Thoracic Pathology E-Book
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Thoracic Pathology E-Book

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1383 pages
English

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Description

Save time identifying and diagnosing diseases of the lung, mediastinum and heart with Thoracic Pathology, a volume in the Highy Yield Pathology series. Edited by noted pathologist Dr. Aliya Husain, this medical reference book is designed to help you review the key pathologic features of a full range of thoracic diseases, recognize the classic look of typical specimens, and quickly confirm your diagnoses for more than 400 discreet entities found in the lung, mediastinum, and heart.

  • Find information quickly and easily with a templated, easy-to-reference format.
  • Confirm your diagnoses with excellent color photographs that demonstrate the classic appearance of each disease.
  • Find the answers you need fast with concise bulleted text.
  • Depend on authoritative information from leading experts in the field.

Sujets

Ebooks
Savoirs
Medecine
Médecine
Chronic obstructive pulmonary disease
Solitary fibrous tumor
Inflammatory myofibroblastic tumor
Hodgkin's lymphoma
Bronchogenic cyst
Radiation-induced lung injury
Basaloid squamous cell carcinoma
Marginal zone B-cell lymphoma
Systemic lupus erythematosus
Epithelioid hemangioendothelioma
Non-specific interstitial pneumonia
Desquamative interstitial pneumonia
Pulmonary hypoplasia
Large cell lung carcinoma
Kaposi's sarcoma
Mucormycosis
Acute chest syndrome
Carcinosarcoma
Adenosquamous carcinoma
Emphysema
Epithelioid cell
Idiopathic pulmonary fibrosis
Lymphomatoid granulomatosis
Pneumocystis pneumonia
Aspergillosis
Diffuse large B cell lymphoma
AIDS
Idiopathic pulmonary haemosiderosis
Allergic bronchopulmonary aspergillosis
Mucoepidermoid carcinoma
Bronchiolitis obliterans
Lung transplantation
Bronchopulmonary dysplasia
Lymphangioma
Plasmacytoma
Lymphoproliferative disorders
Acute interstitial pneumonitis
Coalworker's pneumoconiosis
Eosinophilic pneumonia
Hypoxemia
Pleuropulmonary blastoma
Hamartoma
Hypersensitivity pneumonitis
Carcinoid
Dysplasia
Papilloma
Synovial sarcoma
Langerhans cell histiocytosis
Polymyositis
Lymphangioleiomyomatosis
Chondroma
Aspiration pneumonia
Pulmonary sequestration
Actinomycosis
Neuroendocrine cell
Adenoid cystic carcinoma
Neoplasm
Nocardiosis
Goodpasture's syndrome
Bacterial pneumonia
Fibrosis
Blastomycosis
Melanoma
Pulmonary alveolar proteinosis
Pulmonary hypertension
Chronic granulomatous disease
Silicosis
Pulmonology
Graft-versus-host disease
Rhabdomyosarcoma
Squamous epithelium
Acute respiratory distress syndrome
Human respiratory syncytial virus
Bronchiolitis
Influenza A virus
Asbestosis
Pulmonary edema
Squamous cell carcinoma
Histoplasmosis
Sclerosis
Bronchiectasis
Chronic bronchitis
Carcinoma
Lipoma
Sarcoidosis
Aromaticity
Adenocarcinoma
Severe acute respiratory syndrome
Coccidioidomycosis
Glycogen storage disease
Surfactant
Cytomegalovirus
Trachea
Ulcerative colitis
Pneumonia
Cystic fibrosis
Asthma
Lung
Tuberculosis
Rheumatoid arthritis
Lipid
Cyclophosphamide
Scleroderma
Amiodarone
Méthotrexate
Lymphocyte

Informations

Publié par
Date de parution 14 février 2012
Nombre de lectures 1
EAN13 9781455737888
Langue English
Poids de l'ouvrage 15 Mo

Informations légales : prix de location à la page 0,0527€. Cette information est donnée uniquement à titre indicatif conformément à la législation en vigueur.

Exrait

Thoracic Pathology
High-yield pathology

Aliya N. Husain, MD
Professor of Pathology, The University of Chicago Medical Center, Chicago, Illinois

Saunders
Copyright

1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
THORACIC PATHOLOGY    ISBN: 978-1-4377-2380-9
Copyright © 2012 by Saunders, an imprint of Elsevier, Inc.
All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions .
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notice
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data
Husain, Aliya N.
Thoracic pathology / Aliya N. Husain. — 1st ed.
       p. ; cm. — (High-yield pathology)
Includes index.
ISBN 978-1-4377-2380-9 (alk. paper)
I. Title. II. Series: High-yield pathology.
[DNLM: 1. Thoracic Diseases—pathology—Handbooks. WF 39]
616.24071—dc23            2011041203
Executive Content Strategist: William Schmitt
Content Development Specialist: Christine Abshire
Publishing Services Manager: Patricia Tannian
Senior Project Manager: Kristine Feeherty
Design Direction: Steven Stave
Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1
Dedication
To Dr. Edward Garrity (Professor, Pulmonary Medicine), who, at Loyola University Medical Center 20 years ago, asked if I would be the dedicated pathologist looking at tissue from lung transplant recipients, which launched my career in pulmonary pathology.
To Dr. Vinay Kumar (Chairman of Pathology), who challenged me to prove myself. He asked, “How does one make this line drawn in the sand smaller without touching it?”
To Dr. Thomas Krausz (Director of Anatomic Pathology) for, “Get on with it…now,” thus providing encouragement, support, and an excellent collegial environment at the University of Chicago.
Contributors

Mir Basharath Alikhan, MD
Resident, Department of Pathology, The University of Chicago, Chicago, Illinois

Emaan Alvi, MBBS
Student, Khyber Medical University, Peshawar, Khyber Pakhtunkhwa, Pakistan;
Intern, Department of Pathology, Hinsdale Hospital, Oak Brook, Illinois

Vijayalakshmi Ananthanarayanan, MD
Resident Physician, Department of Pathology, The University of Chicago, Chicago, Illinois

Leonidas D. Arvanitis, MD, PhD
Department of Pathology, Rush University Medical Center, Chicago, Illinois

Mei Lin Z. Bissonnette, MD, PhD
Department of Pathology, The University of Chicago, Chicago, Illinois

Raphael Borok, MD
Dupage Pathology Associates SC, Hinsdale, Illinois

Redouane Boumendjel, MD
Pulmonary/General Surgical Pathology Fellow, Department of Pathology, The University of Chicago, Chicago, Illinois

Richard L. Cantley, MD
Resident, Department of Pathology, Rush University Medical Center, Chicago, Illinois

Yiqing Chi, MD
Attending Pathologist, Department of Pathology, Community Health System, Munster, Indiana

Silver Daniel, MD
Surgical Pathology Fellow, Department of Pathology, The University of Chicago Medical Center, Chicago, Illinois

Ilyssa O. Gordon, MD, PhD
Fellow, Department of Pathology, The University of Chicago Medical Center, Chicago, Illinois

Kammi J. Henriksen, MD
Surgical Pathology Fellow, Department of Pathology, The University of Chicago Medical Center, Chicago, Illinois

Mojgan Hosseini, MD
Resident Physician, Department of Pathology, The University of Chicago, Chicago, Illinois

Nora Eve Joseph, MD
Gastrointestinal and Hepatic Fellow, Department of Pathology, The University of Chicago, Chicago, Illinois

Mei Li, MD, PhD
Thoracic/Surgical Pathology Fellow, Department of Pathology, The University of Chicago Medical Center, Chicago, Illinois

Saptarshi Mandal, MS, MD, MBBS
Fellow of Blood Bank and Transfusion Medicine, Department of Pathology, The University of Chicago Medical Center, Chicago, Illinois

Haresh Mani, MD
Assistant Professor, Department of Pathology, Pennsylvania State Milton S. Hershey Medical Center, Pennsylvania State College of Medicine, Hershey, Pennsylvania

Razan Massarani-Wafai, MD
Associate Professor, Department of Pathology, Loyola University Medical Center, Maywood, Illinois

M. Kamran Mirza, MD, PhD
Department of Pathology, The University of Chicago, Chicago, Illinois

Sara Hanif Mirza, MD
Fellow, Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago, Illinois

Jennifer Pogoriler, MD, PhD
Resident, Department of Pathology, The University of Chicago Medical Center, Chicago, Illinois

Vijaya B. Reddy, MD, MBA
Associate Chairperson and Professor, Department of Pathology, Rush Medical College;
Senior Attending, Department of Pathology, Rush University Medical Center, Chicago, Illinois

Jie Song, MD
Fellow, Section of Dermatology, Department of Medicine, The University of Chicago Medical Center, Chicago, Illinois

Jamie Lee Steinmetz, MD
Department of Pathology, The University of Chicago Medical Center, Chicago, Illinois

Maria S. Tretiakova, MD, PhD
Resident, Department of Pathology, The University of Chicago, Chicago, Illinois

Muge A. Turkyilmaz, MD
Staff Pathologist, Medical Director of Microbiology, Department of Pathology, Adventist Hinsdale Hospital, Hinsdale, Illinois

Girish Venkataraman, MD
Assistant Professor and Molecular Director, Department of Pathology, Loyola University Medical Center, Maywood, Illinois

Benjamin C. Yan, MD, PhD
Assistant Professor, Department of Pathology, The Medical College of Wisconsin, Milwaukee, Wisconsin

Xuefeng Zhang, MD, PhD
Resident, Department of Pathology, The University of Chicago, The University of Chicago Medical Center, Chicago, Illinois
Preface
There are several excellent recent texts published in the field of pulmonary pathology, so why another? First, this book covers the whole thorax (lung, pleura and pericardium, heart, thymus, and mediastinum), as well as vascular diseases, including vasculitis. Second, its format of bulleted text and extensive illustrations is designed to make it an easy reference for a trainee or practicing pathologist looking up the common and not-so-common diseases when faced with a diagnostic question.
Within each organ, the contents are organized by disease categories such as congenital, inflammatory, infectious, and neoplastic. The text gives the salient facts in pathogenesis, epidemiology, and clinical features. Diagnostic elements of gross and microscopic pathology are emphasized. These are illustrated by gross pictures and low-, intermediate-, and high-power photomicrographs. Special stains and immunohistochemical stains are given extensively so that users can compare with their own results easily. Because electronic references are so easily accessible, only a few specific references are given.

Acknowledgment
I would like to thank the residents and pathology assistants who, over the years, have taken many of the gross photographs included in this book. They remain unnamed but are gratefully acknowledged.

Aliya N. Husain, MD
Table of Contents
Cover image
Title page
Copyright
Dedication
Contributors
Preface
I: Lung
A: Normal Lung
Chapter 1: Development of Lung
Chapter 2: Normal Lung
B: Incidental Findings
Chapter 3: Meningothelioid (Meningothelial-Like/Meningothelial) Nodule
Chapter 4: Osseous Metaplasia
Chapter 5: Corpora Amylacea
C: Developmental and Pediatric diseases
Chapter 6: Pulmonary Hypoplasia
Chapter 7: Congenital Pulmonary Airway Malformation (CPAM)
Chapter 8: Pulmonary Sequestration
Chapter 9: Bronchogenic Cyst
Chapter 10: Peripheral Lung Cysts
Chapter 11: Infantile (Congenital) Lobar Emphysema
Chapter 12: Interstitial Pulmonary Emphysema (IPE)
Chapter 13: Congenital Pulmonary Lymphangiectasis
Chapter 14: Alveolar Capillary Dysplasia
Chapter 15: Surfactant Dysfunction Disorders
Chapter 16: Hyaline Membrane Disease
Chapter 17: Bronchopulmonary Dysplasia (BPD)
Chapter 18: Pulmonary Interstitial Glycogenosis (PIG)
Chapter 19: Chronic Granulomatous Disease (CGD) of Childhood
D: Pediatric Tumors
Chapter 20: Pleuropulmonary Blastoma (PPB)
Chapter 21: Inflammatory Myofibroblastic Tumor (IMT)
Chapter 22: Congenital Pulmonary Myofibroblastic Tumor
Chapter 23: Metastatic Pediatric Tumors
E: Obstructive Lung (Airway) Diseases
Chapter 24: Bronchiectasis
Chapter 25: Cystic Fibrosis
Chapter 26: Chronic Bronchitis
Chapter 27: Asthma
Chapter 28: Allergic Bronchopulmonary Aspergillosis
Chapter 29: Acute Bronchiolitis
Chapter 30: Chronic Bronchiolitis
Chapter 31: Follicular Bronchiolitis
Chapter 32: Bronchiolitis Obliterans/Constrictive Bronchiolitis Obliterans/Constrictive Bronchiolitis
Chapter 33: Emphysema
F: Restrictive (Interstitial) Lung Diseases
Chapter 34: Pulmonary Edema
Chapter 35: Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS), Diffuse Alveolar Damage (DAD)
Chapter 36: Acute Interstitial Pneumonia (AIP)
Chapter 37: Usual Interstitial Pneumonia (UIP)
Chapter 38: Nonspecific Interstitial Pneumonia (NSIP)
Chapter 39: Cryptogenic Organizing Pneumonia (COP)
Chapter 40: IgG4-Related Sclerosing Disease
Chapter 41: Rheumatoid Arthritis (RA)
Chapter 42: Systemic Lupus Erythematosus (SLE)
Chapter 43: Scleroderma
Chapter 44: Polymyositis and Dermatomyositis–Associated Lung Disease
Chapter 45: Sjögren Syndrome (SS)
Chapter 46: Inflammatory Bowel Disease (IBD)–Associated Interstitial Lung Disease
Chapter 47: Asbestosis
Chapter 48: Silicosis
Chapter 49: Coal Workers’ Pneumoconiosis (CWP)
G: Granulomatous Diseases (Noninfectious)
Chapter 50: Sarcoidosis
Chapter 51: Hypersensitivity Pneumonitis (HSP) or Extrinsic Allergic Alveolitis
Chapter 52: Aspiration Pneumonitis
H: Smoking-Related Diseases
Chapter 53: Desquamative Interstitial Pneumonia (DIP)
Chapter 54: Respiratory Bronchiolitis–Associated Interstitial Lung Disease (RB-ILD)
Chapter 55: Langerhans Cell Histiocytosis (LCH)
I: Miscellaneous Diseases
Chapter 56: Pulmonary Alveolar Proteinosis (PAP)
Chapter 57: Pulmonary Amyloidosis
Chapter 58: Eosinophilic Pneumonia
Chapter 59: Lipoid Pneumonia
Chapter 60: Lymphangioleiomyomatosis
Chapter 61: Middle Lobe Syndrome (Right Middle Lobe Syndrome)
Chapter 62: Acute Chest Syndrome (ACS) of Sickle Cell Disease
Chapter 63: Intravenous Drug Abuse
J: Diseases of Vascular Origin
Chapter 64: Pulmonary Embolism and Infarction
Chapter 65: Arteriovenous Malformation of the Lung
Chapter 66: Pulmonary Hypertension
Chapter 67: Pulmonary Arterial Hypertension (PAH)
Chapter 68: Pulmonary Venoocclusive Disease (PVOD)
Chapter 69: Pulmonary Capillary Hemangiomatosis (PCH)
Chapter 70: Chronic Thromboembolic Pulmonary Hypertension
Chapter 71: Pulmonary Hypertension Associated with Lung Diseases or Hypoxemia
Chapter 72: Goodpasture Syndrome: Anti–Glomerular Basement Membrane (GBM) Antibody Disease
Chapter 73: Idiopathic Pulmonary Hemosiderosis (IPH)
Chapter 74: Pulmonary Wegener Granulomatosis
Chapter 75: Pulmonary Churg-Strauss Syndrome
K: Pulmonary Infections
Chapter 76: Noninfectious Pulmonary Lesions in HIV/AIDS Patients
Chapter 77: Lobar Pneumonia and Bronchopneumonia
Chapter 78: Aspiration Pneumonia
Chapter 79: Tuberculosis
Chapter 80: Atypical Mycobacterial Infection
Chapter 81: Actinomycosis
Chapter 82: Nocardiosis
Chapter 83: Legionnaires Disease
Chapter 84: Lung Abscess
Chapter 85: Lymphocytic Pneumonia
Chapter 86: Cytomegalovirus (CMV) Pneumonia
Chapter 87: Herpes Simplex Virus (HSV) Pneumonia
Chapter 88: Adenovirus Pneumonia
Chapter 89: Respiratory Syncytial Virus (RSV) Pneumonia
Chapter 90: Measles Pneumonia
Chapter 91: Human Metapneumovirus Pneumonia
Chapter 92: H1N1 Pneumonia
Chapter 93: Severe Acute Respiratory Syndrome (SARS)
Chapter 94: Aspergillosis
Chapter 95: Blastomycosis
Chapter 96: Candidiasis
Chapter 97: Coccidioidomycosis
Chapter 98: Cryptococcosis
Chapter 99: Histoplasmosis
Chapter 100: Pneumocystis Pneumonia (PCP)
Chapter 101: Zygomycosis
L: Complications of Therapies
Chapter 102: Methotrexate
Chapter 103: Amiodarone
Chapter 104: Bleomycin
Chapter 105: Cyclophosphamide
Chapter 106: Radiation Pneumonitis
Chapter 107: Lung Transplantation
Chapter 108: Lung Transplantation: Acute Rejection
Chapter 109: Lung Transplantation: Chronic Rejection (Bronchiolitis Obliterans [BO])
Chapter 110: Graft-Versus-Host Disease (GVHD) and Other Complications of Transplantation in the Lung
M: Tumors of Lung
Chapter 111: TNM Classification of Primary Non–Small Cell Carcinoma, Small Cell Carcinoma, and Carcinoid Tumor of the Lung
Chapter 112: Squamous Papilloma
Chapter 113: Squamous Papillomatosis
Chapter 114: Hamartoma
Chapter 115: Chondroma
Chapter 116: Pneumocytoma (Sclerosing Hemangioma)
Chapter 117: Lipoma of Lung
Chapter 118: Pulmonary Leiomyoma
Chapter 119: Granular Cell Tumor
Chapter 120: Lymphangioma and Lymphangiomatosis
Chapter 121: Rare Benign Tumors of The Lung
Chapter 122: Airway Epithelial Hyperplasia/Metaplasia
Chapter 123: Squamous Dysplasia and Carcinoma in Situ (CIS)
Chapter 124: Atypical Adenomatous Hyperplasia (AAH)
Chapter 125: Adenocarcinoma in Situ (AIS), Formerly Bronchioloalveolar Carcinoma (BAC)
Chapter 126: Adenocarcinoma
Chapter 127: Squamous Cell Carcinoma (SCC)
Chapter 128: Papillary Variant of Squamous Cell Carcinoma (SCC)
Chapter 129: Clear Cell Variant of Squamous Cell Carcinoma (SCC)
Chapter 130: Small Cell Variant of Squamous Cell Carcinoma (SCC)
Chapter 131: Basaloid Variant of Squamous Cell Carcinoma (SCC)
Chapter 132: Alveolar Space–Filling Type of Peripheral Squamous Cell Carcinoma (SCC)
Chapter 133: Lymphoepithelioma-Like Carcinoma
Chapter 134: Adenosquamous Carcinoma
Chapter 135: Large-Cell Carcinoma
Chapter 136: Sarcomatoid Carcinoma
Chapter 137: Pleomorphic Carcinoma
Chapter 138: Spindle Cell Carcinoma
Chapter 139: Giant-Cell Carcinoma
Chapter 140: Carcinosarcoma
Chapter 141: Pulmonary Blastoma
Chapter 142: Adenoid Cystic Carcinoma
Chapter 143: Mucoepidermoid Carcinoma
Chapter 144: Epithelial–Myoepithelial Carcinoma
Chapter 145: Diffuse Neuroendocrine Cell Hyperplasia
Chapter 146: Carcinoid Tumorlet
Chapter 147: Carcinoid Tumor
Chapter 148: Typical Carcinoid
Chapter 149: Atypical Carcinoid
Chapter 150: Small-Cell Carcinoma
Chapter 151: Large-Cell Neuroendocrine Carcinoma
Chapter 152: Solitary Fibrous Tumor (SFT) of the Lung
Chapter 153: Kaposi Sarcoma
Chapter 154: Epithelioid Hemangioendothelioma
Chapter 155: Pulmonary Synovial Sarcoma (SS)
Chapter 156: Pulmonary Artery and Vein Sarcoma
Chapter 157: Rhabdomyosarcoma Lung
Chapter 158: Perivascular Epithelioid Cell Tumor (PEComa, Clear Cell “Sugar” Tumor) of the Lung
Chapter 159: Primary Pulmonary Malignant Melanoma (PPMM)
Chapter 160: Extranodal Marginal Zone B-Cell Lymphoma of Bronchial-Associated Lymphoid Tissue (BALT Lymphoma)
Chapter 161: Lymphoid Interstitial Pneumonia (LIP) (Diffuse Lymphoid Hyperplasia)
Chapter 162: Posttransplant Lymphoproliferative Disorder (PTLD)
Chapter 163: Diffuse Large B-Cell Lymphoma (DLBCL) of the Lung
Chapter 164: Primary Pulmonary Hodgkin Lymphoma (PPHL)
Chapter 165: Lymphomatoid Granulomatosis
Chapter 166: Primary Pulmonary (Extraosseous) Plasmacytoma
Chapter 167: Metastases to the Lungs: Introduction
Chapter 168: Metastatic Carcinomas
Chapter 169: Metastatic Carcinomas: Breast and Female Genital Tract
Chapter 170: Metastatic Carcinomas: Gastrointestinal (GI) Tract
Chapter 171: Metastatic Carcinomas: Genitourinary (GU) Tract and Adrenal
Chapter 172: Metastatic Carcinomas: Head and Neck
Chapter 173: Metastatic Adult Sarcomas
Chapter 174: Benign Metastasizing Leiomyoma (BML)
Chapter 175: Metastasizing Giant Cell Tumor
Chapter 176: Metastatic Melanoma
II: Pleura and Pericardium
A: Nonneoplastic Diseases
Chapter 177: Pleuritis
Chapter 178: Mesothelial Hyperplasia
Chapter 179: Adenomatoid Tumor of the Pleura
B: Neoplastic Diseases
Chapter 180: TNM Classification of Pleural Mesothelioma
Chapter 181: Well-Differentiated Papillary Mesothelioma (WDPM)
Chapter 182: Malignant Mesothelioma of Pleura
Chapter 183: Epithelioid Malignant Mesothelioma
Chapter 184: Sarcomatoid Malignant Mesothelioma
Chapter 185: Desmoplastic Malignant Mesothelioma
Chapter 186: Biphasic Malignant Mesothelioma
Chapter 187: Solitary Fibrous Tumor (SFT) of Pleura and Pericardium
Chapter 188: Calcifying Pseudotumor of Pleura/Calcifying Fibrous Pseudotumor
Chapter 189: Pleural Synovial Sarcoma (SS)
Chapter 190: Primitive Neuroectodermal Tumor/Extraskeletal Ewing Sarcoma
Chapter 191: Desmoplastic Small Round Cell Tumor of Pleura (DSRCT)
Chapter 192: Primary Effusion Lymphoma (PEL)
Chapter 193: Metastases to Pleura
III: Thymus
A: Normal Thymus
Chapter 194: Normal Thymus
B: Nonneoplastic Diseases
Chapter 195: Unilocular and Multilocular Thymic Cysts
Chapter 196: Thymic Dysplasia
Chapter 197: Acute Involution of Thymus (Stress-Induced Thymic Involution)
Chapter 198: True Thymic Hyperplasia
Chapter 199: Lymphoid Hyperplasia of The Thymus
C: Thymoma
Chapter 200: General Features of Thymoma
Chapter 201: WHO Type A Thymoma
Chapter 202: WHO Type AB Thymoma
Chapter 203: WHO Type B1 Thymoma
Chapter 204: WHO Type B2 Thymoma
Chapter 205: WHO Type B3 Thymoma
D: Other Thymic Tumors
Chapter 206: Thymic Carcinoma
Chapter 207: Thymic Neuroendocrine Carcinoma (NEC)/Tumor
Chapter 208: Thymolipoma
IV: Mediastinal Lesions
A: Inflammatory Infectious Lesions
Chapter 209: Mediastinitis
B: Cystic Lesions
Chapter 210: Mediastinal Bronchogenic Cyst
Chapter 211: Esophageal Cyst
Chapter 212: Mediastinal Gastroenteric Cyst
Chapter 213: Pericardial Cyst
C: Ectopic Lesions
Chapter 214: Mediastinal Ectopic Thyroid
Chapter 215: Ectopic Parathyroid
D: Tumors
Chapter 216: Mediastinal Schwannoma (Neurilemmoma)
Chapter 217: Mediastinal Neurofibroma
Chapter 218: Mediastinal Malignant Peripheral Nerve Sheath Tumor (MPNST)
Chapter 219: Mediastinal Neuroblastoma
Chapter 220: Mediastinal Ganglioneuroblastoma
Chapter 221: Mediastinal Ganglioneuroma
Chapter 222: Mediastinal Paraganglioma
Chapter 223: Germ Cell Tumors (GCTs) of Mediastinum
Chapter 224: Hodgkin Lymphoma of the Mediastinum
Chapter 225: Mediastinal T-Lymphoblastic Lymphoma (T-LBL)
Chapter 226: Primary Mediastinal (Thymic) Large B-Cell Lymphoma (PMLBCL)
Chapter 227: Anaplastic Large-Cell Lymphoma (ALCL) of the Mediastinum
Chapter 228: Myeloid Sarcoma (MS)
Chapter 229: Mediastinal Castleman Disease (CD)
Chapter 230: Follicular Dendritic Cell (FDC) Sarcoma
Chapter 231: Mediastinal Lymphangioma
Chapter 232: Mediastinal Liposarcoma
Chapter 233: Rhabdomyosarcoma
V: Heart and Vessels
A: Normal Heart
Chapter 234: Normal Heart
B: Congenital Heart Disease
Chapter 235: Atrial Septal Defect (ASD)
Chapter 236: Ventricular Septal Defect (VSD)
Chapter 237: Hypoplastic Left Heart Syndrome (HLHS)
Chapter 238: Tetralogy of Fallot
Chapter 239: Bicuspid Aortic Valve (BAV)
C: Valvular Diseases
Chapter 240: Aortic Valve Stenosis
Chapter 241: Aortic Valve Insufficiency
Chapter 242: Mitral Valve Stenosis
Chapter 243: Mitral Valve Regurgitation
Chapter 244: Prosthetic Valves
Chapter 245: Infectious Endocarditis
Chapter 246: Nonbacterial Thrombotic Endocarditis (NBTE)
Chapter 247: Acute Rheumatic Fever and Rheumatic Heart Disease (RHD)
D: Myocardial Diseases
Chapter 248: Lymphocytic Myocarditis
Chapter 249: Eosinophilic Myocarditis
Chapter 250: Giant Cell Myocarditis
Chapter 251: Cardiac Amyloidosis (Amyloid Cardiomyopathy)
Chapter 252: Cardiac Sarcoidosis
Chapter 253: Dilated Cardiomyopathy
Chapter 254: Hypertrophic Cardiomyopathy
Chapter 255: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C)
Chapter 256: Cardiac Hemochromatosis
Chapter 257: Hypertensive Heart Disease
Chapter 258: Drug Cardiotoxicity
E: Ischemic Heart Disease
Chapter 259: Myocardial Infarction (MI)
F: Heart Transplantation
Chapter 260: Heart Transplantation: Introduction
Chapter 261: Antibody-Mediated Rejection of the Heart
Chapter 262: Acute Cellular Rejection of the Heart
Chapter 263: Chronic Rejection of the Heart (Cardiac Allograft Vasculopathy [CAV])
Chapter 264: Quilty Lesion
G: Infections
Chapter 265: Opportunistic Cardiac Infections
H: Tumors of the Heart
Chapter 266: Cardiac Myxoma
Chapter 267: Cardiac Rhabdomyoma
Chapter 268: Cardiac Fibroelastoma
Chapter 269: Cardiac Fibroma
Chapter 270: Cardiac Hemangioma
Chapter 271: Cardiac Lipoma
Chapter 272: Lipomatous Hypertrophy of the Interatrial Septum
Chapter 273: Angiosarcoma of the Heart
Chapter 274: Synovial Sarcoma (SS) of the Heart
Chapter 275: Rare Cardiac Sarcomas
Chapter 276: Primary Cardiac Lymphoma (PCL)
Chapter 277: Cardiac Metastasis
I: Diseases of Vessels
Chapter 278: Atherosclerosis
Chapter 279: Thoracic Aortic Aneurysm
Chapter 280: Aortic Dissection
Chapter 281: Infectious Vasculitis
Chapter 282: Giant Cell Arteritis
Chapter 283: Takayasu Arteritis
Chapter 284: Kawasaki Disease
Chapter 285: Churg-Strauss Syndrome
Chapter 286: Polyarteritis Nodosa
Chapter 287: Microscopic Polyangiitis
Chapter 288: Thromboangiitis Obliterans
Chapter 289: Wegener Granulomatosis
Appendix
Index
I
Lung
A
Normal Lung
Development of Lung

Stages of lung development

Embryonic (4-8 weeks)

• The lower respiratory system starts from a bud arising from the laryngotracheal groove; this branches into primary and secondary bronchopulmonary buds by the end of 5 weeks
• Repetitive branching continues and a primordial bronchial tree with five lobes is formed by the end of 8 weeks

Pseudoglandular phase (5-17 weeks)

• The primordial system of passage (air-conducting bronchial tree) with the terminal bronchioles is formed and is initially lined with cuboidal epithelium
• These precursor cells later differentiate into ciliated epithelium and secretory cells in respiratory ducts and also develop into type II pneumocytes in terminal bronchioles
• At this stage, the lung is composed of tubular glandular structures surrounded by undifferentiated mesenchyme

Canalicular phase (13-25 weeks)

• The lumen of tubules becomes wider and some of the lining type II pneumocytes differentiate into flattened type I pneumocytes
• Capillaries invade into the mesenchyme and surround the acini, therefore forming the foundation of the blood–air barrier
• Only by the end of this phase is the fetus able to survive outside the uterus

Terminal sac phase (24 weeks–term)

• Lung epithelium starts to produce amniotic fluid and lung maturation can be measured by surfactant, which is produced by type II pneumocytes
• Airspaces are expanded to form thin, smooth-walled saccules (primitive alveoli) at the end of each respiratory tract passage
• The primary septa between saccules are thick and contain two layers of capillaries from the neighboring saccules
• By the end of this phase (at birth), one third of alveoli are developed

Alveolar phase (36 weeks’ gestation–8-10 years)

• Sacculi are subdivided into smaller subunits (alveoli) by secondary septa, which contain elastic fibers between two capillary networks
• This alveolarization reaches its maximum level in the first 6 months of birth and is significant up to 18 months
• Some alveoli continue to be developed up to 8-10 years of age

Fig 1 Development of lung. Pseudoglandular phase of fetal lung: low (A) and high (B) powers. Note undifferentiated mesenchyme and primitive tubular glands lined by nonciliated, glycogen-rich columnar cells with clear cytoplasm.


Fig 2 Development of lung. Canalicular phase of fetal lung: low (A), medium (B), and high (C) powers. Note the capillary network within the mesenchyme; some of the lining epithelium cells are flattened.

Fig 3 Development of lung. Terminal sac phase of lung development seen in this near term infant.

Fig 4 Development of lung. Alveolar phase of lung development in a 2½-year-old.
Normal Lung

Anatomy and histology

Airways

• The trachea with C-shaped rings of cartilage anteriorly and smooth muscle posteriorly bifurcates at the carina into the right and left mainstem bronchi, which are surrounded by discontinuous plates of cartilage
• At the level of the hilum, the right mainstem bronchus bifurcates into the superior lobar bronchus and the intermediate bronchus, which more distally bifurcates into the middle lobar bronchus and the inferior lobar bronchus
• The left mainstem bronchus bifurcates just distal to the hilum into the superior and inferior lobar bronchi
• Further branching of lobar bronchi occurs into segmental bronchi, large intrasegmental bronchi, small intrasegmental bronchi, and then bronchioles
• Cartilage plates become more sparse, typically present only at branch points more distally, until the level of the bronchioles, which are defined by the lack of cartilage
• The terminal bronchioles branch into the respiratory bronchioles, which end in the alveolar sacs and individual alveoli; this total unit is called a lobule, and the unit excluding the terminal bronchiole is called an acinus
• On cross section, the “bronchial mucosa” consists of the epithelium and basement membrane; the “submucosa” contains elastin-rich connective tissue beneath the basement membrane, smooth muscle, glands, cartilage, nerves, ganglia, and branches of the bronchial arteries
• On cross section of a bronchiole, the layers are similar as described for bronchi; however, there are no cartilage islands or bronchial glands in the bronchiole
• Individual alveoli communicate with the alveolar duct through Pores of Kohn

Interstitium

• Smooth muscle surrounds the airways to the level of the alveolar ducts, while elastic fibers surround all components, including individual alveoli
• Serous and mucinous glands are present between the smooth muscle and the cartilage
• The airway and alveolar interstitium also contains varying numbers of fibroblasts, myofibroblasts, mast cells, tissue macrophages, and nerves of the autonomic nervous system

Cells

• Bronchial epithelium contains ciliated columnar cells (respiratory epithelial cells), as well as goblet cells, basal cells, and neuroendocrine (Kulchitsky) cells
• Bronchiolar epithelium contains ciliated columnar cells and Clara cells
• Alveoli are lined by type I and type II pneumocytes and may contain alveolar macrophages in the airspace

Pleura

• The lung parenchyma is surrounded by the visceral pleura, which consists of a single layer of mesothelial cells overlying a thin layer of collagenous tissue
• Lymphatics and blood vessels are present in the pleura
• The pleura contains a discontinuous thin layer of elastic fibers, which run parallel to the surface and are important for determining pleural invasion by tumor

Vascular supply

• Bronchial arteries branch off the thoracic aorta to supply the bronchi through the terminal bronchioles, as well as the mediastinal pleura
• Bronchial veins drain into the azygos vein on the right and the accessory hemiazygos vein on the left
• The pulmonary artery branch carrying deoxygenated blood from the right side of the heart travels along the bronchus and, beginning at the level of the respiratory bronchiole, forms the capillary plexuses of alveoli
• Newly oxygenated blood is then carried by branches of the pulmonary vein traveling along interlobular septa to the left side of the heart for systemic distribution

Pulmonary lymphoid tissue and lymphatics

• Lymphatic vessels are found in the pleura, interlobular septa, and along bronchi
• Lymphatic drainage from the lungs follows the bronchi to intraparenchymal lymph nodes (levels 14 and 13) then lobar (level 12) and interlobar (level 11) lymph nodes, and hilar (level 10) lymph nodes
• From the hilum, lymphatics drain to the carinal (level 7), lower paratracheal (level 4), upper paratracheal (level 2), and finally supraclavicular (level 1) nodes
• Lymphatic fluid may also drain to aortic nodes (levels 5 and 6), inferior mediastinal nodes at the esophagus (level 8) or the pulmonary ligament (level 9), or prevascular and retrotracheal nodes in the superior mediastinum (level 3)

Incidental tissues

• Occasionally intraparenchymal lymph nodes (levels 14 and 13) may be seen as a “mass” detected on radiological imaging
• Hilar lymph nodes may harbor benign bronchial glands
• Metaplastic bone spicules can be associated with fibrosis or can be in otherwise normal parenchyma
• Megakaryocytes are often seen circulating through alveolar capillaries

Fig 1 Normal lung. This cross section of a normal airway shows bronchial epithelium, basement membrane, a thin layer of elastin-rich connective tissue beneath the basement membrane, smooth muscle, seromucinous glands, and cartilage.


Fig 2 Normal lung. A ganglion (A) or a single ganglion cell (B) can be found in the lung interstitium.

Fig 3 Normal lung. The airway epithelium consists of a single layer of basal cells, ciliated columnar epithelial cells, interspersed mucin-containing goblet cells, and scattered neuroendocrine Kulchitsky cells with clear cytoplasm (right).

Fig 4 Normal lung. Normal alveoli (left) are thin and lined by a single layer of mostly type I pneumocytes. A few alveolar macrophages are normally found in the alveolar spaces. At right is a normal bronchiole.

Fig 5 Normal lung. A normal bronchiole has an adjacent arteriole of similar size. Discrete smooth muscle bundles are present in the airway submucosa, while the smooth muscle surrounding the arteriole is in a continuous band. Paler rounded nerves as well as a branch of bronchial artery are seen in the airway submucosa.

Fig 6 Normal lung. The visceral pleura of the lung consists of a single layer of mesothelial cells overlying collagenous tissue containing elastic fibers, lymphatics, and blood vessels. The interlobular septae (lower right) are contiguous with the pleura and also contain lymphatics and blood vessels.


Fig 7 Normal lung. An intraparenchymal lymph node, as seen here, may be interpreted as a mass on imaging or at surgery.

Fig 8 Normal lung. Pulmonary lymph node with benign bronchial glands at low (A) and high (B) power. These should not be mistaken for metastatic adenocarcinoma. Also note the dense anthracosis, which is common in pulmonary lymph nodes, especially at the hilum.

Fig 9 Normal lung. Metaplastic bone is another common incidental finding in lung biopsies. These findings are often in areas of fibrosis or lung injury but may also be seen in otherwise normal lung tissue.

Fig 10 Normal lung. Circulating megakaryocytes are often seen in alveolar capillaries and should not be mistaken for tumor cells or viral inclusions.
B
Incidental Findings
Meningothelioid (Meningothelial-Like/Meningothelial) Nodule

Definition

• Incidental small nodule(s) found in autopsy or surgical resection lung specimens for unrelated causes

Pathogenesis

• Unknown, may be caused by hypoxia
• May be the precursor lesion for the very rare primary meningioma of the lung

Clinical features

Epidemiology

• Found mostly in adults
• Female to male ratio is 2:1
• Associated with thromboembolic diseases, chronic obstructive lung diseases, interstitial lung diseases, and congestive heart failure
• One study shows higher incidence in lungs with malignant tumors, especially adenocarcinoma

Presentation

• Asymptomatic; incidental finding

Prognosis and treatment

• No clinical significance; no need for treatment

Pathology

Histology

• Usually single, sometimes multiple; found in all lobes
• Small clusters of epithelioid cells with round to oval nuclei and abundant eosinophilic cytoplasm; cells are bland in appearance without atypia
• Located in interstitium of lung, often associated with small blood vessels

Immunopathology/special stains

• Share same immunohistochemical and ultrastructural features with meningiomas
• Positive for EMA, PR, vimentin, and CD56
• Negative for cytokeratin, actin, S100, CD34, chromogranin, and synaptophysin

Main differential diagnosis

• Carcinoid tumorlet: small nodule of spindle cells near bronchioles; cells are darker with amphophilic granular cytoplasm and neuroendocrine nuclear features; positive for cytokeratin and all neuroendocrine markers

Fig 1 Meningothelioid nodule. Lower power views of meningothelioid nodules with oval to spindle-shaped cells forming nests or balls within alveolar septa (A-C).


Fig 2 Meningothelioid nodule. Medium-power views of meningothelioid nodules showing whirling appearance of the cell arrangement similar to that of meningioma ( A and B ).

Fig 3 Meningothelioid nodule. High-power view of meningothelioid nodule showing the cells with bland nuclear features and abundant cytoplasm ( A and B ). Note occasional intranuclear inclusions in A.


Fig 4 Meningothelioid nodule. Core needle biopsy: low power (A), medium power (B), positive EMA (C), negative CAM5.2 (D), negative TTF-1 (E), and negative chromogranin immunostains (F). Note positive staining of normal lung tissue with EMA, CAM5.2 and TTF-1.
Osseous Metaplasia

Definition

• Calcification and ossification (mature bone formation) of lung parenchyma

Pathogenesis

• Considered to be a reactive process, often occurring within a scar

Clinical features

Epidemiology

• Incidental finding; prevalence unknown
• Usually related to chronic lung diseases like interstitial pneumonia, fibrosis, and bronchiectasis

Presentation

• Symptoms of underlying lung disease
• Asymptomatic if not related to chronic lung diseases

Prognosis and treatment

• Treat underlying lung disease
• Prognosis depends on the underlying lung disease
• No clinical significance by itself

Pathology

Histology

• Calcification and mature bone formation of normal or abnormal lung parenchyma
• More common in fibrous lung tissue, such as that in interstitial pneumonia, lung scarring, or pleural plaques
• Sometimes in normal lung parenchyma and cartilage
• Rarely present in malignant lung tissue

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Hamartoma: composed of cartilage, fat, and immature spindle cells
• Bone marrow emboli: present within blood vessels, usually after resuscitation

Fig 1 Osseous metaplasia. Osseous metaplasia of relatively normal lung parenchyma (A) and bronchial cartilage (B).

Fig 2 Osseous metaplasia. Ossification of scarred lung tissue.


Fig 3 Osseous metaplasia. Calcification and ossification of pleural plaque.

Fig 4 Osseous metaplasia. Ossification of the fibrous area of lung with usual interstitial pneumonia (UIP): low power (A) and medium power (B). Note the UIP changes of background lung with extensive bronchiolar metaplasia (upper left), honeycombing (lower left) and secondary arterial hypertensive changes.
Corpora Amylacea

Definition

• Laminated spherical eosinophilic bodies found in lung sections or cytology specimens

Pathogenesis

• Unknown; may be related to dusting powder or products of macrophages

Clinical features

Epidemiology

• Incidental finding, prevalence unknown

Presentation

• No specific symptoms; incidental histological finding in lungs resected for other reason

Prognosis and treatment

• No clinical significance

Pathology

Histology

• Round, concentrically laminated eosinophilic acellular structures, 30 to 200 μm in size
• Usually found in airspaces, rarely within alveolar wall
• Usually free floating, sometimes surrounded by a ring of histiocytes
• Can be found in normal lung or in pathological lung sections
• Can also be seen in cytology specimens or in sputum

Immunopathology/special stains

• PAS positive; usually negative for calcium salts

Main differential diagnoses

• Actinomyces sulfur granules: usually dark purple with a filamentous edge associated with an inflammatory reaction

Fig 1 Corpora amylacea. A and B, Low-power views of corpora amylacea: sporadic spherical to ellipsoidal eosinophilic bodies are present within alveolar spaces.

Fig 2 Corpora amylacea. A and B, High-power views of corpora amylacea: they are concentric and laminated; some have a central purple core.
C
Developmental and Pediatric diseases
Pulmonary Hypoplasia

Definition

• Small, underdeveloped lungs with less than normal weight and fewer than normal alveoli expected for gestational age as determined by lung weight to body weight ratio or radial alveolar count

Clinical features

Epidemiology

• True incidence is unknown but has been noted in less than 10% of neonatal autopsies
• Associated with other fetal anomalies
• Oligohydramnios secondary to renal agenesis or prolonged fetal membrane rupture
• Decreased intrathoracic space secondary to renal cystic disease or diaphragmatic hernia
• Reduced breathing secondary to anencephaly or musculoskeletal disorders

Presentation

• Usually detected on fetal ultrasound
• Severe difficulty in breathing after birth

Prognosis and treatment

• High mortality rate of 70% to 95%
• Lung weight less than 40% of normal is associated with immediate death
• In surviving patients, treatment is supportive

Pathology

Gross

• Small, underdeveloped lungs for gestational age with reduced lung weight to body weight ratio (normal ratio is 0.22)

Histology

• Histologically underdeveloped lungs for gestational age
• Acini are fewer for gestational age, but alveolar and capillary development is unaffected
• There is often an increased amount of connective tissue/mesenchyme giving an immature appearance
• Reduced radial alveolar count
• Draw a line from a terminal bronchiole to the closest septal division or pleural surface. Count the number of intersected alveoli. The mean alveolar count for term infants is 4.4 ± 0.9.

Immunopathology/special stains

• Not contributory

Main differential diagnosis

• Atelectasis: small lungs but weight is normal

Fig 1 Pulmonary hypoplasia. X-ray film of a fetus with pulmonary hypoplasia secondary to diaphragmatic hernia.

Fig 2 Pulmonary hypoplasia. Gross image of a fetus with pulmonary hypoplasia secondary to diaphragmatic hernia.


Fig 3 Pulmonary hypoplasia. Lungs from the case in Fig 2 are both small; the left lung is smaller. Note that the lungs do not reach the apex of the heart—a good indication of pulmonary hypoplasia.

Fig 4 Pulmonary hypoplasia. Cut surface of hypoplastic lungs.

Fig 5 Pulmonary hypoplasia. Low (A) and high ( B and C ) powers show small lobules with fewer acini than would be expected in this term baby with renal agenesis.
Congenital Pulmonary Airway Malformation (CPAM)

Definition

• Developmental anomaly of the lower respiratory tract
• Previously known as congenital cystic adenomatoid malformation (CCAM)

Pathogenesis

• Abnormalities of lung branching morphogenesis thought to occur at different stages and levels of lung development and classified accordingly into five types

Clinical features

Epidemiology

• Most common congenital lung lesion, 1 per 5000 to 35,000 live births
• Most occur sporadically (see Table 1 in the Appendix )

Presentation

• Affected patients may present with respiratory distress in the newborn period or may remain asymptomatic until later in life (see Table 1 in the Appendix )
• Many cases are now detected by routine prenatal ultrasound examination

Prognosis and treatment

• Spontaneous regression can occur but is infrequent
• Immediate surgical resection is indicated in symptomatic patients
• Surgery can be delayed for a few years in asymptomatic patients; there are rare case reports of bronchioloalveolar carcinoma arising in CPAM in the second and third decades

Pathology

• See Table 1 in the Appendix (gross and microscopic)

Immunopathology/special stains

• Alveolar type II cells lining CPAM4 can be highlighted by immunohistochemical analysis for TTF-1, cytokeratins, or surfactant

Main differential diagnoses

• Resolution of an abscess/necrotic process: can resolve forming cysts with lining similar to CPAM. Chronic inflammation and fibrosis are present. These cannot be definitively distinguished from CPAM with superimposed chronic inflammation unless clinical history is clear
• Cystic pleuropulmonary blastoma: cambium layer beneath the epithelial lining of the cysts contains desmin and myogenin-positive malignant cells (rhabdomyoblasts)
• Bronchogenic cyst: seen in older children, not connected to tracheobronchial tree, filled with acellular material (not air), and does not have surrounding smaller cysts
• Persistent interstitial pulmonary emphysema: cystic spaces have foreign body giant cells and no epithelial lining

Fig 1 Congenital pulmonary airway malformation. This computed tomography scan shows a 3-cm central cyst with surrounding smaller cysts in an infant with CPAM type 1.

Fig 2 Congenital pulmonary airway malformation. The main cyst and adjacent smaller cysts have a thick fibrous wall in CPAM type 1.


Fig 3 Congenital pulmonary airway malformation. Multiple clusters of mucogenic cells are present in this CPAM type 1.

Fig 4 Congenital pulmonary airway malformation. This cut surface of the lung shows type 2 CPAM with multiple small cysts and solid areas blending with normal lung.

Fig 5 Congenital pulmonary airway malformation. Type 2 CPAM has numerous bronchiole-like spaces extending into peripheral lung tissue.

Fig 6 Congenital pulmonary airway malformation. This type 2 CPAM has striated muscle cells in the wall.

Fig 7 Cut surface of lung resection with CPAM type 3 shows no grossly visible cysts.

Fig 8 Congenital pulmonary airway malformation. This type 3 CPAM resembles the canalicular stage of lung development.


Fig 9 Congenital pulmonary airway malformation. High power of Fig 8 shows that the spaces are lined by low cuboidal cells.

Fig 10 Congenital pulmonary airway malformation. Type 4 CPAM: A, gross image showing large cysts; B, low power showing thin-walled cysts; and C, high power showing cyst walls lined by pneumocytes and containing histiocytic cells with clear cytoplasm, reminiscent of pulmonary interstitial glycogenosis.
(Courtesy of Dr. J.T. Stocker, Bethesda, Md.)
Pulmonary Sequestration

Definition

• Segment of abnormal lung with no connection to the tracheobronchial tree with its own anomalous systemic arterial blood supply, most commonly occurring on the left side
• Part of the spectrum of bronchopulmonary foregut malformation complex
• Two types: intralobar sequestration (ILS), extralobar sequestration (ELS)

Clinical features

Epidemiology

• ILS is seen in older children and adults; might be acquired; male:female (M:F) ratio is 1:1
• ELS is a true congenital malformation and is seen in younger children (<1 year), M:F is 3-4:1

Presentation

• ILS patients commonly have recurrent pulmonary infections, chest pain, and coughs. Roughly 30% of the patients are asymptomatic, and the sequestration is an incidental finding on chest imaging
• ELS usually is seen in association with other congenital anomalies such as congenital diaphragmatic hernia, vertebral anomalies, congenital heart disease, pulmonary hypoplasia, colonic duplication shortly after birth

Prognosis and treatment

• Treatment is supportive. Surgery is the only definitive treatment

Pathology

Gross

• ILS: the lesion is within a lung lobe but is isolated from the tracheobronchial tree and has its own arterial blood supply
• ELS: the lesion is a discrete mass of pulmonary parenchyma, outside the lung with its own pleura and systemic arterial supply

Histology

• Intralobar (ILS)
• Sharply demarcated from the adjacent normal lung parenchyma, with no pleura
• Replacement of lung parenchyma by chronic inflammation with mucus accumulation and microcyst formation
• Remnants of bronchi and bronchioles within a dense fibrotic stroma with numerous lymphocytes
• A vascular pedicle and thickening of the overlying pleura may be present
• Extralobar (ELS)
• Circumscribed mass, covered with visceral pleura, independent of the normal lung
• Irregular, enlarged (2×-5×) bronchi, bronchioles, and alveoli
• Bronchial structures with normal to irregular lumens lined with pseudostratified columnar epithelium may be present
• No significant inflammation or fibrosis
• Dilated subpleural lymphatics may be present
• Areas of congenital pulmonary airway malformation (CPAM) type 2 can be identified in half of the cases

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Other cystic lung lesions devoid of an independent systemic blood supply
• CPAM
• Bronchogenic cyst
• Congenital lobar emphysema
• Primary lung abscess

Fig 1 Pulmonary sequestration. Intralobar sequestration; gross image of cut surface shows large cystic space filled with mucus.

Fig 2 Pulmonary sequestration. A 5-month-old with ILS with CPAM type 2 (microcyst formation, lined by bronchiolar epithelium).


Fig 3 Pulmonary sequestration. ILS in an 11-year-old, associated with chronic inflammation and fibrosis; low (A) and high (B) powers.

Fig 4 Pulmonary sequestration. ILS in a 34-year-old; elastic stain shows marked secondary pulmonary arterial hypertension with intimal fibrosis.

Fig 5 Pulmonary sequestration. Gross image of ELS: resected specimen (A) and cut surface (B).

Fig 6 Pulmonary sequestration. ELS, bronchial structures with normal to irregular lumens lined with pseudostratified columnar epithelium (CPAM type 2).
Bronchogenic Cyst
See also Mediastinal Bronchogenic Cyst.

Definition

• Cystic lesion arising from anomalous budding of the tracheobronchial anlage of the primitive foregut during development

Clinical features

Epidemiology

• Rare congenital malformation, primarily diagnosed in children

Presentation

• Mostly mediastinal; however, they can be found at any point along the tracheobronchial tree, occasionally found in the lung parenchyma or within the cervical, intrapleural, or suprasternal cutaneous regions, rarely, below the diaphragm or pericardium
• Incidentally detected on chest imaging
• Rarely, patients present with obstruction of tracheobronchial tree, a ruptured cyst, or infection

Prognosis and treatment

• Surgery is curative

Pathology

Gross

• Unilocular cyst containing clear fluid or, rarely, hemorrhagic secretions
• Communication with the tracheobronchial tree is rare

Histology

• Thin-walled cyst lined by ciliated pseudostratified columnar epithelium
• Wall can contain smooth muscle, cartilage, seromucinous bronchial glands, and occasionally linear calcifications
• Squamous metaplasia and/or chronic inflammation may be present
• Bronchogenic cysts lack alveolar tissue
• Cysts do not communicate with the tracheobronchial tree

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Pulmonary sequestration
• Congenital pulmonary airway malformation
• Mediastinal cysts: esophageal cyst, enteric cyst, thymic cyst, cystic teratoma, pericardial cyst
• Abscess
• Cystic bronchiectasis
• Postinfarction cyst
• Interstitial emphysema
• Pleuropulmonary blastoma

Fig 1 Bronchogenic cyst. Chest imaging showing a bronchogenic cyst in the mediastinum.

Fig 2 Bronchogenic cyst. Gross image of the same bronchogenic cyst as in Fig 1 .

Fig 3 Bronchogenic cyst. Thin-walled cyst lined by ciliated pseudostratified columnar epithelium with adjacent cartilage and seromucinous bronchial glands.
Peripheral Lung Cysts

Definition

• Small air-containing cysts at the periphery of lungs in infants and young children

Clinical features

Epidemiology

• Increased incidence in Down syndrome, especially in patients with congenital heart disease
• May be seen after pulmonary infarction, either in utero or in infancy

Presentation

• Incidental finding

Prognosis and treatment

• Same as underlying disorder

Pathology

Gross

• 0.2 to 1 cm subpleural air-filled cysts

Histology

• Cyst walls are lined by alveolar pneumocytes
• Walls have vascular connective tissue
• Postinfarction cysts may contain debris or air

Immunopathology/special stains

• Cytokeratins and TTF-1 are positive in lining cells
• Endothelial markers are negative in lining cells

Main differential diagnoses

• Pulmonary interstitial emphysema: air spaces are along interlobular septa and bronchovascular bundles and lack an epithelial lining
• Congenital pulmonary lymphangiectasis: cystic spaces are subpleural and along septa and are lined by endothelial cells

Fig 1 Peripheral lung cysts. Small cysts are present close to the pleura.

Fig 2 Peripheral lung cysts. Cyst lined by flattened to cuboidal alveolar cells.

Fig 3 Peripheral lung cysts. The epithelial lining of the cyst is positive for TTF-1.
Infantile (Congenital) Lobar Emphysema

Definition

• Lobar hyperinflation or hyperplasia with mass effect presenting in an otherwise normal infant

Pathogenesis

• Partial or complete obstruction of the bronchus supplying the involved lobe
• Intrinsic factors such as congenital bronchial atresia, stenosis, or mucous plugging
• Extrinsic factors such as vascular malformation or neoplasms
• Most are idiopathic

Clinical features

Epidemiology

• Most patients present in the first 6 months of life
• Boys are more frequently affected than girls

Presentation

• Respiratory distress
• Left upper lobe is most commonly involved, followed by the right middle and right upper lobes in congenital cases
• Lower lobe involvement is seen in the rare acquired forms

Prognosis and treatment

• Cure is achieved by surgical excision
• Some patients are managed conservatively by decompressing the affected lobe through the use of selective intubation

Pathology

Histology

• I: Classic pattern (congenital lobar overinflation)
• Uniformly overinflated alveoli
• Has normal number of alveoli, but alveoli can reach 3 to 10 times the normal size
• II: Polyalveolar pattern
• Variable areas of overinflated alveoli
• Increase in the absolute count of acini/alveoli
• Radial count is used to count alveoli by making a line from the last respiratory bronchiole to the pleura or closest interlobular septum
• Normally the count varies between 5 to 12; in infantile lobar emphysema the counts can reach 20 to 30 alveoli

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Congenital pulmonary adenomatoid malformation (congenital cystic adenomatoid malformation): five types with variable abnormalities in airways and alveoli

Fig 1 Infantile (congenital) lobar emphysema. Scanning view shows overinflated lung tissue and an increase in the number of alveoli characteristic of the polyalveolar pattern.

Fig 2 Infantile (congenital) lobar emphysema. Medium-power view shows overinflation of some of the alveolar spaces that can be seen in the polyalveolar pattern.

Fig 3 Infantile (congenital) lobar emphysema. Low-power view shows distended alveoli that are normal in number characteristically seen in the classic pattern.

Fig 4 Infantile (congenital) lobar emphysema. All alveoli are distended in this classic pattern.

Fig 5 Infantile (congenital) lobar emphysema. High-power view shows markedly distended alveolar space that can be seen in both classic and polyalveolar patterns. Note absence of inflammation and fibrosis.
Interstitial Pulmonary Emphysema (IPE)

Definition

• Dissection of air into septal connective tissue, peribronchial tissue, and the perivascular sheath

Pathogenesis

• Rupture of alveoli due to mechanical ventilation allows dissection of air around bronchovascular bundles

Clinical features

Epidemiology

• Incidence is decreasing but may still occur in 5% to 10% of premature infants undergoing ventilation for respiratory distress syndrome
• Rare in healthy infants without mechanical ventilation

Presentation

• X-ray film demonstrates linear streaks and cystic spaces radiating from the hilum
• Persistent IPE (PIPE) occurs in infants with acute IPE (AIPE) for more than a week. It is usually localized but may be diffuse in association with bronchopulmonary dysplasia

Prognosis and treatment

• AIPE may dissect centrally to produce pneumomediastinum, pneumopericardium, or pneumoperitoneum or may dissect peripherally to produce pneumothorax
• AIPE may be reabsorbed or persist as PIPE
• Treatment with oxygen is usually sufficient, and resection is rarely required

Pathology

Gross

• AIPE demonstrates 0.3 to 1.0 cm air-filled subpleural blebs adjacent to interlobular septa and along bronchovascular bundles
• Diffuse PIPE demonstrates 0.1 to 0.3 cm air-filled cysts along the interlobular septa
• Localized PIPE has larger (3 to 4 cm) interconnecting air-filled cysts along interlobular septa

Histology

• In AIPE, irregular air spaces adjacent to bronchovascular bundles are lined by connective tissue
• May rupture into lymphatics, when the outline is round, but does not extend into pleural lymphatics
• In PIPE, irregular air spaces are lined by fibrous tissue with scattered foreign body giant cells

Immunopathology/special stains

• Immunohistochemistry for endothelial and epithelial markers should be negative in the lining of the cyst unless there is rupture into the lymphatics

Main differential diagnoses

• Congenital pulmonary lymphangiectasis: cystic spaces are lined by lymphatic endothelium and extend laterally along the pleura away from interlobular septa
• Peripheral cysts: represent dilated alveoli and are lined by epithelium

Fig 1 Interstitial pulmonary emphysema. Multiple subpleural blebs due to air tracking are seen in this patient with IPE.
(Courtesy of Dr. John Hicks, Texas.)

Fig 2 Interstitial pulmonary emphysema. IPE dissected centrally to produce pneumopericardium (arrow) in this infant.

Fig 3 Interstitial pulmonary emphysema. Diffuse IPE can create large cysts along the septa as seen in the lung of this infant.

Fig 4 Interstitial pulmonary emphysema. Irregularly shaped cystic spaces along the bronchovascular bundle compress a large artery.

Fig 5 Interstitial pulmonary emphysema. The cystic spaces lack endothelial or epithelial lining.

Fig 6 Interstitial pulmonary emphysema. The air spaces extend along the bronchovascular bundles to the pleura, and the round shape suggests that air has dissected into the lymphatics, but pleural lymphatics lateral to the septa are not involved.

Fig 7 Interstitial pulmonary emphysema. In persistent or chronic IPE, air spaces are lined by foreign body giant cells (arrow) as seen in this low power.

Fig 8 Interstitial pulmonary emphysema. High power of Fig 7 .
Congenital Pulmonary Lymphangiectasis

Definition

• Developmental disorder characterized by lymphatic dilatation in the lung

Pathogenesis

• Thought to be due to failure of lymphatics to regress after 20 weeks’ gestation

Clinical features

Epidemiology

• Male predominance
• May be sporadic but is frequently secondary to cardiac anomalies causing obstruction of pulmonary venous return
• Rarely associated with generalized lymphangiectasis
• Occasionally associated with other congenital anomalies in Noonan, Turner or Down syndrome

Presentation

• Respiratory distress in the newborn
• X-ray film demonstrates interstitial distention of lymphatics
• Often associated with chylous pleural effusions and pulmonary hypoplasia

Prognosis and treatment

• Previously fatal within hours to days, but advances in intensive care now allow survival depending on the underlying etiology and associated malformations

Pathology

Gross

• Irregular cystic spaces in lung parenchyma and pleura

Histology

• Cystically dilated lymphatics in interlobular septa, pleura, and along bronchovascular bundles
• There is an increase in number as well as dilatation of normally distributed lymphatic channels
• Extramedullary hematopoiesis may be present in connective tissue

Immunopathology/special stains

• D2-40 highlights lymphatic endothelium
• CD31, CD34 and von Willebrand (factor VIII–related antigen) are also positive

Main differential diagnoses

• Interstitial pulmonary emphysema: air tracks into the interstitium and interlobular septa but does not spread laterally under the pleura. Air may track into the lymphatics, but most cysts are not lined by endothelium

Fig 1 Congenital pulmonary lymphangiectasis. Cystically dilated lymphatics extending along the interlobular septa.

Fig 2 Congenital pulmonary lymphangiectasis. Cystically dilated lymphatics in the pleura distant from the interlobular septa.

Fig 3 Congenital pulmonary lymphangiectasis. Cystically dilated lymphatics around the bronchovascular bundles compressing the adjacent lung parenchyma.

Fig 4 Congenital pulmonary lymphangiectasis. Cystically dilated spaces are lined by flattened endothelial cells.

Fig 5 Congenital pulmonary lymphangiectasis. D2-40 stains the endothelium of a markedly dilated lymphatic adjacent to an artery.
Alveolar Capillary Dysplasia

Definition

• Abnormal location of pulmonary veins within bronchovascular bundles and increased alveolar capillaries

Pathogenesis

• Some cases are associated with mutations in STRA6 on chromosome 15

Clinical features

Epidemiology

• Rare congenital disease
• Familial cases have been described

Presentation

• Presents soon after birth with marked respiratory distress and pulmonary hypertension
• In approximately 50% of cases other anomalies are identified, such as duodenal atresia, congenital heart disease, asplenia, phocomelia, and ureteric and urethral obstruction

Prognosis and treatment

• No effective therapy; lung transplantation could be an option
• Patients usually die within the first few days or weeks of life

Pathology

Histology

• Thickened alveolar septa and increased number of alveolar capillaries
• Abnormally located capillaries within central portion of septa instead of near alveolar lumen
• Pulmonary arteries with medial hypertrophy
• Abnormally muscularized arterioles within bronchovascular bundles
• Dilated pulmonary veins abnormally located near pulmonary arteries in the bronchovascular bundles; although this feature can be focal or diffuse, it is pathognomic of alveolar capillary dysplasia

Immunopathology/special stains

• Not contributory

Fig 1 Alveolar capillary dysplasia. Low-power view shows ectatic abnormally located pulmonary vein (arrow) adjacent to pulmonary arteries. Dilated lymphatics are also present (arrowheads).
(Courtesy of Dr. John Hicks, Children’s Hospital, Houston, Tex.)

Fig 2 Alveolar capillary dysplasia. Medium-power view shows thickened, muscularized arterioles and adjacent ectatic abnormally located pulmonary veins. Note centrally located capillaries in alveolar septae in lower left and upper right.
(Courtesy of Dr. John Hicks, Children’s Hospital, Houston, Tex.)

Fig 3 Alveolar capillary dysplasia. Medium-power view shows an ectatic vein abnormally located next to the pulmonary artery.
(Courtesy of Dr. John Hicks, Children’s Hospital, Houston, Tex.)

Fig 4 Alveolar capillary dysplasia. High-power view shows a bronchovascular bundle with thickened muscularized arterioles and ectatic abnormally located venules.
(Courtesy of Dr. John Hicks, Children’s Hospital, Houston, Tex.)

Fig 5 Alveolar capillary dysplasia. High power of alveolar walls showing centrally located dilated capillaries.
(Courtesy of Dr. John Hicks, Children’s Hospital, Houston, Tex.)
Surfactant Dysfunction Disorders

Definition

• Rare congenital defect in surfactant proteins or in proteins involved in processing and homeostasis of surfactants
• Formerly categorized as congenital pulmonary alveolar proteinosis

Pathophysiology

• Numerous different genetic defects have been described in surfactant protein (Sp)B, SpC, and ABCA3 (involved in surfactant processing and homeostasis)
• Mutations can be autosomal dominant, autosomal recessive, or sporadic

Clinical features

Epidemiology

• Rare cause of neonatal respiratory distress or pediatric interstitial lung disease
• Most often due to genetic defect of ABCA3 or SpB, and rarely SpC
• More common in patients with family history of lung disease or consanguinity

Presentation

• Term neonates presenting with severe respiratory distress lasting longer than 1 week, chest radiography similar to respiratory distress syndrome of premature neonates, and with no improvement after surfactant administration
• Patients with genetic mutation of SpC have variable clinical presentation and age at onset of symptoms, which include poor growth, decreased activity, dyspnea, and nonproductive cough
• Chest radiographic findings are typically much more severe than suggested by the clinical signs and symptoms

Prognosis and treatment

• Poor survival (days to months) in neonates with severe disease
• No specific treatment available
• Lung transplant has had some success but still carries significant mortality

Pathology

Histology

• Accumulation of PAS positive, mucicarmine negative eosinophilic granular alveolar material
• Type II pneumocyte hyperplasia, interstitial fibrosis, and alveolar simplification, which have been descriptively referred to as being consistent with pulmonary alveolar proteinosis, nonspecific interstitial pneumonia, desquamative interstitial pneumonia, or chronic pneumonitis of infancy
• Electron microscopy: disorganized or incomplete lamellar bodies (SpB or SpC defects), small lamellar bodies with eccentric electron dense inclusions with a “fried-egg” appearance (ABCA3 defects)

Immunopathology (including immunohistochemistry)

• Alveolar eosinophilic material is negative for SpB in cases with SpB deficiency and negative for SpC in cases of SpC deficiency

Main differential diagnoses

• Neonatal respiratory distress syndrome
• Pulmonary alveolar proteinosis, secondary type

Fig 1 Surfactant dysfunction disorders. Simplification of alveolar architecture, interstitial fibrosis, and type II pneumocyte hyperplasia, seen at low power in this case of ABCA3 mutation.

Fig 2 Surfactant dysfunction disorders. At higher power, brightly eosinophilic granular material is seen in some of the alveolar spaces.

Fig 3 Surfactant dysfunction disorders. Electron microscopy in this case with an ABCA3 defect reveals a paucity of lamellar bodies, which are small and irregular; several have eccentric electron dense inclusions.

Fig 4 Surfactant dysfunction disorders. Wedge biopsy from a 4-week-old with progressive respiratory distress shows typical intraalveolar granular eosinophilic material.

Fig 5 Surfactant dysfunction disorders. Different area from same patient as in Fig 4 shows foamy macrophages in the alveolar spaces and reactive type 2 pneumocytes, illustrating the variability of surfactant accumulation.
Hyaline Membrane Disease

Definition

• A form of acute lung injury seen in neonates as a result of immaturity and surfactant deficiency; the pathologic correlate of neonatal respiratory distress syndrome

Clinical features

Epidemiology

• Affects approximately 1% of infants born worldwide
• Incidence inversely proportional to gestational age and birth weight: 60% to 80% in infants less than 28 weeks of gestational age, 15% to 30% in those between 32 to 36 weeks, 5% in infants more than 37 weeks
• Rarely, it occurs in mature infants when it is due to dilution of surfactant (inadequate resorption of lung liquid at birth)
• Risk factors include prematurity, white race, male sex, maternal diabetes, birth by cesarean section, multiple gestation, precipitous delivery, asphyxia, cold stress, and a maternal history of prior affected infants

Presentation

• Clinical signs of respiratory distress
• Clinical presentation manifests almost always before 8 hours of age (if symptoms develop after 8 hours of normal breathing, hyaline membrane disease is excluded)
• Typical radiographic finding includes diffuse, bilateral, “granular” opacities with superimposed air bronchograms

Prognosis and treatment

• Best prevention is avoidance of premature labor and delivery
• Antenatal betamethasone therapy is helpful in preventing hyaline membrane disease
• Key treatment measures include exogenous surfactant therapy, oxygen therapy, and mechanical ventilation
• Milder cases usually peak at 2 to 3 days of age; gradual improvement follows
• Infants with severe or untreated disease may develop bronchopulmonary dysplasia or may die of the disease
• Advances in prevention and treatment have decreased mortality and the incidence of subsequent bronchopulmonary dysplasia and markedly improved chances of survival

Pathology

Gross

• Lungs are firm, solid, red, congested, and sink in water
• Relatively airless cut surface with marked atelectasis and a liver-like appearance

Histology

• Alveolar sacs lined by hyaline membranes, which consist of epithelial debris, fibrin, amniotic fluid, and transudate fluid proteins
• Although hyaline membranes start to form within 30 to 60 minutes of high oxygen and respirator therapy, it takes approximately 4 hours of breathing room air for hyaline membranes to be well developed; therefore, hyaline membranes may be inconspicuous in infants who die at less than 4 hours of age
• Hyaline membranes are not specific and may be present in other conditions (see differential diagnosis)
• Immaturity of lung tissue usually apparent (airspaces without hyaline membranes lined by cuboidal epithelium)
• Surrounding lung tissue with congestion, hemorrhage, epithelial desquamation, and lymphatic dilatation
• Atelectasis of distal airspaces and overdistension of proximal airspaces

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Other conditions with the presence of hyaline membranes, such as meconium aspiration and viral or bacterial infections

Fig 1 Hyaline membrane disease. A section of the lung from a newborn of 24 weeks’ gestational age. Open alveolar sacs are lined by homogenous eosinophilic hyaline membranes. The surrounding alveolar sacs are atelectatic and show evidence of immaturity (lined by cuboidal epithelium).

Fig 2 Hyaline membrane disease. High-power view of hyaline membranes involving terminal bronchiole (black arrows) and extending into alveolar sac (white arrows). Note the cuboidal epithelium is partially preserved at the bottom of the alveolar sac.

Fig 3 Hyaline membrane disease. Collapsed airspaces lined by cuboidal epithelium are evident adjacent to (above and below) bronchiole and airspaces involved by hyaline membranes.
Bronchopulmonary Dysplasia (BPD)

Definition

• A chronic lung disease that develops in some preterm infants who survived hyaline membrane disease

Pathogenesis

• Multiple factors play important roles in BPD:
• Lung immaturity and surfactant deficiency
• Barotrauma due to high pressure of oxygen delivery (not seen with current neonatal management)
• Oxygen toxicity (much less important with surfactant therapy and current management)
• Inflammation
• Pulmonary edema
• Nutritional deficiency
• Presurfactant therapy era: immature lungs with surfactant deficiency are more susceptible to barotrauma, which results in necrotizing bronchiolitis and alveolar septal injury
• Postsurfactant therapy: arrest of further lung development after premature birth leads to fewer alveoli that show compensatory dilatation. Fibrosis is minimal to mild

Clinical features

Epidemiology

• Highest incidence in most immature neonates (<27 weeks’ gestation) with low birth weight (<800 g)
• Occurred in 20% of newborns receiving ventilation before surfactant era
• Male infants tend to have more severe disease
• The use of surfactant therapy in preterm neonates with hyaline membrane disease has significantly decreased the incidence of BPD as well as the mortality rate

Presentation

• Early symptoms are those of hyaline membrane disease, requiring oxygen treatment and assisted ventilation
• Infants who then develop BPD have tachypnea, chest retraction, coughing, paroxysmal respiration, wheezing, and rhonchi; they continue to be oxygen dependent 28 days after birth
• Functional deficits include abnormal gas exchange, increased dead space, decreased compliance, increased work of breathing, and ventilation-perfusion mismatch, as well as mild to moderate pulmonary hypertension
• Radiology: diffuse lung haziness, consolidation, bubble-like cystic space; may be mediastinal shift and mass effect due to lobar overinflation

Prognosis and treatment

• Prevention is most important
• Symptomatic treatment includes diuretics, bronchodilators, vasodilators, and corticosteroids
• Infants with severe BPD are at high risk of pulmonary morbidity and mortality during the first 2 years of life
• Since the introduction of surfactant therapies, BPD is less severe and survival has been greatly improved

Pathology

Gross

• Pleural surface of severe BPD is irregular with a knobby or cobblestone appearance; there is shallow or deep fissure formation

Histology

• Nonsurfactant–treated
• Early phases of BPD in infants show diffuse alveolar damage (DAD) with necrotizing bronchiolitis and hyaline membranes followed by repair and organization
• Late stages show variegated pattern with some lobules with alveolar fibrosis and collapse, while adjacent lobules show overdistention and frequent interstitial air accumulation
• Lung tissue supplied by bronchioles with necrotizing bronchiolitis is relatively protected from further injury
• Since surfactant replacement therapy, the most common histological picture seen in BPD is decreased alveolarization and simplification of lung architecture; there is only minimal to mild alveolar septal fibrosis
• Superimposed infection and pulmonary hypertension (often with cor pulmonale) are usually present at autopsy

Main differential diagnoses

• Early stages with DAD
• Late stages: emphysema, fibrosing interstitial pneumonia, mild pulmonary hypertension or chronic constrictive bronchiolitis

Fig 1 Bronchopulmonary dysplasia. Gross picture of the heart and lung from an infant with BPD. Note the presence of deep fissures and variegated appearance of pleura with dark purple indented areas and pale pink nodular areas; the heart shows right ventricular hypertrophy with prominent epicardial fat deposition.

Fig 2 Bronchopulmonary dysplasia. Septal fibrosis of BPD: H&E (A) and trichrome stain (B) showing blue fibrotic area.

Fig 3 Bronchopulmonary dysplasia. With surfactant therapy, lung with mild BPD showing uniformly dilated acini with thin alveolar septa and only focal interstitial fibrosis: low (A) and high (C) powers of H&E stain; low (B) and high (D) powers of trichrome stain highlighting focal fibrosis.
Pulmonary Interstitial Glycogenosis (PIG)

Definition

• Rare infantile lung disease characterized by interstitial widening due to the presence of glycogen-laden cells

Pathogenesis

• Precise etiology remains unknown; studies suggest a developmental abnormality rather than an inflammatory/reactive process
• Thought to be a result of selective dysmaturity of interstitial cells with no defects in type II pneumocytes or endothelial cell differentiation
• PIG has no known association with systemic glycogen storage disease

Clinical features

Epidemiology

• Affects infants younger than 6 months; mostly neonates
• Associated with congenital heart disease, pulmonary hypertension, chronic neonatal lung disease due to hypoplasia or prematurity

Presentation

• Rapid onset of respiratory distress and hypoxemia with bilateral interstitial infiltrates

Prognosis and treatment

• Self-limiting disease, usually with spontaneous resolution
• Glucocorticoid therapy accelerates cellular maturation

Pathology

Histology

• Histologic findings include interstitial widening by immature, bland, glycogen-rich mesenchymal cells without significant inflammation
• Lesions can be patchy or diffuse
• Often associated with superimposed lung injury or remodeling
• Mesenchymal cells are PAS and vimentin stain–positive and contain diastase labile cytoplasmic granules

Main differential diagnoses

• Immature lung
• Bronchopulmonary dysplasia

Fig 1 Pulmonary interstitial glycogenosis. There is interstitial widening with glycogen-laden cells.

Fig 2 Pulmonary interstitial glycogenosis. The glycogen in interstitial cells is highlighted by PAS stain (A), which is sensitive to diastase digestion (B).

Fig 3 Pulmonary interstitial glycogenosis. Electron microscopy reveals abundant intracytoplasmic glycogen granules.
(Courtesy of Dr. John Hicks, Children’s Hospital, Houston, Tex.)
Chronic Granulomatous Disease (CGD) of Childhood

Definition

• Group of hereditary diseases in which there is a decrease in oxidative burst when cells of the immune system are unable to form the superoxide radical that is used to kill certain ingested pathogens. This leads to the formation of granulomas in many organs.

Pathogenesis

• The inherited defect is in the gene encoding components of phagocyte oxidase
• In the X-linked variant the defect is in one of the membrane-bound components (gp91phox)
• In the autosomal recessive variant the defect is in the genes encoding two of the cytoplasmic components (p47phox and p67phox)

Clinical features

Epidemiology

• In the United States it affects 1 in 200,000 people with no race predilection
• Majority (two thirds) of cases X-linked and autosomal recessive; a few sporadic cases

Presentation

• Most patients given diagnosis of primarily gastrointestinal involvement in childhood
• Recurrent episodes of infections (diarrhea, pneumonia, skin abscesses, osteomyelitis, bacteremia, fungemia, cellulitis, and impetigo)
• Some present with atypical infections (catalase-positive bacteria, fungi)
• Lung involvement is rare and can occur at any time in the course of the disease in patients with an established diagnosis of CGD

Prognosis and treatment

• Without treatment children often die in the first decade of life
• Data indicates that X-linked CGD is more severe; most of these patients die in the third or fourth decade of life, even with treatment
• Prophylaxis with antibiotics and antifungal drugs
• Immunomodulation (e.g., interferon gamma-1b)
• Studies using gene therapy are currently under way

Pathology

Histology

• Lung involvement begins in the peribronchial or perivascular areas
• Suppurative inflammation with areas of massive necrosis and pigmented histiocytes
• Subsequently forms necrotizing granulomas
• Infrequently, foreign body and Langhans giant cells

Immunopathology/special stains

• Noncontributory for diagnosis but need to rule out infection (see Differential Diagnoses)

Main differential diagnoses

• Mycobacterial infections: need AFB stain to confirm
• Fungal infections: GMS stain demonstrates fungi
• Wegener granulomatosis: presents in young adults, classic triad (lung, nasal, and renal involvement)
• Aspiration: predominantly lower lobe involvement; foreign material identifiable
• Sarcoidosis: rare in children; usually nonnecrotizing granulomas
• Hypersensitivity pneumonitis: poorly formed granulomas, nonnecrotizing, with eosinophils

Fig 1 Chronic granulomatous disease of childhood. CGD involving the lung in a 10-year-old: A, Scanning view shows necrotizing granulomas involving perivascular area; B, high-power view shows necrotizing granulomas surrounded by mixed acute and chronic inflammatory cell infiltrate. Note multinucleated giant cells and necrotic debris within the granulomas.
D
Pediatric Tumors
Pleuropulmonary Blastoma (PPB)

Definition

• Rare childhood mesenchymal pleural-based tumor that often involves the lung

Pathogenesis

• Germline mutations in DICER1 have been identified in familial PPB. The mutation occurs in the benign epithelium leading to altered regulation of mesenchymal growth, which results in tumor formation

Clinical features

Epidemiology

• Mean age, 2.5 years; rarely occurs in older children and adolescents
• No gender predilection
• A quarter of patients have familial cancer syndrome like thyroid tumors, cystic nephroma, ovarian teratoma, or multiple intestinal polyps
• Type I: least common (<15%), affecting the youngest patient group with a median age of 10 months
• Type II: 40% to 50% of all PPB, affecting older children with a median age of 34 months
• Type III: 40% of all PPB, affecting older children with a median age of 44 months
• PPB progresses from type I to types II and III over time

Presentation

• Usually nonspecific symptoms include coughing, shortness of breath, or chest pain
• Some patients may present with pneumothorax or pleural effusion

Prognosis and treatment

• Treatment: surgical resection with or without chemotherapy
• Types II and III are aggressive tumors with more frequent brain metastasis than other childhood sarcomas

Pathology

Gross

• Type I: purely cystic, usually multicystic
• Type II: mixed cystic and solid pattern with thickened nodules within cystic lesion
• Type III: solid tan-white mucoid mass; partially friable, necrotic, or calcified

Histology

• The tumor is composed of malignant mesenchymal cells, which may be primitive with small undifferentiated blastemic cells or larger malignant sarcoma cells with features of rhabdomyosarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, or osteosarcoma
• The epithelial component is benign and usually represents entrapped mesothelial cells or epithelial cells

Immunopathology/special stains

• Malignant mesenchymal cells are positive for vimentin and negative for cytokeratin and EMA
• Differentiated malignant mesenchymal cells may also be positive for desmin, smooth muscle actin, muscle specific actin, or S100

Main differential diagnoses

• Pulmonary blastoma
• Sarcomatoid carcinoma of adults
• Both epithelial and mesenchymal components are malignant and primitive, resembling fetal lung
• Primary sarcoma of children
• Rhabdomyosarcoma may occur in lung tissue in young patients
• Usually lacks undifferentiated blastemic component
• Metastatic Wilms tumor
• Clinical history of primary Wilms tumor
• Usually triphasic with undifferentiated blastema, fibroblast-like stroma, and epithelial components
• Positive for WT-1
• Congenital pulmonary airway malformation (CPAM)
• Also affects infants and young children and can also be cystic
• Lacks malignant mesenchymal component

Fig 1 Pleuropulmonary blastoma. CT scan of mediastinal type I PPB: purely cystic.
(Courtesy of Dr. Bahig Shehata, Atlanta, Ga.)

Fig 2 Pleuropulmonary blastoma. CT scan of pleural type II PPB: cystic lesion with nodular thickening.
(Courtesy of Dr. Bahig Shehata, Atlanta, Ga.)

Fig 3 Pleuropulmonary blastoma. A and B, Low-power views of type I PPB showing cystic wall with bland epithelial lining.
(Courtesy of Dr. John Hicks, Children’s Hospital, Houston, Tex.)

Fig 4 Pleuropulmonary blastoma. Medium-power views of type I PPB: cystic wall with cartilage and area of undifferentiated mesenchymal cells (A) and rhabdomyosarcomatous area (B).
(Courtesy of Dr. John Hicks, Children’s Hospital, Houston, Tex.)

Fig 5 Pleuropulmonary blastoma. Type II PPB with solid and cystic growth: myxoid spindle and blastemic cells (A) and undifferentiated spindle cells with scattered rhabdoid cells (B).
(Courtesy of Dr. John Hicks, Children’s Hospital, Houston, Tex.)

Fig 6 Pleuropulmonary blastoma. PPB showing heterogeneous malignant mesenchymal cells with rhabdomyosarcomatous (A), blastemic (B), mixture of blastemic and rhabdomyosarcomatous (C), and fibrosarcomatous appearance (D).
(Courtesy of Dr. John Hicks, Children’s Hospital, Houston, Tex.)

Fig 7 Pleuropulmonary blastoma. PPB type III, low power showing pleural tumor with adjacent uninvolved lung (A); B, vascular invasion.
(Courtesy of Dr. John Hicks, Children’s Hospital, Houston, Tex.)
Inflammatory Myofibroblastic Tumor (IMT)

Definition

• A tumor composed of myofibroblastic spindle cells with lymphoplasmacytic inflammation, associated with ALK gene translocations, previously referred to as inflammatory pseudotumor

Clinical features

Epidemiology

• Equal gender distribution
• Typically occurs in children but can be seen at any age
• IMT is the most common childhood mesenchymal endobronchial tumor but overall accounts for less than 1% of all lung tumors
• Some cases have been shown to be associated with a preceding human herpesvirus 8 infection

Presentation

• Peripheral tumors often asymptomatic and discovered incidentally on imaging
• Less commonly, endobronchial location, presenting with signs of airway obstruction, including coughing, wheezing, chest pain, and hemoptysis
• In many cases, patients have symptoms of an associated paraneoplastic syndrome with weight loss, fever, anemia, increased erythrocyte sedimentation rate, leukocytosis, and thrombocytosis, as well as hyperglobulinemia

Prognosis and treatment

• Complete excision usually leads to excellent survival rate
• Incomplete excision can lead to recurrence
• Extrapulmonary invasion and metastases are infrequent but are associated with a poor prognosis

Pathology

Histology

• Well-demarcated unencapsulated mass of varying size (average, 3 cm), which may focally extend beyond its circumscribed edges into the adjacent lung parenchyma
• Bland spindle cells growing in short intersecting fascicles
• Spindle cells have oval nuclei, occasional nucleoli, and abundant eosinophilic cytoplasm
• Mitotic figures are present in variable numbers, but there are no atypical mitotic figures
• Prominent inflammatory infiltrate of lymphocytes, plasma cells, and eosinophils, as well as clusters of foamy histiocytes and scattered Touton-like giant cells
• Stroma may be focally myxoid or fibrous and calcifications may be present
• Endobronchial tumors may have adjacent postobstructive pneumonia and atelectasis

Immunopathology/special stains

• Spindle cells are positive for vimentin, muscle-specific actin, calponin, smooth muscle actin, and occasionally desmin and ALK
• Spindle cells are negative for caldesmon, CD117, S100, CD34, EMA, myogenin, and myoglobin
• p53 may be positive in recurrence or malignant transformation
• Entrapped alveolar pneumocytes are cytokeratin positive

Main differential diagnoses

• Organizing pneumonia: look for characteristic Masson bodies
• Inflammatory sarcomatoid carcinoma: cytokeratin and EMA positive; muscle markers negative; also has more high-grade features: nuclear hyperchromasia, atypia, and necrosis
• Solitary fibrous tumor: CD34-positive spindle cells, less inflammation, fibrohyaline stroma
• Leiomyoma or leiomyomatous hamartoma: caldesmon positive, less inflammation
• Congenital peribronchial myofibroblastic tumor: rare, present at birth, extensively infiltrative with minimal inflammation
• Spindle cell sarcoma, NOS

Fig 1 Inflammatory myofibroblastic tumor. Short intersecting fascicles of eosinophilic spindle cells admixed with inflammatory cells, as seen here, are characteristic of IMT.

Fig 2 Inflammatory myofibroblastic tumor. The fascicles of spindle cells vary from loose bluish (lower right) to fibrotic (upper left).


Fig 3 Inflammatory myofibroblastic tumor. The inflammatory infiltrate can be quite dense, as seen in this case of IMT.

Fig 4 Inflammatory myofibroblastic tumor. At low power, this atypical IMT shows increased cellularity and cellular pleomorphism.

Fig 5 Inflammatory myofibroblastic tumor. At higher power, the atypical cells can be seen along with the more typical features of spindle and inflammatory cells.

Fig 6 Inflammatory myofibroblastic tumor. On this frozen section of an IMT, spindle cells are seen admixed with lymphocytes and plasma cells.

Fig 7 Inflammatory myofibroblastic tumor. Spindle cells are positive for SMA. Note positive staining for vascular smooth muscle at bottom right.

Fig 8 Inflammatory myofibroblastic tumor. ALK-1 shows both granular cytoplasmic and membranous staining.
Congenital Pulmonary Myofibroblastic Tumor

Definition

• A benign spindle cell tumor of the lung presenting at birth or in neonatal life with clinical features of respiratory distress and mediastinal shift
• It has also been termed congenital peribronchial myofibroblastic tumor

Clinical features

Epidemiology

• Rare neoplasm; less than 40 cases reported in the literature

Presentation

• Mass effect leads to respiratory distress
• Has been incidentally detected on prenatal ultrasonography

Prognosis and treatment

• It is a benign tumor that is cured with surgical resection
• Mortality is related to mediastinal shift (preoperatively) or due to complications of surgery (intraoperative and postoperative)

Pathology

Histology

• Well-circumscribed, usually nonencapsulated tumor with broad-pushing front; small foci of infiltrative growth may be present
• Interlacing fascicles of bland spindle cells of variable density; cells lack anaplasia
• Stroma may show myxoid change
• Foci of necrosis and dystrophic calcification may be present
• Mitotic activity varies from zero to four per 10 high-power fields
• Vascularity may be prominent focally and may show a hemangiopericytoma-like pattern
• Entrapped respiratory structures and cartilage usually present

Immunopathology/special stains

• Spindle cells positive for vimentin and may be positive for smooth muscle actin. Hence, in older literature, it was thought to represent a “congenital leiomyosarcoma”
• Desmin and S100 are negative
• Electron microscopy suggests myofibroblastic differentiation, in that the tumor cells have disrupted basal lamina, lack micropinocytotic vesicles, contain bundles of fine actin-like filaments and have crenated nuclei. Others have reported elongated cells with some cytoplasmic processes

Main differential diagnoses

• Sarcomas such as leiomyosarcoma (these will be desmin-positive) and malignant peripheral nerve sheath tumors (at least focally S100 positive). Sarcomas commonly show anaplasia, unlike congenital pulmonary myofibroblastic tumors
• Pleuropulmonary blastoma (PPB): types 1 and 2 PPB have a cystic component. Solid (type 3) PPB is sarcomatous and commonly shows features of a rhabdomyosarcoma

Fig 1 Congenital pulmonary myofibroblastic tumor. Low power shows nodules of tumor with irregular cartilage plates.

Fig 2 Congenital pulmonary myofibroblastic tumor. Intermediate power shows relatively bland tumor cells with islands of cartilage.

Fig 3 Congenital pulmonary myofibroblastic tumor. High power shows uniform spindle cells with one mitotic figure.
Metastatic Pediatric Tumors

Definition

• Secondary malignant lung tumors in pediatric patients

Clinical features

Epidemiology

• Metastatic tumors account for approximately 80% of all lung tumors in children and more than 95% of malignant tumors
• The ratio of primary malignant to secondary malignant neoplasms is 1:12
• Most common pediatric metastases are from osteosarcoma and Wilms tumor, followed by Ewing/primitive neuroectodermal tumor (PNET), neuroblastoma, malignant peripheral nerve sheath tumor (MPNST), hepatoblastoma, rhabdomyosarcoma, and, rarely, other sarcomas and carcinomas
• With the exception of osteosarcoma, the lung is rarely the initial or only site of metastasis for pediatric tumors

Presentation

• Osteosarcoma: solitary or multiple nodules with cavitation and calcification causing coughing, wheezing, and hemoptysis
• Soft tissue sarcomas: multiple peripherally located sharply outlined nodules with central necrosis or endobronchial masses with asthmalike symptoms
• If nodules are subpleural, they can cause formation of bronchopleural fistula and pneumothorax with severe chest pain/Pancoast syndrome
• The lower lobes are more frequently involved in hematogenous metastases
• A reticular or miliary pattern occurs in tumors spreading via lymphatics

Prognosis and treatment

• Metastasectomy (wedge excision) is the mainstay treatment for osteosarcoma, improving 3-year survival rates from 5% to 45%
• Surgical excisions are also used for diagnosis and staging and for tumors resistant to chemotherapy and radiotherapy such as adrenocortical carcinoma, chondrosarcoma, and alveolar soft part sarcoma
• Wilms, Ewing/PNET, neuroblastoma, rhabdomyosarcoma, and germ-cell tumors are treated with chemotherapy and radiotherapy
• Disease-free survival remains poor, except for Wilms tumor and solitary metastases of osteosarcoma

Pathology

Gross

• Well-circumscribed nodules that are either pleural-based or in lymphatic distribution
• Majority are firm, gray, glistening with “fish-flesh” cut surface
• Osteosarcomas commonly have firm, fleshy, and gritty appearance due to osteoid and chondroid production, as well as cystic hemorrhagic spaces and geographic necrosis

Histology

• Histopathology of metastatic tumors is usually similar to that of the primary site; however, chemosensitive tumors could show cellular maturation phenomenon, necrosis, fibrosis, or hemosiderin deposition
• It is critical to assess the percentage of necrosis as an indicator of treatment efficacy

Immunopathology/special stains

• Virtually all sarcomas are vimentin positive
• The most useful immunohistochemical (IHC) markers for metastatic pediatric tumors are listed in Table 2 in the Appendix

Main differential diagnosis

• Pleuropulmonary blastoma: very rare, always involves pleura, no tendency to entrap normal respiratory epithelium, and no history of prior sarcoma elsewhere

Fig 1 Metastatic pediatric tumors. Metastatic osteosarcoma with malignant osteoid production; pleomorphic polygonal cells with abundant cytoplasm and high grade nuclei (A). Note formation of cystic hemorrhagic spaces characteristic in telangiectatic osteosarcomas (B).


Fig 2 Metastatic pediatric tumors. Ewing sarcoma/PNET lung metastasis: vague lobular pattern of monotonous population of small blue cells (A); higher magnification shows scant cytoplasm, round nuclei, small inconspicuous nucleoli, mitotic figures, and apoptotic bodies (B).

Fig 3 Metastatic pediatric tumors. Another example of metastatic Ewing/PNET seen as a large endobronchial mass: low power (A) and higher magnification (B) demonstrate large atypical cells with irregular nuclear outline, conspicuous nucleoli, high pleomorphism, and spindling consistent with atypical large cell variant.

Fig 4 Metastatic pediatric tumors. Well-circumscribed metastatic nodule of MPNST. A, Low power showing long fascicles of uniform, closely spaced, hyperchromatic spindle cells. B, At higher power one can appreciate nuclear atypia, multinucleation, large vesicular nuclei with macronucleoli, and numerous atypical mitotic figures.
E
Obstructive Lung (Airway) Diseases
Bronchiectasis

Definition

• Permanent dilatation of the cartilaginous bronchi often accompanied with inflammatory changes

Clinical features

Epidemiology

• Worldwide problem; less prominent in the United States
• Most common noninherited causes are infection (viral or bacterial), obstruction (tumor or aspiration), and allergic bronchopulmonary aspergillosis
• No age or sex predilection
• Most patients are in their mid 50s at the time of diagnosis
• Younger patient may have inherited disease, such as cystic fibrosis or primary ciliary dyskinesia or immunodeficiency syndromes (inherited or acquired)

Presentation

• Productive cough with purulent sputum, dyspnea, fever and hemoptysis
• Radiographic findings: chest X-ray film may show classic parallel linear opacities (tram tracks) corresponding to thickened bronchial walls; tubular opacities reflect mucus-filled bronchi

Prognosis and treatment

• Irreversible disease
• Treat the underlying causes of the disease (e.g., airway obstruction [tumor or foreign body], infection, or cystic fibrosis)
• Symptomatic treatment

Pathology

Histology

• Grossly dilated bronchi with scarring are filled with mucopurulent material and extend almost to the pleural surface
• Histological findings vary significantly: some cases show minimal changes and some show bronchial dilation, mucopurulent stasis, and acute and chronic inflammation
• In severe cases, the entire bronchial wall can be disrupted, including mucosa, submucosa, muscularis propria, and cartilage

Immunopathology/special stains

• Not contributory

Fig 1 Bronchiectasis. Gross photograph of cut surface of explanted lung showing dilated bronchi extending up to the pleural surface. Some of them contain purulent exudates. Middle lobe is solidified and fibrotic. Prominent anthracotic pigment is present.


Fig 2 Bronchiectasis. Lowest power (A) and low power (B) photomicrographs show dilated airways and fibrosis of adjacent lung. Note organized polypoid inflammatory tissue within the airways.

Fig 3 Bronchiectasis. There is acute and chronic inflammation and ulceration of the airway in this 3-year-old patient with postinflammatory localized bronchiectasis.
Cystic Fibrosis

Definition

• Autosomal recessive disease with mutation of cystic fibrosis transmembrane conductance regulator (CFTR) gene and multisystem involvement. Patients have abnormal transport of chloride and sodium across the respiratory epithelium, resulting in thickened airway secretions and susceptibility to recurrent infections

Clinical features

Epidemiology

• Common hereditary disease in whites, affecting approximately 1/3000 live births
• Less common in blacks, occurring in approximately 1/17,000 live births
• Rare among Asians, seen in approximately 1/90,000 live births

Presentation

• Clinical presentation and severity vary considerably
• Pulmonary manifestations: wheezing, chronic cough, atelectasis, recurrent pneumonia, and bronchiolitis
• Extrapulmonary manifestations: meconium ileus, steatorrhea, malabsorption, recurrent pancreatitis, nasal polyps, absence of sperm in semen

Prognosis and treatment

• Dramatically improved survival with advanced multidisciplinary management
• Management of pulmonary disease includes controlling infection and maintaining airway clearance

Pathology

Histology

• Gross pathologic findings for endstage disease: widespread bronchiectasis (more severe in upper lobe) with thick mucus plugs, pleural fibrosis/adhesions, pneumonic consolidation, and lobar atelectasis
• Microscopic findings: acute and chronic inflammation involving the large and small airways associated with bronchial gland and goblet cell hyperplasia, squamous metaplasia, and mucostasis

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Recurrent pneumonia and bronchitis, bronchiectasia in non–cystic fibrosis patients: may share similar clinical, radiographic and histological features but no CFTR gene mutation

Fig 1 Cystic fibrosis. Cut surface of the explanted lung specimen shows severely dilated airways with thick fibrotic walls and purulent mucous plugs; the lung parenchyma is solidified with significant fibrosis.


Fig 2 Cystic fibrosis. A, The bronchiolar wall is fibrotic and infiltrated with mixed inflammatory cells; the bronchial epithelium is hyperplastic with goblet cell hyperplasia. Intraluminal mucostasis and numerous neutrophils are also present. Note secondary pulmonary arterial hypertensive changes in upper left. B , Florid acute inflammation of a bronchiole and intraluminal neutrophilic abscess. Adjacent alveoli are relatively spared.

Fig 3 Cystic fibrosis. At the late stage of the disease, concentric fibrosis of bronchiolar wall (A) and complete obliteration of the bronchiolar lumen (B) are seen (shown in this explanted lung).
Chronic Bronchitis

Definition

• Clinically defined as a productive cough, occurring on most days for 3 or more months for at least 2 successive years in the absence of any known cause of chronic cough

Clinical features

Epidemiology

• Commonly affects middle-aged adults but can be seen at any age
• Affects approximately 5.4% of the population in the United States
• High-risk population includes people who smoke and those exposed to high concentrations of dust and irritating fumes

Presentation

• Chronic productive cough, dyspnea, wheezing
• Physical examination: coarse rhonchi and wheezes

Prognosis and treatment

• Stop smoking and avoid exposure of stimulating dust and irritating fumes
• Relieve symptoms and prevent complications with bronchodilators and anticholinergics
• 5-year survival is approximately 50% if FEV 1 falls below 50% of predicted values

Pathology

Histology

• Chronic bronchitis with mucostasis, submucosal glandular hyperplasia with increased Reid index (>0.5), goblet cell metaplasia/hyperplasia and chronic inflammation
• Chronic respiratory bronchiolitis

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Because it is defined clinically and the pathological features are nonspecific, the differential is also based on clinical presentation

Fig 1 Chronic bronchitis. Low-power view shows bronchus with goblet cell and mucous gland hyperplasia. Note that some of the mucous glands are small due to adjacent fibrosis.

Fig 2 Chronic bronchitis. High-power view shows goblet cell hyperplasia and chronic inflammation in the submucosa and acute inflammation mixed with intraluminal mucus.

Fig 3 Chronic bronchitis. This patient was followed up in a high-risk clinic (because of a long history of smoking) and had this endobronchial biopsy, which shows squamous metaplasia.
Asthma

Definition

• A chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night and in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment.

Clinical features

Epidemiology

• A major health problem affecting more than 15 million people in the United States
• The incidence and prevalence has increased in the last 3 to 4 decades

Presentation

• Recurrent episodes of shortness of breath, wheezing, coughing, and chest tightness
• These symptoms are associated with airflow obstruction, which is reversible either spontaneously or with treatment
• Spirometry measurement shows significant reversibility of airflow obstruction

Prognosis and treatment

• Children with mild disease have a good prognosis. Approximately half of patients will no longer have the diagnosis after a decade
• Quick-relief medications used to treat acute symptoms (e.g. short-acting β2-adrenoceptor agonists) and long-term control medications used to prevent further exacerbation (e.g., inhaled glucocorticoids)

Pathology

Histology

• Gross autopsy findings of patients with status asthmaticus: mucous plugs occluding primarily medium-sized and small bronchi, associated with overinflation of the lungs
• Small bronchi are usually most severely affected and filled with mucous plugs. The mucus is mixed with eosinophils, shedding epithelium and Charcot-Leyden crystals
• Bronchial epithelium often desquamated but basal layer remains
• Prominent basal membrane thickening, goblet cell hyperplasia, and smooth muscle hyperplasia
• Squamous metaplasia may be seen
• The airways are infiltrated with eosinophils and mixed inflammatory cells
• Chronic asthma
• Constrictive bronchiolitis with submucosal scarring, concentric luminal narrowing, adventitial scarring, and chronic inflammation
• Bronchiectasis: walls of the cartilaginous bronchi are permanently destroyed, which results in permanent dilation of the airways and accompanied inflammatory changes

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Chronic bronchitis: clinically defined as a productive cough of unknown cause, occurring on most days for 3 or more months for at least 2 successive years; often associated with history of smoking; histologically characterized by chronic inflammation with basement membrane thickening, bronchial epithelial hyperplasia, and goblet cell metaplasia
• Eosinophilic pneumonia: clinical presentation is different from asthma. Patients usually do not have recurrent episodes of wheezing, shortness of breath, and coughing. Also they do not respond well to bronchial dilators. Eosinophilic pneumonia can be idiopathic or secondary to infections, drug administration, or associated with immunologic diseases. Clinical history and accessory tests (e.g., pulmonary function test) are helpful for differential diagnosis

Fig 1 Asthma. Endobronchial biopsy shows asthmatic changes including epithelial sloughing, basement membrane thickening, and marked eosinophilic inflammation.


Fig 2 Asthma. A, Bronchiole is severely affected. It has epithelial hyperplasia, prominent goblet cell metaplasia, basement membrane thickening, smooth muscle hyperplasia, and inflammatory cell infiltration with predominant eosinophils. B and C, Same patient with bronchial involvement. Histological findings are similar to that in the bronchiole.

Fig 3 Asthma. Squamous metaplasia of the bronchiolar epithelium is seen in this treated asthmatic patient without inflammation.

Fig 4 Asthma. Hyperplastic bronchial mucous glands are seen in this patient with history of asthma.
Allergic Bronchopulmonary Aspergillosis

Definition

• Clinical syndrome occurring predominantly in patients with chronic asthma or, less often, bronchiectasis who develop hypersensitivity to Aspergillus fumigatus

Clinical features

Presentation

• Individual with asthma develops peripheral blood eosinophilia, transient pulmonary opacity, elevated total serum IgE, immediate cutaneous reaction to Aspergillus, elevated serum IgG and IgE to Aspergillus, as well as central bronchiectasis
• May have positive sputum culture for aspergillosis

Prognosis and treatment

• Corticosteroid is the main treatment. Itraconazole may play a role in patients with resistance to corticosteroids
• Control the underlying asthmatic disease

Pathology

Histology

• “Allergic mucin” is considered the hallmark of the disease. It is composed of abundant eosinophilic mucin, mixed with eosinophils, eosinophil cytoplasmic debris, occasional Charcot-Leyden crystals as well as calcium oxalate crystals
• Rare fungal hyphae are present in the mucin but do not involve the lung parenchyma or vessels
• Various combinations of asthmatic changes, bronchocentric granulomatosis, and eosinophilic pneumonia are commonly seen

Immunopathology/special stains

• GMS stain highlights the fungal hyphae in most cases, but these are sometimes not identified

Main differential diagnoses

• Eosinophilic pneumonia: eosinophilic inflammation of lung and airways
• Hypersensitivity pneumonia: chronic inflammatory interstitial pneumonia accompanied by poorly formed granulomas with interspersed eosinophils and bronchiolitis
• Invasive fungal pneumonia: granulomatous inflammation with fungal hyphae infiltrating the lung parenchyma and vascular wall
• Churg-Strauss syndrome: combination of eosinophilic pneumonia, asthmatic bronchitis, granulomatous inflammation (allergic granulomas), eosinophilic vasculitis as well as eosinophilic abscesses
• Wegener granulomatosis: systemic disease usually manifested by upper respiratory tract and lung involvement along with glomerulonephritis; associated with increased serum c-ANCA; geographically necrotizing granulomatous inflammation with prominent parenchymal necrosis and vasculitis

Fig 1 Allergic bronchopulmonary aspergillosis. At low power, layers of mucin and inflammatory cells are seen in this plug removed from a 10-year-old with asthma.

Fig 2 Allergic bronchopulmonary aspergillosis. Depending on the preservation of cells and staining, eosinophils may be difficult to identify as in this figure; binucleation is helpful when the granules are pale.

Fig 3 Allergic bronchopulmonary aspergillosis. High power shows the characteristic “allergic” mucin, which is pale blue and intermixed with numerous eosinophils.


Fig 4 Allergic bronchopulmonary aspergillosis. Charcot-Leyden crystals are seen in this high power of allergic mucin.

Fig 5 Allergic bronchopulmonary aspergillosis. GMS stain will often stain parts of the mucin as seen here on the left. Fragmented fungal hyphae are present in the middle.

Fig 6 Allergic bronchopulmonary aspergillosis. GMS stain: overstained hyphae can be difficult to identify as seen here.

Fig 7 Allergic bronchopulmonary aspergillosis. GMS stain: branching helps to confirm that these black structures are indeed fungal hyphae.
Acute Bronchiolitis

Definition

• Acute inflammation of bronchioles with variable epithelial sloughing

Clinical features

Epidemiology

• Most often associated with infections, especially in infants and children, toxic fume or gas inhalation, chemotherapy, or acute aspiration

Presentation

• Children with viral infections present with tachypnea, wheezing, and prolonged expirations
• Adults tend to have few specific symptoms

Prognosis and treatment

• Most patients fully recover, especially from infectious causes
• Patients with an idiopathic cause may respond to antibiotics and immunosuppressive therapy but often progress to decreased lung function

Pathology

Histology

• Extension of acute inflammation into the walls of bronchioles and intraluminal collections of neutrophils as well as mucus
• Frequently associated with chronic bronchiolitis

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Bronchopneumonia: acute inflammation extending from the airways into the adjacent alveoli

Fig 1 Acute bronchiolitis. A, Inflammatory cells infiltrate predominantly the bronchiolar wall; mucostasis with abundant neutrophils in the lumen. B, High magnification reveals that mixed inflammatory cells, with neutrophils predominant, expand the subepithelial space; the bronchiolar epithelial cells are attenuated and focally detached; accumulated mucus with mixed numerous neutrophils.

Fig 2 Acute bronchiolitis. Mixed acute and chronic inflammation with mucostasis is seen here. The inflammation extends into peribronchiolar connective tissue, but most of the adjacent alveolar spaces are open.
Chronic Bronchiolitis

Definition

• Chronic inflammation of the small airways characterized by mixed chronic inflammatory cells within and surrounding the bronchiolar walls

Clinical features

• Nonspecific histological finding, usually associated with a wide variety of lung diseases, including infection, autoimmune diseases, asthma, drugs, radiotherapy, chemotherapy, and transplantation
• Infrequently encountered as the only abnormality on a lung biopsy specimen; its clinical significance is unclear

Prognosis and treatment

• Varies depending on underlying diseases

Pathology

Histology

• Chronic inflammatory cells infiltrating the bronchiolar wall and surrounding peribronchiolar connective tissue
• May see accompanying goblet cell hyperplasia, smooth muscle hyperplasia, and mild luminal narrowing
• Sometimes, prominent accumulation of foamy macrophages infiltrate the bronchiolar walls and accumulate in the lumens

Immunopathology/special stains

• Not contributory

Main differential diagnosis

• Follicular bronchiolitis: chronic inflammation of the small airways with formation of lymphoid follicles containing germinal centers

Fig 1 Chronic bronchiolitis. The mixed chronic inflammatory cells infiltrate the submucosa and are present through the smooth muscle layer of the small airway. The bronchiolar epithelium and adjacent alveoli are unremarkable.

Fig 2 Chronic bronchiolitis. The airway is surrounded by lymphocytic infiltrate and variable distortion with focal bronchiolar epithelial sloughing and luminal mucus mixed with neutrophils. Atelectasis is present in the adjacent alveoli.

Fig 3 Chronic bronchiolitis. Mild fibrosis is present in the submucosa accompanied by minimal luminal narrowing. Chronic inflammation is less prominent.

Fig 4 Chronic bronchiolitis. In this case, predominant foamy macrophages infiltrate the bronchiolar wall and extend into the adjacent lung. There are very few inflammatory cells. The bronchiolar epithelial cells are largely sloughed.
Follicular Bronchiolitis

Definition

• Presence of lymphoid follicles next to and confined to the walls of the airways and associated peribronchial tissues

Clinical features

Epidemiology

• May be associated with collagen vascular diseases (e.g., rheumatoid arthritis), immunodeficiency syndromes (e.g., IgA deficiency, congenital variable immunodeficiency, AIDS), bronchiectasis, obstructive pneumonias, chronic infection, and hypersensitivity syndromes

Presentation

• Varies depending on the underlying disease

Prognosis and treatment

• Varies depending on the underlying disease

Pathology

Histology

• Lymphoid follicles containing reactive germinal centers are present in the walls of bronchioles and occasionally pleura, especially in patients with rheumatoid arthritis
• There may be postobstructive changes such as mucostasis and organizing pneumonia
• Absence of significant lymphoid infiltrate in the adjacent lung parenchyma

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Lymphoid interstitial pneumonia: diffuse interstitial infiltrate of mature lymphocytes and admixture of chronic inflammatory cells; associated with infections (HIV, Epstein-Barr virus, hepatitis viruses) and autoimmune diseases (Sjögren); the spectrum of radiographic changes varies from bilateral streaky densities to reticulonodular opacities
• Nodular lymphoid hyperplasia: considered to be late stage of a healing inflammatory process; nodular lymphoid proliferation associated with fibrosis; masslike lesion on radiographic image
• Lymphomas: clonal expansion of neoplastic lymphoid cells with abnormal immunophenotype and cytogenetic or molecular studies; commonly encountered lymphomas include chronic lymphocytic lymphoma, follicular center cell lymphoma, mantle cell lymphoma, MALT lymphoma, Hodgkin lymphoma

Fig 1 Follicular bronchiolitis. Lymphoid follicles confined to the wall of airway; no significant lymphoid involvement in the adjacent lung parenchyma. The airway is dilated and has mucostasis.

Fig 2 Follicular bronchiolitis. Follicular bronchiolitis with adjacent lung parenchyma showing foci of organizing pneumonia, probably after obstruction.

Fig 3 Follicular bronchiolitis. Follicular pleuritis is seen in this patient with rheumatoid arthritis.
Bronchiolitis Obliterans/Constrictive Bronchiolitis Obliterans/Constrictive Bronchiolitis

Definition

• Small airway disease in which variable narrowing or obliteration of airway lumens is seen

Clinical features

Epidemiology

• Most often seen as a manifestation of chronic rejection and graft-versus-host disease in lung transplant and bone marrow transplant recipient, respectively (see Lung Transplantation)
• Associated with different causes, such as infection, drug reaction, radiation, toxic fume exposure (discussed here)

Presentation

• Progressive dyspnea and cough
• Pulmonary function tests show airway obstruction with variable restrictive defects
• Variable chest X-ray findings: ground glass opacities, bronchial wall thickening, overinflation, usually without infiltrates

Prognosis and treatment

• Progressive disease; many patients undergo lung transplantation
• Immunosuppressant and cytotoxic therapy

Pathology

Histology

• In the early stages: concentric and “onion skin” fibrosis beneath the bronchiolar epithelium. Bronchiolar epithelium is compressed and lumen is narrowed
• In the late stages: the lumen is completely occluded by the fibrosis
• Uninvolved lung parenchyma shows obstructive changes or is unremarkable

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Bronchiolitis obliterans–organizing pneumonia: old term for cryptogenic organizing pneumonia that has intraluminal Masson bodies
• Chronic bronchiolitis: predominant peribronchiolar inflammation and periluminal fibrosis

Fig 1 Bronchiolitis obliterans. A, Subtle subepithelial fibrosis and no significant inflammation of bronchiole and alveolar spaces; the lumen is widely open. B, The trichrome stain shows concentric subepithelial fibrosis.


Fig 2 Bronchiolitis obliterans. A, The lumen is narrowed by the concentric subepithelial fibrosis. Smooth muscle layer is distorted, and epithelium is partially attenuated. The adjacent pulmonary acini are unremarkable. B, Trichrome stain highlights fibrosis.

Fig 3 Bronchiolitis obliterans. The lumen is obliterated by the fibrosis. The bronchiole is identifiable only by the presence of smooth muscle bundles or discontinuous elastic tissue around a central scar.
Emphysema

Definition

• Destruction of acinar walls resulting in permanent enlargement of airspaces that are distal to terminal bronchioles; usually no significant fibrosis
• Subclassified into three types according to the portion of affected pulmonary acini: proximal acinar (centrilobular) emphysema, panacinar emphysema, and distal acinar emphysema

Clinical features

Epidemiology

• Tobacco smokers most often have proximal acinar emphysema
• Patients with α1-antitrypsin (A1AT) deficiency usually develop panacinar emphysema
• Patients with spontaneous pneumothorax have distal acinar or irregular emphysema
• Other risk factors include marijuana abuse and dust and chemical exposure

Presentation

• Progressive dyspnea
• Decreased breath sounds, crackles at the bases, distant heart sounds, and depressed diaphragm
• Radiographic images: evidence of overinflation characterized by increased radiolucency of the lungs, flat diaphragm, decreased heart shadow
• Pulmonary function tests: airflow obstruction

Prognosis and treatment

• Stop smoking and avoid adverse stimulators to halt further lung damage
• Patient with A1AT deficiency: goal of treatment is to increase A1AT level in serum and lung interstitium; current major approach is intravenous augmentation therapy by infusion of pooled human A1AT
• Treated symptomatically with anticholinergics, bronchodilators, corticosteroids as well as supplemental oxygen
• At the late stage of the disease, the damage becomes irreversible; patient may need lung volume reduction surgery or a lung transplant

Pathology

Gross

• Terminal airways are dilated and form many cavities

Histology

• Microscopically, there is destruction of acinar walls and dilatation of the airspaces
• Bronchial metaplasia is often present
• Usually not associated with significant inflammation or fibrosis
• Panacinar emphysema: the acinus is uniformly involved; the lower lobes are more predominantly involved
• Proximal acinar emphysema: proximal portion of the acinus around respiratory bronchiole is predominantly involved; upper lobes are more severely affected
• Distal acinar emphysema: the distal acinus, along the interlobular septa and close to pleura, is affected; may form blebs and bullae; spontaneous pneumothorax

Immunopathology/special stains

• Not contributory

Main differential diagnosis

• Congenital lobar emphysema: occurs in infants, congenital malformation of the lung characterized by hyperinflation of one or more pulmonary lobes

Fig 1 Emphysema. Gross photograph of cut surface of formalin-inflated lung shows relatively uniform enlarged acini in this patient with A1AT deficiency.

Fig 2 Emphysema. Alveolar spaces are markedly enlarged while the alveolar walls are of normal thickness (i.e., without fibrosis).


Fig 3 Emphysema. Emphysema and bronchial epithelial metaplasia (occurring in a smoker): some of the alveolar walls are lined by metaplastic bronchial epithelium; low (A) and high (B) powers. Note focal interstitial fibrosis.

Fig 4 Emphysema. Anthracotic pigment is often present in smokers with emphysema, as seen here.

Fig 5 Emphysema. Pulmonary hypertensive changes (intimal fibrosis and muscle hyperplasia) are present in this patient with emphysema.
F
Restrictive (Interstitial) Lung Diseases
Pulmonary Edema

Definition

• An abnormal accumulation of fluid in pulmonary interstitium and alveoli

Pathogenesis

• Increased vascular permeability due to a spectrum of endothelial and epithelial injuries of the lung leading to one or more of the following:
• Increased capillary hydrostatic pressure
• Increased capillary permeability
• Decreased plasma oncotic pressure
• Lymphatic obstruction

Clinical features

Epidemiology

• Incidence varies with inciting cause; left-sided heart failure is the main cause
• Other reasons include lung injury, pneumonia, toxins, medications, and living at high altitude

Presentation

• Shortness of breath, anxiety, and a feeling of drowning
• In patients with long-standing pulmonary edema there may be dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, or coughing
• Radiological features include butterfly pattern of lung infiltrates, pleural effusion(s), Kerley B lines, and loss in radiological sharpness of the vasculature

Prognosis and treatment

• Pulmonary edema can be fatal; therapy and outcome depend on the underlying etiology
• 20% mortality in intensive care unit patients
• Prompt treatment of pulmonary edema along with treatment of the underlying cause improves survival

Pathology

• Gross appearance: heavy lungs, frothy exudates, and dark blue to red cut surface. In long-standing pulmonary edema the cut surface may be firm and brown
• Microscopic appearance
• Pale pink homogenous fluid in alveolar spaces
• Congestion
• Leakage of some red blood cells into airspaces
• In patients with long-standing pulmonary edema, hemosiderin-laden macrophages are present and there may be alveolar septal thickening and fibrosis

Main differential diagnoses

• Diffuse alveolar damage (DAD): presence of hyaline membranes
• Alveolar proteinosis: accumulation of granular proteinaceous material in alveoli
• Fibrin exudates: dark pink strands of fibrin can be seen
• Pneumocystis jiroveci pneumonia

Fig 1 Pulmonary edema. H&E stain of lung section showing alveoli filled with pink proteinaceous material in a patient with heart failure. Note congested vessels in alveolar septa.

Fig 2 Pulmonary edema. Pulmonary edema is often not uniform: some alveoli are completely filled and others only partially, as seen in this figure.


Fig 3 Pulmonary edema. Prussian blue stain highlights hemosiderin-laden macrophages in this patient with congestive heart failure who also has intraalveolar edema.

Fig 4 Pulmonary edema. Ventilator therapy pushes the pale edema fluid to the walls of the alveoli, which suggests the differential diagnosis of DAD.

Fig 5 Pulmonary edema. Hyaline membranes in DAD are bright pink (eosinophilic).
Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS), Diffuse Alveolar Damage (DAD)

Definition

• Temporally uniform acute respiratory insufficiency defined clinically by oxygen requirement, chest infiltrates, and increased pulmonary wedge pressure; also referred to as noncardiogenic pulmonary edema
• There is a spectrum of severity of lung injury in ALI; the most severe disease is termed ARDS
• DAD is the morphological appearance of the lung in ALI/ARDS manifested by formation of hyaline membranes

Pathogenesis

• ALI can be secondary to various forms of lung injury, including sepsis, shock, trauma, and ventilation therapy
• Initial injury leads to the release of inflammatory cytokines, which leads to further injury
• Damage of endothelial and/or epithelial cells leads to leakage of plasma proteins and necrosis of pneumocytes forming hyaline membranes

Clinical features

Epidemiology

• 150,000 new cases per year in the United States

Presentation

• Severe dyspnea, hypoxemia, rapidly progressive respiratory failure
• Intubation within 72 hours in 90% of cases
• Radiological findings include diffuse airspace consolidation and progressive linear opacities with evolving fibrosis

Prognosis and treatment

• High mortality rate (intensive care setting, 37%; overall mortality, 42%)
• Predictors of better prognosis
• Survival in the first 2 weeks
• Age <55 years
• Predictors of poor prognosis
• Age >70 years
• Immunocompromised state
• Chronic liver disease
• Of the survivors, about 50% have residual pulmonary fibrosis

Pathology

• Exudative phase (day 1-7):
• Gross appearance: heavy, dark red, and consolidated
• Microscopic findings:
– Intraalveolar edema
– Dense, eosinophilic hyaline membranes most prominent along the alveolar ducts
– Endothelial cell swelling with widening of interendothelial junctions and intravascular thrombi
– Sparse numbers of neutrophils seen in the alveolar spaces
• Proliferative phase (day 7-21):
• Gross appearance: firm, yellow-gray, and airless
• Microscopic findings:
– Myxoid interstitial fibrosis
– Epithelial cell regeneration; cuboidal cells lining the alveolar wall
– Epithelial cell nuclei are large and vesicular with prominent nucleoli
– Fibroblasts and myofibroblast proliferation and migration through the alveolar basement membrane converting the hyaline membranes into sparsely cellular, dense, fibrous tissue
– Intraalveolar fibrosis may be present
• Fibrotic phase (>21 days):
• Gross appearance: firm, yellow-gray, and airless
• Microscopic findings:
– Alveolar septa composed of thickened, sparsely cellular, collagenous connective tissue
– Irregular enlargement of airspaces

Main differential diagnoses

• Acute pneumonia: significant numbers of intraalveolar neutrophils
• Organizing pneumonia: intraalveolar fibrosis but no hyaline membranes or alveolar wall fibrosis
• Nonspecific interstitial pneumonia: mild interstitial fibrosis with or without chronic inflammation; no hyaline membranes
• Usual interstitial pneumonia: patchy fibrosis with temporal heterogeneity
• Alveolar hemorrhage: intraalveolar fibrin accompanying red cells

Fig 1 Acute lung injury. A 47-year-old with a history of viral pneumonia and ARDS; at autopsy bright pink hyaline membranes are seen lining the alveolar walls.


Fig 2 Acute lung injury. High power showing DAD. Note lack of inflammatory cells.

Fig 3 Acute lung injury. A 55-year-old with progressively worsening respiratory failure after chemotherapy. Wedge biopsy shows early organization of hyaline membranes.

Fig 4 Acute lung injury. An 84-year-old female with hypertension, congestive heart failure, and atrial fibrillation; at autopsy the lungs showed organizing DAD. There is early fibrosis of interstitium as well as some intraalveolar fibrosis seen here at low power.

Fig 5 Acute lung injury. High power of same patient seen in Fig 4 shows enlarged reactive type II pneumocytes.

Fig 6 Acute lung injury. Organizing pneumonia showing intraalveolar Masson bodies; adjacent lung is collapsed but normal.
Acute Interstitial Pneumonia (AIP)

Definition

• Rapidly progressive form of idiopathic interstitial pneumonia with diffuse alveolar damage (DAD) and respiratory failure
• Synonymous with Hamman-Rich syndrome, occurring in patients without preexisting lung disease

Pathogenesis

• Etiology and mechanism of injury unknown

Clinical features

Epidemiology

• Mean age 50 years with a wide range
• No gender predilection

Presentation

• Generally occurs in previously healthy individuals without a history of lung disease who present with symptoms suggestive of upper respiratory tract viral infection and acute respiratory failure (<3 weeks’ duration)
• Pulmonary function tests show a restrictive pattern
• Similar in presentation to acute respiratory distress syndrome (ARDS); probably corresponds to a subset of idiopathic ARDS
• High-resolution CT shows ground-glass attenuation, bronchial dilatation, and architectural distortion

Prognosis and treatment

• Management is largely supportive and consists of oxygen supplementation; ventilation with positive end-expiratory pressure eventually needed
• Greater than 70% mortality in 3 months, despite mechanical ventilation
• In the surviving population, recurrences and chronic interstitial disease are common

Pathology

Histology

• Characterized by the histological pattern of DAD. AIP cannot be distinguished from DAD on histology alone (see DAD section)

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• ARDS: known etiology
• Idiopathic pulmonary fibrosis/usual interstitial pneumonia: patchy fibrosis varying in intensity and time (fibroblastic foci)
• Organizing pneumonia: intraalveolar Masson bodies

Fig 1 Acute interstitial pneumonia. A 72-year-old patient seen with increasing shortness of breath. Wedge lung biopsy shows patchy hyaline membranes. Note that the word diffuse in diffuse alveolar damage implies that the whole alveolus is involved, not the whole lung.

Fig 2 Acute interstitial pneumonia. High power shows bright pink hyaline membranes. There is interstitial edema and early fibrosis.
Usual Interstitial Pneumonia (UIP)

Definition

• Chronic progressive lung injury with parenchymal remodeling characterized by patchy fibrosis with fibroblastic foci and often honeycombing

Clinical features

Epidemiology

• Most common form of chronic interstitial pneumonia; incidence of 7 to 10 cases per 100,000 and prevalence of 13 to 20/100,000
• Most patients are 50 to 70 years old; male to female ratio, 2:1
• A history of smoking is present in 60% of patients
• Familial cases reported especially in younger patients
• UIP is a histological pattern that may be associated with a clinical diagnosis of idiopathic pulmonary fibrosis (IPF), collagen vascular disease, drug toxicity, chronic hypersensitivity pneumonia, asbestosis, familial IPF, or Hermansky-Pudlak syndrome

Presentation

• Progressively worsening dyspnea over months
• High-resolution CT is often diagnostic with lower lobe predominance, patchy subpleural distribution of fibrosis, honeycombing, and traction bronchiectasis

Prognosis and treatment

• Poor prognosis; median survival, 3 years
• Steroid therapy provides no survival benefit
• Lung transplantation is the only definitive therapy

Pathology

Histology

• Patchy fibrosis with subpleural/paraseptal distribution with minimal interstitial inflammation throughout the lung but most severe in the lower lobes
• Spatial variegation: areas of prominent interstitial fibrosis adjacent to normal-appearing lung parenchyma
• Architectural distortion of the lung parenchyma represented by honeycombing: cystically dilated bronchioles lined by ciliated columnar respiratory epithelium within areas of fibrosis
• Temporal heterogeneity: areas of chronic scarring (dense, pink fibrosis) adjacent to areas of active, acute injury (pale, light blue, myxoid fibroblastic foci)
• Fibroblastic foci consist of small palisades of fibroblasts beneath hyperplastic type II pneumocytes or bronchiolar epithelium arranged parallel to the long axis of the alveolar septa
• Minimal interstitial inflammation away from areas of fibrosis
• Decreased vascularity in areas of dense fibrosis
• Secondary traction bronchiectasis and peribronchiolar fibrosis with associated epithelial hyperplasia (“peribronchiolar metaplasia”) can also occur
• Granulomas are absent or rare; when present they are small, poorly formed and nonnecrotizing
• During severe exacerbation, hyaline membranes (diffuse alveolar damage) may be seen

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Chronic hypersensitivity pneumonia with fibrosis: upper lobe predominance and small poorly formed granulomas
• Langerhans cell histiocytosis
• Organizing pneumonia

Fig 1 Usual interstitial pneumonia. Gross photograph of cut surface of lung with UIP. Note the patchy fibrosis most marked in the lower lobe.

Fig 2 Usual interstitial pneumonia. UIP with patchy fibrosis and minimal interstitial inflammation. Note the variation of fibrosis from dense area to almost normal septae.


Fig 3 Usual interstitial pneumonia. UIP with architectural distortion, spatial variegation, and temporal heterogeneity. Note the presence of mild inflammation, including lymphocytes and eosinophils within area of fibrosis.

Fig 4 Usual interstitial pneumonia. Fibroblastic foci appear parallel to the lung air interface (A) or may be rounded but still subepithelial in location (B) depending on the cut.

Fig 5 Usual interstitial pneumonia. This low power of UIP shows extensive honeycombing and multiple fibroblastic foci.
Nonspecific Interstitial Pneumonia (NSIP)

Definition

• NSIP is a chronic idiopathic lung disease with interstitial widening that does not have features of usual interstitial pneumonia (UIP) and has a good prognosis
• Subtypes: cellular, fibrotic, and mixed

Clinical features

Epidemiology

• Second most common type of chronic interstitial pneumonia
• Usually affects people in their early to mid 50s; the cellular subtype is seen earlier in life. It can also develop in children or the elderly
• Slight predominance in women
• Most common interstitial pneumonia in patients with collagen vascular disease

Presentation

• Coughing and dyspnea occurring over a period of several months
• Systemic symptoms, such as fever, are occasionally present

Prognosis and treatment

• In general much better prognosis than UIP
• Nearly all patients with cellular NSIP are alive at 10 years
• Only one third of the patients with fibrotic NSIP are alive at 10 years
• Mixed pattern has a better prognosis than fibrotic variant but not as favorable as cellular
• Corticosteroids are the mainstay of therapy

Pathology

Histology

• Cellular NSIP:
• Uniform in intensity and time, mild diffuse or patchy, interstitial lymphoplasmacytic infiltrate with minimal fibrosis and preservation of lung architecture
• Prominent type II pneumocyte hyperplasia
• Focal organizing pneumonia, lymphoid aggregates, and alveolar macrophages may be present
• Lack of dense fibrosis, honeycombing, granulomas, eosinophils, neutrophils, organisms, hyaline membranes, and necrosis
• Fibrotic NSIP:
• Prominent interstitial fibrosis causing uniform thickening of alveolar walls with preservation of lung architecture and mild lymphocytic inflammation
• Fibroblastic foci are inconspicuous or insignificant in number and lack temporal heterogeneity and honeycombing of UIP
• Organizing pneumonia, lymphoid aggregates, alveolar macrophages, bronchial metaplasia, and metaplastic calcifications/bone formation may be present
• Inconspicuous to rare granulomas and no eosinophils or organisms
• Mixed NSIP:
• Has both inflammation and fibrosis but no fibroblastic foci or honeycombing

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• UIP: patchy fibrosis that distorts/destroys the lung architecture together with fibroblastic foci are the main differentiating features
• Hypersensitivity pneumonitis: poorly formed granulomas and mixed inflammatory infiltrates including eosinophils are characteristic
• Lymphocytic interstitial pneumonia: once low-grade lymphomas are excluded, almost all cases are associated with HIV infection or other immunodeficiency diseases; much more inflammation than NSIP
• Organizing pneumonia: intraalveolar nodules of fibrosis (Masson bodies)
• Diffuse alveolar damage: organizing hyaline membranes

Fig 1 Nonspecific interstitial pneumonia. Cellular variant with uniform, diffuse interstitial lymphoplasmacytic infiltrate, minimal fibrosis, and preservation of lung architecture is seen in this 14-year-old female with juvenile rheumatoid arthritis.

Fig 2 Nonspecific interstitial pneumonia. High-power image of NSIP, cellular variant (same case as in Fig 1 ).


Fig 3 Nonspecific interstitial pneumonia. Cellular variant with multiple lymphoid aggregates (same case as in Fig 1 ).

Fig 4 Nonspecific interstitial pneumonia. Fibrotic variant with uniform interstitial fibrosis and thickening of the alveolar septae, low power.

Fig 5 Nonspecific interstitial pneumonia. Fibrotic variant, high power.

Fig 6 Nonspecific interstitial pneumonia. Fibrotic variant with area of bronchiolar metaplasia. Note absence of honeycombing and fibroblastic foci.

Fig 7 Nonspecific interstitial pneumonia, mixed variant. Both mild chronic inflammation and fibrosis are present in the alveolar septae, low power.

Fig 8 Nonspecific interstitial pneumonia. Mixed variant. High power of Fig 7 .
Cryptogenic Organizing Pneumonia (COP)

Definition

• Idiopathic active fibrosing process involving distal bronchioles, alveolar ducts, and peribronchiolar alveoli with subsequent filling of the airspaces

Clinical features

Epidemiology

• Mean age of onset is 55 years
• Cigarette exposure is not a predisposing factor

Presentation

• Subacute illness consisting of coughing and dyspnea with associated weight loss, sweats, chills, fever, and myalgia developing over several weeks to few months

Prognosis and treatment

• Corticosteroids are the mainstay of therapy
• High relapse rate within 1 to 3 months after cessation of therapy but good long-term outcome

Pathology

Histology

• Active fibrosis involving bronchiolar lumens and peribronchiolar spaces forming intraluminal plugs (Masson bodies) composed of fibroblasts and myofibroblasts, embedded in a loose connective tissue causing airspace occlusion
• Intraluminal plugs extend into adjacent alveoli via the interalveolar pores of Kohn giving a “butterfly” pattern
• Plugs maybe covered with alveolar or bronchiolar epithelial cells
• Lymphocytes, plasma cells, neutrophils, and histiocytes may be present within the plugs
• The bronchiolar component may be minor or not present in the specimen
• Increased capillary proliferation within the plugs resembling granulation tissue
• Patchy, bronchiolocentric distribution with preservation of lung architecture, although sharply demarcated from adjacent normal lung
• Mild chronic interstitial inflammation with foci of foamy macrophages (endogenous lipoid pneumonia) in alveoli not filled with plugs (postobstructive phenomenon)
• Lacks honeycombing, interstitial fibrosis, granulomas, abscess formation, necrosis, hyaline membranes, or airspace fibrin, eosinophilic infiltrates, and vasculitis

Immunopathology/special stains

• Movat stain will show green staining of the loose connective tissue, as opposed to yellow staining seen in dense fibrosis

Main differential diagnoses

• Known lung injuries: organizing pneumonia is commonly seen in resolving infection and rejection, adjacent to tumors, and as part of obstructive pneumonitis
• Usual interstitial pneumonia (UIP): patchy dense fibrosis with honeycombing and fibroblastic foci
• Nonspecific interstitial pneumonia (NSIP): involves alveolar septae rather than alveolar spaces
• Desquamative interstitial pneumonia (DIP): intraalveolar accumulation of smoker’s macrophages without fibrosis
• Acute interstitial pneumonia/diffuse alveolar damage (AIP/DAD): hyaline membranes early; organizing stage can have both interstitial and intraalveolar fibrosis

Fig 1 COP can be diagnosed on transbronchial biopsy, as seen here; low (A) and high (B) powers. Note characteristic intraalveolar Masson bodies.


Fig 2 Cryptogenic organizing pneumonia. Macrophages and lymphocytes are present in the center of this large fibroblastic plug (Masson body).

Fig 3 Cryptogenic organizing pneumonia. Trichrome stain highlights in blue elongated fibroblastic plugs that are extending between alveoli via pores of Kohn. When cut in cross-section, the plug appears rounded (right edge in the middle).

Fig 4 Cryptogenic organizing pneumonia. This high-power view of lung specimen in a patient with COP shows intraalveolar foamy macrophages (postobstructive change).
IgG4-Related Sclerosing Disease

Definition

• A fibrosing inflammatory disease associated with an infiltration of IgG4-positive plasma cells

Clinical features

Epidemiology

• Occurs mainly in adults; male predominance

Presentation

• Patients may be asymptomatic or present with coughing, dyspnea, hemoptysis, or pleural effusion
• Imaging may show ground-glass opacities, lung nodules, peribronchial consolidation, or hilar lymphadenopathy
• Elevated serum levels of IgG4
• Patients frequently have IgG4-related disease in other organs

Prognosis and treatment

• This is a benign condition that responds well to steroids and immunosuppression

Pathology

Gross

• Solid nodular type: distinct gray nodules, more often located peripherally
• Alveolar interstitial type: firm parenchyma and thickened pleura
• Bronchovascular type: irregular areas of fibrosis

Histology

• Inflammatory infiltrate consisting of lymphocytes, plasma cells, and eosinophils
• Lymphoid follicles are present in approximately 50% of cases
• Veins and arteries are commonly involved by a subendothelial lymphoplasmacytic infiltrate that obliterates the lumen
• If involved, the pleura may demonstrate fibrous thickening, fibrinous exudate, and chronic inflammation
• There are several histological patterns:
• Solid nodular (also called inflammatory pseudotumor with IgG4+ plasma cells):
– Tumor-like lesion with sclerosis and lymphoplasmacytic infiltrate
– Surrounding alveoli infiltrated by lymphocytes and plasma cells
– Inflammation and sclerosis of the bronchial wall and bronchial glands
• Bronchovascular:
– Lymphoplasmacytic infiltrate surrounding the bronchovascular bundles and within the alveolar interstitium, interlobular septa, and pleura
– Lymphatics may be filled with histiocytes demonstrating emperipolesis of lymphocytes
• Alveolar interstitial:
– Lymphoplasmacytic infiltrate is present in the alveolar interstitium
– Nonspecific interstitial pneumonia (NSIP) pattern

Immunopathology/special stains

• Increased IgG4+ plasma cells (>50 per high-power field with IgG4/IgG ratio >40%); however, criteria vary in the literature

Main differential diagnoses

• Multicentric Castleman disease
• Connective tissue disease–related lung diseases (e.g., NSIP)

Fig 1 IgG4-related sclerosing disease. Immunohistochemical stain for IgG4 shows many positive plasma cells.


Fig 2 IgG4-related sclerosing disease. NSIP-like pattern of IgG4-related lung disease with varying amounts of lymphoplasmacytic infiltrates in the interstitium (A-C) and airway (D). Note that this case has very little fibrosis.
Rheumatoid Arthritis (RA)
Pulmonary involvement in systemic disease requires clinicopathological correlation. While the majority of patients will already have a diagnosis of a connective tissue disease before the onset of pulmonary symptoms, a few may not, in which case the features described can be suggestive of an association with a connective tissue disease, prompting the clinician to further work up this possibility. Although there are specific features associated with some of the individual diseases, there are many overlaps; therefore, the exact systemic disease cannot be diagnosed based on lung involvement alone. Common features include a pattern of nonspecific interstitial pneumonia (NSIP) alone or in combination with usual interstitial pneumonia (UIP) and heavy chronic inflammatory infiltrate, often with germinal centers.

Definition

• A chronic autoimmune disease with systemic manifestations, including pulmonary involvement by a variety of pathologies

Clinical features

Epidemiology

• In patients with RA, up to half will have lung disease, about a quarter of which will be clinically significant
• Although RA is more common in women, RA-associated lung disease is more common in men
• Lung disease is more common in RA patients who are also smokers

Presentation

• Lung disease is usually diagnosed in patients with known RA; however, rarely, lung disease can precede other RA manifestations
• Positive serologic test for rheumatoid factor or anti-citrullinated protein antibody
• Shortness of breath and coughing
• Imaging may show ground-glass opacities or reticulonodular pattern on CT
• Lung hyperinflation with dyspnea is suggestive of bronchiolitis obliterans

Prognosis and treatment

• RA patients with lung disease have a worse prognosis than RA patients without lung disease
• RA patients with usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP) patterns have a better prognosis than those patients with idiopathic UIP or NSIP
• Bronchiolitis obliterans has a worse outcome
• Immunosuppressive therapies for RA, including corticosteroids, methotrexate, and azathioprine

Pathology

Histology

• Pleural involvement is common and can include lymphoid aggregates with germinal centers, fibrosis, fibrin deposition associated with effusion, mesothelial hyperplasia, multinucleated giant cells, and rheumatoid nodules
• Parenchymal lymphoid aggregates with germinal centers, especially around airways and along interlobular septa (follicular bronchiolitis)
• Chronic lung injury patterns (interstitial fibrosis, lymphoplasmacytic interstitial inflammation [i.e., UIP or NSIP patterns]) with superimposed subacute patterns (organizing diffuse alveolar damage, organizing pneumonia, reactive type II pneumocytes)
• Parenchymal rheumatoid nodules (fibrinoid material with palisading histiocytes) and reactive intrapulmonary lymph nodes may be present
• Other findings may include nonnecrotizing vasculitis, capillaritis, secondary pulmonary hypertensive change, secondary amyloidosis, pulmonary hemorrhage, bronchiolitis obliterans, bronchiectasis, eosinophilic infiltrate, and granulomas
• Look for evidence of superimposed drug reaction or infection

Immunopathology/special stains

• IgM and IgG may be demonstrated in the alveolar septa and capillaries by immunofluorescence, although this is not routinely done

Main differential diagnoses

• Idiopathic interstitial pneumonias (UIP, NSIP, organizing pneumonia): should not have prominent lymphoid aggregates with germinal centers and pleural involvement
• Lung disease associated with other connective tissue diseases
• Hypersensitivity pneumonitis
• Other causes of follicular bronchiolitis
• Wegener granulomatosis: c-ANCA positive in 90%; correlates with clinical presentation

Fig 1 Rheumatoid arthritis. Areas of fibrosis with lymphoid aggregates, bronchial metaplasia, and mucostasis, consistent with UIP are present in this patient with RA.

Fig 2 Rheumatoid arthritis. Hyaline membranes indicative of diffuse alveolar damage are present in other sections from the same patient.

Fig 3 Rheumatoid arthritis. This pulmonary rheumatoid nodule has central neutrophils and fibrin surrounded by palisading histiocytes. Wegener granulomatosis would be in the differential diagnosis.

Fig 4 Rheumatoid arthritis. Pleural involvement in this case of RA consists of lymphoid aggregates, fibrosis, mesothelial hyperplasia, and fibrin deposition.

Fig 5 Rheumatoid arthritis. Follicular bronchiolitis is prominent in this 14-year-old with juvenile RA and pulmonary fibrosis.
Systemic Lupus Erythematosus (SLE)

Definition

• A systemic autoimmune disease with a variety of pleuropulmonary manifestations that may often be the presenting symptom

Clinical features

Epidemiology

• More than half of SLE patients have pleuropulmonary symptoms
• Most common manifestations involve the pleura
• Acute lupus pneumonitis and diffuse alveolar hemorrhage are uncommon

Presentation

• Cough, fever, dyspnea, and pleuritic pain due to fibrinous pleuritis, pleural effusion, and pleural fibrosis
• Alveolar infiltrates seen predominantly in the lower lobe on CT scan; hypoxemia, fever, cough, and dyspnea with rapid onset due to acute lupus pneumonitis
• Hemoptysis, decreased hematocrit, dyspnea, and fever developing over a few days because of diffuse alveolar hemorrhage
• Catastrophic antiphospholipid antibody syndrome presents with acute respiratory distress syndrome and pulmonary thromboemboli
• SLE patients with pleuropulmonary involvement often have high serum rheumatoid factor and anti-nuclear antibody titers

Prognosis and treatment

• Pleural effusion resolves spontaneously or with corticosteroid treatment
• Corticosteroids and methotrexate are effective treatments for interstitial lung disease associated with SLE
• Acute lupus pneumonitis and diffuse alveolar hemorrhage can be treated with high-dose corticosteroids, cyclophosphamide, and plasmapheresis but carry high mortality rates
• High mortality rates for catastrophic antiphospholipid antibody syndrome can be partially overcome by treatment with corticosteroids, plasmapheresis, intravenous immunoglobulin, and anticoagulation

Pathology

Histology

• Pleural effusion has numerous neutrophils and mononuclear cells; lupus erythematosus cells can also be seen
• Pleura with fibrosis, lymphoplasmacytic infiltrate, and fibrinous exudates
• Interstitial lung disease: most often nonspecific interstitial pneumonia in fibrotic or cellular phase, as well as associated follicular or obliterative bronchiolitis and organizing pneumonia
• Pulmonary hypertensive changes, including perivascular fibrosis, medial hypertrophy, and intimal fibrosis
• Lung biopsy of acute lupus pneumonitis shows diffuse alveolar damage and may also show organizing pneumonia, nonspecific interstitial inflammation, and alveolar edema
• Necrotizing vasculitis of capillaries and arterioles, intraalveolar hemorrhage, and alveolar septal necrosis are seen in diffuse alveolar hemorrhage associated with SLE
• Pulmonary thromboemboli and infarction
• Catastrophic antiphospholipid antibody syndrome shows pulmonary thromboemboli, diffuse alveolar damage, and alveolar hemorrhage
• Rarely, amyloidosis

Immunopathology/special stains

• Immunofluorescent staining by immunoglobulin and complement shows a granular pattern along the capillary basement membranes, as well as the alveolar pneumocytes and mesothelial cell nuclei

Main differential diagnoses

• Acute lupus pneumonitis and diffuse alveolar hemorrhage: must rule out bacterial, fungal, and viral infection
• Other causes of alveolar hemorrhage and small vessel vasculitis, including microscopic polyangiitis and Goodpasture’s syndrome
• Other causes of diffuse alveolar damage, nonspecific interstitial lung disease, pulmonary hypertensive changes, and pleural fibrosis and effusion

Fig 1 Systemic lupus erythematosus. An area of nonspecific interstitial pneumonia (lower left) can be seen merging with an area of usual interstitial pneumonia (right) in this patient with SLE.

Fig 2 Systemic lupus erythematosus. Intense chronic inflammation, as seen in this SLE patient, is typical in many types of connective tissue disease–associated interstitial lung disease.

Fig 3 Systemic lupus erythematosus. The presence of a germinal center (far right) in interstitial lung disease strongly suggests an associated connective tissue disease.

Fig 4 Systemic lupus erythematosus. Alveolar hemorrhage with hemosiderin-laden macrophages is seen in this section from a patient with SLE.

Fig 5 Systemic lupus erythematosus. Follicular bronchiolitis can be seen in patients with SLE.
Scleroderma

Definition

• A progressive sclerosing autoimmune disease with frequent lung involvement

Clinical features

Epidemiology

• Almost half of patients with scleroderma develop a fibrosing lung disease
• About a quarter of scleroderma patients develop pulmonary hypertension

Presentation

• Lung disease almost always presents in patients with known scleroderma, and only rarely precedes a diagnosis of scleroderma
• Dyspnea on exertion and dry coughing
• Reticulonodular pattern and ground-glass opacities on chest CT involving the lower lobes

Prognosis and treatment

• Patients with scleroderma and lung disease have a worse prognosis than those without lung disease and have an increased incidence of primary lung adenocarcinoma
• Lung disease and pulmonary hypertension are major causes of death in patients with scleroderma
• Immunosuppressive therapy may stabilize or improve lung function and CT changes

Pathology

Histology

• Interstitial fibrosis predominant in the lower lobes with nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP) patterns
• Early disease has preserved underlying lung architecture with diffuse interstitial fibrosis, in a fibrotic NSIP pattern
• Later disease has more florid fibrosis with loss of lung architecture, resembling UIP pattern, but usually without fibroblastic foci
• Other findings may include chronic aspiration changes, organizing pneumonia, alveolar hemorrhage, adenocarcinoma, and, rarely, diffuse alveolar damage
• Pleural fibrosis and adhesions
• Secondary pulmonary hypertensive changes characterized by medial and intimal hypertrophy of pulmonary arteries and arterioles; also mucinous degeneration of the media, elastic fiber disruption, and concentric intimal fibrosis may be seen

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Other causes of NSIP or UIP pattern interstitial lung disease

Fig 1 Scleroderma. Combined features of NSIP (left) and UIP (right) patterns of interstitial lung disease are present in this patient with scleroderma.

Fig 2 Scleroderma. Florid interstitial fibrosis with bronchiolar metaplasia and mucostasis without obvious fibroblastic foci are seen in this section of lung from a patient with scleroderma.

Fig 3 Scleroderma. Alveolar foamy macrophages consistent with postobstructive pneumonitis are seen at high power.

Fig 4 Scleroderma. Severe secondary pulmonary hypertensive change with myxoid features is seen in the same patient as in Figs 2 and 3 .

Fig 5 Scleroderma. Pleural and subpleural pulmonary fibrosis is seen here in an area of early UIP. Note fibroblastic focus.
Polymyositis and Dermatomyositis–Associated Lung Disease

Definition

• A chronic interstitial lung disease which is part of the disease spectrum of polymyositis/dermatomyositis (PM/DM)

Clinical features

Epidemiology

• Interstitial lung disease occurs in about a third of patients with PM/DM and can be associated with the presence of antisynthetase antibodies, such as anti-Jo1 (antisynthetase syndrome)
• Lung involvement can occur at any age but most often affects older women
• Most patients present with lung involvement already have a diagnosis of PM/DM; however, lung disease may occasionally present first

Presentation

• Dyspnea, nonproductive cough, fever
• Acute respiratory distress syndrome (ARDS) may precede the diagnosis of PM/DM
• Can be asymptomatic with early chest CT changes, including ground-glass and linear opacities at the lung bases, and restrictive pattern on pulmonary function tests
• Aspiration pneumonia can occur due to respiratory muscle dysfunction
• Infectious bronchopneumonia can occur as a complication of immunosuppressive therapy

Prognosis and treatment

• ARDS/diffuse alveolar damage (DAD) and interstitial lung disease: treat with corticosteroids and other immunosuppressants; poor prognosis despite current therapy
• Complications from lung disease are a common cause of morbidity and mortality in patients with PM/DM

Pathology

Histology

• DAD: hyaline membranes, vascular thrombi
• Nonspecific interstitial pneumonia (NSIP) or mixed NSIP and usual interstitial pneumonia (UIP):
• NSIP: cellular or mixed cellular and fibrotic forms are characterized by uniform widening of alveolar septa by chronic inflammatory cells and fibroblasts
• UIP pattern: more solid patches of fibrosis and microscopic honeycombing resembling idiopathic UIP, but fibroblastic foci are rare and the fibrosis is not necessarily subpleural in PM/DM
• Organizing pneumonia: fibroblast nodules within alveolar spaces; may be seen alone or in combination with NSIP
• Superimposed aspiration pneumonia: clusters of giant cells, foamy macrophages, and polarizable material
• Superimposed infectious bronchopneumonia: acute inflammatory infiltrate within bronchioles and alveoli
• Rarely, pulmonary hemorrhage, vasculitis, and/or pulmonary hypertensive changes may be the only finding(s)

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Other causes of NSIP, UIP, and DAD
• Drug-induced interstitial lung disease associated with methotrexate or cyclophosphamide

Fig 1 Polymyositis and dermatomyositis–associated lung disease. Lung biopsy from this patient with polymyositis and interstitial lung disease shows organizing pneumonia. Other areas have a minor component of eosinophilic pneumonia in a background of mixed cellular and fibrotic NSIP.

Fig 2 Polymyositis and dermatomyositis–associated lung disease. Higher magnification of an area of organizing pneumonia from the patient in Fig 1 .

Fig 3 Polymyositis and dermatomyositis–associated lung disease. Higher magnification of an area of NSIP from the patient in Fig 1 .

Fig 4 Polymyositis and dermatomyositis–associated lung disease. This patient with dermatomyositis has mixed histological features with densely fibrotic UIP areas (upper right) as well as areas with more preserved alveolar architecture and an NSIP pattern (lower left).

Fig 5 Polymyositis and dermatomyositis–associated lung disease. Another area of mostly UIP (right) with prominent microscopic honeycombing with bronchiolar metaplasia and mucostasis transitioning into an area of NSIP (left) from the same patient as in Fig 4 .

Fig 6 Polymyositis and dermatomyositis–associated lung disease. Organizing pneumonia is seen in this patient with dermatomyositis; low (A) and high (B) powers.

Fig 7 Polymyositis and dermatomyositis–associated lung disease. Microscopic honeycombing consistent with UIP is seen in this patient with an undifferentiated connective tissue disease with clinical features favoring polymyositis or dermatomyositis; low power (A) and high power (B) showing fibroblastic foci at an advancing edge of fibrosis.
Sjögren Syndrome (SS)

Definition

• An autoimmune disease characterized by T-lymphocyte infiltration of salivary glands with atrophy and dryness of mucous membranes; frequently involves the lungs

Clinical features

Epidemiology

• Half of cases occur as primary SS, whereas half occur as SS associated with other connective tissue diseases
• Lung involvement is more common in women with SS than in men

Presentation

• Dry cough, dyspnea, and recurrent respiratory infections in a patient with xerostomia, xerophthalmia, and arthritis
• Positive serological tests for ANA, RF, anti-SSA, and anti-SSB

Prognosis and treatment

• Good prognosis with corticosteroids and other immunosuppressant therapy
• Usual interstitial pneumonia (UIP) pattern may have worse prognosis

Pathology

Histology

• Most common finding is of nonspecific interstitial pneumonia (NSIP), characterized by a bronchiolocentric uniform thickening of alveolar septa by lymphocytes and/or fibrosis and associated type II pneumocytic hyperplasia
• Mucous glands of the large airways are atrophic and have lymphocytic infiltrates
• Small, nonnecrotizing interstitial granulomas and multinucleated giant cells may be seen
• Lymphocytic infiltrates may obscure underlying lung architecture and may be due to benign entities, such as lymphoid interstitial pneumonia or follicular bronchiolitis, or to malignant entities such as lymphomatoid granulomatosis or lymphoma
• Secondary pulmonary infection in the presence of significant lymphocytic infiltrates due to decreased mucous production and abnormal mucociliary clearance from the large airways
• Occasionally bronchiectasis, pulmonary cysts, and bullae may be present
• UIP pattern of geographical and temporal heterogeneity of interstitial fibrosis with microscopic honeycombing is seen occasionally
• Other infrequent findings include amyloidosis, pulmonary hypertensive changes, pulmonary hemorrhage, and pleuritis

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Other causes of NSIP and UIP
• Other lung diseases with granulomas and multinucleated giant cells, such as hypersensitivity pneumonitis, infection, and aspiration
• Primary lymphoproliferative lesions or lymphomas of the lung

Fig 1 Sjögren syndrome. NSIP and pleural fibrosis are seen in this wedge biopsy from a patient with SS.

Fig 2 Sjögren syndrome. Extensive interstitial inflammation, as seen here, is often seen in lung disease associated with SS.

Fig 3 Sjögren syndrome. UIP pattern with pleural fibrosis and chronic inflammation with lymphoid aggregates and germinal centers is seen in this case of SS-associated lung disease.

Fig 4 Sjögren syndrome. Lymphoid aggregates can be seen abutting the pleura.

Fig 5 Sjögren syndrome. Type II pneumocyte hyperplasia and extensive mixed inflammatory infiltrate of the interstitium is seen at high power.
Inflammatory Bowel Disease (IBD)–Associated Interstitial Lung Disease

Definition

• Interstitial lung disease arising in patients with a gastrointestinal chronic inflammatory condition manifesting as ulcerative colitis or as Crohn disease

Clinical features

Epidemiology

• Up to half of IBD patients may have respiratory tract involvement
• Respiratory symptoms are more common in ulcerative colitis than in Crohn disease
• Women are more often affected than men; age of onset is variable
• Pulmonary involvement typically occurs in patients known to have IBD but infrequently may be the presenting condition
• The degree of inflammatory changes in the lungs tends to correlate with that in the gastrointestinal tract

Presentation

• Airway inflammation: coughing, wheezing, obstruction, abnormal pulmonary function tests
• Pulmonary parenchymal disease: dyspnea, coughing, fever, abnormal pulmonary function tests, basilar lung opacities or infiltrates on chest CT

Prognosis and treatment

• High-dose corticosteroids
• Prognosis varies with type and extent of pulmonary involvement

Pathology

Histology

• Airway inflammation: tracheitis, bronchitis, bronchiectasis, acute or chronic bronchiolitis, bronchopneumonia-like pattern, lung abscess
• Parenchymal disease: interstitial lung disease (most often nonspecific interstitial pneumonia), organizing pneumonia, eosinophilic pneumonia
• Nonnecrotizing granulomas may be present in Crohn disease
• Pulmonary thromboemboli
• Patients with IBD-associated pyoderma gangrenosum of the skin may rarely have similar necrobiotic nodules with acute and chronic inflammatory cells in the lungs

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Sulfasalazine or mesalamine (used in IBD) therapy-related pneumonitis: frequently associated with peripheral blood eosinophilia; more alveolar than airway involvement
• Infection
• Other causes of interstitial lung disease
• Hypersensitivity pneumonitis
• Sarcoidosis

Fig 1 Inflammatory bowel disease–associated interstitial lung disease. Eosinophilic pneumonia is present in this transbronchial biopsy from a patient with Crohn disease.

Fig 2 Inflammatory bowel disease–associated interstitial lung disease. At higher power, several eosinophils and an eosinophilic alveolar exudate are seen.

Fig 3 Inflammatory bowel disease–associated interstitial lung disease. The presence of granulomas can be a clue to Crohn disease–associated lung disease; however, a meningothelial-like nodule, as seen here, should not be mistaken for a granuloma.
Asbestosis

Definition

• Pulmonary interstitial fibrosis caused by inhalation of asbestos fibers

Pathogenesis

• Due to substantial and significant exposure to asbestos fibers
• Different forms of asbestos:
• Serpentine/chrysotile:
– Curly and flexible
– More commonly seen in industry but less pathogenic
– Usually caught in upper respiratory tract and removed with mucus by coughing
• Amphibole:
– Straight and stiff
– More pathogenic
– Usually goes deep in lung; reaches small airways
• Both forms are fibrogenic; macrophages at the small airways ingest fibers and release chemotactic factors and fibrogenic mediators, causing peribronchiolar and interstitial fibrosis
• Asbestos exposure also increases the risk of malignancy (lung cancer and mesothelioma)
• Asbestos fibers may also absorb toxic chemicals from tobacco smoke; therefore, asbestos exposure increases the risk of lung cancer significantly (10 times higher risk in smokers than in those with asbestos exposure alone)

Clinical features

Epidemiology

• Occurs in a variety of occupational settings:
• Asbestos mining and milling
• Asbestos products manufacturing: insulator, shipyard worker, construction worker, and others
• Household contacts of asbestos workers
• Long latent period, usually develops 10 years or more after exposure

Presentation

• Initially shortness of breath on exertion, later dyspnea even at rest; may progress to heart failure with hypoxia and cor pulmonale
• Restrictive changes on pulmonary function tests
• Disease starts from lower lobes and subpleurally; later extends to middle and upper lobes

Prognosis and treatment

• Treatment: stop asbestos exposure and stop smoking; relieve symptoms and prevent complications
• Disease is irreversible; prognosis depends on the amount of lung fibrosis

Pathology

Histology

• Initially, peribronchiolar fibrosis with asbestos bodies
• Later, diffuse interstitial fibrosis with honeycombing, mucostasis, and type II pneumocytic hyperplasia with eosinophilic cytoplasmic hyaline; rarely, fibroblastic foci may be seen, mimicking usual interstitial pneumonia (UIP)
• Some have prominent intraalveolar macrophages, which resemble desquamative interstitial pneumonia
• Asbestos body is the hallmark finding: a beaded or dumbbell-shaped rod with a central clear core and golden brown coating; it may be straight or curved
• Asbestos bodies can be found in peribronchiolar macrophages, alveolar spaces or septum, or even within thoracic lymph nodes
• Ferruginous body is a general term for an inorganic particle coated with iron; asbestos body is a ferruginous body that contains asbestos fibers coated with iron-containing proteinaceous material

Immunopathology/special stains

• Iron stain: helps identify asbestos bodies by staining the iron coating blue
• Electron microscopy: facilitates the characterization of asbestos fibers

Main differential diagnoses

• UIP: lacks asbestos bodies
• Other forms of diffuse pulmonary fibrosis

Fig 1 Asbestosis. Asbestos bodies can be seen in peribronchiolar macrophages (A), intraalveolar space (B), and alveolar septum or interstitium ( C and D ). Note beaded, rod-like structures with a central core and variable length.

Fig 2 Asbestosis. Multinucleated giant cells containing asbestos bodies and asteroid bodies: low (A) and medium (B) powers.

Fig 3 Asbestosis. Asbestosis in a UIP pattern with interstitial fibrosis, microscopic honeycombing, and fibroblastic focus: A, low power; B, medium power showing fibroblastic focus; inset, demonstrating amplified asbestos fiber.

Fig 4 Asbestosis. Asbestos bodies can also be identified on frozen section: low (A) and high (B) powers. This frozen section was done for diagnosis of adenocarcinoma, which is shown in B.
Silicosis

Definition

• A fibrotic pneumoconiosis that is caused by the inhalation of fine particles of crystalline silicon dioxide (silica), mostly in occupational settings

Pathogenesis

• Quartz is the most common form of crystalline silica but is less fibrogenic than tridymite or cristobalite. Examples of occupations associated with silicosis include mining, quarrying, sandblasting, surface drilling, stone cutting, construction, pottery making, silica flour mill operations, and tunneling
• Nonoccupational environmental exposure to crystalline silica is also common because of its abundance in soil. Silica can become airborne in arid, windy conditions or during agricultural, urban, and construction activities
• The pathogenesis of lung injury is dictated by the interplay between particle and host factors. Silica crystals that measure from 0.5 to 2 microns are the most fibrogenic. The presence of impurities such as iron, aluminum or an amorphous silica coating (“Beilby layer”) reduces toxicity. The most fibrogenic form of silica is tridymite
• Alveolar macrophages take up silica and play a central part in fibrogenesis. Surface hydroxyl groups (SiOH) cause membrane damage and activate free radical cascades and cytokines that result in inflammation, epithelial proliferation, and fibrogenesis

Clinical features

Epidemiology

• Silicosis is the oldest known pneumoconiosis, having been recognized in Egyptian mummies
• Crystalline silica exposure is associated with silicosis, lung cancer (still debated), pulmonary tuberculosis, and chronic obstructive pulmonary disease. Recent studies have also suggested an association between crystalline silica exposure and rheumatoid arthritis
• In 1983 the National Institute for Occupational Safety and Health (NIOSH) estimated that approximately 2.3 million workers at 238,000 work sites may be exposed to silica dust. NIOSH estimates that as many as 59,000 workers may be at risk of developing some degree of silicosis, and 250 deaths per year may be attributed to silica exposure. Approximately 1500 cases of silicosis are diagnosed annually in the United States
• Risk of silicosis varies depending on the presence of other minerals in the dust, percentage of quartz in the dust, and whether the dust contains freshly fractured silica crystals. Lung dysfunction may occur only after 30 to 40 years of exposure

Presentation

• Clinical forms of the disease include acute silicosis, accelerated silicosis, chronic silicosis, and conglomerate (complicated) silicosis
• Acute silicosis may have a latency period of up to a few years and manifests as alveolar proteinosis (so-called silicoproteinosis). Most affected patients are sandblasters and present with dyspnea, coughing, and weight loss. Imaging studies show diffuse ground-glass opacities. High-resolution CT (HRCT) scans may show the characteristic crazy paving appearance, caused by airway filling and interlobular septal thickening
• Accelerated silicosis is also associated with heavy exposures. In addition to the silicoproteinosis that is seen in acute silicosis, patients with the accelerated form also tend to have silicotic nodules of chronic silicosis
• Chronic silicosis is the classic form characterized by an interstitial reticulonodular disease. Patients with simple chronic silicosis are often asymptomatic, and chest radiographs also often show normal results. HRCT scans show upper lobe dominance, and nodules are usually seen in centrilobular, paraseptal, and subpleural regions, with a perilymphatic distribution
• Simple silicosis may progress to so-called conglomerate or complicated silicosis, with coalescence of the nodules. In conglomerate silicosis, there is cavitation and necrosis in the nodules and the development of progressive massive fibrosis, with extensive pleural involvement. Hilar lymph nodes are almost always involved and are identified radiologically as eggshell calcification
• On CT scans, progressive massive fibrosis is characterized by focal soft tissue masses, often with irregular or ill-defined margins and calcifications, surrounded by areas of emphysematous change
• Extrathoracic silicotic nodules may be seen in spleen, liver, bone marrow, abdominal lymph nodes, and peritoneum. These lesions are thought to occur after lymphatic or hematogenous dissemination of silica particles

Prognosis and treatment

• Tuberculosis is a potential complication of silicosis, occurring in up to 60% of cases of conglomerate silicosis. Tuberculosis should always be suspected in the presence of cavitary lesions, although cavitation may be secondary to ischemia in the center of the nodules
• The etiologic association between silicosis and carcinoma is controversial, although the International Agency for Research on Cancer has classified silica as a definite human carcinogen
• Acute silicosis is a progressive disease refractory to therapy, resulting in death due to respiratory failure or cor pulmonale
• Complicated silicosis with progressive massive fibrosis is also refractory to therapy and requires lung transplantation

Pathology

Histology

• Acute silicosis is characterized by alveolar proteinosis, with abundant intraalveolar granular eosinophilic material that is PAS-positive but Alcian blue–negative
• Silicotic nodules are composed of concentric acellular whorled collagen. Pigment-laden macrophages are present, more prominent in the peripheral portions of the nodules. The nodules range from slate gray to dense black, depending on the mineral contents in the silica dust. Brightly birefringent silicate (not silica) crystals (1 to 3 microns long) are highlighted with polarized microscopy
• With progression, there is coalescence of nodules, cavitation, and necrosis with dystrophic calcification

Immunopathology/special stains

• Not contributory

Main differential diagnoses

• Old or healed granulomas: usually solitary and unilateral, lack polarizable pigment and often show giant cells, even after healing
• Nodules of coal workers’ pneumoconiosis: abundant dense black pigment
• Alveolar proteinosis: detailed occupational history, GM-CSF antibodies in serum
• Tuberculosis: AFB stains on multiple sections and microbiology studies

Fig 1 Silicosis. This early lesion shows a spindle cell proliferation with gray-black pigmentation in a lymphangitic (peribronchial and paraseptal) distribution.

Fig 2 Silicosis. Collagenization starts in the center of the nodules.

Fig 3 Silicosis. Silicotic nodules are comprised of dense collagen with scattered pigment (A). The pigment is a mix of silica and silicates, the latter being strongly birefringent on polarization (B).

Fig 4 Silicosis. This nodule shows central breakdown with dystrophic calcification. The presence of necrosis warrants exclusion of tuberculosis.
Coal Workers’ Pneumoconiosis (CWP)

Definition

• A progressive parenchymal lung disease resulting from coal dust inhalation

Pathogenesis

• Coal is a fossil fuel, and the most significant source of coal dust exposure is coal mining. Although the major component—carbon—is relatively inert, coal mine dust also contains hydrogen, oxygen, nitrogen, trace metals, inorganic minerals, and crystalline silica, many of which may be cytotoxic
• Anthracite coal mining has been associated with higher rates of pneumoconiosis than that found in bituminous miners, probably because the former contains more surface free radicals as well as a greater content of crystalline silica
• Cumulative exposure to dust determines progression to progressive massive fibrosis (PMF). Other factors that may impact progression to PMF include high silica content of the mine dust, infection with Mycobacterium tuberculosis, and immunological factors

Clinical features

Epidemiology

• The incidence and rate of CWP progression is related to the amount of respirable coal dust to which miners were exposed during their working lifetime
• Approximately 200,000 workers are employed in the coal mining industry in the United States. In a recent study of 145,512 miners, it was found that the prevalence of CWP is increasing in mines of all sizes, while CWP and PMF are much more prevalent among workers from underground mines with fewer than 50 workers (“small mines”)
• A National Institute for Occupational Safety and Health analysis estimated that during the period 1968 to 2006, a total of 22,625 years of potential life lost before age 65 years (YPLL) were attributed to CWP (mean per decedent, 5.7). Disturbingly, annual YPLL from CWP increased from 135 YPLL in 2002 to 169 YPLL in 2006, suggesting a need for strengthening CWP prevention measures

Presentation

• Coal miners typically develop one of two forms of disease patterns—simple CWP or complicated CWP:
• Simple form: chest radiographs in simple CWP show small, round nodular opacities and, occasionally, reticular or reticulonodular opacities (1-5 mm). Calcifications are seen in up to 20% of patients. CT scan features of CWP may be similar to those of silicosis with upper lobe dominant diffusely distributed small nodules in a perilymphatic distribution
• Complicated form: with chronic exposure, the milder form of CWP may become complicated CWP, with enlargement and fibrosis. This form is synonymous with PMF. These patients often have mixed restrictive and obstructive defects on pulmonary function tests and have hypoxemia. On chest radiographs, large opacities may be seen, similar to that in complicated silicosis. Radiologically, PMF may be confused for lung cancer. The distinction between these two may be possible on MR imaging (high signal intensity on T2-weighted images in lung cancer versus low signal intensity in PMF). FDG-PET may show high uptake in fibrotic masses of PMF and is not helpful in making the distinction
• The term black lung is more a legal term than a medical term and is used to include a wide range of lung diseases (including CWP, bronchitis, emphysema, and silicosis) found in association with employment history in coal mines

Prognosis and treatment

• Patients with CWP are at risk for tuberculosis, as are those with silicosis
• Chronic obstructive pulmonary disease is a common association and contributes to mortality
• Workers with a high degree of PMF have a significantly increased mortality rate. They become progressively hypoxemic and may develop cor pulmonale, despite cessation of coal dust exposure. It is estimated that 4% of coal miners die of causes directly related to CWP

Pathology

Histology

• Simple CWP is characterized by the presence of black coal dust macules. These macular lesions are seen around respiratory bronchioles, mostly in the upper lobes of the lung. They range in size from 1 to 6 mm in diameter and are irregular in shape. They are composed of coal dust–laden macrophages with a fine network of reticulin but no fibrosis. Associated centriacinar emphysema (so-called focal emphysema) is characteristic. These lesions are usually asymptomatic. As with silicosis, septal and subpleural deposits (lymphatic distribution) may be present
• When there is significant silica content in the inhaled dust, patients develop palpable nodular lesions, as in silicosis. However, in CWP, these nodules contain abundant black pigment in addition to slate gray silica (“silicoanthracotic nodules”). Based on size, the nodules are classified as micronodules (up to 0.7 cm) or macronodules (0.7 to 2 cm)
• PMF predominantly affects upper and posterior lung zones and is asymmetric in distribution. Gross lesions are at least 2 cm in size and are rubbery black. Cavitation may occur and, as in silicosis, suggests tuberculosis or ischemic necrosis. The necrotic material is black. Unlike in complicated silicosis, the fibrotic mass of CWP consists of haphazardly arranged collagen with abundant intervening pigment, both free and within macrophages. Vascular structures are also often obliterated. The fibrous masses are characteristically nonnodular and have irregular borders with surrounding cicatricial emphysema. Histological overlap, however, may be seen with silicosis, depending on the silica content in the inhaled coal dust. Numerous silicate particles may be seen under polarized light
• Caplan syndrome—this refers to the presence of pulmonary nodules in coal miners with circulating rheumatoid factor. It is also referred to as rheumatoid pneumoconiosis. It has been reported most frequently in Welsh miners. Macroscopically, the nodules range from 0.5 to 5 cm in size and are pale yellow, with eosinophilic granular centers. Microscopically, the centers show necrobiosis, and the periphery of the lesion is composed of concentrically arranged collagen with lymphocytes, plasma cells, and palisaded histiocytes, similar to rheumatoid nodules. It has been described in patients with circulating rheumatoid factor even in the absence of clinical arthritis. It has also been described in those exposed to silica

Immunopathology/special stains

• Not contributory for diagnosis
• AFB stains in cavitary and necrotic lesions to evaluate for tuberculosis

Main differential diagnoses

• Silicosis: nodules are well-defined at the margins and more solid/uniform in appearance on radiology. Calcification develops as a central nodular dot in CWP but tends to be more diffuse in silicosis. Eggshell calcification of hilar nodes is more typical of silicosis. Histologically, silicotic nodules may be a component of both diseases, although CWP also shows abundant black pigment
• Simple anthracosis: much more common than CWP. Black pigment accumulation may be seen in lungs and hilar nodes of cigarette smokers and most adults residing in urban industrialized regions. Occupational history is therefore paramount in the diagnosis of CWP
• Graphite workers’ pneumoconiosis: although graphite miners may have the same pathological changes observed in silicosis and CWP, they also commonly have intraalveolar giant cells. Dust from graphite consists of approximately 50% crystalline carbon or graphite and 25% quartz; the remainder is composed of various silicates
• Carbon electrode makers’ pneumoconiosis: may have pathological changes similar to CWP
• Lung cancer
• Idiopathic pulmonary fibrosis: a usual interstitial pneumonia pattern of fibrosis has been described in PMF; however, there is only minimal to mild anthracosis in idiopathic pulmonary fibrosis

Fig 1 Coal workers’ pneumoconiosis. Dust macules show peribronchiolar and perivascular collection of black dust–laden macrophages accompanied by little collagen fibrosis. Mild centrilobular emphysema is seen.
(Case courtesy of Dr. Dani S. Zander, Hershey, Pa.)

Fig 2 Coal workers’ pneumoconiosis. Large airways may also be affected.
(Case courtesy of Dr. Dani S. Zander, Hershey, Pa.)

Fig 3 Coal workers’ pneumoconiosis. Coalescence of nodules and dense fibrosis is seen in PMF (A). Note the abundant black pigment in the background. A higher-power view shows adjacent cicatricial emphysema (B).
(Case courtesy of Dr. Dani S. Zander, Hershey, Pa.)
G
Granulomatous Diseases (Noninfectious)
Sarcoidosis

Definition

• Multisystem granulomatous disease of unknown cause with frequent lung involvement

Clinical features

Epidemiology

• Frequently affects young to middle-aged adults
• Higher risk in blacks and females
• Rare in Asians

Presentation

• Majority asymptomatic or with mild, nonspecific pulmonary complaints of dyspnea, coughing
• Abnormal pulmonary function tests such as restrictive defects or low diffusing capacity
• Radiographic abnormalities: bilateral interstitial opacities associated with hilar lymph node enlargement or, less frequently, solitary or multiple nodular densities; localized area of consolidation

Prognosis and treatment

• Variable clinical course
• Slowly progressive disease, although most patients experience remission after treatment
• Some develop extensive pulmonary fibrosis and may require lung transplantation
• Treatment includes immunosuppressants and antifibrotic agents in symptomatic patients

Pathology

Histology

• Classic sarcoidosis
• Nonnecrotizing granulomatous inflammation is distributed primarily along the bronchovascular bundle and lymphatics
• The granulomas predominantly involve airway submucosa and the pulmonary interstitium rather than airspaces; up to 10% of cases have pleural involvement
• Diagnostic tissue is often obtained by transbronchial and endobronchial biopsies
• Accompanied by granulomatous vasculitis characterized by the presence of nonnecrotizing granulomas within the intima and media of blood vessels without causing necrosis of the blood vessel walls
• Granulomas are well circumscribed and composed of tightly clustered epithelioid histiocytes and occasional multinucleated giant cells with few intervening lymphocytes and other inflammatory cells
• Nonspecific cytoplasmic inclusions may be present within giant cells and histiocytes, such as asteroid or Schaumann/conchoid bodies
• Hyalinized fibrous tissue may replace portions of granulomas or even entire granulomas
• Necrotizing sarcoid granulomatosis
• Differs histologically from classic sarcoidosis by the presence of large areas of parenchymal necrosis in the middle of confluent granulomas as well as nonnecrotizing granulomas
• More widespread and prominent granulomatous vasculitis

Immunopathology/special stains

• Epithelioid histiocytes are positive for CD68
• Special stains and tissue culture are needed to rule out acid-fast bacilli and fungal infection
• Serum angiotensin-converting enzyme is elevated in 30% to 80% of patients

Main differential diagnoses

• Infectious diseases: fungi (histoplasmosis, blastomycosis, or coccidioidomycosis) and acid-fast mycobacteria
• Hypersensitivity pneumonia: poorly formed granulomas with eosinophils; no lymph node involvement
• Wegener granulomatosis: geographical dirty blue necrotizing granulomas and serological abnormalities (increased c-ANCA)
• Occupational diseases (berylliosis): clinical history of exposure and foreign body granulomas
• Intravenous drug abuser’s lung: clinical history and foreign body granulomas with exogenous materials

Fig 1 Sarcoidosis. Well-formed nonnecrotizing granulomas distributed along the bronchovascular bundle.

Fig 2 Sarcoidosis. A, Granulomas involve airway submucosa rather than airspaces. B, Multiple giant cells with intracytoplasmic calcifications.

Fig 3 Sarcoidosis. Granulomas involve the pulmonary interstitium (transbronchial biopsy). The adjacent alveolar septa were not inflamed.

Fig 4 Sarcoidosis. A, Pleural involvement with confluent nonnecrotizing granulomas. B, Nonnecrotizing granulomas infiltrate into pleural adipose tissue.

Fig 5 Sarcoidosis. Granulomatous vasculitis characterized by presence of nonnecrotizing granuloma within the vessel wall without causing vascular necrosis.

Fig 6 Sarcoidosis. Granuloma involving the lymphatic vessel wall.

Fig 7 Sarcoidosis. Well-formed granuloma composed of tightly clustered epithelioid histiocytes, multinucleated giant cell, and a few inflammatory cells.

Fig 8 Sarcoidosis. Nonspecific cytoplasmic asteroid inclusion within giant cell.

Fig 9 Sarcoidosis. Hyalinized fibrous tissue replacing portions of granulomas or even entire granulomas; only multinucleated giant cells are present in this treated patient.

Fig 10 Sarcoidosis. Necrotizing granuloma with small area of necrosis present within the granuloma.
Hypersensitivity Pneumonitis (HSP) or Extrinsic Allergic Alveolitis

Definition

• Bilateral inflammatory interstitial lung disease caused by inhaled organic antigens or chemicals with poorly formed nonnecrotizing granulomas and upper lobe predominance

Pathogenesis

• Immune-mediated reaction (hypersensitivity) to repeated inhalations of airborne environmental antigens; usually type III and IV hypersensitivity reactions

Clinical Features

Epidemiology

• More than 300 organic antigens have been reported; farming, birds, and water contamination (typically in basements, leading to molds) account for about 75% of cases
• Prototype HSPs includes “farmer’s lung,” which is caused by thermophilic actinomyces in hay, and “bird fancier’s lung” caused by avian antigens

Presentation

• Main respiratory symptoms are dyspnea and coughing; however, the clinical course is variable
• Acute HSP: acute onset within 4 to 8 hours of antigen exposure (usually heavy) with resolution within 24 to 48 hours; fever, chills, and chest tightness in addition to dyspnea and coughing
• Subacute HSP: slowly progressive respiratory symptoms developing over months’ or years’ continuous exposure to low levels of antigen, with episodes of discrete attacks caused by intermittent heavy antigen exposure
• Chronic HSP: similar to subacute form without discrete attacks; patients present with increasing shortness of breath and chronic coughing; some patients present with extensive end-stage fibrotic disease without ever having been given a diagnosis of HSP

Prognosis and treatment

• Treatment:
• Antigen avoidance is most effective
• Corticosteroids are used to control the symptoms but do not improve overall long-term outcome
• Prognosis:
• Acute and subacute HSP: disease is reversible if antigen exposure can be identified and eliminated
• Chronic HSP: fibrosis is irreversible but may not progress if antigen exposure can be avoided

Pathology

Histology

• Acute HSP: tissues are rarely sampled, and little is known
• Subacute HSP: interstitial pneumonitis characterized by
• Interstitial lymphoplasmacytic infiltrates
• Cellular bronchiolitis
• Interstitial and/or intraalveolar poorly formed nonnecrotizing granulomas comprised of clusters of epithelioid histiocytes with multinucleated giant cells together with lymphocytes and plasma cells; the granulomas are usually small and ill-defined; giant cells may contain occasional cholesterol clefts or asteroid bodies
• A triad of the aforementioned three features are present in more than 80% of cases
• In some cases obliterative bronchiolitis may also be present
• Organizing pneumonia can also be present, and in some cases, it may be the most prominent feature
• Chronic HSP:
• Fibrosis develops in addition to subacute HSP; it may present in three distinct histological patterns:
– Usual interstitial pneumonia (UIP)-like pattern: subpleural, patchy, paucicellular fibrosis with fibroblastic foci and microscopic honeycombing; features to distinguish from UIP:
Upper lobe predominance
Giant cells and poorly formed granulomas
– Nonspecific interstitial pneumonia (NSIP)-like pattern: interstitial fibrosis with preservation of alveolar architecture
Usually there are giant cells and poorly formed granulomas
Sometimes NSIP may be the only histological finding; careful correlation with antigen exposure history is very important
– Irregular peribronchiolar pattern: peribronchiolar fibrosis

Immunopathology/special stains

• GMS and AFB stains are negative

Main differential diagnoses

• Microaspiration pneumonitis:
• Usually with lower lobe predominance
• Poorly formed nonnecrotizing granulomas; giant cells may have large vacuoles (exogenous lipoid pneumonia); foreign body material (e.

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