Muller's Imaging of the Chest E-Book : Expert Radiology Series [2 ed.] 9780323531795, 0323531792

Citation preview

Any screen. Any time. Anywhere. Activate the eBook version of this title at no additional charge.

Expert Consult eBooks give you the power to browse and find content, view enhanced images, share notes and highlights—both online and offline.

Unlock your eBook today. 1 Visit expertconsult.inkling.com/redeem 2

Scan this QR code to redeem your eBook through your mobile device:

Scratch off your code

3 Type code into “Enter Code” box 4

Click “Redeem”

5

Log in or Sign up

6

Go to “My Library” Place Peel Off Sticker Here

It’s that easy! For technical assistance: email [email protected] call 1-800-401-9962 (inside the US) call +1-314-447-8200 (outside the US)

Use of the current edition of the electronic version of this book (eBook) is subject to the terms of the nontransferable, limited license granted on expertconsult.inkling.com. Access to the eBook is limited to the first individual who redeems the PIN, located on the inside cover of this book, at expertconsult.inkling.com and may not be transferred to another party by resale, lending, or other means. 2015v1.0

2nd

EDITION

MÜLLER’S

IMAGING OF THE CHEST EDITORS

CHRISTOPHER M. WALKER, MD Associate Professor of Radiology University of Kansas Medical Center Kansas City, Kansas

JONATHAN H. CHUNG, MD Associate Professor Section Chief of Thoracic Radiology Interim Vice Chair for Quality Department of Radiology The University of Chicago Medicine Chicago, Illinois

ASSOCIATE EDITORS STEPHEN B. HOBBS, MD Assistant Professor Department of Radiology and Medicine University of Kentucky Lexington, Kentucky

BRENT P. LITTLE, MD Division of Thoracic Imaging Department of Radiology

Massachusetts General Hospital Boston, Massachusetts

CAROL C. WU, MD Associate Professor Department of Diagnostic Radiology The University of Texas MD Anderson Cancer Center Houston, Texas

1600 John F. Kennedy Blvd. Ste 1600 Philadelphia, PA 19103-2899

MÜLLER’S IMAGING OF THE CHEST, SECOND EDITION Copyright © 2019 by Elsevier, Inc. All rights reserved.

ISBN: 978-0-323-46225-9

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2008 by Saunders, an imprint of Elsevier Inc. Library of Congress Control Number: 2018953443

Publisher: Russell Gabbedy Senior Content Development Specialist: Ann Ruzycka Anderson Publishing Services Manager: Catherine Albright Jackson Senior Project Manager: Claire Kramer Design Direction: Ryan Cook

Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1

To Eunhee, thank you for your constant support and pushing me to take on this project. You truly make me a better man. To Elsie, thank you for always loving me and making me aware of the things that matter most in life. To Lillian, thank you for always making me laugh and giving the biggest hugs a dad could ever ask for. CMW

To my parents, Kyu Youl and Bok Hee: Thank you for endlessly encouraging my curiosity. To my daughter, Alexandra: Thank you for always being so excited to see me when I come home; it is the only time I have felt like a rock star. And to my loving wife, Aimee-Sue: Thank you for being the backbone of our family. Your unending support and love always inspire me. JHC

CONTRIBUTORS

Kiran Batra, MD

Stephane L. Desouches, DO

Assistant Professor Department of Radiology UT Southwestern Medical Center Dallas, Texas

Assistant Professor of Radiology Medical College of Wisconsin Milwaukee, Wisconsin

Matthew Bentz, MD Assistant Professor Department of Diagnostic Radiology Oregon Health and Science University Portland, Oregon

Assistant Professor of Radiology Uniformed Services University of the Health Sciences Bethesda, Maryland Landstuhl Regional Medical Center Landstuhl, Germany

Marcelo F. Benveniste, MD

Jeremy J. Erasmus, MD

Associate Professor Department of Diagnostic Radiology Thoracic Section The University of Texas MD Anderson Cancer Center Houston, Texas

Professor Department of Diagnostic Radiology The University of Texas MD Anderson Cancer Center Houston, Texas

Anupama Brixey, MD

Chief Medical Officer Professor of Medicine Division of Pulmonary, Critical Care, and Sleep Medicine Department of Medicine National Jewish Health Denver, Colorado

Department of Diagnostic Radiology Oregon Health and Science University Portland, Oregon

Juliana Bueno, MD Assistant Professor of Radiology Department of Radiology and Medical Imaging University of Virginia Charlottesville, Virginia

Suzanne C. Byrne, MD, FRCPC Clinical Assistant Professor of Radiology Department of Radiology Memorial University St. John’s, Newfoundland, Canada

Brett W. Carter, MD Associate Professor Department of Diagnostic Radiology The University of Texas MD Anderson Cancer Center Houston, Texas

Jonathan H. Chung, MD Associate Professor Section Chief of Thoracic Radiology Interim Vice Chair for Quality Department of Radiology The University of Chicago Medicine Chicago, Illinois

Robert M. DeWitt, MD, Major, USAF MC

Stephen K. Frankel, MD

Tomás Franquet, MD Chief, Section of Thoracic Imaging Department of Radiology Hospital de Sant Pau Barcelona, Spain

Cristina S. Fuss, MD Associate Professor Department of Diagnostic Radiology Oregon Health and Science University Portland, Oregon

Sherief Garrana, MD Resident Physician Department of Thoracic Radiology University of Missouri–Kansas City/Saint Luke’s Hospital of Kansas City Kansas City, Missouri

Matthew D. Gilman, MD Division of Thoracic Imaging and Intervention Massachusetts General Hospital Boston, Massachusetts

Patricia M. de Groot, MD

J. David Godwin, MD

Associate Professor Department of Diagnostic Radiology The University of Texas MD Anderson Cancer Center Houston, Texas

Professor of Radiology Department of Radiology University of Washington Seattle, Washington

vi

Contributors

Daniel R. Gomez, MD

John P. Lichtenberger, MD

Associate Professor Department of Radiation Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Associate Professor of Radiology Uniformed Services University of the Health Sciences Bethesda, Maryland

Ashish Gupta, MD

Assistant Professor Department of Radiology Mayo Clinic Rochester, Minnesota

Assistant Professor Department of Medical Imaging University of Ottawa Ottawa, Ontario, Canada

Vedant Gupta, MD

Rebecca M. Lindell, MD

Brent P. Little, MD

Assistant Professor of Medicine University of Kentucky College of Medicine Lexington, Kentucky

Division of Thoracic Imaging Department of Radiology Massachusetts General Hospital Boston, Massachusetts

Thomas E. Hartman, MD

Jaume Llauger, MD

Professor Department of Radiology Mayo Clinic Rochester, Minnesota

Chief, Section of Musculoskeletal Imaging Department of Radiology Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona Barcelona, Spain

Stephen B. Hobbs, MD Assistant Professor Department of Radiology and Medicine University of Kentucky Lexington, Kentucky

Yeon Joo Jeong, MD Department of Radiology Pusan National University Hospital Pusan National University School of Medicine Busan, South Korea

Michael A. Kadoch, MD Assistant Professor of Clinical Radiology Department of Radiology University of California–Davis Sacramento, California

Jeffrey S. Klein, MD A. Bradley Soule and John P. Tampas Green and Gold Professor of Radiology Department of Radiology University of Vermont College of Medicine Burlington, Vermont

Sarah T. Kurian, MD Department of Radiology University of Missouri–Kansas City Kansas City, Missouri

Kyung Soo Lee, MD Department of Radiology Samsung Medical Center Sungkyunkwan University School of Medicine Seoul, South Korea

Andrea L. Magee, MD Resident Radiologist Department of Radiology The University of Chicago Chicago, Illinois

Victorine V. Muse, MD Assistant Professor of Radiology Harvard Medical School Massachusetts General Hospital Boston, Massachusetts

Justin M. Oldham, MD, MS Assistant Professor Department of Internal Medicine Division of Pulmonary, Critical Care, and Sleep Medicine University of California–Davis Sacramento, California

Melissa Price, MD Instructor in Radiology Division of Thoracic Imaging and Intervention Massachusetts General Hospital Boston, Massachusetts

Steven L. Primack, MD Professor and Vice Chair Department of Diagnostic Radiology Oregon Health and Science University Portland, Oregon

vii

viii

Contributors

Bradley S. Sabloff, MD

Mylene T. Truong, MD

Professor Department of Diagnostic Radiology The University of Texas MD Anderson Cancer Center Houston, Texas

Professor Department of Diagnostic Radiology The University of Texas MD Anderson Cancer Center Houston, Texas

Jean M. Seely, MDCM, FCRPC

Emily B. Tsai, MD

Associate Professor University of Ottawa Head of Breast Imaging Section Department of Medical Imaging The Ottawa Hospital Clinician Investigator Ottawa Hospital Research Institute Ottawa, Ontario, Canada

Department of Radiology Stanford University Stanford, California

Phillip A. Setran, MD Radiology Resident Department of Diagnostic Radiology Oregon Health and Science University Portland, Oregon

Girish S. Shroff, MD Associate Professor Department of Diagnostic Radiology The University of Texas MD Anderson Cancer Center Houston, Texas

Justin T. Stowell, MD Resident Department of Radiology University of Missouri–Kansas City Kansas City, Missouri

Nicola Sverzellati, MD, PhD Professor of Radiology Department of Medicine and Surgery University of Parma Parma, Italy

Chitra Viswanathan, MD Professor Department of Diagnostic Radiology Division of Diagnostic Imaging The University of Texas MD Anderson Cancer Center Houston, Texas

Christopher M. Walker, MD Associate Professor of Radiology University of Kansas Medical Center Kansas City, Kansas

Charles S. White, MD Professor Department of Diagnostic Radiology University of Maryland Baltimore, Maryland

Carol C. Wu, MD Associate Professor Department of Diagnostic Radiology The University of Texas MD Anderson Cancer Center Houston, Texas

FOREWORD

The aim of this second edition of Imaging of the Chest is to provide a succinct, state-of-the art overview of imaging of the thorax. We congratulate Drs. Christopher Walker and Jonathan Chung in achieving this goal by combining their outstanding talents as editors and their ability to obtain the collaboration of an exceptional team of internationally renowned chest radiologists to write chapters in their fields of expertise. The new edition includes a truly up-to-date review of the clinical, radiologic, and pathologic manifestations of lung diseases and several hundred new images that provide excellent illustrations of the latest technologic advances. The emphasis of this book, similar to daily practice, is on chest radiography and computed tomography (CT). However, as is also required in clinical practice, it includes the indications and characteristic findings on magnetic resonance imaging and, when applicable, scintigraphy, positron emission tomography (PET), integrated PET-CT imaging, and ultrasound. The book also provides a summary of the clinical manifestations and pathologic findings. The clinical history is always helpful and often essential for an accurate diagnosis or appropriate differential

diagnosis, while knowledge of the pathologic findings allows a better understanding of the patterns of abnormalities seen on the radiologic images. As the editors, we were delighted with the quality of the first edition and very thankful to the numerous authors who were responsible for its success. There have been, however, many major changes and new developments since the publication of that edition in 2008, which led to the need for a major revision and update. We chose to pass on the new edition to a young team of editors with the talent, energy, and dedication required in planning, organizing, and completing this monumental endeavor. We are very pleased to see that they managed to improve the quality of the book and believe that it will be extremely useful to radiology residents, chest radiology fellows, pulmonary physicians, thoracic surgeons, and general radiologists with an interest in chest imaging. Nestor L. Müller C. Isabela Silva Müller

ix

PREFACE

We are honored and humbled to be the editors of the second edition of Müller’s Imaging of the Chest. We are indebted to the previous editors, Drs. Nestor Müller and Isabela Silva, as well as their Associate and Assistant Editors, Drs. David Hansell, Kyung Soo Lee, and Martin Rémy-Jardin, for their extraordinary work in directing and creating the first edition of this textbook and organizing a team of some of the most esteemed chest radiologists. The authoritative and comprehensive content in the first edition of Imaging of the Chest made it the clear gold standard reference in thoracic imaging. When we were first offered the opportunity to edit this textbook, we were reluctant because the first edition was a hard act to follow. However, the opportunity to have a hand in the second iteration of the textbook, which we used as our personal go-to reference, was too hard to turn down. Thankfully, our wives urged us to take on this project lest we kick ourselves in the future. Given the daunting task of updating and editing the authoritative content assembled by the previous world-class team of chest radiologists, we knew we would need help. Our associate editors, Drs. Stephen Hobbs, Brent Little, and Carol Wu, were all obvious choices to help us direct this endeavor given their superior clinical training, unique clinical backgrounds, and complementary clinical and academic interests. Chest radiography continues to be the most commonly obtained imaging study throughout the world. In many patients, a high-quality chest radiograph, combined with appropriate clinical information, allows for accurate diagnosis. However, in many cases, it is helpful to obtain chest computed tomography (CT) imaging given its higher contrast resolution. In recent years, the line between high-resolution CT of the chest and standard CT has blurred as volumetric helical CT acquisition becomes the norm, allowing for reconstruction of images in any plane and in virtually any slice thickness. Contrast-enhanced chest CT and chest CT angiography are highly valuable tools in the assessment of suspected malignancy, vascular abnormalities, and thromboembolic disease. Magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging are useful adjuncts in thoracic imaging, specifically in the setting of known or suspected malignancy. Although specialized centers have used MRI and PET imaging for evaluation of nonmalignant pulmonary abnormalities, these are still mostly avenues for research rather than accepted clinical standards. In the second edition of this textbook, we aim to provide a comprehensive review of thoracic imaging while simultaneously compressing the size of the textbook from a two-volume set to

x

a single-volume reference. Needless to say, this was challenging, but we are quite proud of the end product and hope you will agree that essential content has not been excluded. The first part of this book deals with normal imaging appearance of the thorax on chest radiography and CT with detailed discussions of thoracic anatomy. Truly, one does not know what abnormal is until one knows what normal is. The second part of this book approaches thoracic imaging from the “findings” aspect rather than from the diagnosis side. This is likely most relevant to readers of this textbook, given that this is how patients present: with an unknown diagnosis but with abnormalities on chest imaging. Finally, the third part is arranged in a diagnosis or diagnostic category approach, as is typical of most textbooks. Specific highlights include updates on lung cancer screening and an updated review of pulmonary fibrosis and interstitial lung disease management and diagnosis. In addition, four new chapters were created to more fully include topics pertinent to chest imagers: Leukemia, Idiopathic Pleuroparenchymal Fibroelastosis, Interstitial Pneumonia with Autoimmune Features, and Noninfectious Lung and Stem Cell Transplantation Complications. This book would not have been possible without the support of our colleagues and mentors. We thank, first, all our mentors at the University of Washington and the Massachusetts General Hospital for cultivating our passion for cardiopulmonary imaging and guiding us in the gauntlet of academic radiology; second, specific leaders in the field, including Drs. David A. Lynch and J. David Godwin, whom we had the pleasure of working with and who continually provided their support and advice on all matters; and third, our trainees, who have always kept us honest in regard to what we knew (or thought we knew). We hope you enjoy reading this textbook (although based on your track record, we assume you will get around to it next rotation). Finally, we thank the wonderful staff at Elsevier who have made this endeavor possible, including but not limited to Robin Carter, Ann Anderson, Claire Kramer, and Margaret Nelson. This book is aimed at clinical radiologists, pulmonologists, trainees, and any other health care professionals interested in thoracic imaging. It provides a concise but comprehensive overview of imaging findings of thoracic diseases. We hope that the second edition of Müller’s Imaging of the Chest will be a valuable resource for the thoracic health care community and will ultimately improve patient care. Jonathan H. Chung, MD Christopher M. Walker, MD

CONTENTS

SECTION 1  Normal Chest

1 Normal Chest Radiography and Computed Tomography 1

JULIANA BUENO  |  CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

SECTION 2  Radiologic Manifestations of Lung Disease

2 Consolidation  57 JONATHAN H. CHUNG  |  CHRISTOPHER M. WALKER

3 Atelectasis  71 BRENT P. LITTLE

4 Nodules and Masses  91 SARAH T. KURIAN  |  CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

5 Interstitial Patterns  109 JONATHAN H. CHUNG  |  CHRISTOPHER M. WALKER

6 Decreased Lung Density  138 CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

SECTION 3  Developmental Lung Disease

7 Airway and Parenchymal Anomalies  147 JUSTIN T. STOWELL  |  CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

8 Congenital Malformations of the Pulmonary Vessels in Adults  167 BRENT P. LITTLE

SECTION 4  Pulmonary Infection

9 Bacterial Pneumonia  193 STEPHANE L. DESOUCHES  |  CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

10 Pulmonary Tuberculosis  219 KYUNG SOO LEE  |  YEON JOO JEONG

11 Nontuberculous (Atypical) Mycobacterial Infection 241 BRENT P. LITTLE

12 Fungal Infections  251 SUZANNE C. BYRNE  |  REBECCA M. LINDELL  |  THOMAS E. HARTMAN

13 Viruses  273 CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

14 Parasites  287 CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

15 Human Immunodeficiency Virus Infection  300 CAROL C. WU  |  JOHN P. LICHTENBERGER  |  KIRAN BATRA

SECTION 5  Pulmonary Neoplasms

16 Screening for Lung Cancer  317 SUZANNE C. BYRNE  |  THOMAS E. HARTMAN

17 Lung Cancer: Radiologic Manifestations and Diagnosis 324

CAROL C. WU  |  JEFFREY S. KLEIN

18 Pulmonary Carcinoma Staging  341 KYUNG SOO LEE  |  YEON JOO JEONG

19 Neuroendocrine Hyperplasia, Pulmonary Tumorlets, and Carcinoid Tumors  365

STEPHANE L. DESOUCHES  |  CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

20 Pulmonary Hamartoma  376 CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

21 Inflammatory Pseudotumor  381 JONATHAN H. CHUNG  |  CHRISTOPHER M. WALKER

22 Pulmonary Metastases  384 STEPHANE L. DESOUCHES  |  CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

SECTION 6  Lymphoproliferative Disorders and Leukemia

23 Pulmonary Lymphoid Hyperplasia

and Lymphoid Interstitial Pneumonia (Lymphocytic Interstitial Pneumonia)  393 JONATHAN H. CHUNG  |  CHRISTOPHER M. WALKER

24 Non-Hodgkin Lymphoma  401 PATRICIA M. DE GROOT  |  CAROL C. WU  |  BRETT W. CARTER  |  KYUNG SOO LEE

25 Hodgkin Lymphoma  413 EMILY B. TSAI  |  CAROL C. WU  |  VICTORINE V. MUSE  |  KYUNG SOO LEE

26 Leukemia  423 GIRISH S. SHROFF  |  CAROL C. WU  |  CHITRA VISWANATHAN  |  MYLENE T. TRUONG

SECTION 7  Diffuse Lung Diseases

27 Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis  429

JONATHAN H. CHUNG  |  CHRISTOPHER M. WALKER

28 Nonspecific Interstitial Pneumonia 440

JONATHAN H. CHUNG  |  CHRISTOPHER M. WALKER

29 Cryptogenic Organizing Pneumonia/

Secondary Organizing Pneumonia  449 JONATHAN H. CHUNG  |  CHRISTOPHER M. WALKER

xi

xii

Contents

30 Acute Interstitial Pneumonia  456 JONATHAN H. CHUNG  |  CHRISTOPHER M. WALKER

31 Sarcoidosis  461 JONATHAN H. CHUNG  |  CHRISTOPHER M. WALKER

32 Hypersensitivity Pneumonitis  478 ANDREA L. MAGEE  |  CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

33 Pulmonary Langerhans Cell Histiocytosis  494 STEPHEN B. HOBBS

34 Smoking-Related Interstitial Lung Disease 502 STEPHEN B. HOBBS

35 Lymphangioleiomyomatosis and Tuberous Sclerosis 513 NICOLA SVERZELLATI

36 Idiopathic Pleuroparenchymal Fibroelastosis 524

ROBERT M. DEWITT  |  STEPHEN K. FRANKEL

37 Eosinophilic Lung Diseases  527

48 Behçet Disease  611 JONATHAN H. CHUNG  |  CHRISTOPHER M. WALKER

49 Takayasu Arteritis  616 CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

50 Acute Pulmonary Embolism  622 CAROL C. WU  |  MATTHEW D. GILMAN

51 Chronic Pulmonary Thromboembolism  633 BRENT P. LITTLE

52 Nonthrombotic Pulmonary Embolism  642 CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

53 Pulmonary Arterial Hypertension  658 VEDANT GUPTA  |  STEPHEN B. HOBBS

54 Hydrostatic Pulmonary Edema  674 CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

55 Permeability Pulmonary Edema  685 STEPHEN B. HOBBS

MELISSA PRICE  |  CAROL C. WU  |  MATTHEW D. GILMAN

38 Metabolic and Storage Lung Diseases  535 CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

SECTION 11  Diseases of the Airways

56 Tracheal Diseases  694 BRENT P. LITTLE

SECTION 8  Connective Tissue Diseases

39 Rheumatoid Arthritis  552 STEPHEN B. HOBBS

40 Systemic Sclerosis (Scleroderma)  561 BRENT P. LITTLE

41 Systemic Lupus Erythematosus  565 BRENT P. LITTLE

42 Polymyositis/Dermatomyositis  571 STEPHEN B. HOBBS

43 Sjögren Syndrome  576 STEPHEN B. HOBBS

44 Mixed Connective Tissue Disease  581 BRENT P. LITTLE

45 Interstitial Pneumonia With Autoimmune Features 585

MICHAEL A. KADOCH  |  JUSTIN M. OLDHAM

SECTION 9  Vasculitis and Granulomatosis

46 Antineutrophil Cytoplasmic Antibody– Associated Vasculitis  592

STEPHANE L. DESOUCHES  |  CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

47 Goodpasture Syndrome (Anti–Basement Membrane Antibody Disease)  606

JONATHAN H. CHUNG  |  CHRISTOPHER M. WALKER

57 Bronchiectasis and Other Bronchial Abnormalities 713 BRENT P. LITTLE

58 Asthma  733 JONATHAN H. CHUNG  |  CHRISTOPHER M. WALKER

59 Bronchiolitis  745 SHERIEF GARRANA  |  CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

60 Emphysema  765 STEPHEN B. HOBBS

SECTION 12  Inhalational Diseases and Aspiration

61 Asbestos-Related Disease  775 STEPHEN B. HOBBS

62 Silicosis and Coal Workers’ Pneumoconiosis 793 STEPHEN B. HOBBS

63 Uncommon Pneumoconioses  809 STEPHEN B. HOBBS

64 Aspiration  822 TOMÁS FRANQUET

SECTION 13  Iatrogenic Lung Disease and Trauma

65 Drug-Induced Lung Disease  836 SARAH T. KURIAN  |  CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

Contents

66 Therapeutic Radiation and Radiation-Induced Lung Disease  847

MARCELO F. BENVENISTE  |  DANIEL R. GOMEZ  |  BRADLEY S. SABLOFF  |  JEREMY J. ERASMUS

67 Blunt Thoracic Trauma  863 PHILLIP A. SETRAN  |  STEVEN L. PRIMACK  |  CRISTINA S. FUSS

68 Postoperative Complications  885 MYLENE T. TRUONG  |  CAROL C. WU  |  CHARLES S. WHITE

69 Chest Radiography in the Intensive Care Unit  907

ANUPAMA BRIXEY  |  MATTHEW BENTZ  |  STEVEN L. PRIMACK

70 Noninfectious Lung and Stem Cell

Transplantation Complications  929

73 Benign Pleural Thickening  988 CAROL C. WU  |  JEAN M. SEELY

74 Pleural Neoplasms  1008 BRETT W. CARTER  |  PATRICIA M. DE GROOT  |  JEAN M. SEELY

SECTION 15 Mediastinum

75 Pneumomediastinum  1030 TOMÁS FRANQUET

76 Mediastinitis  1039 TOMÁS FRANQUET

77 Mediastinal Masses  1051 BRETT W. CARTER

BRENT P. LITTLE

SECTION 14  Pleural Disease

71 Pneumothorax  942 ASHISH GUPTA  |  JEAN M. SEELY

72 Pleural Effusion  963 ASHISH GUPTA  |  JEAN M. SEELY

xiii

SECTION 16  Diaphragm and Chest Wall

78 Diaphragm  1070 CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG  |  J. DAVID GODWIN

79 Chest Wall  1088 TOMÁS FRANQUET  |  JAUME LLAUGER

SECTION 1

Normal Chest

1 

Normal Chest Radiography and Computed Tomography* JULIANA BUENO  |  CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

Radiography Technique PROJECTIONS The standard radiographic views for evaluation of the chest are the posteroanterior (PA) and lateral projections with the patient standing; such projections provide the essential requirement for proper three-dimensional (3D) assessment (Fig. 1.1). In patients who are unable to stand, anteroposterior (AP) upright or supine projections offer alternative but considerably less satisfactory views. The AP projection is of inferior quality because of the shorter focal-detector distance, the greater magnification of the heart, and the restricted ability of many such patients to suspend respiration or achieve full inspiration. BASIC RADIOGRAPHIC TECHNIQUES Diagnostic accuracy in thoracic pathology is related partly to the quality of the radiographic images themselves, and multiple variables require attention. Patient Positioning and Respiration Images are ideally acquired at full inspiration to avoid magnification of the cardiomediastinal silhouette and vascular crowding, which decrease diagnostic capability. A well-centered x-ray beam, lack of rotation, and exclusion of the scapulae from the field of view are essential for adequate positioning. The distance between the medial ends of the clavicles (anterior structures) and the spinous processes of the thoracic vertebrae (posterior structures) are reliable landmarks to assess position. In a properly centered radiograph the medial ends of the right and left clavicles are equidistant from the spinous processes (Fig. 1.2). The American College of Radiology standards for performance of standard chest radiography in adults specify the use of at least a 72-inch (1.8-m) tube-detector distance for PA radiographs and a minimum of 40 inches in portable radiographs.1,2 *The editors and the publisher would like to thank Drs. Nestor L. Müller and C. Isabela Silva Müller for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

Exposure Exposure factors should be such that there is faint visualization of the thoracic spine and the intervertebral disks on the PA radiograph so that lung markings behind the heart are clearly visible.1 Kilovoltage A high-kilovoltage technique (115–150 kVp) should be used for PA and lateral chest radiographs.1 The high kVp allows better penetration of the mediastinum and shorter exposure times, thus minimizing cardiac motion artifacts and providing sharper outline of the pulmonary and mediastinal structures.1 IMAGE ACQUISITION Conventional screen-film radiography has a number of limitations and therefore has been replaced by computed radiography (CR) and digital radiography (DR). The process of acquisition, transmission, display, and storage of digital images has many advantages over conventional screenfilm systems,3,4 and it is widely used as the primary technology in conventional radiographic studies. A potential disadvantage of CR and DR is that patients may receive unnecessarily high radiation doses, which may not be detected because they do not result in perceivable alterations in image quality. The wider latitude of digital systems allows them to be used under a much broader range of exposure conditions and makes them an ideal choice for applications in which exposure is highly variable or difficult to control, such as bedside radiography. This results in a reproducible quality and considerable decrease in the repeat rate for bedside chest radiographs when using CR, compared with screen-film radiography.5 Two main types of digital systems are available commercially: systems based on photostimulable storage phosphor image receptors, known as CR, and systems based on flat-panel x-ray detectors or array of detectors that directly capture the radiographic image, known as DR. Computed Radiography CR (storage phosphor radiography) involves the use of a reusable photostimulable phosphor plate rather than film to record the image. Plates coated with the phosphor are loaded into special cassettes that are outwardly similar to screen-film cassettes. During exposure the receptor stores the x-ray energy and is then scanned by a laser beam, which results in the creation of visible or infrared 1

2

SECTION 1  Normal Chest

A

B Fig. 1.1  Normal chest radiograph. (A) Posteroanterior projection. (B) Lateral projection.

eliminating the step of reading out the detector. The detectors in DR are selenium based and provide the additional advantage of having considerably greater quantum efficiency than conventional screen-film systems and photostimulable phosphor detectors do,7,8 which results in an image quality superior to that of screen-film systems and existing storage phosphor detectors at a comparable or lower radiation dose.9

Fig. 1.2  Properly centered chest radiograph. A view from a frontal radiograph shows that the medial ends of the right and left clavicles (highlighted in black) are equidistant to the spinous process (arrow) of the vertebra at the same level, thus indicating that the radiograph is properly centered.

radiation, the intensity of which corresponds to the absorbed x-ray energy. The resultant luminescence is measured and recorded digitally.6 Digital Radiography DR uses a flat-panel x-ray detector or an array of detectors to directly capture the radiographic image numerically, thus

Normal Anatomy of the Chest AIRWAYS Trachea and Bronchi The trachea is a midline structure, and the tracheal walls are parallel except on the left side just above the bifurcation, where the aorta commonly causes a smooth indentation (Fig. 1.3). The trachea measures 10 to 12 cm in length and has 16 to 20 C-shaped cartilage rings on its lateral and anterior aspects and a fibromuscular posterior margin. Calcification of the cartilage rings is a common normal finding in patients older than 40 years, particularly women, but it is seldom evident on radiographs (Fig. 1.4). The upper limits of normal for coronal and sagittal

1  Normal Chest Radiography and Computed Tomography

3

AA

AA

A

B Fig. 1.3  Normal trachea and main bronchi. (A) Frontal radiograph shows that the tracheal air column is fairly straight and located in the midline except at the level of the aortic arch (AA), where the trachea is indented and may be slightly deviated to the right. The trachea divides into a short right main bronchus and a longer and more horizontal left main bronchus. (B) Coronal reformatted image from a CT scan demonstrating the normal anatomy of the trachea, the slight indentation at the level of the aortic arch (AA), and the main bronchi. Approximately 2 cm after its origin, the right main bronchus branches into the right upper lobe bronchus and the bronchus intermedius.

diameters of the trachea in men are 25 and 27 mm, respectively; in women, they are 21 and 23 mm, respectively.10 The lower limit of normal for both dimensions is 13 mm in men and 10 mm in women.10 The trachea divides into the left and right main bronchi at the carina, at approximately the level of the fifth thoracic vertebra. The subcarinal angle ranges widely from 35 to 90 degrees (mean, 61 degrees)11; thus routine measurement of this angle has no diagnostic value. The right main bronchus measures approximately 2 cm in length and has a more vertical course than the left main bronchus does (see Fig. 1.3). It divides into the right upper lobe bronchus and the bronchus intermedius. The bronchus intermedius continues distally for 3 to 4 cm from the takeoff of the right upper lobe bronchus and then bifurcates into bronchi to the middle and lower lobes. The left main bronchus is approximately 5 cm in length and divides into the left upper and lower lobe bronchi. The lobar bronchi branch into segmental bronchi. Segmental bronchi are visible on chest radiographs only when they are seen end-on as ring shadows or when they are abnormally thickened. The most commonly seen segmental bronchi on a chest radiograph are the anterior segmental bronchi of the upper lobes; seen as ring shadows adjacent to the accompanying segmental pulmonary artery (Fig. 1.5).

KEY POINTS: TRACHEA • Normal diameter in men is 13–27 mm. • Normal diameter in women is 10–23 mm. • The tracheal cartilages are C shaped and spare the posterior tracheal wall, which is membranous.

PULMONARY ARTERIAL AND VENOUS CIRCULATION Pulmonary Arteries The pulmonary trunk or main pulmonary artery originates in the mediastinum at the pulmonary valve and extends cranially and slightly to the left for 4 to 5 cm before bifurcating within the pericardium into the shorter left and longer right pulmonary arteries (Fig. 1.6). The left pulmonary artery continues until it reaches the hilum, where it arches over the left main bronchus and gives off the left upper lobe and interlobar arteries, from which segmental and subsegmental branches arise. The left interlobar artery lies posterolateral to the upper lobe bronchus. The right pulmonary artery courses behind the ascending aorta before dividing in front of the right main bronchus into ascending (truncus anterior) and descending (interlobar) branches.

4

SECTION 1  Normal Chest

A

B

C Fig. 1.4  Tracheal and bronchial wall calcification. A magnified view from a posteroanterior chest radiograph (A) in an elderly patient shows calcification of the tracheal and bronchial walls. Coronal (B) and sagittal (C) reformatted images from a CT scan show the extent of tracheal and bronchial calcification. Airway wall calcification is a normal finding in elderly patients.

1  Normal Chest Radiography and Computed Tomography

5

Fig. 1.5  Anterior segmental bronchus of the right upper lobe seen end-on. A view from a frontal radiograph shows a ring shadow (curved arrow) corresponding to the anterior segmental bronchus of the right upper lobe seen end-on and the adjacent anterior segmental pulmonary artery (straight arrow). The outer diameter of the bronchus on the upright chest radiograph is slightly larger than that of the adjacent artery.

MPA RI BI

TA

RPA LPA

RI

RPA

LPA

A

AA

B

* MPA

RV

C

Fig. 1.6  Normal anatomy of the central pulmonary arteries. (A) A maximum-intensity projection image obtained from a CT scan demonstrates that the main pulmonary artery (MPA) courses posteriorly and branches into the right (RPA) and left (LPA) pulmonary arteries. The right pulmonary artery branches shortly after its origin into the truncus anterior, which courses cephalad to supply most of the right upper lobe, and a larger right interlobar pulmonary artery (RI), which courses just anterior and then lateral to the bronchus intermedius (BI). (B) Coronal image from a CT scan demonstrating the orientation of the RPA and LPA in the same projection as the frontal radiograph. The right pulmonary artery and the central portion of the left pulmonary artery are in the mediastinum and therefore cannot be identified on the chest radiograph. The right pulmonary artery branches into the truncus anterior (TA) and RI. (C) Sagittal image demonstrating the orientation of the right and left pulmonary arteries that corresponds to the lateral chest radiograph. The MPA originates from the right ventricle (RV) and courses cephalad and posteriorly. AA, Aortic arch; asterisk, aortopulmonary window.

6

SECTION 1  Normal Chest

Fig. 1.7  Normal right interlobar artery visualized on a frontal chest radiograph. The upper limit of normal of the transverse diameter of the interlobar artery measured from its lateral aspect to the air column of the bronchus intermedius (black bar) is 16 mm in men and 15 mm in women.

Measurements of pulmonary arterial diameter can be helpful in the assessment of pulmonary vascular disease, although in conventional radiography, it is limited to the measurement of the right interlobar artery. The upper limit of normal of the transverse diameter of the right interlobar artery (measured from its lateral aspect to the air column of the bronchus intermedius) is 16 mm in men and 15 mm in women (Fig. 1.7).12 Dilation of the interlobar pulmonary artery may result from increased pressure (e.g., pulmonary arterial hypertension), increased flow (e.g., left-to-right shunts), or aneurysm formation (e.g., Behçet disease) (Fig. 1.8).

Fig. 1.8  Enlarged central pulmonary arteries from severe pulmonary arterial hypertension. A frontal radiograph shows markedly enlarged central pulmonary arteries.

RA

AA

LA DA

KEY POINTS: PULMONARY ARTERIES • The pulmonary trunk or main pulmonary artery is not normally visualized on radiography in adults. • Normal diameter of the right interlobar pulmonary artery is 7 cm) may result from dilation of the great vessels (supine position, pregnancy, increased blood volume, left heart failure), mediastinal abnormality (mediastinal lipomatosis, lymph node enlargement, masses, fluid collections), or pleural disease.33 MEDIASTINUM Anatomy The mediastinum separates the thorax vertically into two compartments and can be defined anatomically as the partition between the lungs. Although there is variability in the description of the mediastinum, the most widely used classification on radiography divides it anatomically (and for diagnostic purposes) into three compartments: anterior (prevascular), middle (cardiovascular), and posterior (postvascular).34 The anterior mediastinal compartment is bounded anteriorly by the sternum and posteriorly by the pericardium, aorta, and brachiocephalic vessels. It merges superiorly with the anterior aspect of the thoracic inlet and extends down to the level of the diaphragm. The compartment

1  Normal Chest Radiography and Computed Tomography

A

13

B Fig. 1.19  Azygos fissure. (A) Posteroanterior chest radiograph showing the azygos fissure as a curvilinear line (arrowheads) extending obliquely across the upper portion of the right lung. Note the azygos vein (arrow) coursing within the fissure. (B) Coronal reformatted image from a CT scan showing the azygos fissure (arrow).

A

B Fig. 1.20  Accessory fissures. (A) Posteroanterior chest radiograph showing the right minor fissure (long arrow) and right inferior accessory fissure (short arrow). (B) Coronal reformatted CT image showing the right minor fissure (long straight arrow), right inferior accessory fissure (short straight arrow), and right superior accessory fissure (curved arrow). Also noted are several accessory fissures in the left lung.

contains the thymus gland, branches of the internal mammary artery and vein, lymph nodes, the inferior sternopericardial ligament, and variable amounts of fat. On a chest radiograph the thymus is visible only in infants and young children, in whom it fills much of the anterior mediastinal space. The middle mediastinal compartment contains the pericardium and its contents, the ascending and transverse portions of the aorta, the superior and inferior venae cavae, the brachiocephalic (innominate) arteries and veins, the phrenic nerves and

the cephalad portion of the vagus nerves, the trachea and main bronchi and their contiguous lymph nodes, and the main pulmonary arteries and veins. The posterior mediastinal compartment is bounded anteriorly by the pericardium and the vertical part of the diaphragm, laterally by the mediastinal pleura, and posteriorly by the bodies of the thoracic vertebrae. It contains the descending thoracic aorta, esophagus, thoracic duct, azygos and hemiazygos veins, autonomic nerves, fat, and lymph nodes.

14

SECTION 1  Normal Chest

T1

Fig. 1.21  Thoracic inlet. A detailed view from a posteroanterior chest radiograph shows the right and left first ribs as they originate posteriorly from the first thoracic vertebra (T1) and course anteriorly and inferiorly. The thoracic inlet parallels the first ribs (arrowheads) and is therefore higher posteriorly.

BCV

BCV BCA CA

LSA

SC

SVC

Fig. 1.22  Structures in the thoracic inlet. A CT scan at the level of the thoracic inlet shows the right and left brachiocephalic veins (BCV), the right brachiocephalic artery (BCA) immediately anterior to the trachea, the left common carotid artery (CA) slightly to the left of the trachea, and the left subclavian artery (SC) more posteriorly. The esophagus lies posterior to the trachea.

Given the variability in the visualization of anatomic structures in the lateral radiograph, it is preferable to classify abnormalities seen on radiographs into three groups based on the likelihood of their anatomic location: (1) the anterior mediastinum when a mass is situated between the sternum and a line drawn along the anterior border of the trachea and the posterior border of the heart,35 (2) the middle-posterior mediastinum when a mass is located predominantly between this line and a line drawn 1 cm behind the anterior margin of the vertebral bodies, and (3) the paravertebral region when a mass is situated predominantly in the potential space adjacent to a vertebral body (Fig. 1.24). Although the vertebral bodies are not properly considered part of the posterior mediastinum, lesions in the paravertebral region are not infrequent causes of opacities projecting over the posterior mediastinal compartment on the lateral chest radiograph and thus should be considered within the differential diagnosis. Accurate assessment of the anatomic location of these abnormalities can readily be accomplished with CT or magnetic resonance imaging (MRI). Frontal Chest Radiograph On a frontal chest radiograph the mediastinal shadow to the right of the trachea is formed by the right brachiocephalic vein and the SVC, and the contour of the lower mediastinal shadow is formed by the right atrium (Fig. 1.25). The interface between the right brachiocephalic vein and the SVC is seen in almost all patients from the level of the medial end of the right clavicle to

Fig. 1.23  Vascular pedicle. A detailed view from a posteroanterior (PA) chest radiograph shows the width of the vascular pedicle, which is measured from the lateral edge of the superior vena cava (SVC) as it crosses the right main bronchus to a vertical line drawn inferiorly from the point where the left subclavian artery (LSA) arises from the aortic arch. The normal width of the vascular pedicle on an upright PA chest radiograph is less than 6 cm.

the level of the right bronchus (see Fig. 1.25). The density of the SVC is generally less than that of the aortic arch, and its interface with the lung is normally slightly concave laterally.36 Increased opacity in the region of the SVC and the lateral convexity of its interface with the lung may result from increased size of the SVC (supine position, pregnancy, and right heart failure), paratracheal lymph node enlargement, a mediastinal mass, mediastinal hemorrhage, or a pleural abnormality.36 The trachea is normally bordered on its right lateral aspect by pleura covering the right upper lobe. Contact of the right lung in the supraazygos area with the right lateral wall of the trachea

1  Normal Chest Radiography and Computed Tomography

15

AA A

Fig. 1.25  Normal right paratracheal region. A detail view from a frontal chest radiograph shows a normal mediastinum at the level of the aortic arch (AA). The right lateral border is delimited by the faint opacity of the superior vena cava (SVC) (arrowheads). The SVC normally has a straight outer contour and lower opacity than the aortic arch does. Note the right paratracheal stripe (arrow) and the azygos vein (A) at the level of the right tracheobronchial angle. Fig. 1.24  Mediastinal compartments on a lateral chest radiograph. A mass can be considered to probably lie in the anterior mediastinum if it is situated predominantly in the region in front of a line drawn along the anterior border of the trachea and the posterior border of the heart. A mass probably lies in the middle or posterior mediastinum if it is situated between this line and a line drawn 1 cm posterior to the anterior aspect of the vertebral bodies. Extrapulmonary masses posterior to this line are typically paravertebral in location.

creates a thin stripe of soft tissue density that is usually visible on frontal chest radiographs and is known as the right paratracheal stripe (see Fig. 1.25).37 This stripe is formed by the right wall of the trachea, contiguous parietal and visceral pleura, and a variable quantity of mediastinal fat. The thickness of this stripe above the level of the azygos vein generally ranges from 1 to 4 mm. Widening of the paratracheal stripe (>5 mm) may be due to thickening of the tracheal wall by inflammation or space-occupying lesions, paratracheal lymph node enlargement, mediastinal hemorrhage, or pleural disease.36,37 Widening of the paratracheal stripe is not a particularly sensitive sign for lymphadenopathy in that it is present in only approximately 30% of patients who demonstrate paratracheal lymph node enlargement on CT.36 A slightly flattened elliptical opacity can frequently be seen in the region of the right tracheobronchial angle corresponding to the azygos vein being viewed tangentially as it enters the SVC (see Fig. 1.25). The azygos vein originates in the upper lumbar region at the level of the renal veins as a continuation of the right ascending

lumbar vein. Along its course the vein receives tributaries from the 5th to 11th intercostal veins on the right, the right subcostal vein, the right superior intercostal vein, the right bronchial veins, and the superior and inferior hemiazygos veins.38 It drains into the SVC. Contact of the right lower lobe with the esophagus and the ascending portion of the azygos vein results in the azygoesophageal recess.38,39 This recess is frequently identified on a well-penetrated PA radiograph as an interface that extends from the diaphragm to the level of the azygos arch (Fig. 1.26). A focal right-sided convexity of the azygoesophageal recess interface should raise suspicion of an underlying pathologic process, such as a hiatal hernia, esophageal tumor or duplication cyst, azygos vein dilation, or subcarinal lymph node enlargement. The left lateral wall of the trachea is rarely visible on a PA chest radiograph because of contiguity of the left subclavian artery and mediastinal fat. On a frontal chest radiograph the mediastinal shadow to the left of the trachea above the level of the aortic arch is typically a low-density arcuate opacity (concave laterally) extending from the aortic arch to a point at or just above the medial end of the clavicle (Fig. 1.27). The lateral margin of this density corresponds to the course of the left subclavian artery and may be formed by the artery or, more commonly, by adjacent fat. The first convexity of the left aspect of the mediastinum is formed by the posterior portion of the aortic arch. Contact of the lateral aspect of the descending aorta and the left lung results in the left paraaortic interface. A lateral

16

SECTION 1  Normal Chest

AA

A

AE recess Azygos

DA

Esophagus

B Fig. 1.26  Azygoesophageal recess. (A) Detail view from a frontal chest radiograph showing the azygoesophageal recess as a smooth continuous arc (arrowheads) as it extends from the diaphragm to the level of the azygos arch. (B) Contrast-enhanced CT scan showing the azygos vein and the esophagus forming the medial border of the azygoesophageal (AE) recess. DA, Descending thoracic aorta.

convexity of the left paraaortic interface may result from tortuosity of the aorta (normally seen in the elderly), an aortic aneurysm, a paraaortic mediastinal mass, hemorrhage, or enlarged lymph nodes. A small triangular or round opacity is seen immediately lateral to the aortic arch on approximately 1% of chest radiographs.27 This opacity, known as the “aortic nipple,” is caused by the left superior intercostal vein as it courses cephalad and forward to enter the left brachiocephalic vein (Fig. 1.28). The opacity seen immediately below the level of the aortic arch and above the left main bronchus is the main pulmonary

Fig. 1.27  Normal left mediastinal shadow. A detail view from a frontal chest radiograph shows the outer margin of the left mediastinum above the aortic arch (AA) as an arcuate opacity concave laterally (arrowheads) and extending from the aortic arch to a point just above the medial end of the clavicle. The lateral margin of this opacity corresponds to the course of the left subclavian artery and may be formed by the artery or, more commonly, by adjacent fat. The first convexity of the left aspect of the mediastinum is formed by the posterior portion of the aortic arch. Extending from the aortic arch, the left border of the descending aorta (arrows) can be seen coursing medially down to the level of the diaphragm.

artery. The space between the arch of the aorta and the left pulmonary artery is known as the aortopulmonary window, which is usually concave or straight (Fig. 1.29). It is occupied largely by mediastinal fat; its medial boundary is the ductus ligament, and its lateral boundary is the mediastinal and visceral pleura over the left lung, which creates the aortopulmonary window interface. Convexity of the aortopulmonary window interface may result from lymph node enlargement, a mediastinal tumor, or an aortic aneurysm. Because the left recurrent laryngeal nerve courses in the aortopulmonary window, pathologic processes in this region may be associated with left vocal cord palsy and hoarseness. The interfaces between the anterior and posterior mediastinal contents and the lungs just inferior to the thoracic inlet result in linear shadows known as the anterior and posterior junction lines, respectively. The anterior junction line is formed by contact of the right and left lungs with the adjacent prevascular mediastinum in the retrosternal space. On a PA chest radiograph this line is typically oriented obliquely from upper right to lower left behind the sternum (Fig. 1.30), seen in approximately 20% of cases.

1  Normal Chest Radiography and Computed Tomography

17

AA MPA LPA LMB LAA

RA LV

Fig. 1.28  Aortic nipple. Detail view from a frontal radiograph showing a small triangular opacity (arrow) immediately lateral to the aortic arch. This opacity, known as the aortic nipple, is caused by the left superior intercostal vein as it courses cephalad and forward to enter the left brachiocephalic vein.

The pleural apposition between the upper lobes and along with any intervening mediastinal tissue creates the posterior junction line (see Fig. 1.30). On a PA radiograph the posterior junction line usually projects through the air column of the trachea; it may be straight or slightly convex to the left. Lateral Chest Radiograph The trachea can be readily seen on a lateral radiograph as it descends in a straight course obliquely caudally and posteriorly (Fig. 1.31). The anterior wall of the trachea is seldom visible because it is obscured by the mediastinum, but the posterior wall can usually be seen because it abuts the lung. The posterior wall together with adjacent fat forms the posterior tracheal stripe or band, which generally measures less than 4 mm in diameter. Measurement of this stripe, however, is seldom helpful because the esophagus may be interposed between the posterior trachea and lung and result in a stripe thickness of 1 cm or greater. The region posterior to the tracheal stripe and anterior to the spine above the level of the aortic arch is known as the retrotracheal triangle (Fig. 1.31), which is a characteristically lucent space, and it contains the esophagus, lymph nodes, and posterior segments of the upper lobes. Increased opacity in the retrotracheal triangle in the lateral radiograph is abnormal, and although commonly resulting from an aberrant subclavian artery, other entities, such as an esophageal tumor, a thyroid mass, lymph node enlargement, or a foregut duplication cyst, may cause an abnormal density. KEY POINTS: HILA AND MEDIASTINUM • Left hilum normally 1–2 cm higher than the right • Normal diameter of the vascular pedicle: 40 years of age or in suspicious cases 70 years), malnutrition, cancer, immunosuppressive therapy, HIV infection, end-stage renal disease, and diabetes • Characteristic manifestations • Granulomatous inflammation—that is, necrotic focus with surrounding epithelioid histiocytes and multinucleated giant cells • Primary infection • Initial parenchymal lesion (Ghon focus) and lymph node inflammation (Ranke complex), usually heal but remain as a dormant infection (latent tuberculosis infection) • Postprimary tuberculosis • Eventually, 10% of patients with primary infection develop reactivation or reinfection by new strains. • New concept • The only independent predictor of radiographic appearance of tuberculous lung infection is integrity of the host immune response, not time from acquisition of infection to development of clinical disease.

upper lobes and the superior segments of the lower lobes (Fig. 10.2; see Fig. 10.1).15,16 Another common finding is the presence of poorly defined nodules and linear opacities (fibronodular pattern of TB). In one review of the radiographic features of 158 patients with postprimary TB, approximately 55% presented with consolidation, 25% with a fibronodular pattern, and 5% with a mixed pattern.16 Single or multiple cavities

10  Pulmonary Tuberculosis

221

A

C

B

are evident radiographically in 20% to 45% of patients15–17 (Figs. 10.3 and 10.4). Air-fluid levels are seen in 10% to 20% of tuberculous cavities.16,17 In approximately 85% of patients the cavities involve the apical or posterior segments of the upper lobes and, in approximately 10%, the superior segments of the lower lobes.15 Endobronchial spread, manifested as 4- to 10-mmdiameter nodules distant from the site of the cavity, is evident radiographically in 10% to 20% of cases16,18 (see Fig. 10.3).

Fig. 10.2  Pulmonary tuberculosis manifesting as small nodular clustering. (A) Chest radiograph shows focal parenchymal opacity in the right upper lobe. (B) CT scan obtained at the level of the azygos arch demonstrates variable-sized nodular clustering in the posterior segment of the right upper lobe. One of the nodules shows cavitation. Also note associated tree-in-bud opacities (arrows). (C) Coronal reformatted CT image shows typical tree-in-bud opacities (arrows) in the right upper lobe.

In approximately 5% of patients with postprimary TB, the main manifestation is a tuberculoma, defined as a sharply marginated round or oval lesion measuring 0.5 to 4.0 cm in diameter (Fig. 10.5).16,17 Histologically, the central part of the tuberculoma consists of caseous material and the periphery of epithelioid histiocytes and multinucleated giant cells and a variable amount of collagen. Tuberculomas usually occur in the upper lobes; approximately 80% are single and 20% are multiple. Satellite

222

SECTION 4  Pulmonary Infection

A

C

B

Initial

2 months

D

Fig. 10.3  Cavitary multidrug-resistant pulmonary tuberculosis demonstrating progressive disease over 2 months. (A) Initial chest radiograph shows patchy opacities and extensive small nodular clustering in both lungs. Also note segmental consolidation in the right upper lobe and a small left pleural effusion. (B) Follow-up radiograph obtained 2 months later shows increased extent of disease with main pattern of airspace consolidation in both lungs. Also note cavitating lesions (arrows). (C) Composite image with CT scan obtained at the time of initial presentation and the first chest radiograph (left image), and 2 months later at the same time as the second chest radiograph (right image) shows progressive right upper lobe cavitating (arrows) and noncavitating consolidation, tree-in-bud opacities (arrowheads), and variable-sized nodular lesions (curved arrows). (D) Photomicrography of right pneumonectomy pathologic specimen demonstrates abscess (arrows) containing yellowish creamy necrotic materials, nodules, small nodules of centrilobular location, and nodular branching lesions (arrowheads). Branching means that lesions are airway centered.

nodules histologically identical to the larger focus of disease and measuring 1 to 5 mm in diameter are present in most cases (see Fig. 10.5). In immunocompromised hosts, pulmonary TB manifests as miliary TB, hilar or mediastinal lymphadenopathy, and pleural effusion. Hilar or mediastinal lymphadenopathy is uncommon in postprimary TB, being seen in approximately 5% to 10% of

patients.16,17 Pleural effusion, typically unilateral, occurs in 15% to 20% of patients.19 Although pleural effusion is usually associated with parenchymal abnormalities (Fig. 10.6), it may be the only radiologic manifestation of TB (Fig. 10.7). Pleural effusion can be caused by rupture of a tuberculous cavity into the pleural space. This may result in the formation of tuberculous empyema and, occasionally, a bronchopleural fistula with pleural air-fluid level.20

10  Pulmonary Tuberculosis

B

A

C Fig. 10.4  Cavitary multidrug-resistant pulmonary tuberculosis. (A) Chest radiograph shows nodular and cavitary (arrow) lesions in both lungs. (B) CT scan obtained at the level of the aortic arch demonstrates thin-walled cavitary lesions (arrows) and small centrilobular nodules (curved arrows). Images of the lower lobes (not shown) demonstrated tree-in-bud opacities indicating endobronchial spread of infection. (C) Sagittal section of a right upper lobectomy pathologic specimen demonstrates a cavity (arrows) and calcified (arrowhead) and noncalcified (curved arrow) small nodules in right upper lobe.

223

224

SECTION 4  Pulmonary Infection

A

B

N

C

D Fig. 10.5  Tuberculoma. (A) Chest radiograph shows a poorly defined nodule (arrow) in the right lower lung zone. (B) Composite image with CT scan obtained at the level of the basal segmental bronchi (left image), and a 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scan (right image) shows an FDG-avid nodule (arrow) in the lateral basal segment of the right lower lobe. (C) Photomicrography of a wedge resection pathologic specimen shows a tuberculoma (arrows) containing areas of caseation necrosis (N). (D) Magnified view of granulomas demonstrates epithelioid histiocytic infiltration and multinucleated giant cells (arrows).

10  Pulmonary Tuberculosis

A

B Fig. 10.6  Tuberculous pleurisy and pulmonary tuberculosis. (A) Chest radiograph shows a small left pleural effusion (arrowhead) and left middle lung zone nodular densities (arrow). (B) CT scan obtained at the level of the left upper lobar bronchus demonstrates tree-in-bud opacities (arrows) in the left upper lobe. Also note the left pleural effusion (arrowheads).

Fig. 10.7  Tuberculous pleurisy. Composite image with chest radiograph (left image) and axial CT scan (right image) shows a left pleural effusion with homogeneous parietal pleural enhancement (arrow).

225

226

SECTION 4  Pulmonary Infection

cystic lesions may develop in patients recovering from ARDS or in patients with extensive consolidation resulting from TB.27 The cystic lesions may resemble pneumatoceles or bullae. They may resolve over several months or persist27 (see Fig. 10.10). Vascular complications of pulmonary TB include pulmonary and bronchial arteritis and thrombosis, bronchial artery pseudoaneurysm, and Rasmussen aneurysm (Fig. 10.12).20 Rasmussen aneurysm is a pseudoaneurysm that results from weakening of the pulmonary artery wall by adjacent cavitary TB. Mediastinal complications include esophagomediastinal or esophagobronchial fistula, constrictive pericarditis (Fig. 10.13), and fibrosing mediastinitis.20 Pleural complications include tuberculous pleurisy and empyema, empyema necessitatis, fibrothorax, pneumothorax, and bronchopleural fistula.20,22 Empyema necessitatis (Fig. 10.14) results from leakage of tuberculous empyema through the parietal pleura with discharge of its contents into the subcutaneous tissues of the chest wall or, less commonly, pericardium, vertebral column, or esophagus.22 The main chest wall complications are tuberculous osteomyelitis and chondritis, tuberculous spondylitis (Fig. 10.15), and empyema necessitatis.20,22 A

KEY POINTS: RADIOGRAPHIC FINDINGS OF PULMONARY TUBERCULOSIS • Immunocompromised hosts • Lymph node enlargement, pleural effusion, miliary dissemination, lower lobe consolidation • Immunocompetent hosts • Focal or patchy consolidation in apical and posterior segments of upper lobes and superior segments of lower lobes • Cavitation (20%–45%) • Small nodules away from primary lesion (20%–25%)

MULTIDETECTOR OR HIGH-RESOLUTION COMPUTED TOMOGRAPHY B Fig. 10.8  Miliary tuberculosis. (A) Chest radiograph shows numerous 1- to 2-mm-diameter nodules throughout both lungs (miliary pattern). (B) CT scan obtained at the level of the main bronchi demonstrates random distribution of numerous small nodules.

Miliary spread of TB can occur in both primary and recurrent disease21 (Figs. 10.8 and 10.9). In the latter situation it may be seen in association with typical parenchymal changes as described previously or may be the sole pulmonary abnormality. Each focus of miliary infection results in local granulomas, which when well developed consist of a region of central necrosis surrounded by a relatively well-delimited rim of epithelioid histiocytes and fibrous tissue (see Fig. 10.9). Pulmonary TB may result in a number of complications and sequelae.20,22,23 Parenchymal and airway complications include acute respiratory distress syndrome (ARDS),24–26 extensive lung destruction and cicatrization, multiple cystic lung lesions (Fig. 10.10), aspergilloma, bronchiectasis, tracheobronchial stenosis (Fig. 10.11), and broncholithiasis.20,23 The radiologic manifestations of ARDS secondary to TB include extensive bilateral ground-glass opacities or consolidation superimposed on findings of miliary or endobronchial spread of TB. Multiple

The most common CT findings of parenchymal pulmonary TB are centrilobular nodules and branching linear and nodular opacities (tree-in-bud pattern), patchy or lobular areas of consolidation, and cavitation (see Figs. 10.2 to 10.4).28–30 The centrilobular nodules and tree-in-bud pattern are due to the presence of caseation necrosis and granulomatous inflammation filling and surrounding terminal and respiratory bronchioles and alveolar ducts.29,31 Clusters of small nodules or tree-in-bud pattern may result in localized CT galaxy sign(s) on thin-section CT32 (Fig. 10.16). Multilobar and widespread involvement of small centrilobular nodules and tree-in-bud opacities reflects the presence of endobronchial spread of TB. Coalescence of small nodules or clustering of small nodules leads to formation of a large nodule (Fig. 10.17). The majority of tuberculous cavities are thick walled, but thin-walled cavities are also common, particularly in patients undergoing treatment. According to a report30 in which CT findings were assessed in 29 patients with newly diagnosed pulmonary TB and 12 patients with recent reactivation, the most common abnormality on CT was the presence of 2- to 4-mm-diameter centrilobular nodules and/or branching linear structures (tree-in-bud pattern) seen in 95% of patients. Other common findings included cavitary nodules (69% of patients), lobular consolidation (52% of patients), interlobular septal thickening (34% of patients), and Text continued on p. 233

10  Pulmonary Tuberculosis

227

A

B

Fig. 10.9  Miliary tuberculosis in a 40-year-old man with chronic myeloid leukemia. (A) Composite image with CT scans obtained at the levels of the right inferior pulmonary vein (left image) and segmental bronchi (right image) shows small nodules with random distribution in both lungs. Also note the smooth interlobular septal thickening (arrows). (B) Photomicrography of a video-assisted thoracoscopic surgery biopsy specimen demonstrates small granulomas along alveolar walls (arrows) and interlobular septa (arrowhead).

228

SECTION 4  Pulmonary Infection

A

D

B

E

C

F Fig. 10.10  Pulmonary tuberculosis manifesting as extensive parenchymal consolidation and subsequently as cystic lung disease. (A) Initial chest radiograph shows multiple nodules in both lungs with airspace consolidation in both upper lobes. Note small left pleural effusion. (B) and (C) Initial CT scans obtained at the levels of the sternal notch (B) and manubrium (C) show upper lobe centrilobular nodules, tree-in-bud opacities, cavitary nodules, and airspace consolidation. (D) A follow-up chest radiograph obtained 4 months after (A) with antituberculous therapy demonstrates a decreased extent of parenchymal opacities in both lungs but new cystic lesions (arrow) in the right upper lung zone. (E) and (F) Follow-up CT scans obtained at the same levels of (B) and (C) and at the same time as (D) show multiple cystic lesions in the right upper lobe. The extent of airspace consolidation and centrilobular nodules decreased.

10  Pulmonary Tuberculosis

A

C

B

D Fig. 10.11  Serial follow-up of bronchial tuberculosis in a 31-year-old woman. (A) Initial chest radiograph shows right upper lobe volume loss and bilateral lower lung zone parenchymal opacities (arrows). (B) Composite image with CT scans obtained at the levels of the aortic arch (left image) and main bronchi (right image) demonstrates luminal narrowing and wall thickening in the distal trachea (arrows) and nearly completely obliterated right main bronchus lumen (arrowhead) with marked wall thickening. (C) Volume-rendering image shows luminal narrowing of the intrathoracic trachea (arrows) and obliterated lumen of the right main bronchus (arrowhead). (D) Volume-rendering image of a 6-month follow-up CT study with antituberculous chemotherapy demonstrates improvement of airway disease with reconstitution of the right main bronchus. However, findings of smooth luminal narrowing in the distal trachea (arrow) and right main bronchus (arrowhead) (fibrotic stage of airway tuberculosis) remain.

229

230

SECTION 4  Pulmonary Infection

A

A

B

B Fig. 10.12  Rasmussen aneurysm in chronic destructive pulmonary tuberculosis. (A) Contrast-enhanced CT image obtained at the level of the bronchus intermedius shows a contrast-filling aneurysm (arrow) within parenchymal consolidation in the superior segment of the left lower lobe. Also note the enlarged lymph nodes (arrowheads) in the subcarinal station. (B) Nonselective left pulmonary angiography shows a contrastfilling aneurysm (arrow) from a branch of the left pulmonary artery.

Fig. 10.13  Tuberculous constrictive pericarditis. (A) Chest radiograph shows cardiomegaly and bilateral pleural thickening/effusions. (B) CT scan obtained at the left atrial level shows pericardial effusion and bilateral pleural effusions. Also note the markedly enhancing and thickened parietal pericardium (arrows).

10  Pulmonary Tuberculosis

B

A

Fig. 10.14  Tuberculous empyema necessitatis. (A) Chest radiograph shows increased opacity (arrows) in the right lower lung zone. (B) Contrast-enhanced CT image obtained at the level of the suprahepatic inferior vena cava shows loculated fluid collection (arrow) in the right pleural space. Also note the soft tissue attenuation (arrowheads) in the extrapleural subcostal tissue. (C) CT scan obtained 10 mm inferior to (B) demonstrates fluid collection in the extrapleural subcostal tissue (arrows) and in the right chest wall (arrowheads).

C

231

232

SECTION 4  Pulmonary Infection

B

A

C Fig. 10.15  Tuberculous spondylitis. (A) Chest radiograph shows patchy distribution of small nodular and tubular densities in both lungs. Also note the laterally displaced right paraspinal interface (arrow). (B) Contrast-enhanced CT scan obtained at the level of the liver caudate lobe shows a calcified, heterogeneous, and low-attenuation soft tissue lesion in the paraspinal region, bilaterally. Note the vertebral body osseous destruction and intraspinal extension (arrow) of the soft tissue lesion with cord compression (arrowhead). (C) T2-weighted MR image obtained at a similar level to (B) demonstrates intraspinal extension of the lesion (arrow) with cord compression (arrowhead).

10  Pulmonary Tuberculosis

233

Fig. 10.17  Pulmonary tuberculosis showing coalescence of small nodules and tree-in-bud opacities. CT scan obtained at the level of the aortic arch shows a parenchymal lesion composed of coalescence of tree-in-bud opacities, suggestive of active pulmonary tuberculosis.

A

B Fig. 10.16  Active pulmonary tuberculosis manifesting the CT galaxy sign. (A) Coronal CT image depicts the galaxy sign (arrows) in the right upper lobe with a larger nodule and smaller peripheral nodules. (B) Low-magnification photomicrograph shows aggregation of small granulomas, which forms the galaxy sign on the CT scan. Inset: multiple TB granulomas on high-magnification photomicrograph.

bronchovascular distortion (17% of patients). Findings of endobronchial spread of TB were often present in the absence of cavitation. In 11 of 12 patients with recent reactivation TB, CT clearly differentiated old fibrotic lesions from new active lesions by demonstrating centrilobular nodules or a tree-in-bud

pattern. Patients having follow-up high-resolution CT during treatment showed a gradual decrease in lobular consolidation. Most of centrilobular nodular and branching opacities disappeared within 5 months after the start of treatment. On the other hand, bronchovascular distortion, fibrosis, emphysema and bronchiectasis increased on follow-up scans.30 Hatipoglu and coworkers33 compared the high-resolution CT findings in 32 patients who had newly diagnosed active pulmonary TB and 34 patients who had inactive disease. Findings seen only in patients who had active TB included centrilobular nodules (91% of patients), tree-in-bud pattern (71% of patients), nodules 5 to 8 mm in diameter (69% of patients), and consolidation (44% of patients). Cavitation was present in 50% of patients who had active TB and 12% of patients who had inactive disease.33 Poey coworkers34 performed high-resolution CT before and after 6 months of antituberculosis treatment in 27 patients with postprimary pulmonary TB. Centrilobular nodules and poorly marginated nodules were present only before treatment. Reticular pattern (intralobular and septal thickening) and fibrosis were seen both before and after treatment.34 Tuberculomas are most commonly smoothly marginated on CT (Fig. 10.18); however, fibrosis related to vessels, interlobular septa or lung parenchyma adjacent to the nodule may result in a spiculated margin.13,28,35 Calcification within the nodule or satellite nodules around the periphery of the dominant nodule is present in 20% to 30% of cases (see Fig. 10.5). Cavitation within the dominant nodule or the surrounding satellite nodules may be also seen. After intravenous administration of contrast, tuberculomas often show no enhancement or ring-like or curvilinear enhancement on CT (see Fig. 10.18). The latter corresponds histologically to the fibrous tissue/granulomatous inflammatory tissue capsule, whereas the nonenhancing area corresponds to the central necrotic material (see Fig. 10.18).35 In miliary TB the characteristic high-resolution CT findings consist of 1- to 3-mm-diameter nodules randomly distributed

234

SECTION 4  Pulmonary Infection

A

B

N

C

D Fig. 10.18  Tuberculoma. (A) CT scan obtained at the level of the right bronchus intermedius shows a well-margined mass with a satellite nodule (arrow) in the left lower lobe. (B) Composite image with nonenhanced (left image) and contrast-enhanced (right image) CT scans demonstrates this mass does not show any enhancement. (C) Photography of a wedge resection pathologic specimen shows a mass containing a granular and cheese-like substance. (D) Photomicrograph (hematoxylin and eosin, ×12.5) of a wedge resection pathologic specimen shows a tuberculoma (arrows) containing areas of caseation necrosis (N).

throughout both lungs (see Figs. 10.8 and 10.9).21,36 Thickening of interlobular septa and fine intralobular linear opacities are frequently evident.30 Hilar and mediastinal lymph node enlargement is commonly seen on CT in patients who have active TB.37,38 In the study by Im and coworkers,30 mediastinal lymph node enlargement was seen on high-resolution CT in 9 of 29 (31%) patients who had newly diagnosed disease and in 2 of 12 (17%) patients who had reactivation. Enlarged lymph nodes in patients with active TB typically showed central areas of low attenuation on contrastenhanced CT, with peripheral rim enhancement39 (Fig. 10.19). Moon and coworkers40 assessed the role of CT in the diagnosis of tuberculous mediastinal lymphadenitis in 37 patients who

had active disease and 12 patients who had inactive disease. In the 37 patients who had active disease, mediastinal lymph nodes ranged in size from 1.5 to 6.7 cm (mean, 2.8 ± 1.0 cm), and all had central low-attenuation and peripheral rim enhancement. Foci of calcification were seen within the lymph nodes in 7 patients (19%). In the 12 patients who had inactive disease, the nodes were usually smaller than nodes in patients who had active disease, and they appeared homogeneous without lowattenuation areas. Calcifications within the nodes were seen in 10 of the 12 (83%) patients who had inactive disease. Lowattenuation areas within the lymph nodes in patients who had active TB corresponded pathologically to caseous necrosis. In all 25 patients followed after treatment, enlarged mediastinal

10  Pulmonary Tuberculosis

235

B

A

C Fig. 10.19  Tuberculous lymphadenitis. (A) Chest radiograph shows a left hilar enlargement (arrow). (B) and (C) CT scans obtained at the levels of the carina (B) and left upper lobar bronchus (C) show enlarged left hilar and peribronchial lymph nodes (arrows) with central low attenuation and peripheral rim enhancement.

nodes decreased in size, and low-attenuation areas within the nodes disappeared.40 Airway TB has been reported in 10% to 20% of all patients with pulmonary TB.41 The characteristic CT findings of airway TB are circumferential wall thickening and luminal narrowing, with involvement of a long segment of the bronchi.41 In active disease the airways are irregularly narrowed and have thick walls, whereas in fibrotic disease the airways are smoothly narrowed and have thin walls (Fig. 10.20). In tuberculous pleural effusion CT usually shows homogeneous fluid in the pleural space. After contrast administration, pleural layers enhance and are revealed as a smooth thickening of the visceral and parietal pleural surfaces separated by a variable amount of fluid (split pleura sign).42 New subpleural lung nodules may develop after 3 to 12 weeks after taking medication for TB pleural effusion (Fig. 10.21). It should not be regarded as treatment failure. These paradoxical subpleural nodules will eventually show improvement with continued medication.43 The manifestations of TB in acquired immune deficiency syndrome (AIDS) patients are influenced by the degree of immunosuppression and whether or not the patient is receiving HAART.44 In mildly immunosuppressed (>200 CD4 cells/µL) patients, the radiologic manifestations are similar to those in the normal host, with focal consolidation and nodular opacities involving mainly the upper lobes. Patients with moderate or severe immunosuppression ( 7 cm in greatest dimension or associated with separate tumor nodule(s) in a different ipsilateral lobe to that of the primary or direct invasion of any of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina Regional lymph node cannot be assessed No regional lymph node metastasis Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes involved by direct extension of the primary tumor Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s) Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) Presence of distant metastasis cannot be assessed No distant metastasis Distant metastasis present M1a: separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural or pericardial effusionc M1b: single extrathoracic metastasisd M1c: multiple extrathoracic metastases in one or more organs

a

The uncommon superficial tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified as T1a. b Solitary adenocarcinoma, ≤3 cm with a predominantly lepidic pattern and ≤5-mm invasion in any one focus. c Most pleural (pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple microscopical examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and is not an exudate. When these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element, and the patient should be classified as M0. d This includes involvement of a single distant (nonregional) lymph node.

accuracies of MRI were 82% to 94.3%, which were comparable to those of PET-CT (86%–91.4%).15–17 Positron Emission Tomography Integrated PET-CT provides morphologic as well as metabolic data of lung cancer and is widely accepted to be the first-line imaging tool for staging. It has been shown to be more useful than CT alone in determining the T stage of the primary tumor and in assessing chest wall invasion.18–20 According to a report, although statistically not significant (P =.25), integrated PET-CT accurately staged the primary tumor (T stage) in 86% (91 of 106) of patients, whereas CT accurately staged the primary tumor in only 79% (84 of 106) of patients.19 The main limitation of PET-CT in the T staging is false positivity in cases of inflammatory lesions. In this context, the newly introduced PET-MRI system with superior soft tissue contrast and dedicated sequences has the potential to compensate the shortcomings of PET-CT. According to the studies with comparison of PET-MRI and PET-CT in the preoperative staging of NSCLC, the diagnostic accuracy of PET-MRI (65%–94.3%) in the T staging was comparable to that of PET-CT (70%– 91.4%).16,17,21,22

KEY POINTS: T STAGING • Chest radiography is generally unreliable in detecting invasion of the chest wall, diaphragm, or mediastinum. • Computed tomography (CT) can reliably detect invasion of the mediastinum, provided that major mediastinal vessels or bronchi are surrounded by tumor. • Magnetic resonance imaging (MRI) is superior to CT in the demonstration of the pericardium, cardiac chambers, and mediastinal vessels, with the added advantage of not requiring intravenous (IV) contrast medium. Recent analyses of T staging using advanced MRI protocols showed that diagnostic accuracies of MRI were 82%–94.3%, which were comparable to those of positron emission tomography (PET)-CT (86%–91.4%).

N (LYMPH NODES) Radiography and Computed Tomography Lymph node involvement in lung cancer is categorized according to the location of the metastatic lymph nodes as N0 (no nodes involved), N1 (ipsilateral peribronchial, interlobar, or hilar node involvement), N2 (ipsilateral mediastinal or subcarinal node involvement), or N3 (contralateral mediastinal, contralateral

344

SECTION 5  Pulmonary Neoplasms

TABLE 18.3  PROPOSED STAGE GROUPINGS FOR THE EIGHTH EDITION OF THE TUMOR-NODEMETASTASIS CLASSIFICATION FOR LUNG CANCER6 Stage

TNM Subset

Occult carcinoma 0 IA1

TXN0M0 TisN0M0 T1a(mi)N0M0 T1aN0M0 T1bN0M0 T1cN0M0 T2aN0M0 T2bN0M0 T1a-cN1M0 T2aN1M0 T2bN1M0 T3N0M0 T1a-cN2M0 T2a-bN2M0 T3N1M0 T4N0M0 T4N1M0 T1a-cN3M0 T2a-bN3M0 T3N2M0 T4N2M0 T3N3M0 T4N3M0 Any T, Any N M1a Any T, Any N M1b Any T, Any N M1c

IA2 IA3 IB IIA IIB

IIIA

IIIB

IIIC IVA IVB

hilar, or supraclavicular node involvement), regardless of the number of involved lymph nodes.23 Analysis of the new IASLC database with respect to the N staging has shown that the N categories in the seventh edition of TNM staging for lung cancer are still useful for distinguishing among tumors with significantly different prognoses in both clinical and pathologic staging.4 However, with regard to pathologic staging, the survival curves for N1 at multiple stations and N2 at a single station with N1 involvement overlapped each other, and N2 at a single station without N1 involvement had a better prognosis than N1 at multiple stations, although the difference was not significant. The following represents the most widely accepted criteria for radiologic assessment. 1. Lymph nodes should be classified according to a standardized lymph node map. The one adopted by the American Joint Committee on Cancer and the International Union Against Cancer in 2009 (Fig. 18.7 and Table 18.4) is the IASLC nodal map and anatomic definitions, and it is still the recommended means of describing regional lymph node involvement for lung cancers in the proposed eighth edition.4,24 2. The most reliable and practical measurement of lymph node size on CT is its short-axis diameter (i.e., the shortest diameter on the cross-sectional image); this parameter correlates better than the long-axis diameter with the node volume and is less influenced by the spatial orientation of the node.25 Although some authors have suggested the use of various nodal size criteria specific for each mediastinal nodal station,26,27 for practical reasons we and others consider a diameter greater than 10 mm in short axis as abnormal, regardless of nodal station.28

A

B Fig. 18.1  T4 squamous cell carcinoma with surgically proven chest wall and right hemidiaphragmatic invasion. (A) CT scan obtained at level of liver dome shows enhancing, heterogeneous mass in the right lower lobe, abutting the chest wall. Erosion of a posterior right rib (arrow) indicates chest wall invasion. (B) CT scan obtained 15 mm caudal to (A) demonstrates overt chest wall and probable right hemidiaphragmatic invasion.

Fig. 18.2  T4 large-cell lung cancer. Contrast-enhanced axial CT scan obtained at the level of the great vessels shows a large left upper lobe heterogeneous mass invading the adjacent vertebral body (arrow).

18  Pulmonary Carcinoma Staging

A B

C

D

E Fig. 18.3  T4 squamous cell lung cancer showing descending thoracic aortic invasion. (A) Contrastenhanced CT scan obtained at left atrial level shows a mass (arrows) in the superior segment of the left lower lobe partially encircling the descending thoracic aorta over about 180 degrees of the aortic circumference. (B) and (C) T1W turbo-field-echo (B) and T2W triple inversion black-blood (C) MR images show the high-signal intensity mass abutting descending thoracic aorta over approximately 180 degrees. (D) Integrated PET-CT shows tumor with high FDG uptake abutting aorta over about 180 degrees. (E) Gross pathologic specimen shows that tumor (arrows) has invaded into the aortic adventitia (arrowheads). Microscopic examination (not shown here) confirmed aortic invasion.

345

346

A

B

SECTION 5  Pulmonary Neoplasms

C

Fig. 18.4  Superior sulcus tumor (adenocarcinoma). (A) Chest radiograph shows a large mass in the right upper lung zone. (B) Coronalreformation CT image shows an oval mass in the right upper lobe. (C) Enhanced coronal T1W MR image shows a heterogeneously enhancing mass in the right upper lobe with focal penetration (arrow) of extrapleural fat, consistent with chest wall invasion.

18  Pulmonary Carcinoma Staging

347

A A

B

B Fig. 18.5  Contrast-enhanced CT image compared with MR image in a 71-year-old man with large cell neuroendocrine carcinoma. (A) Contrastenhanced axial CT scan obtained at the level of the right upper lobar bronchus shows a mass lesion in the right upper lobe with post–obstructive pneumonia. (B) Axial T2W triple inversion black-blood MR image obtained at similar level to (A) demonstrates a right upper lobe mass and accompanying post–obstructive pneumonia. Tumor encircles the truncus anterior (arrow), but the superior vena cava (arrowhead) appears to be intact.

3. Factors that facilitate visualization of mediastinal lymph nodes include the presence of mediastinal fat, use of IV contrast material, and thinner CT section. IV contrast material is particularly helpful in the distinction of the truncus anterior from a right paratracheal lymph node and in the assessment of the aortopulmonary window region, where the superior aspect of the main or left pulmonary artery may be misinterpreted as an enlarged lymph node on scans performed without IV contrast material. Despite these advantages, we believe that IV contrast material is not required routinely for the assessment of mediastinal nodes when using spiral CT technique and collimation of 5 mm or less.29 Although IV contrast material is not required for the evaluation of mediastinal lymph nodes, assessment of hilar lymph nodes requires the use of IV injection of contrast material and dynamic incremental or spiral CT. IV contrast material is recommended in patients in whom hilar lymph node enlargement is suspected on the radiograph.30–32

Fig. 18.6  MRI in squamous cell lung carcinoma. (A) T1W turbo-field-echo MR image shows an intermediate signal intensity lesion in the right upper lobe. Also note enlarged lymph node (arrow) in the lower right paratracheal station. (B) T2W triple inversion black-blood MR image shows a lung mass (arrowheads) and surrounding atelectatic right upper lobe. Also note enlarged right paratracheal lymph node (arrow) with high signal intensity. Patient had proven T2N2 lung cancer.

Although there is no question that CT is superior to chest radiography in the detection of mediastinal lymph node metastases, the specificity for the diagnosis is slightly less. For example, in one study of 418 patients, the sensitivity and specificity of chest radiography for the detection of mediastinal lymph node metastases were 40% and 99%, respectively; CT had sensitivity and specificity of 84.4% and 84.1%, respectively.33 In another investigation of 170 patients, the sensitivity and specificity of the radiograph were 9% and 92%, respectively, whereas the corresponding figures for CT were 52% and 69%, respectively.34 Visualization of mediastinal lymph node enlargement on radiography almost invariably indicates the presence of metastatic carcinoma. A known limitation of CT in staging mediastinal lymph node involvement is that mediastinal lymph node metastases are assessed only on the basis of nodal size (Figs. 18.8 and 18.9). False-negative CT scans are due to the presence of metastases in normal-sized lymph nodes, and false-positive CT findings are due to lymph node enlargement secondary to benign inflammatory processes. As the results of the previous studies suggest, there has been considerable variability in the reported sensitivity and specificity of CT in the assessment of mediastinal nodal metastases. Although several groups have shown a sensitivity greater than 85%,35,36 others have reported values of 40% to 70%.34,37 According to the most recently published meta-analysis, CT has 57% sensitivity and 82% specificity for staging the mediastinal lymph nodes.38 This variability

348

SECTION 5  Pulmonary Neoplasms

Supraclavicular zone 1R

1 Low cervical, supraclavicular, and sternal notch nodes

1L

SUPERIOR MEDIASTINAL NODES 2L

2R 4R

14R

Upper zone 2R Upper paratracheal (right)

Ao

4L

14L

2L Upper paratracheal (left)

mPA 13 3a Prevascular

11R 14R 12R

11L

7

12R

12L

8

8

14L

14R

3p Retrotracheal 4R Lower paratracheal (right) 4L Lower paratracheal (left)

Eso

AORTIC NODES AP zone 5 Subaortic 6 Paraaortic (ascending aorta or phrenic) 6

INFERIOR MEDIASTINAL NODES Subcarinal zone

Ao

5

mPA

7 Subcarinal

Lower zone 8 Paraesophageal (below carina) 9 Pulmonary ligament

N1 NODES Hilar/Interlobar zone 3p

T

3a SVC

Eso

10 Hilar

11 Interlobar

Peripheral zone 12 Lobar

13 Segmental 14 Subsegmental

Fig. 18.7  The International Association for the Study of Lung Cancer (IASLC) lymph node map, including the grouping of lymph node stations into “zones” for the purpose of prognostic analyses. Ao, Aorta; AP, aortopulmonary zone; Eso, esophagus; mPA, main pulmonary artery; SVC, superior vena cava; T, trachea. (Reprinted with permission from the International Association for the Study of Lung Cancer. The IASLC Lung Cancer Project. A proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thoracic Oncol. 2009;4:568–577.)

is related to several factors, including different size criteria for abnormal lymph nodes, different patient populations studied, and use of a per-patient versus a per-nodal station analysis, interobserver variability, and differences in the diagnostic gold standard. Therefore, given the limitations of mediastinal staging by CT, biopsy is

recommended for the confirmation of regional lymph node metastases. Mediastinoscopy and/or ultrasound-guided bronchoscopic or transesophageal endoscopic biopsy of nodes are performed to accurately determine the presence and location of nodal metastasis.39,40 Guidelines for staging of lung cancer suggest that

18  Pulmonary Carcinoma Staging

349

TABLE 18.4  LYMPH NODE MAP DESCRIPTION Nodal Station 1. Low cervical, supraclavicular and sternal notch nodes 2. Upper paratracheal nodes 3. Prevascular and retrotracheal nodes

4. Lower paratracheal nodes

5. Subaortic (aortopulmonary window) 6. Paraaortic nodes (ascending aorta or phrenic) 7. Subcarinal nodes 8. Paraesophageal nodes (below carina) 9. Pulmonary ligament nodes 10. Hilar nodes

11. 12. 13. 14.

Interlobar nodes Lobar nodes Segmental nodes Subsegmental nodes

Anatomic Landmarks Upper border: lower margin of cricoid cartilage; lower border: clavicles bilaterally and, in the midline, the upper border of the manubrium The oncologic midline is the midline of the trachea. 2R and 2L: upper border: apex of lung and pleural space and, in the midline, the upper border of the manubrium; 2R lower border: intersection of caudal margin of innominate vein with the trachea 2L lower border: superior border of the aortic arch (the oncologic midline is along the left lateral border of the trachea) 3a: prevascular Right: upper border: apex of chest; lower border: level of carina; anterior border: posterior aspect of sternum; posterior border: anterior border of superior vena cava Left: upper border: apex of chest; lower border: level of carina; anterior border: posterior aspect of sternum; posterior border: left carotid artery 3p: retrotracheal Upper border: apex of chest; lower border: carina; anterior border: posterior tracheal wall 4R: includes right paratracheal nodes, and pretracheal nodes extending to the left lateral border of trachea Upper border: intersection of caudal margin of innominate vein with the trachea; lower border: lower border of azygos vein 4L: includes nodes to the left of the left lateral border of the trachea, medial to the ligamentum arteriosum Upper border: upper margin of the aortic arch; lower border: upper rim of the left pulmonary artery Subaortic nodes lateral to the ligamentum arteriosum Upper border: the lower border of the aortic arch; lower border: upper rim of the left pulmonary artery Nodes lying anterior and lateral to the ascending aorta and the aortic arch Upper border: a line tangential to the upper border of the aortic arch; lower border: the lower border of the aortic arch Upper border: the carina of the trachea; lower border: the upper border of the lower lobe bronchus on the left; the lower border of the bronchus intermedius on the right Nodes lying adjacent to the wall of the esophagus and to the right or left of the midline, excluding subcarinal nodes Upper border: the upper border of the lower lobe bronchus on the left; the lower border of the bronchus intermedius on the right; lower border: the diaphragm Nodes lying within the pulmonary ligament Upper border: the inferior pulmonary vein; lower border: the diaphragm Includes nodes immediately adjacent to the mainstem bronchus and hilar vessels including the proximal portions of the pulmonary veins and main pulmonary artery Upper border: the lower rim of the azygos vein on the right; upper rim of the pulmonary artery on the left Lower border: interlobar region bilaterally Between the origin of the lobar bronchi Nodes lying adjacent to the lobar bronchi Nodes lying adjacent to the segmental bronchi Nodes lying adjacent to the subsegmental bronchi

endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) should be considered the best first test of nodal staging for radiologically abnormal lymph nodes that are accessible by EBUS-TBNA.41 Positive nodes missed on CT scan are less likely to be associated with extracapsular spread of tumor than nodes larger than 1 cm in diameter. Patients who have metastasis to normal-sized nodes are more likely to have negative results at mediastinoscopy and to have the affected nodes discovered only at subsequent thoracotomy. There is evidence that patients who have microscopic metastases discovered at the time of thoracotomy have an improved survival rate if the primary tumor and the involved mediastinal nodes are resected.42,43 Magnetic Resonance Imaging Similar to CT, MRI relies on size criteria to determine nodal abnormalities and is comparable to CT in the assessment of mediastinal nodal metastasis.10 According to a recent meta-analysis, MRI has an overall high sensitivity (0.87 [95% confidence interval (CI): 0.78–0.92]) and high specificity (0.88 [95% CI: 0.77–0.94])

on a per-patient basis and 0.88 (95% CI: 0.78–0.94) and 0.95 (95% CI: 0.87–0.98) on a per-node basis, respectively.44 Studies of MRI with quantitative diagnostic assessment, such as apparent diffusion coefficients (ADC) or lesion-to-phantom ratios (LPR) of metastatic hilar and mediastinal lymph nodes, showed significantly higher diagnostic performance on a per-node basis than studies with qualitative assessment with visual inspection of lesion size and morphology of individual metastatic regional lymph nodes (relative diagnostic odds ratio, 7.25 [95% CI: 1.75–30.09]; P = .01).44 Hilar and mediastinal lymph node metastases usually show high signal on T2W MR images (Fig. 18.10; see Fig. 18.8). Quantitative assessment of LPR using STIR TSE MRI showed a direct relationship between LPR and the likelihood of a metastatic lymph node.45–50 Diffusion-weighted images (DWI) can also be used in the quantitative assessment of metastatic lymph nodes. In a prospective study with histopathologic validation, the ADCs of metastatic lymph nodes were reported to be significantly lower than the ADCs of lymph nodes without metastasis.50,51 However, because DWI is currently obtained with the echo-planar imaging (EPI) sequence without

350

SECTION 5  Pulmonary Neoplasms

A

C

B

D Fig. 18.8  True positive mediastinal nodal metastasis (N2 disease) detected at CT in squamous cell lung carcinoma. (A) Contrast-enhanced axial CT scan obtained at the level of the aortic arch shows 2.3-cm nodule in the right upper lobe. (B) CT scan obtained at level of azygos arch shows an enlarged lymph node with evidence of extracapsular invasion (arrow) in the lower right paratracheal station (nodal station 4R). (C) and (D) T1W turbo-field-echo (C) and T2W triple inversion black-blood (D) MR images demonstrate enlarged nodes in right lower paratracheal station. The absent fatty hilum (arrow in C) on T1W image and high-signal intensity (arrow in D) on T2W image suggest metastasis.

18  Pulmonary Carcinoma Staging

A

351

B

C Fig. 18.9  False-positive mediastinal node at CT in pulmonary adenocarcinoma. (A) Axial CT scan obtained at level of azygos arch shows a spiculated 2.4-cm nodule in the left upper lobe. (B) CT scan obtained at carinal level shows a slightly enlarged lymph node (arrow) in the lower left paratracheal station (nodal station 4L). (C) CT and corresponding PET images show increased FDG uptake (arrow) in the spiculated left upper lobe nodule but not in the lymph node. There was no evidence of lymph node metastasis at surgery.

any motion correction, this may result in relatively lower spatial resolution and less anatomic information than can be obtained with STIR TSE imaging. Recently, advanced DWI based on the fast advanced SE (FASE) sequence has been developed, and the accuracy of N-stage assessment using STIR-FASE imaging (84.2% [80%–95%]) and DWI-FASE (83.2% [79%–95%]) was significantly higher than that using DWI-EPI (76.8% [73%–95%]) and PET-CT(73.7% [70%–95%]).52

Positron Emission Tomography Although CT and MR imaging rely on the anatomic assessment of lymph nodes, PET relies on the increased metabolic rate of neoplastic cells compared with normal cells. Mediastinal nodes containing carcinoma cells have been shown to have increased uptake and accumulation of fluorodeoxyglucose (FDG) (Fig. 18.11). Several groups have shown that PET is superior to CT in the assessment of mediastinal nodal metastases.53,54 In one study of

352

SECTION 5  Pulmonary Neoplasms

Fig. 18.10  True positive mediastinal nodes on turbo MR images in pulmonary adenocarcinoma. T2-weighted TIBB turbo SE (left) and T1-weighted three-dimensional turbo-field-echo (right) images show a cavitary mass in the right upper lobe with a small but high signal intensity lymph node in the lower right paratracheal station (arrows). Involvement of the paratracheal nodes was confirmed at surgical biopsy.

99 patients, the sensitivity and specificity for the diagnosis of N2 disease were 83% and 94%, respectively, for PET compared with 63% and 73%, respectively, for CT.55 In another investigation of 100 patients, mediastinal lymph nodes were staged correctly in 85% of cases with PET compared with 58% on CT.56 The authors of a meta-analysis of 14 studies published between 1990 and 1998 concluded that the sensitivity of PET for the detection of mediastinal nodal metastases is 79% to 84%, and the specificity is 89% to 91%.57 By comparison, meta-analysis of 29 studies using CT published during the same period showed a sensitivity of 60% and a specificity of 77%.57 The sensitivity of PET in the metaanalysis of the studies published in the 1990s is similar to the previously mentioned meta-analysis of CT studies performed in the 1980s,58 whereas that of CT has become substantially lower. The main limitation of PET imaging is a low spatial resolution. This limitation has been minimized by the development of integrated PET-CT scanners. PET-CT allows fusion of the PET and CT images and thus combines the functional information from PET with the anatomic information from CT (Fig. 18.12). According to an initial study,59 integrated PET-CT results in improved sensitivity, specificity, and overall accuracy (78%, 95%, and 89%, respectively) for the detection of malignant lymph nodes, compared with visually correlated PET and CT (67%, 95%, and 86%, respectively). The greater sensitivity and accuracy of integrated PET-CT have since been corroborated by several studies.19,20,60 According to a recent meta-analysis of nodal staging in NSCLC with integrated PET-CT, sensitivity and specificity on a per-node basis were 0.62 (95% CI: 0.54, 0.70) and 0.92 (95% CI: 0.88, 0.95), respectively, and sensitivity and specificity on a per-patient basis were 0.67 (95% CI: 0.54, 0.79) and 0.87 (95% CI: 0.82, 0.91), respectively.61 Studies from

tuberculosis-endemic countries showed lower sensitivity (0.56 vs. 0.68, P = .03) on a node basis and lower specificity (0.83 vs. 0.89, P < .01) on a patient basis. According to the studies with comparison of PET-MRI and PET-CT in the preoperative staging of NSCLC, the diagnostic accuracy of PET-MR (57.1%–77%) in the N staging was comparable to that of PET-CT (52.4%–86%).21,22,62 However, diagnostic accuracy of PET-MRI with signal intensity assessment (91.4%) in the N staging was significantly higher than that of PET-CT (80.7%).16 KEY POINTS: N STAGING • The most reliable and practical measurement of lymph node size on CT is the short-axis diameter (i.e., the shortest diameter on the cross-sectional image). Nodes are enlarged if they measure >10 mm in short-axis diameter. • False-negative CT scans are due to the presence of metastasis in normal-sized lymph nodes, and false-positive scans are due to lymph node enlargement secondary to benign inflammatory processes. • Meta-analysis of studies performed in the 1980s showed 83% sensitivity and 81% specificity for CT in detecting mediastinal nodal metastases; however, meta-analysis in the 1990s showed sensitivity of 60% and specificity of 77%, presumably because of more careful surgical staging. • MRI with quantitative diagnostic assessment with apparent diffusion coefficients or lesion-to-phantom ratios of metastatic hilar and mediastinal lymph nodes showed significantly higher diagnostic performance. • Recent meta-analysis showed that MRI has a high sensitivity and specificity on a per-node and a per-patient basis; however, integrated PET-CT has a high specificity but a low sensitivity for detecting lymph node metastasis.

18  Pulmonary Carcinoma Staging

353

A

A

B

B Fig. 18.11  Positive nodes on PET in lung adenocarcinoma. (A) Contrastenhanced CT scan shows a mass in the right upper lobe and a right paratracheal lymph node measuring less than 10 mm (arrow). This node was interpreted as negative for malignancy. (B) PET scan obtained at same level to (A) demonstrates increased FDG uptake within the right upper lobe mass. The lymph node in the right paratracheal station also shows markedly increased FDG uptake (maximum standardized uptake value, 6.1), which proved to be a metastatic node. (Reprinted with permission from Shim SS, Lee KS, Kim B-T, et al. Non-small cell lung cancer: prospective comparison of integrated FDG PET-CT and CT alone for preoperative staging. Radiology. 2005;236:1011–1019.)

M (DISTANT METASTASES) Since the seventh edition of the TNM staging classification for NSCLC was published in 2009, several developments in diagnosis, imaging, and treatment of NSCLC have been added to lung cancer management. They include common use of PET in diagnostic practice, minimally invasive endoscopic and surgical methods for diagnosing and treating small pleural and pulmonary lesions, precise radiotherapy techniques such as brain or body stereotactic

Fig. 18.12  True positive integrated PET-CT in lung adenocarcinoma. (A) Contrast-enhanced CT scan shows enlarged lymph nodes in the paraaortic (station 6, arrow) and subaortic (station 5, arrowhead) stations. Also note obstructive atelectasis in the left upper lobe. (B) PET and integrated PET-CT show increased FDG uptake (maximum standardized uptake value, 11.5) in enlarged nodes (arrows) as well as primary lung cancer. The patient had surgically confirmed lymph node metastases.

radiotherapy, and molecular-targeted agents. Therefore it is necessary to reanalyze the new IASLC database for the development of proposals for the new M descriptors of the eighth edition of TNM classification. On the basis of analysis of the new database, the prognosis of the former M1a descriptor (including pleural or pericardial effusions, contralateral or bilateral lung nodules, or pleural/pericardial nodules) is similar. Therefore, in the eighth edition of TNM staging classification for NSCLC, the M1a descriptor is maintained as the use of the seventh edition of the M1a category.5 The new database also showed that the number of metastatic lesions may be more prognostic than the number of

354

SECTION 5  Pulmonary Neoplasms

organs involved. Therefore the proposed eighth edition of the TNM staging system reclassified M1 categories as M1a, M1b (single metastatic lesion in one organ), and M1c (multiple metastases in either a single organ or multiple organs) (see Table 18.3).

in the detection of osseous metastases located in the spine and pelvis and in the distinction of osseous metastases from primary bone tumors.71 Overall, bone scintigraphy is inferior to MRI or PET in the detection of osseous metastases.55

Conventional Staging The most widely used techniques to investigate patients who have possible extrathoracic metastases are CT (to show metastases to the adrenal glands and liver), MR imaging (to detect brain and adrenal metastases), and radionuclide scans (to identify skeletal metastases). The use of these techniques should be considered in the context of clinical findings. In patients who have an NSCLC, brain MRI and radionuclide scanning of bone generally are indicated only if there is clinical or laboratory evidence of metastatic disease. Such evidence includes not only organ-specific signs and symptoms (liver enlargement, bone pain) but also nonspecific symptoms of anorexia, weight loss, and fatigue. In one study of 309 patients who had an NSCLC in an early stage (T1 or T2, N0 or N1), routine bone, brain, and liver scans or bone scan and abdominal and brain CT were done before anticipated surgery. Only 1 of the 472 studies (0.2%) revealed an unexpected metastasis; all other metastatic disease detected was associated with clinical signs and symptoms or abnormal biochemical profiles.63 In a 1995 meta-analysis of 25 studies that addressed the issue of the appropriateness of preoperative evaluation of metastatic disease, the authors concluded that a negative clinical evaluation had a high negative predictive value (consistently exceeding 90%) for finding occult metastases by bone scan and CT evaluation of the brain and abdomen.64 These values were more impressive (>97%) when an expanded clinical evaluation, which included consideration of constitutional symptoms, was used. Although some investigators have reported occult brain metastases in asymptomatic individuals, especially those who have adenocarcinoma,65–67 such findings must be balanced against the low cost-effectiveness of the procedure. In the meta-analysis cited previously, the prevalence of brain metastases in asymptomatic patients was only 5%. Because gadolinium-enhanced MRI is more sensitive than CT in the detection of such metastases, it is possible that the prevalence is higher than that suggested by the CT data.

Whole-Body Positron Emission Tomography Whole-body PET imaging has the advantage over other imaging modalities of demonstrating not only adrenal metastases but also other metastases that may not be apparent on CT (Fig. 18.14), MRI, or bone scintigraphy. In one investigation of 100 patients with newly diagnosed pulmonary carcinoma, PET correctly indicated the M status in 40 (91%) of 44 patients with metastatic disease compared with 35 (80%) with conventional imaging. PET and CT correctly identified all sizes of adrenal metastases (sensitivity 100%), but PET has a specificity and positive predictive value of 100% compared with 93% and 46%, respectively, for CT. PET correctly identified 11 (91%) of 12 patients with bone metastases compared with 6 (50%) identified on scintigraphy; both modalities had a specificity of 92%55 (Fig. 18.15).

Computed Tomography Abdominal CT scans have been obtained for the detection of liver or adrenal metastasis (note description on adrenal imaging to follow). Magnetic Resonance Imaging Dedicated liver MRI or whole-body MRI (with breath-hold fat-suppressed T2W imaging of the liver and dynamic T1W data acquisition) imaging has been shown to be the most accurate tool for noninvasive detection and characterization of hepatic mass lesions.68 MRI (gadolinium–diethylene triamine pentaacetic acid [DTPA] T1W sequence) is also more sensitive than CT in the detection of brain metastases, especially for small lesions.67,69 MRI is comparable to PET in the detection of bone metastases70; both modalities are superior to bone scintigraphy. Bone Scintigraphy Scintigraphy provides a rapid overview of the skeletal system. It is superior to MRI in the assessment of the ribs, the scapula, and skull (Fig. 18.13). However, MRI is superior to scintigraphy

Whole-Body Magnetic Resonance Imaging Recent advances in scanner technology and the introduction of moving patient platforms with integrated surface-coil technology have enabled whole-body MRI within a single session.72 Wholebody MRI similar to whole-body PET imaging allows the overall assessment of the presence of metastases (Fig. 18.16). In one study of 154 patients with NSCLC,15 whole-body MRI had an accuracy of 86% for detecting M stage, which was comparable to that of PET-CT. Although the differences were not statistically significant, whole-body MR imaging was more useful for detecting brain and hepatic metastases, whereas PET-CT was more useful for detecting lymph node and soft tissue metastases. Whole-Body Positron Emission Tomography–Magnetic Resonance Imaging Recent technical advances in image registration have made it possible to combine PET with MRI information as coregistered or integrated PET-MRI. The combination of the molecular component of the PET with MRI’s capability for tissue discrimination allows more accurate preoperative staging of NSCLC (Fig. 18.17).17 For the assessment of the presence of distant metastasis, diagnostic accuracy of coregistered PET-MRI with signal intensity assessment (98.6%) was significantly higher than that of whole-body PET-MRI without signal intensity assessment (91.4%) and integrated PET-CT (90.7%).16 Another study with integrated PET-MRI showed no significant differences in the accuracy of metastasis staging between PET-CT and PET-MRI.22 Adrenal Imaging Routine contrast-enhanced CT through the liver for the staging of lung cancer rarely changes tumor stage and is therefore not warranted.64,73 However, because the adrenal glands are common sites for metastatic pulmonary carcinoma and because of the ease of examination, most radiologists extend the chest CT scan to include the adrenal glands in patients who have a pulmonary tumor. In one study of 110 patients who had pulmonary carcinoma (cell type not specified), adrenal masses were identified in 11 (10%); in 5 patients the adrenal glands were the only site of metastasis.74 Text continued on p. 359

18  Pulmonary Carcinoma Staging

Rt

A

B

Anterior

Anterior

Fig. 18.13  Bone metastasis detected by bone scintigraphy in lung adenocarcinoma. (A) Axial CT scan obtained at level of azygos arch shows a 2.3-cm right upper lobe nodule with fissural retraction. (B) Initial (left) and 3-month follow-up (right) whole-body bone scintigraphs show progressive osseous metastases, most numerous in the ribs.

355

356

SECTION 5  Pulmonary Neoplasms

65

–320.50nn

65

–320.50nn

65

–320.50nn

Fig. 18.14  Rib metastasis detected at integrated PET-CT but not at CT in large cell carcinoma. PET and integrated PET-CT images show increased FDG uptake (arrows) in an anterior right rib, which is not apparent on the CT image alone.

18  Pulmonary Carcinoma Staging

A

B

C

D

E Fig. 18.15  Pelvic bone metastasis detected at integrated PET-CT but not at CT in lung adenocarcinoma. (A) Axial CT scan shows a right upper lobe nodule with lobulated and spiculated margins. Axial (B) and coronal (C) PET images show increased FDG uptake (arrows) in the right ilium. (D) Coronal T2W MR image shows a low–signal intensity lesion (arrow) in the right ilium. (E) Enhanced T1W MR image shows a high–signal intensity lesion (arrow) with trabeculation. MRI suggested the possibility of both metastasis or hemangioma, but bone biopsy demonstrated metastatic adenocarcinoma.

357

358

SECTION 5  Pulmonary Neoplasms

T2WI

TFE

Enhanced TFE

A

B Fig. 18.16  Left arm metastasis in pulmonary adenocarcinoma. (A) Coronal whole-body MR images show metastatic soft tissue lesion (arrows in T2WI and enhanced T1W TFE images) in left axillary area. T2W is a T2-weighted image; T1W TFE is a T1-weighted turbo-field-echo image. (B) Whole-body PET-CT image shows increased FDG uptake in the left arm lesion (arrows) (maximum standardized uptake value, 3.0) at the same area observed on whole-body MR images.

18  Pulmonary Carcinoma Staging

359

A

B

C

The other main differential diagnosis of an adrenal mass in a patient who has pulmonary carcinoma is a nonfunctioning adenoma. The most helpful diagnostic features on CT scan for distinguishing between a metastasis and an adenoma are tumor size and attenuation value. Lesions 1 cm or less in diameter are more likely to be adenomas, whereas lesions 3 cm or larger usually are metastases (Fig. 18.18). A more reliable distinction is obtained by measuring the attenuation of the mass on an unenhanced CT scan: Adrenal adenomas typically have homogeneous low attenuation, whereas metastases have high attenuation values. A meta-analysis of 10 studies to determine an optimal threshold for differentiating benign from malignant lesions yielded a sensitivity of 71% and a specificity of 98% for characterizing adrenal masses with a threshold of 10 HUs.75 Based on the data in the literature prior to 2000, one group of investigators has shown that unenhanced CT with a 10-HU threshold is currently the most cost-effective method for distinguishing adrenal adenoma from metastasis in patients with newly diagnosed pulmonary

Fig. 18.17 Brain metastasis in pulmonary adenocarcinoma. (A) Coregistered PET-MR image demonstrates an enhancing, FDG-avid right middle lobe mass. (B) Enhanced T1W MR image shows an enhancing nodule (arrow) in the right frontal lobe. (C) Coregistered PET-MR image demonstrates an enhancing nodule (arrow) in the right frontal lobe.

carcinoma.76 On adrenal dynamic CT the relative percentage washout value can be calculated, and lesions of greater than 50% relative percentage washout are benign (Fig. 18.19). Ninety-nine (98%) of 101 lesions were correctly characterized as benign or malignant with this technique. Therefore calculation of relative percentage washout on dynamic and delayed enhanced CT scans is a highly specific test for adrenal lesion characterization, thus reducing the need for, and possibly obviating, follow-up imaging or biopsy.77 Several groups of investigators have assessed the diagnostic accuracy of MRI in the detection of adrenal metastases and in their distinction from adenomas. The results of the initial studies showed considerable overlap between the MRI signal characteristics of malignant and benign lesions on conventional spin-echo and gradient-recalled echo images. The ability to distinguish metastases from adenomas has improved considerably with the introduction of more sophisticated MRI techniques, such as fat saturation, chemical-shift, and dynamic gadolinium-enhanced MRI.78–82

360

SECTION 5  Pulmonary Neoplasms

A

B Fig. 18.18  Adrenal metastasis in pulmonary adenocarcinoma. (A) Contrast-enhanced CT scan shows a 10-cm left adrenal mass (arrow) with central low attenuation. (B) Integrated FDG–PET-CT scan shows increased uptake (maximum standardized value, 12.8) in the left adrenal mass (arrow).

On spin-echo MRI performed using the fat-saturation technique, adrenal adenomas have a characteristic hyperintense rim; in one study of 48 patients, this sign was seen in 26 of 28 (92%) adenomas and in only 1 of 20 (5%) metastases.79 One group of investigators correlated the MRI findings with histologic results in 114 patients with 134 adrenal masses. Chemical-shift and dynamic gadolinium-enhanced MRI had a sensitivity of 91% and a specificity of 94% in distinguishing benign and malignant adrenal masses.82 In chemical-shift MRI the percentage signal intensity decrease is calculated, normalizing signal intensity to the kidney or the spleen parenchyma. All malignant nodules showed less than 20% signal intensity decrease, even if they had high attenuation (>10 HUs) at CT83 (Fig. 18.20). According to a recent study,84 FDG-PET showed excellent diagnostic performance in differentiating 50 adrenal lesions detected on CT or MRI, with a sensitivity of 100%, a specificity of 94%, and an accuracy of 96%. Because FDG-PET has the additional advantage of evaluating the primary lesions as well as metastases, it can be cost effective and the modality of choice for the characterization of adrenal lesions, especially in patients with malignancy. Integrated PET-CT improves the performance of 18F-FDG-PET alone in discriminating benign from malignant adrenal lesions in oncology patients (Fig. 18.21). In one study of 175 adrenal masses in 150 patients,85 PET data alone using a standardized uptake value cutoff of 3.1 yielded a sensitivity, specificity, and accuracy of 99% (67 of 68 nodules), 92% (98 of 107), and 94% (165 of 175), respectively. For combined PET-CT data, the sensitivity, specificity, and accuracy were 100% (68 of

68 nodules), 98% (105 of 107), and 99% (173 of 175), respectively. Specificity was significantly higher for PET-CT (P < .01).

KEY POINTS: M STAGING • The most widely used imaging techniques to investigate patients who have possible extrathoracic metastases are CT (to assess the adrenal glands and liver), MRI (to assess the brain and adrenals), and radionuclide bone scans (to identify skeletal metastases). • The most helpful diagnostic features on CT scan for distinguishing between adrenal metastasis and adenoma are tumor size and attenuation value. Lesions 1 cm or less in diameter are more likely to be adenomas, whereas lesions 3 cm or larger are usually metastases. Lesions with attenuation values less than 10 Hounsfield units (HUs) on unenhanced CT are adenomas. • Dynamic CT (analyzing wash-in and washout characteristics), chemical-shift MRI, and PET imaging have an accuracy of greater than 90% in characterizing adrenal lesions in patients with an NSCLC. • Whole-body PET imaging has the advantage over other imaging modalities of showing not only adrenal metastases but also other metastases that may not be apparent on CT, MRI, or bone scintigraphy. • Recent advances in scanner technology and image registration have enabled whole-body MRI and PET-MRI. Diagnostic accuracy of PET-MRI with signal intensity assessment (98.6%) was significantly higher than that of whole-body PET-MRI without signal intensity assessment (91.4%) and integrated PET-CT imaging (90.7%)

18  Pulmonary Carcinoma Staging

A

361

B Fig. 18.19  Adrenal adenoma showing high percentage of washout in non–small cell lung carcinoma. Early (A) and delayed (B) contrast-enhanced adrenal CT scans show a 3.4-cm, ovoid mass (arrows) in the left adrenal gland. Percentage of washout value is calculated as 68%, suggesting benign adrenal adenoma.

STAGING FOR LUNG CANCERS WITH MULTIPLE PULMONARY SITES OF INVOLVEMENT The seventh edition of the TNM classification for lung cancer contained some ambiguity with respect to the classification of lung cancer with multiple pulmonary sites of involvement. To provide better clarity for the eighth edition of the TNM classification, the IASLC project defined four patterns associated with multiple pulmonary sites of lung cancer: synchronous primary lung cancers, primary lung cancer with a separate tumor nodule (intrapulmonary metastases), multifocal lung cancer presenting as multiple nodules with ground-glass/lepidic features, and diffuse pneumonic-type adenocarcinoma.7 Proposed recommendations for TNM classification are as follows: synchronous primary lung cancers are classified with a T, N, and M category for each tumor; separate tumor nodules result in a T3, T4, or M1a category depending on the separate nodule’s location relative to the primary tumor; multifocal ground glass/lepidic feature tumors are classified by the highest T lesion, with the number or m for multiple in parentheses (number/m) and an N and M category for all tumor nodules collectively; and for pneumonic-type adenocarcinoma, the T component is classified by size or as T3 if in one lobe, as

T4 if in two ipsilateral lobes, and M1a if in contralateral lobes, with a single N and M category for all sites of pulmonary involvement collectively.7 TUMOR-NODE-METASTISIS STAGING FOR SMALL CELL LUNG CANCER Early staging systems for SCLC divided them into two subgroups: limited and extensive. Limited disease is characterized by tumors confined to one hemithorax, although local extension and ipsilateral or supraclavicular nodes could also be present if they could be encompassed in the same radiation portal as the primary tumor. All other cases are classified as extensive disease. However, when the seventh edition of TNM classification was published in 2009, it was recommended to favor the TNM classification for staging of patients with SCLC. Analysis of the new database of IASLC suggested that clinical and pathologic TNM staging in patients with SCLC has a prognostic value, and the use of proposed T, N, M descriptors for NSCLC is recommended in patients with SCLC.8,86 However, for M descriptors, it remains uncertain whether survival differences in patients with single-site metastasis in the brain simply

362

SECTION 5  Pulmonary Neoplasms

A

B

C Fig. 18.20  Metastatic adrenal nodule on chemical-shift MRI in lung adenocarcinoma. (A) Enhanced axial CT scan shows a homogeneously enhancing nodule (arrow) in the left adrenal gland. (B) and (C) Chemical-shift MR images show no change of signal intensity in the adrenal nodule (arrows) between in-phase (B) and out-of-phase (C) images.

18  Pulmonary Carcinoma Staging

A

363

B Fig. 18.21  False-negative interpretation PET image, but true positive interpretation with integrated PET-CT in a 33-year-old woman with adrenal metastasis from lung adenocarcinoma. (A) FDG-PET demonstrates increased uptake (arrow) in the left adrenal gland area with maximum standardized uptake value of 3.5. Uptake was regarded as benign by PET alone because the uptake was interpreted as being in the left kidney. (B) On integrated PET-CT image, the uptake (arrow) corresponds to the left adrenal gland, thus enabling a correct interpretation as positive uptake (uptake intensity is equal to that of liver).

reflect better treatment options rather than better survival based on anatomic extent of disease.

Synopsis of Treatment Options NON–SMALL CELL LUNG CANCER For stage I to IIIA disease, complete surgical resection remains the most effective therapy for patients who can tolerate surgery. In many clinical centers, induction chemotherapy with or without radiation therapy is given prior to surgery, particularly for those with stage IIB and IIIA disease, to reduce tumor burden and increase the probability of achieving a tumor-free resection margin.87 The type of surgical resection is dependent on tumor size and location. Lobectomy or pneumonectomy is usually performed with en bloc resection of locally invaded chest wall structures and sampling or removal of all accessible mediastinal lymph nodes.33 Sublobar resections (segmentectomy or nonanatomic wedge resection) are sometimes performed for patients with small, peripherally located, incidentally or screen-detected lung cancer, particularly in patients with multiple lesions and/ or poor pulmonary reserve. Stereotactic body radiation therapy and image-guided thermal ablation are treatment options for poor surgical candidates with early-stage disease without nodal involvement. In selected stage IV patients with oligometastases in the brain or adrenal glands, resection of metastatic lesions has been shown to improve survival.87 Cisplatin-based adjuvant chemotherapy is the standard of care for resected stage II and IIIA NSCLC and sometimes also offered to patients with resected stage IB disease. Adjuvant radiation therapy is often given for resected stage III disease. Platinum-based regimens are the firstline therapy for locally advanced (i.e., stage III) or metastatic (i.e., stage IV) NSCLC because they provide modest 5% to 13% improvements in 5-year survival rates.88 More recently, molecularly targeted therapy has revolutionized the care of lung cancer patients. Tyrosine kinase inhibitors (such

as gefitinib and erlotinib) against the epidermal growth factor receptors (EGFR) that are overexpressed on the cell surface of NSCLCs carrying EFGR mutations have been shown to result in higher response and longer progression-free survival compared with chemotherapy treatment in the setting of advanced-stage disease. The EGFR mutation is more commonly found in women, nonsmokers, and East Asians. Similarly, in patients with tumors harboring translocations of anaplastic lymphoma kinase (ALK), treatment with crizotinib (an ALK inhibitor) has been found to be very effective.89 Because of the benefits of targeted therapy, it is now recommended that all resected adenocarcinomas and mixed lung cancers with an adenocarcinoma component should undergo EGFR and ALK testing. In addition, EGFR mutation and ALK rearrangement testing should also be performed on biopsy specimens at the time of diagnosis in patients who present with advanced-stage disease and in those with recurrence or progression who were not previously tested.90 Immunotherapy modulates the patient’s immune system to fight cancer. Programmed death-1 (PD-1) inhibitors disrupt the immune checkpoint interaction to enable the host immune system to destroy tumors. Nivolumab and pembrolizumab are two PD-1 inhibitors approved as second-line treatment of advanced-stage NSCLC.89 In patients treated with immunotherapy agents, the response to treatment may be delayed. Pseudoprogression or transient enlargement of responding tumor can occur, which is postulated to be due to infiltration of the tumor by immune cells. In patients with multiple persistent pulmonary nodules suspected to represent multifocal synchronous adenocarcinomas, the timing of follow-up imaging and tissue sampling is usually based on the most suspicious-appearing lesion(s). The designation of the most suspicious lesion is not based purely on size but instead should take into consideration rate of growth and nodule features, such as size, attenuation, and margin. Similarly, the treatment is usually driven by the stage, with the T category determined by the highest level T lesion.91

364

SECTION 5  Pulmonary Neoplasms

SMALL CELL LUNG CANCER Small cell lung cancer is generally believed to represent a systemic disease at the time of diagnosis and as such is not considered to be a surgically resectable disease. In a minority of cases where SCLC manifests as a solitary pulmonary nodule without identifiable nodal or distant metastases, surgical resection can be performed. Limited-stage SCLC can be treated with platinum-based chemotherapy and thoracic and prophylactic cranial radiation with 20% to 25% long-term survival. Extensive stage disease is usually treated with combination chemotherapy to prolong survival and improve quality of life. Thoracic radiation and prophylactic cranial radiation are given to those who respond to chemotherapy. Most patients, particularly patients with extensive disease beyond the thorax, relapse and die of their

disease. Targeted therapy and immunotherapy for SCLC are being evaluated in clinical trials.92 SUGGESTED READINGS Nicholson AG, Chansky K, Crowley J, et al. The International Association for the Study of Lung Cancer staging project: proposals for the revision of the clinical and pathologic staging of small cell lung cancer in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11:300–311. Rami-Porta R, Bolejack V, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2015;10:990–1003.

The full reference list for this chapter is available at ExpertConsult.com.

18  Pulmonary Carcinoma Staging 364.e1

REFERENCES 1. Goldstraw P, ed. Staging Manual in Thoracic Oncology. Orange Park, FL: Editorial Rx Press; 2009:57–65. 2. Rami-Porta R, Bolejack V, Giroux DJ, et al. The IASLC Lung Cancer Staging Project: the new database to inform the eight edition of the TNM classification of lung cancer. J Thorac Oncol. 2014;9:1618–1624. 3. Rami-Porta R, Bolejack V, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2015;10:990–1003. 4. Asamura H, Chansky K, Crowley J, et al. The International Association for the Study of Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming 8th edition of the TNM classification for lung cancer. J Thorac Oncol. 2015;10:1675–1684. 5. Eberhardt WE, Mitchell A, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the M descriptors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol. 2015;10:1515–1522. 6. Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (eight) edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11:39–51. 7. Detterbeck FC, Nicholson AG, Franklin WA, et al. The IASLC Lung Cancer Staging Project: summary of proposals for revisions of the classification of lung cancers with multiple pulmonary sites of involvement in the forthcoming eight edition of the TNM classification. J Thorac Oncol. 2016;11:639–650. 8. Nicholson AG, Chansky K, Crowley J, et al. The International Association for the Study of Lung Cancer Staging Project: proposals for the revision of the clinical and pathologic staging of small cell lung cancer in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11:300–311. 9. Primack SL, Lee KS, Logan PN, Miller RR, Müller NL. Bronchogenic carcinoma: utility of CT in the evaluation of patients with suspected lesions. Radiology. 1994;193:795–800. 10. Webb WR, Gatsonis C, Zerhouni EA, et al. CT and MR imaging in staging non-small cell bronchogenic carcinoma: report of the Radiologic Diagnostic Oncology Group. Radiology. 1991;178:705–713. 11. Gay SB, Black WC, Armstrong P, Daniel TM. Chest CT of unresectable lung cancer. Radiographics. 1988;8:735–748. 12. Mayr B, Lenhard M, Fink U, Heywang-Kobrunner SH, Sunder-Plassmann L, Permanetter W. Preoperative evaluation of bronchogenic carcinoma: value of MR in T- and N-staging. Eur J Radiol. 1992;14:245–251. 13. Hatabu H, Gaa J, Tadamura E, et al. MR imaging of pulmonary parenchyma with a half-Fourier single-shot turbo spin-echo (HASTE) sequence. Eur J Radiol. 1999;29:152–159. 14. Yamashita Y, Yokoyama T, Tomiguchi S, Takahashi M, Ando M. MR imaging of focal lung lesions: elimination of flow and motion artifact by breath-hold ECG-gated and black-blood techniques on T2-weighted turbo SE and STIR sequences. J Magn Reson Imaging. 1999;9:691–698. 15. Yi CA, Shin KM, Lee KS, et al. Non-small cell lung cancer staging: efficacy comparison of integrated PET/CT versus 3.0-T whole-body MR imaging. Radiology. 2008;248:632–642. 16. Ohno Y, Koyama H, Yoshikawa T, et al. Three-way comparison of whole-body MR, coregistered whole-body FDG PET/MR, and integrated whole-body FDG PET/CT imaging: TNM and stage assessment capability for non-small cell lung cancer patients. Radiology. 2015;275:849–861. 17. Kim HS, Lee KS, Ohno Y, et al. PET/CT versus MRI for diagnosis, staging, and follow-up of lung cancer. J Magn Reson Imaging. 2015;42: 247–260. 18. Shim SS, Lee KS, Kim B-T, et al. Integrated PET/CT and the dry pleural dissemination of peripheral adenocarcinoma of the lung: diagnostic implications. J Comput Assist Tomogr. 2006;30:70–76. 19. Shim SS, Lee KS, Kim B-T, et al. Non-small cell lung cancer: prospective comparison of integrated FDG PET/CT and CT alone for preoperative staging. Radiology. 2005;236:1011–1019. 20. Lardinois D, Weder W, Hany TF, et al. Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med. 2003;348:2500–2507. 21. Huellner MW, de Galiza Barbosa F, Husmann L, et al. TNM staging of non-small cell lung cancer: comparison of PET/MR and PET/CT. J Nucl Med. 2016;57:21–26. 22. Lee SM, Goo JM, Park CM, et al. Preoperative staging of non-small cell lung cancer: prospective comparison of PET/MR and PET/CT. Eur Radiol. 2016;26:3850–3857.

23. UICC International Union Against Cancer. TNM Classification of Malignant Tumours. 7th ed. New York: Wiley-Blackwell; 2009. 24. Rusch VW, Asamura H, Watanabe H, et al. The IASLC Lung Cancer Staging Project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2009;4:568–577. 25. Quint LE, Glazer GM, Orringer MB, Francis IR, Bookstein FL. Mediastinal lymph node detection and sizing at CT and autopsy. AJR Am J Roentgenol. 1986;147:469–472. 26. Buy JN, Ghossain MA, Poirson F, et al. Computed tomography of mediastinal lymph nodes in nonsmall cell lung cancer: a new approach based on the lymphatic pathway of tumor spread. J Comput Assist Tomogr. 1988;12: 545–552. 27. Ikezoe J, Kadowaki K, Morimoto S, et al. Mediastinal lymph node metastases from nonsmall cell bronchogenic carcinoma: reevaluation with CT. J Comput Assist Tomogr. 1990;14:340–344. 28. Quint LE, Francis IR, Wahl RL, Gross GH, Glazer GM. Preoperative staging of non-small-cell lung carcinoma of the lung: imaging methods. AJR Am J Roentgenol. 1995;164:1349–1359. 29. Patz EF, Erasmus JJ, McAdams HP, et al. Lung cancer staging and management: comparison of contrast-enhanced and nonenhanced helical CT of the thorax. Radiology. 1999;212:56–60. 30. Glazer GM, Francis IR, Gebarski K, et al. Dynamic incremental computed tomography in evaluation of the pulmonary hila. J Comput Assist Tomogr. 1983;7:59–64. 31. Remy-Jardin M, Duyck P, Remy J, et al. Hilar lymph nodes: identification with spiral CT and histologic correlation. Radiology. 1995;196:387–394. 32. Shimoyama K, Murata K, Takahashi M, Morita R. Pulmonary hilar lymph node metastases from lung cancer: evaluation based on morphology at thin-section, incremental, dynamic CT. Radiology. 1997;203:187–195. 33. Lewis JW, Pearlberg JL, Beute GH, et al. Can computed tomography of the chest stage lung cancer? Yes and no. Ann Thorac Surg. 1990;49:591–595. 34. McKenna RJ, Libshitz HI, Mountain CE, McMurtrey MJ. Roentgenographic evaluation of mediastinal nodes for preoperative assessment in lung cancer. Chest. 1985;88:206–210. 35. Daly BD, Faling LJ, Pugatch RD, et al. Computed tomography: an effective technique for mediastinal staging in lung cancer. J Thorac Cardiovasc Surg. 1984;88:486–494. 36. Glazer GM, Orringer MB, Gross BH, Quint LE. The mediastinum in non-small cell lung cancer: CT-surgical correlation. AJR Am J Roentgenol. 1984;142:1101–1105. 37. McLoud TC, Bourgouin PM, Greenberg RW, et al. Bronchogenic carcinoma: analysis of staging in the mediastinum with CT by correlative lymph node mapping and sampling. Radiology. 1992;182:319–323. 38. Toloza EM, Harpole L, Detterbeck F, McCrory DC. Invasive staging of non-small cell lung cancer: a review of the current evidence. Chest. 2003;123:157S–166S. 39. Annema JT, Veselic M, Versteegh MI, et al. Mediastinal restaging: EUS-FNA offers a new perspective. Lung Cancer. 2003;42:311–318. 40. Fritscher-Ravens A, Soehendra N, Schirrow L, et al. Role of transesophageal endosonography-guided fine-needle aspiration in the diagnosis of lung cancer. Chest. 2000;117:339–345. 41. Nakajima T, Yasufuku K, Fujiwara T, Yoshino I. Recent advances in endobronchial ultrasound-guided transbronchial needle aspiration. Respir Investig. 2016;54:230–236. 42. Pearson FG, DeLarue NC, Ilves R, Todd TR, Cooper JD. Significance of positive superior mediastinal nodes identified at mediastinoscopy in patients with resectable cancer of the lung. J Thorac Cardiovasc Surg. 1982; 83:1–11. 43. Gross BH, Glazer GM, Orringer MB, Spizarny DL, Flint A. Bronchogenic carcinoma metastatic to normal-sized lymph nodes: frequency and significance. Radiology. 1988;166:71–74. 44. Peerlings J, Troost EG, Nelemans PJ, et al. The diagnostic value of MR imaging in determining the lymph node status of patients with non-small cell lung cancer: a meta-analysis. Radiology. 2016;281:86–98. 45. Ohno Y, Hatabu H, Takenaka D, et al. Metastases in mediastinal and hilar lymph nodes in patients with non-small cell lung cancer: quantitative and qualitative assessment with STIR turbo spin-echo MR imaging. Radiology. 2004;231:872–879. 46. Takenaka D, Ohno Y, Hatabu H, et al. Differentiation of metastatic versus non-metastatic mediastinal lymph nodes in patients with non-small cell lung cancer using respiratory-triggered short inversion time inversion recovery (STIR) turbo spin-echo MR imaging. Eur J Radiol. 2002;44:216–224. 47. Kim HY, Yi CA, Lee KS, et al. Nodal metastasis in non-small cell lung cancer: accuracy of 3.0-T MR imaging. Radiology. 2008;246:596–604.

364.e2

SECTION 5  Pulmonary Neoplasms

48. Morikawa M, Demura Y, Ishizaki T, et al. The effectiveness of 18F-FDG PET/CT combined with STIR MRI for diagnosing nodal involvement in the thorax. J Nucl Med. 2009;50:81–87. 49. Ohno Y, Koyama H, Nogami M, et al. STIR turbo SE MR imaging vs. coregistered FDG-PET/CT: quantitative and qualitative assessment of N-stage in nonsmall-cell lung cancer patients. J Magn Reson Imaging. 2007;26:1071–1080. 50. Ohno Y, Koyama H, Yoshikawa T, et al. N stage disease in patients with non-small cell lung cancer: efficacy of quantitative and qualitative assessment with STIR turbo spin-echo imaging, diffusion-weighted MR imaging, and fluorodeoxyglucose PET/CT. Radiology. 2011;261:605–615. 51. Nakayama J, Miyasaka K, Omatsu T, et al. Metastases in mediastinal and hilar lymph nodes in patients with non-small cell lung cancer: quantitative assessment with diffusion-weighted magnetic resonance imaging and apparent diffusion coefficient. JCAT. 2010;34:1–8. 52. Ohno Y, Koyama H, Yoshikawa T, et al. Diffusion-weighted MR imaging using FASE sequence for 3T MR system: preliminary comparison of capability for N-stage assessment by means of diffusion-weighted MR imaging using EPI sequence, STIR FASE imaging and FDG PET/CT for non-small cell lung cancer patients. Eur J Radiol. 2015;84:2321–2331. 53. Patz EF, Lowe VJ, Goodman PC, Herndon J. Thoracic nodal staging with PET imaging with 18FDG in patients with bronchogenic carcinoma. Chest. 1995;108:1617–1621. 54. Vansteenkiste JF, Stroobants SG, De Leyn PR, et al. Mediastinal lymph node staging with FDG-PET scan in patients with potentially operable non-small cell lung cancer: a prospective analysis of 50 cases. Leuven Lung Cancer Group. Chest. 1997;112:1480–1486. 55. Valk PE, Pounds TR, Hopkins DM, et al. Staging non-small cell lung cancer by whole-body positron emission tomographic imaging. Ann Thorac Surg. 1995;60:1573–1581. 56. Marom EM, McAdams HP, Erasmus JJ, et al. Staging non-small cell lung cancer with whole-body PET. Radiology. 1999;212:803–809. 57. Dwamena BA, Sonnad SS, Angobaldo JO, Wahl RL. Metastases from non-small cell lung cancer: mediastinal staging in the 1990s — meta-analytic comparison of PET and CT. Radiology. 1999;213:530–536. 58. Dales RE, Stark RM, Raman S. Computed tomography to stage lung cancer: approaching a controversy using meta-analysis. Am Rev Respir Dis. 1990;141:1096–1101. 59. Magnani P, Carretta A, Rizzo G, et al. FDG/PET and spiral CT image fusion for mediastinal lymph node assessment of non-small cell lung cancer patients. J Cardiovasc Surg. 1999;40:741–748. 60. Antoch G, Stattaus J, Nemat AT, et al. Non-small cell lung cancer: dualmodality PET/CT in preoperative staging. Radiology. 2003;229: 526–533. 61. Pak K, Park S, Cheon GJ, et al. Update on nodal staging in non-small cell lung cancer with integrated positron emission tomography/computed tomography: a meta-analysis. Ann Nucl Med. 2015;29:409–419. 62. Kim YN, Yi CA, Lee KS, et al. A proposal for combined MRI and PET/CT interpretation criteria for preoperative nodal staging in non-small-cell lung cancer. Eur Radiol. 2012;22:1537–1546. 63. Ichinose Y, Hara N, Ohta M, et al. Preoperative examination to detect distant metastasis is not advocated for asymptomatic patients with stages 1 and 2 non-small cell lung cancer. Preoperative examination for lung cancer. Chest. 1989;96:1104–1109. 64. Silvestri GA, Littenberg B, Colice GL. The clinical evaluation for detecting metastatic lung cancer: a meta-analysis. Am J Respir Crit Care Med. 1995;152:225–230. 65. Ferrigno D, Buccheri G. Cranial computed tomography as a part of the initial staging procedures for patients with non-small-cell lung cancer. Chest. 1994;106:1025–1029. 66. Mintz BJ, Tuhrim S, Alexander S, Yang WC, Shanzer S. Intracranial metastases in the initial staging of bronchogenic carcinoma. Chest. 1984;86:850–853. 67. Lee HY, Lee KS, Kim BT, et al. Diagnostic accuracy of PET/CT plus brain MR imaging for detection of extrathoracic metastases in patients with lung adenocarcinoma. J Korean Med Sci. 2009;24:1132–1138. 68. Hawighorst H, Schoenberg SO, Knopp MV, Essig M, Miltner P, van Kaick G. Hepatic lesions: morphologic and functional characterization with multiphase breath-hold 3D gadolinium-enhanced MR angiography— initial results. Radiology. 1999;210:89–96. 69. Golfieri R, Cherryman GR, Olliff JF, Husband JE. Comparative evaluation of computerized tomography/magnetic resonance (1.5 T) in the detection of brain metastasis. Radiol Med (Torino). 1991;82:27–34.

70. Antoch G, Vogt FM, Freudenberg LS, et al. Whole-body dual-modality PET/ CT and whole-body MRI for tumor staging in oncology. JAMA. 2003;290: 3199–3206. 71. Eustace S, Tello R, DeCarvalho V, et al. A comparison of whole-body turbo STIR MR imaging and planar 99mTc-methylene diphosphonate scintigraphy in the examination of patients with suspected skeletal metastases. AJR Am J Roentgenol. 1997;169:1655–1661. 72. Barkhausen J, Quick HH, Lauenstein T, et al. Whole-body MR imaging in 30 seconds with real-time true FISP and a continuously rolling table platform: feasibility study. Radiology. 2001;220:252–256. 73. Quint LE, Francis IR. Radiologic staging of lung cancer. J Thorac Imaging. 1999;14:235–246. 74. Ekholm S, Albrechtsson U, Kugelberg J, Tylen U. Computed tomography in preoperative staging of bronchogenic carcinoma. J Comut Assist Tomogr. 1980;4:763–765. 75. Boland GW, Lee MJ, Gazelle GS, et al. Characterization of adrenal masses using unenhanced CT: an analysis of the CT literature. AJR. 1998;171: 201–204. 76. Remer EM, Obuchowski N, Ellis JD, Rice TW, Adelstein DJ, Baker ME. Adrenal mass evaluation in patients with lung carcinoma: a cost-effectiveness analysis. AJR Am J Roentgenol. 2000;174:1033–1039. 77. Pena CS, Boland GW, Hahn PF, Lee MJ, Mueller PR. Characterization of indeterminate (lipid-poor) adrenal masses: use of washout characteristics at contrast-enhanced CT. Radiology. 2000;217:798–802. 78. Reinig JW, Stutley JE, Leonhardt CM, Spicer KM, Margolis M, Caldwell CB. Differentiation of adrenal masses with MR imaging: comparison of techniques. Radiology. 1994;192:41–46. 79. Ichikawa T, Ohtomo K, Uchiyama G, et al. Adrenal adenomas: characteristic hyperintense rim sign on fat-saturated spin-echo MR images. Radiology. 1994;193:247–250. 80. Korobkin M, Lombardi TJ, Aisen AM, et al. Characterization of adrenal masses with chemical shift and gadolinium-enhanced MR imaging. Radiology. 1995;197:411–418. 81. Schwartz LH, Panicek DM, Koutcher JA, et al. Adrenal masses in patients with malignancy: prospective comparison of echo-planar, fast spin-echo, and chemical shift MR imaging. Radiology. 1995;197:421–425. 82. Heinz-Peer G, Honigschnabl S, Schneider B, Niederle B, Kaserer K, Lechner G. Characterization of adrenal masses using MR imaging with histopathologic correlation. AJR Am J Roentgenol. 1999;173:15–22. 83. Haider MA, Ghai S, Jhaveri K, Lockwood G. Chemical shift MR imaging of hyperattenuating (> 10 HU) adrenal masses: does it still have a role? Radiology. 2004;231:711–716. 84. Yun M, Kim W, Alnafisi N, Lacorte L, Jang S, Alavi A. 18F-FDG PET in characterizing adrenal lesions detected on CT or MRI. J Nucl Med. 2001;42: 1795–1799. 85. Metser U, Miller E, Lerman H, Lievshitz G, Avital S, Even-Sapir E. 18F-FDG PET/CT in the evaluation of adrenal masses. J Nucl Med. 2006;47:32–37. 86. Jhun BW, Lee KJ, Jeon K, et al. Clinical applicability of staging small cell lung cancer according to the seventh edition of the TNM staging system. Lung Cancer. 2013;81:65–70. 87. Varela G, Thomas PA. Surgical management of advanced non-small cell lung cancer. J Thorac Dis. 2014;6(suppl 2):S217–S223. 88. Laskin JJ, Sandler AB. State of the art in therapy for non-small cell lung cancer. Cancer Invest. 2005;23:427–442. 89. Chuang JC, Liang Y, Wakelee HA. Neoadjuvant and adjuvant therapy for non-small cell lung cancer. Hematol Oncol Clin North Am. 2017;31(1): 31–44. 90. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol. 2013;8(7):823–859. 91. Detterbeck FC, Marom EM, Arenberg DA, et al., IASLC Staging and Prognostic Factors Committee; Advisory Boards; Multiple Pulmonary Sites Workgroup. The IASLC Lung Cancer Staging Project: background data and proposals for the application of TNM staging rules to lung cancer presenting as multiple nodules with ground glass or lepidic features or a pneumonic type of involvement in the forthcoming eighth edition of the TNM classification. J Thorac Oncol. 2016;11(5):666–680. 92. Kalemkerian GP, Schneider BJ. Advances in small cell lung cancer. Hematol Oncol Clin North Am. 2017;31(1):143–156.

19 

Neuroendocrine Hyperplasia, Pulmonary Tumorlets, and Carcinoid Tumors* STEPHANE L. DESOUCHES  |  CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

Neuroendocrine Hyperplasia and Pulmonary Tumorlets ETIOLOGY, PREVALENCE, AND EPIDEMIOLOGY Normal lung tissue contains scattered neuroendocrine (Kulchitsky) cells within the bronchial and bronchiolar epithelium. These cells play a role in the detection of hypoxia as well as fetal lung development1 and may be involved in local epithelial cell growth and regeneration.2,3 Hyperplasia of these cells can be seen as a response to chronic airway inflammation, such as in patients with emphysema or chronic bronchitis.4 When no known cause can be identified, this hyperplasia is designated diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Extension of hyperplastic neuroendocrine cells beyond the basement membrane is termed a tumorlet if the cell mass is less than 5 mm and carcinoid tumor if the cell mass is 5 mm or greater in diameter.5 Neuroendocrine cell hyperplasia and tumorlets may coexist with carcinoid tumors.2,5–7 In the absence of lung injury (leading to reactive pulmonary neuroendocrine cell hyperplasia), DIPNECH is considered a preinvasive condition that may develop into carcinoid tumors, and imaging follow-up is required.6 DIPNECH typically manifests in the fifth to sixth decades of life, with women affected nearly four times as often as men.4 DIPNECH usually occurs in nonsmokers, but former and current smokers are occasionally affected. Tumorlets also demonstrate a female preponderance (>4 : 1) and are often seen in patients 60 to 70 years old.4 In the 2015 update to the World Health Organization (WHO) classification of lung tumors,8 DIPNECH is classified as a preinvasive lesion. Although the diagnosis remains purely histologic, some authors have proposed the term DIPNECH syndrome be used to indicate patients with respiratory symptoms and appropriate imaging findings.9 Although initially thought to be rare, with few cases described in the literature, DIPNECH is likely an underrecognized condition. CLINICAL PRESENTATION Up to half of patients with DIPNECH or tumorlets are asymptomatic, and the diagnosis is made incidentally on chest computed tomography (CT) or surgical lung biopsy performed for other *The editors and the publisher would like to thank Drs. Nestor L. Müller and C. Isabela Silva Müller for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

reasons. When patients are symptomatic, they often present with a history of protracted nonproductive cough and/or dyspnea and are often mistakenly diagnosed with asthma.10,11 Pulmonary function tests may show obstructive or obstructive/restrictive alterations, likely caused by airway obstruction from the hyperplasia as well as constrictive bronchiolitis from peribronchial fibrosis.2 PATHOPHYSIOLOGY Neuroendocrine cell hyperplasia (NECH) is characterized by single, clustered, or linear arrays of Kulchitsky cells confined by the basement membrane.6 Tumorlets are distinguished by extension beyond the basement membrane. Both of these entities show no mitoses or necrosis per 10 high-power fields on histologic examination.7 NECH and tumorlets are usually an incidental finding in lung parenchyma scarred by bronchiectasis or other chronic inflammatory processes. As stated earlier, constrictive bronchiolitis in patients is secondary to submucosal fibrosis of affected airways in regions with and regions without tumorlets and NECH.2 IMAGING FINDINGS Radiography Chest radiographs of patients with DIPNECH or pulmonary tumorlets may demonstrate pulmonary micronodules (Fig. 19.1)7 but are more often normal. Secondary signs of constrictive bronchiolitis, including hyperinflation and attenuation of peripheral pulmonary vasculature, can occasionally be seen. Computed Tomography High-resolution CT of the chest with inspiratory and expiratory imaging will demonstrate multifocal pulmonary micronodules with or without associated mosaic attenuation or air trapping.10 These micronodules are typically in a centrilobular distribution and can be ground-glass or solid in attenuation.4 Nodules less than 5 mm correspond to carcinoid tumorlets, whereas nodules 5 mm or greater represent carcinoid tumors at histopathologic examination. Asymptomatic patients are more likely to demonstrate micronodules without significant mosaic attenuation as the extent of mosaic attenuation often correlates with physiologic airflow obstruction.4,5 Bronchial wall thickening with or without bronchiectasis is occasionally seen. Nodular bronchial wall thickening is the most direct radiologic-pathologic correlation of NECH, corresponding to the histologic findings of intraluminal protrusion of the proliferating cells. There are no imaging features to distinguish NECH from pulmonary tumorlets. This distinction 365

366

SECTION 5  Pulmonary Neoplasms

A

Fig. 19.2  Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Maximum-intensity projection (MIP) axial CT accentuates the mosaic attenuation and small pulmonary nodules. MIP imaging can be very useful for evaluating the extent of disease.

Definitive diagnosis, however, requires open lung or thoracoscopic biopsy (Fig. 19.3).5 SYNOPSIS OF TREATMENT OPTIONS Asymptomatic patients are usually managed conservatively, with a good long-term prognosis of 83% survival at 5 years. Longterm imaging follow-up is recommended to exclude nodule growth, development of carcinoid tumors, or metastatic disease.5 Patients presenting with worsening lung function can be managed more aggressively, with some showing a response to steroids, interferon-α, or chemotherapeutic agents.10 The use of so­ matostatin receptor analogues (given the neuroendocrine origin of cells) has shown good results with limited side effects.11–13 B Fig. 19.1  Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. (A) Posteroanterior chest radiograph shows multiple small nodules (arrows). (B) Coronal CT shows small pulmonary nodules measuring 2–8 mm (arrows). Note mosaic attenuation from associated constrictive bronchiolitis.

can only currently be made on histology.2 A recent study, evaluating 30 patients with DIPNECH, proposed nonsurgical diagnostic criteria. These included clinical presentation, pulmonary function, imaging findings on high-resolution CT, findings from transbronchial biopsy, and serum markers such as elevated serum chromogranin A levels.11 DIFFERENTIAL DIAGNOSIS Detection of one or more pulmonary nodules is a common diagnostic dilemma on CT. The differential considerations for a single nodule or multiple pulmonary nodules include infectious, inflammatory, and neoplastic etiologies. The diagnosis of DIPNECH may be suggested based upon typical imaging findings, mosaic attenuation of the lung parenchyma on inspiratory imaging (Fig. 19.2), and air trapping on expiratory imaging.

KEY POINTS: NEUROENDOCRINE HYPERPLASIA AND PULMONARY TUMORLETS • Neuroendocrine cell hyperplasia represents proliferation of Kulchitsky cells within the bronchial and bronchiolar epithelium. • Pulmonary tumorlets are nodular proliferations of these same cells with extension beyond the basement membrane. By definition, they measure less than 5 mm in diameter; if 5 mm or greater, they are referred to as carcinoid tumors. • Most patients are asymptomatic; however, when symptoms are present, they are nonspecific and are most commonly a history of protracted nonproductive cough and/or dyspnea that is often initially mistaken for asthma. • Chest radiographs are predominantly normal but may show increased lung volumes. • Inspiratory CT may show mosaic attenuation (usually in symptomatic patients), and expiratory CT may show air trapping. • New WHO classification categorizes diffuse idiopathic pulmonary neuroendocrine cell hyperplasia as a preinvasive entity, and long-term imaging follow-up is recommended to exclude nodule growth, development of carcinoid tumors, or metastatic disease.

19  Neuroendocrine Hyperplasia, Pulmonary Tumorlets, and Carcinoid Tumors

A

367

B Fig. 19.3  Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. (A) Lung biopsy specimen shows focal neuroendocrine cell proliferation (arrowheads) in the bronchovascular sheath. (B) Histologic specimen from another area shows carcinoid tumorlets. The patient was a 72-year-old woman with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia with multiple pulmonary tumorlets and carcinoid tumors and constrictive bronchiolitis. (Courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Vancouver, Canada.)

Typical and Atypical Carcinoid Tumors ETIOLOGY, PREVALENCE, AND EPIDEMIOLOGY The respiratory tract is the second most common location for carcinoid tumors, accounting for 10% to 30% of carcinoids.14,15 Pulmonary carcinoids have shown an increase in prevalence relative to other primary sources over the past few decades.15 Carcinoid tumors constitute about 1% to 2% of all primary lung malignancies.6,16,17 As noted previously, carcinoid tumors represent an extension of the proliferative neuroendocrine cells within the bronchial epithelium beyond the basement membrane, with the cell mass measuring 5 mm or greater in diameter. Carcinoid tumors are further subdivided into typical (84%–90%) and atypical (10%–16%) types. Typical carcinoid tumors demonstrate a nearly 1 : 1 male to female ratio, whereas atypical carcinoid tumors have a 2 : 1 female predominance.18 Although lung inflammation secondary to smoking has been correlated with atypical carcinoid development, no such association has been seen with the more common typical carcinoid tumor. Typical carcinoid tumors have a mean age of presentation of 46 years,7,19,20 whereas patients with atypical carcinoid tumors are typically 50 to 60 years old.14,20 Carcinoid tumors are the most common primary pulmonary neoplasm in children and adolescents. CLINICAL PRESENTATION Centrally located carcinoid tumors usually manifest with symptoms, most commonly cough and hemoptysis.8 Patients present less commonly with wheeze, recurrent infection, chest pain, dyspnea, and constitutional symptoms. Peripheral tumors are usually asymptomatic and are discovered incidentally because of a CT performed for other reasons.10 Despite the neuroendocrine cell origin of these neoplasms, paraneoplastic syndromes are rare.8 Cushing syndrome is reported in approximately 2% of bronchial carcinoids and manifests with hypokalemia and elevation of adrenocorticotropic hormone.14,21

Although carcinoid syndrome can be seen when gastrointestinal carcinoid tumors metastasize to the liver and release serotonin into the systemic blood system, this is extremely rare with pulmonary carcinoids. When patients develop carcinoid syndrome from a pulmonary primary, it is typically in those with metastatic disease to the liver.19 The carcinoid syndrome is characterized by skin flushing, severe diarrhea, bronchoconstriction, and right-sided valvular disease. PATHOPHYSIOLOGY Typical carcinoid tumors are defined as cell masses 5 mm or greater in size that lack necrosis and demonstrate fewer than 2 mitoses per 10 high-power fields (HPFs). Atypical carcinoid tumors are diagnosed when there is cellular necrosis or 2 to 10 mitoses per 10 HPFs.8 Although diagnosis of these entities is usually evident on hematoxylin-eosin staining, antibodies directed to CD56 or components of the neurosecretory granules, including chromogranin and synaptophysin, can be used in equivocal cases.22 Carcinoid tumors are typically composed of polygonal cells with eosinophilic cytoplasm and finely granular chromatin most commonly arranged in an organoid or trabecular pattern.8,10 No single staining method is diagnostic for differentiating typical from atypical carcinoid tumors. Differentiation of carcinoid from more aggressive neoplasms, such as small cell lung cancer, may be difficult with crushed biopsy specimens. In these cases staining with Ki-67 may be helpful as it assesses proliferation rate and is elevated in small cell lung cancer and large cell neuroendocrine carcinoma.8,10 IMAGING FINDINGS Radiography Typical and atypical carcinoids share similar imaging features. Most often this is a centrally located well-defined solitary nodule

368

SECTION 5  Pulmonary Neoplasms

A A

B Fig. 19.4  Central typical carcinoid tumor. (A) Posteroanterior chest radiograph shows a tumor in the right main bronchus (arrows). The right lung is slightly smaller than the left and shows decreased vascularity. (B) Axial CT confirms the presence of an intraluminal tumor in the right main bronchus (arrow). Note decreased attenuation and vascularity of the right lung compared with the left lung, as a result of reflex vasoconstriction.

or mass with or without lobular borders in the main (Fig. 19.4), lobar, or segmental bronchi. Tumors range in size from 2 to 5 cm, and calcification within the lesion is infrequently detected on radiography. They frequently cause post–obstructive atelectasis (Fig. 19.5) and/or pneumonia.7,14,23 Segmental atelectasis or pneumonia may show periodic exacerbations and remissions, likely secondary to the ball-valve mechanism of the central lesion. Peripheral carcinoid tumors appear as a well-defined solitary nodule or mass with round or oval morphology and possibly slightly lobulated contour (Fig. 19.6).24 Atypical carcinoid tumors

B Fig. 19.5  Central carcinoid tumor with obstructive atelectasis of the left upper lobe. (A) Posteroanterior chest radiograph shows poorly defined increased opacity of the left hemithorax associated with superior displacement of the left hilum and elevation of the left hemidiaphragm characteristic of left upper lobe atelectasis. (B) Lateral chest radiograph shows anterior displacement of the left major fissure (arrows) and compensatory overinflation of the left lower lobe. The obstructing carcinoid tumor was not visible radiographically.

19  Neuroendocrine Hyperplasia, Pulmonary Tumorlets, and Carcinoid Tumors

A

B Fig. 19.6  Peripheral typical carcinoid. Posteroanterior (A) and lateral (B) chest radiographs show a 2.5-cm smoothly marginated nodule in the right lower lobe (arrows).

tend to be larger and more peripheral than typical carcinoids. More than 40% of carcinoid tumors are detected incidentally on chest radiography performed for other reasons.25 Computed Tomography Multidetector CT typically demonstrates a central soft tissue nodule with or without distal obstructive atelectasis (Fig. 19.7)

369

or a peripheral solitary nodule (Fig. 19.8). The lesion usually appears as a well-defined slightly lobulated spherical or ovoid nodule or mass. The carcinoid tumor may be completely or partially endoluminal, and CT allows identification of the affected bronchus and any associated signs, such as distal bronchiectasis, mucoid impaction, or air trapping.10 In some cases carcinoid tumors may demonstrate a “tip of the iceberg” morphology, wherein only a small portion of the carcinoid is intraluminal compared with the bulk of the tumor.14 Occasionally, the tumor is seen within and surrounding a bronchus, creating the so-called bronchus sign (Fig. 19.9). Transbronchial biopsy is expected to have greater yield in lesions with this sign as a direct path to biopsy is present.18 On histology approximately 30% of carcinoids demonstrate internal calcification, which can often be visualized with CT imaging.14,23 This calcification may be punctate, eccentric (Fig. 19.10), or diffuse.14,23,26 Carcinoids are highly vascular and may demonstrate avid homogeneous enhancement on CT after intravenous contrast administration. Atypical carcinoids tend to show more heterogeneous enhancement (Fig. 19.11) compared with typical variants. Additionally, these enhanced studies may help to differentiate the centrally obstructing carcinoid tumor from the adjacent/ distal atelectasis or pneumonia.10 CT imaging also allows evaluation for mediastinal and hilar lymphadenopathy (seen in 6%–25% of cases) or other evidence of metastatic disease, such as liver, bone (sclerotic metastases) or adrenal gland lesions.14,27 At presentation regional lymph node metastasis is present in 10% to 15% of typical carcinoids and 40% to 50% of atypical carcinoids.8 It should be noted that although enlarged thoracic lymph nodes may represent metastatic disease, the enlargement could be secondary to reactive hyperplasia from recurrent or chronic infection.14 Magnetic Resonance, Scintigraphy, and Positron Emission Tomography Magnetic resonance imaging is not typically used in the imaging workup of pulmonary carcinoid. When seen, lesions usually show high T2 signal intensity and intense enhancement during the arterial phase of imaging that is likely secondary to a parasitized blood supply from the bronchial arteries.28,29 The neoplastic cells of carcinoid tumors have membrane receptors with high affinity for the neuroregulatory peptide somatostatin.30 Scintigraphy using a radiolabeled somatostatin analogue (indium-111 [111In]-octreotide) can be used to identify occult primary lesions (Fig. 19.12), although it is more often used for staging and to assess response to therapy.15,31 Imaging with metaiodobenzylguanidine (MIBG) is considered less sensitive for detection when compared with octreotide. Typical carcinoid tumors usually do not show increased metabolic activity on fluorodeoxyglucose positron emission tomography (FDG-PET), limiting its usefulness for distinguishing typical carcinoids from benign lesions. Some studies have shown an application of FDG-PET in differentiating typical (Fig. 19.13) from atypical carcinoid tumors (Fig. 19.14). Increased standardized uptake value (SUV) of 6 or greater was shown to have a greater than 95% predictive value for atypical histology.32 Recently approved in the United States, 68Ga-Dotatate PET imaging has shown improved spatial resolution and lesion detectability compared with octreotide and MIBG scintigraphy.33 Specifically in pulmonary imaging, 68gallium-labeled somatostatin Text continued on p. 374

370

A

SECTION 5  Pulmonary Neoplasms

B Fig. 19.7  Endobronchial carcinoid tumor with obstructive atelectasis of the left upper lobe. (A) Axial CT shows tumor (curved arrow) obstructing the left upper lobe bronchus with associated complete left upper lobe atelectasis (straight arrows). Note anterior and medial shift of the left major fissure (straight arrows), compensatory overinflation of the left lower lobe, and decreased volume and attenuation of the left lung compared with the normal right lung. (B) Contrast-enhanced CT shows enhancing endobronchial tumor (curved arrow) and distal atelectasis (straight arrows).

Fig. 19.8  Peripheral endobronchial typical carcinoid. Axial CT shows an endobronchial nodule (curved arrow) obstructing a subsegmental bronchus of the right middle lobe, resulting in partial middle lobe atelectasis (arrow).

19  Neuroendocrine Hyperplasia, Pulmonary Tumorlets, and Carcinoid Tumors

A

B

C Fig. 19.9  Peripheral carcinoid tumor. Axial (A) and sagittal (B) CT show a small tumor (curved arrow) in the left upper lobe and its relationship to a subsegmental bronchus (arrow). (C) Surgical specimen from a different patient shows characteristic features of typical carcinoid: cells with a moderate amount of cytoplasm and nuclei with small nucleoli and scarce mitotic figures. The immunohistochemical panel was positive for the neuroendocrine markers synaptophysin and chromogranin. (C courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Vancouver, Canada.)

371

372

SECTION 5  Pulmonary Neoplasms Fig. 19.10  Calcification of carcinoid tumor. Coronal CT shows a wellcircumscribed, heterogeneously enhancing mass obliterating the left lower lobe bronchus. Scattered eccentric calcification (arrow) can be seen within the tumor.

Fig. 19.11  Atypical carcinoid tumor. Composite image with axial precontrast (left image) and axial postcontrast (right image) CT shows a large heterogeneously enhancing right hilar mass containing coarse eccentric calcification. (Courtesy Emily Tsai, Carol Wu. Atypical carcinoid. In: Rosado-de-Christenson ML, Carter BW. Specialty Imaging: Thoracic Neoplasms. 1st ed. Philadelphia: Elsevier; 2015.)

19  Neuroendocrine Hyperplasia, Pulmonary Tumorlets, and Carcinoid Tumors

373

A

A

B Fig. 19.13  Typical carcinoid tumor on PET-CT. (A) Axial contrastenhanced CT shows a peripheral lesion (arrow) with distal mosaic attenuation of the right lower lobe. (B) Corresponding PET shows mild FDG uptake (arrow), similar to less than mediastinal uptake. The patient had surgically proven typical carcinoid.

B Fig. 19.12  Typical carcinoid tumor on OctreoScan. (A) Coronal CT shows a partially calcified nodule (arrow) in the right lower lobe adjacent to the hemidiaphragm. (B) Coned image from whole-body 111In-octreoscan shows a focus of uptake (arrow) corresponding to the lesion seen on CT. Carcinoid tumors express somatostatin receptors, allowing visualization with somatostatin analogues.

374

SECTION 5  Pulmonary Neoplasms

Fig. 19.14  Atypical carcinoid tumor on PET-CT. Composite image with axial CT (left) and axial fused FDG–PET-CT (right) shows an intensely FDG-avid left lower lobe mass containing an endobronchial component (arrow). (Courtesy Emily Tsai, Carol Wu. Atypical carcinoid. In: Rosado-de-Christenson ML, Carter BW. Specialty Imaging: Thoracic Neoplasms. 1st ed. Philadelphia: Elsevier; 2015.)

analogues have shown improved sensitivity compared with 111 In-octreotide scintigraphy (sensitivity 100% vs. 85%).34 DIFFERENTIAL DIAGNOSIS The differential diagnosis of carcinoid tumors includes bronchogenic carcinoma, hamartoma, mucoepidermoid carcinoma, and benign lesions such as papilloma, and distinction cannot be reliably made radiographically. Diagnosis of carcinoid tumor requires microscopic tissue evaluation, which can be obtained through endobronchial biopsy, thoracotomy, or image-guided percutaneous biopsy. Although carcinoid tumors are highly vascular, most investigators have experienced no serious problems with hemorrhage after biopsy.27,35 SYNOPSIS OF TREATMENT OPTIONS Treatment of limited disease depends upon the location of the carcinoid tumor (central or peripheral) and accessibility and degree of invasion (entirely intraluminal vs. local invasion). For peripheral lesions, segmentectomy or lobar resections are the

treatment of choice, with or without lymphadenectomy. Central lesions may be amenable to lung-parenchymal–sparing surgery, although given the high rate of lymph node involvement (10%–15% of typical carcinoids and 40%–50% of atypical carcinoids), systematic regional and mediastinal nodal dissection should be performed concurrently. In the case of carcinoid tumors without extraluminal extension, endobronchial laser or cryotherapy can be quite effective in treatment.25 After surgical resection of typical carcinoid, CT imaging is carried out at 3 and 6 months posttreatment and then every 12 months for the first 2 years. Subsequently, annual chest radiography and biochemical profile should be obtained with a CT every 3 years. For atypical carcinoid, closer monitoring is recommended. After the initial 3-month follow-up CT, CT should be obtained every 6 months for 5 years, followed by annual CT after 5 years. Scintigraphic octreotide imaging should be obtained at 1 year posttreatment and then on suspicion of recurrence.25 In patients with known metastatic disease or known atypical carcinoid tumor, nonsurgical therapy with chemotherapy, immunotherapy, or radiolabeled somatostatin analogues should be considered.25

19  Neuroendocrine Hyperplasia, Pulmonary Tumorlets, and Carcinoid Tumors

Prognosis is good for patients with typical carcinoid, with 5-, 10-, and 15-year survival rates of 91%, 89%, and 81%, respectively, compared with 76%, 49%, and 35% for patients with atypical carcinoid.36 The presence or absence of lymph node metastases is the feature most strongly correlated with survival rates. KEY POINTS: CARCINOID TUMORS • Carcinoid tumors account for 1%–2% of primary pulmonary neoplasms and are the most common primary pulmonary neoplasm in children and adolescents. • The two types of tumors are typical carcinoid (80%–90% of cases) and atypical carcinoid (10%–20% of cases). • Most common presenting symptoms are cough and hemoptysis. Most patients are asymptomatic at diagnosis. • Paraneoplastic syndromes associated with carcinoid tumors include Cushing syndrome, carcinoid syndrome, and acromegaly. • Radiological manifestations of carcinoid tumors include: • 80%–85% are central in the main, lobar, or segmental bronchi • Distal atelectasis or pneumonia • Endobronchial nodule or mass on radiography or CT • Positive uptake on somatostatin receptor scintigraphy • Usually negative uptake on FDG-PET (except in some cases of atypical carcinoid)

375

SUGGESTED READINGS Benson RE, Rosado-de-Christenson ML, Martínez-Jiménez S, et al. Spectrum of pulmonary neuroendocrine proliferations and neoplasms. Radiographics. 2013;33:1631–1649. Caplin ME, Baudin E, Ferolla P, et al. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26:1604–1620.

The full reference list for this chapter is available at ExpertConsult.com.

19  Neuroendocrine Hyperplasia, Pulmonary Tumorlets, and Carcinoid Tumors 375.e1

REFERENCES 1. Foran P, Hayes S, Blair D, Zakowski M, Ginsberg M. Imaging appearances of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Clin Imaging. 2015;39:243–246. 2. Aguayo SM, Miller YE, Waldron JA Jr, et al. Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med. 1992;327(18):1285–1288. 3. Van Lommel A, Bollé T, Fannes W, Lauweryns JM. The pulmonary neuroendocrine system: the past decade. Arch Histol Cytol. 1999;62(1):1–16. 4. Lee JS, Brown KK, Cool C, Lynch DA. Diffuse pulmonary neuroendocrine cell hyperplasia: radiologic and clinical features. J Comput Assist Tomogr. 2002;26(2):180–184. 5. Davies SJ, Gosney JR, Hansell DM, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognized spectrum of disease. Thorax. 2007;62(3):248–252. 6. Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med. 2010;134(11):1628–1638. 7. Koo CW, Baliff JP, Torigian DA, Litzky LA, Gefter WB, Akers SR. Spectrum of pulmonary neuroendocrine cell proliferation: diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, tumorlet, and carcinoids. AJR Am J Roentgenol. 2010;195(3):661–668. 8. Travis WD, Brambilla E, Muller-Hermelink K, Harris C, eds. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: International Agency for Research on Cancer; 2015. 9. Rossi G, Cavazza A, Spagnolo P, Sverzellati N, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia syndrome. Eur Respir J. 2016;47:1829–1841. 10. Benson RE, Rosado-de-Christenson ML, Martínez-Jiménez S, et al. Spectrum of pulmonary neuroendocrine proliferations and neoplasms. Radiographics. 2013;33:1631–1649. 11. Carr L, Chung J, Achcar R, Lesic Z, et al. The clinical course of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Chest. 2015;147(2): 415–422. 12. Chauhan A, Ramirez R. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and the role of somatostatin analogs: a case series. Lung. 2015;193:653–657. 13. Wirtschafter E, Walts A, Liu S, Marchevsky A. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH): current best evidence. Lung. 2015;193:659–667. 14. Rosado de Christenson ML, Abbott GF, Kirejczyk WM, Galvin JR, Travis WD. Thoracic carcinoids: radiologic-pathologic correlation. Radiographics. 1999;19(3):707–736. 15. Pinchot SN, Holen K, Sippel RS, Chen H. Carcinoid tumors. Oncologist. 2008;13(12):1255–1269. 16. Travis WD. Advances in neuroendocrine lung tumors. Ann Oncol. 2010;21(suppl 7):vii65–vii71. 17. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003;97:934–959. 18. Ernst A, Anantham D. Bronchus sign on CT rediscovered. Chest. 2010;138: 1290–1292.

19. Detterbeck FC. Management of carcinoid tumors. Ann Thorac Surg. 2010;89(3):998–1005. 20. Soga J, Yakuwa Y. Bronchopulmonary carcinoids: an analysis of 1,875 reported cases with special reference to a comparison between typical carcinoids and atypical varieties. Ann Thorac Cardiovasc Surg. 1999;5(4):211–219. 21. Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM. Bronchopulmonary neuroendocrine tumors. Cancer. 2008;113(1):5–21. 22. Martin JM, Maung RT. Differential immunohistochemical reactions of carcinoid tumors. Hum Pathol. 1987;18:941–945. 23. Chong S, Lee KS, Chung MJ, Han J, Kwon OJ, Kim TS. Neuroendocrine tumors of the lung: clinical, pathologic, and imaging findings. Radiographics. 2006;26(1):41–58. 24. Nessi R, Basso Ricci P, Basso Ricci S, et al. Bronchial carcinoid tumors: radiologic observations in 49 cases. J Thorac Imaging. 1991;6:47–53. 25. Caplin ME, Baudin E, Ferolla P, et al. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26:1604–1620. 26. Zwiebel BR, Austin JH, Grimes MM. Bronchial carcinoid tumors: assessment with CT of location and intratumoral calcification in 31 patients. Radiology. 1991;179(2):483–486. 27. Rea F, Rizzardi G, Zuin A, et al. Outcome and surgical strategy in bronchial carcinoid tumors: single institution experience with 252 patients. Eur J Cardiothorac Surg. 2007;31(2):186–191. 28. Jeung MY, Gasser B, Gangi A, et al. Bronchial carcinoid tumors of the thorax: spectrum of radiologic findings. Radiographics. 2002;22(2):351–365. 29. Douek PC, Simoni L, Revel D, et al. Diagnosis of bronchial carcinoid tumor by ultrafast contrast-enhanced MR imaging. AJR Am J Roentgenol. 1994;163: 563–564. 30. Belhocine T, Foidart J, Rigo P, et al. Fluorodeoxyglucose positron emission tomography and somatostatin receptor scintigraphy for diagnosing and staging carcinoid tumours: correlations with the pathological indexes p53 and Ki-67. Nucl Med Commun. 2002;23:727–734. 31. Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM. Bronchopulmonary neuroendocrine tumors. Cancer. 2008;113(1):5–21. 32. Moore W, Frieberg E, Bishawi M, et al. FDG-PET imaging in patients with pulmonary carcinoid tumor. Clin Nucl Med. 2013;38(7):501–505. 33. Mojtahedi A, Thamake S, Tworowska I, et al. The value of 68Ga-DOTATATE PET/CT in diagnosis and management of neuroendocrine tumors compared to current FDA approved imaging modalities: a review of the literature. Am J Nucl Med Mol Imaging. 2014;4(5):426–434. 34. Sollini M, Erba PA, Fraternali A, et al. PET and PET/CT with 68gallium-labeled somatostatin analogues in non GEP-NETs tumors. ScientificWorldJournal. 2014;2014:194123. 35. Ducrocq X, Thomas P, Massard G, et al. Operative risk and prognostic factors of typical bronchial carcinoid tumors. Ann Thorac Surg. 1998;65:1410–1414. 36. Wei S, Hao C, Gong L, et al. Survival and bronchial carcinoid tumors: development of surgical techniques in a 30-year experience of 82 patients in China. Thorac Cancer. 2012;3:48–54.

20 

Pulmonary Hamartoma* CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

Etiology, Prevalence, and Epidemiology Pulmonary hamartomas are benign neoplasms, probably derived from bronchial wall mesenchymal cells.1 Hamartomas are the most common benign pulmonary neoplasm and account for about 8% of primary lung tumors.2 Although they may be seen in adolescents and young adults, most cases occur in patients older than 40 years; the peak incidence is in the seventh decade of life.2,3 Men are affected two to three times more often than women. Endobronchial hamartomas are much less common than parenchymal lesions, accounting for 5% to 20% of pulmonary hamartomas. Although hamartomas are benign neoplasms, they may rarely coexist with pulmonary carcinoma.4 Occasionally, they may be multiple.5 Multiple pulmonary hamartomas may be part of the Carney triad or, rarely, the Cowden syndrome.6 The Carney triad consists of pulmonary chondroma (often multiple), gastric epithelioid leiomyosarcoma, and functioning extraadrenal para­ ganglioma.7,8 This rare disease usually affects women younger than 35 years. It is recommended that patients with multiple pulmonary hamartomas have further examinations to rule out gastric leiomyosarcoma and extraadrenal paragangliomas.6

Clinical Presentation Pulmonary hamartomas usually do not cause symptoms.3 Occasionally, patients may present with hemoptysis or cough.9 Endobronchial hamartomas may result in bronchial obstruction, and patients may present with cough, hemoptysis, and recurrent pneumonia.3

Pathophysiology Most hamartomas are solitary, well-circumscribed, slightly lobulated tumors located within the parenchyma, usually in a peripheral location.10 Most measure 1 to 4 cm in diameter, but tumors 25 cm in diameter have been described.11 On cut section the tumors consist of lobules of white, cartilaginousappearing tissue.10 Histologically, the lobules are often composed of a central area of more or less well-developed cartilage sur­ rounded by loose fibroblastic tissue. Adipose tissue, smooth muscle, and seromucinous bronchial glands also may be seen. Calcification and ossification of the cartilage can be present and are occasionally extensive. Although endobronchial ham­ artomas can be morphologically identical to the parenchymal variety, more often they appear as fleshy, polypoid tumors attached *The editors and the publisher would like to thank Drs. Nestor L. Müller and C. Isabela Silva Müller for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

376

to the bronchial wall by a narrow stalk.10 Endobronchial ham­ artomas typically contain more macroscopic fat than parenchymal hamartomas.

Manifestations of the Disease RADIOGRAPHY The radiologic manifestations of parenchymal tumors usually consist of a well-circumscribed, smoothly marginated solitary nodule without lobar predilection (Fig. 20.1).12,13 Most are smaller than 4 cm in diameter. Although calcification has been identified pathologically in 15% of tumors in some series, it is visible on the chest radiograph in less than 10% of cases. The radiographic pattern of calcification may resemble popcorn; although virtually diagnostic, this appearance is uncommon.13 Endobronchial hamartomas usually manifest radiographically by the effects of airway obstruction with distal atelectasis and obstructive pneumonitis (Fig. 20.2). The endobronchial lesion is uncommonly visible. COMPUTED TOMOGRAPHY The characteristic finding on CT consists of a sharply defined, smoothly marginated nodule. Up to 60% of larger hamartomas have focal areas of fat density (see Fig. 20.1).14 The presence of fat can be ascertained by comparison of the areas of low density with that of subcutaneous fat or by measurement of attenuation values (fat can be considered present when the CT attenuation values are −40 to −120 Hounsfield units (HUs) in at least eight voxels).14 In review of the CT findings in 47 hamartomas, CT allowed diagnosis in 28 (60%) cases by identifying the presence of fat or fat alternating with areas of calcification (Fig. 20.3).14 Of the remaining cases, 17 showed no discernible calcium or fat (the diagnosis being made by other means), and 2 revealed diffuse calcification.14 Hamartomas also may manifest as nodules with soft tissue attenuation and single or multiple foci of calcification. Multiple coarse foci of calcification are referred to as “popcorn calcification” (see Fig. 20.2). With the increasing use of CT, smaller hamartomas are being detected but often lack diagnostic CT features. In a recent review of 21 cases of pathologically proven hamartomas (median diameter, 10 mm), none had characteristic internal fat or calcification, but all were well circumscribed with a round or lobular shape (Fig. 20.4).15 Occasionally, pulmonary hamartoma may have the appearance of a collection of multiple tiny nodules.16 This appearance results when pulmonary alveoli and bronchioles are entrapped within the hamartoma with tumor buds appearing in a multicentric manner.16 Serial chest radio­ graphs or CT may show slow growth, with a doubling time usually greater than 450 days (Fig. 20.5).15 Endotracheal and endobronchial hamartomas may appear on CT to be composed entirely of fat or a mixture of fat and

20  Pulmonary Hamartoma

A

B Fig. 20.1  Pulmonary hamartoma: characteristic radiographic and CT findings. (A) Composite image of posteroanterior (left) and lateral (right) chest radiographs show a well-defined, 5-cm right lower lobe mass. (B) Axial contrast-enhanced CT shows a smoothly marginated mass containing large amounts of central fat. This CT appearance is diagnostic of pulmonary hamartoma despite its large size.

377

378

SECTION 5  Pulmonary Neoplasms

A

B Fig. 20.2  Endobronchial hamartoma. (A) Posteroanterior chest radiograph shows left lung volume loss and left lower lobe atelectasis (arrows). Note bronchiectatic airways in the atelectatic left lower lobe, suggestive of chronic collapse. (B) Axial contrast-enhanced CT shows a hypoattenuating left lower lobe endobronchial nodule with macroscopic fat (arrow), surgically proven to represent an endobronchial hamartoma. Endobronchial lipoma could also be considered in the differential diagnosis but would exhibit only fat attenuation on CT. (From Walker CM. Tracheobronchial hamartoma. In: Rosado-de-Christenson ML, Carter BW. Specialty Imaging: Thoracic Neoplasms. Philadelphia: Elsevier; 2016.)

Fig. 20.3  Pulmonary hamartoma. Axial CT shows a smoothly marginated nodule in the right lower lobe containing several coarse foci of calcification (popcorn calcification) and macroscopic fat (arrows). Fig. 20.4  Pulmonary hamartoma. Axial CT shows a well-defined, round nodule (arrow) in the medial right upper lobe without macroscopic fat or calcification. Smaller hamartomas often lack internal fat or calcification and must be followed with CT or biopsied to exclude malignancy.

20  Pulmonary Hamartoma 1998

379

2008

Fig. 20.5  Composite image of two axial CT images obtained 10 years apart shows slow growth of a right lower lobe hamartoma. The doubling time for most hamartomas is greater than 450 days.

soft tissue or calcification, or they may have soft tissue attenuation with or without foci of calcification (Fig. 20.6; see Fig. 20.2).17,18 Endobronchial hamartomas may be associated with obstructive atelectasis or pneumonitis (see Fig. 20.2). MAGNETIC RESONANCE IMAGING Magnetic resonance imaging has a limited role in assessment. In a review of the findings in six patients, fat was not evident in any, and focal areas of calcification caused signal void or were missed.19 The hamartomas had intermediate signal intensity (higher than that of skeletal muscle but lower than that of fat) on T1-weighted images and high signal intensity on T2-weighted images. They frequently contained septa that had high signal intensity on T1-weighted images and low signal intensity on T2-weighted images. Gadolinium-enhanced T1-weighted images showed marked enhancement of the septa that separated the tumors into less well-enhanced lobules. Restricted diffusion is usually absent.20 POSITRON EMISSION TOMOGRAPHY Pulmonary hamartomas are slow-growing benign tumors, with the majority showing fluorodeoxyglucose (FDG) uptake less than mediastinal blood pool on positron emission tomography (PET).

A review of 42 consecutive cases showed suspicious or malignant FDG uptake in about 20% of pathologically proven hamartomas (usually of a large size with a mean diameter of 23 mm). Suspi­ cious FDG uptake was defined as FDG uptake greater than normal lung parenchyma, and malignant FDG uptake was defined as FDG uptake greater than mediastinal blood pool.21 IMAGING ALGORITHM In most cases pulmonary hamartomas are incidental findings on chest radiography or CT. In up to 60% of cases a confident diagnosis can be made on CT by the presence of focal areas of fat density in a smoothly marginated nodule. PET may be helpful in confirming the benign nature of the tumor. In patients with nonspecific CT findings, definitive diagnosis of hamartoma can be made by transthoracic core needle biopsy of peripheral hamartomas and bronchoscopic biopsy of endobronchial hamartomas.

Differential Diagnosis The presence of focal areas of fat density (−40 to −120 HUs) in a smoothly marginated lung nodule is considered a reliable indicator of a hamartoma.14 Caution should be exercised when subjective or even quantitative areas of fat attenuation are small

380

SECTION 5  Pulmonary Neoplasms

Fig. 20.6  Endotracheal hamartoma with foci of calcification. Axial contrast-enhanced CT at the level of the great vessels shows a large soft tissue mass originating from the tracheal wall and extending into the tracheal lumen and right paratracheal region. Note punctate calcification within the mass.

in size, as other entities such as metastatic disease or primary lung cancer may occasionally manifest similarly, likely related to internal necrosis rather than true macroscopic fat (Fig. 20.7).22 In the absence of focal areas of fat attenuation on CT, the dif­ ferential diagnosis of pulmonary hamartomas must include all other solitary pulmonary nodules, particularly carcinoma. Transthoracic fine-needle aspiration has a low sensitivity in the diagnosis of hamartomas and may lead to misdiagnosis of carcinoma. In one study the specificity of fine-needle aspiration for making the correct general reference interpretation of benign was 78%.23 The false-positive rate was 22%, with the most common false-positive diagnoses being carcinoid tumor, adeno­ carcinoma, and small cell carcinoma.23 Because of the low yield of needle aspiration in the diagnosis of hamartomas and other benign nodules, an increasing number of centers are performing transthoracic core needle biopsy, a procedure in which a core of tissue is obtained using a cutting needle. This procedure has a sensitivity of 97% for malignant and benign lung nodules.24

Fig. 20.7  Metastatic breast cancer masquerading as hamartomas. Axial noncontrast CT shows two small nodules in the right upper lobe with central low attenuation, suggesting macroscopic fat. The region of interest (not shown) showed Hounsfield units of −43. These nodules were confirmed to be malignant via transthoracic needle biopsy. (From Oh JK, Han DH. False-positive multi-detector CT finding for hamartomas. Ann Thorac Surg. 2010;90:1398; author reply 1398–1399.)

KEY POINTS • Pulmonary hamartoma is the most common benign neoplasm of the lung. • Pulmonary hamartoma accounts for approximately 8% of lung tumors. • Most pulmonary hamartomas occur in patients older than 40 years (median age, 50–60 years). • The most common radiologic findings include: • 1- to 4-cm diameter, smooth or slightly lobulated nodule • Popcorn calcification characteristic but uncommon • 60% of larger hamartomas have foci of fat density (−40 to −120 HUs) on CT and are virtually diagnostic in a smoothly marginated nodule. • Small hamartomas (1 cm or less in diameter) often lack internal fat and calcification. • FDG uptake on PET is usually less than the mediastinal blood pool.

Synopsis of Treatment Options Hamartomas are benign, and adequate surgical excision results in cure in most patients. Excision of peripheral lesions can be made by video-assisted thoracoscopic surgery; more central lesions may require thoracotomy and enucleation, wedge resection, or occasionally lobectomy.25 Endobronchial hamartoma can often be resected by transbron­ chial endoscopic surgery to preserve the lung parenchyma.26 Large lesions may require a combination of bronchoplasty and trans­ bronchial endoscopic surgery or occasionally lobectomy.26

SUGGESTED READINGS Gaerte SC, Meyer CA, Winer-Muram HT, et al. Fat-containing lesions of the chest. Radiographics. 2002;22:S61–S78. Ngo AV, Walker CM, Chung JH, et al. Tumors and tumorlike conditions of the large airways. AJR Am J Roentgenol. 2013;201(2):301–313. Siegelman SS, Khouri NF, Scott WW, et al. Pulmonary hamartoma: CT findings. Radiology. 1986;160:313–317.

The full reference list for this chapter is available at ExpertConsult.com.

20  Pulmonary Hamartoma 380.e1

REFERENCES 1. van den Bosch JM, Wagenaar SS, Corrin B, et al. Mesenchymoma of the lung (so called hamartoma): a review of 154 parenchymal and endobronchial cases. Thorax. 1987;42:790–793. 2. Hansen CP, Holtveg H, Francis D. Pulmonary hamartoma. J Thorac Cardiovasc Surg. 1992;104:674–678. 3. Gjevre JA, Myers JL, Prakash UB. Pulmonary hamartomas. Mayo Clin Proc. 1996;71:14–20. 4. Lee BJ, et al. Squamous cell carcinoma arising from pulmonary hamartoma. Clin Nucl Med. 2011;36:130–131. 5. Yalcin S, Kars A, Firat P, et al. Multiple bilateral chondromatous hamartomas of the lung. A rare entity mimicking metastatic carcinoma. Respiration. 1997;64:364–366. 6. Ribet M, Jaillard-Thery S, Nuttens MC. Pulmonary hamartoma and malig­ nancy. J Thorac Cardiovasc Surg. 1994;107:611–614. 7. Carney JA, Sheps SG, Go VL, Gordon H. The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma. N Engl J Med. 1977;296:1517–1518. 8. de Jong E, Mulder W, Nooitgedacht E, et al. Carney’s triad. Eur J Surg Oncol. 1998;24:147–149. 9. Sharkey RA, Mulloy EM, O’Neill S. Endobronchial hamartoma presenting as massive haemoptysis. Eur Respir J. 1996;9:2179–2180. 10. Fraser RS, Colman N, Müller NL, Pare PD. Pulmonary neoplasms. In: Fraser RS, Colman N, Müller NL, Pare PD, eds. Synopsis of Diseases of the Chest. Philadelphia: Saunders; 2005:337–422. 11. Hutter J, Reich-Weinberger S, Hutarew G, Stein HJ. Giant pulmonary hamartoma—a rare presentation of a common tumor. Ann Thorac Surg. 2006;82:5–7. 12. Bateson EM. An analysis of 155 solitary lung lesions illustrating the differential diagnosis of mixed tumors of the lung. Clin Radiol. 1965;16:51–65. 13. Gaerte SC, Meyer CA, Winer-Muram HT, et al. Fat-containing lesions of the chest. Radiographics. 2002;22:S61–S78.

14. Siegelman SS, Khouri NF, Scott WW, et al. Pulmonary hamartoma: CT findings. Radiology. 1986;160:313–317. 15. Huang Y, et al. CT- and computer-based features of small hamartomas. Clin Imaging. 2011;35:116–122. 16. Shinkai M, Kobayashi H, Kanoh S, et al. Pulmonary hamartoma: unusual radiologic appearance. J Thorac Imaging. 2004;19:38–40. 17. Ahn JM, Im JG, Seo JW, et al. Endobronchial hamartoma: CT findings in three patients. AJR Am J Roentgenol. 1994;163:49–50. 18. Yilmaz S, Ekici A, Erdogan S, Ekici M. Endobronchial lipomatous hamartoma: CT and MR imaging features (2004:5b). Eur Radiol. 2004;14:1521–1524. 19. Sakai F, Sone S, Kiyono K, et al. MR of pulmonary hamartoma: pathologic correlation. J Thorac Imaging. 1994;9:51–55. 20. Hochhegger B, et al. Chemical-shift MRI of pulmonary hamartomas: initial experience using a modified technique to assess nodule fat. AJR Am J Roentgenol. 2012;199:W331–W334. 21. De Cicco C, et al. Imaging of lung hamartomas by multidetector computed tomography and positron emission tomography. Ann Thorac Surg. 2008;86:1769–1772. 22. Oh JK, Han DH. False-positive multi-detector CT finding for hamartomas. Ann Thorac Surg. 2010;90:1398, author reply 1398–1399. 23. Hughes JH, Young NA, Wilbur DC, et al. Fine-needle aspiration of pulmonary hamartoma: a common source of false-positive diagnoses in the College of American Pathologists Interlaboratory Comparison Program in Nongyne­ cologic Cytology. Arch Pathol Lab Med. 2005;129:19–22. 24. Loubeyre P, Copercini M, Dietrich PY. Percutaneous CT-guided multisampling core needle biopsy of thoracic lesions. AJR Am J Roentgenol. 2005;185: 1294–1298. 25. Landreneau RJ, Hazelrigg SR, Ferson PF, et al. Thoracoscopic resection of 85 pulmonary lesions. Ann Thorac Surg. 1992;54:415–419, discussion 419–420. 26. Ishibashi H, Akamatsu H, Kikuchi M, et al. Resection of endobronchial hamartoma by bronchoplasty and transbronchial endoscopic surgery. Ann Thorac Surg. 2003;75:1300–1302.

21 

Inflammatory Pseudotumor* JONATHAN H. CHUNG  |  CHRISTOPHER M. WALKER

Etiology, Prevalence, and Epidemiology Inflammatory pseudotumor, also known as inflammatory myofibroblastic tumor, is a quasineoplastic lesion that clinically and radiologically tends to mimic a malignant neoplasm and that histologically consists of a mixture of inflammatory cells, myofibroblastic spindle cells, and plasma cells.1,2 The proportion of the various cells varies considerably from pseudotumor to pseudotumor. Pseudotumors with a predominance of plasma cells are commonly referred to as plasma cell granulomas, and pseudotumors with approximately equal numbers of fibroblasts, and histiocytes are referred to as fibrous histiocytomas.2 In most cases the etiology is unknown, although infection, infarcts, and radiation have been implicated as risk factors. Up to a half of pseudotumors demonstrate abnormality at the anaplastic lymphoma kinase receptor tyrosine kinase gene (2p23 locus), suggesting an underlying genetic defect.3 Organisms found in association with pulmonary inflammatory pseudotumor include various bacteria and Mycoplasma.4 Inflammatory pseudotumors are rare. They may affect individuals of any age but have a predilection for children and young adults.5 They are the most common primary lung mass seen in children.6

Clinical Presentation

lymphocytes and plasma cells with only minimal fibrous connective tissue.1

Manifestations of the Disease RADIOGRAPHY The most common radiologic manifestation consists of a solitary peripheral sharply circumscribed lobulated nodule or mass.1,6 The lesion may have smooth or spiculated margins and range from 1 to more than 6 cm in diameter (Fig. 21.1).8 Calcification is present occasionally, particularly in children, and cavitation is present rarely.1,6 Endobronchial tumors can cause obstructive pneumonitis and atelectasis.1,6 Hilar or mediastinal lymph node enlargement and pleural effusion occur occasionally. COMPUTED TOMOGRAPHY Inflammatory pseudotumors may have smooth or spiculated margins (Fig. 21.2; see Fig. 21.1), homogeneous or heterogeneous attenuation, and either no enhancement or variable enhancement after intravenous administration of contrast medium.1,6,9 On computed tomography (CT) the nodules are usually closely associated with a bronchus.10 Multiple lesions are seen in 5% of cases.1 Approximately 10% of inflammatory pseudotumors manifest as endobronchial masses.1 Occasionally, they may be endotracheal.10

Most patients are asymptomatic, and the pseudotumor is an incidental finding seen on chest radiography or CT. The most common symptoms are cough, fever, dyspnea, and hemoptysis.7,8

MAGNETIC RESONANCE IMAGING

Pathophysiology

Inflammatory pseudotumors tend to have intermediate signal intensity at T1-weighted magnetic resonance imaging (MRI), have high signal intensity on T2-weighted MRI, and enhance after intravenous administration of gadolinium.6

Inflammatory pseudotumors are fibroinflammatory lesions that are believed to result from an exaggerated response to tissue injury.5 Histologically, they consist of a mixture of inflammatory cells, myofibroblastic spindle cells, and plasma cells.1,2 The proportion of these cells varies, but it is believed that the progenitor cell of the various pseudotumors is the myofibroblast.5 These lesions also are commonly referred to as inflammatory myofibroblastic tumors.5 On the basis of the predominant histopathologic features, inflammatory pseudotumors can be divided into three histologic types: (1) focal organizing pneumonia pattern, characterized by small airways and adjacent parenchyma filled with fibroblasts and foamy histiocytes; (2) fibrous histiocytic pattern, characterized by spindle-shaped myofibroblasts arranged in whorls; and (3) lymphohistiocytic pattern, characterized by a mixture of *The editors and the publisher would like to thank Drs. Nestor L. Müller and C. Isabela Silva Müller for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

POSITRON EMISSION TOMOGRAPHY Inflammatory pseudotumors tend to have high-intensity uptake on positron emission tomography (PET) with fluorodeoxyglucose (FDG-PET), indicating a high degree of metabolic activity (see Fig. 21.2).11 They also have high uptake on PET performed with rubidium-82, indicating the presence of increased perfusion.11

Differential Diagnosis The radiologic differential diagnosis for inflammatory pseudotumor occurring as a solitary pulmonary nodule or mass includes primary or secondary neoplasm and granuloma.

Synopsis of Treatment Options The biological potential of inflammatory pseudotumor varies. Long-term follow-up often shows no change in size or configuration. 381

382

SECTION 5  Pulmonary Neoplasms

A

Fig. 21.1  Inflammatory pseudotumor confirmed after surgical resection. (A) Posteroanterior chest radiograph shows a right upper lobe nodule with spiculated margins. (B) and (C) CT scans obtained at lung (B) and soft tissue (C) windows show a spiculated right upper lobe nodule. Note mild emphysema (B).

B

C

21  Inflammatory Pseudotumor

A

383

B Fig. 21.2  Inflammatory pseudotumor. Axial image from chest CT (A) shows a nodule in the left lower lobe shown to represent an inflammatory pseudotumor. Coronal image from FDG-PET (B) shows high FDG avidity within the nodule (arrow).

Some lesions have been shown to regress with or without steroid therapy.1,12 Some lesions increase in size, however, and may infiltrate the pulmonary vessels, the chest wall, or medi­astinum.1 Complete surgical resection is the treatment of choice in adults.1,8 Local recurrence may occur in some cases even after apparent complete surgical resection.8 KEY POINTS • Inflammatory pseudotumors consist of variable proportions of inflammatory cells, myofibroblastic spindle cells, and plasma cells. • Inflammatory pseudotumors are rare, affecting mainly children and young adults. • Inflammatory pseudotumors are usually benign but occasionally may be invasive and recur after surgical resection. • Radiologic manifestations are as follows: • Nodules or masses 1–6 cm in diameter (average, 3 cm) • May have foci of calcification (more common in children) • Smooth, lobulated, or spiculated margins • Most commonly peripheral; approximately 10% are endobronchial • Homogeneous or heterogeneous attenuation on CT • Homogeneous or heterogeneous enhancement with intravenous contrast material • High uptake on FDG-PET imaging

SUGGESTED READINGS Narla LD, Newman B, Spottswood SS, et al. Inflammatory pseudotumor. Radiographics. 2003;23:719–729. Surabhi VR, Chua S, Patel RP, Takahashi N, Lalwani N, Prasad SR. Inflammatory myofibroblastic tumors: current update. Radiol Clin North Am. 2016;54:553–563.

The full reference list for this chapter is available at ExpertConsult.com.

21  Inflammatory Pseudotumor 383.e1

REFERENCES 1. Narla LD, Newman B, Spottswood SS, et al. Inflammatory pseudotumor. Radiographics. 2003;23:719–729. 2. Fraser RS, Colman N, Müller NL, et al. Pulmonary neoplasms. In: Fraser RS, Colman N, Müller NL, eds. Synopsis of Diseases of the Chest. Philadelphia: Saunders; 2005:337–422. 3. Coffin CM, Hornick JL, Fletcher CD. Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol. 2007;31:509–520. 4. Dehner LP. The enigmatic inflammatory pseudotumours: the current state of our understanding, or misunderstanding. J Pathol. 2000;192:277–279. 5. Kovach SJ, Fischer AC, Katzman PJ, et al. Inflammatory myofibroblastic tumors. J Surg Oncol. 2006;94:385–391. 6. Agrons GA, Rosado de Christenson ML, Kirejczyk WM, et al. Pulmonary inflammatory pseudotumor: radiologic features. Radiology. 1998;206: 511–518.

7. Cohen MC, Kaschula RO. Primary pulmonary tumors in childhood: a review of 31 years’ experience and the literature. Pediatr Pulmonol. 1992;14:222–232. 8. Melloni G, Carretta A, Ciriaco P, et al. Inflammatory pseudotumor of the lung in adults. Ann Thorac Surg. 2005;79:426–432. 9. Diederich S, Theegarten D, Stamatis G, et al. Solitary pulmonary nodule with growth and contrast enhancement at CT: inflammatory pseudotumour as an unusual benign cause. Br J Radiol. 2006;79:76–78. 10. Kim TS, Han J, Kim GY, et al. Pulmonary inflammatory pseudotumor (inflammatory myofibroblastic tumor): CT features with pathologic correlation. J Comput Assist Tomogr. 2005;29:633–639. 11. Slosman DO, Spiliopoulos A, Keller A, et al. Quantitative metabolic PET imaging of a plasma cell granuloma. J Thorac Imaging. 1994;9:116–119. 12. Bando T, Fujimura M, Noda Y, et al. Pulmonary plasma cell granuloma improves with corticosteroid therapy. Chest. 1994;105:1574–1575.

22 

Pulmonary Metastases* STEPHANE L. DESOUCHES  |  CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

Etiology, Prevalence, and Epidemiology Pulmonary metastases are common—present at autopsy in 20% to 54% of patients with extrapulmonary malignancy.1 The most common primary sites associated with pulmonary metastases in biopsy series are the breast, colon, kidney, uterus, bladder, melanoma, and head and neck.2

Clinical Presentation Most pulmonary metastases occurring as single or multiple nodules are asymptomatic. When present, symptoms are nonspecific and include cough, hemoptysis, and shortness of breath. The most common clinical manifestation of lymphatic spread of tumor is dyspnea. The dyspnea is typically insidious in onset but tends to progress rapidly.3 Similarly, the most common symptom of endobronchial metastases is dyspnea; other common symptoms include cough, recurrent infection, and hemoptysis.4

Pathophysiology Pulmonary metastases may occur by hematogenous, lymphatic, or aerogenous spread. HEMATOGENOUS SPREAD Most pulmonary metastases spread to the lungs through the arterial system, lodging within small pulmonary arterioles or arteries. In most cases the newly formed tumor extends into the surrounding lung parenchyma, forming a relatively well-defined nodule.3,5 Hematogenous metastases are usually bilateral and manifest with randomly distributed nodules in the outer third of the lower lung zones.6 Occasionally, hematogenous metastases to the lungs may result in tumor growth only in the vessel lumen and wall without extension into the extravascular tissue. This condition is known as tumor embolism and is seen most commonly in metastatic renal cell carcinoma; hepatocellular carcinoma; and carcinomas of the breast, stomach, and prostate.7 LYMPHATIC SPREAD Lymphatic metastases are most often indirect with first hematogenous spread to pulmonary arteries and arterioles with subsequent invasion of the adjacent interstitial space and lymphatics.8 Less commonly, lymphatic spread of tumor is retrograde from mediastinal and hilar lymph node metastases. Although *The editors and the publisher would like to thank Drs. Nestor L. Müller and C. Isabela Silva Müller for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

384

virtually any metastatic neoplasm can result in lymphatic spread, the most common extrathoracic cell type is adenocarcinoma from breast and gastrointestinal origin, as well as melanoma, lymphoma, and leukemia.5 Pathologically, lymphangitic carcinomatosis ranges from a slight accentuation of the interlobular septa and peribronchovascular connective tissue to marked thickening of these structures.3 Microscopically, neoplastic cells can be present within the lymphatic spaces or in the adjacent peribronchovascular and interlobular interstitial tissue. Edema or a desmoplastic reaction to the tumor can contribute significantly to the interstitial thickening (Fig. 22.1). AEROGENOUS SPREAD Airway spread of tumor occurs through direct invasion or seeding of the bronchi by tumor, usually from pulmonary adenocarcinoma or bronchial carcinoid, although upper airway malignancies, such as laryngeal carcinoma, can also progress this way.3,9 Endobronchial metastases from hematogenous spread are a different entity and are discussed separately.

Manifestations of the Disease Pulmonary metastases may result in four main types of imaging manifestations: nodules, lymphatic spread, tumor emboli, and endobronchial tumor. RADIOGRAPHY Lung Nodules The most common manifestation of pulmonary metastases consists of multiple nodules, most numerous in the basal portions of the lungs, reflecting the effect of gravity on blood flow.10 They range in size from barely visible to large masses (Fig. 22.2). The nodules usually are of varying size; although less often, they are approximately equal, suggesting a single shower of tumor emboli. Rarely, nodular deposits are so numerous and of such minute size as to suggest the diagnosis of miliary fungal infection or tuberculosis (Fig. 22.3). Certain primary neoplasms are more likely than others to produce solitary metastases on radiography, including carcinoma of the kidney, testicle, breast, and rectosigmoid colon; sarcomas (particularly sarcomas originating in bone); and malignant melanoma.11 Lymphatic Spread (Lymphangitic Carcinomatosis) The characteristic radiographic pattern consists of septal lines and thickening of the bronchovascular markings, simulating interstitial pulmonary edema (Fig. 22.4). The linear accentuation sometimes is associated with a nodular component, resulting in a coarse reticulonodular pattern.12 Hilar and mediastinal lymph node

22  Pulmonary Metastases

385

A Fig. 22.1  Lymphangitic carcinomatosis: pathologic findings. Pathologic specimen shows thickening of interlobular septum by edema and focal accumulations of tumor cells (arrows) within dilated lymphatics. (Courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Vancouver, Canada.)

enlargement is seen radiographically in 20% to 40% of patients, and pleural effusion is seen in 30% to 50%.12,13 Although characteristic, these findings lack specificity and sensitivity for the diagnosis. The chest radiograph is normal in 30% to 50% of patients who have pathologically proven lymphangitic carcinomatosis.12 COMPUTED TOMOGRAPHY Lung Nodules On computed tomography (CT), nodular metastases range from a few millimeters to several centimeters in diameter and are usually of varying size with smooth or irregular margins (see Fig. 22.2B). The nodules tend to be most numerous in the outer third of the lungs, particularly the subpleural regions of the lower zones, and have a random distribution within the secondary pulmonary lobules.5 Surrounding ground-glass opacities may result from airspace disease, lepidic growth of neoplasm, or hemorrhage.6 Metastatic nodules with hemorrhage often manifest the CT halo sign and are most common with choriocarcinoma, melanoma, renal cell carcinoma, angiosarcoma, and Kaposi sarcoma.5 Cavitation occurs most often in metastatic squamous cell carcinoma or transitional cell carcinoma but may also be seen with metastatic adenocarcinoma.1 The wall of a cavitated metastasis is generally thick and irregular (Fig. 22.5), although thin-walled cavities can be found with metastases from sarcomas and adenocarcinomas.1 Cavitation may also be induced by chemotherapy.1 Calcification of metastatic nodules is uncommon and suggests certain primary neoplasms, such as osteogenic sarcoma, mucinous carcinoma, or papillary thyroid carcinoma (Fig. 22.6). Small calcified nodules may mimic benign lesions, especially if eccentric calcification is difficult to ascertain.14 Calcification can develop at the site of pulmonary metastases that have vanished after successful chemotherapy.15 This chemotherapeutic effect may manifest with persistent nodules that, on histologic examination,

B Fig. 22.2  Pulmonary metastases: nodules and masses. (A) Posteroanterior chest radiograph shows multiple pulmonary nodules and masses ranging from a few millimeters to greater than 3 cm in diameter (arrows). The lesions have smooth margin and, while in all five lobes, demonstrate a basilar predominance. (B) Coronal CT shows the dominant right upper lobe mass and multiple bilateral pulmonary nodules (arrows), showing a basilar predominance.

show only necrosis and fibrosis without residual viable neoplastic tissue.16,17 Although hematogenous pulmonary metastases usually result in soft tissue nodules, metastases from adenocarcinoma may spread into the lung along the intact alveolar walls (lepidic growth), in a fashion similar to a primary pulmonary adenocarcinoma.1,17 The CT findings of metastases from adenocarcinoma include nodules, consolidation, ground-glass opacities, and nodules with CT halo sign (Fig. 22.7).1,18 Spontaneous pneumothorax resulting from metastatic disease to the lung is rare and should suggest sarcoma, choriocarcinoma, or cavitary metastasis.19 It has been suggested that the

386

A

SECTION 5  Pulmonary Neoplasms

B Fig. 22.3  Pulmonary metastases: miliary pattern. (A) Posteroanterior chest radiograph shows subtle small nodules throughout both lungs. (B) Coronal reformatted CT shows that the small nodules (arrows) have a random distribution in relation to the secondary pulmonary lobules. Note several conspicuous interlobular septa.

A

B Fig. 22.4  Lymphangitic carcinomatosis from metastatic breast cancer. (A) Posteroanterior chest radiograph shows diffuse interstitial opacities with thickened interlobular septa. (B) Axial CT shows nodular septal thickening in the lower lobes. Note tree-in-bud opacities and a beaded appearance to several peripheral pulmonary arteries (arrows) likely representing coexistent intravascular metastases.

22  Pulmonary Metastases

Fig. 22.5  Hemorrhagic and cavitating angiosarcoma metastases. Axial CT of the right lung shows several nodules and masses of various sizes, many surrounded by a halo of ground-glass opacity. Note cavitation of some of the nodules and masses.

complication is more frequent in patients undergoing chemotherapy. It may also occur before radiographic visibility of metastases.20 Solitary pulmonary nodules representing metastatic disease from extrathoracic primaries are rare, accounting for 2% to 10% of solitary pulmonary nodules in some studies. This percentage is based on radiographic findings and with the routine use of CT for screening; solitary metastases are much less common. Many of the nodules identified on CT in patients with extrathoracic malignancies represent granulomas or intrapulmonary lymphoid tissue.21 Munden and associates22 determined that 3-month follow-up imaging of patients with extrathoracic malignancies and small, less than 5 mm, incidentally detected pulmonary nodules for the first year and every 6 months thereafter effectively determines the malignant potential of the nodules. Multiple studies have shown greater than 50% of solitary pulmonary nodules in patients with a history of prior extrapulmonary neoplasia turned out to be primary lung malignancies or benign lesions on surgery or autopsy.23 The distinction between a new primary and a metastasis has important prognostic and therapeutic implications. Although new chemotherapeutic, and even molecular, therapies continue to develop, pulmonary metastasectomy remains the treatment of choice for most solitary pulmonary metastases.24 With few exceptions, there are no criteria by which a solitary metastasis can be distinguished definitively from a primary pulmonary carcinoma by imaging.25,26 Despite this lack of criteria, certain features of the pulmonary nodule as well as the particular primary neoplasm are associated with an increased probability of one or the other.27 A solitary nodule in a patient who has a high-grade sarcoma or deeply invasive melanoma is much more likely to be a metastasis than a new primary. A nodule in a patient who has a squamous cell carcinoma of the

387

A

B Fig. 22.6  Foci of calcification in metastatic colorectal adenocarcinoma. (A) Posteroanterior chest radiograph shows a right upper lobe mass with foci of increased opacity suggesting underlying calcification. (B) Axial CT confirms the presence of punctate calcification (arrow) within the right upper lobe mass. The extent of calcification increased on a subsequent CT (not shown).

388

SECTION 5  Pulmonary Neoplasms

Fig. 22.8  Lymphangitic carcinomatosis: nodular septal thickening. High-resolution CT shows bilateral nodular thickening (arrows) of the interlobular septa.

Fig. 22.7  Metastatic mucinous adenocarcinoma. Coronal reformatted CT shows a superior right lower lobe consolidation with surrounding ground-glass opacity. Note the smaller consolidation with surrounding ground-glass opacity in the left lower lobe. This represents airway spread of lung cancer.

head and neck is more likely a primary pulmonary carcinoma. The time interval between the initial tumor and the appearance of the pulmonary lesion is also important with most metastatic lesions occurring within 5 years of the original diagnosis. The major exception to this rule are carcinomas originating in the breast or kidney, in which metastases can occur many years after the original tumor is identified. Older age and a history of cigarette smoking increase the likelihood that the tumor is primary in the lung. Overall, detection of pulmonary nodules in patients with extrapulmonary malignancy is high, although most nodules are benign, especially if they are smaller than 10 mm in diameter or are less than 10 mm from the pleural surface.28 KEY POINTS: METASTATIC PULMONARY NODULES • Metastatic pulmonary nodules are usually multiple. • A single nodule is most common in carcinoma of the colon or kidneys and osteosarcoma. • Metastatic pulmonary nodules have smooth or irregular margins and are randomly distributed, with predilection for the peripheral middle and lower lung zones. • Cavitation occurs in 4% of metastases, most commonly in squamous cell carcinoma of the head and neck or cervix. • Calcification is uncommon and occurs with osteogenic sarcoma; chondrosarcoma; synovial sarcoma; or carcinoma of the colon, ovary, breast, or thyroid. • Small, less than 5-mm pulmonary nodules detected in cancer patients are usually benign. Malignant potential can be determined by looking for growth on 3-month follow-up CT examinations.

Lymphatic Spread (Lymphangitic Carcinomatosis) Lymphangitic carcinomatosis has a characteristic high-resolution CT appearance, consisting of smooth or nodular thickening of

Fig. 22.9  Lymphangitic carcinomatosis: mild abnormalities. Highresolution CT shows mild, smooth, bilateral, interlobular septal thickening (arrows). Lymphangitic carcinomatosis manifests with smooth septal thickening in about half of all cases.

the interlobular septa and peribronchovascular interstitium with preservation of normal lung architecture (Figs. 22.8 to 22.11).13,29 The abnormalities may be initially subtle but tend to progress to extensive bilateral disease with associated ground-glass opacities. There is a great deal of overlap between the imaging findings of lymphangitic carcinomatosis and pulmonary edema as the conditions often coexist because of the obstruction of normal lymphatic drainage of fluid from the lungs by the tumor. Pleural effusion is seen on CT in about 30% of cases, and hilar or mediastinal lymph node enlargement is seen in 40%.13 At the time of diagnosis, the CT findings of lymphangitic carcinomatosis are unilateral or markedly asymmetric in 50% of cases (see Fig. 22.11).13,30 Unilateral disease is particularly common in patients with lung cancer, whereas bilateral involvement is more common with extrapulmonary metastases. Disease may be obvious on CT in patients who have normal or nonspecific radiographic findings.29,31 Intravascular Tumor Emboli Tumor emboli are visualized histopathologically in many patients who have nodular metastases, but they tend to occur in arterioles

22  Pulmonary Metastases

389

pulmonary arteries, or as nodular and branching centrilobular opacities (tree-in-bud pattern) representing enlarged centrilobular arteries (Fig. 22.13).7,32,33 Intravascular tumor emboli usually coexist with another pattern of pulmonary involvement, most often lymphangitic carcinomatosis (see Fig. 22.4B). When emboli are the sole manifestation, the chest radiograph may be normal or may show dilation of central pulmonary arteries and the right ventricle, reflecting pulmonary hypertension. KEY POINTS: INTRAVASCULAR TUMOR EMBOLI

Fig. 22.10  Lymphangitic carcinomatosis: diffuse abnormalities. Highresolution CT shows extensive bilateral septal thickening with multiple polygonal arcades. Also noted are diffuse ground-glass opacities and trace bilateral pleural effusions caused by pulmonary edema.

• Intravascular tumor emboli are rarely identified radiographically. • Common primaries include carcinomas of the breast, stomach, prostate, and kidney. • Findings on CT include: • Wedge-shaped peripheral opacities • Intravascular filling defects on contrast-enhanced CT • Nodular or beaded thickening of the peripheral pulmonary arteries • Nodular and branching centrilobular opacities (tree-in-bud pattern)

Bronchial and Tracheal Metastases Endobronchial metastases usually are secondary to carcinoma of the breast, colorectum, kidney, and cervix or to melanoma or sarcoma.4,34 Endobronchial metastases are often radiographically occult. When present, the usual findings are those of bronchial obstruction, either partial (causing oligemia and expiratory airtrapping) or complete (with atelectasis and obstructive pneumonitis).1,35 Metastases to the trachea are rare (Fig. 22.14). Similar to endobronchial metastases, the most common primary sites are breast, kidney, colon, and melanoma.35–37 Endobronchial and endotracheal metastases result in single or, less commonly, multiple endoluminal soft tissue lesions that usually can be readily identified on CT.37,38 The tumors may be polypoid or have a glove-finger appearance with bronchial dilation. They typically enhance after intravenous administration of contrast material.38 Fig. 22.11  Lymphangitic carcinomatosis: unilateral distribution. Highresolution CT shows septal thickening and ground-glass opacities in the left upper lobe caused by lymphangitic carcinomatosis from adenocarcinoma of the lung.

KEY POINTS: LYMPHANGITIC CARCINOMATOSIS • Common primaries include carcinomas of the lung, breast, stomach, and pancreas. • Lymphangitic carcinomatosis usually is bilateral except in pulmonary carcinoma. • Imaging findings include: • Smooth or nodular thickening of interlobular septa and peribronchovascular interstitium • Lymphadenopathy in 30% • Pleural effusion in 30%–50%

or small arteries and are below the resolution of CT. Tumor emboli occasionally manifest indirectly as pulmonary infarcts with peripheral wedge-shaped opacities.5 Uncommonly, tumor emboli manifest as filling defects in the central pulmonary arteries (Fig. 22.12), as nodular or beaded thickening of the peripheral

KEY POINTS: BRONCHIAL AND TRACHEAL METASTASES • Bronchial and tracheal metastases are uncommon. • Common primaries include melanoma and carcinomas of the breast, rectum, and kidney. • Bronchial and tracheal metastases are seldom evident on chest radiography but may manifest indirectly with distal air-trapping or atelectasis. • Bronchial and tracheal metastases are usually solitary, manifesting as a soft tissue attenuating nodule.

MAGNETIC RESONANCE IMAGING Although initial studies showed a low sensitivity of magnetic resonance imaging (MRI) compared with CT in the evaluation of pulmonary nodules,39 the sensitivity of MRI has increased considerably with the improvement of MRI quality and development of specialized sequences. CT remains more sensitive than MRI for the detection of small (60 years or ≤60 years), Eastern Cooperative Oncology Group (ECOG) performance status, elevated serum lactate dehydrogenase, stage, and number of extranodal sites of disease are used to predict prognosis. Some other variations of this system are also used.1 SYNOPSIS OF TREATMENT OPTIONS B cell: The monoclonal antibody rituximab has revolutionized treatment of B-cell lymphomas. The addition of rituximab to existing chemotherapy regimens containing cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has significantly improved survival. It is the most common treatment regimen for DLBCL and follicular lymphoma. Bendamustine

24  Non-Hodgkin Lymphoma

*

*

*

411

*

B

A

Fig. 24.14  Implant-associated non-Hodgkin lymphoma of the breast. (A) Axial CT image demonstrates a small oblong opacity (arrows) slightly hyperdense to muscle at the superior margin of the left breast prosthesis in this woman with anaplastic large cell lymphoma of the breast. (B) Axial fused PET-CT image shows mild FDG uptake within this nodule (arrow). Breast prostheses (asterisks).

*

FI

*

*

A

FI

*

B Fig. 24.15  Implant-associated non-Hodgkin lymphoma of the breast. (A) Axial contrast-enhanced CT image shows asymmetry of the breasts resulting from a pericapsular fluid collection (Fl, arrows) around the left breast implant in this 42-year-old woman. Fluid cytology was positive for anaplastic large cell lymphoma of the breast. (B) Axial fused PET-CT image shows only minimal focal FDG activity (arrow) at the posterior medial margin of the prosthesis. Breast prostheses (asterisks).

plus rituximab and single-agent rituximab are also used in follicular lymphoma. Radiotherapy alone may be curative for localized DLBCL, but generally radiotherapy is used after chemotherapy. Traditionally, the indications for neoadjuvant radiation included bulky disease and osseous involvement. Patients with relapsed or incompletely responding disease may be candidates for potentially curative autologous stem cell transplantation if they respond to salvage chemotherapy.1 T cell: Because so much less is known about the pathophysiology and course of T-cell lymphomas, data are generally not adequate to inform treatment decisions, and therapy is based on expert consensus. Patients with peripheral T-cell lymphoma not otherwise specified have often been treated with CHOP. Autologous hematopoietic stem cell transplantation during remission can improve survival.1

KEY POINTS • Non-Hodgkin lymphoma (NHL) is a heterogeneous group of hematologic malignancies with varied presentation. Primary or secondary thoracic involvement is common. • PET-CT is the imaging modality of choice in the initial evaluation and staging of FDG-avid NHL and posttherapy assessment of response. • Non–FDG-avid NHL is staged by CT. • Thoracic MRI is useful for evaluation of mediastinal lymphomas, chest wall invasion, and spinal involvement. It is the preferred modality to evaluate cardiac lymphoma. • The differential diagnosis for thoracic manifestations of NHL includes other primary malignancies, metastatic malignancies, infections, and, in some instances, vasculitides.

412

SECTION 6  Lymphoproliferative Disorders and Leukemia

SUGGESTED READINGS

*

*

Fig. 24.16  Implant-associated non-Hodgkin lymphoma of the breast. Axial fused PET-CT image demonstrates mild circumferential FDG avidity around the right breast prosthesis (asterisks). Histology revealed a CD30positive anaplastic lymphoma kinase–negative anaplastic large cell lymphoma infiltrating the capsule of the implant.

Armitage JO, Gascoyne RD, Lunning MA, Cavalli F. Non-Hodgkin lymphoma. Lancet. 2017;390:298–310. Barrington SF, Kluge R. FDG PET for therapy monitoring in Hodgkin and non-Hodgkin lymphomas. Eur J Nucl Med Mol Imaging. 2017;44(suppl 1):97–110. Carter BW, Wu CC, Khorashadi L, et al. Multimodality imaging of cardiothoracic lymphoma. Eur J Radiol. 2014;83:1470–1482. Cheson BD. Staging and response assessment in lymphomas: the new Lugano classification. Chin Clin Oncol. 2015;4:5. Evens AM, Blum KA, eds. Non-Hodgkin Lymphoma: Pathology, Imaging and Current Therapy. Cancer Treatment and Research. Vol. 165. Switzerland, New York: Springer; 2015. Kligerman SJ, Franks TJ, Galvin JR. Primary extranodal lymphoma of the thorax. Radiol Clin North Am. 2016;54:673–687.

The full reference list for this chapter is available at ExpertConsult.com.

24  Non-Hodgkin Lymphoma 412.e1

REFERENCES 1. Armitage JO, Gascoyne RD, Lunning MA, Cavalli F. Non-Hodgkin lymphoma. Lancet. 2017;390:298–310. 2. Shankland KR, Armitage JO, Hancock BW. Non-Hodgkin lymphoma. Lancet. 2012;380:848–857. 3. Nogai H, Dorken B, Lenz G. Pathogenesis of non-Hodgkin’s lymphoma. J Clin Oncol. 2011;29(14):1803–1811. 4. Chiu BC, Hou N. Epidemiology and etiology of non-hodgkin lymphoma. Cancer Treat Res. 2015;165:1–25. 5. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–E386. 6. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. 7. Müller AM, Ihorst G, Mertelsmann R, Engelhardt M. Epidemiology of non-Hodgkin’s lymphoma (NHL): trends, geographic distribution, and etiology. Ann Hematol. 2005;84(1):1–12. 8. Carter BW, Wu CC, Khorashadi L, et al. Multimodality imaging of cardiothoracic lymphoma. Eur J Radiol. 2014;83(8):1470–1482. 9. Cancer Stat Facts: non-Hodgkin lymphoma; 2017. Available at https://seer .cancer.gov/statfacts/html/nhl.html. 10. Non-Hodgkin lymphoma statistics; 2017. Available at http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/ non-hodgkin-lymphoma. 11. Non-Hodgkin lymphoma: estimated incidence, mortality and prevalence for both sexes, 2012. International Agency for Research on Cancer (IARC); 2017. Available at: http://eco.iarc.fr/eucan/Cancer.aspx?Cancer=38. 12. Deleted in review. 13. Jeudy J, Burke AP, Frazier AA. Cardiac Lymphoma. Radiol Clin North Am. 2016;54(4):689–710. 14. Cadranel J, Wislez M, Antoine M. Primary pulmonary lymphoma. Eur Respir J. 2002;20(3):750–762. 15. Basso K, Dalla-Favera R. Germinal centres and B cell lymphomagenesis. Nat Rev Immunol. 2015;15(3):172–184.

16. Sibon D, Fournier M, Briere J, et al. Long-term outcome of adults with systemic anaplastic large-cell lymphoma treated within the Groupe d’Étude des Lymphomes de l’Adulte trials. J Clin Oncol. 2012;30(32):3939–3946. 17. Schaefer NG, Hany TF, Taverna C, et al. Non-Hodgkin lymphoma and Hodgkin disease: coregistered FDG PET and CT at staging and restaging. Do we need contrast-enhanced CT? Radiology. 2004;232(3):823–829. 18. Weiler-Sagie M, Bushelev O, Epelbaum R, et al. (18)F-FDG avidity in lymphoma readdressed: a study of 766 patients. J Nucl Med. 2010;51:25–30. 19. Kligerman SJ, Franks TJ, Galvin JR. Primary extranodal lymphoma of the thorax. Radiol Clin North Am. 2016;54(4):673–687. 20. Kelemen K, Cao W, Peterson LC, Evens AM, Variakojis D. Primary mediastinal large B-cell lymphoma in HIV: report of two cases. J Hematop. 2009;2(1): 45–49. 21. Wilson WH, Pittaluga S, Nicolae A, et al. A prospective study of mediastinal gray-zone lymphoma. Blood. 2014;124(10):1563–1569. 22. Castellino RA, Billingham M, Dorfman RF. Lymphographic accuracy in Hodgkin’s disease and malignant lymphoma with a note on the “reactive” lymph node as a cause of most false-positive lymphograms 1974. Investig Radiol. 1990;25(4):412–422. 23. Parissis H. Forty years literature review of primary lung lymphoma. J Cardiothorac Surg. 2011;6:23. 24. Lewis ER, Caskey CI, Fishman EK. Lymphoma of the lung: CT findings in 31 patients. AJR Am J Roentgenol. 1991;156(4):711–714. 25. Radkani P, Joshi D, Paramo JC, Mesko TW. Primary breast lymphoma: 30 years of experience with diagnosis and treatment at a single medical center. JAMA Surg. 2014;149(1):91–93. 26. Joks M, Mysliwiec K, Lewandowski K. Primary breast lymphoma—a review of the literature and report of three cases. Arch Med Sci. 2011;7(1):27–33. 27. Shim E, Song SE, Seo BK, Kim YS, Son GS. Lymphoma affecting the breast: a pictorial review of multimodal imaging findings. J Breast Cancer. 2013;16(3):254–265. 28. Cheson BD. Staging and response assessment in lymphomas: the new Lugano classification. Chin Clin Oncol. 2015;4(1):5.

25 

Hodgkin Lymphoma EMILY B. TSAI  |  CAROL C. WU  |  VICTORINE V. MUSE  |  KYUNG SOO LEE

Etiology, Prevalence, and Epidemiology Hodgkin lymphoma (HL) is a neoplasm of B lymphocytes characterized by the presence of Reed-Sternberg cells. HL accounts for 10% of all cases of lymphoma and approximately 0.6% of all cancers diagnosed annually, with an annual incidence of 2 to 3 per 100,000 in Europe and the United States. Peak incidence occurs in two main age groups: young adults in the third decade and adults older than 50 years. It is slightly more common in men than in women, with a male to female ratio of 1.3:1 in the United States.1,2 HL is less common in Asia. Risk factors for HL include Epstein-Barr virus infection, human immunodeficiency virus infection, and positive family history. Intrathoracic involvement in HL is common and occurs most often in the form of lymph node enlargement. Approximately 85% of patients with HL have intrathoracic disease at initial presentation. Intrathoracic involvement usually is associated with evidence of HL elsewhere in the body. In one series of 1470 patients, only 44 (3%) had purely intrathoracic disease after appropriate clinical and pathologic staging.3 Primary HL limited to the lung parenchyma is uncommon (1 cm in diameter) also can be seen and may warrant follow-up to evaluate for malignancy.29,37 Rarely, a solitary pulmonary nodule may be the only manifestation. As the disease progresses the nodules tend to cavitate, and a combination of cysts and nodules is characteristic (Figs. 33.10 and 33.11).29,37 The distribution of cysts is the same as that of nodules, and the craniocaudal distribution of abnormalities may be convincingly shown on coronal and sagittal reformats.46 The cysts initially

33  Pulmonary Langerhans Cell Histiocytosis

A

497

B Fig. 33.5  Pulmonary Langerhans cell histiocytosis: progression of radiographic findings in a young man. (A) Chest radiograph shows confluent nodules with a middle and upper zone predominance. Ring shadows consistent with cysts also are seen. Note the characteristic sparing of the costophrenic angles. The corresponding high-resolution CT scan is shown in Fig. 33.12. (B) Chest radiograph 3 years later shows the typical progression to thin-walled cysts.

Fig. 33.6  Pulmonary Langerhans cell histiocytosis: reticular pattern. Chest radiograph shows subtle reticular pattern with a middle and upper zone predominance in histopathologically proven pulmonary Langerhans cell histiocytosis. The corresponding high-resolution CT scan is shown in Fig. 33.14.

Fig. 33.7  Pulmonary Langerhans cell histiocytosis: “emphysemaappearance.” Chest radiograph shows hyperinflation, large bullae, and areas of scarring. Lung biopsy specimen (see Figs. 33.1 and 33.2) showed pulmonary Langerhans cell histiocytosis.

498

SECTION 7  Diffuse Lung Diseases

Fig. 33.9  Pulmonary Langerhans cell histiocytosis: micronodules on high-resolution CT. High-resolution CT scan shows subtle centrilobular nodules (arrows), some of which are branching in a tree-in-bud pattern. Also evident is minimal emphysema. Fig. 33.8  Pulmonary Langerhans cell histiocytosis: end-stage. Chest radiograph shows widespread reticular pattern and pulmonary distortion. Note enlarged central pulmonary arteries in keeping with associated pulmonary hypertension.

A

C

B

Fig. 33.10  Pulmonary Langerhans cell histiocytosis: cysts and nodules on CT. (A) High-resolution CT scan at the level of the main bronchi shows numerous bilateral cystic lesions of various sizes. Note relatively normal intervening lung parenchyma. The visualized bronchi are normal in diameter, and these do not communicate with the cysts. (B) Highresolution CT scan at the level of the right middle lobe bronchus shows numerous bilateral cysts. A few irregularly marginated small nodules are visible. (C) High-resolution CT scan through the lung bases shows only a few localized cysts. (From Müller NL, Fraser RS, Colman NC, et al. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: Saunders; 2001.)

33  Pulmonary Langerhans Cell Histiocytosis

499

B

A

Fig. 33.11  Pulmonary Langerhans cell histiocytosis: progression of characteristic CT findings. (A) Highresolution CT scan shows the characteristic combination of micronodules and spherical cysts. (B) Highresolution CT scan 2 years later shows regression of the nodules and progression of the thin-walled cysts.

research suggested that cysts remain stable or enlarge on CT, suggesting irreversible damage.29 However, more recent evidence does suggest that even thin-walled cysts contain active inflammatory cells on histopathology and as such can exhibit improvement on follow-up CT.49 POSITRON EMISSION TOMOGRAPHY Recent studies have shown that positron emission tomographic (PET) scanning is a useful imaging modality to determine the extent of disease involvement in affected patients. Positive PET scans in pulmonary LCH usually occur in predominantly nodular lung disease, thick-walled cysts, bone, liver, and other extrapulmonary sites of involvement.50,51 Fig. 33.12  Pulmonary Langerhans cell histiocytosis: characteristic thick-walled cysts. High-resolution CT scan of the same patient in Fig. 33.5 shows widespread thick-walled spherical cysts and a few irregular nodules.

may be thick walled and spherical with a diameter greater than 1 cm (Fig. 33.12; see Fig. 33.11) and then become thinner walled and more eccentric with coalescence in more advanced disease (Fig. 33.13; see Fig. 33.10).37 Other features that have been described are centrilobular branching opacities (see Fig. 33.9), a reticular pattern (Fig. 33.14), and thickening of interlobular septa.45 Large bullae may be seen,29 resulting in difficulties in differentiation from extensive emphysema and end-stage pulmonary LCH. Ground-glass opacification also has been described but is not a common feature37,45 (see Figs. 33.13 and 33.14) and is generally related to coexisting respiratory bronchiolitis, respiratory bronchiolitis–interstitial lung disease, and desquamative interstitial pneumonia. This is further histopathologic-radiologic evidence that there is a spectrum of smoking-related interstitial lung disease.27 The diagnostic accuracy of high-resolution CT is high,47,48 and the combination of cysts and nodules with an appropriate distribution is relatively specific in the context of an adult cigarette smoker. This frequently obviates the need for open lung biopsy. Serial CT studies have shown that nodules may regress completely, indicating potentially reversible disease.29 In contrast, older

ECHOCARDIOGRAPHY Right heart failure and pulmonary arterial hypertension (PAH) are common in long-term disease patients and can be a significant cause of morbidity and mortality.52 Echocardiography should be considered for all symptomatic patients to evaluate for pulmonary hypertension regardless of pulmonary artery disease on CT.53 Referral for right heart catheterization should be obtained if echocardiography suggests PAH.54 IMAGING ALGORITHMS Chest radiography is often the initial investigation and may be useful for follow-up or to show complicating pneumothorax. As in other diffuse interstitial lung diseases, high-resolution CT is more sensitive and specific and may provide information about disease reversibility, treatment response, and extrapulmonary disease sites.

Differential Diagnosis The differential diagnosis based on clinical data includes emphysema and other diffuse interstitial lung diseases, especially ones related to smoking (e.g., respiratory bronchiolitis-interstitial lung disease and desquamative interstitial pneumonia). There is some overlap in appearance with other cystic lung diseases, however, and biopsy confirmation may be required in atypical cases.45

500

SECTION 7  Diffuse Lung Diseases

B

A C

D

Fig. 33.13  Pulmonary Langerhans cell histiocytosis: nodules, cysts, and reticular pattern. (A) Chest radiograph shows diffuse reticular pattern in the upper and middle lung zones with sparing of the lower lung zones. (B) High-resolution CT scan at the level of the lung apices shows numerous bilateral thin-walled cysts. Conglomeration of cysts in the left upper lobe has led to the formation of large cysts with bizarre shapes. (C) High-resolution CT scan slightly above the level of the aortic arch shows numerous bilateral cysts, a few small nodules, and ground-glass opacities. (D) High-resolution CT scan at the level of the lung bases shows minimal abnormalities. The ground-glass opacities reflect the presence of respiratory bronchiolitis (“smoker’s bronchiolitis”).

The most frequent mimickers include lymphangioleiomyomatosis (LAM), lymphocytic interstitial pneumonia (LIP), and emphysema.45 Distinguishing LAM and LIP from LCH is frequently possible by evaluating the distribution of cysts in the craniocaudal plane and the cyst shape. LCH cysts are upper lung predominant and bizarrely shaped; LAM cysts are more diffusely distributed and round; LIP cysts are lower lung predominant and frequently perivascular.

Synopsis of Treatment Options MEDICAL

Fig. 33.14  Pulmonary Langerhans cell histiocytosis: cysts and reticular pattern. High-resolution CT scan of the same patient in Fig. 33.6 shows thin-walled cysts and a fine reticular pattern. Note associated ground-glass opacities reflecting the presence of smoking-related respiratory bronchiolitis.

• Smoking cessation is critical, with many patients stabilizing or improving. Some patients may progress despite cessation. • Medical treatment includes chemotherapeutic agents, such as vinblastine, cyclophosphamide, and busulfan, with or without corticosteroids. • There is no consensus regarding optimal treatment; a formal clinical trial has been suggested.

33  Pulmonary Langerhans Cell Histiocytosis

501

SURGICAL

SUGGESTED READINGS

• Pneumothorax is a frequent complication and may require surgical pleurodesis. • Patients with end-stage pulmonary LCH may develop pulmonary hypertension, and lung transplantation is a therapeutic option in this context, despite a disease recurrence rate of approximately 20%. • Surgical options include single-lung transplant, double-lung transplant, and heart-lung transplant.

Abbott GF, Rosado de Christenson ML, Franks TJ, et al. From the archives of the AFIP: pulmonary Langerhans’ cell histiocytosis. Radiographics. 2004;24: 821–841. Kim HJ, Lee KS, Johkoh T, et al. Pulmonary Langerhans cell histiocytosis in adults: high-resolution CT-pathology comparisons and evolutional changes at CT. Eur Radiol. 2011;21(7):1406–1415. Seely JM, Salahudeen S, Cadaval-Goncalves AT, et al. Pulmonary Langerhans cell histiocytosis: a comparative study of computed tomography in children and adults. J Thorac Imaging. 2012;27(1):65–70. Sundar KM, Gosselin MV, Chung HL, et al. Pulmonary Langerhans’ cell histiocytosis: emerging concepts in pathobiology, radiology, and clinical evolution of disease. Chest. 2003;123:1673–1683. Vassallo R, Ryu JH. Pulmonary Langerhans’ cell histiocytosis. Clin Chest Med. 2004;25:561–571. Vassallo R. Diffuse lung diseases in cigarette smokers. Semin Respir Crit Care Med. 2012;33(5):533–542.

KEY POINTS • Langerhans cell histiocytosis (LCH) may involve a single or multiple organs. • Pulmonary LCH in an adult occurs almost exclusively in current or ex-smokers. • Pulmonary disease is the most common form of single-organ disease. • Radiographic appearances are nonspecific, most commonly consisting of a nodular or reticulonodular pattern. • High-resolution CT usually progresses from ill-defined micronodules (1–5 mm in diameter) to a combination of cysts and nodules, with regression of nodules and increasing cysts (which may be bizarrely shaped) in more advanced disease. • Pulmonary LCH has a characteristic upper and middle zone distribution with sparing of the costophrenic angles and tips of the lingula and right middle lobe. • High-resolution CT findings often allow confident diagnosis; biopsy may be required in atypical cases.

The full reference list for this chapter is available at ExpertConsult.com.

33  Pulmonary Langerhans Cell Histiocytosis 501.e1

REFERENCES 1. Lichtenstein L, Histiocytosis X. integration of eosinophilic granuloma of bone: “Letterer-Siwe disease” and “Schüller-Christian disease” as related manifestations of a single nosologic entity. Arch Pathol. 1953;56:84–86. 2. Groopman JE, Golde DW. The histiocytic disorders: a pathophysiologic analysis. Ann Intern Med. 1981;94:107. 3. Arico M, Girschikofsky M, Genereau T, et al. Langerhans’ cell histiocytosis in adults: report from the International Registry of the Histiocyte Society. Eur J Cancer. 2003;39:2341–2348. 4. Mierau GW, Wills EJ, Steele PO. Ultrastructural studies in Langerhans’ cell histiocytosis: a search for evidence of viral aetiology. Pediatr Pathol. 1994;14: 895–904. 5. Willman CL, McClain KL. An update on clonality, cytokines and viral etiology in Langerhans’ cell histiocytosis. Hematol Oncol Clin North Am. 1998;12: 407–416. 6. Smets A, Mortele K, de Praeter G, et al. Pulmonary and mediastinal lesions in children with Langerhans’ cell histiocytosis. Pediatr Radiol. 1997;27: 873–876. 7. Hance AJ, Basset F, Saumon G, et al. Smoking and interstitial lung disease: the effect of cigarette smoking on the incidence of pulmonary histiocytosis X and sarcoidosis. Ann NY Acad Sci. 1986;465:643–656. 8. Howarth DM, Gilchrist GS, Mullan BP, et al. Langerhans’ cell histiocytosis: diagnosis, natural history, management and outcome. Cancer. 1999;85: 2278–2290. 9. Soler P, Kambouchner M, Valeyre D, et al. Pulmonary Langerhans’ cell histiocytosis (histiocytosis X). Annu Rev Med. 1992;43:105–115. 10. Vassallo R, Ryu JH, Colby TV, et al. Pulmonary Langerhans’ cell histiocytosis. N Engl J Med. 2000;342:1969–1978. 11. Colby TV, Lombard C. Histiocytosis X in the lung. Hum Pathol. 1983;14: 847–856. 12. Travis WD, Borok Z, Roum JH, et al. Pulmonary Langerhans’ cell histiocytosis (histiocytosis X): a clinicopathologic study of 48 cases. Am J Surg Pathol. 1993;17:971–986. 13. Zeid NA, Muller HK. Tobacco smoke induced lung granulomas and tumours: association with pulmonary Langerhans’ cells. Pathology. 1995;27:247–254. 14. Casolaro MA, Bernaudin JF, Saltini C, et al. Accumulation of Langerhans’ cells on the epithelial surface of the lower respiratory tract in normal subjects in association with cigarette smoking. Am Rev Respir Dis. 1988;137:406–411. 15. Aricó M, Nichols K, Whitlock JA, et al. Familial clustering of Langerhans’ cell histiocytosis. Br J Haematol. 1999;107:883–888. 16. Scappaticci MA, Danesino C, Rossi E, et al. Cytogenetic abnormalities in PHA-stimulated lymphocytes from patients with Langerhans’ cell histiocytosis. Br J Haematol. 2000;111:258–262. 17. Vassallo R, Ryu JH. Pulmonary Langerhans’ cell histiocytosis. Clin Chest Med. 2004;25:561–571. 18. Agostini C, Albera C, Bariffi F, et al. First report of the Italian register for diffuse infiltrative lung disorders (RIPID). Monaldi Arch Chest Dis. 2001;56:364–368. 19. Lacronique J, Roth C, Battesti JP, et al. Chest radiological features of pulmonary histiocytosis X: a report based on 50 adult cases. Thorax. 1982;37:104–109. 20. Malpas JS, Norton AJ. Langerhans’ cell histiocytosis in the adult. Med Pediatr Oncol. 1996;27:540–546. 21. Dunmore LA Jr, El-Khoury SA. Eosinophilic granuloma of the lung: a report of three cases in Negro patients. Am Rev Respir Dis. 1964;90:789–791. 22. Morley TF, Silverstein SD, Giudice JC, et al. Multifocal eosinophilic granuloma. Respiration. 1988;54:89–93. 23. Friedman PJ, Liebow AA, Sokoloff J. Eosinophilic granuloma of lung: clinical aspects of primary histiocytosis in the adult. Medicine (Baltimore). 1981;60:385–396. 24. Vassallo R, Ryu JH, Schroeder DR, et al. Clinical outcomes of pulmonary Langerhans’cell histiocytosis in adults. N Engl J Med. 2002;346:484–490. 25. Mendez JL, Nadrous HF, Vassallo R, et al. Pneumothorax in pulmonary Langerhans’ cell histiocytosis. Chest. 2004;125:1028–1032. 26. Marchal J, Kambouchner M, Tazi A, et al. Expression of apoptosis-regulatory proteins in lesions of pulmonary Langerhans’ cell histiocytosis. Histopathology. 2004;45:20–28. 27. Vassallo R, Jensen EA, Colby TV, et al. The overlap between respiratory bronchiolitis and desquamative interstitial pneumonia in pulmonary Langerhans’ cell histiocytosis: high-resolution CT, histologic and functional correlations. Chest. 2003;124:1199–1205.

28. Kambouchner M, Basset F, Marchal J, et al. Three-dimensional characterization of pathologic lesions in pulmonary Langerhans’ cell histiocytosis. Am J Respir Crit Care Med. 2002;166:1483–1490. 29. Brauner MW, Grenier P, Mouelhi MW, et al. Pulmonary histiocytosis X: evaluation with high-resolution CT. Radiology. 1989;172:255–258. 30. Sundar KM, Gosselin MV, Chung HL, et al. Pulmonary Langerhans’ cell histiocytosis: emerging concepts in pathobiology, radiology, and clinical evolution of disease. Chest. 2003;123:1673–1683. 31. Soler P, Bergeron A, Kambouchner M, et al. Is high-resolution computed tomography a reliable tool to predict the histopathological activity of pulmonary Langerhans’ cell histiocytosis? Am J Respir Crit Care Med. 2000;162:264–270. 32. Stern EJ, Webb WR, Golden J, et al. Cystic lung disease associated with eosinophilic granuloma and tuberous sclerosis: air trapping at dynamic ultrafast high resolution CT. Radiology. 1992;182:325–329. 33. Vassallo R, Ryu JH. Pulmonary Langerhans’ cell histiocytosis. Clin Chest Med. 2004;25:561–571. 34. Paciocco G, Uslenghi E, Bianchi A, et al. Diffuse cystic lung diseases: correlation between radiologic and functional status. Chest. 2004;125:135–142. 35. Kulweic EL, Lynch DA, Aguayo SM. Imaging of pulmonary histiocytosis X. Radiographics. 1992;12:515–526. 36. Schönfeld N, Frank W, Wenig S, et al. Clinical and radiologic features, lung function and therapeutic results in histiocytosis X. Respiration. 1993;69: 38–44. 37. Moore ADA, Godwin JD, Muller NL, et al. Pulmonary histiocytosis X: comparison of radiographic and CT findings. Radiology. 1989;172: 249–254. 38. Weber WN, Margolin FR, Nielsen SL. Pulmonary histiocytosis X: a review of 18 patients with reports of 6 cases. AJR Am J Roentgenol. 1969;107: 280–289. 39. Brambilla E, Fontaine E, Pison CM, et al. Pulmonary histiocytosis X with mediastinal lymph node involvement. Am Rev Respir Dis. 1990;142: 1216–1218. 40. Guardia J, Pedeira JD, Esteban R, et al. Early pleural effusion in histiocytosis X. Arch Intern Med. 1979;139:934–936. 41. Tittel PW, Winkler CF. Chronic recurrent pleural effusion in adult histiocytosisX. Br J Radiol. 2006;54:68–69. 42. Fichtenbaum CJ, Kleinman GM, Haddad RG. Eosinophilic granuloma of the lung presenting as a solitary pulmonary nodule. Thorax. 1990;45: 905–906. 43. Chaowalit N, Pellikka PA, Decker PA, et al. Echocardiographic and clinical characteristics of pulmonary hypertension complicating pulmonary Langerhans’ cell histiocytosis. Mayo Clin Proc. 2004;79:1269–1275. 44. Kulwiec EL, Lynch DA, Aguayo SM, et al. Imaging of pulmonary histiocytosis X. Radiographics. 1993;12:515–526. 45. Koyama M, Johkoh T, Honda O, et al. Chronic cystic lung disease: diagnostic accuracy of high-resolution CT in 92 patients. AJR Am J Roentgenol. 2003;180:827–835. 46. Johkoh T, Müller NL, Nakamura H. Multidetector spiral high-resolution computed tomography of the lungs: distribution of findings on coronal image reconstructions. J Thorac Imaging. 2002;17:291–305. 47. Grenier P, Valeyre D, Cluzel P, et al. Chronic diffuse interstitial lung disease: diagnostic value of chest radiography and high-resolution CT. Radiology. 1991;179:123–132. 48. Bonelli FS, Hartman TE, Swensen SJ, et al. Accuracy of high-resolution CT in diagnosing lung diseases. AJR Am J Roentgenol. 1998;170:1507–1512. 49. Kim HJ, Lee KS, Johkoh T, et al. Pulmonary Langerhans cell histiocytosis in adults: high-resolution CT-pathology comparisons and evolutional changes at CT. Eur Radiol. 2011;21(7):1406–1415. 50. Krajicek BJ, Ryu JH, Hartman TE, Lowe VJ, Vassallo R. Abnormal fluorodeoxyglucose PET in pulmonary Langerhans cell histiocytosis. Chest. 2009;135(6):1542–1549. 51. Kaste SC, Rodriguez-Galindo C, McCarville ME, Shulkin BL. PET-CT in pediatric Langerhans cell histiocytosis. Pediatr Radiol. 2007;37(7):615–622. 52. Fartoukh M, Humbert M, Capron F, et al. Severe pulmonary hypertension in histiocytosis X. Am J Respir Crit Care Med. 2000;161(1):216–223. 53. Chaowalit N, Pellikka PA, Decker PA, et al. Echocardiographic and clinical characteristics of pulmonary hypertension complicating pulmonary Langerhans cell histiocytosis. Mayo Clin Proc. 2004;79(10):1269–1275. 54. Vassallo R. Diffuse lung diseases in cigarette smokers. Semin Respir Crit Care Med. 2012;33(5):533–542.

34 

Smoking-Related Interstitial Lung Disease* STEPHEN B. HOBBS

Currently, the worldwide number of tobacco smokers is estimated at 1.1 billion people, with the World Health Organization estimating that tobacco use is responsible for approximately 6 million premature deaths each year.1 In the United States 42 million adults are still smokers despite overall decreasing rates of smoking in the United States.2 Despite a majority of the morbidity and mortality of smoking being related to lung cancer, coronary atherosclerosis, and chronic obstructive pulmonary disease, the smoking-related interstitial lung diseases are a commonly encountered and important clinical and radiologic entity. The smoking-related interstitial lung diseases include a range of conditions, from those highly associated with smoking, such as respiratory bronchiolitis (RB), desquamative interstitial pneumonia (DIP), and pulmonary Langerhans cell histiocytosis (PLCH, see Chapter 33), to other conditions that are worsened or precipitated by smoking, such as acute eosinophilic pneumonia (AEP, see Chapter 37), pulmonary hemorrhage (see Chapter 2), and even pulmonary fibrosis.3 This chapter focuses on the smokingrelated interstitial pneumonias (RB, respiratory bronchiolitis– associated interstitial lung disease [RB-ILD], and DIP) and the smoking-related patterns of pulmonary fibrosis, including usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), and combined pulmonary fibrosis and emphysema (CPFE).

Respiratory Bronchiolitis and Respiratory Bronchiolitis–Associated Interstitial Lung Disease Etiology RB is a common histopathologic finding in smokers,4 which typically is not associated with symptoms or functional deficit. A few smokers develop symptoms and are classified as having RB-ILD. RB-ILD is a symptomatic clinical condition with radiologic and functional abnormalities that was first recognized in heavy cigarette smokers in the late 1980s.5 Subsequent studies have confirmed a strong link with cigarette smokers, with very rare reports in nonsmokers,6,7 although a link with inhalation of noxious substances in the workplace also has been suggested.8

Prevalence and Epidemiology Despite the common habit of cigarette smoking in the general population and the frequency of RB in smokers approaching *The editors and the publisher would like to thank Dr. Susan J. Copley for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

502

100% in some studies,9 the clinicopathologic entity of RB-ILD is comparatively rare, making accurate evaluation of prevalence difficult. RB-ILD was not yet a recognized disease in the earlier large milestone multicenter studies of interstitial lung disease that predated the 1990s.10 In a study from a large tertiary referral center in the United Kingdom, the biopsy specimens in 168 cases over an 18-year period were retrospectively reviewed, and 13 (8%) of these showed a dominant pattern of RB-ILD.8 The usual age at presentation is in the 30s and 40s, and men and women are almost equally affected, with a slight male preponderance.5–8

Clinical Presentation Patients with RB-ILD are invariably middle-aged smokers and present with dyspnea that may be of insidious onset.11 Cough also may be a feature and is sometimes severe. Less commonly, chest pain and, rarely, hemoptysis have been described. Bilateral end-inspiratory crackles, which may be predominantly basal, are common, but finger clubbing is very rare.8

Pathophysiology PATHOLOGY RB is characterized histologically by intraluminal and peribronchiolar airspace accumulation of pigmented macrophages (Fig. 34.1). These macrophages are called “smoker’s macrophages” because they typically have granular brown cytoplasm. The pigmentation most likely represents the metabolites of cigarette smoke, given that the intensity of pigmentation correlates with pack-years of cigarettes smoked.7 An ongoing inflammatory process is denoted by a mild peribronchiolar mononuclear inflammatory submucosal infiltrate, which may be associated with fibroblasts and collagen deposition, resulting in stellate fibrous scarring extending into surrounding alveolar walls.5,6 Similar to macrophage pigmentation, peribronchiolar fibrosis also has been shown to correlate with the number of pack-years smoked.7 Additional histopathologic findings include thickening of the peribronchiolar alveolar septa and alveolar ducts and histiocytes within the peribronchiolar fibrous tissue displaying anthracotic pigment, foci of goblet cell metaplasia, and metaplastic cuboidal epithelium in the airway epithelium.6 Mild emphysema in the surrounding lung parenchyma is relatively common,8 but honeycombing is not a recognized histopathologic feature and should raise the possibility of alternative diagnoses, with RB being an incidental finding. Histopathologic findings in RB-ILD (Fig. 34.2) and DIP are similar, and differentiation between the two entities may be difficult. The distribution in RB-ILD is typically more patchy and bronchiolocentric, whereas DIP results in extensive uniform alveolar macrophage accumulation.6 Currently, RB-ILD and DIP

34  Smoking-Related Interstitial Lung Disease

503

Fig. 34.1  Respiratory bronchiolitis: histologic findings. Histopathologic specimen shows respiratory bronchiole with increased intraluminal macrophages (curved arrow) and mural inflammation. Extension of the inflammation and macrophages (straight arrows) into the surrounding alveoli also is noted. (Courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Vancouver, Canada.)

findings in RB-ILD are a mixed obstructive-restrictive defect. The carbon monoxide–diffusing capacity is often reduced, and the total lung capacity may be normal, reduced, or slightly increased.5,6,8 In one study the most common functional deficit was a reduction in diffusing capacity.14 There is an inverse correlation between the computed tomography (CT) extent of ground-glass opacity and arterial oxygen saturation.15

Manifestations of the Disease RADIOGRAPHY The radiographic features of biopsy-proven cases of RB-ILD have been described in numerous studies and are variable and nonspecific. A fine diffuse reticulonodular pattern with normal lung volumes has been described (Fig. 34.3).6,8 In one study the main finding was the presence of ill-defined small nodules with lower zone predominance.5 In another study the main abnormalities consisted of ground-glass opacities (Fig. 34.4) and airway wall thickening, with no cases showing a prominent reticulonodular pattern.15 One-third of patients may have a normal radiograph, despite biopsy-proven disease.5,6 Fig. 34.2  Respiratory bronchiolitis–interstitial lung disease: histologic features. Histopathologic specimen shows extensive accumulation of pigmented macrophages in alveoli and bronchioles in a bronchiolocentric distribution. (Courtesy Dr. S.R. Desai.)

are considered to be a spectrum of smoking-related parenchymal disease that also may include PLCH.6,12,13 Correlation with clinical and radiologic findings is vital in the diagnosis of RB-ILD, owing to the almost universal, usually incidental, histopathologic observation of RB in asymptomatic smokers.8 LUNG FUNCTION Individuals with uncomplicated RB usually do not have lung function deficits. In contrast, the usual pulmonary function

COMPUTED TOMOGRAPHY Comparison of the high-resolution CT (HRCT) findings in 98 asymptomatic cigarette smokers with 175 nonsmoking controls showed ill-defined, upper zone–predominant parenchymal micronodules in 27% of smokers but not in control subjects.16 Comparable differences were noted for areas of ground-glass opacity (20% of smokers and none of the control group). In a later study of heavy smokers with histopathologic correlation, parenchymal micronodules indicating the presence of RB (Fig. 34.5) and areas of ground-glass opacification, representing accumulations of inflammatory cells and a variable degree of fine interstitial fibrosis, were observed.17 In another study investigating CT features in 57 smokers at baseline and follow-up

504

SECTION 7  Diffuse Lung Diseases

A

B Fig. 34.3  Respiratory bronchiolitis–interstitial lung disease: radiologic findings. (A) Chest radiograph shows subtle reticulonodular pattern in the middle and lower zones. (B) The appearances are more apparent on a concurrent high-resolution CT scan, which shows ill-defined micronodules.

examinations, the percentages of patients with ground-glass opacity, emphysema, and ill-defined micronodules increased, respectively, from 28% to 42%, 26% to 40%, and 33% to 35% on follow-up.18 Five patients displaying micronodules at baseline examination showed a replacement of this pattern by emphysema at follow-up.18 The HRCT findings of RB-ILD were initially described in five patients with biopsy-proven diagnosis.19 Areas of ground-glass opacity (Fig. 34.6) were the most common finding. One patient had interlobular and intralobular thickening (Fig. 34.7). No patient had nodular opacities.19 By contrast, a more recent study of 21 patients with pathologically proven RB-ILD documented centrilobular nodules in 71% of cases (see Fig. 34.7), areas of ground-glass opacity in 67%, and patchy areas of decreased attenuation (likely reflecting small airways disease) in 38%.15 End-expiratory CT may emphasize the regional differences in lung density (Fig. 34.8). Most patients in the latter study showed

wall thickening of proximal and distal airways, a similar appearance to that seen in chronic bronchitis. In another series of eight patients with RB-ILD, no single HRCT finding predominated.12 Diffuse ground-glass opacification and centrilobular nodules were major features in about half of the patients, and emphysema was present in most patients.12 Despite the fact that many patients are heavy smokers, the severity of the emphysema is usually mild or trivial, confined to the upper lobes, and with a centrilobular or paraseptal distribution. Some patients show thickening of interlobular septa, and features of established interstitial fibrosis are unusual but coexist in some patients with RB-ILD.8,12 A mosaic attenuation pattern, representing constrictive bronchiolitis, is not usually a prominent feature, but when present, it is most obvious in the lower lobes. The combination of HRCT features of an infiltrative and small airways disease is similar to that seen in patients with subacute hypersensitivity pneumonitis (HP), and the distinction between these two conditions often rests on

34  Smoking-Related Interstitial Lung Disease

Fig. 34.4  Respiratory bronchiolitis–interstitial lung disease: ground-glass opacities. Chest radiograph shows poorly defined hazy opacities (ground-glass opacities) in the middle and lower lung zones.

Fig. 34.5  Respiratory bronchiolitis: high-resolution CT (HRCT) findings in an asymptomatic heavy smoker. HRCT scan shows bilateral poorly defined centrilobular nodules.

505

506

SECTION 7  Diffuse Lung Diseases

Fig. 34.6  Respiratory bronchiolitis–interstitial lung disease: characteristic CT findings. High-resolution CT scan shows bilateral ground-glass opacities and mild paraseptal emphysema. Note a few poorly defined micronodules.

A

C

B

Fig. 34.7  Respiratory bronchiolitis–interstitial lung disease: characteristic CT findings. (A) and (B) High-resolution CT (HRCT) scans show patchy ground-glass opacities, ill-defined centrilobular micronodules, and a few thickened interlobular septa. Note mild paraseptal and centrilobular emphysema. (C) HRCT scan at the level of lower lobes shows bilateral ground-glass opacities and areas of decreased attenuation and vascularity (arrow).

34  Smoking-Related Interstitial Lung Disease

A

507

B Fig. 34.8  Respiratory bronchiolitis–interstitial lung disease: air trapping on high-resolution CT (HRCT). (A) HRCT scan at inspiration shows mosaic attenuation. (B) CT scan at end expiration shows accentuation of the mosaic attenuation as a result of air-trapping.

the smoking history because hypersensitivity pneumonitis is uncommon in smokers. The HRCT appearances of RB-ILD are variable and nonspecific. The CT features of RB are often subtle. IMAGING ALGORITHMS The chest radiograph may be normal in RB and RB-ILD. When the radiograph is abnormal, the findings are often nonspecific. HRCT is more sensitive, especially in subtle disease.

Differential Diagnosis The differential diagnosis based on clinical data includes other diffuse interstitial lung diseases, especially those related to smoking (e.g., desquamative interstitial pneumonia). The HRCT appearance of RB-ILD is very similar to HP. The history of smoking can be very useful to distinguish between RB-ILD and subacute HP. Additionally, bronchoalveolar lavage demonstrating smokers’ macrophages and a lack of lymphocytosis is strongly suggestive of RB-ILD and may prevent the need for surgical lung biopsy in a majority of patients when combined with appropriate HRCT findings.

Synopsis of Treatment Options • The prognosis seems to be improved in individuals with RB-ILD who stop smoking, although persisting radiologic and functional abnormalities may be seen. • The response to corticosteroids is unclear; most patients report a symptomatic improvement, which may be associated with improvement of lung function indices but may not result in complete disease resolution.

Desquamative Interstitial Pneumonia Etiology Desquamative interstitial pneumonia (DIP) is a rare condition that is strongly linked with cigarette smoking. DIP was first described by Liebow in 196520 and was initially thought to be

KEY POINTS: RESPIRATORY BRONCHIOLITIS AND RESPIRATORY BRONCHIOLITIS–INTERSTITIAL LUNG DISEASE • Respiratory bronchiolitis (RB) is a common histopathologic finding in smokers but is not usually associated with symptoms. • Respiratory bronchiolitis–interstitial lung disease (RB-ILD) is a rare symptomatic interstitial lung disease linked with cigarette smoking and part of the spectrum of smoking-related interstitial lung disease. • RB and RB-ILD have nonspecific radiographic features, such as reticulonodular pattern, bronchial wall thickening, and ground-glass opacities. Radiographs may be normal. • High-resolution CT (HRCT) usually shows poorly defined centrilobular nodules and ground-glass opacities with an upper zone predominance. There may be evidence of emphysema. • HRCT features of RB-ILD may be subtle and similar to HP.

an early “cellular” or inflammatory phase of idiopathic pulmonary fibrosis (IPF). Subsequent clinical and radiologic longitudinal studies have shown, however, that the prognosis and natural history of the condition vastly differ from the inexorable decline invariably seen in patients with IPF.21–23 Similarly, the predominant histopathologic pattern was initially thought to be that of desquamated pneumocytes (hence the term desquamative interstitial pneumonia) but subsequently was recognized as widespread alveolar filling with macrophages. The original term continues to be used despite it being a now recognized misnomer. Despite the fact that DIP is currently classified as an “idiopathic” interstitial pneumonia,24 greater than 90% of cases of DIP are in smokers,21 and the condition is considered to represent part of the histopathologic spectrum of smoking-related interstitial lung diseases, including PLCH and RB-ILD. A “DIP-like” histopathologic pattern also has been associated with dust inhalation,25 metabolic diseases,26 drug reactions,27 and connective tissue diseases.28 DIP has been described in children as well.29 In infants a similar pattern has been described that is related to mutations in the surfactant protein C gene, a familial condition that is unrelated to cigarette smoke exposure.30

508

SECTION 7  Diffuse Lung Diseases

Prevalence and Epidemiology

Pathophysiology

DIP as a “pure” entity is extremely rare, and accurate data on the prevalence are not reliable. There is a male-to-female ratio of 2 : 1 in DIP, and 90% are smokers. Individuals usually present in their 30s to 50s.21,28,31 DIP has been reported in children and, although rare, is one of the more common histopathologic patterns of interstitial lung disease in this age group.29,32

PATHOLOGY

Clinical Presentation Patients usually present with insidious onset of dyspnea and nonproductive cough.21,28 On clinical examination more than half of patients have crepitations (i.e., lung crackles), and approximately 50% display finger clubbing, which is not normally seen in RB-ILD.21,28

The histopathologic features of DIP are similar to RB-ILD in that there is pigmented macrophage accumulation in alveolar spaces. The discriminating factor between these conditions is the extent of involvement, with RB-ILD being typically patchy and bronchiolocentric, whereas DIP is more uniform and diffuse, a feature that can be recognized at low magnification (Fig. 34.9). Despite the apparently straightforward difference, there is overlap in appearances between these two conditions, making definitive histopathologic diagnosis problematic in some cases.28 Eosinophils may be seen in addition to macrophages, a feature not normally seen in RB-ILD. The background architecture of the alveoli is generally well maintained; however, the alveolar septa may

A

B Fig. 34.9  Desquamative interstitial pneumonia: pathologic findings. (A) Low-power view shows fairly homogeneous pattern with numerous pigmented macrophages in the alveolar airspaces. The findings are diffuse, a distinguishing feature from respiratory bronchiolitis–associated interstitial lung disease, which has a bronchiolocentric distribution. (B) High-power view shows pigmented macrophages and mild inflammation and thickening of alveolar walls. (Courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Vancouver, Canada.)

34  Smoking-Related Interstitial Lung Disease

be minimally thickened owing to inflammatory cells and fibrosis, a more extensive feature than in RB-ILD. Extensive fibrosis with honeycomb change is not a feature usually associated with DIP, compared with UIP, although mild honeycombing may occur.33 LUNG FUNCTION A restrictive defect with reduction in diffusing capacity and lung volumes is a typical finding, but a less severe deficit than in IPF is typical.21,31

Manifestations of the Disease

509

treatment, and the exact histopathologic significance of this finding is unclear. Of cases, 32% to 75% develop small cystic airspaces within areas of ground-glass opacification (see Fig. 34.11).22,32 These small microcysts, which may be a minor CT feature of DIP, sometimes resolve over time, and their exact nature is unclear. Histopathologic correlation suggests that some of these cysts represent bronchiolectasis and dilated alveolar ducts or possibly emphysema. IMAGING ALGORITHMS Chest radiography is often the initial investigation but may be normal. HRCT is more sensitive and specific, as in other diffuse interstitial lung diseases.

RADIOGRAPHY The radiographic appearance is bilateral basal predominant, hazy, increased opacification with a reduction in lung volumes.21,28 Other features that also have been reported are of a nonspecific reticular or reticulonodular pattern, again with a basal distribution31; however, the radiographic findings may be subtle or even normal, similar to RB-ILD.34 COMPUTED TOMOGRAPHY Because “pure” DIP is a rare entity, the largest study to date of the thin-section CT features included only 22 patients, despite being collaborative from multiple tertiary referral centers.35 The typical HRCT features that have been described in this condition are of diffuse ground-glass opacity with a peripheral and lower lung predominance (Fig. 34.10).35,36 A mild reticular pattern is seen in roughly half of cases (Fig. 34.11) and mild honeycombing in a small percentage of cases.22,35–37 Similarly, architectural distortion of lung parenchyma and traction bronchiectasis are uncommon features (Fig. 34.12).22 Serial CT studies have shown that the areas of ground-glass opacity tend to remain stable over time or improve with corticosteroid treatment, as opposed to usual interstitial pneumonia, in which these areas enlarge or progress to honeycombing.37 A few patients show increasing extent of disease over time, however, despite corticosteroid

Fig. 34.11  Desquamative interstitial pneumonia: ground-glass opacities, small cysts, and reticulation. High-resolution CT scan shows a mixed ground-glass and fine reticular pattern. Note presence of microcysts. The microcysts are within areas of ground-glass opacity, are not associated with architectural distortion, have very thin walls, and are not contiguous, features that distinguish them from honeycombing.

Fig. 34.10  Desquamative interstitial pneumonia: high-resolution CT (HRCT) findings. HRCT scan shows bilateral ground-glass opacities and minimal irregular linear opacities. Note the predominantly subpleural distribution of the abnormalities.

Fig. 34.12  Desquamative interstitial pneumonia (DIP) and emphysema. High-resolution CT scan shows a combination of ground-glass opacity and emphysema. There is some distortion of the lung parenchyma, an unusual feature in this patient with histopathologically proven DIP.

510

SECTION 7  Diffuse Lung Diseases

Differential Diagnosis Differential diagnosis based on clinical data includes other diffuse interstitial lung diseases, especially related to smoking (e.g., RB-ILD). Differential diagnosis based on supportive diagnostic techniques includes NSIP, RB-ILD, drug toxicity, infection, and HP. Confident diagnosis may require surgical lung biopsy.

Synopsis of Treatment Options • Spontaneous improvement may occur in untreated patients. • Most patients are advised to stop smoking because the prognosis seems to be improved in individuals with DIP who quit, although persistent radiologic and functional abnormalities may be seen. • The response to corticosteroids is unclear; however, most patients report a symptomatic improvement, which is often associated with improvement of lung function indices and imaging appearances but may not result in complete disease resolution. • Roughly 25% of cases worsen despite treatment with corticosteroids. • Lung transplant has been performed in selected patients; there are reports of disease recurrence in single-lung transplants.

KEY POINTS: DESQUAMATIVE INTERSTITIAL PNEUMONIA • The “pure” form of desquamative interstitial pneumonia (DIP) is a very rare condition associated with cigarette smoking. • DIP reaction is part of the spectrum of smoking-related interstitial lung disease. • Radiographic features are nonspecific. • CT appearances are of bilateral, predominantly lower lobe, ground-glass opacities with or without associated mild reticulation and superimposed cystic spaces.

Smoking-Related Pulmonary Fibrosis Etiology The link between pulmonary fibrosis and cigarette smoking has existed for many years.20 There is evidence to suggest that cigarette smoking may increase the risk of developing IPF; approximately 40% to 80% of patients with IPF are current smokers or exsmokers.21–24 It has been shown that cigarette smoking independently increases the risk of developing IPF (odds ratio, 1.6).25 There are problems, however, in the accurate interpretation of these studies because the inclusion criteria varied, and confirmation of histopathologic pattern was not obtained in all cases. In addition, many earlier studies predated the more recent rigorous definition of histopathologic subsets in the consensus classification of the chronic fibrosing interstitial pneumonias (UIP and NSIP), and these may have been distorted by inclusion of cases of desquamative interstitial pneumonia, previously thought to be an early “cellular” phase of IPF. A recent study demonstrated evidence of fibrosis in 3.8% of patients undergoing lung cancer

screening.38 The fibrotic patterns of ILD are increasingly recognized to have an increased prevalence and/or worsened prognosis in patients with a history of cigarette smoking.

Usual Interstitial Pneumonia Several studies have identified smoking as a potential risk factor in the development of UIP pattern pulmonary fibrosis with an odds ratio of 1.6 to 2.9.39,40 Additionally, one study demonstrated that survival is higher in nonsmokers than in former smokers with IPF. However, outcome was actually improved in current smokers, which was attributed to the ”healthy smoker effect,” where current smokers tend to have less severe disease at presentation and have not yet felt compelled to stop smoking for health reasons.41 MANIFESTATIONS OF THE DISEASE Radiography Early in the disease course, radiographs can appear normal, but with more advanced disease, there are decreased lung volumes and lower lung–predominant reticular markings and bronchiectasis. Computed Tomography On HRCT lower lung– and subpleural-predominant reticulation, with associated bronchiectasis and honeycomb cyst formation, is classic. There should be a relative paucity of ground-glass opacity and nodules. Lung volumes are low unless there is coexisting emphysema (see next section for a discussion on CPFE). See Chapter 27 for a greater discussion of findings in UIP pattern pulmonary fibrosis.

Combined Pulmonary Fibrosis and Emphysema CPFE is increasingly recognized as a discrete clinical entity rather than simply pulmonary fibrosis superimposed on emphysema. It is more common in men and affects a slightly older population compared with IPF. Although clinical symptoms may be similar to IPF and emphysema, patients frequently have preserved to increased lung volumes despite profoundly limited gas exchange. Despite this, the overall survival of CPFE is nearly double that of IPF, with an average survival of 6 years.42,43 However, the rate of pulmonary hypertension is higher in patients with CPFE than with IPF alone, and in those patients with pulmonary hypertension, there is a corresponding decreased rate of survival.44 Finally, the rates of lung cancer in patients with CPFE are higher than either emphysema or IPF. One study demonstrated a 42% incidence of lung cancer in patients with CPFE compared with a 14% incidence in emphysema and 10% to 15% in IPF.45,46 In practice, many reserve using the term CPFE for those cases with at least moderate emphysema and moderate pulmonary fibrosis, but the evidence for such a distinction is lacking and requires further study. MANIFESTATIONS OF THE DISEASE Radiography Upper lung–predominant emphysema and lower lung–predominant fibrosis are seen with preserved overall lung volumes.

34  Smoking-Related Interstitial Lung Disease

A

511

B Fig. 34.13  Combined pulmonary fibrosis and emphysema. (A) CT scan through the upper lungs shows marked upper lobe–predominant bullous emphysema. (B) CT scan through the lower lungs shows lower lung subpleural-predominant fibrosis with reticulation, bronchiectasis, and honeycombing.

Computed Tomography Coexisting upper lung–predominant centrilobular and/or paraseptal emphysema and lower lung fibrosis are the hallmarks of CPFE on HRCT (Fig. 34.13). The basal-predominant fibrosis may be in a pattern of UIP or NSIP (discussed next). There is a subset of CPFE patients who have superimposed RB, which is sometimes termed RB with fibrosis (RBF). Distinguishing between these patterns is important as the patterns of disease have different natural histories, with RBF being generally stable and with improved survival relative to both UIP and NSIP patterns in the setting of CPFE.47–49

Nonspecific Interstitial Pneumonia The diagnosis of NSIP has an improved prognosis compared with UIP. Patients tend to present at a younger age than in IPF, and the numerous other causes of an NSIP pattern of fibrosis should be excluded, such as connective tissue disease, drug-related lung injury, and HP. The pattern of fibrosis most frequently seen in the setting of smoking is fibrotic NSIP rather than cellular NSIP.50

Fig. 34.14  Nonspecific interstitial pneumonia and emphysema. Highresolution CT scan shows bilateral ground-glass opacities and mild reticulation. Centrilobular and paraseptal emphysema or areas of traction bronchiolectasis within areas of ground-glass opacity may be difficult to distinguish from honeycomb cysts.

MANIFESTATIONS OF THE DISEASE Radiography Lower lung–predominant fibrosis is seen with varying degrees of bronchiectasis and airspace opacities. COMPUTED TOMOGRAPHY Bibasilar ground-glass opacities with underlying reticular abnormality and traction bronchiectasis are classic, often with

a more bronchovascular distribution than that seen in UIP. In the setting of underlying emphysema, distinguishing UIP from NSIP may be aided by evaluating the degree of traction brochiolectasis and extent of ground-glass attenuation.51 See Chapter 28 for a more in-depth discussion of the radiologic manifestations of NSIP pattern pulmonary fibrosis. In the setting of NSIP, ground-glass opacities superimposed on emphysema can be an imaging mimicker of honeycombing (Fig. 34.14).

512

SECTION 7  Diffuse Lung Diseases

KEY POINTS: SMOKING-RELATED PULMONARY FIBROSIS • Pulmonary fibrosis associated with smoking can occur in a usual interstitial pneumonia or nonspecific interstitial pneumonia pattern. • Patients with combined pulmonary fibrosis and emphysema (CPFE) have a significantly increased risk of lung cancer. • Patients with CPFE have worsened survival relative to emphysema alone but improved survival compared with those with idiopathic pulmonary fibrosis without emphysema. • Separation of the spectrum of “smoking-related interstitial lung disease” may be histopathologically and radiologically challenging.

SUGGESTED READINGS Kligerman S, et al. Clinical-radiologic-pathologic correlation of smoking-related diffuse parenchymal lung disease. Radiol Clin North Am. 2016;54(6):1047–1063. Madan R, et al. Spectrum of smoking-related lung diseases: imaging review and update. J Thorac Imaging. 2016;31(2):78–91.

The full reference list for this chapter is available at ExpertConsult.com.

34  Smoking-Related Interstitial Lung Disease 512.e1

REFERENCES 1. World Health Organization. WHO Global Report on Trends in Prevalence of Tobacco Smoking. Geneva: World Health Organization; 2015. 2. National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health. The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: Centers for Disease Control and Prevention; 2014. 3. Madan R, et al. Spectrum of smoking-related lung diseases: imaging review and update. J Thorac Imaging. 2016;31(2):78–91. 4. Niewoehner DE, Kleinerman J, Rice DB. Pathologic changes in the peripheral airways of young cigarette smokers. N Engl J Med. 1974;291:755–758. 5. Myers JL, Veal CFJ, Shin MS, et al. Respiratory bronchiolitis causing interstitial lung disease: a clinicopathological study of six cases. Am Rev Respir Dis. 1987;135:880–884. 6. Yousem SA, Colby TV, Gaensler EA. Respiratory bronchiolitis-associated interstitial lung disease and its relationship to desquamative interstitial pneumonia. Mayo Clin Proc. 1989;64:1390. 7. Fraig M, Shreesha U, Savici D, et al. Respiratory bronchiolitis: a clinicopathologic study in current smokers, ex-smokers, and never-smokers. Am J Surg Pathol. 2002;26:653. 8. Moon J, du Bois RM, Colby TV, et al. Clinical significance of respiratory bronchiolitis on open lung biopsy and its relationship to smoking related interstitial lung disease. Thorax. 1999;59:1009–1014. 9. Travis WD, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733–748. 10. Gaensler EA, Carrington CB. Open biopsy for chronic diffuse infiltrative lung disease: clinical, roentgenographic, and physiological correlations in 502 patients. Ann Thorac Surg. 1980;30:411–426. 11. King TE Jr. Respiratory bronchiolitis-associated interstitial lung disease. Clin Chest Med. 1993;14:693–698. 12. Heyneman LE, Ward S, Lynch DA, et al. Respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, and desquamative interstitial pneumonia: different entities or part of the spectrum of the same disease process? AJR Am J Roentgenol. 1999;173:1622. 13. Vassallo R, Jensen EA, Colby TV, et al. The overlap between respiratory bronchiolitis and desquamative interstitial pneumonia in pulmonary Langerhans cell histiocytosis: high-resolution CT, histologic and functional correlations. Chest. 2003;124:1199–1205. 14. Ryu JH, Myers JL, Capizzi SA, et al. Desquamative interstitial pneumonia and respiratory bronchiolitis-associated interstitial lung disease. Chest. 2005;127:178–184. 15. Park JS, Brown KK, Tuder RM, et al. Respiratory bronchiolitis-associated interstitial lung disease: radiologic features with clinical and pathologic correlation. J Comput Assist Tomogr. 2002;26:20. 16. Remy-Jardin M, Remy J, Boulenguez C, et al. Morphologic effects of cigarette smoking on airways and pulmonary parenchyma in healthy adult volunteers: CT evaluation and correlation with pulmonary function tests. Radiology. 1993;186:107–115. 17. Remy-Jardin M, Remy J, Gosselin B, et al. Lung parenchymal changes secondary to cigarette smoking: pathologic-CT correlations. Radiology. 1993;186: 643–651. 18. Remy-Jardin M, Edme J-L, Boulenguez C, et al. Longitudinal follow-up study of smoker’s lung with thin-section CT in correlation with pulmonary function tests. Radiology. 2002;222:261–270. 19. Holt RM, Schmidt RA, Godwin JD, et al. High resolution CT in respiratory bronchiolitis-associated interstitial lung disease. J Comput Assist Tomogr. 1993;17:46–50. 20. Liebow AA, Steer A, Billingsley JG. Desquamative interstitial pneumonia. Am J Med. 1965;39:369–404. 21. Carrington CB, Gaensler EA, Coutu RE, et al. Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med. 1978;298:801–808. 22. Akira M, Yamamoto S, Hara H, et al. Serial computed tomographic evaluation in desquamative interstitial pneumonia. Thorax. 1997;52:333–337. 23. Nicholson AG, Colby TV, du Bois RM, et al. The prognostic significance of the histological pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med. 2000;162:2213–2217.

24. American Thoracic Society. American Thoracic Society/European Thoracic Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2002;165: 277–304. 25. Corrin B, Price AB. Electron microscopic studies in desquamative interstitial pneumonia associated with asbestosis. Thorax. 1972;27:324–331. 26. Amir G, Ron N. Pulmonary pathology in Gaucher’s disease. Hum Pathol. 1999;30:666–670. 27. Bone RC, Wolfe J, Sobonya RE, et al. Desquamative interstitial pneumonia following long term nitrofurantoin therapy. Am J Med. 1976;60:697–701. 28. Yousem SA, Colby TV, Gaensler EA. Respiratory bronchiolitis-associated interstitial lung disease and its relationship to desquamative interstitial pneumonia. Mayo Clin Proc. 1989;64:1390. 29. Stillwell PC, Norris DG, O’Connell EJ, et al. Desquamative interstitial pneumonitis in children. Chest. 1980;77:165–171. 30. Nogee LM, Dunbar AE, Wert SE, et al. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med. 2001;344:573–579. 31. Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med. 1998;157: 1301–1315. 32. Bokulic RE, Hilman BC. Interstitial lung disease in children. Pediatr Clin North Am. 1994;41:543–567. 33. Ryu JH, Colby TV, Hartman TE, et al. Smoking-related interstitial lung disease: a concise review. Eur Respir J. 2001;17:122–132. 34. Gaensler EA, Goff AM, Prowse CM. Desquamative interstitial pneumonia. N Engl J Med. 1966;274:113–128. 35. Hartman TE, Primack SL, Swensen SJ, et al. Desquamative interstitial pneumonia: thin-section CT findings in 22 patients. Radiology. 1993;187: 787–790. 36. Heyneman LE, Ward S, Lynch DA, et al. Respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, and desquamative interstitial pneumonia: different entities or part of the spectrum of the same disease process? AJR Am J Roentgenol. 1999;173:1622. 37. Hartman TE, Primack SL, Kang E, et al. Disease progression in usual interstitial pneumonia compared with desquamative interstitial pneumonia. Chest. 1996;110:378–382. 38. Jin GY, et al. Interstitial lung abnormalities in a CT lung cancer screening population: prevalence and progression rate. Radiology. 2013;268(2): 563–571. 39. Baumgartner KB, et al. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1997;155(1):242–248. 40. Iwai K, et al. Idiopathic pulmonary fibrosis. Epidemiologic approaches to occupational exposure. Am J Respir Crit Care Med. 1994;150(3):670–675. 41. Antoniou KM, et al. Idiopathic pulmonary fibrosis: outcome in relation to smoking status. Am J Respir Crit Care Med. 2008;177(2):190–194. 42. Cottin V, Cordier JF. The syndrome of combined pulmonary fibrosis and emphysema. Chest. 2009;136(1):1–2. 43. Cottin V, et al. Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity. Eur Respir J. 2005;26(4):586–593. 44. Cottin V, et al. Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema syndrome. Eur Respir J. 2010;35(1):105–111. 45. Nakayama M, et al. Risk of cancers in COPD patients. Chest. 2003;123(5): 1775–1776. 46. Sakai F, et al. Imaging diagnosis of interstitial pneumonia with emphysema (combined pulmonary fibrosis and emphysema). Pulm Med. 2012;2012:816541. 47. English C, et al. Respiratory bronchiolitis with fibrosis: prevalence and progression. Ann Am Thorac Soc. 2014;11(10):1665–1666. 48. Katzenstein AL, et al. Clinically occult interstitial fibrosis in smokers: classification and significance of a surprisingly common finding in lobectomy specimens. Hum Pathol. 2010;41(3):316–325. 49. Reddy TL, et al. Respiratory bronchiolitis with fibrosis. High-resolution computed tomography findings and correlation with pathology. Ann Am Thorac Soc. 2013;10(6):590–601. 50. Travis WD, et al. Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project. Am J Respir Crit Care Med. 2008;177(12):1338–1347. 51. Akira M, et al. Usual interstitial pneumonia and nonspecific interstitial pneumonia with and without concurrent emphysema: thin-section CT findings. Radiology. 2009;251(1):271–279.

35 

Lymphangioleiomyomatosis and Tuberous Sclerosis NICOLA SVERZELLATI

Etiology Lymphangioleiomyomatosis (LAM) is a systemic disease of unknown etiology, affecting almost exclusively women. LAM is characterized by idiosyncratic smooth muscle cell proliferation (LAM cells), which leads to lung cysts, systemic lymphatic abnormalities, and abdominal tumors. The main manifestation is a progressive destructive process of the lungs, which may result in respiratory failure.1 LAM cells can be isolated from peripheral blood, indicating the ability to spread hematogenously to the lung. LAM cells have been detected in donor lungs of patients who had lung transplantation, suggesting migration of LAM cells to the lungs from other sites, such as the kidney, lymphatic system, or uterus. Indeed, LAM is also defined as a low-grade, destructive, metastasizing neoplasm.2–4 LAM can occur without evidence of other disease (sporadic LAM [S-LAM]) or in association with tuberous sclerosis complex (TSC).5 TSC is a neurocutaneous disease characterized by hamartomatous changes in the brain, kidneys, skin, heart, lungs, and other organs.6 TSC is an autosomal-dominant inherited disorder resulting from a germline mutation in one of two tumor suppressor genes, TSC-1 (encoding hamartin on chromosome 9q34) and TSC-2 (encoding tuberin on chromosome 16p13.3).7 In S-LAM somatic mutations have been found in LAM cells in the lungs, lymph nodes, and angiomyolipomas (AMLs), predominantly for TSC-2.7,8 S-LAM has been considered a forme fruste of TSC by some investigators, causing speculation that S-LAM results from somatic mutations associated with perinatal or early life events, possibly modified by hormonal factors.9,10 Hamartin or tuberin deficiency or dysfunction results in upregulated activity of mammalian target of rapamycin (mTOR), which leads to increased protein translation and ultimately inappropriate cellular proliferation, migration, and invasion.11 Indeed, both sirolimus and everolimus—two mTOR inhibitors— have both demonstrated treatment benefit in LAM. These drugs are now recognized as the standard therapy for patients with declining lung function, symptomatic chylous effusions, lymphangioleiomyomas, or large AMLs.12 However, patients with advanced disease may require lung transplantation. The median transplantfree survival is approximately 29 years from the onset of symptoms and a 10-year transplant-free survival of 86%.13,14 Disorganized lymphangiogenesis has an important role in the pathogenesis of LAM. An important biomarker of value in diagnosing LAM is vascular endothelial growth factor (VEGF)-D, a lymphangiogenic growth factor that is increased in the serum of patients with LAM, especially those with lymphatic involvement.15,16 In the appropriate clinical and radiologic setting, a VEGF-D serum level greater than 800 pg/mL is rarely found in other cystic lung diseases. VEGF-D may be of value in grading the severity of disease and monitoring therapeutic response.17

Estrogen has also been implicated in the pathogenesis of LAM on the basis of the observation that LAM may be exacerbated by the administration of exogenous estrogens and during pregnancy or menstruation.18–20 Hormonal receptors are inconsistently expressed in affected tissues, however, and hormonal treatment has proved, at best, to be of only modest benefit.20,21

Prevalence and Epidemiology Prevalence of S-LAM is approximately 3.4 to 7.8 per million women in the United States and Europe.11,22,23 Most individuals who seek medical attention for LAM have S-LAM,20,24 as reported by the National Heart, Lung, and Blood Institute LAM Registry, which recorded the presence of TSC in 18.3% of 230 patients with pulmonary LAM.20 The expected prevalence of TSC-LAM should be higher than S-LAM because TSC affects 1 in 6000 children.25,26 This paradox of S-LAM being more common than TSC-LAM remains unresolved, but possible explanations include the suggestion that TSC-LAM may be less aggressive than S-LAM or that subclinical S-LAM is much more common than is currently appreciated.21 Mother-daughter transmission of TSC-LAM, but not S-LAM, has been documented, although two-thirds of cases of TSC-LAM are sporadic and likely are related to spontaneous mutations or incomplete penetrance.27 Occurrence of cystic lung disease in women with TSC ranges from 26% to 49%.28,29 However, it was estimated that up to 80% of women older than 40 years with TSC will develop lung cysts. Lung cysts are not uncommon in men with TSC, affecting about 38%.30 Conversely, pulmonary involvement has been rarely reported in men with S-LAM.31,32 LAM is usually diagnosed in women of childbearing age, with a mean age of 40 years.27,33,34 There are increasing reports, however, of women developing LAM after menopause, including women in their 80s.20 KEY POINTS: ETIOLOGY, PREVALENCE, AND EPIDEMIOLOGY • The etiology of lymphangioleiomyomatosis (LAM) is unknown. • LAM occurs almost exclusively in women, usually during childbearing age. • Prevalence of sporadic LAM is approximately 5 per million. • Prevalence of TSC is 1 in 6000–9000.

Clinical Presentation The most frequent presenting symptoms of patients with pulmonary LAM are dyspnea, often exacerbated by exertion, and fatigue.5,22 Dyspnea is due to airflow obstruction, replacement of the lung parenchyma by cysts, and, if the dyspnea is acute, 513

514

SECTION 7  Diffuse Lung Diseases

A

C

B

pneumothorax. Pneumothorax is the sentinel event in 40% to 50% of patients (Fig. 35.1).35,36 In one study of 395 patients, 260 patients reported at least one spontaneous pneumothorax (incidence, 66%), and 200 of 260 patients (77%) had subsequent pneumothoraces.37 It was shown that screening for LAM by computed tomography (CT) in women presenting with spontaneous pneumothorax can be cost-effective in an appropriately selected patient population (e.g., nonsmoking women, age 25–54 years, with a history of at least two episodes of pneumothorax and dyspnea before the pneumothorax).38 Other possible accompanying symptoms of pneumothorax are chest pain and cough. Pleural effusions occurring in patients with LAM are nearly always chylous.39 Chylothorax has been described in 14% of patients with LAM at presentation and in 22% to 39% during the course of the disease (Fig. 35.2).39 Chylothorax may result from obstruction of the thoracic duct or its tributaries, leakage from pleural lymphatics, or transdiaphragmatic flow from associated chylous ascites.40 Less common manifestations are hemoptysis and chyloptysis (expectoration of milky chyle), which are likely due to LAM cell obstruction of pulmonary venules or capillaries and lymphatics. In rare cases

Fig. 35.1  Tuberous sclerosis complex–associated lymphangioleiomyomatosis in a 34-year-old woman. (A) Posteroanterior chest radiograph shows a moderate-sized right pneumothorax (arrow). There is a fine reticular pattern most prominent in the lower zones. Tethering of the lateral aspect of the left hemidiaphragm was thought to be a consequence of a previous pneumothorax. (B) High-resolution CT scan shows the small right pneumothorax and several thin-walled cysts uniformly distributed throughout the lungs. (C) Noncontrast CT of the head shows calcified nodules consistent with multifocal tubers.

patients with LAM may develop a chylous pericardial effusion (see Fig. 35.2).23 Cyanosis, respiratory failure, and cor pulmonale can occur in advanced disease. Physical examination is often normal at presentation, unless a pneumothorax or chylous effusion is present.41 Wheezing is heard in a few patients, and clubbing is a very rare accompaniment.42 Pulmonary hypertension secondary to chronic respiratory failure may be present in advanced cases of LAM.43 Abdominal examination may reveal the presence of ascites or masses, usually from AMLs or axial lymphatic involvement.41 Occasionally, extrapulmonary manifestations are the first symptoms of LAM, most commonly bleeding from a renal AML. Multiple renal AMLs and AMLs greater than 4 cm are more likely to grow and cause symptoms, such as flank pain, hematuria, and, rarely, shock secondary to acute hemorrhage.41 Renal AMLs occur in approximately 93% of patients with TSC-LAM, and they are found in 32% to 60% of patients with S-LAM.20,44,45 In a study by Avila and colleagues, extrapulmonary manifestations of S-LAM were documented in 61 of 80 patients (76%) and included renal AMLs (43%), lymphadenopathy (39%), lymphangioleiomyomas (16%), ascites (10%), dilation of the thoracic duct (9%), and

35  Lymphangioleiomyomatosis and Tuberous Sclerosis

A

515

B Fig. 35.2  Chylous pleural and pericardial effusions in lymphangioleiomyomatosis. (A) Posteroanterior chest radiograph shows an enlarged cardiac silhouette shown to represent a chylous pericardial effusion. Note a moderate right pleural effusion. Several small cysts were identified on an accompanying highresolution CT scan (not shown). (B) Posteroanterior chest radiograph from a different patient shows a large left pleural effusion and a contralateral right apical pneumothorax (arrow). The left pleural effusion was chylous on diagnostic and therapeutic thoracentesis. (Fig. 35.2B from Jawad H, Walker CM, Wu CC, Chung JH. Cystic interstitial lung diseases: recognizing the common and uncommon entities. Curr Probl Diagn Radiol. 2014;43:115–127.)

Fig. 35.3  Lymphangioleiomyomas in a 55-year-old woman with sporadic lymphangioleiomyomatosis. Contrast-enhanced CT of the lower abdomen shows a large low-attenuation lobulated mass (arrows), consistent with a lymphangioleiomyoma.

hepatic AMLs (4%).45a Lymphangioleiomyomas occur along the lymphatic system and may lie between, and displace, abdominal or pelvic structures (Fig. 35.3).45 The most common symptoms associated with lymphangioleiomyomas are abdominal bloating, lower extremity edema, and urinary incontinence. These symptoms

may worsen during the day because of an increase in size, likely owing to increased lower limb lymph accumulation as the day progresses.46 Overdistention of the fluid-filled lymphangioleiomyoma may result in rupture and chylous ascites.47 LAM is also associated with an increased frequency of meningioma.48 Early reports of LAM suggested a pessimistic view of survival, with most patients dying within 10 years.36 More recent studies have reported a longer survival; however, this may reflect lead time bias as a consequence of earlier diagnosis.14,49 Some patients with LAM remain stable for years or decades, with only mild ventilatory impairment, whereas others experience rapid disease progression leading to respiratory failure or death within a few years of disease onset.41,50 The rate of decline in lung function tends to be greater in premenopausal women than in postmenopausal women.51 It has been suggested that greater age at presentation and presence of AML were associated with less risk of mortality.14 However, at present, there is still no good way of predicting the prognosis of an individual with LAM because the natural course varies. Clinical features differ slightly among women with S-LAM and patients with TSC-LAM (Table 35.1). Patients with TSC-LAM are more likely to be asymptomatic or to present with gradual onset of dyspnea, whereas patients with S-LAM are more likely to present with a pneumothorax. Chylothoraces occur less commonly in patients with TSC.33 TSC is a disorder with a high penetrance but variable expression. Not all patients have the complete triad of symptoms of

516

SECTION 7  Diffuse Lung Diseases

include right ventricular hypertrophy, pleural adhesions, and chylous effusion.18,41

TABLE 35.1  DIFFERENCES BETWEEN SPORADIC LYMPHANGIOLEIOMYOMATOSIS (S-LAM) AND TUBEROUS SCLEROSIS COMPLEX–ASSOCIATED LYMPHANGIOLEIOMYOMATOSIS (TSC-LAM)

PATHOLOGY

S-LAM

TSC-LAM

TSC-1 gene TSC-2 gene

− +

+ ++

CLINICAL FEATURES Dyspnea Pneumothorax Chylothorax Asymptomatic

++ ++ ++ −

+ + + +

COMPUTED TOMOGRAPHY FEATURES Pulmonary cysts ++ Nodules − Angiomyolipoma + Lymphangioleiomyomas + Lymphadenopathy ++

+ + ++ ++ +

TSC—epileptiform seizure, facial angiofibromas, and mental retardation—because half of all patients are of normal intellect, and a quarter do not have seizures.52 A panel of international experts considered the diagnostic criteria for TSC, recognizing that there are truly no pathognomonic clinical signs for TSC, and a detailed analysis of the hierarchy of clinical and imaging features necessary for a definitive, presumptive, or suspect diagnosis of TSC was undertaken.53 The latest diagnostic criteria consist of major features (e.g., cortical tuber, pulmonary LAM, facial angiofibroma, retinal hamartoma, renal AML) and minor features (e.g., gingival fibroma, hamartomatous rectal polyp, bone cyst).53 A diagnosis of TSC is definite when two major features or one major and two minor features exist, probable if one major and one minor feature are present, and possible when more than two minor features or only one major feature is present.53 When LAM and AML occur in the same patient, however, they should be considered as one major feature of TSC, not two.53 KEY POINTS: CLINICAL PRESENTATION • Dyspnea, fatigue, and pneumothorax are the most common initial manifestations of lymphangioleiomyomatosis (LAM). • Patients with tuberous sclerosis complex–LAM tend to be less symptomatic than patients with sporadic LAM. • Abdominal manifestations occasionally precede the diagnosis of pulmonary LAM.

Pathophysiology ANATOMY On macroscopic examination, lungs affected by LAM are enlarged, with a striking appearance of subpleural blebs. The cut surface shows a honeycombing appearance owing to air-filled or fluidfilled (chylous or serosanguineous) cysts ranging in diameter from millimeters to centimeters.18,40 Axillary, cervical, subclavian, mediastinal, retroperitoneal, and pelvic lymph nodes may be involved in LAM. The nodes are pale and spongy, tan or white.26 The thoracic duct may be enlarged, resembling a spongy sausage-like structure. Other gross findings

Two key microscopic features characterize LAM: cyst formation and proliferation of LAM cells (Fig. 35.4). LAM cells express smooth muscle actin, desmin, and vimentin consistent with a smooth muscle lineage, although they also have features that are not typical of normal muscle cells—electron-dense granules, which contain melanoma-related proteins, including glycoprotein 100 (the target of the antibody HMB45) and tyrosinase and receptors for estrogen and progesterone (see Fig. 35.4).41 LAM lesions express VEGF-C and VEGF-D and often contain an abundance of lymphatic channels lined by vascular endothelial growth factor receptor (VEGFR)-3–expressing endothelial cells.54,55 LAM cells tend to proliferate to form microscopic nodules, the centers of which contain predominantly spindle-shaped LAM cells, which show strong immunoreactivity for actin and focal positivity for melanoma-associated antigens, whereas the periphery comprises larger epithelioid LAM cells, which reveal the opposite phenotypic profile.56 LAM cells typically are found at the edges of the cysts and along pulmonary blood vessels, lymphatics, and bronchioles.24 Involvement of small pulmonary vessels is associated with thickened arterial walls and areas of venous occlusion, resulting in hemorrhage and hemosiderosis.40 In the lymphatics LAM cells form haphazard clumps, leading to thickening of lymphatic walls and, variably, obliteration of the vessel lumen and cystic dilation. Obstruction of lymphatics may cause chylous effusions of the thorax and abdomen. Microscopic examination of involved lymph nodes reveals interlacing bundles of smooth muscle cells with intervening sinuses. Similarly, in thoracic duct and retroperitoneal involvement, anastomosing cords of cells enclosing lined spaces are seen.18 LAM nodules line distal airways, leading to airway inflammation, air-trapping, and bullae and pneumothorax, perhaps by a check-valve mechanism.57,58 It has been suggested that proteolytic enzymes (matrix metalloproteinases) released by the LAM cells play a role in the formation of these cysts, whereas there is no evidence for an imbalance in the α1-antitrypsin system.24 The thin-walled cysts contain foci of LAM nodules covered by hyperplastic type II cells and patches of bronchiolar epithelium.18 Focal proliferations of type II pneumocytes (multifocal micronodular pneumocyte hyperplasia [MMPH]) may occur, almost exclusively, in patients affected by TSC. MMPH has been reported, however, in men and women with and without TSC, in men and women with TSC and LAM, and in women with S-LAM.27,34,59,60 MMPH as a histologic lesion does not seem to be clinically important, although there is one case report of a patient without underlying TSC or S-LAM who died of respiratory failure ascribed to MMPH.60,61 Besides MMPH, the spectrum of pulmonary lesions associated with S-LAM and TSC continues to broaden and now comprises AML, focal clear cell tumors, and micronodular/interstitial proliferation of clear cells, atypical adenomatous hyperplasia, and lepidic adenocarcinoma.56,62–64 In addition, there is an assortment of abdominal lesions, many TSC-related, characterized by the proliferation of LAM cells. These include AML and its morphologic variants (leiomyoma-like AML, lipoma-like AML, oncocytoma-like AML, monotypic epithelioid AML), extrapulmonary clear cell “sugar” tumors, lymphangioleiomyoma, and renal capsuloma.56,65

35  Lymphangioleiomyomatosis and Tuberous Sclerosis

A

517

B Fig. 35.4  Lymphangioleiomyomatosis, microscopic features. (A) Low-power photomicrograph shows several thin-walled cysts within otherwise normal parenchyma. (B) Spindle cells within the cyst wall show patchy but strong staining (brown) for HMB45 in the lesional spindle cells, a feature typical of lymphangioleiomyomatosis.

LUNG FUNCTION Normal spirometry may be present in nearly one-third of patients with S-LAM and in half of patients with TSC-LAM.20 The most frequent abnormalities of pulmonary function in patients with LAM are airflow obstruction, characterized by a reduction in forced expiratory volume in 1 second (FEV1) and the FEV1-to– forced vital capacity ratio, and decreased diffusion capacity for carbon monoxide.19,23,36,57 Abnormalities of gas transfer and FEV1 do not parallel each other, however.57 Fixed and reversible airflow obstruction is thought to be caused by airway dysfunction more than by loss of lung elastic recoil, whereas decreased diffusion capacity for carbon monoxide probably reflects loss of gas exchange area because it is most closely paralleled by the LAM histologic score.57 Restriction or combined restriction and obstruction are frequent functional deficits, particularly in patients with history of pleurodesis.66 Increased total lung capacity and an increased residual volume–to–total lung capacity ratio also are frequent.18 Hypoxemia occurs even in patients with near-normal diffusion capacity for carbon monoxide and FEV1.67 Cardiopulmonary exercise testing uncovers the presence of exercise-induced hypoxemia and assists in grading the severity of disease and may be helpful in determining supplemental oxygen requirements in patients with LAM.67

Fig. 35.5  Sporadic lymphangioleiomyomatosis in a 78-year-old woman with cough and dyspnea. Posteroanterior chest radiograph shows a diffuse reticular pattern with preserved lung volume.

Manifestations of the Disease RADIOGRAPHY The most common radiographic abnormality is a widespread fine reticular or reticulonodular pattern, reflecting the superimposition of the thin-walled cysts (Fig. 35.5).19,35,36,68,69 The chest radiograph is often normal in early disease and in up to 26% of symptomatic patients.23 In general, radiographic abnormalities are subtle and delicate but correlate roughly with disease severity, with more apparent and coarser reticulation and cystic changes in patients with more advanced pulmonary involvement.40 The

reticular pattern is less coarse and prominent than the honeycombing of end-stage interstitial fibrosis. Sometimes linear opacities, analogous to Kerley B lines and representing dilated or obstructed lymphatic channels, can be identified.70,71 Ill-defined or ground-glass opacities may reflect pulmonary hemorrhage, edema, or hyperperfusion of normal residual lung parenchyma. Large nodules and miliary opacities have been described; some of them likely reflect MMPH in patients affected by TSC.60,72–76 Solitary nodules or masses also may represent clear cell sugar tumor, pulmonary AML, or atelectasis.77–79

518

SECTION 7  Diffuse Lung Diseases

Patients with S-LAM and patients with TSC-LAM have similar frequencies of radiographic abnormalities.40,70 Perihilar opacities resulting from pulmonary artery aneurysms and patchy bony sclerosis in the ribs and spine are uncommon manifestations described only in patients with TSC.80,81 Hilar and mediastinal lymphadenopathy is not a radiographic feature of LAM. The distribution of the interstitial opacities tends to be symmetric and diffuse, although a slight predominance at the lower lung zones may be observed.40,82 Lung volumes are normal initially but tend to increase over time, likely because of small airways disease, air-trapping, and cyst formation.58 The combination of delicate reticular opacities and normal or expanded lungs is typical of LAM. The chest radiograph may reveal an unsuspected pneumothorax, with or without underlying parenchymal opacities (see Figs. 35.1 and 35.2).40 The incidence and recurrence rates of secondary spontaneous pneumothorax in LAM are higher than in other chronic pulmonary disorders.83 LAM is a recognized cause of bilateral pneumothoraces and should be a primary differential diagnosis in a woman of childbearing age presenting with bilateral pneumothoraces without an obvious explanation.84 Pleural effusion, typically chylothorax, is another characteristic finding in patients with LAM. The pleural effusions are more often unilateral than bilateral and tend to be large and recurrent (see Fig. 35.2).39 COMPUTED TOMOGRAPHY Pulmonary cysts are the cardinal CT feature of LAM. CT may show cysts even when the chest radiograph appears normal or may reveal a radiographically occult pleural effusion or pneumothorax (see Fig. 35.1).36,40,70,85 Thin-section CT is more sensitive

A

than 5-mm-thick section CT at detecting cysts and assessing their extent and distribution.40,70 The minimum-intensity projection algorithm may be useful for improving visualization and assessment extent of the LAM cysts (Fig. 35.6). The CT appearance of pulmonary LAM is often striking and characteristic (Figs. 35.6 to 35.8; see Fig. 35.1).86 The first challenging step for radiologists is to identify pulmonary changes confidently as cysts per se, particularly because the CT appearances can be similar to centrilobular emphysema as discussed later (Fig. 35.9). Cysts are distributed equally and symmetrically throughout the central and peripheral lung parenchyma (Fig. 35.10; see Figs. 35.6 to 35.8).40,71,85 Either relative apical or basal sparing has been reported, however, and a focal unilateral disease has been described in a patient with TSC-LAM.23,68–70,76 However, in the early stages of the disease, cysts are small, few, and scattered.84,87 The European Respiratory Society guidelines for the diagnosis and management of LAM consider the CT features, respectively, as characteristic of LAM when the cysts’ number is greater than 10, and as compatible with LAM when greater than 2 and less than or equal to 10.88 Lung cysts are generally more extensive in S-LAM than in TSC-LAM (see Table 35.1).45 Cysts may be ovoid or polygonal and may coalesce to form more bizarre shapes, resulting in a diffuse architectural distortion in patients with more severe parenchymal involvement (see Figs. 35.8 and 35.10).40,84 Cysts are usually small, mostly 2 to 20 mm, although cysts of several centimeters may occur.23,40,68,85,89 It has been observed that cysts may decrease in size on expiration, suggesting that they communicate with the airways.90 The mechanism of cyst formation in LAM and the relation of the cysts to small airways disease remain controversial. Oligemic

B Fig. 35.6  Sporadic lymphangioleiomyomatosis in a 38-year-old woman with dyspnea. (A) Coronal thin-section CT image shows scattered thin-walled cysts, randomly distributed throughout both lungs. (B) Coronal minimum-intensity projection reformatted image better demonstrates the lung cysts.

35  Lymphangioleiomyomatosis and Tuberous Sclerosis

A

519

B Fig. 35.7  Sporadic lymphangioleiomyomatosis in a 75-year-old woman with dyspnea. (A) Thin-section CT scan through the upper lobes shows diffuse and relatively uniform size, thin-walled cysts. (B) Coronal reformatted CT image shows the cysts equally and symmetrically distributed throughout the craniocaudal and the central peripheral planes.

B

A

Fig. 35.8  Sporadic lymphangioleiomyomatosis (LAM) in a 62-year-old woman with dyspnea, hemoptysis, and cough. (A) Thin-section CT scan shows relatively severe lung involvement by cysts of various sizes and shapes. Some cysts have thick walls, and pulmonary vessels tend to be at the periphery of the cysts. (B) An area of ground-glass opacity (an occasional finding in LAM) in the right lower lobe is consistent with hemorrhage. (Courtesy Professor M. Zompatori, Radiology, University of Bologna, Italy.)

areas attributable to air-trapping are a very rare finding, being reported in two patients.58,68,91 The lung parenchyma between the cysts is usually normal. Thickening of interlobular septa, thought to represent edema caused by obstruction of pulmonary lymphatics, may be sporadically observed.68,82 Ground-glass opacities have been observed in approximately a quarter of cases in three studies and probably represent foci of pulmonary hemorrhage (see Fig. 35.8).19,23,36,71 Very rarely, small nodules without a pathologic correlate have been reported in S-LAM.40,76,92 By contrast, nodules are a common feature in patients with TSC (Fig. 35.11).45 Franz and colleagues27 have described a pattern of either scattered nodules 3 to 10 mm

in size or numerous miliary nodules 1 to 3 mm in 10 of 23 patients with TSC; pulmonary nodules were more common in patients with pulmonary cysts than in patients without cysts. In a study by Moss and coworkers,93 nodules were found in 2 of 10 men with TSC. Subsequently, multiple ill-defined nodules on CT have been correlated histologically with MMPH, atypical adenomatous hyperplasia, and diffuse interstitial clear cell proliferation, whereas solitary nodules have been correlated with MMPH,50 pulmonary AML,55 or clear cell sugar tumor.a a

References 56, 62, 73, 74, 77, 78.

520

SECTION 7  Diffuse Lung Diseases

Fig. 35.9  Sporadic lymphangioleiomyomatosis in a 56-year-old woman with dyspnea. High-resolution CT scan shows scattered small cystic airspaces, some of which resemble centrilobular emphysema. In a few cysts the walls are hardly visible, and vessels are seen at the periphery of the lesions. Fig. 35.11  Tuberous sclerosis complex–lymphangioleiomyomatosis in a 37-year-old woman. Coronal reformatted CT image shows a right pneumothorax, scattered lung cysts in the lower lobes, and a subsolid nodule in the right upper lobe likely representing multifocal micronodular pneumocyte hyperplasia (arrow).

Fig. 35.10  Severe sporadic lymphangioleiomyomatosis in a 45-year-old woman. Coronal reformatted CT image shows cysts equally and symmetrically distributed throughout the craniocaudal and the central peripheral planes. Cysts in the middle lung zones have coalesced to cause more extensive lung destruction.

Occasionally, a chylous effusion is identified at chest CT on the basis of its relatively low-attenuation (approximately −17 HU) fluid that reflects its fat content.40 More often, the high protein content of chylous effusions results in higher attenuation values, rendering the pleural collections indistinguishable from pleural effusions of other causes.40 CT almost invariably shows pulmonary cysts associated with pneumothorax and chylothorax (see Fig. 35.1), but their occurrence does not necessarily correlate with the extent of lung cysts. Pericardial effusion is a rare finding.23 Fatty foci in the myocardium are frequent in the interventricular septum or left ventricular wall of patients with TSC and pathologically represent unencapsulated fat differentiating them from true

lipomas containing capsules.94 Two case reports have described pulmonary artery aneurysms in patients with TSC.95,96 Although Sherrier and coworkers97 reported lymphadenopathy in four of seven patients, hilar or mediastinal lymphadenopathy seems to be an uncommon finding, being observed in 0% to 6% of cases in larger series.a Supraclavicular, intrathoracic, or retroperitoneal nodes may show low-attenuation areas on CT and marked high intensity on magnetic resonance imaging (MRI) T2-weighted images, suggesting fluid accumulation.98 The four major abdominopelvic abnormalities in patients with S-LAM and in patients with TSC-LAM are renal AML, lymphadenopathy, lymphangioleiomyoma, and chylous ascites.89 They almost invariably occur in association with lung cysts, although solitary extrapulmonary manifestation has been reported.99 Lymphangioleiomyomas are more common in S-LAM, whereas AML are more common in TSC-LAM (see Table 35.1).45 Noncontrast CT depicts the fatty components of AMLs better than sonography (Fig. 35.12).89 Careful focal sampling of the low-attenuation regions within the mass must be performed because the masses frequently are heterogeneous.89 Diagnostic difficulty may arise with the rare instances of AMLs that do not contain fat; these require tissue biopsy to differentiate from renal cell carcinoma. Likewise, hemorrhagic AML may appear as a complex renal mass that may be misdiagnosed as hemorrhagic renal cell cancer.47 This is particularly important because patients with TSC have an increased risk of renal cell carcinoma (1%–2%) and clear cell carcinoma.89,100 In most patients AMLs are located in the kidneys; uncommonly, they have been found in the liver and adrenal glands.101 It has been observed that the prevalence of abdominal lymphadenopathy increases with the severity of lung disease.89 Lymphangioleiomyomas are usually located along the axial lymphatics in the thorax and abdomen, retroperitoneum around a

References 19, 23, 36, 40, 68, 82, 97.

35  Lymphangioleiomyomatosis and Tuberous Sclerosis

521

R

Fig. 35.12  Incidentally discovered lymphangioleiomyomatosis (LAM) in a 62-year-old woman who underwent abdominal CT for evaluating a left renal mass detected by ultrasound. Coronal reformatted CT of the upper abdomen shows a 4-cm mass (red circle) arising from the lower pole of the left kidney; the zoomed axial image, reformatted with a soft tissue window setting, better defines the fat and soft tissue–containing mass (red arrow), consistent with an angiomyolipoma. Note small lung cysts in both lower lobes (white arrows), suggesting LAM.

the aorta, renal and superior mesenteric arteries, and pelvic region.46 They contain elements of water density, but their characteristics are nonspecific, and they are often similar in appearance to malignant abdominal and pelvic masses, such as lymphoma and ovarian cancer (see Fig. 35.3). Visualization of diurnal variation in lymphangioleiomyomas, on either sonography or CT, excludes a diagnosis of malignancy and avoids the need for biopsy.102 Furthermore, the decreasing volume of the lymphangioleiomyomas during the fasting state represents another diagnostic clue.46 Sclerotic osseous lesions represent another extrapulmonary finding. They are often round in shape and range in size from 0.2 to 3.2 cm. They do not expand the bone or deform or extend beyond the cortex. They are more numerous in TSC-LAM than in S-LAM. It was shown, the presence of four or more sclerotic osseous lesions at whole-body CT differentiates patients with S-LAM from those with TSC-LAM or TSC, with high sensitivities and specificity.103 Of importance, this observation suggests that any patient with LAM who is found to have multiple sclerotic bone lesions at CT should have a complete evaluation for TSC. CT not only has a key diagnostic role but is also useful in assessing the severity of the disease and identifying complications. In general, the size of the cysts tends to be larger in more severe disease (see Figs. 35.8 and 35.10).40,85,89 In a study by Müller and associates,85 parenchymal involvement of less than 25% generally correlated with cysts measuring less than 0.5 to 1 cm, disease involving 25% to 80% of the lung correlated with cysts measuring 0.5 to 1 cm, and disease involving greater than 80% of the lung correlated with cysts measuring greater than 1 cm. The correlation between the extent of cysts on CT and the severity of symptoms seems to be unpredictable, however.20,69 A subjective scoring method and quantitative thresholding technique provide measures of parenchymal disease extent that correlate directly with pulmonary function tests.69,85,89,104,105 The prognostic value of CT will likely improve with the use of computer grading of the severity of disease based on texture patterns. It was shown that

Fig. 35.13  Lymphangioleiomyomatosis with history of chemical pleurodesis in a 41-year-old woman. Axial CT image shows a calcified left pleural mass and high attenuation right pleural thickening located anteriorly and posteriorly secondary to the pleurodesis.

texture-based objective quantitative CT analysis correlated with subjective assessment, pulmonary functions, and progression of disease over time.106 Because of the high frequency of pleurodesis secondary to recurrent pneumothorax, an awareness of consequent CT findings is useful for the correct interpretation of pleural abnormalities in these patients.107 Pleural abnormalities consist of pleural thickening, pleural effusion, loculated effusion, pneumothorax, focal or continuous plaque of high attenuation (probably caused by dystrophic calcification of the inflamed pleura after installation of talc or other sclerosing agents), and masses resulting from confluent fibrotic tissue or consistent with round atelectasis (Fig. 35.13).107 An awareness of the posttransplantation imaging features also is mandatory for radiologists who work in lung transplantation centers. In addition to common transplant-related complications, morbidity is usually due to underlying disease.13,108 LAM-related complications include native lung pneumothorax, chylothorax, chylous ascites, complications from renal AMLs, and recurrent LAM that might be evident only in lymph node sites.108,109 A study of transplanted lungs with recurrent LAM has suggested metastatic spread of LAM cells to the graft from residual LAM tissue.3 IMAGING ALGORITHMS The initial imaging modality used to evaluate patients with suspected LAM is the chest radiograph. If clinical data or chest radiography findings or both are supportive of LAM (young nonsmoking woman with unexplained pneumothoraces, chylous effusions, or obstructive functional impairment), a high-resolution CT study is indicated and may be supplemented, especially if TSC is suspected, with whole-body CT or MRI. The presence of a characteristic CT scan in the absence of extrapulmonary findings is not diagnostic of LAM.110 Therefore it is important to extend the chest CT scan down through the kidneys when evaluating patients with suspected LAM, and, conversely, it is important to carefully inspect the basal lung

522

SECTION 7  Diffuse Lung Diseases

parenchyma for lung cysts on abdominal CT scans performed for renal AML evaluation (see Fig. 35.12). There is less certainty as to whether patients with known TSC should be screened for pulmonary LAM.28,88,93 The European Respiratory Society LAM task force recommends chest CT screening for females with TSC at the age of 18 years and, if negative, again at 30 to 40 years of age. If persistent respiratory symptoms develop, scanning should be performed as clinically appropriate.88 CLASSIC SIGNS • The CT appearances of sporadic lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC)-LAM are similar, consisting of scattered, bilateral, thin-walled cysts without a zonal predominance. • Surrounding parenchyma is usually normal, but occasionally ground-glass opacities or interlobular septal thickening may be observed, usually representing foci of pulmonary hemorrhage. • Spontaneous, often recurrent pneumothorax is the initial manifestation in half of patients. • Angiomyolipoma is often associated with LAM. • Chylous pleural effusion is more common in sporadic LAM and affects 14% of patients at presentation. • Sclerotic osseous lesions, intramyocardial fat, and pulmonary nodules are more common with TSC-LAM.

Differential Diagnosis The diagnosis of LAM may be delayed by 5 years after the onset of symptoms because it is often confused with more common lung disorders, such as asthma or chronic obstructive pulmonary disease.111–113 The radiologist may be the first to suggest the diagnosis of LAM. On chest radiography the combination of a delicate reticular pattern and hyperexpansion of the lungs is typical of LAM, in contrast to the progressive loss of volume of most other fibrosing interstitial disorders. Such a combination may also occur in a few other conditions, including pulmonary Langerhans cell histiocytosis, sarcoidosis, and, rarely, hypersensitivity pneumonitis. LAM can be confidently and correctly diagnosed in most cases on CT.114,115 In some cases the distinction between LAM and centrilobular emphysema may present difficulties, particularly when centrilobular emphysema takes on a “cyst-like” morphology.111 In LAM cysts are variably demarcated by a thin wall that ranges from invisible44,47 to nearly 2-mm thick in most cases; as a rule, cyst walls are exquisitely thin. Vessels are seen at the periphery of the cysts and generally are not displaced (see Fig. 35.9), as is often the case in centrilobular and bullous emphysema. LAM cysts do not contain a “dot-like” centrilobular core structure.111,116 Indeed, identification of residual core lobular structures in the center of “cysts,” typical of emphysema, may be helpful in differentiating these conditions. Other cystic lung diseases occasionally may be confused with LAM, particularly pulmonary Langerhans cell histiocytosis. In pulmonary Langerhans cell histiocytosis, cavitating nodules are present, particularly in the early stages of the disease, and the resulting cysts are more irregular with thicker walls and tend to occur predominantly in the upper and middle lung zones, sparing the costophrenic sulci. Nevertheless, advanced pulmonary Langerhans cell histiocytosis, when the distribution characteristics are less obvious, may be difficult to distinguish from severe LAM. Even neoplastic lesions, such as multiple mesenchymal cystic hamartomas, benign metastasizing leiomyoma, and metastases

from primary squamous cell carcinoma, occasionally can be confused with LAM, although these cystic lesions generally have thicker walls, are associated with solid nodules, and tend to be less numerous.111,112 Birt-Hogg-Dubé syndrome (BHDS) is an autosomal-dominant inherited genodermatosis stemming from a defect in the folliculin gene that has to be differentiated from LAM.117 The two diseases have similar radiologic manifestations, including pulmonary cysts, pneumothorax, and renal tumors. In contrast to LAM cysts, the cysts in BHD are less numerous, larger in size, oval in shape, and tend to predominantly involve the lower lung zones, particularly the paracardial regions. Furthermore, patients with BHDS often report family history of pneumothorax.117 Usually, the clinical history and other parenchymal features rule out more easily the possibility of lymphoid interstitial pneumonia, usual interstitial pneumonia, and Pneumocystis jirovecii pneumonia. KEY POINTS: DIFFERENTIAL DIAGNOSIS • The absence of residual core lobular structures and the presence of vessels at the periphery of thin walls suggest lymphangioleiomyomatosis (LAM) instead of centrilobular emphysema. • Cavitating nodules and cysts sparing the costophrenic sulci occur in Langerhans cell histiocytosis, not in LAM. • LAM cysts are more numerous and smaller than those associated with Birt-Hogg-Dubé syndrome. DIAGNOSTIC CRITERIA • Diagnosis of tuberous sclerosis complex (TSC) should be made according to established criteria.53 It is usually made clinically by recognition of the somatic features; imaging plays a pivotal role in detection of associated pulmonary or extrapulmonary pathology. • It is important to consider sporadic LAM or TSC-LAM in a young or middle-aged woman who presents with pneumothorax, dyspnea, or obstructive lung disease. • Biopsy confirmation of LAM is not required when the CT appearance is characteristic in a patient with known TSC or when pulmonary cysts are associated with other typical manifestations (i.e., angiomyolipoma [AML]), lymphangioleiomyoma, chylous pleural effusion, or chylous ascites).41,118 • Vascular endothelial growth factor (VEGF)-D testing is recommended to establish the diagnosis of LAM before proceeding to lung biopsy in patients whose CT scan shows abnormalities characteristic of LAM but who have no other confirmatory clinical or extrapulmonary radiologic features of LAM.118 • Elevated VEGF-D level has a sufficient positive predictive value for use as a diagnostic test for LAM. When used in combination with the European Respiratory Society diagnostic criteria, 80% of patients could avoid lung biopsy for diagnosis.17,88 • The gold standard for the diagnosis of LAM is thoracoscopic lung biopsy. In patients unable to undergo a thoracoscopic lung biopsy, the diagnosis can be made on the basis of a transbronchial biopsy, especially in conjunction with immunohistochemical staining with HMB45.88 • All patients with LAM should undergo a careful clinical examination for stigmata of TSC. The diagnosis of TSC is often difficult because an increasing number of patients with mild disease are being identified in adulthood, including some with LAM as the initial manifestation. • All patients with LAM or suspected LAM should have an abdominal and pelvis CT at diagnosis or during workup to identify AML and other abdominal lesions. Brain imaging is recommended for all patients with TSC and in women with sporadic LAM before treatment with progesterone. Patients with TSC should undergo annual brain MRI studies until 21 years of age and then every 2–3 years to diagnose and monitor giant cell tumors.84

35  Lymphangioleiomyomatosis and Tuberous Sclerosis

SUGGESTED READINGS Abbott GF, Rosado de Christenson ML, Frazier AA, et al. From the archives of the AFIP: lymphangioleiomyomatosis: radiologic-pathologic correlation. Radiographics. 2005;25:803–828. Avila N, Dwyer AJ, Moss J. Imaging features of lymphangioleiomyomatosis: diagnostic pitfalls. AJR Am J Roentgenol. 2011;196:982–986. Gupta N, Meraj R, Tanase D. Accuracy of chest high-resolution computed tomography in diagnosing diffuse cystic lung diseases. Eur Respir J. 2015;46:1196–1199. Hancock E, Osborne J. Lymphangioleiomyomatosis: a review of the literature. Respir Med. 2002;96:1–6. Johnson SR. Lymphangioleiomyomatosis. Eur Respir J. 2006;27:1056–1065. Johnson SR, Cordier JF, Lazor R, et al. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J. 2010;35:14–26. McCormack FX. Lymphangioleiomyomatosis. Medgenmed. 2006;8:15. McCormack FX, Gupta N, Finlay GR, et al. Official American Thoracic Society/ Japanese Respiratory Society Clinical Practice Guidelines: lymphangioleiomyomatosis diagnosis and management. Am J Respir Crit Care Med. 2016;194:748–761.

523

Pacheco-Rodriguez G, Kristof AS, Stevens LA, et al. Filley Lecture. Genetics and gene expression in lymphangioleiomyomatosis. Chest. 2002;121:56–60. Pallisa E, Sanz P, Roman A, et al. Lymphangioleiomyomatosis: pulmonary and abdominal findings with pathologic correlation. Radiographics. 2002;22: S185–S198. Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. J Child Neurol. 2004;19:643–649. Tobino K, Hirai T, Johkoh T, et al. Differentiation between Birt-Hogg-Dubé syndrome and lymphangioleiomyomatosis: quantitative analysis of pulmonary cysts on computed tomography of the chest in 66 females. Eur J Radiol. 2012;81:1340–1346.

The full reference list for this chapter is available at ExpertConsult.com.

35  Lymphangioleiomyomatosis and Tuberous Sclerosis 523.e1

REFERENCES 1. Taveira-DaSilva AM, Moss J. Clinical features, epidemiology, and therapy of lymphangioleiomyomatosis. Clin Epidemiol. 2015;7:249–257. 2. McCormack FX, Travis WD, Colby TV, Henske EP, Moss J. Lymphangioleiomyomatosis: calling it what it is: a low-grade, destructive, metastasizing neoplasm. Am J Respir Crit Care Med. 2012;186(12):1210–1212. 3. Karbowniczek M, Astrinidis A, Balsara BR, et al. Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a metastatic mechanism. Am J Respir Crit Care Med. 2003;167(7):976–982. 4. Bittmann I, Rolf B, Amann G, Lohrs U. Recurrence of lymphangioleiomyomatosis after single lung transplantation: new insights into pathogenesis. Hum Pathol. 2003;34(1):95–98. 5. Cohen MM, Pollock-BarZiv S, Johnson SR. Emerging clinical picture of lymphangioleiomyomatosis. Thorax. 2005;60(10):875–879. 6. Lonergan GJ, Smirniotopoulos JG. Case 64: tuberous sclerosis. Radiology. 2003;229(2):385–388. 7. Strizheva GD, Carsillo T, Kruger WD, Sullivan EJ, Ryu JH, Henske EP. The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis. Am J Respir Crit Care Med. 2001;163(1): 253–258. 8. Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA. 2000;97(11):6085–6090. 9. Valensi QJ. Pulmonary lymphangiomyoma, a probable forme frust of tuberous sclerosis. A case report and survey of the literature. Am Rev Respir Dis. 1973;108(6):1411–1415. 10. Whale CI. Lymphangioleiomyomatosis: a case-control study of perinatal and early life events. Thorax. 2003;58(11):979–982. 11. Gupta N, Vassallo R, Wikenheiser-Brokamp KA, McCormack FX. Diffuse cystic lung disease. Part I. Am J Respir Crit Care Med. 2015;191(12):1354–1366. 12. McCormack FX, Inoue Y, Moss J, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011;364(17):1595–1606. 13. Ussavarungsi K, Hu X, Scott JP, et al. Mayo clinic experience of lung transplantation in pulmonary lymphangioleiomyomatosis. Respir Med. 2015;109(10):1354–1359. 14. Oprescu N, McCormack FX, Byrnes S, Kinder BW. Clinical predictors of mortality and cause of death in lymphangioleiomyomatosis: a populationbased registry. Lung. 2013;191(1):35–42. 15. Yu J, Henske EP. mTOR activation, lymphangiogenesis, and estrogen-mediated cell survival: the “perfect storm” of pro-metastatic factors in LAM pathogenesis. Lymphat Res Biol. 2010;8(1):43–49. 16. Seyama K, Kumasaka T, Souma S, et al. Vascular endothelial growth factor-D is increased in serum of patients with lymphangioleiomyomatosis. Lymphat Res Biol. 2006;4(3):143–152. 17. Young L, Lee HS, Inoue Y, et al. Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. Lancet Respir Med. 2013;1(6):445–452. 18. Kelly J, Moss J. Lymphangioleiomyomatosis. Am J Med Sci. 2001;321(1): 17–25. 19. Urban T, Lazor R, Lacronique J, et al. Pulmonary lymphangioleiomyomatosis. A study of 69 patients. Groupe d’Études et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM“O”P). Medicine (Baltimore). 1999;78(5): 321–337. 20. Ryu JH, Moss J, Beck GJ, et al. The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med. 2006;173(1):105–111. 21. McCormack FX. Lymphangioleiomyomatosis. Medgenmed. 2006;8(1):15. 22. Harknett EC, Chang WY, Byrnes S, et al. Use of variability in national and regional data to estimate the prevalence of lymphangioleiomyomatosis. QJM. 2011;104(11):971–979. 23. Chu SC. Comprehensive evaluation of 35 patients with lymphangioleiomyomatosis. Chest. 1999;115(4):1041. 24. Ferrans VJ, Yu ZX, Nelson WK, et al. Lymphangioleiomyomatosis (LAM): a review of clinical and morphological features. J Nippon Med Sch. 2000;67(5):311–329. 25. Maria BL, Deidrick KM, Roach ES, Gutmann DH. Tuberous sclerosis complex: pathogenesis, diagnosis, strategies, therapies, and future research directions. J Child Neurol. 2004;19(9):632–642. 26. Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008;372(9639):657–668. 27. Franz DN, Brody A, Meyer C, et al. Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med. 2001;164(4):661–668.

28. Adriaensen ME, Schaefer-Prokop CM, Duyndam DA, Zonnenberg BA, Prokop M. Radiological evidence of lymphangioleiomyomatosis in female and male patients with tuberous sclerosis complex. Clin Radiol. 2011; 66(7):625–628. 29. Costello LC, Hartman TE, Ryu JH. High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex. Mayo Clin Proc. 2000;75(6):591–594. 30. Ryu JH, Sykes AM, Lee AS, Burger CD. Cystic lung disease is not uncommon in men with tuberous sclerosis complex. Respir Med. 2012;106(11): 1586–1590. 31. Sandrini A, Krishnan A, Yates DH. S-LAM in a man: the first case report. Am J Respir Crit Care Med. 2008;177(3):356; author reply 357. 32. McCormack FX, Moss J. S-LAM in a man? Am J Respir Crit Care Med. 2007;176(1):3–5. 33. Hancock E, Osborne J. Lymphangioleiomyomatosis: a review of the literature. Respir Med. 2002;96(1):1–6. 34. Aubry MC, Myers JL, Ryu JH, et al. Pulmonary lymphangioleiomyomatosis in a man. Am J Respir Crit Care Med. 2000;162(2 Pt 1):749–752. 35. Taylor JR, Ryu J, Colby TV, Raffin TA. Lymphangioleiomyomatosis. Clinical course in 32 patients. N Engl J Med. 1990;323(18):1254–1260. 36. Kitaichi M, Nishimura K, Itoh H, Izumi T. Pulmonary lymphangioleiomyomatosis: a report of 46 patients including a clinicopathologic study of prognostic factors. Am J Respir Crit Care Med. 1995;151(2 Pt 1):527–533. 37. Almoosa KF, Ryu JH, Mendez J, et al. Management of pneumothorax in lymphangioleiomyomatosis: effects on recurrence and lung transplantation complications. Chest. 2006;129(5):1274–1281. 38. Hagaman JT, Schauer DP, McCormack FX, Kinder BW. Screening for lymphangioleiomyomatosis by high-resolution computed tomography in young, nonsmoking women presenting with spontaneous pneumothorax is cost-effective. Am J Respir Crit Care Med. 2010;181(12):1376–1382. 39. Ryu JH. Chylothorax in lymphangioleiomyomatosis. Chest. 2003;123(2): 623–627. 40. Abbott GF, Rosado-de-Christenson ML, Frazier AA, Franks TJ, Pugatch RD, Galvin JR. From the archives of the AFIP: lymphangioleiomyomatosis: radiologic-pathologic correlation. Radiographics. 2005;25(3):803–828. 41. Johnson SR. Lymphangioleiomyomatosis. Eur Respir J. 2006;27(5):1056– 1065. 42. Pacheco-Rodriguez G. Genetics and gene expression in lymphangioleiomyomatosis. Chest. 2002;121(suppl 3):56S. 43. Cottin V, Harari S, Humbert M, et al. Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in 20 patients. Eur Respir J. 2012;40(3): 630–640. 44. Matsui K, Tatsuguchi A, Valencia J, et al. Extrapulmonary lymphangioleiomyomatosis (LAM): clinicopathologic features in 22 cases. Hum Pathol. 2000;31(10):1242–1248. 45. Avila NA, Dwyer AJ, Rabel A, Moss J. Sporadic lymphangioleiomyomatosis and tuberous sclerosis complex with lymphangioleiomyomatosis: comparison of CT features. Radiology. 2007;242(1):277–285. 45a.  Avila NA, Kelly JA, Chu SC, Dwyer AJ, Moss J. Lymphangioleiomyomatosis: abdominopelvic CT and US findings. Radiology. 2000;216(1):147–153. 46. Taveira-DaSilva AM, Jones AM, Julien-Williams P, et al. Effect of fasting on the size of lymphangioleiomyomas in patients with lymphangioleiomyomatosis. Chest. 2015;148(4):1027–1033. 47. Avila NA, Dwyer AJ, Moss J. Imaging features of lymphangioleiomyomatosis: diagnostic pitfalls. AJR Am J Roentgenol. 2011;196(4):982–986. 48. Moss J, DeCastro R, Patronas NJ, Taveira-DaSilva A. Meningiomas in lymphangioleiomyomatosis. JAMA. 2001;286(15):1879–1881. 49. Johnson SR, Whale CI, Hubbard RB, Lewis SA, Tattersfield AE. Survival and disease progression in UK patients with lymphangioleiomyomatosis. Thorax. 2004;59(9):800–803. 50. Lazor R, Valeyre D, Lacronique J, Wallaert Bt, Urban T, Cordier J-F. Low initial KCO predicts rapid FEV1 decline in pulmonary lymphangioleiomyomatosis. Respir Med. 2004;98(6):536–541. 51. Taveira-DaSilva AM, Stylianou MP, Hedin CJ, Hathaway O, Moss J. Decline in lung function in patients with lymphangioleiomyomatosis treated with or without progesterone. Chest. 2004;126(6):1867–1874. 52. O’Callaghan FJ, Osborne JP. Advances in the understanding of tuberous sclerosis. Arch Dis Child. 2000;83(2):140–142. 53. Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. J Child Neurol. 2004;19(9):643–649. 54. Kumasaka T, Seyama K, Mitani K, et al. Lymphangiogenesis in lymphangioleiomyomatosis: its implication in the progression of lymphangioleiomyomatosis. Am J Surg Pathol. 2004;28(8):1007–1016. 55. Kumasaka T, Seyama K, Mitani K, et al. Lymphangiogenesis-mediated shedding of LAM cell clusters as a mechanism for dissemination in lymphangioleiomyomatosis. Am J Surg Pathol. 2005;29(10):1356–1366.

523.e2

SECTION 7  Diffuse Lung Diseases

56. Pileri SA, Cavazza A, Schiavina M, et al. Clear-cell proliferation of the lung with lymphangioleiomyomatosis-like change. Histopathology. 2004;44(2): 156–163. 57. Taveira-DaSilva AM, Hedin C, Stylianou MP, et al. Reversible airflow obstruction, proliferation of abnormal smooth muscle cells, and impairment of gas exchange as predictors of outcome in lymphangioleiomyomatosis. Am J Respir Crit Care Med. 2001;164(6):1072–1076. 58. Stern EJ, Webb WR, Golden JA, Gamsu G. Cystic lung disease associated with eosinophilic granuloma and tuberous sclerosis: air trapping at dynamic ultrafast high-resolution CT. Radiology. 1992;182(2):325–329. 59. Popper HH. Micronodular hyperplasia of type II pneumocytes. Histopathology. 1992;20(3):281. 60. Muir TE, Leslie KO, Popper H, et al. Micronodular pneumocyte hyperplasia. Am J Surg Pathol. 1998;22(4):465–472. 61. Cancellieri A, Poletti V, Corrin B. Respiratory failure due to micronodular type II pneumocyte hyperplasia. Histopathology. 2002;41(3):263–265. 62. Hironaka M, Fukayama M. Regional proliferation of HMB-45-positive clear cells of the lung with lymphangioleiomyomatosislike distribution, replacing the lobes with multiple cysts and a nodule. Am J Surg Pathol. 1999;23(10):1288–1293. 63. Cho HH, Shim SS, Kim Y, Han WS. Sporadic lymphangioleiomyomatosis with multiple atypical adenomatoid hyperplasia: differentiation from multifocal micronodular pneumocyte hyperplasia. Clin Radiol. 2010;65(9): 765–767. 64. Carneiro C, Gupta N. Broncheoalveolar carcinoma associated with pulmonary lymphangioleiomyomatosis and tuberous sclerosis complex: case report. Clin Imaging. 2011;35(3):225–227. 65. Tazelaar HD, Batts KP, Srigley JR. Primary extrapulmonary sugar tumor (PEST): a report of four cases. Mod Pathol. 2001;14(6):615–622. 66. Avila NA, Kelly JA, Dwyer AJ, Johnson DL, Jones EC, Moss J. Lymphangioleiomyomatosis: correlation of qualitative and quantitative thin-section CT with pulmonary function tests and assessment of dependence on pleurodesis. Radiology. 2002;223(1):189–197. 67. Taveira-DaSilva AM, Stylianou MP, Hedin CJ, et al. Maximal oxygen uptake and severity of disease in lymphangioleiomyomatosis. Am J Respir Crit Care Med. 2003;168(12):1427–1431. 68. Kirchner J, Stein A, Viel K, et al. Pulmonary lymphangioleiomyomatosis: high-resolution CT findings. Eur Radiol. 1999;9(1):49–54. 69. Aberle DR, Hansell DM, Brown K, Tashkin DP. Lymphangiomyomatosis: CT, chest radiographic, and functional correlations. Radiology. 1990;176(2): 381–387. 70. Lenoir S, Grenier P, Brauner MW, et al. Pulmonary lymphangiomyomatosis and tuberous sclerosis: comparison of radiographic and thin-section CT findings. Radiology. 1990;175(2):329–334. 71. Pallisa E, Sanz P, Roman A, Majo J, Andreu J, Caceres J. Lymphangioleiomyomatosis: pulmonary and abdominal findings with pathologic correlation. Radiographics. 2002;22:S185–S198. 72. Ristagno RL, Biddinger PW, Pina EM, Meyer CA. Multifocal micronodular pneumocyte hyperplasia in tuberous sclerosis. AJR Am J Roentgenol. 2005;184(suppl 3):S37–S39. 73. Rossi G, Cavazza A, Casali C, Cesinaro AM, Cinquantini F, Morandi U. Tuberous sclerosis complex presenting as a pulmonary solitary nodule. Histopathology. 2006;48(6):769–771. 74. Kamiya H, Shinoda K, Kobayashi N, et al. Tuberous sclerosis complex complicated by pulmonary multinodular shadows. Intern Med. 2006;45(5): 275–278. 75. Suzuki K, Tanaka H, Shiratori M, et al. Pulmonary lymphangioleiomyomatosis; unusual radiological manifestation of multiple large nodules. Intern Med. 2002;41(10):879–882. 76. Keyzer C, Bankier AA, Remmelinck M, Gevenois PA. Pulmonary lymphangiomyomatosis mimicking Langerhans cell histiocytosis. J Thorac Imaging. 2001;16(3):185–187. 77. Flieder DB, Travis WD. Clear cell “sugar” tumor of the lung: association with lymphangioleiomyomatosis and multifocal micronodular pneumocyte hyperplasia in a patient with tuberous sclerosis. Am J Surg Pathol. 1997;21(10):1242–1247. 78. Wu K, Tazelaar HD. Pulmonary angiomyolipoma and multifocal micronodular pneumocyte hyperplasia associated with tuberous sclerosis. Hum Pathol. 1999;30(10):1266–1268. 79. Kishi K, Homma S, Miyamoto A, et al. Rounded atelectasis associated with pulmonary lymphangioleiomyomatosis. Intern Med. 2005;44(6):625– 627. 80. Burrows NJ, Johnson SR. Pulmonary artery aneurysm and tuberous sclerosis. Thorax. 2004;59(1):86. 81. Halabi S. Progressive dyspnea in a 49-year-old woman with long-standing epilepsy. Chest. 2002;122(1):352–355.

82. Lim KE, Tsai YH, Hsu Yl Y, Hsu Wc W. Pulmonary lymphangioleiomyomatosis. High-resolution CT findings in 11 patients and compared with the literature. Clin Imaging. 2004;28(1):1–5. 83. Almoosa KF, McCormack FX, Sahn SA. Pleural disease in lymphangioleiomyomatosis. Clin Chest Med. 2006;27(2):355–368. 84. Trotman-Dickenson B. Cystic lung disease: achieving a radiologic diagnosis. Eur J Radiol. 2014;83(1):39–46. 85. Müller NL, Chiles C, Kullnig P. Pulmonary lymphangiomyomatosis: correlation of CT with radiographic and functional findings. Radiology. 1990;175(2):335–339. 86. Gupta N, Meraj R, Tanase D, et al. Accuracy of chest high-resolution computed tomography in diagnosing diffuse cystic lung diseases. Eur Respir J. 2015;46(4):1196–1199. 87. Theilig D, Doellinger F, Kuhnigk JM, et al. Pulmonary lymphangioleiomyomatosis: analysis of disease manifestation by region-based quantification of lung parenchyma. Eur J Radiol. 2015;84(4):732–737. 88. Johnson SR, Cordier JF, Lazor R, et al. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J. 2010;35(1):14–26. 89. Avila NA, Chen CC, Chu SC, et al. Pulmonary lymphangioleiomyomatosis: correlation of ventilation-perfusion scintigraphy, chest radiography, and CT with pulmonary function tests. Radiology. 2000;214(2):441–446. 90. Worthy SA, Brown MJ, Müller NL. Technical report: cystic air spaces in the lung: change in size on expiratory high-resolution CT in 23 patients. Clin Radiol. 1998;53(7):515–519. 91. Gupta N, Han MK, McCormack FX. Regional sparing in an oligemic lung segment supports hematogenous spread as a pathogenic mechanism in lymphangioleiomyomatosis. Ann Am Thorac Soc. 2015;12(8):1247–1248. 92. Xu KF, Zhang W, Liu H. Miliary pulmonary lymphangioleiomyomatosis. Am J Respir Crit Care Med. 2013;187(8):e15. 93. Moss J, Avila NA, Barnes PM, et al. Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med. 2001;164(4):669–671. 94. Adriaensen ME, Schaefer-Prokop CM, Duyndam DA, Zonnenberg BA, Prokop M. Fatty foci in the myocardium in patients with tuberous sclerosis complex: common finding at CT. Radiology. 2009;253(2):359–363. 95. Burrows NJ. Pulmonary artery aneurysm and tuberous sclerosis. Thorax. 2004;59(1):86. 96. Carette MF, Antoine M, Bazelly B, Cadranel J, Khalil A. Primary pulmonary artery aneurysm in tuberous sclerosis: CT, angiography and pathological study. Eur Radiol. 2006;16(10):2369–2370. 97. Sherrier RH, Chiles C, Roggli V. Pulmonary lymphangioleiomyomatosis: CT findings. AJR Am J Roentgenol. 1989;153(5):937–940. 98. Kamitani T, Yabuuchi H, Soeda H, et al. A case of lymphangioleiomyomatosis affecting the supraclavicular lymph nodes. J Comput Assist Tomogr. 2006;30(2):279–282. 99. Possekel AK, Katenkamp D, Brambs HJ, Pauls S. Lymphangioleiomyomatosis: solitary abdominal manifestation (2009: 9b). Eur Radiol. 2009;19(12): 3015–3018. 100. Zimmerhackl LB, Rehm M, Kaufmehl K, Kurlemann G, Brandis M. Renal involvement in tuberous sclerosis complex: a retrospective survey. Pediatr Nephrol. 1994;8(4):451–457. 101. Sutter R, Boehler A, Willmann JK. Adrenal angiomyolipoma in lymphangioleiomyomatosis. Eur Radiol. 2007;17(2):565–566. 102. Avila NA, Dwyer AJ, Murphy-Johnson DV, Brooks P, Moss J. Sonography of lymphangioleiomyoma in lymphangioleiomyomatosis: demonstration of diurnal variation in lesion size. AJR Am J Roentgenol. 2005;184(2): 459–464. 103. Avila NA, Dwyer AJ, Rabel A, Darling T, Hong CH, Moss J. CT of sclerotic bone lesions: imaging features differentiating tuberous sclerosis complex with lymphangioleiomyomatosis from sporadic lymphangioleiomymatosis. Radiology. 2010;254(3):851–857. 104. Crausman RS, Lynch DA, Mortenson RL, et al. Quantitative CT predicts the severity of physiologic dysfunction in patients with lymphangioleiomyomatosis. Chest. 1996;109(1):131–137. 105. Schmithorst VJ, Altes TA, Young LR, et al. Automated algorithm for quantifying the extent of cystic change on volumetric chest CT: initial results in lymphangioleiomyomatosis. AJR Am J Roentgenol. 2009;192(4):1037– 1044. 106. Yao J, Avila N, Dwyer A, Taveira-Dasilva AM, Hathaway OM, Moss J. Computer-aided grading of lymphangioleiomyomatosis (LAM) using HRCT. Proc IAPR Int Conf Pattern Recogn. 2008;2008(8–11 Dec. 2008):1–4. 107. Avila NA, Dwyer AJ, Rabel A, DeCastro RM, Moss J. CT of pleural abnormalities in lymphangioleiomyomatosis and comparison of pleural findings after different types of pleurodesis. AJR Am J Roentgenol. 2006;186(4): 1007–1012.

35  Lymphangioleiomyomatosis and Tuberous Sclerosis 523.e3 108. Boehler A, Speich R, Russi EW, Weder W. Lung transplantation for lymphangioleiomyomatosis. N Engl J Med. 1996;335(17):1275–1280. 109. Collins J, Müller NL, Kazerooni EA, McAdams HP, Leung AN, Love RB. Lung transplantation for lymphangioleiomyomatosis: role of imaging in the assessment of complications related to the underlying disease. Radiology. 1999;210(2):325–332. 110. Chang WY, Cane JL, Blakey JD, Kumaran M, Pointon KS, Johnson SR. Clinical utility of diagnostic guidelines and putative biomarkers in lymphangioleiomyomatosis. Respir Res. 2012;13:34. 111. Beddy P, Babar J, Devaraj A. A practical approach to cystic lung disease on HRCT. Insights Imaging. 2011;2(1):1–7. 112. Raoof S, Bondalapati P, Vydyula R, et al. Cystic lung diseases: algorithmic approach. Chest. 2016;150:945–965. 113. Seaman DM, Meyer CA, Gilman MD, McCormack FX. Diffuse cystic lung disease at high-resolution CT. AJR Am J Roentgenol. 2011;196(6):1305–1311. 114. Koyama M, Johkoh T, Honda O, et al. Chronic cystic lung disease: diagnostic accuracy of high-resolution CT in 92 patients. AJR Am J Roentgenol. 2003;180(3):827–835.

115. Bonelli FS, Hartman TE, Swensen SJ, Sherrick A. Accuracy of high-resolution CT in diagnosing lung diseases. AJR Am J Roentgenol. 1998;170(6): 1507–1512. 116. Hansell DM, Bankier AA, MacMahon H, McLoud TC, Müller NL, Remy J. Fleischner Society: glossary of terms for thoracic imaging. Radiology. 2008;246(3):697–722. 117. Tobino K, Hirai T, Johkoh T, et al. Differentiation between Birt-Hogg-Dubé syndrome and lymphangioleiomyomatosis: quantitative analysis of pulmonary cysts on computed tomography of the chest in 66 females. Eur J Radiol. 2012;81(6):1340–1346. 118. McCormack FX, Gupta N, Finlay GR, et al. Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: lymphangioleiomyomatosis diagnosis and management. Am J Respir Crit Care Med. 2016;194(6):748–761.

36 

Idiopathic Pleuroparenchymal Fibroelastosis ROBERT M. DEWITT  |  STEPHEN K. FRANKEL

Amitani and colleagues1 first described a unique pattern of upper lobe–predominant, idiopathic pulmonary fibrosis (IPF) in 13 patients in the Japanese literature in 1992. The currently preferred term in the English-language literature, idiopathic pleuroparenchymal fibroelastosis (iPPFE), was coined by Frankel and colleagues2 in 2004 in a case series of five patients presenting with unique clinical and radiographic findings distinct from any of the previously characterized idiopathic interstitial pneumonias (IIPs).2 Since that time, a number of cases of pleuroparenchymal fibroelastosis (PPFE) have been identified in patients with compelling etiologic correlates commonly associated with the development of interstitial lung disease (ILD), including familial interstitial pneumonitis3; recurrent lower respiratory tract lung infections4; lung, bone marrow, and hematopoietic cell transplantation5; chemotherapeutic medications (drug-induced PPFE)6; occupational exposure to aluminosilicate dust7 or asbestosis8; and systemic autoimmune diseases, such as rheumatoid arthritis and scleroderma. As with the other IPs/ILDs, PPFE is described as idiopathic when no associated causative etiology can be identified. iPPFE was recently recognized as a distinct entity in the American Thoracic Society/European Respiratory Society 2013 update on the IIPs and was categorized as one of the two rare IIPs, along with lymphoid IP.9

Prevalence and Epidemiology As of January 2017, approximately 120 cases have been reported overall in the published literature.10 To date, iPPFE appears to have no gender preference and no association with cigarette smoking. The average age at presentation is highly variable, ranging from 13 to 87 years with a median of approximately 53 years.11

Clinical Presentation Patients most often present with insidious onset of dyspnea, exercise intolerance, and nonproductive cough, similar to other patients with fibrosing ILD. Additional symptoms include chest discomfort (pain, tightness, inability to take a satisfying breath), pneumothorax, and constitutional symptoms, such as fatigue, malaise, and weight loss. Patients have been described as having a slender stature with associated “flattened thoracic cage” or “platythorax,” potentially signifying a decrease in the anteriorposterior dimension of the thorax.12

Pathology Although there are no well-defined consensus criteria regarding the histopathologic diagnosis of PPFE, in a 2013 review von der 524

Thüsen13 proposed a working definition of iPPFE with “definite” and “consistent with” histologic criteria. “Definite” criteria of iPPFE include (1) upper zone fibrosis of the visceral pleura; (2) prominent, homogeneous, subpleural intraalveolar fibrosis with alveolar septal elastosis; (3) sparing of the parenchyma distant from the pleura; (4) at most, mild, patchy lymphoplasmocytic infiltrates; and (5) at most, small numbers of fibroblastic foci. Criteria that are “consistent with” iPPFE also have intraalveolar fibrosis as just described; however, (1) this may not be associated with significant pleural fibrosis, (2) may not be predominantly subpleural, or (3) may not occur in an upper lobe biopsy. Additional criteria for iPPFE were proposed by Rosenbaum and colleagues14 in 2015, which included (1) fibrous IP with 80% fibroelastic changes in nonatelectatic lung; (2) subpleural and/ or centrilobular distribution; (3) overall inflammation absent to mild; (4) no specific lobe predilection, typically multilobar; and (5) rare or no granulomas. A recent quantitative assessment of elastic fibers (EF) demonstrated twice the number of EF in iPPFE compared with IPF.15 That said, it is important to note that the two conditions are not mutually exclusive and often appear to coexist.4,16 Although an experienced pathologist may be able to recognize the characteristic features of PPFE on standard eosin and hematoxylin stains, incorporating the routine use of EF-specific agents, such as orcein or Verhoeff–van Gieson stains, could greatly facilitate identifying PPFE histologically (Fig. 36.1).

Physiology The main physiologic abnormality is a restrictive ventilatory impairment similar to other fibrosing ILDs. Often there is a disproportionate reduction in forced vital capacity relative to the reduction seen in the diffusion capacity of carbon monoxide compared with the degree of impairment seen in these parameters in patients with other ILDs, such as IPF. Additionally, disproportionate upper lobe fibrotic collapse with compensatory hyperinflation of the lower lobes may increase the ratio of residual volume to total lung capacity distinguishing PPFE from IPF.12

Imaging Radiographs in early iPPFE may demonstrate bilateral apical pleural irregularity or be normal as subtle visceral pleural nodularity, and intraalveolar fibrosis may be radiographically occult (Fig. 36.2). Indeed, patients often present with physiologic impairment and symptoms that are more pronounced than what would be expected based upon the radiographic findings alone. Later-stage disease classically demonstrates increased severity in the apical pleural thickening, with upper lobe–predominant reticulonodular opacities and retracted, elevated hila. Lateral

36  Idiopathic Pleuroparenchymal Fibroelastosis

radiographs may illustrate anterior-posterior dimensional narrowing. Recurrent pneumothorax may occur in PPFE.12,17 Early in the disease course, high-resolution computed tomography demonstrates apical-predominant subpleural nodular and reticular opacities that may coalesce into areas of dense consolidation with associated traction bronchiectasis, architectural distortion, and intraalveolar fibrosis (Fig. 36.3). As with chest radiography, the upper lobe volume loss may be associated with superior hilar retraction. As the disease progresses, multilobar

525

pleuroparenchymal thickening can be seen, and the apical disease may evolve to include upper lobe bullae or cysts. Again, additional ILD patterns may coexist with PPFE, most commonly usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP) patterns of lung fibrosis.4,16

Differential Diagnosis Differential diagnosis includes those entities that manifest with apical or upper lobe–predominant disease, as well as those entities that manifest with a combination of parenchymal and pleural abnormalities. As such, competing diagnostic considerations may include apical capping, tuberculosis, sarcoidosis, silicosis, hypersensitivity pneumonitis, radiation-induced lung injury/fibrosis, asbestos-related lung disease and connective tissue disease– associated lung diseases, such as rheumatoid arthritis and ankylosing spondylitis.

Treatment and Management

Fig. 36.1  Pleuroparenchymal fibroelastosis: histologic findings. Micrograph shows pentachrome (Movat)-stained sections photographed at 4× objective magnification showing fibroelastotic changes in the subpleural parenchyma of the lower right portion of the image, contrasted against the preserved normal architecture of the lung in the upper left corner. Yellow corresponds to the mature collagen of fibrotic lung, whereas the black highlights the increased number and fragmentation of the elastin fibers embedded within the fibrosis. (Courtesy Dr. Steve Groshong, Department of Pathology, National Jewish Health, Denver, Colorado.)

A

Prognosis is highly variable with clinically significant disease progression occurring in 60% of patients and death attributable to the disease occurring in 40%.4,10 A worse prognosis appears to exist in patients with PPFE plus a concomitant UIP pattern,17 as well as those with familial forms of the disease. Patients are often treated empirically with corticosteroids and/or immunosuppressive/ cytotoxic agents, although efficacy has not been confirmed. In one case report pirfenidone treatment appeared to sustain pulmonary function.18 In patients with a combination of iPPFE and IPF, the antifibrotic agents pirfenidone and nintedanib have been used to treat the IPF, but the secondary effects on the PPFE are as of yet unknown/unreported. Lung transplant has been successfully performed in advanced cases.19

B Fig. 36.2  Idiopathic pleuroparenchymal fibroelastosis: radiographic findings. (A) Chest radiograph shows no lung fibrosis. There is a small left pleural effusion. (B) Chest radiograph 4 years later demonstrates apical predominant pleural thickening with diffuse, course reticular markings, retracted and elevated hila, and right greater-than-left lung volume loss with compensatory rightward tracheal deviation.

526

SECTION 7  Diffuse Lung Diseases

A

B Fig. 36.3  Idiopathic pleuroparenchymal fibroelastosis: high-resolution CT findings. Axial (A) and coronal (B) high-resolution CT scan shows apical predominant subpleural thickening, dense subpleural consolidation and volume loss with right apical bullae. Basilar honeycombing is consistent with patient’s concomitant usual interstitial pneumonia.

Beyond directed pharmacologic therapy, many experts emphasize the importance of a comprehensive approach to disease management, including pulmonary rehabilitation, oxygen therapy, achieving and maintaining ideal body weight through proper nutrition and exercise, and vaccinations per Advisory Committee on Immunization Practices guidelines. Additionally, screening for and treatment of commonly seen comorbid conditions, such as gastric esophageal reflux disease, pulmonary hypertension, bronchiectasis, osteoporosis, UIP/NSIP, depression, and anxiety, is also recommended. Longitudinal care with a team of experts in the care of ILD patients may often be beneficial given the rarity of the disease. KEY POINTS • Idiopathic pleuroparenchymal fibroelastosis (iPPFE) requires a multidisciplinary approach for accurate diagnosis. • iPPFE is likely to increase in prevalence as more specialists become aware of this distinct entity. • Although classically upper lobe predominant, at time of diagnosis, PPFE often evolves with disease progression to be a multilobar process. • iPPFE may coexist with other histopathologic lesions, such as usual interstitial pneumonia and nonspecific interstitial pneumonia. • Further study is necessary to establish optimal idiopathic PPFE management and treatment guidelines.

SUGGESTED READINGS ATS/ERS Committee on Idiopathic Interstitial Pneumonias. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733–748. Reddy TL, Tominaga M, Hansell DM, et al. Pleuroparenchymal fibroelastosis: a spectrum of histopathological and imaging phenotypes. Eur Respir J. 2012;40(2):377–385.

The full reference list for this chapter is available at ExpertConsult.com.

36  Idiopathic Pleuroparenchymal Fibroelastosis 526.e1

REFERENCES 1. Amitani R, Niimi A, Kuze F. [Idiopathic pulmonary upper lobe fibrosis]. Kokyu. 1992;11:693–699 [in Japanese]. 2. Frankel SK, Cool CD, Lynch DA, Brown KK. Idiopathic pleuroparenchymal fibroelastosis: description of a clinicopathologic entity. Chest. 2004;126:2007– 2013. 3. Azoulay E, Paugam B, Heymann MF, et al. Familial extensive idiopathic bilateral pleural fibrosis. Eur Respir J. 1999;14(4):971–973. 4. Reddy TL, Tominaga M, Hansell DM, et al. Pleuroparenchymal fibroelastosis: a spectrum of histopathological and imaging phenotypes. Eur Respir J. 2012;40(2):377–385. 5. Mariani F, Gatti B, Rocca A, et al. Pleuroparenchymal fibroelastosis: the prevalence of secondary forms in hematopoietic stem cell and lung transplantation recipients. Diagn Interv Radiol. 2016;22:400–406. 6. Baroke E, Heussel CP, Warth A, et al. Pleuroparenchymal fibroelastosis in association with carcinomas. Respirology. 2016;21(1):191–194. 7. Huang Z, Lis S, Zhu Y, et al. Pleuroparenchymal fibroelastosis associated with aluminosilicate dust: a case report. Int J Clin Exp Pathol. 2015;8(7):8676– 8679. 8. Wick M, Kendall T, Ritter J. Asbestosis: redemonstration of distinctive interstitial fibroelastosis. A pilot study. Ann Diagn Pathol. 2009;13:297–302. 9. Travis W, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society Statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188:733–748.

10. Bonifazi M, Montero MA, Renzoni EA. Idiopathic pleuroparenchymal fibroelastosis. Curr Pulmonol Rep. 2017;6:9–15. 11. Cheng SK, Chuah KL. Pleuroparenchymal fibroelastosis of the lung: a review. Arch Pathol Lab Med. 2016;140(8):849–853. 12. Watanebe K. Pleuroparenchymal fibroelastosis: its clinical characteristics. Curr Respir Med Rev. 2013;9:229–237. 13. von der Thüsen JH. Pleuroparenchymal fibroelastosis: its pathological characteristics. Curr Respir Med Rev. 2013;9:238–247. 14. Rosenbaum JN, Butt YM, Johnson KA, et al. Pleuroparenchymal fibroelastosis: a pattern of chronic lung injury. Hum Pathol. 2015;46(1):137–146. 15. Enomoto N, Kusagaya H, Oyama Y, et al. Quantitative analysis of lung elastic fibers in idiopathic pleuroparenchymal fibroelastosis (IPPFE): comparison of clinical, radiological, and pathological findings with those of idiopathic pulmonary fibrosis (IPF). BMC Pulm Med. 2014;14:91. 16. Nakatani T, Arai T, Ktaichi M, et al. Pleuroparenchymal fibroelastosis from a consecutive database: a rare disease entity? Eur Respir J. 2015;45(4):1183– 1186. 17. Oda T, Ogura T, Kitamura H, et al. Distinct characteristics of pleuroparenchymal fibroelastosis with usual interstitial pneumonia compared with idiopathic pulmonary fibrosis. Chest. 2014;146(5):1248–1255. 18. Sato S, Hanibuchi M, Takahashi M, et al. A patient with idiopathic pleuroparenchymal fibroelastosis showing a sustained pulmonary function due to treatment with pirfenidone. Intern Med. 2016;55(5):497–501. 19. Chen F, Masubara K, Miyagawa-Hayashino A, et al. Lung transplant for pleuroparenchymal fibroelastosis after chemotherapy. Ann Thorac Surg. 2014;98:115–117.

37 

Eosinophilic Lung Diseases* MELISSA PRICE  |  CAROL C. WU  |  MATTHEW D. GILMAN

Eosinophilic diseases of the lung include a heterogeneous group of pulmonary disorders that characteristically feature peripheral or tissue eosinophilia.1 Patients with these illnesses have a variable clinical presentation and may be asymptomatic or may exhibit organ dysfunction or clinical symptoms of severe respiratory illness.1,2 Histologically, eosinophilic lung diseases demonstrate infiltration of eosinophils in the pulmonary interstitium and alveolar spaces with preservation of the lung architecture. As a result, these illnesses respond dramatically to corticosteroid treatment and typically heal without significant lung parenchymal damage.3 The diseases are classified as idiopathic or secondary to a known primary disease process or well-defined cause.2 Established causes of eosinophilic lung disease include primary airways diseases, such as allergic bronchopulmonary aspergillosis (see Chapter 57), drug reaction (see Chapter 65), and toxin exposure and parasitic infections (see Chapter 14).3 The idiopathic eosinophilic diseases of the lung are simple pulmonary eosinophilia (Löffler syndrome), acute and chronic eosinophilic pneumonia, and the systemic conditions such as hypereosinophilic syndrome and eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss, which is discussed in Chapter 46).2 The diagnosis of eosinophilic lung disease can be made in the presence of one of the following criteria: (1) peripheral eosinophilia (>1000/mm3) in conjunction with pulmonary parenchymal opacities on chest radiography, (2) tissue eosinophilia on surgical or transbronchial lung biopsy, or (3) eosinophilia in bronchoalveolar lavage (BAL) fluid (differential cell count > 25).1,3

Simple Pulmonary Eosinophilia Etiology, Prevalence, and Epidemiology Simple pulmonary eosinophilia (SPE) was originally identified and described in 1932 by Löffler. Patients with SPE typically have fleeting pulmonary opacities on chest radiography in the presence of blood eosinophilia. Approximately one-third of cases of SPE are idiopathic. The majority of cases occur secondary to drug toxicity or parasitic infection.4,5 The incidence of SPE in oncologic patients undergoing follow-up CT imaging has been reported to be 0.95%. These individuals typically lack respiratory symptoms and have subsolid nodules on chest CT.6

*The editors and the publisher would like to thank Dr. Takeshi Johkoh for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

Clinical Presentation Individuals may be asymptomatic or may experience minimal respiratory symptoms, fever, or malaise. Symptoms and radiologic findings are self-limited and resolve spontaneously within 30 days with or without treatment.7

Pathophysiology Data is limited on the pathophysiology of this disease entity, but there is an association with alveolar infiltration with eosinophils and giant cells.5

Manifestations of the Disease RADIOGRAPHY The characteristic radiographic findings are nonsegmental opacities, which are frequently ill-defined and peripheral in distribution.1,7 The opacities may be unilateral or bilateral and are characteristically transient or migratory8,9 (Fig. 37.1). COMPUTED TOMOGRAPHY Ground-glass opacities and consolidation, the most common CT findings, either showed a random distribution or upper and middle lung zone predominance (Fig. 37.2; see Fig. 37.1). Pulmonary parenchymal nodules were reported to be present in 42% of cases.10 The CT features and distribution of opacities present in SPE and chronic eosinophilic pneumonia are similar; the important distinguishing feature is that the imaging findings in SPE will spontaneously fluctuate over a period of days as opposed to chronic eosinophilic pneumonia (CEP), where the consolidations and ground-glass opacities will persist for weeks to months and be accompanied by more significant respiratory symptoms.11 In individuals with SPE found at oncologic surveillance or routine screening, pulmonary nodules (either solitary or multiple) with a ground-glass halo are the most common CT finding.6,9,12

Differential Diagnosis The presence of consolidation on chest radiography can be seen in the setting of pneumonia, alveolar pulmonary edema, or diffuse alveolar damage. The absence of or minimal pulmonary symptoms associated with SPE, along with peripheral blood eosinophilia, strongly suggests the diagnosis. It is important to exclude known associations with pulmonary eosinophilia, the most common of which are parasitic infection and drug toxicity. 527

528

SECTION 7  Diffuse Lung Diseases

A

C

Synopsis of Treatment Options No treatment is required because SPE is asymptomatic and self-limited. KEY POINTS: SIMPLE PULMONARY EOSINOPHILIA • Approximately one-third of cases are idiopathic; infectious etiologies and drug toxicity are more common and should be excluded. • Clinical course is mild and self-limited, with symptoms resolving spontaneously within a month. • Radiography shows nonsegmental, peripheral opacities that are transient and/or migratory. • Subsolid nodules, ground-glass opacities, and consolidation may be seen on CT.

B

Fig. 37.1  Simple pulmonary eosinophilia. (A) Chest radiograph shows peripheral predominant consolidations. (B) Chest radiograph obtained 9 days later shows new peripheral opacities with improvement or resolution of previously seen opacities. (C) Axial CT image from the same patient demonstrates bilateral ground-glass opacities, small nodules, and confluent opacities.

Chronic Eosinophilic Pneumonia Etiology, Prevalence, and Epidemiology Idiopathic chronic eosinophilic pneumonia (ICEP) is a respiratory illness characterized by alveolar eosinophilia, typically greater than 25% at BAL and/or blood eosinophilia of at least 6%.1,13 Although blood eosinophilia is present in most patients, up to 12% of patients with ICEP do not have peripheral eosinophilia.13 The disease is more common among women14 and tends to occur around the fifth decade.1,14,15 There is an association of ICEP with asthma,13,16–18 which has been reported to occur in up to 53% of patients with ICEP.15 Unlike in eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome (HES),

37  Eosinophilic Lung Diseases

529

A Fig. 37.2  Simple pulmonary eosinophilia. Sagittal CT image shows nodular subpleural consolidation in the posterior segment of the right upper lobe with adjacent ground-glass opacity in this man with peripheral eosinophilia. The consolidation nearly resolved at follow-up CT imaging 4 weeks later.

extrathoracic symptoms and organ dysfunction are not present in ICEP.16

Clinical Presentation Systemic symptoms associated with ICEP, such as fever, weight loss, and night sweats in addition to dyspnea and cough,14 are typically present for 1 month on average before clinical presentation.18 The mean time to diagnosis is 7.7 months,13 reflecting the confounding factors that make the diagnosis of ICEP challenging. Other features seen in a minority of patients include anorexia, chills, and hemoptysis.13

Pathophysiology At histology there is an alveolar infiltration of eosinophils and to a lesser extent macrophages, lymphocytes, and plasma cells,14 and in approximately half of patients, there will be foci of interstitial fibrosis.13 In more rare cases, eosinophilic microabscesses and regions of intraalveolar necrosis will also be present.13

B Fig. 37.3  Chronic eosinophilic pneumonia. (A) Chest radiograph in a woman with a 7-month history of cough shows bilateral upper lobe opacities, greater on the left. (B) Coronal CT image reveals ground-glass opacity in the apical left upper lobe with surrounding peripheral consolidation. The patient had a bronchoalveolar lavage eosinophilia of 71% at bronchoscopy.

Manifestations of the Disease RADIOGRAPHY The characteristic radiographic finding in ICEP is peripheral airspace opacities.1,14 In their 1969 article that first described the disease, Carrington and colleagues14 identified the unique presence of three features in ICEP: progressive peripheral dense consolidations, prompt resolution with corticosteroid treatment, and recurrence in the same unique locations upon relapse. The dense peripheral consolidation in ICEP has been described as the “photographic negative” of pulmonary edema.14,19 There is typically no lobar or segmental distribution to the opacities,

which can be unilateral or bilateral and show ill-defined margins. An apical or axillary location is common (Fig. 37.3), and opacities may be mistaken for loculated pleural fluid.19 COMPUTED TOMOGRAPHY Subpleural and upper lung zone–predominant consolidation and areas of ground-glass opacity are present in the vast majority of patients (Figs. 37.4 and 37.5).10 In some patients mediastinal lymphadenopathy will be evident on CT (Fig. 37.6).10,11 Unlike in acute eosinophilic pneumonia, pleural effusions are rare.10

530

SECTION 7  Diffuse Lung Diseases

A Fig. 37.4  Chronic eosinophilic pneumonia. Coronal CT image shows patchy bilateral consolidation and ground-glass opacities without craniocaudad zonal predominance.

B

Fig. 37.5  Chronic eosinophilic pneumonia. Axial CT image demonstrates lower lobe consolidations, an atypical distribution for chronic eosinophilic pneumonia as the disease is generally upper lung zone predominant.

Less common CT findings include nodules, bronchiectasis, and interlobular septal thickening.10 In patients who have had at least 2 months of symptoms at the time of CT imaging, band-like opacities and lobar atelectasis can be seen.20

Differential Diagnosis The primary differential consideration in patients who have ICEP is an infectious pneumonia, given the airspace opacities and febrile respiratory illness that characterize the disease. Other

Fig. 37.6  Chronic eosinophilic pneumonia. (A) Axial CT image with soft tissue window shows right hilar and subcarinal lymphadenopathy in this man with a history of asthma and recurrent sinusitis who presented with 3 months of productive cough and a 10-lb weight loss. (B) Axial CT image shows bilateral peripheral ground-glass and confluent opacities. The patient’s bronchoalveolar lavage eosinophilia was 65%.

diagnoses that may be considered include organizing pneumonia, drug toxicity, and sarcoidosis.1 The upper lobe–predominant opacities, constitutional symptoms, and rare hemoptysis may raise concern for tuberculosis.14,19 SPE may appear identical to ICEP on imaging; however, patients with SPE will have transient opacities that fluctuate over a period of days, a relative paucity of constitutional symptoms, and spontaneous resolution.8,11 The presence of blood and alveolar eosinophilia, dramatic clinical and radiographic response to steroids, and peripheral airspace opacities favor the diagnosis of ICEP.

37  Eosinophilic Lung Diseases

Synopsis of Treatment Options

Manifestations of the Disease

ICEP is extremely steroid sensitive, and opacities seen on imaging improve or resolve rapidly on initiation of corticosteroid therapy.8,11,14,19 After discontinuation or tapering of steroid therapy, there is a tendency for symptoms to recur and opacities to reappear, often in the same location and configuration as seen initially.14

RADIOGRAPHY

531

The radiographic findings are variable but may include both bilateral reticular and diffuse or patchy confluent opacities. Alternatively, either the reticular pattern or confluent opacity pattern may only be visible (Figs. 37.7 and 37.8).30,34 Small bilateral

KEY POINTS: CHRONIC EOSINOPHILIC PNEUMONIA • Idiopathic chronic eosinophilic pneumonia features filling of the alveoli with a mixed inflammatory infiltrate, primarily of eosinophils. • Peripheral eosinophilia is typically present, but absence of elevated blood eosinophils does not exclude the diagnosis. • Systemic symptoms include fever, nonproductive cough, weight loss, and dyspnea. In contrast to acute eosinophilic pneumonia, hypoxemic respiratory failure is uncommon. • As many as 50% of patients have a history of asthma or atopy. • The characteristic pattern is peripheral opacities favoring the upper lobes: “photographic negative” of pulmonary edema. • Response to corticosteroids is rapid, although recurrence is frequent with steroid withdrawal.

Acute Eosinophilic Pneumonia Etiology, Prevalence, and Epidemiology Acute eosinophilic pneumonia (AEP) is an idiopathic respiratory illness associated with cigarette smoking—in particular, new-onset cigarette smoking.21–24 There was a relatively high incidence of AEP among military personnel who had been stationed in Iraq or nearby during Operation Iraqi Freedom, and 78% of these individuals reported recent-onset cigarette smoking. The illness has also been linked with toxin inhalation25,26 and various medications.27,28 Unlike CEP, there is no association of AEP with asthma; however, allergic rhinitis has been found in 38% of patients with AEP in one series.18

A

Clinical Presentation AEP is a febrile respiratory illness in which patients present with acute dyspnea and hypoxemic respiratory failure.1,29 The average age of presentation of AEP is early adulthood,30 and it occurs more frequently among males.18,30 Fever, dyspnea, cough, and pleuritic chest pain are the most common clinical symptoms.1,30

Pathophysiology AEP affects the lung diffusely, with histology demonstrating diffuse alveolar damage and eosinophilic infiltration of the lung interstitium and alveoli. Acute interstitial pneumonia (i.e., idiopathic acute respiratory distress syndrome) also demonstrates a diffuse alveolar damage pattern at histology but lacks the tissue eosinophilia.31 AEP is diagnosed when there are greater than 25% eosinophils in BAL fluid and diffuse pulmonary opacities are present on chest radiograph in the absence of an infectious source.29,32 Peripheral eosinophil levels are often normal at the time of diagnosis but may become elevated several days after treatment.18,29,33

B Fig. 37.7  Acute eosinophilic pneumonia. (A) Portable chest radiograph in a young man with acute eosinophilic pneumonia shows bilateral confluent and patchy opacities involving the lung periphery. The patient had a history of asthma and developed hypoxemic respiratory failure over a period of days, which required mechanical ventilation. (B) Coronal CT image shows bilateral consolidations with surrounding ground-glass opacities and diffuse bronchial wall thickening.

532

SECTION 7  Diffuse Lung Diseases

A A

B B Fig. 37.8  Acute eosinophilic pneumonia. (A) Portable chest radiograph in a 41-year-old male firefighter who presented with acute respiratory failure shows bilateral reticular and confluent opacities. (B) Axial CT image shows peripheral ground-glass opacities and interlobular septal thickening producing the “crazy paving” pattern as well as small bilateral pleural effusions, which are commonly present in acute eosinophilic pneumonia.

pleural effusions are common. The disease often appears similar to pulmonary edema.34 COMPUTED TOMOGRAPHY On CT a patient with AEP shows smooth interlobular septal thickening, diffuse ground-glass opacities, consolidation, and bilateral pleural effusions (Fig. 37.9; see also Figs. 37.7 and 37.8).10,35,36 There is typically no zonal predominance in the cephalocaudad plane for these findings.10,35 Pulmonary nodules

Fig. 37.9  Acute eosinophilic pneumonia. (A) and (B) Coronal and axial CT images of a 38-year-old man who presented with one week of fever, night sweats, fatigue, and shortness of breath, show multifocal, bilateral consolidations and ground-glass opacities with small bilateral pleural effusions.

occur in some of the patients.10 Thickening of the peribronchovascular interstitium is also frequently observed.35,36 The diffuse ground-glass opacities in conjunction with interlobular septal thickening can produce the nonspecific “crazy paving” pattern in patients with AEP (see Fig. 37.8).35 Cardiac enlargement, in contrast to cardiogenic pulmonary edema, is not associated with the illness. Intrathoracic lymphadenopathy may be present but is not common.10

Differential Diagnosis Pulmonary edema, multifocal pneumonia, pulmonary hemorrhage, and acute interstitial pneumonia are differential considerations. Suspecting the diagnosis of AEP can be particularly challenging in the absence of bronchoscopy and BAL because

37  Eosinophilic Lung Diseases

at initial presentation blood eosinophils are usually normal. The presence of BAL eosinophilia in conjunction with the clinical and radiologic findings should raise suspicion for the illness. In all cases it is important to exclude an underlying infection and drug toxicity.1

Synopsis of Treatment Options Many patients will require mechanical ventilation at some time during their illness.30 AEP resolves rapidly with steroids or spontaneously, which is a distinguishing feature from CEP.18,30 After recovery from AEP, patients do not relapse,30,37 and there is typically no residual fibrosis after recovery.34

KEY POINTS: ACUTE EOSINOPHILIC PNEUMONIA • Rapidly progressive hypoxic respiratory failure with fever and dyspnea in the absence of infectious source are characteristic features of acute eosinophilic pneumonia. • Bronchoalveolar lavage eosinophilia should be present for diagnosis: differential cell count of >25% eosinophils. • Absence of blood eosinophilia does not exclude the diagnosis and is common. • Infection and drug toxicity should be excluded. • Tends to occur in young adults with a slight male predominance. • Associated with recent-onset cigarette smoking. • Response to corticosteroid therapy is rapid, but patients may recover spontaneously. • Imaging findings often closely resemble pulmonary edema.

533

HES may also develop cutaneous, cardiac, and neurologic involvement and dysfunction resulting from eosinophil infiltration.43 Cardiac involvement, present in 40% to 60% of patients, can result in complete heart block, eosinophilic myocarditis, ventricular thrombus formation, and cardiomyopathy.40,43–45 In advanced stages of disease the eosinophilic-induced cardiac damage features fibrosis and mitral and tricuspid valvular regurgitation leading to a restrictive cardiomyopathy.38 Eosinophilic infiltration of the lung is difficult to distinguish from other eosinophilic pneumonias.

Clinical Presentation The initial presentation of HES can vary greatly. Some of the reported presenting symptoms include fever, recurrent abdominal pain, pruritic rash, and weight loss.46 Patients with M-HES can present with hepatosplenomegaly, anemia, and thrombocytopenia typical of myeloproliferative diseases. The disease involves the lung in 40% of cases, with symptoms of cough, bronchospasm, and dyspnea.43 In cases with cardiac involvement, patients experience congestive heart failure.42

Manifestations of the Disease RADIOGRAPHY Cardiac enlargement and findings related to pulmonary edema are among the more common radiographic findings.42 Pleural effusions may also be present. In many cases the chest radiograph of patients with HES will be normal.46,47 Focal or diffuse opacities can also be seen.40 COMPUTED TOMOGRAPHY

Hypereosinophilic Syndrome Etiology, Prevalence, and Epidemiology Hypereosinophilic syndrome (HES) is a rare condition characterized by marked peripheral eosinophilia with organ infiltration and resultant dysfunction.7,38 The diagnostic criteria of HES based on the 2010 revision by Simon and colleagues39 include (1) an elevation of the absolute eosinophil count (AEC) greater than 1500/mm3 on at least two occasions or evidence of prominent tissue eosinophilia with associated symptoms and marked blood eosinophilia and (2) exclusion of secondary causes of eosinophilia, such as parasitic or viral infections, allergic disease, drug-induced or chemical-induced eosinophilia, hypoadrenalism, and neoplasms. Subcategories of HES include a myeloproliferative form that includes myeloproliferative-HES (M-HES) and chronic eosinophilic leukemia, lymphocytic form (L-HES), and other HES variants.39,40 The mean age at diagnosis is 52.5 years,41 and the disease is more common in men.41,42 Cardiac dysfunction in HES has the highest associated mortality.

Pathophysiology Patients with M-HES have mutations of hematopoietic stem cells and expansion of the eosinophil population. In L-HES, activated T lymphocytes generate increased amounts of at least one eosinophil hematopoietin (interleukin [IL]-3 and/or IL-5), resulting in polyclonal blood hypereosinophilia. Patients with

Patients with HES may have pulmonary nodules, which when present often have a surrounding ground-glass halo.47 Other CT findings include interlobular septal and bronchial wall thickening and patchy or diffuse opacities (Fig. 37.10). Unlike ICEP, there is no zonal predominance of opacities in the craniocaudad plane.10 Pulmonary embolism and intrathoracic lymphadenopathy with mildly enlarged mediastinal or hilar lymph nodes have also been reported.48

Synopsis of Treatment Options HES is typically treated with corticosteroids and hydroxyurea. Survival has improved since the disease was first described; however, the prognosis remains poorer than other eosinophilic lung diseases.44 Imatinib, a tyrosine kinase inhibitor, is used in M-HES.40

KEY POINTS: HYPEREOSINOPHILIC SYNDROME • Rare disease featuring marked peripheral eosinophilia. • Clinical presentation is variable, and pulmonary involvement is seen in approximately half of cases. • CT findings include pulmonary nodules with ground-glass halos, interlobular septal thickening, and consolidation and ground-glass opacities. • Greatest morbidity and mortality is associated with cardiac involvement.

534

SECTION 7  Diffuse Lung Diseases

B

A

Fig. 37.10  Hypereosinophilic syndrome. (A) Coronal CT image of a 70-year-old man demonstrates upper lobe and peripheral predominant ground-glass opacities and interlobular septal thickening. The patient was admitted with dyspnea and cough and found to have myocarditis and cardiogenic shock. He had marked peripheral eosinophilia, and bronchoalveolar lavage showed 44% eosinophils. (B) Postcontrast short-axis cardiac MRI shows late gadolinium enhancement in the basal inferolateral wall (arrow) of the left ventricle.

SUGGESTED READINGS Bernheim A, McLoud T. A review of clinical and imaging findings in eosinophilic lung diseases. AJR Am J Roentgenol. 2017;208(5):1002–1010. Cottin V. Eosinophilic lung diseases. Clin Chest Med. 2016;37(3):535–556. Curtis C, Ogbogu P. Hypereosinophilic syndrome. Clin Rev Allergy Immunol. 2016;50(2):240–251. Price M, Gilman MD, Carter BW, Sabloff BS, Truong MT, Wu CC. Imaging of eosinophilic lung diseases. Radiol Clin North Am. 2016;54(6):1151–1164.

Rose DM, Hrncir DE. Primary eosinophilic lung diseases. Allergy Asthma Proc. 2013;34(1):19–25.

The full reference list for this chapter is available at ExpertConsult.com.

37  Eosinophilic Lung Diseases 534.e1

REFERENCES 1. Allen JN, Davis WB. Eosinophilic lung diseases. Am J Respir Crit Care Med. 1994;150(5 Pt 1):1423–1438. 2. Fernandez Perez ER, Olson AL, Frankel SK. Eosinophilic lung diseases. Med Clin North Am. 2011;95(6):1163–1187. 3. Cottin V, Cordier JF. Eosinophilic lung diseases. Immunol Allergy Clin North Am. 2012;32(4):557–586. 4. Im JG, Whang HY, Kim WS, Han MC, Shim YS, Cho SY. Pleuropulmonary paragonimiasis: radiologic findings in 71 patients. AJR Am J Roentgenol. 1992;159(1):39–43. 5. Bain GA, Flower CD. Pulmonary eosinophilia. Eur J Radiol. 1996;23(1): 3–8. 6. Kim SJ, Bista AB, Park KJ, et al. Simple pulmonary eosinophilia found on follow-up computed tomography of oncologic patients. Eur J Radiol. 2014;83(10):1977–1982. 7. Alberts WM. Eosinophilic interstitial lung disease. Curr Opin Pulm Med. 2004;10(5):419–424. 8. Citro LA, Gordon ME, Miller WT. Eosinophilic lung disease (or how to slice P.I.E.). Am J Roentgenol Radium Ther Nucl Med. 1973;117(4):787–797. 9. Kim Y, Lee KS, Choi DC, Primack SL, Im JG. The spectrum of eosinophilic lung disease: radiologic findings. J Comput Assist Tomogr. 1997;21(6): 920–930. 10. Johkoh T, Müller NL, Akira M, et al. Eosinophilic lung diseases: diagnostic accuracy of thin-section CT in 111 patients. Radiology. 2000;216(3): 773–780. 11. Mayo JR, Müller NL, Road J, Sisler J, Lillington G. Chronic eosinophilic pneumonia: CT findings in six cases. AJR Am J Roentgenol. 1989;153(4): 727–730. 12. Kim HY, Naidich DP, Lim KY, et al. Transient pulmonary eosinophilia incidentally found on low-dose computed tomography: findings in 40 individuals. J Comput Assist Tomogr. 2008;32(1):101–107. 13. Jederlinic PJ, Sicilian L, Gaensler EA. Chronic eosinophilic pneumonia. A report of 19 cases and a review of the literature. Medicine (Baltimore). 1988;67(3):154–162. 14. Carrington CB, Addington WW, Goff AM, et al. Chronic eosinophilic pneumonia. N Engl J Med. 1969;280(15):787–798. 15. Fox B, Seed WA. Chronic eosinophilic pneumonia. Thorax. 1980;35(8): 570–580. 16. Marchand E, Cordier JF. Idiopathic chronic eosinophilic pneumonia. Semin Respir Crit Care Med. 2006;27(2):134–141. 17. Marchand E, Etienne-Mastroianni B, Chanez P, et al. Idiopathic chronic eosinophilic pneumonia and asthma: how do they influence each other? Eur Respir J. 2003;22(1):8–13. 18. Hayakawa H, Sato A, Toyoshima M, Imokawa S, Taniguchi M. A clinical study of idiopathic eosinophilic pneumonia. Chest. 1994;105(5):1462– 1466. 19. Gaensler EA, Carrington CB. Peripheral opacities in chronic eosinophilic pneumonia: the photographic negative of pulmonary edema. AJR Am J Roentgenol. 1977;128(1):1–13. 20. Ebara H, Ikezoe J, Johkoh T, et al. Chronic eosinophilic pneumonia: evolution of chest radiograms and CT features. J Comput Assist Tomogr. 1994;18(5): 737–744. 21. Brackel CL, Ropers FG, Vermaas-Fricot SF, Koens L, Willems LN, RikkersMutsaerts ER. Acute eosinophilic pneumonia after recent start of smoking. Lancet. 2015;385(9973):1150. 22. Bok GH, Kim YK, Lee YM, et al. Cigarette smoking-induced acute eosinophilic pneumonia: a case report including a provocation test. J Korean Med Sci. 2008;23(1):134–137. 23. Shorr AF, Scoville SL, Cersovsky SB, et al. Acute eosinophilic pneumonia among US military personnel deployed in or near Iraq. JAMA. 2004;292(24): 2997–3005. 24. Nakajima M, Manabe T, Niki Y, Matsushima T. Cigarette smoke-induced acute eosinophilic pneumonia. Radiology. 1998;207(3):829–831. 25. Hirai K, Yamazaki Y, Okada K, Furuta S, Kubo K. Acute eosinophilic pneumonia associated with smoke from fireworks. Intern Med. 2000;39(5):401–403.

26. Rom WN, Weiden M, Garcia R, Yie TA, Vathesatogkit P, Tse DB, McGuinness G, Roggli V, Prezant D. Acute eosinophilic pneumonia in a New York City firefighter exposed to World Trade Center dust. Am J Respir Crit Care Med. 2002;166(6):797–800. 27. Rizos E, Tsigkaropoulou E, Lambrou P, et al. Risperidone-induced acute eosinophilic pneumonia. In Vivo. 2013;27(5):651–653. 28. Tsigkaropoulou E, Hatzilia D, Rizos E, et al. Venlafaxine-induced acute eosinophilic pneumonia. Gen Hosp Psychiatry. 2011;33(4):411 e7–411 e9. 29. Allen JN, Pacht ER, Gadek JE, Davis WB. Acute eosinophilic pneumonia as a reversible cause of noninfectious respiratory failure. N Engl J Med. 1989;321(9):569–574. 30. Philit F, Etienne-Mastroianni B, Parrot A, Guerin C, Robert D, Cordier JF. Idiopathic acute eosinophilic pneumonia: a study of 22 patients. Am J Respir Crit Care Med. 2002;166(9):1235–1239. 31. Tazelaar HD, Linz LJ, Colby TV, Myers JL, Limper AH. Acute eosinophilic pneumonia: histopathologic findings in nine patients. Am J Respir Crit Care Med. 1997;155(1):296–302. 32. Price M, Gilman MD, Carter BW, Sabloff BS, Truong MT, Wu CC. Imaging of eosinophilic lung diseases. Radiol Clin North Am. 2016;54(6):1151– 1164. 33. Buelow BJ, Kelly BT, Zafra HT, Kelly KJ. Absence of peripheral eosinophilia on initial clinical presentation does not rule out the diagnosis of acute eosinophilic pneumonia. J Allergy Clin Immunol Pract. 2015;3(4):597– 598. 34. King MA, Pope-Harman AL, Allen JN, Christoforidis GA, Christoforidis AJ. Acute eosinophilic pneumonia: radiologic and clinical features. Radiology. 1997;203(3):715–719. 35. Daimon T, Johkoh T, Sumikawa H, et al. Acute eosinophilic pneumonia: thin-section CT findings in 29 patients. Eur J Radiol. 2008;65(3):462–467. 36. Cheon JE, Lee KS, Jung GS, Chung MH, Cho YD. Acute eosinophilic pneumonia: radiographic and CT findings in six patients. AJR Am J Roentgenol. 1996;167(5):1195–1199. 37. Jeong YJ, Kim KI, Seo IJ, et al. Eosinophilic lung diseases: a clinical, radiologic, and pathologic overview. Radiographics. 2007;27(3):617–637, discussion 37–39. 38. Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood. 1994;83(10):2759–2779. 39. Simon HU, Rothenberg ME, Bochner BS, Weller PF, Wardlaw AJ, Wechsler ME, Rosenwasser LJ, Roufosse F, Gleich GJ, Klion AD. Refining the definition of hypereosinophilic syndrome. J Allergy Clin Immunol. 2010;126(1): 45–49. 40. Curtis C, Ogbogu P. Hypereosinophilic syndrome. Clin Rev Allergy Immunol. 2016;50(2):240–251. 41. Crane MM, Chang CM, Kobayashi MG, Weller PF. Incidence of myeloproliferative hypereosinophilic syndrome in the United States and an estimate of all hypereosinophilic syndrome incidence. J Allergy Clin Immunol. 2010;126(1): 179–181. 42. Epstein DM, Taormina V, Gefter WB, Miller WT. The hypereosinophilic syndrome. Radiology. 1981;140(1):59–62. 43. Fauci AS, Harley JB, Roberts WC, Ferrans VJ, Gralnick HR, Bjornson BH. NIH conference. The idiopathic hypereosinophilic syndrome. Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med. 1982; 97(1):78–92. 44. Podjasek JC, Butterfield JH. Mortality in hypereosinophilic syndrome: 19 years of experience at Mayo Clinic with a review of the literature. Leuk Res. 2013;37(4):392–395. 45. Mankad R, Bonnichsen C, Mankad S. Hypereosinophilic syndrome: cardiac diagnosis and management. Heart. 2016;102(2):100–106. 46. Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore). 1975;54(1):1–27. 47. Kang EY, Shim JJ, Kim JS, Kim KI. Pulmonary involvement of idiopathic hypereosinophilic syndrome: CT findings in five patients. J Comput Assist Tomogr. 1997;21(4):612–615. 48. Dulohery MM, Patel RR, Schneider F, Ryu JH. Lung involvement in hyper­ eosinophilic syndromes. Respir Med. 2011;105(1):114–121.

38 

Metabolic and Storage Lung Diseases* CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

Metabolic and storage lung diseases are a broad group of diseases and syndromes characterized by underlying biochemical or metabolic dysfunctions. Accurate diagnosis is difficult because these diseases are often indolent, are rarely encountered in clinical practice, and because their manifestations are often vague and nonspecific. These groups of disorders may affect the lung solely or as part of a systemic disorder.

Metabolic Pulmonary Diseases Pulmonary Alveolar Proteinosis ETIOLOGY Pulmonary alveolar proteinosis (alveolar lipoproteinosis) is a rare disease characterized by the accumulation of protein- and lipid-rich material resembling surfactant within the parenchymal airspaces.1 Three distinct subtypes of the disease are recognized: autoimmune or acquired, secondary, and genetic. More than 90% of cases are acquired and likely of autoimmune etiology related to a mutation in the surfactant gene or the presence of an antibody to granulocyte-macrophage colony-stimulating factor. These mutations and antibodies result in the defective clearance of surfactant by alveolar macrophages, as well as impaired function of lung neutrophils.1–3 Less commonly, pulmonary alveolar proteinosis is secondary, occurring in association with conditions that result in functional impairment or reduced numbers of alveolar macrophages, as may occur in inorganic dust inhalation, particularly acute silicosis; immunodeficiency syndromes, such as acquired immunodeficiency syndrome or immunoglobulin deficiency; and hematologic malignant neoplasms, such as acute myelogenous leukemia.1,4 Rarely, it may be congenital and rapidly fatal.2 PREVALENCE AND EPIDEMIOLOGY The prevalence of pulmonary alveolar proteinosis has been estimated to be approximately 4 per million persons.2 Pulmonary alveolar proteinosis occurs predominantly in patients between the ages of 20 and 50 years and has a male-to-female preponderance of about 2.5 : 1.1 About 70% of patients are smokers. CLINICAL PRESENTATION Patients may be asymptomatic in up to a third of all cases.3 The most frequent symptom is shortness of breath on exertion that is *The editors and the publisher would like to thank Drs. Nestor L. Müller and C. Isabela Silva Müller for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

usually slowly progressive. Cough, usually nonproductive, is also common. A low-grade fever develops or is evident at initial evaluation in some patients and should suggest concomitant infection. Clubbing of the fingers has been identified in about a third of patients.5 PATHOPHYSIOLOGY On histologic examination the alveoli can be seen to be filled with finely granular, lipoproteinaceous material that stains eosinophilic with hematoxylin and eosin and purple with periodic acid–Schiff (Fig. 38.1). The alveolar architecture is usually preserved, but septal thickening may be due to edema, dilated lymphatics, or lymphocytic infiltration.5 Ultrastructural examination by transmission electron microscopy shows the intraalveolar material to consist of amorphous granular debris containing numerous relatively discrete osmiophilic granules or lamellar bodies. These structures represent phospholipids and are identical to inclusions found in normal type II pneumocytes.5 Pulmonary function test results may be normal or show a restrictive ventilatory defect with reduction in vital capacity and total lung capacity and a disproportionately severe decrease in the carbon monoxide diffusing capacity (DLCO).4 Extensive disease may result in hypoxemia and increased alveolar-arterial pressure gradient (PAO2-PaO2), which increases further with exercise.5 MANIFESTATIONS OF THE DISEASE Radiography The characteristic radiographic pattern of pulmonary alveolar proteinosis consists of bilateral, symmetric patchy areas of consolidation that have a vaguely nodular appearance.1,5 In up to 50% of cases, the consolidation is perihilar (bat wing or butterfly distribution; Fig. 38.2); in the remaining cases, it is random or has a predominantly peripheral or basal distribution (Fig. 38.3). In up to 84% of cases, there is regional sparing, most commonly the lung apices, costophrenic sulci, or lung periphery.2 Characteristically, patients may have extensive consolidation and relatively mild respiratory symptoms (“clinicoradiologic discrepancy”).5 In patients who have less severe disease, the appearance may be one of ground-glass opacities.6 Frequently, the parenchymal involvement is asymmetric or rarely unilateral.2,7 In some patients a linear interstitial pattern can be seen superimposed on consolidation or ground-glass opacities. High-Resolution Computed Tomography High-resolution computed tomography (HRCT) is superior to chest radiography in assessment of the pattern and distribution of abnormalities and may show lesions even when radiography is normal.7,8 The predominant abnormality typically consists of bilateral ground-glass opacities, although consolidation may also be present, particularly in the dorsal lung regions.8,9 The 535

536

SECTION 7  Diffuse Lung Diseases

A Fig. 38.1  Pulmonary alveolar proteinosis. Histologic specimen shows filling of the alveolar airspaces with a granular eosinophilic proteinaceous material. (Courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Vancouver, Canada.)

ground-glass opacities tend to involve all lung zones to a similar extent but can have a predominant lower zone distribution. In about 75% of cases in one series, a fine linear pattern forming polygonal shapes, measuring 3 to 10 mm in diameter, can be seen superimposed on the ground-glass opacities (“crazy paving” pattern; see Figs. 38.2 and 38.3).2,9,10 The pattern reflects the presence of interstitial edema or the accumulation of lipoproteinaceous material in the airspaces adjacent to the interlobular septa.10,11 There is typically sharp demarcation between normal and abnormal parenchyma. Pleural effusions and lymphadenopathy are always absent and should raise suspicion for an alternative diagnosis, secondary pulmonary alveolar proteinosis, or the possibility of coexistent infection.2 The radiologic manifestations of secondary pulmonary alveolar proteinosis are often similar to those of the more common idiopathic form (Fig. 38.4). However, some subtypes, such as silicoproteinosis, may manifest with dependent consolidation, often containing foci of calcification, as well as diffuse solid centrilobular nodules and patchy ground-glass opacities. Affected patients also have calcified mediastinal and hilar lymph nodes, and the “crazy paving” pattern is usually absent.12,13 In reviewing the radiographic and CT images in a patient with known pulmonary alveolar proteinosis, it is important also to look for complications. The main complication is infection, including community-acquired pneumonia and infection caused by unusual organisms such as Nocardia, Aspergillus, and Pneumocystis.1 The increased susceptibility to pulmonary infection may be due to impaired macrophage and neutrophil function, as well as the presence of intraalveolar lipoproteinaceous fluid that may facilitate the growth of microorganisms.1 The prevalence of opportunistic infections has decreased considerably since the use of bronchoalveolar lavage (BAL) for the treatment of these patients.1 Interstitial fibrosis occasionally develops in patients with pulmonary alveolar proteinosis manifesting as airway irregularity and fissural displacement (Fig. 38.5).2,14,15 Other rare complications include the development of emphysematous bullae and pneumothorax.1 Pulmonary alveolar proteinosis has been shown to demonstrate increased fluorodeoxyglucose uptake, which is

B Fig. 38.2  Pulmonary alveolar proteinosis: imaging findings. (A) Posteroanterior chest radiograph shows airspace consolidation and groundglass opacities mainly in the perihilar regions (butterfly pattern) with sparing of the peripheral regions. Note vaguely nodular appearance. (B) High-resolution CT demonstrates extensive bilateral ground-glass opacities and a superimposed fine linear pattern forming polygonal arcades (“crazy paving” pattern). Note sharp demarcation of normal lung from abnormal lung.

thought to be related to glucose use by the inflammatory components.16 DIFFERENTIAL DIAGNOSIS The findings on the chest radiograph mimic those of pneumonia, pulmonary edema, and hemorrhage, but unlike those other conditions, a patient with pulmonary alveolar proteinosis is much less symptomatic than the radiographic appearance would suggest. The diagnosis of pulmonary alveolar proteinosis can often be suggested by the characteristic manifestations on HRCT. However, although it is characteristic of pulmonary alveolar proteinosis,

38  Metabolic and Storage Lung Diseases

A

537

Fig. 38.4  Secondary pulmonary alveolar proteinosis in an 11-year-old girl undergoing immunosuppressive therapy for aplastic anemia. Highresolution CT shows bilateral ground-glass opacities with sparing of the peripheral lung. Mild superimposed linear opacities (“crazy paving” pattern) are present in the lower lobes.

SYNOPSIS OF TREATMENT OPTIONS

B Fig. 38.3  Pulmonary alveolar proteinosis: imaging findings. (A) Posteroanterior chest radiograph shows asymmetric hazy areas of increased opacity (ground-glass opacities) and faint reticulonodular pattern in the right middle and bilateral lower lung zones. (B) High-resolution CT shows bilateral ground-glass opacities and superimposed fine linear pattern forming polygonal arcades (“crazy paving” pattern). Note the sharp demarcation between normal and abnormal parenchyma, a feature that usually reflects lobular boundaries. Also note the presence of mild emphysema.

the “crazy paving” pattern can also be seen in a variety of other conditions, including primary lung or metastatic adenocarcinoma, lipoid pneumonia, pulmonary hemorrhage or edema, and infections, including bacterial or Pneumocystis pneumonia.17 The diagnosis of pulmonary alveolar proteinosis can usually be confirmed by examination of BAL.5 Characteristic features of pulmonary alveolar proteinosis include milky BAL fluid; relatively few inflammatory cells, including alveolar macrophages; large acellular eosinophilic bodies in a diffuse background of granular basophilic material; periodic acid–Schiff staining of the proteinaceous material; elevated levels of surfactant proteins; and characteristic ultrastructural features with abundant lamellar bodies and cellular debris. The main constituent of the BAL fluid in pulmonary alveolar proteinosis is phospholipid, mainly lecithin, the main component of surfactant.5 If it is deemed necessary to confirm the diagnosis by tissue examination, transbronchial biopsy is likely to be sufficient.

Treatment of acquired pulmonary alveolar proteinosis is with unilateral or bilateral whole-lung lavage. Some patients require only one or two procedures, whereas a few require that lavage be repeated semiannually or annually. The overall prognosis for alveolar proteinosis treated by whole-lung lavage is excellent. Corticosteroids should not be used as empirical treatment of alveolar proteinosis because of its potential to exacerbate opportunistic infections.1 Spontaneous resolution without treatment may occur in up to 25% of patients.5 On occasion, patients may not respond to BAL and may require lung transplantation or experimental therapy with granulocyte-macrophage colonystimulating factor or rituximab.3 As might be expected in view of the pathogenesis, recurrence of the condition has been documented after lung transplantation.18 Therapy for secondary pulmonary alveolar proteinosis is aimed at treatment of the underlying condition. For example, in patients with pulmonary alveolar proteinosis secondary to hematologic malignant disease, the pulmonary findings improve or resolve after successful chemotherapy or bone marrow transplantation.4

KEY POINTS: PULMONARY ALVEOLAR PROTEINOSIS • It is a rare disease, usually of autoimmune etiology. • Lipoproteinaceous material (surfactant) fills the airspaces. • Imaging findings: • Ground-glass opacities or consolidation. • Perihilar, peripheral, or random distribution. • High-resolution CT usually shows a characteristic pattern of smooth interlobular septal thickening and intralobular lines superimposed on ground-glass opacities (“crazy paving” pattern). • Abnormal lung is sharply demarcated from normal lung. • Pleural effusion or lymphadenopathy is rare and should suggest an alternative diagnosis—secondary pulmonary alveolar proteinosis or coexistent infection. • Bronchoalveolar lavage is usually diagnostic.

538

SECTION 7  Diffuse Lung Diseases

A

B Fig. 38.5  Pulmonary alveolar proteinosis with fibrosis. (A) Posteroanterior chest radiograph shows patchy bilateral opacities with reticulation. (B) Coronal CT shows asymmetric ground-glass opacities with interlobular septal thickening and intralobular lines (“crazy paving” pattern). Note traction bronchiectasis and traction bronchiolectasis, as well as bilateral major fissure distortion indicating a component of lung fibrosis. As is typically seen, there are several areas of lung that are relatively spared, best visualized in the right lower lobe.

Amyloidosis ETIOLOGY Amyloidosis is a generic term for a heterogeneous group of disorders characterized by accumulation of various insoluble fibrillar proteins (amyloid).19,20 The abnormal proteins are deposited in the extracellular space and cause disease by compression of the adjacent cells and tissues. Amyloidosis can be hereditary or acquired, localized, or systemic. PREVALENCE AND EPIDEMIOLOGY Amyloidosis is rare. It affects the respiratory tract in about 50% of cases.21 Amyloid may involve the trachea, bronchi, mediastinum, pleura, heart, or, more commonly, the lung parenchyma.22 CLINICAL PRESENTATION Tracheobronchial amyloidosis typically manifests after the fifth decade with dyspnea, cough, and occasionally hemoptysis.19 Less commonly, it causes symptoms that simulate asthma. Discrete tracheal and endobronchial nodules are usually asymptomatic but occasionally may result in airway obstruction with distal atelectasis or bronchiectasis. Symptoms and signs in such cases depend on the volume of lung affected and whether infection is present. The presence of amyloid in other sites is rare.23 The nodular parenchymal form of amyloidosis usually is asymptomatic and is discovered incidentally on the chest radiograph.24 The majority of patients have no evidence of extrathoracic disease (either amyloidosis or otherwise).

Diffuse interstitial amyloidosis frequently results in progressive dyspnea and respiratory insufficiency.24 Diffuse involvement is most often seen as part of multisystem disease (primary amyloidosis), in which amyloid type L is typically present and may be associated with multiple myeloma.25 PATHOPHYSIOLOGY Amyloidosis is a disorder of protein folding rather than of amino-acid sequence, and amyloid deposits consist mainly of protein fibrils.19 Amyloid is not a single substance but consists of several proteins, each of which resembles the others morphologically but is distinctive biochemically.26 The most important proteins associated with respiratory tract disease are amyloid L and amyloid A. Amyloid L is derived from immunoglobulin light chains and is therefore usually associated with abnormal plasma cell function, either as part of a systemic disease, such as multiple myeloma or macroglobulinemia, or, more commonly, localized to the lungs without evidence of systemic disease. Amyloid A is derived from a serum acute-phase reactant synthesized in the liver that can be formed in several chronic inflammatory diseases, including connective tissue disease, particularly rheumatoid arthritis; chronic infection, particularly tuberculosis; bronchiectasis; and certain neoplasms, such as Hodgkin disease.19 The majority of cases of respiratory tract amyloidosis are amyloid type L; the main exceptions are in patients with chronic inflammatory disease or a family history of amyloidosis.19 On histologic examination, amyloidosis is characterized by the presence of amorphous, eosinophilic, extracellular material that shows a characteristic apple-green birefringence when it is

38  Metabolic and Storage Lung Diseases

A

539

B Fig. 38.6  Amyloidosis. (A) Histologic specimen shows extracellular amorphous eosinophilic material. (B) Specimen stained with Congo red and examined with polarizing microscopy shows characteristic apple-green birefringence.

stained with Congo red and examined by polarizing microscopy (Fig. 38.6).20 There are three major forms of amyloidosis in the lower respiratory tract: tracheobronchial, nodular parenchymal, and diffuse parenchymal (alveolar septal, interstitial).27 Although these forms can occur in combination, in many cases the amyloid is deposited predominantly at one site. In addition to airway and pulmonary parenchymal disease, amyloidosis can also affect the hilar and mediastinal lymph nodes, pulmonary arteries, pleura, heart, and diaphragm.27 Airway involvement occurs most commonly in the trachea and proximal bronchi. Although overlap does occur, it is usually manifested in one of two ways: a localized nodule or, more commonly, multiple discrete or confluent intramural plaques that distort the airway wall and cause stenosis of its lumen.27 On histologic examination the amyloid is situated in the subepithelial interstitial tissue and often surrounds tracheobronchial gland ducts and acini.27 The parenchymal nodules of localized pulmonary amyloid can be solitary or multiple and are usually fairly well defined. Amyloid is often identifiable in the alveolar interstitium at the periphery of the nodule; however, in the central region the normal parenchymal architecture is generally obscured by a more or less solid mass of amyloid that typically contains fairly numerous multinucleated giant cells and variable numbers of lymphocytes and plasma cells.27 Calcification and ossification are relatively common. The nodular parenchymal form of amyloidosis is usually of amyloid type L and localized to the lung. It is the most common respiratory form of amyloidosis. In one series of 48 patients with localized respiratory tract amyloidosis, 34 had parenchymal deposits, of which 28 cases were nodular and 6 were diffuse alveolar septal.24 Diffuse interstitial (alveolar septal) amyloidosis involves the parenchymal interstitium and the media of small blood vessels. The amyloid deposition is typically adjacent to endothelial and epithelial basement membranes and can appear in a uniform and more or less linear pattern or as multiple small nodules.27 Lung Function Pulmonary function tests may show evidence of restriction and impaired gas transfer in patients who have diffuse alveolar septal

amyloidosis and air-trapping and fixed upper airway obstruction in those who have proximal tracheobronchial involvement.27 MANIFESTATIONS OF THE DISEASE Radiography In the majority of patients with tracheobronchial amyloidosis, the chest radiograph is normal. When present, the findings include focal or diffuse thickening of the airway wall with associated narrowing of the airway lumen (Fig. 38.7).25 The findings are often difficult to see on the radiograph. Nodular primary parenchymal amyloidosis manifests as solitary or, less commonly, multiple nodules usually ranging from 0.5 to 15 cm in diameter.25 The nodules occur most commonly in the lower lobes and are usually peripheral. Disease may progress slowly during a period of several years, with a slight increase in size of the nodules and the development of additional nodules. Diffuse interstitial (alveolar septal) amyloidosis results in a reticular, nodular, or reticulonodular pattern that may be diffuse or involve mainly the lower lobes.25 Pleural effusions may occur in amyloidosis but are usually due to heart failure caused by cardiac involvement.21 Pleural amyloid deposits are rare. Computed Tomography The CT manifestations of tracheobronchial amyloidosis consist of thickening of the airway wall, narrowing of the lumen, and, in some cases, foci of calcification (Fig. 38.8; see Fig. 38.7).28,29 The airway wall thickening may be focal or diffuse and nodular, plaque-like, or circumferential; it is generally confined to the trachea but can extend to the main, lobar, and segmental bronchi.25,29 Bronchial involvement is frequently associated with distal atelectasis, bronchiectasis, or air-trapping.21 Nodular primary parenchymal amyloidosis manifests as solitary or, less commonly, multiple nodules usually ranging from 0.5 to 5 cm in diameter (Fig. 38.9).30 On occasion, nodular parenchymal amyloidosis may result in a large mass (Fig. 38.10). Calcification is seldom evident on radiographs but is seen in 20% to 50% of nodules on CT.30,31 The nodules tend to be more common in the periphery of the lower lobes but may be seen anywhere in the parenchyma (see Fig. 38.9). Rarely, nodules will

540

SECTION 7  Diffuse Lung Diseases

A

B Fig. 38.7  Diffuse tracheal amyloidosis. (A) Magnified view from a chest radiograph shows narrowing of the mid trachea. (B) Axial CT from a different patient immediately above the level of the aortic arch shows marked circumferential thickening of the trachea (arrows). On CT and at bronchoscopy, the entire trachea was abnormal. (B from Müller NL, Fraser RS, Colman NC, Paré PD. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

Mediastinal and hilar lymphadenopathy is rare in localized disease but occurs in approximately 75% of patients with amyloid L-type systemic amyloidosis (Fig. 38.12). It is seen most commonly with diffuse interstitial amyloidosis.25 DIFFERENTIAL DIAGNOSIS

Fig. 38.8  Diffuse tracheobronchial amyloidosis. Magnified view of the trachea shows circumferential thickening and foci of calcification.

cavitate.22 Cysts may occasionally be present adjacent to the nodules. Cysts and nodular amyloid deposits have been described most commonly in patients with Sjögren syndrome, with or without associated lymphoid interstitial pneumonia (Fig. 38.11).32 The HRCT findings of diffuse interstitial amyloidosis consist mainly of reticular opacities and interlobular septal thickening.21,30 Multiple subpleural micronodules can often be seen in association with the reticular opacities. Less common HRCT findings include ground-glass opacities, consolidation, traction bronchiectasis, and honeycombing.30 Punctate calcification may be seen in some of the nodules and areas of consolidation.

The radiologic and CT findings are relatively nonspecific. The differential diagnosis of tracheal wall thickening includes relapsing polychondritis, tracheobronchopathia osteochondroplastica (TBO), granulomatosis with polyangiitis (formerly Wegener granulomatosis), inflammatory bowel disease, and adenoid cystic carcinoma. Unlike amyloidosis, both relapsing polychondritis and TBO typically spare the noncartilaginous posterior membrane.33 The main differential diagnosis of the parenchymal nodular form of amyloidosis is granulomatous infection or primary or metastatic tumors. The differential diagnosis of the diffuse interstitial form includes a large number of interstitial and airspace lung diseases, such as nonspecific interstitial pneumonia, usual interstitial pneumonia, and primary lung and metastatic adenocarcinoma. The diagnosis of amyloidosis usually requires histologic confirmation by needle, bronchial, transbronchial, or surgical biopsy. The diagnosis is based on demonstration of amyloid by Congo red staining, which produces characteristic apple-green birefringence under crossed polarized light.27 SYNOPSIS OF TREATMENT OPTIONS The treatment of symptomatic tracheobronchial amyloidosis may involve intermittent bronchoscopic resection, surgical resection, or laser ablation.19 Repeated bronchoscopic intervention is considered preferable to surgical resection, but recurrence is

A

B Fig. 38.9  Nodular parenchymal amyloidosis proven at surgical resection. High-resolution CT images at the level of the aortic arch (A) and tracheal carina (B) show bilateral nodules with spiculated margins.

B

A

C

D Fig. 38.10  Nodular parenchymal amyloidosis. Posteroanterior (A) and lateral (B) chest radiographs show a homogeneous mass occupying most of the right hemithorax. CT at the level of the lower trachea (C) and left main bronchi (D) show a large right upper and middle lobe mass with numerous coarse foci of calcification. The mass extends into the mediastinum, is associated with calcified mediastinal lymph nodes, and compresses the trachea and right bronchi.

542

SECTION 7  Diffuse Lung Diseases

common.19 Stenting may have a role in the treatment of airway narrowing and complications thereof. Nodular parenchymal amyloidosis is usually asymptomatic and remains stationary or progresses slowly. It usually has a good prognosis and seldom requires treatment. By contrast, diffuse interstitial amyloidosis frequently progresses. Treatment includes oral melphalan and prednisolone or peripheral stem cell transplantation.19 The natural history and prognosis of disease in patients who have diffuse interstitial pulmonary involvement may be determined by the presence of amyloid elsewhere in the body, particularly the heart and kidneys; however, many patients die of respiratory failure. In one series of 35 patients, the median survival time after diagnosis was only 16 months.25

Pulmonary Alveolar Microlithiasis ETIOLOGY

Fig. 38.11  Nodular parenchymal amyloidosis with lymphoid interstitial pneumonia in a patient with Sjögren syndrome. Axial CT shows calcified nodules and cysts throughout both lungs. Pulmonary cysts associated with amyloidosis are most commonly seen in patients with Sjögren syndrome and may be secondary to coexistent lymphoid interstitial pneumonia or amyloidosis itself.

A

Pulmonary alveolar microlithiasis is a rare disease characterized by innumerable tiny calculi (microliths) within alveolar airspaces.34 Although it can occur at any age, most reported cases have been in patients between the ages of 20 and 50 years.35 The disorder is autosomal recessive and is caused by a mutation in the SLC34A2 gene.36 PREVALENCE AND EPIDEMIOLOGY Alveolar microlithiasis is rare. A total of 500 to 800 cases had been published in the literature before 2016.36,37 Approximately

B Fig. 38.12  Calcified lymph nodes with lung fibrosis from systemic (light-chain) AL amyloidosis associated with monoclonal gammopathy of undetermined significance. (A) Posteroanterior chest radiograph shows enlarged mediastinal and left neck calcified lymph nodes. Note left lung volume loss with fibrosis secondary to long-standing left pulmonary artery and left main bronchus compression. (B) Coronal noncontrast CT shows massive partially calcified mediastinal and hilar lymphadenopathy, which causes occlusion of the distal left main bronchus.

38  Metabolic and Storage Lung Diseases KEY POINTS: AMYLOIDOSIS • Abnormal protein is deposited in extracellular tissues. • Amyloidosis is a disorder of protein folding rather than of amino-acid sequence. • The three main manifestations are tracheobronchial, parenchymal nodular, and diffuse interstitial. • Tracheobronchial amyloidosis • Clinical symptoms: dyspnea and cough; focal or diffuse thickening of the trachea or central bronchi that involves the posterior membrane • Foci of calcification common • Atelectasis and obstructive pneumonitis • Nodular parenchymal amyloidosis • Usually asymptomatic • Single or multiple nodules or masses • Mainly lower lobe and peripheral location • Foci of calcification common • Diffuse interstitial amyloidosis • Clinical symptoms: progressive shortness of breath, dry cough • Reticular pattern • Ground-glass opacities on high-resolution CT (HRCT) • Interlobular septal thickening on HRCT • May be associated with lymphadenopathy and cardiac involvement

43% of cases came from Europe and 41% from Asia; the remaining cases were from the United States and other countries. The disease does not have any preference for specific races, and the incidence is similar in both sexes.35 However, it has been described in premature twins.35 Family history for the disease is found in one-third of the patients and is often associated with consanguineous marriage.34,36,37 CLINICAL PRESENTATION There is typically dissociation between the radiologic findings, which can be striking and extensive, and the clinical manifestations, which are usually mild. More than 50% of patients are asymptomatic when the disease is first discovered, the diagnosis being made on the basis of the typical pattern seen on a chest radiograph.37 The most common symptom is dyspnea on exertion; cough develops occasionally. The disease can remain stable for many years or progress slowly. As the disease progresses, respiratory insufficiency may develop in association with cyanosis, clubbing of the fingers, and evidence of pulmonary hypertension.38 PATHOPHYSIOLOGY The pathogenesis of microlithiasis is related to a defective phosphate transporter that is important for type II pneumocytes, which results in the formation of calcium phosphate microliths in the alveolar spaces.36 On histologic examination, microliths consist of calcareous concentric lamellae placed around a central nucleus. The microliths may fill the pulmonary alveolar airspaces. The microliths are most numerous in the lower lung zones. They range in size from about 250 to 750 µm in diameter and are round, oval, or irregular in shape.39 Chemical analysis and energy-dispersive x-ray microanalysis have shown them to be composed mainly of calcium phosphate.40,41 In early disease the alveolar walls are normal; eventually, interstitial fibrosis develops, sometimes associated with multinucleated giant cell formation.40

543

MANIFESTATIONS OF THE DISEASE Radiography The characteristic radiographic pattern is one of a fine sand–like micronodulation (“sandstorm lung”) that may be diffuse but tends to be most severe in the middle and lower lung zones.34,42 Regardless of the effect of superimposition or summation of shadows, individual deposits are usually identifiable as sharply defined nodules measuring less than 1 mm in diameter. On occasion, there is a reticular pattern or septal lines superimposed on the characteristic sandstorm appearance (Fig. 38.13). Other findings may include bullae in the lung apices, a zone of increased lucency between the lung parenchyma and the ribs (known as a black pleural line), and pleural calcification (Fig. 38.14).42,43 Computed Tomography HRCT manifestations consist of calcific nodules measuring 1 mm or less in diameter, sometimes confluent, and distributed predominantly along the cardiac borders and dorsal portions of the lower lung zones (see Fig. 38.13).42,44 The higher attenuation in the dorsal portion of the lungs persists when scans are obtained with the patient in the prone position. Other common findings on HRCT include ground-glass opacities, interlobular septal thickening (often with apparent extensive calcification), subpleural interstitial thickening, and paraseptal emphysema (see Fig. 38.14).42,44 HRCT-pathologic correlation has shown that the apparent calcification of interlobular septa on CT is due to accumulation of microliths in the periphery of the secondary lobules rather than interstitial disease.11 Correlation of HRCT with radiographic findings has shown that the black pleural line on the radiograph can be caused by subpleural cysts along the costal and mediastinal pleura (see Fig. 38.14) or by a layer of extrapleural fat.44,45 Nuclear Medicine Technetium-99m methylene diphosphonate (99mTc-MDP) bone scintigraphy usually shows diffuse uptake of radiotracer in both lungs.46 DIFFERENTIAL DIAGNOSIS The differential diagnosis of microlithiasis includes miliary tuberculosis, sarcoidosis, talcosis caused by intravenous drug use, amyloidosis, idiopathic pulmonary ossification, and metastatic pulmonary calcification. The diagnosis can generally be made with confidence on the basis of the classic radiographic pattern of sand-like nodules in a predominantly middle and lower lung zone distribution and the striking radiologic-clinical disparity in severity of disease. Values from chemical analysis of blood are invariably within the normal range. Microliths can be identified in sputum, BAL fluid, and transbronchial biopsy specimens.41 SYNOPSIS OF TREATMENT OPTIONS Treatment is palliative and includes the use of diphosphonate, steroids, and therapeutic BAL, although the effectiveness of these therapies is debatable.35,36 On occasion, patients progress to respiratory failure and may require lung transplantation.47 Once the diagnosis has been established, the patient’s family should be screened for the disorder because of its autosomal-recessive inheritance.

544

A

SECTION 7  Diffuse Lung Diseases

B Fig. 38.13  Alveolar microlithiasis. (A) Posteroanterior chest radiograph shows bilateral high-attenuation nodularity with septal lines and thickening of the subpleural interstitium with a middle and lower lung zone predominance. (B) Composite image with axial CT in lung window (left image) and axial CT in bone window (right image) shows extensive high-attenuation deposits involving the periphery of the secondary pulmonary lobules. Note confluent calcification in the lingula adjacent to the heart border. (Courtesy Dr. Christian Cox, Mayo Clinic, Rochester, MN.)

A

B Fig. 38.14  Alveolar microlithiasis. (A) View of the left lung from a posteroanterior chest radiograph shows numerous small calcific opacities, resulting in a sandstorm appearance. Note zone of increased lucency (arrows) between the ribs and the peripheral lung (black pleural line). (B) Axial CT shows diffuse bilateral ground-glass opacities with scattered small calcific nodules. Note subpleural cysts along the periphery of the lung, which give rise to the black pleural line on chest radiography. (Courtesy Dr. Christian Cox, Mayo Clinic, Rochester, MN.)

38  Metabolic and Storage Lung Diseases KEY POINTS: PULMONARY ALVEOLAR MICROLITHIASIS • Idiopathic accumulation of innumerable tiny calculi (microliths) within alveolar airspaces is seen. • It is often asymptomatic and may result in progressive shortness of breath. • Innumerable sand-like nodules (64 years), reduced renal function, anemia, reduced gas diffusing capacity for carbon monoxide (DLCO), reduced total serum protein level, and decreased pulmonary reserve (forced vital capacity).9 Individuals with anticentromere antibody (ACA) have a better prognosis than those with anti–topoisomerase I (Scl-70) antibody.10 The poorer prognosis of those with anti–Scl-70 probably relates to the fact that fibrotic lung disease is more likely to develop in these patients and to be manifested as diffuse systemic sclerosis.

Clinical Presentation Only 1% of patients initially have respiratory symptoms,11 usually shortness of breath on exertion, but in established disease, dyspnea is the most common pulmonary symptom in systemic sclerosis *The editors and the publisher would like to thank Drs. Maureen Quigley and David M. Hansell for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

and occurs in about 60% of patients.11 Approximately 16% of patients with systemic sclerosis have pleuritic chest pain at some time in their disease. Unlike patients with rheumatoid arthritis or systemic lupus erythematosus, clinically significant pleural effusion rarely develops in patients with systemic sclerosis.12 Nevertheless, pleural fibrosis and adhesions are frequently identified at autopsy.13 Approximately 41% of patients with systemic sclerosis have pulmonary hypertension,14 and dyspnea on exertion is usually the first symptom of pulmonary hypertension. The risk for pulmonary hypertension in patients with systemic sclerosis increases with the age at disease onset15; gas diffusing capacity may be significantly decreased for many years before the diagnosis of pulmonary hypertension is made (perhaps indicating subclinical disease).16 Cardiac symptoms reflect a wide range of possible involvement: right-left ventricular dysfunction (fatigue), pulmonary hypertension (dyspnea), congestive heart failure (edema), pericarditis/ angina (chest pain), autonomic dysfunction (palpitations), and rhythm disturbances and conduction defects (dizziness, syncope, sudden death).17 Gastrointestinal symptoms, particularly swallowing difficulties, are common. The severity of esophageal motor involvement in systemic sclerosis has been shown to correlate with the severity of pulmonary manifestations of the disease (quantified by decreased DLCO) and evidence of interstitial lung disease on high-resolution computed tomography (HRCT).18 This may be due to the fact that there is a relationship between gastroesophageal reflux and interstitial lung disease, but an alternative explanation is that they both reflect the severity of the systemic vasculopathy.18 Systemic sclerosis is accompanied by joint pain in 15% of patients and by inflammatory myopathy in 10% of patients. Muscle weakness, cutaneous pruritus, and Raynaud phenomenon are common.13 Renal failure can be manifested as hypertensive/normotensive renal failure or as an abrupt onset of a renal emergency.19 Scleroderma can be localized to the skin or be systemic. Systemic disease is further divided into limited cutaneous and diffuse cutaneous types. Limited cutaneous systemic sclerosis encompasses the now outdated term “CREST variant” (calcinosis, Raynaud disease, esophageal dysmotility, sclerodactyly, and telangiectasia). Limited cutaneous systemic sclerosis is defined by skin thickening in areas distal to the elbows and knees, with or without facial scleroderma. By contrast, diffuse cutaneous systemic sclerosis is defined by the presence of skin thickening proximal as well as distal to the elbows and knees, with or without facial or truncal disease.20 Although lung involvement occurs more frequently in the diffuse form of systemic sclerosis, it is evident in approximately a third of patients with limited cutaneous disease.21 561

562

SECTION 8  Connective Tissue Diseases

Pathophysiology

Manifestations of the Disease

PATHOLOGY

The hallmark of systemic sclerosis is thickened skin. In diffuse scleroderma with facial involvement, a cardinal sign is exaggerated radial furrowing around the lips (tobacco pouch sign). Skin thickening starts with the fingers and hands in virtually all cases; progression of the skin tightening and thickening is variable. Calcinosis is seen over the periarticular surfaces of the hands, elbows, and knees. Telangiectases occur on the hands, face, lips and gastrointestinal mucosal surfaces. The cutaneous macules are a harmless cosmetic problem, but those in the gastrointestinal tract can bleed and lead to iron deficiency anemia.19 Patients with systemic sclerosis commonly have Raynaud phenomenon (reversible vasomotor instability precipitated by cold or emotion). It is usually manifested as changes in color of the extremities (pallor to cyanosis and eventually erythema).

Scleroderma is characterized by fibrosis and vascular obliteration of the skin, gastrointestinal tract, lungs, heart, and kidneys. The lungs are the second most common site of visceral involvement, and pulmonary disease is a major cause of death in patients with systemic sclerosis.22 The two main pulmonary manifestations are interstitial fibrosis and pulmonary hypertension; the latter reflects a primary vasculopathy, but it may be secondary to cardiac or pulmonary disease. A postmortem study has reported that three quarters of patients with systemic sclerosis had interstitial fibrosis.13 Pulmonary fibrosis has been estimated to ultimately develop in 80% of patients with systemic sclerosis and pulmonary arterial hypertension in 50% of cases.23 Patients with systemic sclerosis generally fall into one of two categories: those in whom fibrotic lung disease develops and who have anti–Scl-70 antibodies (and in whom pulmonary hypertension may develop secondary to their heart or lung disease) and those who have solely pulmonary hypertension and positive serology for ACA.24 Of interest, ACA and anti–Scl-70 antibodies are almost always mutually exclusive, being simultaneously present in less than 0.5% of patients with systemic sclerosis. Patients with diffuse cutaneous systemic sclerosis and anti–Scl-70 antibody are at especially high risk for fibrotic lung disease.25 The most frequent histologic subtype of pulmonary fibrosis is nonspecific interstitial pneumonia (NSIP). A review of lung biopsy specimens taken from patients with systemic sclerosis found that more than 75% of this cohort had NSIP on histologic review.26 The high frequency of NSIP in this study can probably be extrapolated to a wider population of patients with systemic sclerosis who have not undergone lung biopsy.27 The prevalence of usual interstitial pneumonia (UIP) in the systemic sclerosis population has been estimated to be less than 10%.26,27 There are case reports of diffuse alveolar damage in systemic sclerosis, but it is rare.28 A few cases of diffuse alveolar hemorrhage have also been reported; in most instances the diffuse alveolar hemorrhage occurs in the setting of preexisting fibrotic lung disease.29,30 Cardiac involvement is virtually always present to some degree in the form of patchy myocardial fibrosis, sometimes causing ventricular diastolic dysfunction.17 Ventricular systolic dysfunction is also seen in patients with concomitant coronary or hypertensive heart disease. Patients with systemic sclerosis are prone to the development of conduction defects and autonomic cardiac neuropathy.17 In a postmortem series, the esophagus was involved in 75% of patients with systemic sclerosis,13 and at autopsy most organs show evidence of patchy fibrosis or atrophy, or both. LUNG FUNCTION In systemic sclerosis, a diffusing capacity (DLCO) of 50% or less of predicted and reduced spirometric reserve predict reduced survival.9 Diminished diffusing capacity is the earliest detectable pulmonary function abnormality in patients with systemic sclerosis, and it correlates with clinical symptoms of dyspnea and the presence of pulmonary fibrosis.31 The diffusing capacity can be reduced because of pulmonary fibrosis or vasculopathy. Reduced diffusing capacity is the best predictor of the extent of fibrotic lung disease in systemic sclerosis.32

RADIOGRAPHY The most frequent abnormality on chest radiography is a widespread, symmetric basal reticulonodular pattern (Fig. 40.1).33 Depending on the severity of the pulmonary fibrosis, honeycombing, reduced lung volumes, and traction bronchiectasis can be appreciated on the chest radiograph. However, as with all interstitial lung disease, chest radiography lacks the sensitivity of HRCT for the detection of limited parenchymal disease.27,34 A dilated air-filled esophagus can be identified in many patients (see Fig. 40.1).35 Because there is no anatomic obstruction, a fluid level is not usually a feature on erect chest radiographs. COMPUTED TOMOGRAPHY The majority of patients with fibrosing lung disease and systemic sclerosis have a histologic pattern of NSIP rather than UIP (Fig. 40.2; see Fig. 40.1). Evidence for this comes from both histopathologic and radiologic studies.26 The typical HRCT appearances of NSIP consist of predominantly ground-glass opacities involving mainly the lower lung zones and often mainly the subpleural regions, reticulation, architectural distortion (traction bronchiectasis and volume loss), and occasional limited honeycombing.36–38 Although ground-glass opacities may initially be the predominant or only abnormality, over time, progressive reticulation, traction bronchiectasis, traction bronchiolectasis, and, less commonly, areas of honeycombing tend to develop (see Fig. 40.2). In many patients traction bronchiectasis is a predominant abnormality. In patients with symptomatic pulmonary involvement in systemic sclerosis, pulmonary fibrosis and ground-glass opacity are common findings, with honeycombing seen more frequently in the limited than the diffuse cutaneous form of systemic sclerosis subtypes.39 The extent of involvement at HRCT correlates with patient prognosis in systemic sclerosis; in an important study, patients with less than 20% involvement of the lungs had an average 10-year survival of 67%, whereas a group with greater than 20% involvement had an average survival of 43%.40 Lymphadenopathy is frequent in patients with systemic sclerosis and interstitial lung disease, and the degree of lymph node enlargement is related to the extent, but not the type, of interstitial disease.41 In patients with isolated pulmonary arterial hypertension (and limited scleroderma), evidence of raised pulmonary artery

40  Systemic Sclerosis (Scleroderma)

A

563

B Fig. 40.1  (A) Systemic sclerosis: radiographic and high-resolution computed tomography (HRCT) findings. Posteroanterior chest radiograph shows left greater than right lower lung zone reticular pattern with decreased lung volumes. Note an air-filled tubular structure in the left paratracheal region caused by a dilated esophagus. (B) HRCT shows ground-glass opacities, extensive reticulation, and traction bronchiectasis and bronchiolectasis in the left lower lobe. Mild fibrosis is seen in the right lower and middle lobes and lingula, along with minimal bilateral subpleural honeycombing. The parenchymal findings were confirmed to be nonspecific interstitial pneumonia. Note the dilated air-filled esophagus.

A

B Fig. 40.2  (A) Nonspecific interstitial pneumonia in systemic sclerosis. High-resolution computed tomography (HRCT) shows diffuse bilateral ground-glass opacities. Note the minimal bilateral peripheral reticulation and dilated esophagus. (B) HRCT approximately 10 years later shows extensive reticulation and traction bronchiectasis superimposed on the ground-glass opacities, consistent with progressive fibrosis.

pressure may be a diameter of the main pulmonary artery greater than 3.2 cm, or a diameter larger than that of the adjacent ascending aorta (Fig. 40.3)42; however, a nondilated pulmonary artery does not necessarily exclude pulmonary hypertension. A number of studies have shown an increased risk for lung cancer (usually adenocarcinoma) in patients with systemic

sclerosis, including nonsmokers,43–45 and this is relevant in the evaluation of incidental pulmonary nodules. There are a few isolated case reports of diffuse alveolar damage28 and diffuse alveolar hemorrhage29,30 in patients with systemic sclerosis, and both diseases have similar and nonspecific appearances on HRCT (widespread consolidation and/or ground-glass opacities).

564

SECTION 8  Connective Tissue Diseases

Fig. 40.3  Pulmonary hypertension confirmed by right heart catheterization with fibrotic lung disease in systemic sclerosis. CT shows bilateral ground-glass opacities and peripheral predominant reticulation and minimal honeycombing, consistent with interstitial fibrosis. The diameter of the pulmonary artery (arrows) is greater than that of the adjacent ascending aorta, indicating pulmonary hypertension.

KEY POINTS: MANIFESTATIONS OF SYSTEMIC SCLEROSIS ON HIGH-RESOLUTION COMPUTED TOMOGRAPHY • Pulmonary fibrosis: fibrotic nonspecific interstitial pneumonia is the most common pattern • Ground-glass opacities with extensive traction bronchiectasis • Fine reticular pattern or limited honeycombing (subpleural and basal) • Dilated esophagus • Dilated main pulmonary artery • Mediastinal and hilar lymphadenopathy • Consolidation possible as a result of infection, aspiration, organizing pneumonia, diffuse alveolar damage, or occasionally diffuse pulmonary hemorrhage

CLASSIC SIGNS The Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association proposed preliminary criteria for systemic sclerosis in 1980. Proximal scleroderma was the single major criterion and had a sensitivity of 91% and a specificity of 99%. Sclerodactyly, digital pitting scars of the fingertips or loss of substance of the distal finger pad and basal pulmonary fibrosis were further minor criteria in the absence of proximal scleroderma.46 Updated criteria were published in 2013 by the American College of Rheumatology and the European League Against Rheumatism. Similar to the prior criteria, skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for a diagnosis of scleroderma. However, several additional criteria were added to increase sensitivity for early or mild scleroderma cases, including nail fold capillary abnormalities, and presence of autoantibodies (anti–Scl-70, anticentromere, and anti–ribonucleic acid polymerase III).47

Differential Diagnosis The differential diagnosis of systemic sclerosis includes connective tissue diseases, such as rheumatoid arthritis, mixed connective tissue disease, and overlap syndromes with other connective tissue

diseases. The serologic autoantibody profile is important in all autoimmune diseases. ACA is associated with limited cutaneous involvement in systemic sclerosis.1 It is relatively specific for scleroderma and in one study had a sensitivity of 32%.48 This antibody is rarely found in healthy patients, and its presence in “normal” sera may predict the future development of systemic sclerosis.1 ACAs are associated with isolated pulmonary hypertension secondary to a proliferative vasculopathy,49 and anti–Scl-70 antibodies are associated with the severity and presence of pulmonary fibrosis.3 The antinucleolar system is also a heterogeneous group of antibodies that are not routinely screened for, but anti–PM-Scl antibodies are found in 50% of patients with overlap of scleroderma and dermatomyositis.50 They are less frequently seen in patients with “pure” systemic sclerosis (3%–8% of patients)4; their presence can predict limited cutaneous involvement.5 Granulocytosis on bronchoalveolar lavage has been shown to predict progression of fibrotic lung disease with deterioration of lung function, which is most sensitively monitored by measurements of DLCO.25

Treatment Immunosuppressive or immunomodulatory agents are often used as systemic disease-modifying therapies. Cyclophosphamide and mycophenolate mofetil have shown modest benefit in systemic disease; cyclophosphamide treatment led to a slower progression of measures of fibrosis at HRCT than did patients treated with placebo in the landmark Scleroderma Lung Study.51,52 Organ-based therapies targeted to specific symptoms include proton-pump inhibitors and H1-blockers for gastroesophageal reflux, vasodilators and calcium channel blockers for digital ulcers, and angiotensin-converting enzyme inhibitors for renal and cardiovascular disease. Additional therapies under consideration include stem cell transplantation and monoclonal antibodies.53 KEY POINTS • Lung involvement occurs in a majority of patients with scleroderma. • Patients with systemic sclerosis and pulmonary involvement have one of two patterns: (1) fibrotic lung disease with or without secondary pulmonary arterial hypertension or (2) “primary” pulmonary arterial hypertension without fibrotic lung disease. The patient’s autoantibody profile determines whether pattern 1 or 2 is more likely. • Fibrotic lung disease is seen in approximately 80% of patients and usually manifests with a nonspecific interstitial pneumonia pattern; a usual interstitial pneumonia pattern is uncommon. • Patients with systemic sclerosis have an increased incidence of lung cancer.

SUGGESTED READINGS Ahuja J, Arora D, Kanne JP, et al. Imaging of pulmonary manifestations of connective tissue diseases. Radiol Clin North Am. 2016;54(6):1015–1031. Arroliga AC, Podell DN, Matthay RA. Pulmonary manifestations of scleroderma. J Thorac Imaging. 1992;7:30–45. Bolster MB, Silver RM. Lung disease in systemic sclerosis (scleroderma). Baillieres Clin Rheumatol. 1993;7:79–97. Goldin JG, Lynch DA, Strollo DC, et al. High-resolution CT scan findings in patients with symptomatic scleroderma-related interstitial lung disease. Chest. 2008;134(2):358–367.

The full reference list for this chapter is available at ExpertConsult.com.

40  Systemic Sclerosis (Scleroderma) 564.e1

REFERENCES 1. Tan FK, Arnett FC. Genetic factors in the etiology of systemic sclerosis and Raynaud phenomenon. Curr Opin Rheumatol. 2000;12:511–519. 2. Volkmann ER, Tashkin DP. Treatment of systemic sclerosis-related interstitial lung disease: a review of existing and emerging therapies. Ann Am Thorac Soc. 2016;13:2045–2056. 3. Artlett CM, Smith JB, Jimenez SA. New perspectives on the etiology of systemic sclerosis. Mol Med Today. 1999;5:74–78. 4. Medsger TA Jr. Epidemiology of systemic sclerosis. Clin Dermatol. 1994;12:207–216. 5. Medsger TA Jr, Masi AT. Epidemiology of systemic sclerosis (scleroderma). Ann Intern Med. 1971;74:714–721. 6. Ferri C, Valentini G, Cozzi F, et al. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine (Baltimore). 2002;81:139–153. 7. Scussel-Lonzetti L, Joyal F, Raynauld JP, et al. Predicting mortality in systemic sclerosis: analysis of a cohort of 309 French Canadian patients with emphasis on features at diagnosis as predictive factors for survival. Medicine (Baltimore). 2002;81:154–167. 8. Simeon CP, Armadans L, Fonollosa V, et al. Mortality and prognostic factors in Spanish patients with systemic sclerosis. Rheumatology (Oxford). 2003;42: 71–75. 9. Altman RD, Medsger TA Jr, Bloch DA, Michel BA. Predictors of survival in systemic sclerosis (scleroderma). Arthritis Rheum. 1991;34:403–413. 10. Kuwana M, Kaburaki J, Okano Y, et al. Clinical and prognostic associations based on serum antinuclear antibodies in Japanese patients with systemic sclerosis. Arthritis Rheum. 1994;37:75–83. 11. Owens GR, Follansbee WP. Cardiopulmonary manifestations of systemic sclerosis. Chest. 1987;91:118–127. 12. Arroliga AC, Podell DN, Matthay RA. Pulmonary manifestations of scleroderma. J Thorac Imaging. 1992;7:30–45. 13. D’Angelo WA, Fries JF, Masi AT, Shulman LE. Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controls. Am J Med. 1969;46:428–440. 14. Hesselstrand R, Scheja A, Shen GQ, et al. The association of antinuclear antibodies with organ involvement and survival in systemic sclerosis. Rheumatology (Oxford). 2003;42:534–540. 15. Schachna L, Wigley FM, Chang B, et al. Age and risk of pulmonary arterial hypertension in scleroderma. Chest. 2003;124:2098–2104. 16. Steen V, Medsger TA Jr. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum. 2003;48:516–522. 17. Ferri C, Giuggioli D, Sebastiani M, et al. Heart involvement and systemic sclerosis. Lupus. 2005;14:702–707. 18. Marie I, Dominique S, Levesque H, et al. Esophageal involvement and pulmonary manifestations in systemic sclerosis. Arthritis Rheum. 2001;45:346–354. 19. Collier DH. Systemic sclerosis. In: West S, ed. Rheumatology Secrets. Philadelphia: Hanley & Belfus; 2002:151–161. 20. Charles C, Clements P, Furst DE. Systemic sclerosis: hypothesis-driven treatment strategies. Lancet. 2006;367:1683–1691. 21. Kane GC, Varga J, Conant EF, et al. Lung involvement in systemic sclerosis (scleroderma): relation to classification based on extent of skin involvement or autoantibody status. Respir Med. 1996;90:223–230. 22. Gonzalez LA, Perez TR. Idiopathic diffuse bronchiolectasis—so-called bronchiolar emphysema. A link between bronchiectasis and chronic pulmonary emphysema. Am J Clin Pathol. 1963;40:157–172. 23. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 20-1989. A 33-year-old woman with exertional dyspnea and Raynaud’s phenomenon. N Engl J Med. 1989;320:1333–1340. 24. Bolster MB, Silver RM. Lung disease in systemic sclerosis (scleroderma). Baillieres Clin Rheumatol. 1993;7:79–97. 25. Witt C, Borges AC, John M, et al. Pulmonary involvement in diffuse cutaneous systemic sclerosis: bronchioalveolar fluid granulocytosis predicts progression of fibrosing alveolitis. Ann Rheum Dis. 1999;58:635–640. 26. Bouros D, Wells AU, Nicholson AG, et al. Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med. 2002;165:1581–1586. 27. Desai SR, Veeraraghavan S, Hansell DM, et al. CT features of lung disease in patients with systemic sclerosis: comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. Radiology. 2004;232:560–567.

28. Muir TE, Tazelaar HD, Colby TV, Myers JL. Organizing diffuse alveolar damage associated with progressive systemic sclerosis. Mayo Clin Proc. 1997;72:639–642. 29. Toyoshima M, Chida K, Enomoto N, et al. [A case of diffuse alveolar hemorrhage associated with interstitial pneumonia and systemic sclerosis]. Nihon Kokyuki Gakkai Zasshi. 2005;43:437–441. 30. Griffin MT, Robb JD, Martin JR. Diffuse alveolar haemorrhage associated with progressive systemic sclerosis. Thorax. 1990;45:903–904. 31. Catterall M, Rowell NR. Respiratory function in progressive systemic sclerosis. Thorax. 1963;18:10–15. 32. Wells AU, Hansell DM, Rubens MB, et al. Fibrosing alveolitis in systemic sclerosis: indices of lung function in relation to extent of disease on computed tomography. Arthritis Rheum. 1997;40:1229–1236. 33. Weaver AL, Divertie MB, Titus JL. Pulmonary scleroderma. Dis Chest. 1968;54:490–498. 34. Schurawitzki H, Stiglbauer R, Graninger W, et al. Interstitial lung disease in progressive systemic sclerosis: high-resolution CT versus radiography. Radiology. 1990;176:755–759. 35. Olive A, Juncosa S, Evison G, Maddison PJ. Air in the oesophagus: a sign of oesophageal involvement in systemic sclerosis. Clin Rheumatol. 1995;14:319–321. 36. Lynch DA. Fibrotic idiopathic interstitial pneumonia: high-resolution computed tomography considerations. Semin Respir Crit Care Med. 2003;24:365–376. 37. Kim EY, Lee KS, Chung MP, et al. Nonspecific interstitial pneumonia with fibrosis: serial high-resolution CT findings with functional correlation. AJR Am J Roentgenol. 1999;173:949–953. 38. Hartman TE, Swensen SJ, Hansell DM, et al. Nonspecific interstitial pneumonia: variable appearance at high-resolution chest CT. Radiology. 2000;217:701–705. 39. Goldin JG, Lynch DA, Strollo DC, et al. High-resolution CT scan findings in patients with symptomatic scleroderma-related interstitial lung disease. Chest. 2008;134(2):358–367. 40. Goh NSL, Desai SR, Veeraraghavan S, et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med. 2008;177(11): 1248–1254. 41. Wechsler RJ, Steiner RM, Spirn PW, et al. The relationship of thoracic lymphadenopathy to pulmonary interstitial disease in diffuse and limited systemic sclerosis: CT findings. AJR Am J Roentgenol. 1996;167:101–104. 42. Ng CS, Wells AU, Padley SP. A CT sign of chronic pulmonary arterial hypertension: the ratio of main pulmonary artery to aortic diameter. J Thorac Imaging. 1999;14:270–278. 43. Peters-Golden M, Wise RA, Hochberg M, et al. Incidence of lung cancer in systemic sclerosis. J Rheumatol. 1985;12:1136–1139. 44. Rosenthal AK, McLaughlin JK, Gridley G, Nyren O. Incidence of cancer among patients with systemic sclerosis. Cancer. 1995;76:910–914. 45. Abu-Shakra M, Guillemin F, Lee P. Cancer in systemic sclerosis. Arthritis Rheum. 1993;36:460–464. 46. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum. 1980;23:581–590. 47. van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2013;72:1747–1755. 48. Spencer-Green G, Alter D, Welch HG. Test performance in systemic sclerosis: anti-centromere and anti–Scl-70 antibodies. Am J Med. 1997;103:242–248. 49. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum. 2005;35:35–42. 50. Wanchu A. Antinuclear antibodies: clinical applications. J Postgrad Med. 2000;46:144–148. 51. Kim HJ, Tashkin DP, Gjertson DW, et al. Transitions to different patterns of interstitial lung disease in scleroderma with and without treatment. Ann Rheum Dis. 2016;75(7):1367–1371. 52. Goldin J, Elashoff R, Kim HJ, et al. Treatment of scleroderma-interstitial lung disease with cyclophosphamide is associated with less progressive fibrosis on serial thoracic high-resolution CT scan than placebo: findings from the scleroderma lung study. Chest. 2009;136(5):1333–1340. 53. Denton CP, Hughes M, Gak N, et al. BSR and BHPR guideline for the treatment of systemic sclerosis. Rheumatology. 2016;55(10):1906–1910.

41 

Systemic Lupus Erythematosus* BRENT P. LITTLE

Etiology The pathogenesis of systemic lupus erythematosus (SLE) involves genetic and environmental factors, hormonal influences, and cell-mediated responses. In SLE, B lymphocytes lose self-tolerance and inappropriately produce autoantibodies. Serologic positivity for antinuclear antibodies (ANAs) is found in nearly all patients,1 but anti–deoxyribonucleic acid (DNA) antibodies, although less frequent than ANAs, are far more specific for SLE. A high titer of anti–double-stranded DNA (dsDNA) is considered the best marker of disease activity in SLE.2 Genetic evidence for a hereditary tendency comes from the concordance rate in monozygotic twins (≈25% vs. 2% in dizygotic pairs).3 The search for lupus susceptibility genes has uncovered considerable genetic variance, and human leukocyte antigen associations vary according to ethnicity.4 Apoptosis (the process of cell death precipitated by various insults) is thought to be crucial to the development of SLE. The autoimmunity of SLE is suspected to be triggered by exposure to both Epstein-Barr virus and cytomegalovirus.5,6 Sex hormones may have a role in developing or modulating SLE because the disease primarily affects women of childbearing age and is exacerbated by estrogen in lupus-prone mice.7

Prevalence and Epidemiology The prevalence of SLE ranges from 17 to 48 per 100,000 population.8 Most patients are female (female-to-male ratio, 8 : 1) and between the ages of 15 and 45 years.9 During childhood and after menopause the female-to-male ratio is closer to 2 : 1. Survival statistics have improved in patients with SLE, and in a large cohort of European patients, 92% were found to have survived for 10 years after onset of the disease.10 The highest mortality is in patients with infections, renal disease, non-Hodgkin lymphoma, and lung cancer. Mortality risk is greatest with female gender, younger age, disease duration of less than 1 year, and African-American ethnicity. Overall, the most frequent causes of mortality in SLE are active disease, thrombotic complications, and infections.2

Clinical Presentation The most frequent symptoms of SLE are arthritis, malar rash, photosensitivity, and neurologic involvement.2 In the first 5 years after a diagnosis of SLE, the most common cause of death is infection, but after this period thrombotic disease becomes the most frequent cause of mortality.2 The diagnosis of SLE is often *The editors and the publisher would like to thank Drs. Maureen Quigley and David M. Hansell for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

elusive, and it may take up to 2 years from the first manifestations of the disease to make a firm diagnosis of SLE.2 Recurrent pleuritic chest pain due to serositis is the most common thoracic symptom in patients with SLE.11,12 Pulmonary embolism is another common cause of pleuritic chest pain, particularly in those who have antiphospholipid syndrome (see later). Finally, pericarditis and/or pericardial effusion may result in chest pain. Lower respiratory tract infections can be caused by either common or opportunistic pathogens because patients are frequently immunosuppressed. Patients with lupus can have fulminant respiratory failure; important causes include opportunistic infections, drugs, impaired renal or cardiac function, diffuse alveolar hemorrhage, or lupus pneumonitis.13 In autopsy studies chronic pulmonary disease is common in SLE, with some form of pleural or parenchymal disease found in up to 98% of patients; however, chronic pulmonary involvement may be mild and asymptomatic in many patients.11,14 “Shrinking lung” syndrome—low lung volumes possibly caused by a combination of diaphragmatic weakness and chest wall restriction—can cause progressive chronic dyspnea that can occasionally be fatal.15 Antiphospholipid syndrome is common in SLE patients, characterized by vascular thrombosis or obstetric complications (or both), thrombocytopenia, and the presence of certain antibodies, such as anticardiolipin and lupus anticoagulant.16 Pulmonary hypertension affects up to 8% of patients with SLE, with half of cases classified as primary and half as secondary pulmonary hypertension in one cohort.17 Patients with SLE are at increased risk for atherosclerosis, and SLE is an independent risk factor for stroke and myocardial infarction. Women 18 to 44 years of age with SLE are twice as likely as those without lupus to have a myocardial infarction or stroke, and heart failure is nearly four times as likely to develop.18 Renal disease affects about a third of patients with SLE and remains one of the most dangerous life-threatening complications.19 Gastrointestinal involvement commonly results in nonspecific abdominal pain and dyspepsia.20 Hepatosplenomegaly can fluctuate with disease activity, and although mesenteric vasculitis is very rare, it can be life threatening.19 Arthralgia and myalgia occur in most patients with SLE; the classic “Jaccoud arthropathy” affects the hands of up to half of patients with SLE and is characterized by reducible, nonerosive joint deformities with preservation of hand function. Skin involvement in SLE is very common and includes the classic malar rash, discoid rash, and generalized photosensitivity. Sun sensitivity, mouth ulcers, and dry mouth can occur. Hematologic features include normocytic normochromic anemia, thrombocytopenia, and leukopenia.21 Manifestations of neuropsychiatric lupus can include headache, seizures, and psychiatric diagnoses, including depression, psychosis, and neuropathy. 565

566

SECTION 8  Connective Tissue Diseases

Pathophysiology PATHOLOGY Other than infection, “lupus pneumonitis” has been described as the most common acute lung disease in lupus patients. However, the incidence of lupus pneumonitis has likely been overestimated and may be lower than 4% overall; although the condition is characterized by diffuse alveolar damage, many cases of pneumonia and aspiration were found to have been mistaken clinically for lupus pneumonitis in a large autopsy series.22 When it occurs, lupus pneumonitis has a high mortality of almost 50%.11 The frequency of acute lupus pneumonitis in hospitalized patients with lupus is up to 6%,13,23 and the outcome of patients with diffuse alveolar damage is either healing and fibrinolysis or parenchymal scarring; chronic fibrotic lung disease occurs in a subset of patients.24 In a description of surgical lung biopsy specimens from two patients with SLE, one demonstrated usual interstitial pneumonia and the other follicular bronchiolitis with a minor component of cellular nonspecific interstitial pneumonia.25 The proportion of patients with SLE who have primarily fibrotic lung disease has been estimated to be less than 10%.26 Organizing pneumonia is not a common pulmonary manifestation of SLE.27–29 Diffuse alveolar hemorrhage is rare in SLE but has a high mortality rate.13 Diffuse alveolar hemorrhage in SLE is pathogenetically similar to lupus renal microangiopathy. There are isolated case reports of lymphoid interstitial pneumonia in SLE, usually in the presence of an overlap with Sjögren syndrome.30,31 The myopathy of SLE can affect the diaphragm and result in a raised diaphragm and basal atelectasis, the so-called shrinking lung syndrome.32 There has been much debate concerning the pathogenesis of this phenomenon,15 and the cause remains controversial. In one study the majority of patients with “shrinking lung” syndrome had normal neuromuscular diaphragmatic function.33 There is an association between SLE and certain neoplasms, particularly hematologic malignancies and non-Hodgkin lymphoma and possibly lung and hepatobiliary cancer.34 LUNG FUNCTION A range of pulmonary function abnormalities occur in patients with SLE, and as a generalization, abnormal pulmonary function test results are reported in approximately two-thirds of patients with SLE.35,36

Manifestations of the Disease RADIOGRAPHY The most common radiographic abnormalities in SLE are the presence of bilateral pleural effusions or pleural thickening (Fig. 41.1) and enlargement of the cardiopericardial silhouette because of pericardial effusion or cardiomegaly. The most common pulmonary finding is consolidation secondary to infection.12 Other acute manifestations of SLE include pulmonary embolism; acute lupus pneumonitis, which occurs in less than 4% of SLE patients; and pulmonary hemorrhage, which occurs in less than 2% of patients.12 In acute lupus pneumonitis the chest radiograph often shows unilateral or bilateral hazy pulmonary opacities or consolidation, predominantly in the lower zones (Fig. 41.2).13 Bacterial pneumonia can have an identical appearance.12 The manifestations of

Fig. 41.1  Bilateral pleural effusions in systemic lupus erythematosus. A chest radiograph shows bilateral small pleural effusions (a left-sided pleural catheter is present).

pulmonary hemorrhage usually consist of bilateral ground-glass opacities or consolidation that may be patchy or diffuse (Fig. 41.3). In “shrinking lung” syndrome the chest radiograph and computed tomography (CT) characteristically show elevated hemidiaphragms, adjacent atelectasis, and occasionally, small pleural effusions (Fig. 41.4).15 The radiographic manifestations of interstitial disease are usually mild and consist mainly of a reticular pattern in a predominantly basal distribution (Fig. 41.5). COMPUTED TOMOGRAPHY There are few high-resolution computed tomography (HRCT) studies of SLE. In a prospective series of 34 consecutive patients with SLE, 70% were found to have HRCT abnormalities.37 The most frequent CT findings were interstitial lung disease in a third of patients, bronchiectasis in 21%, axillary and mediastinal lymphadenopathy in 18%, and pleuropericardial abnormalities in 15%. The proportion of patients with SLE and interstitial lung disease on HRCT was higher than expected from previous studies, which, based mainly on clinical and radiographic findings, estimated that interstitial fibrosis developed in 3% to 8% of patients with SLE.12 The bronchiectasis seen in patients with SLE is usually mild and may be due to repeated infections or reflect an occult overlap disease.38 Another CT study that focused on lung involvement in patients with SLE excluded all those with pulmonary symptoms or an abnormal chest radiograph.39 More than a third of patients had abnormalities on HRCT. Bronchial dilation was seen in 18% of subjects, and 13% had pleural irregularities. A third of patients had interlobular septal thickening and intralobular linear opacities, and 22% had architectural distortion. These abnormalities were located mainly in the subpleural and basal lung regions and were interpreted as representing fibrosis (Fig. 41.6). The proportion of patients with interstitial lung disease is more frequent in SLE patients with respiratory symptoms, up to 60% in

41  Systemic Lupus Erythematosus

A

567

B

Fig. 41.2  Acute lupus pneumonitis. A detailed view of the right lung from a posteroanterior radiograph (A) is normal. Two days later, after the onset of dyspnea and cough in this patient who had systemic lupus erythematosus (B), the right lung shows increased opacity and poorly defined lung markings in the middle and lower portions of the chest, representing acute noncardiogenic pulmonary edema. Similar features were identified in the left lung. (From Müller NL, Fraser RS, Colman N, et al. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

Fig. 41.3  Diffuse pulmonary hemorrhage in a patient with hemoptysis and systemic lupus erythematosus. A chest radiograph shows diffuse left greater than right lung consolidation.

Fig. 41.4  “Shrinking lung” syndrome in systemic lupus erythematosus. A coronal CT image shows elevated hemidiaphragms and adjacent atelectasis. The syndrome refers to the presence of persistently low lung volumes in SLE not explained by parenchymal fibrosis or visible pleural disease.

568

SECTION 8  Connective Tissue Diseases

B

A

C Fig. 41.5  Pulmonary fibrosis in systemic lupus erythematosus. A posteroanterior chest radiograph (A) shows irregular linear opacities in the lower lung zones. High-resolution CT images (B) and (C) show ground-glass opacity, irregular linear opacities, architectural distortion, and traction bronchiectasis indicative of fibrosis. (From Müller NL, Fraser RS, Colman N, et al. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

or diffuse alveolar damage (Fig. 41.8). In acute lupus pneumonitis, extensive ground-glass opacities or confluent consolidation and air bronchograms are evident on HRCT,40 and the consolidation is often accompanied by pleural effusions41; effusions are rarely associated with uncomplicated diffuse alveolar hemorrhage. More than 50% of patients with SLE have antiphospholipid syndrome and are prone to the development of pulmonary embolism (Fig. 41.9). Most of these patients have deep vein thrombosis, although rarely, pulmonary artery or vein thrombosis may occur.42,43 KEY POINTS: COMMON RADIOLOGIC FEATURES OF SYSTEMIC LUPUS ERYTHEMATOSUS

Fig. 41.6  Fibrosis in systemic lupus erythematosus. High-resolution CT in a patient with SLE shows a subpleural, basilar predominant reticular pattern that is suggestive of a fibrotic nonspecific interstitial pneumonia or early usual interstitial pneumonia (UIP) (i.e., probable UIP pattern by Fleischner society criteria).

some studies.38 Frank honeycombing was not described in the two largest CT studies,37,39 which may have been due to the fact that both series focused on SLE patients without known lung disease. The CT appearances of diffuse alveolar hemorrhage are nonspecific and consist of widespread ground-glass opacity and airspace consolidation (Fig. 41.7). The CT features of diffuse alveolar hemorrhage may be indistinguishable from those of pneumonia

• Pleural effusions or pleural thickening (usually bilateral) • Pericardial effusion or cardiac enlargement • Areas of ground-glass opacity and/or consolidation (infection, diffuse alveolar damage, or hemorrhage) • Low lung volumes with elevated hemidiaphragms (“shrinking lung” syndrome) • Interstitial fibrosis in a subpleural and basal distribution with only occasional honeycombing on high-resolution CT • Deep vein thrombosis and pulmonary thromboembolism in the presence of anticardiolipin antibodies and antiphospholipid syndrome • Enlarged pulmonary trunk secondary to pulmonary hypertension

NUCLEAR MEDICINE Patients with suspected pulmonary embolism may be evaluated with ventilation-perfusion scintigraphy.

41  Systemic Lupus Erythematosus

569

A

Fig. 41.9  Acute pulmonary embolism in systemic lupus erythematosus with antiphospholipid syndrome. Contrast-enhanced CT demonstrates a filling defect in the right lower lobe pulmonary artery (arrows). Consolidation is secondary to pulmonary hemorrhage. Small bilateral pleural effusions and cardiomegaly are present.

IMAGING ALGORITHMS

B Fig. 41.7  Diffuse pulmonary hemorrhage in systemic lupus erythematosus. (A) Axial CT at the level of the upper lobes shows bilateral ground-glass opacity, patchy consolidation, mild septal thickening, and poorly defined nodular opacities, more severe on the right. (B) A coronal reformatted image demonstrates the overall extent and asymmetric distribution of the findings.

A patient with SLE and respiratory symptoms may have a chest radiograph that refines the potentially wide differential diagnosis —for example, showing a pleural effusion or signs of a lower respiratory tract infection—and these findings may not require further imaging. Suspected pulmonary embolism should be investigated by pulmonary CT angiography or ventilationperfusion scintigraphy. HRCT is the test of choice for the investigation of known or suspected interstitial lung disease. CLASSIC SIGNS The American College of Rheumatology diagnostic criteria for systemic lupus erythematosus (SLE) were radically altered in 1982, with more recent minor amendments; satisfaction of any 4 of 11 criteria yields a diagnosis of SLE (Box 41.1). More recently, the Systemic Lupus International Collaborating Clinics (SLICC) group published refinements to the diagnostic criteria; satisfaction of 4 of the revised criteria, including at least 1 immunologic criterion, or presence of a biopsy-proven nephritis in the setting of antinuclear antibody or anti–double-stranded deoxyribonucleic acid antibodies is sufficient to establish a diagnosis of SLE.44

Differential Diagnosis FROM CLINICAL DATA

Fig. 41.8  Acute lupus pneumonitis with acute respiratory compromise. High-resolution CT shows widespread ground-glass opacity. Subtle fibrosis eventually developed in the same distribution as the ground-glass opacity.

In patients with multiorgan disease, both rheumatic and nonrheumatic illnesses can mimic SLE. The diagnostic criteria and autoantibody profile refine the differential diagnosis but are not definitive. The nonrheumatic processes that mimic SLE are systemic infections and include human immunodeficiency virus infection, mononucleosis, viral polyarthropathy, and poststreptococcal glomerulonephritis. Lupus can resemble other rheumatic diseases, including rheumatoid arthritis, scleroderma, and mixed connective tissue disease. SLE can also be induced by drugs, most frequently procainamide and hydralazine. Drug-induced lupus typically

570

SECTION 8  Connective Tissue Diseases

BOX 41.1  1982 REVISED CRITERIA FOR THE CLASSIFICATION OF SYSTEMIC LUPUS ERYTHEMATOSUS WITH THE 2005 AMERICAN COLLEGE OF RHEUMATOLOGY RECOMMENDED AMENDMENTS 1. Malar rash: fixed erythema, flat or raised, over the malar eminences; tending to spare the nasolabial folds 2. Discoid rash: erythematous raised patches with scaling and follicular plugging 3. Photosensitivity rash: unusual reactivity to sunlight with rash 4. Oral ulcers: oral or nasopharyngeal ulceration, usually painless 5. Arthritis: nonerosive arthritis involving two or more peripheral joints and characterized by tenderness, swelling, or effusion 6. Serositis: pleuritis or pericarditis 7. Renal disorder: persistent proteinuria or cellular casts—may be red cell, hemoglobin, granular, tubular, or mixed 8. Neurologic disorder seizures or psychosis in the absence of causative drugs 9. Hematologic disorder hemolytic anemia: with reticulosis, leukopenia, lymphopenia, or thrombocytopenia 10. Immunologic disorder anti-DNA antibody to native DNA in abnormal titer or anti-Sm: presence of antibody to Sm nuclear antigen or positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of immunoglobulin (Ig)G or IgM anticardiolipin antibodies, (2) a positive test result for lupus anticoagulant, or (3) falsepositive serologic test for syphilis for at least 6 months and confirmed by Treponema pallidum immobilization or the fluorescent treponemal antibody absorption test 11. Antinuclear antibodies (ANA): elevated titers of ANA in the absence of drugs known to induce lupus From Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfeld NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271–1277.

starts after prolonged drug administration, and the symptoms usually disappear a few weeks after cessation of administration of the drug. Symptoms of drug-induced lupus include muscle and joint pain, flu-like symptoms, and serositis (patients are frequently ANA positive). FROM SUPPORTIVE DIAGNOSTIC TECHNIQUES More than 98% of patients with SLE have elevated ANA. Testing for ANA is especially sensitive for SLE but has low specificity; that is, most individuals with a positive ANA do not have SLE, but most with SLE have a positive ANA. In SLE the ANA titer

does not correlate with disease activity,45 whereas the clinical history, erythrocyte sedimentation rate, anti-dsDNA, and complement levels provide some prognostic information.46 A high titer of anti-Sm antibody is a criterion for the diagnosis of SLE, and although highly disease specific, it is encountered in other connective tissue disease.47

Synopsis of Treatment Options • Corticosteroids • Immunomodulatory therapy agents/disease-modifying antirheumatic drugs • Anticoagulants in cases of thrombotic episodes • Drugs such as theophylline in cases of “shrinking lung” syndrome

KEY POINTS • Systemic lupus erythematosus (SLE) has a wide variety of clinical manifestations and can affect almost any organ system. • Mortality in SLE can be due to acute disease exacerbations, infections, or thrombotic events. • The most common pulmonary complications of SLE are infection, acute lupus pneumonitis, and pulmonary embolism. Occasional pulmonary manifestations include interstitial fibrosis (usual interstitial pneumonia, nonspecific interstitial pneumonia), organizing pneumonia, lymphoid interstitial pneumonia, and bronchiectasis. • The CT findings of interstitial fibrosis in SLE usually consist of a subpleural and basal distribution with only occasional honeycombing. • Patients with SLE have an increased risk for hematologic malignancies, lymphoma, and lung cancer. • Many patients without respiratory symptoms have abnormalities on imaging or on physiologic testing, but the majority of these patients have a subclinical course of lung disease.

SUGGESTED READINGS Manson JJ, Rahman A. Systemic lupus erythematosus. Orphanet J Rare Dis. 2006;1:6. Wiedemann HP, Matthay RA. Pulmonary manifestations of systemic lupus erythematosus. J Thorac Imaging. 1992;7:1–18.

The full reference list for this chapter is available at ExpertConsult.com.

41  Systemic Lupus Erythematosus 570.e1

REFERENCES 1. Worrall JG, Snaith ML, Batchelor JR, Isenberg DA. SLE: a rheumatological view. Analysis of the clinical features, serology and immunogenetics of 100 SLE patients during long-term follow-up. Q J Med. 1990;74:319–330. 2. Cervera R, Abarca-Costalago M, Abramovicz D, et al. Systemic lupus erythematosus in Europe at the change of the millennium: lessons from the “Euro-Lupus Project”. Autoimmun Rev. 2006;5:180–186. 3. Deapen D, Escalante A, Weinrib L, et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum. 1992;35:311–318. 4. Manson JJ, Isenberg DA. The pathogenesis of systemic lupus erythematosus. Neth J Med. 2003;61:343–346. 5. James JA, Neas BR, Moser KL, et al. Systemic lupus erythematosus in adults is associated with previous Epstein-Barr virus exposure. Arthritis Rheum. 2001;44:1122–1126. 6. Newkirk MM, Van Venrooij WJ, Marshall GS. Autoimmune response to U1 small nuclear ribonucleoprotein (U1 snRNP) associated with cytomegalovirus infection. Arthritis Res. 2001;3:253–258. 7. Carlsten H, Tarkowski A, Holmdahl R, Nilsson LA. Oestrogen is a potent disease accelerator in SLE-prone MRL lpr/lpr mice. Clin Exp Immunol. 1990;80:467–473. 8. Tebbe B, Orfanos CE. Epidemiology and socioeconomic impact of skin disease in lupus erythematosus. Lupus. 1997;6:96–104. 9. Gaubitz M. Epidemiology of connective tissue disorders. Rheumatology (Oxford). 2006;45(suppl 3):iii3–iii4. 10. Cervera R, Khamashta MA, Font J, et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. The European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore). 1993;72:113–124. 11. Mulherin D, Bresnihan B. Systemic lupus erythematosus. Baillieres Clin Rheumatol. 1993;7:31–57. 12. Paran D, Fireman E, Elkayam O. Pulmonary disease in systemic lupus erythematosus and the antiphospholipid syndrome. Autoimmun Rev. 2004;3:70–75. 13. Shen M, Wang Y, Xu WB, et al. [Pleuropulmonary manifestations of systemic lupus erythematosus]. Zhonghua Yi Xue Za Zhi. 2005;85:3392–3395. 14. Quadrelli SA, Alvarez C, Arce SC, et al. Pulmonary involvement of systemic lupus erythematosus: analysis of 90 necropsies. Lupus. 2009;18(12): 1053–1060. 15. Warrington KJ, Moder KG, Brutinel WM. The shrinking lungs syndrome in systemic lupus erythematosus. Mayo Clin Proc. 2000;75:467–472. 16. Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999;42:1309–1311. 17. Pan TL, Thumboo J, Boey ML. Primary and secondary pulmonary hypertension in systemic lupus erythematosus. Lupus. 2000;9:338–342. 18. Ward MM. Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus. Arthritis Rheum. 1999;42:338–346. 19. Manson JJ, Rahman A. Systemic lupus erythematosus. Orphanet J Rare Dis. 2006;1:6. 20. Sultan SM, Ioannou Y, Isenberg DA. A review of gastrointestinal manifestations of systemic lupus erythematosus. Rheumatology (Oxford). 1999;38:917–932. 21. Sultan SM, Begum S, Isenberg DA. Prevalence, patterns of disease and outcome in patients with systemic lupus erythematosus who develop severe haematological problems. Rheumatology (Oxford). 2003;42:230–234. 22. Carmier D, Marchand-Adam S, Diot P, Diot E. Respiratory involvement in systemic lupus erythematosus. Rev Mal Respir. 2010;27(8):e66–e78. 23. Pistiner M, Wallace DJ, Nessim S, et al. Lupus erythematosus in the 1980s: a survey of 570 patients. Semin Arthritis Rheum. 1991;21:55–64. 24. Matthay RA, Schwarz MI, Petty TL, et al. Pulmonary manifestations of systemic lupus erythematosus: review of twelve cases of acute lupus pneumonitis. Medicine (Baltimore). 1975;54:397–409.

25. Tansey D, Wells AU, Colby TV, et al. Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis. Histopathology. 2004;44:585–596. 26. Haupt HM, Moore GW, Hutchins GM. The lung in systemic lupus erythematosus. Analysis of the pathologic changes in 120 patients. Am J Med. 1981;71:791–798. 27. Nakamura K, Akizuki M, Ichikawa Y, et al. [Occurrence of bronchiolitis obliterans organizing pneumonia (BOOP) in a flare-up stage of systemic lupus erythematosus (SLE)]. Ryumachi. 1993;33:156–161. 28. Gammon RB, Bridges TA, al-Nezir H, et al. Bronchiolitis obliterans organizing pneumonia associated with systemic lupus erythematosus. Chest. 1992;102:1171–1174. 29. Takada H, Saito Y, Nomura A, et al. Bronchiolitis obliterans organizing pneumonia as an initial manifestation in systemic lupus erythematosus. Pediatr Pulmonol. 2005;40:257–260. 30. Yood RA, Steigman DM, Gill LR. Lymphocytic interstitial pneumonitis in a patient with systemic lupus erythematosus. Lupus. 1995;4:161–163. 31. Filipek MS, Thompson ME, Wang PL, et al. Lymphocytic interstitial pneumonitis in a patient with systemic lupus erythematosus: radiographic and high-resolution CT findings. J Thorac Imaging. 2004;19:200–203. 32. Hoffbrand BI, Beck ER. “Unexplained” dyspnoea and shrinking lungs in systemic lupus erythematosus. Br Med J. 1965;1:1273–1277. 33. Laroche CM, Mulvey DA, Hawkins PN, et al. Diaphragm strength in the shrinking lung syndrome of systemic lupus erythematosus. Q J Med. 1989;71:429–439. 34. Bernatsky S, Boivin JF, Joseph L, et al. An international cohort study of cancer in systemic lupus erythematosus. Arthritis Rheum. 2005;52:1481–1490. 35. Groen H, ter Borg EJ, Postma DS, et al. Pulmonary function in systemic lupus erythematosus is related to distinct clinical, serologic, and nailfold capillary patterns. Am J Med. 1992;93:619–627. 36. Andonopoulos AP, Constantopoulos SH, Galanopoulou V, et al. Pulmonary function of nonsmoking patients with systemic lupus erythematosus. Chest. 1988;94:312–315. 37. Fenlon HM, Doran M, Sant SM, Breatnach E. High-resolution chest CT in systemic lupus erythematosus. AJR Am J Roentgenol. 1996;166:301–307. 38. Ooi GC, Ngan H, Peh WC, et al. Systemic lupus erythematosus patients with respiratory symptoms: the value of HRCT. Clin Radiol. 1997;52:775–781. 39. Bankier AA, Kiener HP, Wiesmayr MN, et al. Discrete lung involvement in systemic lupus erythematosus: CT assessment. Radiology. 1995;196:835–840. 40. Capdevila AA, Irrazabal CL, Gnochi C, et al. Respiratory failure due to lupus pneumonitis: case report and review of the literature. Clin Pulm Med. 2003;10:136–142. 41. Nguyen VA, Gotwald T, Prior C, et al. Acute pulmonary edema, capillaritis and alveolar hemorrhage: pulmonary manifestations coexistent in antiphospholipid syndrome and systemic lupus erythematosus? Lupus. 2005;14:557–560. 42. Luchi ME, Asherson RA, Lahita RG. Primary idiopathic pulmonary hypertension complicated by pulmonary arterial thrombosis. Association with antiphospholipid antibodies. Arthritis Rheum. 1992;35:700–705. 43. Mouri M, Nambu Y, Kobayashi Y, et al. [A case of pulmonary thrombosis associated with primary antiphospholipid syndrome]. Nihon Kyobu Shikkan Gakkai Zasshi. 1995;33:150–155. 44. Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64(8):2677–2686. 45. Habash-Bseiso DE, Yale SH, Glurich I, Goldberg JW. Serologic testing in connective tissue diseases. Clin Med Res. 2005;3:190–193. 46. Egner W. The use of laboratory tests in the diagnosis of SLE. J Clin Pathol. 2000;53:424–432. 47. Maddison PJ, Skinner RP, Vlachoyiannopoulos P, et al. Antibodies to nRNP, Sm, Ro(SSA) and La(SSB) detected by ELISA: their specificity and inter-relations in connective tissue disease sera. Clin Exp Immunol. 1985;62:337–345.

42 

Polymyositis/Dermatomyositis* STEPHEN B. HOBBS

Etiology Immune-mediated muscle inflammation and vascular damage are the hallmarks of polymyositis (PM) and dermatomyositis (DM). In PM the immune system is primed to act against muscle antigens, whereas in DM there is complement-mediated damage to both endomysial vessels and the microvasculature of the dermis. The trigger for the autoimmune malfunction in PM/DM is unknown. As with other connective tissue diseases, B-cell and T-cell autoregulation is disrupted. Viruses have a possible etiologic role, but direct evidence is lacking. However, a seasonal pattern of development of the disorders provides some epidemiologic evidence for an infectious agent having a causative role in PM and DM. In patients with anti–Jo-1 antibodies, weakness is more likely to develop in April, and those with a different autoantibody (anti–signal recognition particle) are more likely to have an onset of weakness in November.1 Animal models have been used to provide supportive evidence for virally induced myositis,2 and many different infectious agents have been proposed, including coxsackievirus, parvovirus, enterovirus, human T-lymphotropic virus, and human immunodeficiency virus.3

Prevalence and Epidemiology PM/DM has an incidence of approximately 5 to 10 cases per million per year,4 and in DM there are two population age peaks: children and young to middle-aged adults.5 PM affects women more frequently than men (2 : 1 ratio) and has a higher incidence in African Americans than in whites.6,7 In PM/DM pulmonary disease can overshadow the primary muscle disorder, and patients with PM/DM and interstitial lung disease (ILD) have higher mortality than those with isolated ILD.8 Estimates of PM/DMrelated death rates vary between 10% and 27%,9–11 and these deaths are usually the consequence of cancer or pulmonary complications. Predictors of poor outcome include old age at onset, male gender, dysphagia, long-standing symptoms before diagnosis or therapy, pulmonary and cardiac involvement, and the presence of anti–Jo-1 antibodies.9 The majority of survivors have a chronic continuous or polycyclic disease course (80%).9

Clinical Presentation PM and DM are usually considered part of the same disease spectrum, and the main clinical difference is thought to be the prominent lilac “heliotrope” facial rash seen in DM. Nevertheless, DM and PM are pathogenetically distinct. DM is a humorally mediated microangiopathy, whereas PM is a cell-mediated immune response to muscle fibers. However, PM and DM are *The editors and the publisher would like to thank Drs. Maureen Quigley and David M. Hansell for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

usually grouped together in many clinical studies, and for the purposes of this discussion they will be frequently considered a single entity. The onset of PM/DM may be acute or insidious. Acute infection can precede or perhaps incite symptoms; children with juvenile DM frequently have symptoms of systemic illness 3 months before the onset of disease.12 DM (but not PM) is seen in the pediatric population, and symptoms are similar in children and adults, although childhood onset is more likely to be acute and florid. The clinical hallmark of PM is proximal muscle weakness with muscle tenderness and myalgia. Patients may also have dyspnea, dysphagia, aspiration pneumonia, fever, weight loss, secondary Sjögren syndrome, Raynaud phenomenon, polyarthritis, and cardiac myopathy. The frequency of ILD is not definitively known in PM/DM patients; however, depending on inclusion criteria and follow-up length, upwards of 75% of patients will have some evidence of ILD.13 With the use of chest radiography alone, the incidence of ILD in patients with PM/DM has been estimated to be much lower at 9% to 10%, but this likely reflects the lesser sensitivity of radiography than high-resolution CT (HRCT).14,15 The association between polyarthritis and ILD in PM/DM is well known,14,16 and the pulmonary manifestations of PM/DM are thought to precede symptoms of the inflammatory myopathy in almost a third of cases.17 There are various modes of pulmonary involvement, ranging from fulminant and acute (diffuse alveolar damage, pneumonia) to chronic progressive symptoms (fibrotic lung disease, pulmonary hypertension, respiratory muscle weakening). Pulmonary involvement may be asymptomatic. Patients with established PM/DM are at risk for infection. They are frequently immunosuppressed, and both opportunistic and nonopportunistic infections develop.18 In one study a majority of PM/DM patients (89%) exhibited an opportunistic infection at some time after the onset of their PM/DM. A variety of organisms were responsible for these infections, but more than half were due to fungi.10 Pulmonary hypertension can develop in patients with PM/ DM, and in concert with the myositis, which affects the respiratory muscles, the result may be markedly abnormal physiologic parameters even with relatively normal imaging results. The pulmonary hypertension seen in those with PM/DM is usually secondary to ILD, although primary pulmonary vascular disease has been described.19 Weakness of the respiratory muscles may lead to respiratory failure; nevertheless, mild respiratory failure has a good prognosis20 and mechanical ventilation is rarely required for respiratory muscle weakness alone.14 Weakness of the laryngeal musculature may cause dysphonia, and esophageal involvement is usually manifested as dysphagia. Esophageal disease is estimated to be present in up to half of patients with inflammatory arthropathy, and the esophageal myopathy can be proximal as a result of striated muscle 571

572

SECTION 8  Connective Tissue Diseases

involvement or distal as a result of smooth muscle involvement, particularly in overlap connective tissue disease.21 Fulminant myositis can precipitate acute renal failure as a consequence of severe rhabdomyolysis and myoglobinuria. Cutaneous eruptions, which occur in DM, tend to be dusky and erythematous. Periorbital edema with a heliotrope (purplish appearance) hue is pathognomonic for DM. The skin lesions frequently fade completely but may be followed by brownish pigmentation, atrophy, scarring, or vitiligo. Subcutaneous calcification may occur, particularly in childhood DM. This is similar in distribution to that encountered in systemic sclerosis but tends to be more extensive (calcinosis universalis), particularly in untreated or undertreated disease. Polyarthralgia, accompanied at times by joint effusions, joint swelling, and other evidence of nondeforming arthritis, occurs in about 30% of patients but tends to be mild.22 Although symptomatic cardiac involvement is not common in PM/DM,21 it is of prognostic importance.9,23 Cardiac involvement is recognized as the third leading cause of death in this condition, after sepsis and malignancy.24 Various cardiac manifestations have been described in the literature, including conduction abnormalities, myocarditis, cardiomyopathy, coronary artery atherosclerosis, valvular disease, and pericardial abnormalities.25 There is an association with malignancy and the inflammatory myopathies, but the association is strongest with adult-onset DM.26 Even though the link was refuted in an analysis of 102 patients with adult-onset DM,27 more recent evidence from population-based cohort studies has confirmed an association between malignancy and DM and PM.28 These studies show an even stronger association between PM and malignancy, with recent data confirming that the association of DM and PM with malignancy is not purely due to various biases.28 The majority of these malignancies are adenocarcinomas, with the strongest correlation with ovarian carcinoma. Other associations include cervical, lung, pancreas, bladder, and gastric adenocarcinomas. Of interest, the peak incidence of cancer diagnosis occurs within the first year of diagnosis of the myopathy. In some patients the diagnosis of cancer occurs during relapse of previously dormant myositis.29,30 The classification of PM/DM is potentially confusing. Amyopathic DM is DM without muscle weakness, and although pulmonary fibrosis is uncommon in these patients, isolated case reports do appear.31 Antisynthetase syndrome occurs in a subgroup of inflammatory myopathy patients who have antisynthetase antibodies; anti–Jo-1 antibody is one of these antisynthetase antibodies. These patients have features similar to those of PM and DM, but they are more likely to have significant ILD. Antisynthetase syndrome is also associated with “mechanic’s hands,” a condition in which the skin of the patient’s fingers is thickened and cracked with accompanying polyarthritis and Raynaud phenomenon.22

Pathophysiology PATHOLOGY The most common parenchymal lung diseases associated with PM/DM are nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), diffuse alveolar damage (DAD), usual interstitial pneumonia (UIP), and alveolar hemorrhage (secondary to capillaritis).32 In a review of surgical lung biopsy specimens from patients with PM/DM, the predominant histologic process was

NSIP.33 In another series by Douglas and coworkers,17 70 patients with PM/DM and ILD were examined. In this group 22 patients underwent surgical lung biopsy, and the majority in this series had NSIP histologically (81%). The remaining patients had DAD, OP, and UIP. PM/DM patients can progress through the pathologic sequence of DAD, then OP, and finally fibrotic NSIP. The first step is acute epithelial injury, and then organization occurs with the production of intraalveolar buds of granulation tissue (OP).34 On serial evaluation this patchy consolidation, which is presumed to be OP, may be partially reversible; alternatively, it may progress to reticular abnormality.35 OP and NSIP are frequently found together on lung biopsy specimens. Acute ILD in patients with PM/DM may have a rapidly progressive course, and in a study of 81 patients with inflammatory myopathy, 5 had acute ILD and all 5 had died within 6 months of disease onset.20 These 5 patients had histologically proven DAD, and in all cases the muscle involvement was typical of DM but was classified as mild. Acute ILD in PM/DM has high mortality, and all the patients were seronegative for antisynthetase antibodies. Seronegativity for antisynthetase antibodies is considered a poor prognostic indicator in DAD associated with PM/DM.20 Active and healed vasculitis has been demonstrated pathologically in PM/DM.8 Unlike rheumatoid arthritis and systemic lupus erythematosus, pleural disease is not commonly described, but fibrinous pleuritis has been recorded at autopsy (12%). Pleural effusions were also present in a quarter of cases and were presumed to be secondary to heart failure or malignancy.8 LUNG FUNCTION Lung function testing is useful for the early diagnosis of pulmonary involvement in PM/DM. The earliest abnormality detected is usually a decrease in the diffusing capacity for carbon monoxide (DLCO). A restrictive pattern subsequently develops if pulmonary fibrosis occurs. An important parameter is KCO, defined as the ratio of the rate of DLCO to the accessible alveolar volume (VA). KCO values less than 70% of predicted in a nonsmoker can be helpful in suggesting an occult vasculopathy.36 In patients with PM, half have a 50% reduction in respiratory muscle strength, and hypercapnia is likely to occur when respiratory muscle strength is less than 30% of normal.37 The hallmark of respiratory muscle weakness is a reduction in maximum inspiratory and expiratory pressure.20

Manifestations of the Disease Primary thoracic manifestations of PM/DM include one or more of the following ILDs: NSIP, OP, UIP, and DAD. Vascular manifestations include vasculitis, capillaritis/hemorrhage, and pulmonary hypertension. Secondary manifestations include respiratory failure, atelectasis, pneumonia, aspiration, drug-related disorders, heart failure, and various neoplasms. RADIOGRAPHY Evidence of ILD, especially OP, may precede the frank myositis and skin lesions.38,39 In PM/DM chest radiographs commonly demonstrate bilateral irregular linear opacities (reticulation) at the lung bases and occasionally consolidation.17 In most series of PM/DM the proportion of patients with evidence of ILD on

42  Polymyositis/Dermatomyositis

573

A A

B

B

Fig. 42.1  Nonspecific interstitial pneumonia in polymyositis. (A) A chest radiograph shows low lung volumes, hazy increased opacity (ground-glass opacities) in the lower lung zones, and mild basal reticulation. (B) Highresolution CT through the lower lungs shows extensive bilateral groundglass opacities and minimal reticulation without honeycombing.

Fig. 42.2  Organizing pneumonia in polymyositis. (A) A chest radiograph shows bilateral areas of consolidation involving mainly the lower lung zones. (B) Axial CT demonstrates bilateral consolidation in a bronchovascular and perilobular distribution.

chest radiography is approximately 10%.14,15 In one of the largest studies of PM/DM-ILD,17 abnormalities on chest radiography included irregular linear opacities (95%), consolidation (25%), honeycombing (4%), and pleural effusions (4%). These findings most commonly reflect the presence of NSIP, OP, or DAD. The most common ILD in patients with PM/DM is NSIP. The main radiographic manifestations of NSIP consist of a reticular pattern and hazy increased opacity (ground-glass opacities) in the lower lung zones (Fig. 42.1). The most frequent manifestations of OP consist of bilateral areas of consolidation that may be patchy, mainly peribronchial or subpleural, and that may involve any lung zone (Fig. 42.2). Patients with PM often have findings of both NSIP and OP radiologically and histologically (Fig. 42.3). DAD is characterized by a sudden onset and rapid progression from ground-glass opacities to extensive bilateral consolidation. The main differential diagnosis of areas of consolidation is aspiration or pneumonia. Pleural disease is relatively

uncommon in PM/DM. The majority of pleural effusions seen in these patients are related to heart failure, infection, or malignancy. COMPUTED TOMOGRAPHY Abnormalities seen on HRCT in PM/DM include linear opacities (63%), consolidation (53%–100%), ground-glass opacities (43%), and rarely, honeycombing.17,40 These abnormalities most commonly reflect the presence of NSIP, OP, or DAD. The manifestations of NSIP typically consist of ground-glass opacities with or without superimposed intralobular linear opacities; these findings result in a reticular pattern that is situated mainly in the lower lung zones (Fig. 42.4). The reticulation may be absent (cellular NSIP) or minimal (see Fig. 42.1), but with progression of fibrosis, it can gradually become the predominant finding (fibrotic NSIP). In patients with fibrosis the reticular pattern is typically associated

574

SECTION 8  Connective Tissue Diseases

Fig. 42.3  Mixed nonspecific interstitial pneumonia and organizing pneumonia in polymyositis. A chest radiograph shows basal reticulation with volume loss. Also noted are focal areas of consolidation in the right lung base.

Fig. 42.5  Mixed nonspecific interstitial pneumonia (NSIP) and organizing pneumonia in a patient with myositis and anti–Jo-1 antibody positivity (antisynthetase syndrome). High-resolution CT shows bilateral peripheral reticulation and peribronchial consolidation (arrow). Mild ground-glass opacity and relative subpleural sparing (arrowheads) of the lung immediately adjacent to the pleura are also evident. These appearances are consistent with mixed organizing pneumonia and NSIP (confirmed on surgical lung biopsy).

reversibility of the morphologic appearance was suggestive of OP or possibly cellular NSIP. The acute manifestation of DAD in PM/DM is a fulminant respiratory failure that clinically resembles acute interstitial pneumonia. The findings in the majority of acute PM/DM cases on HRCT are patchy consolidation and ground-glass opacity with or without features of interstitial fibrosis.43–45 These CT findings are similar to those described in the accelerated phase (acute exacerbation) of patients with idiopathic pulmonary fibrosis.46 MAGNETIC RESONANCE IMAGING

Fig. 42.4  Nonspecific interstitial pneumonia in polymyositis. High-resolution CT shows bilateral ground-glass opacities and mild reticulation.

with architectural distortion, traction bronchiectasis, and traction bronchiolectasis. As mentioned previously, patients with inflammatory myopathies may have CT and histologic features of NSIP and OP simultaneously (Fig. 42.5). The consolidation in PM/DM is usually presumed to be due to areas of OP, with ground-glass opacities representing either DAD or fine intralobular fibrosis. However, lower respiratory tract infection is an important differential diagnosis in patients with PM/DM.10 The consolidation on HRCT in patients with OP can be patchy and random but often has a predominantly subpleural (see Fig. 42.2),40,41 perilobular, or peribronchovascular distribution (see Fig. 42.5).42 Linear opacities or parenchymal bands are nonspecific and may reflect previous OP or interlobular/ intralobular fibrosis. In one study the patchy consolidation, parenchymal bands, and irregular bronchovascular thickening had improved or disappeared in virtually all patients with PM/ DM, and although this study lacked pathologic correlation, the

Gadolinium-enhanced cardiac magnetic resonance imaging (MRI) has been used for the investigation of myocarditis associated with PM; the typical enhancing pattern for myositis is patchy uptake of gadolinium not following a vascular distribution.47 Additionally, MRI can characterize inhomogeneous inflammation in muscle of PM/DM patients and may be used to guide muscle biopsies.48,49 IMAGING ALGORITHMS Chest radiography is performed routinely in patients with PM/ DM, usually to exclude occult disease or lower respiratory tract infection, to which these patients are prone. However, the limited sensitivity of chest radiography for mild interstitial lung disease should prompt consideration for HRCT imaging if there is clinical or radiographic suspicion of thoracic involvement.

Differential Diagnosis FROM CLINICAL DATA There are numerous inflammatory myopathies, including druginduced myopathy, virus-induced myopathy, Cushing syndrome,

42  Polymyositis/Dermatomyositis

hypothyroidism, hyperthyroidism, systemic lupus erythematosus, sarcoidosis, and fibromyalgia. DM can be difficult to distinguish from subacute cutaneous lupus erythematosus, but muscle lesions have different distributions, and cutaneous lupus seldom has the accompanying features of DM.21 FROM SUPPORTIVE DIAGNOSTIC TECHNIQUES Disease assessment in PM/DM is conventionally based on clinical evaluation, muscle biopsy, serum enzyme levels, such as creatine kinase, and electromyography. Antisynthetase antibodies are highly antigen and disease specific. They include multiple different aminoacyl–transfer RNA synthetases—most prominently, anti–Jo-1, anti–PL-7, anti–PL-12, anti-EJ, and anti-OJ. These antibodies target the synthetases for histidine, threonine, alanine, glycine, and isoleucine, respectively. Of these, anti–Jo-1 antibodies are present in 30% of patients with inflammatory myositis,50 and figures of 20% to 30% sensitivity are quoted for anti–Jo-1 in PM.51 The presence of anti–Jo-1 antibodies correlates strongly with the presence of fibrotic lung disease in PM, and the normal incidence of pulmonary fibrosis in PM/DM rises from 10% to 60% to 70% in patients who are antibody positive.52 Patients with antisynthetase antibodies and PM/DM are considered to be a subgroup of those with inflammatory arthropathies and are said to have “antisynthetase syndrome.” Patients with this syndrome have a higher prevalence of ILD than do those who are antibody negative and have an inflammatory myositis. More recently, anti-MDA5 (melanoma differentiation-associated gene 5) antibody has been linked with amyopathic myositis and rapidly progressive ILD, severe skin lesions, and overall poor prognosis.53 Muscle biopsy is crucial in securing the diagnosis of PM and in excluding other rare muscle diseases. In PM muscle biopsy shows muscle fibers in varying stages of inflammation, necrosis, and regeneration. Findings include predominantly endomysial inflammatory infiltrates that are enriched with T-suppressor/ cytotoxic (CD8) cells.54 The finding of endomysial lymphoid inflammation is one of the major diagnostic criteria for PM. By contrast, DM infiltrates are concentrated in a perivascular distribution, and more B lymphocytes and T-helper (CD4) lymphocytes are present than in PM. Bronchoalveolar lavage provides information about lung involvement. Early in the disease, findings compatible with lymphocytic alveolitis with high counts of CD8+ T cells have been reported.51 The presence of eosinophils and neutrophils is less common and indicates fibrosis with adverse prognostic significance. Similarly, in those with antisynthetase syndrome,

575

disappearance of the lymphocytosis in bronchoalveolar lavage fluid indicates progression to fibrosis.22

Synopsis of Treatment Options • • • •

Corticosteroids as the mainstay of treatment Analgesics—for instance, nonsteroidal antiinflammatory drugs Immunoglobulins—for instance, Gamimune Disease-modifying antirheumatic drugs—for instance, azathioprine KEY POINTS • The diagnosis of polymyositis/dermatomyositis (PM/DM) is usually made by following established diagnostic criteria. • As with other connective tissue diseases, PM/DM has a plethora of clinical manifestations and pathologic entities. • Pulmonary manifestations may precede symptoms of the inflammatory myopathy. • The most common diffuse lung diseases in PM/DM are nonspecific interstitial pneumonia (NSIP), organizing pneumonia, and diffuse alveolar damage. • Consolidation may be due to infection, organizing pneumonia, or diffuse alveolar damage. The consolidation in organizing pneumonia tends to be bilateral and to be mainly peribronchial or subpleural (or both). • Diffuse ground-glass opacity may represent NSIP, diffuse alveolar damage, or occasionally, diffuse alveolar hemorrhage or opportunistic infection. • Fibrotic lung disease usually has an NSIP pattern—that is, lower lung zone–predominant ground-glass opacities with superimposed reticulation. • Patients who have antisynthetase antibodies are more likely to have interstitial lung disease. Patients without antisynthetase antibodies in whom acute interstitial pneumonitis develops have an unfavorable prognosis. • Both PM and DM are associated with an increased risk for malignancy, and screening for malignancy may be considered in adult-onset DM, but guidelines for this do not yet exist.

SUGGESTED READINGS Ahuja J, et al. Imaging of pulmonary manifestations of connective tissue diseases. Radiol Clin North Am. 2016;54(6):1015–1031. Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet. 2003;362:971. Kolasinski SL, et al. Current perspectives on imaging for systemic lupus erythematosus, systemic sclerosis, and dermatomyositis/polymyositis. Rheum Dis Clin North Am. 2016;42(4):711–732. Mandel DE, et al. Idiopathic inflammatory myopathies: a review of the classification and impact of pathogenesis. Int J Mol Sci. 2017;18(5).

The full reference list for this chapter is available at ExpertConsult.com.

42  Polymyositis/Dermatomyositis 575.e1

REFERENCES 1. Leff RL, Burgess SH, Miller FW, et al. Distinct seasonal patterns in the onset of adult idiopathic inflammatory myopathy in patients with anti–Jo-1 and anti–signal recognition particle autoantibodies. Arthritis Rheum. 1991;34: 1391–1396. 2. Tam PE, Schmidt AM, Ytterberg SR, Messner RP. Duration of virus persistence and its relationship to inflammation in the chronic phase of coxsackievirus B1–induced murine polymyositis. J Lab Clin Med. 1994;123:346–356. 3. Zampieri S, Ghirardello A, Iaccarino L, et al. Polymyositis-dermatomyositis and infections. Autoimmunity. 2006;39:191–196. 4. Schwarz MI. The lung in polymyositis. Clin Chest Med. 1998;19:701–712, viii. 5. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292:344–347. 6. McCarty DJ, Manzi S, Medsger TA Jr, et al. Incidence of systemic lupus erythematosus. Race and gender differences. Arthritis Rheum. 1995;38: 1260–1270. 7. Oddis CV, Conte CG, Steen VD, Medsger TA Jr. Incidence of polymyositisdermatomyositis: a 20-year study of hospital diagnosed cases in Allegheny County, PA 1963-1982. J Rheumatol. 1990;17:1329–1334. 8. Lakhanpal S, Lie JT, Conn DL, Martin WJ. Pulmonary disease in polymyositis/ dermatomyositis: a clinicopathological analysis of 65 autopsy cases. Ann Rheum Dis. 1987;46:23–29. 9. Bronner IM, van der Meulen MF, de Visser M, et al. Long-term outcome in polymyositis and dermatomyositis. Ann Rheum Dis. 2006;65:1456–1461. 10. Marie I, Hachulla E, Cherin P, et al. Opportunistic infections in polymyositis and dermatomyositis. Arthritis Rheum. 2005;53:155–165. 11. Henriksson KG, Sandstedt P. Polymyositis—treatment and prognosis. A study of 107 patients. Acta Neurol Scand. 1982;65:280–300. 12. Pachman LM, Olufs R, Procknal JA, Levy G. Pharmacokinetic monitoring of salicylate therapy in children with juvenile rheumatoid arthritis. Arthritis Rheum. 1979;22:826–831. 13. Solomon J, et al. Myositis-related interstitial lung disease and antisynthetase syndrome. J Bras Pneumol. 2011;37(1):100–109. 14. Dickey BF, Myers AR. Pulmonary disease in polymyositis/dermatomyositis. Semin Arthritis Rheum. 1984;14:60–76. 15. Frazier AR, Miller RD. Interstitial pneumonitis in association with polymyositis and dermatomyositis. Chest. 1974;65:403–407. 16. Schwarz MI. Pulmonary and cardiac manifestations of polymyositisdermatomyositis. J Thorac Imaging. 1992;7:46–54. 17. Douglas WW, Tazelaar HD, Hartman TE, et al. Polymyositis-dermatomyositis– associated interstitial lung disease. Am J Respir Crit Care Med. 2001;164: 1182–1185. 18. Moore EC, Cohen F, Douglas SD, Gutta V. Staphylococcal infections in childhood dermatomyositis—association with the development of calcinosis, raised IgE concentrations and granulocyte chemotactic defect. Ann Rheum Dis. 1992;51:378–383. 19. Bunch TW, Tancredi RG, Lie JT. Pulmonary hypertension in polymyositis. Chest. 1981;79:105–107. 20. Selva-O’Callaghan A, Labrador-Horrillo M, Munoz-Gall X, et al. Polymyositis/ dermatomyositis-associated lung disease: analysis of a series of 81 patients. Lupus. 2005;14:534–542. 21. Callen JP. Dermatomyositis. Lancet. 2000;355:53–57. 22. Imbert-Masseau A, Hamidou M, Agard C, et al. Antisynthetase syndrome. Joint Bone Spine. 2003;70:161–168. 23. Askari AD. Inflammatory disorders of muscle. Cardiac abnormalities. Clin Rheum Dis. 1984;10:131–149. 24. Bohan A, Peter JB, Bowman RL, Pearson CM. Computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine (Baltimore). 1977;56:255–286. 25. Afzal A, Higgins RS, Philbin EF. Heart transplant for dilated cardiomyopathy associated with polymyositis. Heart. 1999;82(4):e4. 26. Schwarz MI. Pulmonary and cardiac manifestations of polymyositisdermatomyositis. J Thorac Imaging. 1992;7:46–54. 27. Moss AA, Hanelin LG. Occult malignant tumors in dermatologic disease. The futility of radiological search. Radiology. 1977;123:69–71. 28. Buchbinder R, Hill CL. Malignancy in patients with inflammatory myopathy. Curr Rheumatol Rep. 2002;4:415–426. 29. Callen JP. The value of malignancy evaluation in patients with dermatomyositis. J Am Acad Dermatol. 1982;6(2):253–259.

30. Cox NH, et al. Dermatomyositis. Disease associations and an evaluation of screening investigations for malignancy. Arch Dermatol. 1990;126(1): 61–65. 31. Saoud B, Allali F, Hassouni NH. Amyopathic dermatomyositis. Joint Bone Spine. 2006;73:318–320. 32. Aoun NY, Velez E, Aggarwal A, et al. Fatal acute interstitial pneumonitis complicating polymyositis in a 41-year-old man. Respir Care. 2004;49: 1515–1521. 33. Arakawa H, Yamada H, Kurihara Y, et al. Nonspecific interstitial pneumonia associated with polymyositis and dermatomyositis: serial high-resolution CT findings and functional correlation. Chest. 2003;123:1096–1103. 34. Cordier JF. Organising pneumonia. Thorax. 2000;55:318–328. 35. Akira M, Hara H, Sakatani M. Interstitial lung disease in association with polymyositis-dermatomyositis: long-term follow-up CT evaluation in seven patients. Radiology. 1999;210:333–338. 36. Lohr HF, Bocher WO, Hermann E, et al. Interstitial alveolitis as early manifestation of anti–Jo-1 positive polymyositis. Z Rheumatol. 1993;52:307–311. 37. Braun NM, Arora NS, Rochester DF. Respiratory muscle and pulmonary function in polymyositis and other proximal myopathies. Thorax. 1983;38:616–623. 38. Fata F, Rathore R, Schiff C, Herzlich BC. Bronchiolitis obliterans organizing pneumonia as the first manifestation of polymyositis. South Med J. 1997;90:227–230. 39. Korzeniewska-Kosela M, Kus J, Maziarka D, et al. [Pulmonary manifestations of polymyositis and dermatomyositis: a report of 6 cases and a review of literature]. Pol Arch Med Wewn. 2001;105:59–66. 40. Mino M, Noma S, Taguchi Y, et al. Pulmonary involvement in polymyositis and dermatomyositis: sequential evaluation with CT. AJR Am J Roentgenol. 1997;169:83–87. 41. Akira M, Hara H, Sakatani M. Interstitial lung disease in association with polymyositis-dermatomyositis: long-term follow-up CT evaluation in seven patients. Radiology. 1999;210:333–338. 42. Ikezoe J, Johkoh T, Kohno N, et al. High-resolution CT findings of lung disease in patients with polymyositis and dermatomyositis. J Thorac Imaging. 1996;11:250–259. 43. Primack SL, Hartman TE, Ikezoe J, et al. Acute interstitial pneumonia: radiographic and CT findings in nine patients. Radiology. 1993;188: 817–820. 44. Bouros D, Nicholson AC, Polychronopoulos V, du Bois RM. Acute interstitial pneumonia. Eur Respir J. 2000;15:412–418. 45. Ichikado K, Johkoh T, Ikezoe J, et al. Acute interstitial pneumonia: highresolution CT findings correlated with pathology. AJR Am J Roentgenol. 1997;168:333–338. 46. Akira M, Hamada H, Sakatani M, et al. CT findings during phase of accelerated deterioration in patients with idiopathic pulmonary fibrosis. AJR Am J Roentgenol. 1997;168:79–83. 47. Ohata S, Shimada T, Shimizu H, et al. Myocarditis associated with polymyositis diagnosed by gadolinium-DTPA enhanced magnetic resonance imaging. J Rheumatol. 2002;29:861–862. 48. O’Connell MJ, Powell T, Brennan D, et al. Whole-body MR imaging in the diagnosis of polymyositis. AJR Am J Roentgenol. 2002;179:967–971. 49. Zhen-Guo H, et al. Value of whole-body magnetic resonance imaging for screening multifocal osteonecrosis in patients with polymyositis/dermatomyositis. Br J Radiol. 2017;90(1073):20160780. 50. Wanchu A. Antinuclear antibodies: clinical applications. J Postgrad Med. 2000;46:144–148. 51. Sauty A, Rochat T, Schoch OD, et al. Pulmonary fibrosis with predominant CD8 lymphocytic alveolitis and anti–Jo-1 antibodies. Eur Respir J. 1997;10:2907–2912. 52. Zampieri S, Ghirardello A, Iaccarino L, et al. Anti–Jo-1 antibodies. Autoimmunity. 2005;38:73–78. 53. Ceribelli A, Fredi M, Taraborelli M, et al. Prevalence and clinical significance of anti-MDA5 antibodies in European patients with polymyositis/dermatomyositis. Clin Exp Rheumatol. 2014;32:891–897. 54. Dalakas MC, Sivakumar K. The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis. Curr Opin Neurol. 1996;9:235–239.

43 

Sjögren Syndrome* STEPHEN B. HOBBS

Sjögren syndrome can develop at any age, but 59 years of age is the average at diagnosis (range, 43–75 years).3 There are two age peaks for primary disease—the first in the third decade and the second after menopause.4 The worldwide prevalence of Sjögren syndrome is 14.4 per 100,000 population, and the condition is nine times more frequent in women than in men.5

a more insidious onset of salivary gland enlargement can signal lymphomatous transformation.1 Exocrine glandular involvement is typically the first manifestation of Sjögren syndrome, with a subsequent slow deterioration in salivary and lacrimal function.6 In a cohort of patients with primary disease, musculoskeletal (60%), urogenital (40%), hematologic (24%), cutaneous (20%), pulmonary (11%), gastrointestinal (7%), neurologic (8%), and renal (3%) manifestations were noted. Symptoms of myalgia and arthralgia are frequent, whereas arthritis is rare.7 There are few descriptions of the type of arthritis found in these patients, but it tends to be similar to RA.1 Urogenital symptoms are secondary to vulval dryness and pruritus, which leads to dyspareunia.8 Many patients with primary Sjögren syndrome have a normocytic, normochromic anemia, and leukopenia,8 as well as an increased risk for hematologic malignancies (leukemia, myeloma, Hodgkin and non-Hodgkin lymphoma).9 Given that the syndrome is characterized by a lymphocytic infiltrate, it can be anticipated that a spectrum of lymphoproliferative disorders may develop in patients with Sjögren syndrome, including lymphocytic (lymphoid) interstitial pneumonia (LIP), follicular bronchiolitis, nodular lymphoid hyperplasia, and mucosa-associated lymphatic tissue (MALT) lymphoma, in addition to frank lymphoma. Amyloid deposition in conjunction with LIP has also been described.10 The incidence of cutaneous vasculitis has been estimated at 9%, and it is usually manifested as purpura, urticarial lesions, and maculopapules.4 Raynaud phenomenon has been reported in 30% of patients,11 and in patients with primary Sjögren syndrome and Raynaud phenomenon, the density of nail fold capillaries is significantly reduced.12 Patients with primary Sjögren syndrome have an increased risk for additional autoimmune diseases,13 particularly RA, scleroderma, and primary biliary cirrhosis.14 Clinical or biochemical evidence of liver disease, or both, is found in up to 10% of patients,15 and the incidence of Sjögren syndrome in patients with chronic liver disease suggests a link between hepatitis C virus and Sjögren syndrome.16

Clinical Presentation

Pathophysiology

Keratoconjunctivitis, the characteristic ophthalmologic feature of Sjögren syndrome, is caused by a lack of tear film secondary to destruction of the lacrimal gland. Patients complain of dry eyes, irritation, or photophobia. Careful assessment of patients with dry eyes is important; in particular, the integrity of the corneal surface needs to be evaluated. Dryness of the mouth makes swallowing and talking difficult. Sudden swelling of a salivary gland suggests infection, whereas

PATHOLOGY

Etiology Sjögren’s syndrome, or “sicca syndrome,” is a disorder of the immune system that is largely defined by its two most common symptoms—dry eyes and a dry mouth; these symptoms frequently accompany other autoimmune disorders. Distinction is usually made between Sjögren’s syndrome that occurs in the absence of an accompanying connective tissue disease (primary Sjögren’s syndrome) and Sjögren’s syndrome accompanied by another connective tissue disease (secondary Sjögren’s syndrome) such as systemic lupus erythematosus, rheumatoid arthritis (RA), scleroderma, systemic sclerosis, cryoglobulinemia, and polyarteritis nodosa. Both primary and secondary types occur with similar frequency, and virtually all organs may be involved. The etiology of the disease is not fully understood, but it is speculated that environmental factors trigger the human leukocyte antigen (HLA)-DR–dependent immune system, which affects the exocrine glandular vascular endothelium. Infiltration of the exocrine glands by lymphocytes leads to apoptosis and glandular dysfunction.1 There is evidence that certain HLA class II antigens are increased in these patients; in Caucasian individuals, Sjögren syndrome is associated with HLA-DR3 and certain HLA-DQ alleles.2 Possible triggering environmental factors include viruses, such as Epstein-Barr, human T-lymphotropic virus-1, human herpesvirus 6, human immunodeficiency virus, hepatitis C, and cytomegalovirus. Damage or cell death caused by viral infection or other causes may provide triggering antigens to Toll-like receptors on dendritic or epithelial cells.1

Prevalence and Epidemiology

*The editors and the publisher would like to thank Drs. Maureen Quigley and David M. Hansell for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

576

In one of the few computed tomography (CT)-pathology correlative studies of primary Sjögren syndrome, the major histologic patterns of lung disease found on biopsy were nonspecific interstitial pneumonia (NSIP) (61%), bronchiolitis, type not specified (12%), malignant lymphoma (12%), amyloidosis (6%), atelectatic fibrosis (6%), and honeycomb fibrosis, histologic subtype not specified (3%).17 The CT appearance of an NSIP pattern had a high positive predictive value for the presence of NSIP on biopsy.17 The relative scarcity of usual interstitial pneumonia (UIP) in this study may be a result of the small size

43  Sjögren Syndrome

577

of the series and also because those with typical UIP on highresolution CT (HRCT) may not have undergone surgical lung biopsy. Conversely, in a smaller series of lung biopsy specimens (n = 9),18 two-thirds of the patients had histologic UIP, and a third had NSIP. Malignant lymphoma (see Chapter 24) is the major cause of morbidity and mortality in patients with primary Sjögren syndrome, and these patients have a 44-fold increased risk for the development of non-Hodgkin lymphoma.19 LIP is a diffuse interstitial proliferation of mature small lymphocytes and plasma cells,20 and it commonly occurs in patients with Sjögren syndrome, autoimmune thyroid disease, acquired immune deficiency syndrome, and Castleman disease (see Chapter 23).21 Other diffuse interstitial lung diseases encountered in connective tissue diseases, such as diffuse alveolar damage22 and diffuse pulmonary hemorrhage, are not commonly associated with Sjögren syndrome. LUNG FUNCTION It is difficult to obtain a clear picture of the pattern of abnormal pulmonary function in primary Sjögren syndrome from the literature,23 and some studies report both restrictive and obstructive abnormalities. However, a 10-year follow-up of pulmonary function in patients with primary Sjögren syndrome found that most patients do not have progressive lung disease.24

A

Manifestations of the Disease The most frequently observed clinical manifestations of primary Sjögren syndrome are dry mouth, dry eyes, and parotid swelling. The main extraglandular manifestations are arthralgia and myalgia. The range of extraglandular pathology can significantly delay diagnosis in this condition, but in patients with known connective tissue disease, it is important to be alert to symptoms of “sicca syndrome.”

KEY POINTS: THORACIC MANIFESTATIONS OF SJÖGREN SYNDROME Parenchymal disease: common • Nonspecific interstitial pneumonia • Usual interstitial pneumonia • Lymphocytic interstitial pneumonia • Organizing pneumonia • Lymphoma • Amyloid deposits Airway disease: common • Follicular bronchiolitis • Bronchiectasis Vascular disease: uncommon • Pulmonary hypertension Pleural disease: uncommon • Pleural effusion • Pleural thickening

RADIOGRAPHY One in 10 patients with primary Sjögren syndrome has pul­ monary involvement evident on the chest radiograph.25 The most common pulmonary manifestations (NSIP, UIP, or LIP) give rise to a reticular or reticulonodular pattern and ground-glass

B Fig. 43.1  Nonspecific interstitial pneumonia in Sjögren syndrome. (A) Chest radiograph shows hazy increased opacity (ground-glass opacities) in the middle and lower lung zones and a mild reticular pattern at the lung bases. (B) High-resolution CT demonstrates extensive bilateral ground-glass opacities and minimal reticulation.

opacities usually involving mainly the lower lung zones (Fig. 43.1). Patients with pure LIP have a reticulonodular pattern on chest radiography, with or without ground-glass opacities and patchy areas of consolidation.26 The prevalence of chest radiographic abnormalities varies between studies, and in one series, all patients with primary Sjögren syndrome had bilateral consolidation, reticulonodular opacities, or multiple cysts.17 The majority of these abnormalities occurred in the lower zones. Pleural disease is rare in primary Sjögren syndrome. Patients with Sjögren syndrome and supervening lymphoma are likely to have abnormal mediastinal and hilar contours on chest radiography, but a normal chest radiograph does not preclude nodal disease. In patients with the rarer primary lymphomas of lung parenchyma or MALT lymphoma, a chest radiograph may show patchy ground-glass opacity and sometimes

578

SECTION 8  Connective Tissue Diseases

indolent or, indeed, static areas of consolidation on serial radiographs. COMPUTED TOMOGRAPHY Few studies have concentrated exclusively on Sjögren syndrome of the lung, and because its prevalence is approximately equal to that of RA, it can be presumed that Sjögren syndrome either tends to not be associated with lung involvement or runs a subclinical course. The prevalence of HRCT “abnormalities” in those who fulfill the diagnostic criteria is between 34% and 65%,27,28 but the majority of patients recruited to these studies had no respiratory symptoms. Koyama and colleagues29 studied 60 patients with abnormal HRCT findings who fulfilled the diagnostic criteria for primary Sjögren syndrome. The most common CT findings were areas of ground-glass opacity (92%), subpleural small nodules (78%), nonseptal linear opacity (75%), interlobular septal thickening (55%), bronchiectasis (38%), cysts (30%), and airspace consolidation (25%). The nodules and septal thickening, although nonspecific, would be consistent with LIP or follicular bronchiolitis (Fig. 43.2). The cysts are also consistent with LIP, and the consolidation could represent lower respiratory tract infection, lymphoproliferative disease, or organizing pneumonia. Another study that attempted to characterize the appearances of primary Sjögren syndrome on HRCT 27 recruited nonsmokers, and most of the CT abnormalities were found in those with respiratory symptoms. Similar to the previous study, the most frequent findings on HRCT were ground-glass opacities, linear opacities (reticulation), and airspace consolidation. The histologic correlate for the ground-glass opacities (frequently seen in the various HRCT studies of Sjögren syndrome) is uncertain; NSIP, LIP, infection, and organizing pneumonia are all possible explanations for the ground-glass opacity.17 The proportion of patients with honeycombing on HRCT varies between 8% and 25%.27,28 In Sjögren syndrome there is an increased prevalence of

Fig. 43.2  Nonspecific parenchymal findings frequently seen in primary Sjögren syndrome. High-resolution CT shows nonspecific findings, including small peribronchial and subpleural nodules and mild bronchial dilation. These abnormalities are likely to represent follicular bronchiolitis. Cystic changes are also evident in the anterior left upper lobe.

micronodules and interlobular septal thickening,28 but the pathologic correlate for these lesions is unknown. A CT-pathologic correlation in primary Sjögren syndrome found that the NSIP pattern on HRCT had a high positive predictive value (94%) for the presence of NSIP in the pathologic specimen; however, cases without an NSIP pattern correlated poorly with the histologic diagnosis.17 In this study there were no cases of biopsy-proven LIP despite three patients having cysts on CT; in these three patients, amyloidosis and malignant lymphoma were diagnosed histologically. The HRCT manifestations of NSIP consist of predominantly ground-glass opacities commonly with superimposed reticulation, traction bronchiectasis, and bronchiolectasis and typically involving mainly the lower lung zones (see Fig. 43.1). More extensive reticulation, with or without associated honeycombing, may result from NSIP or UIP (Fig. 43.3). The HRCT appearance of LIP is characterized by the presence of ground-glass opacities, poorly defined centrilobular nodules, and interlobular septal thickening (Fig. 43.4.)30 Patients with LIP frequently have cysts and perivascular cysts that may actually be the most distinctive finding or even the sole finding (see Chapter 23). This can lead to a misdiagnosis of lymphangioleiomyomatosis (LAM) in some cases, but the cysts in LIP usually are predominant in the lower lungs around bronchi and vessels in contrast to the more diffuse distribution of LAM-related cysts (see Chapter 35). A spectrum of lymphoproliferative pathology may be encountered in patients with primary Sjögren syndrome (Fig. 43.5). The cardinal feature of nonpulmonary lymphoma on chest radiography or CT is mediastinal or hilar lymphadenopathy, with the anterior mediastinal and paratracheal nodes being the most frequently involved groups.31,32 Primary pulmonary Hodgkin lymphoma is rare, and the frequency of lymphomas primarily arising in the lung is less than 1% of all lymphomas.33 Primary lymphoma is usually manifested as localized areas of consolidation, and air bronchograms are commonly present. Lymphangitic infiltration is the second most frequent radiologic finding in primary lymphoma.33 Patients with pulmonary MALT lymphoma typically do not have mediastinal lymphadenopathy, and MALT lymphomas

Fig. 43.3  Fibrotic lung disease in Sjögren syndrome likely representing nonspecific interstitial pneumonia. High-resolution CT shows a subpleural and basal reticular pattern with areas of subpleural sparing.

43  Sjögren Syndrome

Fig. 43.4  Lymphoid interstitial pneumonia in Sjögren syndrome. Highresolution CT shows cystic airspaces, ground-glass opacities, and small nodules.

Fig. 43.5  Lymphoid interstitial pneumonia (LIP) and B-cell lymphoma in Sjögren syndrome. High-resolution CT shows diffuse ground-glass opacities, bilateral cysts (arrowheads), and an irregular nodule in the left lower lobe (arrow). The patient was a middle-aged woman with LIP proven by surgical biopsy and with B-cell lymphoma proven by bone marrow biopsy.

are generally indolent lesions with single or multiple areas of consolidation or ground-glass opacity, adjacent interlobular septal thickening, and prominent air bronchograms.34,35 However, prominent adenopathy in the chest is not necessarily indicative of lymphoma because benign lymphadenopathy, thymic lymphoid hyperplasia, and multilocular thymic cysts can also occur in the setting of Sjögren syndrome. Systemic lymphoplasmacytic inflammation can result in lymph node enlargement throughout the chest, including the mediastinum, and thymic lymph node hyperplasia can manifest as nodules and increased attenuation in the anterior mediastinal fat as well.36 Multilocular thymic cysts

579

Fig. 43.6  Organizing pneumonia in Sjögren syndrome. High-resolution CT shows bilateral areas of consolidation in a predominantly peribronchial distribution surrounded by a halo of ground-glass opacity. Also noted is a perilobular distribution in the right upper lobe.

can manifest as thin-walled, anterior mediastinal cysts in Sjögren syndrome, likely as the result of chronic noninfectious inflammation. Occasionally, they may demonstrate internal heterogeneity or increased attenuation suggesting internal hemorrhage or proteinaceous fluid.37–39 A significant solid component or irregular wall thickening of these multilocular cysts should raise the possibility of a malignancy (see Chapter 77). Case reports of organizing pneumonia and follicular bronchiolitis have been associated with primary Sjögren syndrome.40 The HRCT manifestations of organizing pneumonia (see Chapter 29) typically consist of bilateral areas of consolidation that frequently have a predominantly peribronchial, perilobular, or subpleural distribution (Fig. 43.6). The cardinal HRCT features of follicular bronchiolitis are centrilobular nodules measuring 1 to 12 mm in diameter, variably associated with peribronchial nodules and patchy areas of ground-glass opacity.41 Follicular bronchiolitis is, however, infrequently described in Sjögren syndrome, and it is difficult to know whether this is because few biopsy studies of Sjögren syndrome have been conducted or whether it reflects the true prevalence of follicular bronchiolitis in these patients. A study that focused on patients who had primary Sjögren syndrome and respiratory symptoms found that large or small airways disease, or both, affected more than half the patients in this cohort.42 Bronchiectasis has been described in HRCT studies in 4% to 38% of patients with primary Sjögren syndrome,27,28,43 and it has been postulated that the bronchiectasis occurs because lymphocytic invasion of the tracheobronchial mucous glands results in atelectasis and recurrent infection (Fig. 43.7). A single case of middle lobe syndrome has been attributed to lymphocytic bronchiolitis in a patient with primary Sjögren syndrome.44 Patients with primary Sjögren syndrome frequently have bronchial hyperresponsiveness and increased epithelial airway damage compared with healthy control persons.45 There are a few descriptions of air-trapping on HRCT in Sjögren syndrome, and in one study the extent of air-trapping did not correlate with pulmonary function test results, and the authors suggested that this may be due to a subclinical bronchiolar inflammatory process that preceded the functional changes.46

580

SECTION 8  Connective Tissue Diseases

or neoplastic disease, but because of the relative insensitivity of the chest radiograph, HRCT is the investigation of choice to exclude interstitial or airway disease.

Differential Diagnosis The imaging differential diagnosis varies widely, depending on the pattern of pulmonary parenchymal disease, airways disease, vascular disease, and pleural disease. Each pattern would result in a tailored differential. For example, if the primary pulmonary parenchymal pattern consisted of an NSIP-type chronic fibrosing interstitial pneumonia, the differential may include other connective tissue diseases, chronic hypersensitivity pneumonitis, or drug toxicity.

KEY POINTS Fig. 43.7  Bronchiectasis in Sjögren syndrome. High-resolution CT shows left upper lobe bronchiectasis (arrow) and focal areas of decreased attenuation and vascularity, consistent with constrictive bronchiolitis. Also evident is minimal bilateral ground-glass opacities.

Primary pulmonary hypertension has been recognized in a few isolated case reports,47 and it may be a rare association of Sjögren syndrome. Antiphospholipid syndrome occurs in a small subgroup of patients and could be a cofactor for the development of pulmonary hypertension. However, the incidence of lupus anticoagulant is estimated to be only 11% in those with primary Sjögren syndrome, and this value is far lower than in systemic lupus erythematosus.48 ULTRASONOGRAPHY Echocardiography in Sjögren syndrome shows a higher-thanexpected rate of pericarditis and diastolic dysfunction, although overt clinical cardiac involvement is rare.49 IMAGING ALGORITHMS Because the frequency of clinically significant interstitial lung disease is not high, patients tend to be imaged only if they have respiratory symptoms. A chest radiograph may be initially performed in a symptomatic patient to exclude gross parenchymal

• Sjögren syndrome can be primary or secondary; primary Sjögren syndrome has its own set of diagnostic criteria, and secondary Sjögren syndrome is associated with other connective tissue diseases. • Sjögren syndrome is relatively common, especially in the older female population, but symptomatic lung disease is infrequent. • The most common clinical manifestations are dry mouth, dry eyes, and parotid swelling. • No curative agent exists. Treatment is essentially for symptom palliation and prevention of complications. • The majority of patients with Sjögren syndrome will have abnormal HRCT findings, but this does not necessarily equate with clinically important disease. • The most common pulmonary manifestations include interstitial fibrosis (most commonly, nonspecific interstitial pneumonia and usual interstitial pneumonia), lymphocytic interstitial pneumonia, bronchiectasis, and lymphoma. • The most common HRCT findings are ground-glass opacities, intralobular linear opacities (reticulation), cystic airspaces, and mild bronchiectasis. • There is an increased risk for malignant lymphoma in patients with primary Sjögren syndrome.

SUGGESTED READINGS Egashira R, et al. CT findings of thoracic manifestations of primary Sjögren syndrome: radiologic-pathologic correlation. Radiographics. 2013;33:1933–1949. Fox RI. Sjögren’s syndrome. Lancet. 2005;366:321–331.

The full reference list for this chapter is available at ExpertConsult.com.

43  Sjögren Syndrome 580.e1

REFERENCES 1. Fox RI. Sjögren’s syndrome. Lancet. 2005;366:321–331. 2. Fox RI. Sjögren’s syndrome: immunobiology of exocrine gland dysfunction. Adv Dent Res. 1996;10:35–40. 3. Pillemer SR, Matteson EL, Jacobsson LT, et al. Incidence of physician-diagnosed primary Sjögren’s syndrome in residents of Olmsted County, Minnesota. Mayo Clin Proc. 2001;76:593–599. 4. Fox RI, Liu AY. Sjögren’s syndrome in dermatology. Clin Dermatol. 2006;24:393–413. 5. Cooper GS, Stroehla BC. The epidemiology of autoimmune diseases. Autoimmun Rev. 2003;2:119–125. 6. Baldini C, Tavoni A, Merlini G, et al. Primary Sjögren’s syndrome: clinical and serological feature of a single centre. Reumatismo. 2005;57:256–261. 7. Kruize AA, Hene RJ, Oey PL, et al. Neuro-musculo-skeletal manifestations in primary Sjögren’s syndrome. Neth J Med. 1992;40:135–139. 8. Fox RI, Howell FV, Bone RC, Michelson P. Primary Sjögren’s syndrome: clinical and immunopathologic features. Semin Arthritis Rheum. 1984;14: 77–105. 9. Söderberg KC, Jonsson F, Winqvist O, et al. Autoimmune diseases, asthma and risk of haematological malignancies: a nationwide case-control study in Sweden. Eur J Cancer. 2006;42:3028–3033. 10. Desai SR, Nicholson AG, Stewart S, et al. Benign pulmonary lymphocytic infiltration and amyloidosis: computed tomographic and pathologic features in three cases. J Thorac Imaging. 1997;12:215–220. 11. Skopouli FN, Talal A, Galanopoulou V, et al. Raynaud’s phenomenon in primary Sjögren’s syndrome. J Rheumatol. 1990;17:618–620. 12. Tektonidou M, Kaskani E, Skopouli FN, Moutsopoulos HM. Microvascular abnormalities in Sjögren’s syndrome: nailfold capillaroscopy. Rheumatology (Oxford). 1999;38:826–830. 13. Lazarus MN, Isenberg DA. Development of additional autoimmune diseases in a population of patients with primary Sjögren’s syndrome. Ann Rheum Dis. 2005;64:1062–1064. 14. Coll J, Rives A, Grino MC, et al. Prevalence of Sjögren’s syndrome in autoimmune diseases. Ann Rheum Dis. 1987;46:286–289. 15. Whaley K, Goudie RB, Williamson J, et al. Liver disease in Sjögren’s syndrome and rheumatoid arthritis. Lancet. 1970;1:861–863. 16. Wattiaux MJ. [Gougerot Sjögren’s syndrome and hepatitis C virus: what relation?]. Presse Med. 1997;26:652–655. 17. Ito I, Nagai S, Kitaichi M, et al. Pulmonary manifestations of primary Sjögren’s syndrome: a clinical, radiologic, and pathologic study. Am J Respir Crit Care Med. 2005;171:632–638. 18. Takahashi T, Satoh M, Satoh H. Unilateral acute exacerbation of pulmonary fibrosis in association with Sjögren’s syndrome. Intern Med. 1996;35: 811–814. 19. Bowman SJ. Collaborative research into outcome measures in Sjögren’s syndrome. Update on disease assessment. Scand J Rheumatol Suppl. 2002;116: 23–27. 20. Liebow AA, Carrington CB. Diffuse pulmonary lymphoreticular infiltrations associated with dysproteinemia. Med Clin North Am. 1973;57:809–843. 21. Johkoh T, Müller NL, Pickford HA, et al. Lymphocytic interstitial pneumonia: thin-section CT findings in 22 patients. Radiology. 1999;212:567–572. 22. Usui Y, Kimula Y, Miura H, et al. A case of bronchiolitis obliterans organizing pneumonia associated with primary Sjögren’s syndrome who died of superimposed diffuse alveolar damage. Respiration. 1992;59:122–124. 23. Gardiner P. Primary Sjögren’s syndrome. Baillieres Clin Rheumatol. 1993;7: 59–77. 24. Davidson BK, Kelly CA, Griffiths ID. Ten year follow up of pulmonary function in patients with primary Sjögren’s syndrome. Ann Rheum Dis. 2000;59:709–712. 25. Strimlan CV, Rosenow EC 3rd, Divertie MB, Harrison EG Jr. Pulmonary manifestations of Sjögren’s syndrome. Chest. 1976;70:354–361. 26. Fishback N, Koss M. Update on lymphoid interstitial pneumonitis. Curr Opin Pulm Med. 1996;2:429–433.

27. Franquet T, Gimenez A, Monill JM, et al. Primary Sjögren’s syndrome and associated lung disease: CT findings in 50 patients. AJR Am J Roentgenol. 1997;169:655–658. 28. Uffmann M, Kiener HP, Bankier AA, et al. Lung manifestation in asymptomatic patients with primary Sjögren’s syndrome: assessment with high resolution CT and pulmonary function tests. J Thorac Imaging. 2001;16:282–289. 29. Koyama M, Johkoh T, Honda O, et al. Pulmonary involvement in primary Sjögren’s syndrome: spectrum of pulmonary abnormalities and computed tomography findings in 60 patients. J Thorac Imaging. 2001;16:290–296. 30. Johkoh T, Müller NL, Pickford HA, et al. Lymphocytic interstitial pneumonia: thin-section CT findings in 22 patients. Radiology. 1999;212(2):567–572. 31. Filly R, Bland N, Castellino RA. Radiographic distribution of intrathoracic disease in previously untreated patients with Hodgkin’s disease and nonHodgkin’s lymphoma. Radiology. 1976;120:277–281. 32. Castellino RA, Hilton S, O’Brien JP, Portlock CS. Non-Hodgkin lymphoma: contribution of chest CT in the initial staging evaluation. Radiology. 1996;199:129–132. 33. Lee KS, Kim Y, Primack SL. Imaging of pulmonary lymphomas. AJR Am J Roentgenol. 1997;168:339–345. 34. O’Donnell PG, Tung KT. Lymphomas in the lung associated with Sjögren’s syndrome. AJR Am J Roentgenol. 1998;171:895. 35. McCulloch GL, Sinnatamby R, Stewart S, et al. High-resolution computed tomographic appearance of MALToma of the lung. Eur Radiol. 1998;8: 1669–1673. 36. Kobayashi H, Ozeki Y, Aida S. Pulmonary and thymic lymphoid hyperplasia in primary Sjögren’s syndrome. Jpn J Radiol. 2009;27(2):107–110. 37. Suster S, Rosai J. Multilocular thymic cyst: an acquired reactive process—study of 18 cases. Am J Surg Pathol. 1991;15(4):388–398. 38. Izumi H, Nobukawa B, Takahashi K, et al. Multilocular thymic cyst associated with follicular hyperplasia: clinicopathologic study of 4 resected cases. Hum Pathol. 2005;36(7):841–844. 39. Kondo K, Miyoshi T, Sakiyama S, Shimosato Y, Monden Y. Multilocular thymic cyst associated with Sjögren’s syndrome. Ann Thorac Surg. 2001;72(4): 1367–1369. 40. Hayashi R, Yamashita N, Sugiyama E, et al. A case of primary Sjögren’s syndrome with interstitial pneumonia showing bronchiolitis obliterans organizing pneumonia pattern and lymphofollicular formation. Nihon Kokyuki Gakkai Zasshi. 2000;38:880–884. 41. Howling SJ, Hansell DM, Wells AU, et al. Follicular bronchiolitis: thin-section CT and histologic findings. Radiology. 1999;212:637–642. 42. Taouli B, Brauner MW, Mourey I, et al. Thin-section chest CT findings of primary Sjögren’s syndrome: correlation with pulmonary function. Eur Radiol. 2002;12:1504–1511. 43. Koyama M, Johkoh T, Honda O, et al. Pulmonary involvement in primary Sjögren’s syndrome: spectrum of pulmonary abnormalities and computed tomography findings in 60 patients. J Thorac Imaging. 2001;16:290–296. 44. Chen HA, Lai SL, Kwang WK, et al. Middle lobe syndrome as the pulmonary manifestation of primary Sjögren’s syndrome. Med J Aust. 2006;184: 294–295. 45. Amin K, Ludviksdottir D, Janson C, et al. Inflammation and structural changes in the airways of patients with primary Sjögren’s syndrome. Respir Med. 2001;95:904–910. 46. Franquet T, Diaz C, Domingo P, et al. Air trapping in primary Sjögren’s syndrome: correlation of expiratory CT with pulmonary function tests. J Comput Assist Tomogr. 1999;23:169–173. 47. Biyajima S, Osada T, Daidoji H, et al. Pulmonary hypertension and antiphospholipid antibody in a patient with Sjögren’s syndrome. Intern Med. 1994;33: 768–772. 48. Fauchais AL, Lambert M, Launay D, et al. Antiphospholipid antibodies in primary Sjögren’s syndrome: prevalence and clinical significance in a series of 74 patients. Lupus. 2004;13:245–248. 49. Manganelli P, Bernardi P, Taliani U, Caminiti C. Echocardiographic findings in primary Sjögren’s syndrome. Ann Rheum Dis. 1997;56:568.

44 

Mixed Connective Tissue Disease* BRENT P. LITTLE

The incidence of MCTD is not known but is estimated to be higher than that of polymyositis, lower than that of systemic lupus erythematosus, and similar to that of systemic sclerosis.4 The majority of patients are women, with an average age at diagnosis of 37 years (range, 4–80 years).4 Pediatric-onset MCTD carries less mortality than adult-onset MCTD,5 probably because pulmonary hypertension is less frequent in the younger group. The prognosis for patients with MCTD is highly variable, but a severe, progressive disease course is unusual.6 In five series of MCTD (total of 194 patients), mortality was generally low (mean, 13%; range, 4%–35%); nevertheless, the fact that MCTD affects young women indicates a greater risk for premature death.6 Pulmonary hypertension is the most serious complication of MCTD, with severe infection secondary to immunosuppression being the other frequent cause of death.6,7

pericarditis; less common cardiac manifestations include myocarditis and complete heart block.4 The most frequent clinical manifestations of pulmonary involvement are dyspnea, pleuritic chest pain, and bibasilar rales.4 Secondary Sjögren syndrome is relatively common.9 Cutaneous manifestations include photosensitivity, livedo reticularis (a net-like vascular skin discoloration in the trunk or extremities), and calcinosis. When Sharp and colleagues10 first described MCTD, it was considered a benign condition requiring little treatment. It is now realized that serious renal11 and pulmonary involvement does occur; interstitial lung disease occurs in 21% to 66% of patients.12 Pleural effusion is one of the most common clinical manifestations of MCTD, but it is usually small and resolves spontaneously. In a retrospective review of the chest radiographs of 81 patients with MCTD, 6% had small pleural effusions, and even fewer had pleural thickening. Although a prospective study of patients with “MCTD” reported “pleuritis” in 35%,13 this study was undertaken before modern diagnostic criteria had been published.14 The incidence of pleuritis and effusions is likely to fall in the middle of this range because chest radiography may underestimate disease (compared with computed tomography [CT]) and, conversely, modern diagnostic criteria for MCTD are more rigorous. MCTD is associated with pulmonary hypertension, commonly manifested insidiously as progressive dyspnea on exertion.15 A surveillance study of a drug (bosentan) used to treat pulmonary hypertension found that connective tissue disease–related pulmonary hypertension and idiopathic pulmonary hypertension were each responsible for approximately a third of cases treated with this drug. In this cohort the majority of patients with connective tissue disease–associated pulmonary hypertension had systemic sclerosis (75%), and the next largest group consisted of patients with MCTD (9%).16 Although having a lower incidence in MCTD than in systemic sclerosis, pulmonary hypertension should be considered as a possible cause of dyspnea in both diseases.

Clinical Presentation

Pathophysiology

Most patients with MCTD have one or more of the following: Raynaud phenomenon, arthralgia, arthritis, swollen hands, sclerodactyly, or acrosclerosis (i.e., stiffness and atrophy of the skin of hands and feet), and two-thirds suffer from frank myositis.7,8 Esophageal dysmotility and reflux are reportedly frequent in MCTD, and generalized lymphadenopathy has been observed in 50% of patients.8 The most common cardiac abnormality is

PATHOLOGY

Etiology Mixed connective tissue disease (MCTD) is a disease with certain features of polymyositis, scleroderma, and systemic lupus erythematosus. Much of the evidence that MCTD is a distinct clinical entity stems from the identification of antiribonucleoprotein (anti-RNP) antibody, disease-specific human leukocyte antigen (HLA) profiles, suggestive clinical features, and because in the vast majority of patients, MCTD does not evolve into other connective tissue disease–related entities.1 The etiology of MCTD is unknown, but the presence of antibodies to RNPs implies that the immune system has become sensitized to ribonucleic acid synthesis or metabolism. Infectious agents have been investigated as a potential trigger for MCTD. Retroviral sequences have been found in a high proportion of MCTD patients,2 and most studies have revealed a strong association with MCTD and HLA-DR4.3

Prevalence and Epidemiology

*The editors and the publisher would like to thank Drs. Maureen Quigley and David M. Hansell for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

In patients with pulmonary hypertension in MCTD, plexiform lesions in small- and medium-sized arteries can occur, similar to primary pulmonary hypertension.17–20 In other connective tissue diseases, pulmonary vasculopathies are often associated with diffuse alveolar hemorrhage, but reports of diffuse alveolar hemorrhage in patients with MCTD are rare.15 Pulmonary thromboembolism may occur,21,22 possibly secondary to coexisting antiphospholipid syndrome. Pulmonary hemorrhage, diffuse alveolar damage, organizing pneumonia, nonspecific interstitial pneumonia, usual interstitial 581

582

SECTION 8  Connective Tissue Diseases

A

C

B

pneumonia (UIP), and airway disease may be seen in MCTD. These findings are consistent with the clinical manifestations of MCTD, which commonly have features of systemic sclerosis, systemic lupus erythematosus, or polymyositis/dermatomyositis. LUNG FUNCTION Pulmonary disease has been reported in 73% of patients with MCTD on the basis of pulmonary function tests, chest radiography, or both.13 The most common abnormality in pulmonary function testing is decreased lung diffusing capacity for carbon monoxide (DLCO)13; nearly half of patients in a small series had a decreased DLCO.23 In this study the value of DLCO correlated with the duration of the disease, but the cause of the impaired diffusing capacity was not explored. Some of this group may have had a proliferative vasculopathy associated with MCTD, but other possibilities include fibrotic lung disease and emphysema. Patients with MCTD have been reported as having functional small airway obstruction, but there is no high-resolution CT (HRCT) or pathologic confirmation of this finding.13,23 However, large airway disease has been described in a single HRCT study that reported bronchiectasis in a few individuals.24

Fig. 44.1  Nonspecific interstitial pneumonia (NSIP) in mixed connective tissue disease. (A) Chest radiograph shows low lung volumes and subtle peripheral reticulation at the lung bases bilaterally. The central pulmonary arteries are mildly enlarged. (B) High-resolution CT shows bilateral ground-glass opacities, fine reticulation, traction bronchiectasis, and traction bronchiolectasis, mainly in the peripheral lung regions. Note the relative sparing of the subpleural lung, a feature characteristic of NSIP. (C) A sagittal reformatted image demonstrates peripheral and basal predominance of the findings.

Manifestations of the Disease RADIOGRAPHY The true burden of lung disease in MCTD is unclear. On chest radiography interstitial lung disease has been reported to affect between 21% and 85% of patients.13,25 The typical radiographic abnormality is a reticular or reticulonodular pattern in the lower zones (Fig. 44.1).13 Pleural effusions or thickening is seen on less than 10% of chest radiographs. Because these patients are often immunosuppressed, it is important to rule out infection in the face of nonspecific pulmonary abnormalities. Chest radiographs are less sensitive than HRCT for the detection of interstitial lung disease,26 and an apparently normal radiograph does not rule out interstitial lung disease. COMPUTED TOMOGRAPHY Nonspecific interstitial pneumonia (NSIP) is the most frequent pattern of interstitial lung disease in MCTD; UIP and lymphocytic interstitial pneumonia are less commonly observed patterns.12 One study of MCTD reviewed 41 HRCT scans with lung abnormalities in patients with MCTD.24 Most patients had an NSIP

44  Mixed Connective Tissue Disease

pattern of disease, with micronodules, ground-glass opacities, and intralobular lines (reticulation), predominantly in the lower zones (see Fig. 44.1). Nearly 50% of scans showed evidence of fibrosis, including intralobular lines, architectural distortion, and traction bronchiectasis.24 A small proportion of patients had airspace consolidation, honeycombing, cysts, and bronchiectasis resembling a UIP pattern of fibrosis (Fig. 44.2). Therefore the HRCT manifestations of MCTD include findings seen in patients with systemic sclerosis, systemic lupus erythematosus, and polymyositis/dermatomyositis. In a second large CT study of pulmonary involvement in MCTD, 144 sequential patients were scanned at diagnosis, and 67% were said to have “active interstitial lung disease” diagnosed on the basis of ground-glass opacity on HRCT and an abnormal clearance time for technetium 99m–labeled diethylenetriaminepentaacetic acid (DTPA).27 In more than two-thirds of patients with active disease at baseline, HRCT findings had reverted to normal at the 6-month follow-up scan. The majority of DTPA scans also normalized at 6 months. The authors suggested that

583

ground-glass opacity may be reversible with early treatment; however, a proportion of patients progressed despite early treatment. The pathologic process that the ground-glass opacities represented is unknown, but a cellular infiltrate or, less likely, hemorrhage would be an explanation for this reversible disease. Pulmonary arterial hypertension may manifest as pulmonary arterial enlargement on chest radiography or CT28; accompanying small pericardial effusion or small poorly defined centrilobular nodules are uncommon.29 Pulmonary arterial hypertension may be associated with interstitial lung disease or may be the only intrathoracic manifestation of MCTD (Fig. 44.3). KEY POINTS: FINDINGS OF MIXED CONNECTIVE TISSUE DISEASE ON HIGH-RESOLUTION COMPUTED TOMOGRAPHY • Small pleural effusions and pleural thickening • Ground-glass opacities representing either fine fibrosis or reversible disease, usually in a nonspecific interstitial pneumonia pattern • Reticulation, traction bronchiectasis and bronchiolectasis, and occasional honeycombing; lower lung zone predominance • Micronodules, presumably reflecting lymphoid hyperplasia • Occasional bronchiectasis • Pulmonary arterial enlargement as a result of pulmonary hypertension

IMAGING ALGORITHMS Although MCTD is estimated to have the same incidence as systemic sclerosis, the frequency of clinically significant lung disease is far less. In symptomatic patients a chest radiograph may show pleural involvement, but suspected interstitial lung disease should be investigated with HRCT. Echocardiography, in conjunction with the clinical history and assessment of DLCO, can assist in identifying pulmonary hypertension.

Differential Diagnosis Fig. 44.2  Honeycombing and usual interstitial pneumonia pattern of lung fibrosis in mixed connective tissue disease. High-resolution CT shows marked honeycombing and a dilated esophagus with a peripheral and lower lung zone predominance.

FROM CLINICAL DATA The differential diagnosis includes primary pulmonary hypertension, systemic sclerosis, systemic lupus erythematosus, polymyositis/

Fig. 44.3  Pulmonary hypertension in mixed connective tissue disease. Contrast-enhanced CT shows marked dilation of the main, right, and left pulmonary arteries. Also note the enlarged bronchial arteries (arrow).

584

SECTION 8  Connective Tissue Diseases

CLASSIC SIGNS Four sets of criteria have been published for the diagnosis of MCTD.10,30–32 The criteria of Alarcon-Segovia and Cardiel have the highest sensitivity when tested on patients with well-defined connective tissue disease (100% specificity and 99.6% sensitivity).30 They are the simplest of the published criteria, and the key component is the presence of anti-RNP antibodies at a hemagglutination titer of 1 : 1600 or greater. At least three of the following five clinical criteria must also be present: (1) edema of the hands, (2) synovitis, (3) myositis, (4) Raynaud phenomenon, and (5) acrosclerosis.30 Returning to the Sharp et al10 original description of MCTD, some of these patients did not have anti-RNP antibodies, and because these antibodies are described in other connective tissue diseases, there is debate about the weight that is put on the serologic profile in MCTD.1

dermatomyositis, rheumatoid arthritis, and Raynaud phenomenon. MCTD is associated with specific autoantibodies, including antiRNP antibodies, but these can also be seen in other connective tissue diseases. A rheumatologic diagnosis is made by applying the specific diagnostic criteria, but patients may “evolve” into other connective tissue diseases. FROM SUPPORTIVE DIAGNOSTIC TECHNIQUES The serologic presence of anti–U1-RNP antibodies is the essential diagnostic criterion for MCTD, but the specificity of the antibody has not been fully defined. Frandsen and coworkers33 studied 151 patients with high-titer U1-RNP, and MCTD was diagnosed in 26% of these patients; 7% had systemic lupus erythematosus, and 3% had systemic sclerosis. There were 84 patients with possible undifferentiated connective tissue disease, but over a mean follow-up of 7 years, MCTD developed in a further 58, systemic sclerosis in 4, and systemic lupus erythematosus in 2. In 64% of those with high-titer anti–U1-RNP antibodies, MCTD subsequently developed.33

Synopsis of Treatment Options • Analgesics, for instance, nonsteroidal antiinflammatory drugs • Corticosteroids • Disease-modifying antirheumatic drugs, for instance, cyclophosphamide, methotrexate • Calcium channel blocking agents to control Raynaud phenomenon • Endothelin receptor blockade with bosentan for pulmonary hypertension

KEY POINTS • Mixed connective tissue disease (MCTD) has defined clinical/ serologic diagnostic criteria. • The literature on pulmonary involvement in MCTD is sparse, which may reflect the difficulty in studying a group undergoing metamorphosis or may reflect a true paucity of lung disease. • Pulmonary hypertension and severe infections are the most serious pulmonary manifestations of MCTD. • A large proportion of patients with early MCTD appear to have steroid-responsive and “reversible” interstitial lung disease

SUGGESTED READINGS Henry TS, Little BP, Veeraraghavan S, et al. The spectrum of interstitial lung disease in connective tissue disease. J Thorac Imaging. 2016;31:65–77. Prakash UB. Lungs in mixed connective tissue disease. J Thorac Imaging. 1992;7:55–61. Prakash UB. Respiratory complications in mixed connective tissue disease. Clin Chest Med. 1998;19:733–746.

The full reference list for this chapter is available at ExpertConsult.com.

44  Mixed Connective Tissue Disease 584.e1

REFERENCES 1. Swanton J, Isenberg D. Mixed connective tissue disease: still crazy after all these years. Rheum Dis Clin North Am. 2005;31:421–436. 2. Prokop J, Jagodzinski PP. Identification of retroviral conserved pol sequences in serum of mixed connective tissue disease and systemic sclerosis patients. Biomed Pharmacother. 2004;58:61–64. 3. Smolen JS, Steiner G. Mixed connective tissue disease: to be or not to be? Arthritis Rheum. 1998;41:768–777. 4. Prakash UB. Lungs in mixed connective tissue disease. J Thorac Imaging. 1992;7:55–61. 5. Mier RJ, Shishov M, Higgins GC, et al. Pediatric-onset mixed connective tissue disease. Rheum Dis Clin North Am. 2005;31:483–496, vii. 6. Lundberg IE. The prognosis of mixed connective tissue disease. Rheum Dis Clin North Am. 2005;31:535–547, vii–viii. 7. Burdt MA, Hoffman RW, Deutscher SL, et al. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum. 1999;42:899–909. 8. Aringer M, Steiner G, Smolen JS. Does mixed connective tissue disease exist? Yes. Rheum Dis Clin North Am. 2005;31:411–420, v. 9. Pope JE. Other manifestations of mixed connective tissue disease. Rheum Dis Clin North Am. 2005;31:519–533, vii. 10. Sharp GC, Irvin WS, Tan EM, et al. Mixed connective tissue disease—an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. 1972;52: 148–159. 11. Kitridou RC, Akmal M, Turkel SB, et al. Renal involvement in mixed connective tissue disease: a longitudinal clinicopathologic study. Semin Arthritis Rheum. 1986;16:135–145. 12. Capobianco J, Grimberg A, Thompson BM, Antunes VB, Jasinowodolinski D, Meirelles GS. Thoracic manifestations of collagen vascular diseases. Radiographics. 2012;32:33–50. 13. Sullivan WD, Hurst DJ, Harmon CE, et al. A prospective evaluation emphasizing pulmonary involvement in patients with mixed connective tissue disease. Medicine (Baltimore). 1984;63:92–107. 14. Alarcon-Sergovia D, Villarreal M. Diagnostic criteria for classification of mixed connective tissue disease. In: Kasukawa R, Sharp GC, eds. Mixed Connective Tissue Diseases and Antinuclear Antibodies. Amsterdam: Elsevier; 1987:33–40. 15. Bull TM, Fagan KA, Badesch DB. Pulmonary vascular manifestations of mixed connective tissue disease. Rheum Dis Clin North Am. 2005;31:451–464, vi. 16. Coghlan JG, Handler C. Connective tissue associated pulmonary arterial hypertension. Lupus. 2006;15:138–142. 17. Itoh O, Nishimaki T, Itoh M, et al. Mixed connective tissue disease with severe pulmonary hypertension and extensive subcutaneous calcification. Intern Med. 1998;37:421–425.

18. Kobayashi H, Sano T, Ii K, et al. Mixed connective tissue disease with fatal pulmonary hypertension. Acta Pathol Jpn. 1982;32:1121–1129. 19. Ueda N, Mimura K, Maeda H, et al. Mixed connective tissue disease with fatal pulmonary hypertension and a review of literature. Virchows Arch A Pathol Anat Histopathol. 1984;404:335–340. 20. Hosoda Y, Suzuki Y, Takano M, et al. Mixed connective tissue disease with pulmonary hypertension: a clinical and pathological study. J Rheumatol. 1987;14:826–830. 21. Miyata M, Kida S, Kanno T, et al. Pulmonary hypertension in MCTD: report of two cases with anticardiolipin antibody. Clin Rheumatol. 1992;11: 195–201. 22. Ueda Y, Yamauchi Y, Makizumi K, et al. Successful treatment of acute right cardiac failure due to pulmonary thromboembolism in mixed connective tissue disease. Jpn J Med. 1991;30:568–572. 23. Izumiyama T, Hida W, Ichinose M, et al. Small airway involvement in mixed connective tissue disease. Tohoku J Exp Med. 1993;170:273–283. 24. Kozuka T, Johkoh T, Honda O, et al. Pulmonary involvement in mixed connective tissue disease: high-resolution CT findings in 41 patients. J Thorac Imaging. 2001;16:94–98. 25. Prakash UB, Luthra HS, Divertie MB. Intrathoracic manifestations in mixed connective tissue disease. Mayo Clin Proc. 1985;60:813–821. 26. Padley SP, Hansell DM, Flower CD, Jennings P. Comparative accuracy of high resolution computed tomography and chest radiography in the diagnosis of chronic diffuse infiltrative lung disease. Clin Radiol. 1991;44:222–226. 27. Bodolay E, Szekanecz Z, Devenyi K, et al. Evaluation of interstitial lung disease in mixed connective tissue disease (MCTD). Rheumatology (Oxford). 2005;44:656–661. 28. Ng CS, Wells AU, Padley SP. A CT sign of chronic pulmonary arterial hypertension: the ratio of main pulmonary artery to aortic diameter. J Thorac Imaging. 1999;14:270–278. 29. Nolan RL, McAdams HP, Sporn TA, et al. Pulmonary cholesterol granulomas in patients with pulmonary artery hypertension: chest radiographic and CT findings. AJR Am J Roentgenol. 1999;172:1317–1319. 30. Alarcon-Segovia D, Cardiel MH. Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients. J Rheumatol. 1989;16:328–334. 31. Kasukawa R, Tojo T, Miyawaki S. Mixed Connective Disease and Antinuclear Antibodies. Amsterdam: Elsevier; 1987. 32. Kahn MF, Appleboom T. Les Maladies Systemiques. 3rd ed. Paris: Flammarion; 1991. 33. Frandsen PB, Kriegbaum NJ, Ullman S, et al. Follow-up of 151 patients with high-titer U1RNP antibodies. Clin Rheumatol. 1996;15:254–260.

45 

Interstitial Pneumonia With Autoimmune Features MICHAEL A. KADOCH  |  JUSTIN M. OLDHAM

Interstitial pneumonia with autoimmune features (IPAF) refers to the clinical entity of interstitial lung disease (ILD) in patients with features of autoimmunity but without overt connective tissue disease (CTD). IPAF was introduced in 2015 by an international consensus panel in an attempt to standardize the nomenclature and diagnostic criteria for this entity, which represents an intermediary on the spectrum between the idiopathic interstitial pneumonias (IIPs) and CTD-associated ILD. The high-resolution computed tomography (HRCT) pattern is a critical component of IPAF criteria, and the prognostic significance of individual patterns and pattern features were recently described. As such, IPAF remains an area of active multidisciplinary investigation, and knowledge of this clinical entity is essential for a comprehensive understanding of ILD.

Background ILD often arises in the context of an established CTD, such as rheumatoid arthritis, systemic lupus erythematosus, polymyositis, dermatomyositis, Sjögren syndrome, scleroderma, and mixed connective tissue disease. Nonspecific interstitial pneumonia (NSIP) is the most commonly encountered ILD pattern on HRCT in those with CTD, with the exception of rheumatoid arthritis, where a usual interstitial pneumonia (UIP) pattern is more commonly observed. Current international guidelines for the diagnosis of the IIPs recommend excluding CTD,1 which is typically performed by assessing for extrathoracic manifestations, autoantibody testing, and multidisciplinary discussion. It is not uncommon, however, for ILD to be the first, or only, manifestation of autoimmunity. Many patients with ILD exhibit features of CTD but do not satisfy rheumatologic criteria for a specific CTD diagnosis. These patients have been previously described in the pulmonary medicine and radiology literature by various names, including: lung-dominant CTD,2 undifferentiated CTD-associated ILD,3 and autoimmune-featured ILD.4 The diagnostic criteria used to define these entities were overlapping but varied. Despite the associated features of autoimmunity, few of these patients will go on to develop overt CTD. The need for a standardized nomenclature and diagnostic criteria for this patient population led to the formation of the European Respiratory Society (ERS)/American Thoracic Society (ATS) Task Force on Undifferentiated Forms of Connective Tissue Disease–Associated Interstitial Lung Disease. In 2015 this group produced an official ERS/ATS research statement proposing criteria for patients with IPAF.5 Patients with IPAF can be thought of as intermediary on the spectrum between the IIPs and those with overt CTD-associated ILD.

Diagnostic Criteria The diagnosis of IPAF requires1: the presence of ILD by HRCT or surgical lung biopsy,2 exclusion of an alternate etiology for the ILD,3 failure to meet criteria for a defined CTD, and4 at least one feature from at least two of these domains: clinical, serologic, and morphologic (Table 45.1).5 The clinical domain comprises features that are strongly associated with CTD. These include distal digital fissuring (“mechanic’s hands”), digital tip ulceration, inflammatory arthritis or polyarticular morning stiffness lasting more than 60 minutes, palmar telangiectasia, Raynaud phenomenon, unexplained digital edema, and unexplained fixed rash on the digital extensor surfaces (Gottron sign). The serologic domain includes autoantibodies with strong CTD association and requires moderately elevated titers for less specific autoantibodies, such as the antinuclear antibody (ANA) and rheumatoid factor (RF). The morphologic domain includes three subdomains: radiologic, pathologic, and multicompartment. The radiologic subdomain is focused on HRCT features that are commonly associated with CTD, including NSIP (Fig. 45.1), organizing pneumonia (OP) (Fig. 45.2), NSIP with OP overlap (Fig. 45.3), and lymphocytic interstitial pneumonia (LIP). UIP is not included in the IPAF criteria because it lacks specificity. The pathologic subdomain similarly includes NSIP, OP, NSIP with OP overlap, and LIP. Interstitial lymphoid aggregates with germinal centers and diffuse lymphoplasmacytic infiltration are also included because they are strongly associated with CTD.6 UIP is again not included because it lacks specificity for CTD. Extraparenchymal thoracic manifestations are commonly encountered in the setting of CTD, leading to the inclusion of a multicompartment subdomain. The multicompartment subdomain includes unexplained pleural or pericardial effusion or thickening, intrinsic airways disease (airflow obstruction, bronchiolitis, or non–traction bronchiectasis), and pulmonary vasculopathy.

Clinical Features Application of IPAF criteria has resulted in the description of highly heterogeneous IPAF cohorts around the world. The largest North American cohort of 144 patients was predominantly white, had a mean age of 63 years, had a slight female predominance, and had a history of smoking in over half.7 Most patients (51%) met IPAF criteria through a combination of serologic and morphologic domains, and only 26% met all three domains. The most common clinical feature was Raynaud phenomenon (28%), and the most common serologic feature was ANA seropositivity 585

586

SECTION 8  Connective Tissue Diseases

TABLE 45.1  DIAGNOSTIC CRITERIA FOR INTERSTITIAL PNEUMONIA WITH AUTOIMMUNE FEATURES CLINICAL DOMAIN

“Mechanic’s hands,” distal digital tip ulceration, inflammatory arthritis, polyarticular morning joint stiffness, palmar telangiectasia, Raynaud phenomenon, unexplained digital edema, Gottron sign

SEROLOGIC DOMAIN

ANA ≥ 1 : 320, RF ≥ 2× upper limit of normal, anti-CCP, anti-dsDNA, anti-Ro (SS-A), anti-La (SS-B), antiribonucleoprotein, anti-Smith, antitopoisomerase (Scl-70), anti-tRNA synthetase, anti–PM-Scl, anti-MDA5

MORPHOLOGIC DOMAIN

HRCT Histopathology

Multicompartment Involvement

NSIP, OP, NSIP with OP overlap, LIP NSIP, OP, NSIP with OP overlap, LIP, interstitial lymphoid aggregates with germinal centers, diffuse lymphoplasmacytic infiltration Unexplained pleural effusion/thickening, unexplained pericardial effusion/thickening, unexplained intrinsic airways disease, unexplained pulmonary vasculopathy

The diagnosis of IPAF requires: (1) the presence of an interstitial pneumonia on HRCT or biopsy, (2) exclusion of alternative etiologies, (3) exclusion of a defined CTD, and (4) at least one feature from at least two of these domains: clinical, serologic, and morphologic. ANA, Antinuclear antibodies; CCP, cyclic citrullinated peptide; CTD, connective tissue disease; dsDNA, double-stranded deoxyribonucleic acid; HRCT, high-resolution computed tomography; IPAF, interstitial pneumonia with autoimmune features; LIP, lymphocytic interstitial pneumonia; MDA5, melanoma differentiation-associated gene 5; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; PM-Scl, polymyositisscleroderma; RF, rheumatoid factor; SS-A, Sjögren syndrome A antibody; SS-B, Sjögren syndrome B antibody; tRNA, transfer ribonucleic acid. Reproduced with permission from the © ERS 2015. Eur Respir J. 2015;46:976-987. DOI: 10.1183/13993003.00150-2015.

Fig. 45.1  A 60-year-old woman with interstitial pneumonia with autoimmune features and a fibrotic nonspecific interstitial pneumonia (NSIP) pattern. Supine axial (A) and coronal (B) high-resolution computed tomography images demonstrate basilar predominant peribronchovascular ground-glass opacities and traction bronchiectasis with some superimposed honeycombing. Findings are most compatible with a fibrotic NSIP pattern.

A

B

45  Interstitial Pneumonia With Autoimmune Features

587

A

B

Fig. 45.2  A 67-year-old woman with interstitial pneumonia with autoimmune features and organizing pneumonia (OP). (A) Composite image with axial high-resolution computed tomography (HRCT) image (left image) demonstrates basilar predominant peripheral and peribronchovascular predominant ground-glass opacities typical of OP, which resolve with immunosuppressive therapy (right image). (B) Axial HRCT image obtained one additional year later demonstrates increased basilar predominant ground-glass opacities with traction bronchiectasis. Some of the opacities demonstrate a perilobular distribution, a finding often seen in OP.

588

SECTION 8  Connective Tissue Diseases

A

B

(76%), which is similar to findings reported in a smaller North American cohort8 and the European cohorts.9,10 There is discrepancy among the various IPAF cohorts with regard to the predominant pattern of ILD (UIP vs. NSIP) on either HRCT or biopsy.

Imaging Features The radiographic patterns of IPAF have not been described but likely resemble those seen with the different CT patterns. The CT patterns of IPAF and their prognostic significance were recently described for the largest North American cohort.11 A definite UIP pattern was most commonly encountered (51%) (Fig. 45.4). Fewer patients had a probable UIP pattern (14%) and findings most consistent with a non-IPF diagnosis (35%). On the basis of the imaging pattern alone, UIP was most common (51%), followed by NSIP (27%), hypersensitivity pneumonitis (HP) (8%), NSIP with OP (7%), and OP (4%) (Table 45.2). These findings are discrepant with previous cohorts that found NSIP to be more common than UIP in IPAF patients.8,10 Of particular interest is the presence of an HP pattern in nearly one-tenth of IPAF patients (Fig. 45.5), suggesting a possible relationship between autoimmunity and HP.12 Three CT findings were recently described that may be more prevalent in a UIP pattern associated with CTDs when compared with a UIP pattern associated with idiopathic pulmonary fibrosis (IPF).13 The “anterior upper lobe sign” represents anterior upper lobe–predominant lung fibrosis with relative sparing of the remainder of the upper lobes, which is associated

C

Fig. 45.3  A 56-year-old woman with interstitial pneumonia with autoimmune features (IPAF) and organizing pneumonia (OP) progressing to fibrotic nonspecific interstitial pneumonia (NSIP). (A) Axial highresolution computed tomography (HRCT) image demonstrates peripheral and peribronchovascular consolidation with central ground-glass opacities (reverse halo configuration), most compatible with OP. A small left pleural effusion is noted, which is a common finding of multi-compartmental involvement in patients with IPAF. (B) and (C) Axial HRCT images obtained one year later demonstrate resolution of the peripheral consolidation and ground-glass opacities with progression of basilar, peripheral, and peribronchovascular predominant ground-glass opacities and traction bronchiectasis most suggestive of fibrotic NSIP.

TABLE 45.2  CT PATTERNS IN A COHORT OF 136 PATIENTS WITH INTERSTITIAL PNEUMONIA WITH AUTOIMMUNE FEATURES CT Pattern Usual interstitial pneumonia Nonspecific interstitial pneumonia Hypersensitivity pneumonitis Nonspecific interstitial pneumonia with overlapping organizing pneumonia Organizing pneumonia Other

Number (%) of Patients 70 37 11 9

(51) (27) (8) (7)

5 (4) 4 (3)

CT, Computed tomography; IPAF, interstitial pneumonia with autoimmune features. 136 patients with diagnostic-quality chest CT scans were available for review among a cohort of 144 total IPAF patients. Adapted from Chung JH, Montner SM, Adegunsoye A, et al. CT findings, radiologic-pathologic correlation, and imaging predictors of survival for patients with interstitial pneumonia with autoimmune features. AJR Am J Roentgenol. 2017;208:1229-1236.

with concomitant lower lobe fibrosis. The “exuberant honeycombing sign” represents extensive honeycombing comprising greater than 70% of the fibrotic portions of lung (see Fig. 45.4). Finally, the “straight edge sign” represents isolation of fibrosis in the lung bases, with a sharp demarcation in the craniocaudal plane and without general extension along the lateral lung margins on coronal images.

45  Interstitial Pneumonia With Autoimmune Features

A

B

C

D

589

Fig. 45.4  A 73-year-old woman with interstitial pneumonia with autoimmune features and a progressive usual interstitial pneumonia pattern (UIP). (A) Prone axial high-resolution computed tomography (HRCT) image demonstrates basilar predominant subpleural reticular opacities and early honeycombing. (B to D) Prone axial and coronal HRCT images obtained three years later demonstrate progression of basilar predominant traction bronchiectasis and honeycombing, which is most pronounced at the costophrenic angles. Findings are compatible with a definite UIP pattern. This is typical of the “exuberant honeycombing sign” (i.e., the majority of fibrosis is composed solely of honeycombing), which has been described as more often associated with connective tissue disease–associated interstitial lung disease.

Most patients in the largest North American cohort had a basilar (89%) and peripheral-predominant (74%) disease distribution. Approximately 60% of patients had honeycombing, which was one of two independent predictors of mortality. Nearly all patients (96%) had traction bronchiectasis. Ground-glass opacity was present in 28% of patients and was the most common finding on CT scans, with a pattern most consistent with a non-IPF diagnosis. Mosaic attenuation without CT evidence of emphysema was present in 35% of patients, and air-trapping was present in 10% of patients. Multicompartment involvement was common, with pleural effusion or thickening present in 13% of patients

and pericardial effusion or thickening present in 2% of patients. Pulmonary artery enlargement (≥3.3 cm), suggestive of possible pulmonary hypertension, was present in 27% of patients and was the only other independent predictor of mortality. Percentage of reticulation and mosaic attenuation corrected for emphysema were not predictive of mortality.

Outcomes and Treatment In the largest North American cohort, IPAF patients demonstrated significantly worse survival than a CTD-associated ILD cohort

590

SECTION 8  Connective Tissue Diseases

A

B

D

C

Fig. 45.5  A 62-year-old woman with interstitial pneumonia with autoimmune features and a hypersensitivity pneumonitis (HP) pattern. Frontal chest radiograph (A) and prone axial high-resolution CT image (B) demonstrate traction bronchiectasis and peribronchovascular ground-glass opacities with a middle to upper lung zone predominance. Frontal chest radiograph (C) along with axial (D) and coronal (E) CT images obtained 2 years later demonstrate progression of upper lung zone–predominant traction bronchiectasis and peribronchovascular ground-glass opacities. Findings are most compatible with a progressive chronic HP pattern.

E

45  Interstitial Pneumonia With Autoimmune Features

591

KEY POINTS: INTERSTITIAL PNEUMONIA WITH AUTOIMMUNE FEATURES • Interstitial pneumonia with autoimmune features (IPAF) criteria are intended to identify patients with ILD and features of autoimmunity who fail to meet overt connective tissue disease (CTD) criteria. • Previous terms used to describe this entity include lungdominant CTD, undifferentiated CTD-associated interstitial lung disease (ILD), and autoimmune-featured ILD. • Diagnosis requires ILD; exclusion of alternative etiologies, including overt CTD; and additional features from defined clinical, serologic, and morphologic domains. • The most common clinical feature is Raynaud phenomenon. • The most common serologic feature is antinuclear antibody seropositivity. • There is discrepancy among the IPAF cohorts with regard to the predominant pattern of ILD (usual interstitial pneumonia

and only marginally better survival than an IPF cohort.7 IPAF patients without UIP had similar survival to CTD-associated ILD patients, whereas those with UIP had similar survival to IPF patients (see Fig. 45.4). Patients who satisfied morphologic subdomain criteria for HRCT had improved survival, whereas those with multicompartment involvement had worse survival. The IPAF cohorts with NSIP predominance8,10 demonstrated more variable outcomes. A history of cigarette smoking was shown to be an independent predictor of mortality in one cohort.10 The optimal treatment strategy for patients meeting IPAF criteria has yet to be defined. Immunosuppression with systemic corticosteroids or steroid-sparing agents, such as mycophenolate mofetil or azathioprine, is commonly pursued but with little data to support this approach. Two recent investigations suggested that immunosuppression was associated with stability in pulmonary function over time.8,14 The role of antifibrotic therapy in appropriately selected IPAF patients is currently under investigation.

• •

• •

[UIP] vs. nonspecific interstitial pneumonia) on high-resolution computed tomography or biopsy. A UIP pattern, along with presence of honeycombing, pulmonary artery enlargement, and a history of cigarette smoking are reported independent predictors of mortality. Multicompartment involvement is common and is associated with worse survival, as this may lead to the inclusion of UIP patients with concurrent airways disease and/or pulmonary vasculopathy. The optimal treatment strategy for patients meeting IPAF criteria has yet to be defined. Outcomes are variable and highly dependent on the center under study and methods used in applying IPAF criteria.

SUGGESTED READINGS Chung JH, Montner SM, Adegunsoye A, Lee C, Oldham JM, Husain AN, et al. CT findings, radiologic-pathologic correlation, and imaging predictors of survival for patients with interstitial pneumonia with autoimmune features. AJR Am J Roentgenol. 2017;208(6):1229–1236. Fischer A, Antoniou KM, Brown KK, Cadranel J, Corte TJ, du Bois RM, et al. An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J. 2015;46(4):976–987.

The full reference list for this chapter is available at ExpertConsult.com.

45  Interstitial Pneumonia With Autoimmune Features 591.e1

REFERENCES 1. Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6): 733–748. 2. Omote N, Taniguchi H, Kondoh Y, Watanabe N, Sakamoto K, Kimura T, et al. Lung-dominant connective tissue disease: clinical, radiologic, and histologic features. Chest. 2015;148(6):1438–1446. 3. Kim HC, Ji W, Kim MY, Colby TV, Jang SJ, Lee CK, et al. Interstitial pneumonia related to undifferentiated connective tissue disease: pathologic pattern and prognosis. Chest. 2015;147(1):165–172. 4. Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung disease: a distinct entity. Chest. 2011;140(5):1292–1299. 5. Fischer A, Antoniou KM, Brown KK, Cadranel J, Corte TJ, du Bois RM, et al. An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J. 2015;46(4):976–987. 6. Song JW, Do KH, Kim MY, Jang SJ, Colby TV, Kim DS. Pathologic and radiologic differences between idiopathic and collagen vascular disease-related usual interstitial pneumonia. Chest. 2009;136(1):23–30. 7. Oldham JM, Adegunsoye A, Valenzi E, Lee C, Witt L, Chen L, et al. Characterisation of patients with interstitial pneumonia with autoimmune features. Eur Respir J. 2016;47(6):1767–1775. 8. Chartrand S, Swigris JJ, Stanchev L, Lee JS, Brown KK, Fischer A. Clinical features and natural history of interstitial pneumonia with autoimmune features: a single center experience. Respir Med. 2016;119:150–154.

9. Ferri C, Manfredi A, Sebastiani M, Colaci M, Giuggioli D, Vacchi C, et al. Interstitial pneumonia with autoimmune features and undifferentiated connective tissue disease: our interdisciplinary rheumatology-pneumology experience, and review of the literature. Autoimmun Rev. 2016;15(1): 61–70. 10. Ahmad K, Barba T, Gamondes D, Ginoux M, Khouatra C, Spagnolo P, et al. Interstitial pneumonia with autoimmune features: clinical, radiologic, and histological characteristics and outcome in a series of 57 patients. Respir Med. 2017;123:56–62. 11. Chung JH, Montner SM, Adegunsoye A, Lee C, Oldham JM, Husain AN, et al. CT findings, radiologic-pathologic correlation, and imaging predictors of survival for patients with interstitial pneumonia with autoimmune features. AJR Am J Roentgenol. 2017;208(6):1229–1236. 12. Adegunsoye A, Oldham JM, Demchuk C, Montner S, Vij R, Strek ME. Predictors of survival in coexistent hypersensitivity pneumonitis with autoimmune features. Respir Med. 2016;114:53–60. 13. Chung JH, Cox CW, Montner SM, Adegunsoye A, Oldham JM, Husain AN, et al. CT features of the usual interstitial pneumonia pattern: differentiating connective tissue disease-associated interstitial lung disease from idiopathic pulmonary fibrosis. AJR Am J Roentgenol. 2018;210:307–313. 14. Collins BF, Spiekerman CF, Shaw MA, Ho LA, Hayes J, Spada CA, et al. Idiopathic interstitial pneumonia associated with autoantibodies: a large case series followed over 1 year. Chest. 2017;152(1):103–112.

SECTION 9

Vasculitis and Granulomatosis

46 

Antineutrophil Cytoplasmic Antibody– Associated Vasculitis* STEPHANE L. DESOUCHES  |  CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

Etiology, Prevalence, and Epidemiology Pulmonary vasculitis is traditionally characterized by size of vessel involvement as defined by the Chapel Hill nomenclature.1 Within the small-vessel vasculitides, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis represents a diverse group of entities, and although the inciting stimulus has not been fully elucidated, an immune-mediated response is implicated. Although rare, with an overall incidence of 20 to 100 cases per million and a prevalence of 150 to 450 cases per million,2 pulmonary vasculitis remains one of the most challenging diagnoses and management concerns in the care of critically ill patients.3 This in part is due to the nonspecific disease manifestations and diagnosis through a combination of clinical and imaging criteria.2,4 Because of the tremendous overlap in clinical and laboratory manifestations among the systemic vasculitides and an absence of validated criteria for diagnosis, determining the exact vasculitis affecting the patient and initiation of the appropriate treatment can be difficult. A recent multinational observational study, endorsed by the American College of Rheumatology and the European League Against Rheumatism, the Diagnostic and Classification Criteria for Vasculitis study (DCVAS) was started, seeking to develop and validate diagnostic and classification criteria for the primary vasculitides.5 Three entities are traditionally grouped within the small-vessel vasculitis class, specifically, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis: granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), eosinophilic granulomatosis with polyangiitis (eGPA, formerly Churg-Strauss syndrome), and microscopic polyangiitis (MPA). Antineutrophil cytoplasmic antibodies activate neutrophils and monocytes that express the ANCA antigens myeloperoxidase (MPO) and proteinase 3 (PR3) on their surfaces. Cytoplasmic-pattern ANCA (c-ANCA) targets the MPO antigen, whereas perinuclear-pattern ANCA (p-ANCA) targets PR3.6 Although each of these entities is associated with a positive ANCA, GPA is associated with c-ANCA reactivity, eGPA is usually associated with perinuclear p-ANCA activity, and MPA can have c-ANCA or p-ANCA positivity. GPA has an annual incidence of *The editors and the publisher would like to thank Drs. Nestor L. Müller and C. Isabela Silva Müller for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

592

approximately 30 cases per million,7 whereas eGPA is the least common ANCA-associated vasculitis, with an annual incidence of approximately 2.4 cases per million.8 MPA has an annual incidence similar to GPA, with 10 to 30 cases per million, and represents the most common cause of pulmonary-renal syndrome.2

Granulomatosis With Polyangiitis (Formerly Wegener Granulomatosis) Clinical Presentation Formerly referred to as Wegener granulomatosis,9 GPA may manifest as a systemic disease or involve primarily or exclusively the respiratory tract.10 This limited GPA is not a distinct process but instead exists along a continuum and often precedes systemic disease.2 Most patients present with upper and lower respiratory symptoms, including epistaxis, sinusitis, cough, hemoptysis, dyspnea, and pleuritic chest pain.11 Systemic symptoms include fever, malaise, weight loss, and fatigue; with joint involvement taking the form of arthralgia or arthritis. Fifty percent to 80% of patients have glomerulonephritis.11

Pathophysiology Characteristic histopathologic findings consist of granulomatous inflammation with vasculitis and parenchymal necrosis.12 A mixed cellular infiltrate of neutrophils, lymphocytes, plasma cells, histiocytes, and eosinophils tends to be aggregated in small microabscess-like clusters. As these clusters become necrotic, they enlarge, coalesce, and result in a characteristic appearance of geographic necrosis (Figs. 46.1 and 46.2). Inflammation is typically parenchymal, although mucosal or submucosal granulomatous inflammation of the airways is also common.13 On occasion, patients may present with or develop capillaritis, which results in focal or diffuse hemorrhage that remains an important cause of morbidity and mortality in patients with GPA.6

Manifestations of the Disease RADIOGRAPHY AND COMPUTED TOMOGRAPHY The most common radiographic abnormality consists of lung nodules or masses, seen in up to 90% of patients with GPA

46  Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

A

593

B Fig. 46.1  Granulomatosis with polyangiitis: geographic necrosis. (A) Histologic specimen demonstrates areas of basophilic necrosis with irregular border, resulting in a geographic appearance. The necrotic regions are surrounded by a mixed inflammatory infiltrate. (B) High-power view demonstrates granulomatous inflammation and multinucleated giant cells (arrows). (Courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Canada.)

* Fig. 46.2  Granulomatosis with polyangiitis: necrosis and cavitation. Histologic specimen shows nodule with necrosis and cavitation (asterisk). (Courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Canada.)

(Fig. 46.3).13,14 The nodules and masses can range from a few millimeters to greater than 10 cm in diameter. The nodules tend to be bilateral and show no apicobasal gradient.13,14 An increase in size and number of nodules is associated with disease progression. Computed tomography (CT) often will show nodules that are not apparent on radiography and is more sensitive for the presence of cavitation, which is evident on CT scan in most nodules larger than 2 cm in diameter (Fig. 46.4).2 When cavitation occurs, masses tend to be thick walled and have an irregular, shaggy inner lining (Fig. 46.5).13,14 In up to 15% of cases, one or more of the nodules or masses are surrounded by a rim of ground-glass opacity representing the CT halo sign (Fig. 46.6).14 Less commonly, areas of ground-glass opacity can be surrounded by consolidation in the so-called reversed halo sign, which likely represents an organizing pneumonia-like reaction (Fig. 46.7).

Fig. 46.3  Granulomatosis with polyangiitis: bilateral nodules and masses. Chest radiograph demonstrates bilateral nodules, masses, and focal areas of consolidation in a central distribution.

Areas of airspace consolidation, or less commonly ground-glass opacities, are seen in approximately 25% to 50% of patients (Figs. 46.8 to 46.10).13 Foci of cavitation may occasionally be seen within the areas of consolidation.15 Diffuse consolidation or ground-glass opacities usually reflects the presence of pulmonary hemorrhage and can be seen in up to 10% of patients (see Fig. 46.9).2 Other less common parenchymal abnormalities include centrilobular nodules, tree-in-bud opacities, septal lines, and foci of calcification within the nodules, masses, or areas of consolidation.13,14,16 Tracheal and bronchial involvement is usually inferred on radiography by secondary signs of airway obstruction, such as Text continued on p. 598

594

SECTION 9  Vasculitis and Granulomatosis

A

B Fig. 46.4  Granulomatosis with polyangiitis: cavitary nodules. (A) Chest radiograph shows bilateral thinwalled cavitary nodules. (B) Coned-down coronal reformatted CT image demonstrates thin-walled left upper lobe cavitary nodule, with mild surrounding ground-glass opacities suggestive of hemorrhage.

46  Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

B

A

C Fig. 46.5  Granulomatosis with polyangiitis: cavitating nodules and masses. (A) Posteroanterior chest radiograph shows multiple large thick-walled cavities with air-fluid levels. The left upper lung zone is oligemic, suggesting the possibility of compromise of the left upper lobe bronchus and resulting hypoxic vasoconstriction. (B) Coronal reformatted CT image from a different patient shows a thick-walled cavitary mass in the left upper lobe perihilar region. (C) CT image from the same patient as (B) shows an air-fluid level within the cavitary mass. (Fig. 46.5A from Müller NL, Fraser RS, Colman NC, Paré PD. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

595

596

SECTION 9  Vasculitis and Granulomatosis

Fig. 46.7  Granulomatosis with polyangiitis: reversed halo sign. CT image shows ground-glass opacity with rim of surrounding consolidation. Histopathologic analysis of these types of nodules usually show central hemorrhage and a rim of organizing pneumonia reaction pattern.

A

B Fig. 46.6  Granulomatosis with polyangiitis: CT halo sign. (A) CT image shows peripheral cavitary nodule in the left upper lobe surrounded by a halo of ground-glass opacity. (B) CT image at the level of the minor fissure shows a noncavitary right upper lobe nodule with surrounding halo of ground-glass opacity. Foci of left upper and bilateral lower lobe ground-glass opacities likely represent pulmonary hemorrhage.

46  Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

A

597

A

B

B Fig. 46.8  Granulomatosis with polyangiitis: ground-glass opacities and consolidation. Chest radiograph (A) and CT image (B) show asymmetric bilateral ground-glass opacities and areas of consolidation. On CT the consolidation in the left upper lobe has a perilobular distribution of consolidation (arrows) that surrounds ground-glass opacities, a finding consistent with organizing pneumonia secondary to pulmonary hemorrhage.

Fig. 46.9  Granulomatosis with polyangiitis: pulmonary hemorrhage. (A) Chest radiograph shows perihilar predominant consolidation that spares the lung apices and bases. (B) Axial CT image shows perihilar predominant consolidation and ground-glass opacities that spare the lung periphery, which is typical of pulmonary hemorrhage. (From Lichtenberger JP 3rd, Digumarthy SR, Abbott GF, et al. Diffuse pulmonary hemorrhage: clues to the diagnosis. Curr Probl Diagn Radiol. 2014;43:128–139.)

598

SECTION 9  Vasculitis and Granulomatosis

A

B Fig. 46.10  Granulomatosis with polyangiitis: mass and consolidation before and after treatment. (A) CT image shows a right upper lobe mass (arrowhead) and left upper lobe consolidation (arrow) containing air bronchograms. (B) Repeat CT image 9 months after initiation of treatment demonstrates considerable improvement of the right upper lobe mass (arrowhead) and left upper lobe consolidation (arrow) with residual scarring. (From Martinez F, Chung J, Digumarthy S, et al. Common and uncommon manifestations of Wegener granulomatosis at chest CT: radiologic-pathologic correlation. Radiographics. 2012;32:51–69.)

atelectasis or air-trapping.15 When focal airway stenosis is visualized, it most commonly affects the subglottic trachea (Fig. 46.11). With CT central bronchial wall thickening is seen in 50% to 60% of patients and tracheal wall thickening in 15% (Fig. 46.12).13,14 Multiplanar reconstructions are essential for optimal imaging assessment of the presence and severity of airway stenosis (see Fig. 46.12).16 Pleural effusions occur in 15% to 20% of patients and pleural thickening in 10%.13,14 Mediastinal lymph node enlargement is seen on CT in approximately 20% of cases and hilar lymph node enlargement in 3%.13 Approximately 50% of nodules and masses will resolve completely with disease treatment, and another 40% will decrease in size.2 However, intralobular linear opacities and areas of bronchiectasis tend to remain stable.17 This reinforces the theory that ground-glass opacities, consolidation, cavitated nodules, and masses represent active inflammatory lesions, whereas intralobular linear opacities and areas of bronchiectasis more often represent chronic fibrosis. Rarely, hemosiderin can accumulate in the alveoli from repeated hemorrhage, resulting in diffuse centrilobular nodules (Fig. 46.13). Interstitial fibrosis with a pattern resembling idiopathic nonspecific interstitial pneumonia or idiopathic pulmonary fibrosis may occasionally be the first manifestation of GPA.18 Uncommonly, GPA will involve the aorta and great vessels, the heart, the cardiac valves, or the pulmonary arteries. NUCLEAR IMAGING Evaluation of multisystem involvement and monitoring treatment response and maintenance can be facilitated with nuclear imaging.

Fig. 46.11  Granulomatosis with polyangiitis: subglottic stenosis. Lateral view of the neck shows focal wall thickening of the subglottic trachea (arrow) with associated stenosis.

46  Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

599

A

C

B

Imaging with gallium-67 has been shown to be helpful as a negative scan virtually excludes active disease. Unfortunately, specificity is lower in these scans as inflammation from other sources, including bacterial or viral infection, can result in a false-positive interpretation.19 Imaging of GPA with fluorodeoxyglucose (FDG) PET with CT improves upper respiratory tract lesion detection.7 Increased uptake on FDG-PET can help localize active lesions for biopsy during initial workup, and maximum standardized uptake value correlates with disease activity, allowing use for treatment response and maintenance.7

Fig. 46.12  Granulomatosis with polyangiitis: tracheal and bronchial stenosis. (A) Unenhanced CT image at the level of the azygos arch shows marked circumferential thickening of the wall of the trachea with associated luminal narrowing. (B) CT image at a lower level demonstrates circumferential thickening of the wall of the left main bronchus causing stenosis. Note associated partial left lower lobe atelectasis. (C) Three-dimensional reformatted image from a virtual bronchoscopy in a different patient shows stenosis (arrows) of the distal trachea and proximal main bronchi. (Fig. 46.11C from Martinez F, Chung J, Digumarthy S, et al. Common and uncommon manifestations of Wegener granulomatosis at chest CT: radiologic-pathologic correlation. Radiographics. 2012;32:51–69.)

Differential Diagnosis The radiologic manifestations of GPA, although multiple and variable, consist mainly of bilateral subpleural or peribronchovascular nodules or masses with and without cavitation. The main differential diagnoses for this pattern include infections (septic embolism, fungal infection, multiple lung abscesses) and neoplasms (hematogenous metastases, lymphoma). Septic emboli and multiple lung abscesses usually favor the lower lobes and seldom measure more than 3 cm in diameter. There is also commonly a clinical history suggestive of infection, such as fever.

600

SECTION 9  Vasculitis and Granulomatosis

A

B Fig. 46.13  Granulomatosis with polyangiitis (GPA): hemosiderosis. Axial (A) and coronal (B) maximumintensity projection images show diffuse bilateral centrilobular nodules. A spiculated right upper lobe nodule is also noted relating to patient’s known GPA. Surgical biopsy showed the centrilobular nodules represented hemosiderin secondary to repeated alveolar hemorrhage.

Hematogenous metastases and lymphoma may be multiple and range in size from a few millimeters to greater than 10 cm in diameter but also usually show a lower lobe predominance and rarely if ever cavitate. The distinction of GPA from these other conditions can usually be made clinically by the presence of upper respiratory symptoms, including sinusitis and epistaxis, laboratory findings indicative of glomerulonephritis, and the presence of serum c-ANCA. A particular issue arises when new nodules or masses are detected in a person who has known GPA, especially when he or she is undergoing immunosuppressive therapy. It is often difficult to differentiate opportunistic infections (e.g., fungal organisms or Nocardia) or a new malignancy from simply a worsening of GPA. In these patients bronchoscopy and occasionally biopsy is needed to exclude infection or malignancy before initiating higher doses of immunomodulatory therapy.

Eosinophilic Granulomatosis With Polyangiitis (Formerly Churg-Strauss Syndrome) Clinical Presentation Formerly referred to as Churg-Strauss syndrome, eGPA nearly always manifests with the classic clinical triad of asthma, hyper­ eosinophilia, and vasculitis.2 This entity exists as three distinct clinical phases; there is prodromal stage of adult-onset asthma, usually lasting years, generally requiring corticosteroid therapy and often preceded by allergic rhinitis. This is usually followed by a second phase with marked peripheral blood eosinophilia and eosinophilic tissue infiltrates. The third stage consists of an often life-threatening vasculitic phase that can manifest with acute respiratory distress syndrome and pulmonary hemorrhage.20,21 The disease can, but does not always, progress through each stage in turn. Cardiac involvement, seen in 13% to 47% of cases, may result in angina, myocardial infarction, myocarditis, left-sided heart failure, and pericarditis.22 The majority of patients

respond to treatment with corticosteroids and immunomodulators, with about 25% experiencing relapses of disease. Among those patients who relapse, most will respond to repeat treatment. Mortality among treated patients who relapse approaches 3%.23

Pathophysiology Although the exact pathophysiology of eGPA is not clear, its association with asthma and atopy, as well as eosinophilia, suggests an autoimmune or allergic process.20 Markers of eosinophil activation parallel disease activity and seem to predict relapses; it is also known that direct tissue injury is caused by eosinophils and neutrophil degranulation products.22 ANCAs are present in about 40% to 75% of patients with eGPA, and both the frequency and levels seem to correlate with disease activity.22,24 The presence or absence of ANCA usually allows a distinction between two subtypes of eGPA. ANCA positivity is associated with a higher prevalence of renal (rapidly progressive glomerulonephritis), nervous system, and skin involvement, as well as alveolar hemorrhage. Alternatively, ANCA-negative disease tends to have more cardiac and nonhemorrhagic pulmonary involvement. The characteristic feature of the early phase of eGPA is extravascular tissue infiltration by eosinophils.25 In the lung this takes the form of eosinophilic pneumonia and often is the only abnormality seen on surgical biopsy.25 In the vasculitic phase eosinophilic tissue infiltration is almost always present, but findings of vasculitis are also seen (Fig. 46.14). These are characterized by an eosinophil-rich necrotizing vasculitis involving primarily small arteries, arterioles, venules, and veins and necrotizing granulomas centered on necrotic eosinophils.25 On histologic examination, the only specific finding of healed vasculitis is thrombosed small vessels.25

Manifestations of the Disease RADIOGRAPHY Radiography typically shows bilateral nonsegmental airspace opacities without an apicobasal gradient (Fig. 46.15).2,20 The areas

46  Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

A

B

C

D

601

Fig. 46.14  Eosinophilic granulomatosis with polyangiitis: CT and histologic findings. (A) CT image shows predominantly peripheral ground-glass opacities bilaterally. Small areas of consolidation are noted in both upper lobes. Also noted are thickening of the interlobular septa best visualized in the anterior right upper lobe. (B) Photomicrograph of histopathologic specimen shows eosinophilic pneumonia pattern with large number of partially necrotic eosinophils (arrows). (C) Photomicrograph from a different patient shows edematous and fibrotic interlobular septa (curved arrows). A focus of very early eosinophilic pneumonia is present between the interlobular septa (straight arrow). Such small foci could result in poorly defined centrilobular ground-glass nodules. A focus of well-developed eosinophilic pneumonia with eosinophil necrosis is present to the right of the thickened septum. (D) Photomicrograph shows necrotizing focus (arrows) in the wall of a large bronchus. (From Silva CI, Müller NL, Fujimoto K, et al. Churg-Strauss syndrome: high-resolution CT and pathologic findings. J Thorac Imaging. 2005;20:74–80.)

of consolidation may have a peripheral distribution, overlapping with findings of chronic eosinophilic pneumonia (Fig. 46.16), or may be transient and migratory and be indistinguishable from simple pulmonary eosinophilia (Löffler syndrome).26,27 In contrast to GPA, even when these airspace opacities become confluent, cavitation is rare.26,27 Cardiac involvement may result in cardiomegaly from myocarditis or ischemic cardiomyopathy and pericardial effusion. Unilateral or bilateral pleural effusions are seen on the chest radiograph in approximately 10% of patients.22

COMPUTED TOMOGRAPHY Seen in up to 90% of patients, bilateral areas of ground-glass opacities or consolidation are the most common abnormalities on CT.20,26,27 These usually have a symmetric distribution and often a peripheral predominance similar to chronic eosinophilic pneumonia (see Fig. 46.16).26,27 Another relatively common finding on CT is the presence of interlobular septal thickening, seen in approximately 50% of patients (see Fig. 46.14), which may reflect the presence of interstitial pulmonary edema secondary to cardiac involvement or eosinophilic infiltration of the

602

SECTION 9  Vasculitis and Granulomatosis

A

A

B Fig. 46.15  Eosinophilic granulomatosis with polyangiitis (eGPA): patchy distribution and tree-in-bud opacities. (A) Chest radiograph shows subtle patchy bilateral airspace opacities (arrowheads). (B) Coronal reformatted CT image demonstrates patchy bilateral ground-glass opacities with tree-in-bud opacities in the right middle lobe. Many of the airwayassociated findings of eGPA (e.g., bronchial wall thickening, endoluminal mucous plugging, tree-in-bud opacities) are in part explained by asthma, which is present in nearly all affected patients.

septa.27,28 Less common findings, partially explained by coexistent asthma, include small centrilobular nodules, bronchial wall thickening, bronchial dilation, and tree-in-bud opacities.21 Unilateral or bilateral pleural effusions are seen on CT in 10% to 50%22 and may be caused by left-sided heart failure resulting from cardiomyopathy or by eosinophilic pleuritis.22,27 Mediastinal lymphadenopathy can be observed but is uncommon.21

Differential Diagnosis In clinical practice the diagnosis of eGPA is made through a combination of imaging findings, chronicity, and clinical presentation. The imaging findings of transient, patchy nonsegmental ground-glass opacities or consolidation without predilection for any lung zone, seen in a patient with a history of asthma, should raise suspicion for eGPA, although simple pulmonary eosinophilia and chronic eosinophilic pneumonia could manifest similarly. By imaging alone, the differential diagnosis would also include allergic bronchopulmonary aspergillosis, simple

B Fig. 46.16  Eosinophilic granulomatosis with polyangiitis: chronic eosinophilic pneumonia pattern. (A) Chest radiograph shows patchy bilateral areas of consolidation in a predominantly subpleural distribution. (B) CT image shows bilateral peripheral, subpleural areas of consolidation.

pulmonary eosinophilia, chronic eosinophilic pneumonia, organizing pneumonia, bacterial pneumonia, fungal pneumonia, and viral pneumonia. The diagnosis of eGPA—as distinct from simple pulmonary eosinophilia or chronic eosinophilic lung disease in patients with asthma—is based on systemic manifestations, including rash, peripheral neuropathy, and presence of serum p-ANCA.23 Pneumonia as a cause of bilateral opacities in patients with asthma, as in other patients, needs to be excluded on the basis of clinical findings and appropriate cultures or serologic tests. The main considerations are infections that may result in symmetric bilateral ground-glass opacities or consolidation. These include mainly bacterial, mycoplasmal, or viral bronchopneumonia and opportunistic infections, such as those caused by Pneumocystis jirovecii and cytomegalovirus, which can be seen in asthmatic patients being treated with corticosteroids.

46  Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Microscopic Polyangiitis Clinical Presentation MPA often has a subacute prodromal phase, including fever, chills, weight loss, arthralgias, and myalgias lasting weeks to months before onset of the more characteristic acute vasculitic symptoms.3 The vasculitis manifestations are usually renal and, less commonly, pulmonary. Rapidly progressive glomerulonephritis occurs in more than 90% of patients and diffuse pulmonary hemorrhage in 10% to 30%.2 Other relatively common manifestations include skin lesions, peripheral neuritis, and gastrointestinal hemorrhage.29 Involvement of the sinuses, upper airway, or the eyes is uncommon in MPA and more often seen in patients with GPA. Although clinical symptoms of MPA and polyarteritis nodosa (PAN) may overlap, involvement of the pulmonary arteries suggests MPA as this is very rare in PAN.30

Pathophysiology Like the other ANCA-associated vasculitides, the pathogenesis of MPA is unknown. Serum ANCAs are present in the majority

of patients, including p-ANCAs directed against MPO in 50% to 75% of cases (as seen in eGPA) and c-ANCAs directed against PR3 in 10% to 15% (as seen in GPA).31 The available data suggest that ANCAs are a pathogenic factor in the development of small-vessel vasculitis.32 However, because not all patients with MPA have serum ANCA positivity and the antibody can be found in association with other diseases, other factors are probably involved. The most common manifestation is renal disease with rapidly progressive glomerulonephritis. The main pulmonary histologic findings are neutrophilic capillaritis and alveolar hemorrhage.33 Alveolar hemorrhage and capillaritis represent a histologic reaction pattern rather than a specific disease entity.34 This pattern may be seen in a variety of diseases, including MPA, GPA, connective tissue diseases (particularly systemic lupus erythematosus), antiphospholipid syndrome, and drug hypersensitivity.34

Manifestations of the Disease RADIOGRAPHY The radiographic features consist of patchy or diffuse bilateral airspace opacities and consolidation representing alveolar hemorrhage (Fig. 46.17).3 These airspace opacities and consolidations

B A

Fig. 46.17  Microscopic polyangiitis and diffuse pulmonary hemorrhage. (A) Chest radiograph shows diffuse right greater than left airspace opacities with more confluent consolidation in the right upper lung zone. Axial (B) and coronal (C) CT images show asymmetric bilateral ground-glass opacities and consolidation.

603

C

604

SECTION 9  Vasculitis and Granulomatosis

are usually widespread but may be more prominent in the perihilar areas and in the middle and lower lung zones.35–37 COMPUTED TOMOGRAPHY Imaging findings on CT usually consist of bilateral ground-glass opacities and consolidation that may be patchy or diffuse (see Fig. 46.17).30 The ground-glass opacity corresponds to alveolar hemorrhage from capillaritis and interstitial chronic inflammation in the alveolar septa. Repeated hemorrhage in patients with MPA can lead to interstitial fibrosis, which portends a worse prognosis. Appropriate treatment can result in complete resolution of symptoms and imaging findings (Fig. 46.18).

Differential Diagnosis The diagnosis of MPA should be suspected in patients with rapidly progressive glomerulonephritis and presence of p-ANCA who present with clinical and radiologic findings consistent with diffuse pulmonary hemorrhage. Lung biopsy shows nonspecific findings, including diffuse alveolar hemorrhage and capillaritis. Similar findings may be seen in GPA, systemic lupus erythematosus, and drug hypersensitivity. Furthermore, lung biopsy is not recommended in patients with immune-mediated alveolar hemorrhage when a specific diagnosis can be established by biopsy of other tissues and by serum ANCA assays.38

Fig. 46.18  Microscopic polyangiitis: resolution after treatment. Chest radiograph from same patient as in Fig. 46.17 obtained 2 months after onset of treatment shows complete resolution of pulmonary opacities.

MPA is the most common cause of the pulmonary-renal syndrome. The main differential diagnosis clinically is with other conditions that may cause pulmonary and renal manifestations, particularly Goodpasture syndrome, GPA, and systemic lupus erythematosus. Goodpasture syndrome is usually diagnosed by demonstration of circulating or tissue-bound anti–glomerular basement membrane antibodies. MPA is distinguished from GPA by the lack of granulomatous inflammation and from systemic lupus erythematosus and other small-vessel vasculitides by the lack of immune deposits on surgical lung biopsy. IMAGING ALGORITHM Chest radiography is the main imaging modality used in the initial assessment and follow-up of patients with ANCA-associated vasculitis. Unless certain findings are seen on chest radiography to suggest a specific diagnosis, such as cavitary nodules in GPA, further evaluation is often warranted using chest CT. If there is high clinical suspicion for vasculitis, high-resolution CT is recommended, allowing evaluation for findings of air-trapping, bronchiectasis, or other signs of airway involvement. Even with high-resolution CT, imaging findings can be indeterminate, and close correlation with clinical history and laboratory results is important to arrive at a specific diagnosis.

Synopsis of Treatment Options Treatment of ANCA-associated vasculitis has significantly improved even over the past decade. Immunosuppression with cyclophosphamide has been a mainstay of treatment since 1971, although high toxicity, including marrow suppression and hemorrhagic cystitis, has limited its use.39 Current treatment strategies revolve around a short course of cyclophosphamide induction with chronic suppression either with corticosteroids or other immunomodulators, such as methotrexate or azathioprine.39 The advent of monoclonal therapies, such as rituximab, have greatly improved the long-term prognosis of patients with ANCA-associated vasculitis with prolonged remission and reduced recurrence of disease. Side effects of these newer medications are also considerably better than older treatment options.39 An additional treatment option for induction of remission is intravenous immunoglobulin, which is highly effective in the acute setting. This treatment is usually reserved for life-threatening illness or in pediatric patients as the side effects of the other medications would be particularly detrimental to the still developing body.40 As with all immunomodulation therapies, patients are at increased risk for opportunistic infections and must be closely monitored for this complication. Before immunosuppressive therapy, almost all patients died within 6 months of diagnosis. Currently, the estimated median survival after diagnosis is in excess of 20 years; most deaths are due to either the disease or complications of therapy.

46  Antineutrophil Cytoplasmic Antibody–Associated Vasculitis KEY POINTS • Chest radiography is the main imaging modality used in the initial assessment and follow-up of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. • CT is indicated in patients with suspected granulomatosis with polyangiitis (GPA) for optimal assessment of the extent of parenchymal abnormalities and detection of mild disease that may not be apparent on the radiograph. In the setting of suspected eosinophilic (e)GPA or microscopic polyangiitis (MPA) with classic radiographic findings, CT seldom adds additional information. • Serum cytoplasmic (c)-ANCA are present in 90% to 95% of cases of systemic GPA and in 60% of cases of organ-limited GPA. Approximately 70% of patients with eGPA have serum perinuclear-pattern (p)-ANCA. The majority of patients with MPA have p-ANCA) reactivity, although a minority may be c-ANCA positive. • Most patients with GPA present with upper and lower respiratory symptoms, including epistaxis, sinusitis, cough, hemoptysis, dyspnea, and pleuritic chest pain. • The most common radiologic findings in GPA are lung nodules or masses, seen in up to 90% of patients. Cavitation occurs eventually in about 50% of cases. • The most common clinical manifestations of eGPA are asthma, allergic rhinitis, neuropathy, and peripheral eosinophilia, which occur in most patients. • Almost exclusively, eGPA occurs in patients with asthma. • The most common radiographic findings in eGPA consist of transient or migratory opacities, or consolidation in a peripheral distribution, resembling those of simple pulmonary eosinophilia (Löffler syndrome) and chronic eosinophilic pneumonia, respectively. • MPA is the most common cause of the pulmonary-renal syndrome, a syndrome characterized by the coexistence of pulmonary hemorrhage and glomerulonephritis. • The radiologic findings in MPA are those of diffuse pulmonary hemorrhage and range from patchy bilateral ground-glass opacities to confluent consolidation that may spare the lung periphery or extreme lung apices and bases.

605

SUGGESTED READINGS Brown KK. Pulmonary vasculitis. Proc Am Thorac Soc. 2006;3:48–57. Castaner E, Alguersuari A, Gallardo X, et al. When to suspect pulmonary vasculitis: radiologic and clinical clues. Radiographics. 2010;30:33–53. Chung MP, Yi CA, Lee HY, et al. Imaging of pulmonary vasculitis. Radiology. 2010;255:322–341. Thickett DR, Richter AG, Nathani N, et al. Pulmonary manifestations of antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. Rheumatology. 2006;45:261–268.

The full reference list for this chapter is available at ExpertConsult.com.

46  Antineutrophil Cytoplasmic Antibody–Associated Vasculitis 605.e1

REFERENCES 1. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides: proposal of an international consensus conference. Arthritis Rheum. 1994;37(2):187–192. 2. Castaner E, Alguersuari A, Gallardo X, et al. When to suspect pulmonary vasculitis: radiologic and clinical clues. Radiographics. 2010;30:33–53. 3. Frankel S, Sullivan E, Brown K. Vasculitis: Wegener granulomatosis, ChurgStrauss syndrome, microscopic polyangiitis, polyarteritis nodosa, and Takayasu arteritis. Crit Care Clin. 2002;18:855–879. 4. Fries JF, Hunder GG, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis: summary. Arthritis Rheum. 1990;33(8):1135–1136. 5. Craven A, Robson J, Ponte C, et al. ACR/EULAR-endorsed study to develop Diagnostic and Classification Criteria for Vasculitis (DCVAS). Clin Exp Nephrol. 2013;17:619–621. 6. Thickett DR, Richter AG, Nathani N, et al. Pulmonary manifestations of anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis. Rheumatology. 2006;45:261–268. 7. Martinez F, Chung J, Digumarthy S, et al. Common and uncommon manifestations of Wegener granulomatosis at chest CT: radiologic-pathologic correlation. Radiographics. 2012;32:51–69. 8. Ramentol-Sintas M, Martinez-Valle F, Solans-Laque R. Churg-Strauss syndrome: an evolving paradigm. Autoimmun Rev. 2012;12:235–240. 9. Falk R, Gross W, Guillevan L, et al. Granulomatosis with polyangiitis (Wegener’s): an alternative name for Wegener’s granulomatosis. Arthritis Rheum. 2011;63(4):863–864. 10. Luqmani RA, Bacon PA, Beaman M, et al. Classical versus non-renal Wegener’s granulomatosis. Q J Med. 1994;87:161–167. 11. Brown KK. Pulmonary vasculitis. Proc Am Thorac Soc. 2006;3:48–57. 12. Travis WD, Hoffman GS, Leavitt RY, et al. Surgical pathology of the lung in Wegener’s granulomatosis. Review of 87 open lung biopsies from 67 patients. Am J Surg Pathol. 1991;15:315–333. 13. Lohrmann C, Uhl M, Kotter E, et al. Pulmonary manifestations of Wegener granulomatosis: CT findings in 57 patients and a review of the literature. Eur J Radiol. 2005;53:471–477. 14. Lee KS, Kim TS, Fujimoto K, et al. Thoracic manifestation of Wegener’s granulomatosis: CT findings in 30 patients. Eur Radiol. 2003;13(1):43–51. 15. Frazier AA, Rosado-de-Christenson ML, Galvin JR, Fleming MV. Pulmonary angiitis and granulomatosis: radiologic-pathologic correlation. Radiographics. 1998;18:687–710, quiz 727. 16. Sheehan RE, Flint JD, Müller NL. Computed tomography features of the thoracic manifestations of Wegener granulomatosis. J Thorac Imaging. 2003;18:34–41. 17. Lohrmann C, Uhl M, Schaefer O, et al. Serial high-resolution computed tomography imaging in patients with Wegener granulomatosis: differentiation between active inflammatory and chronic fibrotic lesions. Acta Radiol. 2005;46:484–491. 18. Bicknell SG, Mason AC. Wegener’s granulomatosis presenting as cryptogenic fibrosing alveolitis on CT. Clin Radiol. 2000;55:890–891. 19. Slart RH, Jager PL, Poot L, et al. Clinical value of gallium-67 scintigraphy in assessment of disease activity in Wegener’s granulomatosis. Ann Rheum Dis. 2003;62:659–662.

20. Choi YH, Im J, Han BK, et al. Thoracic manifestation of Churg-Strauss syndrome: radiologic and clinical findings. Chest. 2000;117:117–124. 21. Kim YK, Lee KS, Chung MP, et al. Pulmonary involvement in Churg-Strauss syndrome: an analysis of CT, clinical, and pathologic findings. Eur Radiol. 2007;17(12):3157–3165. 22. Keogh KA, Specks U. Churg-Strauss syndrome. Semin Respir Crit Care Med. 2006;27:148–157. 23. Noth I, Strek ME, Leff AR. Churg-Strauss syndrome. Lancet. 2003;361: 587–594. 24. Keogh KA, Specks U. Churg-Strauss syndrome: clinical presentation, antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists. Am J Med. 2003;115:284–290. 25. Churg A. Recent advances in the diagnosis of Churg-Strauss syndrome. Mod Pathol. 2001;14:1284–1293. 26. Worthy SA, Müller NL, Hansell DM, Flower CD. Churg-Strauss syndrome: the spectrum of pulmonary CT findings in 17 patients. AJR Am J Roentgenol. 1998;170:297–300. 27. Silva CI, Müller NL, Fujimoto K, et al. Churg-Strauss syndrome: high resolution CT and pathologic findings. J Thorac Imaging. 2005;20:74–80. 28. Johkoh T, Müller NL, Akira M, et al. Eosinophilic lung diseases: diagnostic accuracy of thin-section CT in 111 patients. Radiology. 2000;216:773–780. 29. Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum. 1999;42:421–430. 30. Chung MP, Yi CA, Lee HY, et al. Imaging of pulmonary vasculitis. Radiology. 2010;255:322–341. 31. Brown KK. Pulmonary vasculitis. Proc Am Thorac Soc. 2006;3:48–57. 32. Heeringa P, Schreiber A, Falk RJ, Jennette JC. Pathogenesis of pulmonary vasculitis. Semin Respir Crit Care Med. 2004;25:465–474. 33. Travis WD. Pathology of pulmonary vasculitis. Semin Respir Crit Care Med. 2004;25:475–482. 34. Travis WD, Colby TV, Lombard C, Carpenter HA. A clinicopathologic study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation. Am J Surg Pathol. 1990;14:1112–1125. 35. Primack SL, Miller RR, Müller NL. Diffuse pulmonary hemorrhage: clinical, pathologic, and imaging features. AJR Am J Roentgenol. 1995;164: 295–300. 36. Nemec SF, Eisenberg RL, Bankier AA. Noninfectious inflammatory lung disease: imaging considerations and clues to differential diagnosis. AJR Am J Roentgenol. 2013;201:278–294. 37. Villiger PM, Guillevin L. Microscopic polyangiitis: clinical presentation. Autoimmun Rev. 2010;9:812–819. 38. Collins CE, Quismorio FP Jr. Pulmonary involvement in microscopic polyangiitis. Curr Opin Pulm Med. 2005;11:447–451. 39. Jayne D, Rasmussen N. Twenty-five years of European Union collaboration in ANCA-associated vasculitis research. Nephrol Dial Transplant. 2015;30: i1–i7. 40. Guidelli GM, Tenti S, Pascarelli NA, et al. Granulomatosis with polyangiitis and intravenous immunoglobulins: a case series and review of the literature. Autoimmun Rev. 2015;14:659–664.

47 

Goodpasture Syndrome (Anti–Basement Membrane Antibody Disease)* JONATHAN H. CHUNG  |  CHRISTOPHER M. WALKER

Etiology, Prevalence, and Epidemiology Goodpasture syndrome, also known as anti–basement membrane antibody disease, is an autoimmune disorder characterized by repeated episodes of pulmonary hemorrhage, usually associated with glomerulonephritis and the presence of anti–glomerular basement membrane (anti-GBM) antibodies. Goodpasture syndrome is rare, with an incidence of approximately one patient per million population per year.1 It has a bimodal distribution with respect to age, with peaks at 20 to 30 and 60 to 70 years of age and a male-to-female ratio of approximately 3 : 2.2,3

Clinical Presentation The most common presenting symptom is hemoptysis, which occurs in about 80% to 95% of patients.3,4 The hemoptysis may range from mild to copious and life threatening. In more than 50% of patients, it precedes glomerulonephritis.3 On occasion, the hemoptysis may occur late in the course of the disease or be absent altogether. Other presenting symptoms include dyspnea, fatigue, weakness, pallor, cough, and, occasionally, frank hematuria.3 Although results of the initial urinalysis may be normal, proteinuria, hematuria, and cellular and granular casts almost invariably develop at some stage.5 More than 90% of patients have anti-GBM antibodies, and approximately 80% have crescentic glomerulonephritis on renal biopsy.3 More than 90% of patients have iron deficiency anemia resulting from blood loss from pulmonary hemorrhage.3

Pathophysiology Goodpasture syndrome is an autoimmune disorder characterized by the presence of autoantibodies against the glomerular and alveolar basement membranes.3 It has been suggested that environmental factors, such as smoking, previous hydrocarbon exposure, and infection, may play a role in triggering Goodpasture syndrome.2 In the kidney complement activation and inflammatory cell enzymes are responsible for glomerular damage. The precise pathogenesis of the pulmonary hemorrhage is unknown. The main histologic findings of Goodpasture syndrome consist of pulmonary alveolar capillaritis, which results in diffuse pulmonary hemorrhage, and a segmental necrotizing glomerulonephritis, *The editors and the publisher would like to thank Drs. Nestor L. Müller and C. Isabela Silva Müller for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

606

which progresses to a crescentic nephritis.1 The capillaritis is identical to that of granulomatosis with polyangiitis (formerly Wegener granulomatosis) and microscopic polyangiitis and appears as a neutrophil infiltrate intimately associated with alveolar septa with or without fibrin thrombi and necrosis. Other histologic changes depend on the duration and severity of the disease at the time of examination but usually include hemosiderin-laden macrophages in alveolar airspaces and interstitial tissue and mild to moderate interstitial fibrosis.5 Immunofluorescence studies show characteristic linear staining most readily recognized in the glomerulus but also frequently evident in the alveolar capillary walls.1,6 Immunoglobulin (Ig)G is the usual antibody detected, although IgA and IgM are occasionally present as well.5

Manifestations of the Disease RADIOGRAPHY In the early stages of the disease, the radiographic pattern is one of patchy hazy areas of increased opacity (ground-glass opacities) scattered fairly evenly throughout the lungs (Fig. 47.1). With more severe hemorrhage, the pattern may progress to focal or confluent areas of consolidation often associated with air bronchograms (Fig. 47.2). The opacities usually are widespread but may be more prominent in the perihilar areas and in the middle and lower lung zones.7 The apices and costophrenic angles are often spared. Although parenchymal involvement usually is bilateral, it is commonly asymmetric and occasionally may be unilateral.7,8 The chest radiograph may be normal in patients with diffuse pulmonary hemorrhage. In one review of 39 episodes of diffuse pulmonary hemorrhage in 23 patients, the radiograph was normal in 7 (18%) episodes.8 Serial radiographs show that within 2 to 3 days, the areas of consolidation are gradually replaced by a reticular or reticulonodular pattern, the distribution of which is identical to that of the airspace disease (Fig. 47.3).7,9 This reticular pattern diminishes gradually during the next several days, and the appearance of the chest radiograph usually returns to normal about 10 to 12 days after the original episode.9 With repeated episodes of hemorrhage, increasing amounts of hemosiderin are deposited within the interstitial tissue and are associated with progressive fibrosis. In most cases the chest radiograph shows only partial clearing after each hemorrhagic episode, revealing persistence of a fine reticulonodular pattern indicative of the irreversible interstitial disease.9 Once these changes have developed, new episodes of pulmonary hemorrhage usually result in the typical pattern of airspace consolidation superimposed on the diffuse interstitial disease.

47  Goodpasture Syndrome (Anti–Basement Membrane Antibody Disease)

607

A

C

B

COMPUTED TOMOGRAPHY The computed tomography (CT) manifestations of acute pulmonary hemorrhage consist of bilateral ground-glass opacities and, less commonly, areas of consolidation (see Figs. 47.1 and 47.2).7,10 The ground-glass opacities may have a patchy distribution or be diffuse. CT scans performed 2 to 3 days after the acute episode show decrease in the ground-glass opacities and consolidation and presence of small, poorly defined centrilobular nodules and, less commonly, interlobular septal thickening.10 These findings are presumably secondary to the lymphatic resorption of the blood and gradually resolve during the next 1 to 2 weeks. Pulmonary fibrosis and interstitial hemosiderin deposition may develop in those with recurrent hemorrhage and typically

Fig. 47.1  Goodpasture syndrome with mild diffuse pulmonary hemorrhage: radiographic and CT findings. Chest radiograph (A) shows bilateral subtle hazy increased opacity (ground-glass pattern). Also noted is a hemodialysis catheter. Coronal (B) and sagittal (C) reformatted images from high-resolution CT demonstrate extensive bilateral ground-glass opacities and poorly defined small centrilobular nodules.

manifests as reticulation, traction bronchiectasis, and architectural distortion (Fig. 47.4). Frank honeycombing may develop and signals more severe fibrosis. IMAGING ALGORITHM The chest radiograph is usually the initial imaging modality used in the evaluation of patients with diffuse pulmonary hemorrhage and Goodpasture syndrome. In the proper clinical setting, when the radiograph demonstrates bilateral ground-glass opacities or consolidation, no further imaging is required. In some patients with diffuse pulmonary hemorrhage, the radiograph may be normal or show only questionable abnormalities. Thin-section

608

SECTION 9  Vasculitis and Granulomatosis

B

A

Fig. 47.2  Goodpasture syndrome with severe diffuse pulmonary hemorrhage: radiographic and CT findings. (A) Chest radiograph shows dense consolidation in the lung apices and hazy opacification of the remaining lungs. (B) High-resolution CT at the level of the upper lobes demonstrates extensive ground-glass opacities and areas of consolidation. (C) High-resolution CT at the level of the middle and lower lobes shows diffuse bilateral ground-glass opacities.

CT is indicated in patients with clinically suspected diffuse pulmonary hemorrhage and questionable or nonspecific radiographic findings. Thin-section CT is also indicated in patients with hemoptysis in whom the clinical presentation is not characteristic of Goodpasture syndrome. In these cases thin-section CT is helpful to rule out other causes of hemoptysis, such as bronchiectasis and bronchogenic carcinoma.11

Differential Diagnosis Approximately 20% of patients with glomerulonephritis and pulmonary hemorrhage have Goodpasture syndrome, 50% have some form of systemic vasculitis, and most of the remainder have diffuse alveolar hemorrhage in association with other forms of glomerulonephritis.12 The diagnosis of Goodpasture syndrome should be suspected when an adult patient has hemoptysis and bilateral airspace consolidation on the chest radiograph, particularly when manifestations of renal disease are also present. Confirmation can be obtained by demonstration of circulating or tissue-bound anti-GBM antibodies by enzyme-linked immunosorbent assay or immunofluorescent examination.13 If the diagnosis remains uncertain, it can be confirmed by demonstration of autoantibodies

C

on kidney biopsy. Most other conditions characterized by hemoptysis and renal dysfunction can be recognized by associated clinical and laboratory manifestations of vasculitis or by the observation of Ig and complement deposition in a granular pattern on immunofluorescent examination of a kidney biopsy specimen.5 Because renal involvement in Goodpasture syndrome may not be apparent initially, the diagnosis must be considered in any patient who has radiologic and clinical findings consistent with diffuse alveolar hemorrhage and no evidence of kidney disease.5 The differential diagnosis in this situation is large and includes various connective tissue diseases (especially systemic lupus erythematosus), systemic vasculitis (e.g., granulomatosis with polyangiitis), aspirated blood after vascular disruption, and occasionally certain metastatic neoplasms, such as choriocarcinoma.14,15

Synopsis of Treatment Options The treatment of Goodpasture syndrome is aimed at removal of circulating autoantibodies, which is accomplished by plasmapheresis and stopping the production of anti-GBM antibodies with use of immunosuppressive medications, typically corticosteroids and cyclophosphamide.3

47  Goodpasture Syndrome (Anti–Basement Membrane Antibody Disease)

A

B

C

D

Fig. 47.3  Goodpasture syndrome: changes on sequential radiographs after massive pulmonary hemorrhage. Posteroanterior radiograph (A) shows extensive consolidation of both lungs. A well-defined air bronchogram is visualized. Three days later (B), the pattern was somewhat more granular, and 10 days after the initial episode (C), the pattern had become distinctly reticular. Six days later (D), only a fine reticular pattern remains in an anatomic distribution identical to the original involvement. (From Müller NL, Fraser RS, Colman NC, Paré PD. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

609

610

SECTION 9  Vasculitis and Granulomatosis

A

B

C

Fig. 47.4  Goodpasture syndrome and pulmonary fibrosis. (A) Axial image from chest CT shows nodular, diffuse ground-glass opacities consistent with pulmonary hemorrhage. (B) Four years later, axial image from chest CT shows improvement in ground-glass opacity but development of mild reticulation and traction bronchiectasis consistent with pulmonary fibrosis caused by recurrent pulmonary hemorrhage. (C) Eight years later, reticulation and traction bronchiectasis have progressed.

KEY POINTS • Goodpasture syndrome has a bimodal age distribution with peaks at 20–30 and 60–70 years of age. • It is more common in men than in women (3 : 2). • It is characterized by repeated episodes of pulmonary hemorrhage and presence of serum anti–glomerular basement membrane antibodies. • The presenting symptom is hemoptysis in 80%–95% of patients. • Respiratory symptoms often precede renal manifestations.

With treatment the 5-year survival ranges from 63% to 94%, depending on the initial renal function.16 In one study approximately 20% of patients had normal recovery, 39% were receiving maintenance hemodialysis, 12% received transplants and were doing well, 5% were awaiting transplants, and 24% died.3 The prognosis is closely associated with the degree of initial renal impairment. Predictors of poor prognosis include initial creatinine levels greater than 5 mg/dL, crescent formation in more than 50% of glomeruli, and oligoanuria (i.e., 1 in this case. (B) CT image obtained at a slightly more caudal level demonstrates reflux of contrast into the inferior vena cava (large star) and hepatic veins (small stars).

A

Fig. 50.11  Pulmonary embolism in a dyspneic patient with chronic obstructive pulmonary disease. Contrast-enhanced CT image obtained at the level of the lower lobes shows subsegmental filling defects (arrows) in both lower lobes.

B Fig. 50.12  Acute pulmonary embolism on dual-energy multidetector CT. (A) Axial CT image shows occlusive filling defects (arrows) at the origin of the right middle and lower lobar pulmonary arteries and left lower lobe lateral basal segmental pulmonary artery. (B) Perfusion map demonstrates perfusion deficits as darker colors (arrows) in areas of the lung supplied by the affected pulmonary artery branches.

50  Acute Pulmonary Embolism

Fig. 50.13  Pulmonary embolism in a patient referred from the intensive care unit. Contrast-enhanced CT image shows endoluminal clot (arrow).

adequate breath-holding and to avoid the Valsalva maneuver, which can cause interruption of contrast bolus because of influx of unopacified blood from the inferior vena cava resulting in dense contrast in the superior vena cava and aorta but less opacified blood in the pulmonary arteries.38 Performance of CTPA in middle inspiratory or expiratory phase, instead of at maximal inspiration, can help reduce the incidence of transient interruption of contrast. Patients can be instructed to avoid deep inspiration or expiration and simply hold their breath.39 Alternatively, patients can take a breath in, a breath out, and then suspend breathing.40 To obtain optimal contrast opacification of the pulmonary arteries, high-contrast injection rates of 3 to 4 mL/s are often used. However, in patients with poor peripheral venous access, low flow rates of 2.0 or 2.5 mL/s can be used with diagnostic results in most patients.41 The total volume of contrast administered should be tailored to the patient’s body habitus and renal function.38 Objectively, density of greater than or equal to 200 Hounsfield units in the pulmonary trunk is considered diagnostic for the evaluation of PE.41,42 Triple-rule-out protocols with electrocardiography-gating are performed at some institutions for patients with acute chest pain to simultaneously evaluate for PE, acute coronary syndrome, and acute aortic syndrome (Fig. 50.14).43,44 Gadolinium-based contrast agents have been used as an alternative to iodinated contrast agents for patients with relative or absolute contraindications to iodinated contrast agents in whom contrast-enhanced CT of the chest was the examination of choice. With use of a 16–detector-row system, 92% (55 of 60) of gadolinium-enhanced CT angiographic examinations yielded good to excellent vascular enhancement and enabled radiologists to provide clinicians with diagnostic information, including successful detection of acute PE (Fig. 50.15).45

629

Fig. 50.14  Acute chest pain investigated with electrocardiography (ECG)-gated 64-slice multidetector CT angiography. Curved planar reformatted image of the left circumflex coronary artery was reconstructed from an ECG-gated CT examination of the entire chest. Note the excellent image quality, enabling demonstration of the patency of the vessel lumen despite calcified plaque.

1 1 Min/Max: 319 /387 1 Mean/SD: 352.8 /16

Fig. 50.15  Computed tomography (CT) pulmonary angiography obtained after administration of gadolinium in a patient thought to have acute pulmonary embolism (PE) with a history of severe allergic reaction to iodinated contrast media. Axial CT scan obtained at the level of the lower lobes illustrates the excellent degree of arterial enhancement within the pulmonary arteries, measured at 352 Hounsfield units in the posterobasal segmental artery of the left lower lobe. Findings were negative for acute PE.

Clinical Validity of a Negative Computed Tomography Pulmonary Angiography In a meta-analysis of 15 studies that used contrast-enhanced chest CT to rule out the diagnosis of acute PE in a total of 3500 patients with a minimum of 3-month follow-up, Quiroz and

630

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

colleagues46 concluded that the clinical validity of using a CT scan to rule out PE is similar to that reported for conventional pulmonary angiography—namely, 1% to 2.8% for CT (including single-slice CT, MDCT, and electron-beam CT) versus 1.1% to 2.9% for conventional pulmonary angiography. The majority of studies that were included in this meta-analysis used conventional single-slice CT, which may have missed the diagnosis of peripheral PE. The low incidence of venous thromboembolic events during follow-up across all these studies suggests that even if peripheral pulmonary emboli were missed and subsequently not treated on the basis of a normal CT scan, the patient outcome was not adversely affected. According to the guidelines of the British Thoracic Society, no further examination or treatment is needed for patients with a high-quality normal CT angiogram performed on a multidetector scanner.47 A recent study has also shown that the incidence of PE is only 2.5% on ventilation and perfusion (VQ) imaging performed after suboptimal CTPAs, likely because of the ability of most suboptimal CTPAs to exclude central PE.48 MAGNETIC RESONANCE IMAGING Magnetic resonance imaging (MRI) also allows direct and noninvasive demonstration of acute PE. It has the advantage of not requiring radiation. It can be used in patients with severe allergic reactions to iodinated contrast. Its diagnostic accuracy has been shown to be very high for MR angiography,49 MR perfusion,50 real-time MRI,51 and combined protocols (Fig. 50.16). However, MRI suffers from several disadvantages in the diagnostic workup of PE. First, and despite remarkable results in the detection of acute PE with contrast-enhanced MR

Fig. 50.16  MRI of acute pulmonary thromboembolism. Coronal MRI shows filling defect (arrow) in the right interlobar pulmonary artery. (Case courtesy Dr. Jaime Fdez-Cuadrado, Hospital La Paz, Madrid, Spain. From Müller NL, Fraser RS, Colman NC, Paré PD. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

angiography, the overall image quality is inferior to that achievable on CT angiography because of a lower spatial resolution, motion artifacts, and overlapping pulmonary veins. Second, MRI is suboptimal for the evaluation of pulmonary parenchyma and hence limited in ability to provide differential diagnosis of acute PE. Third, the availability of MRI units is lower than that of CT scanners, especially in the context of emergency departments. Last, an MRI scanner is generally a hostile environment for patients who are clinically unstable, particularly if they need life-support equipment, which frequently is incompatible with a highly magnetized field. ULTRASONOGRAPHY Apart from the detection of DVT with venous duplex sonography, which is beyond the scope of this chapter, thoracic ultrasonography for diagnosis of acute PE is usually limited to the bedside management of massive acute PE. An original approach was reported by Mathis and colleagues,52 who investigated the use of thoracic ultrasonography to diagnose peripheral PE on the basis of the identification of triangular or rounded subpleural parenchymal lesions. In the absence of CTPA, they found that thoracic ultrasonography could be a suitable tool to demonstrate PE at the bedside and in the emergency setting. Transthoracic echocardiography, used to detect evidence of right heart strain, such as dilated right ventricle, abnormal septal motion and tricuspid regurgitation, has been shown to have low sensitivity but relatively high specificity and is used at the bedside in critical care settings in patients who are not able to receive a CTPA.53 NUCLEAR MEDICINE Before the advent of CTPA, VQ scintigraphy was widely used in the evaluation of patients thought to have acute PE. Its use has decreased considerably with the increased availability and improved diagnostic accuracy of MDCT. The diagnosis of acute PE on scintigraphy is based on the identification of VQ mismatch —that is, the presence of ventilation in the absence of perfusion distal to the obstructing emboli (Fig. 50.17; see Fig. 50.6). The findings are classified into five categories—normal, near-normal, low probability, intermediate probability, and high probability— on the basis of the probability of embolism, known as the PIOPED I criteria (Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis I). Because the original PIOPED I criteria led to a large proportion of nondiagnostic scans, several amendments have been made, enabling a decrease in the number of intermediate interpretations and a more accurate assessment of angiographically proven cases of acute PE.54,55 The modified PIOPED II criteria classify findings as “PE present” (high probability), “PE absent” (very low probability or normal), or “nondiagnostic” (intermediate or low probability). These changes allow VQ scans to be more definitive in a majority of patients.56 Another way of improving the diagnostic accuracy of scintigraphy is to eliminate the ventilation scan, focusing on the perfusion scan.57,58 When the chest radiograph is normal, this approach can reduce both cost and radiation dose.59 VQ scan is the preferred imaging modality for evaluation of suspected PE in pregnancy for patients with normal chest radiograph and in the absence of leg symptoms. VQ scan allows lower radiation dose to the maternal breast and lung tissue compared with CTPA, and the radiation dose to the fetus is thought to be low for both imaging modalities.60

50  Acute Pulmonary Embolism Right posterior

Right posterior

Wash-in

Equilibrium

Right posterior

A Wash-out

B

Anterior

Posterior

Right posterior oblique

Left posterior oblique

631

Fig. 50.17  Ventilation-perfusion scintigraphy in acute pulmonary embolism. (A) Xenon-133 posterior inhalation lung scan shows normal ventilation during the wash-in, equilibrium, and wash-out phases. (B) Corresponding Technetium99m labeled macroaggregated albumin perfusion lung scans in anterior, posterior, and right and left posterior oblique projections identify multiple large segmental filling defects throughout both lungs (arrowheads). These findings, in concert with the ventilation study, are virtually diagnostic (high probability) of pulmonary thromboembolism. (From Müller NL, Fraser RS, Colman NC, Paré PD. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

632

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

Differential Diagnosis PITFALLS IN THE INTERPRETATION OF ENDOLUMINAL FILLING DEFECTS ON COMPUTED TOMOGRAPHY PULMONARY ANGIOGRAPHY • Technically related pitfalls • Cardiac and respiratory motion artifacts • Suboptimal opacification of pulmonary arteries • Partial volume averaging • Anatomically related pitfalls • Juxtahilar lymph nodes • Misidentification of a pulmonary vein as a pulmonary artery • Mucus-filled bronchi • Patient-related pitfalls • Unilateral increase in pulmonary vascular resistance: large pleural effusion; extensive consolidation, hyperinflation, hypoxic vasoconstriction, conditions with elevated venous pressure • Left-to-right shunt • Right-to-left shunt (patent foramen ovale) • Right-sided heart failure and pulmonary hypertension • Nonthrombotic emboli • Tumoral: pulmonary artery sarcoma, right heart myxoma, tumor emboli • Foreign body: bullet, catheter fragment, cement used for orthopedic procedures or vertebroplasty • In situ thrombosis • Pulmonary hypertension • Postsurgical (lobectomy, pneumonectomy) • Pulmonary artery stenosis • Chronic atelectasis

Synopsis of Treatment Options Treatment of acute PE is dependent on mortality risks. Patients with massive PE, with an estimated 30-day PE-related mortality rate of greater than 15%, should be treated with systemic thrombolysis in the absence of contraindications. Surgical and catheter-directed pulmonary embolectomy or catheter-directed thrombolysis can be considered in patients with massive PE who failed to respond to thrombolytic therapy during the first hour or in whom thrombolytic therapy is contraindicated. Hemodynamically stable patients are further stratified for close monitoring versus outpatient treatment using signs of right heart dysfunction on CT or echocardiogram; laboratory biomarkers, such as brain-type natriuretic peptides and troponin levels; and clinical criteria, such as the Hestia decision rule or the

Pulmonary Embolism Severity Index (PESI). Low-molecularweight heparin (LMWH) and parallel initiation of vitamin K antagonists (VKAs) has been the treatment of choice. Recently introduced nonvitamin K–dependent oral anticoagulants, which have been shown to be as effective as LMWH/VKAs without the need for frequent laboratory monitoring and preceding LMWH, are increasingly used.61

KEY POINTS • With the advent of multidetector CT technologies resulting in short image-acquisition time and improved image quality, CT pulmonary angiography (CTPA), with high sensitivity and specificity, has become the imaging modality of choice in the evaluation of suspected pulmonary embolism (PE). • The use of clinical decision rule and serum D-dimer level in the evaluation of patients with suspected PE can help decrease use and improve positive yield of CTPA. • CTPA allows direct visualization of PE as endoluminal filling defects within pulmonary artery branches. • CT signs of right heart dysfunction are an important factor in the management of hemodynamically stable patients with acute PE. Right ventricular to left ventricular–diameter ratio greater than or equal to 1 on axial CT images has been shown to be a predictor of poor outcome. • Diagnosis of PE on ventilation-perfusion (VQ) scintigraphy scanning relies on the presence of mismatched VQ defects. The VQ scan is the test of choice in pregnant women suspected of having PE.

SUGGESTED READINGS Albrecht MH, Bickford MW, Nance JW Jr, Zhang L, De Cecco CN, Wichmann JL, Vogl TJ, Schoepf UJ. State-of-the-art pulmonary CT angiography for acute pulmonary embolism. AJR Am J Roentgenol. 2017;208(3):495–504. Konstantinides SV, Barco S, Lankeit M, Meyer G. Management of pulmonary embolism: an update. J Am Coll Cardiol. 2016;67(8):976–990. Metter D, Tulchinsky M, Freeman LM. Current status of ventilation-perfusion scintigraphy for suspected pulmonary embolism. AJR Am J Roentgenol. 2017;208(3):489–494. Meyer M, Haubenreisser H, Sudarski S, Doesch C, Ong MM, Borggrefe M, Schoenberg SO, Henzler T. Where do we stand? Functional imaging in acute and chronic pulmonary embolism with state-of-the-art CT. Eur J Radiol. 2015;84(12):2432–2437. Ruggiero A, Screaton NJ. Imaging of acute and chronic thromboembolic disease: state of the art. Clin Radiol. 2017;72(5):375–388. van der Hulle T, Dronkers CE, Klok FA, Huisman MV. Recent developments in the diagnosis and treatment of pulmonary embolism. J Intern Med. 2016;279(1):16–29.

The full reference list for this chapter is available at ExpertConsult.com.

50  Acute Pulmonary Embolism 632.e1

REFERENCES 1. van Langevelde K, Srámek A, Vincken PW, van Rooden JK, Rosendaal FR, Cannegieter SC. Finding the origin of pulmonary emboli with a total-body magnetic resonance direct thrombus imaging technique. Haematologica. 2013;98(2):309–315. 2. Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol. 2015;12(8):464–474. 3. Bach AG, Meyer HJ, Taute BM, Surov A. The frequency of incidental pulmonary embolism in different CT examinations. Br J Radiol. 2016;89(1058):20150737. 4. Giuntini C, Ricco GD, Marini C, et al. Pulmonary embolism: epidemiology. Chest. 1995;107(suppl):3S–9S. 5. Dalen JE, Alpert JS. Natural history of pulmonary embolism. Prog Cardiovasc Dis. 1975;17:257–270. 6. Fraser RS, Colman N, Müller NL, Paré PD. Thrombosis and thromboembolism. In: Fraser RS, Müller NL, Coleman N, Paré PD, eds. Fraser and Paré’s Diagnosis of Diseases of the Chest. 4th ed. Philadelphia: WB Saunders; 1999: 1773–1843. 7. LeGal G, Righini M, Roy PM, et al. Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med. 2006;144:165–171. 8. Tillie-Leblond I, Marquette CH, Perez T, et al. Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors. Ann Intern Med. 2006;144:390–396. 9. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost. 2000;83: 416–420. 10. Wicki J, Perneger TV, Junod AF, et al. Assessing clinical probability of pulmonary embolism in the emergency ward: a simple score. Arch Intern Med. 2001;161:92–97. 11. Miniati M, Bottai M, Monti S. Comparison of 3 clinical models for predicting the probability of pulmonary embolism. Medicine (Baltimore). 2005;84: 107–114. 12. Hoo GW, Wu CC, Vazirani S, Li Z, Barack BM. Does a clinical decision rule using D-dimer level improve the yield of pulmonary CT angiography? AJR Am J Roentgenol. 2011;196(5):1059–1064. 12a.  Dunne RM, Ip IK, Abbett S, et al. Effect of evidence-based clinical decision support on the use and yield of CT pulmonary angiographic imaging in hospitalized patients. Radiology. 2015;276:167–174. 13. Raja AS, Greenberg JO, Qaseem A, et al; Clinical Guidelines Committee of the American College of Physicians. Evaluation of patients with suspected acute pulmonary embolism: best practice advice from the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med. 2015;163(9):701–711. 14. Expert Panels on Cardiac and Thoracic Imaging, Kirsch J, Brown RKJ, Henry TS, et al. ACR Appropriateness Criteria) acute chest pain-suspected pulmonary embolism. J Am Coll Radiol. 2017;14(5S):S2–S12. 15. Wiener RS, Ouellette DR, Diamond E, Fan VS, Maurer JR, Mularski RA, Peters JI, Halpern SD. An official American Thoracic Society/American College of Chest Physicians policy statement: the Choosing Wisely top five list in adult pulmonary medicine. Chest. 2014;145(6):1383–1391. 16. Tatco VR, Piedad HH. The validity of hyperdense lumen sign in non-contrast chest CT scans in the detection of pulmonary thromboembolism. Int J Cardiovasc Imaging. 2011;27(3):433–440. 17. Casullo J, Semionov A. Reversed halo sign in acute pulmonary embolism and infarction. Acta Radiol. 2013;54(5):505–510. 18. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JR, Wells P, Woller SC, Moores L. Antithrombotic therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315–352. 19. Jaff MR, McMurtry MS, Archer SL, et al; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; American Heart Association Council on Peripheral Vascular Disease; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011;123(16):1788–1830. 20. Oliver TB, Reid JH, Murchison JT. Interventricular septal shift due to massive pulmonary embolism shown by CT pulmonary angiography: an old sign revisited. Thorax. 1998;53:1092–1094. 21. Ghaye B, Ghuysen A, Willems V, et al. Severe pulmonary embolism: pulmonary artery clot load scores and cardiovascular parameters as predictors of mortality. Radiology. 2006;239:884–891.

22. Yalamanchili K, Fleischer AG, Lehrman SG, et al. Open embolectomy for treatment of major pulmonary embolism. Ann Thorac Surg. 2004;77: 819–823. 23. Quanadli SD, El Hajjam M, Vieillard-Baron A, et al. New CT index to quantify arterial obstruction in pulmonary embolism: comparison with angiographic index and echocardiography. AJR Am J Roentgenol. 2001;176:1415–1420. 24. Mastora I, Remy-Jardin M, Masson P, et al. Severity of acute pulmonary embolism: evaluation of a new spiral CT angiographic score in correlation with echocardiographic data. Eur Radiol. 2003;13:29–35. 25. Wu AS, Pezzullo JA, Cronan JJ, et al. CT pulmonary angiography: quantification of pulmonary embolus as a predictor of patient outcome—initial experience. Radiology. 2004;230:831–835. 26. Engelke C, Rummeny EJ, Marten K. Acute pulmonary embolism on MDCT of the chest: prediction of cor pulmonale and short-term patient survival from morphologic embolus burden. AJR Am J Roentgenol. 2006;186:1265–1271. 27. Meinel FG, Nance JW Jr, Schoepf UJ, Hoffmann VS, Thierfelder KM, Costello P, Goldhaber SZ, Bamberg F. Predictive value of computed tomography in acute pulmonary embolism: systematic review and meta-analysis. Am J Med. 2015;128(7):747–759.e2. 28. Lu MT, Demehri S, Cai T, Parast L, Hunsaker AR, Goldhaber SZ, Rybicki FJ. Axial and reformatted four-chamber right ventricle-to-left ventricle diameter ratios on pulmonary CT angiography as predictors of death after acute pulmonary embolism. AJR Am J Roentgenol. 2012;198(6):1353–1360. 29. Shiomi D, Kiyama H, Shimizu M, Yamada M, Shimada N, Takahashi A, Kaki N. Surgical embolectomy for high-risk acute pulmonary embolism is standard therapy. Interact Cardiovasc Thorac Surg. 2017;25:297–301. 30. Dudzinski DM, Giri J, Rosenfield K. Interventional treatment of pulmonary embolism. Circ Cardiovasc Interv. 2017;10(2). 31. Okada M, Kunihiro Y, Nakashima Y, Nomura T, Kudomi S, Yonezawa T, Suga K, Matsunaga N. Added value of lung perfused blood volume images using dual-energy CT for assessment of acute pulmonary embolism. Eur J Radiol. 2015;84(1):172–177. 32. Apfaltrer P, Bachmann V, Meyer M, Henzler T, Barraza JM, Gruettner J, Walter T, Schoepf UJ, Schoenberg SO, Fink C. Prognostic value of perfusion defect volume at dual energy CTA in patients with pulmonary embolism: correlation with CTA obstruction scores, CT parameters of right ventricular dysfunction and adverse clinical outcome. Eur J Radiol. 2012;81(11):3592–3597. 33. Bauer RW, Frellesen C, Renker M, Schell B, Lehnert T, Ackermann H, Schoepf UJ, Jacobi V, Vogl TJ, Kerl JM. Dual energy CT pulmonary blood volume assessment in acute pulmonary embolism—correlation with D-dimer level, right heart strain and clinical outcome. Eur Radiol. 2011;21(9):1914–1921. 34. Remy-Jardin M, Tillie-Leblond I, Szapiro D, et al. CT angiography of pulmonary embolism in patients with underlying respiratory disease: impact of multislice CT on image quality and negative predictive value. Eur Radiol. 2002;12:1971–1978. 35. Wu CC, Lee EW, Suh RD, Levine BS, Barack BM. Pulmonary 64-MDCT angiography with 30 mL of IV contrast material: vascular enhancement and image quality. AJR Am J Roentgenol. 2012;199(6):1247–1251. 36. Chen EL, Ross JA, Grant C, Wilbur A, Mehta N, Hart E, Mar WA. Improved image quality of low-dose CT pulmonary angiograms. J Am Coll Radiol. 2017;14:648–653. 37. Sauter A, Koehler T, Fingerle AA, Brendel B, Richter V, Rasper M, Rummeny EJ, Noël PB, Münzel D. Ultra low dose ct pulmonary angiography with iterative reconstruction. PLoS ONE. 2016;11(9):e0162716. 38. Albrecht MH, Bickford MW, Nance JW Jr, Zhang L, De Cecco CN, Wichmann JL, Vogl TJ, Schoepf UJ. State-of-the-art pulmonary CT angiography for acute pulmonary embolism. AJR Am J Roentgenol. 2017;208(3):495–504. 39. Raczeck P, Minko P, Graeber S, Fries P, Seidel R, Buecker A, Stroeder J. Influence of respiratory position on contrast attenuation in pulmonary CT angiography: a prospective randomized clinical trial. AJR Am J Roentgenol. 2016;206(3):481–486. 40. Mortimer AM, Singh RK, Hughes J, Greenwood R, Hamilton MC. Use of expiratory CT pulmonary angiography to reduce inspiration and breath-hold associated artefact: contrast dynamics and implications for scan protocol. Clin Radiol. 2011;66(12):1159–1166. 41. Gossner J. Feasibility of computed tomography pulmonary angiography with low flow rates. J Clin Imaging Sci. 2012;2:57. 42. Wittram C. How I do it: CT pulmonary angiography. AJR Am J Roentgenol. 2007;188(5):1255–1261. 43. White CS, Kuo D, Kelemen M, et al. Chest pain evaluation in the emergency department: can MDCT provide a comprehensive evaluation? AJR Am J Roentgenol. 2005;185:533–540. 44. Yoo SM, Chun EJ, Lee HY, Min D, White CS. Computed tomography diagnosis of nonspecific acute chest pain in the emergency department: from typical acute coronary syndrome to various unusual mimics. J Thorac Imaging. 2017;32(1):26–35.

632.e2

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

45. Remy-Jardin M, Bahepar J, Lafitte JJ, et al. Multidetector row CT angiography of pulmonary circulation with gadolinium-based contrast agents: prospective evaluation in 60 patients. Radiology. 2006;238:1022–1035. 46. Quiroz R, Kucher N, Zou KH, et al. Clinical validity of a negative computed tomography scan in patients with suspected pulmonary embolism. A systematic review. JAMA. 2005;293:2012–2017. 47. British Thoracic Society Standards of Care Committee Pulmonary Embolism Guideline Development Group. British Thoracic Society guidelines for the management of suspected acute pulmonary embolism. Thorax. 2003;58: 470–483. 48. Curtis BR, Cox M, Poplawski M, Lyshchik A. Low yield of ventilation and perfusion imaging for the evaluation of pulmonary embolism after indeterminate CT pulmonary angiography. Emerg Radiol. 2017;24:525–530. 49. Van Beek EJ, Wild JM, Fink C, et al. MRI for the diagnosis of pulmonary embolism. J Magn Reson Imaging. 2003;18:627–640. 50. Amundsen T, Torkheim G, Kvistad KA, et al. Perfusion abnormalities in pulmonary embolism studied with perfusion MRI and ventilation-perfusion scintigraphy: an intra-modality and inter-modality agreement study. J Magn Reson Imaging. 2002;15:386–394. 51. Kluge A, Müller C, Hansel J, et al. Real time MR with TrueFISP for the detection of acute pulmonary embolism: initial clinical experience. Eur Radiol. 2004;14:709–718. 52. Mathis G, Blank W, Reibig A, et al. Thoracic ultrasound for diagnosing pulmonary embolism. A prospective multicenter study of 352 patients. Chest. 2005;128:1531–1538. 53. Fields JM, Davis J, Girson L, Au A, Potts J, Morgan CJ, Vetter I, Riesenberg LA. Transthoracic echocardiography for diagnosing pulmonary embolism: a systematic review and meta-analysis. J Am Soc Echocardiogr. 2017;30:714–723.e4.

54. Sostman HD, Coleman RE, DeLong DM, et al. Evaluation of revised criteria for ventilation-perfusion scintigraphy in patients with suspected pulmonary embolism. Radiology. 1994;193:103. 55. The PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA. 1990;263:2753–2759. 56. Sostman HD, Miniati M, Gottschalk A, Matta F, Stein PD, Pistolesi M. Sensitivity and specificity of perfusion scintigraphy combined with chest radiography for acute pulmonary embolism in PIOPED II. J Nucl Med. 2008;49(11):1741–1748. 57. Stein PD, Terrin ML, Gottschalk A, et al. Value of ventilation/perfusion scans compared to perfusion scans alone in acute pulmonary embolism. Am J Cardiol. 1992;69:1239–1241. 58. Miniati M, Pistolesi M, Marini C, et al. Value of perfusion lung scan in the diagnosis of pulmonary embolism: results of the Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis (PISA-PED). Am J Respir Crit Care Med. 1996;154:1387–1393. 59. Forbes KP, Reid JH, Murchison JT. Do preliminary chest X-ray findings define the optimum role of pulmonary scintigraphy in suspected pulmonary embolism? Clin Radiol. 2001;56:397–400. 60. Leung AN, Bull TM, Jaeschke R, et al; ATS/STR Committee on Pulmonary Embolism in Pregnancy. American Thoracic Society documents: an official American Thoracic Society/Society of Thoracic Radiology Clinical Practice Guideline–evaluation of suspected pulmonary embolism in pregnancy. Radiology. 2012;262(2):635–646. 61. van der Hulle T, Dronkers CE, Klok FA, Huisman MV. Recent developments in the diagnosis and treatment of pulmonary embolism. J Intern Med. 2016;279(1):16–29.

51 

Chronic Pulmonary Thromboembolism* BRENT P. LITTLE

Etiology Chronic pulmonary thromboembolism is an uncommon entity resulting from an incomplete resolution of thrombi, leading to complex restructuring processes within pulmonary arteries. Extensive clinical experience from the literature suggests that failure of thromboembolic resolution after a single embolic event or after recurrent thromboembolic events represents the predisposing condition in most patients with the disease. Although the clinical signs and symptoms are nonspecific, a confident diagnosis can usually be made on computed tomography angiography (CTA).

Prevalence and Epidemiology It has been estimated that in the United States approximately 600,000 episodes of pulmonary embolism occur each year. Although the natural history of adequately treated acute pulmonary embolism is not well characterized, data based predominantly on clinical follow-up suggest that thromboembolic resolution occurs in the overwhelming majority of patients who experience an acute embolic event (Fig. 51.1). Evolution toward chronic thromboembolic disease has been estimated to range between 2% and 18% of patients when serial perfusion scans have been performed,1–3 and it has been reported in 13% of patients with CT follow-up (Fig. 51.2).4 The basis for this alternative natural history has not been clearly established. Despite extensive investigation the only identifiable thrombotic predisposition has been the presence of lupus anticoagulant in approximately 10% of patients. Less than 1% of patients have had deficiencies of antithrombin III, protein C, or protein S. In a subset of patients, long-standing increase in pulmonary artery pressure resulting from the chronic obstruction of the pulmonary arterial bed leads to chronic thromboembolic pulmonary hypertension, and can be complicated by cor pulmonale and right-sided heart failure. At this stage there is a poor prognosis of the disease with a 5-year survival rate of only 30%.

Clinical Presentation The spectrum of symptoms associated with chronic pulmonary thromboembolism depends on the percentage of the pulmonary arterial bed chronically obstructed and the development of pulmonary hypertension. In the absence of pulmonary hypertension the symptoms are nonspecific, including progressive dyspnea and exercise intolerance. A diagnostic delay, particularly in the absence of an acute history of venous thromboembolism, is common. The mean time from onset of symptoms to diagnosis usually exceeds 3 years. *The editors and the publisher would like to thank Drs. Martine Remy-Jardin and Jacques Remy for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

The symptomatic history has been well described.5 After a documented venous thromboembolic event, symptomatic recovery occurs, although often not to a level equivalent to that before the acute event. In patients without a documented acute thromboembolic event, several data confirm the often subtle clinical manifestations of a venous thromboembolic event and the frequency with which misdiagnosis occurs.6 After a period of clinical stability that may range from months to years, increasing exertional dyspnea, hypoxemia, and right ventricular dysfunction ultimately ensue. Chronic thromboembolic pulmonary hypertension (CTEPH) can develop in up to 3.8% of patients after an acute episode and in up to 10% of patients with recurrent pulmonary embolism. CTEPH is classified as group IV pulmonary hypertension according to the Fifth World Symposium of Pulmonary Hypertension (Nice, France, 2013). The diagnosis can be made in the setting of elevated pulmonary artery pressure (mean pressure ≥25 mm Hg, with wedge pressure ≤15 mm Hg), with evidence of chronic emboli as assessed by a ventilation-perfusion (VQ) scan or cross-sectional imaging, such as CT or magnetic resonance imaging (MRI).7

Pathophysiology ANATOMY Fresh thrombus may fragment and disperse into smaller pulmonary arteries, but within a few days, thrombotic emboli undergo organization and become firmly adherent to the vessel wall. In 4 to 6 weeks they are converted into fibrous tissue, often with recanalization. Some emboli may disappear, and it is presumed that they are destroyed by plasmin. Thin fibrous bands stretching across the lumen of major pulmonary arteries are sometimes the only evidence of previous thromboembolism. More often, the lumen of smaller arteries is divided into multiple channels by the usual process of recanalization.8 A mixed pattern of vascular stenosis, intraluminal webs, and abnormal tapering of vessel diameter can be seen.9 As a consequence of the presence of pulmonary hypertension, a secondary, small-vessel arteriopathy, also described as plexogenic arteriopathy, may develop.10 PATHOLOGY Early resolution of pulmonary vascular obstruction occurs by two mechanisms: mechanical changes in thrombus location and endogenous thrombolysis. After these early events, organization and recanalization further alleviate the degree of pulmonary vascular obstruction.11 However, significant organized residual disease may persist, and therefore abnormal pulmonary hemodynamics at rest or with exercise may be present in patients whose perfusion scans (i.e., the most frequent means of follow-up) return to normal.12 633

634

A

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

B Fig. 51.1  Natural history of acute pulmonary embolism: complete resolution. (A) Axial CT scan shows acute pulmonary emboli in the left main and left upper lobe anterior segmental pulmonary arteries (arrow). Additional right upper lobe pulmonary artery embolism is also noted. (B) Axial CT scan obtained 2 months later, after adequate anticoagulant treatment, shows complete resolution of the endoluminal clot (arrow).

A

B Fig. 51.2  Natural history of acute pulmonary embolism: evolution to chronic pulmonary embolism. (A) Axial CT scan shows acute right lower lobe pulmonary emboli (straight arrow), with a pulmonary infarct (curved arrow). (B) CT image obtained 1 year later, after adequate anticoagulation, shows chronic emboli in the same distribution, with a marked decrease in diameter of the right lower lobe pulmonary arteries (arrow).

51  Chronic Pulmonary Thromboembolism

Chronic pulmonary thromboembolism may show a silent clinical period lasting months or years, followed by clinical deterioration that parallels the loss of right ventricular functional capacity. This decline may be due to recurrent thromboembolism, in situ pulmonary artery thrombosis, and a hypertensive pulmonary arteriopathy similar to that encountered in patients with pulmonary hypertension from other causes.13,14 LUNG FUNCTION The results of spirometry, often performed as part of the evaluation of the patient’s dyspnea, are usually within normal limits.15 Approximately 20% of patients show mild to moderate restriction, to a large extent caused by parenchymal scarring related to prior infarcts. A reduction in single-breath diffusing capacity for carbon monoxide (DLCO) can be observed, ranging from mild to severe; a normal value does not exclude the diagnosis.

COMPUTED TOMOGRAPHY Cardiovascular Signs of Chronic Pulmonary Thromboembolism Vascular Signs.  The CT features of chronic pulmonary thromboembolism are similar to those described with conventional angiography (Box 51.1). Chronic emboli are usually identified on the basis of at least two of the following features: emboli eccentric and contiguous with the vessel wall, recanalization within an area of arterial hypoattenuation, arterial stenosis or web, reduction of more than 50% of the overall arterial diameter, or complete occlusion of a stenosed artery (Figs. 51.3 to 51.7). A recanalized thrombus perpendicular to the artery wall generates webs or bands and focal stenoses with mild poststenotic dilatation

BOX 51.1  VASCULAR COMPUTED TOMOGRAPHIC FEATURES SUGGESTIVE OF CHRONIC THROMBOEMBOLISM

Manifestations of the Disease RADIOGRAPHY

• Organized embolic material • Partial or complete filling defects • Emboli eccentric and contiguous with the vessel wall • Irregular contours of the intimal surface • Retracted embolic material • Complete filling defects at the level of stenosed pulmonary arteries • Abrupt cutoffs and narrowing • Recanalized embolic material • Webs, bands, or stenoses with poststenotic dilatation • Calcified embolic material • Calcifications within filling defects

Chest radiography may be normal or may demonstrate findings of pulmonary hypertension. Asymmetry in size of the central pulmonary arteries can be seen in conjunction with areas of relative hypoperfusion and hyperperfusion. The asymmetry of the central pulmonary arteries may be so dramatic that it may suggest pulmonary artery agenesis, whereas areas of increased perfusion may suggest consolidation with pneumonia or interstitial lung disease. Chest radiography may also reveal parenchymal or pleural scars, consistent with prior infarcts, and enlargement of the right ventricle in the advanced forms of the disease.

A

635

B Fig. 51.3  CT angiographic signs of chronic thromboembolic disease: chronic mural clot. (A) and (B) Axial CT scans show mural defects involving the outer wall of the left main and left interlobar pulmonary arteries (arrowheads). Note linear web in the distal right pulmonary artery (arrow). A dilated pulmonary trunk indicates pulmonary hypertension.

636

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

A

B Fig. 51.4  CT angiographic signs of chronic thromboembolic disease: eccentric filling defect and incomplete recanalization resulting in an intraluminal web. (A) Axial CT scan shows an eccentric filling defect (arrow) within the right interlobar pulmonary artery. (B) Coronal CT image shows a linear web (arrow) in a right lower lobe pulmonary artery.

Fig. 51.5  CT angiographic signs of chronic thromboembolic disease: recanalized embolic material. Axial CT scan obtained at the level of the left upper lobe bronchus shows two circulating channels (arrows) within the left interlobar pulmonary artery, consistent with incomplete recanalization.

(Fig. 51.8). Parallel to the arterial lumen, the incomplete recanalization thickens the artery wall, sometimes resulting in an irregular contour of the intimal surface. Calcifications within chronic thrombi are seen in a small number of patients. Most cases of chronic pulmonary thromboembolism have multiple and bilateral arterial abnormalities. Because partial or complete filling defects of normal-sized pulmonary arteries can be seen in acute and chronic pulmonary embolism, these features alone should not lead to the assessment

Fig. 51.6  CT angiographic signs of chronic thromboembolic disease: retraction of chronically obstructed pulmonary arteries. Axial CT scan obtained at the level of the lower lobes shows complete obstruction and retraction of the right lower lobe pulmonary artery (arrow) compared with the normally perfused left lower lobe pulmonary artery (arrowhead).

of chronic pulmonary embolism. A study has pointed out that the mean attenuation value of chronic clots is higher than that of acute filling defects, possibly because of enhancement of organizing thrombi.16 The additional presence of dilated bronchial arteries (Fig. 51.9) is a strong argument in favor of chronic or

51  Chronic Pulmonary Thromboembolism

637

Fig. 51.7  CT angiographic signs of chronic thromboembolic disease: complete arterial occlusion. Coronal maximum-intensity projection image shows abrupt cutoff of the right interlobar pulmonary artery (arrow).

*

Fig. 51.8  CT angiographic signs of chronic thromboembolic disease: incomplete recanalization leading to focal stenoses. Multiplanar reformatted image of the left interlobar pulmonary artery shows two focal stenoses (arrows) with poststenotic dilatation (star).

recurrent pulmonary embolism instead of acute pulmonary embolism (50% vs. 7%).17 Pulmonary Hypertension.  Pulmonary hypertension can be suspected on the basis of the dilatation of the main pulmonary artery (upper limit of normal, 2.8–3.2 cm). Its diameter can be compared with that of the ascending aorta and is suggestive of pulmonary hypertension when the ratio of the pulmonary artery diameter to the ascending aorta diameter is equal to or greater

Fig. 51.9  Systemic collateral supply in a patient with chronic pulmonary thromboembolism. Axial CT scan shows a large eccentric filling defect in the pulmonary trunk and left pulmonary arteries. Dilated bronchial arteries (arrows) represent collateral circulation to the left lung. (Reproduced with permission from Walker CM, Rosado-de-Christenson ML, Martínez-Jiménez S, et al. Bronchial arteries: anatomy, function, hypertrophy, and anomalies. Radiographics. 2015;35:32–49.)

than 1. The diameters of the right and left pulmonary arteries are also increased (upper limit of normal, 1.6 cm). Arterial dilatation and subsequent changes in lung attenuation on CT scans are unevenly distributed, an important criterion for differential diagnosis between chronic thromboembolic

638

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

pulmonary hypertension and pulmonary hypertension of other causes. The marked variation in the diameter of segmental vessels reported by Bergin and colleagues18 probably reflects the irregular distribution of emboli and subsequent sequelae within the lungs. Systemic Collateral Supply.  CTA allows assessment of the systemic collateral supply frequently seen in patients with chronic pulmonary thromboembolism.19 Bronchial dilation in patients with chronic pulmonary thromboembolism resembles that seen in chronic bronchial disease. The CT findings of bronchial artery hypervascularization consist of abnormal dilatation of the proximal portions of bronchial arteries (i.e., a diameter >1.5 mm) and arterial tortuosity. In chronic pulmonary thromboembolism, the bronchial circulation is considerably increased because of the development of systemic to pulmonary arterial anastomoses. These anastomoses occur beyond the level of arterial obstruction and help maintain pulmonary blood flow (see Fig. 51.9). Systemic perfusion of the peripheral pulmonary arterial bed accounts for areas of ground-glass opacity in patients with chronic pulmonary thromboembolic disease.20 It is likely that subpleural septal lines sometimes identified in these patients reflect the presence of dilated bronchial arteries or other collaterals within interlobular septa. Development of bronchial hypervascularization is also responsible for recurrent or massive hemoptysis.21 In this specific context, CTA of the bronchial arteries may help identify their ostia before a therapeutic embolization procedure. Nonbronchial systemic arteries may also be involved in the collateral systemic supply in chronic thromboembolic disease. Their detection on CTA can help distinguish chronic thromboembolic from primary pulmonary hypertension.22 This systemic to pulmonary collateral shunt has been estimated to represent approximately 30% of the systemic blood flow by studies using a contrast medium dilution method23 and MRI.24 Cardiac Signs.  Over time, right ventricular function deteriorates, even in the absence of recurrent embolism, presumably because of the development of hypertensive vascular abnormalities in the unobstructed pulmonary artery bed. The main signs suggestive of right ventricular dysfunction include right ventricular enlargement, reflux of contrast into dilated hepatic veins and the inferior vena cava, and straightening or leftward bowing of the interventricular septum (Fig. 51.10).25 Parenchymal Signs of Chronic Pulmonary Thromboembolism Mosaic Attenuation.  Mosaic attenuation can be recognized on CT scans as sharply demarcated regions of variable attenuation in the lung parenchyma that predominantly conform to the boundaries of secondary pulmonary lobules, without evidence of destruction or displacement of pulmonary vessels and with obvious disparity in the size of pulmonary vessels compared with areas of decreased attenuation (Fig. 51.11).26,27 As demonstrated by Sherrick and colleagues,27 the mosaic pattern of lung attenuation is more frequently seen in patients with pulmonary hypertension caused by cardiac or pulmonary disease. Prior studies have shown that the areas of low attenuation within the lung parenchyma are due to hypoperfusion,28 which explains the concurrent presence of fewer and smaller vessels within these areas. Regions of increased attenuation are due to the redistribution of blood flow in the patent arterial bed, which is subsequently dilated. A potential limitation in the sensitivity of CT scans for depicting areas of hypoperfusion may be collateral blood flow established from the bronchial circulation, which can be abundant in chronic thromboembolism.

Fig. 51.10  CT features of right ventricular dysfunction in chronic pulmonary thromboembolic disease. Axial CT scan obtained at the level of the ventricles shows right ventricular enlargement and leftward displacement of the interventricular septum (arrows). Note the abnormal thickening of the right ventricular myocardium (arrowhead), suggestive of longstanding pulmonary hypertension.

Parenchymal Scarring.  A common but nonspecific finding is the presence of wedge-shaped peripheral parenchymal areas of high attenuation with their tips pointing to the perihilar area, which are often multiple and favor the lower lung zones.29 These areas do not enhance after administration of contrast material and likely represent fibrosis from pulmonary infarctions. They have been reported to occur in 10% to 15% of the thromboembolic events. Miscellaneous Signs In patients with chronic thromboembolic pulmonary hypertension, enlarged hilar lymph nodes can be seen, which is related to vascular transformation of the lymph node sinuses. An accurate knowledge of the position of hilar lymph nodes in relation to the major pulmonary arteries is essential to differentiate hilar lymphadenopathy from mural thrombi.30 The presence of bronchial dilatation in patients without clinical and functional evidence of chronic obstructive lung disease raises the hypothesis that chronic pulmonary thromboembolism may directly affect airways. In a study of 33 patients with chronic pulmonary thromboembolic disease, Remy-Jardin and colleagues31 reported cylindric bronchial dilatation in 64% of patients (Fig. 51.12). The dilatation was observed at the level of segmental and subsegmental bronchi and was associated with severely stenosed arterial branches. MAGNETIC RESONANCE IMAGING The implementation of high-performance gradient systems decisively improved the quality of contrast-enhanced MR angiography. Hemodynamic parameters of the right ventricle

51  Chronic Pulmonary Thromboembolism

639

Fig. 51.11  Mosaic attenuation. Axial CT image obtained at the level of the carina shows enlarged vessels within areas of increased attenuation. Decreased vessel diameters and lower attenuation are found in the remaining portions of both lungs.

stage of the disease when echocardiography is performed, it may demonstrate variable degrees of right atrial and right ventricular enlargement, abnormal right ventricular systolic function, tricuspid regurgitation, leftward displacement of the interventricular septum, decreased left ventricular size, and abnormal left ventricular systolic and diastolic function.33 Contrast echocardiography may also demonstrate a patent foramen ovale. NUCLEAR MEDICINE

Fig. 51.12  Bronchial dilatation in chronic pulmonary thromboembolism. Axial CT image at the level of the right inferior pulmonary vein shows marked reduction in size of all pulmonary arterial branches in the left lower lobe consistent with chronic pulmonary thromboembolism. Note mild dilatation of the accompanying bronchi (arrows).

and blood flow velocities in the pulmonary arteries can also be assessed with MRI. This combination makes it a promising complementary tool to CT in the preoperative workup of chronic thromboembolic pulmonary hypertension.32 ULTRASONOGRAPHY Transthoracic echocardiography is the initial method of choice for the diagnosis of pulmonary hypertension. Depending on the

VQ scintigraphy remains an important modality for the evaluation of chronic thromboembolic disease. Compared with conventional catheter pulmonary angiography, VQ has a sensitivity, specificity, and accuracy of up to 100%, 93.7%, and 96.5%, respectively.34 In chronic thromboembolic disease, at least one or, more commonly, several segmental or larger mismatched perfusion defects are present on scintigraphy.35 The perfusion defects in chronic thromboembolic disease are often qualitatively different from those encountered in acute disease. Rather than demonstrating a complete absence of perfusion, the scan often is characterized by areas of diminished activity that are the consequence of different resistances and therefore different relative flows within the branches of the pulmonary vascular bed. VQ scan abnormalities often understate, in certain cases to a remarkable degree, the actual extent of vascular obstruction. IMAGING ALGORITHMS Diagnosis and Treatment of Chronic Thromboembolic Pulmonary Hypertension Modalities of Diagnosis.  VQ scintigraphy has a high sensitivity and specificity for detection of chronic thromboembolic disease and is still used as a first-line imaging modality at some institutions.36,37 However, CTA has become a popular technique in the evaluation of suspected CTEPH and also has very high

640

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

accuracy.20,29,38 CTA has the advantage of depicting the location and morphology of emboli, which is important for treatment planning. CTA also accurately depicts peripheral emboli and completely occlusive clots. Reformatted images are mandatory for the detection of mild arterial stenoses and small concentric thrombi that are adherent to the arterial wall or located tangentially at the bottom or the roof of a vessel. Selection of Surgical Candidates The goals of pulmonary endarterectomy are to decrease the extent of pulmonary vascular obstruction, leading to a reduction in pulmonary artery pressure and therefore improved cardiac function. After assessment of hemodynamic dysfunction, the second and most absolute criterion for potential surgical intervention is the accessibility of thrombi.39 Present surgical techniques allow removal of chronic thrombi for which the proximal location extends to the main, lobar, and segmental arteries. Those that begin more distally are not accessible to endarterectomy, which explains why this determination is critical. Several studies have demonstrated that the surgical accessibility of chronic clots is accurately depicted by CTA, which can detect residual thromboembolic material incorporated concentrically in vessel walls.20,29,38,40

Differential Diagnosis The differential diagnosis of vascular features of chronic pulmonary thromboembolism is listed in Box 51.2.

Synopsis of Treatment Options Treatments for CTEPH include surgical therapy with thromboendarterectomy, balloon angioplasty of the pulmonary arteries, and medical therapy. Although thromboendarterectomy is the only potentially curative approach, patients with a peripheral distribution of emboli and extensive arterial remodeling may not benefit from surgery or angioplasty. Medical therapy consists of any of a variety of drugs that have effects on endothelial function, such as sildenafil, bosentan, epoprostenol, and the newer riociguat.41 At experienced centers, the performance of pulmonary thromboendarterectomy in patients with CTEPH can restore normal or nearly normal pulmonary hemodynamics, even in the presence of severe pulmonary hypertension or right-sided heart failure. The risk of recurrence is low because patients generally have preoperative placement of an inferior vena cava filter and are treated indefinitely with oral anticoagulants once surgery has been performed.42 At centers with experience in performing thromboendarterectomy, a mortality rate of less than 5% has been quoted, which is a remarkable achievement when one considers the severity of cardiopulmonary disease and the hemodynamic fragility of these patients. The major cause of death, other than reperfusion pulmonary edema, after pulmonary thromboendarterectomy is persistent postoperative pulmonary hypertension and right ventricular failure in patients for whom pulmonary thromboendarterectomy failed to result in a substantial improvement in pulmonary hemodynamics. This latter group includes patients whose disease involves a substantial component of distal, surgically inaccessible embolic obstruction and patients who have developed severe secondary pulmonary hypertensive changes in their distal pulmonary bed. The ability to identify the central and peripheral component of the disease could help identify that cohort of

BOX 51.2  DIFFERENTIAL DIAGNOSIS OF VASCULAR FEATURES OF CHRONIC THROMBOEMBOLIC DISEASE • Congenital pulmonary artery stenosis • Usually diagnosed in children (vs. diagnosis of chronic thromboembolic disease in adults) • Isolated proximal arterial stenoses versus proximal arterial stenosis associated with mural thrombi and mural and luminal calcifications without poststenotic dilatation in chronic thromboembolic disease • Fibrosing mediastinitis • Partially calcified soft tissue causing narrowing of adjacent pulmonary arteries • Presence of mediastinal lymphadenopathy • Clinical context with history of histoplasmosis, tuberculosis, and other endemic granulomatous diseases. Sarcoidosis can occasionally cause a similar appearance. • Takayasu arteritis • High-attenuation wall thickening • Delayed enhancement after contrast administration (after 1 or 2 minutes) • Smooth tapering of the pulmonary artery without intraluminal thrombus • Systemic arteritis (involvement of the aortic and supraaortic branch vessel walls) • Neurofibromatosis • Severe intimal fibrosis • Responsible for multiple bilateral filling defects on CT scans • Specific clinical context • Pulmonary artery sarcoma • Isolated proximal filling defects, sometimes bilateral • Mass usually extends outside of the vessel lumen • Delayed enhancement after contrast material administration (after 2 or 3 minutes) • Proximal interruption of the pulmonary artery • Abrupt tapering of the pulmonary artery without endoluminal or periluminal changes • Occurs opposite the aortic arch • Acute thromboembolism • Partial or complete filling defects • Smooth margins • Vessel expansion • Absence of any other typical vascular features of chronic thromboembolism • Anatomically and technically related pitfalls • Partial volume effect on obliquely oriented vessels misinterpreted as abrupt narrowing • Hilar lymph nodes misinterpreted as mural thrombi

patients with chronic thromboembolic disease in whom thromboendarterectomy is not indicated, as well as those who might potentially benefit from a combined therapeutic approach— thromboendarterectomy to manage the central component of the disease followed by aggressive medical intervention to manage the distal component.12 In patients with established distal arteriopathy deemed unsuitable for surgical intervention, medical treatment of pulmonary hypertension may offer an option by which to delay the progression of the disease.43,44 KEY POINTS • The diagnosis of chronic pulmonary thromboembolism should be considered in all patients who have unexplained dyspnea. • CT is helpful in determining whether there is surgically treatable disease by demonstrating chronic pulmonary thromboembolism in the main, lobar, and segmental arteries. • Newer medications now allow treatment of chronic pulmonary thromboembolism involving the pulmonary arteries beyond the segmental level.

51  Chronic Pulmonary Thromboembolism

SUGGESTED READINGS Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med. 2001;345:1465–1472. Jamieson SW, Kapelanski DP, Sakakibara N, et al. Pulmonary endarterectomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg. 2003;76(5):1457–1462, discussion 1462–1464. Renapurkar RD, Shrikanthan S, Heresi GA, et al. Imaging in chronic thromboembolic pulmonary hypertension. J Thorac Imaging. 2017;32(2):71–88.

641

Rich S, McLaughlin VV. Chronic thromboembolic pulmonary hypertension. Clin Chest Med. 2001;22:561–581.

The full reference list for this chapter is available at ExpertConsult.com.

51  Chronic Pulmonary Thromboembolism 641.e1

REFERENCES 1. Paraskos JA, Aldestein SJ, Smith RE, et al. Late prognosis of acute pulmonary embolism. N Engl J Med. 1973;289:55–58. 2. Hall RJ, Sutton GC, Kerr IH. Long-term prognosis of treated acute massive pulmonary embolism. Br Heart J. 1977;39:1128–1134. 3. Sutton GC, Hall RJ, Kerr IH. Clinical course and late prognosis of treated subacute massive, acute minor, and chronic pulmonary thromboembolism. Br Heart J. 1977;39:1135–1142. 4. Remy-Jardin M, Louvegny S, Remy J, et al. Acute central thromboembolic disease: posttherapeutic follow-up with spiral CT angiography. Radiology. 1997;203:173–180. 5. Moser KM, Auger WR, Fedullo PF. Chronic major-vessel thromboembolic pulmonary hypertension. Circulation. 1990;81:1735–1743. 6. Stein PD, Terrin ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest. 1991;100:598–603. 7. Renapurkar RD, Shrikanthan S, Heresi GA, et al. Imaging in chronic thromboembolic pulmonary hypertension. J Thorac Imaging. 2017;32(2): 71–88. 8. Corrin B. Vascular diseases. Embolism and infarction. In: Corrin B, ed. Pathology of the Lungs. London: Churchill Livingstone; 2000:361–375. 9. Wagenvoort CA. Hypertension and flow-states. In: Dail DH, Hammar SP, eds. Pulmonary Pathology. New York: Springer-Verlag; 1988:691–710. 10. Corrin B. Vascular diseases. Pulmonary hypertension. In: Corrin B, ed. Pathology of the Lungs. London: Churchill Livingstone; 2000:377–410. 11. Dalen JE, Alpert JS. Natural history of pulmonary embolism. Prog Cardiovasc Dis. 1975;17:259–270. 12. Fedullo PF, Rubin LJ, Auger WR, Channick RN. The natural history of acute and chronic thromboembolic disease: the search for the missing link. Eur Respir J. 2000;15:435–437. 13. Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest. 1993;103:685–692. 14. Kim H, Yung GL, Marsh JJ, et al. Pulmonary vascular remodeling distal to pulmonary artery ligation is accompanied by upregulation of endothelin receptors and nitric oxide synthase. Exp Lung Res. 2000;26:287–301. 15. Rich S, McLaughlin VV. Chronic thromboembolic pulmonary hypertension. Clin Chest Med. 2001;22:561–581. 16. Wittram C, Maher MM, Halpern EF, Shepard JAO. Attenuation of acute and chronic pulmonary emboli. Radiology. 2005;235:1050–1054. 17. Hasegawa I, Boiselle PM, Hatabu H. Bronchial artery dilatation on MDCT scans of patients with acute pulmonary embolism: comparison with chronic or recurrent pulmonary embolism. AJR Am J Roentgenol. 2004;182:67–72. 18. Bergin CJ, Hauschildt JP, Brown MA, et al. Identifying the cause of unilateral hypoperfusion in patients suspected to have chronic pulmonary thromboembolism: diagnostic accuracy of helical CT and conventional angiography. Radiology. 1999;213:743–749. 19. Kauczor HU, Schwickert HC, Meyer E, et al. Spiral CT of bronchial arteries in chronic thromboembolism. J Comput Assist Tomogr. 1994;18:855–861. 20. Tardivon AA, Musset D, Maitre S, et al. Role of CT in chronic pulmonary embolism: comparison with pulmonary angiography. J Comput Assist Tomogr. 1993;17:345–351. 21. Thomas CS, Endrys J, Abul A, Cherian G. Late massive haemoptysis from bronchopulmonary collaterals in infarcted segments following pulmonary embolism. Eur Respir J. 1999;13:463–464. 22. Remy-Jardin M, Duhamel A, Deken V, et al. Systemic collateral supply in patients with chronic thromboembolic and primary pulmonary hypertension: assessment with multidetector-row helical CT angiography. Radiology. 2005;235:274–281.

23. Endrys J, Hayat N, Cherian G. Comparison of bronchopulmonary collaterals and collateral blood flow in patients with chronic thromboembolic and primary pulmonary hypertension. Heart. 1997;78:171–176. 24. Ley S, Kreitner KF, Morgenstern I, et al. Bronchopulmonary shunts in patients with chronic thromboembolic pulmonary hypertension: evaluation with helical CT and MR imaging. AJR Am J Roentgenol. 2002;179:1209–1215. 25. Reid JH, Murchison JT. Acute right ventricular dilatation: a new helical CT sign of massive pulmonary embolism. Clin Radiol. 1998;53:694–698. 26. Bergin CJ, Rios G, King MA, et al. Accuracy of high-resolution CT in identifying chronic pulmonary thromboembolic disease. AJR Am J Roentgenol. 1996;166:1371–1377. 27. Sherrick AD, Swensen SJ, Harman TE. Mosaic pattern of lung attenuation on CT scans: frequency among patients with pulmonary artery hypertension of different causes. AJR Am J Roentgenol. 1997;169:79–82. 28. King MA, Bergin CJ, Yeung DWC, et al. Chronic pulmonary thromboembolism: detection of regional hypoperfusion with CT. Radiology. 1994;191:359–363. 29. Schwickert HC, Schweden F, Schild HH, et al. Pulmonary arteries and lung parenchyma in chronic pulmonary embolism: preoperative and postoperative CT findings. Radiology. 1994;191:351–357. 30. Remy-Jardin M, Duyck P, Remy J, et al. Hilar lymph nodes: identification with spiral CT and histologic correlation. Radiology. 1995;196:387–394. 31. Remy-Jardin M, Remy J, Louvegny S, et al. Airway changes in chronic pulmonary embolism. Radiology. 1997;203:355–360. 32. Ley S, Kauczor HU, Heussel CP, et al. Value of contrast-enhanced MR angiography and helical CT angiography in chronic thromboembolic pulmonary hypertension. Eur Radiol. 2003;13:2365–2371. 33. Menzel T, Wagner S, Kramm T, et al. Pathophysiology of impaired right and left ventricular function in chronic embolic pulmonary hypertension: changes after thromboendarterectomy. Chest. 2000;118:897–903. 34. He J, Fang W, Lv B, et al. Diagnosis of chronic thromboembolic pulmonary hypertension: comparison of ventilation/perfusion scanning and multidetector computed tomography pulmonary angiography with pulmonary angiography. Nucl Med Commun. 2012;33(5):459–463. 35. D’Alonzo GE, Bower JS, Dantzker DR. Differentiation of patients with primary and thromboembolic pulmonary hypertension. Chest. 1984;85:457–461. 36. He J, Fang W, Lv B, et al. Diagnosis of chronic thromboembolic pulmonary hypertension: comparison of ventilation/perfusion scanning and multidetector computed tomography pulmonary angiography with pulmonary angiography. Nucl Med Commun. 2012;33(5):459–463. 37. Renapurkar RD, Shrikanthan S, Heresi GA, et al. Imaging in chronic thromboembolic pulmonary hypertension. J Thorac Imaging. 2017;32(2):71–88. 38. Bergin CJ, Sirlin CB, Hauschildt JP, et al. Chronic thromboembolism: diagnosis with helical CT and MR imaging with angiographic and surgical correlation. Radiology. 1997;204:695–702. 39. Fedullo PF, Auger WR, Channick RN, et al. Chronic thromboembolic pulmonary hypertension. Clin Chest Med. 1995;16:353–374. 40. Bergin CJ, Sirlin C, Deutsch R, et al. Predictors of patient response to pulmonary thromboendarterectomy. AJR Am J Roentgenol. 2000;174:509–515. 41. Ghofrani HA, Humbert M, Langleben D, et al. Riociguat: mode of action and clinical development in pulmonary hypertension. Chest. 2017;151(2): 468–480. 42. Kerr KM, Rubin LJ. Epoprostenol therapy as a bridge to pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension. Chest. 2003;123:319–320. 43. Hoeper MM, Kramm T, Wilkens H, et al. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest. 2005;128:2363–2367. 44. Ghofrani HA, Schermuly RT, Rose F, et al. Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med. 2003;167:1139–1141.

52 

Nonthrombotic Pulmonary Embolism* CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

Fat Embolism Etiology, Prevalence, and Epidemiology The term fat embolism refers to the presence of globules of free fat within the pulmonary vasculature. Fat embolism is common among trauma patients, especially those with long bone or pelvic fractures.1 In the context of trauma, fat embolism is also common after extensive injury to subcutaneous fat, such as occurs in severe beatings or liposuction.1 Fat embolism must be differentiated from fat embolism syndrome, which is defined by the presence of clinical signs and symptoms resulting from fat emboli.1 The clinical manifestations of fat embolism syndrome consist of the triad of hypoxia (95%), confusion (60%), and petechial rash (33%). Unfortunately, the classic triad is rarely present, and the clinical manifestations of fat embolism syndrome range from an indolent course to fulminant respiratory failure.2 The incidence of clinically significant disease in patients who have simple tibial or femoral fractures is generally believed to be about 1% to 3%.3 In individuals who have more severe trauma, the incidence of clinically evident embolism is probably in the range of 10% to 20%.3,4 Less common causes of fat embolism include severe beatings (embolism of subcutaneous fat), orthopedic procedures (e.g., intramedullary prosthesis insertion, arthroplasty), liposuction, severe pancreatitis, sickle cell disease, hematopoietic stem cell (bone marrow) transplantation and harvesting, and venous hyperalimentation.1,2,5

Clinical Presentation The symptoms of fat embolism syndrome usually appear gradually; dyspnea, neurologic symptoms, fever, and petechial rash typically develop 12 to 36 hours after injury.3,6 The delay in the development of clinical symptoms is presumably due to the time required for hydrolysis of neutral fat to toxic free fatty acids.6 Cough, hemoptysis, and pleuritic chest pain occur occasionally. Signs include pyrexia, tachypnea, and tachycardia. Acute cor pulmonale with cardiac failure, cyanosis, and circulatory shock may occur. Symptoms of systemic fat embolism are seen in up to 85% of patients who have pulmonary disease.3 The symptoms are mainly related to the central nervous system and include confusion, restlessness, stupor, delirium, seizures, and coma. A petechial rash often develops 2 to 3 days after embolization, particularly along the anterior axillary folds and in the conjunctiva and retina.

*The editors and the publisher would like to thank Drs. Nestor L. Müller and C. Isabela Silva Müller for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

642

Pathophysiology Two pathogenetic mechanisms have been implicated in the development of pulmonary abnormalities after fat embolism.7 The first is mechanical vascular obstruction, predominantly by fat globules themselves and possibly enhanced in some cases by platelet or red blood cell aggregates. A second potential mechanism involves conversion of neutral triglycerides, the form in which fat appears to be transported to the lungs, into free fatty acids by endothelial lipases. On histologic examination, the presence of fat within pulmonary arterioles and capillaries can be suspected on hematoxylin and eosin–stained sections when there are round to oval spaces, 20 to 40 µm in diameter, apparently compressing red blood cells to one side. Definitive histologic diagnosis requires the use of fat-soluble dyes on unfixed (frozen) tissue or other special techniques.7

Manifestations of the Disease RADIOGRAPHY The radiographic findings may be subtle and consist of bilateral hazy areas of increased opacity (ground-glass opacities) or patchy consolidation (Fig. 52.1). In more severe cases, widespread consolidation resembles the radiographic appearance of acute respiratory distress syndrome from any cause.8 In one review of 22 patients with fat embolism syndrome, 2 had normal chest radiographs throughout hospitalization, and 20 developed pulmonary abnormalities.9 In all cases the radiographic findings consisted of bilateral areas of consolidation consistent with diffuse pulmonary edema. The time to appearance of evident radiographic lung injury was within 24 hours of initial trauma in 50% of cases, between 24 and 48 hours in 20%, and more than 48 hours in 30%. Of the patients with abnormal radiographs, 10 of 20 (50%) had complete resolution of the edema pattern within 1 week of development of opacities and 30% within 1 to 4 weeks; 20% died without resolution of the radiographic findings.9 Pleural effusions are typically absent. COMPUTED TOMOGRAPHY The computed tomography (CT) findings of fat embolism syndrome include bilateral patchy or diffuse ground-glass opacities, patchy or confluent areas of consolidation, and poorly defined centrilobular nodules measuring less than 10 mm in diameter (Fig. 52.2; see also Fig. 52.1).10–13 CT may demonstrate parenchymal abnormalities in patients with normal chest radiographs. In an investigation of 9 patients with fat embolism syndrome who had normal radiographs, all were found to have abnormalities on high-resolution CT; 7 had ground-glass opacities, and 2 had small nodular opacities.14 A CT review of 18 patients with fat embolism syndrome demonstrated consolidation with a dependent distribution (see Fig. 52.2) and

52  Nonthrombotic Pulmonary Embolism

643

Fig. 52.2  Fat embolism after hip arthroplasty: CT findings. Axial CT demonstrates extensive bilateral consolidation, ground-glass opacities, lobular sparing, and a few poorly defined centrilobular nodules (arrows). The consolidation and ground-glass opacities have a dependent distribution.

A

opacities are uncommon but have been reported. Intraarterial fat is usually not seen, but the pulmonary trunk is often dilated (size >29 mm). Rarely, there are reports of patients developing pulmonary fibrosis months after fat embolization.12

Differential Diagnosis

B Fig. 52.1  Mild fat embolism after motor vehicle accident: radiographic and CT findings. (A) Anteroposterior chest radiograph 2 days after motor vehicle collision shows peripheral predominant consolidation. (B) Axial CT demonstrates patchy bilateral ground-glass opacities with well-defined lobular sparing.

patchy or peripheral predominant ground-glass opacities in the majority of patients. There was often lobular sparing with sharp margination between areas of involved and noninvolved lung that is thought to be secondary to variations in perfusion at time of embolization (see Fig. 52.1).12 Less common manifestations included lobular ground-glass opacities or consolidation, smooth septal thickening, bronchial wall thickening, and a crazy paving pattern.13 The degree and extent of consolidation and ground-glass opacities correlate well with disease severity.12 Centrilobular and subpleural nodules are usually seen in association with ground-glass opacities but may be the predominant or only abnormality evident on high-resolution CT in patients with fat embolism.14,15 The nodular opacities tend to be located in the centrilobular regions, along the interlobular septa, and along the interlobar fissures. Tree-in-bud

The time lapse between trauma and radiographic signs of fat embolism is usually 12 to 36 hours.3,6,16 This delay differentiates fat embolism from traumatic lung contusion, in which the radiographic opacity invariably appears immediately after injury. In addition, although the lung contusion usually clears rapidly (in about 24 hours), resolution of fat embolism generally takes 7 to 10 days and occasionally as long as 4 weeks. Further differentiation lies in the extent of lung involvement; contusion seldom affects both lungs diffusely and symmetrically. Several tests have been evaluated to identify fat embolism, but none of these is specific for the diagnosis.6 Thrombocytopenia is frequently present and may be associated with disseminated intravascular coagulation (DIC). Hypocalcemia may develop because of the affinity of calcium ions for free fatty acids released by the hydrolysis of embolized fat.17 Lipiduria is relatively common, and hematuria and proteinuria are seen occasionally.3 The diagnosis can be difficult to make, partly because of the relative nonspecificity of signs and symptoms and partly because clinical abnormalities may be related more directly to the cause of the emboli (e.g., trauma-associated shock). Some investigators have advocated the use of bronchoalveolar lavage and analysis of harvested macrophages for the presence of fat.18 However, patients who do not have fat embolism syndrome may also have lipid-laden macrophages in their bronchoalveolar lavage fluid, and the definitive diagnostic threshold is unclear; some investigators propose a value as low as 5% and others a value as high as 30%.18

Synopsis of Treatment Options There is no specific treatment available for fat embolism syndrome.19 The mainstay of treatment is therefore supportive. Prophylactic corticosteroids (methylprednisolone) and heparin

644

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

may have beneficial effects, but their utility is controversial.2,19 The outcome in patients who receive supportive care is generally favorable; the mortality is less than 10%.19 KEY POINTS: FAT EMBOLISM • Common causes are severe trauma and long bone and pelvic fractures. • Typical symptoms include dyspnea, confusion, and petechial rash, which develop 12 to 36 hours after injury. • Radiographic findings consist of bilateral ground-glass opacities or consolidation. • CT findings include patchy or diffuse ground-glass opacities, patchy or confluent areas of consolidation, lobular sparing, and poorly defined centrilobular nodules. • As distinct from lung contusion, radiographic findings of fat embolism are not present immediately after the injury.

cases of uterine rupture, placenta previa, or cesarean section when the incision involves the site.7 The pathophysiologic consequences of intravascular amniotic fluid are complex and probably related to several processes. These include pulmonary vascular obstruction by amniotic fluid particulates, such as meconium; left ventricular dysfunction, possibly as a result of ischemia secondary to pulmonary hypertension and right ventricular dysfunction; pulmonary edema, related to the left ventricular dysfunction just described or to damage to the vascular endothelium by some constituent of amniotic fluid; and an immunologic reaction pathogenetically similar to anaphylaxis.22 The main histologic abnormality is the presence of squames, mucin, and bile derived from meconium within small pulmonary vessels.7

Manifestations of the Disease Amniotic Fluid Embolism Etiology, Prevalence, and Epidemiology Amniotic fluid embolism is a rare but severe complication of pregnancy. In a population-based cohort of 3 million hospital deliveries in Canada between 1991 and 2002, the total rate of amniotic fluid embolism was 14.8 per 100,000 multiple-birth deliveries and 6.0 per 100,000 singleton deliveries.20 Of the 180 cases of amniotic fluid embolism in women with singleton deliveries during the study period, 24 (13%) were fatal. Medical induction of labor nearly doubled the overall cases of amniotic fluid embolism, and the association was stronger for fatal cases. Maternal age of 35 years or older, cesarean or instrumented vaginal delivery, polyhydramnios, cervical laceration or uterine rupture, placenta previa or abruption, eclampsia, and fetal distress were also associated with an increased risk.20

Clinical Presentation The majority of patients are in the 35th to 42nd week of pregnancy at the time of embolization. The clinical manifestations are typically abrupt, with sudden onset of cardiovascular collapse, cyanosis, and hemorrhage or DIC.21 In less severe cases the initial manifestation is progressive dyspnea.22 Although these abnormalities begin during spontaneous labor in most patients, they occur after delivery in about 30% (10% spontaneous and 20% after cesarean section).23 The majority of patients experience seizures.

Pathophysiology It is likely that little if any amniotic fluid enters the maternal circulation during normal labor and that significant embolism occurs only when there is disruption of the uterine wall in association with rupture of the placental membranes.24 Such disruption can occur at several sites, the most common probably being the endocervix or lower uterine segment. Traumatic tears in the small veins in these regions can occur during normal labor but are of no significance if they are covered by fetal membranes; however, if such veins have separated from the fetal membranes, uterine contractions can “pump” amniotic fluid into the maternal venous circulation.7 Amniotic fluid can also enter the maternal circulation at the placental site, usually in

RADIOGRAPHY AND COMPUTED TOMOGRAPHY The principal radiographic finding is bilateral airspace consolidation with or without pleural effusions, which is indistinguishable from acute pulmonary edema of other causes (Fig. 52.3).25 Whether cardiac enlargement accompanies the edema depends on the severity of pulmonary hypertension and consequent cor pulmonale with or without left ventricular failure. The consolidation may persist or resolve within a few days.25

Differential Diagnosis The diagnosis of amniotic fluid embolism is based on the rapid development of a complex constellation of findings with sudden cardiovascular collapse: acute left ventricular failure with pulmonary edema, DIC, and neurologic impairment. Because the predominant radiographic manifestation is widespread airspace consolidation, the main differential diagnoses are massive pulmonary hemorrhage and aspiration of liquid gastric contents. The diagnosis of amniotic fluid embolism should be considered, particularly in patients with risk factors such as medical induction of labor and placenta previa or abruption; it is supported by identification of squames, mucin, or hair fragments in samples of pulmonary capillary blood aspirated through a pulmonary arterial catheter.26

Synopsis of Treatment Options There are no specific pharmacologic or other therapies that prevent or treat the amniotic fluid embolism syndrome.27 The treatment is therefore supportive and involves aggressive management of multiple types of shock simultaneously.27 The mortality rate of clinically recognized cases remains high at 19% in a recent study and up to 61% in older cohort studies; 25% to 50% of patients die within the first hour of the disease and most of the rest within 12 hours.23,28 Serious neurologic sequelae are common in survivors.23

Tumor Embolism Etiology, Prevalence, and Epidemiology Hematogenous pulmonary metastases are derived from tumor fragments lodged within pulmonary vessels. In most cases these

52  Nonthrombotic Pulmonary Embolism

645

tumor fragments are small and therefore do not result in clinically or radiologically apparent vascular obstruction. However, when tumor emboli are of sufficient size or number, the clinical, pathologic, and radiographic manifestations can be identical to those of pulmonary thromboembolism. The manifestations can include pulmonary infarction, acute cor pulmonale and sudden death, and a slowly progressive syndrome of dyspnea and pulmonary hypertension.29 Tumor embolism is seen most commonly in metastatic renal cell carcinoma, hepatocellular carcinoma, carcinoma of the breast, carcinoma of the stomach, and carcinoma of the prostate.29,30 Tumor embolism may be more frequent after interventions that increase the fragmentation of the tumor mass, such as surgery, radiation therapy, or chemotherapy.31

Manifestations of the Disease RADIOGRAPHY Intravascular tumor emboli are seldom recognized on the chest radiograph. A

COMPUTED TOMOGRAPHY AND NUCLEAR MEDICINE Tumor emboli may be seen as filling defects in the central pulmonary arteries (Fig. 52.4), as nodular or beaded thickening of the peripheral pulmonary arteries, or as nodular and branching centrilobular opacities (tree-in-bud pattern) representing enlarged centrilobular arteries (Fig. 52.5).30,32,33 In contrast to thromboembolic disease, tumor macroembolism is resistant to fibrinolytics and anticoagulation therapy.31 Occasionally, tumor microembolism and lymphangitic carcinomatosis may manifest on nuclear medicine perfusion scintigraphy with contour mapping of the pulmonary segments, whereby numerous small perfusion defects outline the bronchopulmonary segments (see Fig. 52.5).34

B Fig. 52.3  Amniotic fluid embolism. (A) Anteroposterior chest radiograph shows diffuse bilateral consolidation with endotracheal intubation. (B) Axial CT shows bilateral consolidation with ground-glass opacities as well as small pleural effusions. (From Bach AG, Restrepo CS, et al. Imaging of nonthrombotic pulmonary embolism: biological materials, nonbiological materials, and foreign bodies. Eur J Radiol. 2013;82:e120–e41.)

KEY POINTS: AMNIOTIC FLUID EMBOLISM • Amniotic fluid embolism occurs in 14.8 per 100,000 multiplebirth deliveries and 6.0 per 100,000 singleton deliveries and carries a substantial mortality rate. • Main risk factors are multiple-birth deliveries, medical induction of labor, cervical laceration, uterine rupture, placenta previa or abruption, and eclampsia. • Clinical presentation: dyspnea, cyanosis, sudden onset of cardiovascular collapse, hemorrhage, or disseminated intravascular coagulopathy. Symptoms usually begin during labor and before giving birth. • Radiologic manifestation: bilateral airspace consolidation that resembles pulmonary edema.

KEY POINTS: INTRAVASCULAR TUMOR EMBOLISM • Common primaries: renal cell carcinoma; hepatocellular carcinoma; carcinomas of the breast, stomach, and prostate • Seldom evident on the chest radiograph • Findings on CT: • Intravascular filling defects • Nodular or beaded thickening of the peripheral pulmonary arteries • Nodular and branching centrilobular opacities (tree-in-bud pattern)

Air Embolism Etiology, Prevalence, and Epidemiology Air emboli may have their origin in either the greater or the lesser circulation. In venous air embolism the air enters the systemic venous circulation and passes to the right side of the heart and then to the lungs; clinical and functional manifestations are therefore related to obstruction of the pulmonary circulation and affect predominantly the lungs. In systemic (arterial) air embolism air typically enters the pulmonary venous circulation and passes to the left side of the heart and then to the systemic

646

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

A

B Fig. 52.4  Intravascular metastases from renal cell carcinoma. Contrast-enhanced CT images at the level of the right interlobar (A) and lower lobe (B) pulmonary arteries demonstrate large intraluminal filling defects. The appearance is indistinguishable from pulmonary thromboembolism.

arteries; the effects are therefore manifested mainly in the heart, the spinal cord, and the brain. Venous air embolism is a frequent iatrogenic complication, occurring most commonly with surgery, insertion and maintenance of intravenous (IV) devices, diagnostic or therapeutic air injection (e.g., arthrography), and barotrauma caused by positive-pressure ventilation.7,35 Venous air embolism has been reported to occur in more than half of all cesarean sections.36 Small quantities of air can be found in the central veins in up to 23% of patients during contrast material administration for CT.37 Noniatrogenic air embolism sometimes occurs in scuba divers as a result of gas bubble formation in the blood, which is due to rapid reduction in the ambient pressure during a diver’s ascent.38 Systemic air embolism occurs when the wall of a vessel exposed to air is disrupted and the pressure of the air exceeds the pressure in the vessel. The most common cause is probably penetrating thoracic trauma, either iatrogenic or accidental.7 Other causes include open-heart surgery (residual air in pulmonary veins released into the circulation after cross-clamping is terminated), transthoracic needle biopsy, and thoracentesis.7 Embolism can also occur in several situations in which the thorax is intact. One of the most common is scuba diving, in which the pathogenesis may be related to poor ventilation of a bulla or cyst because of partial or complete obstruction of its feeding airway.39 Identical barotrauma of ascent can occur in airplane passengers.40 In both these situations, tissue disruption is related to the increase in air pressure in an enclosed space as a result of a decrease in ambient pressure. Systemic air embolization can also occur in a variety of situations in which there is underlying lung disease, such as severe asthma, and during assisted positive-pressure ventilation.41

Clinical Presentation The majority of patients with pulmonary air embolism are asymptomatic. Clinical symptoms include dyspnea and lightheadedness; chest pain occurs occasionally.7 Physical findings

include tachycardia, tachypnea, and systemic hypotension. Signs of pulmonary edema may also be evident. Migration of air into systemic vessels supplying the brain or heart may result in convulsions, coma, or chest pain.

Pathophysiology The effects of embolized air in the pulmonary circulation depend on its quantity and rate of entry. Rapid injection of a large amount of air may result in the formation of an air block in the outflow tract of the right ventricle that prevents pulmonary arterial blood flow.7 Smaller amounts, infused slowly, appear to exert an effect at the level of the distal pulmonary arteries and arterioles.7 Some of this effect is probably related to vascular obstruction by air bubbles themselves; however, reflex vasoconstriction and the formation of fibrin emboli as blood and air are whipped together in the right-sided heart chambers may also be important. The overall effect of these processes is a transient increase in pulmonary vascular resistance and arterial pressure.42 Both clinical and experimental observations indicate that pulmonary edema complicates some cases of pulmonary air embolism, probably as a result of increased microvascular permeability.43 Another cause of pulmonary air embolism is related to the air that reaches the pulmonary vasculature as part of the decompression syndrome. When a diver spends a prolonged period breathing gas at greater than atmospheric pressure, excess air dissolves in the blood and tissue fluids. With too rapid an ascent and return of partial pressures to lower values, air comes out of solution and forms small bubbles that can be carried in the systemic veins to the right side of the heart and pulmonary vasculature. Oxygen coming out of solution can be disposed of easily by metabolic consumption, but the inert nitrogen is much slower to be cleared. The bubbles cause lung microvascular damage and noncardiac pulmonary edema.7 This form of pulmonary decompression sickness, which has been called the chokes, is a

52  Nonthrombotic Pulmonary Embolism

A

C

B

Post

Rpo

Fig. 52.5  Intravascular metastases from renal cell carcinoma. Views of the right lung at the level of the tracheal carina (A) and bronchus intermedius (B) demonstrate nodular thickening of the pulmonary vessels and centrilobular nodular and branching opacities (tree-in-bud pattern; arrows). (C) Perfusion scintigraphy from a different patient with tumor microembolism and lymphangitic carcinomatosis shows contour mapping where small perfusion defects outline the bronchopulmonary segments. Rpo, Right posterior oblique. (Fig. 52.5C courtesy Daniel Applebaum, MD, University of Chicago, Chicago, IL.)

647

648

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

relatively uncommon form of decompression illness that is sometimes fatal.44

Manifestations of the Disease RADIOGRAPHY The principal sign of air embolism is the presence of gas in cardiac chambers or pulmonary or systemic vessels.35 In pulmonary air embolism the gas is present in the right-sided heart chambers and central pulmonary arteries; in systemic air embolism it can be identified in the left-sided heart chambers, aorta, or more peripheral branches of the systemic arterial tree, such as the neck, shoulder girdles, or upper part of the abdomen. Other manifestations of pulmonary air embolism include pulmonary edema, focal oligemia, enlarged central pulmonary arteries, and atelectasis.35 The radiographic findings associated with air embolism in a study of 31 scuba divers included pneumomediastinum (n = 8), subcutaneous air (n = 3), pneumopericardium (n = 2), and pneumothorax and pneumoperitoneum (n = 1 each).45

Synopsis of Treatment Options Treatment is largely supportive. Therapeutic interventions include mechanical measures, such as positioning and measures aimed at reducing bubble size, including placement in the left lateral decubitus position to prevent right ventricular outflow tract obstruction.31,47 Hyperbaric oxygen therapy is often helpful, particularly if it is started within 6 hours after venous or systemic air embolism.48 KEY POINTS: AIR EMBOLISM • Venous air embolism • Pathogenesis: air typically enters systemic veins and affects mainly the lungs • Common causes: surgery, intravenous (IV) devices • Symptoms: dyspnea, chest pain • Radiographic findings: air in pulmonary vessels; occasionally pulmonary edema • CT findings: small amount of venous air commonly seen during IV administration of contrast material • Systemic air embolism • Pathogenesis: air typically enters pulmonary veins and affects mainly the brain and heart • Common causes: penetrating thoracic trauma, scuba diving • Symptoms: chest pain, seizures, coma • Radiographic and CT findings: air in systemic vessels

COMPUTED TOMOGRAPHY Pulmonary air embolism is seen particularly well on CT (Fig. 52.6). In a study of 100 patients who received IV contrast material that was injected by hand and followed by a drip infusion, asymptomatic venous air embolism was documented in 23.37 The most common site was the pulmonary trunk. In another series of 677 patients who underwent contrast-enhanced CT, air emboli were detected in 79 (12%).46 They were located in the pulmonary trunk in 54 (8%), the superior vena cava in 12 (1.8%), the right ventricle in 10 (1.5%), the subclavian or brachiocephalic vein in 6 (0.9%), and the right atrium in 5 (0.7%).46 Seven patients (1%) had emboli at more than one site. Systemic air embolism is uncommon and is most commonly seen after penetrating or iatrogenic trauma. It manifests as air within the left-sided heart chambers, aorta, or systemic arteries (Fig. 52.7).

A

Embolism of Talc, Starch, and Cellulose (Intravenous Talcosis, Talc Granulomatosis, Cellulose Granulomatosis) Etiology, Prevalence, and Epidemiology Emboli of talc, starch, and cellulose are seen almost invariably in chronic IV drug users.49 In most instances the complication occurs with medications intended solely for oral use; pills are

B Fig. 52.6  Intravenous air embolism after administration of contrast material. Contrast-enhanced CT images at the level of the pulmonary trunk (A) and right ventricular outflow tract (B) demonstrate small amount of air in the pulmonary trunk (arrow in A) and right atrium (arrowhead in B).

52  Nonthrombotic Pulmonary Embolism

A

649

B Fig. 52.7  Systemic air embolism following right lung biopsy. Axial CT images at the level of the right pulmonary artery (A) and lung bases (B) shows air within the ascending aorta (arrow) and left ventricular apex (arrowhead). Note right pneumothorax, right middle lobe nodule, and peripheral reticulation with architectural distortion compatible with interstitial lung disease.

crushed in a spoon or bottle top, water is added, and the mixture is drawn into a syringe and injected. Oral medications misused in this way include amphetamines and closely related drugs, such as methylphenidate hydrochloride (Ritalin), methadone hydrochloride, hydromorphone hydrochloride (Dilaudid), propoxyphene (Darvon), and pentazocine (Talwin).7 All these medications have in common the addition of an insoluble filler to bind the medicinal particles together and to act as a lubricant to prevent the tablets from sticking to punches and dies during manufacture. The commonly used fillers are talc, cornstarch, and microcrystalline cellulose.

Clinical Presentation Most addicts are asymptomatic; granulomas are found incidentally at autopsy in those who die of other causes. Typically, symptoms develop only in heavy users and consist of slowly progressive dyspnea and, occasionally, persistent cough. Cor pulmonale may be evident as a result of extensive disease. As in silicosis, disease may progress, and disability may increase after cessation of exposure.49 Organized thrombi and scars are visible on the forearms of nearly all addicts who inject drugs intravenously. Glistening particles can be seen in the fundi and may be the earliest clue to the drug use.49

Pathophysiology When injected intravenously, the insoluble fillers contained in tablets meant for oral use become trapped within pulmonary arterioles and capillaries and cause vascular occlusion. In time the foreign particles migrate through the vessel wall and come to lie in the adjacent perivascular and parenchymal interstitial tissue, where they result in a foreign-body giant-cell reaction

and fibrosis.7 Chronic pulmonary hypertension typically develops at this stage if the quantity of foreign material is sufficient. On pathologic examination the lungs initially show variable numbers of more or less discrete parenchymal nodules measuring up to 1 mm in diameter. On histologic examination the small nodules consist of loosely formed granulomas containing large multinucleated giant cells.7 In long-standing disease, the nodules tend to become confluent, especially in the upper lobes, and produce large areas of consolidation resembling the progressive massive fibrosis seen in the pneumoconioses. Sections of the large foci of upper lobe consolidation seen in long-standing disease show sheets of multinucleated giant cells, usually not organized in discrete granulomas; a variable degree of fibrosis is also present. Talc is recognized as irregular, plate-like crystals that are strongly birefringent (Fig. 52.8).50 Panacinar emphysema, sometimes with bulla formation, is often evident.51 The pathogenesis of the emphysema is unclear.

Manifestations of the Disease RADIOGRAPHY The earliest radiologic manifestation of IV talcosis is the presence of widespread nodules ranging from barely visible to about 1 mm in diameter (Fig. 52.9). They are distinct and “pinpoint” in character, similar to alveolar microlithiasis. In the early stages the nodules are usually distributed diffusely and uniformly throughout the lungs.52 In more advanced disease the upper lobe nodules may coalesce to form an almost homogeneous opacity that resembles end-stage sarcoidosis or the progressive massive fibrosis of silicosis or coal workers’ pneumoconiosis, except for the frequent presence of an air bronchogram (Fig. 52.10).49 In the late stages of the disease, increasing disability

650

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

Fig. 52.8  Intravenous (IV) talcosis: histologic findings. Lung biopsy specimen from a patient with IV talcosis demonstrates irregular birefringent crystals characteristic of talc.

A and deteriorating function are associated with radiographic evidence of emphysema and bullae.49 In patients who inject crushed Ritalin tablets, the appearance mimics that of α1antitrypsin deficiency with basilar-predominant emphysema.53 COMPUTED TOMOGRAPHY The earliest high-resolution CT findings consist of widespread nodules ranging from barely visible to about 1 mm in diameter, a fine granular pattern, or ground-glass opacities (Fig. 52.11).52,54 The nodules of cellulose granulomatosis have been referred to as a vascular tree-in-bud pattern with nodules distributed diffusely throughout the lungs, differentiating them from the more common tree-in-bud opacities seen with infectious bronchiolitis or aspiration. The nodules are more easily characterized with the help of maximum-intensity projection images. An ancillary clue usually seen with this diagnosis is enlargement of the central pulmonary arteries, indicating coexistent pulmonary hypertension (Fig. 52.12). Over time, the nodules coalesce, resulting in dense foci of consolidation or masses with associated volume loss, superior retraction of the hila, and overinflation of the remaining lung, characteristic of progressive massive fibrosis. These conglomerate areas of fibrosis typically contain foci of high attenuation consistent with talc deposition (see Fig. 52.10).52,55 On occasion, IV talcosis may result in more extensive fibrosis and honeycombing and resemble end-stage sarcoidosis (Fig. 52.13). The radiographic and CT findings of IV abuse of methylphenidate (crushed Ritalin tablets) differ somewhat from those of other types of IV drug abuse. The main abnormality closely mimics α1-antitrypsin deficiency and characteristically consists of bilateral, symmetric emphysema involving mainly the lower lung zones without bulla formation (Fig. 52.14).52,53

Liquid Acrylates and Acrylic Cement Etiology, Prevalence, and Epidemiology Liquid acrylate glues, most commonly isobutyl-2-cyanoacrylate and n-butyl-2-cyanoacrylate, are frequently used in embolization

B Fig. 52.9  Intravenous (IV) talcosis in an IV drug user: diffuse pinpoint nodular pattern on the chest radiograph. (A) Chest radiograph shows diffuse nodular pattern. The nodules measure 1 mm or less in diameter. Also noted is enlargement of the pulmonary trunk indicating pulmonary hypertension. (B) Magnified view of the right middle lung zone better demonstrates the fine nodular pattern.

therapy for vascular malformations and in endoscopic sclerotherapy for gastric variceal bleeding. Acrylic cement (polymethyl methacrylate) is used in vertebroplasty. Asymptomatic pulmonary embolism associated with these procedures is probably more frequent than is generally appreciated, occurring in 4% to 23% of cases31; however, symptomatic embolization is uncommon.56,57

52  Nonthrombotic Pulmonary Embolism Fig. 52.10  Intravenous (IV) talcosis with conglomerate massive fibrosis in an IV drug user. (A) View of the right lung from a chest radiograph shows conglomerate mass in the perihilar region of the right upper lobe with associated superior retraction of the hilum. Also noted are numerous well-defined 1- to 2-mm-diameter nodules. (B) Composite image with high-resolution CT of the right upper lobe in lung window (left image) and soft tissue window (right image) shows numerous small nodules, diffuse ground-glass opacities, and a conglomerate mass with foci of high attenuation consistent with talc deposition. Note associated architectural distortion and anterior tenting of the right major fissure, indicating a component of fibrosis.

A

B

651

652

A

C

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

B

Fig. 52.11  Intravenous (IV) talcosis in an IV drug user (same patient as in Fig. 52.9): diffuse pinpoint nodular pattern on CT. High-resolution CT at the level of the lower trachea (A) and at the level of the bronchus intermedius (B) demonstrates fine granular pattern throughout both lungs. Soft tissue window (C) shows enlarged pulmonary trunk consistent with pulmonary arterial hypertension.

Fig. 52.12  Cellulose granulomatosis from intravenous (IV) injection of crushed morphine tablets. Axial maximum-intensity projection image demonstrates diffuse and uniform tree-in-bud opacities throughout both lungs. Enlarged central pulmonary arteries suggest pulmonary hypertension. A diffuse tree-in-bud pattern may be seen with diffuse panbronchiolitis or after IV injection of crushed oral medications such as opioids or amphetamines.

52  Nonthrombotic Pulmonary Embolism

A

653

B

C

D Fig. 52.13  Intravenous talcosis with extensive fibrosis after intravenous drug use. (A) High-resolution CT at the level of the aortic arch shows conglomerate fibrosis with air bronchograms, architectural distortion, subpleural cyst (arrow) consistent with early honeycombing, and mild emphysema. Also evident are diffuse ground-glass opacities. (B) CT in soft tissue windows shows foci of increased attenuation (arrows) within the conglomerate fibrosis consistent with talc deposition. (C) CT at the level of lower lung zones shows diffuse ground-glass opacities, peribronchial fibrosis with traction bronchiectasis in the right lower and middle lobes, and subpleural honeycombing (arrow). (D) Coronal CT demonstrates predominantly upper lobe distribution of the fibrosis with upward retraction of the hila, overinflation of the lung bases, and tenting of the hemidiaphragms. The predominantly peribronchial and upper lobe distribution of fibrosis resembles end-stage sarcoidosis or an occupational lung disorder such as silicosis.

KEY POINTS: INTRAVENOUS TALCOSIS AND CELLULOSE GRANULOMATOSIS • Intravenous (IV) talcosis is seen almost exclusively in chronic IV drug users. • The complication usually occurs with medications intended solely for oral use. • Most patients are asymptomatic. Symptoms include progressive dyspnea and cough. • Radiographic findings: • Widespread nodules ranging from barely visible to 1 mm in diameter • Upper lobe conglomerate masses

• Lower lobe panlobular emphysema in methylphenidate (Ritalin) users • CT findings: • Widespread nodules ranging from barely visible to 1 mm in diameter and may include a diffuse vascular tree-in-bud pattern • Diffuse ground-glass opacities • Upper lobe conglomerate masses containing areas of high attenuation • Lower lobe panacinar emphysema in methylphenidate (Ritalin) users

654

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

Manifestations of the Disease RADIOGRAPHY Because the acrylate glue is mixed with radiopaque substances to allow accurate localization during embolization therapy, the chest radiograph may show tubular or nodular high-density opacities along the pulmonary vessels (Fig. 52.15).58 Other findings in patients with extensive embolism include subsegmental or segmental areas of consolidation.57 COMPUTED TOMOGRAPHY

A

CT scans show tubular or nodular radiopaque material within the pulmonary vessels (see Fig. 52.15).58 The material is often most easily appreciated on bone windows. Other findings in patients with extensive cyanoacrylate pulmonary embolism include subsegmental, predominantly subpleural wedge-shaped areas of consolidation consistent with infarction.57 On occasion, the filling defects may be large enough to manifest with perfusion defects on nuclear medicine scintigraphy (see Fig. 52.15).

Iodized Oil Embolism In the past, pulmonary oil embolism was usually a complication of lymphangiography with ethiodized poppy seed oil (Ethiodol). More recently, it has been described as a complication of iodinated oil embolism that occurs after transcatheter oil chemoembolization for the treatment of hepatocellular carcinoma.59 Lipiodol is also mixed with n-butyl cyanoacrylate in endoscopic sclerotherapy for gastric variceal bleeding.60 Lipiodol is mixed for the purpose of fluoroscopic monitoring and dilution of the cyanoacrylate to delay hardening.

Clinical Presentation

B Fig. 52.14  Ritalin lung with panacinar emphysema after intravenous use of crushed methylphenidate tablets (Ritalin). (A) High-resolution CT at the level of the lower lobes demonstrates extensive areas of decreased attenuation and focal areas of scarring. (B) Sagittal reformatted CT of the right lung demonstrates increased lung volumes, focal areas of scarring, and predominantly lower lung zone distribution of the areas of low attenuation. This CT appearance closely mimics α1-antitrypsin deficiency.

Clinical Presentation Most patients are asymptomatic. Patients may complain of pleuritic chest pain with or without associated cough and bloody sputum. Severe manifestations can include hypotension and arrhythmia.56

Few patients develop symptoms after lymphangiography.61 Patients with iodinated oil embolism after transcatheter oil chemoembolization are more likely to develop respiratory symptoms, including cough, hemoptysis, and dyspnea.59 In a review of 336 patients with hepatocellular carcinoma who underwent transcatheter oil chemoembolization through the hepatic artery, 14 patients received more than 20 mL of iodized oil. Respiratory symptoms of cough, hemoptysis, and dyspnea developed in 6 of these 14 patients 2 to 5 days after therapy.59

Manifestations of the Disease RADIOGRAPHY The radiographic findings usually consist of a fine reticular pattern, which may persist for 1 to 2 weeks.61 In addition, small peripheral vessels may be so filled with contrast material that they have an arborizing pattern similar to that seen on pulmonary arteriography.62 In patients with extensive embolism the radiograph may demonstrate diffuse ground-glass opacities and consolidation.59 Embolization of Lipiodol mixed with cyanoacrylate in endoscopic sclerotherapy for gastric variceal bleeding may result in multiple radiopaque emboli within the central pulmonary arteries without evidence of pulmonary parenchymal abnormality.60

52  Nonthrombotic Pulmonary Embolism

LPO VENT

A

LPO PERF

B

C Fig. 52.15  Methylmethacrylate embolization following vertebroplasty. (A) Lateral chest radiograph shows multilevel thoracic spine vertebroplasty with methylmethacrylate entering paravertebral veins (arrows) with resultant embolization to the lungs (arrowhead). (B) Oblique axial noncontrast CT shows a high-attenuation filling defect (arrow) in the anterior segmental pulmonary artery of the left upper lobe. (C) Ventilation perfusion scintigraphy shows a large wedge-shaped mismatched perfusion defect (arrow) in the anterior left upper lobe corresponding to the embolized methylmethacrylate. LPO, Left posterior oblique; Perf, perfusion; Vent, ventilation.

655

656

SECTION 10  Pulmonary Embolism, Hypertension, and Edema Fig. 52.16  Mercury injection with suicide attempt. (A) Posteroanterior chest radiograph shows diffuse high-attenuation mercury spherules, many with a branching configuration throughout both lungs. (B) Lateral radiograph of the elbow confirms that the mercury was injected intravenously rather than aspirated, given the presence of mercury in the antecubital fossa. (Fig. 52.16A reproduced with permission from Peterson N, Harvey-Smith W, Rohrmann CA. Radiographic aspects of metallic mercury embolism. AJR Am J Roentgenol. 1980;135:1079-1081; Fig. 52.16B courtesy C. Rohrmann, Seattle, WA.)

Other Materials Mercury

A

The iatrogenic, suicidal, or accidental injection of mercury is generally well tolerated, but patients may have some symptoms of pulmonary obstruction or systemic toxicity. After injection, the high-attenuation mercury spherules are found within the lungs, heart, and other parts of the body (Fig. 52.16). The spherules disappear gradually, remaining within the lungs for a prolonged period of time.63

Bullets and Shrapnel Uncommonly, these agents enter the extrathoracic systemic veins or the right side of the heart, are carried to the lungs, and then lodge within pulmonary arteries.64 Such foreign bodies can remain in the right ventricle or within the pulmonary vasculature for prolonged periods without untoward effects. In one case a bullet was present in the right ventricle 59 years after a bullet wound to the left side of the neck.65 In another report the authors described the case of an 11-year-old girl who was struck in the suboccipital region with a “soft-nosed” bullet fired at close range. Several months later the patient was found to have asymptomatic pulmonary emboli.66

Radiopaque Foreign Bodies A variety of devices, such as wire loops and balloons filled with contrast medium, have been used therapeutically in both the pulmonary and systemic circulations to obliterate arteriovenous malformations or to control intractable hemorrhage. Escape of such material into the systemic veins can result in opacities of metallic density within the lungs.67 Other devices, such as catheter fragments or inferior vena cava filters, may embolize to both the lungs and right-sided cardiac chambers (Fig. 52.17).

Plastic Intravenous Catheters These devices, either whole or in fragments, usually embolize to the lungs when they are cut by the sharp bevel of the needle housing them. On occasion, they are detached from their connector or fracture spontaneously.68 B

Silicone Silicone fluid (polydimethylsiloxane) embolism has been reported in some patients in whom the substance has been injected subcutaneously for breast augmentation.69 Radiographs have shown a combination of interstitial and airspace disease, which

52  Nonthrombotic Pulmonary Embolism

A

657

B Fig. 52.17  Inferior vena cava (IVC) filter embolization with subsequent hemopericardium. (A) Oblique coronal contrast CT shows an embolized IVC filter fragment within the right ventricle. (B) Follow-up oblique axial CT shows perforation of the right ventricular myocardium with the filter fragment (arrow) now residing within the pericardial cavity with resultant large hemopericardium.

in severe cases progresses to a pattern of acute respiratory distress syndrome. SUGGESTED READINGS

Han D, Lee KS, Franquet T, et al. Thrombotic and nonthrombotic pulmonary arterial embolism: spectrum of imaging findings. Radiographics. 2003;23:1521–1539. Talbot M, Schemitsch EH. Fat embolism syndrome: history, definition, epidemiology. Injury. 2006;37:S3–S7.

Bach AG, et al. Imaging of nonthrombotic pulmonary embolism: biological materials, nonbiological materials, and foreign bodies. Eur J Radiol. 2013;82: e120–e141.

The full reference list for this chapter is available at ExpertConsult.com.

52  Nonthrombotic Pulmonary Embolism 657.e1

REFERENCES 1. Talbot M, Schemitsch EH. Fat embolism syndrome: history, definition, epidemiology. Injury. 2006;37:S3–S7. 2. Newbigin K, Souza CA, Torres C, et al. Fat embolism syndrome: state-of-the-art review focused on pulmonary imaging findings. Respir Med. 2016;113: 93–100. 3. Dudney TM, Elliott CG. Pulmonary embolism from amniotic fluid, fat, and air. Prog Cardiovasc Dis. 1994;36:447–474. 4. King MB, Harmon KR. Unusual forms of pulmonary embolism. Clin Chest Med. 1994;15:561–580. 5. Toledo LS, Mauad R. Complications of body sculpture: prevention and treatment. Clin Plast Surg. 2006;33:1–11, v. 6. Husebye EE, Lyberg T, Roise O. Bone marrow fat in the circulation: clinical entities and pathophysiological mechanisms. Injury. 2006;37(suppl 4):S8–S18. 7. Fraser RS, Colman N, Müller NL, Paré PD. Embolic and thrombotic diseases of the lungs. In: Fraser RS, Colman N, Müller NL, Paré PD, eds. Synopsis of Diseases of the Chest. Philadelphia: Elsevier Saunders; 2005:542–580. 8. Feldman F, Ellis K, Green WM. The fat embolism syndrome. Radiology. 1975;114:535–542. 9. Muangman N, Stern EJ, Bulger EM, et al. Chest radiographic evolution in fat embolism syndrome. J Med Assoc Thai. 2005;88:1854–1860. 10. Arakawa H, Kurihara Y, Nakajima Y. Pulmonary fat embolism syndrome: CT findings in six patients. J Comput Assist Tomogr. 2000;24:24–29. 11. Gallardo X, Castaner E, Mata JM, et al. Nodular pattern at lung computed tomography in fat embolism syndrome: a helpful finding. J Comput Assist Tomogr. 2006;30:254–257. 12. Newbigin K, et al. Fat embolism syndrome: do the CT findings correlate with clinical course and severity of symptoms? A clinical-radiological study. Eur J Radiol. 2016;85:422–427. 13. Piolanti M, et al. Fat embolism syndrome: lung computed tomography findings in 18 patients. J Comput Assist Tomogr. 2016;40:335–342. 14. Malagari K, Economopoulos N, Stoupis C, et al. High-resolution CT findings in mild pulmonary fat embolism. Chest. 2003;123:1196–1201. 15. Heyneman LE, Müller NL. Pulmonary nodules in early fat embolism syndrome: a case report. J Thorac Imaging. 2000;15:71–74. 16. Maruyama Y, Little JB. Roentgen manifestations of traumatic pulmonary fat embolism. Radiology. 1962;79:945–952. 17. Burgher LW, Dines DE, Linscheid RL, Didier EP. Fat embolism and the adult respiratory distress syndrome. Mayo Clin Proc. 1974;49:107–109. 18. Mimoz O, Edouard A, Beydon L, et al. Contribution of bronchoalveolar lavage to the diagnosis of posttraumatic pulmonary fat embolism. Intensive Care Med. 1995;21:973–980. 19. Habashi NM, Andrews PL, Scalea TM. Therapeutic aspects of fat embolism syndrome. Injury. 2006;37(suppl 4):S68–S73. 20. Kramer MS, Rouleau J, Baskett TF, Joseph KS. Amniotic-fluid embolism and medical induction of labor: a retrospective, population-based cohort study. Lancet. 2006;368:1444–1448. 21. Ayoub CM, Zreik TG, Dabbous AS, Baraka AS. Amniotic fluid embolus: can we affect the outcome? Curr Opin Anaesthesiol. 2003;16:257–261. 22. Davies S. Amniotic fluid embolus: a review of the literature. Can J Anaesth. 2001;48:88–98. 23. Clark SL, Hankins GD, Dudley DA, et al. Amniotic fluid embolism: analysis of the national registry. Am J Obstet Gynecol. 1995;172:1158–1167, discussion 1167–1169. 24. Roche WD Jr, Norris HJ. Detection and significance of maternal pulmonary amniotic fluid embolism. Obstet Gynecol. 1974;43:729–731. 25. Fidler JL, Patz EF Jr, Ravin CE. Cardiopulmonary complications of pregnancy: radiographic findings. AJR Am J Roentgenol. 1993;161:937–942. 26. Karetzky M, Ramirez M. Acute respiratory failure in pregnancy. An analysis of 19 cases. Medicine (Baltimore). 1998;77:41–49. 27. Moore J, Baldisseri MR. Amniotic fluid embolism. Crit Care Med. 2005;33: S279–S285. 28. Fitzpatrick KE, et al. Incidence, risk factors, management and outcomes of amniotic-fluid embolism: a population-based cohort and nested case-control study. BJOG. 2016;123:100–109. 29. Schriner RW, Ryu JH, Edwards WD. Microscopic pulmonary tumor embolism causing subacute cor pulmonale: a difficult antemortem diagnosis. Mayo Clin Proc. 1991;66:143–148. 30. Han D, Lee KS, Franquet T, et al. Thrombotic and nonthrombotic pulmonary arterial embolism: spectrum of imaging findings. Radiographics. 2003;23: 1521–1539. 31. Bach AG, et al. Imaging of nonthrombotic pulmonary embolism: biological materials, nonbiological materials, and foreign bodies. Eur J Radiol. 2013;82: e120–e141.

32. Franquet T, Gimenez A, Prats R, et al. Thrombotic microangiopathy of pulmonary tumors: a vascular cause of tree-in-bud pattern on CT. AJR Am J Roentgenol. 2002;179:897–899. 33. Shepard JA, Moore EH, Templeton PA, McLoud TC. Pulmonary intravascular tumor emboli: dilated and beaded peripheral pulmonary arteries at CT. Radiology. 1993;187:797–801. 34. Sostman HD, et al. Perfusion scan in pulmonary vascular/lymphangitic carcinomatosis: the segmental contour pattern. AJR Am J Roentgenol. 1981;137:1072–1074. 35. Kizer KW, Goodman PC. Radiographic manifestations of venous air embolism. Radiology. 1982;144:35–39. 36. Lowenwirt IP, Chi DS, Handwerker SM. Nonfatal venous air embolism during cesarean section: a case report and review of the literature. Obstet Gynecol Surv. 1994;49:72–76. 37. Woodring JH, Fried AM. Nonfatal venous air embolism after contrastenhanced CT. Radiology. 1988;167:405–407. 38. Gallagher TJ. Scuba diving accidents: decompression sickness, air embolism. J Fla Med Assoc. 1997;84:446–451. 39. Moon RE, Vann RD, Bennett PB. The physiology of decompression illness. Sci Am. 1995;273:70–77. 40. Zaugg M, Kaplan V, Widmer U, et al. Fatal air embolism in an airplane passenger with a giant intrapulmonary bronchogenic cyst. Am J Respir Crit Care Med. 1998;157:1686–1689. 41. Weaver LK, Morris A. Venous and arterial gas embolism associated with positive pressure ventilation. Chest. 1998;113:1132–1134. 42. Butler BD, Hills BA. Transpulmonary passage of venous air emboli. J Appl Physiol. 1985;59:543–547. 43. Clark MC, Flick MR. Permeability pulmonary edema caused by venous air embolism. Am Rev Respir Dis. 1984;129:633–635. 44. Kizer KW. Diving medicine. Emerg Med Clin North Am. 1984;2: 513–530. 45. Harker CP, Neuman TS, Olson LK, et al. The roentgenographic findings associated with air embolism in sport scuba divers. J Emerg Med. 1993;11: 443–449. 46. Groell R, Schaffler GJ, Rienmueller R, Kern R. Vascular air embolism: location, frequency, and cause on electron-beam CT studies of the chest. Radiology. 1997;202:459–462. 47. Orebaugh SL. Venous air embolism: clinical and experimental considerations. Crit Care Med. 1992;20:1169–1177. 48. Blanc P, Boussuges A, Henriette K, et al. Iatrogenic cerebral air embolism: importance of an early hyperbaric oxygenation. Intensive Care Med. 2002;28:559–563. 49. Paré JP, Cote G, Fraser RS. Long-term follow-up of drug abusers with intravenous talcosis. Am Rev Respir Dis. 1989;139:233–241. 50. Travis WD, Colby TV, Koss MN, et al. Occupational lung diseases and pneumoconioses. In: Travis WD, Colby TV, Koss MN, et al, eds. Atlas of Nontumor Pathology. Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and the Armed Forces Institute of Pathology; 2002:793–856. 51. Schmidt RA, Glenny RW, Godwin JD, et al. Panlobular emphysema in young intravenous Ritalin abusers. Am Rev Respir Dis. 1991;143:649–656. 52. Ward S, Heyneman LE, Reittner P, et al. Talcosis associated with IV abuse of oral medications: CT findings. AJR Am J Roentgenol. 2000;174: 789–793. 53. Stern EJ, Frank MS, Schmutz JF, et al. Panlobular pulmonary emphysema caused by i.v. injection of methylphenidate (Ritalin): findings on chest radiographs and CT scans. AJR Am J Roentgenol. 1994;162:555–560. 54. Demeter S, Raymond GS, Puttagunta L, Barrie JR. Intravenous pulmonary talcosis with complicating massive fibrosis. Can Assoc Radiol J. 1999;50: 413–415. 55. Padley SPG, Adler BD, Staples CA, et al. Pulmonary talcosis: CT findings in three cases. Radiology. 1993;186:125–127. 56. Freitag M, Gottschalk A, Schuster M, et al. Pulmonary embolism caused by polymethylmethacrylate during percutaneous vertebroplasty in orthopaedic surgery. Acta Anaesthesiol Scand. 2006;50:248–251. 57. Pelz DM, Lownie SP, Fox AJ, Hutton LC. Symptomatic pulmonary complications from liquid acrylate embolization of brain arteriovenous malformations. AJNR Am J Neuroradiol. 1995;16:19–26. 58. Hwang SS, Kim HH, Park SH, et al. n-Butyl-2-cyanoacrylate pulmonary embolism after endoscopic injection sclerotherapy for gastric variceal bleeding. J Comput Assist Tomogr. 2001;25:16–22. 59. Chung JW, Park JH, Im JG, et al. Pulmonary oil embolism after transcatheter oily chemoembolization of hepatocellular carcinoma. Radiology. 1993;187:689–693. 60. Marco de Lucas E, Fidalgo I, Garcia-Baron PL, et al. Radiopaque pulmonary arteries on chest radiography. J Thorac Imaging. 2004;19:264–266.

657.e2

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

61. Bron KM, Baum S, Abrams HL. Oil embolism in lymphangiography. Incidence, manifestations, and mechanism. Radiology. 1963;80:194–202. 62. Takahashi M, Abrams HL. Arborizing pulmonary embolization following lymphangiography. Report of three cases and an experimental study. Radiology. 1967;89:633–638. 63. Peterson N, Harvey-Smith W, Rohrmann CA. Radiographic aspects of metallic mercury embolism. AJR Am J Roentgenol. 1980;135:1079–1081. 64. Hafez A, Dartevelle P, Lafont D, et al. Pulmonary arterial embolus by an unusual wandering bullet. Thorac Cardiovasc Surg. 1983;31:392–394. 65. Bett N, Walters L. Delayed presentation of right ventricular bullet embolus. Heart. 2004;90:1298.

66. Hughes BD, Vender JR. Delayed lead pulmonary emboli after a gunshot wound to the head. Case report. J Neurosurg. 2006;105:233–234. 67. Terry PB, Barth KH, Kaufman SL, White RI Jr. Balloon embolization for treatment of pulmonary arteriovenous fistulas. N Engl J Med. 1980;302:1189–1190. 68. Prager D, Hertzberg RW. Spontaneous intravenous catheter fracture and embolization from an implanted venous access port and analysis by scanning electron microscopy. Cancer. 1987;60:270–273. 69. Chen YM, Lu CC, Perng RP. Silicone fluid–induced pulmonary embolism. Am Rev Respir Dis. 1993;147:1299–1302.

53 

Pulmonary Arterial Hypertension* VEDANT GUPTA  |  STEPHEN B. HOBBS

Pulmonary arterial hypertension (PAH) is defined as a mean pulmonary arterial pressure of greater than 25 mm Hg at rest or 30 mm Hg with exercise, with an elevated pulmonary vascular resistance (PVR) greater than 3 Wood units. Although pulmonary pressures may be elevated in many conditions, PAH fundamentally requires changes in the pulmonary vasculature. Mean pressures of 26 to 40 mm Hg are considered mild; 41 to 55 mm Hg, moderate; and greater than 55 mm Hg, severe. Although the inciting factor may be from any number of conditions, PAH is due to progressive increase of PVR, leading to increased right ventricle (RV) pressure load. As PAH progresses, the RV is unable to compensate, leading initially to exertional symptoms (usually dyspnea) but eventually to florid right heart failure, cardiogenic shock, and death. The diagnosis of PAH continues to be a challenge, predominantly because of nonspecific initial symptoms. Although pathologic findings are definitive for the diagnosis, routine biopsies are not performed, and therefore noninvasive imaging is essential for diagnosis. Largely, this is achieved via echocardiography, but this is not ordered unless clinical suspicion of PAH is high. Other imaging modalities are essential in increasing or decreasing the index of suspicion. Once PAH is suspected, imaging is also essential for identifying the underlying etiology and comorbid conditions. However, evaluation of the degree of pulmonary pressure elevation, changes in PVR, and any contribution of left-sided heart disease is best done by hemodynamic catheterization (right heart catheterization), especially if considering PAH-specific therapy.

Etiology and Classification PAH can be usefully classified according to the predominant site of pathologic insult, into precapillary and postcapillary causes (Box 53.1). Precapillary causes include small-vessel vasculopathy affecting the arterioles, thrombotic or embolic disease, proximal vascular obstruction by tumor or vasculitis, congenital heart disease (CHD), and pleuroparenchymal disease. Postcapillary causes of pulmonary hypertension include causes of chronically raised pulmonary venous pressure, such as left ventricular failure, valvular heart disease, atrial myxoma, mediastinal fibrosis, and, rarely, congenital venous stenosis, as well as predominantly postcapillary vasculopathies, such as pulmonary venoocclusive disease, and pulmonary capillary hemangiomatosis (PCH). A more clinically based classification of pulmonary hypertension has been developed and refined, aiming to individualize different categories sharing similarities in pathophysiologic mechanisms, clinical presentation, and therapeutic options. These two classifications inevitably bear many similarities. The World Health Organization meeting in 1973 was the first to endorse *The editors and publisher would like to thank Drs. Nicholas J. Screaton and Deepa Gopalan for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

658

standardized nomenclature.1 Since then, the clinical classification has been reclassified multiple times. The most recent classification system was devised in 2009 in Dana Point, California, and was essentially maintained, with some minor adjustments, at the Fifth World Symposium on Pulmonary Hypertension in Nice, France (Box 53.2).2,3 The last three iterations have largely been minor reclassifications to try to better align the pathophysiology of PAH in different conditions. Group 1 PAH is a varied group of underlying conditions that result in increased pulmonary vascular tone from intrinsic issues in the pulmonary vasomotor tone or a secondary increase in PVR from an increase in pulmonary vascular flow. Group 2 is pulmonary hypertension related to left-sided heart disease, whereas pulmonary hypertension associated with pulmonary parenchymal disease and/or hypoxemia is group 3. Chronic thrombotic or embolic diseases comprise group 4, and group 5 is a heterogeneous group with multifactorial or unclear mechanisms (see Box 53.2). Some important developments in the understanding of group 1 PAH over the years include recognition of specific genetic mutations associated with PAH, as well as drug- and toxinmediated PAH. Familial PAH is an autosomal-dominant condition with incomplete penetrance, caused in 50% of cases by mutations in the bone morphogenetic protein receptor type II, and it is clinically and radiologically indistinguishable from idiopathic PAH.4 The most recognized drugs associated with PAH are the anorexigenic drugs, namely, aminorex fumarate, fenfluramine, and dexfenfluramine. Cocaine, amphetamine, and chemotherapeutic agents have also been implicated. Group 1 PAH may also develop from a sustained congenital left-to-right shunt. This includes both high-pressure shunts, such as truncus arteriosus, ventricular septal defects, and patent ductus arteriosus (PDA), and low-pressure high-flow shunts, such as atrial septal defects and partial anomalous pulmonary venous return. Other conditions, such as chronic renal failure, portopulmonary hypertension, and thyrotoxicosis, which increase pulmonary blood flow, can also result in pulmonary hypertension. Initially, the presence of a shunt exposes the pulmonary circulation to high flow, preventing it from adapting normally to extrauterine life. Ongoing high flow during extended periods results in a progressive pulmonary vasculopathy with associated in situ thrombosis. The position and size of the cardiac defect and the magnitude of the shunt govern the time taken for these changes to occur. Left uncorrected, rising pulmonary arterial pressures lead to bidirectional and then reversed flow across the shunt (Eisenmenger syndrome). Even after apparently effective corrective surgery, patients may go on to develop significant pulmonary hypertension. Pulmonary hypertension occurs in a wide variety of collagen vascular diseases and confers a worse prognosis. Incidences vary among the diseases but can be as high as 12% in patients with the limited form of scleroderma.5 Pulmonary hypertension is

53  Pulmonary Arterial Hypertension BOX 53.1  CAUSES OF PULMONARY HYPERTENSION PRECAPILLARY HYPERTENSION Small-vessel disease Idiopathic pulmonary arterial hypertension Portopulmonary hypertension Anorexigen abuse Connective tissue associated Human immunodeficiency virus infection Pulmonary arterial obstruction and stenosis Chronic thromboembolic disease Nonthrombotic emboli (metastatic neoplasm, parasites, talc) Sickle cell disease Increased blood flow Congenital heart disease or shunts Pleuropulmonary disease Chronic obstructive pulmonary disease Interstitial lung disease Bronchiectasis, cystic fibrosis Chest wall deformities Alveolar hypoventilation Neuromuscular disease Obesity Obstructive sleep apnea POSTCAPILLARY HYPERTENSION Pulmonary venoocclusive disease Pulmonary capillary hemangiomatosis Left-sided heart failure Mitral valve disease Myxoma Mediastinal fibrosis Congenital venous stenosis Anomalous pulmonary venous connections

the cause of up to 50% of disease-related deaths in patients with limited scleroderma. Isolated pulmonary hypertension is less common in diffuse scleroderma; when it is present, it is often seen in patients with the nucleolar antibody anti-U3 ribonucleoprotein.6 In mixed connective tissue disease (CTD), one long-term follow-up study found that pulmonary hypertension was the most common cause of death, occurring in 38% of patients.7 Although elevated PA pressures can be seen with any CTD, it is less frequently seen in systemic lupus erythematosus, rheumatoid arthritis (RA), and polymyositis. In RA, pulmonary hypertension is more frequently a late manifestation of rheumatoid interstitial lung disease than of vasculopathic changes. Systemic lupus erythematosus can be complicated by a hypercoagulable state; therefore chronic thromboembolic pulmonary hypertension (CTEPH) should always be considered an alternative cause of pulmonary hypertension in these patients. Pulmonary hypertension is thought to affect 0.1% of the human immunodeficiency virus (HIV)-infected population annually, representing a relative risk of 500, compared with an HIV-negative individual.8,9 Pulmonary thromboembolic disease represents another cause of pulmonary hypertension in patients with chronic HIV infection, being present in 3% of patients with pulmonary hypertension and HIV infection or acquired immune deficiency syndrome.10,11 Pulmonary venoocclusive disease (PVOD) and PCH are considered together because they share several common features, particularly in relation to their management. Although an arterial component is usually present, both diseases predominantly affect the venules immediately downstream from the capillary bed. The venous occlusion in PCH is due to an abnormal uncontrolled proliferation of capillaries that infiltrate the interstitium, the

659

BOX 53.2  CLINICAL CLASSIFICATION OF PULMONARY HYPERTENSION (NICE, 2013) Group 1. Pulmonary arterial hypertension 1.1. Idiopathic 1.2. Heritable 1.3. Drug and toxin induced 1.4. Associated with 1.4.1. Collagen vascular disease 1.4.2. Human immunodeficiency virus infection 1.4.3. Portal hypertension 1.4.4. Congenital heart disease 1.4.5. Schistosomiasis 1.4.6. Chronic hemolytic anemia 1.5. Pulmonary venoocclusive disease or pulmonary capillary hemangiomatosis 1.6. Persistent pulmonary hypertension of the newborn Group 2. Pulmonary hypertension with left-sided heart disease 2.1. Systolic dysfunction 2.2. Diastolic dysfunction 2.3. Left-sided valvular heart disease 2.4. Congenital/acquired left ventricular inflow or outflow obstruction or congenital cardiomyopathy Group 3. Pulmonary hypertension associated with lung disease or hypoxemia 3.1. Chronic obstructive pulmonary disease 3.2. Interstitial lung disease 3.3. Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4. Sleep-disordered breathing 3.5. Alveolar hypoventilation disorders 3.6. Chronic exposure to high altitude 3.7. Developmental abnormalities Group 4. Pulmonary hypertension resulting from chronic thrombotic or embolic disease Group 5. Pulmonary hypertension with unclear, multifactorial mechanisms 5.1. Hematologic disorders: myeloproliferative disorders, splenectomy 5.2. Systemic disorders: sarcoidosis, Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3. Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4. Others: compression of pulmonary vessels, fibrosing mediastinitis, chronic renal failure on dialysis, segmental pulmonary hypertension

vessels, and, less commonly, the airways. In both PVOD and PCH, venous occlusion results in increased transcapillary hydrostatic pressure, with consequent focal areas of edema and hemorrhage. There is limited epidemiologic data available on both diseases. PVOD is rare, with an incidence of 0.1 to 0.3 per million, although up to 5% to 10% of idiopathic PAH patients have been found on pathology to have PVOD.12–17 PCH is rarer still. Unlike idiopathic PAH, one-third of PVOD cases occur in children, with equal sex distribution; there is a (2 : 1) male predominance in adult patients.18 The etiology of both diseases is unknown and may be multifactorial. Cytotoxic drugs, including bleomycin,19 herbal “bush” tea,20 bone marrow transplantation, and thoracic radiotherapy have all been implicated in PVOD, although the majority of cases are currently considered idiopathic. Clinically, the triad of severe PAH, radiographic evidence of pulmonary edema, and normal pulmonary artery occlusion pressure is considered to be diagnostic of PVOD. In conjunction, these findings can obviate the need for tissue diagnosis. However, many patients with PVOD do not have this triad. As these diseases are often difficult to

660

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

distinguish from idiopathic pulmonary hypertension and from interstitial lung disease, radiologic investigations, particularly computed tomography (CT), have an important role to play in diagnosis. Many chronic lung conditions can lead to pulmonary hypertension through an increase in PVR. This is partly due to destruction of the vascular bed and partly due to vascular remodeling in response to chronic alveolar hypoxia. Although the resulting pulmonary hypertension is often mild and associated with a preserved cardiac output, its presence worsens prognosis. Approximately 90% of patients with severe chronic obstructive pulmonary disease will have pulmonary hypertension.21 In CTEPH thrombi from untreated or recurrent acute emboli organize and become incorporated into the wall of the pulmonary arteries. Thrombi in smaller vessels often recanalize, forming a trabecular mesh. This process, which may occur in repeated cycles, leaves endothelialized residua that obstruct or narrow pulmonary arteries, resulting in progressive pulmonary hypertension, hypoxemia, and right-sided heart failure.22,23 The true prevalence of CTEPH is unknown as many cases may remain undiagnosed. CTEPH may complicate up to 3.8% of cases of acute pulmonary embolism24 and carries a poor prognosis if it is left untreated.25 The importance of aggressively identifying etiology cannot be understated. In particular, PAH-specific vasodilator therapy has been indicated in group 1 (excluding PVOD and PCH). Vasodilator therapy has been studied inconsistently in group 3 (PAH associated with parenchymal lung disease) or group 4 (CTEPH), although it is likely still efficacious. Postcapillary causes of PAH (PVOD, PCH, and group 2 PAH) do not typically benefit from pulmonary vasodilator therapy. Furthermore, the approach to transplantation is varied based on the underlying etiology (single-lung vs. double-lung transplantation vs. multiorgan transplantation).

Epidemiology Given the challenges in recognition and diagnosis, the true incidence and prevalence have been difficult to capture. There are no large international registries, and national registries have some variance. In addition, most of the registry data has been limited to group 1 PAH, and the epidemiology of other PAH groups is still not entirely clear. However, group 1 PAH still remains a relatively rare disease with an annual incidence of 1.1 to 3.6 per million population and a prevalence of 6.6 to 52 per million population.26–31 There is a female preponderance (anywhere from 60%–80%) that has been fairly consistent over time.32 Although early registries suggested this to be a disease of the young, the median age of more recent registries seems to range from 50 to 65 years of age. Idiopathic PAH in these registries represents anywhere from 39% to 60% of all group 1 PAH patients, with anywhere from 11% to 43% being PAH associated with CHD and 15% to 30% PAH associated with CTD.32 Familial or heritable PAH is an increasingly recognized etiology for group 1 PAH; however, idiopathic cases outnumber familial cases of pulmonary hypertension by more than 10 : 1.

Pathophysiology At birth the pulmonary arterial circulation is histologically similar to the systemic circulation. However, as the newborn adapts to

extrauterine life, the pulmonary arterial circulation rapidly develops into a high-flow low-pressure system. Increase in vascular compliance allows the pulmonary circulation to accommodate systemic cardiac outputs with little rise in pulmonary arterial pressure. Pulmonary arteries more than 1 mm in diameter have walls that consist of numerous parallel elastic laminae. These “elastic” arteries act predominantly as conductance vessels and contribute little to resistance. As the vessel diameter narrows to between 1 mm and 100 µm, the elastic component is replaced by smooth muscle. The precapillary “muscular” arteries contribute significantly to PVR and are, in health, the site of the greatest pressure drop within the circulation. In general, the muscular arteries or resistance vessels are also the site most affected in disease, as occurs in idiopathic PAH. PAH, regardless of cause, results in dilation of the large elastic pulmonary arteries and may result in pulmonary arterial atherosclerosis. Other common findings include intimal fibrosis of elastic and large muscular arteries and thickening of the media of small muscular arteries. In addition to muscle hypertrophyhyperplasia, several abnormalities are often present in small- to medium-sized muscular arteries that together characterize plexogenic pulmonary arteriopathy. These abnormalities include cellular intimal proliferation and fibrosis, plexiform lesions, fibrinoid “necrosis,” and vasculitis (Fig. 53.1). Plexiform lesions are seen in small supernumerary arteries a short distance beyond their origin from the parent vessel. The lesion consists of a localized focus of vascular dilation associated with an intraluminal plexus of slit-like vascular channels (see Fig. 53.1). This plexogenic arteriopathy is the hallmark of idiopathic PAH and PAH associated with congenital systemic-pulmonary shunts (most commonly CHD). The histologic findings of pulmonary hypertension resulting from chronic thromboembolism include thrombi in various stages of organization in the large and small pulmonary arteries. The most common findings in small pulmonary vessels are medial hypertrophy and intimal fibrosis, which may be eccentric, concentric, or in a colander pattern consistent with recanalized thrombus (Fig. 53.2). Venoocclusive disease is characterized by stenosis or obliteration of the lumina of small pulmonary veins and venules by intimal fibrous tissue (Fig. 53.3). Other common findings are engorged venules, dilated lymphatics, and septal thickening (see Fig. 53.3). Histologic evidence of PAH is usually present, but changes of plexogenic arteriopathy are absent. The main histologic abnormality in PCH consists of patchy interstitial proliferation of thin-walled blood vessels the size of capillaries. The vessels appear to invade the walls of pulmonary veins and to a lesser extent the pulmonary arteries. The venular infiltration is often accompanied by intimal fibrosis, which may lead to stenosis.

Clinical Presentation and Outcomes Pulmonary hypertension is often difficult to diagnose because it manifests insidiously with nonspecific clinical findings. Patients initially complain of exertional breathlessness, representing rightsided cardiac insufficiency in the face of an increased workload. As disease progresses, exercise tolerance steadily deteriorates, and exertional syncope or chest pain may develop. Once the right ventricle fails to sustain an appropriate cardiac output at rest, patients develop ongoing symptoms of overt right-sided heart failure, including fatigue, loss of appetite, ascites, and pedal edema. Hence, not uncommonly, pulmonary hypertension can be

53  Pulmonary Arterial Hypertension

661

* A

B Fig. 53.1  Histologic findings of pulmonary arterial hypertension (PAH). (A) Histologic specimen (hematoxylin-eosin stain, original magnification ×100) in patient with PAH shows concentric laminar fibrosis. The normal pulmonary artery (arrow) is replaced by a concentrically arranged intimal proliferation of myofibroblasts and collagen with occlusion of the lumen and atrophy of the arterial media. (B) Histologic specimen (hematoxylin-eosin stain, original magnification ×100) shows plexiform and dilation lesions. The plexiform lesion (curved arrow) consists of an aneurysmal segment of pulmonary artery (asterisk) that is typically filled with a knot-like proliferation of endothelium-like cells. Its appearance has been likened to that of a renal glomerulus. The degree of cellularity may vary, and thrombi can sometimes be seen. Dilation lesions (straight arrows) are identified in their characteristic position around the plexiform lesion and probably represent postobstructive or bypass microaneurysms. (Courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Vancouver, Canada.)

Fig. 53.2  Recanalized thrombus in pulmonary arterial hypertension. Histologic specimen (elastic stain, original magnification ×200) shows pulmonary artery with recanalized thrombus (“colander lesion”). The arterial lumen (curved arrow) is occupied by a fibroproliferative lesion that represents an old organized thrombus. The sharply punched-out spaces are recanalized lumina that give the lesion its name and also allow pathologists to distinguish it from a plexiform lesion. The arterial tunica media (straight arrow) is marginally hypertrophic. (Courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Vancouver, Canada.)

misdiagnosed as asthma, hyperventilation syndrome, or lack of fitness. The delay in diagnosis compounded by the fact that the pulmonary circulation has an extensive reserve means that by the time the diagnosis is made, much of the circulation has already been compromised.

Prognosis in PAH is still poor long term but has improved over time. National Institutes of Health registry data published in 1991 estimated median survival of 2.8 years for idiopathic PAH, with 1-year, 3-year, and 5-year survival rates of 68%, 48%, and 34%, respectively.33 More recent data from the REVEAL Registry (Registry to Evaluate Early and Long-Term PAH Disease Management) shows 1-year, 3-year, and 5-year survival rates of 85%, 68%, and 57%, respectively.34 Prognosis does vary based on etiology, with PAH associated with CHD or drugs and toxins having a better long-term prognosis and PAH associated with portopulmonary hypertension and CTD having a worse long-term prognosis, compared with idiopathic PAH, heritable PAH, or PAH associated with HIV (all with similar prognosis). The prognosis in severe portopulmonary hypertension (coexisting portal hypertension and PAH) is poor, with median survival of 6 months and 5-year survival of 10% in one series,35 compared with a 5-year survival of 50% for patients with hepatopulmonary syndrome (hypoxemia caused by pulmonary vasodilation and shunting in the setting of liver disease).36 There are also risk stratification tools proposed by guideline committees that include clinical features (progression of symptoms, syncope), functional parameters (New York Heart Association classification, 6-minute walk distance), and hemodynamic parameters and imaging findings. Specifically, RA area greater than 26 cm2 and presence of pericardial effusion are considered a high risk for early mortality (1-year mortality >10%).37

Synopsis of Treatment Options Originally, treatment for PAH was limited to anticoagulation, calcium channel blockers,38,39 oxygen, and diuretics for symptomatic relief. This is still often the guideline-directed medical

662

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

*

A

*

*

B Fig. 53.3  Venoocclusive disease. (A) Low-power photomicrograph (hematoxylin-eosin stain, original magnification ×12.5) demonstrates thickening of the interlobular septa (straight arrows). Within the thickened septum is a vein that is totally occluded by an old, organized thrombus (curved arrow). (B) Medium-power photomicrograph (Movat pentachrome stain) shows an interlobular septal vein (straight arrow) that contains an old organized thrombus with several recanalization lumina. Surrounding the vein is a leash of dilated and congested venules (curved arrows) and dilated lymphatic channels (asterisks). Some of the pulmonary parenchyma adjacent to the vein is fibrotic. (Courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Vancouver, Canada.)

therapy for patients who show pulmonary vasoreactivity on testing during right heart catheterization. However, targeted therapies have revolutionized the management of patients for many causes. Targeted therapies modify disease by reversal of the vascular remodeling process, inhibiting platelet aggregation, and causing vasodilatation. The first of these, intravenous epoprostenol, has proven benefits in exercise tolerance, hemodynamics, and survival.40,41 Subsequent modifications to improve the stability of the compound have allowed improvement in ease of administration; however, it still remains a continuous infusion with all of the associated risks. Other prostanoids, such as treprostinil (intravenous, subcutaneous, inhaled, and oral formulations) and inhaled iloprost, have subsequently been developed and also appear to be effective in improving functional capacity and survival.42–44 Other classes of vasodilators, such as dual endothelin receptor antagonists, selective endothelin receptor antagonists, phosphodiesterase inhibitors, and cyclic guanosine monophosphate antagonists have also been shown to be efficacious in improving functional capacity.45,46 These are generally administered orally and are therefore easier to take with fewer logistical issues than continuous infusions. As such, targeted therapy is now more accessible to a wider proportion of patients with pulmonary hypertension, reinforcing the need to make an early diagnosis. Also, combination therapy has been shown to be synergistic and is often used.47–61 Apart from lung transplantation, long-term oxygen therapy is the only measure that has been shown to significantly improve survival in patients with PAH associated with parenchymal lung disease (group 3 PAH).62,63 In the diagnostic workup of patients being considered for lung transplantation, particularly in the setting of emphysema, CT permits detection of small primary lung cancers that are not radiographically apparent and can thus significantly influence management. When unilateral lung transplantation is being considered, perfusion scintigraphy is widely used to select the side with the most compromised function. The treatment of CTEPH is discussed in detail in Chapter 51.

Manifestations of the Disease Given the significant crossover in imaging findings of PAH among different subtypes, the remainder of the chapter is organized by specific imaging modalities. As many of the comorbid or inciting disease states, such as acute and chronic pulmonary thromboembolism, intrinsic lung pathologies, and so forth, are discussed separately; specific diagnostic or prognostic findings will be emphasized here. RADIOGRAPHY Chest radiography is usually the initial imaging study in patients with suspected pulmonary hypertension. It is useful to assess heart size, pattern of cardiac chamber dilatation, and enlargement of proximal pulmonary arteries, as well as to detect any underlying pulmonary parenchymal disorder. The radiographic features of pulmonary hypertension consist of central pulmonary arterial dilatation down to the segmental level, with attenuation of peripheral pulmonary blood vessels, giving rise to “peripheral pruning” (Fig. 53.4). Hilar artery enlargement is assessed by measuring the diameter of the interlobar arteries. The upper limit for the transverse diameter of the right interlobar artery measured from its lateral aspect to the bronchus intermedius is 15 mm in women and 16 mm in men.64 The transverse diameter of the left interlobar artery is difficult to appreciate on the posteroanterior view. On a lateral view the upper limit measured from the circular lucency of the left upper lobe bronchus to the posterior margin of the vessel is 18 mm.65 Calcification within the pulmonary arteries may be seen in pulmonary hypertension associated with intracardiac shunts and usually results from prolonged and severe pulmonary hypertension that has resulted in calcific atherosclerosis.66 Pulmonary artery calcification is usually associated with high PVR and irreversible vascular disease.66

53  Pulmonary Arterial Hypertension

663

by vessels being identifiable within 2 cm of the pleural surface. Vasculopathy and the development of pulmonary hypertension may be difficult to identify on the chest radiograph. Peripheral oligemia with rapid tapering of the peripheral vessels and disparity between the proximal and distal calibers is a late manifestation often indicating shunt reversal and Eisenmenger syndrome. The right ventricle and atrium typically enlarge in proportion to the degree of volume overload. Paradoxically, increased PVR and the development of pulmonary hypertension may lead to reduction in size of the cardiac silhouette.69 Atrioseptal defects are characterized by cardiomegaly with enlargement of the right atrium and ventricle (Fig. 53.6); ventriculoseptal defects, by right ventricular hypertrophy and dilatation of the atria and eventually the left ventricle; and PDA, by enlargement of the left atrium, left ventricle, and aortic arch. In addition, there may be calcification of the ductus diverticulum.70

Fig. 53.4  Idiopathic pulmonary arterial hypertension. Posteroanterior chest radiograph demonstrates gross enlargement of the proximal pulmonary arteries with tapering of the peripheral vasculature (peripheral pruning) and cardiomegaly resulting from dilated right-sided heart chambers.

Heart size as assessed by cardiothoracic ratio may be normal or enlarged in pulmonary hypertension. Enlargement of the right ventricle causes reduction of the retrosternal clear space on the lateral radiograph. Right atrial dilatation is seen as a widening of the right border of the heart on the frontal projection. Enlargement of the right atrial appendage causes an increase in the retrosternal opacity above the expected location of the right ventricle on the lateral projection. There is no correlation between the extent of the radiographic abnormalities and the degree of pulmonary hypertension.67 The accuracy of the chest radiograph in detecting pulmonary hypertension is unknown. The chest radiograph is useful in defining coexistent conditions, such as pulmonary venous congestion, chest wall and vertebral deformities, emphysema, interstitial lung fibrosis, and other parenchymal and pleural abnormalities. In 90% of patients with idiopathic PAH, the chest radiograph is abnormal at the time of diagnosis.68 The typical features include enlarged proximal pulmonary arteries with peripheral pruning, cardiomegaly with right-sided chamber enlargement, and pulmonary oligemia (Fig. 53.5). The lungs are otherwise normal, enabling differentiation from pulmonary hypertension secondary to parenchymal lung disease. Congenital Systemic-Pulmonary Shunts (Congenital Heart Disease) The radiographic features of pulmonary hypertension caused by chronic shunt physiology include the familiar complex of a dilated pulmonary trunk and central pulmonary arteries.69 Increased flow results initially in prominence of peripheral pulmonary vessels in proportion to the proximal vessels. On radiographic examination, pulmonary plethora is characterized

Pulmonary Venoocclusive Disease and Pulmonary Capillary Hemangiomatosis The specific diagnosis of PVOD is suggested radiographically when features of PAH are accompanied by evidence of diffuse pulmonary interstitial edema and a normal-sized left atrium.71,72 Back-pressure from the obstructed venular side of the pulmonary circulation results in dilatation of the right-sided heart chambers and central pulmonary arteries, pleural effusions, and signs of pulmonary interstitial edema. The central pulmonary veins and the left atrium are not enlarged, in contrast to patients with mitral stenosis, cor triatriatum, or left atrial myxoma. Mediastinal lymphadenopathy caused by vascular congestion may be present. In PCH the chest radiograph shows the typical features of pulmonary hypertension. In addition, a reticulonodular or fine nodular pattern may be present, which can suggest an interstitial process. Left-Sided Heart Disease Left-sided cardiac diseases, such as myocardial dysfunction, mitral valve disease (Fig. 53.7), and left atrial myxoma, are characterized by pulmonary venous hypertension, interstitial edema, and pleural effusions. Normally, in the erect position the hydrostatic pressure gradient causes higher flow and therefore greater vessel caliber in the dependent lung regions. Pulmonary venous hypertension results in loss or reversal of this normal-caliber gradient, with narrowing of lower lobe and distention of upper lobe vessels. This so-called cephalization, upper zone vascular distention or recruitment, is present in 95% of patients with critical mitral stenosis73 and 33% to 76% of patients with mild left ventricular dysfunction admitted to coronary care.65,74 Upper zone vascular distention is the earliest radiographic feature of pulmonary venous hypertension. The development of pulmonary interstitial edema is characterized by thickening of the interlobular septa (Kerley B lines) and loss of the sharp margins of vessels and bronchi (perihilar haze and peribronchial cuffing). Finally, frank pulmonary edema results in airspace filling. The presence of left atrial enlargement can help distinguish left-sided cardiac lesions from PVOD. Hemosiderosis caused by long-standing pulmonary venous hypertension produces fine reticular opacities on chest radiographs. Small (1–3 mm) calcified ossific nodules are the hallmark of mitral stenosis but are now rarely seen. In rare cases a left atrial myxoma is manifested as a heavily calcified mass.

664

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

A

B Fig. 53.5  Pulmonary arterial hypertension (PAH) in a woman with idiopathic PAH. Posteroanterior (A) and lateral (B) chest radiographs show enlargement of the central pulmonary arteries with rapid tapering of the vessels. On the posteroanterior view, marked enlargement of the main pulmonary artery results in a focal convexity (arrow) immediately below the level of the aortic arch. On the lateral view, right ventricular enlargement and dilation of the pulmonary outflow tract result in filling of the lower retrosternal clear space. (From Müller NL, Fraser RS, Colman NC, Paré PD. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

Chronic Thromboembolic Pulmonary Hypertension Chest radiography in CTEPH reveals the familiar complex of cardiomegaly and right-sided chamber dilatation. The central pulmonary arteries may be asymmetrically enlarged with abrupt cutoff. The peripheral pulmonary vessels are disorganized with regional areas of hypoperfusion and hyperperfusion. Pleural thickening or effusions and peripheral scarring from previous infarction and atelectasis may be present.75 Please see Chapter 51 for a more complete discussion of CTEPH. COMPUTED TOMOGRAPHY

Fig. 53.6  Pulmonary hypertension caused by atrial septal defect. Chest radiograph shows cardiomegaly and enlarged central pulmonary arteries.

CT is an important tool for the assessment of patients with suspected pulmonary hypertension. The combination of CT pulmonary angiography and high-resolution CT allows a comprehensive assessment of the pulmonary vasculature and lung parenchyma, an assessment of the pattern of cardiac chamber dilatation and the severity of tricuspid regurgitation, and a limited evaluation of right-sided heart function.76 Dilation of central pulmonary arteries is a cardinal sign of pulmonary hypertension on CT and magnetic resonance imaging (MRI) (Fig. 53.8). On CT the diameter of the main pulmonary artery is most frequently measured at the level of its bifurcation at a right angle to its long axis and just lateral to the ascending

53  Pulmonary Arterial Hypertension

A

665

B Fig. 53.7  Mitral stenosis and regurgitation. (A) Chest radiograph in a patient with mitral stenosis and regurgitation with classic features of left atrial enlargement, including a double right border of the heart, splaying of the carina, and straightening of the left heart border resulting from enlargement of left atrial appendage. (B) CT image at the level of mitral valve confirms massively enlarged left atrium with calcified mitral valve leaflets, features typical of mitral stenosis and regurgitation.

aorta. The most frequently cited study evaluating absolute pulmonary artery size suggests that a main pulmonary artery of 29 mm or larger on CT is suggestive of pulmonary hypertension with a sensitivity of 69% to 87% and a specificity of 89% to 100%.77 However, more recent studies have called use of absolute pulmonary artery size into question. A study from 2013 suggested that using a cutoff of greater than or equal to 29.5 mm resulted in only a specificity of 79.4%, and the authors suggested using a cutoff of greater than or equal to 32 mm, which results in a specificity of 90.2%.78 A study from 2016 demonstrated an even lower specificity of 62% when using the same cutoff, and the authors suggested that such evaluation of absolute pulmonary artery diameter may not be adequate for clinical use.79 It is our current clinical practice to suggest the possibility of PAH when the main pulmonary artery diameter is greater than or equal to 32.5 mm, while recognizing that a significant number of these patients will be considered falsely positive after evaluation by echocardiography. Of interest, despite these issues with pulmonary artery size, there is some evidence that changes in size over time in an individual patient may have significant prognostic value, with one study demonstrating increasing mortality (hazard ratio, 1.33) for every 1-mm increase in pulmonary artery size over time.80 An alternative simple method is to assess the relative diameters of pulmonary artery and thoracic aorta at the same anatomic level. When pulmonary artery diameter exceeds that of the thoracic aorta, pulmonary hypertension is likely with a specificity of 92% and a positive predictive value of 93%. However, given the propensity for the aorta to dilate, particularly in the elderly, the pulmonary artery to aorta ratio has a relatively low negative predictive value and sensitivity of 44% and 70%, respectively.81 Within the lungs, the diameter of the pulmonary artery should be approximately equal to that of its neighboring bronchus in normal subjects. In patients with pulmonary hypertension or

increased blood flow or volume, significant dilatation of these small vessels relative to adjacent bronchi may be present.82 There may be concomitant attenuation of peripheral pulmonary vascular markings (pruning). In a study by Tan and colleagues,83 a main pulmonary artery diameter of 29 mm or more, accompanied by a segmental artery to bronchus ratio of greater than 1 in three of four pulmonary lobes, had a 100% specificity for pulmonary hypertension in patients with intrinsic lung disease. Cardiac morphology should not be overlooked in evaluating thoracic CT. Dilatation of the right-sided heart chambers and hypertrophy of the right ventricle can be readily appreciated. Although echocardiography and MRI enable assessment of true long and short cardiac axes, measurements have been validated on CT transverse images. The upper limits for the transverse diameter of the right atrium and right ventricle are 35 mm and 45 mm, respectively.84 The enlarged right ventricle may encroach on the left ventricular cavity, resulting in abnormal systolic and diastolic function of the left ventricle. Enlargement of the central pulmonary veins at the level of the left atrium is usually subjective. Early opacification of the inferior vena cava or hepatic veins on first-pass contrast-enhanced CT almost invariably indicates tricuspid regurgitation (see Fig. 53.8).85 CT is also reasonably good for detecting intracardiac shunts and anomalous pulmonary venous drainage. Pericardial thickening or effusion is a frequent finding in patients with severe pulmonary hypertension.86 Rarely, thrombus may be present in the right atrium or ventricle. Ancillary findings indicating right-sided heart failure are the presence of ascites, features of hepatic congestion and cirrhosis, and peripheral edema. Idiopathic PAH shows a dilated main pulmonary artery on CT with abrupt tapering of tortuous peripheral pulmonary vessels. As with other forms of pulmonary hypertension, there is rightsided cardiac chamber enlargement that may or may not be associated with tricuspid regurgitation. In a study by Baque-Juston

666

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

A

B

C

D Fig. 53.8  Idiopathic pulmonary arterial hypertension. (A) Coronal maximum-intensity projection image from a CT scan demonstrates enlarged central pulmonary arteries. (B) Contrast-enhanced CT image at the level of the right pulmonary artery demonstrates dilatation of the main pulmonary artery, which is larger than the adjacent ascending aorta. (C) CT image at the level of the tricuspid valve shows enlargement of the right atrium and ventricle with leftward bowing of the interventricular septum. (D) CT image at the level of the liver shows reflux of contrast medium into the inferior vena cava and hepatic veins, indicating tricuspid regurgitation.

and colleagues,86 moderate pericardial thickening of more than 2 mm or effusion was seen in 53% of a subgroup of patients with severe pulmonary hypertension. The presence of a pericardial effusion is a poor prognostic sign. In general, the lungs are normal; however, cholesterol granulomas are seen in cases of severe pulmonary hypertension and are manifested on CT as small, poorly defined, low-attenuating centrilobular nodules mimicking the appearance of infection, respiratory bronchiolitis, hypersensitivity pneumonitis, or aspiration.87 Regional variations in parenchymal perfusion can cause a mosaic pattern of lung attenuation.88 In situ thrombosis caused by reduced flow in the proximal vessels is often identified on CT in severe idiopathic PAH. It is

typically central and nonocclusive, permitting its differentiation from chronic organized emboli in CTEPH, which is usually occlusive and predominates in the lower lobes.89 Congenital Systemic-Pulmonary Shunts (Congenital Heart Disease) Although CT is not the primary imaging modality in patients with known cardiac shunts, it is a front-line investigation in patients with suspected pulmonary hypertension, and therefore careful evaluation for features suggestive of a shunt is essential, with the caveat that CT has limited use in functional evaluation of shunts (Fig. 53.9). Linear calcification and in situ nonocclusive thrombus may be evident in the central pulmonary arteries at

53  Pulmonary Arterial Hypertension

A

B Fig. 53.9  Pulmonary hypertension caused by congenital shunt detected on CT pulmonary angiogram performed as a part of routine workup for pulmonary hypertension. (A) CT angiogram depicts a large atrial septal defect with in situ thrombus in the left lower lobe pulmonary artery. Peripheral calcification is seen around the thrombus. (B) CT angiogram shows a communication between the left pulmonary artery and the aortic isthmus characteristic of a patent ductus arteriosus. (Fig. 53.9B reproduced with permission from Abbara S, Walker CM. Patent ductus arteriosus. In: Abbara S. Diagnostic Imaging: Cardiovascular. 2nd ed. Philadelphia: Amirsys; 2013.)

CT. In case of a PDA, mural calcification or aneurysmal dilatation of the ductus may be identified. A significant challenge in assessing shunts is the limited functional data CT provides. Pulmonary Venoocclusive Disease and Pulmonary Capillary Hemangiomatosis PVOD causes interstitial edema and fibrosis resulting from venular obstruction. On CT this is manifested by widespread smooth, interlobular septal thickening, which is both more frequent and extensive than in patients with idiopathic pulmonary hypertension

667

Fig. 53.10  Pulmonary venoocclusive disease. High-resolution CT image in a patient with pulmonary hypertension associated with significant venous involvement shows widespread ground-glass opacities with centrilobular nodules and smooth interlobular septal thickening in histologically proven pulmonary venoocclusive disease.

Fig. 53.11  Pulmonary capillary hemangiomatosis (PCH). High-resolution CT image in a patient with pulmonary hypertension associated with significant capillary involvement shows heterogeneous parenchymal attenuation with patchy ground-glass opacity in PCH.

(Fig. 53.10). Other common CT findings include central and gravity-dependent ground-glass opacity, multiple small centrilobular nodules, and areas of consolidation associated with normal-caliber or small central pulmonary veins (see Fig. 53.10).90,91 Ground-glass opacities are more frequent in PVOD than in other causes of pulmonary hypertension.88,92 The pathologic correlate of ground-glass opacity in PVOD is uncertain but may result from alveolar septal thickening with associated hyperplasia of lining epithelium and is believed to represent varying regions of underperfusion and interstitial edema.93 Hilar and mediastinal lymphadenopathy is significantly more frequent in PVOD than in other causes of idiopathic pulmonary hypertension.94 Small pericardial effusions can also be present. The high-resolution CT findings of PCH consist of peribronchial cuffing, patchy areas of ground-glass opacity (Fig. 53.11), and poorly defined centrilobular ground-glass nodules caused by capillary proliferation.95 Smooth interlobular septal thickening may be present as well. There may therefore be overlap between the imaging and hemodynamic findings in PVOD and PCH,

668

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

A

B Fig. 53.12  Pulmonary hypertension in systemic sclerosis and CREST (calcinosis, Raynaud disease, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome. (A) CT image at the level of the main bronchi shows mild peripheral reticulation in keeping with interstitial fibrosis in addition to subtle heterogeneity of lung attenuation consistent with a pulmonary vasculopathy. (B) CT image at the level of the tricuspid valve shows right-sided cardiac chamber enlargement, a small pericardial effusion, and a dilated fluid-filled esophagus in keeping with esophageal dysmotility.

but these differ from those seen in other causes of pulmonary hypertension. Left-Sided Heart Disease CT often complements echocardiography by demonstrating an intracardiac soft tissue mass with additional evidence of extracardiac extension when it is present, interstitial edema, vascular congestion, pleural effusions, and enlargement of central vessels resulting from secondary PAH.96 Cardiac chamber enlargement and valvular abnormalities can be identified sometimes as well (see Fig. 53.7). Pulmonary Arterial Hypertension Associated With Pleuroparenchymal Lung Disease Radiographic and CT findings consist of a combination of the features of the underlying pleuroparenchymal disorder and signs of pulmonary hypertension, with dilated right-sided heart chambers and proximal pulmonary vasculature (Fig. 53.12). In patients with interstitial fibrosis, the severity of pulmonary hypertension in affected individuals correlates with the degree of central pulmonary artery dilatation and the extent of parenchymal disease.97 In CTD, when there is a combination of interstitial fibrosis and pulmonary vasculopathy, the severity of pulmonary hypertension may be disproportionate to the severity of parenchymal lung disease.98 Chronic Thromboembolic Pulmonary Hypertension CT is often used to visualize central- and segmental-vessel thromboembolism.23,99 It has greater sensitivity and accuracy for depicting central CTEPH than either pulmonary angiography or MRI does,100 and it is more specific than scintigraphy.101 Ventilation-perfusion (VQ) scintigraphy has a high sensitivity and specificity for detection of chronic thromboembolic disease and is still used as a first-line imaging modality at some institutions.102,103 However, CTA has become a more popular technique in the evaluation of suspected CTEPH and also has very high accuracy. CT features in CTEPH consist of eccentric flattened mural thrombi that may be occlusive or have areas of recanalization.104 Chronically occluded vessels are

Fig. 53.13  Pulmonary artery sarcoma. Contrast-enhanced CT image shows a large intravascular filling defect in the right pulmonary artery extending into the proximal lobar vessels. This is occlusive and unilateral, features suggestive of tumor.

often smaller than expected. Calcifications can be observed in approximately 10% of patients.105 The wall-adherent organized thrombotic material is much more easily visualized on CT than at angiography. Please see Chapter 51 for a more complete discussion of CTEPH. Primary Pulmonary Artery Sarcoma Sarcoma is an uncommon cause of an intraluminal arterial filling defect. These intravascular tumors are manifested as unilateral, lobulated, heterogeneously enhancing masses at CT. They may demonstrate vascular distention and local extravascular spread. Unlike acute and chronic pulmonary embolism, pulmonary artery sarcoma demonstrates enhancement. Pulmonary artery sarcoma is lobulated and forms acute angles with the vessel wall (Fig. 53.13), whereas chronic pulmonary embolism forms obtuse angles.106

53  Pulmonary Arterial Hypertension

669

sufficient and permanent occlusion of the microvascular bed, cor pulmonale develops, with dilatation of the central pulmonary arteries and evidence of right ventricular hypertrophy.110 MAGNETIC RESONANCE IMAGING

Fig. 53.14  Takayasu arteritis. Contrast-enhanced CT image demonstrates diffuse thickening of the wall of the left and upper lobe pulmonary arteries in a patient with biopsy-proven Takayasu arteritis. The aorta and supraaortic vessels were normal.

Vasculitis Takayasu arteritis is a large-vessel arteritis that affects the proximal pulmonary vasculature (Fig. 53.14). Aortic and systemic artery involvement usually overshadows any pulmonary manifestations, although isolated pulmonary artery involvement with consequent pulmonary hypertension has been described. Multiple pulmonary stenoses resulting from focal thickening of vessel wall can be mistaken for CTEPH, but the vessel contour is smooth, and there may be delayed contrast enhancement on CT and MRI resulting from the inflammatory nature of the disease.107 Fibrosing Mediastinitis Fibrosing mediastinitis can result in pulmonary hypertension and may be difficult to distinguish from unilateral chronic thromboembolism. Pulmonary vascular occlusion is produced by fibrous encasement of the pulmonary arteries or veins in a nonuniform pattern. There may be constriction of individual pulmonary veins with asymmetric mediastinal widening and calcifications accompanied by a hilar mass and ipsilateral Kerley B lines and peripheral wedge-shaped consolidation resulting from venous infarction.108 Pulmonary angiography reveals unilateral or asymmetric narrowing of central pulmonary arteries and distal arterial cutoffs when mediastinal fibrosis affects the arterial side of the pulmonary circulation. With involvement of pulmonary veins, the venous-phase angiograms show nonuniform pulmonary vein obstruction, stenosis, or focal dilatation near the left atrium. Contrast-enhanced CT elegantly demonstrates the degree of vascular compromise while also demonstrating the extent of mediastinal involvement. Nonthrombotic Emboli Please see Chapters 14 and 52 for a complete discussion on nonthrombotic pulmonary emboli, including pulmonary tumor emboli, parasitic emboli, pulmonary talcosis, fat emboli, and foreign-body emboli. In sickle cell disease, recurrent episodes of acute chest syndrome, with capillary obstruction and accompanying in situ thrombosis,109 may lead to chronic changes. Approximately half of patients show evidence of interstitial disease, probably reflecting scarring from small pulmonary infarcts. Ultimately, if there is

MRI techniques enable noninvasive morphologic and functional assessment. MRI permits evaluation of cardiac chamber dimensions, ventricular muscle mass, and wall motion. Contrastenhanced MR angiography (MRA) depicts the pulmonary vasculature, and morphologic images show good correlation with those of angiography. However, the additional functional data provided by velocity-encoded cine phase-contrast MRI also permit accurate and precise assessment of pulmonary and systemic blood flow and shunt quantification. It is important to note that the main role in MRI is to help identify the functional impact of PAH on the right heart, assess prognosis in PAH as well as aid in identification of etiology. However, it lacks necessary sensitivity to rule out PAH. In general, MRI studies of patients with pulmonary hypertension show the characteristic anatomic changes of right ventricular hypertrophy, reversal of septal curvature, and dilatation of pulmonary arteries. Another observation is abnormal intravascular signal corresponding to slow pulmonary arterial blood flow on gated spin-echo MRI in 92% of cases of PAH, notably with a direct relationship to elevated PVR.111 As in CT, a basic linear correlation has been demonstrated between pulmonary arterial pressure and the ratio of pulmonary artery to aortic size.112 Additionally, because the pulmonary artery plays an important role in converting the pulsatile right ventricular flow into nearly steady flow at the capillary level, evaluation of pulmonary artery distensibility or stiffness has been a subject of investigation. Multiple studies dating to 1989 have found that increased stiffness (or decreased distensibility) of the pulmonary artery between diastole and systole corresponds with increased RV workload and increased energy transmission from the RV to the small pulmonary vessels, leading to increased vascular damage.113–120 More recent data suggests that reductions in pulmonary artery elasticity occur before overt pressure elevations occur, and such an evaluation could be useful for early detection of PAH.121 Similar data has been achieved in multiphase CTA as well.122 Gradient-echo and balanced steady-state free precession cine MRI permits assessment of right and left ventricular function and is the gold standard for biventricular structure and function. Specifically, the assessment of right-sided heart structure and function is largely performed via cardiac MRI. Direct measurement of right and left ventricular stroke volume, ejection fraction, cardiac output, and shunt fractions is a sensitive, noninvasive method of detecting hemodynamic changes in patients with pulmonary hypertension.123 In pulmonary hypertension the ventricular geometry is disturbed, and therefore accurate volume estimations are difficult to obtain from single-plane acquisitions. With volumetric MRI, ventricular volumes can be measured independently of any geometric assumption, in contradistinction to echocardiography.124 In addition, MRI is the gold standard examination for the evaluation of CHD, given the ability to not only assess anatomy but also physiology. Velocity-encoded cine phase-contrast MRI allows direct calculation of pulmonic and systemic flow, allowing reliable shunt fractions. It is particularly useful for the evaluation of supracristal ventricular septal defect, atrioventricular septal defect, and partial anomalous pulmonary venous drainage, in which echocardiography and conventional angiography have

670

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

A MPA RPA

A

B

RA

LA Fig. 53.15  Pulmonary arterial hypertension caused by an atrial septal defect. (A) Posteroanterior chest radiograph shows cardiomegaly and marked enlargement of the central pulmonary arteries. Although there is rapid tapering, increased vascularity still is present in the lung periphery, particularly evident on the right. (B) Cardiac-gated spin-echo MRI shows enlargement of the main (MPA) and right (RPA) pulmonary arteries. The diameter of the main pulmonary artery is considerably larger than that of the aorta (A). (C) MRI at the level of the right atrium (RA) and left atrium (LA) shows an atrial septal defect (arrow). (From Müller NL, Fraser RS, Colman NC, Paré PD. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

limited use (Fig. 53.15). The combination of fast MR perfusion imaging and high-spatial-resolution MRA with parallel acquisition techniques also enables the differentiation of idiopathic PAH from CTEPH with high accuracy.125 On MRI, in addition to the generic features such as right ventricular hypertrophy and dilatation, idiopathic PAH demonstrates symmetrically enlarged central pulmonary arteries, diffuse pattern of abruptly tapering and pruned subsegmental vessels, filamentous or “corkscrew” peripheral arteries, and occasionally subpleural collateral vessels, similar to the findings on angiography. MRI permits monitoring of cardiac function in response to therapy in patients with idiopathic pulmonary hypertension without the use of ionizing radiation. A study by Bergin and colleagues126 demonstrated that MRA had accuracy identical to that of radionuclide scanning (92%) in distinguishing patients with CTEPH from those with idiopathic PAH.

C

ECHOCARDIOGRAPHY Doppler echocardiography is the most common and readily available noninvasive method for assessing cardiac anatomy and function. Because echocardiography permits assessment of right-sided heart function and the estimation of pulmonary artery pressure, it forms part of both the initial diagnostic workup and the follow-up of patients with clinically suspected pulmonary hypertension. Tricuspid regurgitation is detected in more than 90% of patients with severe pulmonary hypertension. The velocity of the regurgitant jet across the tricuspid valve as assessed by Doppler echocardiography can be used to estimate peak pulmonary artery pressure, although its accuracy is imperfect. A tricuspid regurgitant velocity of 3.0 m/s on echocardiography corresponds to pulmonary pressure greater than 30 mm Hg. Although in general these estimates correlate well with invasive measurements of right

53  Pulmonary Arterial Hypertension

ventricular pressures, an individual estimate may be inaccurate. In particular, echocardiography has only limited ability to differentiate between mild pulmonary hypertension and normal pulmonary hemodynamics.127 Right ventricular myocardial hypertrophy, paradoxical septal motion, abnormal systolic intervals, and abnormal pulmonary valve motion may become apparent as disease progresses. Transesophageal echocardiography may be used to detect intracardiac shunts, particularly small patent foramen ovale and sinus venosus atrioseptal defects, which are notoriously difficult

671

to diagnose on transthoracic echocardiography. Transesophageal echocardiography is also valuable for the assessment of valvular structures and other structural lesions, such as left atrial myxomas. NUCLEAR MEDICINE The main role of VQ lung scintigraphy is to differentiate chronic thromboembolic disease from other causes of pulmonary hypertension as it is often nonspecifically abnormal in the setting of nonthromboembolic disease (Fig. 53.16). In thromboembolic

A

B

C

D Fig. 53.16  Comparison of idiopathic pulmonary arterial hypertension (PAH) and chronic thromboembolic disease: ventilation and perfusion lung scintigraphy in two different patients. (A) and (B) In a patient with idiopathic PAH, anterior views show normal ventilation (A) with heterogeneous, mottled perfusion pattern (B). (C) and (D) In a patient with chronic thromboembolic disease, anterior views show normal ventilation (C) and multiple segmental perfusion defects (D).

672

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

disease there is segmental reduction in perfusion with maintenance of normal ventilation, leading to mismatch of perfusion and ventilation in the affected bronchopulmonary segment. VQ scintigraphy has a sensitivity of 90% to 100% and a specificity of 94% to 100% for distinguishing between idiopathic pulmonary hypertension and CTEPH, a higher sensitivity than CT angiography.128,129 Mismatched segmental perfusion defects may be seen with other processes that result in obstruction of the central pulmonary arteries, such as mediastinal lymphadenopathy, fibrosing mediastinitis, large-vessel arteritis, pulmonary vascular or bronchogenic tumors, and pulmonary venoocclusive disease. Whereas segmental or lobar perfusion defects are typical in CTEPH, the perfusion scan in idiopathic PAH is either normal or has low probability for pulmonary embolism with patchy subsegmental areas of reduced perfusion or “mottling” (see Fig. 53.16).130 However, there are issues about the potential fallibility of the perfusion lung scan in making the differential diagnosis and the decisions regarding anticoagulant therapy. In some patients with advanced primary pulmonary hypertension, there is scintigraphic evidence of reversed mismatching (i.e., pulmonary perfusion of areas of lung showing little or no ventilation). CT studies have demonstrated that such areas show normal or engorged pulmonary vasculature, with areas of increased parenchymal attenuation that are shown to have ventilatory defects at scintigraphy.95 The role of perfusion scintigraphy in other conditions is less clear. On perfusion scintigraphy in the presence of right-to-left shunt, activity in the thyroid or kidneys can be seen and used to calculate shunt fraction. VQ scintigraphy in parenchymal lung disease may demonstrate matched ventilation and perfusion defects. When unilateral lung transplantation is being considered, perfusion scintigraphy can be used to select the side with the most compromised function. Pulmonary Venoocclusive Disease In PVOD perfusion scans commonly reveal patchy distribution of tracer material without clear segmental or subsegmental defects; ventilation scans are normal. This VQ mismatch may lead to a misdiagnosis of CTEPH. Unilateral absence of perfusion can be due to severe asymmetric involvement of the major pulmonary veins. ANGIOGRAPHY Right-sided heart catheterization is often performed independently but may be performed at the same time as pulmonary angiography. A flotation catheter is passed from the vena cava through to a lobar pulmonary artery. It permits evaluation of pulmonary hemodynamics and cardiac function and assessment of dynamic response to pharmacologic stimuli. Measurement of oxygen saturations in the vena cava, the right chambers of the heart, and the pulmonary artery may identify previously unsuspected left-to-right shunting. In addition, an acute vasodilator challenge can be performed during right-sided heart catheterization to identify patients likely to respond to specific therapy.131 Pulmonary angiography is the gold standard technique for defining the pulmonary vascular anatomy, but modern CT and MRI techniques are now commonplace as noninvasive alternatives. With careful monitoring and modification of standard angiographic procedures, pulmonary angiography can be performed

safely even in patients with severe pulmonary hypertension. The procedure has a 1.5% incidence of serious complications, with a mortality rate of 0.5%.132 It has excellent temporal resolution, with resultant decrease in motion artifact and venous contamination compared with CT and MRI. Pulmonary angiography can also be used in the setting of CTEPH, in which it may help confirm disease location and surgical accessibility in cases where CTA is equivocal. Although pulmonary angiography is now seldom performed in PVOD, it typically shows enlarged central pulmonary arteries and right ventricle, with a prolonged parenchymal enhancement phase resulting in delayed filling of normal-sized or small pulmonary veins and a normal or small left atrium.133 Pulmonary venography shows focal venous obstructions, a finding highly suggestive of the diagnosis of PVOD. IMAGING ALGORITHM Pulmonary hypertension presents with nonspecific symptoms and signs. Imaging plays a pivotal role, not only in confirming the presence of pulmonary hypertension but also in elucidating an underlying cause. Although there exists a range of available imaging modalities, consideration should be given to factors such as ionizing radiation exposure and the invasive nature of some examinations with their attendant risks. The diagnostic strategy should be tailored to suit an individual institution, depending on local expertise, ease of access, and cost. All patients presenting with suspected pulmonary hypertension will have chest radiography. If it shows the now familiar complex of proximal pulmonary artery enlargement and cardiomegaly, further investigation with echocardiography is warranted. In the context of a normal radiograph but high clinical suspicion, echocardiography provides a simple and noninvasive method to rule pulmonary hypertension in or out. Echocardiography not only can confirm pulmonary hypertension but also can provide a clue as to the underlying mechanism. No further investigation is required if the echocardiogram is completely normal. If a cardiac cause of pulmonary hypertension is identified on echocardiography or the patient is seen to have an unexpected shunt, patients should proceed to MRI for definitive evaluation. This might be sufficient if patients need conservative or medical management only. However, when surgery is considered, right-sided heart catheterization is useful for further disease definition. Where there is no definitive cardiac cause on echocardiography, a combination of CT pulmonary angiography and/or highresolution CT provides a diagnosis in the majority of patients. Any further testing will depend on the result of CT. Not infrequently, unexpected intracardiac shunts can be seen on CT angiography. These cases will need further assessment with right-sided heart catheterization and MRI. Parenchymal lung disease is readily detected on CT and should be correlated with lung function test results. Pulmonary venoocclusive disease may be confused with pulmonary edema or interstitial fibrosis. Idiopathic pulmonary hypertension is a diagnosis of exclusion. When the CT findings are equivocal, VQ scintigraphy may be useful to exclude distal thromboembolic disease. Many centers use VQ scintigraphy as a frontline examination before CT. Undoubtedly, it is a useful screening test valuable for the exclusion of CTEPH. However, in other conditions, the findings are too nonspecific to be reliable. In the absence of a normal or highprobability VQ scan, the diagnostic conundrum continues, and the pathway may have to revert to CT or MRI.

53  Pulmonary Arterial Hypertension KEY POINTS: PULMONARY HYPERTENSION • Causes of pulmonary hypertension can be divided into precapillary and postcapillary etiologies. The alternative World Health Organization classification scheme includes pulmonary arterial hypertension (PAH) (group 1), pulmonary hypertension related to left heart disease (group 2), pulmonary hypertension related to pulmonary parenchymal disease (group 3), chronic thromboembolic pulmonary hypertension (group 4), and multifactorial or unclear disease (group 5). • Prognosis in patients with idiopathic PAH has improved with newer targeted medical therapies. • Echocardiography permits estimation of pulmonary artery pressure and is useful as a screening tool and in follow-up. • Echocardiography and MRI are the imaging modalities of choice for detection of cardiac abnormalities. • Right-sided cardiac chamber size, function, and hemodynamics are key predictors of prognosis, with cardiac MRI being the gold standard for assessment. • Radiographs are frequently abnormal in cases of pulmonary hypertension, but a negative chest radiograph does not exclude disease. • CT evaluation of the pulmonary arteries and/or lung parenchyma can provide important insights into the etiology of the pulmonary hypertension. • CT features of pulmonary venoocclusive disease and pulmonary capillary hemangiomatosis include smooth interlobular septal thickening, ground-glass opacities, centrilobular nodules, pleural effusion, and mediastinal lymphadenopathy. Differentiation of these from precapillary vasculopathy is important as vasodilator therapy can lead to fatal pulmonary edema. • The main role of ventilation-perfusion lung scintigraphy is to differentiate chronic thromboembolic disease from other causes of pulmonary hypertension.

673

SUGGESTED READINGS Ascha M, et al. A review of imaging modalities in pulmonary hypertension. Ann Thorac Med. 2017;12(2):61–73. Francois CJ, Schiebler ML. Imaging of pulmonary hypertension. Radiol Clin North Am. 2016;54(6):1133–1149. Ruggiero A, Screaton NJ. Imaging of acute and chronic thromboembolic disease: state of the art. Clin Radiol. 2017;72(5):375–388.

The full reference list for this chapter is available at ExpertConsult.com.

53  Pulmonary Arterial Hypertension 673.e1

REFERENCES 1. Hatano S, Strasser R, eds. Primary Pulmonary Hypertension. Geneva: World Health Organization; 1975. 2. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54:S43–S54. 3. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34–D41. 4. Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet. 2000;37:741–745. 5. Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis. 2003;62:1088–1093. 6. Sacks DG, Okano Y, Steen VD, et al. Isolated pulmonary hypertension in systemic sclerosis with diffuse cutaneous involvement: association with serum anti-U3RNP antibody. J Rheumatol. 1996;23:639–642. 7. Burdt MA, Hoffman RW, Deutscher SL, et al. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum. 1999;42:899–909. 8. Petrosillo N, Chinello P, Vizza D, Cicalini S. Pulmonary hypertension and HIV: implementation of a regional registry [in Italian]. Infez Med. 2005; 13:5–15. 9. Pellicelli AM, Barbaro G, Palmieri F, et al. Primary pulmonary hypertension in HIV patients: a systematic review. Angiology. 2001;52:31–41. 10. Mesa RA, Edell ES, Dunn WF, Edwards WD. Human immunodeficiency virus infection and pulmonary hypertension: two new cases and a review of 86 reported cases. Mayo Clin Proc. 1998;73:37–45. 11. Meyer CA, White CS, Sherman KE. Diseases of the hepatopulmonary axis. Radiographics. 2000;20:687–698. 12. Montani D, Achouh L, Dorfmuller P, et al. Pulmonary venoocclusive disease: clinical, functional, radiologic, and hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine (Baltimore). 2008;87(4): 220–233. 13. Montani D, Price LC, Dorfmuller P, et al. Pulmonary venoocclusive disease. Eur Respir J. 2009;33(1):189–200. 14. Wagenvoort CA. Lung biopsy specimens in the evaluation of pulmonary vascular disease. Chest. 1980;77(5):614–625. 15. Bjornsson J, Edwards WD. Primary pulmonary hypertension: a histopathologic study of 80 cases. Mayo Clin Proc. 1985;60(1):16–25. 16. Yi ES, Kim H, Ahn H, et al. Distribution of obstructive intimal lesions and their cellular phenotypes in chronic pulmonary hypertension. A morphometric and immunohistochemical study. Am J Respir Crit Care Med. 2000;162(4 Pt 1):1577–1586. 17. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173(9):1023–1030. 18. Mandel J, Mark EJ, Hales CA. Pulmonary veno-occlusive disease. Am J Respir Crit Care Med. 2000;162:1964–1973. 19. Lombard CM, Churg A, Winokur S. Pulmonary veno-occlusive disease following therapy for malignant neoplasms. Chest. 1987;92:871–876. 20. Mehta NJ, Karmody AM, McKneally MF. Mediastinal veno-occlusive disease associated with herbal tea ingestion. N Y State J Med. 1986;86: 604–605. 21. Scharf SM, Iqbal M, Keller C, et al. Hemodynamic characterization of patients with severe emphysema. Am J Respir Crit Care Med. 2002;166: 314–322. 22. Moser KM, Auger WR, Fedullo PF. Chronic major-vessel thromboembolic pulmonary hypertension. Circulation. 1990;81:1735–1743. 23. Kauczor HU, Heussel CP, Thelen M. Update on diagnostic strategies of pulmonary embolism. Eur Radiol. 1999;9:262–275. 24. Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350:2257–2264. 25. Riedel M, Stanek V, Widimsky J, Prerovsky I. Longterm follow-up of patients with pulmonary thromboembolism. Late prognosis and evolution of hemodynamic and respiratory data. Chest. 1982;81:151–158. 26. Peacock AJ, Murphy NF, McMurray JJ, et al. An epidemiological study of pulmonary arterial hypertension. Eur Respir J. 2007;30:104–109. 27. Frost AE, Badesch DB, Barst RJ, et al. The changing picture of patients with pulmonary arterial hypertension in the United States: how REVEAL differs from historic and non-US contemporary registries. Chest. 2011;139: 128–137.

28. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France. Results from a national registry. Am J Respir Crit Care Med. 2006;173:1023–1030. 29. Escribano-Subias P, Blanco I, López-Meseguer M, et al. Survival in pulmonary hypertension in Spain: insights from the Spanish registry. Eur Respir J. 2012;40:596–603. 30. Ling Y, Johnson MK, Kiely DG, et al. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am J Respir Crit Care Med. 2012;186:790–796. 31. Jansa P, Jarkovsky J, Al-Hiti H, et al. Epidemiology and long-term survival of pulmonary arterial hypertension in the Czech Republic: a retrospective analysis of a nationwide registry. BMC Pulm Med. 2014;14:45. 32. McGoon MD, Benza RL, Escribano-Subias P, et al. Registries of pulmonary arterial hypertension. JACC. 2013;62(suppl D):D51–D59. 33. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343–349. 34. Benza RL, Miller DP, Barst RJ, et al. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL registry. Chest. 2012;142(2):448–456. 35. Robalino BD, Moodie DS. Association between primary pulmonary hypertension and portal hypertension: analysis of its pathophysiology and clinical, laboratory and hemodynamic manifestations. J Am Coll Cardiol. 1991;17:492–498. 36. Hervé P, Lebrec D, Brenot F, et al. Pulmonary vascular disorders in portal hypertension. Eur Respir J. 1998;11:1153–1166. 37. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67–119. 38. Fuster V, Steele PM, Edwards WD, et al. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. 1984;70: 580–587. 39. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992;327:76–81. 40. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;334:296–302. 41. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106: 1477–1482. 42. Olschewski H, Simonneau G, Galiè N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347:322–329. 43. Simonneau G, Barst RJ, Galiè N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165:800–804. 44. Zheng Y, Yang T, Chen G, Hu E, Gu Q, Xiong C. Prostanoid therapy for pulmonary arterial hypertension: a meta-analysis of survival outcomes. Eur J Clin Pharmacol. 2014;70(1):13–21. 45. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896–903. 46. Wilkins MR, Paul GA, Strange JW, et al. Sildenafil versus endothelin receptor antagonist for pulmonary hypertension (SERAPH) study. Am J Respir Crit Care Med. 2005;171:1292–1297. 47. Ghofrani H-A, D’Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369:319–329. 48. Ghofrani H-A, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330–340. 49. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369: 809–818. 50. Galiè N, Ghofrani HA, Trobicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148–2157. 51. Galiè N, Neuser D, Muller K, et al. A placebo-controlled, double-blind phase II interaction study to evaluate blood pressure following addition of riociguat to patients with symptomatic pulmonary arterial hypertension (PAH) receiving sildenafil (PATENT PLUS). Am J Respir Crit Care Med. 2013;187(suppl):A3530.

673.e2

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

52. Simonneau G, Rubin LJ, Galiè N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008;149:521–530. 53. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010;55:1915–1922. 54. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:1257–1263. 55. Hoeper MM, Leuchte H, Halank M, et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2006;28:691–694. 56. Iversen K, Jensen AS, Jensen TV, et al. Combination therapy with bosentan and sildenafil in Eisenmenger syndrome: a randomized, placebo-controlled, double-blinded trial. Eur Heart J. 2010;31:1124–1131. 57. Galiè N, Negro L, Simonneau G. The use of combination therapy in pulmonary arterial hypertension: new developments. Eur Respir Rev. 2009;18:148–153. 58. Tapson VF, Torres F, Kermeen F, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial. Chest. 2012;142: 1383–1390. 59. Tapson VF, Jing ZC, Xu KF, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. Chest. 2013;144: 952–958. 60. Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004;24:353–359. 61. McLaughlin V, Channick R, Ghofrani HA, et al. Effect of bosentan and sildenafil combination therapy on morbidity and mortality in pulmonary arterial hypertensino (PAH): results from the COMPASS-2 study. Chest. 2014;146:860A. 62. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med. 1980;93:391–398. 63. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party. Lancet. 1981;1:681–686. 64. Chang CH. The normal roentgenographic measurement of the right descending pulmonary artery in 1,085 cases. Am J Roentgenol Radium Ther Nucl Med. 1962;87:929–935. 65. Müller N, Fraser RS, Colman N, Paré P. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001. 66. Gutierrez FR, Moran CJ, Ludbrook PA, et al. Pulmonary arterial calcification with reversible pulmonary hypertension. AJR Am J Roentgenol. 1980;135: 177–178. 67. Schmidt HC, Kauczor HU, Schild HH, et al. Pulmonary hypertension in patients with chronic pulmonary thromboembolism: chest radiograph and CT evaluation before and after surgery. Eur Radiol. 1996;6:817–825. 68. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107:216–223. 69. Higgins C. Essentials of Cardiac Radiology and Imaging. Philadelphia: JB Lippincott; 1992. 70. Virmani RRW. Adult Congenital Heart Disease. Philadelphia: FA Davis; 1987. 71. Scheibel RL, Dedeker KL, Gleason DF, et al. Radiographic and angiographic characteristics of pulmonary veno-occlusive disease. Radiology. 1972;103: 47–51. 72. Chawla SK, Kittle CF, Faber LP, Jensik RJ. Pulmonary venoocclusive disease. Ann Thorac Surg. 1976;22:249–253. 73. Rich S, Rubin LJ, Abenhaim L, et al. Executive summary from the World Symposium on Primary Pulmonary Hypertension; Evian, France; September 6-10, 1998, cosponsored by the World Health Organization. Available at: http://www.who.int/ncd/cvd/pph.html. 74. Mandel J, Mark EJ, Hales CA. Pulmonary veno-occlusive disease. Am J Respir Crit Care Med. 2000;162:1964–1973. 75. Moser KM, Auger WR, Fedullo PF, Jamieson SW. Chronic thromboembolic pulmonary hypertension: clinical picture and surgical treatment. Eur Respir J. 1992;5:334–342. 76. Lee KN, Lee HJ, Shin WW, Webb WR. Hypoxemia and liver cirrhosis (hepatopulmonary syndrome) in eight patients: comparison of the central and peripheral pulmonary vasculature. Radiology. 1999;211:549–553. 77. Kuriyama K, Gamsu G, Stern RG, et al. CT-determined pulmonary artery diameters in predicting pulmonary hypertension. Invest Radiol. 1984;19: 16–22.

78. Mahammedi A, Oshmyansky A, Hassoun PM, Thiemann DR, Siegelman SS. Pulmonary artery measurements in pulmonary hypertension: the role of computed tomography. J Thorac Imaging. 2013;28(2):96–103. 79. Terpenning S, et al. CT measurement of central pulmonary arteries to diagnose pulmonary hypertension (PHTN): more reliable than valid? Clin Imaging. 2016;40(4):821–827. 80. Tonelli AR, Johnson S, Alkukhun L, Yadav R, Dweik RA. Changes in main pulmonary artery diameter during follow-up have prognostic implications in pulmonary arterial hypertension. Respirology. 2017;22:1649–1655. 81. Ng CS, Wells AU, Padley SP. A CT sign of chronic pulmonary arterial hypertension: the ratio of main pulmonary artery to aortic diameter. J Thorac Imaging. 1999;14:270–278. 82. Lee KN, Lee HJ, Shin WW, Webb WR. Hypoxemia and liver cirrhosis (hepatopulmonary syndrome) in eight patients: comparison of the central and peripheral pulmonary vasculature. Radiology. 1999;211:549–553. 83. Tan RT, Kuzo R, Goodman LR, et al. Utility of CT scan evaluation for predicting pulmonary hypertension in patients with parenchymal lung disease. Medical College of Wisconsin Lung Transplant Group. Chest. 1998;113:1250–1256. 84. Resten A, Maitre S, Humbert M, et al. Pulmonary arterial hypertension: thin-section CT predictors of epoprostenol therapy failure. Radiology. 2002;222:782–788. 85. Groves AM, Win T, Charman SC, et al. Semi-quantitative assessment of tricuspid regurgitation on contrast-enhanced multidetector CT. Clin Radiol. 2004;59:715–719. 86. Baque-Juston MC, Wells AU, Hansell DM. Pericardial thickening or effusion in patients with pulmonary artery hypertension: a CT study. AJR Am J Roentgenol. 1999;172:361–364. 87. Nolan RL, McAdams HP, Sporn TA, et al. Pulmonary cholesterol granulomas in patients with pulmonary artery hypertension: chest radiographic and CT findings. AJR Am J Roentgenol. 1999;172:1317–1319. 88. Sherrick AD, Swensen SJ, Hartman TE. Mosaic pattern of lung attenuation on CT scans: frequency among patients with pulmonary artery hypertension of different causes. AJR Am J Roentgenol. 1997;169:79–82. 89. Rich S. The role of thrombosis in pulmonary hypertension. Chest. 1993;103:660–661. 90. Dufour B, Maitre S, Humbert M, et al. High-resolution CT of the chest in four patients with pulmonary capillary hemangiomatosis or pulmonary venoocclusive disease. AJR Am J Roentgenol. 1998;171:1321–1324. 91. Swensen SJ, Tashjian JH, Myers JL, et al. Pulmonary venoocclusive disease: CT findings in eight patients. AJR Am J Roentgenol. 1996;167:937– 940. 92. Bergin CJ, Rios G, King MA, et al. Accuracy of high-resolution CT in identifying chronic pulmonary thromboembolic disease. AJR Am J Roentgenol. 1996;166:1371–1377. 93. Holcomb BW Jr, Loyd JE, Ely EW, et al. Pulmonary veno-occlusive disease: a case series and new observations. Chest. 2000;118:1671–1679. 94. Nicod P, Peterson K, Levine M, et al. Pulmonary angiography in severe chronic pulmonary hypertension. Ann Intern Med. 1987;107:565–568. 95. Hansell DM. Small-vessel diseases of the lung: CT-pathologic correlates. Radiology. 2002;225:639–653. 96. Palmer SM, Robinson LJ, Wang A, et al. Massive pulmonary edema and death after prostacyclin infusion in a patient with pulmonary veno-occlusive disease. Chest. 1998;113:237–240. 97. Austin JH, Yount BG Jr, Thomas HM 3rd, Enson Y. Radiologic assessment of pulmonary arterial pressure and blood volume in chronic, diffuse, interstitial pulmonary diseases. Invest Radiol. 1979;14:9–17. 98. Steckel RJ, Bein ME, Kelly PM. Pulmonary arterial hypertension in progressive systemic sclerosis. Am J Roentgenol Radium Ther Nucl Med. 1975;124: 461–464. 99. Remy-Jardin M, Baghaie F, Bonnel F, et al. Thoracic helical CT: influence of subsecond scan time and thin collimation on evaluation of peripheral pulmonary arteries. Eur Radiol. 2000;10:1297–1303. 100. Bergin CJ, Sirlin CB, Hauschildt JP, et al. Chronic thromboembolism: diagnosis with helical CT and MR imaging with angiographic and surgical correlation. Radiology. 1997;204:695–702. 101. Wittram C, Maher MM, Yoo AJ, et al. CT angiography of pulmonary embolism: diagnostic criteria and causes of misdiagnosis. Radiographics. 2004;24:1219–1238. 102. He J, Fang W, Lv B, et al. Diagnosis of chronic thromboembolic pulmonary hypertension: comparison of ventilation/perfusion scanning and multidetector computed tomography pulmonary angiography with pulmonary angiography. Nucl Med Commun. 2012;33(5):459–463. 103. Renapurkar RD, Shrikanthan S, Heresi GA, et al. Imaging in chronic thromboembolic pulmonary hypertension. J Thora Imaging. 2017;32(2): 71–88.

53  Pulmonary Arterial Hypertension 673.e3 104. Kuzo RS, Goodman LR. CT evaluation of pulmonary embolism: technique and interpretation. AJR Am J Roentgenol. 1997;169:959–965. 105. Schwickert H, Schweden F, Schild H, et al. Detection of chronic recurrent pulmonary emboli using spiral-CT [in German]. Rofo. 1993;158:308–313. 106. Remy-Jardin M, Remy J, Cauvain O, et al. Diagnosis of central pulmonary embolism with helical CT: role of two-dimensional multiplanar reformations. AJR Am J Roentgenol. 1995;165:1131–1138. 107. Yamato M, Lecky JW, Hiramatsu K, Kohda E. Takayasu arteritis: radiographic and angiographic findings in 59 patients. Radiology. 1986;161:329–334. 108. Nasser WK, Feigenbaum H, Fisch C. Clinical and hemodynamic diagnosis of pulmonary venous obstruction due to sclerosing mediastinitis. Am J Cardiol. 1967;20:725–729. 109. Leong CS, Stark P. Thoracic manifestations of sickle cell disease. J Thorac Imaging. 1998;13:128–134. 110. Aquino SL, Gamsu G, Fahy JV, et al. Chronic pulmonary disorders in sickle cell disease: findings at thin-section CT. Radiology. 1994;193:807–811. 111. White RD, Higgins CB. Magnetic resonance imaging of thoracic vascular disease. J Thorac Imaging. 1989;4:34–50. 112. Murray TI, Boxt LM, Katz J, et al. Estimation of pulmonary artery pressure in patients with primary pulmonary hypertension by quantitative analysis of magnetic resonance images. J Thorac Imaging. 1994;9:198–204. 113. Lankhaar JW, Westerhof N, Faes TJ, et al. Quantification of right ventricular afterload in patients with and without pulmonary hypertension. Am J Physiol Heart Circ Physiol. 2006;291:H1731–H1737. 114. Gan CT-J, Lankhaar J-W, Westerhof N, et al. Noninvasively assessed pulmonary artery stiffness predicts mortality in pulmonary arterial hypertension. Chest. 2007;132:1906–1912. 115. Sanz J, Kuschnir P, Rius T, et al. Pulmonary arterial hypertension: noninvasive detection with phase-contrast MR imaging. Radiology. 2007;243:70–79. 116. Bogren HG, Klipstein RH, Mohiaddin RH, et al. Pulmonary artery distensibility and blood flow patterns: a magnetic resonance study of normal subjects and of patients with pulmonary arterial hypertension. Am Heart J. 1989;118:990–999. 117. Paz R, Mohiaddin RH, Longmore DB. Magnetic resonance assessment of the pulmonary arterial trunk anatomy, flow, pulsatility and distensibility. Eur Heart J. 1993;14:1524–1530. 118. Tardivon AA, Mousseaux E, Brenot F, et al. Quantification of hemodynamics in primary pulmonary hypertension with magnetic resonance imaging. Am J Respir Crit Care Med. 1994;150:1075–1080. 119. Jardim C, Rochitte CE, Humbert M, et al. Pulmonary artery distensibility in pulmonary arterial hypertension: an MRI pilot study. Eur Respir J. 2007;29:476–481. 120. Muthurangu V, Atkinson D, Sermesant M, et al. Measurement of total pulmonary arterial compliance using invasive pressure monitoring and

MR flow quantification during MR-guided cardiac catheterization. Am J Physiol Heart Circ Physiol. 2005;289:H1301–H1306. 121. Sanz J, Kariisa M, Dellegrottaglie S, Prat-González S, Garcia MJ, Fuster V, Rajagopalan S. Evaluation of pulmonary artery stiffness in pulmonary hypertension with cardiac magnetic resonance. JACC Cardiovasc Imaging. 2009;2(3):286–295. 122. Revel MP, Faivre JB, Remy-Jardin M, Delannoy-Deken V, Duhamel A, Remy J. Pulmonary hypertension: ECG-gated 64-section CT angiographic evaluation of new functional parameters as diagnostic criteria. Radiology. 2009;250(2):558–566. 123. Roeleveld RJ, Vonk-Noordegraaf A, Marcus JT, et al. Effects of epoprostenol on right ventricular hypertrophy and dilatation in pulmonary hypertension. Chest. 2004;125:572–579. 124. Tardivon AA, Mousseaux E, Brenot F, et al. Quantification of hemodynamics in primary pulmonary hypertension with magnetic resonance imaging. Am J Respir Crit Care Med. 1994;150:1075–1080. 125. Nikolaou K, Schoenberg SO, Attenberger U, et al. Pulmonary arterial hypertension: diagnosis with fast perfusion MR imaging and high-spatialresolution MR angiography—preliminary experience. Radiology. 2005;236: 694–703. 126. Bergin CJ, Hauschildt J, Rios G, et al. Accuracy of MR angiography compared with radionuclide scanning in identifying the cause of pulmonary arterial hypertension. AJR Am J Roentgenol. 1997;168:1549–1555. 127. McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(suppl):14S–34S. 128. Fedullo PF, Auger WR, Channick RN, et al. Chronic thromboembolic pulmonary hypertension. Clin Chest Med. 2001;22:561–581. 129. Tunariu N, Gibbs SJR, Win Z, Gin-Sing W, Graham A, Gishen P, AL-Nahhas A. Ventilation-perfusion scintigraphy is more sensitive than multidetector CTPA in detecting chronic thromboembolic pulmonary disease as a treatable cause of pulmonary hypertension. J Nucl Med. 2007;48:680–684. 130. Powe JE, Palevsky HI, McCarthy KE, Alavi A. Pulmonary arterial hypertension: value of perfusion scintigraphy. Radiology. 1987;164:727–730. 131. Sitbon O, Humbert M, Jagot JL, et al. Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J. 1998;12:265–270. 132. Stein PD, Athanasoulis C, Alavi A, et al. Complications and validity of pulmonary angiography in acute pulmonary embolism. Circulation. 1992;85:462–468. 133. Shackelford GD, Sacks EJ, Mullins JD, McAlister WH. Pulmonary venoocclusive disease: case report and review of the literature. AJR Am J Roentgenol. 1977;128:643–648.

54 

Hydrostatic Pulmonary Edema* CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

Etiology Pulmonary edema is defined as an abnormal accumulation of fluid in the extravascular compartments (interstitial and airspace) of the lung. Traditionally, pulmonary edema has been divided into hydrostatic edema and permeability edema based on the presumed mechanism. Hydrostatic edema is caused by an elevation in pulmonary capillary pressure, and permeability edema is caused by disruption of the capillary endothelium, resulting in protein leakage into the surrounding tissue. This distinction into two categories is problematic. First, severe elevation in pulmonary capillary pressure in left ventricular failure may result in endothelial cell damage, resulting in a mixture of hydrostatic and permeability edema. Second, permeability edema is now known to occur in conditions that do not cause diffuse alveolar damage, such as hantavirus pulmonary syndrome and interleukin therapy. Permeability edema in these settings behaves very differently from permeability edema in patients with diffuse alveolar damage (acute respiratory distress syndrome [ARDS]). For these reasons, a modern definition of pulmonary edema should incorporate four main categories based on pathophysiology: hydrostatic edema, permeability edema with diffuse alveolar damage (DAD), permeability edema without DAD, and mixed edema caused by both hydrostatic and permeability edema.1 The most common cause of hydrostatic pulmonary edema is a rise in pulmonary venous pressure secondary to disease of the left side of the heart. Increased pressure within the left atrium is transmitted to the pulmonary veins as a result of back pressure, most often from a failing left ventricle or obstruction to left atrial outflow. Rarely, venous hypertension is caused by stenosis of the pulmonary veins themselves, such as occurs in congenital or acquired venoocclusive disease or fibrosing mediastinitis.2 Other common causes of hydrostatic pulmonary edema are renal disease, hypervolemia, and liver failure. Both acute and chronic renal disease, with or without uremia, can be associated with acute pulmonary edema. A major contributing cause in these cases is left ventricular failure; however, it is likely that decreased protein osmotic pressure, hypervolemia, and increased capillary permeability also have roles.3 Administration of large volumes of intravenous fluids has been shown to cause pulmonary edema in patients who do not have underlying heart disease.4 Fluid overload is an important cause of hydrostatic edema in the postoperative period, in the elderly, and in patients with borderline cardiac or renal failure. Pulmonary edema occurs with increased frequency in patients who have cirrhosis or acute hepatic failure or have undergone liver transplantation.5 It is likely that *The editors and publisher would like to thank Drs. Nestor L. Müller and C. Isabela Silva Müller for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

674

the edema in these patients is due to a combination of increased capillary pressure, increased endothelial permeability, and decreased plasma osmotic pressure.2 Finally, hydrostatic pulmonary edema is also a well-described but uncommon complication of head trauma, seizures, and raised intracranial pressure. COMMON CAUSES OF HYDROSTATIC PULMONARY EDEMA • Cardiogenic • Left ventricular failure • Mitral valve disease • Left atrial myxoma • Obstruction of the pulmonary veins • Primary (idiopathic) venoocclusive disease • Fibrosing mediastinitis • Neurogenic • Head trauma • Seizures • Increased intracranial pressure • Decreased capillary osmotic pressure • Renal disease • Fluid overload • Cirrhosis

Clinical Presentation The main clinical manifestations of acute hydrostatic pulmonary edema are dyspnea, tachypnea, and orthopnea.2,6 Clinical findings include peripheral and central cyanosis, tachycardia, pallor, peripheral edema, and elevated jugular venous pressure. In the most severe cases the patient may expectorate frothy, blood-tinged fluid. In patients in whom pulmonary edema develops insidiously, the symptoms may be mild, and dyspnea may occur only during exertion. Other suggestive symptoms in these patients include a history of orthopnea and paroxysmal nocturnal dyspnea. Some patients with chronic left-sided heart failure may have minimal symptoms even in the presence of extensive pulmonary edema evident on the chest radiograph.2,6 Laboratory testing, including B-type natriuretic peptide (BNP) and N-terminal fragment (NT-proBNP), are elevated in situations causing increased myocardial stress or in patients with renal failure. A normal laboratory value can be used to essentially rule out heart failure in patients presenting to the emergency department with dyspnea.7

Pathophysiology Under normal steady-state conditions, there is continual flow of fluid and protein from the pulmonary microvasculature to the interstitium; these substances are then returned to the bloodstream

54  Hydrostatic Pulmonary Edema

675

secondary permeability edema manifesting with high protein– content edema fluid.1

Manifestations of the Disease RADIOGRAPHY Hydrostatic edema results in two principal radiologic patterns related to whether the fluid remains localized in the interstitial space or whether it also occupies the airspaces.

Fig. 54.1  Pathologic findings of pulmonary edema. Histologic specimen shows thickening of the interlobular septa (arrowheads) and partial filling of the airspaces by fluid. (Courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Vancouver, Canada.)

by the lymphatics. The volume of water and protein movement is dependent on the balance of pressure across the pulmonary microvasculature and on the permeability of the microvascular membrane. The factors that govern the formation and removal of extravascular water within the lungs are described by the fluid transport equation originally proposed by Starling.8 An increase in microvascular hydrostatic pressure or a decrease in protein osmotic pressure in the microvascular lumen will result in the transudation of fluid from the microvessels into interstitial tissue (hydrostatic pulmonary edema). Sufficient accumulation of fluid in this compartment constitutes interstitial edema; when the storage capacity of the interstitial space is exceeded and epithelial cell damage occurs, edema floods into the alveolar airspaces (Fig. 54.1).9 The pulmonary interstitium itself can be divided into two compartments: an alveolar septal (parenchymal) compartment and a peribronchovascular and interlobular septal (axial) compartment. Although the alveolar septal compartment constitutes a large percentage of the total interstitial space, its relatively low compliance means that fluid tends to accumulate to a much lesser extent within it than in the peribronchovascular and interlobular septal connective tissue.10 The pathogenesis of acute pulmonary edema secondary to head trauma, seizures, and raised intracranial pressure is poorly understood but likely is secondary to both hydrostatic and permeability mechanisms. Most studies suggest that the main mechanism is increased microvascular pressure (hydrostatic pulmonary edema).11,12 Experimental studies have shown transient, massive sympathetic discharge from the central nervous system, which results in generalized vasoconstriction, shift of blood volume into the pulmonary vascular compartment, and elevation of pulmonary microvascular pressure.13 It has also been shown that the sympathetic activity increases pulmonary vasomotor tone, causing constriction of pulmonary veins and a subsequent increase in pulmonary capillary hydrostatic pressure.12 There is also evidence that a direct negative inotropic effect on the heart contributes to the pathogenesis of the edema.14,15 Finally, elevated hydrostatic pressure may cause endothelial injury resulting in

Predominantly Interstitial Edema Transudation of fluid into the interstitial spaces of the lung inevitably constitutes the first stage of pulmonary edema because the capillaries are situated in this compartment. Although this transudation of fluid constitutes the first stage of fluid accumulation in the lungs, classic teaching and radiology dogma state that the initial radiographic sign in interstitial pulmonary edema is pulmonary venous hypertension. This sign manifests with redistribution of blood flow from the lower to the upper lung zones (Fig. 54.2), with the upper lobe arteries becoming larger than the accompanying bronchus (Fig. 54.3).16,17 This redistribution is termed by many authors as cephalization of the vasculature. Unfortunately, this sign is often not present in interstitial pulmonary edema or is difficult to accurately determine on radiography.1,18,19 Furthermore, redistribution of blood flow can be assessed reliably only on radiographs performed at maximal inspiration in the erect position. In a study of 86 patients with acute myocardial infarction, pulmonary vascular redistribution (cephalization) was present in only 1 patient with an elevated wedge pressure.19 Pistolesi and colleagues20 determined that redistribution of pulmonary blood flow (cephalization) does not correlate with wedge pressure but likely reflects chronic structural vascular changes and occurs in patients with chronically elevated venous pressures, such as those with chronic and recurrent heart failure or in patients with long-standing mitral stenosis (see Fig. 54.2). Therefore the first reliable radiographic evidence of interstitial pulmonary edema is fluid accumulating within the perivascular interstitial tissue and interlobular septa. As a result of this localization, edema fluid produces a characteristic radiographic pattern of loss of definition of segmental and subsegmental pulmonary vessels (i.e., vascular indistinctness) and thickening of the interlobular septa (Kerley A and B lines; Fig. 54.4).21 Unfortunately, vascular indistinctness relies on subjective assessment and can be caused by many factors other than interstitial edema, including motion, differences in equipment, lung volume, and patient rotation. A more objective finding, and often the most reliable radiographic sign of early interstitial edema, is subpleural interstitial edema. This sign manifests with thickening of the interlobar fissures (thick fissures) caused by fluid accumulation in the interstitium beneath the visceral pleura (see Fig. 54.4).1 Thick fissures are usually visible earlier than Kerley B lines because there are two layers of visceral pleural that contribute to the thickening, and the fissures are larger and longer than interlobular septa. It is important to note that a thick fissure does not represent pleural effusion within the fissure but rather thickening of the subpleural interstitium.1 In circumstances in which edema fluid accumulates in the parenchymal interstitial tissue before the development of overt airspace edema, the accumulation is usually invisible or only faintly discernible radiographically as a “haze,” which tends to

676

A

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

B Fig. 54.2  Redistribution of blood flow to upper lung zones caused by pulmonary venous hypertension in a woman with mitral stenosis and mitral regurgitation. (A) Posteroanterior radiograph shows unusually prominent vascular markings in the upper lung zones and sparse markings in the lower lung zones. Note left atrial appendage and left atrial dilation indicating mitral stenosis and regurgitation. (B) Detail radiograph of the right lower lung zone shows discrepancy in size of the upper lung zone pulmonary arteries (arrow) relative to lower lung zone pulmonary arteries (arrowhead). Pulmonary venous hypertension (cephalization) is most commonly noted with long-standing heart failure or mitral stenosis and is often not present or discernible in acute interstitial edema.

A

B Fig. 54.3  Increased upper lung zone ratio of pulmonary artery to bronchus diameter in hydrostatic pulmonary edema. (A) View of the right upper lung zone from anteroposterior radiograph shows a normal ratio of pulmonary artery to bronchus diameter. The external diameter of the pulmonary artery (straight arrow) is similar to that of the external diameter of its accompanying bronchus (curved arrow). (B) Erect anteroposterior radiograph 3 years later after acute myocardial infarction and development of pulmonary edema shows increased diameter of the pulmonary artery (arrow). Perihilar haze with vascular indistinctness is also evident. (From Müller NL, Fraser RS, Colman NC, Paré PD. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

54  Hydrostatic Pulmonary Edema

A

B

C

D

677

Fig. 54.4  Interstitial pulmonary edema from left-sided heart failure. Posteroanterior (A) and lateral (B) radiographs show multiple linear opacities throughout both lungs. These lines consist of a combination of long septal lines (Kerley A lines), predominantly in the middle lung zones (arrows in C), and shorter peripheral septal lines (Kerley B lines best seen in D). In lateral projection (B), the interlobar fissures are thick (arrow and arrowhead) as a result of subpleural interstitial edema. (Fig. 54.4A from Gutschow SE, Walker CM. Acute thoracic conditions in the ICU. In: Shepherd J. Thoracic Imaging Requisites, 3rd ed. Philadelphia: Elsevier; 2018; Fig. 54.4C from Müller NL, Fraser RS, Colman NC, Paré PD. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

be predominantly lower zonal or perihilar in distribution. Although the severity of radiographic abnormalities correlates somewhat with pulmonary wedge pressure, there is often a phase lag between the elevation in wedge pressure and radiographic signs of pulmonary edema, possibly because of the time required for transudation of fluid into the extravascular space.22,23 The

heart is generally enlarged; however, like pulmonary vascular redistribution, the heart size may be normal when the cause of the edema is recent myocardial infarction, coronary insufficiency, or restrictive cardiomyopathy.24 Evidence for interstitial pulmonary edema is also provided by an increase in the thickness of the walls of bronchi seen

678

A

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

Oct 1

B

Oct 14

Fig. 54.5  Peribronchial cuffing in pulmonary edema from renal failure. (A) Detailed view of the upper half of the left lung from posteroanterior radiograph shows distended upper lobe vessels, perihilar haze, septal A lines (arrowheads), and thickened bronchial wall viewed end-on (arrow). (B) A few weeks later, after diuretic therapy, signs of pulmonary edema had resolved. Note decreased thickness of the bronchial wall (arrow). (From Müller NL, Fraser RS, Colman NC, Paré PD. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

end-on in the perihilar zones.21 In the absence of chronic airway disease, such as bronchitis or asthma, these structures measure less than 1 mm in thickness. When fluid accumulates in the interstitial tissue surrounding them, their shadow thickens and loses its sharp definition (Fig. 54.5). After adequate treatment of edema, all these radiologic signs may disappear within a matter of hours to as long as a few days. The vascular pedicle is the width of the superior mediastinum measured from the right lateral border of the superior vena cava, at the point where it crosses the right main bronchus, to the left lateral margin of the left subclavian artery, where it arises from the aortic arch. A change in the width of the vascular pedicle is a useful indicator of a patient’s intravascular volume status but only when comparison radiographs performed with similar positioning and depth of inspiration are available.1 In the majority of normal patients, the vascular pedicle measures between 38 and 58 mm wide. Because of its wide normal range, a change in the vascular pedicle as opposed to absolute size, obtained in similar radiographic positions, is a more useful determinant of volume status. With fluid overload, the vascular pedicle widens

(Fig. 54.6), whereas in patients with left-sided heart failure, the vascular pedicle is widened in only 50% of patients. Patients with permeability edema generally do not have a widened vascular pedicle. Airspace Edema Airspace pulmonary edema tends to develop with epithelial damage after the transmural pressure becomes greater than 25 mm Hg.21 Although interstitial edema usually precedes airspace edema, the chest radiograph may show evidence of both simultaneously. The characteristic radiographic abnormality is the presence of patchy or confluent bilateral areas of consolidation that tend to be symmetric and to involve mainly the perihilar regions and the lower lung zones (Fig. 54.7).25 Air bronchograms are uncommon. In the majority of cases the shadows are confluent and create irregular, poorly defined patchy opacities scattered randomly throughout the lungs; in the medial third of the lungs particularly, coalescence of areas of consolidation is common (Fig. 54.8). In less than 10% of cases, airspace hydrostatic pulmonary edema has a central, nongravitational distribution with sparing of the

54  Hydrostatic Pulmonary Edema

679

Fig. 54.6  Fluid overload pulmonary edema. Composite image with frontal radiograph before (left image) and after (right image) the administration of 12 L of intravenous fluids shows widening of the vascular pedicle, enlargement of the azygos vein, and diffuse interstitial pulmonary edema. (From Gutschow SE, Walker CM. Acute thoracic conditions in the ICU. In: Shepherd J. Thoracic Imaging Requisites, 3rd ed. Philadelphia: Elsevier; 2018.)

Fig. 54.8  Airspace pulmonary edema from left-sided heart failure. Anteroposterior radiograph demonstrates extensive bilateral consolidation with slight central predominance. Also noted are a right internal jugular central venous catheter and nasogastric tube.

Fig. 54.7  Interstitial and airspace pulmonary edema in left-sided heart failure. Anteroposterior radiograph demonstrates enlarged and poorly defined pulmonary vessels, perihilar haze in the right lung, and perihilar haze and consolidation in the left lung. Also noted are an endotracheal tube and left subclavian central venous catheter.

680

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

Fig. 54.9  Bat wing pattern of pulmonary edema. Posteroanterior radiograph shows consolidation in the perihilar portions of both lungs, creating a bat wing or butterfly appearance; the periphery of both lungs is relatively unaffected. The consolidation is fairly homogeneous and is associated with well-defined bilateral air bronchograms. Also noted is a left peripherally inserted central catheter with the tip at the superior cavoatrial junction.

peripheral lung, a pattern known as bat wing or butterfly edema (Fig. 54.9).21 Bat wing edema tends to occur with rapidly developing severe cardiac failure as seen in acute mitral insufficiency (associated with papillary muscle rupture or massive myocardial infarct) or renal failure.21 Edema secondary to cardiac disease is generally bilateral and fairly symmetric. On occasion, it is predominantly unilateral or occupies zones of one or both lungs out of keeping with the “expected” distribution of disease arising from a central influence. Unilateral pulmonary edema can occur in a wide variety of conditions in which the pathogenetic mechanism exists either on the same side as the edema (ipsilateral edema) or on the opposite side (contralateral edema). The most common causes of asymmetric hydrostatic pulmonary edema are a patient preferring to lie on one side or morphologic changes in the lung parenchyma in chronic obstructive pulmonary disease. Extensive emphysema or marked destruction and fibrosis as seen in endstage tuberculosis or sarcoidosis will result in pulmonary edema in the regions that are less affected by these disease processes. Mitral regurgitation, particularly in the setting of acute myocardial infarction, tends to result in edema involving mainly the right upper lobe because the reflux stream is directed toward the right superior pulmonary vein (Fig. 54.10).21,26 Such asymmetric distribution occurs in 9% of adults and 22% of children with grade 3 or 4 mitral regurgitation.27,28 Like hydrostatic interstitial pulmonary edema, airspace edema usually clears fairly rapidly in response to adequate treatment of the underlying condition. Resolution appears to be radiographically complete in less than 3 days in most cases. Chest radiography plays an important role in the initial evaluation of patients with hydrostatic pulmonary edema. However, there may be as much as a 12-hour delay between the onset of symptoms and the development of significant radiographic abnormalities when the onset of pulmonary edema is

Fig. 54.10  Right upper lobe pulmonary edema caused by acute mitral regurgitation. Anteroposterior radiograph shows prominent and ill-defined pulmonary vascular markings and septal lines consistent with interstitial pulmonary edema. Also noted is extensive right upper lobe consolidation. Although the upper lobe consolidation is most suggestive of pneumonia, it was proved to be due to airspace pulmonary edema secondary to acute mitral regurgitation after myocardial infarction.

abrupt.27 Additionally, there may be a therapeutic lag with the pulmonary venous pressures returning to normal with resolution of patient symptoms but with persistent edema on chest radiography.19 COMPUTED TOMOGRAPHY Although a diagnosis of hydrostatic pulmonary edema is usually based on clinical information and findings on conventional chest radiography, it is important to recognize its appearance on computed tomography (CT), both because it can mimic other diseases and because it is seen occasionally in patients not suspected clinically to have edema. The most common findings of interstitial pulmonary edema on high-resolution CT consist of septal thickening and groundglass opacities (Fig. 54.11).29,30 Some patients may have almost exclusively septal thickening or ground-glass opacities.29,30 The interlobular septal thickening is smooth and uniform, except for a focal nodular appearance resulting from prominent septal veins or intraparenchymal lymph nodes.30 The edema tends to have a perihilar and gravitational distribution, but this is not always present. Other common findings include increased vascular caliber, thickening of the perihilar peribronchovascular interstitium (peribronchial cuffing), interlobar fissures, prominence of the centrilobular structures caused by interstitial edema, and pleural effusion (Fig. 54.12).30 Airspace pulmonary edema results in ground-glass opacities and consolidation that, similar to the interstitial changes, tend to involve mainly the perihilar and dependent lung regions (Fig. 54.13). Patients with left-sided heart failure have increased prevalence of enlarged mediastinal lymph nodes and hazy opacification of the mediastinal fat (Fig. 54.14). The abnormalities resolve after

54  Hydrostatic Pulmonary Edema

681

A

B Fig. 54.11  Interstitial pulmonary edema in left-sided heart failure: CT findings. (A) CT at the level of the lower lung zones shows smooth interlobular septal thickening perpendicular to the pleura (straight arrows) and more centrally as polygonal arcades (curved arrows). (B) Coronal reformatted CT demonstrates septal pattern mainly in the lower lung zones. The thickened interlobular septa are seen as smooth lines perpendicular to the pleura (straight arrows) and as polygonal arcades (curved arrows). The thickened interlobular septa are the CT equivalent of Kerley B lines seen on radiography.

Fig. 54.12  Interstitial pulmonary edema in left-sided heart failure: septal lines and prominent centrilobular structures on volume-rendering CT. Volumerendered CT image of the right lung shows thickening of the interlobular septa (straight arrows) and prominence of the centrilobular structures (curved arrow) resulting from interstitial edema. Note that the edema involves almost exclusively the dependent regions of the lower lobe.

edema. These lymph nodes manifest as triangular- or rectangularshaped nodules located along fissures and interlobular septa. Lymphadenopathy in patients with left-sided heart failure therefore does not necessarily indicate an infectious process or malignant neoplasm. ECHOCARDIOGRAPHY

successful treatment of the heart failure. In a review of 46 patients who had major and minor clinical signs of congestive heart failure and had undergone chest CT during their symptomatic period, enlarged mediastinal lymph nodes and hazy mediastinal fat were seen in 55% and 33% of cases, respectively.31 A recent retrospective study involving 215 patients with congestive heart failure who underwent CT showed enlarged mediastinal lymph nodes in 68%. Of importance, lymph node enlargement usually involved more than one nodal station and generally spared the hilar lymph node stations.32 It is also common for intraparenchymal lymph nodes to enlarge during episodes of pulmonary

Bedside transthoracic echocardiography allows assessment of myocardial and valvular function and can play an important role in the assessment of patients with hydrostatic pulmonary edema.6,33 In one study of 49 critically ill patients with unexplained pulmonary edema or hypotension, transthoracic echocardiography results were in agreement with data generated from a pulmonary artery catheter in 86% of cases.34 It has been suggested that transthoracic echocardiography should be the first approach to assessment of left ventricular and valvular function in patients in whom the clinical, laboratory, and radiologic findings fail to establish the cause of pulmonary edema.6

682

A

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

B Fig. 54.13  Perihilar distribution of airspace pulmonary edema (bat wing edema) in left-sided heart failure. (A) High-resolution CT shows consolidation and ground-glass opacities in the lower lobes. Note mild interlobular septal thickening (arrows) and small pleural effusions. (B) Coronal reformatted CT demonstrates predominantly perihilar (bat wing) distribution of the consolidation and ground-glass opacities.

Fig. 54.14  Enlarged mediastinal lymph node in patient with pulmonary edema. Composite image with CT at time of pulmonary edema (left image) and 2 months later after resolution of pulmonary edema (right image) shows resolution of small pleural effusions and decreased size of a right paratracheal station lymph node (arrows).

54  Hydrostatic Pulmonary Edema

A

683

B Fig. 54.15  Unilateral pulmonary edema caused by venous obstruction after radiofrequency ablation. (A) High-resolution CT image at the level of the upper lobes demonstrates thickening of the interlobular septa (arrows) and diffuse ground-glass opacities in the left upper lobe. (B) Contrast-enhanced CT at the level of the left upper lobe bronchus shows lack of enhancement of the left superior pulmonary vein (arrow) consistent with complete obstruction.

CLASSIC SIGNS • Thickening of interlobar fissures • Loss of definition of subsegmental and segmental vessels (vascular indistinctness) • Septal (Kerley) lines • Perihilar or diffuse consolidation • Air bronchograms uncommon • Small pleural effusions commonly evident on radiograph • Cardiomegaly common

Differential Diagnosis The differential diagnosis of hydrostatic pulmonary edema includes pneumonia, exacerbation of chronic obstructive pulmonary disease or asthma, pulmonary hemorrhage, and upper airway obstruction.2 Making the diagnosis can be difficult. It has been estimated that the clinical diagnosis of acute heart failure is incorrect in more than 50% of cases, with frequent overdiagnosis and underdiagnosis.35,36 On radiologic examination the most common difficulty is the differentiation of hydrostatic from permeability pulmonary edema with or without diffuse alveolar damage. Findings most suggestive of hydrostatic pulmonary edema include cardiomegaly, predominantly perihilar distribution of the edema, thick fissures, and presence of septal lines and pleural effusion.37,38 Radiographic features most suggestive of permeability edema include inhomogeneous or predominantly peripheral distribution of the edema, presence of air bronchograms, and lack of septal lines and pleural effusion.37,38 A combination of findings permits correct identification of hydrostatic pulmonary edema in 80% to 90% of patients and correct identification of permeability edema in 60% to 90% of cases.37,38 However, patients with ARDS frequently have superimposed hydrostatic edema, and it is often difficult or impossible to determine to what extent the parenchymal abnormalities are due to permeability edema or hydrostatic edema. In these patients measurement of the pulmonary arterial wedge pressure with a pulmonary artery catheter is often required.

The most common causes of hydrostatic pulmonary edema are left-sided heart failure (cardiogenic pulmonary edema), acute and chronic renal disease, and fluid overload. Less commonly, unilateral or bilateral pulmonary edema may be the result of pulmonary venous obstruction. Abnormalities of the pulmonary veins that may result in pulmonary edema include congenital pulmonary vein stenosis, pulmonary venoocclusive disease, stenosis that follows surgery or radiofrequency ablation, fibrosing mediastinitis, and pulmonary vein compression or invasion by tumor. Pulmonary venoocclusive disease is a rare idiopathic condition that results in progressive occlusion of the pulmonary veins, chronic interstitial edema, and severe pulmonary hypertension. The clinical, radiographic, and CT findings are mainly those of pulmonary hypertension (see Chapter 53). However, unlike those with idiopathic and chronic thromboembolic pulmonary arterial hypertension, patients with pulmonary venoocclusive disease typically also have findings of interstitial edema, particularly thickening of the interlobular septa.39 Radiofrequency ablation is commonly used for the elimination of focal arrhythmogenic triggers arising within pulmonary veins in patients with atrial fibrillation. Radiofrequency energy delivery outside the pulmonary vein ostia in these patients may result in vein stenosis or occlusion and pulmonary edema distal to the obstructed vein (Fig. 54.15).40 The pulmonary vein stenosis and obstruction and the edema can be well demonstrated on CT40 and on contrastenhanced MR angiography.41

Synopsis of Treatment Options In patients with acute hydrostatic pulmonary edema, in the absence of contraindications, empirical treatment is often started with diuretic therapy.6 Other fairly standard medical therapy options include supplemental oxygen provided by a face mask, vasodilators, and inotropics. In patients with acute cardiogenic pulmonary edema, noninvasive support ventilation with continuous positive airway pressure or bilevel noninvasive pressure support ventilation has been shown to reduce intubation rate and mortality.42

684

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

KEY POINTS • Common causes of hydrostatic pulmonary edema include left ventricular failure, mitral valve disease, renal failure, liver disease, and fluid overload. • Characteristic findings include thick fissures, ill-defined pulmonary vascular markings, thickened interlobular septa (Kerley B lines), pleural effusions, and cardiomegaly. • Cardiomegaly may not be present in patients with acute pulmonary edema. • Classic bat wing distribution of edema is seen in less than 10% of patients. • There may be a lag of 12 hours or more between the onset of symptoms and the development of radiologically visible abnormalities. Additionally, there may be up to a 3-day lag in clearing of edema after symptom resolution. • Radiographic findings are of limited value in differentiating hydrostatic from permeability edema. The most helpful signs in diagnosing hydrostatic edema are presence of septal lines and pleural effusion, lack of air bronchograms, and predominantly central distribution of edema.

SUGGESTED READINGS Gluecker T, Capasso P, Schnyder P, et al. Clinical and radiologic features of pulmonary edema. Radiographics. 1999;19:1507–1531. Ketai LH, Godwin JD. A new view of pulmonary edema and acute respiratory distress syndrome. J Thorac Imaging. 1998;13:147–471. Ware LB, Matthay MA. Clinical practice. Acute pulmonary edema. N Engl J Med. 2005;353:2788–2796.

The full reference list for this chapter is available at ExpertConsult.com.

54  Hydrostatic Pulmonary Edema 684.e1

REFERENCES 1. Ketai LH, Godwin JD. A new view of pulmonary edema and acute respiratory distress syndrome. J Thorac Imaging. 1998;13:147–171. 2. Fraser RS, Colman N, Müller NL, Paré PD. Pulmonary edema. In: Fraser RS, Colman N, Müller NL, Paré PD, eds. Synopsis of Diseases of the Chest. Philadelphia: Elsevier Saunders; 2005:603–626. 3. Kooman JP, Leunissen KM. Cardiovascular aspects in renal disease. Curr Opin Nephrol Hypertens. 1993;2:791–797. 4. Stein L, Beraud JJ, Cavanilles J, et al. Pulmonary edema during fluid infusion in the absence of heart failure. JAMA. 1974;229:65–68. 5. O’Brien JD, Ettinger NA. Pulmonary complications of liver transplantation. Clin Chest Med. 1996;17:99–114. 6. Ware LB, Matthay MA. Clinical practice. Acute pulmonary edema. N Engl J Med. 2005;353:2788–2796. 7. Weber M, Hamm C. Role of B-type natriuretic peptide (BNP) and NT-proBNP in clinical routine. Heart. 2006;92:843–849. 8. Starling EH. On the absorption of fluids from the connective tissue spaces. J Physiol. 1896;19:312–326. 9. Matthay MA, Folkesson HG, Verkman AS. Salt and water transport across alveolar and distal airway epithelia in the adult lung. Am J Physiol. 1996;270: L487–L503. 10. Staub NC, Nagano H, Pearce ML. Pulmonary edema in dogs, especially the sequence of fluid accumulation in lungs. J Appl Physiol. 1967;22:227–240. 11. Smith WS, Matthay MA. Evidence for a hydrostatic mechanism in human neurogenic pulmonary edema. Chest. 1997;111:1326–1333. 12. Maron MB, Holcomb PH, Dawson CA, et al. Edema development and recovery in neurogenic pulmonary edema. J Appl Physiol. 1994;77:1155–1163. 13. Johnston SC, Darragh TM, Simon RP. Postictal pulmonary edema requires pulmonary vascular pressure increases. Epilepsia. 1996;37:428–432. 14. Bahloul M, Chaari AN, Kallel H, et al. Neurogenic pulmonary edema due to traumatic brain injury: evidence of cardiac dysfunction. Am J Crit Care. 2006;15:462–470. 15. Samuels MA. Neurally induced cardiac damage. Definition of the problem. Neurol Clin. 1993;11:273–292. 16. Ravin CE. Pulmonary vascularity: radiographic considerations. J Thorac Imaging. 1988;3:1–13. 17. Morgan PW, Goodman LR. Pulmonary edema and adult respiratory distress syndrome. Radiol Clin North Am. 1991;29:943–963. 18. Harrison MO, Conte PJ, Heitzman ER. Radiological detection of clinically occult cardiac failure following myocardial infarction. Br J Radiol. 1971;44:265–272. 19. Kostuk W, et al. Correlations between the chest film and hemodynamics in acute myocardial infarction. Circulation. 1973;48:624–632. 20. Pistolesi M, et al. Factors affecting regional pulmonary blood flow in chronic ischemic heart disease. J Thorac Imaging. 1998;365–372. 21. Gluecker T, Capasso P, Schnyder P, et al. Clinical and radiologic features of pulmonary edema. Radiographics. 1999;19:1507–1531. 22. Slutsky RA, Higgins CB. Intravascular and extravascular pulmonary fluid volumes. II. Response to rapid increases in left atrial pressure and the theoretical implications for pulmonary radiographic and radionuclide imaging. Invest Radiol. 1983;18:33–39. 23. McHugh TJ, Forrester JS, Adler L, et al. Pulmonary vascular congestion in acute myocardial infarction: hemodynamic and radiologic correlations. Ann Intern Med. 1972;76:29–33.

24. Dodek A, Kassebaum DG, Bristow JD. Pulmonary edema in coronary-artery disease without cardiomegaly. Paradox of the stiff heart. N Engl J Med. 1972;286:1347–1350. 25. Milne EN. Hydrostatic versus increased permeability pulmonary edema. Radiology. 1989;170:891–894. 26. Schnyder PA, Sarraj AM, Duvoisin BE, et al. Pulmonary edema associated with mitral regurgitation: prevalence of predominant involvement of the right upper lobe. AJR Am J Roentgenol. 1993;161:33–36. 27. Chen JT. Radiographic diagnosis of heart failure. Heart Dis Stroke. 1992;1:58–63. 28. Gudinchet F, et al. Pulmonary oedema associated with mitral regurgitation: prevalence of predominant right upper lobe involvement in children. Pediatr Radiol. 1998;28:260–262. 29. Primack SL, Müller NL, Mayo JR, et al. Pulmonary parenchymal abnormalities of vascular origin: high-resolution CT findings. Radiographics. 1994;14: 739–746. 30. Storto ML, Kee ST, Golden JA, Webb WR. Hydrostatic pulmonary edema: high-resolution CT findings. AJR Am J Roentgenol. 1995;165:817–820. 31. Slanetz PJ, Truong M, Shepard JA, et al. Mediastinal lymphadenopathy and hazy mediastinal fat: new CT findings of congestive heart failure. AJR Am J Roentgenol. 1998;171:1307–1309. 32. Shweihat YR, et al. Congestive adenopathy: a mediastinal sequela of volume overload. J Bronchology Interv Pulmonol. 2016;23:298–302. 33. Duane PG, Colice GL. Impact of noninvasive studies to distinguish volume overload from ARDS in acutely ill patients with pulmonary edema: analysis of the medical literature from 1966 to 1998. Chest. 2000;118:1709–1717. 34. Kaul S, Stratienko AA, Pollock SG, et al. Value of two-dimensional echocardiography for determining the basis of hemodynamic compromise in critically ill patients: a prospective study. J Am Soc Echocardiogr. 1994;7: 598–606. 35. Remes J, Miettinen H, Reunanen A, Pyorala K. Validity of clinical diagnosis of heart failure in primary health care. Eur Heart J. 1991;12:315–321. 36. McCullough PA, Hollander JE, Nowak RM, et al. Uncovering heart failure in patients with a history of pulmonary disease: rationale for the early use of B-type natriuretic peptide in the emergency department. Acad Emerg Med. 2003;10:198–204. 37. Miniati M, Pistolesi M, Paoletti P, et al. Objective radiographic criteria to differentiate cardiac, renal, and injury lung edema. Invest Radiol. 1988;23: 433–440. 38. Aberle DR, Wiener-Kronish JP, Webb WR, Matthay MA. Hydrostatic versus increased permeability pulmonary edema: diagnosis based on radiographic criteria in critically ill patients. Radiology. 1988;168:73–79. 39. Resten A, Maitre S, Humbert M, et al. Pulmonary hypertension: CT of the chest in pulmonary venoocclusive disease. AJR Am J Roentgenol. 2004; 183:65–70. 40. Packer DL, Keelan P, Munger TM, et al. Clinical presentation, investigation, and management of pulmonary vein stenosis complicating ablation for atrial fibrillation. Circulation. 2005;111:546–554. 41. Tamborero D, Mont L, Nava S, et al. Incidence of pulmonary vein stenosis in patients submitted to atrial fibrillation ablation: a comparison of the selective segmental ostial ablation vs the circumferential pulmonary veins ablation. J Interv Card Electrophysiol. 2005;14:21–25. 42. Masip J, Roque M, Sanchez B, et al. Noninvasive ventilation in acute cardiogenic pulmonary edema: systematic review and meta-analysis. JAMA. 2005;294:3124–3130.

55 

Permeability Pulmonary Edema* STEPHEN B. HOBBS

Etiology Pulmonary edema is defined as an excess of fluid in the extravascular compartment of the lung and is classified into four categories based on pathophysiology: hydrostatic edema, permeability edema with diffuse alveolar damage, permeability edema without diffuse alveolar damage, and mixed edema resulting from hydrostatic and permeability edema. Permeability pulmonary edema is almost always a manifestation of capillary endothelial injury or alveolar epithelial damage with resultant loss of fluid and protein into the airspaces or interstitium. Less commonly, permeability edema may occur in the absence of diffuse alveolar damage, such as in patients with the hantavirus pulmonary syndrome or after interleukin therapy.1 Patients who have permeability edema were originally classified clinically into two groups: those with acute lung injury and those with acute respiratory distress syndrome (ARDS).2–4 However, this definition, which was recommended by the AmericanEuropean Consensus Conference in 1994, was refined in 2011, with the new outline being referred to as the Berlin definition.5 That updated definition removes the term acute lung injury and includes four clinical criteria for a diagnosis of ARDS. Those criteria focus on (1) timing (acute onset within 1 week of clinical insult or onset of respiratory symptoms), (2) chest imaging (bilateral opacities representing an airspace process on chest radiography or computed tomography [CT]), (3) origin of edema (respiratory failure not fully explained by cardiac failure or fluid overload), (4) oxygenation (now based on PaO2/FiO2 [partial pressure of oxygen in arterial blood/forced inspiratory oxygen] ratio while on 5 cm of continuous positive airway pressure [CPAP]). The three categories of oxygenation are mild (PaO2/FiO2 of 201–300), moderate (PaO2/FiO2 of 101–200), and severe (PaO2/FiO2 of ≤100). The majority of patients who are at increased risk for the development of ARDS can be classified into two categories: pulmonary (or direct injury) and extrapulmonary (or indirect injury). The main causes of direct lung injury are pneumonia and aspiration; the main causes of indirect lung injury are sepsis, major trauma, and multiple transfusions. A large cohort study reported that the most common risk factor is severe sepsis with a suspected pulmonary source, followed by severe sepsis with a suspected extrapulmonary source.6 In some series, sepsis (pulmonary or extrapulmonary), pneumonia, aspiration of gastric contents, and major trauma account for more than 85% of causes of ARDS.7 Other more rare causes include burns, drug overdose, near drowning, postperfusion injury after cardiopulmonary

*The editors and publisher would like thank Dr. Kazyua Ichikado for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

bypass, pancreatitis, fat embolism, and high-altitude pulmonary edema.

Prevalence and Epidemiology An accurate estimate of the incidence of ARDS has been hampered by the lack of a uniform definition and the heterogeneity of the causes and clinical manifestations. An early estimate by the National Institutes of Health (NIH) suggested that the annual incidence in the United States was 75 per 100,000 population,2 and a more recent study from 2005 demonstrated an incidence of 86 per 100,000.6 It is currently estimated that there are approximately 190,000 case annually in the United States, resulting in 75,000 deaths.6

Clinical Presentation Patients with permeability edema typically present with acute onset of shortness of breath (generally 72 hours after ARDS onset [56%–74%]) most often die of complications (i.e., new organ failures) that arose during the course of ARDS.10,11 Although the mortality rate for patients with ARDS has declined from 50% to 70% in the 1980s to 35% to 46% in 2014, the distribution of causes of death has not changed.3,11,12 Sepsis with multiorgan failure is the most common cause of death (30%–50%), whereas respiratory failure results in a smaller percentage of deaths (13%–19%).11 The increased survival during the past 2 decades is due largely to advances in supportive care, such as dialysis, and a decrease in extrapulmonary organ failure.13 Nevertheless, survival for those patients who have sepsis syndrome has not changed appreciably.11 PREDICTIVE CLINICAL RISK FACTORS Results of multivariate regression analyses have shown an association of death due to ARDS with increasing age (>70 years),8 underlying liver cirrhosis,9 high McCabe score for prognosis of the underlying disease, high Acute Physiology and Chronic Health Evaluation II (APACHE II) score for general severity,10 and high Sequential Organ Failure Assessment (SOFA) score for associated multiorgan failure.10 Pulmonary factors independently associated with mortality are direct lung injury as the cause of ARDS and the extent of oxygenation impairment on day 3 after the onset of 685

686

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

ARDS.10,11 Semiquantitative evaluation of fibroproliferative changes by high-resolution CT scan in patients with a clinically early stage of ARDS is also an independent predictor of survival and shows a significant inverse association with the number of ventilator-free days (i.e., days without mechanical ventilation).14

Pathophysiology The histologic features of ARDS are characterized by diffuse alveolar damage and represent a time-dependent, stereotypic response to acute lung injury.14,15 The changes can be viewed as evolving from epithelial and endothelial necrosis to alveolar collapse and eventually to fibroblast proliferation and fibrosis. Permeability edema is prominent in the early stages and heralds the onset of rapidly progressive fibroblast proliferation,

which predominates in the late phase of disease. The microscopic appearance varies according to both the time interval between injury and biopsy and the extent and localization of the injury. Diffuse alveolar damage has traditionally been divided into three sequential and overlapping phases: the acute exudative phase of edema and hemorrhage, the subacute proliferative phase of organization and repair, and the fibrotic phase of collagen deposition and end-stage fibrosis. The last two phases are designated the fibroproliferative phase. It is of clinical importance that the histologic features of diffuse alveolar damage correlate with the duration of injury more than with its initiating cause. The acute exudative phase predominates within the first 7 days of injury and is characterized by edema, intraalveolar hemorrhage, and hyaline membrane formation (Fig. 55.1). The histologic changes

A

B

C Fig. 55.1  Acute exudative phase of diffuse alveolar damage caused by sepsis. (A) Pathologic specimen shows characteristic intraalveolar hyaline membranes (arrows) and exudates. (B) Chest radiograph shows extensive bilateral ground-glass opacities and consolidation. (C) High-resolution CT scan at the level of the right upper lobe shows patchy ground-glass opacities demarcated by secondary lobules and associated with dependent consolidation.

55  Permeability Pulmonary Edema

687

A

C

B Fig. 55.2  Subacute proliferative phase of diffuse alveolar damage caused by viral pneumonia (3–7 days after the onset of lung injury). (A) Pathologic specimen shows diffuse fibroblastic proliferation (arrows) within the interstitium associated with organized hyaline membranes. (B) Chest radiograph demonstrates bilateral ground-glass opacities, consolidation, and low lung volumes. (C) High-resolution CT scan at the level of the right upper lobe bronchus shows extensive ground-glass opacities with associated reticulation and traction bronchiectasis (arrows).

in the early exudative phase consist of capillary congestion, alveolar edema, and intraalveolar hemorrhage. Hyaline membranes, the histologic hallmark of this stage of the lesion, develop later and are most numerous 3 to 7 days after injury. Fibrin thrombi may be seen in the alveolar capillaries and pulmonary arterioles. In the subacute proliferative phase of diffuse alveolar damage, fibroblast proliferation, mainly within the interstitium but also within airspaces, becomes prominent (Fig. 55.2). The proliferation of alveolar type 2 pneumocytes, which is seen as early as 3 days after injury and is a reparative phenomenon, occurs in the early proliferative phase and persists throughout this phase. Within the interstitium, fibroblasts and myofibroblasts proliferate and subsequently migrate into fibrinous intraalveolar exudate and convert the exudate to cellular granulation tissue. With the proliferation of fibroblasts (subacute proliferative phase), there is remodeling of the parenchyma, resulting in dilatation of the bronchi (traction bronchiectasis) and bronchioles (traction bronchiolectasis). Subsequently, typically 2 weeks or more after the injury, there is progressive fibrosis with collagen deposition

(chronic fibrotic phase; Fig. 55.3). Microcystic airspaces 1 mm or larger in diameter (microscopic honeycombing) and traction bronchiectasis and bronchiolectasis are most pronounced in the late fibrotic phase. Cyst-like spaces in end-stage ARDS may also result from chronic interstitial emphysema.

Manifestations of the Disease RADIOGRAPHY In the initial phase of ARDS, the parenchymal abnormalities may be mild and the chest radiograph normal. In some cases the lung volumes may be decreased because of shallow breathing and tachypnea. Characteristic radiographic findings of the exudative phase of ARDS consist of extensive bilateral groundglass opacities and consolidation (Fig. 55.4; see also Fig. 55.1). Their distribution may be patchy or diffuse and symmetric or asymmetric, and they may involve all lung zones to a similar extent or mainly the upper or lower lung zones. The bronchi

688

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

A

C

B

typically remain patent, resulting in air bronchograms (see Fig. 55.4). With progression to the fibroproliferative phase, a coarse reticular pattern is seen superimposed on the ground-glass opacities, and there is progressive volume loss (see Figs. 55.2 and 55.3). The radiographic findings are markedly influenced by the positive end-expiratory pressure ventilation that is routinely used in patients with extensive permeability edema.16–18 COMPUTED TOMOGRAPHY Similar to the radiograph, the CT findings may be normal in the early phase of ARDS, but an abnormality is usually detected within 12 hours. The CT findings have been shown to correlate well with the pathologic phases of diffuse alveolar damage.19–21 In the exudative and early proliferative phase of diffuse alveolar damage, CT typically shows extensive bilateral ground-glass opacities with or without associated consolidation (Fig. 55.5; see also Fig. 55.1). Interlobular septal thickening is frequently superimposed on the ground-glass opacities, resulting in a pattern

Fig. 55.3  Chronic fibrotic phase of diffuse alveolar damage from acute interstitial pneumonia (2 weeks after the onset of lung injury). (A) Pathologic specimen shows dilated alveolar spaces and architectural distortion caused by interstitial collagen deposition. (B) Chest radiograph shows low lung volumes with bilateral middle and lower lung zone–predominant ground-glass opacities and coarse reticulation. (C) High-resolution CT scan at the level of the right middle lobe shows extensive ground-glass opacities associated with reticulation (crazy paving pattern), traction bronchiectasis, and cystic changes (arrows).

known as crazy paving (Fig. 55.6). This interlobular septal thickening corresponds histologically to edematous thickening in the exudative phase and to alveolar collapse adjacent to interlobular septa and subsequent organization in the proliferative or fibrotic phase of diffuse alveolar damage. In the early stages the consolidation, when present, tends to have a patchy distribution. Later in the exudative phase, the consolidation becomes more homogeneous and gravity dependent (see Fig. 55.6). In the late proliferative and fibrotic phase, the CT findings also include traction bronchiectasis and bronchiolectasis associated with loss of lung volume (as demonstrated by displacement or distortion of interlobar fissures, bronchi, or vessels; see Figs. 55.2 and 55.3). In the fibrotic phase, coarse reticular opacities and small cystic spaces caused pathologically by marked restructuring of distal airspaces and interstitial dense fibrosis are also seen (Fig. 55.7; see also Fig. 55.3). In some patients the distribution of residual fibrosis after resolution of the airspace disease will be anterior lung predominant (Fig. 55.8).

55  Permeability Pulmonary Edema

A

689

B Fig. 55.4  Acute respiratory distress syndrome: radiographic findings. (A) Admission radiograph showing mild bronchial wall thickening and diffuse interstitial opacities. (B) Thirty-six hours later, both lungs show extensive consolidation with air bronchograms.

Fig. 55.5  Diffuse alveolar damage caused by amiodarone. Axial CT demonstrates extensive bilateral ground-glass opacities and dependent areas of consolidation. Note focal lobular areas of sparing and smooth lines superimposed on the ground-glass opacities, resulting in a crazy paving pattern. The patient presented with progressive shortness of breath and developed respiratory failure.

Fig. 55.6  Acute respiratory distress syndrome with crazy paving pattern on CT. High-resolution CT image shows extensive ground-glass opacities with superimposed smooth septal thickening (crazy paving pattern). Also noted are bilateral areas of consolidation with air bronchograms in the dependent lung regions.

MONITORING OF DISEASE PROGRESSION OR REGRESSION

result in increased lucency and apparent improvement of ARDS. Therefore the radiographs must be interpreted with awareness of the ventilator settings. With regression of disease, the radiographic findings begin to improve and may resolve completely. However, in some cases there may be residual coarse reticular opacities and cysts.17,18

The chest radiograph plays an important role in the diagnosis of ARDS, in monitoring of disease progression, and in assessment of clinically suspected complications.18,19 Chest radiographs are particularly helpful in detecting and monitoring pneumothorax (Fig. 55.9).22,23 The radiographic findings in patients with ARDS are influenced by a number of factors, including stage of diffuse alveolar damage, positive end-expiratory pressure, inspiratory volume, and timing of x-ray exposure. A high positive end-expiratory pressure may

PREDICTION OF ETIOLOGY (DIRECT PULMONARY VS. EXTRAPULMONARY INJURY) The differentiation between pulmonary or direct and extrapulmonary or indirect injury may be supported by findings on

690

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

A

B

C

D Fig. 55.7  Cystic changes in acute respiratory distress syndrome (ARDS) in a woman who developed sepsis and ARDS after cesarean section. High-resolution CT scans 1 week later (A and B) show bilateral loculated pneumothoraces (straight arrows) and cystic changes (curved arrows) in both lungs. Highresolution CT scans 1 month later (C and D) show bilateral areas of ground-glass opacity, irregular linear opacities, and residual cystic changes (D, curved arrows). (Case courtesy Dr. Maura Brown, Vancouver, Canada; from Müller NL, Fraser RS, Colman NC, Paré PD. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

computed tomography,24 respiratory mechanics, and response to positive end-expiratory pressure.25 Goodman and colleagues26 reported that patients with ARDS secondary to direct lung injury tend to have an asymmetric distribution of the ground-glass opacities and consolidation on CT (Fig. 55.10), whereas patients with ARDS secondary to indirect injury tend to have bilateral symmetric distribution of findings (Fig. 55.11). Desai and colleagues27 reported that there was considerable overlap in the findings between ARDS resulting from direct lung injury and ARDS resulting from extrathoracic causes. However, ARDS resulting from extrathoracic causes was more likely to be associated with extensive dependent consolidation, whereas ARDS resulting from direct lung injury was more likely to have more extensive nondependent consolidation and cysts.27 Therefore bilateral symmetric distribution of findings characterized by dependent areas of dense consolidation merging with nondependent ground-glass opacity and apparently normally aerated lung is most frequently seen in patients with ARDS secondary to indirect lung injury.

PREDICTION OF PATHOLOGIC STAGES AND PROGNOSIS As mentioned previously, the high-resolution CT findings correlate with the pathologic stage of diffuse alveolar damage.19–21 Traction bronchiolectasis or bronchiectasis within areas of increased attenuation (ground-glass opacity, consolidation) on highresolution CT usually indicates progression from the exudative to the fibroproliferative and fibrotic phases of diffuse alveolar damage. During these phases, the lung parenchyma undergoes extensive remodeling with some degree of pulmonary fibrosis. The extent of coarse reticular pattern associated with CT signs of lung fibrosis, including architectural distortion and traction bronchiectasis, correlates with the length of time that patients receive pressure-controlled inverse-ratio ventilation.28 Extensive CT abnormalities indicative of fibroproliferative changes were independently predictive of poor prognosis in patients with early ARDS.29 Such findings were also associated with requirements for longer duration of ventilator assistance. The accurate determination of disease stage by means of CT

55  Permeability Pulmonary Edema

691

A Fig. 55.8  Fibrotic stage of acute respiratory distress syndrome after severe influenza virus H1N1 infection. High-resolution CT scan demonstrates bilateral anterior lung reticulation, architectural distortion, and traction bronchiectasis.

B Fig. 55.9  Barotrauma (pneumothorax) in acute respiratory distress syndrome after prolonged ventilator assistance. (A) Chest radiograph shows right pneumothorax associated with bilateral coarse reticulation and volume loss. A right chest tube is in place. (B) High-resolution CT scan at the level of the right upper lobe demonstrates a small anterior right pneumothorax. Also noted are anterior ground-glass opacities, dependent consolidation, and findings of the fibrotic stage of diffuse alveolar damage with coarse reticulation, traction bronchiectasis, and cystic changes. Fig. 55.10  Acute respiratory distress syndrome caused by Streptococcus pneumoniae pneumonia. High-resolution CT scan at the level of the right middle lobe demonstrates dependent consolidation in the middle and lower lobes. The left lung was normal.

692

SECTION 10  Pulmonary Embolism, Hypertension, and Edema

Fig. 55.11  Acute respiratory distress syndrome caused by sepsis. High-resolution CT scan at the level of the right middle lobe shows dependent consolidation and nondependent ground-glass opacity. The left lung showed similar findings.

assessment may be informative regarding the potential for ventilator-induced lung injury and the response to treatment in patients with ARDS. DETECTION OF COMPLICATIONS Computed tomography is superior to radiography in the detection of complications. It has been reported that up to 40% of cases of pneumothorax and 80% of cases of pneumomediastinum seen on the CT scan may not be apparent on the radiograph.30 Pleural effusions and lung abscesses are also detected more frequently on CT than on radiographs.31 The onset of barotrauma (pneumothorax, pneumomediastinum, and subcutaneous air) is more likely to occur late in the course of disease and is related to worsening lung compliance and increased fibroproliferative change over time (see Fig. 55.9).29,32

Differential Diagnosis In the majority of patients the diagnosis of ARDS can be readily made on the basis of a combination of clinical, radiologic, and laboratory findings. In patients with no apparent risk factors for ARDS who present with acute dyspnea and diffuse parenchymal abnormalities, the differential diagnosis includes other causes of acute airspace disease, such as hydrostatic pulmonary edema, diffuse alveolar hemorrhage, drug reaction, and pneumonia. The differential diagnosis requires careful clinical history

and appropriate laboratory tests, including serology.33 Depending on the clinical findings, further investigation may include bronchoscopy with bronchoalveolar lavage. Transbronchial and surgical lung biopsy may be required in selected cases.34,35 Several diffuse parenchymal lung diseases may manifest acutely and mimic the clinical, physiologic, and radiographic criteria for ARDS. These include acute interstitial pneumonia (see Chapter 30), acute eosinophilic pneumonia (see Chapter 37), organizing pneumonia (see Chapter 29), diffuse alveolar hemorrhage (see Chapter 2), and acute hypersensitivity pneumonitis (see Chapter 32).33 Acute interstitial pneumonia is essentially idiopathic ARDS. The patients have clinical, imaging, and histologic findings identical to those of patients with ARDS, but no etiology is identified. Compared with patients with ARDS, patients with acute interstitial pneumonia are more likely to have a predominantly lower lung zone and bilateral symmetric distribution of parenchymal abnormalities.33 Radiographic features most suggestive of permeability edema include patchy or predominantly peripheral distribution of the edema, presence of air bronchograms, and lack of septal lines and pleural effusion.36–38 Findings most suggestive of hydrostatic pulmonary edema include cardiomegaly, blood flow redistribution (upper lobe vessel size > lower lobe vessel size), predominantly perihilar distribution of the edema, thick fissures, and presence of septal lines and pleural effusion.36–38 A combination of findings permits correct identification of hydrostatic pulmonary edema in 80% to 90% of patients and correct identification of permeability edema in 60% to 90%.36–38 However, patients with ARDS frequently have superimposed hydrostatic edema, and it is often difficult or impossible to determine to what extent the parenchymal abnormalities are due to permeability edema or hydrostatic edema. In these patients, measurement of the pulmonary arterial wedge pressure with a Swan-Ganz catheter is often required.

Synopsis of Treatment Options Several large well-controlled trials of ARDS therapies have been completed through the NIH-sponsored ARDS Clinical Trials Network. Currently, there is no specific therapy for ARDS, but treatment of the underlying condition, if known, is critical. Other therapies are supportive, and the mechanical ventilation strategy used has proven most important to overall mortality. Other supportive therapies focus on complication minimalization and include deep venous thrombosis prophylaxis, stress ulcer prophylaxis, and early mobilization. VENTILATOR MANAGEMENT The cornerstone of supportive therapy is mechanical ventilation, but ARDS is characterized by stiff, low-compliance lungs with impaired gas exchange. Correspondingly, there is strong evidence to support the use of volume- and pressure-limited lung-protective ventilation in adult patients with ARDS.39 Because there is often marked heterogeneity of distribution of disease, positive-pressure ventilation must focus on recruitment and ventilation of diseased units and avoidance of injury to healthy units. Mechanical ventilatory support of ARDS has therefore shifted during the past decade to providing smaller (and thus less injurious) tidal volumes. The oxygenation in patients with ARDS is improved when they are maneuvered into the prone position or are ventilated with positive end-expiratory pressure. Prone positioning causes

55  Permeability Pulmonary Edema

693

KEY POINTS • Permeability edema is usually clinically manifested by acute respiratory distress syndrome (ARDS). • Diagnostic criteria of ARDS relate to • Timing (acute onset within 1 week of clinical insult) • Chest imaging (airspace process on chest radiography or CT) • Origin of edema (limited contribution of cardiac failure or fluid overload) • Oxygenation (PaO2/FiO2 [partial pressure of oxygen in arterial blood/forced inspiratory oxygen] ratio while on 5 cm of continuous positive airway pressure) • Etiology • Direct lung injury: pneumonia, aspiration of gastric contents • Extrapulmonary injury: sepsis, major trauma, and multiple transfusions

recruitment of poorly aerated or nonaerated areas of dorsal lung. A study has shown that the alveolar recruitment response to positive end-expiratory pressure is nonuniform; the most recruitment occurs in the nondependent and more cephalic lung.32 PHARMACOLOGIC INTERVENTION No specific pharmacologic therapy has proved effective for ARDS. Corticosteroids Numerous trials of short-course, high-dose corticosteroids in humans at risk for, or in the early phase of, ARDS have failed to demonstrate benefit.3 The ARDS Network has reported that methylprednisolone therapy may be harmful when it is initiated more than 2 weeks (chronic phase) after the onset of ARDS.40

• Chest radiography findings include bilateral ground-glass opacities or consolidation in the exudative phase, which may progress to a superimposed coarse reticular pattern with volume loss in the fibroproliferative and fibrotic phases. • The CT findings mirror the chest radiographic abnormalities, with extensive bilateral ground-glass opacities and predominantly dependent consolidation. Traction bronchiectasis and bronchiolectasis with architectural distortion are seen in the fibroproliferative and fibrotic stages. • The radiologic findings of ARDS are relatively nonspecific. The main radiologic differential diagnosis includes severe pneumonia, hydrostatic pulmonary edema, and diffuse alveolar hemorrhage. • Extrathoracic causes of ARDS are more likely to be associated with extensive dependent consolidation. ARDS caused by direct lung injury is more likely to have more extensive nondependent consolidation and cysts.

SUGGESTED READINGS ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307:2526–2533. Bernard GR. Acute respiratory distress syndrome. A historical perspective. Am J Respir Crit Care Med. 2005;172:798–806. Desai SR. Acute respiratory distress syndrome: imaging of the injured lung. Clin Radiol. 2002;57:8–17. Goodman LR, Fumagalli R, Tagliabue P, et al. Adult respiratory distress syndrome due to pulmonary and extrapulmonary causes: CT, clinical, and functional correlations. Radiology. 1999;213(2):545–552. Milne EN, Pistolesi M, Miniati M, et al. The radiologic distinction of cardiogenic and noncardiogenic edema. AJR Am J Roentgenol. 1985;144(5):879–894.

The full reference list for this chapter is available at ExpertConsult.com.

55  Permeability Pulmonary Edema 693.e1

REFERENCES 1. Ketai LH, Godwin JD. A new view of pulmonary edema and acute respiratory distress syndrome. J Thorac Imaging. 1998;13:147–171. 2. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–1349. 3. Bernard GR. Acute respiratory distress syndrome. A historical perspective. Am J Respir Crit Care Med. 2005;172:798–806. 4. Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994;149:818–824. 5. ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307(23):2526–2533. 6. Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353:1685–1693. 7. Steinberg KP, Hudson LD. Acute lung injury and acute respiratory distress syndrome: the clinical syndrome. Clin Chest Med. 2000;21:401–417. 8. Ely EW, Wheeler AP, Thompson BT, et al. Recovery rate and prognosis in older persons who developed acute lung injury and the acute respiratory distress syndrome. Ann Intern Med. 2002;136:25–36. 9. Estenssoro E, Dubin A, Laffaire E, et al. Incidence, clinical course, and outcome in 217 patients with acute respiratory distress syndrome. Crit Care Med. 2002;30:2450–2456. 10. Monchi M, Bellenfant F, Cariou A, et al. Early predictive factors of survival in the acute respiratory distress syndrome. A multivariate analysis. Am J Respir Crit Care Med. 1998;158:1076–1081. 11. Stapleton RD, Wang BM, Hudson LD, et al. Causes and timing of death in patients with ARDS. Chest. 2005;128:525–532. 12. Bellani G, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788–800. 13. Suchyta MR, Orme JF, Morris AH. The changing face or organ failure in ARDS. Chest. 2003;124:1871–1879. 14. Tomashefski JF Jr. Pulmonary pathology of the adult respiratory distress syndrome. Clin Chest Med. 1990;11:593–619. 15. Tomashefski JF Jr. Pulmonary pathology of the acute respiratory distress syndrome: diffuse alveolar damage. In: Matthay MA, ed. Acute Respiratory Distress Syndrome. New York: Marcel Dekker; 2003:75–108. 16. Greene R. Adult respiratory distress syndrome: acute alveolar damage. Radiology. 1987;163:57–66. 17. Goodman PC. Radiographic findings in patients with acute respiratory distress syndrome. Clin Chest Med. 2000;21:419–433. 18. Desai SR. Acute respiratory distress syndrome: imaging of the injured lung. Clin Radiol. 2002;57:8–17. 19. Ichikado K, Johkoh T, Ikezoe J, et al. Acute interstitial pneumonia: highresolution CT findings correlated with pathology. AJR Am J Roentgenol. 1997;168:333–338. 20. Ichikado K, Suga M, Gushima Y, et al. Hyperoxia-induced diffuse alveolar damage in pigs: correlation between thin-section CT and histopathologic findings. Radiology. 2000;216:531–538. 21. Ichikado K, Suga M, Müller NL, et al. Acute interstitial pneumonia: comparison of high-resolution computed tomography findings between survivors and non-survivors. Am J Respir Crit Care Med. 2002;165:1551–1556.

22. Bekemeyer WB, Crapo RO, Calhoon S, et al. Efficacy of chest radiography in a respiratory intensive care unit: a prospective study. Chest. 1985;88:691–696. 23. Strain DS, Kinasewitz GT, Vereen LE, George RB. Value of routine daily chest x-rays in the medical intensive care unit. Crit Care Med. 1985;13: 534–536. 24. Tomiyama N, Müller NL, Johkoh T, et al. Acute respiratory distress syndrome and acute interstitial pneumonia: comparison of thin-section CT findings. J Comput Assist Tomogr. 2001;25:28–33. 25. Gattinoni L, Pelosi P, Suter PM, et al. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease: different syndromes? Am J Respir Crit Care Med. 1998;158:3–11. 26. Goodman LR, Fumagalli R, Tagliabue P, et al. Adult respiratory distress syndrome due to pulmonary and extrapulmonary causes: CT, clinical, and functional correlations. Radiology. 1999;213:545–552. 27. Desai SR, Wells AU, Suntharalingam G, et al. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary injury: a comparative CT study. Radiology. 2001;218:689–693. 28. Desai SR, Wells AU, Rubens MB, et al. Acute respiratory distress syndrome: CT abnormalities at long-term follow-up. Radiology. 1999;210:29–35. 29. Ichikado K, Suga M, Muranaka H, et al. Prediction of prognosis for acute respiratory distress syndrome with thin-section CT: validation in 44 cases. Radiology. 2006;238:321–329. 30. Gattinoni L, Caironi P, Pelosi P, Goodman LR. What has computed tomography taught us about the acute respiratory distress syndrome? Am J Respir Crit Care Med. 2001;164:1701–1711. 31. Gattinoni L, Bombino M, Pelosi P, et al. Lung structure and function in different stages of severe adult respiratory distress syndrome. JAMA. 1994;271:1772–1779. 32. Puybasset L, Cluzel P, Chao N, et al. A computed tomography scan assessment of regional lung volume in acute lung injury. Am J Respir Crit Care Med. 1998;158:1644–1655. 33. Schwarz MI, Albert RK. “Imitators” of the ARDS. Implications for diagnosis and treatment. Chest. 2004;125:1530–1535. 34. Patel SR, Karmpaliotis D, Ayas NT, et al. The role of open-lung biopsy in ARDS. Chest. 2004;125:197–202. 35. Kao KC, Tsai YH, Wu YK, et al. Open lung biopsy in early-stage acute respiratory distress syndrome. Crit Care. 2006;10:R106. 36. Milne EN, Pistolesi M, Miniati M, et al. The radiologic distinction of cardiogenic and noncardiogenic edema. AJR Am J Roentgenol. 1985;144:879–984. 37. Miniati M, Pistolesi M, Paoletti P, et al. Objective radiographic criteria to differentiate cardiac, renal, and injury lung edema. Invest Radiol. 1988;23: 433–440. 38. Aberle DR, Wiener-Kronish JP, Webb WR, et al. Hydrostatic versus increased permeability pulmonary edema: diagnosis based on radiographic criteria in critically ill patients. Radiology. 1988;168:73–79. 39. Fan E, Needham DM, Stewart TE. Ventilatory management of acute lung injury and acute respiratory distress syndrome. JAMA. 2005;294:2889–2896. 40. The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Network. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354:1671–1684.

SECTION 11

Diseases of the Airways

56 

Tracheal Diseases* BRENT P. LITTLE

The wide variety of tracheal diseases includes both benign and malignant conditions that may manifest as tracheal masses, focal or diffuse tracheal thickening, or tracheal calcification. Tracheal tumors, inflammatory conditions involving the trachea, infections, and posttraumatic or iatrogenic injuries are among the variety of tracheal pathologies that can be characterized at imaging. Structural abnormalities of the trachea include acquired or congenital tracheal stenosis, tracheomalacia, and tracheomegaly. Although a subset of tracheal diseases may be first suspected at chest radiography, computed tomography (CT) is requisite for characterizing the extent and morphology of tracheal pathology. Volumetric acquisitions with multiplanar and threedimensional (3D) reformats can accurately depict tracheal abnormalities, and the use of inspiratory and expiratory imaging is typically used to assess for tracheomalacia and potential airtrapping within the lungs.

Tracheal Neoplasms Etiology A majority of primary tracheal neoplasms in adults are malignant.1,2 The most common cell type is squamous cell carcinoma, which is associated with cigarette smoking.1,2 The second most common cell type is adenoid cystic carcinoma, which is not smoking related.1,2 The most common benign tracheal neoplasm is squamous cell papilloma, which may be solitary or multiple.1,2 Solitary papillomas have an association with cigarette smoking, whereas multiple papillomas (also referred to as papillomatosis) are linked to infection by the human papillomavirus.1,2 A variety of other benign and malignant neoplasms may also arise in the trachea (Box 56.1).

Prevalence and Epidemiology Primary tracheal neoplasms are rare. It has been estimated that a primary tracheal tumor is roughly 180 times less common than a primary lung cancer.3 In a retrospective chart review of all cases of primary tracheal malignancy seen at the MD Anderson Cancer Center between 1945 and 2005, the authors identified 74 patients with primary tracheal cancers.4 Among these, 34 (46%) were squamous cell carcinomas, 19 (26%) were adenoid *The editors and publisher would like to thank Drs. Nestor L. Müller, C. Isabela Silva Müller, Maryellen Sun, Phillip M. Boiselle, and Karen S. Lee for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

694

cystic carcinomas, and 21 (28%) were of other histologic types. Squamous cell carcinoma and squamous cell papilloma have a male predominance and are associated with cigarette smoking, whereas adenoid cystic carcinoma has no sex predilection and is not related to smoking.1,2

Clinical Presentation Primary tracheal neoplasms are often clinically silent until the tracheal lumen is narrowed by approximately 75%.5 At the time of clinical presentation, symptoms include dyspnea, cough, hemoptysis, wheezing, and stridor.1,5 Of interest, up to one-third of adult patients with primary tracheal neoplasms are initially misdiagnosed with “adult-onset” asthma. Thus this diagnosis should always raise the suspicion for a tracheal neoplasm. The average age at presentation of squamous cell carcinoma is between 50 and 60 years.1 In contrast, patients with adenoid cystic carcinoma typically present approximately 1 decade earlier. However, adenoid cystic carcinoma may occur over a broad spectrum of ages, ranging from the third to the ninth decade.1 The average age at presentation for squamous cell papilloma is approximately 50 years, whereas diffuse papillomatosis most commonly presents in childhood.1

Pathophysiology ANATOMY Tracheal neoplasms are usually characterized by an endoluminal tracheal mass, which may have smooth, irregular, or lobulated margins.1,2 Although some overlap exists between benign and malignant lesions, benign lesions are typically less than 2 cm in diameter, with well-defined smooth borders and without evidence of contiguous tracheal thickening or mediastinal invasion. In contrast, malignant lesions usually vary in size between 2 and 4 cm in diameter, with a flat or polypoid shape and irregular or lobulated borders. Contiguous tracheal wall thickening and mediastinal invasion are frequently observed.

Manifestations of the Disease RADIOGRAPHY On careful scrutiny, an intraluminal tracheal mass is often visible on chest radiographs of patients with tracheal neoplasms (Fig. 56.1). However, these lesions are frequently initially overlooked. Extraluminal involvement is not usually detectable by

56  Tracheal Diseases BOX 56.1  MALIGNANT AND BENIGN TRACHEAL NEOPLASMS MALIGNANT TRACHEAL NEOPLASMS Epithelial Squamous cell carcinoma Adenoid cystic carcinoma Carcinoid Mucoepidermoid carcinoma Adenocarcinoma Small cell carcinoma Large cell carcinoma Acinic cell carcinoma Malignant salivary gland–type mixed tumors Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements Mesenchymal Fibrosarcoma Rhabdomyosarcoma Angiosarcoma Kaposi sarcoma Liposarcoma Osteosarcoma Leiomyosarcoma Chondrosarcoma Paraganglioma Spindle cell sarcoma Lymphoma Malignant fibrous histiocytoma BENIGN TRACHEAL NEOPLASMS Epithelial Squamous cell papilloma Papillomatosis Pleomorphic adenoma Glandular papilloma Adenomas of salivary gland type Mucous gland adenoma Monomorphic adenoma Oncocytoma Mesenchymal Hamartoma Neurofibroma Chondroma Fibroma Hemangioma Granular cell tumor Schwannoma Fibrous histiocytoma Pseudosarcoma Hemangioendothelioma Leiomyoma Chondroblastoma Lipoma Glomus tumor

radiographs unless it is sufficiently extensive to distort the normal mediastinal contours. Computed Tomography Multidetector CT has a high sensitivity (97%) for detection of tracheal neoplasms and is typically used for characterization of morphology and the extent of involvement of the trachea and adjacent structures.6 On CT a tracheal mass typically appears as a polypoid or sessile intraluminal mass of soft tissue attenuation (Fig. 56.2; see also Fig. 56.1). Necrosis and ulceration may be observed, especially in squamous cell carcinomas. CT scans frequently suggest whether a lesion is malignant or benign (see

695

Figs. 56.1 and 56.2). Although CT usually cannot distinguish between neoplastic cell types, detection of fat within a lesion on CT is nearly pathognomonic for a hamartoma or lipoma (Fig. 56.3), and identification of calcification within a lesion is highly suggestive of a chondroid tumor (chondroma, chondrosarcoma). CT also provides an assessment of submucosal spread and local extratracheal invasion (see Fig. 56.2). Regional lymph node metastases and complications such as tracheoesophageal fistula may also be detected by CT. However, CT does not reliably detect microscopic mediastinal invasion or neural invasion.7 Eccentric or circumferential tracheal wall thickening is less common than an intraluminal mass as a manifestation of malignant tracheal neoplasms.1,2 This feature is not associated with benign tracheal neoplasms. CT readily detects the presence of circumferential tracheal wall thickening and luminal narrowing. It readily distinguishes an intrinsic tracheal abnormality from extrinsic compression. Multiplanar and 3D reconstructions complement axial images by enhancing the accuracy of assessment of craniocaudad extent of disease and extratracheal extension (Fig. 56.4). Magnetic Resonance Imaging Magnetic resonance imaging (MRI) is useful for tissue characterization and assessment of mediastinal invasion.8 Although most tracheal neoplasms have intermediate signal intensity on T1-weighted images and high signal intensity on T2-weighted images, MRI may show characteristic signal patterns in cases of leiomyomas, fibromas, hamartomas, and lipomas.8 Imaging Algorithms Chest radiographs are typically the first-line imaging test for a patient presenting with central airway symptoms. However, a high level of suspicion is required, as lesions are often overlooked at routine imaging. CT is the imaging modality of choice for the detection and staging of tracheal neoplasms. MRI plays a secondary role complementary to CT in selected cases in which additional information is deemed necessary with regard to tissue characterization or when CT is indeterminate for mediastinal invasion. MRI is more sensitive than CT for detecting mediastinal invasion or submucosal growth of tumor.8 Fluorodeoxyglucose–positron emission tomography (FDGPET)–CT can be helpful in the diagnosis and staging of tracheal malignancies. Tracheal malignancies are almost universally FDG avid, and PET is highly sensitive for the detection of nodal metastases.9 PET-CT is more sensitive for the detection of tracheal tumors than CT alone and may be helpful in characterizing the full extent of tumors with submucosal spread, such as adenoid cystic carcinoma. In addition, PET-CT can be used to detect tumor recurrence after treatment.9

Differential Diagnosis FROM CLINICAL DATA Primary tracheal neoplasms are frequently misdiagnosed clinically as adult-onset asthma. Thus this diagnosis should prompt careful assessment of the trachea on chest radiographs. The clinical symptoms of central airway obstruction also overlap with other tracheal disorders, including tracheal stenosis and tracheomalacia. Thus it is not possible to establish a diagnosis of a tracheal tumor on clinical grounds alone.

696

SECTION 11  Diseases of the Airways

A

B

T

A

C

D Fig. 56.1  Benign tracheal neoplasm, neurofibroma. (A) Lateral chest radiograph demonstrates a smoothly marginated round mass within the tracheal lumen (arrows). (B) Axial CT image shows near complete occlusion of the tracheal lumen (arrow). (C) Coronal reformatted image demonstrates a round contour, a diameter less than 2 cm, smooth margins, and lack of extratracheal extension, all suggestive of a benign lesion. A, Aortic arch; T, tumor. (D) Gross pathology specimen shows round mass with smooth margins.

56  Tracheal Diseases

M

Fig. 56.2  Malignant tracheal neoplasm, metastatic renal cell carcinoma. Axial CT image demonstrates a lobulated intraluminal mass with invasion of the airway wall (arrow). (Figure reproduced with permission from Walker CM, Bueno J. Airway metastases. In: Rosado-de-Christenson ML, Carter BW, eds. Specialty Imaging: Thoracic Neoplasms. 1st ed. Philadelphia: Amirsys-Elsevier; 2015.)

Fig. 56.3  Tracheal hamartoma. Axial CT image demonstrates a tracheal mass (arrow) arising from left lateral wall containing macroscopic foci of fat.

FROM SUPPORTIVE DIAGNOSTIC TECHNIQUES When a discrete tracheal mass is identified on imaging studies, the diagnosis of a primary tracheal neoplasm can usually be made with a high degree of confidence. Cross-sectional imaging, including CT and MRI, readily differentiate a primary tracheal neoplasm from invasion by an extratracheal malignant neoplasm, such as

697

*

Fig. 56.4  Multiplanar reconstruction for assessment of extent of adenoid cystic carcinoma. Coronal reformatted image demonstrates a mass (M) arising at the level of the carina (asterisk), with extension into the right main bronchus (arrow) and paratracheal soft tissues.

thyroid carcinoma. In addition, CT and MRI can often distinguish benign and malignant lesions and may rarely provide a specific diagnosis. Although a discrete tracheal mass usually represents a primary tracheal neoplasm, the differential diagnosis also includes metastatic disease from an extrathoracic primary neoplasm, including breast cancer, colorectal carcinoma, renal carcinoma, melanoma, and lung cancer.10 A variety of nonneoplastic lesions, including granulation polyps, amyloidosis, and retained secretions, may also mimic a tracheal neoplasm on imaging studies. Secretions can sometimes be differentiated from a fixed tracheal lesion by identification of small foci of air within secretions; strands of additional secretions within the airway may also be identified. Alternatively, a repeat CT in a prone position after coughing can document a change in position or clearing of secretions. In contrast, when a tracheal neoplasm manifests as eccentric or circumferential tracheal wall thickening rather than as a discrete mass, the differential diagnosis includes tracheal stenosis from a variety of nonmalignant entities, including iatrogenic (postintubation stenosis), infectious (tuberculosis), and inflammatory causes (e.g., granulomatosis with polyangiitis, relapsing polychondritis). In general, the presence of marked irregularity of tracheal wall thickening and the presence of extratracheal extension favor a primary tracheal neoplasm, but biopsy is usually necessary to establish the diagnosis. TYPES OF TRACHEAL NEOPLASMS Squamous Cell Carcinoma Squamous cell carcinomas are often large (4 cm) at the time of initial diagnosis, and their endoluminal component may be either exophytic or ulcerative.1 These lesions are often sessile and frequently result in asymmetric narrowing of the tracheal lumen.1 Regional lymph node metastases and local mediastinal invasion are relatively common. Extension from the trachea into the main

698

SECTION 11  Diseases of the Airways

KEY POINTS: TRACHEAL NEOPLASMS • Tracheal neoplasms are usually malignant and most commonly manifest as an intraluminal tracheal mass and less commonly as eccentric or circumferential tracheal wall thickening. • The most common cell types are squamous cell carcinoma and adenoid cystic carcinoma. • Features suggestive of malignancy include size larger than 2 cm, irregular margins, contiguous tracheal wall thickening, and extratracheal extension. • Tracheal neoplasms are often overlooked on chest radiographs but can usually be identified retrospectively on careful inspection of the trachea. • CT is the imaging modality of choice; multiplanar and 3D reconstructions enhance assessment of craniocaudal extent of disease and extratracheal involvement.

bronchus and development of a tracheoesophageal fistula are observed in 25% and 15% of cases, respectively.1 Adenoid Cystic Carcinoma Adenoid cystic carcinoma is the most common variety of tracheobronchial gland neoplasm, accounting for about 75% to 80% of cases. It usually arises from the trachea or the main bronchi and only occasionally from more distal bronchi or lung periphery. The mean age at diagnosis is 45 to 50 years.11,12 Cigarette smoking does not seem to be an etiologic factor.13 The most common clinical manifestations are cough, hoarseness, hemoptysis, dyspnea, wheeze, and recurrent pneumonitis.14,15 The symptoms of dyspnea and wheeze frequently lead to a misdiagnosis of asthma.14,15 Adenoid cystic carcinomas grossly appear as polypoid or broad-based and infiltrative intraluminal tracheal masses. At diagnosis, the lesions are usually less than 2 cm, and their surface may be either smooth or ulcerated.1,16 These neoplasms are nonencapsulated and characteristically spread along perineural surfaces or perineural lymphatics.1 At the time of diagnosis, the lesion has often already infiltrated long segments of the tracheal submucosa.1 The extent of microscopic invasion is typically greater than that estimated by imaging assessment and direct visualization at surgery.16 CT is superior to radiography in identifying the tumors and is particularly helpful in assessing the presence of extraluminal extent and mediastinal invasion.15,17 The most common finding on CT consists of a lobulated, polypoid endoluminal mass with associated focal thickening of the airway wall (Fig. 56.5).15,18 Less commonly, adenoid cystic carcinoma may be associated with extensive thickening of the tracheal or bronchial wall (Fig. 56.6).19 Adenoid cystic carcinoma has a tendency to infiltrate beneath the mucosa; its longitudinal extent may be underestimated on CT.14 Optimal assessment requires thin sections (preferably 1 mm or less) and multiplanar or 3D reformations.6,15,20

KEY POINTS: ADENOID CYSTIC CARCINOMA • Adenoid cystic carcinoma is the most common tracheobronchial gland neoplasm and the second most common primary malignant tumor of the trachea (after squamous cell carcinoma). • Most tumors arise in the trachea or main bronchi. • Imaging findings include the following: • Polypoid endoluminal mass • Circumferential tracheal wall thickening

Fig. 56.5  Adenoid cystic carcinoma of the trachea. Axial CT scan shows a lobulated polypoid endotracheal tumor with extensive involvement of the tracheal wall and extension into the adjacent mediastinum (arrows).

Mucoepidermoid Carcinoma Mucoepidermoid carcinoma (MEC) is the second most common form of tracheobronchial gland neoplasm but accounts for less than 0.2% of pulmonary carcinomas.21 Patients vary in age from 3 months to 78 years, but almost half are younger than 30 years.22,23 Symptoms are related predominantly to growth in the airway wall and lumen and include cough, hemoptysis, recurrent pneumonia, and dyspnea.22,24 MECs are composed of cells that show glandular (typically mucus production) and “epidermoid” features and are classified histopathologically into low- and high-grade neoplasms. They usually are located in segmental bronchi and, less commonly, arise within the lobar or main bronchi or trachea.14 Most grow within the airway lumen and produce a polypoid mass with an intact or occasionally ulcerated surface epithelium; peripheral extension within the bronchial lumen may occur.22 Low-grade tumors often are confined to the bronchial wall; by contrast, the high-grade form commonly extends into the peribronchial interstitium or adjacent lung parenchyma with propensity for lymph node metastases. Radiographic findings are related to tumor location and size and may consist of a solitary nodule or mass, lobar or segmental consolidation or atelectasis, or a central mass with associated obstructive pneumonitis or atelectasis (Fig. 56.7).22 The CT manifestations of MECs usually consist of a smoothly oval or lobulated soft tissue nodule or mass measuring at least 1 cm in diameter.19,22 Punctate calcification within the tumor is seen on CT scan in 25% to 50% of cases.22 High-grade MECs typically show high FDG uptake, whereas low-grade tumors show low uptake that may be similar to a mediastinal blood pool.25,26 The tumors are homogeneous and show slight enhancement after the administration of contrast medium (Fig. 56.8). The direction of the longest diameter of the oval or lobulated tumor in the lobar or segmental bronchus is typically parallel to that of the branching pattern in the corresponding airways containing the tumor. Associated CT findings include distal bronchial dilation with mucoid impaction, postobstructive pneumonia, atelectasis, and air-trapping.22 Occasionally, the tumors may involve the trachea rather than the bronchi and appear as a polypoid intraluminal nodule on

56  Tracheal Diseases

699

A

C

B

radiograph and CT scan (Fig. 56.9).22 CT is superior to radiographs in the assessment of intraluminal tumor and the extent of involvement of the bronchial or tracheal wall and mediastinum. Metastatic disease, including hilar or mediastinal lymphadenopathy, pleural nodularity, osseous lesions, and liver lesions, is uncommon except in high-grade MECs.22 KEY POINTS: MUCOEPIDERMOID CARCINOMA • Mucoepidermoid carcinoma (MEC) accounts for less than 0.2% of pulmonary carcinomas. • MEC most commonly involves segmental bronchi. • Imaging findings include the following: • 1- to 4-cm nodule or mass • Distal obstructive pneumonitis, atelectasis, or air-trapping • Close association with bronchus usually evident on CT

Tracheal Papilloma A solitary papilloma typically appears as a small, sessile or pedunculated growth arising from the tracheal wall.1 Larger lesions may demonstrate a cauliflower-like appearance.1,16 A range of squamous dysplasia, as well as in situ or invasive carcinoma, may also be identified within squamous cell papillomas.16

Synopsis of Treatment Options

Fig. 56.6  Adenoid cystic carcinoma of the trachea. CT scans at the level of the great vessels (A) and at the level of the aortic arch (B) show circumferential thickening of the tracheal wall (arrows). (C) Volumetric coronal reformatted image shows the extent of the tracheal narrowing (arrows).

SURGICAL Surgery is the treatment of choice, with resection of the involved portion of the trachea and reconstruction of the remaining uninvolved portions of the trachea.27 Accurate preoperative identification of the precise level and length of resection is critically important.27 Surgical treatment is usually curative for benign tracheal neoplasms. Complete excision of a solitary papilloma is recommended to exclude an invasive malignant neoplasm and to prevent recurrence.16 Treatment of malignant tracheal neoplasms is usually by segmental resection and reconstruction performed in a single stage and adjuvant preoperative and postoperative irradiation.28 For patients in whom squamous cell or adenoid cystic carcinoma is unresectable, palliative methods that yield good success rates are available, including laser photoresection, external beam irradiation, and brachytherapy.28,29 MECs have a 5-year survival after surgery of approximately 80% in patients with low-grade malignancy at histology and 30% in patients with carcinomas with high-grade malignancy.24 It is recommended that MECs be treated by radical surgery with lymph node sampling and dissection.24

Tracheal Stenosis

MEDICAL

Etiology

Medical therapy does not play a primary role in the treatment of tracheal tumors. Antibiotic therapy may be administered to treat postobstructive pneumonia or bronchitis.

Tracheal stenosis refers to narrowing of the tracheal lumen. A variety of iatrogenic, inflammatory, infectious, and neoplastic processes may result in focal or diffuse tracheal narrowing. This

700

SECTION 11  Diseases of the Airways

A

B

C

D Fig. 56.7  Mucoepidermoid carcinoma (MEC) originating in the right main bronchus. (A) Chest radiograph shows a poorly defined soft tissue mass in the right main bronchus (arrow) and marked volume loss of the right lung with ipsilateral shift of the mediastinum and elevation of the right hemidiaphragm. (B) CT scan shows an endobronchial tumor (arrow) with almost complete obstruction of the right main bronchus and associated volume loss of the right lung. (C) CT scan at soft tissue windows shows a large endobronchial tumor (arrows). (D) Low-power view of the surgical specimen after pneumonectomy shows an endobronchial MEC. (Courtesy Dr. Joungho Han, Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.)

section focuses on postintubation tracheal stenosis, which is by far the most common cause of acquired tracheal stenosis.30–32 Postintubation stenosis occurs secondary to injury of the trachea from the high pressure of an endotracheal tube balloon against the wall of the trachea.30,33 This initially results in mucosal necrosis, followed by scarring and stenosis.30,33

Prevalence and Epidemiology The true prevalence of postintubation tracheal stenosis is unknown. Although it was initially reported in up to 20% of cases after endotracheal intubation, its prevalence has decreased substantially to an estimated 1% with the introduction of lowpressure cuff endotracheal tubes.31,33 The prevalence of tracheal

56  Tracheal Diseases

701

A

Fig. 56.9  Mucoepidermoid carcinoma of the trachea. CT scan shows a heterogeneously enhancing tumor along the posterior tracheal membrane. Note left lower lobe consolidation and small left pleural effusion from aspiration pneumonia. (Figure reproduced with permission from Walker CM. Mucoepidermoid carcinoma. In: Rosado-de-Christenson ML, Carter BW, eds. Specialty Imaging: Thoracic Neoplasms. 1st ed. Philadelphia: Amirsys-Elsevier; 2015.)

narrowing is worsened by airway edema and secretions from a coexistent respiratory infection.35

Pathophysiology ANATOMY B Fig. 56.8  Mucoepidermoid carcinoma (MEC) originating in the lingular bronchus. (A) CT scan shows a large tumor (arrow) originating from the lingular bronchus and extending into adjacent hilum and lung parenchyma. Also evident is associated volume loss of the left lung. (B) Positron emission tomography image shows marked fluorodeoxyglucose uptake typical of high-grade MEC (arrow). (Courtesy Dr. Kyung Soo Lee, Samsung Medical Center, Seoul, South Korea.)

stenosis has been estimated at approximately 30% after longstanding tracheostomy tube placement.34 Risk factors include difficult or prolonged intubation, infection, mechanical irritation, steroid administration, and use of positivepressure ventilation.33

Clinical Presentation Affected patients typically present with dyspnea on exertion, stridor, and wheezing.33 Symptoms of upper airway obstruction are often delayed several weeks after extubation. Patients with mild stenoses may initially be asymptomatic. However, such patients may eventually develop symptoms when tracheal luminal

Postintubation stenosis is characterized by eccentric or concentric tracheal wall thickening and associated luminal narrowing. The craniocaudal length usually ranges from 1.5 to 2.5 cm.30,32 In patients who have undergone tracheostomy tube placement, the stenosis occurs most commonly at the stoma site and less commonly at the site where the tip of the tube has impinged on the tracheal mucosa.30,33,36 In patients who have undergone endotracheal intubation, stenosis occurs most commonly in the subglottic region at the level of the endotracheal tube balloon.32 PATHOLOGY Acutely, ischemic necrosis is due to compromise of the blood supply to the tracheal mucosa.30 This is followed by a superficial tracheitis with shallow ulcerations. The exposed cartilaginous rings subsequently soften and become fragmented. This is followed by fibrosis and granulation tissue formation, resulting in concentric or eccentric wall thickening with associated luminal narrowing. LUNG FUNCTION Flow-volume loops may show characteristic changes of airway obstruction.35 Such changes typically precede abnormalities in spirometric volumes.35

702

SECTION 11  Diseases of the Airways

Manifestations of the Disease FOCAL TRACHEAL NARROWING General The most common imaging finding in postintubation stenosis is a focal area of tracheal luminal narrowing measuring approximately 2 cm in craniocaudal length.30,32,33 The focal nature and circumferential narrowing may produce a characteristic hourglass configuration. Less commonly, one may observe a thin membrane projecting into the tracheal lumen or a long segment of eccentric soft tissue thickening.30,33 Radiography Postintubation stenoses are often overlooked on conventional radiographs, in part because of a proximal location.33 On careful scrutiny of radiographs, however, airway narrowing is usually visible in cases of significant stenosis. Computed Tomography CT is the imaging modality of choice to detect and characterize tracheal stenosis. On axial images, CT demonstrates eccentric or concentric soft tissue thickening with associated luminal narrowing (Fig. 56.10).32 Multiplanar reconstruction and 3D external rendering of images help detect focal stenoses and aid in assessment of craniocaudal length, which is often underestimated on axial images (Fig. 56.11, see Fig. 56.10).30 Less commonly, tracheal stenosis may manifest as a thin membrane of granulation tissue projecting into the tracheal lumen.30,33 This finding may be difficult to detect on axial CT images, but thin-section and reformatted images may aid in its visibility. Because long-standing tracheal stenoses may be complicated by coexistent tracheomalacia resulting from weakness and fragmentation of the tracheal cartilage, the addition of a dynamic expiratory CT sequence can help detect excessive airway collapsibility.

A

Magnetic Resonance Imaging Similar to CT, MRI demonstrates eccentric or concentric soft tissue thickening internal to the tracheal cartilage. Multiplanar images along the axis of the trachea accurately depict the craniocaudal extent of stenosis. Imaging Algorithms Chest radiographs are usually the initial imaging obtained for the assessment of patients with central airway symptoms and suspected tracheal stenosis. However, a normal chest radiograph does not exclude this diagnosis. CT with multiplanar and 3D renderings is the study of choice for detection and characterization of tracheal stenosis. MRI may be considered an alternative to CT in younger patients in whom radiation exposure may be a concern. B

Differential Diagnosis FROM CLINICAL DATA Although the symptoms of postintubation stenosis overlap with those of other causes of central airway obstruction, the diagnosis should be suspected when a patient with a recent history of

Fig. 56.10  Postintubation stenosis. (A) Axial CT image of the proximal trachea demonstrates circumferential wall thickening (arrows) and luminal narrowing caused by postintubation stenosis. (B) Three-dimensional (3D) external rendering of the trachea demonstrates hourglass-shaped focal stenosis (arrows). Craniocaudad extent of stenosis was more accurately assessed on the 3D image than on the contiguous axial CT images.

56  Tracheal Diseases

703

of the airway walls or supporting cartilage and may be congenital or acquired.37,38 Primary or congenital tracheomalacia is associated with congenital weakness of the airway wall, which may arise in the setting of abnormal cartilaginous matrix, inadequate maturity of cartilage (e.g., premature infants), or congenital tracheoesophageal fistula.37 Secondary or acquired tracheomalacia has been associated with a variety of conditions, including chronic obstructive pulmonary disease (COPD), prior intubation, prior surgery (e.g., lung resection or transplantation), radiation therapy, long-standing extrinsic compression (e.g., thyroid goiter or vascular ring), and chronic inflammation (e.g., relapsing polychondritis).37 Acquired tracheomalacia may also be idiopathic in some cases.

Prevalence and Epidemiology

Fig. 56.11  Postintubation stenosis. Three-dimensional external rendering of the trachea demonstrates focal high-grade subglottic stenosis (arrows). The stenosis was nearly overlooked on axial CT images (not shown).

intubation or tracheostomy tube placement presents with upper airway symptoms. FROM SUPPORTIVE DIAGNOSTIC TECHNIQUES The diagnosis may be suggested by the detection of focal airway narrowing on chest radiographs or CT scans. A characteristic hourglass narrowing at the typical location of the endotracheal tube cuff is highly suggestive of this diagnosis in a patient with a prior history of tracheostomy or endotracheal intubation. Biopsy may be required in equivocal cases to exclude underlying neoplasms.

Synopsis of Treatment Options A variety of interventional bronchoscopic (balloon dilation, laser therapy, stent placement) and surgical (resection and end-to-end anastomosis) techniques may be used to treat symptomatic tracheal stenoses.35 Specific treatment decisions depend on patient factors, characteristics of the stenosis, and local expertise. KEY POINTS: TRACHEAL STENOSIS • Tracheal stenosis is the most common complication of endotracheal intubation and tracheostomy tube placement, although the prevalence has decreased substantially since the introduction of low-pressure cuffs. • Postintubation stenosis most commonly manifests as a focal, hourglass-shaped tracheal stenosis. • CT with multiplanar and three-dimensional reconstructions is the imaging modality of choice. • A variety of bronchoscopic and surgical interventions may be used to treat this condition.

The true prevalence of tracheomalacia is unknown because this functional disorder usually escapes detection on routine chest radiographs and routine CT scans.38 The congenital form is most commonly observed in premature infants37 and is often associated with cardiovascular abnormalities, bronchopulmonary dysplasia, and gastroesophageal reflux. The acquired form of tracheomalacia has been reported in 5% to 23% of bronchoscopic studies performed in patients with respiratory symptoms.38

Clinical Presentation The congenital form typically manifests in the first weeks to months of life with symptoms of expiratory stridor, cough, and difficulty feeding.37 Patients with the acquired form may present at any age, but the prevalence of this condition increases with advancing age.37 When tracheomalacia occurs secondary to prior intubation, symptoms may arise several weeks to several years after intubation. The most common symptoms in patients with acquired tracheomalacia are intractable cough, dyspnea, wheezing, and recurrent respiratory infections.37

Pathophysiology ANATOMY The trachea is often normal in appearance on routine endinspiratory imaging studies, but it may also show preferential widening of the coronal (lunate) or sagittal (saber-sheath) dimension in some cases. At autopsy in patients with acquired tracheomalacia, the pars membranacea is often dilated and flaccid.37 PATHOLOGY Tracheomalacia is characterized pathologically by weakening of the cartilage or posterior membranous wall, with degeneration and atrophy of the longitudinal elastic fibers.37 LUNG FUNCTION

Tracheomalacia Etiology Tracheomalacia is a condition characterized by increased compliance and excessive collapsibility of the trachea caused by weakness

Pulmonary function test results may be suggestive of tracheomalacia, but they are not diagnostic.37 Spirometry usually shows obstruction proportional to the severity of tracheomalacia. The characteristic pattern is a decreased forced expiratory volume in 1 second (FEV1) and a low peak flow rate with a rapid decrease in flow.37

704

SECTION 11  Diseases of the Airways

Manifestations of the Disease GENERAL

characteristic appearance may aid in the detection of tracheomalacia on routine CT scans in which patients inadvertently breathe during the CT acquisition.

The hallmark of tracheomalacia is excessive expiratory collapse. Although once defined as more than 50% reduction in crosssectional luminal area of the trachea during expiration, many now suggest using a threshold of 70% collapse39 because healthy subjects have been shown to demonstrate degrees of collapse that overlap with this value.40

MAGNETIC RESONANCE IMAGING

RADIOGRAPHY

Fluoroscopy is highly operator dependent and has been supplanted by cross-sectional imaging with CT or MRI. Paired inspiratory– dynamic expiratory CT is the imaging method of choice and provides simultaneous information about airway anatomy and compliance. Because MRI lacks ionizing radiation, it may be considered an alternative imaging modality for younger patients and those undergoing serial follow-up examinations.

Because it escapes detection on routine end-inspiratory imaging studies, tracheomalacia is not detectable on routine chest radiographs. Fluoroscopy may be rarely used to diagnose this condition.

Dynamic MRI during breathing maneuvers or coughing may be used to diagnose tracheomalacia.46 IMAGING ALGORITHMS

COMPUTED TOMOGRAPHY Paired inspiratory-expiratory CT imaging is the method of choice for diagnosis of this condition (Fig. 56.12). Dynamic expiratory imaging (during a forced exhalation) is more sensitive than end-expiratory imaging for detection of this condition.38,41,42 Cine CT imaging during a coughing maneuver is highly sensitive for detection of tracheomalacia but requires multiple acquisitions to image the entirety of the trachea.43 A “lunate” configuration of the trachea, in which the coronal tracheal diameter is larger than the sagittal diameter, is uncommon but highly specific for tracheomalacia.44 The detection of a lunate configuration on inspiratory CT should always prompt consideration of tracheomalacia, which can be confirmed at expiratory CT.39 Although precise cross-sectional area measurements are recommended for diagnosis of mild to moderate tracheomalacia, the presence of complete expiratory collapse is diagnostic of severe tracheomalacia. At expiratory imaging, a crescentic, frownlike configuration of the tracheal lumen with less than 6 mm of distance between the anterior and posterior walls is highly suggestive of tracheomalacia (Fig. 56.13).45 Recognition of this

A

Fig. 56.13  Tracheomalacia with frown sign. Dynamic expiratory CT image demonstrates frown-like crescentic configuration of the tracheal lumen (arrow), highly suggestive of tracheomalacia.

B Fig. 56.12  Tracheomalacia. (A) Axial CT image at end inspiration demonstrates patency of the tracheal lumen. Note relative widening of the coronal dimension with respect to the sagittal dimension (“lunate” shape), which is suggestive of underlying tracheomalacia. (B) Axial CT image during dynamic expiration demonstrates near-complete collapse of the tracheal lumen (arrow), consistent with severe tracheomalacia.

56  Tracheal Diseases

Differential Diagnosis FROM CLINICAL DATA There are no clinical features that allow one to distinguish tracheomalacia from other respiratory conditions such as emphysema, chronic bronchitis, and asthma.37 Moreover, these conditions often coexist with tracheomalacia. The diagnosis requires a high index of suspicion among patients at risk for this condition. FROM SUPPORTIVE DIAGNOSTIC TECHNIQUES A definitive diagnosis can be made by identifying excessive expiratory tracheal lumen collapse by paired inspiratory–dynamic expiratory CT, dynamic MRI, fluoroscopy, or bronchoscopy. Tracheomalacia should be distinguished from the entity known as “excessive dynamic airway collapse” (EDAC). Although tracheomalacia is due to abnormal cartilage and results in collapse of the anterior and posterior walls of the trachea, EDAC is thought to be a result of peripheral airway obstruction (as in asthma or COPD) and results in collapse of primarily the posterior membranous trachea.47

Synopsis of Treatment Options MEDICAL Treatment of patients with mild to moderate symptoms is conservative. Continuous nasal positive airway pressure helps with nocturnal symptoms.37 Antibiotics are used to treat respiratory infections. SURGICAL Severely symptomatic patients may benefit from surgical intervention with tracheoplasty.37,48,49 This surgical technique involves remodeling of the tracheal lumen and an increase in its rigidity by placement of a graft along the posterior wall. It is best suited to patients with excessive expiratory motion of the posterior wall of the trachea. Stents are a potential option for severely symptomatic patients who are not surgical candidates, but long-term use of stents is limited by a relatively high complication rate.37 KEY POINTS: TRACHEOMALACIA • Tracheomalacia refers to excessive expiratory collapsibility of the trachea. • It may be congenital or acquired. • It is widely considered an underdiagnosed condition. • Paired inspiratory–dynamic expiratory CT imaging is the best imaging method of diagnosis. • The frown sign and lunate configuration of the trachea are highly suggestive of this condition. • Treatment is usually conservative, but severely symptomatic patients may benefit from surgery.

Relapsing Polychondritis

705

Its etiology is unknown, but it is likely to be immune mediated.50 Recent research suggests a genetic susceptibility, an overlap with other disorders associated with immunologic abnormalities, and the potential for multiple inciting events, including chemical insults.51

Prevalence and Epidemiology Relapsing polychondritis is very rare, with an estimated prevalence of 4.5 to 9 per million individuals.52,53 It is most prevalent among white individuals. Most studies report that men and women are equally affected,51 but a female predominance has also been reported.50 Airway involvement is present in up to 50% of patients and is a major cause of morbidity and mortality.50,51,54 Women are more likely than men to experience serious airway problems.51

Clinical Presentation The average age at onset is the fifth and sixth decades, but the disease may rarely occur in childhood.51 The diagnosis is established when any three of the following clinical features are present: bilateral auricular chondritis, nonerosive seronegative inflammatory arthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis, or audiovestibular damage.55 Alternative diagnostic criteria include one or more of these clinical findings with positive histologic confirmation or chondritis at two or more separate anatomic locations with response to steroids or dapsone.56 The clinical manifestations and course of disease are highly variable. For this reason, there is often a substantial delay in diagnosis of approximately 3 years.50 Auricular involvement is the most common clinical feature.51 A saddle-nose deformity, which results from collapse of the cartilaginous nasal septum but preservation of the bony nasal septum, is highly characteristic of this condition. Patients with laryngotracheobronchial involvement may present with a variety of symptoms, including hoarseness, aphonia, wheezing, inspiratory stridor, nonproductive cough, dyspnea, and recurrent infections.51 Notably, airway involvement may be asymptomatic in the early stages. Airway involvement may uncommonly occur as an isolated manifestation of relapsing polychondritis, without other perceptible features of this condition.57

Pathophysiology ANATOMY The airway may be involved focally or diffusely. The larynx and upper trachea are most commonly affected, but the disease may also involve the airways more distally to the level of the subsegmental bronchi.51 Glottic, subglottic, laryngeal, or tracheobronchial inflammation may result in luminal encroachment. Loss of structural cartilaginous support resulting from cartilaginous inflammation and destruction may result in excessive compliance and dynamic expiratory collapsibility (tracheomalacia). In the late stages of the disease, there is fibrosis-induced luminal contraction of the airway, with severe luminal narrowing.

Etiology

PATHOLOGY

Relapsing polychondritis is a multisystem disorder characterized by recurrent inflammation of the cartilaginous structures of the external ear, nose, peripheral joints, larynx, trachea, and bronchi.50,51

The tracheal mucosa may be edematous. The tracheal cartilaginous rings may demonstrate abnormalities varying from mild inflammation to total resorption by granulation tissue.51

706

SECTION 11  Diseases of the Airways

There is no biopsy finding that is pathognomonic for relapsing polychondritis, but specimens of inflamed cartilage may show characteristic features.50 Histologic features of the cartilage include loss of basophilic staining of the matrix and perichondral inflammation.51 Eventually, the cartilage is destroyed and replaced by fibrous tissue. LUNG FUNCTION The effects of this condition on major airways can be fixed or variable. Variable obstruction is due to increased expiratory compliance and flaccidity, resulting in tracheomalacia. In late stages the airway obstruction is fixed because of cicatricial narrowing of the airway. The degree of airflow obstruction, as measured by FEV1, may be severe and does not improve after inhalation of bronchodilators.51 Pulmonary function tests, especially flow-volume loops, are helpful for discerning the nature (fixed or dynamic) of airway obstruction and its location (intrathoracic or extrathoracic).50 Pulmonary function tests have also been reported to be useful for monitoring of disease status over time.50

thickness is also common and may be calcified or noncalcified (Fig. 56.15; see also Fig. 56.14). Both of these features characteristically spare the posterior membranous wall of the trachea unless the inflammation is severe, at which point it may secondarily involve the posterior wall.59–62 CT readily identifies wall thickening, but it is unable to distinguish fibrosis from inflammation. Tracheal luminal narrowing is a common manifestation of airway involvement, ranging in prevalence from 33% to 89%.58–61 It may be diffuse or focal in distribution and is often accompanied by bronchial narrowing (Fig. 56.16). Compared with axial CT images, multiplanar and 3D external renderings of the trachea improve the detection of subtle airway stenoses and enhance the accuracy of determining the craniocaudad extent of disease (see Fig. 56.16).63 Paired inspiratory– dynamic expiratory CT is highly sensitive for the detection of tracheomalacia in patients with known or suspected relapsing polychondritis (Fig. 56.17).64–66 Early in the course of disease, this finding may precede detectable morphologic abnormalities; thus dynamic expiratory CT should be routinely performed in the assessment of symptomatic patients with known or suspected relapsing polychondritis.66

Manifestations of the Disease

MAGNETIC RESONANCE IMAGING

RADIOGRAPHY

Increased wall thickness may be observed at MRI, but calcification is better visualized with CT. A potential advantage of MRI is its ability to distinguish fibrosis from inflammation.67 Dynamic MRI is a potential CT alternative for the evaluation of tracheomalacia.68

Calcification of the tracheal wall or airway narrowing is occasionally visible on chest radiographs, but it is better visualized at CT. COMPUTED TOMOGRAPHY Increased attenuation of the tracheal wall is the most common imaging manifestation of relapsing polychondritis and may range from subtle to frankly calcified (Fig. 56.14).58–61 Increased wall

Fig. 56.14  Tracheal wall thickening and calcification resulting from relapsing polychondritis. Axial CT image at the thoracic inlet demonstrates marked tracheal wall thickening with calcification (arrow). Note the characteristic sparing of the posterior noncartilaginous wall.

IMAGING ALGORITHMS Chest radiographs play a minor role in patients with relapsing polychondritis and are most useful for the assessment of

Fig. 56.15  Tracheal wall thickening without calcification in relapsing polychondritis. Axial CT image at the top of the aortic arch demonstrates marked tracheal wall thickening (arrows) without calcification.

56  Tracheal Diseases

707

FROM SUPPORTIVE DIAGNOSTIC TECHNIQUES When imaging studies depict the presence of characteristic smooth thickening of the anterior and lateral walls of the trachea, a diagnosis of relapsing polychondritis can be made with a high degree of confidence. Although tracheobronchopathia osteochondroplastica also spares the posterior membranous wall of the trachea, it is distinguished from relapsing polychondritis by the presence of discrete nodules arising from the submucosa of the tracheal wall and protruding into the airway lumen. Other causes of tracheal wall thickening and stenoses can generally be distinguished at CT or MRI by circumferential involvement of the airway wall, without sparing of the posterior membranous portion. When tracheomalacia is the only imaging finding, the differential diagnosis includes other causes of this condition, including COPD, prior intubation, and prior radiation therapy.

Synopsis of Treatment Options MEDICAL Pharmacologic options for the general treatment of patients with relapsing polychondritis include nonsteroidal antiinflammatory drugs, corticosteroids, and dapsone.51,69 Other immunosuppressive medications, such as cyclophosphamide, azathioprine, and methotrexate, are second-line treatment options.51,69 High-dose oral prednisone is usually necessary for the treatment of respiratory tract involvement, and intravenous pulse steroids may be useful for the treatment of acute airway obstruction.50 SURGICAL Fig. 56.16  Tracheal and bronchial luminal narrowing in relapsing polychondritis. External three-dimensional rendering CT image demonstrates mild diffuse luminal narrowing of the trachea and severe stenosis of the left main bronchus (arrow).

Surgical options include tracheostomy, tracheal stenting, external airway splinting, and tracheal reconstruction.51,70 KEY POINTS: RELAPSING POLYCHONDRITIS

complications such as pneumonia and atelectasis. However, in patients with advanced disease, careful inspection of the airway on radiographs may reveal tracheal calcification and narrowing. CT is the main imaging tool in the evaluation of patients with known or suspected relapsing polychondritis. It is highly sensitive for detection of tracheal wall thickening, calcifications, and narrowing. Paired inspiratory–dynamic expiratory CT is the preferred imaging method for the assessment of tracheobronchomalacia. MRI is less sensitive than CT and is more susceptible to artifact from respiratory motion. However, MRI may aid in the distinction between fibrosis and inflammation and is a potential alternative to CT for patients in whom radiation exposure from CT may be a concern.

Differential Diagnosis FROM CLINICAL DATA In a patient with airway symptoms and characteristic findings of relapsing polychondritis (e.g., saddle-nose deformity), the diagnosis is relatively easy to establish. However, when airway involvement is isolated, the differential diagnosis for airway symptoms is broad and includes granulomatosis with polyangiitis, postintubation injury, amyloidosis, and neoplastic tracheal involvement.

• Average age at onset is in the fifth and sixth decades. • Relapsing polychondritis is characterized by recurrent inflammation of the cartilaginous structures of the external ear, nose, peripheral joints, larynx, trachea, and bronchi. • Airway involvement occurs in approximately 50% of cases. • Respiratory complications (pneumonia, respiratory failure) are the leading cause of mortality. • Common radiologic findings: • Increased attenuation of the tracheal wall (spares the posterior wall) • Tracheal wall thickening (usually spares the posterior wall) • Focal or diffuse tracheobronchial narrowing • Tracheobronchomalacia

Tracheomegaly Etiology Tracheobronchomegaly, also referred to as Mounier-Kuhn syndrome, is of uncertain etiology. An underlying defect in elastic tissue has been suggested as a potential causative mechanism.71 An association with Ehlers-Danlos syndrome, Marfan syndrome, and cutis laxa has been described.71,72 In addition, a familial form has been reported with a possible autosomal-recessive inheritance.72 However, most cases occur sporadically. Secondary tracheomegaly may also develop in the setting of long-standing pulmonary fibrosis.71,73

708

SECTION 11  Diseases of the Airways

A

B Fig. 56.17  Tracheomalacia in relapsing polychondritis. (A) End-inspiratory CT demonstrates mild luminal narrowing of the trachea with thickening of the anterior and lateral tracheal walls. (B) Dynamic expiratory CT shows >70% cross-sectional area lumen reduction, consistent with tracheomalacia.

Prevalence and Epidemiology The prevalence of tracheobronchomegaly is unknown. Although once considered extremely rare, it has been recognized with increasing frequency in the past 2 decades, probably as a result of improved visualization of the trachea with CT.74 There is a male predominance.71–76 Acquired tracheomegaly has been estimated to occur in roughly 30% of patients with diffuse pulmonary fibrosis.73 In this population a potential causative relationship with chronic cough and recurrent respiratory infections has been suggested.73

Clinical Presentation Patients with tracheobronchomegaly typically present in the third and fourth decades.71–75 The clinical presentation is variable and ranges from minimal to severe respiratory symptoms, including productive cough, copious sputum production, and, rarely, hemoptysis. When tracheobronchomegaly has been complicated by recurrent infections, patients may present with progressive dyspnea and respiratory failure. In contrast, secondary tracheomegaly is usually an incidental finding on CT scans of patients with long-standing pulmonary fibrosis. Such patients typically present with symptoms related to pulmonary fibrosis, including progressive dyspnea and dry cough.73

Pathophysiology ANATOMY Severe atrophy of the longitudinal elastic fibers and thinning of the muscularis mucosa allow both the cartilaginous and

membranous portions of the trachea and main bronchi to dilate, resulting in increased luminal diameter.75 Redundant musculomembranous tissue may protrude between the cartilaginous rings, resulting in diverticular protrusions that range in size from several millimeters to several centimeters. When it is diffuse, the condition is referred to as tracheobronchial diverticulosis.71 PATHOLOGY Both the cartilaginous and membranous portions of the trachea and bronchi demonstrate atrophy of muscular and elastic tissue.72 Recurrent infections may be complicated by bronchiectasis, emphysema, and parenchymal scarring.72,76 LUNG FUNCTION Pulmonary function test results of patients with tracheobronchomegaly typically demonstrate a decrease in expiratory flow rates, an enlarged dead space, and an increased tidal volume.72 Increased compliance of the trachea may result in excessive expiratory collapsibility (malacia), which can be detected by bronchoscopy or dynamic expiratory CT scanning.

Manifestations of the Disease RADIOGRAPHY On radiographs the diagnosis can be made by measuring the coronal (transverse) and sagittal (anteroposterior) diameters of the trachea. Tracheomegaly is defined in women as tracheal diameter greater than 21 mm (coronal) and 23 mm (sagittal) and in men as tracheal diameter greater than 25 mm (coronal) and 27 mm (sagittal).75 Bronchomegaly is defined in women by

56  Tracheal Diseases

diameters of right and left bronchi greater than 19.8 and 17.4 mm, respectively, and in men by diameters greater than 21.1 and 18.4 mm, respectively.75 A corrugated or undulated appearance of the tracheal wall may be visible on the lateral chest radiograph. This appearance is due to the presence of outpouchings between the cartilaginous rings of the trachea. COMPUTED TOMOGRAPHY Dilation of the internal lumen of the airway is easily visualized on axial CT scans (Figs. 56.18 and 56.19). Although not necessary for diagnosis, external 3D renderings may help demonstrate the distribution of the dilated airways. An undulated appearance of the wall of the trachea and main bronchi is commonly observed on CT (Fig. 56.20). Discrete diverticula may be visualized as tubular blind-ended outpouchings arising from the tracheal and bronchial walls (Fig. 56.21). Tracheal diverticula are a frequent manifestation of tracheobronchomegaly in association with Mounier-Kuhn syndrome. However, they are not usually observed

709

in secondary tracheomegaly that arises in the setting of longstanding, diffuse pulmonary fibrosis. MAGNETIC RESONANCE IMAGING Dilation of the internal lumen of the airway and tracheal diverticula may be visualized on MRI. IMAGING ALGORITHMS Chest radiography generally suffices for the detection of tracheobronchomegaly and thus serves as the first-line imaging

Fig. 56.20  Tracheobronchomegaly. Three-dimensional external rendering of the central airways demonstrates diffuse tracheobronchomegaly.

Fig. 56.18  Tracheobronchomegaly. Axial CT image at the level of the carina demonstrates an enlarged trachea with an undulating anterior wall and several small diverticula (arrow) arising from the posterior wall.

Fig. 56.19  Secondary tracheomegaly due to lung fibrosis. Axial CT image at the lung apices demonstrates enlarged tracheal diameter of 3 cm. Note fibrosis with traction bronchiectasis at the right lung apex.

Fig. 56.21  Tracheal diverticulosis. Sagittal reformatted CT image of the trachea demonstrates multiple tubular, air-filled structures (arrows) arising from the posterior trachea, representing diverticulosis. Also note the tracheomegaly and corrugated contour of the anterior wall.

710

SECTION 11  Diseases of the Airways

study. CT provides more detailed information about the tracheal wall and displays characteristic undulations and diverticula of the airway wall with greater detail than radiographs do. CT is also more sensitive than radiography for the detection of complications, including bronchiectasis, emphysema, and pulmonary fibrosis. Dynamic expiratory CT may be helpful for detecting excessive expiratory collapse (malacia). MRI may be considered an alternative to CT in young patients for whom radiation exposure may be a potential concern.

have been proposed: (1) enchondrosis or exostosis from the tracheal cartilaginous rings and (2) cartilaginous and osseous metaplasia of elastic tissue in the internal elastic fibrous membrane of the tracheal wall.77

Prevalence and Epidemiology Its prevalence at routine bronchoscopy is well below 1%.33

Clinical Presentation Differential Diagnosis FROM CLINICAL DATA There are no specific clinical features that will differentiate this condition from isolated bronchiectasis or chronic bronchitis.

The clinical presentation is variable. The disorder is typically diagnosed during the fifth and sixth decades and has a 3 : 1 male predilection.33 TBO may be an incidental finding in an asymptomatic patient or may present with a variety of respiratory symptoms, including dyspnea on exertion, cough, wheezing, recurrent infections, and hemoptysis.77

FROM SUPPORTIVE DIAGNOSTIC TECHNIQUES The diagnosis can be made with confidence on radiography, CT, or MRI by demonstration of enlargement of the internal lumen of the trachea accompanied by a corrugated contour of the airway wall.

Synopsis of Treatment Options MEDICAL Treatment is conservative and includes chest physiotherapy for assistance with clearing of secretions and antibiotics for treatment of pulmonary infections.71

Pathophysiology ANATOMY TBO is characterized by multiple submucosal osteocartilaginous nodules that project into the tracheal lumen. PATHOLOGY At histopathologic examination the nodules are recognized as submucosal osteocartilaginous growths. The mucosal surface is usually intact, and a connection between the nodule and the perichondrium of the tracheal cartilaginous ring is frequently identified.33

SURGICAL Tracheoplasty or stent placement may be considered in selected patients with tracheobronchomegaly and severe tracheomalacia. KEY POINTS: TRACHEOBRONCHOMEGALY • Tracheal dimensions should routinely be assessed on chest radiographs and CT scans of patients with recurrent infections and chronic sputum production. • Key imaging features of tracheobronchomegaly are increased luminal diameter and corrugated appearance of airway walls. • Tracheobronchomegaly may be complicated by tracheomalacia, bronchiectasis, emphysema, and fibrosis. • Secondary tracheomegaly may be observed as an incidental finding on imaging studies of patients with long-standing pulmonary fibrosis. In this condition the wall of the trachea is smooth, and diverticula are usually absent.

Tracheobronchopathia Osteochondroplastica Etiology Tracheobronchopathia osteochondroplastica (TBO) is an uncommon, benign disease of unknown etiology.33,77–80 Various causes or associations have been postulated, including chronic inflammatory or degenerative processes, chemical irritation, amyloidosis, infection, and hereditary factors.77,78 Two theories of histogenesis

Manifestations of the Disease RADIOGRAPHY In advanced cases chest radiographs may demonstrate tracheal narrowing with a scalloped and nodular configuration.33,77 Calcification may also be identified radiographically, especially on the lateral radiograph.78 COMPUTED TOMOGRAPHY CT is the imaging modality of choice for this condition.77 It demonstrates a characteristic pattern of calcified nodules arising from the anterior and lateral walls of the trachea and protruding into the lumen, which may result in diffuse luminal narrowing (Figs. 56.22 and 56.23). The individual nodules typically range in size from 3 to 8 mm.79 Thickening of the tracheal cartilage is also typically visible at CT.33,77,79,80 Similar to relapsing polychondritis, there is sparing of the noncartilaginous posterior membranous wall. A saber-sheath configuration (sagittal to coronal diameter ratio >2) of the trachea, which is most commonly associated with COPD, is also frequently observed in patients with TBO.77

Differential Diagnosis FROM CLINICAL DATA There are no distinguishing clinical features of this condition.

56  Tracheal Diseases

FROM SUPPORTIVE DIAGNOSTIC TECHNIQUES The identification of calcified nodules arising from the anterior and lateral walls of the trachea at CT or bronchoscopy is considered diagnostic of this condition.33,78 TBO can be distinguished

711

from entities such as amyloidosis and infectious tracheitis that have circumferential tracheal involvement. Although relapsing polychondritis has a distribution similar to that of TBO, it characteristically manifests with calcified wall thickening without discrete intraluminal nodules. Moreover, relapsing polychondritis is frequently associated with tracheomalacia, whereas TBO is not usually associated with increased expiratory collapsibility.

Synopsis of Treatment Options MEDICAL

*

Treatment is usually supportive and conservative. There is currently no medical therapy to treat this condition or to prevent the growth of new nodules.33 SURGICAL There is no standard interventional therapy. Treatment options for advanced cases include laser resection, radiation therapy, surgical resection, and stent placement.77 Interventional therapy is usually tailored for individual cases.

KEY POINTS: TRACHEOBRONCHOPATHIA OSTEOCHONDROPLASTICA • Diagnosis is typically made during the fifth and sixth decades. • There is a 3 : 1 male predilection. • It is often an incidental finding in an asymptomatic patient but may result in variable respiratory symptoms. • Identification of calcified nodules arising from the anterior and lateral walls of the trachea is diagnostic and is best visualized with CT.

Fig. 56.22  Tracheobronchopathia osteochondroplastica. Axial CT image above the aortic arch demonstrates diffuse thickening and calcification of the tracheal cartilage with nodularity that spares the posterior wall. Also note the saber-sheath configuration of the tracheal lumen. A calcified thyroid nodule (asterisk) is incidentally noted. (Courtesy Michael Gotway, MD.)

Ao Ao

A

B Fig. 56.23  Tracheobronchopathia osteochondroplastica. (A) Coronal CT image shows thickening, nodularity, and calcification of the tracheal cartilage. (B) Coronal CT image at lung windows better demonstrates the marked nodularity of the tracheal wall. Ao, Aortic arch.

712

SECTION 11  Diseases of the Airways

SUGGESTED READINGS Kligerman S, Sharma A. Radiologic evaluation of the trachea. Semin Thorac Cardiovasc Surg. 2009;21(3):246–254. Little BP, Duong P-AT. Imaging of diseases of the large airways. Radiol Clin N Am. 2016;54(6):1183–1203. Prince JS, Duhamel DR, Levin DL, et al. Nonneoplastic lesions of the tracheobronchial wall: radiographic findings with bronchoscopic correlation. Radiographics. 2002;22:S215–S230.

Ridge CA, O’Donnell CR, Lee EY, Majid A, Boiselle PM. Tracheobronchomalacia: current concepts and controversies. J Thorac Imaging. 2011;26(4): 278–289.

The full reference list for this chapter is available at ExpertConsult.com.

56  Tracheal Diseases 712.e1

REFERENCES 1. McCarthy MJ, Rosado-de-Christenson ML. Tumors of the trachea. J Thorac Imaging. 1995;10:180–198. 2. Fraser RS, Colman N, Müller NL, Paré PD. Upper airway obstruction. In: Fraser RS, Colman N, Müller NL, Paré PD, eds. Fraser and Paré’s Diagnosis of Diseases of the Chest. 4th ed. Philadelphia: WB Saunders; 1999:2035– 2036. 3. Houston HE, Payne WS, Harrison EG Jr, et al. Primary cancers of the trachea. Arch Surg. 1969;99:132–140. 4. Webb BD, Walsh GL, Roberts DB, et al. Primary tracheal malignant neoplasms: the University of Texas MD Anderson Cancer Center experience. J Am Coll Surg. 2006;202:237–246. 5. Weber AL, Grillo HC. Tracheal tumors: a radiological, clinical, and pathological evaluation of 84 cases. Radiol Clin North Am. 1978;16:227–246. 6. Finkelstein SE, Schrump DS, Nguyen DM, et al. Comparative evaluation of super high-resolution CT scan and virtual bronchoscopy for the detection of tracheobronchial malignancies. Chest. 2003;124:1834–1840. 7. Kwak SH, Lee KS, Chung MJ, et al. Adenoid cystic carcinoma of the airways: helical CT and histopathologic correlation. AJR Am J Roentgenol. 2004;183: 277–281. 8. Parsons RB, Milestone BN, Adler LP. Radiographic assessment of airway tumors. Chest Surg Clin North Am. 2003;13:63–77. 9. Wang S, Wang S, Liao J, Chen G. 18F-FDG PET/CT and contrast-enhanced CT of primary malignant tracheal tumor. Clin Nucl Med. 2016;41(8): 595–605. 10. Chong S, Kim TS, Han J. Tracheal metastasis from lung cancer: CT findings in 6 patients. AJR Am J Roentgenol. 2006;186:220–224. 11. Maziak DE, Todd TR, Keshavjee SH, et al. Adenoid cystic carcinoma of the airway: thirty-two-year experience. J Thorac Cardiovasc Surg. 1996;112:1522– 1531, discussion 1531–1532. 12. Moran CA, Suster S, Koss MN. Primary adenoid cystic carcinoma of the lung: a clinicopathologic and immunohistochemical study of 16 cases. Cancer. 1994;73:1390–1397. 13. Moran CA. Primary salivary gland-type tumors of the lung. Semin Diagn Pathol. 1995;12:106–122. 14. Fraser RS, Colman N, Müller NL, et al. Pulmonary neoplasms. In: Fraser RS, Colman N, Müller NL, et al, eds. Synopsis of Diseases of the Chest. Philadelphia: Saunders; 2005:337–422. 15. Kwak SH, Lee KS, Chung MJ, et al. Adenoid cystic carcinoma of the airways: helical CT and histopathologic correlation. AJR Am J Roentgenol. 2004;183: 277–281. 16. Litzky L. Epithelial and soft tissue tumors of the tracheobronchial tree. Chest Surg Clin North Am. 2003;13:1–40. 17. Kwong JS, Adler BD, Padley SP, et al. Diagnosis of diseases of the trachea and main bronchi: chest radiography vs CT. AJR Am J Roentgenol. 1993;161: 519–522. 18. McCarthy MJ. Rosado-de-Christenson ML. Tumors of the trachea. J Thorac Imaging. 1995;10:180–198. 19. Kwong JS, Müller NL, Miller RR. Diseases of the trachea and main-stem bronchi: correlation of CT with pathologic findings. Radiographics. 1992;12:647–657. 20. Boiselle PM, Reynolds KF, Ernst A. Multiplanar and three-dimensional imaging of the central airways with multidetector CT. AJR Am J Roentgenol. 2002;179:301–308. 21. Yousem SA, Hochholzer L. Mucoepidermoid tumors of the lung. Cancer. 1987;60:1346–1352. 22. Kim TS, Lee KS, Han J, et al. Mucoepidermoid carcinoma of the tracheobronchial tree: radiographic and CT findings in 12 patients. Radiology. 1999;212:643–648. 23. Tsuchiya H, Nagashima K, Ohashi S, et al. Childhood bronchial mucoepidermoid tumors. J Pediatr Surg. 1997;32:106–109. 24. Vadasz P, Egervary M. Mucoepidermoid bronchial tumors: a review of 34 operated cases. Eur J Cardiothorac Surg. 2000;17:566–569. 25. Yousem SA, Hochholzer L. Mucoepidermoid tumors of the lung. Cancer. 1987;60(6):1346–1352. 26. Park CM, Goo JM, Lee HJ, et al. Tumors in the tracheobronchial tree: CT and FDG PET features. Radiographics. 2009;29(1):55–71. 27. D’Cunha J, Maddaus MA. Surgical treatment of tracheal and carinal tumors. Chest Surg Clin North Am. 2003;13:95–110. 28. Kanematsu T, Yohena T, Uehara T, et al. Treatment outcome of resected and nonresected primary adenoid cystic carcinoma of the lung. Ann Thorac Cardiovasc Surg. 2002;8:74–77. 29. Aggarwal A, Tewari S, Mehta AC. Successful management of adenoid cystic carcinoma of the trachea by laser and irradiation. Chest. 1999;116: 269–270.

30. Fraser RS, Colman N, Müller NL, Paré PD. Upper airway obstruction. In: Fraser RS, Colman N, Müller NL, Paré PD, eds. Fraser and Paré’s Diagnosis of Diseases of the Chest. 4th ed. Philadelphia: WB Saunders; 1999:2033– 2036. 31. Stauffer J, Olson D, Petty T. Complications and consequences of endotracheal intubation and tracheostomy. A prospective study of 150 critically ill adult patients. Am J Med. 1981;70:65–76. 32. Webb EM, Elicker BM, Webb WR. Using CT to diagnose nonneoplastic tracheal abnormalities. AJR Am J Roentgenol. 2000;174:1315–1321. 33. Prince JS, Duhamel DR, Levin DL, et al. Nonneoplastic lesions of the tracheobronchial wall: radiographic findings with bronchoscopic correlation. Radiographics. 2002;22:S215–S230. 34. Norwood S, Vallina V, Short K, et al. Incidence of tracheal stenosis and other late complications after percutaneous tracheostomy. Ann Surg. 2000;232: 233–241. 35. Williamson JP, Phillips MJ, Hillman DR, Eastwood PR. Managing obstruction of the central airways. Intern Med J. 2010;40:399–410. 36. Marom EM, Goodman PC, McAdams HP. Focal abnormalities of the trachea and bronchi. AJR Am J Roentgenol. 2001;176:707–711. 37. Carden K, Boiselle PM, Waltz D, Ernst A. Tracheomalacia and tracheobronchomalacia in children and adults: an in-depth review of a common disorder. Chest. 2005;127:984–1005. 38. Boiselle PM, Feller-Kopman D, Ashiku S, Ernst A. Tracheobronchomalacia: evolving role of multislice helical CT. Radiol Clin North Am. 2003;41: 627–636. 39. Ridge CA, O’Donnell CR, Lee EY, Majid A, Boiselle PM. Tracheobronchomalacia: current concepts and controversies. J Thorac Imaging. 2011;26(4): 278–289. 40. Stern EJ, Graham CM, Webb WR, Gamsu G. Normal trachea during forced expiration: dynamic CT measurements. Radiology. 1993;187:27–31. 41. Gilkeson RC, Ciancibello LM, Hejal RB, et al. Tracheobronchomalacia: dynamic airway evaluation with multidetector CT. AJR Am J Roentgenol. 2001;176:205–210. 42. Baroni R, Feller-Kopman D, Nishino M, et al. Tracheobronchomalacia: comparison between end-expiratory and dynamic-expiratory CT methods for evaluation of central airway collapse. Radiology. 2005;2:635–641. 43. Boiselle PM, Lee KS, Lin S, Raptopoulous V, Cine CT. during coughing for assessment of tracheomalacia: preliminary experience with 64-multidetectorrow CT. AJR Am J Roentgenol. 2006;187:438. 44. Boiselle PM, Ernst A. Tracheal morphology in patients with tracheomalacia: prevalence of inspiratory lunate and expiratory “frown” shapes. J Thorac Imaging. 2006;21(3):190–196. 45. Boiselle PM, Ernst A. Tracheal morphology in patients with tracheomalacia: prevalence of inspiratory “lunate” and expiratory “frown” shapes. J Thorac Imaging. 2006;21:190–196. 46. Suto Y, Tanabe Y. Evaluation of tracheal collapsibility in patients with tracheomalacia using dynamic MR imaging during coughing. AJR Am J Roentgenol. 1998;171:393–394. 47. Murgu S, Colt H. Tracheobronchomalacia and excessive dynamic airway collapse. Clin Chest Med. 2013;34:527–555. 48. Baroni RH, Ashiku S, Boiselle PM. Dynamic-CT evaluation of the central airways in patients undergoing tracheoplasty for tracheobronchomalacia. AJR Am J Roentgenol. 2005;184:1444–1449. 49. Wright CD. Tracheomalacia. Chest Surg Clin North Am. 2003;13:349–357. 50. Trentham DE, Le CH. Relapsing polychondritis. Ann Intern Med. 1998;129:114–122. 51. Mathian A, Miyara M, Cohen-Aubart F, et al. Relapsing polychondritis: a 2016 update on clinical features, diagnostic tools, treatment and biological drug use. Best Pract Research Clin Rheumatol. 2016;30:316–333. 52. Mathew SD, Battafarano DF, Morris MJ. Relapsing polychondritis in the Department of Defense population and review of the literature. Semin Arthritis Rheum. 2012;41(1):70–83. 53. Mathew SD, Battafarano DF, Morris MJ. Incidence and mortality of relapsing polychondritis in the UK: a population-based cohort study. Rheumatology. 2015;54(12):2181–2187. 54. Letko E, Zafirakis P, Baltatzis S, et al. Relapsing polychondritis: a clinical review. Semin Arthritis Rheum. 2002;31:384–395. 55. McAdam LP, O’Hanlan MA, Bluestone R, Pearson CM. Relapsing polychondritis: prospective study of 23 patients and a review of the literature. Medicine (Baltimore). 1976;55:193–215. 56. Damiani JM, Levine HL. Relapsing polychondritis. Laryngoscope. 1979;89: 929–946. 57. Tsunezuka Y, Sato H, Shimizu H. Tracheobronchial involvement in relapsing polychondritis. Respiration. 2000;67:320–322. 58. Behar JV, Choi YW, Hartman TA, et al. Relapsing polychondritis affecting the lower respiratory tract. AJR Am J Roentgenol. 2002;178:173–177.

712.e2

SECTION 11  Diseases of the Airways

59. Prince JS, Duhamel DR, Levin DL, et al. Nonneoplastic lesions of the tracheobronchial wall: radiologic findings with bronchoscopic correlation. Radiographics. 2002;22:S215–S230. 60. Webb EM, Elicker BM, Webb WR. Using CT to diagnose nonneoplastic tracheal abnormalities. AJR Am J Roentgenol. 2000;174:1315–1321. 61. Marom EM, Goodman PC, McAdams HP. Diffuse abnormalities of the trachea and main bronchi. AJR Am J Roentgenol. 2001;176:713–717. 62. Ngo AV, Walker CM, Chung JH, Takasugi JE, Stern EJ, Kanne JP, Reddy GP, Godwin JD. Tumors and tumorlike conditions of the large airways. AJR Am J Roentgenol. 2013;201(2):301–313. 63. Boiselle PM, Reynolds KF, Ernst A. Multiplanar and three-dimensional imaging of the central airways with multidetector CT. AJR Am J Roentgenol. 2002;179:301–308. 64. Gilkeson RC, Ciancibello LM, Hejal RB, et al. Tracheobronchomalacia: dynamic airway evaluation with multidetector CT. AJR Am J Roentgenol. 2001;176:205–210. 65. Zhang J, Hasegawa I, Feller-Kopman D, Boiselle PM. Dynamic expiratory volumetric CT imaging of the central airways: comparison of standard-dose and low-dose techniques. Acad Radiol. 2003;10:719–724. 66. Lee KS, Ernst A, Trentham D, et al. Prevalence of functional airway abnormalities in relapsing polychondritis. Radiology. 2006;240:565–573. 67. Heman-Ackhah YD, Remley KB, Goding GS Jr. A new role for magnetic resonance imaging in the diagnosis of laryngeal relapsing polychondritis. Head Neck. 1999;21:484–489. 68. Suto Y, Tanabe Y. Evaluation of tracheal collapsibility in patients with tracheomalacia using dynamic MR imaging during coughing. AJR Am J Roentgenol. 1998;171:393–394. 69. Gergely P Jr, Poor G. Relapsing polychondritis. Best Pract Res Clin Rheumatol. 2004;18:723–738.

70. Sarodia BP, Dasgupta A, Mehta AC. Management of airway manifestations of relapsing polychondritis. Case reports and review of the literature. Chest. 1999;116:1669–1675. 71. Lazzarini-de-Oliveira LC, Costa de Barros Franco CA, Gomes de Salles CL, de Oliveira AC. A 38-year-old man with tracheomegaly, tracheal diverticulosis, and bronchiectasis. Chest. 2001;120:1018–1020. 72. Fraser RS, Colman N, Müller NL, Paré PD. Upper airway obstruction. In: Fraser RS, Colman N, Müller NL, Paré PD, eds. Fraser and Paré’s Diagnosis of Diseases of the Chest. 4th ed. Philadelphia: WB Saunders; 1999: 2046–2048. 73. Woodring JH, Barrett PA, Rehm SR, Nurenberg P. Acquired tracheomegaly in adults as a complication of diffuse pulmonary fibrosis. AJR Am J Roentgenol. 1989;152:743–747. 74. Shin MS, Jackson RM, Ho K. Tracheobronchomegaly (Mounier-Kuhn syndrome): CT diagnosis. AJR Am J Roentgenol. 1988;150:777–778. 75. Woodring JH, Smith Howard R, Rehn SR. Congenital tracheobronchomegaly (Mounier-Kuhn) syndrome: a report of 10 cases and review of the literature. J Thorac Imaging. 1991;6:1–10. 76. Roditi GH, Weir J. The association of tracheomegaly and bronchiectasis. Clin Radiol. 1994;49:608–611. 77. Restrepo S, Pandit M, Villamil MA, et al. Tracheobronchopathia osteochondroplastica: helical CT findings in 4 cases. J Thorac Imaging. 2004;19:112–116. 78. Fraser RS, Colman N, Müller NL, Paré PD. Upper airway obstruction. In: Fraser RS, Colman N, Müller NL, Paré PD, eds. Fraser and Paré’s Diagnosis of Diseases of the Chest. 4th ed. Philadelphia: WB Saunders; 1999:2042. 79. Webb EM, Elicker BM, Webb WR. Using CT to diagnose nonneoplastic tracheal abnormalities. AJR Am J Roentgenol. 2000;174:1315–1321. 80. Marom EM, Goodman PC, McAdams HP. Diffuse abnormalities of the trachea and main bronchi. AJR Am J Roentgenol. 2001;176:713–717.

57 

Bronchiectasis and Other Bronchial Abnormalities* BRENT P. LITTLE

Bronchiectasis Etiology Diseases of the airways are surprisingly common in clinical practice, and imaging tests have a central role in the evaluation of the patient. Bronchiectasis is an important yet, in historic terms, a surprisingly neglected disorder characterized pathologically by abnormal permanent dilatation of the bronchi, leading to significant morbidity and mortality.1–3 The causes and associations of bronchiectasis are diverse and summarized in Box 57.1. However, the relative impact of the various etiologic factors, such as infection, has changed over time, and there is considerable variation dependent on geographic and ethnic factors.4–7 The availability of effective antimicrobial therapy and the policy of widespread childhood immunization in many countries have had a significant impact, leading not only to a decrease in the prevalence of postinfectious bronchiectasis but also to a decline in overall mortality. In the developed world, including the United States and many countries in Europe, postinfectious bronchiectasis is now less of a clinical problem; the more common causes include cystic fibrosis and immunologic deficiencies, which may be primary (as seen in patients with panhypogammaglobulinemia or more selective immunoglobulin subclass defects) or secondary to immunosuppression (as may be seen in the context of hematologic malignant disease or human immunodeficiency virus–related disease).8–11 In stark contrast, infections such as tuberculosis continue to account for the majority of patients with bronchiectasis in developing countries.6,12 Defects of mucociliary clearance (either congenital, as in primary ciliary dyskinesia, or acquired), mechanical obstruction (intrinsic or extrinsic), and congenital abnormalities (such as intralobar sequestration) are among the less common but recognized causes of bronchiectasis.13 However, a cause for bronchiectasis may not be identified in 30% to 70% of patients.9,11,14 Another complicating factor in the evaluation of patients with bronchiectasis is that in a small proportion of cases, more than one causative factor may be identified.9

has stemmed from the relatively widespread misconception that bronchiectasis is no longer a significant clinical entity. The corollary is that the index of clinical suspicion for a diagnosis of bronchiectasis has been low, and physicians often attribute the symptoms and signs of bronchiectasis to other respiratory diseases (e.g., smokingrelated chronic bronchitis) that are perceived to be more common. Nevertheless, the prevalence of bronchiectasis is known to be remarkably high in select populations; for instance, high rates of bronchiectasis are known to be a problem in indigenous Australians16 and also native Alaskans.5 Similarly, bronchiectasis unrelated to cystic fibrosis is strikingly prevalent in parts of New Zealand, where there is an estimated overall prevalence of 1 in 3000 in children younger than 15 years and a staggering prevalence of 1 in 625 for children of Pacific ancestry.7 These data in contrast to the comparatively low prevalence of bronchiectasis in Finnish children of a similar age.17 Finally, in most large series of patients with bronchiectasis, a consistent finding has been the preponderance of female patients.1,6,18,19

Clinical Presentation Pulmonologists generally agree that the once dramatic clinical presentation of bronchiectasis (the classic patient with cough and large volumes of purulent and frequently foul-smelling sputum production) is now uncommon.13 In its place, there is a more insidious form of bronchiectasis in which patients give a typical story of so-called wheezy bronchitis during childhood and chronic purulent rhinosinusitis9,13; just less than half of those patients with bronchiectasis will also report an antecedent history of pneumonia or another respiratory tract infection.9 There is then often something of a “remission” in the teenage years, only to be followed, typically after a viral respiratory tract infection, by the more classic symptoms associated with bronchiectasis— namely, chronic cough and mucopurulent sputum production. Many patients also complain of breathlessness, intermittent hemoptysis, pleuritic chest pain, weight loss, and fatigue.6,11,13,18 The findings on physical examination are nonspecific and include early to midinspiratory crackles and wheezing.6,20 Digital clubbing is seen in up to one-quarter of patients with bronchiectasis.6

Prevalence and Epidemiology The true prevalence of bronchiectasis is unknown. Because it has long been the paradigm of an “orphan” lung disease,15 reliable published data on the prevalence of bronchiectasis have been frustratingly difficult to come by. One of the fundamental problems *The editors and publisher would like to thank Drs. Nestor L. Müller and C. Isabela Silva Müller for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

Pathophysiology ANATOMY With successive generations of bronchial branching, there is a progressive diminution of airway caliber; a lack of tapering is abnormal. The bronchial tree is composed of the large (bronchi) and small (bronchioles) airways. The traditional distinction is based on the presence or absence of cartilage in the wall; airways reinforced by cartilage and typically greater than 1 mm in diameter are termed 713

714

SECTION 11  Diseases of the Airways

BOX 57.1  CAUSES AND ASSOCIATIONS OF BRONCHIECTASIS Idiopathic Congenital Cystic fibrosis Mounier-Kuhn syndrome (tracheobronchomegaly) α1-Antitrypsin deficiency Williams-Campbell syndrome Intralobar sequestration Postinfectious or postinflammatory Bacterial, mycobacterial, viral, protozoal Swyer-James (MacLeod) syndrome Aspiration of gastric contents Inhalation of toxic fumes Immunodeficiency Primary: selective immunoglobulin deficiency, panhypogammaglobulinemia Secondary: malignant neoplasia, chemotherapy Mechanical airway obstruction Inhaled foreign bodies Neoplastic Broncholithiasis Bronchostenosis Defective mucus transport Primary ciliary dyskinesia Secondary ciliary dyskinesia Young syndrome Immunologic Allergic bronchopulmonary aspergillosis After heart-lung, lung, or bone marrow transplantation Miscellaneous associations Middle lobe syndrome Rheumatoid arthritis Sjögren syndrome Systemic lupus erythematosus Ulcerative colitis Yellow nail syndrome Celiac disease Human immunodeficiency virus infection

bronchi, whereas those without cartilage and typically less than 1 mm in diameter are termed bronchioles.21 Although larger airways are conducive to maximum rate of airflow, a rapid increase in total cross-sectional diameter at the level of the small airways facilitates gas exchange across the alveolar-capillary membrane.22–24 PATHOLOGY The vicious circle hypothesis for the pathogenesis of bronchiectasis, first advocated by Cole and colleagues,13 is the most widely accepted. The theory is based on the premise that there is initial damage to or disruption of the process of normal mucociliary clearance. This may have been as a result of a viral respiratory infection or a genetic susceptibility, as is the case in patients with cystic fibrosis. The inability to clear mucus permits the “normal” oropharyngeal flora, including Haemophilus influenzae, Pseudomonas aeruginosa, and Streptococcus pneumoniae, to persist within the airways. The organisms lead to further epithelial damage, reducing mucociliary clearance and encouraging further colonization. An inflammatory host response also contributes to further airway damage and dilatation of the airways. With time, there is loss of the elastin layer in the bronchial wall and destruction of cartilage. Some data, based on serial observations by use of computed tomography (CT), suggest that the vicious circle theory may need some refinement, particularly in the pediatric population, because bronchial

dilatation diagnosed by high-resolution CT is not always irreversible or progressive.25,26 Three different patterns of bronchiectasis are recognized: cylindrical, varicose, and cystic.27 In cylindrical bronchiectasis, there is relatively uniform bronchial dilatation, and the implication is that this is perhaps the least severe morphologic type. This should be contrasted with varicose bronchiectasis, in which there are focal narrowings along otherwise dilated airways, and cystic bronchiectasis, which, as the term suggests, indicates grossly dilated airways that have a cystic appearance. Although these morphologic subtypes of bronchiectasis are generally identifiable on high-resolution CT, the clinical utility of making these distinctions is questionable. LUNG FUNCTION The classic physiologic defect in bronchiectasis is airflow obstruction, which in some patients is partially reversible.28,29 The obstructive defect has been variably attributed to the presence of coexistent emphysema,30 airway hyperreactivity or asthma,31 constrictive bronchiolitis,32 and expiratory large airway collapse.33 However, CT studies suggest that areas of decreased attenuation, possibly reflecting constrictive bronchiolitis at the pathologic level, and severity of bronchial wall thickening are the best correlates of obstructive physiology.34–36 In some patients with bronchiectasis, there is an associated restrictive ventilatory defect, possibly related to patchy peribronchial fibrosis (presumably consequent on inflammation) and atelectasis.29

Manifestations of the Disease RADIOGRAPHY The chest radiograph is generally the first radiologic test requested by the pulmonologist when a diagnosis of bronchiectasis is suspected. However, radiography has low sensitivity and specificity in the diagnosis (Fig. 57.1). However, before the advent of CT and before the conception of the high-resolution CT technique, pulmonologists and radiologists were necessarily reliant on chest radiography, followed in many cases by the then gold standard, but now obsolete, investigation of bronchography, in patients with suspected bronchiectasis (Fig. 57.2). In the frequently quoted study by Gudbjerg,37 the conclusion was that a mere 10% of patients with bronchiectasis would have a normal chest radiograph. However, although this would have been true at the time, the study was published more than 50 years ago, and as discussed before, the clinical manifestations of bronchiectasis have changed. Moreover, many of the radiographic signs described by Gudbjerg (e.g., linear markings, bronchial wall thickening, and patchy or confluent shadows) are nonspecific. This was clearly illustrated by the later study from the Brompton Hospital that compared chest radiographic diagnoses of bronchiectasis with bronchography and confirmed the highly insensitive nature of chest radiography, also showing considerable disagreement between two experienced pulmonary radiologists simply for confirming the presence or absence of individual features of bronchiectasis.38 When identified, bronchial dilatation is the key radiographic feature of bronchiectasis. Thus the observer may see poorly defined ring shadows (reflecting the dilated bronchus with peribronchial inflammation when it is seen end-on) or “tram-line” opacities (denoting the nontapering airway), depending on the

57  Bronchiectasis and Other Bronchial Abnormalities

715

A

Fig. 57.2  Bronchiectasis on bronchography. Bronchogram shows normal diameter and tapering of the left upper lobe and lingular bronchi and cylindrical and varicose left lower lobe bronchiectasis. (Courtesy Dr. Reynaldo T. Rodrigues, Federal University of São Paulo, São Paulo, Brazil.)

B Fig. 57.1  Bronchiectasis evident only on CT. (A) Chest radiograph shows no abnormality. (B) High-resolution CT image shows dilatation of subsegmental bronchi (in relation to adjacent pulmonary artery) characteristic of bronchiectasis.

orientation of the individual airway with respect to the x-ray beam (Fig. 57.3). With more severe disease, obvious thinwalled cysts, with or without air-fluid levels, may be apparent (Fig. 57.4). The other recognized features of bronchiectasis on chest radiographs include tubular and branching opacities caused by plugging of dilated airways with mucus, volume loss or hyperexpansion, and foci of subsegmental atelectasis. These are ancillary radiographic signs and must not be regarded as diagnostic of bronchiectasis. COMPUTED TOMOGRAPHY In the era before the development of the thin-section CT technique, data on the value of CT in diagnosis of bronchiectasis

were disappointing, with sensitivities in the range of 66% to 79%.39–41 However, with the realization that spatial resolution could be improved significantly by reducing slice collimation, the reported sensitivities for the CT diagnosis of bronchiectasis improved, with sensitivities approaching 100% using thin-section (1–1.5 mm) imaging.42,43 A factor to be considered in review of the airways on thinsection CT is the window setting because, in the context of a diagnosis of bronchiectasis, this may have a significant influence on the assessment of luminal diameter.44–46 In their experimental study, Webb and colleagues46 showed that for airways surrounded by air, a window centered at −450 Hounsfield units (HUs) provided the most accurate measurement of wall thickness. Indeed, at this window mean, the window width had an imperceptible effect on the evaluation of wall thickness. When the window center was set lower than −450 HUs, wall thickness was overestimated, and the converse was true when the setting was higher.46 Computed Tomographic Features of Bronchiectasis CT signs of bronchiectasis were first described by Naidich and colleagues47 in 1982, albeit on non–high-resolution CT (10-mm collimation) images. The features identified by these investigators have, with some modifications, largely been validated in subsequent series. Although bronchial dilatation is the key morphologic abnormality, bronchial wall thickening, patchy areas of decreased parenchymal attenuation and vascularity (termed mosaic attenuation), plugging of large and small airways, volume loss, crowding of airways, and, in some patients with idiopathic disease, thickening of interlobular septa can be seen in association with bronchiectasis.39,41–43,48,49

716

SECTION 11  Diseases of the Airways

A

B Fig. 57.3  Radiographic signs of bronchiectasis in cystic fibrosis. Magnified views of frontal (A) and lateral (B) chest radiographs demonstrate multiple ring shadows (arrowheads) and tram-line opacities (straight arrows) consistent with bronchiectasis.

Fig. 57.4  Cystic bronchiectasis on chest radiography. Chest radiograph shows multiple thin-walled cystic opacities in the right lung. Although it is less conspicuous, there is evidence of disease in the left lower lobe.

Bronchial Dilatation.  Bronchiectasis is abnormal permanent dilatation of the airways, with or without associated thickening of the walls of the airways. In the normal state the internal diameter of the airway is roughly equal to the transverse diameter of the accompanying pulmonary artery; a bronchoarterial ratio greater than 1 should generally be regarded as abnormal.50 The CT appearance of bronchiectatic airways depends on the orientation of abnormal bronchi relative to the plane of section. Thus, for airways that are perpendicular to the imaging plane, the radiologist will look for a dilated airway next to a dot representing the normal adjacent pulmonary arterial branch, an appearance that has been likened to a signet ring (Fig. 57.5). In contrast, for bronchi that lie in the plane of section, as in the middle lobe and lingula, the radiologist should look for an absence of normal tapering (Fig. 57.6). The identification of airway dilatation in patients with severe (varicose or cystic) bronchiectasis does not usually pose a challenge.51 However, the majority of patients with bronchiectasis now present with mild disease, and the recognition of less severe (cylindrical) bronchial dilatation is certainly problematic. A spurious increase in the bronchoarterial ratio may be seen because the accompanying pulmonary artery can divide before the airway.52 In this way, the bronchial diameter will appear to be increased compared with the homologous arterial branch. Another consideration is that a bronchoarterial ratio greater than 1 is not always abnormal because it may be seen in up to one-fifth of healthy subjects.48 Furthermore, it has been shown that there is

57  Bronchiectasis and Other Bronchial Abnormalities

Fig. 57.5  Bronchiectasis: “signet ring” on CT. High-resolution CT shows several bronchi with a luminal diameter greater than the adjacent pulmonary artery. This appearance of a dilated airway and the normal-size adjacent pulmonary artery in patients with bronchiectasis has been likened to a signet ring (arrows).

717

Fig. 57.7  Varicose bronchiectasis in cystic fibrosis. High-resolution CT image shows varicose bronchiectasis in both upper lobes. Note striking mosaic attenuation from small airways disease.

of the patients with bronchiectasis but in none of the normal subjects.

Fig. 57.6  Bronchiectasis: lack of normal bronchial tapering. Highresolution CT image shows bilateral upper lobe bronchiectasis (arrows) as denoted by the lack of tapering of the bronchi after they bifurcate.

a normal but progressive increase in the internal diameter of the airways with age, with a bronchoarterial ratio exceeding 1 in just more than 40% of asymptomatic subjects older than 65 years.53 Finally, altitude may have a bearing on the relationship between airways and their adjacent pulmonary arteries; 50% of healthy subjects had evidence of bronchial dilatation by conventional CT criteria in one study performed in Colorado.54 Another study confirmed higher bronchoarterial ratios at high altitude compared with sea level.50 Although the exact mechanisms are not clear, it is conceivable that the increase in bronchoarterial ratio at altitude might be due to vasoconstriction associated with hypoxia,55 coupled possibly with the phenomenon of hypoxic bronchodilatation.56 Kim and colleagues48 looked for features on CT that would differentiate normal subjects from patients with surgically proven bronchiectasis. This study showed that, in contrast to an increased bronchoarterial ratio and lack of tapering, the visualization of airways within 1 cm of the costal or paravertebral pleura and the identification of airways abutting the mediastinal pleura were more discriminatory, being seen in 81% and 53%, respectively,

Ancillary Computed Tomographic Features of Bronchiectasis Although dilatation of bronchi is the cardinal morphologic manifestation of bronchiectasis, there are a number of ancillary signs on CT. A diagnosis of bronchiectasis cannot be made on the basis of these ancillary CT features in the absence of bronchial dilatation. These additional signs of bronchiectasis are discussed briefly. Bronchial Wall Thickening.  Thickening of the bronchial wall commonly accompanies bronchiectasis on CT47 and is likely to reflect an inflammatory component. As has already been mentioned, appreciation of wall thickening is subject to technical factors; window settings that are too narrow can lead to an overestimation of bronchial wall thickness. Interpretation of bronchial wall thickening is also hampered by the lack of consensus on what constitutes normal wall thickness at CT. In an attempt to address this, Remy-Jardin57 considered bronchi to be thick walled if the wall of any individual airway was at least twice as thick as that of a normal airway. However, the obvious drawback is the assumption that a normal comparable bronchus will be visible; naturally, this cannot be guaranteed when bronchiectasis is severe and widespread. An alternative definition of wall thickening is internal diameter of the airway lumen less than 80% of its external diameter.58 This definition is useful but only when bronchial dilatation is relatively mild; plainly, if the dilatation is marked (as in cystic bronchiectasis), wall thickening will be underestimated. Mosaic Attenuation.  Patchy areas of decreased attenuation, within which there is a reduction in the number or caliber of pulmonary vessels, are not only common but also a functionally important finding on CT in patients with bronchiectasis (Fig. 57.7).34–36 The extent of areas of decreased attenuation on expiratory CT does not correlate with indices of gas transfer such as diffusing lung capacity for carbon monoxide, suggesting that areas of mosaic attenuation are due to associated constrictive bronchiolitis.34,35

718

SECTION 11  Diseases of the Airways

Regions of air-trapping on expiratory CT tend to be most prevalent in lobes with either extensive or cystic bronchiectasis or in association with large mucous plugs and plugging within the centrilobular bronchioles.34 However, an additional intriguing finding is the presence of areas of decreased attenuation in some lobes without overt bronchiectasis (Fig. 57.8).34 On this basis, it has been hypothesized that constrictive bronchiolitis may be the key initial pathologic lesion in bronchiectasis.34 Airway Plugging.  Inflammatory mucous secretions may fill the ectatic bronchi, resulting in tubular and nodular opacities representing bronchi seen along their long axis and short axis, respectively. Care must be taken not to miss bronchiectasis in these cases (Fig. 57.9). Mucous secretions within the distal airways and inflammatory thickening of the bronchiolar walls may produce a tree-in-bud pattern, which manifests as Y- or V-shaped

opacities or a linear branching structure (Fig. 57.10), depending on the orientation of the airway relative to the imaging plane.59 Volume Loss. Crowding of the airways and volume loss (including, in some patients, complete collapse of a lobe) are recognized features of bronchiectasis that are readily appreciated at CT (Fig. 57.11). It is reasonable to hypothesize that these features of bronchiectasis are a consequence of inflammation and fibrosis around the airways. However, this is not to be confused with the entity of traction bronchiectasis; as the term suggests, this refers to tractional dilatation of airways from adjacent fibrotic interstitial lung diseases (see later).60 MAGNETIC RESONANCE IMAGING Magnetic resonance imaging (MRI) has a limited role in the diagnosis of bronchiectasis (Fig. 57.12), and the clinical utility of such tests for routine clinical management of patients with bronchiectasis remains debatable. IMAGING ALGORITHMS Despite its constraints, chest radiography is often the first imaging modality obtained for the evaluation of patients with bronchiectasis. However, given the limited sensitivity and the likelihood that the majority of patients now present with less severe disease, many will require thin-section CT imaging.52

Differential Diagnosis

Fig. 57.8  Bronchiectasis and small airways disease. High-resolution CT image shows cystic bronchiectasis in the left lower lobe. No bronchiectasis is seen in the right lower lobe, but there is mosaic attenuation consistent with constrictive bronchiolitis.

A

The challenge for radiologists in making a diagnosis of bronchiectasis is twofold: first, in ensuring that the diagnosis is not being overcalled, because of one of the potential mimics, and second, in trying to determine a possible cause of bronchiectasis. The distinction between true bronchiectasis and lung diseases characterized by cysts, such as pulmonary Langerhans cell histiocytosis and lymphangioleiomyomatosis, may be rendered difficult,

B Fig. 57.9  Mucus-filled bronchi. (A) High-resolution CT image shows tubular and nodular (arrows) opacities in the right middle lobe and lingula. (B) High-resolution CT performed after expectoration of the mucus shows that the opacities represented ectatic bronchi filled with secretions. In this case, bronchiectasis was a result of previous tuberculosis. (From Müller NL, Fraser RS, Colman NC, Paré PD. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

57  Bronchiectasis and Other Bronchial Abnormalities

Fig. 57.10  Mucoid impaction in bronchiectasis. High-resolution CT image shows numerous V- and Y-shaped branching opacities and a tree-in-bud pattern in the left lower lobe.

719

Fig. 57.12  Mucus-filled bronchi on MRI. T1-weighted MRI shows branching opacity in the right middle lobe consistent with mucoid impaction. Note mucus filling the bronchus intermedius.

particularly if they are severe. In practice, the experienced radiologist will take care to check adjacent sections; plainly, dilated airways will demonstrate continuity, whereas in diseases characterized by intrapulmonary cysts, such continuity will not be seen. Finally, mention must be made again of the term traction bronchiectasis, which is occasionally a source of confusion to physicians on radiologic reports (Fig. 57.13).60 It seems likely that such dilatation of airways, a relatively common finding in patients with interstitial fibrosis, is due to the radial traction on the airways by thickened alveolar attachments in areas of fibrosis.21,61,62 The important clinical point for the pulmonologist, of course, is that patients with this finding do not present with the clinical picture of patients with true bronchiectasis. The craniocaudal and axial distribution of abnormalities may help narrow the differential diagnosis of a particular case of bronchiectasis. Bronchiectasis in cystic fibrosis is more common in the upper zones.63–65 Similarly, allergic bronchopulmonary aspergillosis is generally regarded as a central and upper zonal disease,66 whereas bronchiectasis that is related to aspiration, immunodeficiency, α1-antitrypsin deficiency, or iatrogenic causes appears to have a predilection for the lower zones. Finally, it might reasonably be expected that bronchiectasis occurring after pneumonia would be relatively localized, occurring in the area affected by the pneumonia. However, consideration of both imaging findings and clinical scenario may lead to a more accurate diagnosis than imaging alone.67,68

Fig. 57.11  Right middle lobe atelectasis in a patient with right middle lobe bronchiectasis caused by chronic nontuberculous mycobacterial infection. Sagittal CT image shows varicose bronchiectasis and volume loss of the right middle lobe. The minor fissure is displaced inferiorly and posteriorly (long arrow), and the right major fissure is displaced anteriorly and superiorly (short arrow).

Specific Causes of Bronchiectasis Cystic Fibrosis ETIOLOGY, PREVALENCE, AND EPIDEMIOLOGY Cystic fibrosis (CF) is an autosomal-recessive hereditary disease. It is the most common lethal genetically transmitted disease in white individuals; the estimated incidence is about 1 per 2000

720

SECTION 11  Diseases of the Airways

Lung Function Pulmonary function tests show progressive airway obstruction and air-trapping, with decreased forced expiratory volume at 1 second, increased vital capacity, and increased residual volume.75 MANIFESTATIONS OF THE DISEASE

Fig. 57.13  Traction bronchiectasis and bronchiolectasis in idiopathic pulmonary fibrosis. High-resolution CT image shows peripheral predominant reticulation, architectural distortion, and honeycombing. Note associated dilatation and beading of bronchi and bronchioles (traction bronchiectasis and traction bronchiolectasis) (arrows).

to 3500 live births.69,70 CF is uncommon in nonwhites. There is no sex preponderance. The diagnosis is made before age 5 years in about 80% of cases, during adolescence in 10%,71 and during adulthood in 10% of cases.72 The fundamental abnormality consists of the production of abnormal secretions from exocrine glands, such as the salivary and sweat glands, and the pancreas, large bowel, and tracheobronchial tree. The major clinical manifestations are obstructive pulmonary disease, which is found in varying degrees of severity in almost all patients, and pancreatic insufficiency, present in 80% to 90%.69,70 CF is the most common cause of pulmonary insufficiency in the first 3 decades of life.73 CLINICAL PRESENTATION The pulmonary manifestations of CF include recurrent respiratory infections associated with productive cough, wheezing, and dyspnea. The infection is predominantly caused by bacteria, such as Pseudomonas aeruginosa, Staphylococcus aureus, and Haemophilus influenzae, although viruses, mycoplasma, and fungi are occasionally responsible. The presence of Burkholderia cepacia is usually associated with advanced disease.72 Common complications include hemoptysis and pneumothorax. Most patients eventually progress to respiratory insufficiency accompanied by pulmonary arterial hypertension and cor pulmonale. PATHOPHYSIOLOGY Pathology The earliest pathologic lesion of CF is obstruction of bronchioles and small bronchi by abnormal mucus, which is followed by airway inflammation and infection.74 Pulmonary disease in patients with CF typically progresses from bronchiolitis and bronchitis to bronchiectasis owing to chronic infection and airway obstruction by the inspissated mucus.70 Focal emphysema and bullae also can be seen. Histologic examination typically reveals chronic inflammation and fibrosis of the bronchial wall, partial or complete luminal occlusion by purulent material, focal epithelial ulceration, and cartilage destruction.75

Radiography The earliest manifestations of CF consist of round or poorly defined linear opacities measuring 3 to 5 mm in diameter that are located within 2 to 3 cm of the pleura.76 Less common early manifestations include thickened bronchial walls without bronchial dilation, usually seen as ring shadows, and mild hyperinflation.76 Progression of disease is characterized by increases in bronchial diameter, bronchial wall thickness, lung volume, and number and size of peripheral nodular opacities and by the development of mucoid impaction and focal areas of consolidation (Figs. 57.14 and 57.15).76 Bronchiectasis, bronchial wall thickening, and mucous plugging are particularly frequent and are evident in almost all adult patients.77 The chest radiographic abnormalities have been incorporated into numerous semiquantitative scoring schemes that are believed to be of value in predicting prognosis and directing therapy.78,79 Recurrent foci of consolidation occur in most patients, and lobar or segmental atelectasis occurs in many. Hilar enlargement may be due to lymph node enlargement or dilation of the central pulmonary arteries secondary to pulmonary arterial hypertension (see Fig. 57.15).79 Pneumothorax occurs in 3% to 19% of patients.70,80 Computed Tomography The main manifestation of CF is bronchiectasis, which is present in virtually all adult patients (Fig. 57.16; see Fig. 57.14).81–83 Bronchiectasis usually involves all lobes but tends to be most severe in the upper lobes.82,84 The bronchiectasis may be cylindrical, varicose, or cystic.81 Other common findings are bronchial wall thickening, peribronchial interstitial thickening, and mucous plugging.81,83 Consolidation or atelectasis can be seen in 80% of cases.81 Cystic or bullous lung lesions also can be seen and typically predominate in the subpleural regions of the upper lobes (see Fig. 57.16).81 Branching or nodular centrilobular opacities (tree-in-bud pattern) are frequently present and may be an early sign of disease.85 They reflect the presence of bronchiolar dilation with associated mucous impaction, infection, or peribronchiolar inflammation. Focal areas of decreased attenuation and vascularity on inspiratory CT and air-trapping on expiratory CT are common. Hilar or mediastinal lymph node enlargement and pleural abnormalities may be present, largely reflecting chronic infection. Pulmonary artery dilation resulting from pulmonary hypertension is common in patients who have long-standing disease. Magnetic Resonance Imaging MRI may be used as an alternative tool to assess parenchymal and functional abnormalities and to monitor treatment in patients with CF. Although MRI has lower spatial resolution than CT and plays a limited role in the assessment of airway disease, it has the advantage of no radiation exposure, an important consideration in these young patients. MRI may be useful in the follow-up of patients with CF (Fig. 57.17) and could be used to screen for early liver disease, given the increased life expectancy of CF patients in recent years.

57  Bronchiectasis and Other Bronchial Abnormalities

A

B

C

D

721

Fig. 57.14  Cystic fibrosis, radiographic and high-resolution CT findings. Posteroanterior (A) and lateral (B) chest radiographs show poorly defined nodular and linear opacities mainly in the upper lobes. Mild hyperinflation with increase in the retrosternal airspace is noted. High-resolution CT scans at the level of the lung apices (C) and tracheal carina (D) show extensive bilateral bronchiectasis and areas of decreased attenuation and vascularity (mosaic attenuation).

Imaging Algorithms The chest radiograph is the main imaging modality used in the initial evaluation and follow-up of patients with CF. High-resolution CT can show abnormalities in patients who have early CF and normal chest radiographs. In one study of 38 patients who had mild CF with normal pulmonary function, chest radiographs were normal in 17 (45%), showed mild bronchial wall thickening in 17, and showed mild bronchiectasis in 4 (10%).86 On highresolution CT in this group, bronchiectasis was present in 77%

of all patients and in 65% of patients with normal chest radiographs; only 3 patients had a normal high-resolution CT scan.86 When performing repeated high-resolution CT scans in young patients, the risk of radiation has to be considered and the radiation dose minimized. Axial high-resolution chest CT with interspace gaps can be performed at a much lower dose than volumetric scans. When volumetric CT is required, it is recommended that this be performed with low milliamperage (40 mA) and low kilovoltage.

722

SECTION 11  Diseases of the Airways

DIFFERENTIAL DIAGNOSIS The radiologic findings of CF may mimic those of other causes of bronchiectasis, such as allergic bronchopulmonary aspergillosis and postinfectious bronchiectasis. The most characteristic features of bronchiectasis in CF are bilateral symmetric distribution and upper lobe predominance. In one study, bronchiectasis in CF involved mainly the upper lobes in 79% of patients and was

usually bilateral and fairly symmetric, whereas the bronchiectasis in the other conditions, such as prior tuberculosis, was most frequently unilateral or asymmetric.84 Although the diagnosis of CF may be suggested by a positive family history, persistent respiratory disease, clinical evidence of pancreatic insufficiency, or fatty (or less common cystic) replacement of the pancreas on imaging, confirmation requires a positive sweat test or identification of two abnormal copies of the CF gene. Incorporation of molecular biologic techniques into rapid, cost-efficient, and specific diagnostic tests for most CF genotypes is now possible by using the multiplex polymerase chain reaction.87 SYNOPSIS OF TREATMENT OPTIONS Therapy typically includes antibiotics, physiotherapy, and replacement of pancreatic enzymes. Once a disease with a life expectancy confined to the adolescent years, now most patients reach adulthood. The median survival of CF patients has increased significantly over the past few decades to almost 41 years in the United States and approximately 51 years in Canada.88 KEY POINTS: CYSTIC FIBROSIS • The estimated incidence is 1 per 2000–3500 live births in whites; it is uncommon in nonwhites. • The main clinical manifestations are obstructive pulmonary disease and pancreatic insufficiency. • Radiographic findings include bronchial wall thickening, bronchiectasis, hyperinflation, and areas of consolidation or atelectasis. • The main CT manifestation is upper lobe–predominant bronchiectasis. • Other common findings are bronchial wall thickening, peribronchial interstitial thickening, mucous plugging, branching or nodular centrilobular opacities (tree-in-bud pattern), focal areas of decreased attenuation and vascularity on inspiratory CT, and expiratory air-trapping. • Judicious use of CT scans and certain CT dose-reduction techniques is important in minimizing radiation exposure in CF patients.

Fig. 57.15  Cystic fibrosis, radiographic findings. Posteroanterior chest radiograph shows marked bronchial wall thickening (straight arrows) and extensive varicose (arrowheads) and cystic (curved arrows) bronchiectasis. Note hyperinflation and enlarged central pulmonary arteries consistent with pulmonary arterial hypertension.

A

B Fig. 57.16  Cystic fibrosis, high-resolution CT findings. (A) High-resolution CT scan at the level of the lung apices shows extensive bronchiectasis and bullous changes. (B) High-resolution CT scan at the level of the inferior pulmonary veins shows bilateral varicose and cystic bronchiectasis and areas of decreased attenuation and vascularity.

57  Bronchiectasis and Other Bronchial Abnormalities

A

723

B Fig. 57.17  Cystic fibrosis. Comparison between high-resolution CT and MRI findings in a child. (A) High-resolution CT scan shows right upper lobe cystic and varicose bronchiectasis. Cylindrical and varicose bronchiectasis is evident in the left upper lobe. Note mosaic lung attenuation. (B) T1-weighted MR image obtained at a similar level as in (A) shows bronchiectasis in the right upper lobe. Milder areas of bronchiectasis in the left upper lobe and findings of small airway disease are not apparent on the MR image. (Courtesy Dr. Pedro Daltro, Clínica de Diagnóstico Por Imagem, Rio de Janeiro, Brazil.)

Primary Ciliary Dyskinesia (Dyskinetic Cilia Syndrome) ETIOLOGY, PREVALENCE, AND EPIDEMIOLOGY The term primary ciliary dyskinesia refers to a group of autosomalrecessive disorders associated with defective ciliary structure and function, also known as dyskinetic cilia syndrome.89 The structurally abnormal cilia move ineffectively and predispose to sinusitis, recurrent pulmonary infections, and bronchiectasis. Situs inversus totalis or, less commonly, heterotaxy syndrome is seen in about 50% and 12% of patients, respectively.90–92 Men have reduced fertility as a result of decreased motility of the spermatozoa.90,91 Although primary ciliary dyskinesia has an autosomal-recessive pattern of inheritance, the variety of ultrastructural defects associated with the clinical syndrome suggests considerable genetic heterogeneity.93,94 The incidence of the syndrome in white individuals is estimated to be 1 in 12,500 to 40,000; a higher prevalence has been reported in Japan.95,96 CLINICAL PRESENTATION The age of presentation ranges from 4 months to 51 years.97,98 The clinical manifestations include infertility, chronic rhinitis, sinusitis, otitis, and recurrent lower respiratory tract infections. The most common bacterial organism found in sputum is H. influenzae, but Pseudomonas isolates also are common.89 Half of patients have Kartagener syndrome, defined by the triad of situs inversus totalis, bronchiectasis, and either nasal polyps or recurrent sinusitis.89 Morbidity in primary ciliary dyskinesia is predominantly related to chronic suppurative airway disease secondary to chronic infection. PATHOPHYSIOLOGY Pathology Ultrastructural abnormalities in primary ciliary dyskinesia seen on electron microscopy include a lack of outer dynein arms,

absent or short radial spokes, absent or defective inner dynein arms, absent or disoriented central microtubules, and transposition of peripheral microtubules.99,100 A combination of structural defects is often present.101 Lung Function Many patients develop mild to moderate airflow obstruction.102 MANIFESTATIONS OF THE DISEASE Radiography Radiographically, abnormalities progress from bronchial wall thickening to bronchiectasis, hyperinflation, segmental atelectasis, and consolidation.103 In one study of 30 patients ranging from newborn to 26 years old, radiographic abnormalities were evident in all patients.103 Findings usually have a lower zone distribution, but radiologic features may resemble the features of bronchiectasis from a variety of other causes; when present, the combination of lower zone–predominant bronchiectasis and situs inversus is nearly pathognomonic for the diagnosis (Fig. 57.18). Computed Tomography High-resolution CT typically shows extensive central or diffuse bilateral bronchiectasis in adults (Fig. 57.19).92 Associated endobronchial mucous plugging, tree-in-bud opacities, and centrilobular nodules are common. Although bronchiectasis can be widespread, in approximately 50% of patients, it involves predominantly or exclusively the lower lobes.104 In pediatric patients, high-resolution CT shows bronchiectasis in 56% of patients.92 Pectus excavatum is seen in 9% of patients.92 DIFFERENTIAL DIAGNOSIS The diagnosis of primary ciliary dyskinesia usually is made by assessing ciliary motility in bronchial wall or nasal biopsy specimens or in semen samples or by electron microscopy that shows abnormal ciliary morphology.89,90

724

SECTION 11  Diseases of the Airways

A

Fig. 57.19  Kartagener syndrome. CT image shows bronchial wall thickening and scattered tree-in-bud opacities bilaterally. Note right lingular cylindrical bronchiectasis.

Allergic Bronchopulmonary Aspergillosis ETIOLOGY, PREVALENCE, AND EPIDEMIOLOGY Allergic bronchopulmonary aspergillosis (ABPA) is a condition characterized by chronic airway inflammation and airway damage resulting from persistent colonization and sensitization by Aspergillus fumigatus and related species.105 ABPA is seen almost exclusively in patients with asthma or CF. The estimated prevalence ranges from 2% to 25% in patients with CF and from 1% to 8% in patients with asthma.106 The pathogenesis of ABPA is unclear, but it is believed that genetic factors and T-cell reactivity to Aspergillus play important roles.105,106

B Fig. 57.18  Kartagener syndrome. (A) Posteroanterior chest radiograph shows situs inversus totalis, bronchial wall thickening, and bronchiectasis in the left middle lobe (arrow). (B) CT image through the lower lungs in the same patient shows bronchial wall thickening and cystic and varicoid bronchiectasis, particularly within the left middle lobe.

SYNOPSIS OF TREATMENT OPTIONS Treatment consists mainly of antibiotics and physiotherapy.97 Patients usually have a normal life expectancy.97 KEY POINTS: PRIMARY CILIARY DYSKINESIA • Primary ciliary dyskinesia refers to a group of autosomalrecessive disorders associated with defective ciliary structure and function. • The clinical manifestations include chronic rhinitis, sinusitis, otitis, recurrent lower respiratory tract infections, and infertility. • Approximately 50% of patients have situs inversus totalis, and 12% have heterotaxy syndrome. • Radiographic and CT findings include bronchiectasis, bronchial wall thickening, hyperinflation, tree-in-bud opacities, segmental atelectasis, and consolidation.

CLINICAL PRESENTATION ABPA is frequently first suspected clinically by the presence of peripheral blood eosinophilia and pulmonary opacities in patients who have asthma or CF.106 The patients may be asymptomatic or present with worsening of asthma, increased cough and wheezing, and expectoration of brown mucous plugs.106 Physical examination in ABPA is often normal, except for underlying manifestations of asthma or CF. PATHOPHYSIOLOGY Pathology At histology, segmental and proximal subsegmental bronchi are dilated and distended with mucus that contains numerous eosinophils; cell debris consisting of degenerate eosinophils with associated Charcot-Leyden crystals; and scattered, typically fragmented fungal hyphae.107,108 MANIFESTATIONS OF THE DISEASE Radiography The typical radiographic pattern consists of homogeneous branching opacities, usually involving the upper lobes and almost always in the central segmental bronchi, rather than peripheral

57  Bronchiectasis and Other Bronchial Abnormalities

725

B A

Fig. 57.20  Allergic bronchopulmonary aspergillosis. (A) Posteroanterior chest radiograph shows multiple upper lobe branching opacities with a “finger-in-glove” appearance (arrows). (B) CT image shows central, upper lobe–predominant bronchiectasis, bronchial wall thickening, and tree-in-bud opacities. A tubular opacity (arrow) representing mucoid bronchial impaction is present within the left upper lobe. (C) CT image on soft tissue windows shows high-attenuation mucus filling dilated bronchi (arrows).

branches.109 These bifurcating opacities have been described as having a gloved-finger, an inverted Y or V, or a cluster-of-grapes appearance (Fig. 57.20). The opacities tend to be transient, but they may persist unchanged for weeks or months or may enlarge. Computed Tomography The characteristic CT manifestations of ABPA consist of bronchiectasis and mucoid impaction involving mainly the segmental and subsegmental bronchi of the upper lobes (Fig. 57.21; see also Fig. 57.20).110–112 Other common findings include centrilobular nodules and a tree-in-bud pattern; the latter reflects the presence of dilated bronchioles filled with mucus (see Fig. 57.20).108 In approximately 30% of patients, the mucous plugs have high attenuation, presumably because of the presence of calcium salts (see Fig. 73.20), which is highly specific for the diagnosis.113 Although bronchiectasis and mucoid impaction tend to be bilateral and involve mainly the central regions of the upper lobes, they may be unilateral, be patchy, or involve mainly the lower lobes.104 Because ABPA occurs almost exclusively in asthmatics, the presence of central bronchiectasis and mucoid impaction in these patients is highly suggestive of the diagnosis. Patients with asthma

C

have an increased prevalence of bronchiectasis, however, and may have filling of the ectatic bronchi with secretions without having ABPA. In one study the authors retrospectively assessed the accuracy of CT in the diagnosis of ABPA in asthmatic patients; bronchiectasis, centrilobular nodules, and mucoid impaction were all more common in ABPA than in patients with asthma alone.112 As noted by others, patients who had ABPA consistently had more severe and extensive disease compared with asthmatics, especially when present in three or more lobes.112 DIFFERENTIAL DIAGNOSIS Diagnostic criteria include the presence of underlying asthma or CF, peripheral blood eosinophilia, immediate cutaneous reactivity to A. fumigatus antigen, precipitation antibodies against A. fumigatus antigen, elevated total serum immunoglobulin E levels, and radiographic or CT findings of central bronchiectasis or mucous impaction.106 Confidence in diagnosis depends on the numbers and types of abnormalities that are identified and the presence of characteristic histologic findings on specimens obtained by bronchoscopy and positive sputum culture for Aspergillus species.114

726

SECTION 11  Diseases of the Airways

A

B Fig. 57.21  Allergic bronchopulmonary aspergillosis in an asthmatic. (A) High-resolution CT scan through the upper lobes shows severe bilateral bronchiectasis and marked bronchial wall thickening. Mucoid impaction (arrows) is noted. (B) High-resolution CT scan at the level of the lower lobe bronchi shows central bronchiectasis, areas of decreased attenuation and vascularity, and mucoid impaction (arrows). (From Silva CI, Colby TV, Müller NL. Asthma and associated conditions: high-resolution CT and pathologic findings. AJR Am J Roentgenol. 2004;183:817–824.)

SYNOPSIS OF TREATMENT OPTIONS Treatment includes optimal therapy of the underlying asthma or CF and oral corticosteroids.106 Antifungal agents, such as itraconazole, may be helpful in some patients but are not curative.106

condition has been reported as a complication of diffuse pulmonary fibrosis,117 in association with ankylosing spondylitis,118 and, occasionally, in rheumatoid arthritis.119 Most patients are in their third or fourth decade of life at diagnosis (age range, 18 months to 76 years).120 CLINICAL PRESENTATION

KEY POINTS: ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS • Allergic bronchopulmonary aspergillosis is frequently first suspected clinically by the presence of peripheral blood eosinophilia and pulmonary opacities in patients who have asthma or cystic fibrosis. • The typical radiographic pattern consists of homogeneous branching gloved-finger opacities. • The characteristic CT manifestations consist of bronchiectasis and mucoid impaction involving mainly the segmental and subsegmental bronchi of the upper lobes. • In about 30% of patients, the mucoid impaction has high attenuation on CT.

Tracheobronchomegaly (Mounier-Kuhn Syndrome) ETIOLOGY, PREVALENCE, AND EPIDEMIOLOGY Tracheobronchomegaly (Mounier-Kuhn syndrome) is a rare condition characterized by dilation of the tracheobronchial tree that tends to involve the trachea and main bronchi115 but that may extend from the larynx to the periphery of the lungs (see Chapter 56).116 Tracheobronchomegaly is more common in men, and most cases are congenital.115 It has been described in association with other congenital abnormalities of the trachea, EhlersDanlos syndrome, and cutis laxa.115 An acquired form of the

The increased compliance of the trachea in tracheobronchomegaly results in abnormal flaccidity and easy collapsibility during forced expiration and coughing. The inefficient cough mechanism leads to retention of mucus with resultant recurrent pneumonia and bronchiectasis.121 PATHOPHYSIOLOGY Pathology The pathologic features consist of marked dilation of the trachea and main bronchi owing to absence of the longitudinal elastic fibers and thinning of the muscular layer of the airway walls.115,122 Most patients have mucosal herniation between the tracheal rings resulting in tracheal diverticulosis.122 Other common findings are bronchiectasis and emphysema. Dynamic imaging of the airways shows marked ballooning of the trachea and main bronchi on inspiration and collapse on expiration.115 This renders the cough mechanism ineffective and, together with the retention of secretions, predisposes to recurrent infection. MANIFESTATIONS OF THE DISEASE Radiography The calibers of the trachea and major bronchi are increased, and the air columns have an irregular corrugated appearance caused by the protrusion of mucosal and submucosal tissue between the cartilaginous rings, an appearance that has been termed

57  Bronchiectasis and Other Bronchial Abnormalities

A

B

C

D

727

Fig. 57.22  Tracheobronchomegaly (Mounier-Kuhn syndrome): radiographic and CT findings. Posteroanterior (A) and lateral (B) chest radiographs show a marked increase in the caliber of the trachea (arrows) and main bronchi. High-resolution CT scans of another patient at the level of the trachea (C) and main bronchi (D) show tracheomegaly and increased caliber of main bronchi and intraparenchymal bronchi. The dilated intraparenchymal bronchi have thin walls, which is distinct from the bronchial wall thickening typically seen in patients who have bronchiectasis. Minimal bilateral bronchial diverticulosis is present (D, arrows).

tracheal diverticulosis (Fig. 57.22).115 This appearance often is visualized best in lateral projection. In women the upper limits of normal of transverse and sagittal diameters of the trachea are 21 mm and 23 mm, respectively, and 19.8 mm and 17.4 mm for the right and left mainstem bronchi, respectively.115 In men these measurements are 25 mm and 27 mm for the transverse and sagittal tracheal diameters, respectively, and 21.1 mm and 18.4 mm for the right and left mainstem bronchi, respectively; patients

with tracheobronchomegaly usually have tracheal and main bronchial diameters significantly exceeding these upper limits.115 Computed Tomography The tracheal and bronchial dilation is well seen on CT (see Fig. 57.22).116,123 CT also frequently reveals dilation of the intrapulmonary bronchi (see Fig. 57.22).116,124 As distinct from patients with other causes of bronchiectasis, the dilated bronchi

728

SECTION 11  Diseases of the Airways

A

B Fig. 57.23  Tracheomegaly: collapse on expiration. (A) Inspiratory CT scan shows an increased caliber of the trachea. Incidental note is made of mild emphysema. (B) Expiratory CT shows abnormal reduction in caliber with “frown” configuration typical of tracheomalacia.

of patients who have tracheobronchomegaly typically have thin walls.116 Dynamic CT and expiratory CT show ballooning of the airways on inspiration and collapse on expiration typical of tracheobronchomalacia (Fig. 57.23).

KEY POINTS: TRACHEOBRONCHOMEGALY (MOUNIER-KUHN SYNDROME) • Tracheobronchomegaly is a rare congenital abnormality characterized by marked dilation of the trachea and bronchi. The increased compliance of the trachea in tracheobronchomegaly results in abnormal flaccidity and easy collapsibility during forced expiration and coughing. The inefficient cough mechanism leads to retention of mucus with resultant recurrent pneumonia and bronchiectasis. • Typically there is an irregular corrugated appearance of the posterior tracheal wall caused by the protrusion of mucosal and submucosal tissue between the cartilaginous rings (tracheal diverticulosis), which is best visualized on the lateral radiograph or sagittal CT reformatted images.

Williams-Campbell Syndrome ETIOLOGY, PREVALENCE, AND EPIDEMIOLOGY Williams-Campbell syndrome is a rare congenital form of bronchiectasis caused by deficiency of cartilage in subsegmental bronchi.125 The condition shows familial clustering and may be associated with other congenital abnormalities.126 Affected individuals usually are identified in infancy because of repeated chest infections and evidence of bronchiectasis. Occasionally, Williams-Campbell syndrome is first recognized in an adult.127 CLINICAL PRESENTATION The clinical manifestations consist of repeated chest infections since early childhood. PATHOPHYSIOLOGY Pathology Pathologic examination of the lungs in an adult who underwent bilateral lung transplantation showed absence of cartilage in the walls of the medium to small airways, resulting in cystic bronchiectasis.125

MANIFESTATIONS OF THE DISEASE Radiography The radiographic findings include bronchial wall thickening and cystic spaces (Fig. 57.24). Computed Tomography The thin-section CT findings are characteristic and consist of varicose and cystic bronchiectasis limited to the fourth-generation, fifth-generation, and sixth-generation bronchi (i.e., distal to the first-generation segmental bronchi) (see Fig. 57.24).127–129 Expiratory CT shows collapse of the bronchi and distal air-trapping.127,130 Thin-section CT plays a major role in distinguishing WilliamsCampbell syndrome from other causes of cystic bronchiectasis.131 CT bronchoscopy shows absence of the cartilage ring impressions in the bronchial wall consistent with cartilage deficiency.130 KEY POINTS: WILLIAMS-CAMPBELL SYNDROME • Williams-Campbell syndrome is a rare congenital form of bronchiectasis caused by a deficiency of cartilage in the subsegmental bronchi. • Clinical manifestations consist of repeated chest infections since early childhood. • The high-resolution CT findings are characteristic and consist of cystic bronchiectasis limited to the fourth-generation, fifth-generation, and sixth-generation bronchi (i.e., distal to the first-generation segmental bronchi).

SYNOPSIS OF TREATMENT OPTIONS Medical The treatment of the specific cause of bronchiectasis, when it is identifiable (e.g., immunoglobulin replacement in patients with immunoglobulin deficiencies, recombinant human deoxyribonuclease in cystic fibrosis), may be important. Associated conditions, such as chronic rhinosinusitis, are treated. The mainstays of therapy, when a definite underlying cause cannot be established, include effective clearance of airway secretions (physiotherapy and mucolytics) and vigorous treatment of exacerbations caused by infection. Surgical Surgery for bronchiectasis is essentially restricted to patients with troublesome symptoms that are refractory to conventional medical therapy and then only to those with localized (single-lobe) disease.

57  Bronchiectasis and Other Bronchial Abnormalities

729

B

A

C

D Fig. 57.24  Williams-Campbell syndrome. (A) Chest radiograph shows multiple bilateral thin-walled cysts and pulmonary hyperinflation. (B) High-resolution CT scan shows extensive cystic bronchiectasis. Several ectatic bronchi contain fluid levels. Anterior segmental bronchus of right upper lobe is normal, and bronchiectasis starts at subsegmental bronchi (fourth-sixth order). Curved axial reformation (C) of left lung and coronal reformation (D) of right lung show typical distribution of bronchiectasis distal to the segmental bronchi.

Broncholithiasis Etiology Broncholithiasis is a disorder characterized by either the presence of calcified or ossified material within the lumen of bronchi or

the distortion of the tracheobronchial tree by calcified peribronchial nodes but without obvious erosion into the lumen. In most cases the finding of broncholiths is due to the extrusion of calcified material from adjacent lymph nodes and erosion into the airways; the calcification in lymph nodes is usually the consequence of chronic necrotizing granulomatous infection, including tuberculosis, histoplasmosis, and rarely actinomycosis.132–137 In

730

SECTION 11  Diseases of the Airways

KEY POINTS: BRONCHIECTASIS • The true prevalence of bronchiectasis is difficult to predict, but it is known to be higher in specific populations. • Plethora of causes: Postinfectious bronchiectasis remains a major etiologic factor in developing countries, whereas cystic fibrosis and hypogammaglobulinemia are important causes in Western nations. There is no identifiable cause of bronchiectasis in a significant proportion of patients. • Clinical features include productive cough, recurrent infection, breathlessness, and intermittent hemoptysis. • High-resolution CT is the optimal test for diagnosis as radiography is insensitive. The cardinal CT sign is bronchial dilatation. • Specific findings: bronchoarterial diameter ratio >1 (highly sensitive but limited specificity), lack of bronchial tapering, bronchus visualized within 1 cm of costal pleura or abutting the mediastinal pleura. • Important ancillary CT findings include bronchial wall thickening, mosaic attenuation, airway plugging, and volume loss.

occasional patients the luminal calcification is secondary to the calcification of a foreign body or the migration of calcific material from a more distant source (e.g., a calcified pleural plaque) through a fistulous communication. A rare association with silicosis has also been reported.138

Fig. 57.25  Broncholithiasis from prior tuberculosis. A coronal reformatted image in the soft tissue window demonstrates calcified nodules (arrows) in the bronchus intermedius compatible with broncholiths.

Prevalence and Epidemiology Despite the relatively widespread worldwide prevalence of granulomatous infections, broncholithiasis remains a rare entity. The peak incidence is in the sixth decade, although there is a broad overall age range. There is no gender predilection.

Clinical Presentation The common symptoms of broncholithiasis are hemoptysis, which in rare instances might be catastrophic, and cough, which is usually nonproductive.139,140 However, breathlessness, chest pain, and, because of obstructive effects, symptoms resulting from recurrent infections are also reported.139 Lithoptysis (literally, the expectoration of calcific material) is a characteristic symptom but infrequently reported by patients.139,141 Rarely, broncholithiasis masquerades as asthma with wheeze as the dominant feature.139,142

Pathology The basic pathogenetic mechanism is thought to be the extrusion and subsequent erosion of dystrophic calcific material from lymph nodes into adjacent structures. The calcification typically affects the tracheobronchial tree, but erosion into the lung parenchyma and mediastinum is known to occur143; this may be complicated by the formation of a mediastinal abscess or a fistulous communication.144,145

Manifestations of the Disease RADIOGRAPHY The radiographic findings in broncholithiasis may be divided into those resulting from the primary pathologic process itself— namely, the presence of calcified foci—and those that are a

consequence of erosion and obstruction. As regards the former, there is evidence of either central hilar, the more common scenario, or peripheral calcification.146,147 A useful clue to the diagnosis, when serial radiographs are available, is the movement of a previously noted focus of calcification in its relationship to an adjacent airway.148 Depending on the severity and duration of obstruction, there may be segmental atelectasis, lobar atelectasis, or recurrent consolidation from pneumonia146,149–152; in rare patients broncholithiasis may be responsible for the so-called middle lobe syndrome.153 COMPUTED TOMOGRAPHY Thin-section, multiplanar CT is the best noninvasive technique for the diagnosis of broncholithiasis (Fig. 57.25).146,154,155 In one study of patients with proven broncholithiasis, there was calcified endobronchial material in 10 of 15 subjects and peribronchial calcification with airway distortion in 5.146 Of interest, there was no evidence of an associated soft tissue density mass in any case, contrasting with findings of fibrosing mediastinitis, another condition that may be secondary to histoplasmosis or tuberculosis. CT was also able to demonstrate the effects of obstruction, such as bronchiectasis and atelectasis. IMAGING ALGORITHMS The chest radiograph and thin-section CT are the mainstays of the imaging diagnosis of broncholithiasis. A demonstration on serial radiographic examinations of the change in position of a previously noted calcified focus (e.g., at the hilum) is certainly a strong suggestion of the diagnosis. However, in most cases CT is required for confirmation, especially when therapy is being considered.

57  Bronchiectasis and Other Bronchial Abnormalities

Differential Diagnosis There are a number of diagnostic pitfalls and mimics of broncholithiasis of which the radiologist should be aware. These have been elegantly described and illustrated in a review by Seo and colleagues154 and include calcified balls of fungal hyphae; endobronchial tumors, such as carcinoid, that may rarely calcify156; tracheobronchial amyloidosis; tracheobronchopathia osteochondroplastica; and hypertrophy of the bronchial artery with protrusion into the lumen of the airway.

Synopsis of Treatment Options MEDICAL Regular observation with no intervention may be considered in some patients with “uncomplicated” disease. Bronchoscopic removal of partially eroded or free broncholiths may be considered in some patients but is used sparingly in many cases because of the risk of hemorrhage. Fragmentation of intraluminal broncholiths may be performed by bronchoscopically delivered laser (Nd-YAG or holmium) energy. SURGICAL Surgical resection (segmentectomy, lobectomy, and pneumonectomy) may be considered in some patients. Indications for surgery include the development of significant complications (massive hemoptysis, mediastinal abscess, fistulas) and the failure of previous bronchoscopic broncholith removal (bronchoscopic broncholithectomy).

731

now regarded as somewhat outdated; the reality is that emphysema and features of chronic bronchitis frequently coexist, and the “catch-all” term COPD is of value.160–162 The dominant cause of chronic bronchitis, by far, is cigarette smoke, and there is a clear, demonstrable relationship between a smoking history and the frequency of chronic bronchitis.163 However, factors other than smoking tobacco that have a putative role in the development of chronic bronchitis and COPD have been identified and include a history of childhood infection, socioeconomic status, occupation, air pollution, age, gender, and possibly climate.162,164–168

Prevalence and Epidemiology As might be expected in a condition whose definition is entirely based on clinical criteria, precise estimates of the prevalence of chronic bronchitis are not forthcoming; symptoms are, by their very nature, subjective and prone to variation over time.169 Nevertheless, given the worldwide prevalence of smoking in both industrialized and developing countries, it can safely be assumed that chronic bronchitis is very common, affecting 20% of adults in one study.170

Clinical Presentation By definition, patients with chronic bronchitis complain of cough productive of sputum, and symptoms are typically first reported after subjects have smoked for some years. Acute exacerbations are common and are usually from lower respiratory tract infections.

Pathophysiology PATHOLOGY

KEY POINTS: BRONCHOLITHIASIS • Broncholithiasis is a rare disorder with a peak incidence in the sixth decade of life that is most commonly related to previous granulomatous infection. • Broncholithiasis occurs when there is extrusion of and subsequent erosion into an airway of calcific material, typically from an adjacent lymph node. • The typical symptoms are cough and hemoptysis; lithoptysis is uncommon. • CT findings: endobronchial broncholiths and peribronchial calcification. • Treatment options include observation, bronchoscopic removal or laser therapy, and surgical resection of affected lobes.

Chronic Bronchitis Etiology Chronic bronchitis, one of the traditional syndromes of chronic obstructive pulmonary disease (COPD), has been defined in clinical terms. A diagnosis was traditionally made when there was a history of chronic sputum expectoration (on most days) for 3 months of the year for 2 consecutive years.157–159 Pulmonary emphysema is one of the other classic syndromes of chronic airflow limitation. However, although it is perhaps convenient to think of these conditions as discrete entities, the concept is

In chronic bronchitis there is a background of chronic inflammation that causes lung damage. The key pathologic finding in chronic bronchitis is the presence of enlarged mucous glands and goblet cell hyperplasia. Chronic airway remodeling can occur, leading to the “fixed” airway obstruction that is so characteristic a feature of COPD.171 LUNG FUNCTION The results of lung function tests in patients with “pure” chronic bronchitis (i.e., without associated emphysema) may be entirely normal.167 Episodic declines in lung function may be seen and might be attributed to airway hyperreactivity during infections.

Manifestations of the Disease RADIOGRAPHY The majority of patients with chronic bronchitis have no abnormality on chest radiography.172 In those with findings, bronchial wall thickening and a general sense of an increase in lung markings, sometimes referred to as “dirty” or “busy” lungs in reports of old, are common (Fig. 57.26). However, the exact pathologic meaning of these radiographic features is difficult to predict. Although some older studies of chest radiographs reported hyperinflation in chronic bronchitis, the inclusion of patients with significant emphysema may have been responsible for this finding.173

732

SECTION 11  Diseases of the Airways

attenuation on inspiratory CT scans and air-trapping on expiratory CT scans.175 IMAGING ALGORITHMS Imaging has a limited role in the evaluation of chronic bronchitis. The chest radiograph perhaps has the greatest value in the detection of infection and in the exclusion of alternative diagnoses.162 CT should have little if any role in the routine evaluation of patients with chronic bronchitis. A possible exception is the “difficult” case in which the exclusion of other entities (e.g., bronchiectasis) that might manifest with similar chronic respiratory symptoms is important.

Differential Diagnosis The major differential diagnosis to be considered is that of asthma, a distinction that is potentially problematic, particularly when asthma is chronic and associated with a component of fixed airflow obstruction.162 Other considerations that may cause bronchial wall thickening on CT include bronchiectasis, constrictive bronchiolitis, diffuse panbronchiolitis, and congestive heart failure. Fig. 57.26  Chronic bronchitis. Chest radiograph shows a generalized increase in lung markings and bronchial wall thickening in the lower zones. An ill-defined opacity in the right lower lung was subsequently proven to be a lung cancer.

Synopsis of Treatment Options MEDICAL Smoking cessation is the most important aspect of the management of patients with chronic bronchitis and COPD. Influenza vaccination is recommended. Bronchodilator therapy, sometimes with corticosteroids, is prescribed for patients with symptomatic chronic bronchitis or COPD. A pulmonary rehabilitation program improves exercise tolerance and provides symptomatic benefit. Treatment is also directed to the management of acute exacerbations, generally resulting from infection.

KEY POINTS: CHRONIC BRONCHITIS • Chronic bronchitis is a clinical diagnosis based on a history of chronic sputum expectoration (on most days) for 3 months of the year for 2 consecutive years. • Imaging plays a limited role in the evaluation of these patients, except to exclude other findings such as bronchiectasis. The major CT findings include bronchial wall thickening and endobronchial mucous plugging. Fig. 57.27  Chronic bronchitis in a long-term smoker. High-resolution CT image shows thick-walled (but not bronchiectatic) subsegmental airways in both lower lobes. There is mild mosaic attenuation suggesting small airways involvement.

COMPUTED TOMOGRAPHY Bronchial wall thickening and endobronchial mucous plugging are readily depicted but nonspecific features on thin-section CT (Fig. 57.27).57,174 In the study by Remy-Jardin and colleagues,57 there was evidence of wall thickening in one-third of smokers. However, there was also evidence of thick-walled bronchi in just less than 20% of normal controls. In some smokers there are signs of small airway involvement with focal areas of mosaic

SUGGESTED READINGS Bruzzi JF, Remy-Jardin M, Delhaye D, et al. Multi-detector row CT of hemoptysis. Radiographics. 2006;26:3–22. Gibson PG. Allergic bronchopulmonary aspergillosis. Semin Respir Crit Care Med. 2006;27:185–191. Milliron B, Henry TS, Veeraraghavan S, Little BP. Bronchiectasis: mechanisms and imaging clues of associated common and uncommon diseases. Radiographics. 2015;35:1011–1030. Rosen MJ. Chronic cough due to bronchiectasis: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(suppl):122S–131S. Virnig C, Bush RK. Allergic bronchopulmonary aspergillosis: a US perspective. Curr Opin Pulm Med. 2007;13:67–71.

The full reference list for this chapter is available at ExpertConsult.com.

57  Bronchiectasis and Other Bronchial Abnormalities 732.e1

REFERENCES 1. Ellis DA, Thornley PE, Wightman AJ, et al. Present outlook in bronchiectasis: clinical and social study and review of factors influencing prognosis. Thorax. 1981;36:659–664. 2. Keistinen T, Saynajakangas O, Tuuponen T, Kivela SL. Bronchiectasis: an orphan disease with a poorly-understood prognosis. Eur Respir J. 1997;10:2784–2787. 3. Kolbe J, Wells AU. Bronchiectasis: a neglected cause of respiratory morbidity and mortality. Respirology. 1996;1:221–225. 4. Nicotra MB. Bronchiectasis. Semin Respir Infect. 1994;9:31–40. 5. Singleton R, Morris A, Redding G, et al. Bronchiectasis in Alaska native children: causes and clinical courses. Pediatr Pulmonol. 2000;29:182–187. 6. Palwatwichai A, Chaoprasong C, Vattanathum A, et al. Clinical, laboratory findings and microbiologic characterization of bronchiectasis in Thai patients. Respirology. 2002;7:63–66. 7. Twiss J, Metcalfe R, Edwards E, Byrnes C. New Zealand national incidence of bronchiectasis “too high” for a developed country. Arch Dis Child. 2005;90:737–740. 8. Fraser RS, Müller NL, Colman N, Paré PD. Bronchiectasis and other bronchial abnormalities. In: Fraser RS, Müller NL, Colman N, Paré PD, eds. Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 1999:2265–2297. 9. Pasteur MC, Helliwell SM, Houghton SJ, et al. An investigation into causative factors in patients with bronchiectasis. Am J Respir Crit Care Med. 2000;162:1277–1284. 10. Sethi GR, Batra V. Bronchiectasis: causes and management. Indian J Pediatr. 2000;67:133–139. 11. King PT, Holdsworth SR, Freezer NJ, et al. Characterisation of the onset and presenting clinical features of adult bronchiectasis. Respir Med. 2006;100:2183–2189. 12. Karakoc GB, Yilmaz M, Altintaz DU, Kenderli SG. Bronchiectasis: still a problem. Pediatr Pulmonol. 2001;32:175–178. 13. Cole PJ, Flower CDR, Lavender JP. Clinical and imaging aspects of bronchiectasis. In: Potchen EJ, Grainger RG, Greene R, eds. Pulmonary Radiology: The Fleischner Society. Philadelphia: WB Saunders; 1993:242–258. 14. Nikolaizik WH, Warner JO. Aetiology of chronic suppurative lung disease. Arch Dis Child. 1994;70:141–142. 15. Barker AF, Bardana EJ. Bronchiectasis: update of an orphan disease. Am Rev Respir Dis. 1988;137:969–978. 16. Chang AB, Grimwood K, Mulholland EK, Torzillo PJ. Bronchiectasis in indigenous children in remote Australian communities. Med J Aust. 2002;177:200–204. 17. Saynajakangas O, Keistinen T, Tuuponen T, Kivela SL. Evaluation of the incidence and age distribution of bronchiectasis from the Finnish hospital discharge register. Cent Eur J Public Health. 1998;6:235–237. 18. Nicotra MB, Rivera M, Dale AM, et al. Clinical, pathophysiologic, and microbiologic characterization of bronchiectasis in an aging cohort. Chest. 1995;108:955–961. 19. Lynch DA, Newell J, Hale V, et al. Correlation of CT findings with clinical evaluations in 261 patients with symptomatic bronchiectasis. AJR Am J Roentgenol. 1999;173:53–58. 20. Nath AR, Capel LH. Lung crackles in bronchiectasis. Thorax. 1980;35: 694–699. 21. Kuhn CI. Normal anatomy and histology. In: Thurlbeck WM, Churg AM, eds. Pathology of the Lung. New York: Thieme; 1995:1–36. 22. Horsfield K, Cumming G. Angles of branching and diameters of branches in the human bronchial tree. Bull Math Biophys. 1967;29:245–259. 23. Weibel ER. Looking into the lungs: what can it tell us? AJR Am J Roentgenol. 1979;133:1021–1031. 24. Parker H, Horsfield K, Cumming G. Morphology of distal airways in the human lung. J Appl Physiol. 1971;31:386–391. 25. Eastham KM, Fall AJ, Mitchell L, Spencer DA. The need to redefine non–cystic fibrosis bronchiectasis in childhood. Thorax. 2004;59:324–327. 26. Gaillard EA, Carty H, Heaf D, Smyth RL. Reversible bronchial dilatation in children: comparison of serial high-resolution computer tomography scans of the lungs. Eur J Radiol. 2003;47:215–220. 27. Reid LM. Reduction in bronchial subdivision in bronchiectasis. Thorax. 1950;5:233–247. 28. Bates DV. Cysts and bullae, bronchiectasis, and cystic fibrosis. In: Bates DV, ed. Respiratory Function in Disease. Philadelphia: WB Saunders; 1989:236–243. 29. Pande JN, Jain BP, Gupta RG, Guleria JS. Pulmonary ventilation and gas exchange in bronchiectasis. Thorax. 1971;26:727–732. 30. Loubeyre P, Paret M, Revel D, et al. Thin-section CT detection of emphysema associated with bronchiectasis and correlation with pulmonary function tests. Chest. 1996;109:360–365.

31. Ip MS, So SY, Lam WK, et al. High prevalence of asthma in patients with bronchiectasis in Hong Kong. Eur Respir J. 1992;5:418–423. 32. Culiner MM. Obliterative bronchitis and bronchiolitis with bronchiectasis. Dis Chest. 1963;44:351–361. 33. Gayrard P, Charpin J. Evaluation of the role of large bronchi in the genesis of air obstruction in normal subjects and in various diseases. Am Rev Respir Dis. 1968;97:1076–1088. 34. Hansell DM, Wells AU, Rubens MB, Cole PJ. Bronchiectasis: functional significance of areas of decreased attenuation at expiratory CT. Radiology. 1994;193:369–374. 35. Roberts HR, Wells AU, Milne DG, et al. Airflow obstruction in bronchiectasis: correlation between computed tomography features and pulmonary function tests. Thorax. 2000;55:198–204. 36. Sheehan RE, Wells AU, Copley SJ, et al. A comparison of serial computed tomography and functional change in bronchiectasis. Eur Respir J. 2002;20:581–587. 37. Gudbjerg CE. Roentgenologic diagnosis of bronchiectasis: an analysis of 112 cases. Acta Radiol. 1955;43:209–217. 38. Currie DC, Cooke JC, Morgan AD, et al. Interpretation of bronchograms and chest radiographs in patients with chronic sputum production. Thorax. 1987;42:278–284. 39. Phillips MS, Williams MP, Flower CDR. How useful is computed tomography in the diagnosis and assessment of bronchiectasis? Clin Radiol. 1986;37: 321–325. 40. Cooke JC, Currie DC, Morgan AD, et al. Role of computed tomography in diagnosis of bronchiectasis. Thorax. 1987;42:272–277. 41. Silverman PM, Godwin JD. CT/bronchographic correlations in bronchiectasis. J Comput Assist Tomogr. 1987;11:52–56. 42. Grenier P, Maurice F, Musset D, et al. Bronchiectasis: assessment by thinsection CT. Radiology. 1986;161:95–99. 43. Munro NC, Cooke JC, Currie DC, et al. Comparison of thin section computed tomography with bronchography for identifying bronchiectatic segments in patients with chronic sputum production. Thorax. 1990;45:135–139. 44. Koehler PR, Anderson RE, Baxter B. The effect of computed tomography viewer controls on anatomical measurements. Radiology. 1979;130: 189–194. 45. Baxter BS, Sorensen JA. Factors affecting the measurements of size and CT number in computed tomography. Invest Radiol. 1981;4:337–341. 46. Webb WR, Gamsu G, Wall SD, et al. CT of a bronchial phantom: factors affecting appearance and size measurements. Invest Radiol. 1984;19:394–398. 47. Naidich DP, McCauley DI, Khouri NF, et al. Computed tomography of bronchiectasis. J Comput Assist Tomogr. 1982;6:437–444. 48. Kim JS, Müller NL, Park CS, et al. Cylindrical bronchiectasis: diagnostic findings on thin-section CT. AJR Am J Roentgenol. 1996;21:306–311. 49. Sibtain NA, Ujita M, Wilson R, et al. Interlobular septal thickening in idiopathic bronchiectasis: a thin-section CT study of 94 patients. Radiology. 2005;237:1091–1096. 50. Kim JS, Müller NL, Park CS, et al. Bronchoarterial ratio on thin-section CT: comparison between high altitude and sea-level. J Comput Assist Tomogr. 1997;21:306–311. 51. Kang EY, Miller RR, Müller NL. Bronchiectasis: comparison of preoperative thin-section CT and pathological findings in resected specimens. Radiology. 1995;195:649–654. 52. Dodd JD, Souza CA, Müller NL. Conventional high-resolution CT versus helical high-resolution MDCT in the detection of bronchiectasis. AJR Am J Roentgenol. 2006;187:414–420. 53. Matsuoka S, Uchiyama K, Shima H, et al. Bronchoarterial ratio and bronchial wall thickness on high-resolution CT in asymptomatic subjects: correlation with age and smoking. AJR Am J Roentgenol. 2003;180:513–518. 54. Lynch DA, Newell JD, Tschomper BA, et al. Uncomplicated asthma in adults: comparison of CT appearances of the lungs in asthmatic and healthy subjects. Radiology. 1993;188:829–833. 55. Moudgil R, Michelakis ED, Archer SL. Hypoxic pulmonary vasoconstriction. J Appl Physiol. 2005;98:390–403. 56. Wetzel RC, Herold CJ, Zerhouni EA, Robotham JL. Hypoxic bronchodilation. J Appl Physiol. 1992;73:1202–1206. 57. Remy-Jardin M, Remy J, Boulenguez C, et al. Morphologic effects of cigarette smoking on airways and pulmonary parenchyma in healthy adult volunteers: CT evaluation and correlation with pulmonary function tests. Radiology. 1993;186:107–115. 58. Diederich S, Jurriaans E, Flower CD. Interobserver variation in the diagnosis of bronchiectasis on high-resolution computed tomography. Eur Radiol. 1996;6:801–806. 59. Rossi SE, Franquet T, Volpacchio M, et al. Tree-in-bud pattern at thin-section CT of the lungs: radiologic-pathologic overview. Radiographics. 2005;25: 789–801.

732.e2

SECTION 11  Diseases of the Airways

60. Westcott JL, Cole SR. Traction bronchiectasis in end-stage pulmonary fibrosis. Radiology. 1986;161:665–669. 61. Linhartová A, Anderson AE Jr, Foraker AG. Radial traction and bronchiolar obstruction in pulmonary emphysema: observed and theoretical aspects. Arch Pathol. 1971;92:384–391. 62. Desai SR, Wells AU, Rubens MB, et al. Traction bronchiectasis in cryptogenic fibrosing alveolitis: associated computed tomographic features and physiological significance. Eur Radiol. 2003;13:1801–1808. 63. Hansell DM, Strickland B. High-resolution computed tomography in pulmonary cystic fibrosis. Br J Radiol. 1989;62:1–5. 64. Santis G, Hodson ME, Strickland B. High resolution computed tomography in adult cystic fibrosis patients with mild lung disease. Clin Radiol. 1991;44:20–22. 65. Gurney JW, Habbe TG, Hicklin J. Distribution of disease in cystic fibrosis: correlation with pulmonary function. Chest. 1997;112:357–362. 66. Currie DC, Goldman JM, Cole PJ, Strickland B. Comparison of narrow section computed tomography and plain chest radiography in chronic allergic bronchopulmonary aspergillosis. Clin Radiol. 1987;38:593–596. 67. Reiff DB, Wells AU, Carr DH, et al. CT findings in bronchiectasis: limited value in distinguishing between idiopathic and specific types. AJR Am J Roentgenol. 1995;165:261–267. 68. Cartier Y, Kavanagh PV, Johkoh T, et al. Bronchiectasis: accuracy of highresolution CT in the differentiation of specific diseases. AJR Am J Roentgenol. 1999;173:47–52. 69. Bye MR, Ewig JM, Quittell LM. Cystic fibrosis. Lung. 1994;172:251–270. 70. Gershman AJ, Mehta AC, Infeld M, et al. Cystic fibrosis in adults: an overview for the internist. Cleve Clin J Med. 2006;73:1065–1074. 71. Fitzpatrick SB, Rosenstein BJ, Langbaum TS. Diagnosis of cystic fibrosis during adolescence. J Adolesc Health Care. 1986;7:38–43. 72. Nick JA, Rodman DM. Manifestations of cystic fibrosis diagnosed in adulthood. Curr Opin Pulm Med. 2005;11:513–518. 73. Stern RC. The diagnosis of cystic fibrosis. N Engl J Med. 1997;336: 487–491. 74. Wood BP. Cystic fibrosis: 1997. Radiology. 1997;204:1–10. 75. Fraser RS, Colman N, Müller NL, et al. Disease of the airways. In: Fraser RS, Colman N, Müller NL, et al, eds. Synopsis of Diseases of the Chest. Philadelphia: Saunders; 2005:627–713. 76. Friedman PJ, Harwood IR, Ellenbogen PH. Pulmonary cystic fibrosis in the adult: early and late radiologic findings with pathologic correlations. AJR Am J Roentgenol. 1981;136:1131–1144. 77. Grum CM, Lynch JP 3rd. Chest radiographic findings in cystic fibrosis. Semin Respir Infect. 1992;7:193–209. 78. Conway SP, Pond MN, Bowler I, et al. The chest radiograph in cystic fibrosis: a new scoring system compared with the Chrispin-Norman and Brasfield scores. Thorax. 1994;49:860–862. 79. Shale DJ. Chest radiology in cystic fibrosis: is scoring useful? Thorax. 1994;49:847. 80. Flume PA. Pneumothorax in cystic fibrosis. Chest. 2003;123:217–221. 81. Bhalla M, Turcios N, Aponte V, et al. Cystic fibrosis: scoring system with thin-section CT. Radiology. 1991;179:783–788. 82. Helbich TH, Heinz-Peer G, Eichler I, et al. Cystic fibrosis: CT assessment of lung involvement in children and adults. Radiology. 1999;213: 537–544. 83. Helbich TH, Heinz-Peer G, Fleischmann D, et al. Evolution of CT findings in patients with cystic fibrosis. AJR Am J Roentgenol. 1999;173:81–88. 84. Cartier Y, Kavanagh PV, Johkoh T, et al. Bronchiectasis: accuracy of highresolution CT in the differentiation of specific diseases. AJR Am J Roentgenol. 1999;173:47–52. 85. Lynch DA, Brasch RC, Hardy KA, et al. Pediatric pulmonary disease: assessment with high-resolution ultrafast CT. Radiology. 1990;176: 243–248. 86. Santis G, Hodson ME, Strickland B. High resolution computed tomography in adult cystic fibrosis patients with mild lung disease. Clin Radiol. 1991;44:20–22. 87. Kant JA, Mifflin TE, McGlennen R, et al. Molecular diagnosis of cystic fibrosis. Clin Lab Med. 1995;15:877–898. 88. Stephenson AL, Sykes J, Stanojevic S, et al. Survival comparison of patients with cystic fibrosis in Canada and the United States: a population-based cohort study. Ann Intern Med. 2017;166(8):537–546. 89. Rosen MJ. Chronic cough due to bronchiectasis: ACCP evidence-based clinical practice guidelines. Chest. 2006;129:122S–131S. 90. Geremek M, Witt M. Primary ciliary dyskinesia: genes, candidate genes and chromosomal regions. J Appl Genet. 2004;45:347–361. 91. Roomans GM, Ivanovs A, Shebani EB, et al. Transmission electron microscopy in the diagnosis of primary ciliary dyskinesia. Ups J Med Sci. 2006;111: 155–168.

92. Kennedy MP, Noone PG, Leigh MW, et al. High-resolution CT of patients with primary ciliary dyskinesia. AJR Am J Roentgenol. 2007;188: 1232–1238. 93. Chao J, Turner JA, Sturgess JM. Genetic heterogeneity of dynein-deficiency in cilia from patients with respiratory disease. Am Rev Respir Dis. 1982;126: 302–305. 94. Matwijiw I, Thliveris JA, Faiman C. Aplasia of nasal cilia with situs inversus, azoospermia and normal sperm flagella: a unique variant of the immotile cilia syndrome. J Urol. 1987;137:522–524. 95. Katsuhara K, Kawamoto S, Wakabayashi T, et al. Situs inversus totalis and Kartagener’s syndrome in a Japanese population. Chest. 1972;61:56–61. 96. Kroon AA, Heij JM, Kuijper WA, et al. Function and morphology of respiratory cilia in situs inversus. Clin Otolaryngol Allied Sci. 1991;16: 294–297. 97. Bush A, Cole P, Hariri M, et al. Primary ciliary dyskinesia: diagnosis and standards of care. Eur Respir J. 1998;12:982–988. 98. Turner JA, Corkey CW, Lee JY, et al. Clinical expressions of immotile cilia syndrome. Pediatrics. 1981;67:805–810. 99. Sturgess JM, Chao J, Wong J, et al. Cilia with defective radial spokes: a cause of human respiratory disease. N Engl J Med. 1979;300:53–56. 100. Wilton LJ, Teichtahl H, Temple-Smith PD, et al. Kartagener’s syndrome with motile cilia and immotile spermatozoa: axonemal ultrastructure and function. Am Rev Respir Dis. 1986;134:1233–1236. 101. Min YG, Shin JS, Choi SH, et al. Primary ciliary dyskinesia: ultrastructural defects and clinical features. Rhinology. 1995;33:189–193. 102. Mossberg B, Camner P. Impaired mucociliary transport as a pathogenetic factor in obstructive pulmonary diseases. Chest. 1980;77:265–266. 103. Nadel HR, Stringer DA, Levison H, et al. The immotile cilia syndrome: radiological manifestations. Radiology. 1985;154:651–655. 104. Reiff DB, Wells AU, Carr DH, et al. CT findings in bronchiectasis: limited value in distinguishing between idiopathic and specific types. AJR Am J Roentgenol. 1995;165:261–267. 105. Gibson PG. Allergic bronchopulmonary aspergillosis. Semin Respir Crit Care Med. 2006;27:185–191. 106. Virnig C, Bush RK. Allergic bronchopulmonary aspergillosis: a US perspective. Curr Opin Pulm Med. 2007;13:67–71. 107. Bosken CH, Myers JL, Greenberger PA, et al. Pathologic features of allergic bronchopulmonary aspergillosis. Am J Surg Pathol. 1988;12:216–222. 108. Silva CI, Colby TV, Müller NL. Asthma and associated conditions: highresolution CT and pathologic findings. AJR Am J Roentgenol. 2004;183: 817–824. 109. Franquet T, Müller NL, Gimenez A, et al. Spectrum of pulmonary aspergillosis: histologic, clinical, and radiologic findings. Radiographics. 2001;21: 825–837. 110. Angus RM, Davies ML, Cowan MD, et al. Computed tomographic scanning of the lung in patients with allergic bronchopulmonary aspergillosis and in asthmatic patients with a positive skin test to Aspergillus fumigatus. Thorax. 1994;49:586–589. 111. Neeld DA, Goodman LR, Gurney JW, et al. Computerized tomography in the evaluation of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis. 1990;142:1200–1206. 112. Ward S, Heyneman L, Lee MJ, et al. Accuracy of CT in the diagnosis of allergic bronchopulmonary aspergillosis in asthmatic patients. AJR Am J Roentgenol. 1999;173:937–942. 113. Logan PM, Müller NL. High-attenuation mucous plugging in allergic bronchopulmonary aspergillosis. Can Assoc Radiol J. 1996;47:374–377. 114. Aubry MC, Fraser R. The role of bronchial biopsy and washing in the diagnosis of allergic bronchopulmonary aspergillosis. Mod Pathol. 1998;11: 607–611. 115. Woodring JH, Howard RS 2nd, Rehm SR. Congenital tracheobronchomegaly (Mounier-Kuhn syndrome): a report of 10 cases and review of the literature. J Thorac Imaging. 1991;6:1–10. 116. Kwong JS, Müller NL, Miller RR. Diseases of the trachea and main-stem bronchi: correlation of CT with pathologic findings. Radiographics. 1992;12:647–657. 117. Vidal C, Pena F, Rodriguez Mosquera M, et al. Tracheobronchomegaly associated with interstitial pulmonary fibrosis. Respiration. 1991;58: 207–210. 118. Padley S, Varma N, Flower CD. Tracheobronchomegaly in association with ankylosing spondylitis. Clin Radiol. 1991;43:139–141. 119. Celenk C, Celenk P, Selcuk MB, et al. Tracheomegaly in association with rheumatoid arthritis. Eur Radiol. 2000;10:1792–1794. 120. Genta PR, Costa MV, Stelmach R, et al. A 26-yr-old male with recurrent respiratory infections. Eur Respir J. 2003;22:564–567. 121. Smith DL, Withers N, Holloway B, et al. Tracheobronchomegaly: an unusual presentation of a rare condition. Thorax. 1994;49:840–841.

57  Bronchiectasis and Other Bronchial Abnormalities 732.e3 122. Shah SS, Karnak D, Mason D, et al. Pulmonary transplantation in Mounier-Kuhn syndrome: a case report. J Thorac Cardiovasc Surg. 2006;131:757–758. 123. Dunne MG, Reiner B. CT features of tracheobronchomegaly. J Comput Assist Tomogr. 1988;12:388–391. 124. Shin MS, Jackson RM, Ho KJ. Tracheobronchomegaly (Mounier-Kuhn syndrome): CT diagnosis. AJR Am J Roentgenol. 1988;150:777–779. 125. Palmer SM Jr, Layish DT, Kussin PS, et al. Lung transplantation for WilliamsCampbell syndrome. Chest. 1998;113:534–537. 126. Lee P, Bush A, Warner JO. Left bronchial isomerism associated with bronchomalacia, presenting with intractable wheeze. Thorax. 1991;46:459–461. 127. Kaneko K, Kudo S, Tashiro M, et al. Computed tomography findings in Williams-Campbell syndrome. J Thorac Imaging. 1991;6:11–13. 128. Hartman TE, Primack SL, Lee KS, et al. CT of bronchial and bronchiolar diseases. Radiographics. 1994;14:991–1003. 129. McAdams HP, Erasmus J. Chest case of the day. Williams-Campbell syndrome. AJR Am J Roentgenol. 1995;165:190–191. 130. George J, Jain R, Tariq SM. CT bronchoscopy in the diagnosis of WilliamsCampbell syndrome. Respirology. 2006;11:117–119. 131. Di Scioscio V, Zompatori M, Mistura I, et al. The role of spiral multidetector dynamic CT in the study of Williams-Campbell syndrome. Acta Radiol. 2006;47:798–800. 132. Kelley WA. Broncholithiasis: current concepts of an ancient disease. Postgrad Med. 1979;66:81–86. 133. Gurney JW, Conces DJ. Pulmonary histoplasmosis. Radiology. 1996;199:297–306. 134. Nollet AS, Vansteenkiste JF, Demedts MG. Broncholithiasis: rare but still present. Respir Med. 1998;92:963–965. 135. Kim TS, Han J, Koh WJ, et al. Endobronchial actinomycosis associated with broncholithiasis: CT findings for nine patients. AJR Am J Roentgenol. 2005;185:347–353. 136. Bouros D, Nicholson AG, Polychronopoulos V, du Bois RM. Acute interstitial pneumonia. Eur Respir J. 2000;15:412–418. 137. Seo JB, Lee JW, Ha SY, et al. Primary endobronchial actinomycosis associated with broncholithiasis. Respiration. 2003;70:110–113. 138. Antao VCS, Pinheiro GA, Jansen JM. Broncholithiasis and lithoptysis associated with silicosis. Eur Respir J. 2002;20:1057–1059. 139. Olson EJ, Utz JP, Prakash UBS. Therapeutic bronchoscopy in broncholithiasis. Am J Respir Crit Care Med. 1999;160:766–770. 140. McLean TR, Beall AC Jr, Jones JW. Massive hemoptysis due to broncholithiasis. Ann Thorac Surg. 1991;52:1173–1175. 141. Arrigoni LS, Bernatz PE, Donoghue FE. Broncholithiasis. J Thorac Cardiovasc Surg. 1971;62:231–237. 142. Low SY, Eng P. All that wheezes is not asthma: broncholithiasis, a forgotten disease. Ann Acad Med Singapore. 2002;31:528–530. 143. Travis WD, Colby TV, Koss MN, et al. Bronchial disorders. In: Travis WD, Colby TV, Koss MN, et al, eds. Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and the Armed Forces Institute of Pathology; 2002:381–433. 144. Studer SM, Heitmiller RF, Terry PB. Mediastinal abscess due to passage of a broncholith. Chest. 2002;121:296–297. 145. Ford MAP, Mueller PS, Morgenthaler TI. Bronchoesophageal fistula due to broncholithiasis: a case series. Respir Med. 2005;99:830–835. 146. Conces DJ Jr, Tarver RD, Vix VA. Broncholithiasis: CT features in 15 patients. AJR Am J Roentgenol. 1991;157:249–253. 147. Menivale F, Deslee G, Vallerand H, et al. Therapeutic management of broncholithiasis. Ann Thorac Surg. 2005;79:1774–1776. 148. Vix VA. Radiographic manifestations of broncholithiasis. Radiology. 1978;128:295–299. 149. Dixon GE, Donnerberg RL, Scholfeld SA, Whitcomb ME. Advances in the diagnosis and treatment of broncholithiasis. Am Rev Respir Dis. 1984;129:1028–1030. 150. Hodgson NC, Inculet RI. Acute airway obstruction secondary to bilateral broncholithiasis. Chest. 2000;117:1205–1207.

151. Ferguson JS, Rippentrop JM, Fallon B, et al. Management of obstructing pulmonary broncholithiasis with three-dimensional imaging and holmium laser lithotripsy. Chest. 2006;130:909–912. 152. Snyder RW, Unger M, Sawicki RW. Bilateral partial bronchial obstruction due to broncholithiasis treated with laser therapy. Chest. 1998;113: 240–242. 153. Kwon KY, Myers JL, Swensen SJ, Colby TV. Middle lobe syndrome: a clinicopathological study of 21 patients. Hum Pathol. 1995;26:302–307. 154. Seo JB, Song KS, Lee JS, et al. Broncholithiasis: review of the causes with radiologic-pathologic correlation. Radiographics. 2002;22:S199–S213. 155. Kowal LE, Goodman LR, Zarro VJ, Haskin ME. CT diagnosis of broncholithiasis. J Comput Assist Tomogr. 1983;7:321–323. 156. Shin MS, Berland LL, Myers JL, et al. CT demonstration of an ossifying bronchial carcinoid simulating broncholithiasis. AJR Am J Roentgenol. 1989;153:51–52. 157. Fletcher CM, Hugh-Jones P, McNicol MW, Pride NB. The diagnosis of pulmonary emphysema in the presence of chronic bronchitis. Q J Med. 1963;32:33–49. 158. Burrows B, Fletcher CM, Heard BE, et al. The emphysematous and bronchial types of chronic airways obstruction: a clinicopathological study of patients in London and Chicago. Lancet. 1966;1:830–835. 159. Fletcher CM, Pride NB. Definitions of emphysema, chronic bronchitis, asthma and airflow obstruction: 25 years on from the CIBA symposium. Thorax. 1984;39:81–85. 160. Thurlbeck WM. Aspects of chronic airflow obstruction. Chest. 1977;72: 341–349. 161. Calverley PM, Walker P. Chronic obstructive pulmonary disease. Lancet. 2003;362:1053–1061. 162. Pauwels RA, Buist AS, Calverley PM, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 2001;163:1256–1276. 163. Tager IB, Speizer FE. Risk estimates for chronic bronchitis in smokers: a study of male-female differences. Am Rev Respir Dis. 1976;113:619–625. 164. Burrows B, Lebowitz MD. Characteristics of chronic bronchitis in a warm, dry climate. Am Rev Respir Dis. 1975;112:365–370. 165. Holma B, Kjaer G. Alcohol, housing, and smoking in relation to respiratory symptoms. Environ Res. 1980;21:126–142. 166. Becklake MR. Chronic airflow limitation: its relationship to work in dusty occupations. Chest. 1985;88:608–617. 167. Bates DV. Syndromes of chronic airflow limitation. In: Bates DV, ed. Respiratory Function in Disease. Philadelphia: WB Saunders; 1989: 172–187. 168. Sherrill DL, Lebowitz MD, Burrows B. Epidemiology of chronic obstructive pulmonary disease. Clin Chest Med. 1990;11:375–387. 169. Sharp JT, Paul O, McKean H, Best WR. A longitudinal study of bronchitis symptoms and spirometry in a middle-aged, male, industrial population. Am Rev Respir Dis. 1973;108:1066–1077. 170. Mueller RE, Keble DL, Plummer J, Walker SH. The prevalence of chronic bronchitis, chronic airway obstruction, and respiratory symptoms in a Colorado city. Am Rev Respir Dis. 1971;103:209–228. 171. Leopold JG, Geoff J. Centrilobular form of hypertrophic emphysema and its relationship to chronic bronchitis. Thorax. 1957;12:219–235. 172. Gamsu G, Nadel JA. The roentgenologic manifestations of emphysema and chronic bronchitis. Med Clin North Am. 1973;57:719–733. 173. Simon G, Galbraith H-JB. Radiology of chronic bronchitis. Lancet. 1953;2:850–852. 174. Remy-Jardin M, Remy J, Gosselin B, et al. Lung parenchymal changes secondary to cigarette smoking: pathologic-CT correlations. Radiology. 1993;186:643–651. 175. Verschakelen JA, Scheinbaum K, Bogaert JG, et al. Expiratory CT in smokers: correlation between areas of decreased lung attenuation, pulmonary function tests and smoking history. Eur Radiol. 1998;8:1391–1399.

58 

Asthma* JONATHAN H. CHUNG  |  CHRISTOPHER M. WALKER

Asthma is an inflammatory disease characterized by increased airway reactivity and by airflow obstruction that is at least partially reversible and results in recurrent episodes of wheezing, breathlessness, and cough.1

Etiology Asthma can be divided into two main categories: extrinsic and intrinsic. Extrinsic asthma occurs in patients who are atopic, a term used to refer to the genetic predisposition to respond to antigenic challenge with excessive immunoglobulin E (IgE) production. The inheritance is complex but usually incomplete, and evidence of it is much greater if both parents are atopic. Although patients with extrinsic asthma are invariably atopic, atopy itself is not synonymous with asthma. Atopy occurs in more than 30% of the population, whereas the incidence of asthma is generally less than 10%. In addition to atopy and elevated blood levels of IgE, extrinsic asthma is characterized by high incidences of eczema and rhinitis, onset during the first 3 decades of life, seasonal symptoms, and a tendency for remission in later life.2 Intrinsic asthma occurs in patients in whom atopy or specific external triggers of bronchoconstriction cannot be identified.3 Affected patients are characterized by being older than patients with extrinsic disease and by having no or a less convincing family history of asthma or atopy, an absence of elevated blood levels of IgE or positive skin or bronchial response to allergen challenge, increased numbers of blood and sputum eosinophils, decreased responsiveness to therapy, and a tendency to persistent and progressive disease resulting in fixed airflow obstruction.2

Prevalence and Epidemiology Asthma is a common disease, and there is good evidence that its prevalence and the prevalence of other allergic disorders is increasing worldwide.1 The reasons for this increase are unclear. Estimates of prevalence vary by definition, geography, ethnicity, and age. The prevalence of asthma in most countries with available statistics ranges from approximately 5% to 25% in children and 2% to 12% in adults.1 The highest prevalences are found in the United Kingdom, Australia, and New Zealand (≈12% each) and in Tristan da Cunha, a group of remote islands in the South Atlantic Ocean in which 56% of the population has asthma.1 Concomitant sinusitis is common, occurring in 47% to 76% of asthma cases.4 The prevalence of asthma is highest in childhood and decreases during adolescence and adulthood. The prevalence before the age of 10 years is higher in boys than in girls; after that, it is higher *The editors and publisher would like to thank Drs. C. Isabela Silva Müller and Nestor L. Müller for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

in females.2 Females are also more likely to visit the emergency department and to be admitted for acute severe asthma.5 Asthma is the most common chronic lung disease and an important health problem worldwide.6 In the United States, it accounts for nearly 2 million emergency department visits, 500,000 hospitalizations, and 5000 deaths each year.7 Data from Australia, Canada, and Spain indicate that acute asthma accounts for 1% to 12% of all adult emergency department visits.6 In a study in France, 7% of adult patients with acute asthma who presented to the emergency department were transferred to an intensive care unit.8

Clinical Presentation The diagnosis of asthma is based largely on a history of periodic paroxysms of dyspnea, alternating with intervals of complete or nearly complete remission. Cough can be a prominent symptom and occasionally the only symptom.6 The onset of acute asthma (asthma attack) is characterized by gradual increase in shortness of breath, cough, and wheezing and by a decrease in expiratory airflow. The exacerbations may progress during hours, days, or weeks.6 Physical findings include hyperventilation, inspiratory and expiratory rhonchi and wheezes, decreased breath sounds, and prolonged expiration.2 Cough and wheezing are the result of bronchial inflammation and bronchoconstriction. Contraction of airway smooth muscle, edema, and hypersecretion also affect the bronchioles and result in small airway closure.1 To compensate, the patient breathes at a higher lung volume to increase outward retraction of the airways, thereby helping to maintain airway patency. The more severe the airflow limitation, the greater the tendency for airway closure to occur and the higher the lung volume must be to keep airways open. The combination of hyperinflation and airflow limitation markedly increases the work of breathing.1 Acute asthma attacks may range from mild to life-threatening. In a study of 3772 patients with acute asthma who presented at various emergency departments in France, 975 (26%) had lifethreatening attacks, 1834 (49%) had severe exacerbations without life-threatening features, and 963 (26%) had mild to moderate exacerbations.8 The overall admission rate was 54%, and mean hospital stay was 6 days. Three patients died in the hospital.8

Pathophysiology The basic pathophysiologic abnormality that determines the functional and symptomatic status of an asthmatic patient is airway narrowing, which can occur by four mechanisms: (1) airway smooth muscle contraction, (2) edema and congestion of the airway wall, (3) plugging of the airway lumen by mucous and inflammatory exudate, and (4) airway wall remodeling.1 Airway remodeling is a heterogeneous process leading to changes in connective tissue deposition and to altered airways structure.9 For the most part, it is difficult to determine in a given patient 733

734

SECTION 11  Diseases of the Airways

what proportion of airway obstruction is caused by each of these mechanisms. However, it may reasonably be concluded that when obstruction is rapidly reversible after the inhalation of smooth muscle relaxants, the pathogenesis is smooth muscle contraction. On the other hand, when obstruction responds during a period of days to steroids and other therapeutic interventions, it is probably caused predominantly by edema and mucous plugging.2 Asthma is a chronic inflammatory disorder of the airways associated with airway hyperresponsiveness, an exaggerated bronchoconstrictor response to a wide variety of exogenous and endogenous stimuli that results in acute episodes of dyspnea and wheezing.1 These include environmental allergens, respiratory viral infections, exercise, analgesics, air pollution, weather changes, cigarette smoke, occupational sensitizing agents, indoor allergens, and irritants, such as household sprays and paint fumes.1,10–22 Specific antigens can provoke asthmatic attacks in sensitized persons. These individuals frequently suffer from other allergic manifestations, such as hay fever and eczema. Potential antigens are innumerable. Exercise-induced asthma can be considered to be present when airway narrowing accompanies moderate or vigorous exercise.11 Rather than being a separate form of asthma, exercise-induced asthma should be considered a trigger for airway narrowing in patients who have asthma. In fact, it occurs in 70% to 80% of patients with asthma who exercise at 80% to 90% of their maximal workload for 6 to 8 minutes.12 The association of asthma and gastroesophageal reflux is common; various investigators have estimated the concordance to be 30% to more than 80%.16 There is evidence that gastroesophageal reflux can induce asthma and that asthma can cause a worsening of gastroesophageal reflux. It is possible that gastroesophageal reflux triggers airway narrowing in susceptible persons by reflex bronchoconstriction secondary to stimulation

*

of afferent nerves in the esophagus or pharynx or by direct aspiration of a small amount of esophageal contents.17 PATHOLOGY On histologic examination, asthma is characterized by the presence of chronic inflammation of the airways that involves mainly the medium-sized and small bronchi.23 The bronchi are thickened because of a combination of edema and an increase in smooth muscle and in the size of the mucous glands (Fig. 58.1).23 Bronchiolar abnormalities include wall thickening, mucostasis, and constrictive bronchiolitis (Fig. 58.2).23 Between clinical episodes, the bronchioles may be nearly normal, as viewed in tissue from asthmatics taken for other reasons.23 Histologic changes in the bronchial and bronchiolar walls involve the epithelium, lamina propria, muscularis mucosae, and submucosa.24 The constellation of abnormalities is referred to as airway wall remodeling and consists of changes in the composition, quantity, and organization of the cellular and molecular constituents of the airway wall as a consequence of chronic injury and repair.25 Collagen deposition in the subepithelial layer, as well as in the adventitia, may underlie the decreased airway distensibility that may be seen in asthmatic patients.26 An increase in smooth muscle is also a characteristic feature; it is the result of both hyperplasia and hypertrophy and is most pronounced in subjects who die of the disease.27 Eosinophils are the most characteristic and numerous inflammatory cells in the airway wall; however, there may also be increases in lymphocytes, macrophages, neutrophils, and mast cells.1,28 LUNG FUNCTION Measurements of airflow limitation, its reversibility, and its variability are important in the diagnosis and management of asthma.1

*

Fig. 58.1  Bronchial abnormalities in asthma. Photomicrograph of autopsy specimen obtained in a 10-year-old boy with fatal status asthmaticus reveals bronchus with luminal mucous plug (asterisks), thinning of surface mucosa (arrowheads), submembranous fibrosis (so-called basement membrane thickening, vertical straight arrows), muscle hypertrophy (horizontal straight arrow), and inflammatory infiltrate (curved arrows) that is rich in eosinophils. (From Silva CI, Colby TV, Müller NL. Asthma and associated conditions: high-resolution CT and pathologic findings. AJR Am J Roentgenol. 2004;183: 817–824.)

58  Asthma

A

735

B Fig. 58.2  Bronchiolar abnormalities in asthma. (A) Photomicrograph of histopathologic specimen obtained in a 10-year-old boy with fatal status asthmaticus shows a small bronchiole (outside diameter, 0.5 mm from adventitia to adventitia) with muscle hypertrophy (short straight arrow), submucosal and submembranous fibrosis (long straight arrows), and inflammatory infiltrate (curved arrows) rich in eosinophils. Goblet cell metaplasia (more typically seen in bronchi of patients with asthma) is prominent and seen as pale swollen cells (arrowheads) replacing much of the columnar ciliated epithelium. The extent of submembranous and submucosal fibrosis (structural remodeling) indicates mild constrictive bronchiolitis. (B) Photomicrograph of histopathologic specimen (trichrome stain, intermediate magnification) obtained in a 48-year-old woman with a long history of asthma shows a bronchiole with submucosal thickening that was caused by fibrous tissue (arrows) and resulted in luminal narrowing. These findings are characteristic of mild constrictive bronchiolitis. (From Silva CI, Colby TV, Müller NL. Asthma and associated conditions: high-resolution CT and pathologic findings. AJR Am J Roentgenol. 2004;183:817–824.)

The main measurements used for the evaluation of these patients are forced expiratory volume in 1 second (FEV1), forced vital capacity, the ratio of FEV1 to forced vital capacity, and peak expiratory flow.1 A 12% or greater improvement in FEV1 or 15% or greater improvement in peak expiratory flow spontaneously, after inhalation of a bronchodilator, or in response to a trial of glucocorticosteroid therapy favors a diagnosis of asthma.1 Diffuse airway narrowing is the basic functional abnormality of symptomatic asthma; the resulting increase in resistance leads to decreased flow, hyperinflation, gas trapping, and ultimately an increase in the work of breathing. It is most easily detected and quantified by measurements of maximal expiratory flow. The increase in airway resistance is also associated with hyperinflation, as manifested by an increase in functional residual capacity and, to a lesser extent, total lung capacity.29 As an asthmatic episode resolves, there is improvement in expiratory flow (peak expiratory flow and FEV1) and vital capacity and a decrease in functional residual capacity. The single-breath diffusing lung capacity for carbon monoxide is often elevated in both stable and acute asthma.30 The most plausible explanation for this apparent paradox is the transient increase in pulmonary capillary blood volume that is a result of the more negative inspiratory intrathoracic pressure secondary to obstruction of the airways.2 Most patients experiencing an acute attack have some degree of hypoxemia as a result of ventilation-perfusion mismatch.2 There is not a close relationship between measures of airway obstruction and gas exchange in asthma.31 However, in severe acute attacks, partial pressure of oxygen in arterial blood generally drops to less than 60 mm Hg, FEV1 is less than 1 L, and peak flow is less than 60 L/min.2 As the severity and duration of obstruction increase, patients become exhausted, their respiratory

muscles fatigue, and values of partial pressure of carbon dioxide in arterial blood rise into the hypercapnic range.2

Manifestations of the Disease RADIOGRAPHY The most common radiographic abnormalities in patients who have asthma are hyperinflation and bronchial wall thickening (Figs. 58.3 and 58.4); less frequent manifestations are prominence of the hila, increased central lung markings, and peripheral oligemia (Fig. 58.5).32 The prevalence of these abnormalities is influenced by several factors, including the age at onset, the severity of asthma, and the presence of other diseases or complications of asthma.33 Pulmonary hyperinflation is manifested as an increase in the depth of the retrosternal space, an increase in lung height, and flattening of the diaphragm (see Fig. 58.3). Thickening of the airways occurs in both segmental and subsegmental bronchi and can be seen either as ring shadows viewed end-on or as “tram-line” opacities viewed en face. Prominence of the main pulmonary artery and its hilar branches with rapid tapering is indicative of transient precapillary pulmonary arterial hypertension secondary to hypoxia. Additional vascular findings include diffuse narrowing and blood flow redistribution into the upper lobes, the latter in the absence of other signs of postcapillary hypertension, and a paucity of vessels in the outer 2 to 4 cm of the lungs. Despite the observations just outlined, the chest radiograph has a limited role in the diagnosis of asthma. It is often normal, even during an acute attack; moreover, when it is abnormal, the

736

SECTION 11  Diseases of the Airways

A

B Fig. 58.3  Radiographic manifestations of acute asthma. (A) Posteroanterior chest radiograph shows increased lung volumes and reduction of the peripheral vascular markings. (B) Lateral view demonstrates increased retrosternal airspace.

include pneumonia, atelectasis (Fig. 58.6), pneumomediastinum (Fig. 58.7), pneumothorax, and occasionally pneumorrhachis (i.e., air within the spinal canal).1,37 COMPUTED TOMOGRAPHY

Fig. 58.4  Radiographic manifestations of asthma. A detailed view of the right lung from a frontal radiograph shows bronchial wall thickening (arrowhead), a nonspecific finding that may be seen in asthma.

findings are nonspecific.34 The two main indications for chest radiography are to exclude other conditions that cause wheezing— particularly emphysema, left-sided heart failure, and obstruction of the trachea or major bronchi by tumor or foreign body—and to identify complications.35,36 Complications of asthma that may be seen on radiography or computed tomography (CT)

Thin-section CT findings include thickening and narrowing of the bronchi (Fig. 58.8), endobronchial mucous plugging, bronchial dilatation, patchy areas of decreased attenuation and vascularity, and air-trapping.23 The bronchial wall thickening and luminal narrowing reflect the presence of bronchial wall edema and the increase in smooth muscle and in the size of the mucous glands (see Fig. 58.1). The bronchial abnormalities seen on CT can be quantified subjectively and objectively and have been shown to increase with increasing severity of disease.25,38 The prevalence of bronchial thickening on high-resolution CT in patients with asthma reported in different studies ranges from 16% to 96% and may be seen in up to 19% of normal controls.38–41 The wide variability is presumably related to different populations of patients and the subjectivity of the finding. Park and colleagues38 identified bronchial wall thickening in 17 of 39 (44%) asthmatic patients compared with only 4% of normal controls. Bronchial wall thickening was more prevalent among patients with severe airflow obstruction (83% of patients with FEV1 less than 60% predicted) than in patients with mild obstruction (35% of patients with FEV1 greater than 60%). Although the majority of bronchi of patients with asthma have normal or decreased internal diameter, approximately 31% to 77% of adult patients with uncomplicated asthma have one

58  Asthma

A

737

B

Fig. 58.5  Peripheral oligemia in acute asthma. (A) A detailed view of the left lung from a posteroanterior chest radiograph of a young man during an episode of acute bronchospasm reveals moderate hyperinflation. The vasculature in the outer 2–3 cm of lung is inconspicuous and barely visible, thus creating a subpleural shell of oligemic lung. (B) A repeat study 1 year later during remission shows less hyperinflation; the pulmonary vessels now taper normally, and most are visible well into the lung periphery. (From Müller NL, Fraser RS, Colman NC, Paré PD. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

or more bronchi that are dilated (Fig. 58.9).38,39,41 The bronchiectasis seen in patients with uncomplicated asthma typically is cylindrical, and the bronchoarterial ratio is usually less than 1.5.40 Follow-up studies suggest that the bronchial dilatation seen in asthmatic patients is not reversible.42 High-resolution CT manifestations of bronchiolar abnormalities in patients with asthma include areas of decreased attenuation and vascularity, air-trapping, and small centrilobular opacities.23 Areas of decreased attenuation and vascularity are seen on highresolution CT scans performed at end inspiration in approximately 20% of patients with asthma (Fig. 58.10).38–40 A more common finding is the presence of air-trapping on high-resolution CT images obtained after maximal expiration (Fig. 58.11). In the study by Park and colleagues,38 air-trapping involving a total volume equivalent to one pulmonary segment or more was seen in 50% of asthmatic patients compared with 14% of healthy

subjects. Although the extent of air-trapping increases during an acute attack, air-trapping is also often present in stable patients. This presumably reflects the presence of chronic inflammation and muscle hypertrophy of the small airways or, in some patients, development of constrictive bronchiolitis. Prominent centrilobular structures or small centrilobular opacities have been reported in 10% to 20% of patients with asthma.39,40 These presumably reflect the presence of mucostasis in bronchioles or peribronchiolar inflammation (Fig. 58.12; see also Fig. 58.2). Parenchymal abnormalities in asthma include hyperinflation, emphysema, and occasionally cystic spaces.23 Emphysema is uncommon in asthmatic nonsmokers; when it is present, it is usually mild and secondary to cicatricial peribronchiolar fibrosis.43 Rarely, cystic changes may result from overinflation distal to chronic inflammatory bronchiolitis (Fig. 58.13).23 Text continued on p. 742

738

SECTION 11  Diseases of the Airways

A

B Fig. 58.6  Right middle lobe collapse in acute asthma affecting a pediatric patient. Frontal (A) and lateral (B) chest radiographs show right middle lobe atelectasis.

Fig. 58.7  Pneumomediastinum in acute asthma. Posteroanterior chest radiograph in a young man with acute asthma demonstrates hyperinflation and pneumomediastinum (arrows).

Fig. 58.8  Bronchial wall thickening in chronic asthma in a nonsmoker. (A) High-resolution CT at the level of the lower lobes shows several bronchi with thickened walls (straight arrows). Also noted are several normal-appearing bronchi (curved arrows). (B) Coronal reformatted image shows bronchial wall thickening (straight arrows) in the middle and upper lung zones.

A

B

740

SECTION 11  Diseases of the Airways Fig. 58.9  Bronchiectasis in chronic asthma. High-resolution CT at the level of the lower lobes shows left lower lobe bronchiectasis (arrows), areas of decreased attenuation and vascularity in the left lower lobe, and volume loss.

Fig. 58.10  Mosaic attenuation and expiratory air-trapping in severe chronic asthma. (A) High-resolution CT performed at end inspiration shows extensive bilateral areas of decreased attenuation and vascularity with blood flow redistribution to normal lung, resulting in a mosaic attenuation pattern. (B) High-resolution CT performed after maximal expiration demonstrates extensive air-trapping.

A

B

A

B Fig. 58.11  Air-trapping in asthma. (A) High-resolution CT performed at end inspiration shows subtle areas of decreased attenuation and vascularity. (B) High-resolution CT performed after maximal expiration demonstrates extensive air-trapping.

A

B Fig. 58.12  Asthma: CT findings. (A) High-resolution CT image demonstrates extensive areas of decreased attenuation and vascularity consistent with constrictive bronchiolitis and a few small nodular opacities in the peripheral regions of the lower lobes. (B) Maximum-intensity projection image better demonstrates that the peripheral nodular opacities have a centrilobular distribution (arrows). The centrilobular nodules presumably reflect the presence of mucostasis or peribronchiolar inflammation.

Fig. 58.13  Cysts in chronic asthma in patient never a smoker. High-resolution CT shows bilateral thin-walled cysts (arrows) and localized areas of decreased attenuation and vascularity.

742

SECTION 11  Diseases of the Airways

A relatively common complication seen on high-resolution CT in asthmatic patients is the presence of mucoid impaction. If mucoid impaction is associated with central bronchiectasis, this finding should raise the possibility of allergic bronchopulmonary aspergillosis, a condition characterized by hypersensitivity reaction to endobronchial growth of Aspergillus fumigatus.23 The CT manifestations of allergic bronchopulmonary aspergillosis include homogeneous tubular, finger-in-glove, or branching endobronchial opacities and bronchiectasis involving mainly the segmental and subsegmental bronchi of the upper lobes.23 In approximately 30% of cases, the impacted mucus has increased attenuation, secondary to the deposition of calcium salts (Fig. 58.14).44 The mucous plugging can extend into bronchioles, resulting in centrilobular nodules and tree-inbud opacities. Obstructive atelectasis may also be seen but is uncommon (see Fig. 58.14). Studies have shown that abnormalities suggestive of allergic bronchopulmonary aspergillosis as opposed to asthma include bronchiectasis, centrilobular nodules, and mucoid impaction.45,46 The bronchiectasis in allergic bronchopulmonary aspergillosis tends to be central and varicoid (Fig. 58.15) as opposed to the cylindrical bronchiectasis seen in simple asthma. Other complications that are seen with increased prevalence in asthmatic patients, such as chronic eosinophilic pneumonia and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome), are reviewed in Chapters 37 and 46, respectively. The main role of CT is in the assessment of tracheal and bronchial abnormalities that may mimic asthma and in the assessment of complications such as allergic bronchopulmonary

A

aspergillosis. The value of CT in the diagnosis of endotracheal and endobronchial tumors that may mimic asthma clinically and that may be difficult to visualize on the radiograph is well known (Fig. 58.16).47,48 CT also can play a major role in distinguishing asthma from tracheobronchomalacia (see Chapter 56), a condition that is being recognized with increasing frequency as a potential mimic of asthma.36,49 OTHER IMAGING MODALITIES Various research tools have been developed that attempt to assess ventilation and perfusion to the lungs in the setting of asthma.50–54 Although early data is promising, the difficulties with implementation, high costs, and uncertainty of additional benefit of these tools in the clinical setting must be addressed before any new modality can be considered outside the research realm.

Differential Diagnosis The main differential diagnosis of asthma in patients present­ ing with wheezing and shortness of breath is airway obstruction by tumor, inhaled foreign body, or tracheobronchomalacia. The differential diagnosis of airway wall thickening includes acute and chronic bronchitis, constrictive bronchiolitis, inflammatory diseases such as sarcoidosis, inflammatory bowel disease, and interstitial pulmonary edema. The differential diagnosis of air-trapping includes other causes of small airways disease, such as hypersensitivity pneumonitis and constrictive bronchiolitis.

B Fig. 58.14  Allergic bronchopulmonary aspergillosis. (A) Axial maximum-intensity projection image from chest CT shows consolidation and atelectasis within the anterior segment of the right upper lobe resulting from hyperdense mucous plugging within bronchiectatic airways, essentially diagnostic of allergic bronchopulmonary aspergillosis. (B) Axial image from a follow-up chest CT scans 6 months later shows resolution of right upper lobe opacity and bronchial mucous plugging; the underlying bronchiectasis is now clearly visible.

Fig. 58.15  Allergic bronchopulmonary aspergillosis. (A) Highresolution CT image shows extensive varicose bronchiectasis in the upper lobes. (B) Coronal reformatted image demonstrates the upper lobe and central distribution of the bronchiectasis (arrows).

A

B

A

B Fig. 58.16  Endobronchial atypical carcinoid tumor in patient who presented with history of “asthma.” (A) Inspiratory high-resolution CT image shows endoluminal tumor in right main bronchus. Note decreased size of right lung and diffuse decrease in attenuation and vascularity compared with the left lung. (B) Expiratory CT image demonstrates marked air-trapping within the right lung.

744

SECTION 11  Diseases of the Airways

Synopsis of Treatment Options Treatment of acute asthma usually consists of supplemental oxygen, rapid-acting inhaled β2-agonists, and, particularly in moderate and severe attacks, oral or intravenous glucocorticosteroids.1 Subcutaneous or intramuscular injection of epinephrine (adrenaline) may be used in the treatment of severe acute exacerbations of asthma if β2-agonists are not available.1 However, it has greater risk of adverse side effects, particularly in hypoxic patients. Long-term control of asthma consists of treatment with inhaled corticosteroids, leukotriene modifiers, long-acting β-agonists, and combination inhalers. KEY POINTS • Asthma is a chronic inflammatory disorder of the airways associated with an exaggerated bronchoconstrictor response to a wide variety of stimuli, resulting in recurrent episodes of dyspnea and wheezing. The most important inciting cause is indoor allergens (house dust). • Pathologic features: thickening of the airway walls by a combination of edema and an increase in smooth muscle and in the size of the mucous glands. • Imaging findings • Chest radiography: often normal or near-normal; may show hyperinflation and bronchial wall thickening. • Thin-section CT: thickening and narrowing of the bronchi with mucous plugging, bronchiectasis, patchy areas of decreased attenuation and vascularity, air-trapping; centrilobular nodules are uncommon. • The main role of imaging is to exclude other conditions that cause wheezing—particularly, obstruction of the trachea or main bronchi by tumor or foreign body—and to identify complications, including pneumonia, atelectasis, pneumomediastinum, pneumothorax, and allergic bronchopulmonary aspergillosis.

SUGGESTED READINGS Kligerman SJ, Henry T, Lin CT, Franks TJ, Galvin JR. Mosaic attenuation: etiology, methods of differentiation, and pitfalls. Radiographics. 2015;35(5):1360–1380. Richards JC, Lynch D, Koelsch T, Dyer D. Imaging of asthma. Immunol Allergy Clin North Am. 2016;36(3):529–545. Silva CI, Colby TV, Müller NL. Asthma and associated conditions: high-resolution CT and pathologic findings. AJR Am J Roentgenol. 2004;183:817–824. Trivedi A, Hall C, Hoffman EA, Woods JC, Gierada DS, Castro M. Using imaging as a biomarker for asthma. J Allergy Clin Immunol. 2017;139(1):1–10.

The full reference list for this chapter is available at ExpertConsult.com.

58  Asthma 744.e1

REFERENCES 1. Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA). 2002 Original: Workshop Report. Available at http:// www.ginasthma.com. NIH publication 02-3659. 2. Fraser RS, Colman N, Müller NL, Paré PD. Disease of the airways. In: Fraser RS, Colman N, Müller NL, Paré PD, eds. Synopsis of Diseases of the Chest. Philadelphia: Elsevier Saunders; 2005:627–713. 3. Kroegel C, Jager L, Walker C. Is there a place for intrinsic asthma as a distinct immunopathological entity? Eur Respir J. 1997;10:513–515. 4. Slavin RG. Asthma and sinusitis. J Allergy Clin Immunol. 1992;90(3 Pt 2):534–537. 5. Skobeloff EM, Spivey WH, St Clair SS, Schoffstall JM. The influence of age and sex on asthma admissions. JAMA. 1992;268:3437–3440. 6. Rodrigo GJ, Rodrigo C, Hall JB. Acute asthma in adults: a review. Chest. 2004;125:1081–1102. 7. Mannino DM, Homa DM, Akinbami LJ, et al. Surveillance for asthma—United States, 1980-1999. MMWR Surveill Summ. 2002;51:1–13. 8. Salmeron S, Liard R, Elkharrat D, et al. Asthma severity and adequacy of management in accident and emergency departments in France: a prospective study. Lancet. 2001;358:629–635. 9. Bousquet J, Jeffery PK, Busse WW, et al. Asthma. From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med. 2000;161:1720–1745. 10. Platt-Mills TA, Sporik RB, Chapman MD, Heymann PW. The role of indoor allergens in asthma. Allergy. 1995;50:5–12. 11. McFadden ER Jr. Exercise-induced airway obstruction. Clin Chest Med. 1995;16:671–682. 12. Custovic A, Arifhodzic N, Robinson A, Woodcock A. Exercise testing revisited. The response to exercise in normal and atopic children. Chest. 1994;105: 1127–1132. 13. Korppi M, Reijonen T, Poysa L, Juntunen-Backman K. A 2- to 3-year outcome after bronchiolitis. Am J Dis Child. 1993;147:628–631. 14. Welliver RC. RSV and chronic asthma. Lancet. 1995;346:789–790. 15. Namazy JA, Simon RA. Sensitivity to nonsteroidal anti-inflammatory drugs. Ann Allergy Asthma Immunol. 2002;89:542–550, quiz 550, 605. 16. Ayres JG, Miles JF. Oesophageal reflux and asthma. Eur Respir J. 1996;9: 1073–1078. 17. Boyle JT, Tuchman DN, Altschuler SM, et al. Mechanisms for the association of gastroesophageal reflux and bronchospasm. Am Rev Respir Dis. 1985;131:S16–S20. 18. Etzel RA. How environmental exposures influence the development and exacerbation of asthma. Pediatrics. 2003;112:233–239. 19. Bates DV. The effects of air pollution on children. Environ Health Perspect. 1995;103(suppl 6):49–53. 20. Millqvist E, Lowhagen O. Placebo-controlled challenges with perfume in patients with asthma-like symptoms. Allergy. 1996;51:434–439. 21. Gilmour MI, Jaakkola MS, London SJ, et al. How exposure to environmental tobacco smoke, outdoor air pollutants, and increased pollen burdens influences the incidence of asthma. Environ Health Perspect. 2006;114:627–633. 22. Venables KM, Chan-Yeung M. Occupational asthma. Lancet. 1997;349: 1465–1469. 23. Silva CI, Colby TV, Müller NL. Asthma and associated conditions: highresolution CT and pathologic findings. AJR Am J Roentgenol. 2004;183: 817–824. 24. Jeffery PK. Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit Care Med. 2001;164:S28–S38. 25. Nakano Y, Müller NL, King GG, et al. Quantitative assessment of airway remodeling using high-resolution CT. Chest. 2002;122:271S–275S. 26. Wilson JW, Li X, Pain MC. The lack of distensibility of asthmatic airways. Am Rev Respir Dis. 1993;148:806–809. 27. Carroll N, Elliot J, Morton A, James A. The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis. 1993;147: 405–410. 28. Saetta M, Di Stefano A, Rosina C, et al. Quantitative structural analysis of peripheral airways and arteries in sudden fatal asthma. Am Rev Respir Dis. 1991;143:138–143.

29. Blackie SP, al-Majed S, Staples CA, et al. Changes in total lung capacity during acute spontaneous asthma. Am Rev Respir Dis. 1990;142:79–83. 30. Collard P, Njinou B, Nejadnik B, et al. Single breath diffusing capacity for carbon monoxide in stable asthma. Chest. 1994;105:1426–1429. 31. Wagner PD, Hedenstierna G, Rodriguez-Roisin R. Gas exchange, expiratory flow obstruction and the clinical spectrum of asthma. Eur Respir J. 1996;9:1278–1282. 32. Lynch DA. Imaging of asthma and allergic bronchopulmonary mycosis. Radiol Clin North Am. 1998;36:129–142. 33. Paganin F, Trussard V, Seneterre E, et al. Chest radiography and high resolution computed tomography of the lungs in asthma. Am Rev Respir Dis. 1992;146:1084–1087. 34. Zieverink SA, Harper AP, Holden RW, et al. Emergency room radiology in asthma: an efficacy study. Radiology. 1982;145:27–29. 35. Rossi OV, Lahde S, Laitinen J, Huhti E. Contribution of chest and paranasal sinus radiographs to the management of acute asthma. Int Arch Allergy Immunol. 1994;105:96–100. 36. Sung A, Naidich D, Belinskaya I, Raoof S. The role of chest radiography and computed tomography in the diagnosis and management of asthma. Curr Opin Pulm Med. 2007;13:31–36. 37. Eesa M, Kandpal H, Sharma R, Misra A. Spontaneous pneumorrhachis in bronchial asthma. Acta Radiol. 2006;47:672–674. 38. Park CS, Müller NL, Worthy SA, et al. Airway obstruction in asthmatic and healthy individuals: inspiratory and expiratory thin-section CT findings. Radiology. 1997;203:361–367. 39. Grenier P, Mourey-Gerosa I, Benali K, et al. Abnormalities of the airways and lung parenchyma in asthmatics: CT observations in 50 patients and inter- and intraobserver variability. Eur Radiol. 1996;6:199–206. 40. Lynch DA, Newell JD, Tschomper BA, et al. Uncomplicated asthma in adults: comparison of CT appearance of the lungs in asthmatic and healthy subjects. Radiology. 1993;188:829–833. 41. Richards JC, Lynch D, Koelsch T, Dyer D. Imaging of asthma. Immunol Allergy Clin North Am. 2016;36(3):529–545. 42. Takemura M, Niimi A, Minakuchi M, et al. Bronchial dilatation in asthma: relation to clinical and sputum indices. Chest. 2004;125:1352–1358. 43. Travis WD, Colby TV, Koss MN, et al. Bronchial disorders. In: Travis WD, Colby TV, Koss MN, et al, eds. Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: Armed Forces Institute of Pathology; 2002:381–471. 44. Logan PM, Müller NL. High-attenuation mucous plugging in allergic bronchopulmonary aspergillosis. Can Assoc Radiol J. 1996;47:374–377. 45. Ward S, Heyneman L, Lee MJ, et al. Accuracy of CT in the diagnosis of allergic bronchopulmonary aspergillosis in asthmatic patients. AJR Am J Roentgenol. 1999;173:937–942. 46. Mitchell TA, Hamilos DL, Lynch DA, Newell JD. Distribution and severity of bronchiectasis in allergic bronchopulmonary aspergillosis (ABPA). J Asthma. 2000;37:65–72. 47. Dipaolo F, Stull MA. Bronchial carcinoid presenting as refractory asthma. Am Fam Physician. 1993;48:785–789. 48. Mehra PK, Woessner KM. Dyspnea, wheezing, and airways obstruction: is it asthma? Allergy Asthma Proc. 2005;26:319–322. 49. Murgu SD, Colt HG. Tracheobronchomalacia and excessive dynamic airway collapse. Respirology. 2006;11:388–406. 50. Harris RS, Winkler T, Tgavalekos N, et al. Regional pulmonary perfusion, inflation, and ventilation defects in bronchoconstricted patients with asthma. Am J Respir Crit Care Med. 2006;174:245–253. 51. Musch G, Venegas JG. Positron emission tomography imaging of regional lung function. Minerva Anestesiol. 2006;72:363–367. 52. Tgavalekos NT, Tawhai M, Harris RS, Musch G, Vidal-Melo M, Venegas JG, Lutchen KR. Identifying airways responsible for heterogeneous ventilation and mechanical dysfunction in asthma: an image functional modeling approach. J Appl Physiol. 2005;99(6):2388–2397. 53. Trivedi A, Hall C, Hoffman EA, Woods JC, Gierada DS, Castro M. Using imaging as a biomarker for asthma. J Allergy Clin Immunol. 2017;139(1):1–10. 54. Venegas JG, Schroeder T, Harris S, Winkler RT, Melo MF. The distribution of ventilation during bronchoconstriction is patchy and bimodal: a PET imaging study. Respir Physiol Neurobiol. 2005;148(1–2):57–64.

59 

Bronchiolitis* SHERIEF GARRANA  |  CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

Bronchiolitis refers to a wide variety of inflammatory and fibrotic disease processes affecting the small airways.1–3 Bronchiolitis is common and may be the primary manifestation in various clinical settings (e.g., infections, connective tissue diseases (CTDs), inhalational injuries, cigarette smoking, drug reactions, and transplantation). Bronchiolitis, however, frequently occurs in association with large airway disease and in association with parenchymal and interstitial lung disease (Table 59.1). In this chapter the discussion is limited to conditions that primarily affect the bronchioles. Bronchiolitis associated with large airway disease and with diffuse parenchymal and interstitial lung diseases, such as hypersensitivity pneumonitis and organizing pneumonia, is discussed elsewhere. Bronchiolitis is the most common form of small airways disease. Multiple classification systems have been proposed, some of which are based on the clinical features along with the presumed etiology and the pulmonary or systemic diseases with which it is associated, some on computed tomography (CT) findings and others on histologic features. Histologic classification into cellular (proliferative) or constrictive (fibrotic) bronchiolitis is valuable as it correlates most directly with the imaging features of small airways disease.2–5 Given the nonspecific nature of histologic findings, interpretation in the context of the clinical and radiologic findings is crucial.2 Therefore, in this chapter, we use a classification system based on histologic features in the clinical and radiologic contexts (Table 59.2).

Anatomic Features of the Small Airways and Secondary Pulmonary Lobule Small airways by definition are airways having a diameter of less than 2 mm.6 Those include membranous bronchioles, respiratory bronchioles, and alveolar ducts. Membranous bronchioles measure between 0.5 and 1 mm in diameter and are characterized by the absence of cartilage. They are lined by ciliated columnar epithelium and nonciliated Clara cells, surrounded by a layer of smooth muscle, which diminishes distally, and a layer of adventitia. Few goblet cells and seromucinous glands may be present. Terminal bronchioles, the final generation of membranous bronchioles, mark the end of the conducting division of airflow in the lungs and give rise to respiratory bronchioles, which are the beginning of the respiratory division where gaseous exchange occurs.2,3,6,7 Respiratory bronchioles can arise from terminal bronchioles or from other respiratory bronchioles and then branch into multiple alveolar ducts, alveolar sacs, and alveoli. An acinus is formed by a terminal bronchiole—with its first-order respiratory bronchioles, their branching alveolar *The editors and publisher would like to thank Drs. C. Isabela Silva Müller and Nestor L. Müller for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

ducts, alveolar sacs, and alveoli—and is a functional unit of the lung in which all airways participate in gas exchange. Bronchioles maintain their mechanical support, structure, and patency through a complex network of elastic fibers attaching bronchioles to each other and to neighboring alveoli. This network is particularly important for maintaining small airway patency during expiration. Collateral ventilation occurs via small accessory channels connecting various portions of the distal small airways. Canals of Lambert provide direct connections between some membranous bronchioles and adjacent alveoli, channels of Martin provide direct interbronchiolar connections, and pores of Kohn provide interalveolar connections.3,6,7 The secondary pulmonary lobule (SPL) is the smallest functioning subunit of lung. It consists of 3 to 10 acini enclosed by an interlobular septum of connective tissue and measures 1 to 2.5 cm.6,8,9 The bronchioles and their accompanying pulmonary artery branches are located near the center of SPLs, and the pulmonary veins are located in the interlobular septa. Thorough understanding of these anatomic features is imperative for accurate radiologic interpretation (Figs. 59.1 and 59.2). Normal bronchioles cannot be identified on CT because of size limitations. The smallest intralobular structures visible on CT are intralobular pulmonary arteries measuring approximately 0.2 mm in diameter, which corresponds to the tip of the terminal bronchiole and the first-generation respiratory bronchiole (Fig. 59.3).6 Therefore the centrilobular portion is recognized as an area around the tip of the visible pulmonary artery on CT.10

Imaging of Small Airways Disease Conventional radiography is often insensitive for detecting small airways disease, particularly in the early and localized phases of disease. Over the past several decades, technologic advances in CT have revolutionized imaging of the small airways. Highresolution volumetric datasets allow the generation of high-quality, multiplanar, and three-dimensional images. Low-dose volumetric expiratory high-resolution computed tomography (HRCT) is invaluable in detecting small airway obstruction.11 When used in conjunction, inspiratory and expiratory techniques provide the most reliable assessment of both the extent and severity of disease. Interpretation of characteristic radiologic findings in the appropriate clinical context is often sufficient for clinical diagnosis and initiation of treatment without biopsy confirmation, thus avoiding unnecessary invasive procedures. CT has also become a reliable, noninvasive method for assessing response to therapy without the need for repeated biopsy.6,7,11 Magnetic resonance imaging (MRI) has also undergone significant progress over the past decade with efforts to overcome the limitations of other imaging modalities. Technical advances in hardware, sequencing, and contrast media have significantly improved the quality of morphologic and functional MRI assessment of airway pathology. Although MRI utility in the evaluation 745

746

SECTION 11  Diseases of the Airways

TABLE 59.1  BRONCHIOLITIS ASSOCIATED WITH LARGE AIRWAY, PULMONARY PARENCHYMAL, AND INTERSTITIAL DISEASE Bronchiolitis Associated With Large Airways Disease

Bronchiolitis Associated With Parenchymal and Interstitial Lung Disease

Chronic bronchitis/ chronic obstructive pulmonary disease Asthma Bronchiectasis

Hypersensitivity pneumonitis Respiratory bronchiolitis–associated interstitial lung disease Desquamative interstitial pneumonia Lymphoid interstitial pneumonia Organizing pneumonia

TABLE 59.2  HISTOLOGIC CLASSIFICATION OF BRONCHIOLITIS INTO CELLULAR (PROLIFERATIVE) OR CONSTRICTIVE (FIBROTIC) BRONCHIOLITIS Cellular Bronchiolitis

Constrictive Bronchiolitis

Infectious bronchiolitis Aspiration bronchiolitis Respiratory bronchiolitis Follicular bronchiolitis Diffuse panbronchiolitis

Postinfectious Transplantation Connective tissue diseases Inhalational lung diseases Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia Miscellaneous

of small airways disease is still being researched, it has proven valuable in several other clinical settings, particularly with obstructive airway diseases, including cystic fibrosis.11 DIRECT AND INDIRECT SIGNS ON COMPUTED TOMOGRAPHY Although normal bronchioles cannot be visualized, bronchiolar diseases may result in direct and indirect signs on CT.4,12 Direct signs occur resulting from bronchiolar secretions, wall thickening, or peribronchiolar inflammation and include centrilobular nodules, branching centrilobular opacities (tree-in-bud), and occasional small centrilobular lucencies resulting from bronchiolectasis (Fig. 59.4).4,12 Centrilobular opacities can be recognized because they are centered 3 mm or more from the periphery of the secondary lobule—that is, from the interlobular septa, pleura, and large pulmonary vessels. Indirect signs include areas of decreased attenuation and vascularity (mosaic attenuation) on inspiratory CT and areas of air-trapping on expiratory CT (Fig. 59.5).4,7,12 The presence of both direct and indirect signs on CT is sensitive and specific for diagnosing small airways disease (Table 59.3).3,4,6,8 Accurate interpretation of direct and indirect signs on CT can be challenging, Indirect signs, in particular, warrant further elaboration. By definition, mosaic attenuation is an imaging pattern on inspiratory CT with differing lung attenuation as a result of variable aeration and vascular perfusion, resulting in a heterogeneous parenchymal appearance. It is associated with a broad differential diagnosis, most commonly with diseases affecting the small airways, pulmonary vasculature, alveoli, and interstitium, alone or in combination.7 Parenchymal lung disease is the most common cause of mosaic attenuation, seen in approximately 50% of cases, followed by small airways disease constituting nearly 33% of cases.7,13,14 Mild mosaic attenuation can be seen in up to 20% of normal patients. Parenchymal

A

B Fig. 59.1  Normal pulmonary lobule: anatomy of the bronchioles and secondary pulmonary lobules (SPLs). (A) Radiograph of a 1-mm-thick lung slice shows interlobular septa (straight arrows) marginating the SPLs. The lobular and terminal bronchioles (curved arrows) and adjacent pulmonary arteries can be seen to course near the center of the pulmonary lobule. (B) Radiograph of specimen with bronchioles filled with barium shows the pattern of centrilobular branching lines and nodular opacities that can be expected from bronchiolar and peribronchiolar inflammation. The bronchioles and alveolar ducts are located a few millimeters away from the pleural surface and interlobular septa (arrows). (Courtesy Dr. Harumi Itoh, Department of Radiology, Fukui Medical University, Fukui, Japan. From Müller NL, Fraser RS, Colman NC, Paré PD. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

TABLE 59.3  DIRECT AND INDIRECT COMPUTED TOMOGRAPHY MANIFESTATIONS OF SMALL AIRWAYS DISEASE Direct Signs

Indirect Signs

Centrilobular nodules (solid and/ or ground-glass attenuation) Tree-in-bud opacities Bronchiolectasis

Mosaic attenuation (inspiratory CT) Air-trapping (expiratory CT)

CT, Computed tomography.

heterogeneity is gradient dependent, with the more dependent portions of the lung being of slightly higher attenuation. Perfusion heterogeneity, with increased perfusion and attenuation more centrally than peripherally, may also be seen.7,15,16 Concurrent expiratory imaging for evaluation of air-trapping is the best method for differentiating between the different causes of mosaic attenuation. In a normal expiratory CT, lung attenuation

59  Bronchiolitis

747

A Bronchiole Pulmonary vein

Interlobular septa

B

Artery

Fig. 59.3  Normal lobules and vessels on high-resolution CT (HRCT). HRCT shows normal interlobular septa (curved arrows). Two pulmonary veins (arrowheads) can be seen as focal opacities within interlobular septa in the right middle lobe. The nodular opacity (straight arrows) in the center of the lobule corresponds to the lobular artery. The adjacent lobular bronchiole is not seen because its wall is too thin to be identified on CT.

Interlobular septa Visceral pleura

Fig. 59.2  Normal pulmonary lobule. (A) Lung specimen shows secondary lobule surrounded by connective tissue septa (arrowheads). The lobular bronchiole and pulmonary artery (curved arrow) are located in the center of the lobule, and the draining pulmonary veins (straight arrows) are located in the interlobular septa. (B) Schematic representation shows normal anatomy of two adjacent pulmonary lobules. (A, Courtesy Dr. Reynaldo T. Rodrigues, Federal University of São Paulo, São Paulo, Brazil.)

increases as the proportion of air to tissue decreases with expiration of air. The Fleischner Society defines air-trapping as “parenchymal areas with less than normal increase in attenuation and lack of volume reduction” as seen on end expiration CT scans (see Fig. 59.5B).17 These areas appear as polygonal regions of low attenuation adjacent to areas of lung that have the normal increased attenuation with expiration. A simple measure of the degree of air-trapping is subdivision into mild (25%), moderate (25%–50%), and severe (50%) air-trapping, based on a subjective estimation of the total lung volume of air-trapped lung.18 If air-trapping is present on expiratory CT with concurrent mosaic attenuation on inspiratory CT, then small airways disease is the most likely culprit, with the hyperlucent foci representing the diseased portions of the lung (Fig. 59.6).7 In fact, small airways disease is the most common cause of mosaic attenuation where the hyperlucent lung is the abnormal finding. As with inspiratory imaging, a similar physiologic gradient of parenchymal

Fig. 59.4  Direct signs of bronchiolitis in a patient with recurrent infection. Axial CT shows several direct signs of small airways disease with centrilobular nodules, tree-in-bud opacities, and peripheral centrilobular lucencies consistent with bronchiolectasis. Cylindrical bronchiectasis is also noted more centrally.

heterogeneity is seen on expiratory imaging. Additionally, areas of lobular air-trapping can be seen in 40% to 80% of normal patients on CT. Several studies have shown mild, moderate, and sometimes even extensive air-trapping in individuals with normal pulmonary function tests.19,20 The specific clinicopathologic forms of bronchiolitis are discussed in the following sections.

748

SECTION 11  Diseases of the Airways

A

B Fig. 59.5  Indirect signs in a patient with constrictive bronchiolitis. (A) Image acquired at full inspiration, as indicated by the cylindrical tracheal contour, demonstrates a heterogeneous parenchymal appearance (mosaic attenuation pattern) with decreased vascular caliber peripherally in the hypoattenuated lung. (B) Concurrent expiratory phase imaging shows exaggerated segmental hypoattenuation in the dependent portions of the lung, consistent with air-trapping.

A

B Fig. 59.6  Indirect signs of constrictive bronchiolitis in hematopoietic stem cell transplantation. (A) Inspiratory CT acquired just above the carina demonstrates relatively normal appearance to the lung parenchyma. (B) Expiratory CT demonstrates widespread low attenuation within the lungs and small vascular caliber within the hypoattenuated lung, consistent with air-trapping and hypoxic oligemia.

KEY POINTS: COMPUTED TOMOGRAPHY FINDINGS OF BRONCHIOLITIS • Direct signs • Cause: bronchiolar secretions, bronchiolar wall thickening, peribronchiolar inflammation • Manifestation: centrilobular nodules, tree-in-bud opacities, bronchiolectasis • Indirect signs • Cause: small airway obstruction • Manifestations: mosaic attenuation on inspiratory CT, air-trapping on expiratory CT

syncytial virus), followed by Mycoplasma pneumonia. Less common etiologies include Chlamydia, bacteria, and fungi, particularly Aspergillus in immunocompromised patients.12,21,22

INFECTIOUS BRONCHIOLITIS

Clinical Presentation Infants and young children usually present with symptoms of an upper respiratory tract infection, followed by dyspnea, tachypnea, and fever approximately 2 to 3 days later; cyanosis and extreme weakness may be seen in severe cases. Adults are probably infected with respiratory viral infections as often as infants are; however, the severity and consequences of infection in otherwise healthy individuals are usually much less, likely because their small airways contribute less to total pulmonary resistance.23 Nonetheless, severe and sometimes fatal disease can occur.

Etiology Acute infectious bronchiolitis is most common and severe in children, most often caused by viruses (e.g., adenovirus, respiratory

Pathophysiology Histologically, inflammatory cells (mainly neutrophils) are present within the airway walls and in inflammatory exudate and mucus

Cellular Bronchiolitis

59  Bronchiolitis

in the airway lumens (Fig. 59.7).12 These findings account for the direct signs on CT.12 Bronchiolar epithelial necrosis may occur in severe cases.24 Biopsy is rarely required for diagnosis. Manifestations of the Disease Radiography.  Conventional radiography in infants and children may demonstrate bronchial wall thickening (peribronchial cuffing) and peribronchial (central) areas of consolidation.25 Other findings include hyperinflation (caused by partial small airway obstruction)

749

and patchy bilateral consolidations (indicating progression to bronchopneumonia).26 In adults findings are often subtle, manifesting as multifocal nodular or reticulonodular opacities. As with children, progression to bronchopneumonia results in patchy bilateral consolidations (Fig. 59.8).27,28 Computed Tomography/High-Resolution Computed Tomography.  Characteristic CT findings include small well-defined centrilobular nodules and tree-in-bud opacities, which can be patchy and unilateral or asymmetric and bilateral. While tree-in-bud opacities, in particular, are highly suggestive of endobronchial spread of small airways infection, they can also been seen with noninfectious etiologies (e.g., aspiration, cystic fibrosis, follicular bronchiolitis).29–31 Progression to bronchopneumonia results in 5- to 10-mm-diameter airspace nodules and patchy lobular, subsegmental, or segmental ground-glass opacities and consolidations (Fig. 59.9). Differential Diagnosis Similar histologic and CT findings may be seen with aspiration or with CTDs, inflammatory bowel disease, and allergic bronchopulmonary aspergillosis.2,10,29,30,32–34 Acute infectious and/or aspiration bronchiolitis (AB) frequently occur in the setting of preexisting bronchiectasis.2 ASPIRATION BRONCHIOLITIS

Fig. 59.7  Infectious bronchiolitis: histologic findings. Low-power view shows severe bronchiolitis with an intense lymphoplasmacytic infiltrate in the bronchiolar wall and around the airway. The bronchiolar lumen (arrows) contains neutrophils. (Courtesy Dr. Andrew Churg, Department of Pathology, University of British Columbia, Vancouver, Canada.)

A

Etiology, Prevalence, and Epidemiology AB refers to chronic inflammation of the bronchioles secondary to chronic and recurrent aspiration of gastric and other foreign material. The disease primarily affects individuals with oropharyngeal dysphagia and other patients at high risk for aspiration (elderly, neurologic disorders, dementia). AB may also manifest acutely in certain clinical scenarios, such as in patients presenting

B Fig. 59.8  Chest radiograph findings in an adult with respiratory syncytial virus infectious bronchiolitis. (A) Coned posteroanterior and (B) lateral chest radiographs show bilateral multifocal hazy and reticulonodular opacities and peribronchial cuffing.

750

SECTION 11  Diseases of the Airways

with drug overdose–related respiratory depression, acute trauma, or altered mental status resulting from strokes or seizures.3,35 Clinical Presentation Patients usually present with signs of persistent airway disease, such as increased secretions and sputum production, productive cough, wheezing, and dyspnea, all of which are exacerbated by oral intake.32,35 Pathophysiology Histologic findings are very similar to infectious bronchiolitis, with bronchial and bronchiolar inflammation, bronchial wall thickening, and inflammatory exudate and mucus in the airway lumens. A

Manifestations of the Disease Radiography.  Conventional radiographic findings are nonspecific and manifest as unilateral or bilateral small nodular and/or patchy opacities with or without lung hyperinflation (Fig. 59.10). Computed Tomography/High-Resolution Computed Tomography.  As with infectious bronchiolitis, diffuse small centrilobular nodules and tree-in-bud opacities are present, which can be patchy and unilateral or asymmetric and bilateral. Patchy lobular consolidations are often present and frequently progress to confluent segmental or lobar consolidations. A distinguishing feature of aspiration is the pattern of distribution within the lungs, which is dependent on patient positioning at time of aspiration. Bedridden patients who remain in a supine position will often present with disease affecting the posterior dependent segments of the upper and lower lobes, hospitalized patients who remain in a midline semiupright position will present with lower lobe–predominant disease, and patients who spend most of their time lying on their right or left side will present with disease involving the right-dependent lung or left-dependent lung, respectively (see Fig. 59.10).3,22,32 KEY POINTS: ASPIRATION BRONCHIOLITIS

B Fig. 59.9  CT findings in respiratory syncytial virus bronchiolitis. (A) Axial CT shows multifocal bilateral centrilobular nodules, tree-in-bud opacities, and a few patchy areas of ground-glass opacity. (B) Coronal CT better demonstrates the diffuse distribution of the disease process, with coalescing upper lobe lobular ground-glass opacities, consistent with developing bronchopneumonia.

KEY POINTS: INFECTIOUS BRONCHIOLITIS • Etiology • Viruses, Mycoplasma, bacteria (early bronchopneumonia), and fungi (particularly Aspergillus) • Symptoms • Often severe in infants; usually mild in adults • Radiographic findings • Children: peribronchial cuffing, hyperinflation • Adults: bilateral nodular/reticulonodular opacities • Patchy bilateral consolidations indicating bronchopneumonia • Computed tomography/high-resolution computed tomography • Centrilobular nodules, tree-in-bud opacities, patchy ground-glass opacities, or consolidations • Tree-in-bud opacities highly suggestive of small airways infection

• Etiology • Aspiration of gastric and/or other foreign material • Symptoms • Persistent airway disease and productive cough exacerbated by oral intake • Radiographic findings • Unilateral or bilateral nodular or patchy opacities, +/− hyperinflation • Frequent patchy bilateral consolidations indicating bronchopneumonia • Computed tomography/high-resolution computed tomography • Centrilobular nodules, tree-in-bud opacities, patchy ground-glass opacities or consolidations • Distribution dependent on patient positioning at time of aspiration

RESPIRATORY BRONCHIOLITIS Etiology, Prevalence, Epidemiology, and Clinical Presentation Respiratory bronchiolitis (RB) is predominantly a smoking-related entity, which can occur rarely in nonsmokers or with other inhalational exposures, such as asbestos, nonasbestos dusts, and various fumes.36 RB is present histologically in virtually all smokers and by definition is not associated with symptoms or functional

59  Bronchiolitis

751

B

A

Fig. 59.10  Aspiration pneumonia: radiographic and CT findings. (A) Frontal radiograph shows left greater than right middle– and lower lung zone–predominant consolidations and reticulonodular opacities. (B) Axial CT confirms the radiographic findings, showing bilateral centrilobular nodules, tree-in-bud opacities, patchy ground-glass opacities, and left lower lobe nodular opacities. (C) Coronal CT demonstrates the positional-dependent distribution, with nodular opacities developing predominantly in the dependent posterior and lateral basal segments of the lower lobes, a characteristic finding frequently seen with aspiration pneumonia.

impairment. When involvement is symptomatic or leads to functional decline, the process is referred to as RB-associated interstitial lung disease, discussed separately in further detail (see Chapter 34).37 Pathophysiology RB is characterized histologically by intraluminal and peribronchiolar accumulation of macrophages that contain a finely granular yellow-brown cytoplasmic pigment referred to as smoker’s macrophages (Fig. 59.11).37–39 Other common findings include chronic peribronchiolar mononuclear cell infiltration, mild inflammation, airspace enlargement with fibrosis, and diffuse hyaline-like acellular fibrotic thickening of alveolar septa.8,21,40 The intensity of macrophage pigmentation and peribronchiolar fibrosis correlates with the number of pack-years smoked.38 Emphysema is almost always present.37 Manifestations of the Disease Radiography.  RB rarely results in any demonstrable abnormality on chest radiography. Subtle upper lung zone–predominant

C

lucencies (representing emphysema), peribronchial cuffing, and small poorly defined nodular or patchy opacities may be present in some patients. Computed Tomography/High-Resolution Computed Tomography.  CT is usually normal or may show mild centrilobular and/ or paraseptal emphysema.41 When present, findings include small, multifocal, poorly defined ground-glass centrilobular nodules; patchy ground-glass opacities; and mosaic attenuation (Fig. 59.12).42,43 Findings most commonly are upper lung zone predominant, however, and may be diffuse in some patients. Several studies have shown that smoking cessation does not always lead to complete resolution of the radiologic and pathologic features of RB, with the extent of disease often remaining similar among current smokers and ex-smokers, even years after smoking cessation.36,38,42,43 Differential Diagnosis The differential diagnosis for RB on CT includes hypersensitivity pneumonitis (HP), follicular bronchiolitis (FB), infectious bronchiolitis, cholesterol granulomas, pulmonary capillary

752

SECTION 11  Diseases of the Airways

A

B Fig. 59.11  Respiratory bronchiolitis: histologic findings. (A) Histologic specimen shows peribronchiolar airspace clusters of pigmented (smoker’s) macrophages. The appearance is characteristic of respiratory bronchiolitis. (B) Magnified view better demonstrates the typical appearance of the pigmented macrophages. (Courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Vancouver, Canada.)

hemangiomatosis, and occasionally pneumoconioses.8,9 Significant radiologic overlap may be seen with cases of RB and the subacute inflammatory phase of HP, which includes centrilobular groundglass nodules, patchy ground-glass opacities, and mosaic attenuation on inspiratory CT. Although CT manifestations may be diffuse in both conditions, RB tends to produce a more upper lung zone–predominant pattern when compared with HP. Conversely, focal/lobular air-trapping is more commonly seen with HP on expiratory CT.8,44 Thus an upper lung zone– predominant or diffuse imaging pattern with concurrent findings of emphysema favors the diagnosis of RB, although diffuse parenchymal involvement with areas of lobular air-trapping favors subacute HP. However, as RB and HP are clinically and histologically distinct entities, a multidisciplinary approach integrating clinical history, histology, and imaging findings is imperative for accurate diagnosis. Recent studies have shown that the combination of smoking history, typical CT findings, and lack of lymphocytosis on bronchoalveolar lavage is highly suggestive of RB.8,45 Furthermore, cigarette smoking has been shown to have a protective effect against the development of HP. For example, in a study of 400 consecutive patients with various interstitial lung diseases, only 6% of 116 patients with a final diagnosis of hypersensitivity pneumonitis were smokers, compared with 20% of the 284 remaining patients.46 Cholesterol granulomas and pulmonary capillary hemangiomatosis are two entities seen in the setting of pulmonary hypertension that may also manifest with centrilobular ground-glass nodules. Of importance, these entities should be considered when centrilobular ground-glass nodules are seen in conjunction with known pulmonary hypertension or an enlarged pulmonary trunk on CT. PULMONARY LYMPHOID HYPERPLASIA (FOLLICULAR BRONCHIOLITIS) Etiology Pulmonary lymphoid hyperplasia or FB is characterized by peribronchial and peribronchiolar inflammation secondary to the abundance of lymphoid follicles.47 Several clinical conditions

KEY POINTS: RESPIRATORY BRONCHIOLITIS • Etiology/definition • Accumulation of pigmented macrophages in the lumen of respiratory bronchioles and adjacent alveoli • Almost always associated with smoking • Symptoms • By definition, not associated with symptoms or functional impairment • Radiographic findings: usually normal • Computed tomography/high-resolution tomography • Often normal or showing only emphysema • Poorly defined centrilobular nodules, patchy bilateral ground-glass opacities, predominantly in the upper lobes or diffuse

are associated with FB, which are identical to those seen with lymphoid interstitial pneumonia, most commonly in association with CTDs (particularly rheumatoid arthritis [RA] and Sjögren syndrome), immunologic disorders (Hashimoto thyroiditis, pernicious anemia, autoimmune hemolytic anemia, chronic active hepatitis, primary biliary cirrhosis, and myasthenia gravis), congenital or acquired immunodeficiency diseases (common variable immunodeficiency, human immunodeficiency virus/ acquired immune deficiency syndrome), systemic hypersensitivity reactions, infection, allergy (including asthma), bone marrow transplantation, and as a reactive process distal to bronchiectasis or in association with middle lobe syndrome.3,47–49 Clinical Presentation FB occurs most frequently among middle-aged adults, presenting with progressive dyspnea and cough. Less common symptoms include fever, weight loss, and recurrent pneumonia. Pulmonary function tests may reveal an obstructive, restrictive, or mixed pattern. FB may occasionally be seen in children. Pathophysiology FB is characterized histologically by the presence of abundant lymphoid follicles in bronchiolar walls and, to some extent, along

59  Bronchiolitis

A

C

bronchi, interlobular septa, and pleura.47 Obstructive pneumonia may sometimes occur as a result of airway compression.49 Manifestations of the Disease Radiography.  FB findings on radiography tend to be subtle, and in many cases the chest radiograph may be normal. When findings are present, they usually manifest as bilateral reticular or reticulonodular opacities (Fig. 59.13).3,22,47 Computed Tomography/High-Resolution Computed Tomography.  Typical FB results in small diffuse and poorly defined centrilobular nodules. Other less common and variable findings include peribronchial and subpleural nodules, patchy ground-glass opacities, bronchial wall thickening, and mosaic attenuation.

753

B

Fig. 59.12  Respiratory bronchiolitis in a smoker. (A) Axial CT shows diffuse poorly defined centrilobular nodules and bronchial wall thickening. (B) Coronal and (C) sagittal CT show mild apical emphysema and small patchy ground-glass opacities in addition to the findings seen on the axial image.

Expiratory CT may show lobular areas of air-trapping. In one study CT showed bilateral centrilobular nodules (100%), patchy ground-glass opacities (75%), peribronchial nodules (42%), and subpleural nodules (25%) (see Fig. 59.13).3,50 DIFFUSE PANBRONCHIOLITIS Etiology, Prevalence, and Epidemiology Diffuse panbronchiolitis is a progressive form of cellular bronchiolitis associated with chronic inflammation of the respiratory bronchioles and paranasal sinuses.51 Etiology and pathogenesis remain unknown; however, the disease has been recognized almost exclusively in Asia, particularly in Japan. This distribution is

754

SECTION 11  Diseases of the Airways

B A

Fig. 59.13  Follicular bronchiolitis in a patient with long-standing rheumatoid arthritis. (A) Frontal radiograph shows diffuse bilateral reticulonodular opacities. (B) Axial CT shows bilateral poorly defined centrilobular nodules, tree-in-bud and patchy ground-glass opacities, and bronchial wall thickening. (C) Coronal CT demonstrates the diffuse nature of the disease process and additionally shows a right lower lobe subpleural nodule. Mosaic attenuation is also better appreciated on the coronal image.

C

KEY POINTS: PULMONARY LYMPHOID HYPERPLASIA (FOLLICULAR BRONCHIOLITIS) • Etiology • Peribronchial and peribronchiolar inflammation resulting from abundance of lymphoid follicles • Associated with multiple clinical conditions: CTDs, most commonly rheumatoid arthritis, immunologic disorders, immunodeficiency, systemic hypersensitivity, infection, hematopoietic stem cell transplantation • Symptoms • Progressive dyspnea and cough • Less commonly, fever, weight loss, recurrent pneumonia

• Radiographic findings • Often normal • Bilateral nodular or reticulonodular opacities • Computed tomography/high-resolution tomography • Poorly defined small bilateral centrilobular nodules • Patchy bilateral ground-glass opacities • Peribronchial nodules/bronchial wall thickening • Subpleural nodules • Mosaic attenuation on inspiratory CT; lobular air-trapping on expiratory CT

59  Bronchiolitis

believed to be highly associated with genetic predisposition located between human leukocyte antigens A and B loci.52 The average age of onset is approximately 40 years; male-to-female ratio is approximately 2 : 1.53 Clinical Presentation Diffuse panbronchiolitis manifests insidiously with productive cough and progressive dyspnea, worse on exertion. Features of chronic sinusitis are also typical. Pseudomonas aeruginosa frequently colonizes the respiratory tract of affected individuals. Pulmonary function tests reveal a marked obstructive and mild restrictive pattern.22,54 Pathophysiology Histologically, mononuclear inflammatory cells (predominantly lymphocytes, plasma cells, and foamy histiocytes) are found within the walls of respiratory bronchioles, alveolar ducts, and, to a lesser extent, adjacent alveoli.55 Mucus and aggregates of neutrophils may be seen within the airway lumen. The late stage of the disease is frequently complicated by Pseudomonas aeruginosa colonization, which is associated with a significantly worse prognosis. In one study the 10-year survival rate for those infected

A

755

with the organism was only 12%, compared with 73% for those who remained uninfected.56 Manifestations of the Disease Radiography.  Chest radiography may show small diffuse nodular or reticulonodular opacities, peribronchial cuffing, and mild to moderate hyperinflation. Computed Tomography/High-Resolution Computed Tomography.  CT often shows diffuse small centrilobular nodules, tree-in-bud opacities, mosaic attenuation, bronchiolectasis, and bronchiectasis.57 The presence of these findings correlates to the stage of the disease; the earliest manifestation consists of centrilobular nodules, followed by tree-in-bud opacities, bronchiolectasis, and eventually bronchiectasis. Cystic bronchiectasis may be seen in the late stage (Fig. 59.14).58 Treatment Options The majority of patients respond to low-dose macrolide therapy (erythromycin, clarithromycin).59 The beneficial effect of macrolides has been well established and is related to their antiinflammatory activity and is independent of their bactericidal effect.60

B Fig. 59.14  Diffuse panbronchiolitis: high-resolution CT findings. (A) View of the left upper lobe from a high-resolution CT scan shows extensive areas of decreased attenuation and vascularity, mild bronchiectasis, and a few centrilobular nodules and branching opacities. (B) View of the left lung at the level of the inferior pulmonary vein shows varicose and cystic bronchiectasis in the left lower lobe and lingula. Also noted is diffuse decreased attenuation and vascularity in the lingula. (Courtesy Dr. Noriyuki Tomiyama, Department of Radiology, Osaka University Graduate School of Medicine, Osaka, Japan.)

756

SECTION 11  Diseases of the Airways

KEY POINTS: DIFFUSE PANBRONCHIOLITIS • Etiology • Unknown etiology • Characterized by accumulation of foamy macrophages in the walls of respiratory bronchioles and alveolar ducts • Occurs almost exclusively in Asia, particularly in Japan • Average age at onset is approximately 40 years; 2 : 1 male-to-female ratio • Symptoms • Cough and progressive dyspnea • Chronic sinusitis • Radiographic findings • Small diffuse nodules or reticulonodular opacities • Mild to moderate hyperinflation • Computed tomography/high-resolution computed tomography • Diffuse small centrilobular nodules • Tree-in-bud opacities • Mosaic attenuation on inspiratory CT • Bronchiolectasis • Bronchiectasis

respiratory tract infection.3 Additional associated symptoms may include chest pain, respiratory distress, and cyanosis. The disease is usually chronic and insidious; however, in rare cases, rapid progression may occur.2,3 In many cases CB is first detected on CT in asymptomatic patients or patients with symptoms secondary to associated conditions, such as bronchiectasis or asthma. PATHOPHYSIOLOGY Characteristic histologic findings include submucosal accumulation of mucopolysaccharide proteins and submucosal and peribronchiolar fibrosis (Fig. 59.15).2,36 The fibrosis surrounds rather than fills the airway lumen, resulting in extrinsic compression and eventually complete obliteration of the bronchiolar lumen. The areas of bronchiolar fibrosis are typically patchy,

BOX 59.1  SPECIFIC ETIOLOGIES ASSOCIATED WITH CONSTRICTIVE BRONCHIOLITIS

Constrictive Bronchiolitis

• Postinfectious • Viruses (e.g., adenovirus, respiratory syncytial virus, influenza, parainfluenza) • Mycoplasma • Connective tissue diseases (e.g., rheumatoid arthritis, Sjögren syndrome) • Transplant • Lung transplant • Heart-lung transplant • Bone marrow transplant • Inhalational lung diseases (e.g., nitrous oxide, nitrous dioxide, sulfur dioxide, ammonia, chlorine, phosgene, hot air) • Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia • Inflammatory bowel disease • Paraneoplastic autoimmune multiorgan syndrome • Drugs (e.g., penicillamine, gold, cocaine, lomustine) • Idiopathic

ETIOLOGY, PREVALENCE, AND EPIDEMIOLOGY Constrictive bronchiolitis (CB), also known as obliterative bronchiolitis or bronchiolitis obliterans, is characterized by peribronchiolar fibrosis, resulting in narrowing or obliteration of the bronchiolar lumen.2,36 Various pulmonary and systemic conditions have been linked to CB, most commonly CTDs, postinfectious diseases, and transplantation.60–62 Rarely, the cause may be idiopathic (Box 59.1).3 CLINICAL PRESENTATION Patients typically present with a chronic dry cough and progressive dyspnea. Symptoms may first become apparent after a lower

A

B Fig. 59.15  Constrictive bronchiolitis: histologic findings in two patients. (A) Histologic specimen (Movat pentachrome stain) shows narrowing of the bronchiole caused by deposition of acid mucopolysaccharide ground substance proteins (straight arrows) in the lamina propria and mild peribronchiolar fibrosis (curved arrows). (B) Histologic specimen (hematoxylin-eosin stain) demonstrates complete obliteration of the bronchiolar lumen (arrow) by eosinophilic fibrosis. Also noted are lymphoid aggregates surrounding the obliterated airway, suggestive of connective tissue disease. (Courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Vancouver, Canada.)

59  Bronchiolitis

757

even in severely affected patients, and therefore the diagnosis can be missed if lesions are inadequately biopsied.60 MANIFESTATIONS OF THE DISEASE Radiography The chest radiograph is often normal in patients with mild to moderate disease. When findings are present, they primarily manifest as hyperinflation and peripheral attenuation/decrease of vascular markings (Fig. 59.16). Additional findings may also include peribronchial cuffing, bronchiectasis, and nodular or reticulonodular opacities.63–65 Computed Tomography/High-Resolution Computed Tomography The main manifestation of CB is mosaic attenuation on inspiratory CT with concurrent moderate to severe air-trapping on expiratory CT in 40% to 80% of patients.14,66 Several studies have shown that the end-expiratory CT finding of air-trapping has a higher sensitivity for detecting constrictive bronchiolitis, as inspiratory CT findings may be subtle and easily missed (Fig. 59.17).67–69 Contrast between normal and abnormal lung may be enhanced by using CT postprocessing techniques, such as minimum-intensity projection reconstructions, which are particularly useful when clinical suspicion for CB is high and CT findings appear normal (Fig. 59.18).70,71 Additional findings include central and peripheral bronchiectasis, bronchiolectasis, and bronchial wall thickening, seen in 20% to 90% of patients (Fig. 59.19).14,62,72 Small centrilobular nodules and tree-in-bud opacities representing thick-walled bronchioles with or without intraluminal debris may occasionally be seen.66,73 The extent of air-trapping must be taken into consideration when interpreting expiratory CT. As discussed earlier, a simple measure of the degree of air-trapping is subdivision into mild (50%) air-trapping based on a subjective estimation of the total lung volume of air-trapped lung.18 Air-trapping is frequently seen in asymptomatic subjects with normal pulmonary function, particularly in elderly patients and smokers.15,74 Lobular air-trapping involving fewer than three adjacent SPLs can be seen in 40% to 80% of normal patients on CT, and several studies have shown mild, moderate, and sometimes even extensive air-trapping in individuals with normal pulmonary function tests.19,20 Integrating inspiratory and expiratory CT findings provides the highest sensitivity and specificity for a diagnosis of CB.

A

DIFFERENTIAL DIAGNOSIS A presumptive diagnosis of CB can often be made with a high degree of confidence by using a multidisciplinary approach, combining clinical history (including pulmonary function testing), histology (when available), and typical CT/HRCT findings. Other causes of chronic airway obstruction with similar imaging findings to CB, including emphysema, chronic bronchitis, asthma, and hypersensitivity pneumonitis, must be excluded before a presumptive diagnosis of CB is made. When abnormal air-trapping is present on expiratory CT, indicating obstructive airway pathology, both bronchial dilation and mosaic attenuation on inspiratory CT have been shown to be sensitive and specific findings in identifying CB and differentiating it from other diseases that cause airway obstruction.66,75 Mosaic attenuation occurring as an indirect sign of small airways

B Fig. 59.16  Radiographic findings of constrictive bronchiolitis associated with bilateral lung transplantation. (A) Posteroanterior chest radiograph shows hyperinflation and marked attenuation of the peripheral vascular markings. (B) Lateral view demonstrates an increased retrosternal clear space.

758

SECTION 11  Diseases of the Airways

A

B Fig. 59.17  CT findings of constrictive bronchiolitis in a hematopoietic stem cell transplant recipient. (A) Inspiratory CT shows subtle bilateral areas of decreased attenuation and perfusion, resulting in parenchymal heterogeneity, which could be easily missed. (B) Expiratory CT shows extensive bilateral air-trapping.

transbronchial biopsy specimens are obtained.79 Even on surgical biopsy specimens, subtle changes or completely scarred bronchioles may be missed on routine hematoxylin-eosin stains.80 Optimal assessment requires the use of elastic tissue stains.80 TREATMENT OPTIONS CB is essentially irreversible.61 Corticosteroids and immunosuppressive medications may slow disease progression in some cases.61 Lung transplantation or lung volume reduction surgery is sometimes considered for patients with persistent severe obstructive symptoms and impairment in lung function.81

Specific Causes of, and Underlying Diseases Associated With, Constrictive Bronchiolitis INFECTION

Fig. 59.18  Postprocessing technique to better demonstrate mosaic attenuation. Coronal CT minimum-intensity projection image clearly demonstrates diffuse mosaic attenuation, with well-demarcated areas of low attenuation, corresponding to air-trapping and hypoperfusion in the diseased portions of lung.

disease can usually be differentiated from vascular causes, such as chronic pulmonary thromboembolism, by the presence of bronchial dilatation and the lack of enlargement of the pulmonary trunk (main pulmonary artery).7,76 However, bronchial dilatation may also occur in patients with chronic pulmonary thromboembolism,7,77 and there are no reliable differentiating features between mosaic attenuation resulting from CB or from other small airways diseases. Furthermore, air-trapping can also be seen in up to 60% of patients with acute or chronic pulmonary thromboembolism.78 Lung biopsy is required for a definitive diagnosis of CB. Patchy disease distribution results in frequent misdiagnosis when

Childhood infection is a uncommon cause of constrictive bronchiolitis, usually occurring in children younger than 8 years.3,82 Typical infections are viral, particularly after adenovirus infection (Fig. 59.20).62,83,84 Mycoplasma pneumoniae, and rarely measles, have also been implicated.21,85 An estimated 1% of patients with acute viral bronchiolitis develop CB.86 The condition usually does not become apparent until adulthood, and patients are usually asymptomatic or have mild to moderate clinical findings. Some patients may develop features of Swyer-James-MacLeod (SJM) syndrome (discussed in further detail later in this chapter). CB may also be seen in patients with cystic fibrosis, likely sequelae of recurrent pulmonary infection.3,12 Overall, the majority of patients have a good prognosis; however, severe and sometimes fatal disease may occur.62,87–89 TRANSPLANTATION Lung and Heart-Lung Transplantation CB is the leading cause of morbidity and mortality in patients with lung and heart-lung transplantation (Fig. 59.21). It is a late complication, occurring at least 3 months after transplantation (median, 16–20 months), and is considered a manifestation of

59  Bronchiolitis

A

759

B Fig. 59.19  CT findings of constrictive bronchiolitis in a stem cell transplant patient. (A) Inspiratory CT shows subtle bilateral mosaic attenuation and central bronchial wall thickening. (B) Expiratory CT shows extensive bilateral air-trapping.

A

B Fig. 59.20  Postinfectious constrictive bronchiolitis after severe childhood viral infection during infancy. (A) High-resolution CT (HRCT) image at the level of left main bronchus shows extensive bilateral areas of decreased attenuation and vascularity with blood flow redistribution (mosaic attenuation). (B) HRCT image at the level of the lung bases shows areas of decreased attenuation and vascularity mainly in the right middle and left lower lobes. Also note left lower lobe bronchiectasis.

chronic allograft dysfunction or chronic rejection.3,90–92 The prevalence of CB after lung transplantation is approximately 20% at 1 year and 50% at 3 to 5 years, with a reported 5-year survival of approximately 30% to 40% after disease onset.90,93–96 Acute rejection is the most important risk factor, especially when severe and/or recurrent.3,91,92 Infection, especially cytomegalovirus pneumonia, is also a common risk factor.97 The International Society for Heart and Lung Transplantation has established the concept of bronchiolitis obliterans syndrome (BOS) and a staging system based on deterioration of pulmonary function, to quantify the severity of airflow obstruction.98 A clinical diagnosis of BOS requires a decline of 20% or more in FEV1 during the posttransplant period, after other causes of graft dysfunction have been excluded (Table 59.4). The category of potential BOS, or

stage BOS 0-p, remains controversial regarding its prognostic utility.92,99 Air-trapping on expiratory CT is the most sensitive and accurate radiologic indicator of CB after transplantation; however, it has been shown to be relatively insensitive in the diagnosis of early CB and detecting early-stage BOS.14,19,67,99–102 The severity of CT findings, such as bronchial dilatation, bronchial wall thickening, mosaic attenuation, and air-trapping, have only been shown to have a weak correlation with BOS severity.3,103 Hematopoietic Stem Cell Transplantation CB is the most common noninfectious late pulmonary complication of hematopoietic stem cell transplantation, with a prevalence of approximately 5% and typically developing more than 100 days

760

SECTION 11  Diseases of the Airways

(median, 400–450 days) after transplantation (Fig. 59.22).90,91,104,105 CB is more commonly reported in cases of allogeneic transplantation; however, it has also been reported in patients who received autologous transplants. The prevalence in allogeneic hematopoietic stem cell transplant patients is approximately 9%, with some studies reporting values up to 48%. Reported 5-year survival ranges between 10% and 27% after disease onset.91 The pathogenesis is thought to be secondary to the graft-versus-host effect.90 Major risk factors include old age, chronic graft-versus-host disease, and methotrexate therapy.3,91 CT findings are identical to CB seen with lung and heart-lung transplant recipients.

Less commonly, CB may be seen with Sjögren syndrome,108 systemic lupus erythematosus,109 scleroderma (systemic sclerosis),7,110–112 and mixed CTD.7 CB in association with CTD varies in severity and natural course, with most patients showing slow progression of disease. CB is rarely the sole manifestation of RA.34,106,107,113 Penicillamine therapy and, less commonly, gold therapy have been implicated as potential causative agents of CB in some patients with RA.113–115 DIFFUSE NEUROENDOCRINE CELL HYPERPLASIA, CARCINOID TUMORLETS, AND CARCINOID TUMORS

CONNECTIVE TISSUE DISEASES

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is an increasingly recognized condition characterized by extensive proliferation of neuroendocrine cells as clusters or linear arrays of cells along the bronchial and bronchiolar basement membrane.116 Approximately 50% of patients with DIPNECH and multiple pulmonary carcinoid tumorlets may develop

CTDs as a group are considered the most common cause of CB and most frequently seen with RA, usually affecting women in their fifth or sixth decade of life, and with long-standing disease.106,107

TABLE 59.4  BRONCHIOLITIS OBLITERANS SYNDROME STAGING SYSTEM BASED ON DETERIORATION OF PULMONARY FUNCTION BOS Stage BOS 0 BOS 0-p BOS 1 BOS 2 BOS 3

Fig. 59.21  Constrictive bronchiolitis after lung transplantation: mosaic attenuation on high-resolution CT (HRCT). HRCT image shows extensive bilateral areas of decreased attenuation and vascularity and areas of normal or increased attenuation and vascularity (mosaic attenuation). Note associated bronchiectasis.

A

Disease Severity

Pulmonary Function Testing

No constrictive bronchiolitis Potential constrictive bronchiolitis Mild constrictive bronchiolitis Moderate constrictive bronchiolitis Severe constrictive bronchiolitis

FEV1: >90% of baseline and FEF25–75: >75% of baseline FEV1: 81%–90% of baseline and FEF22–75: ≤75% of baseline FEV1: 66%–80% of baseline FEV1: 51%–65% of baseline FEV1: ≤50% of baseline

BOS, Bronchiolitis obliterans syndrome; BOS 0-p, bronchiolitis obliterans syndrome stage 0-potential; FEF, forced expiratory flow (rate); FEV1, forced expiratory volume in 1 second.

B Fig. 59.22  Air-trapping in constrictive bronchiolitis after stem cell transplantation. (A) High-resolution CT image shows subtle areas of decreased attenuation and vascularity. (B) Expiratory CT image demonstrates extensive bilateral air-trapping.

59  Bronchiolitis

Fig. 59.23  Constrictive bronchiolitis in diffuse idiopathic neuroendocrine cell hyperplasia. Expiratory CT shows multifocal bilateral nodules and micronodules, bronchial wall thickening, and geographic areas of air-trapping.

symptomatic constrictive bronchiolitis.117,118 CB in these patients is likely due to a combination of intraluminal obstruction by hyperplastic neuroendocrine cells and peribronchiolar fibrosis from peptide secretory products.116 Characteristic histologic findings include submucosal bronchial and bronchiolar wall fibrosis in both regions with, and regions away, from tumorlets/neuroendocrine hyperplasia.116 Clinically symptomatic patients are usually women ranging from 50 to 70 years of age.116,117,119 Chest radiograph may demonstrate multiple pulmonary micronodules, and CT usually shows multifocal pulmonary micronodules with or without mosaic attenuation on inspiratory CT and air-trapping on expiratory CT (Fig. 59.23).117 Bronchiectasis, bronchial wall thickening, and atelectasis have also been described.117,118,120

Bronchiolitis Related to Toxic Gases, Fumes, and Dust A variety of inhaled agents, including toxic fumes (e.g., diacetyl exposure), smoke, toxic gases (e.g., nitric oxide, nitric dioxide, sulfur dioxide, chlorine, hydrochloric acid, phosgene), inorganic agents (e.g., silica, asbestos), and organic agents are associated with CB.121 Several studies have shown various occupational lung diseases manifesting as severe CB. One specific example involves workers exposed to flavoring vapors in North American food processing industries. “Popcorn worker’s lung,” first reported by Kreiss and colleagues122 in 2000, refers to CB resulting after exposure to diacetyl vapors, a ketone with butter flavoring used in popcorn manufacturing plants.122,123 Multiple additional studies have since validated the etiologic association between diacetyl exposure and CB, including case series in former employees, cross-sectional epidemiologic studies in current employees, explorative exposure studies, and a few animal exposure studies.123,124 The best understood disease process, commonly known as “silo filler’s disease,” occurs with the inhalation of nitric oxide (NO) and nitrogen dioxide (NO2), which are byproducts from the anaerobic fermentation of silage. The earliest phase of silo filler’s lung is characterized clinically by the abrupt onset of cough, dyspnea, weakness, and a choking or globus sensation.23 Pulmonary edema can develop within 4 to 24 hours but usually

761

abates without residual lung damage, if the patient survives. The second phase of disease is typically an asymptomatic period, lasting 2 to 5 weeks. The third phase becomes apparent up to 5 weeks after the initial exposure and is characterized by progressive dyspnea caused by CB.23 Although some studies have shown that exposure to low concentrations of NO2 in humans is rarely problematic, moderate to severe exposure often results in a rapid onset of acute bronchiolitis; diffuse alveolar damage has also been documented in some patients.21,125 The majority of patients fully recover; however, some will continue on to develop CB.21 Airway abnormalities and pulmonary parenchymal disease are common complications of smoke inhalation. Smoke consists of gases and a suspension of carbon particles coated with combustible products, such as organic acids and aldehydes, in hot air. Acute bronchiolitis from smoke inhalation often resolves but may occasionally progress to CB. Direct heat exposure can cause severe tissue damage to airway mucosa, particularly seen in burn victims.126,127 CT plays a main role in the assessment of late complications, demonstrating findings such as tracheal stenosis, bronchiectasis, and bronchiolectasis. Mosaic attenuation on inspiratory CT and air-trapping on expiratory CT are frequently seen (Fig. 59.24).

Miscellaneous Causes of Constrictive Bronchiolitis SAUROPUS ANDROGYNUS Sauropus androgynus is commonly found in Malaysia, Indonesia, southwest China, and Vietnam. Consumption of juice prepared from the uncooked leaves of the vegetable S. androgynus, which is alleged to help weight control, has a known association with constrictive bronchiolitis.128–130 The patients usually have a poor prognosis and present with rapidly progressive shortness of breath and persistent cough 3 to 4 months after ingestion of blended vegetable juice, with moderate to severe airflow obstruction.128–131 They typically do not respond to bronchodilator therapy or corticosteroids. INFLAMMATORY BOWEL DISEASE Inflammatory bowel disease (IBD) typically involves the intermediate-sized central bronchi. Rarely, the small airways can be involved.132,133 Chest radiographs are usually normal but may sometimes show hyperinflation, peripheral pulmonary vascular attenuation, and poorly defined reticular or reticulonodular opacities. Typical CT findings include findings of intermediate and small airway involvement and may show central and peripheral bronchiectasis, bronchiolectasis, and bronchial wall thickening, small solid centrilobular nodules that are often related to mucoid impaction, small ground-glass nodules, and mosaic attenuation. Expiratory CT shows air-trapping.132,133 Correlation with a known history of IBD and evaluation of concurrent involvement of the large- and intermediate-sized airways are important diagnostic clues differentiating IBD as the etiologic cause for small airways disease. PARANEOPLASTIC AUTOIMMUNE MULTIORGAN SYNDROME Paraneoplastic autoimmune multiorgan syndrome is a severe autoimmune disorder secondary to an underlying benign or malignant tumor. Mortality rates may be as high as 90% when

762

SECTION 11  Diseases of the Airways

B

A

C Fig. 59.24  Constrictive bronchiolitis and bronchiectasis years after smoke inhalation. (A) Posteroanterior chest radiograph shows increased lung volume, bronchiectasis, and decreased peripheral vascular markings. (B) and (C) High-resolution CT show extensive bronchiectasis and areas of decreased attenuation and vascularity as a result of constrictive bronchiolitis. (Courtesy Dr. Christopher Griffin, Department of Radiology, Veterans Affairs Hospital, Portland, Oregon. From Müller NL, Fraser RS, Colman NC, Paré PD. Radiologic Diagnosis of Diseases of the Chest. Philadelphia: WB Saunders; 2001.)

malignancy is involved.134,135 The most commonly associated neoplasms are non-Hodgkin lymphoma, chronic lymphocytic leukemia, Castleman disease, retroperitoneal sarcomas, and Waldenström macroglobulinemia. The disease process is characterized by immunoglobulin-mediated destruction acantholysis (destruction of intercellular desmosomal protein connections) affecting the skin and mucous membranes, including the mucosa of the large and small airways.134,135 Respiratory failure occurs in approximately 30% of patients and is usually secondary to CB.134 Patients often present with progressive dyspnea, deterioration of pulmonary function and hypoxia, and eventually death. Chest radiograph findings are usually normal. CT findings are typical for severe CB. Prognosis is poor when airway involvement is present, and patients are usually nonresponsive to immunosuppressive therapy.134

Swyer-James-Macleod Syndrome ETIOLOGY, PREVALENCE, EPIDEMIOLOGY, AND CLINICAL PRESENTATION Swyer-James-MacLeod syndrome (SJM) is an uncommon condition characterized radiographically by a hyperlucent lobe or lung and functionally by normal or reduced total lung capacity and presence

KEY POINTS: CONSTRICTIVE BRONCHIOLITIS • Etiology/definition • Characterized by submucosal and peribronchiolar fibrosis with resulting bronchiolar narrowing or obliteration of the bronchiolar lumen. • Most common causes are previous infection, connective tissue diseases (mainly rheumatoid arthritis), transplantation (mainly lung and stem cell transplantation), inhalational lung disease, and miscellaneous conditions, such as Sauropus androgynous ingestion, inflammatory bowel disease, paraneoplastic pemphigus, and drug-related (gold and penicillamine). • Clinical symptoms • Dry cough and progressive dyspnea • Radiographic findings • Often normal • May show central peribronchial cuffing, decreased peripheral vascular markings, and hyperinflation • Computed tomography/high-resolution tomography • Mosaic attenuation on inspiratory CT • Air-trapping on expiratory CT; needs to involve more than 25% of the lung to be considered abnormal • Bronchiectasis

59  Bronchiolitis

of expiratory air-trapping.136,137 The syndrome falls along the spectrum of postinfectious constructive bronchiolitis. Patients are typically young adults who are either asymptomatic or complaining of mild dyspnea, with a history of prior childhood viral infection. In some cases the disease is recognized, or at least suspected, in childhood when chest radiography is performed for evaluation of recurrent respiratory infections. Most cases of SJM, therefore, probably begin as an acute bronchiolitis that eventually progresses to constrictive bronchiolitis, characterized by fibrous obliteration of the airway lumen. The peripheral parenchyma is largely unaffected and remains inflated because of collateral ventilation with resultant air-trapping. However, destructive changes characteristic of emphysema also supervene in some cases.138

763

lung or lobe, and air-trapping on expiratory CT (Fig. 59.26). These findings are also frequently seen in the contralateral lung, although one lung is usually more severely affected, leading to the false sense of unilateral involvement on radiography. Unilateral or bilateral bronchiectasis is not uncommon.140,141

PATHOPHYSIOLOGY The main histologic abnormalities are those of CB, characterized by submucosal accumulation of mucopolysaccharide proteins and submucosal and peribronchiolar fibrosis.139 Other common findings include bronchiectasis and a variable degree of lung parenchymal destruction.138 MANIFESTATIONS OF THE DISEASE Radiography Inspiratory radiography performed at total lung capacity typically shows a marked difference in radiolucency of both lungs, or the affected and unaffected lobes, caused by decreased perfusion. The ipsilateral hilum is also diminutive but is present (Fig. 59.25). The expiratory chest radiograph shows persistent hyperlucency/ air-trapping in the involved lobe or lung. Computed Tomography/High-Resolution Computed Tomography Similar to radiography, inspiratory CT shows hyperlucency, decreased vascularity, normal or decreased size of the involved

A

Fig. 59.25  Swyer-James-MacLeod syndrome. Chest radiograph shows hyperlucency and decreased vascularity of the left lung as well as a small left hilum. The mediastinum is shifted to the left, consistent with decreased left lung volume.

B Fig. 59.26  Swyer-James-MacLeod syndrome. (A) High-resolution CT shows decreased attenuation and vascularity of the left lung with associated bronchiectasis and mild volume loss leading to ipsilateral shift of the mediastinum and anterior junction line. (B) Expiratory CT image at the same level shows air-trapping in the left lung. The mediastinum and anterior junction line are now in the midline.

764

SECTION 11  Diseases of the Airways

KEY POINTS: SWYER-JAMES-MACLEOD SYNDROME (UNILATERAL HYPERLUCENT LUNG OR LOBE) • Etiology/definition • Characterized radiologically by a hyperlucent lobe or lung and functionally by normal or reduced total lung capacity and presence of expiratory air-trapping • Usually sequela of childhood viral infection resulting in constrictive bronchiolitis • Symptoms • Majority are asymptomatic; occasionally, dyspnea or recurrent infections may occur • Radiographic findings • Hyperlucency • Decreased vascularity

• Normal or decreased size of the involved lobe or lung • Expiratory chest radiograph shows air-trapping • Computed tomography/high-resolution computed tomography • Hyperlucency and decreased vascularity of the involved lung or lobe on inspiratory CT • Air-trapping on expiratory CT • Bronchiectasis (in the majority of cases)

DIFFERENTIAL DIAGNOSIS

SUGGESTED READINGS

The diagnosis of SJM can often be made on the chest radiograph, given the marked difference in radiolucency between the affected and unaffected areas. Although the ipsilateral hilum is diminutive, it is still present, which makes it a feature of value in the differentiation from proximal interruption of a pulmonary artery (pulmonary artery agenesis). The presence of expiratory airtrapping is essential for accurate diagnosis of SJM, as it is a reflection of airway obstruction and is invaluable in differentiating the syndrome from other conditions that may give rise to unilateral lung or lobar hyperlucency. An important diagnostic dilemma may arise if the patient presents with the radiographic triad of low lung volume, expiratory air-trapping, and diffusely decreased vascularity resulting from hypoxic vasoconstriction—a triad that makes differentiation of SJM syndrome from an underlying partially obstructive endobronchial neoplasm impossible. CT can then be used to definitively confirm the presence or absence of an obstructing ipsilateral endobronchial lesion. Sequelae of bronchopulmonary dysplasia or chronic lung disease of prematurity may also manifest with similar, but often more extensive, findings of diffuse patchy hypoattenuating lung parenchyma. An important clue to this diagnosis is the history of prematurity with long-term ventilation at birth.

Abbott GF, Rosado-de-Christenson ML, et al. Imaging of small airways disease. J Thorac Imaging. 2009;24:285–298. Elicker BM, Jones KD, et al. Multidisciplinary approach to hypersensitivity pneumonitis. J Thorac Imaging. 2016;31:92–103. Kligerman S, Franks TJ, et al. Clinical-radiologic-pathologic correlation of smoking-related diffuse parenchymal lung disease. Radiol Clin North Am. 2016;54:1047–1063. Kligerman AJ, Henry T, et al. Mosaic attenuation: etiology, methods of differentiation, and pitfalls. Radiographics. 2015;35:1360–1380. Miller WT Jr, Chatzkel J, et al. Expiratory air-trapping on thoracic computed tomography: a diagnostic subclassification. Ann Am Thorac Soc. 2014;11(6):874–881. Winningham PJ, Martínez-Jiménez S, Rosado-de-Christenson ML, Betancourt SL, Restrepo CS, Eraso A. Bronchiolitis: a practical approach for the general radiologist. Radiographics. 2017;37(3):777–794.

The full reference list for this chapter is available at ExpertConsult.com.

59  Bronchiolitis 764.e1

REFERENCES 1. Colby TV. Bronchiolitis. Pathologic considerations. Am J Clin Pathol. 1998;109:101–109. 2. Visscher DW, Myers JL. Bronchiolitis: the pathologist’s perspective. Proc Am Thorac Soc. 2006;3:41–47. 3. Abbott GF, Rosado-de-Christenson ML, et al. Imaging of small airways disease. J Thorac Imaging. 2009;24:285–298. 4. Pipavath SJ, Lynch DA, Cool C, et al. Radiologic and pathologic features of bronchiolitis. AJR Am J Roentgenol. 2005;185:354–363. 5. Poletti V, Costtable U. Bronchiolar disorders: classification and diagnostic approach. Semin Respir Crit Care Med. 2003;24:457–464. 6. Lynch DA. Imaging of small airways disease and chronic obstructive pulmonary disease. Clin Chest Med. 2008;29:165–179. 7. Kligerman AJ, Henry T, et al. Mosaic attenuation: etiology, methods of differentiation, and pitfalls. Radiographics. 2015;35:1360–1380. 8. Elicker BM, Jones KD, et al. Multidisciplinary approach to hypersensitivity pneumonitis. J Thorac Imaging. 2016;31:92–103. 9. Okada F, Ando Y, et al. Clinical/pathologic correlations in 552 patients with primary centrilobular findings on high-resolution CT scan of the thorax. Chest. 2007;132:1939–1948. 10. Takahashi M, Murata K, Takazakura R, et al. Bronchiolar disease: spectrum and radiological findings. Eur J Radiol. 2000;35:15–29. 11. Grenier PA. Advances in imaging of the airways: update and perspectives. J Thorac Imaging. 2011;26:247. 12. Müller NL, Miller RR. Diseases of the bronchioles: CT and histopathologic findings. Radiology. 1995;196:3–12. 13. Arakawa H, Webb WR, McCowin M, et al. Inhomogeneous lung attenuation at thin-section CT: diagnostic value of expiratory scans. Radiology. 1998;206:89–94. 14. Worthy SA, Park CS, Kim JS, Müller NL. Bronchiolitis obliterans after lung transplantation: high resolution CT findings in 15 patients. AJR Am J Roentgenol. 1997;169:673–677. 15. Park CS, Müller NL, Worthy SA, et al. Airway obstruction in asthmatic and healthy individuals: inspiratory and expiratory thin-section CT findings. Radiology. 1997;203:361–367. 16. Webb WR, Stern EJ, Kanth N, Gamsu G. Dynamic pulmonary CT: findings in normal adult men. Radiology. 1993;186:117–124. 17. Hansell DM, Bankier AA, et al. Fleischner society: glossary of terms for thoracic imaging. Radiology. 2008;246:697–722. 18. Miller WT Jr, Chatzkel J, et al. Expiratory air-trapping on thoracic computed tomography: a diagnostic subclassification. Ann Am Thorac Soc. 2014;11(6):874–881. 19. Lee ES, Gotway MB, Reddy GP, et al. Early bronchiolitis obliterans following lung transplantation: accuracy of expiratory thin-section CT for diagnosis. Radiology. 2000;216:472–477. 20. Nobuyuki T, Matsumoto T, et al. Air-trapping at CT: high prevalence in asymptomatic subjects with normal pulmonary function. Radiology. 2003;227:776–785. 21. Travis WD, Colby TV, Koss MN, et al. Bronchiolar disorders. In: Travis WD, Colby TV, Koss MN, et al, eds. Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: Armed Forces Institute of Pathology; 2002:351–380. 22. Naidich DP, Webb WR, Grenier PA, et al. Small airway disease. In: Naidich DP, Webb WR, Grenier PA, et al, eds. Imaging of the Airways. Philadelphia: Lippincott Williams & Wilkins; 2005:146–176. 23. Fraser RS, Colman N, Müller NL, Paré PD. Disease of the airways. In: Fraser RS, Colman N, Müller NL, Paré PD, eds. Synopsis of Diseases of the Chest. Philadelphia: Elsevier Saunders; 2005:627–713. 24. Adesina AM, Vallyathan V, McQuillen EN, et al. Bronchiolar inflammation and fibrosis associated with smoking. A morphologic cross-sectional population analysis. Am Rev Respir Dis. 1991;143:144–149. 25. Kern S, Uhl M, Berner R, et al. Respiratory syncytial virus infection of the lower respiratory tract: radiological findings in 108 children. Eur Radiol. 2001;11:2581–2584. 26. Osborne D. Radiologic appearance of viral disease of the lower respiratory tract in infants and children. AJR Am J Roentgenol. 1978;130:29–33. 27. Lerida A, Marron A, Casanova A, et al. Respiratory syncytial virus infection in adult patients hospitalized with community-acquired pneumonia. Enferm Infecc Microbiol Clin. 2000;18:177–181 [in Spanish]. 28. Reittner P, Müller NL, Heyneman L, et al. Mycoplasma pneumoniae pneumonia: radiographic and high-resolution CT features in 28 patients. AJR Am J Roentgenol. 1999;174:37–41. 29. Aquino SL, Gamsu G, Webb WR, Kee SL. Tree-in-bud pattern: frequency and significance on thin section CT. J Comput Assist Tomogr. 1996;20:594–599. 30. Collins J, Blankenbaker D, Stern EJ. CT patterns of bronchiolar disease: what is “tree-in-bud”? AJR Am J Roentgenol. 1998;171:365–370.

31. Gruden JF, Webb WR, Naidich DP, McGuinness G. Multinodular disease: anatomic localization at thin-section CT—multireader evaluation of a simple algorithm. Radiology. 1999;210:711–720. 32. Barnes TW, Vassallo R, Tazelaar HD, et al. Diffuse bronchiolar disease due to chronic occult aspiration. Mayo Clin Proc. 2006;81:172–176. 33. Hayakawa H, Sato A, Imokawa S, et al. Bronchiolar disease in rheumatoid arthritis. Am J Respir Crit Care Med. 1996;154:1531–1536. 34. Remy-Jardin M, Remy J, Cortet B, et al. Lung changes in rheumatoid arthritis: CT findings. Radiology. 1994;193:375–382. 35. Matsuse T, Oka T, Kida K, Fukuchi Y. Importance of diffuse aspiration bronchiolitis caused by chronic occult aspiration in the elderly. Chest. 1996;110:1289–1293. 36. Wright JL, Cagle P, Churg A, et al. Diseases of the small airways. Am Rev Respir Dis. 1992;146:240–262. 37. Moon J, du Bois RM, Colby TV, et al. Clinical significance of respiratory bronchiolitis on open lung biopsy and its relationship to smoking related interstitial lung disease. Thorax. 1999;54:1009–1014. 38. Fraig M, Shreesha U, Savici D, Katzenstein AL. Respiratory bronchiolitis: a clinicopathologic study in current smokers, ex-smokers, and never-smokers. Am J Surg Pathol. 2002;26:647–653. 39. Kligerman S, Franks TJ, et al. Clinical-radiologic-pathologic correlation of smoking-related diffuse parenchymal lung disease. Radiol Clin North Am. 2016;54:1047–1063. 40. Kawabata Y, Hoshi E, et al. Smoking-related changes in the background lung of specimens resected for lung cancer: a semiquantitative study with correlation to postoperative course. Histopathology. 2008;53:707–714. 41. Remy-Jardin M, Remy J, Gosselin B, et al. Lung parenchymal changes secondary to cigarette smoking: pathologic-CT correlations. Radiology. 1993;186:643–651. 42. Heyneman LE, Ward S, Lynch DA, et al. Respiratory bronchiolitis, respiratory bronchiolitis–associated interstitial lung disease, and desquamative interstitial pneumonia: different entities or part of the spectrum of the same disease process? AJR Am J Roentgenol. 1999;173:1617–1622. 43. Remy-Jardin M, Remy J, Boulenguez C, et al. Morphologic effects of cigarette smoking on airways and pulmonary parenchyma in healthy adult volunteers: CT evaluation and correlation with pulmonary function tests. Radiology. 1993;186:107–115. 44. Prather AD, Smith TR, et al. Aspiration-related lung diseases. J Thorac Imaging. 2014;29:304–309. 45. Travis WD, Costabel U, et al. An official American Thoracic Society/European Thoracic Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188:733–748. 46. Lacasse Y, Selman M, Costabel U, et al. Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med. 2003;168:952–958. 47. Travis WD, Galvin JR. Non-neoplastic pulmonary lymphoid lesions. Thorax. 2001;56:964–971. 48. Couture C, Colby TV. Histopathology of bronchiolar disorders. Semin Respir Crit Care Med. 2003;24:489–498. 49. Corrin B, Nicholson AG, Burke MM. Diseases of the airways. In: Corrin B, Nicholson AG, eds. Pathology of the Lungs. 2nd ed. Philadelphia: Churchill Livingstone; 2006:87–130. 50. Howling SJ, Hansell DM, Wells AU, et al. Follicular bronchiolitis: thin-section CT and histologic findings. Radiology. 1999;212:637–642. 51. Iwata M, Colby TV, Kitaichi M. Diffuse panbronchiolitis: diagnosis and distinction from various pulmonary diseases with centrilobular interstitial foam cell accumulations. Hum Pathol. 1994;25:357–363. 52. Azuma A, Kudoh S. Diffuse panbronchiolitis in East Asia. Respirology. 2006;11:249–261. 53. Krishnan P, Thachil R, Gillego V. Diffuse panbronchiolitis: a treatable sinobronchial disease in need of recognition in the United States. Chest. 2002;121:659–661. 54. Homma H, Yamanaka A, Tanimoto S, et al. Diffuse panbronchiolitis. A disease of the transitional zone of the lung. Chest. 1983;83:63–69. 55. Randhawa P, Hoagland MH, Yousem SA. Diffuse panbronchiolitis in North America. Report of three cases and review of the literature. Am J Surg Pathol. 1991;15:43–47. 56. Hoiby N. Diffuse panbronchiolitis and cystic fibrosis: East meets West. Thorax. 1994;49:531–532. 57. Nishimura K, Kitaichi M, Izumi T, Itoh H. Diffuse panbronchiolitis: correlation of high-resolution CT and pathologic findings. Radiology. 1992;184: 779–785. 58. Akira M, Kitatani F, Lee YS, et al. Diffuse panbronchiolitis: evaluation with high-resolution CT. Radiology. 1988;168:433–438. 59. Keicho N, Kudoh S. Diffuse panbronchiolitis: role of macrolides in therapy. Am J Respir Med. 2002;1:119–131.

764.e2

SECTION 11  Diseases of the Airways

60. Ryu JH, Myers JL, Swensen SJ. Bronchiolar disorders. Am J Respir Crit Care Med. 2003;168:1277–1292. 61. Chan A, Allen R. Bronchiolitis obliterans: an update. Curr Opin Pulm Med. 2004;10:133–141. 62. Kim CK, Kim SW, Kim JS, et al. Bronchiolitis obliterans in the 1990s in Korea and the United States. Chest. 2001;120:1101–1106. 63. Skeens JL, Fuhrman CR, Yousem SA. Bronchiolitis obliterans in heart-lung transplantation patients: radiologic findings in 11 patients. AJR Am J Roentgenol. 1989;153:253–256. 64. Morrish WF, Herman SJ, Weisbrod GL, Chamberlain DW. Bronchiolitis obliterans after lung transplantation: findings at chest radiography and high-resolution CT. Radiology. 1991;179:487–490. 65. Garg K, Lynch DA, Newell JD, King TE. Proliferative and constrictive bronchiolitis: classification and radiologic features. AJR Am J Roentgenol. 1994;162:803–808. 66. Jensen SP, Lynch DA, Brown KK, et al. High-resolution CT features of severe asthma and bronchiolitis obliterans. Clin Radiol. 2002;57: 1078–1085. 67. Leung AN, Fisher K, Valentine V, et al. Bronchiolitis obliterans after lung transplantation: detection using expiratory HRCT. Chest. 1998;113:365–370. 68. Lucidarme O, Grenier PA, Cadi M, et al. Evaluation of air-trapping at CT: comparison of continuous- versus suspended-expiration CT techniques. Radiology. 2000;216:768–772. 69. Stern EJ, Frank MS. Small-airway diseases of the lungs: findings at expiratory CT. AJR Am J Roentgenol. 1994;163:37–41. 70. Fotheringham T, Chabat F, Hansell DM, et al. A comparison of methods for enhancing the detection of areas of decreased attenuation on CT caused by airways disease. J Comput Assist Tomogr. 1999;23:385–389. 71. Wittram C, Rappaport DC. Bronchiolitis obliterans after lung transplantation: appearance on expiratory minimum intensity projection images. Can Assoc Radiol J. 2000;51:103–106. 72. Lentz D, Bergin CJ, Berry GJ, et al. Diagnosis of bronchiolitis obliterans in heart-lung transplantation patients: importance of bronchial dilatation on CT. AJR Am J Roentgenol. 1992;159:463–467. 73. Padley SPG, Adler BD, Hansell DM, Müller NL. Bronchiolitis obliterans: high-resolution CT findings and correlation with pulmonary function tests. Clin Radiol. 1993;47:236–240. 74. Lee KW, Chung SY, Yang I, et al. Correlation of aging and smoking with air-trapping at thin-section CT of the lung in asymptomatic subjects. Radiology. 2000;214:831–836. 75. Copley SJ, Wells AU, Müller NL, et al. Thin-section CT in obstructive pulmonary disease: discriminatory value. Radiology. 2002;223:812–819. 76. Worthy SA, Müller NL, Hartman TE, et al. Mosaic attenuation pattern on thin-section CT scans of the lung: differentiation among infiltrative lung, airway, and vascular diseases as a cause. Radiology. 1997;205:465–470. 77. Remy-Jardin M, Remy J, Louvegny S, et al. Airway changes in chronic pulmonary embolism: CT findings in 33 patients. Radiology. 1997;203:355–360. 78. Arakawa H, Kurihara Y, Sasaka K, et al. Air-trapping on CT of patients with pulmonary embolism. AJR Am J Roentgenol. 2002;178:1201–1207. 79. Chamberlain D, Maurer J, Chaparro C, Idolor L. Evaluation of transbronchial lung biopsy specimens in the diagnosis of bronchiolitis obliterans after lung transplantation. J Heart Lung Transplant. 1994;13:963–971. 80. Schlesinger C, Meyer CA, Veeraraghavan S, Koss MN. Constrictive (obliterative) bronchiolitis: diagnosis, etiology, and a critical review of the literature. Ann Diagn Pathol. 1998;2:321–334. 81. Bloch KE, Weder W, Boehler A, et al. Successful lung volume reduction surgery in a child with severe airflow obstruction and hyperinflation due to constrictive bronchiolitis. Chest. 2002;122:747–750. 82. Chiu CY, Wong KS, Huang YC, et al. Bronchiolitis obliterans in children: clinical presentation, therapy and long-term follow-up. J Paediatr Child Health. 2008;44:129–133. 83. Marrie TJ, Poulin-Costello M, Beecroft MD, Herman-Gnjidic Z. Etiology of community-acquired pneumonia treated in an ambulatory setting. Respir Med. 2005;99:60–65. 84. Rocholl C, Gerber K, Daly J, et al. Adenoviral infections in children: the impact of rapid diagnosis. Pediatrics. 2004;113:e51–e56. 85. Kim CK, Chung CY, Kim JS, et al. Late abnormal findings on high-resolution computed tomography after Mycoplasma pneumonia. Pediatrics. 2000;105: 372–378. 86. Milner AD, Murray M. Acute bronchiolitis in infancy: treatment and prognosis. Thorax. 1989;44:1–5. 87. Chang AB, Masel JP, Masters B. Post-infectious bronchiolitis obliterans: clinical, radiological and pulmonary function sequelae. Pediatr Radiol. 1998;28:23–29. 88. Zhang L, Irion K, Kozakewich H, et al. Clinical course of postinfectious bronchiolitis obliterans. Pediatr Pulmonol. 2000;29:341–350.

89. Chuang YY, Chiu CH, Wong KS, et al. Severe adenovirus infection in children. J Microbiol Immunol Infect. 2003;36:37–40. 90. Cordier JF. Challenges in pulmonary fibrosis. 2: Bronchiolocentric fibrosis. Thorax. 2007;62:638–649. 91. Angel LA, Homma A, Levine S. Bronchiolitis obliterans. Semin Respir Crit Care Med. 2000;21:123–134. 92. de Jong PA, Dodd JD, Coxson HO, et al. Bronchiolitis obliterans following lung transplantation: early detection using computed tomographic scanning. Thorax. 2006;61:799–804. 93. Reichenspurner H, Girgis RE, Robbins RC, et al. Obliterative bronchiolitis after lung and heart-lung transplantation. Ann Thorac Surg. 1995;60: 1845–1853. 94. Reichenspurner H, Girgis RE, Robbins RC, et al. Stanford experience with obliterative bronchiolitis after lung and heart-lung transplantation. Ann Thorac Surg. 1996;62:1467–1472, discussion 1472–1473. 95. Sundaresan S, Trulock EP, Mohanakumar T, et al. Prevalence and outcome of bronchiolitis obliterans syndrome after lung transplantation. Washington University Lung Transplant Group. Ann Thorac Surg. 1995;60:1341–1346, discussion 1346–1347. 96. Valentine VG, Robbins RC, Berry GJ, et al. Actuarial survival of heart-lung and bilateral sequential lung transplant recipients with obliterative bronchiolitis. J Heart Lung Transplant. 1996;15:371–383. 97. Collins J. Imaging of the chest after lung transplantation. J Thorac Imaging. 2002;17:102–112. 98. Cooper JD, Billingham M, Egan T, et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 1993;12:713–716. 99. Konen E, Gutierrez C, Chaparro C, et al. Bronchiolitis obliterans syndrome in lung transplant recipients: can thin-section CT findings predict disease before its clinical appearance? Radiology. 2004;231:467–473. 100. Bankier AA, Van Muylem A, Knoop C, et al. Bronchiolitis obliterans syndrome in heart-lung transplant recipients: diagnosis with expiratory CT. Radiology. 2001;218:533–539. 101. Berstad AE, Aalokken TM, Kolbenstvedt A, Bjortuft O. Performance of long-term CT monitoring in diagnosing bronchiolitis obliterans after lung transplantation. Eur J Radiol. 2006;58:124–131. 102. Siegel MJ, Bhalla S, Gutierrez FR, et al. Post–lung transplantation bronchiolitis obliterans syndrome: usefulness of expiratory thin-section CT for diagnosis. Radiology. 2001;220:455–462. 103. Choi YW, Rossi SE, Palmer SM, et al. Bronchiolitis obliterans syndrome in lung transplant recipients: correlation of computed tomography findings with bronchiolitis obliterans syndrome stage. J Thorac Imaging. 2003;18:72–79. 104. Afessa B, Litzow MR, Tefferi A. Bronchiolitis obliterans and other late onset noninfectious pulmonary complications in hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;28:425–434. 105. Chien JW, Martin PJ, Gooley TA, et al. Airflow obstruction after myeloablative allogeneic hematopoietic stem cell transplantation. Am J Respir Crit Care Med. 2003;168:208–214. 106. Geddes DM, Corrin B, Brewerton DA, et al. Progressive airway obliteration in adults and its association with rheumatoid disease. Q J Med. 1977;46: 427–444. 107. Wells AU, du Bois RM. Bronchiolitis in association with connective tissue diseases. Clin Chest Med. 1993;14:655–666. 108. Papiris SA, Maniati M, Constantopoulos SH, et al. Lung involvement in primary Sjögren’s syndrome is mainly related to the small airway disease. Ann Rheum Dis. 1999;58:61–64. 109. Weber F, Prior C, Kowald E, et al. Cyclophosphamide therapy is effective for bronchiolitis obliterans occurring as a late manifestation of lupus erythematosus. Br J Dermatol. 2000;143:453–455. 110. Boehler A, Vogt P, Speich R, et al. Bronchiolitis obliterans in a patient with localized scleroderma treated with d-penicillamine. Eur Respir J. 1996;9: 1317–1319. 111. Hakala M, Paakko P, Sutinen S, et al. Association of bronchiolitis with connective tissue disorders. Ann Rheum Dis. 1986;45:656–662. 112. Yousem SA. The pulmonary pathologic manifestations of the CREST syndrome. Hum Pathol. 1990;21:467–474. 113. Schwarz MI, Lynch DA, Tuder R. Bronchiolitis obliterans: the lone manifestation of rheumatoid arthritis? Eur Respir J. 1994;7:817–820. 114. Epler GR, Snider GL, Gaensler EA, et al. Bronchiolitis and bronchitis in connective tissue disease. JAMA. 1979;242:528–532. 115. Zitnik RJ, Cooper JA Jr. Pulmonary disease due to antirheumatic agents. Clin Chest Med. 1990;11:139–150. 116. Aguayo SM, Miller YE, Waldron JA Jr, et al. Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med. 1992;327:1285–1288.

59  Bronchiolitis 764.e3 117. Benson RE, Rosado-de-Christenson ML, et al. Spectrum of pulmonary neuroendocrine proliferations and neoplasms. Radiographics. 2013;33: 1631–1649. 118. Davies SJ, Gosney JR, Hansell DM, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease. Thorax. 2007;62(3):248–252. 119. Brown MJ, English J, Müller NL. Bronchiolitis obliterans due to neuroendocrine hyperplasia: high-resolution CT–pathologic correlation. AJR Am J Roentgenol. 1997;168:1561–1562. 120. Koo CW, Baliff JP, Torigian DA, Litzky LA, Gefter WB, Akers SR. Spectrum of pulmonary neuroendocrine cell proliferation: diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, tumorlet, and carcinoids. AJR Am J Roentgenol. 2010;195(3):661–668. 121. Wright JL. Inhalational lung injury causing bronchiolitis. Clin Chest Med. 1993;14:635–644. 122. Kreiss K, Gomaa A, et al. Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant. N Engl J Med. 2002;347:330–361. 123. Akpinar-Elci M, Travis WD, et al. Bronchiolitis obliterans syndrome in popcorn plant workers. Eur Respir J. 2003;24:298–302. 124. van Rooy FG, Rooyackers JM, et al. Bronchiolitis obliterans syndrome in chemical workers producing diacetyl for food flavorings. Am J Respir Crit Care Med. 2005;172:1139–1145. 125. Douglas WW, Hepper NG, Colby TV. Silo-filler’s disease. Mayo Clin Proc. 1989;64:291–304. 126. Janigan DT, Kilp T, Michael R, McCleave JJ. Bronchiolitis obliterans in a man who used his wood-burning stove to burn synthetic construction materials. CMAJ. 1997;156:1171–1173. 127. Tasaka S, Kanazawa M, Mori M, et al. Long-term course of bronchiectasis and bronchiolitis obliterans as late complication of smoke inhalation. Respiration. 1995;62:40–42. 128. Chang H, Wang JS, Tseng HH, et al. Histopathological study of Sauropus androgynus–associated constrictive bronchiolitis obliterans: a new cause of constrictive bronchiolitis obliterans [see comments]. Am J Surg Pathol. 1997;21:35–42.

129. Ger LP, Chiang AA, Lai RS, et al. Association of Sauropus androgynus and bronchiolitis obliterans syndrome: a hospital-based case-control study. Am J Epidemiol. 1997;145:842–849. 130. Lai RS, Chiang AA, Wu MT, et al. Outbreak of bronchiolitis obliterans associated with consumption of Sauropus androgynus in Taiwan. Lancet. 1996;348:83–85. 131. Luh SP, Lee YC, Chang YL, et al. Lung transplantation for patients with end-stage Sauropus androgynus–induced bronchiolitis obliterans (SABO) syndrome. Clin Transplant. 1999;13:496–503. 132. Betancourt SL, Palacio D, et al. Thoracic manifestations of inflammatory bowel disease. AJR Am J Roentgenol. 2011;197:W452–W456. 133. Black H, Mendoza M, et al. Thoracic manifestations of inflammatory bowel disease. Chest. 2007;131:524–532. 134. Nousari HC, Deterding R, et al. The mechanism of respiratory failure in paraneoplastic pemphigus. N Engl J Med. 1999;340:1406–1410. 135. Osmanski JP II, Fraire AE, Schaefer OP. Necrotizing tracheobronchitis with progressive airflow obstruction associated with paraneoplastic pemphigus. Chest. 1997;112:1704–1707. 136. MacLeod WM. Abnormal transradiancy of one lung. Thorax. 1954;9: 147–153. 137. Müller NL. Unilateral hyperlucent lung: MacLeod versus Swyer-James. Clin Radiol. 2004;59:1048. 138. Reid L, Simon G. Unilateral lung transradiancy. Thorax. 1962;17:230–239. 139. Hardy KA, Schidlow DV, Zaeri N. Obliterative bronchiolitis in children. Chest. 1988;93:460–466. 140. Marti-Bonmati L, Ruiz PF, Catala F, et al. CT findings in Swyer-James syndrome. Radiology. 1989;172:477–480. 141. Moore ADA, Godwin JD, Dietrich PA, et al. Swyer-James syndrome: CT findings in eight patients. AJR Am J Roentgenol. 1992;158:1211–1215.

60 

Emphysema* STEPHEN B. HOBBS

Definition and Etiology Emphysema is defined as a “condition of the lung characterized by abnormal, permanent enlargement of the airspaces distal to the terminal bronchiole, accompanied by destruction of their walls.”1 Because emphysema decreases the elastic recoil force that drives air out of the lung and thereby reduces maximal expiratory airflow, the disease is clinically classified as one of the chronic obstructive pulmonary diseases (COPDs).2 In morphologic appearance, two main subtypes of emphysema exist. The centrilobular (or centriacinar) form of emphysema results from dilatation or destruction of the respiratory bronchioles and is the type of emphysema most closely associated with cigarette smoking.1 The panlobular, or panacinar, form of emphysema is associated with α1-antitrypsin deficiency and results in an even dilatation and destruction of the entire acinus.1 It has been suggested that one or the other of these two subtypes predominates in severe disease and that the centrilobular subtype is associated with more severe small airways obstruction.3 There is a relation between the severity of emphysema and the pack-years of cigarette smoking, but this relation is weak. Indeed, only 40% of heavy smokers develop substantial lung destruction resulting from emphysema. On the other hand, emphysema can occasionally be found in individuals with normal lung function who have never smoked.4

Prevalence and Epidemiology The overall prevalence and epidemiology of emphysema are almost impossible to determine for three major reasons. First, the prevalence of emphysema strongly depends on regional factors, such as smoking habits, social standards, and environmental air pollution. Given that these factors largely vary, the prevalence of emphysema will show equally varying features, even in relatively small geographic areas. Second, emphysema becomes clinically evident in advanced disease, whereas mild or moderate disease can remain clinically silent. There are no screening programs dedicated to emphysema, although lung cancer screening with low-dose computed tomography (CT) may incidentally detect it, and a substantial number of individuals with emphysema will remain undiagnosed during their lifetime if no comorbidity exists that can bring to light emphysema as an incidental finding. Third, emphysema is clinically classified as a chronic obstructive lung disease.5 In this group of diseases the clinical findings may overlap with airways disorders. Furthermore, epidemiologic data exist for COPD as a group of diseases but not for the individual diseases such as emphysema.6,7 According to the Centers for Disease Control and Prevention, as of 2015 there are 36.5 million people who smoke cigarettes in the United States (1.1 billion smoke worldwide).8,9 Smoking is the *The editors and publisher would like to thank Dr. Alexander A. Bankier for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

leading cause of preventable death in the United States, accounting for more than 480,000 deaths per year.10

Clinical Presentation In many cases the clinical manifestations of emphysema are entirely nonspecific. In early stages, patients are often asymptomatic, and emphysema may be detected as an incidental finding on a CT examination performed for other purposes.11 In more advanced cases symptoms may overlap with symptoms caused by coexisting airway abnormalities and can therefore be difficult to attribute to the existence of emphysema. Patients with moderate to advanced disease, however, often complain of cough, either dry or productive, with increased frequency in the morning hours. Depending on the severity of the disease, breathlessness can occur either under exertion or at rest. Patients with severe emphysema can be susceptible to pulmonary infections that can occur at increased frequency or heal with increased delay.

Pathophysiology PATHOLOGY The definition of emphysema clearly refers to the acinus as a basic lung structure.12 The acinus is defined as the lung parenchyma that subtends from the terminal membranous bronchiole and consists of three generations of respiratory bronchioles, alveolar ducts, saccules, and alveoli.13 As opposed to the secondary pulmonary lobule, the acinus is not grossly identifiable. The terms centrilobular and panlobular are derived from their gross distributions within the secondary pulmonary lobule as defined by Miller.14,15 Because of the central location of the terminal bronchioles, the terms centriacinar, centrilobular, panacinar, and panlobular are roughly equivalent, and both terms are commonly used interchangeably.13 The use of animal models and, particularly, genetically modified animals has produced extensive information about the pathogenesis of emphysema.16–23 The concept of a proteaseantiprotease imbalance has been expanded but continues to include the inflammatory cascade, with involvement of the interleukins with Th1 cytokines and both serine proteases and metalloproteases.22 Neutrophils and macrophages have been joined by CD4-positive and CD8-positive T lymphocytes as important effector cells. The presence of apoptosis in emphysematous lungs has introduced a concept of disordered lung maintenance and repair, and there has been a suggestion of an immune basis for lung destruction.2,13,16 PATHOLOGIC SUBTYPES OF EMPHYSEMA Centrilobular Emphysema Centrilobular emphysema is characteristically found in cigarette smokers. Causes of centrilobular emphysema or bullae besides 765

766

SECTION 11  Diseases of the Airways

structures. In more severe disease the abnormal enlargement becomes more obvious, even though the destruction is relatively uniform within the individual lobules (Fig. 60.2).13 On microscopic examination the uniformity of the enlargement throughout the lobules persists (see Fig. 60.2). Airspaces adjacent to the venous septa are similar in size to those adjacent to the airways. Subtle signs of inflammation can be present.13 Panlobular emphysema is highly associated with α1-antitrypsin deficiency. Less likely causes of this pattern include hypocomplementemic urticarial vasculitis syndrome, intravenous methylphenidate abuse (so-called Ritalin lung), and some elastin abnormalities, such as cutis laxa and Ehlers-Danlos.24

Fig. 60.1  Centrilobular emphysema. Low-power view of a lung specimen shows focal areas of enlargement of the airspaces near the center of the secondary lobules. (Courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Vancouver, Canada.)

cigarette smoking include human immunodeficiency virus (HIV), Salla disease, Marfan syndrome, and Menke syndrome.24 On gross specimen, centrilobular emphysema is usually more common and more severe in the upper lung zones. In the upper lobe the posterior and apical segments are commonly affected; in the lower lobe the superior segment is more involved. Assessment of the secondary pulmonary lobule will demonstrate the central position of destruction, with sharply demarcated emphysematous areas separated from the acinar periphery by intact alveolar ducts and sacs of normal size (Fig. 60.1). In more severe lesions the destruction will advance toward the periphery of the lobule, which can make the differentiation between centrilobular and panlobular emphysema difficult.13 On microscopy airspace enlargement can be associated with a distorted respiratory bronchiole to form the classic centrilobular emphysema lesion. With increasing severity, isolated strands of alveoli can be seen. They are a useful indicator of the presence of emphysema. Collections of macrophages within the airspaces or adjacent to the bronchiole are common (representing respiratory bronchiolitis; see Chapter 34), and pigment can be seen both within the macrophages and in the bronchiolar fibrous tissue.13 Panlobular Emphysema On gross specimen, panlobular emphysema can be difficult to detect. In normal lungs the smaller alveoli can be clearly distinguished from the alveolar ducts and respiratory bronchioles; in panlobular emphysema, this distinction becomes lost because alveoli lose their sharp angles, enlarge, and eventually lose their contrast in size and in shape with the ducts. The lung architecture thus can appear simplified, with formation of small box-like

Other “Subtypes” of Emphysema Paraseptal Emphysema.  This emphysematous destruction pattern is located in the periphery of the lung adjacent to the pleura or along interlobular septa. It is thus mainly subpleural in location and bound by the interlobular septa. It may occasionally occur as an isolated finding. However, it is usually seen in association with either severe centrilobular or panlobular emphysema. Paraseptal emphysema can be one of the many causes of spontaneous pneumothorax. Although the exact pathogenesis is unclear, the relationship between paraseptal emphysema and thin and tall body habitus has led to the suggestion that this subtype of emphysema is due to the effects of gravitational pull on the lungs, with a greater negative pleural pressure at the lung apices.13 There is some evidence that smoking of marijuana cigarettes may be more highly associated with paraseptal emphysema than regular cigarettes. Some malnutrition syndromes can also cause paraseptal emphysema related to underlying elastase injury.24 Vanishing lung syndrome (Fig. 60.3), also referred to as giant bullous emphysema, is a rare syndrome characterized by severe paraseptal emphysema and large bullae formation, with the bullae occupying at least one-third of a hemithorax and compressing the adjacent parenchyma. Disease can be unilateral but is more frequently bilateral, and spontaneous pneumothorax is frequent. The disease classically affects young male smokers, but there are few case reports with a possible hereditary component and some possible additional associations with marijuana use and HIV. Bullectomy can result in significant improvements in pulmonary function, but further decline 3 to 4 years after surgery is typical.27–29 Paracicatricial Emphysema.  Lung destruction, and therefore emphysema, is commonly found adjacent to areas of scarring, which explains the term attributed to this alteration. Because the destruction has no particular position within the lobule, it was also termed irregular emphysema. Per definition, it is limited in extent and of little clinical relevance, with patient symptomatology generally attributed to the primary pulmonary diagnosis causing the emphysema, such as pulmonary fibrosis or sarcoidosis.13 PHYSIOLOGY The destruction of pulmonary parenchyma by emphysema creates a decreased mass of functioning lung tissue and thereby decreases the amount of gas exchange that can take place. As lung tissue is destroyed, it loses its elastic recoil and its volume expands. When destruction and expansion occur in a nonuniform manner, the most affected lung tissue can crowd the relatively spared lung tissue and prevent adequate ventilation of the latter. Eventually, obstruction of the small airways can occur, with obstruction being caused by a combination of reversible bronchospasm and

60  Emphysema

767

Fig. 60.2  Panlobular emphysema. (A) Low-power view of a lung specimen demonstrates severe uniform enlargement of the airspaces. (B) Histologic specimen shows uniform diffuse enlargement and destruction of the alveoli throughout the acinus. (Courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Vancouver, Canada.)

A

B

irreversible loss of elastic recoil by adjacent lung parenchyma. The suitability of a patient for a given treatment will largely depend on the relative contributions of lung destruction, lung recoil, and small airways obstruction to the overall physiologic and clinical impairment of the patient.30 In patients with emphysema, the forced expiratory volume in 1 second (FEV1), the forced vital capacity (FVC), the forced expiratory volume as a percentage of vital capacity (FEV/FVC%), the forced expiratory flow (FEF25%–75%), and the maximum expiratory flow at 50% and 75%, respectively, of exhaled vital capacity (Vmax50% and Vmax75%, respectively) will all be reduced. All of these parameters reflect functional obstruction, whether this is caused by alteration of the airway itself or by loss of radial traction resulting from emphysema. The FVC is reduced because the airways close prematurely at an abnormally high lung volume, which is at the source of an increased residual volume.31,32 On the other hand, the total lung capacity, the functional residual capacity, and the residual volume are typically increased. In severe disease the expiratory flow-volume curve is grossly abnormal. Flow is strikingly reduced as the airways collapse, and

flow limitation by dynamic compression occurs. A scooped-out appearance of the curve is often seen. Flow is greatly reduced in relation to lung volume and ceases at high lung volume because of premature airway closure. Simultaneously, the inspiratory flow-volume curve may be nearly normal. As elastic recoil of the lung is reduced in emphysema, the pressure-volume curve is displaced up and to the left. This probably reflects the disorganization and perhaps loss of elastic tissue as a result of destruction of alveolar walls.31,32

Manifestations of the Disease RADIOGRAPHY The only direct sign of emphysema on radiographs is the presence of bullae (see Fig. 60.3). However, because of the limited contrast resolution of the chest radiograph, these focal areas of increased lucency can be difficult to detect.33 Indirect signs of lung destruction caused by emphysema include the focal absence of pulmonary vessels and the reduction of vessel caliber with tapering toward the lung periphery. Abnormalities of the vascular pattern are

768

SECTION 11  Diseases of the Airways

B

A

Fig. 60.3  Vanishing lung syndrome. (A) Frontal chest radiograph shows severe upper lung zone bullae formation resulting in significant vascular crowding of the lung bases. (B) Axial CT confirms large peripheral bullae occupying more than one-third of each hemithorax in this young man. (C) Coronal minimum-intensity projection image better demonstrates the large middle and upper lung zone bullae occupying more than one-third of each hemithorax.

indeed highly suggestive of emphysema, but their sensitivity is low. These findings have a sensitivity of only 40% in detecting emphysema.34 Findings related to hyperinflation of the lungs include flattening of the diaphragm and an increased retrosternal space on the lateral view (Figs. 60.4 and 60.5). These findings are more common than abnormalities of the vascular pattern, but their specificity is also low.34 The combined signs of hyperinflation and vascular alterations have been shown to allow the diagnosis of emphysema in 29 of 30 autopsy-proven, symptomatic patients but in only 8 of 17 autopsy-proven, asymptomatic patients.35 Taking the above into consideration, limitations of radiography in the assessment of emphysema include its low specificity, its low sensitivity in the evaluation of mild disease, its considerable interobserver variability in the interpretation of findings, and its inability to quantify the severity of emphysema.12,33–35

C

COMPUTED TOMOGRAPHY Computed tomography is superior to chest radiography in the detection of emphysema and in the assessment of its distribution and extent. On CT emphysema is characterized by the presence of areas of low attenuation that contrast with the surrounding lung parenchyma with normal attenuation (Fig. 60.6).14,36 Mild to moderate centrilobular emphysema is characterized by the presence of multiple rounded and small areas of low attenuation that have diameters of several millimeters and usually have upper lung zone predominance (Fig. 60.7). The lesions have no walls, as they are limited by the surrounding lung parenchyma. Sometimes, the lesions may appear to be grouped around the center of secondary pulmonary lobules (Figs. 60.8).14,37 Panlobular emphysema is characterized by a uniform destruction of the secondary pulmonary lobule. This leads to widespread and relatively homogeneous patterns of low attenuation.14,38 Panlobular

60  Emphysema

A

769

B Fig. 60.4  Severe panlobular emphysema. Frontal (A) and lateral (B) chest radiographs show increased intrathoracic volume and flattened diaphragm resulting from overinflation. Simultaneously, transparency of the lung is increased, lung structure is rarified, and increased interstitial markings are shown.

Fig. 60.5  Centrilobular emphysema: radiographic findings. Transparency of the lung parenchyma is nearly normal. In the lung apices, deviation of vascular structures and subtle curvilinear opacities suggest the presence of emphysema and bullae.

Fig. 60.6  Centrilobular emphysema: classic CT findings. CT image targeted to the right lung shows well-defined “holes” in the centrilobular portions of the secondary pulmonary lobule surrounding small vessels. Note the lack of visible walls.

770

SECTION 11  Diseases of the Airways

Fig. 60.7  Centrilobular emphysema: coronal reconstruction. Coronal reformatted CT image shows apical predominant emphysema. Fig. 60.9  Moderate panlobular emphysema. High-resolution CT section through the left upper lobe shows areas of hypoattenuation with effacement of the lung structure. Structures suggestive of secondary pulmonary lobules can barely be detected.

Fig. 60.8  Moderate centrilobular emphysema: coronal reconstruction of high-resolution CT image of the right lung. Although emphysematous lesions can be seen in the entire lung, emphysema predominates in the upper lobe and the uppermost parts of the lower lobe.

emphysema can involve the entire lung in a homogeneous manner or show lower lung zone predominance (Figs. 60.9 and 60.10). On CT, paraseptal emphysema is seen as single or multiple bullae adjacent to the pleura or along interlobular septa (Fig. 60.11). It may be an isolated finding or be associated with centrilobular or panlobular emphysema (Fig. 60.12). The assessment of mild emphysema can further benefit from the use of minimum-intensity projection technique (Fig. 60.13). This technique uses dedicated software that identifies only areas of lung parenchyma with the lowest attenuation values and simultaneously suppresses normal lung and pulmonary vessels. The technique is based on “slabs” of contiguous high-resolution CT sections through a sample of lung tissue. Comparing minimumintensity projection and 1-mm high-resolution CT sections, a study has found that the minimum-intensity projection technique is more sensitive for the detection of subtle emphysema.39 Of note, the distribution of emphysema in the craniocaudal plane is an important point to recognize and include in the radiology report. Lung volume reduction surgery (LVRS) is a good treatment option for patients with end-stage emphysema and preserved exercise tolerance. CT characterization of the distribution of disease is critical for preoperative evaluation of surgical candidacy. Those patients with a majority of the emphysema in the upper lungs, so-called nonhomogeneous distribution, benefit from LVRS. Those patients with a more diffuse distribution, so-called homogeneous distribution, do not benefit from surgical resection.

60  Emphysema

771

emphysema objectively with CT: first, the use of a threshold density value below which emphysema is considered to be present (threshold technique); second, the assessment of a range of densities present in a CT section and displayed as a distribution curve (histogram technique); and third, the measurement of the overall CT density of the lung parenchyma. In 1988 Müller and colleagues41 used a commercially available CT program called Density Mask (General Electric Medical Systems, Milwaukee, WI) that highlights pixels within a given attenuation range and automatically calculates the area of highlighted pixels. In their study the highest correlation was observed with attenuation values lower than −910 Hounsfield units (HU), and as consequence, this threshold was recommended for the identification of emphysema. This work has been built upon by several others, and a more frequently used cutoff for this technique is now −950 HU, which provides better sensitivity and specificity, with thresholds below this value underestimating emphysema and thresholds above it overestimating emphysema. All of these CT techniques for quantifying emphysema remain in the research stage and are not yet in general use outside of academic medical centers and trials.

A

B Fig. 60.10  Advanced panlobular emphysema in a patient with α1antitrypsin deficiency. (A) Frontal chest radiograph showing hyperinflation with greatest lucency resulting from a vessel attenuation in the lower lung zones. (B) High-resolution CT image through the lower lobes shows extensive emphysematous destruction affecting the entire secondary pulmonary lobule. The lack of lung structures gives the resulting areas of hypoattenuation a relatively homogeneous appearance.

Objective Computed Tomographic Quantification of Emphysema The inherent limitations of subjective visual scoring, the characteristic CT morphology of emphysema, and the digital nature of the CT data set have raised considerable interest in the use of CT as an objective tool for quantification of pulmonary emphysema.40 Three main approaches have been used to quantify

Tissue Characterization Quantifications of pulmonary emphysema by computer-assisted methods are based on mathematic approaches, called metrics, that may be used to describe the heterogeneity of the spatial distribution of the attenuation values within the reconstructed image.42 These metrics include simple parameters, such as the mean lung density to areas of low attenuation based on a single or a range of density.42 Textural analyses are more complex metrics. There is considerable interest in these techniques. For example, Ginsburg and colleagues43 showed that a texture-based approach could differentiate between the lungs of never-smokers, smokers without visual emphysema, and smokers with emphysema. As such, textural analysis may be able to differentiate the very early stages of smoking-related lung injury before the development of emphysema. Comparison Between Computed Tomographic Quantification and Pulmonary Function Tests Although pulmonary function tests may be short- and long-term reproducible tests, they represent global measurements of lung function of more than 10 million airways that contribute unequally to airflow.44 They are of limited value in the measurement of the obstruction of airways, particularly small airways that are predominantly affected in emphysema,44 and autopsy studies have shown that up to one-third of the lung can be destroyed by emphysema before respiratory function becomes impaired.45 The insensitivity of pulmonary function tests to diagnose mild emphysema was confirmed by Sanders and colleagues,46 who found that features of emphysema were visually detected on CT scans in 69% of smokers with normal diffusing lung capacity for carbon monoxide with or without associated obstructive deficit. These authors concluded that CT may be more sensitive than pulmonary function tests in detecting mild emphysema. The lack of sensitivity of pulmonary function tests for the detection of pulmonary emphysema can be explained by two reasons related to pulmonary zones in which ventilatory disorders are not assessed by conventional pulmonary function tests. First, the total airflow resistance of all respiratory bronchioles contributes little to the total airflow resistance of the lung.44

772

A

SECTION 11  Diseases of the Airways

P

B

Fig. 60.11  Paraseptal emphysema: typical CT findings in two patients. (A) CT image through the lower lungs shows paraseptal emphysema and blebs adjacent to the pleura and along interlobular septa. (B) CT image at the level of the aortic arch shows multiple bullae adjacent to the pleura, typical of paraseptal emphysema. Fig. 60.12  Centrilobular and paraseptal emphysema. Highresolution CT image shows centrilobular emphysema (arrowheads) with preserved centrilobular core structures (small arrows). In subpleural location, paraseptal emphysema is seen (curved arrows).

A

B Fig. 60.13  Minimum-intensity projection images to diagnose subtle emphysema. (A) CT image shows subtle centrilobular emphysema in the upper lobes. (B) Lesions are much better seen on the minimumintensity projection image.

60  Emphysema

Despite the high airflow resistance through one single respiratory bronchiole, the parallel connection of a large number of bronchioles leads to a wide total cross-sectional area and dramatically reduces the airflow resistance.47 Second, the upper lung zone has a relatively high ventilation-perfusion ratio compared with the lower lung zone. Thus, in the relatively underventilated upper lung zone, emphysema produces less measurable pulmonary dysfunction than in the lower zone. MAGNETIC RESONANCE IMAGING Conventional magnetic resonance imaging (MRI) of the lung parenchyma is difficult to perform. Hyperpolarized helium-3 (3He)-enhanced MRI is still an investigational technique whereby the airspaces are visualized after the inhalation of polarized helium. Using this technique, it has been demonstrated that the apparent diffusion coefficient values in the lungs of patients with clinical symptoms of emphysema are increased relative to those in subjects without emphysema,48 and there is some evidence suggesting that regional emphysematous changes can be identified by such MRI techniques at an early stage when there are no clinical symptoms.48,49 More recently, developments in diffusionweighted MRI by use of hyperpolarized xenon-129 gas, which is substantially less expensive than 3He and more readily available, are also encouraging.49 IMAGING ALGORITHMS If concomitant signs of hyperinflation are absent, the chest radiograph in patients with mild disease may be normal. Even the changes in patients with moderate disease can be so subtle that they are overlooked on chest radiographs. Patients with suspected emphysema because of either a smoking history or a known α1-antitrypsin deficiency should therefore proceed to CT early in the course of their disease. CT should be performed in typical full-suspended inspiration. The intravenous administration of contrast material and expiratory CT sections are not required in the evaluation of emphysema, but expiratory CT may be useful for evaluating other causes of small airways disease that could be present.

Differential Diagnosis CENTRILOBULAR EMPHYSEMA Given the distinct morphologic features and the distribution of the disease, correctly diagnosing centrilobular emphysema is not difficult in typical cases. Panlobular emphysema shows more homogeneous patterns of destruction than centrilobular emphysema with regard to the secondary pulmonary lobule. The panlobular emphysema craniocaudal distribution is also more uniform to lower lung predominance. It is important to recognize that severe centrilobular emphysema may demonstrate a confluent pattern that is identical to panlobular emphysema. However, because of the strong association of panlobular emphysema with α1-antitrypsin deficiency, the use of panlobular as a descriptor should be reserved for those cases where the radiologist specifically wants the referring clinician to consider α1-antitrypsin deficiency as a possible underlying etiology rather than merely severe smoking-related emphysema. In addition, α1-antitrypsin deficiency is associated with liver cirrhosis and hepatocellular carcinoma, so a careful evaluation of the hepatic parenchyma for

773

evidence of these is important in suspected cases. Rarer complications of α1-antitrypsin deficiency include panniculitis and vasculitis. Pulmonary Langerhans cell histiocytosis is another smokingrelated disorder. Other than in centrilobular emphysema, the “holes” seen here are preceded by nodules that evolve to cysts. The disease, however, can have an upper lung zone distribution that is similar to the one seen in centrilobular emphysema. Cysts in the lung parenchyma can be lined by fibrous tissue or bronchiolar epithelium. This always gives them a visible “wall,” which distinguishes them from the lesions seen in centrilobular emphysema. The same is true for the large group of entities summarized as “cystic lung lesions,” such as lymphangioleiomyomatosis or lymphocytic interstitial pneumonia; all of these have walls, but lesions in centrilobular emphysema do not. PANLOBULAR EMPHYSEMA In panlobular emphysema the differential diagnosis can be more difficult than in centrilobular emphysema. As mentioned earlier, the distribution of disease in the craniocaudal plane tends to be more uniform to lower lung predominance. Similar to centrilobular emphysema, the cystic lung diseases can be considered in the differential but would demonstrate more definable walls. Panlobular emphysema may be difficult to distinguish from constrictive bronchiolitis. Both conditions may result in diffuse areas of decreased attenuation and vascularity. The main distinguishing features are parenchymal destruction and vascular distortion in panlobular emphysema; absence of these features is characteristic of constrictive bronchiolitis. PARASEPTAL EMPHYSEMA It is usually easy to identify paraseptal emphysema on CT and to distinguish it from other lung diseases. The main differential diagnosis is with honeycombing in patients who have ground-glass opacities superimposed on areas of paraseptal emphysema. The areas of low attenuation in paraseptal emphysema tend to be larger (1 cm or more) and have thinner walls (1 mm or less) than areas of honeycombing. Furthermore, areas of honeycombing tend to be associated with volume loss and other signs of fibrosis, such as reticulation and traction bronchiectasis. Finally, the craniocaudal distribution of paraseptal emphysema tends to be upper lung zone predominant, and honeycomb cysts tend to be lower lung zone predominant.

Synopsis of Treatment Options MEDICAL • Smoking cessation can substantially slow or even stop the progression of pulmonary emphysema. • Antibiotic administration aims to prevent pulmonary infection. • Corticosteroids or bronchodilators are used mainly in patients with coexisting small airways disease. • Pulmonary rehabilitation aims to improve functional exercise capacity and health-related quality of life and to reduce the use of health care resources. • α1-Antitrypsin substitution, sometimes called augmentation, is available.

774

SECTION 11  Diseases of the Airways

KEY POINTS CENTRILOBULAR EMPHYSEMA • Strongly associated with cigarette smoking • Well-defined “holes” in the centrilobular portions of the secondary pulmonary lobule • Well-defined margins between normal and emphysematous lung create an inhomogeneous appearance • Anatomic borders of the secondary pulmonary lobule are preserved • Predominantly involves upper lung zones • Differential diagnoses include panlobular emphysema, pulmonary Langerhans cell histiocytosis, and “cystic” lung lesions

PANLOBULAR EMPHYSEMA • Strongly associated with α1-antitrypsin deficiency • Ill-defined absence of lung parenchyma • Ill-defined margins between normal and emphysematous lung create a homogeneous appearance • Anatomic borders of the secondary pulmonary lobule are not preserved • Homogeneously distributed, occasionally with lower lung zone predominance • Differential diagnoses include severe centrilobular emphysema, constrictive bronchiolitis, and cystic lung diseases, such as pulmonary Langerhans cell histiocytosis, lymphocytic interstitial pneumonia, and lymphangioleiomyomatosis

SURGICAL

SUGGESTED READINGS

• Endobronchial valves: This intervention consists of the endoscopic implantation of endobronchial valves to collapse distal parts of the lung and to improve respiratory mechanics. • Bullectomy aims to increase the intrathoracic volume occupied by lung tissue participating in gas exchange by resection of one or more bullae, which by definition do not participate in gas exchange. • In lung volume reduction surgery, the most emphysematous part of the lung is resected to improve the respiratory mechanics and the expansion of the remaining lung tissue. • Lung transplantation is reserved for advanced cases of emphysema.

Edwards RM, et al. Imaging of small airways and emphysema. Clin Chest Med. 2015;36(2):335–347, x. Lee P, et al. Emphysema in nonsmokers: alpha 1-antitrypsin deficiency and other causes. Cleve Clin J Med. 2002;69(12):928–929, 933, 936 passim. Lynch DA, Al-Qaisi MA. Quantitative computed tomography in chronic obstructive pulmonary disease. J Thorac Imaging. 2013;28(5):284–290. Matsuoka S, et al. Quantitative CT assessment of chronic obstructive pulmonary disease. Radiographics. 2010;30(1):55–66. Milanese G, et al. Lung volume reduction of pulmonary emphysema: the radiologist task. Curr Opin Pulm Med. 2016;22(2):179–186. Takahashi M, et al. Imaging of pulmonary emphysema: a pictorial review. Int J Chron Obstruct Pulmon Dis. 2008;3(2):193–204.

The full reference list for this chapter is available at ExpertConsult.com.

60  Emphysema 774.e1

REFERENCES 1. Snider GL, Kleinerman JL, Thurlbeck WM, Bengali ZH. The definition of emphysema: report of a National Heart, Lung, and Blood Institute, Division of Lung Disease Workshop. Am Rev Respir Dis. 1985;132:182–183. 2. MacNee W. Pathogenesis of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2:258–266, discussion 290–291. 3. Kim WD, Eidelman DH, Izquierdo JL, et al. Centrilobular and panlobular emphysema in smokers. Two distinct morphologic and functional entities. Am Rev Respir Dis. 1991;144:1385–1390. 4. Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet. 2004;364:709–721. 5. Pauwels RA, Buist AS, Ma P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD): executive summary. Respir Care. 2001;46:798–825. 6. Viegi G, Maio S, Pistelli F, et al. Epidemiology of chronic obstructive pulmonary disease: health effects of air pollution. Respirology. 2006;11:523–532. 7. Mannino DM. COPD: epidemiology, prevalence, morbidity and mortality, and disease heterogeneity. Chest. 2002;121:121S–126S. 8. Centers for Disease Control and Prevention. Cigarette smoking among adults—United States, 2005–2015. MMWR Morb Mortal Wkly Rep. 2016; 65(44):1205–1211. 9. World Health Organization. WHO Global Report on Trends in Prevalence of Tobacco Smoking, 2015. Geneva: World Health Organization Press; 2015. Available at http://apps.who.int/iris/bitstream/10665/156262/1/9789241564922_eng.pdf. 10. U.S. Department of Health and Human Services. The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2014. 11. Bankier AA, Madani A, Gevenois PA. CT quantification of pulmonary emphysema: assessment of lung structure and function. Crit Rev Comput Tomogr. 2002;43:399–417. 12. Thurlbeck WM, Müller NL. Emphysema: definition, imaging, and quantification. AJR Am J Roentgenol. 1994;163:1017–1025. 13. Wright JL, Churg A. Advances in the pathology of COPD. Histopathology. 2006;49:1–9. 14. Webb WR, Stein MG, Finkbeiner WE, et al. Normal and diseased isolated lungs: high-resolution CT. Radiology. 1988;166:81–87. 15. Webb WR. Thin-section CT of the secondary pulmonary lobule: anatomy and the image—the 2004 Fleischner lecture. Radiology. 2006;239:322–338. 16. Wright JL, Churg A. Animal models of cigarette smoke–induced COPD. Chest. 2002;122:301S–306S. 17. Tuder RM, McGrath S, Neptune E. The pathobiological mechanisms of emphysema models: what do they have in common? Pulm Pharmacol Ther. 2003;16:67–78. 18. Shapiro SD. Animal models for chronic obstructive pulmonary disease: age of Klotho and Marlboro mice. Am J Respir Cell Mol Biol. 2000;22:4–7. 19. Shapiro SD. Evolving concepts in the pathogenesis of chronic obstructive pulmonary disease. Clin Chest Med. 2000;21:621–632. 20. Shapiro SD. Transgenic and gene-targeted mice as models for chronic obstructive pulmonary disease. Eur Respir J. 2007;29:375–378. 21. Shapiro SD, Demeo DL, Silverman EK. Smoke and mirrors: mouse models as a reflection of human chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;170:929–931. 22. Churg A, Wright JL. Proteases and emphysema. Curr Opin Pulm Med. 2005;11:153–159. 23. Mahadeva R, Shapiro SD. Chronic obstructive pulmonary disease. 3: Experimental animal models of pulmonary emphysema. Thorax. 2002;57:908–914. 24. Lee P, et al. Emphysema in nonsmokers: alpha 1-antitrypsin deficiency and other causes. Cleve Clin J Med. 2002;69(12):928–929.

25. Deleted in review. 26. Deleted in review. 27. Anile M, et al. Unilateral vanishing lung syndrome. Thorax. 2016;71(7): 671–672. 28. Tashtoush B, et al. Vanishing lung syndrome in a patient with HIV infection and heavy marijuana use. Case Rep Pulmonol. 2014;2014:285208. 29. Sharma N, et al. Vanishing lung syndrome (giant bullous emphysema): CT findings in 7 patients and a literature review. J Thorac Imaging. 2009;24(3): 227–230. 30. Meyers BF, Patterson GA. Chronic obstructive pulmonary disease. 10: Bullectomy, lung volume reduction surgery, and transplantation for patients with chronic obstructive pulmonary disease. Thorax. 2003;58:634–638. 31. Westcott RN. The physiology of ventilation in chronic lung disease. Postgrad Med. 1952;12:329–338. 32. West JB. Teaching slide–tape set on respiratory physiology. J Physiol. 1975;246:14P. 33. Müller NL, Coxson H. Chronic obstructive pulmonary disease. 4: Imaging the lungs in patients with chronic obstructive pulmonary disease. Thorax. 2002;57:982–985. 34. Thurlbeck WM, Simon G. Radiographic appearance of the chest in emphysema. AJR Am J Roentgenol. 1978;130:429–440. 35. Sutinen S, Christoforidis AJ, Klugh GA, Pratt PC. Roentgenologic criteria for the recognition of nonsymptomatic pulmonary emphysema. Correlation between roentgenologic findings and pulmonary pathology. Am Rev Respir Dis. 1965;91:69–76. 36. Hruban RH, Meziane MA, Zerhouni EA, et al. High resolution computed tomography of inflation-fixed lungs. Pathologic-radiologic correlation of centrilobular emphysema. Am Rev Respir Dis. 1987;136:935–940. 37. Murata K, Itoh H, Todo G, et al. Centrilobular lesions of the lung: demonstration by high-resolution CT and pathologic correlation. Radiology. 1986;161: 641–645. 38. Murata K, Khan A, Herman PG. Pulmonary parenchymal disease: evaluation with high-resolution CT. Radiology. 1989;170:629–635. 39. Remy-Jardin M, Remy J, Gosselin B, et al. Sliding thin slab, minimum intensity projection technique in the diagnosis of emphysema: histopathologic-CT correlation. Radiology. 1996;200:665–671. 40. Gevenois PA, Yernault JC. Can computed tomography quantify pulmonary emphysema? Eur Respir J. 1995;8:843–848. 41. Müller NL, Staples CA, Miller RR, Abboud RT. “Density mask.” An objective method to quantitate emphysema using computed tomography. Chest. 1988;94:782–787. 42. Hoffman EA, McLennan G. Assessment of the pulmonary structure-function relationship and clinical outcomes measures: quantitative volumetric CT of the lung. Acad Radiol. 1997;4:758–776. 43. Ginsburg SB, Lynch DA, Bowler RP, et al. Automated texture-based quantification of centrilobular nodularity and centrilobular emphysema in chest CT images. Acad Radiol. 2012;19:1241–1251. 44. Gurney JW. Pathophysiology of obstructive airways disease. Radiol Clin North Am. 1998;36:15–27. 45. Uppaluri R, Mitsa T, Sonka M, et al. Quantification of pulmonary emphysema from lung computed tomography images. Am J Respir Crit Care Med. 1997;156:248–254. 46. Sanders C, Nath PH, Bailey WC. Detection of emphysema with computed tomography. Correlation with pulmonary function tests and chest radiography. Invest Radiol. 1988;23:262–266. 47. Rienmüller RK, Behr J, Kalender WA, et al. Standardized quantitative high resolution CT in lung diseases. J Comput Assist Tomogr. 1991;15: 742–749. 48. Salerno M, de Lange EE, Altes TA, et al. Emphysema: hyperpolarized helium 3 diffusion MR imaging of the lungs compared with spirometric indexes— initial experience. Radiology. 2002;222:252–260. 49. de Lange EE. Science to practice: what is new about detecting emphysema? Radiology. 2006;239:619–620.

SECTION 12

Inhalational Diseases and Aspiration

61 

Asbestos-Related Disease* STEPHEN B. HOBBS

Etiology Asbestos is the general term given to a group of magnesium silicate minerals that have in common a tendency to separate into fibers.1 The fibers are resistant to heat and acid, thus the name asbestos, which is derived from the Greek meaning inextinguishable (a-, “not,” and sbestos, “extinguishable”). Because asbestos is not combustible, has great tensile strength, and is durable, it has been widely used in insulation materials, brake pads and linings, floor tiles, electric wiring, paints, and cements. Asbestos can be divided mineralogically into two major groups: the serpentines, of which the only member of commercial importance is chrysotile (white asbestos); and the amphiboles, which include amosite (brown asbestos), crocidolite (blue asbestos), and tremolite (a common contaminant of chrysotile). Chrysotile fibers are typically curved, whereas the amphiboles are straight. These physical properties and chemical differences are responsible for the varying uses of asbestos and for their ability to cause disease. Chrysotile is more easily cleared from the lung than the amphiboles, has a weaker fibrinogenic and carcinogenic potential, and is the only type of asbestos fiber that is still widely used. The current products are mainly cements, friction materials, and plastics.2

Prevalence and Epidemiology The widespread use of asbestos in the first 7 decades of the 20th century resulted in an epidemic of asbestos-related illness that continues into the 21st century in spite of a major decline in use after documentation of its major hazards, particularly for amphibole asbestos fibers (crocidolite and amosite) in the 1970s and 1980s.1 Although the use of asbestos has now been banned in many Western countries, the prevalence of asbestos-related pulmonary and pleural complications has been increasing.3 For example, surveys in the United States and in Europe have shown a doubling of the prevalence of asbestos-related pleural complications, including mesothelioma, between the early 1970s and 2000.3 Similarly, whereas mortality rates for the other pneumoconioses decreased between 1968 and 2000, the mortality of asbestosis increased steadily, and it is now the most frequently recorded pneumoconiosis on death certificates.4 It has been estimated that 8 to 9 million people in the United States have had occupational exposure to asbestos and that such exposure will *The editors and the publisher would like to thank Drs. C. Isabela Silva Müller and Nestor L. Müller for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

eventually result in 300,000 deaths.5 These complications are still occurring because the interval between initial exposure and subsequent biological consequences of asbestos exposure is variable, ranging from approximately 1 year for some cases of pleural effusion to more than 40 years for mesothelioma.3 The four main settings in which asbestos-related disease is seen in the Western world are 1. The historical legacy of asbestos exposure affecting older workers 2. The current risk experienced by the work force engaged in certain occupations managing the remaining asbestos hazard, such as building and facility maintenance 3. Asbestos abatement operations for removal of insulation and other asbestos-containing products 4. Renovation and demolition of structures containing asbestos1 Most asbestos in North America today exists in building and machinery insulation and old products, such as appliances. New products that may contain asbestos today in the United States include friction surfaces (brake pads), roofing materials, vinyl tiles, and imported cement pipe and sheeting.1 It is estimated that asbestos is currently still a hazard for approximately 1.3 million workers in the construction industry in the United States and for workers involved in maintenance of buildings and equipment.1 The risk of asbestos exposure is considerably higher in countries where it continues to be used.1 Currently, the majority of asbestos is mined in Russia, with other mining operations existing in China, Brazil, and Kazakhstan.6 Until 2011 Quebec, Canada, operated two asbestos mines, but those mines are now closed despite a 2012 legislative attempt to restart one of the mines.

Clinical Presentation Most patients who have asbestos-related pleuropulmonary disease are asymptomatic. Patients with asbestosis, chronic airflow obstruction, or diffuse pleural fibrosis may present with shortness of breath.7 The onset of dyspnea in asbestosis is typically insidious, beginning with dyspnea on exertion.1 The dyspnea related to asbestosis is generally progressive, even in the absence of continued dust exposure. In patients who have asbestosis, shortness of breath seldom occurs sooner than 20 to 30 years after initial exposure.7 A nonproductive cough is also commonly present.1 Pleuritic chest pain may accompany the development of benign asbestos effusion or mesothelioma. Benign asbestos effusions are generally less than 500 mL in volume, are often serosanguineous, and may persist for 2 weeks to 6 months.7 They are recurrent in 15% to 30% of cases. The presence of pleural effusion or diffuse pleural thickening should raise the possibility of mesothelioma. 775

776

SECTION 12  Inhalational Diseases and Aspiration

Pathophysiology The pathogenesis of asbestos-related pleuropulmonary disease is complex and incompletely understood. Fiber dose, dimension, and chemical composition may all influence fibrogenicity and carcinogenicity; longer, thinner, more durable fibers (amphiboles) are the most important.8 Factors related to the host, including pulmonary clearance, immunologic status, and exposure to other noxious substances, such as cigarette smoke, are also important in determining the nature and severity of the reaction to inhaled fibers.7 Asbestos fibers are deposited at airway bifurcations and in respiratory bronchioles and alveoli.1 They migrate into the interstitium, in part through an uptake process involving type I alveolar epithelial cells. Once they reach the interstitium, the asbestos fibers cause an alveolar macrophage-dominated alveolitis, inflammation in the surrounding interstitium, and inflammation followed by fibrotic change in the respiratory bronchioles that extends into the adjacent alveolar tissue.1

on the presence of two findings: diffuse interstitial fibrosis, which in advanced cases is identical to that seen in usual interstitial pneumonia, and asbestos bodies, fibers of asbestos to which the lung has added an iron-protein coating (Figs. 61.2 and 61.3).11 The development of asbestosis requires heavy exposure to asbestos and therefore is seen mainly in asbestos miners and millers, asbestos textile workers, and asbestos insulators. Fibrosis of adjacent visceral pleura is common and often accompanied by parietal pleural adhesions.11 Asbestosis is commonly associated with prolonged exposure, usually over 10 to 20 years, and the degree of fibrosis is dose dependent.1 Transport of the asbestos fibers to the pleural surface along lymphatic channels or by direct penetration results in pleural inflammation and fibrosis.1 Rounded Atelectasis.  Rounded atelectasis, also known as folded lung, consists of a more or less spherical focus of collapsed parenchyma in the periphery of the lung.7 The overlying pleura is invariably fibrotic and shows one or more invaginations 1 mm

PATHOLOGIC CHARACTERISTICS Asbestos-Related Pulmonary Abnormalities Asbestosis.  The earliest pulmonary abnormality seen in association with asbestos exposure consists of fibrosis in the walls of respiratory bronchioles (Fig. 61.1). This process, however, is pathogenetically distinct from pulmonary parenchymal fibrosis and may be seen in patients with a history of exposure to mineral dust other than asbestos.7,9 Peribronchiolar fibrosis is probably better considered a form of asbestos airway disease separate from asbestosis.9,10 Asbestosis itself is defined as diffuse interstitial pulmonary fibrosis caused by the inhalation of excessive amounts of asbestos fibers. The interstitial fibrosis involves mainly the lower zones; the worst disease is generally seen closest to the pleura, with relative sparing of the central portions of the lung.11 The microscopic appearance varies from a slight increase in interstitial collagen to complete obliteration of normal lung architecture and the formation of thick fibrous bands and honeycombing. The microscopic diagnosis of asbestosis is based

Fig. 61.2  Asbestosis. Low-power view shows diffuse fibrosis. (Courtesy Dr. Andrew Churg, Department of Pathology, University of British Columbia, Vancouver, Canada.)

Fig. 61.1  Asbestos-induced peribronchiolar fibrosis. Histologic specimen shows thickening of airway wall (arrows) resulting from peribronchiolar fibrosis and pigmented dust. (Courtesy Dr. Andrew Churg, Department of Pathology, University of British Columbia, Vancouver, Canada.)

Fig. 61.3  Asbestos body. Pathologic specimen from same case as in Fig. 61.1 shows typical beaded appearance and gold color of asbestos body (arrow). (Courtesy Dr. Andrew Churg, Department of Pathology, University of British Columbia, Vancouver, Canada.)

61  Asbestos-Related Disease

to 3 cm in length into the adjacent lung. Although rounded atelectasis is not related solely to asbestos, the majority of cases are associated with it. The lesion is believed to develop secondary to infolding of thickened visceral pleura with atelectasis of the intervening lung parenchyma.1 Rounded atelectasis may be multiple and bilateral. Lung Cancer.  Asbestos exposure is associated with an increased risk of lung cancer, and this risk is markedly increased in smokers (supraadditive effect—an effect greater than the sum of either risk alone).12 Amphiboles, particularly crocidolite, are more potent than chrysotile in inducing lung cancer (between 10 and 50 times greater potency).13 The risk of lung cancer in commercial chrysotile is believed to be largely determined by the varying content of tremolite.14 The mechanism of carcinogenesis is unclear. The latent period is variable. Some cases occur less than 10 years after exposure, but the majority of cases occur much later.2 In a study of 3383 asbestos-exposed workers, 63 (1.9%) had pulmonary carcinoma; the mean latency period for the development of carcinoma was 45.8 ± 9.4 years, and the mean age of patients was 67.6 ± 8.4 years.15 Asbestos-related cancers can occur anywhere in the lungs and be of any cell type. Although it is clear that asbestos exposure is associated with an increased incidence of lung cancer, it is controversial whether asbestos-related lung cancer arises only in the presence of pulmonary fibrosis. The various epidemiologic studies assessing the carcinogenic role of asbestos in the presence and absence of fibrosis were recently reviewed, and the conclusion of the reviewers was that the evidence is not conclusive and that the “question of whether or not asbestos-related lung cancer in man arises only in the presence of pulmonary fibrosis may be unanswerable epidemiologically.”16 Asbestos-Related Pleural Abnormalities Pleural Plaques.  These are the most common form of asbestosrelated pleuropulmonary disease.1 They are usually first seen 20 to 30 years after exposure.2 Pleural plaques consist of well-defined, pearly white foci of firm fibrous tissue, usually 2 to 5 mm thick and up to 10 cm in diameter.7 The major determinant of the thickness of the pleural plaques is duration from first exposure.1 The plaques may have a smooth surface or show fine or coarse nodularity and can be round, elliptical, or irregularly shaped. Histologic examination typically shows them to consist of dense, almost acellular collagen with a basket-weave pattern (Fig. 61.4).7,10 Pleural plaques are usually limited to the parietal pleura, although they may occasionally be seen in the interlobar fissures. Approximately 10% to 15% of pleural plaques calcify.2,17 Calcification is seldom evident in workers with a less than 30-year interval from time of first exposure.3 The calcification may be punctate, linear, or coalescent. Pleural Effusion. Although only a small percentage of individuals exposed to asbestos develop a benign pleural effusion (3%), this is the most common asbestos-related abnormality seen within the first 20 years after exposure.18 The effusion is exudative and often hemorrhagic.1 It may occur as early as 1 year after exposure or much later.19 Although usually asymptomatic, acute pleural effusions caused by asbestos may also be exuberant, with fever and severe pleuritic pain. Acute pleuritis is thought to underlie many cases of diffuse pleural thickening, with studies demonstrating diffuse pleural thickening in patients with prior benign asbestos effusion in 31% to 80% of patients.19,20 Diffuse Pleural Thickening.  Diffuse pleural thickening extends continuously over a portion of the visceral pleura and therefore

777

Fig. 61.4  Pleural plaque. Histologic specimen shows acellular collagen and basket-weave pattern characteristic of pleural plaque. (Courtesy Dr. Andrew Churg, Department of Pathology, University of British Columbia, Vancouver, Canada.)

is quite different in appearance from the circumscribed parietal pleural plaque. It may be extensive and cover the whole lung and obliterate lobar fissures; it ranges from less than 1 mm up to 1 cm or more in thickness. Adhesions to the parietal pleura are common. The thickening may extend for a few millimeters into the lung parenchyma and into the lobular septa. These features do not constitute asbestosis.1 Diffuse pleural thickening is seen in 9% to 22% of asbestos-exposed workers with pleural disease.1 The frequency of diffuse pleural thickening increases with time from first exposure and is believed to be dose related.1 Diffuse pleural thickening frequently develops after benign asbestos-related pleural effusion.19 Less commonly, it may be caused by extension of interstitial fibrosis to the visceral pleura, consistent with the pleural migration of asbestos fibers.1 Both circumscribed (pleural plaques) and diffuse pleural thickening may be present in the same hemithorax. Mesothelioma.  There is a strong association between asbestos exposure and the development of malignant mesothelioma; the majority of cases of mesothelioma are related to asbestos exposure.21 The risk of mesothelioma is much greater after exposure to amphiboles, particularly crocidolite (blue asbestos), than after exposure to chrysotile (white asbestos).22 Although it was initially believed that the risk of mesothelioma from exposure to chrysotile was due to contamination with the amphibole tremolite, similar to other lung cancers, current evidence suggests that chrysotile itself may cause malignant mesothelioma, although the risk is much lower than for amphiboles.22,23 Mesothelioma has occurred in three main cohorts of asbestos-exposed individuals: workers exposed to asbestos during its mining or milling; workers exposed in the manufacture and use of asbestos products, such as plumbers, carpenters, and installers of asbestos insulation; and persons who were exposed to asbestos unknowingly and incidentally.22 The last group accounts for 20% to 30% of current cases of malignant mesothelioma in industrialized countries.22 The incidence of mesothelioma has markedly increased during the past 30 years, currently being as common in men as carcinomas of the liver, bone, and bladder in many industrialized countries.21 In countries no longer using asbestos, the incidence of mesothelioma is now expected to start decreasing. However,

778

SECTION 12  Inhalational Diseases and Aspiration

in developing countries that have recently used asbestos or continue to use it, the rate of mesothelioma may continue to increase.24 The risk of mesothelioma is almost zero for the first 10 to 15 years after first exposure to asbestos but increases progressively thereafter throughout life.21 Although the role of asbestos in the development of mesothelioma has been extensively studied, and several explanations have been proposed as to how asbestos may result in the development of malignant disease,21 the pathogenesis of mesothelioma remains unclear. See Chapter 74 for additional discussion of mesothelioma. PULMONARY FUNCTION TESTS Patients with asbestosis may have restrictive lung function, mixed restrictive and obstructive disease, or airflow obstruction alone.7 When restriction is present, total lung capacity, vital capacity, residual volume, and diffusing capacity are decreased, but good ventilatory function is maintained.25 Many patients, however, show some degree of airway obstruction as a result of asbestos-induced bronchiolar fibrosis.25 In addition, emphysema is evident on computed tomography (CT) scans in about 50% of workers who have early asbestosis, a figure double that of those who do not.26 Restrictive lung function in asbestos workers may result from asbestosis or from asbestos-related pleural disease.25 The lung restriction (i.e., the decrease in vital capacity) is much more marked in patients who have diffuse pleural thickening than in those who have only plaques.27,28 This effect is unrelated to the radiographic extent of pleural thickening; a reduction in vital capacity with little more than costophrenic angle blunting can be similar to that with extensive involvement.29

Manifestations of the Disease RADIOGRAPHY Interpretation According to the International Classification of Radiographs of the Pneumoconioses The chest radiograph is an important tool for the detection of asbestos-related pleural and parenchymal abnormalities and to assess the progression of ensuing disease. For it to be useful in epidemiologic studies, however, it is essential that an acceptable classification of the extent of involvement be followed and a standard nomenclature be used. The most widely used schema is the International Labour Office (ILO) International Classification of Radiographs of Pneumoconioses, which was revised most recently in 2011.30 The objective of this classification is to codify the radiographic changes associated with the pneumoconioses in a simple and reproducible manner such that international comparability of pneumoconiosis statistics has some validity. Because this schema uses radiographic descriptors that are somewhat different from those generally used throughout this book, a short glossary of terms relevant to the interpretation of radiographs of asbestosexposed workers and other pneumoconiosis patients follows. Small Rounded Opacities. These opacities are wellcircumscribed nodules ranging in diameter from barely visible to up to 10 mm. The qualifiers p, q, and r subdivide the predominant opacities into three diameter ranges: p, up to 1.5 mm; q, 1.5 to 3.0 mm; and r, 3 to 10 mm. Small Irregular Opacities.  This term is used to describe a pattern that elsewhere in this book has been designated linear or reticular—in other words, a net-like pattern. Although the nature of these opacities is such that establishment of quantitative

dimensions is considerably more difficult than with rounded opacities, three categories have been created: s, width up to 1.5 mm; t, width exceeding 1.5 mm and up to 3.0 mm; and u, width exceeding 3 mm and up to 10 mm. To record shape and size, two letters must be used. If the reader of the radiograph thinks that all or virtually all opacities are one shape and size, this is noted by recording the symbol twice, separated by an oblique stroke (e.g., q/q). If another shape or size is appreciated, this is recorded as the second letter (e.g., q/t). The designation q/t means that the predominant small opacity is round and of size q, but in addition there are a significant number of small irregular opacities of size t. In this way, any combination of small opacities can be recorded. Profusion.  This term refers to the number of small opacities per unit area or zone of lung. There are four basic categories: category 0, small opacities absent or less profuse than in category 1; category 1, small opacities definitely present but few in number (normal lung markings are usually visible); category 2, numerous small opacities (normal lung markings are generally partly obscured); and category 3, very numerous small opacities (normal lung markings are usually totally obscured). These categories can be further subdivided by use of a 12-point scale to describe a continuum of changes from complete normality to the most advanced category or grade: 0/− 0/0 0/1; 1/0 1/1 1/2; 2/1 2/2 2/3; 3/2 3/3 3/+. When this scale is used, the radiograph is first classified into one of the four categories 0, 1, 2, or 3. If the category above or below is considered a serious alternative during the process, it is recorded (e.g., a radiograph in which profusion is considered to be category 2 but for which category 1 was seriously considered would be graded 2/1). If no alternative is considered (i.e., the profusion was definitely category 2), it would be classified 2/2. A subdivision is also possible within category 0. If the absence of small opacities is particularly obvious, profusion should be recorded as 0/−. Such a category might be seen in a healthy nonsmoking adolescent. The ILO standard radiographs are the final arbiters of opacity profusion and take precedence over any application of a verbal description of profusion. Thus this reading should always be done side by side with the ILO standard radiographs.30 A separate classification for large opacities (>1 cm in diameter) exists whereby A denotes one or more opacities greater than 1 cm but smaller than 50 mm; B denotes one or more opacities greater than A, combined area less than the right upper zone; and C denotes one or more opacities whose combined area is greater than the area of the right upper zone. Other Findings.  Pleural abnormalities are also assessed with respect to location, width, extent, and degree of calcification. Finally, other abnormal features of the chest radiograph can be noted. All of these abnormalities are more completely illustrated and described in the Guidelines for the Use of the ILO International Classification of Radiographs of Pneumoconioses.30 There is little doubt that expert readings are superior to nonexpert readings in the detection of disease and avoidance of “overreading.”31 However, use of the radiograph as a definitive tool for the diagnosis of pneumoconiosis in any given individual is limited by a significant prevalence of small opacities sufficient for “diagnosis” in nonexposed working populations, as well as by a significant degree of interreader and intrareader variability.32,33 Asbestos-Related Pulmonary Abnormalities Asbestosis.  The initial radiographic manifestation of asbestosis consists of bilateral small irregular linear opacities (reticular

61  Asbestos-Related Disease

pattern, s and t opacities in the ILO classification) in the lower lung zones.1 With progression of disease, the distribution and extent or profusion of opacities increases and may spread to the middle and upper lung zones (Fig. 61.5). Fibrosis in the right middle lobe and lingula may result in obscuration of the heart border (“shaggy heart sign”). Extensive fibrosis was more common in the past, with more patients currently having only mild fibrosis. In a study of 3383 asbestos-exposed workers referred for independent medical evaluation, most subjects (79%) had an ILO score below 1/1.15 The extent of parenchymal abnormalities (ILO classification profusion score) correlates strongly with functional impairment, particularly reduction in diffusing capacity and ventilatory capacity, and with mortality risk.1,34 In the assessment of radiographs of asbestos-exposed individuals, a critical distinction is made between radiographs that are suggestive but not presumptively diagnostic (0/1) and those that are presumptively diagnostic but not unequivocal (1/0). This dividing point is generally taken to separate radiographs that are considered to be “positive” for asbestosis (1/0 or higher profusion score) from those that are considered to be “negative” (0/1 or less).1 A chest radiograph showing the characteristic findings of asbestosis in the presence of a compatible history of exposure is adequate for the diagnosis; further imaging is not required.1 However, the chest radiograph has limited sensitivity and specificity in cases of mild fibrosis and may not provide sufficient additional information, such as degree of progression from prior imaging, for use in a given clinical case.1 Rounded Atelectasis.  The characteristic radiologic manifestation of rounded atelectasis is a rounded or oval, subpleural opacity associated with loss of volume and curving of adjacent pulmonary vessels and bronchi into the edges of the opacity (the “comet tail sign”; Fig. 61.6).35 The opacity typically abuts an area of pleural thickening or a pleural effusion. The abnormality may occur anywhere in the lungs, but it is most common in the middle and lower lung zones (see Fig. 61.6).36 In one review of 89 cases of rounded atelectasis in 74 patients, the lower lobes were affected in 33 cases (45%), the lingula in 33 (45%), the middle lobe in 16 (22%), and the upper lobes in 7 (9%).36 Rounded atelectasis may be unilateral or bilateral and usually measures 2 to 7 cm in diameter. Most cases of rounded atelectasis are associated with asbestos exposure; however, some have been described in association with other causes of pleural thickening or effusion.36 The lesion may develop and progress during a few months or several years. In a series of 74 patients, it occurred on a background of benign asbestos effusion in 9 and slowly increasing pleural thickening in 13; in the remaining 52 patients, it was a new finding, with earlier radiographs showing only plaques or being normal.36 Asbestos-Related Pleural Abnormalities Pleural Plaques.  Pleural plaques are the most common radiologic manifestation of asbestos-related disease.1 The characteristic findings on the chest radiograph consist of focal pleural opacities that have irregular margins when seen in profile and sharp, often foliate borders when seen en face (Fig. 61.7).1 The typical distribution of plaques on chest radiographs is the posterolateral chest wall between the 7th and 10th ribs, the lateral chest wall between the 6th and 9th ribs, the dome of the diaphragm (virtually diagnostic), and the paravertebral pleura (Fig. 61.8).2,17 The plaques may be bilateral and symmetric or bilateral and asymmetric and less commonly appear unilateral on the chest

779

radiograph.37 They may be smooth or nodular and can measure as much as 1 cm in thickness. Although noncalcified pleural plaques are the most common radiographic manifestation of asbestos-related disease, they are more striking when calcified, a finding that is seen in 10% to 15% of cases (Figs. 61.9 and 61.10).2,17 Although calcified plaques may be seen at any location, they are most common in relation to the diaphragm. The prevalence of pleural plaques is related to duration from first exposure; they are rare before 20 years.1 Calcification of pleural plaques is similarly related to duration and is more common 30 years after first exposure (see Fig. 61.10).1 Although detection of plaques radiographically is highly specific for a history of asbestos exposure, its sensitivity is relatively poor. Only 50% to 80% of cases of documented pleural thickening demonstrated by autopsy or thin-section CT are detected on the chest radiograph (Fig. 61.11).1 Diffuse Pleural Thickening.  Diffuse pleural thickening is seen in 9% to 22% of asbestos-exposed workers with pleural disease.1 The latency period ranges from 10 to 40 years or more. Diffuse pleural thickening is manifested radiologically as a generalized, more or less uniform increase in pleural width (Fig. 61.12). Diffuse thickening of the visceral pleura is not sharply demarcated and is often associated with fibrous strands (“crow’s feet”) extending into the parenchyma.1 Both circumscribed and diffuse pleural thickening may be present in the same hemithorax. The frequency of diffuse pleural thickening increases with time from first exposure and is believed to be dose related.1 The abnormality is generally considered to be present when there is a smooth, uninterrupted pleural density extending over at least a fourth of the chest wall on the chest radiograph. The ILO classification recognizes pleural thickening as diffuse “only in the presence of and in continuity with an obliterated costophrenic angle.”30 Localized subpleural parenchymal fibrosis is often present without diffuse interstitial fibrosis. Calcification of the pleura occurs with the passage of time and may involve the interlobar fissures.1 Separating diffuse pleural thickening from extrapleural fat is important but sometimes difficult.1 Extrapleural fat pads typically result in bilateral, symmetric “apparent pleural thickening” with gradually tapering or indistinct edges that does not extend into the costophrenic angles. These fat pads also typically occur in the midthoracic wall, between the fourth and eighth ribs, and do not have adjacent parenchymal linear opacities. Differentiation of fat from pleural plaques may be difficult on the radiograph but is readily made on CT (Fig. 61.13). Pleural Effusion.  Benign pleural effusion occurs in approximately 3% of asbestos-exposed individuals and is the most common asbestos-related abnormality seen within the first 20 years after exposure.18 In one review of 73 benign asbestos-related pleural effusions in 60 patients, the mean latency time from the first exposure to asbestos was 30 years, with a range of 1 to 58 years.38 The effusion may be asymptomatic or associated with fever and pleuritic chest pain. It may be unilateral or bilateral, persist for months, or recur on the same or the opposite side.38 The most comprehensive report of the prevalence of asbestosrelated pleural effusion was a study of 1135 exposed workers and 717 control subjects in whom benign asbestos effusion was defined by (1) a history of exposure to asbestos; (2) confirmation of the presence of effusion by radiography, thoracentesis, or both; (3) absence of other nonneoplastic disease that could have caused the effusion; and (4) absence of malignant tumor within 3 years.18 According to these criteria, 34 benign effusions (3%)

780

SECTION 12  Inhalational Diseases and Aspiration

A

B

C Fig. 61.5  Asbestosis: radiographic and CT findings. Chest radiograph (A) shows extensive bilateral reticulation and hazy increased opacity mainly in the lower lobes. Also note enlargement of the hilar pulmonary arteries consistent with pulmonary arterial hypertension. Magnified views of the right lung from high-resolution CT at the level of the right upper lobe bronchus (B) and right inferior pulmonary vein (C) demonstrate reticulation, minimal ground-glass opacities, and honeycombing, mainly in the subpleural and lower lung zones. Also note emphysema.

Fig. 61.8  Pleural plaques: characteristic distribution. Volume-rendered image from thin-section CT demonstrates calcified plaques along the ribs (arrows), diaphragm, and paravertebral region (arrowheads). Also noted is more extensive linear pleural calcification along the right paravertebral region.

Fig. 61.6  Rounded atelectasis: radiographic features. Magnified view of the left lung from a posteroanterior chest radiograph shows an oval opacity. The lateral margins (straight arrows) are well defined (where the opacity abuts the lung), and the medial margins are poorly defined (where the opacity abuts the pleura). Pulmonary vessels (curved arrows) can be seen to curve toward the opacity (comet tail sign).

Fig. 61.9  Calcified pleural plaques. Posteroanterior chest radiograph shows numerous bilateral calcified pleural plaques.

Fig. 61.7  Pleural plaques: radiographic findings. Posteroanterior chest radiograph shows multiple focal pleural opacities along the chest wall (straight arrows) and diaphragm (curved arrows) characteristic of pleural plaques.

782

SECTION 12  Inhalational Diseases and Aspiration

B

A

Fig. 61.10  Pleural plaques: development of calcification. (A) View of the right lower chest from a frontal radiograph shows noncalcified pleural plaques along anterior ribs (arrowheads) and right hemidiaphragm (arrow). (B) View from chest radiograph obtained 18 years later demonstrates calcification of the plaques along the anterior ribs (arrowheads) and right hemidiaphragm (arrow).

B

A

Fig. 61.11  Pleural plaques not evident on the radiograph. (A) Posteroanterior chest radiograph shows no definite pleural plaques. (B) Highresolution CT (HRCT) shows a noncalcified left pleural plaque (arrow). (C) HRCT at the level of the diaphragm shows bilateral noncalcified diaphragmatic pleural plaques (arrows).

C

61  Asbestos-Related Disease

were identified in the exposed workers versus none in the control subjects. The likelihood of the presence of effusion was dose related. The latency period was shorter than for other asbestosrelated disorders, effusion being the most common abnormality detected during the first 20 years after exposure. Most effusions

783

were small, 28% recurred, and 66% were asymptomatic.18 Asbestosrelated pleural effusion may resolve completely or result in residual pleural thickening that may be mild, resulting in blunting of the costophrenic angle, or diffuse.1,19 Mesothelioma.  The radiologic features of mesothelioma are discussed in Chapter 74. COMPUTED TOMOGRAPHY

Fig. 61.12  Diffuse pleural thickening: radiographic findings. Chest radiograph shows diffuse left pleural thickening. The pleural thickening along the lateral chest wall is seen in profile as a broad band of homogeneous increased opacity; the thickening along the posterior chest wall is seen en face as a hazy increased opacity over the left lower hemithorax.

A

Asbestos-Related Pulmonary Abnormalities Asbestosis.  The most common high-resolution CT (HRCT) manifestations of asbestosis are intralobular linear opacities (reticular pattern), irregular thickening of the interlobular septa, nondependent ground-glass opacities, subpleural small rounded or branching opacities, subpleural curvilinear opacities, and parenchymal bands (Figs. 61.14 and 61.15).39–41 The abnormalities involve mainly the peripheral and dorsal regions of the lung bases. Ground-glass opacities are defined as areas of increased attenuation that do not obscure the underlying vascular margins. Nondependent ground-glass opacities in asbestos-exposed persons may reflect the presence of mild alveolar wall fibrosis beyond the resolving power of CT, inflammation, or edema.42 Dependent ground-glass opacities are commonly seen, particularly in patients with chronic obstructive pulmonary disease, and represent atelectasis rather than asbestos-related disease. Groundglass opacities immediately adjacent to thick pleural plaques also usually represent compressive atelectasis rather than fibrosis or inflammation. Small, round (dot-like), and branching subpleural opacities are the earliest asbestos-related pulmonary abnormality evident on HRCT.41 Typically, they are visible a few millimeters from the pleural surface in a centrilobular location (Fig. 61.16). They reflect the earliest pulmonary abnormality seen in association with asbestos exposure—that is, fibrosis in

B Fig. 61.13  Extrapleural fat mimicking diffuse pleural thickening. (A) Posteroanterior radiograph shows apparent extensive bilateral pleural thickening (arrows). (B) Axial CT scan demonstrates that the apparent pleural thickening is due to abundant extrapleural fat (arrows). Unlike diffuse pleural thickening, extrapleural fat is generally symmetric, does not involve the costophrenic angles, and does not have adjacent lung fibrosis.

784

SECTION 12  Inhalational Diseases and Aspiration

B

A

C

D Fig. 61.14  Asbestosis: high-resolution CT (HRCT) findings. (A) HRCT image performed with the patient supine shows bilateral, predominantly subpleural intralobular lines and irregular thickening of interlobular septa. Also noted are nondependent ground-glass opacities and architectural distortion in the anterolateral aspect of the left upper lobe. (B) Soft tissue windows show calcified bilateral pleural plaques (arrows) and diffuse irregular left pleural thickening. Coronal (C) and sagittal (D) reformatted images demonstrate predominant subpleural distribution of the fibrosis.

the walls of respiratory bronchioles (see Fig. 61.1).41 Subpleural dot-like and branching opacities are often evident on CT in patients with normal radiographs and have been shown to progress to subpleural fibrosis.41 Subpleural curvilinear opacities are areas of increased attenuation of variable length located

within 1 cm of the pleura and parallel to the inner chest wall (Fig. 61.17).43 Most measure 5 to 10 cm in length. They are seen most commonly in early disease; they may reflect atelectasis adjacent to pleural plaques or fibrosis.41,42 Parenchymal bands are linear opacities measuring 2 to 5 cm in length that course

61  Asbestos-Related Disease

A

785

B Fig. 61.15  Asbestosis with severe fibrosis: high-resolution CT (HRCT) findings. (A) and (B) HRCT images performed with the patient prone show bilateral, predominantly subpleural intralobular lines and irregular thickening of interlobular septa with associated architectural distortion and mild subpleural honeycombing. Also noted are nondependent ground-glass opacities. The HRCT findings resemble those of idiopathic pulmonary fibrosis.

Fig. 61.16  Subpleural nodules in early asbestos-related lung disease. High-resolution CT image with the patient prone shows small, round (dot-like) subpleural opacities (arrows) and traction bronchiolectasis (arrowheads). They reflect the earliest pulmonary abnormality seen in association with asbestos exposure—that is, fibrosis in the walls of respiratory bronchioles. (Courtesy Dr. Jorge Kavakama, São Paulo, Brazil.)

through the lung and usually abut an area of pleural thickening (Fig. 61.18).44 Pathologic correlation has shown them to correspond to foci of peribronchovascular or interlobular septal fibrosis associated with distortion of the parenchymal architecture.42 The bands are more common in asbestosis than in other causes of pulmonary fibrosis; for example, in one study they were present in 79% of patients who had asbestosis, compared with 11% of patients who had idiopathic pulmonary fibrosis.45 As in other causes of interstitial pulmonary fibrosis, architectural distortion of secondary lobules and irregular thickening of interlobular septa are commonly seen in asbestosis. With progression of fibrosis, irregular linear opacities and honeycombing predominate.46,47 At all stages the abnormalities involve predominantly the subpleural regions of the lower lung zones.42,47 The fibrosis is frequently associated with thickening of the adjacent

Fig. 61.17  Subpleural curvilinear opacity. High-resolution CT with the patient prone shows curvilinear opacity and ground-glass opacities in the dependent lung adjacent to a pleural plaque. Although subpleural curvilinear opacities may represent fibrosis, there is no evidence of fibrosis in this patient; the curvilinear opacity and the dependent ground-glass opacities are due to atelectasis. (Courtesy Dr. Jorge Kavakama, São Paulo, Brazil.)

visceral pleura (see Fig. 61.14). Asbestosis tends to progress over time even after cessation of exposure (Fig. 61.19).48 Similar to other cases of possible fibrosis, dependent atelectasis may mimic or obscure early fibrosis, and it is essential that CT scans in these patients be obtained in the supine and prone positions or only in the prone position.46,49 CT also allows detection of parenchymal abnormalities not evident on the chest radiograph.39,40,44 In a review of the HRCT findings and pulmonary function test results of 169 asbestos-exposed workers who had normal chest radiographs (ILO profusion score below 1/0), CT abnormalities consistent with asbestosis were found in 57; these patients had significantly lower vital capacity and carbon

786

SECTION 12  Inhalational Diseases and Aspiration

monoxide diffusing capacity than did the workers who had normal CT scans.40 Asbestos-related pleural disease can be seen in 95% to 100% of patients who have evidence of asbestosis on HRCT.39,40,44 Rounded Atelectasis.  The characteristic findings of rounded atelectasis on CT consist of a round or oval opacity that is peripheral in location and abuts an area of pleural thickening and is associated with crowding and curving of pulmonary vessels and bronchi into the edge of the lesion (comet tail sign; Fig. 61.20).50 Rounded atelectasis may have acute or obtuse angles where it contacts the pleura and be unilateral or bilateral (Fig. 61.21). Because it represents collapsed lung parenchyma, rounded atelectasis can show marked enhancement after intravenous administration of contrast material and generally shows direct signs of volume loss, such as fissural displacement.51 Optimal depiction of rounded atelectasis, particularly when it is adjacent to the diaphragm, may require assessment with multiplanar reconstructions. In the majority of cases the diagnosis of rounded atelectasis can be confidently made by CT on the basis of the characteristic features listed earlier. However, atypical cases with an irregular

Fig. 61.18  Parenchymal bands in early asbestosis. High-resolution CT image with the patient prone shows bilateral parenchymal bands (curved arrows), small round opacities (straight arrows), nondependent groundglass opacities, and minimal reticulation. Also noted are bilateral diaphragmatic pleural plaques.

A

shape, with an area of increased opacity out of proportion for the volume loss, or not associated with curving of adjacent vessels require close follow-up or needle biopsy to rule out carcinoma (Fig. 61.22). Asbestos-Related Pleural Abnormalities Pleural Plaques.  HRCT has greater sensitivity than chest radiography for the detection of pleural plaques (see Fig. 61.11).39,44 The characteristic manifestation of pleural plaques on HRCT consist of circumscribed areas of pleural thickening separated from the underlying ribs and extrapleural soft tissues by a thin layer of fat (Figs. 61.23 and 61.24). Pleural plaques are usually bilateral, although they may be asymmetric. According to the literature, calcification of plaques is seen in 10% to 15% of cases, although many find that percentage to be much lower than expected based on their clinical practice (Fig. 61.25).2,17 The calcification may be punctate, linear, or coalescent. Pleural plaques are easiest to recognize internal to visible rib segments because only the pleura, extrapleural fat, and endothoracic fascia pass internal to ribs, and these are too thin in most normal patients to be recognized on CT.52 Pleural plaques measuring as little as 1 to 2 mm in thickness can be readily diagnosed in this location. Pleural thickening is also easy to identify in the paravertebral region because of the lack of any normal soft tissue stripe in this region (Fig. 61.26). Mediastinal pleural plaques are visible on CT in approximately 40% of patients with asbestos-related pleural disease (see Fig. 61.26).39,44 Less commonly, plaques may involve the pericardium (Fig. 61.27). On occasion, asbestos exposure may result in pericardial fibrosis with or without associated effusion or calcification and, rarely, constrictive pericarditis.53,54 Pleural plaques frequently involve the diaphragmatic pleura, but uncalcified plaques in this location can be difficult to detect on CT because the diaphragm lies roughly in the plane of the scan (see Fig. 61.24), and uncalcified plaques are more readily visualized on coronal or sagittal reconstructions (Fig. 61.28). In some patients, however, diaphragmatic pleural plaques are visible deep in the posterior costophrenic angle below the lung base; in this location the pleural disease can be localized with certainty to the parietal pleura because only parietal pleura is present

B Fig. 61.19  Asbestosis: progression of fibrosis over time. (A) High-resolution CT (HRCT) image with the patient prone shows reticulation, traction bronchiectasis, and early honeycombing in the left lower lobe. Mild fibrosis is present in the right lung base. (B) Follow-up HRCT image 5 years later demonstrates marked progression of the fibrosis. (Courtesy Dr. Jorge Kavakama, São Paulo, Brazil.)

61  Asbestos-Related Disease

A

C

A

787

B

Fig. 61.20  Rounded atelectasis. (A) High-resolution CT (HRCT) image shows irregular mass in the left upper lobe with band-like opacities extending toward an area of pleural thickening. Also note volume loss of the left upper lobe causing curvilinear anterior displacement of the left major fissure (straight arrow). (B) Soft tissue windows demonstrate bilateral calcified and noncalcified pleural plaques (arrowheads). (C) HRCT image at a more cephalad level shows pulmonary vessels (curved arrow) curving toward the area of pleural thickening. Also noted are superior and anterior displacement of the left major fissure (straight arrow) and a right pleural plaque (arrowhead).

B Fig. 61.21  Rounded atelectasis. (A) CT image in a patient with previous asbestos exposure shows a left lower lobe mass with pulmonary vessels curving toward it, consistent with rounded atelectasis. Note the severe degree of left lower lobe volume loss with deviation of the left major fissure posteriorly (arrow). (B) Soft tissue windows demonstrate pleural thickening adjacent to the mass (arrowheads).

788

SECTION 12  Inhalational Diseases and Aspiration

A

B Fig. 61.22  Lung cancer mimicking rounded atelectasis. (A) CT images show right upper lobe mass abutting an area of pleural thickening. Note that the vessels curve toward the edges of the mass and that there is associated right upper lobe volume loss. (B) Soft tissue windows confirm that the mass abuts an area of pleural thickening. The presence of extrapleural fat at this level suggests that the pleural thickening is long standing. Although some of the features are consistent with rounded atelectasis, the size of the mass is out of proportion to the degree of volume loss. A completely collapsed lung occupies only approximately 10% of its original volume. Lung biopsy confirmed the presence of a pulmonary carcinoma. Desmoplastic reaction to a bronchogenic malignancy can mimic the volume loss seen in rounded atelectasis.

Fig. 61.23  Pleural plaques: high-resolution CT (HRCT) findings. HRCT image shows characteristic appearance of pleural plaques as sharply circumscribed focal areas of pleural thickening (arrows) separated from the underlying ribs and extrapleural soft tissues by a thin layer of fat.

below the lung base. Rarely, pleural plaques may involve an interlobar fissure, localizing the plaque to the visceral pleural surface (Fig. 61.29). Diffuse Pleural Thickening.  Diffuse pleural thickening is defined on CT by the presence of a sheet of thickened pleura at least 5 cm in lateral dimension and 8 cm in craniocaudal dimension (Fig. 61.30).55 As mentioned previously, the ILO classification recognizes pleural thickening as diffuse “only in the presence of and in continuity with an obliterated costophrenic angle.”30 In one study of 100 asbestos-exposed workers, 7 had diffuse pleural thickening evident on CT.55 Diffuse pleural thickening related to asbestos exposure may calcify (see Fig. 61.30). The calcification is usually focal and mild but occasionally may be extensive (Fig. 61.31).

Fig. 61.24  Diaphragmatic and costal pleural plaques. High-resolution CT image shows parietal pleural plaques along the intercostal spaces and paravertebral region (arrows) and along the right hemidiaphragm (arrowheads). (Courtesy Dr. Jorge Kavakama, São Paulo, Brazil.)

On HRCT the margin between an area of diffuse pleural thickening and the adjacent lung is frequently irregular as a result of parenchymal fibrosis, in contrast to the usually sharply circumscribed margins of pleural plaques.56 The abnormality is generally associated with contralateral pleural abnormalities, either diffuse pleural thickening or plaques.57 Diffuse thickening rarely involves the mediastinal pleura, although it frequently affects the parietal pleura abutting the paravertebral gutters (Fig. 61.32).57,58 The absence of mediastinal pleural involvement can be assessed readily on CT scan and is often helpful in distinguishing benign from malignant pleural thickening; in a study of 19 patients, only 1 of 8 with fibrothorax had thickening

61  Asbestos-Related Disease

789

Fig. 61.25  Calcified pleural plaques. High-resolution CT image shows bilateral calcified and noncalcified pleural plaques.

Fig. 61.27  Pericardial plaques. High-resolution CT image shows foci of thickening and calcification (arrows) of the pericardium consistent with pericardial plaques. Also noted are calcified and noncalcified paravertebral and costal pleural plaques.

Fig. 61.26  Paravertebral and mediastinal pleural plaques. High-resolution CT image shows paravertebral (curved arrows), mediastinal (straight arrow), diaphragmatic (arrowhead), and costal pleural plaques.

Fig. 61.28  Diaphragmatic pleural plaques. Coronal reformatted CT image shows bilateral calcified and noncalcified diaphragmatic pleural plaques (arrows).

of the mediastinal pleura, compared with 8 of 11 with mesothelioma.57 There is a significant correlation between the presence and severity of pleural disease and the presence and severity of asbestosis.44 In one study HRCT findings of parenchymal fibrosis were visible in 14% of exposed patients who did not have evidence of pleural thickening, in 56% of those with focal plaques, and in 88% of those with diffuse pleural thickening.59 However, pleural thickening and plaques commonly occur in the absence of pulmonary fibrosis,60 and asbestosis can sometimes be seen in the absence of visible pleural plaques,59 although this is more unusual. Pleural Effusion.  Disease in some individuals with a history of asbestos exposure is manifested as pleural effusion. The effusion is exudative and often hemorrhagic (Fig. 61.33).1

Mesothelioma.  The CT findings of mesothelioma are discussed in Chapter 74. IMAGING ALGORITHMS Individuals with a history of exposure to asbestos but no manifestations of disease, and for whom the time since initial exposure is 10 years or more, may be monitored with chest radiographs and pulmonary function tests every 3 to 5 years to identify the onset of asbestos-related disease.1 Individuals with a history of exposure to asbestos are also at risk for asbestos-related malignant neoplasms, but guidelines for periodic health surveillance for lung cancer or mesothelioma do not yet exist for these patients.1 The sensitivity of the chest radiograph for identifying asbestosis at a profusion level of 1/0 (in the ILO classification system) has

790

A

SECTION 12  Inhalational Diseases and Aspiration

B Fig. 61.29  Pleural plaque in left major fissure. (A) View of the left lung from high-resolution CT shows focal nodular thickening (arrows) of the left major fissure consistent with pleural plaque. (B) Soft tissue windows confirm presence of pleural plaque and demonstrate extensive thickening of the left costal and paravertebral pleura (arrows).

A

B Fig. 61.30  Diffuse pleural thickening: CT findings. (A) CT image in a patient with previous asbestos exposure shows diffuse pleural thickening (straight arrows) on the right and pleural plaques (curved arrows) on the left. (B) CT image obtained 6 years later shows extensive calcification (arrow) of the diffuse pleural thickening. (Courtesy Dr. Jorge Kavakama, São Paulo, Brazil.)

61  Asbestos-Related Disease

Fig. 61.31  Calcified diffuse pleural thickening. Coronal reformatted CT image in a patient with previous asbestos exposures shows diffuse right pleural thickening and calcification and calcified left paravertebral pleural plaques.

791

Fig. 61.33  Benign pleural effusion. CT image shows calcified right pleural plaques and small left pleural effusion. The presence of calcified plaques suggests that the first exposure to asbestos in this patient occurred more than 30 years previously. The presence of pleural effusion after such a long latency time should raise the possibility of mesothelioma. Diagnosis of benign asbestos-related pleural effusion was based on clinical history, lack of evidence of mesothelioma at the time of the effusion, spontaneous resolution, and lack of recurrence on follow-up. Benign asbestos-related pleural effusions have been reported to occur 1–58 years after asbestos exposure.

normal HRCT scan cannot completely exclude asbestosis.46 HRCT is also much more sensitive than chest radiography in the detection of pleural plaques and also has greater specificity, allowing distinction of pleural thickening from extrapleural fat.

Differential Diagnosis

Fig. 61.32  Diffuse pleural thickening. CT image in a patient with previous asbestos exposure shows diffuse bilateral pleural thickening involving the paravertebral pleura and costal pleura but sparing the mediastinal pleura. Sparing of the mediastinal pleura is helpful in distinguishing benign from malignant pleural thickening.

been estimated at or slightly below 90% and the corresponding specificity at 93%.1 HRCT plays an important role, particularly when experienced readers disagree about the presence or absence of abnormalities on the radiograph, when the radiographic findings are equivocal, when the radiograph is normal but the patient has functional impairment, and when extensive overlying pleural abnormalities do not allow a clear interpretation of the lung parenchyma.1 HRCT is much more sensitive than chest radiography in the detection of asbestosis,61,62 although even a

The diagnosis of asbestosis requires the presence of pulmonary fibrosis and history of exposure of sufficient duration, latency, and intensity to be causal.1 The latency period is influenced by the duration and intensity of exposure. Under current conditions of exposure in North America, the latency period is often 2 decades.1 The abnormal chest radiograph and its interpretation remain the most important initial factor in establishing the presence of pulmonary fibrosis,1 given the strong link of ILO classification to occupational lung disease compensation systems.1 When the chest radiograph or lung function abnormalities are indeterminate, HRCT scanning is often helpful in demonstrating the presence of fibrosis and pleural changes highly suggestive of asbestos exposure.1 Clinically and radiologically, asbestosis resembles other interstitial lung diseases, particularly idiopathic pulmonary fibrosis. The differential diagnosis is based mainly on the history of asbestos exposure and on the radiologic demonstration of pleural abnormalities consistent with asbestos exposure. In some cases definitive diagnosis may require lung biopsy. The main differential diagnosis of rounded atelectasis is with pulmonary carcinoma (see Fig. 61.22). Although this differential diagnosis can be made on CT in the majority of cases, these patients often require follow-up. Rounded atelectasis is typically static or grows very slowly. The most reliable feature in distinguishing rounded atelectasis from carcinoma is the convergence of bronchovascular markings around the edges of the atelectasis. In one study the authors compared the CT findings of 12 cases

792

SECTION 12  Inhalational Diseases and Aspiration

KEY POINTS: ASBESTOS-RELATED PULMONARY AND PLEURAL DISEASE • It has been estimated that 8–9 million people in the United States have had occupational exposure to asbestos and that such exposure will eventually result in 300,000 deaths. • The chest radiograph plays an important role in the detection of asbestos-related pleural and parenchymal abnormalities and in the assessment of progression of disease. However, the radiograph is falsely normal in 15%–20% of patients with asbestosis and in 20%–50% of patients with pleural plaques. • Asbestosis • The latency period is usually more than 20 years (average, 40 ± 10 years). • Degree of fibrosis is dose dependent. • The chest radiograph is normal in 15%–20% of cases. • High-resolution CT (HRCT) including prone positioning is the optimal imaging modality. • HRCT demonstrates a reticular pattern with subpleural curvilinear opacities and parenchymal bands in the lower lungs. • The majority of patients with asbestosis will also have pleural plaques or diffuse pleural thickening evident on CT. • Rounded atelectasis • Estimated latency times are 10–40 years. • Diagnosis can usually be made on CT as a rounded or oval opacity with significant volume loss abutting focal pleural thickening. • Curving of adjacent pulmonary vessels and bronchi into the edges is frequently seen (comet tail sign). • It enhances markedly with intravenous administration of contrast material. • Usually, uptake is equal to or less than mediastinal blood pool on fluorodeoxyglucose–positron emission tomography imaging. • Follow-up is often required to confirm stability. • Lung cancer • Asbestos-related carcinoma likely accounts for 2%–3% of all lung cancer deaths. • The latency time is 10 years to more than 60 years (mean, 46 years).

of rounded atelectasis with 12 cases of “look-alike” masses. Of all the features examined, the presence of converging bronchovascular markings discriminated best between rounded atelectasis and look-alikes, but the sensitivity was only 83% and the specificity 92%.63 Furthermore, cancer has been shown to develop within an area of rounded atelectasis.64 In patients with nondiagnostic CT findings, further evaluation may be obtained with needle biopsy or fluorodeoxyglucose–positron emission tomography (FDG-PET) scanning. In one study of 10 cases of rounded atelectasis seen in 9 patients, all lesions were negative on FDG-PET (i.e., FDG uptake similar or less than mediastinal blood pool).65 Bilateral pleural plaques are almost invariably associated with asbestos exposure.1 However, isolated plaques and diffuse pleural thickening may be associated with tuberculosis, trauma, and hemothorax.1 The main differential diagnostic consideration in patients with pleural effusion or diffuse pleural thickening is

•

•

•

•

• It is most common in patients with radiologic evidence of asbestosis. • There is greater likelihood of location in the lower lobe. Pleural plaques • Most common manifestation of asbestos exposure. • Usually first seen 20–30 years after exposure. • Calcified plaques are seldom evident until more than 30 years after exposure and are likely much more common than reported in the literature. • Circumscribed focal areas of pleural thickening, separated from the underlying ribs and extrapleural soft tissues by a thin layer of fat. Diffuse pleural thickening • Occurs in 9%–22% of asbestos-exposed workers with pleural disease. • The latency period is 10–40 years. • Smooth, uninterrupted pleural thickening extending for at least 5 cm in lateral dimension and 8 cm in craniocaudal dimension. • Fibrothorax frequently involves the paravertebral region, but mediastinal pleural thickening occurs in less than 15% of cases. Pleural effusion • Occurs in approximately 3% of asbestos workers. • It is the most common asbestos-related abnormality seen within the first 20 years after exposure. • The latency period is large, 1–58 years after exposure. • Usually small; may be unilateral or bilateral, persist for months, or recur. Mesothelioma (see Chapter 74) • Risk is almost zero for the first 10–15 years after the first exposure but increases progressively thereafter. • The mean latency time is 46 ± 12 years. • Unilateral sheet-like or lobulated pleural thickening in approximately 80%–90% of cases. • Thickening of the mediastinal pleura in approximately 85% of cases.

mesothelioma, which is typically progressive and more likely to be symptomatic at the time of detection. On occasion, when fibrosis and mesothelial proliferation are exuberant, the distinction may be difficult clinically, radiologically, and histologically. The manifestations of mesothelioma are discussed in Chapter 74. SUGGESTED READINGS Champlin J, et al. Imaging of occupational lung disease. Radiol Clin North Am. 2016;54(6):1077–1096. Cox CW, et al. State of the art: imaging of occupational lung disease. Radiology. 2014;270(3):681–696. Norbet C, et al. Asbestos-related lung disease: a pictorial review. Curr Probl Diagn Radiol. 2015;44(4):371–382.

The full reference list for this chapter is available at ExpertConsult.com.

61  Asbestos-Related Disease 792.e1

REFERENCES 1. American Thoracic Society. Diagnosis and initial management of nonmalignant diseases related to asbestos. Am J Respir Crit Care Med. 2004;170:691–715. 2. Roach HD, Davies GJ, Attanoos R, et al. Asbestos: when the dust settles an imaging review of asbestos-related disease. Radiographics. 2002;22:S167–S184. 3. Cugell DW, Kamp DW. Asbestos and the pleura: a review. Chest. 2004;125: 1103–1117. 4. Centers for Disease Control and Prevention. Changing patterns of pneumoconiosis mortality—United States, 1968-2000. MMWR Morb Mortal Wkly Rep. 2004;23:627–632. 5. Landrigan PJ. Commentary: environmental disease—a preventable epidemic. Am J Public Health. 1992;82:941–943. 6. U.S. Geological Survey Mineral Resources Program. Asbestos. Reston, VA: U.S. Geological Survey; January, 2016. 7. Fraser RS, Colman N, Müller NL, Paré PD. Pulmonary disease caused by inhaled inorganic dust. In: Fraser RS, Colman N, Müller NL, Paré PD, eds. Synopsis of Diseases of the Chest. Philadelphia: Elsevier/Saunders; 2005:714–743. 8. Donaldson K, Brown RC, Brown GM. New perspectives on basic mechanisms in lung disease. 5. Respirable industrial fibres: mechanisms of pathogenicity. Thorax. 1993;48:390–395. 9. Churg A, Wright JL. Small-airway lesions in patients exposed to nonasbestos mineral dusts. Hum Pathol. 1983;14:688–693. 10. Travis WD, Colby T, Koss MN, et al. Occupational lung diseases and pneumoconioses. In: Travis WD, Colby T, Koss MN, et al, eds. Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: Armed Forces Institute of Pathology; 2002:793–856. 11. Mossman BT, Churg A. Mechanisms in the pathogenesis of asbestosis and silicosis. Am J Respir Crit Care Med. 1998;157:1666–1680. 12. Markowitz SB, et al. Asbestos, asbestosis, smoking, and lung cancer. New findings from the North American Insulator Cohort. Am J Respir Crit Care Med. 2013;188(1):90–96. 13. Hodgson JT, Darnton A. The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure. Ann Occup Hyg. 2000;44:565–601. 14. McDonald JC, McDonald AD. Chrysotile, tremolite and carcinogenicity. Ann Occup Hyg. 1997;41:699–705. 15. Ohar J, Sterling DA, Bleecker E, Donohue J. Changing patterns in asbestosinduced lung disease. Chest. 2004;125:744–753. 16. Hessel PA, Gamble JF, McDonald JC. Asbestos, asbestosis, and lung cancer: a critical assessment of the epidemiological evidence. Thorax. 2005;60: 433–436. 17. Peacock C, Copley SJ, Hansell DM. Asbestos-related benign pleural disease. Clin Radiol. 2000;55:422–432. 18. Epler GR, McLoud TC, Gaensler EA. Prevalence and incidence of benign asbestos pleural effusion in a working population. JAMA. 1982;247: 617–622. 19. Lilis R, Lerman Y, Selikoff IJ. Symptomatic benign pleural effusions among asbestos insulation workers: residual radiographic abnormalities. Br J Ind Med. 1988;45:443–449. 20. McLoud TC, Woods BO, Carrington CB, et al. Diffuse pleural thickening in an asbestos-exposed population: prevalence and causes. AJR Am J Roentgenol. 1985;144:9–18. 21. Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet. 2005;366:397–408. 22. Robinson BW, Lake RA. Advances in malignant mesothelioma. N Engl J Med. 2005;353:1591–1603. 23. Roggli VL, Sharma A, Butnor KJ, et al. Malignant mesothelioma and occupational exposure to asbestos: a clinicopathological correlation of 1445 cases. Ultrastruct Pathol. 2002;26:55–65. 24. Panou V, Vyberg M, Weinreich UM, Meristoudis C, Falkmer UG, Røe OD. The established and future biomarkers of malignant pleural mesothelioma. Cancer Treat Rev. 2015;41(6):486–495. 25. Miller A. Pulmonary function in asbestosis and asbestos-related pleural disease. Environ Res. 1993;61:1–18. 26. Begin R, Filion R, Ostiguy G. Emphysema in silica- and asbestos-exposed workers seeking compensation. A CT scan study. Chest. 1995;108:647– 655. 27. Bourbeau J, Ernst P, Chrome J, et al. The relationship between respiratory impairment and asbestos-related pleural abnormality in an active work force. Am Rev Respir Dis. 1990;142:837–842. 28. Schwartz DA, Fuortes LJ, Galvin JR, et al. Asbestos-induced pleural fibrosis and impaired lung function. Am Rev Respir Dis. 1990;141:321–326. 29. Ohlson CG, Bodin L, Rydman T, Hogstedt C. Ventilatory decrements in former asbestos cement workers: a four year follow up. Br J Ind Med. 1985;42:612–616.

30. International Labour Office. Guidelines for the Use of ILO International Classification of Radiographs of Pneumoconiosis. Occupational Safety and Health Series No. 22. Geneva, International Labour Office, 2011. 31. Albin M, Engholm G, Fröström K, et al. Chest x ray films from construction workers: International Labour Office (ILO 1980) classification compared with routine readings. Br J Ind Med. 1992;49:862–868. 32. Meyer JD, Islam SS, Ducatman AM, McCunney RJ. Prevalence of small lung opacities in populations unexposed to dusts. A literature analysis. Chest. 1997;111:404–410. 33. Welch LS, Hunting KL, Balmes J, et al. Variability in the classification of radiographs using the 1980 International Labor Organization Classification for Pneumoconioses. Chest. 1998;114:1740–1748. 34. Markowitz SB, Morabia A, Lilis R, et al. Clinical predictors of mortality from asbestosis in the North American Insulator Cohort, 1981 to 1991. Am J Respir Crit Care Med. 1997;156:101–108. 35. Mintzer RA, Gore RM, Vogelzang RL, Holz S. Rounded atelectasis and its association with asbestos-induced pleural disease. Radiology. 1981;139: 567–570. 36. Hillerdal G. Rounded atelectasis: clinical experience with 74 patients. Chest. 1989;95:836–941. 37. Hu H, Beckett L, Kelsey K, Christiani D. The left-sided predominance of asbestos-related pleural disease. Am Rev Respir Dis. 1993;148:981–984. 38. Hillerdal G, Ozesmi M. Benign asbestos pleural effusion: 73 exudates in 60 patients. Eur J Respir Dis. 1987;71:113–121. 39. Friedman AC, Fiel SB, Fisher MS, et al. Asbestos-related pleural disease and asbestosis: a comparison of CT and chest radiography. AJR Am J Roentgenol. 1988;150:268–275. 40. Staples CA, Gamsu G, Ray CS, Webb WR. High resolution computed tomography and lung function in asbestos-exposed workers with normal chest radiographs. Am Rev Respir Dis. 1989;139:1502–1508. 41. Akira M, Yokoyama K, Yamamoto S, et al. Early asbestosis: evaluation with high-resolution CT. Radiology. 1991;178:409–416. 42. Akira M, Yamamoto S, Yokoyama K, et al. Asbestosis: high-resolution CT–pathologic correlation. Radiology. 1990;176:389–394. 43. Yoshimura H, Hatakeyama M, Otsuji H, et al. Pulmonary asbestosis: CT study of subpleural curvilinear shadow. Work in progress. Radiology. 1986;158:653–658. 44. Aberle DR, Gamsu G, Ray CS, Feuerstein IM. Asbestos-related pleural and parenchymal fibrosis: detection with high-resolution CT. Radiology. 1988;166:729–734. 45. Al-Jarad N, Strickland B, Pearson MC, et al. High-resolution computed tomographic assessment of asbestosis and cryptogenic fibrosing alveolitis: a comparative study. Thorax. 1992;47:645–650. 46. Gamsu G, Salmon CJ, Warnock ML, Blanc PD. CT quantification of interstitial fibrosis in patients with asbestosis: a comparison of two methods. AJR Am J Roentgenol. 1995;164:63–68. 47. Primack SL, Hartman TE, Hansell DM, Müller NL. End-stage lung disease: CT findings in 61 patients. Radiology. 1993;189:681–686. 48. Shepherd JR, Hillerdal G, McLarty J. Progression of pleural and parenchymal disease on chest radiographs of workers exposed to amosite asbestos. Occup Environ Med. 1997;54:410–415. 49. Murray K, Gamsu G, Webb WR, et al. High-resolution CT sampling for detection of asbestos-related lung disease. Acad Radiol. 1995;2:111–115. 50. McHugh K, Blaquiere RM. CT features of rounded atelectasis. AJR Am J Roentgenol. 1989;153:257–260. 51. Taylor PM. Dynamic contrast enhancement of asbestos-related pulmonary pseudotumours. Br J Radiol. 1988;61:1070–1072. 52. Im JG, Webb WR, Rosen A, Gamsu G. Costal pleura: appearances at highresolution CT. Radiology. 1989;171:125–131. 53. Davies D, Andrews MI, Jones JS. Asbestos induced pericardial effusion and constrictive pericarditis. Thorax. 1991;46:429–432. 54. Trogrlic S, Gevenois PA, Schroeven M, De Vuyst P. Pericardial effusion associated with asbestos exposure. Thorax. 1997;52:1097–1098. 55. Aberle DR, Gamsu G, Ray CS. High-resolution CT of benign asbestos-related diseases: clinical and radiographic correlation. AJR Am J Roentgenol. 1988;151:883–891. 56. Hillerdal G, Malmberg P, Hemmingsson A. Asbestos-related lesions of the pleura: parietal plaques compared to diffuse thickening studied with chest roentgenography, computed tomography, lung function, and gas exchange. Am J Ind Med. 1990;18:627–639. 57. Leung AN, Müller NL, Miller RR. CT in differential diagnosis of diffuse pleural disease. AJR Am J Roentgenol. 1990;154:487–492. 58. Müller NL. Imaging the pleura. Radiology. 1993;186:297–309. 59. Schwartz DA, Galvin JR, Dayton CS, et al. Determinants of restrictive lung function in asbestos-induced pleural fibrosis. J Appl Physiol. 1990;68: 1932–1937.

792.e2

SECTION 12  Inhalational Diseases and Aspiration

60. Ren H, Lee DR, Hruban RH, et al. Pleural plaques do not predict asbestosis: high-resolution computed tomography and pathology study. Mod Pathol. 1991;4:201–209. 61. Gevenois PA, De Vuyst P, Dedeire S, et al. Conventional and high-resolution CT in asymptomatic asbestos-exposed workers. Acta Radiol. 1994;35: 226–229. 62. Neri S, Boraschi P, Antonelli A, et al. Pulmonary function, smoking habits, and high resolution computed tomography (HRCT) early abnormalities of lung and pleural fibrosis in shipyard workers exposed to asbestos. Am J Ind Med. 1996;30:588–595.

63. O’Donovan PB, Schenk M, Lim K, et al. Evaluation of the reliability of computed tomographic criteria used in the diagnosis of round atelectasis. J Thorac Imaging. 1997;12:54–58. 64. Nakazono T, Nakamura Y, Satoh T, et al. Squamous cell carcinoma coexisting in rounded atelectasis: diagnostic pitfalls. AJR Am J Roentgenol. 2004;182: 79–80. 65. McAdams HP, Erasmus JJ, Patz EF, et al. Evaluation of patients with round atelectasis using 2-[18F]-fluoro-2-deoxy-D-glucose PET. J Comput Assist Tomogr. 1998;22:601–604.

62 

Silicosis and Coal Workers’ Pneumoconiosis* STEPHEN B. HOBBS

Etiology Silicosis and coal workers’ pneumoconiosis (CWP) are occupational lung diseases; silicosis is caused by continued exposure to excessive amounts of respirable silica, and CWP is caused by exposure to carbonaceous material (anthracosis). Respirable crystalline silicate and coal dust embed in the lungs, causing granulomatous and fibrotic changes that lead to radiographic and pathologic abnormalities. Silica is a naturally occurring mineral that is mainly composed of silicon dioxide (SiO2). It exists in two forms: crystalline silica, which causes silicosis, and amorphous silica, which is not toxic. The three most common forms of crystalline silica are quartz, cristobalite, and tridymite, but quartz is the most common form of inhaled silica. The diagnosis of silicosis and CWP is based on the typical radiographic appearance of diffuse nodules or reticulonodular pattern in the presence of a strong occupational exposure to silica and coal dust. The guidelines for the use of the ILO (International Labour Organization) International Classification of Radiographs of Pneumoconiosis were recently updated in 2011 to include criteria for the interpretation of digital images and is the most widely accepted classification of the extent of involvement of the pneumoconioses and one in which the presence or absence of pneumoconiosis is established in workers exposed to mineral dust, including silica.1 The ILO system uses a stepby-step method to evaluate chest radiographs, which are compared with standard reference film-screen or digital radiographs available from the ILO, with standard nomenclature to describe the shape, size, location, and abundance of opacities.

Prevalence and Epidemiology Workers engaged in occupations such as tunneling, mining, sandblasting, and quarrying are inevitably exposed to silica owing to its ubiquity in the earth’s crust. Other workers engaged in occupations that predispose to silica exposure include jade polishers,2–4 foundry and pottery workers,5–7 glass and silica brick workers,5 goldworking jewelers,8 and electric cable manufacturers.9 More newly recognized causes of silica exposure, resulting in accelerated silicosis and silicoproteinosis, include sandblasting in denim clothing and manufacturing engineered stone countertops containing quartz.10–12 Environmental silica arises as a result of crystalline silica becoming airborne in arid, windy conditions or during agricultural, urban, or construction activities. Inhalation of environmental silica and mixed dust has led to lung fibrosis.13 *The editors and the publisher would like to thank Dr. Clara G. Ooi for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

Hnizdo and Sluis-Cremer14 showed the relationship between exposure to silica and silicosis. The cumulative exposure for the entire cohort in their study was about 2 mg/m3 per year over an average exposure period of 25 years. No silicosis occurred when the cumulative exposures were less than 0.9 mg/m3 per year. In contrast, the cumulative risk of silicosis was approximately 25% at a cumulative exposure of 2.7 mg/m3 per year and 77% at the highest observed cumulative exposure level of 4.5 mg/m3 per year. This dose-response relationship between the duration of exposure to the quartz-containing dust and the prevalence of silicosis also has been observed by other investigators.15,16 The effects of smoking on the prevalence of silicosis were illustrated in a cross-sectional survey of 3258 workers in a Dutch fine-ceramic industry, in which the prevalence of silicosis among heavy smokers with 20 years’ or more exposure to quartz-containing dust was 50% higher than in light smokers and nonsmokers.16 The prevalence and incidence of silicosis worldwide are difficult to determine because of variable industrial practices and work safety standards. The National Institute for Occupational Safety and Health estimated that in 1983 approximately 2.3 million workers at 238,000 work sites were exposed to silica dust.17 It was more recently estimated that 59,000 workers may be at risk of developing some degree of silicosis, with 250 deaths per year being attributed to silica exposure.18 Approximately 1500 cases of silicosis are diagnosed annually in the United States; silicosis was cited as the primary or contributing cause of death in 13,744 deaths between 1968 and 1990 in the United States.19 There has been a trend of decreasing annual death rates correlating with a decreased incidence since a peak during World War II. Specifically, deaths decreased from 1157 in 1968 to 301 in 1988 in the United States,19 although the prevalence rates in developing nations remain significantly higher. In Colombia and India, respectively, 1.8 million and 1.69 million workers are estimated to be exposed to and at risk of developing silicosis. Workers in India who are involved in quarrying shale sedimentary rocks have a 55% prevalence rate of silicosis, whereas 50% of Latin American miners older than 55 years develop silicosis.20 A study in Northern Thailand of 266 mortar and pestle workers documented a 21.1% prevalence rate for silicosis.15 In a separate study involving workers from 33 stone-grinding factories in Thailand, 31 of the factories (93.6%) were found to have levels of total or respirable dust exceeding acceptable levels.21 The prevalence of silicosis was 9%. CWP occurs after exposure to coal dust for longer than 20 years on average, but some cases have been reported with less than 10 years of exposure. The severity and prevalence of CWP are related to the duration of exposure, the amount of coal dust inhaled, and the carbon content (rank) of the coal dust. Higher concentrations of coal dust exposure are associated with higher prevalence of CWP. Similarly, a high rank of coal dust, such as anthracite, increases the risk of CWP.22 The prevalence of CWP 793

794

SECTION 12  Inhalational Diseases and Aspiration

varies from country to country, within different regions of a country, and from mine to mine. The overall prevalence of CWP in the United States was reported to be 30% in an interagency study in the 1960s. Although this percentage may be decreased in more recent years as a result of federal legislation that mandated substantially lower dust levels in coal mines,23 some recent studies have demonstrated areas of increased prevalence of progressive massive fibrosis (PMF) among underground U.S. coal miners despite exposure after implementation of those federal dust regulations.24–26 Currently, it is estimated that 2% to 12% of U.S. coal miners develop category 2 or greater disease after a 40-year working life, with an estimated prevalence of PMF of 1% to 7%.27,28 In comparison, the predicted prevalences for CWP and PMF in British coal miners are 9% and 0.7%, respectively.29

Clinical Presentation SILICOSIS The three main clinical presentations of silicosis are acute silicosis (silicoproteinosis), accelerated silicosis, and classic silicosis, and they are determined primarily by the intensity and the length of exposure to silica. Silicoproteinosis (acute silicosis) is an acute and progressive form of silicosis that often results in death from respiratory failure. This variant of silicosis can develop within a few weeks or months of exposure to very high concentrations of silica and is associated with occupations such as sandblasting, surface drilling, tunneling, silica flour milling, and quartzite milling.30–35 The lungs show a ground-glass appearance similar to that of pulmonary edema and alveolar proteinosis. The lesion may consolidate into appearances more characteristic of PMF over a short time. Workers usually present with rapidly progressive dyspnea, cough, and weight loss and develop cyanosis and respiratory failure. Death usually occurs within a short time despite intensive treatment. It has been proposed that acute silicosis occurs in workers exposed to freshly fractured silica dust and that surface Si* and SiO* radicals generated during fracturing play an important role in the rapid onset of this variant of silicosis.36,37 With accelerated silicosis, the exposure time after which the disease becomes clinically evident is much shorter than classic silicosis, ranging from 5 to 10 years of exposure, with the rate of disease progression noticeably faster. The symptom of breathlessness occurs 1 year after exposure, with the patient’s condition rapidly deteriorating to hypoxic respiratory failure and death within 5 years.38,39 High concentrations of dust in a relatively confined space are thought to predispose an individual to this form of silicosis, which is common in certain occupations, such as sandblasting, stone masonry, and other crushing operations.40,41 Except for this aggressive time course, the radiographic, clinical, and pathologic features of this entity are nearly indistinguishable from classic silicosis. Long-term exposure to low concentrations of silica is associated with a slow progressive nodular infiltration in both lungs, predominantly in the upper lung zones. Classic silicosis is the most common presentation whereby patients remain asymptomatic until after 10 to 20 years of continuous silica exposure, by which time radiographic abnormalities are evident. In contrast to other inhalational occupational lung diseases, lung changes in silicosis often progress even after the individual has been removed from the causative environment.42,43 Although most patients are asymptomatic initially, dyspnea on exertion and then at rest is common. A relationship between severity of dyspnea

and radiographic abnormalities has been documented.44,45 The lung lesions are usually progressive and may result in PMF. PMF is the result of the coalescence and agglomeration of several smaller nodules together with increased profusion and enlargement of nodules. According to the Silicosis and Silicate Disease Committee, a PMF lesion is defined as a lesion greater than 2 cm in diameter, in contrast to the 1 cm or larger radiographic size established by the ILO. Cavitation and extensive destruction of the lung parenchyma, including bronchioles and blood vessels, are common in PMF and may signify superimposed infection from anaerobic bacteria or tuberculosis. With progressive lung damage, pulmonary hypertension and right heart failure eventually supervene. Emphysema is common in silicosis and has been considered the major cause of cor pulmonale and disability by some investigators.46 Additionally, risk of other cardiovascular diseases is increased, including stroke,47 peripheral vascular disease,48 and congestive heart failure.49 Pneumothorax can complicate silicosis and occurs more frequently among patients with accelerated or acute silicosis. Other conditions that may complicate silicosis include Caplan syndrome, tuberculosis, carcinoma, and connective tissue disease. The two most serious complications, lung cancer and tuberculosis, may affect the prognosis and natural history of the underlying disease. Chronic silica inhalation is associated with a threefold increased risk of mycobacterial infections (silicotuberculosis). The risk increases with more severe disease in terms of nodular profusion and PMF50; this predisposition depends on the prevalence of tuberculosis in the population from which the workers originate.51 Rheumatoid pneumoconiosis (Caplan syndrome) was initially identified in CWP but is now known to occur in silicosis as well,52 although rarely. The incidence of this disease ranges from 0.48% to 0.74% and is characterized by rapidly developing large opacities (1–5 cm) located mostly in the periphery of the lungs, often with only mild silicosis.52 The association between silicosis and lung cancer has been documented in several studies and recognized as an occupational carcinogen by the International Agency for Research on Cancer since 1996.53–55 The risk is greatest for workers with established silicosis.56–58 The strength of the association between silicosis and connective tissue disease varies with the type of connective tissue disorder. The risk of developing systemic sclerosis particularly in workers with high exposure to silica dust is well established, although such causal associations between silicosis, rheumatoid arthritis, and systemic lupus erythematosus are less widely reported.59–61 COAL WORKERS’ PNEUMOCONIOSIS Inhalation of coal mine dust can lead to the development of several disease entities, including CWP, bronchitis, emphysema, Caplan syndrome, and silicosis.62,63 The two most common patterns of disease found in coal miners are simple CWP and complicated CWP. With increasing duration of coal dust exposure, CWP may progress to complicated CWP, in which the nodules coalesce to form black, rubbery parenchymal masses usually in the upper posterior lungs, resulting in PMF. Progression from simple CWP to PMF has been related to radiographic severity of disease, coal mine dust–exposure level, and total dust burden, with the average transition from simple CWP to complicated CWP occurring over 12.2 years.25 CWP is usually asymptomatic, and most chronic pulmonary symptoms in coal miners are attributed to other lung conditions,

62  Silicosis and Coal Workers’ Pneumoconiosis

such as industrial bronchitis from coal dust or coincident emphysema from smoking. The main symptom even in nonsmokers is chronic cough, which persists even after patients leave the workplace. PMF causes progressive dyspnea with production of black sputum (melanoptysis) when the PMF lesion liquefies and ruptures into the airways.64,65 As with silicosis, PMF lesions often progress to pulmonary hypertension with right ventricular and respiratory failure.66 An association between CWP and features of rheumatoid arthritis is well described. It is unclear whether CWP predisposes miners to developing rheumatoid arthritis, whether rheumatoid arthritis takes on a unique form in patients with CWP, or whether rheumatoid arthritis alters the response of miners to coal dust. Multiple rounded nodules in the lung appearing over a relatively short time (Caplan syndrome) represent an immunopathologic response related to rheumatoid diathesis. In contrast to lesions caused by PMF, which congregate in the upper lobes, these new lesions (known as Caplan lesions) tend to coalesce in the lung periphery. Histologically, the lesions resemble rheumatoid nodules, but they have a peripheral region of more acute inflammation. As in silicosis, patients with CWP are at an increased risk of developing active tuberculous and nontuberculous mycobacterial infections. Weak associations have been reported between CWP and progressive systemic sclerosis and stomach cancer.67–69 Cumulative dust exposure has been shown to have a significant relationship with increased mortality from cancers of the digestive system. It has been suggested that nitrosation of ingested coal dust in the acidic gastric environment could result in the production of carcinogenic products, which may lead to the higher incidence of gastric cancer in coal miners.70 Silicosis in coal miners is usually found in conjunction with simple CWP and rarely as an isolated form of pneumoconiosis. It is difficult to distinguish between silicosis and CWP on chest radiography. The prevalence of silicosis in coal miners can be reliably determined only in autopsy studies. In the National Coal Workers’ Autopsy Study from 1972 to 1996, pathologic evaluations of 4115 autopsy cases found 23% of coal miners with pulmonary silicosis and 58% with lymph node silicosis.71

Pathophysiology PATHOLOGY The pathogenesis of most pneumoconioses is a result of chronic inflammation that involves phagocytosis of the inhaled dust by alveolar and tissue macrophages and its deposition in the lung interstitium.72–76 Free particulate silica that is not ingested by macrophages enters the perivascular lymphatic channels to be translocated to the draining mediastinal lymph nodes as free particles or within macrophages.72–74,77,78 Inflammatory cytokines, such as tumor necrosis factor-α and interleukin-1, also are released by damaged epithelial cells and macrophages. These inflammatory mediators destroy the lung parenchyma by attracting other inflammatory cells (macrophages, neutrophils, and lymphocytes), resulting in alveolitis. In vivo and in vitro studies have shown that these silica-exposed macrophages release fibroblast growth factors that facilitate the accumulation of fibroblasts and fibroblast products, which induce inflammatory and fibrogenic reactions in the interstitium, alveoli, and lymph nodes.78–86 Various growth factors stimulate fibroblast and type II pneumocyte activity. Collagen and fibronectin production rapidly increase and

795

eventually lead to fibrosis. Animal models have shown that even after the exposure to silica ceases, dust-laden macrophages continue to produce inflammatory mediators, such as interleukin1β and tumor necrosis factor-α, propagating the inflammationfibrosis cycle.87 Silicoproteinosis Silicoproteinosis is characterized by pulmonary edema, interstitial inflammation, and the presence of surfactant protein similar to that seen in alveolar proteinosis filling the alveolar spaces.88 The exudate in the alveoli is eosinophilic, with a fine granular appearance. Silicotic nodules are sparse and poorly demarcated, or absent, probably because they form shortly after exposure.89,90 Collagen deposition and fibrosis are rarely seen in silicoproteinosis.91 Accelerated Silicosis Accelerated silicosis is similar in many respects to acute silicosis, exhibiting an exudative alveolar lipoproteinosis associated with chronic inflammation. In addition, accelerated silicosis is associated with fibrotic granulomas containing collagen, reticulin, and numerous silica particles. The granulomas consist of numerous mononuclear cells, fibroblasts, and collagen fibers, with a predisposition for circular orientation showing the characteristics of immature silicotic nodules.92 The alveolar septa are lined with hypertrophic and hyperplastic alveolar type II epithelial cells with increased numbers of lamellar bodies. Classic (Nodular) Silicosis Nodular silicosis is characterized by the presence of small rounded nodules 3 to 6 mm in diameter.88,93 The nodules of silicosis are well defined and located in the perivascular and peribronchiolar interstitium and the paraseptal and subpleural interstitium, and they are preferentially distributed in the upper lobes. Adjacent vessels and bronchioles may become involved and destroyed by these nodules, with occlusion of their lumen. Hilar and mediastinal lymph nodes are enlarged and pigmented, similar to that found in the silicotic nodule. Calcification also is a frequent finding. Progressive Massive Fibrosis Conglomeration of the nodules frequently occurs to form large masses of PMF, usually in the upper lobes where nodular profusion is greatest. The lower lobes are less frequently involved. PMF lesions sometimes cross the interlobar fissure to form elongated masses from the lung apex to the lower lobe. PMF usually is associated with adjacent emphysema and composed histologically of hyalinized collagen without the concentric lamellar appearance found in silicotic nodules. Cavitation occurs as a consequence of infection by anaerobic organisms, ischemia, or tuberculosis. Although conglomeration usually occurs in a heavily dust-laden lung with a high profusion of nodules, its development does not always parallel nodular profusion. Rheumatoid Pneumoconiosis Nodules of rheumatoid pneumoconiosis are similar to necrobiotic nodules found in rheumatoid arthritis and can be classified as either classic or silicotic type.52 The former correspond to the original cases described by Caplan and are large nodules characterized by uniform necrosis and associated with little background pneumoconiotic nodules. The silicotic type consists of multiple smaller nodules, with the necrotic area retaining some characteristics of a silicotic nodule.

796

SECTION 12  Inhalational Diseases and Aspiration

Mixed Dust Fibrosis Although the radiographic characteristics of mixed dust fibrosis have not been a subject of interest in recent literature, this entity is frequently described in pathology textbooks and is of some clinical importance within the context of lung damage in exposed silica workers.88,93 Exposure to high content (>18% of total dust deposited in lung) of free crystalline silica results in classic silicosis, whereas mixed dust fibrosis develops in the presence of low silica content (70 years), alcoholism, loss of consciousness (stroke), structural abnormalities of the pharynx and esophagus, neuromuscular disorders, and deglutition abnormalities. • Types of aspiration • Aspiration pneumonia: pulmonary infection caused by aspiration of colonized oropharyngeal secretions • Aspiration pneumonitis (chemical pneumonia): acute lung injury caused by the aspiration of materials inherently toxic to the lungs, such as gastric acid, milk, mineral oil, and volatile hydrocarbons • Aspiration of inert and nontoxic fluids: acute lung injury caused by the aspiration of inert fluids, such as water, saline, and barium • Aspiration of lipids • Aspiration of foreign bodies • Pulmonary complications caused by aspiration usually involve the posterior segment of the upper lobes or the superior segment of the lower lobes. • The radiographic findings most commonly consist of patchy areas of consolidation. Abscess or empyema may develop. • Esophagram is the imaging modality of choice to demonstrate the presence of tracheoesophageal fistula. • CT is the modality of choice in establishing the diagnosis of exogenous lipoid pneumonia, which can result from aspiration of mineral oil or a related substance.

B Fig. 64.23  Gastric aspiration and constrictive bronchiolitis in a woman with achalasia. (A) Posteroanterior chest radiograph shows a hyperlucent right lower lung zone with associated loss of volume and a reduced number of lung vessels (arrows). (B) Expiratory CT shows a hyperlucent right lower lobe with a reduced size and number of vessels. These findings correlate with the presence of localized small airway disease (air-trapping).

SUGGESTED READINGS DiBardino DM, Wunderink RG. Aspiration pneumonia: a review of modern trends. J Crit Care. 2015;30(1):40–48. Franquet T, Gimenez A, Roson N, Torrubia S, Sabate JM, Perez C. Aspiration diseases: findings, pitfalls, and differential diagnosis. Radiographics. 2000;20(3):673–685. Marik PE. Pulmonary aspiration syndromes. Curr Opin Pulm Med. 2011;17(3):148–154. Pereira-Silva JL, Silva CI, Araujo Neto CA, Andrade TL, Müller NL. Chronic pulmonary microaspiration: high-resolution computed tomographic findings in 13 patients. J Thorac Imaging. 2014;29(5):298–303.

The full reference list for this chapter is available at ExpertConsult.com.

64  Aspiration 835.e1

REFERENCES 1. DiBardino DM, Wunderink RG. Aspiration pneumonia: a review of modern trends. J Crit Care. 2015;30(1):40–48. 2. Marik PE. Pulmonary aspiration syndromes. Curr Opin Pulm Med. 2011; 17(3):148–154. 3. Franquet T, Gimenez A, Roson N, Torrubia S, Sabate JM, Perez C. Aspiration diseases: findings, pitfalls, and differential diagnosis. Radiographics. 2000;20(3): 673–685. 4. Mirzakhani H, Williams JN, Mello J, et al. Muscle weakness predicts pharyngeal dysfunction and symptomatic aspiration in long-term ventilated patients. Anesthesiology. 2013;119(2):389–397. 5. Huxley EJ, Viroslav J, Gray WR, Pierce AK. Pharyngeal aspiration in normal adults and patients with depressed consciousness. Am J Med. 1978;64(4): 564–568. 6. Drinka P. Pneumonia versus aspiration pneumonitis. J Am Geriatr Soc. 2009;57(12):2374–2375. 7. Guillon A, Montharu J, Cormier B, Vecellio L, Diot P, de Monte M. New insights into the pathophysiology of aspiration pneumonia. Br J Anaesth. 2011;106(4):608–609. 8. Komiya K, Ishii H, Umeki K, et al. Impact of aspiration pneumonia in patients with community-acquired pneumonia and healthcare-associated pneumonia: a multicenter retrospective cohort study. Respirology. 2013;18(3): 514–521. 9. Marik PE, Careau P. The role of anaerobes in patients with ventilator-associated pneumonia and aspiration pneumonia: a prospective study. Chest. 1999;115(1): 178–183. 10. El-Solh AA, Pietrantoni C, Bhat A, et al. Microbiology of severe aspiration pneumonia in institutionalized elderly. Am J Respir Crit Care Med. 2003; 167(12):1650–1654. 11. Bartlett JG, Finegold SM. Anaerobic infections of the lung and pleural space. Am Rev Respir Dis. 1974;110(1):56–77. 12. Alcon A, Fabregas N, Torres A. Pathophysiology of pneumonia. Clin Chest Med. 2005;26(1):39–46. 13. Yoneyama T, Yoshida M, Matsui T, Sasaki H. Oral care and pneumonia. Oral Care Working Group. Lancet. 1999;354(9177):515. 14. DePaso WJ. Aspiration pneumonia. Clin Chest Med. 1991;12(2):269–284. 15. Gleeson K, Eggli DF, Maxwell SL. Quantitative aspiration during sleep in normal subjects. Chest. 1997;111(5):1266–1272. 16. Yamauchi Y, Yasunaga H, Matsui H, et al. Comparison of clinical characteristics and outcomes between aspiration pneumonia and community-acquired pneumonia in patients with chronic obstructive pulmonary disease. BMC Pulm Med. 2015;15:69. 17. Komiya K, Ishii H, Kadota J. Healthcare-associated pneumonia and aspiration pneumonia. Aging Dis. 2015;6(1):27–37. 18. Marrie TJ. Community-acquired pneumonia: epidemiology, etiology, treatment. Infect Dis Clin North Am. 1998;12(3):723–740. 19. Marik PE. Aspiration syndromes: aspiration pneumonia and pneumonitis. Hosp Pract (1995). 2010;38(1):35–42. 20. Marom EM, McAdams HP, Erasmus JJ, Goodman PC. The many faces of pulmonary aspiration. AJR Am J Roentgenol. 1999;172(1):121–128. 21. Unger JD, Rose HD, Unger GF. Gram-negative pneumonia. Radiology. 1973;107(2):283–291. 22. Bogs T, Zwink N, Chonitzki V, et al. Esophageal atresia with or without tracheoesophageal fistula (EA/TEF): association of different EA/TEF subtypes with specific co-occurring congenital anomalies and implications for diagnostic workup. Eur J Pediatr Surg. 2017;[Epub ahead of print]. 23. Ho AM, Kwok WH. Congenital tracheoesophageal fistula. Paediatr Anaesth. 2012;22(3):300–301. 24. Hajjar WM, Iftikhar A, Al Nassar SA, Rahal SM. Congenital tracheoesophageal fistula: a rare and late presentation in adult patient. Ann Thorac Med. 2012;7(1):48–50. 25. Saxena P, Tam R. Late manifestation of a large congenital tracheoesophageal fistula in an adult. Tex Heart Inst J. 2006;33(1):60–62. 26. Moorhead JM, Reid RA, Vontz FK. Congenital tracheoesophageal fistula in an adult. South Med J. 1982;75(8):1030–1031. 27. Grant DM, Thompson GE. Diagnosis of congenital tracheoesophageal fistula in the adolescent and adult. Anesthesiology. 1978;49(2):139–140. 28. Berkmen YM, Auh YH. CT diagnosis of acquired tracheoesophageal fistula in adults. J Comput Assist Tomogr. 1985;9(2):302–304. 29. Han YM, Song HY, Lee JM, et al. Esophagorespiratory fistulae due to esophageal carcinoma: palliation with a covered Gianturco stent. Radiology. 1996;199(1):65–70. 30. Anbari MM, Levine MS, Cohen RB, Rubesin SE, Laufer I, Rosato EF. Delayed leaks and fistulas after esophagogastrectomy: radiologic evaluation. AJR Am J Roentgenol. 1993;160(6):1217–1220.

31. Lepke RA, Libshitz HI. Radiation-induced injury of the esophagus. Radiology. 1983;148(2):375–378. 32. Wechsler RJ. CT of esophageal-pleural fistulae. AJR Am J Roentgenol. 1986;147(5):907–909. 33. Berson W, Adriani J. Silent regurgitation and aspiration during anesthesia. Anesthesiology. 1954;15(6):644–649. 34. Neelakanta G, Chikyarappa A. A review of patients with pulmonary aspiration of gastric contents during anesthesia reported to the Departmental Quality Assurance Committee. J Clin Anesth. 2006;18(2):102–107. 35. Marom EM, McAdams HP, Sporn TA, Goodman PC. Lentil aspiration pneumonia: radiographic and CT findings. J Comput Assist Tomogr. 1998;22(4):598–600. 36. Ros PR. Lentil aspiration pneumonia. JAMA. 1984;251(10):1277–1278. 37. Sakamoto O, Saita N, Yamasaki H, Tamanoi M, Ando M. Pulmonary granulomatosis caused by aspirated green tea. Chest. 1994;106(1):308–309. 38. Dines DE, Titus JL, Sessler AD. Aspiration pneumonitis. Mayo Clin Proc. 1970;45(5):347–360. 39. Tuddenham WJ. Glossary of terms for thoracic radiology: recommendations of the Nomenclature Committee of the Fleischner Society. AJR Am J Roentgenol. 1984;143(3):509–517. 40. Groskin SA, Panicek DM, Ewing DK, et al. Bacterial lung abscess: a review of the radiographic and clinical features of 50 cases. J Thorac Imaging. 1991;6(3):62–67. 41. Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and the Armed Forces Institute of Pathology; 2002. 42. Allewelt M. Aspiration pneumonia and primary lung abscess: diagnosis and therapy of an aerobic or an anaerobic infection? Expert Rev Respir Med. 2007;1(1):111–119. 43. Carpenter LM, Merten DF. Radiographic manifestations of congenital anomalies affecting the airway. Radiol Clin North Am. 1991;29(2):219–240. 44. Gaur P, Dunne R, Colson YL, Gill RR. Bronchopleural fistula and the role of contemporary imaging. J Thorac Cardiovasc Surg. 2014;148(1):341–347. 45. Kikawada M, Iwamoto T, Takasaki M. Aspiration and infection in the elderly: epidemiology, diagnosis and management. Drugs Aging. 2005;22(2):115–130. 46. Kim SR, Jung LY, Oh IJ, et al. Pulmonary actinomycosis during the first decade of 21st century: cases of 94 patients. BMC Infect Dis. 2013;13:216. 47. Komiya K, Ishii H, Umeki K, et al. Computed tomography findings of aspiration pneumonia in 53 patients. Geriatr Gerontol Int. 2013;13(3): 580–585. 48. Tomiyama N, Müller NL, Johkoh T, et al. Acute parenchymal lung disease in immunocompetent patients: diagnostic accuracy of high-resolution CT. AJR Am J Roentgenol. 2000;174(6):1745–1750. 49. Niederman MS, Fein AM. Sepsis syndrome, the adult respiratory distress syndrome, and nosocomial pneumonia. A common clinical sequence. Clin Chest Med. 1990;11(4):633–656. 50. Ayres JG, Miles JF. Oesophageal reflux and asthma. Eur Respir J. 1996;9(5):1073–1078. 51. Primack SL, Müller NL. High-resolution computed tomography in acute diffuse lung disease in the immunocompromised patient. Radiol Clin North Am. 1994;32(4):731–744. 52. Reittner P, Müller NL, Heyneman L, et al. Mycoplasma pneumoniae pneumonia: radiographic and high-resolution CT features in 28 patients. AJR Am J Roentgenol. 2000;174(1):37–41. 53. Reittner P, Ward S, Heyneman L, Johkoh T, Muller NL. Pneumonia: highresolution CT findings in 114 patients. Eur Radiol. 2003;13(3):515–521. 54. Tew J, Calenoff L, Berlin BS. Bacterial or nonbacterial pneumonia: accuracy of radiographic diagnosis. Radiology. 1977;124(3):607–612. 55. Vilar J, Domingo ML, Soto C, Cogollos J. Radiology of bacterial pneumonia. Eur J Radiol. 2004;51(2):102–113. 56. Boiselle PM, Tocino I, Hooley RJ, et al. Chest radiograph interpretation of Pneumocystis carinii pneumonia, bacterial pneumonia, and pulmonary tuberculosis in HIV-positive patients: accuracy, distinguishing features, and mimics. J Thorac Imaging. 1997;12(1):47–53. 57. Janzen DL, Padley SP, Adler BD, Müller NL. Acute pulmonary complications in immunocompromised non-AIDS patients: comparison of diagnostic accuracy of CT and chest radiography. Clin Radiol. 1993;47(3):159–165. 58. Chastre J, Trouillet JL, Vuagnat A, et al. Nosocomial pneumonia in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1998;157(4 Pt 1):1165–1172. 59. Seidenfeld JJ, Pohl DF, Bell RC, Harris GD, Johanson WG Jr. Incidence, site, and outcome of infections in patients with the adult respiratory distress syndrome. Am Rev Respir Dis. 1986;134(1):12–16. 60. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344(9):665–671.

835.e2

SECTION 12  Inhalational Diseases and Aspiration

61. Bynum LJ, Pierce AK. Pulmonary aspiration of gastric contents. Am Rev Respir Dis. 1976;114(6):1129–1136. 62. Garvey BM, McCambley JA, Tuxen DV. Effects of gastric alkalization on bacterial colonization in critically ill patients. Crit Care Med. 1989;17(3):211–216. 63. Bonten MJ, Gaillard CA, van der Geest S, et al. The role of intragastric acidity and stress ulcus prophylaxis on colonization and infection in mechanically ventilated ICU patients. A stratified, randomized, double-blind study of sucralfate versus antacids. Am J Respir Crit Care Med. 1995;152(6 Pt 1):1825–1834. 64. David P, Denis P, Nouvet G, Pasquis P, Lefrancois R, Morere P. Lung function and gastroesophageal reflux during chronic bronchitis (author’s transl). Bull Eur Physiopathol Respir. 1982;18(1):81–86. 65. Gray C, Sivaloganathan S, Simpkins KC. Aspiration of high-density barium contrast medium causing acute pulmonary inflammation—report of two fatal cases in elderly women with disordered swallowing. Clin Radiol. 1989;40(4):397–400. 66. Pracy JP, Montgomery PQ, Reading N. Acute pneumonitis caused by low density barium sulphate aspiration. J Laryngol Otol. 1993;107(4):347–348. 67. Brander PE, Taskinen E, Stenius-Aarniala B. Fire-eater’s lung. Eur Respir J. 1992;5(1):112–114. 68. Franquet T, Gomez-Santos D, Gimenez A, Torrubia S, Monill JM. Fire eater’s pneumonia: radiographic and CT findings. J Comput Assist Tomogr. 2000; 24(3):448–450. 69. Sladen A, Zanca P, Hadnott WH. Aspiration pneumonitis—the sequelae. Chest. 1971;59(4):448–450. 70. Landay MJ, Christensen EE, Bynum LJ. Pulmonary manifestations of acute aspiration of gastric contents. AJR Am J Roentgenol. 1978;131(4):587–592. 71. van Beeck EF, Branche CM, Szpilman D, Modell JH, Bierens JJ. A new definition of drowning: towards documentation and prevention of a global public health problem. Bull World Health Organ. 2005;83(11):853–856. 72. Modell JH. Drowning. N Engl J Med. 1993;328(4):253–256. 73. Weinstein MD, Krieger BP. Near-drowning: epidemiology, pathophysiology, and initial treatment. J Emerg Med. 1996;14(4):461–467. 74. Clemens T, Tamim H, Rotondi M, Macpherson AK. A population based study of drowning in Canada. BMC Public Health. 2016;16:559. 75. Salomez F, Vincent JL. Drowning: a review of epidemiology, pathophysiology, treatment and prevention. Resuscitation. 2004;63(3):261–268. 76. Idris AH, Berg RA, Bierens J, et al. Recommended guidelines for uniform reporting of data from drowning: the “Utstein style. Circulation. 2003;108(20): 2565–2574. 77. Hunter TB, Whitehouse WM. Fresh-water near-drowning: radiological aspects. Radiology. 1974;112(1):51–56. 78. Rosenbaum HT, Thompson WL, Fuller RH. Radiographic pulmonary changes in near-drowning. Radiology. 1964;83:306–313. 79. Ender PT, Dolan MJ. Pneumonia associated with near-drowning. Clin Infect Dis. 1997;25(4):896–907. 80. Dunagan DP, Cox JE, Chang MC, Haponik EF. Sand aspiration with neardrowning. Radiographic and bronchoscopic findings. Am J Respir Crit Care Med. 1997;156(1):292–295.

81. Franquet T, Gimenez A, Bordes R, Rodriguez-Arias JM, Castella J. The crazy-paving pattern in exogenous lipoid pneumonia: CT-pathologic correlation. AJR Am J Roentgenol. 1998;170(2):315–317. 82. Gondouin A, Manzoni P, Ranfaing E, et al. Exogenous lipid pneumonia: a retrospective multicentre study of 44 cases in France. Eur Respir J. 1996;9(7): 1463–1469. 83. Annobil SH, Ogunbiyi AO, Benjamin B. Chest radiographic findings in childhood lipoid pneumonia following aspiration of animal fat. Eur J Radiol. 1993;16(3):217–220. 84. Kennedy JD, Costello P, Balikian JP, Herman PG. Exogenous lipoid pneumonia. AJR Am J Roentgenol. 1981;136(6):1145–1149. 85. Lee JS, Im JG, Song KS, Seo JB, Lim TH. Exogenous lipoid pneumonia: high-resolution CT findings. Eur Radiol. 1999;9(2):287–291. 86. Lee KH, Kim WS, Cheon JE, Seo JB, Kim IO, Yeon KM. Squalene aspiration pneumonia in children: radiographic and CT findings as the first clue to diagnosis. Pediatr Radiol. 2005;35(6):619–623. 87. Lee KS, Muller NL, Hale V, Newell JD Jr, Lynch DA, Im JG. Lipoid pneumonia: CT findings. J Comput Assist Tomogr. 1995;19(1):48–51. 88. Rossi SE, Erasmus JJ, Volpacchio M, Franquet T, Castiglioni T, McAdams HP. “Crazy-paving” pattern at thin-section CT of the lungs: radiologicpathologic overview. Radiographics. 2003;23(6):1509–1519. 89. McGuirt WF, Holmes KD, Feehs R, Browne JD. Tracheobronchial foreign bodies. Laryngoscope. 1988;98(6 Pt 1):615–618. 90. Pattison CW, Leaming AJ, Townsend ER. Hidden foreign body as a cause of recurrent hemoptysis in a teenage girl. Ann Thorac Surg. 1988;45(3): 330–331. 91. Richards AM. Pediatric respiratory emergencies. Emerg Med Clin North Am. 2016;34(1):77–96. 92. Bissonnette RT, Connell DG, Fitzpatrick DG. Preoperative localization of low-density foreign bodies under CT guidance. Can Assoc Radiol J. 1988;39(4):286–287. 93. Newton JP, Abel RW, Lloyd CH, Yemm R. The use of computed tomography in the detection of radiolucent denture base material in the chest. J Oral Rehabil. 1987;14(2):193–202. 94. Choi J, Lee GL. Common pediatric respiratory emergencies. Emerg Med Clin North Am. 2012;30(2):529–563, x. 95. Matsuse T, Oka T, Kida K, Fukuchi Y. Importance of diffuse aspiration bronchiolitis caused by chronic occult aspiration in the elderly. Chest. 1996;110(5):1289–1293. 96. McArthur MS. Pulmonary complications of benign esophageal disease. Am J Surg. 1986;151(2):296–299. 97. Stark P, Thordarson S, McKinney M. Manifestations of esophageal disease on plain chest radiographs. AJR Am J Roentgenol. 1990;155(4):729–734. 98. Worthy SA, Park CS, Kim JS, Müller NL. Bronchiolitis obliterans after lung transplantation: high-resolution CT findings in 15 patients. AJR Am J Roentgenol. 1997;169(3):673–677. 99. Pereira-Silva JL, Silva CI, Araujo Neto CA, Andrade TL, Müller NL. Chronic pulmonary microaspiration: high-resolution computed tomographic findings in 13 patients. J Thorac Imaging. 2014;29(5):298–303.

SECTION 13

Iatrogenic Lung Disease and Trauma

65 

Drug-Induced Lung Disease* SARAH T. KURIAN  |  CHRISTOPHER M. WALKER  |  JONATHAN H. CHUNG

Etiology The number of drugs recognized to cause an adverse pulmonary reaction of one kind or another is reported to be more than 6001 and continues to rise yearly with the advent of new medications. Pharmacologic groups associated with pulmonary toxicity include chemotherapeutic agents, antimicrobials, antiinflammatory agents, cardiovascular drugs, and illicit drugs.2,3 Drug reactions are usually the result of either direct (toxic and idiosyncratic reactions) or indirect effects of the drug.4,5 The development of injury can be influenced by the age of the patient, concomitant administration of oxygen, prior radiotherapy, and synergism with other drugs.6

Prevalence and Epidemiology Drug therapy is common and may result in a great variety of adverse effects. In 2006 82% of the US population reported use of at least one prescription medication, over-the-counter medication, or dietary supplement in the previous week, and 29% reported use of five or more of these drugs.7,8 Adverse drug events accounted for 1.7% to 2.5% of estimated emergency department (ED) visits for all unintentional injuries,9 with 27.3% of these ED visits resulting in hospitalization in 2013 and 2014.10 Individuals aged 65 years or older were twice as likely than younger individuals to develop adverse drug events.11 The majority of adverse drug effects are dermatologic, gastrointestinal, and neurologic. Respiratory complications are estimated to account for approximately 54,000 adverse drug events in the United States per year or approximately 7.7% of all adverse drug events.11 Drug reactions are even more common in inpatients. One English study showed that nearly 1 in 7 hospital inpatients experience an adverse drug reaction.12 Fatal drug reactions occur in 0.1% of medical inpatients and 0.01% of surgical inpatients.13 The prevalence of drug-induced lung disease varies considerably among different drugs, ranging from approximately 1 in 100,000 treatments for nitrofurantoin to more than 40% in women who receive nitrosourea-based chemotherapy for the treatment of breast cancer.14 The estimated prevalence rate of pulmonary reactions for each drug can be found on the Pneumotox website (http://www.pneumotox.com).

*The editors and the publisher would like to thank Drs. C. Isabela Silva Müller and Nestor L. Müller for contributing material on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

836

Clinical Presentation and Pathophysiology The most common clinical manifestations of patients with pulmonary drug reaction are cough, dyspnea, fatigue, fever, chest pain, and weight loss. Drug-induced lung disease may manifest as an acute, subacute, or chronic process. Adverse reactions to drugs can be classified into those that may occur in any individual taking the drug and those that occur only in susceptible individuals.13 Reactions that may occur in anyone taking the drug include drug side effect, defined as undesirable pharmacologic effect at recommended doses; drug interaction, defined as action of a drug on the effectiveness or toxicity of another one; and drug overdose. These drug reactions are predictable and account for at least 80% of adverse drug reactions.15 Reactions that occur only in susceptible individuals include drug intolerance, defined as a threshold to the normal pharmacologic action of a drug; drug idiosyncrasy, defined as a genetically determined, qualitatively abnormal reaction to a drug related to a metabolic or enzyme deficiency; and drug allergy, defined as an immunologically mediated reaction, characterized by specificity, transferability by antibodies or lymphocytes, and recurrence on reexposure.13 An example of an allergic respiratory drug reaction is asthma, most commonly caused by aspirin and nonsteroidal antiinflammatory drugs.13 Allergic drug reactions, however, account for less than 10% of adverse pulmonary drug reactions.15 The pathogenesis of most pulmonary drug reactions is unknown.15 The histologic findings of pulmonary drug reactions are often nonspecific and mimic those of various acute and chronic lung diseases.3,16 The most common histologic patterns are diffuse alveolar damage, nonspecific interstitial pneumonia, organizing pneumonia, eosinophilic pneumonia, hypersensitivity pneumonitis, and acute or chronic diffuse alveolar hemorrhage,4,17,18 Pulmonary damage caused by intravenous injection of crushed oral tablets leading to Ritalin lung and talcosis are discussed in Chapter 52. Drug-related constrictive bronchiolitis is discussed in Chapter 59. Certain drugs tend to cause a predictable pattern of lung injury (Table 65.1); however, this is not always the case, and patterns of lung injury may overlap (Fig. 65.1). CHOICE OF IMAGING MODALITY Thin-section CT more precisely assesses the presence and characterizes the pattern and distribution of parenchymal and airway abnormalities than chest radiography does, and it may demonstrate abnormalities in patients with normal radiographs.19,20 Padley and colleagues20 detected abnormal findings on CT in all 23 patients

65  Drug-Induced Lung Disease

837

TABLE 65.1  COMMON DRUGS ASSOCIATED WITH VARIOUS PATTERNS OF LUNG INJURY Pattern of Injury

Common Drugs

Diffuse alveolar damage Nonspecific interstitial pneumonia (NSIP) Organizing pneumonia

Busulfan, cyclophosphamide, carmustine, bleomycin, paclitaxel, docetaxel, checkpoint inhibitors Amiodarone, methotrexate, nitrofurantoin, bleomycin, hydrochlorothiazide, carmustine

Eosinophilic pneumonia Hypersensitivity pneumonitis Diffuse alveolar hemorrhage

Amiodarone, acebutolol, minocycline, nitrofurantoin, bleomycin, gold salts, cyclophosphamide, methotrexate, penicillamine, phenytoin, carbamazepine, mesalamine, hydralazine, interferon Amiodarone, bleomycin, nitrofurantoin, phenytoin, β-blockers, nonsteroidal antiinflammatory drugs, antidepressants, hydrochlorothiazide, minocycline, sulfonamides, sulfasalazine, mesalamine Methotrexate, cyclophosphamide, mesalamine, fluoxetine, amitriptyline, docetaxel, paclitaxel Anticoagulants, amphotericin B, amiodarone, cyclophosphamide, carbamazepine, methotrexate, mitomycin, nitrofurantoin, penicillamine, phenytoin, propylthiouracil

Adapted from Rossi SE, Erasmus JJ, McAdams HP, Sporn TA, Goodman P. Pulmonary drug toxicity: radiologic and pathologic manifestations. Radiographics. 2000;20(5):1245–1259.

underlying histologic pattern.17,25 Thin-section CT is also of value in monitoring the appearance, progression, and resolution of pulmonary damage in these patients. IMAGING PATTERNS Drug-induced lung disease typically manifests in five characteristic patterns in the lung. These are diffuse alveolar damage, nonspecific interstitial pneumonia, organizing pneumonia, hypersensitivity pneumonitis, and alveolar hemorrhage. The pathophysiology and imaging features of each entity is discussed herein. Of note, all patterns of chronic interstitial pneumonias have been reported as manifestations of drug reactions; however, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, and usual interstitial pneumonia are uncommon manifestations of drug-induced lung disease. For example, a fibrotic process that mimics idiopathic pulmonary fibrosis, characterized by the presence of usual interstitial pneumonia on surgical lung biopsy, has been well characterized for nitrofurantoin.17

Fig. 65.1  Drug-induced lung injury resulting in a combination of nonspecific interstitial pneumonia and hypersensitivity pneumonitis patterns caused by lenalidomide and bortezomib therapy in a patient with relapsed multiple myeloma. Axial CT at the lung bases demonstrates bilateral ground-glass opacities, tiny (100 Gy). Because the target volume is small, SBRT is being used more frequently with curative intent in patients with peripheral early-stage NSCLC (Fig. 66.1). In these patients SBRT is used rather than conventional radiation therapy or surgical resection as it achieves local control rates of 80% to 95%58 and improves overall survival compared with conventional radiation therapy.59–64

Recent Innovations in Radiation Therapy Radiation therapy has improved considerably during the past few decades by refinements of existing techniques and introduction of new technology, including positron emission tomography (PET)-CT using the radiopharmaceutical 18F-deoxyglucose, a D-glucose analog labeled with fluorine-18 (18F-FDG–PET-CT), four-dimensional (4D) treatment planning, and proton therapy. The increasing use of advanced CRT techniques such as IMRT and SBRT in thoracic radiation oncology makes precise target

delineation important as these techniques have a higher likelihood of geographic misses.65 Use of FDG–PET-CT and 4D treatment planning improves the precision in radiation therapy by increasing the accuracy of tumor delineation and minimizing damage to surrounding structures.66,67 FDG–PET-CT improves delineation of the extent of the tumor compared with CT alone when there is associated postobstructive atelectasis. The use of FDG–PET-CT results in less variation in lung cancer contouring compared with CT alone and reduces the risk of geographic misses with SBRT.68 In addition, because tumor volume delineation by FDG–PET-CT is typically smaller than that defined by CT, this can potentially facilitate dose escalation without increasing side effects.69–72 Also, the detection of unsuspected nodal metastases by FDG–PET-CT improves the target accuracy for nodal radiation and decreases isolated nodal failures.73 In addition to assisting with target volume delineation, PET-CT imaging may have an important role in adaptive planning. Adaptive planning is the modification of a radiation treatment plan during the course of therapy to account for changes in the tumor and/or adjacent tissue. The use of FDG–PET-CT has been reported to allow a smaller target volume to be radiated during radiotherapy delivery and to facilitate dose escalation.74 The use of 4D imaging in radiation treatment planning introduces the concept of time to the 3D conformal treatment planning and compensates for tumor motion, patient movement, and movement occurring either during a single fraction (intrafraction) or between multiple fractions (interfraction) of radiation.75 Intrafractional movement can cause significant target deformation resulting from respiratory motion, and interfractional variation can interfere in tumor delineation as tumor and anatomy may change significantly between each treatment session. 4D treatment planning allows an assessment of tumor motion across an entire respiratory cycle, and radiation therapy is delivered accordingly. 4D-CT is currently being used in conjunction with 3D-CRT and IMRT to achieve high-precision radiation dose delivery to the tumor.75 In addition, in the treatment of lung cancer, using SBRT with 4D-CT imaging allows a significant reduction of target volumes and decreased dose to surrounding tissue when compared with conventional 3D-CT.76–78 4D-CT–based planning has also optimized radiation delivery in patients with lung cancer receiving proton therapy.79 In patients with target volumes that have a large amount of motion (typically >1 cm), two approaches can be used to further reduce the amount of lung treated. The first, respiratory gating, allows delivery of radiation only during certain phases of the respiratory cycle while the patient breathes normally. The second, deep inspiratory breath hold, has the patient “hold his or her breath” after deep inspiration. Because radiation is delivered when the tumor is in a relatively “fixed” position with either of these approaches, the full extent of the tumor motion does not need to be delineated. Proton therapy can allow high-dose radiation delivery to the tumor with minimal radiation exposure to the adjacent organs. The advantage of proton therapy relies on the physical characteristics of the proton particles, which deposit nearly all the therapeutic dose at a particular depth (Bragg peak), and this typically results in a negligible exit dose beyond the target. However, in aerated lung, proton beams travel beyond the distal edge of the tumor and can cause damage to adjacent lung tissue. A study assessing dosimetric values for stage I and III NSCLC treated with proton therapy, compared with 3D-CRT and IMRT, has shown that all three techniques provide adequate tumor coverage, but proton therapy delivers lower doses to the adjacent

66  Therapeutic Radiation and Radiation-Induced Lung Disease

849

A Absolute 6000.0 cGy 5000.0 cGy 4500.0 cGy 4080.0 cGy 3500.0 cGy 3000.0 cGy 2000.0 cGy 1000.0 cGy 500.0 cGy

C

Final Iso

B

lung, esophagus, and spinal cord than the two other techniques.80 Sejpal and colleagues81 compared photon and proton-based RT and showed that proton therapy resulted in lower rates of esophagitis and severe pneumonitis than 3D-CRT and IMRT. However, the use of proton therapy in patients with lung cancer is not clearly defined.82 Currently, proton therapy has been indicated for centrally located tumors adjacent to the heart, spinal cord, and esophagus (Fig. 66.2) as well as tumors close to the brachial plexus.83 In addition, a recent phase II randomized study from The University of Texas M.D. Anderson Cancer Center highlighted the need for adequate patient selection for this approach. Patients with locally advanced NSCLC were randomized to IMRT or passive scattering proton therapy (proton therapy using 3D-conformal techniques). The coprimary end points were

Fig. 66.1  Stereotactic body radiotherapy (SBRT) in a woman with lung adenocarcinoma receiving definitive radiation therapy because of poor performance status. (A) CT image obtained before treatment shows a spiculated right upper lobe nodule (arrow). (B) Computed dosimetric axial reconstruction obtained for radiation treatment plan shows the tumor delineated by red color and the green target. The white line surrounding the tumor defines the area that will receive the highest radiation dose, 6000 cGy in this case. Each isodose line farther away from the tumor demarcates an area that will receive a progressively smaller radiation dose. (C) CT image obtained 16 months after treatment shows decrease in size of radiated primary lung malignancy (arrow). In addition, there are subtle opacities within the radiation treatment field corresponding to radiation-induced lung disease. Note how precise target delineation minimizes radiation doses and damage to surrounding tissues.

the incidence of radiation pneumonitis and locoregional control, and in this unselected patient population, there was no difference between the two modalities.84 Further analyses are underway comparing IMRT with intensity-modulated proton therapy (proton therapy incorporating features of inverse planning and with greater conformality than the passive scattering approach), which use selective dose escalation based on normal tissue doses.

Dose and Fractionation External-beam radiation therapy is an established treatment option for patients with nonresectable locally advanced (stage III) NSCLC. Typically, a standard dose of 60 Gy, given in a single fraction per day, 5 days a week, during 6 weeks is used. The use

850

SECTION 13  Iatrogenic Lung Disease and Trauma A

Isodoses (cGy) 6600.0 6300.0 6000.0 5500.0 5000.0 4500.0 4000.0 3500.0 3000.0 2000.0 1000.0 500.0

1000

*

500

R

6300 6300 6300

6300 6300

6300

6300 6000 3500 6300

6300

5000 6300 5500

4000 4500

6300

A 2000

B

C

of this dose has been recently confirmed in a comparison study as 74 Gy in a phase III national trial.85,86 However, because changing the time interval and the dose of radiation can influence the response of both normal and tumor tissues to radiotherapy and can optimize radiation treatment, different fractionation schedules have also been assessed as treatment options for stage I to III NSCLC.87 In the hyperfractionation scheme, there is delivery of more than one fraction in 24 hours, using a larger number of fractions per week (between 10 and 25 fractions) and using a dose per fraction of less than 1.8 Gy.88 Although several hyperfractionation regimens have been tested in randomized trials for NSCLC, it has not been shown to be superior to standard fractionated regimens. Currently, a hyperfractionated schedule is selectively used for patients with NSCLC located near the spinal cord and brachial plexus, as late side effects can occur after high doses with a standard fractionation regimen. However, in the setting of small cell lung cancer, a hyperfractionated regimen of 1.5 Gy delivered twice daily to 45 Gy is one of a limited number of acceptable treatment options and is currently being further assessed in a phase III randomized trial.

Fig. 66.2  Proton radiation in a woman with lung adenocarcinoma. (A) CT image obtained before treatment shows a left lower lobe mass extending to the left hilar region and subcarinal nodal metastasis (asterisk). (B) Computed dosimetric axial reconstruction obtained for proton radiation plan shows primary lung malignancy and nodal metastatic disease receiving maximal isodose (6600 cGY). (C) CT image obtained 3 years after radiation therapy shows focal lung opacities confined to treatment field and normal adjacent lung.

In addition, accelerated fractionation can be used. Accelerated fractionation is related to the intensity of the treatment over time in which the rate of dose accumulation is greater than 10 Gy per week. One type of accelerated radiotherapy is called continuous hyperfractionated accelerated radiotherapy (CHART), which combines hyperfractionation and accelerated schemes in a 54-Gy treatment, given in three fractions a day, 1.5 Gy per fraction, during 12 days. Saunders and colleagues89 compared the CHART scheme with standard radiation therapy and demonstrated improved survival in NSCLC patients. An alternative to hyperfractionation is hypofractionation, which includes a larger dose per fraction (>3.0 Gy) and fewer fractions, 1 to 4 days a week, and is the basis of SBRT.

Clinical Presentation The description of classic radiation-induced lung injury has three main phases: (1) an initial latent phase (first 3–4 weeks after completion of therapy); (2) an early phase: acute exudative pneumonitis (3 weeks to 6 months); and (3) a late phase: pulmonary

66  Therapeutic Radiation and Radiation-Induced Lung Disease

fibrosis (6 months and later).31,90 Radiation-induced lung disease usually manifests clinically as acute pneumonitis 4 to 12 weeks after completion of radiation therapy, although symptoms occasionally occur as early as 1 month after the beginning of radiation therapy and as late as 6 months after completion of treatment.22,24 The earlier clinical presentation of acute pneumonitis can occur with the newer treatment regimens that use hyperfractionated accelerated radiation. For instance, in a study evaluating escalated hyperfractionated accelerated radiation therapy in locally advanced NSCLC, acute pneumonitis developed in 40% of the patients, and onset was typically before the completion of treatment (median, 4 weeks after beginning of treatment; range, 3–5 weeks).16 In general, clinical symptoms are proportional to the extent of the radiation-induced lung injury and pretreatment pulmonary function of the patient. Symptomatic patients typically present with cough and mild dyspnea, although patients can have severe respiratory compromise.22,91 In addition, patients can occasionally present with chest pain, fever associated with nonproductive cough, or cough productive of small amounts of blood-tinged sputum.22,31,91 Acute radiation-induced pneumonitis manifesting as mild to moderate dyspnea generally resolves with treatment.24,92 In the 6.7% to 16% of patients with NSCLC who develop severe respiratory distress, morbidity and mortality can be high.31,36,93,94 In fact, Wang and colleagues31 reported that severe acute radiationinduced pneumonitis was associated with a mortality rate approaching 50% in the first 2 months after the onset of symptoms. Also, although IMRT after extrapleural pneumonectomy in patients with pleural mesothelioma has not typically been associated with radiation-induced injury in the remaining lung,95 6 of 13 patients (46%) in a study developed severe pneumonitis in the contralateral lung 5 to 57 days (mean, 30 days) after completion of therapy, with subsequent demise of all 6 patients.51 It is important to be aware that (1) symptomatic radiationinduced pneumonitis does not predict subsequent fibrosis, and (2) the clinical manifestations of acute radiation-induced pneumonitis often cannot be accounted for by the radiation therapy received by the patient (i.e., the dyspnea is more severe than would be expected from the volume of lung irradiated). It is postulated that a hypersensitivity reaction occurs in response to localized lung irradiation and results in an out-of-field pneumonitis.31,96,97 In the late phase of radiation-induced lung injury, pulmonary fibrosis localized to the region of the irradiated lung typically develops after 6 months. Most patients with radiation fibrosis are asymptomatic, although dyspnea that varies from minimal to severe can be present. Symptoms are usually minimal if fibrosis is limited to less than 50% of one lung.91 Chronic respiratory failure and cor pulmonale secondary to fibrosis of a large volume of lung can occasionally occur as late manifestations of radiationinduced lung disease.22

Pathophysiology Radiation-induced lung injury has classically been described as separate phases encompassing acute pneumonitis and fibrosis that occur at different times after radiation therapy. However, radiation-induced lung injury can be viewed as a continuum, with no distinct separation between the temporal sequences of the different phases of injury.98 In terms of the pathophysiologic process, radiation therapy initiates a sequence of molecular and

851

genetic changes resulting in lung injury.91,98 The biologic effects of ionizing radiation begin with the overproduction of oxygen free radicals, more generally known as reactive oxygen species.99,100 Reactive oxygen species result in damage to endothelial cells and exudation of proteinaceous material into the alveoli, desquamation of epithelial cells from the alveolar wall, and infiltration of inflammatory cells.91,100 Depending on the severity of injury, these pathologic exudative changes may resolve in a few weeks to months or result in an acute radiation pneumonitis. The continuous overproduction of reactive oxygen species after the initial injury may occur for months or years after the completion of radiation therapy and result in the progressive tissue damage, loss of parenchymal cells, and fibrosis that are histologically typical of late radiation lung injury.101,102 Uncommonly, radiation-induced lung injury is manifested as organizing pneumonia, most commonly outside the expected radiation field,103–105 and chronic eosinophilic pneumonia, particularly in patients with history of asthma or atopy.106 LUNG FUNCTION The severity of pneumonitis (grade 1–5) is usually defined clinically by the Southwest Oncology Group standard response criteria or the toxicity criteria of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer, according to the absence or presence of dyspnea and cough and the treatment required by the patient.24,25,91,107 However, unfortunately, these grading systems are to a large extent subjective and difficult to correlate with pulmonary function test results. Fifty percent to 90% of patients experience a decline in pulmonary function test results after radiation therapy, and these tests have been comprehensively evaluated in an effort to predict the incidence and severity of radiation-induced pneumonitis.24,50,91,108–110 Pulmonary function test results are relatively normal in most patients in the 4 to 8 weeks after completion of radiation therapy.91 Subsequently, a wide range of changes can occur in pulmonary function in both the acute pneumonitis phase and late fibrotic phase. Decreases have been noted in vital capacity, inspiratory capacity, total lung capacity, residual volume, forced expiratory volume in 1 second, and carbon monoxide diffusing capacity (DLCO).24,110 DLCO is generally the most severely affected parameter, and the impairment can progress with a reported annual decrease of 3.5% after the first year that follows radiation therapy completion.24,109–112

Manifestations of the Disease GENERAL The histopathologic response of the lungs to radiation injury is limited and manifested radiologically as two major distinct patterns. To describe these patterns of radiation-induced lung disease, the end of radiation therapy has traditionally been used as a reference point for the temporal sequence of changes because the length of treatment varies, and thus reference from the beginning of treatment would be inconsistent. Typically, acute radiation pneumonitis occurs 4 to 12 weeks after completion of radiation therapy and is followed within 6 to 12 months by radiation-induced fibrosis in the region of the radiation-induced lung injury.19,28–30,113–116 The criteria for the diagnosis of radiation-induced organizing pneumonia include radiotherapy within 12 months, symptom

852

SECTION 13  Iatrogenic Lung Disease and Trauma

A

B Fig. 66.3  Radiation pneumonitis in a woman with non–small cell lung cancer in the left lung. (A) Chest radiograph obtained 1 month after completion of radiation therapy shows radiation pneumonitis manifesting as increased hazy opacities in left lung (arrows) within the radiation field. (B) Chest radiograph obtained several months after completion of radiation therapy shows consolidation, volume loss, and traction bronchiectasis consistent with fibrosis.

duration of at least 2 weeks, pulmonary airspace opacities outside the radiation treatment field on chest radiography or CT, and exclusion of other causes.105 Diagnostic criteria for radiationinduced chronic eosinophilic pneumonia are similar to those associated with organizing pneumonia but include the presence of blood eosinophilia higher than 1 × 109/L or more than 40% eosinophils in the differential cell count of bronchoalveolar lavage fluid.106 RADIOGRAPHY The acute phase of radiation-induced lung disease initially is manifested radiographically as ground-glass opacities or consolidation in the treatment field (Fig. 66.3). Although radiation pneumonitis usually occurs within the irradiated lung, radiation pneumonitis outside the treatment fields has been reported.117–123 Ipsilateral pleural effusions can occur after radiation therapy and usually develop at the time of radiation pneumonitis (i.e., within 6 months after completion of therapy).7,20 Pleural effusions that develop after 6 months, continue to increase in size, or present as large effusions may require thoracentesis for differentiation of benign from malignant disease. Although the opacities of radiation pneumonitis can gradually resolve without radiologic sequelae when the injury to the lung is limited, in cases of more severe injury, there is usually a progression to fibrosis.20,124 The majority of fibrosis will occur within the first 12 months, and the development commonly progresses slowly in the 6 to 12 months after completion of therapy and stabilizes within 2 years. Radiation fibrosis is manifested radiologically as a well-defined area of volume loss, linear scarring, consolidation, and traction bronchiectasis. Consolidation usually coalesces and typically has a relatively sharp margin that conforms to the treatment field rather than to anatomic boundaries

(Fig. 66.4).20,27,29,30,124 With the evolution of radiation fibrosis, the demarcation between normal and irradiated lung parenchyma often becomes more sharply defined. COMPUTED TOMOGRAPHY CT is more sensitive than chest radiography in detecting radiationinduced lung disease. Ground-glass opacities representing early radiation pneumonitis (Fig. 66.5) can be seen a few weeks after completion of radiation therapy, although the radiograph is often normal.20,120–122 With some of the newer treatment regimens, opacities can sometimes be observed on CT before or at completion of radiation therapy. On occasion, acute pneumonitis detected on CT can appear nodular and simulate metastatic nodules.125,126 Typically, the nodules of radiation pneumonitis will be within the lung that underwent radiation therapy and are irregular or poorly marginated (Fig. 66.6). The nodules usually coalesce into areas of consolidation and eventually become a component of the radiation fibrosis. CT is the optimal modality for assessment of the evolution and chronic manifestations of radiation-induced lung injury (Fig. 66.7) and for the detection of locoregional recurrence of malignant disease (see the section on differential diagnosis). The technique used to deliver radiation will affect the CT manifestations of radiation-induced lung disease. Radiationinduced lung disease varies in shape and distribution with new radiation delivery techniques as the radiation dose is altered according to the location, extent, and type of malignant neoplasm for delivery of a tumoricidal dose while limiting the dose of radiation to adjacent lung. Recognition of imaging manifestations of this treatment can be facilitated with computed dosimetric reconstruction, whereby treatment volumes are superimposed on CT images (Figs. 66.8 and 66.9).127 In addition, the use of

66  Therapeutic Radiation and Radiation-Induced Lung Disease

A

853

B Fig. 66.4  Temporal evolution of radiation-induced lung disease in a woman with non–small cell lung cancer. (A) Chest radiograph obtained after resection of right lung cancer and 5 months after completion of radiation therapy shows radiation pneumonitis manifesting as increased hazy opacity (arrow) within radiation field. (B) Chest radiograph obtained 19 months after completion of radiation therapy shows evolution of postradiation findings with consolidation, traction bronchiectasis, and volume loss associated with architectural distortion. Note sharp demarcation between normal and irradiated lung parenchyma (arrows).

A

C

B

Fig. 66.5  Radiation pneumonitis in a woman with non–small cell lung cancer after intensity-modulated radiotherapy (IMRT) (same patient as in Fig. 66.3). (A) Pretreatment CT image shows mass in left upper lobe. (B) and (C) CT images obtained 3 weeks after completion of IMRT show radiation pneumonitis manifesting as ground-glass opacities and thickening of interlobular septa and intralobular lines (crazy paving pattern). Note decrease in size of lung mass (C).

854

A

C

A

SECTION 13  Iatrogenic Lung Disease and Trauma

B

Fig. 66.6  Nodular radiation pneumonitis in a man with right upper lobe non–small cell lung cancer (NSCLC) treated with intensitymodulated radiotherapy. (A) Pretreatment CT shows NSCLC manifesting as an irregular right upper lobe nodule (arrow). Also noted is bilateral paraseptal emphysema. (B) CT image obtained 4 months after completion of radiation therapy shows the primary tumor (arrow) and new poorly marginated nodular opacities caused by radiation injury. (C) CT image obtained 6 months after completion of radiation therapy shows radiation-induced fibrosis.

B Fig. 66.7  Radiation fibrosis in a man after resection of right lower lobe non–small cell lung cancer and conventional radiation therapy. (A) CT scan obtained 4 months after conventional radiation therapy shows ground-glass opacities in the right lung. Note sharp demarcation between normal lung and ground-glass opacities (arrows). (B) CT scan obtained 10 months after completion of radiation therapy shows opacity with sharp margin, traction bronchiectasis, and volume loss consistent with fibrosis.

66  Therapeutic Radiation and Radiation-Induced Lung Disease

855

Absolute 6400.0 cGy 5940.0 cGy 5400.0 cGy 4500.0 cGy 3600.0 cGy 3000.0 cGy 2000.0 cGy

A

B Fig. 66.8  Radiation-induced fibrosis in a man with a history of non–small cell lung cancer treated by intensity-modulated radiotherapy (IMRT). (A) Computed dosimetric reconstruction axial image used for planning IMRT shows a right middle lobe mass. The highest area of radiation (59.4 Gy) is a red line surrounding the region of the mass. Note that with IMRT, the highest dose of radiation is delivered to the tumor, whereas with standard radiation therapy, the highest dose would be at the chest wall. (B) CT image obtained 5 months after completion of radiation therapy shows that areas of consolidation resulting from radiation-induced lung injury (arrow) correlate with areas with the highest radiation dose on computed dosimetric reconstruction image used for planning IMRT. Also noted are volume loss and focal consolidation in the right lower lobe. Note loculated pleural fluid adjacent to the vertebral body. Composite Absolute 6600.0 cGy 5000.0 cGy 4500.0 cGy 4000.0 cGy 3000.0 cGy 2000.0 cGy 1000.0 cGy

A

C

B

Fig. 66.9  Radiation-induced lung disease in a man with emphysema and stage I non–small cell lung cancer treated with three-dimensional conformal radiotherapy (3D-CRT) because of poor respiratory function. (A) Pretreatment CT image shows a small left upper lobe nodule (arrow). (B) Computed dosimetric reconstruction used for 3D-CRT shows the area of lung receiving the highest radiation dose of 66 Gy delineated by the white line surrounding the location of the nodule. (C) CT image obtained 3 years after completion of radiation therapy shows focal opacity corresponding to the area of the lung receiving the highest radiation dose consistent with radiation-induced fibrosis.

856

SECTION 13  Iatrogenic Lung Disease and Trauma

Fig. 66.10  Radiation-induced fibrosis in a woman with non–small cell lung cancer after lung injury resulting from three-dimensional conformal radiotherapy. CT scan obtained 7 years after completion of radiation therapy shows only a linear band of fibrosis with traction bronchiectasis that resembles scar.

the newer methods of delivering radiation can result in lung opacities at unusual locations away from the site of disease that can be mistaken for other disease entities. For instance, when an NSCLC is treated, radiation-induced lung disease can manifest as modified conventional (consolidation, volume loss, and bronchiectasis similar to but less extensive than conventional radiation fibrosis), scar-like (linear opacity in the region of the original tumor (Fig. 66.10), and mass-like patterns (Fig. 66.11). Although diagnostic confusion is unlikely to arise from the modified conventional and scar-like patterns, the mass-like pattern can easily be misinterpreted as malignant neoplasia in the absence of a history of new methods of radiation therapy delivery.128 In accordance, it is important to be aware that the newer techniques of 3D-CRT, IMRT, SBRT, and proton therapy often distribute dose to unexpected areas, and to avoid diagnostic confusion, the specific isodose patterns associated with each individual patient plan need to be recognized. It is also important that the typical radiologic manifestations of radiation-induced lung disease associated with traditional radiation treatment fields be recognized. NSCLC typically has treatment fields that encompass the primary tumor with an additional 2-cm margin around the visualized edge of the tumor and a 1-cm margin around regional lymph nodes that are to be treated.129 Nodal regions that are not grossly involved are no longer electively treated in NSCLC. In patients with small cell lung cancer, two types of radiation field arrangements have typically been used: extensive fields encompassing the hila, the mediastinum, and both supraclavicular areas and limited fields encompassing only the primary tumor and adjacent nodal stations with a high likelihood of neoplastic involvement.129 In patients with breast cancer, the use of tangential radiation fields can result in radiation-induced lung disease that characteristically is manifested on CT as parenchymal opacities confined to the anterolateral subpleural region of the lung (Fig. 66.12).122,130 To avoid confusion with infection such as tuberculosis, it is important to know that supraclavicular treatment fields are also occasionally used in breast cancer patients and will often result in apical radiation-induced lung disease (see Fig. 66.12). In patients with

esophageal cancer, radiation fields with a 5-cm margin above and below the tumor are generally used. The radiation beams are angled to limit radiation exposure of the spinal cord and result in paramediastinal opacities in the lower lobes. Radiation therapy for head and neck cancer patients often includes the apical aspect of the thorax and results in bilateral apical radiationinduced lung disease. The mantle field used for definitive radiation therapy for Hodgkin or non-Hodgkin lymphomas includes all the major lymph node regions above the diaphragm and results in a classic appearance of radiation pneumonitis and fibrosis in the paramediastinal areas and in the apices (Fig. 66.13).131,132 The imaging findings of radiation-induced organizing pneumonia and chronic eosinophilic pneumonia are similar to those seen in patients with the idiopathic forms of these conditions (see Chapters 29 and 37) and may overlap with those of radiation pneumonitis. However, unlike typical radiation pneumonitis, the opacities may be migratory and are typically outside the radiation treatment field (Fig. 66.14).105,106 The newer methods of delivering radiation can also result in lung opacities at unusual locations away from the site of the treated malignant neoplasm. Therefore parenchymal abnormalities outside the radiation treatment field can be related to radiation pneumonitis, organizing pneumonia, chronic eosinophilic pneumonia, infection, and tumor recurrence. Pericardial effusions can occur after radiation therapy, are usually small in volume, and are accordingly usually detected by CT rather than by chest radiography. Pericardial effusions usually occur 6 to 9 months after completion of therapy.133,134 In addition, chronic cardiac complications can occur, and these include chronic pericarditis, cardiomyopathy, myocardial infarction, coronary artery disease, conduction abnormalities, and valvular disease.134 COMPUTED TOMOGRAPHY–POSITRON EMISSION TOMOGRAPHY Integrated CT-PET imaging performed with the radiopharmaceutical 18F-FDG is increasingly used for posttreatment follow-up of various malignancies to facilitate early detection of locoregional recurrence and distant metastases. FDG-PET has been reported to be more accurate than CT in the evaluation of recurrent malignant disease after radiation therapy.135–144 Acute radiation pneumonitis can manifest as increased FDG activity on PET, and this can persist in regions of radiation-induced fibrosis for up to 18 months.135 The high negative predictive value of a normal FDG-PET study in patients with radiation-induced lung disease is clinically useful, and focal pulmonary opacities with low FDG uptake can be observed (Fig. 66.15). Focal, intense FDG uptake or FDG uptake that increases over time in the irradiated lung is suggestive of recurrent malignant disease (Fig. 66.16). However, a limitation of PET imaging is that false-positive uptake of FDG is not uncommon early after completion of radiation therapy and can persist. Because radiation pneumonitis can have increased FDG uptake that mimics recurrent disease, FDG-PET imaging is best performed 6 months after radiation therapy completion.

Differential Diagnosis Patients with thoracic neoplasms treated with radiation can develop radiation-induced lung disease as well as superimposed lung disease. Diagnosis requires a high index of suspicion because the clinical and imaging manifestations of infection and recurrence

66  Therapeutic Radiation and Radiation-Induced Lung Disease 6900.0 cGy 6600.0 cGy 6300.0 cGy 5000.0 cGy 4500.0 cGy 4000.0 cGy 3000.0 cGy 2000.0 cGy 1000.0 cGy 500.0 cGy

A

B

C

D Fig. 66.11  Mass-like pattern of radiation-induced-lung disease in a woman with non–small cell lung cancer after intensity-modulated radiotherapy (IMRT). (A) Pretreatment CT image shows a right upper lobe nodule consistent with a primary lung malignancy. Right hilar adenopathy due to nodal metastatic disease is not shown. (B) Computed dosimetric axial reconstruction used for IMRT planning shows primary lung malignancy and right hilar adenopathy receiving maximal isodoses with sparing of the spinal cord. (C) CT image obtained 6 years after completion of radiation therapy shows mass-like opacity resulting from radiation-induced lung injury. Note how correlation with the radiation treatment plan can prevent misinterpretation of this opacity as malignancy. (D) Integrated positron emission tomography–CT obtained 6 years after completion of IMRT shows low-grade fluorodeoxyglucose uptake in mass-like opacity consistent with focal fibrosis and absence of recurrent malignancy. Note dystrophic calcification within the focal fibrosis.

A

B Fig. 66.12  Radiation-induced fibrosis in a woman with left breast cancer treated with tangent fields matched to supraclavicular fields. (A) CT scan obtained 6 years after completion of radiation therapy shows apical fibrosis. (B) CT image more caudad to (A) shows typical pattern of subpleural radiation fibrosis in lung (arrows) adjacent to treated chest wall.

857

858

SECTION 13  Iatrogenic Lung Disease and Trauma

Fig. 66.13  Paramediastinal radiation-induced lung disease in a man with large cell lymphoma. CT image obtained 10 weeks after completion of radiation therapy shows subtle paramediastinal groundglass opacities (arrows) in upper lobes indicative of radiation pneumonitis.

A

B Fig. 66.14  Organizing pneumonia in a woman with early right breast carcinoma treated by conventional radiation therapy. (A) CT image at the level of great vessels shows localized ground-glass opacities and dilated bronchi in the right upper lobe. Note sharp demarcation between normal lung and groundglass opacities. The findings are similar to those of radiation pneumonia. (B) CT image at the level of bronchus intermedius demonstrates bilateral peribronchial opacities outside the radiation treatment field. Note ring-like consolidation (arrowheads) surrounding ground-glass opacity (reversed halo sign) in both lower lobes typical of organizing pneumonia. Also noted is a small nodule (arrow) in the left lower lobe and a right pleural effusion.

66  Therapeutic Radiation and Radiation-Induced Lung Disease

A

*

*

B Fig. 66.15  Radiation-induced fibrosis in a man with a history of non–small cell lung cancer treated by intensity-modulated radiotherapy (IMRT). CT (A) and composite image (B) containing positron emission tomography (PET) (left image), and integrated CT-PET (right image) 13 months after IMRT show homogeneous low-grade fluorodeoxyglucose (FDG) uptake within an area of radiation fibrosis in the right lung. High negative predictive value of FDG-PET scan allows conservative management. Note physiologic FDG uptake in the myocardium (asterisks).

859

860

SECTION 13  Iatrogenic Lung Disease and Trauma

*

A

*

B

*

*

C

of the underlying neoplasm are often similar.145 Knowledge of the temporal relationship of the imaging manifestations to radiation therapy completion date, radiation dose administered, and technique used can be useful in suggesting the diagnosis. In general, radiation pneumonitis should be suspected in patients who have received more than 40 Gy of radiation if the imaging findings occur within the radiation treatment fields and within an appropriate time course. When radiologic manifestations atypical for radiation-induced lung disease are observed, the possibility of infection and local recurrence of malignant disease should be considered.27,125,126,146,147 Infection should be considered if the chest radiograph or CT image shows pulmonary opacities occurring before completion of radiation therapy and/or outside of the radiation treatment fields. Because radiation pneumonitis normally has a more indolent course than an infection, an abrupt onset is suggestive of an infection unless there has been recent discontinuation of steroids.145 Additional findings can also suggest the presence of infection. For example, radiation-induced lung disease in the lung apices corresponding to supraclavicular radiation fields (Fig. 66.17) may be confused with pulmonary tuberculosis.20 In these cases CT findings of centrilobular nodules or tree-in-bud opacities are more likely to be due to tuberculosis than to radiation-induced lung disease.148 Cavitation within an

Fig. 66.16  Recurrent tumor in a woman with a history of middle lobe non–small cell lung cancer treated by resection and chemoradiation therapy. CT (A), positron emission tomography (PET) (B), and integrated CT-PET (C) images 3 years after chemoradiation therapy show focal increased fluorodeoxyglucose (FDG) uptake within an area of radiation fibrosis (arrows). Transthoracic needle biopsy confirmed recurrence of malignant disease. Note physiologic FDG uptake in the myocardium (asterisks).

area of radiation fibrosis generally represents superimposed infection.7 Local tumor recurrence can be difficult to diagnose during the evolution of radiation-induced lung disease. However, as radiation-induced lung disease stabilizes, alteration in the contour of the fibrosis, particularly the development of convex margin, should suggest tumor recurrence. Multiplanar reformatted images are often helpful in evaluating the size and contour alterations in postradiation opacities detected on axial images. The reformatted images often better delineate the linear configuration, volume loss, or sharp margin of the fibrotic lung. Alternatively, if volume expansion or convex margin is confirmed on multiplanar images, the possibility of recurrent malignancy or superimposed infection should be considered. In addition, filling in of bronchi within radiation-induced fibrosis is abnormal and usually results from local recurrence of malignant disease (Fig. 66.18) or a superimposed infection. Other signs of local recurrence include development of nodules outside of radiation treatment fields, irregularity of central airways, and pleural effusion development more than 12 months after completion of treatment. The clinical and imaging manifestations of radiation-induced organizing pneumonia and chronic eosinophilic pneumonia may be similar. The differentiation between the two entities is based

66  Therapeutic Radiation and Radiation-Induced Lung Disease

A

861

B Fig. 66.17  Radiation-induced fibrosis misinterpreted as infection in a woman with chronic cough, weight loss, and history of left breast cancer treated with supraclavicular fields 44 years prior. (A) Chest radiograph shows heterogeneous opacities in the left upper lobe with associated volume loss. (B) CT scan reveals well-marginated atelectatic lung and traction bronchiectasis, findings typical of radiationinduced fibrosis. Sputum cultures were negative for Mycobacterium tuberculosis and nontuberculous mycobacterial infection.

A

C

B

Fig. 66.18  Recurrent tumor in a woman with non–small cell lung cancer. (A) CT scan obtained 4 years after completion of radiation therapy shows radiation fibrosis in the right lower lobe (arrow). (B) CT scan obtained 4 months after (A) shows soft tissue filling the bronchi, indicative of recurrent tumor (arrows). (C) CT scan obtained 26 months after (B) shows an increase in size of the recurrent malignancy.

862

SECTION 13  Iatrogenic Lung Disease and Trauma

KEY POINTS • Radiologic manifestations of radiation-induced lung disease are common, and correlation of imaging findings with the radiation technique, field, and dose, as well as date of radiation completion, is vital in providing the correct diagnosis. • Acute radiation-induced lung disease typically occurs 4–12 weeks after completion of radiation therapy but can occur before completion of radiation therapy with some of the newer treatment regimens. • Acute radiation-induced lung disease is manifested as groundglass opacities or consolidation in the radiation treatment field and can have increased fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) imaging. • Ipsilateral pleural effusions develop within 6 months after completion of radiation therapy. • Fibrosis occurs in the region of acute radiation-induced lung disease 6–12 months after completion of radiation therapy. • Fibrosis is manifested as consolidation with air bronchograms and sharp borders and is associated with volume loss, architectural distortion, and traction bronchiectasis. • Fibrosis can progress for 6–12 months after completion of radiation therapy and stabilizes within 2 years.

on the presence of parenchymal and peripheral blood eosinophilia in chronic eosinophilic pneumonia and the typical histologic findings of intraluminal granulation tissue polyps within alveolar ducts and surrounding alveoli associated with chronic inflammation of the surrounding lung parenchyma in organizing pneumonia.149

Synopsis of Treatment Options Corticosteroids are the most commonly used therapy for radiation-induced acute pneumonitis.22 However, there is no consensus as to when treatment should be initiated, and there are no controlled trials on the efficacy of corticosteroid therapy in patients with acute radiation-induced pneumonitis.150 In general, corticosteroids are given on the basis of the severity of symptoms, and although they can result in an objective response, pneumonitis may progress with therapy.

• Local tumor recurrence can be difficult to diagnose with PET, radiography, and CT during the evolution of radiation-induced lung disease. • Fibrosis is typically not FDG avid or only mildly FDG avid on PET imaging, although increased FDG uptake can persist for up to 18 months after completion of radiation therapy. • The high negative predictive value of a normal FDG-PET study in patients with radiation-induced lung disease is clinically useful in excluding recurrence of malignant disease. • Imaging manifestations of radiation-induced organizing pneumonia and chronic eosinophilic pneumonia are similar to those of idiopathic forms. The parenchymal opacities may occur outside of the port field and be migratory. These features are helpful in distinguishing these entities from radiation pneumonitis. • After radiation-induced lung disease stabilizes, an alteration in the contour of the fibrosis, particularly development of a convex margin, should suggest tumor recurrence. • Filling in of bronchi within radiation fibrosis is usually due to local recurrence of malignant disease or superimposed infection.

SUGGESTED READINGS Benveniste MF, Welsh J, Godoy MC, Betancourt SL, Mawlawi OR, Munden RF. New era of radiotherapy: an update in radiation-induced lung disease. Clin Radiol. 2013;68:e275–e290. Huang K, Palma DA, IASLC Advanced Radiation Technology Committee. Follow-up of patients after stereotactic radiation for lung cancer: a primer for the nonradiation oncologist. J Thorac Oncol. 2015;10:412–419. Larici AR, del Ciello A, Maggi F, et al. Lung abnormalities at multimodality imaging after radiation therapy for non–small cell lung cancer. Radiographics. 2011;31:771–789. Ulaner GA, Lyall A. Identifying and distinguishing treatment effects and complications from malignancy at FDG PET/CT. Radiographics. 2013;33:1817–1834. Viswanathan C, Carter BW, Shroff GS, Godoy MC, Marom EM, Truong MT. Pitfalls in oncologic imaging: complications of chemotherapy and radiotherapy in the chest. Semin Roentgenol. 2015;50:183–191.

The full reference list for this chapter is available at ExpertConsult.com.

66  Therapeutic Radiation and Radiation-Induced Lung Disease 862.e1

REFERENCES 1. Abratt RP, Morgan GW. Lung toxicity following chest irradiation in patients with lung cancer. Lung Cancer. 2002;35:103–109. 2. Park KJ, Chung JY, Chun MS, Suh JH. Radiation-induced lung disease and the impact of radiation methods on imaging features. Radiographics. 2000;20:83–98. 3. Ooi GC, Kwong DL, Chan KN, et al. Serial HRCT lung changes after 3-field radiation treatment of breast cancer. Clin Radiol. 2000;55:817–824. 4. Mesurolle B, Qanadli SD, Merad M, et al. Unusual radiologic findings in the thorax after radiation therapy. Radiographics. 2000;20:67–81. 5. Loyer E, Fuller L, Libshitz HI, Palmer JL. Radiographic appearance of the chest following therapy for Hodgkin disease. Eur J Radiol. 2000;35: 136–148. 6. Logan PM. Thoracic manifestations of external beam radiotherapy. AJR Am J Roentgenol. 1998;171:569–577. 7. Libshitz HI, DuBrow RA, Loyer EM, Charnsangavej C. Radiation change in normal organs: an overview of body imaging. Eur Radiol. 1996;6:786–795. 8. Wang S, Liao Z, Wei X, et al. Analysis of clinical and dosimetric factors associated with treatment-related pneumonitis (TRP) in patients with non–small-cell lung cancer (NSCLC) treated with concurrent chemotherapy and three-dimensional conformal radiotherapy (3D-CRT). Int J Radiat Oncol Biol Phys. 2006;66:1399–1407. 9. Kong FM, Hayman JA, Griffith KA, et al. Final toxicity results of a radiationdose escalation study in patients with non–small-cell lung cancer (NSCLC): predictors for radiation pneumonitis and fibrosis. Int J Radiat Oncol Biol Phys. 2006;65:1075–1086. 10. Tsujino K, Hirota S, Kotani Y, et al. Radiation pneumonitis following concurrent accelerated hyperfractionated radiotherapy and chemotherapy for limited-stage small-cell lung cancer: dose-volume histogram analysis and comparison with conventional chemoradiation. Int J Radiat Oncol Biol Phys. 2006;64:1100–1105. 11. Yorke ED, Jackson A, Rosenzweig KE, et al. Correlation of dosimetric factors and radiation pneumonitis for non–small-cell lung cancer patients in a recently completed dose escalation study. Int J Radiat Oncol Biol Phys. 2005;63:672–682. 12. Chen M, Hayman JA, Ten Haken RK, et al. Long-term results of high-dose conformal radiotherapy for patients with medically inoperable T1-3N0 non–small-cell lung cancer: Is low incidence of regional failure due to incidental nodal irradiation? Int J Radiat Oncol Biol Phys. 2006;64: 120–126. 13. Kong FM, Ten Haken RK, Schipper MJ, et al. High-dose radiation improved local tumor control and overall survival in patients with inoperable/ unresectable non–small-cell lung cancer: long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys. 2005;63:324–333. 14. Manon RR, Jaradat H, Patel R, et al. Potential for radiation therapy technology innovations to permit dose escalation for non–small-cell lung cancer. Clin Lung Cancer. 2005;7:107–113. 15. Bentzen SM, Saunders MI, Dische S. From CHART to CHARTWEL in non–small cell lung cancer: clinical radiobiological modelling of the expected change in outcome. Clin Oncol (R Coll Radiol). 2002;14:372–381. 16. Chen GY, Jiang GL, Qian H, et al. Escalated hyperfractionated accelerated radiation therapy for locally advanced non–small cell lung cancer: a clinical phase II trial. Radiother Oncol. 2004;71:157–162. 17. Grutters JP, et al. Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non–small cell lung cancer: a metaanalysis. Radiother Oncol. 2010;95(1):32–40. 18. Ricardi U, et al. Stereotactic body radiotherapy for early stage lung cancer: history and updated role. Lung Cancer. 2015;90(3):388–396. 19. Rubin P, Casarett GW. Clinical Radiation Pathology. Philadelphia: WB Saunders; 1968. 20. Libshitz HI, Southard ME. Complication of radiation therapy: the thorax. Semin Roentgenol. 1974;9:41–49. 21. Movsas B, Raffin TA, Epstein AH, Link CJ Jr. Pulmonary radiation injury. Chest. 1997;111:1061–1076. 22. Abid SH, Malhotra V, Perry MC. Radiation-induced and chemotherapyinduced pulmonary injury. Curr Opin Oncol. 2001;13:242–248. 23. Roach M, Gandara DR, Yuo HS, et al. Radiation pneumonitis following combined modality therapy for lung cancer: analysis of prognostic factors. J Clin Oncol. 1995;13:2606–2612. 24. Mehta V. Radiation pneumonitis and pulmonary fibrosis in non–small-cell lung cancer: pulmonary function, prediction, and prevention. Int J Radiat Oncol Biol Phys. 2005;63:5–24. 25. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995;31:1341–1346.

26. Davis SD, Yankelevitz DF, Henschke CI. Radiation effects on the lung: clinical features, pathology, and imaging findings. AJR Am J Roentgenol. 1992;159:1157–1164. 27. Fennessy JJ. Irradiation damage to the lung. J Thorac Imaging. 1987;2:68–79. 28. Warren S, Spencer J. Radiation reaction in the lung. AJR Am J Roentgenol. 1940;43:682–701. 29. Gross NJ. Pulmonary effects of radiation therapy. Ann Intern Med. 1977;86:81–92. 30. Roswit B, White DC. Severe radiation injuries of the lung. AJR Am J Roentgenol. 1977;129:127–136. 31. Wang JY, Chen KY, Wang JT, et al. Outcome and prognostic factors for patients with non–small-cell lung cancer and severe radiation pneumonitis. Int J Radiat Oncol Biol Phys. 2002;54:735–741. 32. Rancati T, Ceresoli GL, Gagliardi G, et al. Factors predicting radiation pneumonitis in lung cancer patients: a retrospective study. Radiother Oncol. 2003;67:275–283. 33. Taghian AG, Assaad SI, Niemierko A, et al. Risk of pneumonitis in breast cancer patients treated with radiation therapy and combination chemotherapy with paclitaxel. J Natl Cancer Inst. 2001;93:1806–1811. 34. Hope AJ, Lindsay PE, El Naqa I, et al. Modeling radiation pneumonitis risk with clinical, dosimetric, and spatial parameters. Int J Radiat Oncol Biol Phys. 2006;65:112–124. 35. Castellino RA, Glastein E, Turbow MM, et al. Latent radiation injury of lungs or heart activated by steroid withdrawal. Ann Intern Med. 1974;80: 593–599. 36. Komaki R, Lee JS, Milas L, et al. Effects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non–smallcell lung cancer: report of a randomized comparative trial. Int J Radiat Oncol Biol Phys. 2004;58:1369–1377. 37. Andreassen CN, Grau C, Lindegaard JC. Chemical radioprotection: a critical review of amifostine as a cytoprotector in radiotherapy. Semin Radiat Oncol. 2003;13:62–72. 38. Antonadou D, Coliarakis N, Synodinou M, et al. Randomized phase III trial of radiation treatment +/− amifostine in patients with advanced-stage lung cancer. Int J Radiat Oncol Biol Phys. 2001;51:915–922. 39. Johnke RM, Sattler JA, Allison RR. Radioprotective agents for radiation therapy: future trends. Future Oncol. 2014;10(15):2345–2357. 40. Delaney G, Jacob S, Featherstone C, Barton M. The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidencebased clinical guidelines. Cancer. 2005;104:1129–1137. 41. Featherstone C, Delaney G, Jacob S, Barton M. Estimating the optimal utilization rates of radiotherapy for hematologic malignancies from a review of the evidence: part I—lymphoma. Cancer. 2005;103:383–392. 42. Foroudi F, Tyldesley S, Walker H, Mackillop WJ. An evidence-based estimate of appropriate radiotherapy utilization rate for breast cancer. Int J Radiat Oncol Biol Phys. 2002;53:1240–1253. 43. Tyldesley S, Boyd C, Schulze K, et al. Estimating the need for radiotherapy for lung cancer: an evidence-based, epidemiologic approach. Int J Radiat Oncol Biol Phys. 2001;49(4):973–985. 44. Gagliardi G, Bjohle J, Lax I, et al. Radiation pneumonitis after breast cancer irradiation: analysis of the complication probability using the relative seriality model. Int J Radiat Oncol Biol Phys. 2000;46:373–381. 45. Lingos TI, Recht A, Vicini F, et al. Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys. 1991;21:355–360. 46. Allen AM, Prosnitz RG, Ten Haken RK, et al. Body mass index predicts the incidence of radiation pneumonitis in breast cancer patients. Cancer J. 2005;11:390–398. 47. De Petris L, Lax I, Sirzen F, Friesland S. Role of gross tumor volume on outcome and of dose parameters on toxicity of patients undergoing chemoradiotherapy for locally advanced non–small cell lung cancer. Med Oncol. 2005;22:375–381. 48. Koontz BF, Kirkpatrick JP, Clough RW, et al. Combined-modality therapy versus radiotherapy alone for treatment of early-stage Hodgkin’s disease: cure balanced against complications. J Clin Oncol. 2006;24: 605–611. 49. Moiseenko V, Craig T, Bezjak A, Van Dyk J. Dose-volume analysis of lung complications in the radiation treatment of malignant thymoma: a retrospective review. Radiother Oncol. 2003;67:265–274. 50. Marks LB, Fan M, Clough R, et al. Radiation-induced pulmonary injury: symptomatic versus subclinical endpoints. Int J Radiat Biol. 2000;76: 469–475. 51. Allen AM, Czerminska M, Janne PA, et al. Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma. Int J Radiat Oncol Biol Phys. 2006;65:640–645.

862.e2

SECTION 13  Iatrogenic Lung Disease and Trauma

52. International Commission on Radiation Units and Measurements (ICRU). Prescribing, Recording and Reporting Photon Beam Therapy. Report 50. Bethesda, MD: ICRU Press; 1993. 53. Bradley JD, et al. Gross tumor volume, critical prognostic factor in patients treated with three-dimensional conformal radiation therapy for non–smallcell lung carcinoma. Int J Radiat Oncol Biol Phys. 2002;52(1):49–57. 54. Fang LC, et al. Comparison of outcomes for patients with medically inoperable Stage I non–small-cell lung cancer treated with two-dimensional vs. threedimensional radiotherapy. Int J Radiat Oncol Biol Phys. 2006;66(1):108–116. 55. Rosenzweig KE, et al. Results of a phase I dose-escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable nonsmall cell lung carcinoma. Cancer. 2005;103(10):2118–2127. 56. Staffurth J, Radiotherapy Development Board. A review of the clinical evidence for intensity-modulated radiotherapy. Clin Oncol (R Coll Radiol). 2010;22(8):643–657. 57. Murshed H, Liu. HH, Liao Z. Dose and volume reduction for normal lung using intensity-modulated radiotherapy for advanced-stage non–small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2004;58(4):1258–1267. 58. Timmerman R, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303(11):1070–1076. 59. Armstrong JG, Minsky BD. Radiation therapy for medically inoperable stage I and II non–small cell lung cancer. Cancer Treat Rev. 1989;16(4):247–255. 60. Baumann P, et al. Stereotactic body radiotherapy for medically inoperable patients with stage I non–small cell lung cancer—a first report of toxicity related to COPD/CVD in a non-randomized prospective phase II study. Radiother Oncol. 2008;88(3):359–367. 61. Chang JY, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non–small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol. 2015;16(6):630–637. 62. Coy P, Kennelly GM. The role of curative radiotherapy in the treatment of lung cancer. Cancer. 1980;45(4):698–702. 63. Haffty BG, et al. Results of radical radiation therapy in clinical stage I, technically operable non–small cell lung cancer. Int J Radiat Oncol Biol Phys. 1988;15(1):69–73. 64. Onishi H, et al. Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non–small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study. J Thorac Oncol. 2007;2(7 suppl 3):S94–S100. 65. Kesarwala AH, et al. Intensity-modulated proton therapy for elective nodal irradiation and involved-field radiation in the definitive treatment of locally advanced non–small-cell lung cancer: a dosimetric study. Clin Lung Cancer. 2015;16(3):237–244. 66. Mancosu P, et al. Contrast enhanced 4D-CT imaging for target volume definition in pancreatic ductal adenocarcinoma. Radiother Oncol. 2008;87(3):339–342. 67. Rietzel E, et al. Design of 4D treatment planning target volumes. Int J Radiat Oncol Biol Phys. 2006;66(1):287–295. 68. Morarji K, et al. Impact of FDG-PET on lung cancer delineation for radiotherapy. J Med Imaging Radiat Oncol. 2012;56(2):195–203. 69. Bradley J, et al. Impact of FDG-PET on radiation therapy volume delineation in non–small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2004;59(1): 78–86. 70. Hanna GG, et al. Defining target volumes for stereotactic ablative radiotherapy of early-stage lung tumours: a comparison of three-dimensional 18F-fluorodeoxyglucose positron emission tomography and four-dimensional computed tomography. Clin Oncol (R Coll Radiol). 2012;24(6): e71–e80. 71. MacManus M, et al. Use of PET and PET/CT for radiation therapy planning: IAEA expert report 2006-2007. Radiother Oncol. 2009;91(1):85–94. 72. Nestle U, et al. Comparison of different methods for delineation of 18F-FDG PET-positive tissue for target volume definition in radiotherapy of patients with non–small cell lung cancer. J Nucl Med. 2005;46(8):1342–1348. 73. Mac Manus MP, et al. The use of fused PET/CT images for patient selection and radical radiotherapy target volume definition in patients with non–small cell lung cancer: results of a prospective study with mature survival data. Radiother Oncol. 2013;106(3):292–298. 74. Ding X, et al. A clinical study of shrinking field radiation therapy based on (18)F-FDG PET/CT for stage III non–small cell lung cancer. Technol Cancer Res Treat. 2013;12(3):251–257. 75. Li G, et al. Advances in 4D medical imaging and 4D radiation therapy. Technol Cancer Res Treat. 2008;7(1):67–81. 76. D’Souza WD, et al. The use of gated and 4D CT imaging in planning for stereotactic body radiation therapy. Med Dosim. 2007;32(2):92–101. 77. Hof H, et al. 4D-CT-based target volume definition in stereotactic radiotherapy of lung tumours: comparison with a conventional technique using individual margins. Radiother Oncol. 2009;93(3):419–423.

78. Wang L, et al. Dosimetric comparison of stereotactic body radiotherapy using 4D CT and multiphase CT images for treatment planning of lung cancer: evaluation of the impact on daily dose coverage. Radiother Oncol. 2009;91(3):314–324. 79. Zhao L, et al. Dosimetric impact of intrafraction motion for compensator-based proton therapy of lung cancer. Phys Med Biol. 2008;53(12):3343–3364. 80. Chang JY, et al. Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or intensitymodulated radiation therapy in Stage I or Stage III non–small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2006;65(4):1087–1096. 81. Sejpal S, et al. Early findings on toxicity of proton beam therapy with concurrent chemotherapy for nonsmall cell lung cancer. Cancer. 2011;117(13): 3004–3013. 82. Chang JY, et al. Consensus statement on proton therapy in early-stage and locally advanced non–small cell lung cancer. Int J Radiat Oncol Biol Phys. 2016;95(1):505–516. 83. Hoppe BS, et al. Cardiac sparing with proton therapy in consolidative radiation therapy for Hodgkin lymphoma. Leuk Lymphoma. 2010;51(8):1559–1562. 84. Liao XL, Lee JJ, Komaki R, Gomez DR, O’Reilly M, Allen P, Fossella F, Heymach J, Blumenschein G, Choi N, Delaney T, Hahn S, Lu C, Cox J, Mohan R. Bayesian randomized trial comparing intensity modulated radiation therapy versus passively scattered proton therapy for locally advanced non–small cell lung cancer. J Clin Oncol. 2016;34: 15_suppl8500. Available at: http://ascopubs .org/doi/abs/%2010.1200/jco.2017.74.0720. 85. Perez CA, et al. A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non–oat-cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer. 1980;45(11):2744–2753. 86. Bradley JD, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non–small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16(2):187–199. 87. Stuschke M, Pottgen C. Altered fractionation schemes in radiotherapy. Front Radiat Ther Oncol. 2010;42:150–156. 88. De Ruysscher D, Khoo VS, Bentzen SM. Biological Basis of Fractionation and Timing of Radiotherapy. Philadelphia: Lippincott Williams & Wilkins; 2010. 89. Saunders M, et al. Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non–small cell lung cancer: mature data from the randomised multicentre trial. CHART Steering committee. Radiother Oncol. 1999;52(2):137–148. 90. Gross NJ. The pathogenesis of radiation-induced lung damage. Lung. 1981;159:115–125. 91. McDonald S, Rubin P, Phillips TL, Marks LB. Injury to the lung from cancer therapy: clinical syndromes, measurable endpoints, and potential scoring systems. Int J Radiat Oncol Biol Phys. 1995;31:1187–1203. 92. Magana E, Crowell RE. Radiation pneumonitis successfully treated with inhaled corticosteroids. South Med J. 2003;96:521–524. 93. Inoue A, Kunitoh H, Sekine I, et al. Radiation pneumonitis in lung cancer patients: a retrospective study of risk factors and the long-term prognosis. Int J Radiat Oncol Biol Phys. 2001;49:649–655. 94. Robnett TJ, Machtay M, Vines EF, et al. Factors predicting severe radiation pneumonitis in patients receiving definitive chemoradiation for lung cancer. Int J Radiat Oncol Biol Phys. 2000;48:89–94. 95. Ahamad A, Stevens CW, Smythe WR, et al. Promising early local control of malignant pleural mesothelioma following postoperative intensity modulated radiotherapy (IMRT) to the chest. Cancer J. 2003;9:476–484. 96. Morgan GW, Breit SN. Radiation and the lung: a reevaluation of the mechanisms mediating pulmonary injury. Int J Radiat Oncol Biol Phys. 1995;31:361–369. 97. Roberts CM, Foulcher E, Zaunders JJ, et al. Radiation pneumonitis: a possible lymphocyte-mediated hypersensitivity reaction. Ann Intern Med. 1993;118:696–700. 98. Rubin P, Johnston CJ, Williams JP, et al. A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys. 1995;33:99–109. 99. Valko M, Leibfritz D, Moncol J, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39:44–84. 100. Anscher MS, Chen L, Rabbani Z, et al. Recent progress in defining mechanisms and potential targets for prevention of normal tissue injury after radiation therapy. Int J Radiat Oncol Biol Phys. 2005;62:255–259. 101. Vujaskovic Z, Anscher MS, Feng QF, et al. Radiation-induced hypoxia may perpetuate late normal tissue injury. Int J Radiat Oncol Biol Phys. 2001;50:851–855.

66  Therapeutic Radiation and Radiation-Induced Lung Disease 862.e3 102. Fu XL, Huang H, Bentel G, et al. Predicting the risk of symptomatic radiationinduced lung injury using both the physical and biologic parameters V(30) and transforming growth factor beta. Int J Radiat Oncol Biol Phys. 2001;50:899–908. 103. Schlesinger C, Koss MN. The organizing pneumonias: an update and review. Curr Opin Pulm Med. 2005;11:422–430. 104. Schlesinger C, Koss MN. The organizing pneumonias: a critical review of current concepts and treatment. Treat Respir Med. 2006;5:193–206. 105. Crestani B, Valeyre D, Roden S, et al. Bronchiolitis obliterans organizing pneumonia syndrome primed by radiation therapy to the breast. Am J Respir Crit Care Med. 1998;158:1929–1935. 106. Cottin V, Frognier R, Monnot H, et al. Chronic eosinophilic pneumonia after radiation therapy for breast cancer. Eur Respir J. 2004;23:9–13. 107. Green S, Weiss GR. Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs. 1992;10: 239–253. 108. Fan M, Marks LB, Lind P, et al. Relating radiation-induced regional lung injury to changes in pulmonary function tests. Int J Radiat Oncol Biol Phys. 2001;51:311–317. 109. De Jaeger K, Seppenwoolde Y, Boersma LJ, et al. Pulmonary function following high-dose radiotherapy of non–small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2003;55:1331–1340. 110. Gopal R, Starkschall G, Tucker SL, et al. Effects of radiotherapy and chemotherapy on lung function in patients with non–small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2003;56:114–120. 111. Takeda S, Funakoshi Y, Kadota Y, et al. Fall in diffusing capacity associated with induction therapy for lung cancer: a predictor of postoperative complication? Ann Thorac Surg. 2006;82:232–236. 112. Miller KL, Zhou SM, Barrier RC Jr, et al. Long-term changes in pulmonary function tests after definitive radiotherapy for lung cancer. Int J Radiat Oncol Biol Phys. 2003;56:611–615. 113. Evans WA, Leucutia T. Intrathoracic changes induced by heavy radiation. AJR Am J Roentgenol. 1925;13:209–220. 114. Desjardins AU. The reaction of the pleura and lungs to roentgen rays. AJR Am J Roentgenol. 1926;16:444–453. 115. Chu FCH, Philips R, Nickson JJ, McPhee JG. Pneumonitis following radiation therapy of cancer of the breast by tangential technique. Radiology. 1955;64: 642–653. 116. Smith JC. Radiation pneumonitis: a review. Am Rev Respir Dis. 1963;87: 647–655. 117. Bennett DE, Million RR, Ackerman LV. Bilateral radiation pneumonitis, a complication of the radiotherapy of bronchogenic carcinoma. Cancer. 1969;23:1001–1018. 118. Stone DJ, Schwartz MJ, Green RA. Fatal pulmonary insufficiency due to radiation effect upon the lung. Am J Med. 1956;21:211–226. 119. Smith JC. Radiation pneumonitis: case report of bilateral reaction after unilateral irradiation. Am Rev Respir Dis. 1964;89:264–269. 120. Mah K, Poon PY, Van Dyk J, et al. Assessment of acute radiation-induced pulmonary changes using computed tomography. J Comput Assist Tomogr. 1986;10:736–743. 121. Ikezoe J, Takashima S, Morimoto S, et al. CT appearance of acute radiationinduced injury in the lung. AJR Am J Roentgenol. 1988;150:765–770. 122. Bell J, McGivern D, Bullimore J, et al. Diagnostic imaging of post-irradiation changes in the chest. Clin Radiol. 1988;39:109–119. 123. Ikezoe J, Morimoto S, Takashima S, et al. Acute radiation-induced pulmonary injury: computed tomography evaluation. Semin Ultrasound CT MR. 1990;11:409–416. 124. Libshitz HI, Brosof AB, Southard M. Radiographic appearance of the chest following extended field radiation therapy for Hodgkin’s disease. Cancer. 1973;32:206–215. 125. Pagani JJ, Libshitz HI. CT manifestations of radiation-induced change in chest tissue. J Comput Assist Tomogr. 1982;6:243–248. 126. Libshitz HI, Schuman LS. Radiation-induced pulmonary change: CT findings. J Comput Assist Tomogr. 1984;8:15–19. 127. Wechsler RJ, Ayyangar K, Steiner RM, et al. The development of distant pulmonary infiltrates following thoracic irradiation: the role of computed tomography with dosimetric reconstruction in diagnosis. Comput Med Imaging Graph. 1990;14:43–51.

128. Koenig TR, Munden RF, Erasmus JJ, et al. Radiation injury of the lung after three-dimensional conformal radiation therapy. AJR Am J Roentgenol. 2002;178:1383–1388. 129. Emami B, Graham MV. Lung. In: Perez CA, Brady LW, eds. Principles and Practice of Radiation Oncology. 3rd ed. Philadelphia: Lippincott-Raven; 1998:1181–1220. 130. Coscina WF, Arger PH, Mintz MC, Coleman BG. CT demonstration of pulmonary effects of tangential beam radiation. J Comput Assist Tomogr. 1986;10:600–602. 131. Hoppe RT. Hodgkin’s disease. In: Perez CA, Brady LW, eds. Principles and Practice of Radiation Oncology. 3rd ed. Philadelphia: Lippincott-Raven; 1998:1963–1986. 132. Gospodarowicz MK, Wasserman TH. Non-Hodgkin’s lymphomas. In: Perez CA, Brady LW, eds. Principles and Practice of Radiation Oncology. 3rd ed. Philadelphia: Lippincott-Raven; 1998:1987–2012. 133. Cosset JM, Henry-Amar M, Girinski T, et al. Late toxicity of radiotherapy in Hodgkin’s disease: the role of fraction size. Acta Oncol. 1988;27: 123–129. 134. Stewart JR, Fajardo LF, Gillette SM, Constine LS. Radiation injury to the heart. Int J Radiat Oncol Biol Phys. 1995;31:1205–1211. 135. Bury T, Corhay JL, Duysinx B, et al. Value of FDG-PET in detecting residual or recurrent nonsmall cell lung cancer. Eur Respir J. 1999;14:1376–1380. 136. Erdi YE, Macapinlac H, Rosenzweig KE, et al. Use of PET to monitor the response of lung cancer to radiation treatment. Eur J Nucl Med. 2000;27:861–866. 137. Conti PS, Lilien DL, Hawley K, et al. PET and [18F]-FDG in oncology: a clinical update. Nucl Med Biol. 1996;23:717–735. 138. Frank A, Lefkowitz D, Jaeger S, et al. Decision logic for retreatment of asymptomatic lung cancer recurrence based on positron emission tomography findings. Int J Radiat Oncol Biol Phys. 1995;32:1495–1512. 139. Hubner KF, Buonocore E, Singh SK, et al. Characterization of chest masses by FDG positron emission tomography. Clin Nucl Med. 1995;20: 293–298. 140. Ichiya Y, Kuwabara Y, Otsuka M. Assessment of response to cancer therapy using fluorine-18-fluorodeoxyglucose and positron emission tomography. J Nucl Med. 1991;32:1655–1660. 141. Inoue T, Kim EE, Komaki R, et al. Detecting recurrent or residual lung cancer with FDG-PET. J Nucl Med. 1995;36:788–793. 142. Kim EE, Chung S, Haynie TP. Differentiation of residual or recurrent tumors from posttreatment changes with F-18 FDG PET. Radiographics. 1992;12: 269–279. 143. Kubota K, Yamada S, Ishiwata K, et al. Positron emission tomography for treatment evaluation and recurrence detection compared with CT in long-term follow-up cases of lung cancer. Clin Nucl Med. 1992;17: 877–881. 144. Patz EF, Lowe VJ, Hoffman JM, et al. Persistent or recurrent bronchogenic carcinoma: detection with PET and 2-[18F]-2-deoxy-D-glucose. Radiology. 1994;191:379–382. 145. Salinas FV, Winterbauer RH. Radiation pneumonitis: a mimic of infectious pneumonitis. Semin Respir Infect. 1995;10:143–153. 146. Bachman AL, Macken K. Pleural effusions following supervoltage radiation for breast carcinoma. Radiology. 1959;72:699–709. 147. Bourgouin P, Cousineau G, Lemire P, et al. Differentiation of radiationinduced fibrosis from recurrent pulmonary neoplasm by CT. Can Assoc Radiol J. 1987;38:23–26. 148. Im JG, Itoh H, Shim YS, et al. Pulmonary tuberculosis: CT findings—early active disease and sequential change with antituberculous therapy. Radiology. 1993;186:653–660. 149. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med. 2002;165:277–304. 150. Sekine I, Sumi M, Ito Y, et al. Retrospective analysis of steroid therapy for radiation-induced lung injury in lung cancer patients. Radiother Oncol. 2006;80:93–97.

67 

Blunt Thoracic Trauma* PHILLIP A. SETRAN  |  STEVEN L. PRIMACK  |  CRISTINA S. FUSS

Blunt thoracic trauma is a common indication for hospital admission, with the predominant cause of trauma being motor vehicle collisions. The thorax is the fourth most injured area in unrestrained passengers, but it is the most commonly injured area in individuals who are restrained by a seat belt.1 Other common causes of blunt thoracic trauma include falls from heights of greater than 10 feet and motor vehicle collisions involving pedestrians/bicyclists. Radiologists must know the typical injuries associated with thoracic trauma to provide the proper diagnosis and contribute to the immediate treatment plan. The initial screening test in thoracic trauma is the frontal chest radiograph obtained in the trauma bay. After the chest radiograph, computed tomography (CT) is the next most used diagnostic modality, although in the stable patient, cross-sectional imaging is often performed concurrently with radiographs. CT allows evaluation of the airways, pulmonary parenchyma, aorta and great vessels, pericardium, pleura, chest wall, diaphragm, and osseous structures. The rapid acquisition of data with multidetector helical CT scanners has led to a significant increase in cross-sectional imaging in the setting of trauma.2,3 The value of multiplanar reformation, as allowed by the current CT scanners, cannot be overemphasized in the trauma setting.

Acute Traumatic Aortic Injury Acute traumatic aortic injury (ATAI) is a common cause of prehospital mortality, accounting for approximately 15% to 20% of prehospital traumatic deaths.3 Of individuals with ATAI, 70% to 90% die at the trauma scene.3 Surviving trauma patients require prompt and accurate diagnosis to allow timely repair of the injury, especially given that 60% may have no overt clinical sign of thoracic trauma.3 The incidence of ATAI is approximately 1/100,000 per year.1 Seven criteria have been described as important clinical predictors for the presence of ATAI.4 They are age older than 50 years; unrestrained patient; hypotension (defined as systolic blood pressure