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Page 1: Diagnostic Atlas of Non-Neoplastic Lung Disease: A ... · Flock Workers’ Lung 216 10. Pulmonary Hypertension and Other Noninfl ammatory Vascular Disorders 219 Pulmonary Hypertension—General
Page 2: Diagnostic Atlas of Non-Neoplastic Lung Disease: A ... · Flock Workers’ Lung 216 10. Pulmonary Hypertension and Other Noninfl ammatory Vascular Disorders 219 Pulmonary Hypertension—General

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Diagnostic Atlas of Non-Neoplastic Lung Disease

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Diagnostic Atlas of Non-Neoplastic Lung Disease

A Practical Guide for Surgical Pathologists

Anna-Luise A. Katzenstein, MDEmeritus Professor of PathologySUNY Upstate Medical UniversitySyracuse, New York

NEW YORK

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Visit our website at www.demosmedical.com

ISBN: 978-1-62070-064-8e-book ISBN: 978-1-61705-229-3

Acquisitions Editor: David D’AddonaCompositor: Newgen KnowledgeWorks

Copyright © 2016 Springer Publishing Company. Demos Medical Publishing is an imprint of Springer Publishing Company, LLC.

All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher.

Medicine is an ever-changing science. Research and clinical experience are continually expanding our knowledge, in particu-lar our understanding of proper treatment and drug therapy. The authors, editors, and publisher have made every effort to ensure that all information in this book is in accordance with the state of knowledge at the time of production of the book. Nevertheless, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the contents of the publication. Every reader should examine carefully the package inserts accompanying each drug and should carefully check whether the dosage schedules mentioned therein or the contraindications stated by the manufacturer differ from the statements made in this book. Such examination is particularly important with drugs that are either rarely used or have been newly released on the market.

Library of Congress Cataloging-in-Publication DataNames: Katzenstein, Anna-Luise A., author.Title: Diagnostic atlas of non-neoplastic lung disease : a practical guide for surgical pathologists / Anna-Luise A. Katzenstein.Description: New York, NY : Demos Medical Publishing, LLC/Springer Publishing Company, [2016] | Includes bibliographical references and index.Identifi ers: LCCN 2016006254 | ISBN 9781620700648 | ISBN 9781617052293 (ebook)Subjects: | MESH: Lung Diseases—diagnosis | Lung Diseases—pathology | Pathology, Surgical | AtlasesClassifi cation: LCC RC756 | NLM WF 17 | DDC 616.2/4—dc23LC record available at http://lccn.loc.gov/2016006254

Special discounts on bulk quantities of Demos Medical Publishing books are available to corporations, professional asso-ciations, pharmaceutical companies, health care organizations, and other qualifying groups. For details, please contact:

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Printed in the United States of America by Publishers’ Graphics.16 17 18 19 20 / 5 4 3 2 1

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Lest we forget whence we came. . . .

This book is dedicated to Dr. Averill A. Liebow (1911–1978), on whose works modern pulmonary pathology is based.

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4. Airspace-Predominant Diseases 85 Organizing Pneumonia (OP) 85 Eosinophilic Pneumonia 91 Aspiration Pneumonia 95

Exogenous Lipoid Pneumonia 97 Respiratory Bronchiolitis Interstitial

Lung Disease/Desquamative Interstitial Pneumonia (RBILD/DIP) 99

Alveolar Hemorrhage Syndromes 104 Pulmonary Alveolar Proteinosis (PAP) 110 Pulmonary Alveolar Microlithiasis (PAM) 113

5. Diffuse Alveolar Damage, Acute Interstitial Pneumonia 115

Diffuse Alveolar Damage (DAD) 115 Acute Interstitial Pneumonia (AIP) 125

6. Necrotizing Noninfectious Diseases 127 Granulomatosis With Polyangiitis

(GPA) 127 Eosinophilic Granulomatosis With

Polyangiitis (EGPA) (Formerly Churg–Strauss Syndrome) (CSS) 137

Necrotizing Sarcoid Granulomatosis (NSG) 140

Bronchocentric Granulomatosis (BCG) 143 Rheumatoid Nodule 146 Lymphomatoid Granulomatosis (LYG) 147

7. Infections I: Nongranulomatous Pneumonias 155

Viral Pneumonia 155 Cytomegalovirus Pneumonia (CMV) 155 Herpes Simplex/Varicella-Zoster

Pneumonia 157 Adenovirus Pneumonia 159 Measles Pneumonia 161 Infl uenza and Other Viral Pneumonias 161

Fungal Pneumonia 163 Invasive Aspergillosis/Mucormycosis 163

List of Abbreviations xiPreface xiiiAcknowledgments xv

1. Normal Lung, Common Artifacts, and Incidental Findings 1

Normal Lung Architecture 1 Handling of Tissue Specimens 3 Approach to Diagnosis 3 Artifacts 5 Incidental Findings 6

2. Interstitial Diseases I: Cellular Variants 23 Cellular Nonspecifi c Interstitial

Pneumonia (NSIP) 23 Hypersensitivity Pneumonia (HP) 26 Lymphoid Interstitial Pneumonia (LIP) 31 Langerhans Cell Histiocytosis (LCH) 34 Sarcoidosis 40 Lymphangiomyomatosis (LAM) 44 Diffuse Meningotheliomatosis 50

3. Interstitial Diseases II: Fibrotic Variants 55 Usual Interstitial Pneumonia (UIP) 55 Fibrotic Nonspecifi c Interstitial

Pneumonia (NSIP) 66 Scarred Langerhans Cell

Histiocytosis (LCH) 68 Smoking-Related Interstitial

Fibrosis (SRIF) 70 Collagen Vascular Disease–Associated

Interstitial Fibrosis 73 Nonclassifi able Interstitial Fibrosis 78 Rare, Unproven Entities 80

Pleuroparenchymal Fibroelastosis (PPFE) 80

Bronchiolocentric Interstitial Pneumonia 81

Contents

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Pu lmonary Veno-Occlusive Disease (PVOD) 233

Extrapulmonary Venous Obstruction 236

Pulmonary Capillary Hemangiomatosis 237 Pulmonary Emboli 241

Thromboemboli 241 Other Emboli 243

11. Large and Small Airway Diseases 247 Asthma 247 Bronchiectasis 247

Middle Lobe Syndrome 248 Mucoid Impaction of Bronchi (MIB) 250 Tracheobronchial Amyloidosis 253 Tracheobronchopathia

Osteochondroplastica (TO) 254 Respiratory Bronchiolitis (RB) 255 Follicular Bronchiolitis 256 Diffuse Panbronchiolitis 258 Acute Cellular Bronchiolitis 260 Constrictive Bronchiolitis Obliterans

(CBO) 261 Diffuse Idiopathic Pulmonary

Neuroendocrine Cell Hyperplasia (DIPNECH) 264

12. Miscellaneous Nodules, Depositions, and Cysts 269

Pulmonary Hyalinizing Granuloma (PHG)/ Fibrosing Mediastinitis (FM) 269

Amyloid Nodule (Nodular Amyloidosis) 274

Nodular Lymphoid Hyperplasia/ Infl ammatory Pseudotumor 278

Intraparenchymal Lymph Node 280 Pulmonary Infarct 281 Round Atelectasis 283 Pulmonary Apical Cap 283 Alveolar Septal Amyloidosis 286 Metastatic Calcifi cation 289 Metaplastic Ossifi cation 292 Blebs, Bullae, Other Cysts, and

Pneumothorax-Related Changes 294 Blebs and Bullae 294 Other Cys ts 294 Pneumothorax- Related Changes 296

13. Pediatric Disorders 301 Pulmonary Sequestration 301

Intralobar Sequestration 301 Extralobar Sequestration 304

Congenital Cystic Adenomatoid Malformation (CCAM)/Congenital Pulmonary Airway Malformation (CPAM) 305

Candida Pneumonia 166 Mycetomas 166 Pneumocystis Pneumonia 169

Bacterial Pneumonia 174 Nocardiosis 174 Actinomycosis 175 Legionnaires’ Disease 176 Rhodococcus Equi Pneumonia/

Malakoplakia 178

8. Infections II: Granulomatous Infections 181 Evaluation of Necrotizing

Granulomas 181 Histoplasmosis 182 Cryptococcosis 186 Coccidioidomycosis 190 Blastomycosis 193 Tuberculosis 195 Nontuberculous Mycobacterial Infections 196 Dirofi larial Nodule (Dog Heartworm

Disease) 198

9. Pneumoconiosis 201 Asbestosis 201 Silicosis 204

Nodular Silicosis 204 Acute Silicosis 208

Mixed Dust Pneumoconiosis 209 Hard Metal Pneumoconiosis 209 Miscellaneous Pneumoconiosis 214

Berylliosis 214 Talc Pneumoconiosis (Talcosis) 214 Coal Workers’ Pneumoconiosis

(CWP) 216 Aluminosis 216 Siderosis 216 Flock Workers’ Lung 216

10. Pulmonary Hypertension and Other Noninfl ammatory Vascular Disorders 219

Pulmonary Hypertension—General Features 219

Pulmonary Arterial Hypertension 226 Primary Pulmonary Hypertension

(PPH) 226 Thrombotic/Thromboembolic Pulmonary

Hypertension 227 Embolic Pulmonary Hypertension 229 Intravenous Drug Abusers’ Lung (Talc

Granulomatosis) 229 Other Emboli 232 Other Causes of Pulmonary

Arte rial Hypertension 232 Pulmonary Venous Hypertension 233

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Chronic Pneumonitis of Infancy (CPI) 315

Pulmonary Interstitial Glycogenosis (PIG) 316

Interstitial Pneumonias 318 Neuroendocrine Cell Hyperplasia of Infancy

(NEHI)/Persistent Tachypnea of Infancy 319

Index 321

Bronchogenic Cyst 309 Congenital Pulmonary Overinfl ation

(Emphysema) 309 Pulmonary Interstitial Emphysema 310 Congenital Pulmonary

Lymphangiectasis 313 Diffuse Lymphangiomatosis 315 Interstitial Lung Disease in Children 315

Bronchopulmonary Dysplasia (BPD) (Chronic Neonatal Lung Disease) 315

CONTENTS ■ ix

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ABPA allergic bronchopulmonary aspergillosisABPFD allergic bronchopulmonary fungal diseaseAFB acid-fast bacilliAFOP acute fi brinous and organizing pneumoniaAIP acute interstitial pneumoniaAIS adenocarcinoma in situANA antinuclear antibodyANCA antineutrophil cytoplasmic antibodyARDS acute respiratory distress syndromeBALT bronchial-associated lymphoid tissueBCG bronchocentric granulomatosisBML benign metastasizing leiomyomaBMPR2 bone morphogenetic protein receptor 2BOOP bronchiolitis obliterans–organizing pneumoniaBPD bronchopulmonary dysplasiaCBO constrictive bronchiolitis obliteranschILD syndrome children’s interstitial lung disease syndromeCMV cytomegalovirusCNS central nervous systemCOP cryptogenic organizing pneumoniaCPI chronic pneumonitis of infancyCSS Churg–Strauss SyndromeCT Computed tomographyCWP coal worker’s pneumoconiosisDAD diffuse alveolar damageDIP desquamative interstitial pneumoniaDIPNECH diffuse idiopathic pulmonary neuroendocrine cell hyperplasiaEBER EBV-encoded small RNAEBV Epstein–Barr virusEG eosinophilic granulomaEGPA eosinophilic granulomatosis with polyangiitisEMA epithelial membrane antigenFM fi brosing mediastinitisGGO ground glass opacityGIP giant cell interstitial pneumoniaGM-CSF granulocyte-macrophage colony stimulating factorGMS Gomori methenamine silver stainGPA granulomatosis with polyangiitis

List of Abbreviations

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GPS Goodpasture SyndromeH and E hematoxylin and eosinHP hypersensitivity pneumoniaHRCT high-resolution computed tomographyIHC immunohistochemistryIIP idiopathic interstitial pneumoniaILD interstitial lung diseaseIPF idiopathic pulmonary fi brosisIPH idiopathic pulmonary hemosiderosisLAM lymphangiomyomatosisLCH Langerhans cell histiocytosisLIP lymphoid interstitial pneumoniaLYG lymphomatoid granulomatosisMAC mycobacterium avium complexMALT mucosal-associated lymphoid tissueMERS Middle East respiratory syndromeMIB mucoid impaction of bronchiMLN meningothelial-like noduleMNPH micronodular pneumocyte hyperplasiaMPA microscopic polyangiitisMPO myeloperoxidaseNEHI neuroendocrine cell hyperplasia of infancyNSG necrotizing sarcoid granulomatosisNSIP nonspecifi c interstitial pneumoniaOP organizing pneumoniaPAM pulmonary alveolar microlithiasisPAP pulmonary alveolar proteinosisPAS periodic acid-SchiffPBM peribronchiolar metaplasiaPCP pneumocystis carinii pneumoniaPCR polymerase chain reactionPHG pulmonary hyalinizing granulomaPIG pulmonary interstitial glycogenosisPMF progressive massive fi brosisPPFE pleuroparenchymal fi broelastosisPPH primary pulmonary hypertensionPR3 proteinase 3PVOD pulmonary veno-occlusive diseaseRB respiratory bronchiolitisRBILD respiratory bronchiolitis interstitial lung diseaseREP reactive eosinophilic pleuritisRSV respiratory syncytial virusSARS severe acute respiratory syndromeSRIF smoking-related interstitial fi brosisTO tracheobronchopathia osteochrondroplasticaTSC tuberous sclerosis complexUIP usual interstitial pneumoniaURT upper respiratory tractWG Wegener granulomatosisWHO World Health Organization

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Lung Disease, fourth edition, Elsevier, 2006), which emphasized disease process over pattern. It also dif-fers in that it offers more in-depth histologic details with less discussion of the ancillary particulars of each disease. Some fi gures are duplicated from the previous book, but most are new. Reference lists are short and include only selected classic articles or new papers that contribute to diagnosis.

The face of pathology is changing, and it seems likely that molecular diagnostic techniques may supersede the histologic diagnosis of many diseases in the coming years. Accurate molecular diagnosis, however, ultimately depends on strong histologic cri-teria for diagnosis. Another aim of this book, there-fore, is to provide a robust histologic basis on which modern molecular diagnostic technologies can be appropriately developed.

Anna-Luise A. Katzenstein, MD

The main purpose of this book is to provide patholo-gists with a practical guide for diagnosing non-neo-

plastic lung diseases. The emphasis is on those diseases likely to be diagnosed by lung biopsy or excision, and, thus, many common diseases usually diagnosed clini-cally or at autopsy are not included. Numerous pho-tomicrographs are supplied to illustrate each disease, and the discussion is focused primarily on diagnostic features and differential diagnosis with inclusion of clinical fi ndings only as they facilitate diagnosis.

The chapters are organized mainly according to a histologic pattern with the intent of allowing the pathologist to move easily from reviewing the micro-scopic slides to fi nding the areas of the book that offer a pertinent differential diagnosis. This approach is different from that of my previous book (Katzenstein and Askin’s Surgical Pathology of Non-Neoplastic

Preface

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Acknowledgments

This book could not have been completed without the support of Dr. Robert Corona, chairman of the

Department of Pathology at SUNY Upstate Medical University. Likewise, Deborah Rexine in the Medical Photography Department was another key fi gure who printed; arranged and rearranged; added insets, circles, and arrows; and otherwise improved the qual-ity of the photomicrographs. Her hard work and ded-ication along with her cheerful demeanor were much appreciated. The author also thanks Rich Winters,

formerly with Demos, who helped get this project started, David D’Addona, acquisitions editor, and Norman Graubart who skillfully ushered it through, and Joseph Stubenrauch, managing editor, for careful oversight of the fi ne details of production.

Much of the material illustrated in the photomicro-graphs came from the author’s consultation fi le, and she would especially like to thank the many patholo-gists who trusted her for consultations throughout the years.

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C H A P T E R

4

Normal Lung, Common Artifacts, and Incidental Findings

1

This chapter briefl y reviews architectural landmarks in the lung that are important for understanding

pathologic alterations and explains how they are used in formulating diagnoses. Commonly encountered artifacts and incidental lesions that may cause confusion in his-tologic interpretation are reviewed. Suggestions for the optimal handling of tissue specimens are also provided.

TOPICS

• Normal Lung Architecture• Handling of Tissue Specimens• Approach to Diagnosis• Artifacts

• Artifactual Collapse• Fresh Hemorrhage• Bubble Artifact

• Incidental Findings• Corpora Amylacea• Interstitial Megakaryocytes• Bone Marrow Emboli• Blue Bodies• Cytoplasmic (Mallory) Hyaline• Minute Meningothelial-Like Nodules (MLNs)• Entrapped Pleural Fragments• Nodular Histiocytic/Mesothelial Hyperplasia

NORMAL LUNG ARCHITECTURE

Detailed reviews of the microscopic anatomy of the lung can be found in other textbooks, but a few basic

landmarks are important to remember when evaluat-ing biopsy or surgical specimens:

• Pulmonary arteries and bronchioles course together, and are similar in size (Figure 1.1). This relationship helps one to confi rm that a particular blood vessel is an artery, and it also confi rms bron-chiolocentricity of an infl ammatory process if the affected bronchiole is destroyed (see Figures 6.23 and 6.24).

• Terminal (membranous) bronchioles contain a full lining of ciliated respiratory tract epithelium and have a continuous smooth muscle layer in their walls (Figure 1.1).

• Respiratory bronchioles are partially lined by cili-ated respiratory tract epithelium and open up into alveolar ducts (Figure 1.2).

• Small collections of chronic infl ammation, bron-chial-associated lymphoid tissue (BALT), are com-mon in the walls of bronchioles and by themselves are not a signifi cant abnormality.

• Smooth muscle bundles protrude along the interstitium at the mouth of alveolar ducts and are present along the wall of alveolar ducts (Figure 1.2B). They may appear hyperplastic in emphysema.

• Alveolar septa are thin, membranous struc-tures within which only scattered nuclei, mostly from endothelial cells, can be seen (Figure 1.1B). Alveolar lining cells are generally not visible in normal lung, and when prominent are indicative of prior injury or interstitial lung disease.

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FIGURE 1.1 Normal lung. (A) At low magnifi cation, a terminal bronchiole (TB) is seen adjacent to a pulmonary artery. Note that the artery and the bronchiole are similar in size. The surrounding alveoli are normal. (B) Higher magnifi cation of the alveolated parenchyma shows thin, membranous, alveolar septa containing only scattered nuclei mainly from capillary endothelium. Distinct alveolar lining cells are not visible. A few macrophages are scattered within the airspaces.

FIGURE 1.2 Normal lung. (A) A respiratory bronchiole (RB) is seen adjacent to a pulmonary artery in this fi eld, and it opens into alveolar ducts (AD). (B) Higher magnifi cation view of the RB shows its discontinuous smooth muscle layer, as well as the smooth muscle bundles (arrows) that are present at the mouth of the adjacent AD.

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APPROACH TO DIAGNOSIS

Histologic Examination

The lung can be considered broadly to consist of two main compartments: interstitium and airspace. The inter-stitium is the supporting structure of the lung and includes alveolar septa, tissue surrounding bronchovascular bun-dles, and interlobular septa. The airspaces include the lumens of bronchi and alveolar spaces and all structures in between. An important fi rst step in examining lung for non-neoplastic disease is to assess which compartment is primarily involved by the disease process. Many dis-eases affect the interstitium or airspaces predominantly and are reviewed in Chapters 2, 3, and 4, whereas others may affect both compartments relatively equally (diffuse alveolar damage, Chapter 5). Not all conditions can be categorized in this way, however, as some destroy lung in a cross-country fashion, replacing normal architecture altogether (nodular infi ltrates and necrotizing processes, Chapters 6, 7, 8, and 12), while others involve blood ves-sels or bronchioles primarily (Chapters 10 and 11) and largely spare the adjacent parenchyma. Of course, not every disease fi ts nicely into these patterns, but systematic examination of the specimen with regard to the predomi-nant site of involvement is a good starting point in the evaluation. Determining the distribution of the process, whether mainly peribronchiolar, perivascular, lymphan-gitic, or random, provides additional important informa-tion for synthesizing a diagnosis.

Rarely, biopsies appear superfi cially normal; yet patients are said to have severe respiratory compro-mise. Although such specimens may have not ade-quately sampled an abnormal area, subtle vascular (pulmonary hypertension, Chapter 10) or bronchio-lar (constrictive bronchiolitis obliterans, Chapter 11) changes should be suspected and carefully excluded.

A number of common special stains are routinely used in evaluating lung biopsy or excision specimens. Organism stains are used when indicated by the histo-logic fi ndings or a history of immunocompromise, and we recommend Ziehl–Neelsen or auramine–rhodamine stain for acid-fast bacilli, and Gomori methenamine

• Alveolar spaces may contain scattered alveolar macrophages, but numerous macrophages within contiguous alveoli are abnormal.

• Pulmonary veins course separately from arter-ies and are located within interlobular septa (see Figures 10.19 and 10.20).

• Interlobular septa are connective tissue structures that extend from the visceral pleura into portions of underlying lung, and they contain lymphatic spaces in addition to veins.

• Pulmonary lymphatic spaces are located within the bronchovascular bundles, interlobular septa, and the pleura. They are normally inconspicuous, but they may be artifactually dilated in specimens that have been fi xed by infl ation.

HANDLING OF TISSUE SPECIMENS

Although some pathologists advocate infl ating sur-gical biopsy specimens with formalin using a syringe and needle, we have never found this technique to be necessary. In fact, infl ation has its own haz-ards, including overinfl ation of airspaces, dilution of airspace exudates, and dilatation of lymphatic spaces, and we do not recommend it. Rather, the most important step in handling these specimens is immersing them immediately after excision in for-malin, because leaving them exposed to air pro-motes atelectasis. A second important step is to use a fresh, sharp blade and to section with a gentle sawing motion, being careful not to compress the specimen during cutting or with one’s fi ngers. All staples should be removed before sectioning and the sections made perpendicular to the pleura starting at the (soft) excision margin and extending to the (fi rmer) pleural surface.

For transbronchial biopsy specimens, as with sur-gical biopsies, the most important step is to put the tissue into formalin immediately, because the main cause of atelectasis in these specimens is exposure to air. It is frustrating to receive relatively large tissue fragments that are uninterpretable because of atelec-tasis, and the clinicians should be advised about cor-recting this problem.

Gentle sectioning with sharp knives should also be used on lobectomy or pneumonectomy specimens. These specimens may be infl ated fi rst with formalin through the bronchi and fi xed for 1 to 2 hours before sectioning. Infl ation is not necessary, however, but it can facilitate dissection and help one to precisely localize lesions to determine their relationship with bronchi and other structures.

Helpful Tip—Handling of Tissue Specimens

• Careful handling of the fresh tissue is the most important step in ensuring optimal microscopic interpretation: Do not allow the specimen to air dry, and do not unduly com-press during sectioning.

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Radiographic Findings

As mentioned earlier, superfi cial knowledge of the basic radiographic fi ndings, whether localized or dif-fuse, is usually suffi cient to interpret most lung biop-sies. However, it helps pathologists to understand the radiology jargon to some extent, especially as addi-tional, more detailed radiographic descriptions can contribute to diagnosis in pathologically diffi cult cases. Some common radiology terms and their signifi cance are listed in Table 1.1.

silver (GMS) stain for fungi. Elastic tissue stains can be helpful in evaluating blood vessels. Some pathologists advocate connective tissue stains, especially Trichrome, to evaluate fi brosis in interstitial lung disease. We have not found this stain to be either necessary or useful. In fact, we would advise against its use in small transbron-chial biopsy specimens because it obscures underlying cellular details and wastes tissue that could have been used for additional H and E or other more helpful stains.

Clinical Input

A clinical history is always helpful in interpreting lung biopsies, but it does not have to be detailed, and is not necessary in all cases. Knowing the basic presenting manifestations, whether acute or chronic, the patient’s immune status, whether immunocompromised or immunocompetent, and whether the radiographic fi nd-ings are localized or diffuse is suffi cient in most cases. A more detailed clinical history with radiographic descrip-tion can be elicited if needed in more diffi cult cases.

The clinical history should be viewed as a useful ancillary fi nding that not only helps the pathologist for-mulate a diagnosis, but, more importantly, may prevent him or her from making erroneous diagnoses. It is best, however, that pathologists examine the slides initially before the clinical situation is known and formulate a differential diagnosis based on the morphologic features alone. The clinical history then can be used to refi ne the pathologic differential diagnosis. Reviewing the clini-cal history before examining the microscopic slides is not recommended, however, as it steers the pathologist toward the clinical impression and it may prevent an unbiased evaluation of the pathologic fi ndings.

TABLE 1.1 Common Radiology Terms and Correlation With Pathology Findings

Radiology Term Chest CT Appearance Pathology Correlates

Air bronchogram Air-fi lled bronchus visible within consolidated lung Occurs in airspace fi lling process

Consolidation Dense opacifi cation, often with air bronchograms, all other lung landmarks obscured, usually localized

Acute pneumonia, organizing pneumonia, other airspace fi lling processes

Crazy paving Thickened interlobular and intralobular lines within ground glass opacity, usually diffuse or multifocal

Classically in alveolar proteinosis, also in other diseases

Ground glass opacity (GGO)

Incomplete, hazy opacifi cation in which bronchial and vascular structures are visible, localized or diffuse

Active infl ammatory process, either interstitial or airspace or both

Honeycomb change Small uniform spaces with well-defi ned walls, often at lung periphery, associated with reticular opacities

Corresponds to gross honeycombing, characteristic of usual interstitial pneumonia

Mosaic attenuation Patchwork of regions of differing attenuation Air trapping, as in small airways disease, or patchy interstitial disease

Reticular/reticulonodular infi ltrates

Thin linear densities, sometimes with tiny nodules, usually diffuse

Interstitial diseases with fi brosis

Traction bronchiectasis Dilated bronchi within fi brotic lung and honeycomb change

Associated with parenchymal scarring and honeycomb change

Helpful Tips—Approach to Diagnosis

• Examine the microscopic slides fi rst and formu-late a differential diagnosis based on pathologic fi ndings before reviewing clinical information.

• Determine the predominant site of involve-ment, whether interstitial, airspace, or cross-country, but remember that diseases are only rarely strictly confi ned to a single compart-ment, and judgment is required to determine the predominant one.

• Consider pulmonary hypertension or con-strictive bronchiolitis obliterans when biop-sies from patients with severe respiratory compromise appear otherwise normal.

• Use clinical information to confi rm the patho-logic impression or to prevent an erroneous diagnosis, but do not be biased by the clinical history before looking at the slides.

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patients with signifi cant acute lung hemorrhage have hemoptysis and sometimes anemia. Often, also, in true alveolar hemorrhage, the airspaces are dilated and packed with blood in contrast to artifactual blood in which the airspaces retain their normal size and confi guration. Sometimes, acute infl ammation and necrosis of alveolar septa are seen and indicate acute capillaritis (see Chapters 4 and 6) in the etiol-ogy of the bleeding.

ARTIFACTS

Several artifacts that mimic an actual disease may be encountered in biopsy specimens. Helpful features in their distinction are summarized in Table 1.2.

Artifactual Collapse

Artifactual collapse is commonly encountered because of improper fi xation, air drying, or heavy-handed sectioning, and it can be avoided or dimin-ished by careful specimen handling. Atelectasis is greatest in specimens containing normal or near-normal lung, whereas severely abnormal lung is least affected. Transbronchial biopsy specimens are especially prone to this artifact (Figure 1.3; see also Figure 1.25), but it can be seen in surgical specimens as well. In such cases, the question arises whether the abnormal area is collapsed normal lung or interstitial fi brosis. Examination of parenchyma adjacent to the collapsed areas usually answers the question, because normal alveolar septa directly abut the edge of col-lapsed areas, while a transition from abnormal to normal is seen in interstitial fi brosis. The presence of hyperplastic alveolar lining cells within the abnormal area is another helpful fi nding that supports intersti-tial fi brosis.

Fresh Hemorrhage

Fresh blood within airspaces is common in all types of lung biopsy specimens, although transbronchial biopsy specimens seem to be disproportionately affected by this artifact (Figure 1.4). The question arises in such cases whether the bleeding is caused by an underlying lung disease or whether it is secondary to the biopsy procedure. The presence of hemosiderin deposits is the most helpful feature in distinguishing these two possibilities. As hemosiderin takes about 3 days to form from blood breakdown, its presence indicates that the bleeding preceded the biopsy and therefore is “real.” In cases of early alveolar hem-orrhage in which hemosiderin has not yet formed, knowledge of the clinical situation is helpful, as most

TABLE 1.2 Features That Distinguish Artifactual Changes From Actual Diseases

Artifact Potential Mimic Distinguishing Features of Artifact

Artifactual collapse Interstitial fi brosis Normal alveolar septa at the edge of the collapsed area without transition, absent alveolar pneumocyte hyperplasia

Intra-alveolar blood Alveolar hemorrhage syndrome Absent hemosiderin; absent hemoptysis, anemia clinically

Bubble artifact Exogenous lipoid pneumonia Branching of bubbles, absent intracytoplasmic and interstitial bubbles, no foreign-body giant cells

FIGURE 1.3 Artifactual collapse. In this fi eld, from a transbronchial biopsy specimen, the entire central area is collapsed and uninterpretable. The sharp demarcation from the adjacent relatively normal parenchyma (right) is characteristic of artifactual collapse and differs from the gradual transition from abnormal to normal, seen around fi brotic areas. See also Figure 1.25.

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INCIDENTAL FINDINGS

Corpora Amylacea

Corpora amylacea are large, rounded amphophilic to eosinophilic structures that are found within alve-olar spaces (Figure 1.6). They measure from 30 to 200 μm and may fi ll an entire alveolus. They are often surrounded by a rim of alveolar macrophages and occasionally elicit a foreign-body giant cell reac-tion. Usually, only scattered forms are present, but they can be numerous and even form small clusters. At higher magnifi cation, they have a distinct lamellar morphology, and well-fi xed cases also show spoke-like structures radiating from the center (Figures 1.6B and 1.7A). Frequently, inclusions are seen in their centers and include lightly stained geometric shapes, darkly pigmented structures, and birefringent crystal-loid areas (Figure 1.7). Distortion related to fi xation and sectioning, such as wrinkling resembling chatter, and partial loss of architecture are common, but close examination reveals the characteristic lamination at least focally (Figure 1.8).

Corpora amylacea have no known signifi cance, and their origin is unknown. They are most promi-nent in older adults. As they are passive occupants of alveolar spaces, they may be entrapped in any abnor-mal process affecting the alveoli, and it is important not to confuse them with any aspirated foreign mate-rial, especially when they are entrapped in an area of organizing pneumonia (Figures 1.9 and 1.10). Attention to morphologic details at high magnifi ca-tion, especially the presence of lamination, should clarify the issue.

Bubble Artifact

The so-called bubble artifact is another fi nding that tends to be most prominent in transbronchial biopsy specimens, but can also occur in surgical biopsies. It is seen in cases containing an airspace exudate, commonly blood or macrophages, and is character-ized by round to irregularly shaped, often branch-ing clear spaces of varying sizes (Figures 1.4 and 1.5). When present in the background of numerous macrophages (as in patients with respiratory bron-chiolitis, eg, see Chapters 4 and 11), it may sug-gest the diagnosis of exogenous lipoid pneumonia (Chapter 4) (compare Figure 1.5 with Figures 4.18, 4.19, and 4.20). The presence of odd branching or budding shapes to the spaces, the absence of bub-bles within macrophage cytoplasm, no interstitial bubbles, and no foreign-body giant cells all sup-port bubble artifact and militate against exogenous lipoid pneumonia.

FIGURE 1.4 Fresh hemorrhage. Many alveolar spaces in this transbronchial biopsy are fi lled with fresh blood, but none appears unusually expanded by the blood. The alve-olar septa are normal without evidence of infl ammation or necrosis, and no hemosiderin is seen. Bubble artifact (see Figure 1.5) is also present.

Helpful Tips—Artifacts in Biopsies

• Look for hyperplastic alveolar pneumocytes to distinguish interstitial fi brosis from artifac-tual collapse.

• Hemosiderin is necessary to confi rm that intra-alveolar blood is “real” rather than an artifact secondary to the biopsy, unless features of capillaritis or another source of bleeding are present, but it takes 3 days to form; a clini-cal history of hemoptysis or anemia should be present in earlier cases without hemosiderin.

• When clear vacuoles are present, make cer-tain that they are located within macrophage cytoplasm in both airspaces and interstitium before considering a diagnosis of exogenous lipoid pneumonia rather than bubble artifact.

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FIGURE 1.5 Bubble artifact. (A) At low magnifi cation, the airspaces are fi lled with a cellular exudate in which numerous varying-sized, clear vacuoles often having odd shapes are present. (B) A higher magnifi cation better demonstrates the varying-sized, often-budding clear vacuoles that are intermingled among intra-alveolar macrophages. The vacuoles are not present within macrophage cytoplasm, however, and foreign-body giant cells are absent. This 35-year-old smoker had severe respiratory bronchiolitis as well as Langerhans cell histiocytosis elsewhere.

Interstitial Megakaryocytes

Megakaryocytes are frequently observed within alveolar septa, and they may be numerous. They are characterized by large, darkly staining nuclei that are easily visible at low magnifi cation (Figure 1.11). The nuclei are irregularly shaped, often elongated, curved, or branching, and sometimes multilobated, but cytoplasm is usually not visible (Figure 1.11). High magnifi cation indicates that they are present within capillary lumens (Figure 1.12). Although they have no relevance to the diagnosis of an underlying lung disease, they tend to be more numerous in patients with febrile illnesses, sepsis, cardiovascular diseases, and underlying malignancies. They should not be confused with tumor cells or fungal organisms.

Bone Marrow Emboli

Bone marrow emboli are common fi ndings in sur-gical lung biopsy specimens, and are of no known

signifi cance. The marrow varies from fatty and nearly acellular to cellular, and it contains the usual marrow components (Figure 1.13). Single or multiple arter-ies may be involved. Bone marrow emboli are most common at autopsy where they are usually attributed to broken ribs related to resuscitation attempts. The pathogenesis of marrow emboli following surgical lung biopsies is not known, but may be related to rib manipulation during surgery.

Blue Bodies

Blue bodies are round, often fragmented, blue-gray structures that may appear laminated and are found within alveolar macrophages (Figure 1.14; see also Figure 4.24). They stain weakly for iron, and are positive with the von Kossa stain for calcium. They are thought to represent breakdown products of cell metabolism and they are entirely nonspecifi c. Blue bodies occur under any condition in which there are large numbers of intra-alveolar macrophages, and

(text continued on page 11)

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FIGURE 1.6 Corpora amylacea. (A) At low magnifi cation, numerous corpora amylacea are seen within alveolar spaces in an area of otherwise normal lung. The photograph is from a random section of a lobectomy performed for tumor. (B) The classic concentric lamellae are seen in this corpus amylacea, which is partly rimmed by alveolar macrophages.

FIGURE 1.7 Corpora amylacea. In addition to the classic concentric lamellae, these corpora amylacea contain irregularly shaped central structures that appear clear in (A) and pigmented in (B). Note also the spoke-like structures radiating from the center in (A).

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FIGURE 1.8 Sectioning-induced changes in corpora amylacea. (A) Wrinkles resembling chatter artifact and fragmentation are common. (B) Concentric lamellae can still be visualized focally at higher magnifi cation in this distorted corpus amylacea.

FIGURE 1.9 Corpora amylacea in organizing pneumonia. (A) A corpus amylacea is entrapped within this area of organiz-ing pneumonia and even surrounded by a multinucleated giant cell. Although the appearance may initially suggest aspi-ration pneumonia, the fi nding of the typical lamellar structure at high magnifi cation (B) distinguishes corpora amylacea from foreign material.

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FIGURE 1.10 Distorted corpora amylacea in organizing pneumonia. (A) Sometimes corpora amylacea are distorted and diffi cult to identify, as in this example from an area of organizing pneumonia. (B) Higher magnifi cation shows oddly shaped central degeneration, but preservation of the characteristic ring structure allows diagnosis.

FIGURE 1.11 Megakaryocytes in the lung. (A) In this case of organizing diffuse alveolar damage (see Chapter 5), numer-ous darkly staining, irregularly shaped megakaryocytes (arrows) are visible in the interstitium. (B) and (C) are higher mag-nifi cation views showing the characteristic densely stained elongated and branching nuclei of megakaryocytes.

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FIGURE 1.12 Megakaryocytes in the lung. (A) In this case of mild chronic interstitial fi brosis, several elongated and curved nuclei of megakaryocytes are seen within the thickened alveolar septa. As illustrated at higher magnifi cation in (B) and (C), they are present within spaces indicative of capillaries. Note the bilobed megakaryocyte in (C).

FIGURE 1.13 Bone marrow emboli. This small pulmonary artery is fi lled with bone marrow containing a mixture of normal marrow cells and fat in approximately equal proportions.

they should not be confused with inhaled or aspirated particles.

Cytoplasmic (Mallory) Hyaline

Cytoplasmic accumulation of amorphous, densely eosinophilic, globular material is sometimes encoun-tered within alveolar lining cells (Figure 1.15; see also Figure 3.11). The involved cells are enlarged with reactive features, and the changes are usually vis-ible at low magnifi cation. Mallory hyaline has been described most often in usual interstitial pneumonia (see Chapter 3), but it occurs under other conditions as well, such as acute interstitial pneumonia (see Chapter 5) and asbestosis (see Chapter 9), for exam-ple, and should be considered a nonspecifi c fi nding.

The hyaline material resembles Mallory hyaline seen in alcoholic and other liver diseases, hence the name, but there is no correlation of the lung depos-its with a history of liver disease or alcoholism. The structural composition is similar, however, consisting of intermediate keratin fi laments.

Minute Meningothelial-Like Nodules (MLNs)

In the past, MLNs were termed chemodecto-mas because of a superfi cial resemblance to

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FIGURE 1.14 Blue bodies. Numerous macrophages fi ll airspaces adjacent to interstitial fi brosis in this case of usual inter-stitial pneumonia (see Chapter 3) in a smoker. Even at low magnifi cation (A), the large blue-gray structures are visible, and at higher magnifi cation (B), they are seen to be present mainly within the macrophage cytoplasm. The inset in (A) is a high-magnifi cation view showing the fragmented, focally laminated blue-gray appearance. See also Figure 4.24.

FIGURE 1.15 Cytoplasmic (Mallory) hyaline. (A) In this case of usual interstitial pneumonia, enlarged, reactive-appear-ing alveolar pneumocytes containing intracytoplasmic eosinophilic inclusions (circle) are visible at low magnifi cation. The densely eosinophilic, rope-like, and somewhat blurry appearance of the hyaline material is better appreciated at high magnifi cation (inset). (B) At high magnifi cation in this fi eld, typical hyaline material is seen within multinucleated, reactive-appearing alveolar pneumocytes.

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chemodectomas (paragangliomas) in other locations, and when neuroendocrine differentiation was found to be absent, the term “so-called chemodectoma” was applied. Subsequently, ultrastructural and immuno-histochemical studies showed evidence of meningo-thelial differentiation, hence the current terminology. MLNs were previously lumped with carcinoid tumor-lets under the heading “tumorlet,” a term that is now reserved for carcinoid tumorlets.

MLNs are common fi ndings occurring in almost 15% of routine biopsy specimens, and they can be found in nearly one half of lobectomy specimens if extensively sampled. They are most common in adults older than 50 years, with women affected twice as often as men. They are uncommon in individuals younger than 20 years and are quite rare in children. They are often associated with chronic lung disease, but they have no known clinical signifi cance.

At low magnifi cation, MLNs appear as well-demarcated rounded- to stellate-shaped nodules in the interstitium, and they frequently are multiple (Figures 1.16 and 1.17). They average about 1.0 mm

in size, but may vary from only a few cells to sev-eral millimeters (Figure 1.18). They are composed of uniform epithelioid cells with a moderate amount of eosinophilic cytoplasm and indistinct cell bor-ders. Their nuclei are bland, round to oval shaped with homogeneous chromatin and occasional nuclear clearing. The cells usually form rounded clusters that are reminiscent of the “cell balls” characteristic of paragangliomas. Variable fi brosis may be present between the cell clusters, and hemosiderin deposition is occasionally seen. MLNs are randomly distributed throughout the lung, although many occur near or around blood vessels. They are usually present in areas of normal lung, but may be entrapped within scars or other processes, such as granulomas and even tumors (Figures 1.19 and 1.20).

Immunostaining is usually not necessary for diag-nosis because the H and E appearance is so distinct, but the cells are typically positive for vimentin, epi-thelial membrane antigen (EMA), and progesterone receptors (Figure 1.21). It is important to note that the cells are negative for cytokeratin, synaptophysin,

FIGURE 1.16 Meningothelial-like nodule. (A) At low magnifi cation, the typical stellate shape of the interstitial cellular infi ltrate is seen, and there is surrounding traction emphysema. (B) A high-magnifi cation view of the circled area shows the characteristic groups of uniform epithelioid cells with bland, oval nuclei, abundant cytoplasm, and indistinct cell bor-ders. This was an incidental fi nding in a 69-year-old woman with respiratory bronchiolitis (see Chapter 11; note also the characteristic intra-alveolar macrophages at top left in A).

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FIGURE 1.17 Multiple MLNs. (A) At low magnifi cation, two nodules are present within normal-appearing alveolated paren-chyma. The inset is a high-magnifi cation view showing the characteristic bland nuclei within abundant cytoplasm. (B) This intermediate magnifi cation view highlights the stellate shape and the interstitial location of the cellular infi ltrate. The lesions were incidental fi ndings in a 63-year-old woman with organizing pneumonia elsewhere. MLN, meningothelial-like nodule.

FIGURE 1.18 Small MLN. (A) This MLN consists of a tiny cluster of meningothelial-like cells around a small artery. (B) Higher magnifi cation shows the characteristic oval-shaped cells immediately adjacent to a small artery (top and bot-tom). MLN, meningothelial-like nodule.

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FIGURE 1.19 Large MLN in scarred parenchyma. (A) At low magnifi cation, small groups of cells are clustered together forming a fairly large MLN within an area of parenchymal scar. (B) Higher magnifi cation shows the tightly grouped bland cells within stromal fi brosis. Note the nuclear chromatin clearing present in some cells (top right). MLN, meningothelial-like nodule.

FIGURE 1.20 Large MLN within honeycomb lung. (A) This example from a case of usual interstitial pneumonia shows a size-able cellular area present within honeycomb change (bottom) and adjacent interstitial fi brosis (top). (B) Higher magnifi ca-tion of the area outlined by the square in (A) shows the typical bland oval-shaped cells. MLN, meningothelial-like nodule.

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neuroendocrine cell hyperplasia (DIPNECH, see Chapter 11), should not be considered.

Histologically, carcinoid tumorlets are usually found in the vicinity of bronchioles that may be obstructed or obliterated by the lesions, and the accom-panying fi brosis is often prominent (Figure 1.22). The component cells are typically bland with salt-and- pepper nuclear chromatin features, and they are oval to spindle shaped. Neuroendocrine cell hyperplasia commonly accompanies carcinoid tumorlets and blends into them. It is characterized by a prolifera-tion of neuroendocrine cells within and beneath the normal bronchiolar epithelium (Figure 1.23).

Because they are small and composed of bland epithelial cells, carcinoid tumorlets and MLNs may be confused, and in the older literature both were lumped together as “tumorlets.” Their differentiat-ing features are contrasted in Table 1.3. Although not usually necessary, in questionable cases, immu-nostaining for chromogranin or synaptophysin will identify the neuroendocrine features of carcinoid tumorlets, which are absent in MLNs (Figure 1.24).

Entrapped Pleural Fragments

Bits of pleura are frequently sampled in trans-bronchial biopsy specimens especially in patients

and chromogranin, thus distinguishing the lesion from neuroendocrine proliferations and other epithe-lial neoplasms. It is interesting to note that the cells may stain for CD56, a fi nding considered nonspecifi c in this setting.

Rarely, MLNs are so numerous that they cause interstitial changes radiographically as well as symp-toms clinically, and the name diffuse meningothe-liomatosis (see Chapter 2) has been applied to this entity. Histologically, the lesions comprising this condition are indistinguishable from ordinary MLNs, except that they tend to be larger and they may be nearly confl uent in places (see Figure 2.36). As ordi-nary MLNs are commonly multiple, diffuse menin-gotheliomatosis should only be considered in persons with clinical and radiographic evidence of interstitial lung disease and no other pathologic fi ndings.

Carcinoid Tumorlets

Carcinoid tumorlets are small proliferations of neu-roendocrine (Kulchitsky-like) cells that, by defi nition, measure less than 5 mm. They are most commonly associated with bronchiectasis, parenchymal scars, and peripheral carcinoid tumors. They are often mul-tiple, but in the absence of supporting clinical fea-tures, a diagnosis of the rare entity, diffuse idiopathic

FIGURE 1.21 Immunostaining in MLNs. Positive staining is seen for vimentin (A), EMA (B), and progesterone receptor (C). EMA, epithelial membrane antigen; MLN, meningothelial-like nodule.

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FIGURE 1.22 Carcinoid tumorlet. (A) A stellate-shaped cellular nodule is present that partially replaces a bronchiole (Br, bottom). Stromal fi brosis is prominent in the upper portion of the lesion. (B) Higher magnifi cation shows the characteris-tic uniform, oval to elongated epithelial cells that contain bland nuclei with a salt-and-pepper nuclear chromatin pattern. Note the compressed overlying ciliated bronchiolar epithelium on the right.

FIGURE 1.23 Carcinoid tumorlet and neuroendocrine cell hyperplasia. (A) This tumorlet has almost completely obstructed a small bronchiole identifi ed by the residual smooth muscle layer on the left (arrows) and the adjacent pulmonary artery on the bottom. The residual bronchiole lumen at the top is partially fi lled by neuroendocrine cell hyperplasia. (B) Higher magnifi cation of neuroendocrine cell hyperplasia, which forms beneath normal bronchiolar epithelium and protrudes into the lumen.

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Histologically, visceral pleural fragments consist of a mixture of mesothelial cells and variable sur-rounding fi brosis. They may appear as solid clusters, or they may form gland-like spaces, and mixtures of both patterns may be present (Figures 1.25 and 1.26). They can be found within the substance of the lung fragments as well as on the edge, and some fragments

with interstitial lung disease and peripheral nod-ules or infi ltrates. Although usually small and inconspicuous, they can form solid clusters or gland-like structures that raise the possibility of a neoplasm, an especially challenging situation in biopsies taken for evaluation of clinically suspicious nodules.

TABLE 1.3 Contrasting Features of MLNs and Carcinoid Tumorlets

MLN Carcinoid Tumorlet

Clusters (“cell balls”) of bland, round to oval cells Nests of bland oval to spindle-shaped cells. Neuroendocrine cell hyperplasia also often present.

Homogeneous nuclear chromatin, occasional clearing

Salt-and-pepper nuclear chromatin

Random distribution, often perivascular Bronchiolar and peribronchiolar distribution, often associated with scarring

Negative IHC staining for cytokeratin, chromogranin, synaptophysin

Positive IHC staining for cytokeratin, chromogranin, synaptophysin

Positive IHC staining for vimentin, EMA, progesterone receptor

Usually negative IHC staining for vimentin, EMA, progesterone receptor

EMA, epithelial membrane antigen; IHC, immunohistochemistry; MLN, meningothelial-like nodule.

FIGURE 1.24 Immunostaining in carcinoid tumorlet. (A) This carcinoid tumorlet is composed of the characteristic spindle-shaped cells containing a salt-and-pepper nuclear chromatin pattern (inset), and it partially replaces a bronchiole (bot-tom). (B) Immunostaining for chromogranin is strongly positive in the tumorlet.

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FIGURE 1.25 Entrapped pleura in transbronchial biopsy. (A) At low magnifi cation, a cluster of epithelioid cells is present on the edge of this lung fragment. Note also the severe artifactual collapse that involves almost the entire piece of tissue except for a tiny area of relatively normal lung that abuts the collapsed portion (lower left). (B) At high magnifi cation, the cells are relatively bland with abundant cytoplasm, and they stain strongly for calretinin (inset). This biopsy was from a 72-year-old woman with a 4.0-cm opacity suspicious for neoplasm. No changes were present to explain the opacity, and therefore the biopsy was considered nondiagnostic.

FIGURE 1.26 Visceral pleura in transbronchial biopsy. (A) In this case, the pleura comprises an entire tissue fragment, and the appearance superfi cially suggests tumor within a bronchial wall. Both a solid portion (top, shown at high mag-nifi cation in [B]) and a gland-like confi guration (center, shown at high magnifi cation in [C]) are present. The cells contain relatively uniform, bland nuclei and abundant cytoplasm. This 78-year-old man underwent biopsy to evaluate bilateral infi ltrates and hypoxia. Findings that would explain his presenting complaints were not present elsewhere.

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pleura fragments present elsewhere. It is interesting to note that the presence of pleura, even parietal pleura, on transbronchial biopsy specimens does not seem to correlate with postbiopsy pneumothorax.

Any abnormality affecting pleura may also be sampled on transbronchial biopsy specimens, includ-ing nonspecifi c infl ammatory reactions and tumors. Nodular histiocytic/mesothelial hyperplasia is a reactive cellular process that is composed predomi-nantly of clusters of histiocytes admixed with fewer mesothelial cells and lymphocytes. When sampled on transbronchial biopsy specimens, cellular aggre-gates of bland-appearing cells with abundant cyto-plasm are present that may mimic a low-grade neoplasm (Figure 1.28). Immunohistochemistry will clarify the issue, showing a mixture of cytokeratin-negative, CD68-positive histiocytes and cytokeratin-positive, calretinin/WT-1-positive mesothelial cells (Figure 1.29).

may be detached. The component cells are usually bland and uniform, although there may be mild nuclear atypia, and they contain abundant cytoplasm. Often the typical hobnail shape of mesothelial cells is recognizable, and a papillary confi guration may be present. It is most important to consider pleura in the differential diagnosis of bland-appearing or mildly atypical cellular proliferations in transbronchial biopsies in order to avoid misdiagnosing a neoplasm. In diffi cult cases, immunostaining can confi rm the diagnosis because mesothelial markers (calretinin and WT-1) are positive, whereas stains for other lesions in the differential diagnosis (chromogranin, synapto-physin, TTF-1, etc.) would be negative. In addition to visceral pleura fragments, pieces of parietal pleura are also occasionally encountered. They are easier to identify, because they consist mainly of adipose tissue covered by a mesothelial layer (Figure 1.27), and their presence should be a clue to the identity of the visceral

FIGURE 1.27 Parietal pleura in transbronchial biopsy. Same patient as in Figure 1.26. (A) At low magnifi cation, this detached piece of parietal pleura consists mainly of adipose tissue. (B) At higher magnifi cation, a typical single layer of hobnail-shaped mesothelial cells covers the adipose tissue. A small focus of nonspecifi c chronic infl ammation is present as well.

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FIGURE 1.28 Nodular histiocytic/mesothelial hyperplasia in a transbronchial biopsy. (A) A prominent, well-circumscribed cellular nodule is present within this lung fragment. (B) At higher magnifi cation, the nodule is composed of bland-appearing epithelioid cells. Note the pigmented macrophages (respiratory bronchiolitis) present within airspaces in the lower right. The patient was a 74-year-old heavy smoking woman with weight loss and a suspicious mass radiographically.

FIGURE 1.29 Nodular histiocytic/mesothelial hyperplasia. Same case as in Figure 1.28. (A) Higher magnifi cation shows the central bland epithelioid appearing cells with abundant cytoplasm as well as a rim of smaller cells with darker cytoplasm. Although initially thought to represent a low-grade neoplasm, immunostaining for CD68 was strongly positive in most of the cells (B), while calretinin (and cytokeratin, not shown) marked only surrounding smaller mesothelial cells (C). As this lesion and the respiratory bronchiolitis were incidental fi ndings, the biopsy was considered nondiagnostic in this clinical setting.

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Incidental Findings

Aubry M-C, Thomas CF Jr, Jett JR, et al. Signifi cance of multiple carcinoid tumors and tumorlets in surgical lung specimens. Analysis of 28 patients. Chest. 2007;131:1635.

Bejarano PA, Garcia MT, Ganjei-Azar P. Mesothelial cells in transbronchial biopsies: a rare complication with a potential for diagnostic pitfall. Am J Surg Pathol. 2007;31:914.

Chan JK, Loo KT, Yau BK, Lam SY. Nodular histiocytic/mesothelial hyperplasia: a lesion potentially mistaken for a neoplasm in transbronchial biopsy. Am J Surg Pathol. 1997;21:658.

Koss MN, Johnson FB, Hochholzer L. Pulmonary blue bodies. Hum Pathol. 1981;12:258.

Mizutani E, Tsuta K, Maeshima AM, et al. Minute pulmonary meningothelial-like nodules: clinicopathologic analysis of 121 patients. Hum Pathol. 2009;40:678.

Mukhopadhyay S, El-Zammar OA, Katzenstein A-LA. Pulmonary meningothelial-like nodules. New insights into a common but poorly understood entity. Am J Surg Pathol. 2009;33:487.

Warnock M, Press M, Churg A. Further observations on cytoplasmic hyaline in the lung. Hum Pathol. 1980;11:59.

Helpful Tips—Incidental Findings

• Corpora amylacea may be entrapped within any airspace fi lling process and may be sur-rounded by histiocytes. Look for character-istic lamination to distinguish them from foreign material.

• The most reliable distinguishing features of MLNs and carcinoid tumorlets on routine stains include nuclear chromatin appearance (homogeneous vs. salt and pepper) and loca-tion (often perivascular vs. bronchiolar).

• CD56 immunostaining may be positive in MLNs, but in the absence of positive chro-mogranin or synaptophysin staining should not be considered evidence of neuroendo-crine differentiation.

• Entrapped pleural fragments should be con-sidered in the differential diagnosis of any cluster of bland to mildly atypical, unusual-appearing epithelioid cells occurring in trans-bronchial biopsy specimens.

SELECTED REFERENCES

Approach to Diagnosis

Hansell DM, Bankier AA, MacMahon H, et al. Glossary of terms for thoracic imaging. Radiology. 2008;246:697.

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C H A P T E R

4

Diffuse Alveolar Damage, Acute Interstitial Pneumonia

5

Diffuse alveolar damage (DAD) and its clini-copathologic counterpart, acute interstitial

pneumonia (AIP), are reviewed in a separate chap-ter because they represent a unique manifestation of acute lung injury, and their pathologic changes cannot be pigeonholed into interstitial or airspace predominant categories.

TOPICS

• Diffuse Alveolar Damage (DAD)• Acute Interstitial Pneumonia (AIP)

DIFFUSE ALVEOLAR DAMAGE (DAD)

Diffuse alveolar damage (DAD) isa purely descriptive term for the spectrum of pathologic changes that fol-low acute lung injury. Most patients clinically mani-fest the acute respiratory distress syndrome (ARDS). Usually, the cause of the lung injury is known, but when it cannot be identifi ed, the resultant idiopathic condition is known as AIP. It is discussed in the sub-sequent section, “Acute Interstitial Pneumonia.”

Histologic Features

• Hyaline membranes and/or fi broblast proliferation• Epithelial hyperplasia and metaplasia, often with

cytologic atypia• Small arterial thrombi

The pathologic changes in DAD comprise roughly two stages: acute (early), occurring within the first week or so following injury, and orga-nizing (proliferative, later), occurring after a week or two. In reality, as illustrated schematically in Figure 5.1, there is no sharp division between the two stages because features of both are often present together in a given case. Nonetheless, the approximate time interval following injury can be estimated from the relative proportion of abnor-malities present.

The histologic hallmark of the acute stage is the presence of hyaline membranes. Although edema, both interstitial and intra-alveolar, is the earliest change in DAD, edema is difficult to recognize in routine sections and to separate from biopsy-related artifactual changes. Hyaline membranes develop a day or so following injury and become most prominent in 3 or 4 days. They appear as glassy, eosinophilic structures within airspaces that are plastered along alveolar septa (Figure 5.2). They comprise a mixture of fibrin and other serum proteins and usually appear fairly homogeneous, although they sometimes contain scattered bare nuclei or other cellular debris. Remnants of edema fluid and fibrinous exudates as well as some nuclear debris may be seen in alveolar spaces, but intra-alveolar inflammation is scant if present at all (Figure 5.3).

Alveolar septa are mildly thickened by edema or alveolar wall collapse. Occasional acute or chronic infl ammatory cells may also be present within alveo-lar septa, but interstitial infl ammation is usually not prominent. Alveolar pneumocyte hyperplasia begins

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The organizing stage of DAD is a reparative response to the injury and is characterized by intersti-tial fi broblast and myofi broblast proliferation along with alveolar pneumocyte hyperplasia. At low magni-fi cation, the process is characterized by hypercellular,

FIGURE 5.1 Schematic representation of the time course of the pathologic changes in DAD. Note the overlapping spectrum of the changes over time. DAD, diffuse alveolar damage.

FIGURE 5.2 DAD, acute stage. (A) Low magnifi cation showing prominent hyaline membrane formation along mildly thickened alveolar septa. (B) At higher magnifi cation, the hyaline membranes appear homogeneous and eosinophilic with only scattered entrapped nuclear fragments. The alveolar septal thickening is due mainly to alveolar collapse. The appearance fi ts with injury occurring 3 to 4 days previously. DAD, diffuse alveolar damage.

after 3 to 4 days, and becomes most prominent after a week or so (Figure 5.4). Fibrin thrombi often under-going organization are frequently found in small arteries in both acute and organizing stages, and they may be numerous (Figure 5.5).

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FIGURE 5.3 DAD, acute stage. (A) In this example, hyaline membranes are plastered against alveolar septa that are thick-ened by edema, scattered mononuclear infl ammatory cells, and a few fi broblasts. (B) At higher magnifi cation, occasional pyknotic nuclei and cellular debris are seen within the hyaline membranes and in alveolar spaces. The appearance fi ts with injury occurring 5 to 7 days previously. DAD, diffuse alveolar damage.

FIGURE 5.4 Alveolar pneumocyte hyperplasia in DAD. (A) At low magnifi cation, hyaline membranes are seen lining thickened alveolar septa and there are areas of prominent alveolar pneumocyte hyperplasia (circle). These fi ndings indi-cate injury occurring a week or more previously. (B) Higher magnifi cation of the circled area shows the typical hobnail confi guration of the hyperplastic alveolar pneumocytes, some of which are cytologically atypical. DAD, diffuse alveolar damage.

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the acute stage, fi brin thrombi are common in small arteries (Figure 5.5B).

Epithelial hyperplasia is often prominent in the organizing stage and includes squamous metapla-sia in and around bronchioles in addition to alveo-lar pneumocyte hyperplasia (Figures 5.4, 5.9B, and 5.11). Cytologic atypia is common in both the alveo-lar epithelium and the squamous metaplasia areas, and it may be severe. The hyperplastic lining cells are often enlarged, irregular, and hobnail shaped with vesicular nuclei and prominent nucleoli, and they can cause false-positive cytology diagnoses (Figure 5.12). Mitotic fi gures are often present, and some may be atypical. Atypia in the squamous metaplasia is fre-quently present as well and may be so striking as to suggest invasive carcinoma (Figure 5.13). The location of the squamous metaplasia in and around bronchioles along with the associated DAD should indicate the correct diagnosis.

Occasionally, in severely hypoxemic patients, small infarcts are seen, usually in peripheral, sub-pleural parenchyma. They are likely caused by severe

temporally uniform thickening of alveolar septa that varies from mild to marked (Figures 5.6 and 5.7). Spindle-shaped fi broblasts and myofi broblasts embedded within lightly staining, often myxoid stroma are prominent within the thickened alveo-lar septa and account for much of the cellularity. In addition to the spindled cells, remnants of entrapped, often collapsed alveoli lined by hyperplastic pneumo-cytes comprise a portion of the interstitial cellular-ity and contribute to the alveolar wall thickening. The entrapped pneumocytes can be highlighted with cytokeratin immunostaining, which shows more cells than appreciated on hematoxylin and eosin (H and E) stains (Figure 5.8). A mild chronic infl ammatory cell infi ltrate may be associated with the other changes but is usually a minor component, and collagen depo-sition is minimal. Remnants of hyaline membranes may still be seen along alveolar septa in places, but are not prominent (Figure 5.9). In advanced cases, the fi broblast proliferation may be so extensive that the parenchyma appears solid with only slit-like lumens of alveolar spaces remaining (Figure 5.10). As in

FIGURE 5.5 Thrombi in DAD. Recent and organizing thrombi are present in small arteries in cases of acute DAD (A) and organizing DAD (B). DAD, diffuse alveolar damage.

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FIGURE 5.6 Organizing DAD. (A) At low magnifi cation, relatively uniform cellular thickening of alveolar septa is noted, and adjacent airspaces appear dilated. (B) At higher magnifi cation, the interstitial thickening is due mainly to fi broblasts within lightly staining stroma. Scattered tiny, partially collapsed airspaces lined by hyperplastic pneumocytes are also present (arrows), and there is a hyaline membrane remnant (arrow head). These fi ndings indicate injury occurring at least 2 weeks earlier. DAD, diffuse alveolar damage.

FIGURE 5.7 Organizing DAD. (A) At low magnifi cation, striking interstitial thickening is appreciated with small residual airspaces in some areas and dilated airspaces in others. The thickened interstitium appears cellular. (B) Higher magni-fi cation of the circled area in (A) shows prominent entrapped and collapsed alveoli lined by hyperplastic pneumocytes (hobnail-shaped cells with eosinophilic cytoplasm, center top) that are present in the thickened interstitium in addition to fi broblasts. Mild chronic infl ammation accompanies the changes as well. The fi ndings indicate injury occurring at least 2 weeks previously. DAD, diffuse alveolar damage.

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FIGURE 5.8 Cytokeratin immunostaining in organizing DAD. (A) At low magnifi cation, numerous entrapped alveolar pneu-mocytes are highlighted within the thickened interstitium. (B) A higher magnifi cation better illustrates the numerous small and often collapsed alveolar remnants (dark brown) within the background fi broblast proliferation. The light brown stained areas represent hyaline membrane remnants that have also been incorporated into the interstitium. DAD, diffuse alveolar damage.

FIGURE 5.9 Hyaline membrane remnants in organizing DAD. (A) Hyaline membrane remnants are seen along alveolar septa thickened by fi broblasts in this area of otherwise typical organizing DAD. A few mononuclear infl ammatory cells are also present within airspaces. (B) Nearby, typical organizing DAD is present with prominent, entrapped, partially collapsed alveoli lined by hyperplastic pneumocytes in the thickened interstitium along with fi broblasts. Stars indicate adjacent alveolar spaces. DAD, diffuse alveolar damage.

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FIGURE 5.10 Organizing DAD. (A) In this case, the fi brosis is so severe that the alveolated parenchyma appears almost solid. (B) A higher magnifi cation shows the marked interstitial fi broblast proliferation with resultant reduction of air-spaces to slit-like spaces. This severe fi brosis occurs after several weeks following injury. DAD, diffuse alveolar damage.

FIGURE 5.11 Squamous metaplasia in DAD. (A) Low magnifi cation showing prominent epithelial proliferation around a bronchiole. (B) At higher magnifi cation, the squamous differentiation is better appreciated, and there is mild atypia. DAD, diffuse alveolar damage.

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FIGURE 5.12 Alveolar pneumocyte atypia in DAD. (A) In this example, some alveolar lining cells are enlarged and contain prominent nucleoli. (B) The alveolar pneumocytes in this example are more severely atypical with vesicular nuclei and prominent nucleoli as well as varying size and loss of orientation (top). Inset from another area shows an atypical mitotic fi gure in addition to cytologic atypia. DAD, diffuse alveolar damage.

FIGURE 5.13 Florid squamous metaplasia with atypia in organizing DAD. (A) Low and (B) high magnifi cation of a squa-mous proliferation that is so marked that it may suggest invasive squamous cell carcinoma. DAD, diffuse alveolar damage.

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hypoxemia, and the arterial thrombi may also be a contributing factor.

It is not uncommon to fi nd areas of acute DAD superimposed on organizing DAD. Although remnants of hyaline membranes may be present in ordinary orga-nizing DAD, combined acute and organizing DAD cases contain areas of well-formed hyaline membranes in a background of organizing DAD (Figure 5.14). The changes are indicative of ongoing or recurrent injury, and they should be diagnosed as acute and organizing DAD. For estimating the time of onset of injury, the most advanced changes should be used.

Differential Diagnosis

Very few entities enter the differential diagnosis of the acute stage of DAD because hyaline membranes are quite specifi c. As infections in immunocompromised persons, especially viral and pneumocystis, can cause acute DAD, a careful search for organisms should be undertaken in this setting.

The main lesion in the differential diagnosis of organizing DAD is organizing pneumonia (OP; see Chapter 4, Figures 4.1 to 4.5), as both are

characterized by prominent fi broblast proliferation. Their main distinguishing features are contrasted in Table 5.1. In most cases, the diagnosis is not diffi -cult, as OP involves predominantly the airspaces in peribronchiolar parenchyma, whereas organizing DAD is predominantly interstitial, involving distal parenchyma unrelated to bronchioles. The diagno-sis may be diffi cult, however, when the OP areas are more diffuse causing loss of the peribronchiolar location and blurring of the distinction between air-space and interstitial involvement. The most help-ful feature for identifying DAD in diffi cult cases is fi nding other changes indicative of acute lung injury, such as hyaline membrane remnants, alveolar pneu-mocyte hyperplasia, squamous metaplasia in bron-chiolar epithelium, and fi brin thrombi. Knowledge of the clinical situation is also helpful, as most patients with DAD receive mechanical ventilation in contrast to most patients with OP.

The situation is further complicated in that focal areas of OP are frequently found in a background of otherwise typical organizing DAD. Even if OP areas are present in the background of organizing DAD, they are of no signifi cance in this situation, and they

FIGURE 5.14 Combined acute and organizing stages of DAD. (A) In this fi eld, well-formed hyaline membranes are pres-ent along alveolar septa that are thickened by fi broblasts, whereas in other areas (B) alveolar septal fi broblast prolifera-tion and alveolar pneumocyte hyperplasia are present without hyaline membranes. DAD, diffuse alveolar damage.

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Unfortunately, with only a few exceptions, the his-tologic fi ndings in DAD are identical regardless of cause, and identifi cation of the etiology rests on clinical investigation. Infection is an important treatable cause of DAD, and in immunocompro-mised persons special stains for organisms, espe-cially pneumocystis, may be productive (Chapter 7). Viral infections that produce specifi c cytopathic changes are another example of histologically iden-tifi able causes, although the most common viral pneumonias in immunocompetent persons (infl u-enza and parainfl uenza) have no specifi c markers (see Chapter 7).

In a few cases, reactive lymphocytes and plasma cells may be focally prominent in alveolar septa. This fi nding should suggest viral infection or underlying collagen vascular disease in the etiology. If signifi cant chronic infl ammation is a diffuse fi nding, however, exacerbation of an underlying chronic interstitial pneumonia (especially NSIP) is more likely.

Pathogenesis

Injury to alveolar epithelium and capillary endothe-lium is central to the cascade of events that produce DAD (Figure 5.15). Capillary endothelial damage results in leakage of plasma fl uids into the interstitium

do not need to be diagnosed. The prognosis in such cases, unfortunately, is that of DAD (see subsequent section, “Clinical Features”), which is considerably worse than that of OP.

Although interstitial thickening is prominent in organizing DAD, chronic interstitial pneumonias are not strong considerations in the differential diagnosis because they are characterized by interstitial infl am-mation or collagen formation but not diffuse fi bro-blast proliferation. Also, they lack other features of acute lung injury. It should be remembered, however, that DAD can complicate other processes, includ-ing chronic interstitial pneumonias. This occurs especially in usual interstitial pneumonia (UIP) and is known as exacerbation of UIP (see Chapter 3, Figures 3.13 and 3.14), and it has been described in nonspecifi c interstitial pneumonia (NSIP) as well as in hypersensitivity pneumonia (Chapters 2 and 3). Therefore, slides should be carefully reviewed in order not to overlook an underlying or coexisting disease in cases of DAD.

Etiology

DAD is a manifestation of severe acute lung injury, and there are a large number of potential causes, of which the most common are listed in Table 5.2.

TABLE 5.1 Contrasting Features of Organizing DAD and OP

Features Organizing DAD OP

Fibroblast proliferation Yes, interstitial, distal alveoli Yes, airspace, peribron-chiolar

Hyaline membrane remnants Yes No

Epithelial hyperplasia/metaplasia Yes No

Arterial thrombi Yes No

Patient on ventilator Usually Not usually

DAD, diffuse alveolar damage; OP, organizing pneumonia.

TABLE 5.2 Common Causes of DAD

• Infection (viruses, pneumocystis, rickettsia, mycoplasma, Legionella, etc)• Toxic inhalants (fumes, smoke, crack cocaine, other)• Drug toxicity (chemotherapy, amiodarone, others, heroin)• Ingestants (paraquat, kerosene, rapeseed oil)• Shock• Sepsis• Aspiration• Radiation therapy• Exacerbation of UIP• Collagen vascular disease (especially lupus, scleroderma, dermatomyositis, mixed connective tissue disease,

rheumatoid arthritis)• Hematopoietic stem cell or solid organ transplantation• Idiopathic (AIP)

AIP, acute interstitial pneumonia; DAD, diffuse alveolar damage; UIP, usual interstitial pneumonia.

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ACUTE INTERSTITIAL PNEUMONIA (AIP)

AIP, referred to in the past as Hamman–Rich disease, idiopathic DAD, or idiopathic ARDS, is an uncommon idiopathic interstitial pneumonia, and the only one that is associated with an acute onset and rapid clinical course. AIP is a clinical syndrome, and, therefore, knowledge of the clinical history is necessary for diagnosis.

Histologic Features

• DAD, Organizing Stage

The histologic fi ndings in AIP are indistinguishable from the organizing stage of DAD with interstitial fi broblast proliferation and alveolar pneumocyte hyperplasia as well as other features of acute lung injury (see Figures 5.6, 5.7, and 5.10). Surprisingly, however, well-formed hyaline membranes and other features of the acute stage of DAD are generally not found.

Clinical Findings

AIP occurs in previously healthy individuals in whom there is no identifi able cause of lung injury. Persons of middle age are most commonly affected, but there is a wide age range, with occasional cases reported in children and the elderly. The onset is acute with severe dyspnea occurring over several days usually accom-panied by fever. An antecedent fl u-like syndrome with myalgias, arthralgias, fever, chills, and malaise is common. Bilateral ground glass opacifi cation and/

and then into alveolar spaces, whereas injury to alve-olar epithelium causes sloughing with denudation of the alveolar epithelial basement membrane. The combination of serum fl uids and necrotic epithelial components results in hyaline membrane formation. Alveolar pneumocyte hyperplasia intervenes as a reparative phenomenon to repopulate the denuded alveolar epithelial basement membranes. Fibroblast proliferation within alveolar septa is another attempt at repair, which is somewhat analogous to scarring that occurs during wound healing. Alveolar collapse occurs because of loss of alveolar epithelial lining cells, and the collapsed alveoli are incorporated into alveolar walls, thus further contributing to the inter-stitial thickening.

Clinical Features

DAD is characterized clinically by the acute onset of shortness of breath. Patients develop diffuse lung infi ltrates and severe hypoxemia indicative of the acute respiratory distress syndrome (ARDS), and most require intubation with mechanical ventilation. Mortality rates are high, averaging 35% to 50% depending on the cause and patient age. Treatment is mainly supportive, although corticosteroids may be used in some cases.

FIGURE 5.15 Pathogenesis of DAD (see text for explana-tion). DAD, diffuse alveolar damage.

Helpful Tips—DAD

• The “diffuse” in DAD refers to diffuse involvement (endothelium, epithelium, and interstitium) of a single alveolus rather than to involvement of the entire lung; therefore, fi nding some areas of normal lung microscop-ically should not detract from the diagnosis.

• Consider superimposed acute bacterial bron-chopneumonia if neutrophils are prominent within alveolar spaces.

• In histologically diffi cult cases, knowledge of the clinical fi ndings should help in diagnosis, as most patients with DAD are on a ventila-tor with features of ARDS clinically.

• Be cautious in diagnosing DAD in patients who are not receiving mechanical ventilation.

• DAD can complicate underlying more chronic lung diseases in which case both processes should be diagnosed.

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SELECTED REFERENCES

Diffuse Alveolar Damage (DAD)

Katzenstein A-LA. Pathogenesis of “fi brosis” in interstitial pneumonia. An electron microscopic study. Hum Pathol. 1985;16:1015.

Parambil JG, Myers JL, Aubry M-C, Ryu JH. Causes and prognosis of diffuse alveolar damage diagnosed on surgical lung biopsy. Chest. 2007;132:50.

Thille AW, Esteban A, Fernandez-Segoviano P, et al. Chronology of histological lesions in acute respiratory distress syndrome with diffuse alveolar damage: a prospective cohort study of clinical autopsies. Lancet Respir Med. 2013;1:395.

Tomashefski JF Jr. Pulmonary pathology of acute respiratory distress syndrome. Clin Chest Med. 2000;21:435.

Yazdy A, Tomashefski J, Yagan R, Klienerman J. Regional alveolar damage (RAD). A localized counterpart of diffuse alveolar damage. Am J Clin Pathol. 1989;92:10.

Acute Interstitial Pneumonia (AIP)

Bouros D, Nicholson AC, Polychronopoulos V, du Bois RM. Acute interstitial pneumonia. Eur Respir J. 2000;15:412.

Katzenstein A-LA, Myers JL, Mazur MT. Acute interstitial pneumonia. A clinicopathologic, ultrastructural, and cell kinetic study. Am J Surg Pathol. 1986;10:256.

Olsen J, Colby T, Elliott C. Hamman–Rich syndrome revisited. Mayo Clin Proc. 1990;65:1538.

Vourlekis JS, Brown KK, Cool CD, et al. Acute interstitial pneumonitis: case series and review of the literature. Medicine. 2000;79:369.

or consolidation is found on chest CT examination. Respiratory failure with severe hypoxemia requir-ing mechanical ventilation (ARDS) rapidly ensues, and mortality is high, exceeding 70% in some series. Corticosteroid therapy may be used, although there is little evidence for a benefi cial effect.

Terminology: DAD Versus AIP

DAD is a purely descriptive pathologic term that has no implications for etiology, whereas AIP refers to a specifi c clinical syndrome that is pathologically char-acterized by DAD and is of unknown etiology. The diagnosis of AIP, therefore, requires knowledge of the clinical setting and cannot be made from the patho-logic fi ndings alone. The situation is analogous to diagnosing cryptogenic organizing pneumonia versus organizing pneumonia (Chapter 4), idiopathic pulmo-nary fi brosis versus UIP (Chapter 3), or sarcoidosis versus non-necrotizing granulomatous infl ammation. DAD should be the diagnosis in most cases, unless unequivocally supportive clinical history is provided.

Helpful Tips—AIP

• Despite the term “acute” interstitial pneumo-nia, acute infl ammatory cells are not a feature in AIP. Rather, the “acute” refers to the clini-cal onset and course and not to the histologic fi ndings.

• Be cautious about considering AIP if the biopsy shows acute DAD, because almost all cases manifest organizing DAD.

• Diagnose AIP only in the appropriate clinical setting and after all other potential causes of DAD have been excluded.

• Do not diagnose AIP if evidence of an under-lying chronic interstitial fi brosing process, especially honeycomb change, is present, since in that setting exacerbation of UIP (Chapter 3) is more likely.

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