Robbins
`PATHOLOGIC
`BASIS OF
`DISEASE
`
`5th Edition
`
`Dallas, Texas
`
`Ramzi S. Cotran, M.D.
`Frank Burr Mallory Professor of Pathology
`Harvard Medical School
`Chairman, Departments of Pathology
`Brigham and Women’s Hospital
`The Children's Hospital
`Boston, Massachusetis
`
`Vinay Kumar, M.D.
`Vermie A. Stembridge Chair in Pathology
`The University of Texas
`Southwestern Medical Schocl
`
`Stanley L. Robbins, M.D.
`Visiting Professor of Pathology
`Harvard Medical School
`Senior Pathologist
`Brigham and Women’s Hospital
`Boston, Massachusetts
`
`8ee
`
`Complex Ex. 1015
`
`1
`
`

`

`Library of Congress Cataloging-in-Publication Data
`
`94-2629
`
`Cotran, Ramzi5.
`Robbins pathologic basis of disease. —-5th ed, / Ramzi §. Cotran,
`Stanley L. Robbins, Vinay Kumar.
`p-
`cm.
`Includes bibliographical references and index.
`ISBN 0-7216-5032-5
`1. Pathology.
`I. Robbins, Stanley L. (Stanley Leonard).
`II. Kumar, Vinay.
`IIL. Title.
`IV. Title: Pathologic basis of disease.
`[DNLM: 1. Pathology. QZ 4 C845r 1994]
`RB111.R62 1994
`616.07 —dc20
`DNLM/DLC
`
`ISBN 0-7216-5032-5
`Robbins Pathologic Basis of Disease, 5th edition
`Copyright © 1994, 1989, 1984, 1979, 1974 by W.B. Saunders Company.
`All rights reserved. No part of this publication may be reproducedor transmitted in any form or
`by any means, electronic or mechanical,
`including photocopy, recording, or any information
`storage and retrieval system, without permission in writing from the publisher.
`Printed in the United States of America.
`Last digit is the printnumber:
`9
`
`8
`
`7
`
`6
`
`5
`
`4
`
`3.
`
`2
`
`2
`
`

`

`
`
`
`Contributors
`
`Douglas C. Anthony, M.D., Ph.D.
`Assistant Professor of Pathology, Harvard Medical
`School; Director of Neuropathology, The Children’s
`Hospital; Neuropathologist, Brigham and Women’s Hos-
`pital, Boston, Massachusetts
`
`George F. Murphy, M.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 Pennsy!vania, Philadelphia, Pennsyl-
`vania
`
`James M. Crawford, M.D., Ph.D.
`Assistant Professor of Pathology, Harvard Medical
`School; Pathologist, Brigham and Women’s 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
`
`Umberto De Girolami, 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, Hs.vard Medical School, Harvard
`School of Public Health; Pathologist, Brigham and
`Women’s Hospital, Boston, Massachusetts
`
`Martin C. Mihm, Jr., M.D.
`Professor of Pathology and Chief of Dermatology and
`Dermatopathology, Albany Medical College, Albany,
`New York
`
`Andrew E. Rosenberg, M.D.
`Assistant frofessor of Pathology, Harvard Medical
`School; Associate Pathologist, Massachusetts General
`Hospital, Boston, Massachusetts
`
`John Samuelson, M.D., Ph.D.
`Associate Professor, Department of Tropical Public
`Health, Harvard School of Public Health, Boston, Massa-
`
`chusetts
`
`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 Schofield, M.D.
`Assistant Professor of Pathology, Harvard Medical
`School and The Children’s Hospital, Boston, Massachu-
`setts
`
`Franz von Lichtenberg, 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 Jaunching 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.
`® 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.
`¢ To organize the presentations into logical and uniform ap-
`proaches,
`thereby facilitating readability, comprehension, and
`learning.
`e 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 biclogic importance.
`© 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.
`® To makethis 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 sufficient detail
`and depth to meet the needs of more advanced readers.
`We hopethat we have, at least in some measure, achieved these goals;
`any shortcomings are surely notfor 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. Whenever appropriate, newer mor-
`phologic techniques relevant
`to the identification of particular lesions or
`
`4
`
`

`

`x PREFACE
`
`tumors have been incorporated. Theclinical significance of the morphologic
`and molecular changes has been integrated throughout thetext.
`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 canilluminate the text.
`Wehope 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 theyare “‘classic.”
`The same three authors of previous editions prepared most of the chap-
`ters themselves, but reviewed, edited, and critiquedall of them. They were
`measurably helped by the advice and reviews of many experts who were
`sought outto ensure the accuracy, completeness, and authenticity of areas of
`their expertise, as detailed in the acknowledgmentssection.
`Wehope that we have succeeded in transmitting to the readers ofthis
`text the beauty and excitement of our expanding knowledgeofthe 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 ofactivity-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 brenchitis 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
`
`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 ofthe 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 importantclinically (Fig. 15-8).
`
`CENTRIACINAR (CENTRILOBULAR EMPHYSEMA). The
`distinctive feature of this type of emphysema is the
`pattem of involvement of the lobules; the central
`or proximal parts of the acini, formed by resplra-
`fory brenchioles, are affected, whereas distal al-
`veoll are spared (Fig. 15-9A). Thus, both emphy-
`sematous and normal airspaces exist within the
`same acinus and lobule. The lesions are more com-
`mon and usually more severe in tha upper lobes,
`particularly in the apical segments. The walls of the
`emphysematous
`spaces
`often
`contain
`large
`amounts of black pigment.
`Inflammation around
`bronchi and bronchioles and in the septa Js com-
`mon. In severe centriacinar emphysema, the distal
`acinus may be Involved, and differentiation from
`ponacinar emphysema becomes difilcult. 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’ pneumoconiosis (see later
`in this chapter) bear a striking|\resemblance to cen-
`tracinar emphysema. These polnts suggest an Im-
`
`webs Table 15-3.DISORDERSASSOCIATEDAIRFLOWOBSTRUCTION:THESPECTRUMOFCOPDWITH
`
`
`
`
`
`CLINICAL
`ANATOMIC
`MAJOR PATHOLOGIC
`TERM
`SITE
`CHANGES
`
`
`SIGNS/SYMPTOMS
`
`ETIOLOGY
`
`Chronic
`bronchitis
`Bronchlectasis
`
`Asthma
`
`Bronchus
`
`Bronchus
`
`Bronchus
`
`Mucus gland hyperplasia,
`hypersecretion
`Alrway dilatation and
`scaring
`Smooth muscle hyperplasia,
`excess Mucus,
`inflammation
`Inflammatory scaring/
`obliteration
`
`Tobacco smoke,alr
`pollutants
`Persistent or severe
`Infections
`Immunologic or undefined
`causes
`
`Tobacco smoke, air
`pollutants, misc.
`
`Cough, sputum
`production
`Cough: purulent sputum;
`fever
`Episodic wheezing, cough.
`dyspnea
`
`Cough, dyspnea
`
`Bronchicle
`
`“Small airway
`disease,”
`bronchiolitis
`Emphysema
`
`Acinus
`
`Airspace enlargement; wall
`destruction
`
`Tobacco smoke
`
`Dyspnea
`
`6
`
`