side A (PBD9: 757; BP9: 561) ERRNVPHGLFRVRUJ Questions A 42-year-old man has a 10-year history of postprandial epigastric pain. A biopsy specimen obtained 4 cm above the gastroesophageal junction has the microscopic appearance shown. 1. What is his chronic condition? 2. What is the microscopic diagnosis? 3. What complications can occur? 4. How is this condition treated? ERRNVPHGLFRVRUJ Answers: Side B 1. A large, irregular, and ulcerated mass ( ■) in the lower esophagus contrasts with the normal pink stratified squamous epithelial mucosa ( ♦) shown above. Almost all esophageal adenocarcinomas arise in the setting of GERD. 2. The precursor lesion is Barrett esophagus . The development of dysplasia within columnar metaplasia signifies a high risk for evolution to carcinoma. Patients with Barrett esophagus have a 10% lifetime risk of adenocarcinoma. 3. Esophageal cancer has a poor prognosis because most lesions are detected at an advanced stage. ERRNVPHGLFRVRUJ 17.3 Side B (PBD9: 758; BP9: 562) ERRNVPHGLFRVRUJ Questions A 59-year-old man with a 15-year history of gastroesophageal reflux disease (GERD) recently developed odynophagia and dysphagia with a 6-kg weight loss. After endoscopy and biopsy, an esophagectomy is performed (shown). 1. What kind of neoplasm is this most likely to be? 2. What is the precursor lesion? 3. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has gastroesophageal reflux disease. 2. Barrett metaplasia involves the replacement of normal squamous mucosa at this location with intestinal-type epithelium that contains occasional goblet cells ( ▸) and that has been derived from traumatized epithelial stem cells. It is putatively better able to withstand the ravages of recurrent gastric acid baths. 3. Inflammation in association with Barrett metaplasia can lead to bleeding and stricture, but the most feared complication is the development of an adenocarcinoma . 4. Antacids, H receptor antagonists, and proton-pump inhibitors all have a role in reducing the gastric juice pH. 2 ERRNVPHGLFRVRUJ 17.4 Side A (PBD9: 758; BP9: 562) ERRNVPHGLFRVRUJ Questions A 62-year-old man with long-standing gastroesophageal reflux disease (GERD) now has a 2-month history of hematemesis and dysphagia. His lower esophagus would appear as shown. 1. Describe the findings. 2. What is a biopsy specimen likely to show? 3. How might the GERD have been treated to reduce the risk of this outcome? ERRNVPHGLFRVRUJ Answers: Side B 1. The ill-defined mass ( ▴) has nodular, exophytic excrescences and hemorrhagic ulceration ( ▸) that narrows the lumen. 2. This is likely squamous cell carcinoma , which is the most common form of esophageal cancer worldwide; 20% are located in the upper third of the esophagus, 50% are found in the middle third, and 30% are in the lower third. 3. This patient has two major risk factors: smoking and alcohol abuse. Others include vitamin deficiencies, the ingestion of foods with nitrites or nitrosamines, zinc or molybdenum deficiency, and long-standing chronic esophagitis. Human papillomavirus is implicated in high-incidence regions (e.g., China, South Africa). ERRNVPHGLFRVRUJ 17.4 Side B (PBD9: 759; BP9: 563) ERRNVPHGLFRVRUJ Questions A 65-year-old woman with a history of chronic alcohol abuse and cigarette smoking develops persistent dysphagia. The appearance of her upper esophagus at endoscopy is shown. 1. Describe the findings. 2. What is a biopsy specimen likely to show? 3. What are the risk factors for this disease? ERRNVPHGLFRVRUJ Answers: Side A 1. There is an irregular mass ( ▸) with ulceration ( ▾) and hemorrhage just above the gastroesophageal junction, in a reddish area of Barrett esophagus ( ▴). 2. Given the history of GERD and the mass, this is most likely to be adenocarcinoma that has arisen in an area of Barrett metaplasia . 3. GERD can be treated with a proton-pump inhibitor such as omeprazole or an H blocker such as cimetidine to reduce gastric acidity. A promotility agent such as metoclopramide enhances gastric emptying, and it may also reduce reflux. ERRNVPHGLFRVRUJ 2 17.5 Side A (PBD9: 763; BP9: 566) ERRNVPHGLFRVRUJ Questions A 43-year-old woman with a 5-year history of intermittent nausea, vomiting, and epigastric pain has an endoscopic examination that reveals gastric erythema and erosions. The microscopic appearance of a biopsy specimen is shown. 1. What is your diagnosis? 2. What cytokines are increased? 3. What microbial genes contribute to the pathogenesis? 4. Are these organisms present in the duodenum? ERRNVPHGLFRVRUJ Answers: Side B 1. There is thickening of the wall ( ▴) of the gastric antrum, pylorus, and a duodenal bulb caused by inflammation. The patient's history of bleeding and anemia suggests an acute gastritis . 2. Causes of this condition include the use of nonsteroidal anti-inflammatory drugs (NSAIDs) . Cyclooxygenase inhibition by NSAIDs reduces prostaglandin production, which reduces gastric blood flow and mucus and bicarbonate production while at the same time increasing parietal cell acid production. Other causes include excessive alcohol consumption, smoking, severe stress, ischemia, and the ingestion of compounds that contain caustic acid or alkali. ERRNVPHGLFRVRUJ 17.5 Side B (PBD9: 760; BP9: 564) ERRNVPHGLFRVRUJ Questions A 55-year-old woman with epigastric discomfort is also found to have a microcytic and hypochromic anemia with otherwise normal WBC and platelet counts. Her abdominal CT scan is shown. 1. What is your diagnosis? 2. What are common risk factors for this condition? ERRNVPHGLFRVRUJ Answers: Side A 1. The curved rods ( ▴) in the lumen above the columnar epithelial cells are Helicobacter pylori . 2. These organisms induce proinflammatory cytokines such as interleukin-1, interleukin6, and interleukin-8 as well as tumor necrosis factor. 3. Virulence factors include flagella for motility, urease production (making ammonia), and bacterial adhesins. Organisms that express cytotoxin-associated antigen (CagA) usually also have a cassette of 29 associated genes (the so-called Cag pathogenicity island ) that promotes inflammation and tissue damage. One of the most important of these is the vacuolating toxin ( VacA), which is a gene product that causes direct cell injury. 4. No. The H. pylori organisms live in gastric mucus and inflict duodenal damage via cytokine and toxin production. ERRNVPHGLFRVRUJ 17.6 Side A (PBD9: 766; BP9: 568) ERRNVPHGLFRVRUJ Questions A 71-year-old man with sudden onset of severe abdominal pain has a distended abdomen with absent bowel sounds. His CT scan is shown. 1. What is your diagnosis? 2. What could cause this? 3. What complications can occur? 4. What treatment is needed? ERRNVPHGLFRVRUJ Answers: Side B 1. There is duodenal perforation . The yellow exudate ( ▾) over the peritoneal surfaces represents acute peritonitis. 2. This is likely to be polymicrobial , with organisms such as Escherichia coli, Bacteroides fragilis, Clostridium perfringens, streptococci, and enterococci. 3. The pH is likely to be less than 7.1, the protein level should be high to reflect the presence of an exudate , the lactate dehydrogenase level would be elevated to reflect cell injury, and the cell count would show many leukocytes (mostly neutrophils). A Gram stain would likely show multiple organisms. ERRNVPHGLFRVRUJ 17.6 Side B (PBD9: 817; BP9: 568) ERRNVPHGLFRVRUJ Questions A 66-year-old woman with a 3-month history of intermittent epigastric pain now has severe generalized abdominal pain, with fever and rigors. Her WBC count is 13,980/mm (nl 3800 to 10,800/mm ), with neutrophilia and left shift. Metabolic acidosis is present. During an exploratory laparotomy, the surgeon encounters what is shown in the image. 3 3 1. What is your diagnosis? 2. What might a culture grow? 3. What is peritoneal fluid analysis likely to show? ERRNVPHGLFRVRUJ Answers: Side A 1. There is ascites ( ▴), but the ominous finding is the free air ( ◂) that is collecting above the liver, which indicates a ruptured viscus . 2. Perforated peptic ulcer, ruptured cholecystitis, perforated appendicitis, perforated diverticulitis, or rupture of infarcted bowel can cause this condition. 3. Perforation leads to peritonitis, the release of enteric bacteria, and often sepsis with shock. 4. Emergent surgery is needed to repair the rupture site and lavage the peritoneum. ERRNVPHGLFRVRUJ 17.7 Side A (PBD9: 771; BP9: 570) ERRNVPHGLFRVRUJ Questions A 69-year-old man with a 3-month history of nausea and upper abdominal pain has also had a concurrent 7-kg weight loss. His abdominal CT scan is shown. 1. What is your diagnosis? 2. What are the associated risk factors? 3. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side B 1. This signet ring ( ▴) type of gastric adenocarcinoma is most commonly associated with diffusely infiltrating carcinoma (often leading to a linitis plastica or “leather bottle”–type appearance of the stomach). 2. These include hereditary nonpolyposis colon cancer (HNPCC) syndrome, which is caused by defects in DNA mismatch repair, and E-cadherin mutations (familial gastric carcinoma syndrome). 3. Reduced consumption of smoked, cured, or salted foods may be helpful. A diet that includes fruits and vegetables also seems to help reduce cancer risk. There is no apparent association with alcohol ingestion or antacid therapies. ERRNVPHGLFRVRUJ 17.7 Side B (PBD9: 771; BP9: 570) ERRNVPHGLFRVRUJ Questions A 66-year-old woman with a 5-month history of nausea, vomiting, and a 5-kg weight loss undergoes endoscopy. There is loss of antral rugal folds and a 4-cm, irregular, shallow ulceration. A biopsy specimen is obtained of the ulceration at its edge, and the microscopic appearance is shown. 1. What is your diagnosis? 2. Give associated familial genetic factors. 3. What dietary approaches might reduce the risk for this condition? ERRNVPHGLFRVRUJ Answers: Side A 1. The stomach has a diffusely thickened wall ( ▸) that is consistent with the linitis plastica form of gastric adenocarcinoma . 2. Risk factors for gastric adenocarcinoma include any cause of chronic gastritis, such as infection with Helicobacter pylori; diets rich in smoked, salted, or pickled foods; ingestion of nitrites; and smoking. 3. Few gastric cancers are diagnosed at an early stage; with linitis plastica in particular, the prognosis is extremely poor (<10% 5-year survival). ERRNVPHGLFRVRUJ 17.8 Side A (PBD9: 775; BP9: 572) ERRNVPHGLFRVRUJ Questions After an episode of hematemesis, a 49-year-old man undergoes endoscopy, which is followed by the surgical resection of the lesion shown. Histologically, the mass is a monomorphic storiform collection of spindled cells; according to immunohistochemical staining, they are c-KIT (CD117)-positive. 1. What is your diagnosis? 2. What immunohistochemical markers may be present? 3. Is this lesion benign or malignant? ERRNVPHGLFRVRUJ Answers: Side B 1. The bundles of spindle cells are typical for a gastrointestinal stromal tumor (GIST) . 2. GISTs are thought to arise from the interstitial cells of Cajal that form part of the myenteric plexus. 3. Imatinib mesylate , which is a tyrosine kinase inhibitor, can be used for treatment. This is the same drug that inhibits the chimeric protein kinase formed as a result of the BCR-ABL translocation in patients with chronic myelogenous leukemia. ERRNVPHGLFRVRUJ 17.8 Side B (PBD9: 775; BP9: 572) ERRNVPHGLFRVRUJ Questions A 55-year-old woman with a 1-year history of abdominal pain has occult blood in her stool and an abdominal CT scan that shows a 5-cm mass in the ileum. Histologically, the mass has the appearance shown by H&E (top ) and by immunohistochemistry for CD117 (bottom ). 1. What is your diagnosis? 2. What is the cell of origin? 3. How can this be treated other than with resection? ERRNVPHGLFRVRUJ Answers: Side A 1. This gastrointestinal stromal tumor (GIST) arises in the muscular wall of the stomach and grows exophytically toward the lumen. It retains a covering of mucosa, except in the central ulcerated area ( ▾). 2. Vimentin and desmin are positive, which is typical for neoplasms of mesenchymal (connective tissue) origin. S100 and neuron-specific enolase can be positive, which is typical of neural origin. 3. The biologic potential of GISTs is difficult to evaluate . The most important features are mitotic count, size, and cellularity. This is a large tumor with increased cellularity; however, because of its relative lack of mitotic activity, it has been classified as a stromal tumor of uncertain malignant potential (STUMP). ERRNVPHGLFRVRUJ 17.9 Side A (PBD9: 751) ERRNVPHGLFRVRUJ Questions The bowel anomaly shown is from a neonatal autopsy. It is a common incidental finding, although later in life it can be associated with gastrointestinal tract hemorrhage. 1. What is your diagnosis? 2. From what embryonic structure is it derived? 3. How can bleeding occur? 4. How can this anomaly cause bowel obstruction? ERRNVPHGLFRVRUJ Answers: Side B 1. Bowel obstruction prevents gas, fluid, and solid stool from being passed. The condition shown is toxic megacolon ( ▸) proximal to the affected region ( ▴). 2. Hirschsprung disease is caused by the absence of ganglion cells in submucosal and myenteric plexuses. It can occur in either a segment of the colon (short-segment disease) or the entire colon (long-segment disease). The incidence of Hirschsprung disease is 1 in 5000 live births, with a 4 : 1 male-to-female predominance. 3. About half of familial cases and 15% of sporadic cases are associated with RET gene mutations . RET is a receptor kinase that provides direction to migrating neural crest cells during the formation of the bowel ganglionic plexuses. ERRNVPHGLFRVRUJ 17.9 Side B (PBD9: 751; BP9: 573) ERRNVPHGLFRVRUJ Questions An infant who was born at term after an uncomplicated pregnancy has not passed meconium by 2 days of age. On examination, his abdomen is distended and tympanitic, and an emergent colectomy is performed. The gross appearance of his colon is shown. 1. Why is the abdomen distended? 2. What is the lesion present? 3. Explain the genetics of this disorder. ERRNVPHGLFRVRUJ Answers: Side A 1. This outpouching ( ▾) is a Meckel diverticulum , which is present in about 2% of individuals. 2. It represents the proximal remnant of the vitelline duct . It is a “true” diverticulum, with all of the layers of the bowel present. 3. Ectopic gastric mucosa may be present, with associated acid production and mucosal ulceration. More commonly, an ectopic pancreas is present, but this only rarely causes problems. 4. A Meckel diverticulum can be associated with intussusception . ERRNVPHGLFRVRUJ 17.10 Side A (PBD9: 777; BP9: 574) ERRNVPHGLFRVRUJ Questions A 40-year-old man with a 2-day history of nausea, vomiting, and left lower quadrant pain is found to have a distended abdomen and high-pitched bowel sounds. Pain is elicited on palpation of the left inguinal region. His abdominal CT scan is shown. 1. What is your diagnosis? 2. What is the pathogenesis? 3. Name the persistent embryologic structure responsible for this lesion. 4. What complications can occur? ERRNVPHGLFRVRUJ Answers: Side B 1. There is bulging ( ▾) of the left inguinal region that extends to the scrotum; this is consistent with an inguinal hernia . 2. This is most likely to be “indirect,” beginning at the internal inguinal ring through a persistent process vaginalis. A “direct” hernia is less common; it results from weakness in the transversalis fascia that comprises the Hesselbach triangle. A femoral hernia follows the femoral canal below the inguinal ligament medial to the femoral vein and lateral to the lacunar ligament. ERRNVPHGLFRVRUJ 17.10 Side B (PBD9: 777; BP9: 574) ERRNVPHGLFRVRUJ Questions A 56-year-old man with a 3-month history of inguinal “achiness” finally seeks medical attention. The gross appearance of the problem is shown; bowel sounds are auscultated over the area of bulging. 1. What is your diagnosis? 2. Is this process “direct” or “indirect”? ERRNVPHGLFRVRUJ Answers: Side A 1. There are loops of small bowel ( ▴) in the left inguinal region that represent herniation . 2. A weakness in the lower abdominal wall allows for the herniation of abdominal contents (usually loops of bowel) into a hernia sac. Most often this is an “indirect” hernia that follows the inguinal ring. 3. Persistent processus vaginalis 4. The bowel may become trapped ( incarcerated ) in the hernia sac, which leads to obstruction (as in this case). If the vascular supply to this entrapped bowel is compromised, a strangulated hernia results, and the bowel becomes ischemic; if it is untreated, bowel infarction results. ERRNVPHGLFRVRUJ 17.11 Side A (PBD9: 766; BP9: 568) ERRNVPHGLFRVRUJ Questions A 65-year-old man with a history of peptic ulcer disease has sudden and severe abdominal pain with absent bowel sounds on physical examination. His WBC count is markedly elevated, with a left shift. At surgery, the gross appearance of a lesion in the peritoneal cavity beneath the reflected liver is shown. 1. What are the irregular brown-red areas? 2. What is your diagnosis? 3. What would a microbiologic culture reveal? ERRNVPHGLFRVRUJ Answers: Side B 1. There are multiple air-filled, rounded outpouchings ( ▾) in the distal colon that are consistent with diverticulosis . These are actually pseudodiverticula, because they do not involve all layers of the bowel wall. 2. Diverticular perforation has occurred, which has resulted in an abscess with an airfluid level and inflammation that extends into the adjacent soft tissues. 3. There would be an increased cell count, with many neutrophils. ERRNVPHGLFRVRUJ 17.11 Side B (PBD9: 803; BP9: 586) ERRNVPHGLFRVRUJ Questions An 83-year-old woman with a 15-year history of intermittent lower abdominal pain develops abrupt and severe acute lower abdominal pain; occult blood is found in her stool. Her abdominal CT scan is shown. 1. What is the underlying disease? 2. What complication has occurred? 3. What would peritoneal lavage reveal? ERRNVPHGLFRVRUJ Answers: Side A 1. There is a hemorrhagic ( ◂) and fibrinous ( ▾) inflammatory exudate on the peritoneal surfaces, which is consistent with peritonitis . Note the adjacent liver ( •) and gallbladder ( ♦). 2. Perforated duodenal ulcer 3. Microbiologic culture is likely to yield polymicrobial infection with organisms spilled from the bowel lumen, including gram-positive cocci (streptococci, enterococci, staphylococci) in the upper gastrointestinal tract and gram-negative bacilli ( Escherichia coli, Enterobacter) in the lower gastrointestinal tract. Although gastric Helicobacter pylori infection can lead to peptic ulceration, it is not a cause of peritonitis. ERRNVPHGLFRVRUJ 17.12 Side A (PBD9: 789; BP9: 584) ERRNVPHGLFRVRUJ Questions A 25-year-old woman with a week-long history of malaise, fever, diarrhea, and abdominal pain has hepatosplenomegaly and a salmon-colored maculopapular skin rash. If we had looked at her small bowel mucosa, it would appear as shown. 1. What are the darker oval regions on the mucosal side? 2. What is the disease and the infecting organism? 3. What other species from this genus would typically cause a less severe disease? ERRNVPHGLFRVRUJ Answers: Side B 1. Salmonella typhi infection produces typhoid fever . The organism is identified by its growth on specific media and its biochemical profile. 2. Typhoid fever is spread via fecal-oral transmission through contaminated food and water, most often poultry and beef products. Humans are the only hosts for S. typhi. 3. The microfold (“M”) cells that line the intestinal villi admit Salmonella organisms, which are aided by bacterial genes that code for adhesion proteins and for compounds that resist phagolysosome degradation. ERRNVPHGLFRVRUJ 17.12 Side B (PBD9: 789; BP9: 584) ERRNVPHGLFRVRUJ Questions A 30-year-old man with fever and diarrhea has a complete blood count that shows leukopenia. Gram staining of the cultured microorganism is shown at the top; it ferments glucose, and it is citrate-positive and H S-positive. Stool cultures show growth on MacConkey agar (middle ) and S/S agar (bottom ). 2 1. What is the causative organism? 2. How is this infection spread? 3. What cell serves as a portal of entry in the small intestine? ERRNVPHGLFRVRUJ Answers: Side A 1. Oval-shaped Peyer patches ( ▴) represent aggregates of lymphoid tissue in the distal small intestine. The infection often produces the enlargement and ulceration of these areas. 2. This patient has typhoid fever as a result of Salmonella typhi infection. 3. Less severe Salmonella infections include Salmonella enteritidis and Salmonella typhimurium, which can be carried by infected beef and chicken. These infections are most often the result of ingesting poultry products (e.g., meat, eggs) without adequate washing or cooking after fecal contamination. ERRNVPHGLFRVRUJ 17.13 Side A (PBD9: 754; BP9: 560) ERRNVPHGLFRVRUJ Questions A 33-year-old man with odynophagia is found to have oral thrush and an HIV1-RNA level of 6800 copies/mL. Esophageal endoscopy reveals lesions that are similar to those shown from an autopsy from a similar case. 1. What infectious agent is likely causing the esophageal lesion? 2. What infectious agent is likely causing the oral thrush? 3. What underlying disease does this patient have? 4. What is his CD4+ lymphocyte count? ERRNVPHGLFRVRUJ Answers: Side B 1. The herpes simplex viral cytopathic effect includes multinucleation ( ◂) and ground-glass ( ▴) intranuclear inclusions. Ulceration is evidenced by acute inflammation associated with necrotic debris. 2. The patient is immunosuppressed because she has acute myelogenous leukemia . 3. Treatment with acyclovir (or its modified versions) is effective for producing lesion regression, but it cannot eliminate latent virus within the dorsal root ganglia. ERRNVPHGLFRVRUJ 17.13 Side B (PBD9: 754; BP9: 560) ERRNVPHGLFRVRUJ Questions A 22-year-old woman with odynophagia is found to have a total WBC count of 97,800/mm (nl 3800 to 10,800/mm ), with a peripheral blood smear showing myeloblasts that contain Auer rods. Gastrointestinal endoscopy reveals 1- to 3-mm round vesicles in her mid esophagus, some of which have central ulcers with raised edges. A biopsy specimen of one lesion has the microscopic appearance shown. 3 3 1. What is your diagnosis? 2. What underlying disease does this patient have? 3. How could this lesion be treated? ERRNVPHGLFRVRUJ Answers: Side A 1. These sharply demarcated (“punched out”) ulcers ( ▾) of the esophageal squamous mucosa are typical for herpes simplex esophagitis . 2. This patient's oral thrush is likely the result of infection with Candida fungal organisms. The growth appears as a gray-to-white pseudomembrane that can extend to the esophagus. 3. He has HIV infection with the infectious criteria needed to establish an AIDS diagnosis. 4. His CD4+ cell count is likely less than 200/µL. ERRNVPHGLFRVRUJ 17.14 Side A (PBD9: 791; BP9: 584) ERRNVPHGLFRVRUJ Questions Two weeks into a prolonged course of antibiotics for endocarditis, a 38-year-old woman develops abdominal pain with distention and diarrhea. If we had gone immediately to autopsy at this point, her small intestine would appear as shown. 1. What is your diagnosis? 2. What antibiotics can cause this? 3. What bacterial organism is likely present? 4. What toxins does this organism produce? ERRNVPHGLFRVRUJ Answers: Side B 1. There is a loss of mucosal folds with erythema ( ◂); this is typical for ischemic colitis . Bowel is difficult to infarct as a result of atherosclerotic narrowing or thromboembolization because of the anastomosing blood supply. Most cases of bowel ischemia and infarction result from generalized hypotension. 2. The restoration of adequate perfusion would prevent further ischemic injury. However, when necrosis occurs (particularly if it is transmural), the resection of nonviable bowel is often necessary. ERRNVPHGLFRVRUJ 17.14 Side B (PBD9: 779; BP9: 574) ERRNVPHGLFRVRUJ Questions A 59-year-old woman with severe congestive heart failure develops persistent hypotension despite multiple pressor agents. Shortly thereafter, she has abdominal pain with bloody diarrhea; colonoscopy reveals the appearance shown. 1. What is the pathogenesis of this problem? 2. How can this be treated? ERRNVPHGLFRVRUJ Answers: Side A 1. This greenish exudate ( ▴) is typical of antibiotic-associated (pseudomembranous) enterocolitis . 2. Broad-spectrum antibiotics such as clindamycin are most often implicated, although almost any antibiotic can cause this condition. 3. The antibiotic therapy depletes the bowel flora that normally impedes the overgrowth of Clostridium difficile. After antibiotic treatment, resistant C. difficile organisms expand. 4. The C. difficile organisms elaborate conjoined A and B toxins. B binds enterocyte epithelium and permits the delivery of the A subunit, which causes cytokine production and apoptosis. ERRNVPHGLFRVRUJ 17.15 Side A (PBD9: 816; BP9: 600) ERRNVPHGLFRVRUJ Questions A 22-year-old woman initially developed nausea with periumbilical pain 1 day before hospital admission; the pain is now in her right lower quadrant, and she has rebound tenderness. Her abdominal CT scan is shown. 1. What is the diagnosis? 2. What CT changes are seen? 3. What complications can occur? ERRNVPHGLFRVRUJ Answers: Side B 1. The columnar mucosa is ulcerated ( ▸) and inflamed ( •). 2. Acute appendicitis can be mimicked by mesenteric lymphadenitis, inflammatory bowel disease, infectious enterocolitis (e.g., Yersinia), ectopic pregnancy in women, diverticulitis, and even ovulation (mittelschmerz). 3. Neutrophilia with a left shift is typical of acute inflammation. Elevations in blood proteins that are acute-phase reactants (principally fibrinogen but also C-reactive protein, serum amyloid A protein, and immunoglobulins) lead to reduced repellant forces among erythrocytes; this results in stacks of RBCs (rouleaux) that precipitate more readily, which also increases the erythrocyte sedimentation rate. ERRNVPHGLFRVRUJ 17.15 Side B (PBD9: 816; BP9: 600) ERRNVPHGLFRVRUJ Questions A 31-year-old man has had severe abdominal pain and fever for 2 days. On examination, he has a right iliopsoas sign. His WBC count is elevated, with 72% neutrophils and 9% band forms, and a peripheral blood smear shows rouleaux formation. Laparoscopic abdominal surgery is performed, and the microscopic appearance of the resected lesional tissue is shown. 1. Describe the findings. 2. Give the differential diagnoses. 3. Explain the laboratory findings. ERRNVPHGLFRVRUJ Answers: Side A 1. She has acute appendicitis . 2. The enlarged appendix ( ◂) contains a bright fecalith (inspissated stool blocking the movement of mucus and sloughed epithelium out of the appendix). Bright inflammatory stranding ( ▴) extends into adipose tissue. 3. Untreated appendicitis can lead to rupture, with peritonitis and sepsis. Less common complications include pylephlebitis (with portal vein thrombosis) and hepatic abscess. ERRNVPHGLFRVRUJ 17.16 Side A (PBD9: 782; BP9: 577) ERRNVPHGLFRVRUJ Questions A 33-year-old man with a 5-year history of chronic diarrhea has recently lost 6 kg and become chronically fatigued. A biopsy specimen of his jejunum (top ) is compared with a normal jejunal biopsy specimen (bottom ). After a change in diet, he improves. 1. What is your diagnosis? 2. What serologic tests can aid in diagnosis? 3. What was the dietary change? 4. What skin condition can accompany this disease? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has lactase deficiency . Disaccharidases are secreted from apical enterocytes, with infants expressing more than adults. Europeans typically have more lactase expression than Asians do. 2. When disaccharides are not absorbed, gut bacteria have increasing substrate to ferment, which produces hydrogen that is absorbed and exhaled. It is the bacterial overgrowth and osmotic diarrhea that cause the unpleasant symptoms. 3. Foods containing lactose sugar include dairy products; avoiding these will reduce the symptoms. ERRNVPHGLFRVRUJ 17.16 Side B (PBD9: 784; BP9: 579) ERRNVPHGLFRVRUJ Questions A 23-year-old woman from Hong Kong who is living in Zurich has had bouts of explosive, watery diarrhea with abdominal bloating since her arrival 6 months ago. Her stool has no occult blood, ova, parasites, or bacterial pathogens. Her laboratory findings are shown. 1. What is your diagnosis? 2. What is the pathogenesis? 3. How can this be treated? ERRNVPHGLFRVRUJ Answers: Side A 1. The flattening with atrophy of the villi, the loss of goblet cells, and the chronic inflammation are features of celiac disease (nontropical sprue or gluten-sensitive enteropathy). 2. Testing for antiendomysial antibodies (directed against transglutaminase in epithelial cells), antigliadin antibodies, and antireticulin antibodies may be helpful. 3. Gluten (found in wheat, rye, or barley flour) contains the gliadin protein that binds to epithelial cells; cytotoxic T cell injury directed against gliadin-modified cells leads to cell loss. The removal of gluten (gliadin) from the diet removes the antigenic stimulus to the T cells, and the epithelium is eventually restored. 4. Dermatitis herpetiformis , with sub-basilar skin blistering and associated IgA deposition, may occur with this condition. ERRNVPHGLFRVRUJ 17.17 Side A (PBD9: 798; BP9: 589) ERRNVPHGLFRVRUJ Questions A 28-year-old woman develops cramping abdominal pain with diarrhea and fever. Her stool culture grows no pathogens. Colonoscopy shows lesions that are separated by normal mucosa (shown), and an abdominal CT scan indicates small bowel involvement. 1. What is your diagnosis? 2. What microscopic features are typically present? 3. Is there a risk for malignancy? ERRNVPHGLFRVRUJ Answers: Side B 1. There are areas of stricture ( ▸) and a fistula ( ◂) between small bowel loops (enteroenteric fistula) that are consistent with Crohn disease . 2. The patient could develop perforation with peritonitis, septicemia, or both. 3. Extraintestinal manifestations include primary sclerosing cholangitis, sacroiliitis, ankylosing spondylitis, migratory polyarthritis, and erythema nodosum . ERRNVPHGLFRVRUJ 17.17 Side B (PBD9: 798; BP9: 589) ERRNVPHGLFRVRUJ Questions A 19-year-old man with a 2-year history of intermittent abdominal pain with diarrhea now presents with bowel obstruction. A radiographic contrast study is shown. 1. What is your diagnosis? 2. What complications could develop from this? 3. What extraintestinal manifestations may occur? ERRNVPHGLFRVRUJ Answers: Side A 1. This is Crohn disease involving both the large and small bowel, with “skip” lesions. The normal mucosal folds are absent. There is erythema with granularity and focal ulceration ( ◂). 2. Microscopic features classically associated with Crohn disease include granuloma formation and transmural inflammation. 3. Yes. The risk fivefold to sixfold greater, but it is lower than that associated with ulcerative colitis. Because the lesions can occur from the stomach to the rectum, the prophylactic resection of bowel is not indicated; surgery may precipitate the formation of fistulous tracts in some cases. ERRNVPHGLFRVRUJ 17.18 Side A (PBD9: 800; BP9: 590) ERRNVPHGLFRVRUJ Questions A 28-year-old woman with a 2-year history of bloody mucoid diarrhea undergoes colonoscopy. The lesions shown extend from the rectum to the transverse colon. 1. What is the diagnosis? 2. What microscopic findings are present? 3. What immune cell plays a key role? ERRNVPHGLFRVRUJ Answers: Side B 1. There is severe colonic mucosal erosion leaving behind only small islands of residual mucosa; these are so-called pseudopolyps ( ▸). 2. The gross appearance and course are typical for chronic ulcerative colitis . 3. Hepatic manifestations of inflammatory bowel disease include pericholangitis and primary sclerosing cholangitis ; these can occur even after total colectomy. 4. The risk for adenocarcinoma is so high (roughly 10% increased risk for each decade with disease) that colectomy is often performed. ERRNVPHGLFRVRUJ 17.18 Side B (PBD9: 800; BP9: 590) ERRNVPHGLFRVRUJ Questions A 40-year-old man with a 15-year history of intermittent diarrhea and cramping pain undergoes colectomy; the gross appearance of his colon is shown. 1. Describe the features shown. 2. What is the underlying disease? 3. What hepatic complication can occur? 4. What is a serious long-term complication of this condition? ERRNVPHGLFRVRUJ Answers: Side A 1. The loss of the haustral folds and the focal mucosal ulcerations ( ▸), with continuous involvement beginning in the rectum, are consistent with chronic ulcerative colitis . 2. Features that are more characteristic of ulcerative colitis include inflammation limited to the mucosa, crypt abscesses, and the absence of granulomas . 3. Cell-mediated immune derangements are involved in inflammatory bowel disease; specifically, overly exuberant CD4+ lymphocyte responses to normal intestinal flora are a key element driving the ongoing inflammation. ERRNVPHGLFRVRUJ 17.19 Side A (PBD9: 780; BP9: 576) ERRNVPHGLFRVRUJ Questions A 70-year-old man with an 8-month history of increasing fatigue is found to have a hemoglobin level of 8 g/dL (nl 13.8 to 17.2 g/dL) with an MCV of 71 fL (nl 78 to 102 fL). His serum ferritin level is 80 ng/dL (nl 18 to 350 ng/dL). Cardiac evaluation reveals a murmur of aortic stenosis. Gastrointestinal evaluation includes a colonoscopy; an abnormal area is shown. 1. What do this patient's laboratory findings indicate? 2. What is your diagnosis of the lesion? 3. What is the pathogenesis? ERRNVPHGLFRVRUJ Answers: Side B 1. There is a stellate arborization ( ▾) of irregular vessels that is consistent with angiodysplasia . 2. These are tortuous and dilated (ectatic) thin-walled vessels. 3. The right colon and the cecum are most often involved, probably because the luminal diameter is greater, which increases the pressure on submucosal vessels. 4. No. This is a benign vascular malformation (other than its propensity to bleed). ERRNVPHGLFRVRUJ 17.19 Side B (PBD9: 780; BP9: 576) ERRNVPHGLFRVRUJ Questions After passing maroon-colored stool, an otherwise healthy 79-year-old woman presents for evaluation. Her colonoscopy shows no lesions. Angiography of the superior mesenteric artery reveals the lesion shown. 1. What is your diagnosis? 2. What would be the typical histologic appearance? 3. Where are these lesions most often seen? 4. Is there a risk for malignancy? ERRNVPHGLFRVRUJ Answers: Side A 1. The findings indicate microcytic anemia that is consistent with iron-deficiency anemia caused by chronic blood loss. 2. There is a focal area of abnormal vessels ( ◂) with dark red irregular channels seen beneath the mucosa. This is angiodysplasia . 3. There may be degenerating small blood vessels, mucosal hypoperfusion from cardiac disease (e.g., aortic stenosis), diminished type IV collagen, or the increased expression of angiogenic factors associated with age-related endothelial dysfunction. ERRNVPHGLFRVRUJ 17.20 Side A (PBD9: 803; BP9: 586) ERRNVPHGLFRVRUJ Questions An 83-year-old man with a lifetime of chronic constipation has a 5-year history of mild lower abdominal discomfort. His examination reveals active bowel sounds, no masses, and no tenderness. His abdominal CT scan is shown. 1. What is shown in the CT scan? 2. Is he at increased risk for cancer? 3. What important complication can occur? ERRNVPHGLFRVRUJ Answers: Side B 1. Diverticula ( ▸) and a small adenoma ( ◂) are present. 2. This patient has borderline microcytic anemia , which is typical among patients with iron deficiency anemia associated with blood loss. The small adenoma is one possible source. The diverticula may become impacted with stool that erodes the narrow neck of the outpouchings, with resultant bleeding from small submucosal vessels. ERRNVPHGLFRVRUJ 17.20 Side B (PBD9: 803; BP9: 586) ERRNVPHGLFRVRUJ Questions A 74-year-old woman with occult blood in her stool has a hematocrit level of 35.7% (nl 35% to 46%), an MCV of 79 fL (nl 78 to 102 fL), and normal platelet and WBC counts. Pertinent findings at colonoscopy are shown. 1. What two diagnoses can you make? 2. Explain the laboratory findings. ERRNVPHGLFRVRUJ Answers: Side A 1. The dark, air-filled outpouchings ( diverticulosis ) ( ▴) are in the rectosigmoid region. The bowel lumen shows a mixture of air and fluid that is typical for stool. 2. There is no increased risk for cancer with diverticular disease. Decreased dietary fiber and constipation play roles in the development of the diverticula, but the role of fiber in cancer is inconclusive. 3. Diverticulitis occurs if diverticula become inflamed (e.g., as a result of inspissated stool). The perforation of an inflamed diverticulum can lead to peritonitis and abscess formation. ERRNVPHGLFRVRUJ 17.21 Side A (PBD9: 778; BP9: 573) ERRNVPHGLFRVRUJ Questions A 42-year-old man with a 2-day history of increasing abdominal pain has a distended abdomen and high-pitched bowel sounds. His abdominal CT scan is shown. 1. What is your diagnosis? 2. Surgery is recommended. Why? 3. How could this have happened? ERRNVPHGLFRVRUJ Answers: Side B 1. The dilated bowel with air-fluid levels ( ▴) results from bowel obstruction . 2. Obstruction may be due to (a) neoplasm such as carcinoma of the colon or pancreas that impinges on bowel; (b) adhesions after surgery that can create an “internal hernia,” in which a loop of bowel becomes trapped; or (c) volvulus , in which mobile cecum or sigmoid twists on itself. Small bowel volvulus occurs with twisting on the mesentery. 3. The term would be ileus or paralytic ileus. This condition characteristically occurs postoperatively after abdominal surgery. Ileus can also occur with inflammation, such as peritonitis. ERRNVPHGLFRVRUJ 17.21 Side B (PBD9: 777; BP9: 573) ERRNVPHGLFRVRUJ Questions A 53-year-old woman with a 3-day history of worsening abdominal pain without flatus or bowel movement has the upright radiograph shown. 1. What is your diagnosis? 2. What is the likely cause if (a) multiple lung nodules are present; (b) she had prior abdominal surgery; or (c) the cecum or the sigmoid colon is involved? 3. What term describes nonmechanical obstruction? ERRNVPHGLFRVRUJ Answers: Side A 1. The target-like intussusception ( ▸) occurs when bowel telescopes on itself, thereby leading to bowel obstruction. Note the dilated and air-filled proximal bowel. 2. Blood supply to the bowel is compromised, and infarction leading to perforation with peritonitis and sepsis can occur. 3. In adults, an intraluminal mass (e.g., a polyp) may be the leading point of the intussusception. The presence of melanotic oral, genital, or palmar lesions suggest Peutz-Jeghers syndrome . In infants, no underlying abnormality may be present. In children, rotavirus infection has also been implicated. ERRNVPHGLFRVRUJ 17.22 Side A (PBD9: 804; BP9: 593) ERRNVPHGLFRVRUJ Questions Screening evaluation for an asymptomatic 55-year-old woman reveals no occult blood in her stool. However, routine colonoscopy shows this finding at 20 cm. 1. What is your diagnosis? 2. What is the malignant potential? 3. In what region of the colon is it located? ERRNVPHGLFRVRUJ Answers: Side B 1. This hyperplastic polyp is composed of well-formed glands ( ▾) that are more cellular and crowded than the normal colonic mucosa. Infoldings can produce a serrated appearance. 2. Hyperplastic polyps account for 90% of all colonic epithelial polyps, which are far more common than tubular adenomas. 3. Most occur during the sixth and seventh decades of life, but they can appear at any age. 4. They are not clinically significant, although they need to be distinguished from sessile serrated adenomas that do have malignant potential. 5. Juvenile polyps and Peutz-Jeghers polyps are forms of hamartomatous, nonneoplastic polyps. ERRNVPHGLFRVRUJ 17.22 Side B (PBD9: 804; BP9: 593) ERRNVPHGLFRVRUJ Questions On routine screening colonoscopy, a 60-year-old man has three small 0.5-cm diameter nipple-like lesions that are found at 15 cm and 25 cm. The microscopic appearance of one is shown. 1. What is your diagnosis? 2. Is this lesion more or less common than a tubular adenoma? 3. At what age are they most likely to occur? 4. What is their clinical significance? 5. Name two forms of hamartomatous colonic polyps. ERRNVPHGLFRVRUJ Answers: Side A 1. These small projections ( ▴) are hyperplastic polyps . They can occur singly, but they are most often multiple. 2. There is no malignant potential with hyperplastic polyps. 3. This image is of the rectosigmoid (20 cm above the anal verge), where most hyperplastic polyps reside. ERRNVPHGLFRVRUJ 17.23 Side A (PBD9: 807; BP9: 593) ERRNVPHGLFRVRUJ Questions In accordance with screening guidelines, a 51-year-old man has a colonoscopy. The procedure uncovers a lesion that results in a partial colonic resection. The gross appearance of the solitary lesion is shown. 1. What is your diagnosis? 2. What is the pathogenesis? 3. What are the potential dietary contributions? ERRNVPHGLFRVRUJ Answers: Side B 1. This is a tubular adenoma ; the glands are well differentiated but hypercellular ( ▾), with hyperchromatic and atypical nuclei that are indicative of dysplasia. There is no invasion at the lower base ( ◂). 2. The patient's relatively young age and the microsatellite instability suggest that she has hereditary nonpolyposis colorectal cancer syndrome (Lynch syndrome) ; this is due to the inactivation of a DNA mismatch repair gene. Familial adenomatous polyposis syndrome (caused by mutations in the APC gene, which is involved in Wnt/βcatenin signaling) typically manifests within the first 2 decades of life via hundreds of polyps. 3. This patient is at risk for extracolonic cancer, including endometrial, ovarian, gastric, and small bowel carcinoma. ERRNVPHGLFRVRUJ 17.23 Side B (PBD9: 807; BP9: 593) ERRNVPHGLFRVRUJ Questions A 38-year-old woman with a positive fecal occult blood test is found on colonoscopy to have multiple hyperplastic polyps in the ascending colon and more than 10 0.5- to 1-cm polypoid lesions in the transverse and descending colons. One of these larger polyps is shown after biopsy. 1. What is your diagnosis? 2. If genetic analysis reveals microsatellite instability, what is the patient's likely inherited syndrome? 3. What other malignancies are possible? ERRNVPHGLFRVRUJ Answers: Side A 1. This circumscribed, pedunculated, polypoid lesion on a long stalk is a colonic adenoma . The larger the size, the more likely it is that carcinoma is present. 2. A sporadic lesion in an adult is likely to be the result of random events that led to mutational “hits” on certain genes (e.g., APC, K-RAS, p53, SMAD) and DNA mismatch repair genes. 3. Diets that are higher in total calories, refined carbohydrates, and red meat as well as diets that include decreased fiber and micronutrient intake increase the risk for colonic carcinogenesis. ERRNVPHGLFRVRUJ 17.24 Side A (PBD9: 809; BP9: 595) ERRNVPHGLFRVRUJ Questions A 17-year-old girl with severe iron deficiency anemia is found to have occult blood in her stool. Colonoscopy is followed in short order by total colectomy, with the gross appearance shown. A sibling is similarly affected. 1. What syndrome does this patient have? 2. What is the genetic mutation? 3. What syndrome with a similar gene mutation involves bone, skin, and soft-tissue lesions? 4. Why is colectomy performed? ERRNVPHGLFRVRUJ Answers: Side B 1. This is hereditary nonpolyposis colon carcinoma (HNPCC) syndrome , in which there are fewer polyps as compared with FAP. Carcinoma typically develops at an older age compared with adenomatous polyposis coli (APC). 2. HNPCC involves the autosomal-dominant inheritance of a faulty DNA mismatch repair gene, which leads to microsatellite instability . Microsatellites are tandem repeats of one to six nucleotides; these are uniform within all tissues. With mismatch repair defects, the expansion and contraction of the number of these repeats is seen in tumor cells. 3. Yes. However, the mutations take longer to acquire. ERRNVPHGLFRVRUJ 17.24 Side B (PBD9: 810; BP9: 596) ERRNVPHGLFRVRUJ Questions A 38-year-old man with a family history of colon cancer undergoes a colonoscopy, and shortly thereafter, a partial colectomy. His ascending colon has the appearance shown. 1. What inherited disease does he likely have? 2. What is the genetic basis for this disease? 3. Do sporadic colon cancers have similar genetic abnormalities? ERRNVPHGLFRVRUJ Answers: Side A 1. This is familial adenomatous polyposis (FAP) . The colonic mucosal surface is carpeted by polyps ( ▴)—at least 100 and often many more. 2. The APC gene produces a protein that regulates levels of β-catenin, which acts in the Wnt signaling pathway to regulate epithelial proliferation. APC is a tumor-suppressor gene. 3. Gardner syndrome involves osteomas, epidermal cysts, and fibromatosis in addition to polyposis. 4. There is a 100% risk for eventually developing adenocarcinoma. ERRNVPHGLFRVRUJ 17.25 Side A (PBD9: 810; BP9: 596) ERRNVPHGLFRVRUJ Questions A 57-year-old man has occult blood in his stools. His hematocrit level is 35.7% (nl 41% to 50%) and his MCV is 75 fL (nl 78 to 102 fL), with normal platelet and WBC counts. Colonoscopy reveals the lesion shown. 1. What is the most likely diagnosis? 2. What genetic mutations may be present? 3. What do the laboratory findings indicate? ERRNVPHGLFRVRUJ Answers: Side B 1. The “ napkin ring ” lesion ( ◂) results from a mass that encircles the colon, narrows the lumen, and gives the mucosa an irregular appearance. 2. A biopsy specimen would show adenocarcinoma with irregular hyperplastic glands exhibiting nuclear hyperchromasia and pleomorphism, possibly with necrosis and invasion. 3. At this patient's age, a sporadic tumor with the slow accumulation of multiple mutations is likely; this is not related to the inheritance of an abnormal gene such as APC. There are no additional polyps to suggest a polyposis syndrome. 4. Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors may reduce the risk for colon cancer by blocking cyclooxygenase-2 activity, which may regulate angiogenesis and apoptosis. ERRNVPHGLFRVRUJ 17.25 Side B (PBD9: 810; BP9: 596) ERRNVPHGLFRVRUJ Questions A 77-year-old man notes a 1-year history of fewer stools with smaller caliber; his stool guaiac test is positive. A barium enema with air contrast reveals the lesion shown. 1. Describe this lesion. 2. What histology would be seen on a biopsy specimen? 3. Is this lesion likely hereditary or sporadic? 4. What drugs reduce the risk for such lesions? ERRNVPHGLFRVRUJ Answers: Side A 1. The large sessile mass ( •) with irregular margins and overlying ulceration with hemorrhage is typical for adenocarcinoma . 2. Colorectal carcinogenesis involves the accumulation of genetic mutations, including APC, K-RAS, p53, SMAD-2, and SMAD-4 as well as components of the Wnt/β-catenin system and telomerase activation. 3. This patient has hypochromic microcytic anemia as a result of chronic blood loss and its associated iron deficiency. ERRNVPHGLFRVRUJ 17.26 Side A (PBD9: 773; BP9: 571) ERRNVPHGLFRVRUJ Questions A 45-year-old man with a 6-month history of abdominal cramps and watery diarrhea, dyspnea with wheezing, and cutaneous flushing is found to have an increased liver span and a tricuspid valve murmur. His abdominal CT scan is shown. 1. What syndrome does he have? 2. What is the duodenal neoplasm likely to be? 3. What compounds may be found in his serum and urine? ERRNVPHGLFRVRUJ Answers: Side B 1. This carcinoid tumor has nests and ribbons of monotonous round cells that have arisen from the neoplastic expansion of a normal neuroendocrine cell population. Gastrin production by this neoplasm would result in Zollinger-Ellison syndrome . 2. The elaboration of ACTH by carcinoid tumors can lead to increased adrenal corticosteroid output, which in turn leads to Cushing syndrome . ERRNVPHGLFRVRUJ 17.26 Side B (PBD9: 773; BP9: 571) ERRNVPHGLFRVRUJ Questions A 39-year-old man with small bowel obstruction undergoes segmental resection. The microscopic appearance of the tumor is shown with immunohistochemical staining for a specific hormone. 1. What would this hormone be if the patient had multiple gastric and duodenal ulcers? 2. What would this hormone be if the patient had hypertension, secondary diabetes, fat redistribution centrally, and easy bruisability? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has carcinoid syndrome , caused by a tumor that produces histamine, serotonin, and other vasoactive mediators that are normally degraded by the liver. Symptoms occur only after the development of significant hepatic metastases ( ▸) that directly dump their neuroendocrine content into the venous circulation. 2. The circumscribed enhancing duodenal mass ( ▾) is likely a primary carcinoid tumor . Most carcinoids follow an indolent course, even with metastases. Although the appendix is the most common primary site, it is rarely a source of metastases. 3. Elevated levels of 5-hydroxytryptamine (5-HT) and its metabolite 5hydroxyindoleacetic acid (5-HIAA) may be present. ERRNVPHGLFRVRUJ 18 ERRNVPHGLFRVRUJ Liver and Biliary Tract ERRNVPHGLFRVRUJ 18.1 Side A (PBD9: 845; BP9: 625) ERRNVPHGLFRVRUJ Questions A 41-year-old man has an increased liver span. His abdominal CT scan is shown. 1. Describe the CT findings. 2. If his hemoglobin A is 9%, what is the likely cause of the liver disease? 1c 3. If his body mass index is 35 (nl 18.5 to 25), how does this explain the findings? ERRNVPHGLFRVRUJ Answers: Side B 1. Macrovesicular (large droplet) steatosis within the hepatocyte cytoplasm (clear holes [▪]) can be due to increased peripheral triglyceride mobilization, impaired metabolism of fatty acids to triglycerides, lack of apoprotein synthesis, or impaired lipoprotein release into the circulation. Steatosis is reversible. 2. Diminished albumin synthesis leads to hypoalbuminemia , decreased intravascular oncotic pressure, and ascites . 3. To calculate this value, start with the following: 14% of 750 mL = 105 mL = 83 mg of ethanol. This is then distributed in 30 L of total body water to give a concentration of 277 mg/dL = 0.28 g/dL, which is a level of severe mental impairment. ERRNVPHGLFRVRUJ 18.1 Side B (PBD9: 842; BP9: 623) ERRNVPHGLFRVRUJ Questions A 49-year-old man with a history of alcohol abuse has had increasing abdominal girth for the past year. The microscopic appearance of his liver is shown. 1. Describe the microscopic findings. 2. Explain the increasing abdominal girth. 3. If he weighs 60 kg and has 50% body water, what is his blood ethanol level after consuming a bottle of wine (750 mL at 14% ethanol, with a specific gravity of 0.79)? ERRNVPHGLFRVRUJ Answers: Side A 1. The enlarged liver (♦) shows diminished attenuation (increased darkness) compared with the spleen as a result of increased lipid content from steatosis (compare with subcutaneous fat [▪]). 2. An elevated hemoglobin A level is consistent with diabetes mellitus, which is a risk factor for nonalcoholic fatty liver . 1c 3. Obesity can also drive hepatic steatosis . Severe malnutrition increases fat mobilization from the extremities, and, when this is coupled with inadequate apolipoprotein synthesis, steatosis can result. ERRNVPHGLFRVRUJ 18.2 Side A (PBD9: 827; BP9: 607) ERRNVPHGLFRVRUJ Questions A 42-year-old man received blood transfusions 7 years ago. He now has increased abdominal girth and ballotable fluid. His total protein level is 5 g/dL (nl 6 to 8.5 g/dL), his albumin level is 2.5 g/dL (nl 3.5 to 5 g/dL), his AST level is 150 U/L (nl ≤42 U/L), and his ALT level is 170 U/L (nl ≤48 U/L). He develops uncontrollable hematemesis and dies. His liver at autopsy is shown. 1. Suggest possible causes of this condition. 2. What caused his fluid wave? 3. What do the laboratory findings indicate? 4. What caused his death? ERRNVPHGLFRVRUJ Answers: Side B 1. Cirrhosis with chronic inflammation, bridging fibrosis, hepatocyte regeneration, and a small amount of steatosis are present. 2. The patient was also likely experiencing superinfection with hepatitis D virus (or hepatitis delta virus). 3. Approximately 80% to 90% of affected individuals experience complete recovery; 5% to 10% will become carriers. Only 4% of hepatitis B infections are persistent; 10% to 33% of these cases become chronic hepatitis, and 20% to 50% of chronic hepatitis cases go on to become cirrhosis. Superinfection with hepatitis D virus leads to chronic hepatitis in 80% of cases. Patients with chronic hepatitis and cirrhosis have a 10% risk for the development of hepatocellular carcinoma . ERRNVPHGLFRVRUJ 18.2 Side B (PBD9: 827; BP9: 607) ERRNVPHGLFRVRUJ Questions A 48-year-old intravenous drug abuser with known chronic hepatitis B develops worsened icterus and malaise 1 month after sharing needles. Her serum AST level is 220 U/L (nl ≤42 U/L), and her ALT level is 244 U/L (nl ≤48 U/L). Her liver biopsy specimen is shown. 1. Describe the findings. 2. What additional infection likely caused the acute worsening of her health status? 3. What are common outcomes with hepatitis B infection? ERRNVPHGLFRVRUJ Answers: Side A 1. Many nodules are more than 3 mm in diameter. This is consistent with a macronodular cirrhosis pattern that suggests chronic hepatitis B or C infection . 2. The fluid wave results from ascites caused by diminished hepatic albumin synthesis (and decreased intravascular oncotic pressure) coupled with portal hypertension. 3. Elevated transaminases indicate ongoing cytotoxic T-cell killing of virally infected hepatocytes. 4. Portal hypertension led to esophageal varices , which can rupture and cause exsanguination. ERRNVPHGLFRVRUJ 18.3 Side A (PBD9: 863; BP9: 634) ERRNVPHGLFRVRUJ Questions A 31-year-old woman with a 2-day history of worsening right upper quadrant pain has elevated hepatic aminotransferase levels. Ultrasound shows hepatic vein and inferior vena cava occlusion. Her abdominal CT scan is shown. 1. What is your diagnosis? 2. If she has an elevated partial thromboplastin time that is not corrected by 1 : 1 mixing with normal plasma, what coagulopathy could be present? 3. If her hemoglobin level is 20 g/dL (nl 12 to 15.6 g/dL), what might you suspect? ERRNVPHGLFRVRUJ Answers: Side B 1. Note the microvesicular steatosis (▸) and central vein thrombosis . This patient's preeclampsia progressed to acute fatty liver of pregnancy (as part of the HELLP syndrome [hemolysis, elevated liver enzymes, and low platelets]). Increased placental production of circulating fms-like tyrosine kinase-1 (sFlt1) receptor occurs; this binds and neutralizes the endothelial growth factors (e.g., vascular endothelial growth factor [VEGF]) necessary to maintain normal liver endothelial integrity. 2. In severe cases of preeclampsia, definitive treatment requires the termination of the pregnancy. 3. Reye syndrome would be suspected. The cause is unknown, but it may involve mitochondrial toxicity. ERRNVPHGLFRVRUJ 18.3 Side B (PBD9: 866; BP9: 626) ERRNVPHGLFRVRUJ Questions A 26-year-old woman develops peripheral edema, hypertension, and proteinuria during week 30 of her first pregnancy. In short order, she develops nausea, vomiting, and icterus, and her hepatic aminotransferases are markedly elevated. The representative microscopic appearance of her liver would be as shown. 1. What is your diagnosis? 2. How is this treated? 3. What syndrome in a child given aspirin results in similar microvesicular steatosis? ERRNVPHGLFRVRUJ Answers: Side A 1. Extensive hepatic infarction (▸) is present as a result of venous outflow occlusion ( Budd-Chiari syndrome , which often results from a severe hypercoagulable diathesis or a myeloproliferative disorder). Note the distended subcutaneous veins and splenomegaly caused by portal hypertension. 2. Antiphospholipid syndrome could be present. These antibodies promote in vivo thrombosis, although they prolong in vitro partial thromboplastin time clotting. 3. Polycythemia is one form of myeloproliferative disorder that leads to Budd-Chiari syndrome. ERRNVPHGLFRVRUJ 18.4 Side A (PBD9: 853; BP9: 605) ERRNVPHGLFRVRUJ Questions A 45-year-old woman has a 1-week history of scleral icterus and colicky right upper quadrant abdominal pain. Although her aminotransferase levels are only mildly elevated and her liver synthetic capacity is normal, her alkaline phosphatase level is 202 U/L (nl 20 to 125 U/L), and her total bilirubin level is 9 mg/dL (nl ≤1.3 mg/dL), with a direct bilirubin level of 8 mg/dL (nl ≤0.4 mg/dL). The microscopic appearance of her liver biopsy specimen is shown. 1. What is your diagnosis? 2. What enzyme is responsible for the conjugation of the material in the canaliculi? 3. What is causing this patient's pain? ERRNVPHGLFRVRUJ Answers: Side B 1. Patient 1 has hemolysis, which leads to the overproduction of bilirubin. The amount of bilirubin exceeds the liver's capacity to process it, which results in primarily unconjugated (indirect) hyperbilirubinemia . 2. Patient 2 probably has intrinsic hepatic disease (e.g., viral hepatitis), with elevated direct (excretion) and indirect (uptake and conjugation) bilirubin level; the elevated AST and ALT suggest concurrent hepatocyte injury. ERRNVPHGLFRVRUJ 18.4 Side B (PBD9: 853; BP9: 605) ERRNVPHGLFRVRUJ Questions The laboratory data from two patients with generalized jaundice are shown. 1. Why might patient 1 have hyperbilirubinemia? 2. Why might patient 2 have hyperbilirubinemia? ERRNVPHGLFRVRUJ Answers: Side A 1. Yellow-brown bile pigment (▴) is accumulating within bile canaliculi and as feathery droplets within hepatocyte parenchyma. This pattern of intrahepatic cholestasis is consistent with the elevated alkaline phosphatase level. In addition to being a result of gallstone obstruction, which is suggested by the colicky right upper quadrant pain, this pattern could be caused by certain drugs (e.g., isoniazid, ethanol), viral hepatitis, or early primary biliary cirrhosis. The bilirubin levels are a little too high for familial syndromes such as Dubin-Johnson syndrome. 2. Bilirubin UDP-glucuronyl transferase (UGT1A1) is located within the endoplasmic reticulum. 3. This patient likely has biliary tract lithiasis. A stone occluding the common bile duct can cause obstructive jaundice with mostly direct hyperbilirubinemia. Obstruction is evidenced further by the elevated alkaline phosphatase level. ERRNVPHGLFRVRUJ 18.5 Side A (PBD9: 842; BP9: 623) ERRNVPHGLFRVRUJ Questions A 42-year-old man with a history of alcohol abuse develops jaundice. His total serum bilirubin level is 5 mg/dL (nl ≤1.3 mg/dL), his direct bilirubin level is 4 mg/dL (nl ≤0.4 mg/dL), his AST level is 356 U/L (nl ≤42 U/L), his ALT level is 350 U/L (nl ≤48 U/L), his alkaline phosphatase level is 148 U/L (nl 20 to 125 U/L), his INR is 2 (nl 0.9 to 1.1), and his WBC count is 12,650/mm (nl 3800 to 10,800/mm ). His liver biopsy specimen is shown. 3 1. What complication has he developed? 2. What intermediate metabolite of alcohol is implicated? 3. What do the laboratory findings indicate? ERRNVPHGLFRVRUJ 3 Answers: Side B 1. The liver is nodular (▪), which is consistent with cirrhosis , and there is marked peritoneal fluid (♦) (i.e., ascites). 2. Portosystemic shunting and reduced hepatic function impair the urea cycle's clearance of ammonia as well as the clearance of mercaptans produced by gastrointestinal flora. Elevated levels of these compounds cause cerebral edema and hepatic encephalopathy. Asterixis is one manifestation of this. 3. Hepatorenal syndrome results from systemic vasodilation, increased renal sympathetic tone with afferent arteriole vasoconstriction, and increased renin production. ERRNVPHGLFRVRUJ 18.5 Side B (PBD9: 842; BP9: 623) ERRNVPHGLFRVRUJ Questions A 50-year-old man with a history of alcohol abuse has increasing abdominal girth and asterixis. His blood ammonia level is increased, and he has oliguria with elevated blood urea nitrogen and creatinine levels. His abdominal CT scan is shown. 1. Describe the features shown here. 2. Why is this patient's blood ammonia level increased? 3. Why is his kidney function affected? ERRNVPHGLFRVRUJ Answers: Side A 1. The hepatocyte injury includes swelling, necrosis, Mallory bodies (▴), neutrophilic infiltrates, and fatty change, all of which are consistent with alcoholic hepatitis . 2. Acetaldehyde induces lipid peroxidation and acetaldehyde-protein adduct formation. 3. The inflammation leads to neutrophilia. Reduced hepatocyte synthetic function leads to reduced vitamin K–dependent coagulation factors (II, V, VII, and X). Hepatocyte necrosis increases the release of AST and ALT. The hyperbilirubinemia of alcoholic hepatitis reflects intrahepatic biliary obstruction. ERRNVPHGLFRVRUJ 18.6 Side A (PBD9: 875; BP9: 639) ERRNVPHGLFRVRUJ Questions A 46-year-old woman with a week-long history of clay-colored stools and colicky right upper quadrant pain has a total bilirubin level of 5.5 mg/dL (nl ≤1.3 mg/dL), with most being direct. Her abdominal ultrasound scan is shown. 1. What is your diagnosis? 2. What is the pathogenesis? 3. Explain the symptoms. ERRNVPHGLFRVRUJ Answers: Side B 1. The opened gallbladder reveals two composite (mixed) gallstones. The pain is due to cholelithiasis and mechanical duct obstruction ( choledocholithiasis ) with accompanying inflammation ( cholecystitis ). 2. Hyperlipidemia favors the formation of cholesterol stones . 3. The direct hyperbilirubinemia is also consistent with choledocholithiasis (stones in the duct) causing biliary tract obstruction. Primary hepatic diseases tend to produce a mixed direct and indirect hyperbilirubinemia. A high indirect fraction suggests acute hemolysis. ERRNVPHGLFRVRUJ 18.6 Side B (PBD9: 875; BP9: 639) ERRNVPHGLFRVRUJ Questions A 51-year-old man with hyperlipidemia has a 2-year history of intermittent right upper quadrant pain. His liver span is normal, but there is tenderness along the margin. His total bilirubin level is 7 mg/dL (nl ≤1.3 mg/dL), mostly direct (conjugated) bilirubin. After surgery, the culprit lesion is shown. 1. What is your diagnosis? 2. Explain the pathogenesis. 3. Explain the laboratory findings. ERRNVPHGLFRVRUJ Answers: Side A 1. The bright, echodense, rounded objects (◂) within the echolucent, bile-filled gallbladder represent gallstones . 2. Cholelithiasis most often occurs among obese individuals who are more than 40 years old and predominantly among women (remember the “four f's”: fat, fecund, forty, female). Choleliths precipitate out as a result of imbalances of cholesterol, bile salts, and bilirubin in the bile. 3. Pain is caused by gallbladder inflammation ( cholecystitis ) and by stones passing into the common bile duct ( choledocholithiasis ). Mechanical duct obstruction blocks bile excretion, which leads to clay-colored stools and jaundice (hyperbilirubinemia). ERRNVPHGLFRVRUJ 18.7 Side A (PBD9: 847; BP9: 629) ERRNVPHGLFRVRUJ Questions A 43-year-old man with worsening arthritis and darkening skin is diagnosed with newonset congestive heart failure. His hemoglobin A level is 10% (nl ≤6%), with a fasting glucose level of 152 mg/dL (nl ≤110 mg/dL). His liver biopsy specimen is shown with Prussian blue stain. 1c 1. What is your diagnosis? 2. What is the likely gene mutation? 3. How does this mutation affect intestinal crypt cells? 4. Explain the laboratory findings. 5. Why might women be protected against hemochromatosis until they are postmenopausal? ERRNVPHGLFRVRUJ Answers: Side B 1. Most patients with Wilson disease are compound heterozygotes for mutations in the ATP7B gene that encodes for a copper-transporting ATPase . 2. The serum ceruloplasmin level is decreased . The urinary copper level is increased in this autosomal-recessive condition. 3. Corneal Kayser-Fleischer rings that result from copper deposition in the Descemet membrane may be present. 4. The basal ganglia show atrophy and cavitation, most often involving the putamen. ERRNVPHGLFRVRUJ 18.7 Side B (PBD9: 849; BP9: 630) ERRNVPHGLFRVRUJ Questions A 21-year-old woman who has been diagnosed with psychosis has a tremor on examination and difficulty initiating movement. Her AST and ALT values are both moderately elevated. Her liver biopsy specimen is shown stained for copper. 1. What is your diagnosis? 2. What other laboratory findings could be present? 3. What ocular finding is often present? 4. What part of the brain is usually involved? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has hereditary hemochromatosis. There is hepatic cirrhosis with marked hepatic iron accumulation. 2. The most common mutation in northern European populations involves the HFE gene, typically C282Y. 3. HFE is part of a hepatocyte complex that senses circulating iron levels. Mutant HFE results in reduced hepcidin production, which leads to increased iron transport from enterocytes into the bloodstream. 4. Iron accumulation in the pancreatic islets causes free-radical–induced injury and diabetes mellitus. 5. Menstrual blood loss is a way to deplete iron stores. Therapy for many such patients is regular phlebotomy. ERRNVPHGLFRVRUJ 18.8 Side A (PBD9: 850; BP9: 631) ERRNVPHGLFRVRUJ Questions A 40-year-old man with increasing fatigue and confusion presents with asterixis and a palpable liver with a firm, nodular edge. His plasma ammonia level is elevated. His liver biopsy specimen with periodic acid–Schiff (PAS) stain after diastase treatment (to remove glycogen) is shown. 1. What is your diagnosis? 2. What is the pathogenesis? 3. What condition might he have had as a neonate? ERRNVPHGLFRVRUJ Answers: Side B 1. The normal allele for α -antitrypsin is PiM, and the two most common abnormal alleles are PiS and PiZ. 1 2. The heterozygotes PiMS and PiMZ sometimes may develop pulmonary disease, liver disease, or both, but these are usually not severe. 3. The homozygotes PiSS and PiZZ and the compound heterozygote PiSZ are more likely to develop significant chronic obstructive pulmonary disease, liver disease, or both. Individuals with PiZZ are most likely to develop severe complications of AAT deficiency. About 1 in 10 individuals of European ancestry has one of the five abnormal phenotypes. ERRNVPHGLFRVRUJ 18.8 Side B (PBD9: 850; BP9: 631) ERRNVPHGLFRVRUJ Questions A family pedigree is shown for a cohort with α -antitrypsin (AAT) deficiency. Affected family members have panlobular emphysema, cirrhosis, or both. 1 1. Which alleles are normal, and which are abnormal? 2. What happens to heterozygotes? 3. What happens to homozygotes and compound heterozygotes? ERRNVPHGLFRVRUJ Answers: Side A 1. The round, cytoplasmic, PAS-positive, diastase-resistant globules (▴) are near the portal tract, which is characteristic of α -antitrypsin ( AAT ) disease . The blood ammonia level is increased as a result of hepatic failure (hepatic encephalopathy is also suggested by the confusion and asterixis). 1 2. AAT deficiency results from gene mutations that cause protein misfolding with retention in the hepatocyte endoplasmic reticulum. The resulting unfolded protein response (also called endoplasmic reticulum stress response) leads to the activation of apoptotic and autophagocytic pathways and culminates in fatty change, chronic hepatitis, and cirrhosis. 3. About 10% to 20% of newborns with AAT deficiency develop neonatal hepatitis . ERRNVPHGLFRVRUJ 18.9 Side A (PBD9: 858; BP9: 627) ERRNVPHGLFRVRUJ Questions A 45-year-old woman with worsening pruritus, abdominal discomfort, and steatorrhea for 2 years has xanthelasmas and tendon xanthomas, with hepatomegaly. Her serum alkaline phosphatase level is 341 U/L (nl 20 to 125 U/L). Her liver biopsy specimen is shown. 1. What is your diagnosis? 2. Explain the xanthomas and the xanthelasmas. 3. Why might she be at risk for vertebral compression fractures? ERRNVPHGLFRVRUJ Answers: Side B 1. This is antimitochondrial antibody ( AMA ). 2. AMA has reasonably good specificity for primary biliary cirrhosis ( PBC ), although whether the antibody is causal or just an epiphenomenon is unknown. 3. PBC follows a chronic course, eventually culminating in hepatic cirrhosis with portal hypertension and the development of portosystemic shunts, including esophageal varices. As liver function declines, hepatocytes cannot metabolize ammonia, and encephalopathy ensues. ERRNVPHGLFRVRUJ 18.9 Side B (PBD9: 858; BP9: 627) ERRNVPHGLFRVRUJ Questions A 48-year-old woman with increasing jaundice has a firm, nodular liver edge and a total serum cholesterol value of 308 mg/dL, which is markedly elevated. She develops esophageal variceal bleeding and hepatic encephalopathy. A serologic test shows bright fluorescence (▾) for renal tubular cell mitochondria. 1. What is this autoantibody? 2. What diagnosis is suggested by the presence of this autoantibody? 3. Explain this patient's variceal bleeding and encephalopathy. ERRNVPHGLFRVRUJ Answers: Side A 1. A chronic inflammatory infiltrate (◂) with the destruction of bile ductules is present in the portal tracts; this is consistent with primary biliary cirrhosis (PBC) . 2. The serum cholesterol level is elevated in patients with PBC, with subsequent cholesterol deposition forming mass lesions. 3. Decreased bile output leads to steatorrhea with the malabsorption of fat-soluble vitamins A, D, E, and K. The malabsorption of vitamin D leads to osteopenic fractures. ERRNVPHGLFRVRUJ 18.10 Side A (PBD9: 859; BP9: 628) ERRNVPHGLFRVRUJ Questions A 38-year-old man with a 6-year history of chronic fatigue now has ascites, weight loss, pruritus, and icterus. Serum autoantibodies (e.g., antimitochondrial antibodies) are not present. His cholangiogram is shown. 1. What is your diagnosis? 2. What is the pathogenesis of this disease? 3. What intestinal disease can also be associated with this condition? ERRNVPHGLFRVRUJ Answers: Side B 1. Extensive collagen deposition with onion-skin fibrosis (◂) and obliteration of the bile ducts is present. This suggests primary sclerosing cholangitis ( PSC ). 2. Biliary tree obstruction leads to the elevation of the alkaline phosphatase level. 3. No. 4. The end stage of PSC is similar to biliary cirrhosis, with marked cholestasis and cirrhosis . Biliary cirrhosis can occur as a result of chronic biliary tract obstruction, although this is uncommon because of the prompt diagnosis and treatment of most mechanical causes of biliary tract disease (e.g., cholelithiasis). ERRNVPHGLFRVRUJ 18.10 Side B (PBD9: 859; BP9: 628) ERRNVPHGLFRVRUJ Questions A 37-year-old man previously underwent colectomy for ulcerative colitis. He now presents with jaundice, upper gastrointestinal bleeding, and encephalopathy. His liver biopsy specimen with trichrome stain (collagen is blue) is shown. 1. What is your diagnosis? 2. What serum marker is most likely elevated? 3. Is the risk for hepatic neoplasia increased? 4. What is secondary biliary cirrhosis? ERRNVPHGLFRVRUJ Answers: Side A 1. A beaded pattern with bile duct stricture (▸) and pruning (▾) as a result of irregular segmental fibrosis suggests primary sclerosing cholangitis ( PSC ). 2. Hepatic macrophages secrete cytokines in response to an unknown stimulus, thereby attracting T cells into portal tracts and inducing fibrosis. 3. Patients with inflammatory bowel disease (ulcerative colitis in particular) can develop sclerosing cholangitis. ERRNVPHGLFRVRUJ 18.11 Side A (PBD9: 867; BP9: 635) ERRNVPHGLFRVRUJ Questions For the last 3 months, since she began taking oral contraceptives, a 23-year-old woman has experienced abdominal pain. Ultrasound shows a right hepatic mass with an enlarged afferent blood vessel, central arterial hypervascularity, and centrifugal filling to the periphery. The resected mass is shown. 1. What is your diagnosis? 2. What is the pathogenesis? 3. Why did she become symptomatic after beginning oral contraception? 4. Suggest a related lesion that might involve the entire liver. ERRNVPHGLFRVRUJ Answers: Side B 1. This is focal nodular hyperplasia (FNH) . There is a localized hepatic mass (▪). With contrast enhancement in the arterial phase, the lesion shows intense homogeneous enhancement of the lesion and nonenhancement of a central scar. 2. FNH is the proliferation of normal, non-neoplastic hepatocytes arranged in multiple spherical aggregates within a fibrous meshwork. There are usually one or more large central scars. ERRNVPHGLFRVRUJ 18.11 Side B (PBD9: 867; BP9: 635) ERRNVPHGLFRVRUJ Questions A 36-year-old man with a year-long history of vague right upper quadrant pain has normal liver function tests. A CT scan of his abdomen is shown. 1. What is your diagnosis? 2. What microscopic findings do you expect to see? ERRNVPHGLFRVRUJ Answers: Side A 1. This is focal nodular hyperplasia ( FNH ). 2. FNH is a localized hyperplastic hepatocyte response to an underlying vascular anomaly. The normal constituents of the liver are present but in a disorganized pattern. Note the central scar ( •). 3. Oral contraceptive pills can provoke hemorrhage or infarction within the mass. 4. Nodular regenerative hyperplasia can diffusely involve the entire liver. When that occurs, spherical regenerative nodules are not typically accompanied by fibrosis, but they can nevertheless lead to portal hypertension. ERRNVPHGLFRVRUJ 18.12 Side A (PBD9: 867; BP9: 636) ERRNVPHGLFRVRUJ Questions An otherwise healthy 26-year-old woman with right upper quadrant pain has imaging that shows a well-circumscribed 3- to 4-cm mass. The gross appearance of a similar liver lesion after formalin fixation is shown. 1. What is your diagnosis? 2. Is this benign or malignant? 3. What does the lesion look like histologically? 4. Name a risk factor for this lesion. ERRNVPHGLFRVRUJ Answers: Side B 1. The small, focal lesion (▸) of uniform density located within the liver is a hepatic adenoma . 2. These neoplasms are almost uniformly benign. When they are located near the liver capsule, however, they can occasionally rupture to produce hemoperitoneum. 3. During pregnancy, these lesions can increase in size in response to prolonged estrogenic stimulation. ERRNVPHGLFRVRUJ 18.12 Side B (PBD9: 867; BP9: 636) ERRNVPHGLFRVRUJ Questions A 30-year-old woman (G2, P1) woman is in her third trimester of pregnancy. She is bothered by increasing right upper quadrant pain. Tests of her hepatic function are normal. Her abdominal CT scan is shown. 1. What is your diagnosis? 2. What would be the cause if she had sudden severe abdominal pain with peritoneal lavage yielding bloody fluid? 3. Why is this lesion often diagnosed during pregnancy? ERRNVPHGLFRVRUJ Answers: Side A 1. This is an hepatic adenoma . The green color (▾) is caused by biliverdin, which is bilirubin that has been oxidized by formalin. If the neoplasm is making bile, it is of hepatocyte origin. 2. The small, circumscribed appearance is more consistent with a benign neoplasm, although these tumors can occasionally conceal hepatocellular carcinoma. 3. Sheets and cords of hepatocytes often have associated clearing as a result of abundant glycogen. No portal tracts—only prominent arteries and veins—are widely distributed. 4. These lesions tend to occur among young women who are taking oral contraceptives; they regress after cessation of the exogenous estrogenic stimulus. ERRNVPHGLFRVRUJ 18.13 Side A (PBD9: 870; BP9: 637) ERRNVPHGLFRVRUJ Questions A 54-year-old man has had right upper quadrant discomfort, nausea, and weight loss for 8 months. His abdominal CT scan is shown. 1. What is your diagnosis? 2. What laboratory test result might you expect to be elevated? ERRNVPHGLFRVRUJ Answers: Side B 1. This large hepatic mass (◂) with irregular borders and a greenish cut surface is hepatocellular carcinoma . 2. Because of the elevated transaminase levels, she likely has chronic hepatitis (viral hepatitis B or C). 3. In addition to viral hepatitis, hepatocellular carcinomas can arise in patients with alcoholic cirrhosis, in those who have ingested aflatoxins from Aspergillus flavus, and in those with hereditary hemochromatosis. 4. This patient's elevated transaminase levels are consistent with hepatic cell death from chronic active hepatitis. Reduced hepatocyte function reduces the production of albumin and of the vitamin K–dependent coagulation factors (II, V, VII, IX), thereby prolonging the prothrombin time. ERRNVPHGLFRVRUJ 18.13 Side B (PBD9: 870; BP9: 637) ERRNVPHGLFRVRUJ Questions A 61-year-old woman with a 10-year history of malaise and intermittent jaundice has right upper quadrant tenderness and splenomegaly. Her serum AST level is 310 U/L (nl ≤42 U/L), her ALT level is 344 U/L (nl ≤48 U/L), her total protein level is 5 g/dL (normal 6 to 8.5 g/dL), her albumin level is 3 g/dL (nl 3.5 to 5 g/dL), and her prothrombin time is 18 seconds (nl 10 to 12.5 seconds). Had we looked, her liver would appear as shown. 1. What is your diagnosis? 2. What underlying disease may have led to her condition? 3. What are other risk factors for this condition? 4. Explain the laboratory results. ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has hepatocellular carcinoma . There is a large solitary mass (▸) in the right lobe of the liver; the solitary nature suggests that it is primary in the liver, whereas the large size with heterogeneity (differences in attenuation or brightness) suggests that it is malignant. 2. Primary liver cancers are frequently associated with an elevated serum level of αfetoprotein . ERRNVPHGLFRVRUJ 18.14 Side A (PBD9: 874; BP9: 643) ERRNVPHGLFRVRUJ Questions A 58-year-old man who is known to be chronically infected with Clonorchis sinensis has right upper quadrant abdominal pain and pruritus. His total serum bilirubin level is 4.5 mg/dL (nl ≤1.3 mg/dL), almost all of which is direct. His alkaline phosphatase level is 296 U/L (nl 20 to 125 U/L). His abdominal CT scan is shown. 1. What is your diagnosis? 2. What are other risk factors for this neoplasm? 3. Explain the laboratory findings. ERRNVPHGLFRVRUJ Answers: Side B 1. A normal pattern of liver cords (▸) is present at the bottom, with a gland-forming (◂) neoplasm at the top; this is consistent with cholangiocarcinoma . Because it is derived from ductal epithelium, it does not make bile. 2. Cholangiocarcinomas can also arise in extrahepatic bile ducts. If such a lesion arises distal to the cystic duct, a palpably enlarged gallbladder would represent the gross correlate to the Courvoisier sign . 3. The liver is a common site for metastases, most of which are metastatic adenocarcinomas . Metastatic disease in the liver is substantially more common than primary cholangiocarcinoma. ERRNVPHGLFRVRUJ 18.14 Side B (PBD9: 874; BP9: 643) ERRNVPHGLFRVRUJ Questions A 62-year-old woman who has had a 4-kg weight loss over the last 2 months also notes increasing jaundice, pale stools, and dark urine. On examination, there is a firm right upper quadrant mass; radiologic staging reveals no other lesions. The microscopic appearance of a biopsy specimen of the mass is shown. 1. What is your diagnosis? 2. Where else could this neoplasm arise? What would an acutely enlarging, palpable gallbladder indicate? 3. What would you suspect if the imaging had shown a lesion elsewhere? ERRNVPHGLFRVRUJ Answers: Side A 1. The large, solitary hepatic mass ( •) with variably decreased attenuation is likely primary; given the patient's history of infection, it is most likely cholangiocarcinoma . 2. Primary sclerosing cholangitis (accompanying inflammatory bowel disease) and choledochal cysts are other risk factors for this condition. Hepatitis viruses B and C are more strongly associated with hepatocellular carcinoma. 3. The direct hyperbilirubinemia and elevated alkaline phosphatase levels suggest biliary tract obstruction . ERRNVPHGLFRVRUJ 19 ERRNVPHGLFRVRUJ The Pancreas ERRNVPHGLFRVRUJ 19.1 Side A (PBD9: 892; BP9: 652) ERRNVPHGLFRVRUJ Questions A 78-year-old woman has had constant epigastric pain and a 5-kg weight loss over 6 months. Her serum bilirubin and hepatic aminotransferase levels are normal, but her alkaline phosphatase level is 165 U/L (nl 20 to 125 U/L). Her abdominal CT scan is shown. 1. What is present on the CT scan? 2. Explain the laboratory data. 3. What are possible risk factors for this condition? ERRNVPHGLFRVRUJ Answers: Side B 1. There are irregularly shaped glands ( ▴) in a fibrous stroma, which is consistent with adenocarcinoma and an associated desmoplastic reaction . 2. K-RAS, p16, SMAD4, and p53 gene mutations have been found in pancreatic cancers. 3. She likely has a hypercoagulable state ( Trousseau syndrome or migratory thrombophlebitis ) that can cause venous and arterial thrombosis driven by the procoagulants produced by the neoplastic cells. The patient's pulmonary embolism could have been derived from a deep venous thrombosis in her lower extremities. ERRNVPHGLFRVRUJ 19.1 Side B (PBD9: 892; BP9: 652) ERRNVPHGLFRVRUJ Questions A 90-year-old woman who has had constant abdominal pain for 3 months is found to have a mass in the tail of her pancreas. The histology of the resected lesion is shown. She subsequently develops a pulmonary embolism, which requires the placement of an inferior vena cava filter. 1. Describe the microscopic appearance. 2. What genetic mutations may be present in these cells? 3. What paraneoplastic syndrome might she have? ERRNVPHGLFRVRUJ Answers: Side A 1. The CT scan shows a large, irregular mass ( ■) involving the body and tail of the pancreas; this is consistent with pancreatic adenocarcinoma . There are also metastases ( ▴) to the liver. 2. An elevated alkaline phosphatase level without hyperbilirubinemia or ongoing hepatocyte necrosis is consistent with focal mass obstruction in the liver, which is commonly caused by metastasis. 3. Risks for pancreatic adenocarcinoma include smoking , chronic pancreatitis , and cancer syndromes (i.e., hereditary pancreatitis with PRSS1 mutation, Peutz-Jeghers syndrome, FAMMM syndrome, and BRCA2 mutations). ERRNVPHGLFRVRUJ 19.2 Side A (PBD9: 884; BP9: 646) ERRNVPHGLFRVRUJ Questions A 51-year-old woman with a year-long history of intermittent right upper quadrant pain now has diffuse severe abdominal pain. Her serum total bilirubin level is 5 mg/dL (nl ≤1.3 mg/dL), predominantly direct; her alkaline phosphatase level is 184 U/L (nl 20 to 125 U/L); and her amylase level is 461 U/L (nl 30 to 170 U/L). Her abdominal CT scan is shown. 1. What is your diagnosis? 2. What is this patient's risk factor? 3. What is the pathogenesis? ERRNVPHGLFRVRUJ Answers: Side B 1. The pancreas ( •) is swollen and hemorrhagic as a consequence of acute pancreatitis . 2. A point mutation in the PRSS1 gene, which encodes cationic trypsinogen , results in the loss of a critical failsafe: trypsin no longer has the capacity to inactivate itself by proteolysis. This causes an autosomal-dominant pattern of chronic pancreatitis. 3. The hypocalcemia results from fat necrosis with subsequent calcium soap formation. ERRNVPHGLFRVRUJ 19.2 Side B (PBD9: 884; BP9: 646) ERRNVPHGLFRVRUJ Questions A 22-year-old man with a 3-day history of abdominal pain has boardlike abdominal rigidity. His serum lipase level is 338 U/L (nl 7 to 60 U/L), and his calcium level is 7.1 mg/dL (nl 8.5 to 10.3 mg/dL). Had we looked, his pancreas would have appeared as shown. Notably, his father and his sister have had similar episodes. 1. What is your diagnosis? 2. What is the genetic cause? 3. Explain the resulting hypocalcemia. ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has acute pancreatitis with fluid density ( ♦) from fat necrosis; her gallbladder ( ▴) is dilated from obstruction. Peritoneal fluid collections ( ▸) are attributable to inflammation. 2. The patient's symptoms and the conjugated hyperbilirubinemia suggest biliary tract obstruction ; gallstones in the common bile duct can lodge at the ampulla of Vater, thereby causing pancreatic duct obstruction and triggering acute pancreatitis . 3. Enzyme activation behind a ductal obstruction triggers pancreatic autodigestion. This is compounded by the release of proinflammatory cytokines such as tumor necrosis factor and interleukin-1β. Subsequent edema can compromise vascular perfusion, which promotes ischemic necrosis. ERRNVPHGLFRVRUJ 19.3 Side A (PBD9: 888; BP9: 649) ERRNVPHGLFRVRUJ Questions A 48-year-old man with a 10-year history of intermittent abdominal pain now presents with steatorrhea and the abdominal CT scan shown. 1. Describe the findings. 2. Why does he have steatorrhea? 3. What is the likely pathogenesis? 4. What are some of the genetic causes of acute pancreatitis? ERRNVPHGLFRVRUJ Answers: Side B 1. The pancreatic duct ( ▸) is dilated and tortuous, which is typical of the changes that occur with chronic pancreatitis. 2. Contrast material fills a pancreatic pseudocyst ( ◂) in the region of the pancreatic head. 3. Chronic alcohol abuse predisposes patients to pancreatitis and pseudocyst formation. This occurs as a result of alcohol promoting increased protein secretion from the acinar cells while decreasing bicarbonate and fluid release from ductal cells, thereby favoring the formation of inspissated ductal secretions that lead to ductal obstruction with inflammation, fibrosis, and atrophy. ERRNVPHGLFRVRUJ 19.3 Side B (PBD9: 889; BP9: 649) ERRNVPHGLFRVRUJ Questions A 56-year-old man with a 25-year history of alcohol abuse presents with a 2-year history of episodic abdominal pain. The radiographic findings of endoscopic retrograde cholangiopancreatography are shown. 1. What is the underlying diagnosis? 2. What is the focal lesion (◂)? 3. What is the pathogenesis? ERRNVPHGLFRVRUJ Answers: Side A 1. The small, shrunken pancreas ( ◂) with bright calcifications is typical for chronic pancreatitis . The enlarged liver ( ♦) has low attenuation (is dark) as a result of marked fatty change . 2. The loss of pancreatic acinar function reduces the lipase production that is required for fat digestion. Ingested fats are neither catabolized nor absorbed, and the diarrhea fluid has high stool fat content ( steatorrhea ). 3. In the United States, 80% of pancreatitis is attributable to biliary tract obstruction or alcoholism . The fatty liver suggests alcohol abuse as a risk factor. 4. Mutations of the SPINK1 gene (serine protease inhibitor) or the PRSS1 gene (cationic trypsinogen that abrogates the protease cleavage site normally involved in self-inactivation) can lead to unregulated trypsin activity. ERRNVPHGLFRVRUJ 19.4 Side A (PBD9: 889; BP9: 649) ERRNVPHGLFRVRUJ Questions A 53-year-old man with a history of chronic alcohol abuse develops midepigastric pain that radiates to his back. His serum amylase and lipase levels are elevated, and his abdominal CT scan is shown. 1. What is your diagnosis? 2. What is the likely microscopic appearance of this lesion? 3. What is another risk factor for this lesion? ERRNVPHGLFRVRUJ Answers: Side B 1. Hypoglycemia along with an increased plasma insulin level would likely be present. 2. This islet cell adenoma ( •) is composed of cells that resemble the β cells of the islets of Langerhans. 3. Such neoplasms would be secreting (a) vasoactive intestinal peptide (VIP) or (b) gastrin . ERRNVPHGLFRVRUJ 19.4 Side B (PBD9: 1121; BP9: 752) ERRNVPHGLFRVRUJ Questions A 43-year-old man complains of episodes of weakness with headache, tachycardia, tremor, and anxiety, often after exercise. An abdominal CT scan shows a 1-cm mass in his pancreas. After resection, it has the microscopic appearance shown. 1. What laboratory finding is likely present during one of the patient's episodes? 2. What cell type comprises this neoplasm? 3. What would be secreted by a similar lesion in a patient with (a) high-volume watery diarrhea, hypokalemia, and achlorhydria or (b) multiple gastric and duodenal ulcers? ERRNVPHGLFRVRUJ Answers: Side A 1. The pancreas has a cystic lesion ( ▾) in the tail. This is most likely a pseudocyst arising in the setting of chronic pancreatitis. 2. Granulation tissue and fibrosis comprise the wall of the lesion; the inner mass is largely filled with amorphous necrotic fatty debris. 3. Abdominal trauma can lead to pancreatitis and pseudocyst formation. ERRNVPHGLFRVRUJ 20 ERRNVPHGLFRVRUJ The Kidney ERRNVPHGLFRVRUJ 20.1 Side A (PBD9: 960) ERRNVPHGLFRVRUJ Questions A 56-year-old man came to autopsy for reasons unrelated to the anomaly shown; he was completely unaware of his unique anatomy. 1. What is your diagnosis? 2. What is the embryology of this anomaly? 3. What might occur with the absence of one or both kidneys? 4. What could potentially complicate this anomaly? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has horseshoe kidney , with connection ( ▸) at the lower poles. 2. Each metanephros normally remains separate, but fusion occurs in roughly 1 of every 500 individuals. The fusion is most often at the lower poles. 3. Any abnormal ureteral course has the potential for some degree of obstruction, which increases the risk for infection. The course of these ureters over the bridge of renal parenchyma is an example of a topology that can cause a partial obstruction. In most cases, a horseshoe kidney is a completely incidental finding. ERRNVPHGLFRVRUJ 20.1 Side B (PBD9: 945) ERRNVPHGLFRVRUJ Questions A 35-year-old woman with a 9-year history of recurrent pyelonephritis has MRI performed. 1. What is your diagnosis? 2. What is the embryology of this anomaly? 3. Explain the recurrent pyelonephritis. ERRNVPHGLFRVRUJ Answers: Side A 1. There is bilateral duplication of the ureters ( ◂). 2. Each ureteric bud grows cephalad to the metanephros, which gives rise to the ureters, the pelves, the calyces, and the collecting ducts. The divergence of the ureteric bud before reaching the metanephros results in duplication. A partial or complete ureteral duplication occurs in about 1 of every 160 individuals. 3. If the ureteric bud does not reach the metanephros, the kidney may not form; this is called renal agenesis. If there is bilateral agenesis, intrauterine oligohydramnios will occur. Congenital absence of one kidney will lead to compensatory hyperplasia of the remaining kidney. 4. The abnormal insertion of ureters into the urinary bladder can potentially cause obstruction or reflux that increases the risk for ascending urinary tract infections. ERRNVPHGLFRVRUJ 20.2 Side A (PBD9: 945; BP9: 542) ERRNVPHGLFRVRUJ Questions A 60-year-old man with a history of hypertension has recent onset of abdominal pain and associated hematuria. He has elevated creatinine and urea nitrogen levels. His abdominal CT scan is shown. 1. What is your diagnosis? 2. What liver pathology can also be seen? 3. What cardiac valvular pathology is present? 4. What cerebrovascular pathology can occur? ERRNVPHGLFRVRUJ Answers: Side B 1. This is autosomal-dominant polycystic kidney disease (ADPKD) . Note the marked renal enlargement with parenchymal replacement by large cysts. 2. The PKD1 gene encodes polycystin-1 , a large transmembrane protein that forms a complex on apical surfaces of various epithelia that are localized to primary cilia. It is hypothesized to act as a mechanosensor to maintain the differentiated state of renal tubular and biliary epithelial cells. PKD2 encodes polycystin-2 protein, which has calcium channel activity. 3. Cysts in patients with ADPKD develop slowly; renal failure usually occurs during later adult life. Hemorrhage into the cysts can cause pain and hematuria. ERRNVPHGLFRVRUJ 20.2 Side B (PBD9: 945; BP9: 542) ERRNVPHGLFRVRUJ Questions A 69-year-old woman with a 5-year history of back pain, hypertension, and persistent malaise is found to have a moderately elevated creatinine level and a urea nitrogen level of 41 mg/dL (nl 7 to 20 mg/dL), with reduced creatinine clearance. Urinalysis shows 1+ protein, but no glucose, ketones, or blood. Had we looked, her kidneys would have appeared as shown. 1. What is your diagnosis? 2. What gene mutations may be present? 3. Describe the clinical course of this disease. ERRNVPHGLFRVRUJ Answers: Side A 1. The kidneys ( ♦) are enlarged and cystic, which is consistent with autosomaldominant polycystic kidney disease . 2. Cysts may be present in other organs, including the liver, and occasionally in the pancreas, spleen, and lungs. 3. Mitral valve prolapse 4. Intracranial cerebral (berry) aneurysm ERRNVPHGLFRVRUJ 20.3 Side A (PBD9: 9389; BP9: 539) ERRNVPHGLFRVRUJ Questions A 61-year-old man with hypertension and diabetes receives heparin as prophylaxis for pulmonary embolism after femoral fracture repair. A week later, his platelet count declines from 230,000/mm to 50,000/mm (nl 130,000 to 400,000/mm ), and he develops hematuria and increasing blood urea nitrogen and creatinine levels. His kidneys have the appearance shown. 3 3 1. Describe the renal findings. 2. What is this complication of heparin therapy? ERRNVPHGLFRVRUJ 3 Answers: Side B 1. The creatinine clearance level is halved to 17.4 mL/min. 2. With reduced renal blood flow in patients with hypertensive nephrosclerosis, the glomerular filtration rate is maintained by the prostaglandin-mediated relaxation of afferent arterioles and by the angiotensin II–mediated efferent arteriolar constriction. ACE inhibitors decrease efferent arteriolar tone and decrease the glomerular capillary perfusion pressure. Nonsteroidal anti-inflammatory drugs inhibit prostaglandin synthesis and increase afferent arteriolar constriction. After drug administration, renal blood flow is markedly reduced, with the left side being worse than the right. ERRNVPHGLFRVRUJ 20.3 Side B (PBD9: 938; BP9: 539) ERRNVPHGLFRVRUJ Questions A 55-year-old man with long-standing hypertension has a serum creatinine level of 2 mg/dL (nl ≤1.2 mg/dL) and 1 g of creatinine in a 24-hour urine collection of 1.5 L. His renal blood flow scan is shown after the administration of lisinopril (an angiotensinconverting enzyme [ACE] inhibitor) and ibuprofen. His serum creatinine level increases to 4 mg/dL. 1. Assuming a body surface area (SA) of 1.7 m , the creatinine clearance level ([Cr × Urine flow/Cr ] × 1.73/SA) before the drugs are taken is 34.7 mL/min (nl 82 to 125 mL/min). After the drugs are taken, what is the creatinine clearance level? 2 serum 2. Explain the appearance of the renal scan after lisinopril and ibuprofen. ERRNVPHGLFRVRUJ urine Answers: Side A 1. Both kidneys show finely granular cortical surfaces, which are consistent with benign nephrosclerosis . Hypertension and diabetes contribute to renal arteriolosclerosis and glomerular ischemia. The left kidney has a dark red mottled appearance, which suggests infarction. 2. In about 5% of patients who are receiving heparin, autoantibodies develop to a complex of heparin and platelet factor 4. This leads to endothelial cell injury and platelet activation and aggregation, with a net prothrombotic state. This is heparininduced thrombocytopenia ; a feared complication is arterial or venous thrombosis. ERRNVPHGLFRVRUJ 20.4 Side A (PBD9: 909; BP9: 529) ERRNVPHGLFRVRUJ Questions Approximately 2 weeks after an episode of pharyngitis, a 13-year-old girl abruptly becomes tired, febrile, and nauseous. She has markedly reduced urine output, and her urine is cola-colored. Urinalysis shows proteinuria, hematuria, and RBC casts. The microscopic appearance of her renal biopsy specimen is shown. 1. What is the key histologic finding of this disease? 2. Name other infections that produce similar renal disease. 3. Describe the immunologic pathogenesis. ERRNVPHGLFRVRUJ Answers: Side B 1. The serologic tests indicate prior group A β-hemolytic streptococcal infection. This is a common antecedent to postinfectious glomerulonephritis . 2. Beneath the podocyte ( •) are subepithelial electron-dense immune deposits ( ▾) (“humps”). The capillary lumen is filled with a leukocyte ( ♦) (note the cytoplasmic granules). 3. More than 95% of children with this condition recover completely. However, some children and 40% of adults can progress to chronic glomerulonephritis. ERRNVPHGLFRVRUJ 20.4 Side B (PBD9: 909; BP9: 529) ERRNVPHGLFRVRUJ Questions A 10-year-old boy has a 3-day history of periorbital puffiness and malaise. His urinalysis is notable for nephrotic range proteinuria (≥3 g/day). His serum antistreptolysin O, anti–DNase B, and antihyaluronidase titers all are increased. The electron microscopic appearance of his renal biopsy specimen is shown. 1. What is your diagnosis? 2. Describe the electron microscopic findings. 3. Describe the clinical course of this disease. ERRNVPHGLFRVRUJ Answers: Side A 1. Note the hypercellularity of poststreptococcal (postinfectious) glomerulonephritis. 2. Other infections that precede postinfectious glomerulonephritis include staphylococcal endocarditis, pneumococcal pneumonia, meningococcemia, viral hepatitis B or C, infectious mononucleosis, and HIV. 3. Infection elicits an immunoglobulin response that involves antibodies forming immune complexes with circulating microbial antigens. These deposit in the glomerular basement membrane to cause injury by activating complement and recruiting Fc receptor–bearing neutrophils and macrophages. ERRNVPHGLFRVRUJ 20.5 Side A (PBD9: 912; BP9: 5532) ERRNVPHGLFRVRUJ Questions A 27-year-old man with new-onset hemoptysis and hematuria develops peripheral edema and hypertension. Urinalysis shows proteinuria and RBC casts. The immunofluorescent microscopic appearance of his renal biopsy specimen stained with anti-IgG antibody is shown. 1. What is your diagnosis? 2. What serologic test is likely to be positive? 3. Describe the immunologic pathogenesis. 4. Generically, what is the syndromic name for hypertension, proteinuria, and hematuria? ERRNVPHGLFRVRUJ Answers: Side B 1. A glomerular crescent ( ▸) is present. This was formed as a result of parietal epithelial cell proliferation within the Bowman space. 2. This patient has granulomatosis with polyangiitis (previously called Wegener granulomatosis ). Essentially, this is a rapidly progressive pauci-immune glomerulonephritis that is part of a systemic vasculitis caused by anti-neutrophil cytoplasmic antibodies (ANCA). 3. The antiproteinase 3 (PR3) ANCA test is positive in 95% of patients with multiorgan involvement. Antinuclear antibody (a marker for lupus) and anti–DNA topoisomerase I (a marker for diffuse scleroderma) are usually negative. ERRNVPHGLFRVRUJ 20.5 Side B (PBD9: 912; BP9: 532) ERRNVPHGLFRVRUJ Questions A 41-year-old man with a 1-week history of cough, fever, and skin rash is found to have nasopharyngeal ulcerations, with nodular and cavitary lesions seen on chest radiography. He develops rapidly progressive renal failure, with hematuria and RBC casts in the urine. A lung biopsy specimen shows necrotizing vasculitis. The microscopic appearance of his renal biopsy specimen is shown. 1. What is the glomerular lesion shown? 2. What form of vasculitis does he have? 3. What serologic tests should be assessed? ERRNVPHGLFRVRUJ Answers: Side A 1. Goodpasture syndrome is a form of rapidly progressive glomerulonephritis. Note the linear IgG deposition ( ▸) on the glomerular basement membrane (GBM). 2. Anti-GBM antibody 3. Autoantibody bound to the noncollagenous domain of the α chain of type IV collagen, which is present in pulmonary alveoli and GBM leads to complement activation as well as to leukocyte recruitment and activation via Fc receptor binding. 3 4. Nephritic syndrome ERRNVPHGLFRVRUJ 20.6 Side A (PBD9: 917; BP9: 524) ERRNVPHGLFRVRUJ Questions A 6-year-old boy with a 1-week history of lethargy now has periorbital edema. Urinalysis shows albuminuria and lipiduria. A 24-hour urine collection has 4 g of protein; this is in the nephrotic range. Glomeruli in a renal biopsy appear normal by light microscopy, but they have the electron microscopic appearance shown. 1. What is your diagnosis? 2. What is the pathogenesis? 3. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has focal and segmental glomerulosclerosis . There is segmental scarring ( ♦) of the glomerulus, and only some glomeruli are affected. 2. Mutations in the NPHS1 gene that encodes for nephrin and the NPHS2 gene that encodes for podocin can be present. Both of these are components of the slit diaphragm, and they are probably important for regulating glomerular permeability. 3. The course of this condition is variable. About 20% of affected individuals progress to chronic renal failure within 2 years. The recurrence rate in renal allografts is 25% to 50%. ERRNVPHGLFRVRUJ 20.6 Side B (PBD9: 918; BP9: 525) ERRNVPHGLFRVRUJ Questions A 17-year-old girl with edema, hypertension, and proteinuria has negative antinuclear antibody and antineutrophil cytoplasmic antibody titers. She does not improve with corticosteroid therapy. Three of 10 glomeruli in her renal biopsy specimen have the appearance shown (lower panel, trichrome stain; collagen = blue ). 1. What is your diagnosis? 2. What gene mutations may be present? 3. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side A 1. The only lesion is effacement (simplification) of podocyte foot processes ( ▸), which is consistent with minimal change disease (MCD) . 2. MCD is associated with immunizations, infections, atopy, and Hodgkin lymphoma. The current theory is that immunologic dysfunction leads to cytokine elaboration that injures podocyte epithelium; this in turn leads to a loss of glomerular polyanions and changes in membrane permeability. 3. More than 90% of children recover completely with a course of corticosteroids. A few become steroid dependent, but progression to chronic renal disease is rare. ERRNVPHGLFRVRUJ 20.7 Side A (PBD9: 915; BP9: 526) ERRNVPHGLFRVRUJ Questions A 38-year-old woman with a 2-week history of malaise is found to be hypertensive, with peripheral pitting edema. Her serum creatinine level is 2.5 mg/dL (nl ≤1.3), and a 24-hour urine specimen contains 3.7 g of protein, which is in the nephrotic range. The patient's antinuclear antibody titer is negative, and she does not respond to corticosteroid therapy. Her renal biopsy specimen has the electron microscopic findings shown. 1. What is your diagnosis? 2. What is the patient's prognosis? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has membranous glomerulonephritis . The capillary loops are diffusely thickened ( ▸), and silver stain highlights the “spikes” in which the immune complexes in the basement membrane appear as black projections ( ◂). 2. Many different drugs have been implicated; captopril and penicillamine are classic culprits. 3. Associated malignancies include colon and lung cancers and melanomas. Lupus nephritis can also have this appearance. In addition, chronic infection with hepatitis B or C virus, malaria, schistosomiasis, or syphilis can cause this condition. ERRNVPHGLFRVRUJ 20.7 Side B (PBD9: 915; BP9: 526) ERRNVPHGLFRVRUJ Questions After 1 month of heavy ibuprofen use, a 57-year-old man presents with peripheral edema and hypertension. Urinalysis shows proteinuria but no hematuria or glucosuria. The microscopic appearance of his renal biopsy specimen (upper panel, H&E; lower panel, silver stain) is shown. 1. What is your diagnosis? 2. What other drugs can cause this disease? 3. What other underlying conditions may be associated? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has membranous glomerulonephritis . The darker electron-dense immune deposits ( ♦) are seen scattered within the thickened basement membrane. This immunologically mediated disease involves deposits of IgG and complement in the basement membrane. 2. This indolent disease has a worse prognosis when the proteinuria is nonselective (i.e., when there are proteins other than albumin) and more severe. About 10% of patients progress to chronic renal failure within 10 years. ERRNVPHGLFRVRUJ 20.8 Side A (PBD9: 949; BP9: 542) ERRNVPHGLFRVRUJ Questions A 70-year-old man develops sudden right flank pain. Urinalysis shows hematuria; his serum creatinine level is normal (0.8 mg/dL). His abdominal CT scan is shown. 1. What is your diagnosis? 2. Why is his renal function unaffected? 3. Is this an inherited condition? ERRNVPHGLFRVRUJ Answers: Side B 1. Hydronephrosis ( ▴) is evident; the pelvis and the calyces are enlarged and filled with fluid. The bright triangular object ( ◂) is a staghorn calculus. These are often associated with pyelonephritis , and they typically involve ammonia-splitting organisms such as Proteus. 2. Acute pyelonephritis 3. The hydronephrosis and pyelonephritis is unilateral, so the unaffected right kidney has retained its function. ERRNVPHGLFRVRUJ 20.8 Side B (PBD9: 950; BP9: 545) ERRNVPHGLFRVRUJ Questions A 63-year-old man with a 1-month history of fever and right flank pain has a urinalysis that shows WBCs and WBC casts. His serum creatinine is normal (1 mg/dL). His abdominal CT scan is shown. 1. What is your diagnosis? 2. What do the WBC casts indicate? 3. Why is the serum creatinine level not elevated? ERRNVPHGLFRVRUJ Answers: Side A 1. There is a large fluid-filled cyst on the right ( ♦) and a smaller cyst on the left ( ▾); both have thin walls and smooth contours. These are simple renal cysts , which are very common findings. The right flank pain may be related to hemorrhage into the larger cyst. 2. Simple cysts are scattered and focal, and they leave sufficient renal parenchyma to maintain normal renal function. It is possible to have reasonably normal renal function with only half of one normal kidney. 3. These are likely somatic; inherited renal cystic diseases are much more extensive. ERRNVPHGLFRVRUJ 20.9 Side A (PBD9: 952) ERRNVPHGLFRVRUJ Questions A 17-year-old girl with a history of seizures and mental retardation has a 3-month history of abdominal pain and a recent onset of fever and nausea. Examination reveals hypomelanotic macules and ash leaf spots. An MRI of her abdomen is shown. 1. What is your diagnosis? 2. What is the likely genetic abnormality? 3. What additional tumors are commonly associated with this? ERRNVPHGLFRVRUJ Answers: Side B 1. Note the presence of adipocytes ( ■), smooth muscle ( ♦), and blood vessels ( ▾); these are typical for an angiomyolipoma . 2. This is histologically benign; occasionally, however, angiomyolipomas are multiple, which makes surgical removal difficult. 3. Most cases are familial, and they are often associated with tuberous sclerosis . Sporadic cases are more likely to be solitary and asymptomatic. ERRNVPHGLFRVRUJ 20.9 Side B (PBD9: 952) ERRNVPHGLFRVRUJ Questions A 43-year-old man with 1-month history of abdominal pain also has hematuria. A palpable abdominal mass is found on CT scan to derive from a left perinephric lesion. The microscopic appearance of this mass is shown after resection. 1. What is your diagnosis? 2. Is this benign or malignant? 3. Are these lesions more often sporadic or familial? ERRNVPHGLFRVRUJ Answers: Side A 1. The mass ( ▴), which is eccentric to the right kidney, is circumscribed, and it has areas of bright attenuation that are similar to the surrounding adipose tissue. This is an angiomyolipoma . 2. Tuberous sclerosis 3. Additional lesions include peculiar hamartomatous lesions of the cerebrum known as cortical tubers, cardiac rhabdomyomas, retinal or rectal hamartomas, gingival fibromas, and facial angiofibromas . ERRNVPHGLFRVRUJ 20.10 Side A (PBD9: 923; BP9: 530) ERRNVPHGLFRVRUJ Questions Ten days after recovering from a mild respiratory tract infection, an otherwise healthy 22-year-old man starts passing dark urine; urinalysis shows dysmorphic erythrocytes. The hematuria subsides after 1 week, only to return four more times during the next year. The patient's renal biopsy specimen is shown. 1. What is your diagnosis? 2. Why are the RBCs in the urine dysmorphic? 3. What predicts the prognosis of patients with this condition? ERRNVPHGLFRVRUJ Answers: Side B 1. This is Henoch-Schönlein purpura. 2. Celiac disease (gluten-sensitive enteropathy) 3. The serum IgA level is increased; this is driven by mucosal IgA-secreting plasma cells that are presumably responding to infectious challenges or food antigens. IgA1 isotype antibodies in particular form immune complexes ( ♦) that can deposit in glomeruli (primarily mesangial) and other tissues such as skin; these complexes activate the alternative complement pathway, which leads to tissue damage. ERRNVPHGLFRVRUJ 20.10 Side B (PBD9: 926; BP9: 530) ERRNVPHGLFRVRUJ Questions A 7-year-old girl develops abdominal pain with vomiting, arthralgias, and purpura over the extensor surfaces of her arms and legs. Urinalysis shows proteinuria and hematuria. Her renal biopsy specimen is shown with immunofluorescent antibody staining against IgA. 1. What is your diagnosis? 2. What malabsorptive gastrointestinal disease can also be associated with these renal findings? 3. What is the pathogenesis? ERRNVPHGLFRVRUJ Answers: Side A 1. This is IgA nephropathy (Berger disease) with mesangial hypercellularity ( ♦). 2. RBCs that traverse the glomeruli involved by glomerulonephritis often become damaged and misshapen. Ordinary hemorrhage does not do this. 3. Forty percent of patients will slowly progress to chronic renal failure over 20 years. Patients with hypertension, more severe proteinuria, and onset at an older age tend to have a worse prognosis. ERRNVPHGLFRVRUJ 20.11 Side A (PBD9: 1118; BP9: 746) ERRNVPHGLFRVRUJ Questions A 68-year-old man with a body mass index of 40 (nl 18.5 to 24.9), peripheral neuropathy, retinopathy, and abdominal aortic aneurysm has declining renal function with an increasing serum creatinine level. His fasting blood glucose level is 209 mg/dL (nl ≤110). On examination, his peripheral pulses are diminished. The microscopic appearance of a renal biopsy specimen is shown. 1. What is your diagnosis of the lesion shown? 2. What is the underlying disease? 3. Explain the pathogenesis of the glomerular injury. ERRNVPHGLFRVRUJ Answers: Side B 1. This is diffuse glomerulosclerosis . There is an increase in mesangial matrix ( ♦), a slight increase in mesangial cellularity, and capillary basement membrane thickening. These changes gradually advance until the entire glomerulus is sclerotic. 2. The markedly thickened arterioles ( ▾) are typical of the hyaline arteriolosclerosis seen in the kidneys of patients with diabetes. 3. Diabetes mellitus type 1 (insulin-dependent) ERRNVPHGLFRVRUJ 20.11 Side B (PBD9: 1118; BP9: 746) ERRNVPHGLFRVRUJ Questions A 40-year-old woman with a 25-year history of recurrent episodes of ketoacidosis (she is not very good at titrating her insulin) now has a creatinine clearance value of only 30 mL/min (nl 75 to 115 mL/min). The microscopic appearance of her renal biopsy specimen after periodic acid–Schiff (PAS) staining is shown. 1. What is your diagnosis of the glomerular lesion? 2. What vascular lesion is also present? 3. What is the underlying disease? ERRNVPHGLFRVRUJ Answers: Side A 1. This is nodular glomerulosclerosis (Kimmelstiel-Wilson lesion) , with increased focal deposits of mesangial matrix ( ♦). 2. Diabetes mellitus, type 2 (non–insulin dependent) 3. The marked increase in mesangial matrix is the result of the nonenzymatic glycosylation of proteins and altered glomerular filtration. Hemodynamic alterations with glomerular hypertrophy may also play a role. ERRNVPHGLFRVRUJ 20.12 Side A (PBD9: 927; BP9: 537) ERRNVPHGLFRVRUJ Questions A 40-year-old man with a history of polysubstance abuse and intermittent gastrointestinal bleeding with hypotension presents with progressive oliguria for 2 days, and his serum urea nitrogen level is now 40 mg/dL (nl 7 to 30 mg/dL). For the next 3 weeks, his urine output remains low, his urea nitrogen value increases, and the associated hyperkalemia eventually requires emergent hemodialysis. During the next week, his urine output dramatically increases to reach 3 L/day, and hypokalemia supervenes. Eventually, all of his renal parameters normalize, as do his electrolyte levels. Possible areas of damage are shown in blue. 1. What is this form of renal injury? 2. What is the mechanism for the injury pattern shown in the upper panel ? Give examples. 3. What is the mechanism for the injury pattern shown in the lower panel ? Give examples. ERRNVPHGLFRVRUJ Answers: Side B 1. The epithelium ( ▸) of the tubules is ragged and thinned, with a smattering of neutrophils; this is acute tubular necrosis . 2. The crush injury led to rhabdomyolysis with the release of myoglobin, which is toxic to renal tubular epithelium. Globins (e.g., hemoglobin, myoglobin) turn the blood block of the dipstick positive. The absence of RBCs suggests myoglobin. ERRNVPHGLFRVRUJ 20.12 Side B (PBD9: 927; BP9: 537) ERRNVPHGLFRVRUJ Questions After a crush injury to his lower extremities, a 30-year-old man develops oliguria. A urinalysis dipstick test is positive for blood, but no RBCs are present according to microscopy. The microscopic appearance of his renal biopsy specimen is shown. With supportive measures only, his renal function returns to normal after 1 month. 1. What is your diagnosis of the biopsy specimen? 2. What substance is likely causing the renal damage? ERRNVPHGLFRVRUJ Answers: Side A 1. This is acute tubular necrosis ( ATN ). 2. Patchy areas of tubular injury (in blue) are characteristic of an ischemic form of ATN. This could result from global hypotension with heart failure, hemorrhagic shock, or more focal renal blood flow reduction caused by vasculitis. 3. Confluent areas of tubular injury are characteristic of a toxic form of ATN. This could result from an adverse drug reaction (e.g., to aminoglycosides) or from exposure to heavy metals or toxins such as ethylene glycol (i.e., antifreeze). ERRNVPHGLFRVRUJ 20.13 Side A (PBD9: 935; BP9: 536) ERRNVPHGLFRVRUJ Questions After beginning triple-drug therapy for tuberculosis (i.e., isoniazid, rifampin, and ethambutol), a 51-year-old man develops fevers and begins passing dark urine. His serum creatinine level is 2.8 mg/dL (nl ≤1.3 mg/dL), and his urine microscopy shows eosinophils. His renal biopsy specimen is shown. 1. What is your diagnosis? 2. What is the likely cause? 3. What is the pathogenesis? ERRNVPHGLFRVRUJ Answers: Side B 1. This is analgesic nephropathy . 2. The dark-appearing areas ( ▾) are necrotic renal papillae, which eventually slough into the calyces and are passed in the urine. 3. Chronic renal disease leads to reduced erythropoietin levels. She could also have aspirin-induced gastrointestinal blood loss. ERRNVPHGLFRVRUJ 20.13 Side B (PBD9: 935; BP9: 536) ERRNVPHGLFRVRUJ Questions A 39-year-old woman with recurrent tension headaches now presents with increasing fatigue and a recent history of passing a 0.5-cm red-brown tissue fragment in her urine. She reports ingesting more than 3 g of analgesics that contain phenacetin and aspirin each day for the past 5 years to treat her headaches. Her serum urea nitrogen level is 40 mg/dL (nl 7 to 30 mg/dL), and her hemoglobin level is 7.5 g/dL (nl 12 to 15.6 g/dL). Had we removed them for examination, her kidneys would have the gross appearance shown. 1. What is your diagnosis? 2. What did she pass in her urine? 3. Why is her anemia so severe? ERRNVPHGLFRVRUJ Answers: Side A 1. There is an interstitial nephritis with eosinophils ( ▾), which is consistent with acute drug-induced nephritis . 2. Of the trio of antimycobacterial agents, rifampin is most likely to blame for this condition. Other antibiotics that often cause this complication include methicillin and ampicillin. 3. Such drugs combine with tubular epithelial proteins as haptens to elicit type I and type IV hypersensitivity reactions. These responses damage the drug-modified epithelium. ERRNVPHGLFRVRUJ 20.14 Side A (PBD9: 953; BP9: 547) ERRNVPHGLFRVRUJ Questions A 56-year-old woman presenting for the work-up of “palpitations” is found to have a cardiac arrhythmia with a short Q–Tc interval. She has a serum calcium level of 12.2 mg/dL (nl 8.5 to 10.3 mg/dL), with phosphorus level of 2.1 mg/dL (nl 2.5 to 4.5 mg/dL). MRI of her abdomen is shown. 1. What is your diagnosis? 2. What paraneoplastic syndrome is present? 3. Where are metastases most likely to be? 4. What gene mutation can be associated with this lesion? ERRNVPHGLFRVRUJ Answers: Side B 1. The variegated mass ( ♦) in the kidney is a renal cell carcinoma . 2. Polycythemia 3. The polycythemia presumably led to Budd-Chiari syndrome , with hepatic vein thrombosis that led to hepatic outflow obstruction and hepatic infarction. ERRNVPHGLFRVRUJ 20.14 Side B (PBD9: 953; BP9: 547) ERRNVPHGLFRVRUJ Questions A 55-year-old man with acute-onset abdominal pain is found via CT scan to have hepatic infarction. His hemoglobin level is 21 g/dL (nl 13.8 to 17.2 g/dL), and hematocrit value is 60.5% (nl 41% to 50%); his platelet and WBC counts are normal. A surgical resection is performed (shown). 1. What is your diagnosis? 2. What paraneoplastic syndrome is present? 3. Explain the hepatic infarction. ERRNVPHGLFRVRUJ Answers: Side A 1. The heterogeneous mass ( ♦) that involves the right kidney is consistent with renal cell carcinoma . 2. Hypercalcemia may be present as a result of the production of parathormonerelated peptide , but it may also be caused by bony metastases through the increased production of 1,25-dihydroxyvitamin D or by the elaboration of prostaglandin E– inducing osteoclast-mediated bone resorption. 3. The lung, bone, lymph node, liver, adrenals, thyroid, and brain are the most likely sites, although any site is possible. 4. The VHL tumor-suppressor gene yields a protein that is part of a ubiquitin ligase complex that targets intracellular regulatory proteins (e.g., HIF-1α) for proteasomemediated degradation. ERRNVPHGLFRVRUJ 20.15 Side A (PBD9: 925) ERRNVPHGLFRVRUJ Questions A 55-year-old man with a 5-year history of chronic fatigue has a serum creatinine level of 7 mg/dL (nl ≤1.3 mg/dL), a creatinine clearance level of 10 mL/min (nl 82 to 125 mL/min), and a hemoglobin level of 8 g/dL (nl 13.8 to 17.2 g/dL). He has a pericardial friction rub on examination. His CT scan is shown. 1. What is your diagnosis? 2. Why is a renal biopsy not indicated? 3. What is the likely renal histology? 4. Why is there a friction rub? ERRNVPHGLFRVRUJ Answers: Side B 1. The end result of many renal diseases—whether renovascular diseases, glomerulonephritis, or chronic pyelonephritis—is end-stage renal disease , which involves small kidneys bilaterally and markedly elevated blood urea nitrogen and serum creatinine levels. 2. These are features of chronic glomerulonephritis . 3. Chronic renal failure can be treated with dialysis or kidney transplantation. The native kidneys ( ▾) are typically left in place; this results in less patient morbidity, and they may produce some erythropoietin. It is also technically easier (and allows for easier access for follow-up biopsies) to put the transplanted kidney ( ▴) in the pelvis. ERRNVPHGLFRVRUJ 20.15 Side B (PBD9: 925) ERRNVPHGLFRVRUJ Questions A 49-year-old woman with a 7-year history of chronic renal failure receives definitive therapy to improve her renal function. She subsequently dies from unrelated causes. At autopsy, the gross appearance of her urologic organs is shown. The microscopic features of her native kidneys include hyaline obliteration of the glomeruli and arterial and arteriolar sclerosis with tubular atrophy. 1. What term best describes her condition? 2. What diagnosis may be applied to the microscopic findings? 3. What therapy is shown? ERRNVPHGLFRVRUJ Answers: Side A 1. The patient's kidneys ( ◂) are atrophic : they are small, with minimal remaining renal parenchyma. These are “end-stage” kidneys. 2. The biopsy of an end-stage kidney yields little useful information, because the cause of the kidney disease was obscured by scarring and atrophy long ago. In addition, little can be done therapeutically to reverse such changes. 3. The microscopic appearance of an end-stage kidney is similar regardless of cause: a fibrotic cortex, sclerotic glomeruli, scattered chronic inflammatory cell infiltrates, and thickened arteries. The tubules are dilated and filled with pink proteinaceous casts. 4. The friction rub results from a uremia-induced fibrinous pericarditis . ERRNVPHGLFRVRUJ 20.16 Side A (PBD9: 951; BP9: 545) ERRNVPHGLFRVRUJ Questions A 27-year-old woman with a 2-day history of colicky pelvic pain is also passing reddish urine. A serum pregnancy test is negative, but her parathyroid hormone and serum calcium levels are elevated. Her abdominal CT scan is shown. 1. What is your diagnosis? 2. What is the likely composition of the offending object? 3. Explain the laboratory findings. ERRNVPHGLFRVRUJ Answers: Side B 1. This round, rough-surfaced object is a urinary tract calculus . 2. Recurrent infections with Proteus organisms and some staphylococci are associated with magnesium ammonium phosphate stones (also known as triple phosphate or struvite stones), which account for approximately 15% to 20% of all bladder stones. This patient's recurrent urinary tract infections may be due to prostatic hyperplasia , with urinary retention and stasis. ERRNVPHGLFRVRUJ 20.16 Side B (PBD9: 951; BP9: 545) ERRNVPHGLFRVRUJ Questions A 70-year-old man with a 5-year history of gradually increasing difficulty with urination and recurrent urinary tract infections now has a urinalysis that shows WBCs and RBCs. After experiencing considerable pain, he passes the entity shown from his urinary bladder. 1. What is your diagnosis? 2. What is a possible pathogenesis? ERRNVPHGLFRVRUJ Answers: Side A 1. The bright, round object ( ▾) at the left ureteral orifice is a urinary tract calculus . 2. The radiopacity of this calculus indicates that it likely contains calcium; 70% of urinary calculi contain calcium (struvite calculi are also radiopaque). Calcium oxalate stones are the most common in this category, and they are usually associated with idiopathic hypercalciuria rather than hypercalcemia or hyperoxaluria. 3. In this case, the patient has primary hyperparathyroidism with hypercalcemia and hypercalciuria that is driving stone formation. ERRNVPHGLFRVRUJ 20.17 Side A (PBD9: 931; BP9: 533) ERRNVPHGLFRVRUJ Questions A 34-year-old woman with a 3-day history of fever, dysuria, and flank pain has costovertebral angle tenderness. Urinalysis shows numerous WBCs and WBC casts, and her urine dipstick is positive for leukocyte esterase and nitrite. Had we obtained a renal biopsy specimen at this point, the histology would appear as shown. 1. Where is the renal inflammation seen? 2. What microbiologic testing needs to be performed? 3. Explain the presence of WBC casts. ERRNVPHGLFRVRUJ Answers: Side B 1. Chronic interstitial nephritis ( ♦) is composed of “round cells” (i.e., lymphocytes and plasma cells). 2. Chronic pyelonephritis with scarring at the poles suggests vesicoureteral reflux , a condition that often has a congenital origin. 3. Pyelonephritis is most often an ascending bacterial infection from the bladder. The most common bacterial organisms include coliforms ( Escherichia coli, Proteus, Klebsiella, Enterobacter), streptococci, and staphylococci. ERRNVPHGLFRVRUJ 20.17 Side B (PBD9: 933; BP9: 535) ERRNVPHGLFRVRUJ Questions A 35-year-old woman with a lifelong history of recurrent urinary tract infections now has a creatinine clearance level of 20 mL/min (nl 75 to 115 mL/min). Renal ultrasound shows decreased renal size bilaterally, with a greater loss of parenchyma at the poles. A renal biopsy specimen would have the microscopic appearance shown. 1. What is your diagnosis? 2. What predisposing factor may have led to this condition? 3. What microbial organisms are most often associated with this? ERRNVPHGLFRVRUJ Answers: Side A 1. This is tubulointerstitial nephritis . Numerous PMNs ( ♦) are seen filling the renal tubules. The glomeruli ( ) are relatively spared. 2. Urine culture with antibiotic sensitivity would identify the causative bacterial organisms and determine the most appropriate antibiotic therapy. 3. Neutrophils invading the distal tubules and collecting ducts are condensed and passed in the urine as WBC casts. ERRNVPHGLFRVRUJ 20.18 Side A (PBD9: 947; BP9: 544) ERRNVPHGLFRVRUJ Questions A male infant is delivered at 36 weeks' gestation after a pregnancy that was notable for minimal fetal movement and marked oligohydramnios. He dies shortly after birth as a result of respiratory failure. Relevant gross autopsy findings are shown. 1. What is the abnormality? 2. Explain the oligohydramnios. ERRNVPHGLFRVRUJ Answers: Side B 1. These elongated cysts ( •) that fill the renal parenchyma are typical for autosomalrecessive polycystic kidney disease (ARPKD) , which has a 25% recurrence risk. 2. This disorder is associated with mutations in the PKHD1 gene that codes for fibrocystin , a large receptor-like protein involved in normal renal tubule and biliary differentiation. 3. ARPKD is also accompanied by congenital hepatic fibrosis ; in children with milder forms of the renal manifestations, the hepatic disease often predominates. ERRNVPHGLFRVRUJ 20.18 Side B (PBD9: 947; BP9: 544) ERRNVPHGLFRVRUJ Questions A neonate has renal failure, with a serum creatinine level of 4 mg/dL (nl ≤1.2 mg/dL). The microscopic appearance of a renal biopsy specimen is shown. 1. What is the recurrence risk for this condition in this family? 2. What genetic mutation is likely present? 3. What hepatic lesion may be present? ERRNVPHGLFRVRUJ Answers: Side A 1. The bilaterally and symmetrically enlarged kidneys ( •) displace the abdominal contents anteriorly and to the side. The descending colon runs over the surface of the left kidney. Such markedly enlarged kidneys and perinatal renal failure are consistent with autosomal-recessive polycystic kidney disease . 2. The lack of normal fetal tubule differentiation results in little or no fetal urine output; fetal urine forms the bulk of amniotic fluid during late gestation. At earlier time points, amniotic fluid has a composition that is similar to that of maternal plasma, but it also contains vernix, lanugo, and old fetal erythrocytes. ERRNVPHGLFRVRUJ 21 ERRNVPHGLFRVRUJ The Lower Urinary Tract and Male Genital System ERRNVPHGLFRVRUJ 21.1 Side A (PBD9: 983; BP9: 665) ERRNVPHGLFRVRUJ Questions A 78-year-old man with a 1-cm prostatic nodule that is palpable on digital examination and confined to the prostate on imaging studies has a serum prostate-specific antigen (PSA) level of 14 ng/mL (nl ≤ 4 ng/mL). A biopsy specimen of this lesion is shown. 1. What is your diagnosis? 2. What is a common genetic alteration? 3. What is the stage of this disease? 4. What is the patient's prognosis? ERRNVPHGLFRVRUJ Answers: Side B 1. The focal area ( ▴) of epithelium with nuclei that are crowded and hyperchromatic is prostatic intraepithelial neoplasia (PIN) . 2. Low-grade PIN tends to be indolent. High-grade PIN is a precursor to prostatic adenocarcinoma; it may also be adjacent to a focus of adenocarcinoma. 3. This patient's PSA level is higher than normal, but it is in the range seen with hyperplasia and inflammation. One could repeat the PSA test in a few months to see if it continues to rise. ERRNVPHGLFRVRUJ 21.1 Side B (PBD9: 983; BP9: 665) ERRNVPHGLFRVRUJ Questions A 65-year-old man is found on examination to have a slightly enlarged prostate and a prostate-specific antigen (PSA) level of 7 ng/mL (nl ≤ 4 ng/mL). Prostate biopsy specimens of six random areas of the prostate yield the same microscopic appearance (shown). 1. What is your diagnosis? 2. Should this patient worry? 3. Explain his PSA level. ERRNVPHGLFRVRUJ Answers: Side A 1. The irregularly shaped glands with nuclei that have prominent nucleoli ( ▴) and occasional mitoses ( ▾) are characteristic of prostatic adenocarcinoma . 2. Hypermethylation of the glutathione S transferase ( GSTP1 ) gene promoter is present in more than 90% of prostatic adenocarcinomas. 3. Stage 2 (clinically evident but confined to the prostate) 4. This low stage has a good prognosis . Because of the patient's age, the tumor is likely to follow an indolent course; even if the prostate adenocarcinoma is untreated, it is more likely that the patient will die of other causes. ERRNVPHGLFRVRUJ 21.2 Side A (PBD9: 982; BP9: 664) ERRNVPHGLFRVRUJ Questions A 75-year-old man has a 10-year history of increasing difficulty with urination, including frequency, hesitancy, and dribbling. The cause of his urinary symptoms (7 cm in diameter) is shown. 1. What is the diagnosis? 2. What therapy targets the hormonal mechanism associated with this condition? 3. What complications could occur if this is left untreated? ERRNVPHGLFRVRUJ Answers: Side B 1. There are increased glands with little intervening stroma, but the epithelial cells are well differentiated and in two layers, which is consistent with prostatic hyperplasia . 2. No. Nodular hyperplasia of the prostate is not a precursor to cancer. The prevalence of prostatic hyperplasia increases with age, however, just as the prevalence of prostate cancer does. 3. The volume of prostate epithelium correlates with the serum PSA level. Benign prostatic hypertrophy is one cause that leads to elevated levels of PSA. The PSA level with BPH is likely to remain constant over time, however, whereas the PSA level associated with prostate adenocarcinoma is likely to increase. ERRNVPHGLFRVRUJ 21.2 Side B (PBD9: 982; BP9: 664) ERRNVPHGLFRVRUJ Questions An 81-year-old man has a uniformly enlarged prostate on digital rectal examination. His prostate-specific antigen (PSA) level is twice the normal reference interval maximum. His prostate biopsy specimen is shown. 1. What is the diagnosis? 2. Is this premalignant? 3. Why is the PSA level elevated? ERRNVPHGLFRVRUJ Answers: Side A 1. This markedly enlarged prostate has a firm, white-tan appearance that is consistent with nodular prostatic hyperplasia , primarily from fibromuscular hyperplasia. 2. Finasteride is a 5α-reductase inhibitor that reduces the conversion of testosterone to dihydrotestosterone (DHT). A lower DHT level means less binding, less activation of nuclear androgen receptors, and decreased growth factor transcription. 3. Urinary tract obstruction and an increased residual volume of urine increases the risk for urinary tract infection, bladder hypertrophy, hydroureters, and hydronephrosis; hydronephrosis leads to a loss of renal cortex and chronic renal failure . ERRNVPHGLFRVRUJ 21.3 Side A (PBD9: 970; BP9: 657) ERRNVPHGLFRVRUJ Questions A 50-year-old man with the congenital penile abnormality shown has no major health problems. 1. What is your diagnosis? 2. How common is this anomaly? 3. What problems might this anomaly cause? 4. What is the name of the condition when the orifice shown is too small? ERRNVPHGLFRVRUJ Answers: Side B 1. This is epispadias with a groove ( ▾) on the dorsal aspect of the penis that extends from the urethral meatus. 2. Epispadias is rare; it occurs in about 1 of every 30,000 live births. 3. An open defect that extends to the bladder is called exstrophy . 4. Epispadias can be accompanied by incontinence , or it can result in a urethral stricture and a urinary tract obstruction that predisposes the affected individual to infection. Epispadias and hypospadias are associated with the failure of testes to descend and other congenital malformations of the urinary tract. ERRNVPHGLFRVRUJ 21.3 Side B (PBD9: 970; BP9: 657) ERRNVPHGLFRVRUJ Questions A 10-year-old boy has recurrent urinary tract infections. The gross appearance of his penis is shown. 1. What is your diagnosis? 2. How common is this anomaly? 3. If the defect extended to the bladder, what would your diagnosis be? 4. Why might he have recurrent urinary tract infections? ERRNVPHGLFRVRUJ Answers: Side A 1. This is hypospadias . The catheter lies in a groove ( ◂) on the ventral surface, below the tip of the penis. 2. Such an anomaly, with some degree of abnormal ventral opening, occurs in about 1 : 300 live births. 3. Hypospadias can lead to problems with urination ( incontinence ). It can also be associated with an abnormal curvature of the penis ( chordee ), and problems with ejaculation may lead to infertility . 4. If the orifice of the prepuce is too small, the patient has phimosis. This may be congenital, but it is more often a consequence of repeated inflammation caused by infection. ERRNVPHGLFRVRUJ 21.4 Side A (PBD9: 962; BP9: 668) ERRNVPHGLFRVRUJ Questions A 33-year-old woman with a 4-day history of suprapubic pain and dysuria has a urinalysis that is notable for hematuria and glucosuria but no proteinuria. Urine microscopic examination shows RBCs and WBCs but no casts. A cystoscopic examination would reveal the gross appearance of the bladder as shown. 1. What is your diagnosis? 2. What is a possible predisposing condition? 3. If she developed fever with flank pain, what complication might you suspect? ERRNVPHGLFRVRUJ Answers: Side B 1. The dense inflammatory infiltrate of neutrophils in the urothelium ( ♦) and the submucosa ( ■) of the bladder suggests acute cystitis . 2. The shorter urethra in women facilitates the ascent of microbial organisms to the bladder. 3. Bacterial organisms would be present. Coliforms such as Escherichia coli as well as Proteus, Klebsiella, and Enterobacter species are the most frequent organisms cultured. “Negative” bacterial cultures suggest chlamydial, fungal, or viral agents. ERRNVPHGLFRVRUJ 21.4 Side B (PBD9: 962; BP9: 668) ERRNVPHGLFRVRUJ Questions A 52-year-old woman with urinary frequency and burning pain on urination has a urinalysis that is notable for copious WBCs and a dipstick that is positive for nitrite and leukocyte esterase. A biopsy specimen of her bladder would appear as shown. 1. What is your diagnosis? 2. Why is this more common in women than men? 3. What would a urine culture show? ERRNVPHGLFRVRUJ Answers: Side A 1. This is acute cystitis . Note the marked bladder mucosal erythema (redness) as a result of the inflammation. 2. The glucosuria suggests diabetes mellitus. Calculi, instrumentation (e.g., catheterization), obstruction, and immunosuppression all also increase the risk for urinary tract infections. 3. Lower urinary tract infections can ascend to the kidneys and result in pyelonephritis and possibly sepsis . ERRNVPHGLFRVRUJ 21.5 Side A (PBD9: 964; BP9: 669) ERRNVPHGLFRVRUJ Questions A 58-year-old man with severe emphysema and a 6-month history of urinary frequency and urgency now has red-tinged urine. Analysis reveals numerous RBCs but few WBCs. The gross appearance of his bladder after further work-up and surgical resection is shown. 1. What is your diagnosis? 2. What is his likely risk factor? 3. If he had lived in Egypt, what cause might you suspect? 4. What are some known bladder carcinogens? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has urothelial carcinoma in situ (CIS) . Cytologically malignant cells extend the full thickness of the urothelium but not through the basement membrane ( ◂); submucosal vascular dilation accounts for the erythema seen on cystoscopy. 2. If all lesions are CIS, local resection may be sufficient to control this cancer, but invasion into the muscularis propria generally dictates cystectomy. Hematuria is worrisome for invasion in one of the lesions, even if we cannot document it on a biopsy specimen. 3. Urothelial carcinomas are multifocal and recurrent, so ongoing surveillance with urine cytology, cystoscopy, and radiologic imaging is required to detect additional malignancies. ERRNVPHGLFRVRUJ 21.5 Side B (PBD9: 964; BP9: 669) ERRNVPHGLFRVRUJ Questions A 61-year-old woman with microscopic hematuria on routine urinalysis undergoes cystoscopy, which shows multiple flat, erythematous lesions that are all less than 1 cm in size. The microscopic appearance of one such biopsied lesion is shown. 1. What is your diagnosis? 2. How would you determine the need for cystectomy? 3. Why is follow-up needed after therapy? ERRNVPHGLFRVRUJ Answers: Side A 1. This large papillary, exophytic mass ( ♦) is a urothelial carcinoma . 2. Cigarette smoking is the most frequent risk factor for urothelial cancers and for chronic obstructive pulmonary disease. 3. Chronic schistosomiasis ( Schistosoma haematobium) can predispose individuals to bladder cancer, including squamous cell carcinoma. 4. Arylamines (e.g., 2-naphthylamine), analgesic abuse (phenacetin, aspirin), and chemotherapy with cyclophosphamide predispose patients to urothelial carcinoma. ERRNVPHGLFRVRUJ 21.6 Side A (PBD9: 971; BP9: 657) ERRNVPHGLFRVRUJ Questions A 41-year-old man with a 1-year history of the macular expanding penile lesion shown has the lesion completely excised. It is confined to the epithelium above the basement membrane. 1. What is your diagnosis? 2. Why should this lesion be excised? 3. What is the infectious risk factor? 4. What diagnosis is given to younger patients with multiple similar lesions? ERRNVPHGLFRVRUJ Answers: Side B 1. This is invasive penile squamous cell carcinoma ( ▾). 2. The presence of lymph node metastases reduces 5-year survival to roughly 25%; it is 65% without nodal involvement. 3. The presence of an uncircumcised foreskin increases an individual's exposure to potential carcinogens in trapped smegma. 4. Human papillomavirus (HPV) infection, particularly with subtypes 16 and 18, increases the risk for penile carcinoma. ERRNVPHGLFRVRUJ 21.6 Side B (PBD9: 971; BP9: 657) ERRNVPHGLFRVRUJ Questions A 63-year-old man with a 3-year history of a slowly enlarging lesion now reports ulceration and bleeding. Enlarged nontender inguinal lymph nodes are also palpable. Penectomy is performed and shown. 1. What is your diagnosis? 2. What is the prognosis for 5-year survival? 3. What risk factor is grossly evident? 4. What infectious agent is associated with this lesion? ERRNVPHGLFRVRUJ Answers: Side A 1. This is penile squamous cell carcinoma in situ ( CIS ), also called Bowen disease ( ▸). 2. If left untreated, 10% of CIS lesions evolve into invasive squamous cell carcinoma . 3. Squamous epithelial dysplasias and carcinomas in the genital region of men and women are associated with human papillomavirus ( HPV ) infection. HPV type 16 is most strongly associated with Bowen disease. 4. Such lesions would represent bowenoid papulosis . Although this condition presents with multiple lesions, it is unlikely to progress to invasive carcinoma. ERRNVPHGLFRVRUJ 21.7 Side A (PBD9: 972; BP9: 658) ERRNVPHGLFRVRUJ Questions An otherwise healthy 10-year-old boy has only one testis palpable in his scrotum. His testes would appear as shown. 1. Which is the abnormal testis? 2. Where was the abnormal testis located? 3. Will this patient be infertile after puberty? 4. What long-term risk is associated with preserving a nondescended testis? ERRNVPHGLFRVRUJ Answers: Side B 1. The seminiferous tubules ( ▴) are completely atrophic , and there is no spermatogenesis. 2. Atrophic descended testes can be the result of inflammatory orchitis or Klinefelter syndrome (47,XXY karyotype). Unlikely causes at this patient's age include radiation or chemotherapy for malignancy or hyperestrinism as a result of estrogen therapy or hepatic cirrhosis. Cryptorchidism is bilateral in one fourth of cases. 3. Hypopituitarism and decreased Leydig cell function can account for seminiferous tubular atrophy. However, in both cases, one would expect subsequent diminished development of the secondary sex characteristics. ERRNVPHGLFRVRUJ 21.7 Side B (PBD9: 973; BP9: 658) ERRNVPHGLFRVRUJ Questions During a work-up for primary infertility, a 22-year-old man is found to have normal male sexual development, including bilaterally descended testes. A semen analysis shows azoospermia, however, and a testicular biopsy specimen shows the histology shown. 1. What is your diagnosis? 2. What could be the cause of this atrophy? 3. What cause is excluded by his sexual development? ERRNVPHGLFRVRUJ Answers: Side A 1. The smaller, pale, atrophic testis ( ♦) is typical of cryptorchidism , which is the failure of the testis to descend into the scrotum. 2. A cryptorchid testis may be found anywhere from within the lower abdominal cavity to the inguinal canal. 3. The normally descended testis produces spermatozoa. Although the sperm count might be reduced, fertility is still possible. 4. There is an increased risk for testicular carcinoma with a cryptorchid testis, even in the normally descended testis, which suggests that cryptorchidism is perhaps just a marker for abnormal testicular development. ERRNVPHGLFRVRUJ 21.8 Side A (PBD9: 974; BP9: 659) ERRNVPHGLFRVRUJ Questions A 14-year-old healthy boy is awakened from sleep by sudden and severe scrotal pain. Examination reveals a swollen, tender testis high in the scrotal sac. External maneuvers are unsuccessful for relieving the pathology, and the testis is eventually removed. The gross and microscopic appearances are shown. 1. What is your diagnosis? 2. What caused this event? 3. What can be done to prevent this from happening in the opposite testis? ERRNVPHGLFRVRUJ Answers: Side B 1. Pulsatile blood flow is absent ( ▾). This is characteristic of testicular torsion . 2. In newborns, before the fixation of the testis to the tunica, the testis can freely rotate on the spermatic cord. 3. If the torsion can be reversed with the restoration of blood flow within 6 to 8 hours, the testis can often be salvaged. If torsion persists for more than 24 hours, however, infarction with permanent loss of function is likely. ERRNVPHGLFRVRUJ 21.8 Side B (PBD9: 974; BP9: 659) ERRNVPHGLFRVRUJ Questions A newborn boy is irritable and feeding poorly. On examination, the scrotal skin is found to be fixed to a hard scrotal mass. An ultrasound study with Doppler from this patient (lower panel ) is shown and compared with a normal study (top panel ). 1. What is your diagnosis? 2. How did this happen? 3. What is the time frame for preventing irreversible damage? ERRNVPHGLFRVRUJ Answers: Side A 1. In children and adolescents, abnormal testicular descent leaves the testis free to rotate on the spermatic cord within the tunica vaginalis; this is a “bell-clapper” deformity that causes testicular torsion . 2. Grossly, the testis ( ♦) is dark as a result of hemorrhagic infarction ; microscopically, the testicular tubules ( ▴) show coagulative necrosis with extensive hemorrhage. This testis is nonviable. 3. The opposite testis can be affixed to the tunica to prevent possible torsion. ERRNVPHGLFRVRUJ 21.9 Side A (PBD9: 976; BP9: 659) ERRNVPHGLFRVRUJ Questions A 36-year-old man with a 5-month history of a dragging scrotal sensation is found to have an enlarged left testis; ultrasound reveals a solid mass. The gross appearance is shown after resection. 1. What germ cell tumor is this most likely to be? 2. Is this neoplasm commonly associated with a paraneoplastic syndrome? 3. What are the risk factors for this neoplasm? ERRNVPHGLFRVRUJ Answers: Side B 1. The sheets of large polyhedral cells ( ▴) with watery cytoplasm and intervening lymphoid stroma ( ♦) are characteristic of seminoma . 2. An isochromosome of the short arm of chromosome 12 ( i12p ) is often present in germ cell tumors. 3. Germ cell tumors, including seminomas, may contain syncytiotrophoblastic cells that produce human chorionic gonadotropin. 4. These tumor cells are exquisitely radiosensitive, likely because they are developmentally akin to primordial spermatogonia. ERRNVPHGLFRVRUJ 21.9 Side B (PBD9: 976; BP9: 659) ERRNVPHGLFRVRUJ Questions A 33-year-old man with a 1-year history of right testicular enlargement undergoes ultrasound imaging that shows a solid 4-cm mass. He has a positive pregnancy test (!). The microscopic appearance of the mass is shown. 1. What is your diagnosis? 2. Name the karyotypic abnormality. 3. Why is the pregnancy test positive? 4. What forms of therapy are effective as treatment? ERRNVPHGLFRVRUJ Answers: Side A 1. This lobulated tan mass ( ♦) is a seminoma , which is the most common form of testicular germ cell tumor. Roughly 50% of all germ cell tumors are seminomas, and their peak age of occurrence is during the fourth decade of life. 2. Seminomas are not usually associated with paraneoplastic syndromes. Although seminomas do not tend to produce significant amounts of androgenic or estrogenic hormones, elevated human chorionic gonadotropin can induce gynecomastia. 3. Disorders of testicular development (e.g., cryptorchidism, androgen insensitivity syndrome, Klinefelter syndrome) increase the risk for germ cell tumors. ERRNVPHGLFRVRUJ 21.10 Side A (PBD9: 977; BP9: 659) ERRNVPHGLFRVRUJ Questions A 28-year-old man who has had unilateral testicular enlargement for 1 year undergoes ultrasound examination, which reveals a 6-cm left testicular solid and cystic mass. Abdominal CT scan shows enlarged para-aortic lymph nodes. His chest radiograph shows bilateral lung nodules. His serum lactate dehydrogenase (LDH), α-fetoprotein (AFP), and human chorionic gonadotropin (HCG) levels are all elevated. The gross appearance of the testis after resection is shown. 1. What is the probable diagnosis? 2. What histologic elements might you expect to see? 3. What is the stage of this neoplasm? 4. How can the tumor's response to therapy be assessed? ERRNVPHGLFRVRUJ Answers: Side B 1. The alveolar ( •) and tubular ( ♦) growth pattern of large, poorly differentiated cells coupled with an elevated AFP level is consistent with embryonal carcinoma . 2. A testicular tumor confined to the testis, epididymis, or spermatic cord is stage I. 3. An elevated human chorionic gonadotropin level can drive bilateral breast enlargement, which is called gynecomastia . ERRNVPHGLFRVRUJ 21.10 Side B (PBD9: 977; BP9: 659) ERRNVPHGLFRVRUJ Questions A 26-year-old man with left testicular enlargement has a markedly elevated serum αfetoprotein (AFP) level. Imaging studies show no metastases. The microscopic appearance of the orchiectomy specimen is shown. 1. What is your diagnosis? 2. What is the stage of this neoplasm? 3. What paraneoplastic syndrome can be associated with germ cell tumors? ERRNVPHGLFRVRUJ Answers: Side A 1. This variegated mass ( ♦) is a mixed germ cell tumor . 2. The elevated AFP level suggests a yolk sac/embryonal carcinoma component . The elevated HCG level comes from syncytiotrophoblasts; if these are mixed with cytotrophoblasts, a choriocarcinoma component is suggested. Variegation suggests teratoma , with many possible tissue types. 3. Metastases outside of the retroperitoneal lymph nodes and above the diaphragm denote the highest stage: stage III. 4. The amount of LDH correlates roughly with the tumor burden. Decreasing levels of HCG or AFP also indicate tumor response to therapy. ERRNVPHGLFRVRUJ 22 ERRNVPHGLFRVRUJ The Female Genital Tract ERRNVPHGLFRVRUJ 22.1 Side A (PBD9: 1039; BP9: 701) ERRNVPHGLFRVRUJ Questions A 20-year-old woman (G2, P1) is large for dates at 12 weeks' gestation. Ultrasonography shows a “snowstorm” of cystic spaces but no fetus. A dilation and curettage (D&C) yields the tissue shown. 1. Describe the findings. 2. Why should serial human chorionic gonadotropin (HCG) levels be obtained after D&C? ERRNVPHGLFRVRUJ Answers: Side B 1. The villi (▪) are uniformly enlarged and avascular, and they have increased amounts of surrounding trophoblastic cells (♦); this is consistent with complete mole . 2. More than 90% of complete moles have a 46,XX karyotype , and all are derived from paternal chromosomes . In about 90% of complete moles, an ovum that lacks maternal chromosomes is fertilized by a single sperm, with subsequent chromosomal duplication. In the remaining cases, an “empty” ovum is fertilized by two sperm. 3. This apparent complete mole could have a component of choriocarcinoma (2% of complete moles) or invasion into the uterus. ERRNVPHGLFRVRUJ 22.1 Side B (PBD9: 1041; BP9: 702) ERRNVPHGLFRVRUJ Questions A 22-year-old woman has not experienced fetal movement by 18 weeks' gestation. She subsequently develops vaginal bleeding followed by the passage of grapelike structures. The uterine contents are evacuated, and the histology is shown. 1. Describe the microscopic findings. 2. What is the most likely karyotype of cells from this tissue? 3. After evacuation, the patient's serum human chorionic gonadotropin remains elevated. What should you be concerned about? ERRNVPHGLFRVRUJ Answers: Side A 1. The normal placental architecture is completely replaced by numerous grapelike masses, a complete hydatidiform mole , and the most common form of gestational trophoblastic disease. 2. Molar pregnancies are associated with high HCG levels. After the evacuation of a complete mole, HCG levels should disappear. If they do not, invasive mole or choriocarcinoma should be considered. ERRNVPHGLFRVRUJ 22.2 Side A (PBD9: 1010; BP9: 689) ERRNVPHGLFRVRUJ Questions A 35-year-old primigravida has had lower abdominal pain (worse during menses), dysmenorrhea, and dyspareunia for 10 years. She has a palpable left adnexal mass. Her CT scan is shown. At laparoscopy, multiple 0.2- to 0.4-cm, purple-brown nodules are grossly evident on the pelvic peritoneum. 1. What is the diagnosis? 2. What is the ovarian lesion? 3. How do these lesions arise? ERRNVPHGLFRVRUJ Answers: Side B 1. A diagnosis of endometriosis requires that endometrial stroma ( ▪) be present; glands (♦) with recent hemorrhage ( ●) or hemosiderin deposition from remote hemorrhage are also often present. 2. Her pain is related to bleeding with peritoneal irritation. The ectopic endometrium responds to hormonal changes similar to the way that normal endometrium does. Recurrent cycles of hemorrhage and the sloughing of endometriotic tissue into the ovaries or the peritoneal cavity cause scarring that interferes with normal ovulation or that physically blocks the fallopian tubes. ERRNVPHGLFRVRUJ 22.2 Side B (PBD9: 1010; BP9: 689) ERRNVPHGLFRVRUJ Questions A 30-year-old woman with a 5-year history of intermittent lower abdominal pain and infertility undergoes a laparoscopy that reveals multiple lesions with the microscopic appearance shown. 1. What microscopic elements are needed for diagnosis? 2. Explain this patient's clinical findings and her infertility. ERRNVPHGLFRVRUJ Answers: Side A 1. This is endometriosis . Small lesions (described grossly as “powder burn” lesions) may not be detected by physical examination or radiologic imaging, but they can be excruciatingly painful. 2. The ovarian lesion ( ▪) is a well-circumscribed endometrioma . It is not a true tumor but rather the accumulation of blood within a cystic mass after years of cyclic hemorrhaging from ectopic endometrial tissue. 3. Theories include the following: (a) retrograde menstruation through the fallopian tubes with the implantation of endometrial tissue in the peritoneal cavity; (b) metaplasia of the peritoneal epithelium; and (c) vascular dissemination of endometrial tissue through venous or lymphatic channels. ERRNVPHGLFRVRUJ 22.3 Side A (PBD9: 1039; BP9: 701) ERRNVPHGLFRVRUJ Questions A 22-year-old primigravida has experienced marked hyperemesis gravidarum throughout the 17 weeks of her pregnancy, but she still has not felt fetal movement. After the patient passes a small amount of blood from her vagina, an ultrasound is performed. The findings are shown. 1. What is the diagnosis? 2. How would this be treated? 3. What laboratory finding is used for follow-up? ERRNVPHGLFRVRUJ Answers: Side B 1. A large hemorrhagic mass invades through ( ◂) the uterine wall. Although this could be an invasive mole , the extensive necrosis is more suggestive of choriocarcinoma . 2. Approximately 2% of complete moles ( diploid ) evolve into choriocarcinomas, but partial moles ( triploid ) only rarely do so. 3. The prognosis is good. Most of these masses respond to surgical resection and chemotherapy, even if they are metastatic. 4. Most complete moles have a diploid (46XX or 46XY) karyotype; both chromosomes are paternally derived via the fertilization of an “empty” ovum, either by two sperm or by a single sperm with subsequent duplication of its DNA. Partial moles are triploid (69XXY or 69XXX) and result from the fertilization of a normal haploid egg with two sperm or with one diploid sperm. ERRNVPHGLFRVRUJ 22.3 Side B (PBD9: 1041; BP9: 703) ERRNVPHGLFRVRUJ Questions A 29-year-old woman is very large for dates at 20 weeks' gestation, with a markedly elevated β-human chorionic gonadotropin (HCG) level. An ultrasound shows no fetus, and a dilation and curettage (D&C) reveals a hydatidiform mole. After the D&C, the βHCG level declines but then starts to increase again. Hysterectomy is performed 1 month later, with the findings shown. 1. What is the diagnosis? 2. What was the probable karyotype of the original mole? 3. What is the prognosis? 4. What could the ploidy of this lesion be? ERRNVPHGLFRVRUJ Answers: Side A 1. There is a multicystic appearance ( ▴) with no gestational sac or fetus present. This is consistent with either a complete or partial hydatidiform mole . 2. Dilation and curettage will be performed to remove the tissue completely. An invasive mole or choriocarcinoma requires additional therapy, such as hysterectomy, chemotherapy, or both. 3. The β-human chorionic gonadotropin level should return to nondetectable if the mole is benign and totally removed. ERRNVPHGLFRVRUJ 22.4 Side A (PBD9: 997; BP9: 683) ERRNVPHGLFRVRUJ Questions A 31-year-old woman has a 6-month history of nonpruritic, nonhemorrhagic warty lesions on her perineum as shown. 1. What is the diagnosis? 2. What causative agent is most often implicated? 3. How do high-risk subtypes of this agent act on the cell cycle to drive proliferation? ERRNVPHGLFRVRUJ Answers: Side B 1. This is benign squamous epithelial hyperplasia that was likely caused by human papillomavirus (HPV) infection. There is acanthosis (thickening) of the squamous epithelium, and the keratinocytes that are present have clear perinuclear cytoplasmic vacuoles ( koilocytosis ). Keratinocyte nuclei persist into the keratin layer ( parakeratosis ), and the keratin layer is thickened ( hyperkeratosis ). Koilocytotic atypia is characteristic of HPV infection . 2. No, this is not premalignant. However, sexually active individuals can also acquire high-risk subtypes of HPV, which increase the likelihood of the development of squamous dysplasias and carcinoma. 3. Immunocompetent individuals clear the virus within 1 to 2 years, and the lesions spontaneously regress. ERRNVPHGLFRVRUJ 22.4 Side B (PBD9: 997; BP9: 683) ERRNVPHGLFRVRUJ Questions A sexually active young adult has multiple genital verrucous lesions. A biopsy specimen has the microscopic appearance shown. 1. What is the diagnosis? 2. Is this premalignant? 3. What is the likely outcome? ERRNVPHGLFRVRUJ Answers: Side A 1. These pale verrucous lesions ( ▾) are condylomata acuminata . 2. Human papillomavirus (HPV) subtypes 6 and 11 are most often associated with condylomata. 3. The HPV E6 and E7 proteins enhance the degradation of the p53 gene product protein, thereby blocking apoptosis and decreasing the activity of the p21 cell cycle inhibitor. E7 also binds to the hyperphosphorylated form of the RB tumor suppressor, thereby blocking its complexing with the E2F transcription factor and allowing entry into the cell cycle S-phase. ERRNVPHGLFRVRUJ 22.5 Side A (PBD9: 1010; BP9: 689) ERRNVPHGLFRVRUJ Questions A 33-year-old woman has a 6-year history of dyspareunia, severe dysmenorrhea, and dysuria. Laparoscopy reveals numerous small, purplish lesions, and the woman elects to undergo a hysterectomy and a bilateral salpingo-oophorectomy, as shown. 1. What is the diagnosis? 2. What are the theories regarding the origin of these lesions? ERRNVPHGLFRVRUJ Answers: Side B 1. The endometrial glands ( ▪) with endometrial stroma (♦) and hemorrhage are characteristic features of endometriosis . 2. About 10% of women are affected. The lesions are small, which makes diagnosis challenging. 3. Endometrioid carcinomas of the ovary may develop in women with a history of endometriosis. 4. Endometriosis involving the ovary may give rise to an endometrioma, which is a large mass that contains old blood and hemosiderin. It looks like dark milk chocolate, and this appearance has given rise to its nickname of “chocolate cyst.” ERRNVPHGLFRVRUJ 22.5 Side B (PBD9: 1010; BP9: 689) ERRNVPHGLFRVRUJ Questions A 28-year-old woman has had disabling pelvic pain and pain on defecation for 4 years. No abnormalities are noted on the physical examination. Laparoscopy reveals multiple 1- to 3-mm, dark-red, raised lesions on her pelvic peritoneum, with the histology shown. 1. What is the diagnosis? 2. How many women are affected by this condition? 3. What malignancy may be related to these lesions? 4. What benign ovarian mass lesion can develop? ERRNVPHGLFRVRUJ Answers: Side A 1. The dark brown “powder burn” lesions ( ▸ ) on the cul-de-sac, the left ovary, and the right tube are the foci of endometriosis. 2. Theories include retrograde menstruation through the tube out the fimbriated end, with implantation on peritoneal surfaces. Alternatively, venous or lymphatic dissemination or metaplasia of the epithelium that lines the peritoneal surfaces during embryogenesis could account for these foci. Endometriosis within the myometrium is called adenomyosis . ERRNVPHGLFRVRUJ 22.6 Side A (PBD9: 1022; BP9: 695) ERRNVPHGLFRVRUJ Questions A 30-year-old woman with a 3-year history of hirsutism and oligomenorrhea presents for work-up. Her body mass index is 35 (nl 18.5 to 25). She has a fasting glucose level of 138 mg/dL (nl ≤110 mg/dL), and her hemoglobin A value is 8% (nl ≤6%). An MRI of her pelvis is shown. 1c 1. What is the ovarian abnormality? 2. What condition does she have? 3. What are her serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone likely to be? ERRNVPHGLFRVRUJ Answers: Side B 1. The ovarian cortex ( ▪) is thickened and lacks follicles, which is indicative of hyperthecosis . 2. This patient has metabolic syndrome . 3. She also has polycystic ovarian syndrome . There is increased adenohypophyseal production of LH that increases ovarian androgen production. This has been linked—in a manner similar to type 2 diabetes—with insulin resistance, hence the frequent association with obesity, dyslipidemia, and diabetes. ERRNVPHGLFRVRUJ 22.6 Side B (PBD9: 1022; BP9: 695) ERRNVPHGLFRVRUJ Questions A 29-year-old woman presents for a fertility work-up after a 2-year inability to conceive. She has abdominal obesity, dyslipidemia with a total cholesterol level of 210 mg/dL (nl ≤200 mg/dL) and an HDL cholesterol level of 28 mg/dL (nl ≥35 mg/dL), and elevated androgen levels. An ovarian wedge biopsy is performed, and the sample is shown. 1. What is abnormal about this ovary? 2. What do abdominal obesity and dyslipidemia indicate? 3. What endocrine disorder does she have? ERRNVPHGLFRVRUJ Answers: Side A 1. The ovary is enlarged and contains numerous bright, fluid-filled follicular cysts ( ▸ ). 2. This spectrum of findings is consistent with polycystic ovarian syndrome (formerly called Stein-Leventhal syndrome). 3. Her LH/FSH ratio is likely to be greater than 3, and her testosterone level is increased as a result of excessive ovarian androgen production. Although the primary defect is unknown, increased LH production stimulates the follicular thecal cells to overproduce androstenedione. ERRNVPHGLFRVRUJ 22.7 Side A (PBD9: 1041; BP9: 703) ERRNVPHGLFRVRUJ Questions A 22-year-old woman who delivered a term infant 1 month previously now has brownred vaginal discharge and pelvic pain. Her β-human chorionic gonadotropin level is markedly elevated. A CT scan of her pelvis is shown. 1. What is the diagnosis? 2. In what situations does this neoplasm arise? ERRNVPHGLFRVRUJ Answers: Side B 1. This choriocarcinoma with anaplasia and no chorionic villi mimics the syncytiotrophoblast and cytotrophoblast of the placenta. 2. Metastases 3. Despite metastases, most choriocarcinomas respond to chemotherapy, often with methotrexate, actinomycin D, and etoposide along with cyclophosphamide and vincristine. 4. She would be followed by obtaining serial β-human chorionic gonadotropin levels. With successful therapy, these levels disappear. ERRNVPHGLFRVRUJ 22.7 Side B (PBD9: 1041; BP9: 703) ERRNVPHGLFRVRUJ Questions An 18-year-old woman who had a hydatidiform mole evacuated 2 months ago now has a foul-smelling brown vaginal discharge. Chest radiography reveals multiple nodules, and her brain MRI shows a left parietal hemorrhagic mass. An endometrial biopsy specimen is shown. 1. What does this neoplasm mimic? 2. What do the lung and brain lesions represent? 3. How is this neoplasm treated? 4. What laboratory test is used to follow up her treatment? ERRNVPHGLFRVRUJ Answers: Side A 1. There is a solid and cystic mass ( ▪) in the region of the uterus that extends into the pelvis (♦); this is consistent with choriocarcinoma . 2. Fifty percent of choriocarcinomas arise in complete hydatidiform moles, and 25% occur after a normal pregnancy. Only 2% of moles—and only 1 in 150,000 normal pregnancies—develop into choriocarcinoma. They can also arise with ectopic pregnancy, with miscarriage, or with a teratoma. ERRNVPHGLFRVRUJ 22.8 Side A (PBD9: 1036; BP9: 701) ERRNVPHGLFRVRUJ Questions A 26-year-old woman who missed her last menstrual period now has a sudden onset of severe lower abdominal pain. Although her β-human chorionic gonadotropin level is positive, an ultrasound scan shows no intrauterine gestational sac. An emergency laparotomy is performed, and the lesion shown is removed. 1. What is the diagnosis? 2. What are the risk factors for this condition? ERRNVPHGLFRVRUJ Answers: Side B 1. This ectopic pregnancy is diagnosed by the presence of chorionic villi ( ▪) along with the blood clot (♦). 2. Prior surgery can lead to adhesions and tubal scarring that can impede the normal transit of fertilized ova to the endometrial cavity. 3. More than 90% of ectopic pregnancies occur in the tube, but the ovary and the abdominal peritoneum are also potential sites for implantation. 4. A ruptured ectopic pregnancy can lead to hemorrhagic shock and disseminated intravascular coagulopathy . ERRNVPHGLFRVRUJ 22.8 Side B (PBD9: 1036; BP9: 701) ERRNVPHGLFRVRUJ Questions A 30-year-old woman has a 2-day history of vaginal bleeding and abdominal pain. Her β-human chorionic gonadotropin level is positive. Culdocentesis yields bloody fluid, and an endometrial biopsy specimen shows decidual change. Laparoscopy is performed, and the microscopic appearance of the lesion from her fallopian tube is shown. 1. What microscopic features are seen? 2. How does prior abdominal surgery relate to this condition? 3. Where else might this lesion be found? 4. What is a serious complication of this condition? ERRNVPHGLFRVRUJ Answers: Side A 1. This excised fallopian tube is greatly enlarged, and it has ruptured to reveal a blood clot and two small twin embryos ( ▪). This is a tubal ectopic pregnancy . 2. The most common risk factor is prior salpingitis , a condition that causes scarring and that is often the result of pelvic inflammatory disease caused by sexually transmitted diseases such as Chlamydia trachomatis and Neisseria gonorrhoeae. Nevertheless, 50% of ectopic pregnancies occur in apparently normal tubes. ERRNVPHGLFRVRUJ 22.9 Side A (PBD9: 1029; BP9: 698) ERRNVPHGLFRVRUJ Questions A 44-year-old woman with a 7-year history of lower abdominal discomfort has an ultrasound scan that shows a cystic left ovarian mass and a solid right ovarian mass. The findings at hysterectomy and salpingo-oophorectomy are shown. 1. What three separate diagnoses can you make? 2. Are these lesions benign or malignant? ERRNVPHGLFRVRUJ Answers: Side B 1. This is a mature cystic teratoma that exhibits squamous epithelium ( ▸ ) with sebaceous glands and adjacent stroma with glandlike areas ( ▴). 2. Teratomas contain tissue elements derived from ectoderm, mesoderm, and endoderm. The mature cystic teratomas (dermoid cysts) have a preponderance of ectodermal tissues, and most patients are brunettes, with few redheads and rarely blonds being affected. 3. All benign teratomas have a 46,XX karyotype; they are derived from totipotential meiotic germ cells in the ovum, after the first meiotic division. ERRNVPHGLFRVRUJ 22.9 Side B (PBD9: 1029; BP9: 698) ERRNVPHGLFRVRUJ Questions A 35-year-old woman with vague pelvic “heaviness” has a CT scan that shows a right ovarian 8-cm cystic mass; cartilage and bone density is seen focally in the cyst wall. The surgically resected right ovary has the microscopic appearance shown. 1. What is the diagnosis? 2. What three embryologic elements are present? 3. What is the probable karyotype? ERRNVPHGLFRVRUJ Answers: Side A 1. The large cystic left ovarian mass ( ▪) filled with hair and greasy dark material is a mature cystic teratoma (dermoid cyst) , which is composed of variable amounts of mature tissues from all three germ cell layers. The solid tan right ovarian mass ( ▸ ) is a cystadenofibroma (columnar lining epithelium and abundant fibrous stroma). There are also two leiomyomas ( ◂) within the uterine myometrium. 2. All three lesions are likely benign based on their size and appearance. Immature and malignant teratomas are usually solid. About 1% of teratomas undergo malignant transformation. ERRNVPHGLFRVRUJ 22.10 Side A (PBD9: 1008; BP9: 690) ERRNVPHGLFRVRUJ Questions A 16-year-old girl with irregular menstrual cycles since her menarche 18 months ago undergoes endometrial curetting at day 25 of her menstrual cycle (upper panel ); shown for comparison is a normal 25-day endometrium (lower panel ). 1. What is your diagnosis? 2. What hormone is likely insufficient in this girl? 3. How can this be treated? ERRNVPHGLFRVRUJ Answers: Side B 1. The small, inactive glands ( ▾) are scattered within a decidualized stroma (large pink cells). This is a predominantly progesterone effect . 2. Most oral contraceptives consist of a progestin combined with estrogen. They primarily work by suppressing ovulation through the feedback inhibition of pituitary and hypothalamic axis hormones. In addition, the endometrium does not reach a welldeveloped secretory phase that supports implantation. 3. With the discontinuation of oral contraceptives, the normal cycling pattern from proliferative to secretory after ovulation returns. ERRNVPHGLFRVRUJ 22.10 Side B (PBD9: 1009; BP9: 690) ERRNVPHGLFRVRUJ Questions A 30-year-old woman has regular 28-day menstrual cycles when using oral contraceptives. The microscopic appearance of her endometrium is shown at day 25. 1. Why does her endometrium appear like this? 2. How do oral contraceptives work? 3. What happens when oral contraceptives are discontinued? ERRNVPHGLFRVRUJ Answers: Side A 1. She has dysfunctional uterine bleeding with anovulatory cycles. Note the small proliferative gland ( ▸ ) in a hemorrhagic stroma compared with normal secretory endometrium (♦) at day 25. 2. If the luteinizing hormone surge does not occur, ovulation does not occur, a corpus luteum does not form, and levels of progesterone do not increase to support a secretory phase. Instead, proliferative glands persist in a stroma that eventually undergoes necrosis and bleeds irregularly. 3. Hormonal therapy , often with oral contraceptives that contain progestational agents, promotes controlled endometrial cycling. ERRNVPHGLFRVRUJ 22.11 Side A (PBD9: 1026; BP9: 697) ERRNVPHGLFRVRUJ Questions A 44-year-old woman with a 1-year history of increasing abdominal girth and fullness has the CT scan shown. At hysterectomy, the lesions comprise multicystic structures with copious thick, gelatinous fluid contents. The solid portions of the lesions show the invasion of focally necrotic atypical columnar epithelial cells that are not clearly forming glands. 1. Describe the findings. 2. What condition is associated with marked ascites and peritoneal tumor implants? ERRNVPHGLFRVRUJ Answers: Side B 1. This mass shows areas of papillary growth on the surface ( ▴); these are indicative of invasion that signifies malignancy. This is a serous cystadenocarcinoma ; serous tumors constitute 40% of all malignant ovarian neoplasms. 2. These lesions are often diagnosed at an advanced stage, which often results in a poor prognosis. ERRNVPHGLFRVRUJ 22.11 Side B (PBD9: 1024; BP9: 697) ERRNVPHGLFRVRUJ Questions A 38-year-old woman with an 8-month history of abdominal pain and enlargement is found to have a right ovarian mass on CT. Paracentesis yields cloudy fluid that contains psammoma bodies and cuboidal cells in clusters. The gross appearance of the right ovary is shown. 1. What is the diagnosis? 2. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side A 1. There are bilateral multiloculated masses ( ▪) arising in the ovaries. The gross and microscopic findings suggest that these are malignant mucinous tumors ( mucinous cystadenocarcinoma ). Although they are not usually bilateral, mucinous tumors tend to form larger cystic masses than their serous counterparts. Mucinous tumors account for 25% of ovarian neoplasms; only about 15% are malignant. 2. Pseudomyxoma peritonei secondary to tumor cell implants with mucin production can be extensive and produce intestinal obstruction. In many cases, these are due to an extraovarian primary tumor (typically appendix) with ovarian and peritoneal spread. ERRNVPHGLFRVRUJ 22.12 Side A (PBD9: 1003; BP9: 685) ERRNVPHGLFRVRUJ Questions A 33-year-old woman with a vaginal discharge with a fishy odor has a Pap smear that contains “clue cells” (i.e., shed vaginal epithelial cells with a distinctive stippled appearance caused by a covering of bacteria) along with dysplastic cells. On colposcopy, a biopsy specimen of a 3-mm cervical lesion at the 5 o'clock position is obtained, and the microscopic appearance is shown. 1. What kind of vaginal infection does this patient have? 2. What is your diagnosis of the biopsy specimen? 3. What infectious agent is associated with the changes seen on this biopsy specimen? 4. How might this lesion have been prevented? ERRNVPHGLFRVRUJ Answers: Side B 1. This exophytic, irregular lesion around the cervical os is a squamous cell carcinoma . 2. A lesion ( ▾) this large and irregular is unlikely to be in situ. It is very likely to be invasive, because it goes beyond the 3 mm that would allow it to be called microinvasion. The fact that a hysterectomy was performed also indicates that invasion was seen on the original biopsy specimen. 3. Early age at first intercourse, multiple sexual partners, a partner with other sexual partners, persistent HPV, oral contraceptive use, smoking, and chlamydial infection are all risk factors for this condition. ERRNVPHGLFRVRUJ 22.12 Side B (PBD9: 1004; BP9: 685) ERRNVPHGLFRVRUJ Questions A 44-year-old woman who has had blood-tinged vaginal discharge for 1 month has a biopsy followed by hysterectomy; the gross appearance of her uterus is shown. 1. What is your diagnosis? 2. Is this likely in situ, or is it invasive? 3. Name the risk factors for human papillomavirus (HPV)–associated cervical carcinoma. ERRNVPHGLFRVRUJ Answers: Side A 1. The fishy odor and clue cells suggest bacterial vaginosis , which is typically caused by organisms such as Gardnerella vaginalis. Such infections are not associated with dysplasia. 2. The dysplastic cells extend the full thickness of the squamous epithelium, but they do not penetrate the basement membrane ( ◂). This is consistent with cervical intraepithelial neoplasia III (CIN III or cervical carcinoma in situ) . 3. Cervical squamous cell carcinoma and its precursor dysplasias are driven by human papillomavirus (HPV) infection. 4. Aside from avoiding sexual activity or routinely using condoms, HPV vaccination against high-risk types 16 and 18 can be preventive. Routine Pap smears detect early lesions. ERRNVPHGLFRVRUJ 22.13 Side A (PBD9: 1010; BP9: 689) ERRNVPHGLFRVRUJ Questions A 36-year-old woman (G4, P4) with a 5-year history of persistent dysmenorrhea and pelvic pain is not helped by either hormonal therapy or dilation and curettage. Her pelvic MRI is shown. 1. What is your diagnosis? 2. How does this occur? 3. What happens after menopause? ERRNVPHGLFRVRUJ Answers: Side B 1. This is a heterotopic focus (not invasion) of benign endometrial glands ( ▾) and stroma (♦) that represents adenomyosis . 2. Usually multiple foci are present, with hypertrophy of adjacent smooth muscle. The glands and stroma are at least partially responsive to the hormonal cycle. With the end of each cycle, bleeding occurs in the heterotopic foci; this irritates the surrounding tissue, and it can interfere with the overlying endometrial cycling. 3. At least 20% of uteri that are examined microscopically have foci of adenomyosis, although symptomatic cases are less frequent. ERRNVPHGLFRVRUJ 22.13 Side B (PBD9: 1010; BP9: 689) ERRNVPHGLFRVRUJ Questions A 44-year-old woman with a 2-year history of menorrhagia and pelvic pain is found to have a uniformly enlarged and boggy uterus with no adnexal masses. She undergoes a hysterectomy. The microscopic appearance of the uterine wall away from the stratum basalis is shown. 1. What is your diagnosis? 2. Explain her large, boggy, painful uterus and menorrhagia. 3. How common is this? ERRNVPHGLFRVRUJ Answers: Side A 1. The symmetrically enlarged uterus has bright foci ( ◂) within the myometrium that represent islands of heterotopic endometrial tissue. This is consistent with adenomyosis . 2. Endometrial glands and stroma grow into the myometrium below the stratum basalis, giving rise to these heterotopic foci. Inflammation, instrumentation, and prior pregnancies can contribute to the disruption of the endometrial-myometrial border and lead to increased amounts of adenomyosis. 3. A lack of hormonal cycling leads to the regression of the lesions. ERRNVPHGLFRVRUJ 22.14 Side A (PBD9: 1032; BP9: 698) ERRNVPHGLFRVRUJ Questions A 59-year-old postmenopausal woman with a 1-month history of vaginal bleeding is found to have a left adnexal mass. Her serum inhibin level is markedly increased. A total abdominal hysterectomy is done, and the gross appearance of her ovarian mass is shown. 1. What is your diagnosis? 2. What histologic elements might be present? 3. From what cellular element of ovary is this tumor derived? 4. Why did she have vaginal bleeding? ERRNVPHGLFRVRUJ Answers: Side B 1. This proliferation (♦) is endometrial hyperplasia ; it can be (a) simple or (b) complex atypical hyperplasia. 2. Prolonged estrogen exposure underlies endometrial hyperplasia. This can come from exogenous estrogen, anovulatory cycles, polycystic ovarian syndrome, and estrogen-secreting tumors such as granulosa/theca cell tumors. 3. PTEN tumor-suppressor gene inactivation makes endometrium more sensitive to estrogen stimulation. ERRNVPHGLFRVRUJ 22.14 Side B (PBD9: 1012; BP9: 691) ERRNVPHGLFRVRUJ Questions A 51-year-old perimenopausal woman with a 7-month history of irregular vaginal bleeding undergoes a hysterectomy; the resected uterus is opened to reveal the gross appearance shown. 1. What term applies if microscopically there are (a) variably sized and cystic glands or (b) irregular gland shapes with crowding and mitoses? 2. What are the major risk factors? 3. What gene mutation can lead to a worse outcome? ERRNVPHGLFRVRUJ Answers: Side A 1. Elevated serum inhibin (a peptide inhibitor of follicle-stimulating hormone synthesis and secretion) is a marker for granulosa cell tumors ; the gross appearance is also consistent with this. 2. Such tumors often also have a thecoma component. 3. Granulosa cell tumors are derived from the ovarian stroma. 4. Ovarian sex cord–stromal tumors, which also include fibromas and thecomas, are often hormonally active and can produce large amounts of estrogen. Consequently, the patient may initially present with bleeding as a result of endometrial hyperplasia. ERRNVPHGLFRVRUJ 23 ERRNVPHGLFRVRUJ The Breast ERRNVPHGLFRVRUJ 23.1 Side A (PBD9: 1060; BP9: 710) ERRNVPHGLFRVRUJ Questions A 71-year-old woman has a 5-month history of rough, scaling skin over the left breast. On examination, there is an underlying, ill-defined, 5-cm mass. Cells of the mass are estrogen receptor (ER)/progesterone receptor (PR) negative but Her2/neu positive according to a fluorescence in situ hybridization assay. 1. Explain the skin's appearance. 2. What treatment option is suggested by the molecular analysis of the cells? ERRNVPHGLFRVRUJ Answers: Side B 1. Dilated lymphatic spaces filled with small clusters of carcinoma cells ( ▾) are consistent with “ inflammatory carcinoma .” This is not a specific histologic type but rather a description of dermal lymphatic invasion. 2. There is likely to be a breast carcinoma, which can be occult. 3. This is a stage III cancer because of the skin lymphatic involvement, which suggests a poorer prognosis. ERRNVPHGLFRVRUJ 23.1 Side B (PBD9: 1060; BP9: 712) ERRNVPHGLFRVRUJ Questions A 64-year-old woman with dimpled, reddish-orange skin over her left breast undergoes biopsy and then mastectomy; the microscopic appearance of the skin surface is shown. 1. What is present in the dermis? 2. What is likely present in the underlying breast? 3. What is the stage of this patient's disease? ERRNVPHGLFRVRUJ Answers: Side A 1. The area of roughened, orange-red–appearing skin ( ▪)—along with the edema— represents dermal lymphatic invasion by the carcinoma. 2. ER/PR negativity suggests that hormonal therapy with tamoxifen would not work. Her2/neu positivity suggests that the tumor may respond to treatment with the monoclonal antibody trastuzumab, because this reflects the overexpression (as a result of a gene amplification) of epidermal growth factor receptor 2, a transmembrane glycoprotein that can regulate cell proliferation. ERRNVPHGLFRVRUJ 23.2 Side A (PBD9: 1046; BP9: 705) ERRNVPHGLFRVRUJ Questions A 24-year-old woman (G3, P3) who was born and raised in Belgium presents with a 2cm right breast lump that was discovered after weaning her most recent child. Her maternal aunt had breast cancer diagnosed at age 66. Her body mass index is 30. Her mammogram is shown. 1. What could this lesion be? 2. What is the significance of her family history? 3. List her positive and negative risk factors. ERRNVPHGLFRVRUJ Answers: Side B 1. Although there are increased numbers of dilated ductular structures in a fibrous stroma with multilayered epithelial cells lining the ducts, no atypia is evident. This is part of the spectrum of fibrocystic change . 2. Cysts, apocrine change, and duct ectasia are part of a spectrum of nonproliferative breast changes that do not increase the risk of breast cancer. In the absence of atypia, proliferative changes such as ductal hyperplasia and sclerosing adenosis only modestly (1.5- to 2-fold) increase breast cancer risk. ERRNVPHGLFRVRUJ 23.2 Side B (PBD9: 1048; BP9: 705) ERRNVPHGLFRVRUJ Questions A 32-year-old woman has an irregular left breast lump. When fine-needle aspiration is not diagnostic, a biopsy is performed; the microscopic appearance of the specimen is shown. 1. What is the diagnosis? 2. Is there a risk for cancer? ERRNVPHGLFRVRUJ Answers: Side A 1. There is a suspicious density with microcalcifications (▸). Microcalcifications or altered tissue densities are not necessarily malignant. Most breast lumps are benign, but all merit investigation. 2. The history of postmenopausal breast cancer in the aunt modestly increases this patient's risk for breast cancer; the risk is higher if a first-degree relative (i.e., mother or sister) has breast cancer or if a relative has breast cancer at a younger age. 3. Factors that increase this woman's risk for breast cancer include obesity and European (or American) geographic influences. Increased parity (particularly at a younger age) and breastfeeding are protective against breast cancer. ERRNVPHGLFRVRUJ 23.3 Side A (PBD9: 1057; BP9: 710) ERRNVPHGLFRVRUJ Questions A 63-year-old woman undergoes biopsy for a 2 × 3 cm rough, red, scaling, pruritic patch of skin on her left nipple. The histologic results are shown. 1. What is this lesion? 2. What could be present in the underlying breast? 3. Does the skin involvement affect the prognosis? ERRNVPHGLFRVRUJ Answers: Side B 1. This ductal carcinoma in situ (DCIS) has a comedocarcinoma pattern, with large neoplastic cells surrounding a prominent central zone of necrosis ( ▪). Her2/neu overexpression is often present. 2. Mastectomy is curative in up to 98% of patients with DCIS. The major risks for recurrence are grade, size, and margins. 3. Increased mammographic screening detects more DCIS, which is rarely palpable; such early detection (at essentially Stage 0 disease) likely improves the breast cancer survival rate. ERRNVPHGLFRVRUJ 23.3 Side B (PBD9: 1057; BP9: 710) ERRNVPHGLFRVRUJ Questions A suspicious density is found on a routine screening mammography of an otherwise healthy 59-year-old woman. She has no axillary lymphadenopathy. An excisional biopsy is performed with the results shown, and this is followed by a simple mastectomy. 1. What is the diagnosis? 2. What is the likely prognosis? 3. Explain the apparently increasing incidence of this lesion (from <5% to now almost 25% of breast cancer diagnoses). ERRNVPHGLFRVRUJ Answers: Side A 1. The large, pale, neoplastic Paget cells ( ▪) infiltrate into the epidermis. This is ductal carcinoma in situ (DCIS) , which extends from the ducts into the ductal system of the nipple and into the skin without invading across a basement membrane. Paget disease occurs in 1% to 2% of breast cancers. 2. In about half of cases of Paget disease of the breast, there is a palpable underlying mass. This is usually an invasive breast carcinoma. 3. The prognosis depends on the characteristics of the underlying cancer, and it does not change because there is DCIS affecting the skin. ERRNVPHGLFRVRUJ 23.4 Side A (PBD9: 1060; BP9: 711) ERRNVPHGLFRVRUJ Questions A 29-year-old woman notes a right breast lump that has been present for 5 months. On examination, she has a firm, irregular, 7-cm mass but no palpable axillary lymphadenopathy. After resection, the gross appearance of the breast lesion is shown; it is ER/PR positive, but it shows no HER2/neu amplification. 1. Is this benign or malignant? 2. What type of chemotherapy is likely to be beneficial? 3. Can there be metastases despite nonpalpable nodes? ERRNVPHGLFRVRUJ Answers: Side B 1. This is infiltrating ductal carcinoma . Irregular cords of cells ( ▪) grow within a collagenous stroma ( ♦) that imparts a firm, dense, gritty “scirrhous” feel on palpation and sectioning. 2. Breast cancers associated with BRCA1 are more likely to be poorly differentiated and to overexpress HER2/neu , whereas cancers with BRCA2 mutations do not have specific morphologic patterns. The risk for ovarian cancer is higher with BRCA1 than BRCA2. ERRNVPHGLFRVRUJ 23.4 Side B (PBD9: 1060; BP9: 711) ERRNVPHGLFRVRUJ Questions The 31-year-old sister of the patient on Side A has a mammogram that reveals a suspicious density; a biopsy specimen has the microscopic appearance shown. Another sister was diagnosed with ovarian cancer last year. 1. What is present here microscopically? 2. What inherited mutation is likely present? ERRNVPHGLFRVRUJ Answers: Side A 1. The irregularly infiltrating areas of tan tissue ( ▪) are likely to be breast carcinoma. 2. On the basis of the ER/PR positivity, a treatment protocol that includes tamoxifen would be valuable. Tamoxifen competitively binds to ER receptors , thereby blocking estrogen stimulation. HER2/neu negativity indicates that trastuzumab immunotherapy would not be useful. 3. Yes. Metastases are statistically likely on the basis of size alone. More than 90% of palpable masses (typically >2 cm) at presentation are invasive carcinomas, and more than half already have axillary nodal metastases. Most (80%) of these are carcinomas of no special type (i.e., “ductal” carcinomas), with fewer incidences of other varieties (e.g., lobular, medullary). ERRNVPHGLFRVRUJ 23.5 Side A (PBD9: 1054; BP9: 709) ERRNVPHGLFRVRUJ Questions A 33-year-old woman has a family history that is notable for a sister with breast cancer at age 36, a mother with ovarian cancer at age 48, and an uncle with prostate cancer at age 60. A previous genetic analysis revealed no germline mutations in PTEN (Cowden syndrome) or p53 (Li-Fraumeni syndrome). Her mammogram is shown. The lesion (arrow ) is excised, which reveals infiltrating ductal carcinoma; the cells that comprise the lesion are PR negative and Her2/neu negative. 1. What is her likely genetic mutation? 2. What other markers might her tumor express? 3. What is the prognosis for this type of tumor? ERRNVPHGLFRVRUJ Answers: Side B 1. There are large, poorly differentiated cells ( ▪) in a lymphoid stroma ( ♦) without significant desmoplasia; this is typical for medullary carcinoma . 2. Two thirds of medullary carcinomas have hypermethylation of BRCA1 promoter . Germline mutations in BRCA1 are not typically seen. ERRNVPHGLFRVRUJ 23.5 Side B (PBD9: 1054; BP9: 709) ERRNVPHGLFRVRUJ Questions A 30-year-old woman has a breast lump resected, with the microscopic appearance shown. It is ER/PR negative and HER2/neu negative. There are no nodal metastases. 1. What is the diagnosis? 2. What genetic change is typically present? ERRNVPHGLFRVRUJ Answers: Side A 1. The family history of cancer suggests a BRCA mutation ; it is more likely to be BRCA1 because of the onset at a young age, the family history of ovarian cancer, and the tumor marker phenotype. Mutations in BRCA1 and BRCA2 tumor-suppressor genes account for 3% of all breast cancers. Other cancers associated with BRCA mutations include prostate, colon, and pancreas. 2. Such tumors often have a phenotype similar to the basal myoepithelial (breast progenitor) cells, and they frequently express basal keratins and p-cadherin. 3. Generally, basal-like breast cancers tend to be high grade and highly proliferative, to respond less well to chemotherapy, and to have a worse prognosis. ERRNVPHGLFRVRUJ 23.6 Side A (PBD9: 1059; BP9: 710) ERRNVPHGLFRVRUJ Questions A 41-year-old woman with an irregular density in her left breast on screening mammogram has a subsequent biopsy specimen that reveals sclerosing adenosis and the microscopic findings shown. 1. What is your diagnosis? 2. What is the likelihood of the opposite breast being involved? 3. Would ER/PR (estrogen/progesterone receptors) and HER2/neu be expressed? 4. What genetic changes can be present? ERRNVPHGLFRVRUJ Answers: Side B 1. These malignant cells infiltrate the stroma in single file, which is typical for infiltrating lobular carcinoma . This type of neoplasm arises in terminal ductules, and it constitutes about 5% to 10% of all breast cancers. 2. There is about a 20% chance that the contralateral breast is involved; many infiltrating lobular carcinomas are also multifocal within the same breast. 3. Invasive lobular carcinomas tend to metastasize to the peritoneum , the retroperitoneum , and the meninges (“carcinomatous meningitis”). ERRNVPHGLFRVRUJ 23.6 Side B (PBD9: 1065; BP9: 711) ERRNVPHGLFRVRUJ Questions A 62-year-old woman has some “stromal thickening” on screening mammography, but no discrete mass is identified. She has no lymphadenopathy, but she does have ascites. Brain MRI shows meningeal enhancement. A breast biopsy specimen has the microscopic appearance shown. 1. What is your diagnosis? 2. Would the opposite breast be involved? 3. Why might she have ascites and meningeal changes? ERRNVPHGLFRVRUJ Answers: Side A 1. Lobular carcinoma in situ is a neoplastic proliferation in terminal breast ducts and acini. The cells are small and round. 2. Although these lesions are low-grade, there is a 20% to 40% risk for developing invasive carcinoma in the same or the opposite breast. 3. ER/PR expression is often observed, whereas HER2/neu is not. 4. Lobular carcinomas often have a 16q deletion with a loss of e-cadherin or β-catenin genes. ERRNVPHGLFRVRUJ 23.7 Side A (PBD9: 1069; BP9: 707) ERRNVPHGLFRVRUJ Questions A 54-year-old woman has had an enlarging right breast for the last 4 years. There is no family history of breast cancer. On examination, a large, firm mass is present. Her mammogram is shown. The mass does not recur after removal with wide margins. 1. Is this neoplasm of stromal or epithelial origin? 2. Is it benign or malignant? 3. Would ER/PR and HER2/neu be expressed? ERRNVPHGLFRVRUJ Answers: Side B 1. The bulbous protrusions ( ♦) of the stroma are compressing the epithelium ( ▾). Hence, this tumor is given the name phyllodes , which is Greek for “ leaflike .” 2. Fibroadenomas have stromal proliferation that compresses and distorts the adjacent epithelium. The phyllodes tumor shown has a more cellular stroma. 3. It is resected with a wide margin. Because metastases are infrequent, lymph node dissection is not routine. 4. More cellular, high-grade phyllodes tumors are more aggressive, with a greater risk for recurrence and hematogenous metastases. ERRNVPHGLFRVRUJ 23.7 Side B (PBD9: 1069; BP9: 707) ERRNVPHGLFRVRUJ Questions A 57-year-old woman has a screening mammogram that shows a 2-cm circumscribed mass deep in her left breast. She has no lymphadenopathy. A biopsy specimen of this mass has the microscopic appearance shown. 1. Why is this histologic pattern described as “leaflike”? 2. What common mass lesion of younger women does this resemble? 3. How is this neoplasm treated? 4. What are the potential complications? ERRNVPHGLFRVRUJ Answers: Side A 1. This large and slow-growing neoplasm ( ♦) is likely to be a phyllodes tumor , which is of stromal origin . 2. The biologic behavior of these masses is difficult to predict. Low-grade lesions may recur, but they rarely metastasize. 3. ER/PR and HER2/neu are expressed in the epithelial cells of the breast. HER2 is expressed only in cancer cells. ERRNVPHGLFRVRUJ 23.8 Side A (PBD9: 1069; BP9: 707) ERRNVPHGLFRVRUJ Questions A 22-year-old woman has a 1.5-cm freely movable left breast lump that becomes more prominent and tender before each menstrual cycle. The mammogram is shown. Fineneedle aspiration reveals no diagnostic cells, and the lesion is excised. 1. What is this lesion likely to be? 2. Why did it change during the menstrual cycle? 3. How would it change after menopause? ERRNVPHGLFRVRUJ Answers: Side B 1. This is a fibroadenoma with epithelial ductular structures ( ▾) that are compressed by a myxoid stroma ( ♦). The expansile element is the stroma, which in some cases can even be clonal with cytogenetic changes. 2. These lesions are hormonally responsive , particularly to estrogen. Cyclosporine also increases stromal hyperplasia and the incidence of fibroadenomas. 3. Benign fibroadenomas can commonly occur in both breasts. This represents multicentric origin rather than metastases. ERRNVPHGLFRVRUJ 23.8 Side B (PBD9: 1069; BP9: 707) ERRNVPHGLFRVRUJ Questions A 19-year-old woman has a left breast lump that enlarged during pregnancy. It was eventually excised, with the microscopic appearance shown. 1. What is the diagnosis? 2. Why did it increase in size during pregnancy? 3. What is the significance of having lesions bilaterally? ERRNVPHGLFRVRUJ Answers: Side A 1. This small, round mass ( ▾) with discrete borders suggests a benign process. The most common benign breast neoplasm is a fibroadenoma , which typically yields few cells on aspiration (see the histology of such a lesion to the right). 2. Fibroadenomas are hormonally responsive . In women of reproductive age, they can enlarge during the latter half of the menstrual cycle as estrogen and progesterone levels increase. 3. The removal of hormonal stimulation leads to regression with denser stroma, often with calcifications that radiologically can mimic carcinoma. ERRNVPHGLFRVRUJ 23.9 Side A (PBD9: 1046; BP9: 707) ERRNVPHGLFRVRUJ Questions A 22-year-old woman who is 3 weeks postpartum has a swollen and painful right breast in addition to fever. On examination, there is marked tenderness in the lower inner quadrant. The gross and microscopic appearances of this region are shown. 1. What microorganism is the most likely cause? 2. What is the localized lesion seen grossly? 3. What is the predominant cell type? 4. What name is given to a similar gross process beneath the areola in smokers? ERRNVPHGLFRVRUJ Answers: Side B 1. The stromal adipose tissue shows changes of fat necrosis , with the loss of adipocyte nuclei and macrophage infiltration (▸) with foreign body giant cells ( ◂). Grossly, this lesion can mimic a breast carcinoma. 2. Trauma to the breast is the most likely cause. 3. The pattern of injuries suggests abuse from a spouse or partner. 4. The firm, painless mass, sometimes with skin thickening and retraction, can mimic a breast carcinoma. ERRNVPHGLFRVRUJ 23.9 Side B (PBD9: 1047; BP9: 707) ERRNVPHGLFRVRUJ Questions A 40-year-old woman has had a palpable mass in her left breast for 1 month. On examination, the 2-cm mass is firm. Multiple contusions of varying ages are noted on the skin of the patient's face, torso, arms, and legs. The microscopic appearance of the mass is shown. 1. What part of the breast tissue is involved? 2. What is the probable cause of this lesion? 3. What do the contusions suggest? 4. What does the gross appearance of this lesion mimic? ERRNVPHGLFRVRUJ Answers: Side A 1. Localized acute mastitis is most often caused by Staphylococcus aureus. Streptococcal infections often spread throughout the breast. 2. The localized collection of yellow-tan pus ( ♦) is an abscess . 3. Collections of neutrophils ( ▾) are present. 4. Periductal mastitis is usually subareolar, with ductal squamous metaplasia. A fistula may develop to the overlying skin. ERRNVPHGLFRVRUJ 24 ERRNVPHGLFRVRUJ The Endocrine System ERRNVPHGLFRVRUJ 24.1 Side A (PBD9: 1099; BP9: 734) ERRNVPHGLFRVRUJ Questions A 37-year-old man with an enlarging mass in his left thyroid lobe has increased serum calcitonin levels. His neck CT scan is shown. His brother and mother have similar lesions. 1. What is the likely diagnosis? 2. What gene mutation is likely? 3. What syndrome might he have? ERRNVPHGLFRVRUJ Answers: Side B 1. Note the amyloid ( ▪) deposition, which is almost certainly from calcitonin produced by neoplastic cells arising in a medullary carcinoma derived from parafollicular C cells . The serum calcitonin level is often elevated with this condition. Other paraneoplastic syndromes may also occur (e.g., cortisol and Cushing syndrome ; serotonin and carcinoid syndrome ; parathyroid hormone and hypercalcemia). 2. Elevated urinary catecholamine levels suggest pheochromocytoma and elevated serum calcium parathyroid hyperplasia , which likely represent multiple endocrine neoplasia type IIA ( Sipple syndrome ). ERRNVPHGLFRVRUJ 24.1 Side B (PBD9: 1099; BP9: 734) ERRNVPHGLFRVRUJ Questions A 40-year-old woman has a neck mass that is causing dysphagia, respiratory difficulty, and hoarseness from recurrent laryngeal nerve compression. She has increased 24-hour urine catecholamine levels, and her serum calcium level is 12.8 mg/dL (nl 8.5 to 10.3 mg/dL), with a normal phosphorus level. The microscopic appearance of a thyroid biopsy specimen stained with Congo red is shown. 1. Explain this microscopic appearance. 2. Explain the laboratory findings. ERRNVPHGLFRVRUJ Answers: Side A 1. His increased serum calcitonin level and family history point to medullary thyroid carcinoma . About 25% of such tumors are familial, and most of these occur as multiple masses ( ▪), as in this man. 2. Affected individuals likely have an RET gene missense mutation coding for a receptor protein tyrosine kinase. 3. This could be either multiple endocrine neoplasia (MEN) type IIA (Sipple syndrome) or MEN IIB (if there were a marfanoid habitus or mucocutaneous ganglioneuromas; parathyroid hyperplasia is also not part of MEN IIB). ERRNVPHGLFRVRUJ 24.2 Side A (PBD9: 1089; BP9: 726) ERRNVPHGLFRVRUJ Questions A 37-year-old woman has tachycardia and heat intolerance, with a 5-kg weight loss occurring over the course of 4 months. On examination, there is diffuse thyroid enlargement. Her thyroid scintigraphy scan is shown. 1. What is the diagnosis? 2. What life-threatening complication could she develop? 3. What ocular finding might she have? ERRNVPHGLFRVRUJ Answers: Side B 1. There is diffuse papillary hyperplasia of the thyroid epithelium and lymphoid aggregates (▴), which are typical for Graves disease . 2. Increased thyroid hormone production in patients with Graves disease elevates the serum thyroxine level, with feedback inhibition of pituitary TSH production. 3. Propylthiouracil and methimazole inhibit thyroid peroxidase, thereby inhibiting iodide oxidation and blocking its addition to the thyroglobulin protein. 4. An elevated TSH level with an elevated serum thyroxine level would suggest the presence of a TSH-secreting pituitary adenoma. ERRNVPHGLFRVRUJ 24.2 Side B (PBD9: 1089; BP9: 726) ERRNVPHGLFRVRUJ Questions A 40-year-old woman has tremulousness, palpitations, and congestive heart failure. Her serum thyroid-stimulating hormone (TSH) level is 0.1 mIU/L (nl 0.5 to 4.7 mIU/L), and her thyroxine level is 16 µg/dL (nl 4.5 to 12.5 µg/dL). A biopsy specimen of her thyroid is shown. 1. Describe this microscopic appearance. 2. Explain the laboratory findings. 3. Suggest possible pharmacologic therapies and their mechanisms of action. 4. What would you suspect if the TSH level was 8 mIU/L? ERRNVPHGLFRVRUJ Answers: Side A 1. There is diffusely increased uptake in the thyroid, which is typical for Graves disease . With this condition, the thyroid is usually two to three times the normal size. 2. Thyroid storm can rarely complicate Graves disease; this involves malignant hyperthermia and heart failure. 3. Thyroid ophthalmopathy can involve a combination of proptosis and lid lag as a result of the increased sympathetic stimulation of the levator palpebrae superioris muscle and the periorbital deposition of hydrophilic mucopolysaccharides and fibrosis. ERRNVPHGLFRVRUJ 24.3 Side A (PBD9: 1093; BP9: 729) ERRNVPHGLFRVRUJ Questions A 44-year-old woman with a palpable left thyroid nodule has a serum TSH level of 3 mIU/L (nl 0.5 to 4.7 mIU/L) and a thyroxine level of 9 µg/dL (nl 4.5 to 12.5 µg/dL). Her thyroid scintigraphy is shown. 1. Explain the appearance of this lesion. 2. What microscopic finding do you expect to find? ERRNVPHGLFRVRUJ Answers: Side B 1. There is a discrete nodule ( ▪) of red-brown thyroid that is consistent with a benign adenoma . 2. The T level is increased, whereas the TSH level is low; the T level is normal. This is consistent with a “toxic” adenoma that is secreting excess T . 3 4 3 3. The patient's findings are consistent with hyperthyroidism. 4. Graves disease, toxic multinodular goiter, and hyperfunctioning thyroid carcinoma can also produce hyperthyroidism. ERRNVPHGLFRVRUJ 24.3 Side B (PBD9: 1093; BP9: 729) ERRNVPHGLFRVRUJ Questions A 47-year-old woman with a 6-month history of palpitations, diarrhea, polyphagia, tremulousness, anxiety, and insomnia has borderline hypertension at 150/85 mm Hg. Her serum thyroid-stimulating hormone (TSH) level is 0.2 mIU/L (nl 0.5 to 4.7 mIU/L), her thyroxine (T ) level is 6 µg/dL (nl 4.5 to 12.5 µg/dL), and her triiodothyronine (T ) level is 380 ng/dL (nl 60 to 181 ng/dL). The gross appearance of her resected thyroid is shown. 4 3 1. What is the likely diagnosis? 2. Explain the laboratory findings. 3. Explain the patient's signs and symptoms. 4. Name the thyroid lesions that produce similar findings. ERRNVPHGLFRVRUJ Answers: Side A 1. This “cold” nodule ( ◂) is making less colloid and taking up less iodine than the surrounding thyroid. 2. Most solitary nodules in the thyroid are benign tumors, cysts, or inflammatory lesions (benign neoplasms outnumber malignant neoplasms by 10 : 1), but a cold nodule has a greater likelihood of being malignant. Without the invasion of the capsule or the vasculature, this lesion is likely to be a benign follicular adenoma. ERRNVPHGLFRVRUJ 24.4 Side A (PBD9: 1095; BP9: 732) ERRNVPHGLFRVRUJ Questions A 46-year-old woman with left thyroid lobe enlargement and a large nontender left anterior cervical lymph node has normal TSH and thyroxine levels. Her neck CT is shown. 1. What is the likely diagnosis? 2. Are gene mutations present? 3. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side B 1. The papillary pattern and the empty-appearing nuclei are typical for papillary carcinoma of the thyroid. Additional features include psammoma bodies and, at higher magnification, nuclei with a ground-glass appearance. 2. Although this tumor is clearly not making thyroid hormone, there must be a sufficient amount of remaining normal thyroid gland to maintain a euthyroid state. 3. Exposure to ionizing radiation , particularly during the first two decades of life, is a risk for thyroid carcinoma. There are also medullary thyroid carcinomas associated with MEN type II syndromes and resulting from RET mutations. ERRNVPHGLFRVRUJ 24.4 Side B (PBD9: 1095; BP9: 732) ERRNVPHGLFRVRUJ Questions A 49-year-old woman has a 9-month history of right neck discomfort. Scintigraphy shows a “cold” right thyroid lobe nodule. Her TSH and thyroxine levels are normal. The microscopic appearance of her resected thyroid mass is shown. 1. What is your diagnosis? 2. Explain the laboratory findings. 3. What is a risk factor for this disease? ERRNVPHGLFRVRUJ Answers: Side A 1. The left lobe shows a cystic mass ( ▾) with an associated enlarged lymph node (▸). The nodal lesion is probably a metastasis, so this is a malignant thyroid tumor, most likely papillary carcinoma (75% to 85% of malignant thyroid tumors are papillary carcinomas, 10% to 20% are follicular carcinomas, 5% are medullary, and <5% are anaplastic). 2. Gene mutations are almost certainly present. Gene mutations in papillary carcinomas include RET and NTRK1 (tyrosine kinase receptors), BRAF, and RAS. 3. Despite metastasis, the prognosis remains good, with a 10-year survival rate of more than 95%. ERRNVPHGLFRVRUJ 24.5 Side A (PBD9: 1086; BP9: 724) ERRNVPHGLFRVRUJ Questions A 52-year-old woman with a 1-year history of fatigue, apathy, and cold intolerance has a painless and diffusely enlarged thyroid. Her twin sister previously had similar symptoms. The microscopic appearance of a representative thyroid biopsy specimen is shown. 1. What is the diagnosis? 2. What is the pathogenesis? 3. What serologic tests help with the making of the diagnosis? 4. What will her thyroid function be in 10 years? ERRNVPHGLFRVRUJ Answers: Side B 1. Thyroiditis with granulomatous inflammation and giant cells (▴) is present; this is consistent with de Quervain thyroiditis . 2. There is transient hyperthyroidism from the disruption of thyroid follicles and the release of hormone. Typically, after the resolution of the inflammation, completely normal thyroid function returns. 3. Subacute granulomatous thyroiditis is attributed to a postviral inflammatory disorder. ERRNVPHGLFRVRUJ 24.5 Side B (PBD9: 1088; BP9: 725) ERRNVPHGLFRVRUJ Questions A 49-year-old woman has a 1-month history of heat intolerance, tremulousness, and tachycardia after an upper respiratory tract infection. A painful and diffusely enlarged thyroid is palpated. Her serum TSH level is 0.3 mIU/L (nl 0.5 to 4.7 mIU/L), and her thyroxine level is 13.4 µg/dL (nl 4.5 to 12.5 µg/dL). The microscopic appearance of a thyroid biopsy specimen is shown. Her symptoms resolve, and her laboratory tests normalize 2 months later. 1. What is the diagnosis? 2. Explain the laboratory findings. 3. What is the pathogenesis of this disease? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has Hashimoto thyroiditis , with dense lymphocytic infiltrate that includes many lymphoid follicles with germinal centers ( ▪). 2. This has an autoimmune pathogenesis. CD8+ cells target thyroid epithelium via FAS– FAS ligand interactions; CD4+ cells elaborate cytokines such as interferon-γ and activate macrophages, whereas B cells synthesize various antithyroid antibodies. 3. Antithyroid peroxidase and antithyroglobulin antibodies are often present. 4. There is evolution into thyroid atrophy with hypothyroidism . ERRNVPHGLFRVRUJ 24.6 Side A (PBD9: 1081; BP9: 721) ERRNVPHGLFRVRUJ Questions A 15-year-old boy has a 5-month history of worsening headaches. He is short for his age, and he appears to be prepubertal. His brain MRI is shown. 1. What is the diagnosis? 2. Name the lesion's embryologic origin. 3. Explain this patient's clinical appearance. ERRNVPHGLFRVRUJ Answers: Side B 1. This mass (▸) in the region of the sella could be either a craniopharyngioma or a pituitary adenoma . 2. This patient has diabetes insipidus with hyponatremia caused by a loss of antidiuretic hormone secretion from the disruption of the hypothalamus or tracts to the posterior pituitary. 3. The bitemporal hemianopsia results from the compression of the optic chiasm by the mass; this affects the visual tracts from the medial retina, which perceive the lateral visual fields. 4. If it is less than 5 cm in size and noninvasive, a craniopharyngioma has a good prognosis. Pituitary adenomas are slow growing and generally noninvasive, and they have excellent prognoses. ERRNVPHGLFRVRUJ 24.6 Side B (PBD9: 1081; BP9: 721) ERRNVPHGLFRVRUJ Questions A 58-year-old woman has a 7-month history of worsening headaches, constant thirst, and visual problems that she describes as “tunnel vision.” Her serum sodium level is 155 mmol/L (nl 135 to 146 mmol/L), and her chloride level is 118 mmol/L (nl 95 to 108 mmol/L), with normal potassium and CO levels. On examination, she has bitemporal hemianopsia. If she had come to autopsy, the causative lesion would have appeared as shown. 2 1. What could this be? 2. Explain the laboratory findings. 3. Explain her visual symptoms. 4. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side A 1. There is a suprasellar focally calcified cystic mass (▴) just posterior and superior to the sphenoid sinus and extending into the sella, which is consistent with craniopharyngioma . 2. Craniopharyngiomas are squamous epithelial tumors derived from Rathke pouch remnants. 3. The neoplasm encroaches on normal adenohypophysis; this leads to the decreased production of both growth hormone and follicle-stimulating hormone/luteinizing hormone. ERRNVPHGLFRVRUJ 24.7 Side A (PBD9: 1079; BP9: 719) ERRNVPHGLFRVRUJ Questions A 35-year-old man has noted a change in his appearance, with coarse facial features and gloves that no longer fit. He also has polyarthritis with joint deformity. His brain MRI is shown. 1. What is the diagnosis? 2. What laboratory finding is likely? 3. Explain this patient's appearance. 4. What would a child with this lesion have? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has Sheehan syndrome as a result of postpartum pituitary necrosis . 2. Adenohypophyseal hormones such as prolactin, FSH/LH, TSH, and ACTH are decreased, which leads to panhypopituitarism. 3. During pregnancy, hyperplasia of the adenohypophysis makes its portal blood supply tenuous. When this patient had blood loss as a result of the abruption, there was ischemic necrosis and hemorrhage (▸), as shown grossly. 4. Yes. The neurohypophysis has an arterial supply that is less likely to be compromised. ERRNVPHGLFRVRUJ 24.7 Side B (PBD9: 1080; BP9: 721) ERRNVPHGLFRVRUJ Questions A 23-year-old primigravida has placental abruption at term. She is unable to lactate postpartum, and she has amenorrhea, lethargy, hyperkalemia, and hypotension. The causative lesion is shown within the sella turcica. 1. What is her diagnosis? 2. What laboratory findings could she have? 3. Why did this occur? 4. Does she have sufficient ADH? ERRNVPHGLFRVRUJ Answers: Side A 1. This mass ( ◂) in the pituitary is enhancing; it is a microadenoma . 2. An elevation in growth hormone (GH) is likely, and this stimulates the hepatic production of insulin-like growth factor I (IGF-I). This patient may have secondary diabetes mellitus , with abnormal glucose tolerance. 3. He has acromegaly as a result of the growth of soft tissues as well as hyperostosis with appositional bone enlargement. 4. A child with a GH-secreting adenoma would have gigantism . ERRNVPHGLFRVRUJ 24.8 Side A (PBD9: 1134; BP9: 760) ERRNVPHGLFRVRUJ Questions A 31-year-old man with intermittent headache, tachycardia, tremor, and anxiety also periodically becomes hypertensive. His abdominal CT scan is shown. 1. What is the diagnosis? 2. What laboratory findings are likely? 3. Explain the symptoms. 4. Name the associated inherited disorders. ERRNVPHGLFRVRUJ Answers: Side B 1. These nests ( ▪) of round blue cells in this location indicate that this is a paraganglioma , which likely arose in the carotid body. 2. Paragangliomas are unlikely to secrete significant amounts of hormone, even though they are of neuroendocrine origin. Nevertheless, some can secrete catecholamines, which are similar to adrenal pheochromocytomas. 3. The carotid body is putatively a chemoreceptor for oxygen and carbon dioxide to stimulate brainstem respiratory centers. ERRNVPHGLFRVRUJ 24.8 Side B (PBD9: 1134; BP9: 760) ERRNVPHGLFRVRUJ Questions A 50-year-old man with dysphagia has a left lateral neck mass and absent activity of left cranial nerves IX, X, and XI. A left parapharyngeal space mass is resected, and the microscopic appearance is shown. 1. What is the diagnosis? 2. What are the likely laboratory findings? 3. What is the physiologic function of this structure? ERRNVPHGLFRVRUJ Answers: Side A 1. The right adrenal mass (▴) and the symptoms are highly suggestive of a pheochromocytoma . Ten percent of pheochromocytomas are malignant, 10% are bilateral, 10% are extra-adrenal, and 10% arise as part of a familial syndrome. 2. Elevations in urinary catecholamines, metanephrines, and vanillylmandelic acid as well as serum norepinephrine, epinephrine, and dopamine levels can occur. 3. Catecholamines have a sympathomimetic effect with increased blood pressure, heart rate, and tremulousness. 4. Pheochromocytomas can be present in multiple endocrine neoplasia (MEN) IIA and IIB and in von Hippel–Lindau syndrome . ERRNVPHGLFRVRUJ 24.9 Side A (PBD9: 1125; BP9: 755) ERRNVPHGLFRVRUJ Questions A 60-year-old man with poorly controlled hypertension has an incidental adrenal lesion found during a CT scan that was performed to assess abdominal trauma. The resected lesion is shown. 1. What is the diagnosis if he also has hypokalemia? 2. What is the diagnosis if he has glucose intolerance, plethora, and osteoporosis? 3. What if there are no other associated findings? ERRNVPHGLFRVRUJ Answers: Side B 1. There is extensive hemorrhage ( ▪) within enlarged adrenal glands. This is Waterhouse-Friderichsen syndrome , with bilateral adrenal hemorrhage and necrosis leading to acute adrenal insufficiency. It typically occurs in the setting of disseminated intravascular coagulopathy as a result of infectious causes, and it results in intractable hypotension. 2. Most cases are caused by infection with Neisseria meningitidis ( meningococcus ), although Pseudomonas, Haemophilus, Streptococcus pneumoniae, and Staphylococcus aureus can also be causative. ERRNVPHGLFRVRUJ 24.9 Side B (PBD9: 1129; BP9: 757) ERRNVPHGLFRVRUJ Questions A 22-year-old woman presents with pharyngitis and a severe headache, and she develops hypotension and palpable purpura within 12 hours. Schistocytes are present on her peripheral blood smear, her platelet levels are low, and her coagulation parameters are all prolonged. Despite the prompt administration of antibiotics and pressor support, she dies. The appearance of her adrenals at autopsy is shown. 1. What diagnosis is suggested by the appearance of these adrenals? 2. What did her blood culture likely grow? ERRNVPHGLFRVRUJ Answers: Side A 1. This adrenal gland contains a golden yellow mass ( ♦) with an appearance that is similar to adrenal cortex ( ◂); this is an adenoma . If the adenoma secretes aldosterone, sodium retention and potassium excretion occur, thereby leading to hypertension and hypokalemia ( Conn syndrome ). 2. If the adenoma secretes cortisol, Cushing syndrome results. 3. Nonfunctioning adrenal adenomas can typically be left alone; when they are less than 2 cm in size, they are virtually always benign. Such an incidentaloma can be found on abdominal CT scans that are performed for other reasons. ERRNVPHGLFRVRUJ 24.10 Side A (PBD9: 1090; BP9: 728) ERRNVPHGLFRVRUJ Questions This 66-year-old woman with a 10-year history of a progressively enlarging neck mass finally sought medical attention. Her TSH level is 4 mIU/L (nl 0.5 to 4.7 mIU/L), and her thyroxine level is 7.8 µg/dL (nl 4.5 to 12.5 µg/dL). 1. What is the most likely diagnosis? 2. What nutritional deficiency can cause this finding? 3. What would accompany such a lesion in a child? 4. What complication may occur from this lesion? ERRNVPHGLFRVRUJ Answers: Side B 1. There is an irregular mass displacing the trachea ( ▪) to the right and compressing the esophagus posteriorly. This is likely a nodular goiter . 2. Cruciferous vegetables such as Brussels sprouts, cabbage, cauliflower, turnips, and cassava contain goitrogenic compounds (e.g., glucosinolates) that interfere with normal thyroid hormone synthesis. Typical levels of consumption usually have minimal effect. 3. No. Malignancies do not arise within a goiter. An asymmetric nodular goiter like this one could grossly and radiographically mimic thyroid carcinoma. ERRNVPHGLFRVRUJ 24.10 Side B (PBD9: 1090; BP9: 728) ERRNVPHGLFRVRUJ Questions A 53-year-old woman with neck discomfort, dysphagia, and upper respiratory tract wheezing has the CT scan shown. 1. What is the diagnosis? 2. How can diet be related to this lesion? 3. Could this become malignant? ERRNVPHGLFRVRUJ Answers: Side A 1. This is a multinodular goiter ( ▪) that is probably the result of an intrinsic variation in the responses of follicular epithelial cells to TSH. Most patients are euthyroid . 2. In parts of the world where iodine is deficient in the diet and where patients have insufficient thyroid hormone production, this is known as endemic goiter . 3. A child with a goiter likely has an inherited biosynthetic defect and would probably present with cretinism . 4. Occasionally, in a nontoxic multinodular goiter, an isolated de novo mutation in the TSH-signaling pathway can cause an autonomously functioning nodule (“hot” nodule) and result in a toxic goiter (with runaway thyroid hormone production). ERRNVPHGLFRVRUJ 24.11 Side A (PBD9: 1130; BP9: 757) ERRNVPHGLFRVRUJ Questions A 54-year-old woman with a 6-month history of fatigue, anorexia, weight loss, skin hyperpigmentation, and diarrhea develops hypotension and lapses into a coma after a minor upper respiratory tract infection. At autopsy, her adrenals are small (▾) as compared with normal adrenals (▴ ). 1. What is a possible diagnosis? 2. What laboratory findings would you have expected when this patient was alive? 3. What is the most likely cause? ERRNVPHGLFRVRUJ Answers: Side B 1. There is marked atrophy of the adrenal cortex ( ▪), which is consistent with chronic adrenal insufficiency . 2. The adrenal cortex produces aldosterone (zona glomerulosa), sex steroids (zona fasciculata and zona reticularis), and glucocorticoids (all layers). Catecholamines (norepinephrine and epinephrine) come from adrenal medulla. 3. The autoimmune regulator ( AIRE ) gene can be mutated with autoimmune polyendocrine syndrome type I . The autoimmune destruction of adrenal cortex and other target organs is mediated by self-reactive T lymphocytes. ERRNVPHGLFRVRUJ 24.11 Side B (PBD9: 1130; BP9: 757) ERRNVPHGLFRVRUJ Questions A 49-year-old woman with chronic mucocutaneous candidiasis and ectodermal dystrophy with skin, tooth enamel, and fingernail abnormalities also has pernicious anemia. Had we checked at this point, her adrenals would have appeared as shown. 1. What is your diagnosis? 2. What hormones are produced in the adrenals? 3. What gene mutation may she have? ERRNVPHGLFRVRUJ Answers: Side A 1. The clinical history and these atrophic adrenals are characteristic of primary chronic adrenal insufficiency, which is also known as Addison disease . 2. Inadequate amounts of mineralocorticoids (mainly aldosterone) and glucocorticoids result in hyponatremia, hyperkalemia, and hypoglycemia. 3. Most cases of Addison disease are autoimmune . Tuberculosis, AIDS, and metastatic cancer round out the top four causes; lesser causes include hemochromatosis, amyloidosis, sarcoidosis, and lymphoma. ERRNVPHGLFRVRUJ 24.12 Side A (PBD9: 1121; BP9: 752) ERRNVPHGLFRVRUJ Questions A 26-year-old woman with epigastric pain and hematemesis has an upper gastrointestinal endoscopy that reveals multiple antral and duodenal bulb ulcers. Her abdominal CT scan is shown. 1. What is the most likely diagnosis? 2. What laboratory finding do you expect? 3. What other lesion could cause this? 4. What syndrome would she have if hypercalcemia, hyperprolactinemia, and Cushing syndrome were also present? ERRNVPHGLFRVRUJ Answers: Side B 1. There is an islet cell adenoma surrounded by a fibrous capsule ( ▪), with normal pancreas below, including a single normal islet of Langerhans ( ♦); hypoglycemia in this patient would be the probable cause of the syncope. 2. His plasma insulin level is increased, and his serum glucose level is decreased. 3. The factitious administration of insulin would also produce hypoglycemia, but the plasma C-peptide level would not be elevated. ERRNVPHGLFRVRUJ 24.12 Side B (PBD9: 1121; BP9: 751) ERRNVPHGLFRVRUJ Questions A 39-year-old man with a 1-year history of syncopal episodes has a pancreatic lesion that is resected; the microscopic appearance is shown. 1. What is the diagnosis? 2. What laboratory findings would he have? 3. How could you distinguish this from a factitious case? ERRNVPHGLFRVRUJ Answers: Side A 1. There is a small, discrete mass ( ▾) of the pancreatic tail that is consistent with an islet cell adenoma ; in this case, this is likely a gastrinoma that is resulting in Zollinger-Ellison syndrome . At the time of diagnosis, more than half of such tumors are locally invasive or have metastasized. 2. An elevated serum gastrin level 3. Gastrin-producing neuroendocrine cells in other sites can form adenomas in peripancreatic tissue, in the wall of the duodenum, or in ectopic pancreatic rests such as within a Meckel diverticulum. 4. Multiple endocrine neoplasia type I (MEN-I) . A mutant MEN1 gene leads to pituitary adenomas, islet cell neoplasms, and parathyroid hyperplasia or adenomas. ERRNVPHGLFRVRUJ 24.13 Side A (PBD9: 1093; BP9: 729) ERRNVPHGLFRVRUJ Questions A 45-year-old woman has become increasingly anxious during the past year. On examination, she has right thyroid lobe enlargement. Her serum TSH level is 0.5 mU/L (nl 0.5 to 4.7 mU/L), and her thyroxine level is 12 µg/dL (nl 4.5 to 12.5 µg/dL). Her thyroid scintigraphic scan is shown. 1. Explain the appearance of this lesion. 2. What is this lesion most likely to be? 3. What signaling pathway likely has a gain of function mutation in this lesion? ERRNVPHGLFRVRUJ Answers: Side B 1. There are uniformly sized epithelial cells forming smaller-than-normal thyroid follicles ( ♦). This appearance is consistent with a follicular adenoma . The eosinophilic cytoplasm is described as having an oxyphil, or Hürthle cell, change. 2. The normal TSH and thyroxine levels suggest that this nodule is not functioning to release excessive thyroid hormone. 3. About 10% of thyroid adenomas with a follicular pattern that appear “ cold ” on scan eventually prove to be malignant. About half of follicular carcinomas have an RAS oncogene mutation; about a third have a PAX8-PPARγ1 fusion gene. ERRNVPHGLFRVRUJ 24.13 Side B (PBD9: 1093; BP9: 729) ERRNVPHGLFRVRUJ Questions A 47-year-old woman notes a nodule in her right neck that has slowly enlarged for the last 4 years. Her serum TSH level is 3.3 mU/L (nl 0.5 to 4.7 mU/L), and her thyroxine level is 7 µg/dL (nl 4.5 to 12.5 µg/dL). An ultrasound shows a 3-cm right thyroid lobe solid mass with distinct borders. The microscopic appearance of this lesion is shown. 1. Describe this microscopic appearance and diagnosis. 2. Explain the laboratory findings. 3. How would you explain the appearance of a lung nodule in this patient 10 years later? What mutations could be present in the cells of such a lesion? ERRNVPHGLFRVRUJ Answers: Side A 1. The scan shows a “ hot ” nodule ( ▾), because it is taking up more iodine than the surrounding thyroid tissue. 2. This is a follicular adenoma ; the rest of the thyroid is not enlarged, so it is not likely to be a toxic multinodular goiter. 3. An activating somatic mutation in the TSH receptor signaling pathway has increased the production of cyclic adenosine monophosphate to drive follicular epithelial proliferation. ERRNVPHGLFRVRUJ 24.14 Side A (PBD9: 1080; BP9: 720) ERRNVPHGLFRVRUJ Questions An obese 35-year-old woman (G6, P6) develops amenorrhea, lethargy, cold intolerance, weakness, and diffuse skin pigmentation. An MRI of her head is shown. 1. What is your diagnosis? 2. What laboratory findings are likely? 3. How might this have occurred? ERRNVPHGLFRVRUJ Answers: Side B 1. There is a mass ( ▪) arising in the region of the pineal gland; possibilities include germinoma and pineocytoma . 2. The mass compresses the aqueduct of Sylvius, thereby causing obstructive hydrocephalus with third and lateral ventricular enlargement. Compression of the superior colliculi causes the upward gaze palsy. The mass also compresses the pituitary, which interferes with the posterior pituitary production of antidiuretic hormone (ADH) and leads to diabetes insipidus , with hypernatremia resulting from a loss of free water reabsorption in the renal collecting ducts. ERRNVPHGLFRVRUJ 24.14 Side B (PBD9: 1137) ERRNVPHGLFRVRUJ Questions A 13-year-old boy with headache, nausea, vertical gaze palsy, and increased thirst has a serum sodium level of 158 mmol/L (nl 135 to 146 mmol/L), with a urine sodium level of 10 mmol/L (this is low, given his serum sodium value). His plasma osmolarity is 320 mOsm/mL (nl 278 to 305 mOsm/mL), and his urine osmolarity is 40 mOsm/mL (nl 50 to 1200 mOsm/mL). His brain MRI is shown. 1. What is your diagnosis? 2. Explain this patient's signs and symptoms. ERRNVPHGLFRVRUJ Answers: Side A 1. The lack of tissue within the unexpanded sella turcica (▴) is consistent with empty sella syndrome . 2. This patient has panhypopituitarism with hypothyroidism (low TSH), adrenal insufficiency ( Addison disease , low ACTH), and amenorrhea (lack of FSH/LH). 3. A defect in the diaphragma sella allows for arachnoid herniation with compression atrophy of the pituitary. Postpartum pituitary necrosis ( Sheehan syndrome ) also leads to anterior pituitary loss. ERRNVPHGLFRVRUJ 24.15 Side A (PBD9: 1127; BP9: 756) ERRNVPHGLFRVRUJ Questions A 9-year-old girl with ambiguous genitalia and coarse pubic hair has the abdominal CT scan shown. Serum sodium and potassium levels are normal, and the patient is normotensive. 1. What is the diagnosis? 2. Explain the biochemistry. ERRNVPHGLFRVRUJ Answers: Side B 1. In this form of congenital adrenal hyperplasia (CAH) , the functional CYP21B gene on chromosome 6 is typically recombined with (and replaced by) an adjacent nonfunctional pseudogene CYP21A. 2. The lack of adrenal 21-hydroxylase activity and the subsequent deficient mineralocorticoid production leads to salt wasting and hypotension with hyperkalemia; deficient cortisol production leads to an elevated ACTH level that drives adrenal hyperplasia with the overproduction of sex steroids. 3. Exogenous glucocorticoids replace the cortisol requirement and suppress the ACTH overproduction; mineralocorticoids must also be given to patients with the salt-wasting form of CAH. ERRNVPHGLFRVRUJ 24.15 Side B (PBD9: 1127; BP9: 756) ERRNVPHGLFRVRUJ Questions A 10-year-old girl has increased serum testosterone, decreased aldosterone, and increased ACTH levels. Her testosterone decreases after she is given low-dose dexamethasone. Her adrenal would appear as shown (bottom ) as compared with a normal organ (top ). 1. What gene abnormality is likely present? 2. Explain the laboratory findings. 3. How might this be treated? ERRNVPHGLFRVRUJ Answers: Side A 1. The bilaterally enlarged adrenal glands ( ▪) are adjacent to the diaphragmatic crura. On the basis of the patient's clinical history, this is congenital adrenal hyperplasia (CAH) with adrenogenital syndrome but without salt wasting . 2. This patient has a partial 21-hydroxylase deficiency . The enzyme normally converts progesterone to 11-deoxycorticosterone in the pathway to aldosterone and 17hydroxyprogesterone to 11-deoxycortisol in the pathway to cortisol. Partial deficiency in the enzyme leads to low but physiologically adequate levels of mineralocorticoids but inadequate cortisol levels. The result is elevated pituitary ACTH production and increased adrenal steroidogenesis into the only remaining pathway, which yields elevated adrenal production of the sex steroids and precocious puberty with the potential for virilization. ERRNVPHGLFRVRUJ 25 ERRNVPHGLFRVRUJ The Skin ERRNVPHGLFRVRUJ 25.1 Side A (PBD9: 1147; BP9: 867) ERRNVPHGLFRVRUJ Questions A 62-year-old man has noted the enlargement of the right upper back skin lesion shown over the past 5 months. 1. What features suggest that this is malignant? 2. What is a biopsy specimen likely to show? 3. What is the major risk factor? 4. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side B 1. The large pleomorphic polygonal cells ( ▸) have abundant brown melanin within their cytoplasm; this is consistent with a malignant melanoma . 2. The p16/INK4A gene that encodes for CDNK2 is frequently deleted, particularly when there is a family history of melanoma. Mutations that involve the CDK4 and BRAF genes may also occur. 3. When the melanoma begins a vertical growth phase, metastases are more likely to occur. Of all malignancies, melanomas have the greatest potential to metastasize to many different sites (e.g., brain, heart, spleen), although the initial metastases are often to regional lymph nodes. ERRNVPHGLFRVRUJ 25.1 Side B (PBD9: 1147; BP9: 867) ERRNVPHGLFRVRUJ Questions A 44-year-old woman has noted an enlarging brown and black skin nodule on her left upper arm that bleeds easily with even minor trauma. On examination, the lesion has irregular borders and surface ulceration. A biopsy specimen has the microscopic appearance shown (Fontana-Masson stain). 1. What is the diagnosis? 2. What molecular alterations are likely present? 3. How is this lesion most likely to spread? ERRNVPHGLFRVRUJ Answers: Side A 1. Rapid increase in size, irregular borders (▾), and irregular pigmentation ( ▸) suggest that this is a malignant melanoma . 2. Microscopic features include hyperchromatic and pleomorphic polygonal and spindle cells, often with cytoplasmic melanin granules . 3. Prolonged exposure to ultraviolet light, particularly UVB , induces pyrimidine dimers and increases the risk for melanoma. 4. Prognosis depends on the size and particularly on the depth of invasion . Lesions less than 0.75 mm deep have a good prognosis (>95% 5-year survival); lesions more than 1.5 mm deep have a poor prognosis (<50% 5-year survival). ERRNVPHGLFRVRUJ 25.2 Side A (PBD9: 1155; BP9: 864) ERRNVPHGLFRVRUJ Questions A 78-year-old man enjoys sport fishing, and he spends many hours outdoors. He has noted that the lesion shown has been slowly enlarging for the past 4 years. 1. What is the diagnosis? 2. What is the major risk factor for this lesion, and what is the molecular mechanism for its growth? 3. How is this treated? ERRNVPHGLFRVRUJ Answers: Side B 1. The dark-blue cells in nests ( ♦) dropping into the dermis mimic the normal basal cells ( ▸) of the epidermis. 2. Basal cell carcinoma remains localized for a long time, but it slowly invades adjacent tissue. Extensive local invasion may make complete excision difficult. These tumors rarely metastasize. 3. Xeroderma pigmentosum , which is an autosomal-recessive condition, arises from mutation in one of several genes ( XPa through XPg) that direct DNA nucleotide excision repair (NER) pathways. The autosomal-dominant nevoid basal cell nevus syndrome (Gorlin syndrome) involves germline mutation of the PTCH gene, which normally inactivates the SMO transmembrane protein that upregulates transcription factors. ERRNVPHGLFRVRUJ 25.2 Side B (PBD9: 1155; BP9: 864) ERRNVPHGLFRVRUJ Questions A 69-year-old woman has a 6-year history of a slowly enlarging pearly pink papule on the helix of her left ear. The lesion is excised; its microscopic appearance is shown. 1. What normal skin cells do these tumor cells mimic? 2. What could happen if this lesion was not removed? 3. Name the predisposing inherited disorders of DNA repair genes and the PTCH gene. ERRNVPHGLFRVRUJ Answers: Side A 1. This lower eyelid nodular skin lesion with central ulceration ( ▴) is typical of basal cell carcinoma . 2. Sun exposure is the major risk factor. Ultraviolet light, mainly UVB , induces pyrimidine dimer formation in DNA. Nucleotide excision repair pathways are overwhelmed by ongoing UVB damage. 3. Treatment requires complete surgical excision. The careful assessment of the margins (typically with frozen section examination at the time of surgery) can limit the amount of tissue removed in critical areas such as the eyelid, where function must be maintained. ERRNVPHGLFRVRUJ 25.3 Side A (PBD9: 1151; BP9: 862) ERRNVPHGLFRVRUJ Questions A 77-year-old woman has had minimal sun exposure to her trunk, where the lesions shown are found. Similar lesions appear on her head and neck. They have slowly increased in size over the past 14 years. 1. Are these lesions benign or malignant? 2. What might you see on inspection with a magnifying lens? 3. What could happen with excoriation? 4. What would the appearance of many lesions suggest in a patient with an underlying malignancy? ERRNVPHGLFRVRUJ Answers: Side B 1. This seborrheic keratosis has an exophytic growth pattern of sheets of basal-like cells ( ▾) with pronounced keratin production that invaginates and produces keratinfilled horn cysts ( ▸). 2. These lesions accompany aging. They are less common in individuals with more darkly pigmented skin. 3. The dermis at the right shows homogeneous blue-gray elastic fibers ( elastosis ) that are characteristic of actinic (sun) damage ( ♦). ERRNVPHGLFRVRUJ 25.3 Side B (PBD9: 1151; BP9: 862) ERRNVPHGLFRVRUJ Questions A 62-year-old man has 12 slowly enlarging, sharply demarcated, uniformly dark-brown skin lesions that range from 0.3 to 1 cm and that appear on his face, trunk, and upper arms. The microscopic appearance of the lesions is shown. 1. Describe the findings. 2. What is the most likely risk factor? 3. What additional change seen here in the dermis is associated with sun exposure? ERRNVPHGLFRVRUJ Answers: Side A 1. These seborrheic keratoses ( ▾) have smooth, regular borders and uniform pigment distribution, which are benign characteristics. They appear coinlike, as though they were “stuck on” the surface. 2. There are often porelike ostia that are filled with keratin. 3. Excoriation or scratching can produce local hemorrhage and increase the risk for secondary infection. 4. The paraneoplastic syndrome ( Leser-Trélat sign ) results from excessive transforming growth factor-α production by neoplastic cells, which drives the explosive appearance of seborrheic keratoses. ERRNVPHGLFRVRUJ 25.4 Side A (PBD9: 1167; BP9: 858) ERRNVPHGLFRVRUJ Questions A 55-year-old man with painful oral mucosal erosions from ruptured bullae develops flaccid skin blisters filled with clear fluid on his scalp, axilla, and inguinal regions over the following 3 months. The immunofluorescent staining pattern for IgG of one biopsy specimen from a lesion is shown. 1. What is your diagnosis? 2. What does the autoantibody in this disease recognize? 3. How do the blisters form? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has bullous pemphigoid . There is linear staining ( ◂) at the dermalepidermal junction for IgG and complement. 2. IgG autoantibodies are directed against hemidesmosome proteins at the dermalepidermal junction (e.g., BPAg2 [type XVII collagen], a transmembranous protein with a collagenous extracellular domain). 3. Immune-mediated basement membrane damage (via complement activation and through the activity of Fc receptor–bearing inflammatory cells) leads to hemidesmosome degradation and subepidermal separation. ERRNVPHGLFRVRUJ 25.4 Side B (PBD9: 1170; BP9: 859) ERRNVPHGLFRVRUJ Questions A 65-year-old woman has had skin blisters for 2 years. Recurrent crops of tense bullae 3 cm or less in diameter appear on her abdomen, groin, thighs, and forearms. They always spontaneously regress, and they heal without scarring. The immunofluorescent microscopic appearance of one such lesion that has been stained for IgG (or C3) is shown. 1. What is your diagnosis? 2. What immune mechanism is involved? 3. How do the bullae form? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has pemphigus vulgaris . There is a lacelike (“reticular”) pattern ( ▴) of immunofluorescent staining around the individual keratinocytes. 2. The autoantibody recognizes desmoglein-3 , a component of the desmosomes that hold keratinocytes together in the stratum spinosum. 3. Bound antibody on the surface of keratinocytes activates them to release a urokinaselike plasminogen activator (serine protease) that degrades desmosome junctions. This leads to acantholysis ( ▾) as the epidermal cells lose adhesion. The blister that forms is usually above the basal layer of cells. ERRNVPHGLFRVRUJ 25.5 Side A (PBD9: 1145; BP9: 865) ERRNVPHGLFRVRUJ Questions A 51-year-old woman has had the calf lesion shown here, without any change in its appearance, for as long as she can remember. 1. What is your diagnosis? 2. What is this lesion called if it is present from birth? 3. What similar pink-red lesion is found in children? 4. What condition should be considered in the setting of hundreds of such lesions? ERRNVPHGLFRVRUJ Answers: Side B 1. These are common, benign, melanocytic nevi . 2. Melanocytes are normally interspersed in the epidermis with keratinocytes. A nevus typically contains round, transformed melanocytes that proliferate in nests ( ▸). 3. There is no risk for malignancy. Melanocytic nevi are not precursors to melanoma, although they must be distinguished from melanoma. 4. Common nevi tend to undergo maturation. Melanocytic cells are initially found at the dermal-epidermal junction ( junctional nevus ), but they later extend into the dermis ( compound nevus ), and they are eventually found entirely within the dermis ( intradermal nevus ). ERRNVPHGLFRVRUJ 25.5 Side B (PBD9: 1144; BP9: 865) ERRNVPHGLFRVRUJ Questions A 35-year-old woman has 17 pale tan to dark-brown lesions on her torso and her upper extremities. They range from macules to small papules that are 2 to 6 mm in diameter. They have smooth borders and uniform pigmentation. The microscopic appearance of one lesion is shown. 1. What is your diagnosis? 2. What is the cell of origin? 3. Is there a risk for malignancy? 4. How do these lesions mature? ERRNVPHGLFRVRUJ Answers: Side A 1. This pigmented lesion with sharp borders ( ◂) is a nevus . Most common nevi are less than 6 mm in diameter. 2. Congenital nevus 3. Spitz nevus 4. Dysplastic nevi , which are also called BK moles (these are the first letters of the surnames of the two families first described as having such lesions). These nevi are larger than most acquired nevi; they have a tendency to occur in non–sun-exposed areas, and they carry a risk of developing into malignant melanoma. ERRNVPHGLFRVRUJ 25.6 Side A (PBD9: 1155; BP9: 863) ERRNVPHGLFRVRUJ Questions A 66-year-old man with a 5-year history of a slowly enlarging nonpigmented nodule on his ear pinna now states that it bleeds easily when scratched. A wide excision is performed and is shown. 1. What is your diagnosis? 2. What are the risk factors? ERRNVPHGLFRVRUJ Answers: Side B 1. Large, pink, polygonal cells of squamous cell carcinoma infiltrate ( ◂) into the dermis. 2. Ultraviolet (UV) light from sun exposure is responsible for this condition. UVB rays are the most carcinogenic. 3. UV light induces pyrimidine dimer formation in DNA; this is a process that is ordinarily efficiently repaired by nucleotide excision and base pair reinsertion. UV light induces p53 protein, which arrests the cell cycle until repair can be effected. However, recurring sun exposure eventually results in errors that are not corrected before cell division occurs. In addition, UV light depresses the immune surveillance function of epidermal dendritic (Langerhans) cells. 4. Xeroderma pigmentosum is an autosomal-recessive condition that involves mutations in DNA excision repair genes. ERRNVPHGLFRVRUJ 25.6 Side B (PBD9: 1155; BP9: 863) ERRNVPHGLFRVRUJ Questions A 52-year-old woman with a 3-year history of a 2-cm, slowly enlarging, irregular, ulcerated, nodular lesion on her upper eyelid presents for resection. The microscopic appearance of the lesion is shown. 1. What is your diagnosis? 2. What form of environmental radiant energy induces this lesion? 3. What pathways normally prevent this neoplastic event? 4. What genetic condition predisposes affected individuals to having multiple such lesions? ERRNVPHGLFRVRUJ Answers: Side A 1. This raised, rough, nodular lesion ( ▾) is a squamous cell carcinoma . Note the extent of excision (ear removal); this is an extremely invasive malignancy with a propensity for local recurrence or metastasis if not adequately excised. Melanoma and basal cell carcinoma are other malignancies that can manifest as nodular lesions. 2. Sun exposure is the most likely risk factor. Individuals who are immunocompromised (e.g., transplant recipients) are also at risk. ERRNVPHGLFRVRUJ 25.7 Side A (PBD9: 1163; BP9: 852) ERRNVPHGLFRVRUJ Questions A 30-year-old woman with the recent onset of the red, oozing area shown reports that, by week's end, the area has evolved to raised, scaling plaques. 1. What is your diagnosis? 2. What could cause this lesion? 3. What is a potential complication? ERRNVPHGLFRVRUJ Answers: Side B 1. This is acute eczematous dermatitis. 2. The epidermis has extensive edema with spongiosis and spongiotic vesicles ( ▸) filled with fluid. 3. Epidermal Langerhans cells present antigen to CD4+ helper T lymphocytes, which become activated and secrete cytokines (type IV hypersensitivity). Some CD4+ cells become memory cells so that antigen re-exposure results in a more rapid and exuberant inflammatory response. Perivascular T cells secrete inflammatory mediators that act on endothelial cells to promote increased permeability and inflammatory cell egress (e.g., an exudate ). ERRNVPHGLFRVRUJ 25.7 Side B (PBD9: 1163; BP9: 852) ERRNVPHGLFRVRUJ Questions A 25-year-old woman who has been prescribed carbamazepine for a seizure disorder develops a papulovesicular skin rash with the microscopic appearance shown. 1. What is the general term for this histologic appearance? 2. Describe the microscopic changes. 3. What inflammatory cell types play a role in the pathogenesis of this condition? ERRNVPHGLFRVRUJ Answers: Side A 1. Eczema is a general term for the acute appearance of red, oozing, and crusted lesions ( ▸) that, in time, become scaling plaques. 2. Taking a patient history can help to identify potential causes, including contact dermatitis, atopic dermatitis, insect bite, drug reaction, chemical exposure, and photosensitivity. 3. Bacterial superinfection can occur as a result of the compromise of the otherwise intact epidermal barrier. ERRNVPHGLFRVRUJ 25.8 Side A (PBD9: 1165; BP9: 854) ERRNVPHGLFRVRUJ Questions A 20-year-old man has symmetrically distributed lesions similar to those shown over his elbows, knees, and scalp. These are fine, dry, silvery-white scales, and the skin underneath is red and glossy. Scratching makes these lesions more likely to appear. 1. What is your diagnosis? 2. What are the risk factors for this condition? 3. What can happen to this patient's fingernails? 4. What joint disease may be associated with this? ERRNVPHGLFRVRUJ Answers: Side B 1. This is psoriasis with acanthosis , with thinning of the stratum granulosum ( ▴), parakeratotic scale ( ▾), downward elongation of the rete ridges ( ▸), and dilated vessels ( ◂) in the dermal papillae. 2. This is probably a T 1 immune response driven by an autoimmune interaction of Langerhans cells and CD4+ cells, with the activation of CD8+ cells and the release of cytokines such as tumor necrosis factor (TNF). H 3. Topical corticosteroids, psoralens with phototherapy, and systemic immunosuppressants such as methotrexate are used to treat this condition. ERRNVPHGLFRVRUJ 25.8 Side B (PBD9: 1165; BP9: 854) ERRNVPHGLFRVRUJ Questions A 58-year-old woman with 1- to 3-cm, pruritic, elevated, plaquelike areas of scaling skin over her genital region and her buttocks as well as under her breasts and her arms has a biopsy specimen with the microscopic appearance shown. 1. What is your diagnosis? 2. What is the pathogenesis? 3. What drugs can be used to treat this disease? ERRNVPHGLFRVRUJ Answers: Side A 1. This is plaque psoriasis . 2. In addition to skin trauma ( Koebner phenomenon ), emotional stress, cigarette smoking, alcohol consumption, and drugs such as nonsteroidal anti-inflammatory drugs increase the risk for an outbreak. 3. Nail psoriasis occurs in one third of patients with this condition; it consists of yellow-brown discoloration with pitting and separation of the nail plate ( onycholysis ). 4. Psoriatic arthritis involves the distal interphalangeal joints of the hands and feet being affected with inflammation similar to that of rheumatoid arthritis. ERRNVPHGLFRVRUJ 25.9 Side A (PBD9: 1164; BP9: 853) ERRNVPHGLFRVRUJ Questions A 35-year-old man who is being treated with a cephalosporin for an upper respiratory tract infection develops the lesions shown over the extensor surfaces of his extremities as well as his palms, neck, and face. They subside in 3 weeks. 1. What is your diagnosis? 2. What is the immunologic basis for this condition? 3. What can precede the development of this lesion? ERRNVPHGLFRVRUJ Answers: Side B 1. This is toxic epidermal necrolysis (TEN) . Note the necrosis ( ▸) of the epidermal keratinocytes and the separation of the epidermis at the dermal-epidermal junction ( ▴). This is the most severe variant of erythema multiforme, and it is usually associated with prior drug therapy. 2. Stevens-Johnson syndrome (SJS) has mucosal involvement that typically affects the oral cavity, the conjunctiva, the urethra, and the genital and perianal regions. 3. The mortality rate with SJS can be 5%, and the mortality rate with TEN can be 40%. ERRNVPHGLFRVRUJ 25.9 Side B (PBD9: 1164; BP9: 853) ERRNVPHGLFRVRUJ Questions A 47-year-old woman begins treatment with a sulfonamide for a fever and sore throat, and she develops symmetric erythematous skin lesions on her face and torso 2 days later. These progress to flaccid bullae that slough. The microscopic appearance of a biopsy specimen of a lesion is shown. 1. What is your diagnosis? 2. What similar condition has mucosal involvement? 3. How serious is this condition? ERRNVPHGLFRVRUJ Answers: Side A 1. This is erythema multiforme with the classic targetoid lesions exhibiting a central pale vesicle ( ▴) surrounded by a zone of erythema ( ▾). Macules, papules, vesicles, and bullae can also occur with this “multiform” condition. 2. Erythema multiforme is a delayed-type hypersensitivity reaction, typically against an agent that haptenates self-proteins and elicits an inflammatory response. 3. Preceding infections include herpes simplex virus, Mycoplasma, and many bacteria and fungi. Drugs such as antibiotics, anticonvulsants, antipyretics, and antituberculosis agents have been implicated. An underlying carcinoma or lymphoma may be present, or this may also occur with a collagen vascular disease such as systemic lupus erythematosus. ERRNVPHGLFRVRUJ 25.10 Side A (PBD9: 1175; BP9: 857) ERRNVPHGLFRVRUJ Questions A 16-year-old boy has a 5-year history of the lesions shown. He reports that they subsequently regressed over the course of a year. There is no associated pain, swelling, itching, or redness. 1. What is your diagnosis? 2. What are similar lesions on the palms or soles called? 3. What grossly similar lesion may appear in the genital region? 4. Why did these lesions spontaneously regress? ERRNVPHGLFRVRUJ Answers: Side B 1. This verruca vulgaris has papillomatous epidermal hyperplasia ( ▸) with marked overlying hyperkeratosis ( ♦). The viral cytopathic effect is marked by koilocytotic change (cytoplasmic vacuolization [ ◂]) in the keratinocytes. 2. Human papillomavirus (HPV) infection causes these lesions by driving keratinocyte proliferation. There are many subtypes, a few of which are also linked to dysplasia and carcinoma, including subtypes 16 and 18 in cervical carcinoma. Venereal warts are most often associated with subtypes 6 and 11. ERRNVPHGLFRVRUJ 25.10 Side B (PBD9: 1175; BP9: 857) ERRNVPHGLFRVRUJ Questions A 10-year-old girl with a 0.6-cm, dark tan, roughened papule on the dorsum of her left hand has it resected. The microscopic appearance is shown. 1. What is your diagnosis? 2. What is the pathogenesis? ERRNVPHGLFRVRUJ Answers: Side A 1. These rough-surfaced tan lesions ( ◂) are common warts, or verruca vulgaris . 2. Verruca plantaris occurs on the soles; verruca palmaris occurs on the palms. 3. Condylomata acuminata (venereal warts) occur in the genital region. 4. Regression is associated with the development of cytotoxic T cells that are capable of eradicating infected cells. Circulating neutralizing antibodies may also participate by preventing viral spread. ERRNVPHGLFRVRUJ 26 ERRNVPHGLFRVRUJ Bones, Joints, and Soft-Tissue Tumors ERRNVPHGLFRVRUJ 26.1 Side A (PBD9: 1214; BP9: 786) ERRNVPHGLFRVRUJ Questions A 46-year-old man has had episodic left metacarpophalangeal joint pain as well as joint enlargement, tenderness, warmth, and decreased range of motion for 10 years. He takes hydrochlorothiazide for hypertension. A radiograph of the affected area is shown. 1. What is the diagnosis? 2. Explain the metabolic defect. 3. What factors can exacerbate this disease? ERRNVPHGLFRVRUJ Answers: Side B 1. Negatively birefringent ( yellow) needle-shaped crystals ( ▸) are consistent with sodium urate . 2. Uricosuria and an acid urine pH lead to radiolucent uric acid calculus formation with ureteral colic. 3. Aggregates of urate crystals with inflammation form tophi in the joints, tendons, bursae, and other soft tissues. 4. Primary uric acid overproduction accounts for 90% of gout. Although a lack of hypoxanthine guanine phosphoribosyltransferase (HGPRT) can lead to uric acid overproduction (partial deficiency or the rarer Lesch-Nyhan syndrome), 85% to 90% of patients with gout do not have a specific enzyme defect. Secondary forms of gout account for 10% of cases. ERRNVPHGLFRVRUJ 26.1 Side B (PBD9: 1214; BP9: 786) ERRNVPHGLFRVRUJ Questions A 55-year-old man with colicky flank pain has urine with a pH of 5.5 (nl 4.6 to 8.0) and multiple RBCs. An abdominal CT scan shows a round 0.5-cm radiolucent lesion in his left ureter. Aspiration of an olecranon bursa nodule yields cloudy fluid with neutrophils and, under polarized light, the findings shown (red compensator axis in direction of arrow ). 1. What is present? 2. What is the urinary tract lesion? 3. What is the soft-tissue lesion? 4. How does the uric acid level become elevated? ERRNVPHGLFRVRUJ Answers: Side A 1. He has gouty arthritis with bone erosion ( ■). The tophaceous deposits that gradually collect form a mass that erodes and destroys the bone and the joint. 2. Crystal deposition in joints produces acute arthritis with neutrophilic inflammation. 3. Risk factors include older age; obesity; alcohol consumption; drugs such as thiazides; and foods rich in purines, such as red meat, seafood, spinach, and asparagus. ERRNVPHGLFRVRUJ 26.2 Side A (PBD9: 1217; BP9: 789) ERRNVPHGLFRVRUJ Questions An 87-year-old man with a 3-day bout of right knee pain and swelling has the radiograph shown. A previous similar episode resolved with ibuprofen. 1. What are the radiographic features? 2. What is the diagnosis? ERRNVPHGLFRVRUJ Answers: Side B 1. The joint fluid contains a positively birefringent ( blue) rhomboid crystal ( ■) that is consistent with calcium pyrophosphate dihydrate ( CPPD ). 2. Pseudogout caused by CPPD deposition is most often seen with advancing age (30% to 60% of patients are >85 years old). It can also be related to abnormalities in the hyaline cartilage, and osteoarthritis can be a precursor. Secondary forms of CPPD deposition disease occur with hereditary hemochromatosis, hyperparathyroidism, hypophosphatemia, hypomagnesemia, and hypothyroidism. It can have a familial component; some cases are related to rare autosomal-dominant mutations in the ANKH gene, which codes for a transmembrane inorganic pyrophosphate transport channel. ERRNVPHGLFRVRUJ 26.2 Side B (PBD9: 1217; BP9: 789) ERRNVPHGLFRVRUJ Questions A 79-year-old man with a painful and swollen right knee undergoes a joint aspirate procedure that yields cloudy fluid with numerous neutrophils and the appearance under polarized light that is shown (red compensator axis indicated by the arrow ). His knee feels better after the aspiration and a corticosteroid injection. 1. What is shown here? 2. What are the risk factors for this disease? ERRNVPHGLFRVRUJ Answers: Side A 1. The radiograph shows osteophyte formation ( ▸), subchondral cysts ( ▾), microfractures , and meniscal calcification ( ◂). 2. The history and radiographic findings suggest pseudogout , which is attributable to calcium pyrophosphate dihydrate ( CPPD ) deposition. An acute episode of monoarthritis or oligoarthritis can be initiated by the shedding of CPPD crystals from the cartilage into the synovial fluid. The knee is the most common site. ERRNVPHGLFRVRUJ 26.3 Side A (PBD9: 1200; BP9: 777) ERRNVPHGLFRVRUJ Questions A 22-year-old man has a 6-month history of intermittent posterolateral knee discomfort at the level of the patella. His MRI is shown. 1. What is the diagnosis? 2. Is this a neoplasm? 3. What are the potential complications? ERRNVPHGLFRVRUJ Answers: Side B 1. This is an osteochondroma with an overlying bluish cartilaginous cap ( ■) and underlying cancellous bone ( ♦). 2. Men are affected with this condition three times more often than women. There is a male predominance for nearly all primary bone neoplasms (an exception is a giant cell tumor). 3. Osteochondromas are most common in long tubular bones around the knee, but they can also occur in the pelvis, scapula, and ribs. 4. Osteochondromatosis (multiple hereditary exostosis) is an autosomal-dominant disease that is associated with the loss of EXT1 or EXT2 gene copies in growth plate chondrocytes. ERRNVPHGLFRVRUJ 26.3 Side B (PBD9: 1200; BP9: 777) ERRNVPHGLFRVRUJ Questions A 26-year-old man with right lower leg pain has a lesion excised from the tibia, with the gross appearance shown. 1. Describe this lesion. 2. Is this more common in men or women? 3. Where are these lesions most likely to be found? 4. Is there a hereditary form of this disease? ERRNVPHGLFRVRUJ Answers: Side A 1. There is a 2-cm-long bony exostosis ( ◂) just above the growth plate of the lower femur; this is also called an osteochondroma . 2. This is not a true neoplasm but rather an exaggeration of the endochondral bone growth plate in the metaphyseal region of a long bone. Men have bigger bones with more growth during adolescence, and they are affected more often than women. 3. Most osteochondromas are solitary, slow-growing lesions that are asymptomatic, unless they impinge on a soft-tissue structure such as a nerve or are subjected to repeated external pressure. Solitary lesions rarely give rise to a chondrosarcoma. ERRNVPHGLFRVRUJ 26.4 Side A (PBD9: 1189; BP9: 770) ERRNVPHGLFRVRUJ Questions A 24-year-old woman with a 10-year history of chronic low back pain has the radiograph shown. 1. What is the diagnosis? 2. What may cause this condition? ERRNVPHGLFRVRUJ Answers: Side B 1. Severe curvature of the vertebral column ( ■) is seen; severe curvature of more than 20% affects roughly 1 in 2500 individuals. 2. A reduction in the size of the patient's chest cavity as a result of her severe scoliosis also reduces her lung volumes, which results in a restrictive lung disease. 3. For scoliosis in a child, virtually around-the-clock bracing is an option until such time that bone growth has ceased. However, this may not be a successful treatment for severe disease. For adults after epiphyseal growth plate fusion, treatment involves surgery with spinal fusion, the use of metal rod implants, or both. ERRNVPHGLFRVRUJ 26.4 Side B (PBD9: 1189; BP9: 770) ERRNVPHGLFRVRUJ Questions A 45-year-old woman has a severe chest deformity and back pain as a result of the abnormality shown. She develops dyspnea, and spirometry reveals diminished total and residual volume as well as a normal FEV . 1 1. Describe what is shown here. 2. Explain this patient's spirometry findings. 3. How can this be treated? ERRNVPHGLFRVRUJ Answers: Side A 1. Scoliosis involves marked curvature ( ■) of the vertebral column and often includes superimposed areas of osteoarthritis. 2. Scoliosis most often manifests during adolescence, when bone growth accelerates. Any asymmetric bone growth results in vertebral column instability, and it is considerably more common in women. Factors that increase bone growth and asymmetry or that diminish vertebral column stability (e.g., cerebral palsy, spinal muscular atrophy) can promote scoliosis. Although congenital defects can be causal, the most common form is adolescent idiopathic scoliosis ; this variety has a mendelian inheritance pattern with incomplete penetrance. ERRNVPHGLFRVRUJ 26.5 Side A (PBD9: 1234) ERRNVPHGLFRVRUJ Questions A 53-year-old man has an 8-month history of sciatica-type pain in his left leg; it is worse with heavy lifting, prolonged sitting, coughing, and back flexion. There is also a loss of light touch over the posterolateral thigh that extends to the posterolateral calf and the lateral foot. The patient's MRI is shown. 1. What is your diagnosis? 2. What is the likely mechanism of injury? ERRNVPHGLFRVRUJ Answers: Side B 1. In the transverse view, the herniation compresses ( ▾) the nerve roots on the left. 2. Weakness and degeneration of the anulus fibrosus and the posterior longitudinal ligament allow for the herniation of the nucleus pulposus posteriorly into the spinal canal and posterolaterally to compress the nerve roots. 3. Disk herniation in the cervical region is most likely to occur at C6–C7 or C5–C6. ERRNVPHGLFRVRUJ 26.5 Side B (PBD9: 1234) ERRNVPHGLFRVRUJ Questions A 43-year-old man with a 1-year history of worsening low back pain develops a loss of sensation in an L4–L5 dermatomal distribution. His MRI is shown. 1. What is your diagnosis? 2. How does this occur? 3. Where does this occur in the cervical region? ERRNVPHGLFRVRUJ Answers: Side A 1. The sagittal MRI shows a bulge ( ◂) of the intervertebral disk into the spinal canal at the L5–S1 level. Most disk herniations occur at either L4–L5 or L5–S1. 2. Compression can result in pain ( radiculopathy ) that radiates along the dermatome served by that nerve root. Because the involved nerve roots are commonly L5 or S1 and because those contribute to the sciatic nerve, the term sciatica is frequently used. Sciatic nerve compression can also occur outside of the vertebral column, either in the pelvis or the buttocks. ERRNVPHGLFRVRUJ 26.6 Side A (PBD9: 1198; BP9: 776) ERRNVPHGLFRVRUJ Questions A 16-year-old boy with a 4-month history of right knee pain eventually has a work-up that results in a major surgical resection. The gross appearance of the lower femur is shown. 1. What is your diagnosis? 2. What are the microscopic features of this lesion? 3. Where do metastases from this lesion most often go? ERRNVPHGLFRVRUJ Answers: Side B 1. This is almost certainly an osteosarcoma , which is the most common primary malignant tumor of bone. This lesion arises in the metaphysis ( ■) of the distal femur, and there is destruction of the bony cortex ( ♦), with extension of the tumor into soft tissues ( •). Bone formation by the tumor cells is suggested by the increase in the irregular bright areas within the metaphysis. 2. Most osteosarcomas have an RB gene mutation . Other mutations include TP53, MDM2, and INK4α. Germline mutations in RB increase an individual's risk 1000-fold. 3. A second peak in age distribution occurs in elderly individuals with a history of Paget disease of the bone. ERRNVPHGLFRVRUJ 26.6 Side B (PBD9: 1198; BP9: 776) ERRNVPHGLFRVRUJ Questions A 19-year-old man with a 6-month history of lower right thigh pain has the radiograph shown. 1. What is your diagnosis? 2. What mutation is likely present? 3. What is the risk factor for this disease in older individuals? ERRNVPHGLFRVRUJ Answers: Side A 1. This is likely an osteosarcoma . The large destructive mass ( ■) arises in the metaphysis and breaks through bone cortex ( ♦) to invade adjacent soft tissue ( •). More than 60% of osteosarcomas arise around the knee, with the hip, the proximal humerus, and the jaw representing the other major sites. Three quarters of these tumors occur in individuals who are less than 20 years old. 2. Osteosarcomas have pleomorphic spindle cells that form an osteoid matrix and bone . 3. Sarcomas are most likely to metastasize hematogenously , with the lung being most commonly involved. ERRNVPHGLFRVRUJ 26.7 Side A (PBD9: 1203; BP9: 780) ERRNVPHGLFRVRUJ Questions A 10-year-old boy with a 3-month history of left lower leg pain presents with a fever along with warmth, swelling, and tenderness over the midlateral left leg. An MRI of his leg is shown. 1. What is your diagnosis? 2. What chromosomal translocation is likely present? 3. What name is this neoplasm given if it has neural differentiation? ERRNVPHGLFRVRUJ Answers: Side B 1. These are small round blue cells that are consistent with Ewing sarcoma/primitive neuroectodermal tumor (PNET) . The granular PAS-positive ( red) cytoplasmic staining results from large amounts of cytoplasmic glycogen deposition. This patient has findings that are typical of anemia and leukocytosis. An elevated erythrocyte sedimentation rate may also be present. 2. Approximately 80% of cases occur in children who are less than 20 years old; there is also a male predominance. 3. Surgery and chemotherapy may be combined with radiation therapy. There is longterm survival in approximately 50% of cases. ERRNVPHGLFRVRUJ 26.7 Side B (PBD9: 1203; BP9: 780) ERRNVPHGLFRVRUJ Questions A 15-year-old boy with a 5-month history of pelvic pain has a radiograph that shows a 7-cm lytic left ilium mass with cortical destruction and soft-tissue invasion. Laboratory studies show a hemoglobin level of 9 g/dL (nl 13.8 to 17.2 g/dL) and a WBC count of 15,000/mm (nl 3800 to 10,800/mm ). The microscopic appearance of the excised mass with periodic acid–Schiff (PAS) stain is shown. 3 3 1. What is your diagnosis? Why is it PAS-positive? 2. What are the typical demographics of patients with this neoplasm? 3. How is this neoplasm treated? ERRNVPHGLFRVRUJ Answers: Side A 1. The diaphyseal region of the fibula has irregular bright areas ( ▸) of increased signal intensity. The patient's age and the location and symptoms suggest Ewing sarcoma . These tumors characteristically arise in the diaphyses of long tubular bones and the flat bones of the pelvis. 2. In 85% of cases, there is a t(11;22) translocation with a resulting EWS-FLT1 fusion gene that produces a chimeric protein that is a constitutively active transcription factor. 3. Primitive neuroectodermal tumor (PNET) ERRNVPHGLFRVRUJ 26.8 Side A (PBD9: 1187; BP9: 768) ERRNVPHGLFRVRUJ Questions A 76-year-old woman with a stooped posture and recurrent back pain eventually dies of unrelated causes. The gross appearance of her vertebral column at autopsy is shown. 1. What is your diagnosis? 2. What condition likely predisposed her to this problem? 3. Why was her risk increased after menopause? 4. What is the major determinant of peak bone mass? ERRNVPHGLFRVRUJ Answers: Side B 1. There is increased lucency ( ▸) of bone, particularly adjacent to the interphalangeal joints. 2. This osteopenia could be due to osteoporosis or osteomalacia . Poor diet with decreased vitamin D and calcium intake increases the risk for osteomalacia. 3. In a child, vitamin D deficiency causes rickets ; it is far worse than adult osteomalacia, because significant bone deformity can ensue. ERRNVPHGLFRVRUJ 26.8 Side B (PBD9: 1187; BP9: 768) ERRNVPHGLFRVRUJ Questions A 70-year-old man with poor nutrition had a pathologic fracture of the left femoral neck after a minor fall. The evaluation of his bone density includes this hand radiograph. 1. Describe the findings. 2. What are the possible diagnoses? 3. What would this process be in a child? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has a vertebral body compressed fracture ( ◂). Unfractured vertebrae also show decreased cancellous bone density. Multiple compressed fractures can lead to kyphosis and a reduction in overall height. 2. She had osteoporosis . 3. Postmenopausal declines in estrogen increase tumor necrosis factor, interleukin-1, and interleukin-6 release from monocytes; these increase the RANK (receptor activator for nuclear factor κβ) and RANK-L expression that drives increased osteoclast activity. 4. Inherited vitamin D receptor alleles help to determine the amount of bone mass achieved during young adulthood. Type 1 collagen, estrogen receptor, and insulin-like growth factor genes also play a role. Diet and exercise help with the achievement of maximal peak bone mass. ERRNVPHGLFRVRUJ 26.9 Side A (PBD9: 1195; BP9: 773) ERRNVPHGLFRVRUJ Questions A 64-year-old woman with recurrent urinary tract infections and a recent history of acute pyelonephritis and sepsis now complains of right lower extremity pain. Her radiograph is shown. 1. What is your diagnosis? 2. What organisms may have been cultured from her blood 1 month ago? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has acute pyogenic osteomyelitis . There is an island of devitalized bone ( ♦) surrounded by inflammation that includes neutrophils. 2. Growing bone in a child is more vascular, which allows for hematogenous dissemination to metaphyseal or epiphyseal regions. 3. Osteomyelitis in a patient with sickle cell anemia is often associated with Salmonella infection . ERRNVPHGLFRVRUJ 26.9 Side B (PBD9: 1195; BP9: 773) ERRNVPHGLFRVRUJ Questions A 5-year-old boy with a recent deep skin abrasion over his right knee develops fever and chills with intense right knee pain that has lasted for 2 days. He has a WBC count of 16,390/mm (nl 3800 to 10,800/mm ), and a blood culture grows Staphylococcus aureus. Had we sampled it, his lower femoral metaphysis would have the microscopic appearance shown. 3 3 1. What is your diagnosis? 2. Why is this region of bone preferentially involved? 3. What organism might be present if this patient had sickle cell anemia? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has chronic osteomyelitis . There is a pale necrotic “sequestrum” ( ▾) surrounded by irregular remodeled “involucrum” ( ◂) that produces marked distortion as a result of bony destruction and remodeling, with sclerosis and adjacent rarefaction of bone. Bone destruction has produced the “saucerization” ( ▸) of cortical bone. 2. Urinary tract infections are often caused by Escherichia coli, Klebsiella, and Pseudomonas spp. ERRNVPHGLFRVRUJ 26.10 Side A (PBD9: 1193; BP9: 772) ERRNVPHGLFRVRUJ Questions A 20-year-old man involved in a high-speed motor vehicle accident experiences marked pain in his thigh. On examination, the affected leg is shortened and externally rotated. His radiograph is shown. 1. What is your diagnosis? 2. What could impede healing? 3. Why might even minimal trauma cause this? ERRNVPHGLFRVRUJ Answers: Side B 1. Woven (new) bone forms callus ( ♦) at the fracture site. 2. Osteoblasts ( ▴) are stimulated to produce new osteoid, which becomes osteocytes ( ▸) when embedded in the new bone. Osteoclasts ( ▾) remodel new bone by secreting hydrogen chloride to decalcify the ossified matrix and to activate proteases. The inactive proteases necessary for degrading the extracellular matrix proteins are already in the bony matrix; they have been deposited in an inactive form as the bone was originally synthesized by osteoblasts. 3. A nonhealing or nonunion fracture remains unstable, and a pseudarthrosis (“false joint”) may form at the fracture site. ERRNVPHGLFRVRUJ 26.10 Side B (PBD9: 1193; BP9: 772) ERRNVPHGLFRVRUJ Questions A 10-year-old child sustained an ulnar fracture after falling out of a tree. Two weeks later, the microscopic appearance of his fracture would be as shown. 1. Describe the findings. 2. What are the important cells involved in this process? 3. What would have happened if this site of injury looked the same 1 year later? ERRNVPHGLFRVRUJ Answers: Side A 1. A complete, comminuted, and displaced fracture of the lower femoral shaft extends across the entire bone ( ◂), with fragments ( ▸). The fracture is closed (i.e., it does not extend through the skin), and some fragments are not aligned. 2. Healing is impeded by foreign bodies, bone fragments, infection, poor nutrition (inadequate calcium, vitamin D, or both), and corticosteroid therapy. 3. Osteopenia with osteoporosis or osteomalacia would weaken the bone. A preexisting lesion (e.g., a neoplasm) can lead to “pathologic” fracture from a minor trauma with injury that is not otherwise expected to cause fracture. ERRNVPHGLFRVRUJ 26.11 Side A (PBD9: 1208; BP9: 782) ERRNVPHGLFRVRUJ Questions A 70-year-old man with a 20-year history of progressively worsening knee pain— especially with ambulation—has crepitus and a limited range of motion on examination. His radiograph is shown. 1. What is your diagnosis? 2. What is the pathogenesis? 3. What are the risk factors? ERRNVPHGLFRVRUJ Answers: Side B 1. This is degenerative osteoarthritis of the spine; pronounced osteophytes ( ◂) protrude from the margins of the vertebral bodies. 2. Osteophytes impinge on nerve roots to cause this pain. 3. Osteoarthritis typically involves weight-bearing joints such as hips, knees, hands, and feet; wrists, elbows, and shoulders are usually spared (except in athletes who subject them to repeated bouts of nonphysiologic motion, such as a pitcher throwing curve balls in baseball). Osteoarthritis may be asymmetric, and it may affect only isolated joints. ERRNVPHGLFRVRUJ 26.11 Side B (PBD9: 1208; BP9: 782) ERRNVPHGLFRVRUJ Questions A 66-year-old man has had progressively increasing low back pain and reduced range of motion for 10 years. He develops radicular pain in a T10 distribution. His vertebral column would appear as shown. 1. What is your diagnosis? 2. Explain the radicular pain. 3. What other sites might be involved by this disease? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has osteoarthritis with joint space narrowing ( ◂), osteophytes ( ▾), and mild subluxation ( ▸) of femur on tibia. 2. There is a loss of proteoglycans and type II collagen in hyaline cartilage with a loss of tensile strength. Chondrocyte proliferation and matrix synthesis are inadequate to balance damage, so overlying cartilage is lost and underlying bone is exposed; pain and bony sclerosis (to buttress exposed bone) result. 3. “Wear and tear” plays a role. Excessive stressful movements and obesity are also contributory, although more recent evidence suggests that the regular moderate loading and unloading of cartilage (i.e., with moderate walking or running) may help to increase joint cartilage matrix synthesis. ERRNVPHGLFRVRUJ 26.12 Side A (PBD9: 1194; BP9: 773) ERRNVPHGLFRVRUJ Questions In an effort to make some extra money, a 28-year-old deep-sea diver exceeds the recommendations for the number, length, and depth of dives in a salvage operation. He now presents with chronic shoulder pain. His MRI is shown. 1. What is your diagnosis? 2. What is the pathogenesis? ERRNVPHGLFRVRUJ Answers: Side B 1. The nuclei of the osteocytes ( ▾) are absent, which is consistent with avascular necrosis . Devitalized bone undergoes remodeling, and the joint becomes painful and dysfunctional. 2. The pathogenesis is obscure, but patients who receive long-term, low-dose steroids or even short-course, high-dose regimens (and occasionally even with joint injections) are at risk for avascular necrosis of bone. 3. The bone of the humeral and femoral heads has a tenuous blood supply that can be traumatically disrupted or affected by many conditions, such as infection, radiation, and hemoglobinopathies. ERRNVPHGLFRVRUJ 26.12 Side B (PBD9: 1194; BP9: 773) ERRNVPHGLFRVRUJ Questions A 61-year-old man with a long history of corticosteroid therapy for vasculitis now reports a 2-month course of worsening shoulder pain. The microscopic appearance of his femoral head would be as shown. 1. What is your diagnosis? 2. What was his risk factor? 3. What are other causes of such pathology? ERRNVPHGLFRVRUJ Answers: Side A 1. There is avascular necrosis of the humeral head, with brighter areas ( ▾) of subchondral, devitalized bone; the cortical bone and cartilage remain intact. 2. In this case, the avascular necrosis resulted from caisson disease . After returning to normal air pressures, intravascular and tissue nitrogen bubbles can form from the solubilized nitrogen that accumulates during repeated dives; these bubbles can then embolize to the skeletal system (most commonly to the femurs, tibias, and humeri) and cause bone ischemia. More acute systemic nitrogen bubble formation after rapid ascents, which is typically associated with acute pain, is known as “ the bends .” ERRNVPHGLFRVRUJ 26.13 Side A (PBD9: 1209; BP9: 784) ERRNVPHGLFRVRUJ Questions A 32-year-old woman with a 7-month history of malaise and fatigue complains of pain and swelling in her hands and feet as well as marked morning stiffness. Her hand, which is shown here, is warm and painful. 1. What is your diagnosis? 2. What is the pathogenesis? 3. What laboratory findings might be expected? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has rheumatoid arthritis . There are extensive round cell infiltrates forming a lymphoid nodule ( ♦) beneath the synovium ( ▸). 2. The (presumed autoimmune) inflammatory process produces a mass of synovium with stroma that grows steadily over articular surfaces and erodes them and that extends into bone. This leads to subluxation and bony ankylosis, with marked deformity. 3. This patient has a rheumatoid nodule over an extensor surface at a pressure point. Such nodules can also occur in visceral organs, such as the lung and the heart. ERRNVPHGLFRVRUJ 26.13 Side B (PBD9: 1209; BP9: 784) ERRNVPHGLFRVRUJ Questions A 40-year-old woman has had waxing and waning multiarticular arthritic pain involving her hands, wrists, ankles, elbows, and knees for 1 year. On examination, she has a painful subcutaneous nodule. Microscopically, her metacarpophalangeal joint would appear as shown. 1. What is your diagnosis? 2. How does this process destroy a joint? 3. What is the subcutaneous nodule? ERRNVPHGLFRVRUJ Answers: Side A 1. Rheumatoid arthritis (RA) caused metacarpophalangeal joint and proximal interphalangeal joint enlargement ( ▾), with phalangeal displacement and pronounced ulnar deviation ( ◂) as a result of joint subluxation. 2. RA is presumably an autoimmune disease that involves inflammation driven by CD4+ lymphocytes, which produce cytokines such as TNF. This stimulates synovial proliferation and matrix metalloproteinase production, which destroys cartilage and bone. Activated T cells also produce RANK-L, which induces osteoclast bone resorption. 3. Rheumatoid factor (an IgM directed against IgG) and cyclic citrullinated peptide antibodies are frequently found, but neither is completely sensitive nor specific. ERRNVPHGLFRVRUJ 26.14 Side A (PBD9: 1203; BP9: 781) ERRNVPHGLFRVRUJ Questions A 33-year-old man with a 3-week history of pain from the left buttock to the thigh has the pelvic CT scan shown. After resection, the lesion microscopically contains numerous multinucleated giant cells in a background of mononuclear stromal cells. 1. What is your diagnosis? 2. Is this lesion benign or malignant? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has a giant cell tumor of bone . Osteoclast-like giant cells ( ▸) lie in a background of mononuclear stromal cells ( ◂). 2. These lesions are thought to arise from a monocyte-macrophage lineage that leads to osteoclast-type giant cells (hence the other term osteoclastoma ). Although they are generally considered benign, they can be locally aggressive. Most are solitary, but multicentric tumors do occasionally occur. 3. A “brown tumor” of bone driven by increased parathyroid hormone contains numerous activated osteoclasts. Chondroblastoma, pigmented villonodular synovitis, and giant cell reparative granuloma are other lesions that exhibit similar giant cell morphology. ERRNVPHGLFRVRUJ 26.14 Side B (PBD9: 1203; BP9: 781) ERRNVPHGLFRVRUJ Questions A 16-year-old boy with recent-onset right knee pain has a radiograph that shows an expansile lytic mass with a sclerotic rim of new bone confined to the proximal tibial metaphysis. The lesion is curetted, and it has the microscopic appearance shown. The lesion recurs within a year. A second lesion is found in the patient's distal right radius. 1. What is your diagnosis? 2. What is the cell of origin of this mass? 3. What is the differential diagnosis of this lesion? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has a giant cell tumor of bone . The large, lytic mass ( ♦) arises in the left ischial ramus and expands into the soft tissue. It does not have infiltrative borders, and it has a prominent sclerotic rim ( ▴) of reactive new bone. 2. Most of these lesions act in a benign fashion and are treated by local curetting. Half or more may recur locally after curetting, and 4% eventually metastasize to the lungs. Sarcomatous transformation is extremely rare. ERRNVPHGLFRVRUJ 26.15 Side A (PBD9: 1222; BP9: 793) ERRNVPHGLFRVRUJ Questions A 27-year-old woman (G2, P2) notes a painful lump in her lower anterior abdomen 1 month after the delivery of a term infant. Her original CT scan is shown; the lesion recurs after resection. 1. What is your diagnosis? 2. If this lesion was located in the mesentery or the pelvic wall, what gene mutations may be present? 3. What could cause this lesion to regress? ERRNVPHGLFRVRUJ Answers: Side B 1. This a palmar fibromatosis called Dupuytren contracture . Note the myofibroblastic cells that form the mass ( ■) and the interspersed collagen ( ♦). The lesion interdigitates into the adjacent muscle ( •). 2. Dupuytren contractures occur more frequently in patients after trauma to the hand. They are also associated with alcohol abuse, diabetes mellitus, and cigarette smoking. 3. These are aggressive fibroblastic proliferations that can occur in the shoulder, the chest wall, the neck, and the thigh, with equal frequency in both men and women. ERRNVPHGLFRVRUJ 26.15 Side B (PBD9: 1221; BP9: 793) ERRNVPHGLFRVRUJ Questions A 44-year-old woman has a flexion contracture that involves the proximal interphalangeal and metacarpophalangeal joints of her right ring finger. An irregular, firm palmar mass is excised, and it has the microscopic appearance shown. 1. What is your diagnosis? 2. What are the risk factors for this lesion? 3. Where else might these lesions arise? ERRNVPHGLFRVRUJ Answers: Side A 1. The mass ( ▾) in the abdominal wall is a desmoid , which is a form of deep-seated fibromatosis . Although these growths are grossly circumscribed, they are infiltrative, and they will recur if not widely removed. An abdominal desmoid often arises in the rectus abdominis muscle, commonly during the peripartum or postpartum period. 2. Intra-abdominal desmoids can occur with Gardner syndrome and familial adenomatous polyposis , which are often associated with APC or β-catenin gene mutations. 3. Desmoids may regress after menopause, with oral contraceptive use, or with tamoxifen therapy. ERRNVPHGLFRVRUJ 26.16 Side A (PBD9: 1191; BP9: 771) ERRNVPHGLFRVRUJ Questions A 43-year-old man with bilateral hand pain also has renal calculi and peptic ulcers. His radiograph is shown. 1. What is your diagnosis? 2. What laboratory findings do you suspect? 3. What endocrine lesions might you suspect? ERRNVPHGLFRVRUJ Answers: Side B 1. The sharply demarcated lucent area ( ◂) in the upper femoral cortex, with a brighter central nidus, is an osteoid osteoma . Most of these occur in children and young adults. 2. These lesions produce prostaglandins that are responsible for the pain; aspirin irreversibly inhibits cyclooxygenase and blocks the synthesis of prostaglandins from arachidonic acid. 3. Surgical excision or percutaneous radiofrequency ablation under CT guidance can be used to treat this condition. ERRNVPHGLFRVRUJ 26.16 Side B (PBD9: 1197; BP9: 776) ERRNVPHGLFRVRUJ Questions A 19-year-old man has left thigh pain, which is worse at night and relieved by aspirin. His CT scan is shown. 1. What is your diagnosis? 2. What chemical mediator causes this patient's pain? 3. How is this lesion treated? ERRNVPHGLFRVRUJ Answers: Side A 1. The radiograph shows osteitis fibrosa cystica with multiple areas of rarefaction ( ▼) within the bone; this is characteristic of primary hyperparathyroidism . Increased parathyroid hormone levels lead to osteoclast activation and bone resorption, which is best seen in the subperiosteal regions of the phalanges. Hypercalcemia also explains the renal calculi and the increased gastric acid production that is causing his ulcers. 2. He likely has increased parathyroid hormone, elevated serum calcium, and decreased phosphorus levels. 3. In the absence of renal failure, this patient likely has primary hyperparathyroidism . A solitary parathyroid adenoma is most likely, followed by parathyroid hyperplasia. Parathyroid carcinoma is uncommon. ERRNVPHGLFRVRUJ 26.17 Side A (PBD9: 1220; BP9: 792) ERRNVPHGLFRVRUJ Questions A 38-year-old woman has a soft, mobile, painless lump in her anterior abdominal wall that has been unchanged for more than 10 years. Nevertheless, for vanity reasons, she elects to have it removed; the in situ gross appearance is shown. 1. What is your diagnosis? 2. What is the anticipated microscopic appearance? 3. If it recurs after resection, what should be suspected? ERRNVPHGLFRVRUJ Answers: Side B 1. This large irregular and invasive retroperitoneal mass ( ■) has a low-density attenuation with focal inhomogeneity that is suggestive of hemorrhage or necrosis. The location and appearance are worrisome for sarcoma . 2. Liposarcoma 3. It would be a malignant fibrous histiocytoma . Despite its name, it has a fibroblastic lineage. The more accepted terminology is now undifferentiated pleomorphic sarcoma. 4. Sarcomas tend to arise in deep soft tissues, where they can reach substantial size before detection and thus can be difficult to completely resect. More indolent sarcomas often recur; more aggressive sarcomas (as marked histologically by mitotic index and areas of necrosis) have a poor prognosis. ERRNVPHGLFRVRUJ 26.17 Side B (PBD9: 1224; BP9: 794) ERRNVPHGLFRVRUJ Questions A 61-year-old man has a 1-year history of constant gnawing abdominal pain. His abdominal CT scan is shown. 1. What kind of neoplasm is most likely? 2. What is the lesion if it contains lipoblasts? 3. What is the lesion if it has a storiform pattern of spindle cells? 4. What is the biologic behavior likely to be? ERRNVPHGLFRVRUJ Answers: Side A 1. This well-demarcated and uniformly yellow mass ( ♦) is a lipoma , which is one of the most common benign neoplasms; these can be found in virtually any location. 2. Most well-differentiated benign neoplasms are composed of cells that resemble the normal cell of origin. Lipomas are composed of mature adipocytes. 3. The original lesion may have been an “atypical” or pleomorphic lipoma or even a well-differentiated liposarcoma . ERRNVPHGLFRVRUJ 26.18 Side A (PBD9: 1189; BP9: 770) ERRNVPHGLFRVRUJ Questions A 77-year-old man with a 9-year history of increasing left shoulder, right hip, and lower back pain has a decreased range of motion but no warmth, tenderness, or deformity in these regions. His serum alkaline phosphatase level is increased. Radiography reveals densely sclerotic bone in these areas, which would appear histologically as shown. 1. What is your diagnosis? 2. Why is there joint pain? 3. What cardiovascular complication could occur? 4. What infectious agent is implicated? ERRNVPHGLFRVRUJ Answers: Side B 1. Osteosclerosis ( ■) along with osteolysis ( ♦) indicates the mixed phase of Paget disease of bone. In this case, it is the monostotic form. 2. The initial phase is osteolytic; this is followed by the mixed phase, and it ultimately evolves into the sclerotic (“burnt out”) phase. 3. One percent of all patients and 10% of patients with the polyostotic form can develop a sarcoma at an affected site. These are most frequently osteosarcomas . ERRNVPHGLFRVRUJ 26.18 Side B (PBD9: 1189; BP9: 770) ERRNVPHGLFRVRUJ Questions An 81-year-old man with a 12-year history of increasing knee pain develops microfractures and secondary osteoarthritis of the knee. His radiograph is shown. 1. What is your diagnosis? 2. What is the pathology of this disease? 3. What is the most serious long-term complication? ERRNVPHGLFRVRUJ Answers: Side A 1. The dense mosaic of bone with irregular cement lines ( ▴) seen with H&E stain, with lamellae running in all directions under polarized light ( ▸), is characteristic for Paget disease . In this case, it is the polyostotic form. 2. The Paget bone is expanded but weaker, and it leads to secondary osteoarthritis as a result of abnormal joint alignment. Pathologic fractures also occur. 3. Increased bone remodeling leads to increased vascularity and increased blood flow, thereby potentially causing high-output congestive heart failure. 4. Paramyxovirus infection has been suggested as an antecedent. ERRNVPHGLFRVRUJ 27 ERRNVPHGLFRVRUJ Peripheral Nerve and Skeletal Muscle ERRNVPHGLFRVRUJ 27.1 Side A (PBD9: 1231; BP9: 799) ERRNVPHGLFRVRUJ Questions A 50-year-old woman with a 2-year history of waxing and waning symmetric motor and sensory loss in her extremities undergoes a sural nerve biopsy with the microscopic appearance shown. 1. What is your diagnosis? 2. What would happen to denervated muscle? 3. Name an acute neuropathy with ascending paralysis. ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has Wallerian degeneration . The nerve distal to the injury has vacuoles ( ◂) that are filled with axonal and myelin fragments. 2. Recovery depends on the extent of nerve injury. Neurapraxia is conduction loss without axonal or myelin sheath damage; functional recovery occurs quickly (one's foot “falling asleep” is a simple example). Axonotmesis is axonal loss without damage to the nerve sheath; Wallerian degeneration occurs, but the regrowing axon has an intact path to follow. Neurotmesis is the disruption or transection of the entire nerve so that regrowth cannot occur unless the cut ends are carefully realigned. ERRNVPHGLFRVRUJ 27.1 Side B (PBD9: 1228; BP9: 797) ERRNVPHGLFRVRUJ Questions After a fracture of the fibular neck, a 25-year-old man has a loss of motor function to his foot extensors. The microscopic appearance of the common peroneal nerve distal to this site would appear as shown. 1. What is your diagnosis? 2. How can recovery occur? ERRNVPHGLFRVRUJ Answers: Side A 1. This is chronic inflammatory demyelinating polyneuropathy . There is recurrent demyelination and remyelination with an “onion bulb” appearance as a result of layering by Schwann cells ( ▴) in response to injury. 2. There would be denervation atrophy followed by type grouping with reenervation; subsequent reinjury would lead to group atrophy . 3. Guillain-Barré syndrome is an acute inflammatory neuropathy that often follows an influenza-like infection. ERRNVPHGLFRVRUJ 27.2 Side A (PBD9: 1242; BP9: 802) ERRNVPHGLFRVRUJ Questions A 6-year-old boy with progressive diffuse weakness can no longer rise from a sitting position unassisted. On examination, his calves are prominent. His serum creatine kinase level is 2270 U/L (nl ≤235 U/L). The microscopic appearance of his gastrocnemius biopsy specimen is shown. 1. What is your diagnosis? 2. What protein is absent? 3. What is the inheritance pattern? 4. What complications can be anticipated? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has Becker muscular dystrophy . Note the variations in the size of the muscle fibers and the markedly diminished dystrophin ( ◂). 2. This is a different mutation of the dystrophin gene than that seen with Duchenne muscular dystrophy; there is diminished (or dysfunctional) dystrophin, but it is not absent. The onset of the disease is delayed into adult life, and symptoms typically progress more slowly. Additional myopathic changes seen in striated muscle include the degeneration and regeneration of muscle fibers. ERRNVPHGLFRVRUJ 27.2 Side B (PBD9: 1242; BP9: 802) ERRNVPHGLFRVRUJ Questions A 33-year-old man has had increasing muscular weakness for 13 years. On examination, he has primarily proximal weakness with associated atrophy. His serum creatine kinase level is elevated. The microscopic appearance of his muscle biopsy specimen with immunohistochemical staining for dystrophin is shown. 1. What is your diagnosis? 2. Why did the weakness have its onset during adulthood? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has Duchenne muscular dystrophy. 2. Dystrophin is absent; it is responsible for linking sarcomeric contraction to the extracellular matrix. 3. This is an X-linked disorder ; one third to one half of cases represent new spontaneous mutations. Female carriers may exhibit mild weakness and some elevation in their creatine kinase levels; they also may develop dilated cardiomyopathy later in life. 4. Muscle with inflammation ( ♦) is progressively replaced by fat ( ◂) and fibrous connective tissue ( ▾). Death from progressive muscular weakness, which eventually affects the diaphragm and the myocardium, often occurs by age 20. ERRNVPHGLFRVRUJ 27.3 Side A (PBD9: 1243; BP9: 804) ERRNVPHGLFRVRUJ Questions A 40-year-old man with a 25-year history of difficulty ambulating has more recently developed hand weakness and marked atrophy of his facial and neck muscles. He has dilated cardiomyopathy and congestive heart failure. The microscopic appearance of his deltoid muscle biopsy specimen is shown. 1. What is your diagnosis? 2. What is the genetic basis of this patient's disease? 3. What other complications could he develop? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has myotonic dystrophy . Chains of central nuclei ( ◂) are seen in this longitudinal section, with fibrous replacement ( ♦) of the muscle fibers. 2. There is ongoing expansion of the CTG triple nucleotide repeats in successive generations. This is the result of a genetic process called anticipation . ERRNVPHGLFRVRUJ 27.3 Side B (PBD9: 1243; BP9: 804) ERRNVPHGLFRVRUJ Questions A 34-year-old man with a 25-year history of progressive muscle weakness involving the hands, arms, shoulder girdle, neck, and face has a persistently elevated serum creatine kinase level. The microscopic appearance of his deltoid muscle biopsy specimen is shown. 1. What is your diagnosis? 2. Why are individuals in his family affected at an earlier age and more severely in successive generations? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has myotonic dystrophy . There is variation in fiber size, with multiple central nuclei ( ▸). 2. There is a CTG triple nucleotide repeat expansion in the gene that encodes for dystrophia myotonica–protein kinase ( DMPK ) ; expanding numbers of triple repeats lead to diminished mRNA production and decreased protein. 3. Visual difficulty with cataracts occurs in nearly every case. Gonadal atrophy and frontal balding are frequent. Glucose intolerance occurs, and some patients develop dementia. ERRNVPHGLFRVRUJ 27.4 Side A (PBD9: 1245) ERRNVPHGLFRVRUJ Questions A 10-year-old girl with a history of exercise intolerance develops headaches and vomiting followed by a generalized tonic-clonic seizure and hemiplegia. Evaluation in the emergency department reveals elevated serum lactate and creatine kinase levels, and cerebral MRI shows areas of remote infarction. The girl's muscle biopsy specimen is shown. 1. What is your diagnosis? 2. What is the genetic basis of this disease? 3. What type of headache is commonly seen? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has mitochondrial myopathy. 2. The disorder has a maternal pattern of inheritance, because mtDNA is passed to offspring only via mitochondria provided by the ovum. All embryonic mitochondria are maternal in origin. 3. mtDNA has a higher mutation rate than nuclear DNA. ERRNVPHGLFRVRUJ 27.4 Side B (PBD9: 1245; BP9: 805) ERRNVPHGLFRVRUJ Questions A 3-year-old child with lifelong failure to thrive now presents with learning disabilities, hearing problems, external ophthalmoplegia, and weakness with hypotonia. The pedigree of other affected family members is shown. 1. What is your diagnosis? 2. Describe the inheritance pattern. 3. What is the mutation rate of mitochondrial DNA (mtDNA) as compared with nuclear DNA? ERRNVPHGLFRVRUJ Answers: Side A 1. This myopathy has features of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) . The histology is confirmatory, showing a ragged red fiber with subsarcolemmal aggregates ( ▸) of mitochondria. With electron microscopy, these often show characteristic paracrystalline “parking lot” inclusions in the cristae. 2. Typically, mutations in mitochondrial DNA (mtDNA) cause this condition. The mitochondrial genome is a small circular DNA strand that codes for 22 mitochondrialspecific tRNAs; 2 rRNA species; and many of the proteins involved in oxidative phosphorylation (20% of the mitochondrial oxidative phosphorylation proteins are coded by mtDNA). Mutations lead to inefficient ATP synthesis. 3. Migraine headache is common among these patients. ERRNVPHGLFRVRUJ 27.5 Side A (PBD9: 1239; BP9: 805) ERRNVPHGLFRVRUJ Questions A 41-year-old woman has had progressive proximal muscular weakness for 4 years. She now has difficulty climbing stairs or lifting objects. Her fine muscle movement and deep tendon reflexes are not affected. Her serum creatine kinase level is elevated, and her muscle biopsy specimen is shown. 1. What is your diagnosis? 2. What is the pathogenesis for this disease? 3. What autoantibody may be present? 4. What would a skin rash indicate? ERRNVPHGLFRVRUJ Answers: Side B 1. The patient has inclusion body myositis . Note the “rimmed vacuoles” ( ▾) within the muscle fibers. There is variation in fiber size and fibrous replacement ( ♦), which is typical for a myopathic disease. 2. Filamentous inclusions that contain amyloid and hyperphosphorylated tau proteins are seen. 3. Intracellular β-amyloid deposits, amyloid fibrils, and hyperphosphorylated tau suggest an aging phenomenon. Although CD8 + T cells are found in the lesions, the lack of response to immunosuppressive therapy suggests that this condition is not autoimmune in origin. Hereditary forms of this disease are also described. ERRNVPHGLFRVRUJ 27.5 Side B (PBD9: 1240; BP9: 805) ERRNVPHGLFRVRUJ Questions A 57-year-old woman presents with a 5-year history of progressive asymmetric muscular weakness involving distal muscle groups, including the knee extensors and the wrist flexors. Her trichrome-stained muscle biopsy specimen is shown. 1. What is your diagnosis? 2. What can be seen with electron microscopy? 3. What is the pathogenesis? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has polymyositis . There is marked lymphocytic infiltration ( ◂) with necrosis ( ♦) as well as the regeneration ( ▸) of muscle fibers. 2. With polymyositis, there are cytotoxic CD8 + T lymphocytes that can cause myocyte killing. 3. Anti-histidyl-t-RNA-synthetase (Jo1) may be present, in addition to antinuclear antibody. Although the anti-tRNA synthetase antibodies are specific, they do not have a clear-cut causal role in the disease. 4. Skin involvement with a violaceous rash suggests dermatomyositis . ERRNVPHGLFRVRUJ 28 ERRNVPHGLFRVRUJ The Central Nervous System ERRNVPHGLFRVRUJ 28.1 Side A (PBD9: 1287; BP9: 836) ERRNVPHGLFRVRUJ Questions A 77-year-old man with a 3-year history of progressive withdrawal and apathy is found on formal examination to have severe short-term memory loss. He is not oriented to place or time. Before further work-up can be performed, he commits suicide. The medical examiner finds the brain to be as shown. 1. What is the diagnosis? 2. What are the possible gene mutations associated with this pathology? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has Alzheimer disease . Diagnostic neuritic plaques ( ▴) (as a result of hyperphosphorylated tau protein) and numerous diffuse plaques ( ▸) (masses of amyloid beta-protein [Aβ] derived from amyloid precursor protein [APP]) are present. 2. This patient's findings suggest a major depressive disorder , but the onset was more insidious, and the loss of mental function was more severe. ERRNVPHGLFRVRUJ 28.1 Side B (PBD9: 1287; BP9: 836) ERRNVPHGLFRVRUJ Questions An 81-year-old woman has become progressively dependent on her daughter for routine activities of daily living for the past 5 years. She has no focal neurologic signs, but she cannot remember three objects after 5 minutes, and she cannot count backward from 100 by 7s. She is frequently depressed. She falls and sustains a hip fracture; subsequently, she dies of a pulmonary embolism. At autopsy, her neocortex exhibits the changes shown on silver stain. 1. What is your diagnosis? 2. What mood disorder is suggested by her history? ERRNVPHGLFRVRUJ Answers: Side A 1. The marked cortical atrophy with the relative sparing of the occipital lobe is consistent with Alzheimer disease (AD) . 2. Mutations in the APP gene (chromosome 21) increase the production of Aβ and are found in familial AD. Trisomy 21 (Down syndrome) is also associated with increased Aβ production. The E4 allele of apolipoprotein E (chromosome 19) increases Aβ and the risk for late-onset AD. Early-onset AD is associated with mutations in the presenilin 1 gene (chromosome 14) and the presenilin 2 gene (chromosome 1), which are involved in Aβ processing. ERRNVPHGLFRVRUJ 28.2 Side A (PBD9: 1292; BP9: 838) ERRNVPHGLFRVRUJ Questions A 63-year-old woman with a 3-year history of difficulty with activities of daily living becomes increasingly irritable and irresponsible, and she eventually develops speech difficulties. She dies of an aspiration pneumonia. Her brain at autopsy is shown. 1. What is your diagnosis? 2. Why did aspiration occur? 3. What neurodegenerative condition would involve a vertical gaze palsy and truncal rigidity? ERRNVPHGLFRVRUJ Answers: Side B 1. A characteristic but nondiagnostic radiographic feature of dementias is cortical atrophy, which is shown here as prominently involving the frontal ( ▸) and parietal ( ▴) regions. The clinical history and severity of the atrophy suggest a form of frontotemporal lobar degeneration known as Pick disease . 2. Tau filaments accumulate within Pick bodies ; the latter are round to oval inclusions found in residual neurons. ERRNVPHGLFRVRUJ 28.2 Side B (PBD9: 1292; BP9: 838) ERRNVPHGLFRVRUJ Questions A 73-year-old woman has a 2-year history of behavioral changes, worsening confusion, and speech pathology. Although she can name three objects after 5 minutes, she cannot draw a clock. Her MRI is shown. 1. What is your diagnosis? 2. What paired helical filaments are present in round cytoplasmic inclusions in patients with this disorder? ERRNVPHGLFRVRUJ Answers: Side A 1. The marked atrophy is primarily in a frontal lobe distribution ( ▸). The gross and clinical findings suggest a frontotemporal dementia such as Pick disease . 2. Any condition that reduces or alters consciousness, including any condition that reduces the gag reflex, increases the risk of aspiration pneumonia. 3. Progressive supranuclear palsy with neuronal loss in the globus pallidus, colliculi, and periaqueductal gray is present. In contrast with Pick disease, mutations in tau proteins have not been identified with this type of condition. ERRNVPHGLFRVRUJ 28.3 Side A (PBD9: 1261; BP9: 821) ERRNVPHGLFRVRUJ Questions A 16-year-old boy who was demonstrating motorcycle stunts while not wearing a helmet falls and strikes the left side of his head on the pavement. Within minutes, he develops a severe headache, vomits, and has a seizure. His head CT scan is shown. 1. What is your diagnosis? 2. What is the mechanism for this pathology? ERRNVPHGLFRVRUJ Answers: Side B 1. There is a large, dark, reddish-black, left-sided epidural hematoma ( ◂). 2. The patient had a “lucid” interval after his initial concussion. Less than 20% of patients with epidural hematoma exhibit a “lucid” interval after injury. 3. Unless the blood is expeditiously evacuated, the expanding hematoma within the closed intracranial cavity can cause herniation . ERRNVPHGLFRVRUJ 28.3 Side B (PBD9: 1261; BP9: 821) ERRNVPHGLFRVRUJ Questions A 65-year-old man falls off a ladder and strikes the left side of his head. He initially loses consciousness, but he then remains alert (albeit with a bad headache) for 2 hours, when he again becomes unconscious. At that time, his pulse is 55 beats/min, his respiratory rate is 10 breaths/min, and his blood pressure is 160/100 mm Hg. He develops papilledema on the right, and then he dies. His brain is shown in situ at autopsy. 1. Where is this hematoma located? 2. Explain this patient's clinical course. 3. What could cause his death? ERRNVPHGLFRVRUJ Answers: Side A 1. The large, lens-shaped ( ▪) epidural collection of blood on the left is bounded by parietal bone suture lines. 2. The middle meningeal artery can be torn in association with a skull trauma, with or without fracture. Arterial bleeding under pressure leads to the rapid onset of symptoms. ERRNVPHGLFRVRUJ 28.4 Side A (PBD9: 1283; BP9: 832) ERRNVPHGLFRVRUJ Questions A 27-year-old woman who presented with transient visual difficulty 1 year ago has since developed fatigue, difficulty concentrating, dizziness, right arm paresthesias, difficulty with urination, loss of bowel control, and dysarthria. Her brain MRI is shown. 1. What is your diagnosis? 2. Explain the pathophysiology. 3. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side B 1. This is multiple sclerosis (MS) . Plaques of demyelination ( ▪) appear as pale tan to gray areas as compared with normal white matter ( ♦). This is putatively an autoimmune disorder that involves cellular immunity directed against the oligodendroglial cells responsible for synthesizing myelin. 2. The CSF findings are typical for MS . The oligoclonal antibodies reflect increased B-cell proliferation, but these immunoglobulins are directed against multiple epitopes rather than myelin or other oligodendroglial antigens. ERRNVPHGLFRVRUJ 28.4 Side B (PBD9: 1283; BP9: 832) ERRNVPHGLFRVRUJ Questions A 22-year-old man with ataxia, diplopia on lateral gaze, and flashes of light on eye movement has a cerebrospinal fluid (CSF) protein level of 69 mg/dL (nl 20 to 45 mg/dL), with 14 WBCs/mm (all mononuclear) and an increased CSF IgG level with oligoclonal bands. His glucose level is normal. Gross brain lesions typical for his disease are shown. 3 1. What is your diagnosis? 2. What do the laboratory findings represent? ERRNVPHGLFRVRUJ Answers: Side A 1. Note the bright areas ( ▸) within the white matter. These are typical of the demyelinating lesions of multiple sclerosis . 2. The patient's visual changes may be due to optic neuritis. Her newer symptoms are attributable to transverse myelitis (bladder and bowel dysfunction). Motor tract involvement can cause weakness or spasticity. Cerebellar findings (ataxia), intranuclear ophthalmoplegia, and sensory paresthesias are also common. 3. Most patients have a relapsing-remitting course with acute exacerbations followed by partial to full remissions; one third of patients have complete recovery within 2 months of onset. ERRNVPHGLFRVRUJ 28.5 Side A (PBD9: 1306; BP9: 842) ERRNVPHGLFRVRUJ Questions A 47-year-old man with a 3-month history of worsening headaches has a seizure. His initial MRI is shown, after which he undergoes surgical debulking followed by radiation and chemotherapy. 1. What is your diagnosis? 2. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has a glioblastoma . This is a highly cellular neoplasm with vascular proliferation ( ▴) and densely packed malignant cells arranged around areas of necrosis ( ♦) (pseudopalisading). 2. Glioblastomas can arise from low-grade astrocytomas that acquire inactivating mutations of p53, the overexpression of PDGF-A, or both. Primary glioblastomas tend to have mutations in PTEN, p16 deletion, and MDM2 overexpression. 3. The high CSF protein and normal glucose levels in this case are consistent with neoplasia. The few mononuclear cells may be reactive. ERRNVPHGLFRVRUJ 28.5 Side B (PBD9: 1306; BP9: 842) ERRNVPHGLFRVRUJ Questions A 53-year-old woman has a grand mal seizure. Her CSF values reveal a total protein value of 117 mg/dL (nl 20 to 45 mg/dL), normal glucose levels, and 3 WBCs/µL (all mononuclear; upper limit of normal), with no organisms seen with Gram staining. A large right cerebral mass is resected and has the microscopic appearance shown. 1. What is your diagnosis? 2. What genetic alterations can be present? 3. Explain the CSF findings. ERRNVPHGLFRVRUJ Answers: Side A 1. This is almost certainly a glioblastoma . The large right cerebral mass ( ▪) infiltrates across the midline and impinges on the cerebral ventricles. Glioblastoma is the most aggressive of the gliomas; it can infiltrate widely and seed through the CSF. 2. Because it is difficult to eradicate such large neoplasms surgically, most patients survive less than 1 year. ERRNVPHGLFRVRUJ 28.6 Side A (PBD9: 1314; BP9: 846) ERRNVPHGLFRVRUJ Questions A 38-year-old woman has a 1-year history of increasingly frequent headaches that crescendo with her menstrual cycle. The headaches are now worsening with her recent pregnancy. Her MRI is shown. 1. What is your diagnosis? 2. Explain the effect of pregnancy. ERRNVPHGLFRVRUJ Answers: Side B 1. This meningioma is composed of whorled nests ( ▪) of cells with abundant pink cytoplasm ( psammoma bodies may also be seen in this kind of neoplasm). Common locations are subfrontal and parasagittal. 2. Neurofibromatosis type 2 would be suspected. The most common genetic abnormality in meningiomas is the deletion of 22q12, where the NF2 gene is located. 3. This patient has an anxiety disorder as a result of a general medical condition. ERRNVPHGLFRVRUJ 28.6 Side B (PBD9: 1314; BP9: 846) ERRNVPHGLFRVRUJ Questions A 45-year-old woman with a 6-month history of worsening headaches develops new unilateral anosmia. She has also developed obsessive anxiety about her health and her children, and she is calling the school that they attend several times per day. A left subfrontal 5-cm mass is resected and has the microscopic appearance shown. 1. What is your diagnosis? 2. If she had other similar lesions and an acoustic neuroma, what syndrome would you suspect? 3. What is her behavioral disorder? ERRNVPHGLFRVRUJ Answers: Side A 1. There is a circumscribed mass ( ◂) in the parasagittal region that is impinging on the frontal lobe; this is consistent with meningioma . 2. Meningiomas often express progesterone receptors , so their growth is stimulated during menstrual cycles or pregnancy. Most are benign lesions; approximately 10% are atypical (having more aggressive growth) or frankly malignant. ERRNVPHGLFRVRUJ 28.7 Side A (PBD9: 1281; BP9: 831) ERRNVPHGLFRVRUJ Questions A 63-year-old man has had a rapidly progressive decline in mental function over the past 5 weeks. He has clumsiness when walking or eating. Neurologic examination shows impairment of his attention span, verbal and nonverbal memory, spatial skills, and judgment. The microscopic appearance of his neocortex is shown. 1. What is the diagnosis? 2. What is the pathophysiology of this disease? ERRNVPHGLFRVRUJ Answers: Side B 1. His EEG shows high-voltage slow (1 to 2 Hz) and sharp wave complexes ( ▴) on an increasingly slow and low-voltage background. 2. Sporadic Creutzfeldt-Jakob disease has an incidence of 1 in 1 million, with a mean age at onset of 62 years and survival of less than 1 year. The rarer variant CreutzfeldtJakob disease is presumed to be related to bovine spongiform encephalopathy, which has a mean age at onset of 28 years and a longer course. ERRNVPHGLFRVRUJ 28.7 Side B (PBD9: 1281; BP9: 831) ERRNVPHGLFRVRUJ Questions A 66-year-old previously healthy man has dementia that has been worsening for the past 3 months. He is no longer able to perform any activities of daily living, and he exhibits myoclonic jerks of his entire body whenever anyone touches him. His EEG is shown. 1. Describe this EEG. 2. How common is this disease? ERRNVPHGLFRVRUJ Answers: Side A 1. This is spongiform encephalopathy with numerous clear vacuolar spaces ( ▪) in the neocortex, which is consistent with Creutzfeldt-Jakob disease. 2. Creutzfeldt-Jakob disease is a prion disease. Prion protein (PrP) coded by the PRNP gene is present in many cells of the body, but it is expressed at the highest levels in neocortical neurons. Exposure to an abnormal variant PrP known as PrP (or PrP for its proteinase resistance), similar to an infectious disease, results in a conformational change of normal PrP that can accumulate in the CNS of affected individuals. The accumulated abnormal protein drives the loss of neuronal cell function, vacuolization, and death, thereby leading to the extensive and rapid destruction of the brain. SC ERRNVPHGLFRVRUJ res 28.8 Side A (PBD9: 1268; BP9: 817) ERRNVPHGLFRVRUJ Questions A 77-year-old man with medical history significant only for poorly controlled hypertension develops a sudden and severe headache followed by obtundation. His head CT scan is shown. 1. What is your diagnosis? 2. Explain the pathophysiology. 3. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side B 1. In the United States, 20% of strokes are intracerebral hemorrhages ; most of these result from hypertension , and most occur in the basal ganglia and the thalamus ( ▪). Intracerebral hemorrhage accounts for approximately 15% of mortality in patients with chronic hypertension. 2. Complications include edema, ischemia, and infarction. A large hemorrhage can cause obstructive hydrocephalus by compressing the foramen of Monro, the third ventricle, or the aqueduct of Sylvius. The extension of hemorrhage into the ventricles can cause hydrocephalus. ERRNVPHGLFRVRUJ 28.8 Side B (PBD9: 1268; BP9: 817) ERRNVPHGLFRVRUJ Questions A 55-year-old man with lifelong hypertension has a sudden loss of consciousness. His CSF has normal protein and glucose levels, but it also has 860 RBCs/mm (normally there are none). He develops bilateral “blown” pupils and becomes unresponsive, dying within 1 hour. The gross appearance of his brain at autopsy is shown. 3 1. Give the likely cause of his condition. 2. What are possible complications of hypertension-associated hemorrhage? ERRNVPHGLFRVRUJ Answers: Side A 1. The bright attenuation is in the right basal ganglia ( ▪); this is consistent with hypertensive hemorrhage . 2. With chronic hypertension, smaller penetrating cerebral arteries undergo hyaline arteriosclerosis and subintimal fibroblast proliferation, ultimately leading to wall weakening; focal Charcot-Bouchard microaneurysms can also occur. Severe hypertension can also result in frank arteriolar necrosis. All of these changes make the vessels prone to rupture and bleeding. 3. The prognosis for hemorrhages in the basal ganglia, thalamus, and brainstem is poor. The surgical evacuation of cerebellar lesions can result in a better outcome. ERRNVPHGLFRVRUJ 28.9 Side A (PBD9: 1269; BP9: 818) ERRNVPHGLFRVRUJ Questions A 24-year-old man with no significant medical history has a sudden, new-onset grand mal seizure. During a subsequent work-up, he is normotensive. The angiogram of his left internal carotid artery is shown. 1. What is your diagnosis? 2. Explain the pathophysiology of this disease. ERRNVPHGLFRVRUJ Answers: Side B 1. There is a focus of abnormal ectatic venous channels ( ▪) with intervening gliotic tissue ( ♦); this is consistent with an arteriovenous malformation . Other vascular malformations include cavernous hemangiomas , which lack intervening nervous tissue, and capillary telangiectasias , which have ectatic thin-walled vessels with interspersed neural tissue. 2. This vascular malformation results in hemorrhage into the brain parenchyma, which causes a seizure disorder, or into the subarachnoid space, which leads to erythrocytes in the CSF. ERRNVPHGLFRVRUJ 28.9 Side B (PBD9: 1269; BP9: 818) ERRNVPHGLFRVRUJ Questions A 17-year-old boy with a 7-month history of headaches has CSF with normal protein and glucose levels but with 775 RBCs/mm (normally there are none). A head CT scan shows left superior subarachnoid hemorrhage that extends from an underlying left cerebral hemispheric lesion. He is treated via the endovascular injection of acrylic material to thrombose the lesion. A representative microscopic appearance of what his brain lesion could look like is shown. 3 1. What is your diagnosis? 2. What is the likely cause of this condition? ERRNVPHGLFRVRUJ Answers: Side A 1. There is a focal area that consists of irregular vascular channels ( ▸), which is consistent with a vascular malformation . The most common site of this condition is the territory of the middle cerebral artery. Men are affected twice as frequently as women. 2. The abnormal vasculature associated with this malformation has a tendency to bleed within the brain or to extend into the subarachnoid space. ERRNVPHGLFRVRUJ 28.10 Side A (PBD9: 1268; BP9: 817) ERRNVPHGLFRVRUJ Questions A 47-year-old previously healthy woman with a sudden severe headache has the vertebral artery angiogram shown. 1. What is your diagnosis? 2. How does this lesion form? 3. How common is this disease? ERRNVPHGLFRVRUJ Answers: Side B 1. There is extensive subarachnoid hemorrhage ( ▪), particularly at the base of the brain in the vicinity of the circle of Willis and tracking up over the left convexity ( ♦). 2. It is likely that bleeding has occurred as a result of the rupture of a saccular (berry) aneurysm. Most of these occur in the circle of Willis and bleed at a rate of about 1.3% per year. Aneurysms that are 10 mm or larger in size have a 50% annual risk of bleeding. 3. Patients with autosomal-dominant polycystic kidney disease (ADPKD) have a greatly increased risk for berry aneurysms. ERRNVPHGLFRVRUJ 28.10 Side B (PBD9: 1268; BP9: 817) ERRNVPHGLFRVRUJ Questions A 48-year-old woman experiences the “worst headache” of her life before suddenly losing consciousness and dying. The gross appearance of her brain at autopsy is shown. 1. What is shown here? 2. What likely happened? 3. What might you think about if the clinical history also included adult-onset renal failure? ERRNVPHGLFRVRUJ Answers: Side A 1. Note a large saccular (berry) aneurysm ( ▴) at the branching of the basilar artery into the posterior cerebral arteries. 2. The cause of this condition is unknown, and most occur sporadically. Although these are considered congenital, most are not present at birth; rather, they develop with time as a result of focal vascular wall weakness. Adult polycystic kidney disease, EhlersDanlos syndrome, Marfan syndrome, neurofibromatosis, aortic coarctation, and fibromuscular dysplasia are associated conditions. 3. Berry aneurysms (ruptured or not) are found in 2% of autopsies. ERRNVPHGLFRVRUJ 28.11 Side A (PBD9: 1261; BP9: 821) ERRNVPHGLFRVRUJ Questions A 63-year-old woman slips on a loose area rug and falls, striking the back of her head; she does not lose consciousness. She has no subsequent neurologic problems other than right-sided anosmia. Many years later, she dies of unrelated causes; her brain at autopsy is shown. 1. What is your diagnosis? 2. How could her fall have led to this result? ERRNVPHGLFRVRUJ Answers: Side B 1. Note a posterior occipital skull fracture ( ▴) with soft-tissue swelling ( ♦) at the occiput as a result of blunt force trauma. 2. He fell backward. 3. The moving skull striking an object transmits the force to the opposite side, which results in a contrecoup injury such as subfrontal or temporal tip contusions. The contusions can also bleed into the subarachnoid space. 4. Falls in older individuals who have cerebral atrophy are more prone to the tearing of cerebral veins and subsequent subdural hematoma from the venous bleeding. ERRNVPHGLFRVRUJ 28.11 Side B (PBD9: 1261; BP9: 821) ERRNVPHGLFRVRUJ Questions A 92-year-old man slips in the bathtub and falls. He develops a worsening headache. A head CT scan is performed and shown here; the bone window setting is shown, which makes all soft-tissue density appear gray. 1. What is your diagnosis? 2. In which direction did he fall? 3. What complication can develop on the opposite side of his head? 4. If he develops mental status changes 3 weeks later, what complication should be suspected? ERRNVPHGLFRVRUJ Answers: Side A 1. The depressed right subfrontal lobe area with brown discoloration ( ▪) represents a remote contusion . The right olfactory bulb (compare with the left bulb [ ♦]) is absent from the trauma. 2. When the patient fell backward, her moving skull struck the floor and transmitted the force anteriorly ( contrecoup injury ). ERRNVPHGLFRVRUJ 28.12 Side A (PBD9: 1261; BP9: 821) ERRNVPHGLFRVRUJ Questions After bumping her head against a cabinet door 1 month earlier, an 82-year-old woman has become more irritable and confused, with new-onset headaches. Her head CT scan is shown. 1. What is your diagnosis? 2. Why is there a 1-month delay in symptom onset? ERRNVPHGLFRVRUJ Answers: Side B 1. Blood has collected beneath the dura and over the left cerebral hemisphere. The pale tan to green region ( ▪) suggests prior injury and resolution, whereas the dark red region ( ♦) suggests more recent hemorrhage. 2. This subdural hematoma likely represents bleeding from traumatized and torn cerebral veins. 3. Blood collecting in the cranial cavity increases pressure and leads to medial temporal lobe herniation against the third nerve near the midbrain. 4. Duret hemorrhages can develop in the midbrain and pons as a result of medial temporal lobe herniation. ERRNVPHGLFRVRUJ 28.12 Side B (PBD9: 1261; BP9: 821) ERRNVPHGLFRVRUJ Questions A 59-year-old man falls outside of his favorite tavern (where he has fallen more than once before on his wobbly way home). Despite a headache and confusion, he violently refuses any assistance. He collapses and dies. His brain is shown at autopsy. 1. Describe the findings shown. 2. How does this condition develop? 3. Why might he develop a cranial nerve III palsy? 4. What lesion could develop in his midbrain? ERRNVPHGLFRVRUJ Answers: Side A 1. This is a chronic subdural hematoma . There is fluid collection ( ▪) beneath the dura on the right, with compression of the underlying cerebral hemisphere and left shift to efface ( ♦) the lateral ventricles on the right. The hemorrhage crosses the cranial sutures, so this cannot be an epidural hematoma. 2. After trauma—especially when there is some cerebral atrophy and the vessels are less well tethered—there can be slight tearing and slow blood collection; symptoms can develop over the course of days to weeks. ERRNVPHGLFRVRUJ 28.13 Side A (PBD9: 1300; BP9: 841) ERRNVPHGLFRVRUJ Questions A 51-year-old man with a 1-year history of increasing hand and forearm weakness and clumsiness develops dysarthria and dysphagia. He dies as a result of an acute aspiration event. Two levels of his spinal cord are shown, with the corticospinal tracts (◂) being lighter in appearance. 1. What is your diagnosis? 2. What is the pathologic mechanism for these findings? 3. What is the course of this disease? ERRNVPHGLFRVRUJ Answers: Side B 1. This is amyotrophic lateral sclerosis (ALS) . The ventral nerve roots ( ▸) in the patient are quite thin as compared with normal. 2. A loss of anterior horn cells would be present in the cord. 3. The diagnosis of ALS was initially withheld from baseball player Lou Gehrig in 1939, which is an example of “paternalism” in medicine. He died 2 years later. Astrophysicist Stephen Hawking also has ALS, but he has survived for more than three decades with it. ERRNVPHGLFRVRUJ 28.13 Side B (PBD9: 1300; BP9: 841) ERRNVPHGLFRVRUJ Questions A 48-year-old woman who is too weak to climb a flight of stairs reports bilateral leg spasticity. On examination, her thigh and leg muscles are atrophic, and a biopsy specimen shows muscle fiber group atrophy. Her spinal cord would appear as shown on the right (▸); a normal cord is shown on the left. 1. What is your diagnosis? 2. What would microscopy of the spinal cord show? 3. A famous person—for whom this disease is named—was never given his diagnosis by his neurologist, even after his consecutive game streak of 2130 was broken by this disease. For 10 points, what is his name? What other high-profile individual has this disease (and has continued his work despite it)? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient had amyotrophic lateral sclerosis ( ALS ). 2. There is a loss of upper motor neurons in the motor cortex and the cranial nerve nuclei and a loss of anterior horn cells in the spinal cord. The result is progressive motor weakness. 3. The neuronal loss is inexorable, with death within 2 years occurring in most cases. Death may occur more quickly if bulbar signs are present, as they are in this man. ERRNVPHGLFRVRUJ 28.14 Side A (PBD9: 1263; BP9: 814) ERRNVPHGLFRVRUJ Questions A 66-year-old woman with rheumatic heart disease develops sudden left lower leg paralysis. This is followed in short order by a loss of consciousness and death. Her brain is shown at autopsy. 1. What is your diagnosis? 2. What is the pathologic mechanism? 3. What microscopic process is present? 4. Had this patient lived, would function be recovered? ERRNVPHGLFRVRUJ Answers: Side B 1. A loss of distinction between the gray and white matter along with signal attenuation consistent with edema ( ▪) is the result of a massive stroke : a CNS infarction . 2. Patients with diabetes mellitus can have advanced atherosclerosis involving the cerebral arteries, which leads to occlusion with ischemia, or they may have thromboembolism with infarction caused by unstable plaque. Coronary artery atherosclerosis can lead to myocardial infarction that is complicated by ventricular mural thrombosis; subsequent embolization causes infarction that can become hemorrhagic as the embolus fragments and the blood flow is restored into necrotic tissue. ERRNVPHGLFRVRUJ 28.14 Side B (PBD9: 1263; BP9: 814) ERRNVPHGLFRVRUJ Questions A 58-year-old man with diabetes mellitus has a sudden loss of consciousness and remains in a persistent vegetative state. His CT scan is shown. 1. What is your diagnosis? 2. How could diabetes mellitus contribute to this? ERRNVPHGLFRVRUJ Answers: Side A 1. The area of reddish, glistening parietal lobe is a cerebral infarct ( ▴). 2. This stroke can be ischemic, secondary to cerebral artery thrombosis, or can result from embolus of a cardiac mural thrombus (e.g., in a patient with a dilated left atrium caused by rheumatic mitral valve stenosis). 3. There is liquefactive necrosis . As macrophages clear the debris, the lesion becomes cystic. 4. Some function can be recovered as the brain “rewires” itself, but such plasticity declines with aging. ERRNVPHGLFRVRUJ 28.15 Side A (PBD9: 1294; BP9: 839) ERRNVPHGLFRVRUJ Questions A 44-year-old man has a 2-year history of increasing difficulty initiating movement. At rest, he has a hand tremor that ceases when he is making a purposeful motion. His midbrain (and specifically his substantia nigra) would appear as shown in the upper panel as compared with normal midbrain as shown in the lower panel. 1. What is your diagnosis? 2. What pharmacologic therapy can be used? 3. What gene alterations may be present? ERRNVPHGLFRVRUJ Answers: Side B 1. Pink Lewy bodies ( ▸) in the substantia nigra and the neocortex are seen in dementia with Lewy bodies (DLB) . These are composed of aggregated α-synuclein (admixed with other proteins), an abundant lipid-binding protein that is associated with the synapses. 2. Parkinson-like features are often present in patients with DLB. Varying levels of attention, greater visuospatial impairment, and hallucinations are more characteristic for DLB than other dementias. Otherwise, DLB often seems similar to Alzheimer disease. ERRNVPHGLFRVRUJ 28.15 Side B (PBD9: 1294; BP9: 839) ERRNVPHGLFRVRUJ Questions A 69-year-old woman with recent progressive decline in carrying out activities of daily living frequently sits motionless and staring into space; she also has frank visual hallucinations. She has difficulty initiating movement, and she exhibits muscular rigidity and resting tremor of her left hand. Her neocortex is shown (immunohistochemical staining for α-synuclein is shown in the lower panel ). 1. What is your diagnosis? 2. What is her movement disorder? ERRNVPHGLFRVRUJ Answers: Side A 1. This patient has Parkinson disease (PD) with a loss of pigmented neurons in the substantia nigra. 2. L-dopa (L-dihydroxyphenylalanine) is the immediate precursor to dopamine, and it has the advantage of passing across the blood-brain barrier. It transiently increases local CNS dopamine levels. 3. Such an early onset suggests a familial form of PD. There may be Parkin mutations in the α-synuclein gene ; Parkin mutations tend not to form Lewy bodies. Sporadic PD in older individuals is not typically associated with such mutations. ERRNVPHGLFRVRUJ 28.16 Side A (PBD9: 1278; BP9: 828) ERRNVPHGLFRVRUJ Questions A 39-year-old man with AIDS and a CD4+ lymphocyte count of 80/mm (nl 490 to 1740/mm ) has a 1-month history of headaches with right arm weakness, speech difficulties, cognitive changes, and a gait disorder. He dies of Pneumocystis pneumonia. His brain is shown at autopsy. 3 3 1. What is your diagnosis? 2. What is the likely cause? ERRNVPHGLFRVRUJ Answers: Side B 1. The hyperintense area ( ▪) that involves the white matter in the left frontoparietal region spares the gray matter. This is typical of progressive multifocal leukoencephalopathy . 2. Microscopic features would include demyelination, with enlarged nuclei of oligodendrocytes, scattered microglial cells, and bizarre astrocytes. 3. Immunosuppression with a loss of cell-mediated immunity allows for the reactivation of prior JC polyomavirus infection, which is evident serologically in about 90% of normal young adults. ERRNVPHGLFRVRUJ 28.16 Side B (PBD9: 1278; BP9: 828) ERRNVPHGLFRVRUJ Questions A 40-year-old woman who underwent chemotherapy for breast cancer develops visual disturbances with diplopia, cognitive changes, and new-onset seizures. Her brain MRI is shown. 1. What is your diagnosis? 2. What would you expect to see microscopically? 3. What is the pathophysiology of this disease? ERRNVPHGLFRVRUJ Answers: Side A 1. This is progressive multifocal leukoencephalopathy . Note the granularity ( ▪) that primarily involves the white matter. 2. This is likely the result of JC polyomavirus , an opportunistic infection that preferentially causes a lytic infection of oligodendrocytes, which leads to CNS demyelination. Pneumocystis jiroveci infection is typically seen in immunocompromised hosts. ERRNVPHGLFRVRUJ 28.17 Side A (PBD9: 1310; BP9: 844) ERRNVPHGLFRVRUJ Questions A 4-year-old child with a 2-month history of unremitting headaches, lethargy, nausea, and vomiting has an MRI showing marked ventricular enlargement above the fourth ventricle. Before any intervention can be undertaken, the child has an unwitnessed aspiration event and dies. His posterior fossa contents are shown. 1. From where is this mass likely arising? 2. What is the diagnosis? 3. Explain the symptoms. 4. What underlying syndrome may be present? ERRNVPHGLFRVRUJ Answers: Side B 1. There is an enhancing, lobulated mass ( ▪) in the region of L4–S2. 2. This is likely an ependymoma . 3. Most ependymomas in the cauda equina region have a myxopapillary pattern microscopically. 4. Ependymomas can seed into the CSF. 5. Spinal ependymomas often involve an NF2 gene mutation. ERRNVPHGLFRVRUJ 28.17 Side B (PBD9: 1310; BP9: 844) ERRNVPHGLFRVRUJ Questions A 28-year-old woman with a 3-month history of worsening low back pain and leg weakness has objective muscle atrophy and fasciculations, with sensory loss in the perianal region. Her spine MRI is shown. 1. Where is this lesion located? 2. What is your diagnosis? 3. What do you expect to see microscopically? 4. What could be seen in the CSF? 5. Name an associated gene mutation. ERRNVPHGLFRVRUJ Answers: Side A 1. This circumscribed mass ( ▪) is within the fourth ventricle, and it is arising from the ependymal cells that line the ventricle. 2. This is an ependymoma . This location in the fourth ventricle is common when the tumor arises during the first two decades of life. 3. This patient has obstructive hydrocephalus. 4. This patient likely has neurofibromatosis type 2 ; mutations in the NF2 gene on chromosome 22 seem to be associated only with cord ependymomas. ERRNVPHGLFRVRUJ 28.18 Side A (PBD9: 1312; BP9: 844) ERRNVPHGLFRVRUJ Questions A 5-year-old child presents with a wide-based gait and truncal ataxia. MRI reveals third and lateral ventricular enlargement, along with the lesion shown. 1. What is your diagnosis? 2. Explain the symptoms. 3. What do you expect to see microscopically? 4. What is the prognosis? ERRNVPHGLFRVRUJ Answers: Side B 1. This is a pilocytic astrocytoma . The cerebellar mass ( ◂) is well circumscribed and mostly cystic, with a mural nodule ( ▴) that contains most of the tumor cells. 2. Tumor cells are bipolar, with long, thin, glial fibrillary acidic protein (GFAP)– positive processes. Rosenthal fibers (long, thick, eosinophilic structures that are typical of sites with reactive gliosis) are also characteristically present. 3. Most of these tumors are slow growing, noninfiltrative, and amenable to surgical resection, with a good prognosis. 4. Inhibiting the BRAF signaling pathway may be useful, particularly for lesions in unresectable locations. ERRNVPHGLFRVRUJ 28.18 Side B (PBD9: 1309; BP9: 842) ERRNVPHGLFRVRUJ Questions A 7-year-old girl develops worsening headache, nausea, vomiting, and a gait abnormality. Her brain would appear as shown. 1. What is your diagnosis? 2. What do you expect to see microscopically? 3. What is the prognosis? 4. Biotherapy that targets what signaling pathway may be useful? ERRNVPHGLFRVRUJ Answers: Side A 1. This is a medulloblastoma ; the circumscribed but irregular mass ( ▸) is within the midline of the cerebellum, above the fourth ventricle. Medulloblastomas account for 20% of childhood brain tumors. 2. The patient has obstructive hydrocephalus ; tumor cells can also seed into the CSF. 3. This is one of the “small round blue cell” tumors of childhood. The highly cellular mass has poorly differentiated cells, which sometimes form Homer-Wright rosettes . 4. The tumor is highly malignant but also highly radiosensitive. With complete surgical resection and radiotherapy, 5-year survival approaches 75%. ERRNVPHGLFRVRUJ 28.19 Side A (PBD9: 1313; BP9: 845) ERRNVPHGLFRVRUJ Questions A 41-year-old man with AIDS and a CD4+ count of 66/mm (nl 490 to 1740/mm ) has a 6-week history of lethargy and confusion. He develops a severe headache and then has a seizure. A stereotaxic biopsy specimen of the mass shown on MRI reveals large cells with scant cytoplasm expressing CD20. 3 1. What is your diagnosis? 2. What viral genome is likely present? ERRNVPHGLFRVRUJ 3 Answers: Side B 1. Multiple masses with neuroendocrine markers suggest metastases from a lung primary small-cell carcinoma . The anterior masses ( ▸) are near the cerebral gray-white junction; the posterior mass ( ▴) impinges on the corpus callosum. 2. Half of brain metastases originate from a lung primary. Other primary tumors (near the top of a long list) that metastasize to the CNS include breast and kidney carcinomas as well as melanoma (which is often widely metastatic). ERRNVPHGLFRVRUJ 28.19 Side B (PBD9: 1315; BP9: 846) ERRNVPHGLFRVRUJ Questions A 67-year-old male smoker becomes irritable and emotionally labile, with headaches and nausea. His brain MRI is shown, and a stereotaxic biopsy specimen of a left frontal mass shows small dark cells with scant cytoplasm that stains for neuroendocrine markers. 1. What is your diagnosis? 2. What are the probable sources of these lesions? ERRNVPHGLFRVRUJ Answers: Side A 1. Based on the location and the history, this is likely to be a primary non-Hodgkin lymphoma ; most are large B-cell lymphomas. The enhancing periventricular mass ( ▴) has adjacent darker regions that are consistent with edema. 2. Virtually all primary CNS lymphomas (with or without AIDS) are associated with Epstein-Barr virus (EBV) infection. ERRNVPHGLFRVRUJ 28.20 Side A (PBD9: 1254; BP9: 812) ERRNVPHGLFRVRUJ Questions A healthy infant left with a caregiver is unresponsive when the parents return; the caregiver asserts, “I only accidentally dropped the baby.” On physical examination, there are retinal hemorrhages and soft-tissue contusions on both arms. The infant's head CT scan is shown. 1. What are the CT findings? 2. What is likely to have happened? 3. If the infant dies, what is the manner of death? ERRNVPHGLFRVRUJ Answers: Side B 1. The Purkinje cells ( ▪) between the granular ( ♦) and molecular ( •) layers are necrotic. Neurons are the CNS cells that are most vulnerable to injury. 2. The patient had global cerebral ischemia as a consequence of his cardiac arrest, with markedly reduced cardiac output. About 15% of the resting cardiac output and about 20% of the total oxygen consumption go to support the CNS. 3. Widespread neuronal death leads to “brain death,” with a loss of EEG activity, a loss of spontaneous respiration, a loss of reflexes, and absent cerebral perfusion. ERRNVPHGLFRVRUJ 28.20 Side B (PBD9: 1263; BP9: 814) ERRNVPHGLFRVRUJ Questions A 70-year-old man with ischemic heart disease has a sudden cardiac arrest; 10 minutes elapse before a cardiac rhythm can be reestablished. He does not regain consciousness. His EEG is isoelectric, and he is allowed to die quietly. The microscopic appearance of his cerebellum is shown. 1. What major cell in this tissue has been injured? 2. How did this happen? 3. Is this “brain death”? ERRNVPHGLFRVRUJ Answers: Side A 1. There is diffuse low attenuation that is characteristic of diffuse cerebral edema. The bright areas ( ▸) represent hemorrhage in the subarachnoid space. The lateral ventricles are effaced. 2. These findings result from the violent shaking seen with “ shaken baby syndrome ”; there can be extensive intracranial damage with subarachnoid and subdural bleeding as well as cerebral damage and edema. 3. The manner of death would be homicide . ERRNVPHGLFRVRUJ 28.21 Side A (PBD9: 1316; BP9: 847) ERRNVPHGLFRVRUJ Questions A 13-year-old girl has a history of seizures. She has cutaneous shagreen patches, a subungual fibroma, and retinal glial hamartomas. A characteristic CNS lesion for this syndrome is shown. 1. What is your diagnosis? 2. What is the genetic basis for this syndrome? 3. What lesion may this patient have in her heart? 4. What renal lesions might she develop? ERRNVPHGLFRVRUJ Answers: Side B 1. The von Hippel–Lindau ( VHL ) gene acts as a tumor suppressor. It regulates the expression of vascular endothelial growth factor (VEGF) through hypoxia-inducible factor-1. 2. VHL syndrome is associated with several neoplasms; capillary hemangioblastomas ( ▪) are common in the CNS. These hemangioblastomas can also secrete erythropoietin and cause polycythemia (hence the patient's florid facies and elevated hematocrit level). 3. Pheochromocytoma and renal cell carcinoma ERRNVPHGLFRVRUJ 28.21 Side B (PBD9: 1316; BP9: 847) ERRNVPHGLFRVRUJ Questions A 20-year-old man is plethoric, with a hemoglobin level of 21 g/dL (nl 13.8 to 17.2 g/dL). He is hypertensive, and he has elevated urinary catecholamine levels. An abdominal CT scan reveals adrenal and renal masses with hepatic cysts. MRI reveals cerebellar and cervical spinal cord lesions. The gross and microscopic appearances of a characteristic spinal cord lesion from a similar patient are shown. 1. What gene has mutated? 2. What is the cord lesion? 3. What are the patient's adrenal and renal lesions likely to be? ERRNVPHGLFRVRUJ Answers: Side A 1. This is a cortical “tuber” or hamartoma ( ▪) found in a patient with tuberous sclerosis . 2. The most commonly mutated gene is TSC2, which encodes for the tuberin protein; this protein may have GTPase-activating activity. The less common TSC1 gene mutation affects the protein hamartin , which does not have a known function. Together, both proteins are suggested to regulate cellular proliferation. 3. Cardiac rhabdomyoma 4. Renal angiomyolipomas ERRNVPHGLFRVRUJ 28.22 Side A (PBD9: 1297; BP9: 840) ERRNVPHGLFRVRUJ Questions A 44-year-old man with a 1-year history of worsening jerky, hyperkinetic (choreoathetoid) movements of all limbs subsequently develops bradykinesia and rigidity. After another 8 years, he dies of pneumonia. The gross appearance of his brain is shown. 1. What is your diagnosis? 2. What is the genetic mechanism for this disease? 3. Why might individuals with the abnormal gene not manifest the disease? ERRNVPHGLFRVRUJ Answers: Side B 1. Note the loss of neurons and the gliosis ( ▴), which are typical for Huntington disease . 2. There is an autosomal-dominant pattern of inheritance. Spontaneous new mutations are uncommon. 3. The expansion of CAG tandem repeats occurs during spermatogenesis, so fathers can pass expanded numbers of repeats to offspring, who manifest more severe disease at an earlier age (“ anticipation ”). ERRNVPHGLFRVRUJ 28.22 Side B (PBD9: 1297; BP9: 840) ERRNVPHGLFRVRUJ Questions A 49-year-old woman with a 10-year history of a choreoathetoid movement disorder develops depression and memory loss that progress to profound dementia. She dies of aspiration pneumonia. The microscopic appearance of her caudate nucleus is shown. 1. What is your diagnosis? 2. What inheritance pattern does this disease have? 3. Why was her father affected at an older age? ERRNVPHGLFRVRUJ Answers: Side A 1. The corpus striatum is most affected by Huntington disease (HD) . Note the marked caudate nucleus atrophy ( ▴) with hydrocephalus ex vacuo ( ♦). 2. This is an example of a trinucleotide repeat disorder . Increased repeats of CAG in the huntingtin gene coding sequence lead to increased numbers of linked glutamines. These presumably lead to protein misfolding, aggregation, and toxic intranuclear inclusions. 3. Normal HD genes have 6 to 35 repeats. Although 36 to 38 repeats may not lead to disease, 39 or more usually do. Repeats tend to expand in successive generations (“ anticipation ”). ERRNVPHGLFRVRUJ 28.23 Side A (PBD9: 1254; BP9: 812) ERRNVPHGLFRVRUJ Questions A 24-year-old man with a 1-week history of headache, vomiting, and blurry vision is found to have papilledema. His head CT scan after treatment is shown. The CT scan revealed a tumor at the base of the brain. 1. What is your diagnosis? 2. How was this treated? 3. Describe the normal flow of CSF. ERRNVPHGLFRVRUJ Answers: Side B 1. The findings point to normal-pressure hydrocephalus . Note the enlarged lateral ventricles ( ♦) and third ventricle ( •) shown. 2. A neoplasm or an organization of hemorrhage or infection at the base of the brain can block CSF outflow from the foramina. Obstruction leads to noncommunicating hydrocephalus . 3. The obliteration of arachnoid granulations can occur after meningitis, thereby interfering with CSF reabsorption. A choroid plexus papilloma will occasionally produce excess CSF. ERRNVPHGLFRVRUJ 28.23 Side B (PBD9: 1254; BP9: 812) ERRNVPHGLFRVRUJ Questions A 77-year-old woman who has had progressive dementia and incontinence for 1 year is found on examination to have gait apraxia. Papilledema is not present. The representative gross appearance of her brain is shown. 1. What is your diagnosis? 2. What could block the flow of CSF? 3. Why might CSF pressure be increased in the absence of a blockage to flow? ERRNVPHGLFRVRUJ Answers: Side A 1. The lateral ventricles are enlarged ( ♦), and the history is consistent with acute hydrocephalus. 2. Two ventriculostomy shunts ( ▴) were placed to relieve the increased pressure acutely. 3. About 0.5 L of CSF per day is produced in choroid plexuses. This fluid circulates from lateral ventricles to the third ventricle, down the aqueduct of Sylvius, into the fourth ventricle, and out the foramina of Luschka and Magendie into the subarachnoid space. The CSF is then reabsorbed in arachnoid granulations at the vertex. ERRNVPHGLFRVRUJ 28.24 Side A (PBD9: 1279; BP9: 829) ERRNVPHGLFRVRUJ Questions A 32-year-old HIV-positive man with newly diagnosed Kaposi sarcoma has a 3-day history of headache and confusion followed by seizures and hemiparesis. A CT scan of his brain shows multiple ring-enhancing lesions. The corresponding gross appearance of his brain is shown. 1. What is your general diagnosis? 2. Why does it cause “ring enhancement” on CT? 3. Suggest likely infectious causes in this patient. 4. Suggest other causes in this patient. ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has Toxoplasma gondii as evidenced by pseudocysts filled with bradyzoites ( ▴). Tachyzoites ( ▸) are identified with immunostaining. 2. Congenital toxoplasmosis causes periventricular leukomalacia with necrosis and calcification. 3. Cats (definitive host) ingest bradyzoites that transform into gametocytes; these fuse to form zygotes, which sporulate and divide to form sporozoites within an oocyst that is finally shed. Ingested oocysts in humans release sporozoites that infect enterocytes, which rupture to release tachyzoites. These infect adjacent cells or are disseminated via the lymphatics and the bloodstream; they can infect a variety of cell types, including neurons and cardiac myocytes. ERRNVPHGLFRVRUJ 28.24 Side B (PBD9: 1279 BP9: 829) ERRNVPHGLFRVRUJ Questions A 40-year-old woman with progressive weakness and ataxia for 10 days becomes lethargic and then comatose. MRI of her brain shows multiple areas of abnormal signal intensity with rim enhancement. The microscopic appearance of a stereotaxic biopsy specimen is shown (top, H&E; bottom, immunostain). 1. What is your diagnosis? 2. What complication could occur if she were pregnant? 3. Describe the life cycle of this organism. ERRNVPHGLFRVRUJ Answers: Side A 1. Abscess 2. Organization with increased vascularity at the margins of abscesses ( ▸) yield the “ring enhancement” seen with imaging. 3. CNS infections in patients with AIDS that yield this picture include toxoplasmosis and fungal diseases (e.g., cryptococcosis ). Other causes of brain abscesses include nocardiosis and bacterial infections. 4. In this patient, ring-enhancing lesions could also include lymphoma (Epstein-Barr virus–driven) and progressive multifocal leukoencephalopathy (JC virus); Kaposi sarcoma in the brain is rare. ERRNVPHGLFRVRUJ 29 ERRNVPHGLFRVRUJ The Eye ERRNVPHGLFRVRUJ 29.1 Side A (PBD9: 1339; BP9: 260) ERRNVPHGLFRVRUJ Questions A 5-year-old boy has a 1-year history of deteriorating vision in his right eye. On examination, he has leukocoria in that eye (i.e., a whitish mass without the typical retinal “red reflex”). The gross appearance of his enucleated eye after surgery is shown. 1. What is your diagnosis? 2. What gene mutation is present? 3. What is the typical microscopic appearance? 4. Where should you expect metastases? ERRNVPHGLFRVRUJ Answers: Side B 1. This intraocular malignant melanoma ( ♦) nearly fills the posterior chamber. Note the dark pigmentation from melanin production. 2. Ocular melanomas are most common in adults. They typically arise in the uvea , which is composed of the iris, the choroid, and the ciliary body. 3. Retinal detachment occurred. 4. Hematogenous metastases occur, with the liver being a common site. ERRNVPHGLFRVRUJ 29.1 Side B (PBD9: 1331) ERRNVPHGLFRVRUJ Questions A 53-year-old man with a 1-year history of deteriorating vision in the left eye suddenly loses almost all vision in that eye. His enucleated eye after surgery is shown. 1. What is your diagnosis? 2. In what part of the eye did this condition arise? 3. What sudden complication likely occurred? 4. Where are metastases most likely to be found? ERRNVPHGLFRVRUJ Answers: Side A 1. The large intraocular tumor ( ♦) that extends into the vitreous of the posterior chamber is a retinoblastoma . This tumor is blocking the funduscopic view of the retina and yielding a “white pupil” on examination. 2. There is a mutation in the tumor-suppressor gene RB . Retinoblastomas that appear at a young age are often familial and bilateral because there is an inherited germline mutation in one gene; the second mutational “hit” in the residual normal gene occurs early in life. 3. This is one of the “small round blue cell tumors” of childhood. The cells are often arranged in rosettes. 4. The brain and bone marrow are favored sites; lung metastases occur infrequently. ERRNVPHGLFRVRUJ 29.2 Side A (PBD9: 1334; BP9: 747) ERRNVPHGLFRVRUJ Questions A 54-year-old woman has had deteriorating vision for 5 years. She has an irregular loss of visual fields on objective testing. Her hemoglobin A level is 9% (nl <6%), and she had a myocardial infarction 1 year ago. Funduscopic examination reveals the findings shown. 1c 1. What is the underlying diagnosis? 2. How has this disease affected the retina? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has diabetes mellitus. 2. The neovascularization ( ◂) of proliferative diabetic retinopathy is shown, with the angiogenesis of small vessels near the optic disc. These delicate new vessels grow toward the vitreous humor; they are prone to bleeding and producing vitreal hemorrhages that obscure vision. 3. The proliferation of fibrovascular and glial tissue ensues; when this contracts, there is a risk for retinal detachment . 4. Endothelium and pericytes transport glucose independently of insulin levels. Consequently, a high level of circulating glucose leads to high intracellular concentrations (by conversion to sorbitol) and thus accompanying hyperosmolar damage and increased oxidative stress. High glucose levels also lead to endothelial advanced glycation end products (AGEs), which lead to dysfunction. ERRNVPHGLFRVRUJ 29.2 Side B (PBD9: 1335; BP9: 747) ERRNVPHGLFRVRUJ Questions A 60-year-old man with a 6-year history of progressively worsening vision has noted an acceleration of this process during the past 3 months. His fasting serum glucose level is 200 mg/dL (nl <110 mg/dL). Funduscopic examination reveals the findings shown. 1. What is the underlying disease? 2. Describe the findings shown. 3. What sudden complication can occur? 4. What biochemical abnormalities contribute to the tissue damage? ERRNVPHGLFRVRUJ Answers: Side A 1. The elevated hemoglobin A level and the early age of myocardial infarction (presumably as a result of advanced atherosclerosis) suggest diabetes mellitus . 1c 2. This is preproliferative (“background”) diabetic retinopathy . Microangiopathy at this stage is associated with the loss of pericytes, with aneurysm formation and basement membrane changes. As a consequence, there is edema in addition to retinal exudates that represent either “soft” microinfarcts ( ▸) or “hard” yellowish waxy exudates ( ◂) composed of deposits of plasma proteins and lipids . ERRNVPHGLFRVRUJ 29.3 Side A (PBD9: 1323) ERRNVPHGLFRVRUJ Questions A 4-year-old girl with a 1-month history of right eye irritation (and associated rubbing) is found to have enlarged upper tarsal conjunctival lymphoid follicles. The microscopic appearance of a conjunctival scraping (Giemsa stain) is shown. 1. What is your diagnosis? 2. What complication can occur with chronic infection? 3. What are risk factors for this disease? ERRNVPHGLFRVRUJ Answers: Side B 1. This patient has herpetic keratitis as a result of herpes simplex virus (HSV) infection . Fluorescein dye has been placed on the surface of the eye, and it is collecting at the top and bottom of the conjunctival margins. The lesion seen is a characteristic dendritic ulceration ( ▾) in the corneal epithelium. 2. Such a dendritic ulcer can penetrate through the cornea to rupture the globe, so it must be treated promptly. HSV infection of the eye may become recurrent. ERRNVPHGLFRVRUJ 29.3 Side B (PBD9: 1325) ERRNVPHGLFRVRUJ Questions A 27-year-old woman has a 1-day history of visual clouding, pain, photophobia, and excessive tearing in her right eye. On examination, she is found to have blepharoconjunctivitis, with vesicles on the skin of her eyelids. She undergoes a slitlamp examination under fluorescent light, which reveals the findings shown. 1. What is your diagnosis? 2. What sudden complication can occur? ERRNVPHGLFRVRUJ Answers: Side A 1. The conjunctival scraping reveals an intracytoplasmic elementary body ( ▴) of Chlamydia trachomatis. 2. Trachoma is a chronic progressive infection of the eye. Eventually, trichiasis occurs, which involves the lid turning inward so that eyelashes impinge on the conjunctiva and induce further trauma and scarring (e.g., conjunctival scarring, possible blindness from corneal opacity). Antibiotic therapy (e.g., azithromycin) is useful for controlling trachoma. Eyelid surgery can be helpful to treat the trichiasis. 3. This occurs mainly as a result of social conditions in which there is poor hygiene. It typically results from a lack of clean water for washing the hands and face. ERRNVPHGLFRVRUJ 29.4 Side A (PBD9: 1327) ERRNVPHGLFRVRUJ Questions A 77-year-old man has an 8-year history of painless deterioration of vision. On examination, he has the finding shown. 1. What is your diagnosis? 2. What is the effect on his visual fields? 3. How does this lesion develop? ERRNVPHGLFRVRUJ Answers: Side B 1. This is a pterygium ( ▸). It is an area of elastosis and basophilic degeneration of the substantia propria collagen. 2. Pinguecula 3. This raised, whitish yellow lesion is associated with advancing age. It is thought to be the result of environmental or solar exposure over a lifetime. 4. Conjunctival irregularity caused by this lesion can interfere with tear film distribution. This may lead to focal corneal dryness, which predisposes the eye to epithelial damage and ulceration. ERRNVPHGLFRVRUJ 29.4 Side B (PBD9: 1323) ERRNVPHGLFRVRUJ Questions A 69-year-old man has an 18-month history of the progressively enlarging lesion of the sclera shown. He now reports that it is beginning to interfere with his vision. 1. What is your diagnosis? 2. What would it be called if it did not involve the cornea? 3. How does this lesion develop? 4. Why could corneal ulceration occur? ERRNVPHGLFRVRUJ Answers: Side A 1. Opacification of the crystalline lens is a cataract ( ♦). 2. The center of the visual field would be affected first, with gradual expansion as the cataract enlarges. 3. The opacification results from a series of events that begin in the lens cortex with the rarefaction and then liquefaction of cortical cells. This leads to the fragmentation of lens fibers and extracellular globule formation. In the lens nucleus, there is a progressive increase in insoluble proteins, which leads to hardening (sclerosis) and brownish discoloration (brunescence). ERRNVPHGLFRVRUJ 29.5 Side A (PBD9: 1328) ERRNVPHGLFRVRUJ Questions A 64-year-old woman with hyperopia has had deteriorating vision for the last 4 years. She undergoes an excavation of the optic nerve heads with funduscopic examination. The appearance of her visual field is shown. 1. What is your diagnosis? 2. Can you relate this patient's hyperopia to the visual loss? 3. What pharmacologic treatments can be given? ERRNVPHGLFRVRUJ Answers: Side B 1. Tonometry would show the increased intraocular pressure of glaucoma ; this typically involves a device that blows a puff of air into the eye. A more exact measurement can be made with an applanation tonometer as part of a slit-lamp examination. 2. Gonioscopy with a goniolens views the angle of the anterior chamber to determine if open-angle or closed-angle glaucoma is present. This patient likely has open-angle glaucoma (the most common form of glaucoma). 3. Concurrent ocular disease—including intraocular hemorrhage, uveitis, neoplasia, and lens displacement—may cause secondary glaucoma. ERRNVPHGLFRVRUJ 29.5 Side B (PBD9: 1328) ERRNVPHGLFRVRUJ Questions A 52-year-old African-American man has a 3-year history of deteriorating vision; everything seems darker to him. The objective map of his visual field is shown. 1. What is tonometry likely to show? 2. What is gonioscopy likely to show? 3. What causes a secondary form of this disease? ERRNVPHGLFRVRUJ Answers: Side A 1. She most likely has primary angle closure glaucoma (the most common form of glaucoma) with increased intraocular pressure. 2. Her hyperopia potentially results from an elongated eyeball yielding a more acute angle to the anterior chamber margin; this results in the diminished reabsorption of aqueous humor. 3. Topical agents such as prostaglandin receptor agonists (e.g., latanoprost) are often used initially to increase aqueous humor outflow. β-Adrenergic receptor–blocking agents (e.g., timolol), carbonic anhydrase inhibitors (e.g., dorzolamide), and α adrenergic agonists (e.g., brimonidine) all decrease the production of aqueous humor. 2 ERRNVPHGLFRVRUJ 29.6 Side A (PBD9: 1340) ERRNVPHGLFRVRUJ Questions A 44-year-old man has had a severe headache for the past day. On examination, he has a fever, nuchal rigidity, and the funduscopic finding shown. An MRI of his brain shows flattening of the gyri and narrowing of the sulci. 1. What does funduscopy show? 2. What could cause this finding? 3. Would you do a lumbar puncture? 4. What is the most likely diagnosis? ERRNVPHGLFRVRUJ Answers: Side B 1. This is age-related macular degeneration (ARMD) . The macula with the greatest density of photoreceptors is the most sensitive area for visual acuity and is affected the most. The Amsler grid reveals central visual field distortion. 2. The atrophic form of ARMD is associated with deposits known as drusen . 3. Choroidal neovascular membranes represent angiogenesis . These new leaky vessels penetrate through the Bruch membrane beneath the retinal pigment epithelium; their intrinsic leakiness results in the characteristic exudates. ERRNVPHGLFRVRUJ 29.6 Side B (PBD9: 1338) ERRNVPHGLFRVRUJ Questions A 75-year-old woman has a 5-year history of increasing visual impairment. On funduscopic examination, she has discrete yellowish deposits in the Bruch membrane and geographic atrophy of the retinal pigment epithelium. Her visual defect is shown on the Amsler grid. 1. What is your diagnosis? 2. Name these deposits in the Bruch membrane. 3. What microscopic changes are present? ERRNVPHGLFRVRUJ Answers: Side A 1. The indistinct and blurred optic disk margins ( ▾) indicate papilledema . 2. Any condition that increases intracranial pressure (e.g., edema, hemorrhage, mass lesions) produces papilledema. The intracranial pressure must be relieved, or the patient may experience herniation (i.e., of the cerebellar tonsils, the uncus of the hippocampus, or the cingulate gyrus). 3. No. Lumbar puncture could potentiate herniation. 4. These findings suggest diffuse cerebral edema from infection, probably meningitis . ERRNVPHGLFRVRUJ ERRNVPHGLFRVRUJ Figure Credits 1.6A , 2.4B , 2.8B , 3.8B , 7.3B , 8.1B , 8.9A , 8.11A , 16.1B , 16.2B , 16.6B , 17.5A , 17.8B , 17.13B , 17.23B , 18.4A , 18.5A , 18.8A , 20.4A , 20.5B , 20.6B , 20.7B , 20.10A , 21.9B , 24.13B , 25.1B , 25.3B , 26.12B , 26.15B : Courtesy John A. Blackmon, MD, Florida State University College of Medicine, Tallahassee, Fla. 11.3A : Courtesy Amy Theos, MD, The University of Alabama at Birmingham, Birmingham, Ala. 25.7A and B , 25.9A : Courtesy Sate Hamza, MD, University of Manitoba, Winnipeg, Manitoba, Canada. 18.1A , 18.11A : Courtesy Avinash Kambadakone Ramesh, MD, Massachusetts General Hospital, Boston. 3.4A and B (modified), 7.7A and B (modified), 7.8A and B (modified), 15.4B (modified), 25.10A , 25.13A and B : From Kumar V, Abbas A, Fausto N: Robbins and Cotran Pathologic Basis of Disease, ed 7, Philadelphia, 2005, Saunders. 11.5A : Courtesy Helmut Rennke, MD, Brigham and Women's Hospital, Boston. 3.2A : Modified and redrawn from Rodan GA, Harada S: The missing bone. Cell 89:677, 1997. 5.6B : Courtesy Dr. Nancy Schneider, Department of Pathology, University of Texas Southwestern Medical Center, Dallas. 1.9A , 18.3A : Courtesy Mary Ann Sens, MD, PhD, University of North Dakota School of Medicine & Health Sciences, Grand Forks, N Dak. 3.2B : Modified from Wyngaarden JB, et al, editors: Cecil Textbook of Medicine, ed 19, Philadelphia, 1992, Saunders, p 820. ERRNVPHGLFRVRUJ Table of Contents Title page Table of Contents Copyright Acknowledgments Answers Preface Unit I General Pathology 1 Cellular Responses to Stress and Toxic Insult 1.1 Side A Questions Answers: Side B 1.1 Side B Questions Answers: Side A 1.2 Side A Questions Answers: Side B 1.2 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 1.3 Side A Questions Answers: Side B 1.3 Side B Questions Answers: Side A 1.4 Side A Questions Answers: Side B 1.4 Side B Questions Answers: Side A 1.5 Side A Questions Answers: Side B 1.5 Side B Questions Answers: Side A 1.6 Side A Questions Answers: Side B 1.6 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 1.7 Side A Questions Answers: Side B 1.7 Side B Questions Answers: Side A 1.8 Side A Questions Answers: Side B 1.8 Side B Questions Answers: Side A 1.9 Side A Questions Answers: Side B 1.9 Side B Questions Answers: Side A 1.10 Side A Questions ERRNVPHGLFRVRUJ Answers: Side B 1.10 Side B Questions Answers: Side A 1.11 Side A Questions Answers: Side B 1.11 Side B Questions Answers: Side A 2 Acute and Chronic Inflammation 2.1 Side A Questions Answers: Side B 2.1 Side B Questions Answers: Side A 2.2 Side A Questions Answers: Side B 2.2 Side B Questions ERRNVPHGLFRVRUJ Answers: Side A 2.3 Side A Questions Answers: Side B 2.3 Side B Questions Answers: Side A 2.4 Side A Questions Answers: Side B 2.4 Side B Questions Answers: Side A 2.5 Side A Questions Answers: Side B 2.5 Side B Questions Answers: Side A 2.6 Side A Questions Answers: Side B ERRNVPHGLFRVRUJ 2.6 Side B Questions Answers: Side A 2.7 Side A Questions Answers: Side B 2.7 Side B Questions Answers: Side A 2.8 Side A Questions Answers: Side B 2.8 Side B Questions Answers: Side A 2.9 Side A Questions Answers: Side B 2.9 Side B Questions Answers: Side A 3 Tissue Renewal, Repair, and Regeneration ERRNVPHGLFRVRUJ 3.1 Side A Questions Answers: Side B 3.1 Side B Questions Answers: Side A 3.2 Side A Questions Answers: Side B 3.2 Side B Questions Answers: Side A 3.3 Side A Questions Answers: Side B 3.3 Side B Questions Answers: Side A 3.4 Side A Questions Answers: Side B 3.4 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 3.5 Side A Questions Answers: Side B 3.5 Side B Questions Answers: Side A 3.6 Side A Questions Answers: Side B 3.6 Side B Questions Answers: Side A 3.7 Side A Questions Answers: Side B 3.7 Side B Questions Answers: Side A 3.8 Side A Questions ERRNVPHGLFRVRUJ Answers: Side B 3.8 Side B Questions Answers: Side A 4 Hemodynamic Disorders, Thromboembolic Disease, and Shock 4.1 Side A Questions Answers: Side B 4.1 Side B Questions Answers: Side A 4.2 Side A Questions Answers: Side B 4.2 Side B Questions Answers: Side A 4.3 Side A Questions Answers: Side B 4.3 Side B Questions ERRNVPHGLFRVRUJ Answers: Side A 4.4 Side A Questions Answers: Side B 4.4 Side B Questions Answers: Side A 4.5 Side A Questions Answers: Side B 4.5 Side B Questions Answers: Side A 4.6 Side A Questions Answers: Side B 4.6 Side B Questions Answers: Side A 4.7 Side A Questions Answers: Side B ERRNVPHGLFRVRUJ 4.7 Side B Questions Answers: Side A 4.8 Side A Questions Answers: Side B 4.8 Side B Questions Answers: Side A 5 Genetic Disorders 5.1 Side A Questions Answers: Side B 5.1 Side B Questions Answers: Side A 5.2 Side A Questions Answers: Side B 5.2 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 5.3 Side A Questions Answers: Side B 5.3 Side B Questions Answers: Side A 5.4 Side A Questions Answers: Side B 5.4 Side B Questions Answers: Side A 5.5 Side A Questions Answers: Side B 5.5 Side B Questions Answers: Side A 5.6 Side A Questions Answers: Side B 5.6 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 5.7 Side A Questions Answers: Side B 5.7 Side B Questions Answers: Side A 5.8 Side A Questions Answers Side B 5.8 Side B Questions Answers Side A 5.9 Side A Questions Answers: Side B 5.9 Side B Questions Answers: Side A 5.10 Side A Questions ERRNVPHGLFRVRUJ Answers: Side B 5.10 Side B Questions Answers: Side A 6 Diseases of the Immune System 6.1 Side A Questions Answers: Side B 6.1 Side B Questions Answers: Side A 6.2 Side A Questions Answers: Side B 6.2 Side B Questions Answers: Side A 6.3 Side A Questions Answers: Side B 6.3 Side B Questions ERRNVPHGLFRVRUJ Answers: Side A 6.4 Side A Questions Answers: Side B 6.4 Side B Questions Answers: Side A 6.5 Side A Questions Answers: Side B 6.5 Side B Questions Answers: Side A 6.6 Side A Questions Answers: Side B 6.6 Side B Questions Answers: Side A 6.7 Side A Questions Answers: Side B ERRNVPHGLFRVRUJ 6.7 Side B Questions Answers: Side A 6.8 Side A Questions Answers: Side B 6.8 Side B Questions Answers: Side A 6.9 Side A Questions Answers: Side B 6.9 Side B Questions Answers: Side A 6.10 Side A Questions Answers: Side B 6.10 Side B Questions Answers: Side A 6.11 Side A ERRNVPHGLFRVRUJ Questions Answers: Side B 6.11 Side B Questions Answers: Side A 6.12 Side A Questions Answers: Side B 6.12 Side B Questions Answers: Side A 6.13 Side A Questions Answers: Side B 6.13 Side B Questions Answers: Side A 6.14 Side A Questions Answers: Side B 6.14 Side B Questions ERRNVPHGLFRVRUJ Answers: Side A 7 Neoplasia 7.1 Side A Questions Answers: Side B 7.1 Side B Questions Answers: Side A 7.2 Side A Questions Answers: Side B 7.2 Side B Questions Answers: Side A 7.3 Side A Questions Answers: Side B 7.3 Side B Questions Answers: Side A 7.4 Side A Questions ERRNVPHGLFRVRUJ Answers: Side B 7.4 Side B Questions Answers: Side A 7.5 Side A Questions Answers: Side B 7.5 Side B Questions Answers: Side A 7.6 Side A Questions Answers: Side B 7.6 Side B Questions Answers: Side A 7.7 Side A Questions Answers: Side B 7.7 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 7.8 Side A Questions Answers: Side B 7.8 Side B Questions Answers: Side A 7.9 Side A Questions Answers: Side B 7.9 Side B Questions Answers: Side A 7.10 Side A Questions Answers: Side B 7.10 Side B Questions Answers: Side A 7.11 Side A Questions Answers: Side B 7.11 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 7.12 Side A Questions Answers: Side B 7.12 Side B Questions Answers: Side A 8 Infectious Diseases 8.1 Side A Questions Answers: Side B 8.1 Side B Questions Answers: Side A 8.2 Side A Questions Answers: Side B 8.2 Side B Questions Answers: Side A 8.3 Side A ERRNVPHGLFRVRUJ Questions Answers: Side B 8.3 Side B Questions Answers: Side A 8.4 Side A Questions Answers: Side B 8.4 Side B Questions Answers: Side A 8.5 Side A Questions Answers: Side B 8.5 Side B Questions Answers: Side A 8.6 Side A Questions Answers: Side B 8.6 Side B Questions ERRNVPHGLFRVRUJ Answers: Side A 8.7 Side A Questions Answers: Side B 8.7 Side B Questions Answers: Side A 8.8 Side A Questions Answers: Side B 8.8 Side B Questions Answers: Side A 8.9 Side A Questions Answers: Side B 8.9 Side B Questions Answers: Side A 8.10 Side A Questions Answers: Side B ERRNVPHGLFRVRUJ 8.10 Side B Questions Answers: Side A 8.11 Side A Questions Answers: Side B 8.11 Side B Questions Answers: Side A 9 Environmental and Nutritional Diseases 9.1 Side A Questions Answers: Side B 9.1 Side B Questions Answers: Side A 9.2 Side A Questions Answers: Side B 9.2 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 9.3 Side A Questions Answers: Side B 9.3 Side B Questions Answers: Side A 9.4 Side A Questions Answers: Side B 9.4 Side B Questions Answers: Side A 9.5 Side A Questions Answers: Side B 9.5 Side B Questions Answers: Side A 9.6 Side A Questions Answers: Side B 9.6 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 9.7 Side A Questions Answers: Side B 9.7 Side B Questions Answers: Side A 9.8 Side A Questions Answers: Side B 9.8 Side B Questions Answers: Side A 9.9 Side A Questions Answers: Side B 9.9 Side B Questions Answers: Side A 9.10 Side A Questions ERRNVPHGLFRVRUJ Answers: Side B 9.10 Side B Questions Answers: Side A 10 Diseases of Infancy and Childhood 10.1 Side A Questions Answers: Side B 10.1 Side B Questions Answers: Side A 10.2 Side A Questions Answers: Side B 10.2 Side B Questions Answers: Side A 10.3 Side A Questions Answers: Side B 10.3 Side B Questions ERRNVPHGLFRVRUJ Answers: Side A 10.4 Side A Questions Answers: Side B 10.4 Side B Questions Answers: Side A 10.5 Side A Questions Answers: Side B 10.5 Side B Questions Answers: Side A 10.6 Side A Questions Answers: Side B 10.6 Side B Questions Answers: Side A 10.7 Side A Questions Answers: Side B ERRNVPHGLFRVRUJ 10.7 Side B Questions Answers: Side A 10.8 Side A Questions Answers: Side B 10.8 Side B Questions Answers: Side A 10.9 Side A Questions Answers: Side B 10.9 Side B Questions Answers: Side A 10.10 Side A Questions Answers: Side B 10.10 Side B Questions Answers: Side A 10.11 Side A ERRNVPHGLFRVRUJ Questions Answers: Side B 10.11 Side B Questions Answers: Side A Unit II Systemic Pathology: Diseases of Organ Systems 11 Blood Vessels 11.1 Side A Questions Answers: Side B 11.1 Side B Questions Answers: Side A 11.2 Side A Questions Answers: Side B 11.2 Side B Questions Answers: Side A 11.3 Side A Questions Answers: Side B ERRNVPHGLFRVRUJ 11.3 Side B Questions Answers: Side A 11.4 Side A Questions Answers: Side B 11.4 Side B Questions Answers: Side A 11.5 Side A Questions Answers: Side B 11.5 Side B Questions Answers: Side A 11.6 Side A Questions Answers: Side B 11.6 Side B Questions Answers: Side A 11.7 Side A ERRNVPHGLFRVRUJ Questions Answers: Side B 11.7 Side B Questions Answers: Side A 11.8 Side A Questions Answers: Side B 11.8 Side B Questions Answers: Side A 11.9 Side A Questions Answers: Side B 11.9 Side B Questions Answers: Side A 12 The Heart 12.1 Side A Questions Answers: Side B 12.1 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 12.2 Side A Questions Answers: Side B 12.2 Side B Questions Answers: Side A 12.3 Side A Questions Answers: Side B 12.3 Side B Questions Answers: Side A 12.4 Side A Questions Answers: Side B 12.4 Side B Questions Answers: Side A 12.5 Side A Questions ERRNVPHGLFRVRUJ Answers: Side B 12.5 Side B Questions Answers: Side A 12.6 Side A Questions Answers: Side B 12.6 Side B Questions Answers: Side A 12.7 Side A Questions Answers: Side B 12.7 Side B Questions Answers: Side A 12.8 Side A Questions Answers: Side B 12.8 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 12.9 Side A Questions Answers: Side B 12.9 Side B Questions Answers: Side A 12.10 Side A Questions Answers: Side B 12.10 Side B Questions Answers: Side A 12.11 Side A Questions Answers: Side B 12.11 Side B Questions Answers: Side A 12.12 Side A Questions Answers: Side B 12.12 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 12.13 Side A Questions Answers: Side B 12.13 Side B Questions Answers: Side A 13 Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus 13.1 Side A Questions Answers: Side B 13.1 Side B Questions Answers: Side A 13.2 Side A Questions Answers: Side B 13.2 Side B Questions Answers: Side A 13.3 Side A ERRNVPHGLFRVRUJ Questions Answers: Side B 13.3 Side B Questions Answers: Side A 13.4 Side A Questions Answers: Side B 13.4 Side B Questions Answers: Side A 13.5 Side A Questions Answers: Side B 13.5 Side B Questions Answers: Side A 13.6 Side A Questions Answers: Side B 13.6 Side B Questions ERRNVPHGLFRVRUJ Answers: Side A 13.7 Side A Questions Answers: Side B 13.7 Side B Questions Answers: Side A 13.8 Side A Questions Answers: Side B 13.8 Side B Questions Answers: Side A 13.9 Side A Questions Answers: Side B 13.9 Side B Questions Answers: Side A 13.10 Side A Questions Answers: Side B ERRNVPHGLFRVRUJ 13.10 Side B Questions Answers: Side A 13.11 Side A Questions Answers: Side B 13.11 Side B Questions Answers: Side A 13.12 Side A Questions Answers: Side B 13.12 Side B Questions Answers: Side A 14 Red Blood Cell and Bleeding Disorders 14.1 Side A Questions Answers: Side B 14.1 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 14.2 Side A Questions Answers: Side B 14.2 Side B Questions Answers: Side A 14.3 Side A Questions Answers: Side B 14.3 Side B Questions Answers: Side A 14.4 Side A Questions Answers: Side B 14.4 Side B Questions Answers: Side A 14.5 Side A Questions Answers: Side B 14.5 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 14.6 Side A Questions Answers: Side B 14.6 Side B Questions Answers: Side A 14.7 Side A Questions Answers: Side B 14.7 Side B Questions Answers: Side A 14.8 Side A Questions Answers: Side B 14.8 Side B Questions Answers: Side A 15 The Lung 15.1 Side A ERRNVPHGLFRVRUJ Questions Answers: Side B 15.1 Side B Questions Answers: Side A 15.2 Side A Questions Answers: Side B 15.2 Side B Questions Answers: Side A 15.3 Side A Questions Answers: Side B 15.3 Side B Questions Answers: Side A 15.4 Side A Questions Answers: Side B 15.4 Side B Questions ERRNVPHGLFRVRUJ Answers: Side A 15.5 Side A Questions Answers: Side B 15.5 Side B Questions Answers: Side A 15.6 Side A Questions Answers: Side B 15.6 Side B Questions Answers: Side A 15.7 Side A Questions Answers: Side B 15.7 Side B Questions Answers: Side A 15.8 Side A Questions Answers: Side B ERRNVPHGLFRVRUJ 15.8 Side B Questions Answers: Side A 15.9 Side A Questions Answers: Side B 15.9 Side B Questions Answers: Side A 15.10 Side A Questions Answers: Side B 15.10 Side B Questions Answers: Side A 15.11 Side A Questions Answers: Side B 15.11 Side B Questions Answers: Side A 15.12 Side A ERRNVPHGLFRVRUJ Questions Answers: Side B 15.12 Side B Questions Answers: Side A 15.13 Side A Questions Answers: Side B 15.13 Side B Questions Answers: Side A 15.14 Side A Questions Answers: Side B 15.14 Side B Questions Answers: Side A 15.15 Side A Questions Answers: Side B 15.15 Side B Questions ERRNVPHGLFRVRUJ Answers: Side A 15.16 Side A Questions Answers: Side B 15.16 Side B Questions Answers: Side A 15.17 Side A Questions Answers: Side B 15.17 Side B Questions Answers: Side A 15.18 Side A Questions Answers: Side B 15.18 Side B Questions Answers: Side A 16 Head and Neck 16.1 Side A Questions ERRNVPHGLFRVRUJ Answers: Side B 16.1 Side B Questions Answers: Side A 16.2 Side A Questions Answers: Side B 16.2 Side B Questions Answers: Side A 16.3 Side A Questions Answers: Side B 16.3 Side B Questions Answers: Side A 16.4 Side A Questions Answers: Side B 16.4 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 16.5 Side A Questions Answers: Side B 16.5 Side B Questions Answers: Side A 16.6 Side A Questions Answers: Side B 16.6 Side B Questions Answers: Side A 16.7 Side A Questions Answers: Side B 16.7 Side B Questions Answers: Side A 16.8 Side A Questions Answers: Side B 16.8 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 16.9 Side A Questions Answers: Side B 16.9 Side B Questions Answers: Side A 16.10 Side A Questions Answers: Side B 16.10 Side B Questions Answers: Side A 16.11 Side A Questions Answers: Side B 16.11 Side B Questions Answers: Side A 17 The Gastrointestinal Tract 17.1 Side A ERRNVPHGLFRVRUJ Questions Answers: Side B 17.1 Side B Questions Answers: Side A 17.2 Side A Questions Answers: Side B 17.2 Side B Questions Answers: Side A 17.3 Side A Questions Answers: Side B 17.3 Side B Questions Answers: Side A 17.4 Side A Questions Answers: Side B 17.4 Side B Questions ERRNVPHGLFRVRUJ Answers: Side A 17.5 Side A Questions Answers: Side B 17.5 Side B Questions Answers: Side A 17.6 Side A Questions Answers: Side B 17.6 Side B Questions Answers: Side A 17.7 Side A Questions Answers: Side B 17.7 Side B Questions Answers: Side A 17.8 Side A Questions Answers: Side B ERRNVPHGLFRVRUJ 17.8 Side B Questions Answers: Side A 17.9 Side A Questions Answers: Side B 17.9 Side B Questions Answers: Side A 17.10 Side A Questions Answers: Side B 17.10 Side B Questions Answers: Side A 17.11 Side A Questions Answers: Side B 17.11 Side B Questions Answers: Side A 17.12 Side A ERRNVPHGLFRVRUJ Questions Answers: Side B 17.12 Side B Questions Answers: Side A 17.13 Side A Questions Answers: Side B 17.13 Side B Questions Answers: Side A 17.14 Side A Questions Answers: Side B 17.14 Side B Questions Answers: Side A 17.15 Side A Questions Answers: Side B 17.15 Side B Questions ERRNVPHGLFRVRUJ Answers: Side A 17.16 Side A Questions Answers: Side B 17.16 Side B Questions Answers: Side A 17.17 Side A Questions Answers: Side B 17.17 Side B Questions Answers: Side A 17.18 Side A Questions Answers: Side B 17.18 Side B Questions Answers: Side A 17.19 Side A Questions Answers: Side B ERRNVPHGLFRVRUJ 17.19 Side B Questions Answers: Side A 17.20 Side A Questions Answers: Side B 17.20 Side B Questions Answers: Side A 17.21 Side A Questions Answers: Side B 17.21 Side B Questions Answers: Side A 17.22 Side A Questions Answers: Side B 17.22 Side B Questions Answers: Side A 17.23 Side A ERRNVPHGLFRVRUJ Questions Answers: Side B 17.23 Side B Questions Answers: Side A 17.24 Side A Questions Answers: Side B 17.24 Side B Questions Answers: Side A 17.25 Side A Questions Answers: Side B 17.25 Side B Questions Answers: Side A 17.26 Side A Questions Answers: Side B 17.26 Side B Questions ERRNVPHGLFRVRUJ Answers: Side A 18 Liver and Biliary Tract 18.1 Side A Questions Answers: Side B 18.1 Side B Questions Answers: Side A 18.2 Side A Questions Answers: Side B 18.2 Side B Questions Answers: Side A 18.3 Side A Questions Answers: Side B 18.3 Side B Questions Answers: Side A 18.4 Side A Questions ERRNVPHGLFRVRUJ Answers: Side B 18.4 Side B Questions Answers: Side A 18.5 Side A Questions Answers: Side B 18.5 Side B Questions Answers: Side A 18.6 Side A Questions Answers: Side B 18.6 Side B Questions Answers: Side A 18.7 Side A Questions Answers: Side B 18.7 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 18.8 Side A Questions Answers: Side B 18.8 Side B Questions Answers: Side A 18.9 Side A Questions Answers: Side B 18.9 Side B Questions Answers: Side A 18.10 Side A Questions Answers: Side B 18.10 Side B Questions Answers: Side A 18.11 Side A Questions Answers: Side B 18.11 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 18.12 Side A Questions Answers: Side B 18.12 Side B Questions Answers: Side A 18.13 Side A Questions Answers: Side B 18.13 Side B Questions Answers: Side A 18.14 Side A Questions Answers: Side B 18.14 Side B Questions Answers: Side A 19 The Pancreas 19.1 Side A ERRNVPHGLFRVRUJ Questions Answers: Side B 19.1 Side B Questions Answers: Side A 19.2 Side A Questions Answers: Side B 19.2 Side B Questions Answers: Side A 19.3 Side A Questions Answers: Side B 19.3 Side B Questions Answers: Side A 19.4 Side A Questions Answers: Side B 19.4 Side B Questions ERRNVPHGLFRVRUJ Answers: Side A 20 The Kidney 20.1 Side A Questions Answers: Side B 20.1 Side B Questions Answers: Side A 20.2 Side A Questions Answers: Side B 20.2 Side B Questions Answers: Side A 20.3 Side A Questions Answers: Side B 20.3 Side B Questions Answers: Side A 20.4 Side A Questions ERRNVPHGLFRVRUJ Answers: Side B 20.4 Side B Questions Answers: Side A 20.5 Side A Questions Answers: Side B 20.5 Side B Questions Answers: Side A 20.6 Side A Questions Answers: Side B 20.6 Side B Questions Answers: Side A 20.7 Side A Questions Answers: Side B 20.7 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 20.8 Side A Questions Answers: Side B 20.8 Side B Questions Answers: Side A 20.9 Side A Questions Answers: Side B 20.9 Side B Questions Answers: Side A 20.10 Side A Questions Answers: Side B 20.10 Side B Questions Answers: Side A 20.11 Side A Questions Answers: Side B 20.11 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 20.12 Side A Questions Answers: Side B 20.12 Side B Questions Answers: Side A 20.13 Side A Questions Answers: Side B 20.13 Side B Questions Answers: Side A 20.14 Side A Questions Answers: Side B 20.14 Side B Questions Answers: Side A 20.15 Side A Questions ERRNVPHGLFRVRUJ Answers: Side B 20.15 Side B Questions Answers: Side A 20.16 Side A Questions Answers: Side B 20.16 Side B Questions Answers: Side A 20.17 Side A Questions Answers: Side B 20.17 Side B Questions Answers: Side A 20.18 Side A Questions Answers: Side B 20.18 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 21 The Lower Urinary Tract and Male Genital System 21.1 Side A Questions Answers: Side B 21.1 Side B Questions Answers: Side A 21.2 Side A Questions Answers: Side B 21.2 Side B Questions Answers: Side A 21.3 Side A Questions Answers: Side B 21.3 Side B Questions Answers: Side A 21.4 Side A Questions Answers: Side B ERRNVPHGLFRVRUJ 21.4 Side B Questions Answers: Side A 21.5 Side A Questions Answers: Side B 21.5 Side B Questions Answers: Side A 21.6 Side A Questions Answers: Side B 21.6 Side B Questions Answers: Side A 21.7 Side A Questions Answers: Side B 21.7 Side B Questions Answers: Side A 21.8 Side A ERRNVPHGLFRVRUJ Questions Answers: Side B 21.8 Side B Questions Answers: Side A 21.9 Side A Questions Answers: Side B 21.9 Side B Questions Answers: Side A 21.10 Side A Questions Answers: Side B 21.10 Side B Questions Answers: Side A 22 The Female Genital Tract 22.1 Side A Questions Answers: Side B 22.1 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 22.2 Side A Questions Answers: Side B 22.2 Side B Questions Answers: Side A 22.3 Side A Questions Answers: Side B 22.3 Side B Questions Answers: Side A 22.4 Side A Questions Answers: Side B 22.4 Side B Questions Answers: Side A 22.5 Side A Questions ERRNVPHGLFRVRUJ Answers: Side B 22.5 Side B Questions Answers: Side A 22.6 Side A Questions Answers: Side B 22.6 Side B Questions Answers: Side A 22.7 Side A Questions Answers: Side B 22.7 Side B Questions Answers: Side A 22.8 Side A Questions Answers: Side B 22.8 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 22.9 Side A Questions Answers: Side B 22.9 Side B Questions Answers: Side A 22.10 Side A Questions Answers: Side B 22.10 Side B Questions Answers: Side A 22.11 Side A Questions Answers: Side B 22.11 Side B Questions Answers: Side A 22.12 Side A Questions Answers: Side B 22.12 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 22.13 Side A Questions Answers: Side B 22.13 Side B Questions Answers: Side A 22.14 Side A Questions Answers: Side B 22.14 Side B Questions Answers: Side A 23 The Breast 23.1 Side A Questions Answers: Side B 23.1 Side B Questions Answers: Side A 23.2 Side A ERRNVPHGLFRVRUJ Questions Answers: Side B 23.2 Side B Questions Answers: Side A 23.3 Side A Questions Answers: Side B 23.3 Side B Questions Answers: Side A 23.4 Side A Questions Answers: Side B 23.4 Side B Questions Answers: Side A 23.5 Side A Questions Answers: Side B 23.5 Side B Questions ERRNVPHGLFRVRUJ Answers: Side A 23.6 Side A Questions Answers: Side B 23.6 Side B Questions Answers: Side A 23.7 Side A Questions Answers: Side B 23.7 Side B Questions Answers: Side A 23.8 Side A Questions Answers: Side B 23.8 Side B Questions Answers: Side A 23.9 Side A Questions Answers: Side B ERRNVPHGLFRVRUJ 23.9 Side B Questions Answers: Side A 24 The Endocrine System 24.1 Side A Questions Answers: Side B 24.1 Side B Questions Answers: Side A 24.2 Side A Questions Answers: Side B 24.2 Side B Questions Answers: Side A 24.3 Side A Questions Answers: Side B 24.3 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 24.4 Side A Questions Answers: Side B 24.4 Side B Questions Answers: Side A 24.5 Side A Questions Answers: Side B 24.5 Side B Questions Answers: Side A 24.6 Side A Questions Answers: Side B 24.6 Side B Questions Answers: Side A 24.7 Side A Questions Answers: Side B 24.7 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 24.8 Side A Questions Answers: Side B 24.8 Side B Questions Answers: Side A 24.9 Side A Questions Answers: Side B 24.9 Side B Questions Answers: Side A 24.10 Side A Questions Answers: Side B 24.10 Side B Questions Answers: Side A 24.11 Side A Questions ERRNVPHGLFRVRUJ Answers: Side B 24.11 Side B Questions Answers: Side A 24.12 Side A Questions Answers: Side B 24.12 Side B Questions Answers: Side A 24.13 Side A Questions Answers: Side B 24.13 Side B Questions Answers: Side A 24.14 Side A Questions Answers: Side B 24.14 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 24.15 Side A Questions Answers: Side B 24.15 Side B Questions Answers: Side A 25 The Skin 25.1 Side A Questions Answers: Side B 25.1 Side B Questions Answers: Side A 25.2 Side A Questions Answers: Side B 25.2 Side B Questions Answers: Side A 25.3 Side A Questions Answers: Side B ERRNVPHGLFRVRUJ 25.3 Side B Questions Answers: Side A 25.4 Side A Questions Answers: Side B 25.4 Side B Questions Answers: Side A 25.5 Side A Questions Answers: Side B 25.5 Side B Questions Answers: Side A 25.6 Side A Questions Answers: Side B 25.6 Side B Questions Answers: Side A 25.7 Side A ERRNVPHGLFRVRUJ Questions Answers: Side B 25.7 Side B Questions Answers: Side A 25.8 Side A Questions Answers: Side B 25.8 Side B Questions Answers: Side A 25.9 Side A Questions Answers: Side B 25.9 Side B Questions Answers: Side A 25.10 Side A Questions Answers: Side B 25.10 Side B Questions ERRNVPHGLFRVRUJ Answers: Side A 26 Bones, Joints, and Soft-Tissue Tumors 26.1 Side A Questions Answers: Side B 26.1 Side B Questions Answers: Side A 26.2 Side A Questions Answers: Side B 26.2 Side B Questions Answers: Side A 26.3 Side A Questions Answers: Side B 26.3 Side B Questions Answers: Side A 26.4 Side A Questions ERRNVPHGLFRVRUJ Answers: Side B 26.4 Side B Questions Answers: Side A 26.5 Side A Questions Answers: Side B 26.5 Side B Questions Answers: Side A 26.6 Side A Questions Answers: Side B 26.6 Side B Questions Answers: Side A 26.7 Side A Questions Answers: Side B 26.7 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 26.8 Side A Questions Answers: Side B 26.8 Side B Questions Answers: Side A 26.9 Side A Questions Answers: Side B 26.9 Side B Questions Answers: Side A 26.10 Side A Questions Answers: Side B 26.10 Side B Questions Answers: Side A 26.11 Side A Questions Answers: Side B 26.11 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 26.12 Side A Questions Answers: Side B 26.12 Side B Questions Answers: Side A 26.13 Side A Questions Answers: Side B 26.13 Side B Questions Answers: Side A 26.14 Side A Questions Answers: Side B 26.14 Side B Questions Answers: Side A 26.15 Side A Questions ERRNVPHGLFRVRUJ Answers: Side B 26.15 Side B Questions Answers: Side A 26.16 Side A Questions Answers: Side B 26.16 Side B Questions Answers: Side A 26.17 Side A Questions Answers: Side B 26.17 Side B Questions Answers: Side A 26.18 Side A Questions Answers: Side B 26.18 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 27 Peripheral Nerve and Skeletal Muscle 27.1 Side A Questions Answers: Side B 27.1 Side B Questions Answers: Side A 27.2 Side A Questions Answers: Side B 27.2 Side B Questions Answers: Side A 27.3 Side A Questions Answers: Side B 27.3 Side B Questions Answers: Side A 27.4 Side A Questions Answers: Side B ERRNVPHGLFRVRUJ 27.4 Side B Questions Answers: Side A 27.5 Side A Questions Answers: Side B 27.5 Side B Questions Answers: Side A 28 The Central Nervous System 28.1 Side A Questions Answers: Side B 28.1 Side B Questions Answers: Side A 28.2 Side A Questions Answers: Side B 28.2 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 28.3 Side A Questions Answers: Side B 28.3 Side B Questions Answers: Side A 28.4 Side A Questions Answers: Side B 28.4 Side B Questions Answers: Side A 28.5 Side A Questions Answers: Side B 28.5 Side B Questions Answers: Side A 28.6 Side A Questions Answers: Side B 28.6 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 28.7 Side A Questions Answers: Side B 28.7 Side B Questions Answers: Side A 28.8 Side A Questions Answers: Side B 28.8 Side B Questions Answers: Side A 28.9 Side A Questions Answers: Side B 28.9 Side B Questions Answers: Side A 28.10 Side A Questions ERRNVPHGLFRVRUJ Answers: Side B 28.10 Side B Questions Answers: Side A 28.11 Side A Questions Answers: Side B 28.11 Side B Questions Answers: Side A 28.12 Side A Questions Answers: Side B 28.12 Side B Questions Answers: Side A 28.13 Side A Questions Answers: Side B 28.13 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 28.14 Side A Questions Answers: Side B 28.14 Side B Questions Answers: Side A 28.15 Side A Questions Answers: Side B 28.15 Side B Questions Answers: Side A 28.16 Side A Questions Answers: Side B 28.16 Side B Questions Answers: Side A 28.17 Side A Questions Answers: Side B 28.17 Side B ERRNVPHGLFRVRUJ Questions Answers: Side A 28.18 Side A Questions Answers: Side B 28.18 Side B Questions Answers: Side A 28.19 Side A Questions Answers: Side B 28.19 Side B Questions Answers: Side A 28.20 Side A Questions Answers: Side B 28.20 Side B Questions Answers: Side A 28.21 Side A Questions ERRNVPHGLFRVRUJ Answers: Side B 28.21 Side B Questions Answers: Side A 28.22 Side A Questions Answers: Side B 28.22 Side B Questions Answers: Side A 28.23 Side A Questions Answers: Side B 28.23 Side B Questions Answers: Side A 28.24 Side A Questions Answers: Side B 28.24 Side B Questions Answers: Side A ERRNVPHGLFRVRUJ 29 The Eye 29.1 Side A Questions Answers: Side B 29.1 Side B Questions Answers: Side A 29.2 Side A Questions Answers: Side B 29.2 Side B Questions Answers: Side A 29.3 Side A Questions Answers: Side B 29.3 Side B Questions Answers: Side A 29.4 Side A Questions Answers: Side B ERRNVPHGLFRVRUJ 29.4 Side B Questions Answers: Side A 29.5 Side A Questions Answers: Side B 29.5 Side B Questions Answers: Side A 29.6 Side A Questions Answers: Side B 29.6 Side B Questions Answers: Side A Figure Credits ERRNVPHGLFRVRUJ
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