Fundamentals of Pathology PDF - Pathoma (2011) - Medical Textbook

https://afratafreeh.com/pathomavideos/ FUNDAMENTALS OF PATHOLOGY MEDICAL COURSE AND STEP 1 REVIEW FIRST EDITION HUSAIN A. SATTAR, MD Assistant Professor of Pathology Associate Director of Clinical Pathophysiology and Therapeutics...

https://afratafreeh.com/pathomavideos/ FUNDAMENTALS OF PATHOLOGY MEDICAL COURSE AND STEP 1 REVIEW FIRST EDITION HUSAIN A. SATTAR, MD Assistant Professor of Pathology Associate Director of Clinical Pathophysiology and Therapeutics The University of Chicago Pritzker School of Medicine Chicago, Illinois Pathoma.com C h i c a g o 2 0 1 1 PATHOMA.COM Fundamentals of Pathology: Medical Course and Step I Review, First Edition ISBN 978-0-9832246-0-0 Printed in the United Slates of America. Copyright © 2011 by Pathoma LLC. All rights reserved. No part of this publication may be reproduced, distributed, or transmitted in any form, or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without prior permission in writing from the publisher (email: [email protected]). Disclaimer Fundamentals of Pathology aims at providing general principles at pathology and its associated disciplines and is not intended as a working guide to patient care, drug administration or treatment. Medicine is a constantly evolving field and changes in practice regularly occur. It is the responsibility of the treating practitioner, relying on independent expertise and knowledge of the patient, to determin e the best treatment and method of application for the patient. Neither the publisher nor the author assume any liability for any injury a n d / o r damage to persons or property arising f r o m or related to the material within this publication. Furthermore, although care has been taken to ensure the accuracy of information present in this publication, the author and publisher make no representations or warranties whatsoever, express or implied, with respect to the completeness, accuracy or currency of the contents of this publication. '1 his publication is not meant to be a substitute for the advice of a physician or other licensed and qualified medical professional. Information presented in this publication may refer to drugs, devices or techniques which are subject to government regulation, and it is the responsibility of the treating practitioner to comply with all applicable laws. 'f his book is printed on acid-free paper. Published by Pathoma LLC, http://www.pathoma.com [email protected] Cover and page design by Olaf Nelson, Chinook Design, Inc. h t tp://ww w. chiiiooktype.com  CONTENTS Chapter 1. Growth Adaptations, Cellular Injury, and Cell Death 1 Chapter 2. Inflammation, Inflammatory Disorders, and Wound Healing... 11 Chapter 3, Principles of Neoplasia 23 Chapter 4. Hemostasis and Related Disorders - 31 Chapters, Red Blood Cell Disorders 41 chapters. White Blood Cell Disorders 53 Chapter 7. Vascular Pathology 65 Chapters. Cardiac Pathology 73 Chapter9. Respiratory Tract Pathology 85 Chapter 10. Gastrointestinal Pathology 99 Chapter 11. Exocrine Pancreas, Gallbladder, and Liver Pathology 115 Chapter 12, Kidney and Urinary Tract Pathology 125 Chapter 13. Female Genital System and Gestational Pathology 137 Chapter 14. Male Genital System Pathology 151 Chapter 15. Endocrine Pathology 159 Chapter 16. Breast Pathology 171 Chapterl7. Central Nervous System Pathology 177 Chapter IS. Musculoskeletal Pathology 191 Chapter 19. Skin Pathology 201 Index 209  USING THIS BOOK This work is intended as a review for students during their preclinical years and while preparing for examinations, such as the USMLEi". To this effect, the organization of (his book follows thai of most primary texts in the field and parallels the syllabus used in pathophysiology courses in medical schools throughout the United States. Ample space is provided for students to make notes during course study and while viewing the online videos that cover each section of the text (www.pa.thoma.com). We recommend that students use Fundamentals of Pathology during their medical courses, taking notes in the margin as pertinent topics are covered. When exam time comes around, these notes will likely be invaluable. for examination preparation, we suggest students read the material first, then listen to the online lecture, and then reread the material to develop a solid grasp of each topic. One should not become disheartened if they are not able to retain all the information contained herein. This deceptively slim volume covers a tremendous amount of materia!, and repetition will be a key aid as you progress in your studies. An effort has been made to emphasize concepts and principles over random facts, the forest rather than the trees. Attention to the same by the student will provide a deeper, more meaningful understanding of human disease. We must always remind ourselves that ultimately our goal is to learn, to share, and to serve. Fundamentals of Pathology was developed with this goal in mind. Husai n A, Sattar, M D Chicago, Illinois ACKNOWLEDGMENTS This work would not have been possible without the support and encouragement of those around me. To begin with, I would like to acknowledge Shaykh Zulftqar Ahmad, whose clear vision has guided me to horizons I would never have known. My family is to be acknowledged tor their limitless sacrifice, in particular the constant encouragement and support of my wife Amina, who has proved through the years to be the wind under my wings, Thomas Krausz, M D a n d Aliya Husain, MD (both Professors of Pathology at the University of Chicago) deserve particular mention for their valuable advice and guiding vision, both in the development of this book as well as my career. Special thanks to the multiple reviewers at medical centers throughout the country for their critical comments, in particular Mir Basharath Alikhan, MD (Pathology resident, University of Chicago) and Joshua T.B. Williams (Class of 2013, Pritzker School of Medicine, University of Chicago) for their extensive review. Olaf Nelson (Chinook Design, Inc.) is to be commended for his excellent layout and design. Finally, 1 would be remiss without acknowledging my students, who give meaning to what I do. TO MY PARENTS AND EACH OF M Y T E A C H E R S — Y O U R S A C R I F I C E F O R M S T H E F O U N D A T I O N UPON W H I C H OUR W O R K IS BUILT  Growth Adaptations, Cellular Injury, and Cell Death i GROWTH ADAPTATIONS I. BASIC P R I N C I P L E S A. An organ is in homeostasis with the physiologic stress placed oil it. B. An increase, decrease, or change in stress on an organ can result in g r o w t h adaptations. II, H Y P E R P L A S I A A N D H Y P E R T R O P H Y A. An increase in stress leads to an increase in organ size. 1. O c c u r s via an increase in the size (hypertrophy) a n d / o r the n u m b e r (hyperplasia) ot cells B. Hypertrophy involves gene activation, protein synthesis, and p r o d u c t i o n of organelles. C. Hyperplasia involves the production of new cells f r o m stem cells. D. Hyperplasia and h y p e r t r o p h y generally occur together (e.g., uterus d u r i n g pregnancy). 1. P e r m a n e n t tissues (e.g., cardiac muscle, skeletal muscle, and nerve), however, cannot m a k e new cells and u n d e r g o h y p e r t r o p h y only. 2. For example, cardiac myocytes u n d e r g o hypertrophy, not hyperplasia, in response to systemic hypertensio n (Kg, 1,1). E. Pathologic hyperplasia (e.g., e n d o m e t r i a l hyperplasia) can progress to dysplasia and , eventually, cancer. 1, A notable exception is benign prostatic hyperplasia (BPH), which does not increase the risk for prostate cancer, III. A T R O P H Y A. A decrease in stress (e.g., decreased h o r m o n a l stimulation, disuse, or decreased nutrients/blood supply) leads to a decrease in organ size (atrophy). 1. Occur s via a decrease in the size and n u m b e r of cells B. Decrease in cell n u m b e r occurs via apoptosis. C. Decrease in cell size occurs via u b k j u i t i n - p r o t e o s o me degradatio n of the cyloskeleton a n d autophag y of cellular c o m p o n e n t s. 1. In u b i q u i t i n - p r o l e o s o m e degradation, intermediate filaments of the cytoskeleton are "tagged" with ubiquitin and destroyed by proteosomes. 2. Autophagy of cellular c o m p o n e n t s involves generation of autophagic vacuoles. These vacuoles fuse with lysosomes whose hydrolytic e n z y m e s breakdown cellular c o m p o n e n t s. IV, M E T A P L A S I A A, A change in stress on an organ leads to a change in cell t y p e (metaplasia). 1. Most c o m m o n l y involves change of one type of surface epithelium (squamous, columnar, or urothelial) to anothe r 2. Metaplastic cells are better able to handle the new stress. B. Barrett esophagus is a classic example. pathoma.com 1 12 FUNDAMENTALS OF PATHOLOGY 1. Esophagus is normally lined by nonkeratinizing s q u a m o u s epithelium (suited lo handle friction of a food bolus). 2. Acid reflux f r o m the stomach causes metaplasia to nonciliated, mucin-producing c o l u m n a r cells (better able to handle the stress of acid, Fig. 1.2). C. Metaplasia occurs via « p r o g r a m m i n g of stem cells, which then produce the new cell type. 1. Metaplasia is reversible, in theory, w i t h removal of the driving stressor. 2. For example, treatment of gastroesophageal reflux may reverse Barrett esophagus. D. Under persistent stress, metaplasia can progress to dysplasia and eventually result in cancer. 1. For example, Barrett esophagus may progress So adenocarcinoma of the esophagus. 2. A notable exception is apocrine metaplasia of breast, which carries no increased risk for cancer. E. Vitamin A deficiency can also result in metaplasia, 1. Vitamin A is necessary for differentiation of specialized epithelial surfaces such as the conjunctiva covering the eye. 2. In vitamin A deficiency, the thin s q u a m o u s lining of the conjunctiva undergoes metaplasia into stratified keratinizing s q u a m o u s epithelium. Ibis change is called keratoma lac la (Fig. 1.3). ¥. Mesenchymal (connective) tissues can also undergo metaplasia. 1. A classic example is myositis ossificans in which muscle tissue changes to bone d u r i n g healing after t r a u m a (Fig. 1,4). V. DYSPLASIA A, Disordered cellular growth B, Most often refers to proliferation of precancerous cells 1, For example, cervical intraepithelial neoplasia (CIN) represents dysplasia and is a precursor to cervical cancer, C. Often arises f r o m longstanding pathologic hyperplasia (e.g., endometrial hyperplasia) or metaplasia (e.g., Barrett esophagus) D. Dysplasia is reversible, in theory, with alleviation of inciting stress. I. If stress persists, dysplasia progresses to carcinoma (irreversible). VI. APLASIA A N D H Y P O P L A S I A A. Aplasia is failure of cell production d u r i ng enibryogenesis (e.g., unilateral renal agenesis), B. Hypoplasia is a decrease in cell production d u r i ng embryogenesis, resulting in a relatively small organ (e.g., streak ovary in Turner syndrome). Fig, 1.1 Left ventricular hypertrophy. (Courtesy of Fig. 1,2 Barrett esophagus. Aliya Husain. MD)  Growth Adaptations, Cellular Injury, and Cell Death 13 CELLULAR INJURY i. BASIC P R I N C I P L E S A. Cellular i n j u r y o c c u r s w h e n a stress e x c e e d s t h e eel Is ability to a d a p t. B. The likelihoo d of i n j u r y d e p e n d s on t h e t y p e of stress, its severity, a n d the t y p e of cell affected. 1. N e u r o n s a r e h i g h l y susceptible to i s c h e m i c i n j u r y ; whereas, skeletal muscle is relatively m o r e resistant. 2. Slowly developing ischemia (eijj., renal artery atherosclerosis) resuhs in atrophy, whereas, acute ischemia (e.g., renal artery embolus) results in injury. C. C o m m o n causes o f cellular i n j u r y include i n f l a m m a t i o n , n u t r i t i o n a l deficiency o r excess, h y p o x i a , t r a u m a , a n d genetic m u t a t i o n s. II, HYPOXIA A. Low oxygen delivery to tissue; i m p o r t a n t cause of cellular i n j u r y 1. O x y g e n is the final electron acceptor in the electron t r a n s p o r t chai n of oxidative phosphorylation. 2. Decrease d oxygen i m p a i r s oxidative p h o s p h o r y l a t i o n , r e s u l t i ng in d e c r e a s e d ATP p r o d u c t i o n. 3. Lack of ATP (essential e n e r g y source) leads to cellular injury. Li, Cause s of h y p o x i a i n c l u d e ischemia, h y p o x e m i a , a n d d e c r e a s e d 0 2 - c a r r y i n g capacity of b l o o d. C. Ischemia is d e c r e a s e d blood flow t h r o u g h an o r g a n. A r i s e s w i t h 1. Decreased a r t e r i a l p e r f u s i o n (e.g., atherosclerosis) 2. Decreased v e n o u s d r a i n a g e (e.g., B u d d - C h i a r i s y n d r o m e ) 3. Shock—generalized h y p o t e n s i o n r e s u l t i n g in p o o r tissue p e r f u s i o n D. H y p o x e m i a is a low partial p r e s s u r e of oxygen in the blood ( P a o , < 60 mm Hg, Sao, < 90%). Arises w i t h 1. H i g h a l t i t u d e — D e c r e a s e d b a r o m e t r i c p r e s s u r e results in d e c r e a s e d Pao,. 2. H y p o v e n t i l a t i o n — I n c r e a s e d P a c o , results in d e c r e a s ed Pao.. 3. D i f f u s i o n defect—PAO, not able to p u s h as m u c h O, into Lhe b l o o d d u e to a thicker d i f f u s i o n barrier (e.g., interstitial p u l m o n a r y fibrosis) 4. V / Q m i s m a t c h — B l o o d b y p a s s e s o x y g e n a t e d l u n g (circulation p r o b l e m , e.g., right-to-left shunt), or o x y g e n a t e d air c a n n o t reach b l o o d (ventilation p r o b l e m , e.g., atelectasis). E. Decreased O , - c a r r y i n g capacity arises w i t h h e m o g l o b i n ( H b ) loss or d y s f u n c t i o n. E x a m p l e s include 1. A n e m i a (decrease in RBC m a s s ) — P a o , n o r m a l ; Sao, n o r m a l 2. Carbon monoxide poisoning Fig. 1.3 Keratomalacia. (Courtesy of Fig. 1.4 Myositis Ossificans. (Reprinted with fnotherchildnutrition.org) permission from orthopaedia.com)  FUNDAMENTALS OF PATHOLOGY i. CO binds hemoglobin more avidly l h a n oxygen—Pat), normal; Sao 3 decreased ii. Exposures include smoke f r o m fires and exhaust f r o m cars or gas heaters. iii. Classic finding is cherry-red appearance of skin. iv. Early sign of exposure is headache; significant exposure leads to coma and death. i. Methemoglobinemia i. Iron in heme is oxidized to F e J \ which cannot bind oxygen — Pao normal; Sao,decreased ii. Seen with oxidant stress (e.g., sulfa and nitrate drugs) or in n e w b o r n s iii. Classic finding is cyanosis with chocolate-colored blood. iv. Treatment is intravenous methylene blue, which helps reduce Fe J ' back to Fe !+ state. III. REVERSIBLE A N D IRREVERSIBLE CELLULAR INJURY A, Hypoxia impair s oxidative phosphorylation resulting in decreased ATP. H, Low ATP disrupts key cellular functions including 1. Na^-fC p u m p , resulting in sodium and water buildup in the cell 2. Ca ; * p u m p , resulting in Ca ; T buildup in thecytosol of the cell 3. Aerobic glycolysis, resulting in a switch to anaerobic glycolysis. Lactic acid buildup results in low pH, which denatures proteins and precipitates DMA. C. The initial phase of injury is reversible. The hallmark of reversible i n j u r y is cellular swelling. 1. Cytosol swelling results in loss or microvilli and m e m b r a n e blebbing. 2. Swelling of the rough endoplasmic reticulum (RF.R) results in dissociation of ribosomes and decreased protein synthesis. D. Eventually, the damage becomes irreversible. The hallmark of irreversible injury is membrane damage. 1. Plasma m e m b r a n e d a m a g e results in i, Cytosol ic enzymes leaking into the serum {e.g., cardiac troponin) ii. Additional calcium entering into the cell 2. Mitochondrial m e m b r a n e d a m a g e results in i. Loss of the electron transpor t chain (inner mitochondrial membrane) ii. C y t o c h r o me c leaking into cytosol (activates apoptosis) 3. Lysosome m e m b r a n e damage results in hydrolytic enzymes leaking into the cytosol, which, in t u r n , are activated by the high intracellular calcium. E. The end result of irreversible injury is cell death. Fig. 1.5 Coagulattve necrosis of kidney. A, Gross appearance. B, Microscopic appearance C, Normal kidney histology for comparison, [ft, Courtesy of Aliya Husain, MD}  13 Growth Adaptations, Cellular Injury, and Cell Death CELL DEATH I. BASIC P R I N C I P L E S A. The m o r p h o l o g i c h a l l m a r k of cell d e a t h is loss of the nucleus, w h i c h o c c u r s via n u c l e a r c o n d e n s a t i o n (pyknosis), f r a g m e n t a t i o n ( k a r y o r r h e x i s ) , a n d dissolutio n (karyolysis), B, The t w o m e c h a n i s m s of cell deat h are necrosis a n d apoptosis. II. NECROSIS A. Death of large g r o u p s of cells followed by a c u t e i n f l a m m a t i o n B. D u e to s o m e u n d e r l y i n g p a t h o l o g ic process; never physiologic C. Divided into several t y p e s b a s e d on gross f e a t u r e s III. G R O S S P A T T E R N S OF N E C R O S I S A. C o a g u l a t i v e necrosis 1. Necrotic tissue that r e m a i n s f i r m (Fig, 1.5A); cell shape a n d o r g a n s t r u c t u r e are p r e s e r v e d by c o a g u l a t i on of p r o t e i n s , but t h e n u c l e u s d i s a p p e a r s (Fig. 1.5B). 2. C h a r a c t e r i s t i c of i s c h e m ic i n f a r c t i o n of any o r g a n except the brain 3. Area of i n f a r c t e d tissue is o f t e n w e d g e - s h a p e d ( p o i n t i n g to f o c u s of v a s c u l a r occlusion) a n d pale. 4. Red i n f a r c t i o n arises if blood r e - e n t e r s a loosely o r g a n i z e d tissue (e.g., p u l m o n a r y or testicula r i n f a r c t i o n , Fig. 1.6). B. l i q u e f a c t i v e necrosis 1. Necrotic tissue t h a t b e c o m e s liquefied; e n z y m a t i c lysis of cells a n d p r o t e i n results in liquefaction. 2. C h a r a c t e r i s t i c of i. Brain i n l a r c l i o n — P r o t e o l y t i c e n z y m e s f r o m microglial cells liquefy t h e brain. ii. A b s c e s s — P r o t e o l y t i c e n z y m e s f r o m n e u t r o p h i l s liquefy tissue. iii. P a n c r e a t i t i s — P r o t e o l y t i c e n z y m e s f r o m p a n c r e a s liquefy p a r e n c h y m a. C. G a n g r e n o u s necrosis 1. C o a g u l a t i ve necrosis that resembles m u m m i f i e d tissue ( d r y g a n g r e n e , Fig. 1.7) 2. C h a r a c t e r i s t i c of i s c h e m i a of lower l i m b a n d GI tract 3. If s u p e r i m p o s e d infection of dead tissues o c c u r s , t h e n liquefactive necrosis e n s u e s (wet gangrene). D. C a s e o u s necrosis 1. Soft a n d friable necrotic tissue w i t h "cottage c h e e s e - l i k e " a p p e a r a n c e (Fig. 1.8) 2. C o m b i n a t i o n of coagulativ e a n d liquefactive necrosis 3. C h a r a c t e r i s t ic o f g r a n u l o m a t o u s i n f l a m m a t i o n d u e t o t u b e r c u l o u s o r f u n g a l infection Fig. 1.6 Hemorrhagic infarction of testicle. Fig. 1.7 Dry gangrene. Fig. 1.8 Caseous necrosis of lung. (Courtesy of (Courtesyofhumpath.com) Yale Rosen, MD)  12 FUNDAMENTALS OF PATHOLOGY E. Fat necrosis 1. Necrotic adipose tissue with chalky-white appearance due to deposition of calcium {Fig. 1.9) 2. Characteristic of t r a u m a to fat (e.g., breast) and pancreatitis-mediated damage of peripancreatic fat 3. Fatty acids released by trauma (e.g., to breast) or lipase [e.g., pancreatitis) join with calcium via a process called saponification. i. Saponification is an example of dystrophic calcification in which calcium deposits on dead tissues. In dystrophic calcification, the necrotic tissue acts as a nidus for calcification in the set ting of normal serum calcium and phosphate. ii. Dystrophic calcification is distinct f r o m metastatic calcification, in which high serum calcium or phosphate levels lead to calcium deposition in normal tissues (e.g., hyperparathyroidism leading to nephrocalcinosis), F, Fibrinoid necrosis 1, Necrotic damage to blood vessel wall 2, Leaking of proteins (including fibrin) into vessel wall results in bright pink staining of the wall microscopically (Fig. 1.10). 3, Characteristic of malignant hypertension and vasculitis IV. A P O P T O S I S A. Energy (ATP)-dependent, genetically p r o g r a m m e d cell death involving single cells or small groups of cells. Examples include 1. Endometrial shedding d u r i n g m e n s t r u a l cycle 2. Removal of cells d u r i n g embryogenesis 3. CD8 + T cell-mediated killing o f v i r a l l y infected cells H. Morphology 1. Dying cell shrinks, leading cytoplasm to become more eosinophilic (pink, Fig. 1.11). 2. Nucleus condenses (pyknosis) and fragments (karyorrhexis). 3. Apoptotic bodies fall f r o m the cell and are removed by macrophages; apoptosis is not followed by inflammation. C. Apoptosis is mediated by caspases that activate proteases and endonucleases, t. Proteases break down the cytoskeleton. 2. Endonucleases break down DNA, L), Caspases are activated by multiple pathways. 1. Intrinsic mitochondrial pathway i. Cellular injury, DNA damage, or loss of hormonal stimulation leads to inactivation of Bcl2. ii. Lack of Bel 2 allows cytochrome c to leak f r o m the inner mitochondrial matrix into the cytoplasm and activate caspases. Fig. 1.9 Fat necrosis of peri-pancreatic adipose Fig, 1,10 Fibrinoid necrosis of vessel. Fig, 1,11 Apoptosis. tissue. (Courtesy of humpath.com)  Growth Adaptations, Cellular Injury, and Cell Death 13 2. Extrinsic receptor-ligand pathway i. FAS ligand binds FAS death receptor (CD95) on the target cell, activating caspases (e.g., negative selection of t h y m o c y t e s in thymus). ii. T u m o r necrosis factor (TNF) binds T N F receptor on the target ccll, activating caspases. 3, Cytotoxic CD8 + T c e l l - m e d i a t e d pathway i. Perforins secreted by CD8 + T cell create pores in m e m b r a n e of target cell, ii. G r a n z y m e f r o m CD8 + T cell enters pores a n d activates caspases. iii. CDS'" T-eell killing of virally infected cells is an example. FREE RADICAL INJURY 1 BASIC P R I N C I P L E S A. Free radicals are chemical species with an unpaired electron in their outer orbit. R. Physiologic generation of free radicals occurs d u r i n g oxidative phosphorylation. 1. C y t o c h r o m e c oxidase (complex IV) transfers electrons to oxygen. 2. Partial reduction of yields superoxide (Op, hydrogen peroxide ( H , 0 , ) , a n d hydroxyl radicals ('OH). C. Pathologic generation of free radicals arises with 1. Ionizing radiation—water hydrolyzed to hydroxyl free radical 2. I n f l a m m a t i o n — N A D P H oxidase generates superoxide ions d u r i n g oxygen- dependent killing by neutrophils. 3. Metals (e.g., copper and i r o n ) — F e " generates hydroxyl free radicals (Fenton reaction). 4. D r u g s and chemicals—P450 system of liver metabolizes d r u g s (e.g., acetaminophen), generating free radicals. D. Free radicals cause cellular i n j u r y via peroxidation of lipids and oxidation of DNA and proteins; DNA d a m a g e is implicated in aging a n d oncogenesis. E. Elimination of tree radicals o c c u r s via multiple m e c h a n i s m s. 1. Antioxidant s (e.g., glutathione and v i t a m i n s A , C, a n d E) 2. Enzymes i. Superoxide dismuiase (in mitochondria)—Superoxide ( O p —» H , 0 , ii. Glutathione peroxidase (in m i t o c h o n d r i a ) — G S H + free radical GSSH and H,0 iii. Calalase (in peroxisomes)—H.O, —> O, and H , 0 3. Metal carrier proteins (e.g., t r a n s f e r r i n and ceruloplasmin) D. FREE RADICAL INJURY A. C a r b o n tetrachloride (CC^) 1. O r g a n i c solvent used in the d r y cleaning i n d u s t r y 2. Converted to CC1, free radical by P450 system of hepatocytes 3. Results in cell i n j u r y with swelling of RER; consequently, ribosomes detach, i m p a i r i n g protein synthesis. 4. Decreased apolipoproteins lead to fatty change in the liver (Fig. 1.12). B. Reperfusion i n j u r y L R e t u r n of blood to ischemic tissue results in production of O,-derived free radicals, which f u r t h e r d a m a g e tissue. 2. Leads to a c o n t i n u ed rise in cardiac e n z y m e s (e.g., t r o p o n i n ) after r e p e r f u s i on of infarcted myocardial tissue  12 FUNDAMENTALS OF PATHOLOGY AMYLOIDOSIS I. BASIC P R I N C I P L E S A. Amyloid is a misfolded protein tli.it deposits in the extracellular space, thereby d a m a g i n g tissues. B. Multiple proteins can deposit as amyloid. Shared features include 1. [}-pleated sheet configuration 2. Congo red staining and apple-green birefringence when viewed microscopically under polarized light (Fig. 1.13) C. Deposition can be systemic or localized, II. S Y S T E M IC A M Y L O I D O S I S A. P r i m a ry amyloidosis is systemic deposition of AL amyloid, which is derived from i m m u n o g l o b u l i n light chain. 1. Associated with plasma cell dyscrasias (e.g., multiple myeloma) B. Secondary amyloidosis is systemic deposition of AA amyloid, which is derived f r o m serum amyloid-associated protein (SAA). 1. SAA is an acute phase reactant that is increased in chronic i n f l a m m a t o r y states, malignancy, and Familial Mediterranean fever (FMF). 2, FMF is due to a dysfunction of neutrophils (autosomal recessive) and occurs in persons of Mediterranean origin. i. Presents with episodes of fever and acute serosal inflammation (can mimic appendicitis, arthritis, or myocardial infarction) ii. High SAA d u r i ng attacks deposits as AA amyloid in tissues. C. Clinical findings of systemic amyloidosis include 1. Nephrotic syndrome; kidney is the most c o m m o n organ involved. 2. Restrictive cardiomyopathy or a r r h y t h m i a 3. Tongue enlargement, malabsorption, and hepatosplenomegalv D. Diagnosis requires tissue biopsy. Abdominal fat pad and r e c t u m are easily accessible biopsy targets. E. Damaged organs must be transplanted. Amyloid cannot be removed. III. L O C A L I Z E D A M Y L O I D O S I S A. Amyloid deposition usually localized to a single organ. B. Senile cardiac amyloidosis 1. Non-mutated scrum transthyretin deposits in the heart. 2. Usually asymptomatic; present in 25% of individuals > 80 years of age C. Familial amyloid cardiomyopathy 1. Mutated serum transthyretin deposits in the heart leading to restrictive ca rd iomyopathy. 2. 5% of African Americans carry the mutated gene. Fig. 1.12 Fatty change of liver. Fig, 1.13 Amyloid. A, Congo red. B, Apple-green birefringence. (Courtesy of Ed Uthman, MD)  13 Growth Adaptations, Cellular Injury, and Cell Death D. Noiv-insu 1 i n - d e p e n d e n t diabetes mellitus (type II) i, Aniylin (derived from insulin) deposits in the islets of the pancreas, E. Alzheimer disease 1. A|i amyloid (derived from (J-amyloid precurso r protein) deposits in the brain f o r m i n g amyloid plaques, 2. Gene tor (5-APP is present on c h r o m o s o m e 21. Most individuals with Down s y n d r o m e (trisomy 21) develop Alzheimer disease by the age of 40 (early-onset). F. Dialysis-associated amyloidosis 1, ^ - m i c r o g l o b u l i n deposits in joints, G. Medullary carcinoma of the thyroid 1. Calcitonin (produced by t u m o r cells) deposits within the t u m o r ( ' t u m o r cells in an amyloid background').  Inflammation, Inflammatory Disorders, 2 and Wound Healing INTRODUCTION 1. INFLAMMATION A. Allows inflammatory cells, plasma proteins (e.g., complement), and fluid to exit blood vessels and enter the interstitial space B. Divided into acute and chronic inflammation ACUTE INFLAMMATION I. BASIC P R I N C I P L E S A, Characterized by the presence of edema and neutrophils in tissue (Fig. 2.1 A) B, Arises in response to infection (to eliminate pathogen) or tissue necrosis (to clear necrotic debris) C, Immediate response with limited specificity (innate i m m u n i t y ) II. MEDIATORS OF ACUTE I N F L A M M A T I O N A. Toll-like receptors (Tl.Rs) 1. Present on cells of the innate i m m u n e system (e.g., macrophages and dendritic cells) 2. Activated by pathogen-associated molecular patterns (PAMPs) that are commonly shared by microbes i, CDI4 (a TLR) on macrophages recognizes I ipo polysaccharide (a PAMP) on the outer m e m b r a n e of gram-negative bacteria. 3. TLR activation results in upregulation of NF-kB, a nuclear transcription factor that activates i m m u n e response genes leading to production of multiple i m m u n e mediators. 4. TLRs are also present on cells of adaptive i m m u n i t y (e.g., lymphocytes) and, hence, play an importan t role in mediating chronic inflammation. B. Arachidonic acid (AA) metabolites 1. AA is released f r o m the phospholipid cell m e m b r a n e by phospholipase A, and then acted upon by cyclooxygenase or 5-lipoxygenase. i. Cyclooxygenase produces prostaglandins (PG). a. PGI,, P G D „ and PGE 3 mediate vasodilation and increased vascular permeability. b. PGEj also mediates pain. ii. 5-lipoxygenase produces leukotrienes (LT). a. LTB, attracts and activates neutrophils. b. LTC^ LTD 4 , and LTE4 (slow reacting substances of anaphylaxis) mediate vasoconstriction, broncho spasm, and increased vascular permeability. C. Mast cells 1, Widely distributed throughout connective tissue 2. Activated by (1) tissue trauma, (2) complement proteins C3a a n d C5a, or (3) cross-linking of cell-surface IgE by antigen pathoma.com 11 12 FUNDAMENTALS OF PATHOLOGY i. Immediate response involves release of preformed histamine granules, which mediate vasodilation of arterioles and increased vascular permeability. ii. Delayed response involves production of araehidonic acid metabolites, particularly leukotrienes. D Complement 1. Proinflammator y serum proteins that "complement" inflammation 2. Circulate as inactive precursors; activation occurs via i. Classical pathway-—CI binds IgG or IgM that is bound to antigen. ii. Alternative pathway—Microbial products directly activate complement. iii. Mannose-binding lectin (MBL) pathway—MBL binds to m a n n o s e on microorganisms and activates complement. 3, All pathways result in production of C3 convertase (mediates C3 — C3a and C3b), which, in t u r n , produces C5 convertase (mediates C5 — C5a and C5h). C5b complexes with C 6 - C 9 to form the m e m b r a ne attack complex (MAC), i. C3a and C5a (anaphylatoxins)—trigger mast cell degranulation, resulting in hi st a mine-media ted vasodilation and increased vascular permeability ii. C5a—chemotactic for neutrophils iii. O b — o p s o n i n for phagocytosis iv. MAC—Ivses microbes by creating a hole in the cell m e m b r a n e Ii. llageman factor (Factor XII) 1. Inactive p r o i n f l a m m a t o r y protein produced in liver 2. Activated upon exposure to subendothelial or tissue collagen; in turn, activates i. Coagulation and fibrinolytic systems ii. Complement iii. Kinin system—Kinin cleaves high-molecular-weight kininogen (HMYVK) to bradvkinin, which mediates vasodilation and increased vascular permeability (simitar to histamine), as well as pain. III. CARDINAL SIGNS OF I N F L A M M A T I O N A. Redness (rubor) and w a r m t h (calor) 1, Due to vasodilation, which results in increased blood flow 2. Occurs via relaxation of arteriolar smooth muscle; key mediators are histamine, prostaglandins, and bradvkinin. B. Swelling (tumor) 1. Due to leakage of fluid f r o m postcapillary venules into the interstitial space (exudate) 2, Key mediators are (1) histamine, which causes endothelial cell contraction and (2) tissue damage, resulting in endothelial cell disruption, C. Pain (dolor) !. Bradvkinin and PGE, sensitize sensory nerve endings. WW I* f * f,. >' Z *. » J '. " v^ V c- _ i Fig. 2.1 Inflammation A, Acute inflammation with neutrophils. B. Chronic inflammation with lymphocytes and plasma cells.  Inflammation, Inflammatory Disorders, and Wound Healing 13 D. Fever 1. Pyrogens (e.g., LPS f r o m bacteria) cause macrophages to release IL-1 and TNF, which increase cyclooxygenase activity in perivascular cells of the hypothalamus, 2. Increased PGR, raises temperature set point. IV, N E U T R O P H I L A R R I V A L A N D F U N C T I O N A. Step 1—Marginatu m 1. Vasodilation slows blood flow in postcapillary venules. 2. Cells marginate from center of flow to the periphery. B. Step 2—Rolling 1. Select in "speed b u m p s " are upregulaled on endothelial cells. i. P-seleclin release f r o m Weibel Patade bodies is mediated by histamine. ii. E-selectin is induced by T N F and IL-1. 2. Selectins bind sialyl Lewis X on leukocytes. 3. Interaction results in rolling of leukocytes along vessel wall, C. Step 3—Adhesion 1. Cellular adhesion molecules (ICAM and V C A M ) are upregulated on endothelium by T N F and IL-L 2. Integrins are upregulated on leukocytes by C5a a n d I.TB(. 3. Interaction between C A M s and integrins results in firm adhesion of leukocytes to the vessel wall, 4. Leukocyte adhesion deficiency is most c o m m o n l y due to an autosomal recessive defect of integrins (CD18 suhunit). i. Clinical features include delayed separation of the umbilical cord, increased circulating neutrophils (due to impaired adhesion of marginated pool of leukocytes), and recurrent bacterial infections that lack p u s formation. D. Step 4—Transmigration a n d C h e m o t a x i s 1. Leukocytes transmigrat e across the endothelium of'postcapillary venules and move toward chemical attractants (chemotaxis). 2. Neutrophils are attracted by bacterial products, IL-8, CSa, a n d LTB.. E. Step 5—Phagocytosis 1. C o n s u m p t i o n of pathogens or necrotic tissue; phagocytosis is e n h a n c e d by opsonins (IgG a n d C3a). 2. Pseudopods extend f r o m leukocytes to f o r m phagosomes, which are internalized and merge with lysosomes to p r o d u c e phagolysosomes. 3. Chediak-Higashi s y n d r o m e is a protein trafficking defect (autosomal recessive) characterized by impaired phagolysosome f o r m a t i o n. Clinical features include i. Increased risk of pyogenic infections ii. Neutropenia (due to i n t r a m e d u l l a r y death of neutrophils) iii. Giant granules in leukocytes (due to fusion of granules arising f r o m the Golgi apparatus) iv. Defective p r i m a r y hemostasia (due to a b n o r m a l dense granules in platelets) v. Albinism vi. Peripheral neuropath y F. Step 6—Destruction of phagocytosed material 1. O , - d e p e n d e n t killing is the most effective m e c h a n i s m. 2. HOC!" generated by oxidative burst in phagolysosomes destroys phagocytosed microbes. i. O, is converted to O", by N A D P H oxidase (oxidative burst). ii. O' is converted to H , 0 , by superoxide dismutase (SOD). iii. 11,0, is converted to H O C (bleach) by myeloperoxidase (MPO). 12 FUNDAMENTALS OF PATHOLOGY 3. Chronic granulomatous disease (CGD) is characterized by poor O.-dependent killing. i. Due to NADPH oxidase defect (X-linked or autosomal recessive) ii. Leads to recurrent infection and granuloma formation with catalase-positive organisms, particularly Staphylococcus aureus, Pseudpmonas cepacia, Serratia marcescens, Nocardia, and Aspergillus iii. Nitrobiue tetrazolium test is used to screen for CCD. Leukocytes are incubated with NBT dye, which turns blue if NADPH oxidase can convert 0, to O', but remains colorless if NADPH oxidase is detective. 4. M PO deficiency results in defective conversion of H , 0 , to HO CI'. i.Increased risk for Candida infections; however, most patients are asymptomatic. ii. NBT is normal; respiratory burst (O, to H , O J is intact. 5. O,-independent killing is less effective than O.-dependent killing and occurs via enzymes present in leukocyte secondary granules (e.g., lysozyme in macrophages and major basic protein in eosinophils). G. Step 7—Resolution 1, Neutrophils undergo apoptosis and disappear within 24 hours after resolution of the inflammatory stimulus. V. MACROPHAGES A. Macrophages predominate after neutrophils and peak 2 - 3 days after inflammation begins. 1, Derived from monocytes in blood B. Arrive in tissue via the margination, rolling, adhesion, and transmigration sequence C. Ingest organisms via phagocytosis (augmented by opsonins) and destroy phagocytosed material using enzymes (e.g., lysozyme) in secondary granules ( 0 , - independent killing) D. Manage the next step of the inflammatory process. Outcomes include 1. Resolution and healing—Anti-inflammatory cytokines (e.g., 1L-10 and TGF-(i) are produced by macrophages. 2. Continued acute inflammation—marked by persistent pus formation; IL-8 from macrophages recruits additional neutrophils. 3. Abscess—acute inflammation surrounded by fibrosis; macrophages mediate fibrosis via fibrogenic growth factors and cytokines. 4. Chronic inflammation—Macrophages present antigen to activate CD4 T helper T cells, which secrete cytokines that promote chronic inflammation. C H R O N I C INFLAMMATION I BASIC PRINCIPLES A. Characterized by the presence of lymphocytes and plasma cells in tissue (Fig. 2. IB) B. Delayed response, but more specific (adaptive immunity) than acute inflammation C. Stimuli include (1) persistent infection (most common cause); (2) infection with viruses, mycobacteria, parasites, and fungi; (3) autoimmune disease; (4) foreign material; and (5) some cancers. II. T LYMPHOCYTES A. Produced in bone marrow as progenitor T cells B. Further develop in the thymus where the T-cell receptor (TCR) undergoes rearrangement and progenitor cells become CD4* helper T cells or CD{T cytotoxic T cells 1, T cells use TCR complex (TCR and CD3) for antigen surveillance.  Inflammation, Inflammatory Disorders, and Wound Healing 13 2. TCR complex recognizes antigen presented on M H C molecules. i. CD4 + T cells—MHC class II ii. C D 8 + T cells—MHC class! 3. Activation of T cells requires (1) b i n d i n g of a n t i g e n / M H C complex and (2) an additional 2nd signal. C. CD4* helper T-cel] activation 1. Extracellular antigen (e.g., foreign protein) is phagocytosed, processed, and presented on M H C class II, which is expressed by antigen presenting cells (A PCs). 2. B7 on APC binds C D 2 8 on C D 4 4 helper T cells providing 2nd activation signal. 3. Activated CD4 < helper T cells secrete cytokines that "help" i n f l a m m a t i o n and are divided into two subsets. i, T H 1 subset secretes IL-2 (T cell g r o w t h factor and CD8* T cell activator) and IFN-y (macrophage activator). ii. T l ( 2 subset secretes 1L-4 (facilitates B-cell class switching to IgG and IgE), IL-5 (eosinophil chemotaxis and activation, m a t u r a t i o n of B cells to plasma cells, and class switching to IgA), a n d IL-10 (inhibits T H 1 phenotype). D. CDS* cytotoxic T-cell activation 1. Intracellular antigen (derived from proteins in the cytoplasm) is processed and presented on M H C class I, which is expressed by all nucleated cells and platelets. 2. IL-2 from CD4 + T H 1 cell provides 2nd activation signal. 3. Cytotoxic T cells are activated for killing. 4. Killing occurs via i. Secretion of perforin and granzyme; perforin creates pores that allow g r a n z y m e to enter the target cell, activating apoptosis. it. Expression of FasL, which binds Fas on target cells, activating apoptosis III. B LYMPHOCYTES A. I m m a t u r e B cells are produced in the bone m a r r o w and u n d e r g o i m m u n o g l o b u l i n r e a r r a n g e m e n t s to b e c o m e naive B cells that express surface IgM and IgD. R. H-cell activation occurs via 1. Antigen b i n d i n g by surface IgM or IgD; results in m a t u r a t i o n to IgM- or IgD- secreting plasma cells 2. B-cell antigen presentation to CD4* helper T cells via M H C class II, i. CD40 receptor on R cell binds CD40L on helper T cell, providing 2nd activation signal. ii. Helper T cell then secretes IL-4 and IL-5 (mediate B-cell isotype switching, h y p e r m u t a t i o n , and m a t u r a t i o n to plasma cells), IV. G R A N U L O M A T O U S I N F L A M M A T I O N A. Subtype of chronic i n f l a m m a t i o n B. Characterized by g r a n u l o m a , which is a collection of epithelioid histiocytes (macrophages with a b u n d a n t pink cytoplasm), usually s u r r o u n d e d by giant cells a n d a rim of lymphocytes C. Divided into noncaseating and caseating subtypes 1. Noncaseating g r a n u l o m a s lack central necrosis (Fig, 2.2A). C o m m o n etiologies include reaction to foreign material, sarcoidosis, beryllium exposure, C r o h n disease, and cat scratch disease, 2. Caseating g r a n u l o m a s exhibit central necrosis and are characteristic of tuberculosis and fungal infections (Fig. 2.2B), D. Steps involved in g r a n u l o m a formation 1. Macrophages process and present antigen via M H C class 11 to CD4 4 helper T cells. 12 FUNDAMENTALS OF PATHOLOGY 2. Interaction leads macrophages to secrete IL-12, inducing C D 4 4 helper T cells to differentiate i n t o T H l subtype. 3. T M 1 cells secrete IFN-y, which converts macrophages to epithelioid histiocytes a n d giant cells. PRIMARY I M M U N O D E F I C I E N C Y I. DIGEORGE S Y N D R O M E A. Developmental failure of t h e third and fourth pharyngeal pouches 1, D u e t o 2 2 q l l microdeletion B. Presents with T-cell deficiency {lack of thymus); hypocalcemia (lack of parathyroids); and abnormalities of heart, great vessels, and face II. S E V E R E C O M B I N E D I M M U N O D E F I C I E N C Y (SCID) A. Defective cell-mediated and h u m o r a l i m m u n i t y B. Etiologies include 1. Cytokine receptor defects—Cytokin e signaling is necessary for proliferation and maturation of B and T c e l l s. 2. Adenosine d e a m i n a s e (ADA) deficiency—ADA is necessary to d e a m i n a t e adenosine and deoxyadenosine for excretion as waste products; b u i l d u p of adenosine and deoxyadenosine is toxic to lymphocytes. 3. M H C class II deficiency—M HC class II is necessary for C D 4 + helper T cell activation a n d cytokine production, C. Characterized by susceptibility to fungal, viral, bacterial, and protozoal infections, including opportunistic infections and live vaccines D. Treatmen t is sterile isolation ('bubble baby ) and stem cell transplantation. in. X-UNKED AGAMMAGLOBULINEMIA A. Complet e lack of i m m u n o g l o b u l i n d u e to disordered B-cell maturation 1. Naive B cells canno t m a t u r e to plasma cells. B. Due to mutated Bruton tyrosine kinase; X-linked C. Presents after 6 m o n t h s of life with recurrent bacterial, enterovirus (e.g., polio and coxsackievirus), and Giardia lamblia infections; maternal antibodies present d u r i n g the first fi m o n t h s of life are protective. D. Live vaccines (e.g., polio) must be avoided. IV. C O M M O N V A R I A B L E I M M U N O D E F I C I E N C Y ( C V I D ) A. Low i m m u n o g l o b u l i n due to B-cell or helper T-cell defects B. Increased risk for bacteria], enterovirus, and Giardia lamblia infections, usually in late childhood Fig. 2.2 Granuloma. A, Noncaseating, B, Cheating.  Inflammation, Inflammatory Disorders, and Wound Healing 13 C. I n c r e a s e d risk f o r a u t o i m m u n e disease a n d l y m p h o m a V. I g A D E F I C I E N C Y A. L o w s e r u m a n d m u c o s a l IgA; m o s t c o m m o n i m m u n o g l o b u l i n deficiency B. Increased risk tor m u c o s a l infection, especially viral; however, m o s t p a t i e n t s are asymptomatic. VI. H Y P E R - l g M S Y N D R O M E A. C h a r a c t e r i z e d by elevated IgM B. D u e to m u t a t e d C D 4 0 L (on helper T cells) or C D 4 0 receptor (on B cells) 1. Second signal c a n n o t be delivered to helper T cells d u r i n g B-cell activation. 2. C o n s e q u e n t l y , c y t o k i n e s n e c e s s a r y for i m m u n o g l o b u l i n class s w i t c h i n g are not produced, C. Low IgA, IgG, a n d IgE result in r e c u r r e n t pyogenic i n f e c t i o ns (due to p o o r o p s o n i z a t i o n ) , especially at m u c o s a l sites. VII. W I S K O T T - A L D R I C H S Y N D R O M E A. Characterized by thrombocytopenia , eczema, a n d recurrent infections {defective humoral and cellular immunity) B. D u e to m u t a t i o n in the W A S P gene; X-linked VIII.COMPLEMENT DEFICIENCIES A. C 5 - C 9 deficiencies—increase d risk for Neisseria i n f e c t i o n (Ngonorrhoeae a n d N meningitidis) B. CI i n h i b i t o r deficiency—result s in h e r e d i t a r y a n g i o e d e m a , w h i c h is c h a r a c t e r i z e d by e d e m a of t h e s k in (especially periorbital , Fig. 2.3) a n d m u c o s a l s u r f a c e s AUTOIMMUNE DISORDERS L BASIC P R I N C I P L E S A. C h a r a c t e r i z e d by i m m u n e - m e d i a t e d d a m a g e of tissues I. !% prevalence in the US B. Involves loss of self-tolerance I. Self-reactive l y m p h o c y t e s a r e regularly generate d but u n d e r g o a p o p t o s i s (negative selection) in t h e t h y m u s (T cells) or b o n e m a r r o w (B cells) or b e c o m e a n e r g i c (due to recognition of a n t i g e n in p e r i p h e r a l l y m p h o i d tissues with no 2 n d signal). C. M o r e c o m m o n in w o m e n ; classically affects w o m e n of c h i l d b e a r i n g age D. Etiology is likely an e n v i r o n m e n t a l t r i g g e r in genetically s u s c e p t i b l e i n d i v i d u a l s (increased i n c i d e n c e in t w i n s a n d associated w i t h c e r t a i n HLA subtypes). Fig. 2.3 Angioedema. (Courtesy of James Heilmsn, MD. Wikipedia)  12 FUNDAMENTALS OF PATHOLOGY IL SYSTEMIC LUPUS ERYTHEMATOSUS A. Systemic a u t o i m m u n e disease 1. Antibodies against tbe host damage multiple tissues via type !1 (cytotoxic) and type III (antigen-antibody complex) hypersensitivity. 2. More c o m m o n in women, especially African American females B. Clinical features include 1. Fever and weight loss 2. Malar 'butterfly' rash (Fig, 2.4), especially upon exposure to sunlight 3. Arthritis 4. Pleuritis and pericarditis (involvement of serosal surfaces) 5. C N S psychosis 6. Renal damage—Diffus e proliferative glomerulonephritis is the most c o m m o n injury, though other patterns of injury also occur. 7. Endocarditis, myocardit is, or pericard itis (can a ffect any 1 aver of the heart) i. Libman-Sacks endocarditis is a classic finding and is characterized by small, sterile deposits on both sides of the mitral valve. 8. Anemia, thrombocytopenia , or leukopenia (due to autoantibodies against cell surface proteins) 9. Renal failure and infection are c o m m o n causes of death. C. Characterized by a n t i n u d e a r antibody (ANA; sensitive, but not specific) and anti dsDNA antibodies (highly specific) D. Antihistone antibody is characteristic of drug-induced SLE. 1. Hydralazine, procainamide, and isoniazid are c o m m o n causes, 2. Removal of d r u g usually results in remission. E. Antiphospholipid antibody s y n d r o me is associated with SLE (30% of cases). 1. Characterized by autoantibody against proteins bound to phospholipids. 2. Anlicardiolipin and lupus anticoagulant are the most c o m m o n antibodies, i. Lead to false-positive syphilis test and falsely-elevated P T T lab studies, respectively 3. Results in arterial and venous thrombosis including deep venous thrombosis, hepatic vein thrombosis, placental thrombosis (recurrent pregnancy loss), and stroke 4. Requires lifelong anticoagulation III. S J Ö G R E N S Y N D R O M E A, A u t o i m m u n e destruction of lacrimal and salivary glands 1. Lymphocyte-mediated d a m a g e (type IV hypersensitivity) with fibrosis B. Classically presents as d r y eyes (keratoconjunctivitis), dry m o u t h (xerostomia), and recurrent dental carries in an older w o m a n ( 5 0 - 6 0 years)—"Can't chew a cracker, dirt in my eyes" Fig. 3.4 Malar 'butterfly' rash, SLE. Fig. 2.5 Intestinal crypts. Fig. 2.6 Basal layer of skin.  Inflammation, Inflammatory Disorders, and Wound Healing 13 C. Characterized by ANA and anti-ribonucleoprotein antibodie s (anti-SS-A/Ro a n d anti-SS-B/La) D. Often associated with other a u t o i m m u n e diseases, especially r h e u m a t o id arthritis E. Increased risk for B-cell (marginal zone) lymphoma , which presents as unilateral enlargement of the parotid gland late in disease course IV. SCLERODERMA A. A u t o i m m u n e tissue d a m a g e with activation of fibroblasts and deposition of collagen (fibrosis) B Divided into diffuse a n d localized Lypes C. Diffuse type exhibits skin and early visceral involvement. 1. Almost any organ can be involved; esophagus is c o m m o n l y affected, resulting irt disordered motility (dysphagia for solids and liquids). 2. Characterized by ANA and anti-DNA topoisomerase i (Scl-70) antibody D. Localized type exhibits local skin and late viscera! involvement. 1. Prototype is CREST syndrome: Calcinosis/anti-Centronier e antibodies, Raynaud p h e n o m e n o n. Esophageal dysmotility, Sclerodactyly, and Telangiectasias of the skin. V. M I X E D C O N N E C T I V E TISSUE DISEASE A. A u t o i m m u n e - m e d i a t e d tissue d a m a g e with mixed features of SLE, systemic sclerosis, and polymyositis B. Characterized by s e r u m antibodies against U1 ribonucleoprotein WOUND HEALING 1, BASIC P R I N C I P L E S A. Healing is initiated when i n f l a m m a t i o n begins. B. Occurs via a combination of regeneration a n d repair II REGENERATION A. Replacement of d a m a g ed tissue with native tissue; d e p e n d e n t on regenerative capacity of tissue B. Tissues are divided into three types based on regenerative capacity: labile, stable, and permanent. C. Labile tissues possess stem cells that continuously cycle to regenerate the tissue. 1. Small a n d large bowel (stem cells in mucosal crypts, Fig. 2.5) 2. Skin (stem cells in basal layer. Fig. 2.6) 3. Bone m a r r o w (hematopoietic stem cells) D. Stable tissues are comprised of cells that are quiescent {G_), but can reenter the cell cycle to regenerate tissue when necessary. 1. Classic example is regeneration of liver by c o m p e n s a t o r y hyperplasia after partial resection. Each hepatocyte produces additional cells and then reenters quiescence. E. Permanen t tissues lack significant regenerative potential (e.g., m y o c a r d i u m , skeletal muscle, a n d neurons). III. REPAIR A. Replacement of damage d tissue with fibrous scar B. O c c u r s when regenerative stem cells are lost (e.g., deep skin cut) or when a tissue lacks regenerative capacity (e.g., healing after a myocardial infarction, Fig. 2,7) C. Granulation tissue formation is the initial phas e of repair (Fig. 2.8). 12 FUNDAMENTALS OF PATHOLOGY 1. Consists of fibroblasts (deposit type 111 collagen), capillaries (provide nutrients), and myofibroblasts (contract w o u n d ) D. Eventually results in scar formation, in which type 111 collagen is replaced with type 1 collagen 1. Type III collagen is pliable and present in granulation tissue, embryonic tissue, uterus, and keloids. 2. Type I collagen has high tensile strength and is present in skin, bone, tendons, and most organs, 3. Collagenase removes type 111 collagen and requires zinc as a cofactor. IV. M E C H A N I S M S OF TISSUE REGENERATION A N D REPAIR A. Mediated by paracrine signaling via growth factors (e.g., macrophages secrete growth factors that target fibroblasts) R Interaction of growth factors with receptors (e.g.. epidermal growth factor with growth factor receptor) results in gene expression and cellular growth. C. Examples of mediators include 1. TGI : -a—epithelial and fibroblast growth factor 2. TGF-p — important fibroblast growth factor; also inhibits inflammation 3. Platelet-derived g r o w t h factor—growth factor for endothelium, smooth muscle, and fibroblasts 4. Fibroblast growth factor—important for angiogenesis; also mediates skeletal development 5. Va sc u la r e n dot he I ia! gro w t h fa c tor (V EG F)—i m por ta n t for a ngioge n esi s V. N O R M A L A N D A B E R R A N T W O U N D HEALING A. Cutaneous healing occurs via p r i m a ry or secondar y intention. 1. P r i m a r y intention—Wound edges are brought together (e.g., s u t u r i n g of a surgical incision); leads to minimal scar formation 2. Secondary intention—Edges are not approximated. Granulation tissue fills the defect; myofibroblasts then contract the w o u n d , forming a scar. B. Delayed wound healing occurs in 1. Infection (most c o m m o n cause; S aureus is the most c o m m o n offender) 2. Vitamin C, copper, or zinc deficiency ). Vitamin C is an importan t cofactor in the hydroxvlation of proline and lysine procollagen residues; hvdroxylation is necessary for eventual collagen cross-linking. ii. Copper is a cofactor forlysyl oxidase, which cross-links lysine and hydroxy lysine to form stable collagen. iii. Zinc is a cofactor for collagenase, which replaces the type 111 collagen of granulation tissue with stronger type I collagen. Fig, 2.7 Myocardial scarring. (Courtesyof Aliya Fig. 2.8 Granulation tissue. Husain, MD)  Inflammation, Inflammatory Disorders, and Wound Healing 13 3. O t h e r c a u s e s i n c l u d e foreign b o d y , i s c h e m i a, d i a b e t e s , a n d m a l n u t r i t i o n , C- D e h i s c e n c e is r u p t u r e of a w o u n d ; m o s t c o m m o n l y seen a f t e r a b d o m i n a l s u r g e r y D. H y p e r t r o p h i c scar is excess p r o d u c t i o n of scar tissue t h a t is l o c a l i z e d to t h e w o u n d {Fig. 2.9). F. Keloid is excess p r o d u c t i o n of scar tissue t h a t is o u t of p r o p o r t i o n to the w o u n d (Fig. 2.10). 1. C h a r a c t e r i z e d by excess t y p e III collagen 2. Genetic predisposition (more c o m m o n in African Americans) 3. Classically affect s earlobes, face, a n d u p p e r e x t r e m i t i e s Fig. 2.9 Hypertrophic scar. [Reprinted with Fig. 2.10 Keloid, permission, http; //e med ic i ne. med sc a pe.com / artide/1128404-overview)  Principles of Neoplasia NEOPLASIA I. BASIC P R I N C I P L E S A. Neoplasia is new I issue growth that is unregulated, irreversible, and monoclonal; these features distinguish it f r o m hyperplasia and repair. B. Monoclonal means that the neoplastic cells are derived f r o m a single mother cell. C. Q o n a l i t y can be determined by glucose-6-phosphate dehydrogenase (G6PD) enzyme iso forms. 1. Multiple isoforms (e.g., G6PD A , G6PD.,, and G 6 P D ( ) exist; only one isoform is inherited f r o m each parent. 2. In females, one isoform is randomly inactivated in each cell by lyonization (G6PD is present on the X chromosome). 3. Normal ratio of active isoforms in cells of any tissue is 1:1 (e.g., 50% of cells have G 6 P D a , and 50% ofcells have G6PD G ). 4. 1:1 ratio is maintained in hyperplasia, which is polyclonal (cells are derived from multiple cells). 5. Only o n e isoform is present in neoplasia, which is monoclonal. 6. Clonality can also be determined by androgen receptor isoforms, which are also present on the X chromosome. D. Clonality of B lymphocytes is determined by immunoglobulin (Ig) light chain phenotype. 1. fg is comprised of heavy and light chains. 2. Each B cell expresses light chain that is either kappa or lambda. 3. Normal kappa to lambda light chain ratio is 3:1. 4. T h i s j a t i o is m a i n t a i n e d in hyperplasia, which is polyclonal. 5. Ratio increases to > 6:1 or is inverted (e.g., kappa to lambda ratio = 1:3) in lymphoma, which is monoclonal, E. Neoplastic t u m o r s arc benign or malignant. 1. Benign t u m o r s remain localized and do not metastasize. 2. Malignant t u m o r s (cancer) invade locally and have the potential to metastasize. F. T u m o r nomenclature is based on lineage of differentiation (type of tissue produced) and whether the t u m o r is benign or malignant (Table 3.1). Table 3.1: Examples of Tumor N o m e n c l a t u re LINEAGE OF MALIGNANT BENIGN DIFFERENTIATION (CANCER) Epit helium Adenoma Adenocarcinoma Papilloma Papillary carcinoma Mesenchyme Lipoma Liposarcoma Lymphocyte {Does not exist) Ly mphoma / Leu kemia Meîanocylc Nevus (mole) Melanoma pathoma.com 26 12 FUNDAMENTALS OF PATHOLOGY li. EPIDEMIOLOGY A. C a n t e r is the 2nd leading cause of death in both adults and children. 1. The leading causes of death in adults are (1) cardiovascular disease, (2) cancer, and (3) cerebrovascular disease. 2. The leading causes of death in children are (1) accidents, (2} cancer, and (3) congenital defects. B. The most c o m m o n cancers by incidence in adults are (1) breast/prostate, (2) lung, and (3) colorectal. C. The most c o m m o n causes of cancer mortality in adults are (1) lung, (2) breast/ prostate, and (3) colorectal, in, ROLE OF SCREENING A. Cancer begins as a single mutated cell. B. Approximately 30 divisions occur before the earliest clinical symptoms arise. C. Each division (doubling time) results in increased mutations. 1. Cancers that do not produce symptom s until late in disease will have undergone additional divisions and, hence, additional mutations. 2. Cancers that are detected late tend to have a poor prognosis. D. Goal of screening is to catch dysplasia (precancerous change) before it becomes carcinoma or carcinoma before clinical symptoms arise. E. C o m m o n screening m e t h o ds include 1. Pap smear—detects cervical dysplasia (GIN) before it becomes carcinoma 2. Mammography—detects in situ breast cancer (e.g., D O S ) before it invades or invasive carcinoma before it becomes clinically palpable 3. Prostate specific antigen (PSA) and digital rectal exam—detects prostate carcinoma before it spreads 4. Hemoccult test (for occult blood in stool) and colonoscopy—detect colonic adenoma before il becomes colonic carcinoma or carcinoma before it spreads CARCINOGENESIS I. BASIC P R I N C I P L E S A. Cancer formation is initiated by damage to DNA of stem cells. The damage overcomes DNA repair mechanisms, but is not lethal. i. Carcinogens are agents that damage DNA, increasing the risk for cancer. I m p o r t a n t carcinogens include chemicals, oncogenic viruses, and radial ion (Table 3.2). B. DNA mutations eventually disrupt key regulatory systems, allowing for t u m o r promotion (growth) and progression (spread). 1. Disrupted systems include pro to-oncogenes, t u m o r suppressor genes, and regulators of apoptosis. II. O N C O G E N E S A. P roto -oncoge n e s a re essential to r eel I g rowt h a nd d i ffere n t i at ion; m uta l io n s of proto-oncogenes form oncogenes that lead to unregulated cellular growth. B. Categories of oncogenes include growth factors, growth factor receptors, signal transducers, nuclear regulators, and cell cycle regulators (Table 3.3). 1. Growth factors induce cellular growth (e.g., PDGFB in astrocytoma), 2. G r o w t h factor receptors mediate signals f r o m growth factors (e.g., ERBB2 [HF.R2/ueu\ in breast cancer). 3. S ign a 11 ra ns due e rs rel ay recepto r ac t i vat i on to th e n uc le us (e.g., ra s). i. Ras is associated with growth factor receptors in an inactive GDP-bound state.  Principles of Neoplasia 25 Table 3.2: Important Carcinogens and Associated Cancers CARCINOGENIC AGENT ASSOCIATED CANCER COMMENTS CHEMICALS Derived from Aspergillus, which can Aflatoxins Hepatocellular carcinoma contaminate stored grains Alkylating agents I.e u k em ia /1 ympho m a Side effect of chemotherapy Squamous cell carcinoma of oropharynx and Alcohol upper esophagus, pancreatic carcinoma, and hepatocellular carcinoma Squamous cell carcinoma of skin, lung cancer, Arsenic Arsenic is present in cigarette smoke. and angiosarcoma of liver Exposure to asbestos is more likely to lead to Asbestos Lung carcinoma and mesothelioma lung cancer than mesothelioma. Most common carcinogen worldwide; Carcinoma of oropharynx, esophagus, lung, Cigarette smoke polycyclic hydrocarbons are particularly kidney, and bladder carcinogenic. Found in smoked foods; responsible tor high Nitrosamines Stomach carcinoma rate of stomach carcinoma in iapan Naplithy lamine Urothelial carcinoma of bladder Derived from cigarette smoke Occupational exposure; used to make Vinyl chloride Angiosarcoma of liver polyvinyl chlurkle (PVC) for use in pipes Nickel, chromium, Lung carcinoma Occupational exposure beryllium, or silica ONCOGENIC VIRUSES Nasopharyngeal carcinoma, Burkitt EBV lymphoma. andCNS lymphoma in AIDS HHV-8 Kaposi sarcoma HBV and HCV Hepatocel lular carcinoma HTLV-1 Adult T-cell leukemia/lymphoma High-risk HPV (e.g., Squamous cell carcinoma of vulva, vagina, subtypes 16, 18,31,33) anus, and cervix; adenocarcinoma of cervix RADIATION Ionizing (nuclear A M L, C M L. a nd papii 1 a ry ca rci nom a of 1 he reactor accidents and Generates hydroxyl free radicals thyroid radiotherapy) Non Ionizing (UVB Results in formation of pvrimidine dimcrs Basal cell carcinoma, squamous cell sunlight is most common in DNA, which are normally excised by carcinoma, and melanoma of skin source) restriction endonuclease  12 FUNDAMENTALS OF PATHOLOGY ii. Receptor binding causes G D P to be replaced with GTP, activating ras. iii. Activated ras sends growth signals to the nucleus. iv. Ras inactivates itself by cleaving G T P to GDP; this is augmented by GTPase activating protein, v. Mutated ras inhibits the activity of GTPase activating protein. This prolongs the activated state of ras, resulting in increased growth signals. 4, Cell cycle regulators mediate progression through the cell cycle {e.g., cyctin and cyclin-dependent kinase). i. Cyclins and cyclin-dependent kinases (CDKs) form a complex which phosphorylates proteins that drive the cell throug h the cell cycle. ii. For example, the cvclinD/CDK4 complex phosphorylates the retinoblastoma protein, which promotes progression t h r o u g h the G ^ S checkpoint. III. TUMOR SUPPRESSOR GENES A. Regulate cell growth and, hence, decrease ("suppress") the risk of t u m o r formation; p53 and Rb (retinoblastoma) are classic examples. K, p53 regulates progression of the cell cycle from G t to S phase, 1. In response to DNA damage, p53 slows the cell cycle and upregulales DNA repair enzymes. Table 3,3: Important O n c o g e n e s and Associated Tumors FUNCTION MECHANISM ASSOCIATED TUMOR GROWTH FACTOR PDGFB Platelet-derived growth factor Overex press ion, autocrine loop Astrocytoma GROWTH FACTOR RECEPTORS FRBB2 |HER2f Epidermal growth factor Amplification Subset of breast carcinomas neu] receptor MEN 2A, MF:N 211 and sporadic RET Neural growth factor receptor Point mutation medullary carcinoma of thyroid KIT Stem cell growth factor receptor Point mutation Gastrointestinal stromal tumor SIGNAL TRANSDUCERS Carcinomas, melanoma, and RAS gene family GTP-binding protein Point mutation lymphoma Alii Tyrosine kinase !(9;22) with BCR CMl.and some types of ALL NUCLEAR REGULATORS c-MYC Transcription factor t(8;I4) involving IgH Burkitt lymphoma N-MYC Transcription factor Amplification Neuroblastoma L-MYC Transcription factor Amplification Lung carcinoma (small cell) CELL CYCLE REGULATORS CCND1 (cyclin Cyclin 1(1 LJ4) involving IgH Mantle cell lymphoma ©1) CDK4 Cyclin-dependenl kinase Amplification Melanoma  Principles of Neoplasia 25 2. If DNA repair is not possible, p53 induces apoptosis. i. p53 upregulates BAX, which disrupts Bcl2. ii. C y t o c h r o m e c leaks f r o m the mitochondria activating apoptosis, 3. Both copies of the p53 gene must be knocked out for t u m o r formation (Knudso n two-hit hypothesis). i. Loss is seen in > 50% of cancers. ii. G e r m l i n e mutation results in Li-Fraumeni s y n d r o m e (2nd hit is somatic), characterized by the propensity to develop multiple types of c a r c i n o m a s and sarcomas, C, Rb also regulates progression f r o m G, to S phase. 1. Rb "holds" the E2F transcription factor, which is necessary for transition to the S phase. 2. E2F is released when RB is phosphorylated by the cyclinD/cyclin-dependent kinase 4 (CDK4) complex, 3. Rb mutation results in const it utively free E2F, allowing progression t h r o u g h the cell cycle and uncontrolled g r o w t h of cells. 4. Both copies of Rb gene must be knocked out for t u m o r formation ( K n u d s o n two- hit hypothesis). i. Sporadic mutation (both hits are somatic) is characterized by unilateral retinoblastoma (Fig. 3,1). ii, G e r m l i n e mutation results in familial retinoblastoma (2nd hit is somatic), characterized by bilateral retinoblastoma and osteosarcoma. IV. REGULATORS OF A P O P T O S I S A. Prevent apoptosis in normal cells, but promote apoptosis in mutated cells whose DNA c a n n o t be repaired (e.g., Bcl2) 1. Bcl2 normally stabilizes the mitochondria l m e m b r a n e , blocking release of c y t o c h r o m e c. 2, Disruption of Bcl2 allows c y t o c h r o m e c to leave the mitochondria and activate apoptosis. B. Bcl2 is overexpressed in follicular l y m p h o m a , ). t(14;!8) moves Bcl2 ( c h r o m o s o m e 18) to the lg heavy chain locus ( c h r o m o s o m e 14), resulting in increased Bcl2. 2. Mitochondrial m e m b r a n e is f u r t h e r stabilized, prohibiting apoptosis. 3. B cells that would normally u n d e r g o apoptosis d u r i n g somatic h y p e r m u t a t i o n in the lymph n o d e germinal center accumulate, leading to l y m p h o m a. V, O T H E R I M P O R T A N T FEATURES OF T U M O R D E V E L O P M E N T A. Telomerase is necessary for cell immortality. Fig. 3.1 Retinoblastoma. (Courtesy of Jerome Fig. J-2 Carcinoma involving lymph node. Fig. 3.3 Seeding of the omentum by carcinoma, laity, MO) (Courtesy of Jerome Taxy, MO)  12 FUNDAMENTALS OF PATHOLOGY 1. Normally, telomeres shorten with serial cell divisions, eventually resulting in cellular senescence. 2. Cancers often have up regulated lelomerase, which preserves telomeres. B. Angiogenesis (production of new blood vessels) is necessary for t u m o r survival and growth. I. FGF and VEGF (angiogenic factors) are commonly produced by t u m o r cells. C. Avoiding immune surveillance is necessary for tumor survival, 1. Mutations often result in production of abnormal proteins, which are expressed on MHC. class 1. 2. CD8" T cells detect and destroy such mutated cells. 3. Tumor cells can evade immune surveillance by downregyiating expression of MHC class 1. 4. Immunodeficiency (both primar y and secondary) increases risk lor cancer. TUMOR PROGRESSION I. T U M O R INVASION A N D SPREAD A. A ccu m u I at io n of mu t a t ion s eve nt ua 11 y resu It s i n t u mor i j was ion a nd sp read. 1. Epithelial t u m o r cells are normally attached to one another by cellular adhesion molecules (e.g., E-cadherin). 2. Downregulalion of E-cadherin leads to dissociation of attached ceils. 3. Cells attach to laminin and destroy basement membran e (collagen type IV) via collagen a se. 4. Cells attach to fibronectin in the extracellular matrix and spread locally, 5. Entrance into vascular or lymphatic spaces allows for metastasis (distant spread). II. R O U T E S OF METASTASIS A. Lymphatic spread is characteristic of carcinomas, 1. Initial spread is to regional d r a i n i n g lymph nodes (Fig. 3.2). B. I lematogenous spread is characteristic of sarcomas and some carcinomas. 1. Renal cell carcinoma (often invades renal vein) 2. Hepatocellular carcinoma (often invades hepatic vein) 3. Follicular carcinoma of the thyroid 4. Choriocarcinoma C. Seeding of body cavities is characteristic of ovarian carcinoma, which often involves the peritoneum ('omental caking', Fig, 3.3). F i g. 3.4 H isto logic features of neo p lasi a. A. We 11 diff eren i i ated, f oil ic ula r ade noma of thyroid. 8. Fig. 3.5 Immunohistochemical stain for keratin Poorly differentiated, anaplastic carcinoma of thyroid, marking epithelial ceils tin brown).  Principles of Neoplasia 25 CLINICAL CHARACTERISTICS L CLINICAL FEATURES A. Benign t u m o r s tend to be slow g r o w i n g , well circumscribed, distinct, and mobile. B. Malignant t u m o r s are usually rapid growing, poorly circumscribed, infiltrative, and fixed to s u r r o u n d i n g tissues and local structures. C. Biopsy or excision is generally required before a t u m o r can be classified as benign or m a l i g n a n t with certainty. 1. Some benign t u m o r s can grow in a malignant-like fashion, and some malignant t u m o r s can grow in a benign-like fashion. II. HISTOLOGIC FEATURES A. Benign t u m o r s are usually well differentiated (Fig. 3.4A). Characteristics include 1. Organize d growth 2. Uniform nuclei 3. Low nuclear to cytoplasmic ratio 4. M i n i m a l mitotic activity 5. Lack of invasion (of basement m e m b r a n e or local tissue) 6. No metastatic potential B. Malignant t u m o r s are classically poorly differentiated (anaplastic. Fig. 3.4B). Characteristics include 1. Disorganized growth (loss of polarity) 2. Nuclear p l e o m o r p h i s m and hyperchromasia 3. High nuclear to cytoplasmic ratio 4. High mitotic activity with atypical mitosis 5. Invasion (through basement m e m b r a n e or into local tissue) C. Metastatic potential is the h a l l m a r k of malignancy—benign t u m o r s never metastasize. Table 3.4: C o m m o n Immunohistochemical Stains and Target Cell Types IMMUNOHISTOCHEMICAL STAIN TISSUE TYPE INTERMEDIATE FILAMENTS Keratin Epithelium Viinenlin Mesenchyme Desmin Muscle GEAP Neuroglia Neurofilament Neurons OTHERS PSA Prostatic epil helium ER Breast epithelium Thyroglobulin Ihyroid follicular cells Neuroendocrine cells (e.g., small cell Ch romogranin carcinoma of lung and carcinoid tumors) S-100 Melanoma 12 FUNDAMENTALS OF PATHOLOGY D. I m m u n o h i s t o c h e m i s t r y is used to characterize t u m o r s that are difficult to classify on histology (Fig. 3.5, Table 3.4). III. SERUM T U M O R MARKERS A. Proteins released by t u m o r into s e r u m (e.g., PSA) B. Useful for screening, monitoring response to treatment, and m o n i t o r i n g recurrence C. Elevated levels require tissue biopsy for diagnosis of carcinoma (e.g., biopsy of prostate with elevated PSA), IV. G R A D I N G OF CANCER A. Microscopic assessment of differentiation (i.e., how much a cancer resembles the tissue in which it grows); takes into account architectural and nuclear features 1. Well differentiated (low grade)—resembles normal parent tissue 2. Poorly d i ffere n t iat ed (high g rad e)—does no t resem ble pa rent t i s su e B. I m p o r t a n t for d e t e r m i n i n g prognosis; well-differentiated cancers have better prognosis t h a n poorly-differentiated cancers. V. S T A G I N G OF C A N C E R A. Assessment of size a n d spread of a cancer B. Key prognostic factor; more i m p o r t a n t t h a n grade C. Determined after final surgical resection of the t u m o r D. Utilizes T N M staging system 1. T — t u m o r (size a n d / o r depth of invasion) 2. N—spread to regional lymph nodes; second most i m p o r t a nt prognostic factor 3. M—metastasis; single most i m p o r t a n t prognostic factor  Hemostasis and Related Disorders INTRODUCTION HEMOSTASIS A. Integrity of the blood vessel is necessary to carry blood to tissues. I. Damage to the wall is repaired by hemostasis, which involves formation of a thrombus (clot) at the site of vessel injury. B. Hemostasis occurs in two stages: primary and secondary. 1, Primary hemostasis forms a weak platelet plug and is mediated by interaction between platelets and the vessel wall. 2. Secondary hemostasis stabilizes the platelet plug and is mediated by the coagulation cascade. PRIMARY HEMOSTASIS A N D R E L A T E D B L E E D I N G D I S O R D E R S t PRIMARY HEMOSTASIS A. Step 1—Transient vasoconstric