The Thorax: Medical, Radiological, and Pathological Assessment 3031210395, 9783031210396

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Cesar A. Moran Daniel J. Mollura Mylene T. Truong Matthew P. Lungren Patricia M. de Groot Michael R.B. Evans Editors

Clinical Medicine Covertemplate The Thorax Subtitle Medical,for Radiological, and Pathological Clinical Medicine Covers T3_HB Assessment Second Edition

1123 3 2

The Thorax

Cesar A. Moran  •  Mylene T. Truong Patricia M. de Groot Editors

The Thorax Medical, Radiological, and Pathological Assessment

Editors Cesar A. Moran Department of Pathology The University of Texas MD Anderson Cancer Houston, TX, USA

Mylene T. Truong Department of Thoracic Imaging The University of Texas MD Anderson Cancer Houston, TX, USA

Patricia M. de Groot Department of Thoracic Imaging The University of Texas MD Anderson Cancer Houston, TX, USA

ISBN 978-3-031-21039-6    ISBN 978-3-031-21040-2 (eBook) https://doi.org/10.1007/978-3-031-21040-2 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

The thorax is a host of a wealth of conditions that range from reactive, infectious, idiopathic, benign, and malignant tumoral entities representing all the different lineages and etiologies. It is important to highlight that the diagnosis of numerous conditions requires strong clinical information and expert radiological interpretation so that the histopathological findings can be placed in the proper perspective. Also, because the thorax is a common host for metastatic diseases, it is imperative that those involved in the practice and management of patients suffering from thoracic conditions adhere to the practice of proper clinical-radiological-pathological correlations in order to clearly define the process that may be affecting either the pleura, lung, or mediastinum. Although in some instances the finding of a pulmonary mass or a mediastinal mass may be enough, more often than not, the correlation of clinical and pathological findings aids extensively in the understanding of whatever the process might be. In the current text, we provide the collective experience of the many authors who have provided us with their expertise and knowledge to further advance the understanding of thoracic diseases. More importantly is the emphasis that we provide in terms of close clinical-­ radiological-­pathological correlations in the numerous entities addressed in this text. We are also aware that as inclusive as we have been, there are entities that have escaped discussion. However, the text facilitates the daily practice of the most common and also unusual conditions that may affect the thorax. We are fortunate and indebted to the numerous authors who contributed their knowledge to make this text a companion of the daily practice, regardless of whether your interest lies on the medical, radiological, or pathological information of the entities herein presented. The goal of the text is to provide an overall knowledge of the three subspecialties and how global interpretation of many entities can be consolidated so that we can bring it to the bedside whenever it is necessary. Finally, we hope that this text further improves the communication that must exist among clinicians, radiologists, and pathologists involved in the management of thoracic conditions, which in the end can be translated into better patient care. Houston, TX, USA Houston, TX, USA  Houston, TX, USA 

Cesar A. Moran Mylene T. Truong Patricia M. de Groot

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Acknowledgments

To Susan, Kate Leticia, and Elisa Jean for their unwavering love and support. (CAM) To my family for their love, enduring support, and sharing of the joy of learning. My father Dam Thuy, my mother Cam Le, and my siblings Thuy Tien, Ngoc Tien, Pauline, and Angela taught me how to be caring and compassionate. They inspired me to work hard, build resilience, and strive to achieve my goals. (MT) I thank my husband and family for their longstanding support. (PdG)

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Contents

Part I Serosal Surface 1 The Pleura�������������������������������������������������������������������������������������������������������������������   3 Chad D. Strange, Jitesh Ahuja, Saadia A. Faiz, Horiana B. Grosu, William C. Harding, Keerthana Keshava, Carlos A. Jimenez, Vickie R. Shannon, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran Part II The Mediastinum 2 Normal Thymus����������������������������������������������������������������������������������������������������������� 103 Chad D. Strange, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran 3 Thymoma��������������������������������������������������������������������������������������������������������������������� 117 Chad D. Strange, Jitesh Ahuja, Christina Thornton, Erik Vakil, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran 4 Thymic Carcinoma����������������������������������������������������������������������������������������������������� 137 Chad D. Strange, Jitesh Ahuja, Christina Thornton, Erik Vakil, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran 5 Neuroendocrine Neoplasms��������������������������������������������������������������������������������������� 155 Chad D. Strange, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran 6 Mediastinal Germ Cell Tumors��������������������������������������������������������������������������������� 177 Chad D. Strange, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran 7 Mesenchymal  Tumors of the Mediastinum��������������������������������������������������������������� 197 David I. Suster, A. Craig Mackinnon, Jitesh Ahuja, Patricia M. de Groot, and Mylene T. Truong 8 Mediastinal Lymphoproliferative Disorders ����������������������������������������������������������� 221 Sergio Pina-Oviedo and Chad D. Strange 9 Miscellaneous Conditions������������������������������������������������������������������������������������������� 297 Chad D. Strange, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran Part III Lung: Neoplastic Conditions 10 Non-Small Cell Carcinoma ��������������������������������������������������������������������������������������� 311 Donald R. Lazarus, Chad D. Strange, Jitesh Ahuja, Girish S. Shroff, Bradley S. Sabloff, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran

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11 Neuroendocrine  Neoplasms of the Lung������������������������������������������������������������������� 373 Philip G. Ong, Chad D. Strange, Jitesh Ahuja, Girish S. Shroff, Bradley S. Sabloff, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran 12 Salivary  Gland-Type Tumors of the Lung ��������������������������������������������������������������� 411 Ala Eddin Sagar, Mohammed Salhab, Archan Shah, Chad D. Strange, Jitesh Ahuja, Girish S. Shroff, Bradley S. Sabloff, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran 13 Biphasic  Neoplasms of the Lung������������������������������������������������������������������������������� 451 Chad D. Strange, Jitesh Ahuja, Girish S. Shroff, Bradley S. Sabloff, Patricia M. de Groot, Mathieu Marcoux, Mylene T. Truong, and Cesar A. Moran 14 Benign  and Malignant Mesenchymal Tumors of the Lung������������������������������������� 461 David I. Suster, Craig Mackinnon, Jitesh Ahuja, Chad D. Strange, Mathieu Marcoux, Patricia M. de Groot, and Mylene T. Truong 15 Pulmonary Lymphoproliferative Disorders������������������������������������������������������������� 477 Sergio Pina-Oviedo, Girish S. Shroff, Chad D. Strange, Jitesh Ahuja, Bradley S. Sabloff, Labib Gilles Debiane, Angel Rolando Peralta, Avi Cohen, Michael J. Simoff, Vishisht Mehta, Javier Diaz-Mendoza, William P. Brasher, Saadia A. Faiz, Patricia M. de Groot, and Mylene T. Truong 16 Tumors  of Uncertain Histogenesis����������������������������������������������������������������������������� 565 Chad D. Strange, Jitesh Ahuja, Girish S. Shroff, Bradley S. Sabloff, Pushan P. Jani, Alexis Preston, Sarah A. Holevinski, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran 17 Uncommon  Tumors of the Lung������������������������������������������������������������������������������� 581 Cesar A. Moran, Patricia M. de Groot, Mylene T. Truong, Pushan P. Jani, Alexis Preston, Sarah A. Holevinski, Colin Zuchowski, and Diana Palacio Part IV Lung: Non-neoplastic Conditions 18 Interstitial Lung Diseases������������������������������������������������������������������������������������������� 601 Rodeo Abrencillo, Isabel C. Mira-Avendano, Rosa M. Estrada-Y-Martin, Irina Sadovnikov, Colin Zuchowski, Gokhan Kuyumcu, Anjali Taneja, Gabriel Duhancioglu, Usha Jayagurunathan, Matthew LeComte, Diana Palacio, Michelle Hershman, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran 19 Connective  Tissue Disease-Associated Interstitial Lung Disease��������������������������� 661 Reeba Mathew and Sungryong Noh 20 Pneumoconiosis����������������������������������������������������������������������������������������������������������� 693 Sujith V. Cherian, Anupam Kumar, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran 21 Pulmonary Vasculitides ��������������������������������������������������������������������������������������������� 711 Maryam Kaous, Lilit A. Sargsyan, Diana Palacio, Jennifer A. Febbo, Loren Ketai, Matthew D. Gilman, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran 22 Emphysema  and Cystic Lung Disease����������������������������������������������������������������������� 763 Selvin Jacob and Mark T. Warner

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23 Airspace  Diseases and Pulmonary Nodules������������������������������������������������������������� 781 Rodeo Abrencillo, Isabel C. Mira-Avendano, Rosa M. Estrada-Y-Martin, Diana Palacio, Anjali Taneja, Gabriel Duhancioglu, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran 24 Infectious  Diseases That May Mimic Lung Cancer������������������������������������������������� 827 Brandy J. McKelvy, Jose A. B. Araujo-Filho, Myrna C. B. Godoy, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran 25 Miscellaneous Conditions������������������������������������������������������������������������������������������� 853 Rodeo Abrencillo, Isabel C. Mira-Avendano, Rosa M. Estrada-Y-Martin, Diana Palacio, Gokhan Kuyumcu, Labib Gilles Debiane, Angel Rolando Peralta, Avi Cohen, Michael J. Simoff, Vishisht Mehta, Javier Diaz-Mendoza, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran 26 Iatrogenic Conditions������������������������������������������������������������������������������������������������� 871 Diana Palacio, Usha Jayagurunathan, Girish S. Shroff, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran 27 Pathology  of the Lung Allograft ������������������������������������������������������������������������������� 907 Sakda Sathirareuangchai and Jose R. Torrealba Index�����������������������������������������������������������������������������������������������������������������������������������  921

Contributors

Rodeo Abrencillo, MD  Division of Pulmonary, Critical Care and Sleep Medicine, McGovern Medical School, University of Texas Health Houston, Houston, TX, USA Jitesh Ahuja, MD  Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Jose  A.  B.  Araujo-Filho, MD, PhD Hospital Sirio Libanes- Department of Radiology, Sao Paolo, Brazil William P. Brasher, MD  Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, USA Labib Gilles Debiane, MD  Interventional Pulmonology, Pleural Disease Program, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, MI, USA Wayne State University School of Medicine, Detroit, MI, USA Sujith V. Cherian, MD  Department of Medicine, Division of Critical Care, Pulmonary and Sleep Medicine, UT Health-McGovern Medical School, Houston, TX, USA Avi Cohen, MD  Interventional Pulmonology, Advanced Therapeutic Bronchoscopy, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, MI, USA Javier  Diaz-Mendoza, MD, FCCP  Interventional Pulmonology, Bronchoscopy Education Associate Program, Pulmonary and Critical Care Fellowship, Henry Ford Hospital, Detroit, MI, USA Wayne State University, Detroit, MI, USA Gabriel Duhancioglu, MD  Department of Radiology, University of Arizona-Banner Medical Center, Tucson, AZ, USA Rosa M. Estrada-Y-Martin, MD  Division of Pulmonary, Critical Care and Sleep Medicine, McGovern Medical School, University of Texas Health Houston, Houston, TX, USA Saadia  A.  Faiz, MD Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Jennifer  A.  Febbo, MD Department of Radiology, University of New Mexico HSC, Albuquerque, NM, USA Matthew  D.  Gilman, MD Department of Radiology, Harvard University, Massachusetts General Hospital, Boston, MA, USA Myrna C. B. Godoy, MD, PhD  Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Patricia M. de Groot, MD  Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Horiana B. Grosu, MD  Department of Pulmonary Medicine, MD Anderson Cancer Center, Houston, TX, USA William C. Harding, MD  Pulmonary Medicine, Critical Care Medicine and Sleep Medicine, McGovern Medical School at University of Texas Science Center, Houston, TX, USA Michelle  Hershman, MD Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA Sarah A. Holevinski, MD  McGovern Medical School at UT Health, Houston, TX, USA Selvin  Jacob, MD Division of Critical Care Medicine and Sleep Medicine, UT Health McGovern Medical School, Houston, TX, USA Pushan P. Jani, MD  Divisions of Pulmonary, Critical Care Medicine and Sleep Medicine, Department of Internal Medicine, McGovern Medical School at UT Health, Houston, TX, USA Usha  Jayagurunathan, MD Department of Radiology, University of Arizona-Banner Medical Center, Tucson, AZ, USA Carlos A. Jimenez, MD, MS  Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Maryam  Kaous, MD  Division of Critical Care Medicine and Sleep Medicine, UT Health McGovern Medical School, Houston, TX, USA Keerthana  Keshava, MD  Interventional Pulmonology, Department of Pulmonary, Critical Care and Sleep Medicine, New York Presbyterian Brooklyn Methodist Hospital, New York, NY, USA Loren Ketai, MD  Department of Radiology, University of New Mexico HSC, Albuquerque, NM, USA Anupam Kumar, MD  Division of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA Gokhan Kuyumcu, MD  Department of Radiology, University of Arizona-Banner Medical Center, Tucson, AZ, USA Donald  R.  Lazarus, MD  Department of Medicine, Baylor College of Medicine, Houston, TX, USA Matthew LeComte, MD  Department of Radiology, University of Arizona-Banner Medical Center, Tucson, AZ, USA Craig  Mackinnon, MD  Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA Mathieu Marcoux, MD, M.Sc.  Department of Medicine, Centre Hospitalier Universitaire de Québec, Université Laval, Québec City, Canada Reeba Mathew, MBBS  Division of Pulmonary, Critical Care and Sleep Medicine, UTHealth Houston–McGovern Medical School, Houston, TX, USA Brandy J. McKelvy, MD  Division of Critical Care Medicine and Sleep Medicine, UT Health McGovern Medical School, Houston, TX, USA Vishisht Mehta, MD  Interventional Pulmonology, Henry Ford Hospital, Detroit, MI, USA Isabel C. Mira-Avendano, MD  Division of Pulmonary, Critical Care and Sleep Medicine, McGovern Medical School, University of Texas Health Houston, Houston, TX, USA

Contributors

Contributors

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Cesar  A.  Moran, MD Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Sungryong Noh, MD  Division of Pulmonary, Critical Care and Sleep Medicine, UTHealth Houston–McGovern Medical School, Houston, TX, USA Philip G. Ong, MD  Department of Medicine, UT Health – San Antonio, San Antonio, TX, USA Diana  Palacio, MD Department of Radiology, Cardiothoracic Imaging Section, The University of Texas Medical Branch, UTMB, Galveston, TX, USA Angel  Rolando  Peralta, MD Interventional Pulmonology, Bronchoscopy Services, Lung Cancer Screening, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, MI, USA Sergio  Pina-Oviedo, MD Department of Pathology, Duke University Medical Center, Durham, NC, USA Alexis Preston, MD  McGovern Medical School at UT Health, Houston, TX, USA Bradley  S.  Sabloff, MD Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Irina  Sadovnikov, MD Department of Radiology, University of Arizona-Banner Medical Center, Tucson, AZ, USA Ala Eddin Sagar, MD  Department of Onco-Medicine, Banner MD Anderson Cancer Center, Gilbert, AZ, USA Mohammed  Salhab, MD Department of Onco-Medicine, Banner MD Anderson Cancer Center, Gilbert, AZ, USA Lilit A. Sargsyan, MD  Division of Critical Care Medicine and Sleep Medicine, UT Health McGovern Medical School, Houston, TX, USA Sakda Sathirareuangchai, MD  Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA Department of Forensic Medicine, Mahidol University, Bangkoknoi, Thailand Archan  Shah, MD  Department of Onco-Medicine, Banner MD Anderson Cancer Center, Gilbert, AZ, USA Vickie R. Shannon, MD  Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Girish  S.  Shroff, MD Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Michael J. Simoff, MD, FACP, FCCP  Wayne State University School of Medicine, Detroit, MI, USA Bronchoscopy and Interventional Pulmonology, Lung Cancer Screening Program, Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, MI, USA Chad  D.  Strange, MD Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA David  I.  Suster, MD Department of Pathology, Rutgers University School of Medicine, Newark, NJ, USA

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Anjali Taneja, MD  Department of Radiology, University of Arizona-Banner Medical Center, Tucson, AZ, USA Christina Thornton, MD, PhD  Division of Respirology, University of Calgary, Calgary, AB, Canada Jose R. Torrealba, MD  Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA Mylene  T.  Truong, MD Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Erik  Vakil  Interventional Pulmonary Medicine, University of Calgary Arnie Charbonneau Cancer Institute, Calgary, AB, Canada Mark T. Warner, MD  Division of Critical Care Medicine and Sleep Medicine, UT Health McGovern Medical School, Houston, TX, USA Colin Zuchowski, MD  Department of Radiology, Emory School of Medicine, Atlanta, GA, USA

Contributors

Part I Serosal Surface

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The Pleura Chad D. Strange, Jitesh Ahuja, Saadia A. Faiz, Horiana B. Grosu, William C. Harding, Keerthana Keshava, Carlos A. Jimenez, Vickie R. Shannon, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran

Introduction Pleural disease is often a mirror of intrathoracic and systemic diseases caused by an extensive list of neoplastic and nonneoplastic conditions. Both neoplastic and nonneoplastic pleural diseases can present with similar clinical features. Nonneoplastic disorders of the pleura may result from a variety of infectious as well as drug- and trauma-related causes. Many of these conditions when persistent or severe, may lead to encasement of the lung by a thick fibrous layer, known as fibrous pleuritis. The management and prognoses of these diverse conditions vary greatly. Thus, accurate diagnosis of pleural diseases is critical. Primary pleural disease owing to a myriad of inflammatory and neoplastic pleural disorders is less common, but nonetheless relevant due to its potential to cause devastatC. D. Strange · J. Ahuja · P. M. de Groot (*) · M. T. Truong Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected]; [email protected]; [email protected]; [email protected] S. A. Faiz · C. A. Jimenez · V. R. Shannon Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected]; [email protected] H. B. Grosu Department of Pulmonary Medicine, MD Anderson Cancer Center, Houston, TX, USA W. C. Harding Pulmonary Medicine, Critical Care Medicine and Sleep Medicine, McGovern Medical School at University of Texas Science Center, Houston, TX, USA K. Keshava Interventional Pulmonology, Department of Pulmonary, Critical Care and Sleep Medicine, New York Presbyterian Brooklyn Methodist Hospital, New York, NY, USA C. A. Moran Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected]

ing respiratory compromise. Moreover, many of the benign tumors of the pleura closely mimic malignant disease in their radiographic and histologic appearance. Thus, early recognition and management are critical components to the successful outcomes of primary pleural disorders. In this chapter, we will discuss the clinical, radiographic, and pathologic correlates of the spectrum of primary and secondary diseases of the pleura. The intent of this multidisciplinary approach is to provide a detailed overview and update of diseases of the pleura that can be directly applied to clinical practice and to stimulate basic research investigations in areas where there are unanswered questions. We begin with a brief discussion of pleural anatomy and radiology concepts as critical background information to understanding pleural disease. This is followed by detailed descriptions of benign and malignant neoplastic and inflammatory disorders affecting the pleura. Pleural effusions are often the first manifestation of many of the diseases affecting the pleura and we end the chapter with a discussion of the pathogenesis, diagnosis, and management of pleural effusions, which will hopefully provide the reader with a more complete understanding of this complex disease.

Pleural Anatomy During early embryogenesis, the coelomic cavity is partitioned into three distinct spaces (pleura, pericardial, and peritoneal). Lung buds invaginate the coelomic cavity, which folds on itself to form the visceral and parietal pleura. In humans, the visceral and parietal pleura merge at the left and right hila, separating the thorax into two noncontiguous spaces. The surface of the pleural membranes is composed of a monolayer of mesothelial cells. The visceral pleura lines the lungs and interlobar fissures while the parietal pleura covers the thoracic wall and diaphragm and is subdivided into the costal, diaphragmatic, mediastinal, and cervical pleura [1, 2]. Under normal conditions, the visceral and parietal pleurae are separated by 10–20 mL of a lubricating, glycoprotein-­rich pleural

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 C. A. Moran et al. (eds.), The Thorax, https://doi.org/10.1007/978-3-031-21040-2_1

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fluid, which is secreted by the mesothelial lining cells [3]. This fluid reduces friction by lubricating the pleural space, thereby facilitating normal lung movements during respiration. Production and absorption of pleural fluid primarily occurs at the level of the parietal pleura. Fluid homeostasis reflects a balance of hydrostatic and oncotic pressure differences between the systemic and pulmonary circulations and the pleural space. The pleural space is equipped with an extensive network of lymphatic vessels that line the parietal pleura and play a critical role in pleural fluid homeostasis. This lymphatic network supplies the costal, diaphragmatic, and mediastinal surfaces of the parietal pleura and is lined by specialized openings between mesothelial cells known as stomata. Excess fluid derived from the lung via the visceral pleura is absorbed through the parietal stomata into underlying lymphatic lacunae, which ultimately empty into larger lymphatic vessels. Lymphatic drainage along with oncotic and hydrostatic pressures maintain the delicate balance of fluid within the pleural space; disturbances in any one of these systems can lead to abnormal accumulation of pleural fluid [4]. Thus, excess production, diminished resorption, or a combination of these two factors substantially overwhelms the ability of lymphatic vessels to resorb fluid resulting in clinically significant effusions [5]. The pleural fluid is bland, with a low protein content of approximately 1.5  g/dL and comprised predominantly of mesothelial cells, macrophages, and lymphocytes. The visceral pleura receives innervation from the pulmonary plexus, which is a network of nerves that originate from the sympathetic trunk and vagus nerve. As such it can detect stretch, but is insensitive to pain, temperature, and touch. The parietal pleura is innervated by sensory fibers of a

the phrenic nerve at its diaphragmatic portion and the intercostal nerves elsewhere. The vascular supply of the visceral pleura is provided by pulmonary and bronchial arteries, while the parietal pleura receives its vascular supply from the systemic circulation [1, 4]. Histologically, distinction between visceral and parietal pleura is not possible, as both of these serosal surfaces are lined by similar type of epithelium. The mesothelial lining is composed of low cuboidal type of epithelium. However examination of large sections of tissue may permit visualization of visceral pleura overlying the lung parenchym (Fig.  1.1a, b), while histological sections from the parietal pleura will demonstrate epithelium (mesothelium) lining adipose tissue (Fig. 1.2). Both neoplastic and nonneoplastic pleural diseases can present with similar clinical features. Nonneoplastic disorders of the pleura may result from a variety of infectious as well as drug- and trauma-related causes. Many of these conditions when persistent or severe, may lead to encasement of the lung by a thick fibrous layer, known as fibrous pleuritis. The management and prognoses of these diverse conditions vary greatly. So, accurate diagnosis of pleural diseases is critical.

General Radiology Concepts Imaging plays a crucial role in the diagnosis and management of patients with pleural diseases. Modalities of imaging include chest radiography, computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), and F-18 fluorodeoxyglucose (FDG) positron emission tomogb

Fig. 1.1 (a) Low power view of a section from the visceral pleura, note the presence of fibroadipose tissue lined by epithelium; (b) closer view of the epithelium composed of low cuboidal cells

1  The Pleura

raphy/computed tomography (PET/CT). Chest radiography remains the initial imaging modality for the evaluation of pleural diseases but it may be normal or may not be able to differentiate benign from malignant conditions. Various

Fig. 1.2  Histological sections showing visceral pleura overlying the lung parenchyma

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cross-sectional imaging modalities are available for further evaluation and characterization of pleural diseases. Thoracic ultrasound is easily available and widely used for detection and characterization of pleural fluid and guidance of thoracentesis and pleural biopsies. CT is the mainstay imaging modality for primary assessment of pleural diseases and exhibits high sensitivity for identification of pleural diseases and in differentiating benign and malignant pleural processes. MRI and PET/CT play important roles in further evaluation and can provide additional staging and prognostic information. Cancer cells show on FDG-PET/CT, increased uptake of glucose due to an overexpression of glucose transporter proteins and increased rate of glycolysis. A glucose analogue, F-18 fluorodeoxyglucose (FDG) undergoes the same uptake as glucose. However, following phosphorylation by hexokinase, FDG is unable to enter intracellular glycolytic pathways due to a downregulation of phosphatase and is sequestered in cancer cells. The most common semiquantitative method of evaluating malignancies using FDG-PET is the standardized uptake value (SUV) calculated as a ratio of tissue radiotracer concentration (mCi/ml) and injected dose (mCi) at the time of data acquisition divided by body weight (g). It should be noted that inflammatory conditions, such as talc pleurodesis, can also cause FDG activity in the pleural space (Fig. 1.3a, b). Imaging features to differentiate pleural lesions from peripheral pulmonary and extrapleural tumors are important. b

Fig. 1.3 (a) Non-contrast axial CT shows high attenuation material in the posterior right pleural space (arrow) consistent with talc pleurodesis. (b) axial PET/CT shows increased radiotracer uptake in the talc deposits

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Fig. 1.4  Contrast-enhanced axial CT shows the left lower lobe mass abuts the posterior pleura and forms acute angles (black arrows) with the chest wall. The angles that a lesion forms with the chest wall are useful to differentiate lung lesions (acute angles) from pleural lesions (obtuse angles)

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Fig. 1.5 (a) Frontal chest radiograph shows the right pleural metastasis forms obtuse angles (arrow) with the chest wall. In contrast, lung lesions that abut the pleura form acute angles with the chest wall; (b) contrast-enhanced axial CT shows the right pleural metastasis forms obtuse angles with the chest wall (long white arrow) and is associated

Tumors arising within the periphery of the lungs form acute angles with the chest wall, are centered within the lungs, and are perfused by pulmonary vessels (Fig. 1.4). Pleural tumors have more obtuse angles with the chest wall and displace the pulmonary parenchyma and vessels inward and the extrapleural fat outward (Fig.  1.5a–c). Typically pleural tumors do not cause adjacent osseous erosive change. Additionally, pleural tumors often demonstrate an “incomplete border sign” on radiographs where only one margin of the tumor (the margin abutting the pulmonary parenchyma) is radiographically identified. Extrapleural tumors arise from the extrapleural fat, muscles, ribs, or neurovascular bundles and will displace extrapleural fat inward [1]. Imaging in general cannot absolutely distinguish between benign and malignant pleural processes; however, there are certain characteristics that favor a malignant etiology. On chest radiographs, nodular or circumferential pleural thickening, especially if greater than 1 cm in thickness, ­involvement of the mediastinal pleura, and larger effusions suggest malignancy. CT and MRI findings that suggest malignancy include pleural nodularity, pleural rind, involvement of the mediastinal pleura, and invasion of adjacent structures (Fig. 1.6a, b). FDG uptake in areas of pleural thickening or nodularity, hypermetabolic pleural effusions, hypermetabolic adenopathy, and evidence of hypermetabolic distant metastasis on PET/CT are highly suggestive of malignancy [6–11].

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with erosive and sclerotic changes in the adjacent rib (black arrow). Note small right axillary nodal metastasis (short white arrow); (c) contrast-­enhanced axial CT shows the right pleural metastasis displaces the lung parenchyma and bronchopulmonary vessels inward (arrow)

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Fig. 1.5 (continued)

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Fig. 1.6 (a) Frontal chest radiograph shows the features of malignant pleural disease, with a right nodular pleural rind of tumor encasing the right lung (white arrows). There is involvement of the minor fissure

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(black arrow); (b) contrast-enhanced axial CT shows nodular configuration, circumferential distribution (white arrows) with extension into the major fissure (black arrow), and pleural thickness greater than 1 cm

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Nonneoplastic Fibrous and Fibrinous Pleuritis Fibrous pleuritis, also referred to as pleural fibrosis, fibrothorax, fibrous pleurisy, fibrosing pleuritis, and dry pleurisy, is an uncommon disorder. The physiologic mechanisms underlying the development of fibrous pleuritis are not well understood; however, disordered fibrin turnover associated with pleural injury and repair are central events in its pathogenesis. Fibrous pleuritis most commonly occurs as a complication of hemothorax or empyema caused by bacterial, mycobacterial, or fungal processes (Fig. 1.7a–c). However, a variety of other inflammatory and infiltrative pleural processes may underlie the development of this disorder (Table 1.1). Metastatic disease and other infiltrative immunologic disorders, such as rheumatoid arthritis or sarcoidosis, may produce pleural

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effusions with varying degrees of pleural fibrosis. Underlying thoracic conditions, such as pneumothorax, improperly drained hemothorax, chest trauma, uremia, lung transplantation, and prior coronary artery bypass surgery also predispose to fibrous pleuritis. Drug-induced pleural effusions have been well described; however, medication-associated fibrous pleuritis is less commonly observed. Other causes include systemic fibrosing diseases that involve the pleura, such as nephrogenic systemic fibrosis and immunoglobulin G4 (IgG-4)-related sclerosing disease [12]. Idiopathic and isolated familial cases of pleural fibrosis have been reported [13]. The integrity of the mesothelial cell and its response to any one of these inciting events dictate whether normal healing or pleural fibrosis occurs after injury. Mesothelial cells initiate and orchestrate inflammatory and exudative reactions via the release of cytokines, chemokines, oxidants, and

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Fig. 1.7 (a) Contrast-enhanced axial CT shows left lower lobe mass-­ like consolidation (arrow); (b) axial FDG-PET/CT shows increased FDG uptake in the consolidation suspicious for malignancy (arrow); (c)

contrast-enhanced axial CT 2  months later shows persistence of the organizing pneumonia (P) and moderate left pleural effusion with pleural thickening consistent with empyema (arrow)

1  The Pleura Table 1.1  Common causes of fibrous pleuritis Diffuse pleural thickening with/without calcification  Pleural infections   Bacterial (Staphylococcus aureus, Streptococcus pneumonia, Tuberculosis, enteric gram-negative bacilli, Actinomycetes, Nocardia)    Fungal (pneumocystis jirovecii, Coccidioides, histoplasma)  Mineral dust exposure    Asbestos    Silica  Drug reactions   Ergot derivatives, methysergide, ergoline, bromocriptine, pergolide, cabergoline nicergoline)    Antibiotics (tetracycline, nitrofurantoin)    Anti-arrhythmics (amiodarone)   Chemotherapeutic agents (cyclophosphamide, bleomycin, procarbazine)  Uremia  Hemothorax    Trauma-related    Iatrogenic   Tumor-related (primary pleural tumors, primary bronchogenic carcinoma, metastatic pleural disease)  Connective tissue diseases    Rheumatoid arthritis    Systemic lupus erythematosus    Wegener’s granulomatosis  IgG4-related  Trauma Localized pleural thickening  Pleural plaques    Apical pleural plaques    Mineral dust related (Asbestos, silica)    Hemothorax    Organized empyema  Cardiac surgery (coronary artery bypass graft)  Connective tissue diseases    Rheumatoid arthritis    Systemic lupus erythematosus    Wegener’s granulomatosis  Drug-induced   Ergot derivatives, methysergide, ergoline, bromocriptine, pergolide, cabergoline nicergoline)    Antibiotics (tetracycline, nitrofurantoin)    Anti-arrhythmics (amiodarone)   Chemotherapeutic agents (cyclophosphamide, bleomycin, procarbazine)  IgG4-related  Pleuroparenchymal fibroelastosis

proteases [14]. With persistent and/or severe inflammatory injury, the pleural space may become focally or diffusely obliterated due to the formation of dense fibrous adhesions. Acute fibrinous pleuritis is potentially reversible. With continued fibrin deposition, irreversible fibrous pleuritis associated with trapped lung may ensue. The propensity for some insults to the pleura to cause irreversible pleural fibrosis while others trigger reversible fibrinous pleuritis with complete resolution is not well understood.

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Fibrothorax represents the most severe form of fibrous pleuritis in which progressive fibrosis of the visceral and parietal pleural surfaces leads to pleural adhesion. The dense pleural peel disallows lung expansion, resulting in trapped lung. Trapped lung implies chronicity of a remote inciting inflammatory event, unassociated with active disease and resulting in restrictive physiology that is usually irreversible. Associated pleural effusions are commonly small to moderate in size and transudative. Lung entrapment is also associated with a restrictive defect; however, entrapment typically arises from an active inflammatory process or malignancy and is potentially reversible. Pleural effusions in this setting are usually exudates. Therapeutic pleural drainage in either case results in a post-procedure pneumothorax, also known as pneumothorax ex-vacuo, which signifies the inability of the lung to reexpand into the evacuated pleural space. Distinguishing pneumothorax ex-vacuo from pneumothorax due to breach of the pleural membrane is crucial in directing appropriate therapy. Pleural manometry during pleural drainage procedures may be helpful in assessing abnormal lung expansion. Abnormal lung expansion is signified by a sharp decline in pleural pressure with minimal fluid drainage and may be accompanied by pleuritic chest pain [15–18]. Fibrothorax may be associated with mild to moderate restrictive pattern on pulmonary function testing. With extensive disease, particularly in cases of bilateral fibrothorax, hypercapnic respiratory failure associated with a severe restrictive defect may develop and necessitate noninvasive ventilation.

Histological Features Histologically, one can separate fibrous pleuritis from fibrinous pleuritis, as the former lacks the presence of a fibrinous exudate. Clinical correlation is paramount to determine the etiology of the histologic findings. • Fibrous pleuritis/pleurisy: The histological hallmark of this process is the presence of a thickened pleura with minimal inflammatory and conspicuous fibroblastic components (Fig.  1.8a, b). In focal areas, the spindle cell fibroblastic component appears to dissect sections of hyalinized pleura. However, it is important to highlight that such process although may present as thickened pleura, does not invade adjacent adipose tissue or skeletal muscle. Those latter features are commonly associated with mesothelioma, which with these particular features would make it suspicious for desmoplastic mesothelioma (see below discussion on mesothelioma). In some other cases, the process may show more cellular component in the form of prominent spindle cell fibroblastic proliferation admixed with vascular structures and minimal inflammatory cells, namely, lymphocytes and plasma cells (Fig. 1.9a, b). Very likely due to the inflammatory insult, the cellular proliferation may become more reactive

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Fig. 1.8 (a) Low power view of fibrous pleuritis, note the presence of uninvolved adipose tissue, (b) higher magnification showing only focal areas of spindle cellular proliferation

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Fig. 1.9 (a) Dense fibrocollagen admixed with vessels and fibroblastic cells, (b) fibrous pleuritis showing more cellularity admixed with dilated vessels and minimal inflammatory response

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Fig. 1.10 (a) Cellular fibrous pleuritis with minimal inflammatory response, (b) fibrous pleuritis with cellular atypia

owing to inflammation, which results in atypical mesothelial proliferation showing larger cells with round to oval nuclei and in some cells with prominent nucleoli (Fig. 1.10a, b). In some cases, mitotic figures may also be present. The use of immunohistochemical studies in these cases has limited value, as reactive mesothelial cells will show positive staining for the common markers used for mesothelioma, such as keratin, keratin 5/6, and/or calretinin. In unusual cases in which the biopsy specimen is limited, the use of molecular studies such as p16 by fluorescence in situ hybridization (FISH) may aid in the diagnosis as the presence of a homozygous deletion will be more compatible with mesothelioma (see discussion of mesothelioma below). • Fibrinous pleuritis: As the term implies, the presence of fibrinous exudates that may be admixed with acute and chronic inflammatory cells are the hallmark for this process (Figs. 1.11a–c). Frequently, the use of histochemical stains (AFB and GMS) to rule out the possibility of microorganisms is commonly requested. However, the use of tissue cultures is also helpful in identifying organisms. • Xanthomatous pleuritis: The inflammatory component in this process is based on the marked presence of foamy histiocytes (Fig.  1.12a, b) with minimal inflammatory reaction and the absence of fibrinous exudates. Commonly, this type of process occurs as a reaction to drug therapy or radiation [19].

• Eosinophilic pleuritis: This process has been linked to pneumothorax, infections, and adverse drug reactions [20–22]. It is more commonly seen in adult individuals. Eosinophilic pleuritis is characterized histologically by the presence of sheets of eosinophils admixed with other inflammatory cells and occasionally giant cells (Fig. 1.13a–c).

Pleural Infections The prevalence of fibrous pleuritis varies broadly with the specific inciting organism. The gamut of infectious processes that can seed the pleural surface is vast and theoretically any organism, whether bacterial or fungal, can be the leading cause of the infection. Bacterial or tuberculous pneumonia is the most common infectious cause of fibrous pleuritis, which typically occurs as a sequela of empyema, lung abscess, or aspiration. Staphylococcus aureus, streptococcus pneumoniae, and enteric gram-negative bacilli are the principal organisms implicated in the general population, while infections caused by Actinomycetes and Nocardia are primarily implicated in the setting of aspiration and immunocompromised states, respectively [23, 24]. Tuberculous pleuritis is the most common extrapulmonary manifestation of tuberculosis, with sequelae of residual pleural fibrosis occurring in 20–50% of patients [25–28]. Most of these patients have mild disease. Associated dyspnea and functional restric-

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Fig. 1.11 (a) Low power view of fibrinous pleuritis. Note the presence of fibrinous exudate, (b) fibrinous exudate with areas of acute and chronic inflammation, (c) closer view of fibrinous pleuritis showing the fibrinous exudate and hyperplastic mesothelial cells

tive physiology are seen in only 10% [21–24, 29–32]. The development of post tuberculous pleural fibrosis does not appear to correlate with clinical symptoms, or with the size and microbiologic characteristics of the preceding pleural fluid [31]. Neither early drainage of the pleural effusion nor systemic corticosteroids has been shown to be of definitive

clinical benefit in limiting the subsequent development of pleural fibrosis [26, 33–35]. Tuberculous pleuritis may clinically and radiographically mimic pleural neoplasms [28, 36]. The prevalence of fibrous pleuritis owing to fungal empyemas varies with geographic distribution and immunocompromised states. For example, the ubiquitous environmental

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Fig. 1.12 (a) Low power view of Xanthomatous pleuritis, note the diffuse presence of histiocytes with minimal inflammatory response, (b) higher magnification showing foamy histiocytes admixed with mesothelial cells

fungi, Pneumocystis jirovecii, may contribute to fibrous pleuritis among immunocompromised patients with empyema while patients residing in endemic areas for coccidioidomycosis (Southwestern United States) or histoplasmosis (Ohio River Valley) may develop fibrinous pleuritis as a sequela of empyema associated with these specific infectious organisms.

Histopathological Features Evaluation of pleural fluid cultures may potentially provide invaluable information and guide specific treatment. Pleural biopsies may offer additional information. The basic histochemical stains used will depend largely on the histological features present in the biopsy. Light microscopic examination typically demonstrates an acute inflammatory reaction in which inflammatory cells are embedded in a fibrinous exudate (Fig.  1.14a–d). The predominant cells are polymorphonuclear cells admixed with plasma cells and lymphocytes. Bacterial cultures and histochemical stains, such as Gram’s may be of aid in attempting to demonstrate the presence of bacterial organisms. In addition to an inflammatory exudate, granulomatous inflammation, characterized by the presence of slightly nodular architecture with the presence of numerous multinucleated giant cells admixed with other inflammatory cells,

predominantly histiocytes can be found (Fig.  1.14a–d). Other inflammatory cells that may be present include lymphocytes, plasma cells, and eosinophils. In such cases the use of silver stains such as Gomori Methenamine Silver (GMS) can identify fungal organisms (Fig.  1.14e). The use of histochemical stains for acid fast bacteria (AFB) is important to properly exclude the possibility of mycobacterial infection [36].

Uremia Pleural abnormalities of uremia, including fibrinous pleuritis have been observed in up to 20% of patients at autopsy [37]. The mechanism of uremic fibrous pleuritis has not been established, however, abnormal filtration forces and lymphatic absorption across subpleural surfaces have been implicated [38]. Pleural disease in this setting ranges from subclinical pleural thickening to severe dyspnea associated with pleural deposition of a gelatinous material and formation of a thick pleural peel. Uremic fibrosing pleuritis typically develops several years after initiation of dialysis. Pleural thickening may initially respond to dialysis, or wax and wane spontaneously [39]. Optimal therapies, including the therapeutic

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Fig. 1.13 (a) Low power view of strip of pleura with inflammatory cells, (b) higher magnification shows sheets of eosinophils, (c) eosinophilic pleuritis with areas of mesothelial hyperplasia

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Fig. 1.14 (a) Low power view of acute pleuritis; (b) higher magnification showing the presence of an inflammatory reaction composed predominantly of histiocytes; (c) predominantly fibrinous exudate in

fibrinous pleruritis; (d) pleuritis showing numerous multinucleated giant cells with inflammatory reaction; (e) GMS stain showing numerous fungal organisms

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benefit of systemic corticosteroids, are not well defined. As pleural deposition progresses, irreversible restrictive physiology requiring surgical decortication may occur.

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Hemothorax Hemothorax, or the accumulation of blood into the pleural space, has been reported most frequently after trauma to the chest or in association with iatrogenic causes (Fig. 1.15a, b). Primary or metastatic pleural tumors, bleeding diatheses, anticoagulation, pleural endometriosis, arteriovenous malformations, and vascular rupture are other attributable causes. Fibrothorax associated with trapped lung is a rare late complication of hemothorax. Early and complete chest tube drainage of the hemothorax is generally recommended to mitigate the complications of fibrothorax. Operative therapies, including video-assisted thoracoscopic surgery (VATS), are generally reserved for hemodynamically unstable patients with more than 1000 ml of blood drainage from the initial thoracotomy or brisk ongoing blood losses of more than 100–200  ml/h [40, 41]. Decortication may alleviate fibrothorax and trapped lung; however, operative risk is substantial.

Fig. 1.14 (continued)

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Fig. 1.15 (a) Frontal chest radiograph shows complete opacification of the right hemithorax; (b) contrast-enhanced axial CT shows heterogeneous attenuation in the right pleural fluid in the pneumonectomy space consistent with blood products (arrow)

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 oronary Artery Bypass Surgery C Pleural effusions occur throughout the perioperative and postoperative period following a variety of cardiac surgeries, including coronary artery bypass grafting (CABG). Diagnostic thoracentesis should be performed for patients with large symptomatic pleural effusions or fever after CABG surgery. Early effusions may spontaneously resolve, while late effusions may persist 6 or more months after the surgery. Many of the early pleural effusions post CABG may be directly attributable to pleural injury during surgery. Persistent late effusions, however, have been ascribed to lymphatic damage, and/or immune mechanisms [42–44]. Over time, these lymphocyte-predominant exudates are replaced with fibrin deposition and subsequent trapped lung. In patients with advanced disease, significant dyspnea associated with a severe restrictive defect often requires surgical decortication [45].

under-perfusion, causing chronic low-grade local ischemia. This ischemia coupled with chronic low-grade inflammation is the proposed mechanism, although the pathogenesis remains unproven. The scars typically remain stable, although minimal enlargement occurring over years has been reported. The prevalence of apical caps increase with age, occurring in 64% of patients over the age of 66 years in one study [46]. There is no sex predilection and no predilection for either side. On light microscopy, apical caps are characterized by the presence of subpleural fibroelastosis or fibrosis with or without the presence of entrapped alveoli and scattered inflammatory cells (Fig.  1.16a, b). Occasionally, alveolar entrapment may have features that are similar histologically to adenocarcinoma.

Apical Pleural Plaques

Pneumoconiosis caused by significant exposure to asbestos and silica are well known causes of pleural fibrosis. Asbestos-­ related pleural fibrosis may exist as pleural plaques or diffuse pleural fibrosis. These two clinically distinct entities may overlap; however, the presence of pleural plaques does not imply or predict the development of asbestosis. Pleural plaques arise along the parietal surface of the pleura and are most commonly distributed along the lateral and posterior walls of the lower half of the thorax, sparing the costophrenic angles. Diaphragmatic, mediastinal, pericardial distribution is also seen.

Localized visceral pleural plaques may exist as apical caps or nodular histiocytic hyperplasia. Apical caps exist morphologically as unilateral or bilateral fibroelastic scars involving the lung apex. These benign lesions are typically identified as asymptomatic findings on chest radiographs. Bilateral lesions may be asymmetric. The pathogenesis of apical caps is not completely understood. The apical segments of the upper and lower lobes are subject to intrinsic physiologic

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Pneumoconiosis

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Fig. 1.16 (a) Low power view of an apical cap showing subpleural fibroelastotic changes, (b) higher magnification showing low cellularity and dilated vessels

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Fig. 1.17 (a) Frontal chest radiograph shows bilateral curvilinear areas of calcification consistent with pleural plaques due to asbestos exposure. A moderate left pleural effusion is present; (b) contrast-­ enhanced axial CT chest shows the left upper lobe lung cancer (T) and

bilateral calcified pleural plaques (arrows) with a left pleural effusion; (c) axial FDG-PET/CT shows the left upper lobe primary tumor is hypermetabolic. Calcified pleural plaques (arrows) due to prior exposure to asbestos are not FDG avid on PET

Calcified bilateral lesions are virtually pathognomonic of significant prior asbestos exposure (Fig. 1.17a–c). Pleural plaques typically develop 20–30  years after initial asbestos exposure and are frequently incidental findings on chest radiographs in asymptomatic patients [46–48]. The mechanism of pleural plaque formation has not been definitively elucidated, however penetration of inhaled asbestos fibers through the visceral pleura, which incites an inflammatory reaction along the parietal pleura has been proposed. In contrast to asbestos-related pleural plaques, asbestos-­associated diffuse pleural thickening involves the visceral pleura, frequently distributes over the costophrenic angles, and may be accompanied by fibrotic parenchymal disease. Patients typically present with dyspnea on exertion ­associated with a restrictive physiology and reduced diffusing capacity on lung function testing [49–51]. The presence of hyalinzed fibroconnective tissue with minimal inflammatory reaction is a hallmark of asbestos-­ related pleural plaques (Fig.  1.18a–c). Despite significant

asbestos exposure, ferruginous bodies on pleural sections are rare findings, which more often occur in alveolated lung parenchyma. Treatment options for asbestos-related diffuse pleural disease are very limited. In the absence of significant p­ ulmonary fibrosis, decortication may be considered, although surgical outcomes have been mixed. Silica-associated fibrous pleuritis occurs in 18–58% of exposed persons. In addition to the traditional mining industry, occupational exposure to silica has been reported in a variety of workplaces, including sandblasting, stone masonry, semiprecious stone manufacturing, electrical cable industries, hydraulic fracturing industries, and construction. Acute, accelerated, and chronic forms of silicosis exist, occurring within weeks to 5  years, less than 10  years, and more than 10 years after significant silica exposure, respectively. Patients commonly present with progressive dyspnea and dry cough in association with recalcitrant, diffuse pleu-

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Fig. 1.18 (a) Low power view of a thick pleural surface overlying lung parenchyma; (b) higher magnification of the pleura showing extensive hyalinization with minimal inflammation; (c) alveolated lung parenchyma showing numerous ferruginous bodies

ral fibrosis and upper-lobe predominant fibrotic parenchymal disease, known as progressive massive fibrosis (PMF) [52, 53]. The diagnostic workup relies on chest CT imaging and pulmonary function testing coupled with a compatible history of silica dust exposure. Mixed inflammatory reaction composed of histiocytes and lymphocytes with fibrosis and the presence of dust-like dark silica particles are noted on histological sections of the pleura (Fig. 1.19a, b). Silica particles are best detected with polarized light or by X-ray diffraction analysis.

Superimposed bacterial infection, in particular, mycobacterial disease, is a well-known complication of silicosis with PMF and should be suspected in patients with fever and other constitutional symptoms, worsening respiratory impairment, hemoptysis, and cavitation in regions of PMF on chest imaging studies. Chronic necrotizing aspergillosis, chronic bronchitis, autoimmune diseases, and lung cancer are other associated conditions [54]. Treatment is primarily supportive. Avoidance of further exposure to respirable silica and tobacco products may help to slow disease progression. A role for glucocorti-

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Fig. 1.19 (a) Low power view of a hyalinized nodule in the pleural surface associated with mixed inflammatory reaction; (b) higher magnification of the inflammatory reaction showing the presence of histiocytes and dark particles (silica), which is best visualized by polarizing microscopy

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Fig. 1.20 (a) Non-contrast axial CT shows left posterior pleural thickening (arrow); (b) axial FDG-PET/CT shows intense FDG avidity of the left pleural thickening (arrow)

coids in the management of acute and chronic forms of silicosis has not been fully established. Successful lung transplantation has been reported in patients with advanced disease [54–56].

Connective Tissue Diseases Pleural pathologic findings associated with systemic connective tissue diseases (CTD), such as rheumatoid arthritis, systemic lupus erythematosus, and granulomatosis

with polyangiitis, may vary from small fibrous plaques to extensive reactive fibrosis. Fibrous pleuritis may presage the clinical diagnosis of primary CTDs or, alternatively, develop in the context of established disease [57, 58]. Among the CTDs, pleural involvement in association with rheumatoid arthritis is most common, occurring in up to 50% of patients (Fig.  1.20a, b). Concomitant interstitial lung disease is reported in 30% of patients. Significant pleural fibrosis may lead to restrictive lung physiology and trapped lung. Systemic and intrapleural steroids have been

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used with variable success. The effect of disease modifying antirheumatic drugs in mitigating rheumatoid fibrous pleuritis is unknown.

without associated parenchymal disease is reported in most cases, however isolated fibrous pleuritis may also occur, particularly following amiodarone exposure [67].

Drug-Induced Fibrous Pleuritis

IgG4-Related Fibrous Pleuritis

Drug reactions are common causes of pleural effusions; however drug-induced pleural thickening and pleural fibrosis are less commonly observed. Ergot-derived dopamine agonists used to treat migraine headaches, including methylsergide and ergoline were among the earliest reports of drug-related pleural fibrosis. Other ergots such as bromocriptine, pergolide, cabergoline, and nicergoline, which are used in the treatment of Parkinson’s disease, have also been implicated. Fibrous pleuritis has been reported in 2–4% of ergot-­treated patients and may occur in isolation or accompanied by fibrosis of other organ systems, including the mediastinum, pericardium, retroperitoneum, and cardiac valves [59–64]. Pleural disease typically develops within the first 6 months following initiation of the drug and is signaled by dyspnea and pleuritic pain associated with bilateral pleural thickening along the lateral and bibasilar aspects of the thorax. Late fibrosis, occurring many years after drug exposure, has also been described. Thus vigilance throughout the treatment period must be maintained. Cessation of the drug halts disease progression in most cases, though complete resolution is rare. Other classes of drugs that have been implicated in the development of fibrous pleuritis include antibiotics (tetracycline, nitrofurantoin), anti-arrhythmics (amiodarone), and chemotherapeutic agents (cyclophosphamide, bleomycin, procarbazine) [65–69]. Antecedent pleural effusions with or

Tissue infiltration by immunoglobulin G4 positive plasma cells is known to cause systemic fibroinflammatory injury to diverse tissues, including the pleura. This multisystem disorder most often occurs in middle-aged men. Pleural manifestations of IgG4-related disease include fibrous pleuritis, pleural mass, and effusions (Fig. 1.21a, b). Fibrous pleuritis typically occurs in the context of other organ system disease, such as pancreatitis, sialadenitis, or hepatitis, but has been increasingly identified without other organ involvement. The diagnosis should be made in the context of clinical, radiological, and histological correlations. Histologically, sections of the pleura show areas of pleural thickening with fibrosis admixed with an inflammatory reaction composed predominantly of plasma cells (Fig. 1.22a, b). Immunohistochemical stains to determine the presence of IgG4 will light up most of the plasma cells present with the inflammatory reaction. The presence of more than 10 IgG4-­ positive plasma cells per high-power field and an IgG4/IgG-­ positive plasma cell ratio of more than 40% is suggestive of IgG4-related pleural disease. Close monitoring is reasonable in asymptomatic patients with isolated pleural effusions. Systemic corticosteroids are recommended for patients with multi-organ disease and/or fibrous pleuritis. Treatment delays may result in irreversible pleural fibrosis and other organ dysfunction [70–72].

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Fig. 1.21 (a) Contrast-enhanced axial CT shows right pleural thickening with a small right pleural effusion; (b) contrast-enhanced axial CT shows interlobular septal thickening and an irregular 2 cm right upper lobe solid nodule (N)

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Fig. 1.22 (a) Low power view showing a thickened pleural surface with inflammatory reaction; (b) higher magnification shows the presence of discrete areas of fibrosis admixed with numerous plasma cells

Pleuroparenchymal Fibroelastosis Pleuroparenchymal fibroelastosis (PPFE) is a rare type of interstitial pneumonia in which there is upper-lobe predominant fibrosis involving the visceral pleura and elastinrich fibroelastotic changes that are most conspicuous in the subpleural lung parenchyma of the upper lobes (Fig. 1.23a, b). Most cases are considered idiopathic, although secondary forms of PPFE associated with autoimmunity (scleroderma, rheumatoid arthritis, inflammatory bowel disease), infections (Aspergillus, nontuberculous mycobacteria), and hematopoietic stem cell transplantation have been described [73, 74]. Patients typically present between 40 and 70 years of age. Dyspnea, dry cough, weight loss, and recurrent infections associated with worsening volume loss of the upper lobes typically progress slowly over years. Rarely, PPFE may take an inexorably progressive course that culminates in platythorax and irreversible respiratory failure with early death [75, 76] The diagnosis is predicated on the exclusion of competing conditions associated with upper lobe disease, including sarcoidosis, hypersensitivity pneumonitis, atypical nontuberculous mycobacterial infection, pneumoconiosis, malignancy, apical pleural cap, and post–lung injury remodeling. Coexisting usual interstitial pneumonia (UIP) and idiopathic pulmonary fibrosis (IPF) have been reported in some cases [77, 78]. The diagnosis is suggested by CT findings of intense upper-lobe predominant pleural fibrosis, pronounced parenchymal fibroelastosis, and sparing of the lung away from the pleura. These observations help to distinguish PPFE from other interstitial lung diseases.

On imaging, fibrous and fibrinous pleuritis are usually seen as diffuse pleural thickening. Benign pleural thickening typically manifests as a continuous process more than 5  cm wide, 8  cm in craniocaudal extent, and 3  mm thick, all of which are best measured on CT [79]. The costal and paravertebral regions are most commonly involved; the mediastinal pleura are rarely affected. The appearance of benign pleural thickening is similar regardless of the cause. However, certain associated features on CT may give clues as to the etiology. Pleural calcification, volume loss, thickened extra-pleural fat layer, and associated parenchymal abnormality may favor prior empyema (particularly tuberculosis), whereas pleural calcification with rib deformity and normal lung parenchyma would indicate previous traumatic hemothorax (Fig.  1.24a–c). Talc pleurodesis on CT typically demonstrates high attenuation talc material in the pleura and increased soft tissue visceral pleural thickening [80].

Mesothelial Hyperplasia Mesothelial hyperplasia, also referred to as benign reactive mesothelial hyperplasia (RMH), may cause pleural effusions and pleural thickening and occurs in a variety of clinical ­settings [81]. Histologically, the hallmark of this benign condition is a dense proliferation of mesothelial cells, which must be distinguished from malignant mesothelioma. Patients with mesothelial hyperplasia are typically asymptomatic and no specific treatment is required.

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Fig. 1.23 (a) Non-contrast axial CT shows the right pleural thickening (arrows) in the upper thorax; (b) non-contrast coronal CT shows reticulonodular lung fibrosis in the subpleural distribution (arrows) typical of PPFE. Note lung emphysematous changes

A critical difficulty lies in differentiating benign RMH from malignant disease, which is fraught with a spectrum of diagnostic challenges. The diagnostic gold standard is based on the histopatholgical assessment of the lesion. Biopsy specimens should be large enough to permit examination of mesothelial cell proliferation as well as assessment of adjacent tissue landmarks, such as skeletal muscle and adipose tissue. Infiltration of mesothelial cells into adipose tissue or the skeletal muscle is a key criterium for the diagnosis of mesothelioma. Tissue biopsies of 1 mm in size or less may not include key landmarks that allow definitive diagnosis of malignant pleural mesothelioma (MPM). Florid mesothelial proliferation without infiltration into adipose tissue and/or muscle is indicative of mesothelial hyperplasia rather than malignant mesothelioma. Common immunohistochemical markers such as keratin 5/6 and calretinin are positive in reactive as well as in malignant mesothelial proliferations. Thus, immunohistochemical stains are of minimal benefit in distinguishing malignant versus hyperplastic pleural proliferation. The tumor suppressors, p16 (cyclin-dependent kinase 2A, CNDK2A) and breast cancer-1-associated protein (BAP-1) are two of the most frequently mutated genes

in MPM pathogenesis and have been identified as potentially useful molecular markers in distinguishing benign reactive hyperplasia from malignant disease. However, a small percentage of true malignant mesotheliomas may not demonstrate homozygous deletion of p16 as assessed by fluorescent in situ hybridization (FISH). Retention of BAP1 expression on immunohistochemistry suggests reactive changes, whileloss of BAP1 staining, may suggest the possibility of mesothelioma in situ [82–87].

Pleural Endometriosis Ectopic endometrial tissue, or endometriosis, is believed to affect 6–10% of reproductive-age women. Nearly 50% of these women are infertile [88]. Endometriosis of non-­ reproductive organs most often occurs within the thoracic cavity where it may involve the lung parenchyma, diaphragm, and pleural surfaces. Intrathoracic endometriosis produces a range of clinical and radiological manifestations, collectively referred to as thoracic endometriosis syndrome (TES) that includes catamenial pneumothorax, hemothorax,

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Fig. 1.24 (a, b) Frontal and lateral chest radiographs show coarse calcifications are seen in the right pleural space in the lower thorax (arrows); (c) contrast-enhanced axial CT shows densely calcified pleu-

ral rind along the posterior and lateral aspect (arrows) with volume loss in the right hemithorax due to prior history of tuberculous empyema

hemoptysis, and pulmonary nodules, catamenial chest pain, endometriosis-related pleural effusion, and diaphragmatic hernia (Fig. 1.25a, b). Catamenial pneumothorax and catamenial hemothorax are the most common manifestations of pleural TES, occurring in 74% and 14% of all patients, respectively [89–91]. Catamenial hemoptysis occurs in 7% of patients, and is usually mild. Pulmonary nodules may be seen in 6% of patients and have no predilection for laterality [92]. Although TES may occur in isolation, 50–84% of patients have extensive pelvic disease, which may predate TES by 5–7  years [93]. Thus, the absence of an associa-

tion with pelvic endometriosis does not exclude TES.  The pathogenesis of TES is not completely understood. Retrograde movement of endometrial cells into the peritoneum with subsequent implantation of cells on the lung, diaphragmatic, and pleural surface is the most widely held theory. Other hypotheses include coelomic metaplasia, lymphatic or hematogenous embolization [94]. The constellation of symptoms appears to be temporally related to menstruation and largely correlates with the anatomic location of endometrial cells. For example, presenting symptoms of pleural TES include catamenial pneumothorax, pleuritic chest pain, chest

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Fig. 1.25 (a) Contrast-enhanced axial CT 7  years previously shows large left pneumothorax with mass effect compressing the left lung (arrow); (b) contrast-enhanced axial CT shows large left pleural effu-

sion. The two foci of heterogeneous attenuation (arrows) within the left pleural effusion are consistent with blood clots

and shoulder pain, or referred pain to the periscapular region or neck. Signs and symptoms are predominantly right-sided, although rare cases of left-sided and bilateral disease have been reported [95]. Patients with catamenial pneumothorax or catamenial hemothorax typically present with cough, shortness of breath, and pleuritic chest pain within 48–72 h of the onset of menstruation, however, a temporal association with menstruation is not always recognized [91]. Thus, a high level of clinical suspicion is essential to ensure a timely diagnosis. TES should be considered in any ovulating woman with spontaneous pneumothorax or hemothorax. Imaging findings are usually nonspecific but may be helpful to rule out other diagnoses and to map the endometrial lesions for surgery, if feasible. Chest radiographs may reveal pleural effusion, pneumothorax, or pleural nodules, but they are often normal [96]. Ultrasound of the chest may show echogenic nodules on the pleural surface with pleural effusion or hemothorax. On CT, small soft-tissue pleural nodules representing endometrial implants may be seen along with pneumothorax and hemothorax. These nodules tend to demonstrate homogeneous enhancement after administration of intravenous contrast. MR imaging is said to be more accurate than CT in the detection of pleural endometriosis. Similar to pelvic endometriosis, pleural endometriosis may show different signal intensities on T1 and T2 images, depending on the stage of the lesion. However, a pleural lesion exhibiting homogeneous high signal intensity on T1- and T2-weighted images is highly suggestive of pleural endometriosis. Thoracic CT or MR imaging in patients suspected of thoracic endometriosis should be performed during menstruation to maximize diagnostic sensitivity [96, 97]. Video-assisted thoracoscopy is the method of choice for direct demonstration of nodular or plaque-like endometrial deposits that are usually 4 mitotic figures per 10 high power fields in cases that were considered malignant. Of the 223 cases described 82 were classified as malignant. Even though there has been mentioned that size of the tumor is an important factor in clinical behavior of these tumors, the problem is that size of the tumor and histological features do not necessarily correlate; therefore, the histological parameters are the ones more commonly associated with clinical outcome. Nevertheless, larger tumors are likely to invade adjacent organs and become locally aggressive. Immunohistochemical Features More recently the use of immunohistochemical stains has become an important tool in the diagnosis of SFT mainly in those cases that do not show the conventional features of the tumor. In that regard, the most reliable stain appears to be STAT-6 [258–260], which shows nuclear staining in tumor cells. This immunostain appears to consistently stain more than 90% of these tumors. However, it is also important to highlight that SFT may also show positive staining for vimentin, Bcl-2, CD-34, and CD99 (Fig. 1.63a–d), while in general SFT is negative for epithelial markers such as keratin and EMA, even though in some cases weak focal staining may be present.

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most common extra-abdominal sites include the chest wall, shoulder girdle, inguinal region, and head and neck [261]. Desmoid tumors in the chest wall usually present as a palpable mass with occasional extension into the pleura. The estimated incidence of desmoid tumors in the general population is 2–4 cases per million per year. These tumors most commonly occur in the third and fourth decades, but may occur at any age. Racial and ethnic groups are not disproportionally affected [262, 263]. There is no gender predilection [264]. The etiology of desmoid tumors is unclear but several commonly associated factors have been identified. There is a significant association with previous trauma in up to 25% of patients [265]. Desmoid tumor occurs frequently in patients with familial adenomatous polyposis, especially Gardner syndrome [266]. The majority of desmoid tumors are asymptomatic masses detected as incidental finding on imaging. Symptoms vary with the location of the tumor. Chest pain owing to nerve involvement, dyspnea, and pleural effusion are common presenting symptoms [264]. Incisional biopsies offer larger tissue samples and are preferred over core needle biopsies. Wide surgical resection is the treatment of choice with radiotherapy reserved for patients in whom wide local excision cannot be accomplished or surgical resection is not feasible. Local recurrence despite aggressive surgical intervention occurs in 29% of patients. The overall prognosis is good, with a 5-year survival rate of 93% [267]. Most desmoid tumors of the thorax originate from the chest wall and imaging shows a soft tissue mass (Fig. 1.64a–d). True intrathoracic desmoid tumors originating within the pleura or mediastinum with minimal chest wall involvement are exceedingly rare [268]. Intrapleural tumors are often significantly larger at the time of diagnosis due to the lack of symptoms. The most common intrathoracic tumors resembling desmoid tumors are solitary fibrous tumors. They are indistinguishable on preoperative radiologic imaging. Solitary fibrous tumors generally are not as invasive as desmoid tumors and are differentiated on histopathologic criteria [267–269].

Pathological Features

Desmoid Tumor

Macroscopic Features These tumors have been described as white in color and firm consistency. Based on the cases that have been reported in the pleura, the tumor may involve the visceral and parietal pleura and the size of the tumor may range from a few centimeters to more than 10 cm in greatest diameter. The presence of marked areas of necrosis and hemorrhage is not common in these tumors. The tumors are not encapsulated but rather show infiltrative features.

Desmoid tumors are unusual, locally aggressive fibrous neoplasms that arise from fascia at any anatomical site in the body. Intra-abdominal sites comprise 50% of desmoid tumors. The

Histological Features The same as desmoid tumors in other locations, those described in the pleura share similar histological features.

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Fig. 1.63 (a) Immunohistochemical stain for STAT-6 showing positive nuclear staining, (b) immunohistochemical stain for Bcl-2 showing positive staining in tumor cells, (c) immunohistochemical stain for

CD-34 showing positive staining in tumor cells, (d) Immunohistochemical stain for CD-99 showing positive staining in tumor cells

The tumor characteristically shows fascicles of spindle cells with tapered, wavy to elongated nuclei, embedded in finely fibrillary matrix with numerous vessels. Nuclear atypia and mitotic activity are not common in these tumors (Fig. 1.65a– c).

tive for S-100 protein [269, 270]. More importantly, the use of STAT-6 becomes very important in separating desmoid tumors from SFT.

Immunohistochemical Features In cases reported in the pleura or in other locations, desmoid tumor may show positive staining for vimentin, desmin smooth muscle actin, cyclin D1, and beta-catenin, but nega-

Calcifying Fibrous Tumor Calcifying fibrous tumors (CFT) are rare benign tumors of mesenchymal origin, which ubiquitously localize to the soft tissues, extremities and, rarely, the pleura. The stomach is

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Fig. 1.64  Desmoid tumor. (a) Axial CT shows peripheral soft tissue mass in the right anterior pleura with adjacent rib erosion (arrow), (b) axial T1-weighted MRI shows the mass has low signal intensity, (c)

axial T2-weighted MRI shows the mass has heterogeneous high signal intensity, (d) contrast-enhanced axial T1-weighted MRI shows heterogeneous enhancement of the tumor

the most common soft tissue site. Pleural tumors are seen in 10% of cases [271]. There are no known etiologic factors [271]. A slight female predilection (ratio 1:1.27), and trimodal age ­distribution, with the first peak at 0–4  years, and a second and third peak in the mid second and third decades of life have been reported [271]. Each age distribution may reflect different pathogenic phenotypes, with the third spike representing a form of late sclerosing myofibroblastic tumor [272–274]. Genetic and/ or embryologic factors are postulated in the pathogenesis of childhood calcifying fibrous tumors, while trauma may underlie the development of early adulthood tumors [275–277]. In the majority of patients, calcifying fibrous tumors are identified as an incidental finding on imaging studies in

asymptomatic patients. Occasionally, chest pain and nonproductive cough are presenting symptoms. The differential diagnosis varies with the location. An extensive list of benign and malignant disorders share clinical and/or morphologic features with calcifying fibrous tumors and include fibromatosis, solitary fibrous tumor (SFT), chronic fibrous pleuritis, calcified granulomas, calcified pleural plaques, dendrocytoma, desmoplastic mesothelioma, inflammatory ­myofibroblastic tumor (IMT), intermediate fibrous histiocytoma, and amyloid tumor. Biopsy is needed to confirm the diagnosis. Surgical resection is the treatment of choice and is usually curative. Recurrent disease is unusual but has been reported in non-pleural CFT and overall prognosis is excellent [271].

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Fig. 1.65 (a) Desmoid tumor of the pleura showing a spindle cell proliferation embedded in a loose stroma, (b) haphazard distribution of the spindle cell proliferation in a fibrillary matrix, (c) higher magnification

of the spindle cell proliferation lacking nuclear atypia and mitotic activity

Pathological Features

Histological Features The hallmark of these tumors is the presence of extensive areas of collagenization with an associated bland spindle cell proliferation and the presence of scattered calcifications of different sizes (Fig.  1.66a–d). Inflammatory reaction composed of lymphocytes and plasma cells may be seen but it is not marked. Nuclear atypia, increased mitotic activity, areas

Macroscopic Features Up to 10% of all CFTs have been reported in the pleura [271]. Calcifying fibrous tumor of the pleura is generally a solitary nonencapsulated, well-­circumscribed, solid mass but it may present with multiple nodules [278].

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a

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Fig. 1.66 (a) Low power view of a pleural Calcifying Fibrous Tumor (CFT) showing numerous calcifications, (b) the tumor may show focal calcifications and inflammatory reaction, (c) focal calcifications with

areas resembling SFT, (d) conventional areas of CFT showing collagenization and numerous calcifications

of necrosis and hemorrhage are generally absent in these tumors. In general terms, without the presence of calcification, the histological features of this tumor mimic closely those of SFT. Therefore, the need for immunohistochemical stains properly categorized the tumor.

ing for CD-34 and for STAT-6 that are commonly associated with SFT. In general, calcifying fibrous tumor is also negative for epithelial markers such keratin and EMA and also has been found negative for muscle markers such as smooth muscle actin, desmin, and h-caldesmon. D2–40, which is a vascular marker has also been reported as negative. However, it is important to highlight that the majority of these tumors have been reported prior to the discovery of STAT-6; therefore, even though one would expect negative results for calcifying fibrous tumor, it is uncertain at this point.

Immunohistochemical Features Because the histological features of this tumor mimic those of SFT, the main goal is to separate both neoplasms. In that regard, calcifying fibrous tumors should show negative stain-

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Vascular Neoplasms Vascular tumors that have been most frequently identified as primary pleural neoplasms are epithelioid hemangioendothelioma and angiosarcoma. These two neoplasms share similar morphohistologic and immunohistochemical phenotypes and are distinguished by the presence of necrosis, nuclear atypia, and increased mitotic activity on resected tissue. Molecular tools can also aid in the final classification of these tumors. Because of the similarities between these two tumors, histology, immunohistochemistry, and molecular diagnosis will be presented together.

Epithelioid Hemangioendothelioma Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor that may arise in soft tissue, bone, and other organs throughout the body. Intrathoracic tumors involving the lung, pleura, and mediastinum have been described. Primary pleural epithelioid hemangioendothelioma (PEH) appears to be more aggressive than EHE tumors at other locations (including pulmonary EHE) with poor clinical outcomes [279, 280]. Epidemiologic data for these rare tumors are limited to case reports and case series and risk factors have not been well defined. However, limited information suggests a male predominance with an average age of 52 years at diagnosis. Loose associations with asbestos and radiation exposure have been suggested [279, 281–284]. Nonspecific symptoms of dyspnea, chest pain, cough, and fever are the most common at presentation. Back pain associated with extensive pleural disease has also been reported. These tumors may be widely metastatic at diagnosis, resulting in a variety of ­clinical symptoms. The diagnosis of PEH requires histopathological examination of specimens derived preferably from thoracoscopic pleural biopsies. Poor prognosticators include the presence of respiratory symptoms or pleural effusion at presentation, fibrous/fibrinous pleuritis with extrapleural extensive intravascular, endobronchial, or interstitial tumor spread, distant metastases to the liver and peripheral lymph nodes, and the presence of spindle cells in the tumor. For the rare case of localized pleural disease, surgical resection is recommended, although the tumor may quickly recur postoperatively in up to 20% of patients. A variety of conventional chemotherapeutic agents as well as targeted therapies (mTOR kinase inhibitors), and taxane-based chemotherapy regimens have been used. In one report, combination therapy with etoposide and carboplatin resulted in complete remission 18  months after the diagnosis [285]. However, no treatment strategy has demonstrated consistent and durable benefit, which underscores the critical need for new therapeutic strategies.

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Diffuse pleural thickening, associated with pleural EHE, is an unusual manifestation of this tumor [286]. Imaging characteristics of pleural EHE are nonspecific and overlap with other pleural pathology. Pleural effusions, pleural thickening, and pleural nodules are common findings on chest imaging studies. Pleural disease is frequently unilateral and right-sided. Routine radiographs generally demonstrate unilateral effusion that can vary from small to large, with complete opacification of the hemithorax. Depending on the degree of solid soft tissue pleural disease, pleural thickening or nodularity can sometimes be visualized. CT scans are superior to chest radiographs in identifying loculated effusions, which are occasionally seen. Pleural thickening and nodularity are generally seen with variable extension into the hemithorax (Fig.  1.67). Mediastinal adenopathy, mediastinal invasion, interlobular septal thickening suggesting lymphangitic spread, and pulmonary metastases are variably demonstrated. Limited data on MRI of pleural EHE showed circumferential pleural thickening, nodularity, and loculated effusion [282]. FDG-avid lesions on PET/CT imaging help to distinguish PEH from benign pleural lesions and also to guide pleural biopsies [286, 287].

Fig. 1.67 Epithelioid Hemangioendothelioma (EHE). Contrast-­ enhanced axial CT of a pleural EH, which demonstrates pleural-based masses (M), which extend into ill-defined lung parenchymal opacities. The tumor is often associated with simple and complex pleural fluid collections

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Pleural Angiosarcoma Primary pleural angiosarcoma (PPA) is a subtype of sarcoma of vascular origin [288]. Skin and subcutaneous soft tissues are the most common sites for angiosarcomas with metastasis accounting for the majority of angiosarcoma cases involving the lungs and pleura. Primary pleural angiosarcoma (PPA) is exceedingly rare with only a few dozen cases reported in the English literature [289]. Primary angiosarcomas of the pleura account for less than 1% of all soft tissue sarcomas [290]. Information derived from case series suggests associations with chest irradiation, chronic tuberculous pyothorax, anabolic steroid therapy, and exposure to minerals and gases, including asbestos, arsenic, and vinyl chloride. However, these associations are primarily anecdotal and have not been well studied [290–298]. The age at diagnosis ranges from 22 to 79  years, with peak incidence in the seventh decade of life. Men are more commonly affected than women [299]. Pleuritic chest pain, dyspnea, hemoptysis, and weight loss are the most common presenting symptoms. The disease is rapidly progressive in most cases and commonly fatal within the first few months of presentation [291, 295, 300]. Histological and immunohistochemical studies of the pleural samples are required for definitive diagnosis. Pleural fluid cytology is often negative. Exploration of the pleural cavity with VATS allows direct visualization and biopsies of the involved pleura and is the preferred diagnostic approach. Hilar lymph node dissection during VATS exploration has been suggested, although the prognostic significance of lymph node invasion remains uncertain, due to the small number of reported cases. Complete surgical resection is often difficult due to ­multifocal disease. Chemotherapy and chemoradiation therapy combinations have been attempted with variable success. No specific treatment modality has been established. The prognosis remains poor despite aggressive therapy. Imaging findings are nonspecific and cannot differentiate PPA from other primary or metastatic processes of the pleura. Routine radiographs generally demonstrate unilateral or bilateral pleural effusions, pleural thickening, or pleural mass lesions. Non-enhanced and contrast-enhanced CT can detect the often bloody effusions, based on elevated attenuation of the fluid and/or hematocrit layer. CT additionally shows heterogeneous enhancing lobulated pleural masses with hemorrhagic cystic components (Fig.  1.68). PET/CT generally demonstrates FDG avid pleural nodules or thickening [289]. Surgical resection is the preferred treatment option followed by radiotherapy. Histopathological Features Epithelioid Hemangioendothelioma (EH) P-EH shows similar histological features as its counterparts in the lung, liver, and soft tissues. The tumor characteristically shows the cords, strands of a solid proliferation of medium size cells with round to oval nuclei, prominent

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Fig. 1.68  Pleural angiosarcoma. Contrast-enhanced axial CT demonstrates a heterogeneously enhancing pleural mass (M) in the medial left lower hemithorax and a small malignant pleural effusion (*)

nucleoli embedded in a myxoid or chondromyxoid stroma (Fig.  1.69a–g). In some cases, the tumor cells may show “rhabdoid” features. Often these epithelioid cells appear to be engulfing red cells or forming intracellular lumens. Similarly as cases of epithelioid mesothelioma, the tumor cells in EH may also extend into the adipose tissue. In general, increased mitotic activity or necrosis are not part of EH and its presence should alert the possibility of a highergrade neoplasm. Pleural Angiosarcoma Also the tumor shares similar histological features as its counterparts in soft tissues. The tumor may show sheets of neoplastic cells or the tumor may show cords or strands of neoplastic cells embedded in a collagenous stroma. The neoplastic cells may show different morphological features ranging from spindle to epithelioid with eosinophilic cytoplasm, and prominent nucleoli, more often seen in the epithelioid variant of angiosarcoma (Fig.  1.70a–e). Necrosis and hemorrhage are common features, while mitotic activity is easily identified.

Immunohistochemical Features Both tumors shared similar immunohistochemical profile, namely, positive staining for vascular markers including CD-34, CD-31 (Fig.  1.71a, b), Factor VIII-related antigen, Erg, and in some cases D2–40. In addition, it has been stated that nuclear staining for CAMTA1 is a feature of epithelioid

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Fig. 1.69 (a) Pleural biopsy of an EHE showing an epithelioid neoplasm infiltrating adipose tissue, (b) wedge biopsy of lung showing an epithelioid neoplasm along the pleural surface, (c) epithelioid neoplasm infiltrating adipose tissue, (d) Strands of neoplastic cells infiltrating

fibroconnective tissue, (e) epithelioid cells embedded in a myxoid stroma, (f) spindle and epithelioid components of a pleural EHE mimicing biphasic mesothelioma, (g) EHE showing spindle cells engulfing red cells with lumen formation

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f

g

Fig. 1.69 (continued)

hemangioendothelioma [299]. It is also important to highlight that these tumors may also show positive staining for epithelial markers, namely, keratin and CEA.

Molecular Features The presence of reciprocal translocations t(1:3)(p36q25), WWTR1-CAMTA1 fusion gene, and YAP1-TFE fusion gene have been associated with epithelioid hemangioendothelioma and may be of aid in cases in which minimal tissue is available for diagnosis or in difficult cases [301].

Neuroectodermal Tumors Primitive neuroectodermal tumors (PNET) comprise several subclasses of small round tumors that occur in the brain and peripheral sites, including bone, soft tissues, and chest wall. These highly malignant neoplasms must be distinguished from other tumors with small round cells, such as non-­ Hodgkin lymphoma, neuroblastoma, rhabdomyosarcoma, retinoblastoma, mesenchymal chrondrosarcoma, malignant peripheral sheath tumor, and melanoma. Peripheral PNETs are histologically and molecularly similar to Ewing’s sar-

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coma. Those growing outside of bone are known as extraosseous Ewing sarcomas and those of thoracopulmonary origin are designated as Askin tumors. Askin tumors are highly aggressive neoplasms of the chest wall or perihilar region. Primary pleural PNETs are extremely rare (Fig.  1.72a, b) [302]. These tumors are most frequently encountered in the pediatric population and in young adults under the age of 35 and should be included in the differential diagnosis of chest wall tumors in this age group, although isolated cases

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have been described in patients of all ages. A slight male predominance has been observed. PNETs may develop de novo in association with a genomic alteration that involves translocation between the long arms of chromosomes 11 and 22 (t11:22) [303]. Radiation-induced PNET has also been reported [304–306]. Patients may present with nonspecific symptoms of cough, fever, dyspnea, hemoptysis, or chest pain. Multimodality treatment strategies that include early surgical resection and chemoradiation therapy are generally

a

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Fig. 1.70 (a) Pleural biopsy of a primary angiosarcoma of the pleura, (b) angiosarcoma showing more cellular atypia and a pseudopapillary growth pattern, (c) strands of tumor cells dissecting fibroconnective tis-

sue, (d) epithelioid angiosarcoma with areas of necrosis; (e) easily identifiable mitotic figures

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e

Fig. 1.70 (continued)

a

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recommended. This aggressive approach coupled with better understanding of the pathobiology of PNET/Ewing sarcoma has resulted in an improved 1-year survival, however, the 5 year survival remains poor at 25% [302–309]. Primary pleural PNETs often present with nonspecific imaging findings, including chest wall soft tissue mass evidence of rib invasion, and pleural effusions [302]. Routine radiographs show a pleural mass with or without associated pleural effusion. Contrast-enhanced CT demonstrates heterogeneously enhancing pleural masses with areas of central cystic change or necrosis with rare calcification (Fig.  1.73). Evidence of chest wall invasion and distal metastases, which commonly involve the lungs, bones, marrow, liver, and brain are best seen of CT. Tumor localization and extent of chest wall invasion are better determined with MRI. Masses are hyperintense on T1-weighted images and intermediate to hyperintense on T2-weighted sequences and mild to intense avidity with intravenous contrast enhancement [303]. PET/CT demonstrates increased uptake in the region of the pleural tumor and in areas of chest wall invasion.

b

Fig. 1.71 (a) Immunohistochemical stain for CD34 (vascular marker showing positive staining in tumor cells, (b) immunohistochemical stain for CD = 31 (vascular marker) showing positive staining in tumor cells

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Fig. 1.72  Primitive neuroectodermal tumor (PNET). (a) Contrast-­ 2 months later shows marked growth of pleural tumor (M) and interval enhanced axial CT shows a small heterogeneously enhancing right development of a small malignant pleural effusion (arrow) and a metaparatracheal pleural nodule (M), (b) contrast-enhanced axial CT static right axillary lymph node (L)

Multimodality treatment strategies that include early surgical resection and chemoradiation therapy are generally recommended. This aggressive approach coupled with better understanding of the pathobiology of PNET/Ewing sarcoma has resulted in an improved 1-year survival, however, the 5-year survival remains poor at 25%.

Pathological Features Macroscopic Features In general these tumors may range in size from a few centimeters to larger than 10 cm in greatest diameter. They are commonly hemorrhagic and necrotic, not encapsulated but with infiltrative borders. Microscopic Features In the original description by Angerval and Enzinger, the authors noted the similitude of primary tumors of the bone and those of the soft tissues; therefore, the original designation was extraskeletal Ewing sarcoma. However, it was Askin who later on reported 20 additional cases in the thorax and designated those tumors as small round cell tumors of the thoracopulmonary region (Askin tumor) [310]. EssenFig. 1.73 Primitive neuroectodermal tumor (PNET). Contrast-­ tially those tumors shared similar characteristics as those in enhanced axial CT shows a heterogeneous mass (M) with subtle areas of decreased attenuation (*) consistent with cystic components and the soft tissues described by Enzinger [311]. Currently, all those tumors have been designated under the name of PNET. small pleural effusion (arrow). Rarely, calcifications can be seen

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These tumors essentially show the presence of a neoplastic cellular proliferation composed of small cells with scant cytoplasm, round to oval nuclei and inconspicuous nucleoli, rosettes, increased mitotic activity, necrosis, and hemorrhage (Fig.  1.74a–c). However, those features may be present in different proportion in each tumor. Immunohistochemical Features By immunohistochemistry, there is not one single immunostain that is specific for PNET. However, these tumors are often posia

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tive for CD99 (Fig. 1.75) and NSE. Keratin, S-100 protein, and Synaptophysin may be seen focally positive in these tumors. Other stains that may be positive include NB84 and WT1 [312]. Molecular Features Because there is not a single immunostain that is diagnostic of PNET, often the use of molecular techniques aids in the final interpretation of these tumors. Common translocations that have been associated with PNET include: t(11;22) (q24;q12) and t(21;22)(q22;1q12). b

c

Fig. 1.74 (a) Low power view of a PNET showing sheets of small cell malignant cells, (b) PNET with areas of fibrinoid necrosis and hemorrhage, (c) higher magnification showing cellular atypia and mitotic activity

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Fig. 1.75  Immunohistochemical stain for CD-99 positive in PNET

Other Pleural Sarcomas Other sarcomas arising from the pleura have been rarely described. Among these, smooth muscle tumors and synovial sarcomas are the most commonly mentioned.

 rimary Smooth Muscle Tumors of the Pleura P Primary smooth muscle tumors of the pleura are exceptionally rare pleural sarcomas. Information has been limited to case reports and case series, which describe nonspecific symptoms of cough and chest pain in predominantly male adults. Tumors of variable sizes may present as solitary pleural-­based neoplasms or rarely, diffuse pleural thickening that mimics mesothelioma [313–315]. The clinical behavior of smooth muscle tumors of the pleura may mimic the behavior of smooth muscle tumors originating in soft tissues. Treatment options including surgery, radiation, and chemotherapy are guided by the grade of tumor. Histologically, a spectrum of behaviors have been reported, ranging from aggressive tumors that mimic leiomyosarcoma with characteristic spindle cell proliferation, cellular pleomorphism, necrosis, and mitotic activity (Fig.  1.76a–c) to tumors of uncertain malignant potential that display minimal cellular atypia and mitotic activity [313–315]. Synovial Sarcoma Primary pleuroparenchymal synovial sarcomas (PPSS) are rare tumors. Only a few small case series and single case reports have been reported [316, 317]. Originally thought to arise from synovial cells, these tumors are now known to originate from pluripotential mesenchymal cells that are

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capable of partial or aberrant epithelial differentiation [318]. Synovial sarcomas are most frequently seen in soft tissues of the extremities and head and neck regions, but have also been recognized in other locations, including the esophagus, heart, retroperitoneum, chest wall, mediastinum, lung, and pleura. The median age at diagnosis is 40  years, but may appear at any age. A 2:1 male predominance has been observed [119]. Chest pain, pleural effusion, hemoptysis, and dyspnea are common presenting symptoms, although occasionally patients are asymptomatic with incidental findings on chest CT. Pneumothorax is a frequent finding in patients with cystic variants of synovial sarcoma. In those reports, the age of the patients has varied from childhood to adulthood. Surgical resection in combination with radiotherapy and/ or chemotherapy is the preferred treatment strategy. Prognostic factors, including younger age, tumor size 0.5 cm have a higher probability of pneumothorax compared to cysts 0.5 cm are also at higher risk of recurrent pneumothorax [393]. CT grading is a radiomics and computer aided detection (CAD) measurement of the difference in lung  texture between areas adjacent to or remote from the cysts. Measured lung texture correlates with lung function at baseline and during follow up, including deterioriation over time [404].

18  Interstitial Lung Diseases

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Fig. 18.41  Massive left pleural effusion and dilated lymphatics in the left neck area. The patient also had abdominal lymphangiomas (not shown). Thoracentesis yielded pleural fluid with chylous appearance. She was diagnosed with S-LAM.  Chylothorax and lymphangiomas resolved completely with mTOR inhibitors

Fig. 18.40  Notice bilateral diffuse pulmonary air cysts up to 1 cm in diameter without pleural effusions, reticulations or GGO

Abdominal Imaging There are multiple extrapulmonary manifestations of LAM including lymphatic involvement with mediastinal, retroperitoneal or pelvic lymphangiomas, and chylous pleural or abdominal effusions, angiomyolipomas mainly in the kidneys but also in the liver [405, 406] (Figs. 18.41 and 18.42). Lymphangiomas are smaller in size during the morning than later during the day after meals [407, 408] and this may have some diagnostic utility differentiating a mass from a lymphangioma. AMLs are recognizable on abdominal CT or MRI by the presence of smooth muscle, blood vessels, and macroscopic fat (HU −20) in a renal mass [409]. They are highly vascular and can be very large (Fig. 18.43a, b). TSC patients should be screened for LAM starting at age 18 and followed depending on the initial chest CT findings, approximately every 5–10 years in asymptomatic individuals. TSC patients with LAM should be followed like S-LAM patients [386], although some have recommended

Fig. 18.42  Pleural fluid obtained after thoracentesis from patient in Fig. 18.2 demonstrating chylothorax

screening at age 21 rather than 18, considering the potential impact of ionizing radiation on breast development and the decreased  probability of having severe LAM [410]. The risk of LAM in TSC is age-dependent, estimated to be 8% every year or 81% in TSC patients older than 40 [410–412].

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b

Fig. 18.43 (a, b) Large left renal mass with multiple areas of low density consistent with fat in an AML

Diagnostic Evaluation Laboratory Tests Serum VEGF-D correlates with disease severity and treatment response. The VEGF-D was higher in patients with LAM with hypoxemia requiring oxygen and those who had bronchodilator response. The VEGF-D declined after treatment with sirolimus. Higher serum VEFG-D correlates with higher improvement in FEV1 and FVC in patients treated with sirolimus and at the same time, decreased VEGF-D with treatment is associated with improvement in lung function [413] (Fig. 18.44). VEGF-D but not C in patient with S-LAM and TSC-LAM has diagnostic implications. Elevated VEGF-D > 800 pg/mL with a characteristic HRCT of chest obviates the need for lung biopsy; however, a VEGF-D  1 is highly suggestive of lupus pleuritis, although a high ANA titer can occasionally be found in other conditions, such as malignancy [62, 63]. Other laboratory evaluation should include complete blood count with differential, BUN, creatinine, serum LDH, and protein and N-terminal pro-BNP (NT-proBNP). Pleural biopsy is rarely needed and may be performed in cases of diagnostic uncertainty [60]. Rarely, in long-standing cases of lupus pleuritis fibrothorax may develop [64]. Drug-induced pleuritis must be considered in the evaluation of pleural effusion in an SLE patient. Drug-­ induced effusions can be seen in nearly half of the patients with procainamide-induced lupus, 22% of quinidineinduced lupus, and < 1% of minocycline-induced lupus [65]. If drug-­induced lupus pleuritis or effusion is suspected,

R. Mathew and S. Noh

the first step is to stop the offending agent; treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids may be needed.

Parenchymal Disease I nterstitial Lung Disease Chronic interstitial lung disease (ILD) is uncommon in SLE, and when present it is associated with increased morbidity and mortality. The prevalence of symptomatic ILD ranges from 1 to 4%, which progressively increases with the duration of SLE [53, 54, 66–68]. Disease activity, low complement levels, and high anti-dsDNA levels are risk factors for SLE-associated ILD (SLE-ILD) [52]. Presence of anti-Ro/SSA antibodies was seen in an SLE-ILD cohort suggesting its potential role in the pathogenesis [69]. Acute lupus pneumonitis has a high risk of progression into chronic SLE-ILD [70]. The clinical manifestations of SLE-ILD include dyspnea on exertion, dry cough, and decreased exercise tolerance. Bibasilar crackles are present on physical examination. The onset is typically insidious, and clinical course is less severe than that of other CTD-ILDs and idiopathic pulmonary fibrosis [71, 72]. Patients may be asymptomatic in the early stages, with abnormalities seen on pulmonary function test (PFT), chest radiograph, or HRCT [73, 74]. Transthoracic echocardiography (TTE) and NT-proBNP should be obtained to differentiate SLE-ILD from heart failure and to screen for pulmonary hypertension. PFTs reveal a restrictive pattern with reduced vital capacity and total lung capacity (TLC) along with reduction in diffusing capacity of carbon monoxide (DLCO). Serial PFTs are useful in assessing the degree of physiologic impairment and clinical course of the disease. Common HRCT findings are lower lobe-predominant reticular opacities, interlobular septal thickening, ground-glass opacities, and honeycombing. HRCT is useful in revealing abnormal interstitial changes in patients with normal chest radiographs and equivocal PFT findings. HRCT findings also provide guidance regarding areas of particular interest if decision for lung biopsy or bronchoalveolar lavage (BAL) is made [75, 76]. Analysis of BAL may be abnormal in patients without respiratory symptoms indicating subclinical alveolitis. This may help identify patients who are at risk for the development of ILD in the future [77]. A lymphocytic or neutrophilic predominance can be seen in SLE-ILD; utility is more for ruling out infections and other pathology [78]. Lung biopsy is occasionally performed if the diagnosis remains uncertain. It is not necessary in patients who are asymptomatic or in patients without progression of disease [72]. The most common pattern is nonspecific interstitial pneumonia (NSIP); other patterns reported include usual interstitial pneumonia (UIP), organizing pneumonia, lymphocyte interstitial pneumonia (LIP), and follicular bronchitis [79].

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 cute Lupus Pneumonitis A Acute lupus pneumonitis (ALP) is uncommon with a prevalence of between 1 and 4%, but it has high mortality rate of up to 50% in fulminant cases. ALP patients who survive have a high risk of developing interstitial lung disease [57, 70, 80]. Presenting symptoms include acute onset of dyspnea with hypoxemia, cough, fever, pleuritic chest pain, and hemoptysis. Examination is notable for tachypnea, tachycardia, and bibasilar inspiratory crackles. Chest radiograph typically shows bilateral lower lobe-predominant alveolar infiltrates which may be associated with pleural effusions in about 50%. Unfortunately, clinical features and chest radiographs are neither sensitive nor specific for the diagnosis of ALP and diagnosis can be challenging. Other acute processes including pulmonary infections and alveolar hemorrhage have a similar presentation and diagnostic evaluation should be undertaken early to exclude other possibilities [51, 72]. NT-proBNP and TTE may be helpful to exclude cardiogenic pulmonary edema. Early bronchoscopy with BAL may be warranted if initial infectious workup is unremarkable. The role of lung biopsy is limited in ALP due to nonspecific histopathologic findings. ALP is more likely to occur along with an SLE flare when there is multisystem involvement, such as serositis, nephritis, and arthritis. More than 80% of patients with ALP have anti­Ro/SSA antibodies, which suggests that these autoantibodies may be involved in the pathogenesis [69, 80]. ALP should be considered in the differential in patients with acute respiratory symptoms and abnormal chest imaging in the setting of multisystem involvement and positive anti-Ro/SSA antibodies. This is especially important to consider as in about half of the patients that develop ALP, it is the initial presenting feature of SLE [76].

count with differential, coagulation parameters, BUN, creatinine, NT-proBNP, and antiphospholipid antibodies should be obtained. As clinical features of DAH overlap with pulmonary infections in many cases, bronchoscopy with BAL is necessary, both for diagnosis and to rule out other conditions. BAL is diagnostic when saline lavage aliquots are progressively hemorrhagic and demonstration of hemosiderin-laden macrophages using Prussian blue staining is additionally helpful. Greater than 20% of at least 200 macrophages that stain positive for hemosiderin confirms DAH. A concurrent pulmonary infection was found in more than half of the patients with DAH in one study, and this may lead to a higher mortality [87]. Lung biopsy is rarely performed in critically ill patients with alveolar hemorrhage and severe hypoxemic respiratory failure. Early recognition and prompt management are critical to improving outcomes in patients with DAH which has a high mortality at 30–50%, although improved over the years [83].

Vascular Disease Diffuse Alveolar Hemorrhage Diffuse alveolar hemorrhage (DAH) is a rare life-threatening complication that can develop in patients with SLE, occurring mostly in patients who already have a diagnosis of SLE.  An incidence of 2% is reported and it occurs more commonly in women, younger patients, and in patients with extrapulmonary disease, particularly lupus nephritis, serositis, and neuropsychiatric involvement [81–84]. Risk factors include hypocomplementemia and presence of antiphospholipid antibodies [85]. Most patients demonstrated capillaritis with antiphospholipid antibodies suspected to be contributory to the pathogenesis [83, 86]. Clinically, patients present with dyspnea, fever, hemoptysis, anemia, hypoxemia, and bilateral although sometimes unilateral alveolar infiltrates. Hemoptysis is absent in 30% of the patients. The onset of symptoms is abrupt, developing over hours to days and there can be an acute drop in hemoglobin [83]. Complete blood

Pulmonary Hypertension Pulmonary arterial hypertension (PAH) is a leading cause of mortality and morbidity in patients with CTD. Among CTD-­ related PAH, SLE is the second most common cause after systemic sclerosis. Prevalence of pulmonary hypertension (PH) in patients with SLE varies from 3.8 to 17.5% [88–90], depending on the diagnostic test and definition used, although when right heart catheterization (RHC) was used to diagnose PH, the prevalence was 9 is consistent with Systemic Sclerosis Item Sub-item Score Skin thickening of the fingers of both 9 hands, extending proximal to the metacarpophalangeal joints Skin thickening of the fingers (only Puffy fingers 2 count the higher score) Sclerodactyly of the 4 fingers Fingertip lesions (only count the Digital tip ulcers 2 higher score) Fingertip pitting 3 scars Telangiectasia 2 Abnormal nailfold capillaries 2 Pulmonary arterial hypertension and/ Pulmonary arterial 2 or interstitial lung disease hypertension (maximum score 2) Interstitial lung 2 disease Raynaud phenomenon 3 Systemic sclerosis-related Anticentromere 3 autoantibodies Antitopoisomerase I (maximum score 3) Anti-RNA polymerase III

Etiology SSc is a complex, clinically heterogenous immune-mediated disease wherein genetics, environmental factors, and epigenetics are suspected to play key roles in the pathogenesis [178]. Exposure to unclear environmental risk factors such as chemicals and infections in genetically susceptible patients is hypothesized to lead to endothelial cell dysfunction, which triggers an abnormal inflammatory and autoimmune response involving cytokines, autoantibodies, and fibroblasts [179]. Endothelial dysfunction in addition to causing vasoconstriction also induces secretion of endothelin-­1, an endogenous vasoconstrictor which plays an important role in the progressive fibrosis seen in SSc patients by inducing fibroblast proliferation and their transformation into myofibroblasts [179]. Although multiple cytokines may be implicated in the pathogenesis of SSc, transforming growth factor-beta is an important mediator in the fibrogenesis in SSc. Accelerated fibroblast proliferation leads to fibrosis of the skin and multiple organs [180]. In the lung parenchyma, this leads to alveolar damage, thickened interstitium, and fibrosis. Understanding and characterizing the pathogenesis better may have treatment implications [178].

Diagnosis Diagnosis is based on the revised 2013 criteria by the American College of Rheumatology and the European League against Rheumatism [181]. This is a revised version of the original criteria proposed in 1980 [182].

Disease Presentation SSc occurs more commonly in women than in men with the peak incidence in the fifth decade. Women also have a higher risk for pulmonary arterial hypertension (PAH) than men who are more at risk for interstitial lung disease (ILD). African Americans have an earlier age of onset and are at risk for more severe disease [183]. Presentation depends on the organ system involved and can be generalized nonspecific symptoms such as fatigue, pruritis, and myalgias or more specific to the organ involved such as skin, musculoskeletal, gastrointestinal, renal, cardiac, or lung-related manifestations [175]. Symptoms from skin and gastrointestinal involvement are the commonest, with nearly all patients affected by the same. Pulmonary involvement can be parenchymal (interstitial lung disease), vascular (pulmonary arterial hypertension), or related to manifestations from cardiac involvement, infections, drug toxicity, and due to aspiration from gastrointestinal reflux. Other etiologies for pulmonary symptoms include myopathy-related weakness, deconditioning, and reduction in chest wall compliance due to the skin changes. Disease progression varies among patients, with some having a chronic and more indolent course and others following a rapidly progressive course. The disease presents as three predominant phenotypes—limited cutaneous systemic sclerosis, diffuse cutaneous systemic sclerosis, and the less common systemic sclerosis sine scleroderma which lacks the characteristic skin thickening [184]. Pulmonary manifesta-

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tions are seen in all these sub-groups. PAH occurs more commonly in limited cutaneous SSc and ILD is seen predominantly in diffuse cutaneous SSc. SSc can also present in overlap syndromes with the other rheumatologic syndromes in about 11-38% of the patients [185–187].

Development of cardiac disease requires yearly echocardiogram, testing for troponin and brain natriuretic peptide, and cardiac MRI in some cases.

Evaluation

The reported prevalence of SSc-ILD varies from 43% to 81% depending on the mode used to define ILD [194–196]. Although majority of the patients had evidence of parenchymal disease based on autopsy studies and with HRCT, clinically significant ILD is seen in about a third of patients with SSc [197–199]. ILD is more likely to develop in diffuse cutaneous SSc (42–53%) than limited cutaneous SSc (22–35%) [200, 201]. Severe ILD typically develops early in the course of the disease, usually within 5 years after onset of symptoms and is the number one cause of death in SSc, being responsible for 33-35% of deaths [202, 203]. Hence, screening for ILD and follow-up is essential and is cornerstone in the ambulatory management of these patients, with early identification being key. Although SSc is seen more commonly in women, male gender is a risk factor for SSc-­ ILD.  Additional risk factors include African American ethnicity, presence of arthritis, and skin fibrosis. The presence of anti-Scl-70 (or antitopoisomerase I antibody) is associated with elevated risk for development of ILD, whereas presence of anticentromere antibodies is associated with a lower risk for ILD [201, 204]. Biomarkers such as fractional exhaled nitric oxide, which is increased in SSc-ILD and surfactant D levels in serum may have a role for detection of early SSc-ILD [205]. A lower baseline DLCO with worsening DLCO trends over 3 years after diagnosis and lower baseline FVC predicted mortality [206]. Close monitoring is required to detect progression of ILD. A ≥10% relative decline in FVC or ≥5% to 55 years, reduced diffusing capacity for carbon monoxide (DLCO) and forced vital capacity (FVC), anti-Ro52 antibodies, muscle weakness, and increased fibrosis score on HRCT. Prognosis of antisynthetase syndrome is worse than the other inflammatory myopathies, with ILD being the major determining factor. Presence of anti-Jo-1 antibodies, however, was associated with improved prognosis and survival in antisynthetase syndrome-­related ILD [255–257]. Anti-MDA-5 antibodies is independently associated with death from rapidly progressive ILD in DM, the pathophysiology of which is unclear [234]. A viral syndrome leading to excessive immune activation and generation of these autoantibodies has been theorized as a cause [258]. Anti-MDA-5 antibodies are rare in PM.

Myositis-specific antibodies Lung disease Anti-Ro52 severe ILD

Anti-PM/Scl Anti-MDA-5

high ILD risk    • rapidly progressing acute interstitial pneumonitis    • increased risk of death from ILD in DM [234]

Anti-155/140 Anti-SRP Anti-Mi-2 Antisynthetase antibodies Anti-Jo-1    • high ILD risk    • better ILD-related prognosis Anti-Ej Anti-PL-7 Anti-PL-12 Anti-KS Anti-OJ Anti-Zo Anti-YRS

severe ILD severe ILD ILD ILD

Other features frequent in antisynthetase syndrome skin ulcers

malignancy severe myopathy skin involvement   

• commonest antisynthetase antibody    • myositis

frequent in blacks

Interstitial Lung Disease True prevalence data for ILD in DM and PM are unavailable; with various methods used for detection, prevalence varies from 19.9% to 78% [235–238]. Although muscle involvement generally precedes ILD in these patients, ILD can precede myositis in about a third of the patients. Commonest pulmonary symptoms are dyspnea and nonproductive cough, although some patients are asymptomatic. Dyspnea occurs not only due to lung involvement, but also from the myositis and associated muscle weakness. Muscle weakness can also increase risk of aspiration. Lung examination may reveal dry bibasilar crackles. ILD is most commonly NSIP (61%), followed by organizing pneumonia (22%) and usual interstitial

Pulmonary Hypertension Pulmonary hypertension in DM and PM is not well recognized and data available are limited to a few case reports

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[259]. Reduction in DLCO on pulmonary function testing (PFT) merits a screening transthoracic echocardiography and evaluation for pulmonary hypertension. Presence of Raynaud phenomenon and antinuclear antibodies (ANA) were associated with worsening of DLCO that was out of proportion when compared to the FVC; this was seen with a trend to higher prevalence of pulmonary hypertension in this population [260]. This is important as progressive worsening of DLCO portends a worse prognosis in patients with connective tissue disease-ILD due to worsening of the pulmonary hypertension. Pulmonary hypertension prevalence in antisynthetase syndrome is unclear and one retrospective cohort noted a prevalence of 7.9%, with a poor 3-year survival of 58%. The severity of pulmonary hypertension appeared to be out of proportion to the ILD, suggesting the occurrence of vascular remodeling leading to pre-capillary pulmonary hypertension [261].

upregulation of pro-coagulants, downregulation of anticoagulants, and impairment of fibrinolysis are possible mechanisms [269]. Diffuse alveolar hemorrhage has been reported in DM and PM, although the occurrence is rare [270]. Pleural effusions are also rare. Testing includes laboratory evaluation, pulmonary function testing, and HRCT.  In addition to basic laboratory workup, CK, aldolase, and myositis-specific antibody panel can be helpful in the evaluation. ANA is also obtained especially when the DM and PM is suspected to have an overlap with the other connective tissue disorders (such as systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue disease, Sjogren syndrome). A restrictive pattern with reduction in FVC and total lung capacity (TLC) is seen on PFTs in patients with ILD along with reduction in DLCO.  The restrictive process is mostly attributed to parenchymal involvement, although muscle weakness from myositis may also be contributing. In this case, there is proportionately more restrictive impairment Spontaneous Pneumomediastinum than diffusing capacity abnormality [237]. FVC in the sitting and supine position, maximum voluntary ventilation, maxiAlthough rare, there is increased incidence of spontaneous mum expiratory pressures, and maximum inspiratory prespneumomediastinum in DM, including CADM and to a sures can be obtained to test for respiratory muscle weakness. lesser extent in PM. Although this may be due to the ILD and A disproportionate reduction in DLCO may suggest pulmorupture of blebs, it has also been seen in patients without nary hypertension which would indicate a need for screening ILD. Underlying etiology is unclear and may be attributed to transthoracic echocardiography and evaluation for pulmovasculopathy. Mortality is high with 2-year survival of 55% nary hypertension. HRCT is obtained in supine and prone in a retrospective cohort [262, 263]. positions and reveals basilar reticular changes, ground-glass opacities, honeycombing, and consolidative changes. Need for bronchoscopy is infrequent although it can be helpful to Malignancy rule out infectious complications. Lung biopsies may be needed if there is uncertainty regarding the diagnosis and if Increased risk of malignancy is seen in inflammatory myopa- malignancy is suspected. Additional imaging such as CT of thies, with the risk being much higher in DM including the abdomen and pelvis is obtained if malignancy is susCADM at above 20% [264]. Adenocarcinomas of the lung, pected [250, 271]. ovaries, stomach, pancreas, bladder, and cervix and non-­ Prognosis is worse if ILD is present in DM and PM than Hodgkin lymphoma are the most common malignancies in those without ILD [239]. Mortality in DM and PM withseen in this population. Risk is worse at the time of diagnosis out ILD is 8.6% when compared to those with ILD at 34.8% and in the initial few years [265–267]. The relationship [272]. Male gender, anti-MDA-5 antibodies, and a presentabetween the two entities is not entirely understood; one of tion of AIP were negative prognostic factors [235, 258]. the proposed theories is that DM/PM is believed to be a para- Prognosis of antisynthetase syndrome is worse than the other neoplastic feature of the malignancy. The role of immuno- inflammatory myopathies, with ILD being the major detersuppressive drugs in the increased risk of malignancy in this mining factor [250]. Recognizing the presence of certain population is less clear [268]. autoantibodies and the specific phenotype is crucial as certain antibodies drive outcomes by virtue of higher ILD risk in DM and PM.

Other

There is increased risk for venous thromboembolism (VTE) in inflammatory myopathies with the highest risk in the 1st year after the diagnosis. Decreased mobility from joint involvement leading to venous stasis, the effect of inflammation on the endothelium, and on promoting thromboses by

Ankylosing Spondylitis Ankylosing spondylitis (AS) is a chronic progressive autoimmune disorder involving the spine, the sacroiliac joints, and less commonly the peripheral joints. AS belongs to a

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family of disorders called spondyloarthritis. Other conditions in this group of disorders include psoriatic arthritis, reactive arthritis, and arthritis associated with inflammatory bowel disease. Overall prevalence of AS in the United States is 0.5% [273]. Genetic factors are important in the development of AS, with the major histocompatibility complex (MHC) being the primary mediator of genetic susceptibility. AS has a strong association with HLA-B27, a major histocompatibility class 1 antigen and the prevalence of AS parallel HLA-­ B27 positivity [274]. The prevalence of HLA-B27  in the USA is 6.1%, with higher prevalence among non-Hispanic whites and Mexican Americans at 7.5% and 4.6%, respectively, when compared to non-Hispanic blacks at 1.2% [275]. The most recent prevalence study by Dean et  al showed higher prevalence of AS per 10,000  in USA (31.9) and Europe (23.8) when compared to Asia (16.7) and Latin America (10.2) [276]. Greater than 90% of patients with AS are HLA-B27-positive [277–279].A familial predisposition is seen with higher risk of AS among first-degree relatives with HLA-B27 positivity [280, 281]. There is a gender predilection with 70% of the disease occurring in men, although the disease activity and functional limitation are more severe in women, and this may be the result of a delayed diagnosis [282, 283]. Pathogenesis is complex with AS being the result of an immunologic flare precipitated by certain bacteria or other microbes in patients with HLA-B27 positivity [284]. Diagnostic criteria for AS are based on the modified New York criteria proposed in 1984; the criteria have limited use in early disease as radiographic evidence of sacroiliitis may not be apparent and this can lead to a delay in diagnosis [285]. To overcome this limitation, based on the proposal by the Assessment of SpondyloArthritis International Society, the patients are classified into 2 groups: 1. axial disease (axial SpA) that includes AS and non-radiographic axial SpA and 2. peripheral SpA.

Modified New York criteria [285] Definite AS is diagnosed if the radiologic criterion plus 2 of the 3 clinical criteria are present Radiologic criterion Bilateral sacroiliitis grade > II or unilateral sacroiliitis grade III to IV

Clinical criteria 1. Low back pain and stiffness > 3 months duration improved by exercise and not relieved by rest 2. Limitation of motion of the lumbar spine in both the sagittal and the frontal planes 3. Limitation of chest expansion relative to values normal for age and sex

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 ssessment of SpondyloArthritis International A Society (ASAS) Criteria [286] In patients with back pain >3 months and age at onset < 45 years SpA features Sacroiliitis on imaging Active inflammation on MRI highly Inflammatory back suggestive of sacroiliitis associated with pain SpA Arthritis or Enthesitis Definite radiographic sacroiliitis according Uveitis to modified New York Criteria Dactylitis Psoriasis Crohn’s disease/ Ulcerative colitis Good response to NSAIDS Family history of SpA HLA-B27 Elevated CRP Criteria: Sacroiliitis on imaging + > 1 SpA feature or HLA-B27 + > 2 SpA features

Patients typically present with low back pain and early morning joint stiffness. Loss of functional capacity is seen in advanced disease [287]. When AS affects the spine, it can cause the characteristic flattening of the lumbar lordosis and in severe cases kyphosis. Extra-articular manifestations involve cardiac, pulmonary, ocular, and renal systems.

 ulmonary Apical Fibrocystic Disease P Pulmonary involvement can be seen in up to a third of the patients with higher prevalence if radiologic criteria are used; pleuroparenchymal abnormalities were seen on HRCT in 60% of the patients [288, 289]. Pulmonary manifestations were initially described in 1941 by Dunham and Kautz with description of apical lung disease in 2 patients with AS, believed to be healed apical tuberculosis then, which based on current understanding were likely apical fibrous disease classically seen in AS [290]. Pulmonary apical fibrosis is one of the commonest pulmonary features seen, with 7% of AS patients noted to have this finding on HRCT.  This is more common in men and is typically seen in advanced AS [288]. This can be seen as apical pleural thickening early in the disease. Pulmonary apical fibrosis appears on imaging as coalesced lesions with cystic, bullous, or cavitary changes and can have nodular and bronchiectatic areas. Unilateral disease may be seen if early, but it is most often seen as bilateral disease [284, 288]. Etiology of the apical fibrosis is unclear, with several factors postulated to be contributing. The spine fusion and rigidity, kyphosis and involvement of the costovertebral, sternoclavicular and manubriosternal joints causes impaired mobility of the chest cage essentially leading to a rigid thorax. This is believed to result in reduced chest expansion,

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abnormal chest wall mechanics with impaired ventilation and altered local responses to recurrent aspiration and pneumonitis [291]. Radiation therapy to the chest wall and spine were used for management of AS patients several years back, until this was discontinued due to the increased occurrence of malignancy and increased cancer-related mortality [292]. This may have contributed to the development of the apical fibrocystic lesions, although the pulmonary apical changes are also known to occur in patients without a prior history of radiation therapy [284]. In addition to the above, the rotation of the diaphragm in the sagittal plane in kyphotic patients may be a contributory factor to the pulmonary impairment [293]. Secondary spontaneous pneumothorax although rare can be seen in the presence of apical fibrocystic lung disease. Patients who developed this complication were also smokers; hence, this may be a contributory factor [294]. Although the apical fibrotic process is largely asymptomatic, aspergillus and tubercular infections of the pulmonary apical lesions can occur. The infections have been seen in patients on immunosuppression, but also in patients not on immunosuppression. Aspergillus infections were previously reported to be the commonest, although pulmonary tubercular infections are reported more commonly in recent years [295–298]. Mycobacterium tuberculosis and non-­tuberculous mycobacterial infections can occur. The cause of such infections is likely due to chest wall rigidity leading to impaired ventilation of the lung apices, inadequate airway clearance, and locally altered defenses. Erroneous diagnosis of pulmonary tuberculosis has occurred in patients with AS with apical lung involvement and differentiating pulmonary disease due to AS from pulmonary tuberculosis with apical involvement may be challenging [299]. Thorough investigation including AFB stains and culture, nucleic acid amplification testing, and interferon-gamma release assays may help with the same. This is especially important in AS patients on tumor necrosis factor (TNF)-alpha inhibitors, which are known to increase latent tuberculosis re-activation risk. Aspergillus infections leading to massive hemoptysis have been reported requiring selective bronchial artery embolization and lobectomy in some cases [284, 297].

 bstructive Sleep Apnea O Obstructive sleep apnea (OSA) is seen more frequently in patients with AS, especially in older patients than in the general population. The prevalence of OSA in AS patients is 22.6% as compared to the prevalence in the general population (2–7%) [300]. The risk of OSA is higher in patients with longer disease duration (>5 years) and prevalence is 40% in AS patients aged 35 years and greater [301]. Snoring and daytime fatigue were common presenting symptoms. The involved mechanism is unclear but may include anatomic changes in the upper airway due to cervical spine disease and temporomandibular joint involvement. The cervical syndes-

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mophytes compressing the posterior oropharyngeal wall and muscle weakness in patients with neurological involvement from cervical spine involvement are potential causative factors. Theoretically, these patients may be at risk for not only obstructive sleep apnea, but also central sleep apnea due to involvement of the respiratory control centers in the medulla from cervical spine disease including sub-luxation. Higher index of suspicion for OSA is essential in this population and treatment should be undertaken with positive airway pressure if diagnosis of OSA is confirmed [301].

Other Other forms of pulmonary involvement seen include interstitial infiltrates, bronchiectasis, emphysema, and tracheobronchomegaly [295]. Amyloid deposition in the lungs has been seen uncommonly in AS patients [302]. Pulmonary hypertension is not a common feature of AS, unlike other connective tissue diseases such as scleroderma, rheumatoid arthritis, mixed connective tissue disease, or systemic lupus erythematosus. Occurrence is rare although cases are reported [303]. Cricoarytenoid joint involvement seen more commonly in rheumatoid arthritis can be seen in AS, although rare. This manifests as throat pain, hoarseness, and can rarely present as an emergent airway [304, 305]. Cardiac manifestations seen in up to 30% of patients involve inflammation of the thoracic aorta and the aortic valve, leading to dilation of the aortic root and aortic regurgitation. Cardiomyopathy, pericarditis, and cardiac conduction abnormalities can also be seen [306]. Laboratory evaluation should include HLA-B27 and acute phase reactants such as ESR and CRP which are elevated depending on disease activity [307, 308]. Bronchoscopy with bronchoalveolar lavage (BAL) is often required in patients with evolving apical fibrotic changes to rule out infections. BAL in AS patients reveals a lymphocytic predominance with reduced neutrophils and testing for infections should include mycobacterium tuberculosis and aspergillus [309]. Pulmonary function testing shows a restrictive ventilatory defect due to the rigidity of the thoracic cage and the pleuro-parenchymal involvement [284, 310]. Vital capacity, total lung capacity, and airway conductance are reduced, increased closing volume/vital ­ capacity ratio is seen, and diffusing capacity of carbon monoxide is normal [311]. Reduction in maximal expiratory pressures and maximal inspiratory pressures can be seen and occur due to atrophy of the intercostal muscles [312]. Typical findings on radiological testing are scoliosis and kyphosis. Symmetrical marginal syndesmophytes (calcification of the spinal ligament and the annulus fibrosis) giving the appearance of the classic “bamboo spine” is a unique radiologic feature seen in AS patients. Smoking increases rate of progression of disease in AS and is associated with worse outcomes [307]. Cause of death

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was predominantly due to cardiac disease (35%) and renal causes (21.5%) with pulmonary cause of death being less common at 6.3% [313].

1. >3 of McAdam’s diagnostic criteria, histologic confirmation not necessary. 2. >1 of McAdam’s signs with positive histologic confirmation. 3. Chondritis in two or more separate anatomic locations with response to steroids and/or Dapsone.

Relapsing Polychondritis Introduction Relapsing polychondritis (RP) is a rare relapsing–remitting autoimmune disorder that causes inflammation predominantly of cartilaginous tissue at various sites, while also involving non-cartilaginous tissue. The inflammation is directed at proteoglycan-rich structures that includes cartilaginous structures in the external ear, inner ear, nasal septum, joints, larynx, trachea, bronchi, and non-cartilaginous structures such as the eye, the cardiac valves, and vasculature. RP was first described by Jaksch-Wartenhorst in the year 1923, who named the condition Polychondropathia [314]. Many names have since been used until the term Relapsing Polychondritis was introduced by Pearson and colleagues in 1960 and this was widely accepted [315]. Estimated incidence is 3/1,000,000 [316]. The disease is mostly seen in Caucasians, although it can be seen in all racial groups. The onset is generally between the ages of 40 and 60 years, although RP has been seen in children and the elderly. It occurs with a female predominance (2:1 to 3:1) with more severe airway disease also likely to occur in women [317, 318]. Autoimmune activity in RP is directed against type 2 collagen which is abundant in cartilage and other tissues such as the sclera. Antibodies, specifically IgG and IgA to type 2 collagen, have been demonstrated and are important in the pathogenesis of RP.  Immunologic activity against collagen type 9 and 11 has also been seen [314]. Diagnosis of RP is based on the McAdam criteria proposed in 1976, which is met on having three of the following features with histologic confirmation: [318] 1. Bilateral auricular chondritis. 2. Nonerosive, seronegative inflammatory polyarthritis. 3. Nasal chondritis. 4. Ocular inflammation. 5. Respiratory tract chondritis (laryngeal and/or tracheal cartilages). 6. Cochlear and/or vestibular dysfunction (neurosensory hearing loss, tinnitus, and/or vertigo). Subsequent to McAdam’s criteria, the Damiani diagnostic criteria was developed in 1979 which is a modification of McAdam’s criteria [319]. Criteria for diagnosis were met if one of the following was seen:

Diagnosis of RP is generally delayed by a few years as it is a rare and poorly recognized disease. RP is also often misdiagnosed as asthma, and this is likely to occur with steroid use in asthma that leads to a suppression and hence masking of the inflammation in RP [320]. Symptoms include dyspnea, which is the commonest symptom, cough, chest discomfort, hoarse voice, dysphonia, aphonia, stridor, and wheezing. Impaired vision and hearing may be seen in patients with more advanced disease from involvement of the eye and ear. Tenderness at the thyroid cartilage and anterior cervical tracheal rings can be elicited on physical exam and may be a useful symptom. A characteristic clinical feature, which is often the presenting symptom, is auricular involvement which is present in almost 90% of cases and typically spares the ear lobule. Destruction of the nasal septum leads to the unique saddle-nose deformity and this co-relates with involvement of the respiratory tract [321]. In the absence of typical ear or nose involvement, RP can be a diagnostic challenge [316, 322].

Airway Disease Involvement of the lower respiratory tract can occur in 20-50% of patients [317, 318]. Airway involvement in the form of sub-glottic stenosis, tracheobronchomalacia, thickened and calcified tracheal wall with sparing of the posterior membranous wall, and tracheal stenosis which can be localized or diffuse are frequently seen pulmonary features. Tracheobronchomalacia occurs due to inflammation and destruction of cartilage and resulting loss of the cartilaginous support to the airways. Airway disease leading to stenosis typically occurs in 3 stages: 1. initial inflammatory edema associated with narrowing, 2. progressive destruction and damage of cartilage causing dynamic collapse of the airways and 3. fixed stenosis that occurs from late-stage fibrosis and scarring [323].

Myelodysplastic Syndrome Myelodysplastic syndrome (MDS) is diagnosed in 11% of patients with RP and it is seen with a male predominance. The diagnosis of MDS can be prior to the diagnosis of RP or after. The etiology of this association is unclear. RP being a paraneoplastic feature of MDS is one of the theories pro-

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posed; alternate theories may be that the RP and the MDS as the result of an immunologic aberrancy [321, 324, 325]. Prognosis of RP occurring with MDS is worse than of RP alone [326].

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limb of the flow-volume loop with extrathoracic obstruction or of the expiratory limb of the flow-volume loop with intra-­ thoracic obstruction. A fixed obstruction due to stenosis in stage 1 (inflammatory) or stage 3 (advanced/fibrotic disease) is seen as flattening of both limbs of the flow-volume loop. A reduction in maximum voluntary ventilation also occurs Other mostly due to limitation in exhalation from airway obstruction. Hypercapnic ventilatory impairment can be seen during Interstitial lung disease in RP is rare and is mentioned in case exercise with preserved oxygenation [335]. reports alone. Pulmonary vascular involvement is also rare Dynamic CT of the chest is necessary for optimal airway [316, 327, 328]. Other organ manifestations include eye assessment. Patients especially in the earlier stages manifest involvement in the form of scleritis, episcleritis, uveitis, and narrowing on expiration alone without evidence of narrowed keratitis. Patient can present with symptoms related to airways during inspiration. Hence, it is essential to obtain a involvement of the joints and skin [329]. Joint disease is dynamic CT with inspiratory and expiratory images. CT typically asymmetric and is axial sparing, involving periph- with three-dimensional imaging, MRI, and PET-CT are other eral joints. Costochondritis can also be seen and may be the modalities used for detailed assessment. cause of chest pain. Cardiovascular involvement seen preBronchoscopy can be done for airway assessment in dominantly in men occurs most commonly in the form of symptomatic patients. In early and active disease states, valvular heart disease. Aortic regurgitation is the commonest mucosal inflammation and edema can be seen. Dynamic aircardiovascular abnormality and can occur in up to 10% of way collapse from tracheobronchomalacia, airway narrowRP patients [330]. It occurs due to aortic root dilation and ing including sub-glottic stenosis, and narrowing of other less commonly from destruction of aortic valve cusps. Mitral areas of the tracheobronchial tree are the commonest findregurgitation occurs less frequently in 1.8% of RP patients ings [317]. Tracheomalacia is diagnosed if there is >50% [330]. Conduction abnormalities, aneurysm of aorta and of narrowing of the airway lumen, although more recently a the other vessels, thrombosis secondary to vasculitis, peri- stricter criteria with a higher threshold are being recomcarditis, and myocarditis can also be seen [329, 331]. mended based on studies that showed that a significant proOther connective tissue disorders and vasculitis can co-­ portion of healthy volunteers met the >50% criteria [336]. exist with RP.  Granulomatosis with polyangiitis (GPA), Diagnosis of RP is clinical, and biopsies should be pursued eosinophilic granulomatosis with polyangiitis, and Behcet’s only in cases of diagnostic uncertainty and to rule out altersyndrome are some of the vasculitis seen in patients with RP. nate etiology due to the associated morbidity in this populaMouth and genital ulcers with inflamed cartilage syndrome tion. If the decision is made to biopsy, anterior airway wall (MAGIC syndrome) first described in 1985 by Firestein and biopsies to include cartilaginous tissue should be obtained. colleagues have clinical features of both RP and Behcet’s All airway procedures should be done with caution and airdisease [332, 333]. way emergency should be anticipated and prepared for. Laboratory evaluation reveals nonspecific elevation of Other workup undertaken include audiometry, ophthalmoinflammatory markers (ESR, CRP) which indicates disease logic exam, and cardiac assessment. activity. Antibodies to collagen type 2, 9, and 11 are seen, Management of laryngeal and tracheal edema in the acute although they lack the specificity and sensitivity [316]. setting is with noninvasive ventilation along with steroids. Anticollagen type 2 activity can be helpful in the diagnosis Continuous positive airway pressure or bi-level positive airand is a marker of disease activity [334]. Serology for other way pressure may be of benefit. Close monitoring is essential connective tissue disorders should be obtained if there is as RP with airway involvement is a high-risk condition that concern for associated disease. Antineutrophilic cytoplasmic can lead to an airway emergency necessitating endotracheal antibodies (ANCA) may be seen in some patients with RP intubation and not uncommonly emergent tracheostomy at who have an overlap with vasculitis or it may be nonspecific the bedside. Development of negative pressure pulmonary [316]. ANCA, urine analysis, and renal function testing edema has been reported in a previously undiagnosed patient should be assessed as GPA and RP share many features. presenting with acute laryngeal edema who required a bedPulmonary function testing (PFT) with flow-volume side tracheostomy [337]. Advanced bronchoscopy intervenloops must be obtained in all patients to evaluate for airway tions may be needed. Treatment is with tumor necrosis factor involvement. Large airway obstruction can reveal itself early (TNF)-alpha inhibitors or combination therapy with TNF-­ in the course with flattened contour of the flow-volume loop alpha inhibitors and steroids. and depending on the stage of the involvement can show Although survival in the early years was lower, 8-year varying patterns. PFTs when done in stage 2 can reveal a survival for RP was 94% in 1998 and 4-year survival was dynamic obstruction, i.e., flattening of either the inspiratory 97% in 2008 [317]. Airway involvement affects prognosis

19  Connective Tissue Disease-Associated Interstitial Lung Disease

and pulmonary infections are the commonest cause of death in RP followed by cardiovascular causes. Saddle-nose deformity and presence of vasculitis predicted a worse prognosis [321]. Management should be undertaken in specialized centers offering medical therapy, airway interventions, and survival appears to have improved overall over the past few decades [317].

Mixed Connective Tissue Disease Mixed connective tissue disease (MCTD) is an autoimmune disease that was initially described by Sharp et al in 1972 as an overlap of systemic sclerosis, systemic lupus erythematosus (SLE), and dermatomyositis/polymyositis and the syndrome has since evolved in terms of its understanding [338]. Controversy and a lack of consensus exist with regard to diagnostic criteria for MCTD and also regarding the question of whether this is an entirely separate connective tissue disease (CTD) that overlaps with other CTDs versus a disease process early in its evolution to one of the other CTDs. There are some data on HLA association with MCTD, specifically HLA B08 and HLA DRBI 0401, although it is unclear how it affects the disease [339]. MCTD has a prevalence of 3.8/100,000 and it occurs predominantly in adults, although it can occur in children (juvenile-onset MCTD). There is a female predominance in both adults and children with a female:male ratio of 3.3 in adults [339]. Clinical features of MCTD are presence of Raynaud phenomenon, swollen hands, arthritis, myositis, pleuritis, pericarditis, leukopenia, esophageal dysmotility, trigeminal neuropathy, interstitial lung disease (ILD), and pulmonary arterial hypertension (PAH). Patients presenting with pulmonary-­related symptoms report dyspnea, nonproductive cough, and pleuritic chest pain. Presence of anti-U1 small nuclear ribonucleoprotein particle (anti-U1-RNP) antibodies is characteristic and believed to be pathogenic based on animal studies [339, 340]. Although initial description of MCTD was by Sharp and colleagues, several other diagnostic criteria were proposed with no consensus on the criteria to be used. In addition to Sharp’s criteria, Kasukawa et  al and Alarcon-Segovia et al developed criteria in 1987 followed by Kahn et al in 1991 [338, 341–343]. The Sharp criteria are not used frequently currently and the Kasukawa criteria are used mostly for juvenile MCTD. Sharp Criteria Major criteria Myositis Pulmonary disease Raynaud phenomenon Esophageal dysmotility

Minor Criteria Alopecia Trigeminal neuralgia Leukopenia Malar rash Anemia Thrombocytopenia Pleuritis Myositis

681 Major criteria Myositis Swollen hands or sclerodactyly High anti-U1-RNP, negative anti-Sm Definite: 4 major + serology

Minor Criteria Alopecia Trigeminal neuralgia Pericarditis History of swollen hands Arthritis Probable: 3 major (or) 2 major + 2 minor + serology

Alarcon-Segovia Criteria (A) Serologic criteria Anti-U1-RNP with titer of > 1600

(B) Clinical criteria Swollen hands Myositis Synovitis Raynaud phenomenon Acrosclerosis

Diagnostic Criteria: A + > 3 of B

Kahn Criteria (A) Serologic criteria Anti-RNP corresponding to a speckled ANA of >1:1200

(B) Clinical criteria Swollen fingers Synovitis Myositis Raynaud phenomenon Diagnostic Criteria: A + Raynaud phenomenon + > 2 other criteria

Three subphenotypes are seen in MCTD and have prognostic implications, with sub-phenotype 1 having the worst survival [340, 344]. 1. Phenotype 1—PAH, vascular thrombosis, livedo reticularis, Raynaud phenomenon. 2. Phenotype 2—ILD (98% prevalence), esophageal dysmotility, GERD, myositis. 3. Phenotype 3—elevated anti-CCP antibodies, erosive arthritis.

Interstitial Lung Disease The predominant form of pulmonary involvement in MCTD is ILD with a prevalence of 47-78% [345–347]. ILD seen in MCTD has a basilar predilection with reticular changes ­progressing to lung fibrosis [346]. Most frequent histology is nonspecific interstitial pneumonia (NSIP) followed by usual interstitial pneumonia (UIP) and then lymphocytic interstitial pneumonia (LIP) [340]. There are a few reports of acute pneumonitis [348]. Esophageal dysfunction and acid reflux occur in more than half of MCTD patients; more than 90% of patients with esophageal involvement had ILD [340]. Presence of specific antibodies may be helpful in determining the risk of developing ILD. Anti-SSA (anti-Ro52, anti-­

682

Ro-­60) and anti-SSB antibodies were measured in a national Norwegian MCTD cohort and the presence of anti-Ro antibodies co-related well with the presence of lung fibrosis [349]. Male gender, high anti-U1-RNP titers, presence of anti-Ro52 antibodies, and the absence of arthritis portended a worse outcome in MCTD patients with ILD [350].

Pulmonary Arterial Hypertension

R. Mathew and S. Noh

tial workup and for further management of PAH. Management of PAH in MCTD is the same as for other CTD-PAH. Overall survival is 98% at 5 years and 88% at 15 years [347]. Morbidity and mortality in MCTD are mostly attributed to ILD and PAH. In a nationwide cohort, mortality overall was 7.9%, but worse at 20.8% in patients with severe lung fibrosis [346]. Next to scleroderma, MCTD is the most common cause of lung transplant in CTD-ILD [359]. PAH in MCTD has a more favorable prognosis than other CTD-PAH [352].

PAH secondary to MCTD can occur; however, there is paucity of data. Prevalence of pulmonary hypertension in MCTD References is 8-29%, with MCTD being the 3rd most common cause of 1. Myasoedova E, Crowson CS, Turesson C, Gabriel SE, Matteson CTD-associated PAH [351–354]. PAH in MCTD is similar EL.  Incidence of extraarticular rheumatoid arthritis in Olmsted to PAH that occurs in systemic sclerosis, although it is less County, Minnesota, in 1995-2007 versus 1985–1994: a population-­ severe and has a more favorable prognosis than other CTD-­ based study. J Rheumatol. 2011;38(6):983–9. associated PAH [352]. Higher levels of anti-U1-RNP, anti-­ 2. Chatzidionisyou A, Catrina AI. The lung in rheumatoid arthritis, cause or consequence? Curr Opin Rheumatol. 2016;28(1):76–82. endothelial cell antibody, and anti-beta2-glycoprotein 1 were 3. Klareskog L, Stolt P, Lundberg K, Källberg H, Bengtsson C, seen in MCTD patients with PAH. Grunewald J, et  al. A new model for an etiology of rheumatoid

Other Alveolar hemorrhage is seen infrequently, and available literature is mostly case reports. Etiology is unclear and may be related to immune complex deposition as in SLE [47]. Reports of pleural involvement vary and can occur in up to 35% of patients [355]. In a cohort of 81 patients, 6% had pleural effusion and 2% had pleural thickening [356]. The effusion in MCTD is typically exudative and self-limiting. Along with pleural inflammation, pericardial inflammation can also occur [357]. Cardiac involvement occurs in 13-65% of MCTD patients. A diastolic pathophysiology and accelerated atherosclerosis are seen in these patients [358]. Diagnosis is often delayed due to the uncertainty and controversy over definitions and due to the overlap with other rheumatologic syndromes [339]. Lab testing includes antinuclear antibody (ANA), rheumatoid factor, anticyclic citrullinated peptide (anti-CCP) antibodies, and anti-U1-RNP antibodies. Pulmonary function tests (PFTs) and HRCT are obtained for baseline assessment and follow-up of ILD. PFTs are notable for a restrictive pattern with reduction in diffusing capacity of carbon monoxide (DLCO). Presence of PAH can lead to a more disproportionate reduction of DLCO. Cornerstone of management is immunosuppression and is based on extrapolated data and guidelines for rheumatoid arthritis, SLE, and systemic sclerosis. Raynaud phenomenon can be managed by avoiding cold, smoking, caffeine, and injury, and calcium channel blockers are frequently needed. Annual echocardiography is recommended, and right heart catheterization is done if clinical symptoms or screening echocardiography is concerning for PAH. N-terminal pro-BNP is useful to obtain as part of ini-

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R. Mathew and S. Noh tis: results from the German Spondyloarthritis Inception Cohort. Arthritis Rheum. 2009;60(3):717–27. 309. Scherak O, Kolarz G, Popp W, Wottawa A, Ritschka L, Braun O.  Lung involvement in rheumatoid factor-negative arthritis. Scand J Rheumatol. 1993;22(5):225–8. 310. Berdal G, Halvorsen S, van der Heijde D, Mowe M, Dagfinrud H.  Restrictive pulmonary function is more prevalent in patients with ankylosing spondylitis than in matched population controls and is associated with impaired spinal mobility: a comparative study. Arthritis Res Ther. 2012;14(1):R19. 311. Feltelius N, Hedenström H, Hillerdal G, Hällgren R. Pulmonary involvement in ankylosing spondylitis. Ann Rheum Dis. 1986;45(9):736–40. 312. Vanderschueren D, Decramer M, Van den Daele P, Dequeker J. Pulmonary function and maximal transrespiratory pressures in ankylosing spondylitis. Ann Rheum Dis. 1989;48(8):632–5. 313. Lehtinen K. Cause of death in 79 patients with ankylosing spondylitis. Scand J Rheumatol. 1980;9(3):145–7. 314. Lise Giroux FP, Gubrard-Desjardins MJ. Andrh lefaivre relapsing polychondritis: an autoimmune disease. Semin Arthritis Rheum. 1983;13:182–7. 315. Pearson CM, Kline HM, Newcomer VD. Relapsing polychondritis. N Engl J Med. 1960;263:51–8. 316. Kent PD, Michet CJ Jr, Luthra HS. Relapsing polychondritis. Curr Opin Rheumatol. 2004;16(Issue 1):56–61. 317. Ernst A, Rafeq S, Boiselle P, Sung A, Reddy C, Michaud G, et  al. Relapsing polychondritis and airway involvement. Chest. 2009;135(4):1024–30. 318. McAdam LPOHM, Bluestone R, Pearson CM.  Relapsing polychondritis: prospective study of 23 patients and a review of the literature. Medicine (Baltimore). 1976;55:193–215. 319. Damiani JM, Levine HL. Relapsing polychondritis--report of ten cases. Laryngoscope. 1979;89(6 Pt 1):929–46. 320. Gorard C, Kadri S. Critical airway involvement in relapsing polychondritis. BMJ Case Rep. 2014;2014:bcr2014205036. 321. Michet CJ Jr, McKenna CH, Luthra HS, O’Fallon WM. Relapsing polychondritis. Survival and predictive role of early disease manifestations. Ann Intern Med. 1986;104(1):74–8. 322. Suzuki S, Ikegami A, Hirota Y, Ikusaka M. Fever and cough without pulmonary abnormalities on CT: relapsing polychondritis restricted to the airways. Lancet. 2015;385(9962):88. 323. Mohsenifar Z, Tashkin DP, Carson SA, Bellamy PE. Pulmonary function in patients with relapsing polychondritis. Chest. 1982;81(6):711–7. 324. Hebbar M, Brouillard M, Wattel E, Decoulx M, Hatron PY, Devulder B, et  al. Association of myelodysplastic syndrome and relapsing polychondritis: further evidence. Leukemia. 1995;9(4):731–3. 325. Dion J, Costedoat-Chalumeau N, Sène D, Cohen-Bittan J, Leroux G, Dion C, et al. Relapsing polychondritis can be characterized by three different clinical phenotypes: analysis of a recent series of 142 patients. Arthritis Rheumatol. 2016;68(12):2992–3001. 326. Salahuddin N, Libman BS, Lunde JH, Kay J, Cooper SM.  The association of relapsing polychondritis and myelodysplastic syndrome: report of three cases. J Clin Rheumatol. 2000;6(3):146–9. 327. Burlew BP, Lippton H, Klinestiver D, Haponik EJ.  Relapsing polychondritis: new pulmonary manifestations. J La State Med Soc. 1992;144(2):58–62. 328. Wu S, Sagawa M, Suzuki S, Kumagai-Braesch M, Honda Y, Sato M, et al. Pulmonary fibrosis with intractable pneumothorax: new pulmonary manifestation of relapsing polychondritis. Tohoku J Exp Med. 2001;194(3):191–5. 329. Danve A.  Thoracic manifestations of ankylosing spondylitis, inflammatory bowel disease, and relapsing polychondritis. Clin Chest Med. 2019;40(3):599–608.

19  Connective Tissue Disease-Associated Interstitial Lung Disease 330. Del Rosso A, Petix NR, Pratesi M, Bini A.  Cardiovascular involvement in relapsing polychondritis. Semin Arthritis Rheum. 1997;26(6):840–4. 331. Kingdon J, Roscamp J, Sangle S, D'Cruz D.  Relapsing polychondritis: a clinical review for rheumatologists. Rheumatology (Oxford). 2018;57(9):1525–32. 332. Firestein GS, Gruber HE, Weisman MH, Zvaifler NJ, Barber J, O'Duffy JD.  Mouth and genital ulcers with inflamed cartilage: MAGIC syndrome. Five patients with features of relapsing polychondritis and Behçet’s disease. Am J Med. 1985;79(1):65–72. 333. Letko E, Zafirakis P, Baltatzis S, Voudouri A, Livir-Rallatos C, Foster CS.  Relapsing polychondritis: a clinical review. Semin Arthritis Rheum. 2002;31(6):384–95. 334. Sharma A, Gnanapandithan K, Sharma K, Sharma S.  Relapsing polychondritis: a review. Clin Rheumatol. 2013;32(11):1575–83. 335. Gibson GJ, Davis P. Respiratory complications of relapsing polychondritis. Thorax. 1974;29(6):726–31. 336. Boiselle PM, O'Donnell CR, Bankier AA, Ernst A, Millet ME, Potemkin A, et  al. Tracheal collapsibility in healthy volunteers during forced expiration: assessment with multidetector CT. Radiology. 2009;252(1):255–62. 337. Wu MF, Li YS, Hung CY, Chao WC, Fu ZY, Kao KC, et  al. Relapsing polychondritis with initial presentations of recurrent negative-pressure pulmonary edema and acute respiratory failure. Respir Care. 2015;60(5):e101–4. 338. Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR.  Mixed connective tissue disease--an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. 1972;52(2):148–59. 339. Gunnarsson R, Hetlevik SO, Lilleby V, Molberg Ø. Mixed connective tissue disease. Best Pract Res Clin Rheumatol. 2016;30(1):95–111. 340. Ciang NC, Pereira N, Isenberg DA.  Mixed connective tissue disease-enigma variations? Rheumatology (Oxford). 2017;56(3):326–33. 341. Kahn M.  Syndrome de Sharp. La Revue du praticien. 1990;40(21):1944–5. 342. Kasukawa R. Diagnosis of mixed connective tissue disease : preliminary diagnostic criteria for classification of mixed connective tissue disease. In: Mixed connective tissue disease and anti-­ nuclear antibodies; 1987. p. 41–8. 343. Alarcon SD. Classification and diagnostic criteria for mixed connective tissue disease. In: Mixed connective tissue disease and anti-nuclear antibodies; 1987. p. 33. 344. Szodoray PHA, Kardos L, et  al. Distinct phenotypes in mixed connective tissue disease: subgroups and survival. Lupus. 2012;21:1412–22. 345. Fagundes MN, Caleiro MT, Navarro-Rodriguez T, Baldi BG, Kavakama J, Salge JM, et al. Esophageal involvement and interstitial lung disease in mixed connective tissue disease. Respir Med. 2009;103(6):854–60.

691 346. Gunnarsson R, Aalokken TM, Molberg O, Lund MB, Mynarek GK, Lexberg AS, et al. Prevalence and severity of interstitial lung disease in mixed connective tissue disease: a nationwide, cross-­ sectional study. Ann Rheum Dis. 2012;71(12):1966–72. 347. Hajas A, Szodoray P, Nakken B, Gaal J, Zold E, Laczik R, et al. Clinical course, prognosis, and causes of death in mixed connective tissue disease. J Rheumatol. 2013;40(7):1134–42. 348. Rath E, Zandieh S, Löckinger A, Hirschl M, Klaushofer K, Zwerina J. Life-threatening acute pneumonitis in mixed connective tissue disease: a case report and literature review. Wien Klin Wochenschr. 2015;127(19-20):792–4. 349. Gunnarsson R, El-Hage F, Aaløkken TM, Reiseter S, Lund MB, Garen T, et  al. Associations between anti-Ro52 antibodies and lung fibrosis in mixed connective tissue disease. Rheumatology. 2016;55(1):103–8. 350. Perelas A, Arrossi AV, Highland KB. Pulmonary manifestations of systemic sclerosis and mixed connective tissue disease. Clin Chest Med. 2019;40(3):501–18. 351. Thakkar V, Lau EM.  Connective tissue disease-related pulmonary arterial hypertension. Best Pract Res Clin Rheumatol. 2016;30(1):22–38. 352. Chung L, Liu J, Parsons L, Hassoun PM, McGoon M, Badesch DB, et al. Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype. Chest. 2010;138(6):1383–94. 353. Burdt MA, Hoffman RW, Deutscher SL, Wang GS, Johnson JC, Sharp GC.  Long term outcome in mixed connective tissue disease—longitudinal clinical and serologic findings. Arthritis Rheum. 1999;42(5):899–909. 354. Chung L, Farber HW, Benza R, Miller DP, Parsons L, Hassoun PM, et al. Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the REVEAL registry. Chest. 2014;146(6):1494–504. 355. Sullivan WD, Hurst DJ, Harmon CE, Esther JH, Agia GA, Maltby JD, et  al. A prospective evaluation emphasizing pulmonary involvement in patients with mixed connective tissue disease. Medicine (Baltimore). 1984;63(2):92–107. 356. Prakash UB, Luthra HS, Divertie MB.  Intrathoracic manifestations in mixed connective tissue disease. Mayo Clin Proc. 1985;60(12):813–21. 357. Ruano CA, Lucas RN, Leal CI, Lourenço J, Pinheiro S, Fernandes O, et  al. Thoracic manifestations of connective tissue diseases. Curr Probl Diagn Radiol. 2015;44(1):47–59. 358. Vegh J, Hegedus I, Szegedi G, Zeher M, Bodolay E.  Diastolic function of the heart in mixed connective tissue disease. Clin Rheumatol. 2007;26(2):176–81. 359. Courtwright AM, El-Chemaly S, Dellaripa PF, Goldberg HJ.  Survival and outcomes after lung transplantation for non-­ scleroderma connective tissue-related interstitial lung disease. J Heart Lung Transplant. 2017;36(7):763–9.

20

Pneumoconiosis Sujith V. Cherian, Anupam Kumar, Patricia M. de Groot, Mylene T. Truong, and Cesar A. Moran

Asbestos-Related Lung Diseases: A Review Introduction The International Labor Organization defines pneumoconiosis as the accumulation of dust in the lungs and the tissue reactions to its presence [1]. Asbestos is a general term for a heterogeneous group of hydrated magnesium silicate that tends to break up into fibers [2, 3]. These fibers, when inhaled into the lungs, can cause a spectrum of lung disorders including benign conditions such as pulmonary fibrosis and malignant conditions such as lung cancer and mesothelioma [3]. In spite of early recognition of the various clinical implications associated with asbestos inhalation [4], asbestos continues to be the largest single cause of occupational cancer in the United States and a significant cause of disease and disability from non-malignant disease [3]. Asbestos as a possible pathogen with deleterious effects on the lung was first described as early as 1897 with the first published report in 1899 by Dr. Montague Murray who described the post-mortem findings of asbestos fibers in the fibrotic lungs of a young asbestos-tile worker [4]. Dr. William Cooke was the first to describe that lung fibrosis was entirely S. V. Cherian Department of Internal Medicine, Divisions of Critical Care, Pulmonary and Sleep Medicine, UT Health-McGovern Medical School, Houston, TX, USA e-mail: [email protected] A. Kumar Division of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA e-mail: [email protected] P. M. de Groot · M. T. Truong (*) Department of Thoracic Imaging, The University of Texas MD Anderson Cancer, Houston, TX, USA e-mail: [email protected]; [email protected] C. A. Moran Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected]

due to asbestos exposure based on his findings in an autopsy done on a young textile woman worker whose main work involving spinning asbestos into yarn. Further similar descriptions led to an elaborate investigation in the United Kingdom, which resulted in the establishment of irrefutable evidence of a link between asbestos exposure and lung fibrosis, which was then came to be called as “asbestosis” [4]— leading to the implementation of dust control regulations within the United Kingdom followed by the United States in the 1930s. The link between asbestos exposure and malignancies including lung cancer and mesothelioma was presented in 1950s. In 1960, Wagner described a case series of 30 patients who developed mesothelioma secondary to blue asbestos exposure. Recognition of other clinical entities such as pleural plaques, benign asbestos-related pleural effusions (BAPE), and diffuse pleural thickening secondary to asbestos were all described in 1960s. Growing appreciation of these pathologic entities secondary to asbestos exposure led to the institution of strict industrial control and health protection measures internationally and widespread banning of its production especially in the Western industrialized nations, including the USA [4]. The widespread use of asbestos up to the 1970s and the prolonged latency of asbestos-related illnesses has resulted in an epidemic of these asbestos-related lung diseases which now continues into the twenty-first century [3]. In fact, within the United Kingdom which was one of the first countries to implement regulations on the use of asbestos—cases have been increasing yearly since 1980 and are estimated to have peaked only within the last decade (2011–2020) [5]. On the contrary, the production of asbestos still continues in several parts of the world including China, Russia, South Africa, and South America [3]. Furthermore, workers and their families in developing countries continue to be exposed to asbestos, and in rapidly industrializing countries of Eastern Europe, its use may even be increasing [3]—all of which will have deleterious consequences on several exposed people within these countries.

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 ypes of Asbestos and Occupations Associated T with Exposure As stated above, asbestos fibers refer to well-developed and hair-like long-fibered varieties of heterogeneous hydrated silicates which possess great tensile strength, heat resistance, and acid resistance [3]. These properties have led to its use in many commercial and domestic settings including insulation materials, brake pads and linings, household products, floor tiles, electric wiring, paints, and cements [6]. The fibers of asbestos can be broadly classified into two main groups— mainly serpentine fibers, which are curly and flexible, and amphibole fibers, which are stiff and straight. Chrysolite (white asbestos) is the most important serpentine fiber. Crocidolite (blue asbestos) and amosite (brown asbestos) are the most notable amphibole fibers. The other commercially used asbestos types are anthophyllite (a common contaminant of industrial talc), tremolite (a common contaminant of chrysolite), and actinolite [3, 6]. Out of this, a serpentine fiber, i.e.,—chrysolite remains the only serpentine of commercial importance commonly used today. Although commercial use has declined substantially in recent years in developed countries, asbestos continues to be mined in other parts of the world, such as Russia, China, and Canada. Asbestos and other asbestiform minerals may occur as a natural accessory mineral in other industrial mineral deposits or rocks, e.g.,—tremolite-like asbestiform mineral found in association with vermiculite in Libby, Montana [7], erionite exposure in some Turkish villages and North Dakota [8]. Asbestos exposure can occur thus in a variety of settings, including occupational (Table 20.1), environmental, or indirect exposure—termed bystander exposure [3, 4]. Other than direct exposure during mining and its continued use in developing countries, exposure to asbestos in developed countries Table 20.1  Lost of common sources for human exposure to asbestos Asbestos minerals Types Occupations involved Chrysolite Brake-lining, ship building and repair, stone cutting, polishing of precious stones, foundry operations, asbestos cement products (pipes, gutters), insulation, and fire-proofing Crocidolite Cement products such as pipes, gutters, tiles, and roofing Amosite Pipe insulation and cement products Tremolite Rural domestic uses, stucco Non-asbestos mineral silicates Clay minerals Functional filler in paper, plastic, bricks, cement (e.g., Kaolin) Talc Ceramics, paper making, cosmetics, animal feed, fertilizer, plastic reinforcer Vermiculite Absorbents, plasters, boards, insulation Zeolite, e.g., Houses constructed in erionite rock Erionite Stucco and plaster

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given the stringent rules regarding its production and mining generally occurs/has occurred in these settings: (a) older workers with asbestos exposure, (b) workers involved in maintenance of buildings and facilities built after World War II, (c) asbestos abatement projects such as removing insulation and other asbestos-containing products, and (d) renovation and building of structures containing asbestos. Thus, within the United States, construction industry remains the area with the highest risk of exposure with an estimated 1.3 million workers at risk [3]. Current use of asbestos is limited to production of friction pads, brake linings, gas masks, roofing materials, and cement water pipes [3]. Indirect occupational exposures, also called as bystander exposures—describe the exposure of those whose trades require them to work in the vicinity of others who are working directly with asbestos or asbestos-related products. For example, a study involving US dockyard workers employed in the 1960s reported an increase in lifetime risk for mesothelioma of 14-fold in electricians, 16-fold in sheet metal workers and 18-fold in woodworkers [9]. Otherwise, domestic exposures occur due to asbestos fiber laden clothes being brought to home, with women washing such clothes found to have increased risk of mesothelioma [10, 11]. Environmental and residential exposures take place as a consequence of living close to asbestos mines, mills, or plants. Wagner et  al. first demonstrated this association in South Africa as early as 1960 [12, 13]. Of note, such continuous low-level exposure due to residential proximity to asbestos mining has been shown to result in increased risk of mesothelioma and not asbestosis [11, 14, 15].

 athogenesis of Asbestos-Related Lung P Conditions The biohazard of asbestos results from inhalation of asbestos fibers. Physical properties such as length, diameter, length-­to-­width ratio, texture, and chemical properties play an important part in the pathogenesis of several asbestosrelated pulmonary illnesses [6, 16]. Studies suggest a threshold exposure level should be attained for the development of asbestosis—thus continuous heavy exposure may be associated with a shorter latency compared to low exposure [16, 17]. Fiber type plays an important part in the pathogenesis— with amphibole fibers shown to be much more pathogenic than serpentine fibers with suggested estimates for exposure-­specific risk for mesothelioma as 500: 100: 1 for crocidolite, amosite, and chrysolite, respectively [4, 18]. This is likely related to the shape and nature of the asbestos fibers, i.e.,—chrysolites being curly and serpentine are much more easily cleared by macrophages vs. amphibole fibers, which are less efficiently cleared result-

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ing in persistence within the lung parenchyma and hence consequent deleterious effects [3]. Other factors, which play an important role in the pathogenesis, include the pattern of exposure with intermittent heavy exposures resulting in significantly higher pleural complications rather than parenchymal complications in the range of 20: 1 whereas continuous exposure is associated with pleural: parenchymal abnormalities in range of 2:1 [17]. Exposure at a young age as well as genetic factors plays a role as well [17, 19]. Moreover, shorter lag times (time from first ­exposure to radiological abnormalities) may result in faster progression of lung abnormalities [17].

 ate of Asbestos Fibers in Lungs F Asbestos fibers inhaled into the lung are deposited at airway bifurcations and respiratory bronchioles, which is then taken up by adjoining alveoli, primarily by impaction and interception. This results in an alveolar macrophage-induced alveolitis. Activated macrophages are stimulated to engulf and remove asbestos fibers—a process that is not uniformly successful—resulting in retention of several of these fibers, particularly the long fibers. Chrysolite fibers by virtue of being able to split longitudinally and being curly are cleared much more efficiently by these macrophages [3, 20]. The fibers within the alveolar macrophages, which are not removed, induce apoptosis and stimulate inflammation. Granulocytes are recruited to these sites, which further propagates the process with increased release of other mediators thus stimulating fibroblast proliferation—which in turn promotes collagen synthesis and tissue fibrosis [3, 21]. The net effect is a form of peribronchiolitis with involvement of the walls of the membranous and respiratory bronchioles as well as alveolitis and inflammation in the surrounding interstitium [3]. Of particular mention is the development of asbestos bodies, which refer to the iron-rich proteinaceous “coating” on long asbestos fibers (most commonly amphibole fibers), which help prevent apoptosis and are thus protective. Iron stains help identify them; hence, they are also referred to as ferruginous bodies. This is not possible in most of the asbestos fibers and hence the vast majority of the asbestos fibers within the lung and not coated [3]. Demonstration of asbestos bodies on light microscopy on broncho-alveolar lavage samples is consistent with occupational exposure and implies that there is a significantly high asbestos fiber burden within the lung (generally 5- to 10,000-fold higher-than-coated asbestos) (Fig. 20.1) [22, 23]. Development of pleural abnormalities from asbestos exposure is not well understood [3]. Several theories have been postulated, with the most likely mechanism believed to be secondary to migration of asbestos fibers transpleurally from the lung into the pleural space. These fibers once they exit the pleural space following the lymphatics get lodged in

Fig. 20.1 Hematoxylin–eosin section of lung showing numerous asbestos (ferruginous) bodies

the stomata on parietal pleura and interact with macrophages and other inflammatory resulting in continued inflammation and likely formation of pleural plaques and fibrosis [24]. Although cigarette smoking may result in increased retention of asbestos fibers within the lung [19], a direct causative role in the pathogenesis of asbestos-related pleuropulmonary conditions has not been established [23].

Asbestos-Related Pleuro-pulmonary Conditions Asbestos has been associated with a variety of pleuropulmonary conditions, which can be broadly divided as benign and malignant conditions.

Benign Conditions Pleural Diseases Pleural Plaque

Pleural plaques refer to circumscribed areas of pleural thickening with a linear, band-like, or nodular appearance. They are the most common radiographic abnormalities associated with asbestos exposure [4] and can be seen in up to 60% of asbestos-exposed workers on CT scans [25]. Often found incidentally, they are found on CT scans as early as 10 years after exposure and may not be found on chest X-rays until they calcify, which occurs a median of 17.5 years after exposure [26]—further suggesting that chest X-rays are insensitive to diagnose pleural plaques. In fact, only 15% of chest

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X-rays showed pleural plaques when compared to findings post-mortem/thoracotomy [4]. As mentioned above, pleural plaques are usually discovered incidentally and are not associated with any symptoms, although vague angina-like symptoms have been rarely described [23]. There are no physical examination findings unique to pleural plaques, and in the absence of other pleuropulmonary conditions, the examination is normal [4]. Whether or not respiratory impairment is associated with pleural plaques is controversial and studies have found a small decline in forced vital capacity [27]; however, a variety of other confounders such as age, presence of cigarette smoking exist, and intrinsic lung disease were found which may affect the validity of these findings [28]. Pleural plaques are typically seen on the parietal pleura along the 5th to 9th ribs bilaterally and over the diaphragm but less often seen in the intercostal spaces. They tend to spare the apex and costophrenic angles [3]. Thoracoscopy and biopsies are generally not warranted unless there is clinical suspicion for mesothelioma [4]. While the prognostic significance of pleural plaques has been debated, some studies have shown that apart from the association with increased exposure to asbestos, its presence may also be associated with increased risk for mesothelioma and possibly lung cancer [29]. However, whether this warrants screening imaging tests on a regular basis is controversial in the absence of clear evidence of benefit [3, 29]. It should be noted, however, that greater risk of malignancy is secondary to increased exposure or retained body burden and not due to malignant degeneration of the pleural plaques [3]. In cases in which a pleura biopsy is obtained, the tissue will show predominantly a hyalinized fibroconnective tissue with minimal inflammation and lack of atypical cells. In most cases, the cellularity of the biopsy specimen is also minimal (Fig. 20.2) Benign Asbestos Pleural Effusion

Benign asbestos pleural effusion (BAPE) is usually the earliest disease seen after exposure to asbestos [4, 30]. It may, on occasion, present after a prolonged latency and can occur even with minimal exposure [3]. The term benign implies that they are not associated with mesothelioma. BAPE is usually asymptomatic, but they may be associated with fevers and pleuritic chest pain [30, 31]. The effusion may be present bilaterally, persist for months, or recur in the same side or opposite side. BAPE is exudative, often hemorrhagic with variable numbers of erythrocytes, neutrophils, lymphocytes, and often eosinophils [30, 32]. Pleural fluid eosinophilia (>10%) may be seen in up to onethird of patients affected [33]. Cytology is rarely conclusive and asbestos bodies are rarely found in the pleural fluid. Given the exudative nature, and absence of positive diagnostic findings on pleural fluid cytology, thoracoscopic pleural

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Fig. 20.2  Pleural plaque showing extensive hyalinization with no inflammatory cells and no cellularity

biopsies are necessary to make a definite diagnosis [4]. When thoracoscopy is not possible, diagnostic criteria of BAPE include: (a) exposure history, (b) absence of other causes, and (c) absence of tumor in the subsequent 3 years [3, 23]. Prognosis is generally good for BAPE with most effusions showing spontaneous resolution, if it is either the first episode or presenting as a recurrence. As stated above, they are not associated with future risk of malignancy; however, it may predate the development of diffuse pleural thickening and asbestosis [23, 34]. Rounded Atelectasis

Rounded atelectasis also known as shrinking or contracted pleuritis, folded lung or Blesovsky syndrome [3, 5, 35] presents radiographically as a mass and is frequently mistaken for lung cancer. It develops due to enfolding of thickened fibrotic visceral pleura with resultant collapse and chronic inflammation of the underlying lung parenchyma [5]. Although it may be associated with pleuritis of any case, asbestos exposure may be the most common cause of rounded atelectasis [3]. Rounded atelectasis is usually found incidentally on chest imaging and not associated with any clinical symptoms. CT criteria used as diagnostic criteria include the following: (1) rounded or oval mass (2.5–7 cm), abutting the peripheral pleural surface, (2) curving “comet tail” of bronchovascular structures passing into the mass, resulting in a blurred central margin, referred to as “comet tail sign,” and (3) thickening of the adjacent pleura or hypertrophy of the subpleural fat with or without calcification, which is usually thickest adjacent to the mass [36, 37].

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Differential diagnoses include lung cancer and clues suggesting rounded atelectasis include the presence of a band connecting the mass to a thickened pleura and its slow evolution—thus highlighting the importance of evaluation of previous imaging for comparison [3]. PET scanning may ultimately be necessary in equivocal cases [5, 37]. Differentiation of this entity from lung cancer is important as it may help prevent unnecessary interventions such as surgical excision, which is associated with considerable morbidity for the patient. Moreover, no specific treatment is required for rounded atelectasis. Diffuse Pleural Thickening

Diffuse pleural thickening has been defined based on CT criteria as follows: (1) Pleural thickening that extends more than 8 cm in craniocaudal direction, (2) extends along 5 cm in axial view, and (3) exceeds 3 mm in thickness [38]. It usually occurs after intense pleural inflammation and consequently is not specific to asbestos exposure. Moreover, given that it develops secondary to pleural inflammation, a history of prior BAPE is commonly seen, in at least 40% of patients [4, 39]. It may also be caused by extension of the interstitial fibrosis to the visceral pleura, consistent with pleural migration of asbestos fibers [3]. Diffuse pleural thickening may be seen in 9–22% of asbestos-exposed workers [3] and is seen after a long latency period (up to 34 years) [39]. Exposures implicated are often short, heavy, and remote suggesting a dose-related response [23, 39]. It affects the visceral pleura causing a diffuse thickening that extends into the interlobar fissures and lung parenchyma (appearing as “ crow’s feet” and causing blunting of the costophrenic angles radiologically) [3]—an important distinguishing feature of diffuse pleural thickening from pleural plaques. Moreover, pleural plaques rarely extend over more than 4 rib spaces [37] as compared to diffuse pleural thickening where the whole lung may be affected commonly [3]. Clinical presentation like that of pleural plaques is usually as an incidental radiologic finding, although shortness of breath and occasional chest pain may be reported rarely [23]. Moreover, hypercapnic respiratory failure, cor pulmonale, and death secondary to bilateral diffuse pleural thickening have also been reported [40]. Pulmonary function tests characteristically show restrictive impairment with relative preservation of diffusing capacity (FVC reduction of 270 ml) [28]. Management in patients with ventilatory failure without significant lung involvement may require decortication [3]. Parenchymal Conditions

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pleural thickening with fibrosis extending into the fissures/ interlobular septa does not constitute asbestosis [3]. As mentioned above, asbestosis is the result of a cumulative exposure to asbestos fibers [17] and, with the restrictions currently imposed in workplaces, is likely to occur less frequently. The American College of Pathologists initially developed grading criteria for severity of asbestosis (Table 20.2), with peribronchiolar fibrosis referred to as grade 1 and partial involvement of the acinus and complete involvement of the acinus was referred to as grades 2 and 3, respectively. Honeycomb remodeling with dilated spaces in the lung parenchyma was referred to as grade 4 [3, 22, 41]. Differentiating factors from other advanced interstitial lung diseases such as usual interstitial pneumonia (UIP) is the presence of fibroblast foci and the absence of visceral pleural fibrosis in UIP.  The presence of interstitial fibrosis along with the demonstration of asbestos bodies is required for the histologic diagnosis of asbestosis [41]. Although histopathology is the best means of establishing the diagnosis, the following criteria are proposed: (1) reliable history of asbestos exposure, (2) appropriate lag time between exposure and detection, (3) evidence of lung fibrosis on the chest radiograph or HRCT scan, (4) restrictive pattern of lung function, (5) bilateral fixed crackles, and (6) clubbing of the fingers or toes, or both. Of these, history of exposure and radiographic evidence is considered essential and the others confirmatory [23, 41]. Clinical presentation is characterized by the gradual development of dyspnea and persistent dry cough. Physical examination shows the presence of bibasilar fine rales, and rhonchi along with coarse crackles may be seen in smokers [3, 23]. Clubbing of fingers may be late manifestations of asbestosis [4, 23]. Pulmonary function tests are usually associated with restrictive impairment with reduction in lung volumes, and decreased diffusion capacity and arterial hypoxemia. Although restrictive dysfunction is the norm in asbestosis, obstructive findings may be seen in some patients, even non-­ smokers, due to associated small airway disease [3]. Official radiographic imaging of asbestos-related lung disease, like that of other pneumoconioses, is evaluated pursuant to guidelines promulgated by the International Labor Organization (ILO), currently utilizing the 2011 revised ediTable 20.2  Histologic grading of asbestosis Grade Grade 0 Grade 1 Grade 2

Asbestosis

Grade 3

Asbestosis is the interstitial pneumonitis and fibrosis caused by inhalation of asbestos fibers. It must be noted that diffuse

Grade 4

Description No evidence of fibrosis Fibrosis centered around respiratory bronchioles Fibrosis extending from respiratory bronchioles into the alveolar ducts Fibrosis extending into walls of the alveoli from the respiratory bronchioles Honeycomb lungs

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tion [6]. A posteroanterior (PA) chest radiograph of the patient is compared with a complete set of ILO standard ­format radiographs and graded for the presence and extent of lung and pleural abnormalities by a trained B-reader. Findings of asbestosis on plain chest radiographs include small nodules, ground-glass opacities, and irregular contours of the cardiac and diaphragmatic silhouette [6]. Co-existing pleural plaques can be evident, particularly when calcified [6]. Computed tomography (CT), particularly high-resolution CT (HRCT), is significantly more sensitive than radiographs for the detection of asbestosis [6, 42–44]. Suggested imaging protocols call for thin sections ≤1 mm reconstructed with an ultra-high spatial frequency algorithm, additional imaging sequence during the expiratory phase of respiration to assess for heterogeneity of the lung parenchyma, and images through the lung bases with the patient in prone position to differentiate fibrosis from dependent atelectasis [43]. The most common HRCT findings of asbestosis include curvilinear subpleural lines of varying lengths ≤1 cm from the pleural surface and parallel to it; subpleural linear, branching or dot-like opacities extending medially from the pleural surface; and mosaic perfusion manifesting as sharply marginated areas of differential lung attenuation during expiration (Fig.  20.3a–d). Honeycombing, defined as clustered small subpleural cystic spaces with thickened walls ≤1 cm in diameter, is seen in advanced cases [6, 42, 43, 45]. Unilateral parenchymal bands are often reported, consisting of 2–5 cm non-tapering linear densities extending from the pleural surface into the lung; some authors have argued that these represent a form of visceral pleural fibrosis similar to rounded atelectasis, rather than asbestosis, as they are present only in association with pleural disease [45]. The distribution of lung abnormalities in asbestosis is predominantly the lower lung zones [43]. Similar findings have been seen with environmental exposure to erionite, a zeolite mineral commonly found in central Turkey and also the western United States that has some properties similar to crocidolite [46]. Distinguishing asbestosis from idiopathic pulmonary fibrosis (IPF) can be challenging but is important, as the diseases have different natural courses and management [42, 43]. Imaging features that favor IPF include traction bronchiectasis, bronchiolectasis within consolidation, and visible intralobular bronchioles in conjunction with subpleural fibrosis [43].

The histopathological features of asbestosis in lung will depend on the time in which the biopsy material is obtained (see Table 20.2). The range of changes in the lung may vary from peribronchiolar fibrosis to full interstitial fibrosis with honeycombing and remodeling of the lung parenchyma that may share features with other interstitial lung diseases. However, the interstitial lung fibrosis present in cases of asbestosis also shows the presence of abundant intra-alveolar macrophages, inflammatory reaction, squamous metaplasia, but, more important, the presence of numerous ferruginous (asbestos) bodies (Fig. 20.4a, b). Asbestosis may remain static or progress. The factors that determine progression of the disease are poorly understood. Progression after cessation of exposure is likely related to cumulative exposure [3]. There is currently no specific treatment for asbestosis [5]. Given the absence of inflammation on histopathology, it is unlikely that antiinflammatory or immunosuppressive medications would be beneficial.

Malignant Conditions Pleural Diseases Malignant Pleural Mesothelioma

Malignant mesothelioma is a rare neoplasm, which arises from the mesothelial surface of the pleural cavity, peritoneal cavity, or pericardium where exposure to asbestos remains the single most important risk factor. Epidemiology, clinical presentation, radiological features, pathology, and management are detailed elsewhere. Parenchymal Diseases Lung Cancer

Although debated, several studies have demonstrated the clear association between asbestos exposure and bronchogenic carcinoma [47], which is amplified in the presence of concomitant tobacco exposure. In an earlier series among asbestos workers, the risk of dying of lung cancer was increased 16-fold if they smoked more than 20 cigarettes/ day, 9-fold if they smoked less than 20 cigarettes/day, compared with workers without a smoking history [48]. This topic has been dealt with elsewhere.

Fig. 20.3  Asbestosis. (a) Chest radiograph shows lower lung predominant reticular opacities and a “shaggy” cardiac silhouette. Lobulated pleural-­ based opacities are more prominent along the left lateral thoracic cage and represent asbestos-related pleural disease. (b) Axial CT image in lung windows in a different patient with asbestosis demonstrates typical findings, including linear, branching, and dot-like subpleural opacities in the posterior lung (large arrow), and a curvilinear subpleural line (small arrows) parallel to the pleura along the anterolateral margin of the lung. An underlying calcified pleural plaque can be seen. (c) Axial CT image in lung windows reveals a more severe case of typical asbestosis findings, with a dense curving parallel subpleural line anteriorly and multifocal linear and branching subpleural opacities (arrows). (d) Axial CT image in lung windows illustrates sharply marginated differential attenuation of the lung parenchyma compatible with mosaic attenuation in a patient with mild subpleural asbestosis

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Fig. 20.4 (a) Pulmonary fibrosis associated with asbestosis, (b) presence of numerous ferruginous (asbestos) bodies in the lung parenchyma

Silicosis

Epidemiology

Introduction

Approximately 1.7 million workers, mostly miners and construction workers, are exposed to respirable silica in the USA [51]. A recent prevalence study of medicare beneficiaries (age >65) reported a 16-year prevalence of 20.1–39.5 per 100,000 during the time period from 1999 to 2014 [52]. Notably though, there was a 3–16% decline from 2007 to 2014. Estimates of disease burden from the state of Michigan in USA also demonstrated a decline in incidence from 3.7 per 100,000 from 1988 to 1997, to 0.7 per 100,000 from 2008–2016 [53]. Mortality from silicosis has declined from age-adjusted mortality of 8.9 per million in 1960s to 0.7 in 2004.

Silicosis represents varying degrees of lung disease caused by inhalational exposure to crystalline silica (silicon dioxide), usually in the form of quartz (present in granite and sandstone). Other forms of crystalline silica include cristobalite and tridymite. Over time, exposure to inhaled silica can cause worsening inflammation and some patients may develop pulmonary fibrosis. Patients with advanced lung disease may progress to respiratory failure and death. Despite efforts at mitigating exposure-related risks, silicosis remains as one of the leading causes for pneumoconiosis worldwide, although the true disease burden remains unclear [49]. The harmful effects of silica were first realized within the United States at Hawk’s Nest, West Virginia, in the 1930s— where a tunnel through a mountain was built by an estimated 2500 workers with drilling and blasting through rock with high silica content with little to no respiratory protection. From among them, 764 workers developed acute silicosis and an estimated 1500 workers developed chronic silicosis. Later on, sandblasting in shipyards, offshore oil rigs, and oil refineries in the gulf coast regions of the USA further resulted in several other victims of silicosis—thus resulting in increased recognition for the harmful effects of silica exposure [50].

 ccupational Risk for Silicosis and Risk O Mitigation Silicosis can develop as a result of exposure in the remote past or ongoing exposure in the current workplace. The risks for silicosis depend on the levels of exposure and the duration for which patient was exposed—the cumulative dose is measured a product of respirable dust concentration multiplied by silica content and expose duration [49]. Traditional industries and activities in which silica exposures occur include mining, foundries, sandblasting, quarrying, tunneling, stone masonry, and construction (Table  20.3). Some

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Table 20.3  Most commonly identified specific tasks and industries with silica exposure Task Drilling, cement, and brick manufacturing Abrasive blasting, sandblasting, casting, and molding Cutting and grinding

Industry Construction, concrete work, quarrying, mining, tunneling, excavation Foundry, boiler scaling, sculpture jewelry, tombstone production, fiberglass, furnace installation, and repair Construction, arts, crafts, and sculpture jewelry

areas that have gained recent attention include exposure related to stone countertop work and sandblasting denim for faded jeans [52]. Earliest efforts at reducing exposure-related risk were put forward by NIOSH/OSHA to regulate exposure limit as a time-weighted average. The 2017 OSHA recommended permissible exposure limit (PEL) for inhalation of respirable crystalline silica is 50 micrograms per cubic meter (50 μg/ m3) as a time-weighted average over an 8-hour shift. NIOSH also recommends use of half-face-piece particulate respirators with N95 or better filters for airborne exposures to silica at concentrations less than or equal to 50 μg/m3. NIOSH has also made available recommended surveillance strategies for different industries, including medical monitoring for symptoms and spirometry.

Pathogenesis The exact mechanism that triggers and drives the process of inflammation and fibrosis due to silica inhalation is not fully established. However, the intensity and duration of exposure likely have a direct impact on severity of lung injury. The pathogenicity also likely depends on the structural and chemical properties of the silica particles. Free uncoated silica is considered more toxic to the alveolar macrophages because of its increased redox potential. When other minerals adhere to the surfaces of silica particles (“coated or combined silica”), it typically elicits a relatively non-fibrogenic response. Silica particles, when inhaled, are deposited in the distal airways and the smaller particles that enter the alveoli may attach to the “scavenger receptors” (macrophage receptor with collagenous structure or MARCO), a process now considered key in recognition and uptake of inhaled silica [54, 55]. Ensuing phagocytosis of crystalline silica in the lung causes lysosomal damage, and release into the cytosol, triggering activating the NALP3 inflammasome [55, 56]. Activation of inflammasome activates proinflammatory cytokines (such as IL-1B and IL-18). This process also generates reactive oxygen species (ROS), similar to the pathway in asbestos exposure [16, 49]. The heightened inflammatory

Table 20.4  Conditions associated with silica exposure and silicosis Condition Rheumatoid arthritis Scleroderma

Remarks Rheumatoid nodules associated with silicosis are frequently referred to as Caplan syndrome Combination of scleroderma with silicosis is termed Erasmus syndrome Higher prevalence of topoisomerase antibodies Associated with increased intensity and duration

SLE ANCA vasculitis Sarcoidosis Chronic kidney Direct nephrotoxicity and autoimmune disease involvement Infections Tuberculosis, non-tuberculous mycobacterial infections, and fungal infections Malignancy Lung cancer

response stimulates fibroblasts to produce collagen and causes development of fibrosis. Growth factors, including transforming growth factor-β (TGF-β), have been implicated in fibrogenesis. The extent of inflammation and fibrosis is not only dependent on underlying molecular and cellular mechanisms, but it is possible that individual genetic susceptibility is a contributor. The innate immune system activation and ensuing inflammation also activate the adaptive immune system, along with breaking of immunologic tolerance—this phenomena is hypothesized to generate autoimmunity through development of antibodies. This likely explains the association of silica with other autoimmune diseases [57] (Table 20.4).

Clinico-Pathologic Types of Silicosis Chronic Silicosis  Chronic silicosis, the most common form of silicosis, follows exposure that occurs over decades rather than years. It is characterized by the development of silicotic nodules—which are nodules with dust-laden macrophages (in the periphery) with or without evidence of concentric fibrosis in the center. Silicotic nodules develop first in the hilar lymph nodes and may be confined to this area; they may become encased in calcification and/or erode into the bronchi. Silicotic nodules involving the lung parenchyma usually present as bilateral upper zone dominant phenomena but may progress to involve other areas as well (Fig. 20.5a–e).

Accelerated Silicosis  Accelerated silicosis is similar to chronic silicosis, but arises from intense exposure of short duration (less than 10 years), causing rapid development of silicotic nodules. These nodules are predominantly cellular with less evidence of fibrosis seen in chronic silicotic nodules (Fig. 20.6a–d).

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Fig. 20.5 (a) Low power view of numerous several silicotic nodules replacing lung parenchyma, (b) silicotic nodule with central fibrosis, (c) higher magnification of extensive fibrosis with a rim of histiocytes, (d)

silicotic nodule without central fibrosis, (e) higher magnification of the silica dust

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Fig. 20.6 (a) CT scan of the chest in a 30-year-old construction worker showing multiple nodules in the perilymphatic distribution and extending into the pleural surfaces, (b) CT scan of the chest in the same patient 3 years later showing dense consolidative findings consistent with

accelerated silicosis, (c) histological section of lung parenchyma showing several intrapulmonary nodules more cellular and without fibrosis, and (d) higher magnification showing a cellular nodule without fibrosis and without prominent silica particles

Acute Silicosis  Acute silicosis, or silicoproteinosis, develops due to exposure to extremely high concentrations of respirable silica, causing development of symptoms within weeks or months. Natural history and clinical manifestations of silicoproteinosis are distinct from the other two types of silicosis—silicoproteinosis presents similar to pulmonary alveolar proteinosis (PAP) [58].

PMF (also known as complicated silicosis) is characterized by large upper lobe areas (nodular lesions >10 mm) of dense fibrosis—which may or may not cause cavitation. These areas of cavitation should prompt suspicion for mycobacterium tuberculosis or fungal pneumonia. Silica is classified as a human carcinogen and silicosis is also considered a predisposing factor for lung cancer [59]. Silicotic nodules may also develop in extra-pulmonary areas such as the cervical and intra-abdominal lymph nodes and, occasionally, in the liver, spleen, and bone marrow.

In patients with chronic silica exposure, the silicotic nodules may coalesce leading to formation of confluent opacities, resulting in progressive massive fibrosis (PMF).

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Clinical Features

Pulmonary Function Tests (PFT)

Patients with silicosis may be asymptomatic and suspected only when characteristic radiographic changes are found incidentally on imaging; or patients may present with varying degree of non-specific respiratory symptoms. Cough and sputum production are common symptoms and usually relate to chronic bronchitis. With deterioration in lung function, patients may have progressive dyspnea. A change in cough, associated with weight loss, or fever, or night sweats should prompt workup for tuberculosis. Symptoms such as hemoptysis or weight loss should forewarn development of lung cancer. Clubbing is unusual in silicosis. Chest auscultatory findings are non-specific. Clinical course depends on severity of lung involvement. For patients with chronic silicosis, respiratory function declines gradually and culminates in oxygen-dependent respiratory failure. Acute silicoproteinosis, on the other hand, can have a fulminant course with rapid progression to respiratory failure and death. Other, less common complications of silicosis include pneumothorax, cor pulmonale, broncholithiasis, and tracheobronchial obstruction from enlarged calcified hilar nodes. As mentioned before, silicosis may predispose to development of tuberculosis and non-tuberculous mycobacterial infections, which also confers increased mortality [60]. If suspected, sputum should be sent for AFB and mycobacterial culture. If diagnosis is unclear, particularly in those with systemic symptoms, bronchoscopy with BAL maybe warranted. If malignancy is suspected, tissue biopsy should be considered.

Spirometry may show obstruction, restriction or both [61]. In patients with severe disease, restrictive changes are dominant. In patients with significant lung parenchymal destruction due to emphysema, a reduction in diffusing capacity of carbon monoxide (DLCO) may be observed. PFT abnormalities in silicosis are, however, non-specific.

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Fig. 20.7 (a) CT scan of the chest in a 62-year-old man with previous occupational history of sandblasting for 5–10 years in the 1970s. Note the egg shell calcification in mediastinal lymph nodes, (b) CT scan

Radiographic Features Chest X-ray can demonstrate bilateral upper zone dominant nodules or changes of progressive massive fibrosis. However, CT imaging is superior for better characterization of silicosis. Early or uncomplicated silicosis presents as small round opacities. Silicotic nodules are typically upper zone predominant and are symmetrically distributed. As it progresses, it can involve other areas of the lung as well. Mediastinal and hilar lymphadenopathy is commonly seen and a pattern of “eggshell calcification” has been described, although is not pathognomonic (Fig. 20.7a, b). When patients develop PMF, there is confluence of nodules to form larger lesions. Nodules may cavitate, in which case, mycobacterial disease, fungal pneumonia, or lung cancer should be considered. The rapid development of several large lesions may be suggestive of underlying rheumatoid arthritis. At times, patients may also have typical pattern of idiopathic pulmonary fibrosis, although with more subpleural homogenous attenuation and less traction bronchiectasis [62]. Silicoproteinosis has distinct findings of diffuse bilateral patchy ground-glass pattern

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with interlobular and interlobar sepal thickening, closely resembling CT findings of PAP. Centrilobular nodules, signifying inhalational exposure to silica, may help distinguish silicoproteinosis from autoimmune PAP.

Diagnostic Approach Silicosis is diagnosed based on exposure history and characteristic radiographic features. Bronchoscopy is usually not required for diagnosis. Detection of silica in BAL may be suggestive. BAL may also assist with ruling out tuberculosis. Lung biopsy allows confirmation diagnosis in doubtful cases but also facilitates distinction of advanced silicosis or PMF from an alternate diagnosis. Tissue biopsy also enables ruling out concurrent lung cancer. Histopathology specimens of lungs of patients with silicosis may also demonstrate the features chronic bronchitis and emphysema.

Management Silicosis is a preventable disease that is incurable. Therefore, much of the effort in the area of silicosis has been rightfully targeted toward mitigation of exposure-related risk. The decrease in prevalence and reduction of mortality is the result of occupational surveillance and safety strategies adopted and implemented by the NIOSH (National Institute for Occupational Safety and Health) with OSHA. Employers are also required to implement strategies for medical monitoring of silica-exposed workers. Surveillance includes a history (including occupational history), physical examination, chest X-ray, and pulmonary function test. All subjects with silicosis should have a TB skin test or an interferon-γ (IFN-­ γ) release assay to rule out latent TB. After the initial examination, clinical follow-up must be offered at least every 3 years or earlier as needed. If there is evidence for latent TB, treatment should be initiated. In terms of management, early recognition and stalling further progression by avoidance of further exposure is key. Unfortunately, majority of cases are diagnosed when there is evidence for pulmonary fibrosis and it is considered irreversible. Silicosis may progress even without further exposure. For patients with bronchitis type symptoms, symptomatic support with bronchodilators may be considered. Corticosteroids have no major role in treatment. In advanced cases, patients may develop oxygen-dependent respiratory failure and cause death. For acute or accelerated silicosis, there is potential use of whole lung lavage to remove silica from the lung [63, 64]. However, whether this is significantly beneficial is still not clear. In selected patients, lung transplantation may be considered.

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Hard Metal Lung Disease Introduction Jobs and Ballhausen first described hard metal disease in 1940 in Germany among workers exposed to hard metals, where they showed 8 of 27 workers developed radiographic evidence of reticulation [65]. Studies by Moschinski et  al. [66] and Fairhall et  al. [67] confirmed these findings [68]. Hard metal is different from heavy metal (e.g., lead, chromium, cadmium, mercury) and is produced by compacting powdered tungsten carbide with cobalt (between 3–25%) in a process called sintering which is then heated to approximately 1500 °C rendering it very hard and thus making it suitable for sharpening metals, drills, and polishing hard metal parts [68] to precise dimensions, including diamonds and dental prostheses. Moreover, it is used in varying amounts to make coolants, which when aerosolized is easily inhaled— thus causing downstream effects within the airways and lungs [68, 69]. Hard metal lung disease is a rare disease, even in patients at occupational risk—with most of the medical literature consisting of case reports and case series. Indeed, several cross-sectional studies done among workers exposed to hard metals have found incidence varying from 0 to 0.7% [70–72]. Exposure to hard metals has been implicated in the development of at least three conditions involving the respiratory tract: (1) occupational asthma, (2) hypersensitivity pneumonitis, and (3) interstitial pneumonitis. The term hard metal lung disease generally refers to interstitial pneumonitis caused secondary to hard metal exposure [68].

Pathogenesis Although initially unclear, there is now overwhelming evidence that the small amount of cobalt used in hard metals is responsible for the lung injury caused. This was initially shown in animal models, where bronchiolitis and metaplastic changes in the alveoli were seen only after inhalation of pulverized cobalt, and not with tungsten carbide or titanium [73]. Moreover, observation of interstitial fibrosis in diamond polishers who used high-speed cobalt polishing disks further confirmed these findings [68, 74]. Of note, cobalt is not seen in significant amounts within lung tissue on biopsy given the highly soluble nature and tungsten carbide is seen in much larger amounts within the lung—but it does not cause any lung pathologies and may serve as a marker of exposure to hard metal [68].

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Cobalt-related lung injury is believed to occur through two main mechanisms: (1) an immunologic mechanism and (2) oxidant injury mechanism. The immunologic mechanism postulates that the adaptive immune response by the host to cobalt is primarily responsible for the development of lung disease, which is characterized by formation of granulomas, similar to hypersensitivity pneumonitis. Genetic factors likely play an important role as well, as it develops only in a small percentage of exposed workers, and lacks a linear dose- response relationship. The oxidant injury mechanism is postulated to be secondary to the production of activated oxygen species by cobalt, which may be enhanced by tungsten carbide [75].

Clinical Features Occupational asthma is secondary to an allergic response and is characterized by wheezing, cough, and shortness of breath. This may be accompanied by itching, upper airway symptoms such as sore throat, nasal congestion, and sneezing, all of which improve following removal from the workplace and recur on return to work—underlying the importance of an elaborate elicitation of occupational exposure when evaluating patients with shortness of breath. Moreover, it develops after a latent period of 6 to 48 months of continued exposure [68, 75]. Hypersensitivity pneumonitis (HP) and hard metal lung disease likely represent a continuum of lung pathologies elicited by exposure to hard metals—which presents initially as a subacute form that progresses to a chronic form with continued exposure. Thus, initial episodes of pneumonitis may result in intermittent episodes of fever, anorexia, and shortness of breath (HP episodes), commonly attributed to a

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viral respiratory infection—that resolve when taken off work and recur with return to work. Over time, with continued exposure, there is gradual attenuation of these acute episodes which progress to persistent shortness of breath with exertion, secondary to the development of interstitial fibrosis as seen in hard metal lung disease [68, 69, 75].

Radiology Chest radiograph show airspace and reticular opacities bilaterally. High-resolution thin section CT findings of hard metal pneumoconiosis are variable and non-specific. CT findings include bilateral consolidative or ground-glass opacities in a panlobular or multilobular distribution, associated with reduction in lung volume, parenchymal distortion, and bronchiolectasis. Centrilobular micronodules are often bronchiolar lesions. Reticular opacities in the periphery of both lungs can be seen and interstitial fibrosis can manifest as honeycombing. Small branching areas of hyperattenuation are consistent with peribronchiolar lesions caused by the inhaled dust [76]. In a review of 19 patients with HMLD [77], centrilobular nodules, GGO, reticular opacity, and traction bronchiectasis were observed in 16 (84.2%), 16 (84.2%), 5 (26.3%), and 4 (21.0%) cases (Fig. 20.8a, b). The majority of patients with HMLD are expected to respond favorably to corticosteroid treatment with improvement in centrilobular nodules and GGO. However, fibrotic changes such as reticular opacity and traction bronchiectasis on CT (seen in 20–30% of patients with HMLD) were predictive of the resistance to corticosteroid treatment and poor prognosis of patients with interstitial lung diseases [78].

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Fig. 20.8  Hard metal pneumoconiosis. (a) CT shows micronodules in the upper lungs. (b) CT in the lung bases shows peripheral ground-glass opacities (arrows). Micronodules and ground-glass opacities improved following corticosteroid treatment

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Diagnosis

Bronchoscopy

As mentioned above, the diagnosis of any pneumoconiosis involves a detailed evaluation of exposure to any agent known to cause interstitial lung diseases, which will need a complete occupational history given the long latency of several of these diseases, and exclusion of other causes of ILD. Within this context along with consistent radiographic and pulmonary function abnormalities, a diagnosis of pneumoconiosis can be made with reasonable certainty [79]. Thus, understanding of occupations associated with hard metal exposure is of utmost importance (Table 20.5) [75, 80].

Bronchoscopy with broncho-alveolar lavage (BAL) may be particularly helpful to make a diagnosis. Although BAL findings are relatively non-specific, an increase in cellularity with increased neutrophils, lymphocytes [68], and rarely eosinophils is seen [78, 84], along with the characteristic multinucleated giant cells with emperipolesis (presence of inflammatory cells within cytoplasm, surrounded by clear space), referred to as cannibalistic giant cells [78, 84]. Presence of significant number of these giant cells precludes the need for biopsy, within the appropriate clinical context with characteristic clinical and radiological findings [75].

Pulmonary Function Test Obstructive ventilator defect or a mixed obstructive and restrictive defect [75] is seen if occupational asthma is present. Methacholine challenge testing if performed has a high negative predictive value to exclude occupational asthma. Care, however, should be taken to ensure that the test is done at work, or within 2 h [81]. Restriction along with decrease in diffusion capacity is seen in the subacute (HP) and chronic forms of hard metal lung disease [68, 75, 82].

Laboratory Tests A cobalt lymphocyte proliferation test was developed to simulate the beryllium lymphocyte proliferation test, which is used to diagnose berylliosis; however, this test has only demonstrated positive results in occupational asthma and contact dermatitis secondary to cobalt exposure [75, 77, 83]. In cases where occupational history cannot be clearly ascertained, laboratory testing of serum (Normal range: 0.1–0.5 mcg/L) or urine (90 mmHg, nitrogenated urea >40 mg/dL or creatinine >1.5 mg/dL, HBV, arteriographic abnormalities, or biopsy of a medium or small artery with polymorphonuclear leukocytes [106]. This criteria combine clinical, angiographic, and biopsy findings. When suspected, biopsy of an involved organ should be performed.

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Fig. 21.4 (a) Polyaerteritis nodosa involving a medium size vessel, (b) higher magnification showing partially obliterated lumen by a fibrinoid necrosis and inflammatory reaction around the full thickness of the vessel

Histological sections show the presence of a medium size vessel partially obliterated by fibrinous exudate admixed with inflammatory cells, while in the periphery of the vessel it is possible to observe the presence of an inflammatory infiltrate involving the thickness of the vessel (Fig. 21.4a, b).

relapse, specifically with azathioprine or cyclophosphamide [108]. Presence of underlying disease, such as HBV, also changes management. For mild HBV-PAN, antivirals alone could be trialed first without other immunosuppressants [96].

Laboratory Data No specific laboratory markers are diagnostic of PAN.

Prognosis and Conclusion

Imaging PAN has a characteristic pattern on angiography of arterial microaneurysms that resemble beads. CT or MR angiography is a more accessible and easier means of diagnosing PAN, but both have a lower sensitivity and specificity than conventional angiography [107]. Adams et  al. suggest that once PAN is diagnosed, imaging of the chest should be performed to screen for bronchial artery aneurysms [1].

PAN has a very poor prognosis without treatment, with 5-year survival of only 13%, increasing to 80% with treatment [97, 100]. HBV-PAN portends a worse prognosis than non-HBV-associated PAN [97]. Poor prognostic factors include age >65 years, gastrointestinal or cardiac involvement, or renal insufficiency [109].

Management

Introduction

The severity and extent of PAN dictates the management. For PAN without poor prognostic factors, corticosteroids could be an adequate first-line treatment, although about 40% of patients required additional adjunctive therapy after

Necrotizing sarcoid granulomatosis (NSG) is an exceedingly rare type of vasculitis that is usually confined to the lungs and is a diagnosis of exclusion [110]. It is characterized by sarcoid-like granulomas, granulomatous vasculitis,

Necrotizing Sarcoid Granulomatosis

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and a variable amount of necrosis [111]. When initially described by Liebow in 1973, the question was posed whether "the problem is whether the disease represents necrotizing angiitis with sarcoid reaction, or sarcoidosis with necrosis of the granulomas and of the vessels” [112]. This has been called into question over the decades, but still remains controversial [113]. One thing that all agree on is the need to exclude a variety of other diagnoses, including of infectious (bacterial, fungal, parasitic, and viral infections) and noninfectious (chronic granulomatous disease, lymphoma, drug-induced granulomas, foreign body granulomatosis, and chronic granulomatosis with polyangiitis) etiologies.

Incidence and Risk Factors NSG has been described most commonly in persons between 40 and 50 years of age and can be asymptomatic in 20–25% of cases [113, 114].

Pathogenesis The exact etiology of necrotizing sarcoid granulomatosis, just as that of sarcoidosis, is not well understood, but is thought to involve systemic inflammation that forms granulomas [115]. a

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Clinical Presentation Typically described in the lungs, necrotizing sarcoid granulomatosis has also been described to involve the eyes, the central nervous system with symptoms such as headaches, hemiparesis, and ophthalmoplegia, and the liver [116, 117]. The symptoms are most commonly mild and include cough, chest pain, and dyspnea. Constitutional symptoms also occur and include fever, weight loss, and malaise.

Pulmonary Disease Lung Parenchyma Bilateral solitary or multiple parenchymal nodules, often with hilar adenopathy, are the most common lung manifestations of NSG.  In addition, other cases have been reported with larger masses, cavitation, pneumothorax, and organizing pneumonia [111, 118]. In other words, these pulmonary findings typically need further investigation and usually a biopsy with a pathologic diagnosis. On histological examination, extensive areas of the pulmonary parenchyma are replaced by the presence of a florid granulomatous inflammation in a haphazard pattern. The granulomas in some areas are separated by fibrous tissue. However, in some of those granulomas, it is possible to identify the presence of numerous multinucleated giant cells and areas of necrosis (Fig. 21.5a, b).

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Fig. 21.5 (a) Necrotizing sarcoid involving lung parenchyma, (b) granulomatous inflammation with presence of multinucleated giant cells

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Diagnostic Evaluation

Incidence and Risk Factors

Laboratory Data An elevated erythrocyte sedimentation rate or C-reactive protein is common, but other laboratory evidence of organ dysfunction is typically absent, unless it involves a specific organ in its presentation, such as the liver [114, 116]. Other markers of other vasculitic diseases, such as antineutrophil cytoplasmic antibodies, are also lacking. Interestingly, serum calcium and angiotensin-converting enzyme levels are also normal.

Kawasaki Disease has been reported globally, but there’s a strong geographic and ethnic predominance. The highest incidence is in Japan and has been noted to be rising from 218.6 per 100,000  in 2008 to 330.2 per 100,000  in 2015 [125, 126]. Other countries with high prevalence include China, Korea, and Taiwan. In North America, overall KD incidence is 17 per 100,000 population, with Pacific Islander and Asian populations almost twice that at 30 per 100,000 [127]. The lowest incidence is among Caucasian populations at 9 per 100,000 children [124]. In Europe, rates of KD are around 5–10 per 100,000 children [124]. Of note, those of Asian heritage have higher rates of KD, attesting to the fact that there must be genetic susceptibility in the child exposed to the predisposing factors. KD is seen most among children 15,000 per mm3, low hemoglobin (36 h after IVIG administration [150, 151]. In addition, the incidence of incomplete KD is also higher in that age group, rife with a delayed diagnosis and therefore a higher rate of complications. All infants must be followed with serial echocardiograms, as some develop CAAs after an initially normal echocardiogram [152]. The principal cause of death is myocardial infarction from an acute coronary artery occlusion, but the case mortality rate in the United States and Japan is low at 0.2% [123, 153].

I solated Pauci-immune Pulmonary Capillaritis Introduction Isolated pauci-immune capillaritis (IPPC) is a small-vessel vasculitis that is localized to the lung with no other clinical or serologic markers of a systemic disease. It was first described by Nierman and colleagues in 1995 when they described a patient with fulminant respiratory failure caused by pulmonary capillaritis without alveolar hemorrhage and no other systemic disease [154]. Subsequently, Jennings and colleagues described a case series of patients with biopsy-­ proven isolated pulmonary capillaritis without any other clinical, serologic, or histologic evidence indicating an associated systemic illness [155].

Incidence and Risk Factors Isolated pauci-immune pulmonary capillaritis has been theorized to be a subset of microscopic polyangiitis (MPA), but is typically negative for auto-antibodies such as antineutrophilic cytoplasmic antibodies (ANCAs), bringing this theory into question [156]. Given its rarity and lack of robust literature, the true incidence of IPPC is difficult to surmise. Within the reported case series by Jennings et al, the median age of onset was 30 years, lower respiratory tract symptoms were universal, and most patients also had upper respiratory tract symptoms. Half of the patients required mechanical ventilation [155].

Pathogenesis Etiology of isolated pauci-immune pulmonary capillaritis) is not well understood. Histologically, IPPC is characterized by a neutrophilic infiltrate of the alveolar septa, loss of capillary structural integrity, and erythrocyte infiltration in the alveolo-­

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finding of immune complexes within those cases implies a systemic rather than a localized disease [160].

Diagnostic Evaluation A diagnosis of isolated pauci-immune capillaritis should be made based on clinical, radiologic, and laboratory findings, or lack thereof for the latter. In addition, given the myriad of other systemic causes of pulmonary vasculitis that may require different treatment and have a worse prognosis, lung biopsy to rule out other disease entities may be prudent.

Fig. 21.6  Alveolated areas of lung parenchyma with capillaritis

interstitial spaces (Fig.  21.6). Specifically, the destroyed alveolar-capillary basement membranes allow the infiltration and accumulation of RBCs in alveolar spaces [157, 158].

Clinical Presentation It is important to understand isolated pauci-immune pulmonary capillaritis in the context of diffuse alveolar hemorrhage (DAH), as it is one of the more common causes of DAH associated with capillaritis. DAH is a clinicopathologic syndrome that implies bleeding from the lung, and specifically the accumulation of intraalveolar red blood cells (RBCs) that originate from the alveolar capillaries [157]. DAH is a syndrome of hemoptysis, anemia, diffuse alveolar opacities radiographically, and hypoxemic respiratory failure. At the same time, about a third of patients do not present with initial hemoptysis), and the drop in hemoglobin may not be impressive or noteworthy. In addition, DAH can also have unilateral alveolar opacities, requiring an astute clinician to have a high index of suspicion for DAH [159]. Pathologically, DAH necessitates the accumulation of RBCs and fibrin in the alveoli with presence of hemosiderin-laden macrophages. Numerous etiologies of DAH exist, which have been placed into the following broad categories: pulmonary capillaritis, bland pulmonary hemorrhage, diffuse alveolar damage, and miscellaneous [157]. The details of most causes are discussed elsewhere in this chapter and textbook. Pulmonary capillaritis is the most common reason for DAH, and in some series, what has later been labeled isolated pauci-immune pulmonary capillaritis was the most common among pulmonary capillaritis syndromes, although controversy exists whether the

Laboratory Data IPPC is a diagnosis of exclusion. Other causes of pulmonary capillaritis must be ruled out, including other systemic vasculitides and connective tissue diseases (CTD), among others. In addition, other causes of diffuse alveolar hemorrhage must be sought out. An excellent history must be taken to search for any clues pointing to difficult-to-ascertain causes such as exposures and ingestions. Many of the other entities on the differential diagnosis may have laboratory data supporting them, and those investigations should be carried out carefully. These include but are not limited to basic labs including a blood count with differential (eosinophilic lung diseases), an infectious work-up with cultures and specific labs, a rheumatologic lab panel looking for CTD, and autoantibodies looking to identify other causes of pulmonary vasculitis.  ronchoscopy and Lung Biopsy B Bronchoscopy is mandatory in most cases of suspected DAH, especially when no hemoptysis is present. Classically, DAH is clinically dependent on obtaining a progressively bloodier bronchoalveolar lavage aspirate, which is expected on pathology to show hemosiderin-laden macrophages, although these may take up to 48–72 h to accumulate after the bleeding event [157]. Up to 10% of patients with) Goodpasture syndrome may present with DAH only and no renal involvement, making this presentation identical to isolated pauci-immune pulmonary capillaritis. In this case, a surgical lung biopsy with immunofluorescence studies may distinguish the two different diseases [157]. Imaging Imaging of isolated pauci-immune capillaritis is indistinguishable from that of any other cause of DAH. Classically, a chest radiograph will show bilateral alveolar-filling opacities that likely represent hemorrhage and inflammation but may also be normal. CT of chest is more sensitive for both ground glass opacities as well as more prominent alveolar filling consolidations. In addition, cardiac evaluation is necessary to ensure that pulmonary hemorrhage is not from a cardiac cause such as congestive heart failure from cardiomyopathy or valvular pathology.

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Management Given the paucity of data, there are no specific clinical guidelines for treatment of IPPC.  Traditionally, isolated pauci-­ immune capillaritis has been treated like ANCA-associated vasculitis with glucocorticoids and cyclophosphamide. Recently, some cases have been reported where other agents and treatment modalities have been used successfully, including rituximab, mycophenolate, hydroxychloroquine, azathioprine, and plasmapheresis [161, 162]. As with adults with ANCA-associated vasculitis in the RAVE trial, rituximab is gaining more traction in both induction and disease relapse [162, 163].

Prognosis and Conclusion Jennings and colleagues found that prognosis of IPPC was favorable when compared to DAH occurring in the setting of a systemic vasculitis or a collagen vascular disease [155]. Due to the paucity of reported cases, definitive prognostic indicators and mortality conclusions are difficult to draw, although there have also been reported cases of fulminant respiratory failure and death [158].

Part II: Granulomatosis with Polyangiitis Introduction Granulomatosis with polyangiitis (GPA) is a systemic connective tissue disease, which was first described in the medical literature in a clinical case report in the late nineteenth century, and later formally described in 1936 as a triad by Friedrich Wegener. GPA is an autoimmune condition of necrotizing vasculitis of small- to medium-sized vessels (capillaries, arterioles, venules, arteries) and is usually associated with antineutrophil cytoplasmic antibodies (c-ANCA) directed against the neutrophil serine protease proteinase-3 (PR3) [164]. Clinically, upper and lower respiratory tract symptoms are frequently seen and renal involvement is quite common. However, the disease can have variable additional systemic symptoms, ranging from central nervous system involvement to cardiac and gastrointestinal tract disorders.

Incidence and Risk Factors Annual incidence of GPA is 5–10 cases per million population with equal frequency in males and females. It is very rare in childhood and young adults. Reported peak incidence of GPA is in the 7th decade of life between the ages of 65 and 70 years. Prevalence of GPA ranges between 24 and 157

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cases per million with a higher prevalence in Caucasians, especially in Northern European countries [165].

Pathogenesis Genetic predisposition to ANCA associated vasculitis (AAV) has been studied and familiar association studies report a 1.56 increased relative risk of developing GPA in people who have a first-degree relative with GPA. People who are genetically predisposed to this autoimmune disease may have a trigger from infectious, environmental, chemical, toxic, or pharmacological triggers [166, 167]. Generation of ANCA against proteinase 3 is present in approximately 80% patients with GPA, but can be as high as 95%. Presence of ANCA against myeloperoxidase (MPO) is seen in approximately 10% of cases. However, it is important to remember that up to 20% of cases may be ANCA negative and follow an atypical course. These cases pose a diagnostic challenge [168]. Current studies of pathogenesis of AAV based on mouse models propose that pro-inflammatory pathways are activated in the presence of ANCA.  Neutrophils and monocytes generate and release reactive oxygen species, proteases, cytokines, and neutrophil extracellular trap (NET) products [169, 170]. This ANCA-associated autoimmune response is thought to be enabled by impaired T and B-cell suppression. Regulatory T-cells (with suppressive functions) may be dysfunctional in patients with ANCAassociated vasculitis [171]. B-cells with high expression of CD5 have regulatory capabilities, but these appear to be decreased in patients with ANCA-associated disease [172]. ANCA-activated neutrophils may also lead to enhanced production of ANCAs by stimulating B cells. These proinflammatory factors exacerbate disease, leading to activation of complement pathways causing vascular inflammation and clinical symptoms. Both GPA and eosinophilic granulomatosis with polyangiitis (EGPA) have granuloma formation, which is thought to be an innate inflammatory response to acute extravascular inflammation triggered by ANCA-induced neutrophil activation. Alternatively, granulomatosis may be caused by an antigen-specific type IV adaptive immune response [173].

Clinical Presentation The Chapel Hill criteria define GPA as a necrotizing granulomatous inflammation of both upper and lower respiratory tracts, and necrotizing vasculitis of small- and medium-sized vessels [174]. GPA may be divided into different forms, depending on the extent of disease. The limited form has lesions in the upper and/or lower respiratory tract, without

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other organ lesions. The early systemic form has lesions beyond the respiratory tract, but no significant organ dysfunction is present. The generalized form has symptoms of impending organ failure. The severe generalized form carries symptoms of renal or other organ failure. The disease may also be resistant to treatment [168]. Patients may present with limited disease or constitutional symptoms of disease such as general malaise, myalgias, arthralgia, anorexia, weight loss, and pyrexia. Skin lesions are not characteristic and may be observed in a majority of forms of vasculitis. Cutaneous signs such as leukocytoclastic vasculitis, digital infarcts, purpura, cutaneous ulcers, and gangrene may be seen [175]. Mucocutaneous and orbital manifestations of active GPA include oral ulcers, oral granulomatous lesions, scleritis, and orbital granulomatous masses. A typical symptom of GPA-­ related ophthalmic involvement includes inflammatory infiltrations inside the orbital cavity [176]. Orbital infiltration may be associated with treatment resistance, a higher risk of recurrence, and predisposition for local destructive lesions and complete vision loss. Ear nose throat (ENT) manifestations are quite common with sinusitis being the most common symptom associated with GPA [177]. One may see nasal discharge or impaired nasal patency. An initial misdiagnosis of sinusitis is common. Nasal granulomatous lesions and parasinus and sinus inflammation are common; however, nasal polyps are not. Polyps are more common in EGPA. A detailed ENT examination with endoscopy of the nose and paranasal sinuses is advised, and imaging, including computed tomography of the sinuses, is helpful [178].

Pulmonary Disease Airway Disease When the larynx and trachea are involved, symptoms of cough, dyspnea, and stridor may be present. On endoscopy, tracheal lesions and tracheal stenosis can be seen. Softening of the trachea and bronchi may also lead to fistula formation. Patients with lower respiratory tract involvement in the initial stages can make up to 50% of patients. The most commonly seen pulmonary lesions are nodules and masses, but cavitation and necrosis can be common. Consolidation and thickening of bronchial walls is also noted. The most frequent pulmonary findings seen are pulmonary nodules, ground glass opacities, and patches of consolidation [179]. Pulmonary nodules are often bilateral and can be associated with cavitation. Complications after cavitation can include fungal ball or fistula formation. Up to 15–30% of cases can have tracheobronchial involvement [168]. Abnormalities can include tracheal stenosis, bronchial stenosis, and ulcerations in the tracheobronchial tree. Lung masses

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with organized pneumonia may be seen as well. Alveolar hemorrhage is a prominent pulmonary manifestation of GPA, occurring in around 5% of patients and can be the ­presenting finding [180]. Mediastinal or hilar lymphadenopathy can be present, but is rarer than other pulmonary manifestations. Diffuse alveolar hemorrhage associated with bilateral ground glass nodules and renal failure, or pulmonary-renal syndrome (PRS), may present with diffuse hemorrhage in varying degrees [181]. C-ANCA related PRS is a common manifestation of the disease. In patients with renal disease, pathology shows pauci-immune crescentic necrotizing glomerulonephritis and patients can have hematuria, proteinuria, cellular casts on urine cytology, and renal impairment. Renal dysfunction manifestations for the patients could include acute kidney injury, eventually progressing to chronic kidney disease or even end-stage renal disease requiring renal replacement therapy.

Diagnostic Evaluation Initial diagnostic evaluation should include a thorough history, along with laboratory diagnostic data, radiology, and eventually biopsy of an involved organ. Lab data may show high levels of circulating inflammatory cytokines [173]. Specific clinical manifestations with systemic signs suggestive of a vasculitis may point to the diagnosis, including positive ANCA serology and histological evidence of necrotizing vasculitis, and/or granulomatous inflammation of an organ system. It is important to recognize that ANCA positivity is not essential for diagnosis, and severe forms of GPA with high clinical suspicion should be treated with life-­ saving immunosuppressive therapy even while awaiting ANCA results. One of the scores that may be used to delineate vasculitis severity is the Birmingham vasculitis activity score (BVAS score). Severity categories of GPA are mild, moderate, severe, or life-threatening, depending on extent of organ involvement [182, 183]. In pulmonary disease, pulmonary function tests, bronchoscopy, and lung imaging (including high-resolution computed tomography (HRCT)) are important. Bronchoscopy allows visualization of ulcerative bronchial lesions, stenoses, and fistulas. Bronchoalveolar lavage can also help identify secondary infections. Lung function testing can show airway obstruction, and rarely restriction. The most frequent lung function abnormality is a reduced lung carbon monoxide diffusing capacity (DLCO).

Diagnostic Imaging GPA usually affects both lungs but can also be unilateral. There is no zonal predominance, although the lung apices tend to be spared [184].

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Fig. 21.7  A patient with granulomatosis with polyangiitis and painful mouth sores and fever. (a) Chest radiograph frontal view shows several bilateral faint nodular opacities (arrows) and a dominant patchy consolidation in the left infrahilar region. (b) CT reveals nodular lesions

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with a dominant mass-like consolidation in the left lower lobe medially. The contours are indistinct and, in some cases, surrounded by ground glass halo

Chest Radiography In most patients with GPA, the chest radiograph is abnormal. In a study of 35 patients, pleural and parenchymal pathology was detected in chest radiographs in up to 57% of the patients and on HRCT in a little over 85% of patients [185]. The most common presentation is ill-defined medium-­ sized nodular opacities (Fig.  21.7a, b). However, a wide range of sizes may be seen [184, 186]. Nodules are seen in up to 70% of patients at the onset or during the course of the disease [187–189]. Nodule spiculation and air bronchograms are frequently described. Mild lucencies associated with necrotizing change or overt cavitations are also commonly reported [188, 190]; however, cavitation may not be as easily identified on chest radiograph [184]. The cavitary changes tend to occur in untreated patients. The nodules may also occasionally calcify [184]. A reticulonodular appearance on radiography reflects diffuse micronodularity. Another common manifestation is consolidation, which can be isolated or coexist with the nodular lesions. The airspace opacities can be focal or regional but also bilateral and diffuse (Fig. 21.8). The latter especially can be seen in the setting of underlying alveolar hemorrhage. Both nodules and Fig. 21.8  A patient with granulomatosis with polyangiitis and hemopconsolidative opacities tend to wax and wane. Small to mod- tysis. Chest radiograph frontal view shows consolidation in the right erate pleural effusions may coexist [184]. lung with ill-defined contours in a background of coalescent nodularity. CT and HRCT CT may reveal lesions that are occult on chest radiograph and helps to better identify necrotizing features [184, 185, 190]. The abnormalities encountered on CT reflect the various pathologic findings, including alveolar hemorrhage, pneumonia-like fibrinous exudation, and necrotizing granulomatous vasculitis [184].

The left lung although less involved does demonstrate vague hazy opacities, in some cases with nodular configuration (arrows)

Nodules and Masses The presence of nodules and masses is the hallmark in GPA patients. The macro-nodules predominate in active pulmonary disease and can be as large as 10 cm. Less commonly the nodules can be due to inactive disease [190].

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Fig. 21.9  A patient with granulomatosis with polyangiitis, chest pain, and fever. (a, b) CT Chest with contrast lung window axial views through the mid and lower lungs, respectively. Multiple large nodules and masses are seen, some of them with irregular spiculated contours

Spiculation, a frequent feature in GPA lesions, is not typically found in pulmonary infarcts, septic emboli, or metastases, hence may be helpful to distinguish GPA from these conditions [191] (Fig. 21.9a, b). The nodules may about any portion of the pleura and invade the fissures [186]. Radiating linear scarring and pleural tags are common [187]. A “feeding vessel” leading to a nodule or mass indicates the angiocentric nature of the disease [192] (Fig. 21.10). Cavitation is seen anywhere from 22% to 50% of the patients [188, 192]. Cavities typically occur in nodules larger than 2 cm in diameter and tend to be thick-walled with irregular inner margins [184, 190, 192, 193] (Fig. 21.11a, b). In a study of 225 patients, cavitations in the nodule had no impact on survival but were commonly associated with relapse in comparison to solid nodules or no imaging evidence of ­nodules [194]. Occasionally, a solitary nodular lesion resembling lung cancer may be found [195]. In addition to nodules, the “halo” sign or “atoll” (reverse) halo sign may occur (Fig. 21.7). These two signs could favor GPA, however are not specific of the disease [187, 196, 197]. The halo sign, a solid nodule with a halo of ground glass, is due to perilesional hemorrhage. The reverse halo sign, a ground glass center with a peripheral solid rim, represents organizing pneumonia surrounding a focus of hemorrhage [198]. Diffuse nodularity is less commonly seen. The distribution tends to be random [187]. However, peribronchovascular, subpleural, and rarely centrilobular patterns have also been described [192, 199].

 round Glass Opacities and Consolidation G Ground-glass attenuation and consolidation are the second most described feature in GPA.  They can be patchy, geo-

Fig. 21.10  A patient with granulomatosis with polyangiitis and microscopic hematuria. CT lung window through the upper lobes demonstrates a few small indistinct subpleural nodules (small arrows). The nodule in the left upper lobe demonstrates the “feeding vessel” sign (large arrow) indicative of the angiocentric distribution of the disease

graphic, or diffuse (Fig.  21.11). The ground glass changes may reflect inflammatory alveolitis, infection in patients receiving treatment for GPA, alveolar hemorrhage, or capillaritis and necrotizing microangiitis [186–188, 192, 200–202]. The consolidations can be multilobar, lobar, or segmental, with or without necrosis [200]. Wedge-shaped areas of peripheral consolidation abutting the pleura may mimic pulmonary infarcts. In some cases, consolidation displays a peribronchial distribution [184, 190, 192, 193, 201, 203]. This may be explained by underlying extensive peripheral airway involvement noted in some cases on histopathology [204]. Consolidation associated with organizing pneumonia can also be a manifestation of GPA [205]. Diffuse alveolar hemorrhage (DAH) is more commonly the cause of bilateral and diffuse consolidation [200]

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Fig. 21.11  Granulomatosis with polyangiitis. (a) CT axial image lung window through the lung apices. There are two large cavities with thick walls in the right apex. Note curvilinear band atelectasis/scar in the left apex due to relative chronicity. (b) Axial image through the mid lung

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zone. An additional thick-walled cavity is seen in the left upper lobe. Several nodular lesions are present in the right upper lobe along with focal patchy ground glass changes. There is a small left pleural effusion (*in b)

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Fig. 21.12  A patient with granulomatosis with polyangiitis and acute diffuse alveolar hemorrhage. (a, b) CT lung window axial image through the upper and mid lung zones, respectively. Multifocal exten-

sive dense segmental and lobular airspace and ground glass opacities with air bronchograms are depicted

(Fig. 21.12a, b). The acute phase of diffuse alveolar hemorrhage reveals lobular or lobar areas of ground-glass opacity or consolidation. The ground glass changes represent the partial alveolar filling hemorrhagic changes. These are often associated with the “dark bronchus” sign, which relates to conspicuity of the intervening airways.

active disease on imaging is limited and often requires clinical and bronchoscopic confirmation [188, 190].

 ands and Linear Opacities B Complex bands have been more commonly described as sequela of previous active disease and secondary to fibrotic changes found in pathology specimens after therapy or reparation [190] (Fig. 21.11). In some cases, however, activity in areas of band-like opacity may persist [188]. Both pulmonary nodules and band opacities overlap at various stages of the disease from acute to chronic, in a way that prediction of

Additional Findings Nonspecific findings less frequently described in patients with GPA include thickened interlobular septae, fibrotic changes of parenchyma, such as traction bronchiectasis intermingled with ground glass opacities and small cysts [185, 188]. Complications such as pneumothorax and bronchopleural fistula have also been described [206]. Although not specific, pleural thickening is not uncommon in GPA patients. It may result either from previous effusion, described in as many as 25% of the patients with GPA [190, 192, 198, 200, 201, 203], or represent cicatricial changes resulting from nodular inflammatory lesions [188, 190].

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The large arteries are rarely involved in GPA. If the pulmonary arteries are affected, distinction from chronic pulmonary embolism may be challenging. Vessel dilatation, obstruction, stenosis, and luminal irregularity can be seen [207]. Direct arteriolar involvement may result in centrilobular nodularity appearance [199]. Hilar or mediastinal lymph node enlargement is reported to be rare [184, 193]. In a series of 57 patients, hilar or mediastinal lymph node enlargement was seen in 14% of patients [188].

Evolution Over Time The pulmonary nodules, identified at presentation, may regress without scarring in the majority of cases [188, 200]. They may recur when cytotoxic therapy is discontinued or after a period of remission without drug therapy [184]. Patients on maintenance therapy are also prone to relapse, and the nodules can undergo cavitation during flare [184]. In other cases, the nodular lesions do not necessarily improve with clinical disease remission [188]. Development of new nodules in the absence of clinical exacerbation has also been described [200]. Superimposed infection of cavitary nodules may occasionally occur, resulting in air fluid levels [188, 193]. Acute GPA pulmonary nodules and opacities may leave behind some degree of interstitial fibrosis. CT manifestations include linear attenuation radiating from the hilar regions to the periphery with traction bronchiectasis and/or irregular bands. In follow-up studies of preexistent lesions, linear opacities with bronchiectasis may develop in a different area from the initial lesion [200]. In the case of diffuse alveolar hemorrhage, the ground glass and airspace opacities first detected may become heterogeneous within the next 48–72 h with alveolar and interstitial components. In this setting, smooth interlobular septal thickening and ground glass changes in a “crazy-paving pattern” may be present. Resolution may ensue after hemorrhage reabsorption. However, with recurrent episodes of bleeding, residual interstitial fibrosis may occur. Ill-defined centrilobular nodules may be noted reflecting accumulation of macrophages within the alveolar spaces [208]. In the course of the disease, consolidation may reflect exacerbation, but also superimposed infection, due to immunosuppressive therapy. Infection should always be excluded in the setting of new consolidation or ground glass opacities [188]. GPA can eventually progress to a pattern of usual interstitial pneumonia (UIP) “fibrosing alveolitis” [209]. In this scenario, CT findings may reveal bibasilar, subpleural interlobular septal thickening, intralobular lines and honeycombing, traction bronchiectasis with mild architectural distortion [209]. This is a rare finding, which raises the theory of potential coexistence of GPA and fibrosis [192]. In this regard, fibrotic changes may develop secondary to infection

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during treatment of GPA, or drug-related damage and not necessarily directly related to the disease [193].

Tracheobronchial Abnormalities The CT evaluation of central airway abnormalities is facilitated by the assessment in coronal and sagittal planes as much as in the transverse plane [210], with better delineation of the longitudinal extent. Virtual CT bronchoscopy may be a diagnostic tool for accurate evaluation of the degree and extent of airway involvement in GPA [211]. One advantage over conventional bronchoscopy is the ability to visualize airways beyond stenotic lesions and additional downstream involvement as well as estimation of longitudinal extent. Virtual CT bronchoscopy plays a role in response to treatment surveillance as well as in critical patients unable to tolerate conventional bronchoscopy [211]. On the other hand, certain segments may be incompletely assessed, particularly the right middle lobe bronchus due to orientation in the axial plane and poor longitudinal resolution. Mild stenoses may also be misinterpreted as luminal irregularities due to normal variation [211]. Wegener’s granulomatosis affects the tracheobronchial tree with estimates from 16% up to 55% in some series [184, 210, 212]. The airway involvement can be an isolated presentation, part of the fully developed multisystem disease, or a chronic complication of progressive disease or disease in remission [212]. When airway involvement is the only or presenting feature of GPA, a positive ANCA test result can lead to proper diagnosis. However, this may be undetectable in such patients [212]. Most cases of GPA affect the subglottic region [184, 210]. There may or may not be vocal cord involvement. Length-­ wise, the lesions may be small or as large as 4–5 cm [210]. Circumferential thickening including the cartilaginous and membranous portion of the trachea is the rule, ranging from a few mm up to a cm [210]. The wall thickening can be smooth or nodular [187] (Fig.  21.13a–d). There could be mild, moderate, or severe tracheal lumen narrowing [210]. Involvement of the paratracheal tissues with effacement of the paratracheal fat planes can be seen [210]. Some of the airway lesions may not be associated with upper airway obstruction symptoms [210]. A tracheobronchial distribution of the disease is less recognized and in some cases, early changes may be missed [212]. A rare complication of airway involvement is tracheomalacia or bronchomalacia. Bronchiectasis is infrequent. Thickening of the bronchi is reported as infrequent [186, 200]. However, bronchial wall thickening at segmental and subsegmental levels was seen in 56% in a study of 57 patients [189] and 73% of patients in a study of 30 patients [198]. The authors’ impression is that the findings reflected inflammatory changes commonly demonstrated in GPA on pathology analysis, including acute and chronic bronchitis

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Fig. 21.13  A patient with tracheobronchial granulomatosis with polyangiitis and recurrent bronchopneumonia. CT mediastinal windows (a) coronal (b) Sagittal and (c, d) axial views at the mid tracheal level and carina. There is mild concentric tracheobronchial wall thickening,

resulting in mild irregularity of the airways (arrows). The tracheal involvement is more noticeable along the left lateral wall and posteriorly. The tracheal wall thickness is greatest at the carina

and bronchiolitis, follicular bronchiolitis, and bronchiolitis obliterans [213]. Lobar or segmental atelectasis are possibly secondary to the airway narrowing, occasionally seen in these patients [188].

(18F-FDG PET/CT) in large vessel vasculitis is largely recognized [214]. In the case of small vessel vasculitis and GPA, a few studies have been published. One of them addressed the antineutrophil cytoplasmic antibody (ANCA) vasculitides as a group in 16 patients [215]. There was concordance with the usual definition of organ impairment at baseline and on follow-up studies. Cardiac involvement was diagnosed in 3 patients, confirmed with CT or MR.

 ole of PET and 18F-FDG PET/CT R The value of positron emission tomography (PET) and positron emission tomography with 2-deoxy-2-fluorine-18 fluoro-­D-glucose integrated with computed tomography

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Fig. 21.14  Granulomatosis with polyangiitis and sinusitis and right pleuritic chest pain. CT (a) and PET/CT (b) show FDG avid right lower lobe cavitary nodule. Coronal sinus CT (c) shows mucosal thickening

in the left maxillary sinus and chronic volume loss in the right maxillary sinus with prior sinonasal cavity surgery

In two case series, 18F-FDG-PET/CT did not find occult foci of inflammation compared to other imaging modalities, to alter management [214, 215]. However, other studies have found occult foci not previously detected with usual organ screening with other imaging modalities [216]. 18F-FDG-­PET/CT could be useful in the proper clinical scenario, in which detection of the typical sino-nasal, lung, kidney, and heart involvement may raise the possibility of GPA, or in relapsing situations [215] (Fig. 21.14a–c). The upper respiratory involvement may be better depicted on PET/CT compared to nonenhanced CT alone [217]. 18F-FDG-PET/CT may also better direct biopsy sites and assess response to therapy [216, 217]. There could be also a potential role in the assessment of early inflammatory changes [218, 219] in cases where large vessels may be also affected, or for organ tissue damage visualization [218, 220]. Large vessel involvement has been documented on PET/ CT evaluation. In a study of 21 patients, all patients with GPA show marked aortic FDG uptake [221]. This raises questions about the validity of categorizing vasculitis depending on the size of the vessels, as there seems to be a significant overlap [221, 222].

quantification of ventricular function. This is particularly useful, since complications such as constrictive pericarditis are not infrequent [229]. In a study of 26 patients with GPA and no cardiovascular disease or diabetes mellitus and 25 healthy volunteers with similar cardiovascular risk profile, cardiac MRI was performed. Focal fibrosis was detected in 24% of patients with GPA.  The patients with delayed enhancement were less commonly PR3 ANCA positive and had involvement of the lower respiratory tract and skin. A higher degree of scarring correlated with renal involvement. Native T1 mapping and ECV (extracellular value) reflecting myocardial fibrosis were higher than the controls and ECV was higher in relapsing patients. The left ventricular (LV) function inversely correlated with disease duration. In this study, the authors concluded there may be a role for risk stratification of myocardial involvement in GPA [230]. Additional findings reported in patients with GPA in a group of 35 patients include impaired LV function, regional wall motion abnormalities, and myocardial fibrosis. The latter may be nodular. Both early and delayed contrast enhancement in the same territories may be present indicating inflammation. The abnormal wall motion and LV function appear to be more frequent in patients with chronic GPA, and this study suggested MRI may have prognostic implication [231]. This was however not corroborated in a larger study of 517 patients. In this publication, the incidence of cardiac involvement by GPA was 3.3% and no differences were observed between patients with or without cardiac involvement in terms of demographics, antineutrophil cytoplasmic antibody positivity, relapse rate, or premature death [232].

 ardiac Involvement in GPA C Cardiac involvement in GPA is probably underdiagnosed as it is often subclinical. The incidence ranges from 6% to 44% [223]. It may involve any cardiac structure: coronary vessels, pericardium, myocardium, endocardium, valves, conduction system, and great vessels [224]. Pericarditis and coronary vasculitis are the most frequent findings (50% of cases) [225], but myocarditis, endocarditis, and conduction system granulomata are also described [226–228]. Magnetic resonance imaging is able to demonstrate most of the potential abnormalities, including detailed pericardial assessment, the presence of myocarditis foci, and accurately

Differential Diagnosis Nodules and masses similar to GPA can be seen with septic emboli, hematogenous metastases, pulmonary infarcts, atypical fungal infection [188] or bacterial pneumonia,

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especially Staphylococcus, lymphoma, alveolar sarcoidosis, organizing pneumonia, and necrobiotic nodules from RA [187, 233, 234]. The “halo” sign may also be seen with lesions with surrounding hemorrhage or cellular infiltration, such as adenocarcinoma, hypervascular metastases, and angioinvasive infection such as Aspergillus fumigatus [233]. A centrilobular distribution may mimic tuberculosis, hypersensitivity pneumonitis, or acute bronchiolitis [187]. With predominant airspace opacities, the differential diagnoses include bacterial, viral, or fungal pneumonia, tuberculosis, aspiration pneumonia, organizing pneumonia, lung adenocarcinoma, pulmonary edema, and acute respiratory distress syndrome [187, 233]. In the absence of GPA markers and usual target organ involvement, other causes of isolated subglottic stenosis such as postintubation or post infectious stenosis, idiopathic subglottic stenosis, hypocomplementemic urticarial vasculitis, and extrinsic compression should be explored. Adenoid cystic carcinoma and tracheal amyloidosis are also possibilities [212, 233]. Tracheal diseases such as relapsing polychondritis and tracheobronchopathia osteochondroplastica will typically spare the membranous portion of the trachea,

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Fig. 21.15 (a) Low power view of GPA showing areas of the socalled geographic necrosis, (b) presence of microabscesses, (c) acute inflammatory changes with a mixture of macrophages and neutrophils, (d) inflammatory changes with scattered multinucleated giant cells, (e) in focal areas the presence of multinucleated giant cells can be marked, (f) adjacent lung parenchyma shows areas

helping in differentiating these from GPA [187]. When lymphadenopathy is the predominant finding, other causes such as sarcoidosis, infection, or lymphoma must be excluded [187].

Pathological Features Sections from lung will show the presence of extensive areas of necrosis “geographic necrosis,” areas of microabscesses may also be seen. One of the most important and relevant finding is the presence of vasculitis that may be seen not only within the necrotic areas but also in the periphery of the necrotic areas in what may appear uninvolved lung parenchyma. This vasculitis may affect arteries and veins. In some early cases, the presence of capillaritis may be the initial vascular feature. In addition, there is a conspicuous inflammatory reaction composed of lymphocytes, neutrophils, and macrophages. Also important to highlight is the presence of multinucleated giant cells that may also formed well-defined granulomatous reaction. In some cases in which it may be difficult to identify vascular structures, the use of histochemical stains such as Elastic von-Giesson (EVG) or Movat may be of aid (Fig. 21.15a–j).

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of organizing pneumonia, (g) easily identified involved vascular structure (vasculitis), (h) unrecognizable vascular structure, (i) vascular structures can be identified easier with special stains—Movat histochemical stains outlines the wall of a large vessel, (j) vascular structure involved adjacent to areas of necrosis, also Movat histochemical stain

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Management

Additionally, AZA was shown to be superior to mycophenolate in IMPROVE trial [241]. Treatment of GPA with immunosuppression has been life-­ Guillevan et  al. found that rituximab initiation upon saving. As mentioned previously, relapses are common, and remission with cyclophosphamide decreased the likelihood disease extent should guide treatment. In limited forms of of a severe relapse relative to the standard azathioprine disease where only mild ENT manifestations are seen, a therapy. combination of glucocorticoids and another form of immuProlonged immunosuppression may be needed given high nosuppression (such as methotrexate) may be reasonable rates of relapse [242]. [235, 236]. Treatment with methotrexate may need to be continued for several years as recurrences can occur.

Plasma Exchange

Induction In more extensive stages of GPA, treatment plans should include drugs for induction therapy followed by maintenance therapy. Induction therapy in GPA with Cyclophosphamide and corticosteroid combination therapy is successful at achieving remission in more than 55–80% of patients at 6 months [237]. Cyclophosphamide carries with it a risk of severe immunosuppression, opportunistic infections, bone marrow suppression, hemorrhagic cystitis, bladder cancer, risk of other malignancies, and infertility [238]. MESNA may often be coadministered with cyclophosphamide to minimize incidence of hemorrhagic cystitis. Glucocorticoids can cause hyperglycemia, immunosuppression, and weight gain. Recent trials have also shown that Rituximab may also be used for remission induction. Stone et. al showed noninferiority of rituximab to cyclophosphamide, with a more positive outcome in patients with relapsing disease who received rituximab [163]. EUVAS trial in GPA with renal vasculitis showed that rituximab was effective but not superior to cyclophosphamide in inducing GPA remission [239]. Patient factors, including consideration of fertility, cost, cumulative dose exposures, play a large role in deciding on an induction agent. Currently, cyclophosphamide is still the initial agent of choice for remission induction, but rituximab is a proven choice for patients who are unable to tolerate cyclophosphamide.

Maintenance Maintenance therapy following cyclophosphamide-based induction therapy should be based on patient factors and can include either azathioprine (AZA), methotrexate (MTX), or rituximab. AZA and MTX were found to be equally effective for maintenance therapy in the WEGENT trial [240]. Methotrexate should be avoided in renal failure given renal clearance. AZA may lead to liver toxicity and excessive myelosuppression; however, it is safer in pregnancy.

Plasma exchange (PLEX) in combination with immunosuppressive induction therapy may be a consideration in severe forms of disease. PLEX eliminates ANCA from peripheral circulation. PLEX in conjunction with cyclophosphamide can be used in patients with rapidly progressive life-­ threatening renal vasculitis and/or alveolar hemorrhage. The use of PLEX in these patients may prolong dialysis-free survival. In the MEPEX study [243], plasma exchange was associated with increased renal recovery, a risk reduction for end-stage renal disease, and reduced dialysis dependency compared with methylprednisolone, supporting its use in patients with ANCA-associated vasculitis and renal failure. However, in PEXIVAS study, PLEX showed no benefit in death and progression toward end-stage renal disease in patients with kidney involvement or alveolar hemorrhage in ANCA vasculitis [244].

Other Considerations In patients with specific complications related to the disease such as airway stenosis (including subglottic stenosis, tracheal stenosis, tracheo-bronchial stenosis), patients may need interventional pulmonary services including dilatations or stent placements, or in more severe and refractory cases, surgical resection may be needed [245].

Prognosis and Conclusions GPA is one of the pauci-immune, ANCA-related vasculitides involving the small- to medium-sized vessels, and often involves the upper and lower respiratory tract, as well as the kidneys. It may present as a limited form, but more frequently is systemic and progressive with life-threatening manifestations. Immunosuppressants are key for inducing clinical remission, and have been proven to be life-saving. Maintenance therapy with immunosuppression is important as the disease is known to have a relapsing course. Five-year survival rates with therapy now approach 80% [237].

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ANCA-associated vasculitis is a potentially life-­ based on the pivotal role played by eosinophils found in blood threatening disease if not treated. Outcomes in different or tissues at all EGPA stages, as well as an activated and an forms can vary. Untreated GPA has a progressive and fatal unbalanced T cell response with a decrease in T regulatory prognosis. Mortality increases progressively; however, cells (or decreased function of T regulatory cells) [37, 250]. immunosuppression improves survival dramatically with However, it is unclear if the eosinophils cause the damage or over 90% of the patients achieving remission at 6 months. have another secondary role. There are several cytokines, BVAS score may be helpful in predicting treatment failure. which appear to be overexpressed during EGPA, including Age and pulmonary infections are also predictors of death Il-4, Il-13, and Il-5. Eosinophils further secrete Il-25, which [245]. Alveolar hemorrhage is the main cause of hospitaliza- amplifies the TH2 response. Th2 cells then recruit B cells, tion and hospital ICU admission. In patients with pulmonary leading to activation, mobilization, and antibody secretion capillaritis, alveolar hemorrhage, and severe renal involve- (IGG and IGE and ANCAs). The B cell and humoral response ment, overall mortality is high despite treatment [245]. are further contributors to the EGPA pathogenesis. Eosinophil recruitment is enhanced by these inflammatory mediators, and they are attracted to tissues where they cause further damage. Eosinophilic Granulomatosis Additionally, eosinophils may adhere to endothelium, cause with Polyangiitis tissue infiltration and granuloma formation, ultimately leading to small-vessel occlusion and ischemia [38, 251].

Introduction

Eosinophilic granulomatosis with polyangiitis (EGPA), one of the ANCA-associated vasculitides, which include MPA and GPA, is the least common one of the three. In 1951, Churg and Strauss described a syndrome, which included asthma, fever, and eosinophilia with systemic involvement including cardiac and renal dysfunction, peripheral neuropathy, and inflammatory involvement of small vessels [33, 246]. Histopathology showed tissue eosinophilia, necrotizing and granulomatous vascular lesions, and extravascular granulomas [34, 247]. Formally, EGPA is defined as an eosinophil-rich and necrotizing granulomatous inflammation with necrotizing vasculitis that affects predominantly small- to medium-sized vessels, occurring in patients with asthma and eosinophilia.

Diagnostics Currently, there are no specific biomarkers for EGPA, and its diagnosis is largely clinical. EGPA is characterized by eosinophilia, granulomatous inflammation, and necrotizing vasculitis of the small- and medium-sized vessels [37, 250].

Laboratory Data Work-up can be nonspecific, but should include basic blood work (complete blood count, chemistry panel), inflammatory markers including C-reactive protein, erythrocyte sedimentation rate (ESR), ANCAs, and serum immunoglobulins. Given the prevalence of asthma in patients with EGPA, pulmonary function testing is also an important part of the diagnostic work-up. Incidence and Risk Factors Elevated peripheral eosinophilia (>10% or a count greater than 1500/mm3) is often seen and may correlate with disease EGPA is an exceedingly rare disease, with an annual inci- or herald relapses. IgE levels are often elevated; however, dence of 0.5–4.2 cases per million with a prevalence of they are not necessarily correlated with disease activity. 11–14 cases per million [3, 35, 166, 248]. It does not have a Inflammatory markers like CRP and ESR will be elevated in clear sex or familial predisposition [35, 248]. EGPA is usu- EGPA. ANCA positivity may occur years prior to onset to ally seen in the fifth or sixth decade. Certain immunogenetic vasculitis [39, 252] and may be seen in up to 40% of patients factors may contribute to susceptibility to EGPA. The HLA-­ [40, 253]. A perinuclear immunofluorescence pattern DRB1*04 and HLA-DRB1*07 gene subtypes are associated (P-ANCA) is found in 74–90% of ANCA-positive EGPA with an increased risk of developing EGPA [36, 249]. EGPA cases and usually corresponds to anti-MPO antibodies. is also suspected to be triggered by environmental agents, Though ANCAs play a role in eGPA, studies have not been infections, and drugs. able to clearly show a clinical syndrome associated with ANCA positivity. Biopsies should be a part of work-up. On biopsy of Pathogenesis involved organ systems, eosinophilic infiltrates can be seen with small- and medium-sized vessel vasculitis and extravasGPA is considered an idiopathic disease, and a clear mecha- cular granulomas [41, 254]. Patients with systemic involvenism is not currently understood. The pathogenesis of EGPA ment can be identified by biopsy-proven necrotizing is likely multifactorial and the accepted model currently is vasculitis of any organ involvement.

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Diagnostic Imaging Eosinophilic granulomatosis with polyangiitis (EGPA) demonstrates a variety of manifestations both on chest radiographs and on chest computed tomography (CT). Though the findings are not specific for EGPA and can be seen with a variety of diseases, knowledge of the possible radiologic manifestations of EGPA can suggest the diagnosis in the appropriate clinical setting, such as a history of asthma and elevated eosinophils.

Radiography The most common finding on chest radiograph is bilateral patchy consolidation or hazy opacities. These have been most commonly described in the mid and lower lungs [255, 256], but have also been observed in the upper lungs (Fig.  21.16a–c). Nodules are observed less frequently (Fig. 21.17a–d). Bronchial wall thickening can also be demonstrated. Lymphadenopathy can be seen as widening of the mediastinal or hilar contour at the level of the involved lymph nodes (Fig.  21.18a, b). Pleural effusions are frequently observed. Enlargement of the cardiac silhouette can suggest pericardial effusion. Additionally, radiographs in patients with active EGPA can be normal. CT As on radiography, the most common findings on computed tomography (CT) in EGPA are multifocal, bilateral patchy consolidation and ground glass opacities in

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Fig. 21.16  Eosinophilic granulomatosis with polyangiitis: ground glass opacities and lymphadenopathy. (a) Frontal chest radiograph demonstrates faint opacities in the peripheral left upper lung and in the suprahilar right lung (arrows). There is also bilateral hilar lymphadenopathy. (b) Axial CT image in lung windows demonstrates bilateral

a peripheral and/or peribronchovascular distribution (Figs. 21.16, 21.19a, b, and 21.20a, b). Nodules are the predominant finding in patients less often. Nodules may manifest as centrilobular micronodules, diffuse nodules overlapping parenchymal opacities, and multiple discrete random nodules measuring from 5 mm to several centimeters (Figs.  21.17, 21.18, and 21.21a–c). Cavitating nodules have rarely been reported [257]. Interlobular septal thickening can be observed secondary to interstitial pulmonary edema in patients with cardiac involvement of EGPA with reduced cardiac function. However, interlobular septal thickening has also been seen in patients with normal echocardiography and, in these cases, is likely secondary to eosinophilic infiltration of the interlobular septa, with associated fluid accumulation [255, 258]. Bronchial wall thickening and/or dilation (Figs. 21.16 and 21.20) has been reported in 35–78% of patients [255–258] and is presumably secondary to the asthma seen in these patients. As on radiographs, pleural effusions can be seen on CT (Fig. 21.22). Pericardial and cardiac involvement can manifest as pericardial effusion (Fig.  21.22), pericardial thickening and enhancement, cardiomegaly, and findings of cardiac infarct. In cases of infarct secondary to vasculitis, cardiac MRI may demonstrate subendocardial myocardial late gadolinium enhancement in a vascular distribution (Fig. 21.23a, b).

c

peripheral ground glass opacities. This patient had upper lobe predominance. There is also mild wall thickening of the distal bronchi (curved arrow). (c) Axial CT image in soft tissue windows demonstrates subcarinal and bilateral hilar and lymphadenopathy

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Fig. 21.17  Eosinophilic granulomatosis with polyangiitis: nodules. (a) Chest radiograph demonstrates subtle left upper lobe nodules measuring a few millimeters. (b, c) Axial thin CT images and (d) maximum

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intensity projection image demonstrate multifocal clustered centrilobular nodules with mild ground glass opacities

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Fig. 21.18  Eosinophilic granulomatosis with polyangiitis: Lymphadenopathy. (a) Frontal chest radiograph demonstrates bilateral hilar enlargement. (b) Axial CT image demonstrates bilateral hilar and subcarinal lymphadenopathy

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Fig. 21.19  Eosinophilic granulomatosis with polyangiitis: ground glass opacities. (a, b) Axial CT images of the upper lobes show bilateral peribronchovascular ground glass opacities asymmetrically involving

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the right lung more than the left lung. Some of the ground glass opacities in the right upper lobe show areas of central higher attenuation with peripheral slightly lower attenuation (“halo sign” arrow)

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Fig. 21.20  Eosinophilic granulomatosis with polyangiitis: Ground glass opacities and bronchial wall thickening. (a) Axial CT image in lung window of the upper lobes shows bilateral ground glass nodular opacities in a peribronchovascular distribution. (b) Axial CT image in

soft tissue window at the level of the right main pulmonary artery shows wall thickening of the bilateral mainstem bronchi. There is also mild right hilar lymphadenopathy

Clinical Presentation

Patients may present with hematuria, proteinuria, leukocytoclastic capillaritis and/or eosinophilic infiltration of the arterial wall, or mononeuritis multiplex [251]. Organ systems preferentially involved and manifestations commonly seen in EGPA include the following: asthma (>90%), rhinosinusitis (50–90%), lung opacities on imaging (40–60%), mononeuritis multiplex (50%), skin findings (40– 50%), arthralgias and myalgias (30–50%), cardiac manifestations (20–50%), gastrointestinal (GI) tract symptoms (20–30%), and kidney involvement (20%). Cardiac manifestations of eosinophilic infiltration most commonly cause endomyocardial involvement (Fig. 21.24a, b), although coronary vasculitis, pericarditis, and valvular defects are also

EGPA is generally a systemic disease. However, occasionally, a more limited form confined to a single organ may be seen. EGPA is characterized by three phases. A prodromal phase can include allergic rhinitis, asthma, and sinusitis; an eosinophilic phase with peripheral and tissue eosinophilia; and a systemic vasculitis phase with symptoms such as weight loss, fever, and fatigue [259]. These phases may also overlap. The eosinophilic phase is characterized by major systemic involvement, including lung, cardiac, and gastrointestinal involvement, and is responsible for organ injury occurring through blood eosinophilia and infiltration.

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Fig. 21.21  Eosinophilic granulomatosis with polyangiitis: Nodules. (a–c) Axial CT image demonstrates bilateral solid and ground glass nodules without a specific distribution. The left apical nodule (a) dem-

onstrates a “reverse halo sign” (arrow) of central low attenuation and peripheral high attenuation

seen [260]. GI involvement includes unexplained abdominal pain, eosinophilic infiltration of the GI mucosa, frequently of the small bowel, and occasionally hemorrhage (Fig. 21.25). ENT manifestations are also common [261]. Clinical symptoms can include secretive otitis media, chronic ear drainage, sensorineural hearing loss, and facial nerve palsy. The vasculitic process and granuloma formation further cause organ impairment. ANCA-positive patients are more prone to peripheral neuropathy, purpura, renal involvement, and biopsy-proven vasculitis [250].

Pulmonary Disease Fig. 21.22  Eosinophilic granulomatosis with polyangiitis: pericardial involvement and pleural effusions. Axial CT image in a patient with myo-pericarditis demonstrates a moderate pericardial effusion. There are also small bilateral pleural effusions

Asthma is found in around 95% of patients and may precede the systemic disease manifestations by many years. Generally, asthma with EGPA arises in adulthood and its severity varies. Asthma seen in EGPA does not have seasonal

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Fig. 21.23  Eosinophilic granulomatosis with polyangiitis: Myocardial infarct secondary to vasculitis. Cardiac MR images in (a) short axis and (b) four-chamber views demonstrate late gadolinium enhancement of

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the subendocardium to mid wall in the left anterior descending coronary artery territory involving the anterior wall and septum (arrows)

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Fig. 21.24  EGPA (a) Sections of myocardium showing fibrinoid vasculitis, (b) higher magnification of the myocardial vessels showing fibrinoid necrosis

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Vasculature Fibrinoid necrosis and eosinophilic vessel wall infiltration characterize the vasculitic form of EGPA.  Involvement of mainly small- and medium-sized vessels is seen, leading to significant clinical manifestations. Granulomas may occur in the arteries; however, extravascular granuloma formation with a core of necrotic eosinophilic material surrounded by palisading lymphocytes and epithelioid and multinucleated giant cells may also be seen [250].

Management

Fig. 21.25  EGPA involving the small intestine, note the presence of fibrinoid necrosis in medium-sized vessels in the wall of the intestine

exacerbations as does asthma in the general population. Allergic rhinitis, recurrent sinusitis, and nasal polyposis are typical of the early EGPA phase [262]. Nasal polyps affect 50% of the patients with EGPA. In the eosinophilic phase, lung involvement occurs in up to 2/3 of EGPA patients. Chest X-ray abnormalities generally consist of mainly peripheral, patchy, and migratory opacities [250]. On high-resolution CT (HRCT), lesions appear as ground glass opacities or poorly defined areas of consolidation. Multiple pulmonary abnormalities may coexist on imaging [263]. Tree in bud opacities, bronchial wall thickening, and small centrilobular nodules may also be seen. Though not as common as in GPA or MPA, diffuse alveolar hemorrhage can occur in 3–8% of patients. Pleural effusions may also occur secondary to eosinophilic pleuritis or eosinophilic cardiomyopathy-related ­congestive heart failure. Patients may also have increased risk of venous thromboembolism [264]. The histopathological features include the presence of fibrinoid necrotizing lesion in the lung destroying normal lung parenchyma. Eosinophilic abscess and vasculitis are also commonly seen (Fig.  21.26a–d). In some cases, scattered multinucleated giant cells can also be seen but do not form well-defined granulomatous disease.

EGPA continues to be a poorly understood disease and often goes unrecognized by most physicians. Thus, given the rarity of the disease, assessment and treatment should take place with a multidisciplinary team in a center with vasculitis experts. Immunosuppression with corticosteroids and another induction agent such as cyclophosphamide or azathioprine is the cornerstone of therapy [265, 266]. Corticosteroids induce clinical remission and lead to eosinophilia normalization within several days. Other immunosuppressants may be added using the Five Factor Score (FFS), which is based on the patient’s age and degree of systemic involvement, with a higher score indicating worse 5-year mortality [109]. If FFS > 1, studies suggest using both cyclophosphamide and CS if FFS > 1 disease remission is induced (around 3–6 months) [51, 267]. When the regimen is followed by azathioprine or methotrexate, maintenance therapy is given for 12–18 months or longer [268]. According to the EGPA consensus task force, immunosuppressants are not necessary in asymptomatic patients; however, a more recent recommendation preferred treating all patients with immunosuppression. Thus, in patients with an FFS of 0, a patient-based approach should be used as it is unclear whether corticosteroids alone may be sufficient in these patients [250]. Cyclophosphamide is the immunosuppressant most often used in EGPA. Information on the potential benefit of rituximab for patients with EGPA is currently restricted to case reports. Some studies support the use of rituximab for severe EGPA cases that are refractory or relapsing. Rituximab does appear to be more effective in ANCA-positive patients, although it can also be used in patients who are ANCA negative. The newer biologic agents such as mepolizumab are currently still in investigation for use in patients with asthma and EGPA [269].

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Fig. 21.26  EGPA involving lung (a) extensive fibrinoid exudates replacing lung parenchyma, (b) fibrinoid necrosis admixed with eosinophilic microabscess, (c) eosinophilic abscess involving a pulmonary vessel, (d) extensive fibrinoid necrosis and eosinophilic abscess involving airway

Plasma exchange therapy may be considered for specific patients with pulmonary-renal syndromes; however, data supporting plasma exchange in EGPA is limited. Plasma exchange is also prescribed for severe alveolar hemorrhage [179] although without a proven mortality benefit. Eosinophilic granulomatosis with polyangiitis is a systemic small vessel vasculitis with asthma as one of its hallmark features. Eosinophilic infiltration of tissues and activation in the body play a major role in the pathogene-

sis of the disease. Overall, if treated with immunosuppression, EGPA has a good outcome. Among a cohort of 118 patients followed for 6 years, 29% of the patients achieved long-term remission and 10% died [270]. Among the patients who achieved remission, 38% experienced at least 1 relapse [270]. Overall 5-year survival rates of around 92% have been reported in other retrospective studies. ANCA status has not generally shown to influence mortality.

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Microscopic Polyangiitis

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Clinical Presentation

Introduction

Initial presentation is often nonspecific with constitutional symptoms such as low grade fevers, arthralgia, and weight loss. Friedrich Wohlwill described two patients in 1923 with “a The presentation can be variable and range from limited sysmicroscopic form of periarteritis nodosa,” distinct from the temic disease to more systemic involvement with pulmonary-­ known, classic form, and has now come to be known as renal syndromes being a common presentation [277]. microscopic polyangiitis (MPA) [271]. MPA based on Pulmonary involvement may be seen in up to 50% of patients. Chapel Hill Consensus Conference was defined as an auto-­ MPA most commonly affects the kidneys with almost half immune condition with necrotizing vasculitis of small or more of the patients developing chronic kidney disease vessels (capillaries, venules, arterioles) with few or no [278] with some requiring hemodialysis. ­ immune deposits, and/or necrotizing arteritis involving Neurologic manifestations can also be quite common, medium-sized arteries [174]. Granulomatous inflammation with peripheral neuropathy occurring more frequently than is largely absent. Necrotizing glomerulonephritis can be a central nervous system disorders [279]. Cardiac manifestacommon presentation in as high as 90% of cases and pulmo- tions, though less common, may be seen in 3.8–17.6% of nary capillaritis may be associated with diffuse alveolar patients, with variable forms, including pericardial effusion, hemorrhage. ANCA association with MPA is generally heart failure, pericarditis, myocardial infarction, or coronary p-ANCA, though rarely c-ANCA can also be seen [272]. vessel vasculitis [280]. Typical treatment requires cytotoxic agents and glucocorticoids.

Pulmonary Disease

Incidence and Risk factors

Pulmonary involvement can be seen in 25–55% of patients, and pulmonary-renal syndromes are a common manifestaMPA has a slight male predominance with an onset between tion of MPA.  Patient presentation can include shortness of 50 and 60 years of age. breath, cough, hemoptysis, pleuritis, and diffuse alveolar In the UK, MPA is reported as having an incidence of 5.9 hemorrhage (DAH) [281]. If performed, bronchoscopy with cases per million [273]. bronchoalveolar lavage (BAL) may be grossly hemorrhagic MPA presentation usually peaks around 60–65 years of if DAH is present. Pathology of BAL fluid may also show age. Patients can present acutely or have an indolent course hemosiderin-laden macrophages. before diagnosis. Biopsy of the lung can show intra-alveolar and interstitial red blood cells. Pauci-immune, hemorrhagic, necrotizing alveolar capillaritis, neutrophilic infiltration resulting in Pathogenesis fibrinoid necrosis and dissolution of the arterial and venular walls, as well as intra-alveolar hemosiderosis can also be Studies with animal models support the theory that MPO-­ seen. In pathology specimens from MPA patients, granuloANCAs have a role in pathogenesis in MPA. A two-step matous inflammation is not generally seen. This may be pathway has been theorized in how ANCAs may play a more indicative of GPA.  Lung function testing can show role in pathogenesis of MPA [274]. Neutrophils are either a restrictive or obstructive pattern [282]. primed in MPA via pro-inflammatory cytokines leading to expression of myeloperoxidase. Neutrophils then adhere to the blood vessel endothelial walls, and are further acti- Diagnostic Evaluation vated by binding/interaction of the Fc receptor to MPOANCA [59, 275]. Laboratory Data PR 3 ANCAs can also be seen in patients with Similar to other AAVs, diagnostic evaluation should involve MPA.  However, MPA may also occur in ANCA- basic chemistry, complete blood count, ANCAs, and negative cases and ANCA titers are not correlative to inflammatory markers including CRP and disease activity. Immune deposits are not present in ESR. Inflammatory markers may be elevated in MPA, and MPA.  There have not been any specific genetic links proteinuria is commonly seen in renal disease. MPA generfound in MPA, however, certain environmental expo- ally is associated with perinuclear staining pattern sures such as silica have been proposed as potential (P-ANCA) caused by antibodies against myeloperoxidase triggers for MPA [276]. (MPO-ANCA) [281]. Renal biopsies show focal segmental

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necrotizing glomerulonephritis, and glomerular crescents may be common as well [271].

 ntiglomerular Basement Membrane A Disease

Imaging In patients with MPA and alveolar hemorrhage, chest radiographs show patchy, bilateral airspace opacities, usually involving the upper and lower lung fields [283]. Occasionally, radiographic patterns can include consolidation, pleural effusions, or pulmonary edema. Thickening of the bronchovascular bundles and honeycombing may be seen in patients presenting with an interstitial lung disease (ILD) pattern [284]. Usual interstitial pneumonia (UIP) was the most common type of ILD pattern in MPA [278].

Introduction

Management A two phase treatment plan with induction and maintenance therapy should be made. Induction treatment generally includes cyclophosphamide with corticosteroids. Treatment then continues with immunosuppression with steroids for long term [173]. Remission maintenance may also be achieved with methotrexate or azathioprine. Management should be done in a specialized center where patients can have close long-term follow-up. Treatment for specific conditions like alveolar hemorrhage in the setting of MPA may include aggressive immunosuppression and plasma exchange. Patients may need intensive care support with mechanical ventilation as well depending on level of injury and hypoxemia. Plasma exchange may have a role in cases with severe forms of AAV with renal failure [244]. Studies have so far been unable to demonstrate a decrease in mortality; however, there may be a trend toward renal recovery in patients treated with plasma exchange [243].

Prognosis and Conclusions MPA is a rare systemic small vessel vasculitis. Similar to GPA, significant improvement in mortality has been seen over the past few decades with treatment with immunosuppression. Overall mortality without treatment can approach 80%; however, with treatment, mortality rates have decreased to around 11%. Survival rates at 1 year have been noted to be around 80%, with 5-year survival ranging up to 85% [285].

Initially recognized by Dr. Ernest Goodpasture in 1919, antiglomerular basement membrane (anti-GBM) disease is characterized by circulating antiglomerular basement antibodies with a specificity for type IV collagen [286]. A rapidly progressive glomerulonephritis and pulmonary disease in the form of alveolar hemorrhage ensues. The triad of circulating anti-GBM antibodies, glomerulonephritis, and alveolar hemorrhage is referred to as Goodpasture’s syndrome (GPS) [287].

Incidence and Risk Factors Incidence of GPS is 1–1.5 cases per million per year of the population [288]. Though GPS may occur at any age, the typical age range for the disease is in individuals in their third and sixth decades [289]. Young men are slightly more commonly affected than women. Genetic factors predisposing to anti-GBM) disease include histocompatibility groups HLA DRB1*1501 [290]. Clear environmental triggers have not been identified; however, anti-GBM disease can be precipitated by a viral disease. Tobacco and certain hydrocarbons [75, 291] are also suspected to predispose to disease.

Pathogenesis Mechanism of injury in anti-GBM disease involves circulating autoantibodies directed against the type IV collagen in glomerular and alveolar basement membranes. Typically, antibodies are of the IgG subtype, although) can rarely also be IgA and IgM [292]. Tight binding of these antibodies to the basement membranes leads to activation of the complement cascade and activation of proteases [293]. Eventually, disruption of the filtration barrier and Bowman’s capsule in the kidney occurs. CD4 and CD8 cells further cause damage through inducing migration of macrophages and neutrophils into the kidney [294]. Some reported cases of antibody-­negative anti-GBM disease exist [295]. On histologic specimens of the kidney or the lung, linear immunofluorescence staining of the immunoglobulins along

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the glomerular basement membrane is seen and renal biopsy shows diffuse crescentic injury pattern or necrotizing glomerulonephritis with destruction of the basement membrane [295]. There is a mesangial expansion and hypercellularity progressing to focal and segmental glomerulonephritis) and leukocyte infiltration noted on renal biopsies. If the larger blood vessels demonstrate necrotizing vasculitis on renal biopsy, this should prompt testing for additional causes, including a potential ANCA associated vasculitis [296].

Clinical Presentation Patients may present with a viral prodrome characteristic of an upper respiratory tract infection followed by a rapidly progressive glomerulonephritis that occurs in a time period of days to weeks [288]. Systemic signs of disease include fatigue, shortness of breath, and fever. Renal disease often appears prior to pulmonary abnormalities, with a large proportion of patients having proteinuria on presentation. Other findings on urinalysis include hematuria and pyuria. Degree of renal dysfunction can vary, but patients may develop renal failure requiring dialysis [297, 298]. Anemia is a common presentation of patients and may be related to pulmonary hemorrhage as well. Patients with diffuse alveolar hemorrhage present with dyspnea, cough, with or without hemoptysis, and occasionally respiratory failure.

Diagnostic Evaluation Laboratory Data In patients presenting with rapidly progressive renal failure, anti-GBM disease should be suspected. Diagnosis should involve basic metabolic panel, complete blood count, serologic testing for circulating antibodies, and, importantly, a renal biopsy, whenever possible. Inflammatory markers like erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) are typically elevated. Testing should also include ANCAs, antinuclear antibodies (ANA), anti-DNA, and complement levels, as other disease mimics may have similar presentations. ANCA positivity may also be seen with anti-GBM disease in up to 38% of patients [286]. Urinalysis shows proteinuria, dysmorphic red cells, white cells, and granular casts [288]. Immunofluorescence and electron microscopy should be performed on renal biopsy tissue sample for characteristic linear deposition on immunofluorescent microscopy along the basement mem­ brane and crescentic glomerulonephritis on microscopy [287].

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Pulmonary Disease Pulmonary disease may be reported in around 50% of patients in association with renal disease. Pulmonary pathology alone in anti-GBM disease is rare, but may be seen in around 10% of the patients. Cough and/or hemoptysis can be a common presenting symptom. Though massive hemoptysis is rare, patients presenting with diffuse alveolar hemorrhage can have rapid development of respiratory failure [287]. Chest radiography will show nonspecific bilateral opacities [287]. As disease progresses, these may coalesce and form more of a consolidative pattern. Chest tomography can be helpful as well, and will show an alveolar filling process in DAH. Pulmonary function testing (PFT) will generally show a diffusing capacity for carbon monoxide that may be elevated, as is common in pulmonary hemorrhage, whereas inhaled carbon monoxide may bind to intra-alveolar hemoglobin. Depending on the degree of DAH, a restrictive pattern on PFTs may be seen as well [287].

Management Patients should be referred to a specialty center early, as management should include multidisciplinary discussion. Treatment for anti-GBM disease includes corticosteroids, cyclophosphamide, and plasma exchange in certain cases. Corticosteroids are beneficial in cases of alveolar hemorrhage. With the administration of cyclophosphamide, antibody production is seen to decrease. Use of cyclophosphamide has been extrapolated to anti-GBM disease from use in GPA. Mycophenolate and azathioprine may be used in cases where cyclophosphamide cannot be used. The adjunct of plasma exchange to immunosuppressive therapy leads to a decrease in the number of anti-GBM antibodies [299, 300].

Prognosis and Conclusion Over the past few decades, as management has shifted to immunosuppression and plasma exchange, mortality rates have decreased tremendously. With treatment, 1 year survival is greater than 80% [301], and relapses are not common. Prognosis is also dependent on degree of renal and pulmonary involvement) on presentation. Patients with a milder renal disease tend to have a better prognosis [287]. Patients requiring dialysis within 72 h of diagnosis or with greater than 90% of crescents on biopsy will likely be dependent on dialysis long term, and should be referred for kidney transplantation [86, 302]. Recurrence rates after transplantation have decreased with the advent of immunosuppression [303].

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Pulmonary Hemosiderosis

Clinical Presentation

Introduction

Symptoms range from asymptomatic anemia mild dyspnea, malaise, fatigue to respiratory failure [306]. The hallmark of the disease is anemia, hemoptysis, and radiologic imaging with bilateral alveolar opacities. By definition, IPH has a clinical course with two phases: an active/acute phase and a quiescent phase. In the exacerbation phase, patients will present with shortness of breath, cough, hemoptysis, anemia, and, at times, respiratory failure. The resolution of these symptoms can be slow. In between courses of alveolar hemorrhage, patients are often asymptomatic. However, a small population of patients may have chronic hemoptysis. This chronic phase may include pallor, hepatosplenomegaly, or a completely normal exam.

Idiopathic Pulmonary Hemosiderosis (IPH) is a rare disease and a diagnosis of exclusion in patients with alveolar hemorrhage, pulmonary opacities on imaging, and iron deficiency anemia [304]. Patients often have a relapsing remitting course and may go undiagnosed for many years. A clear understanding of the disease process is still lacking, although an autoimmune process is suspected [305].

Incidence and Risk Factors As IPH can often go unsuspected, an accurate incidence and prevalence of IPH is unknown. IPH is more common in children than in adults. Studies have shown a more female predominance in children. In adults, IPH is more common in men. The disease is relatively rare and has an estimated incidence of 0.24–1.23 cases per million in children and even less in adults [305, 306].

Pathogenesis Though the exact mechanism of disease is unknown, certain environmental, genetic, and immunologic facts have been associated with IPH. The hypotheses of IPH etiology hinge on damage to the alveolar-endothelial membrane, either in the basement membrane or the endothelium. Though no clear genetic factor has been identified, suggestions of familial associations exist, hinting at certain genetic factors that in combination with environmental factors lead to disease. Smoking exposure and certain fungal infections, in particular, Stachybotrys chartarum, have been associated with IPH. In patients with both Celiac disease and IPH, the association is called Lane Hamilton syndrome [307]. In a French study, 28% of patients with IPH had Celiac disease positivity [306, 307]. IPH is brought on by iron deposition and inefficient iron handling by alveolar macrophages. RBCs in the alveoli are phagocytized by alveolar macrophages, and the hemoglobin is broken down into heme and globin molecules. Free heme promotes an inflammatory state in the alveoli, with cytokine release and formation of reactive oxygen species. Further breakdown of heme by heme-oxygenase 1 occurs leading to free iron, bilirubin, and carbon dioxide. Free iron leads to further inflammation by causing cellular damage, producing hydroxyl radicals and causing lipid peroxidation. This inflammatory state and relapsing remitting courses of alveolar hemorrhage eventually lead to fibrotic changes in the lung [306].

Diagnostic Evaluation Laboratory Data Evaluation should start with a thorough history and physical as often the disease can go undiagnosed for over 2 years. The relapsing nature of the disease can be teased out by obtaining a detailed history. Though no specific test for IPH, testing for IgG and IgA tissue transglutaminase should be performed as celiac disease can coexist. Pulmonary hemosiderosis is a diagnosis of exclusion. Ruling out infection, having a baseline chemistry panel to check for renal and hepatic dysfunction as well as ANCA-associated disorders, among others, is important as it can point to another cause for pulmonary hemorrhage [308]. A complete blood count and iron panel will reveal iron deficiency anemia. Involves obtaining a thorough history and physical, imaging, and bronchoscopy. Bronchoscopy Bronchoscopic evaluation shows progressively bloodier return on bronchoalveolar lavage. In pathology, hemosiderin-­laden macrophages are common. BAL samples should also be sent for culture to rule out infection. It is important to note that if the bronchoscopy is done in between episodes of pulmonary hemorrhage, BAL may not demonstrate the classic bloodier return or high numbers of hemosiderin laden macrophages [309]. Though not necessary for diagnosis, lung biopsy can be helpful in ruling out other diseases such as ANCA-associated vasculitis, Goodpasture syndrome, and other immunologic causes [310] as no immunological pathogenesis should be visualized on pathology [311]. On histopathology, alveolar walls appear thickened; fragmented or intact erythrocytes may be present within alveoli and airways. Macrophages are the most predominant cells found in the BAL, and free and intracytoplasmic hemosiderin in macrophages is seen [308, 312]. Pulmonary function tests will vary depending on the phase of disease in which they are performed. If per-

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formed during an acute exacerbation, DLCO may be elevated. PFTs may in general show a variable degree of restrictive ventilatory pattern [313].

Diagnostic Imaging The radiographic manifestations of IPH in children and adults are identical. However not specific. The findings overlap multiple other less rare diseases presenting with diffuse alveolar hemorrhage [157, 313–315] and the differential diagnosis will depend on the age group.  hest Radiograph and Computed Tomography C of IPH Chest radiographs may be normal in up to one-third of the patients [315, 316]. More commonly, diffuse hemorrhage in the lungs typically manifests with bilateral dense or hazy airspace opacities (Fig.  21.27a, b). These are predominantly seen in the lower lungs [314, 316–320] and may have a perihilar distribution [314, 316, 319, 320]. The costophrenic angles and periphery of the lungs are usually spared [314, 321] but may be compromised in severe cases [4, 53, 316]. Unilateral opacities can also occur but are less common [320, 322] (Fig. 21.27). CT provides better delineation of the radiographic findings, defines disease extent, and accurately localizes the abnormalities to the alveolar spaces, interstitium, or both. Furthermore, in patients with suspected lung disease and “normal” chest radiograph, CT may confirm abnormality associated with a slight increase in parenchymal attenuation [315]. The most frequent CT presentation of IPH in the acute phase is diffuse ground-glass opacities and/or overt consoli-

a

Fig. 21.27  Idiopathic pulmonary hemosiderosis. (a) Chest radiograph, frontal view during an acute episode, demonstrates dense airspace opacities in the right upper lung predominantly. In the absence of infection markers, bronchoalveolar lavage was performed and revealed acute

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dation reflecting alveolar hemorrhage. This represents the various degrees of alveolar filling with blood products [157, 311, 313–333]. Other patterns described include diffuse centrilobular micronodules [313, 322, 330, 331, 333], interlobar septal thickening [312, 321, 322, 334], or combined ground glass opacities with underlying interlobular septal thickening, the so-called crazy-paving pattern [314, 318, 326]. After treatment, complete resolution of the airspace opacities tends to occur within 3–14 days [314, 320, 322, 323] (Fig. 21.28). Alternatively, between acute episodes, a reticu-

Fig. 21.28  Idiopathic pulmonary hemosiderosis between crises. Chest radiograph frontal view shows the fine reticulonodular interstitial pattern. The lung apices and costophrenic angles are relatively spared

b

pulmonary hemorrhage. Note a background of fine reticulonodularity. (b) Chest radiograph 3 months later demonstrates resolution of the acute airspace opacities and persistence of the interstitial findings

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lar pattern [314, 322] or a micronodular pattern [328] may continue to be seen on chest radiography, in the areas previously demonstrating alveolar disease. Recurrent exacerbations may demonstrate a background of interstitial reticular or reticulonodular pattern with new alveolar opacities [313]. Nonetheless, the reticular pattern of the disease may still be associated with an acute presentation, as the differentiation between acute and subacute

stages may not be as apparent in patients with frequent hemoptysis events. The CT representation of the subacute radiographic findings consists of diffuse ill-defined or discrete small centrilobular nodular opacities [313, 314, 322, 323, 326, 333] (Fig. 21.29). The relatively high conspicuity of the nodules is attributed to the high-molecular-weight hemosiderin, which results in an increased radiographic density [323].

Fig. 21.29  Idiopathic pulmonary hemosiderosis patient with shortness of breath. Left column panel: T1W 3D GRE postcontrast multilevel axial images showing generalized centrilobular micronodules. Right

column panel: CT axial images, lung window obtained a year earlier shows chronicity of the imaging findings

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Progression into interstitial fibrosis may occur, depending on the severity of the disease, the recurrence of the hemorrhagic episodes, and the duration of the disease [312, 314, 334]. On CT, a coarse linear and reticular pattern is noted with architectural distortion. This is due to the aggregates of hemosiderin-laden macrophages inducing interstitial fibrosis. In some cases, calcium deposition may ensue and attract foreign body giant cells. This has been called “endogenous pneumoconiosis” [326], and more frequently described in hemosiderosis associated with mitral stenosis. In IPH, dendriform pulmonary ossification may rarely occur [335]. The presence of honeycomb cysts is rare as part of the fibrotic changes related to IPH. It is theorized that the cysts are due to a traction phenomenon associated with the recurrent hemosiderin deposition [336]. Cystic changes have been described in the posterobasilar segments of the lower lobes but also in the upper lobes, in a background of high lung density [336, 337] (Fig. 21.30). Pleural abnormalities and lymphadenopathy are rare in IPH [314]. A few publications have reported the presence of pleural effusions or hilar lymph node enlargement, particularly during acute episodes [328]. Hemorrhagic episodes in the pleural space may lead to hemothorax formation [325], which could result in fibrothorax if unresolved. Spontaneous pneumothorax is a rare complication [319, 327].

 ther Imaging Modalities O There is limited data regarding IPH findings on MRI. In the acute phase, hemorrhagic changes will present with high ­signal intensity on T1-weighted images and markedly low signal intensity on T2-weighted images [338, 339]. Magnetic resonance imaging may specifically diagnose new hemorrhagic findings due to the paramagnetic effect of ferric iron [340]. New chest MRI techniques may provide comprehen-

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sive information, such as ventilation, perfusion, inflammation, and structure to better differentiate between active inflammatory and fibrotic changes [341]. Perfusion scintigraphy and positron emission tomography [342] can confirm pulmonary hemorrhage, and in some cases demonstrate subacute or chronic findings attributed to IPH. 18F-FDG PET in patients with IPH may show inflammatory FDG activity in the lungs, hilar and mediastinal lymph nodes [332]. 99m Tc-, 59 Fe, or 51 Cr-based perfusion scintigraphy may demonstrate intrapulmonary hemorrhage in patients with IPH by profile counting with an external detector [343, 344], however are not commonly used and of limited practical value.

Differential Diagnosis The imaging characteristics in patients with IPH have a broad differential diagnosis depending on the various manifestations. Hemorrhagic changes associated with systemic and organ-specific vasculitis or capillaritis, connective tissue disorders, pulmonary embolism, and drug-associated complications may have similar imaging features. Airspace filling manifested by ground glass opacities or consolidation is seen in atypical pneumonias, including viral and Pneumocystis jiroveci infections. Acute hypersensitivity pneumonitis, diffuse alveolar injury, acute lung injury [315]/ acute respiratory distress syndrome [338] (ALI/ARDS) spectrum, acute interstitial pneumonia (AIP), acute eosinophilic pneumonia, progressive organizing pneumonia, and pulmonary alveolar proteinosis are all in the differential. The diagnosis of IPH will be elicited in the context of clinical and laboratory information. In particular, severe IPH should be distinguished from acute interstitial pneumonia and ALI/ ARDS [329]. In the subacute and chronic setting, the reticular and nodular pattern may easily be confused with a miliary pattern associated with disseminated infection, pneumoconiosis, and inflammatory bronchiolar diseases. These however tend to be dynamic, so that chronicity and stability over long periods of time favors the IPH in the appropriate setting.

Histopathological Features

Fig. 21.30  Idiopathic pulmonary hemosiderosis. CT shows chronic findings of relatively high attenuation of the lung parenchyma and vague indistinct fine nodularity (arrows)

Conventional section of lung stained with H&E shows the presence of extensive areas of hemorrhage filling the alveolar spaces. At low and higher magnification, it is possible to observe the presence of prominent pigmented macrophages admixed with fresh blood (Fig. 21.31a, b). The use of histochemical stain for iron stain will highlight the prominent component of pigmented macrophages containing iron pigment.

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b

Fig. 21.31 (a) Low power view of a lung section showing extensive areas of hemorrhage, (b) higher magnification showing prominent pigmented macrophages admixed with hemorrhage—all features of pulmonary hemosiderosis

Management Depending on extent of disease, management for IPH ranges from supportive therapy alone to escalating doses of steroids and other immunosuppressive therapy. Data regarding therapy is based on limited studies given that the incidence of disease is so low. Based on the limited data present, steroids are the cornerstone of therapy. Patients with chronic IPH may need long-term steroid therapy to which they tend to respond well [345]. Other immunosuppressant agents such as hydroxychloroquine, azathioprine, cyclophosphamide [346], and methotrexate have been tried as well [347] with variable results.

Prognosis and Conclusion IPH is a relatively rare disease that is often missed on initial presentations. As PH may have a relapsing remitting course, data regarding prognosis in adults is limited. In studies looking at pediatric populations, earlier age at diagnosis, male sex carried a worse prognosis [348]. In recent literature, five-­ year survival rates have increased, presumably with use of corticosteroids.

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21  Pulmonary Vasculitides 284. Gomez-Puerta JA, et  al. Interstitial lung disease as a presenting manifestation of microscopic polyangiitis successfully treated with mycophenolate mofetil. Clin Exp Rheumatol. 2009;27(1):166–7. 285. Tan JA, et  al. Mortality in ANCA-associated vasculitis: a meta-analysis of observational studies. Ann Rheum Dis. 2017;76(9):1566–74. 286. Hellmark T, et  al. Comparison of anti-GBM antibodies in sera with or without ANCA. J Am Soc Nephrol. 1997;8(3):376–85. 287. Ball JA, Young KR Jr. Pulmonary manifestations of Goodpasture's syndrome. Antiglomerular basement membrane disease and related disorders. Clin Chest Med. 1998;19(4):777–91. ix 288. Greco A, et  al. Goodpasture’s syndrome: a clinical update. Autoimmun Rev. 2015;14(3):246–53. 289. Pusey CD. Anti-glomerular basement membrane disease. Kidney Int. 2003;64(4):1535–50. 290. Phelps RG, Rees AJ. The HLA complex in Goodpasture's disease: a model for analyzing susceptibility to autoimmunity. Kidney Int. 1999;56(5):1638–53. 291. Stevenson A, et al. Biochemical markers of basement membrane disturbances and occupational exposure to hydrocarbons and mixed solvents. QJM. 1995;88(1):23–8. 292. Rutgers A, et  al. High affinity of anti-GBM antibodies from Goodpasture and transplanted Alport patients to alpha3(IV)NC1 collagen. Kidney Int. 2000;58(1):115–22. 293. Hudson BG, et al. Alport’s syndrome, Goodpasture’s syndrome, and type IV collagen. N Engl J Med. 2003;348(25):2543–56. 294. Tipping PG, et  al. Immune modulation with interleukin-4 and interleukin-10 prevents crescent formation and glomerular injury in experimental glomerulonephritis. Eur J Immunol. 1997;27(2):530–7. 295. Liang D, et  al. Clinicopathological features and outcome of antibody-­negative anti-glomerular basement membrane disease. J Clin Pathol. 2019;72(1):31–7. 296. Gulati K, McAdoo SP.  Anti-Glomerular Basement Membrane Disease. Rheum Dis Clin N Am. 2018;44(4):651–73. 297. Bolton WK.  Goodpasture’s syndrome. Kidney Int. 1996;50(5):1753–66. 298. Bolton WK.  Rapidly progressive glomerulonephritis. Semin Nephrol. 1996;16(6):517–26. 299. Peters DK, et  al. Treatment and prognosis in antibasement membrane antibody-mediated nephritis. Transplant Proc. 1982;14(3):513–21. 300. Levy JB, et al. Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med. 2001;134(11):1033–42. 301. van Daalen EE, et al. Predicting outcome in patients with anti-GBM glomerulonephritis. Clin J Am Soc Nephrol. 2018;13(1):63–72. 302. Jindal KK. Management of idiopathic crescentic and diffuse proliferative glomerulonephritis: evidence-based recommendations. Kidney Int Suppl. 1999;70:S33–40. 303. Tang W, et al. Anti-glomerular basement membrane antibody disease is an uncommon cause of end-stage renal disease. Kidney Int. 2013;83(3):503–10. 304. Zhang Y, et al. Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients. J Int Med Res. 2019;47(1):293–302. 305. Chen XY, Sun JM, Huang XJ. Idiopathic pulmonary hemosiderosis in adults: review of cases reported in the latest 15 years. Clin Respir J. 2017;11(6):677–81. 306. Saha BK. Idiopathic pulmonary hemosiderosis: a state of the art review. Respir Med. 2021;176:106234. 307. Agarwal R, Aggarwal AN, Gupta D.  Lane-Hamilton syndrome: simultaneous occurrence of coeliac disease and idiopathic pulmonary haemosiderosis. Intern Med J. 2007;37(1):65–7.

761 308. Salih ZN, Akhter A, Akhter J.  Specificity and sensitivity of hemosiderin-­ laden macrophages in routine bronchoalveolar lavage in children. Arch Pathol Lab Med. 2006;130(11):1684–6. 309. Kabra SK, et al. Idiopathic pulmonary hemosiderosis: clinical profile and follow up of 26 children. Indian Pediatr. 2007;44(5):333–8. 310. Saeed MM, et  al. Prognosis in pediatric idiopathic pulmonary hemosiderosis. Chest. 1999;116(3):721–5. 311. Milman N, Pedersen FM. Idiopathic pulmonary haemosiderosis. Epidemiology, pathogenic aspects and diagnosis. Respir Med. 1998;92(7):902–7. 312. Mukai Y, Agatsuma T, Ideura G.  Early diagnosis of idiopathic pulmonary haemosiderosis: increased haemosiderin-laden macrophages in repeat bronchoscopy. Respirol Case Rep. 2018;6(3):e00304. 313. Ioachimescu OC, Sieber S, Kotch A. Idiopathic pulmonary haemosiderosis revisited. Eur Respir J. 2004;24(1):162–70. 314. Primack SL, Miller RR, Muller NL.  Diffuse pulmonary hemorrhage: clinical, pathologic, and imaging features. AJR Am J Roentgenol. 1995;164:295–300. 315. Cortese G, Nicali R, Placido R, Gariazzo G, Anro P. Radiological aspects of diffuse alveolar haemorrhage. Radiol Med. 2008;113:16–28. 316. Bronson SM.  Idiopathic pulmonary hemosiderosis in adults: report of a case and review of the literature. Am J Roentgenol Radium Therapy, Nucl Med. 1960;83:260–73. 317. Niimi A, Amitani R, Kurasawa T, et al. Two cases of idiopathic pulmonary hemosiderosis: analysis of chest CT findings. Nihon Kyobu Shikkan Gakkai Zasshi. 1992;30:1749–55. 318. Silva P, Ferreira PG.  Idiopathic pulmonary hemosiderosis: Hemorrhagic flare after 6 years of remission. Rev Port Pneumol. 2017;23:368–9. 319. Gencer M, Ceylan E, Bitiren M, Koc A.  Two sisters with idiopathic pulmonary hemosiderosis. Can Respir J. 2007;14:490–3. 320. Miwa S, Imokawa S, Kato M, et al. Prognosis in adult patients with idiopathic pulmonary hemosiderosis. Intern Med. 2011;50:1803–8. 321. Kahraman H, Koksal N, Ozkan F. Eight years follow-up of a case with idiopathic pulmonary hemosiderosis after corticosteroid therapy. N Am J Med Sci. 2012;4:49–51. 322. de Klerk KD, Bau S, Gunther G. Diffuse pulmonary small nodular and patchy infiltrates on chest X-ray with hemoptysis: TB or not TB?-a call for scale up of respiratory medicine services in African TB high burden countries: a case of idiopathic pulmonary hemosiderosis. Pan Afr Med J. 2018;30:121. 323. Chen CH, Yang HB, Chiang SR, Wang PC. Idiopathic pulmonary hemosiderosis: favorable response to corticosteroids. J Chin Med Assoc. 2008;71:421–4. 324. Engelke C, Schaefer-Prokop C, Schirg E, Freihorst J, Grubnic S, Prokop M. High-resolution CT and CT angiography of peripheral pulmonary vascular disorders. Radiographics. 2002;22:739–64. 325. Khorashadi L, Wu CC, Betancourt SL, Carter BW. Idiopathic pulmonary haemosiderosis: spectrum of thoracic imaging findings in the adult patient. Clin Radiol. 2015;70:459–65. 326. Marchiori E, Souza AS Jr, Franquet T, Muller NL. Diffuse high-­ attenuation pulmonary abnormalities: a pattern-oriented diagnostic approach on high-resolution CT.  AJR Am J Roentgenol. 2005;184:273–82. 327. Nickol KH. Idiopathic pulmonary haemosiderosis presenting with spontaneous pneumothorax. Tubercle. 1960;41:216–8. 328. Pacheco A, Casanova C, Fogue L, Sueiro A. Long-term clinical follow-up of adult idiopathic pulmonary hemosiderosis and celiac disease. Chest. 1991;99:1525–6. 329. Toro K, Herjavecz I, Vereckei E, Kovacs M. Fatal idiopathic pulmonary haemosiderosis in association with pregnancy - medico-­ legal evaluation. J Forensic Legal Med. 2012;19:101–4.

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Emphysema and Cystic Lung Disease

22

Selvin Jacob and Mark T. Warner

Introduction Cystic lung diseases can be described as conditions where there are diffuse, round, or irregular thin-walled air cysts within the pulmonary parenchyma. This group of diseases is heterogenous, and in this section, we will focus on a few specific categories of cystic diseases. First of all, emphysema, alpha-1 antitrypsin deficiency and Cystic fibrosis are considered mimickers of diffuse cystic diseases, although they often have cysts and/or bullae as part of their presentation and pathophysiology. An additional category of diffuse cystic lung diseases includes those associated with genetic abnormalities, namely, Birt-Hogg-Dube syndrome, Neurofibromatosis, Proteus syndrome, and Ehlers-Danlos syndrome. Cystic lung diseases associated with lymphoproliferative diseases include Lymphocytic Interstitial Pneumonia and Light Chain Deposition Disease. Congenital cystic adenomatoid malformations, bronchogenic cysts, and placental transmogrification of the lung are related to developmental abnormalities. Tracheo-bronchial papillomatosis is an infectious etiology of cystic disease.

Emphysema Chronic obstructive lung disease (COPD) is a term that was defined by the Global Initiative for Chronic Obstructive Lung Disease as an umbrella term for a set of clinical diseases, which cause a result in airflow limitation due to airway or alveolar abnormalities due to exposure to noxious gases or particles, which also include host factors that lead to abnormal lung development [1]. Emphysema is a subset of COPD, which is a disease that is characterized by an abnormal and permanent enlargement of lung airway spaces distal to the terminal bronchiole. With S. Jacob · M. T. Warner (*) Division of Pulmonary, Critical Care and Sleep Medicine, McGovern Medical School, University of Texas, Austin, TX, USA e-mail: [email protected]; [email protected]

this dilation, destruction and loss of elasticity of the lung parenchyma occur.

Epidemiology Based on large epidemiological studies, the best estimate of the number of COPD cases, with Emphysema being a subset, was 251 million cases in 2016 according to the Global Burden of Disease study [2]. As the increased prevalence of smoking in developing countries and an increase of the aging population occur, it is expected to continue rising, with a projected 5.4 million deaths from COPD by 2060 [2]. The World Health Organization (WHO) estimates that it will be the third leading cause of death as early as 2030.

Pathogenesis A more prominent theory in the pathogenesis of Emphysema lies in the “protease-antiprotease” theory. In this theory, there is a delicate balance between protease and antiprotease activity, which is required for proper lung maintenance. However, derangements in this balance may occur in the setting of increased destruction and inappropriate repair of the lungs [3]. An example is the introduction of cigarette smoke, which can attract alveolar macrophages to the distal terminal bronchioles. These macrophages will then release proteolytic enzymes such as neutrophil elastase, which can enter the secondary pulmonary lobule and result in increased elastase activity in the lung [4]. An imbalance such as this can result in the degradation of the lung matrix and affect alveolar structural maintenance. In addition, more recent studies also support the additional role of apoptosis in emphysema development. Apoptosis of one or more cell types can produce changes similar to emphysema. An example of this is vascular endothelial growth factor. Normally, this factor is abundant in the lung, and its blockade can result in apoptosis-dependent air-

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 C. A. Moran et al. (eds.), The Thorax, https://doi.org/10.1007/978-3-031-21040-2_22

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space enlargement. Similarly, animal models have shown that apoptosis of type II pneumocytes which compromises the production of surfactant can also lead to changes similar to emphysema [4]. Identification of the cellular and molecular mechanisms may have important implications in the future for the development of new targets for therapeutic intervention.

Risk Factors The most common and well-studied risk factor is exposure to cigarette smoking in the development of COPD, and its subset Emphysema. However, it is not the sole risk factor, and there is evidence showing that nonsmokers may also develop COPD and emphysema. Risk factors result from a complex interaction between genes and the environment. An example of such genetic risk factors which have been best documented includes alpha-1 antitrypsin [5]. Age and sex have been noted to be risk factors as well. A longer life expectancy will allow for greater lifetime exposure to risk factors. Some studies, although controversial, have suggested that women may be more susceptible to the effects of tobacco smoke than men [6]. Other risk factors include exposure to other types of tobacco, such as pipe, cigar, water pipe, and marijuana [7]. Passive exposure may contribute to COPD development as well. Occupational exposures including organic and inorganic dusts, chemical agents, and fumes should be noted as well [8]. Indoor air pollution is also a well-recognized cause of COPD with exposure to wood, animal dung, crop residues, and coal, which is typically burned in open fires or poorly functional stoves [9]. Chronic asthma, chronic bronchitis, and history of severe childhood respiratory infections have also been recognized as a cause of decline in lung function [9].

Clinical Features The clinical features of emphysema can be very nonspecific. The usual presentation consists of chronic shortness of breath, wheezing, and cough, which can be accompanied with or without sputum production. With disease progression, exertional dyspnea can occur with significant physical activity. With advance of the disease, weight loss can occur due to systemic inflammation. Exacerbations of COPD and emphysema may present with increased shortness of breath from baseline, increased severity of a cough, and increased sputum production. These exacerbations can occur due to viral or bacterial infections as well as environment factors.

S. Jacob and M. T. Warner

Historically, patients with emphysema are typically referred to as “pink puffers” due to cachexia as well as their expiration through pursed lips [10]. In the early stages of emphysema, the physical examination may be normal. Clubbing of the digits is not typical of COPD and emphysema. Other nonspecific findings are prolonged expiration, increased resonance indicating hyperinflation, distant breath sounds, wheezing, and crackles at the lung bases.

Diagnosis The diagnosis of emphysema is a clinical diagnosis. Pulmonary function tests and imaging are the main indicators of this disease. In a patient who is exhibiting symptoms suggestive of COPD and emphysema, spirometry is the mainstay of diagnosis. A postbronchodilator test with an FEV1/FVC ratio less than 0.7 is diagnostic for COPD. GOLD staging based on the severity of disease is as follows [11, 12]: • • • •

Mild with FEV1 greater or equal to 80% predicted. Moderate with FEV1 less than 80% predicted. Severe with FEV1 less than 50% predicted. Very severe with FEV1 less than 30% predicted.

In emphysema, spirometry will indicate air trapping, which is evident by increased residual volume as well as total lung capacity [12]. Chest X-ray will only aid in the diagnosis in the more severe or later forms of the disease, which can be evident by hyperinflation, alveolar destruction, and air trapping [10]. High-resolution computed tomography (HRCT) is the diagnostic modality of choice for characterization of emphysema as well as providing information of therapeutic options, which can include both medical and surgical options [13]. There are three distinct morphological subtypes of emphysema that have been described according to their locations throughout the secondary pulmonary lobules. They are panlobular, centrilobular, and paraseptal [14]. The most common form of emphysema is centrilobular, which is strongly associated with exposure to cigarette smoking. This is characterized by destruction of alveoli around the proximal respiratory bronchiole. This disease has a tendency to affect the upper portion of the individual lobes. Accordingly, it has a tendency to affect the apical and posterior segments of the upper lobes and the superior segment of the lower lobes. The destruction of these air spaces may enlarge into bullae, which are defined as sharply demarcated area of emphysema more than 1 cm in diameter with a wall less than 1  mm thick. In these emphysematous changes, there may be strands of residual parenchyma or bronchovascular tissue [14].

22  Emphysema and Cystic Lung Disease

Panlobular emphysema, in contrast to centrilobular, has a predilection for the lower lobes. In addition to the lower lobes, it has a uniform distribution across parts of the secondary pulmonary lobule, which are homogeneously reduced in attenuation. This morphology of alveolar destruction is most commonly seen in alpha 1 antitrypsin deficiency [14]. In a patient with signs and diagnostic findings of emphysema at a young age, testing for alpha 1 antitrypsin deficiency is warranted. Paraseptal (distal acinar emphysema is usually a focal or multifocal abnormality, which involves the pulmonary lobule most adjacent to connective tissue septa. The location is most commonly found in the periphery of the lung with a predilection along the fissures and at sharp pleural reflections. Giant bullae may be formed as different focal areas coalesce [14]. Development of multiple large lung bullae (previously termed Bullous emphysema or “vanishing lung syndrome”) has been described in young male smokers. It is a progressive disease characterized by dyspnea on exertion, hemoptysis, and infrequently spontaneous pneumothorax [13]. Chest radiographs in bullous emphysema will show paraseptal bullae in contrast to the centrilobular type found in typical smokers. These large bullae can occupy one-third of the involved hemithorax and compress the surroundings.

Treatment Initial therapy should involve the cessation of cigarette smoke exposure, pulmonary rehabilitation, and pharmacological therapy to improve morbidity [10].

Pharmacotherapy The Global initiative for Chronic Obstructive Lung disease suggests an initial approach based on patient presentation and severity of the disease. A long-acting muscarinic antagonist (LAMA) is the initial drug of choice for patients with COPD and emphysema with mild disease and no exacerbations. If the patient’s presentation is more severe with dyspnea, lung hyperinflation, and severe airflow obstruction, combining an LAMA with a long-acting beta2 agonist (LABA) is more effective [10]. In patients with a history of asthma, wheezing, rhinitis, polyps, allergies, or a blood eosinophil count (>150 per cubic millimeter), a combination of LABA and an inhaled corticosteroid may be warranted. If the severity of the disease continues, a combination of LAMA, LABA, and an inhaled glucocorticoid in a single inhaler device can decrease the risk of exacerbations, improve lung functions, and decrease risk of death [15]. Other pharmacological therapies for patients who are receiving inhaled therapy are oral macrolides. However,

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these agents should be used with caution due to the risk of adverse effects such as cardiac arrhythmias [16]. Another pharmacological therapy is the phosphodiesterase-4 inhibitor roflumilast, which can lower exacerbation rates among patients with severe COPD [10]. Biological agents, such as mepolizumab and benralizumab, have been shown to be beneficial in patients with asthma, however, with only marginal results in patients with COPD and emphysema [10]. Pulmonary rehabilitation is a modality of treatment, which has shown to be beneficial in patients with limited ability to perform activities of daily living. All patients with COPD and emphysema should be evaluated for hypoxemia at rest. In patients with oxygen saturation lower than 88% or a partial pressure of arterial oxygen (PaO2) less than 55 mm Hg, supplemental oxygen will decrease the risk of death [17]. In patients with advanced emphysema and significant hyperinflation refractory to optimized medical care, surgical or bronchoscopic modes of lung volume reduction should be considered such as endobronchial one-way valves, lung coils, or thermal ablation [18]. In patients with large bullae, surgical removal should be considered. In selected patients with very severe COPD and emphysema, a referral to a lung transplant capable center must always be considered.

Alpha 1-Antitrypsin Deficiency Alpha1-Antitrypsin deficiency (AAT) is a common but underrecognized genetic disorder. It is caused by the defective production of alpha-1 antitrypsin protein. The role of this protein is to protect the body from neutrophil elastase enzyme formed and released by white blood cells. In an unregulated state, neutrophil elastase destroys alveoli and causes damage to the lungs. Decreased level of AAT activity in the blood and lung and deposition of excessive AAT in the liver with resulting damage are both characteristics of this disease [19]. It usually develops between ages of 20 and 50, with the rate of lung decline strongly correlated with cigarette smoking.

Epidemiology This condition occurs worldwide; however, the prevalence of the disease varies by population. In individuals with European ancestry, it affects 1500 to 3500 persons. In the United States, it is estimated that there are 80,000 to 100,000 individuals with a severe and usually underrecognized forms of the disease. Worldwide, it is estimated that three million people have allele combinations associated with severe forms of the disease [20].

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Pathophysiology It is inherited by autosomal-codominant transmission. Individuals who have been affected have inherited the abnormal AAT gene from each parent. The SERPINA1 gene located on the long arm of chromosome 14 has been identified as the gene that encodes AAT, so a defect or deficiency can lead to decreased production of AAT [21]: 150 alleles of SERPINA1 have been identified with letter coding, the normal allele being referred to as “M.” In the general population, two copies of the “MM” allele exist in each cell. Different versions of the SERPINA1 gene lead to reduced levels of AAT. For instance, the S allele produces moderate amounts of AAT, whereas the Z allele produces minimal amounts [21]. Individuals who are (ZZ) are likely to have severe AAT deficiency, whereas the SZ, MS, MZ combinations have varied versions of AAT deficiency. Ninety-five percent of severe cases of AAT deficiency result from a homozygous substitution of a single amino acid Glu342Lys, the Z allele, present in 1  in 25 patients of European descent; 1 in 2000 persons of European descent is a homozygote [21]. Whereas mild AAT deficiency results from a different amino acid replacement of Glu264Val, the S allele, found in 1 of 4 persons in the Iberian Peninsula [21]. AAT, first described as a serine protease inhibitor, inhibits neutrophil elastase. When unopposed, neutrophil elastase can cleave many of the structural proteins of the lung as well as immune proteins. Other lung proteases, which are activated by unopposed neutrophil elastase, may also have a role in structural damage. AAT also interacts with a variety of proteins and fatty acids, whose loss with low or deficient levels of AAT may increase inflammation [21]. It should also be noted that AAT accumulation in the liver, notably within the endoplasmic reticulum of the hepatocyte, also causes a well-known form of liver disease in patients who are homozygous for the Z allele.

Risk Factors Cigarette smoking has a strong correlation with increasing the risk of COPD in the Z protein phenotype. Other risk factors include male sex and asthma [22]. Occupational exposure, chronic bronchitis, and pneumonia may also affect the severity of the disease.

Clinical Presentation and Diagnosis The presentation of this disease occurs in the three organs that it is related to, namely, the lung, liver, and, rarely, the skin. Dyspnea is the most prominent symptom; however, chronic cough, or wheezing, may occur [22]. A majority of children with the Z phenotype are recognized through new-

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born screening [22]. Extrapulmonary disease such as adult-­ onset hepatitis, cirrhosis, or hepatocellular carcinoma can occur. Skin manifestations of the disease include the formation of plaques, nodules, and panniculitis [23]. Diagnosis begins with the taking of a full medical history and physical examination, which includes assessment for COPD and signs of liver disease. A detailed family history and exposure to environmental and occupational hazards is crucial. As an underdiagnosed disease, all persons with COPD, poorly reactive asthma, c-ANCA vasculitis, panniculitis, or bronchiectasis, in addition to first-degree family relatives, should be tested [21]. Testing begins with a serum AAT level, with concurrent assessment of C-reactive protein (CRP). AAT and CRP are acute phase reactants that are increased during a period of inflammation. In a normal patient, an AAT level higher than or equal to 1.1 g/L in the presence of a normal CRP is evident of normal AAT status [21]. If the serum AAT level is less than 1.1  g/L, or if the clinical picture is indicative of AAT deficiency, consultation for phenotyping or genotyping should be performed in a specialist laboratory. Isoelectric focusing, a phenotype test, is the gold standard blood test for identifying AAT variants. Gene sequencing is performed in inconclusive cases [21]. All patients with a high clinical suspicion should be referred to a center specializing in AAT deficiency. In terms of imaging, chest radiograph may help to rule out other lung conditions but does not have a high sensitivity for the detection of emphysema. Computed tomography of the chest is an evolving means of diagnosis and characterization. The classic presentation of AAT is severe, early-onset panacinar emphysema with a basilar predominance. Emphysematous changes on CT scan can show a diffuse distribution or upper lobe predominance [22]. Health quality–related questionnaires, spirometry, DLCO, and the 6-min walk test should be monitored in these patients. Frequency depends on the severity of the disease, and monitoring every 6  months for the first few years is helpful in establishing a baseline and signs of rapid decline [21].

Treatment The treatment for lung disease associated with AAT deficiency is the same as treatment for COPD [21]. In 1987, Food and Drug Administration approved the use of intravenous augmentation therapy with plasma purified AAT. This approval was based on biochemical efficacy and pharmacokinetics, without proof of clinical efficacy [21]. Subsequent randomized controlled trials have showed decreased loss of lung density with plasma purified AAT, however, without an effect on FEV1, quality of life, or exacerbation of COPD. For AAT deficiency–induced liver disease, maintenance of a normal body-mass index and consumption of alcohol within recommended limits have been

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recommended [21]. Lung transplantation is a strong consideration for severe AAT deficiency. Although ­improving quality of life, survival was similar for nontransplanted patients [24].

Asian compared to Caucasian patients [27]. Further information will focus on pulmonary manifestations of BHD. Multiple bilateral pulmonary cysts are found in 80% of patients with BHD. Due to the presence of multiple cysts and a propensity to rupture, patients of BHD are predisposed to Birt-Hogg-Dube Syndrome spontaneous pneumothorax with a high recurrence rate, almost 50-fold higher than the general population [25]. Risk Birt-Hogg-Dube (BHD) is a rare inherited autosomal-­ factors for pneumothorax include number, size, and total voldominant disorder caused by germ-line mutations in the ume of pulmonary cysts, as well as family history of pneutumor suppressor gene FLCN, encoding the protein follicu- mothorax. No sexual predilection or association with lin. Clinical features of this condition include cutaneous smoking has been linked to the risk of pneumothorax [25]. fibrofolliculomas, multiple pulmonary cysts, recurrent Other than pneumothorax, patients with pulmonary BHD pneumothoraces, and renal tumors [25]. The use of high-­ are generally asymptomatic. Data has shown that lung funcresolution computed tomography has shown the prevalence tion parameters such as FEV1 and DLCO did not signifiand recognition of elementary lesions known as pulmonary cantly decline over 6  years, suggesting that BHD does not cysts. The diagnosis and forming differentials of cystic lung lead to respiratory insufficiency compared to the other cystic diseases remain challenging. Birt-Hogg-Dube syndrome is lung diseases [28]. one of the three most common causes of cystic lung disease, along with Lymphangioleiomyomatosis (LAM) and pulmonary Langerhans cell histiocytosis (PLCH) [25]. Diagnosis

Epidemiology Inherited as an autosomal-dominant trait, BHD is a rare disorder that affects males and females in equal numbers. It is estimated to affect about 600 families in the world. It is an underdiagnosed entity making it difficult to determine its true prevalence in the general population.

Pathogenesis FLCN is a tumor suppressor gene. The exact function of folliculin is not yet known; however, it is believed to regulate cell growth, proliferation, and survival. The formation of pulmonary cysts is not fully known. A hypothesis suggests that the formation of cysts occurs due to a consequence of deficient cell-cell adhesion and repeated stretch-induced stress caused by breathing, leading to the formation of dilated alveolar spaces leading to cysts. This hypothesis could explain the subpleural and basal distributions of cysts in BHD [26]. Renal cell carcinomas found in BHD are different from sporadic forms due to FLCN.

Clinical Presentation BHD is characterized by a broad phenotypic variance ranging from asymptomatic to varying degrees of cutaneous, pulmonary, or renal features. BHD has no sexual predilection and can arise at any age, although there is a tendency for it to form during the third or fourth decade of life. There is some data suggesting that there is a higher rate of pneumothorax in

BHD is a rare disease; accordingly, it has been underdiagnosed and mistaken for different forms of cystic lung disease. The most frequent expression of the disease is primary spontaneous pneumothorax, comprising almost 5–10% of cases [25]. In these patients, a thorough family history and imaging should be performed. It is important to evaluate for manifestations of the disease on the patient as well as family history of skin lesions, pneumothorax, lung cysts, and renal tumors [25]. HRCT in a patient with primary pneumothorax is a cost-­ effective means of diagnosis and is recommended for patients with a high degree of clinical suspicion. An HRCT will show multiple thin-walled bilateral cysts with normal surrounding parenchyma, which is a hallmark of the disease [29]. The size, shape, and number of cysts vary greatly with a preferential distribution in the basal, subpleural, or paramediastinal regions of the lung. Further features suggestive of BHD also include large irregular lobulated or multiseptated cysts, predominantly in the subpleural lower lung lesions or the presence of cysts proximal to the lower pulmonary vessels [25]. In contrast to LAM, lung cysts in BHD are larger, less circular, and do not to substantially increase over time [25]. Histopathology features of BHD include a predominantly basal distribution of the cysts and the presence of normal surrounding parenchyma without neoplastic cell proliferation or inflammation from an analysis of 229 cysts from 50 BHD patients [30]. Referral for genetic evaluation and counseling should be performed to confirm the diagnosis. Confirmation entails a combination of the identification of clinical features and an FLCH germ-line mutation [25]. Screening for renal tumors from the age of 20 for possible surgical resection and ­dermatological evaluation for skin involvement is recommended [25].

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Lymphoid Interstitial Pneumonia Lymphoid interstitial pneumonia (LIP) is a rare form of interstitial lung disease that has a histopathological characterization of diffuse, polyclonal infiltration surrounding airways and expanding lung interstitium. It is an uncommon disease without incidence and prevalence rates that are largely unknown [31]. Initially described as an idiopathic interstitial pneumonia in 1969, it is now considered a form of cellular nonspecific interstitial pneumonia (NSIP) [31].

Pathogenesis The cause of LIP is still being studied; however, it is found to be more prevalent in systemic conditions, which cause derangement of the immune system, derangement of serum proteins, or manifestations of an underlying infection. LIP is seen in conjunction with other systemic diseases such as infectious, immunodeficiencies, and rheumatic disease. A possible infectious etiology for LIP exists due to increased incidence in persons infected with the HIV or EBV virus [31, 32]. One of the most common associations with LIP is with Sjogren syndrome [31].

Clinical Features The majority of patients with LIP are female, with an onset of symptoms from the age of 40 to 70 years of age. There is no racial predominance in children; however, the majority of patients with HIV LIP are black, while HIV negative adults with LIP are white [33]. Symptoms include a dry cough and progressive dyspnea. In children, LIP presents in the second or third year of age with lung infiltrates, respiratory distress, and failure to thrive. Systemic symptoms such as fevers and night sweats are less common. Bronchospasm and cough may be present in the early forms of the disease prior to detection by radiology [31]. Examination of a patient with LIP will reveal bibasilar crackles. Clubbing is absent. Extrapulmonary lymphatic involvement including peripheral or mediastinal lymphadenopathy or splenomegaly is uncommon [31].

Diagnosis The hallmark of diagnosis of LIP is established by a lung biopsy, which showed septal infiltration of lymphocytes, plasma cells, and histiocytes. An exception to lung biopsy is in HIV-positive children, in which the clinical presentation and radiographic findings are sufficient [34] (More detail histopathological features are discussed in the chapter of lymphoproliferative diseases).

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Chest radiography is not specific for LIP, however classically described as having bilateral, predominantly lower zone, reticular or reticulonodular opacities. This pattern is evident in pneumocystis jirovecii pneumonia, miliary tuberculosis, or cytomegalovirus pneumonitis. However, a distinguishing factor is the indolence and lack of response to treatment [31]. HRCT is the radiologic procedure of choice to distinguish LIP.  Through this diagnostic modality, lymphadenopathy, thickened bronchovascular bundles, nodules of varying size, and ground glass opacities are often found [31]. In a study of 22 patients with LIP, the distribution showed bilateral (95%) diffuse (64%), patchy (23%), and peripheral (14%) patterns. Centrilobular nodules were also observed in 100% of cases, subpleural nodules in 86%, patchy bronchovascular bundle thickening in 86%, interlobular septal thickening in 82%, and 1 to 30 mm cysts in 68%. This differed to those patients with lymphoma, in which 2% of patients had cysts compared to 82% of those with LIP [35]. Spirometry will show restrictive pathology with an elevated FEV1/FVC with reduced total lung capacity. Uncorrected diffusing capacity of the lung is reduced on spirometry [33]. Analysis of BAL fluid in patients with LIP showed an increase in total white blood cell count with predominant lymphocytes. The number of T cells and B cells was within the normal range; however, T-suppressor cells were increased compared to T-helper cells [33]. Histopathology of LIP from a lung biopsy is characterized by interstitial infiltrate of lymphocytes, plasma cells, and histiocytes. According to the ATS/ESR classification, the characteristic feature of LIP is extensive alveolar septal infiltration. It further described the cellular infiltrate to appear along bronchi and vessels. This classification proves to differentiate LIP from diffuse lymphoid hyperplasia, which affects areas of the interstitium rather than alveolar septa [34]. Polyclonality of the infiltrates distinguishes LIP from pulmonary lymphoma [33].

Treatment After a histopathologic diagnosis of LIP is done, investigation of associated conditions and treatment of the underlying conditions must be performed. Controlled clinical trials have not been performed for LIP, rather depending on anecdotal experience from case reports and case series. A majority of these reports use corticosteroids as the primary therapy, with usage of other immunosuppressive agents such as cyclophosphamide and chlorambucil. All these therapies have variable results [36]. Therapies for HIV-induced LIP with three-nucleoside analogue regimen have been reported but need further study [36]. Treatment differs based upon the varying severity of symptoms, and association with rheumatic disease, immunodeficiency, or HIV infection.

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Neurofibromatosis-Related Lung Disease

Clinical Presentation

Neurofibromatosis-1 or von Recklinghausen’s disease is an autosomal-dominant disorder. Initial presenting symptoms include café au lait macules; however, there is varying involvement of skeletal, neurological, and pulmonary organs. The existence of neurofibromatosis-associated diffuse lung disease (NF-DLD) has been a contested topic. It is a manifestation of a disease with nonspecific respiratory symptoms associated with cigarette smoking. It has a pattern of upper lobe cystic and basilar interstitial lung disease.

Presentation of NF-DLD is variable and nonspecific. In patients with NF1, symptoms can range from dyspnea, chest pain, chronic cough, hemoptysis, spontaneous pneumothorax to an incidental finding [40].

Epidemiology The larger incidence and prevalence of NF-DLD remains unclear. An initial study from 1981 observed 200 patients with NF-1; however, none were found to have pulmonary disease. A limitation of this study was that no CT scans were performed [37]. Further studies including one in with 64 patients with NF-1 were reviewed: 8 people had high-­resolution computed tomography (HRCT) scans, which showed 25% with emphysema, 37% with ground glass opacities, and 50% with reticular abnormalities and bullae [38]. In a 2015 study looking at 88 NF1 patients, 13 were positive for cysts, 18 for emphysema, 8 for nodules, and 8 for ground glass nodules [39].

Risk Factors The major risk factor for the development of NF-DLD was hypothesized to be secondary to cigarette smoke. However, recent studies have not shown this correlation. In a study by Ueda et al., 88 patients with NF-1 did not show a difference in the occurrence of cysts between smokers and nonsmokers. In a study by Oikonomou et  al., the conclusion was that smoking is not the cause of diffuse lung disease in NF1; however, it can increase the severity of the disease and manifest at a younger age.

Pathophysiology NF-1 is a tumor suppressor gene, which encodes for neurofibromin. This protein downregulates Ras activity. Mutations in this NF-1 gene can lead to decreased or malfunctioning neurofibromin production, leaving Ras activity unregulated resulting in increased cell growth and proliferation. However, the pathophysiology behind NF-DLD is largely unknown. Previous studies have shown a possible link to increased collagen deposition with amyloid deposition in some cases [40]. The formation of cysts occurs due to increased lymphocytic infiltrates around alveolar septa dilating bronchioles and leading to cyst formation [40].

Diagnosis HRCT is the modality of choice for NF-DLD. Findings include thick and well-defined borders around the cysts and bullae, unlike COPD and emphysema due to cigarette smoking in which the borders are ill defined. The cysts are a result of distal acinar emphysema as compared to centrilobular emphysema in COPD [40]. Pathology findings from lung biopsies of patients with NF-DLD show elevated intra-alveolar eosinophils and pneumocytes instead of macrophages [41]. Pulmonary function tests will show a decreased diffusion capacity for carbon monoxide (DLCO); however, the other modalities in this test can vary from obstructive, restrictive, to mixed or normal patterns [40].

Treatment Currently, there are no known therapies for NF-DLD. Rather, complications are managed symptomatically. Due to the rare presentation of NF, there are no guidelines for the routine screening of NF-DLD.  All patients with respiratory symptoms should have an HRCT and those with cigarette exposure should be counseled on smoking cessation [40].

Ehlers-Danlos Syndrome Ehlers-Danlos Syndrome (EDS) is a hereditary multisystem disorder affecting the soft connective tissue. It is a disorder that is characterized by skin hyperelasticity, hypermobility of joints, atrophic scarring, and fragility of blood vessels [42]. First described by a Russian dermatologist in 1891, it was then reported in 1901 and 1908 by the Danish and French dermatologists Ehlers and Danlos [43]. It is a clinical diagnosis; however, to recognize the type of EDS, gene encoding the collagen or protein interaction is necessary [43] .

Epidemiology The prevalence of EDS is estimated to be approximately 1 in 2500 to 1 in 5000 births, with no racial predisposition. It is underrecognized, and the incidence rises with physician awareness. A new classification system was estab-

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lished in 2017, and epidemiologic data based on this system is minimal [44]. This new classification system described 13 different subtypes. The top five subtypes that are also the most clinically relevant ones are as follows: classical EDS, Classical like EDS, Cardiac valvular EDS, Vascular EDS, and Hypermobile EDS [42, 44]. Pulmonary involvement has not been identified as one of the subtypes. Pneumothoraces have been described as a clinical feature of Vascular EDS [44].

Pathophysiology The multiple subtypes of EDS involve heritable mutations in the synthesis or processing of collagen. Variable inheritance patterns, including autosomal-dominant and autosomal-­ recessive inheritance across different mutations, are responsible for the wide variety of clinical symptoms. The variability of these symptoms exists as collagen is integral to every body system, from the skin, vasculature, lungs, to the heart [45].

Clinical Features Patient presentations can vary based on the subtype, with skin hyperextensibility being the most present sign of EDS [43]. This section will focus on the pulmonary features of EDS. The Vascular type of EDS (vEDS), which involves an autosomal-dominant pattern and is associated with mutations in the genes (COL3A1 and COL1A1), which code for Type III and Type I collagen, bears special mention due to the incidence of pneumothorax and hemothorax in this subgroup. Although the data is scant, a retrospective study in 2019 sought to examine the relation of pulmonary manifestations in vEDS. This multi-institutional study examined cases in which the patients were confirmed to have the COL3A1 mutation: 96 cases were found to have confirmatory testing for vEDS.  A documented hemothorax or pneumothorax occurred in 17, or 17.7% of cases. These complications occurred prior to the diagnosis of vEDS in 81% of cases. Accordingly, it was recommended that a spontaneous pneumothorax or hemothorax in young patients should trigger a differential diagnosis that includes vEDS [43, 46]. Few case reports have reported bullous emphysema present in EDS [47].

Diagnosis A full history and physical examination with a comprehensive family history should be elicited when EDS is clinically suspected.  The work-up is initially limited to the extent of the pathology affecting the body. Ultimately, subtype level diagnosis is performed with a referral to a geneticist.

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There are no studies recommending routine imaging for EDS due to phenotypic variance. Pulmonary manifestations are found incidentally or after a complication such as a pneumothorax or hemothorax.

Treatment Due to the multitude of complications, treatment entails a multidisciplinary approach with focuses on disease prevention of disease progression and subsequent complications. There is no cure for this disease, and specialist evaluation is dependent on the organ involved.

Marfans Syndrome Marfans syndrome (MFS) is an autosomal-dominant condition involving the FBN1 as the causal gene. This gene encodes an important extracellular matrix protein, fibrillin-1. The pathogenesis is still under study. It was first described 100  years ago, by a French pediatrician Antione-Bernard Marfan who described a five-year-old girl with long slender digits, long bone overgrowth, and muscle hypoplasia [43]. This disorder is a systemic process with variable clinical presentations occurring in the cardiovascular, ocular, and ­skeletal systems. Pulmonary complications are not considered a main feature, and its study is ongoing.

Epidemiology An autosomal-dominant inheritance with only case reports of recessive fibrillin 1 (FBN1) mutations. Worldwide, it occurs in 1  in 5000 persons, affecting both sexes equally. Underdiagnosis is common as it can exhibit complete penetrance with variable expression. Twenty five percent of cases present sporadically due to de novo mutations. It is one of the most common single-gene malformation syndromes [48].

Pathogenesis The pathophysiology is still under study. The pathogenesis of lung involvement is largely unknown. The pathophysiology of aortic dilation in MFS may be due to fibrillin-1 interaction and regulation of TGF-beta leading to inflammation and fibrosis [49].

Clinical Characteristics MFS involves the skeletal system, ocular system, cardiovascular system, dura, skin, and the pulmonary system. In the pulmonary system, complications can arise such as pneumothorax, pulmonary emphysema, and dysfunction due

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to alveolar septation defects [43]. Restrictive lung disease can result from severe skeletal deformities such as pectus. Spontaneous pneumothorax can be recurrent and associated with emphysema. Relapsing pneumothorax can affect 5–11% of patients [50, 51]. In a study of 64 patients with MFS, 14% were found to have a previous pneumothorax. Emphysema can affect 5–10% of patients. Cerveri et al. examined the previously mentioned 64 patients with MFS and found 7 (10%) patients with subpleural apical blebs. Restrictive lung disease is much more common in MFS and is found in 70% of patients. This association is due to the high prevalence of skeletal deformities such as pectus [52]. Cerveri et  al. found only 37% patients with normal lung function, 19% with a restrictive pattern, and 44% with an obstructive pattern on spirometry.

Diagnosis Diagnosis is set by clinical criteria known as Ghent nosology, which relies on a required number of major and minor criteria. This criterion was revised in 2010 to place greater weight on aortic root dilation/dissection and ectopia lens [43]. Pulmonary involvement is only defined as minor criteria due to low specificity. The use of spirometry is not routine in MFS. However, in patients with dyspnea and severe deformity, lung function tests should be performed to assess for restrictive lung disease [52]. In patients with significant thoracic deformity, spirometry must be normalized to sitting height rather than body surface area [51]. There are no studies recommending routine computed tomography of the chest for asymptomatic persons. However, it is to be considered for symptomatic persons, or with skeletal or thoracic abnormalities. In MFS, various pulmonary manifestations have been described such as interstitial parenchymal disease and honey combing, diffuse and apical emphysema, congenital malformations of the bronchus, bronchiectasis, and spontaneous recurrent pneumothorax. Lung cysts and bullae are uncommon. In a review of 100 patients with MFS, only five were found to have lung cysts [53]. However, early identification of blebs and bullae may allow for risk stratification for pneumothorax in patients with MFS [54].

Treatment and Management Diagnosis and management of MFS requires a multidisciplinary approach with focus on the complications that arise in the patient. For instance, with the complications of spontaneous pneumothorax, restrictive lung disease, and diseases of the lung parenchyma, evaluation with a Pulmonary specialist must be prompt. For the pulmonary aspect of MFS, evaluation with a pulmonologist should be prompt in the setting of pneumothorax or restrictive lung disease.

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Bronchogenic Cysts Bronchogenic cysts (BC) are congenital, cystic malformations usually encountered in the mediastinum. They can occur anywhere along the developmental pathway of the foregut. Due to the wide variety of clinical and radiological manifestations, diagnosis is difficult. It is especially challenging in countries in which hydatid disease is endemic. Treatment of BC is surgical excision, and diagnosis is established by histopathology. The prognosis with complete resection is favorable [55, 56].

Epidemiology Bronchogenic cysts have a prevalence of 1 per 42,000 to 1 per 68,000 in two hospital series. Between men and women, men have a slightly increased predominance for the disease. The usual diagnosis occurs in the third or fourth decade of life [55, 57]. The area of proliferation of this disease is usually the middle mediastinum. Mediastinal bronchogenic cysts have five types depending on their location, which include paratracheal, carinal, paraesophageal, hilar, and miscellaneous [58]. Case reports have shown that there are other locations, which include the retroperitoneum, diaphragm, pleura, pericardium, and the neck.

Clinical Features Bronchogenic cysts are usually asymptomatic for years, however symptoms from compression of surrounding features or infection can reveal the disease. Chest pain, dysphagia, dyspnea, and cough are symptoms. Infectious is the most serious complication. When cysts communicate with the tracheobronchial tree, it can cause dyspnea, cough, fever, sputum production, and hemoptysis [55]. Compression of the esophagus with growing cyst size can cause chest pain and shortness of breath. Bronchogenic cysts can also compress on the left atrium causing arrhythmias, superior vena cava syndrome, and pulmonary artery stenosis [55]. A rare but serious complication of this disease is the malignant degeneration of bronchogenic cysts. In 1941, Womack and Graham first described abnormal cell growth along the lining of bronchogenic cysts; however, they did not believe that this could be considered to be clinically malignant. Furthermore in 1947, Moersch and Claget stated that the mucosal lining of bronchogenic cysts may develop into carcinoma. Only few case reports in the English language have shown reasonable suspicion to malignant change in congenital bronchogenic cysts. More recent reviews reached the conclusion that the risk of malignancy is minute compared to the risk of other associated complications. A degradation of the cystic component is more likely than the malignant degeneration of a congenital bronchogenic cyst [55, 59].

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Diagnosis Diagnosis is usually incidental on chest radiography. On chest radiography, the finding is a smooth oval or round homogeneous density in close proximity to the major airways. Other than a homogenous water density, presentation can vary to an air-filled cyst, or with an air fluid level [60]. Of the classification system based on location, the hilar is most common, although some authors state that the carinal location is most common in benign bronchogenic cysts [61]. Computed tomography of the chest is the initial diagnostic modality of choice. Presentation can vary from typical water density to high density related to blood, increased calcium content, anthracotic pigment, or increased protein content of the fluid [59]. Further characterization of the cyst can be performed by magnetic resonance imaging. Definitive diagnosis is based on histopathological findings of the surgical specimen. Examination will show ciliated pseudostratified columnar epithelium of respiratory type with possible areas of squamous metaplasia. Cyst wall airway components may include cartilage plates, bronchial glands, and smooth muscle. In very rare instances, the wall can consist of nerve and adipose tissue [55].

Treatment Management of bronchogenic cysts depends on the presentation of symptoms and age. Surgical resection is the choice of therapy, as it can prevent complications and establishes the diagnosis. The route of surgery is either by thoracotomy or video-assisted thoracoscopic surgery (VATS). Surgical removal should be complete, due to the risk of recurrence. However, the prognosis is excellent in the case of complete resection. The treatment of asymptomatic bronchogenic cysts is contested with some studies showing favorable outcomes with a surgical approach [55, 62]. In the case of intrapulmonary bronchogenic cysts, a lobectomy is preferred. In patients with limited lung function, conservative managements such as total pericystectomy, wedge resection, or segmentectomy are recommended [62]. In rare cases of mediastinal bronchogenic cysts, the presence of adhesions can lead to recurrence. However, this complication can be prevented with resection or destruction of the mucosa [62]. Finally, imaging surveillance can be a conservative option to ensure stability [55].

Cystic Fibrosis Cystic fibrosis (CF) is an autosomal-recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The postulation that CF is

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caused by a defect in a single gene was found in 1949 by Lowe et al., based on the inheritance of the disease [63]. It has a historical description, which still is valid today by high levels of salt in the sweat of patients with CF. This description led to the hypothesis that an abnormality in fluid and electrolyte transport in the sweat gland existed. Analysis of airways of patients with CF proved evidence that there also existed a defect of chloride impermeability in the lung. Soon after the discovery of abnormal chloride transport, Collins, Riodran, Tsui, and colleagues identified the gene responsible for the disease [63].

Epidemiology CF, among Caucasians, occurs approximately in 1 in 3000– 4000 live births. In the USA, approximately 1000 persons are diagnosed with CF each year. One in 25–30 Caucasians are carriers of the pathogenic mutation of the CFTR gene. It is uncommon in other races and ethnicities, occurring in approximately 1  in 4000–10,000 Latin Americans, 1  in 15,000–20,000 African Americans, and less commonly in Asian Americans [64]. In 2004, the Center for Disease Control and Prevention recommended that all states consider NBS for the diagnosis of CF. The proportion of individuals who have been diagnosed since then have increased to account for nearly 2/3rds of all diagnoses. Early diagnosis has also led to improved outcomes [64].

Pathophysiology The mutation in the gene encoding the CFTR gene can lead to a decreased secretion of chloride, which then leads to the increased resorption of sodium into the cellular space. The increased resorption of sodium, then leads to water resorption and leads to viscous secretions from exocrine tissues and commonly affect organs, which include the sinuses, lungs, pancreas, biliary and hepatic systems, intestines, and sweat glands. This chapter will focus on the pathobiologic features in the lung [63, 64]. Mucosal obstruction of exocrine glands is the major factor in the morbidity and mortality of patients with cystic fibrosis. In the lung, thick secretions will obstruct the distal airways and submucosal glands, especially in areas where CFTR expression is high. Dilation of these glands due to the blockage of mucus, and the thick, viscous, neutrophil-­dominated mucopurulent debris are the pathobiologic hallmarks of the disease. Dilation will then lead to glandular hyperplasia surrounded by peribronchiolar inflammation and scar tissue. When thick airway secretions can not be cleared, there is an increased risk of infections by Pseudomonas aeruginosa, Burkholderia cepacia, Staphylococcus aureus, and Haemophilus influenzae. Pulmonary infection, shown by the elevated levels of inflammatory markers, is another cause of decline in respiratory function [63, 64]. This may precede the onset of chronic infection.

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It should be also noted that the absence of normal CFTR in other organs as mentioned above. Pancreatic ducts will fibrose from mucinous impaction leading to fatty replacement of the gland. The pediatric population will have intestinal obstruction (meconium ileus) as an early sign in the first few days of life. Infertility can occur in men due to glandular obstruction of the vas deferens in utero. And obstruction of bile canaliculi can cause hepatic damage and lead to fibrosis [63].

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Due to the variety in the ways in which CF is manifested in different organs, it is dependent on age and involvement of the organ. In neonatal patients, diagnosis is made on newborn screens. Meconium ileus, which occurs in 10% of patients with CF causing bowel obstruction with or without perforation and peritonitis is a common presentation [65]. In infants and young children, current respiratory symptoms such as cough, wheezing, pneumonia, and failure to thrive are evident. Exocrine pancreatic insufficiency is present in 85–90% of these cases leading to steatorrhea, diarrhea, and abdominal distention [65]. In older children and adults, respiratory symptoms similar in young children can be present. Along with nasal polyps, sinusitis, male infertility, recurrent acute pancreatitis, liver disease, malabsorption and dehydration, or recurrent pulmonary infections with atypical bacteria [65].

Additional diagnostics such as chest radiography or computed tomography of the chest is invaluable in identifying complications and tailoring treatment of CF. Chest radiographs are less sensitive than high-resolution chest tomography in detecting the early changes. However, changes that can develop in the disease include bronchiectasis, hyperinflation, lobar collapse, and pulmonary arterial enlargement due to pulmonary arterial hypertension. Scoring systems such as the Brasfield scoring system and Chrispin-­Norman score can be used to score severity and structural changes. High-resolution chest tomography (HRCT) has been invaluable in monitoring and therapy. Early findings in the disease are bronchial wall thickening, acute infectious bronchiolitis, tree in bud appearance, centrilobular nodular opacities, or branching opacities. Bronchiectasis can vary in appearance with progression of the disease. Mosaic attenuation patterns can also occur due to air trapping, along with mucus plugging within bronchi [67, 68]. Pulmonary function test is a useful tool to monitor the progression of CF.  Values such as forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and their ratio FEV1/FVC are measured and critical in monitoring the severity of the disease. These values are compared to expected age, height, and gender to generate a normal value. A high FEV1 or FEV1/FVC can show restrictive disease, while a low value could represent obstructive lung disease with airway trapping. FEV1 values can show the severity of the disease as fibrosis and air trapping occur [69].

Diagnosis

Treatment

Newborn screening for CS is a part of the standard panel in the United States. According to the consensus guidelines from the Cystic Fibrosis Foundation, CF is diagnosed when an individual has both a clinical presentation of the disease and evidence of CFTR dysfunction. Evidence of CFTR dysfunction is obtained through sweat chloride testing, with a diagnostic value of greater than or equal to 60 mmol/L. The sweat chloride test is used with a positive newborn screen, clinical features consistent with CF, or a positive family history [66]. In adults, a clinical presentation of CF with a positive stress chloride test greater than or equal to 60  mmol/L is diagnostic. However, in adults with clinical presentation of CF, with an intermediate range of the sweat chloride test (30–59  mmol/L), genetic analysis showing 2 CF causing CFTR mutations is diagnostic. If the genetic analysis shows CFTR genotype that is undefined or unknown, with known clinical symptoms, with CFTR dysfunction on CFTR physiologic testing, it will confirm a diagnosis of CF [66] as well. Diagnosis must still be confirmed by expert opinion and be in accordance with the CF diagnosis consensus guidelines published in 2017 [66].

A multidisciplinary approach is crucial for the treatment and prevention of exacerbations. Aggressive nutritional support, and respiratory clearance of the airways to prevent infection, has a role in avoiding acute illness. Consensus guidelines as determined by the Cystic fibrosis foundation exist for the treatment of an exacerbation of Cystic fibrosis. In times of exacerbation, the goal is to treat the infection, promote respiratory clearance, and to improve oxygenation. Currently, guidelines recommend at least one antibiotic to cover for pathogenic bacteria obtained from respiratory secretions, and two different antibiotics for Pseudomonas aeruginosa infections. Oral, intravenous, or inhaled antibiotics are utilized based on the severity of the exacerbation [70, 71]. Oxygenation is promoted through the routine use of bronchodilators. In addition, respiratory clearance is promoted with the use of inhaled dornase alfa or hypertonic saline along with chest physiotherapy. The CF foundation found insufficient evidence to make a recommendation for the usage of systemic corticosteroids in patients with acute flares [70]. The mode of oxygenation, such as nasal cannula, bilevel positive airway support, and intubation with mechanical ventilation, should be used depending on expert opinion and the clinical situation [70].

Clinical Features

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CFTR modulator therapies are a new class of therapies aimed to correct the production, intracellular processing, and function of the CFTR protein caused by the mutated gene. The uses of these classes of medications are expanding with further studies [72]. The field of treatment for this disease is expanding; however the disease can progress despite treatment. Lung transplantation is the choice for end-stage disease. The timing of the transplant is based on a multidisciplinary decision and expert consensus. The International Society of Heart and Lung transplantations published recommendations on this matter and summarized in a table below [71]. Overall, lung transplant with advanced disease is recommended, and referral to transplant capable facilities for consideration of transplantation should not be delayed if congruent with patient wishes [70]. Transplantation is not a cure; it is to confer symptomatic relief. Referral to lung transplant center  – FEV1 300 200 to 300  45 years, brain death, smoking history, alcohol use, prolonged mechanical ventilation, and hemodynamic instability), prolonged ischemic time, ischemic-­ reperfusion injury after implantation, massive transfusion during operation, and ventilator-induced lung injury. The incidence of PGD is approximately 30% early after transplant and 15–20% for grade 3 PGD at 48 and 72 h, respectively [5]. Notably, the provided definition of PGD by ISHLT is broad with the intention to be inclusive, which allow the clinicians to work up for other identifiable causes of hypoxemia, e.g., infection, allograft rejection, or cardiogenic pulmonary edema. The main histopathology of the allograft with PGD is diffuse alveolar damage (DAD), including reactive pneumocytes, hyaline membrane formation, and alveolar septal thickening. Organization might be seen over time. DAD from PGD is indistinguishable from other etiologies. PGD is an important cause of morbidity and mortality in early posttransplant period. In the long term, PGD is also associated with chronic lung allograft dysfunction [5].

Department of Forensic Medicine, Mahidol University, Bangkoknoi, Thailand e-mail: [email protected]

Anastomotic Complication

J. R. Torrealba (*) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA e-mail: [email protected]

Airway anastomotic complication was a major complication in the early era of lung transplant. At that time, bronchial dehiscence was a major cause of death in many patient post-

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 C. A. Moran et al. (eds.), The Thorax, https://doi.org/10.1007/978-3-031-21040-2_27

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transplant [6]. The more recent improvements in surgical technique, organ procurement and preservation, and immunosuppressive regimen led to a decrease in airway complication after lung transplantation. The reported rate of bronchial anastomotic complication ranged between 1.6% and 33%, with the average of 15% [7]. The most common complication is bronchial stenosis/stricture, followed by necrosis and dehiscence, excessive granulation tissue, tracheobronchomalacia, fistula, and infection. Endobronchial biopsy at the anastomotic site is commonly performed to assess for these complications. Mucosal ulcer with neutrophilic infiltrate, necrotic debris, and granulation can be seen (Fig.  27.1). Fungal stain (e.g., periodic acid-Schiff [PAS], Gomori-­ Grocott methenamine silver stain [GMS]) is frequently performed on this type of specimen, as the colonization/infection by Aspergillus species and other fungi could happen commonly. Bronchial stenosis can be so severe requiring re-­ transplantation (Fig. 27.2).

S. Sathirareuangchai and J. R. Torrealba

Vascular anastomotic complication is rare in lung transplantation, with the rates of 1.8–5.2% [8, 9]. Nonetheless, it is associated with high morbidity and mortality. The vascular anastomotic complications include (1) a kinking of the anastomosis leading to obstruction, (2) a problem of vessel orientation (inversion of the donor vessel), (3) a true stricture of the anastomosis caused by suture, (4) intraluminal obstruction from thrombosis or dissection, and (5) an extraluminal mass lesion from the use of omental pedicles.

Hyperacute Rejection Hyperacute rejection is rapid graft failure that happens early following transplant surgery. It is a prototype of antibody-­ mediated rejection mostly mediated through preformed antibodies against donor human leukocyte antigen (HLA). Hyperacute rejection is extremely rare at the present since pretransplant crossmatch can be performed with accuracy. Pathologic changes can be visible during surgery with graft discoloration, edema, and congestion. Microscopic examination shows primarily acute lung injury pattern, with pulmonary edema, parenchymal hemorrhage, platelet and fibrin thrombi, and alveolar neutrophilic infiltrate [10].

Acute Rejection

Fig. 27.1  Endobronchial biopsy of an anastomotic site shows necrotic debris and acute inflammation. GMS stain (inset) reveals fungal hyphae consistent with Aspergillus species

Fig. 27.2  Microscopic image of bronchial stenosis in the explant lung for re-transplantation. There is marked fibrosis and scarring, mucosal hemorrhage, and extensive proliferation of granulation tissue

Acute rejection is considered clinically when either an abnormality in gas exchange (hypoxemia) or a decline in lung function tests is present [11]. Transbronchial biopsy is still the gold standard for diagnosis of allograft rejection. It can be performed as a part of surveillance protocol or in symptomatic patient. Around one-third of lung transplant patients experienced at least 1 episode of treated acute rejection between discharge and 1  year after transplant [2]. Currently, the rate of acute rejection is on the trend of steady decline. Risk factors for development of acute rejection include recipient age (18–34  years) [2], HLA mismatches [12], and donor factors (young age, blunt head trauma, nonblack race, non-O blood group) [13]. Histologically, acute rejection is characterized by perivascular mononuclear cell infiltrates and lymphocytic bronchitis and bronchiolitis. Acute rejection is the result of adaptive immune response to foreign (donor) major histocompatibility complex (MHC). Lately, regulatory CD4+ Foxp3+ T cells (Tregs) has been shown to be a major component in allograft tolerance. In an animal model study, Tregs was found to modulate graft acceptance through the suppression of interleukin (IL)-17 production by inhibiting Th17 cells response. [14] The original standardized grading system for lung allograft rejection was released by the ISHLT in 1990 [15] and later revised in 1996 [16] and 2007 [17]. The working formulation

27  Pathology of the Lung Allograft

for the standardization of nomenclature in the diagnosis of lung rejection focuses purely on histopathologic findings. As acute rejection can be patchy in nature, at least five pieces of well-expanded alveolated parenchyma are required for adequate morphologic evaluation [17]. At least three levels of routine hematoxylin and eosin should be assessed. Connective tissue stain such as Movat pentachrome, Masson trichrome, or elastic stain can be used to evaluate parenchymal and vascular changes in chronic rejection. When infectious microorganisms are suspected, additional special stains (acid-fast bacilli, GMS, PAS) or immunohistochemical (IHC) stains for viruses (cytomegalovirus, herpes simplex virus, adenovirus, etc.) can be performed. In our institution, it is standard to obtain 13 consecutive 5–6 μM levels from the lung allograft biopsies, and stain levels 1, 4. 6, and 9 with routine hematoxylin and eosin (H&E) stain, level 5 for GMS stain, and level 13 for C4d IHC.

Acute Cellular Rejection

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Transbronchial biopsy with grade A1 shows scattered, infrequent perivascular mononuclear infiltrates in alveolated parenchyma. Lymphocytes form a ring of two to three layers within the adventitia (Fig. 27.3). In grade A2, the infiltrates can be recognizable at scanning magnification. The components of the infiltrates include a mixture of lymphocytes (both inactive and activated), eosinophils, and macrophages (Figs. 27.4–27.6). Endothelialitis, defined as subendothelial lymphocytic infiltrate, can also be seen in grade A2. Grade A3 shows dense perivascular mononuclear cell infiltrates, which are commonly associated with endothelialitis. Eosinophils and occasional neutrophils are commonly seen in the infiltrates. The characteristic feature in grade A3 is the extension of the inflammatory cell into perivascular and peribronchiolar alveolar septa and airspaces (Fig. 27.7). This can also be accompanied by intra-alveolar macrophages and type 2 pneumocyte hyperplasia. Grade A4 is characterized by diffuse perivascular, interstitial, and airspace infiltrates of mononuclear cells with prominent alveolar pneumocyte

Acute cellular rejection (ACR) in lung allograft is reported as the A grade in the 2007 ISHLT classification. Histologically, it is characterized by perivascular and interstitial mononuclear cell infiltrates, with or without acute lung injury. The grading is based on density and extension of the infiltrates as shown in Table 27.2. Table 27.2  2007 ISHLT grading and definition on acute rejection [17] Acute rejection grading A0—no ACR A1— minimal ACR A2—mild ACR

A3— moderate ACR

A4— severe ACR

AX— unable to evaluate

Definition Normal pulmonary parenchyma without evidence of mononuclear infiltration, hemorrhage, or necrosis Circumferential infiltration of perivascular (venules and arterioles) interstitium by mononuclear inflammatory cell, up to 2–3 layers. No evidence of eosinophils and endothelialitis Recognizable mononuclear cell infiltrates at low power magnification. Eosinophils and endothelialitis can be seen. No evidence of obvious infiltration into the adjacent alveolar septa or airspaces Extension of infiltrate into perivascular and peribronchiolar alveolar septa and airspaces with associated polymorphonuclear cells (eosinophils and occasional neutrophils). Endothelialitis is common. Intra-alveolar macrophages collection and pneumocyte type 2 hyperplasia may be present Diffuse perivascular, interstitial, and airspace infiltrates of mononuclear cells with prominent alveolar pneumocytes damage and endothelialitis. Intra-alveolar necrotic epithelial cells, macrophages, hyaline membranes, hemorrhage and neutrophils can be seen. Other findings include parenchymal necrosis, infarction, and necrotizing vasculitis No or minimal alveolar parenchyma

Fig. 27.3  Acute cellular rejection grade A1 is characterized by 2-3 layers of lymphocytic perivascular infiltrate

Fig. 27.4  Perivascular lymphocytic infiltrate in grade A2 can be recognized at low to medium power magnification

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Figs. 27.5 and 27.6  High power view of acute cellular rejection grade A2 shows prominent perivascular lymphocytic infiltrate with endothelialitis. Eosinophils can be seen

mation, foreign body multinucleated giant cells, and mixed interstitial inflammation is a microscopic feature indicating aspiration [18].

 mall Airway Inflammation/Lymphocytic S Bronchiolitis The 2007 ISHLT nomenclature recommends evaluation of airway inflammation in the terminal or respiratory bronchioles as the B grade, hence the name small airway inflammation or lymphocytic bronchiolitis [17]. The grading of small airway inflammation has been reduced to two-tier system in the 2007 classification for better inter- and intra-observer reproducibility. The letter R denotes revised version. The Fig. 27.7  Acute cellular rejection grade A3 shows dense perivascular infiltrate with extension into adjacent alveolar septa and air space, and grading is shown in Table 27.3. foci of AFOP (acute fibrinoid organizing pneumonia) Grade B1R (low-grade small airway inflammation) is defined by mononuclear cells infiltrate within the submucosa damage and endothelialitis. Other features include intra-­ of the bronchioles, which can be infrequent and scattered or alveolar necrotic epithelial cells, hyaline membrane, paren- forming a circumferential band (Fig. 27.8). The infiltrate is chymal necrosis, infarction, and necrotizing vasculitis. In limited to the submucosal layer, and epithelial injury is not general, high-grade rejection (A3 and A4) is associated with evident. Occasional eosinophils may be seen. In grade B2R histomorphologic patterns of acute lung injury including or high-grade small airway inflammation, the mononuclear organizing pneumonia, fibrinous material, or hyaline mem- cells appear larger and activated, with greater numbers of brane [18]. eosinophils and plasmacytoid cells (Figs. 27.9 and 27.10). The main differential diagnosis in acute rejection is Besides acute rejection, peribronchiolar inflammation can infection, both clinically and histologically. Predominant be the result of infection. Neutrophils, necrosis, granulomas, inflammatory response in bacterial infection is neutrophils. and viral cytopathic effect are more commonly seen in infecWhile viral infection can be less obvious, perivascular infil- tion [18]. Even though the 2007 ISHLT classification specitrate by T-lymphocyte can also be seen in viral infection. fies small airway as the B grade, it might not be necessary to Viral cytopathic effect, when identified, clearly favors viral separate small from large airway (cartilaginous airway), infection over rejection. The presence of histiocytic inflam- since both are risk factors for obstructive bronchiolitis [11].

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27  Pathology of the Lung Allograft Table 27.3  2007 ISHLT grading and definition on small airways inflammation [17] Small airways inflammation grading B0—no small airway inflammation B1R—low-grade small airway inflammation B2R—high-grade small airway inflammation BX—ungradable

Definition No small airway inflammation Mononuclear cells within the submucosa of the bronchioles Larger and activated mononuclear cells with eosinophils and plasmacytoid cells. Epithelial damage is evident along with intra-epithelial lymphocytic infiltration Sampling errors, infection, tangential cutting, and artifact

Fig. 27.8  Low grade lymphocytic bronchiolitis (grade B1R) shows lymphocytic infiltrate, which is limited to the submucosal layer

Antibody-Mediated Rejection Antibody-mediated rejection (AMR) is mediated through either preformed or de novo recipient antibodies against donor HLA (donor-specific antibodies, DSA). The antigen-­ antibody complex activates the immune response to the allograft via both complement-dependent and independent pathways, resulting in allograft damage and dysfunction. Unlike in other solid organ transplants, AMR in the lung allograft is not well-understood and clearly defined. Lung AMR was first recognized in the 2007 ISHLT nomenclature, but no definite histologic or immunologic criteria were established, besides a brief mention of histopathologic finding of “capillary injury” in AMR.  In 2013, the Pathology Council of the ISHLT introduced a concept of multidisciplinary approach to lung AMR in a summary statement [19]. This so-called triple test is composed of (1) clinical allograft dysfunction, (2) circulating DSA, and (3) pathologic findings. Later in 2016, ISHLT released a consensus report to clarify a formal definition and diagnostic criteria in lung AMR [20]. The key diagnostic features in lung AMR include the presence of DSA and characteristic lung histology with or without evidence of complement 4d (C4d) within the allograft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Clinical AMR is associated with measurable allograft dysfunction, while allograft function is normal in subclinical AMR. The patients with clinical AMR might be asymptomatic, since the change in lung function can be small. Allograft dysfunction includes alterations in pulmonary physiology,

Figs. 27.9 and 27.10  High grade lymphocytic bronchiolitis (grade B2R) is characterized by intra-epithelial lymphocytic infiltrate

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gas exchange properties, radiologic features, or deteriorating functional performance. The ISHLT 2016 consensus also provides the concept of diagnosis certainty, which range from definite, probable, and possible, depending on the presence of diagnostic criteria. The diagnostic certainty and criteria are shown in Table 27.4. Histologic findings in pulmonary AMR are broad and nonspecific. Common findings are abnormalities in the microvascular structure and interstitium. A number of histologic patterns have been previously described in lung AMR, including “pulmonary capillaritis,” “septal capillary injury

syndrome,” “septal capillary necrosis,” “capillaritis,” and “neutrophil margination.” [19] Due to a variety in terminologies, ISHLT released a summary statement on pathology of pulmonary AMR in 2013, which enumerates the term “neutrophilic capillaritis” and defines as a patchy or diffuse process composed of dense neutrophilic septal infiltrates associated with karyorrhectic debris in the microvasculature (Figs.  27.11 and 27.12) [19]. Other findings include fibrin thrombi, alveolar hemorrhage, and flooding of neutrophils into adjacent airspaces. “Neutrophilic margination” is defined in the ISHLT summary statement as neutrophilic

Table 27.4  Classification, diagnostic criteria, and certainty of antibody-mediated rejection [20, 21] Clinical

Subclinical

Definite Probable Probable Probable Probable Possible Possible Possible Possible Possible Possible Definite Probable Probable Probable Possible Possible Possible

Allograft dysfunction + + + + + + + + + + + − − − − − − −

Other causes excluded + + + + − + + + − − − − − − − − − −

Fig. 27.11  Pathologic findings in antibody-mediated rejection is non-­ specific. Injury to microvasculature, e.g., neutrophilic capillaritis, can be identified, along with reactive pneumocytes, and widening septa. Other acute lung injury in form of organizing pneumonia can also be seen

Lung histology + + + − + + − − + + − + + − + + − −

Lung biopsy C4d + − + + + − − + + − + + − + + − + −

DSA + + − + + − + − − + + + + + − − − +

Fig. 27.12  Neutrophilic capillaritis in antibody-mediated rejection shows septal infiltration by neutrophils with karyorrhectic debris

27  Pathology of the Lung Allograft

infiltrates within the interstitial capillaries and septa in the absence of karyorrhectic changes and fibrinous accumulation. As mentioned earlier, these vascular findings are rather nonspecific and can also be found in infection, high-grade ACR, aspiration, drug toxicity, PGD, and pulmonary vasculitis syndrome. Other patterns of injury seen in AMR include high-grade ACR, high-grade lymphocytic bronchiolitis, persistent low-grade lymphocytic bronchiolitis, arteritis, organizing pneumonia, DAD, and OB. IHC stain for C4d in lung transplant biopsies is still controversial; however, the suggestion is to evaluate interstitial alveolar capillaries for linear, smooth staining, involving 50% or more of capillaries for a positive test result. Only interstitial alveolar capillaries should be assessed for AMR (Fig. 27.13). The current threshold for immunoreactivity is >50% of interstitial capillaries. However, focal staining of C4d might warrant serologic workup for DSA and additional

Fig. 27.13  C4d staining in the interstitial capillaries is one of three criteria for diagnosis of antibody-mediated rejection. Note the positive staining is also present in the serum

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clinical assessment for allograft dysfunction. Unlike kidney and heart transplant, immunofluorescent studies for C3d and C4d are rarely performed on the lung allograft to assess for AMR. However, reproducibility of C4d stain interpretation is a significant issue in reporting AMR. C4d is a relatively dirty stain with elastic fiber, fibrin, and serum. Besides rejection, C4d staining can be seen in various conditions related to complement activation, such as infection, high-grade ACR, or acute lung injury in PGD. Notably, diffuse staining of C4d is rarely seen in practice, thus limiting the usefulness of this stain [22]. DSA have been found to be associated with both acute rejection and obliterative bronchiolitis in lung transplant patient [23, 24]. The Banff 2016 study of pathologic changes in lung allograft biopsy specimen with DSA confirmed the significance presence of acute lung injury (with or without DAD), neutrophilic capillaritis, and endothelialitis, in specimens associated with DSA [22]. Our reported data revealed that 36% of the patients who have positive C4d staining in the interstitial capillaries were shown to have positive serum DSA [25]. Besides interstitial capillaries, C4d staining in the stromal areas and mucosal/ submucosal locations also showed significant correlation with positive serum DSA [25]. Currently, there is no standard recommendation on how to report serum level of DSA. The ISHLT 2016 consensus suggests that DSA level and function should not be assessed by the mean fluorescent intensity (MFI) of the single-antigen bead assay, because the MFI does not represent the titer of circulating HLA antibody. The antibody titer is the true representation of the antibody load. Ultrastructural changes by electron microscopy (EM) have been utilized in the diagnosis of pulmonary AMR. EM findings are mainly endothelial lesions, including swelling, vacuolization, and surface irregularities (Fig.  27.14) [26]. Neutrophil margination can also be identified with EM. b

Fig. 27.14 (a, b): Electron microscopy reveals an alveolar septum with intra-capillary polymorphonuclear cells (margination) and endothelial cells with swollen/reactive nuclei and cytoplasmic vacuoles

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Chronic Lung Allograft Dysfunction (CLAD) Chronic lung allograft dysfunction (CLAD) is an umbrella term, which describes the clinical manifestation of a range of pathologic process in the airway and parenchymal compartments of the lung allograft that leads to a significant and persistent deterioration in lung function and occurs later than 3 months after transplant [27]. CLAD is defined as a substantial and persistent decline (≥20%) in measured FEV1 value from the baseline [27]. The baseline value is computed as the mean of the best two postoperative FEV1 measurements (taken >3 weeks apart). The staging of CLAD is shown in Table 27.5. CLAD can manifest in two clinical phenotypes, namely, obstructive pattern or bronchiolitis obliterans syndrome (BOS) and restrictive pattern or restrictive allograft syndrome (RAS). Features of these CLAD phenotypes are summarized in Table 27.6. The corresponding pathologies in these two phenotypes are obliterative bronchiolitis (OB) and pulmonary pleuroparenchymal fibroelastosis (PPFE), respectively. In contrast to acute rejection, transbronchial biopsy has limited role in the diagnosis of CLAD.  The diagnosis of CLAD is primarily established on pulmonary function test. Table 27.5  CLAD staging based on 2019 ISHLT consensus report [27]) Stage CLAD 0 CLAD 1 CLAD 2 CLAD 3 CLAD 4

Spirometry Current FEV1 > 80% FEV1 baseline Current FEV1 > 65–80% FEV1 baseline Current FEV1 > 50–65% FEV1 baseline Current FEV1 > 35–50% FEV1 baseline Current FEV1 ≤ 35% FEV1 baseline

CLAD chronic lung allograft dysfunction, FEV1 forced expiratory volume in 1 s

Table 27.6  CLAD classification and clinical phenotypes [27]

BOS RAS Mixed (transition between subtypes) Undefined (definite CLAD with 2 combination of variables)

Obstruction (FEV1/FVC  80% of baseline FEV1 > 90% of baseline and FEV25–75% > 75% of baseline – FEV1 > 80–90% of baseline and/ or FEV25–75% ≤ 75% of baseline FEV1 66–80% of FEV1 66–80% of baseline baseline FEV1 51–65% of FEV1 51–65% of baseline baseline FEV1 ≤ 50% of baseline FEV1 ≤ 50% of baseline

BOS Bronchiolitis obliterans syndrome, FEV1 forced expiratory volume in 1 s

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Fig. 27.15  Allograft with obliterative bronchiolitis shows eccentric luminal obstruction by submucosal fibrosis

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Fig. 27.16  Low power view of the bronchovascular bundle in a lung allograft surgical biopsy reveals a bronchiole with obliterative bronchiolitis (left) situated next to pulmonary artery (right)

Fig. 27.17  Movat pentachrome stain can be used to identify obliterated bronchiole. Remnant of smooth muscle cell and elastic fiber can be seen

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 estrictive Allograft Syndrome (RAS)/ R Pleuroparenchymal Fibroelastosis (PPFE) Around one-third of patients with CLAD will develop restrictive physiology [34, 35]. RAS is defined clinically by (1) a persistent ≥20% decline in FEV1 compared with the reference or baseline value, (2) a decrease in total lung capacity (TLC) ≤ 90% of baseline, defined as the average of the two measurements obtained at the same time as or very near to the best two postoperative FEV1 measurements, and (3) the presence of persistent opacities on chest imaging (high-resolution computed tomography scan (HRCT) or chest X-ray if HRCT not available) [27]. If restrictive physiology and imaging opacities persist after 3 months despite appropriate therapeutic efforts, the diagnosis CLAD with RAS phenotype is confirmed [36]. Once diagnosed with RAS, the patient has a significantly worse survival than BOS, with a median survival of 541 vs 1421 days in one study [34]. Early study reported a rather nondiagnostic pathologic finding in the patients who were found to have restrictive pulmonary function test [37]. The biopsies were reported as nonspecific pulmonary fibrosis and predominantly located in the upper lobe. In a later study focusing on the pathology of the allograft, it was found that the correlating histopathology of RAS is pleuroparenchymal fibroelastosis (PPFE) [38]. Microscopic examination of the wedge biopsy, re-transplant lung explant, or autopsy lung shows confluent areas of bland, hypocellular collagen deposition with preservation and thickening of the underlying alveolar septal elastic network (Fig.  27.18). These areas of elastosis are predominantly in subpleural distribution but can also be paraseptal, centrilobu-

a

Fig. 27.18 (a) The lung explant from patient with restrictive allograft syndrome shows pathologic features consistent with pleuroparenchymal fibroelastosis, characterized by patchy, predominantly subpleural

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lar, or random (parenchyma) [38]. A sharp demarcation between uninvolved lung parenchyma and fibroelastotic area, with fibroblast foci, can be seen. Pleural thickening and fibrosis is common. Another frequent finding in RAS is diffuse alveolar damage in various stages (acute and organizing) [34]. Concurrent obliterative bronchiolitis is present in most of the cases. A fibrotic pattern of nonspecific interstitial pneumonia (NSIP) has been found in up to 25% of RAS patient [36]. Histomorphologic pattern in RAS might have an implication on prognosis, as a pattern of emphysema-like has been found to have better survival, while the finding of fibrinous exudate is associated with a worse survival [39].

Chronic Vascular Rejection Chronic vascular rejection is also known as accelerated graft vascular sclerosis. Its clinical significance on transplant outcome has not yet been determined. As well as OB, the development of chronic vascular rejection might be related to autoimmunity to collagen V. An autopsy case report from our institution highlighted a finding of severe fibrosing vasculitis in a lung transplant patient, which was later found to have overexpression of α1 collagen V (IHC stain) in the allograft arteries [40]. Same as CLAD, transbronchial biopsy has limited role in identifying chronic vascular rejection. These changes are more frequently seen in surgical lung biopsy specimen or autopsy. Chronic vascular rejection is considered as the D grade in ISHLT classification and does not need to be reported. Histologic features are fibrointimal thickening of arteries and veins (Fig.  27.19). Mononuclear inflammation or active component may also be identified.

b

fibroelastotic changes. (b) Movat pentachrome stain reveals prominent elastic fiber in the fibroelastotic area

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Fig. 27.19  Chronic vascular rejection or accelerated graft vascular sclerosis is characterized by fibrointimal thickening with fibroblastic proliferation

Fig. 27.20  CMV infected cell shows characteristic viral cytopathic effects including enlarged size with intranuclear inclusion

Infection in Lung Allograft

Viral Infection

Infection is the most common cause of death in transplant patients between 31 days and 1-year after transplantation in adult [2], which the majority (42%) occur in the first 90  days posttransplant [41]. Lung allograft has a higher risk to infection than other solid organs from multiple factors, including (1) constant exposure to the outside environment, (2) colonizing native organism, and (3) absence of usual defense mechanism, including diminished cough reflex, interruption in bronchial circulation, and abnormal ciliary function [42]. Besides the unique characteristic in anatomy and physiology of the lung, lung transplant patient also requires the higher level of immunosuppression.

Cytomegalovirus (CMV) is the most common viral infection in solid organ transplant patient and causes significant morbidity and mortality. The CMV serostatus of donor and recipient. (D/R) is the most important predicting factor of CMV posttransplant and is also used to guide antiviral prophylaxis and therapy. CMV infection is not synonymous with CMV disease. CMV infection is defined as virus isolation or detection of viral proteins (antigen) or nucleic acid, while CMV disease is characterized by evidence of CMV infection with attributable symptoms, i.e., viral syndrome (fever, malaise, leukopenia, and/or thrombocytopenia), or end-organ disease [44]. CMV infection can also alter immune response and increase risk for other opportunistic infections. In the long term, CMV disease is also associated with BOS development [28]. Other herpesvirus infections, such as herpes simplex virus (HSV) and varicella zoster, can also be seen. Histologically, viral infection is characterized by acute lung injury pattern with mononuclear or mixed interstitial pneumonitis. The main differential diagnosis in viral infection is acute cellular rejection, which can also show lymphocytic infiltrate. While the infiltrate is mostly perivascular in acute rejection, the infiltrate in viral infection is mainly in alveolar septa and diffuse and can be composed of mixed inflammatory cells. Viral cytopathic is considered diagnostic in certain viruses, such as CMV (Fig. 27.20) and HSV. When suspected, viral IHC should be performed.

Bacterial Infection Bacterial pneumonia is the most common infection in the lung transplant recipient [43]. Pseudomonas aeruginosa is most common causative organism, followed by Staphylococcus aureus, and Acinetobacter [42]. Histologically, bacterial pneumonia can be differentiated from acute rejection by its nature of suppurative inflammation in the alveolar space, which shows predominantly neutrophils, fibrinous exudate, and hemorrhage.

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Fungal Infection Fungal infection occurs in 15–35% of patients after lung transplant surgery, with >80% consisted of Aspergillus and Candida species [45], while other fungus, such as Zygomycetes, Scedosporium, and Fusarium species occur less commonly [42]. Fungal colonization at the anastomotic site is common and poses a higher risk of infection. Certain fungal infection such as Cryptococcus, Histoplasma, and Coccidioides species can be the result of a reactivation of a latent infection. Most common clinical presentations of Aspergillus infections were tracheobronchitis or bronchial anastomotic infections (58%), followed by invasive aspergillosis (32%), and disseminated infection (22%) [46].

S. Sathirareuangchai and J. R. Torrealba Table 27.8  The fourth WHO classification of PTLD PTLD classification Early lesions  • Florid follicular hyperplasia  • Reactive plasmacytic hyperplasia  • Infectious mononucleosis-­ like lesions Polymorphic PTLD Monomorphic PTLD  • B-cell neoplasms  • T-cell neoplasms Classical Hodgkin lymphoma PTLD

Site Lymph nodes Tonsils Waldeyer’s ring

Clonality Polyclonal

Nodal/ extranodal Nodal/ extranodal

Polyclonal/ monoclonal Monoclonal

Nodal/ extranodal

Monoclonal

PTLD posttransplant lymphoproliferative disorder

Posttransplant Lymphoproliferative Disorder (PTLD) Posttransplant lymphoproliferative disorder (PTLD) is a rare but serious complication following both hematopoietic stem cell transplant and solid organ transplant patient. The reported incidence of PTLD in lung transplant patient was among the highest in solid organ transplant, second only to small intestine transplant [47]. This finding might be contributed by higher immunosuppression and lymphoid tissue in the allograft. The cumulative incidence of PTLD in lung transplant recipient was found to be 1.14% during the first year and 4.12% at 10 years [47]. Epstein-Barr virus (EBV) infection has been shown to be strongly associated with PTLD. The incidence of PTLD in the recipient with the status of EBV donor positive/recipient negative (D+/R-) was 6.2% compared to 1.4% in all other recipients [48]. However, EBV seronegative patients did not have worse mortality when transplanted with lungs from EBV seropositive donors compared with lungs from EBV seronegative donors [48]. The fourth edition of the World Health Organization (WHO) classification on hematolymphoid neoplasm characterizes PTLD into four main categories, based on clonality and immunophenotypic features of the infiltrates [49]. PTLD subtypes are shown in Table 27.8. Monomorphic PTLD, diffuse large B-cell lymphoma (DLBCL), was the most common PTLD reported in lung transplant patient [50, 51]. The majority of PTLD was extranodal in origin (91%), with gastrointestinal tract being the most common site (53%), followed by the allograft (38%) [50].

Fig. 27.21 Transbronchial biopsy from a patient with recurrent lymphangioleiomyomatosis shows spindle cells proliferation. The inset shows the neoplastic positive staining with HMB-45 immunohistochemical stain

Recurrence of Native Disease Native disease rarely reoccurs in the allograft, with the reported recurrent rate of 1% in six transplant centers [52]. In part, this is due to the nature of relatively short survival in recipients comparing to the chronicity of the native lung disease pathology, such as emphysema or interstitial lung disease. However, some native disease has the higher tendency to reoccur in the allograft. For an example, sarcoidosis recurrence rate was 14% [53], but the recurrence does not seem to affect overall survival. [54] Other reported recurrence diseases include lymphangioleiomyomatosis (Fig. 27.21), diffuse panbronchiolitis, alveolar proteinosis, and Langerhan cell histiocytosis [52].

27  Pathology of the Lung Allograft

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919 sies: a perspective from members of the pulmonary pathology society. Arch Pathol Lab Med. 2017;141(3):437–44. 19. Berry G, Burke M, Andersen C, et  al. Pathology of pulmonary antibody-­ mediated rejection: 2012 update from the pathology council of the ISHLT. J Heart Lung Transplant. 2013;32(1):14–21. 20. Levine DJ, Glanville AR, Aboyoun C, et  al. Antibody-mediated rejection of the lung: a consensus report of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2016;35(4):397–406. 21. Roux A, Levine DJ, Zeevi A, et  al. Banff lung report: current knowledge and future research perspectives for diagnosis and treatment of pulmonary antibody-mediated rejection (AMR). Am J Transplant. 2019;19(1):21–31. 22. Wallace WD, Li N, Andersen CB, et al. Banff study of pathologic changes in lung allograft biopsy specimens with donor-specific antibodies. J Heart Lung Transplant. 2016;35(1):40–8. 23. Lobo LJ, Aris RM, Schmitz J, Neuringer IP.  Donor-specific antibodies are associated with antibody-mediated rejection, acute cellular rejection, bronchiolitis obliterans syndrome, and cystic fibrosis after lung transplantation. J Heart Lung Transplant. 2013;32(1):70–7. 24. Safavi S, Robinson DR, Soresi S, Carby M, Smith JD.  De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant. 2014;33(12):1273–81. 25. Butt Y, Hassler J, Kaza V, Torres F, Torrealba J. Histologic patterns of C4d associated with acute antibody mediated rejection of the lung allograft [abstract]. Am J Transplant. 2015;15(suppl 3). 26. Alexander MP, Bentall A, Aleff PCA, Gandhi MJ, Scott JP, Roden AC. Ultrastructural changes in pulmonary allografts with antibody-­ mediated rejection. J Heart Lung Transplant. 2020;39(2):165–75. 27. Verleden GM, Glanville AR, Lease ED, et al. Chronic lung allograft dysfunction: definition, diagnostic criteria, and approaches to treatment-a consensus report from the pulmonary council of the ISHLT. J Heart Lung Transplant. 2019;38(5):493–503. 28. Meyer KC, Raghu G, Verleden GM, et  al. An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome. Eur Respir J. 2014;44(6):1479–503. 29. Cooper JD, Billingham M, Egan T, et  al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 1993;12(5):713–6. 30. Estenne M, Maurer JR, Boehler A, et  al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant. 2002;21(3):297–310. 31. Burlingham WJ, Love RB, Jankowska-Gan E, et  al. IL-17-­ dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest. 2007;117(11):3498–506. 32. Tiriveedhi V, Angaswamy N, Brand D, et al. A shift in the collagen V antigenic epitope leads to T helper phenotype switch and immune response to self-antigen leading to chronic lung allograft rejection. Clin Exp Immunol. 2012;167(1):158–68. 33. Bobadilla JL, Jankowska-Gan E, Xu Q, et al. Reflux-induced collagen type v sensitization: potential mediator of bronchiolitis obliterans syndrome. Chest. 2010;138(2):363–70. 34. Sato M, Waddell TK, Wagnetz U, et al. Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant. 2011;30(7):735–42. 35. Verleden GM, Vos R, Verleden SE, et  al. Survival determinants in lung transplant patients with chronic allograft dysfunction. Transplantation. 2011;92(6):703–8. 36. Glanville AR, Verleden GM, Todd JL, et al. Chronic lung allograft dysfunction: definition and update of restrictive allograft syndrome-

920 a­ consensus report from the pulmonary council of the ISHLT.  J Heart Lung Transplant. 2019;38(5):483–92. 37. Pakhale SS, Hadjiliadis D, Howell DN, et al. Upper lobe fibrosis: a novel manifestation of chronic allograft dysfunction in lung transplantation. J Heart Lung Transplant. 2005;24(9):1260–8. 38. Ofek E, Sato M, Saito T, et al. Restrictive allograft syndrome post lung transplantation is characterized by pleuroparenchymal fibroelastosis. Mod Pathol. 2013;26(3):350–6. 39. von der Thusen JH, Vandermeulen E, Vos R, Weynand B, Verbeken EK, Verleden SE.  The histomorphological spectrum of restrictive chronic lung allograft dysfunction and implications for prognosis. Mod Pathol. 2018;31(5):780–90. 40. Daoud E, Butt Y, Torres F, Torrealba J.  HLA, ANA, and ANCA negative vasculitis in lung transplantation due to overexpression of α1 collagen V. [abstract]. Am J Transplant. 2017;17(suppl 3). 41. Parada MT, Alba A, Sepulveda C. Early and late infections in lung transplantation patients. Transplant Proc. 2010;42(1):333–5. 42. Burguete SR, Maselli DJ, Fernandez JF, Levine SM. Lung transplant infection. Respirology. 2013;18(1):22–38. 43. Campos S, Caramori M, Teixeira R, et  al. Bacterial and fungal pneumonias after lung transplantation. Transplant Proc. 2008;40(3):822–4. 44. Kotton CN, Kumar D, Caliendo AM, et al. The third international consensus guidelines on the Management of Cytomegalovirus in solid-organ transplantation. Transplantation. 2018;102(6):900–31. 45. Sole A, Salavert M.  Fungal infections after lung transplantation. Transplant Rev (Orlando). 2008;22(2):89–104. 46. Singh N, Husain S.  Aspergillus infections after lung transplantation: clinical differences in type of transplant and implications for management. J Heart Lung Transplant. 2003;22(3):258–66.

S. Sathirareuangchai and J. R. Torrealba 47. Zaffiri L, Long A, Neely ML, Cherikh WS, Chambers DC, Snyder LD. Incidence and outcome of post-transplant lymphoproliferative disorders in lung transplant patients: analysis of ISHLT registry. J Heart Lung Transplant. 2020;39(10):1089–99. 48. Courtwright AM, Burkett P, Divo M, et  al. Posttransplant lymphoproliferative disorders in Epstein-Barr virus donor positive/ recipient negative lung transplant recipients. Ann Thorac Surg. 2018;105(2):441–7. 49. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–90. 50. Wudhikarn K, Holman CJ, Linan M, et al. Post-transplant lymphoproliferative disorders in lung transplant recipients: 20-yr experience at the University of Minnesota. Clin Transpl. 2011;25(5):705–13. 51. Romero S, Montoro J, Guinot M, et al. Post-transplant lymphoproliferative disorders after solid organ and hematopoietic stem cell transplantation. Leuk Lymphoma. 2019;60(1):142–50. 52. Collins J, Hartman MJ, Warner TF, et al. Frequency and CT findings of recurrent disease after lung transplantation. Radiology. 2001;219(2):503–9. 53. Le Pavec J, Valeyre D, Gazengel P, et  al. Lung transplantation for sarcoidosis: outcome and prognostic factors. Eur Respir J. 2021;58(2):2003358. 54. Schultz HH, Andersen CB, Steinbruuchel D, Perch M, Carlsen J, Iversen M.  Recurrence of sarcoid granulomas in lung transplant recipients is common and does not affect overall survival. Sarcoidosis Vasc Diffuse Lung Dis. 2014;31(2):149–53.

Index

A Abnormal lung expansion, 9 Absorbent glands, 272 Abt-Letterer-Siwe disease, 237 Acinic cell carcinoma (AcCC), 437–439 Acquired immunodeficiency syndrome (AIDS), 84, 480, 840 Actinomyces israelii, 826 Actinomyces odontolyticus, 826 Actinomycetes, 825–827 Acute cellular rejection (ACR), 907, 908 Acute eosinophilic pneumonia (AEP), 790 chest radiograph, 790 CT, 790 Acute fibrinous pleuritis, 9 Acute lupus pneumonitis (ALP), 665 Acute pleuritis, 15 Acute rejection, 906, 907 Adenocarcinoma, 328–331 AAH, 347, 348 AIS, 347, 348 BAC, 349 definition, 343 histological variants, 346 colloid carcinoma, 349–351 hepatoid, 356 papillary/micropapillary/papillary with morular component, 353–355 secretory endometrioid-like adenocarcinoma, 356 signet ring cells, 351, 353 histopathological features, 345–350 macroscopic features, 345, 346 MIA, 347, 348 Adenocarcinoma in situ (AIS), 347, 348 Adenoid cystic carcinoma (ACC), 151, 418 age variation, 418 complete surgical resection, 418 cylindromatous growth pattern, 419, 422 diagnostic imaging, 418–421 immunohistochemistry, 419, 426 jigsaw pattern, 419 molecular features, 419 prognosis, 418 pulmonary function tests, 418 sampling approaches, 418 solid growth pattern, 419, 425 tubular growth pattern, 419, 424 Adenomatoid tumors, 28, 30 Adenosquamous carcinoma, 333, 334, 359 Adequate tissue, 29 Airway disease, 660, 667, 668 relapsing polychondritis, 677

Rheumatoid arthritis, 660, 661 Sjogren syndrome, 667, 668 Airway involvement, 802 Alarcon-Segovia criteria, 679 Allergic bronchopulmonary aspergillosis (ABPA), 789, 796, 797 Alpha1-antitrypsin deficiency (AAT), 763 diagnosis, 764 epidemiology, 763 pathophysiology, 764 risk factors, 764 treatment, 764 Alveolar adenoma, 589 Alveolar hemorrhage, 680 Alveolar macrophage pneumonia, 604 Alveolar soft part sarcoma, 216, 217 Amosite (brown asbestos), 692 Amyloid deposition in the lungs, 676 Amyloid tumor (amyloidoma), 591, 592 Anaplastic large cell lymphoma (ALCL), 240, 270–272 clinical features, 523 differential diagnosis, 525, 526 histiocytic lymphoma, 523 immunohistochemistry and ancillary studies, 524, 525 molecular findings, 526 pathology, 524 Anaplastic lymphoma kinase (ALK), 885 Anastomotic complication, 905, 906 Aneurysm, 709, 710 Angiogenesis, 885 Angiography, 711 Angioimmunoblastic T-cell lymphoma, 231 Angiolymphoid hyperplasia with eosinophilia, 589–591 Angiosarcoma, 200, 201, 471, 472 Angiotensin converting enzyme (ACE), 809 Ankylosing spondylitis (AS), 674 Assessment of SpondyloArthritis International Society criteria, 675 Modified New York criteria, 675 obstructive sleep apnea, 676 pathogenesis of, 675 prevalence of, 675 pulmonary apical fibrocystic disease, 675, 676 smoking in, 676 Antiarrhythmics, 869 Antibiotics, 869 Antibody-mediated rejection (AMR), 909–911 Anti-collagen type 2 activity, 678 Anti-cyclic citrullinated peptide (anti-CCP) antibodies, 659, 663 Anti-glomerular basement membrane disease, 746, 747 Antineoplastic drugs, 869 Anti-neutrophilic cytoplasmic antibodies (ANCA), 678, 724

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 C. A. Moran et al. (eds.), The Thorax, https://doi.org/10.1007/978-3-031-21040-2

921

922 Antinuclear antibody (ANA), 664, 674 Antiphospholipid syndrome (APS), 666 Antipsychotics, 869 Antirheumatic medications, 869 Antisynthetase syndrome, 673, 674 Aortic regurgitation, 678 Apical pleural plaques, 17 Apparent diffusion coefficient (ADC), 34 Asbestos clinical background, 691 commercial use, 692 exposure and malignancy, 691, 692 pathogenesis of, 692, 693 pleuropulmonary conditions parenchymal disease (see parenchymal disease) pleural diseases (see Pleural diseases) widespread use, 691 Asbestos fibers, 692 Asbestos-associated diffuse pleural thickening, 18 Asbestosis clinical presentation, 695 histologic grading, 695 histopathological features, 696, 698 histopathology, 695 vs. idiopathic pulmonary fibrosis, 696 progression, 696 pulmonary function tests, 695 radiographic imaging, 695, 696 Asbestos-related pleural plaques, 18 Ascaris lumbricoides, 796 Ascaris pneumonia, 796 Askin tumors, 76 Aspergilloma, 825 Aspergillosis, 840 Aspergillus, 842 Assessment of SpondyloArthritis International Society (ASAS) criteria, 675 Associated paraneoplastic syndromes, 60 Associated pleural effusions, 9, 63 Atelectasis, 90 Atypical adenomatous hyperplasia (AAH), 347, 348 Azathioprine, 663 B Bacterial cultures, 13 Bacterial pneumonia, 915 Basaloid carcinoma, 151 Basaloid squamous cell carcinoma, 341 Behcet’s disease (BD), 715 clinical presentation, 716 diagnostic evaluation, 717 incidence and risk factors, 715 lung parenchyma, 717 pathogenesis, 716 pharmacologic treatment, 718 prognosis, 718 pulmonary disease, 716, 717 surgical treatment, 718 Behcet’s syndrome, 678 Benign asbestos–related pleural effusions (BAPE), 691, 694 Bevacizumab-induced cavitation, 886 Bilateral fibrothorax, 9 Biogenesis of lysosome-related organelles complexes (BLOCs), 851 Biphasic mesothelioma, 52 Biphasic neoplasms

Index blastoma, 449 biphasic blastoma, 451, 453, 454 clinical features, 449 diagnostic imaging, 449, 450 monophasic blastoma, 450–453 carcinosarcomas clinical features, 452 diagnostic imaging, 453–455 histological features, 451 pathological features, 455, 456 occurrence, 449 Biphasic synovial sarcoma, 83 Birt-Hogg-Dube (BHD), 765 Blastoma biphasic blastoma, 451, 453, 454 clinical features, 449 diagnostic imaging, 449, 450 monophasic blastoma, 450–453 Blastomycosis, 830, 831 Body cavity lymphoma, 84 Bone and cartilaginous tumors, 214, 215 Bone marrow transplant patients (BMT), 840 Botryomycosis, 828 BRAF V600E mutation, 237 BRCA-associated protein 1 gene (BAP-1) expression, 23, 28 Bronchial (pulmonary) melanoma, 582 clinical features, 582 diagnostic imaging, 582 pathological features, 582, 583 Bronchial hyperresponsiveness, 667 Bronchial obstruction, 90 Bronchial-associated lymphoid tissue (BALT), 475, 476 Bronchiectasis, 668 Bronchiolectasis, 612 Bronchiolitis obliterans organizing pneumonia (BOOP), 782 Bronchiolitis obliterans syndrome (BOS), 912 Bronchioloalveolar carcinoma (BAC), 349 Bronchoalveolar lavage (BAL), 664 desquamative interstitial pneumonia, 608 hypersensitivity pneumonitis, 631 IPF, 602 nonspecific interstitial pneumonia, 611 usual interstitial pneumonia, 621 Bronchogenic cysts (BC), 769 clinical features, 769 diagnosis, 770 epidemiology, 769 treatment, 770 Bronchoscopic lung biopsies, 663 Bronchoscopy, 678 Brugia malayi, 796 Burkitt lymphoma, 84 Bystander exposures, 692 C Calcification, 63 Calcifying fibrous tumors (CFT), 68, 69, 71 Calretinin, 23 Cancer cells, 5 Caplan syndrome, 662 Carcinoid tumors clinical presentation, 375, 376 diagnosis, 375–377 diagnostic imaging, 380, 382–386 epidemiology and demographics, 375

Index Carcinosarcomas clinical features, 452 diagnostic imaging, 453–455 histological features, 451 pathological features, 455, 456 Cardiac magnetic resonance (CMR), 812 Cardiac sarcoid, 814 Cardiac sarcoidosis (CS), 812 Cardiac surgery, 9 Cartilaginous and osseous differentiation, 41 Cartilaginous differentiation, 48 Cartilaginous hamartoma, 459, 460 Castleman disease (CD) clinicopathologic features, 227 general aspects, 227 hyaline vascular, 228–231 plasma cell-rich, 231–234 unicentric/multicentric, 227 Catamenial hemothorax, 24 Catamenial pneumothorax, 24 Catheter infection, 90 Cellular fibrous pleuritis, 11 Cellular proliferation, 28 Cellular-mesenchymal-epithelial transition (c-MET) antibody, 362 Chemotherapy, 31, 73 Chest pain, 67 Chest tube drainage, 25 Chest wall, 6 Chloroma, see Mediastinal myeloid sarcoma Chondrosarcoma, 214, 215, 467, 468 Choriocarcinoma, 191 Chronic eosinopilic pneumonia, 789, 792, 793 differential diagnosis, 794 histopathological features, 794 Chronic interstitial lung disease (ILD), 664 Chronic lung allograft dysfunction (CLAD), 912 Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/ SLL), 86, 481 clinical features, 515 diagnostic imaging, 536, 537 differential diagnosis, 518, 519 immunohistochemistry and ancillary studies, 517–519 molecular findings, 519 pathology, 515–517 Chronic obstructive pulmonary disease (COPD), 761, 840–841 Chronic vascular rejection, 914 Chrysolite (white asbestos), 692 Chrysolite fibers, 693 Classic Hodgkin lymphoma (CHL), 223, 272 classification, 280, 281 clinical features, 273, 530, 531 definition, 529 diagnosis, 531 differential diagnosis, 276–279, 535 evolution, 273 imaging, 279 immunohistochemistry and ancillary studies, 275–278, 533–535 molecular findings, 279, 535, 536 pathology, 274–277, 531–533 “Reed-Sternberg” cells, 273 tuberculosis/granulomatous process, 272 Classic large cell carcinoma (CLCC), 332, 333 Clear cell hyalinizing carcinoma (HCCC), 439, 440 Clear cell squamous cell carcinoma, 338 Clear cell “sugar” tumor (Pecoma), 563–566

923 Clinically amyopathic dermatomyositis (CADM), 672 Coarse calcifications, 24 Cobalt lymphocyte proliferation test, 705 Cobalt related lung injury, 704 Coccidioides, 832 Coccidioidomycosis, 832, 833 Coccidiomycosis, 825 Colloid carcinoma, 349–351 Combined pulmonary fibrosis and emphysema (CPFE), 627 Common immunohistochemical markers, 23 Computed tomography (CT), 88, 896 Congenital cystic adenomatoid malformations (CCAMs), 772, 774 Connective tissue diseases (CTDs), 9, 20, 21, 624, 626, 627, 660, 667, 725 Connective tissue disease-related interstitial lung disease (CTD-ILD), 620 Contrast enhanced CT, 77 Conventional radiation therapy, 896 Coronary artery bypass grafting, 17 Costochondritis, 678 Cough, 313 Cricoarytenoid joint involvement, 676 Cricoarytenoiditis, 660 Crocidolite (blue asbestos), 692 Cryptococcosis, 825, 834 Cryptococcus, 835 Cryptogenic organizing pneumonia, 779 chest radiograph, 780 clinical presentation, 779 CT and HRCT, 782 diagnostic imaging, 779 differential diagnosis, 786–788 fibrotic OP, 785 imaging findings, 785, 786 linear and band opacities, 784 mixed ground glass, 784 multifocal alveolar disease, 783 nodular form, 784 perilobular pattern, 784 Cushing’s disease, 376 Cystic fibrosis (CF), 770–772 Cystic squamous cell carcinomas, 338 Cytomegalovirus (CMV), 915 D Damiani diagnostic criteria, 677 Ddiffusing capacity of carbon monoxide (DLCO), 702 Ddrug-induced interstitial lung disease (DI-ILD), 619 Deciduoid, 41 Deciduoid mesothelioma, 43 Dense fibrocollagen, 10 Dermatomyositis (DM), 672, 673 ILD in, 673 malignancy, 674 pulmonary hypertension in, 673, 674 spontaneous pneumomediastinum, 674 Dermatopathic lymphadenopathy, 240 Desmoid tumor, 67, 69, 70 calcifying fibrous tumors, 68, 69 epithelioid hemangioendothelioma, 72 histological features, 70, 71 immunohistochemical features, 71 macroscopic features, 67, 68, 70 Desmoplastic, 47

924 Desmoplastic mesothelioma, 50 Desquamative interstitial pneumonia (DIP) bronchoalveolar lavage, 608 clinical presentation, 605 diagnostic evaluation imaging findings, 605–607 laboratory testing, 605 pulmonary function test, 605 differential diagnosis, 607, 608 epidemiology, 604 etiologic risk factors cigarette smoking, 604 occupational and environmental exposures, 604 systemic diseases and medications, 604 respiratory bronchiolitis, 608, 609 surgical lung biopsy, 608 transbronchial biopsies, 608 transbronchial lung cryobiopsy, 608 Diaphragmatic involvement, 666 Diffuse alveolar damage (DAD), 786, 870, 872, 889 Diffuse alveolar hemorrhage (DAH), 663, 665, 729, 882 Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) clinical presentation, 374 diagnostic evaluation, 374, 375, 380, 381 epidemiology and demographics, 374 history, 374 treatment and prognosis, 375 2015 WHO classification, 374 Diffuse large B-cell lymphoma (DLBCL), 916 classification, 501 clinical features, 501 differential diagnosis, 503–506 imaging findings, 281, 282 immunohistochemistry and ancillary studies, 502–505 molecular findings, 506 pathology, 501–503 Diffuse pleural thickening, 695 Diffuse pulmonary ossification, 624, 625 Diffusing capacity for carbon dioxide (DLCO), 374 Diffusing capacity of carbon monoxide (DLCO), 664, 680 Dirofilariasis, 845 Dirofilariasis immitis, 844 Disease-modifying anti-rheumatic drugs (DMARDs), 662, 663 Disseminated juvenile xanthogranuloma, 240 Doege-Potter syndrome, 60 “Double-hit” or “triple-hit” lymphomas, 254 Drug-induced fibrous pleuritis, 21 Drug-induced interstitial lung disease (DI-ILD), 620 Drug-induced pleural effusions, 8 Drug-induced pneumonitis, 666 Drug induced sarcoid like reaction (DSIR), 882 Drug reactions, 9 Drug related pleural abnormalities (DRPA), 884 Dry pleurisy, 8 Dyskeratosis congenita, 852 Dyspnea, 89 E Echinococcus, 845, 846 Echocardiography, 812 Ectopic thymoma, 56 Ehlers-Danlos syndrome (EDS), 767, 768 Embryonal carcinoma (EC), 190 Emperipolesis, 241

Index Emphysema clinical features, 762 diagnosis, 762, 763 epidemiology, 761 pathogenesis, 761 pharmacotherapy, 763 risk factors, 762 treatment, 763 Empyema, 90 Endemic mycoses, 830 Endobronchial lipoma, 462, 463 Endometrial implants, 25 Environmental and residential exposures, 692 Eosinophilic granuloma/Otani’s tumor, 237 Eosinophilic granulomatosis with polyangiitis (EGPA), 737, 738, 740–744 Eosinophilic pleuritis, 11, 14 Eosinophilic pneumonia (EP), 880 Eosinopilic lung disorders, 788, 789 Ependymoma, 306 Epidermal growth factor receptor (EGFR), 885 Epithelial-myoepithelial carcinoma, 57, 59, 151 Epitheliod hemangioendothelioma (EHE), 72 Epithelioid FDC sarcoma, 240 Epithelioid hemangioendothelioma (EH), 72–75, 199, 200, 470, 471 Epithelioid interdigitating DC sarcoma, 240 Epithelioid neoplasm, 74 Epstein-Barr virus (EBV) coinfection, 84 Erdheim-Chester disease (ECD), 243 clinical features, 552 diagnostic imaging, 552, 553 differential diagnosis, 552, 554 history, 552 immunohistochemistry and ancillary studies, 552, 553 molecular findings, 554 pathology, 552, 553 Ergot-derived dopamine agonists, 21 Erlotinib-induced pneumonitis, 887 Ethambutol (EMB), 830 Excess fluid, 4 Exophytic squamous cell carcinoma, 339 Extensive stage (ES), 378 Extraosseous plasmacytoma clinical features, 519 diagnostic imaging, 520 differential diagnosis, 522 immunohistochemistry and ancillary studies, 521, 522 molecular findings, 523 pathology, 520, 521 Extrapleural pneumonectomy specimen (EPP), 31, 37, 38 Extraskeletal chordomas, 215 Extraskeletal osteosarcoma, 214 Extrinsic allergic alveolitis, see Hypersensitivity pneumonitis (HP) F Familial idiopathic pulmonary fibrosis, 627 Familial pulmonary fibrosis, 600 Fechner tumor, see Acinic cell carcinoma (AcCC) Felty’s syndrome, 659 F-18 fluorodeoxyglucose (FDG), 5 Fibrinous pleuritis, 11, 12 Fibroadipose tissue, 4 Fibroblastic and fibrohistiocytic tumors low-grade fibromyxoid sarcoma, 202, 203 sclerosing epithelioid fibrosarcoma, 202 solitary fibrous tumor, 201, 202

Index Fibrosarcoma, 41 Fibrosing pleuritis, 8 Fibrosing/sclerosing mediastinitis, 297–300 Fibrothorax, 8, 9 Fibrous pleuritis/ pleurisy, 3, 4, 8–10, 12 Fine needle aspiration biopsies, 60 Florid mesothelial proliferation, 23 Fluid homeostasis, 4 Fluorescent in situ hybridization (FISH), 11, 23, 416 Folded lung or Blesovsky syndrome, 694 Follicular bronchiolitis, 660, 661 Follicular dendritic cell (FDC) sarcoma, 228, 285–288 Follicular hyperplasia clinical features, 480 differential diagnosis, 481, 482 immunohistochemistry and ancillary studies, 480, 481 pathology, 480 Follicular lymphoma clinical features, 515 diagnostic imaging, 536, 537 differential diagnosis, 518, 519 immunohistochemistry and ancillary studies, 517–519 molecular findings, 519 pathology, 515–517 Forced vital capacity (FVC), 671, 771 Fungal infection, 916 G Ganglioneuroblastoma, 207, 586, 587 Ganglioneuromas, 207 Ganglionic tumors, 207, 208 Gardner syndrome, 67 Gastroesophageal reflux (GER), 600 Gaucher disease, 852 Germ cell tumor, 88 Giant cell arteritis (GCA), 712 clinical manifestations, 712, 713 diagnostic evaluation, 713 imaging, 714 incidence and risk factors, 712 laboratory data, 714 management, 715 pathogenesis, 712 pulmonary manifestations, 713 Giant cell carcinoma, 365–367 Giant cell interstitial pneumonia (GIP), 705 Glandular proliferation, 26 Glomangioma/glomangiosarcoma, 579–581 Glucocorticoids (GCs), 19–20, 712 Gomori Methenamine Silver (GMS), 13 Granular cell tumor, 574, 575 Granulocytic or monocytic sarcoma, see Mediastinal myeloid sarcoma Granulomatosis with polyangiitis (GPA), 678, 726, 730 airway disease, 727 cardiac involvement, 733 clinical presentation, 727 diagnostic evaluation, 727 diagnostic imaging, 727, 728 differential diagnosis, 734 evolution over time, 731 ground-glass attenuation, 729, 730 incidence and risk factors, 726 induction, 736 maintenance therapy, 736 nodules and masses, 728, 729

925 nonspecific findings, 730, 731 pathogenesis, 726 pathological Features, 734 positron emission tomography, 732, 733 treatment, 736 Granulomatous lymphadenitis, 224–227 Granulomatous thymoma, 117 Ground glass opacity (GGO), 891 Growth hormone releasing hormone (GHRH), 376 H Hand-Schüller-Christian disease, 237 Hard metal lung disease bronchoscopy, 705 clinical features, 704 cobalt lymphocyte proliferation test, 705 diagnosis, 705 management, 705, 706 pathogenesis, 703, 704 pathology, 705, 706 pulmonary function test, 705 radiology, 704 Hassall’s corpuscles, 109 Hemagiopericytoma, 65 Hemangioblastoma-like clear cell stromal tumor, 576, 577 Hemangiomas, 198, 199 Hematological Involvement, 669 Hematopoietic disorders, 244 Hematopoietic tumors, 244 Hemothorax, 16 Hepatoid, 356 Hepatoid adenocarcinoma, 357 Hermansky-Pudlak syndrome (HPS), 619, 627, 851 High resolution computed tomography (HRCT), 621, 660, 674, 762 Hilar lymph node dissection, 73 Histiocytosis X, 237 Histoplasmosis, 836, 837 Hoarseness, 313 Hodgkin lymphoma (HL), 282–284, 531 Honeycombing, 696 Hormonal therapies, 25 HUMARA assay, 237 Hutchinson-Besnier-Boeck-Schaumann disease, 221 CD-like changes, 230, 231 clinical features, 228 differential diagnosis, 230, 231 immunohistochemistry, 229 “lollipop” lesions, 228, 229 onion skinning, 228, 229 pathogenesis, 231 pathology, 228, 230 twinning, 228, 229 Hyalinized nodule, 20 Hyalinzed fibroconnective tissue, 18 Hyperacute rejection, 906 Hypercapnic respiratory failure, 9 Hypereosinophilic syndrome (HS), 789 Hyperprogression, 890 Hypersensitivity pneumonitis (HP), 615, 620, 704, 881 acute/subacute HP, 635, 636 bronchoalveolar lavage, 631 charactersitics features, 637, 638 chronic HP, 635, 636 clinical presentation, 630, 631 CT findings, 632–635

926 Hypersensitivity pneumonitis (HP)  (cont.) diagnosis, 632 differential diagnosis, 637 epidemiology, 629 exposure questionnaire, 631 histopathological diagnosis, 637 laboratory testing, 631 pathogenesis antigens and physiologic susceptibility, 629–630 cigarette smoking, 630 immune dysregulation, 630 pulmonary function test, 631 radiographic features, 632, 633 surgical lung biopsy, 632 transbronchial biopsies, 632 transbronchial lung cryobiopsy, 632 Hypoalbuminemia, 90 I Idiopathic pulmonary fibrosis (IPF), 696, 851 clinical presentation, 601 diagnostic evaluation bronchoalveolar lavage, 602 chest x-ray, 602 laboratory testing, 601 multidisciplinary approach, 603 pulmonary function test, 601 surgical lung biopsy, 603 transbronchial lung biopsy, 602 transbronchial lung cryobiopsy, 602 epidemiology, 599 natural history, 601 pathogenesis, 599, 600 risk factors cigarette smoking and environmental risk factors, 600 gastroesophageal reflux, 600 genetic risk factors, 600, 601 microbial agents, 600 Idiopathic pulmonary hemosiderosis (IPH), 748–752 IgG4-related lung disease (IgG4-RLD), 235, 236 clinical features, 485 differential diagnosis, 488 history, 485 immunohistochemistry and ancillary studies, 487, 488 pathology, 485–487 Immune checkpoint inhibitors (ICIs), 891 Immune-relate adverse events (irAE), 891 Immunodeficiency, 608 Immunoglobulin G4 (IgG-4)–related sclerosing disease, 8 Immunotherapy, 888 Incisional biopsies, 67 Indirect occupational exposures, 692 Infectious etiologies, 90 Inflammatory cells, 14 Inflammatory pseudotumor (myofibroblastic tumor), 567–570 Intensity-modulated radiation therapy (IMRT), 895, 898 Interferon-γ (IFN-γ) release assay, 703 International Mesothelioma Interest Group (IMIG), 30 Interstitial lung disease (ILD) MCTD in, 679, 680 polymyositis and dermatomyositis, 673 relapsing polychondritis, 678 rheumatoid arthritis-associated, 659, 660 Sjogren syndrome, 668, 669 systemic lupus erythematosus, 664 systemic sclerosis, 671, 672

Index Interstitial pneumonia with autoimmune features (IPAF), 660 Intrapleural tumors, 67 Intrapulmonary thymoma, 585, 586 Intrathoracic endometriosis, 23 Invasive adenocarcinoma, 329–332 Isolated pauci-immune capillaritis (IPPC), 724–726 Isoniazid (INH), 830 J Juvenile xanthogranuloma, 243 K Kahn criteria, 679 Kaposi’s sarcoma (KS), 470, 471 Kawasaki disease (KD), 722–724 Keratin 5/6, 23 Kirsten rat sarcoma virus (KRAS), 885 Kissing nuclei, 286 Kulchitshy cells, 373 L Lactate dehydrogenase (LDH), 89 Langerhans cells histiocytosis (LCH) clinical features, 237, 238, 541, 542 diagnostic imaging, 542 differential diagnosis, 240, 241, 546–548 history, 237, 540, 541 immunohistochemical profile, 240 immunohistochemistry and ancillary studies, 239, 240, 545–547 molecular alterations, 548 pathology, 238, 239, 542–545 treatment, 238 Large cell carcinoma, 360, 361 Large cell neuroendocrine carcinoma (LCNECs) clinical presentation, 379 epidemiology, 379 high-grade, 382, 387, 388 histological features, 398, 400 prognosis, 379 Laryngeal and tracheal edema, 678 Latent tuberculous infection (LTBI), 662 Leiomyoma, 459–462 Leiomyosarcoma, 81 Lepidic predominant invasive ADC (LPA), 330 Light chain deposition disease (LCDD), 774 Limited stage (LS) disease, 378 Lipoid pneumonia, 797 Lipomatous tumors benign lipomatous tumors, 210, 211 malignant lipomatous tumors clinical behavior, 211 dedifferentiated liposarcoma, 211, 212 histologic variants, 210 myxoid liposarcoma, 213 pleomorphic liposarcoma, 213, 214 Localized pleural thickening, 9 Low-grade fibromyxoid sarcoma, 202, 203 Lung adenocarcinoma, 663 Lung allograft, 905, 907 Lung biopsy, 664 Lung buds, 3 Lung cancer, 696 Lung entrapment, 9 Lung mass, 831

Index Lung parenchyma, 19, 64, 710 Lymph Nodes, 36 Lymphadenoma, see Classic Hodgkin lymphoma (CHL) Lymphadenopathy, 806 Lymphangioleiomyomatosis (LAM) clinical phenotypes, 641 diagnosis, 641 differential diagnosis, 641 extrapulmonary manifestations, 640, 643 pathogenesis, 639–641, 643–646 pathological features, 645, 646 prognosis, 647 treatment, 647 vaccinations, 647 Lymphangiomas, 198 LymphGen classification, 506 Lymphocyte-rich thymoma, 267 Lymphocytes, 4 Lymphocytic interstitial pneumonia (LIP), 667 Lymphoepithelioma-like carcinoma (LELC), 333, 360 Lymphogranuloma benignum, 221 Lymphohistocytoid mesothelioma, 47, 51 Lymphoid interstitial pneumonia (LIP)/diffuse lymphoid hyperplasia, 766 clinical features, 482 differential diagnosis, 484, 485 history, 482 immunohistochemistry and ancillary studies, 482, 484 pathology, 482, 483 Lymphomatoid granulomatosis (LyG) clinical features, 508 diagnostic imaging, 508, 509 differential diagnosis, 512, 513, 515 grading system, 512, 514 history, 508 immunohistochemistry and ancillary studies, 509, 511–514 molecular findings, 515 pathology, 509–511 See also Classic Hodgkin lymphoma (CHL) Lymphoplasmacytic lymphoma clinical features, 515 diagnostic imaging, 536, 537 differential diagnosis, 518, 519 immunohistochemistry and ancillary studies, 517–519 molecular findings, 519 pathology, 515–517 M Macrophages, 4 Malignancy, 674 Malignant granuloma, see Classic Hodgkin lymphoma (CHL) Malignant mesothelioma (MM), 28, 30, 31, 42, 53 Malignant peripheral nerve sheath tumors (MPNST), 204, 206 Malignant pleural disease, 7 Malignant pleural effusions (MPEs), 85, 90 Malignant pleural mesothelioma (MPM), 23, 31, 36, 696 Malignant rhabdoid tumor, 216 Malignant teratoma, 179 MAML2, 416 Mantle zone lymphoma clinical features, 515, 536, 537 differential diagnosis, 518, 519 immunohistochemistry and ancillary studies, 517–519 pathology, 515–517 Marfans syndrome (MFS), 768, 769

927 Marginal zone lymphoma of the mucosa-associated lymphoid tissue MALT (MZL/MALT lymphoma), 258 clinical features, 258 differential diagnosis, 260–262 immunohistochemistry, 260, 261 molecular findings, 261 pathology, 258–260 Massive lymphadenopathy with sinus histiocytosis, 241 McAdam’s criteria, 677 Mediastinal adenopathy, 72 Mediastinal diffuse large B-cell lymphoma, 250 clinical features, 250 differential diagnosis, 250, 252, 253 immunohistochemistry and ancillary studies, 251–254 molecular findings, 254 pathology, 251 Mediastinal ependymoma, 307 Mediastinal fibromatosis, 236 Mediastinal germ cell tumors (M-GCT) classification, 177, 178 clinical outcome, 192 clinical symptomatology, 179 diagnostic imaging, 179–183 immunohistochemical features, 191, 192 immunohistochemistry, 183 occurrence, 177, 178 seminoma, 183, 186, 187 staging, 177–179 teratomas, 179, 182–186 Mediastinal granuloma, 299 Mediastinal granulomatous lymphadenitis, 224–227 Mediastinal gray zone lymphoma (M-GZL), 255–257 Mediastinal invasion, 72 Mediastinal involvement, 32 Mediastinal myeloid sarcoma, 284 clinical features, 284 differential diagnosis, 285 immunohistochemistry and ancillary studies, 284, 285 molecular studies, 285 pathology, 284 Mediastinal plasmacytoma, 262–264 Mediastinum compartments, 103, 104 imaging modalities, 104, 105 radiological imaging, 103 vascular and nonvascular structures, 103 Mesenchymal chrondrosarcoma, 75 Mesenchymal tumors benign mesenchymal tumor cartilaginous hamartoma, 459, 460 endobronchial lipoma, 462, 463 leiomyoma, 459–462 schwannomas, 461, 462 SFT, 463–465 malignant mesenchymal tumor angiosarcoma, 471, 472 chondrosarcoma, 467, 468 clinical history, 465 epithelioid hemangioendothelioma, 470, 471 Kaposi’s sarcoma, 470, 471 osteosarcoma, 467, 468 primary pulmonary myxoid sarcoma, 470 pulmonary artery sarcoma, 468–470 skeletal muscle tumors, 466 smooth muscle tumors, 465, 466 synovial sarcoma, 467

928 Mesenchymal tumors of the mediastinum bone and cartilaginous tumors, 214, 215 fibroblastic and fibrohistiocytic tumors low-grade fibromyxoid sarcoma, 202, 203 sclerosing epithelioid fibrosarcoma, 202 solitary fibrous tumor, 201, 202 lipomatous tumors benign, 210, 211 malignant, 210–214 myogenic tumors skeletal muscle tumors, 209, 210 smooth muscle tumors, 209 neurogenic tumors benign peripheral nerve sheath tumors, 203–206 ganglionic tumors, 207, 208 MPNST, 204, 206 types, 197 unknown etiology, 216, 217 vascular tumors angiosarcoma, 200, 201 epithelioid hemangioendothelioma, 199, 200 hemangiomas, 198, 199 lymphangiomas, 198 Mesothelial cells, 4, 8 Mesothelial hyperplasia, 22, 23 Mesothelioma, 48 Metastases, 36, 60 Metastatic carcinoma or metastatic amelanotic melanoma, 279 Metastatic disease, 8 Microcystic squamous cell carcinoma, 341 Microscopic polyangiitis (MPA), 724, 745, 746 Mineral dust exposure, 9 Minimally invasive adenocarcinoma (MIA), 347, 348 Minimum intensity projection (Min-IP), 623 Mixed connective tissue disease (MCTD), 679 Alarcon-Segovia criteria, 679 clinical features of, 679 interstitial lung disease, 679, 680 Kahn criteria, 679 morbidity and mortality in, 680 pulmonary arterial hypertension, 680 Sharp criteria, 679 sub-phenotypes, 679 Monophasic synovial sarcoma, 82, 216 Mouth and genital ulcers with inflamed cartilage syndrome (MAGIC syndrome), 678 Muceoepidernoid carcinoma, 57 Mucocytes, 412 Mucoepidermoid carcinoma (MEC), 58, 59, 149–151, 410 clinical presentation, 410 diagnosis, 410 diagnostic imaging, 410, 411 high grade neoplasms, 417 immunohistochemical stains and molecular studies, 416 low grade neoplasms, 412–416, 418 pathological features, 411, 412 prognosis, 410 staging system, 410 treatment of choice, 410 Mucormycosis, 843 Mucosa-associated lymphoid tissue (MALT), 669 clinical features, 492, 493 diagnostic imaging, 493 differential diagnosis, 497, 499–501 history, 491 immunohistochemistry and ancillary studies, 497–500

Index molecular findings, 500, 501 pathogenesis, 491, 492 pathology, 493–497 Mucous gland adenoma, 441, 443–445 Multidisciplinary discussion (MDD), 611, 612 Multifocal alveolar disease, 783 Multilocular thymic cyst (MTC), 301, 302 Multimodality treatment strategies, 78 Multiple endocrine neoplasia (MEN), 155 Myasthenia gravis, 56 Mycobacteria tuberculosis (MTB), 829 Myelodysplastic syndrome (MDS), 677 Myeloid sarcoma (MS), 85 Myoblastoma, 574 Myofibroblast contraction, 600 Myogenic tumors skeletal muscle tumors, 209, 210 smooth muscle tumors, 209 Myxoid liposarcoma, 213 Myxoid/mucoid, 41 N Necrotizing granulomas, 227 Necrotizing sarcoid granulomatosis (NSG), 720–722 Nephrogenic systemic fibrosis, 8 Neuroblastoma, 75, 207 Neuroectodermal tumors, 78, 79 Neuroendocrine neoplasms clinical features, 155, 156 diagnostic imaging, 157 histological grading and nomenclature, 159 immunohistochemical features, 164 macroscopic features, 159 microscopic features, 159–162 occurrence, 155 paraganglioma, 166–168 parathyroid tumors, 170, 171, 173 pathological staging, 158 Neuroendocrine tumors (NET) carcinoid tumors clinical presentation, 375, 376 diagnosis, 375–377 diagnostic imaging, 380, 382–386 epidemiology and demographics, 375 classifications, nomenclature, definitions, and staging, 391–393 DIPNECH clinical presentation, 374 diagnostic evaluation, 374, 375, 380, 381 epidemiology and demographics, 374 history, 374 treatment and prognosis, 375 2015 WHO classification, 374 immunohistochemical and molecular features, 395–397, 399 intrapulmonary paraganglioma, 384, 390, 391, 403 LCNECs clinical presentation, 379 epidemiology, 379 high-grade, 382, 387, 388 histological features, 398, 400 prognosis, 379 low and intermediate grade carcinomas, 394–398 macroscopic features, 393, 394 pathological features, 403, 404 PNET, 373, 374 SCC, 398, 401, 402

Index SCLC characterization, 377 clinical presentation, 377, 378 diagnostic evaluation, 378 epidemiology and demographics, 377 high-grade, 382, 384, 389, 390 prognosis and prevention, 378, 379 staging systems, 378 Neurofibromatosis, 767 Neurogenic tumors benign peripheral nerve sheath tumors, 203–206 ganglionic tumors, 207, 208 MPNST, 204, 206 Niemann-pick (NP) disease, 851 Nodal sinus histiocytosis, 242 Non-Hodgkin lymphomas, 75, 244 of B-cell origin mediastinal DLBCL, 250–254 mediastinal gray zone lymphoma, 255–257 mediastinal plasmacytoma, 262–264 MZL or MALT lymphoma, 258–262 PM-LBCL, 244–250 of T-cell origin anaplastic large cell lymphoma, 270–272 classic Hodgkin lymphoma (see Classic Hodgkin lymphoma (CHL)) T-ALL/T-LBL, 264–270 Non-invasive thymoma (encapsulated thymoma), 120 Non-neoplastic disorders, 3 Non-seminomatous germ cell tumors, 188 choriocarcinoma, 191 embryonal carcinoma, 190 yolk sac tumor, 188, 189 Non-small cell lung carcinomas (NSCLC), 884 adenocarcinoma, 328–332 AAH, 347, 348 adenomatoid tumors, 356, 357 AIS, 347, 348 BAC, 349 cribriform adenocarcinoma, 356, 358 definition, 343 histological variants, 346, 349, 351–357, 359 histopathological features, 345–350 intestinal type, 356, 358 macroscopic features, 345, 346 MIA, 347, 348 pulmonary adenocarcinoma, 356, 359 adenosquamous carcinoma, 333, 334, 359 clinical presentation, 312, 313 imaging modalities, 313, 314, 316 immunohistochemical antibodies, biomarkers and molecular biology, 362–367 incidence and prognosis, 311, 312 large cell carcinoma, 332, 333, 360, 361 LELC, 333 lymphoepithelioma-like carcinoma, 360 M classification, 317, 319, 322, 323 N classification, 316, 320–322 primary mammary-like carcinoma, 360 rhabdoid carcinoma, 360 risk factors, 312 sarcomatoid carcinoma, 333–336 SQCC, 321, 322, 324, 326–328 histological variants, 336, 338–344 histopathological features, 337–339 macroscopic features, 336–338 mild dysplasia, 336

929 moderate atypia, 336, 337 severe dysplasia/in situ, 336, 337 staging, 315, 317 T classification, 316, 318, 319 TNM-8, 319–321, 324–326 Nonspecific interstitial pneumonia (NSIP), 660, 664, 668, 671, 679, 878 bronchoalveolar lavage, 611 causes and clinical entities, 611 clinical presentations and prognosis, 610 connective tissue diseases, 615 diagnostic evaluation, 610 differential diagnosis, 615–617 evolution, 615 exacerbations vs. infection, 615 histopathologic pattern, 616, 618 imaging findings, 612–614 laboratory testing, 610 multidisciplinary discussion, 611, 612 pulmonary function tests, 610 Non-steroidal anti-inflammatory agents (NSAIDs), 869 Nonsurgical candidates, 31 Non-tuberculosis mycobacteria (NTM), 828, 829 Nuclear protein in testis (NUT) carcinoma, 149 O Obliterative bronchiolitis, 660 Obstructive pneumonitis, 90 Obstructive sleep apnea (OSA), 676 Occupational asthma, 704 Oncocytomas, 441, 442 Opportunistic infections, 666 Organizing pneumonia (OP), 615, 874, 875, 878 Osteosarcoma, 467, 468 P Paracoccidioidomycosis (PCM), 838, 839 Paraganglioma clinical course, 166 diagnostic imaging, 166, 167 occurrence, 166 pathological features, 168 Paragonimiasis, 846 Paramalignant effusions, 90 Parapneumonic effusions, 90 Parathyroid tumors clinical outcome, 170 diagnostic imaging, 170 pathological features, 171, 173 Parenchymal disease acute lupus pneumonitis, 665 benign conditions, 695, 696, 698 interstitial lung disease, 664 lung disease, 800–802 malignant conditions, 696 Parietal pleura, 4 Parkinson’s disease, 21 Pedunculated tumors, 61 Pelomorphic carcinoma, 365 Placental transmogrification, 592, 593 Plasma cell-rich Castleman disease clinical features, 231 differential diagnosis, 233 immunohistochemistry, 233, 234 pathology, 232, 233

930 Plasma exchange (PLEX), 736 Plasmablasts, 232, 234 Plasmacytoid lymphoma, 84 Pleomorphic adenoma (mixed tumor), 427–429, 431 Pleomorphic carcinoma, 364 Pleomorphic liposarcoma, 213, 214 Pleura adenomatoid tumors, 28 apical pleural plaques, 17 body cavity lymphoma, 84 computed tomography, 31, 32, 34 connective tissue diseases, 20, 21 coronary artery bypass grafting, 17 desmoid tumors (see Desmoid tumors) drug-induced fibrous pleuritis, 21 epithelial-myoepithellial carcinoma, 59 fibrous and fibrinous pleuritis, 8, 9 general radiology concepts, 4–6 hemothorax, 16 histological features, 9, 11 histopathological features, 13 IgG4-related fibrous pleuritis, 21 immunohistochemical features, 47 invasive malignant mesothelioma, 38, 41, 47 limitations of routine imaging, 35 lymphatic network, 4 macroscopic features, 37 magnetic resonance imaging, 34 malignant mesothelioma, 28, 30, 31 malignant mesothelioma in situ, 37, 38 management, 90, 91 mesothelial cells, 4 mesothelial hyperplasia, 22, 23 microscopic features, 37 molecular analysis, 47, 52 multidisciplinary approach, 3 neoplastic and non-neoplastic pleural diseases, 4 pathological features, 37, 55 PET/CT, 34, 35 physiologic mechanisms, 8 pleural effusions, 87–90 pleural endometriosis, 24, 25 pleural infections, 11, 13 pleural manifestations, 85, 86 pleural metastasis, 86, 87 pleural thymoma, 56 pleuroparenchymal fibroelastosis, 22 pneumoconiosis, 17–19 primary effusion lymphoma, 84, 85 primary pleuroparenchymal synovial sarcomas, 80, 81 primary salivary gland type tumors, 57–59 primary smooth muscle tumors, 80 production and absorption, 3 pseudomesotheliomatous adenocarcinoma, 52 pyothorax associated lymphoma, 85 radiographic and histologic appearance, 3 radiographs, 31 sarcomas, 80 solitary fibrous tumors (SFTs) (see Solitary fibrous tumors (SFTs)) staging, 36, 37 therapy response assessment, 35 ultrasound, 35 uremia, 13, 16 vascular supply of, 4 visceral and parietal pleura, 3, 4 volumetric and future imaging of MPM, 36 Pleural angiosarcoma, 73 Pleural biopsy, 76

Index Pleural deciduosis, 29 Pleural disease, 661, 664 benign conditions benign asbestos pleural effusion, 694 diffuse pleural thickening, 695 pleural plaques, 693, 694 rounded atelectasis, 694, 695 malignant conditions, 696 Pleural effusions, 3, 8, 661, 664, 669, 674 Pleural endometriosis, 24–26 Pleural epithelial-myoepitheial carcinoma, 60 Pleural fibrosis, 8 Pleural fluid, 4 protein, 89 triglycerides, 90 Pleural infections, 9 Pleural manometry, 9 Pleural metastasis, 86–88 Pleural plaques, 9, 17, 18, 693, 694 Pleural synovial angiosarcoma, 82 Pleural thymoma, 56 Pleural tumors, 6 Pleural-based thymoma, 58 Pleuritis, 15 Pleurodesis, 91 Pleuroparenchymal fibroelastosis (PPFE), 9, 22 PNET/Ewing sarcoma, 77, 78 Pneumoconiosis, 17–19 asbestos (see Asbestos) hard metal lung disease bronchoscopy, 705 clinical features, 704 cobalt lymphocyte proliferation test, 705 diagnosis, 705 management, 705, 706 pathogenesis, 703, 704 pathology, 705, 706 pulmonary function test, 705 radiology, 704 silicosis (see Silicosis) Pneumocystis jirovecii (PCP), 13, 662 Pneumocytoma (sclerosing hemangioma), 571–573 Pneumonic adenocarcinoma, 326 Pneumonitis, 704, 886 Polyarteritis nodosa (PAN) clinical presentation, 719 diagnostic evaluation, 719, 720 imaging, 720 incidence and risk factors, 719 lung parenchyma, 719 management, 720 pathogenesis, 719 vasculature, 719 Polymyositis (PM), 672, 673 ILD in, 673 pulmonary hypertension in, 673, 674 Positron emission tomography (PET), 732 Postcardiotomy syndrome, 87 Posterior pleura, 6 Posttransplant lymphoproliferative disorder (PTLD), 916 Primary effusion lymphoma, 84, 85 Primary graft dysfunction (PGD), 905 Primary mammary-like carcinoma, 360 Primary mediastinal (thymic) large B-cell lymphoma (PM-LBCL), 244, 282 asteroid B-cells, 244, 245 clinical features, 244, 245 differential diagnosis, 247, 249

Index immunohistochemistry and ancillary studies, 246–249 molecular findings, 249, 250 pathology, 245–247 Primary pleural angiosarcoma (PPA), 73, 75 Primary pleural disease, 3 Primary pleural epithelioid hemangioendothelioma (PEH), 72 Primary pleuroparenchymal synovial sarcomas (PPSS), 80 Primary pulmonary myxoid sarcoma, 470 Primary pulmonary paragangliomas (PPPs), 384, 403 Primary Sjogren syndrome (pSS), 667, 669 Primary tumor, 36 Primitive neuroectodermal tumor (PNET), 75, 78 Psedumesotheiomatous adenocarcinoma, 57 Pseudochylous effusion, 661 Pseudoleukemia, see Classic Hodgkin lymphoma (CHL) Pseudomesotheliomatous adenocarcinoma, 52, 56 Pseudomesotheliomatous carcinoma (PMC), 52 Pseudomonas aeruginosa, 797 Pulmonary adenofibroma, 587, 588 Pulmonary alveolar microlithiasis (PAM), 852–854 Pulmonary alveolar proteinosis (PAP), 855, 857–860 classification, 855 diagnostic imaging, 856, 857 differential diagnosis, 860, 861 imaging findings, 860 pathological features, 862 prevalence, 856 primary vs. secondary, 860 Pulmonary amyloidosis, 669 Pulmonary apical fibrocystic disease, 675, 676 Pulmonary arterial hypertension (PAH), 665, 666, 680 Pulmonary artery involvement (PAI), 710 Pulmonary artery sarcoma, 468–470 Pulmonary cryptococcosis (PC), 834 Pulmonary crystal storing histiocytosis, 554–556 Pulmonary disease, 710 Pulmonary drug toxicity, 869 angiogenesis, 885 chest radiograph, 869 diffuse alveolar damage, 870–872 diffuse alveolar hemorrhage, 882 drug induced sarcoid like reaction, 882 drug related pleural abnormalities, 884 eosinophilic pneumonia, 880 hypersensitivity pneumonitis, 881 imaging patterns, 869, 870 immune checkpoint inhibitors, 891 immune-relate adverse events, 891–893 immunotherapy, 888 interstitial lung disease, 878 non-specific interstitial pneumonitis, 879 organizing pneumonia, 874, 875 pathological response to therapy, 893 pulmonary hypertension, 882, 883 radiation pneumonitis, 899 radiation therapy, 895, 896 response assessment, 888, 889 targeted therapy, 885 Pulmonary embolism, 90, 666 Pulmonary epithelial-myoepithelial carcinoma (P-EMC), 431–435 Pulmonary function tests (PFTs), 671, 674, 678, 680, 747 Pulmonary hyalinizing granuloma (PHG), 863 Pulmonary hypertension (PH), 676, 807, 882 polymyositis and dermatomyositis, 673, 674 Rheumatoid arthritis in, 662 Sjogren syndrome, 669 systemic lupus erythematosus, 665, 666 systemic sclerosis, 672

931 Pulmonary infections, 662 Pulmonary intravascular large B-cell lymphoma (LBCL) clinical features, 506 differential diagnosis, 507, 508 immunohistochemistry and ancillary studies, 507 molecular findings, 508 pathology, 506, 507 Pulmonary involvement, 667 Pulmonary Juvenile Xanthogranuloma (PJXG), 554, 555 Pulmonary lymphoma, 669 Pulmonary lymphoproliferative disorders benign lymphoproliferative lesions BALT, 475, 476 follicular bronchiolitis, 480–482 IgG4-RLD, 485–488 LIP/diffuse lymphoid hyperplasia, 482–485 PNLH, 476–479 CHL clinical features, 530, 531 definition, 529 diagnosis, 531 differential diagnosis, 535 immunohistochemistry and ancillary studies, 533–535 molecular findings, 535, 536 pathology, 531–533 crystal storing histiocytosis, 554–556 ECD clinical features, 552 diagnostic imaging, 552, 553 differential diagnosis, 552, 554 history, 552 immunohistochemistry and ancillary studies, 552, 553 molecular findings, 554 pathology, 552, 553 hematopoietic lung neoplasm, 490 histiocytic disorders, 540, 541 LCH (see Langerhans cells histiocytosis (LCH)) lymphomatous nodule, 490, 491 myeloid neoplasms clinical features, 536 differential diagnosis, 540 immunohistochemistry and ancillary studies, 539, 540 molecular findings, 540 pathology, 538, 539 non-Hodgkin lymphomas of B-cell origin CLL/SLL, 515–519, 536, 537 DLBCL, 501–506 extraosseous plasmacytoma, 519–523 follicular lymphoma and lymphoplasmacytic lymphoma, 515–519, 536, 537 LBCL, 506–508 LyG (see Lymphomatoid granulomatosis (LyG)) mantle zone lymphoma, 515–519, 536, 537 marginal zone lymphoma/MALT lymphoma, 491–501 non-Hodgkin lymphomas of T-cell origin PTCL, NOS, 526–528 pulmonary ALCL (see Anaplastic large cell lymphoma (ALCL)) PJXG, 554, 555 RDD clinical features, 548, 549 diagnostic imaging, 549 differential diagnosis, 550, 551 history, 548 immunohistochemistry and ancillary studies, 550, 551 molecular findings, 551 pathology, 549, 550 Pulmonary meningioma, 583, 584

932 Pulmonary meningotheliomatosis, 583–585 Pulmonary neuroendocrine cells (PNET), 373, 374 Pulmonary nodular lymphoid hyperplasia (PNLH) clinical features, 476 differential diagnosis, 478, 479 history, 476 immunohistochemistry and ancillary studies, 478 pathology, 476, 477 Pulmonary oncocytomas (P-oncocytomas), 441, 442 Pulmonary peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) clinical features, 526 differential diagnosis, 528–530 immunohistochemistry and ancillary studies, 527, 528 molecular findings, 528 pathology, 527 Pulmonary pleuroparenchymal fibroelastosis (PPFE), 912 Pulmonary sarcoidosis, 798 airway involvement, 802 cardiac magnetic resonance, 812 cardiac sarcoidosis, 812 chest radiography, 799 clinical features, 798 CT and HRCT, 803 diagnosis, 815 diagnostic imaging, 799 differential diagnosis, 814 echocardiography, 812 fibrotic changes, 805 histological features, 816 large and small airway involvement, 807 lymph node enlargement, 800 lymphadenopathy, 806 macronodules, 803, 805 magnetic resonance imaging, 811 nuclear medicine, 808, 809, 812–814 parenchymal lung disease, 802 pleural involvement, 805 prognosis factors, 815 reticulonodular pattern, 803 staging and prognosis, 798 Pulmonary-renal syndrome (PRS), 727 Pyothorax associated lymphoma (PAL), 85 Pyrazinamide (PZA), 830 R Radiation pneumonitis, 899 Radiation therapy, 676, 895 Radiochemotherapy-induced toxicity, 90 RAS/RAF/MAPK pathway, 237, 238 Raynaud phenomenon, 665, 674, 679, 680 Recurrent aphthous stomatitis (RAS), 716 Relapsing polychondritis (RP), 677 airway disease, 677 autoimmune activity in, 677 diagnosis of, 677 incidence of, 677 interstitial lung disease, 678 myelodysplastic syndrome, 677 symptoms, 677 Respiratory bronchiolitis-interstitial lung disease (RB-ILD), 605 Response evaluation criteria in solid tumors (RECIST) guidelines, 35 Restrictive allograft syndrome (RAS), 914 “Reticuloendothelial” system, 237

Index Reticulo-epitheial thymomas, 120 Retinoblastoma, 75 Rhabdoid carcinoma, 41, 360 Rhabdomyosarcomas, 75, 209, 466 Rheumatoid arthritis (RA), 8, 659 airway disease, 660, 661 caplan syndrome, 662 DMARDs, 663 interstitial lung disease, 659, 660 pleural disease, 661 pulmonary hypertension, 662 pulmonary infections, 662 rheumatoid nodules, 661 Rheumatoid arthritis-related interstitial lung disease (RA-ILD), 620 Rheumatoid nodule, 662 Rheumatoid nodules, 661 Rheumatoid pneumoconiosis, see Caplan syndrome Rifampicin (RIF), 830 Rosai-Dorfman disease (RDD), 240 clinical features, 241, 548, 549 diagnostic imaging, 549 differential diagnosis, 242, 243, 550, 551 due to immune dysregulation/viral infection, 241 histopathologic features, 241 history, 548 immunohistochemistry and ancillary studies, 242, 243, 550, 551 molecular findings, 551 pathology, 241, 242, 549, 550 RAS/RAF/MAPK pathway, 241 Rounded atelectasis, 694, 695 Routine pleural fluid analyses, 89 Rrespiratory bronchiolitis (RB), 608 Rrespiratory bronchiolitis-interstitial lung disease (RB-ILD), 637 S Salivary gland type carcinomas, 149 Salivary gland type tumors of the lung (SGTL) acinic cell carcinoma, 437–439 adenoid cystic carcinoma, 418 age variation, 418 complete surgical resection, 418 cylindromatous growth pattern, 419, 422 diagnostic imaging, 418–421 immunohistochemistry, 419, 426 jigsaw pattern, 419 molecular features, 419 prognosis, 418 pulmonary function tests, 418 sampling approaches, 418 solid growth pattern, 419, 425 tubular growth pattern, 419, 424 clear cell hyalinizing carcinoma, 439, 440 clinical features, 409, 410 mucoepidermoid carcinoma, 410 clinical presentation, 410 diagnosis, 410 diagnostic imaging, 411 immunohistochemical stains and molecular studies, 416 low grade neoplasms, 412–418 pathological features, 411, 412 staging system, 410 treatment of choice, 410 mucous gland adenoma, 441, 443–445 oncocytomas, 441, 442

Index pleomorphic adenoma (mixed tumor), 427–429, 431 prognosis, 410 pulmonary epithelial-myoepithelial carcinoma, 431–435 treatment, 410 Sarcoidosis, 8, 221–224 Sarcomatoid carcinoma, 41, 333–336, 364 Sarcomatoid mesothelioma, 49 Schurawitzki method, 668 Schwannomas, 461, 462 Scleroderma, 680 Scleroderma renal crisis, 672 Sclerosing epithelioid fibrosarcoma, 202 Sclerosing mediastinitis, 235–237 Secondary extramedullary multiple myeloma, 86 Secondary Sjogren syndrome (sSS), 667 Seminoma, 183, 186, 187 Serum angiotensin converting enzyme (SACE), 798 Sharp Criteria, 679 Shrinking lung syndrome (SLS), 666 Shrinking or contracted pleuritis, 694 Silica-associated fibrous pleuritis, 18 Silicosis accelerated silicosis, 699, 701 acute silicosis, 701 chronic silicosis, 699, 700 clinical features, 702 diagnostic approach, 703 epidemiology, 698 management, 703 occupational risk and mitigation, 698, 699 pathogenesis, 699 pulmonary function tests, 702 radiographic features, 702, 703 Simple thymic cyst, 301 6-minute walk test, 663, 666, 671 Sjogren syndrome (SS), 608, 667 airway disease, 667, 668 interstitial lung disease, 668, 669 pulmonary amyloidosis, 669 pulmonary hypertension, 669 pulmonary lymphoma and other hematological involvement, 669 Skeletal muscle tumors, 209, 210, 466 Skleroderma Generale, 670 Small airway inflammation, 908, 909 Small cell lung cancer (SCLC) high-grade, 382, 384, 389, 390 histological features, 398, 401, 402 NET characterization, 377 clinical presentation, 377, 378 diagnostic evaluation, 378 epidemiology and demographics, 377 prognosis and prevention, 378, 379 staging systems, 378 Small cell squamous cell carcinoma, 341, 342 Smooth muscle tumors, 209, 465, 466 Solitary extramedullary plasmacytoma (SEP), 86 Solitary fibrous tumor (SFT), 67, 201, 202, 236, 463–465 histological features, 64 immunohistochemical features, 67 macroscopic features, 64 Spindle cell (medullary) thymomas, 121 Spindle cell fibroblastic proliferation, 9 Spindle cell squamous cell carcinoma, 340, 341

933 Spontaneous pneumomediastinum, 674 Squamous cell carcinoma (SQCC), 321, 322, 324, 326–328 histological variants, 336, 338–344 histopathological features, 337–339 macroscopic features, 336–338 mild dysplasia, 336 moderate atypia, 336, 337 severe dysplasia/in situ, 336, 337 Standard chemotherapy, 31 Standard chest radiographs (CXRs), 88 Staphylococcus aureus, 797 Stereotactic body radiation therapy (SBRT), 895, 897 Steroids, 663 Strongyloides stercolaris infection, 796 Subpleural honeycomb cysts, 622 Superimposed bacterial infection, 19 Superior vena cava (SVC), 313 Surgical lung biopsy (SLB), 603 Symptomatic airway obstruction, 666 Syndrome of inappropriate antidiuretic hormone (SIADH), 377 Synovial sarcoma, 88, 216, 467 Systemic fibroinflammatory injury, 21 Systemic lupus erythematosus (SLE), 663 classifications, 663 diaphragmatic involvement, 666 parenchymal disease acute lupus pneumonitis, 665 interstitial lung disease, 664 pleural disease, 664 pulmonary complications in, 663 pulmonary manifestations caused by, 663 symptomatic airway obstruction, 666 vascular disease diffuse alveolar hemorrhage, 665 pulmonary embolism, 666 pulmonary hypertension, 665, 666 Systemic non-infectious granulomatous process, 227 Systemic sclerosis (SSc), 670 diagnosis of, 670 disease presentation, 670, 671 etiology, 670 evaluation, 671 interstitial lung disease, 671, 672 other manifestations, 672 pulmonary hypertension, 672 T Takayasu arteritis (TA), 709 clinical presentation, 710 diagnostic evaluation, 711 incidence and risk factors, 709 management, 712 pathogenesis, 710 prognosis, 712 T-cell lymphomas, 223 T-cell maturation and capacitation process, 264 Teratocarcinoma, 179 Teratomas, 179, 182–186 Terminal deoxynucleotidyl transferase (TdT), 264 Therapeutic pleural drainage, 9 Thoracentesis, 31 Thoracic conditions, 8 Thoracic ultrasound, 5 Thymic adenocarcinoma, 147–149

934 Thymic carcinoma adenocarcinoma, 147, 148 adenoid cystic carcinoma, 151 basaloid carcinoma, 151 clinical features, 139 diagnostic criteria, 139 diagnostic imaging, 139, 140 different growth patterns, 143 epidemiological features, 139 epithelial differentiation, 137 epithelial-myoepithelial carcinoma, 151 mucoepidermoid carcinomas, 149–151 NUT carcinoma, 149 pathogenesis, 137 pathological features, 143–147 pathological staging, 141, 142 salivary gland type carcinomas, 149 Thymic hyperplasia, 267, 302–305 Thymic hyperplasia with lymphoepithelial sialadenitis (LESA)-like features, 302, 303, 305 Thymic involution, 111 Thymic rebound hyperplasia, 304 Thymoma with ancient changes (sclerosing thymoma), 134 clinical features, 118 clinical outcome, 134 diagnostic imaging, 118–120 different growth patterns, 128, 129 epidemiological features, 117 histological classification, 120, 121 histology, 129 immunohistochemical stains, 129 mixed histologies – atypical and conventional thymoma, 134 pathological features, 128, 129 pathological staging, 121–127 with prominent adenomatoid features, 132 with prominent glandular and papillary features, 132 with prominent plasma cell component, 132 with pseudosarcomatous stroma, 132 Thymus histological features, 108–110 immunohistochemical features, 111–115 practical embryological aspects, 105–108 thymic involution, 111 T-lymphoblastic leukemia/lymphoma (T-ALL/T-LBL), 264 clinical features, 264, 265 differential diagnosis, 267–269 immunohistochemistry and ancillary studies, 266–269 molecular findings, 269, 270 pathology, 265, 266 Tocilizumab, 715 Tracheobronchial abnormalities, 731 Tracheobronchomalacia, 677 Tracheomalacia, 678 Traction bronchiectasis, 612 Transbronchial biopsies (TBBx), 602 IPF, 602 desquamative interstitial pneumonia, 608 transbronchial lung cryobiopsy, 632 Transbronchial lung cryobiopsy (TBLC) desquamative interstitial pneumonia, 608 IPF, 602 transbronchial lung cryobiopsy, 632 Transmogrification, 866 Trauma, 9 Tropical eosinophilia, 796 True intrathoracic desmoid tumors, 67

Index Tuberculosis, 825 Tuberculous pleuritis, 11, 12 Tubular strucures, 40 Tubulopapillary, 40 Tumor cavitation, 885 Tumor localization, 77 Tumor necrosis factor-alpha inhibitors (TNF-inhibitors), 662, 676, 678 Tumor neovascularization, 34 Tumor suppressors, 23 Tumor-node-metastases (TNM) staging system, 30 Type 2 alveolar epithelial cell (AEC), 600 Tyrosine kinase inhibitors (TKI), 885 U Ultrasonography, 88 Uremia, 9 Uremic fibrosing pleuritis, 13 Urinothorax, 89 Usual interstitial pneumonia (UIP), 668, 671, 679, 695 bronchoalveolar lavage, 621 causes and clinical entities, 619, 620 clinical presentations, 619 connective tissue disorder, 624–627 differential diagnosis, 625, 627 histopathologic pattern, 627, 628 HRCT, 621 “indeterminate” and “inconsistent” UIP patterns, 624, 626 laboratory testing, 620 multidisciplinary discussion, 621 patterns, 621–624 pulmonary function tests, 620 radiographic findings, 621 V Vascular disease diffuse alveolar hemorrhage, 665 pulmonary embolism, 666 pulmonary hypertension, 665, 666 Vascular endothelial growth factor (VEGF), 90, 885 Vascular tumors, 72 angiosarcoma, 200, 201 epithelioid hemangioendothelioma, 199, 200 hemangiomas, 198, 199 lymphangiomas, 198 Vasoconstrictors, 665 Venous thromboembolism (VTE), 666, 674 Video-assisted thoracoscopic surgery (VATS), 16, 30, 90, 244 Visceral pleura, 4, 5 W Whole-exome sequencing, 237 Wuchereria bancrofti, 796 X Xanthomatous pleuritis, 11, 13 Y Yolk sac tumor (YST), 188, 189 Z Zygomycosis, 842, 843