`PATHOLOGIC
`BASIS OF
`DISEASE
`
`5th Edition
`
`
`
`Ramzi 8. Cotton, M.D.
`
`Frank Burr Mallow Professor of Pathology
`Howard Medical School
`
`Chalrrnan. Departments of Pathology
`Brigham and Women's Hospital
`The Children's Hospital
`Boston. Massachusetts
`
`Vinay Kumar, M.D.
`
`Vemle A. Stembridge Chair in Pathology
`The University of Texas
`Southwestern Medical School
`Dallas. Texas
`
`Stanley L. Robbins, M.D.
`
`Visiting Professor of Pathology
`Harvard Medical School
`
`Senior Pathologist
`Brigham and Women's Hospital
`Boston, Massachusetts
`
`Complex Ex. 1015
`
`1
`
`
`
`DNLMIDLC Title.
`
`Cotran. Ramzi 5.
`Robbins pathologio basis of disease. —-5th ed. I Iiamzi S. Cotran.
`Kumar.
`Stanley L. Robbins. Vinny
`p.
`cm.
`Includes bibliographical
`ISBN 0-7216-5032-5
`1. Pathology.
`1. Robbins. Stanley L. (Stanley Leonard).
`IV. Title: Pathologic basis of disease.
`II. Kumar, Vinny. DI.
`Q2 4 C845r 1994]
`IDNLM: 1. Pathology.
`RBlll.R62 1994
`616.07-dc20
`
`references and index.
`
`Library of Congress Cataloging-in-Publication Data
`
`94-2629
`
`Robbins Pathologic Basis of Disease. 5th edition
`
`ISBN 0-7216-5032-5
`
`Copyright E1 1994, 1989. 1984. 1979. 1974 by W.B. Saunders Company.
`All rights reserved. No part of this publication may be reproduced or transmitted in any form or
`mechanical.
`including photocopy. recording. or any information
`by any means, electronic or
`without permission in writing from the publisher.
`storage and retrieval system.
`
`Printed in the United States of America.
`
`Last digit is the print number;
`
`9
`
`B
`
`7
`
`6
`
`5
`
`4
`
`3
`
`2
`
`2
`
`
`
`contributors
`
`
`
`Douglas C. Anthony, M.D., Ph.D.
`Assistant Professor of Pathology, Harvard Medical
`School; Director of Neuropathologya The Children's
`Hospital; Neuropathologist, Brigham and Women's Hos-
`pital, Boston, Massachusetts
`
`George F. Murphy, IVl.D.
`Herman Beerman Professor of Dermatology, Professor of
`Pathology, University of Pennsylvania School of Medi-
`cine; Director of Dermatopathology Training, Hospital
`of the University of Pennsylvania, Philadelphia, Pennsyl-
`vanla
`
`James M. crawford, M.D., Ph.D.
`Assistant Professor of Pathology, Harvard Medical
`School; Pathologist, Brigham and Women's Hospital,
`Boston, Massachusetts
`
`Andrew E. Rosenberg, M.D.
`Assistant Professor of Pathology, Harvard Medical
`School; Associate Pathologist, Massachusetts General
`Hospital, Boston, Massachusetts
`
`Christopher P. crum, M.D.
`Associate Professor of Pathology, Harvard Medical
`School; Director, Division of Women's and Perinatal Pa-
`thology, Brigham and Women's Hospital, Boston, Massa-
`chusetts
`
`John Samuelson. M.D., Ph.D.
`Associate Professor, Department of Tropical Public
`Iiealth, Harvard School of Public Health, Boston, Massa-
`c usetts
`
`Umberto De Glrolaml, M.D.
`Associate Professor of Pathology, Harvard Medical
`School; Neuropathologist, Brigham and Women’s Hospi-
`tal and The Children's Hospital, Boston, Massachusetts
`
`Matthew P. Frosch, M.D., Ph.D.
`Instructor in Pathology, Harvard Medical School; Asso-
`ciate Pathologist, Brigham and Women's Hospital; Con-
`sultant in Pathology, Children's Hospital, Boston, Massa-
`chusetts
`
`Lester Kobzik, M.D.
`Assistant Professor, Howard Medical School, Harvard
`School of Public Health; Pathologist, Brigham and
`Women's Hospital, Boston, Massachusetts
`
`Martin c. Mihm, Jr.. MD.
`Professor of Pathology and Chief of Dermatology and
`Dermatopathology, Albany Medical College, Albany,
`New York
`
`Frederick J. schoen, M.D., Ph.D.
`Associate Professor of Pathology, Lawrence J. Hender-
`son Associate Professor of Health Sciences and Technol-
`ogy, Harvard Medical School; Vice-Chairman, Depart-
`ment of Pathology, Brigham and Women's Hospital,
`Boston, Massachusetts
`
`Deborah schofleld, M.D.
`Assistant Professor of Pathology, Harvard Medical
`School and The Children's Hospital, Boston, Massachu-
`setts
`
`Franz von Llchtenberg, M.D.
`Professor of Pathology Emeritus, Harvard Medical
`School; Senior Pathologist, Brigham and Women's Hos-
`pital, Boston, Massachusetts
`
`3
`
`
`
`Preface
`
`
`
`Once again, we are launching a new edition of this book—the fifth. In
`the five years since the previous edition, spectacular advances have been
`made in many areas of the science and practice of pathology—particularly
`in our understanding of the molecular and genetic origins of many diseases
`and in the application of modern techniques to diagnostic pathology. Al-
`though these have necessitated extensive revisions, our goals remain essen-
`tially the same.
`
`0 To integrate into the discussion of pathologic processes and dis-
`orders
`the newest established information available—-mor-
`phologic, molecular, and genetic. This, we hope, will make the
`understanding of disease as up-to-date as possible and will facili-
`tate the application of optimal diagnostic modalities and thera-
`peutic interventions.
`I To organize the presentations into logical and uniform ap-
`proaches,
`thereby facilitating readability, comprehension, and
`learning.
`0 Not to permit the book to become larger and more cumber-
`some, and yet to provide adequate discussion of the significant
`lesions, processes, and disorders, allotting space in proportion to
`their clinical and biologic importance.
`0 To place great emphasis on clarity of writing and good usage of
`language in the recognition that struggling to comprehend is
`time-consuming and wearisome and gets in the way of the learn-
`ing process.
`0 To make this first and foremost a student text (useful to students
`throughout their four years of medical school and into their
`residencies) but, at the same time,
`to provide suflicient detail
`and depth to meet the needs of more advanced readers.
`
`We hope that we have, at least in some measure, achieved these goals;
`any shortcomings are surely not for lack of trying.
`Although the newer body of knowledge has required extensive rewrit-
`ing, the basic organization remains largely unchanged. The chapters on gen-
`eral principles and processes such as cell injury and inflammation are con-
`fined to the first
`third of the text, while the remainder of the book is
`concerned with the disorders of various organs and systems. Every chapter
`has been carefully updated with “state-of-the-art" material, and many have
`been largely rewritten. A new chapter on normal and abnormal cell growth
`has been added to the discussion of general pathology, stimulated by the
`explosion of new information. In systemic pathology emphasis has been
`placed on the origins of functional and structural changes (etiology and
`pathogenesis), but the essential morphology, highlighted by a pink back-
`ground, has been carefully preserved. VVhenever appropriate, newer mor-
`phologic techniques relevant
`to the identification of particular lesions or
`
`4
`
`
`
`X PREFACE
`
`tumors have been incorporated. The clinical significance of the morphologic
`and molecular changes has been integrated throughout the text.
`Particularly newsworthy in this edition is the extensive revision of the
`illustrative material. Fully half of the photographs have been replaced, and
`many of these replacements are in color. A large number of new diagrams
`and charts have also been incorporated where they can illuminate the text.
`We hope that this new infusion not only reinforces the textual matter but
`also makes the reading more pleasurable.
`A liberal but judicious number of references are incorporated into the
`writing to provide source material for those who wish to pursue subjects of
`their own interest. Great effort was made in selecting these references for
`their quality, authenticity, and completeness. While most are recent-
`indeed some appeared in 1994, the year of publication of this text— older
`classics have been retained precisely because they are "classic."
`The same three authors of previous editions prepared most of the chap-
`ters themselves, but reviewed, edited, and critiqued all of them. They were
`measurably helped by the advice and reviews of many experts who were
`sought out to ensure the accuracy, completeness, and authenticity of areas of
`their expertise, as detailed in the acknowledgments section.
`We hope that we have succeeded in transmitting to the readers of this
`text the beauty and excitement of our expanding knowledge of the nature of
`many diseases and have stimulated them to learn more about the pathologic
`basis of disease.
`
`5
`
`
`
`CHRONIC OBSTRUCTIVE
`PULMONARY DISEASE
`
`The term "chronic obstructive pulmonary disease"
`(COPD) refers to a group of conditions that share a
`major symptom—dyspnea—and are accompanied
`by chronic or recurrent obstruction to air flow
`within the lung. Because of the increase in envi-
`ronmental pollutants, cigarette smoking, and other
`noxious exposures, the incidence of COPD has in-
`creased dramatically in the past few decades and
`now ranks as a major cause of activity-restricting
`or bed-confining disability in the United States.
`In their prototypical
`forms,
`these individ-
`ual disorders—chronic bronchitis, bronchiectasis,
`asthma, emphysema—have distinct anatomic and
`clinical characteristics (Table 15-3). For example,
`patients with predominant emphysema and those
`with predominant bronchitis form distinct clinical
`categories, as shown in Table 15-4. However,
`many patients have overlapping features of damage
`at both the acinar (emphysema) and the bronchial
`(bronchitis)
`levels, almost certainly because one
`pathogenic mechanism—cigarette
`smoking-—is
`common to both, as we shall see. Add the frequent
`component of reversible airway hyper-reactivity
`(asthma) in these patients, and one can understand
`the utility and popularity of the broad “umbrella"
`term COPD.
`
`EMPHYSEMA
`
`Emphysema is a condition of the lung character-
`ized by abnormal permanent enlargement of the
`airspaces distal to the terminal bronchiole, accom-
`panied by destruction of their walls, and without
`
`'..- Table 15-3.
`ouuloal.
`AIlA‘loMlc
`MAJOR nnrotoole
`TERM
`SITE
`CHANGES
`
`
`the distention of air-
`for example,
`overinflation,
`spaces in the opposite lung following unilateral
`pneumonectomy.
`
`Types of Emphysema
`
`Not only can emphysema be defined in terms of
`the anatomic nature of the lesion, but also it can be
`further classified according to its anatomic distri-
`bution within the lobule. Recall that the lobule is a
`cluster of acini, the alveolated terminal respiratory
`units. Although the term “emphysema" is some-
`times loosely applied to diverse conditions, there
`are four types: (1) centriacinar, (2) panacinar, (3)
`paraseptal, and (4) irregular. Of these, the first two
`are the most important clinically (Fig. 15-8).
`
`CENTIIIAGIIIAII ¢cEll'lRlI.OIllI.AIt EMPI-IYSEMA). The
`distinctive feature of this type of emphysema is the
`pattern of involvement of the Iobules: the central
`or proximal ports of the racial, tonned by respira-
`tory bronchloles. are atlected, whereas distal al-
`veoli are spared (Fig. T5-'9A). Thus. both emphy-
`semotous and normal alrspaces exist within the
`some acinus and lobule. The lesions are more com-
`mon and usually more severe in the upper lobes,
`particularly in the apical segments. The walls of the
`ernphysematous
`spaces
`often
`contain
`large
`amounts of block pigment.
`Inflammation around
`bronchi and bronchloles and in the septa is com-
`mon. In severe centrlaclnar emphysema. the distal
`acinus may be involved. and dltterentlotlon from
`panacinar emphysema becomes dlfflcult. Moder-
`ate-to-severe degrees of emphysema occur pre-
`dominantly In heavy smokers. often in association
`with chronic bronchitis. In addition. some lesions of
`so-called coal workers’ pneumoconiosls (see later
`in this chapter) bear a sinking resemblance to cen-
`trlaclnar emphysema. These points suggest an Im-
`
`|
`
`ETIOLOOY
`
`slons/svuirroms
`
`Tobacco smoke. air
`pollutants
`Persistent or severe
`Infections
`Immunologic or undefined
`causes
`
`Cough. sputum
`production
`Cough: pumlent sputum:
`fever
`Episodic wheenng. cough.
`dyspnea
`
`Tobacco smoke. air
`pollutants. misc.
`
`Cough. dyspnea
`
`Chronic
`bronchitis
`Bronchlectosls
`
`Asthma
`
`Bronchus
`
`Bronchus
`
`Bronchus
`
`Bronchlole
`
`Mucus gland hyperplasla.
`hypersecretlon
`Airway dilatation and
`scarring
`Smooth muscle hyperplosla.
`excess mucus.
`Inflammation
`Inflammatory scarring]
`obliteration
`
`“Small airway
`disease."
`bronchlolltls
`Dyspnea
`Tobacco smoke
`Airspace enlargement: wall
`Aclnus
`Emphysema
`destruction
` _
`
`6