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 Jaypee Brothers Medical Publishers (P) Ltd Headquarters Jaypee Brothers Medical Publishers (P) Ltd 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 Email: [email protected] Overseas Office J.P. Medical Ltd 83 Victoria...

 Jaypee Brothers Medical Publishers (P) Ltd Headquarters Jaypee Brothers Medical Publishers (P) Ltd 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 Email: [email protected] Overseas Office J.P. Medical Ltd 83 Victoria Street, London SW1H 0HW (UK) Phone: +44 20 3170 8910 Fax: +44 (0)20 3008 6180 Email: [email protected] Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2020, Jaypee Brothers Medical Publishers The views and opinions expressed in this book are solely those of the original contributor(s)/author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Medical knowledge and practice change constantly. This book is designed to provide accurate, authoritative information about the subject matter in question. However, readers are advised to check the most current information available on procedures included and check information from the manufacturer of each product to be administered, to verify the recommended dose, formula, method and duration of administration, adverse effects and contraindications. It is the responsibility of the practitioner to take all appropriate safety precautions. Neither the publisher nor the author(s)/editor(s) assume any liability for any injury and/or damage to persons or property arising from or related to use of material in this book. This book is sold on the understanding that the publisher is not engaged in providing professional medical services. If such advice or services are required, the services of a competent medical professional should be sought. Every effort has been made where necessary to contact holders of copyright to obtain permission to reproduce copyright material. If any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the first opportunity. The CD/DVD-ROM (if any) provided in the sealed envelope with this book is complimentary and free of cost. Not meant for sale. Inquiries for bulk sales may be solicited at: [email protected] Exam Preparatory Manual for Undergraduates—Pathology First Edition : 2015 Second Edition : 2017 Third Edition : 2019 Fourth Edition: 2020 ISBN 978-93-89776-40-9  “ Any intelligent fool can make things bigger and more complex,” said Albert Einstein. To make things understandable and appealing is the persisting and daunting task of a passionate teacher. It is in this context that Dr Ramadas Nayak’s book assumes a considerable significance. In this book, he has provided conceptual clarity that it is both astounding and amazing. The veritable qualities of a review book include simplicity, structure, sequence, and standardization. To this, must be added another ‘s’, i.e., sympathy—sympathy for the reader who is grappling with the essentials. Dr Nayak’s endeavor to have all these qualities in the book is a testimony of his expertise and experience as an effective and exemplary teacher. I am delighted to write this Foreword to Exam Preparatory Manual for Undergraduates—Pathology, which, I am certain, will be an invaluable resource for students and teachers in pathology. We are proud to bring the fourth edition of this Exam Preparatory Manual for Undergraduates—Pathology which has become popular within a few years of publishing the first edition. We had to bring this edition little prematurely to incorporate “Competency-based undergraduate curriculum for the Indian medical graduate” by Medical Council of India (MCI) in 2018. This book is organized to incorporate modification as suggested by this new “Competency-based Medical Education (CBME)”. As per CBME following have been incorporated: v Interpretation of liver function and viral hepatitis along with serology panel. Features to distinguish obstructive from nonobstructive jaundice based on clinical features and liver function tests. Cases have been provided with history and liver function tests for interpretation. v Abnormal urinary findings and few abnormal renal function tests in various disease states are provided with clinical history. Common urinary abnormalities in almost all renal diseases have been included. v Abnormal findings in body fluids in various disease states. v Clinical history with cerebrospinal fluid (CSF) findings has been included so that learner can identify the etiology of meningitis based on CSF parameters. v Core competency is marked as (CC) and non-core competency as (NC). v DOAP (Demonstration-Observation-Assistance-Performance): A practical session that allows the student to observe, demonstrate, assist the performer, perform in a simulated environment, perform under supervision or perform independently has been mentioned in relevant topics. As the saying goes “Change is inevitable”, this book also has undergone changes as per the need of the student. Pathology is one of the rapidly- expanding, ever-changing and interesting field in medicine. This book is an endeavor to present the vast knowledge of pathology in a lucid manner for undergraduate and postgraduate medical students as well as those undergoing training in paramedical courses. The main aim of this book is to provide a sound knowledge of pathology and understand disease mechanisms which lays the foundation for basic science. It gives insight into etiology, pathogenesis, pathology and the disease course. Every attempt has been made to present information in a simplified text augmented with the use of colored illustrations, tables, text boxes and flowcharts. There was a tremendous increase in the understanding of molecular pathology and same is highlighted in all the relevant chapters. Thus, this edition is completely revised, updated, better illustrated and a complete manual for scoring high marks in all pathology examinations. Two chapters have been reorganized to include pediatric diseases and environmental diseases. Two new chapters namely basic diagnostic cytology and blood banking and transfusion as well as many flowcharts are added. Each chapter has been updated incorporating all the core and non-core competencies as per CBME. Few figures and illustrations have been replaced with better quality photomicrographs or illustrations. As far as possible, we have used clear and simple language that can be understood by students who studied their primary school in any of the regional language. Organization This book consists of 27 chapters and is organized into three sections namely General Pathology, Hematology and Clinical Pathology, and Systemic Pathology. Section 1—General Pathology: It provides an overview of the basic pathologic mechanisms underlying diseases including—introduction to pathology; cell injury and adaptation; inflammation and healing; infections and infestations; hemodynamic disorders, thromboembolism, and shock; immunopathology, AIDS, and amyloidosis; neoplasia; genetic and pediatric diseases; environmental and nutritional diseases, and basic diagnostic cytology. Section 2—Hematology and Clinical Pathology: It consists of—introduction to hematology and disorders of red blood cell; disorders of white blood cell, lymph node, and spleen; disorders of hemostasis; clinical pathology, and blood banking and transfusion essential for the undergraduate students. Students are requested to go through the second edition of the book titled Essentials in Hematology and Clinical Pathology authored by Dr Ramadas Nayak and Dr Sharada Rai, M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, for detailed knowledge of hematology and clinical pathology. Section 3—Systemic Pathology: It deals with systemic pathology with chapters devoted to diseases of various organ systems including— cardiovascular disorders; respiratory disorders; disorders of oral cavities and gastrointestinal tract; hepatobiliary and pancreatic disorders; kidney and urinary tract disorders; male genital tract disorders; female genital tract disorders; breast disorders; endocrine disorders; bones, joints, and soft tissue tumors; skin disorders, and disorders of central nervous system and eye. We found that undergraduate students find it difficult to understand, remember and answer the questions during examinations, in a satisfying way. There are many pathology textbooks, but undergraduates face difficulty to refresh their knowledge during examinations. This book fills the niche, to provide basic information to an undergraduate in a nutshell. The text provides all the basic information the student will ever need to know. Keywords are shown in bold words so that the student can rapidly go through the book on the previous day or just before the examination. Most students are fundamentally “visually oriented”. As the saying “a picture is worth a thousand words”, it encouraged us to provide many illustrations. This book can serve as a source of rapid review of pathology for even postgraduates in pathology. Numerous illustrations, gross photographs, photomicrographs, tables, text boxes, flowcharts, and X-rays have been incorporated for easy understanding of the subject. Appendices provide various important bodies and its associated conditions, important cells in various lesions, pathognomonic structures in diseases, and peripheral blood smear. How to use this book Before you start reading We recommend that this book to be used by all students for understanding the basic knowledge and refresh their knowledge during examinations. v CC (core curriculum) and NC (non-core curriculum) is highlighted in a box with lines. v Bold words: The readers are requested to give more emphasis on word in bold letters which represents the keyword to be remembered. v Text boxes: Text boxes have been designed to provide information useful during viva-voce. Most important points to be remembered are presented as text box with yellow background and blue background for not so important points. v Questions: Commonly expected pathology questions during undergraduate examination is also provided at relevant places. In this edition, most frequently asked questions are highlighted in red colored font and not so frequently asked in blue colored font. v Illustration and figures: One of the important notes provided in all pathology theory examination is “Draw diagrams wherever necessary.” Hence, illustrations, figures and flowcharts are provided for those questions where it is mandatory to answer with diagrams. v Definition: One of the frequent viva as well as theory questions is “definition” of the disease. It is provided in a yellow box. v Pathogenesis: As far as possible pathogenesis have been provided with flowchart as well as text for better understanding of difficult concepts. v Classification: Only classifications usually asked in examinations are provided. v Morphology: Another frequent question in theory is “Morphology” which include gross and microscopic findings. Hence, it is also provided in a box to draw your attention during reading. v Clinical cases: Common clinical-oriented questions (asked in few universities) have been incorporated. v Interpretation laboratory results: In “Competency-based undergraduate curriculum for the Indian medical graduate” a skill attribute has been introduced. It test how as student is able to interpret/demonstrate a complex procedure requiring thought, knowledge and behavior. Hence, in this addition following has been provided: – Abnormal urinary findings in disease states and identify and describe common urinary abnormalities in a clinical specimen. – Interpret the abnormalities in renal function tests and liver function tests. – Cerebrospinal fluid analysis. Ramadas Nayak Rakshatha Nayak Pathology is a rapidly-expanding and ever-changing field and lays the foundation for understanding diseases. This book is an endeavor to present the vast knowledge of pathology in a lucid manner for the second year medical and dental students, and those undergoing training in paramedical courses. My aim is to provide a sound knowledge of pathology and hence give insight into etiology, pathogenesis, pathology and the disease course. Every attempt has been made to present information in a simplified text augmented with the use of colored illustrations. Organization This book consists of 23 chapters and is organized into two sections namely general pathology and systemic pathology. Section 1—General pathology: It provides an overview of the basic pathologic mechanisms underlying diseases including cellular adaptations, inflammation, tissue repair, chronic inflammation, hemodynamic disorders, immunological disorders, neoplasia, and genetics. Section 2—Systemic pathology: It deals with chapters devoted to diseases and disorders of various organ systems including vascular, cardiac, respiratory, gastrointestinal, liver and biliary tract, pancreas, kidney, male and female genital tract, bones, endocrines, skin, and central nervous system. For hematology section, readers are requested to refer to Rapid Review of Hematology authored by Dr Ramadas Nayak and Dr Sharada Rai and Essentials in Hematology and Clinical Pathology by Dr Ramadas Nayak, Dr Sharada Rai and Dr Astha Gupta. After many years (more than 34 years) of teaching undergraduates, I found that undergraduate students find it difficult to understand, remember and answer the questions during examinations, in a satisfying way. There are many pathology textbooks, but undergraduates face difficulty to refresh their knowledge during examinations. This encouraged me to write a book to fill the niche, to provide basic information to an undergraduate in a nutshell. The text provides all the basic information the student will ever need to know. Keywords are shown in bold words so that the student can rapidly go through the book on the previous day or just before the examination. Most students are fundamentally “visually oriented.” As the saying “a picture is worth a thousand words”, it encouraged me to provide many illustrations. How to use this book I recommend that this book to be used by all students for understanding the basic knowledge and refresh their knowledge during examinations. The readers are requested to give more emphasis on word in bold letters that represents the keywords to be remembered. One of the aims of the students after getting undergraduate degree is to fetch a good ranking in the postgraduate entrance examination. Most graduates cannot answer multiple choice questions (MCQs) in entrance examination by just reading the usual textbooks in pathology. In this book, text boxes have been designed at the sides of main text that provide information useful in answering these MCQs. These boxes also provide commonly expected pathology questions during undergraduate examination. This book can serve as a source of review of general and systemic pathology for even postgraduates in pathology. About 350 illustrations, 82 gross photographs, 162 photomicrographs, 152 tables, 3 X-rays, and a clinical photograph have been incorporated for easy understanding of the subject. Appendices provide various important bodies and its associated conditions, important cells in various lesions and pathognomonic structures in diseases. Ramadas Nayak Our sincere thanks to all our family members, especially Smt Rekha Nayak, Ms Rashmitha Nayak, Mr Ramnath Kini, andMr Ramanath Nayak (Chartered Accountant), who have patiently accepted our long preoccupation with this work. A special thanks to Master Rishab Kini, who kept us agile throughout the preparation of this book. v We wish to express our gratitude to Mr Yenepoya Abdulla Kunhi, Honorable Chancellor, Yenepoya (Deemed to be University—Accredited by NAAC with “A” grade), Mangaluru, Karnataka, India, for giving us an opportunity to serve this prestigious institution. We are indebted to Mr Farhaad Yenepoya, Director of Finance, Yenepoya (Deemed to be University), Mangaluru, for the inspiration and encouragement. v We are grateful to Dr K Ramnarayan, former Vice-Chancellor, Manipal Academy of Higher Education, Manipal, Karnataka, for writing the Foreword for the first edition and support. v We are thankful to all our friends who contributed fantastic images for this book. Our sincere thanks to Dr Sharada Rai (Professor and Head), and Dr Saraswathy Sreeram (Assistant Professor), Department of Pathology, Kasturba Medical College (Mangaluru), Manipal Academy of Higher Education, Manipal. v We would like to express our gratitude to all our friends, colleagues, undergraduate and postgraduate students (Department of Pathology, Yenepoya Medical College, Mangaluru) who helped us in the different stages of preparing the manuscript; to all those who provided support, talked things over, read, offered comments and assisted in the editing, proofreading and design. v A special thanks to Shri Jitendar P Vij (Group Chairman), Mr Ankit Vij (Managing Director), Mr MS Mani (Group President), of M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India, for publishing the book in the same format as wanted, well in time. We are grateful to Shri Jitendar P Vij, for unmasking our talent as authors. v We would like to offer a huge appreciation to the wonderful work done by Dr Madhu Choudhary (Publishing Head–Education), Ms Pooja Bhandari (Production Head), Ms Sunita Katla (Executive Assistant to Group Chairman and Publishing Manager), Ms Samina Khan (Executive Assistant to Publishing Head–Education), Mr Rajesh Sharma (Production Coordinator), Ms Seema Dogra (Cover Visualizer), Mr Laxmidhar Padhiary and Ms Geeta Rani (Proofreaders), Mr Kulwant Singh (Typesetter), and Mr Rajesh Gurkundi (Graphic Designer) of M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India. v We thank Mr Venugopal V (Associate Director–South) and Mr Vasudev H (Mangaluru) of M/s Jaypee Brothers Medical Publishers (P) Ltd, for taking this book to every corner of Karnataka. v Last but definitely not least, a thank you to our undergraduate and postgraduate students. Without you, we would not write. You make all our books possible. There are many more people we could thank, but space, and modesty compel us to stop here. Images Contribution I am extremely grateful to all my friends who willingly provided required images for this book: v Dr Jagadish Rao PP, MBBS, MD, Diplomate NB, PGDCFS, Dip. Cyber Law, PGCTM, MNAMS, District Medicolegal Consultant (Government Wenlock District Hospital), and Associate Professor, Forensic Medicine and Toxicology; Dr Archith Boloor, Associate Professor, Department of Medicine; Dr Sonali Ullal, Associate Professor, Department of Radiodiagnosis; Dr Sharada Rai, Professor and Head, Department of Pathology, and Dr Sureh Kumar Shetty, Honorary State Medicolegal Consultant, Government of Karnataka and Professor, Department of Forensic Medicine and Toxicology, Kasturba Medical College, Affiliated to Manipal Academy of Higher Education (Manipal), Mangaluru, Karnataka, India. v Dr Seethalakshmi NV (Professor), Dr Annie Jojo (Professor), Dr Ajit Nambiar (Professor and Head), Dr Indu R Nair (Additional Professor), and Dr Meera Subramanian (Senior Lecturer), Department of Pathology, Amrita Institute of Medical Sciences, Ponekkara PO, Kochi, Kerala, India. v Dr N Jayaram, Anand Diagnostic Laboratory, Blue Cross Chambers, Infantry Road Cross, Bengaluru, Karnataka. v Dr Sriram Bhat M, Professor and Head, Department of Surgery, Kasturba Medical College, a constituent of Manipal Academy of Higher Education, Manipal, Mangaluru. v Dr T Reba Philipose (Professor), Dr Muktha R Pai (Professor and Head), and Dr Arvind (Associate Professor), Department of Pathology, AJ Institute of Medical Sciences and Research, Mangaluru. v Dr Krishnaraj Upadhyaya (Professor), Dr Anuradha CK Rao (Professor), Dr Prema Saldhana (Professor), Dr Indra Puthran (Professor), Dr Nisha T (Assistant Professor), and Dr Renuka Patil (Assistant Professor), Department of Pathology, Yenepoya Medical College, Yenepoya (Deemed to be University), Deralakatte, Mangaluru. v Dr Ramesh Chavan (Professor and Head), Dr Ashwini Ratnakar (Assistant Professor), and Mr Sanjay, Department of Pathology,  Jawaharlal Nehru Medical College, Belagavi, KLE (Deemed to be University), Karnataka. v Dr Prasanna Shetty B (Professor and Head), Dr Sulatha Kamath (Professor), and Dr Mansi Khamesra (Tutor), Department of Pathology, MS Ramaiah Medical College, Bengaluru. v Dr Jayashree K (Professor and Head) and Dr Rekha A Nair (Professor), Department of Pathology, Regional Cancer Institute, Thiruvananthapuram, Kerala. v Dr Veena Shenoy, MD, Associate Professor, University of Mississipi Medical Centre, USA. v Dr Tanuj Kanchan, Professor, Department of Forensic Medicine and Toxicology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India. v Dr Mahesh H Karigoudar, Professor, Department of Pathology, BLDE University, Shri BM Patil Medical College, Vijapura, Karnataka. v Dr Surendra Nayak Kapadi, MD, Department of Histopathology, Ministry of Health, Maternity Hospital, Sabha Area, Kuwait. v Dr Pamela Sequeira Prabhu, Neuropathologist and Ambulatory Medical Director, TriHealth Laboratories, Cincinnati, OH, USA, Associate Professor at the Wright State School of Medicine, and Grandview Medical Center, Dayton, OH, USA. v Dr RGW Pinto (Professor and Head), Dr Premila de Sousa Rocha (Associate Professor), Dr Suresh RS Mandrekar, Dr Shruti U Shetye (Tutor), Dr Merline Augustine (Tutor), and Dr Priyanka Raghuvir Mashelkar (Tutor), Department of Pathology, Goa Medical College, Bambolim, Goa, India. v Dr Maria Frances Bukelo, MD, Lecturer, Department of Pathology, St. John’s Medical College, Bengaluru. v Dr GG Laxman Prabhu, Professor and Head, Department of Urology, Kasturba Medical College, a constituent of Manipal Academy of Higher Education, Manipal, Mangaluru. v Dr Grace D’Costa, Professor and Head, Department of Pathology, JJ Hospital, Byculla, Mumbai, Maharashtra, India. v Dr Kanthilatha Pai, Professor and Head, Department of Pathology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka. v Dr Janaki M, MD, DGO, DFWCD, Professor and Head, Department of Pathology, Santhiram Medical College, Nandyal, Kurnool, Andhra Pradesh, India. Chapter 1: Introduction to Pathology v Role of a Pathologist in Diagnosis and Management of Disease v History and Evolution of Pathology Chapter 2: Cell Injury and Adaptation v Types of Cellular Responses to Injury v Cell Injury v Types of Cell Injury v Intracellular Accumulations v Necrosis v Apoptosis v Other Pathways of Cell Death v Pathologic Calcification v Hyaline Change v Mucoid Degeneration v Cellular Adaptations v Cellular Aging Chapter 3: Inflammation and Healing v Inflammation v Recognition of Microbes and Damaged Cells v Acute Inflammation v Reactions of Blood Vessels (Vascular Changes) v Leukocytic/Cellular Events v Chemical Mediators of Inflammation  v Outcomes of Acute Inflammation v Morphological Types/Patterns of Acute Inflammation v Chronic Inflammation v Types of Chronic Inflammation v Systemic Effects of Inflammation v Healing v Stem Cells v Cell Cycle and Cell Proliferation v Healing by Regeneration v Healing by Repair, Scar Formation and Fibrosis v Cutaneous Wound Healing v Factors that Influence Wound Healing v Complications of Wound Healing Chapter 4: Infections and Infestations v Leprosy v Syphilis v Tuberculosis v Bacterial Diseases v Viral Diseases v Rickettsial Infections v Chlamydial Infections v Fungal Infections and Opportunistic Infections v Mycetoma v Parasitic Diseases v Malaria v Other Infections Chapter 5: Hemodynamic Disorders, Thromboembolism, and Shock v Disorders of Perfusion v Hemorrhage v Edema  v Normal Hemostasis v Functions of Normal Endothelium v Thrombosis v Venous Thrombosis (Phlebothrombosis) v Embolism v Pulmonary Embolism v Systemic Thromboembolism v Fat and Marrow Embolism v Air Embolism v Amniotic Fluid Embolism v Miscellaneous Pulmonary Emboli v Infarction v Shock Chapter 6: Immunopathology, AIDS, and Amyloidosis v Immunity v Cells of the Immune System v Cytokines v Hypersensitivity Reactions v Type I (Immediate) Hypersensitivity Reactions v Antibody-mediated (Type II) Hypersensitivity Reactions v Immune Complex-mediated (Type III) Hypersensitivity Reactions v T-Cell Mediated (Type IV) Hypersensitivity Reactions v Autoimmune Diseases v Systemic Lupus Erythematosus v Other Autoimmune Disorders v Major Histocompatibility Complex Molecules v Rejection of Transplants v Immunodeficiency Syndromes v Acquired Immunodeficiency Syndrome v Amyloidosis Chapter 7: Neoplasia v Classification v Nomenclature of Neoplasms v Characteristics of Benign and Malignant Neoplasms v Dysplasia v Carcinoma In Situ v Metastasis v Invasion–Metastatic Cascade (Molecular Events in Invasion and Metastasis) v Environmental Factors and Cancer v Precancerous Conditions/Precursor Lesions v Genetic Lesions in Cancer v Molecular Basis of Cancer v Steps in Normal Cell Proliferation v Hallmarks of Cancer v Genomic Instability v Etiology of Cancer (Carcinogenic Agents) v Laboratory Diagnosis of Cancer v Clinical Aspects of Neoplasia v Paraneoplastic Syndromes v Prognosis v Examples of Benign Tumors Chapter 8: Genetic and Pediatric Diseases v Genes v Classification of Genetic Disorders v Genetic Abnormalities v Mendelian Disorders/Single-Gene or Monogenic Disorders v Developmental Defects v Lyon Hypothesis v Demonstration of Sex Chromatin v Cytogenetics v Chromosomal Aberrations  v Genomic Imprinting v Molecular Genetic Diagnosis v Storage Diseases v Cytogenetic Abnormalities and Mutations in Childhood v Tumors and Tumor-like Lesions of Infancy and Childhood Chapter 9: Environmental and Nutritional Diseases v Environmental Diseases v Effects of Tobacco v Effects of Alcohol v Protein–energy Malnutrition v Starvation v Obesity v Common Vitamin Deficiencies v Fat-soluble Vitamins v Water-soluble Vitamins—Vitamin BComplex Chapter 10: Basic Diagnostic Cytology v Role (Uses) of Cytology v Methods for Obtaining Specimens v Techniques in Exfoliative Cytology v Fine Needle Aspiration Cytology V FNAC Appearance of Some Common Lesions v Other Cytology Techniques Chapter 11: Introduction to Hematology and Disorders of Red Blood Cell v Hematopoiesis Anemia v Definition Anemias of Impaired Red Cell Production v Iron Deficiency Anemia  v Megaloblastic Anemia v Metabolism of Vitamin B12 and Folic Acid v Pernicious Anemia v Aplastic Anemia v Hemolytic Anemias v Hereditary Spherocytosis v Glucose-6-Phosphate Dehydrogenase Deficiency v Hereditary Defects in Hemoglobin v Thalassemia Syndrome v b-Thalassemia Major v b-Thalassemia Minor/Trait v a-Thalassemia Sickle Cell Disease v Sickle Cell Anemia v Sickle Cell Trait Other Anemias v Immunohemolytic Anemias v Hemolytic Disease of the Newborn v Antiglobulin (Coombs) Test v Autoimmune Hemolytic Anemia v Fragmentation Syndrome v Paroxysmal Nocturnal Hemoglobinuria v Anemias of Blood Loss v Sideroblastic Anemias v Approach to the Diagnosis of Hemolytic Anemia v Miscellaneous v Clinical Scenario Chapter 12: Disorders of White Blood Cell,Lymph Node, and Spleen Quantitative and Qualitative Disorders of Leukocytes v Normal Differential Leukocyte Count v Quantitative Disorders of Leukocytes v Qualitative Disorders of Leukocytes v Infectious Mononucleosis (Glandular Fever) Acute Leukemia v Acute Lymphoblastic Leukemia/Lymphoma v Acute Myelogenous Leukemia v Myeloid Sarcoma Myelodysplastic Syndromes Myeloproliferative Neoplasms v Polycythemia or Erythrocytosis v Polycythemia Vera v Essential Thrombocythemia v Primary Myelofibrosis v Chronic Myelogenous Leukemia Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma v Chronic Lymphocytic Leukemia v Hairy Cell Leukemia Plasma Cell Neoplasms v Plasma Cell Myeloma (Multiple Myeloma) Disorders of the Lymph Node v Normal Structure v Lymphadenitis v Lymphoid Neoplasms v Follicular Lymphoma v Diffuse Large B-cell Lymphoma v Burkitt Lymphoma v Mature T-cell and NK Cell Neoplasms Hodgkin Lymphomas v Classical Hodgkin Lymphoma v Nodular Lymphocyte Predominant Hodgkin Lymphoma v Etiology and Pathogenesis of Hodgkin Lymphoma v Laboratory Findings  v Splenomegaly v Clinical Scenario Chapter 13: Disorders of Hemostasis Disorders of Primary Hemostasis v Normal Hemostasis v Classification of Hemostatic Disorders v Bleeding Disorders Caused by Vessel Wall Abnormalities v Bleeding Disorders due to Abnormalities of Platelet v Thrombocytopenia v Immune Thrombocytopenic Purpura v Thrombocytosis v Qualitative Platelet Disorders Bleeding Disorders: Due to Abnormalities of Coagulation/Clotting Factor v Classification of Coagulation Disorders v Hemophilia v Von Willebrand Disease v Acquired Coagulation Disorders v Disseminated Intravascular Coagulation Thrombotic Disorders: Hypercoagulable State v Hypercoagulable State (Thrombophilia) v Acquired Hypercoagulable States Chapter 14: Clinical Pathology v Anticoagulants v Blood Sample v Hemoglobin Estimation v Complete Blood Counts (Hemogram) v Peripheral Blood Smear Examination v Reticulocyte Count v Hematocrit v Erythrocyte Sedimentation Rate  V LE Cell Test v Bone Marrow Examination v Osmotic Fragility Test v Laboratory Evaluation of Hemostatic Disorders v Urine Analysis v Body Fluids v Pleural Fluid v Peritoneal Fluid v Cerebrospinal Fluid Examination v Semen Analysis v Sputum Examination v Liver Function Tests v Renal Function Tests v Thyroid Function Tests v Laboratory Values of Clinical Importance Chapter 15: Blood Banking and Transfusion v Blood Group System v Transfusion Medicine v Pretransfusion and Compatibility Testing v Transfusion-transmitted Diseases v Adverse Transfusion Reactions v Investigation (Work-up) of Suspected Adverse Transfusion Reactions v Autologous Blood Donation and Transfusion Chapter 16: Cardiovascular Disorders Vascular Disorders v Arteriosclerosis v Atherosclerosis v Aneurysms and Dissection v Hypertensive Vascular Disease  v Vasculitis v Vascular Tumors Heart Disorders v Heart Failure v Ischemic Heart Disease v Angina Pectoris v Myocardial Infarction v Infective Endocarditis v Noninfected Vegetations v Rheumatic Fever and Rheumatic Heart Disease v Congenital Heart Disease v Left-to-Right Shunts v Right-to-Left Shunts v Obstructive Congenital Anomalies v Cardiomyopathy v Pericardial Disease v Pericarditis and Pericardial Effusion v Cardiac Myxoma Chapter 17: Respiratory Disorders v Obstructive Lung Diseases v Emphysema v Chronic Bronchitis v Asthma v Bronchiectasis v Pulmonary Infections v Pneumonia v Community-acquired Acute Pneumonias v Lobar Pneumonia v Hospital-acquired Pneumonia v Lung Abscess v Tuberculosis v Sarcoidosis v Acute Lung Injury and Acute Respiratory Distress Syndrome (Diffuse Alveolar Damage)  v Atelectasis (Collapse) v Pneumoconioses v Lung Carcinomas v Metastatic Tumors v Pleural Tumor Chapter 18: Disorders of Oral Cavities and Gastrointestinal Tract Oral Cavity v Precancerous Lesions of Oral Cavity v Squamous Cell Carcinoma v Salivary Gland Neoplasms v Pleomorphic Adenoma v Warthin Tumor v Mucoepidermoid Carcinoma Gastrointestinal Tract v Esophagus v Esophageal Cancer v Stomach v Acute Gastritis v Mucosal Disease Related to Stress v Chronic Gastritis v Peptic Ulcer Disease v Zollinger–Ellison Syndrome v Gastric Adenocarcinoma v Gastrointestinal Stromal Tumor v Meckel Diverticulum v Typhoid Fever v Intestinal Tuberculosis v Shigellosis-Bacillary Dysentery v Amebiasis v Carcinoid Tumor v Inflammatory Bowel Disease v Crohn Disease  v Ulcerative Colitis v Intussusception v Hirschsprung Disease v Polyps of Colon v Colorectal Cancer: Adenocarcinoma v Acute Appendicitis Chapter 19: Hepatobiliary and Pancreatic Disorders Liver v Bilirubin Metabolism and Bile Formation v Jaundice v Hereditary Hyperbilirubinemias v Hepatic Failure v Viral Hepatitis v Chronic Hepatitis v Fulminant Hepatic Failure v Drug- and Toxin-induced Liver Injury v Alcoholic Liver Disease v Nonalcoholic Fatty Liver Disease v Cirrhosis v Portal Hypertension v Hemochromatosis v Wilson’s Disease v Postnecrotic Cirrhosis v Secondary Biliary Cirrhosis v Autoimmune Cholangiopathies v Liver Abscesses v Malignant Tumors of Liver v Cholangiocarcinoma v Metastatic Tumors Gallbladder v Acute Cholecystitis v Chronic Cholecystitis v Cholelithiasis (Gallstones)  v Carcinoma of the Gallbladder Pancreas v Acute Pancreatitis v Chronic Pancreatitis v Pseudocyst of Pancreas v Pancreatic Carcinoma Chapter 20: Kidney and Urinary TractDisorders v Histology of the Kidney v Glomerular Diseases v Pathogenesis of Glomerular Injury v Antibody-mediated Injury v Non-immune Mechanisms of Glomerular Injury v Nephritic Syndrome v Poststreptococcal (Postinfectious) Glomerulonephritis v Rapidly Progressive (Crescentic) Glomerulonephritis v Goodpasture Syndrome v Nephrotic Syndrome v Membranous Nephropathy (Membranous Glomerulopathy) v Minimal-change Disease v Focal Segmental Glomerulosclerosis v Membranoproliferative Glomerulonephritis v C3 Glomerulopathy V IgA Nephropathy (Berger Disease) v Chronic Glomerulonephritis v Glomerular Lesions Associated with Systemic Diseases v Diabetic Nephropathy v Pyelonephritis and Urinary Tract Infection v Pyelonephritis v Vascular Diseases of Kidney v Chronic Kidney Disease v Horseshoe Kidneys v Cystic Diseases of the Kidney v Acute Kidney Injury  v Acute Tubular Injury/Necrosis v Urinary Tract Obstruction (Obstructive Uropathy) v Malignant Tumors of the Kidney v Urothelial Tumors Chapter 21: Male Genital Tract Disorders Penis v Precursor Lesions v Invasive Carcinoma Prostate v Prostatitis v Benign Prostatic Hyperplasia or Nodular Hyperplasia v Adenocarcinoma of Prostate Testis v Cryptorchidism v Testicular Tumors v Germ Cell Tumors v Germ Cell Tumors Derived from Germ Cell NeoplasiaIn Situ v Germ Cell Tumors Unrelated to Germ Cell NeoplasiaIn Situ v Male Infertility Chapter 22: Female Genital Tract Disorders Cervix v Normal Structure v Inflammations V WHO (2014) Classification of Tumors of Uterine Cervix v Cervical Intraepithelial Neoplasia (Squamous Intraepithelial Lesions) v Invasive Carcinoma of Cervix Uterus v Menstrual Cycle v Endometriosis  v Adenomyosis v Endometrial Hyperplasia v Carcinoma of the Endometrium v Malignant Mixed Müllerian Tumors v Leiomyomas v Leiomyosarcoma Ovaries v Ovarian Tumors v Surface Epithelial Tumors v Germ Cell Tumors v Sex Cord-Stromal Tumors v Metastatic Tumors Gestational Disorders v Gestational Trophoblastic Disease Chapter 23: Breast Disorders v Female Breast v Benign Epithelial Lesions v Carcinoma of the Breast v Precursor Lesions/Noninvasive Carcinoma v Invasive (Infiltrating) Carcinoma v Paget Disease of the Nipple v Spread of Breast Carcinoma v Prognostic and Predictive Factors v Stromal/Fibroepithelial Tumors v Male Breast Chapter 24: Endocrine Disorders Thyroid Gland v Thyroiditis v Thyrotoxicosis v Graves’ Disease v Hypothyroidism  v Diffuse and Multinodular Goiters v Neoplasms of the Thyroid v Carcinomas Parathyroid Glands v Hyperparathyroidism v Hypoparathyroidism Adrenal Glands v Adrenal Cortex v Adrenal Neoplasms v Adrenal Medulla v Tumors of the Adrenal Medulla Pituitary v Pituitary Adenomas v Multiple Endocrine Neoplasia Syndromes Diabetes Mellitus v Type 1 Diabetes v Type 2 Diabetes v Pathogenesis of the Complications of Diabetes v Laboratory Diagnosis of Diabetes Chapter 25: Bones, Joints, and Soft TissueTumors v Healing of a Fracture v Infections—Osteomyelitis v Paget Disease of Bone (Osteitis Deformans) v Bone Tumors v Osteoarthritis v Rheumatoid Arthritis v Gout and Gouty Arthritis v Soft Tissue Tumors v Tumors of Adipose Tissue v Tumors and Tumor-like Conditions of Fibrous Origin v Skeletal Muscle Tumors v Smooth Muscle Tumors  v Peripheral Nerve Sheath Tumors v Tumors of Uncertain Origin Chapter 26: Skin Disorders v Melanocytic Nevus (Pigmented Nevus, Mole) v Melanoma v Premalignant Epidermal Tumors v Squamous Cell Carcinoma v Basal Cell Carcinoma Chapter 27: Disorders of Central NervousSystem and Eye v Cerebrovascular Diseases v Intracranial Hemorrhage v Meningitis v Interpretation Cerebrospinal Fluid Findings v Tumors of Central Nervous System v Diffuse Astrocytic and Oligodendroglial Tumors v Other Astrocytic Tumors v Ependymal Tumors v Embryonal Tumors v Meningiomas v Metastatic Tumors v Eye Bibliography Appendices Appendix 1: Important Bodies and its AssociatedConditions Appendix 2: Important Cells and PathognomonicStructures Appendix 3: Peripheral Blood Smear Index  INTRODUCTION Definition: Pathology is the scientific study (logos) of disease (pathos). It mainly focuses on the study of the structural, biochemical and functional changes in cells, tissues and organs in disease. Learning Pathology Study of pathology can be divided into general pathology and systemic pathology. v General pathology: It deals with the study of mechanism, basic reactions of cells and tissues to abnormal stimuli and to inherited defects. v Systemic pathology: This deals with the changes in specific diseases/responses of specialized organs and tissues. Scientific Study of Disease CC: Enumerate common definitions and terms used in pathology. Disease process is studied under following aspects. The common definitions and terms used in pathology are also mentioned below. Etiology The etiology of a disease is its cause and modifying factors which are responsible for the initiation and progression of disease process. It describes why a disease arises or what sets the disease process in motion. The causative factors of a disease can be divided into two major categories: Genetic and acquired (e.g., infectious, chemical, hypoxia, nutritional, physical). v Causative agents: Some diseases are closely linked with etiologic factors and these etiological factors are said to be the causative agents for the disease. For example, microbial pathogens are considered as the causative agents for infectious diseases: Mycobacterium tuberculosis causes pulmonary tuberculosis, human immunodeficiency virus causes HIV disease, Entamoeba histolytica causes amebic dysentery. These diseases cannot develop without pathogens in the body; however, this does not mean that the all individual exposed to infection will have the same consequences, because many host factors affect the clinical course. v Etiological factors: Even when there is a strong link between disease and etiologic agent, only a proportions of the individuals exposed to the etiological factor may develop the disease. For example, if an individual consume large quantities of alcohol he/she may develop liver cirrhosis. In this case, alcohol consumption is considered to be the cause, yet only proportions of individuals who drink alcohol heavily will develop cirrhosis. The concept of one etiologic agent as the cause of one disease is not applicable to the majority of diseases. The exact causes of most disorders remain incompletely understood. v Multifactorial: Most common diseases are multifactorial due to combination of causes (several different etiologic factors that contribute to their development), i.e., inherited genetic susceptibility and various environmental triggers (e.g., coronary heart disease, hypertension, diabetes, and cancer). For example, coronary heart disease is a result of the interaction of genetic predisposition, elevated blood pressure, exposure to cigarette smoke, diet, and many other lifestyle factors acting together. None of these individual factors can be said to cause the disease. v Idiopathic: When the cause of the disease is unknown, a condition is said to be idiopathic. v Iatrogenic: If the cause of the disease is the result of an unintended or unwanted medical intervention, the resulting condition is said to be iatrogenic. v Risk factor: When the link between a causative/etiologic factor and development of a disease is less than certain but the probability is  increased when the factor is present, it is called a risk factor. The identification of risk factors is important for the prevention of the disease. Pathogenesis Pathogenesis refers to the development or evolution of a disease from the initial stimulus to the ultimate expression of the manifestations of the disease. Pathogenesis deals with mechanisms of development, progression of disease and the sequence of physiologic events that follow the exposure of cells or tissues (i.e., from the beginning of any disease process) to an injurious agent (initial contact with an etiologic agent/causative factor). It is a dynamic interplay of changes in cell, tissue, organ, and systemic function. It produces cellular, biochemical and molecular abnormalities and ultimate expression of a disease. With the present advances in technology, it is possible to identify the changes occurring at cellular and molecular level that give rise to the specific functional and structural abnormalities of any particular disease. Thus, it describes how a disease process develops or evolves. This knowledge is helpful for designing new therapeutic approaches. In summary, pathogenesis is a description of how etiologic factors alter physiologic function and lead to the development of clinical manifestations in a particular disorder or disease. Pathophysiology: In pathology, the study and diagnosis of disease is performed through examination of organs, tissues, cells, and bodily fluids. Physiology is the study of the mechanical, physical, and biochemical functions of living organisms. Together, as pathophysiology, the term refers to the study of abnormalities in physiologic functioning (i.e., physiological changes) of an individual or an organ due to a disease. v Latent period: Few causative agents produce signs and symptoms of the disease immediately after exposure. Usually, etiological agents take some time to manifest the disease (e.g., carcinogenesis) and this time period is called as the latent period. It varies depending on the disease. v Incubation period: In disorders caused by infectious (due to bacteria, viruses, etc.) agents, the period between exposure and the development of disease is called the incubation period. It usually ranges from days to weeks. Most of the infectious agents have characteristic incubation period. MORPHOLOGIC CHANGES All diseases start with structural changes (pathologic changes) in cells. Rudolf Virchow (known as the father of modern pathology) proposed that injury to the cell is the basis of all disease. Morphologic changes refer to the gross and microscopic structural changes in cells or tissues affected by disease. Lesion is the term used for the characteristic changes in tissues and cells produced by disease in an individual. The term “pathology” (pathological feature) is sometimes used synonym with morphology. Gross Many diseases have characteristic gross pathology and a fairly confident diagnosis can be given before light microscopy. For example, serous cystadenoma of ovary usually consists of one cystic cavity containing serous fluid; cirrhosis of liver is characterized by total replacement of liver by regenerating nodules. Microscopy Light microscopy: Abnormalities in tissue architecture and morphological changes in cells can be studied by light microscopy. Histopathology: Sections are routinely cut from tissues and processed by paraffin- embedding. The sections are cut from the tissue by a special instrument called microtome and examined under light microscope. In certain situations (e.g., histochemistry, rapid diagnosis) sections are cut from tissue that has been hardened rapidly by freezing (frozen section). The sections are stained routinely by hematoxylin and eosin. – Pathognomonic abnormalities: If the structural changes are characteristic of a single disease or diagnostic of an etiologic process it is called as pathognomonic. Pathognomonic features are those features which are restricted to a single disease, or disease category. The diagnosis should not be made without them. For example, Aschoff bodies are pathognomonic of rheumatic heart disease and Reed-Sternberg cells are pathognomonic of Hodgkin lymphoma (refer Appendix 2). Cytology: The cells from cysts, body cavities, or scraped from body surfaces or aspirated by fine needle from solid lesions can also be studied under light microscope. This study of cells is known as cytology and is used widely especially in diagnosis and screening of cancer. Histochemistry (special stains): Histochemistry (refer Table 2.4) is the study of the chemistry of tissues, where tissue/cells are treated with specific reagent so that the features of individual cells/structure can be visualized, e.g., Prussian blue reaction for hemosiderin (refer Fig. 2.12). Immunohistochemistry and immunofluorescence: Both utilize antibodies (immunoglobulins with antigen specificity) to visualize substances in tissue sections or cell preparations. Former uses monoclonal antibodies linked chemically to enzymes and latter uses fluorescent dyes. Electron microscopy: Electron microscopy (EM) is useful to study the changes at ultrastructural level, and for the demonstration of viruses in tissue samples in certain  diseases. The most common diagnostic use of EM is for the interpretation of biopsy specimen from kidney. Functional Derangements and Clinical Manifestations Functional Derangements The effects of genetic, biochemical and structural changes in cells and tissues are functional abnormalities. For example, excessive secretion of a cell product (e.g., nasal mucus in the common cold); insufficient secretion of a cell product (e.g., insulin lack in diabetes mellitus). Clinical Manifestations The functional derangements produce clinical manifestations of disease, namely symptoms and signs. Symptoms: The subjective feelings of an abnormality in the body are called as symptoms. It is any change in the body or its functions as perceived by the patient. The symptoms are subjective experience of disease and can only be described to an observer by the affected patient. Signs: Manifestations of disease that are observed by physician/observer are termed signs of disease and is an objective evidence of a disease. For example, the feeling of nausea is a symptom, whereas vomiting is objectively observed and is a sign. Signs are apparent to observers, whereas symptoms may be obvious only to the patient.  Fig. 1.1: Steps involved in study of disease. Laboratory tests and investigations: Some signs and symptoms (e.g., fever, headache) are nonspecific and do not indicate a specific cause. In such situation further clinical examination and, often, laboratory tests (biochemical analysis, hematological, microbiological, cytological examination, etc.) and investigations (e.g., X-ray, diagnostic imaging) may be required to know the possible causes of the signs and symptoms. Diagnosis: It is the art or act of identifying (determine the cause) a disease (pathological condition) from its signs and symptoms. Many diseases/disorders are characterized by a particular constellation of signs and symptoms, the knowledge of which is essential for accurate detection and diagnosis. Syndromes: Diseases characterized by multiple abnormalities (symptom complex) are called syndromes. A syndrome is a group (collection) of medical signs, symptoms, laboratory findings, and physiological disturbances occurring together that are often associated with a particular disease or disorder. For example, carpal tunnel syndrome; irritable bowel syndrome; Klinefelter syndrome, Down syndrome. Prognosis The prognosis forecasts (predicts) the known or likely course (outcome) of the disease and, therefore, the fate of the patient. Complications It is a negative pathologic process or event occurring during the disease which is not an essential part of the disease. It usually aggravates the illness. For example, perforation and hemorrhage are complications which may develop in typhoid ulcer of intestine. Sequelae It is a pathologic condition following as a consequence of a disease. For example, intestinal obstruction following healed tuberculosis of intestine, mitral stenosis following healed rheumatic heart disease. Remission and Relapse/Exacerbation Some diseases may pass through several cycles/alteration of remission and relapse/exacerbation. For example, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), some autoimmune diseases. An exacerbation is characterized by a relatively sudden increase in the severity of a disease or any of its signs and symptoms. A remission is characterized by a decline in severity of the signs and symptoms of a disease. If a remission is permanent, the patient is said to be cured. Various steps involved in study of disease are presented in Figure 1.1. ROLE OF A PATHOLOGIST IN DIAGNOSIS AND MANAGEMENT OF DISEASE CC: Describe the role of a pathologist in diagnosis and management of disease. Pathology is a branch of medicine involved in understanding the cause of disease, the processes involved in testing the disease and the reporting of diagnostic tests. TABLE 1.1: Major pathology disciplines and roles. Discipline/subspecialty Role Anatomic pathology Histopathology Study of disease in human tissue samples (e.g., in cancer management through the staging and grading of tumors) Cytopathology Study of disease in individual cells Forensic pathology Determination of cause and manner of death for legal purposes Autopsy Determination of cause and manner of death Hematology Study of the blood and bone marrow Clinical pathology also called It is largely concerned with analysis of blood and other fluids and laboratory medicine involves, for instance, clinical biochemistry, microbiology, and hematology Chemical pathology Study of the biochemical tests to diagnose and treat patients. Also (clinical biochemistry) to understand the biochemical basis/mechanisms of the body related to disease. Body fluids such as blood or urine are used for screening, diagnosis, prognosis and management through chemical and biochemical tests Medical microbiology Study of infection Molecular and genetics Study of the molecular and genetic basis of diseases and heritable pathology conditions. Variety of tests of molecules within organs, tissues or bodily fluids are performed Immunopathology Study of the immunologic basis of disease Transfusion medicine Study of the collection, preparation, storage, and clinical use of blood products Subdivisions of Pathology The study of pathology can be divided into different branches (disciplines) and subspecialties (Table 1.1). Anatomic Pathology/Histopathology In anatomic pathology, microscopic examination is an essential tool for the study. It includes histopathology, cytopathology and autopsy. Histopathology is the classic and most useful method of study. The term histopathology is used synonymously with anatomic pathology or morbid anatomy. Modern anatomic pathology is divided into subspecialities such as renal pathology, dermatopathology, gastrointestinal pathology, cardiac pathology, pulmonary pathology, neuropathology, gynecologic pathology, breast pathology, oral pathology, etc. Surgical Pathology It deals primarily with the study of structure changes in tissues/organs removed from the living patients by biopsy or surgical resection. Surgical pathology includes both gross or naked eye examination referred to as gross or macroscopic changes, as well as examination of processed tissue under a compound light microscope. Intraoperative examination is done by use of frozen tissue sections and is employed for rapid diagnosis. Microscopic examination: It requires tissues be cut with a microtome into thin sections that can be stained with routine stains such as hematoxyline and eosin (H & E). Two types of sectioning methods are most commonly used: frozen sections and paraffin-embedded or permanent sections. v Frozen sections: Frozen sections are cut by using cryostat (microtome in a refrigerated chamber) or freezing microtome from tissue that has been hardened rapidly by freezing (hence termed frozen section). They can be prepared rapidly (within minutes) during the course of surgery while the patient is still under anesthesia (for details refer page 230). v Permanent sections: In most instances, pathologists rely on the study of better-preserved tissue by conventional permanent tissue sections with paraffin embedding technique stained with hematoxylin and eosin. These are prepared from tissues that have been fixed, dehydrated and embedded in paraffin wax as a supporting medium prior to sectioning. Though it needs more time for preparation (about 24 hours), permanent sections have several advantages over frozen tissue sections. These include thinner (typically 5 μm) and better-quality sections without any freezing  artefacts. They permit greater certainty of interpretation. Some tissues (e.g., those containing fat or bone) cut poorly as frozen sections but may be satisfactorily studied in permanent sections. H & E may be further supported by numerous special stains (histochemistry) for specific tissue components (e.g., mucus, glycogen, collagen, bacteria, and fungi) in certain situations. v Ancillary staining and analytical methods: Histochemistry (special stains), immunohistochemistry, and electron microscopy are ancillary technique in surgical pathology that may be helpful or necessary supplements for diagnosis. n Special stains may aid in the diagnosis of one or another type of tumor (i.e., differential diagnosis) and classification. Examples include special stains for mucins, amyloid, lipids and glycogen. Surgical pathology helps to diagnose a disease and determine a treatment plan and has a definitive role in tumor diagnosis. With very few exceptions, definitive therapy for cancer should not be undertaken in the absence of a tissue diagnosis. Role of Pathologists Diagnosis Diagnostic role is a key aspect of pathology laboratories. Pathologist examines the changes in the tissue samples/biopsies of the body (removed at surgery or autopsy), in the cells obtained from needle-aspirated specimens, in blood and other body fluids/secretions (including urine, cerebrospinal fluid, sputum, pleural/ascitic/pericardial fluid and synovial fluid). Some of these changes in test show the causes (e.g., lepromatous leprosy with positive lepra bacilli in the tissue sections, malarial parasites in the peripheral blood smear, Candida albicans in vaginal smear). Tumor Grading, Staging, and Prognosis of Disease Pathologists helps in clinical care by assessing disease severity and prognosis. For example, determining the tumor staging [e.g., the well-known TNM system (refer pages 237-8)] and grading of a cancer to estimate tumor prognosis by histopathology; this information determines the precise type and severity (stage) of the cancer. Staging attempts to measure the extent of spread of a malignant tumor within a patient on the basis of tumor size, lymph node involvement, and the presence of other metastases. Tumor grading is a tumor’s degree of differentiation and growth rate, often graded as I to III where III represents the least differentiated, fastest dividing tumors and presumed to have the worst prognosis. Management of the Disease Some of the test are fundamental in deciding and managing treatment plans for patients. Examples include, use of antiestrogenic agents in estrogen receptor-positive breast cancers. A newer approach has been to target the HER2/neu antigen (refer Fig. 23.14C) which is overexpressed in certain breast and ovarian cancers. The HER2/neu antigen is targeted by a therapeutic agent, trastuzumab (Herceptin, Genentech) consisting of a humanized monoclonal antibody that binds to the HER2/neu. A complete and accurate pathology report is crucial for precise diagnosis and to decide the best treatment plan for patient. In the present era, importance is given to identify markers that help to predict the response to new and different therapeutic modalities. Monitor the Response to Treatment Pathology reports may be helpful in monitoring the clinical response to treatment. For example, analyzing blood levels of markers of renal function (renal function tests) in patients with renal failure, minimal residual disease in lymphomas after treatment. To Comment of Excision Margin in Surgical Specimens An important concern in surgical pathology is the adequacy of tumor excision. Depending on the tissue or type of excision or resected specimen, this decision can be made on either frozen or permanent sections. It is necessary to know the distances between the edges of the tumor and the excision (resection) margins. If the tumor forms a discrete mass and the margins of the specimen are well/clearly recognizable/defined, then determination of excision margins is usually straightforward. Examples of tumors whose excision is likely to have clearly recognizable margins include tumors arising in the gastrointestinal tract, lung, and skin. Excision margins should be identified and painted with ink before any dissection, thus permitting accurate measurement of these distances microscopically. All lymph nodes associated with a cancer specimen need to be dissected out, described along with their location, and processed for histology. Other roles: Pathology plays a number of other key roles. One is quality assurance within the healthcare system. Pathologists routinely supervise the laboratory to ensure pathology results are appropriate and of the highest standard. Cytopathology Cytopathology consists of study of exfoliated cells [i.e., cells shed off from the lesions (exfoliative cytology)] scraped, or brushed cells or fine-needle aspiration cytology (FNAC) of superficial and deep-seated lesions for diagnosis. These can be a rapid, efficient, and low-risk technique for establishing an accurate diagnosis. Role of a cytopathologist in diagnosis and management of disease are discussed in Chapter 10. Forensic Pathology and Autopsy This includes the study of organs and tissues removed at postmortem (autopsy) for medicolegal work and for determining the underlying sequence and cause of death. Forensic pathology is integral to legal system. By this, the course of events that occurred in the patient during life and the probable cause of death can be ascertained. Post-mortem anatomical diagnosis helps the clinician to enhance their knowledge about the disease and their judgement. Forensic autopsy is done for medicolegal purposes. In post- mortem examination ‘the dead teach the living’ and has an important role in patient care, around the world. Hematology Hematology deals with the study of diseases of blood. It includes laboratory hematology and clinical hematology. The hematological diseases include disorders of the red and white blood cells, platelets and the coagulation system. It may be non-neoplastic, certain inflammatory diseases, benign or malignant disorders. Red blood cell (RBC) disorders include disorders of hemoglobin (anemia such as iron deficiency, sickle cell disease) and white blood cell (WBC) disorders include quantitative disorders of white blood cells and malignant disorders such leukemia, lymphoma or myeloma. The disorders of platelets (e.g., thrombocytopenia) and disorders of blood coagulation (e.g., hemophilia) are also part of hematology. Hematologists receive blood samples for checking any abnormalities. They examine the blood film for any abnormality (e.g., anemia, leukemia) and also perform a bone marrow aspiration and biopsy. Common hematologic test is a complete blood count (CBC), which includes white blood cell count, red blood cell count, platelet count, hematocrit/red blood cell volume (HCT), hemoglobin concentration (HB), differential white blood count and red blood cell indices. Other examples of hematologic tests include prothrombin time (PT), and partial thromboplastin time (PTT). Clinical Pathology (Laboratory Medicine) Clinical pathology includes analysis of various fluids including blood and body fluids such as urine, semen, cerebrospinal fluid (CSF) and other body fluids. Such analysis may be qualitative, semiquantitative or quantitative. Wide range of laboratory test results assist clinicians in their diagnosis and treatment of disease. These results help hospital departments including intensive care, operating theaters, special care baby units and oncology. Clinical Biochemistry This includes quantitative determination of various biochemical constituents in serum and plasma, and in other body fluids. There is some overlapping between clinical pathology and clinical biochemistry. Microbiology This includes the study of disease-causing microbes. Depending upon the type of microorganism studied, it is further developed into bacteriology, parasitology, mycology, virology, etc. Immunology In this, abnormalities in the immune system of the body comprising of immunology and immunopathology are studied. Medical Genetics It deals with the relationship between heredity and disease. It is useful in blood grouping, inborn errors of metabolism, chromosomal aberrations in congenital malformations and neoplasms, etc. Molecular Pathology Most of the diseases can be diagnosed by the morphological changes in tissues. But, with the present advances in diagnostic pathology, we realize that cellular disturbances develop due to alterations in molecules (genes, proteins, and others) that influence the survival and behavior of cells. Thus, in the present modern pathology it is necessary to understand the cellular and molecular abnormalities that give rise to diseases. The detection and diagnosis of abnormalities at the molecular level (i.e., DNA of the cell) is performed by molecular pathology. Molecular pathology has revealed the biochemical basis of many diseases, mainly congenital disorders and cancer. These techniques can detect changes in a single nucleotide of DNA and include in situ hybridization, polymerase chain reaction (PCR), etc. In situ hybridization can detect the presence of specific genes or their messenger RNA in tissue sections or cell preparations. Minute quantities of nucleic acids can be amplified by the use of the polymerase chain reaction. DNA microarrays can be used to determine patterns of gene expression (mRNA). These methods are used for research purposes as well as a part of diagnostic pathology reports. Molecular pathology, for example, using nucleic acid probes with or without amplification by the polymerase chain reaction is used to detect expression of specific tumor genes or gene mutations. Transfusion Medicine This branch ensures adequate stocks of safe blood when needed for blood transfusions. The blood bank/center confirms that the donated blood is the right match for the patient’s blood group. This branch deals with blood and transplant service providing vital support for blood transfusion, organ and stem cell transplantation. HISTORY AND EVOLUTION OF PATHOLOGY NC: Describe the history and evolution of pathology. Medicine is as old as humankind. In the beginning of mankind, there was a desire and need to know about the causes, mechanisms and nature of diseases. This knowledge was gained over the centuries from supernatural beliefs to the present knowledge of modern pathology. Pathology has evolved over the years as a distinct discipline or branch apart from others such as anatomy, medicine, surgery, etc. For an undergraduate beginner in pathology, it is necessary to know brief review of history of pathology and personalities with their outstanding contribution. Prehistoric Times to Medieval Period During prehistoric time; religion, magic and medical treatment were quite linked to each other. It was believed that the disease was the outcome of ‘curse from God’ or it had supernatural origin from ‘evil eye of spirits.’ The disease was treated by priests through prayers and sacrifices, and magicians by magic power. Some ancient superstitions still exist in some parts of the world. Religious and magical belief: The link between medicine and religion was firmly believed throughout the world. This has resulted in belief in different societies that there are gods and goddesses of healing. For example, Dhanvantri was considered as the deity of medicine in India, and orthodox Indians’ belief in Mata Sheetala Devi as the pox goddess. Same way Greeks had Aesculapius and Apollo as the principal gods of healing. Philosophical and rational approach: This approach was by the methods of observations and this followed the earlier religious and magical beliefs. This philosophical concept to all-natural phenomena was introduced by Greek philosophers namely Socrates, Plato and Aristotle. Hippocrates: The real practice of medicine began with the great Greek clinical genius Hippocrates (460–370 ). He is regarded as ‘the father of medicine’ and he dissociated medicine from religion and magic. He revolutionized the practice of medicine and established the basic foundations of the role of the physician. He studied patient’s symptoms and described methods of diagnosis. He recorded his observations on cases and his writings called Hippocratic Corpus remained for nearly two thousand years as the mainstay of learning of medicine. However, Hippocates too propagated the prevailing concept on mechanism of disease based on disequilibrium of our basic humors (water, air, fire, and earth). Later this concept was abandoned. Hippocrates set standards for patient care and the physician’s attitudes and philosophies that persist today. Many aspects of the Hippocratic approach to medicine are still with us today. Hippocrates rational and ethical attitudes in practice and teaching of medicine are being respected by the medical profession and ‘Hippocratic oath’ is taken by all medical students at the time of entry into practice of medicine. After Hippocrates, Greek medicine reached Rome (now Italy). After 146 , Rome controlled Greek world and dominated in ancient Europe. Many terms in medicine have their origin from Latin language which was the official language of countries included in ancient Roman empire (Spanish, Portuguese, Italian, French and Greek languages have their origin from Latin). Hippocratic teaching was propagated in Rome by Roman physicians. Prominent among them are Cornelius Celsus (53 to 7) and Claudius Galen ( 130–200). v Celsus first described four cardinal signs of inflammation namely rubor (redness), tumor (swelling), calor (heat), and dolor (pain). v Galen postulated humoral theory, later called Galenic theory. According to this theory, the illness was considered as due to imbalance between four humors (or body fluids): blood, lymph, black bile (believed at that time to be from the spleen), and biliary secretion from the liver. In India, in the centuries before and after Hippocrates, the hypothesis of disequilibrium of four elements of the body (Dhatus) similar to Hippocratic doctrine was mentioned in ancient Indian medicine books during 200. Susruta (Sushruta Samhita) and Chakara (Charaka Samhita) produced encyclopedic founding works of Ayurvedic medicine. Charaka listed 700 plant-derived medicines/remedies and surgical sciences was documented by Sushruta. Backwardness during Medieval period: During Middle Ages (or medieval period that lasted from the 5th to the 15th century) there was marked backwardness in medicine. During this period, there were widespread and devastating epidemics. This resulted in reversal of the process of rational thinking back to supernatural concepts and divine punishment for ‘sins.’ The dominant belief was that life was due to influence of vital substance under the control of soul (theory of vitalism). During this period, the dissection of human body was strictly forbidden because it was considered to hurt the ‘soul.’ Human Anatomy and Era of Gross Pathology Renaissance period: The backwardness during Medieval period was followed by the Renaissance period (i.e., revival of learning). This began from Italy in late 15th century and spread to whole of Europe. During this period, there was quest (an attempt to achieve something) for advances in art and science. There was freedom of thought and emphasis on philosophical and rational attitudes again. Human Anatomy v The development of human anatomy took place at the beginning of this period with the art works and drawings of human muscles and embryos by famous Italian painter Leonardo da Vinci (1452–1519). v Vesalius (1514–1564) dissected human body of freshly executed criminals. His pupils, Gabriel Fallopius (1523–1562) described human oviducts (Fallopian tubes) and Fabricius discovered lymphoid tissue around the intestine of birds (bursa of Fabricius). v The special human anatomic dissection in the form of postmortem came into practice in various parts of ancient Europe. Microscope v Antony van Leeuwenhoek (1632–1723), a cloth merchant by profession in Holland, during his spare time invented the first ever microscope by grinding the lenses. He also introduced histological staining using saffron to examine muscle fibers. v Marcello Malpighi (1624–1694) observed the presence of capillaries by using microscope. He described the malpighian layer of the skin, and lymphoid tissue in the spleen (malpighian corpuscles). Malpighi is known as ‘the father of histology.’ Morbid Anatomy Morbid anatomy (pathologic anatomy) is a branch of medical science concerned with the study of the structure of diseased organs and tissues. v Giovanni B Morgagni (1682–1771): The beginning of study of morbid anatomy was by Italian anatomist, pathologist, Giovanni B Morgagni (1682–1771). He was an excellent teacher in anatomy, a prolific writer and a practicing clinician. Morgagni dismissed the ancient humoral theory of disease and published his life-time experiences based on 700 postmortems and their corresponding clinical findings. Thus, he laid the foundations of clinicopathologic methodology in the study of disease. He introduced the concept of clinicopathologic correlation (CPC), establishing a coherent sequence of cause, lesions, symptoms, and outcome of disease. v Sir Percival Pott (1714–1788) was a famous surgeon in England. He described tuberculosis of the spine (Pott’s disease). He was also first to identify occupational cancer (cancer of scrotal skin) in the chimney sweeps in 1775 and discovered chimney soot as the first chemical carcinogenic agent. v During the latter part of 18th Century, John Hunter (1728–1793) who was a student of Sir Percival Pott became the greatest surgeon-anatomist of all times. His elder brother William Hunter (1718–1788) was a reputed anatomist-obstetrician. These brothers developed the first museum of comparative anatomy and pathology in the world by collecting surgical specimens and arranged them into separate organ systems. This museum knows as the Hunterian Museum, now housed in Royal College of Surgeons of London. v Edward Jenner (1749–1823) who demonstrated inoculation in smallpox. v Matthew Baillie (1760–1823) is a prominent English pathologist published first-ever systematic textbook of morbid anatomy in 1793. v Era of gross pathology: n Richard Bright (1789–1858) described non-suppurative nephritis which was later termed as glomerulonephritis or Bright’s disease. n Thomas Addison (1793–1860) gave an account of chronic adrenocortical insufficiency and was termed as Addison’s disease. n Thomas Hodgkin (1798–1866) observed the complex of chronic enlargement of lymph nodes, often with enlargement of the liver and spleen, which was later called Hodgkin’s disease (presently known as Hodgkin lymphoma). n Xavier Bichat (1771–1802) in France described that organs were composed of tissue and divided the study of morbid anatomy into General Pathology and Systemic Pathology. n RTH Laennec (1781–1826), a French physician had numerous discoveries. These include description of several lung diseases (tubercles, caseous lesions, miliary lesions, pleural effusion, and bronchiectasis), chronic sclerotic liver disease (later called Laennec’s cirrhosis) and invented stethoscope. n Carl F von Rokitansky (1804–1878) is a self-taught German pathologist who performed nearly 30,000 autopsies himself. He described acute yellow atrophy of the liver, wrote monograph on diseases of arteries and congenital heart defects. Unlike most other surgeons during that time, Rokitansky did not do clinical practice of surgery but instead introduced the concept that pathologists should confine themselves to making diagnosis which became the accepted role of pathologist later. Era of Technology Development and Cellular Pathology Correlation of clinical features with autopsy findings: Up to middle of the 19th century, the major method of study of disease was by correlating clinical manifestations of disease with gross pathological findings at autopsy. Advances in Pathology In the 19th century, sophistication in surgical techniques led to advancement in pathology. The anatomist-surgeons of earlier centuries got replaced largely with surgeon-pathologists. In later half of the 19th century, pathology became a diagnostic discipline with the evolution of cellular pathology. This was closely linked to technology advancements in machinery for cutting thin tissue sections, improvement in microscope, and development of dyes for staining. Identification of Microorganisms v French chemist Louis Pasteur (1822–1895) discovered the disease- causing microorganisms and this replaced the prevailing theory of spontaneous generation of disease and firmly established germ theory of disease. v In 1873, GHA Hansen (1841–1912) in Germany identified Hansen’s (lepra) bacillus as the first microbe that caused leprosy (Hansen’s disease). Immunity and Phagocytosis v The basis of immunization was initiated by Edward Jenner while studying infectious diseases. v Metchnikoff (1845–1916), a Russian zoologist, discovered phenomenon of phagocytosis by human defense cells against invading microbes. Staining Developments in chemical industry lead to switching over from earlier dyes of plant and animal origin to synthetic dyes. In 1856, Perkin prepared first synthetic dye namely aniline violet. This led to emergence of a viable dye industry for histological and bacteriological purposes. Various pioneers who contributed the use for dye are as follows: v Paul Ehrlich (1854–1915), German physician, conferred Nobel prize in 1908 for his work in immunology. He described Ehrlich’s test for urobilinogen using Ehrlich’s aldehyde reagent and staining techniques  of cells and bacteria. These developments led to the foundations of clinical pathology. v Christian Gram (1853–1938), Danish physician, used crystal violet for staining bacteria. v DL Romanowsky (1861–1921), Russian physician, developed stain for peripheral blood film using eosin and methylene blue derivatives. v Robert Koch (1843–1910), German bacteriologist described Koch’s postulate and Koch’s phenomena. He also developed techniques of fixation and staining for identification of bacteria. He discovered tubercle bacilli in 1882 and cholera vibrio organism in 1883. v May-Grünwald in 1902 and Giemsa in 1914 developed stains for blood and bone marrow. They applied them for classification of cells in blood and bone marrow. v Sir William Leishman (1865–1926) in 1914 described Leishman’s stain for blood smear/films and observed Leishman-Donovan bodies (LD bodies) in leishmaniasis. v Robert Feulgen (1884–1955) described Feulgen reaction for DNA staining. This laid the foundations of cytochemistry and histochemistry. Technical Advances Advances in techniques and machinery led to development and upgrading of microtomes for obtaining thin sections of organs/tissues and staining by dyes for enhancing detailed study of sections. The presence of cells in thin sections of non-living object cork was first demonstrated by Robert Hooke in 1667. In the 19th century, FT Schwann(1810–1882) was, the first neurohistologist, and Claude Bernarde (1813–1878), was pioneer in pathophysiology. Histopathology Till the end of the 19th century, the study of morbid anatomy was confined largely to autopsy-based study and thus remained as a retrospective science. Rudolf Virchow (1821–1905) in Germany first did the microscopic examination of diseased tissue at cellular level. This became as the histopathology method of investigation. Virchow hypothesized cellular theory and is aptly known as “father of cellular pathology”. According to him: v All cells come from other cells. v Disease is an alteration of normal structure and function of these cells. This led to sound foundation of diagnostic pathology based on microscopy and was followed and promoted by numerous brilliant successive workers. This gave birth to biopsy pathology. Other discoveries by Rudolf Virchow are: v Virchow’s triad: Virchow described etiology of thrombosis [(Virchow’s triad namely (i) slowing of blood-stream, (ii) changes in the vessel wall and(iii) changes in the blood itself)]. v Virchow’s lymph node: Metastatic spread of tumor of carcinoma stomach to supraclavicular lymph node. v Components and diseases of blood (fibrinogen, leukocytosis, leukemia). Frozen section: Julius Cohnheim (1839–1884), student of Rudolf Virchow, described the concept of frozen section examination while the patient was still on the operation table. The concept of surgeon and physician as pathologist started in the 19th century and it continued as late as the middle of the 20th century in most clinical departments. During this period, biopsy pathology work was assigned to some faculty member in the clinical department. The notable pathologists of the first half of 20th century had background of clinical training and these include James Ewing (1866–1943), AP Stout (1885– 1967) and Lauren Ackerman (1905–1993) in United States of America; Pierre Masson (1880–1958) in France, and RA Willis in Australia. Landmarks in Modern Pathology v Karl Landsteiner (1863–1943) described major human blood groups in 1900 and is considered “father of blood transfusion”. He was awarded Nobel prize in 1930. v Ruska and Lorries in 1933 developed electron microscope. This helped to identify the ultrastructure of cell and its organelles. v George N Papanicolaou (1883–1962), a Greek-born, American pathologist is known as ‘father of Exfoliative cytology’. In 1930s, he developed exfoliative cytology for early detection of cervical cancer. v William Boyd (1885–1979), psychiatrist-turned pathologist was by an eminent teacher-author in pathology during 20th century. His textbooks namely ‘Pathology for Surgeons’ (first edition, 1925) and ‘Textbook of Pathology’ (first edition, 1932), dominated and inspired the few generations of students of pathology all over the world due to his flowery language and lucid style. v MM Wintrobe (1901–1986) discovered hematocrit technique. Modern Pathology In the latter half of 20th century and during 21st century, advances made it possible to study diseases at genetic and molecular level. The evidence based and objective diagnosis may enable the physician to institute targeted therapy. The major benefit due to these advances in molecular biology are in the field of diagnosis and treatment of genetic disorders, immunology and in cancer. Some of the discoveries are as follows: v Watson and Crick in 1953 described the structure of DNA of the cell. v Tijo and Levan in 1956, identified chromosomes and their correct number in humans (46 = 23 pairs). v Nowell and Hagerford in 1960, identified Philadelphia chromosome t(9;22) in chronic myeloid leukemia. This was the first chromosomal abnormality detected in any cancer. v In situ hybridization (ISH) was introduced in 1969. In this, a labeled probe is used to detect and localize specific RNA or DNA sequences ‘in situ’ (e.g., in the original place). Its later modification uses fluorescence microscopy (FISH) to detect specific localization of the defect on chromosomes. v Recombinant DNA technique was developed in 1972 using restriction enzymes to cut and paste part/bits of DNA. v Kary Mullis in 1983, introduced polymerase chain reaction (PCR). In this multiple copy of DNA fragments can be done and this has revolutionized the diagnostic molecular genetics. PCR analysis is more rapid than ISH, can be automated by thermal cyclers and requires less amount of DNA for the test. v Barbara McClintock invented flexibility and dynamism of DNA by for which she was awarded Nobel prize in 1983. v Ian Wilmut and his colleagues at Roslin Institute in Edinburgh in 1997, performed mammalian cloning. By using this technique, they performed the somatic cell nuclear transfer to create the clone of a sheep named Dolly. However, reproductive cloning for human beings is very risky and absolutely unethical. v Stem cell research: It started in 2000s by harvesting the primitive stem cells isolated from embryos and maintaining their growth in the laboratory. There are two types of stem cells in humans namely (i) embryonic stem cells and (ii) adult stem cells. Stem cells have many applications in the treatment of many human diseases such as Alzheimer’s disease, diabetes, cancer, strokes, etc. In future, stem cell therapy may be able to replace whole organ transplant and stem cells ‘harvested’ from the embryo may be used as a replacement of damaged tissue/organ. Hematopoietic stem cells are being used for many diseases of the hematopoietic system. v Human Genome Project (HGP): It consisted of a consortium of countries and was completed in April 2003. By HGP, it is possible to read nature’s complete genetic blueprint used in making of each human being (i.e., gene mapping). Clinical trials by gene therapy for the treatment of some single gene defects have resulted in some success, especially in hematological and immunological diseases. Future developments in genetic engineering may be able to design new and highly effective individualized treatment options for genetic diseases and also may suggest preventive action against diseases. v Uses of Human Genome Project: It is listed in Box 1.1. Telepathology and Virtual Microscopy Telepathology is defined as the practice of diagnostic pathology at a distance. In this, a remote pathologist (receiving side) utilizes tissue specimens, histological, cytological electronic (digital) images which are transferred over a telecommunication network from a different location (sending side). Components: The various components of telepathology network include: v A conventional light microscope v Devise to capture the image, i.e., a camera mounted on a microscope BOX 1.1: Uses of Human Genome Project. The understanding of the genome provides clues for: Etiology of cancers, Alzheimer’s disease, etc. Defining the pathogenesis of a disease and to study the disease processes at molecular level Susceptibility of an individual to a variety of illnesses, e.g., carcinoma breast, disorders of hemostasis, liver diseases, cystic fibrosis, etc. Precise new ways to prevent a number of diseases that affect human beings To diagnose and treat disease. Target genes for treatment and management of diseases. Human development and anthropology: Analysis of similarities between DNA sequences from different organisms helps to study evolution Researcher: By visiting the human genome database on the World Wide Web, researcher can examine what other scientists have written about the gene v Telecommunication link between the sending and receiving sites v A work station at the receiving site with a high-quality video monitor Advantages/benefits: Telepathology makes it faster and easier to share medical images. Pathologists in different locations can view images simultaneously and discuss diagnoses through teleconferencing. Pathologist can consult pathologists who are specialized in area of concern, such as liver pathology or lung pathology. It allows pathologists, surgeons and radiologists to communicate with each other over diagnostic dilemmas and overcoming the barrier of distance. Main Categories of Telepathology The types of telepathology include: Static image-based systems In this static telepathology, images are captured from a digital camera connected to a microscope. An image area is selected and transmitted. A limited number of images (1 to 40) are captured and stored in the hard drive of the computer or compact disc-read only memory (CD-ROM) for transmission. It is economical, simple and requires only a standard telephone and internet connection. Disadvantage is that selection of field for images should be done by expert and if done by a non-expert may miss the important areas. Virtual slide systems Pathology specimen slides are scanned and high-resolution digital images created for transmission. Real-time systems This is also termed robotic interactive telepathology and dynamic pathology. In this, the recipient pathologist remotely guides a robotically controlled motorized microscope by means of a joystick (a device that can be moved forwards, backwards and sideways to control a machine or computer) and view ‘real-time’ images on a high-resolution monitor. The section can be viewed entirely and this eliminates the inadequate or inappropriate selection of fields. These instruments allow the remote user to move the microscopic field in any direction, to change magnifications, and even to change the focus (particularly useful for cytological preparations). The resolution of the images is practically the same as that obtained with the actual slide under the microscope. This technique is suitable for routine histological preparations, immunostains, cytology preparations, and electron micrographs. Lesions: Term used for describing the more or less circumscribed pathological changes in tissues and cells produced by disease. Remission: It is the process of conversion from active disease to quiescence. Some of the chronic diseases are interspersed by periods of quiescence when the patient is relatively in good health. Relapse: It is the process in which the signs and symptoms of disease reappear. Normal cell is capable of handling physiological demands and maintains a steady state called homeostasis.  TYPES OF CELLULAR RESPONSES TO INJURY Depending on the nature of stimulus/injury, the cellular responses can be mainly divided into four types (Box 2.1 and Fig. 2.1). Different stages of cellular responses to stress and injurious stimuli are shown in Flowchart 2.1. CELL INJURY CC: Demonstrate knowledge of the causes, mechanisms, types and effects of cell injury and their clinical significance. Definition: Cell injury is the effect of stresses due to variety of etiological agents on the cell. Causes (Etiology) of Cell Injury Q. Write short note on causes of cell injury. They range from gross physical trauma (e.g., road traffic accident), to a single gene defect (e.g., enzyme deficiency resulting in specific metabolic disease). Following are the main categories of causes of cell injury. A. Hypoxia and ischemia: Hypoxia refers to inadequate oxygenation of tissue. It is the most common cause of cell injury. Hypoxia also results in a deficiency of essential nutrients to the tissue affected and builds up toxic metabolites. Causes of hypoxia: n Decreased blood flow is called ischemia and results from an arterial obstruction. This obstruction may be due to thrombosis, embolism, atherosclerosis or external compression of vessel. n Inadequate oxygenation of the blood (hypoxemia): It may be due to lung disease, decreased perfusion of tissues (e.g., cardiac failure, hypotension shock), decreased oxygen-carrying capacity of the blood (e.g., anemia), severe blood loss, carbon monoxide poisoning. Mechanism of injury: Hypoxia causes cell injury by reducing aerobic oxidative respiration and decreasing the synthesis of adenosine triphosphate (ATP). Outcome: Depending on the severity of the hypoxia, cells may adapt, undergo injury, or die. Hypoxia: Most common cause of cell injury. Ischemia: Most common cause of hypoxia. Neurons: Most susceptible to hypoxia and irreversible damage occurs 5 minutes after global hypoxia. First cellular change in hypoxia is decreased oxidative phosphorylation in mitochondria. Watershed areas: Region between terminal branches of arterial blood supply, where blood supply does not overlap. They are susceptible to hypoxic injury. Watershed areas examples: (1) Cerebral vessels; (2) Mesenteric arteries. B. Physical agents: n Mechanical trauma (e.g., blunt/penetrating/crush injuries, gunshot wounds). n Thermal injury: Extremes of temperature (burns and deep cold). n Radiation (ionizing radiation and non-ionizing radiation). n Electric shock. n Pressure changes: Sudden changes in atmospheric pressure. C. Chemical agents, toxins and drugs: n Heavy metals and poisons (e.g., arsenic, mercuric salts or cyanide). n Simple chemicals (e.g., hypertonic concentrations of glucose or salt). n Strong acids and alkalies. n Oxygen at high concentrations is toxic. n Environmental and air pollutants (e.g., insecticides and herbicides).  n Industrial and occupational hazards (carbon monoxide and asbestos). BOX 2.1: Types of cellular responses to injury. 1. Cellular adaptations: Hypertrophy, hyperplasia, atrophy and metaplasia 2. Cell injury – Reversible cell injury – Irreversible cell injury 3. Intracellular accumulations 4. Pathologic calcification  Fig. 2.1: Types of cellular responses to stimuli/injury. Flowchart 2.1: Different stages of cellular responses to stress/injury. n Social/lifestyle choices: Addiction to drugs and alcohol and cigarette smoking. n Therapeutic drugs. D. Infectious agents: Viruses, bacteria, fungi, rickettsiae and parasites. The mechanism by which these infectious agents cause injury varies. E. Immunologic reactions: n Autoimmunity: Immune reactions to endogenous self-antigens are responsible for autoimmune diseases. n Hypersensitivity reactions and other immune reactions: Heightened immune reactions to many external agents (e.g., microbes and environmental agents). F. Genetic derangements: Genetic defects may cause cell injury because of: n Deficiency of functional proteins (e.g., enzyme defects in inborn errors of metabolism). n Accumulation of damaged DNA or misfolded proteins. G. Nutritional imbalances n Nutritional deficiencies:  t Protein-calorie deficiencies t Deficiencies of specific vitamins. n Nutritional excesses: t Excess of cholesterol predisposes to athero-sclerosis. t Obesity is associated with increased incidence of several important diseases, such as diabetes and cancer. t Hypervitaminosis. H. Aging: Cellular aging or senescence in aging decreases the ability of cells to respond to stress and, eventually it results in the death of cells and the individual. I. Idiopathic: Cause is not known. General Principles of Cell Injury 1. Cellular response to injury: It depends on: (1) type of injury, (2) duration of injury and (3) severity of injury. 2. Consequences of injury: It depends on: (1) type of cell involved, (2) adaptability of cell, (3) status of cell and (4) genetic make-up of the cell. 3. Targets and biochemical mechanism of cell injury: These include: (1) mitochondrial damage/dysfunction, (2) disturbance of calcium homeostasis, (3) damage to cellular membranes and (4) damage to DNA and misfolding of proteins. Mechanisms of Cell Injury Q. Long essay: Describe the biochemical and molecular mechanism of cell inju