Specialty Imaging: HRCT of the Lung 032352477X, 9780323524773

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SECOND EDITION

Martínez-Jiménez | Rosado-de-Christenson | Carter

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SECOND EDITION

Santiago Martínez-Jiménez, MD Department of Radiology Saint Luke’s Hospital of Kansas City Professor of Radiology University of Missouri-Kansas City School of Medicine Kansas City, Missouri

Melissa L. Rosado-de-Christenson, MD, FACR Section Chief, Thoracic Radiology Department of Radiology Saint Luke’s Hospital of Kansas City Professor of Radiology University of Missouri-Kansas City School of Medicine Kansas City, Missouri

Brett W. Carter, MD Assistant Professor of Radiology Director of Thoracic CT, Co-Director of Thoracic MRI Department of Diagnostic Radiology, Division of Diagnostic Imaging The University of Texas MD Anderson Cancer Center Assistant Professor of Radiology Department of Diagnostic and Interventional Imaging The University of Texas Medical School at Houston Houston, Texas

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1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

SPECIALTY IMAGING: HRCT OF THE LUNG, SECOND EDITION

ISBN: 978-0-323-52477-3

Copyright © 2017 by Elsevier. All rights reserved. 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.

Publisher Cataloging-in-Publication Data Names: Martínez-Jiménez, Santiago | Rosado de Christenson, Melissa L. | Carter, Brett W. Title: Specialty imaging: HRCT of the lung / [edited by] Santiago Martínez-Jiménez, Melissa L. Rosado-de-Christenson, and Brett W. Carter. Other titles: HRCT of the lung. Description: Second edition. | Salt Lake City, UT : Elsevier, Inc., [2017] | Includes bibliographical references and index. Identifiers: ISBN 978-0-323-52477-3 Subjects: LCSH: Lungs--Tomography--Handbooks, manuals, etc. | MESH: Lung Diseases--diagnostic imaging--Atlases. | Lung--diagnostic imaging--Atlases. Classification: LCC RC734.T64 S634 2017 | NLM WF 600 | DDC 616.2’40754--dc23 International Standard Book Number: 978-0-323-52477-3 Cover Designer: Tom M. Olson, BA Cover Art: Laura C. Wissler, MA Printed in Canada by Friesens, Altona, Manitoba, Canada Last digit is the print number: 9 8 7 6 5 4 3 2 1

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DEDICATIONS To “la mujer que yo quiero” and “esos locos bajitos,” with whom I could have been reading fantastic books or riding bikes for a hundred, or possibly a thousand, more hours. SMJ To my husband, Paul; daughters, Jennifer and Heather; and the rest of my family, for their unconditional love and immense support throughout the completion of this project. To my lead author, practice partner, and dear friend, Santiago Martínez-Jiménez, whose expert guidance, immense knowledge, and tireless efforts helped me expand my own knowledge of thoracic imaging and specifically of HRCT. MRDC I dedicate this project to my parents, Ralph and Joy Carter, without whom this effort would not have been possible. BWC

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CONTRIBUTING AUTHORS Carlos S. Restrepo, MD

Kyung Soo Lee, MD

Professor of Radiology Vice Chairman for Education Director of Cardio-Thoracic Radiology The University of Texas Health Science Center at San Antonio San Antonio, Texas

Professor Department of Radiology Samsung Medical Center Sungkyunkwan University School of Medicine Seoul, South Korea

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

Director Department of Radiology Kinki Central Hospital of Mutual Aid Association of Public School Teachers Itami, Japan

Jorge Alberto Carrillo-Bayona, MD

Paul P. Pettavel, MD

Takeshi Johkoh, MD, PhD

Universidad Nacional de Colombia Hospital Universitario Mayor Mederi Hospital de San José Bogotá, Colombia

Anatomic Pathologist Saint Luke’s Hospital University of Missouri-Kansas City Kansas City, Missouri

Laura E. Heyneman, MD

Phillip A. Muñoz, MD

Professor Department of Radiology Duke University Medical Center Durham, North Carolina

Sonia L. Betancourt Cuellar, MD

Medical Director Golden Valley Memorial Hospital Laboratory Saint Luke’s Pathology Associates Ameripath Kansas City Lenexa, Kansas

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

Additional Contributors Gerald F. Abbott, MD, FACR

John P. Lichtenberger, III, MD, Maj, USAF, MC

Florian J. Fintelmann, MD, FRCPC

Martha Huller Maier, MD

Jud W. Gurney, MD, FACR

Helen T. Winer-Muram, MD

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PREFACE This book has meant a lot to me. First and foremost, it builds on the original work of Dr. Jud Gurney, who authored the first edition almost a decade ago. Unfortunately for all of us in the world of thoracic imaging, Dr. Gurney left us prematurely. However, his spirit and love for teaching live on in the pages of this book as we endeavored to build upon the wonderful foundation he established with the first edition, and for which we are immensely grateful. Writing this book has been an incredible experience for me because it brings together important masters who have made major contributions to the field of thoracic imaging. Many of them are dear friends, which made the experience even more special. A couple of decades ago, when I decided to pursue an academic career in thoracic radiology, HRCT was a trendy topic. I still remember how challenged and puzzled I felt when I faced the interstitial pneumonias. At one time I thought I would never master this knowledge, which further spurred my interest. Thereafter good luck never abandoned me. My first teacher, Tomás Franquet, welcomed me to his radiology department in Barcelona and taught me to navigate the world of HRCT. Subsequently, I learned from fantastic teachers both in Colombia and the USA, such as Jorge Carrillo, Santiago Restrepo, Sonia Betancourt, Lisa Diethelm, Page McAdams, Phil Goodman, and Laura Heyneman, some of whom graciously accepted my invitation to coauthor this book. They need no introduction, as their academic achievements speak for themselves. Finally, for the last decade I have worked with Melissa Rosado-de-Christenson, the most incredible woman, consummate professional, and innovator, who also requires no introduction. Drs. Kyung Soo Lee and Takeshi Johkoh are also part of this book. Anyone who has trained in thoracic imaging has had the opportunity to learn from their seminal papers. In fact, Drs. Franquet, Lee, and Johkoh have contributed an immense body of scientific research to the world of radiology. Their decision to participate is a humbling testimony to their willingness to share their knowledge and expertise with the radiology community despite the immense time demands of their investigative work. It is not an understatement that pathologic correlation is of utmost importance in understanding HRCT findings, perhaps more so than in any other area of radiology. Knowledge and recognition of basic pathologic concepts is critical for understating HRCT. Thus, histologic correlation was provided whenever possible. We were fortunate to partner with two outstanding pathologists at Saint Luke’s Hospital of Kansas City who went above and beyond their duties to contribute the histologic material in this book: Paul Pettavel and Phil Muñoz. These are superb and talented pathologists for whom the demands of private practice have precluded academic recognition. However, they are without a doubt the best pathologists I have had the privilege of working with. Their knowledge, expert interpretation, and commitment to patient care are unparalleled in both private and academic pathology. Their valuable contributions perfectly complement the imaging content of this book. After several years of working on projects with Amirsys/Elsevier, Dr. Rosado-de-Christenson proposed that this book should have three lead authors, with Brett Carter as the third, and instrumental, partner. This resulted in a comprehensive and systematic review of the work submitted by all the authors, which far exceeded that of the books we previously published. This meant much more time spent reviewing, editing, and correcting, and made this the most “peer-reviewed” and exhaustively scrutinized of all our books. I personally think that the extra effort, which at times felt excessive, substantially elevated the book’s quality. Finally, I want to specially thank Amirsys/Elsevier for allowing me to lead this project. I want to particularly thank Matthew Hoecherl, whose editorial assistance was superb. I greatly enjoyed working with the entire team, and this incredible experience has made it difficult, if not impossible, to even consider the possibility of working with other publishers.

Santiago Martínez-Jiménez, MD

Department of Radiology Saint Luke’s Hospital of Kansas City Professor of Radiology University of Missouri-Kansas City School of Medicine Kansas City, Missouri ix

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ACKNOWLEDGMENTS Text Editors Arthur G. Gelsinger, MA Nina I. Bennett, BA Terry W. Ferrell, MS Lisa A. Gervais, BS Karen E. Concannon, MD, PhD Megg Morin, BA

Image Editors Jeffrey J. Marmorstone, BS Lisa A. M. Steadman, BS

Illustrations Lane R. Bennion, MS Richard Coombs, MS Laura C. Wissler MA

Art Direction and Design Tom M. Olson, BA Laura C. Wissler, MA

Lead Editor Matt W. Hoecherl, BS

Production Coordinators Rebecca L. Bluth, BA Angela M.G. Terry, BA Emily C. Fassett, BA

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SECTIONS SECTION 1:

Fundamentals of HRCT SECTION 2:

Pathological Patterns of Injury SECTION 3:

Large Airways Disease SECTION 4:

Small Airways Disease SECTION 5:

Infection

SECTION 6:

Pneumoconiosis SECTION 7:

Neoplasms SECTION 8:

Interstitial Pneumonias SECTION 9:

Autoimmune Diseases SECTION 10:

Vascular Disease SECTION 11:

Inhalational, Inflammatory, Metabolic, and Post Treatment SECTION 12:

Congenital

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TABLE OF CONTENTS

SECTION 1: FUNDAMENTALS OF HRCT 4 8

Overview of HRCT Santiago Martínez-Jiménez, MD Approach to HRCT Interpretation Santiago Martínez-Jiménez, MD

ANATOMY 14 18 20 24

Secondary Pulmonary Lobule Melissa L. Rosado-de-Christenson, MD, FACR Gravitational Changes (Dependent Atelectasis) Santiago Martínez-Jiménez, MD Age-Related (Senescent) Changes Melissa L. Rosado-de-Christenson, MD, FACR Normal Inspiration and Expiration Melissa L. Rosado-de-Christenson, MD, FACR

TERMINOLOGY AND SIGNS 28 29 30 31 32 33 34 35 36

37 38 39 40 41

Micronodules Santiago Martínez-Jiménez, MD Acinar Nodules Melissa L. Rosado-de-Christenson, MD, FACR Tree-in-Bud Opacities Tomás Franquet, MD, PhD Ground-Glass Attenuation Brett W. Carter, MD Crazy-Paving Pattern Tomás Franquet, MD, PhD Mosaic Attenuation Pattern and Air-Trapping Santiago Martínez-Jiménez, MD Head Cheese Sign Brett W. Carter, MD Signet Ring Sign Santiago Martínez-Jiménez, MD Halo Sign Laura E. Heyneman, MD and Santiago Martínez-Jiménez, MD Reversed Halo Sign Santiago Martínez-Jiménez, MD Finger-in-Glove Sign Santiago Martínez-Jiménez, MD Honeycombing Santiago Martínez-Jiménez, MD Cystic Lung Disease Melissa L. Rosado-de-Christenson, MD, FACR Flame-Shaped Nodules Brett W. Carter, MD

DISTRIBUTION 42 46 50 54 55

SECTION 2: PATHOLOGICAL PATTERNS OF INJURY 58 62 66 70 74

Approach to Pathological Patterns of Injury Santiago Martínez-Jiménez, MD and Phillip A. Muñoz, MD Diffuse Alveolar Damage Santiago Martínez-Jiménez, MD and Paul P. Pettavel, MD Diffuse Alveolar Hemorrhage With Capillaritis Santiago Martínez-Jiménez, MD and Paul P. Pettavel, MD Organizing Pneumonia Santiago Martínez-Jiménez, MD and Paul P. Pettavel, MD Constrictive Bronchiolitis Tomás Franquet, MD, PhD

SECTION 3: LARGE AIRWAYS DISEASE 80 82 86 90 92 94

Approach to Large Airways Disease Melissa L. Rosado-de-Christenson, MD, FACR Bronchiectasis Laura E. Heyneman, MD and Jud W. Gurney, MD, FACR Allergic Bronchopulmonary Aspergillosis Melissa L. Rosado-de-Christenson, MD, FACR Williams-Campbell Syndrome Sonia L. Betancourt Cuellar, MD Mounier-Kuhn Syndrome Carlos S. Restrepo, MD Bronchocentric Granulomatosis Jorge Alberto Carrillo-Bayona, MD

SECTION 4: SMALL AIRWAYS DISEASE 100 102 106 110

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Peribronchovascular Santiago Martínez-Jiménez, MD and Paul P. Pettavel, MD Centrilobular Santiago Martínez-Jiménez, MD and Paul P. Pettavel, MD Perilymphatic Kyung Soo Lee, MD Random Brett W. Carter, MD Peripheral Brett W. Carter, MD

Approach to Small Airways Disease Brett W. Carter, MD Infectious Bronchiolitis Laura E. Heyneman, MD Diffuse Aspiration Bronchiolitis Laura E. Heyneman, MD Respiratory Bronchiolitis Jorge Alberto Carrillo-Bayona, MD

TABLE OF CONTENTS 112 116 122 124 128 132 136

142 146 150 156 160 164 168 174

Follicular Bronchiolitis Jorge Alberto Carrillo-Bayona, MD Hypersensitivity Pneumonitis Kyung Soo Lee, MD Diffuse Panbronchiolitis Kyung Soo Lee, MD Idiopathic Constrictive Bronchiolitis Melissa L. Rosado-de-Christenson, MD, FACR Swyer-James-MacLeod Syndrome Laura E. Heyneman, MD Bronchiolitis Obliterans Syndrome Carlos S. Restrepo, MD Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) Melissa L. Rosado-de-Christenson, MD, FACR

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SECTION 5: INFECTION

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Approach to Infection Melissa L. Rosado-de-Christenson, MD, FACR Bacterial Pneumonia Tomás Franquet, MD, PhD Parasitic Infection Tomás Franquet, MD, PhD Viral Pneumonia Tomás Franquet, MD, PhD Invasive Aspergillosis Tomás Franquet, MD, PhD Pneumocystis Pneumonia Jorge Alberto Carrillo-Bayona, MD Tuberculosis Kyung Soo Lee, MD Nontuberculous Mycobacterial Infection Kyung Soo Lee, MD

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SECTION 6: PNEUMOCONIOSIS 182 184 188 194 198 202

Approach to Pneumoconiosis Melissa L. Rosado-de-Christenson, MD, FACR Silicosis and Coal Worker's Pneumoconiosis Brett W. Carter, MD Asbestosis Carlos S. Restrepo, MD and Helen T. Winer-Muram, MD Berylliosis Sonia L. Betancourt Cuellar, MD Talcosis Carlos S. Restrepo, MD and Jud W. Gurney, MD, FACR Hard-Metal Pneumoconiosis Kyung Soo Lee, MD

SECTION 7: NEOPLASMS 206 210 214 218

Approach to Neoplasms Brett W. Carter, MD Invasive Mucinous Adenocarcinoma (Diffuse) Kyung Soo Lee, MD Lymphangitic Carcinomatosis Sonia L. Betancourt Cuellar, MD Hematogenous Metastases John P. Lichtenberger, III, MD, Maj, USAF, MC and Brett W. Carter, MD

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Endovascular Metastases and Tumor Emboli Brett W. Carter, MD, Florian J. Fintelmann, MD, FRCPC, and Gerald F. Abbott, MD, FACR Kaposi Sarcoma Santiago Martínez-Jiménez, MD, Carlos S. Restrepo, MD, and Brett W. Carter, MD Lymphangioleiomyomatosis Melissa L. Rosado-de-Christenson, MD, FACR and Takeshi Johkoh, MD, PhD Reactive Lymphoproliferative Disorders Jorge Alberto Carrillo-Bayona, MD Neoplastic Lymphoproliferative Disorders Jorge Alberto Carrillo-Bayona, MD

SECTION 8: INTERSTITIAL PNEUMONIAS

258 262 266 270 274 278 282 286

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Approach to Interstitial Pneumonias Melissa L. Rosado-de-Christenson, MD, FACR Idiopathic Pulmonary Fibrosis Takeshi Johkoh, MD, PhD Idiopathic Nonspecific Interstitial Pneumonia Kyung Soo Lee, MD Cryptogenic Organizing Pneumonia Jorge Alberto Carrillo-Bayona, MD Acute Exacerbation of Interstitial Lung Disease Takeshi Johkoh, MD, PhD Acute Interstitial Pneumonia Carlos S. Restrepo, MD and Jud W. Gurney, MD, FACR Idiopathic Lymphoid Interstitial Pneumonia Takeshi Johkoh, MD, PhD Pleuropulmonary Fibroelastosis Takeshi Johkoh, MD, PhD Airway-Centered Interstitial Fibrosis Tomás Franquet, MD, PhD Interstitial Pneumonia With Autoimmune Features (IPAF) Takeshi Johkoh, MD, PhD Approach to Smoking-Related Interstitial Lung Diseases Melissa L. Rosado-de-Christenson, MD, FACR Respiratory Bronchiolitis-Interstitial Lung Disease Kyung Soo Lee, MD Desquamative Interstitial Pneumonia Jorge Alberto Carrillo-Bayona, MD Combined Pulmonary Fibrosis and Emphysema Carlos S. Restrepo, MD

SECTION 9: AUTOIMMUNE DISEASES 308

312 316 320 324

Approach to Connective Tissue Disease-Associated Interstitial Lung Disease Carlos S. Restrepo, MD Rheumatoid Arthritis Sonia L. Betancourt Cuellar, MD Progressive Systemic Sclerosis Brett W. Carter, MD Dermatomyositis/Polymyositis Carlos S. Restrepo, MD Sjögren Syndrome Sonia L. Betancourt Cuellar, MD

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TABLE OF CONTENTS 330 332 338 344 348 350 354

Mixed Connective Tissue Disease Laura E. Heyneman, MD Systemic Lupus Erythematosus Laura E. Heyneman, MD Granulomatosis With Polyangiitis (GPA) Kyung Soo Lee, MD Eosinophilic Granulomatosis With Polyangiitis Jorge Alberto Carrillo-Bayona, MD Microscopic Polyangiitis Jorge Alberto Carrillo-Bayona, MD Ankylosing Spondylitis Tomás Franquet, MD, PhD and Martha Huller Maier, MD Inflammatory Bowel Disease Sonia L. Betancourt Cuellar, MD

METABOLIC OR DEGENERATIVE 420 424 426 432 436 438 442

SECTION 10: VASCULAR DISEASE 360 362 368 370 374 376 378

Approach to Vascular Disease Brett W. Carter, MD Pulmonary Edema Melissa L. Rosado-de-Christenson, MD, FACR Hepatopulmonary Syndrome Kyung Soo Lee, MD Pulmonary Hypertension Tomás Franquet, MD, PhD and Jud W. Gurney, MD, FACR Pulmonary Venoocclusive Disease Kyung Soo Lee, MD Pulmonary Capillary Hemangiomatosis Laura E. Heyneman, MD Excipient Lung Disease (Talc/Cellulose Granulomatosis) Santiago Martínez-Jiménez, MD

SECTION 11: INHALATIONAL, INFLAMMATORY, METABOLIC, AND POST TREATMENT 386

Approach to Inhalational, Inflammatory, Metabolic, and Post Treatment Brett W. Carter, MD

POST TREATMENT 444 450

396 400

Spectrum of Aspiration-Related Disorders Tomás Franquet, MD, PhD and Gerald F. Abbott, MD, FACR Lipoid Pneumonia Sonia L. Betancourt Cuellar, MD Inhalational Injury Sonia L. Betancourt Cuellar, MD

INFLAMMATORY 404 410 416

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Sarcoidosis Sonia L. Betancourt Cuellar, MD Histiocytic Disorders Jorge Alberto Carrillo-Bayona, MD Eosinophilic Disorders Tomás Franquet, MD, PhD

Radiation-Induced Lung Disease Sonia L. Betancourt Cuellar, MD Drug-Induced Lung Disease Sonia L. Betancourt Cuellar, MD

SECTION 12: CONGENITAL 456 462 464 466 468 472 474 476

ASPIRATION/INHALATION 392

Amyloidosis Laura E. Heyneman, MD Light-Chain Deposition Disease Takeshi Johkoh, MD, PhD Pulmonary Alveolar Proteinosis Jorge Alberto Carrillo-Bayona, MD Metastatic Pulmonary Calcification Tomás Franquet, MD, PhD and Jud W. Gurney, MD, FACR Diffuse Pulmonary Ossification Carlos S. Restrepo, MD Emphysema Laura E. Heyneman, MD Idiopathic Pulmonary Hemosiderosis Laura E. Heyneman, MD

478 482 486 488 492

Approach to Congenital Brett W. Carter, MD Familial Idiopathic Pulmonary Fibrosis Carlos S. Restrepo, MD Birt-Hogg-Dubé Syndrome Melissa L. Rosado-de-Christenson, MD, FACR Hermansky-Pudlak Syndrome Carlos S. Restrepo, MD Tuberous Sclerosis Carlos S. Restrepo, MD Neurofibromatosis Sonia L. Betancourt Cuellar, MD Alveolar Microlithiasis Jorge Alberto Carrillo-Bayona, MD α-1 Antitrypsin Deficiency Jorge Alberto Carrillo-Bayona, MD Primary Ciliary Dyskinesia Melissa L. Rosado-de-Christenson, MD, FACR Primary Immunodeficiencies Tomás Franquet, MD, PhD Chronic Granulomatous Disease Carlos S. Restrepo, MD Cystic Fibrosis Laura E. Heyneman, MD and Gerald F. Abbott, MD, FACR Childhood Interstitial Lung Disease (chILD) Carlos S. Restrepo, MD

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SECOND EDITION

Martínez-Jiménez | Rosado-de-Christenson | Carter

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Section 1

Fundamentals of HRCT

4 8

Overview of HRCT Approach to HRCT Interpretation

Anatomy Secondary Pulmonary Lobule Gravitational Changes (Dependent Atelectasis) Age-Related (Senescent) Changes Normal Inspiration and Expiration

14 18 20 24

Terminology and Signs Micronodules Acinar Nodules Tree-in-Bud Opacities Ground-Glass Attenuation Crazy-Paving Pattern Mosaic Attenuation Pattern and Air-Trapping Head Cheese Sign Signet Ring Sign Halo Sign Reversed Halo Sign Finger-in-Glove Sign Honeycombing Cystic Lung Disease Flame-Shaped Nodules

28 29 30 31 32 33 34 35 36 37 38 39 40 41

Distribution Peribronchovascular Centrilobular Perilymphatic Random Peripheral

42 46 50 54 55

Fundamentals of HRCT

Overview of HRCT Definition High-resolution computed tomography (HRCT) is a CT technique used for imaging the lung parenchyma. It is defined by the following parameters. • Thin-section CT: With current technology, thin-section CT refers to images ≤ 1.5 mm thick • Inspiration, expiration, and prone imaging: 3 different acquisitions • High-spatial-frequency reconstruction (bone) algorithm: Postprocessing sharpening algorithm • Typically performed without intravenous contrast, but there may be exceptions

Indications There are widespread misconceptions regarding the appropriate indications for HRCT among clinicians who are not thoracic specialists. In some instances, HRCT is thought to represent a "better" CT when compared to conventional unenhanced or contrast-enhanced chest CT. It is our responsibility as radiologists to actively educate our clinical colleagues regarding appropriate indications for this examination. These include the following. • Suspected diffuse lung disease including: Interstitial lung disease, cystic lung disease, emphysema, pulmonary micronodules, bronchiectasis • Suspected small airways disease • Quantification and assessment of diffuse lung disease for evaluating response to treatment • Imaging guidance for selection of optimal biopsy site(s) in patients with diffuse lung disease

Frequent Inappropriate Indications A frequent inappropriate indication for HRCT is the assessment of focal lung disease, including solitary lung nodules or masses. In other cases, the study is performed for assessment of suspected interstitial lung disease in a patient with an acute pulmonary process, such as pulmonary edema or pneumonia, which may obscure underlying interstitial abnormalities.

Technical Details Thin-section CT specifically refers to thin x-ray collimation in order to produce thin-section images. With multidetector CT technology, thin collimation of x-rays is a preprocessing standard. When sequential techniques or older CT scanners are used, adjusting x-ray collimation to the desired slice thickness should always be considered. Although it may seem obvious, image acquisition using a 5-mm x-ray collimation for the generation of 1-mm thick images will not produce diagnostic quality images. Inspiratory Imaging In many institutions, inspiratory HRCT is performed as a fulldose helical acquisition with the patient in the supine position. This allows detection and assessment of both focal and diffuse pulmonary abnormalities, as focal lesions, including lung cancer, may be missed with sequential acquisitions. Expiratory Imaging Expiratory HRCT is often performed as a limited sequential acquisition during full expiration with a significantly decreased radiation dose (as less tissue is radiated). Typically, 1-mm thick slices are obtained every 10 mm but may also be obtained every 20 mm or more. 4

Prone Imaging Prone imaging is often performed as a limited sequential acquisition during full inspiration with significantly reduced radiation dose. Typically, 1-mm thick slices are obtained every 10 mm but may also be obtained every 20 mm or more. The reconstruction algorithm is a postprocessing event (after the completion of image acquisition) and uses the raw data. As a result, any algorithm can be used, but most institutions and manufacturers use and recommend a bone algorithm. All acquisitions are typically performed without intravenous contrast, but inspiratory images may occasionally be acquired as a contrast-enhanced chest CT or as a CT pulmonary angiogram. A common clinical scenario is chest imaging of a patient with known pulmonary hypertension and possible interstitial lung disease for exclusion of chronic pulmonary thromboembolic disease. Such variations in the standard protocol are usually approved after discussion with the referring clinician and after apprising the radiologic technologist regarding the rationale for the change in protocol.

Historical Perspective HRCT was originally described in the 1980s and popularized in the early 1990s. The technique was specifically targeted to assess anatomic landmarks and pathologic processes that were previously not well visualized with the conventional CT technique of that era. An understanding of the premultidetector CT technique allows its implementation and proper use in the era of multidetector CT. During most of the 1980s, the only commercially available CT technique was sequential image acquisition in which each image was the result of information collected by a single x-ray exposure in a 360° gantry rotation. Images were acquired with 1 gantry rotation at a time, and the CT table only moved when the x-ray tube was off. During the 1980s, the technology improved significantly via increasing reductions of the time required for each gantry rotation. HRCT was developed during this era in order to improve spatial resolution to optimally assess both anatomy and pathology. The HRCT technique consisted of a combination of several parameters: Thinsection CT (< 3 mm), high-spatial-frequency reconstruction algorithm (i.e., bone algorithm), and inclusion of inspiratory, expiratory, and prone imaging. The many variations of this technique described by various reference groups is beyond the scope of this discussion. In the late 1980s, helical CT became available. Its major advantage was the ability of the x-ray tube to continuously rotate allowing generation of x-rays and image acquisition simultaneous with the CT table motion. The new technology came with the price of a higher radiation dose. However, an entire study could be performed in a much shorter time period, typically on the order of < 1 minute. On the other hand, beam collimation of ≤ 3 mm was not practical, as x-ray tubes could not be turned on for such long periods of time. As a result, the originally described HRCT technique did not change. With the advent of multidetector CT in the early 2000s, thinsection helical acquisitions became a standard reality. Again, CT doses increased even further. Progressively, the "new" CT machines were able to image wider segments of tissue (using multiple rows of detectors). The acquired images could then be reformatted to very thin slices, given that the x-ray beam

Overview of HRCT

Advantages of Thin-Section CT Thin-section CT (i.e., < 1.5 mm) improves depiction of anatomic structures and pathologic processes that were previously not well visualized (e.g., interlobular septa, micronodules, centrilobular structures, etc.). This is particularly the case when compared to the old sequential acquisitions that provided very thick slices on the order of 1 cm, which generated an image that included the summation of all the densities within a voxel of 1 cm (i.e., volume average) making differentiation of small structures impossible. HRCT also included image postprocessing with a high-spatialfrequency or sharpening algorithm, often referred to as the bone algorithm. The resultant image sharpening allows identification of small anatomic structures and pathologic lesions. For example, CT pulmonary angiography is typically presented for interpretation using a soft tissue algorithm (i.e., a postprocessing image-blurring algorithm), which allows visualization of the pulmonary arteries and minimizes the artifactual filling defects that would appear if a sharpening algorithm were to be used. In spite of the fact that the study is a thin-section CT, small pulmonary anatomic structures and pathologic lesions are typically blurred. However, postprocessing reformation of the images with a bone algorithm could be helpful to assess the lung parenchyma. This is of little clinical value in most scenarios as the purpose of the study is to detect thromboembolic disease and not to assess interstitial lung disease. Finally, the additional expiratory and prone images form an integral part of the HRCT technique. Expiratory imaging is used to detect areas of air-trapping that may either be subtle or invisible on inspiratory imaging. Prone imaging allows differentiation of early subpleural interstitial lung disease from the typical posterior subpleural dependent atelectasis seen on supine inspiratory imaging, as dependent atelectasis resolves on prone imaging. Anecdotally, abnormalities that involve the posterior aspects of the lung are better identified on prone imaging. It is postulated that the presence of dependent atelectasis, even if minimal, may partially obscure anatomic structures and subtle pathologic processes.

multidetector CT, several groups continue to obtain sequential acquisitions with the intrinsic risk of missing subcentimeter lung lesions, which is of particular concern in patients with pulmonary fibrosis who have an increased risk of developing lung cancer. Regardless of the technique used, it is important for radiologists to understand the strengths and limitations of the specific protocols they use.

Troubleshooting

Fundamentals of HRCT

collimation was equally thin. Study times continued to drop. For example, with a 24-channel multidetector CT, images could be < 1 mm thick (i.e., 0.625 mm) or equal to the x-ray beam collimation. As a result,, thin-section CT became readily available. The original HRCT technique had to be reinterpreted in the multidetector CT era. It should be noted that performing an inspiratory supine chest CT followed by an expiratory supine chest CT and a prone inspiratory chest CT with today's technology would result in an unacceptable tripling of the radiation dose. Consequently, protocols were further adjusted to continuously decrease the radiation dose. Many groups continue to acquire sequential images for the supine inspiratory, supine expiratory, and prone acquisitions (identical to the original 1980s HRCT technique) or use multidetector helical acquisitions for only 1 of the acquisitions (typically the supine inspiratory phase) and sequential acquisitions for the expiratory and prone HRCT.

Several technical problems may arise when performing HRCT. Perhaps the most common is the extremely "grainy" resultant images. Graininess may be due to several factors, some of which can be modified in the interest of improved image quality. Large body habitus &/or obesity typically result in increased mottle artifact and greater image graininess. While increasing the CT technique (i.e., kVp and mA) may partially alleviate this problem, it is difficult to completely overcome this limitation. Selection of the wrong postprocessing algorithm may also result in grainy images. For example, while it would seem reasonable to use a "lung" instead of a "bone" algorithm for image postprocessing, the use of a lung algorithm for thin-section CT may result in very grainy images. The lung algorithm provides advantages in postprocessing thick images, which intrinsically have less mottle artifact due to volume averaging. Communication with CT technologists regarding the various nuances of image acquisition and postprocessing algorithms helps avoid such technical limitations. Another common problem that frequently defeats the purpose of the test is breathing/motion artifact. In a percentage of studies, respiratory motion relates to the inability of the patient to maintain apnea. Thus, the patient's ability to perform a short breathhold should be assessed before proceeding with the study, as HRCT imaging of severely dyspneic patients will not result in diagnostic quality images and will not provide useful information. However, it should be noted that many cases of motion/breathing artifact are due to insufficient coaching and training of the patient prior to the study. In the majority of cases, patients are not provided full breathing instructions prior to the test, and they receive such directions during the actual study. It is extremely helpful to coach the patient before the study and perform a few breathholds with the same directions that will be provided during the exam. This will not only train the patient in the interest of a better study but will also allow the identification of patients who are not able to perform the breath hold and are therefore not good candidates for HRCT.

Selected References 1.

2. 3. 4.

The American College of Radiology: ACR–STR practice parameter for the performance of high-resolution computed tomography (HRCT) of the lungs in adults. http://www.acr.org/~/media/17AF593BAF2E47AE9A51B10A60BC09D1.pdf . Revised 2015. Reviewed January 20, 2017. Accessed January 20, 2017. Gotway MB et al: High-resolution CT of the lung: patterns of disease and differential diagnoses. Radiol Clin North Am. 43(3):513-42, viii, 2005 Kazerooni EA: High-resolution CT of the lungs. AJR Am J Roentgenol. 177(3):501-19, 2001 Mayo JR et al: High-resolution CT of the lungs: an optimal approach. Radiology. 163(2):507-10, 1987

Focal Lesions on HRCT After the introduction of HRCT in the late 1980s, it became clear that this technique was to be used to assess diffuse lung disease. While this is still the case, some radiologists remain concerned about the possibility of missing focal disease, such as subcentimeter pulmonary nodules. In the era of 5

Fundamentals of HRCT

Overview of HRCT

(Left) Axial CECT (HRCT) of a patient with lymphangitic carcinomatosis shows interlobular septal thickening ﬈, consolidation ﬊, and scattered septal nodularity ﬉. (Right) Axial CECT of the same patient using imaging parameters employed before the introduction of HRCT shows the same findings. However, it is difficult to identify the abnormalities that appeared obvious on the HRCT image. HRCT is an invaluable tool for identifying interstitial abnormalities and allows the formulation of a focused differential diagnosis.

(Left) Axial HRCT of a patient with sarcoidosis shows classic perilymphatic micronodules present along the bronchovascular ﬈ structures and the subpleural regions of the interlobar fissures ﬉. (Right) Axial NECT using imaging parameters employed before the introduction of HRCT shows that it is impossible to confidently localize the pulmonary micronodules to the perilymphatic regions of the lung. As a result, a differential diagnosis of perilymphatic micronodular disease cannot be provided.

(Left) Axial CECT (HRCT) of a patient with suspected interstitial lung disease shows very subtle subpleural groundglass and reticular opacities ﬈ that could represent either early interstitial lung disease or dependent atelectasis. (Right) Axial prone HRCT of the same patient shows persistence of subpleural abnormalities ﬈ indicating early changes of interstitial lung disease and excluding the possibility of dependent atelectasis. This highlights the importance of prone imaging in the evaluation of interstitial lung disease.

6

Overview of HRCT Fundamentals of HRCT

(Left) Axial HRCT of a 41-yearold woman undergoing evaluation for possible interstitial lung disease shows subtle posterior subpleural ground-glass opacities ﬈. (Right) Axial prone HRCT of the same patient shows resolution of posterior subpleural opacities. Early interstitial lung disease may be difficult to differentiate from dependent atelectasis. Use of prone imaging allows differentiation, as dependent atelectasis typically resolves, whereas interstitial lung disease and senescent changes persist.

(Left) Axial inspiratory HRCT of a 47-year-old woman with rheumatoid arthritis-related constrictive bronchiolitis shows normal pulmonary attenuation on inspiratory imaging. (Right) Axial expiratory HRCT of the same patient shows bilateral airtrapping, a finding of small airways disease that would not be evident without the expiratory HRCT. Expiratory imaging is a critical and integral part of HRCT and should be performed whenever possible. Note image graininess due in part to large body habitus.

(Left) Axial inspiratory HRCT of a patient with cluster 1 hypersensitivity pneumonitis shows diffuse ground-glass opacities and mosaic attenuation ﬈. (Right) Axial prone HRCT of the same patient allows better characterization of the ground-glass opacities, which clearly appear centrilobular in distribution. Prone imaging allows resolution of dependent atelectasis, which may result in better visualization of the lower lobes and the dependent lung parenchyma.

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Fundamentals of HRCT

Approach to HRCT Interpretation Introduction

Nodules and Micronodules

A large number of conditions can be categorized as diffuse lung diseases. Fortunately, only a few of these disease processes are commonly encountered in clinical practice. Imaging evaluation of common and rare diffuse lung diseases requires learning, mastering, and applying several concepts that are only employed in the course of HRCT interpretation. These concepts differ from the universal concepts that can be applied to CT interpretation of other body regions. Although HRCT interpretation may seem complex, command of a finite number of basic concepts can be easily attained. The fundamental concepts required for expert interpretation of HRCT images are presented herein.

A nodule is defined as a well- or poorly defined, rounded opacity that measures ≤ 3 cm. A rounded opacity that measures > 3 cm is referred to as a pulmonary mass. Micronodules are nodules that measure < 3 mm. Identification of nodules, and particularly micronodules on HRCT, is followed by determination of their distribution. Centrilobular micronodules typically represent cellular bronchiolitis or talc/cellulose granulomatosis (also called excipient lung disease). Nodules and micronodules that exhibit a random distribution and involve all interstitial compartments are typically the result of hematogeneous dissemination of disease. Randomly distributed micronodules often exhibit the so-called miliary pattern on CT/HRCT. Understanding the perilymphatic distribution is challenging as there is not a perilymphatic interstitium per se. Perilymphatic encompasses both the central and peripheral interstitia, but as opposed to random distribution, perilymphatic nodules are not evenly distributed but are often clustered and more profuse centrally. In clinical practice, differentiation between these patterns is usually possible. However, differentiation between random (i.e., miliary) and perilymphatic micronodules, especially in subtle cases, may be difficult if not impossible.

The radiologist must become proficient in the identification and characterization of critical HRCT findings that may include nodules, micronodules, cysts, pseudocysts, mosaic attenuation, linear opacities, ground-glass opacities, interlobular septal thickening, and consolidation. Knowledge and understanding of the cross-sectional imaging anatomy of the lung allows determination of the anatomic distribution of these abnormalities, which is useful for formulating an appropriate differential diagnosis.

Anatomy-Based Imaging Issues The pulmonary interstitium refers to the connective tissue that provides structural support to all the other anatomic components of the lung (e.g., bronchi and bronchioles, vessels, lymphatics, alveoli, etc.). It can be broadly divided into that which is continuous with the mediastinum or central interstitium and that which is continuous with the pleura or peripheral interstitium. The central interstitium is further subdivided into that which surrounds the bronchi and central vessels, the peribronchovascular interstitium, and that which surrounds the secondary pulmonary lobular bronchioles and arterioles, the centrilobular interstitium. The peripheral interstitium is also subdivided into that which provides support to the pleural mesothelium, the subpleural interstitium, and that which courses along the interlobular septa (i.e., the periphery of the secondary pulmonary lobule), the interlobular interstitium. Finally, the interstitium that connects the central and peripheral interstitia is referred to as the intralobular interstitium. Classic HRCT abnormalities that affect each interstitial compartment are well described. Thickening of the peribronchovascular interstitium often manifests as bronchial wall thickening or peribronchial cuffing (perivascular thickening may also be identified on contrast-enhanced studies). Thickening of the centrilobular interstitium manifests as centrilobular nodules. It should be noted that centrilobular nodules may not represent an interstitial process but rather a vascular (e.g., cellulose granulomatosis) or bronchial (cellular bronchiolitis) abnormality. Unfortunately, reliable differentiation between interstitial and other centrilobular nodules is not always possible. Thickening of the interlobular interstitium manifests as interlobular septal thickening. Thickening of the subpleural interstitium manifests as fissural thickening. Thickening of the intralobular interstitium is also problematic as the affected anatomic structures are below the limits of resolution of HRCT. Thickening of the intralobular interstitium manifests on HRCT as ground-glass opacity, but in the majority of cases, ground-glass opacities actually represent alveolar filling (e.g., infection, alveolar hemorrhage, etc.). 8

Micronodules should be further characterized based on their attenuation as solid or ground glass, which helps narrow the differential diagnosis. There are not many etiologies of centrilobular ground-glass nodules, and hypersensitivity pneumonitis and respiratory bronchiolitis are the most common.

Cysts and Pseudocysts A cyst is defined as a round parenchymal lucency with a welldefined interface with the adjacent normal lung. While histologically cysts are characterized by the presence of an epithelial or fibrous wall, this feature cannot be ascertained on HRCT. Pseudocysts are also visible on HRCT and may be impossible to differentiate from cysts based on imaging alone, although this is not always the case. The main differential diagnosis of multiple pulmonary cysts includes lymphangioleiomyomatosis, lymphoid interstitial pneumonia, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, and light-chain deposition disease. Centrilobular emphysema may occasionally manifest as cyst-like lesions with well-defined walls and may mimic cysts, which may be problematic. For example, emphysema mimicking multiple pulmonary cysts in a young female smoker may suggest the diagnosis of lymphangioleiomyomatosis or Langerhans cell histiocytosis. It is therefore not surprising that some affected patients go on to open lung biopsy only to be diagnosed with centrilobular emphysema. Honeycombing is often considered in the differential diagnosis of pulmonary cysts. It is important to recognize the unique imaging features of honeycomb cysts (i.e., stacked subpleural cysts that share their walls) to avoid including honeycombing in the differential diagnosis of diffuse cystic lung disease. Centrilobular emphysema is a common cause of pulmonary pseudocysts on HRCT. Correct identification is often possible because the pseudocysts in emphysema exhibit the central dot sign, which refers to visualization of the lobular artery in the center of the emphysematous secondary pulmonary lobule. Bronchiectasis may occasionally mimic lung cysts when

Approach to HRCT Interpretation

Finally, other conditions could potentially mimic cysts on CT/HRCT but are generally not considered in the differential diagnosis of cystic lung disease. These include lung abscess, cavitation, and pneumatocele. These entities are often diagnosed based on correlation with clinical and laboratory findings.

Reticulation and Honeycombing Reticulation and honeycombing are the imaging hallmarks of pulmonary fibrosis of any cause. Honeycombing is defined as clustered, air-filled cysts that are often of similar diameters on the order of 3-10 mm or occasionally larger. They exhibit welldefined walls that are shared by ≥ 2 cysts. Establishing the distribution of reticulation and honeycombing is critical in identifying the etiology of pulmonary fibrosis. For example, in cases of usual interstitial pneumonia and nonspecific interstitial pneumonia, reticulation &/or honeycombing are typically subpleural with an apicobasal gradient (i.e., involving predominantly the lower lobes). In pulmonary fibrosis secondary to sarcoidosis or hypersensitivity pneumonitis, reticulation &/or honeycombing typically occur along bronchovascular bundles and involve the mid and upper lungs.

Mosaic Attenuation Mosaic attenuation refers to a patchwork of regions of differing lung attenuation. Its identification on HRCT may be challenging even for experienced radiologists. Mosaic attenuation is a manifestation of small airways disease, and areas of lower attenuation are secondary to decreased vascularity and air-trapping. However, mosaic attenuation may also occur in occlusive vascular disease (e.g., chronic thromboembolic disease, pulmonary arterial hypertension, etc.). Unfortunately, this finding is so intimately associated with small airways disease that radiologists may neglect to consider vascular disease in the differential diagnosis. An example of the importance of considering occlusive vascular disease as a cause of mosaic attenuation is central chronic thromboembolic disease, as affected patients may be amenable to surgical endarterectomy. This condition often demonstrates mosaic attenuation, but intravenous contrast administration is required for definitive diagnosis, which relies on identification of chronic pulmonary thromboemboli. If the diagnosis is not at least considered, CECT may never be obtained. There are several practical approaches to the assessment of mosaic attenuation. First, one must determine whether mosaic attenuation is related to infiltrative disease (i.e., areas of ground-glass opacity interspersed with normal lung). This is often easily determined by comparing vessel calibers in the areas of different attenuation. If vessel caliber is not different, mosaic attenuation is secondary to alveolar filling rather than small airways or chronic occlusive vascular disease. If the vascular calibers are different based on lung attenuation, then small airways or chronic occlusive vascular disease should be considered. In addition, identification of ancillary findings is also helpful. Small airways disease is often associated with bronchial wall thickening, bronchiectasis, mucus plugging, and centrilobular nodules. Occlusive vascular disease is often

associated with pulmonary hypertension (i.e., dilated pulmonary trunk). Of course, many diseases may exhibit both types of ancillary findings, making imaging assessment very challenging. For example, idiopathic constrictive bronchiolitis may not exhibit bronchial wall thickening, bronchiectasis, mucus plugging, or centrilobular nodules. On the other hand, longstanding constrictive bronchiolitis may exhibit pulmonary hypertension as a result of chronic hypoxia. Fortunately, such cases are uncommon.

Fundamentals of HRCT

imaged in cross section. This is particularly the case in subpleural traction bronchiectasis associated with interstitial lung disease (± honeycombing) involving the lower lobes. Multiplanar imaging should demonstrate the tubular or branching morphology characteristic of bronchiectasis in such cases.

Ground-Glass Opacities Ground-glass opacity is defined as increased pulmonary opacity without obscuration of underlying bronchial and vascular margins (as opposed to consolidation, which obscures visualization of these structures). Ground-glass opacity frequently correlates with alveolar filling processes but may also be a manifestation of interstitial lung disease. In any case, identification of ground-glass opacity is hardly ever problematic (with the exception of differentiation from hyperattenuated lung in mosaic attenuation). Actively trying to differentiate between acute and chronic ground-glass opacities is very helpful for narrowing the differential diagnosis. Common acute etiologies include infection, alveolar hemorrhage, and edema. Common chronic causes include idiopathic interstitial pneumonias (e.g., nonspecific interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis interstitial lung disease), hypersensitivity pneumonitis, drug reaction, chronic eosinophilic pneumonia, vasculitis, and lipoid pneumonia. As with micronodules, determination of distribution may be very helpful. For example, nonspecific interstitial pneumonia is an interstitial lung disease, which may manifest with groundglass opacity as the only finding. In such cases, ground-glass opacity will typically exhibit a subpleural distribution and an apicobasal gradient.

Interlobular Septal Thickening Interlobular septal thickening may be an isolated finding or may be associated with other imaging findings of diffuse lung disease. Smooth interlobular septal thickening is characteristic of interstitial pulmonary edema. Nodular septal thickening may occur in lymphangitic carcinomatosis and sarcoidosis. However, lymphangitic carcinomatosis may also manifest with smooth septal thickening.

Consolidation Consolidation is defined as increased pulmonary opacity with obscuration of bronchial and vascular margins (as opposed to ground-glass opacity, in which such structures are visible through the lung opacity). Radiologists can readily identify pulmonary consolidation. However, it is included here to highlight consolidation as an imaging manifestation of chronic diffuse lung disease. The principal differential diagnosis of chronic consolidation includes chronic eosinophilic pneumonia, organizing pneumonia, lymphoma, and pulmonary adenocarcinoma.

Selected References 1. 2.

Hansell DM et al: Fleischner Society: glossary of terms for thoracic imaging. Radiology. 246(3):697-722, 2008 Screaton NJ et al: Differential diagnosis in chronic diffuse infiltrative lung disease on high-resolution computed tomography. Semin Roentgenol. 37(1):17-24, 2002

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Fundamentals of HRCT

Approach to HRCT Interpretation

(Left) Axial CECT of a patient with acute bacterial bronchiolitis shows scattered centrilobular micronodules and tree-in-bud opacities. Note that the subpleural lung ﬉ is characteristically spared, indicating the centrilobular distribution of the abnormalities. (Right) Sagittal NECT MIP reformation of the same patient shows that the micronodules do not involve the interlobar fissures ﬈, a classic and distinctive feature of centrilobular micronodules that helps differentiate centrilobular from perilymphatic processes.

(Left) Axial NECT of a patient with sarcoidosis shows centrilobular micronodules in a perilymphatic distribution (i.e., profuse nodularity along the peribronchovascular interstitium). Some nodules are peripherally located, resulting in a nodular interlobar fissure ﬈. (Right) Sagittal NECT MIP reformation of the same patient shows micronodules along the bronchovascular bundles ﬉ and interlobar fissures ﬈, which appear thick and nodular. This is known as a perilymphatic distribution.

(Left) Composite axial (left) and axial MIP reformation (right) NECT of a patient with acute miliary histoplasmosis shows randomly distributed (i.e., evenly distributed) micronodules. Note that the MIP reformation enhances visualization of the micronodules. (Right) Sagittal NECT MIP reformation of the same patient shows even and diffuse distribution of pulmonary micronodules with some nodules abutting the fissures. This so-called random distribution is characteristic of hematogenous processes.

10

Approach to HRCT Interpretation Fundamentals of HRCT

(Left) Axial HRCT of a young woman with lymphangioleiomyomatosis shows scattered round, welldefined, thin-walled cysts ﬈ throughout the lungs. (Right) Axial CECT of a patient with Sjögren syndrome shows multiple round, well-defined cysts ﬈. While there are imaging findings that help suggest the diagnosis, it is really the clinical information (e.g., Sjögren syndrome, smoking history, inherited conditions, etc.) that is critical for evaluating patients with cystic lung disease.

(Left) Axial HRCT of a young patient with pulmonary Langerhans cell histiocytosis shows scattered thin-walled pulmonary cysts. Note that some cysts have bizarre ﬈ instead of round shapes, a characteristic feature of this disease. (Right) Axial CECT of a patient with Birt-Hogg-Dubé syndrome shows scattered pulmonary cysts, some of which abut pulmonary vessels ﬈, while others abut the pleura ﬉. These are specific imaging characteristics of lung cysts in Birt-Hogg-Dubé syndrome.

(Left) Axial NECT of a patient with septic emboli shows multiple bilateral cavitary nodules ﬈ with walls of variable thickness. These lesions could potentially simulate pulmonary cysts and may be difficult to differentiate in some cases. (Right) Axial CECT of a patient with centrilobular emphysema shows multiple bilateral, cystlike structures that may simulate cystic lung disease. Note the presence of a central soft tissue attenuation dot ﬈, which is characteristic of emphysema but is not seen in cystic lung disease.

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Fundamentals of HRCT

Approach to HRCT Interpretation

(Left) Axial HRCT of an immunocompromised patient with Pneumocystis jirovecii pneumonia shows mosaic attenuation due to the presence of ground-glass opacities ﬈. Note that the vessels going into the areas of different attenuation are of similar caliber. (Right) Axial NECT of a patient with SwyerJames-MacLeod syndrome shows mosaic attenuation due to areas or air-trapping and decreased vascularity ﬉. Note that the vessels going into the areas of varying attenuation exhibit different calibers.

(Left) Inspiratory axial HRCT of a patient with rheumatoid arthritis shows normal lung attenuation. In the setting of small airways disease, mosaic attenuation may be subtle on inspiratory HRCT and only evident on expiration. (Right) Expiratory axial HRCT of the same patient shows scattered areas of air-trapping ﬉ consistent with small airways disease. Note the decreased caliber of vessels supplying the hypoattenuated regions. In this case, there is no evidence of pulmonary hypertension to suggest chronic occlusive vascular disease.

(Left) Axial CECT of a patient with chronic thromboembolic disease shows bilateral mosaic attenuation. Note the decreased vessel caliber ﬉ in the hypoattenuated lung and the larger vessel caliber ﬊ in the hyperattenuated lung. The dilated pulmonary trunk ﬈ is a helpful ancillary finding in chronic occlusive vascular disease. (Right) Axial CECT MIP reformation of the same patient highlights the difference in pulmonary vessel caliber (smaller ﬈ and larger ﬉) in the areas of different attenuation.

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Approach to HRCT Interpretation Fundamentals of HRCT

(Left) Sagittal HRCT of a patient with idiopathic pulmonary fibrosis shows the classic distribution of honeycombing ﬉ and fibrosis (i.e., subpleural with apicobasal gradient). (Right) Axial HRCT of a patient with end-stage sarcoidosis shows extensive fibrosis with honeycombing ﬉. Note that the honeycombing is peribronchovascular, not subpleural. The distribution of honeycombing is important, as peribronchovascular honeycombing should suggest sarcoidosis or hypersensitivity pneumonitis.

(Left) Coronal CECT of a patient with interstitial pulmonary edema shows extensive smooth, interlobular septal thickening ﬈. (Right) Coronal CECT of a patient with prostate adenocarcinoma and lymphangitic carcinomatosis shows bilateral patchy smooth and nodular interlobular septal thickening ﬈. It is helpful to characterize interlobular septal thickening as smooth or nodular, as the latter should suggest lymphangitic carcinomatosis or sarcoidosis.

(Left) Axial HRCT of a patient with organizing pneumonia shows scattered bilateral ground-glass opacities ﬈. (Right) Axial NECT of a patient with primary pulmonary invasive mucinous adenocarcinoma shows multifocal bilateral groundglass opacities ﬈ and consolidations ﬉. In further characterizing these imaging findings, it is helpful to determine if they are acute or chronic, as this information can help narrow the differential diagnosis.

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Fundamentals of HRCT

Secondary Pulmonary Lobule KEY FACTS

TERMINOLOGY • Secondary pulmonary lobule (SPL): Smallest discrete unit of lung structure marginated by connective tissue septa and supplied by lobular bronchiole and artery • Size: 1-2.5 cm in diameter • Morphology ○ Cuboidal or pyramidal in lung periphery ○ Hexagonal or polygonal in central lung • Components ○ Lobular core: Lobular bronchiole, artery and lymphatics ○ Typically contains ≤ 12 acini (range: 3-24) • Boundaries: Interlobular septa

IMAGING • Radiography: SPL is not visible in normal subjects • CT/HRCT ○ Normal lobular artery may be visible in central SPL ○ Location of normal interlobular septa may be inferred by visualization of peripheral pulmonary veins

(Left) Graphic shows the secondary pulmonary lobule bound by interlobular septa ﬉ and supplied by a lobular bronchiole ﬈ and pulmonary artery ﬈. Pulmonary veins ﬊ course in the interlobular septa. Note peribronchovascular and septal lymphatic network (in green). (Right) Graphic shows a cut section of lung and secondary pulmonary lobules bound by interlobular septa ﬉. The lobular core contains a bronchiole ﬈, a pulmonary artery ﬉, and pulmonary lymphatics surrounded by a connective tissue sheath ﬈.

(Left) Graphic depicts the anatomy of the secondary pulmonary lobule as visualized on HRCT or thin-section chest CT. The location of the interlobular septa is inferred by visualization of pulmonary veins ﬈ and the center of the lobule by visualization of the dot-like lobular artery ﬉. The normal lobular bronchiole ﬊ is not visible on CT. (Right) Normal axial NECT shows structures of the secondary pulmonary lobule including the dot-like central lobular arteries ﬈ and peripheral pulmonary veins ﬉ coursing in the interlobular septa.

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• Imaging of Abnormal SPL ○ Interlobular septal thickening – Smooth □ Interstitial edema, lymphangitic carcinomatosis – Nodular □ Lymphangitic carcinomatosis, sarcoidosis, silicosis – Irregular: Interstitial fibrosis – All may exhibit thickened centrilobular interstitium ○ Centrilobular abnormalities – Increased attenuation: Cellular bronchiolitis – Decreased attenuation: Centrilobular emphysema ○ Panlobular abnormalities – Increased attenuation: Lobular pneumonia – Decreased attenuation □ Hypersensitivity pneumonitis, constrictive bronchiolitis, panlobular/paraseptal emphysema ○ Peripheral lobular abnormalities – Idiopathic pulmonary fibrosis, organizing pneumonia

Secondary Pulmonary Lobule

Abbreviations • Secondary pulmonary lobule (SPL)

Definitions

Imaging of Normal Secondary Pulmonary Lobule

• Primary pulmonary lobule ○ Alveolar ducts, alveolar sacs, and alveoli distal to last respiratory bronchiole ○ No imaging significance • SPL ○ Smallest discrete unit of lung structure – Marginated by connective tissue septa – Supplied by lobular bronchiole and pulmonary artery • Pulmonary acinus ○ Lung distal to terminal bronchiole including: Respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli ○ Largest pulmonary unit (6-10 mm in diameter) in which all airways participate in gas exchange

• Radiography ○ Normal SPL not visible on radiography • CT ○ Airways: Not normally visible – Measure ~ 0.7 mm in diameter, but thin walls preclude visualization – Location inferred from visualization of lobular artery ○ Arteries – Lobular artery visible in central aspect of SPL – Measure ~ 1 mm in diameter – Linear or dot-like opacity in central SPL or within 1 cm from visceral pleura ○ Veins: Occasional visualization in interlobular septa ○ Interlobular septa: Occasional visualization – Septal location inferred by visualization of peripheral pulmonary veins

IMAGING General Features • Size ○ 1-2.5 cm in diameter • Morphology ○ Relatively uniform ○ Cuboidal or pyramidal in lung periphery ○ Hexagonal or polygonal in central lung • Basic unit of lung structure and function • Typically contains ~ 12 acini (range: 3-24)

Components • Lobular core ○ Bronchiole, artery, and lymphatics ○ Surrounded by connective tissue sheath • Airways ○ Lobular bronchiole located in central aspect of SPL ○ Lobular bronchiole gives rise to – Terminal bronchioles – Respiratory bronchioles – Alveolar ducts – Alveoli and alveolar sacs • Arteries ○ Lobular artery in central aspect of SPL – Courses with lobular bronchiole – Supplies alveolar capillary network • Veins ○ Course within interlobular connective tissue septa ○ Drain alveolar capillary network • Lymphatics ○ Course along proximal lobular artery and lobular bronchiole in central SPL ○ Course along pulmonary veins within interlobular connective tissue septa in SPL periphery • Interstitium ○ Fine fibrous network within and around SPL

Boundaries • Interlobular septa ○ Peripheral boundaries of SPL

Fundamentals of HRCT

○ Most conspicuous in lung periphery – Apical, anterior, and lateral upper lobes – Anterior and lateral middle lobe and lingula – Anterior and juxtadiaphragmatic lower lobes

TERMINOLOGY

Imaging of Abnormal Secondary Pulmonary Lobule • Interlobular septal thickening ○ Smooth interlobular septal thickening – Interstitial edema, lymphangitic carcinomatosis ○ Nodular interlobular septal thickening – Lymphangitic carcinomatosis, sarcoidosis, silicosis ○ Irregular interlobular septal thickening – Interstitial fibrosis ○ All may exhibit thickened centrilobular interstitium • Centrilobular abnormalities: Involve central SPL ○ Centrilobular increased attenuation – Cellular bronchiolitis: Centrilobular nodules and treein-bud opacities □ Infection, hypersensitivity pneumonitis, respiratory bronchiolitis, follicular bronchiolitis – Perilymphatic diseases: Thickening of lobular core □ Sarcoidosis, silicosis, lymphangitic carcinomatosis ○ Centrilobular decreased attenuation – Centrilobular emphysema • Panlobular abnormalities ○ Diseases affecting entire SPL ○ Lobular increased attenuation – Lobular pneumonia (bronchopneumonia) □ Ground-glass attenuation &/or consolidation ○ Lobular decreased attenuation – Hypersensitivity pneumonitis – Constrictive bronchiolitis – Panlobular and paraseptal emphysema • Peripheral lobular abnormalities ○ Lung diseases affecting periphery of SPL – Idiopathic pulmonary fibrosis – Organizing pneumonia

SELECTED REFERENCES 1. 2.

Hansell DM et al: Fleischner Society: glossary of terms for thoracic imaging. Radiology. 246(3):697-722, 2008 Webb WR: Thin-section CT of the secondary pulmonary lobule: anatomy and the image--the 2004 Fleischner lecture. Radiology. 239(2):322-38, 2006

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Fundamentals of HRCT

Secondary Pulmonary Lobule

(Left) Axial CECT of a 37-yearold woman with pulmonary edema shows smooth interlobular septal thickening. Edema fluid allows visualization of the polygonal boundaries ﬉ of basilar secondary pulmonary lobules. Note increased conspicuity of the central lobular arteries ﬈ secondary to thickening of the centrilobular interstitium. (Right) Coronal CECT of the same patient shows wellformed secondary pulmonary lobules in the peripheral middle lobe outlined by thick interlobular septa ﬉.

(Left) Axial CECT of a 68-yearold man with metastatic prostate cancer and lymphangitic carcinomatosis shows nodular thickening of interlobular septa ﬉, a small right pleural effusion ﬊, and scattered small pulmonary nodules ﬈ representing hematogenous metastases. (Right) Coronal CECT of the same patient shows nodular interlobular septal thickening ﬉ outlining multiple secondary pulmonary lobules. Note asymmetric pattern of involvement with sparing of some areas characteristic of lymphangitic carcinomatosis.

(Left) Axial HRCT of a 59-yearold woman with sarcoidosis shows bilateral clustered perilymphatic micronodules and nodular thickening of several interlobular septa. Some of the septal micronodules ﬈ outline the boundaries of secondary pulmonary lobules. (Right) Axial HRCT of a 74-year-old woman with pulmonary interstitial fibrosis shows irregular thickening of a few interlobular septa ﬈ and associated traction bronchiectasis ﬊ and bronchiolectasis ﬉.

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Secondary Pulmonary Lobule Fundamentals of HRCT

(Left) Axial HRCT of a 45-yearold smoker with dyspnea shows diffuse centrilobular ground-glass opacities consistent with respiratory bronchiolitis-associated interstitial lung disease. The thin line of spared subpleural lung ﬉ is consistent with the centrilobular location of the abnormalities. (Right) Axial CECT MIP reformation of a 34year-old woman with infectious bronchiolitis shows tree-in-bud opacities located in the central aspects of secondary pulmonary lobules outlined by uninvolved septal lung parenchyma.

(Left) Axial HRCT of a 58-yearold male smoker shows centrilobular emphysema manifesting as multiple foci of centrilobular low attenuation ﬉ secondary to centrilobular lung destruction surrounding central dot-like lobular arteries ﬈. (Right) Axial NECT of a 46-year-old woman with Staphylococcus aureus pulmonary infection shows multiple foci of increased lobular attenuation manifesting as consolidations ﬉ and ground-glass opacities ﬈ characteristic of bronchopneumonia.

(Left) Axial HRCT of a farmer with hypersensitivity pneumonitis shows the socalled headcheese sign characterized by lobular hyperlucency ﬈ (secondary to air-trapping) and lobular ground-glass opacities ﬉ amid normal lung parenchyma. (Right) Axial NECT of a 24-year-old woman with organizing pneumonia shows characteristic perilobular consolidations ﬈ exhibiting the reversed halo and atoll signs. Consolidations surround relatively uninvolved secondary pulmonary lobules ﬉.

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Fundamentals of HRCT

Gravitational Changes (Dependent Atelectasis) KEY FACTS

TERMINOLOGY • Supine CT: Posterior subpleural ground-glass, reticular, or linear opacities may represent normal dependent atelectasis; may simulate early interstitial lung disease • Prone CT: Allows differentiation from interstitial lung disease, as dependent atelectasis resolves

PHYSIOLOGY • Areas of microatelectasis related to gravitational compression

CLINICAL IMPLICATIONS • Assuming subpleural opacities are secondary to dependent atelectasis may prevent timely diagnosis of interstitial lung disease: Usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP)

IMAGING • CT ○ Lower lobe predominance, posterior, subpleural

(Left) Axial HRCT of a 41-yearold woman who was undergoing evaluation for possible interstitial lung disease shows subtle posterior subpleural ground-glass opacities ﬈. (Right) Axial prone HRCT of the same patient shows resolution of posterior subpleural opacities. Early interstitial lung disease may be difficult to differentiate from dependent atelectasis. Use of prone imaging allows differentiation, as dependent atelectasis typically resolves whereas interstitial lung disease and senescent changes persist.

(Left) Axial CECT (left) and follow-up CECT (right) composite image of a 60-yearold woman shows nodular dependent atelectasis ﬈ that resolved on follow-up imaging. Nodular dependent atelectasis, in contrast with pulmonary nodules, may resolve on follow-up imaging. (Right) Axial supine (left) and prone (right) HRCT composite image of a 59-year-old woman shows subtle subpleural reticulations that persist on prone imaging consistent with interstitial lung disease. In this case, prone imaging helps confirm early disease.

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○ Linear, ground-glass, or reticular opacities ○ Subpleural nodularity – Lower lobes, ovoid, obtuse angles with pleura – Average size: 7 x 3 mm – Resolution on prone imaging

TOP DIFFERENTIAL DIAGNOSES • UIP/NSIP ○ Basilar honeycombing and traction bronchiectasis ○ Persists on prone imaging • Asbestosis ○ Early stage: Lower lobe predominant, curvilinear opacities paralleling pleura (common) ○ Basilar honeycombing and traction bronchiectasis ○ Findings persist on prone imaging ○ Bilateral discontinuous pleural plaques ± calcification • Senescent changes (asymptomatic elderly individuals) ○ Subpleural reticulation, bronchial dilatation/thickening ○ Persist on prone imaging

Gravitational Changes (Dependent Atelectasis) Fundamentals of HRCT

(Left) Axial HRCT of a man with dyspnea without interstitial lung disease shows a small right lower lobe subpleural nodule ﬈ with obtuse margins consistent with nodular dependent atelectasis. This abnormality can be differentiated from a true nodule, as it should resolve on prone imaging. (Right) Supine (left) and prone (right) HRCT composite image shows a left lower lobe subpleural nodule ﬉ with obtuse margins, which resolved on prone imaging confirming nodular dependent atelectasis.

(Left) Axial HRCT of a 52-yearold woman with biopsy-proven hypersensitivity pneumonitis shows bilateral lower lobe subpleural ground-glass opacities ﬈. (Right) Axial prone HRCT of the same patient shows persistence of the subpleural ground-glass opacities consistent with early interstitial lung disease. Hypersensitivity pneumonitis typically exhibits a more characteristic imaging appearance, but may also simulate classic findings of nonspecific interstitial pneumonia.

(Left) Axial HRCT of a 47-yearold man with biopsy-proven nonspecific interstitial pneumonia shows subtle subpleural lower lobe predominant ground-glass and reticular opacities. (Right) Axial prone HRCT of the same patient shows persistent subpleural opacities consistent with early changes of interstitial lung disease. Note that subtle subpleural opacities seen on supine imaging can be easily interpreted as dependent atelectasis. This case highlights the importance of prone imaging.

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Fundamentals of HRCT

Age-Related (Senescent) Changes KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Age-related changes: Normal morphologic alterations related to aging

• • • •

IMAGING • CT/HRCT ○ Decreased lung attenuation and complexity ○ Perifissural nodules: Intrapulmonary lymph nodes ○ Subpleural reticulation adjacent to osteophytes; typically in paravertebral right lower lobe ○ Bilateral basilar subpleural reticular opacities ○ Airway alterations – Diffuse calcification of tracheal and bronchial cartilages; elderly women – Increased forced expiratory tracheal collapse; older men – Basilar bronchial dilatation and bronchial wall thickening ○ Expiratory air-trapping

(Left) Axial NECT of an 80year-old man evaluated for a pulmonary nodule identified on radiography shows right lower lobe paravertebral ground-glass opacity and mild architectural distortion ﬉ adjacent to spinal osteophytes and a well-defined right lower lobe thin-walled cyst ﬈. (Right) Axial NECT of the same patient shows right lower lobe paravertebral ground-glass opacities and architectural distortion ﬉ and bilateral thin-walled cysts ﬈. These are well-recognized CT findings in asymptomatic elderly subjects.

(Left) Axial NECT of an asymptomatic 74-year-old man shows subtle scattered basilar linear opacities ﬈ without associated traction bronchiectasis or bronchiolectasis. (Right) Coronal NECT of the same patient shows basilar reticular opacities ﬈ without architectural distortion, traction bronchiectasis, or bronchiolectasis. Note irregular apical pleural surfaces ﬉, which may account for increased visualization of apical caps on radiography of the elderly population.

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Emphysema Interstitial lung disease Pulmonary metastases Bronchiectasis

PATHOLOGY • Loss of elastic recoil of alveoli and airways and reduction in capillary density may explain physiologic alterations seen in normal elderly subjects

CLINICAL ISSUES • Asymptomatic elderly subjects • Pulmonary function: ↓ lung volumes, ↓ forced expiratory volume in 1 second/forced vital capacity (FEV₁/FVC)

DIAGNOSTIC CHECKLIST • Consider age-related changes in asymptomatic elderly subjects with basilar subpleural reticulation and bronchial dilatation

Age-Related (Senescent) Changes

DIFFERENTIAL DIAGNOSIS

Synonyms

Emphysema

• Aging lung • Senile lung • Senescent lung

• History of cigarette smoking • Upper lobe-predominant lucencies with imperceptible walls and central dot-like opacities (lobular arteries)

Definitions

Interstitial Lung Disease

• Age-related or senescent changes: Normal morphologic alterations related to aging

• Nonspecific interstitial pneumonia ○ Basilar subpleural reticulation and ground-glass opacities ○ Traction bronchiolectasis in fibrotic form of disease ○ Absence of honeycombing • Usual interstitial pneumonia ○ Basilar subpleural reticulation and honeycombing ○ Associated traction bronchiectasis/bronchiolectasis

IMAGING Radiographic Findings • Lungs ○ Increased lung volumes (flattening of hemidiaphragms) and decreased basilar lung volumes are both described in normal elderly subjects • Mediastinum ○ ↑ tortuosity and calcification of aorta and branches ○ Mediastinal lipomatosis ○ Calcified central airway cartilages • Pleura ○ Increased apical caps: Subpleural scarring and fibrosis • Chest wall ○ Increased osteophyte formation ○ Increased costal cartilage calcification • Diaphragm ○ Diaphragmatic eventration ○ Diaphragmatic hernias – Hiatus hernia – Bochdalek hernia

CT Findings • Lung ○ Decreased lung attenuation ○ Decreased lung complexity ○ Perifissural nodules – Common with increasing age – Typically intrapulmonary lymph nodes – Lower lung below level of carina, subpleural – < 10 mm in diameter; may exhibit growth on serial imaging – Ovoid, lentiform, triangular: Multiplanar imaging enhances assessment of nodule morphology ○ Subpleural reticulation adjacent to osteophytes; typically in paravertebral right lower lobe ○ Bilateral basilar subpleural reticular opacities – No associated traction bronchiolectasis or honeycombing ○ Other: Lung cysts, ground-glass opacities, parenchymal bands, micronodules • Airway alterations ○ Diffuse calcification of tracheal and bronchial cartilages; elderly women ○ Increased forced expiratory tracheal collapse; older men ○ Basilar bronchial dilatation and bronchial wall thickening – Increased bronchoarterial ratio • Expiratory air-trapping

Fundamentals of HRCT

TERMINOLOGY

Pulmonary Metastases • Known history of malignancy • Multifocal bilateral basilar predominant pulmonary nodules ○ Spherical morphology, not necessarily perifissural

Bronchiectasis • Irreversible airway dilatation; ↑ bronchoarterial ratio • Varying severity: Cylindrical, varicoid, saccular

Tracheomalacia • Excessive expiratory luminal collapsibility • Luminal narrowing, abnormal luminal morphology

PATHOLOGY General Features • Loss of elastic recoil of alveoli and airways and reduction in capillary density may explain physiologic alterations seen in normal elderly subjects

Microscopic Features • Increased size of pulmonary airspaces, alveolar dilatation • Decrease in surface area available for gas exchange • Decreased pulmonary supporting tissues ○ Fragmentation of alveolar wall elastin fibers

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Asymptomatic elderly subjects • Other signs/symptoms ○ Pulmonary function: ↓ lung volumes, ↓ forced expiratory volume in 1 second/forced vital capacity (FEV₁/FVC)

DIAGNOSTIC CHECKLIST Consider • Age-related changes in asymptomatic elderly subjects with basilar subpleural reticulation, bronchial dilatation, perifissural nodules, and scattered thin-walled cysts

SELECTED REFERENCES 1.

Copley SJ: Morphology of the aging lung on computed tomography. J Thorac Imaging. 31(3):140-50, 2016

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Fundamentals of HRCT

Age-Related (Senescent) Changes

(Left) Axial CECT of a 73-yearold woman evaluated with CT pulmonary angiography for acute chest pain shows bilateral lower lobe bronchial dilatation ﬈ without associated mucus plugging or surrounding airspace disease. The increased bronchoarterial ratios are reminiscent of CT findings of cylindrical bronchiectasis. (Right) Coronal CECT of the same patient shows left lower lobe bronchial dilatation ﬈. Dilatation of peripheral basilar bronchi is a common CT finding in asymptomatic elderly individuals.

(Left) Axial NECT of an asymptomatic 80-year-old woman evaluated for a pulmonary nodule identified on radiography shows bilateral basilar bronchial dilatation and mild bronchial wall thickening ﬈. Increased bronchoarterial ratios are reminiscent of bronchiectasis. Note a right lower lobe parenchymal band ﬉, another finding described in the normal senescent lung. (Right) Axial NECT of the same patient demonstrates bilateral basilar bronchial dilatation and mild bronchial wall thickening ﬈.

(Left) Composite image with axial NECT MIP reformations shows a 90-year-old woman with extensive tracheal ﬈ and bronchial ﬉ cartilage calcification. This finding may be seen as a sequela of longterm warfarin therapy but is also a well-recognized finding in asymptomatic elderly individuals and is usually of no clinical significance. (Right) Coronal NECT (bone window) MIP reformation of the same patient shows to better advantage exuberant cartilage calcification involving the trachea and mainstem bronchi.

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Age-Related (Senescent) Changes Fundamentals of HRCT

(Left) Axial NECT of a 75-yearold man who presented with intermittent cough shows bilateral lower lobe reticular ﬈ and band-like ﬉ opacities, which have been described as age-related changes in the lung. Note mild bronchial dilatation and bronchial wall thickening ſt. (Right) Axial NECT of the same patient shows mild bilateral basilar bronchial dilatation in the absence of bronchiolitis and multifocal basilar reticular opacities ﬈ and parenchymal bands ﬉ in the absence of architectural distortion or traction bronchiectasis.

(Left) Coronal NECT of the same patient shows basilarpredominant linear opacities or parenchymal bands ﬉, reticular opacities ﬈, and mild bronchial dilatation ﬊. (Right) Sagittal NECT of the same patient shows mildly dilated airways ﬊, reticular opacities ﬈, and parenchymal bands ﬉. These are all welldescribed CT findings in senescent or aging lungs and are often identified in asymptomatic elderly individuals. These findings should not be mistaken for interstitial lung disease.

(Left) Axial NECT of an asymptomatic 70-year-old man evaluated because of pulmonary nodules identified on radiography shows a small indeterminate polylobular solid lingular nodule ﬉ adjacent to an incomplete accessory left minor fissure ﬈. (Right) Coronal NECT of the same patient shows the flat morphology of the lingular nodule ﬉ on multiplanar imaging. Note an additional elongate perifissural nodule ﬈ along the left major fissure. These nodules likely represent intrapulmonary lymph nodes.

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Fundamentals of HRCT

Normal Inspiration and Expiration KEY FACTS

• Inspiratory CT: Obtained at suspended full inspiration ○ Optimal contrast between normal air-containing lung and high-attenuation normal structures – Blood vessels, airway walls, interlobar fissures ○ Optimal contrast between normal air-containing lung and focal or diffuse pulmonary abnormalities ○ Trachea: Round luminal morphology, posterior displacement of membranous trachea ○ Lungs: Diffuse homogeneous low attenuation, minimal dependent atelectasis • Expiratory CT: Assessment of diffuse and focal airway obstruction and small airways disease ○ Techniques – Expiratory HRCT – Postexpiratory HRCT – Dynamic expiratory HRCT – Volumetric expiratory CT

(Left) Graphic illustrates the anatomy of the anterior trachea and central bronchi. The central large airways are supported by discontinuous cartilage "rings" that sustain and promote the spherical morphology of the airway lumina. (Right) Graphic shows the anatomy of the posterior central large airways. The tracheal C-shaped cartilage rings are connected posteriorly by the membranous portion of the trachea, which accounts for the flat morphology of the posterior central airways during expiration.

(Left) Normal inspiratory axial HRCT shows the spherical morphology of the tracheal lumen during inspiration. The apical lung parenchyma is well expanded at maximal inspiration, which corresponds physiologically to total lung capacity. (Right) Normal axial expiratory HRCT of the same patient shows a flat morphology of the posterior trachea ﬈ that corresponds to the location of its membranous portion. Note decreased lung volumes and diffuse homogeneously increased pulmonary attenuation.

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○ Appearance – Trachea and central airways □ Decreased airway lumen size □ Preserved anterolateral rounded morphology □ Flattening/anterior bowing of posterior membranous airways – Lungs □ Decreased cross-sectional area □ Homogeneous increase in attenuation □ Anteroposterior attenuation gradient □ Increased pulsation artifact □ Elevation of bilateral hemidiaphragms on multiplanar imaging

IMAGING

TOP DIFFERENTIAL DIAGNOSES • • • •

Tracheobronchomalacia Constrictive bronchiolitis Hypersensitivity pneumonitis Occlusive vascular disease and obesity

Normal Inspiration and Expiration

Abbreviations • Total lung capacity (TLC) • Residual volume (RV)

Definitions • TLC: Total volume of intrathoracic air at maximal inhalation • RV: Total volume of intrathoracic air at maximal exhalation

IMAGING Imaging Features: Inspiratory CT and HRCT • General concepts ○ Obtained at suspended full inspiration or TLC ○ Optimal contrast between normal air-containing lung and high-attenuation normal structures – Blood vessels: Pulmonary arteries and veins – Airway walls – Interlobar fissures and pleural surfaces ○ Optimal contrast between normal air-containing lung and focal or diffuse pulmonary abnormalities • Axial imaging ○ Trachea and central airways – Maximal airway diameter – Round morphology of airway lumina – Posterior displacement of membranous trachea ○ Pulmonary parenchyma – Diffuse homogeneous low attenuation of aerated lung parenchyma – Minimal posterior dependent atelectasis • Coronal and sagittal reformations ○ Maximal inferior displacement of hemidiaphragms ○ Maximal lung volume or TLC

Imaging Features: Expiratory CT and HRCT • Indications ○ Exclusion of diffuse and focal airway obstruction, small airways disease, or occlusive vascular disease • Techniques ○ Expiratory HRCT – Imaging at suspended respiration (exhalation) ○ Postexpiratory HRCT – Imaging at full-forced exhalation ○ Dynamic expiratory HRCT – Continuous imaging during full-forced exhalation ○ Volumetric expiratory CT – Volumetric acquisition with thin collimation – Allows quality coronal and sagittal reformations ○ Spirometrically triggered expiratory HRCT – Imaging at predetermined level of exhalation (or lung volume) • Axial imaging ○ Trachea – Decreased airway lumen size – Crescentic morphology due to flattening/anterior bowing of posterior membranous trachea – Anterolateral rounded morphology due to support by C-shaped cartilaginous rings ○ Central bronchi – Flattening of posterior bronchial walls

○ Lungs – Decreased cross-sectional area – Homogeneous increase in lung attenuation – Anteroposterior attenuation gradient – Normal expiratory air-trapping □ Lower lobe superior segments □ Lobular air-trapping common (40-80% of normal subjects): Mild (< 3 adjacent lobules) or moderate (≥ 3 lobules but < 1 segment) □ Dependent lung parenchyma – Increased pulsation artifact • Coronal and sagittal reformations ○ Elevation of bilateral hemidiaphragms ○ Cephalad displacement of lung parenchyma ○ Increased lung density ○ Useful for identification of apicobasal disease gradients

Fundamentals of HRCT

TERMINOLOGY

Abnormal Inspiratory and Expiratory Imaging • Mosaic attenuation ○ Heterogeneous lung attenuation – Differences in vessel sizes in lower attenuation areas compared with higher attenuation areas – Causes: Patchy interstitial lung disease, obliterative small airways disease, or occlusive vascular disease • Expiratory air-trapping ○ Overall air-trapping > 1 pulmonary segment has underlying pathologic basis ○ Persistent lucency or less than normal increase in lung attenuation on expiratory imaging ○ Frequently indicates airway obstruction; difficult to differentiate from vascular mosaic attenuation on CT

DIFFERENTIAL DIAGNOSIS Tracheobronchomalacia • Excessive airway lumen collapsibility on expiration ○ Tracheal/airway cartilage collapse ○ Anterior collapse of posterior membranous airway • Luminal narrowing • Abnormal airway morphology ○ Coronal diameter > sagittal diameter ○ Flattened or frown-shaped tracheal lumen

Constrictive Bronchiolitis • Peribronchiolar fibrosis with resultant bronchiolar luminal narrowing and obliteration • Mosaic attenuation; expiratory air-trapping

Hypersensitivity Pneumonitis • Head cheese sign: Juxtaposition of lobular areas of low (airtrapping), normal, and high pulmonary attenuation • Expiratory lobular air-trapping

Miscellaneous Conditions • Emphysema, chronic obstructive lung disease, asthma, cystic fibrosis, bronchiectasis, sarcoidosis, chronic pulmonary thromboembolism, pulmonary arterial hypertension, pulmonary venoocclusive disease, obesity

SELECTED REFERENCES 1.

Kligerman SJ et al: Mosaic attenuation: etiology, methods of differentiation, and pitfalls. Radiographics. 35(5):1360-80, 2015

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Fundamentals of HRCT

Normal Inspiration and Expiration

(Left) Normal inspiratory HRCT of a 40-year-old man shows normal homogeneous lung attenuation and an ovoid morphology of the mid trachea. Note the rounded morphology ﬉ of the posterior membranous trachea. (Right) Axial expiratory HRCT of the same patient shows a flat morphology ﬈ of the posterior membranous trachea. Note the bilateral decreased lung volumes associated with homogeneous diffusely increased lung attenuation.

(Left) Axial inspiratory HRCT of the same patient shows spherical morphologies of the lumina of the bilateral truncus basalis lower lobe bronchi ﬉. Note the normal homogeneous pulmonary attenuation. (Right) Axial expiratory HRCT of the same patient shows increased lung attenuation with an anteroposterior gradient accentuated by increased posterior dependent atelectasis. Note narrowing of the truncus basalis lower lobe bronchi ﬈ and accentuation of pulsatile motion in the lingula ﬊.

(Left) Normal coronal inspiratory NECT at the level of the tracheal carina shows normal lung volume and homogeneous pulmonary parenchyma. The central airways exhibit maximal luminal diameters. (Right) Normal coronal expiratory NECT of the same subject shows globally decreased lung volume, increased pulmonary attenuation, and superior migration of the bilateral hemidiaphragms. Note expiratory narrowing of the central airways.

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Normal Inspiration and Expiration Fundamentals of HRCT

(Left) Axial NECT of a patient with tracheomalacia shows a very abnormal tracheal morphology characterized by anteroposterior airway narrowing with an associated increase in the transverse tracheal diameter ﬈. These findings are usually accentuated on expiratory imaging. (Right) Axial CECT of a 95-year-old man with bronchomalacia shows expiratory collapse and luminal narrowing of the bilateral mainstem bronchi ﬈. Note mild mosaic attenuation of the lung parenchyma from air-trapping.

(Left) Composite image with axial inspiratory (left) and axial expiratory (right) HRCT of a 62-year-old woman with rheumatoid arthritis and constrictive bronchiolitis shows extensive mosaic attenuation (left) accentuated by expiratory air-trapping (right). (Right) Axial expiratory CECT of a 49-year-old woman with constrictive bronchiolitis secondary to Swyer-JamesMacLeod syndrome shows right upper lobe expiratory air trapping ﬉ amid areas of normal higher attenuation ﬈ pulmonary parenchyma.

(Left) Axial HRCT of a 56-yearold farmer with hypersensitivity pneumonitis shows the so-called head cheese sign characterized by lobular air-trapping amid areas of normal lung and ground-glass opacity. These findings are accentuated on expiratory imaging. (Right) Axial expiratory CECT of a 38year-old woman with hypersensitivity pneumonitis shows scattered areas of airtrapping ﬉, most pronounced in the right lower lobe. Note areas of normal lung attenuation ﬊ and groundglass opacity ﬈.

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Fundamentals of HRCT

Micronodules KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Discrete, small, round, focal opacities, < 3 mm on CT

• Perilymphatic nodules ○ Sarcoidosis ○ Lymphangitic carcinomatosis ○ Silicosis • Centrilobular nodules ○ Airway (cellular bronchiolitis) – Infectious bronchiolitis – Aspiration bronchiolitis – Respiratory bronchiolitis – Hypersensitivity pneumonitis – Follicular bronchiolitis ○ Vascular – Cellulose and talc granulomatosis – Tumor emboli • Miliary ○ Miliary infection (e.g., miliary tuberculosis) ○ Miliary metastases

IMAGING • Radiography ○ Reticular, reticulonodular, or nodular opacities • CT ○ Attenuation: Solid and ground glass ○ Distribution – Perilymphatic □ Involve axial and peripheral interstitium □ Nodular interlobar fissures – Centrilobular □ Involve centrilobular region/interstitium □ Spare subpleural lung and interlobar fissures – Random (miliary nodules) □ Randomly involve all interstitial compartments □ Diffuse and even distribution; occasional fissural nodules

(Left) Drawing shows the classic distributions of micronodules, including random ﬈, centrilobular ﬊, and perilymphatic ﬉. (Right) Sagittal NECT MIP reformation of a patient with infectious bronchiolitis shows scattered centrilobular and tree-in-bud micronodules within multiple lobes that are most conspicuous in the right upper lobe ﬈. Note that these nodules spare the subpleural lung and do not involve the interlobar fissures. These are classic and distinctive features of centrilobular micronodules.

(Left) Sagittal NECT MIP reformation of a patient with sarcoidosis shows multiple clustered micronodules that involve the bronchovascular bundles ﬉ and interlobar fissures ﬈, which appear thick and nodular. This is the socalled perilymphatic distribution. (Right) Sagittal NECT MIP reformation of a patient with miliary histoplasmosis shows even and diffuse distribution of pulmonary micronodules with some nodules abutting the fissures. This is the so-called random distribution.

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Acinar Nodules

TERMINOLOGY • Acinar nodule (consolidated pulmonary acinus) ○ Rounded, poorly defined opacities (consolidations) ○ Size: 5-8 mm in diameter ○ Often clustered and multifocal • Acinus ○ Largest unit in which all airways participate in gas exchange – Structural lung unit distal to terminal bronchiole – Supplied by 1st-order respiratory bronchioles – Contains alveolar ducts and alveoli ○ Size: 6-10 mm in diameter • Secondary pulmonary lobule ○ Contains 3-25 acini

• CT/HRCT ○ Multifocal ○ Ground-glass or part-solid opacities ○ 5-8 mm in size

TOP DIFFERENTIAL DIAGNOSES • • • •

Infection: Bronchopneumonia Aspiration Pulmonary vasculitis Lung cancer: Invasive mucinous adenocarcinoma

Fundamentals of HRCT

KEY FACTS

CLINICAL ISSUES • Signs and symptoms ○ Infection: Cough, fever, leukocytosis ○ Invasive mucinous adenocarcinoma: Bronchorrhea

IMAGING

DIAGNOSTIC CHECKLIST

• Radiography ○ Ill-defined, small, rounded opacities ○ Typically multifocal

• Sputum analysis for diagnosis of infection • Diagnosis of vasculitis or malignancy may require bronchoscopic or open lung biopsy

(Left) Axial NECT of a patient who presented with fever and cough shows bronchopneumonia characterized by acinar nodules ﬉ manifesting as multifocal, rounded, illdefined, ground-glass and part-solid right upper lobe nodular lesions. (Right) Axial NECT of a patient with a moderate hiatus hernia (not shown) and aspiration bronchiolitis shows left lower lobe acinar nodules manifesting as rounded nodular consolidations ﬉ surrounded by ground-glass opacity halos ﬈.

(Left) Axial CECT of a patient with hemoptysis shows a primary lung cancer ﬊ obstructing the right lower lobe bronchus and multifocal, right lower lobe rounded partsolid acinar nodules ﬈ representing postobstructive pneumonia. (Right) Coronal CECT of a patient with multicentric invasive mucinous adenocarcinoma shows multifocal, bilateral lower lobe consolidations and right upper lobe heterogeneous, part-solid acinar nodules with intrinsic lucencies ﬈. The term airspace nodule should generally be avoided.

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Fundamentals of HRCT

Tree-in-Bud Opacities KEY FACTS

TERMINOLOGY • CT: Centrilobular nodules and branching opacities that resemble budding tree ○ Not seen in normal lungs ○ Small airways (bronchiolar) disease (most common) ○ Vascular disease (uncommon)

IMAGING • Centrilobular nodules and branching opacities ○ Y- or V-shaped; resemble childhood metal jacks • Characteristic subpleural lung sparing

TOP DIFFERENTIAL DIAGNOSES • Small airways disease ○ Infectious bronchiolitis – Most common cause of tree-in-bud opacities – Acute: Viral and bacterial (e.g., Mycoplasma) – Chronic: Tuberculosis and nontuberculous mycobacterial infection

(Left) Drawing shows centrilobular and tree-in-bud nodules and branching opacities. Note sparing of the subpleural lung ﬈ also evident along the fissures, a characteristic feature of centrilobular processes. (Right) Axial NECT minIP reformation of a patient with infectious bronchiolitis shows small centrilobular nodules and tree-in-bud opacities ﬈ in the right lower lobe. Interlobular septa are unaffected and manifest as low-attenuation bands ﬊ indicating the centrilobular nature of this process.

(Left) Coronal NECT MIP reformation of a patient with infectious bronchiolitis shows bilateral tree-in-bud opacities and multiple left upper lobe lobular consolidations ﬉, representing areas of associated bronchopneumonia. (Right) Axial NECT of a 37-year-old man with cellulose granulomatosis shows diffuse bilateral tree-in-bud opacities that are evenly distributed throughout the lungs. Note the spared subpleural lung ﬈ characteristic of centrilobular processes.

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○ Aspiration bronchiolitis – Esophageal dysmotility, hiatus hernia, neurological deficits ○ Follicular bronchiolitis – Sjögren syndrome, rheumatoid arthritis, and other immunologic conditions ○ Diffuse panbronchiolitis – Asian population ○ Cellulose granulomatosis – Intravenous injection of crushed oral tablets

PATHOLOGY • Abnormalities in center of secondary pulmonary lobule • Small airways tree-in-bud ○ Bronchiolar filling by mucus, pus, fluid, &/or cells ○ Bronchiolar wall inflammation and dilatation • Vascular tree-in-bud ○ Granulomatous reaction to illicit IV drugs or cellulose ○ Tumoral cells or thrombotic microangiopathy

Ground-Glass Attenuation

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Ground-glass attenuation/opacity ○ Increased lung attenuation or density ○ Does not obscure underlying structures • Results from ○ Alveolar filling/collapse – Edema, blood, tumor, lipoprotein ○ Interstitial thickening ○ Increased blood volume ○ Combination of above mechanisms • Nonspecific finding with broad differential diagnosis

• Acute ○ Pneumonia (including viruses, mycoplasma, and Pneumocystis jirovecii), hemorrhage, edema, acute interstitial pneumonia, acute respiratory distress syndrome, acute eosinophilic pneumonia, and radiation pneumonitis • Chronic ○ Idiopathic interstitial pneumonias: Nonspecific interstitial pneumonia, desquamative interstitial pneumonia, and respiratory bronchiolitis interstitial lung disease ○ Hypersensitivity pneumonitis, drug reaction, chronic eosinophilic pneumonia, vasculitis, lipoid pneumonia • Neoplastic ○ Adenocarcinoma: Preinvasive, minimally invasive, lepidic ○ Pulmonary lymphoma • Preinvasive ○ Atypical adenomatous hyperplasia

IMAGING • Radiography ○ Hazy increased lung density that does not obscure underlying structures • CT ○ Increased lung attenuation ○ Does not obscure underlying bronchovascular structures

Fundamentals of HRCT

KEY FACTS

(Left) Axial CECT of a 48-yearold man with hemoptysis shows patchy ground-glass opacities ﬈ in the middle and bilateral lower lobes, compatible with hemorrhage. Ground-glass opacity refers to increased lung density or attenuation that does not obscure underlying structures. (Right) Axial CECT of a 43year-old woman with acute interstitial pneumonia demonstrates bilateral ground-glass opacity, left upper lobe subpleural reticular opacities ﬈, and small pleural effusions ﬊. Note bilateral traction bronchiectasis ﬉.

(Left) Axial CECT of a 54-yearold man with an extensive smoking history and desquamative interstitial pneumonia demonstrates ground-glass opacity in the left lung. Note associated bronchial wall thickening ﬊ and bronchiectasis ﬉. (Right) Axial CECT of a 56-year-old woman with right breast cancer demonstrates patchy ground-glass opacities ﬉ in the right upper lobe and subpleural reticular opacities ﬈ compatible with radiation pneumonitis and early radiation fibrosis, respectively.

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Fundamentals of HRCT

Crazy-Paving Pattern KEY FACTS

TERMINOLOGY

PATHOLOGY

• Crazy paving ○ Thin-section CT pattern ○ Thick, interlobular septa and intralobular lines on background of ground-glass opacity ○ Resembles irregularly shaped paving stones

• Alveolar filling, interstitial process, or both ○ Linear network: Thick, interlobular septa – Interstitial neoplasm, interstitial edema – Peripheral intraalveolar material ○ Ground-glass opacities: Partial alveolar filling

TOP DIFFERENTIAL DIAGNOSES

CLINICAL ISSUES

• Acute etiologies ○ Pulmonary edema ○ Drug toxicity ○ Acute interstitial pneumonia ○ Diffuse alveolar hemorrhage • Chronic etiologies ○ Pulmonary alveolar proteinosis ○ Exogenous lipoid pneumonia ○ Lung adenocarcinoma (invasive mucinous) ○ Lymphoma

• Pulmonary alveolar proteinosis: Classic association; symptoms less severe than imaging abnormalities • Pulmonary edema: Rapid resolution with treatment • Pneumocystis pneumonia: Cough, dyspnea, hypoxia, fever • Acute interstitial pneumonia: Severe respiratory failure, mechanical ventilation • Diffuse alveolar hemorrhage: Hemoptysis (80%), anemia • Exogenous lipoid pneumonia: Aspiration or inhalation of fatty oily substances, oral laxatives, oil-based nose drops, liquid paraffin

(Left) Axial NECT of a patient with pulmonary edema shows diffuse, bilateral, ground-glass opacities with intrinsic thick, interlobular septa ﬈. Note sharp demarcation ﬉ from the adjacent normal lung and small, bilateral pleural effusions ﬊. (Right) Coronal NECT of a patient with pulmonary alveolar proteinosis shows bilateral geographic areas of crazypaving characterized by ground-glass opacity and superimposed interlobular septal thickening ﬈. Note the sharp demarcation ﬉ from adjacent normal lung.

(Left) Axial CECT of a 55-yearold patient with advanced non-small cell lung cancer and pulmonary opacities related to gefitinib toxicity shows a diffuse crazy-paving pattern ﬈ in the left lung. Note patchy, ground-glass opacities in the right lung ﬉. (Right) Axial NECT of a 67-year-old man with exogenous lipoid pneumonia and mild dyspnea shows bilateral patchy areas of increased lung attenuation and thick, interlobular septa (crazy-paving pattern) ﬈ in the posterior aspects of the bilateral lower lobes.

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Mosaic Attenuation Pattern and Air-Trapping

TERMINOLOGY • Mosaic attenuation (CT): Patchwork of regions of differing density or attenuation ○ Causes: Interstitial lung disease (ILD), small airways disease (e.g., constrictive bronchiolitis), occlusive vascular disease (e.g., chronic thromboembolic disease) • Air-trapping (expiratory CT): Areas with less than normal increase in attenuation and lack of volume reduction on expiratory imaging

IMAGING • CT ○ Mosaic attenuation: Segmental, subsegmental, lobular, or patchy areas of differing attenuation ○ Δ in caliber of vessels in areas of differing attenuation = small airways or occlusive vascular disease – No Δ in cases of ILD ○ Air-trapping (expiration) – Normal lung and ILD uniformly ↑ in attenuation

– Areas affected by small airways disease and occlusive vascular disease remain hypoattenuated ○ Bronchial wall thickening, bronchiectasis, and mucus plugging common in small airways disease ○ Dilated pulmonary trunk or right ventricular strain common in chronic occlusive vascular disease

TOP DIFFERENTIAL DIAGNOSES

Fundamentals of HRCT

KEY FACTS

• Small airways disease ○ Mosaic attenuation tends to be subtle on inspiration, but air-trapping is evident on expiration ○ Any bronchiolitis, especially constrictive bronchiolitis if mosaic attenuation &/or air-trapping predominate • Chronic occlusive vascular disease ○ Mosaic attenuation often evident on inspiration, airtrapping on expiration ○ Any cause of pulmonary hypertension, especially primary pulmonary hypertension and chronic thromboembolic disease

(Left) Drawing shows several patterns of air-trapping: Lobular ﬈, subsegmental ﬊, and segmental ﬉. (Right) Axial NECT of a 35-year-old man with Swyer-JamesMacLeod syndrome shows segmental and subsegmental mosaic attenuation bilaterally. Note the differences in the caliber of pulmonary vessels within areas of different lung attenuation. Also note bronchial wall thickening ﬈ suggesting an airway abnormality as opposed to chronic vascular occlusion.

(Left) Axial CECT of a 38-yearold woman with chronic pulmonary thromboembolic disease shows diffuse mosaic attenuation. Note pulmonary trunk dilatation ﬈ in comparison with the diameter of the ascending aorta ﬉, suggesting pulmonary hypertension. (Right) Composite image with axial inspiratory (left) and expiratory (right) HRCT of a 47-year-old woman with rheumatoid arthritis-related constrictive bronchiolitis shows normal attenuation on inspiration but frank airtrapping on expiration.

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Fundamentals of HRCT

Head Cheese Sign KEY FACTS

TERMINOLOGY • Juxtaposition of lobular regions of low, normal, and high attenuation on CT ○ Results in 3 or more different sharply demarcated CT attenuations ○ Transitions between different CT attenuations reflect margins of secondary pulmonary lobules ○ Reminiscent of variegated appearance of head cheese cold cut meat – Indicates mixed infiltrative and obstructive process • Initially considered highly specific if not pathognomonic for cluster 1 (subacute) hypersensitivity pneumonitis

IMAGING • CT ○ Combination of imaging findings – Normal lung – Consolidation – Ground-glass opacity

(Left) Axial NECT of a patient with hypersensitivity pneumonitis demonstrates well-demarcated regions of normal ﬈ and increased ﬉ lung attenuation resulting in the head cheese sign. Note the background of centrilobular ground-glass nodules ﬊. (Right) Axial NECT of a patient with hypersensitivity pneumonitis shows alternating regions of increased ﬉ and decreased ﬊ lung attenuation and consolidation ﬈ with at least 3 different CT attenuations identified.

(Left) Axial expiratory HRCT of a patient with hypersensitivity pneumonitis demonstrates heterogeneous lung attenuation with areas of increased ﬈, decreased ﬊, and normal ﬉ lung attenuation. (Right) Axial expiratory HRCT of the same patient demonstrates 3 distinct CT attenuations including, normal lung attenuation ﬉, air-trapping (decreased attenuation) ﬊, and ground-glass opacity ﬈. Transitions between different lung attenuations reflect the margins of the secondary pulmonary lobules.

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○ Low-attenuation lobules – Obstructive small airways disease – Air-trapping □ Can be confirmed with expiratory CT □ Contributes to mosaic attenuation pattern – Vasoconstriction from localized hypoxia

TOP DIFFERENTIAL DIAGNOSES • Hypersensitivity pneumonitis (cluster 1, subacute) • Sarcoidosis • Atypical infections associated with bronchiolitis (mycoplasma pneumonia, pneumocystis pneumonia) • Respiratory bronchiolitis • Respiratory bronchiolitis interstitial lung disease • Desquamative interstitial pneumonia

DIAGNOSTIC CHECKLIST • Consider hypersensitivity pneumonitis in patients with unexplained dyspnea and head cheese sign on CT

Signet Ring Sign

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Signet ring sign: Characteristic CT morphology of dilated airway and adjacent pulmonary artery (in cross section) ○ Dilated airway represents "ring" ○ Adjacent pulmonary artery represents "stone" • Bronchial dilatation with bronchoarterial ratio > 1 ○ Bronchoarterial ratio = 1.5 may be normal in elderly asymptomatic individuals and at high altitude • Bronchial dilatation is commonly irreversible

• Congenital (primary ciliary dyskinesia, cystic fibrosis, Williams-Campbell syndrome) • Immunodeficiency (common variable immunodeficiency) • Infection (sequela of prior pneumonia, nontuberculous mycobacteria) • Inflammation (allergic bronchopulmonary aspergillosis) • Proximal airway obstruction (lung cancer) • Interstitial lung disease (traction bronchiectasis)

IMAGING

PATHOLOGY

• Radiography ○ Bronchiectasis may be subtle or not visible ○ Tram-tracking: Parallel thickened bronchial walls ○ Air-fluid levels indicate superimposed infection • CT ○ Dilated bronchus (in cross section) > adjacent artery ○ Lack of bronchial tapering ○ Mosaic attenuation and expiratory air-trapping

• Marked inflammation of bronchial wall • Luminal mucopurulent exudate: Neutrophils, macrophages • Bronchial wall destruction, loss of fibromuscular tissue, and erosion/loss of bronchial wall cartilage • ↓ submucosal glands • Squamous metaplasia of bronchial epithelium • Thin bronchial wall appears thick due to peribronchial fibrosis that involves adjacent lung parenchyma

Fundamentals of HRCT

KEY FACTS

(Left) Drawing shows the signet ring sign ﬈ defined as a bronchial diameter larger than the adjacent pulmonary artery (bronchoarterial ratio > 1) when imaged in cross section. (Right) Axial CECT of a 60-year-old patient with COPD and recurrent infections shows left upper lobe bronchiectasis. A dilated bronchus ﬈ and its adjacent pulmonary artery ﬉ demonstrate the so-called signet ring sign. The dilated airway represents the "ring" and the adjacent vessel the "stone." Bronchiectasis implies bronchial wall damage that is typically irreversible.

(Left) Composite image with axial (left) and sagittal (right) CECT of a patient with postinfectious bronchiectasis shows varicose bronchiectasis ﬉, which exhibits the signet ring sign ﬈ when viewed in cross section. (Right) Axial NECT of a 34-year-old man with ulcerative colitis and bronchiectasis shows diffuse cylindrical bronchiectasis that exhibits bronchial wall thickening and the signet ring sign ﬈ when viewed in cross section. Bronchiectasis is the most common pulmonary manifestation of ulcerative colitis.

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Fundamentals of HRCT

Halo Sign KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Definition: Pulmonary ground-glass opacity surrounding nodule, mass, or consolidation

• Infection: Angioinvasive fungi (classically Aspergillus, also Candida, Mucor), mycobacteria, rickettsia, viruses (e.g.,Varicella zoster, Herpes simplex, Cytomegalovirus), and septic embolism • Inflammatory: Granulomatosis with polyangiitis, eosinophilic pneumonia, cryptogenic organizing pneumonia, endometriosis • Neoplastic: Kaposi sarcoma, pulmonary adenocarcinoma with lepidic features, vascular metastases (e.g., angiosarcoma, choriocarcinoma, osteosarcoma) • Iatrogenic: Posttransbronchial biopsy, catheter-induced pulmonary pseudoaneurysm

IMAGING • CT ○ Soft tissue nodule or mass with variable amount of surrounding ground-glass opacity ○ Ground-glass opacity optimally evaluated on thin-section CT • MR ○ T1WI: Peripheral high signal intensity (hemorrhage) • Differentiation from reversed halo sign ○ Reversed halo sign: Crescentic or ring-like consolidation surrounding ground-glass opacity nodule or mass ○ Differential diagnosis: Cryptogenic organizing pneumonia, infection, granulomatosis with polyangiitis, pulmonary infarction, sarcoidosis, radiofrequency ablation

(Left) Axial NECT of a patient with granulomatosis with polyangiitis shows a nodule with surrounding ground-glass opacity ﬇ consistent with perilesional hemorrhage. (Right) Axial NECT of a patient with acute myelogenous leukemia shows mass-like consolidation with surrounding ground-glass opacity st consistent with hemorrhage surrounding angioinvasive aspergillosis. Identification of the CT halo sign in a neutropenic patient with fever should always suggest the possibility of angioinvasive fungal disease.

(Left) Axial NECT of a patient with metastatic choriocarcinoma shows ground-glass opacity st consistent with hemorrhage surrounding multiple nodular pulmonary metastases. (Right) Coronal NECT of a patient with bacterial endocarditis and septic emboli shows ground-glass opacity st surrounding peripheral soft tissue nodules ﬊. While CT halo sign often correlates with hemorrhage (e.g., infarction, vasculitis, frail neovascular tissue, necrosis), it can also be associated with inflammatory or neoplastic infiltration.

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PATHOLOGY • Ground-glass opacity typically represents hemorrhage but may be due to inflammation or neoplasm ○ Hemorrhage may be due to hemorrhagic infarction, vasculitis, fragile neovascular tissue, or necrosis

Reversed Halo Sign

TERMINOLOGY • Central ground-glass opacity surrounded by concentric or crescentic consolidation on CT • Synonym: Atoll sign (atoll: Coral island with central volcano crater)

IMAGING • Radiography ○ Nodule, mass, or consolidation • CT ○ Nodular or mass-like; rounded, ovoid, or slightly lobulated ○ Ring-shaped or crescentic airspace consolidation with ground-glass opacity center

TOP DIFFERENTIAL DIAGNOSES • Organizing pneumonia • Fungal infection: Angioinvasive aspergillosis, zygomycosis (i.e., Mucor and Rhizopus)

• Other infections: Bacterial pneumonia, paracoccidioidomycosis, tuberculosis, sarcoidosis • Radiofrequency ablation, lymphomatoid granulomatosis, granulomatosis with polyangiitis, tumor, infarction • Differentiation from CT halo sign ○ Consolidation with surrounding ground-glass opacity ○ Etiologies: Angioinvasive fungal disease, granulomatosis with polyangiitis, hemorrhagic metastasis

Fundamentals of HRCT

KEY FACTS

PATHOLOGY • Organizing pneumonia ○ Ring-shaped or crescentic peripheral consolidation corresponds to organizing pneumonia ○ Central ground-glass opacity corresponds to alveolar septal inflammation and intraalveolar cellular debris

DIAGNOSTIC CHECKLIST • Visualization of reversed halo sign should suggest diagnosis of organizing pneumonia

(Left) Axial CECT of a patient with bilateral lung transplantation complicated by mucormycosis shows a left upper lobe ground-glass opacity mass with peripheral crescentic consolidation st consistent with the reversed halo or atoll sign. (Right) Axial NECT of a 25-year-old woman with systemic lupus erythematosus and organizing pneumonia shows subpleural consolidations that exhibit the reversed halo sign ﬈. When the peripheral consolidation is crescentic, as opposed to concentric, it is often referred to as the atoll sign.

(Left) Axial CECT of a 43-yearold man with sarcoidosis shows a right upper lobe nodular consolidation that exhibits the reversed halo sign based on the presence of central ground-glass opacity ﬉. (Right) Axial CECT of a 51year-old man with acute pulmonary thromboembolism shows 2 subpleural nodular opacities ﬈ that exhibit the reversed halo sign. The reversed halo sign should be differentiated from the CT halo sign, which is characterized by central consolidation surrounded by ground-glass opacity.

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Fundamentals of HRCT

Finger-in-Glove Sign KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Finger-in-glove sign ○ Also referred to as gloved finger sign ○ Impaction or inspissation of mucus within dilated bronchi ○ Imaging findings resemble fingers within glove ○ Applicable to findings on radiography &/or crosssectional imaging

• Allergic bronchopulmonary aspergillosis ○ Single most common cause of finger-in-glove sign ○ History of asthma or cystic fibrosis ○ Blood eosinophilia, ↑ total serum IgE, precipitins to Aspergillus ○ Mucus may be hyperdense from deposited calcium salts • Bronchial atresia ○ Asymptomatic (most) ○ Surrounding hyperinflation and oligemia on CT ○ Recurrent infection (~ 20%); enlarging nodule/mass • Malignancy ○ Uncommon manifestation of central squamous cell lung cancer; lung cancer must be excluded when finger-inglove sign present ○ Endobronchial metastases: Breast, kidney, colon, rectum, uterus, and skin • Less common: Foreign body, lipoma, hamartoma, carcinoid

IMAGING • Radiography ○ Branching/tubular soft tissue opacities – Converge towards ipsilateral hilum ○ May manifest as nodules or masses – May be round, ovoid, or polylobular • CT ○ Endobronchial soft tissue or fluid mucoid secretions – Hyperdense mucus common in allergic bronchopulmonary aspergillosis ○ May be indistinguishable from endoluminal neoplasm

(Left) PA chest radiograph of a 42-year-old woman with allergic bronchopulmonary aspergillosis shows right lower lobe branching opacities ﬈ that exhibit the finger-in-glove sign. (Right) Composite image with coronal NECT MIP (left) and sagittal MPR (right) reformations of the same patient shows the finger-inglove sign in the right lower lobe. Hyperdense mucus ﬉ is characteristic of allergic bronchopulmonary aspergillosis. The finger-inglove sign may be used to describe both radiographic and CT abnormalities.

(Left) Composite image with PA chest radiograph (left) and axial CECT (right) shows an illdefined nodule ﬈ that manifests as a branching opacity (i.e., mucocele) ﬊ on CT. Note oligemia and airtrapping around the mucocele, a characteristic feature of bronchial atresia. (Right) Composite image of a patient with squamous cell lung cancer with PA chest radiograph (left) and coronal CECT (right) shows right upper lobe tubular branching opacities ﬈ that exhibit the finger-in-glove sign.

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Honeycombing

TERMINOLOGY • Synonym: Pulmonary fibrosis • Term applies to both pathology and CT

IMAGING • Radiography ○ Closely approximated ring shadows ○ Cyst size: 3-10 mm ○ Wall thickness: 1-3 mm • CT ○ Clustered cysts that share their walls ○ Average size: 3-10 mm, but as large as 25 mm ○ Cysts are subpleural and multilayered/stacked

TOP DIFFERENTIAL DIAGNOSES • Interstitial pneumonias ○ Usual interstitial pneumonia and nonspecific interstitial pneumonia ○ Distribution: Lower lobe and subpleural

• Sarcoidosis and cluster 2 hypersensitivity pneumonitis ○ Distribution: Peribronchovascular • Adult respiratory distress syndrome (late stage) ○ Distribution: Anterior and subpleural

PATHOLOGY • Injured, remodeled fibrotic lung characterized by cystic airspaces and loss of normal lung architecture ○ Cysts – Range from few mm to several cm – Variable wall thickness – Lined by metaplastic bronchiolar epithelium

Fundamentals of HRCT

KEY FACTS

DIAGNOSTIC CHECKLIST • Early subpleural honeycombing may be difficult to differentiate from paraseptal emphysema on CT ○ Honeycombing: Stacked layers of subpleural cysts ○ Paraseptal emphysema: Single layer of subpleural cysts

(Left) PA chest radiograph of a patient with usual interstitial pneumonia shows low lung volumes and extensive diffuse coarse reticular opacities that are more conspicuous in the lower lobes. (Right) Axial prone HRCT of a patient with usual interstitial pneumonia shows stacked layers of cysts that share their walls and exhibit a typical lower lobe and subpleural distribution. If not associated with autoimmunity, this pattern is indicative of idiopathic pulmonary fibrosis with such certainty that lung biopsy is not required.

(Left) Axial HRCT of a patient with end-stage sarcoidosis shows extensive honeycombing ﬈ distributed along bronchovascular bundles. This distribution is common in both end-stage sarcoidosis and cluster 2 hypersensitivity pneumonitis. (Right) Low-power photomicrograph (H&E stain) of a specimen with usual interstitial pneumonia shows dense fibrosis ﬈ and honeycomb cysts ﬉, which correlate with the subpleural layered cystic spaces seen on CT.

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Fundamentals of HRCT

Cystic Lung Disease KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Cyst ○ Circumscribed spherical space surrounded by thin (typically < 2 mm) fibrous or epithelial wall ○ Term not applicable to bulla, bleb, pneumatocele, abscess, or cavity • Cystic lung disease ○ Diffuse &/or multifocal pulmonary cysts

• Lymphangioleiomyomatosis: Sporadic or associated with tuberous sclerosis complex; thin-walled spherical cysts • Pulmonary Langerhans cell histiocytosis: Smoking related; upper lung predominant irregular cysts with nodular walls • Lymphoid interstitial pneumonia: Sjögren syndrome; cysts, ground-glass opacities and centrilobular nodules • Birt-Hogg-Dubé syndrome: Autosomal dominant disorder; multiseptate subpleural cysts, facial papules (fibrofolliculomas), and malignant renal neoplasms • Pneumocystis jirovecii pneumonia: Acquired immune deficiency syndrome; ground-glass opacities and upper lung zone cysts • Light-chain deposition disease: Lymphoproliferative or autoimmune disorder with systemic immunoglobulin lightchain deposition; diffuse lung cysts and pulmonary nodules • Cystic metastases: Secondary epithelial, mesenchymal, or hematopoietic malignancy • Honeycomb cysts: Lung fibrosis, layers of subpleural cysts

IMAGING • Radiography ○ Small pulmonary cysts may not be visible ○ Cystic lung disease: Diffuse reticular opacities; rarely thinwalled spherical pulmonary lucencies • CT/HRCT ○ Optimal assessment of size, shape, number, and distribution of pulmonary cysts – Variable size and wall thickness ○ Roughly spherical air-filled spaces

(Left) Axial CECT of a patient with lymphangioleiomyomatosis shows multifocal lung cysts ﬉ of varying sizes with intervening normal lung parenchyma. The cysts are diffusely distributed throughout the lungs, the cyst walls are thin but perceptible, and there are no associated lung nodules. (Right) Axial NECT of a smoker with pulmonary Langerhans cell histiocytosis shows upper lobe predominant small pulmonary nodules and pulmonary cysts ﬈, some with thick nodular walls and bizarre shapes.

(Left) Axial CECT of a patient with lymphoid interstitial pneumonia shows scattered, thin-walled pulmonary cysts ﬊ in the left lung. Lymphoid interstitial pneumonia characteristically occurs in the setting of autoimmune disease, especially Sjögren syndrome. (Right) Axial HRCT of a patient with idiopathic pulmonary fibrosis shows numerous clustered bibasilar honeycomb cysts ﬉, which occur in layers and share walls. Note associated traction bronchiectasis ﬈, consistent with fibrosis.

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Flame-Shaped Nodules

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Lung nodules that emanate from hila and demonstrate flame-shaped configuration on CT • Classic CT manifestation of Kaposi sarcoma ○ AIDS-Kaposi sarcoma (AIDS-KS): Epidemic KS ○ Iatrogenic Kaposi sarcoma

• • • • • •

IMAGING • Pulmonary nodules ○ Ill defined, poorly marginated ○ > 1 cm in diameter ○ Peribronchovascular distribution ○ May exhibit CT halo sign characterized by ground-glass opacity surrounding pulmonary nodule • Pulmonary nodules may coexist with other findings ○ Peribronchovascular and interlobular septal thickening ○ Pleural effusions ○ Lymphadenopathy

Kaposi sarcoma Sarcoidosis Lymphoma Lymphangitic carcinomatosis Bacillary angiomatosis Infectious bronchiolitis

Fundamentals of HRCT

KEY FACTS

CLINICAL ISSUES • Signs and symptoms ○ Dyspnea ○ Cough • Laboratory abnormalities ○ CD4 lymphocyte count (< 150-200 cells/mm³)

DIAGNOSTIC CHECKLIST • Consider Kaposi sarcoma in setting of flame-shaped pulmonary nodules on CT and immunosuppression with depressed CD4 lymphocyte count (< 150-200 cells/mm³)

(Left) Axial NECT of a patient with AIDS and Kaposi sarcoma demonstrates numerous illdefined, peribronchovascular, ground-glass nodular opacities ﬈ in the left lung, some of which are flame-shaped. (Right) Axial CECT of a patient with iatrogenic Kaposi sarcoma shows dense, flameshaped right lower lobe nodular opacities ﬈ that exhibit a peribronchovascular distribution, as well as nodular opacities ﬉ in the medial aspect of the right upper lobe.

(Left) Axial NECT of a patient with AIDS and Kaposi sarcoma demonstrates right lower and right upper lobe large, dense, peribronchovascular nodular opacities ﬈ that are flameshaped in configuration. (Right) Axial NECT of a patient with AIDS and Kaposi sarcoma shows numerous ill-defined, peribronchovascular nodules ﬈ in the right lung, many of which are flame-shaped and demonstrate ground-glass opacity halos. Interlobular septal thickening ﬊ is also present but is less common in patients with Kaposi sarcoma.

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Fundamentals of HRCT

Peribronchovascular KEY FACTS

TERMINOLOGY • Diseases that characteristically compromise peribronchovascular interstitium • Peribronchovascular distribution often coexists with perilymphatic distribution given continuum of peribronchovascular lymphatic channels

IMAGING • CT ○ General – Bronchial wall thickening, nodularity – Peribronchovascular consolidation – Peribronchial lucency ○ Hydrostatic pulmonary edema – Peribronchovascular thickening/consolidation and septal thickening ○ Organizing pneumonia – 1/3 exhibit peribronchovascular consolidations, nodules, or masses (bronchocentric pattern)

(Left) Axial NECT of a patient with cardiogenic pulmonary edema shows peribronchovascular groundglass opacities and consolidations and small bilateral pleural effusions ﬉. The abnormalities are distributed along the bronchovascular bundles ﬈. (Right) Axial NECT of a patient with cardiogenic pulmonary edema shows bilateral peribronchovascular consolidations with subpleural sparing. The process is typically peribronchovascular with eventual involvement of the peripheral interstitium.

(Left) Axial CECT of a patient with AIDS-related Kaposi sarcoma shows predominantly peribronchovascular mass-like consolidations ﬈ and few abnormalities of the peripheral interstitium ﬉. (Right) Low-power photomicrograph (H&E stain) of a specimen of AIDS-related Kaposi sarcoma shows the characteristic perivascular distribution ﬈ of atypical spindle cell proliferations. Kaposi sarcoma extends from the mediastinum along bronchovascular bundles with eventual involvement of the peripheral interstitium.

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○ Kaposi sarcoma – Peribronchovascular thickening and flame-shaped nodules (i.e., ill defined and irregular) ○ Pulmonary interstitial emphysema – Peribronchial or perivascular lucency ○ Interstitial pulmonary arterial hemorrhage – Hyperdensity along central pulmonary arteries on NECT in patients with coexisting acute aortic syndrome

PATHOLOGY • Peribronchovascular infiltration by edema, blood, tumor, granulation tissue, or air • Cryptogenic organizing pneumonia: Intraluminal polypoid granulation tissue (i.e., Masson bodies) • Kaposi sarcoma: Neoplastic spindle cells with interlacing fascicles about peribronchovascular interstitium • Recognition of peribronchovascular pattern requires knowledge of anatomy of secondary lobule lobule

Peribronchovascular

Definitions • Diseases that characteristically compromise peribronchovascular interstitium • Peribronchovascular distribution often coexists with perilymphatic distribution given continuum of peribronchovascular lymphatic channels (e.g., sarcoidosis, lymphangitic carcinomatosis, silicosis, and bronchusassociated lymphoid tissue lymphoma or BALToma) • Predominant peribronchovascular involvement ○ Hydrostatic pulmonary edema ○ Organizing pneumonia ○ Kaposi sarcoma ○ Pulmonary interstitial emphysema ○ Interstitial pulmonary hemorrhage

IMAGING General Features • Best diagnostic clue ○ Bronchial wall thickening &/or nodularity

Radiographic Findings • Central pulmonary opacities • Peribronchial cuffing

CT Findings • General ○ Bronchial wall thickening, nodularity ○ Perivascular thickening (better characterized with IV contrast) ○ Perivascular nodularity ○ Peribronchovascular consolidation ○ Peribronchial/perivascular lucency ○ Perilymphatic findings often coexist: Septal and fissural thickening &/or nodularity • Hydrostatic pulmonary edema ○ Peribronchovascular thickening/consolidation and septal thickening ○ Common ancillary findings: Pleural effusion, cardiomegaly, enlarged hilar/mediastinal lymph nodes • Organizing pneumonia ○ 1/3 exhibit peribronchovascular consolidations, nodules, or masses (often referred to as bronchocentric pattern) ○ Common in polymyositis/dermatomyositis • Kaposi sarcoma ○ Peribronchovascular thickening and flame-shaped nodules (i.e., ill defined and irregular) ○ Common ancillary findings: Septal thickening, pleural effusions, and hilar/mediastinal/axillary lymphadenopathy • Pulmonary interstitial emphysema ○ Peribronchial or perivascular lucency • Interstitial pulmonary arterial hemorrhage ○ Hyperdensity along central pulmonary arteries on NECT in patients with coexisting acute aortic syndrome

DIFFERENTIAL DIAGNOSIS Diseases With Peribronchovascular and Coexistent Perilymphatic Distribution • Sarcoidosis ○ Nodular fissures, septa, and bronchovascular bundles • Lymphangitic carcinomatosis ○ Nodular fissures and interlobular septa • Silicosis ○ Bilateral, symmetric and often calcified centrilobular and subpleural micronodules • Mucosa-associated lymphoid tissue lymphoma (MALToma): May mimic lymphangitic carcinomatosis

Fundamentals of HRCT

TERMINOLOGY

PATHOLOGY General Features • Knowledge of anatomy of secondary lobule critical for identifying characteristic imaging findings on thin-section CT • Secondary pulmonary lobule ○ Smallest unit of lung marginated by connective tissue, contains ~ 8 acini ○ Diameter: 1-2.5 cm ○ Shape: Polyhedral ○ Identifiable grossly and on thin-section CT ○ Centrilobular: Centrilobular interstitium, pulmonary arteries/arterioles, bronchioles, and lymphatics ○ Periphery: Subpleural &/or interlobular interstitium, pulmonary veins/venules, and lymphatics • Peribronchovascular infiltration by edema, blood, tumor, granulation tissue, or air • Cryptogenic organizing pneumonia: Intraluminal polypoid granulation tissue (i.e., Masson bodies) • Kaposi sarcoma: Neoplastic spindle cells with interlacing fascicles about peribronchovascular interstitium

CLINICAL ISSUES Natural History & Prognosis • Hydrostatic pulmonary edema may occur in acute or chronic heart failure • Cryptogenic organizing pneumonia is idiopathic; organizing pneumonia may be associated with connective tissue diseases, drug reactions, interstitial pneumonias, etc. • Kaposi sarcoma rare; typical at-risk population homosexuals with AIDS • Pulmonary interstitial emphysema ○ Common in ventilated neonates, rare in adults ○ May occur in adults with barotrauma (i.e., Macklin effect) • Interstitial pulmonary hemorrhage ○ Common adventitia of ascending aorta and pulmonary trunk ○ Aortic blood extravasation may extend along pulmonary trunk and beyond

SELECTED REFERENCES

Imaging Recommendations

1.

• Best imaging tool ○ Thin-section CT or HRCT

2.

Eguchi T et al: Pneumomediastinum and retropneumoperitoneum due to the Macklin effect. Ann Thorac Surg. 94(1):298, 2012 Castañer E et al: Diseases affecting the peribronchovascular interstitium: CT findings and pathologic correlation. Curr Probl Diagn Radiol. 34(2):63-75, 2005

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Fundamentals of HRCT

Peribronchovascular

(Left) Axial CECT of a patient with AIDS-related Kaposi sarcoma shows multifocal bilateral ill-defined spiculated peribronchovascular nodules that exhibit a characteristic flame-shaped morphology ﬉ and spare the subpleural lung parenchyma. (Right) Axial CECT of a patient with AIDSrelated Kaposi sarcoma shows a right upper lobe heterogeneous mass ﬈ surrounding the right upper lobe pulmonary arteries and bronchi, indicating its peribronchovascular location. Note small right pleural effusion ﬉.

(Left) Axial HRCT of a patient with cryptogenic organizing pneumonia shows multifocal irregular peribronchovascular nodules ﬈ in the left lung. A common imaging pattern of organizing pneumonia is the presence of peribronchovascular nodules, as shown in this case. (Right) AP chest radiograph of a patient with acute inhalational injury shows nonspecific centrally located bilateral ill-defined heterogeneous opacities ﬉. Note relative sparing of the subpleural lung parenchyma.

(Left) Axial NECT of the same patient shows multifocal bilateral peribronchovascular consolations ﬈ that demonstrate relative sparing of the peripheral subpleural lung parenchyma. (Right) Coronal NECT of the same patient shows scattered bilateral peribronchovascular consolidations ﬈ that exhibit relative sparing of the peripheral subpleural lung. The pattern of distribution is directly related to the areas of lung that are primarily and initially affected by inhalational injury.

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Peribronchovascular Fundamentals of HRCT

(Left) Axial NECT of a patient with type A aortic dissection shows a calcified intimomedial defect ﬈ in the descending aorta. Note interstitial hemorrhage manifesting with hyperdense thickening along the pulmonary trunk ﬉ and right pulmonary artery ﬊. (Right) Axial NECT of the same patient shows concentric hemorrhage ﬈ along the left lower lobe pulmonary artery. The findings relate to the common sheath shared by the proximal ascending aorta and pulmonary trunk, which allows involvement of the bronchovascular bundle.

(Left) Axial CECT of a patient with barotrauma from intractable vomiting shows pneumomediastinum with extension of air along the bronchovascular bundle ﬈ and subsequent extension into the peripheral interstitium ﬉. (Right) AP chest radiograph of a newborn with pulmonary interstitial emphysema shows centrally located tubular lucencies ﬈ in the left lung. This abnormality was further evaluated with chest CT to distinguish between a focal cystic lung lesion and pulmonary interstitial emphysema.

(Left) Axial CECT of the same patient shows air ﬈ surrounding segmental pulmonary arteries ﬉ in the left lung. (Right) Coronal CECT of the same patient shows air ﬈ surrounding segmental pulmonary arteries ﬉ in the left lung. Pulmonary interstitial emphysema often results from barotrauma, which frequently allows air to dissect along bronchovascular bundles to the level of the secondary pulmonary lobule. Associated pneumothorax and pneumopericardium can also be present.

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Fundamentals of HRCT

Centrilobular KEY FACTS

TERMINOLOGY • Diseases that distinctively exhibit micronodules at centers of secondary pulmonary lobules • Bronchiolitis (most common) ○ Infectious bronchiolitis ○ Aspiration bronchiolitis ○ Respiratory bronchiolitis ○ Hypersensitivity pneumonitis ○ Follicular bronchiolitis • Vascular ○ Excipient lung disease (talc and cellulose granulomatosis) ○ Tumor embolism • Other: Cholesterol granulomas, pulmonary capillary hemangiomatosis

IMAGING • Centrilobular micronodules ○ Solid micronodules ○ Ground-glass micronodules

(Left) Graphic demonstrates a centrilobular distribution of micronodules ﬊. The micronodules are located at the center of the secondary pulmonary lobule and may involve the bronchus ﬈ or the adjacent pulmonary artery ﬉. Thus, no micronodules are visualized in the peripheral secondary pulmonary lobule, along the fissures, or interlobular septa. (Right) Low-power photomicrograph (H&E stain) of a biopsy specimen from a patient with tumor embolism shows tumor ﬈ expanding centrilobular pulmonary arteries.

(Left) Axial HRCT of a patient with lentil pneumonia shows diffuse pulmonary micronodules that spare the subpleural lung, characteristic of a centrilobular distribution. Note that there is no nodularity along the pleura or interlobar fissures ﬈. (Right) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows bronchiolocentric noncaseating granulomas ﬈ surrounding central leguminous starch granules. Note that the abnormalities are always located along the bronchovascular bundles.

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• Multiplanar reformations allow for better characterization of relationship of nodules to interlobar fissures ○ Absence of nodularity suggests centrilobular disease • Ancillary findings for bronchiolitis: Mosaic attenuation, air-trapping, bronchial wall thickening, bronchiectasis • Ancillary findings for vascular nodules: Dilated pulmonary trunk from pulmonary hypertension, right ventricular strain

TOP DIFFERENTIAL DIAGNOSES • Sarcoidosis • Miliary micronodules

PATHOLOGY • Bronchiolitis: Luminal or submucosal infiltration, bronchiolar narrowing • Excipient lung disease: Birefringent crystals lodged within lumina of centrilobular arterioles • Cholesterol granulomas: Interstitial and alveolar stellate fibrotic lesions with needle-like cholesterol clefts, multinucleated giant cells, and lymphocytes

Centrilobular

Synonyms • Small airways disease = bronchiolitis • Excipient lung disease ○ Cellulose granulomatosis ○ Angiocentric systemic granulomatosis ○ Pulmonary angiothrombotic granulomatosis ○ Pulmonary granulomatous vasculitis ○ Talc embolism

Definitions • Diseases that distinctively exhibit micronodules at centers of secondary pulmonary lobules ○ Bronchiolitis (most common) – Infectious bronchiolitis – Aspiration bronchiolitis – Respiratory bronchiolitis (smoking related) – Hypersensitivity pneumonitis (allergic) – Follicular bronchiolitis (autoimmune disease and chronic immunosuppression) – Panbronchiolitis ○ Vascular – Excipient lung disease (talc and cellulose granulomatosis) – Tumor embolism ○ Other – Cholesterol granulomas (related to pulmonary hypertension) – Pulmonary capillary hemangiomatosis • Micronodule: Discrete round opacity < 3 mm in diameter

IMAGING General Features • Best diagnostic clue ○ Micronodules sparing pleura and interlobar fissures

Radiographic Findings • Normal (common) • Micronodular or reticular opacities

CT Findings • Centrilobular micronodules ○ Solid micronodules – Bronchiolitis □ Infectious bronchiolitis □ Aspiration bronchiolitis □ Follicular bronchiolitis □ Panbronchiolitis – Vascular □ Excipient lung disease (talc and cellulose granulomatosis) □ Tumor emboli ○ Ground-glass micronodules – Bronchiolitis □ Respiratory bronchiolitis □ Hypersensitivity pneumonitis □ Follicular bronchiolitis – Other □ Cholesterol granulomas

Imaging Recommendations

Fundamentals of HRCT

□ Pulmonary capillary hemangiomatosis ○ Ancillary findings for bronchiolitis: Mosaic attenuation, air-trapping, bronchial wall thickening, bronchiectasis, mucus plugging ○ Ancillary findings for vascular nodules: Dilated pulmonary trunk from pulmonary hypertension, right ventricular strain

TERMINOLOGY

• Best imaging tool ○ Thin-section CT or HRCT • Protocol advice ○ Multiplanar reformations allow visualization of relationship of micronodules to interlobar fissures: Absence of nodularity suggests centrilobular disease

DIFFERENTIAL DIAGNOSIS Sarcoidosis • Perilymphatic micronodules (i.e., involve centrilobular, subpleural, and interlobular interstitia)

Miliary Micronodules • Miliary micronodules often occur in infection (e.g., tuberculosis and histoplasmosis) and metastases (e.g., thyroid, renal, and breast cancer) • Miliary nodules are diffusely and evenly distributed in all interstitial compartments

PATHOLOGY General Features • Knowledge of secondary anatomy lobule is critical for understanding imaging findings on thin-section CT/HRCT • Secondary pulmonary nodule ○ Smallest unit of lung marginated by connective tissue, contains ~ 8 acini ○ Diameter: 1.0-2.5 cm ○ Shape: Polyhedral ○ Identifiable on gross specimens and at thin-section CT ○ Center (centrilobular): Centrilobular interstitium, pulmonary arteries/arterioles, bronchioles, and lymphatics ○ Periphery: Subpleural &/or interlobular interstitium, pulmonary veins/venules, and lymphatics • Centrilobular micronodules ○ Bronchiolitis: Luminal or submucosal infiltration, bronchiolar narrowing ○ Excipient lung disease: Birefringent crystals lodged within lumina of centrilobular arterioles ○ Cholesterol granulomas: Interstitial and alveolar stellate fibrotic lesions with needle-like cholesterol clefts, multinucleated giant cells, and lymphocytes ○ Pulmonary capillary hemangiomatosis: Proliferation of capillaries within alveolar walls may produce welldemarcated nodules, often centrilobular, amid intervening normal lung

SELECTED REFERENCES 1. 2.

Griffin CB et al: High-resolution CT: normal anatomy, techniques, and pitfalls. Radiol Clin North Am. 39(6):1073-90, v, 2001 Colby TV et al: Anatomic distribution and histopathologic patterns in diffuse lung disease: correlation with HRCT. J Thorac Imaging. 11(1):1-26, 1996

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Fundamentals of HRCT

Centrilobular

(Left) Axial NECT of a patient with aspiration bronchiolitis after laryngectomy for malignancy shows lower lobedependent centrilobular nodules with areas of coalescence. Note that, overall, the nodules spare the subpleural regions ﬉ and interlobar fissures ﬈. (Right) Coronal HRCT of a patient with respiratory syncytial virus bronchiolitis shows diffuse tree-in-bud nodules ﬈ and upper lobe ground-glass opacities ﬉. Respiratory syncytial virus is one of the most common causes of acute infectious bronchiolitis.

(Left) Composite image with axial CECT (left) and MIP reformation (right) of a patient with respiratory bronchiolitis shows centrilobular ground-glass nodules, more conspicuous on the MIP reformation. The nodules spare the subpleural lung indicating their centrilobular location. (Right) Axial prone HRCT of a patient with hypersensitivity pneumonitis (cluster 1) shows ground-glass centrilobular nodules. In spite of extensive compromise, there is less involvement of the subpleural lung ﬈.

(Left) Axial NECT of a patient with rheumatoid arthritis and follicular bronchiolitis shows scattered centrilobular micronodules. Note relative sparing ﬈ of the subpleural lung parenchyma. (Right) Lowpower photomicrograph (H&E stain) of a biopsy specimen of follicular bronchiolitis shows germinal centers ﬈ surrounding bronchioles ﬊. Note sparing of the pleura ﬉ and adjacent pulmonary parenchyma highlighting the centrilobular nature of the process.

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Centrilobular Fundamentals of HRCT

(Left) Axial CECT of a patient with talc granulomatosis shows diffuse bilateral centrilobular micronodules with a tree-in-bud pattern. Note that these nodules are purely centrilobular and spare the subpleural lung parenchyma ﬈. Note associated enlargement of the pulmonary trunk ﬉. (Right) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows innumerable small nodular lesions ﬈ centered about the bronchovascular bundles. The pleura ﬊ is spared by this process.

(Left) Composite image with axial NECT (left) and axial MIP reformation (right) of a patient with miliary histoplasmosis shows diffuse distribution of pulmonary micronodules with some nodules ﬈ abutting the pleura. This is the so-called random distribution. (Right) Sagittal NECT MIP reformation of the same patient shows even and diffuse distribution of pulmonary micronodules with some nodules abutting the interlobar fissures ﬈, the socalled random distribution of pulmonary micronodules.

(Left) Axial NECT of a patient with sarcoidosis shows multiple clustered micronodules that involve the bronchovascular bundles ﬉ and the interlobar fissures ﬈, which appear thick and nodular, the so-called perilymphatic distribution of micronodules. (Right) Sagittal NECT MIP reformation of the same patient shows multiple clustered micronodules that involve the bronchovascular bundles ﬉ and interlobar fissures ﬈, which appear thick and nodular, the so-called perilymphatic distribution of micronodules.

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Fundamentals of HRCT

Perilymphatic KEY FACTS

• Perilymphatic distribution: Concomitant involvement of peripheral (i.e., subpleural and interlobular) and axial (i.e., peribronchovascular and centrilobular) interstitium

IMAGING • Thick axial interstitium (i.e., peribronchovascular and centrilobular) ○ Peribronchovascular interstitium – Peribronchial (bronchial wall) thickening – Perivascular nodularity: Pipe-cleaner sign (beaded bronchovascular bundles) – Perivascular thickening (CECT) ○ Centrilobular interstitium – Centrilobular micronodules • Thick peripheral interstitium (i.e., subpleural and interlobular) ○ Subpleural: Pleural and fissural – Nodularity

(Left) Graphic demonstrates perilymphatic distribution of micronodules. Pulmonary lymphatics are located along bronchovascular bundles ﬈ (i.e., axial interstitium), interlobular septa ﬊, and subpleural ﬉ regions (i.e., peripheral interstitium). (Right) Axial CECT of a patient with sarcoidosis shows diffuse bilateral perilymphatic micronodules manifesting with nodular ﬈ and smooth ﬉ septal lines, the pipecleaner sign ﬊ (i.e., peribronchovascular thickening and nodularity), and fissural nodularity st.

(Left) Sagittal CECT of the same patient shows profuse perilymphatic micronodules manifesting with fissural nodularity ﬈. Centrilobular nodules typically spare the fissures. Although miliary nodules may exhibit scattered fissural nodules, they are not as profuse as perilymphatic micronodules. (Right) Lowpower photomicrograph (H&E stain) of a biopsy specimen from a patient with sarcoidosis shows small, noncaseating, coalescent granulomas along the interlobular ﬈ and centrilobular ﬊ interstitium.

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– Pleural thickening – Pleural pseudoplaques (from aggregation of micronodules) ○ Interlobular – Nodular (beaded) &/or smooth septal lines (Kerley B lines on radiography)

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES • • • • •

Lymphangitic carcinomatosis Sarcoidosis Pneumoconiosis (silicosis and coal worker's) Amyloidosis (alveoloseptal) Pulmonary edema (interstitial)

PATHOLOGY • Perilymphatic distribution correlates with anatomic distribution of lymphatics within lung parenchyma • Lymphatics run predominantly along axial and peripheral interstitium

Perilymphatic

Definitions • Perilymphatic distribution: Concomitant involvement of peripheral (subpleural and interlobular) and axial (peribronchovascular and centrilobular) interstitium

IMAGING General Features • Best diagnostic clue ○ HRCT: Fissural and septal thickening ± nodularity • Location ○ Upper and middle lung zone predominance – Pneumoconiosis □ Silicosis □ Coal worker's pneumoconiosis – Sarcoidosis ○ Middle and lower lung zone predominance – Lymphangitic carcinomatosis – Amyloidosis (alveoloseptal) – Interstitial pulmonary edema (cardiogenic)

CT Findings • HRCT ○ Thick axial interstitium (peribronchovascular and centrilobular) – Peribronchovascular interstitium □ Peribronchial (bronchial wall) thickening □ Perivascular nodularity: Pipe-cleaner sign (beaded bronchovascular bundles) □ Perivascular thickening (CECT) – Centrilobular interstitium □ Centrilobular micronodules ○ Thick peripheral interstitium (subpleural and interlobular) – Subpleural □ Pleural and fissural nodularity □ Pleural thickening □ Pleural pseudoplaques (aggregates of micronodules) – Interlobular □ Nodular (beaded) &/or smooth septal lines (Kerley B lines on radiography) • Differentiation from centrilobular and miliary micronodules ○ Centrilobular: No micronodules along interlobar fissures or septa ○ Miliary: Evenly and diffusely distributed micronodules consistent with hematogenous dissemination – Few nodules may be located along interlobar fissures

DIFFERENTIAL DIAGNOSIS

• Polygonal arcades: Septal thickening outlining secondary pulmonary lobule • Nodular interlobar fissures • Other findings: Pleural effusion, lymphadenopathy

Sarcoidosis • • • • •

Associated with lymphadenopathy Upper and mid lung zone distribution Nodular interlobular septal thickening Nodular interlobar fissures Peribronchial nodularity

Fundamentals of HRCT

TERMINOLOGY

Pneumoconiosis (Silicosis and Coal Worker's) • Upper and mid lung zone distribution • Centrilobular and subpleural micronodules ○ May calcify ○ May coalesce into mass (progressive massive fibrosis) ○ Coalescent subpleural nodules may manifest as pseudoplaques • Interlobular septal thickening (uncommon)

Amyloidosis (Alveoloseptal) • • • • • •

Mid and lower lung zone distribution, usually subpleural Nodular interlobular septal thickening Bronchovascular thickening Diffuse micronodular opacities (± calcification) Scattered ground-glass opacities Instrinsic calcification

Pulmonary Edema (Interstitial) • Cardiogenic pulmonary edema • Smooth pleural, interlobular septal, and peribronchovascular thickening • Common ancillary findings: Pleural effusion, cardiomegaly • Micronodules are uncommon

PATHOLOGY General Features • Perilymphatic distribution correlates with anatomic distribution of pulmonary lymphatics ○ Lymphatics normally located along – Axial interstitium (peribronchovascular and centrilobular) – Peripheral interstitium (interlobular and subpleural)

DIAGNOSTIC CHECKLIST Image Interpretation Pearls • Differential diagnosis ○ Perilymphatic nodules: Lymphangitic carcinomatosis, sarcoidosis, and pneumoconiosis ○ Smooth interstitial thickening: Interstitial edema, amyloidosis

Lymphangitic Carcinomatosis • Infiltration of lymphatics by tumor emboli or retrograde tumor spread from affected lymph nodes • Commonly associated with adenocarcinoma (e.g., breast, lung, colon, stomach, and prostate) • Mid and lower lung zone predominance • Smooth or nodular interlobular septal thickening

SELECTED REFERENCES 1.

2.

Shroff GS et al: Beyond metastatic disease: a pictorial review of multinodular lung disease with computed tomographic pathologic correlation. Can Assoc Radiol J. 66(1):16-23, 2015 Gruden JF et al: Multinodular disease: anatomic localization at thin-section CT--multireader evaluation of a simple algorithm. Radiology. 210(3):711-20, 1999

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Fundamentals of HRCT

Perilymphatic

(Left) Axial CECT of 60-yearold patient with simple silicosis shows clustered ﬈ subpleural and ﬊ centrilobular micronodules. (Right) Coronal CECT of the same patient shows subpleural ſt and centrilobular ﬊ micronodules. Scant micronodules are also visible along the right oblique fissure ﬈. The distribution of silicotic nodules is typically perilymphatic. This process must be differentiated from other entities with similar findings such as sarcoidosis.

(Left) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows silicotic nodules (central mature collagen and peripheral particle-laden macrophages) in the subpleural interstitium ﬈ and along bronchovascular bundles ﬊. (Right) Axial NECT of a patient with clear cell vaginal adenocarcinoma and lymphangitic carcinomatosis shows extensive smooth thickening of interlobular septa (i.e., interlobular interstitium) ﬈, centrilobular nodules ﬊, and fissural nodules ﬉.

(Left) Axial NECT of the same patient shows extensive smooth and nodular septal lines (i.e., interlobular interstitium) ﬈, polygonal arcades ﬊, centrilobular nodules ﬉, and fissural nodules st. (Right) Low-power photomicrograph (H&E stain) of a transbronchial lung biopsy specimen from a patient with breast cancer and lymphangitic carcinomatosis shows cancer cells forming nodular deposits ﬈ along perivascular ﬉ interstitial lymphatics and cancer cells along interlobular lymphatics ﬊.

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Perilymphatic Fundamentals of HRCT

(Left) Axial HRCT of a patient with diffuse alveoloseptal amyloidosis shows scattered ground-glass opacities with marked interlobular ﬈ and subpleural ﬊ interstitial thickening. Note coalescent micronodules ﬉ involving the axial and peripheral interstitia, reflecting deposition of amyloid in all interstitial compartments. (Right) Axial HRCT (soft tissue window) of the same patient shows middle lobe consolidation with intrinsic punctate calcifications ﬊. Note also small right pleural effusion ﬈.

(Left) Low-power photomicrograph (H&E stain) of a specimen from a patient with alveoloseptal amyloidosis shows amyloid deposits ﬉ along alveolar walls. Also note amyloid deposits along bronchovascular bundles ﬊ and interlobular septa ﬈. Aggregates of amyloid deposits correspond to the nodules seen on imaging. (Right) High-power photomicrograph (Congo red stain) of the same specimen shows intense red staining in amyloid deposits ﬈.

(Left) Axial CECT of a patient with acute interstitial cardiogenic pulmonary edema shows subpleural ﬈ and interlobular ﬉ interstitial thickening and peribronchovascular (bronchial wall) thickening ﬊. (Right) Sagittal CECT of the same patient shows extensive interlobular septal ﬈, subpleural ﬉, and marked bronchial wall thickening ﬊, demonstrating a characteristic perilymphatic distribution. This correlates with engorged lymphatics draining excess fluid related to increased hydrostatic pressure.

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Fundamentals of HRCT

Random KEY FACTS

• Pulmonary nodules that appear randomly distributed in lung on CT; may abut interlobar fissures ○ No specific pattern of involvement with respect to secondary pulmonary lobule and lung architecture

IMAGING

TOP DIFFERENTIAL DIAGNOSES

• Radiography ○ May be normal – Small nodules may not be visible ○ Pulmonary nodules more readily apparent when numerous &/or confluent ○ Difficult to determine distribution of nodules and structures affected • CT ○ Uniform distribution of nodules – Usually bilateral, diffuse, and symmetrical – May be upper or lower lobe predominant

• • • •

(Left) Axial CECT of a 62-yearold man with colorectal cancer shows numerous pulmonary metastases of various sizes ﬈. Hematogenous metastases are typically randomly distributed, in that there is no consistent relationship with anatomic structures such as the pleural surfaces or interstitium. (Right) Axial NECT of a patient with a history of tuberculosis shows innumerable small pulmonary nodules that exhibit a miliary pattern in the right lung, compatible with hematogenous spread of tuberculosis.

(Left) Axial CECT of an immunocompromised patient with acute lymphocytic leukemia demonstrates innumerable small (miliary) nodules in a characteristic random distribution, which resolved after antifungal drug therapy. (Right) Axial NECT of a patient with adenocarcinoma of the lung demonstrates bronchovascular thickening ﬈ and a random distribution of micronodules in the left lung, consistent with lymphangitic carcinomatosis and pulmonary metastases. Note the small left pleural effusion ﬊.

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○ Nodules may be related (but have no consistent relationship) to – Pleural surfaces – Interlobular septa – Small vessels

TERMINOLOGY

Hematogenous metastases Miliary tuberculosis Miliary fungal disease Langerhans cell histiocytosis (occasionally, early nodular stage) • Sarcoidosis (occasionally)

CLINICAL ISSUES • Consider hematogenous metastases and miliary pulmonary infection by tuberculous &/or fungal organisms in setting of uniformly distributed (random) nodules without consistent relationship to secondary pulmonary lobule or lung architecture

Peripheral

– Alveolar sarcoidosis: Mediastinal/hilar lymphadenopathy

TERMINOLOGY • Pulmonary opacities located within 1-2 cm of pleural surfaces • Synonym: Subpleural

IMAGING • Peripheral opacities may be visible on chest radiography • Extent of disease and etiology determined with CT ○ Associated findings may help narrow differential diagnosis – Usual interstitial pneumonia and nonspecific interstitial pneumonia: Peripheral and basilar reticular opacities ± honeycombing, traction bronchiectasis/bronchiolectasis – Chronic eosinophilic pneumonia: May be migratory – Pulmonary infarction: Consolidation with intrinsic lucencies and pulmonary embolism – Pulmonary contusion: Other trauma-related abnormalities (e.g., osseous fractures, pneumothorax)

TOP DIFFERENTIAL DIAGNOSES • • • • • • •

Usual interstitial pneumonia Nonspecific interstitial pneumonia Chronic eosinophilic pneumonia Pulmonary infarction Organizing pneumonia Pulmonary contusion Alveolar sarcoidosis

Fundamentals of HRCT

KEY FACTS

CLINICAL ISSUES • Chronic eosinophilic pneumonia is associated with markedly elevated blood eosinophil count • Organizing pneumonia may be associated with infection, medications, and inflammatory conditions, or may be idiopathic (cryptogenic) • Pulmonary infarction often associated with chest pain

(Left) Axial CECT of a patient with organizing pneumonia demonstrates a peripheral, curvilinear consolidation ﬈ in the left lower lobe. Organizing pneumonia may result from infections, drugs and other therapies, and inflammatory diseases, or may be idiopathic or cryptogenic. (Right) Axial NECT of a patient with eosinophilic pneumonia shows curvilinear consolidation and ground-glass opacities ﬈ in the subpleural right lung. The pulmonary opacities of eosinophilic pneumonia tend to be transient and migratory.

(Left) Axial CECT of a patient who presented with rightsided chest pain demonstrates right lower lobe consolidation ﬈ with intrinsic lucencies. (Right) Axial CECT (soft tissue window) of the same patient shows right lower lobe segmental pulmonary emboli ﬈, which resulted in right lower lobe pulmonary infarction. In the setting of a peripheral, subpleural pulmonary opacity and the clinical presentation of chest pain, the possibility of pulmonary embolism resulting in pulmonary infarction must be entertained.

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SECTION 2

Pathological Patterns of Injury

Approach to Pathological Patterns of Injury Diffuse Alveolar Damage Diffuse Alveolar Hemorrhage With Capillaritis Organizing Pneumonia Constrictive Bronchiolitis

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Pathological Patterns of Injury

Approach to Pathological Patterns of Injury Introduction The art and science of establishing medical diagnoses is much like the process of solving a jigsaw puzzle. Some puzzles have only a few pieces, which are easily assembled to form a coherent solution, while others have numerous, often complex pieces that require an extraordinary effort to solve. The diagnosis of interstitial lung disease is perhaps among the most complex of medical puzzles and routinely requires the integration of clinical history, imaging studies, laboratory findings, and histopathology. Further, these components are not static in time. Rather, the intrinsic nature of the disease, the consequences of therapy, the superimposition of complications, and the contribution of unrelated comorbidities can profoundly influence the interpretation of individual findings. Thus, a multidisciplinary approach is mandatory to achieve optimal patient outcomes. Advances in imaging technology have placed the thoracic radiologist center stage in the diagnosis and evaluation of progression of interstitial lung disease. Their observations are most successfully integrated at institutions that routinely schedule multidisciplinary meetings to discuss all relevant components of the complex medical puzzle and establish the best management path to optimize patients' outcome.

Pathologic Issues An understanding of basic patterns and chronology of lung injury is central to the interpretation of imaging studies. Conceptually, injury patterns may be divided into acute, subacute, and chronic time frames, recognizing that these divisions are arbitrary and may overlap (e.g., acute on chronic disease). Acute patterns generally manifest in hours to several days, subacute patterns develop over weeks to several months, and chronic patterns are seen over months to years. While the pathologist may describe detailed patterns of inflammation and fibrosis of a single biopsy, the radiologist is uniquely tasked with extrapolating the biopsy findings to the entire lung as the findings evolve over time. The quality of the biopsy should also be considered when weighing the contribution of pathologic information. When properly performed, video-assisted thoracoscopic (VAT) biopsies of involved and “uninvolved” lung currently represent the diagnostic gold standard. Often the most “normal” areas of lung provide the earliest and most specific diagnostic insights, while areas of more advanced involvement are fibrous and less specific. At times, VAT biopsies sample only the immediate subpleural lung and show only end-stage disease without other diagnostic features. Image-guided needle biopsies, transbronchial biopsies, and cytology impose progressive constraints on the relevance of pathologic information. Prebiopsy therapeutic intervention can also significantly alter pathologic findings. Cellular infiltrates (e.g., eosinophils and lymphocytes) can be significantly diminished by corticosteroid therapy. Granulomatous inflammation and other acute phase changes can be introduced by methotrexate therapy. In addition, superimposed opportunistic infections may complicate interpretation of underlying disease in patients undergoing immunosuppressive therapy. The lexicon used by pathologists to describe these patterns may not directly translate to a specific disease entity. For example, the clinical entity known as idiopathic pulmonary fibrosis (IPF) is pathologically characterized by the term usual 58

interstitial pneumonia (UIP). However, the UIP pattern may also be seen in fibrotic stages of nonspecific interstitial pneumonia (NSIP), cluster 2 hypersensitivity pneumonitis, and interstitial pneumonias attributed to connective tissue disease [connective tissue disease-associated interstitial lung disease (CTD-ILD)]. Another example is the pathologic diagnosis of diffuse alveolar damage (DAD). This pattern of injury is associated with clinical syndromes of acute respiratory distress syndrome (ARDS), acute interstitial pneumonia (AIP), and acute exacerbation of IPF.

Pathology-Based Imaging Patterns Acute-Phase Patterns The DAD pattern is an acute-phase pathologic pattern associated with clinical syndromes, such as the ARDS, idiopathic AIP, and exacerbation of chronic interstitial lung disease. The DAD pattern when associated with eosinophilia may represent the clinical entity acute eosinophilic pneumonia (EP). DAD results from alveolar endothelial and epithelial damage associated with a variety of infections, acute aspiration, drug toxicities, connective tissue diseases, and oxygen toxicity, among many other insults. Acute fibrinous and organizing pneumonia (AFOP) is a rare acute-phase pattern occurring in clinical settings similar to those in which the DAD pattern occurs. These cases often show sufficient histologic overlap as to consider AFOP a variant of DAD. Histologically, AFOP is characterized by intraalveolar fibrinous exudates with varying degrees of organization. However, hyaline membranes are not formed, and significant tissue eosinophilia should not be seen. A variant of AFOP can occur in the subacute setting and behaves more like organizing pneumonia (OP). As in DAD, AFOP may be idiopathic or associated with autoimmunity, drug reaction/toxicity, and occupational exposure and infection. Diffuse alveolar hemorrhage (DAH) with capillaritis refers to intraalveolar hemorrhage resulting from neutrophilic vasculitis of septal capillaries with alveolar septal necrosis and subsequent intraalveolar hemorrhage. This constellation of disorders should be considered distinct from DAH without capillaritis, which may occur in the setting of traumatic contusion, bleeding diathesis, or surgical biopsy. Besides capillaritis, the presence of intraalveolar hemosiderin-laden macrophages (which are coarsely granular and stain goldenbrown on H&E-stained specimens), typically occurring after 48 hours, is important in the differentiation from bland alveolar hemorrhage. The pattern of DAH with capillaritis occurs in a variety of clinical syndromes, including Goodpasture syndrome, systemic lupus erythematosus, and the polyangiitis syndromes. Subacute-Phase Patterns Eosinophilic pneumonia (EP) is typically a subacute pathologic pattern in which alveolar spaces are distended by eosinophils, fibrin, and histiocytes. The interstitium may be slightly expanded, and eosinophilic vasculitis may be present. The classic radiographic pattern is apical and peripheral air space consolidation with sparing of the central lungs, often referred to as the so-called “photographic negative of pulmonary edema.” EP is often idiopathic but may be attributed to parasitic and fungal infections, drug toxicities, asthma and a variety of collagen vascular diseases. Uncommonly, EP may manifest as an acute phase process that may exhibit clinical features of acute EP or Löffler syndrome

Approach to Pathological Patterns of Injury

Chronic-Phase Patterns Fibrosis is the accumulation of dense collagen in the lung parenchyma resulting in structural remodeling and alveolar loss. Fibrosis is a common clinical observation and numerous patterns of fibrosis are encountered. UIP and NSIP are specific pathologic patterns of fibrosis. The term "temporal heterogeneity" is prototypic of UIP and refers to the coexistence of normal lung adjacent to areas of fibrosis, variable architectural remodeling, and ultimately end-stage honeycombing. Likewise, the term "temporal uniformity" is used to describe NSIP wherein the foci of disease exhibit nearly the same stage of inflammation and fibrosis with relative sparing of the alveoli (i.e., little scar confluence). Clinically, when the UIP and NSIP patterns are associated with autoimmune disorders, they are collectively referred to as CTD-ILD. Fibrosis with pleuritis is also seen in CTD-ILD. Chronic hypersensitivity pneumonitis, chronic aspiration, healed infectious pneumonias, and radiation damage are among the many causes of interstitial fibrosis. However, most cases are idiopathic. Airway-centered fibrosis refers to scarring occurring around bronchioles, often reflecting inhalation damage (e.g., hypersensitivity pneumonitis) or aspiration, although it can also be idiopathic. Fibrosis with isolated stellate scar is typically seen in pulmonary Langerhans cell histiocytosis. These lesions correlate with stellate or irregular pulmonary nodules measuring up to 10 mm, which are characteristic HRCT findings. Desquamative interstitial pneumonia (DIP) represents a subacute or chronic pathologic pattern of reaction characterized by intraalveolar accumulation of histiocytes with mild interstitial inflammation. DIP is most commonly regarded as a smoking-related pulmonary disease. DIP-like reactions can also be seen in cases of obstructive pneumonia, lipoid pneumonia, pulmonary Langerhans cell histiocytosis, and pneumoconiosis (e.g., talcosis, hard metal pneumoconiosis, and asbestosis). Miscellaneous Patterns Like fibrosis, necrosis also exhibits many different histologic patterns. Caseation necrosis is seen with granulomatous inflammation and suggests mycobacterial or fungal infection. Suppurative necrosis is most commonly associated with acute bacterial infection. Coagulation necrosis suggests infarction and may be associated with thromboembolic disease, vasculitis, or occult neoplasm. In the setting of airspace disease, imaging is important to identify necrosis, which may manifest as areas of low attenuation or frank cavitation.

A granulomatous reaction is a type of inflammatory response often reflecting delayed hypersensitivity to various insults. Necrotizing granulomatous reactions should always alert us of the possibility of granulomatous infection (e.g., tuberculosis or nontuberculous mycobacteria), whereas nonnecrotizing reactions may be associated with sarcoidosis, berylliosis, aspiration, and excipient lung disease. Histologically, early granulomas are cellular but may become more fibrotic &/or calcify with age. Bronchocentric granulomatosis (BG) is a rare pathologic pattern of reaction consisting of a destructive granulomatous process involving bronchi and bronchioles and is sometimes associated with mucoid impaction. Although BG may be idiopathic, almost 1/2 of the cases are associated with asthma and allergic bronchopulmonary fungal disease. Other described associations include necrotizing infection (fungal and mycobacterial), autoimmune disease, chronic granulomatous disease, red cell aplasia, lung cancer, etc.

Pathological Patterns of Injury

Organizing pneumonia (OP) is a patchy subacute pathologic pattern in which loose tufts of granulation tissue are found in the lumina of small respiratory bronchioles, alveolar ducts, and alveolar spaces with relative preservation of the underlying pulmonary architecture. Air spaces may also collect some degree of alveolar fibrin and histiocytes. Intervening areas of lung are relatively normal. Idiopathic cases are referred to as cryptogenic organizing pneumonia (COP). Associated disorders include infection, connective tissue diseases, and drug reactions. Despite the American Thoracic Society and European Respiratory Society recommendation to abandon use of the term bronchiolitis obliterans OP, some physicians still use this term to refer to COP.

Constrictive bronchiolitis is a pathologic pattern resulting in stenosis of small airways potentially leading to complete luminal obliteration. Often, the pathologic findings are subtle and may exhibit a patchy distribution. There are varying degrees of submucosal fibrotic thickening, peribronchiolar scarring, muscular hypertrophy, chronic inflammation, bronchiolectasis, mucostasis, and bronchiolar metaplasia. While this pattern may be idiopathic, other etiologies include infection, autoimmunity, and allograft rejection.

Summary Contemporary medicine has ushered in the multidisciplinary approach to patient care. As lung biopsies grow smaller or are supplanted by high-resolution imaging techniques, it has become more critical for the radiologist to help the multidisciplinary team “fill in the blanks." A deeper understanding of the underlying pathology greatly facilitates better patient care and promotes enhanced survival.

Selected References 1. 2.

3.

4.

5. 6. 7. 8.

Hughes KT et al: Pulmonary manifestations of acute lung injury: more than just diffuse alveolar damage. Arch Pathol Lab Med. ePub, 2016 Feinstein MB et al: A comparison of the pathological, clinical and radiographical, features of cryptogenic organising pneumonia, acute fibrinous and organising pneumonia and granulomatous organising pneumonia. J Clin Pathol. 68(6):441-7, 2015 Kligerman SJ et al: From the radiologic pathology archives: organization and fibrosis as a response to lung injury in diffuse alveolar damage, organizing pneumonia, and acute fibrinous and organizing pneumonia. Radiographics. 33(7):1951-75, 2013 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. 188(6):733-48, 2013 Jones KD et al: Histopathologic approach to the surgical lung biopsy in interstitial lung disease. Clin Chest Med. 33(1):27-40, 2012 Beasley MB: The pathologist's approach to acute lung injury. Arch Pathol Lab Med. 134(5):719-27, 2010 Leslie KO: My approach to interstitial lung disease using clinical, radiological and histopathological patterns. J Clin Pathol. 62(5):387-401, 2009 Beasley MB et al: Acute fibrinous and organizing pneumonia: a histological pattern of lung injury and possible variant of diffuse alveolar damage. Arch Pathol Lab Med. 126(9):1064-70, 2002

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Pathological Patterns of Injury

Approach to Pathological Patterns of Injury

(Left) Axial NECT of a patient with acute interstitial pneumonia shows diffuse pulmonary consolidations ﬈ with air bronchograms. (Right) Intermediate-power photomicrograph (H&E stain) of a specimen of diffuse alveolar damage shows intraalveolar edema, acute inflammation, and eosinophilic hyaline membranes ﬈ lining the alveolar walls. Diffuse alveolar damage is the pathologic manifestation of acute lung injury syndromes, such as acute respiratory distress syndrome and acute interstitial pneumonia.

(Left) Axial CECT of a patient with acute fibrinous organizing pneumonia shows multifocal bilateral groundglass opacities ﬈ alternating with areas of normal pulmonary attenuation. (Right) Intermediate-power photomicrograph (H&E stain) of a specimen from the same patient shows air spaces filled with fibrinous exudates ﬈, lymphocytes, histiocytes, and reactive pneumocytes. The absence of hyaline membranes distinguishes this pattern from diffuse alveolar damage.

(Left) Axial HRCT of a patient with Crohn disease and organizing pneumonia shows upper lobe ground-glass opacities, one of which exhibits the atoll sign ﬈ (central ground-glass opacity and peripheral consolidation), a nonspecific, but characteristic, finding. (Right) Low-power photomicrograph (H&E stain) of a specimen of cryptogenic organizing pneumonia shows intraalveolar plugs of loose connective tissue ﬊ associated with interstitial lymphocytic and plasma cell infiltration ﬈.

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Approach to Pathological Patterns of Injury Pathological Patterns of Injury

(Left) Axial HRCT of a patient with idiopathic interstitial fibrosis shows a usual interstitial pneumonia pattern with subpleural, lower lobepredominant marked honeycombing ﬈ and traction bronchiectasis. (Right) Lowpower photomicrograph (H&E stain) of a specimen from the same patient shows extensive honeycombing. Usual interstitial pneumonia is characterized histologically by temporal heterogeneity where extensively remodeled lung resides adjacent to relatively normal lung (not shown).

(Left) Axial CECT of a patient with chronic eosinophilic pneumonia shows bilateral peripheral consolidations ﬈ with relative sparing of the central lungs. Both acute and chronic eosinophilic pneumonia may be idiopathic or associated with toxic inhalation, drug reaction, and fungal/parasitic infections. (Right) High-power photomicrograph (H&E stain) of a specimen from the same patient shows alveolar spaces distended with histiocytes ﬉ and eosinophils ﬈, characteristic of eosinophilic pneumonia.

(Left) Composite image with axial NECT of a patient with idiopathic bronchocentric granulomatosis shows clustered right upper lobe centrilobular nodules ﬈, which did not resolve on follow-up imaging. (Right) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows bronchioles surrounded by intense lymphohistiocytic inflammation ſt and necrotic debris filling the bronchiolar lumen ﬇.

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Pathological Patterns of Injury

Diffuse Alveolar Damage KEY FACTS

TERMINOLOGY • Diffuse alveolar damage (DAD) • Acute lung injury (ALI) • Adult respiratory syndrome (ARDS): Acute inflammatory lung injury leading to increased vascular permeability with resultant hypoxemia and bilateral opacities on imaging ○ Acute onset, within 7 days of defined event ○ Partial pressure of arterial oxygen:fraction of inspired oxygen ratio (PaO₂:FiO₂) ≤ 200 mm Hg ○ Bilateral opacities on chest radiography or CT

IMAGING • Radiography ○ Exudative (acute) phase (1-7 days) – Bilateral heterogenous opacities, often symmetrical ○ Proliferative (organizing) phase (8-14 days) – Coarse reticular opacities ○ Fibrotic (late) phase (> 15 days) – Resolving heterogenous or coarse reticular opacities

(Left) AP chest radiograph of a patient with acute respiratory distress syndrome in the exudative phase shows diffuse bilateral heterogeneous opacities. The presence of bilateral heterogeneous opacities, often symmetrical, is the most frequent radiologic abnormality in patients with the exudative phase of acute respiratory distress syndrome. (Right) Gross photograph of the cut surface of the lung of a patient with diffuse alveolar damage shows beefy, red, congested, and edematous lung parenchyma. (From DP: Thoracic, 2e.)

(Left) Axial CECT of a patient with acute respiratory distress syndrome, exudative phase, shows diffuse bilateral ground-glass opacities. The clinical history is critical for differentiating ARDS from cardiogenic pulmonary edema, diffuse alveolar hemorrhage, and diffuse pulmonary infection. (Right) High-power photomicrograph (H&E stain) shows diffuse alveolar damage characterized by hyaline membranes ﬉ lining the airspaces and thick alveolar septa ﬊ containing an inflammatory exudate. (From DP: Thoracic, 2e.)

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• CT ○ Early phase – Bilateral airspace or ground-glass opacities ○ Late phase – Coarse reticular opacities – Ground-glass or reticular opacities

TOP DIFFERENTIAL DIAGNOSES • Cardiogenic pulmonary edema • Pneumonia • Alveolar hemorrhage

CLINICAL ISSUES • Dyspnea, cyanosis • Hypoxemia, acute respiratory alkalosis, and ↑ alveoloarterial oxygen gradient

DIAGNOSTIC CHECKLIST • DAD may mimic cardiogenic edema, alveolar hemorrhage, and pneumonia and may coexist with these entities

Diffuse Alveolar Damage • Complications: Pneumonia, abscess, pneumothorax, pneumomediastinum, pulmonary interstitial emphysema

Abbreviations • Diffuse alveolar damage (DAD)

DIFFERENTIAL DIAGNOSIS

Definitions

Cardiogenic Pulmonary Edema

• Acute respiratory syndrome (ARDS) ○ Acute diffuse, inflammatory lung injury leading to increased pulmonary vascular permeability with resultant hypoxemia and bilateral opacities on imaging ○ Criteria – Acute onset, within 7 days of defined event (e.g., sepsis, pneumonia, etc.) – Partial pressure of arterial oxygen:fraction of inspired oxygen ratio (PaO₂:FiO₂) ≤ 200 mm Hg – Bilateral pulmonary opacities on radiography or CT – Abnormalities not fully explained by cardiac failure or fluid overload based on clinical parameters ○ Grading – Mild: 200 mm Hg < PaO₂/FiO₂ ≤ 300 mm Hg; formerly acute lung injury (ALI) – Moderate: 100 mm Hg < PaO₂/FiO₂ ≤ 200 mm Hg – Severe: PaO₂/FiO₂ ≤ 100 mm Hg • DAD is histologic manifestation of ALI/ARDS • Acute interstitial pneumonia: Idiopathic DAD • Transfusion-related ALI is ALI/ARDS occurring during or within 6 hours after blood products administration

• Cardiomegaly, septal lines, and effusion

IMAGING Radiographic Findings • Exudative (acute) phase (1-7 days) ○ May be normal ○ Bilateral heterogenous opacities, often symmetrical ○ Absence of temporal change, cardiomegaly, or septal lines, but ARDS and cardiogenic edema may coexist • Proliferative (organizing) phase (8-14 days) ○ Coarse reticular opacities ○ New heterogenous opacities should suggest superimposed infection • Fibrotic (late) phase (> 15 days) ○ Resolving heterogeneous and coarse reticular opacities

CT Findings • Early phase ○ Bilateral ground-glass opacities &/or consolidations – Anterior-posterior gradient – Dense opacities in nondependent regions should prompt exclusion of superimposed infection ○ Bronchial dilatation within areas of ground-glass opacities; may be related to traction bronchiectasis or may be reversible ○ Pleural effusions (common) • Late phase ○ Coarse reticular opacities ○ Ground-glass and reticular opacities – Diffuse (most) – Nondependent lucencies (honeycombing/bullae) postulated to relate to fibrosis, as these areas are less protected from barotrauma than consolidated lung ○ Traction bronchiectasis

Pneumonia • Symmetrical opacities are more common in ARDS

Alveolar Hemorrhage • Hemoptysis &/or ↓ hemoglobin/hematocrit

Pathological Patterns of Injury

TERMINOLOGY

PATHOLOGY Gross Pathologic & Surgical Features • Congestion and edema in early phases • Rubbery consistency in late phases

Microscopic Features • Exudative (acute) phase ○ Capillary congestion, edema, and intraalveolar damage ○ Hyaline membranes ○ Exudation of proteins and fluid into interstitium ○ Interstitial inflammatory exudates ○ Microvascular thromboemboli • Proliferative (organizing) phase ○ Organization with proliferation of type II pneumocytes and fibroblasts ○ Pneumocytes may exhibit large nucleoli and atypia ○ Fibroblast organization mimics organizing pneumonia ○ Peripheral lung infarcts from vascular thromboemboli • Fibrotic (late) phase ○ Interstitial fibrosis with thickened alveolar septa ○ Squamous metaplasia of terminal bronchiolar epithelium ○ May progress to honeycombing

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Dyspnea, cyanosis ○ Hypoxemia, acute respiratory alkalosis, and ↑ alveoloarterial oxygen gradient

DIAGNOSTIC CHECKLIST Image Interpretation Pearls • DAD may be difficult to differentiate from and may coexist with cardiogenic edema, alveolar hemorrhage, &/or pneumonia

SELECTED REFERENCES 1. 2. 3.

ARDS Definition Task Force et al: Acute respiratory distress syndrome: the Berlin Definition. JAMA. 307(23):2526-33, 2012 Sheard S et al: Imaging of acute respiratory distress syndrome. Respir Care. 57(4):607-12, 2012 Beasley MB: The pathologist's approach to acute lung injury. Arch Pathol Lab Med. 134(5):719-27, 2010

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Pathological Patterns of Injury

Diffuse Alveolar Damage

(Left) High-power photomicrograph (H&E stain) of a specimen of diffuse alveolar damage shows hyaline membranes ﬈ manifesting as thick bands of dense, eosinophilic material covering the surfaces of the alveolar walls. (From DP: Thoracic, 2e.) (Right) AP chest radiograph of a patient with transfusion-related acute lung injury shows diffuse bilateral heterogeneous opacities. This represents acute lung injury acute respiratory distress syndrome occurring during or within 6 hours after blood products administration.

(Left) Axial NECT of a patient with acute respiratory distress syndrome shows extensive ground-glass opacities and superimposed septal thickening. (Right) Coronal NECT of the same patient shows extensive bilateral ground-glass opacities with superimposed interlobular septal thickening. This CT appearance is often referred to as the crazy-paving pattern. The abnormalities are diffuse and involve all pulmonary lobes. Affected patients often require endotracheal intubation ﬈ and mechanical ventilation.

(Left) AP chest radiograph of a patient with acute respiratory distress syndrome that evolved through exudative and proliferative phases shows diffuse bilateral heterogeneous opacities that developed within a few days. (Right) AP chest radiograph of the same patient obtained 10 days later and after extubation shows evolution of the pulmonary abnormalities to diffuse reticular opacities. The latter often correlate with the organization phase of the disease characterized by type II pneumocyte and fibroblast proliferation.

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Diffuse Alveolar Damage Pathological Patterns of Injury

(Left) Axial CECT of the same patient shows diffuse bilateral ground-glass and reticular opacities amid areas of recovering normal-appearing lung. These opacities are more commonly seen in the proliferative phase of diffuse alveolar damage. (Right) Axial CECT of the same patient shows diffuse bilateral ground-glass and reticular opacities. These opacities may progressively resolve or evolve into areas of fibrosis often with honeycombing. The histologic appearance is reminiscent of organizing pneumonia.

(Left) High-power photomicrograph (H&E stain) shows the proliferative (organizing) phase of diffuse alveolar damage with type II pneumocyte and fibroblast proliferation. (From DP: Thoracic, 2e.) (Right) Axial CECT of a patient with the fibrotic phase of the acute respiratory distress syndrome shows subpleural honeycombing ﬈ and scattered consolidations ﬉. Honeycombing often affects the anterior subpleural lung and is thought to relate to oxygen toxicity affecting these areas during the acute phase.

(Left) Axial CECT of the same patient shows subpleural honeycombing with associated traction bronchiectasis ﬉ and bronchiolectasis ﬈ and scattered pulmonary consolidations ﬊. (Right) High-power photomicrograph (H&E stain) shows the chronic phase of diffuse alveolar damage characterized by dense interstitial fibrosis. There is thickening of alveolar septa by dense collagenous fibrosis ﬉ with minimal inflammatory infiltrates and complete resolution of the hyaline membranes. (From DP: Thoracic, 2e.)

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Pathological Patterns of Injury

Diffuse Alveolar Hemorrhage With Capillaritis KEY FACTS

TERMINOLOGY

PATHOLOGY

• Diffuse alveolar hemorrhage (DAH) • Acute lung reaction characterized by alveolar hemorrhage ○ Most frequently autoimmune; may be idiopathic or due to infection or drug reaction

• Intraalveolar red blood cells • Hemosiderin-laden macrophages with coarse hemosiderin granules • Capillaritis ○ Neutrophilic infiltration of alveolar septa ○ Alveolar capillaries may exhibit endothelial swelling, thrombosis, and fibrinoid necrosis ○ Dumbbell-shaped fibrin clots projecting from capillary wall into alveolar space

IMAGING • Radiography ○ Patchy or diffuse opacities; resolve in 10-14 days • CT ○ Patchy or diffuse airspace or ground-glass opacities ○ Crazy-paving pattern (often subacute stage) ○ Honeycombing and traction bronchiectasis with recurrent episodes (i.e., hemosiderosis)

TOP DIFFERENTIAL DIAGNOSES • Pulmonary edema, noncardiogenic • Pulmonary edema, cardiogenic • Pulmonary infection

(Left) AP chest radiograph of a 65-year-old woman with idiopathic alveolar hemorrhage and capillaritis shows asymmetric, diffuse, bilateral heterogeneous airspace disease and consolidations. (Right) Axial CECT of the same patient shows multifocal airspace disease and ground-glass opacities bilaterally. The imaging findings of diffuse alveolar hemorrhage are often nonspecific and may be indistinguishable from those of pulmonary edema and multifocal pneumonia.

(Left) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows blood-filled alveolar spaces ﬈ with relatively scant inflammatory infiltration. (Right) Highpower photomicrograph (H&E stain) of the same specimen shows blood-filled alveolar spaces, acute inflammation, and capillaritis. The latter is characterized by abundant neutrophilic infiltration ﬈. Coexistent endothelial swelling, thrombosis, and fibrinoid necrosis is often encountered.

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CLINICAL ISSUES • Symptoms ○ Hemoptysis, dyspnea, anemia • Treatment ○ Autoimmune disease: Glucocorticoids ± additional immunosuppressive therapy (e.g., cyclophosphamide, rituximab) • Variable prognosis depending on underlying cause

Diffuse Alveolar Hemorrhage With Capillaritis

Abbreviations • Diffuse alveolar hemorrhage (DAH)

Definitions • Histologic pattern of acute lung reaction characterized by intraalveolar hemorrhage ○ Most frequently autoimmune; may be idiopathic or due to infection or drug reaction

IMAGING General Features • Best diagnostic clue ○ Diffuse airspace opacities on chest radiography or CT

Radiographic Findings • • • •

Patchy or diffuse airspace opacities Focal consolidation (uncommon) Resolution of airspace disease in 10-14 days Reticular opacities with recurrent episodes (i.e., hemosiderosis)

CT Findings • • • •

Patchy or diffuse airspace or ground-glass opacities Ill-defined centrilobular nodules Crazy-paving pattern (subacute stage) Honeycombing and traction bronchiectasis with recurrent episodes (i.e., hemosiderosis)

Imaging Recommendations • Protocol advice ○ Thin-section CT or HRCT

DIFFERENTIAL DIAGNOSIS Pulmonary Edema, Noncardiogenic • Hemoptysis not prominent feature • Ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2:FIO2) ≤ 200 mm Hg • Clinical profile not explained by cardiac failure or fluid overload

Pulmonary Edema, Cardiogenic • Associated with cardiovascular disease (e.g., acute myocardial infarction, chronic heart failure)

Pneumonia • Typically focal • Often due to atypical microorganisms (e.g., Mycoplasma pneumoniae, Pneumocystis jirovecii) • Infectious symptoms and absence of hemoptysis &/or decreasing hematocrit

PATHOLOGY General Features • Etiology ○ Idiopathic ○ Autoimmune disease (common) – Polyangiitis with granulomatosis – Microscopic polyangiitis – Systemic lupus erythematosus

Pathological Patterns of Injury

– Goodpasture syndrome – Other: Primary antiphospholipid antibody syndrome, mixed cryoglobulinemia, Behçet syndrome, HenochSchönlein purpura ○ Drug reaction – Propylthiouracil – Diphenylhydantoin – Retinoic acid – Hydralazine ○ Infection – Human immunodeficiency virus (HIV) – Listeria – Leptospirosis

TERMINOLOGY

Gross Pathologic & Surgical Features • Cut lung surface appears red or purple • Spongy lung consistency with acute hemorrhage • Firm &/or fibrotic with chronic/recurrent hemorrhage

Microscopic Features • Intraalveolar red blood cells • Hemosiderin-laden macrophages with coarse hemosiderin granules • Capillaritis ○ Neutrophilic infiltration of alveolar septa ○ Alveolar capillaries may exhibit endothelial swelling, thrombosis, and fibrinoid necrosis ○ Dumbbell-shaped fibrin clots project from capillary walls into alveolar spaces

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Hemoptysis – May be absent in 30% of affected patients ○ Dyspnea ○ Anemia ○ Hypoxemic respiratory failure

Natural History & Prognosis • Repeated episodes may result in interstitial fibrosis • Variable prognosis depending on underlying cause ○ High early mortality (i.e., 25-50%) in systemic lupus erythematosus, vasculitis, Goodpasture syndrome, and idiopathic pulmonary hemosiderosis • Post-DAH syndrome ○ Recurrent DAH due to microscopic polyangiitis ○ Progressive obstructive lung disease and emphysema

Treatment • Autoimmune disease: Glucocorticoids ± additional immunosuppressive therapy (e.g., cyclophosphamide, rituximab) ○ Goodpasture syndrome: Plasmapheresis • Cessation of implicated drug

SELECTED REFERENCES 1. 2.

Hughes KT et al: Pulmonary manifestations of acute lung injury: more than just diffuse alveolar damage. Arch Pathol Lab Med. ePub, 2016 Castañer E et al: Imaging findings in pulmonary vasculitis. Semin Ultrasound CT MR. 33(6):567-79, 2012

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Pathological Patterns of Injury

Diffuse Alveolar Hemorrhage With Capillaritis

(Left) AP chest radiograph of a 75-year-old man with microscopic polyangiitis and diffuse alveolar hemorrhage shows bilateral heterogenous airspace disease mostly affecting the right lung. (Right) Axial NECT of the same patient shows bilateral airspace and ground-glass opacities representing intraalveolar blood. Microscopic polyangiitis is a necrotizing vasculitis that involves small vessels, is commonly associated with necrotizing glomerulonephritis, and involves the lung in 50% of cases.

(Left) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows multifocal areas of intra-alveolar hemorrhage ﬈. (Right) High-power photomicrograph (H&E stain) of the same specimen shows abundant hemosiderin-laden macrophages with coarse hemosiderin granules ﬈ and interstitial thickening ﬉. Approximately 70% of patients with microscopic polyangiitis exhibit myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) positivity.

(Left) AP chest radiograph of a patient with Goodpasture syndrome and diffuse alveolar hemorrhage shows diffuse, bilateral, ill-defined asymmetric opacities. (Right) Axial NECT of the same patient shows bilateral ground-glass opacities. Goodpasture syndrome is characterized by antiglomerular basement membrane antibodies, resulting glomerulonephritis, and diffuse alveolar hemorrhage. While acute renal failure is common, pulmonary involvement occurs in 40-60% of cases.

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Diffuse Alveolar Hemorrhage With Capillaritis Pathological Patterns of Injury

(Left) AP chest radiograph of a patient with systemic lupus erythematosus and diffuse alveolar hemorrhage shows illdefined, bilateral airspace opacities. (Right) Axial HRCT of the same patient shows diffuse, bilateral ground-glass opacities. As with other causes of diffuse alveolar hemorrhage, an acute decrease in hematocrit may help differentiate alveolar hemorrhage from other entities with similar findings such as pulmonary edema or pneumonia. Bronchoscopy with bronchoalveolar lavage often confirms the diagnosis.

(Left) AP chest radiograph of a patient with granulomatosis with polyangiitis and diffuse alveolar hemorrhage shows bilateral upper lung zone predominant heterogeneous airspace disease. (Right) Axial HRCT of the same patient shows diffuse, bilateral ground-glass opacities affecting the central lung parenchyma. Imaging manifestations of granulomatosis with polyangiitis also include pulmonary nodules and masses that may be cavitary (70%) and focal or multifocal consolidations.

(Left) Axial HRCT of a patient with Goodpasture syndrome and diffuse alveolar hemorrhage shows diffuse, bilateral ground-glass opacities with superimposed thick interlobular septa, the so-called crazy-paving pattern, which often correlates with the subacute stage of diffuse alveolar hemorrhage. (Right) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows intraalveolar red blood cells and interstitial thickening ﬈ secondary to interstitial fibrosis and type 2 pneumocyte hyperplasia.

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Pathological Patterns of Injury

Organizing Pneumonia KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Organizing pneumonia (OP) • Cryptogenic organizing pneumonia (COP): Idiopathic OP • Acute fibrinous and organizing pneumonia (AFOP): Similar to diffuse alveolar damage • Granulomatous organizing pneumonia (GOP) • OP, AFOP, and GOP: Histologic patterns of lung reaction

• • • •

IMAGING • Radiography ○ OP: Nonspecific multifocal bilateral opacities • CT ○ OP: Bilateral peripheral or peribronchial consolidations – Reversed halo (or atoll) sign – Migratory pulmonary opacities ○ AFOP: Nodule/mass ± air bronchograms – Multifocal ground-glass opacities or consolidations ○ GOP: Not well described; may mimic malignancy – Nodules, masses (common), consolidations

(Left) Axial HRCT of a patient with Crohn disease and organizing pneumonia shows upper lobe ground-glass opacities and the reversed halo sign ﬈ (central groundglass opacity and peripheral consolidation) in the right upper lobe, a nonspecific but characteristic finding of organizing pneumonia. (Right) Coronal HRCT of the same patient shows bilateral upper lobe ground-glass opacities and the reversed halo sign ﬈ in the right upper lobe. Organizing pneumonia may be associated with a variety of disease processes.

(Left) High-power photomicrograph (H&E stain) of a specimen of organizing pneumonia shows areas of young fibrous plugs (Masson bodies) ﬈ in alveolar spaces that correlate with airspace disease on imaging. (Right) Low-power photomicrograph (H&E stain) of a specimen of organizing pneumonia shows polypoid young fibrous tissue ﬉ inside an airway lumen. Such Masson bodies are typically seen within alveolar ducts and alveoli but may also occur within bronchiolar lumina. (From DP: Thoracic 2e.)

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Pneumonia Chronic eosinophilic pneumonia Pulmonary lymphoma Lung cancer

PATHOLOGY • OP: Polypoid intraluminal plugs of loose organizing connective tissue in distal airways

CLINICAL ISSUES • Signs and symptoms: Cough, dyspnea, fever, malaise, weight loss • Treatment: Glucocorticoids are 1st-line drugs ○ 2nd-line drugs: Cyclophosphamide, rituximab, azathioprine

DIAGNOSTIC CHECKLIST • Consider OP in patients with peribronchovascular or perilobular opacities ± reversed halo sign on CT/HRCT

Organizing Pneumonia

Abbreviations • • • •

Organizing pneumonia (OP) Cryptogenic organizing pneumonia (COP) Acute fibrinous and organizing pneumonia (AFOP) Granulomatous organizing pneumonia (GOP)

Synonyms • Bronchiolitis obliterans organizing pneumonia formerly synonym for COP, but term no longer used

Definitions • OP, AFOP, and GOP: Related histologic patterns of lung reaction resulting from variety of insults ○ AFOP considered acute pattern similar to diffuse alveolar damage (DAD) – Subacute cases of AFOP may behave clinically like OP • COP: Idiopathic OP ○ Nonspecific pulmonary reaction of unknown etiology

IMAGING General Features • Best diagnostic clue ○ OP – Multifocal ground-glass opacities and consolidations ○ AFOP – Diffuse bilateral ground-glass opacities and consolidations • Location ○ OP – Peribronchovascular distribution

Radiographic Findings • OP ○ Nonspecific multifocal bilateral pulmonary opacities ○ Migratory opacities on serial chest radiography • AFOP ○ Bilateral pulmonary consolidations ○ Similar to DAD

CT Findings • HRCT ○ OP – Diffuse □ Scattered bilateral peripheral or peribronchial consolidations □ Ill-defined curvilinear or polygonal (perilobular) opacities located around secondary pulmonary lobule □ Reversed halo sign (or atoll sign if rim of peripheral consolidation incomplete) □ Peribronchovascular nodules; may exhibit airbronchograms □ Diffuse micronodules or tree-in-bud opacities (uncommon) – Unilateral □ Solitary nodule, mass, consolidation □ Ground-glass opacity (uncommon) – Migratory opacities – Opacities resolve with corticosteroid therapy

– May progress to pulmonary fibrosis [similar to nonspecific interstitial pneumonia (NSIP)] □ While controversial, it is postulated that some cases of NSIP may be sequela of OP □ Peribronchovascular ground-glass opacities, reticulation and traction bronchiectasis □ Occasional subpleural sparing – Cavitation (rare) ○ AFOP – Imaging findings not well described □ Likely similar to those of pneumonia – Nodule/mass ± air bronchograms – Multifocal ground-glass opacities or consolidations ○ GOP – Imaging findings not well described □ Likely similar to those of malignancy – Nodules and masses (common) – Consolidations

Pathological Patterns of Injury

TERMINOLOGY

Nuclear Medicine Findings • PET/CT ○ OP typically exhibits FDG avidity

Imaging Recommendations • Best imaging tool ○ Thin-section CT or HRCT

DIFFERENTIAL DIAGNOSIS Pneumonia • Acute presentation; may be multifocal • Lack of response to antibiotics should suggest OP

Chronic Eosinophilic Pneumonia • Similar to OP on imaging • Chronic eosinophilic pneumonia may transition to OP • Peripheral &/or tissue eosinophilia

Pulmonary Lymphoma • Diagnosis relies on histologic and immunohistochemical features

Lung Cancer • OP manifesting as solitary pulmonary nodule or mass may be indistinguishable from lung cancer on CT and PET/CT • As in OP, diagnosis may have to be established after resection

PATHOLOGY General Features • Etiology ○ OP may be idiopathic or associated with – Autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, granulomatosis with polyangiitis, etc) – Drugs □ Amiodarone, chemotherapy □ Recreational: Cocaine – Infections □ Bacteria (e.g., Mycoplasma, nontuberculous mycobacteria) □ Viruses [e.g., human immunodeficiency virus (HIV)] 71

Pathological Patterns of Injury

Organizing Pneumonia □ Fungi (e.g., Pneumocystis jirovecii) □ Parasites (e.g., Plasmodium vivax) – Pulmonary disease □ Hypersensitivity pneumonitis, airway obstruction, alveolar hemorrhage, abscess, infarction, neoplasm, aspiration – Radiation ○ AFOP may be idiopathic or associated with – Autoimmune disease – Drugs – Occupational or environmental exposures – Infection • Presence of OP has variable clinical implications ○ May manifest with clinical symptoms and signs ○ Little significance if found surrounding granulomatous processes or malignancy; may be minor component of hypersensitivity pneumonitis, eosinophilic pneumonia, and Langerhans cell histiocytosis

– Subacute and subclinical varieties require no mechanical ventilation; frequent eventual recovery • Clinical profile ○ Pulmonary function tests – OP □ Mild to moderate restrictive pattern (common) □ Obstructive pattern in 20% □ Reduced diffusing capacity for carbon monoxide □ Resting &/or exercise arterial hypoxemia ○ Bronchoalveolar lavage – OP: Nonspecific findings; may help exclude hemorrhage, malignancy and infection ○ Elevated erythrocyte sedimentation rate and C-reactive protein

Gross Pathologic & Surgical Features

Natural HIstory and Prognosis

• Nonspecific macroscopic features • GOP more likely to manifest with nodules or masses

• OP ○ Overall good response to treatment over weeks to months in 2/3 of affected patients ○ Airspace opacities tend to respond better than reticular opacities ○ Patients with clinical response may continue to exhibit slowly resolving parenchymal abnormalities ○ Some cases progress to fibrosis ○ Patients who are unresponsive to treatment frequently exhibit fibrosis on imaging ○ COP type 1 (without fibrin): Better response to therapy ○ COP type 2 (containing fibrin): Poor response to therapy • AFOP ○ Severe AFOP carries poor prognosis similar to that of DAD ○ Subacute AFOP carries better prognosis; affected patients often recover

Microscopic Features • OP ○ Polypoid intraluminal plugs of loose organizing connective tissue (Masson bodies) in distal airways (mainly alveolar ducts and alveoli); bronchioles frequently involved but may be spared – Plugs of spindle-shaped cells in pale-staining matrix with variable morphology – Masson bodies with loose cellularity and myxoid appearance (often described as COP type 1) – Masson bodies containing fibrin (often described as COP type 2) ○ Patchy distribution ○ Preservation of underlying lung architecture ○ Mild interstitial chronic inflammation • AFOP ○ Organizing fibrin deposition within alveolar spaces, interstitial thickening, lymphoplasmacytic infiltrate ○ Type II pneumocyte hyperplasia is seen in all cases, commonly diffusely distributed ○ Organizing fibroblastic tissue may be present but is not dominant finding ○ Absence of hyaline membranes typical of DAD • GOP ○ OP + intrinsic multiple nonnecrotizing poorly formed granulomas

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ OP – Chronic nonproductive cough – Dyspnea – Fever – Malaise, weight loss ○ AFOP – Clinically similar to DAD (i.e., fever, cough, severe shortness of breath) 72

Diagnosis • Open lung biopsy is required for diagnosis of OP, AFOP, and GOP

Treatment • OP ○ Glucocorticoids are 1st line of drug therapy ○ 2nd-line drugs: Cyclophosphamide, rituximab, azathioprine • AFOP: Glucocorticoids

DIAGNOSTIC CHECKLIST Consider • OP in patients with peribronchovascular or perilobular opacities ± reversed halo or atoll signs on CT/HRCT

SELECTED REFERENCES 1. 2.

Saxena P et al: Acute fibrinous and organizing pneumonia: A rare form of nonbacterial pneumonia. Indian J Crit Care Med. 20(4):245-7, 2016 Feinstein MB et al: A comparison of the pathological, clinical and radiographical, features of cryptogenic organising pneumonia, acute fibrinous and organising pneumonia and granulomatous organising pneumonia. J Clin Pathol. 68(6):441-7, 2015

Organizing Pneumonia Pathological Patterns of Injury

(Left) Axial HRCT of a patient with cryptogenic organizing pneumonia shows welldemarcated right lower lobe peribronchovascular groundglass opacities, at least 1 of which exhibits the reversed halo sign ﬈. (Right) Axial HRCT of the same patient obtained 6 months after treatment shows migratory right lower lobe ground-glass opacities. The diagnosis of organizing pneumonia is always one of exclusion and almost always warrants pathologic confirmation, as the findings may mimic several other entities.

(Left) Axial fused FDG PET/CT of a patient with organizing pneumonia shows a large, FDG-avid left upper lobe mass ﬊, which mimics primary lung cancer, and a small ipsilateral left pleural effusion ﬈. Organizing pneumonia typically exhibits FDG avidity and may mimic malignancy. (Right) Axial NECT of a patient with granulomatous organizing pneumonia who presented with growing nodules on radiography shows a right upper lobe polylobular solid nodule ﬈ with surrounding ground-glass opacity.

(Left) Axial CECT of a patient with acute fibrinous organizing pneumonia shows multifocal bilateral groundglass opacities alternating with areas of normal pulmonary attenuation. (Right) Coronal CET of the same patient shows multifocal bilateral ground-glass opacities alternating with areas of normal lung attenuation. The imaging findings of acute fibrinous organizing pneumonia are not well described, but the presence of multifocal airspace or ground-glass opacities has been reported.

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Pathological Patterns of Injury

Constrictive Bronchiolitis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Constrictive bronchiolitis: Submucosal and peribronchiolar fibrosis with bronchiolar narrowing or luminal obliteration • Synonyms: Obliterative bronchiolitis, bronchiolitis obliterans

• Asthma • Chronic obstructive pulmonary disease (COPD) • Hypersensitivity pneumonitis

IMAGING • Radiography ○ Usually normal • HRCT ○ Inspiratory and expiratory imaging essential ○ Mosaic attenuation ○ Air-trapping on expiratory HRCT – Patchy, lobular, segmental, occasionally lobar • Minimum intensity projection (minIP) reformations improve detection of lobular areas of decreased attenuation • Extent of air-trapping correlates with severity of airflow obstruction on pulmonary function studies

(Left) Axial inspiratory NECT of a patient with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) shows subtle bilateral mosaic attenuation ﬉ and scattered small nodules ﬈. (Right) Coronal expiratory minIP reformation of the same patient shows heterogeneous bilateral areas of subsegmental and lobular airtrapping ﬈ consistent with constrictive bronchiolitis. Areas of decreased attenuation are optimally visualized using thick minIP reformations.

(Left) Low-power photomicrograph (H&E stain) of a specimen of constrictive bronchiolitis shows dilated airways ﬉ and prominent vessels ﬈ on a background of relatively normal appearing lung with normal alveoli and alveolar septa. The patchy disease distribution correlates with the nonuniform imaging abnormalities. (Right) Highpower photomicrograph (H&E stain) of a specimen of constrictive bronchiolitis shows peribronchiolar smooth muscle hypertrophy ﬈, chronic inflammation ﬉, and endoluminal mucostasis ﬊.

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PATHOLOGY • Cryptogenic or associated with variety of diseases • Microscopic findings ○ Concentric peribronchiolar fibrosis and luminal narrowing

CLINICAL ISSUES • Progressive dyspnea, nonproductive cough, and air-flow obstruction • Pulmonary function tests: Obstructive pattern

DIAGNOSTIC CHECKLIST • Bronchiolar lesions may be very subtle histologic findings in biopsies of patients with profound airflow obstruction

Constrictive Bronchiolitis

Abbreviations • Constrictive bronchiolitis (CB) • Bronchiolitis obliterans syndrome (BOS)

Imaging Recommendations • Best imaging tool ○ HRCT with inspiratory and expiratory imaging

Synonyms • Bronchiolitis obliterans • Obliterative bronchiolitis

Definitions • Specific pattern of pulmonary response to diverse injuries; may be idiopathic ○ Submucosal and peribronchiolar fibrosis with bronchiolar narrowing or luminal obliteration – Concentric fibrosis of bronchiolar wall □ Between bronchiolar epithelium and muscularis mucosa – Bronchiolar narrowing &/or obliteration □ Absence of intraluminal granulation tissue polyps □ No surrounding parenchymal inflammation

IMAGING Radiographic Findings • Often normal (mild to moderate disease) • Common findings ○ Peripheral attenuation of vascular markings ○ Increased lung lucency • Late findings ○ Hyperinflation ○ Flattening of diaphragm ○ Increased retrosternal clear space • Ancillary findings ○ Prominent bronchial markings, bronchiectasis, nodular or reticulonodular opacities

CT Findings • Indirect signs related to small airway obstruction ○ Mosaic attenuation (inspiratory CT) from small airways disease – Geographic heterogeneity of lung attenuation (4080%) – Areas of decreased attenuation □ Oligemia in areas of ↓ perfusion resulting from hypoventilated alveoli – Other causes of mosaic attenuation: Vascular and infiltrative diseases □ Occlusive pulmonary vascular disease: Chronic pulmonary thromboembolism, pulmonary hypertension □ Sarcoidosis – Hypersensitivity pneumonitis (cluster 1): Mosaic attenuation from small airways disease + infiltrative disease ○ Air-trapping (expiratory CT) – Extent of air-trapping correlates with severity of airflow obstruction on pulmonary function tests ○ Post processing of CT images – Minimum intensity projection (minIP) reformations improve detection of lobular areas of decreased attenuation

DIFFERENTIAL DIAGNOSIS Idiopathic Constrictive Bronchiolitis • Rare clinicopathologic syndrome • Confused with asthma, chronic bronchitis, cystic fibrosis, or α-1-antitrypsin deficiency • Adults (more often women) ○ No history of smoking, collagen vascular disease, or other cause of airflow obstruction • Diagnosis based on clinical criteria, bronchoalveolar lavage data, and histologic findings

Pathological Patterns of Injury

○ Bronchiectasis and bronchial wall thickening not as frequent but may occur

TERMINOLOGY

Organ Transplantation • Manifestation of chronic rejection ○ Often referred to as BOS • Common in lung and bone marrow transplantation • Hematopoietic stem cell transplantation (HSCT) ○ Graft-vs.-host disease – Late complication of HSCT – Incidence: 2% to 20% • Lung or heart-lung transplantation ○ Incidence: 50%; 3-5 years post transplant ○ Irreversible decrease in pulmonary function ○ Mosaic attenuation, air-trapping, and bronchial dilation

Autoimmunity • • • • • •

Rheumatoid arthritis (common) Sjögren syndrome (common) Polymyositis/dermatomyositis Systemic lupus erythematosus Scleroderma Inflammatory bowel disease ○ Ulcerative colitis ○ Crohn disease • Paraneoplastic pemphigus ○ Non-Hodgkin lymphoma • Paraneoplastic autoimmune multiorgan syndrome (PAMS) ○ Chronic lymphocytic leukemia, Castleman disease, thymoma, and Waldenström macroglobulinemia

Postinfectious (Swyer-James-MacLeod Syndrome) • Postinfectious CB • Viruses ○ More severe in children than in adults ○ Adenovirus, respiratory syncytial virus (RSV), influenza, parainfluenza • Mycoplasma pneumoniae ○ Tropism for ciliated and secretory columnar cells ○ Most frequent cause of atypical pneumonia ○ Common among children and young adults • Diffuse but asymmetric process • Common cause of unilateral hyperlucent lung on radiography

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Pathological Patterns of Injury

Constrictive Bronchiolitis Environmental • Inhalation-associated bronchiolar injury ○ Inorganic toxic and irritant gases and fumes – Tropism for ciliated cells > Clara cells > secretory cells □ Nitrogen dioxide (silo-fillers lung), sulfur dioxide □ Ground-Zero (9/11) dust inhalation □ Volatile butter-flavoring microwave popcorn additive (diacetyl) □ Fire smoke – Mineral dusts □ Occupational history is critical □ Usually requires years of exposure □ Talc, silica, asbestos, coal, aluminum oxide, stearate of zinc powder, iron oxide, sheet silicates, activated charcoal □ Organic dusts: Nylon flock, extrinsic allergic alveolitis □ Grain dusts

Drug Related • Free-base cocaine • Treatment for rheumatoid arthritis ○ Penicillamine ○ Gold salts

Miscellaneous • Hypersensitivity pneumonitis • Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) ○ 60% have obstructive physiology on pulmonary function studies ○ 50% smokers; M:F = 1:4 • Ingested toxins ○ Sauropus androgynus – Leafy vegetable from Southeast Asia – Touted for weight control

PATHOLOGY

Natural History & Prognosis • Varies with underlying etiology

Treatment • High-dose corticosteroids, azathioprine, OKT3 monoclonal antibody, tacrolimus, mycophenolate mofetil, and statins ○ Variable responses • Posttransplantation immunosuppression • Retransplantation (lung)

DIAGNOSTIC CHECKLIST

Histologic Features

Clinically Relevant Pathologic Features

• Purely bronchiolar lesion, few changes in distal lung parenchyma • Bronchiolar wall thickening by submucosal collagenization ○ Subtle, especially with early disease • Progressive concentric bronchial luminal narrowing ○ Luminal distortion, mucostasis ○ Variable degrees of chronic inflammation ○ Frequent histologic finding in clinical syndrome of bronchiolitis obliterans

• Diagnosis: Based on patient history, pulmonary function test results, and lung biopsy

CLINICAL ISSUES Presentation • Associated with variety of diseases ○ Component of cystic fibrosis, bronchiectasis, asthma, or chronic bronchitis • Progressive dyspnea, nonproductive cough, and air-flow obstruction ○ Progression over weeks to months • Auscultation: Crackles and mid inspiratory squeaks • Occasionally, pneumothorax and pneumomediastinum 76

• Pulmonary function tests: Obstructive pattern ○ Small airways contribute 25% to total airway resistance – Reduction in forced expiratory volume in 1 second (FEV1) – Increased residual volume (RV) and ratio of RV to total lung capacity – Normal carbon monoxide diffusing capacity • Chronic occult aspiration ○ Gastroesophageal reflux • Mineral dusts ○ Occupational history and years of exposure • Inhalation-associated bronchiolar injury ○ Acute symptoms – Vary with severity of exposure □ Airway irritation, cough, fatigue, dyspnea, cyanosis, headache, somnolence, and loss of consciousness □ Severe cases: Pulmonary edema, acute respiratory distress syndrome – May progress to CB • Inflammatory bowel disease • DIPNECH ○ CT features of CB – Air-trapping and bronchial wall thickening • Paraneoplastic pemphigus and PAMS • Exclusion of other causes of chronic airflow obstruction ○ Emphysema, asthma, and chronic bronchitis

Pathologic Interpretation Pearls • Bronchiolar lesions may be very subtle histologic findings in biopsies of patients with profound airflow obstruction

SELECTED REFERENCES 1. 2. 3. 4.

5. 6. 7.

Kligerman SJ et al: Mosaic attenuation: etiology, methods of differentiation, and pitfalls. Radiographics. 35(5):1360-80, 2015 Abbott GF et al: Imaging of small airways disease. J Thorac Imaging. 24(4):285-98, 2009 Chen CZ et al: Small airways obstruction syndrome in clinical practice. Respirology. 14(3):393-8, 2009 Pipavath SJ, Lynch DA, Cool C, Brown KK, Newell JD. Radiologic and pathologic features of bronchiolitis. AJR Am J Roentgenol. 2005 Aug;185(2):354-63. Couture C et al: Histopathology of bronchiolar disorders. Semin Respir Crit Care Med. 24(5):489-98, 2003 Ryu JH et al: Bronchiolar disorders. Am J Respir Crit Care Med. 168(11):127792, 2003 Colby TV: Bronchiolitis, pathologic considerations. M J Clin Pathol 1998;109:101-109.

Constrictive Bronchiolitis Pathological Patterns of Injury

(Left) Axial inspiratory HRCT of a patient with postinfectious constrictive bronchiolitis shows only a small focus of nodularity ﬈ and tree-in-bud opacities in the right upper lobe. (Right) Axial expiratory HRCT of the same patient demonstrates diffuse, bilateral mosaic attenuation and multifocal, bilateral expiratory airtrapping ﬉. The small vessel caliber within areas of airtrapping correlates with hypoxic vasoconstriction ﬈.

(Left) Intermediate-power photomicrograph (H&E stain) of a specimen of constrictive bronchiolitis shows a branching alveolar duct ﬈ with smooth muscle hypertrophy of alveolar duct walls and normal surrounding lung. Recognition of this abnormality is hampered by absence of long segments of peribronchiolar fibrosis. (Right) High-power photomicrograph (H&E stain) of the same specimen shows a longitudinal section of an alveolar duct with prominent smooth muscle hypertrophy ﬈.

(Left) Axial HRCT of a patient with prior childhood viral bronchiolitis shows left lower lobe bronchial wall thickening ﬈, subsegmental atelectasis ﬉, and subtle decreased peripheral pulmonary vasculature ﬊. (Right) Coronal expiratory minIP reformation of the same patient shows localized airtrapping ﬈ in the left lower lobe, secondary to focal constrictive bronchiolitis. minIP reformations are useful in the identification and characterization of pulmonary hypoattenuating areas.

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SECTION 3

Large Airways Disease

Approach to Large Airways Disease Bronchiectasis Allergic Bronchopulmonary Aspergillosis Williams-Campbell Syndrome Mounier-Kuhn Syndrome Bronchocentric Granulomatosis

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Large Airways Disease

Approach to Large Airways Disease Introduction Several diseases affect the large airways, including neoplasms, infections, inflammatory disorders, posttraumatic and iatrogenic conditions, and congenital abnormalities. These disorders may produce focal, diffuse, or regional airway abnormalities. Patients with diseases of the airways may present with nonspecific complaints that may include cough, dyspnea, and wheezing. Acute stridor (high-pitched breath sounds produced by turbulent air flow around central airway obstruction) demands immediate diagnostic evaluation and intervention to restore airway lumen patency. Chest radiographic abnormalities in affected patients may include airway dilatation, airway stenosis, endoluminal filling defects, or mass effect from adjacent space-occupying lesions. Secondary effects of large airway obstruction may include atelectasis or recurrent pulmonary infection. Bronchiectasis may manifest with tram-track opacities, ring shadows, tubular opacities indicating mucoid impaction, &/or air-fluid levels within airway lumina. Associated abnormalities, including consolidations, masses, lymphadenopathy, and pleural effusion, can also be identified. Thin-section chest CT is the preferred imaging modality for evaluation of the large airways. The advent of multidetector computed tomography has brought about a growing body of experience with image postprocessing techniques for advanced airway imaging, including virtual bronchoscopy and volume- and surface-rendered displays. Large airway imaging during forced expiration allows identification and characterization of tracheobronchomalacia. HRCT evaluation of patients with diffuse lung disease provides concurrent assessment of the large airways. In some cases, airway abnormalities are the primary imaging finding, while in others, airway abnormalities occur in association with diffuse infiltrative lung disease. An understanding of the various morphologic features and distribution of large airways diseases correlated with the patient's clinical profile, and pertinent laboratory findings allows the radiologist to provide a focused differential diagnosis and direct appropriate patient evaluation and management.

Anatomic Considerations The airways are tubular structures that conduct air through their lumina and represent 24 generations of dichotomous branching. They are divided into large (trachea, bronchi) and small (bronchioles, terminal bronchioles, respiratory bronchioles, and alveolar ducts) airways. The large airways are purely conductive (serving the function of air conduction), whereas the small airways may be conductive &/or respiratory (serving the function of gas exchange).

Large Airways Diseases Introduction Neoplastic, infectious, congenital, and acquired diseases that affect the large airways may produce morphologic alterations, such as stenosis, dilatation, airway wall thickening, and endoluminal lesions. All of these are optimally evaluated with chest CT. Malignant neoplasms, such as lung cancer, frequently involve the large airways. Although CT is invaluable for initial diagnosis and clinical staging, assessment of these neoplasms does not require HRCT. 80

Large Airway Stenosis Saber-sheath trachea is a morphologic tracheal abnormality associated with chronic obstructive pulmonary disease and characterized by decreased coronal and increased sagittal tracheal diameters. Tracheal stenosis may occur as a complication of endobronchial intubation, may be focal or diffuse, and may require dilatation, stent placement, or surgical correction. Congenital tracheal stenosis is rare, may be associated with other congenital anomalies, and characteristically affects neonates and infants. Tracheomalacia and tracheobronchomalacia represent functional large airway narrowing secondary to cartilage weakness, which results in expiratory airway collapse and may be evaluated with dynamic CT and expiratory imaging. However, it should be noted that a broad range of expiratory large airway collapse has been observed in normal subjects. Large airway stenosis due to mural thickening may also occur in association with granulomatosis with polyangiitis, amyloidosis, and relapsing polychondritis. These entities may cause focal or diffuse tracheal involvement and may also affect the central bronchi. Thus, radiologists must thoroughly assess the large airways of affected patients to exclude significant stenoses that may require treatment. Large Airway Dilatation Tracheal and central bronchial dilatation are the characteristic imaging abnormalities of Mounier-Kuhn syndrome, a rare congenital disorder related to atrophy of elastic tissue and smooth muscle. Bronchiectasis is much more common, is defined as irreversible bronchial dilatation, and may be categorized as cylindrical, varicose, or cystic in increasing order of severity. Although it may be identified on radiography, bronchiectasis is optimally evaluated on CT. Normal bronchial diameter is generally equal to that of the adjacent pulmonary artery. Bronchial diameters larger than those of adjacent pulmonary arteries typify bronchiectasis. Bronchiectasis often results from aspiration or chronic or recurrent pulmonary infection. The latter may be seen in association with congenital or acquired immunodeficiencies, immune reactions, or functional airway alterations. In the setting of fibrosing interstitial lung disease, bronchiectasis (traction bronchiectasis) is commonly encountered as a result of the retractile effects of fibrosis. Knowledge of the various etiologies and distribution of bronchiectasis allows the radiologist to provide a cogent differential diagnosis, particularly in cases in which bronchiectasis is the dominant finding. Peribronchial Distribution of Disease Some diffuse and multifocal inflammatory and neoplastic pulmonary diseases may exhibit a characteristic peribronchovascular distribution typified by airspace disease and nodular opacities disposed about the large airways. Recognition of these findings on HRCT may help narrow the differential diagnosis and suggest histologic correlation with tissues obtained via bronchoscopy based on identification of the most affected areas.

Selected References 1.

Little BP et al: Imaging of diseases of the large airways. Radiol Clin North Am. 54(6):1183-1203, 2016

Approach to Large Airways Disease Large Airways Disease

(Left) Axial expiratory NECT of a 50-year-old man with chronic dyspnea shows severe narrowing of the intrathoracic trachea ﬈ characteristic of tracheomalacia. The bilateral mainstem bronchi (not shown) were also affected. (Right) Coronal CECT of a 65-year-old man with Mounier-Kuhn syndrome or tracheobronchomegaly shows marked dilatation of the trachea ﬈ and mainstem bronchi ﬉ with associated peripheral bronchiectasis ﬊. Note the characteristic corrugated appearance of the walls of the central airways.

(Left) Coronal NECT of a 38year-old woman with asthma and allergic bronchopulmonary aspergillosis shows bilateral upper lobe central bronchiectasis ﬊ and segmental postobstructive volume loss in the right upper lobe. Bronchiectasis in a patient with asthma should suggest the diagnosis. (Right) Axial NECT of a 35-year-old woman with selective immunoglobulin A deficiency, chronic cough, and dyspnea shows severe cystic bronchiectasis ﬈ secondary to recurrent infection.

(Left) Axial HRCT of a patient with scleroderma and nonspecific interstitial pneumonia shows bilateral severe lower lobe bronchiectasis ﬈. In this case, bronchiectasis is secondary to the retractile effects of interstitial fibrosis. (Right) Coronal CECT of a patient with sarcoidosis shows bilateral central mass-like fibrosis with intrinsic cavitation. Although an atypical appearance, the central peribronchovascular distribution of fibrosis is entirely consistent with the diagnosis of sarcoidosis.

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Large Airways Disease

Bronchiectasis KEY FACTS

TERMINOLOGY

PATHOLOGY

• Irreversible bronchial dilatation usually associated with inflammation of bronchial wall

• Integrity of bronchial wall is dependent on normal immune system, normal structural integrity of airways (normal cartilage), and normal ciliary function ○ Infection (most common etiology) ○ Cystic fibrosis ○ Allergic bronchopulmonary aspergillosis ○ Chronic aspiration ○ Obstruction: Tumor, foreign body, or extrinsic compression from lymph node enlargement • No specific histologic features; bronchial wall exhibits acute and chronic inflammation • Bronchial wall granulomatous inflammation is more common in tuberculosis or aspiration

IMAGING • HRCT/thin-section CT ○ ↑ bronchoarterial ratio (B/A); signet ring sign – B/A > 1 not specific, seen in normal elderly subjects (> 65 years) or those at high altitude (due to mild hypoxia that causes bronchial dilatation and vasoconstriction) ○ Lack of bronchial tapering: Earliest and most sensitive sign of bronchiectasis ○ Visualization of airway within 1 cm of costal pleura or abutting mediastinal pleura

TOP DIFFERENTIAL DIAGNOSES • Bronchitis • Bronchial atresia • Cystic lung disease

(Left) Graphic shows degrees of severity of bronchiectasis. Cylindrical ﬈ bronchiectasis is the mildest form and manifests with uniform bronchial dilatation and lack of tapering. Varicoid ﬊ bronchiectasis manifests as beaded bronchi. Saccular ﬉ bronchiectasis results when dilated bronchi exhibit a rounded, cystic morphology. (Right) Axial NECT of a patient with Williams-Campbell syndrome shows dilated bronchi ﬈ in cross section that are larger than the adjacent pulmonary arteries ﬊, the signet ring sign.

(Left) Coronal NECT of a patient with pulmonary fibrosis shows dilated bronchi ﬈ indicative of traction bronchiectasis amid extensive reticulation and honeycombing. Note the beaded appearance and absence of tapering as the bronchi course toward the periphery of the lung. (Right) Sagittal NECT of a patient with pulmonary fibrosis and traction bronchiectasis shows visible bronchioles ﬈ within 1 cm of the costal pleura, indicative of bronchiolectasis.

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DIAGNOSTIC CHECKLIST • Consider central bronchial obstruction by neoplasm or lymphadenopathy in patients with focal bronchiectasis

Bronchiectasis

Definitions • Irreversible bronchial dilatation usually associated with bronchial wall inflammation

IMAGING General Features • Best diagnostic clue ○ Lack of bronchial lumen tapering • Spectrum of severity of bronchiectasis ○ Cylindrical: Mild; uniformly increased bronchial diameter ○ Varicose: Moderate; string of pearls appearance; alternating dilatation and narrowing ○ Saccular or cystic: Severe; cluster of grapes appearance; rounded, spherical dilatation

Radiographic Findings • Linear opacities due to thickened bronchial walls or ring lucencies representing dilated airways • Bronchial lumina seen en face greater in diameter than adjacent vessel • Tram-track appearance of cylindrical bronchiectasis ○ Parallel linear opacities representing longitudinal thickened walls of dilated bronchi • ± air-fluid levels within saccular bronchiectasis

CT Findings • Direct signs ○ Bronchial dilatation – ↑ bronchoarterial ratio (B/A); signet ring sign □ Normal B/A: 0.65-1.00 – 1.0 < B/A < 1.5: Nonspecific finding; may be seen in normal elderly subjects (> 65 years) or those at high altitude (due to mild hypoxia that causes bronchial dilatation and vasoconstriction) – B/A > 1.5: Indicative of bronchiectasis ○ Lack of bronchial tapering – Earliest and most sensitive sign of bronchiectasis ○ Visualization of airway within 1 cm of costal pleura or abutting mediastinal pleura • Indirect signs (may or may not be present) ○ Bronchial wall thickening ○ Mucoid impaction, fluid-filled bronchi ○ Centrilobular nodules or tree-in-bud opacities – Dilated bronchioles filled with mucus or fluid ○ Mosaic perfusion (inspiratory) and air-trapping (expiratory) due to associated constrictive bronchiolitis • Distribution ○ Focal bronchiectasis – Confined to 1 lobe, most often postinfectious or secondary to aspiration – May be secondary to central obstructive lesion (slowgrowing tumor, broncholith, foreign body) ○ Central bronchiectasis (normal peripheral airways) – Allergic bronchopulmonary aspergillosis – Tracheobronchomegaly – Cystic fibrosis ○ Upper lobe predominant bronchiectasis – Cystic fibrosis

– Allergic bronchopulmonary aspergillosis – Tuberculosis ○ Middle lobe and lingular bronchiectasis – Nontuberculous mycobacterial infection (Lady Windermere syndrome)

MR Findings • Increasingly utilized for serial examinations in young patients given no ionizing radiation • T1-weighted and T2-weighted turbo spin-echo sequences provide anatomic imaging of large airways ○ Bronchial wall thickening, bronchial dilatation, mucus plugging • Hyperpolarized gas (most often helium but occasionally xenon) provides functional evaluation of air-trapping

Large Airways Disease

TERMINOLOGY

Imaging Recommendations • Best imaging tool ○ HRCT/thin-section CT • Protocol advice ○ Volumetric CT imaging more sensitive in detecting bronchiectasis than incremental axial imaging ○ Minimum-intensity projection images may improve detection of bronchiectasis and air-trapping

DIFFERENTIAL DIAGNOSIS Chronic Bronchitis • Bronchial wall thickening but normal diameter and morphology

Bronchial Atresia • Dilated, mucus-filled bronchus distal to atretic airway segment (bronchocele) • Associated with marked hyperlucency and hypoperfusion of involved pulmonary segment • Most commonly affects apicoposterior segment of left upper lobe

Cystic Lung Disease • Saccular bronchiectasis may be confused with cystic lung disease ○ Pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis • Bronchiectasis characterized by continuity of cystic lucencies with airways, whereas in cystic lung disease, there is no connection between cystic lucencies and airways ○ Continuity with airways may be more apparent on multiplanar reformations than on axial images • Pulmonary Langerhans cell histiocytosis ○ Predominantly affects upper lung zones ○ Usually associated with subcentimeter solid nodules or nodules with small central lucencies • Lymphangioleiomyomatosis ○ Uniform distribution of thin-walled, round cysts affecting young women • Cavitary disease ○ Cavitary metastases: Sarcoma, squamous cell carcinoma, transitional cell carcinoma ○ Laryngeal papillomatosis – Often endobronchial nodules

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Large Airways Disease

Bronchiectasis

PATHOLOGY General Features • Etiology ○ Cole vicious cycle model – Airway irritant causes inflammatory response with subsequent bronchial wall tissue damage – Tissue damage leads to poor airway clearance that results in further inflammation and progressive airway wall destruction ○ Infection – Chronic inflammation of bronchial wall is most common cause of bronchiectasis – Typical and atypical mycobacteria, Staphylococcus, Bordetella pertussis, Pseudomonas, viral infection ○ Congenital – Cystic fibrosis – Primary ciliary dyskinesia □ Congenital □ Impaired ciliary function results in poor bronchial clearance and resultant inflammation/infection – Tracheobronchomegaly (Mounier-Kuhn syndrome) □ Congenital □ Atrophy or absence of elastic fibers and smooth muscle of trachea and 1st-4th order bronchi – Williams-Campbell syndrome □ Congenital □ Deficiency of bronchial cartilage in 4th-6th order bronchi – Deficiencies of cellular or humoral immunity (variable immunodeficiency) – Yellow nail syndrome (lymphatic hypoplasia): Yellow nails, chronic pleural effusions, bronchiectasis ○ Immunologic or inflammatory – Allergic bronchopulmonary aspergillosis – Chronic aspiration – Toxic fume inhalation, especially ammonia – Rheumatoid arthritis ○ Proximal bronchial obstruction – Tumor, foreign body, postinfectious/inflammatory stenosis, extrinsic compression from lymph node enlargement ○ Traction from adjacent fibrosis – Idiopathic interstitial pneumonias – Sarcoidosis – Fibrotic hypersensitivity pneumonitis – Radiation fibrosis • Genetics ○ Integrity of bronchial wall dependent on normal immune system, normal structural integrity of airways (normal cartilage), and normal ciliary function • Epidemiology ○ > 110,000 patients [exclusive of cystic fibrosis (CF)] receive treatment for bronchiectasis in USA

Gross Pathologic & Surgical Features • Irreversible dilatation due to loss of cartilage and elastic fibers ○ Bronchial artery hypertrophy in response to chronic inflammation 84

○ Bronchiectasis most commonly involves medium-sized bronchi of 4th-9th generations • Bronchiectatic airways often colonized with 1 or more organisms ○ Haemophilus influenzae, Pseudomonas aeruginosa, Streptococcus, Branhamella catarrhalis, Staphylococcus

Microscopic Features • No specific histologic features, bronchial wall exhibits acute and chronic inflammation • Granulomatous inflammation of airway wall, more common in tuberculosis or aspiration

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Nonspecific: Cough, sputum production, and hemoptysis ○ Mild bronchiectasis can be asymptomatic • Other signs/symptoms ○ Pulmonary function tests – Obstructive: ↓ FEV₁ with increased lung volumes

Demographics • Age ○ Prevalence (exclusive of CF) increases with age – Range: 4 per 100,000 for ages 18-34 years to 270 per 100,000 for age ≥ 75 years • Gender ○ Higher prevalence among women at all ages

Natural History & Prognosis • Good prognosis; outcome depends on treatment of underlying cause

Treatment • Nonoperative ○ Smoking cessation ○ Appropriate vaccinations ○ Postural drainage ○ Antibiotic treatment for superimposed infection ○ Bronchodilators • Operative/interventional ○ Bronchial artery embolization to control severe hemoptysis ○ Surgical resection for localized disease if recurrent infections and hemoptysis ○ Lung transplantation for selected cases

DIAGNOSTIC CHECKLIST Consider • Central bronchial obstruction by neoplasm or lymphadenopathy in patients with focal bronchiectasis

SELECTED REFERENCES 1. 2. 3.

Milliron B et al: Bronchiectasis: Mechanisms and imaging clues of associated common and uncommon diseases. Radiographics. 35(4):1011-30, 2015 McShane PJ et al: Non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med. 188(6):647-56, 2013 Javidan-Nejad C et al: Bronchiectasis. Radiol Clin North Am. 47(2):289-306, 2009

Bronchiectasis Large Airways Disease

(Left) Axial NECT shows a patient with bronchiectasis secondary to nontuberculous mycobacterial infection. Note the dilated lingular bronchiole ﬈ abutting the mediastinal pleura, indicative of bronchiolectasis. The middle lobe and lingula are often involved in this type of pulmonary infection. (Right) Coronal NECT of a patient with traction bronchiectasis secondary to pulmonary fibrosis shows cylindrical bronchiectasis ﬈ characterized by absence of bronchial tapering and uniform dilatation.

(Left) Axial NECT of a patient with varicoid traction bronchiectasis secondary to pulmonary fibrosis shows a beaded appearance of a right lower lobe bronchus ﬈, characteristic of varicoid bronchiectasis. (Right) Axial NECT of a patient with cystic fibrosis shows that the right lower lobe is virtually replaced by saccular bronchiectasis ﬈ that results in cystic dilatation of the airways. Patients with cystic fibrosis have recurrent pulmonary infections that eventually lead to the development of bronchiectasis.

(Left) Axial NECT of a patient with cystic fibrosis shows focal saccular bronchiectasis ﬈ in the right lower lobe. The markedly dilated airway may be confused with a lung cyst. (Right) Coronal NECT of the same patient shows continuity of the cystic space ﬈ with an adjacent airway ﬊, indicative of saccular bronchiectasis. Multiplanar imaging is often helpful for differentiating bronchiectasis from other cystic lung diseases. MIP reformations help highlight bronchiectasis and mosaic attenuation.

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Large Airways Disease

Allergic Bronchopulmonary Aspergillosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Allergic bronchopulmonary aspergillosis (ABPA): Chronic airway inflammation and injury in patients with hypersensitivity to Aspergillus antigens

• • • •

IMAGING • Radiography ○ Migratory upper lung zone pulmonary opacities ○ Bronchiectasis – Tram-track parallel linear opacities ○ Mucoid impaction: May exhibit finger-in-glove sign • CT/HRCT ○ Central upper lobe bronchiectasis ○ Bronchial wall thickening ○ Mucoid impaction – Soft tissue attenuation branching opacities – High-attenuation or calcified mucus (30%) ○ Centrilobular nodules, tree-in-bud opacities ○ Mosaic attenuation, expiratory air-trapping

(Left) PA chest radiograph of a patient with allergic bronchopulmonary aspergillosis (ABPA) shows bilateral upper lung zone perihilar opacities ﬉, most pronounced on the right. (Right) Axial NECT of the same patient obtained several months later shows bilateral upper lobe central varicoid bronchiectasis ﬉, with small mucus plugs on the left ﬈ and no endoluminal content on the right. Interim expectoration of mucus plugs accounts for the migratory nature of the pulmonary opacities seen on radiography.

(Left) Composite image with axial NECT in lung (left) and soft tissue (right) window of a patient with allergic bronchopulmonary aspergillosis shows right upper lobe central bronchiectasis ﬉ with high-attenuation mucus plugs ﬊. (Right) High-power photomicrograph (GMS stain) shows septated hyphae with 45° angle branching ﬊. Aspergillus organisms are often found in expectorated mucus of patients with bronchopulmonary aspergillosis. (From: DP Thoracic, 2e.)

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Cystic fibrosis Primary ciliary dyskinesia Congenital bronchial atresia Postinfectious bronchiectasis

PATHOLOGY • Inspissated mucus plugs contain Aspergillus and eosinophils

CLINICAL ISSUES • Up to 6% of patients with chronic asthma have ABPA • 2-15% of patients with cystic fibrosis have ABPA • Signs and symptoms: Cough, dyspnea, expectoration (golden-brown mucus plugs), wheezing, hemoptysis • Treatment: Oral corticosteroids, antifungals

DIAGNOSTIC CHECKLIST • Consider ABPA in patients with asthma and central bronchiectasis with high-attenuation mucus plugs

Allergic Bronchopulmonary Aspergillosis

Abbreviations

Imaging Recommendations • Best imaging tool ○ CT/HRCT: Imaging modality of choice

• Allergic bronchopulmonary aspergillosis (ABPA)

Definitions • ABPA: Chronic airway inflammation and injury in patients with hypersensitivity to Aspergillus antigens ○ Allergic response to inhaled Aspergillus spores ○ Typically affects patients with asthma and cystic fibrosis • Allergic bronchopulmonary mycoses: Chronic airway inflammation/injury due to hypersensitivity to other fungi • Serological ABPA (ABPA-S): Mild form of disease with positive serology and other criteria, but without bronchiectasis

IMAGING General Features • Best diagnostic clue ○ Central bronchiectasis and mucoid impaction in asthmatic patient • Location ○ Central bronchiectasis with normal peripheral airways ○ Upper lobe predominant

Radiographic Findings • Radiography ○ May be normal (ABPA-S) ○ Migratory upper lung zone pulmonary opacities – Consolidations, perihilar opacities, postobstructive pneumonia – Atelectasis – Reticular opacities and volume loss related to fibrosis ○ Bronchiectasis – Tram-track parallel linear opacities – Mucoid impaction demonstrating finger-in-glove sign □ May disappear post coughing or with treatment – May exhibit intrinsic air-fluid levels and mycetoma formation

CT Findings • Bronchiectasis (95%) ○ Upper lobe involvement ○ Central bronchiectasis is typical – Peripheral airways may also be involved ○ Multilobar, bilateral, asymmetric ○ Cylindrical (early), varicose, saccular ○ May be air-filled or filled with soft tissue ○ May exhibit mycetoma formation • Bronchial wall thickening • Mucoid impaction (70%) ○ Homogeneous tubular &/or branching opacities ○ Soft tissue attenuation mucus ○ High-attenuation or calcified mucus (30%) • Centrilobular nodules, tree-in-bud opacities • Mosaic attenuation, expiratory air-trapping • Associated findings ○ Consolidation, atelectasis ○ Architectural distortion, bullae ○ Pleural effusion

DIFFERENTIAL DIAGNOSIS Cystic Fibrosis • ABPA in up to 15% of patients with cystic fibrosis • Positive sweat chloride skin test • Similar distribution of bronchiectasis

Large Airways Disease

TERMINOLOGY

Primary Ciliary Dyskinesia • Poor mucociliary clearing predisposes to recurrent infection and bronchiectasis • ~ 50% have Kartagener syndrome • Basilar predominant bronchiectasis

Congenital Bronchial Atresia • Vascular insult to airway in early fetal development • Focal short-segment airway atresia • Mucocele distal to atresia ○ Round, ovoid, or tubular branching opacities • Surrounding pulmonary hyperlucency

Postinfectious Bronchiectasis • Recurrent pulmonary infection ○ Bacteria, mycobacteria, viruses • Transient ciliary dysfunction and poor mucus clearance with resultant airway damage

Immune Deficiency Disorders • Human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) • Common variable immunodeficiency • Recurrent pulmonary infection with resultant bronchiectasis

Williams-Campbell Syndrome • Rare congenital cartilage deficiency in subsegmental bronchi • Bronchiectasis limited to 4th, 5th, and 6th generation bronchi

Bronchocentric Granulomatosis • Inflammatory response characterized by necrotizing granulomas along bronchi and bronchioles • May be seen in ABPA or as response to infection • Mimics ABPA, but may predominantly affect distal airways • May manifest with mass, consolidation, or atelectasis

Asthma • Mild cylindrical bronchiectasis, bronchial wall thickening • Atelectasis, consolidation, air-trapping • Mucoid impaction may be seen without ABPA

Endobronchial Neoplasm • Mucoid impaction distal to slow-growing neoplasm ○ Carcinoid, hamartoma, lung cancer • Usually unilateral in single lobar or segmental distribution

Airway Obstruction From Foreign Body • Most are radiolucent ○ Look for radiopaque foreign body or broncholith 87

Large Airways Disease

Allergic Bronchopulmonary Aspergillosis • Unilateral distribution in single segment or lobe

PATHOLOGY General Features • Etiology ○ Aspergillus fumigatus antigen stimulation – Type I IgE-mediated hypersensitivity reaction □ ↑ levels of IgE and ↑ A. fumigatus-IgE and A. fumigatus-IgG antibodies – Type III (IgG-mediated) and type IV (cell-mediated) reactions ○ Other fungi: Allergic bronchopulmonary mycosis • Genetics ○ Higher frequency of HLA-DR2 and HLA-DR5 genotypes • Epidemiology ○ Up to 6% of patients with chronic asthma have ABPA ○ 2-15% of patients with cystic fibrosis have ABPA

Staging, Grading, & Classification • Several and evolving diagnostic criteria • Rosenberg-Patterson: Most well-acknowledged criteria ○ Major criteria – Asthma – Migratory pulmonary opacities – Immediate cutaneous reactivity to A. fumigatus – Elevated total serum IgE – Precipitating antibodies against A. fumigatus – Peripheral blood eosinophilia – Elevated serum IgE and IgG specific for A. fumigatus – Central bronchiectasis ○ Minor criteria – Expectorated golden-brown mucus plugs – Positive sputum culture for Aspergillus spp. – Late skin reactivity to A. fumigatus • International Society for Human and Animal Mycology (ISHAM): Require validation and further refinement ○ Obligatory: Both must be present for diagnosis – + immediate cutaneous hypersensitivity to Aspergillus antigen or ↑ IgE levels against A. fumigatus – ↑ total IgE levels > 1,000 IU/mL ○ Other: At least 2 must be present – + precipitating or IgG antibodies against A. fumigatus in serum – Pulmonary opacities consistent with ABPA on imaging – Total eosinophil count > 500 cells/μL • Clinical staging ○ Stage I: Acute ○ Stage II: Remission ○ Stage III: Exacerbation ○ Stage IV: Corticosteroid dependent asthma ○ Stage V: Fibrotic lung disease • Radiologic staging ○ Stage I: ABPA-S ○ Stage II: ABPA with bronchiectasis ○ Stage III: ABPA with high-attenuation mucus ○ Stage IV: ABPA with chronic pleuropulmonary fibrosis

Microscopic Features • Inspissated mucus plugs contain Aspergillus and eosinophils ○ Aspergillus: Septate hyphae with 45° angle branching 88

• No invasion of bronchial epithelium • Eosinophilic pneumonia • Bronchocentric granulomatosis: Necrotizing granulomatous inflammation that destroys walls of small bronchi and bronchioles • Other responses: Granulomatous and exudative bronchiolitis, lipoid pneumonia, lymphoid interstitial pneumonia, vasculitis, obliterative bronchiolitis

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Cough, dyspnea, expectoration, wheezing, hemoptysis – Thick, golden-brown plugs in sputum ○ Cyanosis, digital clubbing, cor pulmonale in severe cases • Other signs/symptoms ○ May occur in association with allergic Aspergillus sinusitis – Immunologic reaction to Aspergillus antigens in paranasal sinuses • Laboratory abnormalities ○ Peripheral eosinophilia: Usually > 1,000/μL; commonly > 3,000/μL ○ Elevated IgE: Usually > 1,000 ng/mL

Natural History & Prognosis • Recurrent ABPA may result in widespread bronchiectasis and fibrosis ○ 35% of exacerbations are asymptomatic but may result in lung damage • Lung biopsy is not usually required for diagnosis • ABPA may recur in patients with cystic fibrosis treated with lung transplantation

Treatment • Oral corticosteroids are mainstay of therapy: Long-term therapy may be required • Antifungal agents: Reduction of fungal load and antigenic stimulus to decrease inflammatory response • Potential benefit of monoclonal antibody (against IgE) therapy • Allergic fungal sinusitis: Initial surgical debridement, postoperative oral corticosteroids, supportive measures

DIAGNOSTIC CHECKLIST Consider • ABPA in patients with asthma and central upper lobe bronchiectasis, particularly when associated with soft tissue or high-attenuation mucus plugs

SELECTED REFERENCES 1.

2. 3. 4. 5.

Phuyal S et al: High-attenuation mucus impaction in patients with allergic bronchopulmonary aspergillosis: objective criteria on high-resolution computed tomography and correlation with serologic parameters. Curr Probl Diagn Radiol. 45(3):168-73, 2016 Shah A et al: Allergic bronchopulmonary aspergillosis: a perplexing clinical entity. Allergy Asthma Immunol Res. 8(4):282-97, 2016 Chabi ML et al: Pulmonary aspergillosis. Diagn Interv Imaging. 96(5):435-42, 2015 Greenberger PA: When to suspect and work up allergic bronchopulmonary aspergillosis. Ann Allergy Asthma Immunol. 111(1):1-4, 2013 Bains SN et al: Allergic bronchopulmonary aspergillosis. Clin Chest Med. 33(2):265-81, 2012

Allergic Bronchopulmonary Aspergillosis Large Airways Disease

(Left) Axial HRCT of a 38-yearold woman with allergic bronchopulmonary aspergillosis shows severe right lower lobe central bronchiectasis ﬉ and right upper lobe subsegmental atelectasis ﬈. (Right) Coronal NECT of the same patient shows bilateral upper lobe central bronchiectasis ﬉ and bronchial wall thickening, right upper lobe subsegmental atelectasis ﬈, and subtle right apical cellular bronchiolitis ﬊. Pulmonary opacities in affected patients may reflect atelectasis, consolidation, or mucus plugs.

(Left) Axial HRCT of a patient with allergic bronchopulmonary aspergillosis shows bilateral upper lobe irregular consolidations ﬉ with surrounding centrilobular micronodules ﬈. (Right) Highpower photomicrograph (H&E stain) of a specimen from a patient with bronchopulmonary aspergillosis demonstrates profuse pulmonary eosinophils ﬈ characterized by their intensely red-staining cytoplasm. Affected patients may develop postobstructive or eosinophilic pneumonia.

(Left) Axial HRCT of a patient with bronchopulmonary aspergillosis shows right upper lobe varicose bronchiectasis ﬉ involving segmental and subsegmental bronchi and adjacent architectural distortion ﬊ related to chronic lung disease. (Right) Axial HRCT of a patient with allergic bronchopulmonary aspergillosis shows bilateral upper lobe central bronchiectasis ﬉ with small mucus plugs ﬈ and a dense right upper lobe anterior segment consolidation ﬊ representing pneumonia.

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Large Airways Disease

Williams-Campbell Syndrome KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Williams-Campbell syndrome ○ Rare congenital syndrome ○ Partial or complete absence of cartilage in subsegmental bronchi

• Cystic fibrosis • Primary ciliary dyskinesia • Allergic bronchopulmonary aspergillosis

IMAGING

• Congenital syndrome • Acquired hypothesis: Adenovirus infection → bronchomalacia → bronchiectasis • Defective or completely absent bronchial wall cartilages of 4th-6th generation bronchi

• • • •

Diffuse bilateral cylindrical/cystic bronchiectasis Normal trachea and mainstem/segmental bronchi Bronchial air-fluid levels may be associated with infection Dynamic CT ○ Inspiratory phase: "Ballooning" of bronchiectasis ○ Expiratory phase: Complete collapse of bronchiectatic airways • Virtual bronchoscopy ○ May be useful for clinicians to determine extent of involvement ○ Highlights absence of cartilage ring impressions along bronchial walls

(Left) Graphic illustrates the airway abnormalities in Williams-Campbell syndrome, a congenital disorder characterized by bronchiectasis affecting the 4th-6th generation bronchi due to complete or partial absence of bronchial wall cartilage. (Right) Axial NECT of a 20-year-old patient with Williams-Campbell syndrome shows bronchiectasis involving subsegmental bronchi. Patients with WilliamsCampbell syndrome often have recurrent pulmonary infections.

(Left) Axial NECT of a 24-yearold patient with WilliamsCampbell syndrome shows bilateral central bronchiectasis. The differential diagnosis includes cystic fibrosis, allergic bronchopulmonary aspergillosis, and primary ciliary dyskinesia. (Right) Coronal NECT of the same patient shows bilateral bronchiectasis and normal central airways ﬈ characteristic of WilliamsCampbell syndrome. Multiplanar reformations may help demonstrate the distribution of bronchiectasis.

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PATHOLOGY

CLINICAL ISSUES • Signs and symptoms ○ Recurrent pneumonia, cough, wheezing • Prognosis ○ Depends on extent of bronchial wall cartilage deficiency • Treatment ○ Antibiotic prophylaxis for disease exacerbations

Williams-Campbell Syndrome

Synonyms • Bronchomalacia • Noncystic fibrosis

Definitions • Rare congenital syndrome characterized by partial or complete absence of cartilage in subsegmental bronchi

IMAGING General Features • Best diagnostic clue ○ Bilateral bronchiectasis • Location ○ 4th-6th generation bronchi (1st generation of subsegmental bronchi) • Morphology ○ Cylindrical/cystic bronchiectasis

Radiographic Findings • Radiography ○ Bronchiectasis, bronchial wall thickening, and cystic lesions

CT Findings • • • •

Diffuse bilateral cylindrical/cystic bronchiectasis Normal trachea, mainstem bronchi, and segmental bronchi Bronchial air-fluid levels may be associated with infection Dynamic CT ○ Inspiratory phase: "Ballooning" of bronchiectasis ○ Expiratory phase: Complete collapse of bronchiectatic airways (absence of cartilaginous plates) • Virtual bronchoscopy ○ May be useful for clinicians to determine extent of involvement ○ Highlights absence of cartilage ring impressions along bronchial walls

Imaging Recommendations • Best imaging tool ○ CT inspiratory/expiratory phases ○ Multiplanar CT reformations to evaluate distribution and location of bronchiectasis ○ 3D reformations may be useful to clinicians

DIFFERENTIAL DIAGNOSIS Cystic Fibrosis • 80% of cases diagnosed before 5 years of age • Diffuse, cylindrical bronchiectasis with upper lobe predominance

Primary Ciliary Dyskinesia • Variable age: Infancy to 50 years of age • Varicoid-type bronchiectasis with middle lobe and lingula predominance • Kartagener syndrome: Situs inversus totalis, bronchiectasis, and sinusitis

Allergic Bronchopulmonary Aspergillosis

• Asthma + peripheral blood eosinophilia + skin reactivity or presence of serum IgE to Aspergillus fumigatus + precipitating antibodies or serum IgG to A. fumigatus + elevated serum IgE (> 1,000 kU/L) • Bronchiectasis with central/upper lung zone distribution, mucoid impaction: Finger-in-glove opacities ○ Mucus often hyperdense secondary to calcium deposits

PATHOLOGY

Large Airways Disease

TERMINOLOGY

General Features • Etiology ○ Congenital syndrome ○ Acquired hypothesis: Adenovirus infection → bronchomalacia → bronchiectasis • Associated abnormalities ○ Congenital heart disease, bronchial isomerism, situs inversus, polysplenia, malrotation of abdominal viscera

Gross Pathologic & Surgical Features • Defective or completely absent bronchial wall cartilage of 4th-6th order bronchi

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Recurrent pneumonia ○ Coughing and wheezing

Demographics • Children, occasionally adults

Natural History & Prognosis • Prognosis depends on extent of cartilage deficiency

Treatment • Antibiotic prophylaxis for disease exacerbations • Pulmonary resection if at risk for bleeding or severe infection

DIAGNOSTIC CHECKLIST Consider • Distribution of bronchiectasis for formulation of differential diagnosis ○ Central: Allergic bronchopulmonary aspergillosis ○ Upper lobe: Cystic fibrosis ○ Middle lobe, lingula, lower lobes: Primary ciliary dyskinesia

Image Interpretation Pearls • Trachea, mainstem bronchi, and segmental bronchi are normal in patients with Williams-Campbell syndrome

SELECTED REFERENCES 1. 2.

3.

Milliron B et al: Bronchiectasis: Mechanisms and imaging clues of associated common and uncommon diseases. Radiographics. 35(4):1011-30, 2015 Noriega Aldave AP et al: The clinical manifestations, diagnosis and management of williams-campbell syndrome. N Am J Med Sci. 6(9):429-32, 2014 Jones QC et al: Williams-Campbell syndrome presenting in an adult. BMJ Case Rep. 2012, 2012

• Most affected patients have asthma or cystic fibrosis 91

Large Airways Disease

Mounier-Kuhn Syndrome KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Mounier-Kuhn syndrome (MKS): Rare disorder characterized by atrophy of tracheal and mainstem bronchial elastic tissue and smooth muscle leading to significant central airway dilatation

• Williams-Campbell syndrome • Secondary tracheobronchomegaly

IMAGING • Radiography ○ Tracheal diameter > than that of adjacent vertebrae ○ Increased lung volume (from obstructive physiology) • HRCT/CT ○ Consider diagnosis if – Trachea > 30 mm – Left mainstem bronchus > 23 mm – Right mainstem bronchus > 24 mm ○ Tracheobronchial diverticulosis (50%) ○ Bronchiectasis (30-45%) ○ Tracheobronchomalacia (28%)

(Left) Coned-down lateral chest radiograph of a patient with Mounier-Kuhn syndrome shows diffuse tracheal diverticulosis manifesting with a lobulated contour of the anterior and posterior tracheal walls ﬈. Tracheal diverticula result from herniation of redundant mucosa between adjacent tracheal cartilages and especially along the posterior tracheal membrane. (Right) Sagittal CECT of the same patient shows abnormal protrusion of the tracheal mucosa between the cartilaginous rings ﬈, the socalled tracheal diverticula.

(Left) Coronal CECT of the same patient shows abnormal tracheal dilatation and tracheobronchial diverticulosis ﬈. Mounier-Kuhn syndrome is clinically characterized by cough, dyspnea, and recurrent pulmonary infections. Wheezing and stridor are common when complicated by tracheobronchomalacia. (Right) Coronal CECT minIP reformation of the same patient shows tracheal dilatation ﬈ and diverticulosis ﬈; minIP reformations are a useful tool for the evaluation of the central airways.

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PATHOLOGY • Unknown etiology, most likely congenital • Thinning of muscularis mucosa and atrophy of longitudinal muscle and elastic fibers

CLINICAL ISSUES • Cough (> 70%), recurrent respiratory infection (50%), dyspnea (> 40%) • Diagnosis of chronic obstructive pulmonary disease (> 25%) • Male predominance; M:F ratio = 8:1 • Most cases diagnosed after 3rd decade of life, average age of 54 years • Obstructive physiology on pulmonary function tests • Treatment: Mucolytic therapy, physical therapy, and postural drainage

Mounier-Kuhn Syndrome • Difficult differentiation from MKS; ancillary findings, such interstitial lung disease are helpful

Abbreviations • Mounier-Kuhn syndrome (MKS)

PATHOLOGY

Synonyms

General Features

• Tracheobronchomegaly • Congenital tracheobronchomegaly

• Unknown etiology, most likely congenital • Sporadic association MKS with Ehlers-Danlos, Marfan, and cutis laxa syndromes suggests smooth muscle and connective tissue disorder • No documented hereditary pattern • History of cigarette smoking is common

Definitions • Rare disorder likely secondary to congenital defect or atrophy of elastic and smooth muscle components of trachea and mainstem bronchi with resultant significant central airway dilatation

IMAGING General Features • Best diagnostic clue ○ Abnormal dilatation of trachea and bronchi + protrusion of redundant musculomembranous tissue between adjacent cartilaginous rings with formation of tracheal diverticula – Scalloped or lobulated appearance of air column along tracheal and central bronchial walls

Radiographic Findings • Consider diagnosis when tracheal diameter exceeds that of adjacent vertebral bodies • Increased lung volume (from obstructive physiology)

CT Findings • Maximum normal tracheal diameters (mean + 3 standard deviations); measured 20 mm cephalad to aortic arch ○ Men: 27 mm (sagittal) and 25 mm (coronal) ○ Women: 23 mm (sagittal) and 21 mm (coronal) • Consider the diagnosis if ○ Trachea > 30 mm ○ Left mainstem bronchus > 23 mm ○ Right mainstem bronchus > 24 mm ○ Measurements > 3 standard deviations above normal are diagnostic of tracheobronchomegaly • Tracheobronchial diverticulosis (50%) ○ Best appreciated on sagittal reformatted images • Bronchiectasis (30-45%) • Tracheobronchomalacia (28%) ○ Significant tracheal luminal collapse (> 75% of inspiratory diameter) and expiratory air-trapping

Imaging Recommendations • Best imaging tool ○ HRCT: Expiratory imaging is critical to assess for associated tracheobronchomalacia

Large Airways Disease

TERMINOLOGY

Staging, Grading, & Classification • Type 1: Slight symmetric tracheal and mainstem bronchial dilatation • Type 2: Distinct tracheal dilatation and diverticula • Type 3: Diverticular and saccular structures involving distal bronchi

Gross Pathologic & Surgical Features • Numerous saccular diverticula between cartilages; bulging dilatation along posterior wall

Microscopic Features • Thinning of muscularis mucosa and atrophy of longitudinal muscle and elastic fibers • Loss of respiratory tract elastic fibers may be partial, complete and may exhibit patchy distribution • Absence of tracheal wall myenteric plexus

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Cough (> 70%), recurrent respiratory infection (50%), dyspnea (> 40%) ○ Common diagnosis of chronic obstructive pulmonary disease (> 25%) • Other signs/symptoms ○ Bronchial rales and wheezing on auscultation ○ Finger clubbing (common) ○ Obstructive physiology on pulmonary function tests

Demographics • Male predominance; M:F ratio = 8:1 • Most cases diagnosed after 3rd decade of life; average age of 54 years

Natural History & Prognosis • No definitive data available regarding disease progression • Anecdotal data suggest that once certain degree of airway dilatation has occurred, anatomic changes do not progress

Treatment

DIFFERENTIAL DIAGNOSIS Williams-Campbell Syndrome • Central bronchiectasis with normal trachea, mainstem bronchi, and segmental bronchi

Secondary Tracheobronchomegaly • Associated with some chronic pulmonary conditions (e.g., pulmonary fibrosis, chronic infection, emphysema)

• Mucolytic therapy, physical therapy, and postural drainage to facilitate expectoration

SELECTED REFERENCES 1. 2.

Krustins E: Mounier-Kuhn syndrome: a systematic analysis of 128 cases published within last 25 years. Clin Respir J. 10(1):3-10, 2016 Payandeh J et al: A clinical classification scheme for tracheobronchomegaly (Mounier-Kuhn syndrome). Lung. 193(5):815-22, 2015

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Large Airways Disease

Bronchocentric Granulomatosis KEY FACTS

TERMINOLOGY

PATHOLOGY

• Nonspecific inflammatory response pattern of lung parenchyma characterized by necrotizing granulomatous lesions along bronchi &/or bronchioles

• Bronchocentric granulomatosis should not be considered disease, but rather a descriptive pathological diagnosis • History of asthma in 50% of patients; associated with ABPA • 50% of patients are nonasthmatics ○ Associated with fungal, mycobacterial, bacterial, viral, and parasitic infections ○ Noninfectious associations: Rheumatoid arthritis, granulomatosis with polyangiitis, lung cancer, chronic granulomatous diseases

IMAGING • • • •

Soft tissue nodule(s)/mass(es) Consolidations (focal or multifocal) Atelectasis Findings of allergic bronchopulmonary aspergillosis (ABPA) in asthmatics (i.e., bronchiectasis and mucoid impaction)

TOP DIFFERENTIAL DIAGNOSES • • • • • •

Granulomatosis with polyangiitis Lung cancer Septic embolism Pulmonary metastases Bacterial pneumonia Lymphoma

(Left) Axial NECT of a patient with asthma and bronchocentric granulomatosis shows middle lobe varicose bronchiectasis ﬉ and an adjacent soft tissue mass ﬈. (Right) Axial NECT of the same patient shows a soft tissue mass ﬈ with a highattenuation component ﬉ related to inspissated mucus from allergic bronchopulmonary aspergillosis. Bronchiectasis and mucoid impaction are common in asthmatic patients with bronchocentric granulomatosis.

(Left) Composite image of the same patient with axial HASTE (left) and FIESTA MR (right) shows a middle lobe consolidation and an adjacent low signal intensity mass ﬉. (Right) Low-power photomicrograph (H&E stain) shows abundant intraluminal inflammatory infiltrate ﬈ and admixed fibrin ﬊. In some areas there is preservation of the bronchial wall and epithelium st, and in other areas there is airway wall destruction by granulomatous inflammation ﬉.

94

CLINICAL ISSUES • Asthmatics: Younger patients (20-40 years) • Nonasthmatics: Older patients (30-70 years)

DIAGNOSTIC CHECKLIST • In asthmatic patients ± ABPA, soft tissue nodules, &/or persistent consolidations not related to infection should suggest bronchocentric granulomatosis

Bronchocentric Granulomatosis

Abbreviations

Imaging Recommendations • Best imaging tool ○ HRCT

• Bronchocentric granulomatosis (BCG) • Allergic bronchopulmonary aspergillosis (ABPA)

DIFFERENTIAL DIAGNOSIS

Definitions

Granulomatosis With Polyangiitis

• Nonspecific inflammatory pulmonary response pattern characterized by necrotizing granulomatous lesions along bronchi &/or bronchioles

• • • • • •

IMAGING General Features • Best diagnostic clue ○ Imaging findings of BCG are typically nonspecific – Asthmatic patients with ABPA exhibit airway abnormalities such as central bronchiectasis and mucoid impaction – Nonasthmatic patients with ABPA exhibit nodules, masses, and consolidations • Location ○ Peribronchovascular distribution

Radiographic Findings • • • •

Nodule(s)/mass(es) Consolidations Atelectasis Reticulonodular opacities

CT Findings • HRCT ○ Nodule/mass – Single or multiple – Soft tissue attenuation – Variable size – Margins may be well or ill defined ○ Consolidation – Focal or multifocal – Upper lobe predominance – May exhibit mild associated atelectasis ○ Cavitation ○ Atelectasis ○ Other findings – Airways disease □ Tree-in-bud opacities □ Centrilobular nodules □ Bronchiectasis □ Mucoid impaction (may exhibit intrinsic high attenuation secondary to calcium deposits) □ Bronchial/bronchiolar wall thickening – Diffuse nodular or reticular opacities □ Correlates with diffuse granulomatous infiltration – Cystic lung disease □ Described in patient with associated tuberculosis – Hilar lymphadenopathy – Pleural effusion

Nuclear Medicine Findings • PET/CT ○ Anecdotal reports of intermediate FDG uptake in BCG lesions

Nodule &/or mass, usually multiple Halo and reversed halo signs Consolidation Large nodule, mass, or consolidation with cavitation Ground-glass opacity (related to alveolar hemorrhage) Systemic disease with renal and upper respiratory tract involvement; no extrapulmonary involvement in BCG

Large Airways Disease

TERMINOLOGY

Lung Cancer • • • • •

Most common cause of lung mass in adult Upper lobe predominance Irregular, lobulated, or spiculated borders Lymphadenopathy Smoking history

Septic Embolism • • • • •

Multiple well-defined nodules Peripheral predominance Varying degrees of cavitation Feeding vessel sign Systemic infection or infected distant site

Pulmonary Metastases • • • •

Multiple well- or ill-defined nodules Peripheral predominance Halo sign (hypervascular primary malignancy) Known primary malignancy

Bacterial Pneumonia • • • •

Lobar or peribronchial consolidation Air bronchograms Pleural effusion Acute clinical presentation

Lymphoma • Nodule/mass ○ Single or multiple ○ Air bronchograms ○ Cavitation • Consolidation • Interlobular septal thickening • Peribronchovascular and interstitial thickening • Mediastinal/hilar lymphadenopathy • Pleural effusion

Organizing Pneumonia • Consolidation ○ Peribronchovascular/subpleural, lower lobe predominance ○ Migratory opacities • Nodule/mass ○ Single or multiple ○ Reversed halo sign • Ground-glass opacity 95

Large Airways Disease

Bronchocentric Granulomatosis

PATHOLOGY General Features

Presentation

• BCG is not considered a specific disease but is rather a descriptive pathological diagnosis ○ Patients with asthma (50%) – Associated with ABPA □ Considered local hypersensitivity response to fungus – Some cases of BCG are described in asthmatic patients without evidence of ABPA ○ Nonasthmatic (50%) – Associated infections □ Fungi: Aspergillus fumigatus, Aspergillus terreus, Histoplasma capsulatum, Blastomyces dermatitidis □ Mycobacteria: Mycobacterium tuberculosis, Mycobacterium avium-intracellulare □ Bacteria: Enterobacter cloacae, Actinomyces meyeri, Nocardia spp. □ Viruses: Adenovirus, Epstein-Barr virus, influenza A virus □ Parasites: Echinococcus granulosus – Noninfectious associations □ Autoimmune disease: Rheumatoid arthritis, granulomatosis with polyangiitis □ Neoplasms: Lung cancer □ Others conditions: Heart-lung transplantation, bone marrow transplantation, red cell aplasia, and chronic granulomatous disease (and all its variants including p67phox deficiency; least common) □ In patients with rheumatoid arthritis, nodules associated with BCG may mimic necrobiotic nodules; definitive diagnosis requires biopsy □ Presence of BCG in lung mass biopsy specimen does not exclude lung cancer with postobstructive effects □ BCG in patients with lung cancer may represent immunologic response to tumor detritus, lipid, or mucoid impaction

• Most common signs/symptoms ○ Asthmatic patients – Men > women – Chronic asthma – Cough, fever, and wheezing – Peripheral eosinophilia – Positive prick test or precipitins to Aspergillus ○ Nonasthmatic patients – Equal gender distribution – Varied clinical manifestations range from absent or minimal symptoms to acute, febrile respiratory illness – No evidence of colonization or Aspergillus hypersensitivity • Other signs/symptoms ○ Hemoptysis, often associated with cavitary parenchymal lesions ○ Pneumothorax and acute respiratory failure (sporadic cases)

Gross Pathologic & Surgical Features • Nodules &/or masses • Peribronchovascular consolidation

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CLINICAL ISSUES

Demographics • Age at presentation varies according to associated condition ○ Asthmatics – Young patients (20-40 years) ○ Nonasthmatics – Older patients (30-70 years)

Natural History & Prognosis • May resolve spontaneously • Good response to corticosteroids • Some cases relapse when steroids are discontinued

Treatment • Treatment is often required • When single lesion is present, surgical resection (often performed for diagnosis) may be curative • When multiple lesions are present, treatment of choice is corticosteroid therapy

DIAGNOSTIC CHECKLIST

Microscopic Features

Consider

• Pattern of necrotizing granulomatous inflammation • Destroys bronchiolar walls and vascular elastica, replaced by palisading histiocytic reaction; giant cells may be present • Ulcerations of respiratory epithelium • Dilated airways with mucopurulent debris containing neutrophils and eosinophils may be prominent in cases associated with ABPA • Other associated pathogens include: Mycobacteria spp., B. dermatitides, H. capsulatum, E. granulosus, or Mucor spp. • Secondary inflammation involving vessel walls without necrotizing vasculitis • Eosinophils and fungal hyphae may be evident in lung lesions

• In asthmatic patients ± ABPA, presence of soft tissue nodules, &/or persistent consolidations not related to pulmonary infection should suggest diagnosis of BCG

SELECTED REFERENCES 1. 2. 3. 4.

Umezawa H et al: Idiopathic bronchocentric granulomatosis in an asthmatic adolescent. Respir Med Case Rep. 16:134-6, 2015 Bes C et al: Bronchocentric granulomatosis in a patient with rheumatoid arthritis. Rheumatol Int. 32(10):3261-3, 2012 Hurwitz LM et al: A 73-year-old woman with a cough. Chest. 128(2):1018-21, 2005 Ward S et al: Bronchocentric granulomatosis: computed tomographic findings in five patients. Clin Radiol. 55(4):296-300, 2000

Bronchocentric Granulomatosis Large Airways Disease

(Left) Axial NECT MIP reformation of a patient with bronchocentric granulomatosis and chronic cough shows clustered right upper lobe centrilobular nodules ﬈. Given the chronic symptoms and unchanged opacities on imaging, a sublobar resection was performed. (Right) Low-power photomicrograph (H&E stain) of the same patient shows bronchioles surrounded by intense lymphohistiocytic inflammation ſt. Note necrotic debris ﬇ in the bronchiolar lumen.

(Left) Axial NECT of a patient with bronchocentric granulomatosis shows upper lobe predominant peripheral consolidations ﬈ and groundglass opacities ﬉. (Right) Axial NECT of the same patient shows scattered centrilobular micronodules ﬊. Pulmonary nodules and consolidations are a more common manifestation of bronchocentric granulomatosis in patients without asthma. On the other hand, patients with asthma more commonly exhibit bronchiectasis and mucoid impactions.

(Left) Axial HRCT of a 46-yearold woman with bronchocentric granulomatosis shows peribronchovascular consolidations ﬊ surrounded by ground-glass opacities ﬉. (Right) Axial CECT of a 35year-old man with asthma and allergic bronchopulmonary aspergillosis shows right upper lobe consolidation with extensive intrinsic highattenuation inspissated mucus ﬈. In the setting of allergic bronchopulmonary aspergillosis, high-attenuation mucus is often related to deposits of calcium salts.

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SECTION 4

Small Airways Disease

Approach to Small Airways Disease Infectious Bronchiolitis Diffuse Aspiration Bronchiolitis Respiratory Bronchiolitis Follicular Bronchiolitis Hypersensitivity Pneumonitis Diffuse Panbronchiolitis Idiopathic Constrictive Bronchiolitis Swyer-James-MacLeod Syndrome Bronchiolitis Obliterans Syndrome Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH)

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Small Airways Disease

Approach to Small Airways Disease Introduction A wide variety of disease processes may involve the small airways, including neoplasms, infections, inflammatory disorders, iatrogenic conditions, and congenital abnormalities. Conditions affecting the small airways may result in focal, diffuse, or regional airway abnormalities, and affected patients may present with nonspecific clinical symptoms, such as cough and dyspnea. In contrast to conditions affecting the large airways, symptoms such as wheezing and stridor are uncommon. Imaging plays an important role in the evaluation of patients with suspected small airways disease and can usually lead to the correct diagnosis when paired with pertinent clinical information.

Imaging Chest radiography is typically the 1st imaging examination performed to evaluate patients who present with symptoms related to small airways disease. In many instances, the abnormalities are subtle and may not be detectable on radiography. Abnormalities, such as postobstructive atelectasis, pneumonitis, and consolidation, are more likely to be detected as well as associated findings such as masses, lymphadenopathy, and pleural effusion. However, the imaging modality of choice for the evaluation of airway abnormalities is thin-section CT. The continued expansion of image postprocessing techniques has enabled advanced methods of evaluating the airways, such as virtual bronchoscopy. Volume and surface-rendered displays provide 3D views of the external airway walls and the airway lumina. Disease processes affecting the small airways can generally be classified into conditions resulting in bronchiolitis due to infection, inflammation, and antigenic exposure, those affecting the lungs and airways, such as hypersensitivity pneumonitis (HP), and neoplasms. A few of these entities are discussed herein. In the majority of cases, pulmonary nodules are the predominant abnormality. Infectious Bronchiolitis Infectious bronchiolitis is classified as a type of cellular bronchiolitis resulting from bacterial, fungal, or viral infection. On HRCT/CT, the most common findings include centrilobular micronodules (measuring ≤ 3 mm) that spare the subpleural lung. These nodules represent bronchiolar filling in the centers of secondary pulmonary lobules. Chronic disease is typically the result of infection by nontuberculous mycobacteria (NTMB) and Pseudomonas organisms, which produce bronchiectasis in the middle lobe and lingula, or tuberculosis and cavitary NTMB, which result in upper lobepredominant abnormalities, including cavitation, tree-in-bud opacities, nodules, masses, &/or consolidations. Diffuse Aspiration Bronchiolitis Diffuse aspiration bronchiolitis represents chronic bronchiolar inflammation secondary to recurrent aspiration of foreign particles. Several risk factors that predispose patients to aspiration have been identified, including conditions of esophageal (e.g., achalasia, esophagitis, esophagectomy, dysmotility, gastroesophageal reflux, hiatus hernia), neurologic (e.g., cerebrovascular accident, brain injury, Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis, myotonic dystrophy, dementia), and gastric (e.g., gastroparesis, gastric banding) etiology. On HRCT/CT, diffuse aspiration bronchiolitis manifests as centrilobular nodules &/or tree-in-bud opacities, most of 100

which are of solid attenuation, although ground-glass nodules may also occur. These nodules tend to be most pronounced in the dependent regions of the lungs but may be identified in the antidependent lung due to dispersion of aspirated material. Other findings include scattered ground-glass opacities, bronchial wall thickening &/or cylindrical bronchiectasis secondary to chronic inflammation, mosaic attenuation and expiratory air-trapping, and aspirated material in the airways. Respiratory Bronchiolitis Respiratory bronchiolitis (RB) is classified as a smoking-related lung disease but is a common incidental histopathological finding in current or former smokers. By definition, affected patients are asymptomatic. On HRCT/CT, RB results in centrilobular micronodules that are poorly defined and exhibit ground-glass attenuation. These nodules tend to spare the subpleural and interlobular interstitium and may improve or persist after smoking cessation. Other features include upper lobe-predominant ground-glass opacities, bronchial wall thickening, and expiratory air-trapping. Hypersensitivity Pneumonitis HP represents an allergic inflammatory response of the lung parenchyma and airways to inhaled organic antigens. It has classically been divided into acute, subacute, and chronic types based on clinical findings and extrapolated imaging and pathologic features. A newer classification scheme has been proposed with 2 clusters (i.e., 1 and 2) that incorporate clinical, imaging, and pathological findings. Cluster 1 is characterized by symptoms that occur hours after exposure and may be recurrent, and cluster 2 is characterized by chronic signs and symptoms, such as digital clubbing, hypoxemia, and inspiratory crackles. On HRCT/CT, cluster 1 HP results in diffuse ground-glass opacities, interlobular septal thickening, and pleural effusions. Ground-glass centrilobular nodules, mosaic attenuation, and air-trapping may also be present. Cluster 2 HP manifests as peribronchovascular &/or subpleural reticulation ± honeycombing. The presence of preexistent reticular opacities or honeycombing and new diffuse opacities ± new traction bronchiectasis/bronchiolectasis should raise suspicion for acute exacerbation of the disease. Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a neuroendocrine cell proliferation associated with constrictive bronchiolitis, tumorlets, and carcinoid tumors. DIPNECH syndrome is defined as symptomatic neuroendocrine cell proliferations and clinical constrictive bronchiolitis. Because the disease involves the small airways, clinical symptoms at presentation may be mistaken for asthma. On HRCT/CT, multifocal pulmonary nodules are typically present, most measuring < 5 mm, and may exhibit solid or ground-glass attenuation and a bronchiolocentric distribution. Mosaic attenuation on inspiratory imaging may correlate with multifocal air-trapping on expiration.

Selected References 1. 2.

Elicker BM et al: Multidisciplinary approach to hypersensitivity pneumonitis. J Thorac Imaging. 31(2):92-103, 2016 Abbott GF et al: Imaging of small airways disease. J Thorac Imaging. 24(4):285-98, 2009

Approach to Small Airways Disease Small Airways Disease

(Left) Axial CECT of a patient with infectious bronchiolitis shows right lower lobe centrilobular nodules and treein-bud opacities ﬈ and adjacent subsegmental atelectasis or consolidation ﬉. (Right) Axial NECT of a patient with diffuse aspiration bronchiolitis shows numerous small lower lobe nodules, right lower lobe consolidation ﬈ due to recurrent aspiration and pneumonia, and trace right pleural effusion ﬉. Pulmonary abnormalities demonstrate a predilection for the dependent aspects of the lungs.

(Left) Axial NECT of an asymptomatic patient with a long history of cigarette smoking demonstrates numerous ill-defined centrilobular ground-glass micronodules ﬈ in the bilateral upper lobes consistent with respiratory bronchiolitis. (Right) Axial CECT of a patient with hypersensitivity pneumonitis demonstrates numerous illdefined ground-glass centrilobular micronodules ﬈ in the upper lobes. These findings are characteristic of cluster 1 hypersensitivity pneumonitis.

(Left) Axial NECT of a patient with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia shows numerous pulmonary nodules ﬈ in the left lower lobe. The larger nodules were biopsyproven carcinoid tumors ﬊. (Right) Coronal CECT of a patient with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia shows multiple bilateral small pulmonary nodules ﬈ associated with mosaic attenuation ﬉. The constellation of imaging findings should suggest the diagnosis.

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Small Airways Disease

Infectious Bronchiolitis KEY FACTS

TERMINOLOGY • Cellular bronchiolitis resulting from bacterial, fungal, or viral infection

IMAGING • Centrilobular nodules: ≤ 3-mm regularly spaced nodules that spare subpleural lung, representing bronchiolar filling in centers of secondary pulmonary lobules • Acute ○ Centrilobular nodules – Solid, discrete, associated with tree-in-bud pattern ○ Bronchial wall thickening ○ ± ground-glass or consolidation ○ ± air-trapping • Chronic ○ Nontuberculous mycobacteria (NTMB) and Pseudomonas – Bronchiectasis – Middle lobe and lingula tend to exhibit more advanced disease

(Left) PA chest radiograph of a patient with acute infectious bronchiolitis secondary to respiratory syncytial virus shows bilateral ill-defined reticulonodular opacities bilaterally. (Right) Coronal HRCT of the same patient shows diffuse bilateral tree-inbud nodules and scattered upper lobe ground-glass opacities ﬈. Respiratory syncytial virus is the most common viral cause of acute infectious bronchiolitis. RSV infection in children has been linked with an increased incidence of asthma.

(Left) AP chest radiograph of a patient with acute infectious bronchiolitis due to Mycoplasma pneumoniae infection shows bilateral illdefined opacities predominantly involving the right midlung zone ﬈. (Right) Axial HRCT MIP reformation of the same patient shows bilateral tree-in-bud ﬊ and ground-glass ﬈ opacities. Tree-in-bud opacities are the most common manifestation of community-acquired M. pneumoniae pneumonia. These opacities can eventually coalesce into overt consolidations.

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○ Tuberculosis and cavitary NTMB – Upper lobe predominant involvement – Tree-in-bud nodules + cavitation + nodules, masses, or consolidations

TOP DIFFERENTIAL DIAGNOSES • Aspiration bronchiolitis • Diffuse panbronchiolitis

PATHOLOGY • Acute bronchiolar injury, epithelial necrosis, bronchiolar wall inflammation and edema, intraluminal exudate

CLINICAL ISSUES • Acute: Clinical symptoms similar to those of acute pneumonia • Chronic ○ NTMB: Often asymptomatic, chronic cough ○ Tuberculosis: Chronic cough, weight loss, fever • Treatment: Supportive care, antimicrobials

Infectious Bronchiolitis

DIFFERENTIAL DIAGNOSIS

Abbreviations

Aspiration Bronchiolitis

• Nontuberculous mycobacteria (NTMB) • Respiratory syncytial virus (RSV)

• Often indistinguishable from infectious bronchiolitis • Risk factors for aspiration (e.g., esophageal dysmotility, neurologic impairment, head and neck malignancies) • Predilection for dependent lung

Definitions • Cellular bronchiolitis resulting from bacterial, fungal, or viral infection

IMAGING General Features • Best diagnostic clue ○ CT: Centrilobular &/or tree-in-bud nodules • Morphology ○ Centrilobular nodules, usually solid – Ground-glass nodules may occur in setting of viral bronchiolitis

Radiographic Findings • Acute ○ May be normal ○ Normal to increased lung volumes ○ Nodular or reticulonodular opacities ○ Bronchial wall thickening • Chronic ○ NTMB and Pseudomonas: Reticulonodular opacities ○ Tuberculosis (postprimary pattern) and cavitary NTMB: Upper lobe cavitary nodules, masses, or consolidations

CT Findings • Centrilobular nodules: ≤ 3-mm regularly spaced nodules that spare subpleural lung, representing bronchiolar filling in centers of secondary pulmonary lobules ○ Tree-in-bud pattern: Subset of centrilobular nodules in which centrilobular and branching X- or Y-shaped opacities coexist • Acute ○ Centrilobular nodules – Usually solid and discrete, often with associated treein-bud pattern – May exhibit ground-glass attenuation ○ Bronchial wall thickening ○ ± ground-glass opacities or consolidations – May be lobular, particularly when caused by Mycoplasma pneumoniae – Consolidation common in infections from adenovirus, M. pneumoniae, and mycobacteria ○ ± air-trapping – Common in viral infections, particularly RSV • Chronic ○ NTMB and Pseudomonas – Bronchiectasis – Mosaic attenuation, air-trapping – Middle lobe and lingula tend to exhibit more advanced disease ○ Tuberculosis and cavitary NTMB – Upper lobe predominant involvement – Tree-in-bud nodules + cavitation + nodules, masses or consolidations

Diffuse Panbronchiolitis

Small Airways Disease

TERMINOLOGY

• Common clinical context: Asian patients (e.g., from Japan or Korea)

PATHOLOGY General Features • Etiologies ○ Acute – Viral (e.g., RSV, parainfluenza, rhinovirus, metapneumovirus) – Bacterial (e.g., M. pneumoniae, Haemophilus influenzae) – Immunocompromise: Fungal (Aspergillus fumigatus) ○ Chronic – Mycobacteria (tuberculosis and NTMB) – Pseudomonas species

Gross Pathologic & Surgical Features • Histopathology: Acute bronchiolar injury, epithelial necrosis, bronchiolar wall inflammation and edema, intraluminal exudate • ± injury to mucosa, bronchiolar wall fibrosis

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Acute: Similar to acute pneumonia ○ Chronic – NTMB: Often asymptomatic, chronic cough – Tuberculosis: Chronic cough, weight loss, fever

Demographics • Most common cause of hospitalization among infants in USA • Adult disease varies with immune status ○ Immunocompetent: Bacteria (Mycoplasma), viruses (parainfluenza), mycobacteria (tuberculous and NTMB) ○ Immunocompromised with human immunodeficiency virus infection: Fungi (A. fumigatus), tuberculosis ○ Immunocompromised after stem cell transplant: Viruses (RSV, parainfluenza)

Treatment • Supportive care, antimicrobials

SELECTED REFERENCES 1. 2. 3. 4.

Ketai L et al: Imaging infection. Clin Chest Med. 36(2):197-217, viii, 2015 Hasegawa K et al: Infectious pathogens and bronchiolitis outcomes. Expert Rev Anti Infect Ther. 12(7):817-28, 2014 Franquet T: Imaging of pulmonary viral pneumonia. Radiology. Jul;260(1):1839, 2011 Abbott GF et al: Imaging of small airways disease. J Thorac Imaging. 24(4):285-98, 2009

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Infectious Bronchiolitis

(Left) AP chest radiograph of a patient with postprimary pattern of tuberculosis shows right worse than left upper lobe heterogeneous opacities with intrinsic lucency ﬈ concerning for cavitation. (Right) Axial NECT of the same patient shows extensive bilateral tree-in-bud opacities and a right upper lobe cavitary consolidation ﬈. This appearance is classic for the postprimary pattern of tuberculosis. Affected patients should be immediately isolated until tuberculosis is excluded to avoid dissemination of disease.

(Left) Axial CECT of a patient with cavitary (or classic) nontuberculous mycobacterial infection shows multifocal bilateral upper lobe pulmonary cavities ﬈ amid a background of emphysema ﬉. (Right) Axial CECT MIP reformation of same patient shows bilateral centrilobular and tree-in-bud nodules. Cavitary nontuberculous mycobacterial infection is indistinguishable from tuberculosis with postprimary pattern on imaging. Common related mycobacteria include M. avium complex and M. kansasii.

(Left) PA chest radiograph of a patient with bronchiectatic (or nonclassic) nontuberculous mycobacterial infection shows left worse than right mid and lower lung zone reticular opacities. Note obscuration of the right and left heart borders indicating middle lobe and lingular involvement, respectively. (Right) Axial HRCT of the same patient shows extensive bronchiectasis and volume loss involving the middle lobe ﬊ and lingula ﬈ and multifocal bilateral tree-in-bud opacities ﬉ in the lower lobes.

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Infectious Bronchiolitis Small Airways Disease

(Left) Axial NECT of a patient with chronic bronchiectatic nontuberculous mycobacterial infection shows middle lobe ﬊ and lingular ﬈ bronchiectasis and consolidation and centrilobular nodules ﬉ in the bilateral lower lobes, some of which have a branching treein-bud configuration. (Right) Coronal CECT of a patient with acute M. pneumoniae pneumonia demonstrates solid ﬈ and ground-glass ﬊ centrilobular nodules and multifocal lower lobe nodular consolidations ﬉.

(Left) Axial CECT of a patient with acute herpes virus bronchiolitis shows multiple punctate ill-defined centrilobular nodules ﬈ and subtle ground-glass opacities ﬉. Note the regions of hyperlucency ﬊ suggestive of air-trapping. Air-trapping is a common marker of small airways disease and is often present in viral infectious bronchiolitis. (Right) Axial CECT of a patient with adenovirus pulmonary infection shows a dense right lower lobe consolidation ﬉ surrounded by centrilobular micronodules ﬈.

(Left) PA chest radiograph of a young woman with a postprimary pattern of tuberculosis shows a right upper lobe heterogeneous consolidation and volume loss. Note the adjacent ill-defined right lower lobe nodular opacities ﬈. (Right) Axial CECT MIP reformation of the same patient shows right upper lobe tree-in-bud opacities, consolidation ﬉, and a thick-walled cavity ﬊, characteristic of postprimary pattern of tuberculosis. The presence of tree-in-bud nodules is consistent with active tuberculosis infection.

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Small Airways Disease

Diffuse Aspiration Bronchiolitis KEY FACTS

TERMINOLOGY

CLINICAL ISSUES

• Chronic bronchiolar inflammation secondary to recurrent aspiration of foreign particles

• Symptoms: Chronic cough, dyspnea, sputum production • Signs: Wheezing, ± fever, ± decreased diffusing capacity for carbon monoxide (DLCO), ± obstructive pattern on pulmonary function tests • ~ 50% of patients asymptomatic (silent aspiration) • Risk factors ○ Esophageal (e.g., achalasia, esophagitis, esophagectomy, dysmotility, gastroesophageal reflux, hiatus hernia) ○ Neurologic (e.g., cerebrovascular accident, brain injury, Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis, myotonic dystrophy, dementia) ○ Gastric (e.g., gastroparesis, gastric banding) • Treatment directed at underlying condition

IMAGING • Centrilobular nodules with tree-in-bud configuration in dependent portions of lungs • Esophageal abnormality or hiatus hernia

TOP DIFFERENTIAL DIAGNOSES • Infectious bronchiolitis • Nontuberculous mycobacterial infection • Diffuse panbronchiolitis

PATHOLOGY • Lymphocytic infiltration of bronchiolar wall • Foreign material, foreign body granulomas, and multinucleated giant cells in bronchiolar lumen • Aspiration of legumes (lentils): Granulomatous bronchiolitis

(Left) PA chest radiograph of a patient with lentil aspiration pneumonia shows a right lower lung zone consolidation ﬉. Radiographic findings of aspiration bronchiolitis are typically nonspecific. (Right) Axial HRCT of the same patient shows bilateral diffuse micronodules that spare the subpleural lung and fissures, characteristic of a centrilobular distribution. Lentil pneumonia is a subtype of diffuse aspiration bronchiolitis that specifically refers to aspiration of legumes, which may elicit a granulomatous reaction.

(Left) Axial HRCT of the same patient shows middle lobe consolidation ﬈ and bilateral lower lobe centrilobular micronodules. (Right) Lowpower photomicrograph (H&E stain) of the same patient shows bronchiolocentric noncaseating granulomas ﬈ surrounding central leguminous starch granules. The diagnosis of diffuse aspiration bronchiolitis is challenging because it may mimic other entities such as infectious or follicular bronchiolitis, and open lung biopsy is often required for definitive diagnosis.

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DIAGNOSTIC CHECKLIST • Consider diffuse aspiration bronchiolitis in patients with centrilobular nodules in dependent portions of lungs ± risk factors for aspiration

Diffuse Aspiration Bronchiolitis

Abbreviations

Nontuberculous Mycobacterial Infection • Bronchiectatic form may mimic DAB; both may coexist • Predilection for middle lobe and lingular involvement

• Diffuse aspiration bronchiolitis (DAB)

Synonyms

PATHOLOGY

• Aspiration bronchiolitis

Microscopic Features

Definitions

• Chronic bronchiolar wall inflammation ○ Lymphocytic infiltration of bronchiolar wall • Foreign material, foreign body granulomas, and multinucleated giant cells in bronchiolar lumen ○ Foreign material optimally visualized with polarized light • Aspiration of legumes (also known as lentil pneumonia) ○ Granulomatous bronchiolitis

• Chronic bronchiolar inflammation secondary to recurrent aspiration of foreign particles • Lentil pneumonia related to granulomatous reaction from aspiration of legumes (e.g., peas, lentils, or beans)

IMAGING General Features • Best diagnostic clue ○ Centrilobular or tree-in-bud nodules in patient with risk factors for aspiration

Radiographic Findings • Small nodular opacities in dependent portions of lungs, most commonly lower lobes

CT Findings • Centrilobular or tree-in-bud nodules ○ Most often solid; rarely ground-glass opacity nodules ○ May be focal or diffuse ○ More numerous in dependent regions of lungs – Nodules may occur in antidependent lung, as cough can disperse aspirated material • Scattered ground-glass opacities • Bronchial wall thickening &/or cylindrical bronchiectasis secondary to chronic inflammation • Aspirated debris may be visible within central bronchi • Mosaic attenuation and expiratory air-trapping • Focal consolidation (rare) • Esophageal abnormality (e.g., dilatation, air-fluid level, mass, achalasia, hiatal hernia) • Lentil aspiration pneumonia ○ Centrilobular nodules, often in dependent lung ○ Range from micronodules to 1-cm nodules

Imaging Recommendations • Best imaging tool ○ CT demonstrates centrilobular nodules and may show esophageal abnormality ○ MIP reformations increase nodule conspicuity • Protocol advice ○ HRCT or thin-section CT ○ MIP reformations help highlight centrilobular nodules

DIFFERENTIAL DIAGNOSIS Infectious Bronchiolitis • Fever in patients with acute infection • Clinical and CT features may be identical to those of DAB • Clinical risk factors for aspiration and dependent location of abnormalities should favor DAB

Diffuse Panbronchiolitis

Small Airways Disease

TERMINOLOGY

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Chronic cough, dyspnea, sputum production ○ Wheezing, ± fever, ± decreased diffusing capacity for carbon monoxide (DLCO), ± obstructive pattern on pulmonary function tests ○ ~ 50% of patients asymptomatic (silent aspiration) • Clinical profile ○ Risk factors – Esophageal (e.g., achalasia, esophagitis, esophagectomy, dysmotility, gastroesophageal reflux, hiatus hernia) – Neurologic (e.g., cerebrovascular accident, brain injury, Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis, myotonic dystrophy, dementia) – Gastric (e.g., gastroparesis, gastric banding) – Other (e.g., bedridden status, advanced age)

Demographics • Most commonly affects elderly due to increased risk factors • May affect young patients with unsuspected gastroesophageal reflux and silent aspiration

Natural History & Prognosis • Undiagnosed DAB may lead to chronic lung fibrosis • CT abnormalities (centrilobular nodules, ground-glass opacities) typically resolve after aspiration ceases

Treatment • Directed at underlying risk factors such as gastroesophageal reflux or esophageal abnormality

DIAGNOSTIC CHECKLIST Consider • Evaluation for aspiration (e.g., barium swallow, pH probe study) in patients with high suspicion of DAB

SELECTED REFERENCES 1. 2. 3.

Hu X et al: Diffuse aspiration bronchiolitis: analysis of 20 consecutive patients. J Bras Pneumol. 41(2):161-6, 2015 Prather AD et al: Aspiration-related lung diseases. J Thorac Imaging. 29(5):304-9, 2014 Marik PE: Pulmonary aspiration syndromes. Curr Opin Pulm Med. 17(3):14854, 2011

• Diffuse panbronchiolitis is almost exclusively seen in Asians 107

Small Airways Disease

Diffuse Aspiration Bronchiolitis

(Left) Barium esophagram of a patient with diffuse aspiration bronchiolitis secondary to achalasia shows marked dilatation of the esophagus and failure of antegrade flow of contrast. (Right) Axial NECT MIP reformation of the same patient shows bilateral treein-bud nodules ﬈ in the dependent and nondependent lung and marked esophageal dilatation ﬉. MIP reformation images increase the conspicuity of small nodules. Esophageal dilatation should suggest the diagnosis of diffuse aspiration bronchiolitis.

(Left) Axial HRCT of a patient with diffuse aspiration bronchiolitis demonstrates a large hiatal hernia ﬈ as the underlying etiology for aspiration. (Right) Axial HRCT of the same patient shows scattered tree-in-bud nodules ﬈ and some areas of bronchial wall thickening and cylindrical bronchiectasis ﬉. It is postulated that abnormalities in the nondependent regions of the lung represent transbronchial spread of disease related to cough or aspiration and occurring at night in different patient positions.

(Left) Frontal chest radiograph of a patient with diffuse aspiration bronchiolitis secondary to gastric banding ﬈ shows ill-defined nodular opacities throughout the left lung. (Right) Coronal NECT MIP reformation of the same patient shows ill-defined centrilobular nodules and ground-glass opacities in the left lung, most conspicuous in the left lower lobe. Diffuse aspiration bronchiolitis is a common complication of certain bariatric procedures and should be suspected when parenchymal abnormalities are present in such settings.

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Diffuse Aspiration Bronchiolitis Small Airways Disease

(Left) Frontal chest radiograph of a patient with severe gastroparesis shows multifocal ill-defined micronodular opacities bilaterally. (Right) Axial CECT of the same patient shows scattered centrilobular nodules throughout the right lung. Note that these micronodules spare the subpleural lung given their centrilobular distribution. Esophageal abnormalities as well as head/neck, gastric, and neurologic conditions predispose affected patients to chronic aspiration.

(Left) Axial CECT MIP reformation of the same patient shows centrilobular nodules. MIP reformations help differentiate centrilobular from miliary or perilymphatic nodules. (Right) Axial NECT of a patient with bronchoesophageal fistula shows centrilobular nodules ﬉ in the right upper lobe, ground-glass opacities ﬊ in the left upper lobe, and a bronchoesophageal fistula ﬈. Opacities in the anterior lung may be due to prone positioning or dissemination of aspirated material via coughing.

(Left) Axial CECT of a patient with diffuse aspiration bronchiolitis secondary to esophageal cancer shows bilateral centrilobular nodules ﬈, most pronounced in the bilateral posterior basilar lower lobes. Note esophageal wall thickening ﬊ secondary to neoplastic involvement. (Right) Axial CECT of a patient with chronic cough and diffuse aspiration bronchiolitis secondary to a moderate hiatal hernia ﬊ shows left lower lobe centrilobular nodules of solid and part-solid ﬉ attenuation.

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Respiratory Bronchiolitis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Respiratory bronchiolitis (RB) • Incidental histopathological finding in current or former smokers ○ Present in virtually all cigarette smokers

• Respiratory bronchiolitis interstitial lung disease • Desquamative interstitial pneumonia • Hypersensitivity pneumonitis, cluster 1

IMAGING

• RB, respiratory bronchiolitis interstitial lung disease, and desquamative interstitial pneumonia in spectrum of inflammatory lung diseases associated with cigarette smoking • Microscopic features ○ Accumulation of pigmented macrophages in lumina of respiratory bronchioles and alveoli ○ Mild nonspecific peribronchiolar alveolar septal thickening

• Radiography: Usually normal • CT ○ Centrilobular micronodules – Poorly defined, ground-glass attenuation – Spare subpleural and interlobular interstitium – May improve or persist after smoking cessation ○ MIP reformations help enhance visualization of micronodules ○ Ground-glass opacities – Upper lobe predominant ○ Expiratory CT: Air-trapping (lobular) ○ Central and peripheral bronchial wall thickening

(Left) Axial HRCT of a 29-yearold woman with a history of mixed tobacco and cocaine (known as basuko) use and respiratory bronchiolitis shows ground-glass centrilobular micronodules ﬈, tree-in-bud nodules ﬊, and emphysema ﬉. (Right) Composite image with axial CECT (left) and axial MIP reformation CECT (right) of a patient with respiratory bronchiolitis shows centrilobular ground-glass nodules ﬈, more conspicuous on the MIP reformation. Note that these nodules spare the subpleural lung ﬉, indicating their centrilobular location.

(Left) Low-power photomicrograph (H&E stain) shows respiratory bronchiolitis characterized by collections of lightly pigmented macrophages ﬊ within a bronchiole and adjacent alveolar spaces. Chronic bronchiolar and alveolar duct inflammation, interstitial inflammation, and fibrosis are common on histology. (Right) High-power photomicrograph (H&E stain) of the same specimen shows clustered pigmented macrophages with typical cytoplasmic blackyellow granules within a bronchiolar lumen.

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PATHOLOGY

CLINICAL ISSUES • Asymptomatic patients, 3rd-5th decades of life • Normal or slightly abnormal pulmonary function tests

Respiratory Bronchiolitis

Abbreviations • Respiratory bronchiolitis (RB)

Synonyms • Smoker's bronchiolitis

Definitions • Incidental histopathological finding in current or former smokers; present in virtually all cigarette smokers

IMAGING General Features • Best diagnostic clue ○ Centrilobular micronodules

Radiographic Findings • Chest radiographs are typically normal

CT Findings • HRCT ○ Micronodules – Distribution □ Centrilobular □ Spare subpleural and interlobular interstitium – Density □ Ground-glass attenuation – Contours □ Poorly defined – May improve or persist after smoking cessation ○ MIP reformations help enhance micronodule visualization ○ Ground-glass opacities – Diffuse – Upper lobe predominance ○ Expiratory CT – Air-trapping (lobular) ○ Central and peripheral bronchial wall thickening

Imaging Recommendations • Best imaging tool ○ HRCT

DIFFERENTIAL DIAGNOSIS Respiratory Bronchiolitis Interstitial Lung Disease • • • • • •

Symptoms: Wheezing and persistent nonproductive cough Central and peripheral bronchial wall thickening Centrilobular micronodules Upper lobe predominant ground-glass opacities Centrilobular emphysema Intralobular lines/reticular pattern

Desquamative Interstitial Pneumonia • Diffuse ground-glass opacities ○ Bilateral, may be symmetrical ○ Mid and lower zones predominance • Intralobular lines/reticular pattern and cysts • Traction bronchiectasis • Honeycombing usually absent

Hypersensitivity Pneumonitis, Cluster 1 • May be difficult to differentiate; tends to be more extensive • Diffuse ground-glass opacities • Centrilobular ground-glass micronodules • Mosaic attenuation and air-trapping • Upper lobe reticular opacities suggest hypersensitivity pneumonitis, cluster 2

Small Airways Disease

TERMINOLOGY

Aspiration Bronchiolitis • Centrilobular and tree-in-bud micronodules • Bronchial wall thickening, bronchiectasis, and mosaic attenuation • Risk factors: Neurological conditions, hiatus hernia, gastroesophageal reflux disease

PATHOLOGY General Features • RB, respiratory bronchiolitis interstitial lung disease (RBILD), and desquamative interstitial pneumonia form part of spectrum of inflammatory lung diseases associated with cigarette smoking • Patients with RB-ILD have histopathologic pattern of RB associated with pulmonary interstitial abnormalities + respiratory symptoms

Microscopic Features • Mild to moderate chronic inflammation and fibrosis may surround bronchioles and involve adjacent alveolar septa • Accumulation of pigmented macrophages (smoker's macrophages) within respiratory bronchioles and alveoli ○ Macrophages contain finely granular golden brown pigment, which is iron stain (+) • Mild nonspecific peribronchiolar alveolar septal thickening • Ancillary findings such as chronic bronchitis and emphysema are frequently present

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Asymptomatic ○ Normal or slightly abnormal pulmonary function tests without associated clinical manifestations

Demographics • 3rd-5th decades of life

DIAGNOSTIC CHECKLIST Image Interpretation Pearls • Centrilobular nodules in asymptomatic smoker

SELECTED REFERENCES 1. 2. 3. 4.

Madan R et al: Spectrum of smoking-related lung diseases: imaging review and update. J Thorac Imaging. 31(2):78-91, 2016 Margaritopoulos GA et al: Smoking-related idiopathic interstitial pneumonia: a review. Respirology. 21(1):57-64, 2016 Margaritopoulos GA et al: Smoking and interstitial lung diseases. Eur Respir Rev. 24(137):428-35, 2015 Portnoy J et al: Respiratory bronchiolitis-interstitial lung disease: long-term outcome. Chest. 131(3):664-71, 2007

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Follicular Bronchiolitis KEY FACTS

TERMINOLOGY

PATHOLOGY

• Follicular bronchiolitis (FB) • Pathological process characterized by lymphoid follicles with germinal centers along bronchial walls

• Primary or idiopathic FB • Secondary FB more common and may be associated with ○ Connective tissue diseases ○ Immunodeficiency ○ Hypersensitivity reactions ○ Infections

IMAGING • CT ○ Centrilobular nodules, may be diffuse, < 3 mm in diameter – Tree-in-bud opacities ○ Ground-glass opacities ○ Mosaic attenuation and expiratory air-trapping

TOP DIFFERENTIAL DIAGNOSES • • • • •

Lymphoid interstitial pneumonia Respiratory bronchiolitis Diffuse aspiration bronchiolitis Hypersensitivity pneumonitis Viral bronchiolitis

(Left) Axial HRCT of a 50-yearold man with rheumatoid arthritis and follicular bronchiolitis shows centrilobular nodules with a tree-in-bud configuration ﬈ and bronchial wall thickening ﬉. (Right) Axial HRCT of the same patient shows left upper lobe centrilobular micronodules ﬈. While imaging manifestations of follicular bronchiolitis are nonspecific, the presence of centrilobular micronodules in the absence of symptoms of pulmonary infection should raise suspicion for follicular bronchiolitis.

(Left) Low-power photomicrograph (H&E stain) shows follicular bronchiolitis characterized by germinal centers ﬊ surrounding bronchioles ﬈. These germinal centers correlate with centrilobular micronodules on HRCT. Note sparing of the pleura ﬉ typical of a centrilobular process. (Right) Low-power photomicrograph (H&E stain) shows follicular bronchiolitis characterized by lymphoid follicles with germinal centers ﬊ that surround and narrow adjacent bronchioles ﬈.

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CLINICAL ISSUES • Underlying connective tissue disease: Progressively worsening dyspnea (most common symptom) • Immunodeficiency: Recurrent pneumonia and dyspnea • Idiopathic: Cough

DIAGNOSTIC CHECKLIST • Consider FB in patient with connective tissue disease, without clinical evidence of infection, who exhibits centrilobular micronodules on CT

Follicular Bronchiolitis

Abbreviations • Follicular bronchiolitis (FB)

Synonyms • Bronchiolar nodular lymphoid hyperplasia • Hyperplasia of bronchus-associated lymphoid tissue (BALT)

Definitions • Pathological process characterized by lymphoid follicles with germinal centers along bronchial walls

DIFFERENTIAL DIAGNOSIS Lymphoid Interstitial Pneumonia • • • •

IMAGING General Features • Best diagnostic clue ○ CT: Centrilobular micronodules • Size ○ Micronodules (< 3 mm in diameter) • Morphology ○ Airway-centric process characterized by centrilobular micronodules – In contradistinction, micronodules of lymphoid interstitial pneumonia (LIP) are diffuse • May be associated with other patterns of diffuse lung disease ○ Centrilobular micronodules may not be predominant finding ○ Secondary FB: Predominant findings are dictated by underlying disease

Radiographic Findings • Chest radiographs are typically normal • Abnormal findings are nonspecific ○ Lung hyperinflation ○ Bronchial wall thickening ○ Ill-defined, small nodules

CT Findings • HRCT ○ Nodules – Distribution □ Centrilobular (most common): Bilateral and diffuse □ Peribronchovascular and subpleural (uncommon) □ Lower lobe predominant □ Micronodules are more profuse in areas of groundglass opacity – Size □ < 3 mm (i.e., micronodules) (common) □ 3-10 mm □ > 10 mm (rare) – Attenuation □ Ground-glass or soft tissue ○ Ground-glass opacities – Nonsegmental ○ Tree-in-bud opacities ○ Less common findings – Bronchial dilatation – Bronchial wall thickening – Mosaic attenuation – Air-trapping on expiratory CT

Centrilobular nodules Ground-glass opacities Diffuse interstitial involvement LIP vs. FB ○ LIP and FB may coexist ○ Pulmonary cysts more frequent in LIP than in FB ○ Differentiation requires biopsy

Small Airways Disease

– Cysts: Overexpanded air spaces caused by hyperinflation beyond partially obstructed bronchioles – Mediastinal or hilar lymphadenopathy

TERMINOLOGY

Respiratory Bronchiolitis and Respiratory Bronchiolitis Interstitial Lung Disease • • • •

Centrilobular nodules Ground-glass opacities Upper lung zone predominant Reticular opacities [respiratory bronchiolitis interstitial lung disease (RB-ILD)] • Peripheral bronchial wall thickening (RB-ILD) • History of cigarette smoking

Diffuse Aspiration Bronchiolitis • Tree-in-bud opacities and centrilobular micronodules • Bronchiectasis • Risk factors ○ Esophageal disease (hiatus hernia, achalasia, gastroesophageal reflux disease) ○ Neurological impairment affecting deglutition and esophageal motility

Hypersensitivity Pneumonitis • Ground-glass opacities • Ill-defined, centrilobular, ground-glass nodules • Mosaic attenuation and expiratory air-trapping ○ Head-cheese pattern: Coexistence of air-trapping, normal lung, and ground-glass opacities • Bronchial and bronchiolar wall thickening • Cysts • Reticular opacities with upper lobe zone predominance (cluster 2) • Nonsmokers

Pulmonary Langerhans Cell Histiocytosis • • • • •

Irregular stellate nodules Upper lobe predominance Nodules often cavitate Cysts: Bizarre shapes and nodular walls Association with cigarette smoking (95%)

Viral Bronchiolitis • Centrilobular micronodules • Consolidation • Clinical manifestations of acute respiratory infection

Diffuse Panbronchiolitis • Tree-in-bud opacities • Bronchiectasis and bronchiolectasis 113

Small Airways Disease

Follicular Bronchiolitis • Basilar and peripheral predominance • Severe pansinusitis • Patients from Asia (especially Korea and Japan)

Constrictive Bronchiolitis • • • •

Bronchiectasis Mosaic attenuation Expiratory air-trapping Occasionally centrilobular micronodules

PATHOLOGY General Features • Etiology ○ Antigenic stimulation of BALT-producing polyclonal lymphoid hyperplasia – Primary or idiopathic FB □ Variable incidence – Secondary FB □ Connective tissue diseases (rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome ) □ Other immunological disorders (Evans syndrome of autoimmune hemolytic anemia and immune thrombocytopenia; pernicious anemia) □ Immunodeficiency (AIDS, common variable immunodeficiency) □ Hypersensitivity reactions □ Infection (Pneumocystis jirovecii pneumonia, Legionella pneumonia, active hepatitis) □ Nonspecific airway-centered inflammation (bronchiectasis) □ Exposure to nylon; polyethylene flock □ Granulomatous lymphoid interstitial lung disease: Cellular interstitial pneumonia (combined granulomatous and lymphoproliferative disorder that may include FB) – Associated secondary histopathologic component □ Organizing pneumonia (OP) □ Nonspecific interstitial pneumonia (NSIP) □ Usual interstitial pneumonia (UIP) • Pathology ○ BALT – Subset of mucosa-associated lymphoid tissue (MALT) – May be absent in normal lung – Development depends on antigenic stimuli ○ Polyclonal proliferations are consistent with benign disease ○ Monoclonal lymphocyte proliferations are consistent with lymphoma

Microscopic Features • Hyperplastic lymphoid follicles with reactive peribronchiolar germinal centers ○ Minor interstitial component • LIP is similar, but there is widespread lymphocytic infiltration along alveolar septa and interstitium • Polyclonal lymphocytes based on immunohistochemistry • Hyperplastic follicles may be seen in interlobular septa and visceral pleura • Airway obstruction may lead to pneumonia, organizing pneumonia, or bronchiolar intraluminal neutrophilic exudate 114

• Reactive lymphoid follicles stain positively for pan-B-cell markers (CD20, CD79a) • Interstitial component, when present, stains positively for pan-T-cell markers (CD3, CD5) • Staining for Bcl-2 absent in reactive germinal centers but present in interstitial T cells • Polyclonal pattern present on polymerase chain reaction (PCR) for gene rearrangement (IgH-R)

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Underlying connective tissue disease – Progressively worsening dyspnea (most common symptom) – Diagnosis of connective tissue disease often precedes respiratory manifestations ○ Immunodeficiency (congenital or acquired) – Recurrent pneumonia – Dyspnea ○ Idiopathic FB – Cough – Peripheral eosinophilia • Other signs/symptoms ○ Pulmonary function tests with variable restrictive, obstructive, and mixed patterns

Demographics • Age ○ According to clinical presentation (primary or secondary) – Connective tissue disease: 5th decade of life – Immunodeficiency: Young adults or teenagers – Idiopathic FB: Middle-aged or elderly patients

Natural History & Prognosis • Overall good prognosis • Prognosis determined by age and underlying condition

Treatment • Idiopathic FB ○ Good response to corticosteroids • Secondary FB ○ Treatment is related to management of underlying disease • Recurrence may occur after discontinuation of corticosteroids

DIAGNOSTIC CHECKLIST Image Interpretation Pearls • Consider FB in patient with connective tissue disorder without clinical evidence of infection who exhibits centrilobular micronodules on CT

SELECTED REFERENCES 1. 2.

3.

Tashtoush B et al: Follicular bronchiolitis: a literature review. J Clin Diagn Res. 9(9):OE01-5, 2015 Carrillo J et al: Lymphoproliferative lung disorders: a radiologic-pathologic overview. Part I: Reactive disorders. Semin Ultrasound CT MR. 34(6):525-34, 2013 Aerni MR et al: Follicular bronchiolitis in surgical lung biopsies: clinical implications in 12 patients. Respir Med. 102(2):307-12, 2008

Follicular Bronchiolitis Small Airways Disease

(Left) Axial HRCT of a patient with follicular bronchiolitis shows left upper lobe peribronchovascular opacities ﬈ and parenchymal bands ﬉. (Right) Axial HRCT of a 50year-old man with follicular bronchiolitis shows bronchiectasis ﬈ and bronchiolectasis ﬊ in the bilateral upper lobes. While centrilobular micronodules are a common imaging abnormality in patients with follicular bronchiolitis, bronchial wall thickening and bronchiectasis are nonspecific and uncommon manifestations.

(Left) Axial HRCT of a 45-yearold woman with follicular bronchiolitis shows right upper lobe subpleural nodules ﬈. The presence of nodules > 1 cm is an uncommon CT finding in patients with follicular bronchiolitis. (Right) Axial HRCT of 42-year-old woman with follicular bronchiolitis shows bronchial wall thickening ﬊ and air-trapping with a lobular pattern. As any other bronchiolitis, follicular bronchiolitis is often associated with mosaic attenuation on inspiratory HRCT and air-trapping on expiratory HRCT.

(Left) Axial HRCT of a middleaged man with follicular bronchiolitis and organizing pneumonia pattern shows small solid ﬊ and groundglass opacity nodules ﬈ in the right upper lobe. (Right) Axial HRCT of a young man with follicular bronchiolitis and organizing pneumonia shows a right upper lobe, subpleural, mass-like consolidation st and a pulmonary nodule that exhibits the CT halo sign ſt. The presence of a mass or consolidation is an uncommon manifestation of follicular bronchiolitis.

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Hypersensitivity Pneumonitis KEY FACTS

• Allergic inflammatory response of lung parenchyma and airways to inhaled organic antigens or haptens • Historically classified as acute, subacute, and chronic types: Imaging and pathologic findings were extrapolated to fit clinical findings, but were never statistically validated • Newer classification proposes 2 clusters that incorporate clinical, imaging, and pathologic findings ○ Cluster 1: Symptoms occur hours after exposure and may be recurrent ○ Cluster 2: Chronic symptoms (e.g., clubbing, hypoxemia, inspiratory crackles)

IMAGING • HRCT/CT ○ Cluster 1: Diffuse ground-glass opacities, interlobular septal thickening, and pleural effusions – Ground-glass centrilobular nodules – Mosaic attenuation, air-trapping; head cheese sign

(Left) AP chest radiograph of a 57-year-old man with cluster 1 hypersensitivity pneumonitis (bird fancier's lung) demonstrates bilateral illdefined, heterogenous airspace opacities ﬈. (Right) Axial CECT of the same patient shows bilateral ground-glass opacities and interlobular septal thickening amid low-attenuation areas (mosaic attenuation). Groundglass opacities are a nonspecific finding of cluster 1 hypersensitivity pneumonitis. A high index of suspicion is required to suggest the diagnosis.

(Left) Axial HRCT of a patient with cluster 1 hypersensitivity pneumonitis shows diffuse, centrilobular ground-glass nodules and focal lobular airtrapping ﬈. Centrilobular ground-glass nodules are characteristic CT of cluster 1 hypersensitivity pneumonitis. Few entities exhibit similar findings (e.g., respiratory bronchiolitis on rare occasions). (Right) Low-power photomicrograph (H&E) stain of a specimen of cluster 1 hypersensitivity pneumonitis shows peribronchiolar interstitial inflammation and lymphocytic infiltration ﬈.

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○ Cluster 2: Peribronchovascular &/or subpleural reticulation ± honeycombing – Thin-walled, air-filled cysts (rare) – Acute exacerbation: Preexistent reticular opacities or honeycombing + new diffuse opacities ± new traction bronchiectasis/bronchiolectasis

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES • • • •

Acute interstitial pneumonia Respiratory bronchiolitis Idiopathic pulmonary fibrosis Nonspecific interstitial pneumonia

CLINICAL ISSUES • Cluster 1: Recurrent systemic symptoms (e.g., chills, fever, sweats, myalgias) • Cluster 2: Chronic symptoms (e.g., dyspnea, cough), clubbing, hypoxemia, inspiratory crackles • Treatment: Removal from exposure; corticosteroids

Hypersensitivity Pneumonitis

Abbreviations • Hypersensitivity pneumonitis (HP) • Idiopathic pulmonary fibrosis (IPF)

Synonyms • Extrinsic allergic alveolitis

Definitions • Allergic inflammatory response of lungs and airways to inhaled organic antigens or haptens (i.e., low molecular weight inorganic molecules) • Historically classified as acute, subacute, and chronic types (Richerson classification) ○ Predates availability of HRCT ○ Imaging and pathologic findings were extrapolated to fit clinical findings, but were never statistically validated • New classification proposes 2 clusters that incorporate clinical, imaging, and pathologic findings ○ Cluster 1: Symptoms occur hours after exposure and may be recurrent ○ Cluster 2: Chronic symptoms (e.g., clubbing, hypoxemia, inspiratory crackles)

IMAGING

• Cluster 2 ○ Chronic HP in Richerson classification ○ Peribronchovascular &/or subpleural reticulation ± honeycombing – Architectural distortion – Traction bronchiectasis – Superimposed findings of cluster 1 HP – Subpleural abnormalities identical to those of nonspecific interstitial pneumonia (NSIP) or UIP ○ Thin-walled, air-filled cysts (rare) ○ Emphysema (rare): May occur in never smokers ○ Organizing pneumonia (OP) (rare): Patchy peripheral opacities (may be migratory on serial imaging), reversed halo &/or atoll signs ○ Acute exacerbation of HP – Preexistent reticular opacities or honeycombing + new diffuse opacities ± new traction bronchiectasis/bronchiolectasis

Small Airways Disease

TERMINOLOGY

Imaging Recommendations • Best imaging tool ○ HRCT/CT • Protocol advice ○ Expiratory HRCT critical for identification of air-trapping ○ Prone HRCT critical for differentiating subtle subpleural abnormalities from dependent atelectasis

General Features • Best diagnostic clue ○ Cluster 1: Centrilobular ground-glass nodules and airtrapping ○ Cluster 2: Upper lobe peribronchovascular fibrosis

Radiographic Findings • Cluster 1 ○ Chest radiographs frequently normal ○ Nonspecific findings: Ill-defined opacities • Cluster 2 ○ Chest radiographs frequently normal ○ Upper lobe peribronchovascular reticular opacities &/or honeycombing ○ Subpleural honeycombing with apicobasal gradient identical to usual interstitial pneumonia (UIP) ○ Acute exacerbation of HP similar to acute exacerbation of IPF (i.e., development of diffuse opacities amid preexistent reticular opacities; requires exclusion of cardiogenic pulmonary edema)

CT Findings • Cluster 1 ○ May simulate exudative phase of diffuse alveolar damage (acute interstitial pneumonia) – Acute HP in Richerson classification – Diffuse ground-glass opacities – Interlobular septal thickening – Pleural effusions ○ Ground-glass centrilobular nodules – Subacute HP in Richerson classification ○ Mosaic attenuation, air-trapping ○ Head cheese sign – Combination of ground-glass opacities, air-trapping, and normal lung

DIFFERENTIAL DIAGNOSIS Acute Interstitial Pneumonia • Cluster 1 HP may be indistinguishable • Diffuse ground-glass opacities • Diagnosis often established histologically

Respiratory Bronchiolitis • Cluster 1 HP may be indistinguishable • Centrilobular ground-glass micronodules and air-trapping tend to be more severe in cluster 1 HP • Differentiation may require tissue sampling

Idiopathic Pulmonary Fibrosis • Cluster 2 HP may be indistinguishable • Appropriate clinical history is critical • Diagnosis often established on pathology

Nonspecific Interstitial Pneumonia • • • •

Cluster 2 HP may be indistinguishable Honeycombing is uncommon Appropriate clinical history is critical Diagnosis often established on pathology

Lymphoid Interstitial Pneumonia • Cluster 1 HP with cysts may simulate this diagnosis • History of Sjögren syndrome • Differentiation typically requires pathology

Sarcoidosis • Upper lobe-predominant peribronchovascular fibrosis • HP and sarcoidosis may be indistinguishable • Characteristic perilymphatic nodules (i.e., along fissures)

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Hypersensitivity Pneumonitis

PATHOLOGY General Features

Presentation

• Etiology ○ Inhaled antigens &/or haptens deposited along bronchiolar and alveolar epithelium elicit alveolitis and cellular bronchiolitis through type III and type IV immune hypersensitivity reactions – Bacterial, yeast, or avian antigens – Spores from macroscopic fungi – Chemical haptens: Isocyanates, zinc, inks, dyes – Other antigens: Viruses, endotoxins, β-glucan, anthrax vaccination – Other: Colistin, catechin (green tea extract), and methylmethacrylate

• Most common signs/symptoms ○ Cluster 1 – Symptoms occur hours after exposure and may be recurrent □ Systemic or influenza-like symptoms: Chills, fever, sweats, myalgias □ Chest tightness □ Cough, dyspnea – Recurrent systemic symptoms ○ Cluster 2 – Chronic symptoms: Dyspnea, cough – Other: Clubbing, hypoxemia, inspiratory crackles • Other signs/symptoms ○ Bronchoalveolar lavage (BAL) fluid: ↑ lymphocytes and predominance of CD8 cells over CD4 cells ○ Pulmonary function tests: Restrictive physiology, ↓ DLCO ○ Hot tub lung: Clinical, histopathologic, and imaging features of cluster 1 HP – BAL fluid culture shows nontuberculous mycobacteria ○ Acute exacerbation of cluster 2 HP – Rapidly progressive dyspnea (days to weeks) – Cough, fever, flu-like symptoms ○ Summer-type HP – Most prevalent HP in Japan, occurs in summer with recurrent episodes for several years – Symptoms elicited in home environment; demonstrates familial occurrence • Clinical predictors for diagnosis of HP ○ Exposure to known offending antigen ○ Positive precipitating antibodies ○ Recurrent symptoms ○ Inspiratory crackles ○ Symptoms 4-8 hours after antigenic exposure ○ Weight loss

Staging, Grading, & Classification • Historically classified as acute, subacute, and chronic (Richerson classification) based on clinical factors with imaging and pathologic findings; not statistically validated ○ Richerson classification – Acute □ Clinical presentation: Flu-like symptoms; 6-24 hours after exposure □ HRCT: Diffuse ground-glass opacities, interlobular septal thickening, and pleural effusions – Subacute □ Clinical presentation: Cough, dyspnea; gradual onset (days to weeks) □ HRCT: Specific findings; ground-glass centrilobular nodules and patchy (lobular) air-trapping – Chronic □ Clinical presentation: Cough, dyspnea, fatigue, weight loss, clubbing □ HRCT: Nonspecific findings; similar to those of pulmonary fibrosis with honeycombing and traction bronchiectasis • New classification recently proposed to incorporate clinical, imaging, and histologic findings ○ Cluster 1 (includes most former acute and subacute HP) ○ Cluster 2 (includes most chronic HP)

Microscopic Features • Cluster 1 ○ Neutrophil and eosinophil infiltration of alveolar spaces and small vessel vasculitis ○ Lymphocytic interstitial infiltration, poorly formed nonnecrotizing granulomas, cellular bronchiolitis ○ Diffuse alveolar damage • Cluster 2 ○ Poorly formed peribronchial noncaseating granulomas ± multinucleated giant cells ○ Bronchiolocentric lymphocytic and plasmatic alveolar wall infiltration ○ Peribronchiolar fibrosis ○ Constrictive bronchiolitis ○ Histologic features of UIP, NSIP, OP, and centrilobular fibrosis or bridging fibrosis (continuous fibrosis between centrilobular and subpleural locations) ○ Acute exacerbation of HP demonstrates features of diffuse alveolar damage and superimposed fibrosis 118

CLINICAL ISSUES

Demographics • 4-15% of all interstitial lung diseases • 0.5-3% of all farmers will develop HP

Natural History & Prognosis • May progress to fibrosis and death within few years • Factors associated with worse prognosis in chronic HP ○ Long period of antigenic exposure (bird fancier’s lung) ○ Histologic pattern of either fibrotic NSIP or UIP ○ Digital clubbing ○ Older age ○ Extensive bronchiectasis or honeycombing on CT • ↑ mortality among farmers and individuals in agricultural industries

Treatment • Usually responds to treatment ○ Removal from exposure; corticosteroids

SELECTED REFERENCES 1.

Elicker BM et al: Multidisciplinary approach to hypersensitivity pneumonitis. J Thorac Imaging. 31(2):92-103, 2016

Hypersensitivity Pneumonitis Small Airways Disease

(Left) Axial HRCT of a patient with cluster 1 hypersensitivity pneumonitis shows bilateral ground-glass opacities, interlobular septal thickening ﬈, and pleural effusions ﬉ that mimic pulmonary edema. A high index of suspicion and surgical biopsy are often required for diagnosis. (Right) Axial HRCT of a patient with cluster 1 hypersensitivity pneumonitis shows diffuse, illdefined centrilobular groundglass nodules. Note sparing of the perifissural lung ﬈ consistent with the centrilobular distribution of the abnormalities.

(Left) Axial HRCT of a patient with cluster 1 hypersensitivity pneumonitis shows mosaic attenuation and lobular airtrapping ﬈. While it remains a nonspecific finding, lobular air-trapping is characteristic of hypersensitivity pneumonitis. (Right) Composite image with axial inspiratory (left) and expiratory (right) HRCT of a patient with cluster 1 hypersensitivity pneumonitis demonstrates mosaic attenuation and head cheese pattern. While nonspecific, the latter is a common CT finding of hypersensitivity pneumonitis.

(Left) PA chest radiograph of a patient with cluster 2 hypersensitivity pneumonitis shows low lung volumes and extensive mid and upper lung zone reticular opacities. (Right) Axial HRCT of the same patient shows peribronchovascular groundglass and reticular opacities and associated traction bronchiectasis ﬈. Hypersensitivity pneumonitis is a classic example of lung disease leading to peribronchovascular fibrosis, which may progress to honeycombing.

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Small Airways Disease

Hypersensitivity Pneumonitis

(Left) Axial HRCT of a patient with cluster 2 hypersensitivity pneumonitis demonstrates upper lobe predominant peribronchovascular and subpleural reticular opacities ﬈ and honeycombing as well as scattered traction bronchiectasis ﬉. (Right) Low-power photomicrograph (H&E stain) of a specimen of cluster 2 hypersensitivity pneumonitis shows areas of interstitial pulmonary fibrosis ﬈ with temporal homogeneity. Also note loose peribronchiolar granulomas ﬊.

(Left) Axial HRCT of a patient with cluster 2 hypersensitivity pneumonitis shows subpleural fibrosis ﬉ and traction bronchiectasis ﬈ that may mimic other interstitial pneumonias. Coexisting expiratory air-trapping and centrilobular nodules suggest hypersensitivity pneumonitis, but the diagnosis is usually made histologically. (Right) Axial prone HRCT of a patient with cluster 2 hypersensitivity pneumonitis shows subpleural ground-glass opacities ﬈. Prone imaging allows differentiation of this finding from dependent atelectasis.

(Left) Low-power photomicrograph (H&E stain) of a specimen of cluster 2 hypersensitivity pneumonitis shows alveolar walls thickened by lymphocytic infiltration and giant cells ﬈, alveolar spaces filled with fibroblasts and myxoid stroma ﬊, and bronchiolar wall thickening ﬉. (Right) Highpower photomicrograph (H&E stain) of the same specimen shows a peribronchiolar granuloma ﬈ and intraluminal plugs of loose connective tissue in the distal airways ﬉ representing organizing pneumonia.

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Hypersensitivity Pneumonitis Small Airways Disease

(Left) Composite image with axial HRCT at baseline (left) and 4 years later (right) of a patient with hypersensitivity pneumonitis shows evolution from diffuse ground-glass opacities to peribronchovascular fibrosis with traction bronchiectasis ﬈. (Right) Composite image with axial inspiratory HRCT at baseline (left) and 5 years later (right) of a patient with hypersensitivity pneumonitis shows evolution from subtle subpleural ground-glass opacities ﬈ to frank fibrosis ﬉ with traction bronchiectasis ﬊.

(Left) Axial HRCT of a patient with cluster 2 hypersensitivity pneumonitis shows lung cysts ﬈, air-trapping ﬊, and peribronchovascular fibrosis with reticulation and traction bronchiectasis ﬉. (Right) Axial HRCT of a patient with hypersensitivity pneumonitis shows the presence of a thinwalled lung cyst ﬈ amid a background of emphysema. Cysts are a rare but welldescribed finding of hypersensitivity pneumonitis. Emphysema, also rare, may occur even in patients that do not smoke.

(Left) Axial NECT of a patient with hypersensitivity pneumonitis and organizing pneumonia shows multifocal opacities, many exhibiting the reversed halo ﬈ or atoll sign. While this imaging appearance is uncommon in the setting of hypersensitivity pneumonitis, organizing pneumonia is a frequent ancillary finding on histology. (Right) Intermediate-power photomicrograph (H&E stain) of a specimen from the same patient shows budding fibrosis ﬈ protruding into the lumina of alveolar ducts and bronchioles.

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Small Airways Disease

Diffuse Panbronchiolitis KEY FACTS

TERMINOLOGY

PATHOLOGY

• Diffuse panbronchiolitis: Rare syndrome of unknown cause characterized by cellular bronchiolitis and chronic sinusitis

• Infiltration of respiratory bronchiolar walls by lymphocytes, plasma cells, and foamy histiocytes

IMAGING

CLINICAL ISSUES

• Radiography ○ Diffuse small nodules ≤ 5 mm in diameter ○ Mid and lower lung zone reticulonodular pattern • CT ○ Early stage: Centrilobular micronodules and tree-in-bud opacities ○ Bronchiolectasis/bronchiectasis and mosaic attenuation appear as disease evolves

• Symptoms ○ Early stage: Chronic cough, exertional dyspnea, wheezing, and hypoxemia ○ Progression: Fever, Pseudomonas aeruginosa infection ○ Late stage: Large amounts of purulent sputum and eventual respiratory failure • Demographics ○ Mean age: 40 years; male predominance ○ East Asians (i.e., Japan, Korea, and China); sporadic cases worldwide

TOP DIFFERENTIAL DIAGNOSES • • • •

Nontuberculous mycobacterial infection Primary ciliary dyskinesia Primary immunodeficiency syndromes Inflammatory bowel disease

(Left) PA chest radiograph of a female patient from East Asia with diffuse panbronchiolitis shows diffuse bilateral reticulonodular opacities. (Right) Axial HRCT of the same patient shows mosaic attenuation, scattered tree-inbud opacities ﬉, bronchiectasis, and bronchial wall thickening ﬈. The constellation of findings is the most commonly seen in diffuse panbronchiolitis; however, it may occur in other cellular bronchiolitides such as nontuberculous mycobacterial infection and diffuse aspiration bronchiolitis.

(Left) Axial CECT of a 56-yearold Korean man with diffuse panbronchiolitis shows bilateral multifocal bronchiectasis ﬈, bronchial wall thickening, mucus plugging ﬊, peribronchial consolidation ﬉, and mild mosaic attenuation. Sputum culture grew Pseudomonas aeruginosa. (Right) Low-power photomicrograph (H&E stain) of a specimen of diffuse panbronchiolitis shows extensive transmural and peribronchial inflammatory infiltration ﬊ and mildly affected alveoli ﬈.

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DIAGNOSTIC CHECKLIST • Consider DPB in East Asians with chronic sinusitis, tree-inbud opacities, &/or bronchiectasis/bronchiolectasis

Diffuse Panbronchiolitis

CLINICAL ISSUES

Abbreviations

Presentation

• Diffuse panbronchiolitis (DPB)

• Most common signs/symptoms ○ Chronic sinusitis may precede pulmonary symptoms by years or decades ○ Early stage: Chronic cough, exertional dyspnea, wheezing, and hypoxemia ○ Progression: Yellowish sputum, fever, and Pseudomonas aeruginosa superinfection ○ Late stage: Large amounts of purulent sputum related to bronchiolectasis and eventual respiratory failure • Clinical profile ○ Pulmonary function tests – Obstructive pattern – Less degree of hyperresponsiveness than in chronic obstructive pulmonary disease or asthma – ↓ diffusing capacity for carbon monoxide – Hypoxemia ○ Genetic factors – HLA-B54 in Japan and HLA-A11 in Korea ○ Environmental factors: Rare among individuals of Asian ancestry living abroad ○ Underlying systemic disease: Cases of recurrence after lung transplantation

Definitions • Rare syndrome of unknown etiology characterized by cellular bronchiolitis and chronic sinusitis ○ Diffuse: Bilateral lung involvement ○ Panbronchiolitis: Involves all layers of respiratory bronchiole wall

IMAGING General Features • Best diagnostic clue ○ Tree-in-bud opacities, bronchiectasis/bronchiolectasis and peripheral mosaic attenuation

Radiographic Findings • Diffuse small nodules ≤ 5 mm in diameter • Reticulonodular pattern with mid and lower lung zone predominance • Lung hyperinflation • Bronchial wall thickening, bronchiectasis (advanced cases)

CT Findings • Early stage: Centrilobular micronodules and tree-in-bud opacities • Bilateral tree-in-bud opacities, bronchiectasis, bronchiolectasis, and mosaic attenuation as disease evolves

Imaging Recommendations • Best imaging tool ○ HRCT/CT

DIFFERENTIAL DIAGNOSIS Nontuberculous Mycobacterial Infection • Bronchiectasis similar to that of DPB but less diffuse involvement alternating with spared areas • Abnormalities more severely affect middle lobe and lingula • Discrete cavitary and noncavitary nodules may be present

Primary Ciliary Dyskinesia • Chronic rhinosinusitis and bronchiectasis • Earlier onset of symptoms and signs

Primary Immunodeficiency Syndromes • Congenital deficiency of immunoglobulins (IgM, IgG, IgA) • Chronic rhinosinusitis and bronchiectasis

Inflammatory Bowel Disease • Diffuse bronchiectasis • History of abdominal involvement

PATHOLOGY Microscopic Features • Infiltration of respiratory bronchiolar walls by lymphocytes, plasma cells, and foamy histiocytes • Secondary bronchiolectasis of proximal terminal bronchioles, related to narrowing and constriction of respiratory bronchioles

Small Airways Disease

TERMINOLOGY

Demographics • Age ○ Mean: 40 years • Gender ○ Male predominance • Ethnicity ○ East Asia: Japan, Korea, and China; sporadic cases described worldwide ○ 1/2 of cases in Western countries involve Asian immigrants • Epidemiology ○ 2/3 do not smoke; no history of toxic fume inhalation

Natural History & Prognosis • Untreated DPB often progresses to bronchiectasis, bronchiolectasis, respiratory failure and cardiac complications (e.g., pulmonary hypertension and right heart failure)

Treatment • Macrolide antibiotics (e.g., erythromycin) • Lung transplantation

DIAGNOSTIC CHECKLIST Consider • Consider DPB in East Asian individuals (e.g., Japan, Korea, China) with chronic sinusitis, tree-in-bud opacities, &/or bronchiectasis/bronchiolectasis

SELECTED REFERENCES 1. 2. 3. 4.

Sugimoto S et al: Lung transplantation for diffuse panbronchiolitis: 5 cases from a single centre. Interact Cardiovasc Thorac Surg. 22(5):679-81, 2016 Kudoh S et al: Diffuse panbronchiolitis. Clin Chest Med. 33(2):297-305, 2012 Poletti V et al: Diffuse panbronchiolitis. Eur Respir J. 28(4):862-71, 2006 Akira M et al: Diffuse panbronchiolitis: follow-up CT examination. Radiology. 189(2):559-62, 1993

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Idiopathic Constrictive Bronchiolitis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Idiopathic constrictive bronchiolitis: Nonspecific irreversible process characterized by ○ Concentric fibrosis anatomically located between bronchiolar epithelium and muscularis mucosa ○ Affects terminal and respiratory bronchioles with resultant bronchiolar luminal narrowing &/or obliteration ○ Little bronchiolar/peribronchiolar chronic inflammation

• Complication of infection, lung transplantation, and hematopoietic stem cell transplantation • Inhalational lung injury • Connective tissue disease • Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia • Pulmonary hypertension • Asthma

IMAGING • Radiography ○ Normal vs. hyperinflation • HRCT ○ Inspiration: Normal vs. mosaic attenuation ○ Expiration – May exhibit mosaic attenuation with multifocal welldefined areas of decreased attenuation – Accentuation of geographic areas of decreased attenuation identified on inspiratory HRCT

(Left) Axial NECT of a 41-yearold woman with chronic dyspnea and wheezing secondary to biopsy-proven idiopathic constrictive bronchiolitis shows mosaic attenuation of the lung parenchyma characterized by multifocal areas of abnormal pulmonary hyperlucency ﬉ amid normal-appearing lung. (Right) Axial NECT of the same patient shows basilar areas of hyperlucent lung with paucity and small caliber of intrinsic vessels ﬉. Affected patients typically exhibit accentuation of low-attenuation areas or air-trapping on expiratory CT.

(Left) Coronal NECT of the same patient shows multifocal pulmonary hyperlucencies ﬉ with decreased caliber and paucity of intrinsic vascular markings. The diagnosis of idiopathic constrictive bronchiolitis requires exclusion of other known etiologies of this morphologic abnormality. (Right) Intermediate-power photomicrograph (H&E stain) of a biopsy specimen from the same patient shows bronchiolar wall inflammation and thickening ﬊ and a thick alveolar duct wall ﬉ secondary to smooth muscle hyperplasia.

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CLINICAL ISSUES • Dyspnea, malaise, fatigue, nonproductive cough, wheezing • Obstructive physiology on pulmonary function studies • Adult or older women

DIAGNOSTIC CHECKLIST • Idiopathic constrictive bronchiolitis is indistinguishable from constrictive bronchiolitis from a variety of etiologies and is thus diagnosis of exclusion

Idiopathic Constrictive Bronchiolitis

Synonyms • Fibrotic bronchiolitis • Obliterative bronchiolitis • Bronchiolitis obliterans

Definitions • Idiopathic constrictive bronchiolitis ○ Nonspecific, irreversible process ○ Concentric fibrosis anatomically located between bronchiolar epithelium and muscularis mucosa ○ Affects terminal and respiratory bronchioles with resultant bronchiolar luminal narrowing &/or obliteration ○ Little bronchiolar/peribronchiolar chronic inflammation, absence of granulation tissue polyps • Diagnosis of exclusion: Exclusion of known causes of constrictive bronchiolitis • Constrictive bronchiolitis is not to be confused with bronchiolitis obliterans organizing pneumonia, preferably referred to as organizing pneumonia or as cryptogenic organizing pneumonia if idiopathic

○ Expiratory HRCT – Expiratory air-trapping manifesting with multifocal well-defined areas of decreased attenuation □ Relatively unchanged attenuation in affected areas as compared to inspiratory imaging □ Alveolar air cannot exit areas affected by small airway obstruction – Accentuation of geographic areas of decreased attenuation seen on inspiratory HRCT – Higher attenuation areas represent normal lung parenchyma on expiration – Lower attenuation areas represent abnormal lung parenchyma

Small Airways Disease

TERMINOLOGY

Imaging Recommendations • Best imaging tool ○ Supine inspiratory and expiratory HRCT • Protocol advice ○ Minimum-intensity projection reformations may highlight mosaic attenuation &/or air-trapping • Chest radiography ○ Little utility in assessment of constrictive bronchiolitis ○ May help exclude other entities, such as pneumonia

IMAGING General Features • Best diagnostic clue ○ Mosaic attenuation with expiratory air-trapping on CT/HRCT • Location ○ Patchy distribution • Size ○ Variable extent of involvement • Morphology ○ Areas of low attenuation or air-trapping exhibit geographic distribution

Radiographic Findings • Radiography ○ Normal ○ May exhibit hyperinflation

CT Findings • NECT ○ May be normal at full inspiration ○ Mosaic attenuation of lung parenchyma – Heterogeneous lung parenchyma: Well-defined geographic areas of abnormal decreased attenuation interspersed with normal higher attenuation areas ○ Central and peripheral bronchiectasis/bronchiolectasis may be present ○ Decreased size of pulmonary vessels and decreased pulmonary perfusion due to shunting of blood away from affected areas • HRCT ○ Inspiratory HRCT – May be normal – May exhibit mosaic attenuation with multifocal welldefined areas of decreased attenuation – Bronchiectasis/bronchiolectasis and bronchial wall thickening may be present – Rarely centrilobular opacities

DIFFERENTIAL DIAGNOSIS Constrictive Bronchiolitis as Complication of Infection • Typically childhood pulmonary infection; rarely adult infection • Usual infectious etiologies ○ Adenovirus ○ Respiratory syncytial virus ○ Mycoplasma • Imaging ○ Mosaic attenuation and expiratory air-trapping ○ Rarely centrilobular nodules and tree-in-bud opacities ○ May manifest with Swyer-James-MacLeod syndrome – Postulated disruption of alveolar and pulmonary vascular development (prior to 8 years of age); typically from childhood adenovirus infection – Often involves both lungs – Air-trapping may be segmental, lobar, or involve entire lung – Affected lung may exhibit decreased volume, hyperlucency, decreased vascularity, bronchiectasis

Constrictive Bronchiolitis as Complication of Lung Transplantation • Bronchiolitis obliterans syndrome: Form of constrictive bronchiolitis associated with lung transplantation ○ Bronchiolitis obliterans syndrome describes patients with clinical manifestations of disease without histologic documentation ○ Manifestation of chronic allograft rejection • May affect up to 50% of lung transplant recipients; occurs at least 3 months post transplantation • Imaging ○ Mosaic attenuation and expiratory air-trapping ○ Bronchiolectasis and bronchial wall thickening • Poor prognosis 125

Small Airways Disease

Idiopathic Constrictive Bronchiolitis Constrictive Bronchiolitis as Complication of Hematopoietic Stem Cell Transplantation • Manifestation of chronic graft-vs.-host disease in up to 10% of hematopoietic stem cell transplant recipients • Findings of graft-vs.-host disease affecting other organs • Imaging ○ Mosaic attenuation and expiratory air-trapping on HRCT

Constrictive Bronchiolitis Secondary to Inhalational Lung Injury • Various agents implicated ○ Nitrous acid and nitrous oxide chemical compounds ○ Smoke inhalation from house or building fires ○ Pneumoconiosis related to manufacture of popcorn flavorings (diacetyl exposure) • Imaging ○ Expiratory air-trapping on HRCT ○ May exhibit bronchiectasis and bronchial wall thickening

Constrictive Bronchiolitis Associated With Connective Tissue Disease • Association with advanced rheumatoid arthritis • Female patients with severe progressive dyspnea and cough • May be associated with drug therapy (e.g., penicillamine) • Imaging ○ Mosaic attenuation and expiratory air-trapping ○ May coexist with interstitial lung disease

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia

General Features • Constrictive bronchiolitis: Descriptive term for spectrum of histologic changes associated with clinical airflow obstruction due to small airways lesions

Microscopic Features • • • • •

Submucosal and adventitial scarring Concentric luminal narrowing &/or obliteration by scar Little bronchiolar/peribronchiolar chronic inflammation Also: Epithelial metaplasia and smooth muscle hypertrophy Characteristically subtle histologic abnormalities; only minority of airways within given specimen show luminal narrowing/obliteration

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Dyspnea, malaise, fatigue, cough, wheezing • Other signs/symptoms ○ Obstructive physiology on pulmonary function studies

Demographics • Adult or older women

Natural History & Prognosis • Poor prognosis with slow progression over months or years • May exhibit rapidly progressive course

Treatment

• Neuroendocrine cell proliferations in bronchiolar epithelium that may involve basement membranes with resultant luminal narrowing &/or obliteration • Middle-aged or elderly women • Asymptomatic vs. symptoms of cough, dyspnea, or asthma • Imaging ○ Mosaic attenuation and expiratory air-trapping on HRCT ○ Associated small pulmonary nodules corresponding to carcinoid tumorlets or small carcinoid tumors

• Variable response to corticosteroids, macrolides, and bronchodilators • Eventually require lung transplantation

Pulmonary Hypertension

Image Interpretation Pearls

• Enlarged pulmonary trunk and central pulmonary arteries; right ventricular enlargement and hypertrophy • Mosaic attenuation due to mosaic perfusion ○ Pulmonary vessels are smaller in low-attenuation areas compared to vessels in normal (higher)-attenuation areas ○ Generally distinguished from small airways disease by diffuse increased attenuation on expiratory imaging • Etiologies ○ Primary pulmonary hypertension ○ Chronic pulmonary thromboembolism

• Expiratory air-trapping is an indirect sign of small airways disease found in constrictive bronchiolitis, as opposed to centrilobular nodules and tree-in-bud opacities, which are direct signs of small airways disease found in cellular bronchiolitis • Cellular bronchiolitis is only rarely found in association with constrictive bronchiolitis

Asthma • Reversible airway obstruction, inflammation, and hyperreactivity • Cough, dyspnea, wheezing, chest discomfort • Imaging ○ Radiography: Hyperinflation, atelectasis, pneumonia ○ CT: Bronchiectasis, mosaic attenuation, expiratory airtrapping 126

PATHOLOGY

DIAGNOSTIC CHECKLIST Consider • Idiopathic constrictive bronchiolitis is histologically indistinguishable from constrictive bronchiolitis from a variety of etiologies and is thus diagnosis of exclusion

Reporting Tips • Lobular expiratory air-trapping (few adjacent lobules) is reported in normal subjects • Multifocal ground-glass attenuation from various causes may mimic mosaic attenuation

SELECTED REFERENCES 1. 2. 3.

Berniker AV et al: Imaging of small airways diseases. Radiol Clin North Am. 54(6):1165-1181, 2016 Edwards RM et al: Imaging of small airways and emphysema. Clin Chest Med. 36(2):335-47, x, 2015 Kligerman SJ et al: Mosaic attenuation: etiology, methods of differentiation, and pitfalls. Radiographics. 35(5):1360-80, 2015

Idiopathic Constrictive Bronchiolitis Small Airways Disease

(Left) Axial HRCT (obtained at full inspiration) of a 65-yearold woman with constrictive bronchiolitis shows very subtle mosaic attenuation characterized by abnormal low-attenuation lung parenchyma ﬈ adjacent to higher attenuation normal lung. Patients with constrictive bronchiolitis may exhibit near normal pulmonary attenuation on inspiratory CT. (Right) Axial HRCT of the same patient (obtained at full expiration) demonstrates expiratory air-trapping ﬈ characteristic of constrictive bronchiolitis.

(Left) High-power photomicrograph (H&E stain) of a biopsy specimen from a patient with constrictive bronchiolitis shows prominent concentric smooth muscle hypertrophy ﬉ producing mural thickening and luminal narrowing of a small bronchiole. (Right) Axial expiratory HRCT of a 68-yearold woman with constrictive bronchiolitis shows airtrapping ﬉ characterized by geographic low-attenuation areas secondary to bronchiolar air flow obstruction.

(Left) Axial HRCT (obtained at full inspiration) of the same patient demonstrates subtle mosaic attenuation with geographic areas of abnormal low attenuation ﬉ adjacent to higher attenuation normal lung. Mosaic attenuation may be subtle on inspiratory HRCT. (Right) Axial HRCT of the same patient obtained at full expiration shows an accentuation of the lowattenuation areas ﬉ secondary to air-trapping. The adjacent normal lung exhibits higher attenuation, which is not to be confused with ground-glass attenuation.

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Swyer-James-MacLeod Syndrome KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Constrictive bronchiolitis secondary to childhood infectious bronchiolitis • Constrictive bronchiolitis: Irreversible obstructive small airways disease; submucosal and peribronchiolar fibrosis with small airways destruction and scarring

• Asthma • Bronchiectasis • Unilateral primary pulmonary hypoplasia

IMAGING • Radiography ○ Unilateral small or normal-sized hyperlucent lung ○ Decreased vascular markings in regions of hyperlucency • CT ○ Hyperlucent lung with small intrinsic pulmonary vessels – Typically bilateral involvement – May affect entire lung or may be localized to lobe or several pulmonary segments ○ Mosaic attenuation (perfusion) ○ Expiratory air-trapping ○ Frequent bronchiectasis

(Left) PA chest radiograph of an asymptomatic patient with Swyer-James-MacLeod syndrome shows right upper lung hyperlucency ﬈ with intrinsic decreased pulmonary vascularity. The left lung appears normal. (Right) Axial HRCT of the same patient shows that the radiographic abnormality corresponds to right upper lobe hyperlucency amid scattered areas of relatively normal pulmonary attenuation ﬉. The right upper lobe pulmonary vessels ﬈ are diminutive when compared to those in the left upper lobe ﬊.

(Left) Axial HRCT of the same patient shows right upper and right lower lobe hyperlucency with intrinsic bronchiectasis ﬊ and a small size of intrinsic pulmonary vessels. While the left lung is relatively normal, there is a small hyperlucent area ﬉ in the left lower lobe superior segment. (Right) Axial expiratory HRCT of the same patient shows no significant increase in the attenuation of the hyperlucent lung (including the left lower lobe superior segment ﬉) consistent with air-trapping. CT typically reveals bilateral pulmonary involvement.

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PATHOLOGY • Epithelial injury caused by lower respiratory tract infection → peribronchiolar fibrosis → small airways and capillary bed obstruction

CLINICAL ISSUES • Typically asymptomatic • Wheezing, cough, dyspnea on exertion • Typical history of childhood respiratory infection, but most patients diagnosed in adulthood

DIAGNOSTIC CHECKLIST • Consider Swyer-James-MacLeod syndrome in asymptomatic patients with multifocal areas of hyperlucent lung, bronchiectasis, and air-trapping on CT

Swyer-James-MacLeod Syndrome

Synonyms • Swyer-James syndrome • MacLeod syndrome • Controversy regarding eponyms to be ascribed to syndrome ○ MacLeod presented report of 9 patients with "abnormal transradiancy of 1 lung," which was "small or normal size" at the British Thoracic Society meeting in London in February of 1952 ○ Swyer and James published case of "unilateral pulmonary emphysema" in 1953 ○ MacLeod published his work in 1954

Definitions • Constrictive bronchiolitis secondary to childhood infectious bronchiolitis (typically from adenovirus infection) • Constrictive bronchiolitis: Irreversible obstructive small airways disease characterized by submucosal and peribronchiolar fibrosis with resultant destruction and obliterative scarring of small airways

IMAGING General Features • Best diagnostic clue ○ Unilateral small or normal-sized lung ○ Diminished pulmonary vascularity ○ Areas of expiratory air-trapping ○ Bronchiectasis ○ Bronchial wall thickening • Location ○ May affect entire lung ○ May be localized to pulmonary lobe ○ May affect 1 or more pulmonary segments ○ Involvement may be bilateral ○ Radiographic abnormalities are usually unilateral – Bilateral abnormalities are often identified on CT • Morphology ○ Original published description by Swyer and James in 1953 – Unilateral hyperlucent lung – Small ipsilateral pulmonary artery – Incomplete filling of ipsilateral peripheral bronchioles with contrast material at bronchography ○ Decreased size and number of pulmonary artery branches within affected lung ○ Bronchiectasis often present

Radiographic Findings • Unilateral small or normal-sized lung characterized by diffuse or focal hyperlucency • No change in size or degree of lucency of affected lung on expiratory imaging • Decreased vascular markings within regions of hyperlucency • Small ipsilateral pulmonary artery

CT Findings • Regions of hyperlucency with small associated vascular structures

•

• • •

○ Hyperlucent foci predominantly affect 1 lung ○ Smaller affected pulmonary regions identified bilaterally Mosaic attenuation (perfusion) ○ Geographic regions of increased pulmonary attenuation with intrinsic large pulmonary vessels adjacent to regions of decreased pulmonary attenuation or hyperlucency with intrinsic small pulmonary vessels Air-trapping on expiratory imaging Frequent bronchiectasis ○ Saccular bronchiectasis described ± bronchial stenosis or luminal obliteration

Small Airways Disease

TERMINOLOGY

Nuclear Medicine Findings • Perfusion imaging with Tc-99m MAA ○ Areas of photopenia – Hypoxic vasoconstriction in early acute phase of bronchiolar inflammation – Microvascular obstruction in late chronic phase • Ventilation imaging with Tc-99m DTPA ○ Areas of photopenia – Narrowing of small airways due to edema in early acute phase of bronchiolar inflammation – Bronchiolar occlusion in late chronic phase

Imaging Recommendations • Best imaging tool ○ HRCT most sensitive for evaluation and identification of – Mosaic attenuation – Air-trapping – Bronchiectasis • Protocol advice ○ Inspiratory and expiratory HRCT – Expiratory HRCT critical for identifying areas of airtrapping

DIFFERENTIAL DIAGNOSIS Asthma • Diffuse bilateral pulmonary involvement • May exhibit mild mosaic attenuation on CT • Cylindrical bronchiectasis described in asthma ○ Saccular bronchiectasis favors Swyer-James-MacLeod

Bronchiectasis • Cystic fibrosis, primary ciliary dyskinesia, immunodeficiencies • Bronchiolectasis may be associated with hypoxic vasoconstriction with resultant hyperlucent lung and small vessels • Often significant tree-in-bud centrilobular nodules from mucoid impaction or infection within dilated bronchioles • Frequently diffuse and bilateral involvement

Primary Unilateral Pulmonary Hypoplasia • Small lung and ipsilateral pulmonary artery • No air-trapping

Panlobular Emphysema • Lower lobe-predominant hyperlucent lung with small scant pulmonary vessels • Association with α-1 antitrypsin deficiency • Mild cylindrical bronchiectasis may be present 129

Small Airways Disease

Swyer-James-MacLeod Syndrome Congenital Lobar Overinflation • Usually affects single lobe ○ Left upper lobe most frequently affected • Primary bronchial abnormality resulting in luminal narrowing and air-trapping ○ Hyperlucent and hyperexpanded lung ○ Mass effect on mediastinum ○ Mass effect on and atelectasis of adjacent lung • Affected patients typically present with respiratory distress in infancy ○ 50% of affected patients present in first 2 days of life • Associated congenital heart disease in 15% of affected patients

PATHOLOGY General Features • Proposed pathogenesis ○ Epithelial injury caused by lower respiratory tract infection with microbes, such as virus or mycoplasma ○ Severely injured epithelial cells release interleukin 8 and other proinflammatory mediators – Neutrophils and other inflammatory cells recruited to small airways – Bronchoalveolar lavage fluid □ Increased neutrophils □ Increased interleukin 8 ○ Cytokines and mediators released from inflammatory cells with resultant – Matrix degradation – Collagen deposition – Fibroblast proliferation – Peribronchial fibrosis ○ Fibrosis of peribronchiolar alveolar septa obstructs pulmonary capillary bed – Decreased blood flow to affected pulmonary artery segments • Clinical severity determined by degree of epithelial injury and inflammation • Unclear whether degree of morphologic CT abnormalities are directly related to degree of impairment on pulmonary function tests

Staging, Grading, & Classification • In absence of histopathologic sampling, diagnosis rests on clinical criteria ○ History of severe respiratory infection during childhood, especially early childhood ○ Persistent airway obstruction on pulmonary function tests ○ Airway obstruction is unresponsive to systemic steroids or bronchodilators ○ CT findings of hyperlucency, mosaic attenuation, airtrapping, ± bronchiectasis ○ Exclusion of other chronic lung diseases

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Most patients asymptomatic 130

○ Degree of symptomatology depends on percentage of lung parenchyma involved ○ Chronic wheezing, productive cough, dyspnea on exertion ○ Pulmonary function tests: ↓ forced expiratory flow at 25-75% of forced vital capacity, consistent with small airways obstruction • Other signs/symptoms ○ Hemoptysis (rare) ○ Recurrent infections (rare)

Demographics • Respiratory infection most often occurs in childhood, especially early childhood ○ Associated pathogens: Adenovirus, measles virus, influenza virus, respiratory syncytial virus, and Mycoplasma pneumoniae • Most patients diagnosed as adults ○ Often incidental imaging finding

Natural History & Prognosis • CT findings of constrictive bronchiolitis may develop as early as 9 months after infection • Excellent prognosis as most affected patients are asymptomatic • Chronic intermittent wheezing chronic cough with large areas of pulmonary involvement • Bronchiectasis related to end-stage constrictive bronchiolitis may predispose to repeated infections

Treatment • Systemic or inhaled corticosteroids for wheezing and chronic cough • Surgery rarely required; reserved for patients with recurrent infections due to bronchiectasis

DIAGNOSTIC CHECKLIST Consider • Swyer-James-MacLeod syndrome in asymptomatic patients with unilateral hyperlucent lung on radiography and multifocal areas of hyperlucent lung, bronchiectasis, and air-trapping on CT

SELECTED REFERENCES 1. 2.

3. 4. 5. 6. 7. 8. 9.

Milanese G et al: Lung volume reduction of pulmonary emphysema: the radiologist task. Curr Opin Pulm Med. 22(2):179-86, 2016 Yu J: Postinfectious bronchiolitis obliterans in children: lessons from bronchiolitis obliterans after lung transplantation and hematopoietic stem cell transplantation. Korean J Pediatr. 58(12):459-65, 2015 Mosquera RA et al: Dysanaptic growth of lung and airway in children with post-infectious bronchiolitis obliterans. Clin Respir J. 8(1):63-71, 2014 Xie BQ et al: Ventilation/perfusion scintigraphy in children with postinfectious bronchiolitis obliterans: a pilot study. PLoS One. 9(5):e98381, 2014 Wasilewska E et al: Unilateral hyperlucent lung in children. AJR Am J Roentgenol. 198(5):W400-14, 2012 Champs NS et al: Post-infectious bronchiolitis obliterans in children. J Pediatr (Rio J). 87(3):187-98, 2011 Dillman JR et al: Expanding upon the unilateral hyperlucent hemithorax in children. Radiographics. 31(3):723-41, 2011 Müller NL: Unilateral hyperlucent lung: MacLeod versus Swyer-James. Clin Radiol. 59(11):1048, 2004 Lucaya J et al: Spectrum of manifestations of Swyer-James-MacLeod syndrome. J Comput Assist Tomogr. 22(4):592-7, 1998

Swyer-James-MacLeod Syndrome Small Airways Disease

(Left) Axial CECT of a patient with Swyer-James-MacLeod syndrome shows left lower lobe hyperlucency with intrinsic bronchiectasis ﬈. The left lower lobe vessels ﬊ are smaller than those in the right lower lobe ﬉. (Right) Coronal CECT of the same patient shows left lower lobe hyperlucency, intrinsic bronchiectasis ﬈, and decreased caliber of pulmonary vessels. The patient had a history of chronic cough and asthma-like symptoms ever since recovering from a severe pulmonary infection as a young child.

(Left) Coronal NECT of an asymptomatic 18-year-old patient with a history of respiratory syncytial virus infection in infancy shows multifocal bilateral regions of hyperlucency ﬈ with intrinsic small pulmonary vessels. The diagnosis of Swyer-JamesMacLeod syndrome was made presumptively. (Right) Axial HRCT of a patient with SwyerJames-MacLeod syndrome and a history of severe childhood respiratory infection shows multifocal regions of pulmonary hyperlucency and associated bilateral saccular bronchiectasis ﬊.

(Left) PA chest radiograph of a patient with Swyer-JamesMacLeod syndrome due to severe neonatal pneumonia who presented with chronic cough shows subtle left mid lung zone hyperlucency ﬈ and paucity of intrinsic pulmonary vascular markings. (Right) Axial HRCT minIP reformation of the same patient shows severe hyperlucency ﬈ of the left lower lobe and markedly decreased intrinsic pulmonary vascularity. Note mild areas of pulmonary hyperlucency in the lingula ﬊ and right lower lobe ﬉.

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Bronchiolitis Obliterans Syndrome KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Chronic lung allograft dysfunction (CLAD): Includes all variants of post lung transplant chronic pulmonary dysfunction • CLAD phenotypes ○ Restrictive allograft syndrome (RAS) ○ Bronchiolitis obliterans syndrome (BOS) – Neutrophilic reversible allograft dysfunction (NRAD) – Fibrous BOS

• Infectious bronchiolitis • Diffuse aspiration bronchiolitis • Constrictive bronchiolitis

IMAGING

CLINICAL ISSUES

• BOS ○ Mosaic attenuation, expiratory air-trapping, bronchial wall thickening, bronchiectasis • NRAD ○ Centrilobular micronodules and tree-in-bud opacities ○ Expiratory air-trapping • fBOS ○ Expiratory air-trapping, consolidation

• CLAD develops in 50% of patients at 5 years after lung transplant • No effective treatment for BOS: NRAD responds to azithromycin

(Left) PA chest radiograph of a 33-year-old man with a history of hematopoietic stem cell transplantation and bronchiolitis obliterans syndrome who presented with progressive dyspnea shows increased lung volume and diminished pulmonary vascularity ﬈ in the periphery of the mid and lower lung zones. (Right) Axial expiratory HRCT of the same patient shows scattered areas of airtrapping ﬈ with decreased vascularity in the hyperlucent lung. These are classic imaging findings of histologic constrictive bronchiolitis.

(Left) Axial HRCT of a 32-yearold woman with bronchiolitis obliterans syndrome in the setting of bilateral lung transplantation shows patchy ground-glass opacities, scattered areas of mosaic attenuation, and discrete lung nodules ﬈. (Right) Axial expiratory CECT of a 25-yearold man with constrictive bronchiolitis secondary to smoke inhalation shows ground-glass opacities and areas of air-trapping ﬈. Constrictive bronchiolitis may occur in other diseases, including inhalational injury and autoimmune disease.

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PATHOLOGY • BOS: Constrictive bronchiolitis ○ Patchy concentric narrowing or obliteration of bronchiolar lumen by fibrotic/inflammatory process

DIAGNOSTIC CHECKLIST • Consider CLAD in lung transplant recipients with declining lung function and mosaic attenuation or expiratory airtrapping on CT/HRCT

Bronchiolitis Obliterans Syndrome

Abbreviations • Lung transplantation ○ Chronic lung allograft dysfunction (CLAD) ○ Bronchiolitis obliterans syndrome (BOS) ○ Restrictive allograft syndrome (RAS) ○ Neutrophilic reversible allograft dysfunction (NRAD) ○ Fibrous BOS (fBOS) • Hematopoietic stem cell transplantation (HSCT): BOS, graftvs.-host disease (GVHD) • Diffuse alveolar damage (DAD)

Definitions • BOS: Broadly used and well-known term; often incorrectly used to signify chronic rejection ○ Evolving evidence shows that BOS is a form of CLAD • CLAD: Broad term describing spectrum of heterogeneous chronic lung abnormalities in lung transplant recipients ○ Phenotypes – RAS: Restrictive pulmonary function □ Late new-onset DAD (> 3 months post transplantation) suggests near-future development of RAS – BOS: Includes chronic rejection but alloimmune independent factors (gastroesophageal reflux, aspiration, and infection) contribute to pathogenesis □ NRAD: Allograft dysfunction characterized by reversible airway neutrophilia responsive to azithromycin □ fBOS: BOS subtype not responsive to azithromycin • HSCT: In this setting, BOS refers to new-onset obstructive pulmonary dysfunction ○ Histologically identical to BOS after lung transplantation

IMAGING General Features • Best diagnostic clue ○ BOS: Mosaic attenuation, air-trapping, bronchial wall thickening, bronchiectasis

Radiographic Findings • Chest radiography often normal • Abnormalities are typically nonspecific

CT Findings • RAS ○ Early ground-glass opacities ○ Reticulation ○ Peripheral consolidation ○ Septal thickening ○ Pleural thickening • BOS (in both lung transplant and HSCT) ○ Mosaic attenuation ○ Expiratory air-trapping ○ Bronchial wall thickening and bronchiectasis • NRAD ○ Centrilobular micronodules and tree-in-bud opacities (common) ○ Air-trapping (common) ○ Mucus plugging

○ ○ ○ ○ ○

Airway wall thickening Bronchial wall thickening Bronchial dilatation Consolidation During treatment: Improvement of bronchial dilatation, consolidations, and air-trapping • fBOS ○ Expiratory air-trapping, consolidation

Small Airways Disease

TERMINOLOGY

Imaging Recommendations • Best imaging tool ○ HRCT • Protocol advice ○ Expiratory HRCT critical for assessment of air-trapping

DIFFERENTIAL DIAGNOSIS Infectious Bronchiolitis • Clinical evidence of infection • Centrilobular nodules and tree-in-bud opacities • Good response to antibiotic therapy

Diffuse Aspiration Bronchiolitis • Centrilobular nodules and tree-in-bud opacities • Requires further evaluation to document aspiration

Constrictive Bronchiolitis • Mosaic attenuation, expiratory air-trapping • Idiopathic or associated with autoimmunity, inhalational lung disease, drug toxicity

Organizing Pneumonia • Former term bronchiolitis obliterans organizing pneumonia no longer used • Not related to BOS

Recurrent Underlying Lung Disease • Variety of conditions, including chronic obstructive pulmonary disease, diffuse panbronchiolitis, Langerhans cell histiocytosis, lymphangioleiomyomatosis, sarcoidosis • CT may demonstrate specific abnormalities, but histologic confirmation often required

PATHOLOGY General Features • Early-onset (< 3 months after transplantation) DAD shows weak correlation with development of BOS • Late-onset (> 3 months after transplantation) DAD correlates with development of RAS • BOS postulated to result from small airways inflammation, destruction and fibrosis leading to constrictive bronchiolitis

Microscopic Features • RAS: May be preceded by late-onset DAD ○ Peripheral lung inflammation and fibrosis of alveoli, pleura, interlobular septa • BOS ○ Constrictive bronchiolitis – Involves terminal and respiratory bronchioles, spares distal lung parenchyma – Concentric narrowing or obliteration of bronchiolar lumen by fibrotic/inflammatory process 133

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Bronchiolitis Obliterans Syndrome – Ancillary findings: Peribronchiolar inflammation, dilatation and distortion of airway lumina, mucostasis, bronchiolar smooth muscle hypertrophy, and bronchiectasis – Insensitivity of transbronchial biopsy due to heterogeneous distribution of histologic abnormalities • NRAD ○ Airway neutrophilia ○ Lymphocytic bronchiolitis • fBOS: Fibrous constrictive bronchiolitis with minimal or absent inflammation

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Nonspecific: Dyspnea, nonproductive cough • Other signs/symptoms ○ BOS generally suspected at early stage when forced expiratory volume in 1 second (FEV₁) ≤ 90% of baseline &/or FEF 25-75% ≤ 75% of baseline • Clinical profile ○ Pulmonary function tests – RAS: Restrictive physiology □ Total lung capacity < 90% of baseline – BOS: Obstructive physiology □ Absence of restrictive physiology □ Total lung capacity > 90% of baseline □ FEV₁ ≤ 80% of baseline of 2 best posttransplantation values obtained at least 3 weeks apart – NRAD □ ≥ 15% neutrophils at bronchoalveolar lavage in absence of infection □ Functional impairment reversible with azithromycin (increase in FEV₁ ≥ 10% 3-6 months after initiation of azithromycin compared to FEV₁ at onset of treatment on 2 separate measurements at least 3 weeks apart) – fBOS □ No response to azithromycin ○ BOS in HSCT – FEV₁/vital capacity < 0.7 or 5th percentile of predicted – FEV₁ < 75% of predicted with ≥ 10% decline over < 2 years – Absence of respiratory tract infection – 1 of 2 supporting features of BOS □ CT findings of expiratory air-trapping or bronchial wall thickening/bronchiectasis □ Air-trapping on pulmonary function tests • Risk factors ○ CLAD (including BOS) – Lymphocytic bronchiolitis – Refractory acute rejection – Antibody-mediated rejection – Alloimmune-independent factors that contribute to pathogenesis of BOS □ Gastroesophageal reflux disease □ Infection: Cytomegalovirus (CMV) and other viral infections, bacterial colonization 134

○ RAS – CMV and other viral infections – Late new-onset DAD ○ NRAD – Pseudomonas colonization – Airway neutrophilia ○ BOS in HSCT – Older age – History of acute or chronic GVHD – Respiratory viral infection in early posttransplant period

Demographics • Epidemiology ○ CLAD develops in 50% of patients 5 years after lung transplant ○ RAS represents 25-35% of all CLAD ○ BOS represents 75-85% of all CLAD ○ NRAD represents 50% of BOS ○ fBOS represents 50% of BOS ○ BOS is most common long-term noninfectious pulmonary complication of HSCT – 2-3% of all allogeneic HSCT recipients and 6% of patients who develop chronic GVHD

Natural History & Prognosis • RAS: Poor prognosis; irreversible deterioration that progresses despite treatment • BOS: Variable prognosis ○ NRAD: Benign course with possible progression to fBOS ○ fBOS: Rapid progression ○ BOS: Highly variable course – Median survival: 3-4 years after onset (range: 0-9 years) – Higher mortality in BOS within 2 years of transplantation

Treatment • BOS: No effective treatment; immunosuppression is mainstay of therapy • NRAD: Typically responds to azithromycin

DIAGNOSTIC CHECKLIST Consider • CLAD in lung transplant recipients with declining lung function and mosaic attenuation or expiratory air-trapping on HRCT

Image Interpretation Pearls • Chest radiography lacks sensitivity and specificity for diagnosis of CLAD

SELECTED REFERENCES 1. 2.

3.

Royer PJ et al: Chronic lung allograft dysfunction: A systematic review of mechanisms. Transplantation. 100(9):1803-14, 2016 Bergeron A et al: Bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: phenotypes and prognosis. Bone Marrow Transplant. 48(6):819-24, 2013 Sato M: Chronic lung allograft dysfunction after lung transplantation: the moving target. Gen Thorac Cardiovasc Surg. 61(2):67-78, 2013

Bronchiolitis Obliterans Syndrome Small Airways Disease

(Left) PA chest radiograph of a patient who developed bronchiolitis obliterans syndrome as a complication of hematopoietic stem cell transplantation shows bilateral low lung volumes and diffuse bilateral upper lobepredominant coarse reticular opacities. (Right) Axial HRCT of the same patient shows an extensive and severe bronchiectatic process ﬈ predominantly involving the upper lobes. Severe bronchiectasis may occur in late-stage bronchiolitis obliterans syndrome, as in this case.

(Left) Axial NECT of a patient with bronchiolitis obliterans syndrome following bilateral lung transplantation shows extensive lower lobepredominant bronchiectasis ﬉, bronchial wall thickening, and endoluminal fluid as well as scattered areas of airtrapping ﬈. (Right) Coronal NECT of the same patient confirms lower lobepredominant bronchiectasis and bronchial wall thickening. Some of the dilated bronchi exhibit intrinsic retained secretions and mucus plugging.

(Left) PA chest radiograph of a 21-year-old woman after hematopoietic stem cell transplantation who developed bronchiolitis obliterans syndrome shows increased lung volume with preferential overexpansion of the right lung that produces leftward mediastinal shift. (Right) Axial HRCT of the same patient shows scattered areas of mosaic attenuation, bronchiectasis ﬉, and tree-inbud opacities ﬈. Bronchiolitis obliterans syndrome involves the terminal and respiratory bronchioles and spares the peripheral lung parenchyma.

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Small Airways Disease

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Neuroendocrine cell (NEC) hyperplasia (NECH): NEC proliferation in bronchial/bronchiolar epithelium • Diffuse idiopathic pulmonary NECH (DIPNECH): NEC proliferation associated with constrictive bronchiolitis, tumorlets, and carcinoids • DIPNECH syndrome: Symptomatic NEC proliferations and clinical constrictive bronchiolitis

• Cellular bronchiolitis • Pulmonary metastases • Diffuse pulmonary meningothelial nodules

IMAGING • Radiography ○ Normal or multifocal pulmonary nodules • CT/HRCT ○ Multifocal pulmonary micronodules or nodules < 5 mm – May exhibit bronchiolocentric distribution – Large or dominant nodules should suggest carcinoid ○ Bronchial wall thickening ○ Mosaic attenuation on inspiratory imaging ○ Multifocal expiratory air-trapping

(Left) Axial NECT of a 56-yearold woman with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia who presented with chronic dyspnea shows at least 1 right upper lobe solid nodule ﬈ and diffuse mosaic attenuation. (Right) Axial NECT MIP reformation of the same patient shows multifocal bilateral pulmonary nodules ﬈ to better advantage. MIP reformation highlights highattenuation structures, such as nodules and blood vessels. Mosaic attenuation is still apparent on this image.

(Left) Low-power photomicrograph (H&E stain) of a specimen of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia shows patchy lung involvement by neuroendocrine cell hyperplasia ﬉ associated with slight bronchiolar metaplasia and fibrosis ﬊. (Right) Axial NECT minIP reformation of the same patient shows to better advantage mosaic attenuation of the lung parenchyma. MinIP reformations highlight lowattenuation structures.

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PATHOLOGY • DIPNECH: Generalized pulmonary NEC proliferation; associated peribronchiolar fibrosis, may result in constrictive bronchiolitis

CLINICAL ISSUES • • • •

F:M ratio = 10:1; nonsmokers 50-70 years of age; mean age: 58 years May be asymptomatic (up to 50% of cases) Nonproductive cough, exertional dyspnea, wheezing

DIAGNOSTIC CHECKLIST • Consider DIPNECH in middle-aged women with multifocal pulmonary nodules and associated expiratory air-trapping

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) • Random pulmonary micronodules ± central lucencies

Abbreviations • Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) • Neuroendocrine cell (NEC)

Definitions • NEC: Normal component of respiratory epithelium • Neuroendocrine body: Tiny NEC aggregate • NEC hyperplasia (NECH): NEC proliferation in bronchial/bronchiolar epithelium ○ DIPNECH: NEC proliferation associated with constrictive bronchiolitis, tumorlets, and carcinoids ○ Reactive NECH: Associated with chronic lung disease, may occur in response to lung injury and hypoxia ○ NECH near carcinoid tumors; incidental histologic finding • DIPNECH syndrome: Proposed term for symptomatic NEC proliferations and clinical constrictive bronchiolitis

IMAGING

PATHOLOGY General Features • DIPNECH: Considered preneoplastic condition

Microscopic Features • NEC proliferations typically occur in bronchial epithelium of peripheral airways ○ DIPNECH: Generalized NEC proliferation, neuroendocrine bodies, linear NEC proliferation – Peribronchiolar fibrosis resulting in constrictive bronchiolitis • Tumorlet: NEC proliferation that invades bronchiolar basement membrane and measures < 5 mm • Carcinoid tumor: Neoplastic NEC proliferation that invades basement membrane and measures ≥ 5 mm ○ Typical carcinoid: Low-grade malignant neuroendocrine neoplasm, < 2 mitoses per 10 high-power fields (HPF) ○ Atypical carcinoid: Intermediate-grade malignant neuroendocrine neoplasm, 2-10 mitoses per 10 HPF

Small Airways Disease

TERMINOLOGY

Radiographic Findings

CLINICAL ISSUES

• Normal vs. small multifocal pulmonary nodules

CT Findings

Presentation

• Multifocal pulmonary micronodules (< 3 mm) or nodules < 5 mm ○ Larger or dominant nodule should suggest carcinoid • Mosaic attenuation • Bronchial wall thickening

• Most common signs/symptoms ○ May be asymptomatic (up to 50% of patients) ○ Insidious onset of nonproductive cough, exertional dyspnea, wheezing ○ May be misdiagnosed as asthma • Other signs/symptoms ○ Productive cough, hemoptysis, chest pain ○ Obstructive or mixed restrictive/obstructive pulmonary function

HRCT • Multifocal pulmonary micronodules (solid or ground-glass attenuation) ○ May exhibit bronchiolocentric distribution • Mosaic attenuation on inspiratory imaging • Multifocal expiratory air-trapping

Imaging Recommendations • Best imaging tool ○ HRCT with expiratory imaging

DIFFERENTIAL DIAGNOSIS

Demographics • F:M ratio = 10:1; nonsmokers • 50-70 years of age; mean age: 58 years

Natural History & Prognosis • Typically slow disease progression • Rapidly progressive life-threatening disease in < 10% • Variable prognosis

Cellular Bronchiolitis

Treatment

• Infectious bronchiolitis ○ Centrilobular nodules and tree-in-bud opacities ○ Viral, bacterial, mycobacterial, and fungal infections • Aspiration bronchiolitis ○ Basilar predominant centrilobular nodules and tree-inbud opacities ○ Risk factors for aspiration • Follicular bronchiolitis ○ Multifocal centrilobular nodules ○ Expiratory air-trapping

• • • •

Pulmonary Metastases

Inhaled or oral corticosteroids Octreotide, in cases with somatostatin receptors Lung transplantation in patients with respiratory failure Excision of coexistent carcinoid tumors

DIAGNOSTIC CHECKLIST Consider • DIPNECH in middle-aged women with multifocal pulmonary micronodules and associated expiratory airtrapping

SELECTED REFERENCES

• History of malignancy • May manifest as random pulmonary nodules

1.

Diffuse Pulmonary Meningothelial Nodules

2.

• Perivascular distribution

Rossi G et al: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia syndrome. Eur Respir J. 47(6):1829-41, 2016 Benson RE et al: Spectrum of pulmonary neuroendocrine proliferations and neoplasms. Radiographics. 33(6):1631-49, 2013

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Small Airways Disease

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH)

(Left) PA chest radiograph of a 64-year-old woman with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia evaluated because of chronic cough and dyspnea shows a subtle left upper lung zone pulmonary nodule ﬈. (Right) Coronal NECT MIP reformation shows the dominant left upper lobe nodule ﬈ to better advantage. Multiple smaller lung nodules ﬉ are visible in every lung lobe. These nodules correlate with neuroendocrine cell proliferations and tumorlets.

(Left) Axial NECT of the same patient shows small bilateral basilar pulmonary nodules ﬉ on a background of mild mosaic attenuation. The small nodules may mimic other lesions, including cellular bronchiolitis and pulmonary metastases. (Right) Composite image with axial inspiratory (left) and expiratory (right) HRCT shows mild mosaic attenuation, which is accentuated on expiratory imaging. The findings correlate with peribronchiolar fibrosis that may produce clinical symptoms related to constrictive bronchiolitis.

(Left) Axial NECT of a 68-yearold woman evaluated for an incidentally discovered solitary pulmonary nodule shows a dominant bilobed right lower lobe nodule ﬊ and mosaic attenuation. (Right) Axial FDG PET/CT of the same patient shows marked FDG avidity in the posterior aspect of the nodule. Excisional biopsy showed a right lower lobe typical carcinoid tumor ﬈ and adjacent nodular inflammation ﬉. Histologic findings of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia were also documented.

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Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) Small Airways Disease

(Left) Coronal NECT MIP reformation of a symptomatic patient with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia shows multiple small lung nodules ﬈ and prior sublobar resection ﬊ performed to confirm the diagnosis. The patient was treated with octreotide and remains asymptomatic. (Right) High-power photomicrograph (H&E stain) of a specimen of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia shows a carcinoid tumorlet composed of nests of neuroendocrine cells ﬊ amid fibrous tissue ﬈.

(Left) Axial NECT of a 78-yearold woman with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia shows mosaic attenuation, multiple small nodules ﬈, and a larger middle lobe nodule ﬉, suspicious for carcinoid tumor given its size. (Right) Coronal NECT of the same patient shows mosaic attenuation, bronchial wall thickening ﬉, and the dominant middle lobe nodule ﬊. Sublobar resection of this lesion revealed typical carcinoid, multiple surrounding tumorlets, and constrictive bronchiolitis.

(Left) Axial NECT of a 68-yearold woman with suspected diffuse idiopathic pulmonary neuroendocrine cell hyperplasia shows a polylobular soft tissue nodule ﬈ in the right upper lobe and mild mosaic attenuation. (Right) Axial NECT of the same patient shows a dominant polylobular lingular nodule ﬈ and mosaic attenuation. Surgical resection showed typical carcinoid and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Large nodules in affected patients should raise suspicion for carcinoid tumor.

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SECTION 5

Infection

Approach to Infection Bacterial Pneumonia Parasitic Infection Viral Pneumonia Invasive Aspergillosis Pneumocystis Pneumonia Tuberculosis Nontuberculous Mycobacterial Infection

142 146 150 156 160 164 168 174

Infection

Approach to Infection Introduction Pneumonia is generally defined as an infection of the lungs and is caused by a variety of pathogens, including viruses, bacteria, fungi, and parasites. It is a common pulmonary disease and a frequent reason for patients to seek urgent medical attention. In fact, pneumonia is the most common infectious cause of death in children worldwide and accounts for ~ 16% of all deaths in children under the age of 5 years. Affected patients often present with suggestive signs and symptoms that include cough, respiratory distress, and fever. Pneumonia in adults is typically classified as communityacquired pneumonia (CAP), health-care associated pneumonia (HCAP), hospital-acquired (nosocomial) pneumonia (HAP), and ventilator-associated pneumonia (VAP). CAP is defined as an acute pulmonary infection acquired in the community and is common with a rate of 5.16-6.11 cases per 1,000 persons per year. CAP and influenza combined were the 8th most common cause of death in the United States in 2005. Streptococcus pneumoniae and viruses are frequent pathogens. HCAP refers to a pulmonary infection acquired outside the hospital but in association with risk factors related to health care, such as immunocompromised state, nursing home residence, hemodialysis, and prior hospitalization. Affected patients are at risk for infection with multidrug-resistant organisms. HAP is defined as a pulmonary infection that occurs ≥ 48 hours after admission, which was not apparent at the time of admission. VAP is a subset of HAP that develops > 48-72 hours after endotracheal intubation.

Imaging Radiography Imaging of pneumonia is typically performed with posteroanterior (PA) and lateral chest radiography. Portable or bedside radiography can be used to image severely ill and debilitated individuals, but PA and lateral radiography is always preferable for imaging ambulatory patients. Although chest radiography may be normal in patients with pulmonary infection, it typically demonstrates abnormal pulmonary opacities that may manifest as increased lung density and consolidation. Additional findings may include subtle multifocal clustered pulmonary micronodules as a radiographic manifestation of cellular bronchiolitis. Bacterial pneumonias typically manifest with consolidations that may be lobar, sublobar, or multilobar. Lobar pneumonia often manifests with air bronchograms. Associated pleural effusion may also be seen. Bronchopneumonia primarily involves the airways and surrounding interstitium and may manifest with multifocal lobular or confluent airspace disease. Viral pneumonias may manifest with interstitial opacities. Fungal pneumonia may be associated with intrathoracic lymphadenopathy and may mimic malignancy. Pulmonary infection may be complicated by abscess formation and cavitation. Involvement of the pleura may result in empyema, which may be complicated by drainage into the tracheobronchial tree (bronchopleural fistula) or drainage into the chest wall (empyema necessitatis). It should be noted that several pulmonary conditions may mimic the imaging features of pneumonia. These include nonneoplastic and neoplastic processes, such as pulmonary hemorrhage, pulmonary edema, pulmonary 142

thromboembolism with pulmonary infarction, noninfectious inflammatory diseases, primary lung cancer, and pulmonary metastatic disease. Thus, when the clinical presentation does not favor the diagnosis of pneumonia, the radiologist must strive to suggest alternate etiologies based on the available information and the imaging abnormalities. CT CT is not usually employed in the initial evaluation of patients with pulmonary infection. However, CT can be a very useful tool in assessing patients with pneumonia in special situations. A nonresolving pneumonia or a recurrent pneumonia in the same anatomic location should raise the possibility of endobronchial obstruction by neoplasm, which can be easily excluded with CT. CT is also invaluable in the assessment of complications of pneumonia, including abscess formation, cavitation, and involvement of extrapulmonary structures. CT may be very useful in identifying subtle cavitary disease in patients with tuberculosis and may help suggest active infection based on visualization of cavitation associated with cellular bronchiolitis as a marker of transbronchial dissemination of infection. While these findings are helpful in supporting the diagnosis of active disease, recovery of the organism from sputum or tissue is still the gold standard for diagnosis and treatment. Patients with bronchiectatic nontuberculous mycobacterial infection are often assessed with chest CT, which nicely demonstrates characteristic features of middle lobe and lingular bronchiectasis associated with bronchial wall thickening, mucus plugging, and cellular bronchiolitis. However, there is controversy regarding the use of CT surveillance in these individuals given the frequently changing nature of imaging abnormalities in this disease. The appearance of new pulmonary opacities on follow-up imaging is common and often necessitates additional imaging for documentation of stability or resolution. In order to limit radiation exposure in this patient population, use of CT is best restricted to those patients who have a change in symptoms or fail to respond to antimicrobial therapy. HRCT Although chest CT may be employed to assess patients with pulmonary infection, there is hardly ever an indication for imaging assessment with HRCT. The broad availability of multidetector CT allows reconstruction of thin-section images in virtually all cases for identification and characterization of subtle imaging abnormalities. However, expiratory and prone imaging are rarely indicated in patients with suspected pneumonia or in the evaluation of acutely ill subjects. Expiratory imaging may be useful in assessing complications of pulmonary infection, such as constrictive bronchiolitis. For example, patients with Swyer-James-MacLeod syndrome may be entirely asymptomatic, but symptoms of cough, dyspnea, and wheezing may develop in those with extensive lung involvement. These patients may develop constrictive bronchiolitis secondary to prior childhood infection with various pathogens, including adenovirus, influenza virus, respiratory syncytial virus, and Mycoplasma pneumoniae. In these cases, HRCT is sensitive for identification of mosaic attenuation, and expiratory HRCT is useful in documenting airtrapping as a manifestation of small airways disease, particularly in patients with a history of wheezing.

Approach to Infection

General Chest radiography is frequently obtained in all patients presenting with pulmonary complaints. Because symptoms and signs of pulmonary infection may be nonspecific, it is not surprising to identify imaging findings of pneumonia in a patient in whom pneumonia is not suspected clinically. In fact, the radiologist may be the 1st health care provider to raise the possibility of pneumonia. In some cases, a suspected diagnosis of pneumonia does not fit the imaging abnormalities, and discussion with the referring physician is helpful in suggesting other diseases, including infections by atypical organisms. Careful review of the clinical history allows identification of clinical features &/or laboratory findings that support or oppose the diagnosis of pneumonia. As the treatment of pneumonia is dictated by identification of the infectious organism, any information that the radiologist can provide to suggest a likely pathogen or support a clinical diagnostic impression is invaluable. Atypical and unexpected findings should be clearly reported and discussed with the clinical team. For example, the presence of cavitation in an upper lobe consolidation should suggest the possibility of tuberculosis. Such a finding must be promptly communicated to the referring physician to allow for sputum analysis, isolation measures, and protection of uninfected individuals that may come in contact with the patient. Thus, knowledge of the clinical history, including acuity of symptoms, exposure information, and immune status, may help suggest a specific organism in some cases. Atypical or unexpected radiographic abnormalities may require further evaluation with chest CT. This holds true for assessment of cavitary disease, identification of associated lymphadenopathy, and evaluation of pleural abnormalities. In some cases, CT is requested by the clinical team in order to exclude associated abnormalities or complications in at-risk patients and in patients who do not exhibit an expected response to medical treatment. According to Infectious Diseases Society of America/American Thoracic Society consensus guidelines, hospitalized patients with suspected pneumonia and a negative chest radiograph may receive empiric antibiotic therapy and repeat chest radiography 24-48 hours later. In cases in which follow-up chest radiography remains negative, further evaluation with chest CT may be reasonable to identify subtle pulmonary abnormalities. Knowledge of the various clinical scenarios that may accompany pulmonary infection allows the radiologist to provide a focused differential diagnosis that may or may not include pneumonia. In addition, the radiologist should make appropriate management recommendations that may include further imaging &/or additional testing. Microbiology and Biologic Markers Testing for microbial etiology is considered optional in outpatients with suspected CAP. However, hospitalized patients, particularly those in the intensive care unit, may have blood cultures, sputum analysis and culture, urinary antigen tests, and polymerase chain reaction based on specific indications.

These include Legionella species, influenza A and B, and community-associated methicillin-resistant Staphylococcus aureus.

Infection

Role of Radiologist

Procalcitonin is a precursor of calcitonin that is released by tissues in response to bacterial toxins. Procalcitonin levels are used to decide whether or not to use antibiotics in a patient with suspected respiratory infection. Antibiotic treatment is encouraged in patients with procalcitonin levels > 0.25 μg/L and strongly encouraged with levels > 0.50 μg/L. Procalcitonin levels may correlate with severity of pneumonia, help predict bacteremia, and help distinguish bacterial from viral pneumonia, which is particularly helpful during the influenza season. C-reactive protein is also used to predict a bacterial etiology for pneumonia but is less sensitive than procalcitonin. The broad availability of access to patients' electronic medical records allows the radiologist to review relevant clinical and laboratory information in order to support diagnostic impressions. Likewise, when the clinical and laboratory information does not match the diagnostic impression of pulmonary infection, the radiologist may be able to suggest follow-up imaging and additional testing in order to arrive at the correct diagnosis. Immune Status Patients with suspected pulmonary infection should be stratified into 2 different categories: (1) Those with normal immunity and (2) those who are immunocompromised. While outpatients with pulmonary infection and normal immunity typically present with CAP, a variety of opportunistic organisms must be suspected in patients with altered immunity. The radiologist must be familiar with the various forms of immunosuppression and the characteristic organisms that infect affected patients. Patients with acquired immune deficiency syndrome (AIDS) are at risk for CAP as well as opportunistic infections. Pneumocystis jirovecii pneumonia is the most common opportunistic pathogen in patients with AIDS and usually occurs in patients with severe immune suppression, those with CD4 counts < 200 cells/mm³, particularly if they are not on prophylaxis or on antiretroviral therapy. Chest radiographs of such patients may initially be normal, and chest CT may be very useful in identifying subtle ground-glass opacities indicative of active infection. Another group of at-risk patients are allogeneic hematopoietic cell transplant recipients in whom specific pulmonary pathogens depend on the time elapsed after transplantation.

Selected References 1.

2.

3.

4.

Bartlett JG. UpToDate: Diagnostic approach to community-acquired pneumonia. http://www.uptodate.com/contents/diagnostic-approach-tocommunity-acquired-pneumonia-in-adults Reviewed December 11, 2016. Accessed February 2, 2017. Sax PE. UpToDate: Treatment and prevention of Pneumocystis infection in HIV infected patients. http://www.uptodate.com/contents/treatment-andprevention-of-pneumocystis-infection-in-hiv-infected-patients. Reviewed December 11, 2016. Accessed February 2, 2017 Mandell LA et al: Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 44 Suppl 2:S27-72, 2007 Simon L et al: Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis. 39(2):206-17, 2004

Identification of critical microbes is important based on the diagnostic challenges presented by some organisms as well as the fact that these may not respond to empiric therapies. 143

Infection

Approach to Infection

(Left) AP chest radiograph of a 37-year-old obese man admitted with influenza A pneumonia complicated by bacterial infection shows a large right pleural effusion and compressive atelectasis of the right lung. (Right) Coronal NECT of the same patient performed to evaluate suspected empyema shows middle lobe consolidation with intrinsic low attenuation from necrosis ﬈ and areas of frank cavitation ﬉. CT is useful in evaluating complications of pulmonary infection, such as empyema, tissue necrosis, and cavitation.

(Left) PA chest radiograph of a 71-year-old man admitted for treatment of suspected multilobar pneumonia shows right upper lung opacity suggestive of right upper lobe volume loss and a moderate right pleural effusion. The radiologist suggested an alternative diagnosis of malignancy. (Right) Coronal CECT of the same patient confirms a large mass ﬊ replacing the right upper lobe and right supraclavicular ﬉ and contralateral mediastinal ﬈ lymphadenopathy that supports the diagnosis of advanced lung cancer.

(Left) AP chest radiograph of an 86-year-old nursing home resident who presented with cough and malaise shows diffuse bilateral airspace disease, more pronounced on the right than the left, with foci of cavitation ﬈. Note a loculated right basilar pleural effusion ﬊. (Right) Coronal CECT of the same patient shows multifocal upper lobepredominant areas of cavitation ﬈ and surrounding centrilobular micronodules consistent with infectious bronchiolitis and typical of active tuberculosis. Isolation measures were implemented.

144

Approach to Infection Infection

(Left) PA chest radiograph in a 39-year-old man with chronic dyspnea and wheezing shows areas of hyperlucency in right lung but no consolidation. (Right) Coronal NECT (same patient) shows mosaic attenuation of right lung, hyperlucent areas ﬉ corresponding to radiographic abnormalities, and scattered bronchiectasis and bronchial wall thickening ﬈, findings consistent with Swyer-JamesMacLeod syndrome secondary to constrictive bronchiolitis complicating remote childhood adenovirus infection.

(Left) AP chest radiograph of an 80-year-old leukemic patient with febrile neutropenia shows a very subtle left upper lung zone opacity ﬊ concerning for pulmonary infection. (Right) Coronal NECT of the same patient shows a left upper lobe mass ﬈ surrounded by ground-glass attenuation ﬉ (the CT halo sign). In this particular clinical scenario, the most likely diagnosis is opportunistic infection with angioinvasive aspergillosis. The patient responded to empiric treatment with antifungal agents.

(Left) AP chest radiograph of a 62-year-old man with human immunodeficiency virus infection and a CD4 count of < 200 cells/mm³ who presented with severe dyspnea and fever shows diffuse bilateral pulmonary opacities without confluent consolidation. (Right) Coronal CECT of the same patient shows diffuse bilateral ground-glass opacities. Given the clinical history, presenting complaints, laboratory findings, and imaging abnormalities, the most likely diagnosis is Pneumocystis jirovecii pneumonia.

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Infection

Bacterial Pneumonia KEY FACTS

TERMINOLOGY • Community-acquired pneumonia (CAP) ○ Pneumonia diagnosed in outpatient setting or within 48 hours of hospital admission • Hospital-acquired (nosocomial) pneumonia ○ Occurs ≥ 48 hours after hospital admission • Healthcare-associated pneumonia ○ Affects outpatients in contact with health care system and at risk of infections with multidrug-resistant pathogens • Ventilator-associated pneumonia ○ Occurs ≥ 48 hours after endotracheal intubation and mechanical ventilation

IMAGING • Consolidation on radiography associated with purulent secretions, fever > 38° C, and leukocytosis or leukopenia • Lobar consolidation with air bronchograms (variable appearance): Multifocal, patchy, bilateral

(Left) Coronal CECT of a 45year-old man with Pseudomonas aeruginosa pneumonia shows bilateral, multifocal upper lobe consolidations ﬈, areas of ground-glass attenuation ﬉, centrilobular nodules, and right lower lobe tree-in-bud opacities ﬊. (Right) Axial CECT of a patient with Streptococcus pneumoniae pneumonia shows a classic lobar pneumonia with confluent right upper lobe consolidation with intrinsic air bronchograms ﬈, small abscesses ﬉, and a right pleural effusion ﬊.

(Left) Axial CECT of a young patient who presented with high fever and productive cough shows bilateral heterogeneous consolidations, ground-glass opacities, and a thin-walled, air-filled cyst or pneumatocele ﬊. Sputum samples were positive for Staphylococus aureus. (Right) PA chest radiograph of a patient with Klebsiella pneumoniae pneumonia shows a cavitary right upper lobe consolidation ﬈ and characteristic bulging of the major fissure ﬊ caused by the large volume of inflammatory exudate.

146

• Bronchopneumonia: Scattered patchy consolidations, often peribronchovascular • Cavitation, pneumatoceles (Staphylococcus aureus), abscess formation and gangrene (Klebsiella pneumoniae)

TOP DIFFERENTIAL DIAGNOSES • Viral pneumonia • Aspiration pneumonia • Organizing pneumonia

PATHOLOGY • Streptococcus pneumoniae (pneumococcus): Most common pathogen causing CAP • Methicillin-resistant S. aureus: Multidrug-resistant pathogen associated with increased mortality (20-50%) • K. pneumoniae: Mortality in alcoholics of 50-60% • Pseudomonas aeruginosa: Most common nosocomial pulmonary infection • Actinomyces species: May traverse tissue planes

Bacterial Pneumonia

Definitions

•

• Bacteria: Single-celled microorganisms • Often categorized by their shape: Cocci (spheres), bacilli (rods), vibrio (comma-shaped), and spirochetes (spirals)

Classification of Pneumonia and Risk Factors • Community-acquired pneumonia (CAP) ○ Pneumonia diagnosed in outpatient setting or within 48 hours of hospital admission • Hospital-acquired (nosocomial) pneumonia (HAP) ○ Occurs ≥ 48 hours after hospital admission • Healthcare-associated pneumonia (HCAP) ○ Affects outpatients in contact with health care system at risk of infections with multidrug-resistant pathogens • Ventilator-associated pneumonia (VAP) ○ Occurs ≥ 48 hours after endotracheal intubation and mechanical ventilation

IMAGING General Features • Best diagnostic clue ○ Consolidation on radiography associated with purulent secretions, fever > 38° C, and leukocytosis or leukopenia

Radiographic Findings • Radiography ○ Lobar consolidation with air bronchograms (variable appearance): Multifocal, patchy, bilateral – Lobar consolidation and bulging interlobar fissures (Klebsiella pneumoniae) (30%) □ Voluminous inflammatory exudate ○ Bronchopneumonia: Reticular &/or nodular opacities, cavitation, pleural effusion – Primary pattern of tuberculosis (TB): Consolidation, lymphadenopathy, and pleural effusion – Postprimary pattern of TB: Upper lobe heterogeneous consolidation ± cavitation (45%) ○ Miliary pattern of TB: Profuse, bilateral, well-defined nodules (2-3 mm), random distribution ○ Cavitation and pneumatocele formation

CT Findings • May be useful in selected cases • Consolidation (i.e., airspace disease) ○ Segmental or subsegmental consolidation ○ Scattered patchy consolidations, often peribronchovascular (i.e., bronchopneumonia) • Cavitation, pneumatoceles (Staphylococcus aureus), abscess formation and gangrene (K. pneumoniae) • Branching and tree-in-bud opacities ○ Mycobacterial, bacterial, and viral infections ○ Scattered distribution involving all lobes highly associated with Mycobacterium avium-intracellulare infection ○ Aspiration: Common etiology; dependent opacities, associated esophageal abnormalities • Miliary pattern (i.e., micronodules) ○ Profuse, bilateral, well-defined micronodules (2-3 mm), random distribution (hematogenous dissemination)

•

•

•

○ TB (common), histoplasmosis, Pneumocystis pneumonia (rare) Bronchiectatic nontuberculous mycobacteria (NTMB) ○ Middle lobe and lingular bronchiectasis and tree-in-bud opacities; elderly white women (Lady Windermere syndrome) Primary pattern of TB: Consolidation (segmental, lobar, multifocal, nodular, mass-like components) and lymphadenopathy Postprimary pattern of TB and classic/cavitary NTMB: Upper lobe predominant involvement ○ Heterogeneous consolidation: Segmental, lobar, multifocal ○ Cavitation (45%) ○ Endobronchial dissemination: Tree-in-bud opacities, centrilobular (2-4 mm) and acinar nodules, lobular consolidations ○ Bronchial stenosis, bronchial wall thickening Reactive parapneumonic effusion vs. empyema ○ Parapneumonic effusion – Common in Streptococcus pneumoniae pneumonia – Free-flowing (dependent) pleural effusion ○ Empyema associated with loculation, pleural thickening, and pleural enhancement – Split-pleura sign refers to enhancement of thick parietal and visceral pleurae separated by pleural fluid

Infection

TERMINOLOGY

Ultrasonographic Findings • Pleural effusions, may be free or loculated • Exudates may exhibit internal septations • Frequently used for thoracentesis guidance and pleural drain placement

DIFFERENTIAL DIAGNOSIS Viral Pneumonia • Imaging findings similar to those of bacterial pneumonia

Aspiration Pneumonia • Dependent portions of lung • Deglutition, esophageal or neurological abnormalities

Organizing Pneumonia • Subpleural and peribronchovascular consolidations • Subacute or chronic; patients often treated for bacterial pneumonia for variable length of time

PATHOLOGY General Features • Etiology ○ S. pneumoniae (pneumococcus): Gram-positive coccus that grows in pairs or short chains – Most common causative pathogen of CAP – Urinary antigen: Sensitivity (70-90%); specificity (80100%) ○ S. aureus: Gram-positive coccus that grows in clusters – Methicillin-resistant S. aureus (MRSA) □ Multidrug-resistant (MDR) pathogen associated with increased mortality (20-50%) □ Hospitalized patients, nursing home residents, and individuals with long-term indwelling catheters – Community-associated MRSA (CA-MRSA) 147

Infection

Bacterial Pneumonia

○

○

○

○

○

○

○

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□ Individuals in community, usually healthy young individuals without risk factors or comorbidities □ Panton-Valentine leukocidin (PVL) gene found in 85% of CA-MRSA necrotizing pneumonia □ PVL is cytotoxin that causes leukocyte destruction and tissue necrosis K. pneumoniae: Gram-negative bacillus – 0.5–5.0% of all cases of pneumonia □ Mortality rate in alcoholics: 50-60% – Frequently infects elderly, debilitated patients, and alcoholics Pseudomonas aeruginosa: Gram-negative bacillus – Most common cause of nosocomial pulmonary infection – 25% of VAPs Legionella pneumophila: Gram-negative bacillus normally found in aquatic environments – Legionnaires disease Haemophilus influenzae: Gram-negative coccobacillus responsible of 5-20% of CAP – Exacerbations of COPD: H. influenza, S. pneumoniae, Moraxella catarrhalis, and Pseudomonas species – Imaging findings range from ground-glass opacity to frank consolidation Nocardia asteroides: Gram positive, branching, beaded bacilli, weakly acid-fast, ubiquitous – Necrotizing or cavitary pneumonia in immunocompromised patient Actinomyces species: Anaerobic gram-positive bacteria – Alcoholism, poor oral hygiene, and associated dental disease – May transverse tissue planes: Extension to chest wall and mediastinum Mycobacterium tuberculosis: Aerobic, nonmotile bacillus; stains red with Ziehl-Neelsen stain; acid-fast (i.e., resists discoloration with acid alcohol) – Active TB infection: Clinical, radiologic, or bacteriologic evidence of active disease Nontuberculous (atypical) mycobacteria – Water is source of human infection; inhalation, ingestion, or direct inoculation – Hot tub lung: Hypersensitivity reaction to NTMB

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Clinical presentation and diagnosis are complex – Classic symptoms: Fever, generalized fatigue, cough, sputum production, dyspnea, pleuritic chest pain, and hemoptysis – Atypical presentation: Influenced by patient age, comorbid conditions, lifestyle factors, and causative pathogens

Demographics • Epidemiology ○ 6 million cases per year in US population ○ CAP: S. pneumoniae most common pathogen ○ Bacterial HAP: 2nd most common nosocomial infection in US – Up to 25% of all ICU infections 148

– 30 to 70% mortality rate □ P. aeruginosa or Acinetobacter species ○ Bacterial pneumonia in human immunodeficiency virus (HIV) infected patients – Most frequent pulmonary infection in HIV-infected individuals in developed countries – 6x greater than in general population – Highly active antiretroviral therapy (HAART): Decreased incidence of bacterial pneumonia – Infections in advanced acquired immune deficiency syndrome (AIDS): N. asteroides, Rhodococcus equi, and Bartonella henselae ○ HCAP – MRSA ○ VAP – Mechanical ventilation: > 800,000 patients/year in USA – 10-30% among patients who require mechanical ventilation for > 48 hours □ P. aeruginosa, Acinetobacter species, and MRSA

Natural History & Prognosis • Parapneumonic pleural effusions: 20-60% of hospitalized patients with bacterial pneumonia ○ Most pleural effusions are reactive and resolve with antibiotic therapy • Cavitation: Suggests bacterial rather than viral or mycoplasma pneumonia ○ S. aureus, gram negative, and anaerobes • Pulmonary gangrene (tissue necrosis) ○ Typically from S. pneumoniae and Klebsiella ○ Mechanism: Thrombosis of pulmonary vessels

DIAGNOSTIC CHECKLIST Consider • S. pneumoniae in patients with lobar consolidation with air bronchograms • Klebsiella pneumoniae in patients with lobar consolidation and bulging interlobar fissures • MRSA pneumonia in HIV-infected individuals, IV drug abusers, and homeless patients with severe bilateral consolidations, lung destruction, and abscess formation

Image Interpretation Pearls • Lobar pneumonia is usually bacterial in origin (e.g., S. pneumoniae, K. pneumoniae)

SELECTED REFERENCES 1. 2. 3.

4.

Ash SY et al: Pneumococcus. Med Clin North Am. 97(4):647-66, x-xi, 2013 Miller WT Jr et al: Causes and imaging patterns of tree-in-bud opacities. Chest. 144(6):1883-92, 2013 Nguyen ET et al: Community-acquired methicillin-resistant Staphylococcus aureus pneumonia: radiographic and computed tomography findings. J Thorac Imaging. 23(1):13-9, 2008 Tarver RD et al: Radiology of community-acquired pneumonia. Radiol Clin North Am. 43(3):497-512, viii, 2005

Bacterial Pneumonia Infection

(Left) Axial NECT of a 28-yearold man with S. aureus pneumonia shows multifocal patchy areas of air-space consolidation ﬉ consistent with bronchopneumonia. Note associated bronchial wall thickening ﬊. (Right) Coronal NECT shows classic CT features of the postprimary pattern of tuberculosis with bilateral and multifocal centrilobular nodules and treein-bud opacities that represent endobronchial dissemination of disease. Cavitation is often present in immunocompetent patients.

(Left) Axial NECT of a 62-yearold immunosuppressed patient who developed Nocardia pneumonia shows an unilateral mass-like consolidation ﬈ in the left upper lobe with multifocal intrinsic cavitation. The diagnosis of nocardiosis was established via bronchoalveolar lavage. (Right) Axial NECT MIP reformation of a patient with infectious cellular bronchiolitis secondary to bacterial pneumonia shows multiple clusters of tree-in-bud opacities ﬊ in the left lower lobe.

(Left) Coronal CECT of a patient with methicillinresistant S. aureus pneumonia shows right lung consolidation with air bronchograms ﬊, cavitation ﬉, aspirated contrast ﬈, contrast in the esophagus ﬈, and a loculated right pleural effusion ﬊. (Right) Axial NECT of a patient with Mycoplasma pneumoniae pneumonia shows lobular consolidations ﬉, ill-defined centrilobular nodules ﬈, areas of ground-glass opacity ﬇, and associated bronchial wall thickening ſt.

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Infection

Parasitic Infection KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Parasites: Organisms that obtain nourishment and shelter from other organisms (hosts) • Obligate parasites: Can only live in host • Facultative parasites: Can live either in host or independently

• Acute respiratory distress syndrome • Chronic necrotizing aspergillosis • Pneumonia

IMAGING • HRCT/CT ○ Consolidation ○ Transient airspace opacities ○ Nodule/mass; cavitation/focal abscess ○ Miliary nodules ○ Interstitial opacities ○ Bronchopneumonia and patchy airspace opacities ○ Ring-like cysts resembling bronchiectasis ○ Pleural effusion ○ Pulmonary hypertension

(Left) Axial CECT of a 75-yearold patient with strongyloidiasis (hyperinfection syndrome) and chronic lymphocytic leukemia shows bilateral ill-defined ground-glass opacities. (Right) AP chest radiograph of the same patient obtained on ICU admission shows progression of airspace disease secondary to hyperinfection syndrome. The latter is unique to strongyloidiasis, results from larvae reinfecting the lung, and is common in patients with impaired immunity due to cancer or corticosteroid use.

(Left) Axial CECT of the same patient shows extensive, diffuse, bilateral ground-glass opacities and areas of dense consolidation ﬈ that have progressed when compared to the original chest CT. (Right) High-power photomicrograph (Papanicolaou stain) of a bronchoalveolar lavage specimen from the same patient shows a Strongyloides stercoralis larva ﬈. Larvae invade the intestinal wall and reach the lungs hematogenously where they complete their life cycle and are eventually swallowed into the gastrointestinal tract.

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CLINICAL ISSUES • Plasmodium vivax: Most widespread human malaria; 2.5 billion people worldwide at risk of infection • Strongyloidiasis: > 100 million persons with chronic infection worldwide; severe infection may occur in immunosuppressed individuals • Filarial parasites: 8 species infect > 150 million people in tropical and subtropical regions • Hookworm (Ancylostoma duodenale): ~ 25% of world’s population infected • Schistosomiasis: 200 million people infected, 120 million symptomatic, 20 million have severe disease • Echinococcus granulosus: Usual cause of human hydatidosis

Parasitic Infection

Definitions • Parasites: Organisms that obtain nourishment and shelter from other organisms (hosts) ○ Obligate parasites: Can only live in host ○ Facultative parasites: Can live either in host or independently • May cause focal or diffuse pulmonary disease

Classification of Parasites Causing Pulmonary Pathology • Protozoa ○ Amebiasis: Entamoeba histolytica ○ Toxoplasmosis: Toxoplasma gondii ○ Malaria: Plasmodium spp. (P. falciparum, P. vivax, P. ovale, and P. malariae) ○ Trypanosomiasis (Chagas disease): Trypanosoma cruzi • Nematodes ○ Ascariasis: Ascaris lumbricoides ○ Hookworm infection: Ancylostoma duodenale ○ Strongyloidiasis: Strongyloides stercoralis ○ Filarial infections: Wuchereria bancrofti, Brugia malayi, and Brugia timori ○ Dirofilariasis: Dirofilaria immitis ○ Trichinosis: Trichinella spiralis ○ Visceral larva migrans infection (toxocariasis): Toxocara canis and Toxocara cati • Cestodes ○ Hydatidosis: Echinococcus granulosus and Echinococcus multilocularis • Trematodes ○ Paragonimiasis: Paragonimus westermani most prevalent worldwide, Paragonimus kellicotti most prevalent in USA ○ Schistosomiasis: Schistosoma mansoni

IMAGING Radiographic Findings • • • • •

Pulmonary nodules ± cavitation Consolidations ± cavitation Pneumothorax and pleural effusion: P. westermani Diffuse heterogenous opacities: Malaria and Strongyloides Severe cardiomegaly and pulmonary venous hypertension: Chagas disease ○ Septal lines, pulmonary edema, and pleural effusion • One or multiple circumscribed, round or ovoid lung masses (may exhibit intrinsic air and fluid): E. granulosus

CT Findings • Consolidation: Tropical pulmonary eosinophilia (TPE) • Transient airspace opacities: Roundworms [e.g., ascariasis, hookworm (A. duodenale)] • Pulmonary nodules/masses: Dirofilariasis, E. granulosus ○ Well-defined fluid-filled lung cysts; complicated lesions may exhibit air-crescent or water lily signs: E. granulosus • Cavitation/abscess: Amebiasis, strongyloidiasis, and paragonimiasis • Miliary nodules: Strongyloidiasis, toxoplasmosis, and TPE • Interstitial opacities: Lymphatic filariasis, visceral larva migrans (nematodes)

• Bronchopneumonia and patchy airspace opacities • Ring-like cysts resembling bronchiectasis, linear tracts abutting pleura: P. westermani • Pleural effusion: Amebiasis • Pulmonary hypertension: Chronic schistosomiasis

Infection

TERMINOLOGY

DIFFERENTIAL DIAGNOSIS Acute Respiratory Distress Syndrome (ARDS) • Associated with known cause (direct or indirect lung insult) • Consolidation more common than ground-glass opacities

Chronic Necrotizing Aspergillosis • Occurs in patients with depressed immune system • Upper lobe opacities → air crescent sign → cavity ± mycetoma • Adjacent pleural thickening

Community-Acquired Pneumonia • May be difficult to differentiate from parasitic infection and may coexist with it

PATHOLOGY General Features • Parasitic organisms vary widely in size and complexity ○ Simple unicellular protozoans: Amebae ○ Complex multicellular organisms: Worms, flukes

Gross Pathologic & Surgical Features • Amebiasis: Necrotizing abscesses, frequently in contiguity with liver • Hydatidosis: E. granulosus ○ Endocyst: Inner germinal layer ○ Exocyst: Outer laminated chitinous layer ○ Pericyst: Lung reaction around exocyst

Microscopic Features • Toxoplasmosis: Interstitial pneumonia • Malaria: ARDS • Ascaris: Inflammatory reaction, destruction of capillaries and alveolar walls, edema, hemorrhage, and cellular desquamation • Strongyloidiasis: Bronchopneumonia, pulmonary edema, extensive alveolar hemorrhage, and ARDS

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Amebiasis – Pleuropulmonary involvement □ Most common extraintestinal manifestation – Hepatobronchial or bronchobiliary fistula – Pericardial involvement: < 2% of all thoracic complications □ More common when left hepatic lobe affected □ Pain, cardiac tamponade, sepsis ○ Toxoplasmosis – Humans are incidental hosts – T. gondii pneumonia □ Immunocompetent subjects 151

Infection

Parasitic Infection

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□ Patients with human immunodeficiency virus (HIV) infection with CD4 count < 100 cells/mm³ □ Clinical findings: Cough, dyspnea, and fever Malaria – Anopheles mosquito: Vector transmitting Plasmodium spp. to humans – Clinical findings: Fever, chills, sweats, anemia, leukopenia, splenomegaly □ Primary thoracic manifestation: Noncardiogenic pulmonary edema (i.e., ARDS) □ Eosinophilic pneumonia: Secondary to antimalarial drug (e.g., pyrimethamine) Trypanosomiasis (Chagas disease) – Patients usually diagnosed in chronic phase □ Acute trypanosomiasis may be fatal but is rarely diagnosed □ Chagas cardiomyopathy: > 90% of cases □ Myocarditis ± pericardial effusion Ascariasis – Most common worldwide parasitic infection – Löffler syndrome (i.e., simple pulmonary eosinophilia) □ Transient pulmonary opacities and eosinophilia coincide with larval migration through lung □ Nonproductive cough, burning substernal/pleuritic pain, dyspnea, occasional mild hemoptysis Hookworm (A. duodenale) infection – Symptoms depend on location of parasite □ Subclinical in majority of patients – Löffler syndrome similar to that caused by ascariasis Strongyloidiasis – Uncomplicated strongyloidiasis □ Symptoms: Cough, dyspnea, and bronchospasm during migratory phase – Hyperinfection syndrome: High worm burden due to reinfection □ May mimic pulmonary embolism, ARDS, asthma, or chronic obstructive pulmonary disease exacerbation – Disseminated strongyloidiasis: Organ involvement outside normal migration pattern; identification of larvae in stool, sputum, skin □ Extensive alveolar hemorrhage Filarial parasitic infection – W. bancrofti, B. malayi, and B. timori inhabit lymphatics □ Lymphatic obstruction: Elephantiasis, hydrocele □ TPE Dirofilariasis – Infection is frequently asymptomatic – Subcutaneous nodular disease: D. repens – Human pulmonary dirofilariasis: D. immitis □ Incidental detection of solitary pulmonary nodule Visceral larva migrans infection (toxocariasis) – Common symptoms: Chronic cough (paroxysmal and worse at night), wheezing – Chronic eosinophilic pneumonia and noncavitating pulmonary nodules Hydatidosis – Global distribution; high prevalence in Mediterranean area, South and Central America, Russia

– E. granulosus: More common cause of human disease (i.e., hydatid disease) – E. multilocularis – Cyst rupture (tracheobronchial tree or pleura) □ Expectoration of cyst fragments □ Hypersensitivity reactions: Urticaria and wheezing to anaphylaxis ○ Paragonimiasis – Humans infected after ingesting infected raw or undercooked crustaceans – Acute phase (within hours of ingestion) □ Nonspecific abdominal pain, fever and diarrhea – Diaphragm penetration (within 2-3 weeks): Pleural space and lung parenchyma involvement – Chronic phase: May survive for years in lung □ Parenchymal cavities ○ Schistosomiasis – Penetrate skin or intestinal wall, enter systemic veins, and migrate to lungs – Acute infection (Katayama fever) □ Fever, shortness of breath, wheezing, chills, dyspnea, dry cough; fatigue, diarrhea, abdominal pain – Chronic: Cause of pulmonary hypertension

Demographics • Plasmodium vivax: Most widespread human malaria, 2.5 billion people worldwide at risk of infection • Strongyloidiasis: > 100 million persons with chronic infection worldwide ○ 0.4-6% of population of southeast USA • Toxoplasmosis: 0.28-0.45% of patients after stem cell transplant • Filarial parasites: 8 species infect over 150 million people in tropical and subtropical regions • Hookworm (A. duodenale): ~ 25% of world’s population infected • Schistosomiasis: 200 million people infected, 120 million symptomatic, 20 million have severe disease • Amebiasis: Lung disease in 2-7% of invasive amebiasis • Visceral larva migrans: Pulmonary symptoms (33-86%)

Natural History & Prognosis • Amebiasis ○ Direct extension from liver abscess to thorax (6-40%) ○ Hematogenous spread and aspiration • Malaria ○ Several million deaths in endemic areas every year ○ Primary thoracic manifestation: ARDS • Strongyloidiasis ○ Mortality from hyperinfection or dissemination: 70% ○ Complicated by secondary infection: 80%

SELECTED REFERENCES 1. 2. 3.

4.

Cottin V: Eosinophilic lung diseases. Clin Chest Med. 37(3):535-56, 2016 Price M et al: Imaging of eosinophilic lung diseases. Radiol Clin North Am. 54(6):1151-1164, 2016 Skalski JH et al: Fungal, viral, and parasitic pneumonias associated with human immunodeficiency virus. Semin Respir Crit Care Med. 37(2):257-66, 2016 Henry TS et al: Role of imaging in the diagnosis and management of parasitic infections. Curr Opin Pulm Med. 19(3):310-7, 2013

Parasitic Infection Infection

(Left) Coronal NECT of a patient with strongyloidiasis shows multiple lung nodules ﬈ with spiculated and illdefined borders, some of which exhibit intrinsic cavitation ﬉. Also note focal areas of nodular consolidation and tree-in-bud opacities ﬊. (Right) High-power photomicrograph (methylene blue stain) of a bronchoalveolar lavage specimen obtained from the same patient shows a S. stercoralis larva ﬈.

(Left) PA chest radiograph of a patient with acute respiratory distress syndrome due to Plasmodium falciparum infection shows bilateral heterogeneous pulmonary consolidations, largest in the left lung. Acute respiratory distress syndrome is the primary manifestation of pulmonary malaria and is due to severe P. falciparum infection. (Right) High-power photomicrograph (Wright stain) of a specimen from the same patient shows rings of intracellular P. falciparum ﬈ in a thin blood smear.

(Left) Coronal NECT of a 38year-old woman with paragonimiasis due to Paragonimus kellicotti shows a right pleural effusion ﬊ and linear opacities ﬈ abutting the pleura that correspond to parasitic tracts from the pleura into the lung. P. kellicotti may be found along the Mississippi river and may affect patients who consume undercooked or raw crawfish. (Right) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows the microorganism ﬈ in the center of a granuloma.

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Infection

Parasitic Infection

(Left) Axial CECT of a young man with paragonimiasis shows clustered spiculated lingular lung nodules ﬈, adjacent linear opacities ﬊, and a trace left pleural effusion ﬉. (Right) Highpower photomicrograph (H&E stain) of a specimen from the same patient shows intense chronic inflammation with eosinophilic microabscesses ﬈. Most parasitic pulmonary infections elicit an eosinophilic reaction that is an important histologic finding and a clue to the pathologic diagnosis.

(Left) Composite image with axial HRCT of a patient with simple pulmonary eosinophilia from ascariasis, obtained at the time of acute onset of symptoms (left) and 1 month later (right), shows patchy ground-glass opacities ﬈ that nearly resolved on follow-up imaging. Like other roundworms, ascariasis has a life cycle that involves the lungs. (Right) Axial CECT of a 61-year-old woman with pulmonary toxoplasmosis demonstrates numerous small pulmonary nodules that exhibit a miliary pattern.

(Left) AP chest radiograph of a patient with acute trypanosomiasis and tachyarrhythmia that rapidly progressed to pulmonary edema and death shows extensive bilateral pulmonary consolidations. Acute parasitic myocarditis was diagnosed at autopsy. (Right) High-power photomicrograph (Wright stain) of a specimen from the same patient shows Trypanosoma cruzi trypomastigotes ﬈. There was severe acute myocarditis (not shown), a rare manifestation of trypanosomiasis.

154

Parasitic Infection Infection

(Left) Coned-down PA chest radiograph of a patient with dirofilariasis shows an illdefined nodule ﬈ in the right lower lung zone. (Courtesy N. Patz Jr., MD.) (Right) Axial NECT of the same patient shows a solid nodule ﬈ in the subpleural middle lobe. The nodule was excised, and histologic evaluation demonstrated Dirofilaria immitis. This infection is acquired from the bite of infected mosquitoes, which in turn acquire the parasite from infected dogs. (Courtesy N. Patz Jr., MD.)

(Left) Coned-down frontal chest radiograph of a patient with hydatidosis shows a thick-walled cavitary lesion ﬈ containing irregular material representing collapsed membranes ﬊. Note parenchymal consolidation surrounding the cavity ﬉. (Right) Gross photograph of the resected specimen from the same patient shows multiple folded intracystic membranes ﬈ and the outer layer of the cyst wall (pericyst) ﬊ consisting of dense fibrovascular lung tissue with variable numbers of inflammatory cells.

(Left) Composite image with coronal (left) and axial (right) NECT of a patient with hydatidosis shows the crescent ﬈ and water lily signs ﬉, respectively, and illustrates the disease progression from impending cyst rupture to rupture with cyst collapse. (Courtesy P. Boiselle, MD.) (Right) Axial CECT of a patient with chronic schistosomiasis shows marked dilation of the pulmonary trunk ﬈ due to pulmonary hypertension. Note chronic intraluminal thrombus ﬊ and atherosclerosis ﬉. (Courtesy D. Jasinowodolinski, MD.)

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Infection

Viral Pneumonia KEY FACTS

TERMINOLOGY

CLINICAL ISSUES

• Viruses typically affect respiratory epithelium

• Cold: Upper respiratory tract symptoms (tonsillopharyngitis, pharyngitis, epiglottitis, sinusitis, otitis media, and conjunctivitis) • Influenza syndrome: Abrupt fever, headache, myalgias, and malaise • Acute bronchiolitis in infants and children: Wheezing with concomitant signs of respiratory viral infection • High rate of viral infection in patients with communityacquired pneumonia (2-35%)

IMAGING • Radiography ○ May be normal at presentation (20%) ○ Focal or multifocal consolidation • CT/HRCT ○ Mosaic attenuation and expiratory air-trapping ○ Ground-glass opacity and consolidation ○ Nodules, micronodules, and tree-in-bud opacities • Interlobular septal thickening • Bronchial &/or bronchiolar wall thickening

TOP DIFFERENTIAL DIAGNOSES • • • •

Bacterial pneumonia Aspiration Diffuse alveolar hemorrhage Organizing pneumonia

(Left) Coronal HRCT of a patient with acute infectious bronchiolitis secondary to respiratory syncytial virus (RSV) shows diffuse bilateral tree-in-bud nodules and upper lobe ground-glass opacities. RSV is a common cause of infectious bronchiolitis and has been linked to asthma in children. (Right) Coronal HRCT of a 52-year-old woman with rhinovirus pneumonia shows multifocal ground-glass opacities bilaterally. Rhinoviruses are the predominant cause of the common cold but occasionally cause viral pneumonia.

(Left) Axial NECT of a 75-yearold man with herpes simplex virus pneumonia shows multifocal ground-glass opacities and consolidations. Herpes pneumonia is rare but may occur in the setting of burns, transplantation, pregnancy, malignancy, and human immunodeficiency virus infection. (Right) Axial CECT of a 71-year-old woman with human metapneumovirus pneumonia shows bilateral consolidations ﬈ and a small right pleural effusion ﬉. Human metapneumovirus is a common cause of viral pneumonia.

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DIAGNOSTIC CHECKLIST • Diagnosis relies on clinical suspicion: Host risk factors, presentation, and exposure history • Lobar consolidation uncommon in viral pneumonia • Nodules < 10 mm, may exhibit CT halo sign, and do not exhibit cavitation • Branching or centrilobular nodules and mosaic perfusion common in viral bronchiolitis

Viral Pneumonia

Definitions • Pulmonary viral infection typically affects respiratory epithelium from trachea to terminal bronchioles ○ Alveolar involvement less common, but often severe and rapidly progressive

RNA Virus-Related Diseases • Influenza ○ Seasonal community infections, endemic infections, and unpredictable pandemics ○ Influenza type A: Most important respiratory virus affecting general population with regards to morbidity and mortality ○ Major cause of respiratory illness in immunocompromised hosts • Avian influenza (H5N1) ○ Contact with infected birds; usually poultry ○ Overall case fatality rate exceeds 60% • Swine influenza (H1N1) ○ 1st pandemic of 21st century, originally reported in Mexico (spring of 2009) ○ High transmission among humans, but virulence not greater than that observed with seasonal influenza • Parainfluenza virus ○ Common cause of seasonal upper respiratory tract infection in adults and children ○ Parainfluenza virus type 3: Respiratory illness in immunocompromised hosts and solid organ transplant recipients • Respiratory syncytial virus (RSV) ○ Ubiquitous cause of respiratory infection ○ Most frequent viral cause of lower respiratory tract infection in infants • Human metapneumovirus (hMPV) ○ Implicated in 4-21% of infants with acute bronchiolitis – Symptoms clinically indistinguishable from those elicited by RSV ○ 4% of cases among patients with community-acquired pneumonia (CAP) or chronic obstructive pulmonary disease (COPD) exacerbations • Measles ○ One of 3 major infectious diseases worldwide – 1.5 million childhood deaths per year • Coxsackievirus, echovirus, and enterovirus ○ Lower respiratory tract infection may occur sporadically and is not always associated with pneumonia • Human T-lymphotropic virus type 1 (HTLV-1) ○ Etiologic retrovirus of adult T-cell leukemia or lymphoma – Associated with myelopathy, Sjögren syndrome, and lymphocytic pneumonitis • Hantavirus ○ Rodent-borne zoonotic disease – Hantavirus pulmonary syndrome: Severe acute respiratory distress syndrome (ARDS), rapid clinical progression, and high mortality • Severe acute respiratory syndrome (SARS) ○ Atypical pneumonia caused by newly discovered SARSassociated coronavirus (SARS-CoV) in 2012 (Guangdong, China)

• Middle east respiratory syndrome (MERS) ○ Acute viral respiratory disease caused by novel virus currently named MERS coronavirus (MERS-CoV)

Infection

TERMINOLOGY

DNA Viruses • Adenovirus ○ 5-10% of acute respiratory infections in infants and children, but < 1% of respiratory illnesses in adults ○ Swyer-James-MacLeod syndrome: Acquired constrictive bronchiolitis due to childhood adenovirus infection • Varicella virus ○ Common contagious infection in childhood, increasing frequency in adults – Varicella pneumonia: 1 of every 400 cases of adulthood chickenpox infection • Cytomegalovirus (CMV) ○ CMV infection: > 70% of hematopoietic stem cell transplant (HSCT) recipients; ~ 1/3 develop CMV pneumonia – Infection during postengraftment period (30-100 days after transplantation) • Epstein-Barr virus (EBV) ○ Primary infection manifests as infectious mononucleosis ○ EBV pneumonia: Rare in immunocompetent or immunocompromised subjects ○ Associated with development of Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma

IMAGING Radiographic Findings • Variable and overlapping appearance ○ Normal at presentation (20%) • Tracheobronchitis ○ Bronchial wall thickening ○ Atelectasis: Discoid to segmental (mucus plugs) • Pneumonia ○ Focal consolidation: Peripheral, mid, and lower lung zones (40%) ○ Unilateral or patchy bilateral areas of consolidation ○ Diffuse consolidation • Complications ○ Bacterial superinfection: Sudden worsening, cavitation, or enlarging pleural effusion • Uncommon findings ○ Hilar or mediastinal lymphadenopathy: Measles and infectious mononucleosis ○ Splenomegaly: Infectious mononucleosis • Cardiac enlargement (pericardial effusion): Hantavirus • Pleural effusion ○ Rare except for adenovirus, measles, hantavirus, HSV-1

CT Findings • Alterations of parenchymal attenuation ○ Patchy heterogeneous pulmonary attenuation (mosaic attenuation pattern) – Bronchiolar obstruction (inflammation or cicatricial scarring) and secondary vasoconstriction □ Inspiratory/expiratory CT: Differentiation of bronchiolar from pulmonary vascular disease

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Infection

Viral Pneumonia

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□ Bronchiolar disease (air-trapping): Decreased attenuation on inspiration, accentuated on expiration □ Vascular disease: Little increase in attenuation or decrease in volume Ground-glass opacity and consolidation ○ Coexistence of interstitial thickening and partial airspace filling ○ Consolidation: Patchy and poorly defined (bronchopneumonia) vs. focal and well-defined (lobar pneumonia) Nodules, micronodules, and tree-in-bud opacities ○ Nodules 1-10 mm in diameter common in viral infections – Centrilobular nodules □ Inflammation, infiltration, or fibrosis of surrounding interstitium and alveoli – Tree-in-bud opacities: Indicative of small airways disease □ Dilatation of centrilobular bronchioles with lumina impacted with mucus, fluid, or pus – Branching or centrilobular nodules and mosaic perfusion: Common in viral bronchiolitis – Miliary nodules □ Nearly any organism; typically tuberculosis, fungi, varicella-zoster virus Interlobular septal thickening ○ Widespread with associated ARDS Bronchial &/or bronchiolar wall thickening ○ Inflammatory exudates and bronchiolar wall thickening from edema and smooth muscle hyperplasia

CLINICAL ISSUES Presentation

• Consolidation, cellular bronchiolitis • May exhibit cavitation

• Most common signs/symptoms ○ Clinical syndromes – Cold: Upper respiratory tract symptoms (tonsillopharyngitis, pharyngitis, epiglottitis, sinusitis, otitis media, and conjunctivitis) – Influenza syndrome: Abrupt fever, headache, myalgias, and malaise ○ Acute bronchiolitis in infants and children: Wheezing with concomitant signs of respiratory viral infection – RSV (most common), adenovirus, influenza, and parainfluenza ○ CAP: Cough, sputum, or dyspnea with fever or abnormalities at physical examination (rhonchi and rales) – Influenza and RSV □ Comorbidities or risk factors: Smoking, COPD, asthma, diabetes mellitus, malignancy, heart failure, neurologic diseases, narcotic and alcohol use, and chronic liver disease • Clinical profile ○ Role of biomarkers – Procalcitonin: ↓ with viral infection,↑ with bacterial infection, ○ Better quality of diagnostic tests have improved ability to detect multiple viruses

Aspiration

Demographics

• Basilar predominant cellular bronchiolitis • Esophageal abnormalities, neurological and deglutition disorders

• Increasingly frequent cause of pulmonary disease worldwide • High rate of viral infection in CAP (2-35%) ○ Influenza, hMPV, and RSV: 2/3 of all viral pathogens in patients with CAP

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DIFFERENTIAL DIAGNOSIS Bacterial Pneumonia

Diffuse Alveolar Hemorrhage • Ground-glass opacities ± interlobular septal thickening (crazy-paving pattern) • No signs and symptoms of infection

Organizing Pneumonia • Peripheral or peribronchial consolidation • Migratory pulmonary opacities • Reversed halo sign

PATHOLOGY Microscopic Features • Nodules contain infected cells with cytoplasmic inclusions: Cytomegalovirus, adenovirus, herpesvirus • Necrotizing bronchitis &/or bronchiolitis and diffuse alveolar damage (DAD): Influenza, RSV, parainfluenza viruses • Bronchiolitis and bronchiectasis: Adenovirus • Necrotizing bronchopneumonia, multicentric areas of hemorrhage (centered on airways): Herpes simplex virus 158

• Acute interstitial pneumonia ○ Diffuse alveolar thickening by edema and mononuclear cells, airspace fibrinous exudate &/or hyaline membranes ○ CMV, hantaviruses (hantavirus pulmonary syndrome), SARS, and MERS • Endothelial damage to small vessels (focal hemorrhagic necrosis, mononuclear infiltration of alveolar walls, and alveolar fibrinous exudates): Varicella-zoster virus

Natural History & Prognosis • Variable prognosis ○ Complete resolution in immunocompetent individuals

DIAGNOSTIC CHECKLIST Image Interpretation Pearls • Lobar consolidation uncommon in viral pneumonia • Nodules < 10 mm, may exhibit CT halo sign; do not exhibit cavitation • Branching or centrilobular nodules and mosaic perfusion/attenuation common in viral bronchiolitis

SELECTED REFERENCES 1. 2.

Franquet T: Imaging of pulmonary viral pneumonia. Radiology. Jul;260(1):1839, 2011 Kim EA et al: Viral pneumonias in adults: radiologic and pathologic findings. Radiographics. 22 Spec No:S137-49, 2002

Viral Pneumonia Infection

(Left) Axial HRCT of a bone marrow transplant recipient who developed parainfluenza virus 3 pneumonia shows scattered bilateral groundglass opacities ﬈. Influenza, respiratory syncytial virus, rhinovirus, and parainfluenza virus are the most common pathogens in this patient population. (Right) Axial CECT of a woman with influenza virus A pneumonia shows extensive, bilateral, peripheral ground-glass opacities and consolidations. The pattern is reminiscent of organizing pneumonia, which is often present histologically.

(Left) Axial NECT of a patient with cytomegalovirus pneumonia and a history of bilateral lung transplantation shows a left upper lobe nodule ﬈ with surrounding groundglass opacity ﬉, the so-called CT halo sign, which often correlates with perilesional hemorrhage. (Right) Axial NECT of a hematopoietic stem cell transplant recipient with cytomegalovirus infection shows multiple random lung nodules measuring < 10 mm, with surrounding ground-glass opacity ﬈. These findings are highly suggestive of a viral infection.

(Left) Axial CECT of a 28-yearold man with fever and a skin rash due to varicella-zoster virus infection shows profuse, miliary, 1- to 2-mm nodules scattered throughout the lung. (Right) Axial NECT of a patient with hantavirus pulmonary syndrome shows diffuse symmetric ground-glass opacities with superimposed linear and reticular opacities exhibiting the crazy-paving pattern and small bilateral pleural effusions ﬉. The findings were related to diffuse alveolar damage. (Courtesy A.S. Sousa, MD.)

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Infection

Invasive Aspergillosis KEY FACTS

• Infection caused by saprophytic airborne filamentous fungus Aspergillus species (usually Aspergillus fumigatus) • Angioinvasive aspergillosis: Most common form ○ Occlusion of small to medium-sized pulmonary arteries by fungal hyphae • Airway-invasive aspergillosis: Rare form ○ Presence of fungal hyphae beyond airway basement membrane

IMAGING • CT ○ Angioinvasive aspergillosis – Single/multiple pulmonary nodules/masses; consolidation – CT halo sign: Ground-glass opacity surrounding nodule/mass – Other signs: Occluded vessel sign, hypodense sign □ Air-crescent sign: Denotes recovery phase

(Left) Axial NECT of a 54-yearold man with acute myelogenous leukemia and angioinvasive aspergillosis shows a left upper lobe mass ﬉ with central low attenuation ﬈ secondary to necrosis. Note moderate left pleural effusion ﬊ and prevascular lymphadenopathy ſt. (Right) Axial CECT of the same patient confirms the central low-attenuation region within the mass ﬉, which correlates with necrosis. Note the additional smaller necrotic focus ﬈. The hypodense sign is a typical finding of early invasive aspergillosis.

(Left) Composite image with NECT before (left) and after (right) treatment shows invasive aspergillosis manifesting with multiple nodules that exhibit the halo sign ﬉ and develop the aircrescent sign ﬈ after therapy. The latter is associated with neutrophil recovery. (Right) Low-power photomicrograph (H&E stain) of a specimen of invasive aspergillosis shows vessel dilatation, wall destruction, and internal necrotic debris and fibrin ﬈ that extend into adjacent alveolar spaces ﬉. (From DP: Thoracic 2e.)

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○ Airway-invasive aspergillosis – Airway wall thickening; gangrenous mucosa – Bronchiolitis: Tree-in-bud opacities – Bronchopneumonia: Peribronchovascular opacities

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES • • • • • •

Other fungal infection Mycobacterial infection Bacterial pneumonia Granulomatosis with polyangiitis Pulmonary infarction Non-small cell lung cancer

CLINICAL ISSUES • Severe/prolonged neutropenia (most important risk factor) • Treatment: Voriconazole; surgery for massive hemoptysis

DIAGNOSTIC CHECKLIST • Consider invasive aspergillosis in febrile neutropenic patient with pulmonary nodules, masses, or consolidations

Invasive Aspergillosis

Synonyms • Invasive pulmonary aspergillosis

Definitions • Infection caused by saprophytic and ubiquitous airborne filamentous fungus Aspergillus species (usually Aspergillus fumigatus) ○ Other species: Aspergillus flavus, Aspergillus niger ○ Affects almost exclusively immunocompromised patients with severe neutropenia: Absolute neutrophil count < 500 per μL • Angioinvasive aspergillosis ○ Most common form of invasive aspergillosis ○ Occlusion of small to medium-sized pulmonary arteries by fungal hyphae ○ Wedge-shaped subpleural consolidation corresponding to hemorrhagic infarct • Airway-invasive aspergillosis ○ Rare form of invasive aspergillosis ○ Fungal hyphae beyond airway basement membrane

IMAGING General Features • Best diagnostic clue ○ Invasive aspergillosis: Fulminant lung disease in febrile neutropenic patient

Radiographic Findings • Angioinvasive aspergillosis ○ Radiography not sensitive for detecting early disease ○ Pulmonary nodules or consolidations may rapidly progress ○ Air-crescent sign: Crescentic lucency within pulmonary nodule/mass that may occur after initiation of treatment and recovery of immunologic system (recovery phase) • Airway-invasive aspergillosis ○ Clustered nodules ○ Patchy consolidation

CT Findings • Angioinvasive aspergillosis ○ Nodule, mass, or consolidation – Solitary or multiple nodule(s)/mass(es) □ < 10 in number □ 6 mm to 3 cm – CT halo sign (early sign) □ Ground-glass opacity surrounding nodule or mass □ Highly suggestive of angioinvasive aspergillosis in appropriate clinical setting □ Warrants antifungal therapy before confirmation with other tests □ Pathologically represents hemorrhage around foci of invasive aspergillosis – Occluded vessel sign □ Visible with CT pulmonary angiography (CTPA) □ Occlusion of peripheral segmental artery at lesion edge □ May be partial (irregular reduction of vessel diameter) or complete (interruption)

□ Absence of enhancing vessels within lesion (absence of angiogram sign) □ Best demonstrated on MIP reformations – Hypodense sign (early sign) □ Central hypodensity in nodule, mass, or consolidation due to infarction; low sensitivity, high specificity □ 1st CT finding to raise suspicion of angioinvasive aspergillosis; often recognizable on unenhanced CT □ Usually affects > 50% of lesion □ Occurs prior to cavitation and development of aircrescent sign – Reversed halo sign □ < 1% of patients with angioinvasive aspergillosis – Air-crescent sign (late sign) □ Crescentic air collection in nodule, mass, or consolidation: Separates cavity wall from inner mass (necrotic lung); subsequent retraction of infarcted lung □ Limited utility for diagnosis: Seen in up to 50% of affected patients during convalescence and recovery of neutrophil count; typically 2-3 weeks after therapy initiation • Airway-invasive aspergillosis ○ Tracheal or bronchial wall thickening – Linear lucency along airway wall outlining gangrenous mucosa ○ Bronchiolitis: Tree-in-bud opacities ○ Bronchopneumonia: Patchy peribronchovascular opacities

Infection

TERMINOLOGY

Imaging Recommendations • Best imaging tool ○ HRCT/CT for demonstration of: CT halo, hypodense, reversed halo, and air-crescent signs ○ CECT (CTPA) for demonstration of occluded vessel sign

DIFFERENTIAL DIAGNOSIS Other Fungal Infection • Mucormycosis and candidiasis • May produce angioinvasive disease

Mycobacterial Infection • May exhibit consolidation • May exhibit CT halo sign and cavitation

Bacterial Pneumonia • Lung abscess may cavitate • Cavitary disease may mimic invasive aspergillosis

Granulomatosis With Polyangiitis • Multifocal nodules, masses, consolidations • May exhibit cavitation and CT halo sign

Pulmonary Infarction • Peripheral consolidation or mass with central lucency • Bland or septic pulmonary emboli

Non-Small Cell Lung Cancer • Cavitary lung cancer may mimic mycetoma • Tumor may cause vascular invasion and lung infarction 161

Infection

Invasive Aspergillosis – Assay for detection of Aspergillus galactomannan □ Aspergillus galactomannan, polysaccharide cell wall component – Aspergillus galactomannan in bronchoalveolar lavage more sensitive than serum assay □ Sensitivity > 90%

PATHOLOGY General Features • Etiology ○ Severe neutropenia (main risk factor) – Highest risk: Acute leukemia, hematopoietic stem cell transplantation (HSCT) – Prolonged steroids, solid organ transplantation ○ No increased risk in patients with AIDS without additional predisposing factor ○ Most infections caused by Aspergillus species, usually A. fumigatus ○ Invasive aspergillosis may also affect normal host following massive inhalation: Primary aspergillosis • In normal host, inhaled spores rapidly phagocytized and eliminated • In immunocompromised host, inhaled spores change to hyphal forms and produce tissue invasion ○ Angioinvasive (70%) ○ Airway invasive (30%)

Gross Pathologic & Surgical Features • Halo sign ○ Round infarction with gray-yellow necrotic center ○ Thin rim of peripheral hemorrhage • Infiltration of lung tissue by fungus ○ Invasion of small to medium-sized arteries by fungal hyphae – Vascular occlusion – Frequent infarction • Wedge-shaped infarcts when large arteries are occluded • Air-crescent sign ○ Infarction leading to progressive cavitation ○ No preexisting cavitation ○ Resorption of necrotic tissue by neutrophils – Intracavitary ball of devitalized necrotic lung □ Sequestrum □ Mimics aspergilloma

Demographics • Age ○ Any age, depends on underlying predisposing factors • Epidemiology ○ 60% of fungal pneumonias in immunocompromised patients are caused by Aspergillus

Natural History & Prognosis • Common cause of death in severely immunocompromised subjects ○ Mortality rate – > 50% in neutropenic patients – 90% in HSCT recipients – Low risk in autologous HSCT recipients ○ Poor prognosis in human immunodeficiency virus (HIV)positive patients ○ Improved outcome with early diagnosis and aggressive treatment – CT halo sign at baseline: Improved response to treatment, better survival • Invasive aspergillosis progresses over days to weeks

Treatment • Medical therapy ○ Voriconazole more effective than amphotericin B – Survival: 71% vs. 58% • Surgery may be indicated in some cases, particularly for management of massive hemoptysis ○ Reserved for unilateral focal disease ○ Postoperative risks include bleeding, bronchopleural fistula, and empyema

DIAGNOSTIC CHECKLIST CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Mimics bacterial bronchopneumonia – Fever, cough, dyspnea – Pleuritic chest pain – Hemoptysis • Clinical profile ○ Risk factors – Severe or prolonged neutropenia (most important factor) – High doses of corticosteroids – Other drugs or diseases that impair cellular immunity ○ No preexisting lung damage ○ Diagnostic options – Proven invasive aspergillosis □ Histopathological confirmation with tissue sampling □ Positive culture from normally sterile site – Bronchoalveolar lavage: Low diagnostic yield (30% sensitivity) 162

Consider • Angioinvasive aspergillosis in febrile neutropenic patient with pulmonary nodules, masses, or consolidations

Image Interpretation Pearls • HRCT for detection of early signs: i.e., hypodense sign and halo sign • CTPA for detection of occluded vessel sign

SELECTED REFERENCES 1. 2. 3.

4. 5.

6.

Prasad A et al: Pulmonary aspergillosis: what CT can offer before it is too late! J Clin Diagn Res. 10(4):TE01-5, 2016 Chabi ML et al: Pulmonary aspergillosis. Diagn Interv Imaging. 96(5):435-42, 2015 Stanzani M et al: High resolution computed tomography angiography improves the radiographic diagnosis of invasive mold disease in patients with hematological malignancies. Clin Infect Dis. 60(11):1603-10, 2015 Walsh S et al: Importance of the reversed halo sign for the diagnosis of angioinvasive pulmonary aspergillosis. Respir Med. 108(8):1240, 2014 Althoff Souza C et al: Pulmonary invasive aspergillosis and candidiasis in immunocompromised patients: a comparative study of the high-resolution CT findings. J Thorac Imaging. 21(3):184-9, 2006 Franquet T et al: Spectrum of pulmonary aspergillosis: histologic, clinical, and radiologic findings. Radiographics. 21(4):825-37, 2001

Invasive Aspergillosis Infection

(Left) Axial NECT of a 59-yearold man with acute myelogenous leukemia who developed invasive aspergillosis after a bone marrow transplant shows a dense right lower lobe mass ﬈ with peripheral ground glass, the so-called halo sign ﬉. The latter correlates with hemorrhage surrounding the lesion. (Right) Coronal CECT MIP reformation of the same patient shows complete occlusion of the vessels ﬈ that supply the lesion and no vessel visualization inside the lesion (the occluded vessel sign). (Courtesy C. Sassi, MD.)

(Left) Axial HRCT of a patient with invasive aspergillosis shows a left upper lobe mass with cavitation that exhibits the air-crescent sign ﬈. The lesion exhibits mass-like central ground-glass opacity (representing necrotic lung) and peripheral consolidation. This typically occurs after treatment and improvement of immune function. (Right) Gross specimen from the same patient shows crescentic cavitation ﬊ along the inferior aspect of the lesion partially surrounding retracted necrotic lung tissue ﬉.

(Left) Axial NECT of a 51-yearold patient status post renal transplantation on chronic corticosteroids shows invasive aspergillosis manifesting with right lower lobe consolidation surrounded by ground-glass opacity that represented bronchopneumonia. The ipsilateral pleural effusion represented an empyema. Note stenosis and irregularity of the bronchus intermedius ﬈. (Right) Coronal NECT of the same patient shows marked stenosis ﬉ of the bronchus intermedius and linear sphacelated ﬈ or gangrenous mucosa.

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Infection

Pneumocystis Pneumonia KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Pneumocystis pneumonia (PCP): Life-threatening respiratory infection occurring in immunocompromised individuals ○ Caused by fungus Pneumocystis jirovecii

• Cytomegalovirus pneumonia • Diffuse alveolar hemorrhage • Lymphoid interstitial pneumonia

IMAGING • HRCT ○ Ground-glass opacities ○ Lung cysts ○ Crazy-paving pattern ○ Diffuse consolidation ○ Intralobular lines and interlobular septal thickening ○ Spontaneous pneumothorax ○ Less common findings: Lung nodules, mass, lobar consolidation, mediastinal/hilar lymphadenopathy, pleural effusion ○ Chronic PCP: Architectural distortion, traction bronchiectasis

(Left) Axial HRCT of a 42-yearold renal transplant recipient with cough and dyspnea shows diffuse bilateral ground-glass opacities related to pneumocystis pneumonia. (Right) Coronal HRCT of the same patient shows extensive bilateral ground-glass opacities and a geographic distribution of the spared lung parenchyma. While nonspecific, these findings are characteristic of pneumocystis pneumonia in immunocompromised patients, and should always be considered in the appropriate clinical setting.

(Left) High-power photomicrograph (H&E stain) of a specimen from the same patient shows a foamy eosinophilic exudate ﬈ filling the alveolar spaces and thickening of the alveolar septa ﬊ secondary to an inflammatory infiltrate. (Right) High-power photomicrograph (GMS stain) shows clusters of blackstaining cyst forms ſt of the Pneumocystis jirovecii organism. Affected patients are usually infected by HIV and immunocompromised or on chronic immunosuppressive treatments.

164

PATHOLOGY • Intraalveolar foamy exudates containing Pneumocystis organisms and interstitial inflammation

CLINICAL ISSUES • Human immunodeficiency virus (HIV) infected ○ Younger patients ○ Subacute clinical course • Non-HIV infected: Older, abrupt onset of respiratory insufficiency

DIAGNOSTIC CHECKLIST • Consider PCP in HIV-infected patients with severe immunosuppression, subacute respiratory symptoms, and bilateral ground-glass opacities

Pneumocystis Pneumonia

Abbreviations • Pneumocystis pneumonia (PCP)

Synonyms • Pneumocystis jirovecii pneumonia

Definitions • Life-threatening respiratory infection occurring in immunocompromised individuals ○ e.g., human immunodeficiency virus (HIV) infection, immunosuppressive therapy • Caused by fungus Pneumocystis jirovecii, formerly referred to as Pneumocystis carinii

IMAGING General Features • Best diagnostic clue ○ Diffuse bilateral ground-glass opacities – In both HIV-infected patients and in patients without HIV infection • Location ○ Diffuse • Atypical imaging findings in setting of PCP suggest comorbidity (e.g., infectious or neoplastic disease)

Radiographic Findings • Normal (10-30%) • Bilateral perihilar or diffuse symmetric ill-defined or reticular opacities • Multilobar consolidation ○ Secondary to disease progression or development of acute respiratory distress syndrome (ARDS)

CT Findings • HRCT ○ Ground-glass opacities (92%) – Alveolar filling by foamy exudate (surfactant, fibrin, and cellular debris) – Variable distribution: Central distribution with relative peripheral sparing (41%), mosaic attenuation (29%), diffuse involvement (24%) ○ Crazy-paving pattern – Ground-glass opacities with superimposed intralobular lines &/or interlobular septal thickening ○ Lung cysts (10-34%) – Tissue invasion and secondary necrosis – Upper lobe predominance – Variable size – Variable cyst wall thickness – Lower incidence in patients without HIV infection ○ Diffuse consolidation – Disease progression or development of ARDS ○ Intralobular lines ○ Interlobular septal thickening ○ Spontaneous pneumothorax – Associated with rupture of subpleural pneumatoceles • Less common findings ○ Nodule(s): Related to granuloma formation – Usually multiple

– Variable size (1-10 mm); miliary nodules described ○ Mass (3-7 cm) ○ Lobar consolidation (11%) – Upper lobe predominance ○ Mediastinal and hilar lymphadenopathy (22%) ○ Pleural effusion (rare) ○ Punctate calcifications along pleural surface ○ Mosaic attenuation – Associated with constrictive bronchiolitis • Chronic PCP ○ Irregular linear opacities ○ Traction bronchiectasis ○ Pulmonary architectural distortion ○ Large nodule(s)

Infection

TERMINOLOGY

Imaging Recommendations • Best imaging tool ○ HRCT

DIFFERENTIAL DIAGNOSIS Cytomegalovirus Pneumonia • • • • •

Pulmonary consolidation Ground-glass opacities Nodules < 10 mm Tree-in-bud opacities Dense consolidation or mass-like opacities in patients with acquired immune deficiency syndrome (AIDS) • Immunocompromised patient ○ After bone marrow and solid organ transplantation ○ AIDS

Diffuse Alveolar Hemorrhage • • • • •

Ground-glass opacities Pulmonary consolidation Crazy-paving pattern Dyspnea, cough, hemoptysis, and new airspace disease Immunosuppressed patients with AIDS ○ Thrombocytopenia, coagulopathy related to disseminated intravascular coagulation and hepatic dysfunction ○ May be associated with Kaposi sarcoma or lymphoma • Immunosuppressed patients without AIDS ○ Hematologic neoplasms, hematopoietic stem cell transplantation, drug reactions, infections (invasive aspergillosis)

Lymphoid Interstitial Pneumonia • • • • • • •

Centrilobular nodules Ground-glass opacities Pulmonary cysts Pulmonary consolidation Thick bronchovascular bundles Interlobular septal thickening Small subpleural nodules

PATHOLOGY General Features • Pneumocystis jirovecii: Ubiquitous eukaryotic microorganism • Ribosomal RNA homologous to that found in fungi supports classification as fungus 165

Infection

Pneumocystis Pneumonia • Serologic surveys have shown nearly universal seropositivity to Pneumocystis by 2 years of age • Unknown pathophysiology; may relate to reactivation of latent childhood infection, organism transmission between susceptible hosts, or acquisition from environmental sources • Patients with HIV/AIDS and PCP have significantly larger Pneumocystis organism burden and fewer neutrophils when compared to infected patients without HIV

– CD4(+) cell count < 200 cells/μL ○ Patients without HIV infection – Older – Abrupt onset of respiratory insufficiency – Median interval from onset of symptoms until diagnosis: 5 days ○ Diagnosis – Sputum induction with hypertonic saline: 50-90% diagnostic yield – Bronchoalveolar lavage: Identification of organisms with various stains □ Trophic forms: Modified Papanicolaou, WrightGiemsa, Gram-Weigert stains □ Cyst forms: GMS, toluidine blue stains – Monoclonal antibodies: Higher sensitivity and specificity than conventional stains in induced-sputum samples – PCR: Greater sensitivity and specificity than bronchoalveolar lavage and induced sputum

Microscopic Features • Variable disease patterns ○ Typical patterns – Intraalveolar foamy exudate containing Pneumocystis organisms – Interstitial inflammation ○ Atypical patterns – Interstitial pneumonia – Organizing pneumonia – Diffuse alveolar damage – Granulomatous inflammation – Cavitary pulmonary lesions – Calcifications – Vasculitis – Pulmonary alveolar proteinosis-like • Characteristic features ○ Intraalveolar foamy exudate ○ Interstitial chronic inflammation ○ Proliferation of type II pneumocytes ○ P. jirovecii identified within alveolar exudates – Cysts are optimally visualized with GMS stain • Less common features ○ Interstitial fibrosis ○ Granulomas ○ Hyaline membrane formation

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Progressive dyspnea ○ Nonproductive cough ○ Low-grade fever • Other signs/symptoms ○ Acute chest pain – May be associated with pneumothorax ○ Tachypnea ○ Tachycardia ○ Hemoptysis (3%) ○ Asymptomatic (3%) ○ Normal findings on auscultation • Clinical profile ○ AIDS is principal risk factor for PCP ○ Other risk factors: Chemotherapeutic regimens for malignancies, immunosuppression therapy, congenital immune disorders ○ HIV-infected patients – Younger – Subacute clinical course – Median interval from onset of symptoms until diagnosis: 28 days 166

Demographics • Men and women equally affected • Decreased incidence in AIDS population following introduction of highly active antiretroviral therapy and widespread PCP prophylaxis

Natural History & Prognosis • Patients with HIV infection ○ 10-20% mortality during initial infection ○ ↑ mortality in patients requiring mechanical ventilation ○ Smaller number of inflammatory cells correlates with better oxygenation and increased survival • Patients without HIV infection ○ 30-60% mortality ○ Greater risk of death among patients with cancer

Treatment • Treatment of choice: Trimethoprim-sulfamethoxazole with adjunctive corticosteroid therapy (to suppress lung inflammation in patients with severe infection) • Primary prophylaxis against PCP in HIV-infected adults should begin when CD4 < 200 cells/μL • Lifelong prophylaxis for patients with previous episodes of PCP

DIAGNOSTIC CHECKLIST Consider • PCP in HIV-infected patients with severe immunosuppression, subacute respiratory symptoms, and bilateral ground-glass opacities

SELECTED REFERENCES 1. 2.

Bienvenu AL et al: Pneumocystis pneumonia suspected cases in 604 non-HIV and HIV patients. Int J Infect Dis. 46:11-7, 2016 Lu PX et al: Correlation between imaging features of Pneumocystis Jiroveci pneumonitis (PCP), CD(4) (+) T lymphocyte count, and plasma HIV viral load: A study in 50 consecutive AIDS patients. Quant Imaging Med Surg. 2(2):1249, 2012

Pneumocystis Pneumonia Infection

(Left) Axial NECT of a patient with pneumocystis pneumonia shows bilateral apical dense consolidations with intrinsic cysts ﬈. Cysts occur in 1030% of all cases of pneumocystis pneumonia and appear to represent necrosis and cavitation. (Right) Axial HRCT of a 31-year-old man with pneumocystis pneumonia and AIDS shows coalescent upper lobe pneumatoceles and a right pneumothorax ﬈. Such lung cysts are often referred to as pneumatoceles and may be complicated by pneumothorax.

(Left) Axial HRCT of a 25-yearold patient with AIDS and pneumocystis pneumonia shows multifocal ground-glass opacities, parenchymal bands, and irregular linear opacities. Unusual imaging manifestations include solitary or multiple nodules and miliary pulmonary nodules. (Right) Axial HRCT of a patient with HIV and pneumocystis pneumonia shows diffuse bilateral ground-glass opacities on a background of reticular opacities (the socalled crazy-paving pattern).

(Left) Axial HRCT of a 27-yearold man with AIDS and pneumocystis pneumonia shows scattered bilateral ground-glass opacities and subpleural reticulation ﬈. (Right) Coronal HRCT of the same patient shows bilateral ground-glass opacities, left upper lobe subpleural cysts, and lower lobe parenchymal bands. Pneumocystis pneumonia typically affects patients with AIDS and CD4 counts < 200 cells/μL.

167

Infection

Tuberculosis KEY FACTS

• • • • • •

Tuberculosis (TB) Acquired immune deficiency syndrome (AIDS) Mycobacterium tuberculosis (MTB) MTB: Aerobic, nonmotile, non-spore-forming rod Ghon focus: Primary site of pulmonary TB Ranke complex: Ghon focus + affected lymph nodes

IMAGING • Radiography ○ Consolidation, nodules, &/or masses ± cavitation ○ Upper lobes &/or lower lobe superior segments • CT ○ Centrilobular nodules and branching opacities (i.e., treein-bud), most common ○ Cavitary nodules, masses, &/or consolidations ○ TB lymphadenitis – Central low attenuation and peripheral (rim) enhancement

(Left) PA chest radiograph of a 54-year-old man with AIDS (CD4: 327 cells/mm³) and tuberculosis shows a right upper lobe consolidation with intrinsic cavitation ﬉. Note clustered nodular opacities in the left upper and right mid lung zones ﬈. (Right) Axial HRCT of the same patient shows the right upper lobe consolidation with intrinsic cavitation ﬈, lobular consolidation ﬊, and tree-inbud opacities ﬈. Tree-in-bud opacities are the most common sign of active tuberculosis on CT.

(Left) Axial HRCT of the same patient shows a right upper lobe consolidation ﬉ with adjacent tree-in-bud opacities ﬈. Patients with AIDS and relatively preserved immunity generally develop upper lobe cavitary disease similar to that seen in immunocompetent individuals. (Right) Axial HRCT of a 56-year-old woman with tuberculous bronchopneumonia shows left upper lobe heterogeneous nodular consolidations, branching tubular lesions within medium-sized airways ﬊, and tree-in-bud opacities ﬈.

168

○ Human immunodeficiency virus (HIV) positive – Lymphadenopathy involving several lymph node stations – Consolidation in severely immunocompromised patients with AIDS (< 200 CD4 cells/mm³) ○ Miliary TB – Diffuse, random, and bilateral distribution of millet seed-size nodules

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES • • • •

Nontuberculous mycobacterial pulmonary disease Bronchopneumonia Necrotic lymphadenopathy Lung cancer

CLINICAL ISSUES • Signs and symptoms: Chronic cough, hemoptysis • Preferred treatment: Isoniazid, rifampin, ethambutol, and pyrazinamide

Tuberculosis

Abbreviations • Tuberculosis (TB) • Mycobacterium tuberculosis (MTB)

Definitions • MTB: Airborne infection transmitted from person to person via organism-containing droplets • Granuloma: Epithelioid histocytes including Langhans giant cells surrounded by lymphocytes • Ghon focus: Primary site of pulmonary TB • Ranke complex: Ghon focus + affected lymph nodes

IMAGING Radiographic Findings • Pulmonary TB ○ Consolidation, nodules, &/or masses ± cavitation ○ Upper lobes &/or lower lobe superior segments ○ Segmental or subsegmental consolidation common in highly immunocompromised patients with TB lymphadenitis • TB lymphadenitis ○ Mediastinal &/or hilar lymphadenopathy ○ May mimic malignancy • Miliary TB ○ Millet seed-size (< 3 mm) micronodules ○ May manifest with scattered hazy opacities • Tuberculoma ○ Soft tissue or calcified nodule ○ Surrounding satellite nodules (common) • Pleural TB ○ Free or loculated pleural effusion ○ Hydropneumothorax implies bronchopleural fistula

CT Findings • Pulmonary TB ○ Centrilobular nodules and branching opacities (i.e., treein-bud opacities) (most common) – CT galaxy sign refers to nodule surrounded by smaller satellite nodules ○ Cavitary nodules, masses, &/or consolidations – Cavitation (20-45%) ○ Lobular consolidation – Focal or patchy heterogeneous consolidation – Location: Upper lobe apical and posterior segments and lower lobe superior segments ○ Bronchial wall thickening ○ Poorly defined nodules and linear opacities (25%) ○ Tuberculoma (focal nodule/mass) (5%) • TB lymphadenitis ○ Central low attenuation and peripheral (rim) enhancement ○ Unilateral hilar &/or paratracheal lymphadenopathy is typical • Human immunodeficiency virus (HIV) positive ○ Lymphadenopathy in several lymph node stations ○ Consolidation in severely immunocompromised [acquired immune deficiency syndrome (AIDS) < 200 CD4 cells/mm³]

○ Extensive lung parenchymal, extrathoracic lymph node, and extrathoracic organ involvement • Miliary TB ○ Diffuse, random, bilateral distribution of millet seed-size nodules – Innumerable, 1-3 mm micronodules ○ 2-6% of primary TB; more frequent in reactivation TB ○ Interlobular septal thickening and intralobular lines (common) ○ Diffuse or focal ground-glass opacities • Pleural TB ○ Pleural effusion; may be loculated ○ Pleural thickening, enhancement, calcification ○ Associated parenchymal TB (common) – Subpleural and peribronchovascular micronodules; thick interlobular septa – May mimic malignancy – Paradoxical response: Enlarging lung nodules after initiation of successful treatment ○ Pleural effusion ipsilateral to affected lung ○ Bronchopleural fistula – Hydropneumothorax; may exhibit tension physiology ○ Empyema necessitatis – Fluid and soft tissue extending from pleural space into chest wall soft tissues ± cutaneous fistula

Infection

TERMINOLOGY

Nuclear Medicine Findings • PET/CT ○ TB involved tissues are typically FDG-avid

DIFFERENTIAL DIAGNOSIS Nontuberculous Mycobacterial Pulmonary Disease • Mycobacterium avium-intracellulare complex (MAC), Mycobacterium kansasii and others • Classic or cavitary disease indistinguishable from cavitary TB on imaging ○ Presumed diagnosis of TB until proven otherwise ○ Require sputum sampling &/or other laboratory studies

Bronchopneumonia • Centrilobular micronodules &/or tree-in-bud opacities • Upper lobe or lower lobe superior segment involvement with cavitation favor TB

Necrotic Lymphadenopathy • Central necrosis and peripheral rim enhancement ○ Other infections: Fungal infection ○ Metastatic lymphadenopathy: Lung cancer, head and neck squamous cell carcinoma

Miliary Micronodules • Miliary fungal infection • Miliary metastases ○ Thyroid papillary carcinoma • Transbronchial biopsy may yield specific diagnosis

Lung Cancer • May cavitate (e.g., squamous cell carcinoma) • Tree-in-bud opacities not typically present

Sarcoidosis • May exhibit CT galaxy sign 169

Infection

Tuberculosis • More extensive and symmetric mediastinal and bilateral hilar lymphadenopathy • Cavitary nodules are rare • May require biopsy for differentiation from TB

PATHOLOGY General Features • Centrilobular micronodules and tree-in-bud opacities: Caseous necrosis and granulomatous inflammation filling/surrounding terminal/respiratory bronchioles and alveolar ducts • Lobular or segmental consolidation: Granulomatous nodules composed of microabscesses and surrounding epithelioid histiocytes amid fibrinous exudates within alveolar spaces • Cavitation: Centrilobular cavities may progressively coalesce to form larger cavity ○ Cavity wall: Caseous necrosis, epithelioid cells with multinucleated giant cells, granulation tissue, and fibrous capsule • Miliary nodules: Yellowish-white in color, contain caseous necrosis; located in alveolar walls, interlobular septa, and subpleural lungs • Tuberculoma: Well-defined nodular parenchymal TB ○ Center: Caseous necrosis ○ Periphery: Epithelioid histiocytes and multinucleated giant cells with variable amounts of collagen

Gross Pathologic & Surgical Features • Cavitary disease ○ Communication of parenchymal TB with airways and subsequent drainage of necrotic material • TB lymphadenitis ○ Granulomatous inflammation and lymphadenopathy

• Latent TB ○ Individuals at risk for TB should be screened ○ Purified protein derivative (PPD) or interferon-gamma release assay (IGRA) positivity ○ Positive cases: Isoniazid prophylaxis for 6 months • Sputum smear and culture ○ Determination of drug resistance ○ Acid-fast bacilli on sputum or bronchoalveolar lavage (BAL) may represent NTM; culture for definitive diagnosis • Imaging ○ Chest radiography is imaging study of choice – High negative predictive value

Demographics • Epidemiology ○ Global endemic; in Southeast and Western Pacific Asia and Africa: 58% and 28% of new cases, respectively ○ In 2014 – 9.6 million new cases □ 1.2 million (12%) of affected patients had AIDS – 1.5 million deaths – 3.3% of new TB patients had multidrug-resistant TB

Natural History & Prognosis • Mortality smear-positive untreated TB ~ 70% • Mortality in culture-positive, smear-negative, untreated TB ~ 20% • Untreated TB in HIV-positive individuals is rapidly fatal (mean survival < 6 months)

Treatment • Treatment principles ○ Multiple drugs based on sensitivity; preferred treatment: Isoniazid, rifampin, ethambutol, and pyrazinamide

Microbiology

Prognosis

• MTB: Obligatory pathogen in family Mycobacteriaceae and causative agent of tuberculosis • Highly aerobic, requires ↑ levels of oxygen • Ziehl-Neelsen stain or acid-fast stain

• Treatment success rate ~ 80% • Predictors of mortality ○ HIV infection ○ Smear-positive TB ○ Multidrug-resistant TB ○ Previous history of TB

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Chronic cough (> 3 weeks) ○ Chest pain ○ Hemoptysis ○ Fatigue and weight loss ○ Fever, chills, night sweats • Clinical profile ○ Old concept of primary vs. postprimary TB obsolete – Healthy individuals develop postprimary pattern of TB (i.e., cavitary disease) even if never infected before – Immunocompromised patients develop primary pattern of TB (i.e., consolidation &/or lymphadenopathy) even if infected before • Polymerase chain reaction (PCR) ○ Sensitivity and specificity: 74-85% and 88-93%, respectively ○ Sputum smear-negative patients: Sensitivity 53-73% 170

DIAGNOSTIC CHECKLIST Consider • Active assessment for cavitation in upper lobe pneumonia, as it may suggest active tuberculosis ○ If questionable upper lobe cavitary disease, CT can be helpful for confirmation ○ Isolation of patients with upper lobe cavitary disease until TB is excluded

SELECTED REFERENCES 1. 2. 3.

Rozenshtein A et al: Radiographic appearance of pulmonary tuberculosis: dogma disproved. AJR Am J Roentgenol. 204(5):974-8, 2015 Ko JM et al: Pulmonary changes of pleural TB: up-to-date CT imaging. Chest. 146(6):1604-11, 2014 Lee JY et al: Pulmonary tuberculosis: CT and pathologic correlation. J Comput Assist Tomogr. 24(5):691-8, 2000

Tuberculosis Infection

(Left) Axial NECT of a 16-yearold girl with cavitary drugresistant tuberculosis shows multiple cavitary nodules and tree-in-bud opacities ﬈. Note early cavitation ﬊ in the periphery of a lobular nodular consolidation. (Right) Lowpower photomicrograph (H&E stain) of a specimen from the same patient shows granulomas along bronchioles ﬈ and peribronchiolar alveolar walls ﬊ that correspond to tree-in-bud opacities on CT.

(Left) Composite image with axial HRCT (left) and axial FDG PET/CT (right) of a patient with tuberculosis shows an FDG-avid left upper lobe nodule ſt surrounded by small satellite nodules ﬈. Tuberculosis may mimic lung cancer on imaging. The presence of satellite nodules is common in tuberculosis. (Right) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows conglomerate granulomas with central caseous necrosis ﬈.

(Left) Axial HRCT of a 37-yearold man with acute myelogenous leukemia and tuberculosis shows a left upper lobe mass-like consolidation ﬈ with surrounding ground-glass opacities ﬉. This imaging manifestation is very common in immunosuppressed patients with tuberculosis. (Right) Lowpower photomicrograph (H&E stain) of a specimen from the same patient shows granulomas ﬈ with internal caseous necrosis and fibrinous exudation ﬊ interspersed between the granulomas.

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Infection

Tuberculosis

(Left) Axial HRCT of a 27-yearold man with miliary tuberculosis shows random miliary nodules and groundglass opacities. Miliary tuberculosis is more frequent in reactivation tuberculosis. Mortality approaches 100% without appropriate treatment. (Right) Axial HRCT of the same patient shows extensive ground-glass opacity obscuring underlying miliary nodules. Miliary nodules are an indication for empiric treatment in the absence of microbiologic isolation, as it increases survival.

(Left) Low-power photomicrograph (H&E stain) of the same patient demonstrates randomly distributed granulomas along bronchovascular bundles ſt, alveolar walls ﬊, and subpleural interstitium ﬈. (Right) Gross specimen of a lesion of pulmonary tuberculosis shows caseous or cheese-like necrosis in the lesion, corresponding to necrosis seen microscopically.

(Left) Composite image with CECT of a 22-year-old woman with tuberculous lymphadenitis shows enlarged mediastinal lymph nodes ﬈ with peripheral enhancement and central low attenuation related to necrosis. (Right) High-power photomicrograph (H&E stain) of a mediastinoscopy biopsy specimen from the same patient shows an enlarged lymph node replaced by granulomatous inflammation and areas of caseous necrosis ſt.

172

Tuberculosis Infection

(Left) Coronal CECT of a patient with tuberculosis shows bilateral micronodules demonstrating the CT galaxy sign, which refers to coalescent small nodules surrounding a larger nodule. Although there is no larger central nodule in this case, the clustered coalescent micronodules suggest the diagnosis. (Right) Low-power photomicrograph (H&E stain) of the same patient shows small, clustered, caseating pulmonary granulomas that correlate with the CT galaxy sign.

(Left) Composite image with axial CECT in lung (left) and soft tissue (right) window of a young man with tuberculosis shows a right upper lobe consolidation surrounded by tree-in-bud opacities ﬊. Note ipsilateral right pleural effusion and thick, enhancing parietal pleura ﬈. (Right) Composite image with axial CECT of a 29-year-old woman with AIDS (CD4 count of 142 cells/mm³) and tuberculosis shows necrotic supraclavicular ﬈ and mediastinal ﬉ lymphadenopathy involving the adjacent right lung ﬊.

(Left) Axial NECT of a 53-yearold man with tuberculosis shows a tuberculoma manifesting as an irregular soft tissue nodule ﬉. Tuberculomas may simulate primary lung cancer based on morphology as well as FDG avidity on PET/CT. (Right) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows central necrosis ﬈, surrounding granulomatous inflammation, and variable amounts of collagen ﬊ in the tuberculoma. Note a satellite caseating granuloma ﬉.

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Infection

Nontuberculous Mycobacterial Infection KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Nontuberculous mycobacteria (NTM) • Nontuberculous mycobacterial infection (NTMB) • Pulmonary infection with NTM: Indolent and slowly progressive disease

• • • •

IMAGING

PATHOLOGY

• Bronchiectatic form: Middle lobe/lingular bronchiectasis and cellular bronchiolitis • Fibrocavitary form: Upper lobe cavitary disease and pleural thickening • Hot tub lung: Diffuse centrilobular ground-glass micronodules • Immunocompromised patient ○ Consolidation, nodule, or mass ○ Mediastinal/hilar lymphadenopathy • Solitary nodule or mass ○ Mimics lung cancer; may exhibit spiculation • Foci of NTMB typically FDG-avid on PET/CT

• Granulomatous inflammation, necrosis, and fibrosis

(Left) PA chest radiograph of a 72-year-old woman with bronchiectatic nontuberculous mycobacterial infection shows middle lobe and lingular heterogenous opacities ﬈ obscuring the heart borders. (Right) Axial NECT of the same patient shows extensive bronchiectasis and volume loss ﬉ in the middle lobe and lingula. Note less severe bilateral lower lobe multifocal cellular bronchiolitis and bronchiectasis ﬈. These are classic imaging findings of the bronchiectatic pattern of nontuberculous mycobacterial infection.

(Left) Low-power photomicrograph (H&E stain) of a specimen from the resected middle lobe of a patient with bronchiectatic nontuberculous mycobacterial infection shows several ectatic bronchi ﬊ containing intraluminal exudates and mural granulomas ﬈. (Right) Low-power photomicrograph (H&E stain) of the same specimen shows the correlate for small nodules and branching nodular lesions seen on CT, which represent granulomas ﬈ adjacent to bronchioles ﬊. Note adjacent bronchiectasis ﬉.

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Tuberculosis Diffuse aspiration bronchiolitis Hypersensitivity pneumonitis Lung cancer

CLINICAL ISSUES • Symptoms: Cough, productive sputum, fatigue

DIAGNOSTIC CHECKLIST • Consider NTMB in elderly women with middle lobe/lingular bronchiectasis and cellular bronchiolitis on imaging • Fibrocavitary NTMB may mimic tuberculosis • Consider disseminated NTMB in patients with very low CD4 counts and lymphadenopathy • Diagnosis: Fulfillment of clinical and microbiologic criteria

Nontuberculous Mycobacterial Infection

Abbreviations • Nontuberculous mycobacteria (NTM) • Nontuberculous mycobacterial infection (NTMB) • Mycobacterium avium complex (MAC)

Synonyms • Mycobacteria other than tuberculosis (MOTT) • Lady Windermere syndrome ○ Initial description of nodular bronchiectatic NTMB

Definitions • Pulmonary infection with NTM ○ Aliases: Environmental mycobacteria, atypical mycobacteria, or MOTT ○ No person-to-person transmission (isolation of affected patients not required) ○ Acquired from environmental sources (pipeline water supply and contaminated soil) ○ Indolent and slowly progressive disease

IMAGING

• Hot tub lung ○ Hypersensitivity pneumonitis (HP) (cluster 1) – Centrilobular ground-glass micronodules – Mosaic attenuation and air-trapping • Solitary nodule or mass ○ Mimics lung cancer, may exhibit spiculated borders • Immunocompromised patient ○ Consolidation, nodule, or mass ○ Lymphadenopathy with low-attenuation centers

Nuclear Medicine Findings • PET/CT ○ Foci of NTMB typically FDG avid ○ Solitary nodule/mass may simulate lung cancer morphologically and based on FDG avidity

DIFFERENTIAL DIAGNOSIS Tuberculosis • Indistinguishable from postprimary pattern of tuberculosis (TB): Upper lobe cavities and tree-in-bud opacities • Serial imaging: NTMB progresses over months to years, TB progresses over weeks to months

General Features

Diffuse Aspiration Bronchiolitis

• Best diagnostic clue ○ Bronchiectatic form: Middle lobe/lingular bronchiectasis and cellular bronchiolitis ○ Fibrocavitary form: Upper lobe cavitary disease and pleural thickening ○ Hot tub lung: Diffuse centrilobular ground-glass micronodules

• May be indistinguishable from bronchiectatic NTMB • Risk factors for aspiration: Achalasia, esophageal obstruction, esophageal dysmotility disorders, gastric banding procedures, gastroesophageal reflux, neurologic conditions (e.g., dementia), etc.

Radiographic Findings • Fibrocavitary form ○ Upper lobe thin-walled cavitary lesion(s) ○ Apical pleural thickening • Bronchiectatic form ○ Middle lobe and lingular reticular or heterogenous opacities ○ Middle lobe and lingular volume loss and bronchiectasis • Solitary nodule/mass (may mimic lung cancer) • Immunocompromised host ○ Consolidation, nodule, or mass ○ Mediastinal/hilar lymphadenopathy

CT Findings • Fibrocavitary form ○ Upper lobe cavitation with volume loss and apical pleural thickening – Typically thin cavity walls; mild wall thickening and nodular cavity walls also described ○ Ancillary findings – Emphysema (common) – Interstitial lung disease • Bronchiectatic form ○ Classic middle lobe and lingula involvement but may affect any lobe ○ Bronchiectasis, bronchial wall thickening, mucus plugging ○ Centrilobular micronodules (often tree-in-bud nodules) • Mixed fibrocavitary and bronchiectatic forms common

Infection

TERMINOLOGY

Hypersensitivity Pneumonitis • Hot tub lung: Specific type of HP indistinguishable from other forms of HP (Cluster 1)

Lung Cancer • May be morphologically indistinguishable from NTMB manifesting as solitary nodule or mass on CT &/or PET/CT

PATHOLOGY Microscopic Features • General features ○ Similar to TB: Variable degrees of granulomatous inflammation, necrosis, and fibrosis ○ Fibrocavitary: Large upper lobe necrotic cavities and apical pleural thickening ○ Bronchiectatic: Centrilobular nodules, branching nodular lesions, bronchiolectasis, bronchiolar wall thickening; mucus plugging of medium-sized airways • CT/histopathologic correlation ○ Cavity wall: Caseous necrosis; epithelioid cells, multinucleated giant cells, granulation tissue, fibrous capsule ○ Bronchiectatic: Small centrilobular nodules ± tree-in-bud opacities (granulomas and caseous necrosis in terminal or respiratory bronchioles) ○ Nodules > 10 mm in diameter and lobular consolidations: Centrally located caseating granulomas, marginal nonspecific inflammation, and coalescent lymphocytic infiltrates replacing normal alveoli

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Infection

Nontuberculous Mycobacterial Infection

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Cough, productive sputum, fatigue ○ Preexisting lung disease (e.g., chronic obstructive pulmonary disease, cystic fibrosis, bronchiectasis, pneumoconiosis, pulmonary fibrosis, prior TB) ○ Hot tub lung: Dyspnea, cough, fever ○ Immunocompromised patients – Human immunodeficiency virus (HIV) infection: Fever, weight loss, abdominal pain, diarrhea, lymphadenopathy, hepatosplenomegaly – Non-HIV infected: Fever, weight loss, malaise • Clinical profile ○ Bronchiectatic: Caucasian women in 7th and 8th decades – Lady Windermere syndrome □ Based on fastidious character Lady Windermere in play titled "Lady Windermere's Fan" by Oscar Wilde □ Affected patients may voluntarily suppress cough leading to poor drainage of secretions and NTM engraftment ○ Fibrocavitary form: Preexistent lung disease (e.g., emphysema and pulmonary fibrosis) ○ Hot tub lung: MAC may grow in hot water systems (e.g., indoor pools, indoor hot tubs) – Thought to be HP to MAC; but MAC may be identified in bronchoalveolar lavage fluid cultures ○ Immunocompromised host – HIV infected □ CD4 < 200 cells/mm³ □ Disseminated NTMB with very low CD4 (< 50 cells/μL 200 cells/mm³) – Non-HIV infected □ Chemotherapy, solid-organ transplantation, chronic corticosteroids, leukemia/lymphoma

Demographics

176

– Transbronchial or lung biopsy with granulomatous inflammation or acid-fast bacilli (AFB) and positive culture for NTM or biopsy with granulomatous inflammation or AFB and 1 or more positive culture for NTM on sputum or bronchial washings • Transbronchial lung biopsy for diagnosis of hot tub lung • Percutaneous or surgical lung biopsy for diagnosis of NTMB in acquired immune deficiency syndrome (AIDS) • Ancillary tests ○ Immunohistochemistry – Polyclonal antibody against Mycobacterium tuberculosis and other mycobacterial species (Mycobacterium avium-intracellulare, Mycobacterium phlei, and Mycobacterium parafortuitum) – Detection of immunoreactive bacilli, particularly in patients with negative acid-fast staining specimen ○ Polymerase chain reaction (PCR) – Amplification refractory mutational system PCR and real-time PCR methods for rapid detection of singlenucleotide polymorphisms – Discrimination between M. intracellulare and M. avium, differentiation of NTM organisms resistant to clarithromycin

Natural History and Prognosis • Radiologic progression ± treatment in ~ 50% of patients with MAC pulmonary infection • Patients with cavitation or consolidation at initial CT more likely to progress and require treatment • Antibiotic treatment considered when progression of CT involvement identified on follow-up imaging • Prognosis ○ Variable response to antibiotic treatment ○ MAC infection: More severe disease with M. intracellulare infection; lower body mass index, more frequent respiratory symptoms and fibrocavitary disease, higher rate of smear-positive sputum, more extensive disease on CT, and worse prognosis than in M. avium infection

• Epidemiology ○ Slowly increasing prevalence worldwide – > than that of TB in USA and Canada – In USA, from 1994-1996 to 2004-2006, increasing prevalence □ Women, 4.5-7.5/100,000 persons; men, 3.5 4.9/100,000 persons – In Canada, from 1995 through 2003; overall prevalence, 3.2-4.6/100,000 persons

Treatment

Diagnosis

Consider

• Clinical and microbiologic criteria for diagnosis of NTMB ○ Imaging features included in clinical criteria • American Thoracic Society and Infectious Diseases Society of America diagnostic criteria ○ Clinical criteria (both required) – Pulmonary symptoms, nodular or cavitary opacities on radiography or multifocal bronchiectasis and small nodules on CT/HRCT – Exclusion of other diagnoses ○ Microbiologic criteria – + sputum cultures from 2 separate samples or – + culture from at least 1 bronchial wash or lavage or

• NTMB in elderly women with middle lobe and lingular bronchiectasis and cellular bronchiolitis on imaging

• MAC ○ Fibrocavitary: Clarithromycin or azithromycin, ethambutol, rifampin, &/or streptomycin or amikacin ○ Bronchiectatic: Combination of clarithromycin or azithromycin, ethambutol, and rifampin • Mycobacterium abscessus: Difficult to treat

DIAGNOSTIC CHECKLIST

SELECTED REFERENCES 1. 2.

3.

4.

Henkle E et al: Nontuberculous mycobacteria infections in immunosuppressed hosts. Clin Chest Med. 36(1):91-9, 2015 Lee G et al: Serial CT findings of nodular bronchiectatic Mycobacterium avium complex pulmonary disease with antibiotic treatment. AJR Am J Roentgenol. 201(4):764-72, 2013 Griffith DE et al: An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007 Feb 15;175(4):367-416. Review. Erratum in: Am J Respir Crit Care Med. 175(7):744-5, 2007 Martinez S et al: The many faces of pulmonary nontuberculous mycobacterial infection. AJR Am J Roentgenol. 189(1):177-86, 2007

Nontuberculous Mycobacterial Infection Infection

(Left) Lateral chest radiograph of a 65-year-old woman with bronchiectatic nontuberculous mycobacterial infection shows heterogeneous reticular opacities and volume loss of the middle lobe and lingula ﬈. (Right) Axial NECT of the same patient shows extensive bronchiectasis and volume loss in the middle lobe and lingula ﬉, multifocal cellular bronchiolitis, mucus plugs ﬊, and mosaic attenuation ﬈. Bronchiectatic nontuberculous mycobacterial infection characteristically affects elderly Caucasian women.

(Left) Low-power photomicrograph (H&E stain) of a specimen of bronchiectatic nontuberculous mycobacterial infection shows bronchiectasis ﬈ and necrotic airway wall nodules ﬉. (Right) PA chest radiograph of a patient with idiopathic pulmonary fibrosis and fibrocavitary nontuberculous mycobacterial infection shows basilar predominant reticulation and a left upper lobe cavity ﬈. The fibrocavitary pattern tends to occur in preexistent lung disease, such as emphysema and pulmonary fibrosis.

(Left) Coronal NECT of the same patient shows lower lobe honeycombing ﬉ (from pulmonary fibrosis) and a large left upper lobe cavity ﬊. Fibrocavitary nontuberculous mycobacterial infection is usually seen in the setting of emphysema. (Right) Coronal NECT of the same patient shows bilateral lower lobe honeycombing ﬉ (from pulmonary fibrosis) and a smaller cavity ﬊ in the right lower lobe. Small cavities may be difficult to identify on chest radiography possibly due to the presence of coexistent pulmonary disease.

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Infection

Nontuberculous Mycobacterial Infection

(Left) PA chest radiograph of a 37-year-old man with mixed bronchiectatic and cavitary nontuberculous mycobacterial infection shows extensive bilateral upper lobe predominant heterogenous and nodular opacities. (Right) Composite image of the same patient with axial CECT (left) and axial MIP reformation (right) shows right lower lobe cavitary disease ﬉ and extensive right lung cellular bronchiolitis (i.e., centrilobular nodules) ﬊. Bronchiectatic and cavitary nontuberculous mycobacterial infection may coexist in the same patient.

(Left) Gross photograph of a lung specimen of nontuberculous mycobacterial infection shows a tan, irregularly shaped peripheral right upper lobe cavitary lesion ﬊. (Right) Low-power photomicrograph (H&E stain) of a specimen of cavitary nontuberculous mycobacterial infection shows multiple necrotic cavitary granulomas ﬈ adjacent to a large bronchus ﬊ and surrounding granulomatous bronchopneumonia.

(Left) PA chest radiograph of a 53-year-old man with emphysema and cavitary nontuberculous mycobacterial infection shows multifocal right lung heterogenous opacities and a right apical cavitary lesion ﬈. (Right) Axial CECT of the same patient shows upper lobe centrilobular emphysema and a thick-walled right upper lobe cavity ﬈. The cavitary form of the disease typically affects patients with preexistent lung conditions, including emphysema, interstitial lung disease, and cystic fibrosis, among others.

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Nontuberculous Mycobacterial Infection Infection

(Left) Fused axial FDG PET/CT of a patient with mass-like nontuberculous mycobacterial infection shows a left lower lobe mass ﬊ that exhibits increased FDG uptake. Nontuberculous mycobacterial infection may manifest as a solitary pulmonary nodule or mass, which may mimic lung cancer on radiography, CT, and PET/CT. (Right) Axial HRCT of a patient with hot tub lung shows diffuse bilateral ground-glass opacities, micronodules, and mosaic attenuation. This is a common imaging pattern of cluster 1 hypersensitivity pneumonitis.

(Left) PA chest radiograph of a 37-year-old patient with human immunodeficiency virus and nontuberculous mycobacterial infection shows extensive left lung heterogeneous consolidation with intrinsic cavitation ﬈ and subtle small nodules ﬊ in the right upper lung. (Right) Coronal NECT of the same patient shows clustered right upper lobe micronodules ﬊ and extensive left lung cavitation ﬈. The development of cavitation indicates a certain degree of preservation of host immunity.

(Left) Axial CECT of a 32-yearold man with human immunodeficiency virus and nontuberculous mycobacterial infection shows middle lobe consolidation and right lower lobe micronodules ﬈ consistent with infectious bronchiolitis. (Right) Axial CECT of a patient with a history of orthotopic heart transplantation and nontuberculous mycobacterial infection shows bilateral consolidations ﬈ and surrounding micronodules ﬉. Immunosuppressed patients often develop diffuse and severe pulmonary infections.

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SECTION 6

Pneumoconiosis

Approach to Pneumoconiosis Silicosis and Coal Worker’s Pneumoconiosis Asbestosis Berylliosis Talcosis Hard-Metal Pneumoconiosis

182 184 188 194 198 202

Pneumoconiosis

Approach to Pneumoconiosis Introduction

Imaging of Pneumoconiosis

Pneumoconiosis refers to pulmonary disease (typically of restrictive physiology) caused by dust inhalation that occurs as a result of occupational exposure. Pneumoconioses are named according to the particular dust inhaled and include asbestosis, coalworker's pneumoconiosis, silicosis, berylliosis, and siderosis, which result from inhalation of asbestos, coal/carbon, silica, beryllium, and iron, respectively. The variable dust or particle morphology, size, solubility, and ability to produce lung reaction results in various clinical and imaging manifestations. Not all pneumoconioses necessarily result from dust inhalation. For example, inhalation of flavoring chemicals, such as diacetyl during the manufacture of artificial butter flavoring, may produce popcorn worker's lung characterized by constrictive bronchiolitis. The National Institute for Occupational Safety and Health (NIOSH) forms part of the Centers for Disease Control and is charged with conducting research to reduce work-related illnesses and promote safety in the workplace. NIOSH may determine maximum levels of short- and long-term exposure to various agents and may mandate safety measures for respiratory protection in the workplace. In spite of ongoing research and careful monitoring, there are approximately 2,600 pneumoconiosis-related deaths each year.

Radiography The International Classification of Radiographs of Pneumoconiosis was established in 1949 by the International Labor Office (ILO) to provide standards for describing and recording radiographic abnormalities related to pneumoconioses. The presence, type, and severity of imaging abnormalities are determined based on a set of standard radiographs. B readers are physicians who have demonstrated proficiency in employing the ILO classification of radiographs to evaluate patients with pneumoconiosis and achieve certification by passing a B reader examination. B readers serve in national pneumoconiosis programs and engage in epidemiologic research, surveillance, and monitoring programs. There are approximately 270 B readers.

Patients with pneumoconiosis often present with cough (± sputum production), chest tightness, and shortness of breath, which may be exacerbated by activity. In view of such nonspecific presenting symptoms, diagnosis is only achieved by obtaining a detailed exposure history to determine the specific dust particulate inhaled, the duration of occupational exposure, and the date of exposure cessation. It is also important to know the offending agent's latency period; that is, the period of time between onset of exposure and development of clinical symptoms. Because radiologists may not have access to occupational exposure information at the time of imaging interpretation, they must recognize characteristic imaging findings that should suggest pneumoconiosis in order to elicit an exposure history and suggest an appropriate course of clinical and imaging evaluation.

Pathogenesis The type of lung reaction varies with the type of particle inhaled. For example, coal dust is relatively inert (nonfibrogenic), and large quantities must be inhaled before the onset of clinical symptoms. On the other hand, asbestos and silica are fibrogenic dusts that require smaller exposures to produce pulmonary disease. Many inhaled particles are trapped in the larger airways and cleared by the mucociliary escalator. However, particles that reach the peripheral airways interact with alveolar macrophages, which engulf and transport the offending materials. Resultant pathologic lesions and processes include dust macules (dust-filled macrophages in respiratory bronchiole and alveolar duct walls), mineral dust airway disease (dust macule-induced fibrosis), lymphatic clearance of dust (perilymphatic distribution of dust-laden macrophages), nodule formation, interstitial fibrosis (widespread architectural distortion), and progressive massive fibrosis (fibrotic zones > 1 cm). Recognition of the imaging correlates of these processes allows radiologists to provide an appropriate differential diagnosis and in some cases suggest the diagnosis.

182

Most radiologists, including most thoracic radiologists, are not B readers. Thus, we must all learn to recognize characteristic imaging abnormalities of the most common pneumoconioses including asbestosis, silicosis, coalworker's pneumoconiosis, and berylliosis, including the radiographic findings of asbestosrelated pleural disease and those of simple and complicated silicosis and coalworker's pneumoconiosis. CT/HRCT Although radiography is used by expert B readers working in federal surveillance programs, there is no question that CT and specifically HRCT are the most sensitive noninvasive tools available for demonstrating imaging abnormalities in patients with pneumoconiosis. CT and HRCT allow the detection and characterization of early centrilobular abnormalities and subpleural fibrosis produced by fibrogenic dusts. Prone imaging is particularly important in distinguishing physiologic dependent atelectasis from early interstitial fibrosis. In addition, CT allows identification of abnormalities that are specific for certain pneumoconioses. For example, multifocal bilateral discontinuous nodular calcified pleural thickening and plaque-like calcification of the pleura over the central tendinous portions of the hemidiaphragms are pathognomonic of pleural plaques (asbestos-related pleural disease), the imaging hallmark of occupational exposure to asbestos. Likewise, patients with suspected silicosis may exhibit typical upper lobe perilymphatic nodules and intrathoracic lymph node eggshell calcifications, which support the diagnosis. CT is invaluable in the diagnosis of specific complications of pneumoconioses. Identification of a dominant or growing nodule in a smoker with asbestos exposure should raise suspicion for primary lung cancer. Development of cavitary disease and cellular bronchiolitis in a patient with silicosis should prompt immediate evaluation for active tuberculosis or silicotuberculosis. Recognition of imaging features of the pneumoconioses and correlation of these abnormalities with clinical presentation and exposure history allows the radiologist to contribute to the assessment and management of affected patients.

Selected References 1. 2.

Akira M: Imaging of occupational and environmental lung diseases. Clin Chest Med. 29(1):117-31, vi, 2008 Travis WD et al: Occupational lung diseases and pneumoconioses. In: Atlas of Nontumor Pathology. Non-Neoplastic Disorders of the Lower Respiratory Tract. 1st ed. Washington DC:American Registry of Pathology. 793-856., 2002

Approach to Pneumoconiosis Pneumoconiosis

(Left) Axial HRCT of a shipyard worker with chronic dyspnea shows basilar predominant ground-glass and reticular opacities and traction bronchiectasis ﬊ consistent with fibrosis. Calcified pleural plaques ﬉ confirm occupational exposure to asbestos and support the diagnosis of asbestosis. (Right) Intermediate-power photomicrograph (H&E stain) shows interstitial fibrosis. Asbestos bodies ﬈ within the airspaces ﬊ are an essential finding for the histologic diagnosis of asbestosis. (From DP: Thoracic, 2e.)

(Left) Axial HRCT of a 65-yearold man with silicosis shows clustered centrilobular nodules ﬊, peripheral small nodules and pseudoplaques ﬈, and early paracicatricial emphysema ﬉. Note the characteristic dorsal distribution of the pulmonary nodules. (Right) Coronal NECT of a patient with silicosis shows upper lobepredominant perilymphatic micronodules ﬊ and larger nodular coalescent opacities ﬈ representing early imaging findings of progressive massive fibrosis.

(Left) Axial HRCT of a 51-yearold man with berylliosis who presented with dyspnea shows multifocal perilymphatic micronodules distributed along bronchovascular bundles ﬊ and interlobular septa ﬈. (Right) Axial NECT of the same patient shows right hilar ﬉ and mediastinal ﬈ lymphadenopathy characteristic of the disease. Berylliosis may exhibit imaging features identical to those of sarcoidosis, and the correct diagnosis is supported by eliciting a history of beryllium exposure.

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Pneumoconiosis

Silicosis and Coal Worker's Pneumoconiosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Coal worker's pneumoconiosis (CWP) • Progressive massive fibrosis (PMF) • Silicosis and CWP: Lung diseases due to inorganic mineral dust inhalation

• • • •

IMAGING

CLINICAL ISSUES

• Radiography ○ 1-3 mm round nodules; may calcify ○ Predominantly upper lung zones ○ PMF: Upper lobe aggregation of nodules into masses ○ Acute silicoproteinosis: Central alveolar opacities with air bronchograms; mimics alveolar proteinosis • HRCT ○ Perilymphatic micronodules ○ Upper lobe masses ○ Hilar/mediastinal lymphadenopathy, may calcify (eggshell morphology is common)

• Occupations: Sandblasting, quarrying, mining, glassblowing, pottery • Simple silicosis: Asymptomatic • Complicated silicosis (PMF) ○ Symptomatic ○ Death from respiratory failure, pneumothorax, tuberculosis

(Left) PA chest radiograph of a patient with simple silicosis shows bilateral upper lung zone predominant pulmonary micronodules. (Right) Axial NECT of the same patient shows diffuse predominantly peribronchovascular ﬈ micronodules and some nodules disposed along the interlobar fissures ﬉. This combination of peribronchovascular and subpleural nodules is characterized as perilymphatic. Sarcoidosis and lymphangitic carcinomatosis exhibit a similar distribution.

(Left) PA chest radiograph of a patient with complicated silicosis (i.e., progressive massive fibrosis) shows bilateral upper lobe peribronchovascular masses ﬈ with irregular borders. (Right) Axial HRCT of the same patient shows bilateral upper lobe predominant soft tissue masses surrounded by peribronchovascular micronodules. The masses result from coalescence of peribronchovascular micronodules. These masses may cavitate and exhibit FDG uptake, thus mimicking malignancy.

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Sarcoidosis Tuberculosis Hypersensitivity pneumonitis Lung cancer

DIAGNOSTIC CHECKLIST • Consider thorough occupational history review in any patient with upper lobe nodular interstitial lung disease

Silicosis and Coal Worker's Pneumoconiosis

Abbreviations • Coal worker's pneumoconiosis (CWP)

Synonyms • Simple pneumoconiosis, complicated pneumoconiosis, progressive massive fibrosis (PMF), anthracosis, anthracosilicosis

Definitions • Silicosis and CWP: Lung diseases due to inhalation of inorganic mineral dusts • Simple or chronic pneumoconiosis: Lung nodules < 1 cm, more profuse in upper lung zones, often with associated hilar/mediastinal lymphadenopathy • Complicated pneumoconiosis (PMF): Coalescence of nodules into larger lesions > 1 cm in diameter • Acute silicoproteinosis: Resembles alveolar proteinosis, develops within weeks after heavy dust exposure • Caplan syndrome: CWP + rheumatoid arthritis + necrobiotic nodules • Chronic interstitial pneumonia: Pulmonary fibrosis

IMAGING General Features • Best diagnostic clue ○ Perilymphatic micronodules with upper lung zone predominance ± PMF • Location ○ Spherical dusts predominantly affect upper lungs – Coal dust accumulates about respiratory bronchioles – Silica accumulates along lymphatics in centrilobular and peripheral aspects of secondary pulmonary lobule • Size ○ Nodule 1-3 mm in diameter

Radiographic Findings • Abnormalities seen 10-20 years after exposure • Silicosis and CWP are similar, but lung disease is usually less severe in CWP • Hilar and mediastinal lymphadenopathy; may calcify (eggshell morphology common) • Simple pneumoconiosis ○ 1-3 mm nodules with upper lobe predominance; may calcify • Complicated pneumoconiosis (PMF) ○ Nodule > 1 cm diameter ○ Location – Usually bilateral – Right > left – Dorsal lungs – Central migration with time ○ May be lenticular (wide on PA radiography, narrow on lateral radiography) ○ Lateral margin of PMF coarsely parallels chest wall; sharply defined; medial inner edge less well defined ○ Overall nodule profusion decreases due to nodule aggregation into PMF ○ May exhibit foci of amorphous calcification ○ May cavitate; mycetomas may develop within cavities

○ Paracicatricial emphysema peripheral to PMF: Risk for pneumothorax • Acute silicoproteinosis ○ Central "butterfly" alveolar opacities with air bronchograms ○ Frequent hilar/mediastinal lymphadenopathy ○ Rapid progression over months ○ Evolution to fibrosis with severe architectural distortion, bullae, pneumothorax • Caplan syndrome: Association of rheumatoid arthritis with pneumoconiosis ○ Multiple large nodules/masses, < 5 cm in diameter (may cavitate or calcify) ○ Nodules are peripheral and subpleural ○ Cavitation may lead to pneumothorax ○ Nodules may evolve quickly or disappear ○ Nodules enlarge faster than silicotic PMF ○ Skeletal findings of rheumatoid arthritis: Humeral or clavicular erosions; lung abnormalities may precede bone disease

Pneumoconiosis

TERMINOLOGY

CT Findings • HRCT ○ More sensitive than chest radiography ○ Perilymphatic micronodules or nodules < 7 mm – More profuse in dorsal upper lobes, right > left – Silicotic nodules tend to be more sharply defined than those of CWP – Calcification may occur – Aggregate subpleural nodules may produce pseudoplaques ○ Intralobular lines and interlobular septal thickening uncommon ○ Mass (from aggregation of micronodules into PMF) – Irregular elliptical shape with emphysema peripheral to mass – > 4 cm, characteristic low-attenuation areas secondary to necrosis ○ Hilar and mediastinal lymphadenopathy; may calcify (eggshell calcification in 5%) ○ Chronic interstitial pneumonia (12%) – Honeycombing and traction bronchiectasis □ Usual interstitial pneumonia (UIP) pattern or inconsistent with UIP pattern □ Reticulation &/or honeycombing may be subpleural or peribronchovascular □ Ground-glass opacities

Nuclear Medicine Findings • PET/CT ○ PMF may exhibit FDG avidity and mimic lung cancer

Imaging Recommendations • Best imaging tool ○ HRCT more sensitive than radiography for detection of lung disease and detection/evaluation of PMF

DIFFERENTIAL DIAGNOSIS Sarcoidosis • Absence of occupational exposure, PMF less frequent • Clustered nodules (galaxy sign) 185

Pneumoconiosis

Silicosis and Coal Worker's Pneumoconiosis Tuberculosis • Centrilobular or miliary nodules; do not aggregate as masses

Pulmonary Langerhans Cell Histiocytosis • Subpleural nodules unusual; no PMF • Cysts, often irregular in shape; absent in pneumoconiosis

Hypersensitivity Pneumonitis • Ground-glass centrilobular nodules; no PMF; primarily mid lung involvement • Air-trapping common at HRCT, less likely in patients with pneumoconiosis

Lung Cancer • May be indistinguishable from PMF; may cavitate and exhibit FDG avidity on PET/CT • Follow-up imaging or tissue sampling often required

PATHOLOGY General Features • Etiology ○ Inhaled silica dust, silicon dioxide (SiO₂) or coal dust deposited in respiratory bronchioles; removed by macrophages and lymphatics ○ Slow removal, half-time of single dust burden on order of 100 days • Silica more fibrogenic than coal • Increased risk of tuberculosis

Gross Pathologic & Surgical Features • Primarily involves upper lung zones • PMF may progress to end-stage lung fibrosis • Silica content in affected lung 2-3% (up to 20%); silica content in normal dried lung 0.1%

Microscopic Features • Silica ○ Silica particles centered within concentric lamellae of collagen located along bronchioles, small vessels, and lymphatics ○ Birefringent silica crystals (1-3 μ) in nodules on polarized microscopy ○ Silica-laden macrophages carry particles to hilar/mediastinal lymph nodes and form granulomas ○ Silicoproteinosis: High silica concentrations, alveoli filled by lipoproteinaceous material, similar to alveolar proteinosis • Coal ○ Coal macule: Stellate collection of macrophages containing black particles (1-5 μ), in terminal/respiratory bronchioles and pleural lymphatics, little or no collagen ○ Macule surrounded by focal emphysema

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Symptoms – None with simple silicosis – Miners commonly smoke and may have bronchitis or emphysema 186

– Cough, dyspnea, ↑ sputum in complicated disease – Black sputum in coal workers • Other signs/symptoms ○ Cor pulmonale in advanced disease ○ Caplan syndrome: Features of rheumatoid arthritis • Clinical profile ○ Typical occupations: Sandblasting, quarrying, mining, glassblowing, pottery ○ Coal mines usually contain silica ○ Acute silicoproteinosis: Massive exposure to silica dust, usually seen in sandblasters • Pulmonary function tests ○ Simple pneumoconiosis: Usually normal ○ Complicated pneumoconiosis: ↓ diffusion capacity, ↓ lung volume, restrictive defect ○ Often mixed obstruction and restriction: Combined effects of cigarette smoking and interstitial fibrosis ○ Functional impairment correlates more closely with degree of emphysema (as determined by CT) than with nodule profusion

Demographics • Age ○ Simple and complicated pneumoconiosis rare in patients < 50 years of age • Gender ○ More common in men due to occupational exposure • Epidemiology ○ Risk related to dose (intensity of exposure) and time (length of exposure) ○ Up to 15% of miners may exhibit progression to interstitial fibrosis

Natural History & Prognosis • Usually requires > 20 years of exposure • Simple pneumoconiosis: Normal longevity • Complicated PMF: Death from respiratory failure, pneumothorax, tuberculosis • Silicoproteinosis: Death within 2-3 years • Debatable increased risk of lung cancer

Treatment • Prevention: Respirators in dusty environments, reduction of ambient dust concentrations • Removal from work environment exposure • Smoking cessation • No specific treatment for pneumoconiosis available • At risk for tuberculosis: Cavitation in PMF requires culture ○ TB skin tests important

DIAGNOSTIC CHECKLIST Consider • Thorough review of occupational history in any patient with upper lobe nodular interstitial lung disease

SELECTED REFERENCES 1.

2.

Expert Panel on Thoracic Imaging et al: ACR Appropriateness Criteria Review ACR Appropriateness Criteria® Occupational Lung Diseases. J Thorac Imaging. 31(1):W1-3, 2016 Sirajuddin A et al: Occupational lung disease. J Thorac Imaging. 24(4):310-20, 2009

Silicosis and Coal Worker's Pneumoconiosis Pneumoconiosis

(Left) Axial HRCT of a patient with complicated silicosis (i.e., progressive massive fibrosis) shows bilateral perilymphatic nodules. While nodules are more profuse centrally (i.e., peribronchovascular), there is also nodularity along the interlobar fissures ﬈. (Right) Coronal NECT of the same patient shows bilateral upper lobe predominant soft tissue masses that represent coalescent progressive massive fibrosis ﬈. While endstage sarcoidosis may mimic these imaging findings, affected patients do not have a history of silica exposure.

(Left) Axial FDG PET/CT of a patient with complicated silicosis (i.e., progressive massive fibrosis) shows FDGavid upper lobe predominant masses ﬈ amid a background of emphysema and perilymphatic micronodules. (Right) Axial HRCT of a patient with chronic interstitial pneumonia due to silicosis shows bilateral subpleural ground-glass opacities, reticulation ﬈ and traction bronchiolectasis ﬉. Chronic interstitial pneumonia may be a manifestation of silicosis and may mimic idiopathic interstitial pneumonia.

(Left) Axial CECT of a patient with complicated silicosis shows bilateral upper lobe soft tissue masses. Note cavitation ﬈ within the left upper lobe mass and intrinsic dependent soft tissue consistent with mycetoma. Cavitation may occur in complicated silicosis. (Right) Coronal CECT of the same patient shows upper lobe masses with cavitation ﬈ on the left and calcified bilateral hilar and mediastinal lymph nodes ﬉. Peripheral lymph node calcifications are referred to as egg-shell calcifications.

187

Pneumoconiosis

Asbestosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Asbestosis: Interstitial lung disease caused by inhalation of asbestos fibers

• • • • • •

IMAGING • CT/HRCT ○ Reticular (linear) opacities most common manifestation – Intralobular lines &/or interlobular septal thickening ○ Subpleural dot-like (centrilobular) or branching opacities, earliest manifestation ○ Subpleural curvilinear lines: Parallel adjacent chest wall ○ Parenchymal bands: Perpendicular to pleura ○ Lower lobe predominant subpleural fibrosis with traction bronchiectasis and honeycombing in advanced disease – Honeycombing less common than in idiopathic pulmonary fibrosis (IPF) ○ Mosaic attenuation pattern from small airways disease ○ Pleural plaques (80%-95%): Most reliable finding for differentiation of asbestosis from IPF

(Left) Axial HRCT of an 83year-old man with occupational exposure to asbestos and progressive dyspnea shows bilateral subpleural reticular opacities ﬈ with interlobular septal thickening and intralobular lines, traction bronchiectasis ﬉, mosaic attenuation, and calcified pleural plaques ﬊. (Right) Prone axial HRCT of the same patient shows subpleural reticulation ﬈ and traction bronchiolectasis ﬉. The combination of subpleural fibrosis and pleural plaques is virtually diagnostic of asbestosis.

(Left) Low-power photomicrograph (H&E stain) of specimen of asbestosis shows numerous asbestos bodies ﬈ within airspaces. The lung parenchyma in the background is virtually replaced by dense fibroconnective tissue ﬉. (Right) High-power photomicrograph (H&E stain) shows a typical asbestos body ﬈, which is an asbestos fiber coated by a string of rustyorange, beaded small particles composed of iron-rich material derived from ferritin and hemosiderin. (From DP: Thoracic, 2e.)

188

Idiopathic pulmonary fibrosis Systemic sclerosis Rheumatoid arthritis Hypersensitivity pneumonitis Drug-induced lung disease Lymphangitic carcinomatosis

PATHOLOGY • Fibrosis + asbestos bodies = asbestosis

CLINICAL ISSUES • Slowly progressive dyspnea and nonproductive cough • Asbestos is potent carcinogen: Multiplicative risk factor for lung cancer in cigarette smokers

DIAGNOSTIC CHECKLIST • Consider asbestosis in patients with basilar interstitial lung disease and pleural plaques

Asbestosis

Definitions • Interstitial lung disease caused by inhalation of asbestos fibers

IMAGING General Features • Best diagnostic clue ○ Basilar interstitial fibrosis and pleural plaques • Location ○ Posterobasilar subpleural lung • Morphology ○ Fibrosis centered on respiratory bronchioles

Radiographic Findings • Radiography ○ May be normal (10-20%) ○ Pleural plaques (25%) ○ International Labor Office (ILO) classification compared to standard radiograph "B" reading – Asbestosis: s, t, or u opacities ○ Late disease: Basilar reticular opacities related to honeycombing ○ Lung cancer: Nodule or mass ± lymphadenopathy – May exhibit predilection for lower lungs in contrast to upper lung zone predominance in general population of smokers

CT Findings • Reticular (linear) opacities most common manifestation ○ Interlobular septal thickening &/or intralobular lines • Subpleural dot-like (centrilobular) or branching opacities earliest manifestation ○ Fibrosis around small airways related to asbestos fiber deposition • Subpleural curvilinear lines ○ Parallel chest wall within 1 cm of pleura; length 5-10 cm ○ Represent peribronchial confluent fibrosis or atelectasis associated with obstructed respiratory bronchioles ○ Not specific for asbestosis • Parenchymal bands perpendicular to pleura ○ 2-5 cm long ○ Fibrosis along interlobular septa or bronchovascular bundles • Small airways disease from fibrosis related to asbestos fiber deposition ○ May produce mosaic attenuation pattern • Fibrosis with traction bronchiectasis and honeycombing in advanced disease ○ Reflects initial location of deposited asbestos fibers ○ Peripheral basilar lung most commonly affected ○ May exhibit usual interstitial pneumonia (UIP) pattern on HRCT • Pleural plaques (80-95%); most reliable finding to differentiate asbestosis from idiopathic pulmonary fibrosis (IPF) ○ Honeycombing and traction bronchiectasis less common than in IPF

Imaging Recommendations • Best imaging tool ○ CT useful for identification of fibrosis ○ CT for evaluation of nodules, pleural plaques, and rounded atelectasis ○ Screening asbestos-exposed workers – 10% of asbestos-exposed workers screened on CT for asbestosis have lung mass – Patients with clinical asbestosis: Abnormal chest radiographs in 80%; abnormal HRCT in 96% – 33% of patients without clinical or radiographic evidence of asbestosis have abnormal HRCT – False-negatives for early asbestosis (25%) • Protocol advice ○ Prone imaging to differentiate interstitial lung disease from dependent atelectasis

Pneumoconiosis

TERMINOLOGY

DIFFERENTIAL DIAGNOSIS Idiopathic Pulmonary Fibrosis • Basilar subpleural reticulation and honeycombing with traction bronchiectasis/bronchiolectasis • Band-like opacities and mosaic attenuation less common • No pleural plaques

Progressive Systemic Sclerosis • Basilar subpleural opacities • No pleural plaques; but pleural thickening and pseudoplaques common • Dilated esophagus

Rheumatoid Arthritis • Arthritis and joint erosions • Basilar subpleural ground-glass opacities and reticulations • No pleural plaques

Hypersensitivity Pneumonitis • Mosaic attenuation, air-trapping • Upper lung zone fibrosis, less severe in lung bases • No pleural plaques

Drug-Induced Lung Disease • Various patterns of interstitial fibrosis • No pleural plaques

Lymphangitic Carcinomatosis • Nodular interlobular septal and peribronchovascular thickening • Pleural effusion and lymphadenopathy common • No pleural plaques

PATHOLOGY General Features • Associated abnormalities ○ Asbestos-related pleural disease – Multiple discontinuous pleural plaques; characteristic involvement of central diaphragmatic pleura – Benign exudative pleural effusions, diffuse pleural thickening ○ Rounded atelectasis ○ Lung cancer ○ Malignant pleural mesothelioma 189

Pneumoconiosis

Asbestosis • General comments ○ Asbestos: Heat resistant, high tensile strength, flexible, durable – Serpentine (chrysotile or white asbestos, 90% of commercial asbestos) □ Wavy fiber, long (> 100 μm), diameter (20-40 μm) – Amphibole □ Crocidolite (blue asbestos), amosite (brown asbestos), anthophyllite, tremolite, actinolite □ Straight rigid fiber; length:width = 3:1 (aspect ratio) – Retention: Long, thin fibers > short, thick fibers ○ Pathophysiology – Increased lower lung zone fiber deposition from gravitational ventilatory gradient – Fiber deposition in respiratory bronchioles – No fiber removal by lymphatics; largest most harmful fibers too large to be removed by macrophages • Epidemiology ○ Long-term exposure: Asbestos mills, insulation, shipyards, construction ○ Dose-response relationship – Usually high dust concentrations – Typically 20 years following initial exposure but latency period could be as short as 3 years – 1% risk of asbestosis with cumulative dose of 10 fiberyear/mL □ Calculation of cumulative dose: Years of exposure x fibers/mL (fibers/mL = measurement of ambient airborne asbestos)

Gross Pathologic & Surgical Features • Coarse basilar predominant honeycombing and volume loss

Microscopic Features • Asbestosis ○ Early fibrosis: Centered on respiratory bronchioles with centrifugal spread – Histologically different from IPF with airway distortion (traction bronchiolectasis) ○ Patchy distribution, severe honeycombing uncommon ○ Fibrosis associated with > 1 million fibers/g lung tissue • Asbestos (ferruginous) bodies: Fibers coated with ferritin ○ Hemosiderin-coated fiber (mostly amphibole) ○ Incompletely phagocytized by macrophages ○ Not pathognomonic for asbestosis ○ Coated fibers fewer than uncoated fibers ○ No correlation with fibrosis • Fibrosis + asbestos bodies = asbestosis

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Gradual onset of dyspnea on exertion, nonproductive cough ○ Rales (end-inspiratory crackles) ○ Clubbing in 1/3 of affected patients • Other signs/symptoms ○ Pulmonary function tests – Restrictive physiology, decreased diffusion capacity – Decreased small airway flow rates 190

Demographics • Gender ○ Men, typically due to occupational exposure

Diagnosis • Asbestos bodies in bronchoalveolar lavage fluid highly specific for diagnosis of asbestosis • Poor transbronchial biopsy yields • American Thoracic Society 2003 general criteria for diagnosis ○ Evidence of structural pathology consistent with asbestosis as documented by imaging or histology ○ Evidence of causation as documented by occupational and exposure history – Includes pleural plaques and asbestos bodies ○ Exclusion of alternative plausible causes for findings

Natural History and Prognosis • • • •

Latency period: 20-30 years Slowly progressive disease; does not regress Mortality increases with increasing severity of fibrosis Asbestos is potent carcinogen ○ Multiplicative risk factor for lung cancer in cigarette smokers; high proportion of smokers with asbestosis (1 in 4) die of lung cancer • Increased risk of malignant pleural or peritoneal mesothelioma • Increased risk of oropharyngeal, laryngeal, renal, and gastrointestinal cancers, and leukemia

Treatment • • • •

No treatment Smoking cessation Control and regulation of asbestos in workplace Occupationally exposed affected individuals eligible for worker's compensation ○ Pathologic tissue not required to gain compensation

DIAGNOSTIC CHECKLIST Consider • Asbestosis in patients with basilar interstitial lung disease and pleural plaques • Lung cancer screening in cigarette smokers with asbestosis

Reporting Tips • Asbestosis may be reportable disease in some states

SELECTED REFERENCES 1.

2. 3. 4.

5. 6. 7.

Arakawa H et al: Asbestosis and other pulmonary fibrosis in asbestosexposed workers: high-resolution CT features with pathological correlations. Eur Radiol. 26(5):1485-92, 2016 Cha YK et al: Radiologic diagnosis of asbestosis in Korea. Korean J Radiol. 17(5):674-83, 2016 Norbet C et al: Asbestos-related lung disease: a pictorial review. Curr Probl Diagn Radiol. 44(4):371-82, 2015 Roggli VL et al: Pathology of asbestosis- an update of the diagnostic criteria: report of the asbestosis committee of the college of american pathologists and pulmonary pathology society. Arch Pathol Lab Med. 134(3):462-80, 2010 Akira M et al: High-resolution CT of asbestosis and idiopathic pulmonary fibrosis. AJR Am J Roentgenol. 181(1):163-9, 2003 Copley SJ et al: Asbestosis and idiopathic pulmonary fibrosis: comparison of thin-section CT features. Radiology. 229(3):731-6, 2003 Roach HD et al: Asbestos: when the dust settles an imaging review of asbestos-related disease. Radiographics. 22 Spec No:S167-84, 2002

Asbestosis Pneumoconiosis

(Left) Axial HRCT of a 65-yearold man with asbestosis shows bilateral posterior pleural thickening with calcifications ﬈, subpleural reticulations ﬉, and a spiculated left lower lobe mass ﬊ with associated volume loss, which exhibited the comet-tail sign (not shown) and represented rounded atelectasis. (Right) Axial prone HRCT of the same patient shows subpleural ground-glass opacities and reticulations ﬉, parenchymal bands ﬈, and subpleural curvilinear lines ﬊. The latter is a common CT finding but is not specific for asbestosis.

(Left) PA chest radiograph of a 55-year-old man with asbestosis and progressive dyspnea shows low lung volumes and diffuse bilateral reticular opacities. Note bilateral calcified pleural plaques ﬈ over the central diaphragmatic pleura. (Right) Axial HRCT of the same patient shows multifocal bilateral subpleural reticular opacities ﬉ with associated traction bronchiolectasis ſt and basilar subpleural honeycombing ﬊. Note calcified and noncalcified bilateral paravertebral pleural plaques ﬈.

(Left) Axial HRCT of the same patient shows bilateral subpleural reticulations ﬉ and bilateral traction bronchiectasis and bronchiolectasis ﬈. Note partially calcified right-sided diaphragmatic pleural plaque ﬊. (Right) Axial HRCT of the same patient shows bilateral basilar subpleural honeycombing ﬊. The visualization of calcified pleural plaques ﬉ favors the diagnosis of asbestosis over that of idiopathic pulmonary fibrosis.

191

Pneumoconiosis

Asbestosis

(Left) Axial CECT of a 57-yearold man with asbestosis shows a right lower lobe mass ﬊ that represented a primary lung cancer. Note bilateral discontinuous calcified pleural plaques consistent with asbestos-related pleural disease ﬈. Asbestos exposure is a risk factor for both lung cancer and malignant pleural mesothelioma. (Right) Axial CECT of a 79-year-old smoker with asbestosis and primary small cell lung cancer shows bilateral subpleural honeycombing ﬊, calcified pleural plaques ﬈, and a small left pleural effusion.

(Left) Coronal CECT of the same patient shows subpleural reticulations and honeycombing, pleural plaques ﬉, a left upper lobe mass ﬊ representing primary lung cancer, and nodular solid left apical pleural metastases ﬈. (Right) Coronal FDG PET/CT shows intense FDG avidity in the left upper lobe cancer ﬊, the left apical solid pleural metastases ﬈, and in bilateral metastatic hilar ﬉ and mediastinal st lymphadenopathy. Asbestos exposure multiplies the risk of primary lung cancer in cigarette smokers.

(Left) Axial CECT of a patient with asbestosis shows bilateral subpleural reticulations and honeycombing ﬊ with intrinsic traction bronchiolectasis ﬉. Note calcified plaque ﬈ over the central left diaphragmatic pleura. (Right) Axial CECT of the same patient shows bilateral basilar subpleural reticular opacities ﬊ and honeycombing with intrinsic traction bronchiolectasis ﬉. The CT findings of advanced asbestosis may mimic those of idiopathic pulmonary fibrosis.

192

Asbestosis Pneumoconiosis

(Left) PA chest radiograph of a patient with asbestosis shows extensive bilateral discontinuous calcified pleural plaques ﬈ with involvement of the pleura over the central hemidiaphragms ﬊, a pathognomonic finding of asbestos-related pleural disease. (Right) Axial NECT of the same patient shows dense calcifications ﬊ over the pleura that lines the central tendinous portions of the bilateral hemidiaphragms and subpleural reticulation and honeycombing ﬉. The findings are virtually pathognomonic for asbestosis.

(Left) AP chest radiograph of a patient with asbestosis and severe progressive dyspnea shows bilateral low lung volumes and extensive diffuse bilateral reticular opacities with basilar predominance. (Right) Axial HRCT of the same patient shows multifocal bilateral subpleural reticulation ﬈, pleural plaques ﬉, and mosaic attenuation. The latter may result from superimposed small airways disease. Mosaic attenuation may occur in the setting of asbestosis when there is superimposed small airways disease.

(Left) Axial HRCT of the same patient shows bilateral subpleural reticulation (with interlobular septal thickening and intralobular lines) ﬈, traction bronchiolectasis ﬊, and mosaic attenuation. Note calcified and noncalcified bilateral paravertebral pleural plaques ﬉. (Right) Axial HRCT of the same patient shows diffuse basilar subpleural reticulation ﬈ and multifocal calcified pleural plaques ﬉, some over the central diaphragmatic pleura. There is no effective treatment for patients with such advanced asbestosis.

193

Pneumoconiosis

Berylliosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Chronic beryllium disease (CBD) • Beryllium used in multiple industries • Inhalation produces 2 types of lung injury ○ Acute chemical pneumonitis (uncommon) ○ Chronic granulomatous disease • Diagnosis requires ○ History of beryllium exposure ○ Positive beryllium-specific lymphocyte proliferation test (in blood or bronchoalveolar lavage fluid) ○ Noncaseating granulomas on histology

• • • •

IMAGING

• CBD develops ~ 10-20 years after 1st exposure ○ CBD occurs in 2-5% of beryllium-exposed workers • Lung is primarily affected • Extrapulmonary disease is rare ○ Dermatitis, ulcers, dermal granulomas, hepatosplenomegaly (granulomatous infiltration)

• Imaging findings similar to those of sarcoidosis ○ Parenchymal nodules and interlobular septal thickening ○ Mediastinal and hilar lymphadenopathy • Lymphadenopathy is always associated with lung disease • Chronic fibrosis with upper lobe predominance

(Left) PA chest radiograph of a 62-year-old man with over 15 years of exposure to beryllium shows characteristic findings of chronic beryllium disease including bilateral small pulmonary nodules and hilar lymphadenopathy ﬊ [International Labor Organization (ILO) category q]. The radiographic findings mimic those of sarcoidosis. (Right) Axial CECT of a 50year-old man with occupational exposure to beryllium for 20 years shows conglomerate perihilar fibrosis ﬈ similar to that seen in sarcoidosis and silicosis.

(Left) Axial CECT of a 52-yearold woman with occupational exposure to beryllium for over 10 years shows multiple perilymphatic micronodules scattered throughout both lungs. Note nodularity along the left major fissure ﬊, a characteristic finding in patients with chronic berylliosis. (Right) Axial CECT of the same patient shows multiple calcified hilar and mediastinal lymph nodes ﬊. Extensive lymph node calcification is seen in approximately 10% of patients with chronic berylliosis.

194

Sarcoidosis Silicosis Tuberculosis Hypersensitivity pneumonitis (cluster 2)

PATHOLOGY • Noncaseating pulmonary granulomas • May be indistinguishable from sarcoidosis except for demonstration of beryllium-specific immune response

CLINICAL ISSUES

Berylliosis

Abbreviations • Acute beryllium exposure (ABE) • Chronic beryllium disease (CBD) • Delayed-type hypersensitivity to beryllium (BES)

Synonyms • Salem sarcoidosis ○ Seen in young women in fluorescent light industry in Salem, Massachusetts in 1940s

Definitions • Beryllium: Gray, lightweight metal with high thermal stability and conductivity ○ Aerospace, telecommunication, defense, computer, medical, and nuclear industries • Inhalation of dust, aerosol, or fumes produces 2 types of lung injury ○ Acute chemical pneumonitis (uncommon) ○ Chronic granulomatous disease • Diagnosis requires ○ History of beryllium exposure ○ Positive beryllium-specific lymphocyte proliferation test (in blood or bronchoalveolar lavage fluid) ○ Nonnecrotizing granulomas on histology

IMAGING General Features • Best diagnostic clue ○ Hilar and mediastinal lymphadenopathy + parenchymal abnormalities ○ Imaging findings similar to those of sarcoidosis – Parenchymal micronodules (57%) (most common) • Location ○ Mid lung zone perilymphatic micronodules (i.e., peribronchovascular, interlobular, and subpleural) ○ Upper lung zone fibrosis (advanced disease) • Size ○ Micronodules may coalesce into conglomerate masses (7%) • Morphology ○ Imaging pattern resembles that of sarcoidosis – Micronodules (57%) – Interlobular septal thickening (50%) – Ground-glass opacities (32%)

Radiographic Findings • Radiography ○ Acute exposure (ABE) – Usually secondary to single intense exposure □ Diffuse alveolar opacities due to acute noncardiogenic pulmonary edema □ Slow resolution of abnormalities ○ Chronic disease (CBD) – Normal chest radiographs in early stage (~ 50%) – Radiographic abnormalities should be characterized using International Labor Office (ILO) B reading classification □ Upper and mid lung zone diffuse nodular opacities: ILO categories p (1.5 mm) and q (1.5-3.0 mm)

– – – –

□ Reticular opacities: ILO categories s (width: 1.5 mm) and t (width: 1.5-3.0 mm) Lung nodules may be calcified Mediastinal and hilar lymphadenopathy □ May exhibit eggshell calcification Peribronchovascular fibrosis and conglomerate masses Spontaneous pneumothorax (in up to 10%)

Pneumoconiosis

TERMINOLOGY

CT Findings • HRCT ○ Lung – Parenchymal micronodules and interlobular septal thickening (most common) □ Parenchymal micronodules (57%) □ Subpleural micronodules may coalesce as pseudoplaques □ Interlobular septal and peribronchovascular thickening (50%) – Conglomerate masses – Ground-glass opacities (32%) more common than in sarcoidosis – Honeycombing (late stage) – Emphysema ○ Hilar and mediastinal lymphadenopathy (25-40%) – May exhibit amorphous or eggshell calcification ○ Dilated pulmonary trunk (pulmonary hypertension)

Imaging Recommendations • Best imaging tool ○ HRCT

DIFFERENTIAL DIAGNOSIS Sarcoidosis • May be indistinguishable from berylliosis on imaging ○ Bilateral, symmetric hilar (90%), and right paratracheal lymphadenopathy (60%) – May be present without parenchymal involvement ○ Perilymphatic micronodules • Peripheral lymphadenopathy (30%): Cervical, axillary, and inguinal • Multiorgan disease ○ Bone involvement (30%) in hands and feet (osteolytic or sclerotic) ○ Ocular (uveitis) and neurologic manifestations

Silicosis • Occupational exposure to silica • Centrilobular and subpleural micronodules (may be calcified) ○ Upper lobe predominance ○ Nodules may progress to progressive massive fibrosis (PMF) • Calcified mediastinal and hilar lymph nodes • Paracicatricial emphysema

Tuberculosis • Scattered centrilobular micronodules and tree-in-bud opacities • Consolidation • Cavitation 195

Pneumoconiosis

Berylliosis • Miliary tuberculosis: Diffuse and evenly distributed 1- to 3mm micronodules

Idiopathic Pulmonary Fibrosis • • • •

Irregular reticular opacities Traction bronchiectasis/bronchiolectasis Subpleural honeycombing Subpleural, lower lung predominance

Hypersensitivity Pneumonitis • • • •

Persistent or recurrent exposure to antigen/hapten Upper and mid lung zone predominance Cluster 1: Ground-glass opacities and centrilobular nodules Cluster 2: Reticulation, architectural distortion, bronchiectasis, and honeycombing • Air-trapping

PATHOLOGY General Features • Etiology ○ Exposure to beryllium dust, fumes, or aerosols ○ Short exposure time (9 weeks) may result in sensitization • Genetics ○ HLA-DPB1(Glu 69) present in 97% of patients with CBD – Not useful for screening given ↑ prevalence in general population (> 30%)

Staging, Grading, & Classification • ABE causes acute chemical pneumonitis • CBD is chronic granulomatous disease

Gross Pathologic & Surgical Features • Noncaseating pulmonary granulomas • Indistinguishable from sarcoidosis except for demonstration of beryllium-specific immune response

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ ABE (single intense exposure) – Conjunctivitis – Pharyngitis – Laryngotracheobronchitis – Dermatitis ○ Lung is primarily affected – Dyspnea – Cough – Chest pain – End-stage lung disease □ Crackles on auscultation □ Clubbing, cyanosis, cor pulmonale ○ Systemic: Fever, fatigue, anorexia ○ Arthralgias, myalgias • Other signs/symptoms ○ Extrapulmonary disease is rare – Skin manifestations: Dermatitis, ulcers, dermal granulomas – Lymphadenopathy, hepatosplenomegaly (granulomatous infiltration) – Hypercalcemia, renal stones 196

Demographics • Epidemiology ○ Beryllium-exposed workers – Ceramics manufacture – Electronic industries – Nuclear weapon production – Aerospace industry ○ ABE is rare today given strict industrial control measures ○ CBD occurs in 2-5% of beryllium-exposed workers

Natural History & Prognosis • Latency varies from a few months to 40 years after 1st exposure • CBD typically develops approximately 10-20 years after 1st exposure ○ Susceptible workers exposed to beryllium may develop BES – Beryllium stimulates pulmonary proliferation and accumulation of beryllium-specific T cells ○ Small percentage of BES progresses to CBD (2-5%) • Variable clinical course ○ Asymptomatic patient with normal chest radiographs and pulmonary function ○ Symptomatic patient with abnormal chest radiographs and abnormal pulmonary function – Pulmonary function tests: Restrictive pattern, ↓ vital capacity, lung capacity, and diffusing lung capacity □ ↑ alveolar-arterial oxygen gradient during exercise is highly sensitive • Acute exposure (very rare) ○ Mortality (10%) ○ Well-recognized cause of lung cancer

Treatment • Cessation of beryllium exposure ○ Improvement of pulmonary function ○ May be definitive treatment for patients with early stage disease • Corticosteroids for symptomatic patients or abnormal pulmonary function tests • Lung transplantation for end-stage lung disease

DIAGNOSTIC CHECKLIST Consider • Exclude history of beryllium exposure in patients with sarcoid-like imaging findings

Image Interpretation Pearls • Consider diagnosis of berylliosis in patients with mediastinal/hilar lymphadenopathy and perilymphatic micronodules

SELECTED REFERENCES 1. 2. 3. 4.

Mayer A et al: Beryllium and other metal-induced lung disease. Curr Opin Pulm Med. 21(2):178-84, 2015 Mayer AS et al: Sarcoidosis and chronic beryllium disease: similarities and differences. Semin Respir Crit Care Med. 35(3):316-29, 2014 Flors L et al: Uncommon occupational lung diseases: high-resolution CT findings. AJR Am J Roentgenol. 194(1):W20-6, 2010 Sharma N et al: Chronic beryllium disease: computed tomographic findings. J Comput Assist Tomogr. 34(6):945-8, 2010

Berylliosis Pneumoconiosis

(Left) PA chest radiograph of a 64-year-old man exposed to beryllium shows dense opacities in the left upper lobe with associated superior retraction of the left hilum ﬈ (ILO category t). Calcified hilar lymph nodes ﬊ are also present. Similar findings can be seen in sarcoidosis, silicosis, and tuberculosis. (Right) Axial CECT of a 57-year-old man with more than 10 years of occupational exposure to beryllium while working in the electronic industry shows subpleural ﬈ and peribronchial micronodules ﬊.

(Left) Axial CECT of a 50-yearold man with sarcoidosis shows multiple coalescent micronodules ﬈ in a peribronchovascular distribution as well as subpleural ﬊ and perifissural ﬉ micronodules. (Right) Axial CECT of a 49-year-old woman with sarcoidosis shows perilymphatic pulmonary micronodules and peribronchovascular thickening ﬉. Correlation with occupational history is critical in order to differentiate sarcoidosis from berylliosis.

(Left) PA chest radiograph of a 60-year-old man with longterm exposure to silica dust shows upper and mid lung zone predominant micronodules ﬈, subpleural pseudoplaques ﬊, and hilar retraction (ILO category q). (Right) Axial CECT of the same patient shows perilymphatic micronodules with a peribronchovascular ﬈ and subpleural ﬊ distribution. The findings are similar to those seen in berylliosis. Silicosis is a very common pneumoconiosis diagnosed based on silica exposure history and radiologic findings.

197

Pneumoconiosis

Talcosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Inhalational talcosis = talc pneumoconiosis • Intravenous talcosis = talc granulomatosis • 4 forms: 3 inhalational, 1 intravenous ○ Inhalational talcosis (pure talc exposure) ○ Inhalational talcosilicosis ○ Inhalational talcoasbestosis ○ Intravenous talcosis

• • • •

IMAGING • HRCT/CT ○ Inhalational – Centrilobular and subpleural nodules, may calcify – Nodules coalesce into masses; diffuse calcification – Lymphadenopathy may exhibit high attenuation ○ Intravenous – Micronodules: Centrilobular, tree-in-bud, sparing fissures – Ground-glass opacities

(Left) PA chest radiograph of a patient with inhalational talcosis shows bilateral upper and mid lung zone reticular and nodular opacities. (Right) Coronal CECT of the same patient demonstrates diffuse bilateral centrilobular micronodules ﬉, slightly more conspicuous in the upper lobes, and a right upper lobe coalescent opacity ﬈. Given that inhalational and intravenous talcosis can produce progressive massive fibrosis, a useful feature to differentiate them is the absence of emphysema in the former.

(Left) Coronal CECT of the same patient shows diffuse bilateral centrilobular micronodules, slightly more conspicuous in the upper lobes as areas of coalescence ﬈. (Right) Axial NECT of a patient with inhalational talcosis shows diffusely calcified nodular and mass-like opacities ﬈ in the upper lobes. While this appearance is similar to that of silicosis with progressive massive fibrosis, calcifications in the latter tend to be punctate as opposed to diffuse and irregular in talcosis.

198

Sarcoidosis Metastatic pulmonary calcification Silicosis Cellulose granulomatosis

CLINICAL ISSUES • Signs and symptoms ○ Inhalational: Dry cough, chronic dyspnea, cor pulmonale ○ Intravenous: Dyspnea, pulmonary hypertension • Treatment ○ Inhalational: No specific treatment to arrest progression of pneumoconiosis ○ Intravenous: Cessation of intravenous injection

DIAGNOSTIC CHECKLIST • Consider cellulose granulomatosis in patients with diffuse centrilobular ground-glass nodules and pulmonary hypertension; relevant history may be difficult to elicit

Talcosis

Synonyms • Inhalational talcosis = talc pneumoconiosis • Intravenous talcosis = talc granulomatosis or excipient lung disease

Definitions • 4 forms: 3 inhalational, 1 intravenous ○ Inhalational talcosis (pure talc exposure) ○ Inhalational talcosilicosis (exposure to talc and silica) ○ Inhalational talcoasbestosis (exposure to talc and asbestos) ○ Intravenous talcosis – Pure intravenous talcosis – Intravenous talcosis and methylphenidate

IMAGING General Features • Best diagnostic clue ○ Diffuse fine micronodules and high-attenuation progressive massive fibrosis (PMF) • Location ○ Inhalational: Upper lung zone nodules – PMF in all lung zones ○ Intravenous: Diffuse nodules – Lower lobe emphysema – PMF in perihilar regions • Morphology ○ Ground-glass opacities, usually greater in extent than definable nodules

Radiographic Findings • Radiography ○ Inhalational – Upper lung zone-predominant involvement – Peribronchovascular nodules □ May evolve into perihilar PMF – International Labor Office "B" opacity type "p" – Lower lung zone subpleural reticular opacities or honeycombing with discontinuous partially calcified pleural plaques (in patients with coexistent asbestos exposure) – Enlarged hilar lymph nodes with eggshell calcification (in patients with coexistent silica exposure) – Emphysema is rare in inhalational form of talcosis but often occurs in intravenous talcosis ○ Intravenous – Micronodules □ Diffusely and evenly distributed with no zonal predilection – Lymphadenopathy (occasional) – Late stages: PMF in perihilar regions □ Intrinsic calcification usually not visible on radiography – Emphysema (in patients with coexistent methylphenidate exposure) □ Typically lower lung zone-predominant panlobular emphysema (identical to that associated with α-1antitrypsin deficiency)

□ May be sole manifestation in some cases of intravenous methylphenidate drug abuse – Pulmonary hypertension and cor pulmonale may develop from continuous exposure

CT Findings • NECT ○ PMF typically exhibits intrinsic high attenuation • HRCT ○ Inhalational – Centrilobular and subpleural nodules, may calcify – Nodules coalesce into PMF □ Similar appearance to silicosis; calcification tends to be diffuse rather than punctate □ Architectural distortion adjacent to PMF □ PMF may involve all lung zones – Pleural and diaphragmatic plaques identical to those related to asbestos exposure (in talcoasbestosis) – Lymphadenopathy may exhibit high attenuation ○ Intravenous – Micronodules □ 1-2 mm □ Centrilobular (i.e., tree-in-bud), characteristically spare fissures □ Diffuse, bilateral and evenly distributed; emphysematous lung is spared – Ground-glass opacities – Emphysema may be upper or lower lobe predominant (even in absence of smoking) – Methylphenidate may result in severe panlobular emphysema without nodules – Perihilar PMF in late phases – Dilated pulmonary trunk from pulmonary hypertension

Pneumoconiosis

TERMINOLOGY

Imaging Recommendations • Best imaging tool ○ HRCT/CT for characterization of interstitial lung disease and detection of high-attenuation conglomerate masses

DIFFERENTIAL DIAGNOSIS Sarcoidosis • PMF may occur but is less frequent • Nodules usually larger, tend to cluster (galaxy sign) • Perilymphatic nodules (i.e., peribronchovascular and subpleural)

Metastatic Pulmonary Calcification • No PMF • Centrilobular nodules larger and mulberry-shaped, tend to cluster • Predominantly affects upper lobes

Silicosis • Occupational exposure history • Nodules tend to be larger than those of talcosis • PMF usually more cephalad in upper lung zones; no intrinsic high attenuation • Talc and silica may be admixed together • Pleural plaques not seen 199

Pneumoconiosis

Talcosis Cellulose Granulomatosis • Cellulose filler in oral medications inappropriately used intravenously • Cellulose particles trapped in arterioles lead to angiocentric granulomatous reaction • HRCT: Centrilobular nodules and tree-in-bud opacities • No PMF or emphysema

Amyloidosis • May be related to intravenous drug use • Nodular form: Multiple small scattered pulmonary nodules • May calcify, but calcification in small nodules is rare

PATHOLOGY General Features • Etiology ○ Inhalational – Occupational exposure: Mining, milling, packaging of talc – Cosmetic use (talcum powder) common, but lung disease from inhalation extremely rare ○ Intravenous – Talc was common filler in medications intended for oral use that may be inappropriately injected intravenously □ Amphetamines, methylphenidate (Ritalin), hydromorphone (Dilaudid), pentazocine (Talwin), propoxyphene (Darvon) – Particles typically trapped in small arterioles leading to infarction, ischemia, granulomatous inflammation – Reduction of capillary bed may result in panacinar emphysema; methylphenidate itself may result in emphysema – Currently medications progressively contain less or no talc as filler but rather cellulose, crospovidone, and others; excipient lung disease may develop with such substances but typically less inflammatory reaction • General pathology comments ○ Talc: Magnesium silicate – Used in paper, plastics, cosmetics, construction, rubber, and drug industries – Less fibrogenic than silica and asbestos – Leads to granuloma formation both in inhaled and injected forms

Gross Pathologic & Surgical Features • Inhalational: Nodules with perilymphatic distribution • Intravenous: Nodules with perivascular distribution ○ Subpleural lung tends to be spared

Microscopic Features • Inhalational and intravenous ○ Granulomatous interstitial inflammation ○ Birefringent talc crystals, colorless to pale yellow on H&E staining; strongly birefringent needle-like or plate-like crystals; 5-15 μm • Inhaled ○ Interstitial fibrosis or poorly defined fibrotic nodules ○ Difficult to separate talc from contaminants of silica and asbestos 200

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Inhalational: Dry cough, chronic dyspnea, cor pulmonale in end-stage disease ○ Intravenous – Progressive dyspnea, pulmonary hypertension – Patients often deny inappropriate injection, and diagnosis only made with tissue sampling • Other signs/symptoms ○ Pulmonary function tests – Mixed obstruction (from emphysema) and restriction (from interstitial lung disease) – Severe reduction in diffusing capacity

Demographics • Age ○ Inhalational: Middle-aged and older individuals – Men between 4th and 6th decades ○ Intravenous: Younger men • Gender ○ Inhalational and intravenous talcosis more common in men • Epidemiology ○ Latency period of 20 years for inhalational form

Natural History & Prognosis • Talc: Not recognized carcinogen • Natural progression from simple nodularity to PMF that mimics silicosis • Slow progression even without further exposure • Intravenous talcosis may lead to pulmonary hypertension and cor pulmonale

Treatment • Inhalational ○ No specific treatment to arrest progression of pneumoconiosis ○ Prevention: Reduction of ambient dust concentration ○ Removal from or transfer to less dusty environment • Intravenous ○ Cessation of inappropriate intravenous injection ○ Corticosteroids may stabilize PMF

DIAGNOSTIC CHECKLIST Consider • Cellulose granulomatosis in patients with diffuse centrilobular ground-glass nodules and pulmonary hypertension; relevant history difficult to elicit

Image Interpretation Pearls • High-attenuation PMF should suggest inhalational talcosis • Micronodules, ground-glass attenuation and lower lobe emphysema should raise suspicion for intravenous talcosis

SELECTED REFERENCES 1. 2.

Nguyen VT et al: Pulmonary effects of i.v. injection of crushed oral tablets: "excipient lung disease". AJR Am J Roentgenol. 203(5):W506-15, 2014 Marchiori E et al: Pulmonary talcosis: imaging findings. Lung. 188(2):165-71, 2010

Talcosis Pneumoconiosis

(Left) Axial HRCT of a 45-yearold intravenous drug user with progressive shortness of breath and a past medical history of intravenous injection of Ritalin shows pulmonary emphysema ﬈ and diffuse fine micronodules in the pulmonary parenchyma that is not compromised by emphysema. (Right) Axial NECT of same patient shows an area of confluent fibrosis ﬈ in the right midlung zone on a background of diffuse ground-glass and fine micronodular opacities.

(Left) Axial CECT of a patient with intravenous talc granulomatosis who presented with sepsis shows profuse centrilobular micronodules and a dilated pulmonary trunk ﬈ secondary to pulmonary hypertension. Blockage of pulmonary capillaries in this disease process eventually leads to pulmonary hypertension, cor pulmonale, and death. (Right) Axial CECT of the same patient shows extensive diffuse pulmonary micronodules and groundglass opacities.

(Left) Axial HRCT of a patient with intravenous talcosis demonstrates bilateral perihilar lung masses of variable sizes secondary to progressive massive fibrosis ﬈, the largest of which exhibits an angular morphology. (Right) Axial NECT of the same patient shows bilateral perihilar masses ﬈ with diffusely increased attenuation. The latter is a helpful feature to differentiate this entity from progressive massive fibrosis in silicosis, in which calcifications tend to be punctate.

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Pneumoconiosis

Hard-Metal Pneumoconiosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• • • •

• • • •

Giant cell interstitial pneumonia (GIP) Pneumoconiosis resulting from inhalation of hard metal Hard metals: Cobalt and cobalt alloys (e.g., tungsten) Hypersensitivity reaction with histologic features of GIP

IMAGING

PATHOLOGY

• CT ○ Ground-glass opacities – Lower lobe predominance – May improve on serial imaging ○ Reticular opacities – No change on serial imaging ○ Consolidations ○ Centrilobular nodules (rare) ○ Honeycombing (rare); similar morphology and distribution as usual interstitial pneumonia pattern ○ Mediastinal lymphadenopathy

• Constrictive bronchiolitis (earliest manifestation) • Interstitial thickening with fibrous tissue deposition and mononuclear inflammatory cell infiltration • Subacute fibrosing alveolitis: Accumulation of macrophages and multinucleated giant cells in alveolar spaces

(Left) PA chest radiograph of a 47-year-old man with hard metal pneumoconiosis shows bilateral lower lobepredominant patchy airspace opacities ﬈. (Right) Axial HRCT of the same patient shows diffuse bilateral centrilobular ground-glass micronodules ﬈ and patchy ground-glass opacities ﬊. Ground-glass and reticular opacities are considered classic findings of hard metal pneumoconiosis, but consolidations, centrilobular nodules, honeycombing, and lymphadenopathy have also been described.

(Left) Axial HRCT of the same patient shows right lower lobe patchy ground-glass opacities ﬊ and subtle reticulations ﬈. (Right) Axial HRCT of the same patient shows centrilobular ground-glass micronodules ﬉, patchy ground-glass opacities ﬊, and mild subpleural reticulation ﬈. Affected patients often present after 10-12 years of exposure with cough, shortness of breath, weight loss, and fatigue and classically exhibit impaired diffusing capacity and restrictive physiology. Biopsy shows giant cell interstitial pneumonia.

202

Idiopathic pulmonary fibrosis Fibrotic nonspecific interstitial pneumonia Lymphoid interstitial pneumonia Pulmonary alveolar proteinosis

CLINICAL ISSUES • • • •

Cough, exertional dyspnea ↓ diffusing capacity for carbon monoxide Low disease prevalence in exposed workers Treatment: Avoidance of exposure, bronchodilators, corticosteroids

Hard-Metal Pneumoconiosis

PATHOLOGY

Synonyms

General Features

• Giant cell interstitial pneumonia (GIP)

• GIP represents hypersensitivity reaction

Definitions

Staging, Grading, & Classification

• Pneumoconiosis resulting from inhalation of hard metal ○ Hard metals: Cobalt and cobalt alloys (e.g., tungsten) ○ Hypersensitivity reaction with histologic features of GIP

• Progression of disease may produce parenchymal remodeling and honeycombing

IMAGING General Features • Best diagnostic clue ○ Exposure to hard metal ○ HRCT findings of bilateral reticulation ± ground-glass opacity • Location ○ Lower lung zone predominance ○ Bilateral involvement

Radiographic Findings • Reticular opacities ± hazy opacities • Lower lung zone-predominant reticular opacities • Random distribution of hazy opacities

CT Findings • HRCT ○ Ground-glass opacities – Lower lobe predominance – May exhibit improvement on serial imaging ○ Reticular opacities – No change on serial imaging ○ Consolidations ○ Centrilobular nodules (rare) ○ Honeycombing (rare); similar morphology and distribution as usual interstitial pneumonia (UIP) pattern ○ Mediastinal lymphadenopathy

Imaging Recommendations • Best imaging tool ○ HRCT

DIFFERENTIAL DIAGNOSIS Idiopathic Pulmonary Fibrosis • Basilar subpleural honeycombing with UIP pattern • Absence of occupational exposure

Fibrotic Nonspecific Interstitial Pneumonia • Basilar subpleural fibrosis • Absence of occupational exposure

Lymphoid Interstitial Pneumonia • Lung cysts, ground-glass opacities • History of autoimmunity (e.g., Sjögren syndrome, rheumatoid arthritis)

Microscopic Features • Constrictive bronchiolitis (earliest manifestation) • Interstitial thickening with fibrous tissue deposition and mononuclear inflammatory cell infiltration • Subacute fibrosing alveolitis: Accumulation of macrophages and multinucleated giant cells in alveolar spaces • Interstitial fibrosis and cysts are rare but may occur after many years of exposure • Increased concentration of hard metals compared to normal population (10x) on atomic absorption spectrophotometry or ionic coupled plasma emission spectrometry

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Cough, exertional dyspnea, fatigue, weight loss • Other signs/symptoms ○ ↓ diffusing capacity for carbon monoxide ○ Restrictive or mixed restrictive and obstructive pattern on pulmonary function tests • Clinical profile ○ Exposure occurs in hard metal and diamond polishing industries ○ Source of cobalt may not always be clear

Demographics • Low prevalence in exposed workers ○ ~ 11% of 1,039 workers have work-related wheezing; 0.7% have radiographic evidence of interstitial lung disease ○ 45% of patients with radiographic interstitial abnormalities show progressive disease over time

Natural History & Prognosis • Manifests after 10-12 years of exposure (latency period may be as short as 2 years)

Treatment • Acute and subacute phases ○ Avoidance of exposure ○ Bronchodilators and inhaled corticosteroids • Fibrotic phase ○ Systemic corticosteroids

SELECTED REFERENCES 1.

Pulmonary Alveolar Proteinosis • Ground-glass opacities on background of interlobular septal thickening and intralobular lines; so-called crazy-paving pattern

Pneumoconiosis

TERMINOLOGY

2.

3.

Khoor A et al: Giant cell interstitial pneumonia in patients without hard metal exposure: analysis of 3 cases and review of the literature. Hum Pathol. 50:176-82, 2016 Choi JW et al: Giant cell interstitial pneumonia: high-resolution CT and pathologic findings in four adult patients. AJR Am J Roentgenol. 184(1):26872, 2005 Dunlop P et al: Hard metal lung disease: high resolution CT and histologic correlation of the initial findings and demonstration of interval improvement. J Thorac Imaging. 20(4):301-4, 2005

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SECTION 7

Neoplasms

Approach to Neoplasms Invasive Mucinous Adenocarcinoma (Diffuse) Lymphangitic Carcinomatosis Hematogenous Metastases Endovascular Metastases and Tumor Emboli Kaposi Sarcoma Lymphangioleiomyomatosis Reactive Lymphoproliferative Disorders Neoplastic Lymphoproliferative Disorders

206 210 214 218 222 226 230 234 240

Neoplasms

Approach to Neoplasms Introduction A wide variety of neoplastic conditions affect the chest and its various anatomic compartments, including the lung parenchyma and interstitium. In many instances, presenting signs and symptoms are nonspecific and may include chest pain, cough, and dyspnea, which poses a significant diagnostic challenge for the referring clinician tasked with evaluating affected patients. A significant amount of information can be obtained from the medical history and the presenting signs and symptoms. Correlation of this data with physical examination findings, relevant laboratory tests, and imaging abnormalities allows the formulation of an informed presumptive diagnosis. Although chest radiography is frequently the first imaging modality to detect abnormalities due to neoplasms, more advanced imaging with CT, FDG PET/CT, and, in some cases, MR imaging is usually necessary to provide a relevant differential diagnosis and guide management.

Imaging Most thoracic neoplasms are detected on chest radiography and CT, the latter of which may be obtained for further evaluation and characterization of radiographic abnormalities and for planning further interventions, such as image-guided or surgical biopsies. FDG PET/CT is often used for staging and restaging affected patients once a definitive diagnosis of malignancy has been established. MR imaging may also be performed but is primarily employed as a problem-solving tool and can be used to better evaluate neoplasms of the heart and pericardium, vascular structures, and chest wall as well as serving as a substitute for imaging of patients who cannot undergo CECT due to severe allergy to contrast material or impaired renal function.

Approach Neoplasms affecting the lung parenchyma and interstitium may produce a wide variety of imaging findings on chest radiography and CT. Although some lesions [such as invasive mucinous adenocarcinoma (IMA) and hematogenous metastases] may manifest as 1 or more solid pulmonary nodules or masses, others (such as lymphangitic carcinomatosis) result in nodular thickening of the interlobular septa and bronchovascular bundles, Kaposi sarcoma (KS) can produce unique peribronchovascular nodular opacities that exhibit a flame shape, and lymphangioleiomyomatosis (LAM) appears as multiple thin-walled lung cysts. Recognition of these entities and their various imaging manifestations is essential for the practicing radiologist. Invasive Mucinous Adenocarcinoma The updated classification of lung adenocarcinomas released in 2015 by the World Health Organization (WHO) included a novel designation titled IMA, which correlates with the entity previously known as mucinous bronchioloalveolar carcinoma included in the 2004 WHO classification. These lesions are characterized by tumor cells that exhibit goblet or columnar cell morphology with abundant intracytoplasmic mucin and often demonstrate lepidic predominant growth with little invasion. Invasive mucinous adenocarcinoma (IMA) may manifest in several forms, one of the most common of which is a solitary pulmonary nodule or mass that may exhibit solid or part-solid attenuation. Consolidation is another common imaging feature and may be associated with specific imaging signs, 206

such as the CT angiogram and open bronchus signs, the former describing pulmonary vessels traversing an airless lowattenuation consolidation and the latter describing an airway leading to or contained within a pulmonary nodule or lesion. Diffuse IMA is comprised of multiple pulmonary nodules or masses, multifocal ground-glass opacities &/or consolidations, and rarely crazy-paving or the combination of ground-glass opacities and interlobular septal thickening. Morphologicmetabolic dissociation is a term used to describe IMA that tends to demonstrate only low-grade FDG uptake on PET/CT despite a solid or mass-like appearance on CT. Lymphangitic Carcinomatosis Lymphangitic carcinomatosis represents infiltration of lymphatic channels by tumor emboli or direct tumor spread from affected lymph nodes and is most frequently a complication of lung, breast, gastric, pancreas, and prostate cancers. The most common histologic subtype of neoplasm to result in lymphangitic carcinomatosis is adenocarcinoma, and unilateral, bilateral, focal, diffuse, symmetric, or asymmetric patterns have been described. The characteristic finding of lymphangitic carcinomatosis on CT is nodular or smooth thickening of the interlobular, peribronchovascular, and centrilobular interstitia with preservation of the secondary pulmonary lobular architecture. Association with other abnormalities, such as pulmonary nodules, lymphadenopathy, pleural effusion, and distant metastases, often enables the radiologist to suggest the diagnosis. Kaposi Sarcoma KS is a low-grade mesenchymal neoplasm of blood and lymphatic vessels that primarily affects the skin but may also involve the thorax. Several types have been described, including classic or sporadic KS, endemic or African KS, AIDSrelated KS (which is the most common), and idiopathic KS. The most frequent imaging feature of KS on CT is the flameshaped pulmonary nodule, which tends to be multifocal, bilateral, and poorly defined, emanates from the bilateral hila, and exhibits a peribronchovascular distribution. Other findings (such as nodules with surrounding ground-glass opacity and septal thickening) may be present. Radiologists should also carefully evaluate CT scans of affected patients for evidence of an opportunistic pulmonary infection, such as Pneumocystis jirovecii pneumonia. Lymphangioleiomyomatosis LAM represents a proliferation of neoplastic smooth musclelike cells that may be sporadic (LAM-S) or associated with tuberous sclerosis (LAM-TS), a genetic disorder that is inherited in an autosomal dominant fashion and results in multiorgan hamartomas, seizures, and cognitive disorders. The characteristic finding of LAM on CT is diffuse, bilateral, thin-walled cysts with normal intervening lung. Ground-glass opacities related to hemorrhage and septal thickening related to lymphatic obstruction may also be present. Multifocal micronodular pneumocyte hyperplasia, manifesting as solid or ground-glass nodules, can be used to differentiate between LAM-S and LAM-TS, as the latter demonstrates these findings, but the former does not. Associated extrathoracic findings include renal, hepatic, and splenic angiomyolipomas and other abnormalities.

Approach to Neoplasms Neoplasms

(Left) Axial CECT of a patient with invasive mucinous adenocarcinoma demonstrates a mass-like consolidation ﬈ with surrounding ground-glass opacity and small pulmonary nodules in the adjacent lung. (Right) Axial CECT of a patient with invasive mucinous adenocarcinoma shows multifocal bilateral consolidations ﬊ and groundglass opacity nodules ﬈. The diffuse form of mucinous adenocarcinoma may manifest as multifocal nodules, groundglass opacities, &/or consolidations.

(Left) Axial CECT of a patient with invasive mucinous adenocarcinoma demonstrates a large, solid mass ﬈ in the right lower lobe and a mass-like, part-solid opacity ﬊ in the adjacent middle lobe. (Right) Axial CECT (soft tissue window) of the same patient shows that the large right lower lobe mass exhibits the CT angiogram sign characterized by multiple enhancing blood vessels ﬊ traversing the otherwise solid and homogeneous lung lesion.

(Left) Axial CECT of a patient with lung cancer and lymphangitic carcinomatosis demonstrates bronchovascular ﬊ and interlobular septal ﬈ thickening and patchy groundglass opacities in the right lung. These findings are characteristic imaging manifestations of lymphangitic carcinomatosis. (Right) Axial NECT of a patient with metastatic renal cell carcinoma shows extensive lymphangitic carcinomatosis ﬉, innumerable bilateral small nodules ﬈, and moderate bilateral pleural effusions ﬊.

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Neoplasms

Approach to Neoplasms

(Left) Axial CECT of a 41-yearold man with metastatic germ cell neoplasm shows numerous solid pulmonary metastases ﬈ in the left lung, one of which demonstrates internal cavitation ﬊. (Right) Axial CECT of a 48-year-old man with renal cell carcinoma demonstrates numerous metastases ﬈ in the right lung. Metastases from primary malignancies that may hemorrhage (such as renal cell and thyroid cancers, melanoma, choriocarcinoma, and some sarcomas) may manifest as ground-glass opacity nodules.

(Left) Axial CECT of a 54-yearold woman with sarcoma shows numerous pleural nodules and masses ﬈ consistent with metastatic disease. (Right) Axial CECT of a 39-year-old woman with osteosarcoma demonstrates pleural thickening in the inferior right hemithorax with internal mineralization due to osteosarcoma metastases ﬈. Primary malignancies (such as osteosarcoma, sarcoma, and mucinous neoplasms) may result in metastases with mineralization.

(Left) Axial CECT of a patient with renal cell carcinoma demonstrates irregular beading of right lower lobe pulmonary arteries ﬈ consistent with intravascular tumor emboli. (Right) Axial CECT of a 42-year-old woman with sarcoma demonstrates a beaded appearance of several bilateral pulmonary artery branches ﬈ secondary to intravascular tumor emboli. The characteristic imaging appearance of tumor emboli is alternating dilatation and narrowing of affected pulmonary artery branches.

208

Approach to Neoplasms Neoplasms

(Left) Axial CECT of a 37-yearold man with AIDS and Kaposi sarcoma demonstrates numerous irregular nodules and masses ﬈ in the right upper lobe, several of which are flame-shaped. Flameshaped nodules that are peribronchovascular and radiate from the hila are characteristic of Kaposi sarcoma. (Right) Axial NECT of a 43-year-old man with AIDS shows a left upper lobe masslike consolidation ﬈ with adjacent ground-glass opacity ﬊. Biopsy revealed Kaposi sarcoma.

(Left) Axial CECT of a 39-yearold woman with lymphangioleiomyomatosis demonstrates numerous thinwalled cysts ﬈ in the right lung. (Right) Axial CECT of a patient with lymphangioleiomyomatosis shows thin-walled cysts ﬈ on a background of ground-glass opacity. Lymphangioleiomyomatosis typically manifests as diffusely distributed, thin-walled lung cysts that increase in size over time. Note the subtle background of ground-glass opacity that may correlate with alveolar hemorrhage.

(Left) Axial CECT of a patient with mucosa-associated lymphoid tissue lymphoma demonstrates multiple masslike opacities ﬈ in the right lung with intrinsic air bronchograms ﬊. (Right) Axial NECT of a patient with gastrointestinal lymphoma and secondary pulmonary involvement shows a crazypaving pattern ﬈ of pulmonary disease consisting of ground-glass opacities and interlobular septal thickening. Secondary pulmonary lymphoma is much more common than primary pulmonary lymphoma.

209

Neoplasms

Invasive Mucinous Adenocarcinoma (Diffuse) KEY FACTS

TERMINOLOGY • Invasive mucinous adenocarcinoma (IMA): Defined in 2015 World Health Organization (WHO) classification ○ Tumor cells with goblet or columnar morphology with abundant intracytoplasmic mucin, often showing lepidic predominant growth with little invasion

IMAGING • HRCT/CT ○ Pulmonary nodule or mass – Solid or part solid; peripheral > central ○ Lobar consolidation – CT angiogram sign – CT bronchus sign ○ Diffuse form – Multiple pulmonary nodules – Multifocal ground-glass opacities &/or consolidations – Crazy paving: Ground-glass opacities on background of interlobular septal thickening

(Left) PA chest radiograph of a 59-year-old man with chronic cough and bronchorrhea and multifocal invasive mucinous adenocarcinoma shows diffuse bilateral reticulonodular opacities and a dense right lower lobe consolidation. (Right) Coronal NECT of the same patient shows diffuse heterogeneous ground-glass opacities with areas of crazypaving pattern ﬉, small nodules with intrinsic lucency ﬊, and dense right lower lobe consolidation ﬈. Invasive mucinous adenocarcinoma may initially manifest with focal or multifocal disease.

(Left) Axial fused FDG PET/CT of the same patient shows scattered areas of FDG uptake ﬈ within the pulmonary consolidations. Note morphologic-metabolic dissociation (i.e., low-grade FDG uptake in solid tumor components on CT). (Right) Low-power photomicrograph (H&E stain) of a specimen of invasive mucinous adenocarcinoma shows a lepidic growth pattern along alveolar walls without stromal, vascular, or pleural invasion. Intrinsic lucencies on imaging likely correlate with areas of spared lung.

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• FDG PET/CT: Morphologic-metabolic dissociation ○ IMA typically demonstrates low-grade FDG uptake on PET/CT even though it manifests as solid or part-solid lesion(s) on CT

TOP DIFFERENTIAL DIAGNOSES • • • • •

Lung cancer Pulmonary infection Organizing pneumonia Lymphoproliferative disorder Alveolar proteinosis

CLINICAL ISSUES • Treatment ○ Localized tumor (single nodule/mass or consolidation): Surgical resection ○ Multinodular form: Chemotherapy • Overall survival similar to that of patients with intermediate-grade nonmucinous adenocarcinoma

Invasive Mucinous Adenocarcinoma (Diffuse)

DIFFERENTIAL DIAGNOSIS

Abbreviations

Lung Cancer

• Invasive mucinous adenocarcinoma (IMA) • Adenocarcinoma (ADC)

• Nonmucinous ADC ○ Solid or part-solid pulmonary nodule/mass ○ Most demonstrate increased FDG uptake on PET/CT (in contrast to IMA)

Synonyms • Mucinous bronchioloalveolar carcinoma (BAC)

Definitions • 2015 World Health Organization (WHO) classification ○ Neoplastic cells with goblet or columnar morphology and abundant intracytoplasmic mucin; often exhibit lepidic-predominant growth with little invasion ○ Lepidic growth: Restricted neoplastic growth along preexisting alveolar structures without stromal, vascular, or pleural invasion ○ Formerly mucinous BAC in 2004 WHO classification

IMAGING Radiographic Findings

Lung Metastases • Multifocal, well-defined pulmonary nodules/masses • Most metastases in outer 1/3 of lung • Hematogenous nodules may exhibit feeding artery

Pulmonary Infection • Solid, nonsolid, or part-solid nodule(s) • Consolidation • Mass-like consolidation, round pneumonia, lung abscess

Organizing Pneumonia • Multifocal peripheral opacities • Response to steroids

• Pulmonary nodule or mass ○ Solitary or multiple • Segmental or lobar consolidation ○ IMA suspected when consolidation does not resolve after 4-6 weeks or appropriate treatment • Multifocal opacities &/or consolidations

Lymphoproliferative Disorders

CT Findings

• May mimic diffuse IMA on imaging • Bronchoscopy with bronchoalveolar lavage allows accurate distinction

• Pulmonary nodule or mass ○ Solid or part solid ○ Peripheral > central • Lobar consolidation ○ May exhibit CT angiogram or open bronchus sign – CT angiogram sign: Prominent pulmonary vessels traversing airless low-attenuation consolidation on CECT – CT bronchus sign: Bronchus leading to or contained within solitary pulmonary nodule or mass • Diffuse form ○ Multiple pulmonary nodules – May exhibit intrinsic lucencies ○ Multifocal ground-glass opacities &/or consolidations ○ Crazy paving: Ground-glass opacity on background of interlobular septal thickening

MR Findings • White lung sign ○ Signal intensity comparable with that of static fluid on heavily T2WI ○ Uncommon but characteristic finding of IMA

Nuclear Medicine Findings • PET/CT ○ Morphologic-metabolic dissociation – IMA typically demonstrates low-grade FDG uptake on PET/CT (i.e., false-negative) in spite of manifesting as solid or part-solid lesion on CT

Imaging Recommendations • Best imaging tool ○ CT for assessment of morphology and disease extent

Neoplasms

TERMINOLOGY

• • • •

Multiple pulmonary nodules/masses Hilar &/or mediastinal lymphadenopathy Lobar or segmental consolidation Reticulation and bronchovascular thickening

Alveolar Proteinosis

Pneumocystis jirovecii Pneumonia • Similar to diffuse IMA on imaging • History of immunosuppression (e.g., human immunodeficiency virus infection) • Acute presentation

PATHOLOGY General Features • 2011 International Association for Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) lung ADC classification system ○ IMA listed as 1 of various subtypes of invasive ADC ○ Other invasive ADCs: Acinar predominant, papillary predominant, micropapillary predominant, solid predominant with mucin production

Staging, Grading, & Classification • Staging of IMA is same as that for nonmucinous ADC (i.e., TNM) ○ T – T0: No evidence of primary tumor – Tis: Carcinoma in situ – T1: T ≤ 3 cm in greatest dimension surrounded by lung or visceral pleura without bronchoscopic evidence of invasion proximal to lobar bronchus (i.e., not in mainstem bronchus) □ T1a(mi): Minimally invasive ADC □ T1a: T ≤ 1 cm in greatest dimension □ T1b: T > 1 cm but ≤ 2 cm in greatest dimension 211

Neoplasms

Invasive Mucinous Adenocarcinoma (Diffuse) □ T1c: T > 2 cm but ≤ 3 cm in greatest dimension – T2: T > 3 cm but ≤ 5 cm or tumor with any of following features: Mainstem bronchus involvement regardless of distance from carina but without carinal involvement; visceral pleura invasion; atelectasis or obstructive pneumonitis that extends to hilar region, involving part of or entire lung □ T2a: T > 3 cm but ≤ 4 cm in greatest dimension □ T2b: T > 4 cm but ≤ 5 cm in greatest dimension – T3: T > 5 cm but ≤ 7 cm in greatest dimension or associated with separate tumor nodule(s) in same lobe as primary tumor or direct invasion of any of following structures □ Chest wall (including parietal pleura and superior sulcus), phrenic nerve, parietal pericardium – T4: T > 7 cm in greatest dimension or associated with separate tumor nodule(s) in different ipsilateral lobe than that of primary tumor or invasion of any of following structures □ Diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina ○ N – N0: No regional lymph node metastasis – N1: Metastasis to ipsilateral peribronchial &/or ipsilateral hilar and intrapulmonary lymph nodes, including involvement by direct extension – N2: Metastasis in ipsilateral mediastinal &/or subcarinal lymph node(s) – N3: Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) ○ M – M0: No distant metastasis – M1: Distant metastasis □ M1a: Separate tumor nodule(s) in contralateral lung; tumor with pleural or pericardial nodule(s) or malignant pleural or pericardial effusion □ M1b: Single extrathoracic metastasis □ M1c: Multiple extrathoracic metastases in 1 or more organs • Grading and classification ○ Heterogeneous mixture of lepidic, acinar, papillary, micropapillary, and solid growth – Same as nonmucinous ADC in 2011 IASLC/ATS/ERS classification ○ Novel 2015 WHO classification redefined former mucinous BAC – IMA defined as former mucinous BAC in 2004 WHO classification – Often demonstrates lepidic predominant growth

Gross Pathologic & Surgical Features • Tumor appears yellowish-tan due to mucous content • Various patterns ○ Pulmonary nodule or mass ○ Consolidation ○ Diffuse pulmonary involvement – Multiple pulmonary nodules or masses – Multifocal ground-glass opacities or consolidations

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Microscopic Features • Neoplastic cells with goblet or columnar morphology ○ Abundant intracytoplasmic mucin ○ Often exhibits lepidic predominant growth (i.e., neoplastic growth along preexisting alveolar structures without stromal, vascular or pleural invasion)

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Weight loss ○ Bronchorrhea ○ Dyspnea ○ Chest pain ○ Hemoptysis ○ Fever ○ Cough

Demographics • < 10% of resected ADCs

Natural History & Prognosis • Slow growth of localized form • Aerogenous spread of multinodular form • Prognosis and survival ○ Patients with resected IMA demonstrate disease-free survivals somewhere between those with low-grade (lepidic predominant) nonmucinous ADC and those with intermediate-grade (acinar or papillary predominant) nonmucinous ADC • Factors related to mitigating disease-free survival ○ Large tumor size and higher maximum standardized uptake value • Large tumor size is predictor of reduced overall survival

Treatment • Localized tumor (single nodule/mass or consolidation) ○ Surgical resection – Sublobar resection, lobectomy, bilobectomy, or pneumonectomy • Multinodular form: Chemotherapy

DIAGNOSTIC CHECKLIST Consider • IMA in patients with chronic multiple pulmonary nodules/masses or multifocal ground-glass opacities &/or consolidations on HRCT/CT

Image Interpretation Pearls • Importance of correlation between FDG PET/CT and HRCT/CT given morphologic-metabolic dissociation

SELECTED REFERENCES 1.

2.

3.

Lee HY et al: Prognosis in resected invasive mucinous adenocarcinomas of the lung: related factors and comparison with resected nonmucinous adenocarcinomas. J Thorac Oncol. 11(7):1064-73, 2016 Travis WD et al: International association for the study of lung cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 6(2):244-85, 2011 Lee HY et al: Mucinous versus nonmucinous solitary pulmonary nodular bronchioloalveolar carcinoma: CT and FDG PET findings and pathologic comparisons. Lung Cancer. 65(2):170-5, 2009

Invasive Mucinous Adenocarcinoma (Diffuse) Neoplasms

(Left) Axial CECT of a 91-yearold woman with invasive mucinous adenocarcinoma shows multifocal bilateral pulmonary consolidations ﬉ and lung nodules ﬈. (Right) Coronal CECT of the same patient shows multifocal bilateral consolidations ﬈. The findings may mimic those of infectious or inflammatory diseases. Invasive mucinous adenocarcinoma was formerly known as mucinous bronchioalveolar carcinoma, a term that is no longer used.

(Left) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows welldifferentiated tall columnar cells ﬉ growing along alveolar septa with abundant intraalveolar mucin and preserved alveoli ﬈ filled with mucus contents. "Mass effect” is caused by mucus lakes distending alveolar spaces. (Right) Photograph of a gross specimen of invasive mucinous adenocarcinoma demonstrates a pulmonary mass ﬈ with yellowish-tan color due to mucous content.

(Left) Axial CECT of a patient with invasive mucinous adenocarcinoma shows a lowattenuation polylobular masslike consolidation ﬈ in the left lower lobe. The lesion exhibits the CT angiogram sign reflecting pulmonary vessels ﬉ traversing consolidated lung parenchyma without lung destruction on CECT. (Right) Photograph of the gross specimen of an invasive mucinous adenocarcinoma demonstrates an ivory-colored lesion indicating the mucincontaining nature of the neoplasm.

213

Neoplasms

Lymphangitic Carcinomatosis KEY FACTS

• Lymphangitic carcinomatosis (LC) • Tumor infiltration of lymphatic channels secondary to tumor emboli or direct spread from affected lymph nodes • Majority of LC cases secondary to adenocarcinoma • LC may be unilateral (50%), bilateral, focal, diffuse, symmetric or asymmetric ○ Unilateral LC is most frequent in lung cancer

IMAGING • Radiography ○ Normal chest radiograph (~ 50%) ○ Involvement of peripheral interstitium (subpleural and interlobular septal thickening) ○ Involvement of axial interstitium (peribronchovascular thickening) • HRCT ○ Nodular or smooth thickening of interlobular, peribronchovascular, and centrilobular interstitium

(Left) Graphic illustrates the classic perilymphatic distribution of lymphangitic carcinomatosis involving lymphatic channels in both the peripheral ﬉ and axial ﬊ interstitium. Pleural effusions ﬈ and lymphadenopathy are also common. (Right) PA chest radiograph of a 45-year-old man with lung adenocarcinoma shows the primary lung mass ﬊, mediastinal and hilar lymphadenopathy ﬈, and bilateral reticular opacities. Given the clinical context, the findings are suspicious for lymphangitic carcinomatosis.

(Left) Axial CECT of the same patient shows the left upper lobe primary lung cancer ﬊, nodular interlobular septal thickening ﬉, and peribronchial cuffing ﬈, consistent with lymphangitic carcinomatosis. (Right) Lowpower photomicrograph (H&E stain) of a specimen from a patient with squamous cell lung cancer and lymphangitic carcinomatosis shows small tumor foci involving lymphatic channels in the centrilobular ﬈, interlobular ﬉, and subpleural ﬊ interstitium, which correlate with the typical HRCT abnormalities.

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○ Preserved secondary pulmonary lobule architecture ○ Ancillary findings – Metastatic pulmonary nodules, ground-glass opacities (pulmonary edema or superimposed infection), lymphadenopathy, pleural effusion

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES • • • • •

Pulmonary edema Sarcoidosis Idiopathic pulmonary fibrosis Silicosis Pulmonary alveolar proteinosis

CLINICAL ISSUES • Dyspnea and cough (most common symptoms) • LC is marker of disseminated disease and poor survival

DIAGNOSTIC CHECKLIST • Clinical history of intra- or extrathoracic adenocarcinoma

Lymphangitic Carcinomatosis

Abbreviations • Lymphangitic carcinomatosis (LC)

Synonyms • Lymphangitic spread • Interlobular interstitium = interlobular septa ○ Thick interlobular interstitium = septal lines = interlobular septal thickening

Definitions • Tumor infiltration of lymphatic channels from tumor emboli (common) or direct retrograde spread from affected hilar lymph nodes • LC results primarily from adenocarcinomas ○ Lung ○ Breast ○ Other: Stomach, colon, pancreas, prostate • Involvement of lymphatic channels within interlobular and subpleural interstitium (i.e., peripheral interstitium) &/or central lymphatic channels within bronchovascular and centrilobular interstitium (i.e., axial interstitium)

IMAGING

– Centrilobular branching and Y-shaped opacities (center of SPL) ○ Preserved SPL architecture ○ Ancillary findings – Metastatic pulmonary nodules – Ground-glass opacities secondary to associated pulmonary edema or superimposed infection – Mediastinal &/or hilar lymphadenopathy – Pleural effusion (50%) – Visualization of primary lung or breast cancer – Metastatic disease

Nuclear Medicine Findings • PET/CT ○ ↑ FDG uptake in areas involved by LC – Patterns □ Segmental □ Lobar □ Diffuse ○ Focal LC adjacent to primary lung cancer may be missed on PET/CT • V/Q scan ○ Perfusion defects have been described as secondary to LC or tumor microemboli

General Features

Imaging Recommendations

• Best diagnostic clue ○ Nodular or smooth interstitial thickening • Location ○ Unilateral (50%), bilateral, focal, diffuse, symmetric or asymmetric – Unilateral involvement is most common in lung cancer • Size ○ Variable degree of interstitial thickening • Morphology ○ Smooth or nodular

• Best imaging tool ○ HRCT

Radiographic Findings • Radiography ○ Normal chest radiograph (~ 50%) ○ Involvement of peripheral interstitium – Kerley B lines (septal lines) – Fissural thickening ○ Involvement of axial interstitium – Diffuse reticular or reticulonodular opacities – Peribronchial cuffing ○ Distribution – Unilateral: Focal, diffuse – Bilateral: Symmetric or asymmetric ○ Ancillary findings – Pleural effusion (50%) – Mediastinal &/or hilar lymphadenopathy (20-50%)

CT Findings • HRCT ○ Nodular or smooth thickening of interlobular, peribronchovascular, &/or centrilobular interstitium – Polygonal arcades [septal thickening outlining secondary pulmonary lobule (SPL)] – Fissural thickening – Thick bronchovascular bundles

Neoplasms

TERMINOLOGY

DIFFERENTIAL DIAGNOSIS Pulmonary Edema • Acute onset • Cardiomegaly • Smooth basilar-predominant interlobular sepal thickening (Kerley B lines) • Peribronchial (peribronchovascular) cuffing • Airspace opacities with gravitational and central distribution • Bilateral pleural effusions

Sarcoidosis • Multisystem granulomatous disease with eye and skin lesions (erythema nodosum, plaques, or scars) • Lung involvement ○ Bilateral involvement is typical – Small perilymphatic micronodules □ Centrilobular micronodules □ Fissural nodules (highly specific) – Large nodules, masses, or areas of consolidation – Upper-mid lung zones – Architectural distortion (late stage) ○ Lymphadenopathy – Bilateral hilar (90%) and right paratracheal (60%) – Left paratracheal and aortopulmonary window (common) – Partially calcified lymph nodes (3-20%) □ May exhibit eggshell calcification

Idiopathic Pulmonary Fibrosis • Slow progression • Reticular opacities 215

Neoplasms

Lymphangitic Carcinomatosis • • • •

Honeycomb lung and architectural distortion Subpleural, apicobasilar gradient Traction bronchiectasis/bronchiolectasis Nodular septal thickening and pleural effusion (uncommon)

Silicosis

Diagnosis

• Occupational lung disease • Perilymphatic nodules ○ Diffuse distribution with upper lobe and posterior predominance • Multiples nodules/masses ○ Conglomerate masses: Progressive massive fibrosis • Abnormal lymph nodes ○ Enlarged or normal-sized ± eggshell calcification

• Characteristic imaging findings in setting of malignancy • In absence of known primary malignancy or if there is need for confirmation ○ Biopsy (transbronchial or open) ○ Additional diagnostic procedures – Sputum cytology – Pleural fluid cytology

Alveolar Proteinosis • Idiopathic in 90% of cases • May be associated with silica exposure, infection, and lymphatic malignancies • Crazy-paving pattern ○ Patchy distribution ○ Ground-glass opacities ○ Smooth septal thickening • Consolidation

PATHOLOGY General Features • Etiology ○ Frequent form of tumor spread found in 33-50% of patients with solid malignancy at autopsy ○ Common primary malignancies – Lung – Breast – Stomach – Pancreas – Prostate ○ Majority of cases result from hematogeneous dissemination to small pulmonary arterioles with subsequent interstitial and lymphatic invasion – Lymphadenopathy often absent ○ Less frequently from extrathoracic tumors metastatic to mediastinal and hilar lymph nodes with retrograde spread along lymphatic channels into lungs – Lymphadenopathy usually present ○ Primary lung cancer may directly invade pulmonary lymphatics ○ Typical histology: Adenocarcinoma

Staging, Grading, & Classification • Variable thickening of interlobular and peribronchovascular interstitium ○ Septal thickening secondary to – Desmoplastic reaction – Edema – Tumor cells within interstitium and lymphatic spaces

Gross Pathologic & Surgical Features • Delineation of central and peripheral interstitium by tumor infiltration • Polygonal arcades: SPL outlined by thick interlobular septa 216

• Tumoral thickening of bronchovascular and centrilobular interstitium • Lung biopsy (transbronchial or open) is preferred diagnostic tool

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Dyspnea and cough (most common) ○ Weight loss ○ Fatigue ○ Hemoptysis ○ Symptoms often occur before imaging abnormalities

Demographics • Incidence ↑ with age • Same as age of initial manifestation of primary tumor

Natural History & Prognosis • LC is marker of disseminated disease ○ Affected patients have poor survivals • Survival at 6 months ~ 15%

Treatment • Systemic chemotherapy to treat primary malignancy • General support measures

DIAGNOSTIC CHECKLIST Consider • LC in patients with reticular opacities, nodular interlobular septal thickening, pulmonary nodules, and lymphadenopathy

Image Interpretation Pearls • Presence of nodular interlobular septal thickening should always be concerning for LC ○ Must be differentiated from sarcoidosis

Reporting Tips • Clinical history of intra- or extrathoracic adenocarcinoma

SELECTED REFERENCES 1. 2. 3.

4.

Charest M et al: Prognostic implication of the lymphangitic carcinomatosis pattern on perfusion lung scan. Can Assoc Radiol J. 63(4):294-303, 2012 Prakash P et al: FDG PET/CT in assessment of pulmonary lymphangitic carcinomatosis. AJR Am J Roentgenol. 194(1):231-6, 2010 Digumarthy SR et al: Fluorodeoxyglucose positron emission tomography pattern of pulmonary lymphangitic carcinomatosis. J Comput Assist Tomogr. 29(3):346-9, 2005 Johkoh T et al: CT findings in lymphangitic carcinomatosis of the lung: correlation with histologic findings and pulmonary function tests. AJR Am J Roentgenol. 158(6):1217-22, 1992

Lymphangitic Carcinomatosis Neoplasms

(Left) Axial CECT of a 55-yearold man with advanced gastric cancer demonstrates diffuse bilateral nodular thickening of interlobular septa ﬈ consistent with lymphangitic carcinomatosis. In patients with extrapulmonary malignancies, lymphangitic carcinomatosis tends to be bilateral and diffuse. (Right) Axial fused FDG PET/CT of a 60-year-old woman with lymphangitic carcinomatosis shows FDG uptake along thickened peribronchovascular interstitium ſt. Lymphangitic carcinomatosis typically exhibits FDG avidity.

(Left) PA chest radiograph of a 57-year-old woman with breast cancer and lymphangitic carcinomatosis shows right upper lobe reticular opacities ﬈ and bilateral hilar lymphadenopathy ﬊. (Right) Axial CECT of the same patient shows thickening of the peribronchovascular (axial) interstitium ﬈. Lymphangitic carcinomatosis may be segmental, lobar, or diffuse. Unilateral lymphangitic spread is particularly common in advanced lung cancer.

(Left) Axial HRCT of a 62-yearold man with lymphangitic carcinomatosis shows a primary lung cancer ﬊ and interlobular septal thickening ﬈ outlining secondary pulmonary lobules and producing so-called polygonal arcades. Pleural effusion ﬉ is seen in up to 50% of cases of lymphangitic carcinomatosis. (Right) Coronal HRCT of the same patient shows nodular thickening of the minor fissure ﬉ and polygonal arcades ﬈ consistent with involvement of the subpleural and interlobular interstitium, respectively.

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Neoplasms

Hematogenous Metastases KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Distant spread of cancer hematogenously to lung

• Multiple pulmonary nodules ○ Granulomas ○ Infection ○ Arteriovenous malformations (AVMs) ○ Granulomatosis with polyangiitis • Chronic consolidation ○ Adenocarcinoma ○ Organizing pneumonia

IMAGING • Lung most common site of metastases: 50% at autopsy • Radiography ○ Multiple well-defined lung nodules/masses ○ Variably sized: Miliary to "cannonball" ○ Preferential involvement of lung bases and periphery • CT ○ Highly sensitive (> 90%) for nodules ○ Multifocal, well-defined lung nodules/masses ○ Most metastases in outer 1/3 of lung ○ Hematogenous nodules often exhibit feeding artery ○ Halo sign typical of hemorrhagic metastases ○ Beaded, enlarged vessels and branching opacities suggest tumor emboli

(Left) Graphic shows typical morphologic features of hematogenous pulmonary metastases characterized by multifocal pulmonary nodules of various sizes predominantly affecting the peripheral lower lung zones. (Right) PA chest radiograph of a woman with metastatic breast cancer shows innumerable mid and lower lung zone-predominant pulmonary nodules and masses. Hematogenous metastases are often lower lobe predominant due to the dominant blood flow in the lung.

(Left) Axial CECT of a 71-yearold man with renal cell carcinoma demonstrates heterogeneously enhancing lung ﬈ and osseous ﬉ metastases. Small bilateral pleural effusions are also present. (Right) Axial CECT (bone window) of a 22-yearold man with Ewing sarcoma shows calcified pulmonary ﬈, pleural ﬊, and mediastinal lymph node ﬉ metastases. Metastases that calcify include those from osteosarcoma, chondrosarcoma, thyroid carcinoma, and occasionally treated metastases.

218

CLINICAL ISSUES • Symptoms/signs: Variable; may be asymptomatic • Generally poor prognosis

DIAGNOSTIC CHECKLIST • Consider metastatic disease in differential diagnosis of multifocal lung nodules, masses, or consolidations in patients with malignancy

Hematogenous Metastases

Definitions • Distant spread of cancer hematogenously to lung

IMAGING General Features • Best diagnostic clue ○ Sharply defined, multiple pulmonary nodules • Location ○ Most common in lung bases and lung periphery ○ Lung most common site of metastases: 50% at autopsy ○ Branching opacities and peribronchovascular irregular nodules suggest tumor emboli

Radiographic Findings • Multifocal lung nodules, masses, or consolidations ○ Rarely, focal disease or solitary nodule • Variable size; well- or ill-defined borders • Preferential involvement of lower lung zones • May exhibit cavitation • Endobronchial metastases may exhibit postobstructive atelectasis or consolidation • Mediastinal/hilar lymphadenopathy &/or pleural effusion

CT Findings • Multifocal, well-defined pulmonary nodules/masses ○ Solitary metastasis: Renal cell cancer, colon cancer, breast cancer, sarcoma, melanoma • Most metastases in outer 1/3 of lung ○ 80% located within 2 cm of pleura • Vascular pattern ○ Sharply defined, variably sized, spherical lung nodules ○ Ill-defined margins in hemorrhagic metastases (choriocarcinoma, renal cell carcinoma, melanoma) – Halo sign: Nodule surrounded by ground-glass opacity ○ Preferential lower lobe involvement due to gravitational forces and dominant blood flow ○ Cavitation common in squamous cell cancers and sarcomas ○ Miliary pattern: Medullary thyroid carcinoma, melanoma, renal cell carcinoma, ovarian carcinoma ○ "Cannonball" metastases: Colorectal carcinoma, renal cell carcinoma, sarcoma, melanoma ○ Some metastases may calcify (osteosarcoma, chondrosarcoma, thyroid) and may mimic granulomas ○ Occasionally associated with spontaneous pneumothorax, especially in sarcomas ○ Hematogenous nodules often exhibit feeding artery • Endobronchial pattern ○ Bronchogenic airway seeding or hematogenous dissemination to airway wall ○ Lung, lobar, or segmental atelectasis ○ Postobstructive pneumonia: Segmental, lobar, lung ○ Adenocarcinoma, basal cell carcinoma of head/neck, breast and renal cancers, and sarcoma • Pleural pattern ○ Lymphangitic or hematogenous spread ○ Pleural effusion; may be massive, free, or loculated ○ Discrete pleural nodules/masses

• Lymphangitic pattern ○ Lymphangitic tumor spread ○ Asymmetric nodular interstitial thickening, may spare lobe(s) ○ May be associated with small pleural effusions &/or hilar or mediastinal lymphadenopathy • Consolidation pattern ○ Hematogenous spread ○ Mimics pneumonia, peripheral consolidation with airbronchograms ○ Lepidic growth of adenocarcinoma • Tumor embolus pattern ○ Hematogenous spread ○ Beaded, enlarged vessels or irregular, nodular opacities along bronchovascular structures ○ Vascular or branching lesion morphology ○ Pulmonary infarction • Lymph node involvement: Mediastinal or hilar mass ○ Hematogenous or lymphangitic spread ○ Common in genitourinary (prostate, renal, ovarian, testicular, transitional cell), head/neck, breast cancers and melanoma

Neoplasms

TERMINOLOGY

Nuclear Medicine Findings • PET/CT ○ Highly sensitive (> 90%) for nodules and findings of metastatic disease

Imaging Recommendations • Best imaging tool ○ PET/CT most sensitive examination; optimally characterizes pattern and extent of disease

DIFFERENTIAL DIAGNOSIS Multiple Pulmonary Nodules • Granulomas ○ Often exhibit benign patterns of calcification ○ Associated with calcifications in spleen &/or liver ○ Bone-forming primary tumor metastases may mimic granulomas • Infection ○ Miliary tuberculosis, viral pneumonia ○ Septic emboli often cavitate • Arteriovenous malformations (AVMs) ○ Feeding arteries and draining veins • Granulomatosis with polyangiitis ○ Usually cavitary ○ May be associated with subglottic stenosis and pulmonary hemorrhage

Endobronchial Mass • Lung cancer ○ Associated with regional lymphadenopathy ○ More common than endobronchial metastasis ○ Smoking history • Broncholith ○ Calcified endobronchial nodule • Foreign body ○ Most common endobronchial lesion in children

219

Neoplasms

Hematogenous Metastases Interstitial Lung Disease

Gross Pathologic & Surgical Features

• Sarcoidosis ○ Perilymphatic micronodules ○ Frequent lymphadenopathy ○ Miliary nodules described • Silicosis ○ May exhibit multiple pulmonary nodules • Scleroderma and other collagen vascular diseases ○ Septa smooth, not beaded ○ Associated bone changes (rheumatoid arthritis) or esophageal dilatation (scleroderma)

• Lepidic growth (typical of adenocarcinoma) ○ Distal arteriole seeding, growth in interstitium and alveoli ○ No architectural distortion ○ Tumor uses lung as scaffolding to grow • Hilic growth (typical of hematogenous metastases) ○ Expansile growth ○ Concentric enlargement of lesion to form solid nodule or mass

Chronic Consolidation

• Tumor cells invade draining venules, enter venous circulation • Typical behavior of primary neoplasm

• Adenocarcinoma ○ Septa usually not involved ○ Lobular ground-glass pattern in multiple lobes coalescing to frank consolidation • Organizing pneumonia ○ Subpleural basilar distribution • Pulmonary alveolar proteinosis ○ Geographic distribution of ground-glass opacities, interlobular and intralobular lines (crazy-paving pattern)

Primary Malignancies • Lung cancer ○ Large solitary mass, may obstruct airways and vascular structures • Lymphoma ○ Multifocal pulmonary nodules ± lymphadenopathy ○ Common in patients with human immunodeficiency virus (HIV)

Pulmonary Embolus • Transient, acute symptoms • Does not produce beaded vessel appearance

Pulmonary Artery Sarcoma • Common location in pulmonary trunk • Solitary, not multiple

PATHOLOGY General Features • Etiology ○ Pathology reflects metastatic route ○ Metastatic models – Mechanical anatomic model: Metastases filtered in 1st draining organ, commonly lung – Environmental model: Metastases preferentially find target sites due to favorable molecular or cellular environments, "seed and soil" hypothesis ○ Most likely extrathoracic malignancies: Breast, colon, uterine ○ Highest rate of lung metastases: Choriocarcinoma, osteosarcoma, testicular tumors, melanoma • Associated abnormalities ○ Frequent lytic or sclerotic skeletal metastases depending on tumor extent and cell type

Staging, Grading, & Classification • Generally regarded as stage IV for most tumor staging 220

Microscopic Features

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Variable, depends on pattern of spread ○ May be asymptomatic

Demographics • Age ○ Any age, but more common in adults • Epidemiology ○ Metastasis most common lung neoplasm ○ Pleural pattern typical of adenocarcinoma, especially lung and breast ○ Consolidation pattern typical of gastrointestinal adenocarcinoma and lymphoma ○ Tumor embolus pattern typical of hepatocellular carcinoma, breast carcinoma, renal cell carcinoma, choriocarcinoma, and angiosarcoma ○ Endobronchial pattern typical of adenocarcinoma (consolidation), basal cell carcinoma of head and neck (endobronchial)

Natural History & Prognosis • Generally poor, but depends on treatments available for primary tumor type

Treatment • Depends on histology of primary neoplasm; generally palliative radiation or chemotherapy • If lung only site, consider metastasectomy, especially if interval from primary resection to metastases > 1 month ○ Resection of osteosarcoma, solitary, and slow-growing metastases • Percutaneous ablation promising palliative therapy

DIAGNOSTIC CHECKLIST Consider • Metastatic disease in differential diagnosis of multifocal lung nodules, masses, or consolidations in patients with malignancy

SELECTED REFERENCES 1.

Eckardt J et al: Thoracoscopic versus open pulmonary metastasectomy: a prospective, sequentially controlled study. Chest. 142(6):1598-602, 2012

Hematogenous Metastases Neoplasms

(Left) PA chest radiograph of a patient with metastatic lung adenocarcinoma demonstrates innumerable bilateral, tiny pulmonary nodules consistent with miliary pulmonary metastases. (Right) Axial CECT of the same patient shows multiple tiny pulmonary nodules consistent with hematogenous spread of adenocarcinoma. The primary lung adenocarcinoma ﬈ is also visible. Common extrathoracic primary malignancies causing miliary metastases include medullary thyroid carcinoma, renal cell carcinoma, and melanoma.

(Left) Axial NECT of a woman with metastatic choriocarcinoma shows multiple solid pulmonary metastases ﬈ with surrounding ground-glass opacity halos consistent with perilesional hemorrhage. Hemorrhagic metastases may produce the so-called CT halo sign. (Right) Axial CECT of a 47-year-old man with papillary thyroid cancer shows partially calcified pulmonary ﬈ and right hilar/infrahilar lymph node ﬊ metastases. Calcified pulmonary metastases may exhibit varying degrees of calcification.

(Left) Axial CECT of a 41-yearold woman with breast cancer demonstrates a right pleural effusion ﬈ and nodular pleural thickening ﬉ in the right hemithorax. Pleural metastases may be due to lymphangitic or hematogenous spread of malignancy. (Right) Coronal CECT of a patient with metastatic renal cell carcinoma shows dilated and slightly beaded pulmonary arteries ﬈ in the right lower lobe consistent with intravascular tumor emboli.

221

Neoplasms

Endovascular Metastases and Tumor Emboli KEY FACTS

TERMINOLOGY

CLINICAL ISSUES

• Tumor thrombi/fragments embolized into pulmonary arteries

• Tumor thrombus less likely to respond to fibrinolysis and anticoagulation • May result in pulmonary hypertension, right heart strain, and possibly death • Extensive microscopic tumor emboli may cause pulmonary tumor thrombotic microangiopathy (PTTM)

IMAGING • Dilated &/or beaded peripheral pulmonary arteries ○ May increase over time • Tree-in-bud nodules less common • CECT: Modality of choice for detection of endovascular metastases and tumor emboli • MR and PET/CT ○ Characterization of larger emboli ○ Potential to differentiate bland from tumor thrombus

TOP DIFFERENTIAL DIAGNOSES • • • •

Bland venous thromboembolism Pulmonary artery sarcoma Mucus plugging Vascular invasion by tumor

(Left) Axial CECT of a patient with renal cell carcinoma shows focal dilatation of a left upper lobe pulmonary artery branch ﬈ adjacent to a normal air-filled bronchus ﬉, suggestive of endovascular metastasis. (Right) Axial CECT of the same patient obtained 1 year later shows increased dilatation and new beading of the same left upper lobe peripheral pulmonary artery branch ﬈, consistent with endovascular metastasis. The lesion now extends to and involves the adjacent bronchus with resultant narrowing of its air-filled lumen ﬉.

(Left) Axial NECT of a 57-yearold woman with pancreatic adenocarcinoma and tumor embolism shows subpleural tree-in-bud nodules bilaterally ﬈. (Right) High-power photomicrograph (H&E stain) of a specimen from the same patient shows significant tumor burden within a pulmonary artery with resultant marked compression of the vessel lumen ﬊. Although both benign and malignant neoplasms can embolize, most cases are due to the former.

222

DIAGNOSTIC CHECKLIST • Growth of endovascular lesions supports diagnosis of endovascular metastases and tumor emboli • Diagnosis of tumor emboli should prompt search for primary malignancy, unless already known ○ Evaluate right atrium and inferior vena cava for intravascular extension of subdiaphragmatic malignancy • Diagnosis of tumor emboli should prompt assessment for pulmonary hypertension and right ventricular strain ○ Assess for cardiopulmonary compromise: Atelectasis, infarction, edema, pleural/pericardial effusion

Endovascular Metastases and Tumor Emboli

Synonyms • Tumor thrombus

Definitions • Tumor fragments embolized into pulmonary arteries

IMAGING General Features • Best diagnostic clue ○ CT – Dilated and beaded peripheral pulmonary arteries □ Tree-in-bud nodules less common □ Beading and dilatation increase over time • Location ○ Peripheral > central • Size ○ Millimeters to centimeters: Increase in size over time • Morphology ○ Dilatation and beading of peripheral pulmonary arteries ○ Tree-in-bud nodules (enlarged centrilobular arteries)

Radiographic Findings • Nodular and tubular opacities in vascular distribution ○ May develop rapidly, increase in size over time – Multifocal > localized – Bilateral > unilateral • Peripheral subpleural wedge-shaped opacity suggests pulmonary infarction ○ Lower lobe location most common • Associated pulmonary artery enlargement should suggest pulmonary hypertension

CT Findings • NECT ○ Dilated &/or beaded pulmonary artery branches (adjacent to normal air-filled bronchi) – Subsegmental > segmental > lobar > main pulmonary artery branches – Dilatation/beading increases over time – Tree-in-bud pattern: Tumor emboli in centrilobular arterioles • CECT ○ Nodular filling defects in beaded pulmonary artery branches – Subsegmental > segmental > lobar > main pulmonary artery branches – Increase in size over time – May exhibit contrast enhancement ○ Endoluminal nodule/mass within inferior vena cava/right cardiac chambers from endovascular extension of abdominal neoplasm – May exhibit contrast enhancement – May be associated with bland thrombus – Evaluation of associated intraabdominal neoplasm ○ Centrilobular nodules and tree-in-bud opacities • CTA ○ CT pulmonary angiography for optimal evaluation of pulmonary artery filling defects

MR Findings • T1WI C+ ○ Endoluminal filling defect best demonstrated after contrast administration ○ Assessment of cardiac chambers and pulmonary arteries • Delayed enhancement ○ Endovascular tumor may exhibit delayed contrast enhancement – May allow differentiation of tumor emboli from bland thrombus

Neoplasms

TERMINOLOGY

Angiographic Findings • Pruning of 3rd- to 5th-order vessels • Delayed filling of segmental arteries • Subsegmental endovascular filling defects

Nuclear Medicine Findings • Bone scan ○ Tumor emboli from sarcoma may demonstrate Tc-99m MDP uptake • PET/CT ○ Tumor emboli demonstrate more FDG uptake than bland venous thromboemboli – FDG uptake often linear • V/Q scan ○ Reduce dose of macroaggregated albumin to 100,000200,000 particles in patients with pulmonary hypertension ○ Especially useful for patients with normal CT and suspected microvascular disease – Multiple subsegmental mismatched defects

Imaging Recommendations • Best imaging tool ○ CECT: Modality of choice for evaluation of endovascular metastases and tumor emboli ○ MR: May be used in patients with contraindications to iodinated contrast • CECT: Optimal evaluation of pulmonary vasculature ○ Time contrast bolus to assess vessels of interest (i.e., pulmonary embolism protocol) ○ Consider evaluating lower extremities for presence of deep venous thrombosis – Combine with CECT or evaluate with US • MR: Subtracted images are best for demonstrating tumor enhancement • Image review ○ Wide window settings (window width 600 HU; window level 100-150 HU) to detect endovascular filling defects ○ Multiplanar reformatted images to determine location within pulmonary artery

DIFFERENTIAL DIAGNOSIS Bland Venous Thromboembolism • Differentiation from tumor emboli ○ Less (or no) FDG uptake on PET/CT ○ Much more common than tumor emboli • Bland pulmonary emboli shrink over time, whereas tumor emboli may increase in size

223

Neoplasms

Endovascular Metastases and Tumor Emboli

• Typically affects central pulmonary arteries • Endovascular filling defect, may appear lobulated

Mucus Plugging • Occluded airways exhibit tubular or branching tubular morphology • May be traced to proximal patent airways on multiplanar reformatted images

Vascular Invasion by Tumor • Dominant extravascular mass contiguous with endovascular filling defect

Lymphangitic Carcinomatosis • Lymphangitic spread of tumor • Smooth &/or beaded interlobular septal thickening

Parenchymal Pulmonary Metastases • Hematogenous metastases • May occur distal to adjacent feeding vessel but are parenchymal in location

Diseases Resulting in Tree-in-Bud Pattern • Typically small airways disease (cellular bronchiolitis) ○ e.g., infectious, aspiration, or follicular bronchiolitis • Vascular tree-in-bud (less common) ○ Microangiopathic arteriolar disease ○ Talc or cellulose granulomatosis (otherwise called excipient lung disease)

PATHOLOGY General Features • Embolization of tumor cells into pulmonary artery branches ○ Both benign and malignant tumors can embolize

Staging, Grading, & Classification • Microscopic tumor emboli ○ More common – 2.5% of patients in autopsy studies had microscopic tumor emboli ○ Extensive microscopic tumor emboli result in pulmonary tumor thrombotic microangiopathy (PTTM) ○ Tumor in secondary pulmonary lobule arterioles – Carcinomatous endarteritis • Macroscopic tumor emboli ○ Less common; may invade vessel wall ○ Proximal to subsegmental pulmonary artery branches – Dilated and beaded vessel sign

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Progressive shortness of breath and cough ± chest pain ○ Slowly progressive signs of pulmonary hypertension ○ May be asymptomatic • Other signs/symptoms ○ Hypoxemia ○ Tachycardia • Clinical profile ○ Patient with known or unknown malignancy 224

– Typically breast, lung, prostate, colon, stomach, liver, and kidney cancers – Melanoma, pancreatic cancer, and sarcoma also reported

Pulmonary Artery Sarcoma

Natural History & Prognosis • Associated with progression of underlying malignancy • Pulmonary hypertension • May lead to death ○ Extensive microscopic tumor emboli may result in PTTM

Treatment • Fibrinolysis and anticoagulation • In patients with massive tumor emboli &/or contraindications to anticoagulation ○ Aspiration thrombectomy, thrombus fragmentation, and rheolytic thrombectomy • Risks and complications ○ Hemorrhage ○ Refractory emboli

DIAGNOSTIC CHECKLIST Image Interpretation Pearls • Tumor emboli should prompt search for occult primary malignancy ○ Evaluate right atrium and inferior vena cava for intravascular extension of subdiaphragmatic malignancy – Hepatocellular, renal, and adrenocortical carcinomas • Diagnosis of tumor emboli should prompt assessment for pulmonary hypertension ○ Pulmonary trunk > 29 mm ○ Signs of right ventricular strain – Bowing of interventricular septum toward left ventricle – Ratio of right ventricle diameter to left ventricle diameter > 1 – Reflux of contrast into inferior vena cava and hepatic veins • Evaluate for additional features of cardiopulmonary compromise ○ Atelectasis, pulmonary infarct, pulmonary edema, pleural or pericardial effusions

Reporting Tips • Comment on signs of concurrent cardiopulmonary compromise • Prompt communication of findings to clinical staff to raise awareness of potential impending hemodynamic instability

SELECTED REFERENCES 1. 2. 3. 4. 5. 6.

Carter BW et al: Acquired abnormalities of the pulmonary arteries. AJR Am J Roentgenol. 202(5):W415-21, 2014 Sharma P et al: Imaging thrombus in cancer patients with FDG PET-CT. Jpn J Radiol. 30(2):95-104, 2012 Rossi SE et al: Tree-in-bud pattern at thin-section CT of the lungs: radiologicpathologic overview. Radiographics. 25(3):789-801, 2005 Daehee Han et al: Thrombotic and Nonthrombotic Pulmonary Arterial Embolism: Spectrum of Imaging Findings RadioGraphics. 23: 1521, 2003 Roberts KE et al: Pulmonary tumor embolism: a review of the literature. Am J Med. 115(3):228-32, 2003 Seo JB et al: Atypical pulmonary metastases: spectrum of radiologic findings. Radiographics. 21(2):403-17, 2001

Endovascular Metastases and Tumor Emboli Neoplasms

(Left) Coronal CECT of a 45year-old woman with metastatic renal cell carcinoma demonstrates numerous dilated pulmonary artery branches ﬈ resulting from extensive bilateral tumor emboli. (Right) Axial CECT of a patient with hepatocellular carcinoma shows direct intrathoracic tumor extension manifesting as a mass-like right atrial filling defect ﬉. A bland pulmonary embolus is shown in a left lower lobe pulmonary artery ﬇.

(Left) Axial CECT (lung window) of a 41-year-old woman with metastatic osteosarcoma demonstrates a beaded appearance of right lower lobe pulmonary arteries ﬈ with alternating regions of dilatation and constriction. (Right) Axial CECT (soft tissue window) of the same patient demonstrates mild enhancement ﬉ of tumor thrombus occluding the right lower lobe pulmonary arteries ﬈. CECT is the imaging modality of choice for the evaluation of endovascular metastases and tumor emboli.

(Left) Axial CECT of a 52-yearold woman with metastatic renal cell carcinoma shows beading and dilatation of several pulmonary artery branches ﬈, which is the most common manifestation of tumor emboli. (Right) Composite image with axial FDG PET/CT through a right upper lobe peripheral pulmonary artery branch shows beading ſt associated with mild FDG uptake suggestive of endovascular metastasis. A central FDG-avid tumor mass ﬊ is incompletely visualized.

225

Neoplasms

Kaposi Sarcoma KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Kaposi sarcoma (KS) • Acquired immune deficiency syndrome with Kaposi sarcoma (AIDS-KS) • Iatrogenic Kaposi sarcoma (IKS) • Low-grade mesenchymal neoplasm of blood and lymphatic vessels, primarily affecting skin

• • • •

IMAGING • AIDS-KS ○ Nodules – Flame-shaped, > 1 cm in diameter – Peribronchovascular with tendency to coalesce – CT halo sign ○ Peribronchovascular and interlobular septal thickening ○ Fissural nodularity ○ Lymphadenopathy: Mediastinal, hilar, axillary ○ Pleural effusions (common)

(Left) Graphic shows typical morphologic features of pulmonary Kaposi sarcoma (KS) with tumor infiltrating along bronchovascular bundles and extending from the hilum to the lung periphery. (Right) Axial CECT shows poorly marginated nodules (some with groundglass opacity halos) with a peribronchovascular distribution, the so-called flame-shaped appearance, a classic manifestation of AIDSKS. While infection is more likely, KS should be considered in this demographic when such imaging findings are present.

(Left) AP chest radiograph of a patient with AIDS-KS shows diffuse perihilar ill-defined opacities and thickened interlobular septa resembling the appearance of pulmonary edema. Note absence of cardiomegaly. A high index of suspicion is required to suggest the diagnosis of KS on chest radiography. (Right) Axial CECT of the same patient shows peribronchovascular airspace, ground-glass opacities, and thickened interlobular septa ﬈ as well as small bilateral pleural effusions.

226

Sarcoidosis Lymphoma Lymphangitic carcinomatosis Bacillary angiomatosis

PATHOLOGY • Human herpesvirus type 8

CLINICAL ISSUES • Symptoms/signs: Dyspnea, cough, CD4 lymphocyte count (< 150-200 cells/mm³) • Demographics ○ AIDS-KS: Homosexual/bisexual men with AIDS ○ IKS: Rare • Treatment ○ AIDS-KS: Highly active antiretroviral therapy ± chemotherapy ○ IKS: Decrease in immunosuppressive therapy

Kaposi Sarcoma

Abbreviations • Kaposi sarcoma (KS) • Acquired immune deficiency syndrome with Kaposi sarcoma (AIDS-KS): Epidemic KS • Iatrogenic Kaposi sarcoma (IKS)

Definitions • Low-grade mesenchymal neoplasm of blood and lymphatic vessels, primarily affecting skin • Can cause disseminated disease in variety of organs: Lymphatic system, lungs, airways, abdominal viscera, etc. • AIDS-KS: KS related to human immunodeficiency virus (HIV)/AIDS • IKS: KS related to immunosuppression

IMAGING General Features • Best diagnostic clue ○ AIDS-KS: Coexistence of poorly marginated peribronchovascular nodules, lymphadenopathy, and bilateral pleural effusions

MR Findings • Rarely used, but may be useful for assessment of osseous and soft tissue involvement • T1WI: Hyperintense • T2WI: Markedly reduced signal • Strong tumoral enhancement after gadolinium

Neoplasms

TERMINOLOGY

Nuclear Medicine Findings • PET/CT ○ AIDS-KS – Foci of AIDS-KS are FDG avid – Useful for detection of occult lesions – Anecdotal use in monitoring treatment response ○ IKS – FDG-avid lung nodules and lymphadenopathy • Gallium-67 and thallium scintigraphy ○ Combined approach helpful for differentiating epidemic KS from infection and lymphoma ○ Gallium-67: Negative in epidemic KS but positive in infection and lymphoma ○ Thallium: Positive in epidemic KS and lymphoma

DIFFERENTIAL DIAGNOSIS

Radiographic Findings

Pulmonary Edema

• AIDS-KS ○ Mid to lower lung zone perihilar heterogenous or reticulonodular opacities ○ Ill-defined pulmonary nodules ○ Cavitation may occur with concomitant opportunistic infection • IKS ○ Scattered, well-defined pulmonary nodules ○ Reticular or reticulonodular opacities

• Difficult differentiation from KS • History of AIDS or transplantation and presence of skin lesions may be helpful

CT Findings

Lymphoma

• AIDS-KS ○ Nodules – Bilateral, symmetric, poorly marginated, emanating from hila (flame-shaped) – Peribronchovascular with tendency to coalesce, usually > 1 cm in diameter – Ground-glass opacities surrounding nodules (CT halo sign) – Cavitary nodules often associated with opportunistic infection, such as Pneumocystis jirovecii pneumonia ○ Peribronchovascular and interlobular septal thickening ○ Fissural nodularity ○ Lymphadenopathy – Axillary, mediastinal, hilar – Often enhances with contrast ○ Pleural effusions (common) – Chylothorax has been described ○ Pleural implants (rare) ○ Osseous lytic lesions: Sternum, thoracic spine ○ Cutaneous and subcutaneous soft tissue thickening • IKS ○ Scattered pulmonary nodules ○ Lymphadenopathy ○ Pleural effusions

• Peribronchovascular thickening and lung nodules; may mimic KS • Lung nodules vary in size but are often larger than KS nodules • Air bronchograms more common in lymphoma than in KS nodules

Sarcoidosis • Thick bronchovascular bundles, lung nodules, and interlobular septal thickening (often nodular); may mimic KS • Lymphadenopathy more symmetric than that of KS, does not typically enhance

Lymphangitic Carcinomatosis • Peribronchovascular and interlobular septal thickening (often nodular); may mimic AIDS-KS • Unilateral distribution favors lymphangitic carcinomatosis from primary lung cancer over KS

Infectious Bronchiolitis • Mycobacterial and bacterial infections • Nodules < 1 cm • Centrilobular nodules, often with tree-in-bud appearance

Bacillary Angiomatosis • Rare infection due to Bartonella henselae • Skin lesions, enhancing lymph nodes, and lung nodules; may mimic KS • Peribronchovascular thickening not as common • Consider in heterosexual patients with AIDS being evaluated for AIDS-KS 227

Neoplasms

Kaposi Sarcoma

PATHOLOGY General Features • Etiology ○ Human herpesvirus type 8 (HHV8 or KS-associated herpesvirus) – Also associated with primary effusion lymphoma and multicentric Castleman disease ○ Other cofactors – Tumor necrosis factor A – Interleukin 6 – Basic fibroblast growth factor – Vascular endothelial growth factor ○ Mode of transmission not completely understood – Adult homosexual male contact (North America) – Mother-to-child and child-to-child (Africa and Southern Europe) – Reactivation may play role in IKS • Genetics ○ Classic KS – Patients of European or Mediterranean origin and Ashkenazi Jews ○ African KS – East and Central Africa – 9% of all cancer in Uganda • Associated abnormalities ○ Skin lesions present in 85% of patients with pulmonary involvement

Staging, Grading, & Classification • 4 different types ○ Classic, sporadic, or Mediterranean KS (1st described) ○ Endemic or African KS ○ AIDS-KS (most common) ○ IKS • AIDS-KS staging ○ Extent of tumor (T) – T0 (good risk): Localized tumor (e.g., KS only in skin &/or lymph nodes, small amount of disease on palate, flat lesions in mouth) – T1 (poor risk): Widespread KS □ 1 or more of following: Edema, extensive oral KS, lesions in organs other than lymph nodes □ Pulmonary KS carries poor prognosis ○ Immune status (I) – I0 (good risk): CD4 cell count ≥ 200 cells/mm³ – I1 (poor risk): CD4 cell count < 200 cells/mm³ ○ Systemic illness status (S) – S0 (good risk): No systemic illness present □ No history of opportunistic infections or thrush □ No B symptoms (e.g., unexplained fever, night sweats, weight loss, diarrhea) □ Karnofsky performance status score ≥ 70 – S1 (poor risk): Systemic illness present with 1 or more of following □ History of opportunistic infections or thrush □ 1 or more B symptoms present □ Karnofsky performance status score < 70 □ Other HIV-related illness is present, such as neurological disease or lymphoma 228

Gross Pathologic & Surgical Features • AIDS-KS ○ Skin lesions frequently absent ○ Visceral organs affected – Lymph nodes (72%), lung (51%) – Gastrointestinal tract (48%), liver (34%), spleen (27%) ○ Thorax affected in 45% of all cases

Microscopic Features • Spindle-shaped stromal cells • Abnormal endothelial lining of vascular channels • Slit-like spaces with extravasated red cells

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Dyspnea, cough ○ CD4 lymphocyte count (< 150-200 cells/mm³) • Other signs/symptoms ○ Hemoptysis

Demographics • Age ○ Classic KS: 50-80 years of age ○ African KS: 4th decade of life • Gender ○ Classic KS: M:F = 10-15:1 ○ African KS: Male predominance ○ AIDS-KS: Homosexual or bisexual male AIDS patients • Epidemiology ○ Most common AIDS-related neoplasm; decreased prevalence with highly active antiretroviral therapy (HAART)

Natural History & Prognosis • AIDS-KS indicators of shorter survival ○ White homosexual male has better survival than black female IV drug user ○ Prior or coexistent opportunistic infection ○ Systemic symptoms (e.g., unexplained fever > 2 weeks, weight loss > 10%, diarrhea, or night sweats) ○ CD4 lymphocyte count (< 100-300 cells/mm³) ○ Pleural effusion • Opportunistic infections are cause of death in 80% of patients with AIDS-KS

Treatment • AIDS-KS: HAART ± chemotherapy • IKS: Decrease in immunosuppressive therapy

DIAGNOSTIC CHECKLIST Image Interpretation Pearls • Flame-shaped nodules on CT are highly suggestive of AIDS/KS in appropriate clinical setting

SELECTED REFERENCES 1. 2.

Gasparetto TD et al: Pulmonary involvement in Kaposi sarcoma: correlation between imaging and pathology. Orphanet J Rare Dis. 4:18, 2009 Restrepo CS et al: Imaging manifestations of Kaposi sarcoma. Radiographics. 26(4):1169-85, 2006

Kaposi Sarcoma Neoplasms

(Left) PA chest radiograph of a 37-year-old man with AIDS who presented with cough demonstrates diffuse bilateral small irregular pulmonary nodules. (Right) PA chest radiograph of the same patient obtained 4 months later shows marked interval increase in the size and number of the bilateral pulmonary nodules. The disease progression corresponded with the degree of immunosuppression in this patient.

(Left) Axial CECT of the same patient demonstrates numerous irregular, poorlymarginated pulmonary nodules ﬈ in the right lung with the so-called flameshaped configuration. Bronchoscopy and biopsy revealed AIDS-KS. (Right) Axial CECT of the same patient shows smooth and nodular interlobular septal thickening ﬊ and patchy ground-glass opacities ﬈ in the right lung. Findings such as peribronchovascular &/or interlobular septal thickening and ground-glass opacities are comparatively less common.

(Left) Axial NECT of a patient with AIDS-KS and coexistent Pneumocystis pneumonia shows a cavitary right upper lobe nodule ﬊. Cavitary lesions in these patients are almost always related to superimposed infection. (Right) Axial CECT of a patient with AIDS-KS shows bilateral pleural effusions ﬈, conspicuous mediastinal ﬉ and axillary ﬉ enhancing lymph nodes, and left anterior chest wall skin thickening ﬊. All these findings are characteristic of AIDS-KS.

229

Neoplasms

Lymphangioleiomyomatosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Lymphangioleiomyomatosis (LAM) • Tuberous sclerosis complex (TSC) • LAM: Proliferation of neoplastic smooth muscle-like cells ○ Sporadic LAM (S-LAM) ○ LAM associated with tuberous sclerosis (TSC-LAM)

• • • •

IMAGING

• Neoplastic smooth muscle cell proliferation around vessels, bronchioles, alveolar walls, lymphatics, and cyst walls

• Radiography ○ Normal or increased lung volumes ○ Diffuse bilateral reticular opacities ○ Pneumothorax, pleural effusion • CT/HRCT ○ Diffuse bilateral thin-walled cysts; normal intervening lung parenchyma ○ Ground-glass opacities related to hemorrhage ○ Septal thickening related to lymphatic obstruction ○ Pneumothorax, pleural effusion ○ Lymphadenopathy, renal angiomyolipomas

(Left) PA chest radiograph of a 54-year-old woman with lymphangioleiomyomatosis who presented with chronic and progressive dyspnea shows normal lung volumes and no evidence of parenchymal disease. (Right) Axial HRCT of the same patient shows profuse bilateral air-filled thin-walled pulmonary cysts ﬈ that exhibit slight variations in size with at least 1 dominant pulmonary cyst ﬉. The cysts are uniformly distributed throughout the lungs and the intervening lung parenchyma is normal.

(Left) Axial HRCT of the same patient shows profuse bilateral thin-walled cysts ﬈ with normal intervening lung parenchyma. The cysts are uniformly distributed throughout the lungs without an apicobasal gradient. The findings are characteristic of lymphangioleiomyomatosis. (Right) High-power photomicrograph (H&E stain) of a specimen of lymphangioleiomyomatosis shows atypical smooth muscle cell proliferations ﬉ in the wall of a pulmonary cyst and foci of pulmonary hemorrhage ﬈. (From DP: Thoracic, 2e.)

230

Pulmonary Langerhans cell histiocytosis Birt-Hogg-Dubé syndrome Lymphoid interstitial pneumonia Light-chain deposition disease

PATHOLOGY

CLINICAL ISSUES • Women of childbearing age; mean age 34 years • Progressive dyspnea, chest pain, cough, wheezing, hemoptysis • Acute dyspnea and chest pain from spontaneous pneumothorax

DIAGNOSTIC CHECKLIST • Consider LAM in women with diffuse bilateral thin-walled lung cysts ± pneumothorax or pleural effusion

Lymphangioleiomyomatosis

Abbreviations • Lymphangioleiomyomatosis (LAM) • Tuberous sclerosis complex (TSC)

DIFFERENTIAL DIAGNOSIS

Definitions

Pulmonary Langerhans Cell Histiocytosis

• Proliferation of neoplastic smooth muscle-like cells ○ Sporadic LAM (S-LAM) ○ LAM associated with tuberous sclerosis (TSC-LAM) – Neurocutaneous syndrome of multiorgan hamartomas, seizures, and cognitive disorders ○ TSC-LAM is 5-10 times more common than S-LAM

• • • •

IMAGING General Features • Best diagnostic clue ○ Premenopausal woman with diffuse thin-walled lung cysts, spontaneous pneumothorax, &/or chylothorax • Location ○ Diffuse bilateral lung involvement • Size ○ Cysts 2-5 mm, may be as large as 30 mm; may coalesce

Radiographic Findings • • • •

Normal or hyperinflated lungs Diffuse bilateral reticular opacities; no zonal predominance Pneumothorax Pleural effusion (chylous) in 10-20%; unilateral or bilateral

CT Findings • Diffuse bilateral thin-walled cysts; normal intervening lung ○ Typically 2-5 mm cysts; large and dominant cysts occur ○ Spherical or ovoid cysts; polygonal cysts in severe disease ○ Perceptible smooth thin cyst walls ○ Initially mild lung involvement; profuse and severe with disease progression • Ground-glass opacities related to hemorrhage • Septal thickening related to lymphatic obstruction • Multifocal micronodular pneumocyte hyperplasia: Solid or ground-glass nodules (1-10 mm); reported in women with S-LAM • Pneumothorax, pleural effusion (chylous), hydropneumothorax • Thoracic duct enlargement • Pericardial effusion (chylous) • Lymphadenopathy: Thorax, abdomen, pelvis • Lymphangioleiomyomas: Thorax, abdomen, pelvis ○ Encapsulated masses with cystic components • Renal angiomyolipomas (AML) in 32% of S-LAM • Other: Hepatic/splenic AML, ascites (chylous)

Imaging Recommendations • Best imaging tool ○ CT/HRCT more sensitive than radiography • Protocol advice ○ Coronal reformations confirm diffuse lung involvement • Screening recommendations (CT) ○ Women with TSC: Once after age 18; every 5-10 years ○ Young/middle-aged nonsmoking women with pneumothorax

Neoplasms

○ Women with incidental AML, basilar lung cysts on abdomen CT, or chylous pleural effusion/ascites ○ Women with unexplained progressive dyspnea

TERMINOLOGY

M = F; smokers Upper lung zone predominant involvement Small cysts, bizarre shapes, nodular cyst walls Small irregular lung nodules (≤ 10 mm)

Birt-Hogg-Dubé Syndrome • Inherited disorder: Lung cysts, renal and skin lesions • Basilar predominant cysts: Round, ovoid, lentiform • Cysts abut pleura, septa, and vessels

Lymphoid Interstitial Pneumonia • Adult women; 50-60 years of age • Immunosuppression, Sjögren syndrome • Few large cysts, ground-glass opacities, poorly defined nodules

Light-Chain Deposition Disease • Association with lymphoproliferative disorders • Light-chain deposition in alveolar walls, small airways, and vessels • Diffuse lung cysts of variable sizes

Centrilobular Emphysema • Males and females; smokers • Upper lobe predominant involvement • Centrilobular lucencies with imperceptible walls; visualization of central lobular artery

PATHOLOGY General Features • Etiology ○ Classified as low-grade malignant neoplasm by World Health Organization – LAM cells may metastasize via lymphatics • Genetics ○ Growth activating mutations in TSC genes – Inactivation of tumor suppressor genes ○ S-LAM: Acquired mutations in TSC2 gene confined to LAM lesions ○ TSC: Inherited autosomal dominant disorder – Genetic and acquired mutations in TSC1 (encodes hamartin) or TSC2 (encodes tuberin) genes in all cells – TSC-LAM: ~ 40% of women and 15% of men with TSC • Associated abnormalities ○ Chylous ascites ○ Renal, hepatic, splenic AMLs ○ Abdominal and pelvic lymphangioleiomyomas ○ Uterine leiomyomas, lymphaticoureteric and lymphaticovenous communications • Epidemiology ○ S-LAM prevalence: 1-7.5/1 million women

Staging, Grading, & Classification • LAM histology score (LHS) ○ Based on percent of lung involvement by cysts 231

Neoplasms

Lymphangioleiomyomatosis – Probable LAM □ Characteristic HRCT findings and clinical history or □ Compatible HRCT findings with AML or chylous effusion – Possible LAM: Only characteristic HRCT findings ○ Vascular endothelial growth factor D (VEGF-D) > 800 pg/mL in 70% of cases – VEGF-D > 800 pg/mL + lung cysts: Specific for S-LAM and for TSC-LAM in women with TSC ○ Biopsy: Transbronchial, video-assisted thoracoscopic surgery

○ LHS-1: < 25%; LHS-2: 25-50%; LHS-3: > 50% ○ LHS correlates with survival; worse prognosis with higher scores

Gross Pathologic & Surgical Features • Lung enlargement; diffusely distributed lung cysts • Thoracic, abdominal, and pelvic lymphadenopathy • Enlarged thoracic duct and lymphatic channels ○ LAM cells may obliterate thoracic duct with altered lymphatic flow and resultant chylothorax • Lymphangioleiomyoma: Chyle-filled encapsulated mass

Microscopic Features

Natural History & Prognosis

• Neoplastic smooth muscle (LAM) cells around bronchioles, alveolar walls, vessels, axial lymphatics, and cyst walls ○ LAM cell clusters: Central spindle-shaped cells and peripheral epithelioid cells • Type II pneumocyte proliferation, elastin and collagen fiber destruction in cyst walls • Immunoreactivity for α-smooth muscle cell actin, desmin, vimentin, and human melanin black (HMB-45) • Micronodular pneumocyte hyperplasia; virtually pathognomonic for TSC • Lymphangioleiomyomas: Lymphatics infiltrated by LAM cells with intrinsic slit-like vascular channels

• Prognosis (poor long term) ○ Progressive airflow obstruction and respiratory failure ○ Poor prognosis; milder disease in TSC-LAM ○ Poorer outcome in patients diagnosed at a younger age and those with extensive cystic lung disease ○ Lung function deterioration and ↑ pneumothoraces in pregnancy ○ Increased risk of developing meningiomas, which grow with progesterone • Overall 5-year survival ~ 60-70%

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Progressive symptoms – Dyspnea, chest pain, cough, wheezing, hemoptysis, chyloptysis ○ Acute dyspnea and chest pain from pneumothorax – 40-50% at presentation; 60-80% in course of disease ○ Exacerbation of symptoms with menstruation, pregnancy, and exogenous estrogen ○ Pulmonary function tests – Obstructive lung disease, increased lung volume – ↓ FEV1 &/or diffusing capacity for carbon monoxide (DLCO) • Other signs/symptoms ○ Flank pain from rapid growth of renal AMLs ○ Hypotension: Hemorrhage in renal AMLs ○ Abdominal, flank/pelvic pain, abdominal distention, incontinence, chyluria, hematuria, lower extremity lymphedema, and paresthesias from abdominal and pelvic lymphangioleiomyomas

Demographics • Age ○ Women of childbearing age; mean 34 years, median 38 years; documented in postmenopausal women usually in association with exogenous estrogen • Gender ○ Almost exclusively women; women and men in TSC-LAM • Diagnosis ○ European Respiratory Society guidelines – Definite LAM □ Characteristic HRCT findings and (+) lung biopsy or □ Renal AML (on imaging or biopsy), chylous effusion, or lymph node involvement 232

Treatment • Pneumothorax ○ Drainage, pleurodesis, pleurectomy; may complicate lung transplantation • Chylothorax ○ Thoracic duct ligation, pleurovenous shunt • Avoidance of estrogen • Sirolimus or everolimus (mTOR inhibitors) to prevent LAM cell proliferation • Lung transplantation ○ Best treatment option for advanced disease ○ Recurrent disease reported in transplanted lung

DIAGNOSTIC CHECKLIST Consider • LAM in women with unexplained progressive dyspnea and increased lung volume on radiography • LAM in women with diffuse bilateral thin-walled lung cysts ± pneumothorax or pleural effusion

Image Interpretation Pearls • Chest radiographs may appear normal or near normal • Characteristic HRCT appearance (European Respiratory Society LAM task force): Multiple (> 10) thin-walled cysts with normal or increased lung volumes, without other significant interstitial abnormality • Pulmonary manifestations of TSC-LAM are identical to those of S-LAM

SELECTED REFERENCES 1. 2. 3. 4.

Johnson SR et al: Lymphangioleiomyomatosis. Clin Chest Med. 37(3):389403, 2016 Moir LM: Lymphangioleiomyomatosis: Current understanding and potential treatments. Pharmacol Ther. 158:114-24, 2016 Ferreira Francisco FA et al: Multiple cystic lung disease. Eur Respir Rev. 24(138):552-64, 2015 Gillott M et al: Imaging of cystic lung disease. Semin Roentgenol. 50(1):23-30, 2015

Lymphangioleiomyomatosis Neoplasms

(Left) Axial CECT of a 31-yearold woman with lymphangioleiomyomatosis who presented with several years of progressive dyspnea shows profuse bilateral thinwalled pulmonary cysts ﬈ with little intervening normal lung parenchyma. (Right) Coronal CECT of the same patient shows the uniform distribution of the pulmonary cysts ﬈ throughout both lungs. The cyst walls are thin and uniform, and there are no pulmonary nodules. This case illustrates characteristic HRCT features of lymphangioleiomyomatosis.

(Left) Composite image with CECT in lung (left) and soft tissue (right) window of a 48year-old woman with lymphangioleiomyomatosis shows innumerable pulmonary cysts ﬈ and right paraesophageal lymphadenopathy ﬉. (Right) Axial CECT of a 46-year old woman with lymphangioleiomyomatosis shows a large heterogeneously enhancing left renal mass ﬈ with predominant fat attenuation, characteristic of angiomyolipoma, found in 1/3 of affected patients.

(Left) Axial HRCT of a 57-yearold woman with lymphangioleiomyomatosis shows innumerable thinwalled pulmonary cysts with normal intervening lung parenchyma and small bilateral pleural effusions ﬈, left larger than right, that represented bilateral chylothroraces. (Right) Coronal NECT of the same patient obtained 5 years later when she presented with acute left chest pain shows a left pneumothorax ﬊. Note left pleural effusion and a partially visualized left pleural catheter ﬉.

233

Neoplasms

Reactive Lymphoproliferative Disorders KEY FACTS

TERMINOLOGY

PATHOLOGY

• Variety of lymphoproliferative alterations characterized by polyclonal lymphoid infiltrates

• Follicular bronchiolitis: Accumulation of small lymphoid aggregates in peribronchiolar distribution ○ B lymphocytes are typically CD20 and CD79a (+) • LIP: Interstitial infiltrate of mature lymphocytes and admixture of plasma cells and other mononuclear cells ○ Nodular lymphoid aggregates contain germinal follicles • Nodular lymphoid hyperplasia: Reactive follicles without lymphoepithelial lesions [classic of mucosa-associated lymphoid tissue (MALT) lymphomas] • Angiofollicular lymph node hyperplasia (hyaline vascular type): Concentric rings of mantle zone lymphocytes and sclerotic blood vessels in germinal centers • Intrapulmonary lymph nodes: May exhibit reactive follicles and anthracosis

IMAGING • Follicular bronchiolitis ○ Centrilobular nodules and bronchial wall thickening • Lymphoid interstitial pneumonia (LIP) ○ Centrilobular nodules, ground-glass opacities, and lung cysts • Nodular lymphoid hyperplasia ○ Single/multiple nodule(s) or mass(es) – Intrinsic air bronchograms • Angiofollicular lymph node hyperplasia ○ Unicentric: Mediastinal or hilar mass ○ Multicentric: Mediastinal lymphadenopathy and parenchymal abnormalities similar to LIP • Enlarged intrapulmonary lymph nodes ○ Small subpleural, round, ovoid, or triangular nodules

(Left) Axial HRCT of a 60-yearold man with rheumatoid arthritis and follicular bronchiolitis shows extensive bilateral centrilobular micronodules and tree-in-bud opacities. (Right) Coronal HRCT of the same patient shows bilateral centrilobular micronodules, tree-in-bud opacities ﬉, and bronchial wall thickening ﬈. This constellation of findings should suggest the diagnosis of follicular bronchiolitis particularly in patients with rheumatoid arthritis with cellular bronchiolitis and no clinical evidence of infection.

(Left) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows a lymphoid infiltrate with intrinsic germinal follicles ﬈ adjacent to the airways and relatively spared parenchyma ﬉. The nodular lesions correlate with micronodules seen on thinsection CT. (Right) High-power photomicrograph (H&E stain) of the same specimen shows marked lymphocytic infiltration of airway walls and a normal bronchial epithelium ﬉. Lymphocytes may also infiltrate the vessels, interlobular septa, and pleura.

234

CLINICAL ISSUES • Clinical course and prognosis depend on type and extent of lymphoproliferative disorder

Reactive Lymphoproliferative Disorders

Abbreviations

○

• Lymphoid interstitial pneumonia (LIP) • Mucosa-associated lymphoid tissue (MALT) lymphoma

Definitions • Various lymphoproliferative alterations characterized by polyclonal lymphoid infiltrates ○ Follicular bronchiolitis ○ LIP ○ Nodular lymphoid hyperplasia ○ Angiofollicular lymph node hyperplasia (giant lymph node hyperplasia and Castleman disease) ○ Intrapulmonary lymph nodes

○

○

IMAGING General Features • Best diagnostic clue ○ Follicular bronchiolitis – Centrilobular nodules and bronchial wall thickening ○ LIP – Centrilobular nodules, ground-glass opacities, and lung cysts ○ Nodular lymphoid hyperplasia – Single/multiple nodule(s) or mass(es) ○ Angiofollicular lymph node hyperplasia – Unicentric: Mediastinal or hilar mass – Multicentric: Mediastinal lymphadenopathy and parenchymal abnormalities (related to LIP) ○ Enlarged intrapulmonary lymph nodes – Peripheral and basilar pulmonary nodules

○

– Bronchial wall thickening – Mosaic attenuation LIP – Ground-glass opacities – Centrilobular nodules – Thickened bronchovascular bundles – Interlobular septal thickening – Small subpleural nodules – Cystic lung disease Nodular lymphoid hyperplasia – Single/multiple nodule(s) or mass(es) (2-4 cm in diameter) □ Intrinsic air bronchograms – Parenchymal consolidation (mass-like) – Hilar/mediastinal lymphadenopathy Angiofollicular lymph node hyperplasia – Unicentric □ Soft tissue mass with significant enhancement – Multicentric □ Diffuse mediastinal lymphadenopathy □ Centrilobular nodules □ Thin-walled cysts □ Thickening of bronchovascular bundles □ Interlobular septal thickening Intrapulmonary lymph nodes – Nodules □ Soft tissue attenuation □ Well circumscribed □ Round, ovoid, triangular, trapezoid □ < 12 mm in diameter □ Adjacent thin pleural tag or thick interlobular septum extending to pleura

Radiographic Findings

Nuclear Medicine Findings

• Follicular bronchiolitis ○ Radiographs often normal ○ Nonspecific findings: Increased lung volume, bronchial wall thickening, and poorly defined small nodules • LIP ○ Reticulonodular opacities – Lower lobe predominance • Nodular lymphoid hyperplasia ○ Single nodule/mass (65% cases) • Angiofollicular lymph node hyperplasia ○ Unicentric (localized) – Mediastinal or hilar mass; may exhibit calcification ○ Multicentric (disseminated) – Mediastinal widening – Lung parenchymal involvement similar to LIP • Intrapulmonary lymph nodes ○ Peripheral nodules below level of carina (< 20 mm in diameter)

• PET/CT ○ May exhibit variable degrees of FDG avidity ○ Angiofollicular lymph node hyperplasia shows moderately increased FDG avidity

CT Findings • HRCT ○ Follicular bronchiolitis – Micronodules (centrilobular, bilateral, frequently diffuse) – Ground-glass opacities (nonsegmental) – Tree-in-bud opacities

Neoplasms

TERMINOLOGY

DIFFERENTIAL DIAGNOSIS Lymphoma • • • •

Single or multiple nodules/masses, mass-like consolidation Hilar/mediastinal lymphadenopathy Monoclonal proliferation Immunohistochemical stains essential for diagnosis

Pulmonary Metastases • • • •

History of malignancy Well-defined and rounded nodules Peripheral and lower lobe predominance CT halo sign (hypervascular lesions)

Lung Cancer • • • •

Most common cause of lung mass in adult Upper lobe predominance Irregular, lobulated, or spiculated borders History of cigarette smoking

235

Neoplasms

Reactive Lymphoproliferative Disorders

Microscopic Features • Follicular bronchiolitis ○ Small peribronchiolar lymphoid nodules and follicles ○ Lymphoid infiltrates may also occur along interlobular septa, vessels, and pleura ○ B lymphocytes are typically CD20 and CD79a (+) ○ Foci of organizing pneumonia, obstructive pneumonia, or bronchiolar intraluminal neutrophilic exudates sometimes occur as nonspecific associated findings • LIP ○ Interstitial infiltrate of mature lymphocytes and admixture of plasma cells and other mononuclear cells ○ Nodular lymphoid aggregates containing reactive germinal centers ○ Polyclonal population of B cells in lymphoid follicles and T cells in pulmonary interstitium • Nodular lymphoid hyperplasia ○ Numerous reactive follicles without lymphoepithelial lesions – Classic features of MALT lymphomas ○ Germinal centers stain for B-cell marker CD20 and interfollicular lymphocytes stain for T-cell markers CD3, CD43, and CD5 ○ Interfollicular fibrosis of varying degrees • Angiofollicular lymph node hyperplasia ○ Hyaline vascular type – Concentric rings of mantle zone lymphocytes and sclerotic blood vessels in germinal centers ○ Plasma cell type – Prominent interfollicular stroma rich in plasma cells and small vessels ○ Increased follicular dendritic cells in involuted germinal centers are positive for CD21, CD23, or CD35 • Intrapulmonary lymph nodes ○ Anthracosis, silicotic nodules, and reactive follicles

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Follicular bronchiolitis – History of autoimmune disease (e.g., rheumatoid arthritis) – Progressive dyspnea (most common) – Recurrent pneumonia and dyspnea are common in patients with immunodeficiency ○ LIP – History of Sjögren syndrome (less commonly rheumatoid arthritis) – Cough and shortness of breath ≥ 3 years in patients with idiopathic LIP – Secondary LIP □ Clinical manifestations vary with underlying disease ○ Nodular lymphoid hyperplasia – Asymptomatic – Most patients have no identifiable systemic disease ○ Angiofollicular lymph node hyperplasia – Unicentric □ Asymptomatic 236

– Multicentric □ Associated with POEMS syndrome (i.e., polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes), Kaposi sarcoma, and AIDS □ Anemia, weight loss, cough, dyspnea, and fever ○ Intrapulmonary lymph nodes – Asymptomatic – Widespread use of CT has resulted in increased detection of small pulmonary nodules, including intrapulmonary lymph nodes

PATHOLOGY

Demographics • Age ○ Follicular bronchiolitis – Varies according to clinical presentation (primary or secondary) ○ LIP – More common in women – 5th decade of life ○ Nodular lymphoid hyperplasia – Middle-aged or older patients – Similar gender incidence ○ Angiofollicular lymph node hyperplasia – Unicentric □ Variable peak in 4th decade of life – Multicentric □ Female predominance □ 4th decade of life ○ Intrapulmonary lymph nodes – 4th-8th decades of life; peak in 5th decade

Natural History & Prognosis • Follicular bronchiolitis ○ Prognosis related to age at presentation and underlying conditions • LIP ○ Variable clinical course – Parenchymal abnormalities may resolve spontaneously or remain stable ○ Small percentage of patients develop extensive pulmonary fibrosis • Nodular lymphoid hyperplasia ○ Good prognosis • Angiofollicular hyperplasia ○ Unicentric – Benign clinical course and favorable prognosis ○ Multicentric – Poor prognosis • Intrapulmonary lymph nodes ○ Incidental finding, good prognosis

SELECTED REFERENCES 1. 2. 3.

4.

Arcadu A et al: Lymphoid Interstitial pneumonia and other benign lymphoid disorders. Semin Respir Crit Care Med. 37(3):406-20, 2016 Sirajuddin A et al: Primary pulmonary lymphoid lesions: radiologic and pathologic findings. Radiographics. 36(1):53-70, 2016 Carrillo J et al: Lymphoproliferative lung disorders: a radiologic-pathologic overview. Part I: reactive disorders. Semin Ultrasound CT MR. 34(6):525-34, 2013 Shaham D et al: CT features of intrapulmonary lymph nodes confirmed by cytology. Clin Imaging. 34(3):185-90, 2010

Reactive Lymphoproliferative Disorders Neoplasms

(Left) Axial HRCT of a 36-yearold woman with Sjögren syndrome and lymphoid interstitial pneumonia shows thin-walled, air-filled cysts ﬈ and centrilobular nodules ﬊. (Right) Low-power photomicrograph (H&E stain) shows lymphoid interstitial pneumonia manifesting with a diffuse lymphoid infiltrate involving the pulmonary interstitium with scattered reactive lymphoid follicles ﬉. The presence of cysts on imaging is postulated to result from overdistension of the airways distal to bronchiolar narrowing.

(Left) Axial HRCT of a 45-yearold woman with Sjögren syndrome and lymphoid interstitial pneumonia shows thin-walled, air-filled cysts ﬈, thickened bronchovascular bundles ﬊, and subpleural reticulation. (Right) Coronal HRCT of the same patient shows thin-walled, air-filled cysts ﬈ and reticular opacities that suggest pulmonary fibrosis. Longstanding lymphoid interstitial pneumonia may rarely evolve into pulmonary fibrosis and may exhibit classic reticulation and honeycombing.

(Left) Axial NECT of a 41-yearold man with nodular lymphoid hyperplasia shows a spiculated nodule ﬈ in the right upper lobe. Solitary or multiple nodules or masses are the most common imaging manifestation and may be indistinguishable from primary lung cancer. (Right) Lowpower photomicrograph (H&E stain) of a specimen from the same patient shows numerous coalescent reactive lymphoid follicles ﬈ with wellpreserved mantle zones and normal interfollicular plasma cells, which replace the underlying lung.

237

Neoplasms

Reactive Lymphoproliferative Disorders

(Left) Axial CECT of a 51-yearold man with nodular lymphoid hyperplasia shows multiple nodules ﬈ with central lucency representing clustered air bronchograms. Nodular lymphoid hyperplasia may manifest with single or multiple pulmonary nodules. (Right) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows lymphoid follicles ﬈, lymphoid and plasma cell infiltration, and thickened pulmonary interstitium. Variable amounts of fibrosis and occasional giant cells may be present.

(Left) Axial HRCT of a 28-yearold man with nodular lymphoid hyperplasia shows clustered tree-in bud nodular opacities and coalescent irregular nodules. This is an uncommon manifestation of nodular lymphoid hyperplasia. (Right) Axial HRCT of a patient with angiofollicular lymph node hyperplasia shows multiple bilateral pulmonary nodules. Other findings include septal and peribronchovascular thickening, ground-glass opacities, consolidations, and pleural effusions.

(Left) Axial NECT of a patient with unicentric angiofollicular lymph node hyperplasia involving the right hilum shows a large soft tissue mass ﬈ encasing the bronchus intermedius. Unicentric angiofollicular lymph node hyperplasia may manifest as a mediastinal/mass and may exhibit contrast enhancement and calcification. (Right) Axial CECT of a patient with unicentric angiofollicular lymph node hyperplasia involving the prevascular mediastinum shows an enhancing mass ﬈ with intrinsic coarse calcifications.

238

Reactive Lymphoproliferative Disorders Neoplasms

(Left) Axial CECT of a 27-yearold man with angiofollicular lymph node hyperplasia (also known as Castleman disease) and human immunodeficiency virus (HIV) infection shows enhancing bilateral hilar lymph nodes ﬈. (Right) Axial NECT of a patient with unicentric angiofollicular lymph node hyperplasia involving the thymus shows a soft tissue mass ﬈ in the prevascular mediastinum. Note that the mass simulates a primary mediastinal lymphoma, and differentiation is based solely on pathology.

(Left) Coronal FDG PET/CT of the same patient shows abnormal FDG uptake ﬈ within the prevascular mediastinal mass. Angiofollicular lymph node hyperplasia typically exhibits FDG uptake. However, SUV measurements tend to be lower than in high-grade lymphoma. (Right) High-power photomicrograph (H&E stain) of a specimen from the same patient shows characteristic layering of lymphocytes with an onion skin configuration in the mantle zone of lymphoid follicles and prominent interfollicular stroma ﬈.

(Left) Axial HRCT of a 49-yearold woman shows an intrapulmonary lymph node manifesting as a subpleural right lower lobe nodule with a small pleural tag ﬈. Intrapulmonary lymph nodes commonly occur along interlobar fissures. In some cases, their characteristic location and morphology may suffice to avoid further evaluation. (Right) High-power photomicrograph (H&E stain) of a specimen from the same patient shows a subpleural intrapulmonary lymph node ﬈ with intrinsic reactive lymphoid follicles ﬉.

239

Neoplasms

Neoplastic Lymphoproliferative Disorders KEY FACTS

TERMINOLOGY • Primary pulmonary lymphoma (PPL): Pulmonary monoclonal lymphoid tissue proliferation in patients with no detectable extrathoracic lymphoma for at least 3 months after initial diagnosis ○ Mucosa-associated lymphoid tissue (MALT) lymphoma, diffuse large B-cell lymphoma (DLBCL), lymphomatoid granulomatosis (LG) • Secondary pulmonary lymphoma (SPL): Involvement by systemic lymphoma and leukemia • Disorders associated with immunosuppression ○ Acquired immune deficiency syndrome (AIDS)-related lymphoma (ARL) ○ Posttransplant lymphoproliferative disorder (PTLD)

TOP DIFFERENTIAL DIAGNOSES • Metastatic disease • Lung cancer • Fungal pneumonia

IMAGING

PATHOLOGY

• HRCT/CT ○ MALT lymphoma: Single or multiple nodules/masses; mass-like consolidations

• Pulmonary lymphoma is typically secondary lymphoma • Pulmonary involvement by lymphoma is typically from direct extension from affected lymph nodes

(Left) Axial HRCT of a 27-yearold woman with mucosaassociated lymphoid tissue lymphoma shows multifocal ground-glass attenuation nodules ﬈ with small intrinsic air bronchograms. (Right) Coronal HRCT of the same patient shows multifocal right lung ground-glass attenuation nodules ﬈ consistent with mucosa-associated lymphoid tissue lymphoma. This is the most common type of primary pulmonary lymphoma and may manifest as single or multiple pulmonary nodules that often exhibit intrinsic air bronchograms.

(Left) Intermediate-power photomicrograph (H&E stain) of a specimen of mucosaassociated lymphoid tissue lymphoma shows a monotonous small cell proliferation ﬉ replacing the normal lung and encasing a bronchiole ﬊. (Right) Highpower photomicrograph (CD20 stain) of a specimen of mucosa-associated lymphoid tissue lymphoma shows a lymphoepithelial lesion characterized by abnormal lymphocytes within the bronchiolar epithelium ﬉, which stain positive for CD20 (brown areas).

240

○ DLBCL: Single or multiple nodules/masses ± cavitation ○ LG: Nodule/mass; multiple (80%); reticulation/peribronchovascular micronodules ○ Secondary involvement by lymphoma: Multiple nodules/masses; mass-like consolidations ○ Secondary involvement by leukemia: Thickened bronchovascular bundles and interlobular septa ○ ARL: Multiple nodules, pleural effusion ○ PTLD: Single or multiple nodules

Neoplastic Lymphoproliferative Disorders

Abbreviations • • • •

Non-Hodgkin lymphoma (NHL) Hodgkin lymphoma (HL) Primary pulmonary lymphoma (PPL) Posttransplant lymphoproliferative disorder (PTLD)

Definitions • Neoplastic lymphoproliferative lung disorders are classified as primary, secondary, or associated with immunosuppression • PPL ○ Pulmonary monoclonal lymphoid tissue proliferation in patients with no detectable extrathoracic lymphoma for at least 3 months after initial diagnosis – Mucosa-associated lymphoid tissue (MALT) lymphoma (most common) – Diffuse large B-cell lymphoma (DLBCL) (10-19%) – Lymphomatoid granulomatosis (LG) • Secondary pulmonary lymphoma (SPL): Pulmonary involvement by systemic lymphoma or leukemia ○ Patterns: Lymphangitic, nodular, alveolar – NHL, HL, leukemia-associated lung disease • Lymphoproliferative lung disorders associated with immunosuppression ○ AIDS-related lymphoma (ARL) ○ PTLD

IMAGING General Features • Best diagnostic clue ○ Lung involvement more frequent in disseminated or recurrent lymphoma than in primary lymphoma

Radiographic Findings • Single or multiple pulmonary nodules/masses ± cavitation • Lobar/segmental consolidation ○ Peribronchial infiltration; no bronchial wall destruction • Reticular or linear pattern ○ Thick bronchovascular bundles and interlobular septa • Diffuse random micronodules • Endobronchial lesion ○ May produce postobstructive atelectasis &/or pneumonia • Mediastinal &/or hilar lymphadenopathy

CT Findings • PPL ○ MALT lymphoma – Nodule/mass (variable size) □ Single or multiple, well or ill defined □ Bilateral (60-70%) □ Halo sign may be present □ Air bronchograms – Consolidation (mass-like) – Linear opacities □ Peribronchovascular and interlobular septal thickening – Ground-grass opacities

○ DLBCL – Solitary or multiple nodules; frequent cavitation ○ LG – Nodules/masses; multiple (80%) □ Well- or ill-defined borders □ Peribronchovascular distribution □ Peripheral and lower lobe predominance – Reticulation/peribronchovascular micronodules • SPL ○ Nodule/mass; single or multiple – Variable size, air bronchograms ○ Mass-like consolidation ○ Bronchovascular and interlobular septal thickening ○ Secondary pulmonary involvement by leukemia – Smooth or nodular bronchovascular and interlobular septal thickening – Centrilobular nodules – Ground-glass opacities or consolidations □ Peribronchial distribution • ARL ○ Pulmonary mass with air bronchograms ○ Multiple nodules – > 10 mm, peripheral predominance, ± cavitation ○ Mediastinal lymphadenopathy • PTLD ○ Single or multiple nodules ○ Mediastinal lymphadenopathy

Neoplasms

TERMINOLOGY

Nuclear Medicine Findings • FDG PET/CT ○ Optimal imaging study for assessment of response of FDG-avid lymphomas ○ Staging FDG PET/CT with increased FDG uptake in lung lesions – Lymphomatous involvement – Benign conditions (granulomatous disease) ○ Evaluation of treatment response with increased FDG uptake in lung lesions – Opportunistic infection – Radiation pneumonitis/fibrosis – Drug-induced lung disease – Residual/recurrent lymphoma

DIFFERENTIAL DIAGNOSIS Multiple Nodules • • • • • • •

Metastatic disease Neuroendocrine proliferations and neoplasms Lung cancer Fungal pneumonias (histoplasmosis, cryptococcosis) Septic emboli Vasculitides (granulomatosis with polyangiitis) Reactive lymphoproliferative disorders

Consolidation • • • • •

Lung cancer Infection (tuberculosis) Organizing pneumonia Eosinophilic pneumonia Lipoid pneumonia 241

Neoplasms

Neoplastic Lymphoproliferative Disorders

PATHOLOGY General Features

Treatment

• Most common pattern of pulmonary involvement by lymphoma: Direct extension from affected mediastinal &/or hilar lymph nodes • MALT lymphoma growth patterns ○ Nodular ○ Diffuse • LG ○ Angiocentric and angiodestructive polymorphous lymphoid infiltrate • Secondary pulmonary involvement by systemic lymphoma ○ All forms of lymphoma may secondarily involve lungs ○ Mature B-cell neoplasms may be most frequent • Secondary pulmonary involvement by leukemia ○ Leukemias of myeloid and lymphocytic differentiation may involve lung • ARL in patients with human immunodeficiency virus (HIV) infection ○ Vast majority are high-grade B-cell NHL • PTLD ○ Pathologic diagnosis based on World Health Organization (WHO) classification

• Treatment varies with type of lymphoma and extent of disease

Microscopic Features • MALT lymphoma ○ Composed predominantly of small lymphoid cells ○ May exhibit vascular permeation and lymphoepithelial cells ○ Lymphangitic distribution ○ Tumor cells CD20(+), CD79a(+), CD5(-), CD10(-), CD23(-) • LG ○ Vascular infiltration by mixture of small lymphocytes, histiocytes, plasma cells, and large lymphoid cells with atypia or immunoblasts ○ Involvement of arteries and veins ○ Cellular nodules with central necrosis ○ Population of B cells [CD20(+)] admixed with reactive T cells [CD3(+)] • Secondary pulmonary involvement by lymphoma ○ Morphologic features identical to those of primary lymphoma • Secondary pulmonary involvement by leukemia ○ Prominent lymphangitic and angiocentric distribution ○ Involvement of small arteries and arterioles, alveolar septal capillaries and veins ○ Microvascular occlusion by leukemic cell aggregates • ARL ○ Multiple nodules of dense monomorphic cellular infiltrates ○ Subpleural parenchymal or peribronchovascular reticular infiltration ○ Pleural effusion • PTLD ○ Early hyperplastic lesions ○ Polymorphic lesions: Polyclonal or monoclonal ○ Monomorphic lesions ○ Classic HL

242

CLINICAL ISSUES

MALT Lymphoma • • • •

6th-7th decades of life Female predominance Asymptomatic in 50% Associations ○ Smoking (45%) ○ Collagen vascular disease (15-45%) • 5-year survival rate: > 80%

Lymphomatoid Granulomatosis • 30-50 years of age • Male predominance • Isolated or associated with immunosuppression (AIDS, Wiskott-Aldrich syndrome) • Poor prognosis

Secondary Pulmonary Involvement by Lymphoma • Lung involvement at diagnosis ○ HL (12%) ○ NHL (4%) • NHL represents 80-90% of all cases of SPL • HL represents 10-15% of all cases of SPL • 30-40% of patients with HL have pulmonary involvement at some time during course of disease

Secondary Pulmonary Involvement by Leukemia • Most lung abnormalities related to infections, pulmonary hemorrhage, or edema • Leukemic pulmonary infiltration more common in autopsy series (24-64%)

AIDS-Related Lymphoma • Lymphoma is 40-100x more common in patients with AIDS than in general population • CD4 count < 50 cells/mm³ • Incidence: 5-20% • Responsible for death in ~ 20% of HIV(+) patients

Posttransplant Lymphoproliferative Disorder • B- or T-cell disorders that affect solid organ or stem cell transplant recipients • Ebstein-Barr virus seropositivity is most important risk factor • Most cases occur within 2 years of transplantation • Thoracic involvement in 70% of cases

SELECTED REFERENCES 1. 2. 3.

Kligerman SJ et al: Primary extranodal lymphoma of the thorax. Radiol Clin North Am. 54(4):673-87, 2016 Sirajuddin A et al: Primary pulmonary lymphoid lesions: radiologic and pathologic findings. Radiographics. 36(1):53-70, 2016 Carter BW et al: Multimodality imaging of cardiothoracic lymphoma. Eur J Radiol. 83(8):1470-82, 2014

Neoplastic Lymphoproliferative Disorders Neoplasms

(Left) Axial CECT of a 32-yearold man with primary pulmonary mucosa-associated lymphoid tissue lymphoma shows a left upper lobe heterogeneous consolidation with intrinsic areas of groundglass attenuation ﬉. (Right) Coronal fused FDG PET/CT of the same patient shows increased FDG uptake in the left upper consolidation ﬉ and in a larger right lung consolidation ﬈. Mucosaassociated lymphoid tissue lymphoma may manifest as single or multiple pulmonary consolidations.

(Left) Axial CECT of a 52-yearold man with pulmonary diffuse large B-cell lymphoma shows a middle lobe spiculated mass ﬈ with internal cavitation and thick nodular cavity walls. (Right) Coronal CECT of the same patient shows multiple middle lobe masses ﬈, one of which exhibits cavitation ﬉. Diffuse large B-cell lymphoma is a type of primary pulmonary lymphoma that often manifests as single or multiple pulmonary nodules or masses and frequently demonstrates cavitation.

(Left) Axial CECT of a 26-yearold man with lymphomatoid granulomatosis shows an irregular solitary pulmonary nodule ﬈ in the middle lobe. (Right) Axial CECT (soft tissue window) of the same patient shows that the middle lobe nodule ﬈ exhibits central low attenuation consistent with necrosis. Lymphomatoid granulomatosis often manifests as single or multiple pulmonary nodules or masses and may exhibit necrosis or cavitation.

243

Neoplasms

Neoplastic Lymphoproliferative Disorders

(Left) Axial HRCT of a 47-yearold woman with secondary pulmonary involvement by non-Hodgkin lymphoma (NHL) shows multifocal irregular pulmonary nodules ﬈, subpleural nodularity ﬉, and thickened bronchovascular bundles ﬊. (Right) Coronal HRCT of the same patient shows multifocal irregular pulmonary nodules ﬈, interlobular septal thickening ﬉, and patchy ground-glass opacities ﬊. Secondary pulmonary lymphoma due to disseminated or recurrent disease is more common than primary pulmonary lymphoma.

(Left) High-power photomicrograph (H&E stain) of a specimen from the same patient shows a diffuse proliferation of large cells with scant cytoplasm and prominent nucleoli. (Right) High-power photomicrograph (CD20 stain) of a specimen from the same patient shows tumor cell expression of CD20 (brown areas). Secondary pulmonary lymphoma shows histologic and morphologic features identical to those of the primary lymphoma.

(Left) Axial HRCT of a 36-yearold man with Hodgkin lymphoma demonstrates a right lower lobe nodule ﬈ with spiculated borders. Secondary pulmonary involvement is much more common in patients with Hodgkin lymphoma than in those with non-Hodgkin lymphoma. (Right) Axial fused FDG PET/CT of the same patient shows increased FDG uptake in the right lower lobe nodule ſt. FDG PET/CT is the imaging modality of choice for the evaluation, staging, and restaging of FDG-avid lymphomas.

244

Neoplastic Lymphoproliferative Disorders Neoplasms

(Left) Axial CECT of a patient with acquired immune deficiency syndrome and nonHodgkin lymphoma shows multiple bilateral solid pulmonary nodules ﬈ and mediastinal lymphadenopathy ﬊. (Right) Axial HRCT of the same patient shows multiple bilateral lung nodules ﬈, several with surrounding ground-glass opacity, the CT halo sign. Lymphoma is 40100x more common in patients with acquired immune deficiency syndrome than in the general population.

(Left) Axial HRCT of a patient with a history of renal transplantation and posttransplant lymphoproliferative disorder demonstrates multiple solid pulmonary nodules ﬈ in the right lung. (Right) Coronal HRCT of the same patient shows multiple bilateral pulmonary nodules ﬈, some with spiculated borders and others with cavitation. Posttransplant lymphoproliferative disorder typically manifests with multifocal pulmonary nodules and mediastinal lymphadenopathy.

(Left) Axial HRCT of a patient with secondary pulmonary involvement by leukemia shows irregular peribronchovascular consolidations ﬈ and thickened bronchovascular bundles ﬊. (Right) Coronal HRCT of a 25-year-old woman with secondary pulmonary involvement by leukemia shows bilateral nodular septal thickening ﬈, thickening of the interlobar fissures ﬉, and multiple small pulmonary nodules ﬊. Pulmonary involvement by leukemia may range from 24-64% of affected patients.

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Section 8

Interstitial Pneumonias

Approach to Interstitial Pneumonias Idiopathic Pulmonary Fibrosis Idiopathic Nonspecific Interstitial Pneumonia Cryptogenic Organizing Pneumonia Acute Exacerbation of Interstitial Lung Disease Acute Interstitial Pneumonia Idiopathic Lymphoid Interstitial Pneumonia Pleuropulmonary Fibroelastosis Airway-Centered Interstitial Fibrosis Interstitial Pneumonia With Autoimmune Features (IPAF) Approach to Smoking-Related Interstitial Lung Diseases Respiratory Bronchiolitis-Interstitial Lung Disease Desquamative Interstitial Pneumonia Combined Pulmonary Fibrosis and Emphysema

248 252 258 262 266 270 274 278 282 286 292 296 298 302

Interstitial Pneumonias

Approach to Interstitial Pneumonias Introduction

Imaging of Interstitial Pneumonias

The idiopathic interstitial pneumonias are a diverse group of diffuse pulmonary diseases characterized by a host of histologic manifestations that include various degrees of fibrosis and inflammation. The landmark work of pathologists Liebow and Carrington provided the 1st classification of idiopathic interstitial pneumonias in 1969, which described 5 patterns of idiopathic interstitial lung disease, including: Usual interstitial pneumonia (UIP), bronchiolitis obliterans interstitial pneumonia and diffuse alveolar damage, desquamative interstitial pneumonia (DIP), lymphoid interstitial pneumonia, and giant cell interstitial pneumonia. Many of the concepts originally presented by Liebow and Carrington were subsequently challenged: DIP was so named because cells contained within pulmonary airspaces were thought to represent "desquamated" pulmonary pneumocytes but were later identified as alveolar macrophages within the airway lumina, and giant cell interstitial pneumonia was redefined as a hard metal pneumoconiosis. On the other hand, UIP (so called because it was the most frequent histologic pattern) remains the histologic counterpart of the clinical entity idiopathic pulmonary fibrosis (IPF). In 1994, Katzenstein and Fiorelli established the need for an additional category of interstitial lung disease and introduced nonspecific interstitial pneumonia (NSIP) to encompass the substantial number of cases that still defied classification. Subsequent research and histologic observations provided increasing consistency in the pathologic diagnostic criteria for these entities. In 2002, the American Thoracic Society (ATS) and the European Respiratory Society (ERS) published an international multidisciplinary consensus classification of the idiopathic interstitial pneumonias to provide a diagnostic standard and incorporate clinical and imaging criteria brought about by the introduction of HRCT and the increasing importance of separating UIP from the other conditions, given its prognostic implications. In 2011, the ATS, ERS, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax (Latin American Thoracic Association) published evidence-based guidelines for the diagnosis and management of IPF, which incorporate imaging and clinical parameters for diagnosis and management and encourage multidisciplinary discussion between clinicians, radiologists, and pathologists in the interest of increased diagnostic accuracy. In 2013, an update of the international multidisciplinary classification of the idiopathic interstitial pneumonias was published as an official statement from the ATS and ERS, which groups these diseases into 4 general categories: Chronic fibrotic conditions (UIP and NSIP), acute and subacute entities (cryptogenic organizing and acute interstitial pneumonias), smoking-related diseases (respiratory bronchiolitis-interstitial lung disease and DIP), and rare conditions (lymphoid interstitial pneumonia and pleuroparenchymal fibroelastosis).

Patients with interstitial pneumonias may present with a variety of symptoms that may include dyspnea, cough, and wheezing. Initial evaluation typically consists of chest radiography. While some patients may have near normal chest radiographs, identification of volume loss, reticular opacities, and architectural distortion should suggest the possibility of a diffuse interstitial lung disease and should prompt a thorough clinical evaluation followed by chest CT. HRCT is the optimal imaging modality for the evaluation of diffuse interstitial lung disease. Use of prone imaging allows distinction of subpleural abnormalities from physiologic dependent atelectasis, and expiratory HRCT allows identification of small airways disease, which may be unsuspected on inspiratory images.

Radiologists may be the 1st healthcare providers to suspect the presence of a diffuse interstitial lung disease. In some cases, classic imaging findings are identified on a chest CT performed for other reasons. Therefore, all radiologists must be familiar with both imaging criteria for the diagnosis of interstitial lung disease and established reporting recommendations. An understanding of the clinical, imaging, and histologic manifestations of idiopathic interstitial pneumonias allows radiologists to competently report and discuss these cases with clinicians and pathologists and positively impact diagnosis and management. 248

Clinical History Knowledge of the clinical history is of paramount importance in the imaging assessment of interstitial lung disease. Although pulmonary edema is easily the most common interstitial abnormality encountered in clinical practice, it is rarely mistaken for an idiopathic interstitial pneumonia as affected patients characteristically present with acute onset of symptoms or are known to have chronic heart failure. Associated subpleural edema, pleural effusions, and cardiomegaly support the diagnosis. Other interstitial lung diseases of acute or subacute presentation relate to pulmonary infection and often exhibit signs and symptoms of infection or laboratory abnormalities that suggest the diagnosis. Although patients with idiopathic interstitial pneumonia may present acutely due to acute exacerbation of their disease or superimposed infection or edema, they usually have an insidious onset of symptoms, which are often chronic. Physical exam may reveal respiratory crackles, cyanosis, and digital clubbing, particularly in the fibrosing interstitial lung diseases. Description and Assessment of Imaging Abnormalities HRCT allows optimal visualization of the pulmonary parenchyma and description of imaging abnormalities with respect to the anatomic components of the secondary pulmonary lobule. Knowledge and appropriate use of established imaging terminology is of critical importance for accurately communicating with fellow radiologists, pulmonary medicine specialists, and other clinicians. A meticulous description of the findings allows the radiologist to focus on specific disease processes and contributes to both narrowing the differential diagnosis and selecting an appropriate strategy for further evaluation &/or management. As the majority of idiopathic interstitial pneumonias (UIP and NSIP) are characterized by fibrosis, recognition of CT/HRCT findings of architectural distortion, such as subpleural reticulation with interlobular septal thickening and intralobular lines, traction bronchiectasis and bronchiolectasis, and honeycombing, is of paramount importance. Honeycombing, characterized by layers of subpleural cysts of uniform sizes, must be distinguished from the single layered cyst-like changes of paraseptal emphysema. In addition, the distribution of abnormalities should be noted as the fibrosing interstitial pneumonias may exhibit an apicobasal (basilar predilection) gradient, which can be easily identified on multiplanar imaging. Atypical distribution of abnormalities and atypical findings such as micronodules, pulmonary cysts, consolidations, and extensive ground-glass opacity and mosaic attenuation/air-trapping, should be identified as they help

Approach to Interstitial Pneumonias

UIP Pattern

Possible UIP Pattern

Inconsistent With UIP Pattern

Subpleural, basal predominance

Subpleural, basal predominance

Upper or mid lung predominance

Reticular abnormalities

Reticular abnormality

Peribronchovascular predominance

Honeycombing ± traction bronchiectasis

Absence of features listed as inconsistent with UIP pattern

Extensive ground-glass opacity (> reticulation)

Absence of features listed as inconsistent with UIP pattern

Profuse micronodules (bilateral, upper lobe)

Interstitial Pneumonias

HRCT Criteria for Usual Interstitial Pneumonia Pattern

Discrete cysts (multiple, bilateral, distant from honeycombing Diffuse mosaic attenuation/air-trapping (bilateral, ≥ 3 lobes) Segmental/lobar consolidation UIP = usual interstitial pneumonia. Designation as UIP pattern and possible UIP pattern requires all criteria. Designation as inconsistent with UIP pattern requires any of the seven criteria. Adapted from Raghu G et al: An official ATS/ERS/JRS/ALAT Statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 183(6): 788-824, 2011.

exclude UIP and NSIP and may suggest other etiologies. Extrapulmonary findings, such as pleural effusion, thickening, or plaques, are important in that they may suggest a specific disease process or an etiology of the interstitial lung disease. Finally, nonneoplastic intrathoracic lymphadenopathy has been described in interstitial lung disease, and pulmonary trunk enlargement may represent associated pulmonary hypertension, which may carry a poor prognosis in affected patients. Idiopathic Pulmonary Fibrosis and Nonspecific Interstitial Pneumonia IPF is a chronic progressive interstitial pneumonia that affects older adults who present with progressive dyspnea and lung function deterioration and carries a poor prognosis. It is characterized by a UIP pattern on HRCT defined as often asymmetric basilar subpleural reticulation with traction bronchiectasis/bronchiolectasis and honeycombing. Identification of the UIP pattern on HRCT is sufficient for the diagnosis of IPF (without the need for surgical biopsy) after exclusion of known causes of interstitial lung disease. The histologic UIP pattern is characterized by temporal heterogeneity in which areas of fibrosis and honeycombing alternate with areas of less affected or normal lung. However, it should be noted that histologic UIP may be present in patients with no honeycombing on HRCT. The latest update of the classification of idiopathic interstitial pneumonias recognized NSIP as a specific clinicopathologic entity. Patients with NSIP are typically older than those with UIP, often present with subacute dyspnea, nonproductive cough, and low-grade fever and have a better prognosis. NSIP is commonly associated with collagen vascular diseases. In addition, multidisciplinary discussion is particularly important in distinguishing NSIP from hypersensitivity pneumonitis, which from the imaging perspective is only possible when the latter exhibits upper lung zone predominance, centrilobular ground-glass nodules, and expiratory air-trapping on HRCT. NSIP is characterized by HRCT findings of basilar ground-glass opacity and reticulation, which may be peribronchovascular and may exhibit subpleural sparing. Traction bronchiectasis/bronchiolectasis may be extensive compared to the degree of pulmonary involvement, and honeycombing

is rare. Histologically, NSIP is characterized by temporally homogeneous interstitial fibrosis with mild to moderate interstitial inflammation. Reporting Fibrosing Interstitial Pneumonias HRCT criteria for diagnosing a UIP pattern in the setting of interstitial lung disease are now available and should be incorporated into imaging reports of patients with interstitial lung disease. Radiologists play a critical role in the diagnosis, as confident identification of the UIP pattern on HRCT is highly accurate for the presence of UIP on surgical biopsy and renders it unnecessary. When imaging features of UIP are present in the absence of honeycombing, they should be reported as possible UIP pattern, and surgical biopsy is required for making a definitive diagnosis of UIP. Finally, it is just as important to identify findings that are inconsistent with UIP pattern as these should prompt further investigation and consideration of alternative diagnoses. In fact, careful assessment of such findings may allow the radiologist to confidently suggest another interstitial lung disease or provide a focused differential diagnosis based on the morphologic features and distribution of the HRCT abnormalities.

Selected References 1. 2.

3.

4.

5. 6.

Koelsch TL et al: Radiologic evaluation of idiopathic interstitial pneumonias. Clin Chest Med. 36(2):269-82, ix, 2015 Li X et al: Nonspecific interstitial pneumonia and usual interstitial pneumonia: comparison of the clinicopathologic features and prognosis. J Thorac Dis. 6(10):1476-81, 2014 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. 188(6):733-48, 2013 Raghu G et al: An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 183(6):788-824, 2011 Kim DS et al: Classification and natural history of the idiopathic interstitial pneumonias. Proc Am Thorac Soc. 3(4):285-92, 2006 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. 165(2):277-304, 2002

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Approach to Interstitial Pneumonias

(Left) Axial HRCT of a 58-yearold man with progressive dyspnea shows basilar honeycombing characterized by layers of regular subpleural thin-walled cysts associated with traction bronchiectasis ﬈. (Right) Sagittal NECT of the same patient documents basilar-predominant honeycombing. The imaging appearance is characterized as usual interstitial pneumonia pattern. After exclusion of known causes of interstitial lung disease, the diagnosis of idiopathic pulmonary fibrosis can be rendered without lung biopsy confirmation.

(Left) Low-power photomicrograph (H&E stain) shows characteristic features of usual interstitial pneumonia and typical temporal heterogeneity with different stages of organization with areas of interstitial fibrosis ﬊ and interspersed normal lung parenchyma ﬉. (From DP: Thoracic, 2e.) (Right) Highpower photomicrograph (H&E stain) shows honeycombing characterized by peripheral dilated air spaces, often filled with inspissated mucus ﬊. This is usually seen in the more advanced stages of usual interstitial pneumonia.

(Left) Axial HRCT of a patient with chronic dyspnea shows basilar reticulation ﬊ and traction bronchiolectasis ﬈ with sparing of the subpleural lung ﬉ and no honeycombing, best characterized as possible UIP pattern. (Right) Lowpower photomicrograph (H&E stain) shows the typical temporal homogeneity of nonspecific interstitial pneumonia (NSIP). Fibrotic uniformly thickened alveolar walls ﬊ exhibit few residual inflammatory elements. There is no normal intervening lung parenchyma as would be seen in UIP. (From DP: Thoracic, 2e.)

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Approach to Interstitial Pneumonias Interstitial Pneumonias

(Left) Axial HRCT of a patient with scleroderma shows basilar reticulation ﬊, traction bronchiolectasis ﬈, and subpleural sparing ﬉ characteristic of nonspecific interstitial pneumonia. Note mild esophageal dilatation ﬊. (Right) Composite image with axial HRCT of a patient with chronic dyspnea shows basilar subpleural reticulation ﬊, traction bronchiolectasis, and mild honeycombing ﬉. Associated discontinuous calcified and noncalcified pleural plaques ﬈ support the diagnosis of asbestosis.

(Left) Axial HRCT of a patient with chronic dyspnea shows extensive ground-glass opacities, centrilobular ground-glass nodules ﬉, and air-trapping ﬈. The findings are characterized as inconsistent with UIP pattern and suggest cluster 1 hypersensitivity pneumonitis. (Right) Coronal NECT of a patient with chronic dyspnea shows upper lung fibrosis ﬉, traction bronchiectasis ﬈, and mosaic attenuation best characterized as inconsistent with UIP pattern. These findings suggest cluster 2 hypersensitivity pneumonitis.

(Left) Axial HRCT of a patient with end-stage sarcoidosis and chronic dyspnea shows bilateral upper lobe peribronchovascular architectural distortion ﬊ with intrinsic traction bronchiectasis ﬈. (Right) Coronal HRCT of the same patient confirms the upper lung-predominant distribution of architectural distortion, which would be correctly characterized as inconsistent with UIP pattern. The diagnosis of sarcoidosis would be appropriately included in the differential diagnosis based on the imaging findings.

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Idiopathic Pulmonary Fibrosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Idiopathic pulmonary fibrosis (IPF) • Idiopathic usual interstitial pneumonia (UIP) • Fibrosing idiopathic interstitial pneumonia with histologic pattern of UIP on surgical biopsy • ~ 40% of all idiopathic interstitial pneumonias

• • • • • •

IMAGING • Radiography ○ Basilar reticular opacities ○ Low lung volumes ○ Pulmonary hypertension • HRCT/CT ○ Basilar predominant reticulation ○ Traction bronchiectasis or bronchiolectasis ○ Honeycombing ○ Ground-glass opacities (less extensive than reticulation) ○ Persistent/growing nodule/mass suggests lung cancer

(Left) PA chest radiograph of a patient with idiopathic pulmonary fibrosis (IPF) shows diffuse, bilateral peripheral subpleural reticular opacities and basilar predominant distribution of the abnormalities. (Right) Axial CECT of the same patient shows extensive basilar predominant honeycombing with traction bronchiectasis ﬈ and bronchiolectasis that would be reported as usual interstitial pneumonia (UIP) pattern. Honeycombing is the most specific feature of IPF on CT.

(Left) Low-power photomicrograph (H&E stain) of a specimen of usual interstitial pneumonia shows the prototypic temporal heterogeneity of the disease with areas of relatively preserved lung ﬈ and mild interstitial changes ﬊ adjacent to extensively remodeled lung ﬉. (Right) Low-power photomicrograph (H&E stain) of the same specimen shows extensive honeycomb cysts lined by columnar respiratory-type epithelium ﬉.

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Idiopathic nonspecific interstitial pneumonia Asbestosis Chronic hypersensitivity pneumonitis Rheumatoid arthritis Progressive systemic sclerosis Drug-induced lung disease

PATHOLOGY • Usual interstitial pneumonia

CLINICAL ISSUES • Symptoms: Dyspnea, nonproductive cough • Age: 55-70 years of age; M:F ~ 2:1 • Inexorable progression with poor prognosis

DIAGNOSTIC CHECKLIST • Idiopathic subpleural and basilar reticulation with honeycombing enables HRCT diagnosis of IPF

Idiopathic Pulmonary Fibrosis

Abbreviations • Idiopathic pulmonary fibrosis (IPF)

Synonyms • Idiopathic usual interstitial pneumonia (UIP) • Cryptogenic fibrosing alveolitis

Definitions • Fibrosing idiopathic interstitial pneumonia associated with histologic pattern of UIP on surgical biopsy • Represents 40% of all idiopathic interstitial pneumonias

IMAGING General Features • Best diagnostic clue ○ Reticulation and honeycombing with subpleural distribution and apicobasal gradient; traction bronchiectasis and architectural distortion ○ Absence of atypical features: Micronodules, sparing of lung bases, extensive air-trapping, consolidation, &/or ground-glass opacity • Location ○ Subpleural; mid and lower lung zones • Morphology ○ Reticulation, traction bronchiectasis/bronchiolectasis, honeycombing

Radiographic Findings • Radiography ○ Reticular or reticulonodular opacities – Subpleural/peripheral; mid and lower lung zones □ Mild subpleural opacities may affect upper zones ○ Lower lung zone volume loss – Spurious preservation of lung volume with coexistent emphysema ○ Pulmonary hypertension – Enlarged pulmonary trunk and right heart chambers

CT Findings • HRCT ○ More sensitive and specific than radiography ○ Reticular opacities – Subpleural predominance; apicobasal gradient (i.e., lower lobe predominance) – Less prominent in upper lungs ○ Traction bronchiectasis/bronchiolectasis – Predominance in subpleural and basilar lungs – Usually associated with reticular opacities ○ Honeycombing – Most specific manifestation of IPF – Subpleural cysts, usually in clusters or rows □ Cysts may vary in size depending on phase of respiratory cycle □ Average diameter 3-10 mm; but may be as large as 25 mm – Overall extent and severity of honeycombing may change over time ○ Ground-glass opacity – Fine fibrosis below spatial resolution of HRCT

○ ○

○

○

○

– Often in association with reticular opacities, traction bronchiectasis/bronchiolectasis – Less extensive than reticular opacities □ Extensive ground-glass opacity suggests hypersensitivity pneumonitis or nonspecific interstitial pneumonia □ May reflect acute exacerbation of IPF in patients with acute respiratory illness Volume loss (advanced cases) Coexistent emphysema (30%) – Combined pulmonary fibrosis and emphysema: Distinct clinical phenotype □ Usually related to cigarette smoking □ Associated with very poor prognosis Lung nodule/mass – If persistent or growing should raise suspicion for primary lung cancer Mediastinal lymph node enlargement (70%) – Usually occult on radiography – No correlation with extent of disease Acute exacerbation of IPF: New ground-glass opacities &/or consolidations ± bronchial dilatation on background of preexisting reticulation &/or honeycombing and traction bronchiectasis

Interstitial Pneumonias

TERMINOLOGY

Imaging Recommendations • Best imaging tool ○ HRCT for detection and characterization of disease

DIFFERENTIAL DIAGNOSIS Idiopathic Nonspecific Interstitial Pneumonia • May be indistinguishable from UIP • Honeycombing is absent or not predominant feature

Asbestosis • May be indistinguishable from UIP in cases with extensive honeycombing • Subpleural curvilinear opacities: Common early findings • Discontinuous partially calcified pleural plaques often present

Hypersensitivity Pneumonitis, Cluster 2 • Common cause of honeycombing ○ Indistinguishable from IPF if subpleural and lower lobe predominant ○ Peribronchovascular honeycombing is somewhat specific (may also be seen in sarcoidosis) • Expiratory air-trapping (common) • Poorly defined centrilobular nodules common in hypersensitivity pneumonitis; reflect cellular bronchiolitis

Rheumatoid Arthritis • UIP pattern seen more frequently than nonspecific interstitial pneumonia (NSIP) pattern ○ Indistinguishable from idiopathic UIP and NSIP ○ May progress more slowly than IPF • Ancillary findings: Joint erosions, serum markers (e.g., rheumatoid factor), pleural effusion, rheumatoid nodules

Progressive Systemic Sclerosis • NSIP pattern much more common than UIP pattern ○ Predominant ground-glass opacities 253

Interstitial Pneumonias

Idiopathic Pulmonary Fibrosis ○ Honeycombing uncommon except in advanced, longstanding disease • Patulous esophagus common • Cutaneous findings usually present: Sclerodactyly, calcinosis cutis, drawn facies

Drug-Induced Lung Disease • May be indistinguishable from IPF in cases with extensive honeycombing • Typical drugs: Nitrofurantoin or chemotherapy drugs

PATHOLOGY General Features • Etiology ○ Unknown etiology – Suspected but unproven association with cigarette smoking • Genetics ○ Familial cases of IPF reported (probable autosomal dominant inheritance) – Associated with protein surfactant C deficiency – Affected family members may present with different patterns of interstitial pneumonia ○ No genetic markers yet identified ○ No human leukocyte antigen (HLA) associations ○ Putative link with α-1 antitrypsin inhibition alleles on chromosome 14

Staging, Grading, & Classification • Clinical and HRCT features sufficient to establish diagnosis of IPF in 50-70% of patients with > 90% specificity ○ HRCT criteria – UIP pattern: Subpleural and basilar reticular opacities, honeycombing ± traction bronchiectasis, and absence of features listed as inconsistent with UIP pattern – Possible UIP pattern: Subpleural and basilar predominant reticular opacities and absence of features listed as inconsistent with UIP pattern – Inconsistent with UIP pattern: Upper or mid lung predominance, peribronchovascular predominance, extensive ground-glass opacities (extent greater than that of reticular opacities), profuse micronodules (bilateral, predominantly upper lobes), discrete cysts (multiple, bilateral, away from areas of honeycombing), diffuse mosaic attenuation/airtrapping (bilateral, in 3 or more lobes), or consolidation in bronchopulmonary segment(s)/lobe(s)

Gross Pathologic & Surgical Features • Peripheral subpleural honeycombing

Microscopic Features • Fibrosis ○ Subpleural predominant distribution ○ Characteristic fibroblastic foci ○ Dense acellular collagen • Mild to moderate interstitial inflammation ○ Histiocytes, plasma cells, lymphocytes, type II pneumocyte hyperplasia • Honeycombing ○ Cysts lined by bronchiolar epithelium 254

• Spatial and temporal heterogeneity: Prototypic of UIP ○ Refers to coexistence of normal lung adjacent to areas of fibrosis, variable architectural remodeling, and end-stage honeycombing

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Insidious onset of dyspnea on exertion – Usually present for months prior to clinical presentation ○ Nonproductive cough • Other signs/symptoms ○ Digital clubbing ○ Fine inspiratory ("Velcro") crackles ○ Signs of right heart failure ○ Pulmonary function tests: Restrictive physiology with decreased diffusing capacity for carbon monoxide (DLCO)

Demographics • Age ○ 55-70 years of age • Gender ○ M:F ~ 2:1 • Epidemiology ○ True incidence and prevalence difficult to estimate – Incidence: 7-10 cases/100,000 per year – Prevalence: 3-6/100,000 ○ No geographic predisposition

Natural History & Prognosis • Inexorable progression, poor prognosis • Median survival following diagnosis: 3.5 years • Rapid decline and death after period of relatively slower progression (rare) ○ Acute exacerbation of IPF ○ Diffuse alveolar damage on histologic examination • Lung cancer (10%) ○ Most patients current or former smokers ○ Many patients not surgical candidates because of underlying IPF

Treatment • No treatment regimen of proven benefit in improving patient survival • Mild to moderate IPF: Pirfenidone or Nintedanib • Azathioprine, prednisone, and acetylcysteine no longer recommended • Lung transplantation

SELECTED REFERENCES 1.

2.

3.

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. 188(6):733-48, 2013 Raghu G et al: An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 183(6):788-824, 2011 Mueller-Mang C et al: What every radiologist should know about idiopathic interstitial pneumonias. Radiographics. 27(3):595-615, 2007

Idiopathic Pulmonary Fibrosis Interstitial Pneumonias

(Left) Axial NECT of a patient with idiopathic pulmonary fibrosis demonstrates subpleural reticular opacities ﬈ characterized by interlobular septal thickening, intralobular lines and mild honeycombing ﬉. (Right) Axial NECT of the same patient shows more extensive basilar honeycombing ﬉. These findings are consistent with a UIP pattern in patients with idiopathic pulmonary fibrosis. The CT pattern is specific, and histologic confirmation is not required.

(Left) Axial NECT of a patient with idiopathic pulmonary fibrosis demonstrates mild bilateral subpleural reticular opacities ﬈. (Right) Axial NECT of the same patient demonstrates more extensive subpleural reticular opacities ﬈ and mild peripheral airway dilatation ﬊ or traction bronchiolectasis. There is no significant honeycombing.

(Left) Axial NECT of the same patient shows more extensive subpleural reticulation in the lung bases as well as groundglass opacities and traction bronchiectasis and bronchiolectasis ﬊. (Right) Axial NECT of the same patient shows more extensive involvement of the lung bases by ground-glass opacities, reticular opacities, and traction bronchiolectasis ﬊. This case of biopsy-proven UIP shows minimal honeycombing and is best reported as possible usual interstitial pneumonia pattern.

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Idiopathic Pulmonary Fibrosis

(Left) PA chest radiograph of a patient with IPF shows bilateral, peripheral, subpleural, and basilar predominant reticular opacities. Note the diminished lung volumes characteristic of patients with idiopathic pulmonary fibrosis. However, spurious preservation of lung volumes may be seen in patients with coexistent emphysema. (Right) Lateral chest radiograph of the same patient shows basilar and anterior subpleural pulmonary reticulation.

(Left) Axial NECT of the same patient demonstrates peribronchovascular groundglass opacities ﬈ and cystic changes ﬊. Note the small right-sided pneumothorax ﬉, a rare but well-recognized complication of idiopathic pulmonary fibrosis. (Right) Axial NECT of the same patient demonstrates more extensive basilar peribronchovascular opacities as well as traction bronchiectasis and bronchiolectasis ﬊ and subpleural honeycombing ﬈.

(Left) Axial HRCT of a patient with usual interstitial pneumonia shows subpleural honeycombing associated with large pulmonary cysts ﬈. While unusual, honeycomb cysts may be as large as 2.5 cm. (Right) Axial CECT of the same patient demonstrates enlarged pretracheal and aortopulmonary window lymph nodes ﬈. Nonneoplastic mediastinal lymphadenopathy is seen in 70% of affected patients, is often reactive, and does not correlate with the severity of interstitial lung disease.

256

Idiopathic Pulmonary Fibrosis Interstitial Pneumonias

(Left) Axial CECT of a patient with idiopathic pulmonary fibrosis demonstrates asymmetric subpleural reticular opacities ﬈ and traction bronchiectasis and bronchiolectasis ﬊. (Right) Axial NECT of the same patient obtained several months later because of acute development of cough and dyspnea shows new multifocal bilateral airspace and groundglass opacities consistent with acute exacerbation of interstitial lung disease. Note trace bilateral pleural effusions ﬈.

(Left) Coronal CECT through the posterior chest of the same patient shows an extensive bilateral crazypaving pattern and traction bronchiectasis ﬈. Acute exacerbation of idiopathic pulmonary fibrosis should be considered in patients with acute symptoms and extensive ground-glass opacity. (Right) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows cellular interstitial inflammation, acute and organizing hyaline membranes ﬈, and patchy areas of acute inflammation ﬉.

(Left) PA chest radiograph of a patient with idiopathic pulmonary fibrosis shows peripheral and basilar reticulation and a subtle left perihilar nodule ﬈, which can easily be overlooked given the extent of underlying interstitial lung disease. (Right) Axial NECT of the same patient shows a spiculated left upper lobe nodule ﬈ abutting the oblique fissure. As incidence of lung cancer is increased in patients with idiopathic interstitial fibrosis, any discrete nodule should be regarded as highly suspicious for malignancy.

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Interstitial Pneumonias

Idiopathic Nonspecific Interstitial Pneumonia KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Nonspecific interstitial pneumonia (NSIP)

• Usual interstitial pneumonia • Hypersensitivity pneumonitis, cluster 2 • Drug-induced interstitial lung disease

IMAGING • CT/HRCT ○ Bilateral ground-glass and reticular opacities with traction bronchiectasis/bronchiolectasis ○ Absent or sparse honeycombing ○ Subpleural sparing ± peribronchovascular fibrosis ○ Apicobasilar gradient (lower lobe predominant) • MR ○ Multiecho single-shot turbo spin-echo (TSE) – Entire lung mapping with potential for monitoring of progression and response to treatment ○ Multiphase dynamic enhancement studies with turbo field-echo sequence and T2W triple-inversion black blood TSE images – Useful for differentiating inflammatory and fibroticpredominant lesions

(Left) AP chest radiograph of a 61-year-old woman with idiopathic nonspecific interstitial pneumonia shows bilateral heterogeneous reticular opacities with lower lobe predominance ﬈. (Right) Axial HRCT of the same patient shows bilateral ground-glass opacities and subtle reticulations ﬈ along bronchovascular bundles and in the subpleural lungs. Note the presence of associated traction bronchiectasis ﬊. The combination of findings and the absence of honeycombing suggest the correct diagnosis.

(Left) Coronal HRCT of the same patient shows groundglass and reticular opacities with intrinsic traction bronchiectasis ﬈ with a distinct lower lobe predominance also referred to as apicobasilar gradient. (Right) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows pulmonary interstitial fibrosis with temporal and spatial homogeneity (i.e., all areas at a similar stage of interstitial fibrosis), which is characteristic of nonspecific interstitial pneumonia.

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PATHOLOGY • Idiopathic • Variable amounts of interstitial inflammation and fibrosis with uniform distribution • Predominantly fibrotic • Rare cases of isolated cellular NSIP

CLINICAL ISSUES • Dyspnea and nonproductive cough • Pulmonary function tests exhibit restrictive physiology • Patients are 1 decade younger (5th decade) than those with UIP • M 10 mm or large □ Irregular margins (88%) □ Air bronchograms (45%) □ Pleural tags (23%) □ Focal interlobular septal thickening (near nodules) ○ Reversed halo sign (19%) – Ground-glass opacity surrounded by crescent or ring of parenchymal consolidation □ Ground-glass opacity corresponds to alveolar wall inflammation □ Ring of parenchymal consolidation corresponds pathologically to OP in distal airspaces ○ Reticular opacities – Small percentage of patients may develop interstitial fibrosis – Associated with other findings of fibrosis (honeycombing, traction bronchiectasis), ground-glass opacities, &/or consolidation ○ Parenchymal bands – Lines or bands longer than 2 cm, smooth or irregular with air bronchograms, and at least 8 mm in width – Often with multifocal consolidations ○ Bronchial dilatation – Within consolidation or ground-glass opacity ○ Diffuse micronodular pattern – Uncommon – Peribronchial or centrilobular ○ Enlarged mediastinal lymph nodes ○ Pleural effusion

Interstitial Pneumonias

TERMINOLOGY

Nuclear Medicine Findings • PET/CT ○ OP typically demonstrates FDG avidity

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Cryptogenic Organizing Pneumonia

DIFFERENTIAL DIAGNOSIS Chronic Eosinophilic Pneumonia • • • • • •

Subpleural ground-glass opacities &/or consolidations Upper lobe predominance Band-like opacities parallel to chest wall History of asthma (75%) High peripheral blood eosinophilia (usually > 1,500/μL) Alveolar eosinophilia (> 25% and often > 40%)

Lymphoma • Consolidation (not migratory except in lymphomatoid granulomatosis) • Multiple pulmonary nodules • Lymphadenopathy • Pleural effusion

Bacterial Pneumonia • Consolidation (not migratory) • Acute clinical manifestations (fever, shortness of breath) • Other findings described in COP are uncommon

Lung Cancer • Mass-like consolidation (not migratory) • Lymphadenopathy • Smoker (uncommon in COP)

Granulomatosis With Polyangiitis • Migratory ground-glass opacities, nodules, or consolidations • Peripheral blood eosinophilia • Renal disease

Acute Fibrinous and Organizing Pneumonia • Histopathological pattern characterized by intraalveolar fibrin deposits, hyperplasia of type II pneumocytes, associated OP, and absence of hyaline membranes • Acute and subacute forms ○ Acute – Fulminant course, typically leading to respiratory failure and death – Imaging manifestations similar to those of diffuse alveolar damage (noncardiogenic pulmonary edema) ○ Subacute: Imaging manifestations similar to those of OP pattern

PATHOLOGY

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Fever, cough, malaise, and progressive dyspnea ○ Anorexia and weight loss ○ Focal and sparse crackles • Other signs/symptoms ○ Hemoptysis, chest pain ○ Night sweats ○ Pneumothorax/pneumomediastinum • Pulmonary function tests show mild to moderate restrictive ventilatory pattern; may occasionally be normal • Reduced diffusing capacity (DLCO) • Arterial hypoxemia

Demographics • Age ○ 50-60 years • Gender ○ M=F • Epidemiology ○ 1-10 cases/100,000 individuals

Natural History & Prognosis • Diagnosis is often delayed (6-12 weeks) • Video-assisted thoracoscopic lung biopsy is gold standard for diagnosis • Overall prognosis is good • Reticular opacities at initial onset: Less likely to respond to corticosteroids; may progress to lung fibrosis • Relapse occurs in 13-58% of patients

Treatment • Corticosteroids

DIAGNOSTIC CHECKLIST

General Features

Consider

• Etiology ○ Idiopathic by definition ○ Etiologies of secondary OP – Lung injury: Infection, drug toxicity, toxic gas inhalation, gastroesophageal reflux, collagen vascular disease, radiation therapy – Other pulmonary abnormalities: Vasculitides, lung cancer, lymphoma, hypersensitivity pneumonitis, chronic eosinophilic pneumonia

• COP in middle-aged patients with migratory pulmonary opacities on radiography that exhibit peribronchovascular distribution or reversed halo sign on CT • COP is diagnosis of exclusion, as it may be secondary pattern of lung injury related to other diseases

Microscopic Features • Multifocal process characterized by organizing fibrosis of loose connective tissue that occludes bronchioles, alveolar ducts, and surrounding alveoli 264

• Intraluminal polypoid plugs of loose organizing connective tissue (i.e., Masson bodies) within alveolar ducts, alveolar spaces, and frequently bronchioles ○ Intrinsic lymphocytes, plasma cells, and histiocytes in addition to fibroblasts • Hyperplastic type II pneumocytes lining alveolar septa • Mild or moderate interstitial thickening consisting of lymphocytes &/or plasma cells • Foci of endogenous lipoid pneumonia

SELECTED REFERENCES 1.

2.

Mehrian P et al: The spectrum of presentations of cryptogenic organizing pneumonia in high resolution computed tomography. Pol J Radiol. 79:45660, 2014 Kligerman SJ et al: From the radiologic pathology archives: organization and fibrosis as a response to lung injury in diffuse alveolar damage, organizing pneumonia, and acute fibrinous and organizing pneumonia. Radiographics. 33(7):1951-75, 2013

Cryptogenic Organizing Pneumonia Interstitial Pneumonias

(Left) Axial HRCT of a 46-yearold woman with cryptogenic organizing pneumonia shows multifocal subpleural predominant nodular groundglass opacities. (Right) Axial HRCT of a 61-year-old man with cryptogenic organizing pneumonia shows right lower lobe consolidation characterized by central ground-glass opacity and a peripheral rim of consolidation, producing the reversed halo sign ﬈. While nonspecific, the reversed halo sign has been frequently described in cryptogenic organizing pneumonia.

(Left) Axial HRCT of a patient with cryptogenic organizing pneumonia shows bronchiectasis ﬉ and poorly defined, arcade-like opacities ﬈ producing the so-called perilobular pattern of lung involvement. (Right) Axial HRCT of a 57-year-old man with cryptogenic organizing pneumonia shows thin and thick radial lines in the lingula and left lower lobe (band-like pattern) ﬈ and bronchial dilatation ﬊. As opposed to bronchiectasis, bronchial dilatation in patients with organizing is often reversible after appropriate treatment.

(Left) Axial NECT of a patient with cryptogenic organizing pneumonia shows a solid mass in the lingula ﬈ and a small left pleural effusion ﬉. (Right) Axial fused FDG PET/CT of the same patient shows FDG avidity within the left upper lobe mass ﬊. Organizing pneumonia with focal lung involvement may mimic lung cancer on imaging. Foci of organizing pneumonia, whether cryptogenic or occurring as a secondary lung reaction to several other diseases, typically exhibit moderate to high FDG avidity.

265

Interstitial Pneumonias

Acute Exacerbation of Interstitial Lung Disease KEY FACTS

TERMINOLOGY • Acute exacerbation (AE) of interstitial lung disease: Acute, clinically significant respiratory deterioration characterized by new widespread alveolar abnormalities • Diagnostic criteria (should meet all 4 criteria) ○ Diagnosis of idiopathic pulmonary fibrosis ○ Acute worsening or development of dyspnea < 1 month duration ○ New bilateral ground-glass opacities &/or consolidations superimposed on usual interstitial pneumonia (UIP) ○ Deterioration not fully explained by heart failure or fluid overload

IMAGING • CT ○ New ground-glass opacities &/or consolidations ± bronchial dilatation on background of preexisting reticulation &/or honeycombing and traction bronchiectasis

(Left) Axial HRCT of a 70-yearold man with preexisting idiopathic pulmonary fibrosis (IPF) shows lower lobe predominant subpleural reticulation ﬊, ground-glass opacities, and traction bronchiectasis ﬈. (Right) Axial CECT (same patient) after acute exacerbation characterized by increased dyspnea shows interval development of multifocal bilateral ground-glass opacities, new bronchiectasis ﬈ and bronchiolectasis ﬉ consistent with fibrotic (late) phase of diffuse alveolar damage.

(Left) Low-power photomicrograph (H&E stain) of a biopsy specimen from the same patient shows histologic features of diffuse alveolar damage with patchy alveolar hyperinflation ﬉ alternating with areas of atelectasis. (Right) High-power photomicrograph (H&E stain) of the same specimen shows intraalveolar edema, areas of acute inflammation, and eosinophilic hyaline membranes ﬈ lining the alveolar walls. This constellation of histologic findings is referred to as diffuse alveolar damage.

266

○ Classification of distribution of new ground-glass opacities – Peripheral (good prognosis, most affected patients survive) – Multifocal (regarded as early phase of diffuse distribution) – Diffuse (poor prognosis, high mortality)

TOP DIFFERENTIAL DIAGNOSES • Infection • Cardiogenic pulmonary edema • Alveolar hemorrhage

PATHOLOGY • Diffuse alveolar damage and organizing pneumonia superimposed on findings of underlying UIP

CLINICAL ISSUES • Most common symptom: Rapidly progressive dyspnea • Median survival of UIP patients with AE is ~ 3-4 months

Acute Exacerbation of Interstitial Lung Disease

DIFFERENTIAL DIAGNOSIS

Abbreviations

Infection

• Acute exacerbation (AE) of interstitial lung disease (ILD)

• Atypical microorganisms (e.g., Pneumocystis jirovecii) may cause diffuse opacities in patients with underlying IIP • Differentiation often relies on bronchoscopy

Synonyms • Accelerated usual interstitial pneumonia (UIP)

Definitions • Acute deterioration of idiopathic pulmonary fibrosis (IPF) may be due to infection, pulmonary embolism, pneumothorax, heart failure or AE • AE of ILD ○ Acute, clinically significant respiratory deterioration characterized by new widespread alveolar abnormalities ○ Diagnostic criteria (should meet all 4) – Previous or concurrent diagnosis of IPF – Acute worsening or development of dyspnea typically of < 1 month duration – CT with new bilateral ground-glass opacities &/or consolidation superimposed on background pattern consistent with UIP – Deterioration not fully explained by heart failure or fluid overload • AE can occur in other types of idiopathic interstitial pneumonia (IIP): Nonspecific interstitial pneumonia (NSIP), connective tissue disease-associated interstitial lung disease (CTD-ILD), and cluster 2 hypersensitivity pneumonitis

IMAGING Radiographic Findings • Heterogeneous airspace &/or reticular opacities in patient with known ILD

CT Findings • HRCT ○ New ground-glass opacities &/or consolidations ± bronchial dilatation on background of preexisting reticulation &/or honeycombing and traction bronchiectasis – New ground-glass opacities &/or consolidations without new traction bronchiectasis often correlate with histologic findings of early (exudative) diffuse alveolar damage (DAD) and carry better prognosis – New ground-glass opacities &/or consolidations with new traction bronchiectasis/bronchiolectasis often correlate with histologic findings of late (fibrotic) DAD and carry worse prognosis ○ Classification of distribution of new ground-glass opacities – Peripheral (good prognosis, most affected patients survive) – Multifocal (regarded as early phase of diffuse distribution) – Diffuse (poor prognosis, high mortality) ○ Bronchial dilatation extends more widely and proximally as fibrosis progresses ○ AE more common in setting of UIP pattern than in possible UIP or inconsistent with UIP patterns

Cardiogenic Pulmonary Edema • Edema can cause diffuse opacities superimposed on IIP • Pleural effusion, cardiomegaly

Interstitial Pneumonias

TERMINOLOGY

Alveolar Hemorrhage • Patients with autoimmune disease + CTD-ILD are prone to alveolar hemorrhage • ↓ hemoglobin and hematocrit

PATHOLOGY General Features • Etiology ○ Idiopathic (no trigger identified) ○ May be triggered by infection, drug toxicity, or aspiration or may occur postprocedure or postsurgery

Microscopic Features • DAD and organizing pneumonia superimposed on underlying UIP • Pulmonary hemorrhage with capillaritis

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Rapidly progressive dyspnea (days to weeks) ○ Cough, fever, and flu-like symptoms • Clinical profile ○ ↑ C-reactive protein, ↑ lactate dehydrogenase

Demographics • Age ○ Mean: 64-68 years • Epidemiology ○ AE develops in 10-20% of all cases of IPF annually ○ AE occurs less frequently in idiopathic NSIP, CTD-ILD, or hypersensitivity pneumonitis ○ AE in CTD-ILD is more common in rheumatoid arthritis with UIP

Natural History & Prognosis • Up to 46% of deaths in patients with IPF preceded by AE • Median survival of IPF patients with AE is ~ 3-4 months • Survival of patients with AE of UIP and possible UIP HRCT patterns worse than that of patients with inconsistent with UIP HRCT pattern

Treatment • No effective therapy • Immune suppressive therapy (e.g., corticosteroids)

SELECTED REFERENCES 1.

Collard HR et al: Acute exacerbation of idiopathic pulmonary fibrosis. An international working group report. Am J Respir Crit Care Med. 194(3):26575, 2016

267

Interstitial Pneumonias

Acute Exacerbation of Interstitial Lung Disease

(Left) PA chest radiograph of a 62-year-old man with idiopathic pulmonary fibrosis shows low lung volumes and subtle bilateral reticular opacities. (Right) Coronal HRCT of the same patient obtained on the same day shows patchy bilateral ground-glass opacities ﬉ and scattered subpleural reticular opacities ﬊. At the time of imaging, there had been no progression of the patient's symptoms or any clinical deterioration.

(Left) PA chest radiograph of the same patient after development of acute exacerbation of interstitial lung disease characterized by progressive dyspnea shows new diffuse bilateral airspace and reticular opacities. (Right) Coronal HRCT of the same patient obtained on the same day shows diffuse bilateral ground-glass opacities and new traction bronchiectasis ﬈. The presence of traction bronchiectasis and bronchiolectasis is associated with late fibrotic diffuse alveolar damage and implies a worse prognosis.

(Left) Axial NECT of a patient with nonspecific interstitial pneumonia obtained as baseline imaging shows diffuse bilateral subpleural reticulation ﬊ and patchy ground-glass opacities ﬉. (Right) Axial HRCT of the same patient during an episode of acute exacerbation shows increased diffuse bilateral ground-glass opacities and interval development of traction bronchiectasis ﬈ and bronchiolectasis ﬉. Several interstitial lung diseases other than idiopathic pulmonary fibrosis may undergo acute exacerbation.

268

Acute Exacerbation of Interstitial Lung Disease Interstitial Pneumonias

(Left) PA chest radiograph of a 70-year-old man with idiopathic pulmonary fibrosis shows typical findings of basilar predominant and peripheral reticulation. (Right) Axial HRCT of the same patient obtained on the same day shows bilateral asymmetric ground-glass ﬈ and reticular opacities ﬊ associated with traction bronchiectasis ﬉ consistent with known interstitial lung disease.

(Left) PA chest radiograph of the same patient during an episode of acute exacerbation shows interval progression of airspace disease and reticular opacities and a new consolidation ﬈ in the right upper lung zone. (Right) Axial HRCT of the same patient obtained to evaluate acute exacerbation shows progression of ground-glass ﬉ and reticular opacities and traction bronchiectasis and bronchiolectasis ﬈. The latter correlate histologically with fibrotic (late) phase of diffuse alveolar damage, implying a worse prognosis.

(Left) Low-power photomicrograph (H&E stain) of a biopsy specimen of the same patient shows honeycombing typical of usual interstitial pneumonia, characterized by peripheral dilated air spaces ﬉, which are often filled with inspissated mucus ﬊. (Right) Intermediate-power photomicrograph H&E stain of a specimen from the same patient obtained during an acute exacerbation episode shows cellular interstitial inflammation ﬊ and acute and organizing hyaline membranes ﬈.

269

Interstitial Pneumonias

Acute Interstitial Pneumonia KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Acute interstitial pneumonia (AIP): Idiopathic interstitial pneumonia characterized by rapidly progressive respiratory failure of unknown etiology with histologic features of diffuse alveolar damage (DAD)

• • • • •

IMAGING • CT/HRCT ○ Early phase (exudative) – Bilateral ground-glass opacities &/or consolidations – Anterior-posterior gradient ○ Late phase (organizing) – Coarse reticular opacities – Ground-glass and reticular opacities – Traction bronchiectasis associated with poor outcome ○ Complications – Pneumonia, abscess, pneumothorax, pneumomediastinum, pulmonary interstitial emphysema

(Left) AP chest radiograph of a 62-year-old man with acute interstitial pneumonia (early phase) who presented with progressive dyspnea shows diffuse bilateral heterogeneous and reticular opacities. (Right) Axial CECT of the same patient shows "crazy paving" and bronchiectasis ﬈. Acute interstitial pneumonia is not a pathologic diagnosis but requires documentation of histologic findings of diffuse alveolar damage, absence of an identifiable etiology, presence of acute symptoms, and pulmonary opacities on radiography.

(Left) Coronal CECT of the same patient shows bilateral symmetric ground-glass and reticular opacities with upper lobes predominance. While opacities tend to affect all lung lobes, the upper lobes are more commonly involved. Symmetric involvement is also classic. (Right) Low-power photomicrograph (H&E stain) of a specimen of diffuse alveolar damage shows hyaline membranes ﬈ manifesting as layers of pink, amorphous, and homogeneous material lining the alveolar lumina. (From DP: Thoracic, 2e.)

270

Acute respiratory distress syndrome Pneumocystis jirovecii pneumonia Acute exacerbation of interstitial lung disease Hydrostatic pulmonary edema Diffuse alveolar hemorrhage

PATHOLOGY • AIP is not a pathological diagnosis • DAD is a histologic manifestation of AIP; but DAD is seen in other conditions

CLINICAL ISSUES • Flu-like prodrome 7 -14 days prior to presentation: Headache, myalgia, sore throat, malaise, dry cough, fever • Progressive shortness of breath, fever, cough • Treatment: No effective treatment known; corticosteroids with variable response (usually poor) • Poor prognosis; mortality rate usually ≥ 50%

Acute Interstitial Pneumonia

Abbreviations • Acute interstitial pneumonia (AIP) • Diffuse alveolar damage (DAD) • Acute respiratory distress syndrome (ARDS)

Synonyms

•

• Hamman-Rich syndrome

Definitions • Idiopathic interstitial pneumonia characterized by rapidly progressive respiratory failure of unknown etiology with histologic features of DAD • AIP is defined by following criteria ○ Acute onset of respiratory symptoms resulting in severe hypoxia and in most cases acute respiratory failure ○ Bilateral pulmonary opacities on chest radiography ○ Absence of identifiable etiology (e.g., infection, connective tissue disease, trauma, congestive heart failure, drug toxicity, etc.) ○ Histologic documentation of DAD • ARDS and AIP are not equivalent: AIP is an idiopathic form of ARDS, but not all patients with ARDS have AIP

•

IMAGING General Features • Best diagnostic clue ○ Radiography: Diffuse heterogeneous opacities involving all lung lobes ○ CT: Extensive symmetric ground-glass opacities associated with traction bronchiectasis

Radiographic Findings • Nonspecific diffuse bilateral and symmetrical heterogenous opacities • No particular zonal predilection, all lobes involved • Evidence of mechanical ventilation • Pleural effusions/septal lines are less common than in cardiogenic edema • Honeycombing rare (late phases)

• •

Imaging Recommendations • Best imaging tool ○ CT for characterization of diffuse pulmonary disease

DIFFERENTIAL DIAGNOSIS

CT Findings • CT more sensitive than radiography • General ○ Ground-glass opacities and consolidations are predominant abnormalities – Extent: > 50% of lung; patchy (2/3), diffuse (1/3) – Often focal lobular sparing (geographic pattern) – Distribution □ Lower lung zone (40%) □ Upper lung zone (15%) – Symmetric (common) – May be seen in all histologic phases of AIP; reflects acute inflammation or fibrosis – More extensive ground-glass opacities (without traction bronchiectasis) associated with better outcome ○ Consolidation – Involves < 25% of lung; subpleural distribution in 20% – Also seen in all histologic phases of AIP

– More extensive ground-glass opacities (without traction bronchiectasis) may have better outcome ○ AIP may progress to subpleural abnormalities that resemble fibrotic idiopathic interstitial pneumonias – Subpleural reticulation &/or honeycombing with apicobasal gradient and traction bronchiectasis Early phase (exudative) ○ Bilateral ground-glass opacities &/or consolidations ○ Anterior-posterior gradient ○ Bronchial dilatation within areas of ground-glass opacity; may represent traction bronchiectasis or may be reversible ○ Pleural effusions (common) Late phase (organizing) ○ Coarse reticular opacities ○ Ground-glass and reticular opacities – Diffuse (most common) – Nondependent lucencies (honeycombing/bullae) postulated to relate to fibrosis in areas less protected from barotrauma than consolidated lung – Subpleural lower lobe honeycombing suggests acute exacerbation of occult or underlying interstitial lung disease rather than AIP ○ Traction bronchiectasis – Central airways involvement > peripheral □ Mainly segmental and subsegmental airways – Traction bronchiectasis usually out of proportion to severity of reticular opacities or honeycombing – Associated with poorer outcome – May persist in survivors ○ Architectural distortion Complications: Pneumonia, abscess, pneumothorax, pneumomediastinum, pulmonary interstitial emphysema Sequelae of AIP ○ Foci of hypoattenuation, lung cysts, reticulation, and nondependent architectural distortion

Interstitial Pneumonias

TERMINOLOGY

Acute Respiratory Distress Syndrome • • • •

Associated with known cause (direct or indirect insult) Consolidation > ground-glass opacities Honeycombing less common in ARDS More likely asymmetric, areas of normal lung more extensive than in AIP • Interlobular septal thickening more common

Pneumocystis jirovecii Pneumonia • Symmetric ground-glass opacities • History of immunosuppression, typically acquired immune deficiency syndrome (AIDS) or chronic corticosteroids

Acute Exacerbation of Interstitial Lung Disease • Rare complication of interstitial lung disease ○ Criteria: Dyspnea exacerbation within 1 month, new diffuse pulmonary opacities, worsening hypoxemia (minimum 10 mm Hg), absence of infection or heart failure 271

Interstitial Pneumonias

Acute Interstitial Pneumonia • Diffuse but patchy ground-glass opacities on background of characteristic changes of idiopathic pulmonary fibrosis • Honeycombing more profuse than superimposed groundglass opacity • Poor prognosis

Diffuse Alveolar Hemorrhage • Diffuse ground-glass opacities, often evolve into reticular pattern • Features of pulmonary fibrosis may be seen but generally only with repeated episodes • Anemia and hemoptysis (80%) common

Hydrostatic Pulmonary Edema • • • •

Bilateral airspace opacities Cardiomegaly Pleural effusions History of heart disease

Desquamative Interstitial Pneumonia • Symptoms not as severe; mechanical ventilation not required • Heavy smoking history • Diffuse ground-glass opacities, no traction bronchiectasis

Invasive Mucinous Adenocarcinoma • Diffuse bilateral ground-glass opacities • No signs of fibrosis (architectural distortion, traction bronchiectasis) • Insidious onset and progressive course, mechanical ventilation not required

PATHOLOGY General Features • Etiology ○ Idiopathic • Temporal uniformity suggests injury related to single event • AIP is not a pathologic diagnosis • DAD is histologic manifestation of AIP; but DAD is seen in other conditions ○ Infections (22%) – Mycoplasma pneumonia, viruses, Legionella, Pneumocystis ○ Bone marrow transplantation (17%) ○ Acute exacerbation of idiopathic pulmonary fibrosis (16%) ○ Connective tissue disease (16%): Systemic lupus erythematosus, rheumatoid arthritis ○ Drug induced (10%): Bleomycin, busulfan, carmustine (BCNU), gemcitabine, crack cocaine, methotrexate, nitrofurantoin ○ Toxins (< 5%): Nitrogen dioxide, oxygen toxicity, paraquat, chlorine gas ○ Aspiration

Microscopic Features • Acute exudative phase (1st week) ○ Edema ○ Hemorrhagic fluid in air spaces ○ Type 1 pneumocyte necrosis ○ Hyaline membranes [not seen in usual interstitial pneumonia (UIP) or cryptogenic organizing pneumonia] 272

• Proliferative phase (after 2nd week) ○ Type 2 pneumocyte proliferation ○ Fibroblasts exceed collagen • Fibrotic phase ○ Fibrosis within alveoli and interstitium (may be severe) • Fibroblasts more extensive than collagen (in contrast to UIP)

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Flu-like prodrome 7-14 days prior to presentation: Headache, myalgia, sore throat, malaise, dry cough, fever ○ Progressive shortness of breath, fever, cough ○ Hypoxemia (mean PaO₂ 45 mm Hg) ○ Often considered in patients with diagnosis of pneumonia who fail to respond to antibiotics ○ Acute onset (over period of 1-3 weeks) – 50% of patients present during 1st week of onset – 25% have more indolent course and present within 30 days of onset – Rapid progression to respiratory failure, often require mechanical ventilation – 90% meet clinical criteria of ARDS • Other signs/symptoms ○ Clubbing suggests preexisting interstitial lung disease

Demographics • Age ○ Mean age: 50-55 years • Gender ○ M=F

Natural History & Prognosis • Poor prognosis (mortality rate usually ≥ 50%; most deaths within 2 months of onset) • Survivors may experience complete recovery of lung function ○ Persistent stable restrictive physiology also common ○ Recurrence may occur but is rare

Treatment • No effective treatment • Steroids with variable response, usually poor • Supportive care is mainstay of therapy ○ Mean duration of mechanical ventilation: 30 days

DIAGNOSTIC CHECKLIST Consider • AIP in patient with rapid onset of respiratory symptoms and respiratory failure in absence of identifiable cause or predisposing illness with symmetric extensive ground-glass opacities on imaging

SELECTED REFERENCES 1.

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. 188(6):733-48, 2013

Acute Interstitial Pneumonia Interstitial Pneumonias

(Left) Axial CECT of a 50-yearold man with acute interstitial pneumonia (early phase) shows diffuse, bilateral ground-glass opacities on a background of interlobular septal thickening, the socalled crazy-paving pattern. (Right) Axial CECT of the same patient shows extensive diffuse bilateral ground-glass opacities on a background of interlobular septal thickening (crazy-paving pattern) ﬉. Note that the imaging appearance is similar to that of pulmonary edema, infection, and diffuse alveolar hemorrhage.

(Left) Axial CECT of a 57-yearold man with acute interstitial pneumonia (early phase) shows multifocal bilateral areas of ground-glass opacity ﬈ and consolidation ﬉. Note anterior-posterior gradient of involvement with more consolidations in the dependent aspects of the lungs. (Right) Axial CECT of the same patient shows bilateral extensive basilar consolidations with air bronchograms ﬈, most severe in the dependent aspects of the lungs (anterior-posterior gradient).

(Left) Axial CECT of the same patient obtained 3 months later (late phase) shows evolution of lung opacities into areas of reticulation ﬈. Areas of fibrosis tend to primarily involve the nondependent regions of the lung, which are postulated to suffer more barotrauma than the posterior previously consolidated areas. (Right) Axial CECT of the same patient (late phase) shows evolution of pulmonary consolidations into areas of reticulation and irregular opacities.

273

Interstitial Pneumonias

Idiopathic Lymphoid Interstitial Pneumonia KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Lymphoid interstitial pneumonia (LIP): Rare idiopathic interstitial pneumonia and lymphoproliferative disorder characterized by extensive alveolar septal infiltration with lymphocytes and plasma cells • Unknown pathogenesis; often associated with other conditions (e.g., Sjögren syndrome); only rarely idiopathic

• • • •

IMAGING • Radiography ○ Basilar reticular/reticulonodular opacities • HRCT/CT ○ Bilateral ground-glass opacities ○ Poorly defined centrilobular nodules ○ Small subpleural nodules (~ 85%) ○ Bronchovascular bundle thickening (~ 85%) ○ Mild interlobular septal thickening (~ 85%) ○ Thin-walled cysts (~ 70%)

(Left) PA chest radiograph of an asymptomatic 56-year-old man with idiopathic lymphoid interstitial pneumonia demonstrates subtle bilateral slightly asymmetric reticular opacities, more pronounced in the right lung. (Right) Axial HRCT of the same patient shows basilar predominant ground-glass opacities ﬊ and scattered cysts ﬈. Lymphoid interstitial pneumonia may be idiopathic or associated with other conditions, such as Sjögren syndrome. The most common findings on HRCT are ground-glass opacities, cysts, and centrilobular nodules.

(Left) Axial HRCT of the same patient shows scattered basilar predominant thinwalled pulmonary cysts ﬉ and multifocal nodular ground-glass opacities ﬈. (Right) Axial HRCT of the same patient shows basilar predominant ill-defined nodular ground-glass opacities ﬉ and scattered thin-walled pulmonary cysts ﬈. The combination of ground-glass opacities and pulmonary cysts is a characteristic HRCT feature of lymphoid interstitial pneumonia.

274

Nonspecific interstitial pneumonia Pulmonary Langerhans cell histiocytosis Hypersensitivity pneumonitis Lymphangioleiomyomatosis

PATHOLOGY • Etiology: Idiopathic (< 20%), Sjögren syndrome (25%), infection, immunodeficiencies (e.g., common variable immunodeficiency) • Extensive lymphocytic and plasmatic infiltration mainly involving alveolar interstitium and, to lesser extent, bronchovascular and interlobular interstitia

CLINICAL ISSUES • Common symptoms: Cough and dyspnea

DIAGNOSTIC CHECKLIST • < 20% of all cases of LIP are idiopathic, 25% of all cases of LIP are associated with Sjögren syndrome

Idiopathic Lymphoid Interstitial Pneumonia

DIFFERENTIAL DIAGNOSIS

Abbreviations

Nonspecific Interstitial Pneumonia

• Lymphoid interstitial pneumonia (LIP)

• Subpleural ground-glass and reticular opacities with apicobasal gradient • Cysts are uncommon

Synonyms • Lymphocytic interstitial pneumonia

Definitions • Idiopathic LIP: Rare interstitial pneumonia and lymphoproliferative disorder of unknown pathogenesis characterized by extensive alveolar septal infiltration with lymphocytes and plasma cells • LIP is only rarely idiopathic and is more often associated with other conditions (e.g., Sjögren syndrome)

IMAGING General Features • Best diagnostic clue ○ HRCT: Ground-glass opacities ± pulmonary cysts • Location ○ Diffuse distribution

Radiographic Findings • Radiography ○ Basilar predominant reticular or reticulonodular opacities are most common – May be primarily nodular ○ Less common findings – Diffuse or patchy ground-glass opacities – Patchy consolidations ○ Cysts may be visible on radiography

Pulmonary Langerhans Cell Histiocytosis • Cysts exhibit bizarre shapes • Septal thickening and lymphadenopathy are uncommon

Interstitial Pneumonias

TERMINOLOGY

Hypersensitivity Pneumonitis • Profuse centrilobular ground-glass nodules + air-trapping • Cysts, septal and peribronchovascular thickening, and lymphadenopathy are uncommon

Lymphangioleiomyomatosis • Women ± history of tuberous sclerosis • Multifocal bilateral thin-walled pulmonary cysts

PATHOLOGY General Features • Etiology ○ Idiopathic (< 20%) ○ Autoimmune [e.g., Sjögren syndrome (25%)] ○ Infection (e.g., human immunodeficiency virus) ○ Immunodeficiency (e.g., common variable immunodeficiency)

Microscopic Features • Extensive lymphocytic and plasmatic infiltration mainly involving alveolar interstitium and, to lesser extent, bronchovascular and interlobular interstitia

CT Findings • Predominant findings ○ Bilateral ground-glass opacities ○ Poorly defined centrilobular nodules • Other common findings ○ Small subpleural nodules (~ 85%) ○ Bronchovascular bundle thickening (~ 85%) ○ Mild interlobular septal thickening (~ 85%) ○ Thin-walled cysts (~ 70%) – Size range: 1-30 mm in diameter – Perivascular and subpleural distribution – Isolated vs. diffuse lung involvement ○ Mediastinal lymphadenopathy (70%) ○ Less common findings – Larger nodules (1-2 cm) – Consolidation – Bronchiectasis – Honeycombing • Evolution ○ Ground-glass opacities and nodules tend to decrease or resolve with treatment ○ Cysts remain and may gradually enlarge

Imaging Recommendations • Best imaging tool ○ HRCT/CT for optimal characterization of lung and mediastinal abnormalities

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Onset usually gradual over several years ○ Most common symptoms: Cough and dyspnea

Demographics • Age ○ Varies according to underlying disease • Epidemiology ○ < 20% of all cases of LIP are idiopathic ○ 25% all cases of LIP occur in setting of Sjögren syndrome

Natural History & Prognosis • Good overall 5-year survival • May occasionally progress to pulmonary fibrosis

Treatment • Steroids (most commonly used), cytotoxic drugs • Most patients have good initial response • Some patients progress despite therapy ○ Interstitial fibrosis and honeycombing may develop

SELECTED REFERENCES 1.

Johkoh T et al: Rare idiopathic intestinal pneumonias (IIPs) and histologic patterns in new ATS/ERS multidisciplinary classification of the IIPs. Eur J Radiol. 84(3):542-6, 2015

275

Interstitial Pneumonias

Idiopathic Lymphoid Interstitial Pneumonia

(Left) Axial HRCT of a patient with common variable immunodeficiency and lymphoid interstitial pneumonia shows multifocal perilymphatic bilateral nodular ground-glass opacities ﬈. (Right) Axial HRCT of the same patient shows multifocal perilymphatic bilateral nodular ground-glass opacities ﬈ (i.e., involving both the central and peripheral interstitium). Note the absence of pulmonary cysts and the presence of subcarinal lymphadenopathy ﬉.

(Left) AP chest radiograph of a 43-year-old woman with Sjögren syndrome and lymphoid interstitial pneumonia shows low lung volumes and diffuse bilateral heterogeneous opacities with coalescence in the lower lobes. (Right) Axial HRCT of the same patient shows diffuse bilateral ground-glass opacities, scattered small thin-walled cysts ﬈, and a few discrete small solid nodules ﬉. The presence of lung cysts in a patient with Sjögren syndrome should suggest the possibility of lymphoid interstitial pneumonia.

(Left) Low-power photomicrograph (H&E stain) from a biopsy specimen of the same patient shows a diffuse interstitial lymphoid infiltrate ﬈ and scattered reactive lymphoid follicles ﬊. (Right) High-power photomicrograph (H&E stain) of the same specimen shows abundant lymphocytic ﬈ and plasmatic infiltration of the pulmonary interstitium. The cysts seen on imaging are postulated to result from overdistension of airways distal to bronchioles that are narrowed by surrounding lymphoid nodules and infiltration.

276

Idiopathic Lymphoid Interstitial Pneumonia Interstitial Pneumonias

(Left) Axial NECT (soft tissue window) of 43-year-old woman with Sjögren syndrome and lymphoid interstitial pneumonia shows axillary and mediastinal lymphadenopathy ﬈. Lymphadenopathy often occurs in both idiopathic and secondary lymphoid interstitial pneumonia. (Right) PA chest radiograph of a patient with common variable immunodeficiency and longstanding lymphoid interstitial pneumonia shows lower lobepredominant diffuse bilateral reticular opacities.

(Left) Axial HRCT of the same patient shows scattered subpleural honeycombing ﬉ and traction bronchiectasis ﬈. (Right) Axial HRCT of the same patient shows subpleural honeycombing ﬉ and traction bronchiectasis and bronchiolectasis ﬈. Frank subpleural fibrosis (i.e., honeycombing) may occur in chronic burned-out lymphoid interstitial pneumonia. In these cases, the imaging findings are morphologically identical to those of usual interstitial pneumonia.

(Left) Axial CECT of a 47-yearold woman with Sjögren syndrome, lymphoid interstitial pneumonia, and amyloidosis shows multiple bilateral pulmonary cysts ﬈ of various sizes and multifocal amorphous nodular calcifications ﬊. (Right) Axial CECT (soft tissue window) of the same patient shows multiple bilateral coarsely calcified amorphous nodules (i.e., amyloidomas) ﬊. While rare, the association of lymphoid interstitial pneumonia and amyloidosis is well described.

277

Interstitial Pneumonias

Pleuropulmonary Fibroelastosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Pleuroparenchymal fibroelastosis (PPFE) • Rare interstitial pneumonia characterized by upper lobepredominant elastotic fibrosis involving pleura and subpleural lung parenchyma ○ Idiopathic or secondary

• • • •

IMAGING • Radiography ○ Upper lobe-predominant subpleural opacities ○ Apical pleural thickening ○ Upper lobe volume loss, hilar elevation • CT ○ Upper lobe-predominant pleuroparenchymal thickening; may be diffuse ○ Subpleural consolidations and ground-glass opacities ○ Traction bronchiectasis/bronchiolectasis ○ Coexisting usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP)

(Left) PA chest radiograph of an 83-year-old woman with idiopathic pleuroparenchymal fibroelastosis shows upper lobe volume loss (i.e., bilateral upper lobe opacities with associated superior displacement of the minor fissure ﬉ and hila). The radiographic appearance may simulate other causes of upper lobe fibrosis and volume loss, such as tuberculosis or pneumoconiosis. (Right) Axial HRCT of same patient shows upper lobe-predominant pleuroparenchymal thickening ﬈ and traction bronchiectasis ﬉.

(Left) Axial HRCT of the same patient shows multifocal subpleural patchy opacities ﬉ and bronchiectasis ﬈ in the right lung. (Right) Low-power photomicrograph (van Gieson stain) of a specimen of pleuroparenchymal fibroelastosis shows darkstaining elastic tissue ﬈ within areas of subpleural parenchymal fibrosis. Note the abrupt transition from fibrosis to unaffected normal lung parenchyma ﬉. Elastic fibers that typically stain blue-black to black with van Gieson stain are a characteristic feature of this disease.

278

Apical fibrosis Tuberculosis Ankylosing spondylitis Pneumoconiosis

PATHOLOGY • Upper thoracic visceral pleura fibrosis • Subpleural intraalveolar fibrosis with alveolar septal elastosis

CLINICAL ISSUES • Clinical symptoms: Shortness of breath, cough, weight loss, chest pain • No gender predilection • Mean age: 53 years of age • Disease progression occurs in 60% of patients; 40% die from disease • No effective treatment

Pleuropulmonary Fibroelastosis

PATHOLOGY

Abbreviations

General Features

• Pleuroparenchymal fibroelastosis (PPFE)

• Etiology ○ Idiopathic ○ Secondary – Late complication of lung and bone marrow transplantation – Chemotherapy, occupational dust exposure (e.g., asbestos, aluminum), infection (e.g., Aspergillus, Mycobacterium avium-intracellulare), autoimmune disease (e.g., rheumatoid arthritis, ulcerative colitis, ankylosing spondylitis), hypersensitivity pneumonitis – Underlying genetic predisposition

Synonyms • Amitani disease

Definitions • Rare interstitial pneumonia characterized by upper lobepredominant elastotic fibrosis involving pleura and subpleural lung parenchyma ○ Idiopathic or secondary (e.g., late complication of lung or hematopoietic stem cell transplantation)

IMAGING Radiographic Findings • Upper lobe-predominant subpleural opacities • Apical pleural thickening • Upper lobe volume loss with superior displacement of minor fissure &/or hilar structures

CT Findings • Upper lobe-predominant pleuroparenchymal thickening ○ Thickness: 4-15 mm • Architectural distortion and upper lobe volume loss • Dense subpleural opacities • Traction bronchiectasis/bronchiolectasis • Coexistent usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP) • Subpleural cysts (rare) • Complications: Pulmonary hypertension, pneumothorax

Nuclear Medicine Findings • PET/CT ○ May exhibit ↑ FDG uptake in pleuroparenchymal opacities

Imaging Recommendations • Best imaging tool ○ HRCT

DIFFERENTIAL DIAGNOSIS Apical Fibrosis • Difficult to differentiate on imaging; PPFE tends to be more diffuse • Absence of progression, good prognosis

Tuberculosis • Biapical architectural distortion and volume loss • Often chronic and stable; known history of infection

Ankylosing Spondylitis • Bilateral, symmetric, apical opacities; traction bronchiectasis with volume loss • Bamboo spine

Pneumoconiosis • Occupational history ○ Silicosis ○ Coal worker's pneumoconiosis

Interstitial Pneumonias

TERMINOLOGY

Staging, Grading, & Classification • Classified into pure PPFE or PPFE with other interstitial pneumonias (e.g., UIP, NSIP, etc.)

Microscopic Features • Upper thoracic visceral pleura fibrosis (may be histologically indistinguishable from apical cap) ○ Histologic diagnosis requires deep sublobar resection (needle biopsy yields insufficient tissue) • Subpleural intraalveolar fibrosis with alveolar septal elastosis • Scant, patchy lymphoplasmacytic infiltrates • Scant fibroblastic foci • Coexistent lung disease (e.g., UIP, NSIP etc.)

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Shortness of breath, cough, weight loss, chest pain ○ Recurrent infection ○ Pneumothorax

Demographics • Gender ○ No gender predilection • Age ○ Mean age: 53 years • Epidemiology ○ Initially thought to be uncommon – One series has shown PPFE in up to 6% of patients undergoing surgical lung biopsy

Natural History & Prognosis • Disease progression in 60% of patients; 40% die from disease • 30% overall 5-year survival • Amitani disease is variant of idiopathic PPFE: Younger adults with flat chest morphology and progressive respiratory failure; poor prognosis

Treatment • No effective treatment

SELECTED REFERENCES 1.

Johkoh T et al: Rare idiopathic intestinal pneumonias (IIPs) and histologic patterns in new ATS/ERS multidisciplinary classification of the IIPs. Eur J Radiol. 84(3):542-6, 2015

279

Interstitial Pneumonias

Pleuropulmonary Fibroelastosis

(Left) AP chest radiograph of a patient with pleuroparenchymal fibroelastosis shows low lung volumes and diffuse bilateral reticular opacities. Note widespread pulmonary disease and absence of the lower lobepredominant involvement characteristic of idiopathic pulmonary fibrosis. (Right) Axial NECT of the same patient shows right apical reticulation and honeycombing and mild pleural thickening ﬈. Note subpleural ground-glass ﬉ and airspace ﬊ opacities.

(Left) Axial NECT of the same patient shows multifocal ground-glass and airspace opacities ﬉ with associated architectural distortion and traction bronchiectasis ﬈ in the right lung. (Right) Lowpower photomicrograph (H&E stain) of a specimen of pleuropulmonary fibroelastosis shows marked pleural thickening ﬈ extending into the subpleural space, obliterating the alveolar spaces, and entrapping terminal airways ﬉. Note the relative paucity of inflammation.

(Left) PA chest radiograph of a woman with pleuroparenchymal fibroelastosis demonstrates upper lobe-predominant reticular opacities, upper lobe volume loss, and apical subpleural thickening. (Right) Axial HRCT of the same patient shows biapical pleuroparenchymal thickening ﬈, subpleural reticular and ground-glass opacities ﬉, and traction bronchiectasis and bronchiolectasis ﬊. Pleuroparenchymal fibroelastosis exhibits progression in 60% of affected patients.

280

Pleuropulmonary Fibroelastosis Interstitial Pneumonias

(Left) Axial HRCT of the same patient shows bilateral subpleural ground-glass and airspace opacities ﬈ with associated architectural distortion manifesting as traction bronchiectasis and bronchiolectasis ﬉. (Right) Axial HRCT of the same patient shows ill-defined subpleural airspace and ground-glass opacities ﬈. The abnormalities are less conspicuous in the lower lobes. Patients with pleuroparenchymal fibroelastosis may present with dyspnea, cough, weight loss, and chest pain.

(Left) PA chest radiograph of a patient with pleuroparenchymal fibroelastosis shows subtle reticular and airspace opacities in the upper lobes. Note bilateral upper lobe volume loss manifesting with upward displacement of the bilateral hila ﬈. (Right) Axial NECT of the same patient shows bilateral apical subpleural opacities ﬈ with associated mild pleural thickening. The abnormalities of pleuroparenchymal fibroelastosis are much more conspicuous in the upper lobes.

(Left) Axial NECT of the same patient shows subtle subpleural ground-glass ﬈ and airspace ﬊ opacities, bronchial wall thickening, and central right upper lobe bronchiectasis ﬉. (Right) Axial NECT of the same patient shows peripheral subpleural ground-glass ﬈ and airspace ﬉ opacities. At histology, pleuroparenchymal fibroelastosis may be seen in association with histologic findings of usual interstitial pneumonia or nonspecific interstitial pneumonia.

281

Interstitial Pneumonias

Airway-Centered Interstitial Fibrosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Airway-centered interstitial fibrosis (ACIF) suggests inhalation- or aspiration-related injury • Most common etiologies: Hypersensitivity pneumonitis (HP) and gastroesophageal reflux disease (GERD)

• • • • • •

IMAGING • Radiography ○ Diffuse reticulonodular opacities ○ Central and peribronchovascular (80%) distribution ○ Architectural distortion ○ Small, central ring shadows • CT ○ Bronchial wall thickening and traction bronchiectasis ○ Patchy, ground-glass attenuation ○ Diffuse, mosaic attenuation and air-trapping ○ Honeycombing (minimal) ○ Distribution – Predominantly central; lower lobes

(Left) Axial HRCT of a patient with airway-centered interstitial fibrosis (ACIF) shows peribronchial thickening and distortion ﬈ of bronchovascular bundles as well as mosaic attenuation ﬉. (Right) Axial expiratory HRCT of the same patient shows geographic mosaic attenuation ﬈ due to small airways disease. Note small caliber of pulmonary vessels in areas of decreased attenuation ﬇. The most common etiologies of ACIF are hypersensitivity pneumonitis and gastroesophageal reflux disease.

(Left) Axial HRCT of a patient with airway-centered interstitial fibrosis shows bilateral peribronchovascular thickening ﬈, traction bronchiectasis ﬉, and subtle mosaic attenuation. Note lobular area of air-trapping ﬇. (Right) Coronal NECT of the same patient shows multifocal ground-glass opacities ﬈ mostly in a peribronchovascular distribution. Note an asymmetric mosaic attenuation pattern st and right upper lobe focal tree-inbud opacities ﬉.

282

Hypersensitivity pneumonitis (cluster 2) Chronic summer-type hypersensitivity pneumonitis Respiratory bronchiolitis interstitial lung disease Sarcoidosis Idiopathic pulmonary fibrosis Nonspecific interstitial pneumonia

PATHOLOGY • Combined inflammatory and fibrotic reaction • Subpleural spaces not spared • Histologically indistinguishable from chronic (cluster 2) hypersensitivity pneumonitis without granulomas

CLINICAL ISSUES • Middle-aged women (40-50 years) and nonsmokers • Chronic cough and slowly progressive dyspnea • Usually > 1 year in duration

Airway-Centered Interstitial Fibrosis

Abbreviations

Imaging Recommendations • Best imaging tool ○ HRCT/thin-section CT

• Airway-centered interstitial fibrosis (ACIF)

Synonyms • Centrilobular fibrosis • Idiopathic bronchiolocentric interstitial pneumonia • Peribronchiolar metaplasia

Definitions • Distinctive pattern of fibrosis centered on membranous and respiratory bronchioles • Response to variety of environmental exposures or insults ○ Cluster 2 hypersensitivity pneumonitis (HP) ○ Gastroesophageal reflux disease (GERD) – Hiatal hernia – Systemic sclerosis in setting of common variable immune deficiency (CVID) ○ Adverse drug reaction ○ Inhalational injury (e.g., chemical fumes) ○ Chronic/recurrent infection ○ Smoking (< 50%); may contribute to airway injury

IMAGING

DIFFERENTIAL DIAGNOSIS Hypersensitivity Pneumonitis • High index of suspicion ○ Multidisciplinary approach in difficult cases • History of exposure to allergen • ↓ incidence in smokers • Lymphocytosis with predominance of CD8(+) T lymphocytes • More severe in mid and upper lung zones • May exhibit nonspecific interstitial pneumonia (NSIP) pattern • Chest radiography: Diffuse, centrilobular ground-glass opacities • Mosaic perfusion pattern

Chronic Summer-Type Hypersensitivity Pneumonitis • Most common form of HP in Japan • Hypersensitivity reaction to Trichosporon asahii or Trichosporon mucoides • Chest radiography: Diffuse, reticulonodular opacities

General Features

Respiratory Bronchiolitis Interstitial Lung Disease

• Best diagnostic clue ○ Central and peribronchovascular distribution

• Almost all affected patients are smokers • Combination of bronchiolar disease with clinical syndrome of cough, dyspnea, and fine bibasilar end-expiratory crackles • Usually responds to steroids or cessation of smoking • Upper lobe centrilobular ill-defined nodules, mild bronchial wall thickening, lower lobe predominant reticular opacities, centrilobular emphysema

Radiographic Findings • Radiography ○ May be normal ○ Salient abnormalities – Bronchial wall thickening – Central ring shadows – Architectural distortion

CT Findings • More sensitive than radiography ○ Imaging modality of choice • Key findings ○ Peribronchovascular interstitial thickening – Thickened airway walls ○ Traction bronchiectasis and bronchiolectasis ○ Reticular opacities – Often admixed with ground-glass opacities ○ Honeycombing (minimal) ○ Patchy ground-glass opacities – Ill-defined centrilobular nodules – Combined ground-glass and reticular opacities may result in areas of crazy-paving pattern ○ Mosaic lung attenuation: Patchwork of regions of differing attenuation – Air-trapping □ Multilobular, geographic – Secondary vasoconstriction □ Hypoventilation of alveoli distal to bronchiolar obstruction • Distribution ○ Predominantly central; lower lobes

Interstitial Pneumonias

TERMINOLOGY

Sarcoidosis • High rate of spontaneous remission • Peribronchovascular distribution, subpleural nodules, lymphadenopathy • Upper lung zone predominant • Treatment not indicated for asymptomatic disease

Idiopathic Pulmonary Fibrosis • Suspected association with cigarette smoking • Mid and lower lung zone predominance • Subpleural reticulation, traction bronchiectasis, and honeycombing • Ground-glass opacities less common • Poor prognosis

Nonspecific Interstitial Pneumonia • Basilar reticulation and ground-glass opacities • Airway-centered lymphocytic infiltrate around distal bronchioles ○ Plasma cells, eosinophils, and neutrophils often absent ○ Alveolar septa infiltrated by lymphocytes and fibrosis ○ Architectural distortion ○ Honeycombing

283

Interstitial Pneumonias

Airway-Centered Interstitial Fibrosis

PATHOLOGY General Features • Etiology ○ Combined inflammatory and fibrotic reaction ○ Majority of patients are nonsmokers ○ Typical exposure – Japan: Hypersensitivity reaction to Trichosporon asahii or Trichosporon mucoides

Microscopic Features • Distinctive pattern of interstitial fibrosis ○ Variable combination of interstitial fibrosis and inflammation • Bronchiolocentricity ○ Centrilobular chronic inflammation (bronchiolar inflammation) – Membranous and respiratory bronchioles – Extends into interstitium of distal acinus ○ Peribronchovascular interstitial thickening ○ No granulomas, eosinophils, or dark-pigmented cytoplasmic granules • Traction bronchiectasis and bronchiolectasis • Thickened airway walls • Subpleural space is not spared • Microscopic honeycombing (limited number of cases) • Metaplastic bronchiolar epithelia (Lambertosis) ○ Distal extension of respiratory epithelium into alveoli • Histologic similarity to HP ○ Granulomas are absent – Indistinguishable from chronic (cluster 2) HP without granulomas

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Chronic cough and slowly progressive dyspnea – Usually > 1 year in duration – Exposure history often not discovered after radiologic or pathologic diagnosis ○ Exclusion of HP – Detailed work, family, and hobby history ○ Chronic or recurrent aspiration – Exclusion of GERD – Silent aspiration without initial symptoms – May mimic asthma • Other signs/symptoms ○ Some degree of respiratory insufficiency ○ Restrictive physiology ○ Decreased FVC and forced expiratory volume in 1 second (FEV1 ) ○ Decreased or normal residual volume ○ Oxygen desaturation with exercise ○ Low peripheral flow rates

Treatment • Transbronchial or cryobiopsy necessary for diagnosis ○ Useful for exclusion of sarcoidosis, idiopathic pulmonary fibrosis, and respiratory bronchiolitis interstitial lung disease • Questionable effect of corticosteroid treatment • Unknown role of antiinflammatory drugs

DIAGNOSTIC CHECKLIST Consider • Airway-centered interstitial fibrosis in any patient with HP • Must demonstrate functional, clinical, and imaging abnormalities • Histopathological diagnosis of chronic (cluster 2) HP should be further evaluated for possible ACIF ○ Bronchoalveolar lavage: Lymphocytes < 40 %

Image Interpretation Pearls • Chest radiography ○ Peribronchial opacities ○ Architectural distortion • CT ○ Central and peribronchovascular distribution of disease ○ Reticular opacities ○ Ground-glass opacities ○ Air-trapping

SELECTED REFERENCES 1.

2. 3.

4.

5. 6.

Demographics

7.

• Middle-aged women (40-50 years of age)

8.

Natural History & Prognosis

9.

• Prognosis unknown: Small number of cases described 284

• Poor prognostic indicators on histology ○ Degree of fibrosis – Expanding fibrosis to lung parenchyma – Honeycombing ○ Fibroblastic foci or organizing tissue in airways • HRCT prognostic indicators ○ Decreased survival of patients with honeycombing and traction bronchiectasis • Evolution ○ Disease may progress despite elimination of antigen exposure ○ More aggressive course than HP ○ Better survival than idiopathic pulmonary fibrosis ○ High mortality rate in absence of lung transplantation

Bois MC et al: Could prominent airway-centered fibroblast foci in lung biopsies predict underlying chronic microaspiration in idiopathic pulmonary fibrosis patients? Hum Pathol. 53:1-7, 2016 Kuranishi LT et al: Airway-centered interstitial fibrosis: etiology, clinical findings and prognosis. Respir Res. 16:55, 2015 Virk RK et al: Interstitial lung diseases that are difficult to classify: a review of bronchiolocentric interstitial lung disease. Arch Pathol Lab Med. 139(8):9848, 2015 Allaix ME et al: Idiopathic pulmonary fibrosis and gastroesophageal reflux. Implications for treatment. J Gastrointest Surg. 18(1):100-4; discussion 1045, 2014 Herbst JB et al: Hypersensitivity pneumonia: role of surgical lung biopsy. Arch Pathol Lab Med. 136(8):889-95, 2012 Myers JL: Hypersensitivity pneumonia: the role of lung biopsy in diagnosis and management. Mod Pathol. 25 Suppl 1:S58-67, 2012 Fenton ME et al: Hypersensitivity pneumonitis as a cause of airway-centered interstitial fibrosis. Ann Allergy Asthma Immunol. 99(5):465-6, 2007 Churg A et al: Airway-centered interstitial fibrosis: a distinct form of aggressive diffuse lung disease. Am J Surg Pathol. 28(1):62-8, 2004 Colombat M et al: Lung transplantation in a patient with airway-centered fibrosis. Am J Surg Pathol. 28(11):1540-2, 2004

Airway-Centered Interstitial Fibrosis Interstitial Pneumonias

(Left) Axial NECT of a patient with airway-centered interstitial fibrosis shows peribronchovascular thickening and traction bronchiectasis ﬉ and airtrapping ﬈. Cryobiopsy confirmed the diagnosis of airway-centered interstitial fibrosis. (Right) Axial NECT of a patient with airwaycentered interstitial fibrosis shows left upper lobe peribronchovascular thickening with irregular margins and associated architectural distortion ﬉ and faint ill-defined left upper lobe ground-glass opacities ﬈.

(Left) Axial HRCT of a patient with airway-centered interstitial fibrosis shows peribronchovascular thickening and irregular airway dilatation secondary to traction bronchiectasis consistent with mild interstitial fibrosis ﬉. Note scattered areas of air-trapping ﬈. (Right) Coronal HRCT of the same patient shows asymmetric architectural distortion in the left upper lobe, bilateral mosaic attenuation ﬈, bronchial wall thickening ﬊, and traction bronchiectasis ﬉.

(Left) Axial HRCT of a patient with ACIF shows multifocal bilateral, asymmetric, peribronchovascular groundglass opacities with central and peripheral reticular opacities ﬉. When fibrosis is present, findings of architectural distortion are usually mild. Ill-defined centrilobular nodules ﬈ are visible in the periphery of both lungs. (Right) Axial HRCT of the same patient shows bronchial wall thickening ﬈ and peribronchovascular consolidations ﬉ with air bronchograms.

285

Interstitial Pneumonias

Interstitial Pneumonia With Autoimmune Features (IPAF) KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Interstitial pneumonia based on histology or HRCT/CT without complete rheumatologic criteria for specific connective tissue disease (CTD) but with clinical, serological, and morphologic criteria that suggest autoimmunity • Term proposed by task force of European Respiratory Society and American Thoracic Society in 2015 in response to absence of consensus regarding terminology

• • • • •

IMAGING • Nonspecific interstitial pneumonia: Reticular &/or groundglass opacities with apicobasal gradient • Organizing pneumonia: Bilateral consolidations or groundglass opacities with subpleural and lower lung zone predominance • Lymphoid interstitial pneumonia: Lower lobe predominant patchy ground-glass or reticular opacities; lung cysts • Usual interstitial pneumonia: Subpleural honeycombing with apicobasal gradient

(Left) Axial HRCT of a 55-yearold woman with interstitial pneumonia with autoimmune features shows multifocal bilateral ground-glass opacities (which exhibited an apicobasal gradient). The patient did not meet rheumatologic criteria for any specific autoimmune disease. However, antinuclear and anti-EJ antibodies were present. (Right) Axial HRCT of the same patient shows basilar predominant bilateral ground-glass opacities and subtle intrinsic traction bronchiectasis ﬈.

(Left) Axial prone HRCT from the same patient shows persistence of bilateral basilar predominant ground-glass opacities. (Right) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows mild alveolar wall thickening ﬊ consistent with early cellular nonspecific interstitial pneumonia with interspersed areas of normal lung parenchyma ﬉. Note prominent nodular lymphoid hyperplasia ﬈, which is a morphologic criterion for the diagnosis of interstitial pneumonia with autoimmune features.

286

Nonspecific interstitial pneumonia Organizing pneumonia Lymphoid interstitial pneumonia Idiopathic pulmonary fibrosis Connective tissue disease-associated interstitial lung disease

CLINICAL ISSUES • Criteria ○ Presence of interstitial pneumonia by HRCT/CT or surgical lung biopsy and ○ Exclusion of alternative etiologies and ○ Failure to meet criteria of defined CTD and ○ At least 1 feature from at least 2 of 3 domains (clinical, serologic, and morphologic) • Task force does not recommend specific treatment and leaves it to discretion of individual provider

Interstitial Pneumonia With Autoimmune Features (IPAF)

Abbreviations • Interstitial pneumonia with autoimmune features (IPAF)

Synonyms • Undifferentiated connective tissue disease-associated interstitial lung disease (CTD-ILD) • Lung-dominant CTD • Autoimmune-featured ILD

Definitions • Interstitial pneumonia demonstrated by histology or HRCT/CT without complete rheumatologic criteria for specific CTD, but with clinical, serological, and morphologic criteria that suggest autoimmunity

Associated Syndromes • • • •

Usual interstitial pneumonia (UIP) Nonspecific interstitial pneumonia (NSIP) Organizing pneumonia (OP) Lymphoid interstitial pneumonia (LIP)

Historic Perspective • IPAF was proposed in 2015 by task force of European Respiratory Society and American Thoracic Society in response to absence of consensus regarding terminology ○ Term is considered work in progress that requires further scientific testing and validation ○ Revisions of criteria will likely occur as more data becomes available ○ Guidelines or recommendations for clinical care, diagnostic testing, or management are not included in task force proposal

Diagnostic Criteria • Presence of interstitial pneumonia by HRCT/CT or surgical lung biopsy and • Exclusion of alternative etiologies and • Failure to meet criteria of defined CTD and • At least 1 feature from at least 2 of following 3 domains ○ Clinical domain – Distal digital fissuring (i.e., "mechanic hands") – Distal digital tip ulceration – Inflammatory arthritis or polyarticular morning joint stiffness ≥ 60 minutes – Palmar telangiectasia – Raynaud phenomenon – Unexplained digital edema – Unexplained fixed rash on digital extensor surfaces (Gottron sign) ○ Serologic domain – Antinuclear antibodies (ANA) ≥ 1:320 titer, diffuse, speckled, homogeneous patterns or ANA nucleolar pattern (any titer) or ANA centromere pattern (any titer) – Rheumatoid factor ≥ 2x upper limit of normal – Anti-CCP (anticyclic citrullinated peptide) – Anti-dsDNA (antidouble stranded DNA) – Anti-Ro (SS-A): Anti-Sjögren-syndrome-related antigen A, also called anti-Ro

– Anti-La (SS-B): Anti-Sjögren-syndrome-related antigen B, also called anti-La – Antiribonucleoprotein – Anti-Smith – Antitopoisomerase (Scl-70) – Anti-tRSNA synthetase □ Jo-1 (antihistidyl) □ PL-7 (antithreonyl) □ PL-12 (antialanyl) □ Others: EJ (antiglycyl), OJ (antiisoleucyl), KS (antiasparaginyl), Zo (antiphenylalanyl), tRS – Anti-PM-Scl (antiexosome) – Anti-MDA-5 (melanoma-differentiation–associated gene 5) ○ Morphologic domain – Suggestive patterns on HRCT/CT □ NSIP □ OP □ LIP □ NSIP with OP overlap – Histopathology patterns or features by surgical lung biopsy □ NSIP □ OP □ LIP □ NSIP with OP overlap □ Interstitial lymphoid aggregates with germinal centers □ Diffuse lymphoplasmacytic infiltration (± lymphoid follicles) – Multicompartmental involvement (in addition to interstitial pneumonia) □ Unexplained pleural effusion or thickening □ Unexplained pericardial effusion or thickening □ Unexplained intrinsic airways disease (by pulmonary function tests, imaging, or pathology) □ Unexplained pulmonary vasculopathy

Interstitial Pneumonias

TERMINOLOGY

IMAGING CT Findings • NSIP ○ Reticular &/or ground-glass opacities with apicobasal gradient ○ Traction bronchiectasis ○ Peribronchovascular involvement ○ Subpleural sparing • OP ○ Bilateral consolidations or ground-glass opacities with subpleural and lower lung zone predominance ○ Peribronchovascular consolidations, ground-glass opacities or nodules ○ Reversed halo (atoll) sign • LIP ○ Lower lobe-predominant patchy ground-glass or reticular opacities ○ Scattered lung cysts • UIP ○ Subpleural honeycombing with apicobasal gradient

287

Interstitial Pneumonias

Interstitial Pneumonia With Autoimmune Features (IPAF)

•

•

• •

○ HRCT UIP pattern (i.e., subpleural reticular opacities and honeycombing with apicobasal gradient ± traction bronchiectasis) may be seen in IPAF and does not exclude diagnosis but is not included in morphologic domain – Rationale: Pattern alone does not increase likelihood of having CTD – Controversy □ UIP is a common pattern in patients with IPAF □ Not including UIP in morphologic domain may not allow diagnosis of IPAF in patient with UIP pattern with positive serologies but no features in clinical domain; such patients may be classified as having idiopathic pulmonary fibrosis NSIP with OP overlap ○ Feature in morphologic domain – Lower lobe-predominant consolidation, often peridiaphragmatic, associated with features of fibrosis (e.g., traction bronchiectasis, reticular abnormality, or lower lobe volume loss) – Controversy: This term is seldom used by radiologists; description fits imaging features of NSIP Unexplained intrinsic airways disease: Mosaic attenuation pattern, air-trapping (on expiration), bronchial wall thickening, and bronchiectasis Unexplained pulmonary vasculopathy: Dilated pulmonary trunk &/or pulmonary arteries Unexplained pleural or pericardial effusion or thickening

DIFFERENTIAL DIAGNOSIS Nonspecific Interstitial Pneumonia • Identical imaging features • Idiopathic cases do not meet criteria for any autoimmune disease • IPAF diagnosis requires 1 feature in at least 2 domains (i.e., clinical, serologic, and morphologic)

Organizing Pneumonia • Identical imaging features • Does not meet criteria for any autoimmune disease

Lymphoid Interstitial Pneumonia • Identical imaging features • Common associated autoimmune diseases: Sjögren syndrome and rheumatoid arthritis

Idiopathic Pulmonary Fibrosis • Identical imaging features • Does not meet criteria for any autoimmune disease

Connective Tissue Disease-Associated Interstitial Lung Disease • Identical imaging features • Fulfills specific CTD diagnostic criteria

Staging, Grading, & Classification • Histopathology patterns or features by surgical lung biopsy ○ OP ○ NSIP with OP overlap ○ LIP ○ Interstitial lymphoid aggregates with germinal centers ○ Diffuse lymphoplasmacytic infiltration (± lymphoid follicles)

CLINICAL ISSUES Presentation • Other signs/symptoms ○ Unexplained intrinsic airways disease – Reduced forced expiratory volume in 1 second (FEV1) or low FEV1:forced vital capacity (FVC) ratio – Elevated airways resistance ○ Unexplained pulmonary vasculopathy – Pulmonary hypertension defined as mean pulmonary pressure of > 25 mm Hg – Pulmonary capillary wedge pressure M • Ethnicity ○ More common in non-Hispanic white populations • Epidemiology ○ Typically nonsmokers

Natural History & Prognosis • Clinical findings are still unclear; further investigation is required • IPAF survival is similar to that CTD-ILD when HRCT or surgical lung biopsy is different than UIP pattern • IPAF survival is better than that of idiopathic pulmonary fibrosis

Treatment • Task force does not recommend specific treatment and leaves it to discretion of individual provider

SELECTED REFERENCES 1.

2.

3. 4. 5.

PATHOLOGY General Features • Multiple pathologic patterns included within morphologic domain (e.g., NSIP, OP, NSIP with OP, or LIP) • UIP is not listed in morphologic domain, but its presence does not exclude diagnosis 288

6.

7.

Collins B et al: Interstitial pneumonia with autoimmune features: the new consensus-based definition for this cohort of patients should be broadened. Eur Respir J. 47(4):1293-5, 2016 Ferri 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. 15(1):61-70, 2016 Luppi F et al: Interstitial pneumonitis with autoimmune features (IPAF): a work in progress. Eur Respir J. 47(6):1622-4, 2016 Oldham JM et al: Characterisation of patients with interstitial pneumonia with autoimmune features. Eur Respir J. 47(6):1767-75, 2016 Strek ME et al: A call for uniformity in implementing the IPAF (interstitial pneumonia with autoimmune features) criteria. Eur Respir J. 48(6):18131814, 2016 Assayag D et al: Survival in interstitial pneumonia with features of autoimmune disease: a comparison of proposed criteria. Respir Med. 109(10):1326-31, 2015 Fischer A et al: An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J. 46(4):976-87, 2015

Interstitial Pneumonia With Autoimmune Features (IPAF) Interstitial Pneumonias

(Left) High-power photomicrograph (H&E stain) shows insterstitial pneumonia with authoimmune features manifesting with minimally thickened alveolar septa with interstitial lymphoid infiltrates ﬈. (Right) High-power photomicrograph (H&E stain) of the same specimen shows mild septal fibrosis ﬈ and interstitial lymphoid infiltrates. Histologic findings in interstitial pneumonia with autoimmune features includes nonspecific interstitial pneumonia, organizing pneumonia, and lymphoid interstitial pneumonia.

(Left) Axial HRCT of a 68-yearold woman with interstitial pneumonia with autoimmune features shows a nonspecific interstitial pneumonia pattern on HRCT with subpleural lower lobe ground-glass and reticular opacities and traction bronchiolectasis ﬈. Despite the presence of antinuclear antibodies, there were insufficient criteria to diagnose a specific connective tissue disease. (Right) Sagittal HRCT of the same patient shows subpleural ground-glass and reticular opacities and traction bronchiolectasis ﬈.

(Left) Axial HRCT of a 35-yearold woman with interstitial pneumonia with autoimmune features demonstrates subtle subpleural ground-glass opacities ﬉ suggestive of a nonspecific interstitial pneumonia pattern. Despite the presence of antinuclear antibodies, there were insufficient rheumatologic criteria for diagnosing connective tissue disease. (Right) Axial prone HRCT of the same patient shows persistence of subpleural ground-glass opacities that exhibit an inconsistent with UIP pattern.

289

Interstitial Pneumonias

Interstitial Pneumonia With Autoimmune Features (IPAF)

(Left) PA chest radiograph of a 68-year-old patient with interstitial pneumonia with autoimmune features shows low lung volumes and subtle ill-defined hazy bilateral opacities. (Right) Axial HRCT of the same patient shows ground-glass and reticular opacities that demonstrated an apicobasal gradient and associated traction bronchiectasis and bronchiolectasis ﬉. The imaging findings are identical to those seen in idiopathic interstitial pneumonia or connective tissue disorders with interstitial lung disease.

(Left) Axial prone HRCT of the same patient shows persistent lower lobe-predominant reticular opacities and honeycombing ﬈. As in cases of interstitial lung disease, prone imaging is helpful to differentiate early interstitial lung disease from areas of dependent atelectasis. (Right) Sagittal HRCT of the same patient shows posterior subpleural ground-glass and reticular opacities with a distinct apicobasal gradient. Note the presence of associated traction bronchiectasis ﬈.

(Left) Axial HRCT of a 70-yearold man with interstitial pneumonia with autoimmune features shows subpleural lower lobe predominant honeycombing ﬈. (Right) Low-power photomicrograph (H&E stain) of a specimen of interstitial pneumonia with autoimmune features shows fibrotic thickening of alveolar septa ﬈ consistent with cellular nonspecific interstitial pneumonia, coexisting with areas of honeycombing ﬊. Typically fibroblastic foci are not as prominent in areas of nonspecific interstitial pneumonia.

290

Interstitial Pneumonia With Autoimmune Features (IPAF) Interstitial Pneumonias

(Left) Intermediate-power photomicrograph (H&E stain) of the same specimen shows an area of honeycombing with intrinsic bronchiolar metaplasia ﬈. (Right) Highpower photomicrograph (H&E stain) of a specimen of interstitial pneumonia with autoimmune features shows alveolar septa mildly thickened by interstitial lymphoid infiltrates ﬈. Lymphoid aggregates with germinal centers and lymphoplasmacytic infiltration are histologic findings included in the morphologic domain.

(Left) Coronal CECT of a patient with interstitial pneumonia with autoimmune features demonstrates scattered thin-walled cysts ﬈, ill-defined nodules ﬉, and ground-glass opacities consistent with a lymphoid interstitial pneumonia pattern. (Right) High-power photomicrograph (H&E stain) of a specimen of interstitial pneumonia with autoimmune features and a lymphoid interstitial pneumonia morphologic pattern shows interstitial thickening by a lymphoid cell infiltrate.

(Left) Axial CECT of a patient with interstitial pneumonia with autoimmune features and organizing pneumonia shows multifocal bilateral consolidations ﬊. (Right) Low-power photomicrograph (H&E stain) shows organizing pneumonia ﬈ distal to an obliterated bronchiole ﬉ in the setting of follicular bronchiolitis ﬊. Interstitial lymphoid aggregates with germinal centers and diffuse lymphoplasmacytic infiltration are findings included in the morphologic domain for interstitial pneumonia with autoimmune features.

291

Interstitial Pneumonias

Approach to Smoking-Related Interstitial Lung Diseases Introduction Although there has been a continued decline in cigarette smoking in the USA over the last several decades, it continues to be prevalent in our population. According to the Centers for Disease Control, 15.1% of adults in the USA were current smokers in the year 2015. In addition, the World Health Organization estimates that over 1.1 billion persons smoked tobacco products in 2015 worldwide. Primary lung cancer and chronic obstructive pulmonary disease (COPD) are serious pulmonary diseases associated with cigarette smoking. Primary lung cancer carries a high mortality rate as most lesions are diagnosed at an advanced stage. COPD is a physiologic alteration that results in airflow limitation. Although its diagnosis is not based on imaging abnormalities, some of the abnormalities of smoking-related subtypes of COPD are readily assessed and quantified on CT. These include emphysema as well as large and small airway diseases. COPD affects over 5% of the population, is associated with high morbidity, and is the 3rd ranked cause of death in the USA. Emphysema is the most common imaging finding associated with cigarette smoking. While the association with cigarette smoking is irrefutable in cases of centrilobular emphysema, most cases of panlobular and paraseptal emphysema also occur in smokers, and all 3 types of emphysema may coexist in the same subject. Inhaled cigarette smoke contains thousands of toxic and carcinogenic chemicals, gases, and particles that directly affect the airways, the alveolar walls, and the airspaces of the lung. The effects of smoking in the lung comprise a combination of inflammation, lung destruction, lung remodeling, and repair, which produce corresponding histologic and imaging abnormalities. Thus, it is not surprising that there are a number of more indolent smoking-related diseases that may affect the lung.

Smoking-Related Interstitial Pneumonias In 2013, an update of the international multidisciplinary classification of the idiopathic interstitial pneumonias was published as an official statement from the American Thoracic Society (ATS) and the European Respiratory Society (ERS). The compendium of diseases included a subcategory of smokingrelated interstitial pneumonias: Respiratory bronchiolitisinterstitial lung disease (RB-ILD) and desquamative interstitial pneumonia. The ATS/ERS statement acknowledges the general usage of the term "smoking-related interstitial lung disease," which also includes pulmonary Langerhans cell histiocytosis. These entities require distinction from other smoking-related changes, such as an incidental nonneoplastic finding described in resected lung cancer specimens termed airspace enlargement with fibrosis, which may have HRCT and histologic manifestations and may be identified in the setting of combined pulmonary fibrosis and emphysema (CPFE). Although CPFE is a recognized entity, it is not listed as a distinct idiopathic interstitial pneumonia. The updated classification also reports the coexistence of multiple histologic findings and HRCT patterns in the lungs of smokers in addition to the smoking-related interstitial pneumonias including: Respiratory bronchiolitis, pulmonary fibrosis [both usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia], and emphysema. Given the prevalence of cigarette smoking and the broad utilization of chest CT for a variety of indications, not limited to the HRCT work-up of interstitial lung disease, all 292

radiologists must become familiar with the smoking-related lung diseases and their various imaging manifestations. It should be understood that there is frequent overlap of the various imaging findings of smoking-related lung diseases, that the coexistence of the above mentioned conditions is increasingly recognized, and that smoking-related diseases may occur along a spectrum of imaging abnormalities. Thus, patients with pulmonary Langerhans cell histiocytosis may exhibit other smoking-related imaging findings that may include centrilobular emphysema and RB. It is also important to recognize that the diagnosis of interstitial lung disease is no longer purely histologic, but that the ATS/ERS update encourages a "dynamic integrated approach" using multidisciplinary discussion. In such cases, radiologists are equipped to make invaluable contributions and should "have a seat at the table" in order to positively impact the diagnosis and management of affected patients. For example, smokers may have both emphysema (which reduces elastic recoil) and fibrosis (which increases elastic recoil). Both conditions contribute to an additive reduction of diffusing capacity. Thus, affected patients may present with severe dyspnea and normal spirometry with respect to flow rates and total lung capacity. In many of these cases, radiologists will easily identify findings of emphysema and fibrosis, which are generally well visualized on HRCT. However, diffuse fibrosis will be difficult to identify in some affected subjects. RB is a universal incidental histologic finding in the lungs of asymptomatic smokers. Pigmented macrophages within respiratory bronchioles and adjacent airspaces correlate with upper lobe centrilobular ground-glass nodules on HRCT. RB-ILD also exhibits the histologic findings of RB, but affected patients are symptomatic and have more extensive upper lobe centrilobular ground-glass nodules and may exhibit more confluent ground-glass opacities. The diagnosis is frequently made without surgical biopsy in cases with characteristic HRCT findings and smoker's macrophages without lymphocytosis in bronchoalveolar lavage fluid. The latter allows exclusion of hypersensitivity pneumonitis, which may mimic RB on imaging. Desquamative interstitial pneumonia is a rare entity, and a small number of cases are not associated with smoking. Affected patients may exhibit extensive and aggregated pigmented macrophages in their airway lumina, which manifest as more extensive areas of ground-glass opacity with lower lung predominance and associated multiple clustered small thin-walled lung cysts.

Selected References 1.

2.

3.

4. 5. 6.

Centers for Disease Control and Prevention: Current cigarette smoking among adults in the United States. https://www.cdc.gov/tobacco/data_statistics/fact_sheets/adult_data/cig_s moking/. Reviewed February 3, 2017. Accessed February 3, 2017. World Health Organization: Prevalence of tobacco smoking. http://www.who.int/gho/tobacco/use/en/. Reviewed February 3, 2017. Accessed February 3, 2017. Kligerman S et al: Clinical-radiologic-pathologic correlation of smokingrelated diffuse parenchymal lung disease. Radiol Clin North Am. 54(6):10471063, 2016 Franks TJ et al: Smoking-related "interstitial" lung disease. Arch Pathol Lab Med. 139(8):974-7, 2015 Koelsch TL et al: Radiologic evaluation of idiopathic interstitial pneumonias. Clin Chest Med. 36(2):269-82, ix, 2015 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. 188(6):733-48, 2013

Approach to Smoking-Related Interstitial Lung Diseases Interstitial Pneumonias

(Left) Axial NECT of an asymptomatic smoker shows subtle multifocal upper lobepredominant centrilobular ground-glass ﬉ and solid ﬈ pulmonary nodules consistent with respiratory bronchiolitis. (Right) High-power photomicrograph (H&E stain) of a specimen of respiratory bronchiolitis shows collections of pigmented macrophages within an airway lumen ﬈ and in adjacent alveolar spaces ﬊. Respiratory bronchiolitis is an incidental imaging and histologic finding in asymptomatic smokers. (From DP: Thoracic, 2e.)

(Left) Axial HRCT of a smoker with respiratory bronchiolitisinterstitial lung disease who presented with cough and dyspnea shows scattered centrilobular ground-glass opacities ﬉, mild septal thickening, and mild centrilobular emphysema ﬈. (Right) Axial HRCT of the same patient shows scattered bilateral ground-glass opacities ﬉ and mosaic attenuation. The diagnosis may be established based on typical HRCT abnormalities and bronchoalveolar lavage fluid findings that exclude hypersensitivity pneumonitis.

(Left) High-power photomicrograph (H&E stain) of a specimen of respiratory bronchiolitis-interstitial lung disease shows alveolar and airway macrophages ﬈ and partial destruction of a small airway ﬊. (From DP: Thoracic, 2e.) (Right) High-power photomicrograph (H&E stain) of a specimen of respiratory bronchiolitis-interstitial lung disease shows alveolar pigmented macrophages ﬊ and areas of interstitial thickening and scarring ﬈ that replace the normal alveolated architecture. (From DP: Thoracic, 2e.)

293

Interstitial Pneumonias

Approach to Smoking-Related Interstitial Lung Diseases

(Left) Axial HRCT of a smoker with desquamative interstitial pneumonia who presented with severe cough and dyspnea shows extensive bilateral upper lobe groundglass opacities, most pronounced in the left upper lobe. Note associated paraseptal ﬊ and centrilobular ﬈ emphysema. (Right) Axial HRCT of the same patient shows patchy mid and lower lung zone ground-glass opacities. CT manifestations of smoking-related lung disease may occur along a spectrum and may coexist in the same subject.

(Left) Low-power photomicrograph (H&E stain) of a specimen of desquamative interstitial pneumonia shows monotonous pigmented macrophages ﬈ filling alveolar lumina, minimal interstitial fibrosis or inflammation, and a uniform histologic appearance. (From DP: Thoracic, 2e.) (Right) Highpower photomicrograph (H&E stain) of the same specimen shows airspace plugging and distention by luminal alveolar macrophages and scattered multinucleated cells ﬉. (From DP: Thoracic, 2e.)

(Left) Axial NECT of a patient with pulmonary Langerhans cell histiocytosis shows upper lung-predominant small ground-glass ﬉ and solid ﬈ nodules, one with intrinsic cavitation ﬊. (Right) Lowpower photomicrograph (H&E stain) of a specimen of pulmonary Langerhans cell histiocytosis shows a characteristic stellate-shaped lesion that exhibits a monotonous population of small, round-to-oval cells. These lesions are typically distributed about bronchioles and vascular bundles. (From DP: Thoracic, 2e.)

294

Approach to Smoking-Related Interstitial Lung Diseases Interstitial Pneumonias

(Left) Coronal NECT of a patient with pulmonary Langerhans cell histiocytosis shows upper lung zonepredominant small cysts, some with slightly nodular walls ﬉. (Right) High-power photomicrograph (H&E stain) of a specimen of pulmonary Langerhans cell histiocytosis shows a nodular lesion with central cavitation ﬊, a characteristic feature of this smoking-related lung disease that correlates with pulmonary cysts with nodular walls on HRCT/CT imaging. (From DP: Thoracic, 2e.)

(Left) Axial NECT of a smoker with combined pulmonary fibrosis and emphysema who presented with severe dyspnea shows bilateral paraseptal ﬉ and centrilobular ﬈ emphysema and bilateral subpleural ground-glass opacities and reticulation ﬊. (Right) Coronal NECT of the same patient shows paraseptal emphysema ﬉ and basilar predominant subpleural ground-glass opacities and reticulation ﬊ with associated traction bronchiectasis ﬈. This entity is not considered an idiopathic interstitial pneumonia.

(Left) Axial HRCT of a symptomatic smoker shows scattered centrilobular ground-glass and solid nodules ﬈, centrilobular emphysema ﬉, and small cystic lesions ﬊ with slightly nodular walls reminiscent of lesions of Langerhans cell histiocytosis. (Right) Coronal NECT of a patient with biopsy-proven pulmonary Langerhans cell histiocytosis shows upper lobe centrilobular emphysema ﬉ and ill-defined ground-glass opacity nodules ﬊. Various manifestations of smokingrelated lung disease may coexist in the same subject.

295

Interstitial Pneumonias

Respiratory Bronchiolitis-Interstitial Lung Disease KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Respiratory bronchiolitis (RB): Cellular bronchiolitis present in virtually all smokers, characterized by accumulation of pigmented macrophages in airways and alveoli • RB-interstitial lung disease (ILD): Smoking-related ILD closely related to RB but with more severe histologic, imaging, and clinical features; RB causing symptoms and pulmonary function deficits • Spectrum of smoking-related ILD: RB, RB-ILD, and desquamative interstitial pneumonia (DIP)

• Respiratory bronchiolitis • Hypersensitivity pneumonitis • Desquamative interstitial pneumonia

IMAGING

CLINICAL ISSUES

• CT/HRCT ○ Centrilobular micronodules (common) – Ground-glass attenuation (common) ○ Ground-glass opacity (common) ○ Bronchial wall thickening (common) ○ Coexistent emphysema ○ Discrete nodules are suspicious for lung cancer

• Clinical symptoms: Mild cough and dyspnea • Mixed obstructive/restrictive lung function + ↓ diffusing capacity for carbon monoxide • Treatment: Smoking cessation, corticosteroids

(Left) Axial HRCT of a symptomatic patient with respiratory bronchiolitisinterstitial lung disease shows ill-defined ground-glass centrilobular micronodules ﬉, mild bronchial wall thickening ﬊, and right upper lobe paraseptal emphysema ﬈. (Right) High-power photomicrograph (H&E stain) of a specimen from the same patient shows pigmented macrophages ﬈ within alveoli and within a respiratory bronchiole ﬈. Note coexistent emphysema ﬊ and peribronchiolar smooth muscle hypertrophy ﬉.

(Left) Axial HRCT of a patient with respiratory bronchiolitisinterstitial lung disease shows diffuse bilateral ground-glass opacities. The most common CT abnormalities include bronchial wall thickening, centrilobular micronodules, and ground-glass opacities. (Right) Axial HRCT of a patient with respiratory bronchiolitisinterstitial lung disease shows mosaic attenuation characterized by ground-glass opacities admixed with areas of decreased attenuation ﬈ likely reflecting air-trapping. Note associated interlobular septal thickening ﬉.

296

PATHOLOGY • Mild to moderate chronic inflammation and fibrosis around bronchioles and adjacent alveolar septa • Pigmented macrophages in respiratory bronchioles and alveoli

DIAGNOSTIC CHECKLIST • Consider RB-ILD in symptomatic smokers with upper lobepredominant ground-glass centrilobular micronodules

Respiratory Bronchiolitis-Interstitial Lung Disease

PATHOLOGY

Abbreviations

General Features

• Respiratory bronchiolitis-interstitial lung disease (RB-ILD)

• RB histology associated with pulmonary interstitial abnormalities and respiratory symptoms

Definitions • RB: Cellular bronchiolitis present in virtually all smokers, characterized by accumulation of pigmented macrophages in airways and alveoli • RB-ILD: Smoking-related ILD closely related to RB but with more severe histologic, imaging, and clinical features; RB causing symptoms and pulmonary function deficits • Spectrum of smoking-related ILD: RB, RB-ILD, and desquamative interstitial pneumonia (DIP)

IMAGING General Features • Best diagnostic clue ○ Ground-glass opacity and centrilobular nodules with upper lobe predominance

Radiographic Findings • Typically normal chest radiographs • Bilateral reticular/nodular opacities; diffuse with upper lung zone predominance

CT Findings • Centrilobular micronodules (common) ○ Typically ground-glass attenuation; may be solid • Ground-glass opacity (common) • Bronchial wall thickening (common) • Coexistent emphysema • Mosaic attenuation, air-trapping, septal thickening, reticular opacities, nodules, honeycombing (uncommon) • Discrete nodules should be regarded as suspicious for primary lung cancer

Imaging Recommendations • Best imaging tool ○ HRCT/CT • Protocol advice ○ Maximum intensity projection reformations may help identify centrilobular nodules

DIFFERENTIAL DIAGNOSIS Respiratory Bronchiolitis • Identical histology/imaging abnormalities but no clinical symptoms

Hypersensitivity Pneumonitis • May be identical to RB-ILD: Centrilobular ground-glass micronodules, mosaic attenuation, air-trapping • More diffuse and conspicuous findings • Smokers have decreased risk for developing hypersensitivity pneumonitis

Desquamative Interstitial Pneumonia • Lower lung zone-predominant subpleural ground-glass opacities &/or consolidations; clustered thin-walled cysts

Microscopic Features • Centrilobular ground-glass nodules on CT correlate with RB • Ground-glass attenuation on CT correlates with alveolitis • Mild to moderate chronic inflammation and fibrosis, may surround bronchioles and involve adjacent alveolar septa • Accumulation of pigmented macrophages (smoker's macrophages) in respiratory bronchioles and alveoli ○ Macrophages contain finely granular golden-brown pigment, which is iron stain (+) • Mild nonspecific peribronchiolar alveolar septal thickening • Chronic bronchitis and emphysema are frequently present

Interstitial Pneumonias

TERMINOLOGY

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Mild cough and dyspnea ○ Inspiratory crackles • Other signs/symptoms ○ Pulmonary function: Mixed obstructive/restrictive pattern + ↓ diffusing capacity for carbon monoxide

Demographics • Smokers 30-40 years of age ○ Most patients with 30 pack-years or more

Diagnosis • Pulmonary symptoms, abnormal pulmonary function, characteristic CT/HRCT and surgical biopsy findings • Diagnosis without surgical biopsy in symptomatic smokers with characteristic CT/HRCT findings and bronchoalveolar lavage showing smoker's macrophages without lymphocytosis

Natural History & Prognosis • Conflicting information regarding outcomes ○ Some studies show overall good prognosis; others show clinical and physiologic progression despite treatment &/or smoking cessation • No mortality attributed to RB-ILD • Progression to fibrotic lung disease exceedingly rare • Considerable ↑ risk of lung cancer

Treatment • Smoking cessation • Corticosteroids

DIAGNOSTIC CHECKLIST Consider • RB-ILD in symptomatic smokers with upper lobepredominant ground-glass and centrilobular micronodules

SELECTED REFERENCES 1.

Sieminska A et al: Respiratory bronchiolitis-interstitial lung disease. Orphanet J Rare Dis. 9:106, 2014

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Desquamative Interstitial Pneumonia KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Desquamative interstitial pneumonia (DIP): Interstitial lung disease characterized by accumulation of alveolar macrophages

• Respiratory bronchiolitis interstitial lung disease • Nonspecific interstitial pneumonia • Hypersensitivity pneumonitis

IMAGING

PATHOLOGY

• Radiography ○ Ill-defined airspace disease, reticular opacities ○ Mid and lower lung zone involvement • CT/HRCT ○ Ground-glass opacities (83-100%) – ± associated consolidation – Bilateral and moderately symmetric (> 50%) – Lower zone (73%), peripheral (59%), patchy (23%), diffuse (18%) ○ Intralobular lines or reticular opacities (17-63%) – Subpleural predominance – Associated with ground-glass opacities ○ Cysts: Small, round, thin-walled (2-4 mm in diameter)

• Diffuse lung involvement by extensive accumulation of alveolar macrophages

(Left) Axial HRCT of a 67-yearold male smoker who presented with dyspnea shows patchy bilateral ground-glass opacities ﬈ and areas of spared normal pulmonary parenchyma. Note the small, thin-walled pulmonary cysts ﬉, some of which could represent centrilobular emphysema. (Right) Axial HRCT of the same patient shows patchy ground-glass opacities ﬈, multifocal thinwalled lung cysts ﬉, and subtle subpleural intralobular lines ﬊. Note the absence of fibrosis, architectural distortion, or honeycombing.

(Left) Low-power photomicrograph (H&E stain) of a biopsy specimen from a patient with desquamative interstitial pneumonia shows marked expansion and filling of alveolar spaces by a dense monotonous population of alveolar macrophages ﬉. (Right) High-power photomicrograph (H&E stain) of the same specimen shows macrophages filling the alveolar lumina ﬈ and minimal interstitial fibrosis ﬉ or inflammation. The intracellular granular brown pigment ﬊ represents hemosiderin.

298

CLINICAL ISSUES • 40-60 years of age; M:F = 2:1; smokers (58-91%) • Symptoms and signs ○ Dyspnea on exertion ○ Digital clubbing

DIAGNOSTIC CHECKLIST • Consider DIP in smokers with bilateral lower lung zonepredominant ground-glass opacities associated with intralobular lines and thin-walled cysts

Desquamative Interstitial Pneumonia

Abbreviations • Desquamative interstitial pneumonia (DIP)

Definitions • DIP: Interstitial lung disease characterized by accumulation of pigmented macrophages within alveoli and distal pulmonary airspaces • Smokers (58-91%)

IMAGING General Features • Best diagnostic clue ○ Bilateral, lower zone-predominant ground-glass opacities ± subpleural intralobular lines

Radiographic Findings • • • •

Normal (22%) Ill-defined bilateral airspace opacities Bilateral reticular opacities Predominant involvement of mid and lower lung zones

CT Findings • HRCT ○ Ground-glass opacities (83-100%) – ± associated consolidation – Bilateral and moderately symmetric (> 50%) – Lower zone (73%), peripheral (59%), patchy (23%), diffuse (18%) ○ Intralobular lines or reticular opacities (17-63%) – Subpleural predominance – Associated with ground-glass opacities ○ Cysts – Small, round, thin-walled (2-4 mm in diameter) ○ Less common – Traction bronchiectasis – Honeycombing – Emphysema – Subpleural nodules – Centrilobular nodules

Imaging Recommendations • Best imaging tool ○ HRCT

DIFFERENTIAL DIAGNOSIS Respiratory Bronchiolitis Interstitial Lung Disease • • • •

Ground-glass opacities (upper lobe predominance) Centrilobular nodules Intralobular lines/reticular opacities HRCT findings similar to those of DIP

Nonspecific Interstitial Pneumonia • Basilar subpleural ground-glass opacities ○ May exhibit subpleural sparing • Basilar reticular opacities • Traction bronchiectasis and bronchiolectasis

• • • •

Centrilobular nodules (more common than in DIP) Reticular opacities (upper lobe predominance) Cysts (larger than those of DIP) Mosaic attenuation

PATHOLOGY General Features • Etiology ○ Smokers (58-91%) – High smoking index (pack-years) ○ Nonsmokers – Occupational exposure to inorganic particles (Si, Mg, Ti, Fe, Ni, Pb) – Exposure to mycotoxins (aflatoxin) – Connective tissue diseases – Infection (cytomegalovirus, Aspergillus) – Use of marijuana

Interstitial Pneumonias

TERMINOLOGY

Microscopic Features • Diffuse lung involvement by extensive accumulation of alveolar macrophages ○ Uniform histologic appearance: Temporal homogeneity • Mild chronic interstitial inflammation • Mild to moderate fibrotic thickening of alveolar septa

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Dyspnea on exertion ○ Persistent cough ○ Digital clubbing

Demographics • Age ○ 40-60 years • Gender ○ M:F = 2:1

Natural History & Prognosis • Most affected patients have good prognosis • Subgroup of patients may experience disease progression to pulmonary fibrosis in spite of treatment

Treatment • Smoking or exposure cessation • Corticosteroids • Macrolides

DIAGNOSTIC CHECKLIST Consider • DIP in smokers with bilateral lower lung zone-predominant ground-glass opacities associated with intralobular lines and thin-walled cysts

SELECTED REFERENCES 1.

Godbert B et al: Desquamative interstitial pneumonia: an analytic review with an emphasis on aetiology. Eur Respir Rev. 22(128):117-23, 2013

Hypersensitivity Pneumonitis • Ground-glass opacities 299

Interstitial Pneumonias

Desquamative Interstitial Pneumonia

(Left) PA chest radiograph of a patient with desquamative interstitial pneumonia shows multifocal bilateral fine reticular opacities ﬈ more conspicuous in the right upper lung zone. (Right) Axial HRCT of the same patient shows multifocal bilateral groundglass ﬉ and reticular ﬈ opacities. The presence of reticular opacities has been described in desquamative interstitial pneumonia, often with coexisting ground-glass opacities. Frank honeycombing rarely occurs in the setting desquamative interstitial pneumonia.

(Left) Axial HRCT of the same patient shows multifocal bilateral ground-glass ﬉ and reticular ﬈ opacities. Desquamative interstitial pneumonia may occur as an idiopathic interstitial pneumonia unrelated to cigarette smoking in < 10% of all cases. (Right) PA chest radiograph of a patient with desquamative interstitial pneumonia not associated with cigarette smoking shows scattered bilateral ill-defined heterogeneous opacities.

(Left) Axial CECT of the same patient shows multifocal bilateral ground-glass opacities ﬉. Desquamative interstitial pneumonia is characteristically associated with smoking but may develop from exposure to inhaled toxins, drugs, viral infections, and autoimmune diseases. (Right) High-power photomicrograph (H&E stain) of a specimen from the same patient shows alveolar filling by a dense and monotonous population of macrophages ﬈. Note that there is only minimal thickening of the alveolar septa ﬉.

300

Desquamative Interstitial Pneumonia Interstitial Pneumonias

(Left) PA chest radiograph of a patient with desquamative interstitial pneumonia shows bilateral ill-defined opacities ﬉ slightly more conspicuous in the right upper lung zone. Based on imaging findings alone, the differential diagnosis includes acute processes, such as bacterial pneumonia. (Right) Axial CECT of the same patient shows ground-glass opacities, acinar nodules ﬉, and ill-defined consolidations ﬈. Open lung biopsy was performed for diagnosis given persistent imaging abnormalities.

(Left) AP chest radiograph of a patient with desquamative interstitial pneumonia shows subtle bilateral ill-defined hazy opacities. Affected patients may have normal or near normal chest radiography at presentation (in approximately 20% of all patients). (Right) Axial HRCT of the same patient shows bilateral asymmetric groundglass opacities and associated emphysema ﬈. Desquamative interstitial pneumonia typically affects smokers in the 4th-5th decades of life.

(Left) Axial HRCT of the same patient shows diffuse and bilateral ground-glass opacities. While desquamative interstitial pneumonia is usually associated with smoking, the association is less robust than that of respiratory bronchiolitis or pulmonary Langerhans cell histiocytosis. (Right) Low-power photomicrograph (H&E stain) shows desquamative interstitial pneumonia manifesting with uniform intraalveolar macrophages ﬈ with minimal interstitial fibrosis ﬉ or inflammation. (From DP: Thoracic, 2e.)

301

Interstitial Pneumonias

Combined Pulmonary Fibrosis and Emphysema KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Coexistence of upper lobe emphysema and lower lobe pulmonary fibrosis clinically characterized by dyspnea and abnormalities in gas exchange

• • • • •

IMAGING • Radiography ○ Reticular opacities in lung bases and subpleural regions ○ Hyperlucency, diminished vascularity in upper lung zones • CT ○ Upper lobe-predominant centrilobular, paraseptal, &/or panlobular emphysema ○ Subpleural reticulation &/or honeycombing with apicobasal gradient ○ Traction bronchiectasis &/or bronchiolectasis ○ Dilated pulmonary trunk (pulmonary hypertension) ○ Coexisting malignancy is common; nodules and masses should always be regarded as suspicious

(Left) Axial CECT of a 65-yearold male smoker with combined pulmonary fibrosis and emphysema shows advanced bilateral upper lobepredominant centrilobular ﬉ and paraseptal ﬈ emphysema. (Right) Axial CECT (same patient) shows lower lobe-predominant subpleural reticulation ﬉, ground-glass opacities, and traction bronchiectasis ﬈. As patients with combined pulmonary fibrosis and emphysema have an ↑ risk of primary lung malignancy, new nodules or masses should raise suspicion for lung cancer.

(Left) Low-power photomicrograph (H&E stain) of a specimen from a 63-yearold male heavy smoker with combined emphysema and pulmonary fibrosis shows upper lobe dilated airspaces with alveolar wall destruction consistent with centrilobular emphysema. (Right) Lowpower photomicrograph (H&E stain) of the same patient shows lower lobe chronic inflammation with advanced pulmonary fibrosis ﬈, obliteration of alveolar spaces, and thickening of the interstitium consistent with honeycombing.

302

Paraseptal emphysema Idiopathic pulmonary fibrosis Hypersensitivity pneumonitis Asbestosis Silicosis

PATHOLOGY • Upper lobe centrilobular emphysema with histologic features of usual interstitial pneumonia or nonspecific interstitial pneumonia involving lower lobes • Desquamative interstitial pneumonia and respiratorybronchiolitis interstitial lung disease with alveolar fibrosis have also been reported

CLINICAL ISSUES • Exertional dyspnea (most common), cough, finger clubbing • Treatment: No specific treatment, smoking cessation lung transplantation should be considered

Combined Pulmonary Fibrosis and Emphysema

Definitions • Coexistence of upper lobe emphysema and lower lobe pulmonary fibrosis clinically characterized by dyspnea and abnormalities of gas exchange

IMAGING General Features • Best diagnostic clue ○ Upper lobe emphysema and lower lobe pulmonary fibrosis on radiography &/or CT • Location ○ Upper lobe-predominant emphysema ○ Lower lobe-predominant fibrosis

Radiographic Findings • Reticular opacities in lung bases and subpleural regions • Hyperlucency and ↓ vascularity in upper lung zones

CT Findings • HRCT ○ Upper lobe-predominant centrilobular, paraseptal, &/or panlobular emphysema – Decreased lung attenuation – ± bullae ○ Subpleural reticulation &/or honeycombing with apicobasal gradient ○ Subpleural ground-glass opacities with apicobasal gradient ○ Traction bronchiectasis &/or bronchiolectasis ○ Architectural distortion ○ Dilated pulmonary trunk indicating pulmonary hypertension • Coexisting malignancy is common; nodules and masses should always be regarded as suspicious

Imaging Recommendations • Best imaging tool ○ HRCT

DIFFERENTIAL DIAGNOSIS Paraseptal Emphysema • Lower lobe paraseptal emphysema may mimic honeycombing ○ Paraseptal emphysema: 1 layer of cysts ○ Honeycombing (fibrosis): Layers of cysts that share walls

Idiopathic Pulmonary Fibrosis • Basilar honeycombing; absence of emphysema

Hypersensitivity Pneumonitis • Emphysema may be present even in nonsmokers • Typically peribronchovascular fibrosis ○ Hypersensitivity pneumonitis with subpleural fibrosis may be indistinguishable from idiopathic pulmonary fibrosis

• Associated asbestos-related pleural disease

Silicosis • Emphysema may be present even in nonsmokers • Fibrosis (honeycombing) is not common; may be subpleural or peribronchovascular • Peribronchovascular nodules and masses (i.e., progressive massive fibrosis)

PATHOLOGY

Interstitial Pneumonias

TERMINOLOGY

General Features • Upper lobe centrilobular emphysema with histologic features of usual interstitial pneumonia or nonspecific interstitial pneumonia involving lower lobes • Desquamative interstitial pneumonia and respiratorybronchiolitis-associated interstitial lung disease with alveolar fibrosis have also been reported

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Exertional dyspnea (most common) ○ Cough ○ Finger clubbing • Other signs/symptoms ○ Pulmonary function tests: Coexistent obstruction (from emphysema) and restriction (from pulmonary fibrosis) ○ Normal or near normal spirometry (common) – Normal forced vital capacity, forced expiratory volume in 1 second (FEV1), and total lung capacity (TLC) ○ Severely impaired gas exchange with ↓ diffusing capacity of lung for carbon monoxide (DLCO)

Demographics • Strong male predominance (90%)

Natural History & Prognosis • Strong association with cigarette smoking ○ 98% are either current or former smokers • High mortality ○ Median survival: 2-8 years ○ 5-year survival rate: 35-80% • Pulmonary hypertension is common complication (50%) ○ More frequent and more severe than in population with idiopathic pulmonary fibrosis or emphysema alone • Increased risk of lung cancer (> 40%)

Treatment • No specific treatment • Current smokers: Smoking cessation is encouraged • Lung transplantation should be considered

SELECTED REFERENCES 1. 2.

Papiris SA et al: Combined pulmonary fibrosis and emphysema. Expert Rev Respir Med. 7(1):19-31; quiz 32, 2013 Jankowich MD et al: Combined pulmonary fibrosis and emphysema syndrome: a review. Chest. 141(1):222-31, 2012

Asbestosis • Emphysema may be present even in nonsmokers (10-36%) • Fibrosis (honeycombing) is typically subpleural 303

Interstitial Pneumonias

Combined Pulmonary Fibrosis and Emphysema

(Left) PA chest radiograph of a male smoker with combined pulmonary fibrosis and emphysema who presented with dyspnea and cough shows subtle bibasilar reticular opacities. (Right) Axial NECT of the same patient shows bilateral upper lobe-predominant paraseptal emphysema ﬈ manifesting with a single layer of subpleural pulmonary cysts. New nodules or masses in such patients should be regarded as highly suspicious for primary lung cancer.

(Left) Axial NECT of the same patient shows basilar groundglass opacities, reticulation, and minimal traction bronchiolectasis ﬉ without honeycombing. The pattern of involvement is consistent with fibrotic nonspecific interstitial pneumonia. (Right) Sagittal NECT of the same patient shows upper lobe paraseptal emphysema ﬈ and basilar subpleural ground-glass opacities and reticulation ﬊ with an apicobasal gradient, characterized by predominant involvement of the lung bases as opposed to the upper and mid lung zones.

(Left) Axial CECT of a 57-yearold patient with combined pulmonary fibrosis and emphysema shows interstitial fibrosis with reticulation, traction bronchiolectasis ﬈, and honeycombing ﬉. (Right) Axial CECT of the same patient through the lung bases demonstrates more conspicuous bilateral pulmonary fibrosis with interlobular septal thickening, intralobular lines, bronchiectasis, and bronchiolectasis ﬈ in the subpleural lower lobes, demonstrating a characteristic apicobasal gradient.

304

Combined Pulmonary Fibrosis and Emphysema Interstitial Pneumonias

(Left) Axial CECT of a heavy smoker with combined pulmonary fibrosis and emphysema shows upper lung zone-diminished vascularity from panlobular emphysema ﬈ with minimal reticulation and interlobular septal thickening ﬊ in the lung periphery indicating fibrosis. (Right) Axial CECT of a patient with combined pulmonary fibrosis and emphysema shows upper lobe-predominant centrilobular ﬉ and paraseptal ﬈ emphysema and basilar subpleural reticulation and fibrosis.

(Left) Coronal NECT of a patient with combined pulmonary fibrosis and emphysema shows a typical upper lung zone-predominant distribution of advanced emphysema ﬊ and interstitial pulmonary fibrosis ﬉ in the mid and lower lung zones. (Right) Sagittal NECT of the right lung of the same patient shows extensive bullous disease ﬊ in the right upper lobe with minimal residual lung tissue and advanced fibrosis with multilayer honeycombing ﬉ in the posterior subpleural lower lobe.

(Left) Axial CECT of a heavy smoker with combined pulmonary fibrosis and emphysema and progressive dyspnea shows asymmetric confluent centrilobular emphysema and bullous disease ﬉ in the bilateral upper lobes. (Right) Coronal CECT of the same patient shows severe upper lobe centrilobular emphysema ﬉ and mid and lower lung zone subpleural ground-glass opacities and reticulation with traction bronchiolectasis ﬈ indicating fibrosis.

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SECTION 9

Autoimmune Diseases

Approach to Connective Tissue Disease-Associated Interstitial Lung Disease Rheumatoid Arthritis Progressive Systemic Sclerosis Dermatomyositis/Polymyositis Sjögren Syndrome Mixed Connective Tissue Disease Systemic Lupus Erythematosus Granulomatosis With Polyangiitis (GPA) Eosinophilic Granulomatosis With Polyangiitis Microscopic Polyangiitis Ankylosing Spondylitis Inflammatory Bowel Disease

308 312 316 320 324 330 332 338 344 348 350 354

Autoimmune Diseases

Approach to Connective Tissue Disease-Associated Interstitial Lung Disease Introduction Autoimmune diseases encompass a heterogeneous group of over 80 chronic illnesses with variable phenotypic expression and molecular mechanisms in which the immune system attacks its host cells. The broad range of autoimmune diseases includes connective tissue diseases (CTD), also known as collagen vascular diseases, systemic vasculitides, and other conditions less commonly recognized as autoimmune disorders (e.g., pulmonary alveolar proteinosis, relapsing polychondritis, etc.) that can affect the lung parenchyma and other thoracic structures. Systemic autoimmune diseases, which reflect an imbalance between effector and regulatory mechanisms, are commonly associated with inappropriate activation of autoreactive CD4 T cells as well as autoreactive B cells responsible for the formation of pathogenic autoantibodies. Depending on the underlying condition, the autoantibodies will predominantly affect the lung parenchyma, airways, pulmonary vasculature, pleura, or chest wall. The lung parenchyma is a common target of autoimmune diseases with roughly 15% of all patients with interstitial lung disease (ILD) having an underlying CTD. In some CTD, the presence of ILD may be the only, the most common, or the most significant clinical manifestation as well as an important cause of morbidity and mortality. Commonly, ILD is diagnosed concurrently with or after the diagnosis of CTD, but in some patients, the ILD may manifest years prior to the diagnosis of the rheumatologic disorder. Therefore, patients with ILD require a comprehensive evaluation for CTD since the prognosis and treatment of CTD-ILD differs from that of other idiopathic interstitial pneumonias, such as idiopathic pulmonary fibrosis.

Differential Diagnosis The 3 most common thoracic manifestations of CTD are ILD, pulmonary arterial hypertension (PAH), and pleural disease. The most common histopathologic and morphologic (imaging) patterns of ILD are nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), organizing pneumonia (OP), and lymphoid interstitial pneumonia (LIP). NSIP is the most common phenotype of diffuse pulmonary involvement (> 80%) with the exception of rheumatoid arthritis (RA), in which UIP is the most common pattern (> 50%). Likewise, the NSIP pattern is more frequently seen in association with CTD than as a primary or idiopathic disease. For this reason, in a young patient with positive autoantibodies and NSIP-like pulmonary abnormalities, CTD should always be excluded. When an identifiable underlying cause can be excluded with certainty, the ILD is designated idiopathic NSIP. The presence of ground-glass opacities is the hallmark imaging feature of NSIP on CT, regardless of whether it is idiopathic or associated with CTD. Typically the HRCT findings of NSIP include bilateral patchy ground-glass opacities with lower lobe-predominant distribution. The abnormalities may be peripheral and peribronchovascular or associated with interlobular septal thickening and reticulation with mild traction bronchiectasis/bronchiolectasis. Although small subpleural cysts may be appreciated in fibrotic NSIP, honeycombing is not a significant component. As opposed to NSIP, UIP is characterized by a more advanced degree of fibrosis with fibrosis and honeycombing, alternating with areas of normal lung (i.e., temporal and spatial heterogeneity). Ground-glass opacities in UIP are less 308

extensive than in NSIP and are not typically the dominant feature. According to the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association guidelines for the diagnosis of idiopathic pulmonary fibrosis, the typical HRCT findings in UIP (i.e., UIP pattern) include reticular opacities and honeycombing with a basal subpleural predominance, ± traction bronchiectasis, and without imaging features to suggest an alternative diagnosis (e.g., sarcoidosis, lymphangioleiomyomatosis or Langerhans cell histiocytosis, etc.), such as upper lobe predominance, air-trapping, or lung nodules or cysts. OP is characterized by patchy areas of ill-defined air-space opacity and consolidation, which may be unilateral or bilateral. It predominantly affects the lower lobes and has a tendency to more significantly involve the peripheral and peribronchial lung parenchyma. An additional feature of OP is its migratory behavior over time, with waxing and waning patchy or bandlike opacities, which may be associated with ground-glass opacity surrounded by curvilinear dense consolidation (i.e., reversed halo or atoll sign). Bronchial dilatation may occur within the area of consolidation as well as nodular opacities, which may exhibit a tree-in-bud pattern. In patients with CTD with pulmonary involvement, OP is less common than NSIP or UIP, and although it can be seen in the different types of rheumatologic disorders, the most common conditions with this morphologic pattern include RA, polymyositis/dermatomyositis (P/D), and antisynthetase syndrome. LIP, which histologically consists of interstitial infiltration by polyclonal lymphocytes (mostly T lymphocytes), macrophages (histiocytes), and plasma cells, often with lymphoid hyperplasia, can be seen in association with autoimmune diseases, in particular Sjögren syndrome or acquired immunodeficiencies, such as acquired immune deficiency syndrome and, rarely, as a primary idiopathic disorder. The distinctive imaging feature of LIP is the presence of thinwalled peribronchovascular cysts, likely secondary to bronchiolar lymphocytic obstruction, bilateral ground-glass opacities, and centrilobular nodules. PAH, which is commonly associated with CTD, particularly with the limited form of progressive systemic sclerosis (PSS) (30%) and mixed CTD (MCTD) (10%), likely results from destruction of the pulmonary vasculature by progressive interstitial fibrosis in combination with hypoxia-induced vasoconstriction. The majority of patients with PSS also have esophageal involvement that manifests with esophageal dilatation (6080%) and gastroesophageal reflux, which is considered an additional contributing factor in the development of ILD. Patients with PAH associated with ILD have an overall higher mortality than patients with ILD. Furthermore, mortality increases as severity of PAH increases. Diffuse pulmonary opacities from either drug-induced ILD or secondary to immunosuppression and opportunistic infection may also develop as a complication of treatment of CTD. Many antirheumatic drugs and biological agents commonly used to treat CTD are known to produce diffuse interstitial and alveolar pulmonary abnormalities, and drug toxicity should be considered in the differential diagnosis of a patient with known CTD under treatment who develops new pulmonary abnormalities. Methotrexate and cyclophosphamide, the therapeutic agents most commonly associated with pulmonary toxicity in these patients, may produce variable

Approach to Connective Tissue Disease-Associated Interstitial Lung Disease

UIP

NSIP

OP

LIP

Pleural

PAH

RA

(+++)

(++)

(++)

(+)

(++)

(+)

PSS

(+)

(+++)

(+)

(-)

(-)

(+++)

P/D

(+)

(+++)

(+++)

(-)

(-)

(+)

Sjögren

(+)

(++)

(-)

(++)

(+)

(+)

SLE

(+)

(++)

(+)

(+)

(+++)

(+)

MCTD

(+)

(++)

(+)

(-)

(+)

(++)

Autoimmune Diseases

Thoracic Patterns in Collagen Vascular Diseases

UIP = usual interstitial pneumonia; NSIP = nonspecific interstitial pneumonia; OP = organizing pneumonia; LIP = lymphoid interstitial pneumonia; PAH = pulmonary arterial hypertension. Adapted from Capobianco J et al: Thoracic manifestations of collagen vascular diseases. Radiographics. 32(1):33-50, 2012 and Fischer A et al: Interstitial lung disease in connective tissue disorders. Lancet. 380(9842):689-98, 2012

HRCT Criteria for Usual Interstitial Pneumonia Pattern UIP Pattern

Possible UIP Pattern

Inconsistent With UIP Pattern

Subpleural, basal predominance

Subpleural, basal predominance

Upper or mid lung predominance

Reticular abnormalities

Reticular abnormality

Peribronchovascular predominance

Honeycombing ± traction bronchiectasis

Absence of features listed as inconsistent with UIP pattern

Extensive ground-glass opacity (> reticulation)

Absence of features listed as inconsistent with UIP pattern

Profuse micronodules (bilateral, upper lobe) Discrete cysts (multiple, bilateral, distant from honeycombing) Diffuse mosaic attenuation/air-trapping (bilateral, ≥ 3 lobes) Segmental/lobar consolidation

Designation as usual interstitial pneumonia (UIP) pattern and possible UIP pattern requires all criteria. Designation as inconsistent with UIP pattern requires any of the 7 criteria. Adapted from Raghu G et al: An official ATS/ERS/JRS/ALAT Statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 183(6): 788-824, 2011.

imaging morphologic abnormalities that reflect the underlying lung injury, which can be either diffuse alveolar damage, NSIP, hypersensitivity pneumonitis, or OP. Similarly, opportunistic infections (Pneumocystis jirovecii, CMV, etc.) may result in diffuse bilateral ground-glass opacities with septal thickening similar to CTD-ILD. Pleural effusion, either unilateral or bilateral and usually small in size, is the most common thoracic manifestation of systemic lupus erythematosus (SLE) and is found in roughly 1/2 of affected patients. RA is after SLE, the 2nd most common CTD associated with pleural effusion, whereas P/D and PSS are rarely associated with this complication. Pericardial effusion, which is also common in SLE (30%), is rarely seen in other collagen vascular disorders. The clinical and serological differentiation between the different CTDs is not always straightforward. MCTD is a combination or overlap of the clinical and serologic abnormalities of several autoimmune disorders, mainly SLE, PSS, and P/D and, less often, RA. In affected individuals, pulmonary involvement (predominantly NSIP pattern) and PAH are the most common pulmonary abnormalities. Another “gray zone” exists in patients with idiopathic interstitial pneumonia associated with features suggestive, but not conclusive, of a classic CTD, either because the serology or the

clinical manifestation are absent or do not match. The term interstitial pneumonia with autoimmune features (IPAF) has been proposed by the European Respiratory Society and the American Thoracic Society to refer to interstitial pneumonia demonstrated by histology or HRCT without complete rheumatologic criteria for a specific CTD but with some (i.e., at least 1 feature from at least 2 domains) clinical, serological, and morphologic findings that suggest autoimmunity. IPAF is not really a new pathologic entity per se but rather a consensus proposal that aims to facilitate prospective systematic research, which has been historically challenging given the various and heterogeneous terminology that has been used to refer to this matter.

Selected References 1. 2.

3. 4. 5.

Mathai SC et al: Management of interstitial lung disease associated with connective tissue disease. BMJ. 352:h6819, 2016 Fischer A et al: An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J. 46(4):976-87, 2015 Jokerst C et al: An overview of collagen vascular disease-associated interstitial lung disease. Semin Roentgenol. 50(1):31-9, 2015 Katsumata Y et al: Interstitial lung disease with ANCA-associated vasculitis. Clin Med Insights Circ Respir Pulm Med. 9(Suppl 1):51-6, 2015 Ruano CA et al: Thoracic manifestations of connective tissue diseases. Curr Probl Diagn Radiol. 44(1):47-59, 2015

309

Autoimmune Diseases

Approach to Connective Tissue Disease-Associated Interstitial Lung Disease

(Left) Axial CECT of a 58-yearold woman with usual interstitial pneumonia related to rheumatoid arthritis shows extensive subpleural honeycombing ﬈ with lower lobe predominance (i.e., apicobasal gradient), which manifests as multilayered cystic changes with cysts typically sharing their walls. (Right) Coronal CECT of the same patient shows a classic apicobasal gradient with less involvement of the upper and mid lung zones and more extensive disease in the basilar lower lobes.

(Left) Axial HRCT of a 28-yearold woman with systemic lupus erythematosus shows patchy bilateral ground-glass opacities ﬈ with reticulation and traction bronchiectasis. Open lung biopsy confirmed fibrosing nonspecific interstitial pneumonia. (Right) Axial HRCT of a 48-year-old woman with rheumatoid arthritis shows diffuse groundglass opacities and traction bronchiectasis ﬈ but no honeycombing. Open lung biopsy was consistent with nonspecific interstitial pneumonia.

(Left) Axial CECT of a 39-yearold woman with polymyositis and nonspecific interstitial pneumonia shows upper lobepredominant peribronchovascular groundglass and reticular opacities ﬈. Similar findings were seen in other lung zones. (Right) Axial HRCT of a 49-year-old woman with dermatomyositis and organizing pneumonia shows multifocal bilateral patchy airspace opacities ﬈ that exhibit a peribronchovascular distribution.

310

Approach to Connective Tissue Disease-Associated Interstitial Lung Disease Autoimmune Diseases

(Left) Axial HRCT of a 67-yearold woman with Sjögren syndrome and biopsy-proven nonspecific interstitial pneumonia shows minimal subpleural lower lobepredominant ground-glass opacities ﬈. (Right) Axial NECT of a 39-year-old woman with Sjögren syndrome and histologically proven lymphoid interstitial pneumonia shows numerous bilateral thinwalled pulmonary cysts ﬈.

(Left) Axial HRCT of a 28-yearold woman with systemic lupus erythematosus and biopsy-proven nonspecific interstitial pneumonia shows extensive ground-glass opacities ﬈ and traction bronchiectasis ﬉. (Right) Axial CECT of a 32-year-old woman with systemic lupus erythematosus and serositis shows right atrial ﬊ and ventricular ﬉ dilatation related to pulmonary hypertension and lupus myocarditis, which contributed to the development right cardiac enlargement. Note the large right pleural effusion ﬈.

(Left) Axial CECT of a woman with rheumatoid arthritis, pulmonary hypertension, and severe pulmonary fibrosis shows significant dilatation of the pulmonary trunk (which measures > 4 cm) and enlarged central pulmonary arteries. (Right) Axial CECT of the same patient shows right ventricular dilatation and hypertrophy ﬈. Extensive chronic pulmonary fibrosis is noted bilaterally. The explanted lungs (after bilateral lung transplant) showed usual interstitial pneumonia and changes of pulmonary hypertension.

311

Autoimmune Diseases

Rheumatoid Arthritis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Rheumatoid arthritis (RA) • Systemic polyarthritis characterized by chronic inflammation, erosion, and damage of cartilage

• • • • •

IMAGING • Lungs ○ Several patterns of diffuse lung disease – Usual interstitial pneumonia – Nonspecific interstitial pneumonia (NSIP) – Organizing pneumonia (OP) ○ Drug toxicity ○ Necrobiotic nodules • Pleura: Effusion; thickening and enhancement • Large airways: Bronchiectasis • Small airways: Follicular bronchiolitis, bronchiolitis obliterans • Cardiovascular: Pericardial effusion, pulmonary hypertension, myocarditis

(Left) AP chest radiograph of a patient with rheumatoid arthritis and serositis shows left-larger-than-right bilateral pleural effusions and an enlarged cardiac silhouette. (Right) Axial CECT of the same patient shows bilateral pleural effusions ﬈ and a large pericardial effusion ﬉ consistent with serositis. While nonspecific, involvement of the serosa in the form of pleural &/or pericardial effusions or thickening is the most common thoracic manifestation of rheumatoid arthritis.

(Left) PA chest radiograph of a patient with rheumatoid arthritis and usual interstitial pneumonia shows low lung volumes and bilateral reticular opacities and honeycombing. (Right) Axial HRCT of the same patient shows extensive bilateral basilar predominant subpleural honeycombing. Usual interstitial pneumonia is the most common pattern of interstitial lung disease encountered in patients with rheumatoid arthritis and is characterized by basilar honeycombing on thin-section chest CT.

312

Idiopathic interstitial pneumonia Interstitial pneumonia with autoimmune features Progressive systemic sclerosis Polymyositis/dermatomyositis Systemic lupus erythematous

CLINICAL ISSUES • Imaging abnormalities may precede respiratory symptoms • Pleuritic chest pain is most common symptom • Medical therapy is mainstay of treatment ○ Corticosteroids ○ Disease-modifying antirheumatic drugs: Gold, penicillamine, methotrexate ○ Biologic agents: Infliximab, rituximab

DIAGNOSTIC CHECKLIST • Consider RA in patient with arthropathy and pleural effusion

Rheumatoid Arthritis

Abbreviations • Rheumatoid arthritis (RA)

Synonyms • Rheumatoid lung

Definitions • RA: Autoimmune disorder characterized by symmetric polyarthritis with chronic inflammation, erosion, and damage of cartilage ○ Most common connective tissue disease

IMAGING General Features • Best diagnostic clue ○ Articular pain and swelling + pleural effusion and pleuritis • Location ○ Pleural disease is most common intrathoracic abnormality – Pleural inflammation – Related to cardiac disease-associated RA ○ Lung parenchyma and airways may also be affected • Size ○ Necrobiotic (rheumatoid) nodules – Variable size; few mm to several cm

Radiographic Findings • Radiography ○ Lung – Interstitial lung disease (ILD): Reticular or reticulonodular opacities, subpleural distribution – Organizing pneumonia (OP): Patchy consolidation with peripheral distribution – Infection: Lobar, segmental, or subsegmental opacities ○ Pleura – Effusion: Small to moderate in size, usually unilateral ○ Heart and pericardium – Pericardial effusion

CT Findings • CECT ○ Pleura – Effusion: Secondary to inflammation □ Small to moderate in size, unilateral – Thickening and enhancement □ May involve parietal and visceral pleurae □ Smooth or nodular thickening □ Impaired pulmonary expansion leading to "trapped lung" • HRCT ○ Usual interstitial pneumonia – Subpleural reticular opacities ± honeycombing with apicobasal gradient – Subpleural ground-glass opacities with apicobasal gradient – ± traction bronchiectasis

– Increased risk of lung cancer; pulmonary nodule or mass should be regarded with suspicion ○ Nonspecific interstitial pneumonia (NSIP) – Predominantly subpleural ground-glass opacities with apicobasal gradient – Reticular opacities, traction bronchiectasis, lower lobe volume loss ○ OP – Unilateral or bilateral patchy consolidations, peripheral and peribronchial distribution – Polygonal opacities, reversed halo sign (rounded area of ground-glass opacity surrounded by ring of consolidation) ○ Necrobiotic nodules – Well-defined borders, variable size: 0.5-5 cm – Peripheral distribution, cavitation in 50% of cases, may cause pneumothorax – May exhibit instrinsic calcification ○ Infection – Tuberculosis, nocardiosis, aspergillosis, histoplasmosis, coccidioidomycosis, pneumocystis pneumonia, cytomegalovirus infection ○ Other – Reactive amyloidosis □ Severe complication of RA, serious, life-threatening disorder caused by deposition of amyloid A (AA) fibrils in multiple organs – Drug-associated lung toxicity ○ Large airways – Bronchiectasis in 30% of patients with RA ○ Small airways – Follicular bronchiolitis □ Lymphoid hyperplasia of bronchus-associated lymphoid tissue □ Small centrilobular nodules, peribronchial nodules, ground-glass opacities, mosaic attenuation, airtrapping – Bronchiolitis obliterans □ Progressive concentric narrowing of membranous bronchioles □ Mosaic attenuation, bronchiectasis, bronchial wall thickening • Bone CT ○ Sternoclavicular, glenohumeral joints – Periarticular osteoporosis, joint space narrowing, subcortical cysts, erosions, subluxation • CTA ○ Cardiovascular – Pulmonary hypertension (obliterative vasculopathy) □ Enlarged pulmonary arteries, dilatation of right heart chambers, contrast reflux into inferior vena cava and hepatic veins – Myocarditis □ Cardiomegaly, heart failure

Autoimmune Diseases

TERMINOLOGY

MR Findings • T1WI FS ○ Enhancement of erosions or joint spaces suggests hypervascularized synovitis

313

Autoimmune Diseases

Rheumatoid Arthritis Ultrasonographic Findings • Grayscale ultrasound ○ Evaluation of sternoclavicular and glenohumeral joints: Intraarticular fluid, joint space widening, synovial hypertrophy • Power Doppler ○ Increased Doppler signal

Imaging Recommendations • Best imaging tool ○ HRCT • Protocol advice ○ HRCT with inspiratory and expiratory phases

DIFFERENTIAL DIAGNOSIS Idiopathic Interstitial Pneumonia • Indistinguishable from connective tissue disease ILD on imaging • Differentiation relies on clinical and paraclinical criteria

Interstitial Pneumonia With Autoimmune Features • Indistinguishable from connective tissue disease ILD on imaging • Differentiation relies on clinical and paraclinical criteria

Progressive Systemic Sclerosis • NSIP: Most common pattern of ILD, present in up to 80% of patients with systemic disease ○ Bilateral, symmetric ground-glass opacities, subpleural distribution ○ Reticular pattern and traction bronchiectasis ○ Honeycombing in 10-30% of affected patients • Pulmonary hypertension in up to 30% of affected patients • Dilated esophagus

Polymyositis/Dermatomyositis • Cutaneous disease • OP: Patchy areas of consolidation, subpleural or peribronchial distribution • NSIP

Presentation • Most common signs/symptoms ○ Pleuritic pain, exertional dyspnea, cough, wheezing ○ Fatigue, generalized weakness ○ Arthralgia, joint swelling, and stiffness • Other signs/symptoms ○ Nonarticular manifestations: Vasculitis, episcleritis, keratoconjunctivitis sicca, subcutaneous nodules, and mononeuritis multiplex ○ Felty syndrome: RA + splenomegaly + leukopenia

Demographics • Age ○ Peak: Between 45-65 years • Gender ○ F:M ratio = 3:1 • Epidemiology ○ RA affects 1% of adult population – Higher incidence in Native Americans ○ Tobacco has synergistic effect on pulmonary manifestations

Natural History & Prognosis • Imaging abnormalities may precede development of respiratory symptoms

Treatment • Medical therapy is mainstay of treatment ○ Corticosteroids ○ Disease-modifying antirheumatic drugs – Gold, penicillamine, methotrexate ○ Biologic agents – Infliximab, rituximab • Physical therapy • Surgery ○ Synovectomy, tendon repair, total joint replacement

DIAGNOSTIC CHECKLIST

Systemic Lupus Erythematous

Consider

• Pleural disease is the most common thoracic manifestation ○ Pleural effusion • Pericardial effusion • Diffuse pulmonary hemorrhage ○ Bilateral consolidations • Usual interstitial pneumonia • Deep venous thrombosis and pulmonary thromboembolism

• RA in patient with arthropathy and pulmonary disease

PATHOLOGY General Features • Etiology ○ Multifactorial – Genetic susceptibility (up to 70% of patients with RA express HLA-DR4) – Environmental factors (smoking) – Infectious agents

314

CLINICAL ISSUES

Image Interpretation Pearls • Inspiratory and expiratory imaging is necessary to diagnose small airways disease

Reporting Tips • Consider infection or drug toxicity in patients with RA, acute pulmonary symptoms, and new pulmonary opacities • Exclude lung/pleural disease associated with RA in patients with chronic pulmonary symptoms

SELECTED REFERENCES 1. 2.

3.

Aparicio IJ et al: Connective tissue disease-associated interstitial lung diseases: unresolved issues. Semin Respir Crit Care Med. 37(3):468-76, 2016 Chansakul T et al: Intra-thoracic rheumatoid arthritis: Imaging spectrum of typical findings and treatment related complications. Eur J Radiol. 84(10):1981-91, 2015 Ohno Y et al: State-of-the-art imaging of the lung for connective tissue disease (CTD). Curr Rheumatol Rep. 17(12):69, 2015

Rheumatoid Arthritis Autoimmune Diseases

(Left) Axial HRCT of a patient with rheumatoid arthritis and nonspecific interstitial pneumonia shows subpleural and lower lobe-predominant ground-glass and reticular opacities ﬈. Note the absence of honeycombing, which is a feature of usual interstitial pneumonia. (Right) Axial HRCT of the same patient obtained 6 months after treatment with infliximab shows interval improvement with only subtle residual opacities. Nonspecific interstitial pneumonia, unlike usual interstitial pneumonia, may respond to several treatments.

(Left) Axial CECT of a patient with rheumatoid arthritis and follicular bronchiolitis shows scattered tree-in-bud opacities ﬈ amid a background of mosaic attenuation. Follicular bronchiolitis should be suspected when pulmonary opacities do not improve after treatment for infection. (Right) Composite image with axial inspiratory (left) and expiratory (right) HRCT of a woman with rheumatoid arthritis complicated by constrictive bronchiolitis shows normal attenuation on inspiration and air-trapping on expiration.

(Left) PA chest radiograph of a patient with rheumatoid arthritis demonstrates numerous bilateral pulmonary nodules ﬈, which represented necrobiotic nodules. (Right) Axial NECT of the same patient shows multiple soft tissue nodules, some of which exhibit cavitation ﬈. Necrobiotic nodules demonstrate variable size, may be single or multiple, and may exhibit intrinsic cavitation or calcification. Amyloidosis is yet another cause of pulmonary nodules occurring in the setting of rheumatoid arthritis.

315

Autoimmune Diseases

Progressive Systemic Sclerosis KEY FACTS

TERMINOLOGY • Generalized autoimmune connective tissue disorder affecting multiple organs, including skin, lungs, heart, and kidneys

IMAGING • Radiography ○ Symmetric basilar reticulonodular opacities ○ Decreased lung volumes, sometimes out of proportion to severity of lung disease ○ Dilated, air-filled esophagus best seen on lateral chest radiography • CT ○ Interstitial lung disease: Nonspecific interstitial pneumonia > > usual interstitial pneumonia – Subpleural reticulation with apicobasal gradient ○ Diffuse aspiration bronchiolitis: Centrilobular and tree-inbud nodules ○ Esophageal dilatation

(Left) Axial prone HRCT of a patient with progressive systemic sclerosis and nonspecific interstitial pneumonia (NSIP) shows bilateral, basilar-predominant, subpleural ground-glass opacities. In most cases of NSIP, the presence of groundglass opacities correlates with fibrosis rather than with active inflammation. (Right) PA chest radiograph of a patient with progressive systemic sclerosis and NSIP shows low lung volumes and bilateral, lower lobe-predominant reticular opacities.

(Left) Axial HRCT of the same patient shows asymmetric subpleural reticular opacities and traction bronchiectasis ﬉ and bronchiolectasis predominantly involving the right lung. Note the dilated esophagus ﬈ with an intrinsic air-fluid level. (Right) Axial HRCT of the same patient shows subpleural ground-glass and reticular opacities, traction bronchiectasis ﬉, and a dilated distal esophagus ﬈. The presence of interstitial lung disease in a patient with esophageal dilatation should suggest the diagnosis of progressive systemic sclerosis.

316

○ Pulmonary hypertension; entails poor prognosis ○ Lymphadenopathy ○ Nodule or mass should raise suspicion for lung cancer

TOP DIFFERENTIAL DIAGNOSES • Nonspecific interstitial pneumonia • Idiopathic pulmonary fibrosis • Aspiration pneumonia

PATHOLOGY • Collagen overproduction and deposition in tissue

CLINICAL ISSUES • Pulmonary disease usually follows skin manifestations • Increased risk of lung cancer, particularly in patients with pulmonary fibrosis

DIAGNOSTIC CHECKLIST • Consider progressive systemic sclerosis in patients with chronic interstitial lung disease and esophageal dilatation

Progressive Systemic Sclerosis

Abbreviations • Progressive systemic sclerosis (PSS)

Synonyms • Scleroderma • Systemic sclerosis

Definitions • Generalized autoimmune connective tissue disorder affecting multiple organ systems including skin, lungs, heart, and kidneys • Limited cutaneous systemic sclerosis (60%) ○ Skin involvement of hands, forearms, feet, and face ○ Longstanding Raynaud phenomenon ○ CREST syndrome: Calcinosis, Raynaud, esophageal dysmotility, sclerodactyly, and telangiectasias • Diffuse cutaneous systemic sclerosis (40%) ○ Acute onset: Raynaud, acral and truncal skin involvement ○ High frequency of interstitial lung disease • Scleroderma sine scleroderma (rare) ○ Interstitial lung disease without skin manifestations

IMAGING General Features • Best diagnostic clue ○ Subpleural reticular opacities with apicobasal gradient + dilated esophagus • Location ○ Lower lung zones

Radiographic Findings • Radiography ○ Lungs – Symmetric basilar reticulonodular opacities – Progression of fine basilar reticulation (lace-like) to coarse fibrosis – Decreased lung volumes, sometimes out of proportion to severity of lung disease – Diaphragmatic elevation; may be due to diaphragmatic muscle atrophy and fibrosis ○ Associated findings – Dilated, air-filled esophagus best seen on lateral chest radiography – Pleural thickening and effusions rare – Superior and posterolateral rib erosion – Resorption of distal phalanges, tuft calcification – Secondary lung cancer, often adenocarcinoma or adenocarcinoma in situ ○ Cardiomegaly – Pericardial effusion – Pulmonary hypertension – Myocardial ischemia due to small vessel disease – Infiltrative cardiomyopathy

CT Findings • CECT ○ Esophageal dilatation (common) ○ Lymphadenopathy (common) – Rarely identified on chest radiography

– Most often reactive in setting of interstitial lung disease ○ Pulmonary artery enlargement from pulmonary hypertension – May occur without interstitial lung disease – Entails poor prognosis ○ Pleural thickening (pseudoplaques, 33%) – Subpleural micronodules – Pseudoplaques (90%): Confluence of subpleural micronodules < 7 mm in width – Diffuse pleural thickening (33%) • HRCT ○ Interstitial lung disease ○ Nonspecific interstitial pneumonia (NSIP) (most common) – Ground-glass and reticular opacities □ Absent to mild honeycombing – Apicobasal gradient – Traction bronchiectasis and bronchiolectasis □ Bronchiectasis may be out of proportion to severity of interstitial lung disease – Peribronchovascular distribution with subpleural sparing; highly suggestive of NSIP ○ Usual interstitial pneumonia (UIP) (less common) – Similar to NSIP; honeycombing is predominant feature ○ Extensive ground-glass opacities (especially if new) suggest acute exacerbation – Mimic superimposed infection or pulmonary edema on imaging; differentiation based on clinical and laboratory findings including bronchoalveolar lavage ○ Diffuse aspiration bronchiolitis – Scattered centrilobular and tree-in-bud opacities – Bronchiectasis, bronchiolectasis, and bronchial wall thickening ○ Discrete nodules or masses should be evaluated for exclusion of lung cancer (i.e., follow-up &/or biopsy)

Autoimmune Diseases

TERMINOLOGY

Other Modality Findings • Esophagram ○ Dilated esophagus ○ Gastroesophageal reflux ○ Patent gastroesophageal junction

Imaging Recommendations • Best imaging tool ○ HRCT more sensitive than radiography for identification of pulmonary involvement ○ Esophagram for assessment of esophageal motility

DIFFERENTIAL DIAGNOSIS Nonspecific Interstitial Pneumonia • Identical HRCT pattern • No esophageal dilatation

Idiopathic Pulmonary Fibrosis • No esophageal dilatation or musculoskeletal abnormalities • Coarser interstitial lung disease; honeycombing more common • Ground-glass opacities less common • Subpleural distribution 317

Autoimmune Diseases

Progressive Systemic Sclerosis Aspiration Pneumonia • Recurrent opacities and chronic fibrosis in dependent lung • Known esophageal motility disorder • PSS patients at risk

Asbestosis • No esophageal dilatation • Pleural plaques (80%) • UIP pattern of pulmonary fibrosis

Rheumatoid Arthritis • No esophageal dilatation • May exhibit identical HRCT pattern (NSIP or UIP) • Symmetric articular erosive changes

Drug Reaction • No esophageal dilatation • May exhibit identical HRCT pattern

Sarcoidosis • No esophageal dilatation • Upper lung predominant perilymphatic micronodules

PATHOLOGY General Features • Etiology ○ Reduced circulating T-suppressor cells and NK cells; may suppress fibroblast proliferation ○ Antitopoisomerase I (30%), anti-RNA polymerase III, and antihistone antibodies associated with interstitial lung disease ○ Anticentromere antibodies in CREST variant associated with absence of interstitial lung disease • Overproduction and tissue deposition of collagen • Lung is 4th most common organ involved after skin, arteries, and esophagus

Staging, Grading, & Classification • American College of Rheumatology criteria: 1 major or 2 minor criteria required for diagnosis ○ Major criteria: Involvement of skin proximal to metacarpophalangeal joints ○ Minor criteria: Sclerodactyly, pitting scars, loss of finger tip tufts, bilateral pulmonary basal fibrosis

Microscopic Features • Pulmonary hypertension ○ Most distinctive finding: Concentric laminar fibrosis with few plexiform lesions • NSIP: Cellular or fibrotic (80%) • UIP: Fibroblast proliferation, fibrosis, and architectural distortion (10-20%)

CLINICAL ISSUES

– Dyspnea (90%), cough, pleuritic pain, fever, hemoptysis, dysphagia • Other signs/symptoms ○ Skin tightening, induration, and thickening ○ Vascular abnormalities ○ Musculoskeletal manifestations ○ Visceral involvement of lungs, heart, and kidneys ○ Esophageal dysmotility, gastroesophageal reflux, esophageal candidiasis, esophageal stricture, weight loss ○ Renal disease: Hypertension, renal failure ○ Antinuclear antibodies (100%) ○ Pulmonary function tests – Restrictive or obstructive – Decreased diffusion capacity ○ Bronchoalveolar lavage varies from lymphocytic to neutrophilic alveolitis (50%)

Demographics • Age ○ Usual onset: 30-50 years • Gender ○ M:F = 1:3 • Epidemiology ○ 1.2 cases/100,000 persons ○ Pulmonary disease in > 80% at autopsy

Natural History & Prognosis • Lung disease is indolent and progressive • Increased risk for lung cancer; associated with pulmonary fibrosis ○ Often adenocarcinoma or adenocarcinoma in situ • Prognosis: 70% 5-year survival rate ○ Most common cause of death is pulmonary hypertension

Treatment • Directed toward affected organs • Interstitial lung disease ○ Cyclophosphamide ○ Corticosteroids • Aggressive blood pressure control important for prevention of renal failure

DIAGNOSTIC CHECKLIST Consider • PSS in patients with chronic interstitial lung disease and esophageal dilatation • Lung cancer in patients with PSS and new solitary or dominant solid or subsolid pulmonary nodule

SELECTED REFERENCES 1. 2.

Presentation • Most common signs/symptoms ○ Pulmonary disease usually follows skin manifestations – Raynaud phenomenon is most common manifestation at presentation (up to 90%), tendonitis, arthralgia, arthritis 318

3. 4. 5.

Capobianco J et al: Thoracic manifestations of collagen vascular diseases. Radiographics. 32(1):33-50, 2012 Goldin JG et al: High-resolution CT scan findings in patients with symptomatic scleroderma-related interstitial lung disease. Chest. 134(2):358-67, 2008 Madani G et al: The role of radiology in the management of systemic sclerosis. Clin Radiol. 63(9):959-67, 2008 Wells AU: High-resolution computed tomography and scleroderma lung disease. Rheumatology (Oxford). 47 Suppl 5:v59-61, 2008 Desai SR et al: CT features of lung disease in patients with systemic sclerosis: comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. Radiology. 232(2):560-7, 2004

Progressive Systemic Sclerosis Autoimmune Diseases

(Left) Axial HRCT of a patient with progressive systemic sclerosis and NSIP shows bilateral reticular and groundglass opacities with associated traction bronchiolectasis ﬊ and subpleural sparing ﬈, a characteristic finding of NSIP. Note esophageal dilatation ﬉. (Right) Axial CECT of a patient with progressive systemic sclerosis and interstitial lung disease shows a dilated pulmonary trunk ﬈ and left pulmonary artery ﬉ compatible with pulmonary hypertension.

(Left) Axial HRCT of a patient with progressive systemic sclerosis and NSIP shows basilar ground-glass opacities and cyst-like structures corresponding to severe bronchiectasis. (Right) Sagittal HRCT of the same patient helps demonstrate that the cyst-like structures noted on axial imaging correspond to bronchiectasis ﬈ rather than honeycomb cysts. Bronchiectasis out of proportion to the severity of interstitial lung disease is common in patients with progressive systemic sclerosis.

(Left) Axial NECT of a patient with progressive systemic sclerosis and aspiration bronchiolitis shows bilateral ground-glass ﬈ and clustered centrilobular ﬉ nodules, mild bronchiectasis ﬊, and esophageal dilatation ﬈. (Right) Composite image of a patient with progressive systemic sclerosis and lung adenocarcinoma shows interval growth of a right lower lobe nodule ﬉ over a period of 12 months and subpleural fibrosis ﬈. Patients with interstitial lung disease have an increased incidence of lung cancer.

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Autoimmune Diseases

Dermatomyositis/Polymyositis KEY FACTS

• Dermatomyositis/polymyositis (D/P): Autoimmune myopathy manifesting with inflammation and weakness ○ D exhibits variety of cutaneous manifestations ○ P involves proximal muscles over weeks or months

• Diaphragmatic &/or chest wall muscle weakness ± shrinking lung syndrome • Muscular atrophy and fatty replacement • Antisynthetase syndrome: Ground-glass opacities (in NSIP) and peribronchovascular consolidations (in OP)

IMAGING

TOP DIFFERENTIAL DIAGNOSES

• HRCT/CT ○ Connective tissue disease-associated interstitial lung disease (CTD-ILD): May exhibit features of nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (less common) – Basal subpleural ground-glass opacities (85%) – Interlobular septal thickening and reticulation (45%) – Traction bronchiectasis (50%) – Honeycombing (15%) • Organizing pneumonia (OP): Subpleural &/or peribronchovascular consolidations

• • • •

TERMINOLOGY

(Left) Axial CECT of a 49-yearold man with polymyositis shows multifocal bilateral ground-glass opacities ﬈ and mild subpleural reticulation ﬉. (Right) Coronal CECT of the same patient shows bibasilar ground-glass ﬈ and mild reticular opacities with sparing of the mid and upper lung zones. Open lung biopsy showed findings consistent with nonspecific interstitial pneumonia, the most common pattern of interstitial lung disease identified in the setting of dermatomyositis/polymyositis.

(Left) Axial CECT of a 57-yearold man with polymyositis and connective tissue diseaseassociated interstitial lung disease shows bilateral subpleural ground-glass and reticular opacities and early honeycombing ﬈. (Right) Axial CECT of the same patient shows more extensive subpleural ground-glass and reticular opacities and early honeycombing ﬈. Note the dilated pulmonary trunk ﬊ consistent with pulmonary hypertension, which is a marker of worse prognosis in patients with interstitial lung disease.

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Idiopathic interstitial pneumonias Interstitial pneumonia with autoimmune features Systemic lupus erythematosus Other autoimmune diseases

CLINICAL ISSUES • Initial treatment: Systemic corticosteroids • Recurrent or refractory D/P: Rituximab, cyclophosphamide, azathioprine, methotrexate

DIAGNOSTIC CHECKLIST • Consider CTD-ILD in patients with bilateral subpleural pulmonary opacities and idiopathic inflammatory myopathy

Dermatomyositis/Polymyositis

Abbreviations • Dermatomyositis/polymyositis (D/P)

Synonyms • Polymyositis/dermatomyositis interstitial lung disease (ILD) • Idiopathic inflammatory myopathy ILD

Definitions • Autoimmune myopathy ○ Manifests with inflammation and weakness ○ Dermatomyositis exhibits variety of cutaneous manifestations ○ Polymyositis involves proximal muscles over weeks or months • May be complicated by connective tissue diseaseassociated interstitial lung disease (CTD-ILD), aspiration bronchiolitis, &/or hypoventilation from affected respiratory muscles ○ CTD-ILD: Diffuse interstitial pneumonia secondary to D/P ○ Aspiration bronchiolitis: Typically diffuse

IMAGING General Features

Imaging Recommendations

• Best diagnostic clue ○ CTD-ILD: Diffuse bilateral pulmonary abnormalities in patient with known idiopathic inflammatory myopathy • Location ○ CTD-ILD: Lower lobe predominance • Morphology ○ CTD-ILD – Subpleural reticular opacities – ± honeycombing

• Best imaging tool ○ HRCT/CT

Radiographic Findings

Interstitial Pneumonia With Autoimmune Features

• Radiography ○ CTD-ILD – Volume loss – Lower lobe predominant reticular opacities ○ Organizing pneumonia (OP) – Subsegmental consolidations; may be migratory on serial imaging ○ Diaphragmatic &/or chest wall muscle weakness ± shrinking lung syndrome – Low lung volumes ○ Soft tissue calcifications common

• ILD on biopsy or based on HRCT that does not meet full criteria for CTD-ILD but exhibits clinical or serological features suggesting autoimmunity • HRCT and pathologic features include UIP, NSIP, lymphoid interstitial pneumonia (LIP), and OP

CT Findings

• • • • •

• HRCT/CT ○ CTD-ILD – May exhibit features of nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP) – Basilar subpleural ground-glass opacities (85%) – Interlobular septal thickening and reticulation (45%) – Traction bronchiectasis (50%) – Honeycombing (15%) □ Less common than with idiopathic pulmonary fibrosis – Consolidation (55%); usually associated with organizing pneumonia

Autoimmune Diseases

○ OP – Subpleural &/or peribronchovascular subsegmental consolidations – Reversed halo (or atoll) sign – Migratory opacities on serial imaging ○ Antisynthetase syndrome – Ground-glass opacities (in NSIP) and peribronchovascular consolidations (in OP); often occur synchronously ○ Aspiration – Diffuse aspiration bronchiolitis &/or aspiration pneumonia – Tree-in-bud opacities ± bronchiectasis – Consolidations ○ Mediastinal, hilar, and axillary lymphadenopathy (often reactive) ○ Chest wall – Diaphragmatic &/or chest wall muscle weakness ± shrinking lung syndrome □ Low lung volumes without discrete findings of CTDILD – Muscular atrophy and fatty replacement – Subcutaneous calcifications

TERMINOLOGY

DIFFERENTIAL DIAGNOSIS Idiopathic Interstitial Pneumonias • IPF, NSIP, and OP ○ Indistinguishable from ILD associated with D/P ○ Diagnosis and differentiation rely on absence of clinical or serologic evidence of autoimmunity

Systemic Lupus Erythematosus • May manifest with CTD-ILD and OP with identical features • May manifest as shrinking lung syndrome (i.e., restrictive physiology without CTD-ILD)

Other Autoimmune Diseases Rheumatoid arthritis Progressive systemic sclerosis Mixed connective tissue disease Sjögren syndrome May manifest with CTD-ILD, LIP, and OP with identical features

Drug-Induced Lung Disease • May manifest with imaging and pathologic features of UIP, NSIP, or OP • History (often current or recent) of administered medication known to cause pulmonary reaction

321

Autoimmune Diseases

Dermatomyositis/Polymyositis – Conduction abnormalities and arrhythmia – ↑ risk of myocardial infarction ○ Antisynthetase syndrome – Subset of patients with polymyositis/dermatomyositis □ Antisynthetase (anti-ARS) antibodies □ Interstitial lung disease □ Fever □ Arthralgias □ Raynaud phenomenon □ Hand exanthema

Diffuse Aspiration Bronchiolitis • May be due to D/P and progressive systemic sclerosis • Common etiologies ○ Esophageal disorders ± neurologic conditions involving deglutition and esophageal peristalsis (e.g., achalasia, hiatus hernia, gastroesophageal reflux, Parkinson disease, cerebrovascular accident, etc.) • Imaging features identical to those of other causes of diffuse aspiration bronchiolitis

Asbestosis • Manifests as UIP in patients occupationally exposed to asbestos • Discontinuous bilateral pleural thickening or pleural plaques indicative of asbestos-related pleural disease (hallmark of asbestos exposure)

PATHOLOGY Microscopic Features • Various histologic and morphologic patterns have been described in CTD-ILD due to D/P ○ NSIP, UIP, OP, LIP; diffuse alveolar damage (DAD), i.e., acute interstitial pneumonia

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Dermatomyositis and polymyositis: Systemic and autoimmune diseases characterized by chronic inflammation of striated muscle, which predominantly manifest by proximal muscle weakness (upper or lower extremity and trunk) ○ In addition to skin involvement, dermatomyositis and polymyositis are similar enough that term D/P is often used ○ Polymyositis: Absence of skin manifestations ○ Dermatomyositis: At least 1 skin manifestation – Heliotrope rash: Erythematous to violaceous rash of upper eyelids ± edema – Gottron papules: Symmetric erythematous to violaceous papules over dorsal aspects of interphalangeal and metacarpophalangeal joints – Gottron sign: Erythematous to violaceous macules or papules on extensor surfaces of elbows, knees, and ankles – Calcinosis cutis: Dermal calcium deposits – Other: Facial erythema, poikiloderma in areas exposed to light, generalized erythroderma, psoriasiform changes of scalp, etc. • Other signs/symptoms ○ Muscle pain, abnormal electromyogram, nondestructive arthritis or arthralgia, systemic inflammatory signs ○ Laboratory abnormalities – Elevated serum creatine kinase – Abnormal electromyogram – Positive anti-Jo-1 (histadyl tRNA synthetase) antibody – Pathological findings compatible with inflammatory myositis ○ Myocardial involvement – Frequently subclinical 322

Demographics • Higher prevalence in women (F:M = 2:1) • Adults > 20 years; peak incidence: 45-60 years • 20-40% of patients with idiopathic inflammatory myopathy develop ILD • 5-7x increased risk of cancer (70% adenocarcinomas) compared to general population; particularly high in patients with dermatomyositis ○ Lung cancer, ovarian cancer, adenocarcinoma of cervix, pancreas, bladder, and stomach

Natural History & Prognosis • Patients with CTD-ILD associated with D/P have worse prognosis than those without pulmonary involvement • 40% mortality from pulmonary complications • Respiratory muscle weakness leads to hypoventilation, atelectasis, and pneumonia • Pharyngeal muscle dysfunction may result in aspiration diffuse aspiration bronchiolitis &/or aspiration pneumonia • Poor prognostic indicators include: ILD, UIP pattern, pulmonary hypertension, advanced age, and associated malignancy

Treatment • Initial treatment: Systemic corticosteroids • Recurrent or refractory D/P: Rituximab, cyclophosphamide, azathioprine, methotrexate

DIAGNOSTIC CHECKLIST Consider • CTD-ILD in patients with bilateral subpleural pulmonary opacities associated with idiopathic inflammatory myopathy (D/P)

Image Interpretation Pearls • Discrete and dominant nodules in affected patients should be regarded as suspicious for primary lung cancer

SELECTED REFERENCES 1. 2. 3.

4. 5.

Wang H et al: Pulmonary hypertension in polymyositis. Clin Rheumatol. 34(12):2105-12, 2015 Tanizawa K et al: The prognostic value of HRCT in myositis-associated interstitial lung disease. Respir Med. 107(5):745-52, 2013 Hervier B et al: Clinical manifestations of anti-synthetase syndrome positive for anti-alanyl-tRNA synthetase (anti-PL12) antibodies: a retrospective study of 17 cases. Rheumatology (Oxford). 49(5):972-6, 2010 Chen IJ et al: Interstitial lung disease in polymyositis and dermatomyositis. Clin Rheumatol. 28(6):639-46, 2009 Kang EH et al: Interstitial lung disease in patients with polymyositis, dermatomyositis and amyopathic dermatomyositis. Rheumatology (Oxford). 44(10):1282-6, 2005

Dermatomyositis/Polymyositis Autoimmune Diseases

(Left) Axial HRCT of a 48-yearold man with polymyositis and connective tissue diseaseassociated interstitial lung disease shows bilateral ground-glass opacities ﬈, peribronchovascular reticulation and honeycombing ﬉, and subpleural sparing. (Right) Sagittal HRCT of the same patient shows ground-glass opacities, peribronchovascular honeycombing ﬉, and traction bronchiectasis ﬈. Subpleural sparing is a common feature of nonspecific interstitial pneumonia.

(Left) Axial CECT of a 50-yearold woman with antisynthetase syndrome who presented with shortness of breath shows organizing pneumonia manifesting as multifocal bilateral airspace opacities and consolidations ﬈. (Right) Coronal CECT of the same patient shows bilateral peribronchovascular nodular opacities and consolidations ﬈. Transbronchial biopsy showed organizing pneumonia, which may be seen as an isolated abnormality or in association with nonspecific interstitial pneumonia.

(Left) Coronal NECT (bone window) of a 41-year-old woman with dermatomyositis demonstrates patchy subpleural opacities ﬈ in the lower lobes and extensive calcifications ﬉ in the adjacent chest wall soft tissues. (Right) Axial NECT of a patient with polymyositis demonstrates extensive muscle atrophy and fatty replacement with almost no recognizable chest wall musculature, with the exception of small paravertebral muscles ﬈. Note reactive mediastinal lymphadenopathy ﬉.

323

Autoimmune Diseases

Sjögren Syndrome KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Sjögren syndrome (SS): Chronic inflammatory autoimmune disease: Lymphocytic infiltration of exocrine glands and other sites • May be primary or associated with other connective tissue diseases, most commonly rheumatoid arthritis

• • • •

IMAGING • Nonspecific interstitial pneumonia (NSIP) pattern: Subpleural lower lobe reticular and ground-glass opacities • Usual interstitial pneumonia (UIP) pattern: Subpleural reticular opacities, traction bronchiectasis, honeycombing • Lymphoid interstitial pneumonia (LIP): Ground-glass opacities, centrilobular/subpleural nodules; lung cysts • Diffuse lymphoid hyperplasia (DLH): Rare progression to fibrosis in late stages • Organizing pneumonia (OP): Bilateral, patchy, nonsegmental consolidations or ground-glass opacities, predominantly subpleural and peribronchovascular

(Left) AP chest radiograph of a 43-year-old woman with Sjögren syndrome and lymphoid interstitial pneumonia shows low lung volumes and diffuse bilateral heterogeneous opacities with coalescence in the lower lobes. (Right) Axial HRCT of the same patient shows diffuse bilateral ground-glass opacities with scattered small, thin-walled cysts ﬈ and a few discrete small solid nodules ﬉. The presence of lung cysts in a patient with Sjögren syndrome should suggest the possibility of lymphoid interstitial pneumonia.

(Left) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows a diffuse lymphoid infiltrate involving the interstitium with scattered reactive lymphoid follicles ﬉. (Right) High-power photomicrograph (H&E stain) of the same specimen shows abundant lymphocytic and plasmatic infiltration of the pulmonary interstitium. The cysts seen on imaging are postulated to result from overdistension of airways distal to bronchioles that are narrowed by lymphoid nodules and infiltration.

324

Pulmonary cystic diseases Idiopathic pulmonary fibrosis Organizing pneumonia Mucosa-associated lymphoid tissue lymphoma

CLINICAL ISSUES • Middle-aged women (peak: 56 years) • Much more common in women; F:M ratio = 10:1 • 2nd most common multisystem autoimmune disease after rheumatoid arthritis • Diagnostic criteria: Keratoconjunctivitis sicca + xerostomia + extensive lymphocytic infiltrate on minor salivary gland + laboratory evidence of autoimmune disease [rheumatoid factor (+) or antinuclear antibody (+) or SS-A or SS-B (+)]

DIAGNOSTIC CHECKLIST • Consider lymphoma in patients with SS with persistent nodules, masses, or lymphadenopathy

Sjögren Syndrome

Abbreviations • Sjögren syndrome (SS)

Synonyms • Sicca syndrome • Gougerot-Sjögren disease

Definitions • Chronic inflammatory autoimmune disease characterized by lymphocytic infiltration of exocrine glands and other extraglandular sites • May be primary or associated with other connective tissue diseases, most commonly rheumatoid arthritis • Pulmonary involvement occurs in 9-20% of patients, although subclinical lung disease may be more frequent ○ Lung involvement is more common in secondary SS than in primary SS ○ Nonspecific interstitial pneumonia (NSIP) is most common interstitial lung disease (ILD) in patients with SS (45%) • Lymphoproliferative disorders associated with SS ○ Reactive (benign) lymphoproliferative disorders – Follicular bronchiolitis – Lymphoid interstitial pneumonia (LIP) – Diffuse lymphoid hyperplasia (DLH) ○ Malignant lymphoproliferative disorders – Diffuse large B-cell lymphoma – Mucosa-associated lymphoid tissue (MALT) lymphoma or MALToma □ May progress to diffuse large B-cell non-Hodgkin lymphoma (NHL)

IMAGING Radiographic Findings • Radiography ○ NSIP – Bilateral, reticular, or heterogeneous opacities; lower lung zone predominant ○ Usual interstitial pneumonia (UIP): – Subpleural reticular opacities; lower lung zone predominant ○ LIP – Reticulonodular opacities; lower lung zone predominant ○ NHL – Single nodule/mass (65% of cases)

CT Findings • Associated findings ○ Mediastinal abnormalities: Lymphadenopathy, thymic hyperplasia, multilocular thymic cysts, thymic epithelial neoplasms ○ Amyloidosis: Association between SS, LIP, and amyloidosis is reported but is uncommon ○ Pulmonary hypertension ○ Pleural effusion: Uncommon, – Almost exclusively limited to secondary SS, occurring in association with rheumatoid arthritis and systemic lupus erythematosus

• HRCT ○ ILD – NSIP pattern □ Subpleural lower lobe reticular and ground-glass opacities; peribronchovascular distribution is suggestive □ Traction bronchiectasis – UIP pattern □ Subpleural reticular opacities &/or honeycombing □ Traction bronchiectasis – LIP □ Ground-glass opacities, centrilobular and subpleural nodules □ Round, thin-walled cysts, randomly distributed (common) – DLH □ May rarely progress to fibrosis in late stages (i.e., honeycombing) □ Presence of interlobular septal thickening, intralobular linear opacities, and thickening of peribronchovascular interstitium should suggest DLH – Organizing pneumonia (OP) □ Bilateral, patchy, nonsegmental areas of consolidation or ground-glass opacity predominantly in subpleural &/or peribronchovascular regions □ Reversed halo sign may be present ○ Follicular bronchiolitis – Small centrilobular and peribronchial micronodules – Tree-in-bud opacities with areas of ground-glass opacity and rarely bronchial dilatation and interlobular septal thickening ○ Constrictive bronchiolitis – Mosaic attenuation – Air-trapping on expiration ○ Other pulmonary manifestations – Cylindrical bronchiectasis □ Bronchial dilatation □ Air-trapping on expiration – Mucosa-associated lymphoid tissue (MALT) lymphoma or MALToma □ Solitary or multiple nodule(s) or mass(es) □ Areas of airspace consolidation or ground-glass opacity with air bronchograms □ Lymphadenopathy is uncommon unless there is progression to diffuse large B-cell NHL

Autoimmune Diseases

TERMINOLOGY

Imaging Recommendations • Best imaging tool ○ HRCT is optimal imaging modality for demonstrating pattern of disease and extent of pulmonary involvement

DIFFERENTIAL DIAGNOSIS Cystic Lung Diseases • Langerhans cell histiocytosis: Upper lung-predominant cysts with nodular walls and bizarre shapes; smoking-related disease

325

Autoimmune Diseases

Sjögren Syndrome • Lymphangioleiomyomatosis: Thin-walled, spherical cysts; may be sporadic or associated with tuberous sclerosis complex • Birt-Hogg-Dubé syndrome: Lung cysts; autosomal dominant inheritance, associated with facial papules (fibrofolliculomas) and malignant renal neoplasms • Light-chain deposition disease: Systemic deposition of immunoglobulin light chains in lymphoproliferative disorders and autoimmune conditions

Idiopathic Pulmonary Fibrosis • No imaging or pathologic differences between idiopathic and connective tissue disease-associated ILD • Differentiation is based on clinical grounds

Organizing Pneumonia • No imaging or pathologic differences between organizing pneumonia associated with connective tissue or that associated with other diseases

Mucosa-Associated Lymphoid Tissue Lymphoma • May mimic lung cancer and other malignancies on imaging; differentiation relies on histologic features

Rheumatoid Arthritis • • • • • •

Women, rheumatoid factor (+) Arthralgia, joint swelling and stiffness Pleural effusion, pleural thickening UIP > NSIP Bronchiectasis, rheumatoid nodules Skeletal changes: Erosive changes of clavicles, glenohumeral joints, and superior rib notching

PATHOLOGY General Features • Etiology ○ Precise etiology is unclear ○ Combination of genetic and environmental triggers ○ Several conditions may play role – Infection: Viruses (hepatitis C virus, cytomegalovirus, human immunodeficiency virus (HIV), human T-cell leukemia virus) – Genetic predisposition – Hormonal deregulation • Genetics ○ Genetic predisposition not well understood – HLA-DRB1 and HLA-DQB1 may increase predisposition • Associated abnormalities ○ Other autoimmune diseases (e.g., Hashimoto thyroiditis, primary biliary cirrhosis, and autoimmune hepatitis) • Diagnosis of lymphoproliferative disorders requires histopathologic confirmation

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Dry cough and dyspnea • Other signs/symptoms

326

○ Dry skin, dry eyes, skin rashes, joint and muscle pain, swollen salivary glands, prolonged fatigue, cystitis, reflux esophagitis, peptic ulcer, pancreatitis • Clinical profile ○ Positive serum anti-SS-A/Ro &/or anti-SS-B/La (or positive rheumatoid factor and antinuclear antibodies) • Criteria for diagnosis of SS ○ Keratoconjunctivitis sicca + xerostomia + extensive lymphocytic infiltrate of minor salivary glands + laboratory evidence of autoimmune disease – Rheumatoid factor (+) or antinuclear antibody (+) or SS-A or SS-B (+)

Demographics • Age ○ Middle-aged women (peak: 56 years) ○ Most men affected after 65 years • Gender ○ Much more common in women; F:M ratio = 10:1 • Epidemiology ○ 2nd most common multisystem autoimmune disease after rheumatoid arthritis ○ Lymphoma – NHL most common – Incidence 44x higher than in normal population – Develops in 4-8% of patients with SS – 50% have extranodal disease

Natural History & Prognosis • Pulmonary manifestations typically develop late in disease • Patients with SS-related lung disease have impaired quality of life compared with other patients with SS • Pulmonary involvement is associated with 4-fold increase in mortality risk after 10 years of disease

Treatment • Most patients do not require drug therapy ○ Symptom-specific therapy for dry eyes and skin • Low-dose corticosteroids and immunosuppressive therapy may be necessary with exacerbation or progression of ILD

DIAGNOSTIC CHECKLIST Consider • Malignant lymphoma in patients with SS if persistent nodule/(s) or mass(es) + hilar/mediastinal lymphadenopathy

Image Interpretation Pearls • Consider infection or drug toxicity in patients with SS, acute pulmonary symptoms, and radiographic abnormalities

SELECTED REFERENCES 1.

Flament T et al: Pulmonary manifestations of Sjögren's syndrome. Eur Respir Rev. 25(140):110-23, 2016

Sjögren Syndrome Autoimmune Diseases

(Left) PA chest radiograph of a 51-year-old woman with Sjögren syndrome and lymphoid interstitial pneumonia shows subtle bilateral reticular pulmonary opacities ﬊. (Right) Coronal CECT of the same patient shows scattered multifocal, bilateral, thin-walled pulmonary cysts ﬉. Lung cysts are frequently seen in patients with lymphoid interstitial pneumonia and are a specific finding that should suggest the correct diagnosis in the appropriate clinical context.

(Left) Composite image with CECT in soft tissue (left) and lung (right) window of a 47year-old woman with Sjögren syndrome shows multiple thinwalled cysts ﬈ secondary to lymphoid interstitial pneumonia and amorphous nodular calcifications ﬉ consistent with amyloidosis. This association is rare but well described in Sjögren syndrome. (Right) AP chest radiograph of a 53-year-old woman with Sjögren syndrome and nonspecific interstitial pneumonia shows low lung volumes and diffuse bilateral reticular opacities.

(Left) Axial HRCT of the same patient shows scattered bilateral ground-glass opacities and mild bilateral subpleural reticulation ﬈. (Right) Axial HRCT of the same patient shows bilateral ground-glass opacities and mild lower lobe subpleural reticulation ﬈. Note the absence of honeycombing, which is a feature of usual interstitial pneumonia. The presence of ground-glass opacity may be related to inflammation or microscopic fibrosis but in general is a sign of a potentially treatable disease.

327

Autoimmune Diseases

Sjögren Syndrome

(Left) Axial HRCT of a 47-yearold man with Sjögren syndrome and nonspecific interstitial pneumonia shows bilateral subpleural groundglass and reticular opacities ﬈ and traction bronchiolectasis ﬉. (Right) Axial HRCT of the same patient shows ground-glass opacities, subpleural reticulation, focal honeycombing ﬈, and traction bronchiectasis. The predominance of ground-glass opacity is more consistent with nonspecific interstitial pneumonia than with usual interstitial pneumonia.

(Left) Axial inspiratory HRCT of a 65-year-old woman with Sjögren syndrome and constrictive bronchiolitis shows no discrete abnormality. (Right) Axial expiratory HRCT of the same patient shows scattered areas of air-trapping ﬉ consistent with small airways disease. Air-trapping is common in Sjögren syndrome and indicates small airways diseases, such as follicular bronchiolitis, bronchiectasis, or, rarely, constrictive bronchiolitis.

(Left) Axial CECT of a 46-yearold woman with Sjögren syndrome and organizing pneumonia shows bilateral, patchy ground-glass opacities and mild reticulation. Organizing pneumonia may be a manifestation of pulmonary involvement but may also be associated with drug toxicity. (Right) Axial CECT of a 42year-old man with Sjögren syndrome undergoing chronic corticosteroid therapy shows a right lower lobe cavitary nodule ﬊ secondary to nocardiosis. Cavitary nodules in affected patients should suggest infection.

328

Sjögren Syndrome Autoimmune Diseases

(Left) Axial CECT of a 58-yearold woman with Sjögren syndrome and mucosaassociated lymphoid tissue (MALT) lymphoma shows bilateral peribronchovascular nodular opacities ﬈ with air bronchograms ﬉. (Right) High-power photomicrograph (H&E stain) of a specimen from the same patient shows extensive diffuse lymphoid proliferation surrounding a bronchiole ﬊ with vague nodularity. MALT lymphoma is a low-grade lymphoma commonly seen in the setting of Sjögren disease.

(Left) Axial CECT of a 47-yearold man with Sjögren syndrome and MALT lymphoma shows left upper lobe consolidation that did not resolve with medical therapy. MALT lymphoma may manifest as solitary or multiple pulmonary nodules, masses, or consolidations. (Right) Coronal FDG PET of the same patient shows mildly increased FDG uptake within the left upper lobe consolidation ﬊. Note the absence of FDG-avid lymphadenopathy.

(Left) Composite image with coronal FDG PET/CT of a 53year-old woman with Sjögren syndrome and diffuse large Bcell lymphoma shows extensive FDG-avid lymphadenopathy in the neck ﬈, mediastinum ﬉, and abdomen ﬊. (Right) Axial NECT of a patient with Sjögren syndrome shows a multilocular thymic cyst ﬈. Thymic cysts have been described in patients with Sjögren syndrome but also in other autoimmune diseases, such as myasthenia gravis, aplastic anemia, and systemic lupus erythematosus.

329

Autoimmune Diseases

Mixed Connective Tissue Disease KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Mixed connective tissue disease (MCTD): Overlap syndrome that is distinct clinical entity with features of systemic lupus erythematosus (SLE), systemic sclerosis (SS), rheumatoid arthritis (RA), or dermatomyositis/polymyositis (D/P) and high-titer antibodies to ribonucleoprotein

• Other connective tissue diseases • Primary pulmonary hypertension

IMAGING • CT/HRCT ○ Nonspecific interstitial pneumonia (35%) – Cellular: Basilar ground-glass opacities (most common abnormality) and reticular opacities – Fibrotic: Reticular opacities, architectural distortion, traction bronchiectasis, ± subpleural sparing ○ Pulmonary hypertension: Enlarged pulmonary arteries, mosaic attenuation, right ventricular hypertrophy ○ Pleural thickening, effusion (10%) ○ Dilated, patulous esophagus ○ Pulmonary thromboembolism

(Left) Coronal NECT of a patient with mixed connective tissue disease shows right upper lobe honeycombing ﬈ and bronchiectasis ﬉ and lower lobe ground-glass opacities ﬊. Open lung biopsy showed nonspecific interstitial pneumonia. (Right) Axial NECT of a patient with mixed connective tissue disease shows peribronchovascular consolidations ﬈, bronchiectasis ﬉, trace pleural effusions ﬊, and a patulous esophagus ﬊. Biopsy showed organizing pneumonia and nonspecific interstitial pneumonia.

(Left) Axial NECT of a patient with mixed connective tissue disease shows basilar reticulation, bronchiolectasis ﬉, and ground-glass opacities with subpleural sparing ﬈ consistent with fibrotic nonspecific interstitial pneumonia. Note the patulous esophagus ﬊. (Right) Axial NECT of a patient with mixed connective tissue disease shows an enlarged pulmonary trunk ﬈ suggestive of pulmonary hypertension. Cardiac catheterization showed pulmonary artery pressure of 30 mm Hg.

330

PATHOLOGY • Serology showing antibodies directed against U1 ribonucleoprotein

CLINICAL ISSUES • Female > male (9:1 ratio) • No presenting symptoms unique to MCTD ○ Raynaud phenomenon (99% of affected patients) ○ Symptoms of pulmonary hypertension • Possibly responsive to corticosteroids but no randomized controlled trials of treatment for MDCT

DIAGNOSTIC CHECKLIST • Consider MCTD in young women with pulmonary hypertension, interstitial lung disease, &/or patulous dilated esophagus

Mixed Connective Tissue Disease

PATHOLOGY

Abbreviations

General Features

• Mixed connective tissue disease (MCTD) • Systemic sclerosis (SS): Scleroderma

• No specific pathologic feature other than serology showing antibodies directed against U1 ribonucleoprotein • Pulmonary hypertension: Secondary to proliferative vasculopathy rather than underlying interstitial lung disease

Definitions

Staging, Grading, & Classification

• MCTD: Overlap syndrome that is distinct clinical entity with features of systemic lupus erythematosus (SLE), SS, rheumatoid arthritis (RA), or dermatomyositis/polymyositis (D/P) and high-titer antibodies to ribonucleoprotein

• Alarcon-Segovia criteria most commonly used ○ Required criterion: High titer of antibodies directed against U1 ribonucleoprotein ○ 1 of 5 clinical criteria: Raynaud phenomenon; swollen, "puffy" hands; synovitis; myositis, acrosclerosis

Synonyms

IMAGING CT Findings • No specific or unique features of MCTD: Thoracic manifestations of SLE, SS, RA, or D/P • Nonspecific interstitial pneumonia (NSIP) (35%) ○ Cellular: Basilar ground-glass opacities (most common CT abnormality) and reticular opacities ○ Fibrotic: Reticular opacities, architectural distortion, traction bronchiectasis, ± subpleural sparing • Pulmonary hypertension (10-45%): Enlarged central pulmonary arteries, mosaic attenuation/perfusion, right ventricular hypertrophy • Pleural thickening, effusion (10%) • Dilated, patulous esophagus • Pulmonary thromboembolism • Rare manifestations ○ Usual interstitial pneumonia pattern: Basilar subpleural honeycombing ○ Organizing pneumonia: Subpleural or peribronchial consolidation, ± reversed halo sign (central ground-glass opacity and peripheral consolidation) ○ Diffuse alveolar hemorrhage

MR Findings • MR ventilation imaging: Hyperpolarized noble gases (helium³ and xenon¹²⁹) or oxygen-enhanced MR

Imaging Recommendations • Protocol advice ○ HRCT for assessment of interstitial lung disease ○ CTA for diagnosis of thromboembolic disease

DIFFERENTIAL DIAGNOSIS Other Connective Tissue Diseases • • • • •

SS or SLE: Pulmonary hypertension SS: NSIP pattern, esophageal dilatation RA or SLE: Pleural/pericardial effusion SLE: Diffuse alveolar hemorrhage RA: Usual interstitial pneumonia pattern

Primary Pulmonary Hypertension • May be indistinguishable from pulmonary hypertension associated with MCTD

Autoimmune Diseases

TERMINOLOGY

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ No presenting symptoms unique to MCTD; any symptoms may also be seen in SLE, SS, RA, D/P ○ Raynaud phenomenon (99%) ○ Symptoms of pulmonary hypertension: Exercise intolerance, dyspnea, peripheral edema, ascites ○ Inflammatory arthritis ○ Serositis (pleuritis, pericarditis) ○ Myositis ○ Esophageal dysfunction • Other signs/symptoms ○ Chest pain or dyspnea from thromboembolism ○ Hemoptysis from alveolar hemorrhage (rare)

Demographics • Female > male (9:1 ratio) • Peak incidence: Age 40 years; 7-23% with disease onset in childhood

Natural History & Prognosis • Thoracic manifestations in 20-80% patients: Thoracic diseases seen in SLE, SS, RA, D/P • Pulmonary hypertension is most common cause of death in patients with MCTD • Pulmonary hypertension carries poor prognosis ○ Faster progression and shorter survival compared to pulmonary hypertension associated with other connective tissue diseases

Treatment • Thought to respond to corticosteroids, but no randomized control trials of treatment for MDCT have been performed • Therapy based on experience from treatment of other related connective tissue disorders

DIAGNOSTIC CHECKLIST Consider • MCTD in young women with pulmonary hypertension, interstitial lung disease, &/or patulous dilated esophagus

SELECTED REFERENCES 1.

Ahuja J et al: Imaging of pulmonary manifestations of connective tissue diseases. Radiol Clin North Am. 54(6):1015-1031, 2016

331

Autoimmune Diseases

Systemic Lupus Erythematosus KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Systemic lupus erythematosus (SLE): Autoimmune disease of uncertain etiology with multiorgan system involvement

• Rheumatoid arthritis and other collagen vascular diseases • Pneumonia • Acute respiratory distress syndrome

IMAGING • CT/HRCT ○ Pneumonia: Ground-glass opacities, consolidations ○ Diffuse alveolar hemorrhage: Ground-glass opacities ± interlobular septal thickening (crazy-paving pattern) ○ Acute lupus pneumonitis: Ground-glass opacities, consolidation, architectural distortion ○ SLE-related interstitial lung disease: Reticulation, groundglass opacities, traction bronchiectasis ○ Pleuritis: Pleural thickening ± pleural enhancement; small to moderate bilateral pleural effusions ○ Airways: Tracheal wall thickening, bronchiectasis ○ Cardiovascular: Pericardial effusion &/or calcification ○ Complications: Pulmonary thromboembolism, pulmonary hypertension (PH)

(Left) Axial HRCT of a woman with systemic lupus erythematosus and severe dyspnea shows multifocal ground-glass opacities ﬊ and consolidations ﬉. Streptococcal pneumonia was diagnosed on bronchoscopy. (Right) Axial NECT of a 48year-old man with systemic lupus erythematosus and renal failure who presented with chronic fever, shows diffuse bilateral randomly distributed micronodules ﬊ secondary to miliary tuberculosis. Pulmonary infection is a welldocumented complication in affected patients.

(Left) Axial NECT of a patient with systemic lupus erythematosus shows bilateral ground-glass opacities on a background of thick interlobular septa and intralobular lines ﬉ (the crazy-paving pattern) due to alveolar hemorrhage and small bilateral pleural effusions ﬈. (Right) Axial HRCT of a patient with systemic lupus erythematosus and hemoptysis shows diffuse bilateral ground-glass opacities consistent with diffuse alveolar hemorrhage and a trace right pleural effusion ﬉.

332

CLINICAL ISSUES • Relapsing and remitting course; females > males • Multiorgan involvement, including lungs, bones, brain, kidneys, skin • Risk of death from SLE highest in first 3 years after diagnosis • Mortality in SLE ○ Active SLE (~ 30%); infection (~ 20%); cardiovascular disease (~ 10%); cerebrovascular disease (~ 10%)

DIAGNOSTIC CHECKLIST • Consider SLE in women of childbearing age with pulmonary thromboembolism or PH, pleural &/or pericardial effusions

Systemic Lupus Erythematosus

Abbreviations • Systemic lupus erythematosus (SLE)

○

Definitions • SLE: Autoimmune systemic disease of unknown etiology ○ Production of large variety of autoantibodies – Antidouble stranded DNA (dsDNA) and anti-Smith antibodies specific for SLE

○ ○ ○

IMAGING General Features • Best diagnostic clue ○ Pleural &/or pericardial effusions in woman of childbearing age ○ Unexplained thromboembolic disease or pulmonary hypertension (PH) in woman of childbearing age • Location ○ Pleuritis is most common thoracic manifestation ○ May also involve lung, airways, cardiovascular system

Radiographic Findings • Multifocal opacities: Pneumonia, alveolar hemorrhage, acute lupus pneumonitis • Reticular opacities related to interstitial lung disease (ILD) • Small lung volumes in patients with shrinking lung syndrome (SLS) ○ Elevated hemidiaphragms without lung opacities • Pleural effusions: Usually small and bilateral • Enlarged central pulmonary arteries related to PH • Enlarged cardiopericardial silhouette secondary to pericardial effusion or (less likely) myocarditis • Pericardial calcification

CT Findings • Pneumonia: Most common pulmonary complication, often related to immunosuppressive therapy ○ Focal or diffuse ground-glass opacities &/or consolidations • Diffuse alveolar hemorrhage: Multifocal ground-glass opacities ± interlobular septal thickening (crazy-paving pattern) • Acute lupus pneumonitis: Ground-glass opacities &/or consolidations, traction bronchiectasis, architectural distortion • SLE-related ILD: Fine reticulation, multifocal ground-glass opacities, architectural distortion, traction bronchiectasis ○ Usual interstitial pneumonia (UIP) pattern (rare); possible UIP pattern [nonspecific interstitial pneumonia (NSIP)] • Airway involvement ○ Tracheal wall thickening; rarely significant tracheal luminal narrowing ○ Bronchiectasis • Pleuritis: Pleural thickening ± pleural enhancement; small to moderate bilateral pleural effusions • Cardiovascular involvement ○ Pulmonary thromboembolic disease – Acute: Central arterial filling defects, arterial luminal distention

○

– Chronic: Arterial webs, eccentric arterial filling defects, diminutive peripheral arteries, mosaic perfusion/attenuation; often associated with PH SLE-PH (primary or secondary): Enlarged pulmonary arteries (pulmonary trunk:aorta ratio > 1), right heart enlargement, reflux of contrast into inferior vena cava and hepatic veins Pericardial effusion: Small to moderate Pericardial calcification from recurrent inflammatory pericarditis Coronary artery atherosclerosis: 5x increased risk of premature atherosclerosis Libman-Sacks and bacterial endocarditis: Gated CTA – Small valvular vegetations on either side of valve; valvular regurgitation

Autoimmune Diseases

TERMINOLOGY

MR Findings • Pericardial effusion and pericardial thickening • Libman-Sacks and bacterial endocarditis: Valvular thickening, small valvular vegetations, valvular regurgitation • SLE myocarditis ○ Delayed gadolinium enhancement; primarily midmyocardial (nonischemic pattern)

Imaging Recommendations • Best imaging tool ○ HRCT for evaluation of ILD ○ CTA for exclusion of pulmonary thromboembolism and assessment of PH • Protocol advice ○ CECT to identify pleural/pericardial enhancement

DIFFERENTIAL DIAGNOSIS Rheumatoid Arthritis and Other Collagen Vascular Diseases • Both SLE and rheumatoid arthritis (RA) may cause serositis • RA: Higher incidence of ILD; may exhibit cavitary nodules • Common clinical overlap of SLE and other collagen vascular disorders

Pneumonia • Focal or multifocal ground-glass opacities &/or consolidations • Atypical infection and acute lupus pneumonitis may be indistinguishable on imaging

Acute Respiratory Distress Syndrome • Acute lupus pneumonitis may be indistinguishable from acute respiratory distress syndrome (ARDS) • Pleural effusions more common in SLE than in ARDS

Idiopathic Pulmonary Artery Hypertension • Pleural effusions favor SLE

PATHOLOGY General Features • Serositis ○ Pleural involvement more common than in any other collagen vascular disease (60% of patients)

333

Autoimmune Diseases

Systemic Lupus Erythematosus

• • •

•

• •

○ Nonspecific pleural abnormalities: Lymphocytic and plasma cell infiltration, fibrinous pleuritis ○ Pericarditis is most common cardiovascular manifestation of SLE (60% patients, only 25% symptomatic) Acute lupus pneumonitis: Diffuse alveolar damage, ± diffuse alveolar hemorrhage SLS: Uncertain whether related to diaphragmatic myopathy or phrenic neuropathy Diffuse alveolar hemorrhage ○ Most frequently bland hemorrhage ○ Hemorrhage from capillaritis with immune complex deposition may also occur SLE-associated ILD: Typically NSIP ○ UIP and lymphoid interstitial pneumonia also associated with SLE but are rare SLE-PH: Pathology similar to that of idiopathic PH Libman-Sacks endocarditis: 50% patients on echocardiography ○ Immune complex deposition with resultant inflammatory reaction ○ May progress to valvular stenosis or regurgitation

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Multiorgan involvement, including lungs, bones, brain, kidneys, skin ○ Most common presenting manifestations: Photosensitive rash, glomerulonephritis, arthritis ○ Pleural and lung involvement in 50-60% patients • Other signs/symptoms ○ Thoracic manifestations usually occur late in disease ○ Pneumonia common, due to immunosuppression – Higher incidence of tuberculosis in patients with SLE compared with general population ○ Most common thoracic symptom: Pleurisy due to pleuritis (~ 60% patients) – ± exudative pleural effusions ○ SLS, pulmonary vascular disease: Chronic dyspnea, chest pain, fatigue ○ Acute lupus pneumonitis: Rare (1-10% patients) but high morbidity and mortality – Fever, cough, dyspnea, hypoxia, ± hemoptysis ○ Diffuse alveolar hemorrhage: Hemoptysis, dyspnea, cough, ± fever ○ SLE-related ILD: Nonproductive cough, progressive dyspnea ○ SLE-PH: Dyspnea, chest pain, nonproductive cough, fatigue ○ Thromboembolic disease: Chest pain, dyspnea, hypoxia ○ Cardiac involvement – Chest pain: Pericarditis, myocarditis, infarction – Libman-Sacks and subacute bacterial endocarditis: Emboli may lead to stroke, myocardial infarction, pulmonary embolism • Clinical profile ○ Serum antibodies associated with SLE – Anti-dsDNA, anti-Smith antibodies (specific)

○ ○ ○ ○ ○

Demographics • • • •

F>M Women of childbearing age most frequently affected 3x increased incidence in African Americans Genetic component: SLE develops in 5-10% of 1st-degree relatives of patients with SLE

Natural History & Prognosis • Relapsing and remitting course • Risk of death from SLE highest in first 3 years after diagnosis • Mortality in SLE ○ Active SLE (~ 30%) ○ Infection (~ 20%) ○ Cardiovascular disease (~ 10%) ○ Cerebrovascular disease (~ 10%)

Treatment • Nonsteroidal antiinflammatory drugs or low-dose corticosteroids for pleuritis or pericarditis • Acute lupus pneumonitis: Plasmapheresis, mechanical ventilation, high-dose corticosteroids, immunosuppressants (i.e., cyclophosphamide) • SLS: Corticosteroids and immunosuppressants; generally good response • Diffuse alveolar hemorrhage: Plasmapheresis, immunosuppressants • SLE-related ILD: Corticosteroids and immunosuppressants (i.e., cyclophosphamide, azathioprine)

DIAGNOSTIC CHECKLIST Consider • SLE in women of childbearing age with pulmonary thromboembolism or PH • SLE in patients with unexplained pleural &/or pericardial effusions • SLE in patients with hemoptysis and multifocal groundglass opacities on CT/HRCT

SELECTED REFERENCES 1. 2. 3. 4. 5. 6.

334

– Antinuclear autobody (ANA), antiphospholipid antibody (APA), Anti-SSA (less specific) Pleuritis: Exudative effusions SLE-related ILD: Decreased diffusing capacity, restrictive pattern on pulmonary function tests SLS: Normal diffusing capacity, restrictive pattern on pulmonary function tests Diffuse alveolar hemorrhage: Usually in association with active lupus nephritis (pulmonary-renal syndrome) SLE-PH: High prevalence when patients have lupus anticoagulant &/or APA

Serra G et al: Thoracic involvement in connective tissue diseases: radiological patterns and follow-up. JBR-BTR. 98(1):3-19, 2015 Mittoo S et al: Pulmonary manifestations of systemic lupus erythematosus. Semin Respir Crit Care Med. 35(2):249-54, 2014 Goh YP et al: Imaging of systemic lupus erythematosus. Part I: CNS, cardiovascular, and thoracic manifestations. Clin Radiol. 68(2):181-91, 2013 Kanne JP et al: Beyond skin deep: thoracic manifestations of systemic disorders affecting the skin. Radiographics. 31(6):1651-68, 2011 Kamen DL et al: Pulmonary manifestations of systemic lupus erythematosus. Clin Chest Med. 31(3):479-88, 2010 Lynch DA: Lung disease related to collagen vascular disease. J Thorac Imaging. 24(4):299-309, 2009

Systemic Lupus Erythematosus Autoimmune Diseases

(Left) Axial NECT of a patient with systemic lupus erythematosus and immunosuppression shows invasive aspergillosis manifesting with a left apical cavitary mass ﬉ surrounded by peripheral consolidation. (Right) Axial CECT of a patient with systemic lupus erythematosus and septic pulmonary emboli shows bilateral lower lobe consolidations, multifocal lung nodules representing septic emboli ﬈, and small bilateral pleural effusions ﬉. Bacterial endocarditis is a known complication of the disease.

(Left) Axial NECT of a patient with systemic lupus erythematosus, fever, leukocytosis, and positive blood cultures secondary to septic emboli from bacterial endocarditis shows multiple bilateral pulmonary nodules ﬈, many with intrinsic cavitation and variable cavity wall thickness. Note the small left pleural effusion ﬉. (Right) Axial NECT of the same patient shows basilar predominant cavitary pulmonary nodules ﬈ of various sizes representing septic emboli and bilateral basilar consolidations.

(Left) Axial NECT of a patient with systemic lupus erythematosus and acute lupus pneumonitis shows diffuse ground-glass opacities. Note that the appearance may be the same as that of pulmonary edema or an infection. (Right) AP chest radiograph of a patient with systemic lupus erythematosus and shrinking lung syndrome shows bilateral low lung volumes and basilar subsegmental atelectasis ﬈. The resultant restrictive lung disease is postulated to result from diaphragmatic dysfunction.

335

Autoimmune Diseases

Systemic Lupus Erythematosus

(Left) Axial HRCT of a 42-yearold patient with systemic lupus erythematosus and chronic dyspnea shows basilar ground-glass opacities and reticulations with subpleural sparing and associated traction bronchiolectasis ﬈ consistent with nonspecific interstitial pneumonia. (Right) Axial NECT of a patient with systemic lupus erythematosus and progressive dyspnea shows extensive bilateral ground-glass opacities with minimal reticulation ﬈. Lung biopsy revealed the histologic features of cellular nonspecific interstitial pneumonia.

(Left) Axial NECT of a patient with systemic lupus erythematosus reveals right upper lobe ground-glass opacity nodules ﬈ and several discrete thin-walled pulmonary cysts ﬉. Biopsy revealed lymphoid interstitial pneumonia. (Right) Axial NECT of the same patient shows additional multifocal, bilateral thin-walled pulmonary cysts ﬉ of various sizes. Usual interstitial pneumonia and lymphoid interstitial pneumonia are rare but recognized complications of systemic lupus erythematosus.

(Left) Axial NECT of a patient with systemic lupus erythematosus and progressive dyspnea secondary to nonspecific interstitial pneumonia shows basilar ground-glass opacities ﬉ and varicoid bronchiectasis ﬈. (Right) Coronal NECT of the same patient shows bilateral lower lobe varicoid bronchiectasis ﬈ and upper lung zone subpleural groundglass opacities ﬉. Bronchiectasis may occur as a complication of nonspecific interstitial pneumonia (as in this case) or as an isolated finding in affected patients.

336

Systemic Lupus Erythematosus Autoimmune Diseases

(Left) Axial HRCT of a patient with systemic lupus erythematosus shows bilateral nodular subpleural and peribronchovascular groundglass opacities and consolidations that exhibit the reversed halo sign ﬈ characteristic of organizing pneumonia. (Right) Fourchamber SSFP MR of a patient with systemic lupus erythematosus shows a large pericardial effusion ﬈. Note high-signal subepicardial fat ﬉ deep to the serous visceral pericardium ﬊. The parietal pericardium is of normal thickness with no nodularity.

(Left) Axial NECT of a patient with systemic lupus erythematosus shows a moderate right pleural effusion ﬈, trace left pleural effusion ﬉, and anterior pericardial calcification ﬊ related to recurrent inflammatory pericarditis. (Right) Axial CECT of a patient with systemic lupus erythematosus shows multiple central pulmonary arterialfilling defects ﬈ consistent with acute pulmonary thromboembolism. Thromboembolic disease is a common manifestation of systemic lupus erythematosus.

(Left) Axial CECT of a patient with systemic lupus erythematosus and pulmonary hypertension ﬉ secondary to chronic pulmonary thromboembolism shows eccentric pulmonary thromboemboli ﬈ and occlusion of the left lower lobe pulmonary artery ﬊. (Right) Coronal oblique CECT of the same patient shows eccentric pulmonary thromboemboli ﬈ with intrinsic punctate calcifications and occlusion of the left lower lobe pulmonary artery ﬊, consistent with chronic pulmonary emboli.

337

Autoimmune Diseases

Granulomatosis With Polyangiitis (GPA) KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Multisystem necrotizing granulomatous vasculitis of small to medium-sized vessels • Wegener granulomatosis (term no longer used)

• • • • • •

IMAGING • Radiography ○ May be normal (20%) ○ Multiple lung nodules/masses ± cavitation ○ Multifocal consolidation (may represent hemorrhage) • HRCT/CT ○ Multifocal lung nodules/masses/consolidations – Cavitation more common in larger nodules – Air-fluid levels suggest secondary infection ○ Ground-glass opacity (pulmonary hemorrhage) ○ Halo sign, reversed halo sign, feeding vessel sign ○ Pulmonary fibrosis may occur ○ Pleural effusion ○ Airway wall thickening (50-60%)

(Left) Coronal NECT of a patient with granulomatosis with polyangiitis shows multiple pulmonary solid ﬈ and cavitary ﬉ pulmonary nodules. Cavitary nodules are common at presentation, but the differential diagnosis also includes septic emboli, fungal infection, lung abscesses, and cavitary metastases. (Right) Low-power photomicrograph (H&E stain) of a specimen of granulomatosis with polyangiitis shows a relatively well-defined lung nodule that contains multiple areas of intrinsic serpiginous necrosis ﬈.

(Left) Axial HRCT of a patient with granulomatosis with polyangiitis shows multiple small, bilateral, solid and cavitary pulmonary nodules ﬉ and bronchial wall thickening ﬊ of subsegmental airways. (Right) Low-power photomicrograph (H&E stain) of a specimen of granulomatosis with polyangiitis shows a nodular lesion comprised of various types of inflammatory cells and vasculitis of medium-sized vessels ﬈.

338

Pulmonary metastases Septic emboli Lung abscess Tuberculosis Tracheobronchial amyloidosis Relapsing polychondritis

CLINICAL ISSUES • Adults: 40-60 years of age • Symptoms/signs: Cough, hemoptysis, dyspnea • Laboratory: Cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) • Diagnosis: Nasal, paranasal sinus, lung, or renal biopsy • Treatment: Corticosteroids, cyclophosphamide, methotrexate • Remission in ~ 90% of treated patients • Mean 5-year survival: 90-95%

Granulomatosis With Polyangiitis (GPA)

Abbreviations

•

• Granulomatosis with polyangiitis (GPA)

Synonyms • Wegener granulomatosis (term no longer used)

Definitions • Multisystem necrotizing granulomatous vasculitis of autoimmune origin, which affects small to medium-sized vessels

•

IMAGING General Features • Best diagnostic clue ○ Multiple lung nodules or masses ± cavitation • Location ○ Bilateral ○ No zonal predilection; apices tend to be spared • Size ○ Variable: Few mm to 10 cm; most lesions 2-4 cm

Radiographic Findings • Radiography ○ Normal (20%) ○ Pulmonary nodules or masses (most common) – Present in 40-70% of patients – Cavitation (up to 50%) □ Occurs in 25% of nodules > 2 cm □ Thin or thick and nodular cavity walls □ Intracavitary air-fluid levels suggest secondary infection ○ Airspace opacities – Pulmonary hemorrhage, infarction, organizing pneumonia – Subpleural wedge-shaped consolidations – May exhibit central necrosis – May develop cavitation – May mimic pneumonia but do not resolve with treatment ○ Less common findings – Atelectasis; reticular opacities ○ Peripheral airway stenosis may result in segmental or lobar atelectasis ○ Subglottic stenosis often present but overlooked • Radiography may be used to monitor response to therapy ○ Relapse/recurrence – Increase in size &/or number of parenchymal abnormalities ○ Favorable response/improvement – Decrease in nodule size – Increased wall thickness of cavitary lesions – Progression of lesion margin irregularity

CT Findings • Pulmonary nodules/masses (90%) ○ Typically multiple and bilateral; well circumscribed ○ Cavitation (50%) – More common in larger lesions – Thick and irregular or "shaggy" cavity walls

• •

•

•

•

•

– Cavities may disappear and cavity walls may become thin with treatment Ground-glass opacity ○ Diffuse alveolar hemorrhage (10%) – Diffuse involvement, subpleural sparing – Interlobular septal thickening □ Lymphatic congestion □ Hemosiderin-laden macrophages ○ Mosaic perfusion – Arteriolar involvement Multiple signs ○ Halo sign (occasionally) – Ground-glass opacity surrounding nodules, masses, or consolidations ○ Reversed halo sign – Consolidation around central ground-glass opacity – Organizing pneumonia-type reaction in peripheral aspect of pulmonary hemorrhage ○ Feeding vessel sign – Pulmonary vessel coursing directly into pulmonary nodule or mass – Described in 88% of cases in one series Tree-in-bud opacities ○ Arteriolar involvement Pulmonary fibrosis ○ Subpleural reticular opacities and honeycombing ○ Peripheral and lower lung zone distribution Other pulmonary abnormalities ○ Consolidation ○ Centrilobular micronodules from hemosiderosis as complication of recurrent alveolar hemorrhage ○ Parenchymal bands ○ Interlobular septal thickening ○ Bronchial wall thickening Airway wall thickening (50-60%) ○ Trachea to segmental or subsegmental airways ○ Usually mild but may obliterate airway lumina ○ Focal or long segment Pleural abnormalities ○ Pleural effusion is most common ○ Pleural thickening, empyema, and pneumothorax (rare) Mediastinal lymph node enlargement (15%) ○ Always with concomitant pulmonary abnormalities

Autoimmune Diseases

TERMINOLOGY

Nuclear Medicine Findings • Ga-67 scintigraphy ○ Lesions are typically gallium avid ○ May be used to monitor disease activity

Imaging Recommendations • Best imaging tool ○ HRCT/CT for assessment of disease extent ○ Radiography and CT to monitor response to treatment • Protocol advice ○ Thin-section unenhanced chest CT for optimal airway imaging – Multiplanar reformations particularly useful for airway evaluation – Inclusion of glottis helpful because of frequent subglottic involvement 339

Autoimmune Diseases

Granulomatosis With Polyangiitis (GPA)

DIFFERENTIAL DIAGNOSIS Pulmonary Metastases • Well-defined pulmonary nodules or masses • Hemorrhagic metastases may exhibit irregular margins and surrounding ground-glass opacity ○ Renal cell carcinoma, melanoma, choriocarcinoma • Squamous cell carcinomas and sarcomas may cavitate

Septic Emboli • Poorly defined pulmonary nodules or masses • Varying degrees of cavitation

Lung Abscess • Cavitary mass is most common finding • Air-fluid levels may be present • Consolidation or ground-glass opacity may affect adjacent lung parenchyma

Tuberculosis • May be indistinguishable from GPA on radiography • Diagnosis based on culture or special stains

Tracheobronchial Amyloidosis • Typically diffuse airway involvement • Stippled calcifications may be present

Relapsing Polychondritis • Spares posterior tracheal membrane and central bronchi • Involvement of extrathoracic cartilage

PATHOLOGY General Features • Etiology ○ Autoimmune syndrome of unknown etiology ○ Lung most commonly affected (94%) – Paranasal sinuses (91%) – Kidneys (85%)

Gross Pathologic & Surgical Features • Gray-white, solid or cavitary nodules ○ May coalesce as large areas of brown-red necrosis ○ Adjacent discolored areas of consolidation or hemorrhage • Isolated parenchymal involvement may be seen ○ Up to 25% of cases ○ Reddish pulmonary hemorrhage ○ Tan fibrosis ○ Yellow consolidation – Endogenous lipoid pneumonia

Microscopic Features • 3 major histologic features ○ Vasculitis ○ Necrosis ○ Granulomatous inflammation: Mixed cellular infiltrate composed of neutrophils, lymphocytes, plasma cells, histiocytes, and eosinophils • Lung lesions ○ Neutrophils aggregate in small microabscess-like clusters – Progression: Necrosis bordered by rim of macrophages or epithelioid histiocytes 340

– Further progression: Necrotic areas enlarge and coalesce as serpiginous areas that may lead to larger areas of necrosis ○ Surrounding inflammatory cell infiltrate composed of lymphocytes, plasma cells, and histiocytes ○ Airspace filling with blood or fibroblastic tissue (sometimes organizing pneumonia), obstructive pneumonia • Airway involvement ○ Direct extension from parenchymal lesion, mucosal or submucosal inflammation ○ Epithelium may be intact or ulcerated – When ulcerated, endobronchial granulation tissue polyps may produce airway obstruction

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Most common symptoms related to upper airway involvement – Rhinitis, sinusitis, otitis media ○ Variable onset of symptoms related to bronchopulmonary involvement – Cough, fever, dyspnea, hemoptysis, and chest pain ○ Triad of pulmonary disease, febrile sinusitis, and glomerulonephritis • Other signs/symptoms ○ Cardiac involvement – Coronary vasculitis, pancarditis, and valvular lesions – Acute pericarditis, dilated cardiomyopathy, acute valvular insufficiency with pulmonary edema, and cardiac arrest secondary to ventricular arrhythmias • Laboratory findings ○ Cytoplasmic antineutrophil cytoplasmic antibody (ANCA) – Detected by indirect immunofluorescence – Suggestive, but not sufficient, for diagnosis – Levels of ANCA correlate with disease activity □ Sensitivity: 90% (active generalized); 60% active (localized) □ Specificity: 99%

Demographics • 40-60 years of age

Natural History & Prognosis • Nodules/masses increase in size and number with disease progression • Remission rate: ~ 90% with treatment • Mean 5-year survival: 90-95% • Renal failure most common cause of death in untreated patients

Treatment • Immunosuppressive drugs ○ Corticosteroids, cyclophosphamide, or methotrexate

SELECTED REFERENCES 1.

Feragalli B et al: The lung in systemic vasculitis: radiological patterns and differential diagnosis. Br J Radiol. 89(1061):20150992, 2016

Granulomatosis With Polyangiitis (GPA) Autoimmune Diseases

(Left) PA chest radiograph of a patient with granulomatosis with polyangiitis shows bilateral pulmonary nodules and masses ﬈, some of which exhibit intrinsic cavitation. (Right) Axial NECT of the same patient shows multiple lung nodules and masses with intrinsic cavitation consistent with necrosis. The combination of cavitary nodules, masses, and consolidations is one of the most common imaging appearances of granulomatosis with polyangiitis.

(Left) Axial NECT of the same patient obtained several weeks later shows resolving abnormalities, a residual thinwalled cavitary lesion ﬈, and focal left lung fibrosis/scarring ﬉. Lung lesions typically exhibit progressive cavitation and eventual resolution, often with residual nodules or scar. (Right) Axial NECT of the same patient shows mucosal thickening of the maxillary sinuses ﬈. Coexisting paranasal sinus involvement is common in patients with granulomatosis with polyangiitis.

(Left) High-power photomicrograph (H&E stain) of a specimen of granulomatosis with polyangiitis shows vasculitis of a medium-sized artery with thickening of the vascular media by extensive inflammatory cell infiltration ﬈. (Right) Axial CECT of a patient with granulomatosis with polyangiitis shows scattered bilateral groundglass nodules ﬈ and tree-inbud opacities ﬉. These are common imaging findings of granulomatosis with polyangiitis.

341

Autoimmune Diseases

Granulomatosis With Polyangiitis (GPA)

(Left) PA chest radiograph of a patient with granulomatosis with polyangiitis shows a large right lung mass ﬈ that projects over the right hilum, a finding that is highly suspicious for primary lung cancer. (Right) Axial NECT of the same patient shows a right upper lobe mass-like consolidation ﬈ that was proven to represent focal pulmonary involvement by granulomatosis with polyangiitis. Such lesions may be solitary; may mimic primary lung cancer morphologically and metabolically (i.e., CT and PET).

(Left) Axial fused FDG PET/CT of the same patient shows marked FDG avidity in the mass ﬈. The metabolic behavior of this lesion mimics that of primary lung cancer. (Right) Composite image with axial NECT in lung (left) and soft tissue (right) window of a patient with granulomatosis with polyangiitis shows a wellcircumscribed soft tissue nodule ﬈ with intrinsic punctate calcifications ﬉. Nodular lung lesions may also exhibit cavitation and air-fluid levels. The latter often indicate superimposed infection.

(Left) AP chest radiograph of a patient granulomatosis with polyangiitis and diffuse alveolar hemorrhage shows bilateral ill-defined, hazy opacities that are slightly more conspicuous in the right upper lung zone. (Right) Axial NECT of the same patient shows diffuse bilateral ground-glass opacities. Diffuse alveolar hemorrhage with capillaritis is a common imaging abnormality in patients with granulomatosis with polyangiitis who may present with hemoptysis and a decreasing hematocrit.

342

Granulomatosis With Polyangiitis (GPA) Autoimmune Diseases

(Left) PA chest radiograph of a patient with granulomatosis with polyangiitis and alveolar hemorrhage shows a right lower lung zone heterogeneous consolidation. (Right) Axial NECT of the same patient shows ground-glass opacities and nodular consolidations ﬈ involving the middle and right lower lobes and, to a lesser extent, the left lower lobe ﬉. While alveolar hemorrhage is often diffuse, it may occasionally be focal as in this case. Note that this imaging appearance mimics that of pulmonary infection.

(Left) Coronal NECT of a patient with granulomatosis with polyangiitis shows right upper lobe nodules with surrounding ground-glass opacity ﬈ demonstrating the CT halo sign, consistent with perilesional hemorrhage. (Right) Axial HRCT of a patient with granulomatosis with polyangiitis and recurrent pulmonary hemorrhage shows well-defined centrilobular micronodules ﬉ that represent pulmonary hemosiderosis, a rare complication of the disease. Note right upper lobe cavitary nodule ﬈.

(Left) Axial NECT of a patient with granulomatosis with polyangiitis demonstrates marked circumferential soft tissue thickening of the tracheal walls ﬈. (Right) Axial NECT of the same patient shows extensive circumferential soft tissue thickening involving the walls of the proximal mainstem bronchi ﬈. Airway involvement is a known manifestation of the disease and may affect the trachea and the segmental and subsegmental airways. In severe cases, obliteration of the airway lumina may result.

343

Autoimmune Diseases

Eosinophilic Granulomatosis With Polyangiitis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Eosinophilic granulomatosis with polyangiitis (E-GPA): Systemic disease characterized by eosinophil-rich and necrotizing granulomatous inflammation involving respiratory tract and necrotizing vasculitis predominantly affecting small to medium-sized vessels in patients with asthma and eosinophilia

• Allergic bronchopulmonary aspergillosis • Chronic eosinophilic pneumonia • Granulomatosis with polyangiitis

IMAGING

CLINICAL ISSUES

• HRCT/CT ○ Lungs – Ground-glass opacities &/or consolidations (common) – Pulmonary nodules: Centrilobular – Crazy-paving pattern – Mosaic attenuation ○ Airways – Bronchial wall thickening (common) – Small nodules – Bronchiectasis

• Allergic phase: Asthma, allergic rhinitis, and sinusitis • Eosinophilic phase: Eosinophilic infiltration of lungs, heart, or gastrointestinal system • Vasculitis phase: Purpura or neuropathy and constitutional symptoms • Treatment: Corticosteroids ± cyclophosphamide

(Left) Axial NECT of a 43-yearold woman with a history of asthma and eosinophilic granulomatosis with polyangiitis shows patchy ground-glass opacities ﬈ in the lower lobes and scattered mosaic attenuation ﬊. (Right) Coronal NECT of the same patient shows patchy bilateral ground-glass opacities ﬈. Common findings of eosinophilic granulomatosis with polyangiitis include ground-glass opacities and consolidations that may be migratory and correlate with eosinophilic infiltration and granulomatous reaction.

(Left) Low-power photomicrograph (H&E stain) of a specimen of eosinophilic granulomatosis with polyangiitis shows eosinophils and macrophages in the airspaces ﬈ and interstitium ﬉ and small vessels thickened by eosinophilic infiltrates ﬊. (Right) High-power photomicrograph (H&E stain) of the same specimen shows eosinophilic interstitial infiltration ﬈. Histologic features also include asthmatic bronchitis, eosinophilic pneumonia, extravascular granulomas, and vasculitis.

344

PATHOLOGY • Necrotizing vasculitis, tissue eosinophilia, granulomatosis

DIAGNOSTIC CHECKLIST • Consider E-GPA in patient with asthma, eosinophilia, and pulmonary parenchymal abnormalities

Eosinophilic Granulomatosis With Polyangiitis

Abbreviations • Eosinophilic granulomatosis with polyangiitis (E-GPA)

Synonyms • Churg-Strauss syndrome • Allergic angiitis and granulomatosis

Definitions • Systemic disease characterized by eosinophil-rich and necrotizing granulomatous inflammation often involving respiratory tract and necrotizing vasculitis predominantly affecting small to medium-sized vessels in patients with asthma and eosinophilia

MR Findings • Cardiac abnormalities (62%) ○ Wall motion abnormalities, focal fibrosis, &/or obliteration of right ventricular lumen ○ Endomyocarditis: Myocardial, subepicardial, &/or subendocardial delayed hyperenhancement (after gadolinium administration)

Autoimmune Diseases

○ Mediastinal lymphadenopathy ○ Pleural and pericardial effusions

TERMINOLOGY

Imaging Recommendations • Best imaging tool ○ HRCT/CT

DIFFERENTIAL DIAGNOSIS IMAGING General Features • Best diagnostic clue ○ Patchy ground-glass opacities &/or consolidations – Random distribution – ± migratory

Radiographic Findings • Airspace opacities &/or consolidations ○ Nonsegmental ○ Multifocal • Diffuse reticulonodular opacities • Bronchial wall thickening • Pulmonary nodules (less common)

CT Findings • HRCT ○ Lungs – Ground-glass opacities &/or consolidations (common) □ ± migratory □ Random distribution □ Correlates with eosinophilic infiltration of alveoli and alveolar walls – Pulmonary nodules □ 10-30 mm □ Correlate with mixed areas of pulmonary hemorrhage, necrotizing granulomas, or eosinophilic infiltration – Crazy-paving pattern – Interlobular septal thickening (common) ○ Airways – Bronchial wall thickening (common) □ Correlates with eosinophilic and lymphocytic infiltration of airway walls – Small nodules □ Centrilobular distribution □ Correlate with dense eosinophil and lymphocyte infiltration of bronchiolar walls – Bronchiectasis – Tree-in-bud opacities – Mosaic attenuation • Other manifestations ○ Pulmonary mass ○ Halo sign ○ Reversed halo sign

Allergic Bronchopulmonary Aspergillosis • Blood eosinophils > 1000/mm³ • Prior history of chronic bronchial disease ○ 1-2% of asthmatic adults • High serum levels of total IgE • Aspergillus species on bronchoalveolar lavage or sputum and high serum levels of Aspergillus fumigatus-specific IgE • Bronchial abnormalities predominate (bronchiectasis, bronchial wall thickening, and mucoid impaction with finger-in-glove pattern)

Chronic Eosinophilic Pneumonia • High levels of peripheral blood eosinophilia (20-30% of blood leukocytes) • HIstory of asthma (75% of affected patients) • Absence of extrapulmonary manifestations • Antineutrophil cytoplasmic antibodies (ANCA) are typically negative • Subpleural ground-glass opacities &/or consolidation predominantly in upper lobes

Granulomatosis With Polyangiitis • • • • •

Occasional significant eosinophilia No history of asthma Cytoplasmic ANCA(+) Nasal crusts and nasal and paranasal sinus osseous erosions Pulmonary nodules ± cavitation

Hypereosinophilic Syndrome • Blood eosinophils > 1500/mm³ for at least 6 months • Evidence of organ dysfunction secondary to tissue infiltration by eosinophils • Typically negative ANCA • No vasculitis on tissue biopsies • Patchy ground-glass opacities &/or consolidation • Small nodules

IgG4-Related Systemic Disease • • • • • •

Allergic manifestations Peripheral blood eosinophilia Storiform fibrosis in tissue biopsies Absence of vasculitis Tracheobronchial wall thickening ± stenosis Nodules, consolidations, and patchy ground-glass opacities

345

Autoimmune Diseases

Eosinophilic Granulomatosis With Polyangiitis

PATHOLOGY General Features • Necrotizing vasculitis, tissue eosinophilia, and granulomatosis • Unknown pathogenesis • Triggering or adjuvant factors ○ Infection – Actinomyces, Aspergillus, Candida, Ascaris species ○ Drugs – Sulfonamides, diphenylhydantoin, and leukotriene receptor antagonists ○ Exposure to silica ○ Vaccinations • HLA-DRB1*04 and *07 alleles and HLADRB4 gene are associated with an increased risk of developing E-GPA

Microscopic Features • Tissue eosinophilia ○ Eosinophilic abscesses • Necrotizing vasculitis ○ May affect arterioles, venules, or capillaries ○ Fibrinoid necrosis ○ Eosinophilic infiltration of vessel walls • Extravascular eosinophilic granulomas ○ Core of necrotic eosinophilic material surrounded by palisading lymphocytes and multinucleated giant cells • Asthmatic bronchitis

CLINICAL ISSUES

346

– Renal manifestations (25%) □ Isolated urinary abnormalities (microscopic hematuria, proteinuria) □ Rapidly progressive glomerulonephritis • Clinical profile ○ Vasculitic phenotype – 40% of affected patients – ANCA(+): Mostly perinuclear ANCA with antimyeloperoxidase specificity – Glomerular renal disease – Peripheral neuropathy – Purpura – Biopsy-proven vasculitis ○ Eosinophilic tissue disease phenotype – 60% of affected patients – ANCA(-) – Cardiac involvement (endomyocarditis) – Eosinophilic pneumonia – Fever

Demographics • Age ○ 40-60 years of age • Gender ○ No gender predilection • Epidemiology ○ Incidence: 0.5-6.8 cases/1 million persons/year – 34.6- 64.6 cases/1 million persons/year among asthmatics ○ Prevalence: 10.7-13.0 cases/1 million persons

Presentation

Natural History & Prognosis

• Most common signs/symptoms ○ Allergic phase – Asthma (95% of affected patients) □ Classically severe and corticosteroid dependent □ May precede systemic manifestations of disease for many years □ Does not exhibit typical seasonal exacerbations – Chronic rhinosinusitis □ Allergic type □ Nonallergic type – Nasal polyposis, nasal crusting – Otitis media ○ Eosinophilic phase – Peripheral blood eosinophilia > 1500/mm³ &/or alveolar eosinophilia > 25% – Eosinophilic infiltration of lungs, heart, &/or gastrointestinal system □ Endomyocardial infiltration, coronary vasculitis, pericarditis, and valvular defects □ Small bowel infiltration: Abdominal pain &/or gastrointestinal hemorrhage ○ Vasculitis phase – Purpura (25%) □ Lower limb predominance – Peripheral neuropathy (70%) □ Axonal damage on electrophysiological studies □ Mononeuritis multiplex – Constitutional symptoms □ Fever, malaise, and weight loss

• Prognosis is generally good • Overall 5-year survival (97%) • Poor prognostic indicators ○ Age > 65 years ○ Cardiac symptoms ○ Gastrointestinal involvement ○ Renal insufficiency ○ Absence of ear, nose, and throat manifestations

Treatment • Corticosteroids ± cyclophosphamide (depending on disease severity)

DIAGNOSTIC CHECKLIST Consider • E-GPA in patient with asthma, eosinophilia, and pulmonary parenchymal abnormalities

SELECTED REFERENCES 1. 2. 3. 4. 5. 6.

Cottin V: Eosinophilic lung diseases. Clin Chest Med. 37(3):535-56, 2016 Cottin V et al: Respiratory manifestations of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Eur Respir J. 48(5):1429-1441, 2016 Price M et al: Imaging of eosinophilic lung diseases. Radiol Clin North Am. 54(6):1151-1164, 2016 Greco A et al: Churg-Strauss syndrome. Autoimmun Rev. 14(4):341-348, 2015 Dennert RM et al: Cardiac involvement in Churg-Strauss syndrome. Arthritis Rheum. 62(2):627-34, 2010 Silva CI et al: Churg-Strauss syndrome: high resolution CT and pathologic findings. J Thorac Imaging. 20(2):74-80, 2005

Eosinophilic Granulomatosis With Polyangiitis Autoimmune Diseases

(Left) Axial HRCT of a woman with a history of asthma and eosinophilic granulomatosis with polyangiitis shows illdefined small centrilobular nodules ﬈ and interlobular septal thickening ﬉. The presence of interlobular septal thickening often correlates with eosinophilic infiltration &/or interstitial edema secondary to myocardial involvement. (Right) Axial HRCT of the same patient shows small centrilobular nodules ﬈, bronchial wall thickening ﬉, and interlobular septal thickening ﬊.

(Left) Axial NECT of a patient with eosinophilic granulomatosis with polyangiitis shows bilateral interlobular septal thickening ﬈ and patchy ground-glass opacities ﬊. (Right) Axial NECT of the same patient shows bilateral paratracheal lymphadenopathy ﬈. Discrete pulmonary nodules, pericardial effusion, lymphadenopathy, and increased vessel caliber are uncommon and nonspecific abnormalities described in patients with eosinophilic granulomatosis with polyangiitis.

(Left) Composite image with axial NECT of a woman with eosinophilic granulomatosis with polyangiitis shows pulmonary nodules ﬈ in the middle and left lower lobes. (Right) Composite image with short-axis late gadolinium enhancement MR of a patient with eosinophilic granulomatosis with polyangiitis shows concentric endomyocardial increased signal ﬈. Over 50% of all affected patients exhibit cardiac involvement despite the absence of clinical symptoms. (Courtesy D. Vargas, MD.)

347

Autoimmune Diseases

Microscopic Polyangiitis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Microscopic polyangiitis (MPA) ○ Idiopathic autoimmune disease characterized by systemic vasculitis of small caliber vessels ○ Frequent renal (glomerulonephritis) and pulmonary (diffuse alveolar hemorrhage with capillaritis) manifestations

• Diffuse alveolar hemorrhage with capillaritis (other causes) ○ Granulomatosis with polyangiitis ○ Eosinophilic granulomatosis with polyangiitis ○ Systemic lupus erythematosus • Pulmonary edema

IMAGING • Radiography ○ Patchy, bilateral airspace opacities ○ Upper and lower zones involved • CT ○ Diffuse alveolar hemorrhage – Ground-glass opacities – Centrilobular, multifocal or diffuse ○ Pulmonary fibrosis – Subpleural reticulation &/or honeycombing with apicobasal gradient and traction bronchiectasis

(Left) Axial HRCT of a 19-yearold man with microscopic polyangiitis and alveolar hemorrhage shows diffuse illdefined centrilobular groundglass and linear branching opacities. Diffuse alveolar hemorrhage and pulmonary fibrosis are the most common pulmonary manifestations of this disease. (Right) Highpower photomicrograph (Prussian blue stain) of a specimen from the same patient shows blue-staining intraalveolar hemosiderinladen macrophages ﬊. Interstitial neutrophilic infiltration ﬉ is also present.

(Left) Axial NECT of a 75-yearold man with microscopic polyangiitis and diffuse alveolar hemorrhage shows bilateral airspace and groundglass opacities. (Right) Axial CECT of a patient with microscopic polyangiitis and pulmonary fibrosis with a remote history of alveolar hemorrhage shows lower lobe predominant subpleural reticular opacities and honeycombing ﬉ with traction bronchiectasis. These features are similar to those seen in usual interstitial pneumonia and nonspecific interstitial pneumonia.

348

CLINICAL ISSUES • Diffuse alveolar hemorrhage (hemoptysis, dyspnea, cough) (most common) • Pulmonary fibrosis • Antineutrophil cytoplasmic autoantibodies specifically directed against myeloperoxidase • Treatment: Corticosteroids and cyclophosphamide

DIAGNOSTIC CHECKLIST • Consider MPA in patients with alveolar hemorrhage (i.e., ground-glass opacities &/or consolidation) and concomitant renal disease (i.e., glomerulonephritis)

Microscopic Polyangiitis

Abbreviations • Microscopic polyangiitis (MPA)

Definitions • MPA: Idiopathic autoimmune disease characterized by systemic vasculitis of small caliber vessels ○ Frequent renal (glomerulonephritis) and pulmonary (diffuse alveolar hemorrhage with capillaritis) manifestations ○ Presence of antineutrophil cytoplasmic autoantibodies specifically directed against myeloperoxidase

IMAGING Radiographic Findings • Diffuse alveolar hemorrhage (12-55%) ○ Patchy, bilateral airspace opacities ○ Upper and lower zones involved • Pulmonary fibrosis (36%) ○ Lower lobe predominant reticular opacities &/or honeycombing similar to that of usual interstitial pneumonia or nonspecific interstitial pneumonia

CT Findings • HRCT ○ Diffuse alveolar hemorrhage – Ground-glass opacities □ Centrilobular, multifocal or diffuse – Consolidation ○ Thickened bronchovascular bundles – Correlate with lymphocytic infiltration and mild fibrosis along bronchovascular bundles ○ Pulmonary fibrosis – Subpleural reticulation &/or honeycombing with apicobasal gradient and traction bronchiectasis – Pulmonary fibrosis is marker of poor prognosis

Imaging Recommendations • Best imaging tool ○ HRCT

DIFFERENTIAL DIAGNOSIS Diffuse Alveolar Hemorrhage With Capillaritis (Other Causes) • Granulomatosis with polyangiitis ○ Cavitary nodules, masses, or consolidations ○ Classic triad: Upper airway disease, lower respiratory tract involvement, and glomerulonephritis • Eosinophilic granulomatosis with polyangiitis ○ Centrilobular nodules ○ Asthma/eosinophilia (virtually all patients) • Systemic lupus erythematosus vasculitis ○ Acute necrotizing capillaritis (more common than arteriolitis) ○ Autoantibodies (Anti-dsDNA, anti-Sm, anti-CL)

• Noncardiogenic ○ Acute respiratory distress syndrome, neurogenic edema, negative pressure edema, near drowning

PATHOLOGY General Features • Necrotizing vasculitis involving arterioles, venules, and capillaries

Autoimmune Diseases

TERMINOLOGY

Microscopic Features • Hemosiderin-laden macrophages with coarse hemosiderin granules • Neutrophilic infiltration of alveolar septa

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Renal manifestations (80-100%) – Glomerulonephritis (proteinuria, microscopic hematuria, and urinary granular or red blood cell casts) ○ Pulmonary manifestations (25-55%) – Diffuse alveolar hemorrhage (hemoptysis, dyspnea, cough) (most common) – Pulmonary fibrosis ○ Skin manifestations (30-60%) – Palpable purpura, livedo reticularis, nodules, urticaria, and skin ulcers • Other signs/symptoms ○ Fever, weight loss, fatigue • Antineutrophil cytoplasmic autoantibodies specifically directed against myeloperoxidase

Demographics • Age ○ Average age of onset: 50-60 years • Gender ○ M:F = 1.8:1

Natural History & Prognosis • Poor without treatment (mortality of 90% after 1 year) • With treatment: 1- and 5-year survivals of 82% and 76%, respectively

Treatment • Corticosteroids and cyclophosphamide • Plasma exchange

DIAGNOSTIC CHECKLIST Consider • Consider MPA in patients with alveolar hemorrhage (i.e., ground-glass opacities &/or consolidation) and concomitant renal disease (i.e., glomerulonephritis)

SELECTED REFERENCES 1.

Chung SA et al: Microscopic polyangiitis. Rheum Dis Clin North Am. 36(3):545-58, 2010

Pulmonary Edema • Cardiogenic ○ Cardiomegaly, wide vascular pedicle, pleural effusions 349

Autoimmune Diseases

Ankylosing Spondylitis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Chronic seronegative inflammatory arthropathy with predilection for axial skeleton

• • • •

IMAGING • Spinal disease nearly always precedes lung involvement • Radiography ○ Bilateral symmetric apical pleural thickening ○ Upper lobe fibrosis and superior hilar retraction • CT ○ Upper lobe fibrobullous disease ○ Airways disease (80%) – Mosaic attenuation and air-trapping (40%) – Bronchial wall thickening (40%) – Traction bronchiectasis ○ Interstitial lung disease (66%) – Parenchymal bands (33%) – Intralobular lines, subpleural lines, and honeycombing ○ Mycetomas may be found in cysts or cavities

(Left) Graphic shows typical pulmonary involvement by ankylosing spondylitis, consisting of apical fibrosis, interstitial thickening, mild traction bronchiectasis ﬈, and cyst or bulla formation ﬉. (Right) Axial NECT of a patient with ankylosing spondylitis shows classic CT findings of pulmonary involvement, which include bilateral symmetric peripheral subpleural reticular opacities ﬊, mild traction bronchiolectasis ﬉, and honeycombing ﬈. Note bilateral paramediastinal upper lobe bullae ﬊.

(Left) Axial CECT of a patient with ankylosing spondylitis shows biapical subpleural fibrosis ﬈ and apical capping ﬊ related to pulmonary involvement. (Right) Coronal NECT of a patient with ankylosing spondylitis shows flowing spinal syndesmophytes ﬈. Note left apical consolidation with intrinsic traction bronchiectasis and volume loss. Vertebral fractures may occur even in the setting of minor trauma and constitute life-threatening emergencies in this patient population.

350

Tuberculosis Sarcoidosis Silicosis and coal worker's pneumoconiosis Idiopathic pleuroparenchymal fibroelastosis

CLINICAL ISSUES • Most common signs/symptoms ○ Inflammation of the sacroiliac joints (early manifestation) ○ Most serious complication: Spinal fracture, typically of the cervical spine ○ Pulmonary involvement – Cough, dyspnea, fatigue, and occasionally hemoptysis – Upper lobe fibrobullous disease □ Similar to pulmonary tuberculosis • Other signs/symptoms ○ Pulmonary function tests: Restrictive > obstructive physiology ○ Presence of HLA-B27 not necessary for diagnosis

Ankylosing Spondylitis

Definitions

Imaging Recommendations

• Chronic multisystem inflammatory disorder with articular and extraarticular manifestations ○ Predilection for axial skeleton ○ Extraspinal manifestations – Pleuropulmonary involvement – Aortitis – Cardiac conduction abnormalities

• Best imaging tool ○ CT may reveal subtle apical abnormalities undetected on chest radiography ○ CTA or MRA to evaluate aorta

Abbreviations • Ankylosing spondylitis (AS)

Synonyms

IMAGING General Features • Best diagnostic clue ○ Upper lobe fibrobullous disease + spinal ankylosis

Radiographic Findings • Radiography ○ Flowing syndesmophytes in thoracic spine are typical of AS – Easily identified on radiography ○ Parenchymal lesions are not visible in early stages ○ Bilateral symmetric apical pleural thickening ○ Upper lobe fibrosis and superior retraction of hila ○ Upper lung zone cyst/bulla formation (fibrobullous disease) ○ Difficult distinction of AS lung lesions from prior tuberculosis ○ Secondary heart failure – Longstanding disease associated with aortic insufficiency

Autoimmune Diseases

• Bechterew disease

○ Apical fibrobullous areas are prone to Aspergillus colonization – Mycetomas can be found in cysts or bullae – Chronic Aspergillus colonization (50%-65%) – Hemoptysis is common in patients with mycetoma • Mediastinal lymphadenopathy uncommon and difficult to identify radiographically

TERMINOLOGY

DIFFERENTIAL DIAGNOSIS Tuberculosis • Apical fibrocavitary disease ○ Cavitation (50%) ○ Wall thickness variable: Thick > thin, shape may be irregular • Signs of fibrosis may increase with increasing volume loss in affected lung • Apical and posterior segments of upper lobes, superior segments of lower lobes • Chronic nonspecific symptoms: Cough, low-grade fever, malaise, weight loss • Diagnosis requires recovery of Mycobacterium tuberculosis organisms

Sarcoidosis • Pulmonary involvement with upper lung zone and peribronchovascular distribution • Small perilymphatic nodules (1-5 mm) • Nodular consolidations; ground-glass opacities • Symmetric hilar and mediastinal lymphadenopathy; more pronounced than in AS • Noncaseating epithelioid granulomas on histology

CT Findings

Silicosis and Coal Worker's Pneumoconiosis

• Spinal disease nearly always precedes lung involvement ○ Thoracic spine ankylosis (with syndesmophytes) ○ Vertebral body squaring and shiny corners (Romanus lesion) • Lung ○ Airways disease (80%) – Mosaic attenuation and air-trapping (40%) – Bronchial wall thickening (40%) – Traction bronchiectasis – Emphysema (33%) □ Centrilobular > paraseptal □ Irregular (cicatricial) emphysema from scarring and bullous disease ○ Interstitial lung disease (66%) – Parenchymal bands (33%) most common – Subpleural nodules, intralobular lines, subpleural lines, and honeycombing also common ○ Apical disease – Severe traction bronchiectasis with volume loss – Tracheal dilatation (equivalent to traction bronchiectasis) – Bilateral, symmetric, apical, pleural thickening

• Centrilobular and subpleural nodules in upper lung zones • Silicotic nodules tend to be more sharply defined than those of coal worker's pneumoconiosis • Symmetric enlargement (75%) of hilar and mediastinal lymph nodes, generally > 3 cm in diameter ○ "Eggshell" calcification in hilar and mediastinal lymph nodes; not seen in AS

Idiopathic Pleuroparenchymal Fibroelastosis • Chronic idiopathic interstitial pneumonia, described in 2004 ○ Rare idiopathic interstitial pneumonia (IIP) included in 2013 American Thoracic Society/European Respiratory Society (ATS/ERS) classification • Upper lobe subpleural and interstitial proliferation of predominantly elastic fibers ○ Fibrous interstitial pneumonia with > 80% fibroelastic changes in noncollapsed lung ○ Imaging – Pleuroparenchymal thickening in upper zones (most common) – Other: Reticular opacities, honeycombing, bronchiectasis, consolidation, pulmonary hypertension 351

Autoimmune Diseases

Ankylosing Spondylitis ○ Rare or absent granulomas • Associated conditions: Infections, bone marrow transplantation, chemotherapy, autoimmunity, and possible genetic predisposition

PATHOLOGY General Features • Etiology ○ Unclear – Inflammatory or immunologic processes – Environmental causes • Genetics ○ Strong association with histocompatibility antigen HLAB27 ○ Race-related differences in prevalence – > 90% of white patients with AS are HLA-B27(+) – ~ 50% of black African American patients with AS are HLA-B27(+) – Nearly absent (prevalence of HLA-B27 < 1%) in black African and Japanese ○ Strong familial pattern – 10% ↑ likelihood of AS among HLA-B27(+) 1st-degree relatives of HLA-B27(+) patients with AS ○ Antigen present in 6-10% of healthy individuals – 1-6% of HLA-B27(+) patients have AS • Associated abnormalities ○ Pleuropulmonary involvement – Chest wall restriction and upper lobe fibrobullous disease □ Pulmonary abnormalities manifest ~ 11.7 years after onset of disease □ Progressive pulmonary fibrocystic disease • Epidemiology ○ Incidence of AS ~ 6.6/100,000 persons – Incidence of lung disease on chest radiography: 1-3% – Incidence of lung disease on HRCT: 60-88% ○ Worldwide prevalence: 0.1 to 1.4% • Diagnosis based on ○ History of inflammatory back pain ○ Limited lumbar motion and chest expansion ○ Radiographic evidence of sacroiliitis

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Inflammation of the sacroiliac joints, early manifestation of AS – Back pain or morning stiffness ○ Peripheral joints and extraarticular structures may also be affected ○ Pulmonary disease – Rare and late manifestation of AS □ On average, 2 decades after onset of symptoms □ Slowly progressive fibrocystic changes in upper lobes – Respiratory signs/symptoms □ Cough, dyspnea, fatigue, and occasional hemoptysis 352

□ Super-infection with fungi (Aspergillus) or nontuberculous mycobacteria (NTMB) □ Hemoptysis; usually indicates presence of mycetoma ○ Sleep apnea mechanisms – Restrictive pulmonary disease, obstruction of oropharyngeal airway (temporomandibular joint involvement), and compression of medullary respiratory centers (cervical spinal disease) ○ Spontaneous pneumothorax – Incidence, 0.29% (higher than in general population) ○ Chest pain – Early stages of AS – Pain on inspiration; mild to moderate reduction of chest wall expansion • Other signs/symptoms ○ Pulmonary function tests: Restrictive > obstructive physiology – Restriction related to osseous ankylosis – Obstruction secondary to small airways disease ○ Presence of HLA-B27 not necessary for diagnosis

Demographics • Age ○ Disease onset: 15-35 years of age • Gender ○ M:F = 10-16:1

Natural History & Prognosis • Initial involvement of sacroiliac joints with progression to spinal involvement • Mortality: Aortitis, inflammatory bowel disease, nephritis (amyloid) • Most serious complication: Spinal fracture, most commonly of cervical spine • Progressive fibrobullous changes with advanced AS ○ Correlates with disease duration

Treatment • No effective treatment to stop progression of pulmonary involvement • NSAIDs recommended as 1st-line drug treatment for patients with AS with chest pain and stiffness • Symptomatic mycetoma may be treated with antifungal agents ○ Thoracic surgery for insufficient medical treatment ○ Bronchial artery embolization for life-threatening hemoptysis • Sleep apnea ○ CPAP, smoking cessation, and weight loss ○ Adalimumab and golimumab improve sleep and sleep quality

SELECTED REFERENCES 1. 2. 3.

Marquette D et al: Chronic bronchiolitis in ankylosing spondylitis. Sarcoidosis Vasc Diffuse Lung Dis. 30(3):231-6, 2013 Kanathur N et al: Pulmonary manifestations of ankylosing spondylitis. Clin Chest Med. 31(3):547-54, 2010 El Maghraoui A et al: Lung findings on thoracic high-resolution computed tomography in patients with ankylosing spondylitis. Correlations with disease duration, clinical findings and pulmonary function testing. Clin Rheumatol. 23(2):123-8, 2004

Ankylosing Spondylitis Autoimmune Diseases

(Left) Axial HRCT of a patient with ankylosing spondylitis shows right upper lobe subpleural reticulation ﬈ and a left upper lobe mycetoma ﬊. (Courtesy N. L. Müller, MD, PhD.) (Right) Coronal HRCT of the same patient shows right upper lobe subpleural interstitial fibrosis ﬈ and volume loss. The left upper lobe mycetoma ﬊ manifests as a heterogeneous ovoid mass within a preexisting bullous lesion. Apical fibrobullous areas are prone to Aspergillus colonization. (Courtesy N. L. Müller, MD, PhD.)

(Left) Axial NECT of a patient with ankylosing spondylitis obtained at end-inspiration shows subtle areas of decreased attenuation and vascularity ﬈ in the left lower lobe consistent with small airways disease. (Right) Axial expiratory NECT of a patient with ankylosing spondylitis shows bilateral areas of basilar decreased attenuation and hypovascularity (airtrapping) ﬈. Given the frequency of small airways disease, expiratory imaging should be included in the assessment of affected patients.

(Left) AP lumbar spine radiograph of a patient with AS shows bilateral sacroiliac joint ankylosis ﬊, ossification of the interspinous ligament (dagger sign) ﬈, and ankylosis of the facet joints (tram-track sign) ﬈. (Right) PA chest radiograph of a patient with ankylosing spondylitis shows right apical fibrobullous disease ﬈. An ovoid left upper lobe mycetoma ﬊ was confirmed after surgical resection. Note a left spontaneous pneumothorax ﬈.

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Autoimmune Diseases

Inflammatory Bowel Disease KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Inflammatory bowel disease (IBD) likely results from inappropriate immune response to physiologic gut flora in host with genetic susceptibility • Ulcerative colitis: Limited to colon • Crohn disease: Any segment of gastrointestinal tract • May affect lung parenchyma, airways, pleura, or vasculature

• Rheumatoid arthritis • Pulmonary infections causing bronchiectasis (Mycobacterium avium complex) • Asthma

IMAGING • • • • •

Bronchiectasis: Most common manifestation Tracheal wall thickening, tracheal stenosis Bronchiolectasis Cellular and constrictive bronchiolitis Organizing pneumonia, nonspecific interstitial pneumonia, eosinophilic pneumonia • Pulmonary thromboembolism • Pleural effusion, pleural thickening • Drug toxicity, opportunistic infections

(Left) PA chest radiograph of a 37-year-old woman with ulcerative colitis and bronchiectasis shows subtle reticular opacities and central bronchial wall thickening ﬈. (Right) Axial NECT of the same patient shows extensive cylindrical bronchiectasis and bronchial wall thickening ﬈. Bronchiectasis is the most common pulmonary manifestation of inflammatory bowel disease and may be associated with bronchial wall thickening, mucoid impaction, centrilobular nodules ﬉, and mosaic attenuation.

(Left) Axial CECT of a 48-yearold woman with Crohn disease shows subtle upper lobe ground-glass opacities ﬈ and traction bronchiolectasis ﬉. (Right) Axial CECT of the same patient shows basilar groundglass opacities and bronchiectasis. Note the relative subpleural sparing ﬈, a characteristic finding of nonspecific interstitial pneumonia, which may occur in association with inflammatory bowel disease or secondary to drug toxicity. Drug discontinuation usually results in improvement of the pulmonary opacities.

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PATHOLOGY • Postulated etiology of pulmonary involvement ○ Common embryonic origin of respiratory and intestinal tracts ○ Exposure of epithelium to common antigens

CLINICAL ISSUES • Pulmonary manifestations in 75-85% of patients with concomitant IBD symptoms, at same time as IBD symptoms in 5-10%, or before IBD symptoms in 10-15%

DIAGNOSTIC CHECKLIST • Consider pulmonary involvement in patient with thoracic abnormalities or complaints and history of IBD

Inflammatory Bowel Disease

Abbreviations • Inflammatory bowel disease (IBD)

Synonyms • IBD-associated lung disease

Definitions • Likely result of inappropriate immune response to physiologic gut flora in host with genetic susceptibility • Includes ulcerative colitis (UC) and Crohn disease (CD) ○ UC: Limited to colon ○ CD: Any segment of gastrointestinal tract • Extraintestinal manifestations of IBD are present in 16-40% of affected patients but are more common in CD ○ Pulmonary manifestations are rare but often overlooked – May be secondary to disease itself or may occur as complication of drugs used to treat disease (e.g., drug toxicity, opportunistic infection)

IMAGING General Features • Best diagnostic clue ○ Pulmonary abnormalities in patient with history of IBD • Location ○ May affect lung parenchyma, airways, pleura, or vasculature

Radiographic Findings • Radiography ○ May be normal ○ When present, abnormalities are often nonspecific – Patchy airspace opacities/consolidations – Bronchiectasis – Pleural effusion

CT Findings • CECT ○ Pleural disease – Effusion □ Usually unilateral □ May be hemorrhagic – Pleural thickening ○ Pulmonary thromboembolic disease – 0.7-7.7% of affected patients – Filling defects in pulmonary arteries; visualization of additional sites involved by thrombus • HRCT ○ Large airway abnormalities are strongly associated with UC – Tracheal inflammation □ Ulceration of tracheal epithelium: Circumferential thickening of tracheal wall □ Glottic/subglottic stenosis – Bronchiectasis □ Most common manifestation of IBD (66% of cases of airway involvement) ○ Small airways abnormalities – Bronchiolectasis – Other abnormalities

□ Bronchiolar wall thickening □ Mucoid impaction □ Centrilobular ground-glass nodules □ Mosaic attenuation □ Air-trapping ○ Parenchymal disease – Organizing pneumonia □ Scattered opacities/consolidations; nonsegmental, unilateral or bilateral, subpleural &/or peribronchovascular distribution □ Ground-glass opacities □ Centrilobular nodules □ Reversed halo sign: Central ground-glass opacity surrounded by peripheral consolidation – Eosinophilic pneumonia (in patients treated with mesalazine and with peripheral eosinophilia) □ Unilateral or bilateral peripheral consolidations □ Upper lobe predominant involvement – Nonspecific interstitial pneumonia □ Lower lobe predominant ground-glass opacities and reticulation □ Interlobular septal thickening and intralobular lines □ Subpleural sparing and peribronchovascular opacities common □ Traction bronchiectasis, bronchiolectasis ○ Opportunistic infections (in patients treated with antiTNF-α monoclonal antibodies) – Tuberculosis □ Screening for tuberculosis prior to treatment and prophylactic tuberculostatic treatment for latent infection □ Tree-in-bud opacities, patchy consolidations, cavitation – Pneumocystis jirovecii pneumonia □ Upper lobe predominant involvement □ Ground-glass opacity with relative sparing of lung periphery □ Septal lines ± intralobular lines superimposed on ground-glass opacity (i.e., crazy paving pattern) – Nocardiosis □ Consolidations, nodules, and masses □ Cavitation may occur □ Chest wall involvement (uncommon) – Aspergillosis □ Mass-like consolidation, nodules, halo sign, reversed halo sign, cavitation – Other: Actinomycosis, coccidiomycosis, histoplasmosis ○ Additional abnormalities – Colobronchial, ileobronchial, esophagobronchial fistulae □ Splenic flexure-left lower lobe colobronchial or colopleural fistula may cause recurrent pneumonia, empyema, fecopneumothorax – Necrobiotic nodules □ Single or multiple (0.5-7.0 cm); predominantly affect peripheral aspects of mid and upper lung zones – Sarcoidosis □ Incidental finding vs. possibly linked to IBD

Autoimmune Diseases

TERMINOLOGY

355

Autoimmune Diseases

Inflammatory Bowel Disease □ Hilar/mediastinal lymphadenopathy, perilymphatic pulmonary nodules

Imaging Recommendations • Best imaging tool ○ HRCT or thin-section CT

DIFFERENTIAL DIAGNOSIS Rheumatoid Arthritis • Bronchiectasis, pleural effusion, necrobiotic nodules, organizing pneumonia • Arthropathy involving small joints

Pulmonary Infections Causing Bronchiectasis (e.g., Mycobacterium avium Complex) • Bronchiectasis, tree-in-bud opacities, and mosaic attenuation • Middle lobe and lingula more severely involved

Asthma • Bronchiectasis, bronchial wall thickening, narrowing and dilation of airways • Mosaic perfusion/attenuation pattern • Eosinophilia

PATHOLOGY General Features • Etiology ○ Likely multifactorial – Genetic predisposition – Environmental factors – Immunologic dysfunction ○ Postulated pathogenesis of pulmonary involvement in patients with IBD – Common embryonic origin of respiratory and intestinal tracts – Exposure of epithelium to common antigens by inhalation and ingestion, causing sensitization of lymphoid tissue and inflammation • Genetics ○ 10-20% of affected individuals have family history of IBD; highest risk among 1st-degree relatives ○ NOD2 gene recently identified as 1st gene associated with CD • Associated abnormalities ○ Most common extraintestinal manifestations of IBD involve musculoskeletal system and skin – Peripheral and axial arthropathies (sacroiliitis) – Pyoderma gangrenosum – Erythema nodosum ○ Other manifestations – Anterior uveitis, episcleritis, pericholangitis, fatty liver, nephrolithiasis, obstructive uropathy, fistulization of urinary tract ○ Coexistent autoimmune diseases may be present regardless of IBD activity – e.g., hemolytic anemia, primary sclerosing cholangitis, Hashimoto disease

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Nonspecific respiratory symptoms – Shortness of breath, dyspnea, stridor, hoarseness, dysphonia, chronic productive cough, asthma • Other signs/symptoms ○ Pulmonary disease may be secondary to drug toxicity (e.g., methotrexate, azathioprine, sulfasalazine, mesalazine) or opportunistic infections related to immunosuppression ○ Respiratory symptoms may be present before or after diagnosis of IBD; may develop after colectomy ○ Pulmonary function abnormalities are frequently present, even in asymptomatic patients – Up to 50% in patients with UC – Obstructive or restrictive patterns on pulmonary function tests; bronchial hyperresponsiveness

Demographics • Age ○ May occur at any age; typically diagnosed between 15-35 years of age • Gender ○ M=F • Ethnicity ○ More often affects Caucasians and people of Ashkenazi Jewish origin than other racial or ethnic subgroups

Natural History & Prognosis • Pulmonary manifestations ○ 75-85%: After the onset of IBD symptoms ○ 5-10%: Develop at same time as IBD symptoms ○ 10-15%: Develop before IBD symptoms • Exacerbation of respiratory symptoms corresponds with periods of active IBD ○ Serositis is usually associated with active IBD ○ Parenchymal abnormalities often develop in patients with inactive IBD

Treatment • IBD-related pulmonary disease is usually treated with steroids • Drug-related pulmonary disease responds to drug withdrawal, steroids, and supportive measures • Opportunistic infections secondary to anti-TNF drugs are treated with antibiotics or antifungals

DIAGNOSTIC CHECKLIST Consider • Consider pulmonary involvement in patient with thoracic complaints or abnormalities and history of IBD

SELECTED REFERENCES 1. 2. 3.

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Majewski S et al: Pulmonary manifestations of inflammatory bowel disease. Arch Med Sci. 11(6):1179-88, 2015 Ji XQ et al: Pulmonary manifestations of inflammatory bowel disease. World J Gastroenterol. 20(37):13501-11, 2014 Lu DG et al: Pulmonary manifestations of Crohn's disease. World J Gastroenterol. 20(1):133-41, 2014

Inflammatory Bowel Disease Autoimmune Diseases

(Left) PA chest radiograph of a patient with Crohn disease and organizing pneumonia shows diffuse bilateral airspace disease and reticulation. (Right) Axial HRCT of the same patient shows bilateral ground-glass opacities ﬈ producing the reversed halo sign in the right upper lobe, a nonspecific but frequently seen abnormality in cases of organizing pneumonia. Organizing pneumonia may occur in the setting of inflammatory bowel disease itself or as a complication of drug therapy.

(Left) PA chest radiograph of a 39-year-old woman with Crohn disease following treatment with anti-TNF-α monoclonal antibodies shows an ill-defined, right upper lobe consolidation ﬈ secondary to actinomycosis. (Right) Axial CECT of the same patient shows a right upper lobe consolidation and surrounding ground-glass opacities. Opportunistic infections are common complications of suppression of T-cell-mediated immunity in patients undergoing biologic therapies.

(Left) Coronal oblique CECT of a 37-year-old man with Crohn disease shows acute pulmonary thromboembolic disease ﬈ involving a basilar segmental right lower lobe pulmonary artery and a peripheral pulmonary infarction ﬉. (Right) Axial CECT of the same patient shows a wedge-shaped right lower lobe consolidation with intrinsic lucencies very characteristic of pulmonary infarction. Pulmonary thromboembolic disease occurs in 0.7-7.7% of patients with inflammatory bowel disease.

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SECTION 10

Vascular Disease

Approach to Vascular Disease Pulmonary Edema Hepatopulmonary Syndrome Pulmonary Hypertension Pulmonary Venoocclusive Disease Pulmonary Capillary Hemangiomatosis Excipient Lung Disease (Talc/Cellulose Granulomatosis)

360 362 368 370 374 376 378

Vascular Disease

Approach to Vascular Disease Introduction Diffuse lung disease may be caused by a wide variety of conditions, some of which result from disease processes of vascular origin. These conditions comprise a heterogeneous group of disorders that may affect the lung parenchyma &/or pulmonary interstitium and result from abnormalities that affect the pulmonary vasculature, including pulmonary edema, hepatopulmonary syndrome (HPS), pulmonary hypertension, pulmonary venoocclusive disease (PVOD), pulmonary capillary hemangiomatosis, and excipient lung disease.

Imaging Chest radiography is often the 1st imaging modality with which the radiologist may have the opportunity to detect abnormalities related to vascular diseases. This is probably most applicable to pulmonary edema in which interstitial and airspace opacities and related abnormalities, such as cardiac enlargement and pleural effusions, are well visualized and assessed. Many diffuse pulmonary vascular diseases result in pulmonary arterial hypertension (PAH) and right heart dysfunction that manifest with enlargement of the pulmonary trunk and central pulmonary arteries and dilatation of the right cardiac chambers, which can also be assessed on radiography. However, many diseases of vascular origin often exhibit normal or nonspecific findings on chest radiography. Thin-section CT and HRCT are the imaging modalities of choice for identifying and characterizing the pulmonary abnormalities of various types of vascular diseases, their distribution, and relevant associated findings present as well as demonstrating additional important characteristics, such as the distribution of disease and associated findings. For instance, ground-glass opacities and nodules not visible on radiography are readily identified. The frequent associated finding of PAH is most recognizable by identification of an enlarged pulmonary trunk (> 29 mm) and right heart dysfunction, which manifests as enlargement of the right heart chambers relative to the left and flattening of the interventricular septum. Several important vascular etiologies of diffuse lung disease are introduced herein to illustrate the wide range of abnormalities that the radiologist may encounter. Pulmonary Edema Pulmonary edema is defined as the abnormal accumulation of extravascular lung water and may be classified as hydrostatic edema, permeability edema ± diffuse alveolar damage, or mixed edema. Although CT is not the modality of choice for imaging cardiogenic pulmonary edema, its typical crosssectional imaging features are frequently encountered in clinical practice and must be recognized and distinguished from those of other disease processes. Cardiogenic/hydrostatic pulmonary edema is characterized by interlobular septal and bronchial wall thickening, ground-glass opacities, and ancillary findings that include cardiac enlargement, increased attenuation of the mediastinal fat, nonneoplastic lymph node enlargement, and pleural effusions. Acute respiratory distress syndrome produces ground-glass opacities and consolidations that exhibit an anteroposterior gradient in the acute phase, which may progress to nondependent ground-glass and coarse reticular opacities and architectural distortion in the chronic phase. Other etiologies and patterns include high-altitude edema and reexpansion edema that typically result in heterogeneous 360

asymmetric nodular opacities and ground-glass opacities, respectively. Hepatopulmonary Syndrome HPS is a disorder characterized by the triad of chronic liver disease, increased alveolar-arterial oxygen gradient on room air, and intrapulmonary arteriovenous shunting. Its precise etiology is unknown but is postulated to result from diffusionperfusion impairment. The staging system developed for HPS revolves around the clinical response to 100% O₂. On HRCT/CT, HPS manifests as dilated peripheral pulmonary arteries with segmental artery-to-segmental bronchus diameter ratio ≥ 2 and normal central pulmonary arteries. Pulmonary Hypertension Pulmonary hypertension is defined as elevated mean pulmonary artery pressure > 25 mm Hg at rest and > 30 mm Hg during exercise. On HRCT/CT, the most reliable manifestation of PAH is enlargement of the pulmonary trunk. Ancillary pulmonary findings depend on the severity and etiology of PAH. Geographic ground-glass opacities due to mosaic perfusion are the most common findings. Pulmonary edema and centrilobular ground-glass nodules may also be identified. Pulmonary Venoocclusive Disease PVOD is a condition of unknown etiology characterized by stenosis and occlusion of the pulmonary veins and venules by intimal hyperplasia (fibrous tissue) and thrombi. On HRCT/CT, PVOD manifests as interlobular septal and fissural thickening, ground-glass opacities, micronodules, and mosaic attenuation. Imaging findings related to pulmonary hypertension may also be present, and affected patients may develop cor pulmonale. Pulmonary Capillary Hemangiomatosis Pulmonary capillary hemangiomatosis (PCH) is a rare cause of pulmonary hypertension that results from alveolar capillary proliferation. It has been suggested that pulmonary hypertension, PVOD, and PCH represent a spectrum of a single disease. Key differences between these conditions include the anatomic location of capillary proliferation and response to certain therapies. On HRCT/CT, PCH manifests as subtle centrilobular ground-glass nodules, pulmonary hypertension, and right heart dysfunction. PCH and PVOD appear similarly on imaging examinations. Establishing the correct diagnosis is of critical importance as treatment with vasodilators is contraindicated. Excipient Lung Disease Excipient lung disease refers to occlusion of pulmonary arterioles and capillaries by foreign body particles resulting from the intravenous injection of crushed tablets intended for oral use. This phenomenon results in abnormalities involving the vasculature and lung parenchyma and ultimately leads to acute or chronic cor pulmonale. On HRCT/CT, diffuse disease due to talc and cellulose manifests as centrilobular nodules &/or tree-in-bud opacities that are typically diffuse, bilateral, and symmetric. However, talc granulomatosis may result in conglomerate masses that mimic progressive massive fibrosis and occur on a background of small pulmonary nodules. Affected patients may develop pulmonary hypertension and right ventricular strain. Injection of Ritalin (methylphenidate) results in a unique pattern of diffuse lung disease, manifesting as lower lobe-predominant panlobular emphysema that may mimic α-1-antitrypsin deficiency.

Approach to Vascular Disease Vascular Disease

(Left) PA chest radiograph of a patient with cardiogenic pulmonary edema demonstrates an enlarged heart and bilateral interstitial opacities and perihilar haze ﬉ consistent with cardiogenic pulmonary edema. (Right) Axial CECT (soft tissue window) of the same patient shows marked cardiac enlargement and small bilateral pleural effusions ﬈, which are frequent ancillary abnormalities identified in the setting of cardiogenic or hydrostatic edema.

(Left) Axial CECT of the same patient shows ill-defined ground-glass opacities ﬈ and mild interlobular septal thickening ﬉ reflecting edema fluid in the alveolar and interstitial spaces, respectively. Note small bilateral pleural effusions ﬊. (Right) Axial CECT of a patient with cardiogenic pulmonary edema demonstrates diffuse bilateral smooth interlobular septal thickening ﬈, peribronchial thickening ﬉, and scattered ground-glass opacities ﬊ representing a combination of interstitial and alveolar edema.

(Left) Axial CECT of a patient with pulmonary arterial hypertension due to pulmonary capillary hemangiomatosis demonstrates enlargement of the pulmonary trunk ﬈, the most recognizable imaging manifestation of pulmonary hypertension. (Right) PA chest radiograph of a patient with excipient lung disease shows numerous bilateral tiny pulmonary nodules due to intravenous injection of talc. Cellulose and talc granulomatosis typically manifest as numerous small bilateral lung nodules.

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Vascular Disease

Pulmonary Edema KEY FACTS

TERMINOLOGY • Pulmonary edema: Abnormal accumulation of extravascular lung water ○ Hydrostatic edema ○ Permeability edema with diffuse alveolar damage (DAD): Acute respiratory distress syndrome (ARDS) ○ Permeability edema without DAD: Opiate overdose edema, transfusion-related lung injury (TRALI), highaltitude pulmonary edema (HAPE) ○ Mixed edema: Neurogenic pulmonary edema, reexpansion pulmonary edema

IMAGING • Radiography ○ Hydrostatic edema – Perihilar haze, subpleural edema, peribronchial cuffing, septal thickening – Consolidation, batwing edema – Cardiomegaly, pleural effusion

(Left) Coned-down AP chest radiograph of a patient with hydrostatic cardiogenic edema shows short thin (Kerley B) lines ﬈ perpendicular to the lateral pleura and longer oblique (Kerley A) lines ﬉. (Right) Coronal CECT of a patient with hydrostatic cardiogenic edema shows thick interlobular septa ﬈ and interlobar fissures ﬉ representing edema of the peripheral septal and subpleural interstitium, respectively. These are typical radiographic and CT manifestations of interstitial edema.

(Left) Axial CECT of a patient with interstitial edema shows smooth thickening of the interlobular septa ﬈ that form central polygonal arcades ſt outlining the margins of several secondary pulmonary lobules. (Right) Composite image with NECT of a normal right lower lobe (left) and CECT of interstitial edema (right) of the same patient shows bronchial wall thickening ﬈, mild septal thickening ﬊, and a small right pleural effusion ﬉. CT nicely demonstrates the early manifestations of interstitial edema.

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○ ARDS: Airspace disease, absence of cardiomegaly or septal lines ○ HAPE: Asymmetric, perihilar, patchy, nodular airspace disease ○ Reexpansion edema: Ipsilateral to prior effusion or pneumothorax ○ Opiate overdose, TRALI, neurogenic edema: May mimic hydrostatic edema • CT/HRCT ○ Not routinely used in evaluation of pulmonary edema ○ Hydrostatic edema – Smooth septal thickening, fissural thickening, bronchial wall thickening – Centrilobular, lobular, acinar, diffuse ground-glass opacities, consolidation – Cardiomegaly, pleural effusion, lymph node enlargement ○ HAPE: Asymmetric, perihilar nodular airspace disease

Pulmonary Edema

Definitions • Pulmonary edema: Abnormal accumulation of extravascular lung water ○ Hydrostatic edema – Common etiologies □ Cardiogenic edema: Elevated pulmonary capillary pressure (left-sided heart failure) □ Fluid overload: Renal failure ○ Permeability edema with diffuse alveolar damage (DAD) – Acute respiratory distress syndrome (ARDS) ○ Permeability edema without DAD – Opiate overdose edema – Transfusion-related lung injury (TRALI): Dyspnea, hypoxemia and bilateral pulmonary opacities within 6 hours after transfusion of blood products – High-altitude pulmonary edema (HAPE) ○ Mixed edema: Both hydrostatic and permeability edema – Neurogenic pulmonary edema – Reexpansion pulmonary edema

IMAGING Radiographic Findings • Hydrostatic/cardiogenic edema ○ Wide vascular pedicle: Marker of increased central venous pressure and increased circulating blood volume – Measures up to 58 mm in normal subjects – Variable width based on body habitus, mediastinal fat ○ Pulmonary venous hypertension: Chronic elevation of left atrial pressure – Vascular redistribution ○ Interstitial edema – Perihilar haze or vascular indistinctness – Subpleural edema – Peribronchial thickening/cuffing – Interlobular septal thickening: Kerley B, A, and C lines – Increased lung density ○ Alveolar edema – Consolidation: Predilection for right lung – Batwing edema (< 10%): Rapid onset of heart failure – Asymmetry □ Underlying lung disease □ Positional changes □ Acute mitral insufficiency from papillary muscle rupture: Preferential right upper lobe involvement ○ Associated findings – Cardiomegaly – Pleural effusion: Bilateral, right > left; intrafissural fluid • ARDS ○ Evidence of mechanical ventilation ○ Exudative (acute) phase (1-7 days) – Bilateral symmetric heterogeneous opacities – Absence of temporal changes, cardiomegaly, or septal lines ○ Proliferative (organizing) phase (8-14 days) – Coarse reticular opacities ○ Fibrotic (late) phase (> 15 days) – Slow resolution of heterogeneous reticular opacities

• Opiate overdose edema ○ Consolidations: Bilateral, diffuse; may resolve rapidly • TRALI ○ Bilateral interstitial &/or alveolar pulmonary opacities • HAPE ○ Central interstitial edema without septal lines ○ Consolidations: Asymmetric, patchy, nodular – Spare lung apices and lung bases ○ Rapid resolution with treatment • Neurogenic edema ○ Acute onset following significant central nervous system insult ○ Bilateral, upper lobe-predominant airspace disease – Often resolves rapidly • Reexpansion edema ○ Follows rapid reexpansion of previously atelectatic lung (atelectasis duration > 3 days) – Post drainage of pleural effusion or pneumothorax ○ Progressive ipsilateral airspace disease; may progress to bilateral involvement

Vascular Disease

TERMINOLOGY

CT Findings • Hydrostatic/cardiogenic edema ○ Interstitial edema – Interlobular septal thickening □ Smooth; nodularity not typical but may occur □ Outlines boundaries of secondary pulmonary lobule □ Crazy paving: Interstitial and alveolar edema – Subpleural edema: Thickened interlobar fissures – Peribronchovascular bronchial wall thickening ○ Alveolar edema – Ground-glass opacities, diffuse or patchy – Centrilobular ground-glass nodules – Lobular and acinar ground-glass opacities – Consolidation □ Diffuse or patchy □ Dependent (gravitational) □ Central and perihilar in batwing edema ○ Associated abnormalities – Cardiomegaly, pleural effusion, lymphadenopathy, increased attenuation of mediastinal fat • ARDS ○ Early phase – Anteroposterior gradient of lung involvement – Bilateral ground-glass opacities – Dense dependent consolidations – Bronchial dilatation – Pleural effusions ○ Late phase – Ground-glass opacities – Coarse reticular opacities and architectural distortion in nondependent lung • HAPE ○ Asymmetric involvement ○ Perihilar ground-glass opacities and consolidations; nodular, nonuniform • Reexpansion edema ○ Ipsilateral ground-glass opacities • TRALI, neurogenic edema: Rarely imaged with CT 363

Vascular Disease

Pulmonary Edema – Resultant intraalveolar leakage of high molecular weight proteins, cells, and fluid ○ Neurogenic edema – Abrupt increase of intracranial pressure with activation of sympathetic system and resultant catecholamine release – Effects on pulmonary capillary endothelium not understood ○ Reexpansion edema – Postulated acute inflammatory response to reexpansion + alveolar capillary membrane damage

Imaging Recommendations • Best imaging tool ○ Chest radiography ○ CT/HRCT not indicated, but edema often identified when imaging performed for other reasons ○ HRCT may be useful for evaluation of fibrotic ARDS

DIFFERENTIAL DIAGNOSIS Interstitial Edema • Lymphangitic carcinomatosis ○ Nodular interlobular septal thickening ○ Patchy distribution

CLINICAL ISSUES

Alveolar Edema

Presentation

• Pneumocystis jirovecii pneumonia ○ Severely immunocompromised state ○ Ground-glass opacities, cysts • Pneumonia ○ Signs and symptoms of infection ○ Focal or multifocal consolidation, cellular bronchiolitis • Pulmonary hemorrhage ○ Ground-glass opacities, may exhibit crazy-paving pattern ○ Centrilobular nodules

• Most common signs/symptoms ○ Pulmonary edema: Respiratory distress, dyspnea, orthopnea, hypoxemia, cough (pink frothy sputum), crackles ○ Hydrostatic/cardiogenic edema: 3rd heart sound (S₃) (ventricular filling gallop) ○ ARDS: Symptoms within 6-72 hours from inciting event ○ Opiate overdose – High index of suspicion, appropriate history – Symptoms within hours of drug injection – Risk factors: Male gender, short duration of opiate use ○ TRALI: Symptoms within 6 hours of transfusion ○ HAPE – Risk factors: Individual susceptibility, male gender, cold temperature, preexisting pulmonary infection, vigorous exertion – Symptoms 2-4 days after arrival at high altitude ○ Neurogenic edema – Early stage: Symptoms within minutes to hours post neurologic injury – Late stage: Symptoms 12-24 hours post neurologic injury ○ Reexpansion edema – Young patients with extreme sustained atelectasis – ~ 64% with symptoms in 1st hour post pleural puncture

Interstitial and Alveolar Edema • Pulmonary alveolar proteinosis ○ Crazy-paving pattern on CT ○ No cardiomegaly or pleural effusion

PATHOLOGY General Features • Etiology ○ Hydrostatic/cardiogenic edema – Increased capillary hydrostatic pressure □ Left heart failure (may not be purely hydrostatic): Markedly ↑ capillary pressure may damage capillary endothelium leading to permeability edema □ Volume overload; overhydration – Decreased intravascular oncotic pressure □ Hypoalbuminemia, hepatic/renal failure ○ ARDS – Respiratory symptoms within 1 week of clinical insult + bilateral pulmonary opacities on imaging + exclusion of heart failure or fluid overload as cause of symptoms – ↑ permeability of capillary and alveolar endothelial cells ○ Opiate overdose – Unclear pathophysiology; postulated role of direct drug toxicity, hypoxia, and acidosis ○ TRALI – Susceptible recipients: Mechanical ventilation, positive fluid balance, smoking, chronic alcoholism, shock, liver/cardiac surgery – ↑ risk with transfusion of female plasma/whole blood ○ HAPE – Rapid ascent to altitudes > 3000-4000 meters – Excessive pulmonary artery pressures lead to nonuniform hypoxic vasoconstriction

Natural History & Prognosis • Hydrostatic/cardiogenic edema: Prognosis depends on severity and reversibility of underlying hemodynamic dysfunction • ARDS: 26-58% mortality; increases with disease severity • Opiate overdose edema: Rapid resolution with appropriate treatment • TRALI: Majority of affected patients require ICU admission and ventilator support; 5-17% mortality • HAPE: Favorable outcome with early recognition and prompt treatment • Neurogenic edema: Prognosis based on severity of neurologic insult • Reexpansion edema: 20% mortality reported

SELECTED REFERENCES 1. 2.

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Bentz MR et al: Intensive care unit imaging. Clin Chest Med. 36(2):219-234, 2015 Gluecker T et al: Clinical and radiologic features of pulmonary edema. Radiographics. 19(6):1507-31; discussion 1532-3, 1999

Pulmonary Edema Vascular Disease

(Left) Axial NECT of a patient with pulmonary edema shows centrilobular ground-glass opacities ﬊ and smooth interlobular septal thickening ﬈ consistent with alveolar and interstitial edema. Note patchy distribution of airspace opacities and coexistence of normal and abnormal (thick) interlobular septa. (Right) Axial CECT shows interstitial and alveolar edema manifesting with asymmetric right upper lobe ground-glass opacities ﬊, interlobular septal thickening ﬉, and bronchial wall thickening ﬈.

(Left) Axial CECT of a patient with mitral valve disease and pulmonary edema shows diffuse bilateral ground-glass opacities ﬈, small bilateral pleural effusions, and minimal septal thickening ﬉. (Right) Intermediate-power photomicrograph (H&E stain) of a specimen of predominantly alveolar pulmonary edema shows edema fluid ﬈ and red blood cells ﬊ flooding the pulmonary airspaces. In this case, there is little interstitial edema as evidenced by normal thickness of the pulmonary interstitium ﬉.

(Left) Axial CECT shows alveolar edema manifesting as centrilobular and acinar ground-glass opacities ﬉. Note small bilateral pleural effusions ﬈, right larger than left. Alveolar edema has variable CT manifestations ranging from ground-glass opacity to confluent consolidation. (Right) Axial CECT of the same patient shows pulmonary edema manifesting with patchy confluent ﬉ and lobular ﬈ ground-glass opacities. Note fissural pleural thickening ﬊ indicative of subpleural edema.

365

Vascular Disease

Pulmonary Edema

(Left) AP chest radiograph shows asymmetric alveolar edema manifesting as bilateral perihilar haze and consolidations. Note peribronchial cuffing ﬉, fissural pleural thickening ﬈ (subpleural edema), and bilateral pleural effusions. (Right) Axial NECT of a patient with batwing edema shows central perihilar consolidations ﬊ with intrinsic air bronchograms that spare the lung periphery. Batwing edema affects < 10% of patients with pulmonary edema and is associated with rapid onset of heart failure.

(Left) PA chest radiograph of a patient with acute mitral insufficiency shows preferential right upper lobe alveolar edema ﬊ secondary to regurgitant flow of blood from an incompetent mitral valve, cardiomegaly, an enlarged left atrial appendage ﬈, and a right pleural effusion. (Right) AP chest radiograph of a 58-year-old woman who developed acute respiratory distress within 6 hours of receiving a blood transfusion shows bilateral alveolar and interstitial edema consistent with transfusionrelated lung injury.

(Left) AP chest radiograph of a 55-year-old man who developed acute respiratory distress syndrome precipitated by sepsis shows asymmetric bilateral heterogeneous airspace disease. Note the absence of septal lines or pleural effusion. (Right) Axial NECT of the same patient shows diffuse bilateral airspace disease with an anteroposterior gradient characterized by posterior consolidations ﬊ and anterior ground-glass opacities ﬉. The findings are characteristic of pulmonary edema secondary to diffuse alveolar damage.

366

Pulmonary Edema Vascular Disease

(Left) PA chest radiograph of a 30-year-old man with acute pulmonary edema secondary to opiate overdose shows bilateral asymmetric heterogeneous alveolar opacities in the absence of septal lines or pleural effusion. (Right) Axial NECT of the same patient shows bilateral asymmetric nodular consolidations ﬈ predominantly affecting the right lung. These abnormalities typically resolve rapidly with appropriate treatment.

(Left) PA chest radiograph of a young man with high-altitude pulmonary edema shows asymmetric bilateral nodular opacities predominantly affecting the right lung. (Right) Axial NECT of the same patient shows asymmetric bilateral nodular consolidations that spare the lung periphery. The patchy distribution of the abnormalities reflects underlying nonuniform hypoxic vasoconstriction. Note the absence of pleural effusions or septal lines.

(Left) PA chest radiograph of a 26-year-old man with several days of chest pain shows a large left pneumothorax with associated complete atelectasis of the left lung ﬉ and mass effect on the mediastinum. (Right) AP chest radiograph of the same patient after placement of a left thoracostomy tube ﬈ shows reexpansion of the left lung and development of ipsilateral airspace disease ﬊ consistent with reexpansion pulmonary edema. This entity typically affects young patients following relief of severe atelectasis.

367

Vascular Disease

Hepatopulmonary Syndrome KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Hepatopulmonary syndrome (HPS): Arterial oxygenation defect, intrapulmonary vascular dilatation, and liver disease

• Intracardiac shunts • Pulmonary arteriovenous malformation

IMAGING

PATHOLOGY

• Radiography ○ Radiographs are typically normal ○ Bibasilar nodular or reticulonodular opacities ○ Normal central pulmonary artery size • CT ○ Dilated peripheral pulmonary arteries: Segmental artery:segmental bronchus diameter ratio ≥ 2 and normal size of central pulmonary arteries ○ In cases of suspected HPS and positive bubble contrast echocardiography, CT used for exclusion of pulmonary arteriovenous malformation (PAVM) • Bubble contrast echocardiography (intravenous contrast) ○ Bubbles normally trapped by pulmonary capillary bed ○ HPS: Bubbles in left atrium after 3 heart beats

• Etiology: Chronic liver disease (common) • Dilated precapillary and capillary vessels; pleural/pulmonary arteriovenous shunts, portopulmonary anastomoses

(Left) Axial NECT of a patient with hepatopulmonary syndrome shows markedly dilated peripheral pulmonary arteries ﬉ as compared with the diameters of the accompanying peripheral bronchi ﬈. (Right) Axial NECT of the same patient shows markedly dilated peripheral pulmonary arteries ﬉ compared with adjacent peripheral bronchi ﬈. While this may be a helpful finding in suspected hepatopulmonary syndrome, it may also be seen in patients with uncomplicated liver disease. (Courtesy K. Lee, MD.)

(Left) AP pulmonary angiogram of a 68-year-old woman with cirrhosis and hepatopulmonary syndrome shows dilated tortuous segmental and subsegmental right lower lobe pulmonary arteries ﬈ and a normal right interlobar pulmonary artery ﬊. (Right) Four-chamber bubble echocardiography of a 58-year-old man with cirrhosis, hepatopulmonary syndrome, and portopulmonary hypertension shows bubbles ﬈ in the left ventricle, 3 beats after being seen in the right heart. (Courtesy S. Chang, MD.)

368

CLINICAL ISSUES • Symptoms: Dyspnea, platypnea, orthodeoxia • Treatment ○ Mild to moderate: Observation ± oxygen ○ Severe HPS: Oxygen, liver transplantation

DIAGNOSTIC CHECKLIST • Consider HPS in patient with chronic liver disease + positive contrast echocardiography (left atrial air bubbles 3-6 beats after visualization in right heart) + no CT evidence of PAVM

Hepatopulmonary Syndrome

Abbreviations • Hepatopulmonary syndrome (HPS)

Definitions • Triad of arterial oxygenation defect, intrapulmonary vascular dilatation, and liver disease (often chronic)

Pulmonary Arteriovenous Malformation • Bubble contrast echocardiography: Bubbles appear in left atrium after 3 heart beats • CECT optimally demonstrates classic PAVM: Dilated afferent and efferent vessels + nidus

Vascular Disease

TERMINOLOGY

PATHOLOGY General Features

IMAGING General Features • Best diagnostic clue ○ Bubbles in left heart (right-to-left shunt) 3-6 heart beats after visualization in right heart on contrast echocardiography + no CT evidence of pulmonary arteriovenous malformation (PAVM) in patient with chronic liver disease ○ Dilatation of lower lobe pulmonary artery branches

Radiographic Findings • Radiography ○ Typically normal ○ Bibasilar nodular or reticulonodular opacities due to dilated peripheral lower lobe arteries ○ Normal central pulmonary artery size

CT Findings • Dilated peripheral pulmonary arteries ○ Increased segmental artery:segmental bronchus diameter ratio (≥ 2) with normal central artery size – Low specificity; may be seen in patients with uncomplicated liver disease • In patient with clinical suspicion for HPS and positive bubble contrast echocardiography, CT is important to exclude PAVM

Echocardiographic Findings • Bubble contrast echocardiography (intravenous contrast) ○ Bubbles normally trapped by pulmonary capillary bed, not seen in left atrium ○ HPS: Bubbles appear in left atrium after 3 heart beats

Nuclear Medicine Findings • V/Q scan ○ Technetium-macroaggregated albumin (99mTc-MAA) perfusion scan – Brain or kidney uptake indicates arteriovenous shunt – Unable to detect shunt level (intrapulmonary vs. intracardiac)

Imaging Recommendations • Best imaging tool ○ Contrast echocardiography is good screening exam for clinically suspected HPS

DIFFERENTIAL DIAGNOSIS Intracardiac Shunts • Patent foramen ovale, atrial septal defect, ventricular septal defect, etc. • Bubble contrast echocardiography: Bubbles appear in left atrium within 3 heart beats

• Etiology ○ Chronic liver disease (common) ○ Other (rare): Chronic noncirrhotic hepatitis, portal hypertension without underlying liver disease, BuddChiari syndrome, acute liver disease (e.g., fulminant hepatitis A), ischemic hepatitis

Microscopic Features • Dilated precapillary and capillary vessels • Pleural and pulmonary arteriovenous shunts and portopulmonary anastomoses

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Dyspnea ○ Platypnea – ↑ dyspnea induced by upright position and improved by recumbency ○ Orthodeoxia – ↓ arterial oxygen tension > 4 mm Hg or arterial oxyhemoglobin desaturation > 5% induced by upright position ○ Cyanosis and clubbing • Other signs/symptoms ○ Underlying chronic liver disease ○ Decreased diffusing capacity for carbon monoxide ○ Severe hypoxemia (PaO2 < 50 mm Hg); orthodeoxia (improvement in PaO2 in supine position)

Demographics • Age ○ 40-70 years, mean: 58 years

Natural History & Prognosis • Progressive dyspnea

Treatment • Mild to moderate: Observation ± oxygen • Severe HPS: Oxygen, liver transplantation

DIAGNOSTIC CHECKLIST Consider • HPS in patient with chronic liver disease with positive contrast echocardiography (left atrial air bubbles 3-6 beats after visualization in right heart) and no CT evidence of PAVM

SELECTED REFERENCES 1.

Chen YA et al: CT scan does not differentiate patients with hepatopulmonary syndrome from other patients with liver disease. PLoS One. 11(7):e0158637, 2016

369

Vascular Disease

Pulmonary Hypertension KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Pulmonary hypertension (PH): Elevated mean pulmonary artery pressure (> 25 mm Hg at rest; > 30 mm Hg during exercise) • Pulmonary arterial hypertension (PAH) • Chronic thromboembolic pulmonary hypertension (CTEPH)

• Idiopathic pulmonary artery dilatation • Pulmonary valve stenosis • Pulmonary artery sarcoma

IMAGING • CT ○ Mosaic perfusion: Geographic ground-glass opacities ○ Pulmonary edema: Septal thickening, peribronchovascular thickening, ground-glass opacity ○ Ground-glass centrilobular opacities and nodules – Plexogenic arteriopathy in idiopathic PAH – Capillary dilatation: Pulmonary venoocclusive disease and Eisenmenger physiology – Capillary proliferation: Pulmonary capillary hemangiomatosis • V/Q scan is study of choice for screening for CTEPH

(Left) PA chest radiograph of a patient with chronic thromboembolic pulmonary hypertension shows mild cardiomegaly and dilated bilateral central pulmonary arteries ﬈. (Right) Axial CECT of the same patient shows an eccentric filling defect ﬈ in the lumen left pulmonary artery indicative of chronic thromboembolic disease. The clinical spectrum of chronic thromboembolic disease includes not only the presence of arterial filling defects but also pulmonary hypertension, right ventricular strain, and mosaic attenuation.

(Left) Axial CECT of a patient with chronic thromboembolic pulmonary hypertension shows scattered bilateral mosaic attenuation. Note the dilated pulmonary trunk ﬈ indicative of pulmonary hypertension. In general, the diameter of the adjacent ascending aorta should be similar to that of the pulmonary trunk. (Right) Axial CECT of the same patient shows dilation of the right ventricle and right atrium indicative of right ventricular dysfunction, a chronic finding in the setting of chronic thromboembolic disease.

370

CLINICAL ISSUES • Signs and symptoms ○ Dyspnea, easy fatigue, chest pain, Raynaud phenomenon • Demographics ○ Prevalence in men: 10% > 35 years and 25% > 65 years ○ Idiopathic (primary): Women in 3rd decade of life ○ M:F = 1:3 in PAH • Treatment ○ No cure; 30% respond to medical therapy ○ Pulmonary endarterectomy for CTEPH ○ Lung ± heart transplantation • Prognosis ○ 5-year survival of patients with CTEPH is 30%

Pulmonary Hypertension

Abbreviations • Pulmonary hypertension (PH) • Pulmonary arterial hypertension (PAH) • Chronic thromboembolic pulmonary hypertension (CTEPH)

Definitions • Hemodynamic criteria: ↑ mean pulmonary artery pressure: > 25 mm Hg at rest; > 30 mm Hg during exercise • Consensus classification (5th World Symposium on Pulmonary Hypertension, Nice, 2013) ○ Group 1: PAH ○ Group 2: PH due to left heart disease ○ Group 3: PH due to chronic lung disease &/or hypoxia ○ Group 4: CTEPH ○ Group 5: PH due to unclear multifactorial mechanisms

IMAGING General Features • Best diagnostic clue ○ Dilatation of central pulmonary arteries with rapid tapering ○ Right ventricular (RV) hypertrophy/dilatation

Radiographic Findings • Enlargement of pulmonary trunk and central pulmonary arteries ○ Left superior mediastinal convexity on frontal radiography • Abnormal transverse diameter of right interlobar pulmonary artery ○ Men > 16 mm ○ Women > 14 mm

CT Findings • HRCT ○ Mosaic perfusion – Heterogeneous lung attenuation resulting from heterogeneous blood flow – Geographic ground-glass attenuation represents perfused or hyperperfused lung – Hypoattenuation represents hypoperfused lung □ ↓ size of pulmonary vessels: Vascular obstruction or hypoxic vasoconstriction – Expiratory HRCT: Differentiation of mosaic perfusion from small airways disease □ Low-attenuation regions remain lucent (airtrapping) ○ Pulmonary edema – Interlobular septal thickening, peribronchovascular interstitial thickening, patchy/diffuse ground-glass opacity, or combination of these findings ○ Ground-glass centrilobular opacities and nodules – Plexogenic arteriopathy in idiopathic pulmonary hypertension – Capillary dilatation: Pulmonary venoocclusive disease (PVOD) and Eisenmenger physiology – Capillary proliferation: Pulmonary capillary hemangiomatosis (PCH) – Cholesterol granulomas

• CTA ○ Central pulmonary arteries – Normal transverse diameter of pulmonary trunk < 28.6 mm, measured at bifurcation, perpendicular to long axis (sensitivity 85%, specificity 75%) – Intimal pulmonary artery calcification with severe longstanding hypertension ○ Heart – Right ventricular dilatation (transverse diameter wider than that of left ventricular cavity) – Right ventricular wall thickening – Convex deviation of interventricular septum toward left ventricular cavity – Dilated right atrium ○ Mediastinum – Pericardial thickening or effusion regardless of etiology (> 50%) ○ Chronic thromboembolism – Intraluminal clot, often eccentric; fibrous webs • Dual-energy CT ○ Identification of perfusion defects distal to vascular obstruction

Vascular Disease

TERMINOLOGY

MR Findings • Less sensitive or specific than CT, difficult in dyspneic patients • Morphologic, anatomic and functional assessment of heart and pulmonary circulation

Angiographic Findings • Selective pulmonary angiography (digital subtraction angiography) ○ Gold standard for diagnosis and confirmation of chronic thromboembolic disease

Nuclear Medicine Findings • V/Q scan ○ Usually low probability scans ○ Chronic thromboembolic disease: High probability scans ○ V/Q scan, optimal test for chronic thromboembolic disease – Sensitivity rate: CTPA 51% vs. V/Q scan > 96%

Imaging Recommendations • Best imaging tool ○ CT useful for exclusion of chronic pulmonary embolism or postcapillary hypertension ○ Preoperative assessment: Pulmonary angiography is definitive diagnostic technique

Ultrasonographic Findings • Echocardiography widely used as initial diagnostic tool for PH

DIFFERENTIAL DIAGNOSIS Idiopathic Pulmonary Artery Dilatation • Young women, unilateral enlargement of pulmonary trunk and left pulmonary artery

Pulmonary Valve Stenosis • Unilateral enlargement of pulmonary trunk and left pulmonary artery 371

Vascular Disease

Pulmonary Hypertension ○ PH with unclear multifactorial mechanisms (group 5) – Hematologic disorders: Chronic hemolytic anemia, myeloproliferative disorders, splenectomy – Systemic disorders: Sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis – Metabolic disorders: Glycogen storage disease, Gaucher disease, thyroid disorders – Others: Tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH

Pulmonary Artery Sarcoma • Unilateral enlargement of pulmonary artery involved by tumor • Tumor produces irregular filling defect; may exhibit enhancement

PATHOLOGY General Features • Etiology ○ PAH (group 1) – Heritable pulmonary hypertension – Idiopathic – Drugs and toxins □ Aminorex, fenfluramine, dexfenfluramine, toxic rapeseed oil, benfluorex, selective serotonin reuptake inhibitors – Associated with connective tissue disease □ Scleroderma (7-12%); poor prognosis – Associated with HIV infection □ Stable prevalence (0.5%) – Portopulmonary hypertension (up to 2% of patients with portal hypertension) – Congenital heart disease in adults – Schistosomiasis – Chronic hemolytic anemia □ Sickle cell disease, thalassemia, spherocytosis, stomatocytosis – Pulmonary venoocclusive disease &/or pulmonary capillary hemangiomatosis – Persistent pulmonary hypertension of newborn (PPHN) ○ PH due to left heart disease (group 2) – Left ventricular systolic dysfunction – Left ventricular diastolic dysfunction – Valvular disease – Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies □ Eisenmenger syndrome □ Left-to-right shunts □ PAH with coincidental congenital heart disease □ Postoperative PAH ○ PH due to lung diseases &/or hypoxia (group 3) – Chronic obstructive pulmonary disease – Interstitial lung disease □ Idiopathic interstitial fibrosis, sarcoidosis, pulmonary Langerhans cell histiocytosis, pneumoconioses – Other pulmonary diseases with mixed restrictive and obstructive physiology – Sleep-disordered breathing – Alveolar hypoventilation disorders – Chronic exposure to high altitude – Developmental lung diseases ○ Chronic thromboembolic pulmonary hypertension (CTEPH) (group 4) – Chronic obstruction of pulmonary artery □ Episodes of pulmonary embolism and incomplete thrombus resolution – Potentially curable cause of PH 372

Staging, Grading, & Classification • Heath-Edwards microscopic grading ○ Grade 1: Muscularization of pulmonary arteries ○ Grade 2: Intimal proliferation ○ Grade 3: Subendothelial fibrosis ○ Grade 4: Plexiform lesions ○ Grade 5: Rupture of dilated vessels ○ Grade 6: Necrotizing arteritis

Gross Pathologic & Surgical Features • Chronic emboli may manifest with webs, bands, and recanalized thrombi

Microscopic Features • Necrotizing arteritis and capillary plexiform lesions in PAH and left-to-right shunts • Capillary hemangiomatosis in PCH • Pulmonary vein intimal fibrosis, recanalized thrombi and webs in PVOD

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Dyspnea, easy fatigue, chest pain, Raynaud phenomenon

Demographics • Age ○ Prevalence in men: 10% > 35 years and 25% > 65 years ○ Idiopathic (primary): Women in 3rd decade of life • Gender ○ M:F = 1:3 in PAH

Natural History & Prognosis • 5-year survival of patients with CTEPH is 30% • End-stage complications: Right heart failure, pulmonary artery dissection, pulmonary artery thrombosis

Treatment • No cure; 30% respond to medical therapy • Pulmonary endarterectomy with deep hypothermic circulatory arrest: Recommended operative technique for treatment of CTEPH • Lung ± heart transplantation

SELECTED REFERENCES 1.

2. 3.

Rosenkranz S: Pulmonary hypertension 2015: current definitions, terminology, and novel treatment options. Clin Res Cardiol. 104(3):197-207, 2015 Simonneau G et al: Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 62(25 Suppl):D34-41, 2013 Grosse C et al: CT findings in diseases associated with pulmonary hypertension: a current review. Radiographics.30(7):1753-77, 2010

Pulmonary Hypertension Vascular Disease

(Left) AP chest radiograph of a young patient with patent ductus arteriosus and Eisenmenger physiology shows dilatation of the pulmonary trunk ﬈ and central pulmonary arteries as well as cardiomegaly. (Right) Axial SSFP of the same patient shows a markedly dilated pulmonary trunk. For rapid reference, the diameter of the adjacent ascending aorta (providing it is normal) and the pulmonary trunk are typically similar. Pulmonary trunk diameter > 29 mm is often indicative of pulmonary hypertension.

(Left) PA chest radiograph of a patient with pulmonary hypertension associated with remote use of fenfluramine shows markedly enlarged central pulmonary arteries ﬈. (Right) Axial NECT of the same patient shows a dilated pulmonary trunk ﬈ and scattered mosaic attenuation of the lung parenchyma. Fenfluramine is no longer in the market (after 1997) due to the high rate of complications, mainly heart valve disease and pulmonary hypertension.

(Left) PA chest radiograph of a patient with emphysema and pulmonary hypertension shows dilated central pulmonary arteries ﬈. The left upper mediastinal convexity ﬉ correlates with an enlarged pulmonary trunk. (Right) Axial HRCT of the same patient shows centrilobular emphysema and a dilated pulmonary trunk ﬈. Several chronic lung diseases ultimately result in the development of pulmonary hypertension (e.g., chronic obstructive pulmonary disease and interstitial lung disease).

373

Vascular Disease

Pulmonary Venoocclusive Disease KEY FACTS

TERMINOLOGY

PATHOLOGY

• Pulmonary venoocclusive disease (PVOD): Stenosis and occlusion of pulmonary veins and venules by intimal hyperplasia (fibrous tissue) and thrombi

• Pathophysiology: Venous obstruction leads to ↑ capillary hydrostatic pressure and interstitial transudation • Smooth muscle hypertrophy and collagen deposition in veins and venules leads to luminal occlusion • Extravascular changes: Interlobular septal thickening, engorged pulmonary lymphatics, intrathoracic lymphadenopathy, alveolar hemorrhage

IMAGING • HRCT/CT ○ Interlobular septal thickening ○ Thick interlobar fissures ○ Ground-glass opacities: Diffuse, geographic, perihilar, patchy, centrilobular ○ Mosaic attenuation ○ Pulmonary hypertension: Dilated pulmonary trunk and central pulmonary arteries ○ Cor pulmonale: Enlarged right heart chambers

TOP DIFFERENTIAL DIAGNOSES • Pulmonary arterial hypertension • Pulmonary capillary hemangiomatosis

(Left) Axial CECT of a 27-yearold woman with pulmonary venoocclusive disease shows smooth interlobular septal thickening ﬉ and enlarged right heart chambers ﬈. The combination of imaging findings is considered a classic CT/HRCT finding of pulmonary venoocclusive disease. (Right) Coronal CECT of the same patient shows lower lobe predominant smooth interlobular septal thickening ﬉, upper lobe predominant ill-defined centrilobular ground-glass micronodules ﬈, and enlargement of the left pulmonary artery ﬊.

(Left) Axial CECT of a 19-yearold man with pulmonary venoocclusive disease shows thick interlobular septa ﬈ and diffuse ill-defined groundglass micronodules ﬉. (Right) Axial CECT composite image shows mediastinal and hilar lymphadenopathy ﬈ and a dilated pulmonary trunk ﬉ consistent with pulmonary hypertension. While nonspecific, lymphadenopathy and pulmonary trunk enlargement are characteristic findings of pulmonary venoocclusive disease.

374

CLINICAL ISSUES • • • •

Shortness of breath, chest pain, fatigue, syncope Decreased arterial oxygen pressure and diffusing capacity Fatal within 2 years of diagnosis Treatment: Lung transplantation, avoid vasodilators

DIAGNOSTIC CHECKLIST • Consider PVOD in patients with centrilobular ground-glass nodules, thick interlobular septa, and mediastinal lymphadenopathy on HRCT/CT

Pulmonary Venoocclusive Disease • Interlobular septal thickening and pleural effusion; not as common as in PVOD

Abbreviations • Pulmonary venoocclusive disease (PVOD) • Pulmonary arterial hypertension (PAH) • Pulmonary capillary hemangiomatosis (PCH)

Definitions • Stenosis and occlusion of pulmonary veins and venules by intimal hyperplasia (fibrous tissue) and thrombi

IMAGING General Features • Best diagnostic clue ○ Triad of centrilobular ground-glass micronodules, thick interlobular septa, and mediastinal lymphadenopathy • Location ○ Lower lung zone predominance

Radiographic Findings • Radiography ○ Increased conspicuity of central pulmonary vasculature ○ Interlobular septal thickening (Kerley B lines) ○ Progressive right ventricular enlargement

CT Findings • HRCT/CT ○ Interlobular septal thickening ○ Thick interlobar fissures ○ Ground-glass opacities: Diffuse, geographic, perihilar, patchy, centrilobular – Ill-defined centrilobular ground-glass micronodules (most common pattern) ○ Mosaic attenuation ○ Pulmonary hypertension: Dilated pulmonary trunk and central pulmonary arteries ○ Cor pulmonale: Enlarged right heart chambers ○ Normal size of central pulmonary veins and left atrium ○ Mediastinal &/or hilar lymphadenopathy ○ Pleural effusions ○ Multifocal airspace opacities/consolidations (uncommon)

Nuclear Medicine Findings • V/Q scan ○ Usually normal ○ Exclusion of chronic thromboembolic disease ○ Multiple segmental mismatched perfusion defects in setting of negative pulmonary angiogram

Imaging Recommendations • Best imaging tool ○ HRCT/CT

DIFFERENTIAL DIAGNOSIS Pulmonary Arterial Hypertension • Ill-defined centrilobular ground-glass micronodules in 1/3 of PAH • Interlobular septal thickening (uncommon)

Pulmonary Capillary Hemangiomatosis • Widespread ill-defined centrilobular micronodules

PATHOLOGY General Features • Etiology ○ Unknown ○ Pathophysiology: Venous obstruction leads to ↑ capillary hydrostatic pressure and interstitial transudation ○ Key differences between of PAH, PVOD, and PCH – Location of vascular proliferation: Veins/venules in PCH, capillaries/precapillary arterioles in PAH – PVOD and PCH are clinically similar to PAH, but vasodilators may worsen symptoms or lead to death in PVOD and PCH – PCH and PVOD are similar on imaging

Vascular Disease

TERMINOLOGY

Microscopic Features • Smooth muscle hypertrophy and collagen deposition in veins and venules leads to luminal occlusion • Extravascular changes: Interlobular septal thickening, engorged pulmonary lymphatics, intrathoracic lymphadenopathy, alveolar hemorrhage

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Signs of right ventricular dysfunction: Shortness of breath, chest pain, fatigue, syncope ○ Cyanosis, hemoptysis, hepatosplenomegaly from PAH • Other signs/symptoms ○ Risk factors: Connective tissue disease; prior chemotherapy, stem cell transplantation, exposure to organic solvents (e.g., trichloroethylene) • Clinical profile ○ ↓ arterial oxygen pressure (PaO2) and diffusing capacity ○ Genetic mutations may be involved

Demographics • 0.3-1.4 per 1 million persons • Adults 30-50 years of age; heritable form may be seen in young individuals

Natural History & Prognosis • Fatal within 2 years of diagnosis

Treatment • Lung transplantation; avoid vasodilators

DIAGNOSTIC CHECKLIST Consider • PVOD in patients with centrilobular ground-glass nodules, thick interlobular septa, and mediastinal lymphadenopathy on HRCT/CT

SELECTED REFERENCES 1. 2.

Chaisson NF et al: Pulmonary capillary hemangiomatosis and pulmonary veno-occlusive disease. Clin Chest Med. 37(3):523-34, 2016 Frazier AA et al: From the archives of the AFIP: pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. Radiographics. 27(3):86782, 2007

375

Vascular Disease

Pulmonary Capillary Hemangiomatosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Pulmonary capillary hemangiomatosis (PCH): Rare cause of pulmonary hypertension due to proliferation of alveolar capillaries

• • • •

IMAGING • CT/HRCT ○ Subtle ground-glass centrilobular nodules ○ Evidence of pulmonary hypertension – Enlarged central pulmonary arteries and pulmonary trunk – Right ventricular hypertrophy ○ Evidence of right heart dysfunction with progressive pulmonary hypertension – Mild right ventricular enlargement – Leftward bowing of interventricular septum – Reflux of contrast into inferior vena cava and hepatic veins ○ Interlobular septal thickening (rare)

(Left) PA chest radiograph of a patient pulmonary capillary hemangiomatosis who presented with dyspnea shows enlargement of the pulmonary trunk ﬊ and central pulmonary arteries ﬉, which rapidly taper to a normal size, consistent with pulmonary hypertension. The lungs appear normal. (Right) Axial CECT of the same patient shows an enlarged pulmonary trunk ﬊ and diffuse bilateral centrilobular ground-glass nodules ﬈. The diagnosis was established histologically at lung transplantation.

(Left) Sagittal CECT of a patient with pulmonary capillary hemangiomatosis shows poorly defined centrilobular ground-glass nodules ﬈. A thin rim of subpleural sparing ﬊ is noted along the fissures and costal margins. (Right) Axial CECT of a patient with pulmonary capillary hemangiomatosis shows an enlarged pulmonary trunk ﬊ and right pulmonary artery and scattered illdefined ground-glass centrilobular nodules ﬈. The enlarged subcarinal lymph node ﬉ is an unusual imaging finding in this entity.

376

Pulmonary venoocclusive disease Idiopathic pulmonary hypertension Chronic pulmonary thromboembolism Respiratory bronchiolitis

PATHOLOGY • Capillary proliferation at least 2 layers thick

CLINICAL ISSUES • Insidious onset of progressive dyspnea, fatigue, chronic cough; hemoptysis (30%) • Poor prognosis: Rare survival 5 years beyond diagnosis • Lung or heart-lung transplantation curative • Vasodilator infusion contraindicated; may be catastrophic

DIAGNOSTIC CHECKLIST • Consider PCH in cases of pulmonary hypertension, septal thickening and centrilobular ground-glass nodules on CT

Pulmonary Capillary Hemangiomatosis

Synonyms • Pulmonary capillary hemangiomatosis (PCH)

Definitions • Rare cause of pulmonary hypertension due to proliferation of alveolar capillaries

IMAGING General Features • Best diagnostic clue ○ Enlarged central pulmonary arteries and centrilobular ground-glass nodules • Location ○ No zonal predominance

Radiographic Findings • Radiography ○ Pulmonary hypertension – Enlarged central pulmonary arteries that taper rapidly ○ ± subtle poorly defined nodules, usually diffuse but occasionally basilar predominant ○ Small pleural effusions

Respiratory Bronchiolitis • Upper lobe centrilobular ground-glass nodules • No pulmonary hypertension

Hypersensitivity Pneumonitis • CT: Centrilobular ground-glass nodules, lobular air-trapping • Pulmonary hypertension from fibrosis in cluster 2 disease • Fibrosis and lobular air-trapping in patients with pulmonary hypertension distinguishes it from PCH

PATHOLOGY General Features • Key differences between of PAH, PVOD, and PCH ○ Location of capillary proliferation: Veins/venules in PCH, capillaries/precapillary arterioles in PAH ○ PVOD and PCH clinically similar to PAH, but vasodilators may worsen symptoms or lead to death in PVOD and PCH ○ PCH and PVOD similar on imaging

Microscopic Features • Proliferation of capillary vessels at least 2 layers thick

CLINICAL ISSUES

CT Findings

Presentation

• Subtle ground-glass centrilobular micronodules • Pulmonary hypertension ○ Enlarged central pulmonary arteries, pulmonary trunk:aorta ratio > 1.0 ○ Right ventricular hypertrophy ○ Right heart dysfunction: Mild right ventricular enlargement, leftward bowing of interventricular septum, reflux of contrast into inferior vena cava and hepatic veins • Hemorrhagic pleural effusions (25%) • Interlobular septal thickening (rare)

• Most common signs/symptoms ○ Insidious progressive dyspnea, fatigue, and cough ○ Hemoptysis (30%) • Other signs/symptoms ○ Distinctive hemodynamics (also seen in PVOD) – ↑ pulmonary artery pressures and normal or ↓ pulmonary capillary wedge pressures – Distinguishes PCH from postcapillary causes of pulmonary hypertension

DIFFERENTIAL DIAGNOSIS Pulmonary Venoocclusive Disease • Rare; pulmonary hypertension from postcapillary occlusion involving pulmonary veins and venules • Elevated pulmonary artery pressures and normal or low pulmonary capillary wedge pressures • Interlobular septal thickening • Imaging findings of pulmonary hypertension • Presence of interlobular septal thickening and absence of centrilobular nodules distinguish it from PCH

Idiopathic Pulmonary Hypertension • Imaging findings of pulmonary hypertension • Occasional ground-glass centrilobular nodules that represent cholesterol granulomas ○ Indistinguishable from PCH; lung biopsy required for diagnosis

Vascular Disease

TERMINOLOGY

Demographics • Age ○ Infancy to old age; mean: 30 years • Gender ○ M=F

Natural History & Prognosis • Poor prognosis: Rare survival 5 years beyond diagnosis • Surgical lung biopsy required for definitive diagnosis but risky in critically ill patients

Treatment • Lung or heart-lung transplantation curative • Vasodilator therapy (used for idiopathic pulmonary hypertension) contraindicated and may be catastrophic ○ Induces potentially life-threatening pulmonary edema

DIAGNOSTIC CHECKLIST Consider

Chronic Pulmonary Thromboembolism

• PCH in patients with pulmonary hypertension, septal thickening, and diffuse centrilobular ground-glass nodules

• Absence of centrilobular ground-glass nodules • CT: Pulmonary hypertension and chronic thromboemboli (latter distinguishes from PCH)

1.

SELECTED REFERENCES Chaisson NF et al: Pulmonary capillary hemangiomatosis and pulmonary veno-occlusive disease. Clin Chest Med. 37(3):523-34, 2016

377

Vascular Disease

Excipient Lung Disease (Talc/Cellulose Granulomatosis) KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Excipient lung disease • Occlusion of pulmonary arterioles and capillaries by insoluble foreign body particles from intravenous (IV) injection of crushed tablets intended for oral use only, which leads to acute or chronic cor pulmonale

• • • • • •

IMAGING • Talc/cellulose ○ Diffuse centrilobular micronodules &/or tree-in-bud opacities ○ Fissural sparing ○ Absence of signs of airways disease ○ Dilated pulmonary trunk (> 3 cm) indicating pulmonary hypertension ○ Dilated right heart (right ventricular strain) • Ritalin ○ Lower lobe predominant panlobular emphysema ○ Mimics α-1 antitrypsin deficiency

(Left) AP chest radiograph of a 37-year-old patient with talc granulomatosis shows bilateral, ill-defined, micronodular opacities. Note enlargement of the pulmonary arteries ﬈, suggesting pulmonary hypertension, a very common ancillary finding. (Right) Axial CECT of the same patient shows diffuse, bilateral, centrilobular micronodules with a tree-inbud pattern. Note that these nodules spare the subpleural aspects ﬉ of the lungs and are diffusely and evenly distributed.

(Left) Sagittal CECT of the same patient shows diffuse, centrilobular micronodules with a tree-in-bud pattern. Note sparing of the horizontal and oblique fissures ﬈, indicating a centrilobular distribution rather than miliary or perilymphatic. (Right) Coronal CECT MIP reformation of the same patient shows diffuse, tree-inbud opacities and distinct subpleural lung sparing ﬈ indicating a centrilobular distribution of the micronodules. MIP reformations help highlight the tree-in-bud pattern.

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Cellular bronchiolitis Miliary infection Pulmonary hypertension Pulmonary capillary hemangiomatosis α-1 antitrypsin deficiency Sarcoidosis

PATHOLOGY • Foreign bodies produce angiocentric granulomas • Birefringent rod-like cellulose crystals, 20-200 μm • Birefringent needle-like or plate-like talc crystals, 5-15 μm

CLINICAL ISSUES • Patients almost always deny injection, even when confronted • Frequent evolution to pulmonary hypertension and cor pulmonale, which may lead to sudden death • Treatment: Discontinuation of IV injection

Excipient Lung Disease (Talc/Cellulose Granulomatosis)

Synonyms • • • • • • • • • • •

Excipient lung disease (ELD) Angiocentric systemic granulomatosis Pulmonary angiothrombotic granulomatosis Pulmonary granulomatous vasculitis Pulmonary foreign body angiogranulomatosis Pulmonary mainline granulomatosis Talc embolism Foreign body microembolism Foreign body granulomatosis Intravascular talcosis Ritalin lung

•

•

Definitions • Occlusion of pulmonary arterioles and capillaries by insoluble foreign body particles from intravenous (IV) injection of crushed tablets intended for oral use only, which leads to acute or chronic cor pulmonale • Oral tablets contain active and inactive components ○ Inactive components (excipients) – Can be referred to as binders or fillers – Provide stabilization, bulk, substance, or therapeutic enhancement – Cellulose (most common) – Talc (common but decreasing in frequency) – Other (less common) □ Corn starch □ Cotton fibers □ Crospovidone • Ritalin (methylphenidate) contains talc ○ Associated with panlobular emphysema – Likely triggered by drug itself with talc coadjuvancy □ Definite association of emphysema with IV Ritalin abuse □ Association of long-term appropriate oral Ritalin use with emphysema has been postulated

IMAGING General Features • Best diagnostic clue ○ Diffuse centrilobular micronodules &/or tree-in-bud opacities ○ Fissural sparing • Location ○ Cellulose granulomatosis: Diffuse ○ Ritalin (methylphenidate) lung: Lower lobe predominance • Size ○ Micronodules (1-2 mm)

Radiographic Findings • Normal radiograph is common • Cellulose and talc: Diffuse micronodules • Ritalin (methylphenidate): Lower lobe-predominant emphysema and bullae

CT Findings • Cellulose

• •

•

•

○ Centrilobular nodules &/or tree-in-bud opacities common – Diffuse, bilateral, and evenly distributed – Sparing of pleura and interlobar fissures Talc ○ Centrilobular nodules &/or tree-in-bud opacities common – Diffuse, bilateral, and evenly distributed – Sparing of pleura and interlobar fissures ○ Conglomerate masses (similar to progressive massive fibrosis) on background of pulmonary micronodules ○ Ground-glass attenuation ○ Panlobular emphysema Absence of features of airways disease, such as ○ Bronchial wall thickening ○ Bronchiectasis ○ Mucus plugging ○ Mosaic attenuation ○ Air-trapping Dilated pulmonary trunk (> 3 cm) indicates pulmonary hypertension Dilated right heart (right ventricular strain) ○ Right ventricular to left ventricular diameter ratio > 1.0 ○ Flattening of interventricular septum or septal bowing toward left ventricular lumen If serial studies are available ○ Progression and increased conspicuity of centrilobular nodules ○ Progressive dilatation of pulmonary trunk and right heart Ritalin (methylphenidate) ○ Lower lobe predominant panlobular emphysema (most common) – Similar to α-1 antitrypsin deficiency ○ Conglomerate masses (progressive massive fibrosis) ○ Centrilobular micronodules (uncommon)

Vascular Disease

TERMINOLOGY

Imaging Recommendations • Best imaging tool ○ MIP reformations help differentiate centrilobular from miliary and perilymphatic micronodules – Miliary and perilymphatic micronodules involve fissures

DIFFERENTIAL DIAGNOSIS Cellular Bronchiolitis • Principal cause of tree-in-bud nodules ○ Infectious bronchiolitis ○ Diffuse aspiration bronchiolitis • Tree-in-bud pattern may be diffuse but is not typically evenly distributed • Other findings of airway diseases ○ Bronchial wall thickening ○ Bronchiectasis ○ Mucus plugging ○ Mosaic attenuation ○ Air-trapping (expiratory imaging)

Miliary Infection • Hematogenous dissemination of infection ○ Tuberculosis: Dyspnea, cough, hypoxemia 379

Vascular Disease

Excipient Lung Disease (Talc/Cellulose Granulomatosis) ○ Histoplasmosis • Some nodules along pleura and fissures

Pulmonary Hypertension • Plexogenic arteriopathy ○ May exhibit diffuse centrilobular nodules on CT • Cholesterol granulomas occur in 25% ○ May exhibit diffuse centrilobular nodules on CT ○ May be indistinguishable from cellulose granulomatosis

Pulmonary Capillary Hemangiomatosis • Ground-glass centrilobular nodules correlate with angiomatoid proliferation • May be indistinguishable from cellulose granulomatosis

α-1 Antitrypsin Deficiency • Differential diagnosis for Ritalin lung • Same pattern of emphysema ○ i.e., lower lobe predominant and panlobular • Differentiation is based on history, serum α-1 antitrypsin levels, and pathology

Sarcoidosis • Affected patients are frequently asymptomatic • Perilymphatic distribution of micronodules ○ Abundant nodules along pleura and fissures • Hilar and mediastinal lymphadenopathy common

PATHOLOGY General Features • Foreign bodies produce angiocentric granulomas • Cellulose ○ Crystals within granulomas – Translucent and colorless or pale blue-gray on H&E staining – Birefringent rod-like crystals, 20-200 μm ○ Occluded and recanalized pulmonary arterioles ○ Intravascular and perivascular foreign body granulomas with giant cells • Talc ○ Intravascular birefringent talc crystals – Colorless to pale yellow on H&E staining – Strongly birefringent needle-like or plate-like crystals, 5-15 μm ○ Perivascular foreign body giant cells ○ Interstitial granulomas lead to fibrosis (similar to progressive massive fibrosis) with surrounding cicatricial emphysema ○ Small talc particles may pass through capillaries into pulmonary veins and lodge in retina, kidneys, liver, spleen, lymph nodes, bone marrow, and spinal cord

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Affected patients may be asymptomatic ○ Dyspnea, sputum production ○ Fever ○ Arrhythmia and sudden death • Other signs/symptoms 380

○ Funduscopy may reveal talc crystals in retinal arterioles ○ Echocardiography: Pulmonary hypertension, dilated right heart chambers • Clinical profile ○ Risk factors – IV drug abuser – Chronic use of analgesics, stimulants, and antihistamines – Chronic treatment with opioid tablets (e.g., codeine and hydrocodone) □ IV injection of methadone tablets produces severe symptoms □ Common clinical features: Chronic pain, malignancy, multiple sclerosis, migraine, or psychiatric disorder – Chronic Ritalin (methylphenidate) use – Healthcare workers – Long-term central intravascular catheters [e.g., central lines, peripherally inserted central catheters (PICC)], implanted vascular ports, and hemodialysis catheters ○ Following discontinuation of IV talc injection – Progression of lung fibrosis (progressive massive fibrosis in silicosis) and pulmonary hypertension over months and years, with ↑ dyspnea, respiratory failure, and death

Natural History & Prognosis • Patients almost always deny injection, even when confronted ○ Diagnosis requires high index of suspicion ○ Diagnosis frequently requires pathologic confirmation • Most cases result from repetitive injection ○ Recurrent episodes of shortness of breath, fever, arrhythmia ○ Patients may have needle tracks or history of IV drug abuse • Few cases result from single massive injection • Whether massive, acute, or recurrent injection, frequent evolution to pulmonary hypertension and cor pulmonale may lead to sudden death

Treatment • If suspicion is high based on imaging, patient should be closely monitored until disclosure of injection &/or pathologic confirmation • Discontinuation of IV injection

DIAGNOSTIC CHECKLIST Consider • Cellulose granulomatosis in any patient with diffuse, evenly distributed tree-in-bud nodules ○ Denial of IV injection of crushed tablets is common ○ Very high risk of sudden death

SELECTED REFERENCES 1. 2.

Nguyen VT et al: Pulmonary effects of i.v. injection of crushed oral tablets: "excipient lung disease". AJR Am J Roentgenol. 203(5):W506-15, 2014 Bendeck SE et al: Cellulose granulomatosis presenting as centrilobular nodules: CT and histologic findings. AJR Am J Roentgenol. 177(5):1151-3, 2001

Excipient Lung Disease (Talc/Cellulose Granulomatosis) Vascular Disease

(Left) Axial CECT of the same patient shows a dilated pulmonary trunk ﬈ consistent with pulmonary hypertension. Normally the pulmonary trunk exhibits a diameter similar to that of the adjacent ascending aorta. (Right) Axial oblique (4chamber reformation) CTA of the same patient shows dilatation of the right ventricle ﬊, inversion of the interventricular septum ﬈, and a small pericardial effusion ﬉ indicating increased right heart pressures resulting from mechanical obstruction of the pulmonary arteriolar tree.

(Left) Composite image with coronal MIP reformations of the same patient obtained at baseline (left) and months later (right) shows progression of tree-in-bud opacities as the patient continued to intravenously inject crushed tablets intended for oral use. (Right) Low-power photomicrograph (H&E stain) of a specimen (same patient) shows innumerable small nodular lesions ﬉ centered about the bronchovascular bundles. While some nodules are nearly subpleural, the pleura itself ﬈ is free of nodules.

(Left) High-power photomicrograph (H&E stain) of a specimen (same patient) shows a muscular pulmonary artery occluded by extensive foreign body material ﬈ and multinucleated giant cell ﬉ reaction. The latter is the reason why these entities are referred to as talc or cellulose granulomatosis. (Right) Highpower photomicrograph (same patient) under polarized light shows birefringence of endoluminal particles. Talc typically manifests as strongly birefringent needle-like or plate-like crystals, measuring 5-15 μm.

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Vascular Disease

Excipient Lung Disease (Talc/Cellulose Granulomatosis)

(Left) PA chest radiograph of a 35-year-old man with cellulose granulomatosis shows a subtle, diffuse, bilateral micronodular pattern. (Right) Axial NECT of the same patient shows diffusely distributed, bilateral, centrilobular micronodules. Note that these nodules spare the subpleural lungs, confirming their centrilobular distribution. Typical ancillary findings include a dilated pulmonary trunk and right heart strain.

(Left) High-power photomicrograph (H&E stain) of a specimen (same patient) shows a muscular pulmonary artery with luminal occlusion by pale blue-gray foreign material ﬈. (Right) Lowpower photomicrograph (same patient) under polarized light shows birefringent rod-like particles ﬉, 20-200 μm, consistent with cellulose crystals. Patients with excipient lung disease almost always deny injection, even when confronted. Thus, pathologic confirmation may be required in a significant proportion of cases.

(Left) AP chest radiograph of a patient with cellulose granulomatosis shows very subtle micronodular opacities. (Right) Axial CECT of the same patient shows diffuse tree-inbud micronodules, which spare the subpleural lung. While some cases of cellular bronchiolitis may be diffuse, they are not typically as evenly distributed as diseases with a vascular tree-in-bud pattern. Diffuse and even distribution should always suggest the possibility of a vascular treein-bud pattern.

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Excipient Lung Disease (Talc/Cellulose Granulomatosis) Vascular Disease

(Left) PA chest radiograph of a 65-year-old woman with Ritalin (methylphenidate) lung shows hyperinflation and lower lung zone band-like opacities. (Right) Lateral chest radiograph of the same patient shows hyperlucent lower lobes. Methylphenidate is known to produce panlobular emphysema likely related to the drug itself and in coadjuvancy with talc. The pattern of emphysema is similar to that seen in α-1 antitrypsin deficiency and primarily affects the lower lobes.

(Left) Coronal CECT of the same patient shows panlobular emphysema predominantly involving the lower lobes. While centrilobular micronodules related to talc may be present, the predominant finding is typically lower lobe panlobular emphysema. (Right) Sagittal CECT of the same patient shows panlobular emphysema predominantly involving the lower lobes. Note also the band-like opacities that likely represent areas of pulmonary scarring.

(Left) Axial NECT of a patient with excipient lung disease from crospovidone shows faint centrilobular micronodules ﬈, lower lobe consolidation ﬊, and trace bilateral pleural effusions ﬉. (Right) Intermediate-power photomicrograph (Movat pentachrome stain) of a specimen (same patient) shows yellow coral-like particles ﬈ in a muscular pulmonary artery. Crospovidone exhibits unique features including coral-like particles up to 100 μm in length and absence of birefringence.

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SECTION 11

Inhalational, Inflammatory, Metabolic, and Post Treatment

Approach to Inhalational, Inflammatory, Metabolic, and Post Treatment

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Aspiration/Inhalation Spectrum of Aspiration-Related Disorders Lipoid Pneumonia Inhalational Injury

392 396 400

Inflammatory 404 410 416

Sarcoidosis Histiocytic Disorders Eosinophilic Disorders

Metabolic or Degenerative Amyloidosis Light-Chain Deposition Disease Pulmonary Alveolar Proteinosis Metastatic Pulmonary Calcification Diffuse Pulmonary Ossification Emphysema Idiopathic Pulmonary Hemosiderosis

420 424 426 432 436 438 442

Post Treatment Radiation-Induced Lung Disease Drug-Induced Lung Disease

444 450

Inhalational, Inflammatory, Metabolic, and Post Treatment

Approach to Inhalational, Inflammatory, Metabolic, and Post Treatment Introduction Diffuse lung disease may be caused by a wide variety of conditions, including those of inhalational, inflammatory, metabolic, and posttreatment etiology. Inhalational lung diseases are among the most significant lung disorders and result from inhalation of various substances that become deposited in the lungs. The resultant pulmonary disorders depend on several factors such as the susceptibility of the lungs, the size and concentration of the inhaled particles, and the duration of exposure, and include diseases such as aspiration, lipoid pneumonia (LP), and inhalational lung injury. In contrast, inflammatory and metabolic disorders resulting in diffuse lung disease are either idiopathic or due to systemic conditions and include such entities as sarcoidosis, amyloidosis, pulmonary alveolar proteinosis (PAP), and idiopathic pulmonary hemosiderosis (IPH). Finally, due to the incredible improvements in systemic and local therapies for thoracic malignancies such as lung cancer, esophageal cancer, and mediastinal lymphoma, treatment-related effects due to chemotherapy, targeted therapies, immunotherapy, and radiation techniques may result in identifiable abnormalities involving the lung parenchyma and interstitium.

Imaging As in most diffuse lung diseases of other cause, chest radiography is often the first imaging modality with which the radiologist may have the opportunity to detect abnormalities. Chest radiographs can demonstrate findings such as reticular opacities, airspace opacities, consolidations, and honeycombing. In some cases, the distribution and extent of disease may be appreciable on radiography. However, thinsection CT and HRCT are the imaging modalities of choice for identifying and characterizing the types of abnormalities present as well as demonstrating additional important characteristics such as the distribution and extent of disease. Cross-sectional imaging is particularly important for identifying ground-glass opacities, which cannot be reliably identified on chest radiography. Several important inhalational, inflammatory, metabolic, and posttreatment etiologies of diffuse lung disease are introduced herein to illustrate the wide range of abnormalities that the radiologist may encounter.

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Lipoid Pneumonia LP refers to the presence of intrapulmonary endogenous material or to aspiration of exogenous substances. The latter include vegetable, animal, and mineral oils, and the former includes secretions distal to bronchial obstruction. In general, mineral oil and vegetable-based oils tend to cause minimal to mild inflammatory reaction, and the abnormalities detected on imaging studies relate to the type and amount of aspirated or inhaled oils or fats, to the frequency of aspiration episodes, and to the length of time over which aspiration has taken place. The imaging manifestations of LP on HRCT/CT depend on the acuity of aspiration. In acute LP, the primary imaging findings include consolidations &/or ground-glass opacities that are most pronounced in the lower lobes &/or middle lobe. Additionally, the crazy-paving pattern comprised of groundglass opacities and interlobular septal thickening has also been described. Chronic LP may also result in consolidation, groundglass opacities, &/or crazy-paving but may exhibit fat attenuation within consolidations or pulmonary nodules. At times, the fat attenuation may be obscured by inflammatory changes in the adjacent lung. Over time, chronic changes such as pulmonary fibrosis with architectural distortion, interlobular and bronchovascular thickening, &/or bronchiectasis may develop. Inhalational Injury Inhalational injury (II) is diffuse lung disease resulting from the inhalation of smoke or chemical products of combustion. Heated air produces thermal injuries that usually affect the upper airways, whereas chemical or smoke-related toxins and irritants usually affect both the airways and the lungs. Most patients develop symptoms within minutes or hours. It is recommended that asymptomatic patients be observed for at least 6 hours to evaluate for delayed onset of symptoms. On HRCT/CT, a wide variety of findings may be present dependent on whether the airways &/or lungs are affected. The spectrum of airway abnormalities includes airway edema, bronchitis/bronchiolitis, constrictive bronchiolitis, and bronchiectasis. In contrast, abnormalities such as acute respiratory distress syndrome, pneumonia, and organizing pneumonia (OP) may be seen in the lungs.

Inhalational Disease

Inflammatory and Metabolic Disease

Spectrum of Aspiration-Related Disorders Aspiration-related disorders are a heterogeneous group of diseases resulting from the aspiration of solid &/or liquid materials into the airways and lungs. The spectrum of disease includes infection (aspiration pneumonia) and inflammation (aspiration pneumonitis) related to aspiration, foreign bodies, LP, and diffuse aspiration bronchiolitis. Each of these entities tends to manifest in different ways on imaging.

Sarcoidosis Sarcoidosis is a systemic chronic granulomatous disease characterized by noncaseating granulomas in multiple organs. The lungs and mediastinum are involved in over 90% of cases. The diagnosis of sarcoidosis is typically achieved with a combination of clinical history, laboratory findings, tissue sampling with characteristic histopathologic abnormalities, and imaging features.

On HRCT/CT, aspiration pneumonia and pneumonitis result in tree-in-bud opacities and consolidations that may evolve into acute respiratory distress syndrome. Foreign bodies within the airways may be overlooked depending on their location and density; however, complications such as postobstructive atelectasis, pneumonitis, &/or pneumonia are more evident. LP characteristically exhibits fat attenuation within consolidations or pulmonary nodules, although the crazypaving pattern has also been described. Finally, diffuse aspiration bronchiolitis manifests as centrilobular nodules, tree-in-bud opacities, and bronchiectasis.

On CT, bilateral hilar and right paratracheal lymphadenopathy are present in up to 95% of cases and are highly suggestive of the diagnosis of sarcoidosis. On HRCT/CT, the most common abnormality is the presence of multiple small pulmonary nodules in a perilymphatic distribution involving the peribronchovascular and subpleural interstitia as well as the interlobular septa. The upper lobes are predominantly affected, and nodules may coalesce into larger lesions. In endstage disease, upper lobe-predominant reticular opacities, traction bronchiectasis, architectural distortion, and volume loss may be present, as well as confluent mass-like lesions that may mimic progressive massive fibrosis.

Approach to Inhalational, Inflammatory, Metabolic, and Post Treatment

Amyloidosis may involve the lungs &/or the airways with abnormalities detectable on HRCT/CT. Pulmonary parenchymal amyloidosis may manifest as a nodular parenchymal or a diffuse alveolar septal type. The nodular form manifests as well-circumscribed, solitary or multiple lung nodules that commonly contain calcification. Lung cysts may be present in patients with Sjögren syndrome and associated lymphoid interstitial pneumonia. In the diffuse alveolar septal form, interlobular septal thickening, small nodules, and consolidations with calcification are common. When the airways are affected, submucosal deposition may be focal or diffuse with resultant wall thickening and foci of calcification. Pulmonary Alveolar Proteinosis PAP is a syndrome characterized by the accumulation of surfactant in the airways, specifically the alveoli and terminal bronchioles. There are various types of PAP including autoimmune, secondary, hereditary, and congenital, of which autoimmune comprises 90% of cases. Diagnosis is typically made via bronchoalveolar lavage. On HRCT/CT, the characteristic manifestation of PAP is crazypaving pattern comprised of ground-glass opacities and interlobular septal thickening or intralobular lines, which are much more common in primary than in secondary PAP. Ground-glass opacities may be present in either form, but tend to be more geographic in primary in PAP and diffuse in secondary PAP. Other findings such as consolidation, honeycombing, and bronchiectasis may also be present. Idiopathic Pulmonary Hemosiderosis IPH is a disorder of uncertain etiology characterized by recurrent alveolar capillary hemorrhage with resultant pulmonary hemosiderin deposition. Pulmonary hemosiderosis may be primary or idiopathic (IPH) or secondary to any disease that causes alveolar hemorrhage. Several etiologies have been proposed as the underlying cause of IPH, including autoimmunity, environmental factors, and allergies. The appearance of IPH on HRCT/CT depends upon the phase of the disease. In the acute phase, IPH results in multifocal ground-glass opacities &/or consolidations in the perihilar regions and the lower lobes. Superimposition of these findings on a background of interlobular septal thickening &/or intralobular lines may produce the crazy-paving pattern. Interlobular septal thickening and intralobular lines correlate with the the interstitial deposition of hemosiderin-laden macrophages. In the chronic phase, lower lobe-pulmonary fibrosis is the predominant finding, consisting of intralobular lines, architectural distortion, and traction bronchiectasis and bronchiolectasis. Honeycombing may be present and is often lower lung predominant. Associated centrilobular nodules may result from the presence of intraalveolar macrophages.

patients with these neoplasms, treatment-related effects are more commonly encountered on imaging examinations performed for restaging and follow-up purposes. The effects of these treatments on the appearance of the thorax should be recognizable to radiologists. Radiation-Induced Lung Disease Radiation therapy (RT) uses ionizing radiation to control cell growth by damaging the DNA of cancerous tissue ultimately leading to cellular death. RT is used for the treatment/palliation of neoplasms involving the thorax, including lung, breast, and esophageal cancers, thymic epithelial neoplasms, lymphoma, and malignant pleural mesothelioma. On HRCT/CT, the appearance of treatment-related abnormalities due to RT depends primarily on the irradiated region of the thorax and the time that has elapsed from therapy. For instance, radiation pneumonitis typically occurs within the first 6 months and manifests as ground-glass opacities, airspace opacities &/or consolidations. Radiation pneumonitis evolves into radiation fibrosis, which is usually seen in the 6-12 months following RT. Radiation fibrosis manifests as decreasing ground-glass opacities, airspace opacities, and consolidations with associated volume loss, architectural distortion, and traction bronchiectasis and bronchiolectasis.

Inhalational, Inflammatory, Metabolic, and Post Treatment

Amyloidosis Amyloidosis refers to the deposition of abnormal insoluble proteins within various tissues throughout the body. Localized and systemic forms of the disease have been described, with the former affecting 1 organ and the latter being a systemic process. Amyloid deposits classically demonstrate apple-green birefringence under polarized light after staining with Congo red.

Drug-Induced Lung Disease Drug-induced lung disease refers to diffuse lung disease that results from a wide variety of medications, including antibiotics, cardiovascular drugs, antiinflammatory agents, anticonvulsants, chemotherapy agents, and recreational drugs. A wide variety of histopathologic patterns of disease have been described, including diffuse alveolar damage, OP, nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), hypersensitivity pneumonitis, eosinophilic pneumonia, diffuse alveolar hemorrhage, and pulmonary edema. There is strong correlation between these histopathologic patterns and imaging abnormalities on HRCT/CT. HRCT/CT is instrumental in the identification of the predominant abnormality, delineation of the distribution of disease, and reevaluation of patients after treatment. The most common abnormalities include ground-glass opacities, reticular opacities, consolidations, and honeycombing. For instance, OP characteristically manifests as peribronchovascular, peripheral, subpleural opacities that improve with the administration of steroids. NSIP appears as basilar subpleural ground-glass opacities, and its fibrotic form may result in reticular opacities, traction bronchiectasis, &/or bronchiolectasis. The UIP pattern results in subpleural lower lobe predominant reticular opacities, honeycombing, and traction bronchiectasis &/or bronchiolectasis. Recognition of these and other patterns may assist in narrowing the differential diagnosis in the appropriate clinical setting.

Treatment-Related Disease Due to the dramatic expansion of therapies available for thoracic malignancies such as lung cancer, esophageal cancer, lymphoma, and others, as well as the improved survival of 387

Inhalational, Inflammatory, Metabolic, and Post Treatment

Approach to Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Coronal CECT of a patient with head and neck cancer and recurrent aspiration demonstrates bilateral basilar predominant airspace and nodular opacities ﬈ in the lower lobes. (Right) Coronal CECT of a patient with esophageal cancer and recurrent aspiration shows diffuse bilateral ground-glass and airspace opacities in the posterior or dependent aspects of the lungs. Recurrent aspiration is characterized by nodules, ground-glass opacities, &/or consolidations in the dependent lung.

(Left) Axial NECT of a 41-yearold woman with lipoid pneumonia demonstrates a nodular lesion ﬈ in the middle lobe with surrounding ground-glass opacity. (Right) Axial NECT of the same patient shows that the pulmonary nodule ﬈ is composed almost entirely of low-attenuation adipose tissue and is similar in attenuation to the subcutaneous fat. Identification of macroscopic fat attenuation in a nodule or mass should suggest benign entities such as hamartoma and lipoid pneumonia.

(Left) PA chest radiograph of a mechanically ventilated patient following inhalational injury demonstrates diffuse bilateral pulmonary opacities that are more pronounced in the right lung. An endotracheal tube ﬈ is present. (Right) Axial CECT of the same patient shows extensive bilateral airspace disease consisting of groundglass opacities anteriorly ﬈ and dense consolidations posteriorly ﬉. This pattern of lung involvement is consistent with acute respiratory distress syndrome. Trace pleural effusions ﬊ are also present.

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Approach to Inhalational, Inflammatory, Metabolic, and Post Treatment Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Axial NECT of a patient with sarcoidosis demonstrates numerous small, perilymphatic nodules along the bronchovascular bundles that coalesce to form a larger irregular opacity ﬈. (Right) Coronal CECT of a patient with sarcoidosis shows small perilymphatic nodules along the bronchovascular bundles and bilateral foci of pulmonary ground-glass opacity. Bilateral perilymphatic micronodules on CT/HRCT are a common manifestation of sarcoidosis, seen in 75-90% of affected patients.

(Left) PA chest radiograph of a patient with advanced chronic sarcoidosis demonstrates numerous small nodules and coalescent mass-like opacities with architectural distortion in the mid and upper lung zones. (Right) Coronal NECT of the same patient shows central peribronchovascular mass-like regions of fibrosis ﬈ with internal calcification ﬉ and architectural distortion due to end-stage sarcoidosis. Such findings may mimic progressive massive fibrosis complicating pneumoconiosis.

(Left) Axial NECT of a longtime smoker demonstrates emphysema and numerous irregular spiculated nodules and nodular opacities, some of which demonstrate intrinsic cavitation ﬈. (Right) Coronal NECT of the same patient demonstrates emphysema and irregular pulmonary nodules, many with cavitation ﬈. Note preferential involvement of the upper and mid lung zones and relative sparing of the lower lobes. The morphologic features and distribution of these abnormalities are characteristic of pulmonary Langerhans cell histiocytosis.

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Inhalational, Inflammatory, Metabolic, and Post Treatment

Approach to Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Coronal NECT of a patient with acute eosinophilic pneumonia demonstrates multifocal bilateral groundglass opacities ﬈ and bronchial wall thickening ﬊. (Right) Axial CECT of a patient with chronic eosinophilic pneumonia shows subpleural and peripheral heterogeneous consolidations ﬈. The imaging appearance of eosinophilic pneumonia varies based on the acuity of the disease process, as demonstrated in these cases.

(Left) Axial NECT of a patient with amyloidosis demonstrates numerous bilateral pulmonary nodules and masses ﬈ with intrinsic dense calcification. (Right) Axial NECT (soft tissue window) of the same patient shows extensive amorphous calcification ﬈ in the pulmonary nodules and masses as well as in areas of pleural thickening ﬊. CT imaging of pulmonary amyloidosis frequently demonstrates calcification, and this imaging appearance should prompt the radiologist to suggest the diagnosis.

(Left) PA chest radiograph of a patient with pulmonary alveolar proteinosis demonstrates diffuse bilateral pulmonary opacities that are most pronounced in the mid and lower lung zones. (Right) Coronal CECT of the same patient demonstrates extensive bilateral groundglass opacities on a background of interlobular septal thickening, the crazypaving CT pattern, a classic manifestation of pulmonary alveolar proteinosis.

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Approach to Inhalational, Inflammatory, Metabolic, and Post Treatment Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Axial NECT of a patient with idiopathic pulmonary hemosiderosis demonstrates innumerable solid ﬈ and ground-glass ﬊ nodules in the right lung. (Right) Axial CECT of a patient with idiopathic pulmonary hemosiderosis demonstrates an ill-defined area of ground-glass opacity ﬈ in the left upper lobe. The most common imaging manifestation of pulmonary hemosiderosis is ground-glass opacity due to pulmonary hemorrhage.

(Left) Axial CECT of a 71-yearold man obtained 4 months following radiation therapy for lung adenocarcinoma demonstrates right lung consolidation ﬈, consistent with radiation pneumonitis, which typically occurs in the first 6 months after treatment. (Right) Axial CECT of the same patient demonstrates interval decrease in the size of the right lung consolidation ﬈ and new traction bronchiectasis ﬊, reflecting radiation fibrosis. Radiation pneumonitis typically begins to evolve into fibrosis 6 months following therapy.

(Left) Axial NECT of a patient with colon cancer shows subpleural reticular and ground-glass opacities ﬈ most pronounced in the lower lobes, reflecting pulmonary fibrosis from drug-induced lung disease. (Right) Axial NECT of a patient with druginduced lung disease shows subpleural and peripheral ground-glass opacities ﬈ representing organizing pneumonia. There are many imaging manifestations of drug-induced lung disease, and there is strong correlation between the imaging and histologic findings.

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Inhalational, Inflammatory, Metabolic, and Post Treatment

Spectrum of Aspiration-Related Disorders KEY FACTS

TERMINOLOGY • Aspiration-related disorders: Diseases resulting from aspiration of solid &/or liquid materials into airways and lungs ○ Aspiration pneumonia and pneumonitis ○ Foreign bodies: Most common endobronchial lesion in children; food particles (vegetables) and tooth fragments (elderly) ○ Exogenous lipoid pneumonia: Repeated aspiration or inhalation of oily substances ○ Diffuse aspiration bronchiolitis: Recurrent aspiration; typically elderly patients with neurologic disorders, dementia, or oropharyngeal dysphagia

IMAGING • Aspiration pneumonia and pneumonitis ○ Tree-in-bud opacities ○ Consolidations; may evolve into pneumonia or acute respiratory distress syndrome

(Left) AP chest radiograph of a patient who had an episode of massive aspiration during a seizure shows diffuse bilateral heterogeneous opacities. (Right) Axial CECT of the same patient shows a combination of ground-glass opacities and consolidations bilaterally. Note that there are denser consolidations in the dependent regions of the lungs, a finding frequently described in cases of aspiration. However, aspiration may also involve the nondependent regions of the lung when it is massive or due to patient's positioning.

(Left) Axial CECT of a patient with aspiration pneumonia shows multifocal, bilateral ground-glass opacities and nodular consolidations. While such abnormalities commonly affect the dependent areas of the lung, other areas may be involved due to the patient's position during aspiration episodes. (Right) Axial CECT of a 41-year-old patient with lipoid pneumonia shows a left lower lobe consolidation with intrinsic low attenuation due to macroscopic fat. The presence of fat attenuation on CT is an imaging hallmark of lipoid pneumonia.

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• Foreign bodies ○ May be overlooked depending on density ○ Distal lobar or lung atelectasis and airspace consolidation should be traced back to supplying airways • Lipoid pneumonia: Low attenuation (fat) in consolidation, may mimic lung cancer; may exhibit crazy-paving pattern • Diffuse aspiration bronchiolitis ○ Centrilobular nodules and "tree-in-bud" opacities ○ Bronchiectasis

CLINICAL ISSUES • Aspiration pneumonia: Fever, cough, and purulent sputum • Diffuse aspiration bronchiolitis: Esophageal disorders and neurologic impairment • Silent aspiration: 50% of anesthetized patients; may be asymptomatic

DIAGNOSTIC CHECKLIST • Gravity-dependent opacities should suggest aspiration

Spectrum of Aspiration-Related Disorders

Definitions • Aspiration-related disorders: Pulmonary diseases resulting from aspiration of solid &/or liquid materials into airways and lungs ○ Aspiration pneumonia – Pulmonary infection caused by aspiration of oropharyngeal secretions colonized by pathogenic bacteria – Usually manifests as community-acquired pneumonia (CAP) ○ Aspiration pneumonitis (Mendelson syndrome) – Acute lung injury caused by aspiration of sterile gastric contents • Specific aspiration syndromes ○ Foreign bodies: Most common endobronchial lesion in children; food particles (vegetables) and tooth fragments (elderly) – Most commonly lodge in mainstem and lobar bronchi ○ Aspiration of barium sulfate: Mild reaction in early phase due to inert character of barium – Radiopaque material within airways ("tree-in-bud") ○ Exogenous lipoid pneumonia: Repeated aspiration or inhalation of mineral oil or oily nose drops in adults and cod liver oil and milk in children ○ Near drowning: Pulmonary edema after acute aspiration of massive amounts of fresh or salt water – Combination of aspiration and noncardiogenic edema – Secondary pneumonia may occur depending on composition of aspirate ○ Hydrocarbon pneumonia: Accidental, intentional, or occupational aspiration of various toxic substances – Children: Furniture polish – Hydrocarbon containing fluid: Petroleum-based fluids – Flame swallowers (known as fire-eater pneumonia) ○ Diffuse aspiration bronchiolitis: Recurrent aspiration; typically elderly patients with neurologic disorders, dementia, or oropharyngeal dysphagia – Disseminated tree-in-bud opacities with patchy lobular consolidations – Lentil pneumonia: Subset of diffuse aspiration bronchiolitis; granulomatous pneumonitis caused by aspiration of leguminous material (e.g., lentils, beans, peas)

IMAGING General Features • Best diagnostic clue ○ No "gold standard" test to diagnose aspiration – Aspiration is generally not witnessed or subclinical ○ Gravity-dependent opacities ○ Radiopaque material in airway lumen – Solids &/or liquids – Foreign body • Location ○ Gravity-dependent locations; cough may enable dispersion to other areas

Radiographic Findings • Aspiration pneumonia and pneumonitis ○ Unilateral or bilateral consolidations in gravitydependent distribution – Supine position: Superior segments of lower lobes and posterior segments of upper lobes – Upright position: Basilar segments of lower lobes, right > left – Decubitus position: Axillary subsegments of upper lobes – Even large volume aspiration syndromes may be unilateral ○ Diffuse perihilar consolidation, more common with pneumonitis ○ Endotracheal or tracheostomy tubes do not protect from aspiration – Fluid may accumulate above endotracheal balloon, source of aspiration pneumonia ○ Acute aspiration pneumonitis may quickly evolve into acute respiratory distress syndrome (ARDS) ○ Untreated aspiration pneumonia often leads to necrotizing pneumonia and lung abscess ○ Chronic aspiration syndromes may lead to bronchiectasis ○ Recurrent: Multiple episodes, sometimes identical in appearance, may wax and wane over time ○ Variable resolution, depends on quantity and type of aspirate; nontoxic aspirate will clear within hours • Foreign body ○ Atelectasis: Lung, lobar, or segmental depending on size and location of foreign body ○ Hyperinflation and air-trapping more common in children

Inhalational, Inflammatory, Metabolic, and Post Treatment

TERMINOLOGY

CT Findings • Aspiration pneumonia and pneumonitis ○ Variable patterns that depend on quantity and quality of aspirate – Ground-glass opacities and consolidation □ Typically involve dependent lungs □ May evolve into pneumonia or ARDS – Tree-in-bud opacities from aspirated material in small airways – Bronchiectasis: May occur acutely depending on toxicity of aspirate – Interstitial fibrosis related to airspace injury • Foreign bodies ○ May be overlooked depending on density ○ Distal lobar or lung atelectasis and airspace consolidation should be traced back to supplying airways • Lipoid pneumonia: Low attenuation (fat) in consolidation, may simulate lung cancer; may exhibit crazy-paving pattern • Hydrocarbon pneumonia: Development of pneumatoceles in consolidated lung • Near drowning: Diffuse ground-glass or airspace opacities, reticular opacities, and centrilobular nodules; radiopaque "sand bronchogram" if sand (coral) is aspirated along with water • Diffuse aspiration bronchiolitis and granulomatous pneumonitis (lentil pneumonia): Centrilobular ill-defined nodules (foreign body granulomas) and tree-in-bud opacities, bronchiectasis 393

Inhalational, Inflammatory, Metabolic, and Post Treatment

Spectrum of Aspiration-Related Disorders Imaging Recommendations • Best imaging tool ○ CT more sensitive for airspace and airway abnormalities • Protocol advice ○ Maximum intensity projection reformations may optimize visualization of centrilobular nodules and treein-bud opacities ○ Lateral decubitus radiography to identify air-trapping related to aspirated foreign body in infants and young children ○ Esophagram for evaluation of motility and structural abnormalities

DIFFERENTIAL DIAGNOSIS Acute Aspiration • Pulmonary emboli ○ Common cause of acute respiratory distress in hospitalized patients ○ Infarcts often peripheral and associated with pleural effusion • Pulmonary edema ○ Cardiomegaly, often with bilateral pleural effusions ○ Kerley B lines uncommon with aspiration • ARDS ○ Identical radiographic findings

Chronic Aspiration • Endobronchial obstruction ○ Slow-growing endobronchial tumor (carcinoid) or chronic obstructing lesions (broncholithiasis) • Bronchiectasis and tree-in-bud opacities ○ Nontuberculous mycobacterial infection, bronchiectatic type – Elderly women with chronic cough; preferential middle lobe and lingula involvement

Recurrent Aspiration • Eosinophilic pneumonia • Cryptogenic organizing pneumonia ○ Typically peripheral and basilar in location

PATHOLOGY General Features • Etiology ○ Predisposing factors – Loss of consciousness – Alcoholism and drug overdose – Neuromuscular disorders and esophageal dysmotility ○ 50% of adults aspirate oropharyngeal secretions in sleep ○ Poor dentition increases bacterial load and risk of pneumonia – Cavitary mass in edentulous patient is more likely to represent lung cancer than lung abscess ○ Mendelson syndrome: pH < 2.5 and volume of gastric aspirate > 25 mL • Associated abnormalities ○ Hiatal hernia ○ Achalasia ○ Zenker diverticulum ○ Gastroesophageal reflux 394

• Epidemiology ○ 300,000-600,000 cases per year in USA ○ Foreign body aspiration more common in healthy infants and small children ○ Causative factor in 5-15% of cases of CAP

Microscopic Features • Aspiration pneumonia ○ Wide spectrum of injuries depending on aspirate – Bronchioles can be destroyed and replaced by acute inflammation and necrosis – Alveolar edema, hemorrhage, neutrophilic infiltration, and foreign body granulomas

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Aspiration pneumonia – Fever, cough, and purulent sputum □ Less common: Pleuritic chest pain and hemoptysis – Abrupt onset: After meat aspiration, mimics myocardial infarction ("café coronary syndrome") ○ Aspiration pneumonitis (Mendelson syndrome) – Nonspecific; range from asymptomatic to respiratory distress □ Pulmonary edema, hypotension, and hypoxemia □ Severe ARDS and death ○ Diffuse aspiration bronchiolitis – Usually associated with esophageal dysmotility, gastroesophageal reflux disease, and neurologic impairment – May mimic asthma ○ Silent aspiration: 50% of anesthetized patients, may be asymptomatic

Natural History & Prognosis • Up to 50% mortality for patients who develop ARDS from Mendelson syndrome

Treatment • Prevention ○ Drugs to reduce gastric pH, elevation of head of bed ○ Gastric suction with nasogastric tube (should be in gastric fundus where gastric secretions pool in supine position) • Postaspiration ○ Broad-spectrum antibiotics ○ Bronchoscopy to remove foreign bodies

DIAGNOSTIC CHECKLIST Image Interpretation Pearls • Gravity-dependent opacities should suggest aspiration

SELECTED REFERENCES 1. 2.

DiBardino DM et al: Aspiration pneumonia: a review of modern trends. J Crit Care. 30(1):40-8, 2015 Marik PE: Pulmonary aspiration syndromes. Curr Opin Pulm Med. 17(3):14854, 2011

Spectrum of Aspiration-Related Disorders Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Axial NECT of a patient with diffuse aspiration bronchiolitis shows numerous scattered small centrilobular nodules ﬈ and tree-in-bud opacities ﬊ in the basilar segments of the right lower lobe as well as mild bronchial wall thickening ﬉. (Right) High-power photomicrograph (H&E stain) of a specimen from the same patient shows a foreign body multinucleated giant cell, containing a central vegetable particle ﬊, and surrounding concentric fibrosis ﬈. This is a characteristic microscopic feature of lentil pneumonia.

(Left) PA chest radiograph of a patient with prior barium sulphate aspiration shows left worse than right high-density micronodular opacities ﬈ bilaterally. (Right) Axial CECT of a patient with neardrowning in freshwater shows diffuse bilateral ground-glass opacities and scattered centrilobular nodules ﬉. These findings often correlate with a combination of aspiration and noncardiogenic pulmonary edema. Thus ground-glass, reticular, and centrilobular nodular opacities are frequent CT abnormalities in affected patients.

(Left) Axial NECT of a patient with aspiration pneumonia shows bilateral cavitary nodules and consolidations ﬈ within the dependent aspects of the lower lobes. (Right) Axial CECT of a patient with a broncholith ﬈ lodged in the left mainstem bronchus and postobstructive pneumonia shows left lung volume loss and extensive airspace disease with intrinsic bronchiectasis. Foreign bodies in the central airways are frequently associated with chronic pneumonia.

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Lipoid Pneumonia KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Lipoid pneumonia (LP) • LP classified as exogenous or endogenous types based on etiology ○ Exogenous LP: Airspace disease resulting from aspiration of vegetable, animal, or mineral oils with scant or no acute inflammatory reaction ○ Endogenous LP: Airspace disease resulting from accumulation of secretions distal to bronchial obstruction

• • • • • •

IMAGING • CT ○ Consolidation or ground-glass opacities; pulmonary nodule or mass – Macroscopic fat attenuation – Crazy-paving pattern • FDG PET/CT: FDG avidity secondary to superimposed infection/inflammation

(Left) PA chest radiograph of a 43-year-old woman with exogenous lipoid pneumonia shows right upper and left mid lung ill-defined, spiculated, mass-like opacities ﬊. Lipoid pneumonia may mimic primary lung cancer. (Right) Coronal CECT of the same patient shows bilateral lung masses with intrinsic macroscopic fat attenuation. The presence of intrinsic macroscopic fat is the most specific imaging finding of lipoid pneumonia, although it can also be seen in other entities such as pulmonary hamartoma and liposarcoma pulmonary metastases.

(Left) Low-power photomicrograph (H&E stain) of a specimen from the same patient shows numerous "empty" fat droplets ﬈ separated by fibrous tissue and abundant lymphocytes and alveoli filled with foamy histiocytes ﬊. Foamy histiocytes occur within the alveoli and eventually migrate into the interstitium. (Right) High-power photomicrograph (Sudan black stain) of the same specimen confirms the presence of microscopic intraalveolar fat, which manifests as brown-staining areas ﬈.

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Pulmonary hamartoma Lipoma Liposarcoma Pulmonary alveolar proteinosis Lung cancer Pneumonia

PATHOLOGY • Mineral oil and vegetable-based oils tend to cause minimal to mild inflammatory reaction • Abnormalities relate to type, amount, frequency, and length of time of aspirated or inhaled oils or fats

CLINICAL ISSUES • Acute LP: Cough, dyspnea, and low-grade fever • Chronic LP: Often asymptomatic elderly patients • Treatment: Discontinuation of exposure to inciting agent; supportive care

Lipoid Pneumonia

Abbreviations • Lipoid pneumonia (LP)

Synonyms • Lipid pneumonia • Cholesterol pneumonia • Golden pneumonia

Definitions • LP classified as exogenous or endogenous types based on etiology • Exogenous LP: Airspace disease resulting from aspiration of vegetable, animal or mineral oils with scant or no acute inflammatory reaction ○ Acute LP: Uncommon and typically caused by episode of aspiration of large quantity of petroleum-based product ○ Chronic LP: Due to repeated episodes of aspiration or inhalation of animal fat, mineral or vegetable lipids over extended period of time • Endogenous LP: Airspace disease resulting from accumulation of secretions distal to bronchial obstruction ○ Often associated with non-small cell lung cancers; may occasionally be associated with pulmonary infection

IMAGING General Features • Best diagnostic clue ○ Consolidation with macroscopic areas of fat attenuation • Location ○ Lower lobes and middle lobe

Radiographic Findings • Radiography ○ Acute LP – Consolidation or ill-defined opacities □ Lobar or segmental, bilateral or unilateral – Middle &/or lower lobes – Potential complications: Pneumothorax and pneumomediastinum ○ Chronic LP – Consolidations involving the lower lobes &/or middle lobe – Nodule or mass

CT Findings • HRCT ○ Acute LP – Consolidation or ground-glass opacities □ Lower lobes &/or middle lobe □ Crazy-paving pattern: Ground-glass opacities on background of interlobular septal thickening – Complications: Pneumatocele, pneumothorax, and pneumomediastinum ○ Chronic LP – Consolidation or ground-glass opacities involving one or more pulmonary segments □ Lower lobe predominant involvement □ Consolidations may exhibit peribronchovascular distribution

□ Crazy-paving pattern – Intrinsic fat attenuation □ Superimposed inflammatory changes may obscure fat components – Nodule(s) mass(es) ± fat attenuation – Fibrosis □ Architectural distortion associated with consolidation □ Interlobular septal thickening or bronchiectasis • PET/CT ○ FDG avidity secondary to superimposed infection/inflammation

MR Findings • T1WI ○ High signal intensity consistent with lipid content

Imaging Recommendations • Best imaging tool ○ Thin-section CT/HRCT + clinical history (i.e., use, aspiration, or inhalation of oil-based material) • Protocol advice ○ Assessment for presence of fat attenuation on soft tissue window ○ Averaging of soft tissue and air may mimic fat attenuation

Inhalational, Inflammatory, Metabolic, and Post Treatment

TERMINOLOGY

DIFFERENTIAL DIAGNOSIS Pulmonary Hamartoma • Benign neoplasm, common cause of solitary pulmonary nodule • Circumscribed nodule or mass with smooth or lobulated margins • Variable size, most < 4 cm • Cartilage and fat are most prominent tissue components

Lipoma • Uncommon mesenchymal neoplasm originating from adipose tissue • Well-defined nodule or mass with homogeneous fat attenuation ○ Subpleural mass originating from chest wall adipose tissue (often erroneously referred to as pulmonary of pleural lipoma) ○ Endobronchial lipoma appear as fatty or soft tissue intrabronchial nodule

Liposarcoma • Well-differentiated liposarcoma represents most common type of soft tissue liposarcoma • Primary intra- or extrathoracic liposarcomas may metastasize to lungs ○ Well-differentiated liposarcoma metastases may contain variable amounts of fat ○ Multiple well-defined nodules with intrinsic fat attenuation

Pulmonary Alveolar Proteinosis • Rare lung disorder of unknown etiology characterized by alveolar accumulation of surfactant • Strong association with tobacco use; men 3x more frequently affected than women 397

Inhalational, Inflammatory, Metabolic, and Post Treatment

Lipoid Pneumonia • Bilateral central and symmetric opacities with ground-glass attenuation and crazy-paving pattern • Apices and lung bases relatively spared

Lung Cancer • Smokers; men more frequently affected than women • Mass, nodule, or mass-like consolidation • Associated intrathoracic lymphadenopathy may be present

Pneumonia • Acute onset; fever, cough, sputum production • Dense consolidations or ground-glass opacities without specific distribution

PATHOLOGY General Features • Diagnosis of exogenous lipoid pneumonia based on history of ingestion or inhalation of oils with consistent imaging findings • Bronchoalveolar lavage (BAL) or biopsy necessary in cases in which LP manifests as mass or nodule without fat attenuation • LP characterized by presence of intraalveolar foamy (lipidladen) macrophages • Mineral oil and vegetable oils tend to cause minimal to mild inflammatory reaction ○ Mineral oil is inert and may inhibit cough reflex and ciliary motility, thus promoting aspiration • Parenchymal abnormalities in LP depend on type, amount, frequency, and length of time of aspirated or inhaled oils or fats

Microscopic Features • Intraalveolar and interstitial foamy histiocytes • Fat droplets may coalesce in alveoli and become encapsulated by fibrous tissue, producing nodule or mass (paraffinoma) • Foreign body giant cell reaction may be present • Animal fats are hydrolyzed by lung lipases into free fatty acids that may cause severe inflammatory reaction manifesting as focal edema and intraalveolar hemorrhage; may progress to fibrosis

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Symptoms are often nonspecific ○ Acute LP – Cough, dyspnea, and low-grade fever ○ Chronic LP – Frequently asymptomatic – Chronic cough or dyspnea, fever, weight loss, chest pain, and hemoptysis ○ Exposure is often identified retrospectively after diagnosis – Directed questioning to elicit history • Other signs/symptoms ○ Superimposed infection may result in progression of pulmonary findings

Demographics • Age ○ Acute LP: Accidental exposure to oily material – Middle-aged patients ○ Chronic LP – Elderly patients • Epidemiology ○ Occupational exposure: Fire eaters, oil blasting industries, lubricants industry, cleaning oil-containing vats ○ Chronic use of oil-based traditional folk remedies in some cultures ○ Chronic use of laxatives by elderly ○ Predisposing factors: Mental retardation, cleft palate, anatomic or functional swallowing abnormality, Zenker diverticulum, hiatal hernia, gastroesophageal reflux, critically ill patients with nasoenteric feeding

Natural History & Prognosis • Natural history is variable and depends on amount, length of time, and type of aspirated or inhaled oil-based material • Acute LP may manifest radiologically within 30 minutes of aspiration or inhalation ○ Pulmonary opacities visible within 24 hours in most affected patients ○ Clinical and radiologic manifestations improve or resolve within a few weeks • Chronic LP ○ Clinical symptoms improve with cessation of exposure to oil-based substances ○ Radiologic abnormalities may improve slowly over time but typically remain stable even if exposure is discontinued

Treatment • Discontinuation of exposure to inciting agent • Supportive care

DIAGNOSTIC CHECKLIST Consider • LP in asymptomatic elderly patients with chronic lower lobe consolidations

Image Interpretation Pearls • LP may initially manifest as pulmonary mass or nodule without areas of fat attenuation and may be indistinguishable from primary lung cancer

Reporting Tips • Careful clinical history is important in order to identify possible source of aspirated or inhaled lipid material

SELECTED REFERENCES 1. 2. 3. 4. 5.

398

Rea G et al: Exogenous lipoid pneumonia (ELP): when radiologist makes the difference. Transl Med UniSa. 14:64-8, 2016 Byerley JS et al: Clinical approach to endogenous lipoid pneumonia. Clin Respir J. ePub, 2014 Marchiori E et al: Exogenous lipoid pneumonia. Clinical and radiological manifestations. Respir Med. 105(5):659-66, 2011 Betancourt SL et al: Lipoid pneumonia: spectrum of clinical and radiologic manifestations. AJR Am J Roentgenol. 194(1):103-9, 2010 Hadda V et al: Lipoid pneumonia: an overview. Expert Rev Respir Med. 4(6):799-807, 2010

Lipoid Pneumonia Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Axial CECT of a 41-yearold patient with lipoid pneumonia shows a left lower lobe consolidation with intrinsic low attenuation due to macroscopic fat. The presence of fat attenuation on CT is the imaging hallmark of lipoid pneumonia. (Right) Axial HRCT of a 37-year-old fire eater shows exogenous lipoid pneumonia manifesting as multifocal ground-glass opacities and superimposed reticular opacities (crazypaving pattern). This nonspecific and uncommon pattern has been described in cases of lipoid pneumonia.

(Left) Axial CECT of an asymptomatic 48-year-old man with lipoid pneumonia shows ground-glass opacities ﬈ in the middle lobe. (Right) Coronal CECT of the same patient shows multifocal, bilateral, lower lobe groundglass opacities ﬈. On further questioning, the patient disclosed a history of chronic use of oil-based nose drops. Ground-glass opacity is a nonspecific imaging finding, which has been identified in both acute and chronic exogenous lipoid pneumonia.

(Left) PA chest radiograph of a 68-year-old man with lipoid pneumonia shows a welldefined pulmonary nodule in the right mid lung zone ﬈ and bilateral lower lobe consolidations ﬊. (Right) Coronal CECT of the same patient shows the right lung nodule and a left lower lobe consolidation without appreciable intrinsic fat. The patient admitted to the chronic use of laxatives. The history of exposure to mineral oil is often identified retrospectively after the pathologic diagnosis of lipoid pneumonia is rendered.

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Inhalational Injury KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Inhalational injury (II): Caused by inhalation of smoke or chemical products of combustion, typically from accidental spill, explosion, or fire

• • • •

IMAGING • CT/HRCT ○ Airway edema: Tracheal and bronchial wall thickening, luminal narrowing ○ Acute respiratory distress syndrome (ARDS): Bilateral ground-glass opacities, consolidations, septal thickening; volume loss, reticular opacities, traction bronchiectasis/bronchiolectasis ○ Bronchitis/bronchiolitis: Bronchial wall thickening, centrilobular nodules, ground-glass opacities ○ Pneumonia: Patchy dense consolidations; segmental or lobar, unilateral or bilateral ○ Constrictive bronchiolitis: Mosaic attenuation pattern, expiratory air-trapping

(Left) AP chest radiograph of a 25-year-old man with a history of smoke inhalation 6 days previously shows patchy bilateral pulmonary opacities ﬈. (Right) Axial NECT of the same patient shows multifocal bilateral consolidations ﬈ and surrounding ground-glass opacities ﬊ with associated bronchial wall thickening ﬉. These findings are consistent with airway infection or inflammation. Pneumonia is a common complication in patients with inhalational injury and usually occurs approximately 1 week post exposure.

(Left) Axial CECT of a 31-yearold man with respiratory injury resulting from smoke inhalation shows bilateral bronchiectasis ﬊ and multifocal mosaic attenuation with areas of decreased attenuation and vascularity ﬈. (Right) Axial CECT of the same patient shows multifocal bilateral cystic and varicose bronchiectasis ﬈, scattered centrilobular micronodules ﬉, and mosaic attenuation. The findings are consistent with constrictive bronchiolitis, a rare manifestation of inhalational injury.

400

Asthma Aspiration pneumonitis Acute respiratory distress syndrome from other causes Hypersensitivity pneumonitis

PATHOLOGY • Heated air produces thermal injuries that usually affect upper airways • Chemical or smoke-related toxins and irritants usually affect both airways and lungs

CLINICAL ISSUES • Symptoms may develop within minutes or hours • Asymptomatic patients must be observed for at least 6 hours to evaluate for delayed onset of symptoms

DIAGNOSTIC CHECKLIST • Consider airway injury in patient with burns around nose and mouth, hoarseness, wheezing, &/or stridor

Inhalational Injury

Abbreviations • Inhalational injury (II)

Synonyms • Inhalation injury

Definitions • II results from inhalation of smoke or chemical products of combustion typically as result of accidental spill, explosion, or fire ○ Injury to lungs and airways produced by heat or local chemical irritation – Heated air usually produces injury to airway epithelium above carina – Smoke produces chemical injury due to release of toxins that produce damage of epithelial and capillary endothelial cells of lungs and airways – Chemical agents: Gases, aerosols, fumes, and dusts produce epithelial &/or capillary endothelial cell injury • II occurs more frequently in home environment than in workplace

IMAGING General Features • Best diagnostic clue ○ History of exposure, usually accidental • Location ○ Airways, lungs

Radiographic Findings • Radiography ○ Acute complications, within hours to days after exposure – Airway edema □ Narrowing of tracheal lumen – Acute respiratory distress syndrome (ARDS) (24-72 hours) □ Initial phase: Decreased lung volume, extensive bilateral consolidations and ground-glass opacities, air bronchograms; opacities may be patchy or diffuse, symmetric or asymmetric □ Fibroproliferative phase: Coarse reticular opacities, volume loss – Bronchitis/bronchiolitis (12-24 hours) □ Patchy opacities, bronchial wall thickening – Pneumonia (5-7 days) □ Most common complication, especially in cases of thermal injury □ Focal or diffuse opacities; unilateral or bilateral ○ Chronic pulmonary complications (weeks or months after exposure) – Constrictive bronchiolitis □ Hyperinflation, vascular attenuation – Organizing pneumonia □ Bilateral patchy consolidations with subpleural and lower lung zone predominance – Bronchiectasis: Tubular branching opacities, tramtrack opacities, ring shadows ○ Tracheal stenosis (months after exposure) – Concentric subglottic and tracheal narrowing

CT Findings • HRCT ○ Airway edema – Tracheal and bronchial wall thickening, luminal narrowing ○ ARDS – Extensive bilateral ground-glass opacities, consolidations, interlobular septal thickening – Volume loss, reticular opacities, traction bronchiectasis/bronchiolectasis ○ Bronchitis/bronchiolitis – Bronchial wall thickening, centrilobular nodules, ground-glass opacities; diffuse or peribronchiolar distribution ○ Pneumonia – Patchy dense consolidations; segmental or lobar, unilateral or bilateral ○ Constrictive bronchiolitis – Mosaic attenuation pattern (decreased attenuation and vascularity combined with areas of normal or increased attenuation and vascularity), expiratory airtrapping – Central and peripheral bronchiectasis, bronchial wall thickening ○ Organizing pneumonia – Dense consolidations, ground-glass opacities or nodules distributed along bronchovascular bundles or subpleural lung ○ Bronchiectasis – Dilated bronchi, mucous plugging, bronchial wall thickening

Inhalational, Inflammatory, Metabolic, and Post Treatment

TERMINOLOGY

Imaging Recommendations • Best imaging tool ○ HRCT • Protocol advice ○ Chest radiography may be normal ○ Expiratory HRCT is useful for detection of air-trapping related to constrictive bronchiolitis ○ Virtual bronchoscopy may be used to visualize and characterize airway narrowing

DIFFERENTIAL DIAGNOSIS Asthma • Children and young adults, clinical history of previous episodes • Bronchial wall thickening and narrowing • Bronchial dilatation, air-trapping, centrilobular nodules

Aspiration Pneumonia • Associated with altered or reduced consciousness (alcoholism, stroke, drug overdose) • Acute onset or abrupt development of symptoms within few minutes to 2 hours of aspiration event • Consolidation of posterior segments of upper lobes and superior segments of lower lobes

Acute Respiratory Distress Syndrome Secondary to Other Causes • Correlation with clinical history 401

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Inhalational Injury

• Abrupt onset of symptoms within few hours after heavy antigen exposure in previously sensitized patient • Diffuse bilateral ground-glass opacities resembling pulmonary edema • Numerous poorly defined small (< 5 mm) ground-glass nodules

PATHOLOGY General Features • Etiology ○ Inhalation of thermal or chemical irritants, most commonly in metal, chemical, and mining industries or in cases of exposure to accidental fires ○ Chemical irritants and products of fires and combustion produce acute II (chlorine, ammonia, hydrogen sulfide, sulfur dioxide) – Water solubility and particle size determine site of injury – High water solubility: Ammonia (fertilizers, plastics, pesticides, home cleaning products), sulfur dioxide (chemical manufacture, power plants), formaldehyde (textile industry, automobile industry), and hydrogen sulfide (mining industries, petroleum industry, sewers, and barns) – Intermediate solubility: Chlorine (disinfectant for drinking water and swimming pools) – Low solubility: Phosgene (paint removers, solvents, dry cleaning products, insecticides, plastics, and pharmaceuticals), mustard gas (chemical warfare agent), and oxides of nitrogen (fertilizers and production of explosives) ○ Carbon monoxide is nonirritating gas produced by incomplete combustion at scene of fires – Displaces oxygen from hemoglobin

Staging, Grading, & Classification • Highly soluble gas (ammonia, sulfur dioxide) and agents with particle diameters > 10 μm are absorbed in upper respiratory tract, causing rapid development of upper way irritation • Less soluble gases (nitrogen dioxide) and smaller particles (1-5 μm) reach lower respiratory tract producing delayed respiratory symptoms and alveolar damage • Agents with intermediate solubility and particle diameters > 5 μm and < 10 μm cause symptoms of early irritation but may also cause delayed symptoms • Extension of injury affected by several factors: Duration of exposure, concentration of inhaled toxins, and individual patient factors, such as age, history of smoking, and underlying debilitating disease

Gross Pathologic & Surgical Features • Heated air produces thermal injury that usually involves upper airway ○ Massive swelling → obstruction • Chemical or smoke-related toxins and irritants usually affect both airways and lungs ○ Damage of epithelial and capillary endothelial cells → surfactant loss → alveolar collapse and atelectasis

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○ Activated macrophages → inflammatory changes in airways → severe edema → necrotizing bronchitis

Hypersensitivity Pneumonitis

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Cough, wheezing, &/or stridor associated with cutaneous burns around nose and mouth; eye irritation – Symptoms may have delayed onset ○ Persistent respiratory symptoms in patients that develop chronic complications • Other signs/symptoms ○ Hypoxic injury, nervous system damage, and death in cases of carbon monoxide inhalation

Demographics • Exposure may be occupational or accidental (house fires) ○ Accidental occupational exposures occur most commonly in metal and mining industries

Natural History & Prognosis • Symptoms may develop within minutes or hours after exposure depending on water solubility of agent and particle size • Asymptomatic patients must be observed for at least 6 hours to evaluate for delayed onset of symptoms • Pneumonia has been reported to occur in 10-20% of patients with II associated with burns • Constrictive bronchiolitis, organizing pneumonia, and bronchiectasis are rare complications that usually develop weeks or months after exposure

Diagnosis • Bronchoscopy is standard of care for diagnosis of airway II; injury scores are based on bronchoscopic findings

Treatment • Respiratory support, bronchodilators to improve airflow, antibiotics

DIAGNOSTIC CHECKLIST Consider • Airway injury in patient with cutaneous burns around nose and mouth, hoarseness, wheezing, &/or stridor

Reporting Tips • Development of pulmonary opacities in patient with respiratory symptoms 24 hours after inhalational exposure should suggest ARDS

SELECTED REFERENCES 1. 2. 3.

4.

Akira M et al: Acute and subacute chemical-induced lung injuries: HRCT findings. Eur J Radiol. 83(8):1461-9, 2014 Dries DJ et al: Inhalation injury: epidemiology, pathology, treatment strategies. Scand J Trauma Resusc Emerg Med. 21:31, 2013 Oh JS et al: Admission chest CT complements fiberoptic bronchoscopy in prediction of adverse outcomes in thermally injured patients. J Burn Care Res. 33(4):532-8, 2012 Reske A et al: Computed tomography--a possible aid in the diagnosis of smoke inhalation injury? Acta Anaesthesiol Scand. 49(2):257-60, 2005

Inhalational Injury Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Axial CECT of a 45-yearold man with antecedent accidental inhalation of pesticides 4 months previously shows bilateral peripheral subpleural nodular consolidations ﬈ with spiculated borders. (Right) Axial CECT of the same patient shows multifocal bilateral subpleural nodular consolidations ﬈ consistent with organizing pneumonia. Chronic pulmonary complications after inhalational injury affect < 10% of all exposed victims

(Left) Axial CECT of a 63-yearold man with inhalational injury secondary to ammonia exposure 8 months previously demonstrates mild middle and lower lobe bronchiectasis ﬈. (Right) Axial CECT of the same patient shows mild bilateral lower lobe bronchiectasis ﬈. Bronchiectasis associated with inhalational injury may exhibit clinical and radiologic features identical to those of bronchiectasis secondary to other disease processes.

(Left) Axial HRCT of a 51-yearold military man with a history of exposure to toxic fumes from burning pits shows minimal bilateral lower lobe bronchial wall thickening ﬈. (Right) Axial expiratory HRCT of the same patient demonstrates bilateral expiratory air-trapping ﬊ consistent with constrictive bronchiolitis. Patients with constrictive bronchiolitis may present with progressive dyspnea, which may begin months or years after the inhalational injury.

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Sarcoidosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Sarcoidosis: Systemic chronic granulomatous disease characterized by noncaseating granulomas in multiple organs ○ Lung and mediastinum involved in over 90% of cases

• • • •

IMAGING

PATHOLOGY

• CT/HRCT ○ Bilateral hilar lymphadenopathy and right paratracheal lymphadenopathy in up to 95% of patients • HRCT ○ Bilateral perilymphatic micronodules (75-90%) ○ Pulmonary nodules and masses (20%) ○ Solitary nodule or mass (rare) ○ Alveolar opacities (10-20%) ○ Ground-glass opacities (40%) ○ Pulmonary fibrosis (20%) – Upper lobe-predominant reticular opacities, traction bronchiectasis, architectural distortion, volume loss

• Diagnosis based on histologic demonstration of noncaseating granulomas + compatible clinical, laboratory, and imaging findings

(Left) PA chest radiograph of a 27-year-old man with sarcoidosis shows bilateral hilar ﬈, right paratracheal ﬉, and aortopulmonary window ﬊ lymphadenopathy. (Right) Composite image with axial CECT of the same patient shows bilateral symmetric hilar ﬈, paratracheal ﬉, and subcarinal ﬊ lymphadenopathy. Although these are classic demographic, radiographic, and CT findings, sarcoidosis is always a diagnosis of exclusion that requires correlation of clinical, imaging, laboratory, and histologic findings.

(Left) PA chest radiograph of a patient with sarcoidosis shows diffuse bilateral reticulonodular opacities slightly more coalescent toward the hila (peribronchovascular distribution). (Right) Coronal CECT of the same patient shows perilymphatic distribution of profuse peribronchovascular micronodules ﬈, which are also located along the subpleural interstitium. The distribution of micronodules is typical of sarcoidosis but may occur in other perilymphatic processes.

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Silicosis Berylliosis Lymphangitic carcinomatosis Lymphoma

CLINICAL ISSUES • Demographics: Adults < 40 years; peak age 20-29 years • Symptoms and signs ○ Asymptomatic, cough, dyspnea, fatigue

DIAGNOSTIC CHECKLIST • Consider sarcoidosis in patients < 40 years with minimal symptoms and bilateral hilar/mediastinal lymphadenopathy

Sarcoidosis

Synonyms • Sarcoid

•

Definitions • Systemic chronic granulomatous disease characterized by noncaseating granulomas in multiple organs • Lung, hilum, and mediastinum affected in > 90% of patients ○ Greatest morbidity/mortality from thoracic involvement ○ Chronic lung disease in 20% of affected patients

IMAGING

•

General Features • Best diagnostic clue ○ Bilateral hilar and right paratracheal lymphadenopathy in up to 95% of cases • Location ○ Lymphadenopathy: Bilateral hilar (most common) ○ Lung: Upper lung zones • Morphology ○ Lymph node calcification; ↑ incidence with ↑ disease duration

Radiographic Findings

•

•

□ Cavitary nodules or masses (ischemic necrosis or angiitis) ○ Solitary nodule or mass (rare) Consolidations and ground-glass opacities ○ Consolidations (10-20%) – Consolidation secondary to confluent micronodules compressing alveoli – Bilateral, symmetric, may exhibit air bronchograms □ Upper lobe predominance ○ Ground-glass opacities (40%) – Patchy or extensive consolidation – Usually associated with micronodules Small airways disease ○ Mosaic attenuation and air-trapping may occur with small airways involvement Fibrosis ○ Pulmonary fibrosis – Upper lobe-predominant reticular opacities, traction bronchiectasis, architectural distortion, volume loss – Confluent mass-like opacities may mimic progressive massive fibrosis – Peribronchovascular honeycombing – Enlarged pulmonary arteries Other findings ○ Mycetoma formation – Fungus balls in preexisting bullae or cysts ○ Pericardial involvement: Typically pericardial effusion ○ Pulmonary trunk enlargement in pulmonary hypertension

• Radiography ○ Bilateral hilar and symmetric mediastinal lymphadenopathy ○ Multifocal bilateral micronodules, upper lung zone predominant ○ Multifocal large nodules, masses, and mass-like consolidations: Nummular or alveolar sarcoid ○ Fibrosis: Upper lung zone predominant reticular opacities, architectural distortion, volume loss – Mass-like lesions mimic progressive massive fibrosis ○ Pleural effusion is rare

MR Findings

CT Findings

Nuclear Medicine Findings

• Lymphadenopathy ○ Bilateral, symmetric: Hilar, paratracheal, aortopulmonary window, subcarinal lymphadenopathy ○ Lymph node calcification (20% at diagnosis) – Popcorn, amorphous, punctate or eggshell ○ Atypical lymphadenopathy: Asymmetric mediastinal, unilateral hilar, internal mammary, paravertebral, retrocrural (unilateral lymphadenopathy in 5% of cases) • Nodules and masses ○ Bilateral perilymphatic micronodules (75-90%) – Perilymphatic: Peribronchovascular + subpleural interstitium + interlobular septa – Upper lobe predominance – Rounded or long clusters of small nodules, close but not confluent: Sarcoid cluster sign ○ Pulmonary nodules and masses (20%) – Multiple parenchymal nodules and masses – Peripheral and perihilar distribution – Pulmonary nodules or masses may exhibit air bronchograms (5-10%) □ Often referred to as nummular sarcoidosis □ Central mass or large nodules surrounded by small satellite nodules: Galaxy sign

• Ga-67 scintigraphy ○ Panda sign refers to bilateral uptake by lacrimal and parotid glands with normal uptake by nasopharyngeal mucosa ○ Lambda sign refers to uptake by right paratracheal and bilateral hilar lymph nodes • PET/CT ○ FDG uptake in active disease

Inhalational, Inflammatory, Metabolic, and Post Treatment

TERMINOLOGY

• Optimal imaging modality for assessing cardiac involvement • T1WI C+ ○ Localized or patchy ventricular enhancement ○ Diffuse subepicardial enhancement

Imaging Recommendations • Best imaging tool ○ Chest radiography is useful for initial evaluation • Protocol advice ○ HRCT – Identification and characterization of micronodules, nodules, and fibrosis

DIFFERENTIAL DIAGNOSIS Silicosis • Silica exposure • Centrilobular and subpleural micronodules; may calcify • Conglomerate nodules and masses in upper lobe posterior segments 405

Inhalational, Inflammatory, Metabolic, and Post Treatment

Sarcoidosis Staging of Sarcoidosis Based on Chest Radiography Stage

Radiographic Abnormalities

Stage 0

Normal

Stage 1

Lymphadenopathy

Stage 2

Lymphadenopathy and pulmonary abnormalities

Stage 3

Pulmonary abnormalities

Stage 4

Pulmonary fibrosis

• Hilar/mediastinal lymph nodes ± eggshell calcification

Demographics

Berylliosis

• Age ○ Young adults, usually < 40 years ○ Peak age: 20-29 years • Gender ○ M:F = 1:2 • Ethnicity ○ Higher prevalence in African Americans than in other demographic groups

• Exposure to beryllium • Mediastinal and hilar lymphadenopathy; less common than in sarcoidosis • Bilateral, peribronchovascular, interlobar, and subpleural micronodules

Lymphangitic Carcinomatosis • Clinical history of malignancy • Smooth or irregular bronchovascular and interlobular septal thickening • Unilateral or bilateral

Lymphoma • Multicompartment mediastinal and hilar lymphadenopathy (often bulky) • Micronodules are uncommon

PATHOLOGY General Features • Etiology ○ Immune-mediated disease – Postulated antigenic stimulation that triggers inflammatory response – CD4(+) T cells that interact with antigen-presenting cells to initiate formation and maintenance of granulomas • Diagnosis based on histologic demonstration of noncaseating granulomas + compatible clinical, laboratory, and imaging findings

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Asymptomatic ○ Cough, dyspnea, fatigue, night sweats, weight loss ○ Ocular involvement ○ Cutaneous involvement: Erythema nodosum, lupus pernio • Other signs/symptoms ○ Löfgren syndrome (acute presentation) – Fever, erythema nodosum, polyarticular arthralgia, bilateral hilar lymphadenopathy ○ Heerfordt syndrome – Fever, parotid enlargement, facial palsy, anterior uveitis

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Natural History & Prognosis • Patients often present with bilateral hilar lymphadenopathy, pulmonary opacities, and involvement of eyes, skin, and joints • Most patients go into remission or remain stable within a decade of initial diagnosis ○ Up to 20% of patients develop chronic disease and pulmonary fibrosis ○ Sarcoidosis characterized by periods of remission and recurrence • Factors associated with poor prognosis: Advanced age, stage 2 or 3 at initial diagnosis, extrapulmonary disease, pulmonary hypertension

Treatment • Stable or improved symptoms with corticosteroid therapy • Infliximab for refractory sarcoidosis

DIAGNOSTIC CHECKLIST Consider • Sarcoidosis in patients < 40 years with minimal symptoms and bilateral hilar and mediastinal lymphadenopathy

Image Interpretation Pearls • Architectural distortion, traction bronchiectasis, and honeycombing indicate irreversible pulmonary fibrosis

Reporting Tips • Sarcoidosis is diagnosis of exclusion • Imaging stage at presentation correlates with prognosis

SELECTED REFERENCES 1. 2. 3. 4.

Tavana S et al: Pulmonary and extra-pulmonary manifestations of sarcoidosis. Niger Med J. 56(4):258-62, 2015 Al-Jahdali H et al: Atypical radiological manifestations of thoracic sarcoidosis: a review and pictorial essay. Ann Thorac Med. 8(4):186-96, 2013 Nunes H et al: Imaging of sarcoidosis of the airways and lung parenchyma and correlation with lung function. Eur Respir J. 40(3):750-65, 2012 Hawtin KE et al: Pulmonary sarcoidosis: the 'Great Pretender'. Clin Radiol. 65(8):642-50, 2010

Sarcoidosis Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Coronal CECT of a patient with sarcoidosis shows bilateral perihilar mass-like opacities and perilymphatic micronodules along interlobular septa ﬉, bronchovascular bundles ﬊, and subpleural regions ﬈. (Right) Low-power photomicrograph (H&E stain) of a specimen of sarcoidosis shows multiple nodular nonnecrotizing interstitial epithelioid granulomas ﬉ along bronchovascular bundles ﬈, consistent with a perilymphatic distribution of disease. (From DP: Thoracic, 2e.)

(Left) PA chest radiograph of a patient with sarcoidosis shows profuse bilateral pulmonary micronodules and some larger pulmonary nodules ﬈. (Right) Coronal NECT of the same patient shows profuse bilateral irregular nodules and micronodules involving both lungs. Although sarcoidosis often exhibits a characteristic perilymphatic distribution, disease profusion may make it difficult to differentiate perilymphatic micronodules from random or centrilobular nodules typical of metastases or infection, respectively.

(Left) Axial NECT of a patient with sarcoidosis shows a discrete right upper lobe pulmonary nodule ﬉ with an intrinsic air bronchogram and subtle surrounding perilymphatic micronodules (i.e., the galaxy sign) that produce a slightly spiculated margin. (Right) Axial NECT of the same patient shows a similar nodule ﬉ in the right lower lobe. The surrounding perilymphatic micronodules produce an appearance of spiculation. Such nodules are consistent with so-called alveolar or nummular sarcoidosis.

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Sarcoidosis

(Left) Axial CECT of a patient with sarcoidosis shows a dominant spiculated part-solid nodule ﬈ in the posterior segment of the right lower lobe and mediastinal lymphadenopathy ﬉. Solitary nodules are atypical manifestations that should raise the possibility of primary lung cancer. (Right) Axial HRCT of a patient with sarcoidosis shows extensive mosaic attenuation and bilateral hilar ﬈ and mediastinal lymphadenopathy ﬉. Sarcoidosis may involve the small airways and produce air-trapping.

(Left) PA chest radiograph of a patient with stage 4 sarcoidosis shows bilateral upper lobe architectural distortion and volume loss. (Right) Axial HRCT of the same patient shows peribronchovascular architectural distortion, traction bronchiectasis, posterior hilar retraction, and coalescent opacities that mimic progressive massive fibrosis. This appearance is characteristic of end-stage sarcoidosis but may also occur in cluster 2 hypersensitivity pneumonitis and silicosis.

(Left) PA chest radiograph of a patient with end-stage sarcoidosis who presented with hemoptysis shows asymmetric, right-worse-thanleft fibrosis and a right upper lobe mass ﬊ surrounded by crescentic lucency ﬈. The findings are consistent with saprophytic aspergillosis. (Right) Axial NECT of the same patient shows a right upper lobe aspergilloma ﬊ manifesting as a soft tissue mass with intrinsic lucency surrounded by a nondependent crescent of air ﬈. Note bilateral upper lobe fibrosis ﬉.

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Sarcoidosis Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Axial CECT of a patient with end-stage sarcoidosis shows bilateral upper lobe predominant architectural distortion, spiculated perihilar mass-like lesions, and scattered perilymphatic nodules. (Right) Low-power photomicrograph (H&E stain) of a specimen of sarcoidosis shows confluent granulomas forming a large nodular mass ﬈ that could mimic malignancy on imaging. Fibrotic mass-like sarcoid lesions may also mimic progressive massive fibrosis. (From DP: Thoracic, 2e.)

(Left) Axial HRCT of a patient with end-stage sarcoidosis shows upper lung zone and peribronchovascular reticulation and honeycombing ﬉. The distribution of disease differs from that of usual interstitial pneumonia in which fibrosis is basilar and subpleural. (Right) Axial CECT shows end-stage sarcoidosis manifesting with perihilar masses with cavitation or cystic change ﬈ and a small left pneumothorax ﬉. Cavitation is uncommon but may result from necrosis or angiitis.

(Left) Axial-fused FDG PET/CT of a patient with sarcoidosis shows typical distribution of FDG avidity in bilateral hilar and subcarinal lymph nodes. Sarcoidosis lesions typically exhibit FDG avidity and gallium uptake. (Right) Coronal FDG PET of a patient with sarcoidosis shows bilateral hilar, right paratracheal, and subcarinal lymphadenopathy manifesting with FDG avidity. The distribution of lymphadenopathy is characteristic of sarcoidosis, but the diagnosis remains one of exclusion.

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Histiocytic Disorders KEY FACTS

TERMINOLOGY • Pulmonary Langerhans cell histiocytosis (PLCH): Isolated form of Langerhans cell histiocytosis (LCH) in smokers; characterized by granulomatous and Langerhans cell infiltration of distal bronchial walls • Erdheim-Chester disease (ECD): Non-LCH dendritic cell disorder characterized by xanthomatous infiltration of involved tissues by foamy histiocytes • Rosai-Dorfman disease (RDD) (sinus histiocytosis with massive lymphadenopathy): Nonmalignant proliferation of histiocytic &/or phagocytic cells

IMAGING • CT/HRCT ○ PLCH – Early-stage disease: Small centrilobular stellate nodules ± cavitation – Late-stage disease: Cysts (thin- or thick-walled, bizarre shapes, and variable sizes)

(Left) Axial HRCT of a patient with pulmonary Langerhans cell histiocytosis shows irregular pulmonary nodules ﬈, many of which exhibit cavitation or cysts with bizarre shapes ﬊. Note that solid and cavitary nodules spare the subpleural lung indicating their centrilobular distribution. (Right) Axial HRCT of a 40-year-old woman with pulmonary Langerhans cell histiocytosis shows centrilobular micronodules ﬈. In early-stage disease, lung nodules may be completely solid but tend to cavitate as they increase in size.

(Left) Low-power photomicrograph (H&E stain) of a specimen of Langerhans cell histiocytosis shows a nodular cellular infiltrate ﬈ adjacent to relatively normal lung ﬉. These cellular infiltrates are typically distributed along small airways (i.e., bronchioles and alveolar ducts), which correlates with their centrilobular distribution on CT. (Right) High-power photomicrograph (H&E stain) of the same specimen shows sheets of Langerhans cells ﬈ with round or ovoid nuclei amid mature eosinophils ﬉.

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○ ECD – Interlobular septal thickening (32%) – Centrilobular micronodules (21%) ○ RDD – Pulmonary nodules – Perilymphatic thickening – Mediastinal lymphadenopathy

TOP DIFFERENTIAL DIAGNOSES • PLCH ○ Early: Miliary tuberculosis, sarcoidosis, metastases ○ Late: Lymphangioleiomyomatosis, lymphoid interstitial pneumonia • ECD: Lymphoma, lymphangitic carcinomatosis • RDD: Atypical infection, lymphoma, metastases

PATHOLOGY • Accumulation of macrophages, dendritic cells, or monocyte-derived cells in various tissues and organs

Histiocytic Disorders

Abbreviations • Pulmonary Langerhans cell histiocytosis (PLCH) ○ Langerhans cell histiocytosis (LCH) • Erdheim-Chester disease (ECD) • Rosai-Dorfman disease (RDD)

Synonyms • RDD: Sinus histiocytosis with massive lymphadenopathy

Definitions • Rare disorders characterized by accumulation of macrophages, dendritic cells, or monocyte-derived cells in various tissues and organs • PLCH: Isolated form of LCH occurring in smokers characterized by granulomatous infiltration of distal bronchial walls with cells derived from myeloid dendritic cells (i.e., Langerhans cells) • ECD: Non-LCH dendritic cell disorder characterized by xanthomatous infiltration of involved tissues by foamy histiocytes • RDD: Nonmalignant proliferation of histiocytic &/or phagocytic cells

IMAGING Radiographic Findings • PLCH: Nonspecific reticular opacities • RDD: Basilar predominant reticular opacities without honeycombing

CT Findings • CT/HRCT ○ PLCH – Most common lung findings □ Early-stage disease: Nodules (centrilobular, 1-10 mm, stellate morphology, ± cavitation) □ Late-stage disease: Cysts (thin or thick nodular walls, bizarre or irregular shapes, variable sizes related to cyst coalescence) □ Mid and upper lung predominance with sparing of lung bases (near costophrenic angles) – Less common lung findings □ Large nodules (> 10 mm) □ Centrilobular emphysema □ Ground-glass opacities □ Linear opacities – Other abnormalities □ Pneumothorax □ Lymphadenopathy □ Pulmonary hypertension (i.e., dilated pulmonary trunk) ○ ECD – Most common lung findings □ Interlobular septal thickening (32%) □ Centrilobular micronodules (21%) – Less common lung findings □ Ground-glass opacities (12%) □ Consolidation (9%) □ Small cysts (6%); associated bronchial distortion □ Upper lobe-predominant thin-walled cysts (6%)

– Other findings □ Pleural thickening (24%), effusion (21%) □ Thickened interlobar fissures □ Pericardial thickening &/or effusion □ Circumferential periaortic soft tissue (coated aorta) □ Symmetric perirenal infiltration ○ RDD – Lung findings □ Pulmonary nodules □ Perilymphatic thickening (peripheral and basilar predominance) □ Solitary or multiple polypoid tracheobronchial nodules/masses – Other findings □ Lymphadenopathy (cervical, mediastinal, retroperitoneal, axillary, or inguinal) □ Pleural effusion □ Enhancing polypoid masses or diffuse thickening of sinus mucosa □ Extraconal (orbital) soft tissue mass □ Epidural or subdural lesions (may be confused with meningioma) • Bone CT ○ PLCH – Lytic osseous lesions □ May affect long bone diaphysis and metaphysis □ Skull: Punched-out lesions □ Vertebra plana □ "Floating teeth" ○ ECD: Metadiaphyseal patchy medullary osteosclerosis in long bones with epiphyseal sparing ○ RDD: Multicentric lytic osseous lesions

Inhalational, Inflammatory, Metabolic, and Post Treatment

TERMINOLOGY

DIFFERENTIAL DIAGNOSIS Pulmonary Langerhans Cell Histiocytosis • Early stage ○ Miliary tuberculosis ○ Sarcoidosis ○ Silicosis ○ Metastatic disease • Late stage ○ Lymphangioleiomyomatosis ○ Lymphoid interstitial pneumonia ○ Hypersensitivity pneumonitis ○ Centrilobular emphysema ○ Amyloidosis

Erdheim-Chester Disease • • • • •

Lymphoma Lymphangitic carcinomatosis Amyloidosis Sarcoidosis Pulmonary edema

Rosai-Dorfman Disease • • • •

Atypical chronic infections (mycobacterial or fungal) Low-grade lymphoma Immunoglobulin G4-related interstitial lung disease Metastatic disease 411

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Histiocytic Disorders

General Features • Histiocytes are macrophages residing in tissue • Dendritic cells, monocytes, and macrophages are cells of mononuclear phagocyte system • PLCH ○ Lung involvement in 10% of all cases of LCH ○ Lung involvement may occur in isolation or as part of systemic disease ○ Lung is most commonly involved organ in young adults; often only affected organ ○ Pediatric PLCH is rare, usually component of multisystem disease • ECD ○ Symmetric bilateral osteosclerosis of long bone metaphyses and diaphyses ○ Extraskeletal disease (50%) – CNS, lung, cardiovascular system, retroperitoneum, kidney, adrenal gland, skeletal muscle – Pulmonary involvement (20-53%) with perilymphatic distribution (interlobular septa, peribronchovascular and subpleural interstitium) • RDD ○ Painless lymphadenopathy ○ Extranodal disease (20-40%) – Skin, bone, paranasal sinuses, orbits, kidney, and lung – Pulmonary involvement (2-3% of patients with extranodal disease)

Microscopic Features • PLCH ○ Proliferation of Langerhans cells and histiocytes admixed with inflammatory cells and numerous eosinophils ○ Langerhans cells stain positive with S100 and CD1a ○ Langerhans cells exhibit distinctive Birbeck granules on electron microscopy ○ Cellular, intermediate, and fibrotic parenchymal nodules ○ Necrosis or cavitation • ECD ○ Diffuse infiltration by histiocytes with abundant foamy and eosinophilic cytoplasm ○ Multinucleated histiocytes ○ Histiocytes do not stain with periodic acid-Schiff (PAS) ○ Immunochemistry: Stain positive for CD68 and factor XIIIa • RDD ○ Diffuse proliferation of large histiocytes admixed with inflammatory T cells ○ Emperipolesis (histiocytes engulfing lymphocytes) ○ Histiocytes stain strongly for S100 and CD68 but stain negative for CD1a

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ PLCH – Dyspnea, nonproductive cough, fever, malaise, weight loss, hemoptysis – 1/4 asymptomatic 412

○ ECD – Clinical manifestations depend on organ(s) involved – Bone pain (95%) – Diabetes insipidus (CNS involvement) – Exophthalmos – Heart failure ○ RDD – Painless cervical lymphadenopathy – Fever – Elevated erythrocyte sedimentation rate – Mild anemia

PATHOLOGY

Demographics • PLCH ○ Young adults; no gender predilection ○ Occurs almost exclusively in smokers • ECD ○ Middle-aged and older adults • RDD ○ Children and young adults

Natural History & Prognosis • PLCH ○ Stable clinical course (50%), spontaneous regression regardless of smoking cessation (25%), progressive disease despite smoking cessation (25%) • ECD ○ Variable clinical course – Stable to rapidly progressive and fatal disease – Neurologic, pulmonary, and cardiac involvement denote poor prognosis • RDD ○ Overall good prognosis

Treatment • PLCH ○ Smoking cessation ○ Corticosteroids, chemotherapy • ECD ○ Interferon therapy, chemotherapy • RDD ○ 50% of patients do not require therapy ○ Corticosteroids, α-interferon

DIAGNOSTIC CHECKLIST Consider • PLCH in young smokers with upper lung zone-predominant nodules, cysts, or cavitary nodules • ECD in cases of long bone metadiaphyseal patchy sclerosis with diffuse interlobular septal and fissural thickening • RDD in patients with painless lymphadenopathy and pulmonary/airway abnormalities

SELECTED REFERENCES 1. 2. 3.

Vargas D et al: Cardiothoracic manifestations of primary histiocytoses. Br J Radiol. 89(1068):20160347, 2016 Ahuja J et al: Histiocytic disorders of the chest: imaging findings. Radiographics. 35(2):357-70, 2015 Antunes C et al: Thoracic, abdominal and musculoskeletal involvement in Erdheim-Chester disease: CT, MR and PET imaging findings. Insights Imaging. 5(4):473-82, 2014

Histiocytic Disorders Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) PA chest radiograph of a 22-year-old female smoker with pulmonary Langerhans cell histiocytosis who presented with chest pain and dyspnea shows diffuse bilateral upper lung predominant reticular opacities ﬈. (Right) Axial CECT of the same patient shows markedly irregular thinwalled cysts ﬈ that coalesce to form larger cysts with bizarre shapes ﬊. Advanced disease may be difficult to differentiate from advanced confluent centrilobular emphysema or other cystic lung diseases.

(Left) Coronal CECT of the same patient shows multifocal bilateral cystic lesions, some with bizarre shapes ﬊ that exhibit a distinctive upper lobe predominance with relative sparing of the lung bases. (Right) Low-power photomicrograph (H&E stain) of a specimen of end-stage pulmonary Langerhans cell histiocytosis shows hyalinized stellate scars ﬉ that often lack residual Langerhans cells and are typically distributed along small airways (i.e., bronchioles and alveolar ducts). These lesions correlate with stellate nodules on CT.

(Left) AP shoulder radiograph of a young smoker with pulmonary Langerhans cell histiocytosis shows a welldefined lytic lesion of the distal right clavicle ﬉ with cortical disruption and periosteal reaction. Note a subtle right upper lobe cyst ﬈. Lytic bone lesions may occur in affected patients, may be asymptomatic, or may be associated with localized bone pain. (Right) Coronal NECT of the same patient shows bilateral upper lobe cysts with mildly nodular cyst walls ﬈. Note absence of basilar lung involvement.

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Histiocytic Disorders

(Left) Axial NECT of a patient with pulmonary Langerhans cell histiocytosis shows a right upper lobe solitary spiculated nodule ﬈ with a small intrinsic cavity. (Right) Coronal fused FDG PET/CT of the same patient shows increased FDG uptake in the right upper lobe nodule ﬈. In the absence of other findings to suggest pulmonary Langerhans cell histiocytosis, the imaging appearance of this lesion simulates that of primary lung cancer, both on CT and on FDG PET/CT. The final diagnosis was only made after sublobar pulmonary resection.

(Left) Axial HRCT of a patient with Erdheim-Chester disease shows innumerable ill-defined ground-glass centrilobular nodules, scattered interlobular septal thickening ﬈, and a few small pulmonary cysts ﬉. (Courtesy D. Vargas, MD.) (Right) Axial HRCT of the same patient shows diffuse bilateral ground-glass opacities, interlobular septal thickening ﬉, fissural thickening ﬊, and irregular macrocysts ﬈. Pulmonary involvement may occur in 55% of affected patients due to histiocytic infiltration. (Courtesy D. Vargas, MD.)

(Left) Axial CECT of the same patient shows infiltrative soft tissue ﬈ in the paravertebral mediastinum encasing the aorta, the so-called "coated aorta," as well as focal right pericardial thickening ﬊. (Courtesy D. Vargas, MD.) (Right) Coronal CECT of the same patient shows paravertebral infiltrative soft tissue ﬊ and characteristic infiltrative homogeneous perirenal soft tissue ﬈. Perirenal soft tissue infiltration may also occur in lymphoproliferative disorders, such as lymphoma. (Courtesy D. Vargas, MD.)

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Histiocytic Disorders Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) PA chest radiograph of a patient with Erdheim-Chester disease who presented with dyspnea shows diffuse bilateral interstitial opacities. (Right) Axial NECT of the same patient shows thin-walled pulmonary cysts ﬈, extensive interlobular septal thickening ﬊, and thickening of the interlobar fissures ﬉, which correlate histologically with histiocytic infiltration along lymphatic routes (i.e., pleura, interlobular septa, and bronchovascular interstitium) and varying degrees of stromal fibrosis.

(Left) Axial NECT of a patient with Rosai-Dorfman disease shows a left upper lobe illdefined subpleural nodular consolidation with surrounding ground-glass opacity ﬈. (Courtesy D. Vargas, MD.) (Right) Axial fused FDG PET/CT of the same patient shows increased FDG uptake in the left upper lobe lesion ſt. In general, areas of histiocytic infiltration in histiocytic disorders tend to demonstrate FDG avidity and when localized may mimic primary lung cancer. (Courtesy D. Vargas, MD.)

(Left) Axial CECT of the same patient shows lymphadenopathy ﬈ adjacent to the aortic arch. Cervical, and to a lesser extent, retroperitoneal, mediastinal, axillary, and inguinal lymphadenopathy are the most common imaging findings in patients with RosaiDorfman disease. Affected lymph nodes characteristically exhibit increased FDG uptake on PET/CT. (Courtesy D. Vargas, MD.) (Right) Axial CECT of the same patient shows left basilar pleural thickening ﬈. (Courtesy D. Vargas, MD.)

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Eosinophilic Disorders KEY FACTS

TERMINOLOGY • Eosinophilic disorders: Spectrum of pulmonary disorders associated with ○ Peripheral blood or tissue eosinophilia ○ Increased eosinophils in bronchoalveolar lavage fluid

IMAGING • Simple pulmonary eosinophilia: Unilateral or bilateral nonsegmental consolidations • Acute eosinophilic pneumonia: Ground-glass opacities (100%), crazy-paving pattern, mosaic attenuation; may mimic pulmonary edema • Chronic eosinophilic pneumonia (CEP): Peripheral homogeneous consolidations (100%) • Idiopathic hypereosinophilic syndrome: Pulmonary edema secondary to heart failure • Allergic bronchopulmonary aspergillosis (ABPA): Central upper lobe bronchiectasis ± high-attenuation mucous plugs (30%)

(Left) AP chest radiograph of a 40-year-old man with chronic eosinophilic pneumonia who had 30% peripheral eosinophilia and 35% bronchoalveolar lavage fluid eosinophilia shows bilateral, predominantly peripheral pulmonary consolidations ﬈. This so-called "photographic negative of pulmonary edema" is a very specific finding of eosinophilic pneumonia but is present in < 50% of affected patients. (Right) Axial NECT of the same patient shows bilateral peripheral consolidations ﬈, a characteristic CT finding.

(Left) Low-power photomicrograph (H&E stain) of a specimen of chronic eosinophilic pneumonia shows distention of the lumina of small bronchioles ﬊ by numerous eosinophils and histiocytes that "spill" into the adjacent alveolar sacs. This histologic finding correlates with the common CT/HRCT findings of ground-glass &/or airspace opacities. (Right) High-power photomicrograph (H&E stain) of the same specimen shows numerous histiocytes and red-staining eosinophils ﬈ within the alveolar spaces.

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• Bronchocentric granulomatosis (BG): Focal mass or lobar consolidation with atelectasis • Eosinophilic pneumonia secondary to drug reaction or parasitic infestation: Consolidations and ground-glass opacities • Eosinophilic granulomatosis with polyangiitis (E-GPA): Consolidations, ground-glass opacities, and interlobular septal thickening

TOP DIFFERENTIAL DIAGNOSES • Cryptogenic organizing pneumonia • Community-acquired pneumonia • Cardiogenic pulmonary edema

DIAGNOSTIC CHECKLIST • Consider E-GPA, ABPA, and BG in patients with asthma • Consider ABPA in patients with central upper lobe bronchiectasis and hyperdense mucus plugs • CEP may exhibit the so-called photographic negative of pulmonary edema radiographic pattern

Eosinophilic Disorders

Synonyms • Simple pulmonary eosinophilia (SPE): Löffler syndrome • Eosinophilic granulomatosis with polyangiitis (E-GPA): Churg-Strauss syndrome (latter term is no longer used)

Definitions • Spectrum of pulmonary disorders associated with ○ Peripheral blood or tissue eosinophilia ○ Increased eosinophils in bronchoalveolar lavage (BAL) fluid

Classification • Idiopathic eosinophilic pneumonias ○ SPE ○ Acute eosinophilic pneumonia (AEP) ○ Chronic eosinophilic pneumonia (CEP) ○ Idiopathic hypereosinophilic syndrome (IHS) • Eosinophilic pneumonias of known cause ○ Allergic bronchopulmonary aspergillosis (ABPA) ○ Bronchocentric granulomatosis (BG) ○ Eosinophilic pneumonia secondary to drug reaction or parasitic infestation • Eosinophilic vasculitis ○ E-GPA • Diseases occasionally associated with eosinophilic infiltration ○ Idiopathic pulmonary fibrosis, sarcoidosis, cryptogenic organizing pneumonia (COP), hypersensitivity pneumonitis

IMAGING Radiographic Findings • SPE ○ Subsegmental opacities – Peripheral, unilateral or bilateral, transient &/or migratory; typically resolve within 1 month • AEP ○ Mimics cardiogenic pulmonary edema with normal heart size ○ Earliest findings: Septal lines and reticular opacities ○ Rapid progression to extensive bilateral ground-glass opacities and confluent consolidations ○ Small bilateral pleural effusions common • CEP ○ Bilateral, nonsegmental, symmetric consolidations with peripheral (outer 2/3) and upper lung zone predominance (also referred to as "photographic negative of pulmonary edema") • IHS ○ Focal or diffuse, reticular or heterogenous subsegmental opacities ○ Pleural effusion (< 50%) • ABPA ○ Central bronchiectasis: Dilated central bronchi, tramtrack opacities, ring shadows – Mucoid impaction: Finger-in-glove or tubular opacities • BG ○ Nodules or masses (60%) and consolidations (27%)

• Eosinophilic pneumonia secondary to drug reaction ○ Airspace consolidation and ground-glass opacities with peripheral upper lung zone predominance • Eosinophilic pneumonia secondary to parasitic infestation ○ Patchy areas of consolidation that may coalesce in more severe cases (e.g., strongyloides) • E-GPA ○ Bilateral nonsegmental areas of consolidation – Transient or predominantly peripheral ○ Reticular or reticulonodular opacities ○ Unilateral or bilateral pleural effusions

CT Findings • SPE ○ Unilateral or bilateral subsegmental consolidation ○ Patchy subpleural nodules ± halo sign ○ Patchy ground-glass opacities ○ No cavitation or pleural effusion • AEP ○ Ground-glass opacities (100%), crazy-paving pattern or mosaic attenuation ○ Smooth interlobular septal thickening (90%) ○ Bronchovascular thickening (66%) ○ Consolidation (55%) ○ Poorly defined centrilobular nodules (30%) • CEP ○ Upper lobe-predominant peripheral homogeneous consolidations ○ Ground-glass opacities on background of septal thickening (crazy-paving pattern) ○ Nodule or mass (uncommon); may mimic lung cancer • IHS ○ Pulmonary edema secondary to cardiac failure – Smooth septal thickening and thickening of bronchovascular bundles ○ Peripheral nodules (few mm to 1 cm) ± surrounding ground-glass opacities ○ Solitary or multiple ground-glass opacities; peripheral distribution • ABPA ○ Central bronchiectasis more conspicuous in upper lobes – High-attenuation mucous plugging (30%) – Distal atelectasis or collapse • BG ○ Focal mass or lobar consolidation with atelectasis • Eosinophilic pneumonia secondary to drug reaction or parasitic infestation ○ Consolidation, ground-glass opacities, and crazy-paving pattern – Ascariasis: Migratory ground-glass opacities – Strongyloidiasis: Often superinfected with bacterial pneumonia ○ Peripheral and upper lung zone distribution – Tropical pulmonary eosinophilia □ Fine, diffuse reticulonodular opacities in lower lung zones • E-GPA ○ Airspace consolidation or ground-glass opacities – Patchy predominantly peripheral distribution

Inhalational, Inflammatory, Metabolic, and Post Treatment

TERMINOLOGY

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Eosinophilic Disorders ○ Bronchial wall thickening, bronchiectasis, and tree-in-bud nodules ○ Interlobular septal thickening ○ Nodules > 10 mm

– Acute or subacute onset □ SPE-like syndrome vs. fulminant AEP-like syndrome □ Toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome); may be life threatening ○ Eosinophilic pneumonia secondary to parasitic infestation – Parasitic infections vary from one geographic region to another □ Returning travelers from endemic areas – A. lumbricoides: Most common cause of peripheral blood eosinophilia with pulmonary opacities – Strongyloides stercoralis: May cause life-threatening hyperinfection syndrome, more common in immunocompromised patients (e.g., chronic corticosteroid treatment); frequent superimposed bacterial pneumonia – Tropical pulmonary eosinophilia □ Caused by filarial worms Wuchereria bancrofti and Brugia malayi □ BAL: High levels of IgE and IgG ○ E-GPA – Uncommon systemic disease in asthmatics with associated fever, peripheral hypereosinophilia > 10%, transient or migratory pulmonary opacities, paranasal sinus abnormalities, and extravascular eosinophils on biopsy

DIFFERENTIAL DIAGNOSIS Cryptogenic Organizing Pneumonia • • • • • •

May exhibit imaging findings identical to those of CEP Recurrent migratory consolidations Reversed halo sign, common Bronchial dilatation more common in COP COP more likely to exhibit nodules and masses Usually asymmetric

Community-Acquired Pneumonia • Symptomatic patients: Cough, fever, leukocytosis • Response to antimicrobial therapy

Cardiogenic Pulmonary Edema • Cardiomegaly and pleural effusion • Consolidation is usually gravity dependent • Smooth interlobular septal thickening

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ SPE – Self-limited, typically resolves in 1-2 weeks – Immune hypersensitivity to Ascaris lumbricoides and parasitic infections other than those by Ascaris species ○ AEP – Rapid onset of respiratory failure and fever (< 1 month of duration) □ Secondary to progressive eosinophilic pulmonary infiltration – Causes: Recent onset of cigarette smoking, secondhand smoke exposure, smoking flavored cigars, exposure to World Trade Center dust ○ CEP – Dyspnea, cough, and hypoxemia of varying severity □ Lung and blood eosinophilia – Often affects patients with asthma ○ IHS – Blood eosinophil count > 1,500/mm³ (> 6 months) □ BAL fluid eosinophilia as high as 73% – Multiorgan involvement □ Heart commonly affected (congestive heart failure) □ Pulmonary manifestations in up to 40% of patients ○ ABPA – Hypersensitivity reaction to Aspergillus antigens, usually Aspergillus fumigatus ○ BG – Complex tissue response to airway colonization by fungal organisms □ Descriptive pathologic diagnosis – Commonly associated with ABPA ○ Eosinophilic pneumonia secondary to drug reaction – Wide variety of drugs and toxic substances □ Not always related to either cumulative dose or treatment duration 418

Respiratory Symptoms • Self-limited, mild: SPE and IHS • Moderate to severe: CEP, ABPA, E-GPA • Severe: AEP

DIAGNOSTIC CHECKLIST Consider • E-GPA, ABPA, and BG in patients with asthma • Eosinophilic pneumonia due to parasitic infestation in returning travelers from endemic areas • Eosinophilic pneumonia due to drug toxicity in nearly any focal or diffuse pulmonary process • AEP in patients with normal heart size and hydrostatic edema unresponsive to diuresis

Image Interpretation Pearls • CEP may produce photographic negative of pulmonary edema • ABPA is characterized by central upper lobe bronchiectasis and hyperdense impacted mucus • AEP mimics pulmonary edema

SELECTED REFERENCES 1. 2. 3.

4. 5.

Cottin V: Eosinophilic lung diseases. Clin Chest Med. 37(3):535-56, 2016 Cottin V et al: Respiratory manifestations of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Eur Respir J. 48(5):1429-1441, 2016 Katre RS et al: Cardiopulmonary and gastrointestinal manifestations of eosinophil- associated diseases and idiopathic hypereosinophilic syndromes: multimodality imaging approach. Radiographics. 36(2):433-51, 2016 Price M et al: Imaging of eosinophilic lung diseases. Radiol Clin North Am. 54(6):1151-1164, 2016 Cordier JF et al: Hypereosinophilic obliterative bronchiolitis: a distinct, unrecognised syndrome. Eur Respir J. 41(5):1126-34, 2013

Eosinophilic Disorders Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Axial NECT of a 61-yearold woman with idiopathic acute eosinophilic pneumonia shows diffuse ground-glass opacities on a background of thick interlobular septa and intralobular lines ﬈, the socalled crazy-paving pattern. (Right) Coronal NECT of the same patient shows diffuse bilateral ground-glass opacities. Acute eosinophilic pneumonia is characterized by rapid onset of respiratory failure, fever, and eosinophilia and has been associated with recent onset of cigarette smoking and exposure to World Trade Center dust.

(Left) Coronal NECT MIP reformation of a 31-year-old man with allergic bronchopulmonary aspergillosis and peripheral eosinophilia shows bilateral tubular bronchiectasis with mucus plugging ﬈. Some of the mucus plugs show a characteristic finger-in-glove appearance ﬊. (Right) Coronal NECT of the same patient shows a lingular mucus plug that manifests with hyperdense impacted mucus ﬈. This finding occurs in 30% of patients with allergic bronchopulmonary aspergillosis.

(Left) Composite image with axial HRCT of a patient with simple pulmonary eosinophilia obtained at the time of acute onset of symptoms (left) and 1 month later (right) shows patchy ground-glass opacities ﬈ and subsequent nearcomplete resolution. (Right) Axial CECT of a 42-year-old man with idiopathic hypereosinophilic syndrome who presented with dyspnea, an erythematous rash over his entire body, and persistent eosinophilia of 8 months duration shows nonspecific diffuse bilateral ground-glass opacities ﬈.

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Amyloidosis KEY FACTS

TERMINOLOGY

PATHOLOGY

• Amyloidosis: Deposition of abnormal insoluble proteins within tissues throughout body

• Protein deposition within tissues • Proteins: Combination of serum amyloid P, glycosaminoglycans, and fibril proteins • Proteins arranged in sheets that retain Congo red dye with characteristic apple-green birefringence

IMAGING • Pulmonary nodular amyloidosis: Solitary or multiple pulmonary nodules, often with calcification • Diffuse alveolar septal amyloidosis: Interlobular septal thickening, perilymphatic nodules, consolidation • Airway amyloidosis: Focal or diffuse tracheobronchial wall thickening that may be circumferential, ± calcification • Cardiac amyloidosis: Biventricular hypertrophy, diastolic dysfunction, circumferential subendocardial delayed enhancement

TOP DIFFERENTIAL DIAGNOSES • Pulmonary nodular amyloidosis: Granulomatous infection • Alveolar septal amyloidosis: Lymphangitic carcinomatosis • Cardiac amyloidosis: Hypertrophic cardiomyopathy

(Left) Axial NECT (soft tissue window) of a patient with diffuse alveolar septal amyloidosis shows a partially calcified middle lobe consolidation ﬈. The lingula ﬉ is also involved but to a lesser extent. Note a small right pleural effusion ﬊. The patient experienced progressive respiratory failure and eventually underwent lung transplantation. (Right) Axial HRCT of the same patient shows beaded interlobular septal thickening ﬈ as well as subpleural ﬉ and centrilobular ﬊ micronodules.

(Left) Composite image with low-power photomicrographs of a specimen from the same patient with Congo red stain (top) and under polarized light (bottom) shows characteristic apple-green birefringence ſt. Amyloid appears as amorphous interstitial and perivascular eosinophilic deposits on H&E stain. (Right) Axial NECT of a patient with a solitary amyloidoma shows a partially calcified polylobular mass ﬈ in the subpleural left upper lobe. Biopsy confirmed the diagnosis. Note the small left pleural effusion ﬉.

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CLINICAL ISSUES • Pulmonary amyloidosis ○ Nodular: Usually asymptomatic ○ Alveolar septal: Progressive dyspnea, respiratory failure, development of pulmonary hypertension • Tracheobronchial amyloidosis: Symptoms depend on whether proximal, mid, or distal airway involvement ○ Dyspnea, cough, hemoptysis ○ Proximal: Stridor ○ Mid and distal: Wheezing • Cardiac amyloidosis: Diastolic dysfunction; progressive biventricular failure

Amyloidosis

Abbreviations • Amyloid light chain (AL) • Serum amyloid A (AA) • Transthyretin amyloid (ATTR)

Definitions • Amyloidosis: Deposition of abnormal insoluble proteins within tissues throughout body

IMAGING

– Early cardiac involvement: Subendocardial circumferential myocardial enhancement – Late cardiac involvement: Diffuse transmural myocardial enhancement – Atrial walls and cardiac valves may enhance ○ Early clearance of gadolinium from blood pool and retention in cardiac tissues – TI scout sequences: Blood pool nulls before myocardium, which is reverse of normal ○ Small pericardial effusion (common) ○ Emerging: Elevated precontrast T1 relaxation times (T1 maps), indicating infiltrating fibrotic process

General Features

Nuclear Medicine Findings

• Best diagnostic clue ○ Pulmonary parenchyma: Partially calcified nodules or consolidations, interlobular septal thickening ○ Airway: Partially calcified, focal or diffuse airway wall thickening ○ Cardiac: Circumferential, subendocardial, myocardial delayed enhancement

• Amyloid exhibits FDG avidity on FDG PET • F-18 florbetapir emerging as imaging biomarker, binds specifically to AL and ATTR

Radiographic Findings • Pulmonary parenchymal amyloidosis ○ Nodular parenchymal type: Solitary or multiple pulmonary nodules ± calcification ○ Diffuse alveolar septal type: Reticulonodular opacities ± confluent opacities that may contain calcification • Radiography insensitive for diagnosis of airway amyloidosis

CT Findings • Pulmonary parenchymal amyloidosis ○ Nodular parenchymal type – Well-circumscribed, solitary or multiple lung nodules □ Calcification (common) □ Cavitation (rare) – Lung cysts in patients with Sjögren syndrome and associated lymphoid interstitial pneumonia ○ Diffuse alveolar septal amyloidosis – Interlobular septal thickening – Micronodules 2-4 mm; may be centrilobular or perilymphatic – Confluent consolidation ± calcification (common) – Pleural thickening and pleural effusions (common) – Cavitation (rare) • Airway amyloidosis ○ More often localized than systemic ○ Focal or diffuse submucosal airway deposition along any portion of tracheobronchial tree – Long segment wall thickening more common than focal endobronchial lesion – Areas of calcification (common) – Involvement of posterior tracheal membrane • Cardiac amyloidosis: Myocardial hypertrophy • Mediastinal amyloidosis: Asymptomatic lymphadenopathy in setting of systemic disease

MR Findings • Cardiac amyloidosis ○ Biventricular hypertrophy ○ Diastolic dysfunction, decreased diastolic relaxation ○ Delayed gadolinium enhancement

Imaging Recommendations

Inhalational, Inflammatory, Metabolic, and Post Treatment

TERMINOLOGY

• Best imaging tool ○ Alveolar septal amyloidosis: HRCT ○ Cardiac amyloidosis: MR

DIFFERENTIAL DIAGNOSIS Pulmonary Parenchymal Amyloidosis • Nodular type: Granulomatous infection, vasculitis (granulomatosis with polyangiitis), primary lung cancer • Diffuse alveolar septal type: Lymphangitic carcinomatosis, pneumoconiosis, atypical granulomatous infection

Airway Amyloidosis • Cartilaginous lesions: Tracheobronchopathia osteochondroplastica, relapsing polychondritis ○ Cartilaginous lesions spare posterior tracheal membrane, whereas amyloid does not • Neoplasm: Squamous cell carcinoma, adenoid cystic carcinoma • Inflammatory: Granulomatosis with polyangiitis, sarcoidosis

Cardiac Amyloidosis • Sarcoidosis, hypertrophic cardiomyopathy, myocardial infarction

PATHOLOGY General Features • Abnormal insoluble protein deposition throughout body • Protein deposits: Combination of serum amyloid P, glycosaminoglycans, and fibril proteins ○ Fibril proteins are abnormally folded and organized into sheets ○ Amyloid proteins are insoluble, deposit in tissue

Staging, Grading, & Classification • Anatomic classification based on location of abnormal protein deposition ○ Localized: Deposition within single organ ○ Systemic: Deposition within multiple organs – Primary systemic: Associated with plasma cell dyscrasias – Secondary systemic: Patients with chronic infection/inflammation 421

Inhalational, Inflammatory, Metabolic, and Post Treatment

Amyloidosis • Biochemical classification system based on type of fibril protein in deposit ○ > 30 proteins identified ○ AL – Most common type of amyloid in industrialized countries – Abnormal breakdown of normal immunoglobulin light chains produced by plasma cells – Occurs in patients with underlying plasma cell dyscrasia – Patients with AL have deposition of abnormal protein ○ AA: Acute phase reactant, produced by liver – Can be elevated without amyloidosis in setting of systemic infection/inflammation – Amyloidosis: Abnormally folded AA proteins deposit in tissues – Patients with AA and β-2M amyloid: Abnormal deposition of normal but over abundant protein ○ β-2 microglobulin: Dialysis-related protein ○ ATTRwt: Senile systemic amyloidosis ○ Hereditary forms – Hereditary ATTR, ALys, AGel, hereditary β-2 microglobulin

Microscopic Features • Amorphous eosinophilic deposits of amyloid along interstitium and vessels • Calcification and ossification (common) • Congo red stain: Pulmonary amyloid deposits exhibit applegreen birefringence under polarized light

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Diverse clinical symptoms and presentation as any organ can be affected ○ Localized forms are often asymptomatic; systemic forms often symptomatic ○ AL: Macroglossia and periorbital purpura in ~ 1/3 patients ○ Cardiac deposition: Restrictive cardiomyopathy is leading cause of morbidity and mortality – 50% patients with AL amyloidosis; rare in AA amyloidosis □ Usually manifests with diastolic dysfunction with right ventricle > left ventricle failure ○ Pulmonary parenchymal or airway deposition – Localized nodular form, usually asymptomatic, incidental finding on chest radiography – Diffuse alveolar septal form often progresses to respiratory failure, development of pulmonary hypertension – Tracheobronchial amyloidosis □ Symptoms dependent on whether proximal, mid, distal airways □ Dyspnea, cough, stridor, wheezing, hemoptysis, recurrent pneumonia ○ Renal deposition: Most common in AA and AL amyloidosis – Proteinuria – Nephrotic syndrome 422

○ Neuropathy – AL: 1/5 of patients have peripheral neuropathy at presentation ○ Soft tissues: Deposition in muscles and salivary glands; may produce macroglossia, carpal tunnel syndrome

Demographics • Epidemiology ○ Generalized (or systemic) amyloidosis: 80-90% ○ Localized amyloidosis: 10-20% ○ Respiratory system commonly involved (50%), often as part of generalized amyloidosis • Age: 6th and 7th decades of life

Natural History & Prognosis • Pulmonary parenchymal amyloidosis ○ Nodular: Benign course, slow growth, remains asymptomatic ○ Diffuse alveolar septal: Progressive respiratory decline, median survival 16 months • Tracheobronchial amyloidosis: Slowly progressive, proximal airway involvement with worse prognosis than distal airway involvement • Airway amyloidosis: Overall 5-year survival of 30-50% • Cardiac amyloidosis: Progressive disease, poor prognosis

Treatment • Type of amyloid fibril and location of deposition determines therapy • Goals of therapy ○ Reduction in precursor proteins: Most important – AL amyloidosis: Treat underlying plasma cell dyscrasia – AA amyloidosis: Treat underlying infectious/inflammatory disorder ○ Maintain function of affected amyloidotic organs – Airway amyloidosis □ Endobronchial treatment: Laser, stent ○ Organ transplant is last resort

DIAGNOSTIC CHECKLIST Consider • Consider alveolar septal amyloidosis in patient with chronic respiratory symptoms and CT findings of partially calcified consolidation and interlobular septal thickening

Image Interpretation Pearls • Pulmonary nodular amyloidosis: Solitary or multiple pulmonary nodules/masses, often partially calcified • Alveolar septal amyloidosis: Diffuse interlobular septal thickening plus partially calcified consolidation • Tracheobronchial amyloidosis: Diffuse or focal airway wall thickening involving posterior tracheal wall, ± calcification • Cardiac amyloid: Subendocardial circumferential delayed enhancement; myocardium nulls before blood pool on T1 scout sequence

SELECTED REFERENCES 1. 2.

Wechalekar AD et al: Systemic amyloidosis. Lancet. 387(10038):2641-54, 2016 Czeyda-Pommersheim F et al: Amyloidosis: modern cross-sectional imaging. Radiographics. 35(5):1381-92, 2015

Amyloidosis Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Axial NECT of a patient with tracheobronchial amyloidosis shows circumferential tracheal wall thickening ﬈ and intrinsic areas of calcification ﬉ with resultant tracheal stenosis. Note that this process also involves the posterior membranous trachea. (Right) Sagittal NECT of the same patient shows tracheal wall thickening ﬈ with calcification ﬊. Tracheostomy was required due to subglottic stenosis. Tracheobronchial amyloidosis occurs more often as a localized disease than as systemic involvement.

(Left) Coronal NECT of a patient with Sjögren syndrome, lymphoid interstitial pneumonia, and nodular amyloidosis shows multiple bilateral calcified nodules ﬈ and bilateral lung cysts ﬊. The association of amyloidosis with lymphoid interstitial pneumonia is a rare but known entity in the setting of Sjögren syndrome. (Right) High-power photomicrograph (H&E stain) of a specimen from the same patient shows amorphous eosinophilic amyloid deposition ﬈ and foci of ossification ﬉.

(Left) Axial SSFSE MR of a patient with amyloidosis shows biventricular hypertrophy ﬊ and biatrial wall thickening ﬈. Amyloid deposition in the cardiac chamber walls is a common finding in cardiac amyloidosis. (Right) Short-axis delayed enhancement MR shows diffuse delayed enhancement of the entire left ventricular myocardium ﬈ and enhancement of portions of the right ventricular wall ﬊. Amyloid deposition begins in the subendocardial region but eventually extends through the entire myocardial wall.

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Light-Chain Deposition Disease KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Light-chain deposition disease (LCDD): Rare condition characterized by systemic extracellular accumulation of immunoglobulin light chains commonly involving kidneys, liver, and heart

• • • • •

IMAGING • Radiography ○ Chest radiographs are often normal • CT ○ Pulmonary cysts – 4-15 mm (mean: 10 mm) – Thin-walled, spherical, no predominant distribution – Pulmonary vessel within cyst wall &/or traversing cyst ○ Nodules – 3-20 mm (mean: 10 mm) – Solid (common), ground-glass (rare) – No predominant distribution

(Left) Axial HRCT of an 83year-old man with a history of multiple myeloma and lightchain deposition disease shows scattered bilateral upper lobe pulmonary cysts of various sizes. Some of the cysts exhibit pulmonary vessels ﬈ within the cyst walls, a specific feature of lung cysts in patients with light-chain deposition disease. (Right) Coronal NECT of the same patient shows multifocal bilateral pulmonary cysts. Note pulmonary vessels either within the cyst wall ﬈ or traversing the cyst lumen ﬉.

(Left) Coronal HRCT of a 66year-old man with light-chain deposition disease shows a large left upper lobe cyst with small pulmonary vessels ﬈ coursing within its walls. (Right) Axial NECT MIP reformation of the same patient shows small, bilateral, solid, and ground-glass lung nodules ﬈. The presence of pulmonary nodules is also a common manifestation of light-chain deposition disease. The nodules often coexist with pulmonary cysts. Although lung nodules are typically solid, ground-glass nodules also occur.

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Amyloidosis Lymphoid interstitial pneumonia Pulmonary Langerhans cell histiocytosis Lymphangioleiomyomatosis Birt-Hogg-Dubé syndrome

PATHOLOGY • Irregular nodules with amorphous eosinophilic material ○ No staining with Congo red • Foreign body giant cell reaction

CLINICAL ISSUES • Pulmonary involvement often incidental; dyspnea, shortness of breath • Underlying plasma cell dyscrasia with excess of monoclonal light chains (e.g., multiple myeloma) • Treatment: No effective treatment known; lung transplantation for severe cases

Light-Chain Deposition Disease

Abbreviations • Light-chain deposition disease (LCDD)

Definitions • Rare condition characterized by systemic extracellular accumulation of immunoglobulin light chains commonly involving kidneys, liver, and heart ○ Deposition of amorphous nonfibrillary material; does not contain amyloid fibrils

IMAGING Radiographic Findings • Chest radiographs are often normal • Pulmonary cysts may occasionally be seen

CT Findings • Pulmonary cysts ○ 4-15 mm (mean: 10 mm) ○ Thin-walled, spherical ○ No predominant distribution ○ Pulmonary vessel within cyst wall &/or traversing cyst • Nodules ○ 3-20 mm (mean: 10 mm) ○ Solid (common), ground-glass (rare) ○ No predominant distribution • Ground-glass opacity • Bronchial wall thickening • Mediastinal lymphadenopathy (uncommon)

DIFFERENTIAL DIAGNOSIS Amyloidosis • In patients with Sjögren syndrome: Similar cysts and calcified nodules (i.e., amyloidomas) should suggest diagnosis of amyloidosis

Lymphoid Interstitial Pneumonia • Similar imaging findings • History of autoimmunity (e.g., Sjögren syndrome) or immunodeficiency

Lymphangioleiomyomatosis • Women &/or history of tuberous sclerosis • Diffusely distributed spherical cysts • Chylothorax, pneumothorax, lymphadenopathy, renal angiomyolipomas

Pulmonary Langerhans Cell Histiocytosis • History of cigarette smoking • Bizarre-shaped cysts with sparing of lung bases

Birt-Hogg-Dubé Syndrome • Cyst abutting proximal aspects of basilar pulmonary vessels or pleura • Skin fibrofolliculomas, bilateral renal cell cancers

PATHOLOGY General Features • Deposition of nonfibrillary, amorphous material that does not have β-pleated sheet configuration as amyloidosis

• Deposited light chains are mostly κ, but λ chain deposition may also occur

Microscopic Features • Irregular nodules consisting of amorphous eosinophilic material ○ Do not stain with Congo red (exclusion of amyloidosis) • Foreign body giant cell reaction against light chains ○ Associated, poorly formed, nonnecrotizing granulomas ○ Schaumann bodies (i.e., basophilic, lamellated, shell-like bodies found in cytoplasm of multinucleated giant cells in granulomas) reflects evolution from granulomatous process to burnt-out disease • Lymphoid infiltration of areas of light-chain deposition and other uninvolved areas ○ Distribution: Perilymphatic, bronchovascular, interlobular septa, alveolar

CLINICAL ISSUES

Inhalational, Inflammatory, Metabolic, and Post Treatment

TERMINOLOGY

Presentation • Most common signs/symptoms ○ Most common manifestation: Renal involvement – Proteinuria, microscopic hematuria, or renal failure; may progress to end-stage renal failure without treatment – Assessment with evaluation of serum creatinine and urine protein ○ Pulmonary involvement often incidental – Dyspnea, shortness of breath • Clinical profile ○ Underlying plasma cell dyscrasia with excess of monoclonal light chains – Multiple myeloma (2/3) – Lymphoproliferative disorder (e.g., lymphoma)

Demographics • Age ○ 35-76 years; mean: 60 years • Gender ○ Very rare (no accurate statistics) – M:F = 2:1 • Epidemiology ○ Very rare

Natural History & Prognosis • Varies from stable to rapidly progressive disease with poor prognosis

Treatment • No known effective treatment • Lung transplantation in severe cases

SELECTED REFERENCES 1. 2. 3. 4. 5.

Sheard S et al: Pulmonary light-chain deposition disease: CT and pathology findings in nine patients. Clin Radiol. 70(5):515-22, 2015 Rho L et al: Pulmonary manifestations of light chain deposition disease. Respirology. 14(5):767-70, 2009 Colombat M et al: Pathomechanisms of cyst formation in pulmonary light chain deposition disease. Eur Respir J. 32(5):1399-403, 2008 Bhargava P et al: Pulmonary light chain deposition disease: report of five cases and review of the literature. Am J Surg Pathol. 31(2):267-76, 2007 Colombat M et al: Pulmonary cystic disorder related to light chain deposition disease. Am J Respir Crit Care Med. 173(7):777-80, 2006

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Pulmonary Alveolar Proteinosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Pulmonary alveolar proteinosis (PAP): Syndrome characterized by accumulation of surfactant in alveoli and terminal bronchioles ○ Autoimmune (90%) ○ Secondary ○ Hereditary and congenital

• • • •

IMAGING • Ground-glass pattern ○ Geographic distribution in autoimmune PAP ○ Diffuse distribution in secondary PAP • Crazy-paving pattern ○ May be related to surfactant accumulation in periphery of air spaces adjacent to interlobular septa &/or interstitial fibrosis ○ Autoimmune PAP (75%) ○ Secondary PAP (25%) • Consolidation

(Left) Axial HRCT of a 25-yearold woman with autoimmune pulmonary alveolar proteinosis shows classic CT findings of geographic areas of ground-glass opacity with superimposed interlobular septal thickening, the socalled crazy-paving pattern. However, the crazy-paving pattern may also be seen in other conditions. (Right) Photograph of bronchoalveolar lavage fluid of a patient with pulmonary alveolar proteinosis shows a milky appearance due to fluid rich in phospholipids and surfactant proteins.

(Left) Low-power photomicrograph (H&E stain) shows pulmonary alveolar proteinosis manifesting with intraalveolar proteinaceous material ﬈, preserved lung architecture, and intact alveolar walls ﬉. (From DP: Thoracic, 2e.) (Right) Highpower photomicrograph (H&E stain) shows the classic appearance of alveolar proteinosis with granular proteinaceous material surrounding small clumps ﬈ of bright eosinophilic material. Note absence of cellularity, specifically macrophages. (From DP: Thoracic, 2e.)

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Pulmonary edema Diffuse alveolar hemorrhage Acute respiratory distress syndrome Pneumocystis jirovecii pneumonia

PATHOLOGY • Surfactant accumulation in alveoli and terminal bronchioles

CLINICAL ISSUES • Subacute or chronic indolent course with delayed diagnosis • Dyspnea, cough, fatigue, weight loss

DIAGNOSTIC CHECKLIST • Consider PAP in patient with subacute or chronic respiratory symptoms and geographic crazy-paving pattern on CT • Differential diagnosis of ground-glass opacities and crazypaving pattern is broad and should not be limited to PAP

Pulmonary Alveolar Proteinosis

Abbreviations • Pulmonary alveolar proteinosis (PAP)

Synonyms • Pulmonary alveolar lipoproteinosis

Definitions • PAP is syndrome of altered surfactant homeostasis characterized by accumulation of surfactant in alveoli and terminal bronchioli ○ Autoimmune (sometimes called primary): 90% of cases ○ Secondary ○ Hereditary ○ Congenital

IMAGING General Features

Imaging Recommendations

• Best diagnostic clue ○ CT Findings – Crazy-paving pattern in autoimmune PAP – Ground-glass opacities in secondary PAP

• Best imaging tool ○ HRCT

Radiographic Findings

Hydrostatic Pulmonary Edema

• Radiography ○ Pulmonary opacities ranging from ill-defined (or groundglass) opacities to ill-defined consolidations – Related to alveolar filling ○ Variable distribution – Symmetric perihilar or basilar – Asymmetric, unilateral, peripheral, or lobar – Sparing of lung apices ○ Ill-defined nodules – At margins of confluent consolidations ○ Reticular or reticulonodular opacities ○ Pneumothorax – Related to rupture of subpleural cyst ○ Superimposed infection – Common microorganisms: Nocardia species, mycobacteria (tuberculosis, nontuberculous), fungi (Aspergillus, Cryptococcus, Histoplasma, Zygomycetes) – Pleural effusion – Mass or cavitation – Lymphadenopathy

• • • •

CT Findings • HRCT ○ Ground-glass pattern – Geographic distribution in autoimmune PAP – Diffuse distribution in secondary PAP – Subpleural sparing in autoimmune PAP ○ Crazy-paving pattern – Ground-glass opacities with superimposed thickened interlobular septa or intralobular lines – Accumulation of proteinaceous material in periphery of air spaces adjacent to interlobular septa &/or interstitial fibrosis have been postulated as mechanisms that may produce this finding – Autoimmune PAP (75%) – Secondary PAP (25%)

Inhalational, Inflammatory, Metabolic, and Post Treatment

○ Consolidation – Dense opacity that obscures underlying vessels – Few air bronchograms ○ Traction bronchiectasis – Initial HRCT (9%) – Follow-up HRCT (23%) ○ Honeycombing – Follow-up HRCT (5%) ○ Lung cysts (20%) – Related to alveolar wall destruction by fibrosis or cigarette smoking ○ Mediastinal lymphadenopathy – 1 or 2 enlarged lymph nodes – Measure slightly > 1 cm in short-axis diameter ○ Silicoproteinosis – Dependent consolidation with areas of calcification – Crazy-paving pattern is uncommon

TERMINOLOGY

DIFFERENTIAL DIAGNOSIS Ground-glass/crazy-paving pattern/consolidation Gravitational distribution Cardiomegaly, pleural effusion Acute clinical presentation

Acute Respiratory Distress Syndrome • • • •

Ground-glass/crazy-paving pattern/consolidation Anteroposterior gradient of lung involvement Pulmonary &/or extrapulmonary disease Acute clinical presentation

Diffuse Alveolar Hemorrhage • • • •

Ground-glass/crazy-paving pattern/consolidation Variable distribution Anemia, hemoptysis Clinical setting: Autoimmunity, pulmonary-renal syndrome

Pneumocystis jirovecii Pneumonia • • • •

Ground-glass/crazy-paving pattern Lung cysts Subacute clinical course Impaired immune system: Acquired immune deficiency syndrome (AIDS)

Lung Cancer • May exhibit crazy-paving pattern ○ Adenocarcinoma subtype • Focal or multifocal distribution • Lymphadenopathy, pulmonary nodules • Constitutional symptoms

Other Entities That May Exhibit Crazy-Paving Pattern • • • • •

Sarcoidosis Nonspecific interstitial pneumonia Organizing pneumonia Lipoid pneumonia Chronic eosinophilic pneumonia 427

Inhalational, Inflammatory, Metabolic, and Post Treatment

Pulmonary Alveolar Proteinosis

PATHOLOGY

CLINICAL ISSUES

General Features

Presentation

• Autoimmune PAP ○ Disruption of granulocyte-macrophage colonystimulating factor (GM-CSF) signaling caused by high levels of anti-GM-CSF autoantibody • Secondary PAP ○ Diseases that impair alveolar macrophage numbers or functions (including surfactant catabolism) – Hematologic diseases □ Myeloid disorders: Myelodysplastic syndrome, chronic myeloid leukemia, and chronic myeloid leukemia □ Lymphoid disorders: Acute lymphoid leukemia, lymphoma (Hodgkin and non-Hodgkin), and adult Tcell leukemia/lymphoma – Nonhematologic malignancies □ Glioblastoma, lung cancer, and mesothelioma – Autoimmune disorders □ Psoriasis, amyloidosis, immunoglobulin G monoclonal gammopathy – Immunodeficiency □ Thymic alymphoplasia, immunoglobulin A deficiency, severe combined immunodeficiency disorder, and immunosuppression for organ transplant – Toxic inhalation exposures □ Silica, cotton, cement, titanium, aluminum • Surfactant production disorders ○ SFTPB mutations ○ SFTPC mutations ○ ABCA3 mutations ○ TTF1 (NKX2-1) mutations • GM-CSF autoantibody ○ GM-CSF autoantibodies are polyclonal (IgG1, IgG2, and small amounts of IgG3 and IgG4) ○ Risk of PAP is increased when the GM-CSF autoantibody threshold is above > 5 μg/mL ○ GM-CSF autoantibodies: Diagnostic sensitivity and specificity of 100% and 98%

• Most common signs/symptoms ○ Subacute or chronic indolent clinical course with resultant delayed diagnosis for months or years – Dyspnea – Cough – Fatigue – Weight loss • Other signs/symptoms ○ Fever ○ Sputum production ○ Crackles, clubbing, cyanosis • Smoking history (autoimmune PAP) ○ German cohort (79%), Italian cohort (64%), Japanese cohort (57%) • Dust or fume exposure ○ German cohort (54%), Italian cohort (32%), Japanese cohort (26%)

Gross Pathologic & Surgical Features • Bronchoalveolar lavage fluid ○ Milky and turbid with thick sediment ○ Contains phospholipids and surfactant proteins A, B, and D, with lower concentrations of phosphatidylcholine and phosphatidylglycerol

Microscopic Features • Intraalveolar accumulation of eosinophilic proteinaceous granular material ○ May also involve bronchioles and alveolar ducts • Cholesterol clefts, macrophages, and globular clumps of eosinophilic material found within granular eosinophilic material • Proteinaceous material is positive for periodic acid-Schiff • Mild interstitial thickening without inflammation or fibrosis

Demographics • Age ○ Median age at diagnosis: 51-52 years • Gender ○ M:F ratio ranges from 2.1:1 to 2.7:1 • Epidemiology ○ 3.7-6.2 cases per million population

Natural History & Prognosis • Variable course ○ Spontaneous remission (5-7%) ○ Persistent, unceasing symptoms ○ Progressive course with respiratory failure • Good prognosis ○ 5-year survival – 85% without therapy – 94% with whole-lung lavage therapy

Treatment • Whole-lung lavage • Subcutaneous or inhaled GM-CSF, rituximab, plasmapheresis, and lung transplantation

DIAGNOSTIC CHECKLIST Consider • PAP in patient with subacute or chronic respiratory symptoms and geographic crazy-paving pattern on CT

Image Interpretation Pearls • Differential diagnosis of ground-glass opacities and crazypaving pattern is broad and should not be limited to PAP

SELECTED REFERENCES 1. 2. 3.

428

Suzuki T et al: Pulmonary alveolar proteinosis syndrome. Clin Chest Med. 37(3):431-40, 2016 Ben-Dov I et al: Autoimmune pulmonary alveolar proteinosis: clinical course and diagnostic criteria. Autoimmun Rev. 13(4-5):513-7, 2014 Souza CA et al: Comparative study of clinical, pathological and HRCT findings of primary alveolar proteinosis and silicoproteinosis. Eur J Radiol. 81(2):3718, 2012

Pulmonary Alveolar Proteinosis Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Composite image of the right lung (left) and bronchoalveolar lavage fluid (right) shows alveolar proteinosis manifesting with areas of yellowish discoloration ﬈ and the "milky" lipid- and protein-rich fluid. (Right) Axial HRCT of a patient with leukemia and secondary pulmonary alveolar proteinosis shows diffuse ground-glass opacities without thick interlobular septa and mediastinal lymphadenopathy ﬈. The crazy-paving pattern is uncommon in secondary pulmonary alveolar proteinosis.

(Left) PA chest radiograph of a patient with autoimmune pulmonary alveolar proteinosis shows diffuse bilateral heterogeneous airspace disease ﬈ and reticular opacities ﬉. The findings may mimic those of pulmonary edema or alveolar hemorrhage. (Right) Axial HRCT of the same patient shows the classic crazy-paving pattern and right paratracheal lymphadenopathy ﬈. Although nonspecific, the crazy-paving pattern is frequent in autoimmune pulmonary alveolar proteinosis.

(Left) Axial HRCT of the same patient shows geographic areas of crazy paving. The crazy-paving pattern is common in autoimmune pulmonary alveolar proteinosis, but diffuse ground-glass opacities are more common in secondary pulmonary alveolar proteinosis. (Right) Coronal HRCT of the same patient shows geographic areas of crazy-paving opacities. This process is characterized by ground-glass opacities on a background of interlobular septal thickening.

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Inhalational, Inflammatory, Metabolic, and Post Treatment

Pulmonary Alveolar Proteinosis

(Left) PA chest radiograph of a patient with longstanding autoimmune pulmonary alveolar proteinosis shows low lung volumes and diffuse bilateral reticular opacities. (Right) Axial HRCT of the same patient shows diffuse groundglass opacities, as well as peribronchovascular ﬊ and subpleural ﬉ reticulation, honeycombing and traction bronchiectasis ﬈, all features of pulmonary fibrosis. The distribution of abnormalities is not typical of usual interstitial pneumonia (e.g., subpleural and lower lobe predominant).

(Left) Coronal HRCT of the same patient shows diffuse bilateral ground-glass opacities with peribronchovascular and subpleural reticulation and honeycombing and traction bronchiectasis ﬈. (Right) Composite image with axial HRCT of a patient with longstanding pulmonary alveolar proteinosis and pulmonary fibrosis shows heterogeneous reticular opacities with traction bronchiectasis and bronchiolectasis ﬈ and some honeycombing ﬉.

(Left) Axial HRCT of a patient with chronic pulmonary alveolar proteinosis and fibrosis shows bilateral reticular opacities, emphysema, and discrete upper lobe nodules ﬈. The latter should suggest opportunistic infection. (Right) Axial HRCT of the same patient shows subpleural nodular and reticular opacities. Opportunistic pathogens include Nocardia spp., mycobacteria (tuberculosis, nontuberculous), and fungi (e.g., Aspergillus, Cryptococcus, Histoplasma).

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Pulmonary Alveolar Proteinosis Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Axial CECT of a patient with pulmonary alveolar proteinosis and nocardiosis shows diffuse ground-glass opacities and several left upper lobe cavitary nodules ﬈. (Right) Low-power photomicrograph (H&E stain) of a specimen of pulmonary alveolar proteinosis shows partial destruction of an airway ﬈, which is filled with the characteristic proteinaceous material ﬉. Although the term alveolar proteinosis implies alveolar disease, the process may also involve the airways. (From DP: Thoracic, 2e.)

(Left) PA chest radiograph of a patient with autoimmune pulmonary alveolar proteinosis shows diffuse bilateral heterogeneous reticular opacities. (Right) Axial HRCT of the same patient shows a diffuse bilateral crazy-paving pattern with small areas of relative lung sparing. Affected patients are often successfully treated with whole-lung bronchoalveolar lavage. Second-line therapies include subcutaneous or inhaled GMCSF, rituximab, plasmapheresis, and lung transplantation.

(Left) Axial HRCT of a 23-yearold man with leukemia and secondary pulmonary alveolar proteinosis shows groundglass opacities and nodular consolidations in the right lower lobe. (Right) Coronal HRCT of the same patient shows multifocal ground-glass opacities ﬊, centrilobular micronodules ﬈, geographic areas of crazy paving ﬈, and dense consolidations ﬉. Secondary pulmonary alveolar proteinosis may occur in the setting of malignancy, immunodeficiency, autoimmune disorders, and certain inhalational exposures.

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Metastatic Pulmonary Calcification KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Calcium deposition in normal pulmonary parenchyma ○ Abnormal calcium metabolism ○ Predisposing factors: Chronic renal failure, hypercalcemia, increased tissue alkalinity

• • • •

IMAGING

PATHOLOGY

• Tropism for tissues with relative alkaline pH: Upper lung zones, gastric wall, renal medulla • Calcification rarely detected on radiography unless severe • CT ○ High-density (or calcified) focal or diffuse abnormalities ○ Focal: Typically peripheral consolidation of variable size, nearly completely calcified ○ Diffuse: Mulberry- or miniature cotton ball-shaped, amorphous calcifications, 3-10 mm in diameter ○ Centrilobular location, usually forming small rosettes • Associated findings: Small vessel calcification in chest wall, heart, or pulmonary vasculature

• Hypercalcemic conditions (high calcium phosphate product > 70): Chronic renal failure (most common cause) • High V/Q ratio in erect upper lobes leads to alkaline pH (7.51) (also in gastric wall and renal medulla)

(Left) PA chest radiograph of a patient with metastatic pulmonary calcification shows bilateral peripheral, nodular, hyperdense pulmonary consolidations ﬈. Most metastatic calcification lesions are not dense enough to be identifiable on radiography. (Courtesy N.L. Müller, MD, PhD.) (Right) Axial NECT of the same patient shows multifocal left upper lobe peripheral nodular calcifications ﬈. CT is more sensitive than radiography for the identification of calcification. (Courtesy N.L. Müller, MD, PhD.)

(Left) Coned-down frontal chest radiograph of a patient with secondary hyperparathyroidism and metastatic pulmonary calcification shows multiple nodular airspace opacities that spare the subpleural lung ﬊. Note chest wall small vessel calcifications ﬈, a very common and specific ancillary finding. (Right) Axial NECT of the same patient shows highattenuation pulmonary nodular lesions forming rosettes with relative subpleural sparing ﬈, reflecting the centrilobular nature of the disease.

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Sarcoidosis Silicosis Talcosis Alveolar microlithiasis

CLINICAL ISSUES • Frequently asymptomatic, benign course • Several systemic and pulmonary conditions

DIAGNOSTIC CHECKLIST • Lymph node calcification is not seen in metastatic pulmonary calcification

Metastatic Pulmonary Calcification

Abbreviations • Metastatic pulmonary calcification (MPC)

Synonyms • Pulmonary calcinosis

Definitions • Pulmonary calcification ○ Dystrophic calcification – Calcium deposition in injured pulmonary parenchyma – Absence of ↑ serum calcium levels ○ Metastatic calcification – Calcium deposition in normal pulmonary parenchyma – Abnormal calcium metabolism – Predisposing factors: Chronic renal failure, hypercalcemia, and increased tissue alkalinity • Calciphylaxis ○ Small vessel calcification leading to end-organ ischemia ○ May result in rapidly fatal noncardiac edema

IMAGING General Features • Best diagnostic clue ○ High (or calcium) density opacities in upper lung zones • Location ○ Upper lung zones: Tropism for tissues with relatively alkaline pH

Radiographic Findings

– Wedge-shaped, usually peripheral consolidation of variable size – Most of abnormal lung shows calcification – No zonal predilection • Associated findings ○ Small vessel calcification involving chest wall, heart, or pulmonary arteries ○ Parathyroid masses representing parathyroid adenomas ○ Multiple thyroid nodules (medullary thyroid carcinoma) or adrenal masses (pheochromocytoma) suggest multiple endocrine neoplasia 2 (MEN2); 20% develop hyperparathyroidism ○ Pancreatic mass (islet cell), thymic or bronchial carcinoids suggest MEN1; 80% develop hyperparathyroidism ○ Lytic bone lesions from hyperparathyroidism ○ Calcified mediastinal and hilar lymph nodes not seen in patients with MPC

Nuclear Medicine Findings

Inhalational, Inflammatory, Metabolic, and Post Treatment

TERMINOLOGY

• Imaging with technetium-99m-methylene diphosphonate (Tc-99m MDP) ○ Most sensitive technique for early detection of MPC ○ Increased radioactive isotope uptake – Symmetric and sufficiently dense to obliterate rib outlines

MR Findings • Good option for characterizing lung calcium accumulation caused by metabolic disorder ○ Hyperintense signal on T1WI, low calcium concentration of lesion

• Radiography ○ Calcification rarely detected unless severe – Conventional high kVp technique not optimal for detection of calcification – Dual-energy digital radiography more sensitive than conventional radiography ○ Confluent or patchy airspace opacities – Mimic pulmonary edema or pneumonia – Intrinsic calcification seldom identified ○ Discrete or confluent nodules ± calcification ○ Diffuse interstitial process

Imaging Recommendations

CT Findings

Silicosis

• More sensitive than radiography for calcium identification ○ Very small nodules may not appear calcified despite presence of microscopic calcifications ○ Calcification may not be seen in up to 40% of cases • Diffuse or focal patterns ○ Diffuse pattern (more common) – Predilection for upper lung zones: ↑ alkalinity – Punctate within nodular, ring-like, or diffuse opacities □ Centrilobular location, manifests as small rosettes, normal subpleural lung – Mulberry-shaped or miniature "cotton balls," amorphous calcifications 3-10 mm in diameter – Nodules usually admixed with emphysema and ground-glass opacities ○ Focal pattern (less common) – Usually due to vascular occlusion, which may be identified with CT angiography

• Silicotic nodules may calcify; upper lobes primarily involved • History of occupational exposure

• Best imaging tool ○ CT is both sensitive and specific

DIFFERENTIAL DIAGNOSIS Sarcoidosis • Nodule calcification is rare, upper lobes primarily involved • Sarcoidosis associated with hypercalcemia (due to increased production of calcitriol) may increase risk of MPC ○ Hypercalcemia in sarcoidosis is seasonal due to UV light sensitivity

Talcosis • History of intravenous drug use • Upper lobe micronodules (< 1 mm) smaller than those in MPC, tend to coalesce into perihilar fibrotic masses

Alveolar Microlithiasis • Small (~ 1 mm), punctate calcifications • Diffuse involvement, more severe in lower lobes

Tuberculosis • Upper lobes primarily involved, not associated with extensive calcification unless healed • Cavitation not seen in MPC • Prior granulomatous disease more likely to result in traction bronchiectasis and lung scarring 433

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Metastatic Pulmonary Calcification Mitral Stenosis

Gross Pathologic & Surgical Features

• Left atrial enlargement and vascular redistribution (pulmonary venous hypertension) ○ Generalized cardiomegaly and chronic edema also common in patients with MPC • Ossification primarily affects lower lobes

• Rigid and gritty on cut section, preserved lung architecture

Amyloidosis • Large nodules, small nodules generally do not calcify • Often associated with interlobular septal thickening

Dendriform Pulmonary Ossification • Dendritic calcification in lower lobes ○ May be isolated or associated with interstitial lung disease • Typically incidental finding in elderly men

PATHOLOGY General Features • Etiology ○ MPC rarely develops in patients with normal calcium metabolism ○ Hypercalcemic conditions (high calcium phosphate product > 70) ○ Benign causes of hypercalcemia – Chronic renal failure – Steroid and phosphate therapy – Chronic immobilization – Hyperparathyroidism – Hypervitaminosis D – Milk-alkali syndrome – Sarcoidosis – Liver transplantation ○ Malignant causes of hypercalcemia – Skeletal metastases (particularly breast carcinoma) – Multiple myeloma – Lymphoma and leukemia – Head and neck squamous cell carcinoma – Choriocarcinoma – Parathyroid carcinoma ○ Pathophysiology – Chronic acidosis leaches calcium from bone – Hyperparathyroidism causes bone resorption – Decreased renal function causes hyperphosphatemia and elevated calcium phosphate product – Calcium is less soluble in alkaline environment ○ High V/Q ratio in erect upper lobes leads to alkaline pH (7.51) (alkaline pH also in gastric wall and renal medulla) – Favors diffuse upper lung zone calcium deposition ○ Focal calcification suggests vascular occlusion to supplied area (focally increased V/Q ratio) • Associated abnormalities ○ Lung, stomach, kidney, and heart (most common) metastatic calcification • General pathology comments ○ MPC represents calcium deposition in normal tissue in contrast to dystrophic calcification, which affects abnormal tissue

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Microscopic Features • Interstitial location ○ Interstitial abnormalities on CT are rare – CT abnormalities mimic airspace disease • Alveolar septal and vascular deposition (50x > normal) ○ Tropism for elastic tissues (small and medium-sized vessels) • Organization and calcification of intraalveolar exudates • Calcium stains positive with Alizarin red and von Kossa stains • Fibrosis develops in more severe or longstanding cases

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Frequently asymptomatic, benign course ○ Gradual-onset dyspnea; some have sudden onset of symptoms and rapid fulminant course

Natural History & Prognosis • Pulmonary function tests usually normal ○ With severe disease, restrictive pulmonary function and decreased diffusion capacity ○ Inverse correlation between pulmonary function and hypercalcemia • Varies from incidental finding that remains stable for years to fulminant life-threatening course within days • Death from cardiac involvement (alteration of conducting pathways) • MPC may be reversible with correction of hypercalcemia ○ Irreversible in setting of fibrosis

Treatment • Correction of hypercalcemia and treatment of underlying cause • MPC may progress despite renal transplantation • Promising preliminary response to sodium thiosulfate

DIAGNOSTIC CHECKLIST Consider • MPC in patients with pulmonary abnormalities and known specific causative conditions • Diagnosis may require CT, MR, and Tc-99m MDP

Image Interpretation Pearls • Lymph node calcification is not seen in patients with MPC

SELECTED REFERENCES 1.

2. 3.

4.

Arrestier R et al: Successful treatment of lung calciphylaxis with sodium thiosulfate in a patient with sickle cell disease: a case report. Medicine (Baltimore). 95(6):e2768, 2016 Belém LC et al: Metastatic pulmonary calcification: state-of-the-art review focused on imaging findings. Respir Med. 108(5):668-76, 2014 Li YJ et al: Fulminant pulmonary calciphylaxis and metastatic calcification causing acute respiratory failure in a uremic patient. Am J Kidney Dis. 47(4):e47-53, 2006 Hartman TE et al: Metastatic pulmonary calcification in patients with hypercalcemia: findings on chest radiographs and CT scans. AJR Am J Roentgenol. 162(4):799-802, 1994

Metastatic Pulmonary Calcification Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Axial HRCT of a patient with metastatic pulmonary calcification shows right upper lobe multifocal, highattenuation nodular calcifications ﬈ with intrinsic air bronchograms ﬊. (Right) Composite image with axial NECT in lung (left) and soft tissue (right) window of a 46year-old man with chronic renal disease and metastatic pulmonary calcification shows a right upper lobe heterogeneous consolidation with instrinsic calcification ﬈ (optimally visualized on soft tissue window), and subpleural sparing ﬉.

(Left) AP chest radiograph of a 53-year-old man on hemodialysis shows metastatic pulmonary calcification that manifests as a right upper lobe consolidation initially diagnosed as pneumonia. Because of lack of improvement on follow-up chest radiography, a chest CT was obtained for further evaluation. (Right) Axial CECT of the same patient shows a calcified right upper lobe subsegmental consolidation ﬈. Calcification is seldom identified on radiography and is more easily visualized on CT.

(Left) Axial NECT of a 54-yearold woman with metastatic pulmonary calcification in the setting of chronic renal disease shows subtle bilateral upper lobe ground-glass opacities ﬈ and mild reticulation. Note absence of noticeable calcification, which makes definitive diagnosis extremely difficult. (Right) Axial NECT MIP reformation of the same patient obtained 18 months later shows punctate upper lobe peribronchovascular calcifications ﬈. Calcification is visible on CT in up to 60% of affected patients.

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Diffuse Pulmonary Ossification KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Diffuse pulmonary ossification (DPO): Chronic progressive metaplastic ossification and mature bone formation in pulmonary interstitium and alveolar spaces

• Metastatic pulmonary calcification, granulomatous disease

IMAGING • Radiography ○ Small, calcified nodules; may not be visible due to size • CT ○ Calcified subpleural micronodules – May be difficult to identify on lung window due to small size; easily recognized on bone window – Increased conspicuity of micronodules on MIP reformations ○ Subpleural, lower lobe predominant branching calcifications ○ Lower lobe subpleural reticulation and honeycombing should suggest underlying interstitial lung disease

(Left) Axial HRCT of a patient with advanced pulmonary fibrosis and diffuse pulmonary ossification shows bilateral subpleural reticular opacities and honeycombing and scattered areas of dense subpleural calcifications ﬈. Note small anterior right pneumothorax ﬉. (Right) Axial HRCT (soft tissue window) of the same patient shows dendriform branching subpleural calcifications. Two histopathologic and morphologic patterns of involvement have been described (dendriform and nodular).

(Left) Low-power photomicrograph (trichrome stain) of a specimen of dendriform pulmonary ossification shows a branching pattern of bone formation ﬈ with intrinsic bone marrow elements ﬊. (Right) Axial CECT MIP reformation of a patient with chronic heart failure, calcific aortic stenosis ﬉, and nodular diffuse pulmonary ossification shows numerous small, calcified micronodules ﬈ in the bilateral subpleural lower lobes. The nodular type is associated with cardiovascular disorders.

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PATHOLOGY • DPO may be idiopathic or associated with preexisting disorders ○ Histologic patterns: Nodular and dendriform – Dendriform DPO: Interstitial pneumonias (usual interstitial pneumonia or nonspecific interstitial pneumonia), amyloidosis, asbestosis, drug toxicity – Nodular DPO: Mitral valve stenosis, aortic or subaortic stenosis, chronic left ventricular heart failure

CLINICAL ISSUES • Patients often asymptomatic; reported in up to 9% of patients with idiopathic pulmonary fibrosis

DIAGNOSTIC CHECKLIST • Consider DPO in patients basilar subpleural micronodular or branching pulmonary calcifications

Diffuse Pulmonary Ossification

Abbreviations • Diffuse pulmonary ossification (DPO)

Synonyms • • • •

Disseminated pulmonary ossification Idiopathic pulmonary ossification Dendriform pulmonary ossification Nodular pulmonary ossification

Definitions

Microscopic Features

• Chronic progressive metaplastic ossification and mature bone formation in pulmonary interstitium and alveolar spaces

• Histologic patterns: Nodular and dendriform ○ Morphologic overlap may occur ○ Dendriform DPO – Heterotopic bone with delicate dendritic branching pattern; typically affects alveolar interstitium – Often with bone marrow components that exhibit fat &/or hematopoietic elements ○ Nodular DPO – Rounded and discrete nodular ossification; predominantly affects alveolar spaces – Bone marrow elements are not typical; nodules predominantly located in areas of dense fibrosis

IMAGING Radiographic Findings • Small, calcified nodules ○ May not be visible due to size

CT Findings • Calcified subpleural micronodules ○ May be difficult to identify on lung window due to small size; easily recognized on bone window ○ Increased conspicuity of micronodules on MIP reformations • Subpleural, lower lobe predominant branching calcifications • Lower lobe subpleural reticulation and honeycombing should suggest underlying interstitial lung disease (ILD)

Imaging Recommendations • Best imaging tool ○ HRCT including prone imaging to exclude ILD

DIFFERENTIAL DIAGNOSIS Metastatic Pulmonary Calcification • Punctate calcifications within nodular, ring-like, or diffuse opacities; may spare subpleural lung ○ When centrilobular, manifest as small rosettes ○ May be mulberry-shaped or appear as miniature "cotton balls"

Granulomatous Disease • Less abundant nodules, may exhibit miliary pattern

PATHOLOGY General Features • DPO: Formation of mature bone, ± bone marrow islets, in pulmonary interstitium or alveolar spaces ○ Unknown pathogenesis ○ May be idiopathic or associated with preexisting disorders • 2 morphologic patterns ○ Dendriform DPO – Interstitial pneumonia [usual interstitial pneumonia or nonspecific interstitial pneumonia (NSIP)] – Chronic obstructive pulmonary disease – Organizing pneumonia

Inhalational, Inflammatory, Metabolic, and Post Treatment

– Hamman-Rich syndrome – Adult respiratory distress syndrome (ARDS) – Pneumoconiosis: Asbestosis – Amyloidosis – Drug toxicity (e.g., busulfan) – Idiopathic ○ Nodular DPO – Mitral valve stenosis – Aortic or subaortic stenosis – Chronic left ventricular heart failure

TERMINOLOGY

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Patients often asymptomatic • Other signs/symptoms ○ Symptoms due to underlying pulmonary or cardiac disease may be present ○ No role for serum chemistry assessment; calcium and phosphorus levels are normal

Demographics • Exact prevalence unknown • Reported in as many as 9% of patients with idiopathic pulmonary fibrosis • More common in elderly individuals • M:F = 7:1

Natural History & Prognosis • Indolent or very slowly progressive clinical course; frequent slight decline in lung function • Prognosis impacted by patient’s age and underlying medical conditions

Treatment • No known treatment

DIAGNOSTIC CHECKLIST Consider • DPO in patients with micronodular or branching lower lobe peripheral pulmonary calcifications, particularly if associated with cardiopulmonary disease

SELECTED REFERENCES 1.

Reddy TL et al: Idiopathic dendriform pulmonary ossification. J Thorac Imaging. 27(5):W108-10, 2012

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Emphysema KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Emphysema: Destruction of alveolar walls and permanent dilation of airspaces distal to terminal bronchioles

• Cystic lung disease ○ Pulmonary Langerhans cell histiocytosis ○ Lymphangioleiomyomatosis ○ Lymphoid interstitial pneumonia • Idiopathic pulmonary fibrosis • Constrictive bronchiolitis

IMAGING • Centrilobular emphysema (CLE): Focal regions of hyperlucency usually without well-defined walls ○ Central punctate density represents centrilobular artery around which alveoli are destroyed ○ Upper lobe predominant ○ As CLE advances, lucencies coalesce into bullae with walls that represent interlobular septa or atelectatic lung • Paraseptal emphysema: Single layer of subpleural lucencies ○ May exhibit well-defined regularly spaced borders representing interlobular septa • Panlobular emphysema (PLE): Diffuse regions of pulmonary low attenuation ○ Small vessels within regions of hyperlucency due to vasoconstriction from localized hypoxia

(Left) Axial NECT of a patient with centrilobular emphysema shows bilateral upper lobe lucencies without perceptible walls ﬉. The central dot sign ﬈ within several of the lucencies represents the centrilobular artery surrounded by destroyed lung parenchyma. Note a small pneumothorax ﬊, a common complication of emphysema. (Right) Axial HRCT of a patient with paraseptal emphysema shows a single subpleural layer of upper lobe pulmonary "cystic" spaces ﬈ marginated by adjacent interlobular septa ﬉.

(Left) Axial NECT of a patient with panlobular emphysema secondary to α-1 antitrypsin deficiency shows extensive asymmetric regions of pulmonary hyperlucency ﬈ in the lingula and lower lobes. Pulmonary vessels in the regions of lung hyperlucency are small and decreased in number. (Right) PA chest radiograph of a patient with panlobular emphysema secondary to α-1 antitrypsin deficiency shows bilateral lower lobe bullae ﬈ with compressive linear atelectasis ﬉ of the adjacent pulmonary parenchyma.

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CLINICAL ISSUES • CLE and paraseptal emphysema associated with smoking • PLE strongly associated with α-1 antitrypsin deficiency

DIAGNOSTIC CHECKLIST • Consider CLE in smokers with upper lobe lucencies without well-defined walls • Consider paraseptal emphysema in patients with single layer of upper lobe subpleural lucencies • Consider PLE when lower lobes appear uniformly hyperlucent with small intrinsic vessels

Emphysema

Abbreviations • • • • •

Advanced destructive emphysema (ADE) Centrilobular emphysema (CLE) Panlobular emphysema (PLE) Lung volume reduction surgery (LVRS) Usual interstitial pneumonia (UIP)

Synonyms • Panlobular = panacinar • Giant bullous emphysema = vanishing lung syndrome

Definitions • Emphysema: Destruction of alveolar walls and permanent dilation of airspaces distal to terminal bronchioles • Bulla: Focal lucency measuring > 1 cm in diameter with sharply demarcated thin wall • CLE: Destruction of alveolar walls and dilation of alveoli near centrilobular bronchioles ○ Sparing of peripheral alveoli close to interlobular septa • PLE: Destruction of all alveolar walls and dilation of all alveoli throughout secondary pulmonary lobule • Paraseptal emphysema: Destruction of alveolar walls and dilation of alveoli at periphery of secondary pulmonary lobules ○ Centrally located alveoli near centrilobular bronchiole are spared

•

•

IMAGING General Features • Best diagnostic clue ○ CLE: Focal regions of hyperlucency usually without welldefined walls – Central punctate density represents centrilobular artery around which alveoli are destroyed ○ Paraseptal emphysema: Single layer of subpleural lucencies – May exhibit well-defined, regularly spaced borders representing interlobular septa ○ PLE: Diffuse regions of pulmonary low attenuation – Hyperexpansion of lobules – Small vessels within regions of hyperlucency due to vasoconstriction from localized hypoxia – No significant bronchiectasis (distinguishes PLE from constrictive bronchiolitis) ○ Different types of emphysema frequently coexist • Location ○ CLE: Usually upper lobe predominant ○ PLE: Usually lower lobe predominant ○ Paraseptal emphysema: Subpleural, upper lobe predominant • Morphology ○ Regions of hyperlucency (HU < -950)

CT Findings • CLE: Centrilobular alveolar destruction ○ Hyperlucent foci without well-defined walls, surrounded by normal lung ○ Upper lobe predominant

• •

○ Early CLE: Central punctate density (i.e., central dot sign) within hyperlucency represents centrilobular artery surrounded by alveolar destruction ○ As CLE advances, lucencies coalesce into bullae with walls that represent interlobular septa or atelectatic lung – Coalescent lucencies termed confluent emphysema □ Centrilobular distribution difficult to discern – ADE: Generalized decreased lung attenuation □ "End-stage" CLE □ Architectural distortion □ Small central vessels with decreased branching □ May be indistinguishable from PLE Paraseptal emphysema: Alveolar destruction in periphery of secondary lobule ○ Contiguous single layer of subpleural lucencies < 1 cm in diameter ○ Upper lobe predominant ○ Lucencies may have well-defined walls representing thick interlobular septa or atelectatic adjacent lung ○ Lucencies may coalesce into subpleural bullae ○ Giant bullous emphysema: Coalescent lucencies with bullae occupying > 1/3 of hemithorax – Often asymmetric PLE: Diffuse alveolar destruction throughout secondary lobule ○ Diffuse low attenuation ± well-defined walls that represent interlobular septa ○ Lower lobe predominance ○ Small vessels with decreased branching ○ Early PLE may be subtle and difficult to detect; quantitative analysis may be helpful Quantitative CT: Computer software packages may quantify regions of hyperlucency (defined by HU < -950) Combined pulmonary fibrosis and emphysema ○ Upper lobe predominant emphysema (either CLE or paraseptal) ○ Lower lobe predominant fibrosis: UIP pattern or possible UIP pattern per American Thoracic Society criteria

Inhalational, Inflammatory, Metabolic, and Post Treatment

TERMINOLOGY

Imaging Recommendations • Best imaging tool ○ CT: Identification of hyperlucency, location relative to secondary pulmonary lobule, visibility of wall surrounding lucency • Protocol advice ○ Unenhanced volumetric thin-section CT recommended – MinIP reformations may delineate subtle regions of emphysema

DIFFERENTIAL DIAGNOSIS Cystic Lung Disease • Cystic lung disease: Well-defined walls as opposed to CLE ○ Centrilobular arteriole displaced by air cyst; vessel eccentric to air cyst as opposed to centrally located in CLE • Pulmonary Langerhans cell histiocytosis: Bizarrely shaped thick-walled air cysts • Lymphangioleiomyomatosis ○ Diffuse thin-walled round air cysts • Lymphoid interstitial pneumonia 439

Inhalational, Inflammatory, Metabolic, and Post Treatment

Emphysema ○ Few thin-walled air cysts, ground-glass opacities, ± centrilobular nodules

Idiopathic Pulmonary Fibrosis • May mimic paraseptal emphysema • Honeycombing characterized by multiple stacked layers of cysts with thick well-defined walls • Paraseptal emphysema demonstrates single layer of subpleural lucencies ± well-defined thin walls

Constrictive Bronchiolitis • Small airways disease results in hypoxic vasoconstriction with resultant hyperlucency • Hyperlucency of constrictive bronchiolitis may mimic PLE • Inflammation of small airway walls leads to bronchial dilation • Prior to bronchial dilation, constrictive bronchiolitis may be indistinguishable from PLE

Pneumothorax • Apical bullae or giant bullae may mimic pneumothorax, may be difficult to distinguish from pneumothorax • Clinical history may help: Pneumothorax usually causes acute chest pain or acute dyspnea • Visualization of pleural line favors pneumothorax • Septations may be found in either pneumothorax or giant bulla; more common in bullae

PATHOLOGY General Features • CLE ○ Most common subtype of emphysema ○ Alveolar dilatation and alveolar wall destruction within centrilobular portion of secondary pulmonary lobule – With disease progression, entire lobule is eventually destroyed ○ Centrilobular lesions coalesce to form bullae • Paraseptal emphysema ○ Destruction of alveolar walls and dilation of alveoli at periphery of secondary pulmonary lobules ○ Giant bullous emphysema: Bullae communicate with tracheobronchial tree, preferentially fill in inspiration, and result in progressive collapse of adjacent lung parenchyma • PLE: Destruction of alveolar walls of entire secondary pulmonary lobule • Combined pulmonary fibrosis and emphysema ○ Smoking-related lung disease ○ Coexistence of emphysema (either CLE or paraseptal) and fibrosis (either UIP or nonspecific interstitial pneumonia)

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Progressive dyspnea – Chronic cough that may be productive of clear/white sputum ○ Pulmonary function tests – Obstructive physiology – Decreased DLCO 440

• Other signs/symptoms ○ Acute pleuritic chest pain or dyspnea when ruptured bulla leads to pneumothorax

Demographics • CLE and paraseptal emphysema strongly associated with cigarette smoking ○ Paraseptal emphysema may affect nonsmokers ○ Giant bullous emphysema: Most common in young male smokers • PLE strongly associated with α-1 antitrypsin deficiency ○ Particularly in patients who are smokers – Development of emphysema rare in nonsmokers with α-1 antitrypsin deficiency ○ Patients may present at young age ○ May also be caused by intravenous Ritalin abuse

Natural History & Prognosis • Progressive hypoxia and development of pulmonary hypertension and cor pulmonale

Treatment • Pulmonary rehabilitation and medical optimization (bronchodilators, antiinflammatory agents) for all patients • Smoking cessation • LVRS: Patients with paraseptal emphysema with large bullae (including giant bullous emphysema) or heterogeneous emphysema with focal bullae (i.e., target areas for removal) ○ Space-occupying bullae may interfere with normal respiratory mechanics and increase work of breathing ○ Therapeutic goal: Reduction of ventilation/perfusion mismatch, improvement of respiratory mechanics • Bullectomy for giant bullous emphysema • Lung transplantation

DIAGNOSTIC CHECKLIST Consider • CLE in cigarette smokers with upper lobe hyperlucencies without well-defined walls • Paraseptal emphysema in patients with single layer of subpleural lucencies with upper lobe predominance • PLE when lower lobes appear uniformly hyperlucent with small intrinsic vessels

Image Interpretation Pearls • Identification of punctate dot in center of ill-defined hyperlucency should suggest CLE • Paraseptal emphysema exhibits single layer of thin-walled subpleural lucencies as opposed to honeycombing, which exhibits multiple layers of thick walled lucencies

SELECTED REFERENCES 1.

2. 3.

Kligerman S et al: Clinical-radiologic-pathologic correlation of smokingrelated diffuse parenchymal lung disease. Radiol Clin North Am. 54(6):10471063, 2016 Shah PL et al: Lung volume reduction for emphysema. Lancet Respir Med. ePub, 2016 Lynch DA et al: CT-definable subtypes of chronic obstructive pulmonary disease: a statement of the Fleischner Society. Radiology. 277(1):192-205, 2015

Emphysema Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Coronal NECT of a patient with centrilobular emphysema shows coalescent regions of lung destruction without adjacent architectural distortion, consistent with confluent emphysema ﬉. Also note regions of centrilobular emphysema that are less advanced ﬊ as well as foci of paraseptal emphysema ﬈. (Right) Coronal NECT of a patient with emphysema shows hyperexpanded upper lobes virtually replaced by confluent lucencies ﬊ with small intrinsic vessels ﬈, consistent with advanced destructive emphysema.

(Left) Coronal NECT of a male smoker shows lower lobe fine subpleural reticulations ﬈ and upper lobe paraseptal ﬊ and centrilobular ﬉ emphysema consistent with combined pulmonary fibrosis and emphysema. A right apical nodule ﬊ is concerning for primary lung cancer. (Right) Coronal CECT shows lower lobe subpleural fine reticular opacities ﬈ with intrinsic traction bronchiectasis ſt and upper lobe centrilobular ﬉ and paraseptal ﬊ emphysema consistent with combined pulmonary fibrosis and emphysema.

(Left) AP chest radiograph of a 35-year-old man with giant bullous emphysema who presented with progressive dyspnea shows a large lucency occupying most of the right hemithorax. The differential diagnosis includes a large loculated right pneumothorax and giant bullous emphysema. (Right) Coronal CECT of the same patient shows septations ﬈ coursing through the large cystic space consistent with giant bullous emphysema. The normal right lung parenchyma ﬊ is displaced medially. Note paraseptal emphysema ﬉ in the left lung.

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Idiopathic Pulmonary Hemosiderosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Idiopathic pulmonary hemosiderosis (IPH): Disorder of uncertain etiology characterized by recurrent alveolar capillary hemorrhage with resultant pulmonary hemosiderin deposition

• • • •

IMAGING

PATHOLOGY

• CT ○ Acute phase: Multifocal ground-glass opacities &/or consolidations in perihilar and lower lung distribution – Interlobular septal thickening and intralobular lines may be present producing crazy-paving pattern ○ Chronic phase: Lower lobe-predominant fibrosis – Intralobular lines, architectural distortion, traction bronchiectasis, and bronchiolectasis – Lower lung-predominant honeycombing ○ Rare findings – Perihilar masses (progressive massive fibrosis) – High-density pleural effusion from hemorrhage

• Diagnosis of exclusion: Identification of alveolar hemosiderin-laden macrophages

(Left) AP chest radiograph of a 4-year-old child with idiopathic pulmonary hemosiderosis who presented with hemoptysis shows diffuse bilateral homogeneous airspace opacities. (Right) Axial CECT of the same patient shows findings of idiopathic pulmonary hemosiderosis (a diagnosis of exclusion) characterized by bilateral consolidations ﬉ and ground-glass opacities ﬈. Bronchoalveolar lavage revealed hemosiderin-laden macrophages. Work-up for other etiologies of pulmonary hemorrhage was negative.

(Left) Coronal NECT of the same patient obtained 2 years later shows multifocal nodular consolidations ﬉ and scattered ground-glass opacities ﬈. Bronchoalveolar lavage confirmed recurrent hemorrhage. Affected patients with recurrent episodes of hemorrhage may develop pulmonary fibrosis. (Right) High-power photomicrograph (H&E stain) of a specimen of idiopathic pulmonary hemosiderosis shows fresh intraalveolar hemorrhage ﬉ on a background of normal alveolar architecture ﬊. (From DP: Thoracic 2e.)

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Granulomatosis with polyangiitis Systemic lupus erythematosus Goodpasture syndrome Mitral stenosis

CLINICAL ISSUES • Most commonly diagnosed in children < 10 years of age (80% of patients) • Classic triad: Hemoptysis, iron-deficiency anemia, pulmonary opacities on imaging ○ Children: Failure to thrive, dyspnea, and cough ○ Adults: Dyspnea and fatigue on exertion • Systemic corticosteroids may result in decreased episodes of hemorrhage and decreased fibrogenesis

Idiopathic Pulmonary Hemosiderosis • Small (1- to 3-mm pulmonary nodules) ± lower lung reticulation

Definitions • IIdiopathic pulmonary hemosiderosis (IPH): Disorder of uncertain etiology characterized by recurrent alveolar capillary hemorrhage with resultant pulmonary hemosiderin deposition

Associated Syndromes • Lane-Hamilton syndrome: IPH in conjunction with celiac disease

IMAGING General Features • Best diagnostic clue ○ Nonspecific imaging findings ○ Initially airspace opacities from hemorrhage, eventually progressing to fibrosis • Location ○ Perihilar and lower lung predominant, typical sparing of lung bases and apices

Radiographic Findings • Acute phase: Consolidation representing hemorrhage, often in perihilar batwing distribution ○ Usually clears in 3-10 days • Chronic phase: Low lung volumes, reticular opacities related to fibrosis

CT Findings • Acute phase: Multifocal ground-glass opacities &/or consolidations in perihilar and lower lung distribution ○ Interlobular septal thickening and intralobular lines may be present producing crazy-paving pattern • Chronic phase: Lower lobe-predominant fibrosis ○ Intralobular lines, architectural distortion, traction bronchiectasis, and bronchiolectasis ○ Honeycombing may be present, not necessarily subpleural, often lower lung predominant • Rare findings ○ Perihilar confluent masses (progressive massive fibrosis) ○ High-density (HU > 70) pleural effusion from hemorrhage

DIFFERENTIAL DIAGNOSIS Granulomatosis With Polyangiitis • Secondary hemosiderosis from diffuse alveolar hemorrhage (DAH) • Serology (+) for cytoplasmic antineutrophil antibody

Systemic Lupus Erythematosus

PATHOLOGY General Features • Pulmonary hemosiderosis may be primary or idiopathic (IPH) or secondary to any disease that causes alveolar hemorrhage • After bleeding from alveolar capillaries, hemoglobin transformed into hemosiderin • Hemosiderin ingested by macrophages, which in turn produce proinflammatory substances ○ Repeated hemorrhage leads to chronic inflammation and fibrosis • Etiology of IPH uncertain; several theories ○ Autoimmune: 25% of pediatric patients who survive IPH develop autoimmune disorder ○ Environmental: Association of pulmonary hemorrhage with black mold, Stachybotrys chartarum ○ Allergic: Association of IPH with allergy to cow's milk

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Classic triad: Hemoptysis (may be life-threatening), irondeficiency anemia, and pulmonary opacities on imaging ○ Acute phase: Cough, dyspnea, hemoptysis, acute respiratory failure ○ Chronic phase: Clubbing, cyanosis, cor pulmonale ○ Children: Failure to thrive, dyspnea, cough ○ Adults: Dyspnea and fatigue on exertion

Demographics • Most commonly diagnosed in children < 10 years of age (80% of patients) • Diagnosis in adulthood in 20% of patients, usually before 30 years of age

Natural History & Prognosis • Diagnosis of exclusion: Hemosiderin-laden alveolar macrophages in tissue or bronchoalveolar lavage fluid • Average survival after diagnosis in childhood: 2.5 years ○ Relapsing and remitting course; most develop pulmonary fibrosis and cor pulmonale • Adults tend to have more mild course

Treatment • Systemic corticosteroids may be of benefit with decreased episodes of hemorrhage and decreased fibrogenesis

DIAGNOSTIC CHECKLIST

• Secondary hemosiderosis from DAH • Serology (+) for antinuclear and anti-DNA antibodies

Consider

Goodpasture Syndrome

• IPH in child with history of hemoptysis or failure to thrive in whom CT shows perihilar ground-glass opacities or fibrosis

• Cause of secondary hemosiderosis • Serology (+) for antiglomerular basement membrane (GBM) antibodies

Mitral Stenosis

Inhalational, Inflammatory, Metabolic, and Post Treatment

TERMINOLOGY

SELECTED REFERENCES 1.

Khorashadi L et al: Idiopathic pulmonary haemosiderosis: spectrum of thoracic imaging findings in the adult patient. Clin Radiol. 70(5):459-65, 2015

• Severe pulmonary venous hypertension may cause alveolar hemorrhage with resultant pulmonary hemosiderosis 443

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Radiation-Induced Lung Disease KEY FACTS

TERMINOLOGY • Radiation therapy (RT) uses ionizing radiation to control cell growth by damaging DNA of cancerous tissue leading to cellular death • Treatment/palliation of thoracic neoplasms: Lung, breast, and esophageal cancers; thymic epithelial neoplasms; lymphoma; malignant pleural mesothelioma

IMAGING • CT ○ Pulmonary opacities within radiation treatment field with sharply linear or curvilinear margins ○ Location and distribution depend on location of neoplasm, RT technique, treatment plan, and extent of disease ○ Radiation pneumonitis (1-6 months after completion) – Ground-glass opacities, airspace opacities &/or consolidation – Small ipsilateral pleural effusion

(Left) Coronal fused FDG PET/CT of a 67-year-old woman with small cell lung cancer shows extensive FDGavid mediastinal ﬈ and bilateral supraclavicular lymphadenopathy ﬉ as well as left lung postobstructive pneumonitis ﬊. Radiation therapy was administered for cytoreduction. (Right) Axial CT of the same patient obtained for planning intensitymodulated radiation therapy shows the beam configuration used to deliver a palliative radiation dose to the affected mediastinal and left hilar lymph nodes.

(Left) PA chest radiograph of the same patient obtained 8 weeks after therapy shows bilateral heterogeneous opacities in the left upper lobe ﬈ and the paramediastinal right upper lobe ﬉ consistent with radiation pneumonitis. (Right) PA chest radiograph of the same patient obtained 13 months after therapy shows traction bronchiectasis ﬈ in the right upper lobe opacity and residual linear and irregular opacities in the left lung ﬊ consistent with radiation fibrosis. Radiation fibrosis usually stabilizes after 12-24 months.

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○ Radiation fibrosis (6-12 months after completion) – Decreasing opacities, traction bronchiectasis, volume loss, architectural distortion – Smooth pleural thickening, pleural effusion • FDG PET/CT ○ Detection of recurrence and distant metastasis ○ Radiation pneumonitis: Diffuse and homogeneous increased FDG uptake that decreases over time ○ Radiation fibrosis: Focal increased FDG uptake should suggest recurrent disease

TOP DIFFERENTIAL DIAGNOSES • Lung cancer (recurrent) • Pneumonia • Lymphangitic carcinomatosis

DIAGNOSTIC CHECKLIST • Consider radiation-induced lung disease in patients treated with RT and new opacities

Radiation-Induced Lung Disease

Abbreviations • Radiation-induced lung disease (RILD)

Definitions • Radiation therapy (RT) uses ionizing radiation to control cell growth by damaging DNA of cancerous tissue leading to cellular death ○ Treatment/palliation of thoracic neoplasms: Lung, breast, and esophageal cancers; thymic epithelial neoplasms; lymphoma; malignant pleural mesothelioma (MPM) • Conventional 2DRT uses 2 parallel beams with opposed directions (anteroposterior and posteroanterior) • New RT techniques have been developed in order to increase dose to target lesion and decrease dose to surrounding structures ○ 3D image reconstructed from CT data is used to determine target volume; multiple beams are used to conform target and deliver maximal radiation to neoplasm – 3D conformal RT (3DCRT): Each radiation beam is shaped to fit profile of target volume (previously, radiation treatment matched height and width of target lesion) □ 4D conformal RT uses respiratory gating – Intensity-modulated RT (IMRT): Next generation of 3DCRT; allows more precise conformation to 3D shape by modulating intensity of radiation beam in multiple small volumes – Stereotactic body RT (SBRT): Delivers hypofractionated high radiation dose to treat early non-small cell lung cancer (NSCLC) – Proton therapy (PT): Radiation dose is delivered to certain depth with minimal dose beyond target lesion; useful for neoplasms close to mediastinum

IMAGING General Features • Best diagnostic clue ○ Pulmonary opacities within radiation treatment field with sharply linear or curvilinear margins • Location ○ Pulmonary abnormalities relate to location of treated neoplasm – NSCLC: Adjacent to primary lesion; paramediastinal if lymphadenopathy is included in treatment portals; treatment field that includes primary neoplasm has additional 2-cm margin around tumor edge and 1-cm margin around regional lymph nodes – Small cell lung cancer: Radiation portals include primary neoplasm and can be extended to cover supraclavicular, hilar, mediastinal, and upper abdominal lymph nodes; pulmonary opacities may develop in multiple sites – Thymic epithelial neoplasms, esophageal cancer, lymphoma: Paramediastinal opacities; upper lobes in thymic neoplasms, lower lobes in distal esophageal cancer

– MPM: Lung, mediastinum, and chest wall adjacent to the treated site – Breast cancer: Upper lobes, middle lobe, and lingula; anterior subpleural distribution • Size ○ Extent of pulmonary opacities depends on technique – More extensive with conventional 2DRT – Less extensive with 3DCRT, IMRT, SBRT, and PT (limited to radiation portals) • Morphology ○ In early stage, pulmonary opacities follow shape of primary neoplasm

Radiographic Findings • Radiation pneumonitis (1-6 months after completion of radiation): Patchy airspace opacities &/or consolidations • Radiation fibrosis (6-12 months after completion of radiation, stabilizes after 12-24 months): Decreased airspace opacities/consolidation; traction bronchiectasis, volume loss, architectural distortion • Organizing pneumonia: Patchy or nodular consolidation; outside radiation portals, may affect contralateral lung ○ More frequent after RT for breast cancer (within 1 year of completing RT) – Could result from tangential irradiation in breast cancer; does not occur in other thoracic malignancies

Inhalational, Inflammatory, Metabolic, and Post Treatment

TERMINOLOGY

CT Findings • HRCT ○ Radiation pneumonitis – Conventional 2DRT: Ground-glass opacities, airspace opacities, &/or consolidation – Other techniques (3DCRT, IMRT, SBRT, PT) □ Patchy or diffuse ground-glass opacities &/or consolidation – Small ipsilateral pleural effusion – Treated lung neoplasm embedded within radiation pneumonitis – Opacities may resolve over period of 6 months or may evolve to fibrosis – CT findings may occur far from treated malignancy but are limited by radiation portals ○ Radiation fibrosis – 2DRT: Dense consolidations, traction bronchiectasis, volume loss, architectural distortion – Other techniques (3DCRT, IMRT, SBRT, PT) □ Modified conventional pattern (for new techniques): Dense consolidations, traction bronchiectasis, volume loss, architectural distortion (but less extensive than with 2DRT) □ Mass-like pattern □ Scar-like pattern – Smooth pleural thickening, pleural effusion (may be loculated) ○ Organizing pneumonia – Ground-glass opacities &/or consolidations □ Usually bilateral and peripheral; often migratory – Reversed halo sign • Bone CT ○ Rib sclerosis, fracture

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Inhalational, Inflammatory, Metabolic, and Post Treatment

Radiation-Induced Lung Disease Nuclear Medicine Findings • PET/CT ○ Used to detect recurrence and distant metastases ○ Radiation pneumonitis: Diffuse and homogeneous increased FDG uptake that decreases over time ○ Radiation fibrosis: Focal increased FDG uptake should suggest recurrent disease

Imaging Recommendations • Best imaging tool ○ CT for assessment of evolution of postradiation pulmonary abnormalities ○ PET/CT for identification of recurrence/metastases – PET/CT within 3 months after RT completion used to detect distant metastases or nonregional nodes but not to evaluate the primary tumor

DIFFERENTIAL DIAGNOSIS Lung Cancer (Recurrent) • Usually occurs within first 2 years after treatment • CT: Increased attenuation of previously stable radiation fibrosis; development of lobulated contours, new nodules, obliteration of previously bronchiectatic airways ○ Focal contrast-enhancement within radiation fibrosis ○ New lymphadenopathy, new pleural thickening or effusion

Pneumonia • Acute development of pulmonary findings outside radiation treatment field ○ Airspace opacities, consolidations, centrilobular nodules, &/or branching linear opacities

Lymphangitic Carcinomatosis • Known primary intrathoracic or extrathoracic malignant neoplasm • Nodular interlobular septal thickening; peribronchovascular thickening, thickening of fissures, subpleural nodules

PATHOLOGY

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CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Radiation pneumonitis: Dyspnea, cough, low-grade fever ○ Radiation fibrosis: Asymptomatic or chronic dyspnea • Other signs/symptoms ○ Cor pulmonale may complicate radiation fibrosis ○ Pericardial effusion ○ Esophagitis ○ Cardiomyopathy ○ Coronary artery disease ○ Radiation-induced liver injury (in treated distal esophageal carcinoma and MPM)

Natural History & Prognosis • Factors influencing radiation tissue damage ○ Radiation dose ○ Irradiated volume ○ Fractionation ○ Chemotherapy ○ Previous RT ○ Preexisting lung disease (emphysema, pulmonary fibrosis) ○ Age ○ Cigarette smoking • No linear relation between radiation dose and lung damage • Lung injury usually occurs after receiving > 40 Gy but occasionally with doses < 20 Gy • Development of 2nd primary malignancy: 2.4/100 patientyear after chemoradiation for lung cancer

Treatment • Corticosteroids for symptomatic patients

DIAGNOSTIC CHECKLIST Consider • Consider RILD in patients treated with RT who develop new pulmonary opacities

General Features

Image Interpretation Pearls

• RT causes diffuse alveolar damage: Acute exudative phase, proliferative phase, and chronic fibrosis

• Correlate imaging abnormalities with radiation treatment portal and treatment timeline

Microscopic Features

Reporting Tips

• Acute phase ○ Vascular congestion, increased capillary permeability, intraalveolar proteinaceous material, inflammatory cell infiltration • Subacute or proliferative phase ○ Interstitial fibrosis, type 2 alveolar cell proliferation, disruption of capillary function due to microvascular thrombus formation; abnormalities may resolve or may progress to chronic or fibrotic phase • Fibrotic phase ○ Fibroblast proliferation, progressive alveolar septal thickening

• Opacities outside treatment portal or occurring early after or before completion of RT should suggest different etiology

SELECTED REFERENCES 1.

2. 3. 4.

Pastis NJ Jr et al: Assessing the usefulness of 18F-fluorodeoxyglucose PETCT scan after stereotactic body radiotherapy for early-stage non-small cell lung cancer. Chest. 146(2):406-11, 2014 Benveniste MF et al: New era of radiotherapy: an update in radiationinduced lung disease. Clin Radiol. 68(6):e275-90, 2013 Chargari C et al: Complications of thoracic radiotherapy. Presse Med. 42(9 Pt 2):e342-51, 2013 Larici AR et al: Lung abnormalities at multimodality imaging after radiation therapy for non-small cell lung cancer. Radiographics. 31(3):771-89, 2011

Radiation-Induced Lung Disease Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Axial CECT of an asymptomatic 61-year-old woman demonstrates a spiculated nodule ﬈ in the left upper lobe that represented a biopsy-proven adenocarcinoma. (Right) Axial CECT of the same patient obtained 9 weeks after treatment with intensitymodulated radiation therapy shows the primary adenocarcinoma ﬉ surrounded by ground-glass opacity ﬊ and dense peripheral linear consolidations ﬈ consistent with radiation pneumonitis.

(Left) Axial CECT of the same patient obtained 12 months after treatment shows a dense left upper lobe consolidation that obliterates underlying lung markings and exhibits mildly lobular contours ﬈ suspicious for recurrent malignancy. (Right) Axial fused FDG PET/CT of the same patient shows FDG uptake in the consolidation similar to that of mediastinal background and no evidence of recurrent disease. PET/CT is very useful for distinguishing tumor recurrence from radiation fibrosis.

(Left) Axial NECT of a 64-yearold patient who was treated with radiation shows bilateral paramediastinal opacities ﬊ and architectural distortion with intrinsic traction bronchiectasis ﬈ consistent with radiation fibrosis. (Right) Coronal FDG PET of the same patient demonstrates a small focus of increased FDG uptake ﬈ suspicious for recurrent disease, which was confirmed on biopsy. Development of new focal increased FDG uptake strongly suggests recurrent disease and should be confirmed by biopsy.

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Inhalational, Inflammatory, Metabolic, and Post Treatment

Radiation-Induced Lung Disease

(Left) Axial NECT of a patient who received radiation therapy for malignancy shows subtle band-like ground-glass attenuation in the peripheral aspect of the left lung, which crosses the fissure and exhibits a straight border ﬈ with the adjacent uninvolved normal lung. (Right) Axial CECT of a patient with biopsy-proven primary lung cancer shows a polylobular right upper lobe nodule ﬈ on a background of centrilobular emphysema. The patient was not a surgical candidate and was referred to radiation oncology for definitive therapy.

(Left) Axial CECT of the same patient obtained 2 months after completion of radiation therapy to the lesion shows dense heterogeneous consolidation on a background of emphysema and obscuration of the right upper lobe nodule consistent with radiation pneumonitis. PET/CT imaging of this abnormality would show FDG avidity. (Right) Axial NECT of the same patient obtained 10 months after completion of therapy shows decreased right upper lung volume and an arcuate band-like opacity ﬈ that represents radiation fibrosis.

(Left) Axial NECT of a patient treated with radiation for breast cancer shows peripheral right lower lobe heterogeneous consolidations ﬈. Biopsy demonstrated organizing pneumonia. (Right) Axial fused FDG PET/CT of a patient treated with palliative brain radiation for metastases of lung cancer who developed organizing pneumonia shows multifocal bilateral peripheral consolidations ﬈ with FDG avidity. Organizing pneumonia is a well-recognized form of radiation-induced lung disease and occurs outside the radiation field.

448

Radiation-Induced Lung Disease Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) Axial NECT of a patient treated with stereotactic body radiation therapy for primary lung cancer shows a mass-like consolidation ﬈ affecting the left upper lobe and a small portion of the left lower lobe with an intrinsic air bronchogram ﬉. (Right) Sagittal NECT of the same patient demonstrates the linear morphology ﬈ of the left upper and left lower lobe airspace disease consistent with radiation fibrosis. Increasing thickness &/or lobular contours of such a lesion would be suspicious for recurrent malignancy.

(Left) Axial CECT of a patient who underwent left mastectomy ﬈ for breast cancer and received adjuvant irradiation to the surgical bed shows characteristic anterior subpleural reticulation and architectural distortion ﬉ consistent with radiation fibrosis. (Right) Sagittal CECT of the same patient shows the characteristic subpleural location of radiation fibrosis in treated breast cancer characterized by reticulation and ground-glass opacity ﬉ ipsilateral to the radiation treatment field.

(Left) PA chest radiograph of a woman with a remote history of left breast cancer treated with mastectomy and radiation who developed a radiation-induced lung cancer shows a left perihilar mass ﬈. (Right) Axial NECT of the same patient shows a mass-like consolidation of the left upper lobe ﬈ that was pathologically proven to represent primary lung adenocarcinoma developing amid preexistent radiation fibrosis. Radiation is associated with an increased risk of malignancy in the radiation field.

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Inhalational, Inflammatory, Metabolic, and Post Treatment

Drug-Induced Lung Disease KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Drug-induced lung disease (DILD): Antibiotics, cardiovascular and anti-inflammatory drugs, anticonvulsants, chemotherapy, and recreational drugs

• • • • •

IMAGING • HRCT/CT: Optimal characterization of disease patterns ○ Diffuse alveolar damage: Consolidation predominantly in dependent lung; patchy ground-glass opacities ○ Organizing pneumonia: Peribronchovascular, subpleural, perilobular opacities; reversed halo sign ○ Nonspecific interstitial pneumonia (NSIP): Basilar predominant ground-glass opacities; reticular opacities, bronchiectasis &/or bronchiolectasis in fibrotic NSIP ○ Hypersensitivity pneumonitis: Bilateral ground-glass opacities &/or centrilobular nodules, air-trapping ○ Eosinophilic pneumonia: Peripheral subpleural opacities ○ Diffuse alveolar hemorrhage: Bilateral scattered or diffuse ground-glass opacities

(Left) Axial CECT of a 46-yearold woman with dyspnea who was treated for lung cancer ﬉ with cyclophosphamide shows diffuse left lung ground-glass opacities ﬈ and consolidations ﬊. (Right) Coronal CECT of the same patient shows predominantly central left lung ground-glass opacities. Bronchoalveolar lavage showed hemosiderinladen macrophages supporting the diagnosis of pulmonary hemorrhage. Patients with pulmonary hemorrhage usually present with dyspnea, and hemoptysis may be absent.

(Left) Axial NECT of a 72-yearold man with atrial fibrillation treated with amiodarone shows bilateral subpleural ground-glass ﬊ and reticular ﬈ opacities without associated honeycombing, compatible with a nonspecific interstitial pneumonia pattern. Histologic and CT findings are usually not pathognomonic; rarely, amiodarone may produce high-attenuation opacities (not shown). (Right) High-power photomicrograph (H&E stain) of a specimen of amiodarone lung damage shows prominent subpleural lymphocytic infiltrates ﬊.

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Diffuse alveolar damage Organizing pneumonia Nonspecific interstitial pneumonia Hypersensitivity pneumonitis Eosinophilic pneumonia

CLINICAL ISSUES • Symptoms: Dyspnea, cough, fever, eosinophilia • Drug toxicity influenced by ↑ age, smoking, preexisting lung disease, genetic predisposition, prior or concomitant radiation therapy, combination of anticancer agents • Treatment: Drug withdrawal, corticosteroids

DIAGNOSTIC CHECKLIST • Consider DILD in patient with history of drug therapy with new &/or progressive respiratory symptoms • Diagnosis requires knowledge of drug history and specific patterns of injury

Drug-Induced Lung Disease

Abbreviations • Drug-induced lung disease (DILD)

Synonyms • Drug-induced lung injury

Definitions • DILD consists of lung reaction to a variety of drugs and exhibits multiple histologic patterns ○ Common drugs: Reported with antibiotics, cardiovascular drugs, antiinflammatory drugs, anticonvulsants, chemotherapy agents, and recreational drugs

IMAGING General Features • Best diagnostic clue ○ Diagnosis of exclusion – Nonspecific clinical and radiologic abnormalities ○ High index of suspicion after development of lung disease ○ Clinical &/or radiologic improvement may be seen with cessation of therapy

Radiographic Findings • Radiography ○ Abnormalities on radiography may be 1st indicator of disease ○ Several patterns can coexist in same patient • Specific patterns of disease ○ Lung abnormalities – Diffuse alveolar damage (DAD) □ Identical to acute respiratory distress syndrome (ARDS) from other causes (i.e., opacities involving all 4 lung quadrants) □ Chest radiography often normal in early disease – Organizing pneumonia (OP) □ Unilateral or bilateral patchy consolidations; may be migratory □ Peribronchial and subpleural distribution – Nonspecific interstitial pneumonia (NSIP) □ Basilar reticular &/or patchy peripheral opacities – Hypersensitivity pneumonitis (HP) □ Nonspecific opacities □ May develop within hours, days, or months of starting drug – Eosinophilic pneumonia □ Peripheral upper lobe opacities □ So-called photographic negative of pulmonary edema □ May exhibit diffuse airspace disease – Pulmonary edema □ Indistinguishable from noncardiogenic or cardiogenic edema □ Diffuse bilateral interstitial and alveolar opacities – Diffuse alveolar hemorrhage (DAH) □ Patchy or diffuse alveolar opacities (hemoptysis) – Vasculitis □ Patchy interstitial &/or airspace opacities

□ Subsegmental, peripheral distribution □ Cavitation ○ Associated abnormalities – Pleural effusions, pneumothorax – Pneumomediastinum – Lymphadenopathy

CT Findings • HRCT ○ Optimal characterization of pulmonary opacities: Ground-glass, alveolar, interstitial (reticular &/or nodular) ○ Specific pulmonary patterns – DAD □ Consolidation predominantly in dependent lung □ Patchy ground-glass opacities evolve to diffuse involvement – OP □ Peribronchovascular, peripheral, subpleural opacities □ Perilobular opacities □ Reversed halo or atoll signs – NSIP □ Basilar subpleural ground-glass opacities □ Reticular opacities, traction bronchiectasis, &/or bronchiolectasis suggest fibrotic NSIP – HP □ Bilateral ground-glass opacities &/or small poorly defined centrilobular nodules, air-trapping – Eosinophilic pneumonia □ Peripheral upper lobe homogeneous opacities □ Diffuse airspace disease – DAH □ Bilateral patchy or diffuse ground-glass opacities □ May exhibit crazy-paving pattern – Pulmonary edema □ Interlobular septal thickening, ground-glass opacities □ Cardiomegaly, pleural effusion – High-attenuation lung opacities □ Characteristic of amiodarone DILD □ Optimally demonstrated on NECT • Associated abnormalities ○ Pleural effusion, pleural fibrosis ○ Lymphadenopathy – Hilar, mediastinal, &/or cervical lymphadenopathy; may be generalized (mimics lymphoma) ○ Cardiovascular – Thromboembolism, pulmonary hypertension, cardiomyopathy, pericardial effusion

Inhalational, Inflammatory, Metabolic, and Post Treatment

TERMINOLOGY

Nuclear Medicine Findings • FDG PET/CT: Increased FDG uptake reported in early stage disease without symptoms or HRCT abnormalities

Imaging Recommendations • Best imaging tool ○ HRCT: Detection and characterization of DILD ○ NECT: Evaluation of pleural/pericardial disease, lymphadenopathy • Protocol advice ○ Thin-section (1-3 mm) CT 451

Inhalational, Inflammatory, Metabolic, and Post Treatment

Drug-Induced Lung Disease ○ Supine inspiratory and expiratory imaging

DIFFERENTIAL DIAGNOSIS

Gross Pathologic & Surgical Features • Most lung biopsies not pathognomonic; exclusion of other diseases and documentation of injury pattern

Organizing Pneumonia

Microscopic Features

• Viral &/or bacterial infection; environmental triggers

• DAD ○ Acute exudative phase: Hyaline membranes ○ Reparative phase: Proliferation of type II pneumocytes and fibrosis • NSIP ○ Hyperplastic type II pneumocytes, interstitial infiltration by mononuclear cells, mild interstitial fibrosis • UIP ○ Dense interstitial fibrosis; honeycombing • HP ○ Acute stage: Interstitial lymphocytes infiltrates, edema, noncaseating granulomas and bronchiolitis obliterans ○ Chronic stage: Fibrosis • Eosinophilic pneumonia ○ Eosinophil, lymphocyte, and plasma cell infiltration of alveolar septa • OP ○ Immature fibroblasts plug respiratory bronchioles and alveolar ducts

Nonspecific Interstitial Pneumonia • May be idiopathic or secondary to connective tissue disease ○ Scleroderma: Dilated air-filled esophagus ○ Rheumatoid arthritis: Erosion of distal clavicles, synovitis of hands and feet ○ Inflammatory bowel disease: Bronchiectasis

Idiopathic Pulmonary Fibrosis • May be idiopathic or secondary to connective tissue disease • Same imaging findings as DILD

Hypersensitivity Pneumonitis • Exposure to organic dust; multiple previous episodes

Eosinophilic Pneumonia • Environmental triggers, causative drugs typically not anticancer agents, infection

PATHOLOGY General Features • Etiology ○ Mechanism of DILD not fully understood – Drug damage to alveolar and bronchial epithelia □ Most do not produce direct cell toxicity, but drug metabolites lead to cell injury – Possible etiologies □ Higher drug concentration in lung than in other organs □ Specific lung activation pathways □ Induction of immune cascades ○ Most histologic abnormalities are nonspecific; few allow immediate identification of etiology (e.g., amiodarone) ○ DAD/interstitial fibrosis: Cyclophosphamide, methotrexate, gemcitabine, rituximab, interleukin, interferon ○ NSIP: Amiodarone, nitrofurantoin, bleomycin, methotrexate, docetaxel, irinotecan, gefitinib, erlotinib ○ UIP: Amiodarone, azathioprine, flecainide, ifosfamide, melphalan, nitrofurantoin, rituximab ○ HP: Mesalamine, fluoxetine, amitriptyline,cyclophosphamide, paclitaxel ○ OP: Amiodarone, nitrofurantoin, carbamazepine, bleomycin, methotrexate, cyclophosphamide ○ DAH: Anticoagulants, carbamazepine, bevacizumab, cytarabine ○ Pulmonary edema from cardiotoxicity: Rosiglitazone, zidovudine, doxorubicin, daunomycin, cyclophosphamide, sunitinib, imatinib, cocaine, ethyl alcohol (ETOH) ○ Pleural/pericardial effusion: Docetaxel ○ Hilar/mediastinal lymphadenopathy: Methotrexate ○ Thromboembolism: Gemcitabine, cisplatin

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Variable: Dyspnea, cough, fever, variable onset from immediate to years after drug initiation

Demographics • Age ○ Neonate to elderly

Natural History & Prognosis • Drug toxicity influenced by ↑ age, smoking, preexisting lung disease, genetic predisposition, prior or concomitant radiation therapy, combination of anticancer agents • Symptom improvement after drug discontinuation • Prognosis depends on type of drug and underlying clinical, physiologic, and pathologic severity of DILD

Treatment • Drug withdrawal 1st and most important step • Management of pulmonary symptoms • Corticosteroids in very symptomatic patients or in those with DILD progression in spite of drug discontinuation

DIAGNOSTIC CHECKLIST Consider • DILD in patient with history of drug therapy with new &/or progressive respiratory symptoms

Image Interpretation Pearls • Diagnosis requires investigation of drug history and individual pattern of pulmonary injury

SELECTED REFERENCES 1.

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Carter BW et al: Acute thoracic findings in oncologic patients. J Thorac Imaging. 30(4): 233-56, 2015

Drug-Induced Lung Disease Inhalational, Inflammatory, Metabolic, and Post Treatment

(Left) PA chest radiograph of a 42-year-old woman treated with cyclophosphamide shows bilateral reticular and airspace opacities ﬈. (Right) Axial CECT of the same patient shows bilateral opacities on a background of bronchiectasis and bronchiolectasis ﬈. Note patchy consolidations ﬊ and ground-glass opacities ﬉ that exhibit an asymmetric distribution affecting predominantly the right lung. The findings are consistent with a nonspecific interstitial pneumonia pattern. The patient responded to corticosteroid therapy.

(Left) Axial CECT of a 68-yearold woman treated with cisplatin demonstrates bilateral subpleural heterogeneous opacities ﬊ characterized by central ground-glass attenuation and peripheral consolidation (reversed halo sign) compatible with organizing pneumonia. (Right) Axial CECT of the same patient obtained 8 weeks after cessation of therapy shows residual ground-glass opacity ﬈ in the right lung base. Affected patients have a variable prognosis that depends on the severity of lung damage.

(Left) Axial NECT of a 52-yearold man treated with cyclophosphamide, adriamycin, and doxorubicin shows bilateral subpleural nodular airspace opacities ﬈. (Right) Axial fused FDG PET/CT of the same patient shows increased FDG uptake within the peripheral lung opacities ﬈. Biopsy was performed to exclude fungal infection, but revealed organizing pneumonia. Administration of combinations of anticancer agents increases the likelihood of development of druginduced lung disease.

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SECTION 12

Congenital

Approach to Congenital Familial Idiopathic Pulmonary Fibrosis Birt-Hogg-Dubé Syndrome Hermansky-Pudlak Syndrome Tuberous Sclerosis Neurofibromatosis Alveolar Microlithiasis α-1 Antitrypsin Deficiency Primary Ciliary Dyskinesia Primary Immunodeficiencies Chronic Granulomatous Disease Cystic Fibrosis Childhood Interstitial Lung Disease (chILD)

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Congenital

Approach to Congenital Introduction A wide variety of congenital abnormalities and syndromes may result in abnormalities affecting the compartments of the thorax. In some cases, these effects may produce no significant clinical symptoms, and associated abnormalities may be detected incidentally on imaging studies performed for other indications. In other instances, these conditions may result in significant clinical symptoms prompting medical attention. Regardless of the presentation, imaging plays an important role in the identification and characterization of congenital abnormalities involving the chest, particularly the lung parenchyma and the interstitium. In some cases, identification of the predominant abnormality, such as pulmonary fibrosis, cysts, bronchiectasis, and calcified nodules, leads to the appropriate diagnosis. In other cases, a combination of imaging features and clinical history enables generation of a focused differential diagnosis.

Imaging Congenital disorders affecting the thorax may produce abnormalities that are initially detected on chest radiography. However, CT is the imaging modality of choice for fully evaluating and characterizing the findings, determining the extent of involvement, and identifying potential complications. The disease processes affecting the lung parenchyma and interstitium may result in various combinations of CT findings but can generally be classified based on the predominant abnormality, such as pulmonary fibrosis in familial idiopathic pulmonary fibrosis (FIPF) and Hermansky-Pudlak syndrome (HPS), cystic lung disease in BirtHogg-Dubé (BHD) syndrome, micronodular calcifications in alveolar microlithiasis, and bronchiectasis in primary ciliary dyskinesia (PCD) and cystic fibrosis (CF). Familial Idiopathic Pulmonary Fibrosis FIPF is an autosomal dominant disorder characterized by clinical features consistent with idiopathic pulmonary fibrosis (IPF) and compatible HRCT or histologic evidence of usual interstitial pneumonia (UIP). The diagnosis should be suspected when ≥ 2 primary biological family members (parent, sibling, or child) are affected. Numerous genetic mutations have been described, and the disease likely results from interactions between genetic and environmental factors (e.g., cigarette smoking, metal dust exposure, gastroesophageal reflux). Patients diagnosed with FIPF tend to be younger than those with IPF, although the outcomes are similar. On HRCT/CT, FIPF manifests with classic imaging findings of UIP/IPF, including subpleural reticular opacities, honeycombing, and traction bronchiectasis/bronchiolectasis with an apicobasal gradient. Differentiation between FIPF and IPF cannot be made on imaging alone and requires correlation with personal and family history. Birt-Hogg-Dubé Syndrome BHD syndrome is an autosomal dominant disorder that predisposes affected individuals to the development of pulmonary and renal cysts, renal neoplasms, and fibrofolliculomas via a genetic defect on chromosome 17p11.2 (FLCN) that encodes folliculin (tumor-suppressor protein). Specific diagnostic criteria have been established and include major and minor criteria. On HRCT/CT, the most common abnormality is bilateral basilar predominant lung cysts (present in 89% of cases). These cysts 456

are usually thin-walled, variable in size, lower lobe predominant, abut the pleura and interlobar fissures, and may abut or incorporate portions of adjacent pulmonary vessels. BHD syndrome may be complicated by pneumothorax. Hermansky-Pudlak Syndrome HPS is an autosomal recessive genetic disorder characterized by oculocutaneous albinism, platelet dysfunction, and accumulation of ceroid-lipofuscin in lysosomes of cells of multiple organs and the reticuloendothelial system. Ten different types have been identified, and pulmonary fibrosis, which develops in 50-70% of affected patients, is most severe in HPS-1, which is the most common type. In America, HPS is most common in Puerto Rico, where the prevalence is 1 in 1,800 individuals. On HRCT/CT, specific findings may be present in early and advanced disease. In the early stages of the disease, interlobular septal thickening, reticular opacities, perihilar fibrosis, and ground-glass opacities are the most common abnormalities. In advanced disease, typical findings include honeycombing, subpleural cysts, peribronchial thickening, and traction bronchiectasis/bronchiolectasis. HPS may mimic IPF, although there is usually greater lower lobe predominance in the latter. Tuberous Sclerosis Tuberous sclerosis complex (TSC) is a multisystem autosomal dominant genetic disorder characterized by multifocal hamartomas and benign and malignant neoplasms affecting the brain, skin, retina, kidney, heart, and lungs. TSC is the 2nd most common phakomatosis after neurofibromatosis type 1 (NF1) and occurs due to mutations of the TSC1 and TSC2 genes. There are major and minor diagnostic criteria for TSC, and the level of diagnostic certainty (definite, probable, or suspect) can be ascertained by tallying these criteria. On HRCT/CT, the most common findings in the lungs include lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH). LAM manifests the same way as it does in patients without TSC, with diffuse bilateral thin-walled cysts that tend to increase in both number and size over time. MMPH distinguishes TSC from LAM and appears as multiple noncalcified pulmonary micronodules that may be solid or ground-glass in attenuation. Potential complications include pneumothorax and chylous pleural effusion. Other organs involved include the heart (myocardial fatty foci, rhabdomyoma), kidneys (angiomyolipoma, cysts, renal cell carcinoma), and bones (cystlike or osteoblastic lesions, scoliosis). Neurofibromatosis NF1 is an autosomal dominant genetic disorder that results from a mutation in the NF1 gene on human chromosome 17 responsible for making the neurofibromin protein. It is the most common phakomatosis, is associated with systemic manifestations that may involve the thorax, and is classically characterized by focal (neurofibroma) or diffuse (plexiform neurofibromas) benign peripheral nerve sheath neoplasms. Degeneration into malignant peripheral nerve sheath tumors occurs in 2-16% of patients with NF1. On HRCT/CT, thin-walled apical bullae and cysts and pulmonary fibrosis (reticular opacities, honeycombing, and traction bronchiectasis/bronchiolectasis) may be present in the lungs. Intrapulmonary neurofibromas are uncommon but when present manifest as well-defined pulmonary nodules or

Approach to Congenital Pulmonary infection (pneumonia and lung abscess) is the most common complication of CGD.

Pulmonary Alveolar Microlithiasis Pulmonary alveolar microlithiasis is a rare autosomal recessive disorder characterized by the intraalveolar accumulation of nodular calcium phosphate aggregates (known as microliths or calcospherites) due to mutation of the SLC34A2 gene. Although most patients are asymptomatic early on in the disease, progression to cor pulmonale and respiratory failure occurs in most cases.

On HRCT/CT, imaging findings consistent with pulmonary infection are typically present, the most common of which include consolidation and lung abscess formation, reactive lymphadenopathy, pulmonary nodules, tree-in-bud opacities, and mediastinal abscess. Scarring with traction bronchiectasis and emphysema may be present in patients with recurrent pulmonary infections.

On HRCT/CT, the characteristic finding is numerous dense, small (< 1 mm) pulmonary micronodules representing microliths. Other findings include consolidation, ground-glass opacity, interlobular septal thickening, thickening of bronchovascular bundles, and cysts. The so-called crazy-paving pattern may be seen when multiple calcified nodules are present along the interlobular septa. α-1 Antitrypsin Deficiency α-1 antitrypsin deficiency (AATD) is a genetic disorder resulting from a wide variety of abnormalities in the SERPINA1 gene, such as single-point mutations, insertions, and deletions. People with AATD are predisposed to pulmonary and liver abnormalities with associated early-onset chronic obstructive pulmonary disease (COPD), cirrhosis, and malignancies, such as hepatocellular carcinoma. Its primary manifestation is earlyonset panlobular emphysema, and ~ 1-5% of patients with COPD are estimated to have AATD. Although extremely rare, emphysema has been reported in children with AATD. On HRCT/CT, AATD manifests as panlobular emphysema with homogeneous decreased pulmonary attenuation that involves the entirety of the secondary pulmonary lobule and exhibits a lower lobe predominance. A paucity of pulmonary vessels is usually noted in the affected areas. Primary Immunodeficiencies Primary immunodeficiencies (PIDs) are inherited disorders in which 1 or several components of the immune system are decreased, missing, or demonstrate inappropriate function. This group of PID includes > 200 different disorders and syndromes, the clinical presentation and complications of which depend on the type of defect. They can affect primarily either the upper airways (e.g., sinusitis and otitis media) or the lower respiratory tract [e.g., pneumonia, bronchitis, bronchiectasis, and interstitial lung disease (ILD)]. On HRCT/CT, a variety of abnormalities may be identified and differ based on the underlying etiology. Pneumonia is one of the most common findings and may appear as segmental or lobar consolidation, ground-glass opacity, or a crazy-paving pattern. Small airways involvement manifests as tree-in-bud opacities or bronchial wall thickening. Potential complications include pneumatoceles, abscess formation, and pulmonary hemorrhage. Chronic Granulomatous Disease Chronic granulomatous disease (CGD) is an inherited disease that increases the body's susceptibility to infections caused by certain bacteria and fungi. The specific mechanism of CGD is a defect in the gene that encodes nicotinamide adenine dinucleotide phosphate oxidase system, resulting in deficient production of the oxygen radicals needed by phagocytic vacuoles for intracellular killing of microorganisms. X-linked CGD is responsible for 70% of cases, whereas autosomal recessive CGD is responsible for the remaining 30%.

Congenital

masses. Associated findings include nonpulmonary neurofibromas and thoracic meningoceles.

Children's Interstitial Lung Disease Children's ILD (chILD) refers to a diverse group of rare pulmonary disorders, including growth and developmental abnormalities and immunological problems that compromise gas exchange. The chILD syndrome is considered to be present when an infant (< 2 years of age) with diffuse lung disease has the common causes of pulmonary disease excluded as the primary diagnosis and has at least 3 of the following 4 criteria: (1) Respiratory symptoms (e.g., cough); (2) respiratory signs (e.g., retractions, digital clubbing); (3) hypoxemia; and (4) diffuse abnormalities on chest radiography or CT. The initial diagnosis requires exclusion of the more common causes of diffuse lung disease, such as CF, immunodeficiency syndromes, congenital heart disease, bronchopulmonary dysplasia, pulmonary infection, PCD, and recurrent aspiration. HRCT/CT manifestations vary significantly and depend on underlying conditions. The most common abnormalities include diffuse ground-glass opacities, interlobular septal thickening, lung cysts, mosaic attenuation, and air-trapping. Primary Ciliary Dyskinesia PCD is an autosomal recessive genetic disorder characterized by abnormal ciliary ultrastructure with resultant mucociliary dysfunction and otosinopulmonary disease. Kartagener syndrome, a triad of situs inversus, sinusitis &/or nasal polyposis, and bronchiectasis, accounts for 50% of PCD cases. Functional airway abnormalities predispose to recurrent pulmonary infections. On HRCT/CT, PCD results in bronchiectasis with a predilection for the middle lobe and lingula. Other findings include bronchial wall thickening, mucus plugging, centrilobular nodules, tree-in-bud opacities, and consolidations. Associated situs abnormalities may also be present and provide a clue to the diagnosis. Cystic Fibrosis CF is an autosomal recessive genetic disorder characterized by dysfunction in chloride transport and accounts for up to 25% of adult cases of bronchiectasis. On HRCT/CT, bronchiectasis is the most common finding and tends to be diffuse and most severe in the upper lobes. Bronchial wall thickening is the earliest abnormality. Hyperinflation is also present early in the course of the disease and is initially reversible but invariably becomes permanent. It should be noted that CT abnormalities correlate more strongly with deterioration of clinical status than pulmonary function.

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Congenital

Approach to Congenital

(Left) PA chest radiograph of a 47-year-old man with familial idiopathic pulmonary fibrosis demonstrates reticular opacities ﬈ that are most pronounced in the subpleural and basilar lungs. (Right) Axial NECT of the same patient shows pulmonary fibrosis ﬈ characterized by bilateral traction bronchiectasis and bronchiolectasis ﬊ indistinguishable from sporadic idiopathic pulmonary fibrosis. Differentiation between these entities cannot be made on imaging alone and requires correlation with personal and family history.

(Left) Axial CECT of a 41-yearold woman with Birt-HoggDubé syndrome shows multiple thin-walled cysts ﬈ in the right lung and sublobar right lower lobe atelectasis ﬉. (Right) Axial CECT through the abdomen of the same patient demonstrates a heterogeneous mass ﬈ in the right kidney with average Hounsfield units > 50. Patients with Birt-Hogg-Dubé syndrome are at an increased risk for developing renal malignancies, such as renal cell carcinoma.

(Left) Axial NECT of a patient with advanced HermanskyPudlak syndrome demonstrates numerous clustered thin-walled cysts in the lower lobes on a background of ground-glass opacity. (Right) Coronal NECT of the same patient shows the distribution of cysts with a greater preponderance in the lower lobes. In advanced disease, typical findings include honeycombing, subpleural cysts, peribronchovascular thickening, and traction bronchiectasis or bronchiolectasis.

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Approach to Congenital Congenital

(Left) PA chest radiograph of a patient with tuberous sclerosis complex demonstrates bilateral pulmonary reticular opacities and a small right pleural effusion ﬈. (Right) Coronal NECT of the same patient shows numerous thinwalled cysts ﬊ scattered throughout the lungs and a small to moderate right pleural effusion. The most common pulmonary abnormality identified in patients with lymphangioleiomyomatosis is diffuse thin-walled cysts that tend to increase in number and size over time.

(Left) Coronal CECT of a patient with tuberous sclerosis complex demonstrates numerous bilateral groundglass nodules ﬈ consistent with multifocal micronodular pneumocyte hyperplasia. The latter distinguishes tuberous sclerosis complex from lymphangioleiomyomatosis and manifests as multiple solid or ground-glass lung nodules. (Right) Axial CECT through the abdomen of the same patient demonstrates multiple angiomyolipomas arising from and nearly replacing the right kidney.

(Left) Axial CECT through the upper chest of a patient with neurofibromatosis type 1 shows numerous neurofibromas arising from the chest wall ﬈ and mediastinum ﬉ and encroaching on the upper lobes. (Right) Axial CECT of a patient with neurofibromatosis type 1 shows numerous thin-walled cysts ﬈ in the right lung. Additional pulmonary abnormalities include apical bullae and cysts and findings of pulmonary fibrosis.

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Congenital

Approach to Congenital

(Left) Axial CECT of a patient with pulmonary alveolar microlithiasis demonstrates numerous micronodules ﬈ within the peripheral lungs bilaterally. (Right) Axial CECT (bone window) of the same patient shows that many of the pulmonary micronodules demonstrate calcification. This is an atypical manifestation of pulmonary alveolar microlithiasis and mimics diffuse pulmonary ossification.

(Left) PA chest radiograph of a patient with α-1 antitrypsin deficiency shows hyperexpansion of the lungs and emphysema that is most pronounced in the lower lung zones ﬈. (Right) Coronal CECT of the same patient demonstrates lower lobepredominant panlobular emphysema characterized by decreased lung attenuation and paucity of intrinsic pulmonary vessels ﬉. Affected patients are predisposed to early-onset chronic obstructive pulmonary disease, cirrhosis, and hepatocellular carcinoma.

(Left) PA chest radiograph demonstrates dextrocardia ﬉ and other features of situs inversus as well as airspace opacities in the bilateral lower lung zones. (Right) Axial NECT of the same patient shows extensive bilateral basilar bronchiectasis ﬈, bronchovascular opacities, consolidations ﬊, and dextrocardia ﬉. The findings are consistent with primary ciliary dyskinesia in this patient with Kartagener syndrome.

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Approach to Congenital Congenital

(Left) PA chest radiograph of a 19-year-old man with chronic granulomatous disease demonstrates multifocal bilateral pulmonary consolidations ﬈ and a small right pleural effusion. (Right) Coronal NECT of the same patient shows nodular and mass-like consolidations ﬈ with irregular borders. Imaging findings of pulmonary infection are most common and include consolidation, pulmonary nodules, tree-inbud opacities, and reactive lymphadenopathy as well as complications, such as lung or mediastinal abscess.

(Left) PA chest radiograph of a patient with cystic fibrosis demonstrates central bronchiectasis that is most prominent in the upper and mid lung zones. Bronchial wall thickening is also present bilaterally. (Right) Coronal NECT of the same patient demonstrates marked bronchiectasis ﬈ in the upper lobes and, to a lesser extent, the lower lobes. This distribution of bronchiectasis is characteristic of cystic fibrosis.

(Left) Axial NECT of a patient with cystic fibrosis demonstrates multifocal right lung bronchiectasis ﬈ with extensive intrinsic endoluminal mucus plugging ﬉. (Right) Axial CECT of a patient with cystic fibrosis demonstrates a region of severe bronchiectasis in the anterior left upper lobe. A nodular opacity ﬈ in the dependent aspect of an upper lobe bronchiectatic space represents saprophytic fungal colonization (mycetoma).

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Congenital

Familial Idiopathic Pulmonary Fibrosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Familial idiopathic pulmonary fibrosis (FIPF) ○ Should be suspected when ≥ 2 primary biological family members (parent, sibling, or offspring) are affected ○ Clinical features compatible with idiopathic pulmonary fibrosis (IPF) + compatible HRCT or histologic evidence of usual interstitial pneumonia (UIP)

• Idiopathic pulmonary fibrosis • Hermansky-Pudlak syndrome

IMAGING • CT ○ Characteristic findings of UIP – Abnormalities with apicobasal gradient (i.e., lower lobe predominance) – Subpleural reticulation (> 90%) – Traction bronchiectasis (> 80%) – Subpleural honeycombing (30%) ○ Hilar and mediastinal lymphadenopathy ○ HRCT screening of family members of patients with FIPF not recommended

(Left) Axial HRCT of a 57-yearold man (brother #1) with familial idiopathic pulmonary fibrosis shows bilateral subpleural cysts ﬈, honeycombing ﬉, and scattered patchy subpleural opacities that demonstrated an apicobasal gradient. (Right) Axial HRCT of the same patient shows basilar predominant multifocal cysts, subpleural honeycombing ﬊, traction bronchiectasis ﬈, and ground-glass opacities ﬉. Familial idiopathic pulmonary fibrosis should be suspected when ≥ 2 primary biologic family members are affected.

(Left) Axial HRCT of a 55-yearold man (brother #2) with familial idiopathic pulmonary fibrosis shows extensive pulmonary fibrosis characterized by subpleural honeycombing ﬊ and traction bronchiectasis ﬈. Note more advanced disease in the right lung with resultant volume loss. (Right) Axial CECT of the same patient shows asymmetric interstitial fibrosis characterized by traction bronchiolectasis ﬉, which is more pronounced on the right side. Innumerable genetic variants have been linked to this disease.

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PATHOLOGY • Autosomal dominant inheritance with variable penetrance • Genetic testing is available/recommended for telomerase genes or surfactant protein genes • Histologic features of UIP with extensive honeycombing

CLINICAL ISSUES • Clinical symptoms: Dyspnea on exertion (85%), cough (70%) • No notable differences in clinical, radiological, or pathologic features when compared to nonfamilial IPF • Poor prognosis: Median survival time < 3 years

DIAGNOSTIC CHECKLIST • Consider FIPF in patient with UIP pattern of fibrosis and family members with known interstitial pulmonary fibrosis

Familial Idiopathic Pulmonary Fibrosis

Abbreviations • Idiopathic pulmonary fibrosis (IPF) • Familial IPF (FIPF) • Usual interstitial pneumonia (UIP)

Microscopic Features • Histologic features of UIP with extensive honeycombing • Diffuse alveolar damage superimposed on background of UIP has been described

CLINICAL ISSUES

Synonyms

Presentation

• Familial pulmonary fibrosis

• Most common signs/symptoms ○ FIPF is virtually indistinguishable from sporadic IPF with exception of younger age at diagnosis for FIPF ○ Diagnosis should be suspected when ≥ 2 members of same family are affected ○ No notable differences in clinical, radiological, or pathologic features when compared to sporadic IPF • Other signs/symptoms ○ Dyspnea on exertion (85%) ○ Cough (70%) ○ Bibasilar crackles (> 90%) ○ Clubbing (30%) ○ Lung cancer (~ 10%)

Definitions • FIPF is subset of IPF • No widely accepted definition ○ ≥ 2 primary biological family members (parent, sibling, offspring) with IPF ○ Clinical features compatible with IPF + compatible HRCT findings or histologic evidence of UIP

IMAGING CT Findings • Characteristic findings of UIP ○ Abnormalities with apicobasal gradient (i.e., lower lobe predominance) ○ Subpleural reticulation (> 90%) ○ Traction bronchiectasis (> 80%) ○ Subpleural honeycombing (30%) • Hilar and mediastinal lymphadenopathy • HRCT screening of family members of patients with FIPF not recommended

Imaging Recommendations • Best imaging tool ○ HRCT

DIFFERENTIAL DIAGNOSIS Idiopathic Pulmonary Fibrosis • Sporadic or nonfamilial form of IPF • Identical imaging findings

Hermansky-Pudlak Syndrome • Oculocutaneous albinism, platelet dysfunction, pulmonary fibrosis, and granulomatous colitis • Pulmonary fibrosis at young age (20-40 years of age)

PATHOLOGY General Features • Autosomal dominant inheritance with variable penetrance • Likely results from interactions between genetic and environmental factors (e.g., cigarette smoking, metal dust exposure, gastroesophageal reflux) • Described genetic mutations ○ Common: 10 loci (3q26, 4q22, 5p15, 6p24, 7q22, 10q24, 11p15, 13q34, 15q14-15, and 19q13) ○ Rare: 9 genes [TERT, TERC (hTR), DKC1, TINF2, RTEL1 and PARN, SFTPC, SFTPA2, and ABCA3] • Role of genetic testing is yet to be defined but available for telomerase genes [TERT, TERC (hTR), DKC1, TINF2, RTEL1 and PARN] or surfactant protein genes (SFTPC, SFTPA2, and ABCA3)

Congenital

TERMINOLOGY

Demographics • FIPF represents 3-5% of all UIP; may be as high as 20% • Slightly more common in females • Younger age than IPF ○ Due to "genetic anticipation": Disease onset at earlier age or greater disease severity in successive generations • High proportion of affected patients are either current or former smokers

Natural History & Prognosis • Poor prognosis ○ Similar outcomes for FIPF and IPF ○ Median survival time < 3 years • Total number of affected family members correlates with higher risk of earlier mortality ○ Hazard ratio of 1.4 for each additional affected family member • Up to 10% of patients with IPF will eventually have close relative with idiopathic interstitial pneumonia

Treatment • No effective treatment available • As with sporadic IPF, lung transplantation is often required

DIAGNOSTIC CHECKLIST Consider • FIPF in patient with UIP pattern of fibrosis and family members with known interstitial pulmonary fibrosis

SELECTED REFERENCES 1. 2. 3. 4. 5.

Kropski JA et al: Genetic evaluation and testing of patients and families with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. ePub, 2016 Ravaglia C et al: Features and outcome of familial idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis. 31(1):28-36, 2014 Talbert JL et al: Familial Interstitial Pneumonia (FIP). Clin Pulm Med. 21(3):120-127, 2014 Rosas IO et al: Early interstitial lung disease in familial pulmonary fibrosis. Am J Respir Crit Care Med. 176(7):698-705, 2007 Lee HL et al: Familial idiopathic pulmonary fibrosis: clinical features and outcome. Chest. 127(6):2034-41, 2005

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Congenital

Birt-Hogg-Dubé Syndrome KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Rare inherited disorder characterized by triad of lung cysts (pneumothorax) and renal and cutaneous lesions

• • • •

IMAGING • Radiography ○ May be normal, lung cysts are usually not visible ○ May demonstrate pneumothorax (up to 38% of cases) • CT/HRCT ○ Bilateral basilar predominant lung cysts (up to 89% of cases) – Rounded, ovoid, lentiform cysts – Thin-walled cysts; may be lobular &/or multiseptate – Cysts may abut pleura, interlobular septa, and vessels ○ Pneumothorax – Findings of prior lung resection or pleurodesis for treatment of pneumothorax

(Left) Axial CECT of a 68-yearold man with Birt-Hogg-Dubé syndrome demonstrates multifocal bilateral thinwalled pulmonary cysts. One cyst exhibits lentiform ﬉ morphology and another a close relationship to a pulmonary vessel ﬈. (Right) Coronal CECT of the same patient shows that the cysts are bilateral and basilar predominant, exhibit lentiform shapes ﬉, and have a close relationship to the pleural surfaces ﬊. The adjacent lung parenchyma is normal, and the cysts are not associated with pulmonary nodules.

(Left) Axial NECT of a 46-yearold man with Birt-Hogg-Dubé syndrome who presented with a spontaneous pneumothorax ﬈ shows lentiform ﬊ and septated ﬉ pulmonary cysts closely associated with the pleural surfaces. (Right) Axial CECT of a 33-year-old woman with Birt-Hogg-Dubé syndrome shows a left upper lobe ovoid thin-walled pulmonary cyst. Note the small vessel ﬈ that protrudes into the cyst lumen, a characteristic feature. The patient presented with chest pain related to a spontaneous pneumomediastinum ﬉.

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Lymphangioleiomyomatosis Pulmonary Langerhans cell histiocytosis Lymphoid interstitial pneumonia Pneumocystis jirovecii pneumonia

CLINICAL ISSUES • Rare disorder; autosomal dominant inheritance • Typically asymptomatic; diagnosed incidentally • Chest pain and dyspnea related to spontaneous pneumothorax • Chronic cough and dyspnea with severe lung involvement • Typically normal pulmonary function

DIAGNOSTIC CHECKLIST • Consider Birt-Hogg-Dubé syndrome in young patients with spontaneous pneumothorax (or family history of pneumothorax) and skin and renal lesions

Birt-Hogg-Dubé Syndrome

PATHOLOGY

Definitions

General Features

• Rare inherited disorder characterized by triad of lung cysts (often complicated with pneumothorax) and renal and cutaneous lesions

• Genetic defect on chromosome 17p11.2 (FLCN); encodes folliculin (tumor suppressor protein) ○ Postulated overexpression of metalloproteinases may result in alveolar wall breakdown and cyst formation • Diagnostic criteria (1 major, 2 minor) ○ Major: ≥ 5 adult-onset fibrofolliculomas (at least 1 histologically confirmed), FLCN mutation ○ Minor: Bilateral basilar lung cysts ± pneumothorax, early onset (≤ 50 years), multifocal/bilateral renal cell cancer, 1st-degree relative with Birt-Hogg-Dubé syndrome

IMAGING General Features • Best diagnostic clue ○ Bilateral basilar predominant lentiform cysts abutting pleura, septa, and pulmonary vessels

Radiographic Findings • Radiography ○ May be normal; lung cysts usually not visible ○ May demonstrate pneumothorax (recurrent)

CT Findings • Bilateral basilar predominant lung cysts (up to 89% of cases) ○ Rounded, ovoid, or lentiform cysts ○ Thin-walled cysts – Variable number and size, may be > 2 cm – Morphology: Lobular &/or multiseptate – Lower lobe and subpleural predominant – Abut or incorporate portions of pulmonary vessels – Abut pleura and interlobular septa • Pneumothorax (up to 38% of cases) ○ Evidence of prior lung resection &/or pleurodesis for pneumothorax • Pneumomediastinum

Imaging Recommendations • Best imaging tool ○ HRCT for assessment and characterization of lung cysts ○ Abdominal imaging for detection and characterization of renal lesions

DIFFERENTIAL DIAGNOSIS Lymphangioleiomyomatosis • Women of childbearing age, progressive symptoms • Diffuse lung cysts, chylothorax, pneumothorax, lymphadenopathy, renal angiomyolipomas

Pulmonary Langerhans Cell Histiocytosis • Smoking-related disease • Upper lung zone predominant cysts with irregular/bizarre shapes ± small stellate nodules

Lymphoid Interstitial Pneumonia • History of Sjögren syndrome • Lung cysts, ground-glass opacities, centrilobular nodules

Light-Chain Deposition Disease • Lymphoproliferative or autoimmune disorder • Systemic immunoglobulin light chain deposition • Diffuse lung cysts with vessels in cyst walls and pulmonary nodules

Congenital

TERMINOLOGY

Gross Pathologic & Surgical Features • Lung cysts ○ Lentiform, subpleural, involve < 30% of lung • Renal lesions ○ Multifocal bilateral renal carcinomas, renal cysts, occasional angiomyolipomas • Skin lesions ○ Fibrofolliculomas (hair follicle hamartomas), trichodiscomas (hair disk tumors), achordons (skin tags) ○ Other skin lesions, including basal and squamous cancers • Other organs ○ Benign and malignant lesions of numerous organs, including: Thyroid, parathyroid gland, parotid gland, breast, colon, and peripheral nerves

Microscopic Features • Lung cysts lined by pneumocytes, abut septa, vessels, &/or pleura; small pulmonary veins may protrude into cyst

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Typically asymptomatic; diagnosed incidentally ○ Chest pain and dyspnea related to spontaneous pneumothorax ○ Chronic cough and dyspnea with severe lung involvement • Other signs/symptoms ○ Typically normal pulmonary function

Demographics • Rare disorder; autosomal dominant inheritance • ~ 200 affected families described

DIAGNOSTIC CHECKLIST Consider • Birt-Hogg-Dubé syndrome in young patients with spontaneous pneumothorax (or family history of pneumothorax) and skin and renal lesions

SELECTED REFERENCES 1. 2.

Dal Sasso AA et al: Birt-Hogg-Dubé syndrome. State-of-the-art review with emphasis on pulmonary involvement. Respir Med. 109(3):289-96, 2015 Tobino K et al: Characteristics of pulmonary cysts in Birt-Hogg-Dubé syndrome: thin-section CT findings of the chest in 12 patients. Eur J Radiol. 77(3):403-9, 2011

465

Congenital

Hermansky-Pudlak Syndrome KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Hermansky-Pudlak syndrome (HPS) • Autosomal recessive disorder characterized by oculocutaneous albinism, platelet dysfunction, pulmonary fibrosis, and granulomatous colitis

• Idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, collagen vascular disease-associated interstitial lung disease, familial idiopathic fibrosis

IMAGING

• Impaired intracellular trafficking of melanin in retinal and skin melanosomes: Oculocutaneous albinism • Accumulation of ceroid-lipofuscin in multiple organs and reticuloendothelial system: Pulmonary fibrosis, granulomatous colitis, renal failure, cardiomyopathy

• Radiography ○ May be normal ○ Reticular/reticulonodular opacities, interstitial opacities, perihilar fibrosis ○ Upper, mid, and lower lung zone involvement ○ Asymmetric involvement ○ Pleural thickening • CT ○ Early: Ground-glass opacities, interlobular septal thickening, reticular opacities, perihilar fibrosis ○ Advanced: Subpleural cysts, peribronchial thickening, traction bronchiectasis/bronchiolectasis, honeycombing

(Left) Axial NECT of an 8-yearold boy with HermanskyPudlak syndrome who presented with albinism, horizontal nystagmus, congenital neutropenia, and platelet dysfunction shows bilateral ground-glass opacities on a background of reticulation ﬈. Motion artifact is likely related to dyspnea. (Right) Axial NECT of the same patient shows ground-glass opacities, interlobular septal thickening ﬈, and mosaic attenuation. Ground-glass attenuation and interlobular septal thickening are common in early disease.

(Left) Axial HRCT of a 43-yearold man with HermanskyPudlak syndrome and oculocutaneous albinism, nystagmus, and chronic progressive dyspnea shows advanced pulmonary fibrosis in the bilateral upper lobes characterized by architectural distortion, subpleural cysts ﬈, honeycombing ﬊, and traction bronchiectasis ﬉. (Right) Axial HRCT of the same patient shows extensive asymmetric perihilar pulmonary fibrosis with architectural distortion ﬊ and traction bronchiectasis ﬈, typical of advanced disease.

466

PATHOLOGY

CLINICAL ISSUES • Pulmonary fibrosis in 50-70% of affected patients • Prevalence in Puerto Rico: 1 in 1,800 persons

DIAGNOSTIC CHECKLIST • Consider HPS in young patient with albinism and interstitial lung disease

Hermansky-Pudlak Syndrome

Abbreviations • Hermansky-Pudlak syndrome (HPS)

Definitions • Autosomal recessive genetic disorder characterized by ○ Oculocutaneous albinism (i.e., light pigmentation of skin, hair, and eyes) ○ Platelet dysfunction (leading to prolonged bleeding and easy bruising) ○ Pulmonary fibrosis ○ Granulomatous colitis

• Impaired formation of platelet dense bodies: Bleeding disorder • Accumulation of ceroid-lipofuscin in multiple organs and reticuloendothelial system: Pulmonary fibrosis, granulomatous colitis, renal failure, cardiomyopathy

Microscopic Features • Alveolar septal and peribronchial fibrosis due to accumulation of ceroid-lipofuscin in alveolar macrophages • Type 2 pneumocytes: Foamy swelling and degeneration with desquamation into alveolar spaces • Abnormal surfactant accumulation • Usual interstitial pneumonia-like interstitial pneumonia with advanced pulmonary fibrosis and honeycombing

IMAGING Radiographic Findings • • • •

Chest radiography may be normal at presentation Reticular/reticulonodular opacities Interstitial opacities, perihilar fibrosis Upper, mid, and lower lung zone involvement; frequent upper lobe involvement, particularly in advanced disease • Asymmetric pulmonary involvement • Pleural thickening

CT Findings • Early disease ○ Ground-glass opacities, interlobular septal thickening, reticular opacities, perihilar fibrosis • Advanced disease ○ Subpleural cysts, peribronchial thickening, traction bronchiectasis/bronchiolectasis ○ Honeycombing (less than in usual interstitial pneumonia)

DIFFERENTIAL DIAGNOSIS

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Oculocutaneous albinism • Other signs/symptoms ○ Hemorrhagic diathesis, epistaxis, melena, easy bruising ○ Pulmonary fibrosis in 50-70% of patients with HPS – Females; 3rd and 4th decades of life – Associated with variants HPS-1, HPS-2, and HPS-4 – Nonspecific respiratory symptoms

Demographics • Worldwide prevalence: 1 in 50,0000 to 100,0000 • In North America, most patients with HPS are from Puerto Rico ○ Prevalence in Puerto Rico: 1 in 1,800; 5 of every 6 albinos • Pulmonary fibrosis most common in females • Sporadic cases without gender predominance reported in other countries and all races and ethnicities

Idiopathic Pulmonary Fibrosis

Natural History & Prognosis

• Frequently affects patients > 50 years of age • Lower lobe subpleural fibrosis, reticulation, and honeycombing

• Pulmonary fibrosis in patients 20-40 years of age • Most patients with HPS-1 die from complications of pulmonary fibrosis • Death from complications of granulomatous colitis

Nonspecific Interstitial Pneumonia • Bilateral symmetric ground-glass opacities and reticulation • Less honeycombing

Collagen Vascular Disease-Associated Interstitial Lung Disease • History of autoimmunity • Usual interstitial pneumonia and nonspecific interstitial pneumonia patterns

Treatment • • • •

Supplemental oxygen Avoidance of cigarette smoke and other irritants Lung transplantation only effective treatment Pirfenidone (antibiotic) may help slow fibrosis progression in selected patients

DIAGNOSTIC CHECKLIST

Familial Idiopathic Fibrosis

Consider

• ≥ 2 family members affected • Typically manifests with usual interstitial pneumonia pattern

• HPS in young patient with albinism and interstitial lung disease

PATHOLOGY General Features • Autosomal recessive disorder; 10 types of HPS described • Impaired intracellular trafficking of melanin in retinal and skin melanosomes: Oculocutaneous albinism

Congenital

TERMINOLOGY

SELECTED REFERENCES 1. 2.

El-Chemaly S et al: Hermansky-Pudlak syndrome. Clin Chest Med. 37(3):50511, 2016 Vicary GW et al: Pulmonary fibrosis in Hermansky-Pudlak syndrome. Ann Am Thorac Soc. 13(10):1839-1846, 2016

467

Congenital

Tuberous Sclerosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• • • •

• • • •

Tuberous sclerosis complex (TSC) Lymphangioleiomyomatosis (LAM) Multifocal micronodular pneumocyte hyperplasia (MMPH) TSC: Rare multisystem autosomal dominant hereditary neurocutaneous disorder characterized by multifocal hamartomas and benign and malignant neoplasms • Pulmonary involvement may be LAM &/or MMPH

IMAGING • CT ○ LAM – Diffuse, bilateral, thin-walled cysts – Pneumothorax – Pleural effusion (chylothorax) ○ MMPH: Noncalcified nodules; 1-3 mm ○ Myocardial fatty foci, rhabdomyomas ○ Renal angiomyolipomas, renal cysts, renal cell carcinomas

(Left) Axial NECT of a 36-yearold woman with tuberous sclerosis complex shows small multifocal pulmonary nodules ﬈ that correlate with multifocal micronodular pneumocyte hyperplasia and findings of lymphangioleiomyomatosis (LAM), which is characterized by thin-walled pulmonary cysts ﬉. (Right) Axial NECT of the same patient shows numerous small pulmonary nodules ﬈ likely related to multifocal micronodular pneumocyte hyperplasia and small, thin-walled pulmonary cysts ﬉ representing LAM.

(Left) Gross photograph of a cut section of the lung of a patient with tuberous sclerosis complex and end-stage lymphangioleiomyomatosis who underwent lung transplantation shows that normal lung is completely replaced by multifocal pulmonary thin-walled cysts of various sizes. (Right) Lowpower photomicrograph (H&E stain) of the same patient shows a partially collapsed pulmonary cyst with multifocal areas of LAM cell proliferation ﬈ surrounded by normal uninvolved lung parenchyma ﬉.

468

Pulmonary Langerhans cell histiocytosis Birt-Hogg-Dubé syndrome Lymphoid interstitial pneumonia Light-chain deposition disease

PATHOLOGY • TSC: Autosomal dominant inheritance • LAM: Proliferation of neoplastic smooth muscle (LAM) cells • MMPH: Multicentric well-demarcated nodular growth of type II pneumocytes along alveolar septa • Lung enlargement; diffusely distributed lung cysts

CLINICAL ISSUES • May be asymptomatic; cough, dyspnea, hemoptysis

DIAGNOSTIC CHECKLIST • Consider TSC-LAM in patient with skin lesions, neurological symptoms, and cystic lung disease

Tuberous Sclerosis

Abbreviations • Tuberous sclerosis complex (TSC) • Lymphangioleiomyomatosis (LAM) • Multifocal micronodular pneumocyte hyperplasia (MMPH)

Synonyms • Bourneville disease, Bourneville-Pringle disease

Definitions • Rare multisystem autosomal dominant hereditary neurocutaneous disorder characterized by multifocal hamartomas and benign and malignant neoplasms ○ Typically affects brain, skin, retina, kidney, heart, and lung ○ Classic triad of facial angiofibromas, epilepsy, and mental retardation (Vogt triad) ○ Pulmonary involvement: LAM &/or MMPH ○ TSC-LAM is 5-10 times more common than sporadic LAM (S-LAM) • TSC is 2nd most common phakomatosis after neurofibromatosis type 1

IMAGING Radiographic Findings • • • •

Increased lung volume Diffuse fine reticular opacities Secondary spontaneous pneumothorax Unilateral or bilateral pleural effusions ○ 2/3 are chylous (chylothorax)

CT Findings • LAM ○ Cysts – Diffuse (no lung zones spared), bilateral – Thin-walled – Relatively uniform size – Normal intervening lung – Increased cyst profusion and size over time ○ Pneumothorax ○ Pleural effusion: Water attenuation even if chylous ○ Rarely: Involvement of mediastinum and thoracic duct; pulmonary artery aneurysm • MMPH ○ Noncalcified pulmonary nodules; solid or ground glass – Multiple, 2-10 mm in size – Random distribution; may be miliary • Cardiac ○ Myocardial fatty foci; exhibit fat attenuation on CT ○ Rhabdomyoma: Single or multiple myocardial nodule(s) • Renal ○ Angiomyolipomas – Tend to be large, multiple, and bilateral – Heterogeneous, intrinsic macroscopic fat (< -20 HU) – Aneurysm formation ○ Renal cysts, polycystic kidneys; may affect young children ○ Renal cell carcinoma (2-4% in TSC) – Clear cell carcinoma is most common subtype □ Hypervascular on CECT □ May exhibit cystic change and calcification

• Osseous manifestations: Cyst-like lesions, osteoblastic lesions, scoliosis

Imaging Recommendations

Congenital

TERMINOLOGY

• Best imaging tool ○ HRCT for optimal characterization of LAM &/or MMPH ○ European Respiratory Society guidelines for patients with TSC – HRCT recommended for all women at 18 years of age – If normal, follow-up HRCT at 30-40 years of age – HRCT for unexplained respiratory symptoms at any age

DIFFERENTIAL DIAGNOSIS Pulmonary Langerhans Cell Histiocytosis • M = F; smokers • Upper lung zone-predominant involvement ○ Spares basilar lung near costophrenic angles • Small cysts, bizarre shapes, nodular cyst walls • Small irregular lung nodules (≤ 10 mm)

Birt-Hogg-Dubé Syndrome • Rare autosomal dominant inherited genodermatosis with lung cysts, renal, and skin lesions • Pulmonary cysts ± secondary spontaneous pneumothorax ○ Cysts abut pleura, septa, and vessels • Renal tumors (e.g., chromophobe renal cell carcinoma, oncocytoma, hybrid chromophobe-oncocytoma, clear cell carcinoma, papillary renal cancer, angiomyolipoma) • Skin hamartomas (e.g., fibrofolliculomas, trichodiscomas, acrochordons)

Lymphoid Interstitial Pneumonia • Adult women; 50-60 years of age • Immunosuppression, Sjögren syndrome • Few large cysts, ground-glass opacities, poorly defined nodules

Light-Chain Deposition Disease • Association with lymphoproliferative disorders • Light-chain deposition in alveolar walls, small airways, and vessels • Diffuse lung cysts of variable size

PATHOLOGY General Features • LAM may be sporadic (S-LAM) or inherited and associated with TSC (TSC-LAM) ○ TSC – 80% result from de novo mutations – 20% result from inherited mutations • TSC: Autosomal dominant inheritance ○ Mutations – TSC1 encoding hamartin in chromosome 9q34 – TSC2 encoding tuberin on chromosome 16p13.3 – Genetic testing does not identify mutations in up to 25% of patients with TSC (value of clinical diagnostic criteria) ○ TSC-LAM: 1 germline mutation and 1 acquired mutation in either TSC1 or TSC2 ○ S-LAM: 2 acquired mutations typically in TSC2 469

Congenital

Tuberous Sclerosis Gross Pathologic & Surgical Features • • • •

Lung enlargement; diffusely distributed lung cysts Thoracic, abdominal, and pelvic lymphadenopathy Enlarged thoracic duct and lymphatic channels Lymphangioleiomyoma: Chyle-filled encapsulated mass

Microscopic Features • LAM ○ Proliferation of neoplastic smooth muscle (LAM) cells around bronchioles, alveolar walls, lymphatics, blood vessels, and cyst walls ○ Immunoreactivity for α-smooth muscle cell actin, desmin, vimentin, and human melanin black (HMB-45) • MMPH ○ Multicentric well-demarcated nodular growth of type II pneumocytes along alveolar septa – Absence of immunohistochemical staining for HMB45 – Reported in TSC and TSC-LAM

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ LAM – May remain asymptomatic; diagnosed incidentally or during screening – Cough, dyspnea, hemoptysis – Chest pain from spontaneous pneumothorax; higher frequency in TSC-LAM than in S-LAM – Symptoms related to pleural effusion (chylothorax); up to 39% of patients during course of disease – Pulmonary function tests: Airway obstruction; restrictive pattern less frequent □ Better pulmonary function in TSC-LAM than in SLAM ○ MMPH: Asymptomatic, indolent, nonprogressive • Other signs/symptoms ○ Skin lesions (present in most patients): Hypomelanotic macules, angiofibromas, shagreen patches, forehead plaques, ungual fibromas ○ Renal angiomyolipomas (in 70-80% of patients with TSC) – Affect younger patients than those with S-LAM – Tendency to grow and require surgery □ Predictors of rupture: Tumor size > 4 cm, aneurysm size ≥ 5 mm – Palpable mass, abdominal pain, hematuria, anemia ○ Cardiac rhabdomyoma and myocardial fatty foci: Often asymptomatic; rarely arrhythmia or heart failure – ~ 75% occur before 1 year of age ○ Neurologic manifestations: Seizures, cognitive impairment

• MMPH in > 40% of patients with TSC and in ~ 80% of patients with TSC-LAM • 1/3 of TSC patients exhibit both LAM and MMPH

Diagnosis • Identification of cortical tubers, retinal abnormalities, cardiac rhabdomyomas, LAM, and renal angiomyolipomas allow presumptive diagnosis of TSC, particularly in patients with skin lesions • Diagnostic criteria: At least 2 major criteria or 1 major and 2 minor criteria ○ Major criteria: Hypomelanotic macules, facial angiofibromas, ungual fibromas, Shagreen patches, retinal hamartomas, cortical tubers, subependymal nodules, subependymal giant cell astrocytomas, cardiac rhabdomyomas, LAM, renal angiomyolipomas ○ Minor criteria: Confetti-like skin lesions, dental enamel pits, intraoral fibromas, retinal achromic patches, multiple renal cysts, nonrenal hamartomas, cerebral white matter radial migration lines

Natural History & Prognosis • Prognosis ○ Poor prognosis; 45% of affected patients die before 35 years of age ○ Progressive airflow obstruction and respiratory failure – Most patients with TSC-LAM eventually develop respiratory symptoms (63%) and 12.5% die from LAM

Treatment • Pneumothorax ○ Drainage, pleurodesis, pleurectomy; may complicate lung transplantation • Chylothorax ○ Thoracic duct ligation, pleurovenous shunt • Avoidance of estrogen • Sirolimus or everolimus (mTOR inhibitors) to prevent LAM cell proliferation ○ May reduce volume of subependymal giant cell astrocytomas ○ May improve facial angiofibromas ○ May help control angiomyolipoma growth • Treatment with antiestrogen therapies with no conclusive evidence that hormonal suppression effectively modifies natural history of disease • Lung transplantation ○ Best treatment option for advanced disease ○ Recurrent disease reported in transplanted lung

DIAGNOSTIC CHECKLIST Consider • TSC-LAM in patient with skin lesions, neurological symptoms, and cystic lung disease

Demographics • Incidence: 1 in 5,000-10,000 live births ○ 95% penetrance • Prevalence of TSC-LAM: 1-3% (but may be as high as 35%) of women with TSC; also reported in men with TSC • Average age at diagnosis: 35 years of age ○ Risk of TSC-LAM increases ~ 8% per year • TSC-LAM in men (30%) 470

SELECTED REFERENCES 1. 2. 3.

Johnson SR et al: Lymphangioleiomyomatosis. Clin Chest Med. 37(3):389403, 2016 von Ranke FM et al: Tuberous sclerosis complex: state-of-the-art review with a focus on pulmonary involvement. Lung. 193(5):619-27, 2015 Cudzilo CJ et al: Lymphangioleiomyomatosis screening in women with tuberous sclerosis. Chest. 144(2):578-85, 2013

Tuberous Sclerosis Congenital

(Left) PA chest radiograph of a 27-year-old woman with tuberous sclerosis complex and lymphangioleiomyomatosis shows increased bilateral lung volumes and diffuse reticular opacities. (Right) Coronal CECT of the same patient shows extensive, diffuse, bilateral, thin-walled pulmonary cysts ﬉ of various sizes. Note associated small right secondary spontaneous pneumothorax ﬈ and visceral pleural thickening. Pneumothorax is a common complication of lymphangioleiomyomatosis.

(Left) Axial CECT of the same patient shows almost complete replacement of the pulmonary parenchyma by multifocal, thin-walled cysts. Note a small right pneumothorax ﬈. (Right) Axial CECT of a patient with tuberous sclerosis complex shows a cardiac fat-containing lesion or myocardial fatty focus ﬈ in the left ventricular myocardium. Cardiac fatcontaining lesions have been described in approximately 1/3 of patients with tuberous sclerosis complex and may coexist with rhabdomyomas.

(Left) Coronal CECT of a woman with tuberous sclerosis complex and lymphangioleiomyomatosis shows a mass in the left kidney of predominant fat attenuation consistent with a renal angiomyolipoma ﬈. (Right) Sagittal NECT of a 47year-old woman with tuberous sclerosis complex shows innumerable well-defined sclerotic bone lesions along the spine ﬈ and sternum ﬉. Sclerotic lesions are an uncommon manifestation of tuberous sclerosis complex.

471

Congenital

Neurofibromatosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Neurofibromatosis type 1 (NF1): Hereditary, neurocutaneous disorder with systemic manifestations that rarely involve lungs

• Bullous emphysema • Pulmonary fibrosis

IMAGING • CT ○ Lungs – Asymmetric, upper lung predominant, thin-walled bullae and cysts; may be large – Pulmonary fibrosis: Reticulation, traction bronchiectasis, basilar honeycombing – Intrapulmonary neurofibroma: Well-defined intraparenchymal nodule/mass ○ Mediastinum – Neurofibroma: Well-defined paravertebral mass, spherical or fusiform, variable enhancement – Meningocele: Water attenuation, well-circumscribed paravertebral mass

(Left) Axial CECT of a 26-yearold woman with neurofibromatosis type 1 (NF1) shows multiple small, thin-walled upper lobe cysts ﬈ and spinal hardware ﬊ for treatment of scoliosis. (Right) Coronal CECT of the same patient shows the classic upper lobe distribution of the cystic lung lesions that may occur in patients with neurofibromatosis type 1. Pulmonary involvement is uncommon, and it has been suggested that the presence of cysts or bullae in affected patients represents smokingrelated emphysema.

(Left) Axial HRCT of a 20-yearold woman with NF1 shows a small, thin-walled right lower lobe cyst ﬊. Bullae and cysts in affected patients have been reported to have an upper lobe predominance. (Right) Axial CECT of a 22-year-old man shows a well-defined right chest wall mass consistent with a neurofibroma ﬊, which produces erosion of the adjacent rib ﬈. Additional osseous manifestations may include vertebral scalloping, neuroforaminal widening, and transverse process spindling.

472

PATHOLOGY • 50-70% of NF1 cases exhibit autosomal dominant inheritance; mutation in neurofibromin gene

CLINICAL ISSUES • NF1: 1 in 3,000 individuals; M = F • Pulmonary disease uncommon; < 70 cases reported • Signs/symptoms: Dyspnea, cough, chest pain; pneumothorax; dyspnea and syncope from pulmonary hypertension • Treatment: Surgical resection of symptomatic bullae/cysts

DIAGNOSTIC CHECKLIST • Consider NF1 in patients with cystic lung disease and multiple neurogenic neoplasms

Neurofibromatosis

Abbreviations • Neurofibromatosis type 1 (NF1)

Imaging Recommendations

Synonyms

• Best imaging tool ○ HRCT for evaluation of lung abnormalities ○ CECT for evaluation of pulmonary trunk size

• von Recklinghausen disease • Peripheral neurofibromatosis

Definitions • NF1: Hereditary, neurocutaneous disorder with systemic manifestations that rarely involve lungs

IMAGING

DIFFERENTIAL DIAGNOSIS Bullous Emphysema • Cigarette smoking is risk factor • Centrilobular emphysema

Radiographic Findings

Pulmonary Fibrosis

• Radiography ○ Lung – Cysts and bullae: Radiolucent foci – Pulmonary fibrosis: Bilateral, symmetric interstitial opacities; basilar predominance – Intrapulmonary neurofibroma: Well-defined lung nodule or mass – Multiple lung nodules/masses secondary to metastases from malignant degeneration of neurogenic neoplasm ○ Mediastinum – Neurogenic neoplasm (posterior mediastinum): Mediastinal widening; extraparenchymal soft tissue mass with well-defined borders – Pulmonary hypertension (associated with lung disease or with plexiform lesions involving vascular intima): Dilated right ventricle, enlarged central pulmonary arteries ○ Bone: Rib separation and pressure erosion, scoliosis, posterior scalloping of vertebral bodies, enlarged neuroforamina

• Absence of extrapulmonary NF1 findings • Basilar reticulation and honeycombing

CT Findings • Lungs ○ Asymmetric, thin-walled bullae/cysts – Solitary or multiple; may be large – Upper lobe predominant ○ Pulmonary fibrosis: Reticulation, traction bronchiectasis, basilar honeycombing ○ Intrapulmonary neurofibroma: Well-defined lung nodule or mass ○ Multiple nodules/masses secondary to metastases from malignant degeneration of neurogenic neoplasm • Mediastinum ○ Neurogenic neoplasm: Well-defined paravertebral mass, spherical or fusiform, variable contrast enhancement ○ Meningocele: Water attenuation, well-circumscribed paravertebral mass ○ Pulmonary hypertension: Pulmonary trunk 29 mm or larger, mosaic attenuation • Bone ○ Scoliosis: Most common osseous complication of NF1

Congenital

○ Vertebral scalloping, neuroforaminal widening, transverse process spindling, rib penciling of neuroforamen

TERMINOLOGY

PATHOLOGY General Features • Etiology ○ NF1: Mutations in neurofibromin gene • Genetics ○ 50-70% of NF1 cases exhibit autosomal dominant inheritance • Diagnostic criteria ○ At least 2 criteria: Café au lait spots, axillary or groin freckling, neurofibromas, optic glioma, iris hamartomas (Lisch nodules), bone abnormalities (sphenoid wing dysplasia, long bone cortical thinning ± pseudoarthrosis), 1st-degree relative with NF1

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Pulmonary disease uncommon; < 70 cases reported ○ Dyspnea, cough, chest pain ○ Pneumothorax from cyst or bulla rupture ○ Dyspnea and syncope from pulmonary hypertension

Demographics • Epidemiology ○ NF1: 1 in 3,000 individuals; M = F

Treatment • Surgical resection of symptomatic bullae/cysts

DIAGNOSTIC CHECKLIST Consider • NF1 in patients with cystic lung disease and multiple neurogenic neoplasms

SELECTED REFERENCES 1.

Ueda K et al: Computed tomography (CT) findings in 88 neurofibromatosis 1 (NF1) patients: prevalence rates and correlations of thoracic findings. Eur J Radiol. 84(6):1191-5, 2015

473

Congenital

Alveolar Microlithiasis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Pulmonary alveolar microlithiasis (PAM): Rare genetic lung disorder characterized by intraalveolar accumulation of calcium phosphate deposits (microliths or calcospherites)

• Metastatic pulmonary calcification • Diffuse pulmonary ossification • Silicosis

IMAGING

PATHOLOGY

• Imaging findings relate to disease stage ○ Early stage: Micronodular (sand-like) pattern ○ Advanced stage: Dense, irregular and reticular opacities • HRCT ○ Dense nodules < 1 mm – Random or along interlobular septa and bronchovascular bundles ○ Ground-glass opacity, consolidation – Related to confluence of micronodules ○ Crazy paving: Calcification along interlobular septa ○ Subpleural cysts – Black-pleura sign: Subpleural lucency adjacent to calcified micronodules

• Autosomal recessive disorder: Mutation of SLC34A2 gene • Intraalveolar microliths: Round, concentrically laminated nodules

(Left) Coned-down PA chest radiograph shows alveolar microlithiasis manifesting with calcified lungs (obscuring the heart borders) and small, sand-like calcifications ﬊. The black-pleura sign results from small, subpleural, air-filled cysts ﬉ adjacent to alveolar calcification. (Right) Axial HRCT (bone window) of a patient with alveolar microlithiasis shows the crazypaving pattern of calcifications along interlobular septa ﬈ on a background of alveolar calcification and tiny subpleural cysts ﬉.

(Left) High-power photomicrograph (H&E stain) of a specimen of alveolar microlithiasis demonstrates preserved lung architecture and small laminar calcifications (microliths) ﬈ in virtually all alveolar spaces. (Right) Composite image with axial HRCT in lung (left) and bone (right) window of a 35year-old woman with alveolar microlithiasis shows thick calcified interlobular septa ﬈, densely calcified subpleural consolidation ﬉, and traction bronchiectasis ﬊. (Courtesy T. Suárez, MD)

474

CLINICAL ISSUES • Slight male predominance • All ages; 2nd and 3rd decade predominance • Signs and symptoms ○ Asymptomatic (early stage) ○ Dyspnea on exertion, dry cough (late stage) ○ Disease progression to cor pulmonale and respiratory failure in most patients • Treatment: Lung transplantation

Alveolar Microlithiasis

DIFFERENTIAL DIAGNOSIS

Abbreviations

Metastatic Pulmonary Calcification

• Pulmonary alveolar microlithiasis (PAM)

• Associated with chronic renal failure • Poorly defined ground-glass opacities and centrilobular nodules

Definitions • Rare genetic lung disorder characterized by intraalveolar accumulation of calcium phosphate deposits (microliths or calcospherites)

IMAGING General Features • Best diagnostic clue ○ Calcified pulmonary micronodules • Imaging manifestations are related to disease stage, profusion, and distribution of calcified micronodules

Diffuse Pulmonary Ossification • Incidental finding • Dendriform (branch-like lesions along terminal airways)

Silicosis • Soft tissue &/or small calcified nodules • Hilar/mediastinal lymphadenopathy; may exhibit egg-shell calcification

PATHOLOGY

Radiographic Findings

General Features

• Early stage ○ Micronodular pattern (sand-like) ○ Basilar predominance • Advanced stage ○ Dense, irregular nodular and reticular opacities related to confluence of micronodules ○ May obscure heart (vanishing heart phenomenon) and diaphragmatic borders ○ "White lungs" (lungs are almost completely opaque)

• Intraalveolar microliths • Autosomal recessive disorder ○ Mutation of SLC34A2 gene; encodes sodium-phosphate cotransporter NPT2b in alveolar type II cells

CT Findings • HRCT ○ Nodules – Dense, < 1 mm in size – Random or along interlobular septa and bronchovascular bundles ○ Ground-glass opacity – Related to confluence of micronodules ○ Consolidation – Related to confluence of micronodules – Air bronchograms ○ Interlobular septal thickening – High concentrations of calcified micronodules in periphery of secondary pulmonary lobules ○ Crazy-paving pattern from calcifications along interlobular septa ○ Subpleural lines – Parenchymal subpleural calcifications ○ Thickening of bronchovascular bundles ○ Traction bronchiectasis – < 10 mm ○ Subpleural cysts – < 10 mm; dilated alveolar ducts – Black-pleura sign: Subpleural cysts result in subpleural lucency highlighted by adjacent calcified micronodules ○ Bullae – Upper lobes (1-8 cm)

Nuclear Medicine Findings • Tc-99m MDP bone scintigraphy ○ Diffuse bilateral radionuclide uptake

Congenital

TERMINOLOGY

Microscopic Features • Alveoli filled with calcospherites ○ Microliths: Round, concentrically laminated nodules • Ossification and minimal inflammation may occur

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Asymptomatic (early stage) ○ Dyspnea on exertion, dry cough (late stage) • Other signs/symptoms ○ Chest pain, hemoptysis, pneumothorax, digital clubbing • Clinical manifestations often less severe than imaging abnormalities (clinical-radiological dissociation) • Microlith deposition in male genitalia (testicles and seminal vesicles) associated with infertility

Demographics • Age ○ All ages; 2nd and 3rd decade predominance • Gender ○ Slight male predominance • Epidemiology ○ Slightly > 1/2 of reported cases (52.5%) in Turkey, China, Japan, India, and Italy

Natural History & Prognosis • Stable disease in few patients • Disease progression to cor pulmonale and respiratory failure in most patients

Treatment • Lung transplantation

SELECTED REFERENCES 1.

Castellana G et al: Pulmonary alveolar microlithiasis: review of the 1022 cases reported worldwide. Eur Respir Rev. 24(138):607-20, 2015

475

Congenital

α-1 Antitrypsin Deficiency KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• α-1 antitrypsin deficiency (AATD): Genetic disorder characterized by reduced levels of AAT protease inhibitor • Panlobular emphysema: Pathological subtype of emphysema associated with AATD

• Centrilobular emphysema • Paraseptal emphysema • Cystic lung disease

IMAGING • Radiography ○ Normal (mild disease) ○ Lung hyperinflation – Flattened hemidiaphragms – Increased retrosternal air space, > 2.5 cm • HRCT ○ Panlobular emphysema – Homogeneous decreased pulmonary attenuation – Lower lobe predominance – Paucity of pulmonary vessels in affected areas ○ Bronchiectasis

(Left) PA chest radiograph of a 55-year-old woman with α-1 antitrypsin deficiency and panlobular emphysema shows bilateral irregular areas of basilar pulmonary radiolucency ﬊ with paucity of intrinsic vascular markings. (Right) Axial HRCT of the same patient shows characteristic diffuse bilateral lower lobe hyperlucency ﬊ with paucity of pulmonary vessels in contrast with the normalappearing ﬈ bilateral upper lobe lung parenchyma. Note absence of cystic changes or architectural distortion.

(Left) Axial HRCT of a 53-yearold man with α-1 antitrypsin deficiency and panlobular emphysema shows diffuse pulmonary low attenuation ﬊ with paucity of intrinsic pulmonary markings. Note right lower lobe subpleural parenchymal bands ﬈. (Right) Coronal HRCT of the same patient shows basilarpredominant areas of decreased pulmonary attenuation and subpleural parenchymal bands ﬈. Note normal-appearing lung parenchyma ﬉ in the mid and upper lung zones.

476

PATHOLOGY • AAT: Glycoprotein predominantly synthesized in hepatocytes from 2 alleles located on chromosome 14 • AATD has been associated with early-onset chronic obstructive pulmonary disease (COPD)

CLINICAL ISSUES • Dyspnea, wheezing, cough • Symptom onset in 4th or 5th decade of life • ~ 1-3% of patients with COPD are deficient in AAT; ~ 95% of patients with AATD remain undiagnosed

DIAGNOSTIC CHECKLIST • Consider AATD in young patients with panlobular emphysema &/or bronchiectasis

α-1 Antitrypsin Deficiency

Abbreviations • α-1 antitrypsin (AAT) • AAT deficiency (AATD)

Cystic Lung Disease • Multiple discrete lung cysts with well-defined walls • Lymphangioleiomyomatosis, Langerhans cell histiocytosis

PATHOLOGY

Definitions

General Features

• AATD: Genetic disorder characterized by reduced levels of AAT protease inhibitor • Emphysema: Abnormal, permanent enlargement of airspaces distal to terminal bronchiole, associated with destruction of their walls ○ Panlobular emphysema: Pathological subtype of emphysema associated with AATD

• AAT: Glycoprotein predominantly synthesized in hepatocytes from 2 alleles located on chromosome 14 • AATD results from variety of abnormalities in SERPINA1 gene (single-point mutations, insertions, and deletions) ○ May lead to pulmonary and liver disease ○ Associated with early-onset chronic obstructive pulmonary disease (COPD)

IMAGING General Features • Best diagnostic clue ○ Emphysema • Location ○ Basilar predominant • Morphology ○ Panlobular

Radiographic Findings • Radiography ○ Normal (mild disease) ○ Lung hyperinflation – Flattened hemidiaphragms – Increased retrosternal air space > 2.5 cm ○ Paucity of vascular markings within irregular areas of radiolucency

CT Findings • HRCT ○ Panlobular emphysema – Homogeneous decreased pulmonary attenuation □ Involves entirety of secondary pulmonary lobule □ Lower lobe predominance – Paucity of pulmonary vessels in affected areas – May be difficult to distinguish from normal wellexpanded lung ○ Bronchiectasis ○ Quantitative CT measures of emphysema correlate well with pulmonary function abnormalities

Congenital

TERMINOLOGY

Microscopic Features • Panlobular emphysema: Uniform destruction of alveolar and respiratory bronchiolar walls resulting in global airspace expansion • Chronic bronchitis reported in 40% of patients with AATD

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Dyspnea (84%), wheezing with upper respiratory infection (76%), wheezing with dyspnea (51%), ↑ cough and phlegm (50%), usual phlegm (46%), usual cough (40%) • Smoking worsens disease course and prognosis

Demographics • Age ○ Symptom onset in 4th or 5th decade of life • Ethnicity ○ Highest gene frequency for Z allele recorded in subjects of Northern European descent • Epidemiology ○ Global prevalence of AATD (2015): 5.64 million persons ○ ~ 1-3% of patients with COPD are deficient in AAT ○ ~ 95% of patients with AATD remain undiagnosed

Treatment • Same as for COPD • Lung volume reduction surgery and lung transplantation • Augmentation therapy (intravenous infusion of purified pooled human plasma AAT)

Imaging Recommendations • Best imaging tool ○ HRCT

DIFFERENTIAL DIAGNOSIS Centrilobular Emphysema • Upper lobe predominance • Low attenuation in central secondary pulmonary lobule • Central dot sign: Central nodular opacity representing centrilobular artery surrounded by low attenuation

DIAGNOSTIC CHECKLIST Consider • AATD in young patients with panlobular emphysema &/or bronchiectasis

SELECTED REFERENCES 1.

Hatipoğlu U et al: α1-antitrypsin deficiency. Clin Chest Med. 37(3):487-504, 2016

Paraseptal Emphysema • Subpleural single-tier arcade of cystic spaces separated by intact interlobular septa • May be associated with bullae 477

Congenital

Primary Ciliary Dyskinesia KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Primary ciliary dyskinesia (PCD) • Abnormal ciliary ultrastructure with resultant mucociliary dysfunction and otosinopulmonary disease ○ Kartagener syndrome: 50% of patients with PCD

• • • •

IMAGING

CLINICAL ISSUES

• Radiography ○ Hyperinflation ○ Bronchial wall thickening and bronchiectasis ○ Atelectasis, consolidation • CT/HRCT ○ Bronchial wall thickening, mucus plugging ○ Bronchiectasis with predilection for lingula and middle and lower lobes ○ Centrilobular nodules, tree-in-bud opacities, consolidation ○ Mosaic attenuation, expiratory air-trapping ○ Situs abnormalities

• Symptoms/signs ○ Neonatal respiratory distress ○ Chronic/recurrent rhinitis, secretory otitis media, sinusitis ○ Recurrent lower respiratory infection ○ Infertility in men, lowered fertility and ectopic pregnancy in women ○ Situs abnormalities with Kartagener syndrome

(Left) PA chest radiograph of a 44-year-old woman with Kartagener syndrome and primary ciliary dyskinesia who presented with productive cough shows dextrocardia ﬈, a right aortic arch ﬊, and a right gastric bubble ﬉. The right upper lobe bronchus is hyparterial and the left upper lobe bronchus is eparterial consistent with situs inversus. (Right) Lateral chest radiograph of the same patient shows subtle lower lobe linear opacities exhibiting the tram-track sign ﬉ consistent with basilar bronchiectasis.

(Left) Axial CECT of the same patient shows basilar bronchiectasis ﬉, bronchial wall thickening ﬈, mucus plugging ﬊, and mosaic attenuation/perfusion with areas of decreased lung attenuation ﬈ and vascularity. (Right) Axial NECT of the same patient obtained 3 months later because of recurrent pulmonary infection shows new left middle lobe pneumonia ﬈, bilateral lower lobe bronchiectasis, and mucus plugging. The middle lobe, lingula, and lower lobes are preferentially affected in primary ciliary dyskinesia.

478

Cystic fibrosis Allergic bronchopulmonary aspergillosis Postinfectious bronchiectasis Immune deficiency disorders

DIAGNOSTIC CHECKLIST • Consider PCD in patients with chronic rhinitis, otitis, and bronchial/pulmonary infection since infancy and in patients with abnormal situs and bronchiectasis

Primary Ciliary Dyskinesia

Synonyms • Dyskinetic cilia syndrome • Immotile cilia syndrome: Misnomer as ciliary motion is present but abnormal

Definitions • Primary ciliary dyskinesia (PCD) ○ Genetic disorder causing ciliary defects and impaired mucociliary clearance ○ Mucociliary dysfunction and chronic otosinopulmonary disease ○ Abnormalities of situs in 50% of cases • Kartagener syndrome ○ Triad of situs inversus, sinusitis &/or nasal polyposis, and bronchiectasis ○ 50% of patients with PCD ○ Kartagener-Afzelius syndrome – Kartagener described sinusitis, bronchiectasis, and situs inversus – Afzelius described associated infertility; structural abnormalities of motile cilia and sperm

IMAGING General Features • Best diagnostic clue ○ Triad of abnormal situs, bronchiectasis, and sinusitis • Location ○ Bronchiectasis with predilection for lingula and middle and lower lobes

Radiographic Findings • • • • •

Hyperinflation Bronchial wall thickening, bronchiectasis (tram-track sign) Atelectasis, consolidation Dextrocardia and situs abnormalities Findings of prior pulmonary resection

CT Findings • Bronchial wall thickening • Mucus plugging • Bronchiectasis with predilection for lingula and middle and basilar lower lobes ○ Variable severity: Cylindrical, varicose, and cystic ○ Signet ring sign: Bronchial diameter > adjacent pulmonary artery diameter • Mosaic attenuation, expiratory air-trapping • Centrilobular nodules, tree-in-bud and ground-glass opacities, consolidation • Atelectasis, typically subsegmental • Associated abnormalities ○ Abnormal situs: Situs inversus, situs ambiguous ○ Congenital heart disease ○ Sinusitis ○ Pectus excavatum and scoliosis

Imaging Recommendations • Best imaging tool ○ HRCT is imaging study of choice for diagnosis and assessment of bronchiectasis

DIFFERENTIAL DIAGNOSIS

Congenital

○ Chest radiographic abnormalities may suggest diagnosis in cases of Kartagener syndrome

TERMINOLOGY

Cystic Fibrosis • Autosomal recessive condition; abnormal exocrine gland secretions • Caucasian patient; typically diagnosed in childhood • Recurrent infections, wheezing, dyspnea • Severe upper lobe predominant bronchiectasis, mucus plugging, bronchial wall thickening, mosaic attenuation

Allergic Bronchopulmonary Aspergillosis • • • •

Patient with asthma or cystic fibrosis Reactivity to Aspergillus Worsening asthma, cough, wheezing Central upper lobe predominant bronchiectasis ○ Mucoid impaction; may exhibit high attenuation

Postinfectious Bronchiectasis • Recurrent pulmonary infection ○ Bacteria, mycobacteria, viruses • Pulmonary infection may result in transient ciliary dysfunction and poor clearance of airway mucus ○ Subsequent bacterial colonization and host effects may lead to irreversible airway damage

Immune Deficiency Disorders • Human immunodeficiency virus/acquired immune deficiency • Common variable immunodeficiency • Recurrent pulmonary infection; resultant bronchiectasis syndrome ○ Resultant bronchiectasis

Young Syndrome • Abnormal viscosity of airway mucus • Bronchiectasis, rhinosinusitis, infertility ○ Infertility due to functional genital tract obstruction and abnormal sperm transport

PATHOLOGY General Features • Etiology ○ Compromised mucociliary clearance secondary to structural and functional ciliary abnormalities – Cycle of pulmonary infection → airway destruction → pulmonary infection – Airway abnormalities predispose to recurrent pulmonary infection • Genetics ○ Autosomal recessive with genetic heterogeneity ○ 35 genetic mutations account for ~ 70% of cases of PCD – DNAI1 and DNAH5 encode components of outer dynein arms, account for > 30% of cases – Biallelic mutations linked to ~ 70% of known cases • Associated abnormalities ○ Situs abnormalities – Situs inversus in ~ 66% of pediatric patients and ~ 50% of adults in one series ○ Congenital heart disease 479

Congenital

Primary Ciliary Dyskinesia ○ Infertility ○ Abnormal ciliary ultrastructure with abnormal ciliary beat frequency or abnormal ciliary orientation – May exhibit normal ultrastructure and beat frequency – Transient abnormalities of ciliary orientation may occur with airway infection and inflammation

Gross Pathologic & Surgical Features

Diagnosis

• Diffuse bronchiectasis resulting from recurrent infection • Pulmonary infection • Dextrocardia, abnormal situs

• Nasal biopsy or ciliary culture ○ Functional studies – Measurement of ciliary beat frequency, beat pattern, and coordination of ciliary motion ○ Ultrastructural studies – Evaluation of ciliary orientation and ultrastructure on electron microscopy • Genetic testing

Microscopic Features • • • •

Bronchial inflammation, squamous metaplasia, ulceration Bronchial wall fibrosis and destruction Acute and chronic pneumonia, organizing pneumonia Electron microscopy: Ultrastructural ciliary defect ○ Most common: Absence or shortening of outer dynein arms or combined outer and inner dynein arm defects ○ ~ 30% of patients with PCD have normal ciliary structure

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Neonates – Respiratory distress requiring ventilatory support in > 80% of cases, rhinitis, atelectasis, neonatal pneumonia ○ Infants and children: Chronic/acute secretory otitis media, rhinitis, acute/chronic sinusitis, chronic wet cough, recurrent pneumonia ○ Older patients: Recurrent sinus, ear, and pulmonary infections, male infertility ○ Recurrent lower respiratory tract infection – Haemophilus influenzae, Staphylococcus aureus, Streptococcus pneumoniae – S. aureus and nontuberculous mycobacteria are more common in adults ○ Productive cough, wheezing, coarse crackles, exertional dyspnea ○ Pulmonary function – Mild to severe obstructive abnormalities – Mixed obstructive and restrictive abnormalities ○ Infertility in men, lowered fertility and ectopic pregnancy in women • Other signs/symptoms ○ Situs abnormalities in patients with Kartagener syndrome – 23% of patients with situs inversus have PCD ○ Congenital heart disease (~ 6% of patients with PCD); often associated with situs abnormalities ○ Aplasia/hypoplasia of paranasal sinuses ○ Chronic rhinosinusitis, nasal polyposis – History of sinus surgery, adenotonsillectomy, nasal polypectomy ○ Other – Hydrocephalus, retinitis pigmentosa (rare)

Demographics • Age ○ Typically diagnosed in childhood, adolescence, or adulthood 480

– Median age at diagnosis: ~ 5.3 years • Gender ○ No predilection • Epidemiology ○ Prevalence – Range: 1/10,000-20,000 population

Screening • Measurement of nasal nitric oxide ○ Low levels of exhaled nitric oxide in patients with PCD

Natural History & Prognosis • Affected patients often present as newborns • Delayed diagnosis; typically diagnosed in late childhood and adolescence • Good prognosis with early diagnosis and aggressive treatment • Progressive decline in lung function reported

Treatment • Close clinical follow-up • Aggressive airway clearance and lung physiotherapy • Antibiotics: Lung infection treatment and bronchiectasis prevention • Immunization for influenza and pneumococcus • Smoking cessation, removal from exposure to secondhand smoke • Nasal lavage with saline, intranasal steroids for chronic rhinitis and polyposis • Sinus surgery in selected cases • Advanced pulmonary disease ○ Surgical intervention for severe bronchiectasis in selected patients ○ Lung transplantation for end-stage lung disease

DIAGNOSTIC CHECKLIST Consider • PCD in young patients with chronic rhinitis, otitis, and bronchial/pulmonary infection since infancy and in patients with abnormal situs and bronchiectasis

Image Interpretation Pearls • Basilar bronchiectasis in young patient ± situs abnormality

SELECTED REFERENCES 1. 2. 3. 4.

Fitzgerald DA et al: When to suspect primary ciliary dyskinesia in children. Paediatr Respir Rev. 18:3-7, 2016 Harrison MJ et al: Congenital heart disease and primary ciliary dyskinesia. Paediatr Respir Rev. 18:25-32, 2016 Knowles MR et al: Primary ciliary dyskinesia. Clin Chest Med. 37(3):449-61, 2016 Lucas JS et al: Diagnostic methods in primary ciliary dyskinesia. Paediatr Respir Rev. 18:8-17, 2016

Primary Ciliary Dyskinesia Congenital

(Left) Coronal NECT of a 63year-old man with primary ciliary dyskinesia and life-long recurrent pulmonary infections shows bilateral bronchiectasis ﬉, bronchial wall thickening ﬈, and mosaic attenuation. (Right) Coronal NECT of the paranasal sinuses of the same patient shows extensive mucosal thickening and evidence of prior surgical intervention for treatment of recurrent sinusitis and polyposis. Abnormal ciliary function may affect the sinuses, middle ear, airways, and reproductive system.

(Left) Axial NECT of a 44-yearold man with primary ciliary dyskinesia shows basilar bronchiectasis, bronchial wall thickening, and mosaic attenuation. The dilated bronchi and adjacent pulmonary arteries demonstrate the signet ring sign ﬉. (Right) Axial CECT of a patient with situs inversus and primary ciliary dyskinesia shows mild left middle lobe bronchiectasis ﬉. Appropriate antibiotic treatment and aggressive lung physiotherapy may help ameliorate or prevent bronchiectasis in affected patients.

(Left) PA chest radiograph of a young woman with Kartagener syndrome shows situs inversus totalis, dense right lower lobe retrocardiac consolidation ﬊ with intrinsic bronchiectasis, and multifocal bilateral pulmonary nodules. (Right) Axial HRCT of the same patient shows persistent right lower lobe consolidation ﬊ with volume loss, bronchiectasis and cavitation ﬉, and left middle lobe bronchiectasis ﬈, mucus plugging, and bronchiolitis. The findings are related to chronic infection secondary to primary ciliary dyskinesia.

481

Congenital

Primary Immunodeficiencies KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Primary immunodeficiency disorders (PIDD) ○ Disorders of antibody function ○ Cellular and combined immunodeficiency disorders ○ Phagocytic defects

• • • •

IMAGING

CLINICAL ISSUES

• CT/HRCT ○ More sensitive and specific than radiography ○ Useful for demonstrating extent of pulmonary involvement ○ Pneumonia – Segmental or lobar consolidation, ground-glass opacities, crazy-paving pattern ○ Airway involvement: Bronchiectasis, bronchial wall thickening, tree-in-bud opacities ○ Lymphadenopathy ○ Complications – Pneumatocele, abscess, hemorrhage

• Consider immunodeficiency in patients with recurrent respiratory infections • PIDD associated with bronchiectasis: Selective IgA deficiency, common variable immunodeficiency, X-linked agammaglobulinemia, chronic granulomatous disease, chronic mucocutaneous candidiasis

(Left) Photograph of the anterior chest wall of a 6-year old boy with chronic mucocutaneous candidiasis shows multiple reddish raised cutaneous lesions ﬈ of various sizes representing cutaneous abscesses from candida. (Right) Axial NECT of the same patient demonstrates varicose bronchiectasis ﬈ in the posterior basilar segment of the left lower lobe. Chronic mucocutaneous candidiasis increases the risk of developing bronchiectasis in early childhood.

(Left) Coned-down PA chest radiograph of a 21-year-old man with autosomal dominant hyper-IgE syndrome shows multiple pneumatoceles ﬈ in the left upper lobe that developed following a previous episode of Staphylococcus aureus pneumonia. (Right) Axial NECT of the same patient shows multiple air-filled thin-walled cysts ﬈ in the left lung. Potential complications of autosomal dominant hyper-IgE syndrome-related pneumonia include empyema, pneumatocele formation, and bronchiectasis.

482

Allergic bronchopulmonary aspergillosis Primary ciliary dyskinesia Organizing pneumonia Chronic eosinophilic pneumonia

DIAGNOSTIC CHECKLIST • Increased susceptibility to infection, malignancy, and autoimmunity • Respiratory tract infection most common illness PIDD

Primary Immunodeficiencies

Abbreviations • Primary immunodeficiency disorders (PIDD)

Definitions • Heterogeneous group of genetic diseases involving immune system ○ > 300 distinct disorders described • Disorders of antibody function ○ Selective IgA deficiency (SIgAD) – Most common of all inborn defects of humoral immunity – Isolated absence or near absence of serum and secretory IgA □ Serum IgA < 5 mg/dL – > 1% of recurrent infections in children □ Pneumonia: Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma species, enterovirus species □ Asthma and bronchiectasis – Other complications □ Interstitial lung disease: Lymphoid interstitial pneumonia, organizing pneumonia □ Lymphoma: Hodgkin lymphoma, non-Hodgkin lymphoma (B-cell origin) □ Autoimmunity: Immune thrombocytopenic purpura, hemolytic anemia, rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, vasculitis ○ Common variable immunodeficiency (CVID) – Most frequent symptomatic primary immunodeficiency – Familial but not strictly X-linked or autosomally inherited – Increased risk of lymphoreticular tumors and autoimmune diseases □ 20-30% of patients with CVID have autoimmune diseases □ Thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, primary biliary cirrhosis – Associated pulmonary diseases □ Lung infections □ Interstitial lung disease: Granulomatouslymphocytic interstitial lung disease (GLILD), organizing pneumonia, lymphoproliferative disorders □ Chronic airway disease – GLILD □ 10-30% of patients with CVID □ Diffuse lung involvement by granulomas with benign lymphoproliferative infiltrates – Symptoms: Early or late childhood or adulthood □ Acute: Productive cough, change in sputum, and increased dyspnea (should suggest infection) □ Chronic: Fever and lymphadenopathy (should suggest lymphoproliferative disorder) ○ X-linked agammaglobulinemia (XLA) – Autosomal recessive: Interruption of normal B-cell maturation by defect in tyrosine kinase production □ Small adenoids, tonsils, and lymph nodes

– Recurrent otitis: Most common infection prior to diagnosis – Pulmonary infections shortly after birth □ Secondary complications: Sinopulmonary infections (Staphylococcus aureus, S. pneumoniae, H. influenzae) – Up to 30% of affected patients have autoimmune diseases – 5% of affected patients may develop lymphoma and other lymphoreticular malignancies • Cellular and combined immunodeficiency disorders ○ DiGeorge syndrome (thymic hypoplasia) – Gene defects on chromosome 22 □ Impaired function of thymus and parathyroid glands □ Cardiovascular anomalies: Right-sided aortic arch, interrupted aortic arch, truncus arteriosus, tetralogy of Fallot, and atrial or ventricular septal defects – Degree of thymic hypoplasia: Highly variable T-cell number □ Severe immunodeficiency (complete DiGeorge syndrome): Susceptible to viral or Pneumocystis jirovecii infections ○ Severe combined immunodeficiency (SCID) – Absence of T- and B-cell (and sometimes natural killer cell) function – Recurrent severe pneumonia □ Most common pathogens: P. jirovecii, parainfluenza 3, respiratory syncytial virus, adenovirus, cytomegalovirus, bacteria ○ Autosomal dominant hyper-IgE syndrome (AD-HIES) – Otherwise called Job syndrome – Usually diagnosed in infancy □ Classic triad: Staphylococcal infections of skin, cystforming pneumonias, and IgE levels at least 10 times normal – Recurrent pyogenic pneumonias □ Most common pathogens: S. aureus, S. pneumoniae, H. influenzae, Aspergillus fumigatus, Pseudomonas, and P. jirovecii □ Complications: Empyema, pneumatocele formation, bronchiectasis □ Single or multiple pneumatoceles: May expand when superinfected with bacteria and fungi ○ Wiskott-Aldrich syndrome (WAS) – X-linked recessive immunodeficiency disorder: Eczema, thrombocytopenia with small defective platelets, recurrent infections □ Prolonged bleeding from circumcision site, bruising, or bloody diarrhea during infancy – Pyogenic infections before 1st year of age: Meningitis, otitis media, pneumonia, sepsis □ Most common pathogens: S. pneumoniae, P. jirovecii, and herpes viruses – Massive bleeding, infection, vasculitis, autoimmune cytopenias, or lymphoreticular malignancies are common causes of death • Phagocytic defects ○ Chronic granulomatous disease (CGD) – Defect in membrane-associated nicotinamide adenine dinucleotide phosphate oxidase in phagocytic cells

Congenital

TERMINOLOGY

483

Congenital

Primary Immunodeficiencies – Onset in infancy, childhood, or, less commonly, early adolescence □ Male:female ratio of 6:1 – Recurrent bronchopneumonia, empyema, and lung abscess □ Most common pathogens: S. aureus, Klebsiella, Pseudomonas, Aspergillus, and Candida ○ Chédiak-Higashi syndrome (CHS) – Rare autosomal recessive defect □ Impaired microbicidal activity of phagocytes – Up to 30% of affected patients have segmental or lobar pneumonia □ S. aureus, H. influenzae, group A streptococcus, and gram-negative organisms (Klebsiella, Pseudomonas) – Acute respiratory failure □ Extensive histiocytic infiltration of lungs • Other immunodeficiencies ○ Chronic mucocutaneous candidiasis (CMC) – Phenotypic manifestation of complex immunodeficiency – Recurrent or persistent Candida infections of skin, nails, oropharynx, and lung – Risk of developing bronchiectasis in early childhood

IMAGING Radiographic Findings • Airspace disease (pneumonia) ○ Air bronchograms • Lymphadenopathy • Absent adenoid tissue on lateral soft tissue neck radiography: XLA • Acute pulmonary infection and absence of thymic shadow ○ SCID, DiGeorge syndrome

CT Findings • More sensitive and specific than radiography • Useful for demonstrating extent of pulmonary involvement • Pneumonia ○ Segmental or lobar consolidation, ground-glass opacities, crazy-paving pattern – SIgAD, CVID, XLA, CGD, CHS, autosomal dominant hyper-IgE syndrome, CMC • Bronchiectasis: SIgAD, CVID, XLA, CGD, CMC • Small airways involvement ○ Tree-in-bud opacities: SIgAD, CVID ○ Bronchial wall thickening: SIgAD • Lymphadenopathy: CGD, XLA (lymphoma) • Complications ○ Pneumatoceles: AD-HIES ○ Abscess formation: CGD ○ Alveolar hemorrhage: WAS

DIFFERENTIAL DIAGNOSIS

Primary Ciliary Dyskinesia • Basilar predominant bronchiectasis • Situs inversus in 50% of cases; sinusitis is common

Organizing Pneumonia • Consolidation: Peribronchovascular/subpleural, lower lobe predominance; migratory opacities • Nodule/mass: Single or multiple; reversed halo sign • Ground-glass opacity

Chronic Eosinophilic Pneumonia • • • • •

Subpleural ground-glass opacities &/or consolidation Upper lobe-predominant involvement Band-like opacities parallel to adjacent chest wall History of asthma (75%) High-level peripheral blood eosinophilia (usually > 1500 /mm³) • Alveolar eosinophilia (> 25% and often > 40%)

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Consider immunodeficiency in patients with recurrent respiratory infections ○ Immunodeficiency diseases associated with bronchiectasis: SIgAD, CVID, XLA, CGD, CMC

Demographics • • • • •

PIDD incidence: 4.6/100,000 persons SIgAD: 1/700 persons XLA incidence: ~ 1/380,000 persons CVID incidence: 1/30,000 persons X-linked lymphoproliferative syndrome incidence: 1-3/1 million in males

DIAGNOSTIC CHECKLIST Consider • PIDD include broad spectrum of disorders with highly diverse intrinsic defects ○ 1 or more components of immune system may be involved ○ Increased susceptibility to infection, malignancy, and autoimmunity

Image Interpretation Pearls • Respiratory tract infection is most common cause of illness in patients with PIDD

SELECTED REFERENCES 1. 2.

3.

Allergic Bronchopulmonary Aspergillosis • • • •

484

Patient with asthma or cystic fibrosis Reactivity to Aspergillus antigens Worsening asthma, cough, wheezing Central upper lobe-predominant bronchiectasis ○ Mucoid impaction; may exhibit high attenuation

4. 5.

Freeman AF et al: Hyper-IgE syndromes and the lung. Clin Chest Med. 37(3):557-67, 2016 Wu EY et al: Clinical and imaging considerations in primary immunodeficiency disorders: an update. Pediatr Radiol. 46(12):1630-1644, 2016 Nonas S: Pulmonary Manifestations of primary immunodeficiency disorders. Immunol Allergy Clin North Am. 35(4):753-66, 2015 Touw CM et al: Detection of pulmonary complications in common variable immunodeficiency. Pediatr Allergy Immunol. 21(5):793-805, 2010 Tanaka N et al: Lung diseases in patients with common variable immunodeficiency: chest radiographic, and computed tomographic findings. J Comput Assist Tomogr. 30(5):828-38, 2006

Primary Immunodeficiencies Congenital

(Left) AP chest radiograph of a 35-year-old man with common variable immunodeficiency demonstrates multifocal bilateral pulmonary consolidations ﬊. Sputum culture grew Haemophilus influenzae. (Right) AP chest radiograph of a child with chronic granulomatous disease who previously presented with right upper lobe pneumonia shows a new consolidation in the left upper lobe with large areas of intrinsic cavitation ﬈.

(Left) Axial HRCT of a patient with selective IgA deficiency, lymphoid interstitial pneumonia, and asthma shows diffuse bilateral ground-glass opacities, scattered thinwalled cysts, ﬊ and bilateral bronchial wall thickening ﬈. (Right) Axial HRCT of a 25year-old man with common variable immunodeficiency shows clustered small centrilobular nodules ﬈ and tree-in-bud opacities ﬊ in the left lower lobe. These nodules likely represent infectious bronchiolitis that may be secondary to bacterial, viral, or fungal pulmonary infection.

(Left) Axial NECT of a 35-yearold man with autosomal dominant hyper-IgE syndrome shows bronchiectasis ﬊ with bronchial wall thickening in the middle lobe and multiple ill-defined centrilobular nodules ﬈ in both lungs secondary to Staphylococcus aureus infection. (Right) Axial NECT of a patient with severe combined immunodeficiency shows multifocal ground-glass opacities ﬈ in the right upper lobe. Bronchoalveolar lavage fluid culture revealed Pneumocystis jirovecii pneumonia.

485

Congenital

Chronic Granulomatous Disease KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Heterogeneous group of rare genetic disorders that result in recurrent, life-threatening bacterial and fungal infections and granuloma formation

• Cystic fibrosis, hyperimmunoglobulin E syndrome

IMAGING • Radiography ○ Consolidation (60-80%), reticulonodular opacities (40%) • HRCT/CT ○ Consolidation ○ Pulmonary nodules ○ Tree-in-bud opacities ○ Sequela of recurrent infections – Scarring, traction bronchiectasis, emphysema ○ Lung/mediastinal abscess ○ Pulmonary hypertension ○ Reactive lymphadenopathy

(Left) Coronal CECT of a patient with chronic granulomatous disease and necrotizing pneumonia shows left upper lobe consolidation associated with volume loss and air bronchograms ﬊. Intrinsic necrosis resulted in peripheral cavitation ﬈ within the consolidated lung parenchyma. (Right) Autopsy photograph of the left lung of a patient who died from complications of chronic granulomatous disease shows extensive airspace consolidation with focal pulmonary necrosis and cavitation ﬈.

(Left) Coronal NECT of a 20year-old man with chronic granulomatous disease and recurrent pulmonary aspergillosis shows left upper lobe scarring and architectural distortion ﬉ and a spiculated pulmonary nodule ﬈ in the left lower lobe. (Right) Axial NECT of a young man with chronic granulomatous disease and recurrent pulmonary infection who presented with cough shows multifocal bilateral irregular opacities ﬈ and small pulmonary nodules. Cultures were positive for gramnegative enterobacteria.

486

PATHOLOGY • Defective phagocytic function ○ Abnormal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase ○ Inability to contain/destroy certain bacteria/fungi • Pathogens ○ Staphylococcus aureus, gram-negative enterobacteria (e.g., Salmonella spp., Klebsiella spp., Aerobacter spp., Serratia spp., Pseudomonas spp.), Nocardia spp., Aspergillus fumigatus

CLINICAL ISSUES • Recurrent infections of epithelial surfaces exposed to environment • Mortality from recurrent infections: 18%; aspergillosis is most common cause of death

Chronic Granulomatous Disease

PATHOLOGY

Abbreviations

General Features

• Chronic granulomatous disease (CGD)

• Etiology ○ Mutations that encode NADPH oxidase complex – Impaired respiratory burst (i.e., deficient production of oxygen radicals required for phagocytosis) ○ 5 genes involved – X-linked CGD (XL-CGD) mutations at CYBB gene (cytochrome b-245 beta chain) – Autosomal recessive CGD (AR-CGD) mutations: CYBA, NCF1, NCF2, NCF3 genes • Most common pathogens ○ Staphylococcus aureus ○ Gram-negative enterobacteria: Salmonella spp., Klebsiella spp., Aerobacter spp., Serratia spp., Pseudomonas spp. ○ Nocardia spp. ○ Aspergillus fumigatus (most common fungus)

Definitions • Heterogeneous group of rare genetic disorders that result in recurrent, life-threatening bacterial and fungal infections and granuloma formation • Defective phagocytic function ○ Secondary to abnormal nicotinamide adenine dinucleotide phosphatase (NADPH) oxidase ○ Inability to generate free radical superoxide – Normal phagocytes contain and destroy certain bacterial and fungal microorganisms

IMAGING Radiographic Findings • • • •

Consolidation (60-80%) Reticulonodular opacities (40%) Pleural effusion (20%) Pulmonary hypertension ○ Pulmonary artery enlargement (20%) ○ May complicate recurrent pulmonary infection and lung destruction

CT Findings • • • •

Consolidation Pulmonary nodules Tree-in-bud opacities Sequela of recurrent pulmonary infection ○ Scarring ○ Bronchiectasis, traction bronchiectasis ○ Emphysema • Lung/mediastinal abscess • Reactive lymphadenopathy • Pulmonary hypertension

DIFFERENTIAL DIAGNOSIS

CLINICAL ISSUES Presentation • Most common signs/symptoms ○ Recurrent infections of epithelial surfaces exposed to the environment ○ Pneumonia and lung abscess [most common (66-80%)] ○ Suppurative adenitis (53%) ○ Skin infections (e.g., impetigo, cellulitis, and subcutaneous abscess) (52%) ○ Liver abscess (30%) ○ Osteomyelitis (25%) • Other signs/symptoms ○ Granuloma formation with colitis (17%) ○ Gastric outlet obstruction (15%) ○ Urinary tract obstruction (10%) • Clinical profile ○ Impaired neutrophil-function testing followed with immunoblot and genotyping ○ Prenatal diagnosis is available

Cystic Fibrosis

Demographics

• Autosomal recessive disorder ○ Mutation in cystic fibrosis transmembrane conductance regulator protein • Central bronchiectasis is predominant imaging abnormality

• XL-CGD accounts for 70% of cases • AR-CGD accounts for 30% of cases • 1 in 200,000 live births; male predominance (86%)

Hyperimmunoglobulin E Syndrome (Job Syndrome)

• Clinical manifestations with recurrent infections ○ XL-CGD typically starts during 1st year of life ○ AR-CGD may manifest later in life • 50% of affected patients survive to adulthood • Mortality from recurrent infections: 18%; aspergillosis is most common cause of death

• Nonresolving pneumatoceles

Crohn Disease • May mimic CGD colitis • Typically not associated with severe recurrent pulmonary infections

Other Immunodeficiencies With Recurrent Infections • Glucose-6-phosphate dehydrogenase and glutathione synthetase deficiencies ○ Hemolytic anemia (uncommon in CGD)

Congenital

TERMINOLOGY

Natural History & Prognosis

Treatment • Prophylaxis, immunoprophylaxis with interferon-γ, and early aggressive treatment of infection • Promising results with hematopoietic stem cell transplantation

SELECTED REFERENCES 1.

Salvator H et al: Pulmonary manifestations in adult patients with chronic granulomatous disease. Eur Respir J. 45(6):1613-23, 2015

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Congenital

Cystic Fibrosis KEY FACTS

TERMINOLOGY

TOP DIFFERENTIAL DIAGNOSES

• Cystic fibrosis (CF): Autosomal recessive disorder that affects regulation of chloride transport • Accounts for up to 25% of adult cases of bronchiectasis

• Allergic bronchopulmonary aspergillosis • Primary ciliary dyskinesia • Tuberculosis

IMAGING

CLINICAL ISSUES

• Diffuse bronchiectasis with predominant upper lobe involvement ○ Right upper lobe often 1st and most severely affected • Airways are primary site of pathology in CF ○ Bronchial wall thickening is earliest finding ○ Bronchiectasis is most common finding; diffuse involvement, most severe in upper lobes • Hyperinflation is early finding; initially reversible, then permanent (100%) • CT abnormalities correlate more strongly with deterioration of clinical status than pulmonary function • Role of CT tempered by large life-time radiation dose

• Demographics ○ Most patients diagnosed by 3 years; M < F ○ More common in Caucasians, rare in African Americans and Asians • Symptoms and signs ○ Patients with mild disease may be asymptomatic ○ Recurrent pneumonia; cough, dyspnea, wheezing ○ Hemoptysis, may be massive • Sweat chloride test positive in 98% of patients with CF

(Left) Coronal NECT of a patient with cystic fibrosis shows cylindrical ﬉ bronchiectasis in the lower lobes and varicoid ﬈ and cystic ﬊ bronchiectasis in the upper lobes. Centrilobular nodules, tree-in-bud opacities ﬇, and mosaic attenuation are also present. (Right) Coronal NECT of a patient with cystic fibrosis shows a right upper lobe tubular branching mucoid impaction ﬈. Note unopacified right upper lobe bronchiectasis ﬊ and small nodules ﬉ in the left lung apex from bronchiolar mucoid impaction.

(Left) Axial CECT of a patient with cystic fibrosis shows a nonenhancing consolidation in the right lower lobe consistent with pneumonia. Note bronchiectasis ﬈ within the consolidation as well as within the middle lobe. (Right) Axial NECT of a patient with cystic fibrosis shows bronchiectasis ﬈, mucoid impaction ﬉, and scattered regions of hyperlucency, likely reflecting small airways disease with subsequent air trapping.

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DIAGNOSTIC CHECKLIST • Consider CF in any adult with unexplained bronchiectasis, particularly when upper lobe predominant

Cystic Fibrosis

Radiographic Findings

MR Findings

• Radiography ○ Less sensitive for earliest abnormalities of CF ○ Evaluation of acute complications (i.e., lobar pneumonia, pneumothorax) and long-term surveillance

• MR increasingly used for serial imaging of young patients due to lack of ionizing radiation • Structural imaging ○ Bronchial wall edema: High signal on T2W images ○ Inflamed airway walls may enhance after gadolinium administration • Functional imaging ○ Sequences developed to evaluate regional ventilation and perfusion ○ Images after inhalation of hyperpolarized gas provide information regarding regional ventilation

Abbreviations • Cystic fibrosis (CF)

Synonyms • Mucoviscidosis

Definitions • Autosomal recessive disorder causing mutations of CF transmembrane conductance regulator (CFTR) gene, which regulates chloride transport ○ Abnormally viscous secretions from exocrine glands (salivary and sweat glands, pancreas, large bowel, tracheobronchial tree) ○ Multiorgan involvement, primarily lungs and pancreas • Most common fatal hereditary disease in Caucasians • Accounts for up to 25% of adult cases of bronchiectasis

IMAGING General Features

CT Findings • Airways ○ Primary site of pathology in patients with CF ○ Bronchial wall thickening is earliest finding – Airway wall inflammation precedes bronchiectasis ○ Bronchiectasis: Most common finding – Multilobar, most severe in upper lobes, right > left – Affects central and peripheral airways – Cylindrical, varicoid, and saccular ○ Mucous plugging common: Nodules, centrilobular nodules, and tree-in-bud opacities ○ Atelectasis (ranging from subsegmental to lobar) secondary to bronchial obstruction • Lung ○ Air-trapping – Hyperinflation is early finding; initially reversible, then permanent (100%) – Mosaic lung attenuation from small airway involvement is common ○ Recurrent multifocal consolidations – Pneumonia, atelectasis, retained secretions distal to bronchial obstruction, hemorrhage ○ Cystic or bullous changes may occur and are typically upper lobe and subpleural in end-stage disease ○ Evolution of pulmonary abnormalities – Early disease □ Mild bronchial wall thickening

Congenital

• Best diagnostic clue ○ Diffuse bronchiectasis; severe upper lobe involvement • Location ○ Upper lobe predominant abnormalities – Right upper lobe often 1st and most severely affected ○ Both central and peripheral airways may be affected

□ Regional (lobular) air-trapping □ Centrilobular nodules (from mucus plugging in peripheral small airways) – Moderate disease progression □ Increased bronchial wall thickening □ Development of cylindrical bronchiectasis □ Increased air-trapping (segmental to lobar) – End-stage disease □ Progression to varicoid or saccular bronchiectasis □ Chronic/recurrent lobar collapse ○ Correlation with pulmonary function – Dissociation between morphologic CT abnormalities and pulmonary function in many patients □ CT abnormalities correlate more strongly with deterioration of clinical status than pulmonary function – Scoring systems on HRCT: Multiple scoring systems □ No consensus as to which is most appropriate for evaluating new therapies or monitoring disease progression • Heart ○ Increase in right heart size (cor pulmonale; ominous clinical sign) ○ Pulmonary hypertension in end-stage disease • Associated findings ○ Lymphadenopathy (reactive) is common ○ Pneumothorax from rupture of subpleural bullae

TERMINOLOGY

Angiographic Findings • Bronchial artery embolization for hemoptysis

Imaging Recommendations • Best imaging tool ○ Chest radiography every 2-4 years recommended by CF Foundation ○ CT provides more information regarding structural lung disease but increases radiation exposure • Protocol advice ○ Role of CT tempered by large lifetime radiation dose ○ Radiation dose reduction – Incremental CT (8x dose reduction) preferable to volumetric CT – Lower mAs

DIFFERENTIAL DIAGNOSIS Allergic Bronchopulmonary Aspergillosis • Central upper lobe predominant bronchiectasis • Mucoid impaction; may exhibit high attenuation 489

Congenital

Cystic Fibrosis • History of asthma, often with eosinophilia • 10% of patients with CF have allergic bronchopulmonary aspergillosis

Primary Ciliary Dyskinesia • Usually basilar predominant • Situs inversus in 50% cases; sinusitis is common

CLINICAL ISSUES

Tuberculosis

Presentation

• Postprimary pattern may produce upper lobe volume loss; bronchiectasis in 50% • Active infection: Cavitary consolidation with centrilobular nodules from endobronchial spread of infection

• Most common signs/symptoms ○ Patients with mild disease may be asymptomatic; diagnosed in adulthood ○ Recurrent pneumonia; productive cough, dyspnea, wheezing; atypical asthma ○ Symptoms parallel development of chronic airways disease ○ Hemoptysis, may be massive • Other signs/symptoms ○ Sweat chloride test positive in 98% patients with CF

Postinfectious Bronchiectasis • Usually unilateral, lobar, or sublobar; often lower lobe predominant (except for tuberculosis)

Williams-Campbell Syndrome • Rare; congenital deficiency of cartilage in subsegmental bronchi • Bronchiectasis limited to 4th-6th generation bronchi

PATHOLOGY General Features • Etiology ○ Abnormalities related to abnormal chloride transport – Thick and viscous mucus – Failure to expectorate mucus, secondary infection often with fungi or bacteria – Airway destruction from recurrent infections ○ Pathophysiology – Normally ↑ lower lobe excursions (diaphragmatic motion) and ↑ transpulmonary pressures – Upper lobes less effective than lower lobes in removing tenacious secretions • Genetics ○ Transmitted as autosomal recessive trait – Mutation of CFTR gene on long arm of chromosome 7 – Abnormal regulation of chloride transport across cell membrane ○ Phenotypic variation in age of onset, severity of pulmonary disease, magnitude of sweat chloride elevation, presence and severity of pancreatic insufficiency • Associated abnormalities ○ Pancreatic insufficiency – Fatty replacement on CT that may spare pancreatic head; may exhibit pancreatic macrocysts ○ Pansinusitis – Hypodeveloped, opacified paranasal sinuses in most patients ○ Biliary cirrhosis ○ Bone demineralization – Vertebral compression and rib fractures are common ○ Infertility

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• Progression from bronchitis and bronchiolitis to bronchiectasis; chronic infection and airway obstruction • Airway colonization by Pseudomonas aeruginosa (mucoid type), nontuberculous mycobacteria, Candida, and Aspergillus species producing additional airway wall damage

Demographics • Age ○ Most diagnosed by 3 years • Gender ○ M