Shield’s General thoracic surgery. [Eighth edition] 9781451195224, 1451195222

Table of contents :
Cover......Page 1
Title Page......Page 2
Copyright......Page 3
Dedication......Page 4
Contributing Authors......Page 6
Preface to the Eighth Edition......Page 52
Preface to the First Edition......Page 53
Acknowledgments......Page 54
Video List......Page 55
Contents......Page 57
Part A volution of General Thoracic Surgery......Page 71
SECTION I History and Pioneers in Thoracic Surgery......Page 72
1 The History of Thoracic Surgery......Page 73
2 Pulmonary Surgery After Mechanical Ventilation......Page 120
3 Minimally Invasive Thoracic Surgery......Page 140
PART B The Lung, Pleura, Diaphragm, and Chest Wall......Page 148
SECTION II Structure and Function of The Chest Wall and Lungs......Page 149
4 Anatomy of the Thorax......Page 150
5 Embryology of the Lungs......Page 170
6 Ultrastructure and Morphometry of the Human Lung......Page 196
7 Cellular and Molecular Biology of the Lung......Page 244
8 Surgical Anatomy of the Lungs......Page 262
9 Lymphatics of the Lungs......Page 285
10 Mechanics of Breathing and Pulmonary Gas Exchange......Page 330
SECTION III Thoracic Imaging......Page 361
11 Standard Radiographic Evaluation of the Lungs and Chest......Page 362
12 Computed Tomography of the Lungs, Pleura, and Chest Wall......Page 383
13 Magnetic Resonance Imaging of the Thorax......Page 417
14 Radionucleotide Studies of the Lung......Page 482
15 Thoracic PET CT......Page 503
SECTION IV Diagnostic Procedures......Page 524
16 Laboratory Investigations in the Diagnosis of Pulmonary Diseases......Page 525
17 Molecular Diagnostic Studies and Genomic Studies in Pulmonary Disease......Page 577
SECTION V Diagnostic Procedures In Pulmonary Diseases......Page 597
18 Bronchoscopic Evaluation of the Lungs and Tracheobronchial Tree......Page 598
19 Ultrasound and Endoscopic Bronchoscopic Ultrasound in the Evaluation of the Lungs, Mediastinum, and Pleura......Page 628
20 Mediastinoscopy......Page 659
21 Transcervical Mediastinal Lymphadenectomy......Page 683
22 Invasive Diagnostic Procedures......Page 701
SECTION VI Preoperative Assessment of the Thoracic Surgical Patient......Page 732
23 General Risk Assessment of Patients for Thoracic Surgical Procedures......Page 733
24 Pulmonary Physiologic Assessment of Operative Risk......Page 748
SECTION VII Preoperative And Anesthetic Management of The General Thoracic Surgical Patient......Page 779
25 Preoperative Preparation of the General Thoracic Surgical Patient......Page 780
26 Conduct of Anesthesia......Page 793
SECTION VIII Pulmonary Resections......Page 828
27 Thoracic Incisions......Page 829
28 Technical Aspects of Lobectomy......Page 846
29 Pneumonectomy and Its Modifications......Page 888
30 Sleeve Lobectomy......Page 902
31 Tracheal Sleeve Pneumonectomy......Page 930
32 Segmentectomy and Lesser Pulmonary Resections......Page 947
33 Robotic-Assisted Surgery in Pulmonary Diseases......Page 971
34 Video-Assisted Thoracoscopic Surgery for Wedge Resection, Lobectomy, and Pneumonectomy......Page 980
35 Uniportal VATS Lobectomy......Page 1013
36 Awake, Non-Intubated Transpleural Surgery......Page 1049
37 Extended Resection of Pulmonary Carcinoma Including Chest Wall and Mediastinum......Page 1059
38 Surgical Resection of Superior Sulcus Lesions......Page 1113
39 Management of Air Leaks and Residual Pleural Spaces......Page 1160
SECTION IX Postoperative Management of The General Thoracic Surgical Patient......Page 1171
40 General Principles of Postoperative Care......Page 1172
41 Ventilatory Support of the Thoracic Surgical Patient......Page 1189
42 Complications of Thoracic Surgical Procedures......Page 1211
SECTION X The Chest Cage......Page 1236
43 Chest Wall Deformities......Page 1237
44 Hernias of the Chest Wall......Page 1270
45 Infections of the Chest Wall......Page 1280
46 Thoracic Outlet Syndrome......Page 1299
47 Transthoracic Approaches to the Spine......Page 1318
48 Chest Wall Tumors......Page 1332
49 Chest Wall Reconstruction......Page 1356
SECTION XI The Diaphragm......Page 1373
50 Embryology and Anatomy of the Diaphragm......Page 1374
51 Physiology of the Diaphragm and Surgical Approaches to the Paralyzed Diaphragm......Page 1383
52 Congenital Posterolateral Diaphragmatic Hernias and Other Less Common Hernias of the Diaphragm in Infants and Children......Page 1399
53 Foramen of Morgagni Hernia......Page 1432
54 Primary Tumors of the Diaphragm......Page 1436
SECTION XII The Pleura......Page 1453
55 Anatomy of the Pleura......Page 1454
56 Absorption of Gases Within the Pleural Space......Page 1465
57 Pneumothorax......Page 1473
58 Mechanics and Fluid Dynamics of Lung and Pleural Space......Page 1494
59 Benign Pleural Effusion......Page 1506
60 Parapneumonic Effusion, Empyema, and Fibrothorax......Page 1513
61 Postsurgical Empyema......Page 1535
62 Tuberculous and Fungal Infections of the Pleura......Page 1552
63 Thoracoplasty: Indications and Surgical Considerations......Page 1571
64 Anatomy of the Thoracic Duct and Chylothorax......Page 1615
65 Solitary Fibrous Tumors and Other Uncommon Neoplasms of the Pleura......Page 1630
66 Chemotherapy and Alternative Therapies for Malignant Pleural Mesothelioma......Page 1661
67 Surgical Approaches for Diffuse Malignant Pleural Mesothelioma......Page 1685
68 Malignant Pleural Effusions......Page 1707
69 Malignant Pericardial Effusions......Page 1727
SECTION XIII The Trachea and Bronchi......Page 1745
70 Tracheostomy......Page 1746
71 Therapeutic Bronchoscopic Procedures......Page 1762
72 Surgical Anatomy of the Trachea and Techniques of Resection and Reconstruction......Page 1781
73 Management of Nonneoplastic Diseases of the Trachea......Page 1812
74 Benign and Malignant Tumors of the Trachea......Page 1837
75 Compression of the Trachea by Vascular Rings......Page 1863
SECTION XIV Congenital, Structural, and Inflammatory Diseases of the Lung......Page 1895
76 Congenital Parenchymal Lesions of the Lungs......Page 1896
77 Pulmonary Complications of Cystic Fibrosis......Page 1922
78 Congenital Vascular Lesions of the Lungs......Page 1961
79 Chronic Pulmonary Emboli......Page 1985
80 COPD for CT Surgery......Page 2007
81 Bullous and Bleb Diseases of the Lung......Page 2027
83 Bacterial Infections of the Lungs and Bronchial Compressive Disorders......Page 2086
84 Pulmonary Tuberculosis and Other Mycobacterial Diseases of the Lung......Page 2124
85 Surgical Management of Tuberculous and Nontuberculous Mycobacterial Infections of the Lung......Page 2156
86 Thoracic Mycotic and Actinomycotic Infections of the Lung......Page 2170
87 Exotic Infections Requiring Surgical Intervention......Page 2207
88 Lung Transplantation......Page 2239
SECTION XV Carcinoma of The Lung......Page 2296
89 Lung Cancer: Epidemiology and Carcinogenesis......Page 2297
90 Lung Cancer Screening......Page 2326
91 Investigation and Management of Indeterminate Pulmonary Nodules......Page 2339
92 Pathology of Carcinoma of the Lung......Page 2357
93 Ex Vivo Diagnosis of Lung Cancer......Page 2402
94 Staging of Lung Cancer......Page 2418
95 Results of Surgical Treatment of Non-Small Cell Lung Cancer......Page 2443
96 Mediastinal Lymph Node Dissection......Page 2506
97 Unknown Primary Malignancy Metastatic to Thoracic Lymph Nodes......Page 2523
98 Adjuvant Chemotherapy for Non-Small-Cell Lung Cancer......Page 2532
99 Radiation for Lung Cancer......Page 2546
100 Multimodality Therapy for Non-Small Cell Lung Cancer......Page 2566
101 Novel Therapeutic Strategies for Non-Small Cell Lung Cancer......Page 2578
102 Emerging Technologies for Management of Lung Cancer in Patients With Marginal Physiologic Function......Page 2598
103 Small-Cell Lung Cancer......Page 2610
SECTION XVI Other Tumors of the Lung......Page 2634
104 Carcinoid Tumors......Page 2635
105 Adenoid Cystic Carcinoma and Other Primary Salivary Gland–Type Tumors of the Lung......Page 2654
106 Benign Tumors of the Lung......Page 2674
107 Uncommon Primary Malignant Tumors of the Lung......Page 2723
108 Pulmonary Metastases......Page 2762
109 Pulmonary Malignancies in the Immunocompromised Host......Page 2820
SECTION XVII Thoracic Trauma......Page 2842
110 Blunt and Penetrating Injuries of the Chest Wall, Pleura, Diaphragm, and Lungs......Page 2843
111 Barotrauma and Inhalation Injuries......Page 2887
112 Acute Respiratory Distress Syndrome......Page 2907
113 Management of Foreign Bodies of the Aerodigestive Tract......Page 2933
114 Blunt and Penetrating Injuries of the Esophagus......Page 2953
115 Esophageal Perforation......Page 2961
SECTION XVIII Understanding Statistical Analysis And Medical Decision Making......Page 2974
116 Statistics and Medical Decision Making for the Surgeon......Page 2975
117 Clinical Practice Guidelines in General Thoracic Surgery......Page 3008
118 Rationale for and Use of Large National Databases......Page 3015
119 ICD-10: Implications for Future Clinical Research and Reporting......Page 3033
120 Instruments and Resources for Quality Improvement in Thoracic Surgery......Page 3043
PART C The Esophagus......Page 3059
SECTION XIX Structure of the Esophagus......Page 3060
121 Embryology of the Aerodigestive Tract......Page 3061
122 Anatomy of the Esophagus......Page 3069
123 Lymphatic Drainage of the Esophagus......Page 3084
SECTION XX Physiology of The Esophagus......Page 3092
124 Anatomy, Physiology, and Physiologic Studies of the Esophagus......Page 3093
SECTION XXI Diagnostic Studies of The Esophagus......Page 3118
125 Radiologic Evaluation of the Esophagus......Page 3119
126 Endoscopy of the Esophagus......Page 3189
127 Esophageal Ultrasound......Page 3211
SECTION XXII Operative Procedures in The Management of Esophageal Disease......Page 3250
128 Operative Strategies for Esophageal Dysmotility Disorders......Page 3251
129 Surgical Techniques for the Treatment of Reflux Disease......Page 3267
130 Techniques of Esophagectomy......Page 3295
130A Transthoracic Resection of the Esophagus......Page 3300
130B Extended Resection for Esophageal Carcinoma......Page 3317
130C Transhiatal Esophagectomy Without Thoracotomy......Page 3342
130D Vagal-Sparing Esophagectomy......Page 3383
130E Video-Assisted and Robotic Esophagectomy......Page 3388
131 Alternative Conduits for Replacement of the Esophagus......Page 3407
132 Per-Oral Esophageal Procedures......Page 3427
133 Esophageal Stents......Page 3445
SECTION XXIII Congenital, Structural, and Inflammatory Diseases of the Esophagus......Page 3470
134 Congenital Anomalies of the Esophagus......Page 3471
135 Inflammatory Diseases of the Esophagus......Page 3521
136 Esophageal Motility Disorders......Page 3538
137 Gastroesophageal Reflux Disease......Page 3575
138 Barrett’s Esophagus......Page 3590
139 Paraesophageal Hiatal Hernia......Page 3607
140 Esophageal Diverticula......Page 3633
141 Benign Tumors, Cysts, and Duplications of the Esophagus......Page 3649
SECTION XXIV Malignant Lesions of The Esophagus......Page 3667
142 Carcinoma of the Esophagus......Page 3668
142 Appendix: 2009 AJCC/UICC Staging of Esophageal Cancer......Page 3717
143 Staging of Esophageal Cancer......Page 3723
144 Multimodality Therapy for Esophageal Cancer......Page 3732
145 Less Common Malignant Tumors of the Esophagus......Page 3744
146 Palliative Approaches to Inoperable Esophageal Cancer......Page 3765
PART D The Mediastinum......Page 3774
SECTION XXV Structure and Function of The Mediastinal Contents......Page 3775
147 The Mediastinum, Its Compartments, and the Mediastinal Lymph Nodes......Page 3776
148 The Thymus......Page 3792
149 Mediastinal Parathyroids......Page 3806
150 Neurogenic Structures of the Mediastinum......Page 3818
SECTION XXVI Noninvasive Investigations......Page 3832
151 Radiographic, Computed Tomographic, and Magnetic Resonance Investigation of the Mediastinum......Page 3833
152 Radionuclide Studies of the Mediastinum......Page 3879
153 Mediastinal Tumor Markers......Page 3913
SECTION XXVII Invasive Diagnostic Investigations and Surgical Approaches......Page 3961
154 Sternotomy and Thoracotomy for Mediastinal Disease......Page 3962
155 Video-Assisted Thoracic Surgery for Mediastinal Tumors and Cysts and Other Diseases Within the Mediastinum......Page 3972
156 Surgical Techniques for Thymectomy......Page 4010
156A Standard Thymectomy......Page 4011
156B Transcervical Thymectomy......Page 4024
156C Operative Techniques of VATS and Robotic VATS Thymectomy......Page 4041
156D Extended Transsternal Thymectomy With or Without Cervical Incision......Page 4059
SECTION XXVIII Mediastinal Infections, Mass Lesions in the Mediastinum, and Control of Vascular Obstructing Symptomatology......Page 4067
157 Acute and Chronic Mediastinal Infections......Page 4068
158 Primary Mediastinal Tumors and Cysts and Diagnostic Investigation of Mediastinal Masses......Page 4095
159 Lesions Masquerading as Primary Mediastinal Tumors or Cysts......Page 4107
160 Primary Pneumomediastinum......Page 4133
161 Vascular Masses of the Mediastinum......Page 4140
162 Superior Vena Cava Syndrome: Clinical Features, Diagnosis, and Treatment......Page 4160
163 Surgical Management of Benign Sympathetic Nervous System Conditions......Page 4181
SECTION XXIX Primary Mediastinal Tumors and Syndromes Associated With Mediastinal Lesions......Page 4195
164 Myasthenia Gravis......Page 4196
165 Evaluation of Results of Thymectomy for Nonthymomatous Myasthenia Gravis......Page 4214
166 Tumors of the Thymus......Page 4223
167 Benign Lymph Node Disease Involving the Mediastinum......Page 4250
168 Diagnosis and Treatment of Mediastinal Lymphomas......Page 4264
169 Benign and Malignant Germ Cell Tumors of the Mediastinum......Page 4286
170 Benign and Malignant Neurogenic Tumors of the Mediastinum in Children and Adults......Page 4312
171 Less Common Mediastinal Tumors......Page 4373
172 Mesenchymal Tumors of the Mediastinum......Page 4393
SECTION XXX Mediastinal Cysts......Page 4407
173 Foregut Cysts of the Mediastinum in Infants and Children......Page 4408
174 Foregut Cysts of the Mediastinum in Adults......Page 4422
Index......Page 4469

Citation preview

Volume One & Two

Shields′ GENERAL THORACIC SURGERY 8th Edition EDITED BY

Joseph LoCicero III, MD Professor Emeritus of Surgery SUNY Downstate Brooklyn, New York Physician Consultant Mobile County Health Department Mobile, Alabama

Richard H. Feins, MD Professor of Surgery Division of Cardiothoracic Surgery University of North Carolina at Chapel Hill Chapel Hill, North Carolina

Yolonda L. Colson, MD, PhD Michael A. Bell Distinguished Chair in Healthcare Innovation Professor of Surgery Harvard Medical School Brigham and Women’s Hospital Boston, Massachusetts

Gaetano Rocco, MD, FRCSEd Professor Chief, Division of Thoracic Surgery Instituto Nazionale Tumori, IRCCS, Pascale Foundation Naples, Italy

Acquisitions Editor: Keith Donnellan Development Editor: Sean McGuire Development Editor: Brendan Huffman Editorial Coordinator: Jennifer DiRicco Editorial Coordinator: Dave Murphy Marketing Manager: Dan Dressler Production Project Manager: David Saltzberg Design Coordinator: Elaine Kasmer Manufacturing Coordinator: Beth Welsh Prepress Vendor: Aptara, Inc. 8th edition Copyright © 2019 Wolters Kluwer. Copyright © 2009 by Lippincott Williams & Wilkins, a Wolters Kluwer business. Copyright © 2005, 2000 by Lippincott Williams & Wilkins. Copyright © 1994 by Williams and Wilkins. Copyright © 1989, 1983, 1972 by Lea & Febiger. All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at [email protected], or via our website at lww.com (products and services). 9 8 7 6 5 4 3 2 1 Printed in The United States of America Library of Congress Cataloging-in-Publication Data Names: LoCicero, Joseph, III, 1948- editor. | Feins, Richard H., editor. | Colson, Yolonda L., editor. | Rocco, Gaetano, MD, editor. Title: Shields’ general thoracic surgery / [edited by] Joseph LoCicero III, Richard H. Feins, Yolonda L. Colson, Gaetano Rocco. Other titles: General thoracic surgery. Description: 8th edition. | Philadelphia : Wolters Kluwer, [2019] | Preceded by General thoracic surgery / edited by Thomas W. Shields… [et al.]. 7th ed. c2009. | Includes bibliographical references and index. Identifiers: LCCN 2017051947 | ISBN 9781975102241 Subjects: | MESH: Thoracic Surgical Procedures | Thoracic Neoplasms–surgery Classification: LCC RD536 | NLM WF 980 | DDC 617.5/4059–dc23 LC record available at https://lccn.loc.gov/2017051947 This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied, including any warranties as to accuracy, comprehensiveness, or currency of the content of this work. This work is no substitute for individual patient assessment based upon healthcare professionals’ examination of each patient and consideration of, among other things, age, weight, gender, current or prior medical conditions, medication history, laboratory data and other factors unique to the patient. The publisher does not provide medical advice or guidance and this work is merely a reference tool. Healthcare professionals, and not the publisher, are solely responsible for the use of this work including all medical judgments and for any resulting diagnosis and treatments. Given continuous, rapid advances in medical science and health information, independent professional verification of medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made and healthcare professionals should consult a variety of sources. When prescribing medication, healthcare professionals are advised to consult the product information sheet (the manufacturer’s package insert) accompanying each drug to verify, among other things, conditions of use, warnings and side effects and identify any changes in dosage schedule or contraindications, particularly if the medication to be administered is new, infrequently used or has a narrow therapeutic range. To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any injury and/or damage to persons or property, as a matter of products liability, negligence law or otherwise, or from any reference to or use by any person of this work. LWW.com

Dedication to Dr. Thomas W. Shields This 8th edition of General Thoracic Surgery marks the first time Dr. Shields has not been an active member of the editorial directors, yet his influence on the text remains strong. His lifelong interest in lung cancer began in 1951 with a fellowship at the Palmer Memorial Hospital, the cancer building that was part of Deaconess Hospital, now Beth Israel Deaconess Medical Center. His experiences with the thoracic surgeon, dynamic and controversial Richard Overholt inspired him to begin a lifelong study into thoracic lymphatic drainage and lesser pulmonary resections. He traveled the globe gathering data from leading centers making strong bonds with many international colleagues. Using this wealth of knowledge, he compiled the first edition of General Thoracic Surgery published in 1972, updating it every few years. Dr. Shields was a legend to the surgical students and residents of Northwestern University up to the time of his death in 2010. His devotion to clear communication of thought made him a tough taskmaster. His advocacy of evidence-based practice often made him a lightning rod among his colleagues. We hope that this edition continues the tradition of enhancing our understanding and practice of thoracic surgery through assimilation of knowledge and expertise from around the world. —JLIII Dedication to Dr. Carolyn E. Reed, MD This 8th edition of General Thoracic Surgery is dedicated in part to our friend and colleague, Dr. Carolyn E. Reed who was an editor of the 7th edition and was working on this edition until her untimely death. Dr. Reed was an outstanding clinician, teacher, and researcher. Her impact on the field of thoracic surgery was extraordinary. While maintaining a busy clinical practice at the Medical University of South Carolina, she made a major impact on our knowledge of diseases of the chest and how to treat them. She was an NIH-funded researcher and investigator on numerous important national clinical trials. She served our specialty as the first woman chair of the American Board of Thoracic Surgery and the first woman president of the Southern Thoracic Surgical Association. Also, she served as vice-chair of the Residency Review Committee for Thoracic Surgery, treasurer of the Society of Thoracic Surgeons, treasurer of Women in Thoracic Surgery, council member of the American Association for Thoracic Surgery, board member of the Joint Council for Thoracic Surgical Education and the Thoracic Surgery Foundation for Research and Education. Posthumously, she was unanimously elected the first woman president of the Society of Thoracic Surgeons. After her love for providing care to her patients, Dr. Reed’s passion was imparting knowledge to her students and residents. It is our hope that this edition of General Thoracic Surgery will make a fitting completion to her obligations, which were such a large part of her life and that those who use it will continue to experience the wonder of being her student. —RHF To my family and to all succeeding generations of knowledge-seeking, innovative healers around the world to whom we entrust our future health.

—JLIII To the men and women of Thoracic Surgery who have dedicated their lives to the treatment of diseases of the chest. It is a specialty that has embraced the research and new technologies required to serve our patients at the highest level and the spirit of professionalism that is the envy of all of medicine. And to the teachers of Thoracic Surgery who devote themselves day in and day out to ensuring that there will always be outstanding chest surgeons. —RHF To Gina and Raffaele, sempiternal source of energy and inspiration. Amor gignit amorem. —GR To my father for teaching me to dream big, my mother for making hard work and fortitude part of my DNA, my patients for giving me purpose, my collaborator Mark Grinstaff for the gift of creativity and friendship, my husband Gray for providing unlimited love and support and believing in the impossible every day, my two daughters, Karinne and Azuri, and all of my trainees for opening my eyes to the amazing potential of the next generation, and my special team that keeps everything running and makes my work enjoyable. —YLC

Contributing Authors Ghulam Abbas, MD, MHCM, FACS Chief, Division of Thoracic Surgery West Virginia University School of Medicine Morgantown, West Virginia Jay Acharya, MD Assistant Professor Department of Radiology Keck Medicine of USC Los Angeles, California Usman Ahmad, MD Assistant Professor of Surgery Staff Surgeon, Thoracic Surgery Cleveland Clinic Cleveland, Ohio Marco Alifano, MD, PhD Full Professor Department of Thoracic Surgery Paris Descartes University Paris Center University Hospital Paris, France Mark S. Allen, MD Professor of Surgery Division of General Thoracic Surgery Mayo Clinic Rochester, Minnesota Nasser K. Altorki, MB, BCh Professor of Thoracic Surgery Department of Cardiothoracic Surgery Weill Cornell Medical College New York Presbyterian Hospital New York, New York Isabel Alvarado-Cabrero, MD, PhD Department of Pathology Mexican Oncology Hospital, IMSS Mexico City, Mexico Rafael Andrade, MD, MHA Associate Professor

Chief, Division of Thoracic and Foregut Surgery University of Minnesota Minneapolis, Minnesota Marco Anile, MD, PhD Associate Professor Department of Thoracic Surgery Sapienza University of Rome Rome, Italy Beatrice Aramini, MD, PhD Assistant Professor Department of Medical and Surgical Sciences for Children and Adults Division of Thoracic Surgery University of Modena and Reggio Emilia Modena, Italy Saeed Arefanian, MD General Surgery Resident Department of Surgery Washington University in St. Louis St. Louis, Missouri Amrita K. Arneja, MD Neuroradiology Fellow Department of Radiology Mount Sinai Health System New York, New York Oscar Arrieta-Rodriguez, MD, MSc Department Coordinator Thoracic Oncology Unit Instituto Nacional de Cancerología México City, México Hisao Asamura, MD Professor of Surgery Chief Division of Thoracic Surgery Keio University School of Medicine Tokyo, Japan Hugh G. Auchincloss, MD, MPH Division of Thoracic Surgery Massachusetts General Hospital Boston, Massachusetts Diego Avella Patino, MD Assistant Professor of Surgery Division of Cardiac and Thoracic Surgery

University of Missouri Columbia, Missouri Lea Azour, MD Assistant Professor Department of Radiology NYU Langone Medical Center New York, New York Carl L. Backer, MD Professor of Surgery Northwestern University Feinberg School of Medicine Division Head Cardiovascular-Thoracic Surgery Ann & Robert H. Lurie Children’s Hospital of Chicago Chicago, Illinois Patrick Bagan, MD Head of Department Unit of Thoracic and Vascular Surgery Victor Dupouy Hospital Argenteuil, France Erin E. Bailey, MD General Surgeon Department of Surgery Graham Health System Canton, Illinois Brian P. Barrick, MD, DDS Professor Department of Anesthesiology University of North Carolina at Chapel Hill Chapel Hill, North Carolina Thomas L. Bauer II, MD Associate Professor of Surgery Hackensack Meridian School of Medicine at Seton Hall University South Orange, New Jersey Hackensack Meridian Health Jersey Shore University Medical Center Neptune, New Jersey Egidio Beretta, MD, PhD Department of Medicine and Surgery University of Milano-Bicocca Milan, Italy Edward J. Bergeron, MD Munson Medical Center Traverse City, Michigan

Laureline Berteloot, MD Radiologist Department of Pediatric Imaging Necker-Enfants Malades Hospital Paris, France Sanjeev Bhalla, MD Section Chief Professor of Radiology Cardiothoracic Imaging Mallinckrodt Institute of Radiology Washington University St. Louis, Missouri Shanda H. Blackmon, MD, MPH Associate Professor Department of Surgery Division of Thoracic Surgery Mayo Clinic Rochester, Minnesota Eugene H. Blackstone, MD Head of Clinical Investigations The Sydell and Arnold Miller Family Heart & Vascular Institute Staff member Department of Thoracic and Cardiovascular Surgery Quantitative Health Sciences and Transplant Center Cleveland Clinic Cleveland, Ohio Antonio Bobbio, MD, PhD Praticien Hospitalier Service de Chirurgie Thoracique Hôpital Cochin, APHP Paris, France Daniel J. Boffa, MD Associate Professor Department of Surgery Yale School of Medicine New Haven, Connecticut Timothy Brand, MD Department of Cardiothoracic Surgery University of North Carolina at Chapel Hill Chapel Hill, North Carolina Alejandro C. Bribriesco, MD Associate Staff

Department of Thoracic and Cardiovascular Surgery Cleveland Clinic Cleveland, Ohio Lisa M. Brown, MD, MAS Assistant Professor Division of Cardiothoracic Surgery UC Davis Health Sacramento, California Andrew Brownlee, MD Fellow Section of Cardiothoracic Surgery University of Chicago Medicine Chicago, Illinois Alessandro Brunelli, MD Consultant Thoracic Surgeon Honorary Clinical Associate Professor Department of Thoracic Surgery St. James’s University Hospital Leeds, United Kingdom Raphael Bueno, MD Chief Division of Thoracic Surgery Brigham and Women’s Hospital Boston, Massachusetts Timothy F. Burns, MD, PhD Assistant Professor Department of Medicine Division of Hematology Oncology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Peter H. Burri, MD Professor Emeritus of Anatomy Institute of Anatomy University of Bern Bern, Switzerland Bryan M. Burt, MD Associate Professor of Surgery Department of Surgery Baylor College of Medicine Houston, Texas Shamus R. Carr, MD, FACS Assistant Professor

Department of Surgery Division of Thoracic Surgery University of Maryland School of Medicine Baltimore, Maryland Philip Carrott, MD Assistant Professor Section of Thoracic Surgery University of Michigan Ann Arbor, Michigan Ernest G. Chan, MD Department of Cardiothoracic Surgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Patrick G. Chan, MD Department of Cardiothoracic Surgery University of Pittsburgh Medical center Pittsburgh, Pennsylvania John Holt Chaney, MD Attending Physician Lexington, Kentucky Andrew C. Chang, MD John Alexander Distinguished Professor Head of the Section of Thoracic Surgery University of Michigan Ann Arbor, Michigan Stephanie Chang, MD Cardiothoracic Surgery Fellow Department of Surgery Washington University in St. Louis St. Louis, Missouri Delphine L. Chen, MD Associate Professor of Radiology, Medicine, and Biomedical Engineering Mallinckrodt Institute of Radiology Washington University School of Medicine St. Louis, Missouri Aaron M. Cheng, MD Associate Professor Department of Surgery Division of Cardiothoracic Surgery Co-Director UWMC Cardiothoracic ICU University of Washington

Seattle, Washington Mala R. Chinoy, PhD, MBA Professor Department of Biochemistry and Molecular Biology Penn State College of Medicine Hershey, Pennsylvania Priscilla Chiu, MD, PhD Assistant Professor Department of Surgery University of Toronto Staff Surgeon Division of General and Thoracic Surgery The Hospital for Sick Children Toronto, Ontario, Canada Cliff K. C. Choong, MBBS, FRCS, FRACS Associate Professor in Surgery Consultant Thoracic Surgeon Monash University School of Rural Health Latrobe Regional Hospital Victoria, Australia Anna Maria Ciccone, MD, PhD Assistant Professor Division of Thoracic Surgery Sapienza University of Rome Rome, Italy Graham A. Colditz, MD, DrPH Niess-Gain Professor of Surgery Washington University School of Medicine St. Louis, Missouri Stéphane Collaud, MD, MSc Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation Paris-Sud University Marie Lannelongue Hospital Le Plessis-Robinson, France Willy Coosemans, MD, PhD Clinic Head Department of Thoracic Surgery University Hospitals Leuven Leuven, Belgium Traves D. Crabtree, MD Professor of Surgery Southern Illinois University School of Medicine

Springfield, Illinois Gerard J. Criner, MD Professor and Chair Department of Thoracic Medicine and Surgery Lewis Katz School of Medicine at Temple University Philadelphia, Pennsylvania Richard S. D’Agostino, MD Assistant Clinical Professor of Cardiothoracic Surgery Tufts University School of Medicine Boston Massachusetts Chair Division of Thoracic and Cardiovascular Surgery Lahey Hospital and Medical Center Burlington, Massachusetts Walid Leonardo Dajer-Fadel, MD Associate Professor Department of Cardiothoracic Surgery General Hospital of Mexico Mexico City, Mexico Thomas D’Amico, MD Gary Hock Endowed Professor of Surgery Chief, Section of General Thoracic Surgery Program Director, Thoracic Surgery Duke University Medical Center Durham, North Carolina Gail E. Darling, MD, FRCSC Professor of Thoracic Surgery University of Toronto University Health Network, Toronto General Hospital Toronto, Ontario, Canada Philippe Dartevelle, MD Professor of Thoracic and Cardiovascular Surgery University Paris Sud Marie Lannelongue Hospital Le Plessis-Robinson, France Hiroshi Date, MD Professor and Chairman Department of Thoracic Surgery Kyoto University Graduate School of Medicine Kyoto, Japan Jonathan D’Cunha, MD, PhD Associate Professor of Surgery

Vice Chairman Research and Education Chief Division of Lung Transplantation/Lung Failure Surgical Director, ECMO Program Director Thoracic Surgery Traditional Residency Program Director Advanced Lung/Heart Failure Fellowship Department of Cardiothoracic Surgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Herbert Decaluwé, MD, PhD Department of Thoracic Surgery University Hospitals Leuven Leuven, Belgium Malcolm M. DeCamp, MD Fowler McCormick Professor of Surgery Northwestern University Feinberg School of Medicine Chief, Division of Thoracic Surgery Northwestern Memorial Hospital Chicago, Illinois Tracey Dechert, MD, FACS Assistant Professor of Surgery Boston University School of Medicine Division of Trauma and Surgical Critical Care Boston Medical Center Boston, Massachusetts Sebastián Defranchi, MD, MBA Staff General Thoracic Surgeon Chair, Patient Safety Department Chair, Support Services Department Hospital Universitario Fundación Favaloro Ciudad de Buenos Aires, Argentina Pierre Delaere, MD, PhD Professor Department of ENT, Head and Neck Surgery University Hospitals Leuven Leuven, Belgium Paul De Leyn, MD, PhD Professor Chief, Department of Surgery

University Hospitals Leuven Leuven, Belgium Lorenzo Del Sorbo, MD Assistant Professor Interdepartmental Division of Critical Care Medicine University of Toronto University Health Network, Toronto General Hospital Toronto, Ontario, Canada Steven R. DeMeester, MD Thoracic and Foregut Surgery Division of General and Minimally Invasive Surgery The Oregon Clinic Portland, Oregon Todd L. Demmy, MD Professor of Oncology Department of Thoracic Surgery Roswell Park Cancer Institute Professor Department of Surgery University of Buffalo, State University of New York Buffalo, New York Willem Adriaan den Hengst, MD, PhD Resident Department of Thoracic and Vascular Surgery Antwerp University Hospital Antwerp, Belgium Chadrick E. Denlinger, MD Associate Professor Department of Surgery Medical University of South Carolina Charleston, South Carolina Marc de Perrot, MD, MSc, FRCSC Associate Professor of Surgery Division of Thoracic Surgery University of Toronto University Health Network, Toronto General Hospital Toronto, Ontario, Canada Lieven P. Depypere, MD, FEBTS Associate Clinical Head Department of Thoracic Surgery University Hospitals Leuven Leuven, Belgium

Mathieu Derouet, PhD Scientific Associate Department of Thoracic Surgery University Health Network Toronto, Ontario, Canada Daniele Diso, MD, PhD Associate Professor Department of Thoracic Surgery, Sapienza University of Rome Rome, Italy Laura Donahoe, MD Thoracic Surgeon University of Toronto University Health Network Toronto General Hospital Toronto, Ontario, Canada Dean M. Donahue, MD Assistant Professor Department of Thoracic Surgery Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Jessica S. Donington, MD, MSCR Associate Professor Department of Cardiothoracic Surgery NYU School of Medicine New York, New York Frank D’Ovidio, MD, PhD Associate Professor Section General Thoracic Surgery Department of Surgery Columbia University Attending Surgeon NewYork-Presbyterian Hospital New York, New York Nigel E. Drury, PhD, FRCS(CTh) Clinician Scientist & Consultant in Cardiothoracic Surgery Birmingham Children’s Hospital Birmingham, United Kingdom Lingling Du, MD Department of Hematology and Medical Oncology Ochsner Clinic Foundation

New Orleans, Louisiana Mark R. Dylewski, MD Chief of Thoracic Surgery Miami Cancer Institute Baptist Health of South Florida Miami, Florida Janet Edwards, MD, MPH Assistant Professor Division of Thoracic Surgery Cumming School of Medicine at University of Calgary Calgary, Alberta Melanie A. Edwards, MD Assistant Professor Division of Cardiothoracic Surgery Saint Louis University School of Medicine Saint Louis, Missouri Dominic Emerson, MD Fellow Cardiac Surgery Cedars-Sinai Medical Center Los Angeles, California Elie Fadel, MD, PhD Chief Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation Hopital Marie Lannelongue and Université Paris Sud Le Plessis-Robinson, France Pierre-Emmanuel Falcoz, MD, PhD, FECTS Department of Thoracic Surgery Strasbourg University Hospital Strasbourg, France Farhood Farjah, MD, MPH Associate Professor Division of Cardiothoracic Surgery University of Washington Seattle, Washington Richard H. Feins, MD Professor of Surgery Division of Cardiothoracic Surgery University of North Carolina at Chapel Hill Chapel Hill, North Carolina Stanley C. Fell†

Professor of Cardiothoracic Surgery Albert Einstein College of Medicine Bronx, New York Mark K. Ferguson, MD Professor Department of Surgery University of Chicago Pritzker School of Medicine Chicago, Illinois Felix G. Fernandez, MD, MSc Associate Professor of Surgery General Thoracic Surgery Emory University School of Medicine Atlanta, Georgia Hiran C. Fernando, MBBS, FRCS Professor of Surgery Virginia Commonwealth University Richmond, Virginia Inova Fairfax Medical Campus Falls Church, Virginia Pasquale Ferraro, MD Professor Department of Surgery Chief Division of Thoracic Surgery Alfonso Minicozzi and Family Chair in Thoracic Surgery and Lung Transplantation Centre Hospitalier de l’Université de Montréal Montreal, Quebec Raja M. Flores, MD Chairman and Professor Department of Thoracic Surgery Icahn School of Medicine at Mount Sinai New York, New York Seth Force, MD Professor Department of Surgery Emory University School of Medicine Atlanta, Georgia Richard K. Freeman, MD, MBA System Chief Medical Officer St Vincent Health Indianapolis, Indiana Joseph S. Friedberg, MD, FACS

Professor University of Maryland School of Medicine Thoracic Surgeon-in-Chief Department of Surgery Division of Thoracic Surgery University of Maryland Medical System Baltimore, Maryland Henning A. Gaissert, MD Associate Professor of Surgery Harvard Medical School Visiting Surgeon Massachusetts General Hospital Boston, Massachusetts Sidhu P. Gangadharan, MD Chief Division of Thoracic Surgery and Interventional Pulmonology Beth Israel Deaconess Medical Center Associate Professor of Surgery Harvard Medical School Boston, Massachusetts Perry Gerard, MD, FACR Professor of Radiology and Medicine Vice Chairman of Radiology Director of Radiology IT New York Medical College Director of Nuclear Medicine and PET-CT Westchester Medical Center Valhalla, New York Rafael Garza-Castillon, MD Thoracic Surgery Fellow Department of Thoracic Surgery Brigham and Women’s Hospital Boston, Massachusetts Ritu R. Gill, MD, MPH Assistant Professor Department of Radiology Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts Erin A. Gillaspie, MD Assistant Professor Department of Thoracic Surgery

Vanderbilt University Medical Center Nashville, Tennessee Jason P. Glotzbach, MD Assistant Professor Division of Cardiothoracic Surgery University of Utah Salt Lake City, Utah Diego Gonzalez-Rivas, MD, FECTS Director Uniportal VATS Training Program Department of Thoracic Surgery Shanghai Pulmonary Hospital Shanghai, China Andrei-Bogdan Gorgos, MD Associate Professor Department of Radiology University of Montreal Montreal, Quebec Dominique Gossot, MD Head of Thoracic Department—IMM Curie-Montsouris Thorax Institute Paris, France Ramaswamy Govindan, MD Professor of Medicine Anheuser-Busch Endowed Chair in Medical Oncology Director, Section of Oncology Division of Oncology Washington University School of Medicine St. Louis, Missouri Gabriele Simone Grasso, MD Department of Medicine and Surgery University of Milano-Bicocca Milan, Italy Christina L. Greene, MD Integrated Cardiac Resident Department of Cardiothoracic Surgery Stanford University School of Medicine Standford, California Yosef Jose Greenspon, MD, FACS, FAAP Assistant Professor Department of Pediatrics Division of Surgery Cardinal Glennon Children’s Hospital

St. Louis University School of Medicine St. Louis, Missouri Sean C. Grondin, MD, MPH, FRCSC, FACS Professor and Head Department of Surgery Cumming School of Medicine at University of Calgary Calgary Zone Clinical Department Head Alberta Health Services Foothills Medical Centre Calgary, Alberta Federica Grosso, MD Department of Oncology SS Antonio e Biagio General Hospital Alessandria, Italy Shawn S. Groth, MD, MS Assistant Professor Department of Surgery Baylor College of Medicine Houston, Texas Dominique Grunenwald, MD, PhD Professor Emeritus Department of Thoracic and Cardiovascular Surgery Pierre and Marie Curie University Paris, France Claude Guinet, MD Radiologist Department of Radiology Paris Center University Hospital Paris, France Julian Guitron, MD Associate Professor Department of Surgery Division of Thoracic Surgery University of Cincinnati Cincinnati, Ohio Jinny S. Ha, MD Cardiothoracic Surgery Fellow Division of Thoracic Surgery Johns Hopkins Hospital Baltimore, Maryland Hironori Haga, MD Department of Pathology

Kyoto University Hospital Kyoto, Japan Semih Halezeroğlu, MD, FETCS Professor and Chief Department of Thoracic Surgery Acibadem University School of Medicine Istanbul, Turkey Matthew G. Hartwig, MD, MHS Associate Professor of Surgery Division of Thoracic Surgery Duke University Health System Durham, North Carolina Dominik Harzheim, MD Department of Pneumology and Critical Care Thoraxklinik, University of Heidelberg Heidelberg, Germany Stephen Hazelrigg, MD Professor and Chairman Department of Cardiothoracic Surgery Southern Illinois University School of Medicine Springfield, Illinois Mark W. Hennon, MD Assistant Professor Department of Surgery University at Buffalo, State University of New York Assistant Professor of Oncology Department of Thoracic Surgery Roswell Park Cancer Institute Buffalo, New York Claudia I. Henschke, PhD, MD Department of Radiology Icahn School of Medicine at Mount Sinai New York, New York Felix J. F. Herth, MD, PhD, FCCP, FERS CMO Department of Pneumology and Critical Care Medicine Thoraxklinik, University of Heidelberg Heidelberg, Germany Nicholas R. Hess, MD Resident Department of Cardiothoracic Surgery University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania Maxime Heyndrickx, MD Department of Thoracic Surgery University Hospital of Caen Caen, France Wayne Hofstetter, MD Professor of Surgery and Deputy Chair Department of Thoracic and Cardiovascular Surgery University of Texas MD Anderson Cancer Center Houston, Texas Young K. Hong, MD Surgical Oncology and Hepatopancreatobiliary Fellow Department of Surgery Louisville, Kentucky Yinin Hu, MD Resident Department of Surgery University of Virginia Charlottesville, Virginia James Huang, MD Associate Attending Surgeon Thoracic Service, Department of Surgery Memorial Sloan Kettering Cancer Center New York, New York Miriam Huang, MD Clinical Assistant Professor Department of Surgery Jacobs School of Medicine & Biomedical Sciences University of Buffalo Buffalo, New York Charles B. Huddleston, MD Professor Department of Surgery St. Louis University School of Medicine St. Louis, Missouri Jessica L. Hudson, MD, MPHS Surgical Resident Department of Surgery Washington University St. Louis, Missouri Mark D. Iannettoni, MD, MBA

W. Randolph Chitwood, Jr., MD, Distinguished Chair in Cardiovascular Sciences Professor and Chief Division of Thoracic and Foregut Surgery Program Director Thoracic Surgery Residency Chief Cardiovascular Service Line East Carolina Heart Institute at Vidant Medical Center Greenville, North Carolina Carlos Ibarra-Pérez, MD Master and Doctor in Medical Sciences University of México Honorary Consultant in Thoracic Surgery Instituto Nacional de Cardiología Ignacio Chavez México City, Mexico Kendra Iskander, MD, MPH General Surgeon St. Joseph Hospital Eureka, California Dawn E. Jaroszewski, MD, MBA, FACS Professor of Surgery Department of Cardiothoracic Surgery Mayo Clinic Phoenix, Arizona Leila Jazayeri, MD Plastic and Reconstructive Surgeon Kaiser Permanente San Leandro Medical Center San Leandro, California Scott B. Johnson, MD Division Chief, General Thoracic Surgery Department of Cardiothoracic Surgery UT Health San Antonio San Antonio, Texas David W. Johnstone, MD Division of Cardiothoracic Surgery Medical College of Wisconsin Milwaukee, Wisconsin David R. Jones, MD Professor and Chief Thoracic Surgery Service Fiona and Stanly Druckenmiller Chair for Lung Cancer Research Memorial Sloan Kettering Cancer Center

New York, New York Erkan Kaba, MD Assistant Professor Department of Thoracic Surgery Istanbul Bilim University Istanbul, Turkey Mohamed K. Kamel, MD Clinical Fellow Department of Cardiothoracic Surgery Weill Cornell Medical College New York Presbyterian Hospital New York, New York Neil Kapadia, MD Assistant Professor Department of Radiology Temple University Philadelphia, Pennsylvania Brian J. Karlovits, DO Director of Clinical Operations Assistant Professor Department of Radiation Oncology UPMC Hillman Cancer Center—Shadyside Pittsburgh, Pennsylvania Shaf Keshavjee, MD, FRCSC, FACS Professor, Division of Thoracic Surgery University of Toronto James Wallace McCutcheon Chair in Surgery Surgeon in Chief University Health Network Toronto, Ontario, Canada Onkar V. Khullar, MD Assistant Professor Division of Cardiothoracic Surgery Emory University School of Medicine Atlanta, Georgia Biniam Kidane, MD, MSc, FRCSC Assistant Professor Section of Thoracic Surgery Department of Surgery University of Manitoba Winnipeg, Manitoba Min P. Kim, MD

Associate Professor Chief, Division of Thoracic Surgery Department of Surgery Houston Methodist Hospital Houston, Texas Jacob A. Klapper, MD Assistant Professor of Surgery Duke University Hospital Durham, North Carolina Patrick Kohtz, MD Resident Department of Surgery University of Colorado Anschutz Medical Campus Aurora, Colorado Rupesh Kotecha, MD Department of Radiation Oncology Cleveland Clinic, Taussig Cancer Institute Cleveland, Ohio Department of Radiation Oncology Miami Cancer Institute Baptist Health South Florida Miami, Florida Vasileios Kouritas, MD, PhD, CTh Cardiothoracic Surgeon Department of Thoracic Surgery St. James’s University Hospital Leeds, United Kingdom Benjamin D. Kozower, MD, MPH Professor Department of Surgery Washington University School of Medicine St. Louis, Missouri Seth B. Krantz, MD Division of Thoracic Surgery NorthShore University HealthSystem Evanston, Illinois Clinical Assistant Professor Department of Surgery University of Chicago Pritzker School of Medicine Chicago, Illinois Mark J. Krasna, MD Clinical Professor of Surgery

Rutgers New Jersey Medical School Newark, New Jersey Hackensack Meridian School of Medicine at Seton Hall University South Orange, New Jersey Daniel Kreisel, MD, PhD Professor of Surgery, Pathology and Immunology Surgical Director, Lung Transplant Program Washington University School of Medicine St. Louis, Missouri Alexander Krupnick, MD Department of Surgery Division of CT Surgery University of Virginia Charlottesville, Virginia Kiran Lagisetty, MD Assistant Professor Section of Thoracic Surgery Department of Surgery University of Michigan Ann Arbor, Michigan Francesca Lanfranconi, MD, PhD Research Officer Institute of Sport, Exercise and Active Living (ISEAL) Victoria University Melbourne, Australia Jacob C. Langer, MD Professor of Surgery University of Toronto Pediatric Surgeon The Hospital for Sick Children Toronto, Ontario, Canada Nathaniel B. Langer, MD, MSc Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation Marie Lannelongue Hospital Le Plessis-Robinson, France Michael Lanuti, MD Associate Professor of Surgery Harvard Medical School Director of Thoracic Oncology Division of Thoracic Surgery Massachusetts General Hospital Boston, Massachusetts

Rossano Lattanzio, MD, PhD, Dr. Researcher Department of Medical, Oral and Biotechnological Sciences University “G. d’Annunzio” Chieti, Italy Christine Lau, MD, MBA Professor of Surgery Chief, Division of Thoracic Surgery University of Virginia Charlottesville, Virginia Kelvin Lau, MA(Oxon), DPhil(Oxon), FRCS(CTh) Chief of Thoracic Surgery St. Bartholomew’s Hospital London, United Kingdom Richard S. Lazzaro, MD, FACS Associate Professor of Cardiothoracic Surgery Department of Cardiothoracic Surgery Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Chief Division of Thoracic Surgery Lenox Hill Hospital Director, Robotic Thoracic Surgery Northwell Health New York, New York Dong-Seok Daniel Lee, MD Assistant Professor Department of Thoracic Surgery Mount Sinai Health System New York, New York Toni Lerut, MD, PhD Emeritus Professor of Surgery Emeritus Chairman, Department of Thoracic Surgery University Hospitals Leuven, Gasthuisberg Campus Leuven, Belgium Gunda Leschber, MD Head of Department of Thoracic Surgery ELK Berlin Chest Hospital Berlin, Germany Kunwei Li, MD Department of Radiology Icahn School of Medicine at Mount Sinai New York, New York

Moishe Liberman, MD, PhD Director, CETOC Associate Professor of Surgery Division of Thoracic Surgery University of Montreal Montreal, Quebec Michael J. Liptay, MD Professor and Chairman Department of Cardiovascular and Thoracic Surgery Rush University Medical Center Chicago, Illinois Virginia R. Litle, MD Professor of Surgery Chief of Thoracic Surgery Boston University Boston, Massachusetts Joseph LoCicero III, MD Professor Emeritus of Surgery SUNY Downstate Medical Center Brooklyn, New York Consultant Mobile County Health Department Mobile, Alabama Jason Michael Long, MD, MPH Assistant Professor Department of Surgery UNC Medical Center Chapel Hill, North Carolina Christine Lorut, MD Unit of Pneumology Hôpital Cochin, APHP Paris, France Donald E. Low, MD, FACS, FRCS(C) Head of Thoracic Surgery and Thoracic Oncology Department of General, Thoracic and Vascular Surgery Virginia Mason Medical Center Seattle, Washington James D. Luketich, MD, FACS Henry T. Bahnson Professor and Chairman Department of Cardiothoracic Surgery Chief, Division of Thoracic and Foregut Surgery University of Pittsburgh School of Medicine

Pittsburgh, Pennsylvania Audrey Lupo, MD, PhD Department of Pathology Hôpitaux Universitaires Paris Centre Paris, France Ronson J. Madathil, MD Acting Assistant Professor Division of Cardiothoracic Surgery University of Washington Seattle, Washington Mitchell J. Magee, MD, MS Chief Division of Thoracic Surgery Medical City Dallas Hospital Dallas, Texas Raja Mahidhara, MD Thoracic Surgery St Vincent Health Indianapolis, Indiana J. Shawn Mallery, MD Associate Professor of Medicine Department of Medicine Division of Gastroenterology, Hepatology and Nutrition University of Minnesota Minneapolis, Minnesota Mirella Marino, MD Department of Pathology Regina Elena National Cancer Institute Rome, Italy M. Blair Marshall, MD, FACS Professor of Surgery Chief, Division of Thoracic Surgery Department of Surgery MedStar Georgetown University Hospital Washington, District of Columbia Gilbert Massard, MD Professor Department of Thoracic Surgery and Lung Transplantation Strasbourg University Hospital Strasbourg, France Douglas J. Mathisen, MD

Hermes C. Grillo Professor of Surgery Harvard Medical School Chief General Thoracic Surgery Massachusetts General Hospital Boston, Massachusetts Giulio Maurizi, MD Division of Thoracic Surgery Sapienza University of Rome Sant’Andrea Hospital Rome, Italy Donna E. Maziak, MDCM, MSc, FRCSC, FACS Professor University of Ottawa Surgical Oncology Division of Thoracic Surgery Ottawa Hospital—General Campus Ottawa, Ontario Daniel P. McCarthy, MD, MBA Assistant Professor Department of Surgery University of Wisconsin Madison, Wisconsin Paul Michael McFadden, MD Professor of Clinical Cardiothoracic Surgery Surgical Co-Director of Lung Transplantation Division of Cardiothoracic Surgery Department of Surgery University of Southern California Los Angeles, California Rachel L. Medbery, MD Thoracic Surgery Fellow Department of Surgery Division of Cardiothoracic Surgery Emory University School of Medicine Atlanta, Georgia Robert A. Meguid, MD, MPH, FACS Associate Professor Section of General Thoracic Surgery Division of Cardiothoracic Surgery Department of Surgery University of Colorado Anschutz Medical Campus Aurora, Colorado

Babak J. Mehrara, MD Professor and Chief, Plastic and Reconstructive Surgery Service William G. Cahon Chair in Surgery Memorial Sloan Kettering Cancer Center New York, New York Steven J. Mentzer, MD Professor of Surgery Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Robert E. Merritt, MD Associate Professor of Surgery Director The Division of Thoracic Surgery The Ohio State UnviersityWexner Medical Center Columbus, Ohio Giuseppe Miserocchi, MD Professor of Physiology and Biophysics Department of Medicine and Surgery University Milano-Bicocca Milan, Italy John D. Mitchell, MD Courtenay C. and Lucy Patten Davis Endowed Chair in Thoracic Surgery Professor and Chief, Section of General Thoracic Surgery Division of Cardiothoracic Surgery University of Colorado Anschutz Medical Campus Aurora, Colorado Kamran Mohiuddin, MD Director Clinical Research Einstein Medical Center Philadelphia, Pennsylvania Elie Mouhayar, MD Associate Professor of Medicine Department of Cardiology University of Texas MD Anderson Cancer Center Houston, Texas Michael S. Mulligan, MD Professor of Surgery Chief Division of Cardiothoracic Surgery University of Washington Seattle, Washington

Michael S. Mulvihill, MD Resident in Surgery Department of Surgery Duke University Medical Center Durham, North Carolina Sudish C. Murthy, MD, PhD, FACS, FCCP Department of Thoracic and Cardiovascular Surgery Cleveland Clinic Cleveland, Ohio Philippe Nafteux, MD, PhD Clinical Head Department of Thoracic Surgery University Hospitals Leuven Leuven, Belgium Chaitan K. Narsule, MD Assistant Professor Department of Surgery Boston University School of Medicine Boston, Massachusetts Basil Nasir, MBBCh Division of Thoracic Surgery Centre Hospitalier de l’Université de Montréal Montreal, Quebec Keith S. Naunheim, MD The Vallee and Melba Willman Chair of Surgery Chief of Thoracic Surgery Department of Surgery Saint Louis University School of Medicine St. Louis, Missouri Calvin S. H. Ng, BSc, MD, FRCSEd(CTh), FCCP Associate Professor Department of Surgery The Chinese University of Hong Kong Hong Kong, SAR, China Daniel G. Nicastri, MD Assistant Professor Department of Thoracic Surgery Icahn School of Medicine at Mount Sinai New York, New York Francis C. Nichols, MD Professor of Surgery Consultant General Thoracic Surgery

Mayo Clinic Rochester, Minnesota David M. Notrica, MD, FACS, FAAP Associate Professor University of Arizona College of Medicine Tuscan, Arizona Associate Professor of Surgery Mayo Clinic School of Medicine Division of Pediatric Surgery Phoenix Children’s Hospital Phoenix, Arizona Daniel Ocazionez, MD Assistant Professor Department of Diagnostic and Interventional Imaging University of Texas HSC at Houston Houston, Texas Matthias Ochs, MD Professor and Chair Institute of Functional and Applied Anatomy Hannover Medical School Hannover, Germany John A. Odell, MBChB, FRCS(Ed), FACS Emeritus Professor of Surgery Mayo Clinic Jacksonville, Florida Amaia Ojanguren, MD, PhD Associate Professor of Surgery University of Lleida Division of Thoracic Surgery Arnau de Vilanova University Hospital Lleida, Spain Institut Catala de la Salut Barcelona, Spain Anne Olland, MD, PhD Associate Professor Department of Thoracic Surgery Strasbourg University Hospital Strasbourg, France Mark Onaitis, MD Associate Professor of Surgery University of California San Diego La Jolla, California

Raymond P. Onders, MD Professor and Chief of General Surgery Case Western Reserve University School of Medicine University Hospitals Cleveland Medical Center Cleveland, Ohio Isabelle Opitz, MD Associate Professor Department of Thoracic Surgery University Hospital Zurich Zurich, Switzerland Asishana Osho, MD, MPH Clinical Fellow Department of Surgery Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Berker Özkan, MD Associate Professor Department of Thoracic Surgery Istanbul Medical School Istanbul University Istanbul, Turkey Siddharth Padmanabhan, MBBS, LLB, BCom Resident Latrobe Regional Hospital Victoria, Australia Hao Pan, MD Chief Resident Department of Cardiothoracic Surgery UT Health San Antonio San Antonio, Texas Kostas Papagiannopoulos, MD, MMED THORAX (CTH) Honorary Senior Lecturer Leeds University Department of Thoracic Surgery St. James’s University Hospital Leeds, United Kingdom Nadeem Parkar, MD Chief Section of Thoracic and Cardiac Imaging Assistant Professor of Radiology Assistant Professor of Internal Medicine

Saint Louis University School of Medicine Saint Louis, Missouri G. Alexander Patterson, MD Joseph C. Bancroft Professor of Surgery Division of Cardiothoracic Surgery Washington University St. Louis, Missouri Edoardo Pescarmona, MD Department of Pathology Regina Elena National Cancer Institute Rome, Italy Adrienne A. Phillips, MD, MPH Assistant Professor of Medicine Department of Medicine Division of Hematology and Medical Oncology Weill Cornell Medical College New York, New York Joseph D. Phillips, MD Assistant Professor Department of Surgery Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire Anthony L. Picone, MD, PhD, MBA Professor of Oncology Department of Thoracic Surgery Roswell Park Cancer Institute Buffalo, New York Eitan Podgaetz, MD, MPH, FACS Associate Professor Texas A&M University Director of Minimally Invasive Thoracic Surgery Center for Thoracic Surgery Baylor University Medical Center Dallas, Texas Cecilia Pompili, MD Thoracic Surgeon Leeds Institute of Cancer and Pathology University of Leeds St James’s University Hospital Leeds, United Kingdom Jeffrey L. Port, MD Professor of Clinical Cardiothoracic Surgery

Weill Cornell Medical College Associate Attending New York Presbyterian Hospital New York, New York Ciprian Pricopi, MD Department of Thoracic Surgery Georges Pompidou European Hospital Paris, France Varun Puri, MD, MSCI Associate Professor Department of Surgery Washington University St. Louis, Missouri Joe B. Putnam, Jr., MD, FACS Medical Director Baptist MD Anderson Cancer Center Jacksonville, Florida Siva Raja, MD, PhD, FACS Professional Staff, Thoracic Surgery Surgical Director, Center for Esophageal Diseases Heart and Vascular Institute Cleveland Clinic Foundation Cleveland, Ohio Arvind Rajagopal, MBBS Assistant Professor Department of Anesthesiology Rush University Medical Center Chicago, Illinois Ravi Rajaram, MD, MSc General Surgery Resident Department of Surgery Northwestern University Feinberg School of Medicine Chicago, Illinois Pala Babu Rajesh, FRCS Ed, FRCS CTh, FRCS Eng Consultant Thoracic Surgeon Regional Department of Thoracic Surgery Birmingham Heartlands Hospital Birmingham, United Kingdom Prabhakar Rajiah, MBBS, MD, FRCR Associate Professor of Radiology Associate Director of Cardiac CT and MRI Department of Radiology, Cardiothoracic Radiology

UT Southwestern Medical Center Dallas, Texas Karthik Ravi, MD Assistant Professor of Medicine Department of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota Rishindra M. Reddy, MD Associate Professor Department of Surgery, Section of Thoracic Surgery University of Michigan Ann Arbor, Michigan James Regan, MD Department of Surgery Southern Illinois University School of Medicine Springfield, Illinois Jean-François Regnard Professor of Thoracic Surgery Head Department of Thoracic Surgery Paris Descartes University Hôpital Cochin, APHP Paris, France Janani S. Reisenauer, MD Department of Pulmonary Medicine Division of Thoracic Surgery Mayo Clinic Rochester, Minnesota Erino A. Rendina, MD Chief, Division of Thoracic Surgery Sapienza University of Rome Rome, Italy Carlos S. Restrepo Professor of Radiology Director of Cardiothoracic Radiology UT Health San Antonio San Antonio, Texas David Rice, MB, BCh, BAO, FRCSI Department of Thoracic and Cardiovascular Surgery University of Texas MD Anderson Cancer Center Houston, Texas

Thomas W. Rice, MD Professor Department of Surgery Cleveland Clinic Lerner College of Medicine Section Head, Department of Thoracic Surgery Cleveland Clinic Cleveland, Ohio Marc Riquet, MD, PhD Professor Department of Thoracic Surgery Georges Pompidou European Hospital Paris, France Valerie W. Rusch, MD Professor Department of Surgery Weill Cornell Medical College Chief, Thoracic Service William G. Cahan Chair Department of Surgery Memorial Sloan-Kettering Cancer Center New York, New York Michele Salati, MD, PhD Unit of Thoracic Surgery University Hospital Ancona United Hospitals Ancona, Italy Mary Salvatore, MD Associate Professor Department of Radiology Mount Sinai Health System New York, New York Pamela Samson, MD Resident Physician Department of Surgery Washington University in St. Louis St. Louis, Missouri Nicola Santelmo, MD Hôpital Civil de Strasbourg Strasbourg, France Inderpal (Netu) S. Sarkaria, MD Vice Chairman, Clinical Affairs Department of Cardiothoracic Surgery University of Pittsburgh School of Medicine

University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Giorgio V. Scagliotti Professor of Medical Oncology Department of Oncology University of Turin Torino, Italy Eric Sceusi, MD Thoracic Surgeon Piedmont Heart Institute Atlanta, Georgia Lara Schaheen, MD Chief Resident Department of Cardiothoracic Surgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Philip Maximilian Scherer, MD Assistant Professor of Radiology University of Central Florida College of Medicine Florida Hospital Orlando, Florida Radiology Specialists of Florida Maitland, Florida Colin Schieman, MD, FRCSC Clinical Associate Professor Residency Program Director Section of Thoracic Surgery Cumming School of Medicine at University of Calgary Calgary, Alberta David S. Schrump, MD, MBA, FACS Senior Investigator and Chief Thoracic and General Surgical Oncology Branch Center for Cancer Research National Cancer Institute Bethesda, Maryland Matthew J. Schuchert, MD Associate Professor Department of Cardiothoracic Surgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Christopher W. Seder, MD Assistant Professor

Department of Cardiovascular and Thoracic Surgery Rush University Medical School Chicago, Illinois Agathe Seguin-Givelet, MD, PhD Department of Thoracic Curie-Montsouris Thorax Institute Paris, France Joanna Sesti, MD Department of Cardiothoracic Surgery Robert Wood Johnson Barnabas Health System Livingston, New Jersey Farid M. Shamji, MBBS, FRCSC, FACS Professor of Surgery Division of Thoracic Surgery University of Ottawa Ottawa Hospital—General Campus Ottawa, Ontario, Canada Jason P. Shaw, MD Chief Department of General Thoracic Surgery Maimonides Medical Center Brooklyn, New York David D. Shersher, MD Assistant Professor Department of Surgery Cooper Medical School of Rowan University MD Anderson Cancer Center Camden, New Jersey Thomas W. Shields, MD, DSc (Hon.)† Professor Emeritus of Surgery Northwestern University Feinberg School of Medicine Chicago, Illinois Joseph B. Shrager, MD Professor of Cardiothoracic Surgery Stanford University School of Medicine Chief, Division of Thoracic Surgery Stanford Cancer Institute Stanford, California Antonios C. Sideris Research Fellow Division of Thoracic Surgery Brigham and Women’s Hospital

Harvard Medical School Boston, Massachusetts Resident Department of General Surgery Cleveland Clinic Foundation Cleveland, Ohio Alan D. L. Sihoe, MA(Cantab), FRCSEd(CTh), FCSHK, FHKAM, FCCP Clinical Associate Professor Department of Surgery Chief of Thoracic Surgery The University of Hong Kong HKU Shenzhen Hospital Hong Kong, China Mark A. Socinski, MD Executive Medical Director Member, Thoracic Oncology Program Florida Hospital Cancer Institute Orlando, Florida Joshua R. Sonett, MD Professor and Chief Thoracic Surgery Columbia University New York Presbyterian Hospital New York, New York Nathaniel J. Soper, MD, FACS Loyal and Edith Davis Professor and Chair Department of Surgery Northwestern University Feinberg School of Medicine Chief of Surgery Northwestern Medicine Chicago, Illinois James E. Speicher, MD Assistant Professor Department of Cardiovascular Sciences Division of Thoracic and Foregut Surgery East Carolina University Greenville, North Carolina Jonathan D. Spicer, MD, PhD, FRCS Assistant Professor Division of Thoracic Surgery Dr. Ray Chiu Distinguished Scientist in Surgical Research McGill University

Montreal, Canada Laurence N. Spier Chief Division of Thoracic Surgery NYU-Winthrop University Hospital Mineola, New York Sandra Starnes, MD Professor of Surgery John B. Flege Chair in Cardiothoracic Surgery University of Cincinnati College of Medicine Cincinnati, Ohio Kevin L. Stephans, MD Associate Professor Department of Radiation Oncology Cleveland Clinic, Taussig Cancer Center Cleveland, Ohio Joel Miller Sternbach, MD, MBA Bechily-Hodes Fellow in Esophagology Department of Surgery Northwestern University, Feinberg School of Medicine Chicago, Illinois Hon Chi Suen, MBBS, FRCSEd, FRCS, RCPS(Glasg), FCSHK, FACS, DABThS, DABS President Center for Cardiothoracic Surgery, Inc. St. Louis, Missouri David J. Sugarbaker, MD Professor and Chief Division of Thoracic Surgery Baylor College of Medicine Houston, Texas Kei Suzuki, MD Assistant Professor Department of Surgery Boston Medical Center Boston, Massachusetts Scott J. Swanson, MD Director Minimally Invasive Thoracic Surgery Vice Chair Cancer Affairs Brigham and Women’s Hospital Chief Surgical Office

Dana Farber Cancer Institute Professor of Surgery Harvard Medical School Boston, Massachusetts Gunturu N. Swati, MD Government Medical College Akola Visiting student Icahn School of Medicine at Mount Sinai Hospital New York, New York Ezra N. Teitelbaum, MD, MEd Assistant Professor of Surgery and Medical Education Department of Surgery Northwestern University, Feinberg School of Medicine Chicago, Illinois Sara Tenconi, MD Consultant Thoracic Surgeon Sheffield Teaching Hospitals United Kingdom Michael Thomas, MD Assistant Professor Department of Surgery Southern Illinois University School of Medicine Springfield, Illinois Pascal A. Thomas, MD Professor and Chief Department of Thoracic Surgery North University Hospital–Aix-Marseille University Marseille, France Prashanthi N. Thota, MD, FACG Medical Director Esophageal Center Director Center for Swallowing and Motility Disorders Digestive Disease & Surgery Institute Cleveland Clinic Cleveland, Ohio Alper Toker, MD Head Department of Thoracic Surgery Istanbul University, Istanbul Faculty of Medicine Istanbul, Turkey Victor F. Trastek, MD

Director of Science of Healthcare Delivery College of Healthcare Solutions Arizona State University Phoenix, Arizona Consultant in Leadership and Professionalism Mayo Clinic Scottsdale, Arizona H. Adam Ubert, MD Attending Cardiothoracic Surgeon Department of Cardiovascular Medicine Charleston Area Medical Center Charleston, West Virginia Eric Vallières, MR, FRCSC Surgical Director of the Lung Cancer Program Medical Director Division of Thoracic Surgery Swedish Cancer Institute Seattle, Washington Victor van Berkel, MD, PhD Associate Professor Department of Cardiovascular and Thoracic Surgery University of Louisville School of Medicine Louisville, Kentucky Koen van Besien, MD, PhD Director, Stem Cell Transplant Program Division of Hematology/Oncology Weill Cornell Medical College New York, New York Dirk Van Raemdonck, MD, PhD Professor of Surgery KU Leuven University Head of Transplant Center University Hospitals Leuven Leuven, Belgium Paul E. Y. Van Schil, MD, PhD Chair Department of Thoracic and Vascular Surgery Antwerp University Hospital and Antwerp University Antwerp, Belgium Hans Van Veer, MD Assistant Clinic Head Department of Thoracic Surgery

University Hospitals Leuven Leuven, Belgium Ara A. Vaporciyan, MD, FACS Professor and Chairman Department of Thoracic and Cardiovascular Surgery University of Texas MD Anderson Cancer Center Houston, Texas Nirmal K. Veeramachaneni, MD Department of Thoracic Surgery University of Kansas Medical Center Kansas City, Kansas Federico Venuta, MD Professor of Thoracic Surgery and Chief Sapienza University of Rome Policlinico Umberto I Rome, Italy Gregory Videtic, MD, CM, FRCPC, FACR Professor of Medicine Cleveland Clinic Lerner College of Medicine Staff Physician Department of Radiation Oncology Cleveland Clinic Cleveland, Ohio Carlos Vigliano, MD Associate Professor Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB) Favaloro University–CONICET Chief Department of Pathology University Hospital Favaloro Foundation Buenos Aires, Argentina Liza Villaruz, MD Assistant Professor of Medicine Department of Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Robin Vos, MD, PhD Department of Respiratory Medicine, Lung Transplant and Respiratory Intermediate Care Unit University Hospitals Leuven, Gasthuisberg Campus Assistant Professor of Medicine Department of Chronic Diseases, Metabolism and Ageing (CHROMETA) Lab of Respiratory Diseases, KU

Leuven, Belgium David Waller, FRCS(CTh) Consultant Thoracic Surgeon St. Bartholomew’s Hospital London, United Kingdom Garrett L. Walsh, MD Professor of Surgery Department of Thoracic and Cardiovascular Surgery University of Texas MD Anderson Cancer Center Houston, Texas Saiama N. Waqar, MBBS, MSCI Assistant Professor of Medicine Division of Oncology Washington University School of Medicine St. Louis, Missouri William H. Warren, MD† Professor Department of Cardiovascular Surgery Rush University Medical Center Chicago, Illinois Thomas J. Watson, MD, FACS Professor of Surgery Georgetown University School of Medicine Regional Chief of Surgery MedStar Washington Washington, District of Columbia Jon O. Wee, MD Section Chief, Esophageal Surgery Co-Director of Minimally Invasive Thoracic Surgery Director of Robotics in Thoracic Surgery Division of Thoracic Surgery Brigham and Women’s Hospital Boston, Massachusetts Ewald R. Weibel, MD, DSc(hon) Professor Emeritus Institute of Anatomy University of Bern Bern, Switzerland Mark Weir, MBChB Assistant Professor Department of Thoracic Medicine and Surgery Lewis Katz School of Medicine at Temple University

Philadelphia, Pennsylvania Michael J. Weyant, MD Professor of Surgery Department of Surgery Division of Cardiothoracic Surgery University of Colorado Aurora, Colorado Abby White, DO Division of Thoracic Surgery Brigham and Women’s Hospital Boston, Massachusetts Ory Wiesel, MD Clinical Fellow Division of Thoracic Surgery Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Dennis A. Wigle, MD, PhD Associate Professor Division of General Thoracic Surgery Mayo Clinic Rochester, Minnesota Elbert E. Williams, MD Department of Cardiothoracic Surgery Mount Sinai Health System New York, New York Jennifer L. Wilson, MD Department of Thoracic Surgery Beth Israel Deaconess Medical Center Instructor of Surgery Harvard Medical School Boston, Massachusetts Douglas E. Wood, MD, FACS, FRCSEd The Henry N. Harkins Professor and Chair Department of Surgery University of Washington Seattle, Washington Neil McIver Woody, MD, MS Associate Staff Department of Radiation Oncology Cleveland Clinic, Taussig Cancer Institute Cleveland, Ohio

Cameron Wright, MD Douglas Mathisen Professor of Surgery Division of Thoracic Surgery Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Moritz C. Wyler von Ballmoos, MD, PhD, MPH, FACC Clinical Associate in Surgery Division of Cardiothoracic Surgery Duke University Medical Center Durham, North Carolina Alexander Yang, MS MD Candidate, Class of 2020 GW School of Medicine and Health Sciences Washington, District of Columbia Chi-Fu Jeffrey Yang, MD Resident Department of Surgery Duke University Durham, North Carolina Stephen C. Yang, MD The Arthur B. and Patricia B. Modell Endowed Chair in Thoracic Surgery Professor of Surgery and Oncology The Johns Hopkins Medical Institutions Baltimore, Maryland David Yankelevitz, MD Professor Department of Radiology Icahn School of Medicine New York, New York Anjana Yeldandi, MD Associate Professor of Pathology Northwestern Memorial Hospital Feinberg Pavilion Chicago, Illinois Sai Yendamuri, MD, FACS Professor and Chair Department of Thoracic Surgery Roswell Park Cancer Institute Buffalo, New York Jonathan C. Yeung, MD, PhD, FRCSC

Assistant Professor Division of Thoracic Surgery University of Toronto Toronto, Ontario Akihiko Yoshizawa, MD, PhD Associate Professor Department of Diagnostic Pathology Kyoto University Hospital Kyoto, Japan Masaya Yotsukura, MD Assistant Division of Thoracic Surgery Keio University School of Medicine Tokyo, Japan David S. Younger, MD, MPH, MS Clinical Associate Professor Department of Neurology School of Medicine and College of Global Public Health New York University New York City, New York Yachao Zhang, MD Department of Radiology Westchester Medical Center Valhalla, New York Ze-Rui Zhao, MD Department of Surgery Prince of Wales Hospital Hong Kong, China Yifan A. Zheng, MD Resident Department of Surgery Division of Thoracic Surgery Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Brittany A. Zwischenberger, MD Cardiothoracic Surgery Fellow Division of Cardiovascular and Thoracic Surgery Duke University Durham, North Carolina Joseph “Jay” B. Zwischenberger, MD Johnston-Wright Professor and Chairman

Department of Surgery University of Kentucky Lexington, Kentucky †Deceased

Preface to the Eighth Edition In the foreword to the first edition of General Thoracic Surgery published in 1972, Paul Samson noted that Shields published a text dedicated to the General Thoracic Surgeon to the exclusion of the heart. That occurred at a time when the “romance and appeal which have attended the astounding developments in the surgical treatment of cardiac disease” was skyrocketing. During the next 40 years of cardiac surgical dominance on the international stage, Shields’ book remained focused on the diseases of the lungs, esophagus, chest wall, diaphragm, and mediastinum. The first text, penned by 58 specialists, was encyclopedic in scope and depth. Students and practitioners of this specialty needed no other book. Through its many editions, it carried the same thorough approach and served as the de facto bible of the specialty. Over the decades, other books, atlases and manuals on General Thoracic Surgery have come and gone, but this book has remained the only comprehensive text in continuous publication for the practitioner of thoracic diseases, excluding the heart and great arteries. In the current digital age, seekers of knowledge no longer rely solely on the static text. They often begin their search for information by scouring the Internet for a variety of media for articles, videos, meeting reports, videos and other tidbits to understand the nuances of a particular disease or procedure. While more dynamic than searching the texts of old, these searches often are hampered by search terms, are disorganized, narrow in scope, and evanescent. Now, 45 years after the first publication, this edition of Shields’ General Thoracic Surgery is written by over 150 specialists. It has shed its encyclopedic tradition while maintaining its completeness. It includes dynamic audio and visual content, color coordinated graphics, and analyses of the world’s literature and electronic data for the most extensive and concise collection of information for the busy clinician. For the first time, the edition includes a retrospective into the past with particular attention to the milestones of artificial ventilation and the era of minimal invasion, both of which revolutionized the century-old specialty. It also addresses new topics such as deciphering complex statistical analyses, using efficiently the new World Health Organization’s International Classification of Diseases (ICD-10), mining big data sets for specific decision making, and developing and performing effective quality improvement projects for the surgeon’s practice and hospital setting. Long-time users of Shields will enjoy the continued comprehensiveness of the chapters. Millennial practitioners will find this transformed edition less ponderous and intimidating than the tomes of the past, yet more thorough and meaningful than imprecise, often fragmented individual electronic searches.

Preface to the First Edition This volume was prepared to present a comprehensive text on the surgical diseases of the chest wall, pleura, diaphragm, trachea, lung, and mediastinal structures. Initially, an overview of the anatomy and of the physiology of these structures is given. The investigation of the patient’s disease and the management of the patient in the perioperative period are considered next. The various operative approaches and the standard surgical procedures are discussed and these are followed by chapters concerned with the disease entities of the aforementioned structures. The major objectives are to present a summation of the current knowledge and the clinical concepts of the surgical management of trauma and diseases of the thorax. The pathophysiologic alterations produced and the corrections of these by appropriate intervention are emphasized throughout. Presentations of the clinical features, pathologic changes, surgical management, operative results, and prognosis of the various disease states are included as an integral part of the whole. Outstanding surgeons, physicians, and scientists have cooperated in the preparation of the text. As with most multi-authored books, repetition could not be completely eliminated; however, I have tried to keep it at a minimum. In most instances, the repetition serves to emphasize important information relative to the entire subject. Interestingly, conflicting statements are few, and only an occasional footnote has been appended to point out such differences in opinion. This book hopefully will serve as a source of information for the young thoracic surgeon and the person in surgical training. It also should serve as a reference for surgeons, as well as physicians, outside the field of general thoracic surgery who wish to ascertain the current views held by the specialty. TWS

Acknowledgments Any large textbook such as this one, an army of individuals is required to produce a quality work. The editors appreciate the efforts of the publishers, the artists, and the printers assigned to this project. Most of all, it is the volunteers who really make the text worthwhile. We thank the authors and coauthors who composed the original content and those who updated the old content. In addition, we thank their administrative assistants who participated in the production of the content. In particular, the editors wish to acknowledge two volunteers who sacrificed a great deal of personal time and expended their intellectual energy to improve the quality of the book. From the inception of this edition, Bryan F. Meyers, MD has been a strong advocate and a driving force. He participated in the development of the revised table of contents and in the editor discussions of the revised chapter format. Most importantly, he helped recruit a number of national and international authors. Special thanks goes to Martha S. LoCicero, MD, who performed substantial copyediting duties in an effort to make the text readable and relevant. She also provided the much needed advice and encouragement over the long development phase of this project. JLIII

Video List Video 19.1 Pneumothorax. Video 19.2 Sonographic signs of a pneumothorax. Video 20.1 Technique of Videomediastinoscopy. Video 34.1 Thoracoscopic left upper lobe wedge resection. Video 34.2 Thoracoscopic right upper lobectomy. Video 34.3 Thoracoscopic right middle lobectomy. Video 34.4 Thoracoscopic right lower lobectomy. Video 34.5 Thoracoscopic left upper lobectomy. Video 34.6 Thoracoscopic left pneumonectomy. Video 36.1 Non-intubated uniportal VATS right lower lobe wedge resection for colorectal metastasis. Video 36.2 Manipulating and division of the left upper lobe bronchus during non-intubated uniportal VATS left upper lobectomy for early stage non-small cell lung carcinoma. Video 43.1 Ravitch procedure. Video 74.1 Preoperative bronchoscopy of an adenoid cystic carcinoma of the lower trachea and carina. Video 79.1 Correct development of the endarterectomy plane and distal extension of the endarterectomy such that the specimen releases under gentle tension Video 83.1 Bronchoscopic view in two patients with bronchiectasis. Video 83.2 Three-port VATS lobectomy and lingulectomy for bronchiectasis. Video 83.3 Uniportal VATS lobectomy and lingulectomy for bronchiectasis. Video 83.4 Virtual bronchoscopy in middle lobe syndrome. Video 83.5 Uniportal VATS middle lobectomy for middle lobe syndrome. Video 91.1 Localization of intraparenchymal pulmonary nodules using direct intracavitary thoracoscopic ultrasonography. Video 96.1 Anatomy of right paratracheal region. Video 96.2 VATS dissection of right paratracheal region. Video 96.3 VATS Subcarinal dissection from the right thoracic compartment. Video 96.4 VATS inferior mediastinal dissection: Station 8. Video 96.5 VATS inferior mediastinal dissection: Station 9. Video 96.6 VATS aortopulmonary window and para-aortic dissection: Stations 5 and 6. Video 96.7 VATS Subcarinal dissection from the left thoracic compartment. Video 96.8 TEMLA set up. Video 96.9 A: Right paratracheal dissection. B: Right paratracheal dissection.

Video 96.10 A: Subcarinal dissection. B: Subcarinal dissection. Video 96.11 Left paratracheal dissection. Video 96.12 Aortopulmonary dissection. Video 108.1 Technique of clinical isolated lung perfusion. Video 108.2 Technique of clinical isolated lung perfusion as performed at the Antwerp University Hospital in Belgium. Video 113.1 Technique of clinical isolated lung perfusion as performed at the Antwerp University Hospital in Belgium. Video 134.1 Operative exposure of the proximal esophagus. Video 134.2 Tracheomalacia before (A) and after (B) aortopexy. Video 134.3 During the second surgery for repair of EA with TEF in a very small infant, a major chyle leak was noticed and ended. Video 134.4 H-type TEF as well as Fogarty catheter placement. Video 154.1 Division of sternum with lungs deflated. Video 154.2 Reapproximation of sternum using interrupted sutures. Video 155.1 Mediastinal exposure using a throw-off grasping forceps. Video 155.2 Technique for direct aspiration of the liquid component to reduce the volume of a cystic teratoma. Video 156C.1 Operative technique of robotic-assisted VATS thymectomy. Video 174.1 Pus leaking out when infected pericardial cyst being dissected.

Contents VOLUME ONE Contributing Authors Preface to the Eighth Edition Preface to the First Edition Acknowledgments Video List

PART A Evolution of General Thoracic Surgery SECTION I History and Pioneers in Thoracic Surgery 1 The History of Thoracic Surgery John A. Odell 2 Pulmonary Surgery After Mechanical Ventilation Arvind Rajagopal, David D. Shersher, and William H. Warren† 3 Minimally Invasive Thoracic Surgery Stephen Hazelrigg, James Regan, and Michael Thomas PART B The Lung, Pleura, Diaphragm, and Chest Wall SECTION II Structure and Function of The Chest Wall and Lungs 4 Anatomy of the Thorax Anna Maria Ciccone, Federico Venuta, and Erino A. Rendina 5 Embryology of the Lungs Alejandro C. Bribriesco, Mala R. Chinoy, and Daniel Kreisel 6 Ultrastructure and Morphometry of the Human Lung Matthias Ochs, Peter H. Burri, and Ewald R. Weibel 7 Cellular and Molecular Biology of the Lung Steven J. Mentzer 8 Surgical Anatomy of the Lungs Nirmal K. Veeramachaneni 9 Lymphatics of the Lungs Marc Riquet and Ciprian Pricopi

10 Mechanics of Breathing and Pulmonary Gas Exchange Giuseppe Miserocchi, Egidio Beretta, and Francesca Lanfranconi SECTION III Thoracic Imaging 11 Standard Radiographic Evaluation of the Lungs and Chest Dong-Seok Daniel Lee, Mary Salvatore, David Yankelevitz, Claudia I. Henschke, and Raja M. Flores 12 Computed Tomography of the Lungs, Pleura, and Chest Wall Mary Salvatore, Kunwei Li, Lea Azour, David Yankelevitz, and Claudia I. Henschke 13 Magnetic Resonance Imaging of the Thorax Prabhakar Rajiah and Ritu R. Gill 14 Radionucleotide Studies of the Lung Perry Gerard, Amrita K. Arneja, and Yachao Zhang 15 Thoracic PET CT Perry Gerard, Neil Kapadia, and Jay Acharya SECTION IV Diagnostic Procedures 16 Laboratory Investigations in the Diagnosis of Pulmonary Diseases Erin A. Gillaspie and Dennis A. Wigle 17 Molecular Diagnostic Studies and Genomic Studies in Pulmonary Disease Jacob A. Klapper and Chadrick E. Denlinger SECTION V Diagnostic Procedures In Pulmonary Diseases 18 Bronchoscopic Evaluation of the Lungs and Tracheobronchial Tree Dominik Harzheim and Felix J. F. Herth 19 Ultrasound and Endoscopic Bronchoscopic Ultrasound in the Evaluation of the Lungs, Mediastinum, and Pleura Basil Nasir and Moishe Liberman 20 Mediastinoscopy Toni Lerut and Paul De Leyn 21 Transcervical Mediastinal Lymphadenectomy Gunda Leschber 22 Invasive Diagnostic Procedures Michael Lanuti SECTION VI

Preoperative Assessment of the Thoracic Surgical Patient 23 General Risk Assessment of Patients for Thoracic Surgical Procedures Alessandro Brunelli, Cecilia Pompili, and Michele Salati 24 Pulmonary Physiologic Assessment of Operative Risk Diego Avella Patino and Mark K. Ferguson SECTION VII Preoperative And Anesthetic Management of The General Thoracic Surgical Patient 25 Preoperative Preparation of the General Thoracic Surgical Patient Traves D. Crabtree and Seth B. Krantz 26 Conduct of Anesthesia Brian P. Barrick SECTION VIII Pulmonary Resections 27 Thoracic Incisions Dominic Emerson and M. Blair Marshall 28 Technical Aspects of Lobectomy Stanley C. Fell,† Malcolm M. DeCamp, and Richard H. Feins 29 Pneumonectomy and Its Modifications Stéphane Collaud, Philippe Dartevelle, and Elie Fadel 30 Sleeve Lobectomy Paul De Leyn and Herbert Decaluwé 31 Tracheal Sleeve Pneumonectomy Laura Donahoe and Marc de Perrot 32 Segmentectomy and Lesser Pulmonary Resections Chi-Fu Jeffrey Yang, and Thomas D’Amico 33 Robotic-Assisted Surgery in Pulmonary Diseases Richard S. Lazzaro, Andrew Brownlee, Laurence N. Spier, and Mark R. Dylewski 34 Video-Assisted Thoracoscopic Surgery for Wedge Resection, Lobectomy, and Pneumonectomy Miriam Huang, Mark W. Hennon, and Todd L. Demmy 35 Uniportal VATS Lobectomy Diego Gonzalez-Rivas and Alan D. L. Sihoe 36 Awake, Non-Intubated Transpleural Surgery Ze-Rui Zhao and Calvin S. H. Ng 37 Extended Resection of Pulmonary Carcinoma Including Chest Wall and Mediastinum

Kelvin Lau 38 Surgical Resection of Superior Sulcus Lesions Dominique Grunenwald 39 Management of Air Leaks and Residual Pleural Spaces Cameron Wright SECTION IX Postoperative Management of The General Thoracic Surgical Patient 40 General Principles of Postoperative Care Jason P. Shaw 41 Ventilatory Support of the Thoracic Surgical Patient Jonathan C. Yeung, Lorenzo Del Sorbo, and Shaf Keshavjee 42 Complications of Thoracic Surgical Procedures Benjamin D. Kozower SECTION X The Chest Cage 43 Chest Wall Deformities Charles B. Huddleston and Yosef Jose Greenspon 44 Hernias of the Chest Wall Nigel E. Drury and Pala Babu Rajesh 45 Infections of the Chest Wall Edward J. Bergeron, Robert A. Meguid, and John D. Mitchell 46 Thoracic Outlet Syndrome Dean M. Donahue and Asishana Osho 47 Transthoracic Approaches to the Spine Christopher W. Seder and Michael J. Liptay 48 Chest Wall Tumors Daniel G. Nicastri, Gunturu N. Swati, Elbert E. Williams, and Raja M. Flores, with contributions from David R. Jones 49 Chest Wall Reconstruction Kei Suzuki, Leila Jazayeri, Babak J. Mehrara, and David R. Jones SECTION XI The Diaphragm 50 Embryology and Anatomy of the Diaphragm Thomas W. Shields 51 Physiology of the Diaphragm and Surgical Approaches to the Paralyzed Diaphragm

Raymond P. Onders 52 Congenital Posterolateral Diaphragmatic Hernias and Other Less Common Hernias of the Diaphragm in Infants and Children Priscilla Chiu and Jacob C. Langer 53 Foramen of Morgagni Hernia Federico Venuta, Marco Anile, and Erino A. Rendina 54 Primary Tumors of the Diaphragm Thoracic Surgery Min P. Kim and Wayne Hofstetter Diagnostic Imaging Daniel Ocazionez and Carlos S. Restrepo SECTION XII The Pleura 55 Anatomy of the Pleura Isabelle Opitz 56 Absorption of Gases Within the Pleural Space Vasileios Kouritas and Kostas Papagiannopoulos 57 Pneumothorax Federico Venuta, Daniele Diso, and Erino A. Rendina 58 Mechanics and Fluid Dynamics of Lung and Pleural Space Giuseppe Miserocchi, Egidio Beretta, and Gabriele Simone Grasso 59 Benign Pleural Effusion Cliff K. C. Choong and Siddharth Padmanabhan 60 Parapneumonic Effusion, Empyema, and Fibrothorax David Waller and Sara Tenconi 61 Postsurgical Empyema Lisa M. Brown and Eric Vallières 62 Tuberculous and Fungal Infections of the Pleura Gilbert Massard, Anne Olland, Nicola Santelmo, and Pierre-Emmanuel Falcoz 63 Thoracoplasty: Indications and Surgical Considerations Marco Alifano, Antonio Bobbio, Christine Lorut, and Jean-François Regnard 64 Anatomy of the Thoracic Duct and Chylothorax Moritz C. Wyler von Ballmoos and David W. Johnstone 65 Solitary Fibrous Tumors and Other Uncommon Neoplasms of the Pleura Joel Miller Sternbach, Anjana Yeldandi, and Malcolm M. DeCamp 66 Chemotherapy and Alternative Therapies for Malignant Pleural Mesothelioma

Federica Grosso and Giorgio V. Scagliotti 67 Surgical Approaches for Diffuse Malignant Pleural Mesothelioma Bryan M. Burt, Shawn S. Groth, and David J. Sugarbaker 68 Malignant Pleural Effusions Jessica L. Hudson and Varun Puri 69 Malignant Pericardial Effusions David Rice and Elie Mouhayar SECTION XIII The Trachea and Bronchi 70 Tracheostomy Shamus R. Carr and Joseph S. Friedberg 71 Therapeutic Bronchoscopic Procedures Daniel P. McCarthy and Douglas E. Wood 72 Surgical Anatomy of the Trachea and Techniques of Resection and Reconstruction Pierre Delaere and Paul De Leyn 73 Management of Nonneoplastic Diseases of the Trachea Jennifer L. Wilson and Sidhu P. Gangadharan 74 Benign and Malignant Tumors of the Trachea Henning A. Gaissert 75 Compression of the Trachea by Vascular Rings Carl L. Backer SECTION XIV Congenital, Structural, and Inflammatory Diseases of the Lung 76 Congenital Parenchymal Lesions of the Lungs Antonio Bobbio, Laureline Berteloot, Claude Guinet, and Marco Alifano 77 Pulmonary Complications of Cystic Fibrosis Pascal A. Thomas 78 Congenital Vascular Lesions of the Lungs Antonio Bobbio, Laureline Berteloot, Audrey Lupo, and Marco Alifano 79 Chronic Pulmonary Emboli Nathaniel B. Langer, Philippe Dartevelle, and Elie Fadel 80 COPD for CT Surgery Mark Weir and Gerard J. Criner 81 Bullous and Bleb Diseases of the Lung Alan D. L. Sihoe 82 Lung Volume Reduction

Philip Carrott and Christine Lau 83 Bacterial Infections of the Lungs and Bronchial Compressive Disorders Semih Halezeroğlu 84 Pulmonary Tuberculosis and Other Mycobacterial Diseases of the Lung Gilbert Massard, Anne Olland, Nicola Santelmo, and Pierre-Emmanuel Falcoz 85 Surgical Management of Tuberculous and Nontuberculous Mycobacterial Infections of the Lung John D. Mitchell 86 Thoracic Mycotic and Actinomycotic Infections of the Lung Patrick Kohtz and Michael J. Weyant 87 Exotic Infections Requiring Surgical Intervention Alper Toker, Berker Özkan, and Erkan Kaba 88 Lung Transplantation Robin Vos, G. Alexander Patterson, and Dirk Van Raemdonck

VOLUME TWO SECTION XV Carcinoma of The Lung 89 Lung Cancer: Epidemiology and Carcinogenesis Pamela Samson and Graham A. Colditz 90 Lung Cancer Screening Douglas E. Wood 91 Investigation and Management of Indeterminate Pulmonary Nodules Pasquale Ferraro and Andrei-Bogdan Gorgos 92 Pathology of Carcinoma of the Lung Akihiko Yoshizawa, Hironori Haga, and Hiroshi Date 93 Ex Vivo Diagnosis of Lung Cancer Chadrick E. Denlinger and Jacob A. Klapper 94 Staging of Lung Cancer Joe B. Putnam, Jr. 95 Results of Surgical Treatment of Non-Small Cell Lung Cancer Ernest G. Chan, Patrick G. Chan, and Matthew J. Schuchert 96 Mediastinal Lymph Node Dissection Anthony L. Picone, Sai Yendamuri, and Todd L. Demmy 97 Unknown Primary Malignancy Metastatic to Thoracic Lymph Nodes Marc Riquet and Patrick Bagan

98 Adjuvant Chemotherapy for Non-Small-Cell Lung Cancer Lingling Du, Ramaswamy Govindan, and Saiama N. Waqar 99 Radiation for Lung Cancer Kevin L. Stephans, Rupesh Kotecha, Neil McIver Woody, and Gregory Videtic 100 Multimodality Therapy for Non-Small Cell Lung Cancer Onkar V. Khullar and Seth Force 101 Novel Therapeutic Strategies for Non-Small Cell Lung Cancer Saeed Arefanian, Stephanie Chang, and Alexander Krupnick 102 Emerging Technologies for Management of Lung Cancer in Patients With Marginal Physiologic Function Kendra Iskander and Hiran C. Fernando 103 Small-Cell Lung Cancer Liza Villaruz, Brian J. Karlovits, Timothy F. Burns, and Mark A. Socinski SECTION XVI Other Tumors of the Lung 104 Carcinoid Tumors Joanna Sesti and Jessica S. Donington 105 Adenoid Cystic Carcinoma and Other Primary Salivary Gland–Type Tumors of the Lung Richard S. D’Agostino 106 Benign Tumors of the Lung Virginia R. Litle and Ghulam Abbas 107 Uncommon Primary Malignant Tumors of the Lung Sebastián Defranchi and Carlos Vigliano 108 Pulmonary Metastases Paul E. Y. Van Schil, Willem Adriaan den Hengst, Mark S. Allen, and Joe B. Putnam, Jr. 109 Pulmonary Malignancies in the Immunocompromised Host David S. Schrump SECTION XVII Thoracic Trauma 110 Blunt and Penetrating Injuries of the Chest Wall, Pleura, Diaphragm, and Lungs Hao Pan and Scott B. Johnson 111 Barotrauma and Inhalation Injuries Brittany A. Zwischenberger and Joseph B. Zwischenberger 112 Acute Respiratory Distress Syndrome Ronson J. Madathil, Aaron M. Cheng, and Michael S. Mulligan

113 Management of Foreign Bodies of the Aerodigestive Tract Sandra Starnes and Julian Guitron 114 Blunt and Penetrating Injuries of the Esophagus Tracey Dechert and Virginia R. Litle 115 Esophageal Perforation Raja Mahidhara and Richard K. Freeman SECTION XVIII Understanding Statistical Analysis And Medical Decision Making 116 Statistics and Medical Decision Making for the Surgeon Mark K. Ferguson 117 Clinical Practice Guidelines in General Thoracic Surgery Robert E. Merritt 118 Rationale for and Use of Large National Databases Yinin Hu, Varun Puri and Benjamin D. Kozower 119 ICD-10: Implications for Future Clinical Research and Reporting Melanie A. Edwards and Keith S. Naunheim 120 Instruments and Resources for Quality Improvement in Thoracic Surgery Farhood Farjah and Douglas E. Wood PART C The Esophagus SECTION XIX Structure of the Esophagus 121 Embryology of the Aerodigestive Tract Steven J. Mentzer 122 Anatomy of the Esophagus Thomas J. Watson 123 Lymphatic Drainage of the Esophagus Thomas L. Bauer II and Mark J. Krasna SECTION XX Physiology of The Esophagus 124 Anatomy, Physiology, and Physiologic Studies of the Esophagus Siva Raja, Prashanthi N. Thota, and Sudish C. Murthy SECTION XXI Diagnostic Studies of The Esophagus

125 Radiologic Evaluation of the Esophagus Beatrice Aramini and Frank D’Ovidio 126 Endoscopy of the Esophagus Donna E. Maziak and Farid M. Shamji 127 Esophageal Ultrasound J. Shawn Mallery, Rafael Garza-Castillon, Eitan Podgaetz, and Rafael Andrade SECTION XXII Operative Procedures in The Management of Esophageal Disease 128 Operative Strategies for Esophageal Dysmotility Disorders Chaitan K. Narsule and Hiran C. Fernando 129 Surgical Techniques for the Treatment of Reflux Disease Antonios C. Sideris, Yifan A. Zheng, Abby White, and Raphael Bueno 130 Techniques of Esophagectomy Toni Lerut 130A Transthoracic Resection of the Esophagus Philippe Nafteux, Willy Coosemans, Lieven P. Depypere, Hans Van Veer, and Toni Lerut 130B Extended Resection for Esophageal Carcinoma Jeffrey L. Port, Mohamed K. Kamel, and Nasser K. Altorki 130C Transhiatal Esophagectomy Without Thoracotomy James E. Speicher and Mark D. Iannettoni 130D Vagal-Sparing Esophagectomy Steven R. DeMeester 130E Video-Assisted and Robotic Esophagectomy Inderpal S. Sarkaria, Lara Schaheen, and James D. Luketich 131 Alternative Conduits for Replacement of the Esophagus Hugh G. Auchincloss and Douglas J. Mathisen 132 Per-Oral Esophageal Procedures Ezra N. Teitelbaum and Nathaniel J. Soper 133 Esophageal Stents Ory Wiesel, Jon O. Wee SECTION XXIII Congenital, Structural, and Inflammatory Diseases of the Esophagus 134 Congenital Anomalies of the Esophagus David M. Notrica and Dawn E. Jaroszewski 135 Inflammatory Diseases of the Esophagus Joseph D. Phillips and Andrew C. Chang

136 Esophageal Motility Disorders Janani S. Reisenauer, Karthik Ravi, and Shanda H. Blackmon 137 Gastroesophageal Reflux Disease Thomas J. Watson 138 Barrett’s Esophagus Kamran Mohiuddin and Donald E. Low 139 Paraesophageal Hiatal Hernia Janet Edwards, Colin Schieman, and Sean C. Grondin 140 Esophageal Diverticula Pamela Samson and Varun Puri 141 Benign Tumors, Cysts, and Duplications of the Esophagus Kiran Lagisetty and Rishindra M. Reddy SECTION XXIV Malignant Lesions of The Esophagus 142 Carcinoma of the Esophagus Biniam Kidane, Mathieu Derouet, and Gail E. Darling 142 Appendix: 2009 AJCC/UICC Staging of Esophageal Cancer Thomas W. Rice, Valerie W. Rusch, and Eugene H. Blackstone 143 Staging of Esophageal Cancer Mark Onaitis 144 Multimodality Therapy for Esophageal Cancer Abby White and Scott J. Swanson 145 Less Common Malignant Tumors of the Esophagus Kiran Lagisetty and Andrew C. Chang 146 Palliative Approaches to Inoperable Esophageal Cancer Jonathan D. Spicer and Garrett L. Walsh PART D The Mediastinum SECTION XXV Structure and Function of The Mediastinal Contents 147 The Mediastinum, Its Compartments, and the Mediastinal Lymph Nodes Hisao Asamura and Masaya Yotsukura 148 The Thymus Michael S. Mulvihill, Jacob A. Klapper, and Matthew G. Hartwig 149 Mediastinal Parathyroids Daniel J. Boffa

150 Neurogenic Structures of the Mediastinum Ghulam Abbas and Mark J. Krasna SECTION XXVI Noninvasive Investigations 151 Radiographic, Computed Tomographic, and Magnetic Resonance Investigation of the Mediastinum Nadeem Parkar and Sanjeev Bhalla 152 Radionuclide Studies of the Mediastinum Philip Maximilian Scherer and Delphine L. Chen 153 Mediastinal Tumor Markers Mirella Marino, Rossano Lattanzio and Edoardo Pescarmona SECTION XXVII Invasive Diagnostic Investigations and Surgical Approaches 154 Sternotomy and Thoracotomy for Mediastinal Disease Giulio Maurizi, Federico Venuta, and Erino A. Rendina 155 Video-Assisted Thoracic Surgery for Mediastinal Tumors and Cysts and Other Diseases Within the Mediastinum Maxime Heyndrickx, Amaia Ojanguren, Agathe Seguin-Givelet, and Dominique Gossot 156 Surgical Techniques for Thymectomy Joseph LoCicero, III 156A Standard Thymectomy Francis C. Nichols and Victor F. Trastek 156B Transcervical Thymectomy Joseph B. Shrager 156C Operative Techniques of VATS and Robotic VATS Thymectomy Jonathan D’Cunha, Nicholas R. Hess, and Inderpal S. Sarkaria 156D Extended Transsternal Thymectomy With or Without Cervical Incision Jason P. Glotzbach, Mitchell J. Magee, Alper Toker, and Joshua R. Sonett SECTION XXVIII Mediastinal Infections, Mass Lesions in the Mediastinum, and Control of Vascular Obstructing Symptomatology 157 Acute and Chronic Mediastinal Infections Ravi Rajaram and Malcolm M. DeCamp 158 Primary Mediastinal Tumors and Cysts and Diagnostic Investigation of Mediastinal Masses Francis C. Nichols

159 Lesions Masquerading as Primary Mediastinal Tumors or Cysts Chadrick E. Denlinger and Jacob A. Klapper 160 Primary Pneumomediastinum Rachel L. Medbery and Felix G. Fernandez 161 Vascular Masses of the Mediastinum John Holt Chaney, H. Adam Ubert, and Victor van Berkel 162 Superior Vena Cava Syndrome: Clinical Features, Diagnosis, and Treatment Paul Michael McFadden and Christina L. Greene 163 Surgical Management of Benign Sympathetic Nervous System Conditions Stephen Hazelrigg and Erin E. Bailey SECTION XXIX Primary Mediastinal Tumors and Syndromes Associated With Mediastinal Lesions 164 Myasthenia Gravis David S. Younger 165 Evaluation of Results of Thymectomy for Nonthymomatous Myasthenia Gravis Mitchell J. Magee and Joshua R. Sonett 166 Tumors of the Thymus Usman Ahmad and James Huang 167 Benign Lymph Node Disease Involving the Mediastinum Jason Michael Long 168 Diagnosis and Treatment of Mediastinal Lymphomas Adrienne A. Phillips and Koen van Besien 169 Benign and Malignant Germ Cell Tumors of the Mediastinum Carlos Ibarra-Pérez, Isabel Alvarado-Cabrero, Walid Leonardo Dajer-Fadel, and Oscar ArrietaRodriguez 170 Benign and Malignant Neurogenic Tumors of the Mediastinum in Children and Adults Eric Sceusi and Ara A. Vaporciyan 171 Less Common Mediastinal Tumors Alexander Yang, Jinny S. Ha, and Stephen C. Yang 172 Mesenchymal Tumors of the Mediastinum M. Blair Marshall and Young K. Hong SECTION XXX Mediastinal Cysts 173 Foregut Cysts of the Mediastinum in Infants and Children Timothy Brand and Jason Michael Long

174 Foregut Cysts of the Mediastinum in Adults Hon Chi Suen Index †Deceased

Part A EVOLUTION OF GENERAL THORACIC SURGERY

Section

I HISTORY AND PIONEERS IN THORACIC SURGERY

1 The History of Thoracic Surgery John A. Odell “Let me repeat what history teaches, history teaches.” —Gertrude Stein

In this chapter important issues of how a correct diagnosis was achieved, how the pleural space needed to be controlled, and how an ability to control major blood vessels and to close a bronchial stump arose. For the older surgeons, the story is reasonably well known but for those entering the specialty it needs retelling. For the sake of brevity and continuity, I have concentrated on the challenges that needed to be overcome and included within these sections the pioneers who popularized a surgical approach. Inevitably, there will be some who were involved with more than one approach, and some who will be left out of the record. I have not attempted to include every pioneer, nor every surgical variation, nor every surgical first. Many of the early procedures were done in the belief that radical surgery was necessary to deal with the underlying disease process and many were simply published to show that a procedure was possible, but with no evidence that the procedure prolonged or improved the quality of life. It is also difficult to describe the small progressive steps that inevitably take place over a continuum of time. The first faltering steps are obviously described but the reader will need to imagine the further progress to the present. The subject of our surgical history actually deserves space for a book. For those wishing a more comprehensive tome there are two excellent reviews. Mead’s book1 is almost too comprehensive, and many will find the description of virtually every operation until the time of publication irksome, yet gems of information can be found within. Alternatively, the chapter by Molnar2 is excellent and gives a more inclusive European perspective than other historical chapters, but is limited, as this chapter will be, by editorial restrictions imposed in a reference book chapter. Nevertheless, both this chapter and Molnar’s provide references for those wishing to further explore the subject. Most of the developments that affected thoracic surgery occurred between the World Wars. My description will stop in approximately 1950, when advances in anesthesia (paralytic agents, halothane, and pentobarbital [pentothal] all introduced in that decade) enabled routine intratracheal ventilation and thoracic surgery safer. There will be some overlap with the subsequent chapter. Also, at that time, antituberculous drugs became widely available and changed the nature of thoracic surgery in a very dramatic fashion.3 Within a decade and a half of the discovery of antituberculous drugs, specialties of cardiac surgery and pulmonology, started to form.

INTRODUCTION It is not known exactly when the first thoracic surgical procedure was performed, but we can readily

understand the chest pathology the early physician had to deal with: traumatic wounds and the consequences of infection. Two early classic descriptions to set the stage for management of these pathologic processes are provided. The first description is that of Hippocrates translated from Fuchs’ edition.4 If as a result of the treatments the pus does not break through, one should not be surprised, for often it breaks into the body, and the patient seems to be better, because the pus has passed from a narrow space to a larger one. As time goes on, the fever becomes more severe, coughing begins, the side begins to pain, the patient cannot lie any more on the healthy side but on the diseased side, the feet and eyes swell. When the fifteenth day after the rupture has appeared, prepare a warm bath, set him upon a stool, which is not wobbly, someone should hold his hands, then shake him by his shoulders and listen to see on which side a noise is heard. And right at this place—preferably on the left—make an incision, then it produces death more rarely. Those cases of empyema or dropsy which are treated by incision or the cautery, if the water or pus flows rapidly all at once, certainly prove fatal. When empyema is treated either by the cautery or incision, if pure and white pus flow from the wound, the patients recover, but if mixed with blood, slimy and fetid, they die.

The second is by Barron Larrey,5 Napoleon’s surgeon, describing a soldier injured during the Egypt campaign of 1798. A soldier was brought to the hospital of the Fortress of Ibrahym Bey, immediately after a wound penetrated the thorax, between the fifth and sixth true ribs. It was about 8 cm in extent. A large quantity of frothy and vermilion blood escaped from it with a hissing noise at each inspiration. His extremities were cold, pulse scarcely perceptible, countenance discolored, and respiration short and laborious; in short, he was every moment threatened with a fatal suffocation. After having examined the wound, the divided edges of the part, I immediately approximated the two lips of the wound, and retained them by means of adhesive plaster and a suitable bandage around the body. In adopting this plan, I intended only to hide from the sight of the patient and his comrades, the distressing spectacle of a hemorrhage, which would soon prove fatal; and I therefore thought that the effusion of blood into the cavity could not increase the danger. But the wound was scarcely closed, when he breathed more freely and felt easier. The heat of the body soon returned, and the pulse rose. In a few hours he became quite calm, and to my great surprise, grew better. He was cured in a very few days and without difficulty.

Hippocrates, described a possible lung abscess with rupture either into the bronchus or pleural space; his description of the symptoms and signs of a bronchopleural fistula was excellent. He knew that early intervention in the disease process was dangerous and never did drainage until 15 days had passed. In this setting, Hippocrates was able to differentiate pus of a parapneumonic effusion (commonly Streptococcus pneumoniae), which tends to be watery and thin (enzymes streptokinase and streptodornase) from that of a likely staphylococcal empyema (enzyme coagulase results in the formation of a rapid cortex on the surface of the lung) and to recognize, either an anaerobic or amebic empyema. What both these famous clinicians described was an open pneumothorax and its consequences. Hippocrates’ patient with thick white pus has a better prognosis than that with thin watery pus because a cortex has developed on the pleural surface of the lung, preventing collapse when the sub atmospheric pleural space was opened and exposed to higher atmospheric pressure. The lesson was not lost. One of the orders issued in the First World from an Allied Commander about open chest wounds was one issued by WG MacPherson6 for the Director Medical Service, British Armies in France. “An open pneumothorax should be temporarily closed by suture at the earliest opportunity, either in the field ambulance, or at the Casualty Clearing Station. If for any reason suturing is impossible, the wound should be strapped, so as to render it air tight.”

This issue, collapse of the lung and its consequences when the pleural space is entered, was an enormous barrier to early surgery within the chest and hindered surgical development, shape, and type until the first quarter of the 20th century. The history of thoracic surgery has at its core the management of

the pleural space and this problem will rear its head repeatedly in the descriptions that follow. It should be remembered that this was an era without oximeters, EKG monitors, blood banks, endotracheal tubes, and antibiotics. Many of the early procedures pursued were designed simply to avoid entering the pleural space, because it was safer for the patient.

AN ACCURATE DIAGNOSIS One of the tenets of any planned surgical procedure is an accurate diagnosis. In the 19th century, the ability to make a diagnosis was limited. A symptomatic empyema necessitans or a traumatic chest wound was an obvious reason for surgical intervention, but it was difficult to determine if intrathoracic pathology required intervention. Skoda7 had popularized percussion and Laennec8 auscultation, but the ability to use these aids were limited by clinical ability. Nevertheless, some clinicians had confidence in their ability. One such surgeon was Block9 of Danzig, who had performed successful pulmonary resections in rabbits. Convinced he could do it safely in humans he operated on his cousin in 1883 with the presumption that she had bilateral apical tuberculosis. She unfortunately died and at postmortem no evidence of tuberculosis was found. The distraught Block committed suicide. (Authors note: This description of Block operating on his cousin can be found in numerous textbooks dealing with the history of thoracic surgery, but none have been referenced [not too surprising as the protagonist had killed himself].) In the late 1800s and early 1900s, the most common cause of death was tuberculosis. It was apparent to many that tuberculosis was a communicable disease. In fact, Villemin,10 a French army surgeon, had proven so by reproducing the pathologic features of the disease by injecting caseous material from a deceased patient with tuberculosis into the trachea of rabbits, but his research was largely ignored. Medical proof had to await Koch’s presentation, entitled “Die Tuberculose” (On Tuberculosis), to the Berlin Physiologic Society on March 24, 1882. The electrifying atmosphere that developed at the presentation is vividly described in the book “The Forgotten Plague” by Frank Ryan.11 Present in the crowded room were Virchow, Loeffler, and Ehrlich, who described “that evening to be the most important experience of my scientific life.” Three weeks after the presentation, the lecture was published.12 Twelve days later an English summary was published in the London Times, and a few weeks later, on May 3, it was published in The New York Times. The rapidity of the spread of the news and its publication in the lay press testify to how common and threatening tuberculosis was at the time. Naturally it was thought that surgical resection may have a role in management of such a life-threatening disease. This was how planned thoracic surgery started. If we study the history of thoracic surgery we study surgical attempts to control tuberculosis.13

RADIOLOGY Tuberculosis could now be suspected and proven by examining sputa, but the extent of disease had to wait until 1895 when Roentgen discovered x-rays.14 The ability to visualize shadows within the chest and correlate radiographic findings with pathology at autopsy was now at hand.

ESOPHAGOSCOPY The bronchoscope and esophagoscope were developments that followed laryngoscopy and cystoscopy.

Manoel Garcia, a singer, visualized his own larynx by means of two mirrors.15 This technique was later modified by Czermack of Budapest who utilized light reflected off a perforated concave mirror.15 In 1853, Desormeaux introduced what he called an endoscope into the bladder. Light was supplied by burning a mixture of turpentine and alcohol. A condensing lens collected the light rays and rendered them parallel before reflection into a tube.16 In 1868, Adolf Kussmaul modified the Desormeaux urethroscope by lengthening it to diagnose a carcinoma of the esophagus and to enter the stomach.17 Mikulicz developed the technique further. He used a heated platinum wire as illumination at the distal end of the tube.16 In 1902, Max Einhorn18 introduced the idea of an auxiliary channel in the wall of the esophagoscope as the light carrier. This technology soon transferred itself to the bronchoscope.

BRONCHOSCOPY AND BRONCHOGRAPHY Bronchoscopy came later than esophagoscopy. Its initial use was therapeutic—the removal of foreign bodies. Up until the development of the bronchoscope foreign bodies were removed through a tracheostomy. In 1882, Weist reported to the American Surgical Association on 1,000 cases of foreign body. Mortality in the 599 cases not operated on was 23.3% whereas, in those who had tracheotomy for removal, the mortality was 27.4%. He concluded that unless the foreign body was causing dangerous symptoms it should be left alone.19 In 1895, Killian20 performed a direct laryngoscopy and was able to visualize the trachea. He later modified his straight tube by placing lateral openings in the distal end so that respiration could continue.21 In 1897, he was the first to remove a foreign body lodged in the right main bronchus through a bronchoscope.21,22 Chevalier Jackson started to remove foreign bodies and soon became the leading endoscopist in the world and was also known for his training courses. Many of these endoscopic procedures were done under local anesthesia and must have been very uncomfortable for the patient. One of my mentors, an early pioneer, assisting during his first bronchoscopy, had to hold the patients head and place his thumb protected by a thimble between the teeth. The operation for removal of a foreign body took all day; unfortunately the adolescent patient died with extensive surgical emphysema.23 The utility of the bronchoscope broadened to include an aid to diagnosis. Chevalier Jackson24 insufflated barium powder through a bronchoscope to diagnose bronchiectasis. Definition of segmental anatomy was enhanced by Brock’s work. He instilled barium into cadavers mimicking the positions that unconscious patients would take and proved that aspiration was the likely cause of lung abscess.25 An excellent review on the history of bronchography to diagnose bronchiectasis is by Le Roux et al.26 In 1932 Vinson,27 at the Mayo Clinic, established the diagnosis of lung cancer in 71 patients by bronchoscopy.

CONTROL OF THE PLEURAL SPACE SAUERBRUCH Ernst Sauerbruch should be regarded as the prime pioneer of thoracic surgery. Born in 1875, he was 4

years old when his father died of tuberculosis. After qualifying as a medical doctor, he initially worked as a surgical assistant in Kassel and Erfurt. He realized that if he were to be a surgeon, he would need better knowledge of anatomy and therefore took up a position with Paul Langerhans in the department of pathology and anatomy at Berlin-Moabit Hospital. Langerhans encouraged Sauerbruch, who had written a paper on blunt intestinal injuries, to send a copy of the paper to the famous Polish surgeon von MikuliczRadecki, who read it while visiting the Mayo Clinic.28 Mikulicz was impressed and invited Sauerbruch to become an assistant in Breslau. Mikulicz was an autocratic master, an absolute ruler over his clinic, who was disliked by all who worked with him. What kept his assistants in Breslau was the awareness of Mikulicz’s splendid surgical and teaching ability; they could learn more from him than other European surgeons. Some of Mikulicz’s style obviously influenced Sauerbruch because he later became just as autocratic and demanding. As usual, Mikulicz ignored Sauerbruch for weeks, but then confronted him that scientific results were expected of him. We can imagine Sauerbruch asking for guidance. The reply given was, “Hundreds of thousands of people are succumbing to tuberculosis, because as yet no one has been able to operate within the thorax.”29 This statement must have meant much to Sauerbruch as he repeatedly mentions it in his book. The statement also emphasizes that surgery and resection was being considered to deal with the disease of tuberculosis. The main reason chest surgery was not successful was the problem with intrapulmonary collapse mentioned at the beginning of the chapter. This stimulated Sauerbruch to find a solution. He enclosed an animal’s chest in an air-tight, transparent box, which was kept at a negative pressure of 10 cm H2O. Using gloves built into the box wall, he could now operate on the open chest without collapse of the lung (Fig. 1.1). He proudly showed his mentor, Mikulicz, but unfortunately the apparatus sprung a leak and Mikulicz was furious that his time had been wasted. The chastened Sauerbruch continued his experimental work secretly and was later able to convince Mikulicz of its success and the two reconciled. Now with support, Sauerbruch built a low-pressure chamber with 14 cubic meters of space; the neck of the patient and the attending anesthesiologist remained outside the chamber. In April 1904, Sauerbruch presented his results at the annual German surgical congress. But, the concept was to be modified by others (see comments later on Ludolph Brauer).30 A year later, Sauerbruch anesthetized Mikulicz at his laparotomy where widespread metastatic gastric cancer was found. After Mikulicz’s death Sauerbruch moved to Greifswald and later to Marburg as first assistant to Friedrich (see comments later). He was later appointed Professor of Surgery in Zurich in 1910 on the recommendations of the worldfamous Kocher of Berne and Lucius Spengler of Davos (the site of a famous tuberculosis sanatorium, now the venue for the world economic forum meetings and from where he was referred many surgical patients). In 1911, he performed the first thymectomy for myasthenia gravis using the transcervical approach.31 Then, in 1913, he described phrenicotomy for the treatment of pulmonary tuberculosis.4 He did the first successful pericardiectomy for constrictive pericarditis. While in Zurich his reputation grew and he was soon in contact with the famous and elite. His autobiography describes treatment of Lenin, Rothschild, and King Constantine of Greece, among others. When war broke out in 1914, he volunteered and was appointed surgeon to the German army. He was exposed to the carnage at Ypres. While treating many amputees he developed a crude artificial hand. In 1918, he was offered the chair of surgery at Munich. At that stage, Nissen was his assistant, as was Lebsche. In 1927, he succeeded Bier (Bier’s block and father of spinal anesthesia) as the chair of surgery

in Berlin. His operating room became a Mecca for thoracic surgeons worldwide. In recognition of his treatment of Hindenburg, he was given the honorary title of State Councillor by Goering. In 1933, under the Third Reich, Jews were being persecuted. Following a visit to Turkey, he recommended his assistant Nissen, a Jew, for a position there. At this stage, the anesthetic management was largely by local anesthesia, ether, and oxygen. He describes operating on the chest of a 12-year-old boy. The ether vapor exploded as did an oxygen cylinder. “The patient was killed on the spot, the nursing sister and assistant were injured and I lost an ear-drum.”29

FIGURE 1.1 Sauerbruch’s experimental negative chamber. The concept of the head, and thus the lungs at atmospheric pressure and the chest at subatmospheric pressure to maintain lung expansion was transferred to a larger operating chamber. (From Sauerbruch F. Chirurgie der Brustorgane. Berlin: Julius Springer; 1920:383.)

In Berlin, Sauerbruch became a member of the Mittwochsgesellschaft, the Wednesday Society, a club founded in the 18th century by Wilhelm von Humboldt, where a limited membership of 16 eminent people met alternate Wednesdays at one of the member’s houses. At these meetings the host gave a talk on a

subject from his particular field. Five of these members, a third of the society’s members, and close friends of Sauerbruch’s, were involved with the assassination attempt on Hitler and were executed.32 In the purge that followed the failed assassination attempt, where hundreds were imprisoned, tortured, and executed, Sauerbruch’s son Peter was arrested because of correspondence discovered between him and von Stauffenberg, the assassin. Sauerbruch himself was interrogated, but Gebhardt, a former student of Sauerbruch’s working with the SS and as Himmler’s doctor, convinced Hitler of Sauerbruch’s innocence, and he and his son were released from prison. Gebhardt was hanged later after the Nuremberg trials. Sauerbruch continued working at Charite hospital when it was taken by the Russians in May 1945. His eminence was well known, but his dementia caused his downfall. He continued operating, even in his own house, where unfortunately deaths resulted. These poor results did not go unnoticed and unfortunately were accepted and covered up for some time. “In the coming struggle of the proletariat, in the clash between socialism and capitalism, millions will lose their lives. In the face of this fact it is a trivial matter whether Sauerbruch kills a few dozen people on his operating table. We need the name of Sauerbruch.” Dr. Josef Naas. Administrative Director of the German Academy of Sciences in East Berlin.33 In 1949, a contemptuous Sauerbruch was summoned before the Denazification Tribunal where his association with the Nazi regime and his awards were critically examined. Acquittal resulted, most likely because of his association with the conspirators of the bomb attempt. Although neither an ardent Nazi, nor a clear opponent, Sauerbruch cannot be considered an innocent bystander. In 1942, he was appointed Surgeon General to the army and as such accepted experiments with mustard gas on inmates in concentration camps. Later in 1949, he was ultimately dismissed from his position at Charite Hospital and died in July 1951. Despite Sauerbruch’s preeminence in thoracic surgery, his autocratic nature slowed progress in some fields of the specialty. His rejection of Brauer’s positive head chamber, followed later by rejection of intratracheal anesthesia, likely slowed the progress of anesthesia in Europe.34 In 1929, Forssmann,35 who did the first catheterization experiments on himself, visited the eminent Sauerbruch hoping for a position. Sauerbruch at the meeting stated: “You might lecture in a circus about your little tricks, but never in a respectable German University. Get out, leave my department immediately.” A dejected, Forssmann returned to his hospital in Eberswalde and practiced anonymously as an urologist. He later resurfaced, now famous, when awarded the Nobel Prize with Cournand and Richards in 1954.

LUDOLPH BRAUER Ludolph Brauer, a physician, had heard of Sauerbruch’s experiments but recognized that the chamber was expensive and cumbersome. Brauer’s idea was to construct an airtight mask to enclose the face of the patient. A tube carrying oxygen under pressure would pass through ether and into the mask.30 His second concept was a chamber enclosing only the head of the animal (or patient). Later, Sauerbruch and Mikulicz built a chamber with positive pressure around the head of the patient but soon abandoned this concept because of the effects of anesthesia on the anesthesiologist! Brauer,36 Sauerbruch’s nemesis, later became a major proponent of collapse therapy by induced pneumothorax in Germany, following Forlanini’s and Murphy’s work on induced pneumothorax (see later). In Europe, pneumothorax became the most popular form of treatment for pulmonary tuberculosis for many years.

Brauer recognized that induced pneumothorax failed because of pleural adhesions and that a more radical permanent solution was needed. He, also in Marburg at the same time as Sauerbruch, encouraged Friedrich, Sauerbruch’s chief after Mikulicz, to resect 10 to 25 cm of ribs two to nine on a patient, who luckily survived. He felt that it was important to emulate as much as possible the collapse obtained by a pneumothorax. Friedrich later modified the operation to remove, in addition, the 1st and 10th ribs. Of the first seven patients having the procedure, three died. In 1911, Friedrich37 reported on 27 patients with 8 deaths (30%) in 3 weeks and 2 further within a year.

FIGURE 1.2 Diagrammatic representation of the Brauer–Friedrich thoracoplasty. Note resection of portions of ribs 1 to 10. (From Alexander J. The Collapse Therapy of Pulmonary Tuberculosis. Springfield, IL: Charles C Thomas; 1937:452.)

Brauer and Friedrich, the surgeon, made several modifications to reduce the high mortality. The team went through phases, including removing 11 ribs in one stage; performing the procedure in two stages; resecting ribs subperiosteally to allow regeneration and stabilization; combining the procedure with pneumothorax and phrenic nerve avulsion; and, lastly, only removing upper ribs.38 These changes are well documented in Alexander’s book on collapse therapy, the final version known as the Brauer–Friedrich thoracoplasty (Fig. 1.2). Brauer continued his interest in intrapulmonary pressures and became involved with aviation medicine in Germany, establishing in 1927 the first German Institute of Aviation Medicine (GIAM) in Hamburg in affiliation with the Tuberculosis Research Institute with its two large pneumatic chambers. The GIAM

was active in altitude research and the selection of pilots, as well as educating medical students in aviation medicine, training Aviation Medical Examiners, and exploring clinical applications of hyperbaric therapy. Brauer was forced to retire in 1934 for political reasons as the GIAM came under the influence of the military; in 1939 it was made part of the Aeromedical Research Institute of the “Reichsluftfahrt” Ministry.

FURTHER PROGRESS WITH VENTILATION AND ANESTHESIA In 1910, Meltzer and Auer, working with Carrel in the Rockefeller Institute, reported their experience with ventilation in canine experiments. Via a tracheostomy and a cannula positioned in the trachea, a continuous stream of oxygen-enriched air was delivered with moderate pressure and maintained the lungs in an inflated state.39,40 The first case of pulmonary surgery with positive pressure ventilation via an endotracheal tube was reported by Elsberg41 in 1910 when Lilienthal42 performed a thoracotomy to drain a middle lobe abscess. Acceptance of this technique was slow as endotracheal intubation was difficult and initially performed without a laryngoscope, using either ether or cyclopropane as a deep inhalational agent. Many procedures were instead done with a tight fitting mask or intrapharyngeal airway with hand ventilation. One of the first reports of a cuffed tube was by Dorrance,43 also in 1910; the cuffed tube was inflated by blowing into a mouthpiece. Tovell at the Mayo Clinic also described a cuffed tube with the assistance of V Mueller and company. The best part of this paper was the conclusion: “To design this tube was easy. The difficulty has been to find a rubber company that was willing to cooperate in the production of an article that probably would not be salable in large quantities.”44 Pentobarbital (Pentothal) was discovered in 193545 and halothane in 1951.46 Paralytic agents started to be used in the 1950s. Suxamethonium was discovered in 195147 and pancuronium in 196448 although cruder paralytic agents were used by some from 1946.49 Magill, the anesthesiologist working at the Brompton Hospital with active thoracic surgeons such as Tudor Edwards and James Roberts, contributed immensely to improved anesthesia. In fact, the Magill laryngoscope for intratracheal intubation and the Magill forceps for placement of a throat pack are instruments with which we are all familiar.50

TUBE THORACOSTOMY Tube thoracostomy had its origins in the management of empyema. It was well known that empyema pus needed to be drained,51 although disagreement on how it should be done existed. The grooved needle used in the 19th century was ineffective for chest drainage, but improved with a hollow needle introduced through a trocar.52 In 1873, Bowditch,53 in Boston, reported his experience with repeated thoracentesis in 75 cases without seeing “the least permanent evil result.” Trousseau54,55 also reported on chest aspiration and observed that if a “piece of goldbeaters skin (Goldbeater’s skin—the outer membrane of a calf’s intestine—a parchment traditionally used in the process of making gold leaf by beating) or pig bladder is attached to the cannula,” one can prevent the entry of air, but not the outflow of fluid. It is difficult to assign priority to which the physician initiated underwater drainage. The method was likely modified by more than one clinician at the same time. The technique likely started off by placing a cannula and using it to evacuate fluid daily,56 then using suction and finally attaching the cannula to an

underwater system. In 1876, Croswell Hewett57 introduced a rubber tube through a cannula into the pleural cavity and then attached it to a glass tube piercing a cork stopper, which reached the bottom of a glass vessel containing a weak solution of Condy’s fluid (potassium permanganate); von Bülau’s58 method differed from Hewett’s in that he used lime water.59 Early pulmonary resections were initially managed without chest tube drainage and this approach likely contributed to the high early mortality. The chest was either simply closed or packed with sponges that were removed later. The inevitable empyema in these circumstances was managed by prolonged open drainage or thoracoplasty. In 1929, Harold Brunn60 reported his excellent results with lobectomy which he attributed to his method of hilar ligation, but the improved results were more likely due to his management of the pleural space: “the progress of the patient depends on how thoroughly the chest cavity is kept free from air and fluid for the next five to seven days. If the pedicle is a success, if the wound does not leak air, and if by constant suction, either with the hand syringe every two hours day and night or some form of suction apparatus, the chest cavity is kept free of air and fluid and the upper and middle lobes are allowed to expand, the course of convalescence is usually mild …” Nissen and Wilson61 thought this approach was one of the most important advances in thoracic surgery. Pulmonary resections were performed cautiously during the interwar years, but during the Second World War necessary management of chest wounds and their consequences became standard. Familiarity with closed underwater chest tube drainage thus became established for management of traumatic pneumothorax, hemothorax, and postoperative management of the pleural space.62

DRAINAGE OF LUNG CAVITIES AND ABSCESSES The adult form of pulmonary tuberculosis is characterized by cavities predominantly affecting the apex of the upper and lower lobes. Abscess cavities elsewhere in the body are managed with simple drainage, and therefore it is not difficult to imagine that drainage of these tuberculous cavities would be the first surgical procedures pursued in an attempt to control the disease. Isolated reports of this surgical approach can be found63,64; some are from an era before the discovery of radiography by Roentgen in 1885, testifying to the clinical skills of the physicians involved. Until Monaldi65 published a series of cases in 1939, drainage was uncommonly performed; thereafter it had a period of enthusiasm, which waned after the realization that improvement was usually temporary. However, not all cavities were due to tuberculosis. At the turn of the 20th century, lung abscess was common and was associated with a high mortality. The disease was common following surgical procedures (most often tonsillectomy) and was likely due to aspiration occurring in the absence of a protected airway. However, at that time the cause of a lung abscess was uncertain. Holman and colleagues66 believed that postoperative lung complications were due to emboli from the operative field rather than aspiration of infective material. In order to prove his hypothesis he introduced into the jugular vein a small segment of femoral vein containing bacteria and a small portion of lead. The lead portion was to aid with radiographic visualization. Of 17 experiments, lung abscess was produced in 12. Smith,67 a year later, injected into experimental animals scrapings taken from the alveolar borders of people with moderately severe pyorrhea. Fifty percent of his animals developed pneumonia of which 20% developed lung abscesses. His conclusions were that aspiration of infectious material from teeth and tonsils accounted for most lung abscesses. There were many other similar experiments and eventually the agreement that an abscess could develop either by aspiration or embolization. In 1936, Neuhof and Touroff discussed their one-stage procedure instead of the usual two-stage

methods. They set great store in location of the abscess by fluoroscopy and bronchoscopy. At this site they incised a small portion of the rib. The lung was usually adherent; alternatively, it was either sutured to the edges of the defect, or an iodine-soaked sponge was placed around the periphery of the abscess. In this area, the sponge was to stimulate adhesion, thus facilitating later drainage. The abscess was then localized by needle and an incision made through the lung and the abscess drained (Fig. 1.3). In the initial report, only one of the 37 patients died.68 The authors updated their series in subsequent publications69–71 culminating in their late follow-up where they noted that bronchiectasis was often present. They recommended bronchography in all cases once recovery had occurred. In one report72 of 45 consecutive cases, the authors noted a previous surgical procedure: tooth extraction or tonsillectomy in 19 and 17 with severe gingivodental infection, reinforcing the experimental work of Smith. In nine patients the etiology was obscure.

FIGURE 1.3 Diagrammatic representation of an early technique of drainage of a lung abscess. After radiographic localization, a section of rib overlying the area is excised. In this instance the visceral and parietal pleural are not, as usually found, adherent. To stimulate adherence before incision and drainage, an iodine-soaked gauze is packed around the periphery and the wound closed. A few days later after the pleura have become fused the wound is reopened, the gauze is removed, and the abscess drained without spillage of pus into the pleural space. (From Lilienthal H. Thoracic Surgery Vol II. Philadelphia, PA and London: WB Saunders Co; 1925:245.)

Once antibiotics became available, the incidence of lung abscess decreased. As surgical procedures became safer a phase of primary surgical resection for lung abscess became popular. However, the pendulum is swinging back toward Neuhof’s original approach.73 Postma and Le Roux74 clearly showed that drainage first in the acute phase had a much lower mortality than initial resection.

EMPYEMA EVARTS GRAHAM AND THE US ARMY EMPYEMA COMMISSION

An untreated empyema is, as a rule, the direct result of the patient’s neglect or of the surgeon’s delay, or of inadequate or useless surgery. —Stephen Paget, Surgery of the Chest 1896

Evarts Graham is best remembered as being the surgeon who performed the first successful pneumonectomy for lung cancer. In my opinion his greater contribution was that of managing empyema.75,76 The United States initially was neutral when the First World War was declared, but once a decision was made to become involved in April 1917, large numbers of troops needed to be trained. Large training camps were set up; these overcrowded camps became fertile ground for the great influenza epidemic that was ravaging the country at the same time, with approximately 20% to 40% of army personnel being sickened. Influenza and pneumonia killed more American soldiers and sailors during the war than enemy action. In fact, more than 30,000 died before leaving US shores.77 Secondary pneumonia and associated empyema were common. Analysis of a questionnaire sent to the camps documented that a disparity in the mortality rates between civilians and training soldiers existed: in the camps, mortality varied between 30% and 90%, whereas elsewhere it was approximately 30%. A US Army Empyema Commission was set up headed by Graham. A previous US Army Pneumonia Commission had found that the common offending organism in the camps was the β-hemolytic streptococcus, whereas that in the civilian population was commonly due to an α-hemolytic streptococcus (S. pneumoniae or pneumococcal pneumonia).78 The universal approach to treatment of empyema at that time was by means of wide open drainage, usually by resection of one or two segments of the rib. The different organisms causing the empyema resulted in different qualities to the pus. In the military, the massive pleural serofibrinous exudates arose concomitantly with the pneumonia; they were synpneumonic, and the pus was thin and watery. The exudative stage took about 2 weeks to develop and only then did compartmentalization of the empyema occur. Empyema encountered in civilian settings, secondary most often to pneumococcal pneumonia, usually developed after the resolution of acute pneumonia. There was early formation of fibrinous adhesions and the pus was usually thick by the time of drainage. The cortex on the surface of the lung prevented pneumothorax after drainage, whereas an open pneumothorax developed in the recruits. Graham and Bell79 concluded that treatment of acute empyema should be the following: drainage, but avoidance of an open pneumothorax during the period of acute pneumonia; early sterilization and obliteration of the cavity; and maintenance of nutrition of the patient. However, he was cautious about using continuous drainage as he was worried that the delirious patient would interfere with the drain and create an open pneumothorax; instead, repeated chest aspirations became the norm. In Camp Lee, where Graham was stationed, and using the principles advocated, the mortality rate decreased to 50 years of age, their development appearing to be environmentally stimulated. With high-resolution computed tomography (HRCT), some of the small lesions identified in patients with multiple metastases to the lung are proved subsequently to be small peripheral lymph nodes. Tsunezuka and colleagues22 performed exploratory video-assisted thoracic surgery (VATS) in 48 patients suspected of malignant lesions and reported intrapulmonary lymph nodes in 8: their diameter varied from 4 to 10 mm; 6 were located in the lower lobes and 2 in the lingula. Anthracosis was observed in five subpleural nodes. It was not possible to distinguish an intrapulmonary node from a malignant lesion using CT findings in their short series. Over a 2-year period in nine patients, Nagahiro and colleagues23 resected 13 intrapulmonary lymph nodes that had been identified on chest radiographs in three patients and on HRCT in the other six. The characteristics of these nodes on HRCT were that the borders were

sharp, the shapes were ovoid, all were located in the lower portion of the lungs in a subpleural location, and the interval density was high and homogeneous. No borders were irregular, although short spicules could be present, and none contained cavities or calcifications. Nagahiro23 and Yokomise24 and their colleagues, have pointed out that these lesions must be differentiated from small malignant nodules. The aforementioned features of thin-slice HRCT could be helpful to avoid performing an unnecessary operation and also to prevent the improper staging of lung cancer.25,26 Bronchopulmonary Lymph Nodes Nagaishi27 noted that segmental lymph nodes are related to the bifurcation of the segmental bronchi. They may also lie in the bifurcation of the branches of the associated pulmonary arteries and extend out to the fifth- or sixth-order segmental bronchi. The lobar bronchopulmonary lymph nodes are found at the angles formed by the origins of the various lobar bronchi and lie in close association with the bronchus or the adjacent pulmonary vessels. The hilar lymph nodes are situated alongside the lower portions of the main bronchi or the respective pulmonary artery and the pulmonary veins lying within the visceral pleural reflections. In a study of 200 operative specimens of lungs containing lung cancer, Borrie28 identified lymph nodes in 13 locations in the right lung and 15 in the left that are now considered bronchopulmonary lymph nodes. The number of bronchopulmonary lymph nodes is variable in each lung and within each location in the lungs.28 These lymph nodes are more frequently present in greater numbers in children than in adults. Borrie28 suggests that the maximal development of these nodes is reached by the end of the first decade of life, and, then these lymph nodes gradually atrophy and disappear during adulthood. The presence of pulmonary infection or malignancy greatly affects the number of bronchopulmonary lymph nodes that may be identified. Lobar Lymph Nodes The two most common locations in which lobar lymph nodes are found in the right lung are between the upper-lobe bronchus and middle-lobe bronchus: the area that Borrie29 termed the right bronchial sump (the superior interlobar lymph node of Rouvière13) and the region just below the middle-lobe bronchus adjacent to the lower lobe bronchus (the inferior interlobar lymph node of Rouvière13). In the left lung, the most common location is at the angle of the left-upper-lobe bronchus and the lower-lobe bronchus. Borrie7 designated this area as the left lymphatic sump, and the nodes found here correspond to the left interlobar node of Rouvière.13 The number of lobar lymph nodes is variable from one individual to another.30 They are present at birth as well as the hilar and mediastinal lymph nodes.13

LOBAR LYMPH NODES OF THE RIGHT LUNG The lymph nodes in the lymphatic sump of the right lung lie in relation to the bronchus intermedius (Fig. 9.1). According to Nohl-Oser,31 a constant lymph node is found at the upper posterior end of the major fissure in the angle between the right-upper-lobe bronchus and the bronchus intermedius. A branch of the bronchial artery coursing over the posterior aspect of the right main bronchus leads to it (Fig. 9.2). Another lymph node is found on the interlobar portion of the pulmonary artery where this vessel gives off the posterior ascending segmental branch to the posterior segment of the upper lobe and the superior segmental artery to the superior segment of the lower lobe. Inferiorly, this lymph node is contiguous with

a constant node lying above the superior segmental bronchus of the lower lobe. Other lymph nodes of the sump are found at the base of the major fissure lying closely alongside the interlobar portion of the pulmonary artery or in the bifurcations of its branches. Frequently, lymph nodes are identified more anteriorly, lying among the upper lobe branches of the superior pulmonary vein. In addition to the sump nodes, the other interlobar lymph nodes can be grouped, according to Borrie,28 into those of the upper, middle, and lower lobes. The lymph nodes of the right upper lobe are located above the upper-lobe bronchus, medial to it, and just behind it. Those lying above the bronchus merge with the hilar nodes of the distal portion of the right mainstem bronchus. The lymph nodes of the middle lobe, in addition to the subjacent node below the middle-lobe bronchus (the inferior interlobar node of Rouvière13) are located lateral to the middle-lobe bronchus near its confluence with the lower-lobe bronchus as well as medial to it. The right–lower-lobe lymph nodes, in addition to the aforementioned superior and inferior sump nodes, are found medial to the superior segmental bronchus or between it and the basal bronchi. Lymph nodes are present also in relationship to the basal stem of the lower-lobe bronchus and lie on its medial aspect, lateral to it, and between the anterior and medial basal bronchi.

FIGURE 9.1 Diagram showing the collection of lymph nodes lying within the right lymphatic sump (see text). The line drawn through the axis of the superior segmental bronchus of the lower lobe and the middle lobe bronchus represents the level below which nodes are not involved by malignant disease in the upper lobe. Arrows indicate the tendency of lymphatic drainage.

FIGURE 9.2 Diagram showing the posterior aspect of the right main bronchus as seen when the lung is pulled forward during dissection. The subcarinal lymph nodes and the node below the right upper lobe bronchus are seen. A constant bronchial artery leading to the latter node is shown.

LOBAR LYMPH NODES OF THE LEFT LUNG The collection of lymph nodes described by Nohl32,33 and Nohl-Oser31 as composing the left lymphatic sump lies between the upper and lower lobes in the main fissure (Fig. 9.3). A constant node is present in the bifurcation between the upper- and lower-lobe bronchi in close relation to the origin of the lingular (inferior division) branch of the upper lobe (Fig. 9.4). A small bronchial arterial branch passing across the membranous portion of the left main bronchus leads to it. Other lymph nodes are found lying on the interlobar portion of the left pulmonary artery in the fissure and in the angles formed by its branches. Another frequent node is described, which is found above and posterior to the left interlobar bronchus. This node is contiguous with a node lying in the angle formed by the interlobar bronchus and the takeoff of the bronchus to the superior segment of the lower lobe. In addition to the left lymphatic sump nodes, Borrie28 noted that lymph nodes of the left upper lobe are present medial, posterior, and lateral to the upper-lobe bronchus. Lymph nodes are present also between the segmental divisions of this bronchus. The lymph nodes of the left lower lobe are located more commonly in the vicinity of the superior segmental bronchus of the lobe. They are found medial, above, and inferior to it, between it and the basal bronchi. The other lobar nodes of the lower lobe are found medial or lateral to the basilar stem of the lower lobe bronchus.

FIGURE 9.3 Diagram showing the left lymphatic sump found by opening the main fissure. The straight line, drawn through the superior (apical) segmental bronchus of the left lower lobe, represents the level below which lymphatic drainage from the upper lobe does not occur. Arrows indicate tendency of lymphatic drainage.

FIGURE 9.4 Diagram showing the lymph nodes most frequently seen on opening the main fissure of the left lung. A constant node (A) lies in the angle between the upper and lower lobe bronchi, with a bronchial artery leading to it. Other lymph nodes (B) are found on the main pulmonary artery and in the angles of the branches. The constant node (C) behind and above the pulmonary artery, before it enters the fissure, is shown. Another node (D) above the inferior pulmonary vein is seen with its connections to the inferior tracheobronchial nodes higher up.

Hilar Lymph Nodes The hilar lymph nodes are contiguous with the lobar lymph nodes distally as well as with the mediastinal lymph nodes proximally. The hilar lymph nodes lying superior to the right main stem bronchus classically have been considered to extend up to the inferior border of the azygos vein, but the boundary between hilar and mediastinal location may be fuzzy. The lymph nodes medial to the right mainstem bronchus might be considered as hilar nodes when located away from the tracheal carina and within the visceral pleural sheath, but as they become subjacent to this structure, they are best termed subcarinal lymph nodes and thus belong to the lymph nodes of the mediastinal compartment. On the left side, the anatomic separation between the hilar and the mediastinal lymph nodes proximally is at an imaginary plane connecting the lateral surfaces of the ascending and descending portions of the thoracic aorta. The left hilar nodes are located medial, anterior, posterior, and lateral to the left mainstem bronchus in order of decreasing frequency in number. The hilar nodes located anteriorly are found in relation to the left mainstem pulmonary artery. Proximally, these latter nodes are contiguous with the subaortic lymph nodes of the mediastinum, including the lymph node located at the site of the ligament arteriosum, the so-called Bartello’s node. The nodes on the medial surface of the main-stem bronchus, as their position advances upward, become subcarinal in location. In fact, determining whether the hilar nodes are bronchopulmonary or mediastinal nodes is only

oncological questioning and does not matter on a purely anatomical basis. When such lymph nodes are present, their exact location and their size are variable from one individual to another and their anatomical significance is the same wherever they seem to be in that area.34,35

MEDIASTINAL LYMPH NODES The mediastinal lymph nodes are located in the mediastinal compartments: the anterior (prevascular) lymph nodes in the anterior mediastinal compartment, the tracheobronchial lymph nodes, the paratracheal lymph nodes, and the posterior lymph nodes in the posterior area of the visceral compartment of the mediastinum. Anterior Mediastinal Lymph Nodes The anterior mediastinal lymph nodes are in the prevascular compartment of the mediastinum and override the upper portions of the pericardium and great vessels as these extend upward. On the right side, the nodes lie parallel and anterior to the right phrenic nerve, upward to and along the superior vena cava to the area beneath the right innominate vein. On the left, they are in close proximity to the origin of the pulmonary artery and the ligamentum arteriosum (Fig. 9.5). These lie anterior to and along the left phrenic nerve (Fig. 9.5). The others, the para-aortic nodes, lie anterior and lateral to the ascending aorta and the arch in the triangle delineated by the left phrenic and vagal nerves.34,35 They include the lymph nodes lying along the inferior border of the left innominate vein in the region where it is joined by the left superior intercostal vein (Fig. 9.5). Tracheobronchial Lymph Nodes The tracheobronchial lymph nodes lie in three groups around the bifurcation of the trachea. The right and left superior tracheobronchial nodes are located in the obtuse angles between the trachea and the corresponding mainstem bronchus. These nodes lie outside of the pretracheal fascia. The lymph nodes of the right superior tracheobronchial group are medial to (beneath) the arch of the azygos vein and above the right pulmonary artery. These nodes are contiguous with the right superior hilar nodes distally and the right paratracheal nodes proximally. On the left side, the superior tracheobronchial nodes lie deep within the concavity of the aortic arch. Some are closely related to the left recurrent laryngeal nerve. Others are situated slightly more anteriorly and are contiguous with the node at the ligamentum arteriosum and the root of the left pulmonary artery. Their association with these nodes constitutes the link between the nodes in the visceral compartment and those in the anterior mediastinal lymph node group.

FIGURE 9.5 Diagram showing the mediastinal nodes on the left side. The superior tracheobronchial nodes, in relation to the recurrent laryngeal nerve, have connections with the anterior mediastinal group, which ascends upward to the left innominate vein; small nodes anterior to the phrenic nerve are shown; *phrenic nerve; **vagal nerve.

The inferior tracheobronchial nodes, more commonly referred to as the subcarinal nodes, lie in the angle of the bifurcation of the trachea. Some of them, in contrast to the superior tracheobronchial groups, lie within the pretracheal fascial envelope, outside the relatively dense bronchopericardial membrane. These nodes are contiguous with the hilar nodes on the medial aspect of both the right and left mainstem bronchi. Some of the subcarinal lymph nodes lie more posteriorly in relationship to the tracheal bifurcation and are on the anterior surface of the esophagus and are thus connected with the posterior group of lymph nodes. In addition, Brock and Whytehead36 described a low anterior tracheal group lying in front of the lower end of the trachea, which constitutes a bridge between the right superior tracheobronchial lymph nodes and the subcarinal, inferior tracheobronchial lymph nodes. This node is frequently present.34 The paratracheal lymph nodes are situated on the right and left sides of the trachea above the respective superior tracheobronchial nodes and extend upward along the trachea. The right paratracheal lymph nodes lie anterolaterally to the trachea and to the right of the innominate artery. Inferiorly, these nodes are overlapped by the superior vena cava. More superiorly, these nodes lie behind and above the innominate artery to the right of the midline of the trachea and extend to the inlet of the chest. Inferiorly, the left paratracheal nodes lie above the tracheobronchial angle to the left of the trachea behind the aortic arch, mainly located in the groove formed by the esophagus and the trachea, along the left recurrent nerve.34,35 More superiorly, they are situated above the arch but behind the great vessels and extend to the inlet of the chest.

Posterior Mediastinal Lymph Nodes The posterior mediastinal lymph nodes may be separated into two groups: the paraesophageal nodes and those located in either pulmonary ligament. These posterior nodes are identified less commonly in the superior portion than in the inferior portion of the mediastinum. A paraesophageal node occasionally is found retrotracheally at the level of the arch of the azygos vein. There may be nodes lying along the groove formed by the trachea and the esophagus, the most constant being located in the inlet of the chest.34,35 The paraesophageal nodes as a group are more numerous in the inferior portion of the mediastinum and are found more frequently on the left than on the right side. In the pulmonary ligament on either side, usually two or more small lymph nodes may be present. A relatively constant node, and usually the largest, lies in close proximity to the inferior border of the inferior pulmonary vein and is often termed the sentinel node of the pulmonary ligament. Number and Size of Lymph Nodes in the Various Mediastinal Locations The first major report of the number of lymph nodes in the mediastinum was published by Beck and Beattie.37 In cleared specimens of the mediastinum from five autopsies, they reported an average of three nodes in the anterior mediastinum and an average of 50 in the tracheobronchial area of the mediastinum. Of the latter, an average of 16 nodes was located in the peribronchial region, 11 in the subcarinal, and 23 in the paratracheal regions. These data were essentially nonspecific anatomically, as were the data recorded by Genereux and Howie.38 These authors, however, were among the first investigators— including Baron,39 Osborne,40 Ekholm,41 and Moak42 and their colleagues—to record the size of normal mediastinal lymph nodes as identified by CT scanning. Some 85% to 95% of normal lymph nodes identified in these studies were 7 to 10 cm), to be more often located atypically (arising from the parietal pleura, within a fissure, or to exhibit inverted growth into the pulmonary parenchyma), and to show areas of necrosis and hemorrhage (Fig. 65.8).

Microscopic Features Malignant SFTP, according to England et al.,6 reveal (a) high mitotic activity (>4 mitosis per 10 highpower fields), (b) high cellularity with overlapping and crowding of nuclei, (c) the presence of necrosis, and (d) pleomorphism (Fig. 65.9). El-Nagger and colleagues7 also noted higher mitotic counts in malignant SFTP. In addition to the presence of necrosis, extensive areas of myxomatous change and hemorrhage are commonly seen. Other Features Although the immunohistochemical profile of malignant SFTP is essentially the same as that of the benign variety (Table 65.2), there are a few differences of interest. First, although CD34 is present in most malignant tumors, it may be absent in a small percentage; particularly in high-grade tumors. Second, Yokoi and colleagues92 found all malignant SFTP to stain positively for nuclear p53 and that the degree of p53 expression was correlated with recurrence, nuclear atypia, high mitotic activity and local invasion. More recently, p53 positivity was shown to be associated with both a shorter disease-free survival (DFS) and unfavorable histology including higher mitotic rate and presence of nuclear atypia/pleomorphism.86 Finally, increased staining for Ki67, a marker of cellular proliferation, has been demonstrated in malignant SFTP.93 Ambiguous cases of malignant SFTP, such as those that are CD34-negative or are suspected of having undergone dedifferentiation, highlight the potential utility of testing for the presence of the NAB2-STAT6 gene fusion or immunohistochemical staining for nuclear STAT6.94

FIGURE 65.9 Microscopic section of a malignant fibrous tumor of the pleura. Histology demonstrates increased cellularity with cellular pleomorphism and increased number of mitotic figures.

TREATMENT Wide local excision, including pulmonary and pleural resections, is performed with the goal of obtaining negative pathologic margins. Resection of a lesion arising from the parietal pleura should include the

tissue down to the endothoracic fascia when possible. Resection of the adjacent chest wall is done only if involvement is apparent. Localized recurrence of even malignant SFTP should be evaluated for possible resection. Incomplete resection of malignant SFTP has been reported to occur in 7% to 11% of cases.95 Operative spillage is to be avoided during VATS removal of any solitary fibrous tumor (benign or malignant), and each tumor should be protected by a bag as it is extracted through the access port to prevent seeding of the chest wall.

ADJUVANT THERAPY Traditional cytotoxic chemotherapy has shown minimal benefit in the treatment of malignant SFT; Stacchiotti and colleagues96 reviewed the response to anthracycline-based regimens in 30 patients with malignant or dedifferentiated SFT from various sites (including 13 pleuropulmonary) and found a 20% partial response rate (RR) with a median progression-free survival (PFS) of 4 months. Similarly, 19 patients treated with high-dose, single-agent ifosfamide therapy had a 10% RR and median PFS of 3 months. The authors did describe a trend toward increased effectiveness in the dedifferentiated cohort treated with anthracycline (30% RR vs. 11% for malignant SFT). In a subsequent study, the authors demonstrated improved disease control rate when treating a small cohort of patients with malignant SFT with pazopanib, a vascular endothelial growth factor receptor (VEGFR) inhibitor.97 Prior to the discovery of the NAB2-STAT6 mutation, case reports and small case series describing the use of targeted therapies, including sorafenib,98,99 imatinib,100 sunitinib,101 and the monoclonal antibody against IGF1R, figitumumab,102 showed variable effectiveness, with limited evidence of antitumor effect in the majority of patients. Park and colleagues103 found a partial response (PR) in 11 of 14 patients undergoing antiVEGFR treatment with temozolomide and bevacizumab with a median PFS of 10.8 months. Le Jeune and colleagues104 reported a case of refractory NICTH in a patient with an unresectable, metastatic SFT that was successfully controlled following treatment with sorafenib. Trabectedin (ET-743) has shown antitumor effects in a variety of translocation-related sarcomas, including myxoid liposarcoma, and more recently the specific use in malignant SFTP was reviewed by the French Sarcoma Group.105 Eleven patients with metastatic SFTP, after failing first-line treatment with conventional anthracycline-based or targeted chemotherapy, received 1.5 mg/m2 of trabectedin every 3 weeks as salvage therapy; the authors reported a PR in only one patient but a disease control rate of 81.8% and median PFS of 11.6 months. A similar disease control rate (78%) was seen in nine patients with SFTP receiving trabectedin as secondor third-line treatment in a recent study describing the multimodality management of advanced SFT.106 Based on their analysis of growth factor and tyrosine kinase receptor (TKR) pathways in 96 SFT, Demicco and colleagues87 theorized that due to the specific patterns of overexpression, classic, hypocellular SFTs would be more susceptible to anti-EGFR therapies (such as gefitinib), than the hypercellular variants, which expressed high levels of VEGF and PDGF-beta. The authors noted that many tumors overexpressed multiple growth factor and TKR pathways and as a result agents targeting a broader array of TKR pathways, such as sunitinib, may show increased efficacy over more focused therapies. For the same reason, the authors suggest that a dual-therapy approach with a combination of growth factor and TKR inhibitors may also be beneficial. Preclinical studies also support the concept of using broad TKR inhibitors; agents with a larger spectrum of kinase inhibition, including sunitinib, sorafenib and regorafenib, showed increased antitumor effect compared to pazopanib and axitinib in a murine model of dedifferentiated SFT.97 Case reports have described PR to external beam radiotherapy107 and a recent study in soft-tissue

SFTs suggested a potential role for adjuvant radiotherapy in improving local control but additional research is needed before advocating its use in cases other than incomplete resection.108 In summar y, patients with incompletely resected SFTP and those with malignant histology should be considered for inclusion in a clinical trial evaluating the use of targeted molecular therapies. Patients with dedifferentiated SFTP may respond better to traditional cytotoxic chemotherapy targeting the sarcomatous component of their tumor.

PROGNOSIS Inherent to the small sample sizes of published case series, malignant SFTP have shown wide variability in rates of recurrence (7% to 30%) and long-term survival (12% to 45%).6,24,26,91,96 Boddaert and colleagues91 performed a meta-analysis of the largest case series published since 2000, including over 700 patients, and found tumor recurrence to be significantly higher in patients with malignant histology (by England’s criteria, Table 65.3), sessile morphology, and incomplete resection. One of the few areas of consensus in published series has been that the most important indicator of clinical outcome is whether the tumor can be totally excised at the initial operation. Van Houdt and colleagues109 found in a series of 81 patients undergoing resection with curative intent from all sites that a positive resection margin was significantly correlated with local recurrence and that both a high mitotic rate and tumor size >10 cm were significantly correlated with the development of metastatic disease. Furthermore, the subset of patients with both an increased mitotic rate and tumors >10 cm were noted to have the shortest overall survival. Recurrences are typically at the site of excision, however spread to other sites within the thorax or into the abdomen can occur. Lymph node metastases are rarely seen, but may occur, similar to bloodborne metastases, in patients with persistent or recurrent disease. The sites of metastases recorded, in order of decreasing frequency, are the liver, central nervous system, spleen, peritoneum, adrenal gland, gastrointestinal tract, kidney, intra-abdominal lymph nodes, and bone. Most patients with recurrent disease survive 55 (1 point)

0–2

low risk; no metastases seen in this group

Size (>5 cm, / = 15 cm—3 points)

3–4

intermediate risk; 23% with metastases at 5 yrs, 36% at 10 yrs

Mitoses/10 high-powered fields (1–3—1 point, >3—2 points)

5–6

high risk; 85% with metastases at 5 yrs, 100% at 10 yrs

Parietal pleural origin (1 pt)

0–2

Low risk; 0% rate of metastases at up to 20 yrs

Sessile morphology (1 pt)

3–6

High risk; recurrence in 77% of patients at 15 yrs

Long-axis >/= 10 cm (1 pt)





Hypercellularity (1 pt)





Presence of hemorrhage or necrosis (1 pt)





>3 mitoses/10 hpf (1 pt)





Demiccoa,111

Tapiasb,74

Predicted Clinical Course or Recurrence

a Presence of areas of dedifferentiation in this series were associated with a poor prognosis, independent of risk category. b Predicts risk of recurrence in completely resected tumors.

As larger series of SFTP with longer follow-up have been accumulated, a variety of prognostic scoring systems have been proposed in an attempt to correlate clinicopathologic features to risk of recurrence, with the intent of informing follow-up guidelines (Table 65.4). de Perrot et al.110 presented a comprehensive analysis of recurrence risk and developed a clinicopathologic staging system with accompanying management algorithm based on tumor morphology and pathologic classification according to England. Advancing stage was correlated with increased risk of recurrence and suggested the need for closer follow-up in patients with sessile morphology and/or malignant histology. Demicco and colleagues111 proposed a clinicopathologic model for assessing risk of metastasis and disease-specific survival based on age >55, tumor size in 5 cm increments and number of mitoses per 10 high-powered fields (as a continuous variable). Based on a score from 0 to 6, patients are classified as low (0 to 1), intermediate (2 to 4), or high (5 to 6) risk; no patients in the low risk group experienced metastasis while patients with high-risk tumors were found to have rates of metastasis at 5 and 10 years of 85% and 100%. Tapias and colleagues74 analyzed outcomes for 59 patients over a 33-year-period and developed a sixpoint system incorporating the classic histologic and clinical features associated with malignancy to predict risk of recurrence in completely resected SFTPs. Points are assigned for: parietal pleura origin, sessile morphology, size (long axis) > or = to 10 cm, hypercellularity, presence of hemorrhage or necrosis and > or = to 4 mitoses/10 HPFs. A score less than 3 was associated with a 0% recurrence at up to 20 years in the development cohort. The Tapias system was subsequently evaluated in a validation cohort of 113 patients that confirmed the prognostic value in terms of recurrence and overall survival.23 Boddaert

and colleagues91 applied the various prognostic scoring systems to the outcomes of the 80 patients in their series and found the Tapias system to have the highest sensitivity and specificity (100% and 80%, respectively). In addition, multiple studies have demonstrated significantly higher rates of metastasis and disease-specific mortality (100% and 43% respectively) in patients with SFTP containing areas of dedifferentiation compared to histologically benign tumors.111,112

RARE PRIMARY BENIGN TUMORS OF THE PLEURA CALCIFYING FIBROUS TUMOR OF THE PLEURA Pinkard et al.113 first described the occurrence of calcifying fibrous tumors of the pleura in three young adults in 1996. The pleural lesions were identified on standard chest radiography with calcification of the masses subsequently demonstrated on CT. On resection, the masses were found to be unencapsulated and were seen to arise from either the parietal or visceral pleural surface (Fig. 65.10). Suh and colleagues114 reported a multifocal case in a 35-year-old asymptomatic male who underwent thoracotomy with extirpation of a total of 16 nodules, ranging in size from 0.5 to 3 cm, from the visceral and parietal pleura in the right chest. The mean age of patients with the pleural-based lesions is 34 years, compared to the more common occurrence of calcifying fibrous tumors in the soft-tissue of the extremities in the pediatric population (mean age 14.5 years). Two-thirds of the published cases to date have reported the presence of multiple tumors at presentation, however no evidence of malignancy has been seen and complete surgical resection appears to be curative.115

FIGURE 65.10 Gross (A) and microscopic (B) examination of a calcifying fibrous tumor of the pleura. Note the absence of a discreet capsule (A) and numerous, scattered violet-stained spherical calcifications (B).

ADENOMATOID TUMOR Adenomatoid tumors are small nodular pleural lesions typically found incidentally on imaging, intraoperatively or on examination of a resected lung specimen. They have been found in the visceral pleura as well as in the pulmonary ligament and the published cases have reported sizes from 5 mm to 2.5 cm. The nodules are composed of epithelial cells with mesothelial differentiation present in a fibrous stroma (Table 65.2).116 These rare tumors are benign, and their bland cytology allows differentiation from

pleural metastatic disease in patients with a synchronous malignancy as well as the adenomatoid growth pattern of malignant pleural mesothelioma. Surgery appears to be curative, with no reported recurrences following resection.

SCLEROSING PNEUMOCYTOMA (HEMANGIOMA) In the 2015 WHO classification,117 sclerosing hemangioma was reclassified from “miscellaneous tumors” to “adenomas” and the terminology standardized to sclerosing pneumocytoma, reflecting the derivation from, and presence of, embryonic respiratory epithelium (round cells) and cuboidal surface cells, resembling type II pneumocytes. Sclerosing pneumocytoma is almost always a benign epithelial tumor, more commonly found in the lungs, but rare cases have been identified as arising from the pleura.118 A 5:1 female predilection has been reported with an average age at presentation of 46 years.119 These tumors are typically noted incidentally on imaging as noncavitating, peripheral nodules, 12 months) had a PFS of 5.5 months with the rechallenge, whereas patients who relapsed over a shorter time (4 months versus 39% for those treated with chemotherapy alone; corresponding figures for median PFS were 5.1 and 3.4 months, respectively. However, OS (13.3 vs. 12.8 months) did not differ between the two arms. NF2 Suppression The NF2/Hippo signaling pathway is altered by mutation or deletion of the NF2 gene in almost 40% of MPM.38 NF2 is a tumor suppressor gene located on chromosome 22q12 encoding for the protein merlin, but its role in suppressing tumorigenesis is still poorly defined. The absence of merlin causes activation of multiple mitogenic signaling pathways, such as HER1/2, mTOR, ERK, and focal adhesion kinase (FAK); therefore, it has been assumed that merlin inhibits signaling by negatively regulating multiple cell surface receptors.39 Preclinical data indicate that merlin inactivation plays a critical role in the pathogenesis of MPM increasing its invasiveness through upregulation of FAK expression, and merlin deficiency is associated with higher sensitivity to FAK inhibitors40 (Fig. 66.1). A phase I study of the oral FAK inhibitor GSK2256098 included 23 patients with pretreated MPM and showed a better PFS in merlin-negative MPM.41 A phase IIB trial (COMMAND) is currently testing the oral FAK inhibitor defactinib (VS-6063) given continuously as maintenance strategy compared with placebo in advanced MPM42 using merlin status as a stratification factor. TABLE 66.2 Targeted Therapies Targeted Therapies

Rationale

Type of Study References

Arginine deaminase

Arginine succinate deficiency renders mesothelioma cells sensitive to arginine deprivation; Adi-PEG is an arginine-degrading enzyme

Phase II ADAM trial Phase I TRAP trial

33–35

Cell cycle

Cancer cells might be susceptible to pharmacologic disruption of the G2 checkpoint. CBP501 is a cell-cycle disregulator

Phase I trial Phase II trial

36,37

NF2

NF2 is a tumor suppressor gene encoding for the protein merlin; merlin inactivation plays a critical role in the pathogenesis of MPM increasing its invasiveness through upregulation of focal adhesion kinase (FAK) expression

Phase I study of GSK2256098 Phase IIB COMMAND trial

43–45

Phase II trial with Everolimus PI3K/AKT/mTOR pathway

The PI3K/AKT/mTOR pathway is crucial for the regulation of cell growth, proliferation, and protein biosynthesis; in vitro studies have shown that its inhibition may induce apoptosis in mesothelioma cell lines

Phase I studies of inhibitors

49,50

Tyrosine kinase

Many growth factor receptor families such as EGFR, PDGFR, and VEGFR are frequently activated in mesothelioma

Phase I and II studies of inhibitor imatinib Phase II trial of inhibitor dasatinib Phase II trial of inhibitor gefitinib Phase II study of inhibitor erlotinib

55–60 63,66,67

Angiogenesis and blood vessels

Vascular endothelial growth factor levels are increased in the serum and pleural fluid of MPM patients

Phase III NVALT study of thalidomide Phase I/II trials of bevacizumab Phase II study of nintedanib Phase I/II studies of sorafenib Phase I/II studies of sunitinib Phase II study of vatalanib Phase I/II trials of cediranib Phase II study of BNC105P Phase I study of NGR-hTNF Phase II NGR019 trial of NGRhTNF Phase III NGR015 trial of NGRhTNF

74 75–79 80 81–83 84–86 87 88–90 91–93 96 94

Heat shock protein 90

HSP90 stabilizes a number of proteins required for tumor growth and survival of a variety of tumors including mesothelioma

Phase I /II MESO02

99

Merlin loss results in unregulated mTORC1 signaling pathway that is sensitive to rapamycin inhibition through a mechanism involving mTORC1 activation.43 However, the results of a phase II study with the mTOR inhibitor everolimus showed only limited clinical activity.44 An additional phase II trial explored

the role of everolimus in patients selected by merlin status as predictive biomarker; the study has been recently completed but not yet reported.45 PI3K/AKT/mTOR Pathway The PI3K/AKT/mTOR pathway is crucial for the regulation of cell growth, proliferation, and protein biosynthesis, processes that are implicated in tumorigenesis, and its upregulation has been reported in a variety of solid tumors including prostate, colorectal, breast cancer, and melanoma. In an exploratory study of 30 treatment-naive MPM, the aberrant activation/expression of partner proteins of the PI3K/mTOR signaling cascade provided prognostic information.46 and in vitro studies have shown that its inhibition may induce apoptosis in mesothelioma cell lines.47 mTOR inhibition alone generates compensatory upregulation of PI3KCA that allows restoration of PI3K function and therefore the downstream signaling on AKT.48 To overcome this mechanism of resistance, dual PI3K/mTOR inhibitors have been developed. GDC-0980 is a small molecule inhibiting PI3K, mTORC1, and mTORC2 and preliminary data in 26 MPM patients showed 2 objective responses.49 LY3023414 is another dual PI3K/mTOR inhibitor currently under evaluation in phase I studies.50 Tyrosine Kinase Inhibitors (TKIs) Genetic and molecular studies have confirmed that many growth factor receptor families such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptors (VEGFR) are frequently activated in mesothelioma.51 The activity of TKIs tackling these receptors has been explored in several clinical studies. In mesothelioma cells, PDGFR-α and β are overexpressed and high PDGF serum level has been suggested as an independent predictor for adverse outcome.52,53 The coexpression of c-kit, reported in 26% of mesothelioma patients, acted as background information for testing imatinib clinically.54 To date, four phase II studies of single agent imatinib have been performed, including overall 94 patients. Results invariably showed no objective responses and a PFS 1% of stained tumor cells were considered PDL-1 positive. PDL-1 positivity was detected in 20% of patients, associated with nonepithelioid histology and poor prognosis, with median survival in PDL-1-positive MPM significantly worse than in PDL-1-negative (4.79 vs. 16.3 months, respectively).108 In the other study the percentage of positive MPM was 40%.107 The different percentage of PDL-1 positivity in the two series could simply be the consequence of differences in the cut-off values used for positivity and related to technical differences in the diagnostic antibodies.

It remains unknown whether PDL-1 expression could act as a predictive marker and whether its expression can change over time with chemotherapy, since PDL-1 is an inducible protein that can be upand downregulated upon certain conditions. This also raises the question if archival tumor samples can be reliably used for assessing PDL-1 status. In a fashion similar to other cancers, the sensitivity and specificity of PDL-1 detection can vary by the used test, the quality of tissue samples, and the selected cut-off points. Intriguingly, objective responses have been seen in NSCLC patients whose tumors were negative for PDL-1 expression.109 Therapies targeting this pathway are of major interest and under development for MPM patients (Table 66.3). TABLE 66.3 Immunotherapy Immunotherapy Rationale

Type of Study

References

Immune checkpoints

MPM is commonly associated with relevant inflammatory reaction partially related to Phase II asbestos-induced chronic inflammation. Associated protein CTLA-4 and MESOprogrammed cell death 1 (PD-1) are upregulated and expressed on activated TREM effector T cells 2008 study Phase IIB MESOTREM 2012 study Analysis of expression of PD-L1

104,105 108,109

Mesothelintargeted approaches

Mesothelin is overexpressed by most epithelioid mesothelioma but not in normal cells

Phase I trial of amatuximab Phase II trial of amatuximab First-line study of CRS-207 Phase I trials of SS1P Preclinical studies of anetumab ravtansine

113 115 117 120,122 123

Oncolytic viruses

Oncolytic viruses have the capacity to destroy tumor cells, therefore releasing antigens that allow T-cell activation through dendritic cells

Preclinical study Phase I trial

126 127–129

WT1

WT1 is a transcription factor highly overexpressed in mesothelioma. WT1 peptides can elicit T-cells response against mesothelioma cell lines

Phase II trials

130–133

Vaccination with tumor cell lysate

Autologous tumor vaccines have been shown to generate tumor regression through tumor-specific immunity

Phase II trials

134–139

MESOTHELIN-TARGETED AGENTS Mesothelin is a cell surface glycoprotein expressed in pleural and peritoneal mesothelial cells and it is overexpressed in most epithelioid mesotheliomas but not in normal cells.110 Its biologic role has not been fully understood but it binds to CA125 and its overexpression is involved in cell adhesion and tumor

invasion.111 Mesothelin-targeted immune approaches combined with host immune depletion as occurs with chemotherapy have shown encouraging activity in mesothelioma. Three mesothelin-targeted agents are currently in clinical development: amatuximab (MORAb 009), a chimeric anti-mesothelin monoclonal antibody; CRS-207, a live-attenuated Listeria monocytogenes vector encoding human mesothelin; and SS1P, a recombinant immunotoxin. Amatuximab (MORAb 009) is a high-affinity chimeric monoclonal antibody against mesothelin.112 In a phase I trial in 24 previously treated patients, including 13 mesotheliomas, single agent MORAb 009 at 200 mg/m2 in a weekly schedule was well tolerated and 11 patients had stable disease after receiving at least one course of therapy.113 In a single-arm multicenter phase II trial amatuximab at 5 mg/kg was administered on days 1 and 8 with cisplatin and pemetrexed; responsive and stable-disease patients received amatuximab maintenance until disease progression. The study included 89 patients and 56 (62%) received amatuximab maintenance. No overlapping toxicities with chemotherapy were observed and 11 patients experienced amatuximab-related hypersensitivity reactions. Partial responses were observed in 33 (40%) patients and stable disease in 42 (51%). Median PFS was 6.1 and median OS 14.8 months.114 A randomized, placebo-controlled phase III trial is currently evaluating first-line amatuximab 5 mg/kg, administered weekly, in combination with cisplatin and pemetrexed in patients with unresectable mesothelioma.115 CRS-207 is live-attenuated L. monocytogenes strain engineered to express the tumor-associated antigen mesothelin. CRS-207 stimulates innate and adaptive cellular immunity and when combined with chemotherapy synergistically acts by modifying the tumor environment to improve immune-mediated killing.116 In a first-line pivotal study 16 patients received 2 induction vaccinations with CRS-207 every 15 days, and then up to 6 cycles of cisplatin plus pemetrexed and 2 boost CRS-207 vaccinations. Clinically stable patients received CRS-207 maintenance vaccinations every 8 weeks. No serious adverse events were observed, except for manageable infusion-related fever, chills/rigors, hypotension, and nausea/vomiting. Nine patients had confirmed partial response and four had stable disease.117 SS1P consists of an anti-mesothelin Fv (SS1) fused to PE38, a 38-kDa portion of Pseudomonas exotoxin A. After binding to mesothelin, SS1P is internalized by endocytosis and kills cells by arresting protein synthesis and with initiation of programmed cell death.118 In preclinical models, cells with high mesothelin expression, as determined by immunohistochemistry, showed sensitivity to SS1P.119 In a phase I clinical trial of patients with advanced mesothelin-expressing cancers who had failed standard therapies, SS1P every other day for three doses was well tolerated. Pleuritis was the dose-limiting toxicity and the maximum tolerated dose (MTD) was 45 μg/kg.120 The most commonly reported adverse events were hypoalbuminemia and fatigue, and a limited antitumor activity was observed. In addition most patients developed SS1P-neutralizing antibodies after one or two cycles. In a subsequent study an immunosuppressive therapy with pentostatin and cyclophosphamide to deplete T and B cells was implemented. Out of 10 MPM patients refractory to chemotherapy, 3 had major responses with 2 ongoing at 15 months and 2 others responsive to chemotherapy after discontinuing SS1P.121 In mice with mesothelin-expressing human tumor xenografts, SS1P as single agent had modest antitumor activity; however, when combined with chemotherapy remarkable synergy was observed. These preclinical findings guided an additional phase I trial of escalating doses of SS1P administered intravenously on days 1, 3, and 5 during cycles 1 and 2 of cisplatin and pemetrexed, and in 20 chemotherapy-naive MPM patients, marked antitumor activity was noted. Ten out of 13 patients who received the maximal tolerated dose of 45 μg/kg (77%) had a partial response, 1 had stable disease, and 2 had progressive disease. Objective radiologic responses were associated with significant decreases in serum mesothelin,

megakaryocyte potentiating factor, and cancer antigen 125.122 Anetumab ravtansine is a fully humanized anti-mesothelin antibody conjugated to microtubule targeting toxophore DM4 (BAY 94-9343). In preclinical studies it showed selective cytotoxicity against mesothelioma cells, sparing normal mesothelial cells, and clear activity against mesothelioma cell lines and xenografts suggesting it as a potent drug candidate for further development.123 Overall these data suggest that immunotherapy is a relatively new therapeutic strategy in MPM, with manageable toxicity profile. Further definition of predictive factors to improve patients’ selection may result in additional survival advantage. However, because in MPM tissue, cytokines and regulatory T cells that suppress an efficient immune response have been detected124 the combination of cancer vaccines with agents that modulate regulatory T cells, with or without chemotherapy, may result in a synergistic activity.

ONCOLYTIC VIRUSES Oncolytic viruses are emerging as a promising cancer therapy as a result of their capacity to destroy tumor cells while sparing normal tissues, therefore releasing antigens that allow T-cell activation through dendritic cells (DCs).125 Several oncolytic viruses have been tested in preclinical models of pleural mesothelioma, among which vesicular stomatitis virus, adenovirus, Newcastle disease virus, herpes simplex virus, vaccinia viruses, and measles virus (MV) are currently investigated. A preclinical study in a panel of mesothelioma cells derived from patients with pleural effusion investigated the oncolytic activity and the immunoadjuvant properties of a live-attenuated MV strain derived from the Edmonston vaccine lineage. MV strain induced apoptosis of infected mesothelioma cells, which were efficiently phagocytosed by DCs that showed spontaneous maturation and produced proinflammatory cytokines. Furthermore, priming of autologous T cells by DCs loaded with MV-infected mesothelioma cells induced proliferation of tumor-specific CD8 T cells.126 Phase I clinical trials are underway testing the intrapleural application of measles, herpes, and vaccinia viruses in patients with MPM.127–129

WILMS TUMOR SUPPRESSOR GENE 1 (WT1) WT1 is a transcription factor highly overexpressed in mesothelioma and its immunohistochemical staining is routinely used, as part of a panel of appropriate markers for diagnostic purposes, while in mesothelioma cell lines WT1 peptides can elicit T-cells response.130 The safety and the immunogenicity of WT1 vaccine plus GM-CSF in patients with thoracic tumors expressing WT1 have been tested. Nine patients with MPM and 3 with NSCLC were vaccinated; 8 patients received at least 6 vaccinations while 10 patients were evaluable for immune response. One patient with mesothelioma had a prolonged disease stabilization lasting over 3 years and five had documented immune responses with only minimal toxicity.131 Randomized phase II trials are currently testing the adjuvant role of the WT1 vaccine in MPM patients after the completion of a multimodality treatment132,133 (Table 66.3).

VACCINATION WITH TUMOR CELL LYSATE In experimental models, autologous tumor vaccines have been shown to generate tumor regression through tumor-specific immunity.134 Similarly, autologous tumor lysate vaccines in melanoma and prostate cancer patients induce tumor-specific immunity and in some patients tumor regression.135,136 In these studies, the

vaccine was administered with GM-CSF as an adjuvant to improve the recruitment and differentiation of DCs. The antitumor immunity of an autologous mesothelioma cell lysate, administered subcutaneously with GM-CSF, was tested in 22 MPM patients and the laboratory evidence of an immunologic response was documented in 32% of the treated cases. Clinically, the treatment was tolerated, albeit no complete or partial responses were observed while 7 patients had stable disease; the median OS time was 11.5 months, and the 1- and 2-year survival rates were 50% and 27%, respectively.137 ISCOMATRIXTM is a particulate adjuvant consisting of cholesterol, phospholipid, and saponin and its combination with an antigen is known as ISCOMATRIXTM vaccine. It showed the induction of strong antigen-specific cellular and humoral immune responses to a broad range of antigens of viral, bacterial, parasite, or tumor origin in a number of animal species including nonhuman primates and humans. In a phase II study in MPM aimed to evaluate the safety and the activity, ISCOMATRIXTM was combined with tumor cell vaccines plus celecoxib, used to facilitate DC maturation.138 Another study evaluated the allogeneic tumor vaccine K526-GM in combination with celecoxib and cyclophosphamide was also used to decrease the amount of regulatory T cells.139

CELLULAR THERAPIES Dendritic Cells DCs play a critical role in presenting tumor-associated antigens (TAA) to T cells and, consequently, in generating tumor-specific immunity.140 DCs induce activation and proliferation of CD8+ cytotoxic T lymphocytes (CTL) and helper CD4+ lymphocytes. The goal of DC-based cancer immunotherapy is to trigger a specific antitumor immunity with the generation of effector cells able to attack and lyse tumors. The effect of DC-based immunotherapy on the outgrowth of mesothelioma was tested in murine models using tumor cell lysate as antigens to pulse DCs and induced strong tumor-specific CTL responses leading to prolonged survival in mice with the efficacy dependent on the tumor load.141 A clinical study in 10 MPM pretreated patients evaluated the efficacy and safety of autologous tumor lysate pulsed DCs administered intradermally and intravenously, every 2 weeks for a total of three injections. The vaccination was safe with moderate fever as the only side effect and in four patients the vaccination induced cytotoxic T-cell response.142 CAR-T T cells can be redirected to overcome tolerance to cancer by engineering with integrating vectors to express a chimeric antigen receptor (CAR) that enables T cell to destroy target cells. Genetically engineered autologous T lymphocytes may indeed increase antigen recognition or alter the immunosuppressive tumor microenvironment through production of cytokines. As reported above, mesothelin is a tumor-associated antigen overexpressed in a variety of malignancies with relatively limited expression in normal tissues. Investigational agents consisting of autologous T cells expressing an anti-mesothelin CAR have been developed and have shown in vitro and in vivo activities.143 T lymphocytes can be genetically modified by retrovirus or RNA electroporation. Indeed safety concerns associated with viral vector production have limited clinical application of T cells expressing chimeric antigen receptors.144 Mesothelin-specific redirected T cells are currently being tested in early clinical trials.145

The fibroblast activation protein (FAP)-redirected T cells showed promising in vitro activity and are currently under investigation. To minimize the risk of on-target off-tissue toxicity and to maximize the ontarget antitumor effect the adoptive transfer is directly performed in the pleural effusion.146,147

PHOTODYNAMIC THERAPY (PDT) PDT is increasingly being used to treat thoracic malignancies, including MPMs. It is a nonionizing radiation therapy, but a photosensitizer that accumulates in malignant cells and is activated by a specific light wavelength. This combination produces reactive singlet oxygen that can exert anticancer activity through apoptotic, necrotic, or autophagic tumor cell death. PDT may also induce an inflammatory reaction stimulating a tumor-directed host immune response.148,149 Usually PDT in MPM is part of a multimodality treatment and it can be safely combined with macroscopically complete surgical resection and other treatment modalities to improve local control.150,151

INTRAPLEURAL CHEMOTHERAPY In MPM intrapleural chemotherapy (or hyperthermic intrapleural chemotherapy) after cytoreductive surgery (pleurectomy and decortication) may be performed afterwards in an attempt to remove all microscopically residual malignant disease. This approach has been shown to be effective for peritoneal metastases from appendiceal malignancy, peritoneal mesothelioma, and colorectal cancer.152,153

CONCLUSION Unlike other solid cancers, very limited improvements in the systemic treatment of MPM patients have been made in the last years and only limited insights have been gained into the biology of this disease. To date, the doublet of cisplatin and pemetrexed is still the only evidence-based systemic treatment associated with clinically significant survival improvement and better quality of life. For patients unfit for cisplatin, carboplatin may represent a reasonable alternative. Predictive molecular markers unfortunately have no role in the everyday clinical practice. Second-line therapies are an unmet clinical need, in the lack of treatment approaches of proved efficacy. In selected patients with prolonged disease control after first-line pemetrexed-based chemotherapy, the rechallenge with pemetrexed should be considered while vinorelbine remains a viable option for palliation in patients early failing pemetrexed. Many targeted agents have been tested so far with very scanty activity both as single agent and in combination with chemotherapy. Novel immunotherapeutic approaches, including those assessing the inhibition of immune checkpoints, are being explored and hopefully may result in therapeutic advances in the management of MPM patients. Whenever possible, patients should be encouraged to enter in the available clinical trials testing new agents and new strategies. The worldwide increase in the incidence of MPM claims for more effective treatment. Oncogenic driver mutations that have radically changed the management of adenocarcinoma of the lung unfortunately have not yet been detected in MPM. The future development of targeted approaches is focused on the exploration of pathways activated as a consequence of the loss of tumor suppressor genes or other targets associated with the disease phenotype. Biologic therapy addressing angiogenesis and tyrosine kinase

deregulated activity has shown overall disappointing results despite hundreds of patients enrolled in the clinical studies performed so far. A promising area of investigation besides immunotherapy includes the NF2/Hippo pathway. Merlin deficiency leads to deregulation of several pathways such as the PI3K/mTOR, Hedgehog, and FAK pathways. In preclinical models, targeting these pathways results in inhibitions of tumor growth and clinical studies are currently testing these approaches. Further advances in the MPM treatment indeed require well-designed clinical studies addressing the role of therapeutic agents selected on the molecular profiling of the individual tumor. A critical point in implementing these types of studies is the availability of adequate amounts of tumor tissue from each patient. For these reasons, but also for others correlated to diagnostic and staging challenges, patients with MPM should be referred to centers with expertise and dedicated multidisciplinary teams. 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67 Surgical Approaches for Diffuse Malignant Pleural Mesothelioma Bryan M. Burt ■ Shawn S. Groth ■ David J. Sugarbaker

INTRODUCTION Malignant pleural mesothelioma (MPM) is a rare, locally aggressive, and rapidly fatal tumor of the thoracic pleural mesothelium, commonly associated with inhalational exposure to asbestos. Approximately 2,500 to 3,000 new cases, per year, are seen in the United States; however, epidemiologic studies suggest that the incidence of MPM worldwide is underestimated and increasing.1,2 The disease is five times more common in males, which is likely reflective of occupational exposure to asbestos. The clinical presentation is insidious with the most common presenting symptoms being dyspnea and chest pain. MPM is refractory to single modality local or systemic therapy. Multimodality approaches incorporating surgical macroscopic complete resection with chemotherapy and/or radiotherapy, however, are associated with long-duration disease remission and overall survival in selected patients.3,4 An expert panel discussed the role of surgical cytoreduction for MPM at the International Mesothelioma Interest Group Congress in 2012. The panel agreed that surgical macroscopic complete resection and control of micrometastatic disease played a vital role in the multimodality therapy of MPM. Moreover, there is an indication of surgical cytoreduction when macroscopic complete resection is deemed achievable.5 Staging in MPM lacks consensus, and various staging systems exist. The classic staging system described by Butchart et al. in 1976 is relatively simple and descriptive.6 The Brigham staging system, based upon resectability by extrapleural pneumonectomy (EPP), may not be applicable to patients undergoing pleurectomy/decortication (PD).7 The Tumor, Node, Metastasis (TNM) staging system, proposed by the International Mesothelioma Interest Group (IMIG), is the accepted American Joint Commission on Cancer staging system (AJCC).8 In this chapter, we describe our approach to patient selection, preoperative preparation, surgical resection and reconstruction, and the postoperative management of EPP and PD for patients with MPM.

SELECTION OF PATIENTS EPP entails en bloc resection of the parietal pleura, lung, ipsilateral hemidiaphragm, and pericardium, followed by pericardial and diaphragmatic reconstruction. PD involves resection of the parietal and visceral pleura while sparing the lung. Pericardial or diaphragmatic resection may be incorporated into PD when required; in these circumstances, the operation is referred to as an “extended pleurectomy and decortication.” Proponents of EPP endorse this operation, as it provides a complete oncologic resection

and facilitates delivery of hemithoracic radiation (because of the removal of the lung) with significantly less toxicity in comparison to PD (because the lung is left in place). Advocates of PD argue that complete macroscopic resection is, indeed, achievable with this operation and that PD can be performed with less operative morbidity. To date, there is no definitive evidence that either cytoreductive operation (EPP or PD) offers a survival advantage over the other. A retrospective review of 1,494 patients undergoing surgical resection in the large, multicenter initial analysis of the International Association for the Study of Lung Cancer (IASLC) Mesothelioma Database found that there is a connection between stage I tumors resected by EPP and longer median survival (40 months) when compared with those patients managed by PD (23 months). There were no survival differences found between EPP and PD with higher stage disease (Fig. 67.1).4 In contrast, a multi-institution retrospective study of 663 patients surgically treated for MPM suggested that PD may have a long-term survival advantage when compared to EPP.9 Further, a recent meta-analysis of 24 series failed to find differences in 2-year survival in patients receiving either EPP or PD.10 Significant selection bias confounds each of these studies, and the oncologic efficacy of one operation over the other remains undefined. Incorporating pneumonectomy into the resection of pleural mesothelioma will consistently result in higher postoperative morbidity and mortality. In the first reports of “curative” surgery for MPM, Butchart et al. performed EPP with a surgical mortality rate of 30%.6 In a nearly 30-year period since this initial report, advances in patient selection, intraoperative techniques, and postoperative management have decreased the mortality of this operation substantially, especially in centers that perform a high volume of mesothelioma surgery. In the largest published series of EPP for MPM, 529 patients with epithelial MPM underwent EPP with 5% 30-day or in-hospital mortality.11 A recent analysis of the Society of Thoracic Surgeons Database reported operative morbidity rates of 10.5% for EPP and 3.1% for PD, and major complication rates of 25.3% for EPP and 4.6% for PD.12 In the meta-analyses of 24 MPM datasets of 1,512 patients undergoing PD and 1,391 patients undergoing EPP, operative mortality rates of 4.5% for EPP and 1.7% for PD were reported.10

FIGURE 67.1 Overall survival is shown according to type of curative-intent procedure (EPP or P/D) and stage: (A) Stages I to II and (B) stages III to IV. The 95% confidence interval is shown in parenthesis. EPP, extrapleural pneumonectomy; P/D, pleurectomy/decortication. (Reprinted from Rusch VW, Giroux D, Kennedy C, et al. Initial analysis of the International Association For the Study of Lung Cancer Mesothelioma Database. J Thorac Oncol 2012;7(11):1631–1639. Copyright © 2012 International Association for the Study of Lung Cancer. With permission.)

All patients undergoing consideration for EPP or PD require a thorough staging and cardiopulmonary evaluation. Evaluation begins with tumor histology, preferably by evaluation of a thoracoscopically obtained tissue sample. It is well recognized that patients with sarcomatoid and biphasic histology have poor prognosis, which is significantly worse than for patients with epithelioid histology.3,4 For patients with sarcomatoid MPM, it has become our practice to favor operative therapy in the context of a study protocol. Our preoperative workup for a patient with MPM being considered for cytoreductive surgery includes a dedicated chest CT with intravenous contrast to assess the extent of mediastinal involvement. The patient should also have a PET-CT to assess the extent of nodal disease and to assess for disease extending outside of the ipsilateral hemithorax. A chest MRI may be superior to other cross-sectional imaging techniques in assessing discrete foci of chest wall invasion and diaphragmatic muscle

involvement.13 However, it is our experience that MRI may often be misleading in many cases. In contrast, narcotic-dependent chest wall pain is highly suggestive of unresectable disease. Because of the limitations of current imaging studies, exploration is performed in some patients with questionable radiographic evidence of chest wall invasion but without distant disease. Obvious radiologic demonstration of chest wall invasion or palpable tumor by examination is considered unresectable. Extrathoracic chest wall invasion discovered at exploration is typically considered unresectable as well. In rare cases, however, limited chest wall resections will be offered if complete macroscopic resection is achievable otherwise. If there is a suggestion of transdiaphragmatic invasion on preoperative imaging, or if there is significant bulky diaphragmatic disease, diagnostic laparoscopy is performed. Lastly, cervical mediastinoscopy is performed for staging purposes. N3 disease is considered a contraindication to surgical resection. Induction chemotherapy is offered to patients with N2 disease, and those who have a measurable response to systemic therapy will be offered surgical resection. Previous talc pleurodesis is not a contraindication to resection. To determine the patient’s suitability for EPP, the authors use several preoperative physiologic criteria outlined in Table 67.1. Pulmonary function measured by a forced expiratory volume in 1 second (FEV1) of greater than 2 L is considered sufficient for pneumonectomy. If FEV1 is less than 2 L, a ventilationperfusion (VQ) scan is obtained to predict postoperative lung function. If the postoperative FEV1 is less than 0.8 L, we will not offer EPP and will consider PD. Echocardiography with Doppler studies is performed in all patients to assess for pulmonary hypertension, which, if present, may be further assessed by right heart catheterization. TABLE 67.1 Criteria for Selection of Patients for EPP Extent of disease

Limited to the ipsilateral hemithorax without transdiaphragmatic, transpericardial, extensive chest wall involvement, and N2 or N3 disease

Performance status

Karnofsky score >70

Pulmonary function

Postoperative FEV1 >0.8 L

Cardiac function

Left ventricular EF >45%; PA pressure 2 Heart failure Serum albumin 8 units in a larger proportion treated with LVRS compared to medical therapy during 4-years follow-up. Analysis of the long-term follow-up provided additional support for classifying patients using the pattern of emphysema on chest CT and maximum exercise wattage attained on post-pulmonary rehabilitation exercise testing. In 290 patients with upper lobe– predominant emphysema and low exercise capacity, LVRS provided a substantial survival advantage compared to medical treatment (RR 0.57, p = 0.01).137 A secondary goal of NETT was to develop predictors of LVRS mortality and morbidity.138 Numerous predictors of mortality and morbidity were analyzed in non–high-risk patients who underwent LVRS. The presence of non-upper lobe–predominant emphysema was the sole predictor of operative mortality. Pulmonary morbidity was greater in older patients and those with lower FEV1 or DLCO. Cardiovascular morbidity was higher in older patients, those who used oral steroids, and those with non-upper lobe– predominant emphysema. NETT also compared the effects of LVRS surgical approaches via median sternotomy (MS) or video-assisted thoracoscopy (VATS) on patient mortality, morbidity, and functional outcomes.139 It found no difference in 90-day mortality or overall mortality. There were no significant differences between MS and VATS in mean intraoperative blood loss or transfusion needs. Mean operating time was 21.7 minutes shorter for MS compared to VATS, hypoxemia was less frequent with MS compared to VATS, and intraoperative complications were less with MS compared to VATS. Recovery time after VATS was shorter, evidenced by more patients living independently at 30 days. There was no significant difference in functional outcomes between groups during follow-up. Cost related to LVRS and associated hospitalization was less for VATS compared to MS, as were total costs during the 6 months after LVRS. Nonsurgical approaches to lung volume reduction are at different stages of the investigative process. They can be broken down into five main categories. One-way endobronchial valves work by promoting atelectasis by regionally blocking inspiration but permitting expiration. Self-activating coils are placed into the airway inducing atelectasis by assuming their preformed coil shape, bending the airway, and collapsing the surrounding lung tissue. Targeted destruction and remodeling of emphysematous tissue has been accomplished by the regional instillation of biological adhesives and by bronchoscopic thermal vapor ablation (BTVA), which heats and destroys targeted emphysematous lung tissue. Airway bypass tract stenting is the placement of stents endobronchially into emphysematous lung tissue to enhance emptying through collateral circulation. Transpleural ventilation techniques employ a similar rationale in which modified chest tubes are placed transthoracically into emphysematous lung tissue in order to empty trapped air from damaged lung. These techniques all attempt to achieve sustained reductions in endexpiratory lung volume. They differ in terms of approach, the effect of collateral ventilation or pleural

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81 Bullous and Bleb Diseases of the Lung Alan D. L. Sihoe

INTRODUCTION As organs of gas exchange, the lungs have been described as “spongy, air-filled organs.” It is therefore unsurprising that pathology in the lung parenchyma can cause structural damage to the honeycomb-like lung matrix, leading to abnormal air-containing lesions within the organ. Unlike many other lung disease conditions—such as those with inflammatory or infectious etiologies—these lung bullae or blebs are irreversible, anatomic defects.1–3 Therefore, the treatment of these conditions are almost invariably beyond the scope of pharmacotherapy, and surgical intervention may need to be considered. This chapter will focus on the surgical management of discrete bullous and bleb disease of the lung, including giant lung bullae. Often, ruptured bullae and blebs are the causes of pneumothorax. The management of pneumothorax is covered elsewhere in this book. Bullae and blebs are also frequently associated with diffuse pulmonary emphysema and chronic obstructive pulmonary disease (COPD). The surgical management of emphysema involves lung volume resection surgery (LVRS) which is often mistakenly regarded as a similar to surgery for discrete bullous disease.3 This view is erroneous, and, as a result, emphysema surgery and LVRS are also dealt with elsewhere in this book.

TERMINOLOGY DEFINITIONS Bleb and bulla are two terms that describe the same thing: a subpleural air-filled space within the lung. They are a description of the observed lesion, and do not imply any specific etiology. However, in common clinical usage, the two terms have evolved so that they are often used in different contexts. A bleb is nowadays used to refer to smaller air-filled lesions, typically less than 1 to 2 cm in diameter (though a strict numerical cut-off is not usually defined).1,4,5 The most common clinical context for use of this term is in pneumothorax. In primary pneumothorax, where rupture of alveoli is hypothesized to have caused the bleb formation, blebs can form at the lung surface with an outer wall consisting of only the thin visceral pleura, and these are most commonly found at the apices of the upper lobes and of the apical segments of the lower lobes.4–6 However, blebs can refer to similarly sized lesions anywhere on the lungs and related to any other pathology. A bulla typically refers to air-filled lesions larger than 1 to 2 cm in diameter.1,3,7 As superficial lesions may present with pneumothorax even when smaller sized, these larger bullae are more frequently discovered deeper in the lung parenchyma to smaller blebs at the time of presentation. However, the

distinction between bullae and blebs based on size and location is far from clear-cut. Bullae can often coalesce and/or enlarge depending on the underlying pathology.1 A much enlarged bulla is often labelled as a giant bulla. This term is often reserved for a lesion that occupies more than one-third of the volume of the hemithorax, though again this is not a very strict cut-off for definition. Other terms have often been confused with blebs and bullae. A lung cyst specifically refers to an airor fluid-filled lesion that is lined by epithelium.7–9 Unlike bulla, the term cyst is associated with certain specific pathological causes, including, as an example, congenital bronchogenic cysts, cystic adenomatoid malformations, and cystic bronchiectasis. A cavity in the lung typically refers to an air-filled space within a diseased area of the lung, and has often been defined by having an outer wall thickness of 3 mm or more. Typical examples include cavitations occurring within neoplasms or granulomatous inflammations. A pneumatocele is also used interchangeably with bleb and bulla to describe an air-filled lesion within the lung, but is most often used in association with specific disease processes.10–12 In particular, a pneumatocele is used to refer to lesions caused by trauma or by infection. Infectious pneumatoceles are most often related to staphylococcal, pneumocystic, tuberculous and measles infections, and may occasionally be complicated by abscess formation and pneumothorax.

CLASSIFICATIONS Many classification systems exist have been published for lung bullous disease.13–18 These are typically based on the number of bullae, the situation/projection of the bullae, and the condition of the underlying lung (presence and extent of emphysema). Examples of these classifications are given in Table 81.1. However, it must be emphasized that the variety of available classifications merely highlights that none has become established within the thoracic surgical community. In practice, these classifications are useful for academic purposes, but for many surgeons the management of each patient remains individualized rather than classification-based. It should also be stressed that although the etiology of bullae and emphysema overlap, the classification systems do not. One should not confuse classification of bullous disease with that of emphysema—which is described elsewhere in this book.

TABLE 81.1 Selection of Classification Systems Describing Lung Bullae DeVries and Wolfe14 I. Single large bulla

Underlying lung normal

II. Multiple bulla

Underlying lung normal

III. Multiple bulla

Diffuse emphysema

IV. Multiple bulla

Other lung disease

Witz and Roeslin15 I. Bullae with normal underlying parenchyma, paraseptal emphysema II. Bullae with diffuse emphysema; bullae are local exacerbation of diffuse panacinar emphysema III. Vanishing lung syndrome; entire lobe or lung replaced by bullae Wakabayashi16 1. Bullae are balloon-like structures with a smooth internal lining without trabeculae 2. Bullae are usually confined to the apex of the lung or the tip of the superior or anterior segment 3. Bullae are diffusely distributed and contain numerous trabeculae 4. Bullae look similar to type 1 but contain the remnants of trabeculae at the base

ETIOLOGY Because potentially any process that breaks down interalveolar septae can result in an air-filled space lesion, many disease conditions can result in blebs and bullae.1,7,14,19–34 The more common causes are listed in Table 81.2. Blebs associated with primary pneumothorax are said to be “idiopathic” in origin.35,36 Nonetheless, some clinicians hypothesize that, in such patients, there is rupture of the alveoli with subsequent air leakage within the lung. In turn, the air dissecting through the interstitium forms subpleural collections at the lung surface—in other words, blebs. The anatomical changes occurring as the lung rapidly grows and stretches during the pubertal growth spurt may explain why primary pneumothorax is particularly common amongst tall, thin males of adolescent/postpubertal ages. Of the acquired causes, pulmonary emphysema is the most common. In particular, the association between tobacco smoking and emphysema has been extensively documented.19–22 Multiple noxious agents within tobacco smoke can cause alveolar wall destruction directly or through triggering of inflammation. Smoking can also trigger other disease processes that result in bullous lung changes, including Langerhans cell histiocytosis (Fig. 81.1).37 Smoking of other substances—including crack cocaine and marijuana— have also been particularly associated with development of bullous lung disease.30,31,34 Marijuana smoking has further been suggested to be even more harmful than tobacco smoking in the formation of bullae because marijuana smoking may involve larger inspiratory volumes and longer breath-holding that could increase barotrauma. Intravenous drug abuse has also been associated with emphysematous lung disease, although it is unclear whether this is due to direct effects of the injected drug, granulomatous inflammation from additives (talc), septic emboli, or simply the fact that many abusers are also smokers.24

TABLE 81.2 Common Causes of Lung Bulla Formation Substance Abuse: Tobacco smoking Other: e.g., marijuana, cocaine, intravenous drug abuse, etc. Genetic: α1-antitrypsin deficiency Genetic predisposition: e.g., Ehlers–Danlos syndrome Inflammatory: Sarcoidosis Acquired immunodeficiency syndrome (AIDS) Cystic Lung Disease: Congenital: e.g., cystic adenomatoid malformation, sequestration, congenital lobar emphysema, etc. Acquired: e.g., traumatic lung cysts, lymphangioleiomyomatosis, hydatid cysts, cystic fibrosis, etc.

As mentioned above, certain lung infections can cause pneumatocele formation. Acquired immunodeficiency syndrome (AIDS) has been recognized to lead to bullous emphysema.26 Granulomatous inflammation from tuberculosis infection or from sarcoidosis is also a known cause.25,29

PATHOPHYSIOLOGY AND NATURAL HISTORY In the mid-20th century, the common belief was that a lung bulla developed because the underlying pathology caused a one-way valve effect on the affected part of the lung.38,39 In emphysema, for example, it was theorized that the loss of elastic recoil in emphysematous lung resulted in air reaching the affected part during inspiration, but in the air failing to be expelled during exhalation because of collapse of the small airways. The resulting increased pressure in the affected part would cause compression on the surrounding lung, creating a bulla. However, intelligent studies involving intrabulla pressure measurements and CT observation of bulla volumes during respiration have since shown that this was not the case.27,40 Instead, the underlying lung pathology is seen to result in greater lung compliance in the affected lung compared to more normal adjacent lung.7 Thus, during each inhalation, there is preferential ventilation into the bulla, resulting in continued expansion of it over time.41 This causes a vicious circle leading to progressive enlargement of a bulla as a common potential feature of its natural history. Further physiological studies confirmed that ventilation of a bulla is present but slow during normal breathing. Additionally, a range of investigations also confirmed a lack of perfusion in a bullous lung area. Therefore, it has been suggested that a bulla may often contribute to respiratory compromise more through an intrathoracic space-occupying lesion effect rather than through increasing dead space ventilation.42–45 In clinical practice, the above physiological inferences are all borne out.43,46,47 The physiologic disturbance can result in measurable and functional reductions in lung function, although it is difficult to distinguish between the relative contributions of the bulla per se versus the underlying emphysema.26,43,47 It is clear that even if patients are initially asymptomatic, most eventually do develop symptoms or complications from the bulla. In very rare instances, a bulla can clinically regress—either spontaneously or as a result of infection.48,49 However, in most patients, there is progressive enlargement of the bullae and/or increasing symptoms. Mortality, however, appears more closely related with the underlying emphysema than the bulla itself.46 It should also be noted that a lung bulla is a potential risk factor for lung cancer occurrence.50–55 One

early study suggested that the prevalence of lung cancer in men without emphysema was 0.19%, but was as high as 6.1% in men with bullous emphysema. This represented a relative risk of 32:1, which was higher than the relative risk of around 10:1 for heavy smokers compared to nonsmokers at the time. It has since also been noted that the mean age at which patients with bullous emphysema developed lung cancer was lower than that in the general population (46 years vs. 70 years). Case series of patients with lung bulla who subsequently developed cancer in or from the bulla have well been reported, with every histological type of cancer found. It is therefore prudent to follow-up patients with lung bulla closely, and to actively exclude malignancy if any bulla-associated lesion is seen.

FIGURE 81.1 Langerhans cell histiocytosis. A: Diffuse emphysematous change with evidence of chronic inflammation. B: Entire anterior part of left upper lobe has been replaced by giant bullae. C: Discrete bullae also found on other parts of lung.

Other complications have also been reported in association with lung bullae (Table 81.3).1,14,16,48,56–62 Although such complications are rare, pneumothorax is the most common among them. One study has suggested that the pneumothorax accounted for over 90% of all complications of lung bullae. Infection can occur within the bulla. Although appearance of a fluid level within the space is a common radiological sign, it should be remembered that the fluid can be a sterile parapneumonic exudate from a surrounding lung infection. Hence, it is often difficult to distinguish pneumonia in an emphysematous lung from a specific infection within the bulla itself.48 Infected bullae can progress into lung abscesses in some patients, but many can shrink or resolve to a small scar (autobullectomy).56 Hemoptysis has been reported to result from rupture of eroded pulmonary arterial vessels into a bulla, but this is believed to be so rare

that other more common causes of hemoptysis in an emphysematous patient should also be first excluded (e.g., carcinoma, bronchiectasis, etc.).57 Chest pain has also been reported, but is again so relatively rare that other causes (especially cardiac) must be excluded before attributing this symptom to any bulla.16,61 Rare still, isolated case reports of herniation of an apical bulla into the lower neck have also been published.62 TABLE 81.3 Consequences and Complications of Bullous Lung Disease Respiratory compromise (dyspnea) Pneumothorax Infection of bulla Hemoptysis Chest pain Increased risk of lung cancer Rarely: herniation of bulla into lower neck, dysphagia, etc.

INDICATIONS FOR SURGICAL INTERVENTION The main indications for considering surgery in a patient with bullous lung disease are summarized in Table 81.4. TABLE 81.4 Summary of Indications for Surgery I. Asymptomatic, but isolated bullae ≥ 30% to 50% of lung volume with/without evidence of progressive enlargement. Underlying lung relatively nonemphysematous and compressed. II. Symptomatic (dyspneic), with other causes of dyspnea excluded. Underlying lung relatively nonemphysematous and compressed. III. Complications of bulla have occurred which are major, persistent, or recurrent.

PROGNOSIS As can be understood from the above section on natural history, most bullae tend to progress over time, both enlarging and causing eventual symptoms or complications. Although this has not been validated by prospective trials, many clinicians accept that a patient with a discrete lung bulla that occupies 30% to 50% or more of the hemithorax by volume is a candidate for surgery.1,63,64 Furthermore, some clinicians suggest that early surgery is preferable because, over time, the less well-ventilated (and hence effectively nonfunctioning) “normal” lung may suffer a loss of surfactant production, which in turn could lead to development of permanent interstitial brosis. There is some controversy over the timing of surgery. It has been argued by some that in patients with a giant bulla, it is preferable to await the occurrence of symptoms before offering surgery, because of the risk of complications that are hard to justify in the clinically asymptomatic patient.65,66 On the other hand, others advocate early operation for the asymptomatic patient rather than wait until the development of symptoms or complications.63,64 This would allow for safer, planned surgery with less morbidity.

SYMPTOMS If a bulla causes dyspnea, surgery can be considered. First, it should be demonstrated that the symptoms can be attributable to the bulla.61 It must be recalled that patients with bullous disease often have

underlying emphysema. If the symptoms are due to the emphysema or COPD in general, then a bullectomy alone may not necessarily resolve the symptoms. Full lung function testing and imaging must be performed in each patient as described in the section on investigation below. In general, the best results are achieved with CT scan demonstration of a discrete large bulla (and the poorest results with multiple, small, diffuse/bilateral bullae). In more than one study, it was shown that the radiographic volume of a bulla was the single most important factor determining the improvement in FEV1 after bullectomy.14,67 Second, the quantity and quality of “normal” (or less abnormal) lung tissue on the side of resection needs to be considered.14,44,68–70 In some patients, there has been so much parenchymal loss from emphysema that a bullectomy will leave little functional lung left with no improvement (if not worsening) of the patient’s functional status. In general, this factor is best assessed again with CT scanning— sometimes in association with radio-isotope scanning as discussed below.

COMPLICATIONS Should a pneumothorax occur, this must always receive acute treatment to achieve drainage and lung reexpansion in the first instance.58,59 It should again be remembered that many patients have some underlying emphysema or lung pathology and may hence be less tolerant of the respiratory compromise brought about by the pneumothorax than a normal person. Once the patient is stabilized, the usual indications for surgery of pneumothorax apply, including, among others, recurring episodes of pneumothorax and persistent air leak (see chapter on Pneumothorax). However, in the context of a lung bulla, a few points need to be considered.58 First, the rate of persistent air leakage on chest drainage is higher than normal: up to 76% have a leak for over 5 days in one study. Second, the recurrence rate with tube thoracostomy alone is very high: almost 50% after a short follow-up in one series. However, the consideration for surgery should also be mitigated by the observation that pneumothorax surgery in patients with emphysema can sometimes entail high morbidity rates and recurrence rates not much better than with chemical pleurodesis alone.60 Careful selection of patients as discussed below is mandatory. As mentioned above, in cases of an infected bulla, effective antibiotic therapy is often sufficient, and autobullectomy can sometimes occur.48,65 Surgery is considered when there is no response after 2 to 4 weeks of antibiotic therapy, progression into a lung abscess, or enlargement of the bulla.48,65 With hemoptysis and chest pain, as noted above, it is not often that such symptoms are caused by the bulla per se. It is therefore important to exclude other causes of such complications before proceeding to bullectomy.1,61

PREOPERATIVE INVESTIGATIONS AND PATIENT SELECTION PULMONARY FUNCTION TESTING Spirometry The use of spirometry in assessing patients with bullous lung disease must take into account the relative status of the bulla and the underlying lung. In patients with a giant lung bulla but relatively normal underlying lung, studies in the 1970s have demonstrated that compromise in FEV1 correlates very well both the size of the bulla and the improvement in FEV1 following bullectomy.14,67,68,70–75 However, where the bulla is smaller (less than one-third of the hemithoracic volume) and the remaining lung is

emphysematous, the FEV1 may be more reflective of the severity of the emphysema than of the bulla. In such cases, a poorer preoperative FEV1 can be predictive of reduced improvement in symptomatic patients, and lack of improvement in immediate postoperative FEV1 is also predictive of failure of any symptomatic improvement being sustained.14 It has been further shown that the greater the extent of underlying emphysema on CT, the poorer FEV1 becomes at predicting outcomes of bullectomy.73 In fact, with severe underlying emphysema, resection of a giant bulla may also entail increased mortality and morbidity rates. Just as it is difficult to use spirometry to predict outcomes for bullectomy, so it has proven hard to use spirometry to define its contraindications. Conflicting conclusions have been reached by previous studies with some investigators suggesting that FEV1 less than 35% of predicted is being associated with less improvement after surgery in symptomatic patients68,76 while others maintain that a very poor FEV1 can still be associated with good symptomatic improvement after giant bullectomy.14 Diffusion Capacity of the Lung for Carbon Monoxide As noted by some authors, the diffusion capacity of the lung for carbon monoxide (DLCO) is a useful indicator of the severity of underlying emphysema.14,61 Poor DLCO—either alone or in conjunction with deoxygenation during exercise—have been found in clinical studies to be linked to worse outcomes after bullectomy.14,61 It has also been suggested that in a patient with a giant bulla and poor FEV1, the DLCO value may be a reasonable indicator of emphysema severity in the nonbullous lung, with a greater DLCO perhaps suggestive of slowed bulla emptying on exhalation rather than extensively emphysema-related destroyed lung.77,78

RADIOLOGICAL IMAGING Chest X-Ray The simple chest x-ray (CXR) has several helpful uses in patients with bullous lung disease.61 First, serial CXRs are useful for displaying the progression of a bulla over time.61,79 Not only is this useful for charting the trajectory and predicting impending problems, but the correlation of enlargement with worsening of symptoms can help distinguishing whether the symptoms can indeed be fully attributable to the bulla. Second, inspiratory and expiratory CXRs can help suggest that state of the underlying nonbullous lung.61,79 Normal lung tends to change in volume during inhalation and exhalation more than very emphysematous lung. Third, it has been suggested that denser, congested-looking appearances in the nonbullous lung may be more in keeping with relatively normal lung tissue compressed by the bulla.61,79 Computed Tomography of the Thorax Computed tomography (CT) of the thorax has emerged as the most important investigation for patients with bullous lung disease (Fig. 81.2) having proved extremely useful in the delineation of the anatomy of the bulla(e), the evaluation of the underlying nonbullous lung, and, the detection of complications.4,44,69,70,73 Delineation of the primary bulla is important for patient selection for bullectomy. As mentioned above, a giant bulla does not contribute significantly to ventilation and can hinder breathing by acting as an intrathoracic space-occupying lesion. Accordingly, studies have confirmed that the volume of a bulla on

CT may be the most important factor in predicting improvement in FEV1 after bullectomy.14,67 Furthermore, other clinical series have shown that bulla volumes of over 50% to 70% of the hemithorax may be best associated with postoperative improvements in symptoms and FEV1, while volumes of less than 30% may offer worse results and may even be a relative contraindication for surgery.14,38

FIGURE 81.2 55-year-old chronic smoker with a giant left upper lobe lung bulla. A: CXR before surgery. Notice left lung hyperexpanded with splinting of the left hemidiaphragm. The heart and carina have also been mildly shifted rightward. B and C: CT before surgery. There is almost complete absence of lung tissue in the left upper zone. However, the parenchyma in other areas of the lungs shows only relatively mild emphysematous change. The heterogeneity in the distribution of bullous change is a good prognostic indicator for bullectomy surgery. D: CXR after surgery. A degree of lung volume reduction has been achieved, with the diaphragm no longer splinted down and now resuming a more natural doming. The heart and mediastinum are also in a more neutral position.

As alluded to above, CT is perhaps the most reliable assessor of emphysema in the nonbullous lung. CT has been demonstrated to be more sensitive than CXR at detecting emphysema, and better at distinguishing between normal and emphysematous underlying lung than relying on pulmonary function tests alone.44,69,70 Measurement of lung tissue density (with reduced density indicating emphysema) showed that changes in the nonbullous lung correlated very well with impairments in DLCO and FEV1, whereas changes in the bulla itself did not. CT hence help indicate presence or absence of relatively normal underlying tissue, and this information can be used in conjunction with the pulmonary function tests above in assessing patient suitability for surgery.

In detecting complications, CT can help distinguish or suggest tumor development, infection, and so on.53,69 CT may also be very helpful in distinguishing between an intraparenchymal bulla from an interpleural loculated pneumothorax—a distinction that often confounds imaging by CXR alone. Radioisotope Scanning Ventilation–perfusion (VQ) scanning is a useful adjunct to CT in selected patients with bullous lung disease, providing both an assessment of regional distribution of lung function and also a quantitative evaluation of the ventilation in a particular part of the lung.41,80 A bulla produces a matched ventilation and perfusion defect on VQ scanning, so demonstration of underventilation and underperfusion at the location of the bulla was traditional used to corroborate evidence supportive of a good outcome after bullectomy. However, this use of VQ scan for assessment of regional distribution of lung function has largely been rendered obsolete in many cases because CT scanning has already been shown to reliably do this job. Xenon-133 (Xe-133) washout times on ventilation have, however, been reported to be a useful way to study regional ventilation efficiency.68 A bulla typically displays trapping of Xe-133. However, a reduced Xe-133 washout value in other nonbullous parts of the lung is suggestive of underlying emphysema, and hence in turn indicative of poorer outcomes after bullectomy. Pulmonary Angiography Pulmonary angiography can be used to assess the perfusion in the nonbullous parts of the lung: normal lung would show a “capillary blush” around the pulmonary artery vasculature; lung compressed by a large bulla might exhibit crowded vasculature; and very emphysematous lung would show a “pruned tree” appearance of visible main pulmonary arteries with absence of the smaller caliber vessels in the surrounding parenchyma.74 This investigation is nowadays rarely used as CT (with or without intravenous contrast) is usually sufficient for evaluation of the underlying lung.

PATIENT FACTORS There are no absolute demographic criteria indicating or contraindicating bullectomy. Although it has been suggested that younger patients fare better postoperatively, this may be a reflection of the usually more severe emphysema in more elderly patients and age alone should not be a contraindication provided the patient is otherwise suitable for surgery.61,81 The presence of a giant bulla and/or emphysema may be associated with cardiac changes, and it may be prudent to consider cardiac catheterization in patients suspected to have cardiac failure or cor pulmonale.82 Identification of these may indicate higher surgical risk and the need for careful perioperative management (e.g., ICU stay), but are usually not regarded as absolute contraindications for surgery. Indeed, it has been suggested that pulmonary hypertension can be caused by bullous compression of the better perfused nonbullous lung, and therefore bullectomy may help alleviate the situation in some patients. Many patients may have COPD with chronic bronchitis, bronchospasm, copious sputum production, recurrent chest infections, and other respiratory comorbidities. It is recognized that patients with these risk factors may have increased operative risk and increased chance of perioperative complications. Nonetheless, they are regarded as relative rather than absolute contraindications for bullectomy. In any

such patient undergoing bullectomy, it is imperative that perioperative management includes aggressive airway toileting, pain control, and mobilization/physiotherapy. It must also be remembered that many patients with lung bullae are smokers. Patients that continue to smoke after bullectomy not only have increased risk of perioperative complications, but also may incur in a significantly worse deterioration in pulmonary function (FEV1 and DLCO) over time compared to those who quit smoking after surgery. In fact, these patients demonstrate a functional deterioration no worse than expected from aging alone in nonsmokers.61,83 Some surgeons would decline bullectomy for patients who refuse to quit smoking, arguing that smoking renders the operation both high-risk and ultimately futile.83,84

SURGICAL THERAPY PREOPERATIVE PREPARATION Patients with acquired bullous lung disease often have concomitant COPD. They consequently may have problems postoperatively with sputum retention, bronchospasm, and so forth. Where feasible, patients may be given a course of preoperative pulmonary rehabilitation (see chapter on LVRS). In all cases, preoperative chest physiotherapy is mandatory, including deep breathing and incentive spirometry training in preparation for their postoperative use.41,61 Bronchospasm—if suspected to be a problem—should be controlled with appropriate pharmacotherapy. Steroid therapy is common amongst patients with COPD, and whether these need to be stopped before surgery needs to be considered on an individual basis, assessing whether the risk of bronchospasm from cessation may be outweighed by the risks of continuing steroids (including poor healing and increased infection susceptibility). If sputum secretion is noted to be copious, bronchoscopic toileting can be performed at the time of surgery after induction of general anesthesia. It is often considered unethical to deny surgery for patients who continue to smoke.85–87 Nonetheless, the hazards caused by smoking in the perioperative period can be serious in patients undergoing surgery for bullous lung disease. These include, among others, increased risks of chest infection, sputum retention, and, cardiovascular morbidity. Furthermore, failure to stop smoking may result in limited benefit from surgery along with possible recurring symptoms and bullous lesions.61,83 Smokers must therefore be very strongly advised to quit completely prior to surgery.86,87 If necessary, agreeable patients may be referred to smoking cessation programs and/or have their operation postponed until they have quit.

ANESTHETIC CONSIDERATIONS In general, anesthesia with one lung ventilation is used as with any thoracic operation (see chapter on Anesthesia). In practice, one of the concerns during surgery for bullous lung disease is the issue of air trapping within emphysematous lung. Failure of the bullous lung to collapse adequately can hinder surgery, especially if minimally invasive techniques are used. For this reason, double lumen intubation is generally preferred over single-lumen intubation with the use of a bronchial blocker.88 The former allows suction of the nonventilated lung on the operation side, helping the lung collapse if needed. Another intraoperative concern is that of mechanical ventilation causing a pneumothorax on the contralateral side. The risk of this is greater than in other patients given the possibly emphysematous state of the contralateral lung in a patient with bullous lung disease. The surgeon should be present in the operating room during intubation and commencement of ventilation, in case an urgent chest drain insertion

is needed. Thereafter, the operating room staff should always have all necessary equipment to hand for urgent chest drain insertion at all times during the operation—in case a contralateral pneumothorax (especially a tension pneumothorax) may develop. During the surgery, excessively high airway pressures should be avoided in the contralateral lung. If there is particular concern over the possibility of a contralateral pneumothorax during surgery (e.g., history of contralateral pneumothorax), then one option may be preemptive placement of a contralateral chest drain as prophylaxis against a tension pneumothorax on that side. Postoperative sputum retention or failure to fully reinflate the lung can be a particular problem if patients have both copious sputum and significant pain from surgery. The use of a preemptive analgesic strategy, employing preincisional paravertebral blockade, may be a highly effective method of suppressing significant postoperative pain.89,90 At the end of surgery, it may be useful to perform a bronchoscopy prior to reversal of anesthesia and extubation.91 If significant sputum is found, this would be an ideal opportunity to perform toileting, reducing the risks of sputum retention. One emerging development is the use of nonintubated techniques of anesthesia for thoracic surgery.92 This can range from deep sedation/hypnosis with the aid of a laryngeal mask, through to surgery on completely awake patients with the aid of thoracic epidural anesthesia.92,93 It has been argued that allowing spontaneous breathing during surgery in patients with respiratory compromise may be physiologically advantageous.93,94 Initial reported results—including a single-center randomized study— suggest that nonintubated techniques for LVRS gave equivalent treatment outcomes as traditional approach with full general anesthesia, but with shorter hospital stay and fewer side-effects.93,94 A full treatise on this intriguing approach to anesthesia is beyond the scope of this chapter, but may be found elsewhere in this book.

SURGERY Bullectomy is the standard operation for bullous lung disease.63–66,95 This is essentially a nonanatomical wedge resection of the bullous lung tissue. Segmentectomies are usually not considered, and bullous lung disease is almost never neatly confined to a discrete anatomical segment of lung. Lobectomy is sometimes considered if bullous disease has replaced virtually the entire lobe. Nonetheless, patients with bullous lung disease often have compromised lung function to begin with, and it has been previously demonstrated that lung function in the hilar regions of a lobe are often relatively preserved even with severe bullous disease.61,76,77 A number of historical case series have shown that lobectomy may result in poorer outcomes than bullectomy in terms of functional outcomes as well as measured spirometric results. Following the principle that it is best to preserve as much function lung tissue as possible, bullectomy is preferred over lobectomy in most patients.61 The surgical approach was traditionally via an open thoracotomy—including a standard posterolateral, anterolateral, or axillary approach. Today, video-assisted thoracic surgery (VATS) has become the approach of choice for bullectomy in most centers.84,85 The benefits of VATS in terms of reducing postoperative pain, morbidity, and durations of stay have been well documented. If bilateral bullectomies are considered, median sternotomy has been tried in the past, but this is now less common as bilateral VATS—both in the same sitting or as staged operations—have become increasingly popular.78,96 The most conventional VATS approach uses 3 ports sited according to the “baseball diamond” strategy, using 10- to 12-mm incisions and trocars (Fig. 81.3).90,97,98 With the typical apical bullae at the “second base” position, the camera port is sited at “home base” between the mid and anterior axillary lines in the

6th–7th intercostal space. Taking this “home base to second base” axis, a perpendicular line is visualized on which the “first base” and “third base” ports are placed equidistant from that axis. For a right-side operation, for example, that would mean the “first base” port at around the 4th intercostal space near the anterior axillary line, and the “third base” port at the 5th–6th space near the posterior axillary line. These positions are for reference only, and should be freely adapted to suit the individual characteristics of each patient.

FIGURE 81.3 Classic ports placement strategy for 3-port VATS. The home base (camera port) and second base (anticipated target lesion, purple oval) form a straight axis—indicated by the red line—which points toward the video monitor. The first and third bases of the “baseball diamond” (blue line) lie equidistant either side of the axis, allowing comfortable instrumentation. (From Yim APC, Sihoe ADL. VATS as a diagnostic tool. In: Shields TW, Locicero J, Ponn RB, et al., eds. General Thoracic Surgery. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:313–332.)

Today, a great variety of variations on the above “classic” 3-port VATS technique have been reported.90,98 The number, size, and position of the ports can vary greatly. A 3-port needlescopic VATS approach replaces the camera and posterior port with tiny 2- to 3-mm scopes and instruments.35,36 A 2port (or working port) technique is described, eschewing the posterior port and using shared instrumentation via the anterior port. More recently, bullectomy has been described using a single-port or “uniportal” VATS approach.98–100 Through a single 2- to 3-cm incision in the 4th–5th intercostal space between the mid and anterior axillary lines, bullectomy and even lobectomy can be achieved with video-

thoracoscope and instruments used together via the same incision (Fig. 81.4). Furthermore, robot-assisted thoracic surgery has also been reported to be feasible for bullectomy.101 Regardless of the approach, it is necessary when first entering the chest to be aware of pleural adhesions. These are very common—and indeed largely expected—in patients with emphysematous lungs, perhaps because of the usual coexistence of a history or chronic, recurrent inflammatory episodes. When making the first incision, care must be taken not to injure the underlying lung which may be adherent to the chest wall. Such inadvertent injury should best be avoided as the tissue quality may be poor and repairs consequently ineffective, resulting in prolonged air leaks afterward. Once inside the chest, all adhesions should be taken—the precise techniques for which are dealt with elsewhere in this book, and may vary from surgeon to surgeon. Good adhesiolysis is important because the bullectomy often results in a sizeable air space in the chest, and the remaining lung needs to be freed to expand and fill that space.

FIGURE 81.4 Uniportal VATS bullectomy for a giant left upper lobe bulla (same patient as in Fig. 81.2). A: The giant bullae can fill a large volume inside the thorax, making initial visualization with VATS apparently difficult. However, the bullae can usually be retracted away, or punctured and deflated if necessary. It is important to clearly visualize the demarcation between the grossly bullous and relatively normal parts of the lung. B: As emphysema often coexists with chronic bronchitic disease, postinflammatory adhesions are common in patients with bullous lung disease. Adhesions should first be fully released to allow completely free mobilization of the lung, so that optimal grasping and stapling of the bulla can be achieved. C: The stapler is placed and fired across relatively normal lung tissue. D: An ideal stapling shows that the staple line is intact and runs through relatively normal lung tissue. With such good lung tissue at the staple line and newer staple technology offering a stepped cartridge face with graduated compression, staple line buttressing is not usually necessary. E: After resection of a particularly large upper lobe bulla, release of the pulmonary ligament may reduce the chance of a residual apical air space. F: Bullectomy can now be achieved via a uniportal wound. Only one chest tube is normally needed after surgery.

Nowadays, bullectomy is most commonly performed using an endoscopic linear staple-resection device.95,97 The bulla or bullous lung is grasped with one hand, and the stapler is fired across the base (Fig. 81.4). If the bulla is large and cumbersome to manipulate, it can be first deflated by puncturing to allow easier handling. It is very important to place the staple line through relatively normal lung tissue, checking both sides of the stapler for this before firing. The reason is that if the stapler is fired across diseased, bullous lung, there is a potentially risk of air leakage from the staple line itself. Sizing of the staples should be carefully considered: staples that are too small will result in inadequate sealing and even rupture; staples that are too large may allow air leakage along the staple line because of insufficient compression. If the lung tissue is not thick, a staple size of 3.5 mm should suffice in most cases, but if the tissue appears thick (such as with a large wedge resection), then larger staple sizes should be considered. Buttressing of the staple line is common practice, using a variety of commercially available preparations.95,102–104 These include bovine pericardium and other synthetic materials (Fig. 81.5). These have been reported to significantly reduce the incidence and/or severity of air leak in LVRS—which is

very similar to bullectomy. However, serious adverse events associated with buttressing have also been reported over the years, including laceration of adjacent viscera by the buttress material and expectoration of the material.105–107 Alternatives to buttressing may be the application of surgical sealants —including fibrin, albumin-glutaraldehyde, and others—to the staple line. These have been shown in small series to be potentially effective in reducing staple line leakage after bullectomy or LVRS.108–110 Alternatives to simple bullectomy altogether have also been reported. Deslauriers et al. have described their classic technique of longitudinal incision of a giant bulla, followed by plication of the visceral pleura over the raw surface and then stapling at the base of the bulla.111 Ablation of bullae using energy devices (argon beam coagulator, Nd:YAG laser, CO2 laser) has also been reported, although these have not gained widespread favor worldwide.17,112–119 At the end of surgery, some surgeons choose to effect a pleurodesis by mechanical abrasion or pleurectomy of the parietal pleura.95,107 It is believed by many surgeons that the pleurodesis both reduces the risk of future pneumothorax and gives a fibrotic reinforcement of the lung surface to prevent future bullae formation.120,121 Some surgeons continue to argue that bullectomy alone may be sufficient to reduce recurrence risk.110,122 However, longer-term results in a number of studies suggest that better results are achieved with the additional of pleurodesis.120,122 The lung should be fully re-inflated at the end of the procedure. As mentioned above, this may not always occur after removal of a particularly large bulla. Thorough adhesiolysis and possibly release of the pulmonary ligament should be used as a residual pneumothorax can compromise respiration in these patients who may already start with poor lung function. Further measures to reduce residual pleural air space include the creation of an apical pleural tent or a pneumoperitoneum in selected patients.123 It used to be routine to place two chest drains after a bullectomy for fear of significant postoperative air leaks. However, if an intraoperative air leak is not detected on intraoperative testing, one chest tube will usually suffice.90 The issue of suction application is discussed below.

FIGURE 81.5 Use of staple line buttressing for bullectomy. A: Endoscopic stapler with buttress loaded is placed across the base of the bullous part of lung. B: After firing, the buttress material augments the staple line, potentially reducing air leakage from the staple holes.

POSTOPERATIVE MANAGEMENT Whether or not suction should be applied to the chest drain(s) after bullectomy is debatable.124–126 On the

one hand, some negative pressure helps re-expand the lung quickly, and reduces postoperative atelectasis. If pleurodesis was performed during surgery, the suction may also help achieve good contact between the visceral and parietal pleura to ensure effective adhesion. However, there is concern that negative pressure can perpetuate any postoperative air leak, especially given the often poor lung tissue quality in patients with bullous disease. The suction may simply encourage continued seepage of air via any site of parenchymal leakage. Studies have demonstrated that avoidance of suction may be associated with faster spontaneous air leak resolution.124,125 In practice, low suction may be applied if the lung does not expand well after surgery, and discontinued once the lung is reasonably re-expanded. In such cases, the minimum level of suction is used to achieve the desired effect: usually around 10 to 15 cm H2O. In recent years, digital chest drainage systems have become available (Fig. 81.6). These have proven to be very useful in patients with air leaks after bullectomy.127,128 The digital air flow readings not only provide an accurate and objective measurement of the leakage (with minimal interobserver variance), but the air flow over time can also be displayed allowing trends in air leak to be observed.129 These give a clear impression of whether a leak is getting better or worse, and how it may be responding to adjustments in negative pressure or other interventions. (The digital systems can even be used at the end of the operation in the operating room to assess the amount of air leak on-table: a large leak may indicate immediate repair whilst the patient is still on the operating table.) Just as important, the digital systems allow a very consistent or “regulated” negative pressure to be applied, which has been hypothesized to possibly contribute to shortening of air leak durations.130 The level of regulated negative pressure that can be delivered by these digital systems can also be set safely to very low levels—even less “negative” than with water seal alone on a conventional chest drain. This again may help expedite spontaneous air leak resolution.

FIGURE 81.6 Portable digital chest drainage system. The system provides improved patient mobility postoperatively, a regulated negative pressure to the pleural space, and an accurate quantification of any air leakage.

Other than air leak, another common complication to be avoided used to be postoperative atelectasis and pneumonia. As mentioned above, many patients with bullous disease are smokers and/or have COPD, and are at higher risk for sputum retention. However, in this age of VATS, this complication is less frequently seen.90,97 Intensive care unit (ICU) admission is not routinely required if the patient can be extubated uneventfully at the end of the operation. Nonetheless, care should still be taken to prevent this complication, which can still have serious consequences. It is vital to ensure good pain control, and this is initiated before/during surgery with the use of regional blockade (e.g., paravertebral or epidural), preferably given preemptively as noted above.89 Postoperatively, patients should be given regular oral analgesia (such as acetaminophen), supplemented by stronger drugs as required for breakthrough pain (such as tramadol). Stronger opiates should be used with caution to avoid their suppressive effects on respiration and the dizziness which may hinder patient mobilization. Once pain control is achieved, patients should be encouraged to mobilize as soon as possible.95 With VATS approaches, there is no reason why the typical patient after bullectomy should not sit out and mobilize out of bed on the evening of the day of operation, and certainly no later than the first postoperative morning. Mobilization should be

further complemented by aggressive chest physiotherapy and frequent regular use of the incentive spirometer.36,95

ALTERNATIVES TO SURGERY Historically, percutaneous placement of a drain into a lung bulla has been described.131–134 Although it is possible to do this under local anesthesia, it typically involves a thoracic incision (with or without removal of a rib segment), then direct placement of a catheter into the bulla. Pneumothorax is prevented either by prior induction of pleurodesis, or by a placing a purse-string suture between the bulla walls and the chest wall. Talc or fibrin glue injection into the bulla cavity has also been described.108,135 In cases of an infected bullous cyst, instillation of antibiotics via the intracavitary drain has also been used successfully.136 The interest in this approach of external drainage is that it potentially preserves more lung than a bullectomy, and it avoids major surgery under general anesthesia. Nonetheless, evidence for the approach is largely historical and consists mainly of limited case series. Reports suggest that intracavitary drainage gave symptomatic improvement in almost 90% of patients. Whether any purported benefits over surgery are still maintained in this era of minimally invasive bullectomy has also not been investigated. The approach may have a niche role in selected patients unsuitable for surgery, but has not become a mainstream therapy in most centers today. Another alternative to surgery is the use of endobronchial therapy.137,138 The use of endobronchial valve (EBV) therapy for the treatment of emphysema is dealt with in the chapter on LVRS. These are oneway valves that are placed via rigid or flexible bronchoscopy (with newer generation valves) to the segmental bronchi, allowing air out but not back in to that part of the lung. For bullous lung disease, this could allow deflation of a bulla, and there are also reports of improvements in clinical, radiological, and functional parameters after using EBV therapy for such patients. The potential advantage of this method is the avoidance of any respective surgery, and the possibility of removing the EBVs at a later date (whether they succeeded and deflated the bulla, or failed). However, owing to reasons of cost and availability, the use of EBVs has not become very widespread worldwide, and experience in using them for treating bullous lung disease remains relatively limited.

OUTCOMES SAFETY It should not be forgotten that many patients with acquired bullous lung disease are inherently high-risk for any major surgical procedure. In this context, it is not surprising that bullectomy is associated with a definite mortality risk, with most deaths due to respiratory failure, pneumonia, or pleural infection. Table 81.5 shows the results of key case series of bullectomy, demonstrating that the mortality rate can range from 0% to 11%.14,16,139–150 However, many of those series date from many decades ago, and it is possible (though uncertain) whether modern advances may have reduced this in recent years. In comparison, mortality rates for the intracavitary drainage approach—supposedly “less traumatic”—are still reported in the region of 0% to 15%.131–134 In terms of morbidity after bullectomy, rates have been reported ranging from 7% to 79%.14,16,139–150 This wide variation is most likely due to lack of consistent reporting or uniform definition of what constitutes a “complication.” However, it is abundantly clear that by far the most common complication is

air leakage. Prolonged air leak has been typically reported to occur in 50% or more of all patients undergoing bullectomy (although again, variations exist in what is considered “prolonged”). Air leakage is thought to most often occur because the emphysematous lung tissue at the staple or suture holes come under stress as the lung expands after bullectomy. The tearing at these holes results in parenchymal air leak. This emphasizes the need to consider buttressing or sealant coverage of the staple lines as described above. Whether newer stapler designs that aim to reduce tissue stress along the staple lines can also help reduce the tearing and air leak is an intriguing thought that remains to be proven by clinical data. Once an air leak is noted, it can sometimes persist for up to weeks postoperatively because the diseased lung heals poorly. Measures to expedite the air leak cessation may include use of drain/suction manipulation, chemical pleurodesis, digital drainage with regulated pressure, or even EBV placement.151 However, there is relatively little clinical data to definitively prove their usefulness. TABLE 81.5 Selected Reports of Mortality and Morbidity From Bullectomy Study

Patients

Mortality (%)

Complications (%)

FitzGerald et al. (1974)14

84

2.3

24.0

Witz and Roeslin (1980)16

423

1.5–11.0

—

Potgieter et al. (1981)139

21

9.5

42.9

Pearson and Ogilvie (1983)140

12

8.3

—

Laros et al. (1986)141

27

0.0

—

O’Brien et al. (1986)142

20

0.0

—

Connolly and Wilson (1989)143

19

0.0

“low”

Ishida et al. (1995)144

47

0.0

10.6

Tsuchida et al. (1996)145

6

0.0

—

Menconi et al. (1997)146

34

5.9

—

DeGiacomo et al. (1999)147

25

0.0

48.0

Schipper et al. (2004)148

43

2.3

79.0

Palla et al. (2005)149

41

0.0

7.3

Gunnarsson et al. (2012)150

12

0.0

75.0

After air leakage, the most commonly reported complications are atelectasis and chest infections. The need for aggressive pain control and early mobilization of patients has been noted above, and deserves repetition here. The reduction in morbidity seen with the use of minimally invasive surgical techniques is usually the result of the earlier mobilization afforded by their use. In addition, arrhythmias have been reported in around 12% to 13% of patients, and pleural empyema in 6% to 14%.14,75,76,133,139,148

EFFICACY In terms of symptomatic improvement, the results of surgical bullectomy are certainly good.14,16,67,72,140,141,147–150,152 Rates of patient-reported improvement in dyspnea soon after surgery

typically range from 50% to 100% in most series reported to date (Table 81.6). Schipper and colleagues reported that in 81% of patients the improvement was still felt at 3 years after surgery. In terms of measurable improvement in lung function, a number of case series have documented that FEV1 after bullectomy can improve from 26% to 200% (Table 81.6). In the study by Schipper et al., the initial postoperative improvement in FEV1 declined somewhat at 3 years after surgery, but a significant improvement over preoperative values was still observed.148 It has been shown that similar benefits can be achieved whether the bullectomy is performed using a traditional open thoracotomy or by VATS. A number of predictors of short-term improvement after bullectomy have been identified. First, the size of the bulla is important.14,61,67 A large bulla occupying 50% or more of the lung volume is associated with significant improvements in FEV1 postoperatively. However, if the bulla occupies less than a third of the lung volume, then functional improvement may not be demonstrable. Second, as described earlier, the state of the underlying lung apart from the bulla is key.65,139,143,153 CT evidence of relatively normal underlying lung with adequate perfusion—and which has been significantly compressed by the expanding bulla—is a predictor of good functional outcome after bullectomy. Multiple, small, diffusely distributed bulla are not well associated with favorable functional outcomes, and “vanishing lungs” (progressive decrease in the radiographic opacity of the lung with prune vessels and septae with the bulla) may even be associated with worse function after surgery. The lack of significant compression on the nonbullous lung may also suggest relatively little functional improvement. Third, demonstration of asymmetric regional distribution of lung function may have an influence on outcomes.14,68 A demonstration of poor contribution to overall lung function by the bullous part (typically by VQ scan) is linked to better improvement in functional parameters after bullectomy.

TABLE 81.6 Selected Reports of Functional Outcomes After Bullectomy Study FitzGerald et al. (1974)14

50%–200% improvement in FEV1 Bullae >70% lung volume: 100% patients had symptomatic improvement up to 5 years Bullae 50% lung volume—symptomatic improvement Benefits declined after 2 years

Ohta et al. (1992)72

100% patients—symptomatic improvement (early) 80% patients—symptomatic improvement (at 4 years)

Baldi et al. (2001)67

50%–60% improvement in FEV1

DeGiacomo et al. (1999)147

Significant improvement in FEV1 at 3 months

Schipper et al. (2004)148

81% patients—symptomatic improvement (at 3 years) Predicted FEV1 improved from 34% (baseline) to 55% (at 6 months) Predicted FEV1 49% at 3 years

Palla et al. (2005)149

100% patients—symptomatic and FEV1 improvement After 5 years: patients with underlying emphysema returned to preoperative levels; patients with preserved lung has sustained improvement

Gunnarsson et al. (2012)150

Predicted FEV1 improved from 33% (baseline) to 58% (at 1 month) Predicted FEV1 returned to preoperative levels at 5.4 years

On longer-term follow-up, the general consensus from multiple case series suggests that the initial improvements after bullectomy gradually diminish.14,140,141,148 Symptomatic improvement compared to before surgery is still noted in one-third to one-half of patients at 5 years.14,140,141,148 When spirometry values are considered, however, the initial improvements are seen to slowly return to near-preoperative levels after 2 to 10 years.14,140,141,148 It has been estimated that the average annual decline in FEV1 is in the range of 500 to 100 mL/year. It is believed that the decline is due to progression of the underlying emphysema in the rest of each patient’s lungs (patients with an isolated giant bulla but underlying normal lung otherwise do not show this decline). It has not been shown whether such a decline would have affected these patients to the same or greater degree had the bullectomy not been done. A handful of studies have looked at the formation of new bullae after bullectomy surgery. Fitzgerald et al. observed re-occurrence in 12% to 30% of patients, with these manifesting about 10 years after the initial surgery on average.14 However, a number of subsequent studies have found the rate of new giant bulla formation to be 0% to 6.7% only, despite radiographic evidence of progression of emphysema in some patients.134,141,149,154

CONCLUSION Bullous lung disease is a structural pathology that has physiological and functional consequences for the patient. Because it is structural in origin, the only effective means of cure is surgery. In addition, given its functional manifestations, patients often are at increased risk for surgery. Accumulated experience over several decades have defined criteria for selection of candidates for surgery who will have lower risk and higher chance of improvement. For those who do receive surgery, bullectomy can now be performed using a range of minimally invasive approaches. Adjunctive technologies—for both intra- and postoperative use—have also helped reduce surgical morbidity. Surgery can provide good short-term functional outcomes, although long-term benefits are still not guaranteed. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.

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71. Pride NB, Barker CE, Hugh-Jones P. The ventilation of bullae and the effect of their removal on thoracic gas volumes and tests of overall pulmonary function. Am Rev Respir Dis 1973;107:83–98. 72. Ohta M, Nakahara K, Yasumitsu T, et al. Prediction of postoperative performance status in patients with giant bulla. Chest 1992;101:668–673. 73. Gould GA, Redpath AT, Ryan M, et al. Parenchymal emphysema measured by CT lung density correlates with lung function in patients with bullous disease. Eur Respir J 1993;6:698–704. 74. Snider GL. Reduction pneumoplasty for giant bullous emphysema: Implications for surgical treatment of nonbullous emphysema. Chest 1996;109:540–548. 75. DeGiacomo T, Rendina EA, Venuta F, et al. Bullectomy is comparable to lung volume reduction in patients with end-stage emphysema. Eur J Cardiothorac Surg 2002;22:357–362. 76. Wesley JR, Macleod WM, Mullard KS. Evaluation of surgery of bullous emphysema. J Thorac Cardiovasc Surg 1972;63:945–955. 77. 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Thorax 1984;39:140–142. 84. Peters MJ. Should smokers be refused surgery? BMJ 2007;334:20. 85. Glantz L. Should smokers be refused surgery? BMJ 2007;334:21. 86. Owen D, Bicknell C, Hilton C, et al. Preoperative smoking cessation: a questionnaire study. Int J Clin Pract 2007;61(12):2002–2004. 87. Oztürk O, Yılmazer I, Akkaya A. The attitudes of surgeons concerning preoperative smoking cessation: a questionnaire study. Hippokratia 2012;16(2):124–129. 88. Benumof JL. Sequential one-lung ventilation for bilateral bullectomy. Anesthesiology 1987;67:268–272. 89. Sihoe AD, Manlulu AV, Lee TW, et al. Pre-emptive local anesthesia for needlescopic video-assisted thoracic surgery: a randomized controlled trial. Eur J Cardiothorac Surg 2007;31:103–108. 90. Sihoe ADL. The evolution of VATS lobectomy. In: Cardoso P, ed. Topics in Thoracic Surgery. Rijeka, Croatia: Intech; 2011:181–210. 91. Wittekamp BH, van Mook WN, Tjan DH, et al. Clinical review: post-extubation laryngeal edema and extubation failure in critically ill adult patients. Critical Care 2009;13(6):233. 92. Rocco G. Non-intubated uniportal lung surgery. Eur J Cardiothorac Surg 2016;49(suppl. 1):i3–i5. 93. Pompeo E, Rogliani P, Palombi L, et al.; Awake Thoracic Surgery Research Group (ATSRG). The complex care of severe emphysema: role of awake lung volume reduction surgery. Ann Transl Med 2015;3(8):108. 94. Liu Y-J, Hung M-H, Hsu H-H, et al. Effects on respiration of nonintubated anesthesia in thoracoscopic surgery under spontaneous ventilation. Ann Transl Med 2015;3(8):107. 95. Sihoe AD, Chan HH. Surgical management of pulmonary emphysema: an update for primary care physicians. Hong Kong Practitioner 2007;29:43–51. 96. Cooper JD, Nelems JM, Pearson FG. Extended indications for median sternotomy in patients requiring pulmonary resection. Ann Thorac Surg 1978;26:413–420. 97. Sihoe ADL, Yim APC. Video-assisted pulmonary resections. In: Patterson GA, Cooper JD, Deslauriers J, et al. (eds). Thoracic Surgery. 3rd ed. Philadelphia, PA: Elsevier; 2008:970–988. 98. Sihoe AD. The evolution of minimally invasive thoracic surgery: implications for the practice of uniportal thoracoscopic surgery. J Thorac Dis 2014;6(suppl. 6):S604–S617. 99. Salati M, Rocco G. The uni-portal video-assisted thoracic surgery: achievements and potentials. J Thorac Dis 2014;6(suppl. 6):S618– S622. 100. Ooi A, Ling Z. Uniportal video assisted thoracoscopic surgery bullectomy and double pleurodesis for primary spontaneous pneumothorax. J Vis Surg 2016;2:17. 101. Melfi FM, Menconi GF, Mariani AM, et al. Early experience with robotic technology for thoracoscopic surgery. Eur J Cardiothorac Surg 2002;21(5):864–868. 102. Stammberger U, Klepetko W, Stamatis G, et al. Buttressing the staple line in lung volume reduction surgery: a randomized three-center study. Ann Thorac Surg 2000;70:1820–1825. 103. Miller JI, Jr., Landreneau RJ, Wright CE, et al. A comparative study of buttressed versus nonbuttressed staple line in pulmonary resections. Ann Thorac Surg 2001;71:319–323. 104. Murray KD, Ho CH, Hsia JY, et al. The influence of pulmonary staple line reinforcement on air leaks. Chest 2002;122:2146–2149. 105. Shamji MF, Maziak DE, Shamji FM, et al. Surgical staple metalloptysis after apical bullectomy: a reaction to bovine pericardium?. Ann Thorac Surg 2002;74:258–261. 106. Suemitsu R, Tokito T, Ichiki M, et al. Complication of bovine pericardial buttress: pulmonary pseudotumor. Asian Cardiovasc Thorac

Ann 2011;19(1):64–65. 107. Kanai Y, Endo S, Tetsuka K, et al. Massive haemothorax after pulmonary endostapling preloaded with bioabsorbable tissue reinforcement material. Interact Cardiovasc Thorac Surg 2012;14(3):345–346. 108. Hillerdal G, Gustafsson G, Wegenius G, et al. Large emphysematous bullae. Successful treatment with thoracoscopic technique using fibrin glue in poor-risk patients. Chest 1995;107:1450–1453. 109. Potaris K, Mihos P, Gakidis I. Experience with an albumin-glutaraldehyde tissue adhesive in sealing air leaks after bullectomy. Heart Surg Forum 2003;6(5):429–433. 110. Sakamoto K, Takei H, Nishii T, et al. Staple line coverage with absorbable mesh after thoracoscopic bullectomy for spontaneous pneumothorax. Surg Endosc 2004;18(3):478–481. 111. Deslauriers J, Leblanc P, McClish A. General Thoracic Surgery. Philadelphia, PA: Lea & Febiger; 1989. 112. Torre M, Belloni P. Nd:YAG laser pleurodesis through thoracoscopy: new curative therapy in spontaneous pneumothorax. Ann Thorac Surg 1989;47:887–889. 113. Rusch VW, Schmidt R, Shoji Y, et al. Use of the argon beam electrocoagulator for performing pulmonary wedge resections. Ann Thorac Surg 1990;49:287–291. 114. Wakabayashi A, Brenner M, Kayaleh RA, et al. Thoracoscopic carbon dioxide laser treatment of bullous emphysema. Lancet 1991;337:881–883. 115. Lewis RJ, Caccavale RJ, Sisler GE. VATS-argon beam coagulator treatment of diffuse end-stage bullous disease of the lung. Ann Thorac Surg 1993;55:1394–1398. 116. McKenna RJ, Jr., Brenner M, Gelb AF, et al. A randomized prospective trial of stapled lung reduction versus laser bullectomy for diffuse emphysema. J Thorac Cardiovasc Surg 1996;111:317–322. 117. Hazelrigg S, Boley T, Henkle J, et al. Thoracoscopic laser bullectomy: a prospective study with three-month results. J Thorac Cardiovasc Surg 1996;112:319–327 118. Kaseda S, Aoki T, Hangai N, et al. One hundred consecutive treatments with holmium:YAG laser for pulmonary bullae: especially in conjunction with gelatin-resorcinol formaldehyde-glutaraldehyde glue adhesion. Lasers Surg Med 2001;28(3):255–258. 119. Hazama K, Akashi A, Shigemura N, et al. Less invasive needle thoracoscopic laser ablation of small bullae for primary spontaneous pneumothorax. Eur J Cardiothorac Surg 2003;24(1):139–144. 120. Horio H, Nomori H, Kobayashi R, et al. Impact of additional pleurodesis in video-assisted thoracoscopic bullectomy for primary spontaneous pneumothorax. Surg Endosc 2002;16(4):630–634. 121. MacDuff A, Arnold A, Harvey J; BTS Pleural Disease Guideline Group. Management of spontaneous pneumothorax: British Thoracic Society Pleural Disease Guideline 2010. Thorax 2010;65(suppl. 2):ii18–ii31. 122. Nakanishi K. Long-term effect of a thoracoscopic stapled bullectomy alone for preventing the recurrence of primary spontaneous pneumothorax. Surg Today 2009;39(7):553–557. 123. Rocco G. Intraoperative measures for preventing residual air spaces. Thorac Surg Clin 2010;20(3):371–375. 124. Cerfolio RJ, Bass C, Katholi CR. Prospective randomized trial compares suction versus water seal for air leaks. Ann Thorac Surg 2001;71:1613–1617. 125. Brunelli A, Sabbatini A, Xiumé F, et al. Alternate suction reduces prolonged air leak after pulmonary lobectomy: a randomized comparison versus water seal. Ann Thorac Surg 2005;80(3):1052–1055. 126. Sanni A, Critchley A, Dunning J. Should chest drains be put on suction or not following pulmonary lobectomy? Interact Cardiovasc Thorac Surg 2006;5(3):275–278. 127. Cerfolio RJ, Bryant AS. The benefits of continuous and digital air leak assessment after elective pulmonary resection: a prospective study. Ann Thorac Surg 2008;86(2):396–401. 128. Papagiannopoulos K, Kuppusami M, Kefaloyannis EM. The use of Thopaz pump in the management of air leaks. A transition from analogue to standardised digital scoring. Experience of first 100 cases from a single institution. Interact Cardiovasc Thorac Surg 2009;9(suppl. 1):S31. 129. Pompili C, Detterbeck F, Papagiannopoulos K, et al. Multicenter international randomized comparison of objective and subjective outcomes between electronic and traditional chest drainage systems. Ann Thorac Surg 2014;98:490–497. 130. Brunelli A, Salati M, Pompili C, et al. Regulated tailored suction vs regulated seal: a prospective randomized trial on air leak duration. Eur J Cardiothorac Surg 2013;43(5):899–904. 131. Head JR, Avery EE. Intracavitary suction (Monaldi) in treatment of emphysematous bullae and blebs. J Thorac Surg 1949;18:761–776. 132. MacArthur AM, Fountain SW. Intracavitary suction and drainage in the treatment of emphysematous bullae. Thorax 1977;32:668–672. 133. Vigneswaran WT, Townsend ER, Fountain SW. Surgery for bullous disease of the lung. Eur J Cardiothorac Surg 1992;6:427–430. 134. Goldstraw P, Petrou M. The surgical treatment of emphysema. The Brompton approach. Chest Surg Clin North Am 1995;5:777–795. 135. Oizumi H, Hoshi E, Aoyama K, et al. Surgery of giant bulla with tube drainage and bronchofiberoptic bronchial occlusion. Ann Thorac Surg 1990;49:824–825. 136. Chandra D, Soubra SH, Musher DM. A 57-year-old man with a fluid-containing lung cavity: infection of an emphysematous bulla with methicillin-resistant Staphylococcus aureus. Chest 2006;130(6):1942–1946. 137. Yim AP, Hwong TM, Lee TW, et al. Early results of endoscopic lung volume reduction for emphysema. J Thorac Cardiovasc Surg 2004;127:1564–1573. 138. Noppen M, Tellings JC, Dekeukeleire T, et al. Successful treatment of a giant emphysematous bulla by bronchoscopic placement of endobronchial valves. Chest 2006;130:1563–1565.

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Potgieter PD, Benatar SR, Hewitson RP, et al. Surgical treatment of bullous lung disease. Thorax 1981;36:885–890. Pearson MG, Ogilvie C. Surgical treatment of emphysematous bullae: late outcome. Thorax 1983;38:134–137. Laros CD, Gelissen HJ, Bergstein PG, et al. Bullectomy for giant bullae in emphysema. J Thorac Cardiovasc Surg 1986;91:63–70. O’Brien CJ, Hughes CF, Gianoutsos P. Surgical treatment of bullous emphysema. Aust N Z J Surg 1986;56:241–245. Connolly JE, Wilson A. The current status of surgery for bullous emphysema. J Thorac Cardiovasc Surg 1989;97:351–361. Ishida I, Kobdono S, Fukuyama Y, et al. Video-assisted thoracoscopic surgery of bullous and bleb disorders of the lung using endoscopic staphing device. Surg Laparosc Endosc 1995;5:349–353. Tsuchida M, Nakayama K, Shinonaga M, et al. Video-assisted thoracic surgery for thorascopic resection of giant bulla. Surg Today 1996;26(5):349–352. Menconi G, Melfi FM, Janni A, et al. Current trends in the treatment of spontaneous pneumothorax. Binerva Chir 1997;52:1451–1459. DeGiacomo T, Venuta F, Rendina EA, et al. Video-assisted thoracoscopic treatment of giant bullae associated with emphysema. Eur J Cardiothorac Surg 1999;15:753–757. Schipper PH, Meyers BF, Battafarano RJ, et al. Outcomes after resection of giant emphysematous bullae. Ann Thorac Surg 2004;78(3):976–982. Palla A, Desideri M, Rossi G, et al. Elective surgery for giant bullous emphysema: a 5-year clinical and functional follow-up. Chest 2005;128:2043–2050. Gunnarsson SI, Johannesson KB, Gudjonsdottir M, et al. Incidence and outcomes of surgical resection for giant pulmonary bullae—a population-based study. Scand J Surg 2012;101:166–169. Venuta F, Rendina EA, De Giacomo T, et al. Postoperative strategies to treat permanent air leaks. Thorac Surg Clin 2010;20(3):391– 397. Vejlsted H, Halkier E. Surgical improvement of patients with pulmonary insufficiency due to localized bullous emphysema or giant cysts. Thorac Cardiovasc Surg 1985;33:335–336. Foreman S, Weill H, Duke R, et al. Bullous disease of the lung. Physiologic improvement after surgery. Ann Intern Med 1968;69:757– 767. Nickoladze GD. Functional results of surgery for bullous emphysema. Chest 1992;101:119–122.

82 Lung Volume Reduction Philip Carrott ■ Christine Lau

HISTORY It was Brantigan1 in the 1950s who first had the idea that localized lung resection might benefit patients with diffuse end-stage emphysema. It was his hypothesis that the inflammatory process of emphysema leads to destruction of lung tissue, with a resultant loss of parenchymal elasticity. This process resulted in a loss of the “tethering” effect that serves to hold open the walls of bronchioles throughout much of inspiration and expiration (Fig. 82.1). When the lung was destroyed, it led to a loss of this tethering, early closure of the bronchioles and hyperinflation. It was his thought that by removing the most diseased portions of lung, one could restore the tethering effect thus maintaining patency of the bronchioles and improve airflow. Although Brantigan noted that there was subjective improvement in survivors, there were little or no objective data to support his statement and the operation fell into disuse. Several decades later, this operative approach was taken up by de Perrot2 and by Dahan et al.3 in an attempt to improve function in patients with end-stage emphysema. Both investigators, like Brantigan, utilized a unilateral thoracotomy approach with excision of diseased lung. The two French investigators, however, based much of their decisions on the pulmonary hemodynamics and felt that it was perhaps the vascular physiology, with resultant hemodynamic changes, that caused improvement in dyspnea. However, the resultant improvement was not significant enough for this operation to become popular. In 1991, Wakabayashi et al.4 reported his results for the treatment of end-stage emphysema by unilateral parenchymal laser ablation via a thoracoscopic approach. Other investigators failed in their efforts to duplicate his results.5 It was not until 1994 that Cooper et al.6 adapted Brantigan’s theories and performed his own series of lung volume reductions (LVRs); thereafter, the procedure became popular. Cooper utilized a median sternotomy approach with bilateral excision of diseased, emphysematous upper lobes. As a result, his patients demonstrated remarkable improvements in oxygenation, spirometry, quality of life, and exercise capacity. Perhaps most importantly, this occurred without a single operative mortality. Following Cooper’s report in 1995,6 there was a brisk and far-reaching dissemination of the LVR procedure for the treatment of patients with end-stage emphysema, and the modern era of LVR began. There were multiple technical variations, including the employment of a unilateral thoracoscopy approach,7–9 a bilateral thoracoscopy approach,10–12 and bilateral minithoracotomies2 in addition to the median sternotomy approach popularized by Cooper. The initial published reports were almost universally encouraging and documented rates of morbidity and mortality that were relatively favorable. The most recent data from the National Inpatient Sample in 2013 shows that 185 patients were discharged with LVR as their principal diagnosis. This catalogs approximately 20% of hospital discharges, so in theory less than 1,000 LVR operations are performed each year in the United States.13

This is in contrast to approximately 2,000 lung transplant procedures performed in the United States per year.14

FIGURE 82.1 A: The negative intrapleural pressure and elastic fibers of the lung acting together to assert a circumferential pull on the bronchi. B: Loss of normal negative intrapleural pressure and the pull of the elastic fibers with no circumferential pull on bronchi to keep them open. (From Brantigan OC, Mueller E, Kress MB. A surgical approach to pulmonary emphysema. Am Rev Respir Dis 1959;80:194. With permission.)

RATIONALE On the surface, it would not seem rational to treat patients who demonstrate inadequate pulmonary reserve by removing significant amounts of lung tissue. However, in many patients, it does indeed improve their functional status. This has been explained through one of four pathophysiologic pathways.

VENTILATION/PERFUSION MISMATCH Patients with end-stage emphysema have distended alveolar airspaces; these may be inadequately ventilated yet still have some perfusion, resulting in the phenomenon of shunting. In addition, these distended airspaces may continue to expand and compress adjacent, well-perfused alveoli, which then become similarly dysfunctional. Theoretically, resection of such damaged lung would remove some component of the ventilation/perfusion mismatch and potentially allow reexpansion of adjacent alveoli, with a return to more normal function.

AIRWAY RESISTANCE There is an inherent elasticity within lung tissue. After alveoli become maximally distended during inspiration, the elastic properties of the alveolar wall tend to produce a constrictive force driving air outward, similar to what occurs in a deflating balloon. In end-stage emphysema, the alveolar walls become inflamed and are less elastic, which subsequently leads to a loss of elastic recoil, with less outward driving force during exhalation. The combination of the loss of the driving force of elastic recoil and the reduced tethering effect leads to closure of terminal bronchioles earlier in the expiratory cycle than what would normally occur. Over time, these forces result in increased airway resistance and hyperinflation or air trapping of the lung. LVR entails resection of hyperinflated and nonfunctional lung. The lung remaining within the chest is less diseased, and thus the “average” elastic recoil force will rise.15 As the smaller volume of lung tends to expand to fill the remaining pleural space, radial traction on the terminal bronchioles may increase, thus allowing them to stay patent a bit longer through the respiratory cycle and effecting a later closure. Both the aforementioned effects would tend to decrease airway resistance (or increase airway conductance), improve airflow, and ameliorate hyperinflation.16,17

CHEST WALL AND DIAPHRAGM The cycle of inspiration and expiration is controlled by the excursion of two components of the thoracic cavity, the chest wall and the diaphragm. The diaphragm raises and lowers through its cycle of relaxation and contraction and can be thought of as functioning in a piston-like fashion, helping to suck air in and then drive it out of the lung. The chest wall, through its cycle of increasing and decreasing anteroposterior diameter, acts much like a bellows, sucking air in and blowing it out. In patients with end-stage emphysema, the lung becomes hyperinflated, thus distending the chest wall and flattening the diaphragm. The stretching of the intercostals and shortening of the diaphragm limits its contractility and radically decreases the inhaled and exhaled volumes achieved during the inspiratory and expiratory cycle. Excision of nonfunctional hyperinflated lung will lead to a smaller overall lung volume. This provides the opportunity for the chest wall to shrink down to a less hyperexpanded position and the diaphragm to resume its more dome-like appearance. This return of the chest wall and diaphragm to their more normal shape and position will restore the functional capacity and muscular strength, leading to greater volumes of air movement throughout the respiratory cycle. Teschler et al.,18 Benditt et al.,19 and Tschernko17 have all documented changes in respiratory mechanics after LVR that support this mechanism for improvement, which likely represents much of the improvements seen with LVR.

HEMODYNAMICS While end-stage emphysema can result in pulmonary hypertension, LVR is not undertaken in patients who have reached this critical stage. Data on cardiac function and pulmonary hemodynamics in patients with end-stage emphysema are scarce. It is known that the increased intrathoracic pressure generated during forceful expiration in patients with end-stage emphysema can lead to decreased pulmonary venous return, and it has also been suggested that such increases may cause transient extrinsic pressure on pulmonary vasculature and thus increase vascular resistance. LVR would theoretically decrease the size of the lung within the chest cavity and, by decreasing airway resistance, would lead to a lowering of the intrathoracic pressure throughout the respiratory cycle. It might therefore improve venous return, decrease pulmonary vascular resistance, and thus improve right heart output and overall cardiac index. This was in part the pathophysiologic mechanism for improvement promoted by DeLarue et al.20 and Dahan et al.3 The most likely explanation for the LVR physiology is a combination of removing ineffective lung tissue with restoration of the normal sarcomere length for the respiratory musculature. As the NETT trial concluded, only a subset of patients will benefit most, and those with diffuse disease or bronchiolitis will not benefit from LVR, as their lung disease process is diffuse rather than focal and the worst disease cannot be resected with improvement in the less involved tissue.21–23 The normalization of respiratory muscle dynamics allows the remaining lung tissue to be used more efficiently as the muscle physiology is optimized.

PREOPERATIVE ASSESSMENT The criteria necessary for candidacy for LVR include severe heterogeneous emphysema with hyperinflation and adequate cardiopulmonary reserve to allow for recovery following a major operation. Extensive testing is required to identify appropriate candidates for LVR and includes not only imaging studies but also measurements of pulmonary function, cardiac reserve, and exercise capacity.

IMAGING STUDIES Certainly, the first and perhaps the simplest imaging test to be obtained is the chest x-ray. It should demonstrate hyperinflated lungs with an increased anteroposterior diameter and flattened diaphragms as noted on the lateral projection. The absence of these findings or the presence of notably increased markings suggesting interstitial disease can allow the clinician to exclude potential candidates without the need for further costly and time consuming workup.

FIGURE 82.2 Candidate for lung volume reduction surgery who has upper-lobe target areas for surgical resection. A,B: Computed tomography scans through the upper and lower lobes showing a heterogeneous pattern of predominant upper-lobe emphysema typical of patients with a favorable outcome. (Reprinted from Slone RM, Gierada DS, Yusen RD. Preoperative and postoperative imaging in the surgical management of pulmonary emphysema. Radiol Clin North Am 1998;36:57. Copyright © 1998 Elsevier. With permission.)

A computed tomography (CT) scan is an essential portion of the workup, not only to document the presence of emphysema suitable for surgical intervention but also to rule out the presence of infiltrative processes and/or occult lung cancer. During preoperative LVR assessment, it is not uncommon to identify a new solitary pulmonary nodule undetected on chest x-ray, and such a nodule requires a full workup to rule in or rule out the presence of malignancy.24 Even when such a nodule is identified and proved to be a cancer, it is not necessarily a contraindication to surgery if the nodule resides in an area of the lung that is to be resected at the time of LVR surgery.25,26 The high-resolution CT is utilized to first determine whether the emphysema is homogeneous in distribution or heterogeneous. For patients with heterogeneous disease, it is then determined whether or not the disease is upper-lobe–predominant or lower-lobe–predominant. Although Hamacher et al.27 has suggested that patients with homogeneous disease should be considered candidates for surgery, most clinicians would identify the patient with heterogeneous upper-lobe emphysema as the ideal candidate.28 Figure 82.2 demonstrates the CT findings that would be consistent with proceeding to LVR—i.e., relatively severe disease in the upper cuts of the CT scan with relative sparing of the parenchyma in the lower portion. A common clinical evaluation also includes ventilation and perfusion scintigrams obtained on nuclear imaging scans. The ideal findings for LVR would be similar to those in Figure 82.3—for example, a significant lack of perfusion in the upper lobes bilaterally with persistent gas retention in those same regions. This indicates heterogeneous disease, with the most severe involvement in the upper lobes. This picture of regional, focal lung destruction with relative sparing of the remaining parenchyma identifies both the optimal candidate and the appropriate target for excision. Beckers et al. from Germany, found that among patients with focal emphysema, lobar resection had more durable results compared to sublobar resection.29 They used computer-identified low attenuation lung volume to target the resection. The lobar group maintained a −17.2% ± 20.6% change in total lung capacity (TLC), while sublobar resection had a +12.1% ± 14.5% change in TLC. Their resected tissue consisted of either 25% to 30% of one lung in a nonanatomic wedge or anatomic resection of the most affected area, based on the CT scan.

PULMONARY FUNCTION TESTING Full spirometry and lung volume determinations are indicated in all candidates for LVR surgery. The lung volume should be measured via plethysmography rather than the dilution technique, because the former more accurately estimates the degree of lung air trapping and increased residual volume (RV). Optimal candidates are those with severe obstructive disease (forced expiratory volume in 1 second [FEV1] 120% predicted as well as elevated RV >150% predicted.

FIGURE 82.3 Ventilation/perfusion scan showing the amount of xenon retained in various lung zones. Areas of low retention are likely to be functional after resection of target areas. In this figure, the lower curve represents the upper third of the lung, with little ventilation and poor washout at 1 minute (44%). The upper curve represents the lower lung, which has good ventilation and good washout at 1 minute (85%). This is an ideal case for lung volume reduction surgery because the remaining lung (lower lung) has good potential for function based on an excellent washout.

Initial testing also includes determination of resting arterial blood gases (PO2 and PCO2). The diffusing capacity (DLCO) is also measured and, as shown later in this text, proves to be an important parameter that can occasionally contraindicate surgical intervention. Ideally, patients who are candidates for LVR have a PO2 >60, a PCO2 20% predicted.21,22,30 Those patients outside these criteria, particularly the DLCO, should be considered for lung transplantation instead.

MAXIMAL EXERCISE CAPACITY

The maximal exercise capacity has been shown to play a significant role in predicting prognosis and thus is an important determinant of success in patient selection.30 Two forms of maximal exercise capacity testing have been reported. The simpler of the two is the 6-minute walk test (6MWT), which measures the maximal walk distance achieved by the patient with oxygen supplementation as needed. It is important to undertake this in a reproducible fashion, as varying methodologies will yield different results. Appropriate patient instruction and practice are keys to obtaining reliable and reproducible findings.31 In most early clinical series, a 6-minute walk distance of at least 150 m was the lower limit for operative candidacy; patients unable to achieve this minimal requirement were felt to be too disabled to withstand the rigors of surgery. The second and perhaps more important test is the maximal exercise capacity as determined by incremental symptom-limited exercise utilizing a cycle ergometer. This test is done utilizing oxygen supplementation and will yield the maximum number of watts obtainable by any given subject. Results must be gender-corrected and will allow for categorization into groups with high and low exercise capacity.

CARDIOVASCULAR WORKUP Patients with end-stage emphysema are clinically fragile and do not tolerate complications following LVR. Because of this, significant cardiac disease is felt to be a contraindication to LVR and potential candidates are carefully screened for evidence of coronary disease using a pharmacologically induced stress test (i.e., dobutamine infusion) with both electrocardiographic monitoring and radionuclide scanning to assess for ischemic redistribution. Doppler echocardiography is routinely used to rule out significant cardiomyopathy and valvular heart disease. Early in the clinical experience, Doppler echocardiography was utilized to try to identify those patients with pulmonary hypertension, because such patients were felt to have an elevated risk of mortality. However, Fisher et al.32 documented relatively mediocre sensitivity (60%) and specificity (74%) when echocardiography was utilized in this fashion. Patients in whom pulmonary hypertension is suspected on the basis of signs, symptoms, or radiographic findings should therefore undergo right heart catheterization to determine whether pulmonary pressures contraindicate LVR.

PATIENT SELECTION Tables 82.1 and 82.2 outline the inclusion and exclusion criteria that were utilized for the National Emphysema Treatment Trial (NETT). These same criteria continue to be utilized by most surgeons at present and should form the foundation for patient selection. First and foremost is the presence of pulmonary hyperinflation due to obstructive lung disease. Radiographic changes on a plain film (diaphragmatic flattening, increased anteroposterior diameter) provide a good first screening test for patients initially seen in the office. Although there is no absolute upper age limit, most practitioners would prefer to be operating on patients ≤70 years of age. Abstinence from cigarette smoking for a period of at least 6 months is a requirement for consideration of LVR; in those instances where questions arise regarding abstinence, serum and urinary cotinine levels are liberally utilized to confirm the absence of nicotine use.

TABLE 82.1 Inclusion Criteria (Patients Must Meet All Criteria to Participate) History and physical examination

Consistent with emphysema; BMI ≤31.1 kg/m2 (men) or ≤32.3 kg/m2 (women) at randomization; stable on ≤20 mg prednisone (or equivalent) daily

Radiographic

HRCT scan evidence of bilateral emphysema

Pulmonary FEV1 ≤ 45% predicted (≥15% predicted if ≥70 years); TLC ≥100% predicted; RV ≥150% predicted function (prerehabilitation) Arterial blood gas (prerehabilitation)

P CO2 ≤60 mm Hg (Denver: P CO2 ≤55 mm Hg) P O2 ≥45 mm Hg (Denver: P O2 ≥30 mm Hg) on room air

Cardiac assessment

Approval for surgery before randomization by cardiologist if any of the following are present: unstable angina; LVEF cannot be estimated from the echocardiogram; LVEF ≤45%; dobutamine-radionuclide cardiac scan indicates coronary artery disease or ventricular dysfunction; arrhythmia (≥5 PVCs per minute; cardiac rhythm, other than sinus; PACs at rest)

Surgical assessment

Approval for surgery by pulmonary physician, thoracic surgeon, and anesthesiologist after rehabilitation and before randomization

Exercise

Post-rehabilitation 6-minute walk ≥140 m; able to complete 3 minutes of unloaded pedaling in exercise tolerance test (before and after rehabilitation)

Consent

Signed consent forms for screening, rehabilitation, and randomization

Smoking

Plasma cotinine ≤13.7 ng/mL (or arterial carboxyhemoglobin ≤2.5% if using nicotine products); nonsmoking for 4 months before initial interview and throughout screening

Rehabiliation

Must complete pre-randomization assessments, rehabilitation program, and all post-rehabilitation and randomization assessments

BMI, body mass index; FEV1, forced expiratory volume in 1 second; HRCT, high-resolution computed tomography; LVEF, left ventricular ejection fraction; PAC, premature atrial contraction; PVC, premature ventricular contraction; RV, residual volume; TLC, total lung capacity. Reprinted from National Emphysema Treatment Trial Research Group. Rationale and designs of the National Emphysema Treatment Trial (NETT): a prospective, randomized trial of lung volume reduction surgery. J Thorac Cardiovasc Surg 1999;118:518. Copyright © 1999 The American Association for Thoracic Surgery. With permission.

TABLE 82.2 Exclusionary Criteria (Presence of Any Criterion Makes the Patient Ineligible) Previous operation

Lung transplantation; LVRS; median sternotomy or lobectomy

Cardiovascular

Arrhythmia that might pose a risk during exercise or training; resting bradycardia (20% predicted values. Patients 140 m after rehab

FEV1 ≤15% predicted DLCO ≤20% predicted PaO2 ≤55 mm Hg PaCO2 ≥55 mm Hg Mean PA pressure ≥40 mm Hg

6MWT, 6-minute walk test; BMI, body mass index; CAD, coronary artery disease; CHF, congestive heart failure; DLCO, diffusing lung capacity for carbon monoxide; FEV1, forced expiratory volume in 1 second; HTN, hypertension; LVR, lung volume reduction; MI, myocardial infarction; PA, pulmonary artery; PaCO2, arterial partial pressure of carbon dioxide; PaO2, arterial partial pressure of oxygen; RV, residual volume; TLC, total lung capacity.

These data strongly suggest that LVR surgery should be offered to selected patients with end-stage emphysema. These patients include those with upper-lobe emphysema whether or not they have high or low exercise capacity. The patients with upper-lobe emphysema and high exercise capacity will have an excellent chance for marked improvement in both maximal exercise capacity and in quality of life. Patients with upper-lobe emphysema and low exercise capacity will not only enjoy a significant chance for improvement in exercise capacity and quality of life but also have markedly decreased mortality. Thus, in this patient subgroup, LVR surgery can indeed be a lifesaving procedure. Although the functional improvements disappear over a period of 3 to 5 years, LVRS patients maintain a clinical advantage over their medical counterparts throughout the length of follow-up. Thus, LVR surgery should be strongly considered for all end-stage emphysema patients with upper-lobe–predominant disease. Failure to do so will unnecessarily condemn many such patients to highly limited survival and unnecessarily poor quality of life. The attributes that help to differentiate good candidates from poor ones are listed in Table 82.5.

BRONCHOSCOPIC LUNG VOLUME REDUCTION Although the LVR is relatively safe and effective, it does entail significant morbidity, mortality, and cost. As occurs with many successful operations, once their efficacy is established, there arise efforts to accomplish the same goals without the need for an invasive surgical procedure. There are currently three general areas of investigation that seek to recreate the benefits of LVR without the need for incisions or

lengthy hospitalizations. The most developed of the three strategies is the bronchoscopic insertion of prosthetic endobronchial valves. Instead of removing the most diseased lung tissue as occurs with surgical LVR, the goal of this nonoperative strategy is to place miniature one-way valves into the segmental orifices of the most diseased lobes (Fig. 82.9). These valves allow for the efflux of air from the parenchyma but simultaneously prevent the influx of air into the alveoli. The goal is to effect segmental and/or lobar atelectasis in the most diseased lung thus effectively reducing the lung volume by collapse instead of surgical removal.

FIGURE 82.9 The Zephyr endobronchial valve (Emphasys; Redwood City, CA) consists of a self-expanding stent-like shell that encases a tiny one-way valve similar to a Heimlich valve. It is implanted into segmental bronchi to prevent inflow of air to the alveoli while allowing for efflux of air from the lung. (From Venuta F, De Giacomo T, Rendina EA. One-way valves for bronchoscopic LVR. CTSNet http://www.ctsnet.org/portals/thoracic/newtechnology/article-3.html. With permission.)

FIGURE 82.10 Technique for insertion of bronchopulmonary stents. A: The flexible bronchoscope is inserted to the level of the segmental bronchus. B: A radiofrequency probe inserted through the bronchoscope is used to create a hole through the bronchial wall into the adjacent lung parenchyma. C: A balloon-expandable stent is passed down the bronchoscope and expanded with the proximal end just inside the bronchial lumen. (Reprinted from Lausberg HF, Chino K, Patterson GA, et al. Bronchial fenestration improves expiratory flow in emphysematous human lungs. Ann Thorac Surg 2003;75:393–397. Copyright © 2003 The Society of Thoracic Surgeons. With permission.)

One such valve is the Spiration endobronchial valve. Wood et al.65 reported the initial experience with 30 patients in whom an average of six valves were inserted per patient. Testing at 3- and 6-month intervals failed to identify significant improvement in measurements of exercise capacity, gas diffusion, or spirometric parameters. There was some improvement in dyspnea as measured by a change in the SGRQ score; but without concomitant improvement in more objective criteria, one might suspect this to be merely a placebo effect. A different valve produced by Emphasys (Redwood City, CA) has been implanted intrabronchially with marked improvement in spirometry, dyspnea, and exercise capacity.66,67 The second generation of endobronchial valves manufactured by this company (Zephyr, Fig. 82.9) was the prosthesis utilized in the Endobronchial Valve for Emphysema Palliation Trial (VENT), a prospective, multi-institutional, randomized trial sponsored by the National Institutes for Health comparing the Zephyr endobronchial valve with best medical therapy. Although the results of this trial have not yet been published, they have been presented in preliminary form at a national meeting. The results demonstrated that there was no increased morbidity or mortality associated with endobronchial valve placement when these patients were compared with the medical “controls.” There were statistically significant improvements in spirometry, exercise capacity, and dyspnea indices, although these fell short of the marked improvement reported after surgical LVR. Still, these promising results support continued efforts to effect LVR in a nonoperative fashion. There are two additional ongoing efforts to devise a successful noninvasive approach for LVR. One involves a mechanical approach that entails the creation of an extra-anatomic bypass of the bronchial

pathway utilizing tiny expandable stents (Fig. 82.10). This method involves boring tiny holes in bronchial walls at a site adjacent to bullous lung degeneration. Expandable wire stents are then placed through these holes to allow additional pathways for exit of air trapped within the parenchyma. This was first described by Lausberg et al.68 in 2003, utilizing emphysematous lungs explanted at the time of transplantation as the experimental model. He was able to demonstrate markedly increased expiratory flow from the explanted lungs once a stent was placed, and the more stents that were placed, the greater the improvement. There is an ongoing study known as the Exhale Airway Stents for Emphysema (EASE) Trial, which is utilizing this technology for the treatment of end-stage emphysema, but the experience has not yet been reported. Finally, Reilly et al.69 have reported a “biologic” LVR procedure that involves the sequential subsegmental bronchoscopic instillation of a trypsin solution (to deactivate surfactant and detach epithelial cells) followed by a fibrinogen suspension and then thrombin to manufacture intrabronchial fibrin plugs. Theoretically this procedure should induce inflammation and effect atelectasis in localized regions of the lung, thus resulting in reduction of lung volume. The publication described their preliminary safety trials but did document some very mild spirometric improvements. Further work remains to be done to determine whether clinically significant improvements can be achieved with this technique. REFERENCES 1. Brantigan OC, Mueller E, Kress MB. A surgical approach to pulmonary emphysema. Am Rev Respir Dis 1959;80:194–206. 2. de Perrot M, Licker M, Spiliopoulos A. Muscle-sparing anterior thoracotomy for one-stage bilateral lung volume reduction operation. Ann Thorac Surg 1998;66:582–584. 3. Dahan M, Salerin F. Berjaud J, et al. Value of hemodynamics in the surgical indications of emphysema. Ann Chir 1989;43:669–672. 4. Wakabayashi A, Brenner M, Kayaleh RA, et al. Thoracoscopic carbon dioxide laser treatment of bullous emphysema. Lancet 1991;337:881–883. 5. Hazelrigg S, Boley T, Henkle J, et al. Thoracoscopic laser bullectomy: a prospective study with three-month results. J Thorac Cardiovasc Surg 1996;112:319–327. 6. Cooper JD, Trulock EP, Triantafillou AN, et al. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1995;109:106–116. 7. Hazelrigg SR, Boley TM, Magee MJ, et al. Comparison of staged thoracoscopy and median sternotomy for lung volume reduction surgery. Ann Thorac Surg 1998;66:1134–1139. 8. Keenan RJ, Landrenau RJ, Sciurba FC, et al. Unilateral thoracoscopic surgical approach for diffuse emphysema. J Thorac Cardiovasc Surg 1996;111:308–316. 9. Naunheim KS, Keller CA, Krucylak PE, et al. Unilateral video-assisted thoracic surgical lung reduction. Ann Thorac Surg 1996;61:1092–1098. 10. Bingisser R, Zollinger A, Hauser M, et al. Bilateral volume reduction surgery for diffuse pulmonary emphysema by video-assisted thoracoscopy. J Thorac Cardiovasc Surg 1996;112:875–882. 11. Kotloff RM, Tino G, Bavaria JE, et al. Bilateral lung volume reduction surgery for advanced emphysema. A comparison of median sternotomy and thoracoscopic approaches. Chest 1996;110:1399–1406. 12. McKenna RJ, Brenner M, Gelb AF, et al. A randomized, prospective trial of stapled lung reduction versus laser bullectomy for diffuse emphysema. J Thorac Cardiovasc Surg 1996;111:317–322. 13. HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD. http://hcupnet.ahrq.gov/, Accessed April 15, 2016. 14. Organ Procurement and Transplantation Network, U.S. Department of Health & Human Services, Richmond, VA. https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/, Accessed April 15, 2016. 15. Sciurba FC, Rogers RM, Keenan RJ, et al. Improvement in pulmonary function and elastic recoil after lung-reduction surgery for diffuse emphysema. N Engl J Med 1996;334:1095–1099. 16. Keller CA, Ruppel G. Hibbett A, et al. Thoracoscopic lung volume reduction surgery reduces dyspnea and improves exercise capacity in patients with emphysema. Am J Resp Crit Care Med 1997;156:60–67. 17. Tschernko EM, Wisser W, Hofer S, et al. The influence of lung volume reduction surgery on ventilatory mechanics in patients suffering from severe chronic obstructive pulmonary disease. Anesth Analg 1996;83:996–1001. 18. Teschler H, Stamatis G, El-Raouf Farhat AA, et al. Effect of surgical lung volume reduction on respiratory muscle function in pulmonary emphysema. Eur Respir J 1996;9:1779–1784. 19. Benditt J, Wood DE, McCool FD, et al. Changes in breathing and ventilatory muscle recruitment patterns induced by lung volume reduction surgery. Am J Respir Crit Care Med 1997;155:279–284.

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83 Bacterial Infections of the Lungs and Bronchial Compressive Disorders Semih Halezeroğlu The roots of thoracic surgery lie in the management of suppurative diseases of the lung and certain bronchial compressive disorders. As Miller,1 noted, advances in antibiotic treatments and development of modern interventional technologies in the last decades decreased the role of surgery in the management of infectious lung disease. However, these disorders still continue to form an important part of the specialty of general thoracic surgery worldwide. Hood,2 explained the factors contributing to the continued frequency with which these disease entities are currently seen. These include the emergence of antibioticresistant organisms and nosocomial pulmonary infections, the increased numbers of immunosuppressed individuals, the increased drug abuse, and an increasing older population. The prevalence of these conditions requires that the thoracic surgeons have sufficient knowledge and surgical skills to handle these disease entities. An outline of the surgical spectrum of bacterial infections and bronchocompressive disorders of the lung is given in Table 83.1. Patients’ demands for minimally invasive approaches significantly shape the daily practice of the surgeon. In order to reduce postoperative morbidity, even relatively complicated infectious diseases have now to be treated with the new and lesser invasive surgical approaches. In this chapter, contemporary diagnostic modalities as well as the thoracic surgical operations, including standard or uniportal thoracoscopic approaches in inflammatory lung diseases, are discussed and also presented with selfexplanatory videos.

TABLE 83.1 Surgical Spectrum of Bacterial Infections of the Lung and Bronchial Compressive Disease Spectrum of surgical infectious disease Bronchiectasis Lung abscess Organizing pneumonia (diagnosis only) Destroyed lung Pulmonary infection in granulomatous disease of childhood Tuberculosis and fungal disease Thoracic empyema Bronchial compressive pulmonary disorders Right middle lobe syndrome Broncholithiasis Fibrosing mediastinitis Inflammatory lymphadenopathy Congenital processes Cardiovascular disease Congenital Vascular ring Aberrant left pulmonary artery Acquired aortic disease Aortic arch aneurysm Traumatic false aneurysm

BRONCHIECTASIS The term bronchiectasis refers to an abnormal permanent dilatation of subsegmental airways.3 The history of bronchiectasis parallels that of thoracic surgery and has been outlined previously by Lindskog.4 The techniques of segmental resection were developed in large part because of this entity. Detailed anatomic descriptions of segmental anatomy by Boyden,5 led to the development of individual ligation of the hilar bronchovascular structures and significantly decreased postoperative complications. With the development of antibiotics in the 1940s, bronchiectases have not been seen as frequently; however, with the emergence of drug-resistant microorganisms and increasing frequency of drug-resistant tuberculosis, an increased incidence of postinfectious bronchiectasis is being noted. The terms cylindrical or tubular (Fig. 83.1), varicose, and saccular (Fig. 83.2) have been used to describe the morphology of bronchiectasis. A classification of bronchiectasis is given in Table 83.2. Saccular bronchiectasis follows a major pulmonary infection or results from a foreign body or bronchial stricture and is the main type requiring surgical attention. Cylindrical bronchiectasis consists of bronchi that do not end blindly but communicate with lung parenchyma. Hood,2 noted a third type referred to as varicose, a mixture of the former two, distinguished by alternating areas of cylindrical and saccular disease. Pseudobronchiectasis, a term coined by Blades and Dugan,6 is a cylindrical dilatation of a bronchus that is temporary and disappears in several weeks or months and develops after an acute pneumonic process. This type has no surgical implications and should be taken into consideration before diagnosing a bronchiectasis with single CT finding especially in a patient without an acceptably long history of bronchopulmonary symptoms.

FIGURE 83.1 HRCT of the chest in a patient with cylindrical (tubular) bronchiectasis in both lungs.

FIGURE 83.2 HRCT in saccular bronchiectasis.

Certain genetic syndromes may be associated with some form of bronchiectasis. These include cystic

fibrosis, alpha1-antitrypsin deficiency, immunoglobulin A (IgA), and, IgG deficiency. The distribution and frequency of bronchiectasis is given in Tables 83.3 and 83.4. The distribution to some extent is characteristic of the etiology. For example, in patients with Kartagener syndrome, hypogammaglobulinemia, and cystic fibrosis, the areas of involvement are generally diffuse and bilateral and involve multiple cystic segments of both upper and lower lobes. Tuberculosis is either unilateral or bilateral and generally involves the upper lobes or superior segment of the lower lobes. TABLE 83.2 Classification of Bronchiectasis Saccular bronchiectasis Cylindrical bronchiectasis Pseudobronchiectasis Posttuberculosis bronchiectasis Genetic-related bronchiectasis

TABLE 83.3 Anatomic Distribution of Bronchiectasis in Order of Frequency Left lower lobe Lingula, middle lobe Total left lung Total right lung Right upper lobe Left upper lobe

EPIDEMIOLOGY The true incidence of bronchiectasis remains unknown since there is no universally applicable screening test. A previous study conducted in the USA. documented the incidence in the adults to be 52 per 100,000.7 However, this study did not employ modern diagnostic techniques like high-resolution computed tomography (HRCT) scanning. Moreover, recent studies revealed that using HRCT has identified bronchiectasis in up to 50% of patients who were diagnosed by general practitioners to have chronic bronchitis or chronic obstructive pulmonary disease (COPD).8–11 Moreover, an increased incidence is associated with conditions such as suboptimal vaccination against measles and pertussis and limited access to health care.

PATHOPHYSIOLOGY The healthy lung protects itself from the continuously inhaled pathogens with a complex defense system that consists of antibodies and mucociliary clearance. Any condition that interferes with the protection mechanism such as low antibody levels, connective tissue disorders, or impaired clearance of the bronchial airway could lead to colonization of pathogens in bronchopulmonary tissues resulting in further inflammation. As a result, abnormal dilation of the bronchus develops with the destruction of the elastic and muscle layers of the small-sized bronchial airways. In addition, lack of ciliated cells and collection of mucus in the dilated airways serve as perfect media for the bacteria to colonize. Eventually, the vicious cycle of bronchiectasis develops (Fig. 83.3). As seen on the CT scan of a patient with left lower lobe disease in Figure 83.4, the lobar bronchus itself may also be severely destructed together with the smaller bronchial branches. However, whether the destruction of the lobe bronchus is a part of the initiation of

bronchiectasis, or it is only a consequence of the inflammatory process in small-sized bronchi remains a question to be answered by further studies.

ETIOLOGY OF BRONCHIECTASIS Table 83.5 summarizes the causes of bronchiectasis. Recurrent pulmonary infections, immunodeficiency disorders, tuberculosis, allergic bronchopulmonary aspergillosis, slowly growing tumors that obstruct the bronchus, congenital mucociliary disorders, and childhood diseases like measles or pertussis can all induce the disease. However, in almost half of the patients, no initiating event could be identified. In fact, not all patients with a history of measles, whooping cough, or recurrent pneumonia develop bronchiectasis. The exact mechanism of bronchiectasis and the reason why some people with similar history develop bronchiectasis while others do not are not clear. Nevertheless, impaired immunity, connective tissue disorders, cystic fibrosis, ciliary defects as well as previous bronchopulmonary bacterial or viral infections are thought to have a role in the development of the disease. TABLE 83.4 Frequency of Distribution of Bronchiectasis: Area of Involvement Left lung more often than right lung7,9 Left lower lobe, most frequently involved Lingula and middle lobe next most frequently involved Total left bronchiectasis, fourth most commonly involved Right lower and total right are less often involved Right upper lobe is involved more often than left upper lobe1,4

FIGURE 83.3 The viscous cycle of bronchiectasis.

Because of the link between the extent of natural killer cell activation and susceptibility to

bronchiectasis, an innate immune mechanism is thought to be an underlying reason for the development of this condition.10,12,13 Similarly, patients with primary antibody deficiency are likely to develop bronchiectasis. A higher incidence was shown in patients with HLA-Cw*03 alleles and HLA-C group homozygosity.10,12–14 Similarly, ulcerative colitis-associated bronchiectasis is related with IFNγ and CXCR-1 polymorphism.10,15 The association between bronchiectasis and HLA-DR1, DQ5 has also been reported.10,14

FIGURE 83.4 Although bronchiectasis is described as the disease of subsegmental bronchi, this picture demonstrates that not only the small peripheral bronchi but also the large lobe bronchus may be destructed in the disease process.

TABLE 83.5 Etiology of Bronchiectasis Congenital Congenital cystic bronchiectasis Selective immunoglobulin A deficiency Primary hypogammaglobulinemia Cystic fibrosis α1-antitrypsin deficiency Kartagener’s syndrome Congenital deficiency of bronchial cartilage Bronchopulmonary sequestration Acquired Infection Bronchial obstruction Intrinsic: tumor, foreign body Extrinsic: enlarged lymph nodes Middle lobe syndrome Scarring secondary to tuberculosis Acquired hypogammaglobulinemia

DIAGNOSIS OF BRONCHIECTASIS

Clinical Features The diagnosis of bronchiectasis is generally clinical. A mild degree of disease that involves one or two lung segments may be associated with either none or minor symptoms except for periods of infectious exacerbations. A typical patient, however, has classical symptoms of daily purulent, mucopurulent or mucoid sputum discharge, cough, fatigue, low exercise tolerance, and occasional hemoptysis. Patients generally have a history of frequent bronchopulmonary infections necessitating antibiotics as well as hospitalizations for the treatment of infectious recurrences. The requirement for three or more prolonged treatment sessions yearly is not rare. An important proportion of patients have a history of long-standing medical treatment due to the diagnosis of chronic bronchitis, sinusitis, or asthma before the correct diagnosis is made by radiological investigations. Patients’ relatives may give information about bad breath odor, or if specifically asked, a foreign body aspiration during childhood. Finger clubbing may also be seen in severe cases. Children with bronchiectases are likely to be in a stage of developmental deficiency when compared to their age group. Chronic respiratory symptoms in children should alert the physician to the possibility of bronchiectasis. The British Thoracic Society,16 recommends that bronchiectasis should be considered in adults who have persistent productive cough with the following features: young age at presentation, history of symptoms over many years, absence of smoking history, daily expectoration of large volumes of very purulent sputum, haemoptysis, sputum colonization by Pseudomonas aeruginosa, and nonproductive cough. Investigations In general, when the suspicion of bronchiectasis arises, the first investigation needed to confirm the diagnosis is a radiological assessment. Once the diagnosis is established, investigations are directed to identify the underlying cause which is crucial to select the appropriate method of treatment.

FIGURE 83.5 A: Chest radiography of a patient with a history of long-standing, frequent bronchopulmonary infections, and sputum discharge shows a significant displacement of the heart to the left. B: HRCT discloses that the left lower lobe is relatively small due to tubular bronchiectasis. This is the reason for the heart’s displacement toward the left side in this patient.

Radiology Chest x-ray is generally the first radiological examination in a patient with clinically relevant symptoms. The most prominent features are lobar collapse and tramlines shadows. In addition, in its most common location (i.e., the left lower lobe), a significant displacement of the heart to the left may be the only finding of bronchiectasis to be recognized on a chest x-ray (Fig. 83.5A). In mild cases, the radiographic signs are mostly unremarkable. However, if the patient has obvious clinical symptoms, it is rare that the chest x-ray is “completely normal.”16–18 HRCT confirms the diagnosis (Fig. 83.5B) in all patients. Early bronchiectases that cannot be identified on x-ray can indeed be detected by HRCT. Bronchial wall dilation, which is assessed as internal lumen diameter greater than the adjacent pulmonary artery, is the distinguishing feature. Additionally, bronchial wall thickening, lobar collapse, mucus in the bronchus, the mediastinum and fissure displacements may also be seen. HRCT must be evaluated for the presence of features suggestive of cystic fibrosis, tuberculosis, tracheobronchomegaly as in Mounier–Kuhn syndrome (Fig. 83.6) or a foreign body in the bronchial obstruction. Microbiological Analyses All patients with bronchiectasis should have sputum culture done. The most commonly isolated organism is Haemophilus influenza, present in up to one third of the patients.16,19,20 In addition, P. aeruginosa, Streptococcus pneumonia, Staphylococcus aureus, and Moraxella catarrhalis may also be seen. Mycobacteria are generally responsible for the bronchiectasis developing as a late “sequel.” Hence, this bacillus is rarely isolated in the sputum. Bronchoscopy Bronchoscopy is not a routine investigation method for bronchiectasis; its indications are listed in Table 83.6. Rigid bronchoscopy under general anesthesia may be preferred over flexible bronchoscopy in order to suction the excessive amount of sputum and proceed with the lavage of the tracheobronchial tree. Video 83.1 shows the bronchoscopic appearances of tubular bronchiectasis in a patient, and bronchiectasis associated with a tracheobronchomegaly (Mounier–Kuhn syndrome) in another. Large amount of mucus seen in the bronchial tree during bronchoscopy helps understanding the underlying problem of the patients. Browser issues Video 83.1 Bronchoscopic view in two patients with bronchiectasis.

FIGURE 83.6 A CT scan of a patient with Mounier–Kuhn syndrome (tracheobronchomegaly) showing bilateral bronchiectasis.

TABLE 83.6 Indications for Bronchoscopy in Bronchiectasis Diagnosis Foreign body Tumor Sputum culture Treatment Removal of excessive sputum Preoperative Assisting preoperative anesthetic management

Immunological Tests As mentioned above, primary antibody deficiency is one of the major underlying conditions of bronchiectasis. Structural lung destruction will also cause a secondary antibody defect. Thus, it is important to screen newly diagnosed patients for IgG, IgA, and IgM antibody deficiencies.

MANAGEMENT OF BRONCHIECTASIS Because the association of cystic fibrosis (CF) and bronchiectasis, as an individual clinical entity, is discussed in Chapter 73, only the management of non-CF bronchiectasis is presented here. The aim of treatment is to manage underlying disorders, decrease the frequency of infectious episodes, control bronchopulmonary infections, increase the quality of life by reducing daily symptoms, achieve the normal development of the child, and prevent possible complications. Various treatment approaches become necessary during the course of the disease including physiotherapy, pharmacotherapy, rehabilitation, bronchoscopic aspiration, and surgery. Thoracic surgeon must always be a part of the multidisciplinary team along with a chest physician, pediatrician for children, experienced

physiotherapist, and immunology consultant. Radiology and microbiology departments should also provide input. Physiotherapy Physiotherapy constitutes an important part of the management and starts with the education of the patients and relatives about the disease, along with the mechanisms and the importance of airway clearance techniques.16 Commonly used physiotherapy maneuvers are postural drainage, active breath cycle, and manual techniques (i.e., chest clapping).10,16 Patients should be encouraged to remove excessive mucoid bronchial secretions especially in the morning. Postural drainage is performed according to the location of the disease in the lung, necessitating either a left or right side, or head-down position. While a right or left lateral side down position is needed in upper lobe disease, head down is used when the lower lobes are involved. Humidification with nebulized saline before postural drainage is helpful to activate ciliary function and provide more sputum discharge. Medical Treatment Presence of sputum production alone or isolation of a pathogen without clinical signs of active infection is not always an indication for antibiotic treatment.16 Antibiotics are used when the clinical picture deteriorates as demonstrated by an increased cough or sputum production, high fever, shortness of breath, and hemoptysis. Treatment should be started empirically (immediately after the sputum sample is sent for microbiological analysis) based on the previous isolation and continue for 14 days. Because the responsible organism is H. influenza in most cases, treatment with a β-lactam antibiotic (amoxicillin) is rewarding. However, P. aeruginosa responds best to treatment with ciprofloxacin. To avoid the development of antibiotic resistance, it is important to prevent its use without bacterial culture and sensitivity analysis. Bronchodilators with β2 agonist and anticholinergic drugs may be initiated and continued as long as lung function or symptoms improve. There is no evidence for a role of inhaled or oral corticosteroids.16 Allergic bronchopulmonary aspergillosis may occur as a result of a hypersensitivity reaction to Aspergillus and is treated with oral corticosteroids and azole antifungal agents. Immunodeficiency situations require intravenous administration of immunoglobulin. Surgery Bronchiectasis is a debilitating disease associated with a poor quality of life. Patients generally isolate themselves socially because of low exercise tolerance, high susceptibility to infections, and frequent cough and purulent sputum discharge in a public environment. Hence, any possibility for a curative solution that helps patient return to normal daily activities is of utmost importance. Indications and Principles for Surgery in Non-CF Bronchiectasis The most important indication for surgery is the failure of medical treatment (Table 83.7). A long course of conservative management is a must before proceeding with a surgical resection. Periodic hemoptysis warrants surgical treatment if the areas of bronchiectasis are amenable to surgical removal. Otherwise, intensive hospital care and bronchial artery embolization should be considered. In the event of bleeding due to tuberculous sequelae, the source may be a lacerated pulmonary artery. Hence, in these patients,

even minor hemoptysis should be monitored closely and surgery considered early.21 One of the main indications has always been the “localized disease.” It is important to make it clear that the term “localized” does not necessarily refer to the disease being localized in a single segment or a lobe. As an example, the association of bronchiectasis both in left lower lobe and the lingular segment is not rare. In this situation, a lower lobectomy combined to lingular segmentectomy is warranted (Videos 83.2 and 83.3). In a similar fashion, a bilobectomy or a lobectomy together with segmentectomy may be undertaken in patients with bronchiectasis in the right lung (Fig. 83.7). Browser issues Video 83.2 Three-port VATS lobectomy and lingulectomy for bronchiectasis. Browser issues Video 83.3 Uniportal VATS lobectomy and lingulectomy for bronchiectasis. In this context, “bilateral disease” is not an absolute surgical contraindication unless it is disseminated to all lobes.22 As an example, the choice of bilateral lower lobectomy, in the presence of an appropriate cardiopulmonary function, represents a good option in patients with the disease extent seen in the chest CT view on Figure 83.8. In contrast, Figure 83.9 is an example of a disseminated disease where surgical resection is contraindicated. In this setting, the morbidity of bilateral thoracotomy represents a major concern when evaluating patients with bilateral bronchiectasis. However, in the era of video-assisted thoracic surgery (VATS), it is imperative to strike a balance between the morbidity of bilateral sequential operations and the risk of inefficient conservative management. TABLE 83.7 Treatment of Bronchiectasis Medical Prevention and control Physiotherapy—airway clearance Postural drainage Active breath cycle Manual technique (clapping) Antibiotics Immunoglobulins Surgical—Thoracoscopy is preferential over thoracotomy Persistent, recurrent symptoms when medication is discontinued Unilateral, segmental, or lobar distribution Bilateral—no more than one lobe each lung Hemoptysis Patient’s demand Transplantation

FIGURE 83.7 Bronchiectases in the right middle lobe and medial segment of the lower lobe.

FIGURE 83.8 Bilateral lower lobe bronchiectases in a young patient with a long history of bronchopulmonary infections. This patient was treated successfully with sequential bilateral thoracoscopic lower lobectomy.

FIGURE 83.9 Disseminated bronchiectasis in both lungs. Surgery is not an option in the management of this condition.

While some patients with bronchiectasis tolerate several infectious episodes every year, others are disturbed by the symptoms caused by a localized segmental disease. Therefore, in elective situations, the decision for and the timing of surgery should also take patient’s preference into consideration.23 As a rule, neither preoperative pulmonary function measurement nor surgical intervention should be undertaken during an infectious episode. Sensitivity-oriented antibiotics should be used immediately before the operation to decrease sputum production for 7 to 10 days. Postural drainage and chest physiotherapy should also be ordered for 10 days before the operation to lower the probability of

atelectasis and/or pneumonia that might occur due to diminished expectoration of sputum in the early postoperative period. Contraindications for Surgery in Non-CF Bronchiectasis Experienced chest physicians or pediatricians can manage successfully the patients with bronchiectasis who have mild symptoms. For this reason, patients who have not been subjected to an appropriate longterm medical treatment should not be considered for surgery. Other contraindications include disseminated disease that does not allow the target area to be removed successfully by surgery (Fig. 83.9), primary ciliary dyskinesia, or conditions characterized by immunodeficiency, and severe COPD. Surgical Techniques As Dogan and colleagues reported,24 lobectomy is the most frequent procedure followed by segmentectomy. Pneumonectomy can be necessary only in the rare patients who develop a destroyed lung.25 Additionally, disseminated non-CF bronchiectasis can be treated successfully with lung transplantation.26 Currently, there are three approaches available for pulmonary resection for bronchiectasis; thoracotomy, standard 3-port VATS, and uniportal or single incision VATS. Thoracotomy The lateral thoracotomy approach is the same as the one used for other purposes. At thoracotomy, the diseased lobe may be found atelectatic and firmly attached to the surrounding structures like the diaphragm, chest wall, pericardium, aorta, and other lobe(s). It is easier to start releasing the bronchiectatic lobe from the mediastinal surface after the chest wall adhesions are separated by blunt and sharp dissections. When there is a firm symphysis between the lobes due to chronic inflammation, the sharp dissection needed in the fissure may cause tears in the healthy lung resulting in prolonged postoperative air leaks.23 Therefore, careful fissural division, preferentially using a stapling device, is advisable. TABLE 83.8 Results of Surgery for Bronchiectasis Author

Year

No. of Patients

Age (Year)

Mortality (%)

Morbidity (%)

Success Rate (%)

Şahin et al.31

2014

60

9,5

3

20

90

Hiramatsu et al.32

2012

31

54

0

18

74

Çaylak et al.33

2011

339

22,4

0,6

12,7

94

Zhang et al.34

2010

790

41,6

1,1

NA

75

Eren et al.35

2007

143

23,4

1,3

23

92

Due to the long-lasting inflammatory course of the disease, large and firm lymph nodes are frequently encountered at the hilum over the pulmonary artery. The meticulous dissection can be time-consuming. Hence, in contrast to the principles followed when the resection is necessary for lung cancer, the ligation of the pulmonary artery may be done first. This avoids distension of the lobe, and the backflow bleeding

from the parenchyma during laborious arterial dissection that might occur in the “vein first” approach. Thoracoscopic (VATS) Lung Resection for Bronchiectasis The resort to minimally invasive approaches in bronchiectatic children has been made possible by concomitance of technological improvements and increased experience in thoracoscopic surgery,27,28 Zhang and colleagues,27 attempted thoracoscopic lobectomy in 52 patients with bronchiectasis yielding a successful outcome in 45 of them. These authors reported better recovery in the VATS group when compared to thoracotomy. When there is no reasonable experience in VATS and a segmentectomy is needed, an open surgical approach should be preferred instead of settling for a VATS lobectomy. In this context, Video 83.2 demonstrates a 3-port VATS left lower lobectomy and lingular segmentectomy in a patient with bronchiectasis. Browser issues Video 83.2 Three-port VATS lobectomy and lingulectomy for bronchiectasis. Uniportal VATS Lung Resection for Bronchiectasis Rocco and colleagues,29 reported the first uniportal VATS wedge resection in 2004, and since then, uniportal thoracoscopic lung resections have gained an important popularity. VATS lobectomy for bronchiectasis can now be achieved through a single incision as small as 3.5 cm.30 Practical details of uniportal VATS left lower lobectomy and lingulectomy for bronchiectasis can be observed on Video 83.3. Avoiding two additional ports makes the uniportal approach potentially less painful and cosmetically more favorable. Technically, selecting the location of the thoracoscopy port is critical in achieving a successful resection. The 7th intercostal space on the midaxillary line is very convenient in our experience. The further away the port incision from the bronchovascular structures, the easier the movements of the endoscopic instruments. Browser issues Video 83.3 Uniportal VATS lobectomy and lingulectomy for bronchiectasis.

RESULTS OF SURGERY Following lung resection for bronchiectasis, the postoperative mortality figures should be similar to those performed for other indications. However, as in all other operations for inflammatory lung diseases, postoperative morbidity, mainly resulting from postoperative atelectasis and pneumonia caused by mucus plugging, is higher in patients undergoing thoracotomy.21,22,25,26 Nevertheless, the success rate of surgery is excellent, ranging from 74% to 94% in large series.31–35 Table 83.8 summarizes the results of surgery through thoracotomy in recent publications. It is important to note that more favorable recovery has been reported after thoracoscopy compared to thoracotomy.25,27,28 In fact, surgery represents an important alternative in most patients who, after resection of the nonfunctional lobe or segment, can be freed by frequent bronchopulmonary infections, endless sputum production, or a life conducted in isolation.21,22,25–28,31–35 In the modern era of minimally invasive approaches, reconsideration of the place of surgery in appropriately selected patients with bronchiectasis is warranted.

LUNG ABSCESS In the first two decades of the 20th century, the development of a putrid lung abscess was nearly always fatal.36 In a series from the Massachusetts General Hospital covering the years between 1909 and 1923, the mortality rate reached 75%.36,37 Fortunately, the development of antibiotics improved the outcome of treatment and decreased mortality. However, with ever growing numbers of immunosuppressed individuals and increased incidence of nosocomial pneumonia, lung abscess continues to be an area of interest for practicing thoracic surgeons. Lung abscess is a localized pulmonary necrosis caused by the disintegration of the surrounding tissues, mostly as a result of parenchymal damage due to an infection (primary lung abscess). It may also occur as secondary deposit in the lung from an extrathoracic source, like a perforated appendix,38 or even a uterine empyema caused by an intrauterine device.39 Preexisting lung disease, obstructing bronchial carcinoma, foreign body aspiration, bronchoesophageal fistula, or pulmonary infarct may also be associated with lung abscess (secondary lung abscess). Neuhof and Hurwitt,40 pioneers in the surgical treatment of lung abscess, defined as an acute abscess a usually solitary, superficially situated collection of pus of less than 6 weeks’ duration. However, it may occasionally be multiple, particularly in the immunocompromised individual. While abscesses observed from 6 to less than 12 weeks were defined subacute, the ones lasting more than 12 weeks were termed as chronic.36,40,41 Local conditions, host resistance, and infecting agents are all thought to play a role in the formation of lung abscess. The major pathogens are anaerobic bacteria. In comparison, the community-acquired form is more common and tends to be polymicrobial dominated by anaerobic oral flora, that is, Peptostreptococcus, Bacteroides, and Fusobacterium species.42,43 On the other hand, hospital-acquired abscesses are generally associated with aerobic organisms such as P. aeruginosa, S. aureus, and Klebsiella pneumonia.43,44 TABLE 83.9 Contributing Factors to Lung Abscess Dental and periodontal disease Anesthesia Altered mental status Alcohol abuse Seizure disorders Immunosuppression Neuromuscular disorders with bulbar dysfunction Esophageal motor disorders Malignant bronchial obstruction Swallowing disorders Vocal cord paralysis

Contributing factors are listed in Table 83.9. Aspiration most frequently affects the dependent portions of the lung—posterior segment of the right upper lobe and superior segment of the right and left lower lobe. Ninety-five percent of all lung abscesses occur in these locations.1,43 The diagnosis relies on a complete history and physical examination with emphasis on the predisposing factors for possible aspiration. The typical patient presents with a history of an antecedent event suspicious for aspiration, pulmonary infection, or pneumonia. Symptoms are similar to those of pneumonia including an intermittent febrile course with weight loss, night sweats, and cough. Later in the

course of the disease, production of purulent sputum becomes prominent. The patient may have foul breath and often appears quite ill. These signs are highly suggestive of the diagnosis. Radiographic imaging is required to conclusively determine the presence of a lung abscess. Posteroanterior and lateral chest radiography reveals an infiltrative process associated with an air-fluid level. CT scanning of the chest discloses one or more cavitary lesion(s) with adjacent consolidation (Fig. 83.10A). In chronic abscesses, multiple cavitations and fistulization to the pleural space and pleural empyema with or without pneumothorax can also be seen (Fig. 83.10B). Fiberoptic bronchoscopy is useful to rule out an endobronchial tumor or obstruction and to determine whether the abscess is draining internally. Also, it may be necessary to obtain washings for bacteriology.

FIGURE 83.10 A: Sagittal view of a CT scan of a patient with chronic lung abscess in the right lower lobe. Multiple cavities in different sizes together with disseminated infiltration as well as partial pneumothorax are seen. B: Axial CT section demonstrates fistulization from the largest cavity in the superior segment of the right lower lobe to the pleural space. Fistulization was the cause of empyema and pneumothorax in this patient treated with 10 weeks of chest tube drainage and antibiotics.

FIGURE 83.11 An air-fluid level in a large cavitary lesion in the right lung is seen on axial CT scan of thorax in a patient with chest pain and cough. This image mimics lung abscess, however, absence of both septic picture on clinical condition, and adjacent consolidations on the CT scans makes it unlikely. A squamous cell carcinoma was diagnosed on the histological examination of bronchoscopic biopsy.

Besides pyogenic lung abscesses, the differential diagnosis of cavitary lung lesions includes (a) cavitating carcinoma, generally of the squamous cell type (Fig. 83.11); (b) tuberculosis or other fungal diseases; and (c) empyema with bronchopleural fistula. The patient’s history is important in separating these entities. When malignancy is suspected, tumor necrosis may occur as a result of bronchial obstruction and vascular invasion. This is followed by obstructive pneumonia with a suppurative clinical course.45 In this context, an irregular internal wall observed on the CT scan should be considered suspicious. Hood2 suggested that the absence of fever, lack of purulent sputum, and a normal white blood cell count should raise strong suspicion of an underlying neoplasm. In high risk groups, unresponsiveness to appropriate treatment should also be suggestive of a lung cancer. It must be born in mind that even invasive diagnostic methods may fail to establish the exact diagnosis, since infection may cause atypical cell formations in the cytological specimen without clear evidence of malignancy.45 TABLE 83.10 Principles of Therapy for Lung Abscess Identification of etiologic organism Prolonged antimicrobial therapy Adequate drainage in acute stage Chest physiotherapy Bronchoscopy Endoscopic drainage Percutaneous catheter drainage Emergency surgical treatment External drainage (only in emergent situation)

Once the diagnosis is established, appropriate therapy must be instituted. The principles of care are given in Table 83.10. The basis of therapy is antibiotic treatment. Wiedemann and Rice46 reported that 80% to 90% of aerobic lung abscesses respond to medical therapy. The etiologic organisms must be identified as quickly as possible through sputum culture or bronchoscopy, and the appropriate antibiotics

should be instituted based on drug sensitivity. However, because of the polymicrobial nature of the disease and the difficulty in isolating anaerobic microorganisms, the culture of the sputum or the bronchial aspirate should be evaluated with caution. The input by an infectious disease specialist is important in selecting the appropriate antibiotics and monitoring the therapeutic response. In an uncomplicated community-acquired lung abscess, the patient is generally started on monotherapy with clindamycin while awaiting the results of the sensitivity analysis.43,47,48 When an anaerobic pathogen is isolated, monotherapy with metronidazole is generally insufficient due to the involvement of more than one bacteria species.43,49 Antibiotics should be continued for a lengthy period, generally 3 to 4 weeks, which may be extended to 6 to 8 weeks in many cases. Adequate drainage must be achieved by chest physiotherapy, fiberoptic bronchoscopy, or percutaneous catheter drainage when needed. As suggested by Miller,1 external drainage is only indicated when the abscess does not spontaneously drain internally into the tracheobronchial tree. In such a condition, especially if the patient experiences a septic course, external drainage may be achieved by a closed-tube thoracostomy, CT-guided catheter drainage, or pneumonostomy (cavernostomy). TABLE 83.11 Percutaneous Catheter Drainage in Lung Abscess Author

Year

No. of Patients

Mortality (%)

Morbidity (%)

Success Rate (%)

vanSonnenberg et al.50

1991

19

0

21

100

Ha et al.51

1993

6

0

0

83

Zuhdi et al.52

1996

5

0

0

100

Hoffer et al.53

1999

5

0

0

100

Hirshberg et al.54

1999

11

45.5

NA

NA

Yunus et al.55

2009

19

0

37

79

Kelogrigoris et al.56

2011

40

0

25

83

TABLE 83.12 Indications for Surgery in Lung Abscess Acute stage (emergency) Complications Bronchopleural fistula Empyema Bleeding Chronic stage (definitive) Persistent symptoms and signs Recurrent complications (empyema, bronchopleural fistula) Suspicion of carcinoma Persistence of lung abscess larger than 6 cm after 8 weeks of treatment

The development of percutaneous catheter drainage has significantly improved the outcome of treatment, and decreased the need for surgical intervention in patients with lung abscess. The procedure can be performed with low morbidity and mortality.50–53,55,56 However, high mortality has also been reported.54 The results from published series are presented in Table 83.11. Occasionally, it may be used to prepare a septic patient for surgery. Although generally avoidable, surgical resection may be required in up to 30% of patients undergoing percutaneous catheter drainage.

Surgical intervention is now required in about 10% of patients with lung abscess. The indications for surgery are listed in Table 83.12, and include unsuccessful medical management over a period of 8 weeks, suspicion of cancer, complications such as empyema or bronchopleural fistula, persistence of a cavity larger than 6 cm after 8 weeks of treatment, and massive hemoptysis. An algorithm for management is given in Figure 83.12.

ORGANIZING PNEUMONIA Organizing pneumonia (OP) is a clinicopathological entity characterized by excessive buds of fibroblasts and collagen filling the distal airspaces, predominately the alveolus and the bronchiolar lumen. This pattern is not of a particular disease but of a nonspecific inflammatory response to lung injury caused by a series of conditions. In contrast to “pneumonia” in its definition, sequelae of previous pulmonary infection is only one of the etiologic conditions. Thoracic surgeons come across this entity only in two clinical scenarios: (1) a focal lung lesion (Fig. 83.13) removed or biopsied surgically for the suspicion of malignancy but turns out to be OP at histological examination, and (2) patient is referred for surgical biopsy to disclose the etiology of a diffuse lung lesion (Fig. 83.14).

FIGURE 83.12 Algorithm for management of lung abscess. CT, computed tomography; CXR, chest x-ray; PT, pneumothorax.

A well-known entity called bronchiolitis obliterans organizing pneumonia (BOOP) is an idiopathic form of OP. Recently, the term cryptogenic organizing pneumonia (COP) has replaced BOOP to avoid confusion between the BOOP and the constrictive bronchiolitis obliterans situations.57 Pathologists may report OP as an associated feature of conditions such as infectious pneumonia, lung cancer, bronchiectasis, pulmonary fibrosis, adult respiratory distress syndrome, pulmonary infarction, and middle lobe syndrome (MLS).58,59 It occurs equally in women and men generally between 50 and 60 years of age.

No association is present with cigarette smoking.

FIGURE 83.13 An area of ground-glass opacity due to alveolar infiltration in the right lower lobe in the coronal (A) and axial (B) CT scans. Histological examination of the lesion removed by uniportal VATS wedge resection revealed an organizing pneumonia.

The causes of OP can be seen in Table 83.13. It exists in three different categories: (1) with definitive causes, (2) with indefinite causes but in specific and relevant situations, and (3) idiopathic (COP).57 The onset of symptoms is usually nonspecific; cough, chest pain, fever, dyspnea, or weight loss.59 Diagnosis of COP is generally made after symptoms of 6 to 10 weeks’ duration. Multiple bilateral patchy alveolar opacities (Fig. 83.14), solitary small nodule, a large focal area of consolidation or unilateral peripheral nonresolving ground-glass opacity that mimics an adenocarcinoma (Fig. 83.13) can be seen on the CT scan.57,60

FIGURE 83.14 Patchy infiltrations in both lungs in a patient with organizing pneumonia.

TABLE 83.13 Causes of Organizing Pneumonia Definitive causes Infections (bacteria, viruses, parasites and fungi) Rheumatic pneumonia in rheumatic fever Drugs (i.e., bleomycin, amiodarone, busulfan, gold salts, sulfasalazine) Radiation Toxic inhalation Indefinite causes but specific and relevant situations Connective tissue disorders Idiopathic inflammatory myopathies Rheumatoid arthritis Sjögren syndrome Wegener granulomatosis Lung transplantation Bone marrow grafting Ulcerative colitis Crohn disease Behçet disease Sweet syndrome Cancer Granulomatous inflammation Cryptogenic organizing pneumonia or BOOP

The diagnosis of COP is usually suggested by clinical and radiological findings and it is seldom justified without histological confirmation.57,60,61 Although histological examination of the transbronchial biopsy material may reveal OP findings in many cases,62 surgical lung biopsy that allows a large specimen to be examined is useful since it is not uncommon for OP to occur adjacent to a variety of diseases including lung malignancy.57,60,61,63 When clinicoradiological findings are suggestive of OP, videothoracoscopic lung biopsy is preferred over a limited thoracotomy to avoid interfering with the

patient’s ventilation that has already diminished. In this setting, uniportal VATS wedge resection of the lung is an important approach.29

FIGURE 83.15 A: CT scans of a patient with destroyed lung in the left. B: During the disease process, lung becomes a small and fibrotic tissue, heart displaces to the diseased side, and the contralateral lung expands and herniates through the retrosternal area to fill the space left from the destroyed lung.

The use of corticosteroids for 1 to 3 months is the standard treatment of OP, but relapses are not uncommon.57,61–63 Surgical treatment has no role in a patient with proven diagnosis of OP. Although the prognosis is generally excellent in patients with typical COP, it may be difficult to ascertain it in secondary cases due to the heterogeneity of the underlying conditions.54

DESTROYED LUNG Destroyed lung is a distinct clinicoradiological entity characterized by total and irreversible destruction of one lung due to chronic bronchopulmonary infections.25 Most common causes are tuberculosis, aspergilloma, idiopathic bronchiectasis, and recurrent pneumonia. The term destroyed lung defines the disease of an entire lung, and must be differentiated from the damage of one or two lobes that may occur as a sequel of the infectious process. In the recent years, advancements of effective medical treatment have decreased the incidence of this entity significantly. Today, multidrug resistant tuberculosis is the most important underlying cause. Cough, sputum expectoration, fatigue, and hemoptysis are common symptoms. Dyspnea, on the other hand, is usually absent due to the chronic nature of the disease. Diagnosis is generally made on clinical and radiological grounds. CT scans typically show a very small and fibrotic lung tissue, mediastinal displacement, and compensatory enlargement of the contralateral lung (Fig. 83.15). Asymptomatic patients are followed up conservatively, while frequent bronchopulmonary infections, empyema, and severe hemoptysis suggest a surgical option. Additionally, surgery is indicated when a pyothorax-associated lymphoma develop in a patient with destroyed lung.64 Operation is demanding because of firm adhesions, herniation of the healthy lung toward the diseased side, heart’s displacement to the surgical field, and the fragile physical status of the patient. The need for right pneumonectomy, positive sputum culture for mycobacteria before surgery, and presence of preoperative empyema are associated with increased morbidity and mortality. Nevertheless, postoperative complications can be decreased by taking appropriate measures including preoperative antimicrobial treatment and protein-rich diet, perioperative maneuvers like extrapleural pneumonectomy if feasible, and

postoperative management with sensitivity-oriented antibiotics and pleural irrigation.25

BRONCHOCOMPRESSIVE PULMONARY DISORDERS Bronchocompressive disorders of the pulmonary system are an uncommon but important group of disorder the thoracic surgeon must be aware of (Table 83.1). The most frequent of these disorders are middle lobe syndrome, broncholithiasis, and fibrosing mediastinitis.

MIDDLE LOBE SYNDROME In 1937, Brock and colleagues65 described recurrent atelectasis in the middle lobe of the lung caused by the bronchial compression of enlarged tuberculous lymph nodes in eight children. Eleven years later, Graham and colleagues,66 reporting on 12 patients with similar pathology, introduced the term “middle lobe syndrome” (MLS). The patients were suffering from cough, persistent bronchopulmonary infections, and hemoptysis. Two other definitions, namely the “right–middle-lobe syndrome,”1,67 or, because of similar involvement of the lingual segment, the “middle lobe/lingula syndrome,”68 have also been used. Today, the so-called MLS has been the most commonly used expression of the clinical and radiological entity of isolated and recurrent or persistent collapse of the middle lobe (Fig. 83.16). The prevalence of the disease is poorly studied; in one of the rare studies, the incidence of MLS requiring surgical resection in children in Scandinavia was reported as 1.43 and 2.94 per million per year in males and females, respectively.69 Pathophysiology of the Middle Lobe Syndrome MLS exists in obstructive and nonobstructive forms. The enlarged lymph nodes causing stenosis of the narrow, long and acutely angled middle lobe bronchus at its take-off was the initial explanation of the existence of the syndrome.65,66 Other than extrinsic compression by the lymph nodes, endobronchial foreign body or a broncholith may also originate the disease. Additionally, if included, neoplasms were found to be the etiological factor in up to 43% of patients with MLS.70–72 However, a neoplasm could grow arbitrarily in any part of the bronchial tree including the middle lobe, not differently from the other four lobes of the lungs. The individual features of the middle lobe have no role in the development of malignancy. For this reason, to keep the distinct entity of the syndrome, recent studies have frequently preferred to exclude the neoplasm-connected middle lobe collapse in their series.59,73,74

FIGURE 83.16 A 29-year-old female patient with a long history of bronchopulmonary infections. A: The coronal section of the CT scans of the chest illustrates the right middle lobe atelectasis. B: Thoracoscopic appearance of the middle lobe collapse. Mild symphysis with pericardial fatty tissue is a sign of chronic infection.

Having no demonstrable extra- or endobronchial lesion in majority of the patients, necessity arose for a newer theory to explain the chronic collapse of the lung. The nonobstructive MLS is mainly thought to occur due to the anatomically isolated characteristics of the lobe. The chance of reinflation through the aerating effect of collateral ventilation with other lobes by using the pores of Kohn is low when atelectasis has occurred in the middle lobe.1,67–73 This is especially prominent when a complete minor fissure is present.71 Eventually, when the physiological pathways become insufficient to provide recovery from the atelectasis, accumulation of secretions in the sealed middle lobe creates favorable media for microorganisms that leads to a vicious cycle of recurrent infections and inflammation. When neoplastic causes are excluded, the pathological diagnosis is bronchiectasis in up to 50% of the patients followed by foreign body reaction, organizing pneumonia, and chronic bronchial inflammation.69,70,73–75 Clinical Features Chronic cough, repeated episodes of sputum discharge, audible wheezing, fatigue, low-grade fever, haemoptysis, and bad breath odor are the common symptoms. Though not frequently, patients may also be asymptomatic. Since physical examination and plain chest radiography findings are nonspecific, patients often have a history of treatment for upper airway infections, chronic bronchitis, or asthma prior to MLS being discovered by detailed investigations. The disease can be seen in all age groups with a significant predominance of female patients.69,70,74–75 Children with MLS are usually diagnosed during investigations for presumable asthma with long-standing pulmonary symptoms.75–77 Whether asthma is a disease that could be associated with MLS in children or is a causative factor remains a diagnostic dilemma, especially when the skin test sensitization is not extremely positive.76,77 The lingular segment can also be diseased either individually or together with the middle lobe, especially in the nonobstructive form.68,73 Although the etiology, clinical picture, radiological appearance, and the management are similar, an isolated lingular segment collapse can arguably be defined as a MLS, as it may cause confusion. Diagnosis of the Middle Lobe Syndrome

As mentioned above, it is difficult to detect MLS only by physical examination or plain chest x-ray findings. Persistent symptoms of cough and sputum production, together with a history of frequent bronchopulmonary infections, alert the physician for further investigation. When MLS is suspected, a lateral chest x-ray is taken which will demonstrate a characteristic triangle of increased density ranging between 2 and 3 mm to 5 cm at the hilum of the middle lobe.74 However, high-resolution, thin-section CT scans are much more informative in confirming total or segmental middle lobe atelectasis, bronchiectasis (Fig. 83.17), subtle endobronchial abnormalities, lymph node enlargement, or other parenchymal irregularities. A long-standing lobar collapse can turn into a fibrotic structure in time and imitate a neoplasm. However, the calcification in the lesion is the sign of chronic nature of the disease (Fig. 83.18). Virtual bronchoscopy is a helpful and noninvasive tool in defining the patency of the middle lobe, and distinguishing between the underlying obstructive or nonobstructive pathologies (Video 83.4). Browser issues Video 83.4 Virtual bronchoscopy in middle lobe syndrome. Flexible bronchoscopy provides valuable information even in the era of advanced radiological technologies. In addition to evidence on the endo- or extrabronchial obstruction, the degree of stenosis, the grade of mucosal inflammation, and the amount of mucus drainage can be visualized, and sputum sample taken for bacteriological analysis. Nevertheless, its therapeutic effect is much more prominent as to be discussed below. Serum immunoglobulin levels should be investigated in MLS associated with bronchiectasis. Sweat test and tuberculin skin test are recommended especially in children for the diagnosis of the underlying cause.77 Management of the Middle Lobe Syndrome Obstructive and nonobstructive MLS in symptomatic patients are managed according to the underlying causes.

FIGURE 83.17 A 30-year-old female patient with a history of continuous sputum discharge for years and hemoptysis for the last 3 months. Her axial CT scan shows isolated middle lobe bronchiectasis in tubular type.

FIGURE 83.18 A CT scan of a 36-year-old, nonsmoker, female patient with mild hemoptysis shows a dense opacity in the middle lobe mimicking a malignancy. However, calcification in the lesion makes the neoplasia less likely. Arrow indicates calcification in the lesion.

Conservative Treatment With proven or suspected lung infection, the most appropriate antibiotic treatment chosen on the sensitivity result is initiated. Bronchodilators and mucolytics are used to facilitate the mobilization of mucoid secretions filling the middle lobe bronchus. In patients with tuberculous lymph node enlargement, antituberculous treatment may be combined with corticosteroids for its anti-inflammatory effect to reduce bronchial compression.77 Inhaled bronchodilators, corticosteroids, and antibiotics are used in the treatment of patients with asthma associated with MLS.74,76 Bronchial clearance maneuvers like active cycle of breathing technique, postural drainage, and chest physiotherapy are helpful tools in the management of the disease.74–77 Bronchoscopic lavage and aspiration is one of the most effective treatment modalities, which either cured the disease or improved the symptoms successfully in 33% to 92% of patients in different series.78–83 Surgery Removal of the middle lobe is indicated in complicated MLS such as recurrent pulmonary infections in spite of acceptable duration of appropriate therapy (at least 6 months). Other indications include the established treatment-resistant bronchiectasis, hemoptysis, and proven endobronchial obstruction.23,68,70,74–77,79,80 As it was stated by the Author,23 patient’s willingness, which is always influenced differently by a different degree of deterioration of social life, is also an important factor to make the decision between whether to continue conservative treatment or undergo surgery. Three different approaches can be performed for middle lobectomy in MLS: thoracotomy (Fig. 83.19), standard 3-port videothoracoscopy, or uniportal videothoracoscopy (Video 83.5). Thoracotomy must be preferred in patients where middle lobectomy by videothoracoscopy is unachievable either due to the endobronchial obstructive lesion or unremovable firm lymph nodes (especially in tuberculosis) at the hilum. However, videothoracoscopic resection is achievable in the majority of patients including children.81 As it can be seen on Video 83.5, even the uniportal videothoracoscopic middle lobectomy is a feasible approach. Because of the well-documented advantages of videothoracoscopy, it should be

preferred to thoracotomy whenever possible. Browser issues Video 83.5 Uniportal VATS middle lobectomy for middle lobe syndrome. The lymph nodes (that maybe the cause or result of the chronic disease) are almost always found at the hilum overlying the bronchus as well as the pulmonary artery. Consequently, the middle lobe artery becomes rudimentary, and sometimes gets lost within the fibrous process around the bronchus. Hence, dissecting the artery and dividing it individually may not always be possible.23 In this case, the tiny bronchus of the lobe can be stapled after separating the collapsed middle lobe from other lobes and dividing the middle lobe vein. Peri- and postoperative complications are generally minor and the outcome of surgery is highly favorable.23,68,73–75,77,80,81

FIGURE 83.19 Appearance of the lung at thoracotomy in the middle lobe syndrome. A: The middle lobe was so small that it could not be noticed in between the upper and the lower lobes when the chest was opened. B: Nonfunctional, atelectatic middle lobe as a source of repeated bronchopulmonary infections.

BRONCHOLITHIASIS Erosion of the bronchial wall and intraluminal extension of a calcified peribronchial lymph node caused by a long-standing granulomatous infection such as tuberculosis or histoplasmosis is called broncholithiasis. Though much rarer, aspiration of bone tissue, in situ calcification of aspirated foreign material, or erosion of the bronchial tree by calcified or ossified bronchial cartilage plates can also cause broncholithiasis.82 Diseases that mimic broncholithiasis are fungus ball, primary endobronchial actinomycosis, atypical carcinoid with ossification, endobronchial hamartoma, and tracheobronchial diseases with mural calcification.82 Broncholithiasis is uncommon, but the potential complication of massive hemoptysis makes it important for thoracic surgeons.21 The pathogenesis of broncholithiasis is thought to be abnormal tissue response to a healing granulomatous inflammation.83 During the process, calcified nodes erode into the tracheobronchial tree or, in some cases, into the esophagus or the pulmonary vasculature.1 The most common location of the disease is the bronchus intermedius. Hemoptysis, persistent cough, and recurrent pneumonia are the most frequent symptoms. Expectoration

of stone particles (lithoptysis), or symptoms related to the involvement of adjacent structures such as the esophagus and/or major vessel may occasionally be seen. About one fourth of the patients with broncholithiasis are asymptomatic.84 Radiography is generally suggestive of the diagnosis when presence of a calcified nodule and airway obstruction is shown. However, in most cases, helical CT confirms the diagnosis with the demonstration of an endobronchial or peribronchial calcified nodule together with signs of bronchial obstruction (i.e., atelectasis, obstructive pneumonitis, or bronchiectasis).82,84 Endoscopic findings are tracheobronchial distortion, a visible broncholith, bleeding, and inflammation. An occasional patient may have endoscopic findings of a fistula in either the esophagus or the tracheobronchial tree.83 Treatment of Broncholithiasis Treatment decision is given by clinical, radiological, and bronchoscopic findings. Asymptomatic patients need no treatment, yet, regular follow-up is warranted because the clinical course is uncertain. Symptomatic patients are treated to avoid complications such as massive hemoptysis, bronchoesophageal fistula, or recurrent infections. The two main treatment modalities are bronchoscopic removal of the broncholith, and open surgery. Bronchoscopic treatment was once believed to be a dangerous procedure because uncontrollable bleeding thought to be unavoidable during the extraction of the broncholith. Hence, thoracotomy was strongly recommended as the treatment of choice in previous publications.1,83,86 However, recent studies have shown that bronchoscopic stone extraction is safe and effective and thus favored in appropriately selected patients.84,87–90 Recently, Cerfolio and his colleagues,84 performed bronchoscopic removal of the broncholith with no significant morbidity and mortality in 29 out of 38 patients. Elective thoracotomy was needed in only five patients. Olson and his colleagues,87 performed rigid or fiberoptic bronchoscopy to remove 71 broncholiths in 48 patients; they were successful in 65% of the attempts with a 4% morbidity rate whereas thoracotomy was needed in one patient only. Endoscopy can be performed directly with a rigid bronchoscope,87,89 or a fiberoptic bronchoscope inserted through a rigid bronchoscope,84,87,89 depending on the location of the broncholith in the tracheobronchial tree and the experience of the bronchoscopist. Nd:YAG and Holmium lasers can also be used during the intervention to break apart the mobile broncholith when it is too hard to be grasped by an endoscopic forceps or too large to be removed from the upper airway.84,89,90 It is now clear that most symptomatic patients with broncholithiasis are not necessarily candidates for thoracotomy.84,87–90 However, an appropriate algorithm is essential for the application of therapeutic bronchoscopy to avoid catastrophic events. For example, the intervention should be performed by experienced bronchoscopists in an environment where immediate surgical facilities are readily available. Bronchoscopic removal is attempted for uncomplicated, mobile, or partly embedded broncholiths in proximal locations of the bronchial tree and in a removable size. Patients in high surgical risk groups are also candidates for the bronchoscopic technique.84,87,89 Surgery, but not interventional bronchoscopy, should be recommended in patients with CT findings of the broncholith contiguous with the pulmonary artery.84 Thoracotomy is indicated also in complicated cases such as massive hemoptysis, bronchiectasis, lung abscess, bronchoesophageal fistula, or when the broncholith is fixed to the bronchial wall as unremovable by bronchoscopy. The intense inflammatory response makes hilar dissection extremely difficult at the operation. For this reason, Miller1 suggests early proximal control of the pulmonary artery, before the dissection in the area of the calcified nodes, because of the potential of intraoperative hemorrhage. Broncholithectomy and conservative parenchyma-saving approaches must be preferred

whenever possible.1,24,83,84,88,89 However, in patients with irreversible lung damage caused by bronchial obstruction, lung resections in the form of segmentectomy (10% to 48%), lobectomy (21% to 53%), or very rarely pneumonectomy (0% to 7%) may be necessary.89 Long-term results are usually excellent without any recurrence in 68% to 100% of the cases.83,84,87–89

FIBROSING MEDIASTINITIS Definition In fibrosing mediastinitis, collection of excessive amounts of acellular collagen forms dense fibrosis in the mediastinum as well as the hilum of the lungs. This results in the entrapment of major vessels, and compression of tracheobronchial tree and esophagus. It may exist in the diffuse form but focal lesions are far more common. “Granulomatous mediastinitis” may also coexist with calcified mediastinal lymph nodes, however, it must be differentiated from mediastinal fibrosis as the former simply defines large inflammatory nodes compressing the mediastinal structures.91,92 “Sclerosing mediastinitis” and “mediastinal fibrosis” are synonyms used in the description of the disease. Etiology of Fibrosing Mediastinitis Fibrosing mediastinitis was first described by Oulmont in 1855 in a patient with obstruction of the vena cava superior.93 Today, although the exact underlying mechanism is poorly understood, it has been related to the immune-mediated hypersensitivity reaction following exposure to Histoplasma capsulatum or Mycobacterium tuberculosis in endemic zones.1,91,92,94–97 Peikert and colleagues92 concluded in their report that accumulated CD-20 positive B lymphocytes found in tissue samples might be contributive in the pathogenesis of fibrosing mediastinitis due to histoplasmosis. The incidence of disease as a sequela of histoplasmosis is thought to be less than one case per 20,000 events, while broncholithiasis and mediastinal granuloma are more common.95 Histoplasmosis is endemic in certain areas of the North, Central, and South America, Africa, and Asia, but not in Europe.95 Hence, most cases of fibrosing mediastinitis in the USA are attributable to such chronic complication of this mycosis.1,91,92,95–98 In a publication from the United Kingdom though, Mole and colleagues96 reported only one patient with a history of living in an endemic area in the USA, in contrast, half of the 18 patients had tuberculosis previously (TB). The other etiological triggers include autoimmune diseases, Behçet’s disease, rheumatic fever, radiation therapy, Hodgkin disease, and methysergide drug treatment for migraine.98 In areas where neither tuberculosis nor histoplasmosis is endemic, idiopathic cases are more frequent. Clinical Features This progressive illness is more common in young adults with a slight predominance of females.91,92,95,96 Although the condition is defined as “benign,” the natural history of the disease may be life threatening especially in patients with bilateral involvement. Devastating consequences include severe airway occlusion, vena cava superior syndrome, pulmonary artery stenosis with pulmonary hypertension, diaphragmatic paralysis due to phrenic nerve involvement, and esophagorespiratory fistula.1,91,92,94,96 The most frequent complaint is shortness of breath for months to years. Other predominant symptoms are cough, chest pain, hemoptysis, hoarseness, and those related to the vena cava superior syndrome (i.e., facial and arm swelling, headache, syncope) or recurrent pneumonia. Five percent of the patients are

asymptomatic at presentation.92 Right-sided predominance91,92,98 may be explained by the lymphatic drainage pattern of the lungs, which flow toward the subcarinal lymph nodes and then to the right paratracheal area.99 As opposed to the focal form, diffuse fibrosing mediastinitis contains no calcification, and it may be associated with other forms of idiopathic fibrosis, that is, sclerosing cholangitis, orbital pseudotumor, retroperitoneal fibrosis, and Riedel thyroiditis.99 Diagnosis of Fibrosing Mediastinitis Diagnosis is generally made by radiological and clinical findings. A chest radiograph shows focal mediastinal enlargement with irregular borders, and CT scans reveal a localized mass lesion with large calcifications in paratracheal and/or subcarinal area (Fig. 83.20A). In advanced cases, extension down to the hilum may also be shown (Fig. 83.20B). CT angiography will disclose collateral venous circulation as a result of the obstruction of vena cava superior (Fig. 83.20C). MRI poorly depicts calcification but is helpful in defining the fibrotic component as well as demonstrating the extent of cardiac invasion especially in cine-cardiac investigation (Fig. 83.21). This MRI information is critical for the surgeon who plans surgical resection. Though PET-CT will show increased FDG uptake in most cases, this investigation adds nothing when the clinical and radiological findings are clearly suggestive of a benign etiology. In a series of 80 patients from the Mayo Clinic investigated between 1998 and 2007,92 PET-CT was done only in 9% of the patients, all with clinical suspicion for malignancy. Perfusion scintigraphy is also necessary to display the depth of the perfusion defect (Fig. 83.22) when pulmonary artery invasion is seen on radiological investigations (as seen on Fig. 83.20A and B). Finally, tissue biopsy may occasionally be necessary in asymptomatic patients to rule out malignancy. Management of Fibrosing Mediastinitis Therapy aims at relieving obstructive symptoms related to compression or entrapment of the airway, major vessels, and esophagus. No single management modality is available to be applied in all conditions. The underlying causes and the extent of fibrosis should be considered in selecting the therapeutic approach. Medical treatment with neither anti-inflammatory drugs nor corticosteroids has been found encouraging.92,97 There are rare reports of effective antifungal treatment with ketoconazole for histoplasmosis-induced cases.100 Nonetheless, Infectious Diseases Society of America97 does not recommend antifungal treatment for histoplasmosis-related mediastinal fibrosis unless complement fixation antibodies are present and sedimentation rate is high. Similarly, anti-TB treatment is not effective for TB-related cases because the disease does not represent an active mycobacterium infection, but fibrosis. Recently, Westerly and colleagues101 reported favorable response to rituximab therapy in three patients with serology-positive histoplasmosis-related fibrosing mediastinitis. They associated the success of treatment with the elimination of B lymphocytes by targeting the surface antigen CD20.

FIGURE 83.20 CT scans of the chest in a 29-year-old female patient with vena cava superior syndrome and pulmonary hypertension showing right paratracheal fibrosing mediastinitis invading the superior vena cava (A). Hilar extension of the lesion is seen on axial CT scan (B), and venous collaterals on CT angiography (C).

FIGURE 83.21 MRI with cine-cardiac work up (A) shows the relation of fibrosing mediastinitis with the heart. A detailed study of MRI reveals the extent of pulmonary vessel involvement (B). MPA, main pulmonary artery; RPA, right pulmonary artery; LPA, left pulmonary artery.

FIGURE 83.22 Perfusion scintigraphy showing perfusion defect in the right lung of a patient with fibrosing mediastinitis.

Nonsurgical palliative interventions including transbronchoscopic dilation of the tracheobronchial stenosis, endovascular approaches such as balloon angioplasty and stenting of the vena cava superior, the pulmonary artery and vein provide transient success in a selected group of the patients.92,97 Airway palliation is generally not effective, and endovascular stenting needs to be repeated due to frequent restenosis. Surgery is extremely challenging and possibly hazardous, thus advisable in only specialized highvolume tertiary centers and for carefully selected patients in whom death is otherwise unavoidable. Surgical interventions may include decompression of the pulmonary vessels, the tracheobronchial tree, or the esophagus as well as excision of the mass with reconstruction of the vena cava or bronchoplasty. Pneumonectomy (Fig. 83.23) with or without carinal resection, lobectomy, and bilobectomy are the most frequently performed surgical procedures.91,92,102,103 Cardiac bypass may be necessary in complicated cases when pneumonectomy is anticipated especially in patients with proximal involvement of the pulmonary artery. Recently, successful thoracoscopic pneumonectomy was reported in a patient with leftsided fibrosing mediastinitis due to histoplasmosis.103 It is important to note that encouraging outcomes after surgery have only been reported in relatively large series from specialized centers.91,92,102

FIGURE 83.23 The specimen of the en block resection of the right lung and the vena cava superior in a patient with fibrosing mediastinitis with total occlusion of the superior vena cava. Caval reconstruction was performed with a PTFE graft in this patient. Arrows indicate the totally occluded vena cava superior.

INFLAMMATORY LYMPHADENOPATHY Enlargement of mediastinal and bronchial lymph nodes may result in a bronchocompressive disorder. This is most frequently associated with tuberculosis, histoplasmosis, and sarcoidosis. It is particularly common in children with tuberculosis, which may result in significant respiratory distress. This process has been referred to as tuberculosis lymph node compression syndrome. Treatment consists of antibiotic medication. In an occasional patient, surgical resection of the compressive nodes may be required. Worthington and colleagues104 have suggested that when acute airway obstruction occurs, airway decompression may be obtained by incision and curettage of the involved lymph nodes. This precludes major complications when the excision of the lymph node is difficult. Histoplasmosis and sarcoid can likewise cause tracheal, lobar, and segmental compression by enlargement of adjacent lymph nodes, resulting in a bronchocompressive disorder. Discussions of the effect of histoplasmosis have been mentioned previously. Sarcoid frequently responds to corticosteroid therapy.

MEDIASTINAL TUMORS Mediastinal cysts and neoplasms frequently cause respiratory obstruction in children but rarely in adults. A bronchial or esophageal cyst may occasionally occlude either the main bronchus or the trachea. The infant may present with severe respiratory distress and require urgent surgical intervention. Azizkhan and colleagues105 found that of 50 children with mediastinal tumors, 9 had significant symptoms of tracheobronchial compression and all 9 presented with marked obstruction requiring surgical intervention. In adults, bronchial or tracheal obstruction may occasionally occur from malignant neoplasms. This obstruction is most frequently due to bronchial carcinoma occluding a major bronchus by extrinsic

compression or due to metastatic lymph node disease. In adults, lymphomas and small cell lung cancer also can cause tracheobronchial obstruction, resulting in various degrees of respiratory distress.

MISCELLANEOUS CONDITIONS ESOPHAGEAL HIATAL HERNIA In an occasional patient, a large paraesophageal hiatal hernia can cause tracheobronchial obstruction of the left mainstem bronchus, resulting in significant tracheobronchial compression with significant shortness of breath and occasional respiratory distress. Relief of the obstruction by surgical correction of the hiatal hernia is the method of choice.

ACQUIRED AORTIC DISEASE Traumatic false aneurysms of the descending thoracic aorta and acquired descending thoracic aortic aneurysms can cause significant respiratory compromise by extrinsic compression of the left mainstem bronchus. This scenario may result in cough, wheezing, dyspnea, and hemoptysis. The diagnosis is suspected on chest radiography by enlargement of the mediastinum. CT scan, magnetic resonance imaging (MRI), and aortography confirm the diagnosis. Resection of the aneurysm results in the relief of symptoms.

PRIMARY CARDIOVASCULAR DISEASE Table 83.1 lists some of the cardiac and vascular abnormalities that compress the trachea or mainstem bronchi. These abnormalities are frequently a manifestation of airway compression without a history of cardiac or vascular disease. An enlarged left atrium from either acquired mitral valve disease or congenital heart disease can compress or displace the left mainstem bronchus. In addition, varieties of vascular rings can cause respiratory obstruction. These include double aortic arch and a right descending thoracic aorta with a left ligamentum arteriosum. These conditions and other vascular rings are discussed in Chapter 71.

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Ann Intern Med 1983;98:466–471. 48. Gudiol F, Manresa F, Pallares R, et al. Clindamycin vs penicillin for anaerobic lung infections. High rate of penicillin failures associated with penicillin-resistant Bacteroides melaninogenicus. Arch Intern Med 1990;150:2525–2529. 49. Perlino CA. Metronidazole vs clindamycin treatment of anaerobic pulmonary infection. Failure of metronidazole therapy. Arch Intern Med 1981;141:1424–1427. 50. vanSonnenberg E, D’Agostino HB, Casola G, et al. Lung abscess: CT-guided drainage. Radiology 1991;178:347–351. 51. Ha HK, Kang MW, Park JM, et al. Lung abscess. Percutaneous catheter therapy. Acta Radiol 1993;34:362–365. 52. Zuhdi MK, Spear RM, Worthen HM, et al. Percutaneous catheter drainage of tension pneumatocele, secondarily infected pneumatocele and lung abscess in children. Crit Care Med 1996;24:330–333. 53. Hoffer FA, Bloom DA, Colin AA, et al. Lung abscess versus necrotizing pneumonia: implications for interventional therapy. Pediatr Radiol 1999;29:78–91. 54. Hirshberg B, Sklair-Levi M, Nir-Paz R, et al. Factors predicting mortality of patients with lung abscess. Chest 1999;115:746–750. 55. Yunus M. CT guided transthoracic catheter drainage of intrapulmonary abscess. J Pak Med Assoc 2009;59:703–709. 56. Kelogrigoris M, Tsagouli P, Stathopoulos K, et al. CT-Guided percutaneous drainage of lung abscesses: review of 40 cases. JBR-BTR 2011;94:191–195. 57. Cordier JF. Organising pneumonia. Thorax 2000;55:318–328. 58. Bulmer SR, Lamb D, McCormack RJ, et al. Aetiology of unresolved pneumonia. Thorax 1978;33:307–314. 59. Kwon KY, Myers JL, Swensen SJ, et al. Middle lobe syndrome: a clinicopathological study of 21 patients. Hum Pathol 1995;26:302– 307. 60. Zhao F, Yan SX, Wang GF, et al. CT features of focal organizing pneumonia: an analysis of consecutive histopathologically confirmed 45 cases. Eur J Radiol 2014;83:73–78. 61. Pardo J, Panizo A, Sola I, et al. Prognostic value of clinical, morphologic, and immunohistochemical factors in patients with bronchiolitis obliterans-organizing pneumonia. Human Pathology 2013;44:718–724. 62. Lohr RH, Boland BJ, Douglas WW, et al. Organizing pneumonia. Features and prognosis of cryptogenic, secondary, and focal variants. Arch Intern Med 1997;157:1323–1329. 63. Kligerman SJ, Franks TJ, Galvin JR. From the radiologic pathology archives: organization and fibrosis as a response to lung injury in diffuse alveolar damage, organizing pneumonia, and acute fibrinous and organizing pneumonia. Radio Graphics 2013;33:1951–1975. 64. Halezeroglu S, Akcevin A. Extrapleural pneumonectomy for pyothorax-associated lymphoma. Interact Cardiovasc Thorac Surg 2009;9:554–555. 65. Brock RC, Cann RJ, Dickinson JR. Tuberculous mediastinal lymphadenitis in childhood: secondary effects on the lungs. Guy’s Hosp Rep 1937;87:295–317. 66. Graham EA, Burford TH, Mayer JH. Middle lobe syndrome. Postgrad Med 1948;4:29–34. 67. Culiner MM. The right middle lobe syndrome, a non-obstructive complex. Dis Chest 1966;50:57–66. 68. Ayed AK. Resection of the right middle lobe and lingula in children for middle lobe/lingula syndrome. Chest 2004;125:38–42. 69. Dees SC, Spock A. Right middle lobe syndrome in children. JAMA 1966;197:8–14. 70. Bertelsen S, Struve-Christensen E, Aasted A, et al. Isolated middle lobe atelectasis: aetiology, pathogenesis, and treatment of the socalled middle lobe syndrome. Thorax 1980;35:449–452. 71. Wagner RB, Johnson MR. Middle lobe syndrome. J Thorac Surg 1983;35:679–686. 72. Early GL, LaBach P, Crow JR, et al. Right middle lobe syndrome due to an endobronchial angiofibroma. A Case Report. Arch Intern Med 1983;143:560–561. 73. Bradham RR, Sealy WC, Young WG Jr. Chronic middle lobe infection. Factors responsible for its development. Ann Thorac Surg 1966;2:612–616. 74. Gudbjartsson T, Gudmundsson G. Middle lobe syndrome: a review of clinicopathological features, diagnosis and treatment. Respiration 2012;84:80–86. 75. Einarsson JT, Einarsson JG, Isaksson H, et al. Middle lobe syndrome: a nationwide study on clinicopathological features and surgical treatment. Clin Respir J 2009;3:77–81. 76. Sekerel BE, Nakipoglu F. Middle lobe syndrome in children with asthma: review of 56 cases. J Asthma 2004;41:411–417. 77. Romagnoli V, Prifitis KN, de Benedictis FM. Middle lobe syndrome in children today. Paediatr Respir Rev 2014;15:188–193.

78. Priftis KN, Mermiri D, Papadopoulu A, et al. The role of timely intervention in middle lobe syndrome in children. Chest 2005;128:2504– 2510. 79. Livingstone GL, Holinger LD, Luck SR. Right middle lobe syndrome in children. Int J Pediatr Otorhinolaryngol 1987;13:11–23. 80. Saha SP, Mayo P, Long GA, et al. Middle lobe syndrome: diagnosis and management. Ann Thorac Surg 1982;33:28–31. 81. Seitz G, Warman SW, Szavay PO, et al. Thoracoscopic lobectomy as a treatment option for persistent middle lobe syndrome in children. Pediatr Int 2010;52:e79–e81. 82. Seo JB, Song KS, Lee JS, et al. Broncholithiasis: review of the causes with radiologic- pathologic correlation. Radio Graphics 2002;22:S199–S213. 83. Trastek VF, Pairolero PC, Ceithaml EL, et al. Surgical management of broncholithiasis. J Thorac Cardiovasc Surg 1985;90:842–848. 84. Cerfolio RJ, Bryant AS, Maniscalco L. Rigid bronchoscopy and surgical resection for broncholithiasis and calcified mediastinal lymph nodes. J Thorac Cardiovasc Surg 2008;136:186–190. 85. Grenier PA, Beigelman-Aubry C, Brillet PY. Nonneoplastic tracheal and bronchial stenoses. Radiol Clin North Am 2009;47:243–260. 86. Brantigan CO. Endoscopy for broncholith. JAMA 1978;240:1483. 87. Olson EJ, Utz JP, Prakash UB. Therapeutic bronchoscopy in broncholithiasis. Am J Respir Crit Care Med 1999;60:766–770. 88. Potaris K, Miller DL, Trastek VF. Role of surgical resection in broncholithiasis. Ann Thorac Surg 2000;70:248–252. 89. Manivale F, Deslee G, Vallerand H. Therapeutics management of broncholithiasis. Ann Thorac Surg 2005;79:1774–1776. 90. Ferguson FS, Rippentrop JM, Fallon B, et al. Management of obstructing pulmonary broncholithiasis with three dimensional imaging and Holmium laser lithotripsy. Chest 2006;130:909–912. 91. Hammoud ZT, Rose AS, Hage CA, et al. Surgical management of pulmonary and mediastinal sequelae of histoplasmosis: a challenging spectrum. Ann Thorac Surg 2009;88:399–404. 92. Peikert T, Colby TV, Midthun DE, et al. Fibrosing mediastinitis: clinical presentation, therapeutic outcomes, and adaptive immune response. Medicine 2011;90:412–423. 93. Oulmont N. Des obliteration de la veine cave superieure. Paris: JB Baillére; 1855. 94. Sānchez LN, Herrero FS, Fraile JB, et al. Mediastinal fibrosis and superior vena cava syndrome. Arch Bronconeumol 2013;49:340– 342. 95. Loyd JR, Tillman BF, Atkinson JB, et al. Mediastinal fibrosis complicating histoplasmosis. Medicine (Baltimore) 1988;67:295–310. 96. Mole TM, Glover J, Sheppard MN. Sclerosing mediastinitis: a report on 18 cases. Thorax 1995;50:280–283. 97. Wheat JL, Freifeld GA, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807–825. 98. Afrin LB. Sclerosing mediastinitis and mast cell activation syndrome. Pathol Res Pract 2012;208:181–185. 99. Schade MA, Mirani NM. Fibrosing mediastinitis: an unusual cause of pulmonary symptoms. J Gen Intern Med 2013;28:1677–1681. 100. Urschel HC Jr, Razzuk MA, Netto GJ, et al. Sclerosing mediastinitis: improved management with histoplasmosis titer and ketoconazole. Ann Thorac Surg 1990;50:215–221. 101. Westerly BD, Johnson GB, Fabien M, et al. Targeting B lymphocytes in progressive fibrosing mediastinitis. Am J Respir Crit Care Med 2014;190:1069–1071. 102. Mathisen DJ, Grillo HC. Clinical manifestation of mediastinal fibrosis and histoplasmosis. Ann Thorac Surg 1992;54:1053–1058. 103. Kara HV, Javidfar J, Hirji SA, et al. Thoracoscopic pneumonectomy in management of histoplasmosis and fibrosing mediastinitis. Ann Thorac Surg 2014;98:e95–e96. 104. Worthington MG, Brink JG, Odell JA, et al. Surgical relief of acute airway obstruction due to primary tuberculosis. Ann Thorac Surg 1993;56:1054–1062. 105. Azizkhan RG, Dudgeon DL, Buck JR, et al. Life-threatening airway obstruction as a complication of mediastinal masses in children. J Pediatr Surg 1985;20:816–822.

84 Pulmonary Tuberculosis and Other Mycobacterial Diseases of the Lung Gilbert Massard ■ Anne Olland ■ Nicola Santelmo ■ Pierre-Emmanuel Falcoz Mycobacteria include a diverse group of aerobic acid-fast bacilli distributed worldwide in the environment and in animal/human hosts. Many species of mycobacteria have been identified. A number of these are historically important in causing pulmonary disease in humans (Table 84.1), including the Mycobacterium tuberculosis (MTB) complex (m. Tuberculosis, m. Bovis, and m. Africanum), Mycobacterium avium complex (MAC), and Mycobacterium kansasii, to name a few. Disease manifestations in humans are protean, but the lung is the most frequent organ involved. Medically refractory or resistant pulmonary disease is the most common reason for surgical intervention. This chapter discusses the diagnosis, treatment, and other issues related to various mycobacterial diseases and the role of thoracic surgery in their management.

EPIDEMIOLOGY MTB causes tuberculosis (TB). It is spread, almost exclusively, by the inhalation of infected droplet nuclei produced by patients with pulmonary TB. In fact, only a relatively small percentage (about 10%) of patients infected with MTB will develop clinical (i.e., active) disease. Nonetheless, MTB is one of the most common infectious agents affecting humans worldwide. The disease has plagued humanity since antiquity. Only relatively recently has our understanding of the disease evolved sufficiently to allow for the provision of highly effective drug therapy. Indeed, it was more than a half century from 1882 when Koch identified MTB as the causative organism of TB until effective medical treatment became available. Prior to that time, various forms of collapse therapy and surgical interventions such as thoracoplasty and plombage were extensively applied. With the development of streptomycin in 1946 and isoniazid in 1952, the possibility of durable TB cures—which, in turn, could reduce transmission of disease—became a reality. Consequently, the use of various forms of surgical interventions began to recede. By the latter half of the twentieth century, the development of multiple other antituberculous drugs, drug combinations, and strategies led to relatively rapid cures for patients with access to medical therapy. Indeed, eradication of TB has become a realistic public health goal, at least in many resource-rich parts of the world.

TABLE 84.1 Common and Uncommon Causes of Mycobacterial Lung Disease in the United States Common

Less Common

M. tuberculosis M. avium complex M. kansasii M. abscessus

M. fortuitum M. szulgai M. xenopia M. malmoensea M. simiae M. celatum M. asiaticum

a M. xenopi and M. malmoense are more common causes of mycobacterial lung disease in Canada and northern Europe, respectively, but uncommon in the United States.

The attainment of this goal, however, remains elusive, owing in part to the biology of the organism and its relatively slow rate of multiplication, necessitating long periods of treatment. The rising number of cases worldwide since the early 1980s attests to this fact. Additional reasons for this rise include the human immunodeficiency virus (HIV) pandemic (particularly in sub-Saharan Africa), the lack of sufficient resources and infrastructure to combat the infection in high-prevalence areas of the world, the emergence of drug-resistant strains of MTB, and increased immigration from highly endemic areas. It is no surprise that against this background, TB remains one of the most common communicable infectious diseases worldwide, with the nearly one-third of the world’s population who are infected with MTB comprising a pool of several billion infected persons from whom most active cases emerge each year. Annually, about 9 million new cases are caused by this organism. In 2010, WHO estimated that 1.1 million TB patients died, and among them about 350,000 were HIV positive.1 Twenty-two so-called highburden countries within sub-Saharan Africa, former European eastern bloc nations, Latin America, and Asia account for about 80% of the world’s new cases each year. China and India alone account for 35% of all worldwide TB cases. The world health organization estimates 1.1 million individuals present with TB/HIV co-infection, most of them living in the WHO African region (82%).1 A risk of tuberculous disease of 5% to 15% per year has been estimated for individuals coinfected by MTB and HIV.2 Reportedly, other factors contributing to the maintenance of the TB pandemic include multidrug resistance to anti-TB drugs (i.e., at least isoniazid and rifampicin), migrations of population from high incidence countries, and the social determinants of the disease (homelessness, drug abuse, and poverty).1 WHO considers TB as a global emergency because of both its burden in terms of incidence and in terms of related mortality. In 2010, the number of prevalent cases was estimated around 12 million (range 11 to 14). From 1990 to 1997, the incidence of TB declined, but that trend was temporarily reverted by the HIV/AIDS epidemic. Preventive measures as well as the distribution of antiretroviral drugs favored a declining trend since 2004 at an annual rate of −1.3%.1 In 2010, incidence of multidrug resistant TB (MDR TB) was estimated into a range of 210,000 to 380,000 cases, with an estimated prevalence of 650,000 cases. A new resistance profile has emerged in 2006 as extensively drug resistant TB (XDR TB). These strains are MDR TB resistant to fluoroquinolones and to at least one second line injectable drug (amikacin, capreomycin, kanamycin). The percentage of XDR TB amongst MDR TB was 12.2% in the WHO European region.1 In contrast, much less is known about the epidemiology of nontuberculous mycobacteria (NTM), in part because they do not cause reportable diseases for public health purposes. Although infection is very common in some geographic areas, disease due to NTM appears to be much less common.3 However,

there is a general sense that disease due to some species of NTM may be increasing; in the United States, NTM, especially MAC, are now being isolated more commonly than MTB in many laboratories. In the clinical setting, NTM will present as lung infection with parenchymal lung infiltrates or as a colonizing microorganism, especially in bronchiectasis diseased lungs. NTM represent an increasing burden of infectious complication in cystic fibrosis patients; though NTM seem not transmissible by aeric way, the incidence of NTM-infected CF patients has been dramatically increasing in the last decade.4

MICROBIOLOGY AND PATHOGENESIS Mycobacteria are rod-shaped, thin aerobic bacteria measuring approximately 0.5 by 3 μm (Fig. 84.1). Humans are the main reservoir for MTB, although it has been reported in many other animals. Less is known about NTM, sometimes called environmental mycobacteria, because most are presumed to exist in the environment. MTB and many but not all NTM grow slowly, with visible growth apparent by 3 to 6 weeks on solid media. The cell walls of mycobacteria contain high concentrations of mycolic acids and long-chain cross-linked fatty acids, which account for the acid-fast quality of the mycobacteria and whereby the organism cannot be decolorized once treated with Gram stain. This cell wall structure confers very low permeability to macromolecules, which in part accounts for the relative ineffectiveness of many conventional antibiotic agents against MTB.

FIGURE 84.1 Characteristic Mycobacterium tuberculosis acid-fast bacilli (AFB) seen in sputum smear for AFB. Mycobacteria are thin red beaded rods.

Infection with MTB usually occurs via person-to-person spread of aerosolized or airborne tubercle

bacilli from a respiratory tract focus. The so-called infected droplet nuclei are produced through coughing —a particularly effective way of aerosolizing MTB—sneezing, or speaking. Extrapulmonary MTB is only rarely contagious because bacilli are typically not aerosolized from those foci. Although it is less certain, NTM inhalation of infected aerosols from environmental sources rather than human-to-human transmission is thought to be the general mechanism of their transmission. Once aerosolized, mycobacteria can remain suspended for hours; once inhaled, the size of the suspended particle helps determine how distal into the respiratory tree the particle is deposited. Smaller particles can bypass the mucociliary ladder and deposit themselves on the surfaces of alveoli, where they are ingested by host alveolar macrophages. From this point forward, and based on our understanding of the pathogenesis of TB, the following seem to be the possible outcomes of an inhalation of mycobacteria: the tubercle bacilli (and presumably NTM) may be destroyed or otherwise contained by host defense mechanisms; the organism may not be destroyed but may multiply and remain dormant (this is termed latent TB infection or LTBI [90% of infections] when MTB is involved); this latent infection may “reactivate” and cause disease at some later time (about 5% to 10% of LTBI and a much smaller proportion of NTM infections). During the weeks immediately following inhalation and infection, the individual is usually asymptomatic. In the case of MTB, lymphohematogenous spread of the organism and the development of specific immunity as manifest by tuberculin skin test (TST) reactivity occurs. This period of systemic spread from the lungs creates the potential for extrapulmonary as well as pulmonary disease. Uncommonly, MTB may cause clinical tuberculosis immediately, which is then called primary tuberculosis. The lifetime risk of tuberculosis (i.e., disease due to MTB) developing is about 10% among immunocompetent persons infected with MTB. A much higher proportion of immunocompromised persons (e.g., those who are HIVcoinfected) will likely develop active tuberculosis. The progression of MTB infection to TB disease (pulmonary or extrapulmonary) is dependent on factors endogenous to the host and on poorly defined virulence factors of the infecting organism. Host factors include innate (genetic) susceptibility to the disease, the status of cell-mediated immunity (CMI) (e.g., HIV coinfection), and other factors that increase susceptibility, such as diabetes, silicosis, and chronic renal insufficiency. Gagneux and colleagues33 demonstrated an association between specific worldwide mycobacterial lineages and human populations, suggesting a human–pathogen coevolution for infectivity likely based on histocompatibility. The observation that the histocompatibility DRB1*1501 allele is associated with advanced disease and failure to respond to drug therapy whereas the DRB1*1502 allele is associated with less risk of disease progression underscores the importance of genetic susceptibility in individuals.6 The risk for the development of multidrug-resistant TB may also be histocompatibility “conditioned.”7 Specific mutations in the genes responsible for interferon production or interferon receptors (important for the host response to MTB) result in a higher risk of developing active disease.8,9 Other potential non-HLA host factors contributing to susceptibility to active disease include polymorphisms in transporters associated with antigen processing (TAP), Toll-like receptors, SLC11A1, vitamin D receptors, and mannose-binding proteins, to name a few.10 If MTB infection occurs in a host with a normal immune system, particularly a normal CMI, the MTB– host interaction progresses through stages.11 Following ingestion of the MTB by the resident alveolar macrophages, the MTB population within the macrophages increases in what is called the logarithmic stage. In this stage, the CMI has not yet been fully activated against the MTB, and often the innate antimycobacterial properties of the macrophages are not sufficient to destroy the organisms. Cell wall components, such as lipoarabinomannan, may be responsible for interrupting presentation pathways that would normally clear the organism.12 Organisms translocate to regional lymph nodes (i.e., lymphohematogenous dissemination) and spread to other organs of the body. Next is the immunogenic

phase, where the CMI has been activated, with helper T cells activating macrophages in the areas of infection while cytotoxic T cells kill the tubercle-filled macrophages as part of the delayed-type hypersensitivity reaction—a so-called Th1–mediated process. This process is responsible for the formation of a microscopic caseous necrotic center of a tuberculous focus. Tumor necrosis factor alpha (TNF-α) is crucial in this process.13,14 The infection at this point may remain contained locally and at distant sites as a self-limited primary infection; the only manifestation of its presence may be the TST reaction, which develops some 8 to 12 weeks following infection in immune-competent hosts. This defines the concept of latent MTB infection—an enclosed, asymptomatic, nontransmissible state in which MTB is either in a noncycling persistence or a balance of growth and death.15 Latency is dependent on a competent CMI. For reasons that are not completely clear, the host–tubercle bacillus interaction at the center of the granuloma can remain stable or may deteriorate with renewed MTB replication (reactivation) and possibly progress to liquefaction and cavitation. During this phase, endobronchial spread of infection to other lung segments and/or renewed hematogenous dissemination can occur. It is thought that an individual’s immunity, influenced by comorbid factors, determines whether reactivation occurs. Although less is known about the NTM, it is presumed that similar interactions apply to infections with many of these organisms. While some of the same conditions of immune compromise affecting MTB also increase the risk of NTM disease, other conditions such as cystic fibrosis, gastrointestinal conditions such as achalasia, chronic obstructive pulmonary disease (COPD), and prior pulmonary TB may also increase the risk of disease due to certain species of NTM.16–18

CLINICAL MANIFESTATIONS OF PULMONARY AND RELATED TB The lungs are the most common site of TB. However, because of the phase of lymphohematogenous dissemination, tuberculosis can involve any organ system in the body. Following the lungs, in descending order of frequency of involvement, are the lymph nodes, pleura, genitourinary tract, and bones and joints. Generalized spread (i.e., miliary TB) and meningitis are even more uncommon forms of disease. Involvement of the gastrointestinal tract and of the adrenal cortex, producing adrenal insufficiency, is also possible.19,20 Pulmonary disease may coexist with extrapulmonary disease. It is important to remind that TB vaccination aims at preventing and protecting against the lethal and severely extensive variants of the disease such as miliary and meningitis, but not against the respiratory form of TB. In other words, though vaccinated, a patient may present with respiratory TB.

PULMONARY DISEASE Pulmonary disease represents the majority of MTB active disease cases occurring in immunocompetent patients. Clinical syndromes include primary tuberculosis and postprimary tuberculosis. The distinction between these two presentations is based in part on the chest radiograph and history of prior TB infection. Although there is much overlap in these presentations, they are still convenient for the conceptualization of TB. Most adult patients who are not immunocompromised will have the postprimary syndrome, often with a presentation involving the upper lobe or a superior segment of the lower lobe. However, it should be noted that as many as one-third of pulmonary TB patients will present with radiographs that diverge from this classic teaching. Moreover, persons coinfected with HIV can have very atypical radiographs and even clear lung fields when they present with pulmonary TB.21

Primary Pulmonary Tuberculosis Primary tuberculosis occurs soon after the initial MTB inoculum has entered the local alveolar macrophages. In most individuals, the host immune response contains the infection within a few weeks, leaving a small granuloma that may calcify over time (Ghon lesion). However, in patients who cannot contain the initial infection because of impaired host CMI, poor nutrition, or age (i.e., young children), the infection may progress. The clinical and radiographic features of primary TB relate to lung parenchymal involvement with intrathoracic lymph node enlargement, including acute hematogenous dissemination with miliary lung involvement, TB pneumonia with or without pleural effusion, and intrathoracic adenopathy with bronchial compression and atelectasis. Radiographically, most primary TB involves the mid- to lower lung zones, where ventilation is greatest and inhaled MTB-infected droplet nuclei are most likely to have been deposited. The lung involvement is often segmental or lobar, with consolidation suggestive of more common bacterial pneumonia. The presence of centrilobular nodules and branching linear structures around distal airspaces corresponds pathologically to caseous material filling bronchioles mainly in early active disease.22,23 This pattern is the so-called tree-in-bud pattern. Yet this pattern is not pathognomonic of active TB and can be related to a variety of disorders.24 Pleural effusions, due to pleural extension of the parenchymal process with subsequent immunologic reaction in the pleural space, may be seen, as may hilar or mediastinal lymph node enlargement.25,26 Patients can present with constitutional symptoms as well as purulent cough and dyspnea. Additionally, they can have symptoms attributable to mediastinal or hilar lymphadenopathy, or both, such as wheezing or, particularly in children, acute upper airway obstruction. The latter is seen less frequently in the modern era of effective antimycobacterial therapy. If treatment is necessary for lymph node compression, surgery has been the therapy of choice,27,28 although corticosteroids in children with acute bronchial obstruction has also been employed as an adjuvant to medical therapy of the MTB.29 Intrathoracic lymphadenopathy is not limited to primary TB, however. Up to 5% of 56 patients described in one report of adult postprimary disease had sizable nonobstructing intrathoracic lymphadenopathy.30 Younger patients may also have cutaneous immunologic phenomena, such as erythema nodosum or erythema induratum. Quite typically, HIV patients will present with extrapulmonary disease or oligosymptomatic disease due to impaired immune system. Thus the accurate diagnose may be delayed consenquently.1,31 HIVinfected patients represent an important group of patients who may develop progressive primary TB infection, and may demonstrate atypical patterns of disease. According to Long and colleagues32—before the era of effective highly active antiretroviral therapy (HAART)—HIV-seropositive patients with prior AIDS-defining events and advanced HIV infection are the most likely to present with a primary TB radiographic pattern followed by HIV-positive patients without AIDS and immunocompetent HIVseronegative patients with 80%, 30%, and 11%, respectively, of TB cases in each group having a primary pattern. The relative risk for developing TB increases up to more than a 100-fold when T-cells count declines.31 The variability of radiographic findings correlates with CD4 count with more atypical patterns occurring as CD4 count declines.82 Though antiretroviral therapy is initiated, the treatment will remain difficult to manage as the restoration of lymphocytes count may induce a paradoxical worsening of TB symptoms. Sester et al.31,34 defined that phenomenon as “Immune Reconstitution Inflammatory Syndrome” (IRIS). Besides, the physician will have to face complex drug interactions which will hamper pharmacokinetics and delay efficiency on both pathogens.31,34

Postprimary Tuberculosis Postprimary tuberculosis—also referred to as adult-onset TB, reactivation TB, or secondary TB—results from reactivation of LTBI in a variety of at-risk persons (Table 84.2) but can also occur in persons with no identifiable “risk factors.” Any organ system may be the site of reactivation, but the chest is involved in over 80% of immune-competent adults; a much higher proportion of HIV-infected persons will have extrapulmonary disease.20 Addressing LTBI, the accent should be put onto immunocompromised patients. Whenever possible, early identification should be the goal and patients should be treated in case of latent disease.31,34 Before entering immunocompromising treatment (especially TNF-α antagonist therapy or prior to transplantation), patients should be screened for LTBI and treated consequently.34–36 This remains difficult to achieve as immunocompromised patients will present with low-sensitivity of the usual immune-based tests. Eventually, in severely immunocompromised patients, preventive chemotherapy should be given to patients with a positive immune-based test (TST ≥5 to 10 mm depending on the type of immunodeficiency, or interferon gamma release assay [IGRA]), signs of TB on chest radiograph in patients with no or insufficient previous TB treatment, or recent contact with a patient with active TB.1 TABLE 84.2 Persons at Particular Risk for Reactivation of Latent MTB Infection Decreased immunity HIV infection Organ transplant Uremia Lymphoproliferative malignancies Within 3 weeks of live virus vaccination Chronic oral corticosteroid therapy (15-mg prednisone per day or equivalent) Tumor necrosis factor-alpha antagonists Co-stimulation deficiency Other Chronic inflammation Silicosis Recent infection/skin test conversion Malnutrition Postgastrectomy Alcoholism

Radiographically, postprimary TB in the chest often presents in the apical or posterior segments of the upper lobes or the superior segments of the lower lobes, where alveolar oxygen tension is the highest. Upper lobe alveolar infiltrates (TB pneumonia), thick-walled cavities that often have smooth inner walls, and over time, fibrosis with volume loss are some characteristic features of postprimary disease. These features contrast with those of primary TB (Table 84.3). Up to 30% of chest radiographs can have presentations that are considered atypical for postprimary disease (e.g., mediastinal lymphadenopathy, lower lung zone predominance, single or multiple nodules, or isolated pleural effusions).37,38 Indeed, it has become more difficult to discern primary and postprimary disease based on radiographic findings.39 In particular, HIV-positive patients who are severely immunosuppressed (CD4 cell count 80%) exudative effusion that is typically unilateral, small to moderate in size, and rarely compromises the patient’s respiratory status. In the case of TB pleuritis, often large amounts of exudative pleural fluid are observed with some rare mycobacteria making the diagnosis quite difficult because of the scarcity of pathogens. Most of TB pleurisy will tend to spontaneous

resolution. If not, evolution will yield toward TB empyema which on the opposite will require surgical drainage and decortication with anti-TB medication. This condition is relatively rare in comparison to the frequency of TB pleurisy.1 The use of CT or ultrasound may help identify pleural disease.46

DIAGNOSIS DIAGNOSIS OF INFECTION The diagnosis of TB infection can be made through the use of targeted TST or the more recently developed whole blood IGRA. The diagnosis of MTB infection is usually pursued for one of several reasons: as part of an institutional epidemiology program to determine the rate of transmission of MTB; to identify and treat groups of patients with LTBI who are at risk for progressing to disease because infection with MTB is a prerequisite for disease, or to evaluate a patient who may be ill with tuberculosis. The TST is the most commonly used testing method for these two indications. The TST uses purified protein derivative (PPD) from a culture filtrate of MTB. In the United States, it is injected intradermally as a 5–tuberculin unit (TU) dose on a clean area of skin on the forearm. A delayed-type hypersensitivity reaction will usually occur in the form of induration at the site of injection usually 48 to 72 hours later if the patient has an intact CMI and has been infected and sensitized by MTB or antigenically related mycobacteria. The maximal diameter of the induration (not erythema) is then determined. In general, the larger the reaction size, the more likely that the individual is infected with MTB. The test does not determine presence of or extent of disease (i.e., TB). When used in screening for LTBI, TST should be given to persons who are at highest risk for progressing to active disease. By adjusting the threshold for “positive” reaction, the sensitivity of the test can be increased (small reaction size lowers threshold) or decreased (larger reaction size elevates threshold). Reciprocal changes in the test specificity can be expected. Interpretation of the results reflects risk stratification and is summarized in Table 84.4. The lowest threshold for a positive test (i.e., greatest sensitivity) is assigned to the highest risk stratum.47 Unfortunately, the TST has both a limited sensitivity and specificity and may fail to identify patients at highest risk.48 In persons with active TB, a positive TST is supportive of the diagnosis, but a negative test does not exclude the diagnosis. Persons with miliary TB, pleural TB, and TB meningitis, as well as advanced HIV-infected and malnourished patients, can all have negative TSTs even with active TB. There are two available interferon assays: the second-generation enzyme-linked immunosorbent assay (ELISA), based QuantiFERON-TB Gold (Cellestis Limited, Victoria, Australia), and the enzyme-linked immunospot (ELISpot) based T-SPOT.TB (Oxford Immunotec, Oxford, UK). Initial guidelines were published regarding the use of the first-generation QuantiFERON-TB test,49 which is no longer available for use, and recently for QuantiFERON-TB Gold.50 T-SPOT.TB has been approved in Europe and guidelines are available51—it is being reviewed by the U.S. Food and Drug Administration (FDA). Both tests rely on proteins (early secretory antigenic target protein 6, or ESAT-6; culture filtrate protein 10, or CFP10) unique to clinical isolates of MTB but absent from the majority of nontuberculous and BCG strains.52 ESAT-6 and CFP10 are potent targets of T lymphocytes secreting IFN-γ. While these tests have some notable differences, they both seek to overcome the deficiencies of the TST and have shown higher specificity. Recent evidence supports a higher sensitivity/specificity for T-SPOT in latent TB, both in BCG vaccinated individuals and those who are immunocompromised.53–55 Yet within the severely immunocompromised HIV population, falsely negative results should still be expected.56 A newer

formulation of QuantiFERON-TB Gold, “in-tube,” seeks to improve specificity by adding an additional antigen.57 These assays do not currently perform well in the setting of active disease.58 At present in the United States, it is recommended that the new IGRA can be used as alternatives to TST in all settings where TST is currently used to test for LTBI.50 These tests have the advantage of rapid objective diagnosis (15 mm

Persons with no risk factors for TB

>10 mm

Recent immigrants (i.e., within the last 5 years) from high-prevalence countries



Injection drug users



Residents and employeesa of the following high-risk congregate settings: prisons and jails, nursing homes and other long-term facilities for the elderly, hospitals and other health care facilities, residential facilities for patients with acquired immunodeficiency syndrome (AIDS), and homeless shelters



Mycobacteriology laboratory personnel



Persons with the following clinical conditions that place them at high risk: silicosis, diabetes mellitus, chronic renal failure, some hematologic disorders (e.g., leukemias and lymphomas), other specific malignancies (e.g., carcinoma of the head or neck and lung), weight loss of ≥10% of ideal body weight, gastrectomy, and jejunoileal bypass



Children younger than 4 years of age or infants, children, and adolescents exposed to adults at high-risk

>5 mm

HIV-positive persons



Recent contacts of TB case patients



Fibrotic changes on chest radiograph consistent with prior (untreated) TB



Patients with organ transplants and other immunosuppressed patients (receiving the equivalent of ≥15 mg/day of prednisone for 1 month or more)b

a For persons who are otherwise at low risk and are tested at the start of employment, a reaction of ≥15 mm induration is considered positive. b Risk of TB in patients treated with corticosteroids increases with higher dose and longer duration. Adapted with permission from American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221–S247.

DIAGNOSIS OF ACTIVE TUBERCULOSIS Although the TST can indicate the likelihood that an individual has been infected by MTB, history, physical examination, and other tests are required to determine whether TB is active, the anatomic sites of involvement, and the extent of disease. The diagnosis of active pulmonary TB therefore typically requires consideration of the patient’s epidemiologic risk for infection (i.e., probability of infection), clinical and radiographic presentation, the results of TST, and the results of microbiologic evaluation. Patients with a clinical presentation consistent with active pulmonary TB should be placed in respiratory isolation (or told to remain at home). Although a TST can be placed initially, a negative test should not be used to exclude active disease because, as noted above, between 10% to 25% of patients with active disease do not react to the skin test.48 Testing for HIV infection should be considered for all TB patients, whereas testing for the hepatitis viruses (B, C) should be done only for patients who have

risk factors for those infections. Sputum Smears and Cultures Sputum smears and cultures are an integral part of the diagnostic evaluation in a patient suspected of having active pulmonary disease. The sputum smear is often positive in patients with cavitary disease and less often positive when noncavitary or atypical radiographic presentations occur, such as lower lobe predominance or pleural effusions, or both. Most modern mycobacterial laboratories use fluorescence microscopy with auramine-rhodamine staining to screen specimens and Kinyoun or Ziehl–Neelsen acidfast staining to confirm positive fluorescence studies. Acid-fast staining is nonspecific as NTM and other organisms (Nocardia, some Legionella) may also be acid-fast–positive. At least three specimens should be collected in sterile containers on separate days.59 These specimens may need to be induced with hypertonic saline in patients having difficulty expectorating sputum.60 The sensitivity of sputum smear for MTB ranges from 45% to as high as 92% when at least 5 mL is reliably collected.61 Because a positive smear requires a relatively high concentration of organisms, patients who are sputum-positive are typically most infectious. AFB smears or cultures of other potentially infected sites should also be collected, if possible, to confirm concordant extrapulmonary disease. Bacteriologic yield from extrapulmonary sites is often less than from pulmonary specimens, although inclusion of histologic examination for granulomata raises the yield somewhat. Mycobacterial sputum cultures are more sensitive requiring at least a log order lower concentration of organisms to yield a positive result than the sputum smear. Hence, patients with negative sputum smears but positive cultures are typically considered less infectious. The culture can be performed on agar or egg-based media such as Löwenstein–Jensen or Middlebrooks 7H10/7H11 and incubated at 37°C. The mycobacterial colonies can be identified as MTB by their appearance on media (nonpigmented corded colonies), and a variety of biochemical tests. Because MTB is a slow-growing organism, up to 8 or more weeks may be required before colonies are seen on solid media. Growth on liquid media allows mycobacteria to be detected earlier (2 to 3 weeks). BACTEC (BD Diagnostics, Sparks, MD) and mycobacteria growth indicator tube (MGIT) (BD Diagnostics, Sparks, MD) are common liquid media isolation systems, which use radiometric or calorimetric means of detection. Overall, sputum cultures are about 80% to 85% sensitive in pulmonary TB.62 Bronchoscopy with bronchoalveolar lavage may be considered in patients who are unable to raise sputum even after efforts at sputum induction with saline inhalation. Initially, positive sputum cultures should be tested for drug susceptibility for the first-line agents isoniazid, rifampicin, and ethambutol. Testing for other antituberculous agents should be done if the patient has a history of prior treatment or suspected resistance to rifampicin or other first-line agents. Recently more rapid techniques have been developed for identifying MTB and certain other species of mycobacteria. Nucleic acid assay (NAA) tests use RNA probes specific for MTB or other mycobacteria (Gen-Probe MTD, Gen-Probe Inc., San Diego, CA). They can be combined with polymerase chain reaction (PCR) to amplify MTB DNA (Amplicor MTB test, Roche Diagnostic Systems, Inc., Branchburg, NJ). These assays can be completed within a day or two and have sensitivities comparable to culture systems and specificities close to 100%.63 The NAA tests are FDA-approved for sputum smear–positive patients and should, ideally, be performed on all such patients in addition to culture and drug susceptibility testing. Assays have recently been adapted to identify genetic markers of resistance —“molecular beacons”—to commonly used antituberculous drugs, thus creating the possibility of rapid drug susceptibility testing.64,65 In addition, line probe assays that use a combination of PCR and reverse hybridization have been developed for both rapid diagnosis and drug resistance determination with

reported high sensitivity and specificity but are not yet FDA-approved. Genetic arrays may further enhance detection and identification of resistance.66 Nevertheless, nucleic acid amplifications techniques demonstrate a low negative predictive value. Further, their high cost sets a limitation for low income countries. Recently, WHO endorsed a molecular technique (Xpert MTB/RIF; Cepheid, Sunnydale, CA, USA) that should now be preferred for diagnosis of TB and rifampicin resistance as a surrogate marker of MDR TB. The technique is expeditive (1h45) and independent from the operator and his interpretation of the results. This new kind of laboratory test has been recommended by the WHO in all TB programs and should now be widely spread. Since 2012 this technique is recommended as a standard in the European Union for TB care. With regard to pleural TB, characteristics of the pleural fluid may support the diagnosis. In the setting of pleural TB, pleural fluid is often devoid of mesothelial cells (60 U/L)

95

INF gamma

89

Pleural biopsy AFB smear

40

Pleural biopsy culture

75

Pleural biopsy PCR

90

Pleural fluid PCR

100 (culture positive)



30–60 (culture negative)

AFB, acid-fast bacilli; PCR, polymerase chain reaction; INF, interferon. The combination of pleural biopsy culture and pleural histopathology showing granulomas is over 90% sensitive for pleural tuberculosis.

TABLE 84.6 Findings of Diagnostic Studies in Pleural Tuberculosis Test

Typical Findings

Pleural fluid



pH

7.30–7.40 (if lower, consider empyema)

Total protein

>3 g/dL

Cell count

>1,000/mm3

Differential



Lymphocytes

>80% if subacute/chronic; PMN predominance if very early/acute

Cholesterol

Elevated if chronic, with milky appearance to fluid

Glucose

60–100 mg/dL (if lower, consider TB empyema)

LDH

>500 IU/L

Sputum AFB

More likely positive if parenchymal disease is present. However, up to 55% of patients with isolated pleural TB (otherwise clear CXR) may have positive induced sputum cultures.

PPD

Up to one-third initially false negative, but on repeat testing 2 months after diagnosis, almost all have positive PPD

AFB, acid-fast bacilli; CXR, chest x-ray; LDH, lactate dehydrogenase; PPD, purified protein derivative; PMN, polymorphonuclear cells; TB, tuberculosis.

TREATMENT OF ACTIVE PULMONARY TUBERCULOSIS A key to understand the treatment of active disease is appraising that there are three subpopulations of MTB (or tubercle bacilli) within a given area of disease.67 These subpopulations can be conceptualized as existing in three compartments. The first compartment consists of metabolically active extracellular organisms, as might inhabit a tuberculous cavity. This is the largest population of organisms and the one responsible for the patient’s infectivity. Because resistance is dependent on the number of organisms present, this population is also responsible for the emergence of drug resistance if treatment is inadequate. The other two populations, one extracellular and one intracellular within monocytes and macrophages, are smaller, metabolically less active, and slower to respond to treatment. They have been termed “persisters” and represent the populations that must be eliminated to attain a lasting cure and to prevent relapse. Antituberculous drugs have variable efficacy against these three subpopulations. Isoniazid appears to be most effective against the metabolically active extracellular population, while rifampicin and pyrazinamide are more effective against the less metabolically active extra- and intracellular populations, respectively.68 It is the persisters that require antituberculous therapy to be continued for months after the initiation phase of treatment. Indeed, most MTB present in an active case of tuberculosis are killed within the first several weeks of treatment by the drugs used in modern short-course therapy, but much of this killing occurs within the highly metabolically active extracellular population, where killing is most efficiently accomplished by currently available drug regimens. The management of active disease is overwhelmingly medical with surgery used in exceptional situations. The importance of having a clear understanding of microbiologic concepts when treating MTB is illustrated in a study conducted by Mahmoudi and Iseman,69 in which 35 cases of active pulmonary TB were reviewed retrospectively for errors in management. Of these patients, errors were made in 28, with a rate of about four errors per patient. The most common errors included the addition of a single drug to a failing regimen, failure to address or identify nonadherence to the treatment regimen, failure to identify

acquired or preexisting drug resistance, and inappropriate diagnosis of active disease as latent disease, leading to inadequate therapy. These errors led to an increased rate of acquired drug resistance when compared with the no-error group, and to an increased number of antituberculous agents used in the error group. The costs of this added therapy averaged an astounding $180,000 per patient in 1990 dollars. TABLE 84.7 Principles of Therapy for Active Pulmonary Tuberculosis Use multiple drugs to which the organism is susceptible. The choice of initial therapy should be guided by local resistance patterns and modified by in vitro drug susceptibility tests when available. Drug therapy should be for a sufficiently long period of time (in most cases at least 6 months) to provide durable cure of disease. Always add more than one drug to which the organism is believed sensitive to a potentially failing regimen. Use directly observed therapy whenever possible to reduce the chances for nonadherence. Promptly report each case to the local public health department. Outpatient therapy is satisfactory for many patients. Adapted with permission from American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit CareMed 2003;167:603.

Some key principles of drug therapy of active disease are noted in Table 84.7. These principles are followed to achieve the goals of therapy, which are to render the patient noninfectious, to eliminate symptoms, to prevent the emergence of drug-resistant organisms, and to provide a lasting cure. These goals, in turn, are achieved by using multiple drugs to which the organism is susceptible in adequate doses for a sufficient duration of time. The use of initial empiric therapy that reflects prevailing local resistance patterns and which is modified as necessary by the results of in vitro drug susceptibility tests should guide definitive treatment. Assessment of the initial chest radiograph for cavities and assessment of smear and culture at 2 to 3 months into therapy to look for possible nonadherence, drug-resistant organisms, or potentially slow response due to extensive disease is also essential. The importance of using at least two drugs to which the organism is presumed sensitive for the initiation of treatment, and the addition of at least two new drugs to which susceptibility is likely for those patients who may be failing therapy, cannot be overemphasized. In these situations, the use or addition of a single drug to which the organism is sensitive may result in de facto monotherapy if resistance exists to the other agent being used whereas the use of at least two drugs to which the organism is sensitive reduces the likelihood of developing drug-resistant TB. Outpatient therapy can generally be offered if the patient is not seriously ill or debilitated. Directly observed therapy (short course) or DOTS should be considered in most patients to reduce the likelihood of treatment nonadherence.70 Finally, each case of TB should be reported promptly to the local public health department to facilitate application of control measures. For all patients with pulmonary disease, recommended monitoring of therapy includes monthly sputum smears and cultures to document conversion (or the lack thereof). After the first sputum culture is negative, another confirmatory negative culture should be obtained. Monitoring radiographic films assumes less importance than sputum smear and culture, although it is recommended that a chest film be obtained upon completion of therapy so that a baseline for future comparison is available. All patients should have at least initial liver function tests and serum creatinine, platelet count, and uric acid levels obtained. Additional monitoring should be pursued based on individual indications. A high index of suspicion of TB disease should be maintained in caring for at-risk patients. Principles of infection control, with airborne isolation being a cornerstone, should be employed with assistance from local infection control resources.71 Isolation of suspected patients should continue until the disease is excluded, or they are deemed noninfectious, typically, by obtaining three negative AFB smears over separate days. If active TB is found, consideration of contacts both within and outside the hospital need to

be sought and reported. Local and state health department reporting laws differ but reporting is mandatory nationwide in the US health care workers exposed to this population should be screened with the use of annual TST. If a specific exposure has occurred, following the initial contact investigation, a repeat TST should be done at 8 to 10 weeks to ensure lack of transmission. Special circumstances are often encountered in TB patients undergoing surgical procedures. In caring for patients on mechanical ventilation in the ICU setting, respiratory isolation precautions with the use of at least an N95 disposable respiratory mask and airborne isolation should continue, with the addition of ventilation circuit bacterial filters. Within the operating room and recovery areas, these same principles apply. Positive pressure ventilated rooms, high-efficiency particulate air (HEPA) filtration systems, and ultraviolet light (duct or upper-air irradiation) assist in preventing contamination of the surgical field and increase air exchange within the operating room. Minimal ventilation recommendations are reviewed in recent guidelines and are usually expressed in air changes per hour (ACH) units.71

RECOMMENDED REGIMENS The results of over three decades of clinical trials have yielded some basic insights upon which modern chemotherapeutic regimens for active TB are based.72–78 By utilizing drug combinations that target each of the three subpopulations of MTB present, it is possible to give an effective course of treatment over a period of 6 to 9 months (Table 84.8). This represents more than a halving of the duration from just one generation ago. Implicit in using these regimens are the assumptions those organisms are susceptible especially to rifampicin, and that most doses of medication are taken. Regimens are satisfactory for both pulmonary and extrapulmonary disease, although some forms (e.g., TB osteomyelitis) may require a somewhat longer course of therapy. Further, it is now clear that although 6 months of therapy (a so-called short-course regimen) is satisfactory for most patients, some will require longer durations of treatment. Therapy for patients with susceptible organisms can be divided into two phases. The initiation phase generally forms the first 2 months of treatment. Major goals during this phase are to render the patient noninfectious and prevent the emergence of drug resistance by initiating multiple drugs to which the organism is presumed or known to be susceptible. This typically uses a four-drug regimen (isoniazid, rifampicin, pyrazinamide, and ethambutol) in the United States.79 When susceptibility is confirmed, ethambutol can be stopped. Following the initial 2 months is the continuation phase, which lasts for 4 months in most patients, in which a major goal is to eliminate persistent MTB infection. Two drugs, isoniazid and rifampicin, are used during this phase. The dosing of these medications can be daily or intermittent (2 to 3 times per week), with the decision dependent on variables such as cost and perceived patient adherence. If intermittent dosing is considered, directly observed therapy (DOT, in which pills are given and consumed under direct health care giver supervision) is strongly recommended, particularly in high-priority groups. DOT has been shown to be cost-effective, to reduce TB relapse rates, and to reduce acquired and primary resistance of MTB to various antimycobacterial drugs.70,80

TABLE 84.8 Recommendations for the Treatment of Drug-Sensitive Culture and Smear-Positive Pulmonary Tuberculosis Regimen

Drugs

Initiation

Drugs

Phase (Doses)a

Continuation Phase (Doses)a

1

I, R, P, E

8(I7P 7E7R7)

I, R

18(I7R7)





8(I5P 5E5R5)



18(I5R5)







I, R

18(I3R3)







I, RPT

18(I1RPT1)

2

I, R, P, E

2(I7R7P 7E7), then 6(I2R2P 2E2)

I, R

18(I2R2P 2E2)

I, RPT

18(I1RPT1)

3

I, R, P, E

8(I3P 3R3E3)

I, R

18(I3R3)

4

I, R, E

8(I7R7E7)

I, R

28(I7R7)





8(I5R5E5)



28(I5R5)

a The first number in the abbreviation stands for weeks; the subscript number following each letter stands for the number of days medication is given each week. E.g.: 8(I7R7P 7E7) means 8 weeks of daily isoniazid, rifampin, pyrazinamide, and ethambutol. I, isoniazid; R, rifampin; RPT, rifapentine; P, pyrazinamide; E, ethambutol. Patients with cavitary pulmonary disease who also have positive sputum cultures at 2 months should have the continuation phase extended from 4 to 7 months (i.e., total therapy equaling 9 months). Adapted with permission from American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603.

The continuation phase is extended from 4 months to 7 months (to complete a total of 9 months) in persons with both cavitary pulmonary tuberculosis and sputum culture that remains positive at 2 months; patients with silicotuberculosis; patients who did not have pyrazinamide in their initial regimen; and persons who are taking isoniazid and rifapentine (once-a-week dosing) whose sputum cultures are positive at 2 months (see Table 84.9 for drug doses and toxicities). Pleural TB within the United States continues to represent a stable proportion of overall cases of pulmonary TB (3.6%) and reflects similar patterns of resistance.81 Current guidelines by the American Thoracic Society, the Centers for Disease Control and Prevention, and the Infectious Diseases Society of America (2003) recommend treating uncomplicated pleural TB for 6 months with regimens that are used for pulmonary TB.82 Chest tube drainage is usually unnecessary and avoided to prevent super infection of the space. Treatment of Multidrug-Resistant Tuberculosis Patients with MDR TB, who by definition have resistance to at least isoniazid and rifampicin, should be referred to the care of a TB specialist. These patients often have had prior treatment; have immigrated from areas of the world that are endemic for MDR TB83; have failed to respond to initial therapy (sputum smear and culture positive at 2 months); or have HIV infection.84 Worldwide rates of MDR TB are approximately 4.3% of all new cases.85 In the United States, the rate of MDR TB is 1.2%,86 and the incidence of new MDR TB cases is disproportionately within the foreign-born and immigrant population, making case identification a challenge. Regimens for MDR TB may include up to six to eight drugs, including parenteral second-line agents such as streptomycin, with prolonged therapy that requires up to

18 or more months, with variable success. Treatment success can be achieved if a strong commitment to this intensive regimen exists on the part of the patient and strict treatment principles (use of two or more drugs to which the organism is susceptible) are followed by the physician. Recent data support success in treatment of up to 70%. Use of so-called DOTS-plus for the duration of therapy45,85 is recommended to assure adherence. Available second-line agents have been reviewed, and treatment guidelines developed for this difficult problem.82,87,88 TABLE 84.9 Tuberculosis Drug Doses and Toxicities Drugs

Daily

First-line Agents

Intermittenta Serious Toxicities







Isoniazid

5 mg/kg

15 mg/kg

Hepatotoxicity, peripheral neuropathy, agranulocytosis, aplasia, seizures, leukopenia, optic neuritis, renal failure, hepatotoxicity

Rifampin

10 mg/kg

10 mg/kg

Leukopenia, thrombocytopenia, interstitial nephritis, hemolysis

Rifabutin

5 mg/kg

5 mg/kg

Uveitis, neutropenia, leukopenia

Rifapentine

—

10 mg/kg

Anaphylaxis, pancreatitis, hepatotoxicity, interstitial nephritis, leukopenia, thrombocytopenia

Pyrazinamide

1–30 mg/kg

50–75 mg/kg

Hepatotoxicity, interstitial nephritis, thrombocytopenia

Ethambutol

15–25 mg/kg

50 mg/kg

Anaphylaxis, optic neuritis, peripheral neuropathy, thrombocytopenia

Streptomycin

15 mg/kg

25–30 mg/kg

Nephrotoxicity, ototoxicity

Second-line Agents







p-Aminosalicylic acid

8–12 g



Hypersensitivity reactions, GI upset, hepatitis

Capreomycin

15–20 mL/kg



Nephrotoxicity (more than streptomycin), ototoxicity

Ethionamide

15–20 mg/kg



GI upset, hepatitis, impotence, gynecomastia, photosensitive dermatitis

Cycloserine

10–15 mg/kg



Psychosis, seizures, peripheral neuropathy

Kanamycin

15–30 mg/kg



Ototoxicity (more than streptomycin), nephrotoxicity (equal to capreomycin)

Thiacetazoneb

150 mg



Hepatitis, Stevens–Johnson syndrome, marrow suppression

Moxifloxacin

400 mg



Anaphylaxis, phototoxicity, seizures, tendon rupture, torsades, psychosis

a Includes once, twice, or three times a week. Ethambutol, rifampin, and rifabutin should not be given once a week. b Thiacetazone is not available in the United States.

TABLE 84.10 Evidence-Based Recommended Drug Regimens for Treatment of Latent Tuberculosis Infection in Adults Drug

Isoniazid

Interval and Duration

Comments

Ratinga (Evidence)b HIV−

HIV+

Daily for 9 monthsc,d

In HIV-infected patients, isoniazid may be administered concurrently with NRTIs, protease inhibitors, or NNRTIs.

A (II)

A (II)

Twice weekly for 9 monthsc,d

DOT must be used with twice-weekly dosing.

B (II)

B (II)

Daily for 6 monthsd

Not indicated for HIV-infected persons, those with fibrotic lesions on chest radiographs, or children.

B (I)

C (I)

Twice weekly for 6 monthsd

DOT must be used with twice-weekly dosing.

B (II)

C (I)

Rifampine

Daily for 4 months

For persons who are contacts of patients with isoniazid-resistant, rifampin-susceptible TB. In HIV-infected patients, protease inhibitors or NNRTIs should generally not be administered concurrently with rifampin. Clinicians should seek the latest recommendations.

B (II)

B (III)

Rifampin plus

Daily for 2 months

RZ generally should not be offered for treatment of LTBI for HIV-infected or HIVnegative persons. Use with caution because of high hepatitis risk.

D (II)

D (II)

Pyrazinamide (RZ)

Twice weekly for 2–3 months



D (III)

D (III)

Isoniazid

DOT, directly observed therapy; HIV, human immunodeficiency virus; LTBI, latent tuberculosis infection; NNRTI, nonnucleoside reverse transcriptase inhibitors; NRTI, nucleoside reverse transcriptase inhibitor; TB, tuberculosis. a Strength of recommendation: A, preferred; B, acceptable alternative; C, offer when A and B cannot be given; D, adverse outcome supports recommendation against use. b Quality of evidence: I, randomized clinical trial data; II, data from clinical trials that were not randomized or were conducted in other populations; III, expert opinion. cRecommended regimen for children younger than 18 years. d Recommended regimens for pregnant women. eRifapentine is not recommended because of unestablished safety and efficacy. Adapted from CDC. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection. MMWR 2003;52(31):735–739.

XDR TB is defined as MDR strains resistant to any fluoroquinolone and to at least one second-line injectable drug (amikacin, capreomycin, or kanamycin)64 and has high associated mortality.89 Within the United States, 3% of evaluable MDR cases between 1993 and 2006 were XDR.64 Recent reports have suggested emergence of completely resistant forms of tuberculosis. Another treatment option for MDR- or XDR TB that is anatomically localized, particularly in the face of limited medical therapy options, is resectional surgery. There are, however, no randomized studies looking at the role of surgery in MDR TB. Retrospective cohort studies have demonstrated success, both within developed and resource-poor countries.90,91 If surgery is considered for a patient with MDR TB, it should ideally be performed only after several months of chemotherapy and should be followed by up to

18 months of chemotherapy (see Chapter 85). New XDR strains will continue to push the limit of available care and resources,92 and may increase the need for alternative surgical therapies. Various forms of collapse therapy including thoracoplasty have been used in selected cases but there is limited experience to draw upon for recommendations. Treatment of Latent Tuberculosis Infection LTBI therapy is a cornerstone of tuberculosis control and elimination.93 The goal of treating LTBI is to reduce the risk of reactivation and progression to active disease. As noted, the lifetime risk of such reactivation has been estimated as averaging 10% in HIV-seronegative persons, with about 5% progressing to active disease with no LTBI treatment in the first 2 years following infection and TST conversion. However, recent estimates suggest lifetime risks as high as 20% when TST size and other host factors are considered.94 HIV represents the greatest risk for progression and, without LTBI treatment, carries an estimated 10% annual risk.79 HAART therapy decreases this risk, but not to levels of HIV-seronegative persons.95 Moreover, persons with advanced HIV infection may be especially susceptible to acquiring new exogenous MTB infections. Three regimens have been recommended for the treatment of LTBI (Table 84.10), while a fourth regimen using rifampicin/pyrazinamide has been downgraded to “not recommended” owing to significant hepatoxocity.96 Single agents may be used for LTBI treatment, in contrast to active tuberculosis, because the risk of developing drug-resistant disease is small, owing to the low number of organisms present. Because of this, it is essential to exclude the presence of active MTB before giving a single drug for the treatment of LTBI.

SURGERY AS A TREATMENT FOR TB Before the era of anti-TB drugs, surgery was the only treatment available for respiratory TB; it initially relied on the different variants of collapse therapy including intrapleural pneumothorax, extrapleural pneumothorax, extraperiosteal plombage, and thoracoplasty.97,98 Nowadays, excepting MDR TB and XDR TB, well-conducted TB chemotherapy will enable to cure up to 85% of all sputum-positive patients. In the latter patients, the role of surgery will be limited to a diagnostic purpose.1 Surgery still has a predominant place for treating posttuberculosis sequelae and MDR/XDR TB.99,100

SURGERY FOR MDR/XDR TB Addressing MDR/XDR TB, surgery will be mostly helpful to eradicate parenchymal cavitations hosting MTB persisting under well-conducted chemotherapy.100,101 Anatomical resections (lobectomy or pneumonectomy) are the preferred type of resection to avoid opening the tuberculous cavitation and spilling bacterial load into the pleura. In various published series, operative morbidity and mortality rates range from 11% to 35% and up to 4.3%, respectively. According to a meta-analysis, surgery leads to a success rate of 84% for MDR TB, failure in 6% and, relapse in 3%, mortality in 5%. Even in XDR TB, surgery may obtain a success rate of 85%. The profile of the operable candidate is a patient with MDR TB, in whom we may prognose a high risk of relapse or recurrence once chemotherapy is stopped and with localized disease amenable to complete surgical resection. Surgery is performed once sufficient chemotherapy has been administered to diminish the initial burden of bacterial load and favor the

bronchial stump healing. Surgery should be considered in the following cases: (1) MDR TB after 18 to 24 months of anti-TB chemotherapy combining multiple drugs, negative smears, and culture, (2) persistence of TB excretion despite intensive course of anti-TB chemotherapy, and (3) lack of radiological improval of TB sequelae or drug resistance in sputum-positive patients.100,101

SURGERY FOR POST-TB SEQUELAE Post-TB sequelae will be either due to TB itself or more occasionally due to collapse therapy. TB will determine two different types of elementary lesions. Lung lesions present as bronchiectasis, fibrostenosis, or cavitation. Lymph node lesions are characterized as broncholithiasis. These lesions may be further complicated by aspergilloma developing in a parenchymal cavitation, and bronchoesophageal fistula by erosive broncholithiasis. These elementary lesions may also combine and achieve chronic suppurative disease leading to completely a destroyed lung.99 In almost all cases, surgery is to be discussed once these lesions reveal by symptoms. However, preventive surgery has been recommended in case of aspergilloma: surgical outcomes are marked by a decreased mortality and morbidity rate when surgery is performed in asymptomatic patients. On the opposite, emergency surgery in symptomatic patients presenting with acute hemoptysis is credited a substantial mortality and morbidity. In the setting of post-TB sequelae, adjuvant TB chemotherapy may be indicated either because of persistent bacilli or granuloma in the surgical specimen, or because the patient was not compliant with the initial regimen. Performing surgery for post-TB sequelae, some general rules have to be respected. The lung in TB patients undergoes fibrotic changes which interfere with adequate re-expansion after partial resection; the surgeon should keep in mind that immediate or deferred thoracoplasty may be required. Anatomical lung resection, preferably lobectomy, should be preferred to prevent spilling of the pleura. Bronchial fistula is a classic complication; the hilar dissection should be careful and preserve bronchial blood supply to support proper bronchial healing. In case pneumonectomy needs to be performed for a destroyed lung, careful covering of the bronchial stump is mandatory. Last but not least, at each surgical step starting with adhesiolysis, a meticulous hemostasis is required to lower the risk of postoperative bleeding.99 The usual complication of therapeutic pneumothorax is an exudate blowing the residual space of pneumothorax or the extrapleural pocket. This exudate may be sterile, infected with nonspecific flora or present as reactivated tuberculous empyema. Exceptional cases of hematoma in patients on Coumadin have been reported. The best option in these patients is a decortication. Although the underlying lung has low functional value, it will act as a “prosthesis” filling the pleural space, which is the main condition to heal empyema. Long-term complications of extraperiosteal plombage are exceptional, because most of the patients underwent routine removal of the material. Complications include infection of the plombage space and migration of the material. Treatment consists of removal of all plombage material followed by a thoracoplasty achieved by excision of the devitalized ribs surrounding the plombage space.97,98

NONTUBERCULOUS MYCOBACTERIAL LUNG DISEASE NTM are found throughout the environment and are an increasingly important cause of pulmonary and extrapulmonary (most commonly lymph node, cutaneous, and disseminated) disease in humans. Appreciation of NTM as pathogens has grown over the last three decades, with new guidelines for their diagnosis and treatment having been released.3 Although there are more than 125 known species of NTM,

only about 50 cause disease in humans and not all of those cause pulmonary disease (Table 84.1). Pulmonary disease caused by NTM usually occurs in one of three prototypical forms: often cavitary disease in the upper lung zone resembling tuberculosis and typically occurring in middle-aged men with long smoking histories and COPD; nodular (small) infiltrates with or without bronchiectasis often presenting in older nonsmoking women; and hypersensitivity pneumonitis, which is discussed further here. In addition, NTM can complicate underlying disease such as cystic fibrosis, and larger granulomas presenting as pulmonary nodules may be encountered. Lung disease caused by NTM is often progressive, albeit slowly, causing significant morbidity and mortality without treatment. While early diagnosis may yield better outcomes, this can be more difficult than diagnosing MTB pulmonary disease, reflecting both the poor predictive value of an isolated respiratory tract culture of NTM in predicting the presence of a chronic disease and the often subtle and nonspecific findings of early NTM disease. Because NTM, unlike MTB, are common in the environment (e.g., water sources in the community, the hospital, or microbiology laboratory), they can contaminate mycobacterial cultures or cause airway colonization without causing true parenchymal disease. Conversely, it is increasingly appreciated that seeming “colonization” is often early NTM that will progress over a period of years.

EPIDEMIOLOGY AND PATHOGENESIS NTM can be isolated from a variety of environmental sources and diverse geographic locations.102 NTM species, even the “rapid growers,” are relatively slow-growing (as compared with other bacteria), with long-chain fatty acids within their cell walls providing resistance to most environmental hazards. Importantly, chlorination and ozonation techniques do not deter them from surviving in water sources.103 TABLE 84.11 Diagnostic Criteria for Pulmonary Disease Involving Nontuberculous Mycobacteriaa,c Clinical

Microbiologic

Pulmonary symptoms consistent with NTM

Positive culture from at least two separate sputum samplesb,d

Nodular or cavitary opacities on chest radiograph



AND/OR HRCT with multifocal bronchiectasis with multiple small nodules

OR Positive culture (≥1) from at least one bronchial wash or lavageb

AND

OR

Exclusion of other diagnoses

Transbronchial or other biopsy with granulomatous inflammation or AFB



Positive culture (≥1) for NTM by sputum or bronchial wash or lavageb

a Patients suspected of having NTM pulmonary disease who do not meet the above criteria should be followed until the diagnosis is excluded or firmly established. b Expert consultation should be sought with identification of infrequently encountered or suspected environmental contamination. cThe treatment of NTM pulmonary disease should be based on the risks and benefits of therapy. d Sputum should be collected from three early morning samples before more invasive methods. Adapted from Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. An official statement of the ATS/IDSA. Am J Respir Crit Care Med 2007;175:367–416. With permission.

Recent data demonstrate an increase in NTM prevalence in the United States. This likely reflects

enhanced methods of detection, improved awareness of NTM, and an increase in susceptible populations. Indeed, NTM (in particular MAC) have surpassed MTB in frequency of isolation. Skin testing surveys of immunocompetent hosts have shown increases in M. intracellulare reactivity from 11.2% in 1971 to 1972 to 16.6% in 1999 to 2000.104 While skin testing and culture isolates provide some information regarding exposure, true attributable disease is difficult to estimate. Prior estimates of prevalence of pulmonary disease due to NTM within the United States were about 1 per 100,000 population.105 In contrast to M. tuberculosis and M. leprae, NTM are not obligate pathogens, and no person-to-person transmission has been found; thus, required reporting is not available to give true estimates of disease incidence/prevalence. In the United States, four main species of NTM have been identified as a cause of pulmonary disease: MAC, consisting of M. avium and M. intracellulare; M. kansasii; M. abscessus; and M. fortuitum (considered “rapidly” growing mycobacteria [RGM]). While these organisms can be found throughout the United States, there are clusters of disease within geographic areas.18 Persons especially susceptible to such infections include immunosuppressed patients; those with prior lung disease such as COPD, bronchiectasis, or pneumoconiosis; genetic lung diseases such as cystic fibrosis or alpha-1 antitrypsin deficiency; and esophageal motility disorders. Those infected with HIV or with other immune compromise may be more susceptible to certain NTM.106–108 Previous population studies have demonstrated a male predominance, yet recent data supports a population of women without recognized predisposing factors who develop nodular bronchiectasis due to NTM, most often MAC in the United States.60,109 Indeed, it has been reported that up to 37% of individuals may lack recognizable risk factors,110 although associations such as Caucasian race, slender build, pectus deformity, and straight back have been noted.111 The pathogenesis of NTM is not fully understood.3 It is known that a defective T-cell function, specifically of CD4 lymphocytes, predisposes individuals to MAC infection. For example, defects in interferon and interleukin pathways that upregulate macrophage production of TNF-α and may be important in controlling mycobacterial infection have been implicated. It is felt that inhalation is the predominate route of exposure.

CLINICAL PRESENTATION AND DIAGNOSTIC TESTING As noted, NTM pulmonary infection is likely to present in one of three prototypical forms.16 While MAC has been associated with all three patterns and is the most common NTM in the United States, other species are likely capable of producing similar patterns of disease. That said, particular species do seem to have a propensity for producing certain presentations. For example, M. kansasii pulmonary disease is typically associated with an MTB-like presentation and pattern. The symptoms of disease are often protean and nonspecific, with chronic cough and fatigue being typical. Constitutional symptoms are less common than with TB but may be seen in advanced forms of disease. Likewise, dyspnea and hemoptysis are uncommon except in advanced disease or with comorbidity; symptoms of the underlying disease may predominate and complicate interpretation. An evolving view of NTM from usually “benign” colonizers to more often slowly progressive infectious agents is reflected in recent criteria for their diagnosis.3 Given the vague nature of symptoms, radiographic pattern and identification of species by culture are the cornerstones of diagnosis (Table 84.11). In evaluating an individual for NTM, exclusion of other conditions, especially MTB, must be made, given the obvious overlap in symptoms and presentations.

RADIOGRAPHIC IMAGING Chest x-ray films and especially high-resolution CT (HRCT) and x-ray are crucial in making a diagnosis of disease, with HRCT essential for evaluation of bronchiectasis and extent of nodular infiltrates. Subtle but common radiographic findings include small bilateral nodules, tree-in-bud infiltrates, and bronchiectasis (Fig. 84.2).112 Distinguishing characteristics of NTM from MTB include thinner-walled cavities with relatively little surrounding parenchymal infiltrate; contiguous spread of infection; and greater involvement of the pleura adjacent to an area of lung infection.113 Pleural effusions are uncommon with NTM. It has been suggested that as many as one-third of patients with bilateral bronchiectasis and bronchiolitis may have NTM infection107 and that diagnosis should be considered in the setting of a suggestive HRCT pattern. It is also important to note that there is occasional overlap between the aforementioned prototypical presentations. Upper lobe findings are often seen in older men with significant smoking histories and concomitant COPD. The “Lady Windermere syndrome” (possibly due to voluntary suppression of cough and occurring in nonsmoking middle-aged or elderly women), appears radiographically as pneumonitis, bronchiectasis, and nodularity involving the right middle lobe and/or lingual.114

FIGURE 84.2 Computed tomography scan of the chest in a patient treated for multidrug-resistant tuberculosis (TB). A: Large left upper lobe; posterior segment thick-walled cavity with associated area of TB pneumonia prior to treatment. B: Area of treein-bud pattern in the lingula (arrowhead). C: Left upper lobe cavity after 7 months of multiple-drug chemotherapy.

SKIN TESTING, SPUTUM SMEAR, AND CULTURE

Unlike MTB, skin testing in NTM is not used for diagnosis because of cross reactivity with antigens of MTB and the lack of readily available skin-test antigens specific for NTM. The IFN-γ–release assays may be of benefit in differentiating active TB from NTM115 but have not been well studied for this purpose. As in the case of MTB, early morning sputum collections are recommended (ideally at least three on separate days) for obtaining specimens to confirm the presence of NTM. Induced sputum or, if sputum cannot be obtained, bronchoscopy may assist in specimen collection. As with MTB, acid-fast staining using the fluorochrome technique is a useful step in screening specimens for NTM. While negative smears do not ensure the absence of NTM, high numbers of AFB and/or repeatedly positive smears suggest the presence of a clinically significant infection.116 Sputum culture, using a combination of solid and liquid media, is used to identify species and assist in drug susceptibility testing. Liquid media such as MGIT (BD Diagnostics, Sparks, MD) and radiometric systems (BACTEC, BD Diagnostics, Sparks, MD) offer more rapid identification. The time to growth should be indicated to assist in recognition of rapidly growing species; most NTM grow within 2 or 3 (or more) weeks on standard solid media, while RGM can grow within 7 days.3 Colony appearance, such as smoothness and pigmentation, may aid in early speciation of some NTM, although biochemical testing is used for definitive results. Similar to adjunctive techniques used to identify and assist in drug-resistance testing in MTB, gene probing, amplification techniques, and high-performance liquid chromatography methods may be used for some species of NTM. Although drug susceptibility testing is used for some species of NTM, its predictive value for treatment outcome is often less than when dealing with MTB. Such studies should be carefully selected for the relevant species of NTM.3

HIV AND NTM While it is well recognized that disseminated MAC disease is encountered in individuals with advanced HIV disease (e.g., CD4 cell counts 90

Kir et al., 200615

79

0

39

2.5

95

Somocurcio et al., 200721

121

0

23

5

63

Alexander and Biccard, 201611

49

27

10

0

98

Shiraishi et al., 200918

56

0

16

0

95

Kang et al., 201013

72

36

15

1.4

90

Yaldiz et al., 201120

13

0

23

7.6

92

Man et al., 201216

45

0

13

0

83

Kim et al., 200614

79

23

23

1.2

72

Vashakidze et al., 201319

75

32

9

0

82

MDR-TB, multidrug resistant tuberculosis; XDR-TB, extensively drug resistant tuberculosis. Alexander GR, Biccard B. A retrospective review comparing treatment outcomes of adjuvant lung resection for drug-resistant tuberculosis in patients with and without human immunodeficiency virus co-infection. Eur J Cardiothorac Surg 2016;49(3):823–828; Kang MW, Kim HK, Choi YS, et al. Surgical treatment for multidrug-resistant and extensive drug-resistant tuberculosis. Ann Thorac Surg 2010;89(5):1597–1602; and Somocurcio JG, Sotomayor A, Shin S, et al. Surgery for patients with drug-resistant tuberculosis: report of 121 cases receiving communitybased treatment in Lima, Peru. Thorax 2007;62(5):416–421.

POSTOPERATIVE CARE In general, the care of these patients, particularly after VATS resection, is routine. Given the typical degree of pleural symphysis, along with the occasional use of an extrapleural dissection plane, the residual lung will adhere quickly following surgery to the overlying rib cage. For this reason, maintaining full lung expansion is critical early in the postoperative period to minimize “tethering” of the lung in a suboptimal position. When this occurs, reoperation may be required. Air leak is relatively common after these procedures, particularly when significant pleural adhesions are present, and is usually treated expectantly. If a significant apical space is noted postoperatively despite intraoperative measures, an apical thoracoplasty with or without myoplasty through a limited axillary incision is feasible. It is important to maintain the preoperative antibiotic regimen throughout the perioperative period. Later, as the cultures mature, modifications in the antibiotic regimen may be entertained.

OUTCOMES The outcomes of resectional surgery for MDR-TB disease are summarized in Table 85.4, which depicts results from the larger case series in the literature.11,13–21 In general, these operations, despite their complexity, may be performed with low morbidity and mortality. Some of the reported differences may be attributed to the varying patient populations, operations described, and health-care systems. Several of the series had appreciable numbers of XDR-TB patients, which would normally skew the “cure” rate lower. Despite this, favorable outcomes greater than 80% were noted in 8 of the 10 studies, seemingly a clear improvement over medical therapy alone. This impression is underlined by two recent meta-analyses22,24

and one systematic review,23 demonstrating superior outcomes for MDR-TB patients when surgery is employed. Of course, a number of biases must be recognized in all these studies, beginning with patient selection. Better study design could eliminate some, but not all of the bias; it seems unlikely that the utility of surgery will ever be tested in a randomized fashion. TABLE 85.5 Case Series, Surgery for Pulmonary NTM Disease

n.

Morbidity (%)

Mortality (%)

BPF (%)

Cure Rate (%) (Negative Sputum)

Nelson et al., 199835

28

32

7.1

3.6

88

Watanabe et al., 200637

22

NR

0

NR

95

Mitchell et al., 200834

265

23

2.6

4.2

NR

Yu et al., 201138

172

7

0

0

98

Shiraishi et al., 201336

65

12

0

0

100

Kang et al., 201532

70

21

1.4

7.1

81

Koh et al., 200833

23

35

8.7

8.7

91

NTM, Nontuberculous Mycobacteria; BPF, Bronchopleural fistula; NR, Not reported. Mitchell JD, Bishop A, Cafaro A, et al. Anatomic lung resection for nontuberculous mycobacterial disease. Ann Thorac Surg 2008;85(6):1887–1892; discussion 1892–1893; Nelson KG, Griffith DE, Brown BA, et al. Results of operation in Mycobacterium aviumintracellulare lung disease. Ann Thorac Surg 1998;66(2):325–330; Shiraishi Y, Katsuragi N, Kita H, et al. Adjuvant surgical treatment of nontuberculous mycobacterial lung disease. Ann Thorac Surg 2013;96(1):287–291; Watanabe M, Hasegawa N, Ishizaka A, et al. Early pulmonary resection for Mycobacterium avium complex lung disease treated with macrolides and quinolones. Ann Thorac Surg 2006;81(6):2026–2030; Yu JA, Pomerantz M, Bishop A, et al. Lady Windermere revisited: treatment with thoracoscopic lobectomy/segmentectomy for right middle lobe and lingular bronchiectasis associated with non-tuberculous mycobacterial disease. Eur J Cardiothorac Surg 2011;40(3):671–675; Jarand J, Levin A, Zhang L, et al. Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary disease. Clin Infect Dis 2011;52(5):565–571; and Shiraishi Y, Katsuragi N, Kita H, et al. Different morbidity after pneumonectomy: multidrug-resistant tuberculosis versus non-tuberculous mycobacterial infection. Interact Cardiovasc Thorac Surg 2010;11(4):429–432.

Similar results in patients with NTM disease have been published, at least in terms of morbidity and mortality (Table 85.5).32–38 It seems clear that results have improved over time because of better patient selection, advances in surgical technique, postoperative care, and macrolide use. Despite the encouraging results from the individual retrospective case series, there are very little data in the literature specifically examining the long-term influence of surgery in patients with NTM disease. Jarand and colleagues39 were able to demonstrate improved outcomes with the addition of surgical resection in patients with M. abscessus infection. In this report of 107 patients over a 7-year period, the inclusion of surgical therapy in selected patients, compared with medical therapy alone, resulted in significantly more culture conversion and culture negativity at 1 year (57% vs. 28%; p = 0.02). Further study is needed. One interesting finding is the high incidence of BPF in patients following NTM resection, particularly after right pneumonectomy, where rates as high as 40% have been seen.34,40 Shiraishi et al.40 reported a 10-fold increase in the BPF rate after pneumonectomy for NTM compared with MDR-TB. Numerous factors may play a role to account for this difference, such as the degree of uncontrolled infection present and the predilection for left-sided involvement in MDR-TB; as yet a solution has not been found.

SURGERY FOR COMPLICATIONS OF MYCOBACTERIAL INFECTION

HEMOPTYSIS Hemoptysis can occur during or following either tuberculosis or NTM infection in two main forms: massive (>600 cc/24 hr) and recurrent hemoptysis of varying amounts. The former is clearly lifethreatening secondary to asphyxiation; the latter, while not immediately threatening, can serve as a “sentinel” bleed heralding a subsequent tragedy. In patients presenting with hemoptysis and with a history of mycobacterial disease, every effort should be made, if possible, to diagnose recurrent disease. If active disease is found, it should be addressed prior to consideration of therapeutic resection. Unfortunately, this may not be possible in the setting of a massive bleed. In patients with significant hemoptysis, control of the bleeding is important; control of the airway is paramount. Patients can often localize the side of the bleed by symptoms, or imaging can provide clues as to the culprit lesion. The presence of a cavity, significant parenchymal damage, or “blush” indicative of alveolar blood should be sought. Bronchoscopy remains the gold standard for identifying the site of the bleed. In small volume hemoptysis, this can be achieved with flexible bronchoscopy, while in the setting of a significant bleed rigid bronchoscopy in the OR is preferred. Once the offending side is identified, the patient is positioned culprit side down, to allow dependent pooling of blood, maintaining an airway. Ultimate control of the airway is achieved with a double-lumen tube, isolating the bleeding side, although effective control may be equally achieved with the use of a bronchial blocker. Cessation of bleeding is usually spontaneous, and often occurs before presentation for medical care. Left without treatment, the risk of rebleeding approaches 80%.41 Although significant hemoptysis can be controlled with surgical resection, acute control of bleeding in the modern era is best achieved with bronchial artery embolization. High success rates of 80% to 90% are reported, and the procedure itself appears safe with minimal complications.42–45 Unfortunately, the risk of recurrent bleeding after embolization is high; one study noted a rebleed rate of almost 50% at 1 year.42 The reasons for treatment failure are controversial, but include incomplete embolization, destroyed lung or cavitary disease, fungal ball, and concomitant liver disease.46 Bronchial artery embolization should be considered as a temporizing measure, allowing for safety, further workup and treatment, and safe surgical intervention.

BRONCHIAL STRICTURE Posttubercular stricture is an unusual but well-recognized sequelae of prior endobronchial tuberculosis. Progressive fibrosis and contraction of the affected area occurs, producing narrowing of the airway lumen. This reaction may occur due to involvement of the airway wall itself, or be secondary to an adjacent nodal inflammatory process. If diagnosed, one must first rule out active endobronchial TB through biopsy. Treatment options include surgical resection, and stenting; the latter is usually reserved for diffuse disease. When considering surgical resection, both the location and the state of the lung parenchyma distal to the stenosis should be carefully examined. Focal stenoses at the lobar and segmental level may be best treated with lobectomy/segmentectomy rather than airway reconstruction. Further, if the stenosis or the original infection has left poorly functioning, bronchiectatic lung distal to the narrowing, simple resection of both the stenosis and the parenchyma may be the best option. If the lesion is focal and involves the central airway, it can be primarily resected with immediate reconstruction using standard techniques.

SUMMARY

Infection with M. tuberculosis remains an immense public health problem worldwide. The emergence of drug-resistant strains has limited the effectiveness of standard chemotherapy regimens, leading to a current re-examination of the role of surgical resection in the treatment of this disease. Contemporary outcomes combining targeted antibiotic therapy with adjunctive surgery seem superior to medical therapy alone, although direct comparison through randomized trial are lacking. In the United States and other developed countries, there is increasing recognition of the disease caused by pulmonary NTM infection, rivaling that seen with TB. The mechanisms of host susceptibility and better treatment algorithms, including the use of adjunctive surgery, continue to be explored. Thoracic surgeons should be familiar with the disease processes and the techniques available to treat these patients, and recognize the differences in the surgical treatment of infectious lung diseases compared with malignancy. REFERENCE 1. World Health Organization Global Tuberculosis Report. 2016; Available from: http://www.who.int/tb/publications/global_report/en/ 2. World Health Organization Guidelines on the management of latent tuberculosis infection. 2015; Available from: http://www.who.int/tb/publications/latent-tuberculosis-infection/en/ 3. World Health Organization End TB Strategy. 2015; Available from: http://www.who.int/tb/strategy/en/ 4. Diacon AH, Pym A, Grobusch MP, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med 2014;371(8):723–732. 5. Pontali E, Sotgiu G, D’Ambrosio L, et al. Bedaquiline and multidrug-resistant tuberculosis: a systematic and critical analysis of the evidence. Eur Respir J 2016;47(2):394–402. 6. Pym AS, Diacon AH, Tang SJ, et al. Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis. Eur Respir J 2016;47(2):564–574. 7. Gler MT, Skripconoka V, Sanchez-Garavito E, et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med 2012;366(23):2151–2160. 8. Skripconoka V, Danilovits M, Pehme L, et al. Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis. Eur Respir J 2013;41(6):1393–1400. 9. Zumla AI, Gillespie SH, Hoelscher M, et al. New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospects. Lancet Infect Dis 2014;14(4):327–340. 10. Dara M, Sotgiu G, Zaleskis R, et al. Untreatable tuberculosis: is surgery the answer? Eur Respir J 2015;45(3):577–582. 11. Alexander GR. Biccard B. A retrospective review comparing treatment outcomes of adjuvant lung resection for drug-resistant tuberculosis in patients with and without human immunodeficiency virus co-infection. Eur J Cardiothorac Surg 2016;49(3):823–828. 12. Chan ED, Laurel V, Strand MJ, et al. Treatment and outcome analysis of 205 patients with multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2004;169(10):1103–1109. 13. Kang MW, Kim HK, Choi YS, et al. Surgical treatment for multidrug-resistant and extensive drug-resistant tuberculosis. Ann Thorac Surg 2010;89(5):1597–1602. 14. Kim HJ, Kang CH, Kim YT, et al. Prognostic factors for surgical resection in patients with multidrug-resistant tuberculosis. Eur Respir J 2006;28(3):576–580. 15. Kir A, Inci I, Torun T, et al. Adjuvant resectional surgery improves cure rates in multidrug-resistant tuberculosis. J Thorac Cardiovasc Surg 2006;131(3):693–696. 16. Man MA, Nicolau D, Surgical treatment to increase the success rate of multidrug-resistant tuberculosis. Eur J Cardiothorac Surg 2012;42(1):e9–e12. 17. Pomerantz BJ, Cleveland JC Jr, Olson HK, et al. Pulmonary resection for multi-drug resistant tuberculosis. J Thorac Cardiovasc Surg 2001;121(3):448–453. 18. Shiraishi Y, Katsuragi N, Kita H, et al. Aggressive surgical treatment of multidrug-resistant tuberculosis. J Thorac Cardiovasc Surg 2009;138(5):1180–1184. 19. Vashakidze S, Gogishvili S, Nikolaishvili K, et al. Favorable outcomes for multidrug and extensively drug resistant tuberculosis patients undergoing surgery. Ann Thorac Surg 2013;95(6):1892–1898. 20. Yaldiz S, Gursoy S, Ucvet A, et al. Surgery offers high cure rates in multidrug-resistant tuberculosis. Ann Thorac Cardiovasc Surg 2011;17(2):143–147. 21. Somocurcio JG, Sotomayor A, Shin S, et al. Surgery for patients with drug-resistant tuberculosis: report of 121 cases receiving community-based treatment in Lima, Peru. Thorax 2007;62(5):416–421. 22. Fox GJ, Mitnick CD, Benedetti A, et al. Surgery as an adjunctive treatment for multidrug-resistant tuberculosis: an individual patient data metaanalysis. Clin Infect Dis 2016;62(7):887–895. 23. Kempker RR, Vashakidze S, Solomonia N, et al. Surgical treatment of drug-resistant tuberculosis. Lancet Infect Dis 2012;12(2):157–

166. 24. Marrone MT, Venkataramanan V, Goodman M, et al. Surgical interventions for drug-resistant tuberculosis: a systematic review and meta-analysis. Int J Tuberc Lung Dis 2013;17(1):6–16. 25. Falzon D, Schünemann HJ, Harausz E, et al. World Health Organization treatment guidelines for drug-resistant tuberculosis, 2016 update. Eur Respir J 2017;49(3):1602308. 26. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175(4):367–416. 27. Cassidy PM, Hedberg K, Saulson A, et al. Nontuberculous mycobacterial disease prevalence and risk factors: a changing epidemiology. Clin Infect Dis 2009;49(12):e124–e129. 28. Nahid P, Dorman SE, Alipanah N, et al. Official American thoracic society/centers for disease control and prevention/infectious diseases society of America clinical practice guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis 2016;63(7):e147– e195. 29. Krasnov D, Krasnov V, Skvortsov D, et al. Thoracoplasty for tuberculosis in the twenty-first century. Thorac Surg Clin 2017;27(2):99– 111. 30. WHO. The Role of Surgery in the Treatment of Pulmonary TB and Multidrug- and Extensively Drug-Resistant TB. Copenhagen: WHO Regional Office for Europe; 2014. 31. Levin A, Sklyuev S, Felker I, et al. Endobronchial valve treatment of destructive multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2016;20(11):1539–1545. 32. Kang HK, Park HY, Kim D, et al. Treatment outcomes of adjuvant resectional surgery for nontuberculous mycobacterial lung disease. BMC Infectious Diseases 2015;15:76. 33. Koh WJ, Kim YH, Kwon OJ, et al. Surgical treatment of pulmonary diseases due to nontuberculous mycobacteria. J Korean Med Sci 2008;23(3):397–401. 34. Mitchell JD, Bishop A, Cafaro A, et al. Anatomic lung resection for nontuberculous mycobacterial disease. Ann Thorac Surg 2008;85(6):1887–1892; discussion 1892–1893. 35. Nelson KG, Griffith DE, Brown BA, et al. Results of operation in Mycobacterium avium-intracellulare lung disease. Ann Thorac Surg 1998;66(2):325–330. 36. Shiraishi Y, Katsuragi N, Kita H, et al. Adjuvant surgical treatment of nontuberculous mycobacterial lung disease. Ann Thorac Surg 2013;96(1):287–291. 37. Watanabe M, Hasegawa N, Ishizaka A, et al. Early pulmonary resection for Mycobacterium avium complex lung disease treated with macrolides and quinolones. Ann Thorac Surg 2006;81(6):2026–2030. 38. Yu JA, Pomerantz M, Bishop A, et al. Lady Windermere revisited: treatment with thoracoscopic lobectomy/segmentectomy for right middle lobe and lingular bronchiectasis associated with non-tuberculous mycobacterial disease. Eur J Cardiothorac Surg 2011;40(3):671–675. 39. Jarand J, Levin A, Zhang L, et al. Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary disease. Clin Infect Dis 2011;52(5):565–571. 40. Shiraishi Y, Katsuragi N, Kita H, et al. Different morbidity after pneumonectomy: multidrug-resistant tuberculosis versus nontuberculous mycobacterial infection. Interact Cardiovasc Thorac Surg 2010;11(4):429–432. 41. Massard G, Olland A, Santelmo N, et al. Surgery for the sequelae of postprimary tuberculosis. Thorac Surg Clin 2012;22(3):287–300. 42. Anuradha C, Shyamkumar NK, Vinu M, et al. Outcomes of bronchial artery embolization for life-threatening hemoptysis due to tuberculosis and post-tuberculosis sequelae. Diagn Interv Radiol 2012;18(1):96–101. 43. Cremaschi P, Nascimbene C, Vitulo P, et al. Therapeutic embolization of bronchial artery: a successful treatment in 209 cases of relapse hemoptysis. Angiology 1993;44(4):295–299. 44. Pei R, Zhou Y, Wang G, et al. Outcomes of bronchial artery embolization for life-threatening hemoptysis secondary to tuberculosis. PLoS ONE [Electronic Resource] 2014;9(12):e115956. 45. Shin BS, Jeon GS, Lee SA, et al. Bronchial artery embolisation for the management of haemoptysis in patients with pulmonary tuberculosis. Int J Tuberc Lung Dis 2011;15(8):1093–1098. 46. Kim SW, Lee SJ, Ryu YJ, et al. Prognosis and predictors of rebleeding after bronchial artery embolization in patients with active or inactive pulmonary tuberculosis. Lung 2015;193(4):575–581.

86 Thoracic Mycotic and Actinomycotic Infections of the Lung Patrick Kohtz ■ Michael J. Weyant Thoracic surgeons infrequently encounter fungal infections in their daily practice; however, the spectrum of clinical circumstances in which these encounters occur are quite diverse. Fungal pathogens are of two varieties, opportunistic or endemic. Opportunistic fungal pathogens, the more common of the two varieties, are virulent due to the impaired immune defenses of the host. Immunocompromised hosts are most commonly infected by the following opportunistic fungi: Aspergillus, Cryptococcus, Mucormycosis, or Pneumocystis. The endemic fungi, which commonly cause disease in normal hosts as true pathogens, are native to certain regions of a country. These are a significant clinical issue for surgeons in the Ohio and Mississippi River Valleys, where histoplasmosis is endemic in the Midwest and blastomycosis is endemic in the South and Southeast, and the Sonoran desert regions of the southwest United States, where coccidioidomycosis is endemic. Another endemic fungal pathogen less common to the United States is paracoccidioidomycosis, which is native to Central and South America, namely Brazil, Argentina, Colombia, and Venezuela. The surgeon’s role in managing these fungal infections is to assist in diagnosis, more importantly, to differentiate these fungal infections from neoplasms. Unfortunately, the incidence of severe invasive fungal infections is growing as the population of immunologically compromised patients increases. This group includes patients at the extremes of age, patients with diabetes, patients receiving corticosteroids for a variety of illnesses, organ transplant recipients, cancer patients undergoing chemotherapy, and patients with acquired immune deficiency syndrome. This places these immunocompromised patients at high risk of infection from not only the above-mentioned fungal species but also a host of other fungal pathogens. Endemic yeast infections are typically mild infections that form while in their dimorphic state. In nature these are in their mycelial form but in tissue they form spores or spherules. These spores are then inhaled by the host leading to budding yeast within the pulmonary parenchyma. Pulmonary involvement may be the primary site of infection or may be simply a component of a disseminated systemic infection. One example of a pulmonary-involving fungus originating from a different systemic site is Sporothrix, which enters the body subcutaneously and can cause pulmonary or systemic infectious manifestations. The typical presentation, distribution of involvement, and recommended treatment are strongly dependent on the specific type of fungus. Therefore, the thoracic surgeon can play a diagnostic or therapeutic role depending upon the clinical situation of either systemic fungal infection with multiple pulmonary nodules or a single solid or cavitary lesion. This chapter will discuss the different modalities to diagnose and treat patients with suspected fungal infections based upon the fungal pathogen and its proclivity to certain hosts or endemic regions.

ANTIFUNGAL MEDICATIONS Antifungal therapy, similar to antimicrobial therapy, is a field in constant evolution given the critical need for additional effective antifungal agents. A brief summary of the major categories of antifungal agents currently in clinical use, available drugs, mechanisms of action (MOA), and available formulations will be discussed below and are presented in Table 86.1. Amphotericin B is the first drug developed for the treatment of invasive fungal infections that was developed from the actinomycete Streptomyces nodosus. Amphotericin B is a polyene drug. The mechanism works by the drug binding to ergosterol, a component of fungal cell membranes, causing cell disruption. Amphotericin B is poorly absorbed by the gastrointestinal tract and is effective only via the intravenous route. The usage of amphotericin B is limited due to its significant toxicities, including hypotension, fevers, and rigors. It is limited in maximal dosing due to the possibility of significant nephrotoxicity, which is the most common reason for limiting dosing. Amphotericin B is also available in lipid formulations, which are much better tolerated with decreased nephrotoxicity, but are significantly more expensive. First-generation triazoles, including fluconazole and itraconazole, were developed in the 1990s and their MOA works by inhibiting the cytochrome P-450 enzyme. This will convert lanosterol to ergosterol in the fungal cell membrane, causing a fungistatic inhibition to growth. First-generation triazoles are generally well tolerated in both intravenous and oral formulations. First-generation triazoles still remain the first-line therapy for less severe infections but the development of resistance, due to widespread prescribing, has limited their use. The second-generation triazoles, voriconazole, posaconazole, and the investigational drug ravuconazole, appear to have significant activity against a wide range of fungi. This has resulted in their increasing role as first- and second-line therapy (Espinel-Ingroff 2001).1,2 Their primary toxicity is related to mild hepatic dysfunction. These act as inhibitors of the hepatic cytochrome P-450 enzyme and interact with other drugs such as warfarin, cyclosporine, phenytoin, and rifampicin, which can cause worse hepatotoxicity or supra-therapeutic levels of these medications. TABLE 86.1 Currently Available Antifungal Medications Class

Mechanism of Action

Available Drugs

Available Formulations

Polyenes

Bind ergosterol in cell membranes

Amphotericin B

IV (standard) or lipid formulation

First-generation triazoles

Block cell membrane synthesis by inhibiting cytochrome P-450

Fluconazole Itraconazole Ketoconazole

Oral and IV Oral and IV Oral only

Second-generation triazoles

Block cell membrane synthesis by inhibiting cytochrome P-450

Voriconazole Posaconazole Ravuconazolea

Oral and IV Oral only Oral and IV

Micafungin Caspofungin Anidulafungin

IV only IV only IV only

Echinocandins

Inhibit (1,3)-β-d-glucan synthase in the cell wall

a Currently for investigational use only.

Echinocandins are amphiphilic lipopeptides formed during the fermentation of some fungi. Echinocandins inhibit (1,3)-β-D-glucan synthase, which produces an important component of the fungal

cell wall, causing cell lysis (Candida) or fungistatic (Aspergillus).3 This target does not exist in the cell wall of Cryptococcus species, as well as human cells. The lack of presence in humans limits the drug’s toxicity, with the most common side-effects being fever, headache, and reversible hepatic enzyme elevation.

INFECTIONS IN THE NORMAL HOST COMMONLY CAUSED BY FUNGI HISTOPLASMOSIS Histoplasma capsulatum exists throughout the world but is most commonly seen in North America and Central America. In the United States, the organism is endemic in the Ohio and Mississippi River Valleys (Fig. 86.1). It is found in the soil and grows best in areas with large amounts of bird or bat guano. In fact, the fungus can thrive for years in contaminated soil even if the birds or bats are removed from the area. Large-scale studies by the US Public Health Service demonstrated over 80% of young adults from the areas surrounding the Ohio and Mississippi Rivers have a positive skin-test reactivity for histoplasmosis. It is an airborne spore and is responsible for more pulmonary infections than any other fungus. Overall, it is estimated that 3 weeks, weight loss >10% of body weight, and inability to work. Treatment for these patients is either itraconazole 400 mg daily or fluconazole 400 mg daily for 3 to 6 months. Diffuse pneumonia is treated with intravenous amphotericin B (liposomal 5 mg/kg per day or deoxycholate 0.7 to 1.0 mg/kg/day) until clinical improvement, followed by fluconazole or itraconazole, 400 mg daily for at least 1 year. Lifetime prophylaxis is reserved for chronically immunosuppressed patients after resolution of a primary infection. TABLE 86.3 Recommended Therapy for Coccidioidomycosis Based on Clinical Syndrome in Immunocompetent Patients Clinical Syndrome

Treatment

Acute syndromes Pneumonia Uncomplicated Severe infection Diffuse Disseminated disease Meningitis Nonmeningeal

None Fluconazole or itraconazole Amphotericin B followed by fluconazole for at least 12 mo

Sequelae and complications Nodules Asymptomatic, biopsy proven Enlarging or symptomatic Cavity Asymptomatic, stable Symptomatic Progressive enlargement Immediately beneath pleura Ruptured

Follow with serial CT scans Fluconazole, biopsy, or resection

Fluconazole or itraconazole for life Consider intrathecal amphotericin B Fluconazole or itraconazole for at least 1 yr, amphotericin B in severe cases until improvement May require surgical debridement

Follow with serial CT scans Fluconazole or resection Resection Resection Resection and decortication

Meningitis and disseminated disease is treated with high-dose fluconazole or itraconazole. Some cases of meningitis have used intrathecal amphotericin B. Hydrocephalus may develop, necessitating shunt placement. After coccidioidal meningitis, patients should remain on triazole therapy for life even with normal immune status.23 Vertebral column lesions, progression of lesions, or lesions in critical locations may use amphotericin B as treatment. Surgical debridement and/or bony stabilization may be required. Pulmonary nodules that are asymptomatic and stable do not require treatment. These can resolve spontaneously over 1 to 2 years. Enlarging lesions should be biopsied or resected to rule out cancer. Postoperative antifungal therapy is not required if a pulmonary lesion is completely resected. Cavities remaining after 2 years are unlikely to resolve. Enlarging cavities or those immediately beneath the pleura are given consideration for resection in good surgical candidates. Symptomatic cavities can be treated with oral fluconazole, but stopping therapy often leads to recurrence. Many of these patients benefit from surgical resection. Other surgical indications include cavities causing hemoptysis and rupture of a cavity. Cavity rupture with resulting pyopneumothorax is best treated by decortication and resection of the cavity in appropriate surgical candidates. Postoperatively, patients should be treated with fluconazole. Developing a vaccine for the prevention of coccidioidomycosis is an ongoing effort in endemic areas. This is a reasonable target for vaccination given the large number of infected patients (estimated at over 150,000 annually) and the potential severity of infection, even in patients with a normal immune system.21

Development of a recombinant vaccine against specific antigens will hopefully show benefit in clinical trials.24

INFECTIONS IN IMMUNOCOMPROMISED HOSTS COMMONLY CAUSED BY FUNGI ASPERGILLOSIS Aspergillosis is caused by many different species of the pigmented mold Aspergillus. This fungus is considered an opportunistic pathogen, with the majority of significant infections occurring in immunosuppressed patients. Aspergillus fumigatus causes over 90% of invasive disease in Aspergillosis. Other species of Aspergillus are considered emerging pathogens and are discussed in more detail later. The mold is inhaled as very small conidium. Lower respiratory symptoms are predominant because these spores are small enough to bypass the normal defense mechanisms of the upper airways, including both the physical and mucous barriers. Macrophages are the first line of defense, with a significant contribution of cellular immunity, explaining why this type of fungal infection is so common among immunosuppressed patients. The conidia will grow into the angioinvasive filamentous form once established in tissue, which can result in local pulmonary parenchymal invasion and destruction (Fig. 86.14). There are three common clinical forms of aspergillosis: allergic bronchopulmonary aspergillosis, aspergilloma, and invasive pulmonary aspergillosis. Allergic bronchopulmonary aspergillosis is a hypersensitivity-type reaction most often seen in patients with underlying asthma or cystic fibrosis. Patients report fever, episodic wheezing, pleuritic chest pain, and sputum production with brown plugs. The radiologic appearance can vary based on the clinical stage. In the early stages a normal appearance is common to fleeting pulmonary infiltrates during acute exacerbations to central bronchiectasis in the later stages. Chest CT often demonstrates thickened and inflamed bronchi. Eosinophilia is common and positive to skin-test reactivity to Aspergillus fumigatus antigens. Lung biopsy is rarely required to rule out malignancy, as clinical suspicion and laboratory testing are usually sufficient for diagnosis. Bronchiectasis can be prevented by early treatment with corticosteroids. A marker for treatment response to steroids is serum IgE levels.25 Long-term low-dose steroids are used to prevent relapse in most patients. Steroid requirements may be reduced using antifungal therapy with itraconazole or voriconazole.26

FIGURE 86.14 Aspergillus fumigatus organisms in tissues. A: Resected lung carcinoma lesion containing small colony of aspergilli, with mycelia radiating outward from the darker center of the colony (original magnification ×250). (Reprinted from Takaro T. Lung infections and interstitial pneumonopathies. In: Sabiston DC, Spencer FC, eds. Gibbon’s Surgery of the Chest. Philadelphia: Saunders, 1976. Copyright © 1976 Elsevier. With permission.) B: Fragmented, coarse, septate mycelia of A. fumigatus. Cross-section view of mycelia are the round bodies slide (Gomori’s stain, original magnification ×950). (From Takaro T. Thoracic actinomycetic and mycotic infections. In: Goldsmith HS, ed. Practice of Surgery. New York: Harper & Row; 1978. Copyright © Harry S. Goldsmith. With permission.)

The most common form of aspergillosis is the aspergilloma, or fungus ball. Aspergilloma forms by colonizing a preexisting pulmonary cavity (Fig. 86.15). The preexisting cavity can be formed from various infectious causes, sarcoidosis, or cavitary malignancies. Tuberculosis is the most common cause of cavities containing aspergillomas. The fungus ball has a classic radiologic “air crescent sign” due to it being mobile within the cavity and not completely filling the cavity’s space. The fungus rarely invades the surrounding lung tissue or blood vessels; however, chronic irritation can lead to hemoptysis, which is the most common symptom. Hemoptysis is usually mild but occasionally it can be severe or life-threatening. Most patients will have positive serum antibodies to Aspergillus; however, sputum cultures are only positive 50% of the time.27 Aspergilloma is most often treated only when symptoms develop, usually hemoptysis. Antifungals typically do not achieve any significant therapeutic levels in aspergillomas due to lack of blood supply. Patients with significant hemoptysis or lesions close to major vessels are treated by surgery with resection of cavitary lesions. Occasionally, massive hemoptysis can be temporized with bronchial artery embolization, but there is a high risk of rebleeding due to the rich collateral network surrounding these lesions.

FIGURE 86.15 Aspergilloma (fungus ball) that developed in an old cavity originally caused by tuberculosis. Arrows are demonstrating radiolucent space between fungus ball and cavity wall.

Simple aspergillomas arising in thin-walled cavities with little surrounding disease can have a surgical resection of either wedge resection, segmentectomy, or lobectomy. Complex aspergillomas with

thick-walled cavities and surrounding lung with active disease often require more extensive resection, including lobectomy, bilobectomy, and occasionally pneumonectomy. In a report of 90 procedures performed for aspergilloma, Kim et al. had variable resections based on the extent of aspergillomas (simple vs. complex). They were able to perform only a wedge resection for 38% of simple aspergillomas and 20% of complex aspergillomas.28 Lobectomy was required in 50% of simple aspergillomas and 59% of complex aspergillomas. Pneumonectomy was never performed in simple aspergillomas, but needed in 4% of complex aspergillomas. Postoperative complications were more likely to occur in complex aspergillomas, including prolonged air leak (15%), residual pleural space (10%), and empyema (3%). Long-term follow-up showed no difference between simple and complex aspergilloma patients, with a 10- and 15-year actuarial survival of 80%. Two other series of similar size reported their outcomes for surgical resection of aspergilloma. Regnard et al. reported 87 patients with a slightly lower rate of lobectomy (41%) and a slightly higher rate of pneumonectomy (11%).29 They also performed a large number of cavernostomies (19%) for patients not felt to be candidates for resection owing to underlying pulmonary disease. They noted a high operative blood loss (>1,500 mL) in 40% of pneumonectomy patients and 22% of lobectomy patients. They also had a high rate of residual pleural space issues and prolonged air leak after lobectomy. Severely ill patients may benefit from cavernostomy due to a low rate of complications. Babatasi et al.30 reported 85 procedures with a similar distribution of pulmonary resections. Prolonged air leak and significant hemorrhage were the most common complications. Unlike the previous group, Babatasi et al. reported a significant complication rate after cavernostomy regarding prolonged air leak (50%) and hemorrhage (12%). Perioperative morbidity and mortality are most dependent on the patient’s underlying pulmonary function and their ability to tolerate resection, as well as other patient factors such as nutritional and overall functional. The risks and benefits of resection must be carefully considered given the high complication rates, especially for complex aspergillomas. The symptoms of chest pain, cough, and hemoptysis are considered significant enough to merit the risk of resection. Careful operative planning is necessary and consideration should be given to preoperative embolization of large collateral vessels. The risk of complications can be decreased with intrathoracic transposition of chest wall muscle to fill large resulting pleural spaces. Long-term outcomes are typically excellent and show a low risk of recurrence, proving the majority of cases outweigh the up-front risks of resection. Invasive pulmonary aspergillosis is the final and most severe form of aspergillosis, occurring primarily in immunocompromised patients, with neutropenia being the most important risk factor. Clinical presentation is variable and often nonspecific, with fever, cough, pleuritic chest pain, and hemoptysis. The first presentation can be due to neurologic symptoms from a disseminated infection. Radiographic findings range from nodules or cavitary lesions to diffuse infiltrates and small nodules (90% mortality.

ZYGOMYCOSIS Zygomycosis, previously known as mucormycosis, is of the fungi class Zygomycetes that cause a unique group of fungal infections. This class includes the orders of Entomophthorales and Mucoraceae, which was the origin of the name mucormycosis. Each order contains multiple species capable of causing human disease. Zygomycosis is a common disease in immunocompromised patients and those with diabetes (diabetic ketoacidosis). It is characterized by a rapidly evolving clinical picture leading to prominent tissue destruction, vascular invasion, and thrombosis. Zygomycetes are found widely distributed in soil and decaying organic matter. These spores are inhaled, becoming lodged in the nasal and sinus passages or the lungs and under normal conditions they are killed by macrophages. The spores will germinate into hyphae if macrophage function is impaired. It is the hyphae that cause extensive tissue invasion and destruction (Fig. 86.16). Neutrophils become the primary defense system once these organisms are in the hyphal form.34 Invasive infection occurs when these normal defense mechanisms are interrupted. Zygomycosis is classically associated with several patient groups. Diabetic patients, especially those in the setting of ketoacidosis, are most commonly associated with zygomycosis. Neutrophil defense functions have been shown to be inhibited by low serum pH. Zygomycosis has also been reported in other forms of metabolic acidosis, suggesting a role of serum pH in pathogenesis.35 Patients with high serum iron levels (normally the majority of iron is bound to plasma proteins) and those undergoing treatment with iron chelation medications (e.g., deferoxamine) are more susceptible to zygomycosis infection. This is due to the order of fungi Mucorales having the ability to acquire iron from the host or binding iron-deferoxamine complexes directly, directly aiding in their growth.36 Other susceptible patient groups include those undergoing bone marrow transplantation or patients with hematologic malignancies, especially leukemia.

FIGURE 86.16 Zygomycosis with broad-based, non-septate hyphae invading tissue.

Zygomycosis has two common clinical presentations. Sinus and rhinocerebral zygomycosis is the most common form. Two-thirds of patients have diabetes as the predisposing risk factor preceding infection.37 Symptoms begin with facial pain, unilateral headache, swelling, sinusitis, and bloody nasal discharge. This can rapidly progress to local tissue necrosis, including the nose, sinuses, facial bones, eyes, and brain. Pulmonary disease is most common in neutropenic patients undergoing bone marrow transplantation or those with hematologic malignancies. Patients present in a similar fashion when compared to other fungal pneumonias, usually with fever and pulmonary infiltrates refractory to broad-spectrum antibiotics. Zygomycete infection has a rapid course and can invade across anatomic boundaries. Infection can directly invade the chest wall, pericardium, SVC, and other surrounding structures. The infection can lead to pulmonary vascular invasion, infarction, and extensive tissue necrosis. Radiologic findings will show up to one-quarter of patients having unilateral multilobar or bilateral disease, with the characteristic findings of infiltrates, consolidation, and cavitary lesions.38 Immunocompetent hosts more commonly present in the subacute form of zygomycosis.39 Other systemic sites of infection can also be seen, including gastrointestinal, disseminated, and cutaneous diseases. Treatment consists of three key components: reversal of the underlying predisposing condition, antifungal therapy, and aggressive surgical debridement. Early diagnosis and aggressive therapy is the key to all forms of treatment of zygomycosis. This disease is rapidly progressive and once disseminated disease develops it is almost uniformly fatal. In the acute setting, diabetic ketoacidosis must be promptly corrected. Antifungal therapy has been shown to be ineffective for neutropenic patients, which is worrisome given they are at high risk for zygomycosis. Granulocyte-macrophage colony-stimulating factor (GMCSF) promotes rapid recovery of neutrophil numbers and function, playing a significant role in the treatment of these neutropenic patients.40 Transplant patients undergoing immunosuppression should have their immunosuppression therapies decreased or held, especially corticosteroids, until the fungal infection can be controlled. Antifungal therapy has traditionally consisted of high-dose, liposomal amphotericin B (non-CNS

involvement 5 mg/kg per day, CNS involvement 10 mg/kg per day).41 Duration of therapy should be continued until all symptoms have resolved, but no definite recommendations for duration are established. Widespread fungal prophylaxis with various azoles (i.e., fluconazole, voriconazole, itraconazole) for immunosuppressed patients has been implicated in the increased incidence of this disease because these azoles have not shown significant activity against zygomycetes. One exception is posaconazole, which has been shown to have significant clinical activity against Zygomycetes, although not as much as amphotericin B.42 Patients refractory to or intolerant of amphotericin B may use posaconazole (200 mg four times daily or 400 mg twice daily) as an acceptable alternative therapy or as salvage therapy if failure to treat with amphotericin B.41 Surgical debridement is the third important component of treatment against zygomycosis. Surgical lung resection can provide a significant survival benefit if it can clear the involved areas of lung, usually when the disease is isolated to a single lobe or single lung. The review by Lee et al.38 described the therapy and outcomes for 87 reported patients with isolated pulmonary zygomycosis. Thirty-four percent of those patients were felt to be surgical candidates for lobectomy or pneumonectomy. Lee and colleagues’ results for mortality were 96% in untreated patients, 55% in medically treated patients, and 27% in surgical patients. Tedder et al.43 reviewed 255 patients with pulmonary involvement with or without disseminated disease. Overall mortality in that group was 80%, while mortality among different groups varied. Disseminated disease was associated with 96% mortality, medical treatment resulted in 65% mortality, and with surgical therapy mortality was only 11%.

CRYPTOCOCCOSIS Cryptococcosis is caused by the encapsulated fungus Cryptococcus neoformans. This fungus is found worldwide with no specific geographic preference. One particularly favored environment is soil contaminated by pigeon droppings. Most adults have a serum antibody to C. neoformans, indicating widespread distribution of infection among humans.44 Symptomatic cryptococcosis is rare in immunocompetent persons and more common in those with compromised cellular immunity. This suggests that normal cellular immunity is highly effective in containing the disease. Some fungal and mycobacterial infections, such as this one, can have viable fungus persist in tissue, leading to reactivation disease at a later time. Historically, cryptococcosis was considered a rare clinical entity prior to the widespread recognition of AIDS in the 1980s, with 0.001)]. In their experience, the indications for parenchymal resection were giant cysts occupying the entire lobe, multiple cysts, and an unexpandable lobe after the excision of the cyst. In addition, they observed no increase in morbidity when parenchyma-saving techniques were used for cysts occupying more than 80% of a lobe. In our opinion, while segmentectomies may be acceptable in selected cases, the decision for a lobectomy must be individualized and taken by a most experienced surgeon. The correlation between the size and the pressure of hydatid cysts may be insignificant.13 Conversely, there seems to be a significant difference between the mean cystic diameters in age groups of below and over 20 years of age. This is why young patients may carry the same risk of perforation as adults even

though they present with relatively smaller cysts. Therefore, due to the well-known anaphylactic, obstructive, and infectious risks of hydatid cyst perforation, urgent surgical removal is always necessary.13 The decision for parenchymal resection is usually taken during the operation since the evaluation of the lung should be done after the excision of the cyst. The remaining lung is often functional when bronchial secretions are suctioned and the lung is inflated with higher inspiratory pressures. For this reason, even if a cyst occupies more than 50% of the lobe, the quality of parenchyma should be evaluated before proceeding to the resection with only one important exception—a massive hemoptysis. Patients with major hemoptysis, but without a preoperative definitive diagnosis, may undergo a lobectomy yielding a final pathologic result of hydatid disease. In addition, parenchyma-sparing procedures may be more complicated in case of a major hemoptysis. In our experience, two patients required a lobectomy due to massive hemoptysis whereas in additional two patients, a lobectomy was necessary due to intrapulmonary arterial hydatid disease. Even if it has not been mentioned in the literature, intrapulmonary arterial migration of the cysts that have strong attachments to pulmonary arterial intima and wall and are located at the distal part of the pulmonary arterial system may require a segmental or lobar resection (Fig. 87.13). If the intrapulmonary arterial dissection of the hydatid cysts does not reveal high-quality backflow due to an obstruction of the distal pulmonary artery (which is an important finding in our experience), a resection may be mandatory considering segmental resection as the first option. The preferred surgical methods in our clinic are enucleation, cystotomy, and capitonnage. We consider the enucleation technique if the dissection plane is clearly demarcated without strong adhesions, which possibly decreases the risk of rupture of the cyst (Fig. 87.14). In general, however, we perform cystotomy and aspiration. We prefer to aspirate the fluid in the cyst using a three-way stopcock attached to a 50 mL syringe and a line (Fig. 87.15A). The aspirated fluid is excreted to a bottle outside the operating field via the line (Fig. 87.15B). When the cyst is decompressed and the tension relieved, the parenchyma covering the cyst is incised and the endocyst is removed without causing spillage (Fig. 87.15C). If the cyst is located at the periphery of the lung, this procedure may be performed with VATS. In short, the contemporary surgical trend is to manage the disease with conservative surgical procedures.

FIGURE 87.13 Distal intrapulmonary arterial migration of the cysts may require anatomical resection. Our cystectomy trials from distal pulmonary arteries did not provide a backflow from the arteries due to strong attachments to pulmonary arterial intima. Then the smallest anatomical resection should be considered.

FIGURE 87.14 The enucleation technique is considered if the dissection plane is easy without strong adhesions, which possibly decreases the risk of rupture of the cyst.

Selection for the Obliteration of the Pericystic Cavity Cystotomy with capitonnage has been the most commonly performed procedure for the past 60 years with acceptable cure rates and perioperative morbidity. The literature suggests that capitonnage has been performed since 1952 with the intention to decrease the rate of empyema and postoperative prolonged airleak. However, this view has been questioned by several groups. In fact, capitonnage is reported to cause incomplete lung expansion and facilitate atelectasis.51 Unfortunately, some of those who perform only closure of the bronchial openings without a capitonnage have failed to produce better results. Accordingly, we and many authors still think that capitonnage should not be abandoned when treating deeply located intraparenchymal HCD. In this context, meticulous surgical technique is mandatory to avoid inadvertent obliteration of the neighboring bronchi. However, we prefer to close the bronchial openings only without capitonnage if the cyst is located at the fissural and diaphragmatic surfaces of the lungs.

FIGURE 87.15 A–C: Videothoracoscopic application of the technique. We prefer to perform cystotomy and aspiration. The fluid in the cyst is aspirated from the closest part of the cyst to the visceral pleura via the help of a three-way stopcock attached to a 50 ml syringe and a line (A). The aspirated fluid is excreted to a bottle outside the operating field via the line (B). When the cyst is decompressed and the tension is relieved, the parenchyma covering the cyst is incised and the endocyst is removed without causing spillage (C).

FIGURE 87.16 After closure of bronchial openings with prolene 4/0 sutures, capitonnage is performed. The healthy edges are approximated.

Some surgeons prefer to use combinations of different techniques. For example, enucleation (Ugon’s method) can be modified with Barrett’s technique. In this modified technique, the hydatid cyst is exposed via a thoracotomy at the sixth intercostal space. An incision is made on the overlying parenchyma and the cyst is carefully dissected bluntly while the walls of the cavity are gently retracted, the lungs are ventilated, and the cyst delivered with positive pressure ventilation. The bronchial openings are then sutured, the cyst walls are buttressed together, and the healthy edges of the parenchyma are reapproximated (Fig. 87.16). The original idea of avoiding capitonnage comes from Saidi’s study.52 The author maintained that, after the closure of the bronchial openings, the approximation of the cavity is not necessary because the cavity is later obliterated by the pulmonary parenchyma and the pleura. Turna et al.51 studied 34 patients with intact and 37 patients with complicated cysts. He compared capitonnage versus non-capitonnage in both complicated and uncomplicated cysts and demonstrated that capitonnage provided no advantage over the bronchial opening closure–only method. Sonmez and colleagues53 compared eight patients with capitonnage to seven patients without capitonnage and concluded that capitonnage patients have a shorter postoperative stay and a shorter duration of air leaks. Kosar et al.54 replicated the same results on 60 patients and confirmed that capitonnage was superior to non-capitonnage. A single randomized clinical trial on patients with intact cysts has demonstrated that capitonnage yields lower complication rates and should be the preferred approach in patients with uncomplicated hydatid cysts.55 In the largest experience accumulated on 308 consecutive patients treated over 17 years, cystotomy with capitonnage was associated to a low complication rate. The authors reporting on this large series recommended to limit lung resection to patients with parenchymal destruction due to chronic infection.56 It is worth emphasizing that capitonnage may cause tears and laceration in the inflamed wall of pericystic lung tissue; in turn, this

may generate infection and disruption of the sutures of capitonnage, causing prolonged air leak and empyema.57

FIGURE 87.17 Chest CT of a patient with massive hemoptysis which revealed to be a HCD.

FIGURE 87.18 Bronchoscopy may or generally may not show any sign of HCD.

UNCOMMON SCENARIOS AND TREATMENT MODALITIES Massive Hemoptysis Patients may present with severe hemoptysis. An emergency chest CT may demonstrate a parenchymal mass, often without any sign of hydatid disease (Fig. 87.17). An emergency bronchoscopy should be

performed in the operating room readied to continue emergency surgery (Fig. 87.18). As a rule, these patients require a lobectomy. If a pneumonectomy is required, the most experienced surgeon should take over and, by isolating the main pulmonary artery and the pulmonary veins of the ipsilateral side, open the cavity, repair the bronchial openings and the artery through the cyst cavity, and perform the appropriate arterial treatment.

FIGURE 87.19 The lung should be separated from diaphragm. The liver should be repaired by the liver surgeon or a drainage system should be reconstructed through the abdominal wall. Catheters for drainage of bile should be replaced over the dome of the liver and under the diaphragm before the diaphragmatic closure and appropriate lung resection are performed.

Cysts in the Pulmonary Artery (in the Main and Small Vessels) Cysts may migrate to the main pulmonary artery and cause embolism-like symptoms. In this setting, often a pulmonary angio-CT is diagnostic. In endemic regions, dyspnea with HCD in the lung parenchyma may be a sign for the need of an evaluation of the pulmonary arterial system. Operative planning requires cardiopulmonary bypass techniques and generally performed by the cardiac pulmonary thromboendartectomy teams. When the migrated cyst is located at the periphery of the lung in the pulmonary artery, parenchyma-saving procedures like arteriotomy and enucleation of the cyst may or may not work. At this point, lung resections may be required. Liver Complicated Cysts Causing Bronchobiliary Fistula Bronchobiliary fistula is an abnormal communication between the biliary and bronchial tree. It may occur

as a natural complication of liver HCD and after a liver surgery for various reasons including hydatid disease of the liver.58 Bilioptysis is the most common and prominent sign in this condition. Other possible signs are cholangitis, jaundice, and cutaneous fistula.59 Bilioptysis is an uncommon finding that may cause septic or chemical injuries to the lung. The most important procedure is to stop the communication between the lung and liver. Due to the increased bile pressure and negative suction pressure of the ipsilateral thoracic cavity, bile flows toward the lung. The amount of bile secreted from the liver is 620 mL/day. The lung should be isolated from the bile flow either by ERCP or percutaneous techniques. ERCP shows the obstruction in the bile system and the leak. Possible techniques to overcome the obstruction are sphincterotomy alone or in combination with stenting. Octreotide may be used as an adjunct to endoscopic treatment.60 When the sepsis is recovered, the lung should be separated from diaphragm. The liver should be repaired by the liver surgeon or a drainage system should be reconstructed through the abdominal wall. Drains should be placed over the dome of the liver and under the diaphragm before the diaphragmatic closure and the appropriate lung resection (Fig. 87.19). The drains should be removed when bile drainage has completely ceased.

PARAGONIMIASIS Paragonimiasis or lung fluke is a food-borne parasitic subacute or chronic infection most commonly caused by Paragonimus westermani and other Paragonimus (P) species. Although more than 40 species have been identified, P. miyazaki, P. uterobilateralis, P. africanus, P. mexicanus, and P. kellicotti are the other common pathogens causing human lung paragonimiasis.61 The disease affects an estimated 22 million people annually worldwide. Paragonimiasis is rarely seen in Europe or the United States whereas it is common in East Asia, particularly in Japan, Korea, China, Taiwan, and the Philippines, and in some parts of Latin America and Africa. In the late 1950s, more than 300,000 people were infected with the disease. However, with mass screening programs and treatment campaigns, the number of infected people has decreased. In the 1980s and 1990s, a gradual increase was observed. Among the reemergent cases, the most common source of infection was the raw flesh of crab-eating mammals like wild boar.62 Humans become infected by consuming raw or undercooked crab meat or crayfish that contain metacercariae of the Paragonimus species. Considering the increase in Asian restaurants in Europe and North America and international travel, more patients with the infection may be expected.

THE LIFE CYCLE OF PARAGONIMUS The metacercariae excyst in the duodenum of the definitive host penetrates through the intestinal wall into the peritoneal cavity and then migrates through the diaphragm and pleura into the lungs, where they become encapsulated and develop into mature adults (7.5 to 12 mm by 4 to 6 mm). This migration process takes several weeks. They can live in the lungs for many years.63,64 The worms can also penetrate into the other organs and tissues, such as the brain and striated muscle. This situation is called extrapulmonary paragonimiasis. The time from infection to oviposition is 65 to 90 days. Infection may persist for 20 years in humans and harbor in some animals like pigs, dogs, and a variety of feline species. The eggs of the paragonimiasis are excreted unembryonated in the sputum or are alternately swallowed and passed with stool. In the external environment, the eggs become embryonated, and the miracidia hatch and seek the first intermediate host, which is a snail, and penetrate into its soft tissue. Miracidia experience several developmental stages inside the snail as sporocytes and redia, which give rise to many cercariae that

emerge from the snail. The cercariae invade the second intermediate host, a crab or crayfish, where they encyst and become metacercariae. This is the infective stage for the mammalian host. Infection of the final host occurs through the consumption of the flesh of raw crayfish or freshwater crabs contaminated with the metacercariae. When the second intermediate hosts are ingested by mammalian hosts such as wild pigs and boars, juvenile worms excysted from the metacercariae migrate into the muscles of the host where they can remain in an immature state for many years (Fig. 87.20).

FIGURE 87.20 The life cycle of P. westermani.

SYMPTOMS AND FINDINGS Symptoms of paragonimiasis are related to the migration and maturation of the parasite. Typical symptoms of paragonimiasis are similar to those of other common infections of the lung, including fever, chest pain, chronic cough, and hemoptysis. Patients with pulmonary paragonimiasis may present with cough (70%), hemoptysis (35%), and dyspnea (17%). Other symptoms such as a low temperature grade fever (22%), subcutaneous tumors (9%), and diarrhea (4%) are also reported. Physical examination is not diagnostic. However, interestingly, a slow-growing mobile nodular lesion in subcutaneous tissue of the abdominal or anterior chest wall is characteristic in cases of subcutaneous paragonimiasis. If the lesion occurs in the brain, seizures, hemiplegia, and encephalitis may occur. Taking the history of the patient’s eating habits is more characteristic and important than the physical examination. Chest x-ray findings are not unique to the paragonimiasis but they should be considered in patients who live in the endemic areas or visit the endemic zone and may include pleural effusion, pneumothorax, empyema, pleural thickening, patchy infiltration of the lung, nodular or cavitating opacities, and fluid-filled cysts. A combination of the abovementioned findings may be seen.65 Eosinophilia (>500/mm3) is variably present and may be higher in

patients with pleural involvement compared to those with only lung involvement. Peripheral blood eosinophilia may be seen at a rate of 56% of the patients with pulmonary paragonimiasis. Total white blood cell count may be in a normal range. High serum IgG titer for paragonimiasis is strongly detected and some patients (73.1%) show positive reactions on intradermal skin testing for P. westermani.66,67 There is often a delay in the diagnosis due to the rarity of the disease and nonspecific nature of presenting symptoms in areas other than the endemic zone. Chest CT findings are more specific, being single or multiple nodules in pleura or lung parenchyma. Mukae et al.68 report that patients with P. westermani present with a wide variety of CT findings and high frequency of solitary pulmonary nodular lesions mimicking tuberculosis, fungal infections, and lung cancer.68 In CT scans nodules may be located near bronchioles or bronchi, predominantly in the subpleural region, occasionally accompanied by ectatic changes in the bronchi. Mediastinal lymphadenopathies may accompany the CT findings. Pleural lesions such as pleural effusion or pneumothorax are also often observed in infected patients. Forty-eight percent of patients are reported to have CT evidence of pleural effusion.69 Pleural effusion is reported to be a more common finding in Japan (70%) and in Korea (61%).69,70 In short, CT findings may be as follows: worm cysts, migration tract, peripheral density, bronchial wall thickening, and centrilobular nodules in the lung are demonstrated by high-resolution CT. Prolonged bronchial inflammation may contribute to the development of bronchiectasis. Differential diagnosis should include lung cancer, tuberculosis, mesothelioma, and metastatic lung malignancy.

DIAGNOSIS Definitive diagnosis is based on the presence of the eggs in sputum samples, bronchoalveoler lavage obtained by bronchoscopy, transthoracic needle aspiration biopsy, or open biopsy of the suspected lesions. However, the rate of presence of P. westermani in sputum, stool, and pleural fluid is reported to be 12.5%, 7.4%, and 9.1%, respectively.71–74

IMMUNOLOGIC TESTS Because of the low detection rate of the eggs, various immunologic methods have been developed for the diagnosis of paragonimiasis. Intradermal tests have been replaced by the more sensitive ELISA technique because the intradermal tests may remain positive for many years. The immunoblot assay was developed as a more sensitive test for diagnosing paragonimiasis. Kim and colleagues report that ELISA using recombinant P. westermani yolk ferritin has 88.2% sensitivity and 100% specificity, with the limitation of not being useful at the migratory stage.75 In the setting of the differential diagnosis of paragonimiasis, it is not uncommon to be forced to request a PET-CT for the diagnostic evaluation of a solitary pulmonary nodule.76

TREATMENT Praziquantel is generally considered the preferred treatment. In addition to praziquantel, pleural drainage of the pleural effusions should be considered. The cure rate for paragonimiasis oscillates between 75% and 90%.66

AMEBIASIS Amebiasis, one of the most common infections in the world, has been claimed to infect more than 50 million patients each year, with up to 100,000 deaths per year.77 The ingestion of mature Entamoeba histolytica (EH) cysts cause infection. Generally, fecally contaminated food, water, and hands are the source of infection. Stomach acids induce encystation and trophozoites are released into the small intestine. Trophozoites increase in number by binary fission and produce cysts, which may be found in feces (Fig. 87.21). Cysts can survive outside the body from weeks to months because they have chitinous cell walls. Trophozoites, which pass outside the body via diarrheal stools, die when outside the body. They can remain in the intestinal lumens of asymptomatic carriers; cysts are carried outside the body via stool. When trophozoites invade the intestinal mucosa, they cause intestinal disease. When they pass outside the intestine via the bloodstream, they may reach the liver, brain, and lungs.

FIGURE 87.21 The life cycle of E. histolytica.

EPIDEMIOLOGY Entamoeba histolytica (EH) exists in two forms: (1) the cyst, or the infective form, and (2) trophozoites, or the invasive form. The cystic form is excreted via stool by the infected host. The route of transmission is a fecal–oral route (Fig. 87.21). Poor hygiene and a lack of sanitary conditions are the reasons for the dissemination of the disease. The transmission may also occur via anal sexual intercourse and may be seen in homosexual men. Thus, it may also be considered a sexually transmitted disease.78 Immunosuppressed hosts may be predisposed to the invasive extraintestinal disease.79

PATHOGENESIS EH is an intestinal pathogen, but it has the capability to infest extraintestinal organs, even several years after primary infection. Following excystation in the intestines, the invasive form trophozoites occur. They can invade the colonic mucosa and cause ulcerative lesions. Trophozoites have the potential to spread hematogenously to cause extraintestinal disease. Amebic liver abscess is much more common in men than in women.80 EH galactose- or N-acetyl-D-galactosamine-inhibitable adherence lectin mediates the attachment of trophozoites to the target cells.81 Cytolysis of the target cells is mediated by an increase in free cellular calcium caused by EH. Entamoeba dispar and Entamoeba moshkovskii are other species, which are now considered pathogens since they are shown to cause intestinal and liver disease.

CLINICAL FINDINGS Amebiasis may be either acute or chronic. In the acute form, abdominal cramps, diarrhea, and tenesmus are common symptoms. The stool may contain blood. In the chronic form, bouts of constipation and diarrhea may be present. However, the presence of either acute or chronic symptoms may not occur prior to the amebic liver abscess.

DIAGNOSIS The diagnosis is established by the classical clinical findings in combination with radiologic, serologic, and microbiologic analysis. A history of diarrhea is present only in one third of patients who have extraintestinal disease. Most of the time, trophozoites or cysts cannot be demonstrated in the stool. The pus in the pleura is generally sterile unless superinfected. Serologic tests, if positive, may suggest current or previous infection. The ELISA is highly sensitive, fast, and readily available. In endemic areas, the value of this test may decrease. Polymerase chain reaction may be more valuable in the confirmation of diagnosis of amebiasis by the amplification of 16S ribosomal RNA.82 A combination of serologic tests with the detection of the parasite by antigen detection or polymerase chain reaction is the best approach to diagnosis.

AMEBIC LIVER ABSCESS (ALA) After the invasion of the colonic mucosa by trophozoites, particularly in the cecum, they are transmitted to liver via portal venous route. They lodge in the venules and cause thrombosis, followed by infarct, necrosis of liver tissue, and the formation of abscesses. This collection of necrotic liver tissue, amebae,

and white blood cells results in additional necrosis and the enlargement of abscesses. The right liver lobe is the most common side of infection. Thoracic occurrence happens after the direct extension of an ALA across the diaphragm into thoracic structures, including the lungs, pleura, and pericardial spaces. Pain in the right upper quadrant with or without fever is the most common presence. Anorexia and malaise are common findings. Blood in the stool may be present only in 25% of patients. Leukocytosis is the rule. Liver function tests may be elevated. As the parasite causes lysis, it does not form a capsule. Therefore, the abscess has a tendency to rupture, usually transdiaphragmatically to the pleural space instead of toward the infradiaphragmatic area. Thoracic Amebiasis Almost all of the thoracic complications occur due to the extension of amebic liver abscesses through the diaphragm. Most of the patients also have ALA when they are diagnosed to have thoracic amebiasis. The type of thoracic disease depends on the involved area, such as the lung, pleura, and/or pericardium. Pleural Disease ALA may produce diaphragmatic irritation and may cause pleural effusion without any infection. The incidence of sympathetic pleural effusion may be as high as 34% in patients with ALA.83 In this situation, the aspirated fluid may be sterile on culture. This condition does not require a further treatment other than the treatment of ALA. However, when the aspirated fluid is a frank empyema, then an urgent intervention is required. Frank empyema is the most common complication of ALA. In 95% of patients the empyema is on the right side. Elevation of the diaphragm, friction rub, and effusion are findings prior to the diagnosis of amebic empyema. The onset of the pleural clinical findings depends on the size of the perforation and volume of the abscess. A tearing pain sensation, pain in the ipsilateral shoulder, dyspnea, and shock may be present when the volume is high. In severe cases, sepsis, shock, respiratory failure, and death may result. In ALA, the chest x-ray shows elevated diaphragm and pleural effusion. Chest CT, ultrasonography, or MRI may show the presence of pleural fluid and liver abscess. Ameboma may mimic lung cancer if a FDG PET-CT is employed. Thoracentesis is the best diagnostic investigation. The pus is usually reddish or chocolate brown, so-called anchovy sauce. Bacteriologically, it may be sterile, and amebae may be demonstrated only in half of the abscesses. During drainage, the chest surgeon should correctly and carefully localize the liver in order not to place the drain into the liver because the diaphragm is already elevated. Secondary infection is common. Drainage with the largest possible available drain (36 F) may offer the best chance for treatment. Le Roux and colleagues84 recommend considering the drainage of the liver abscess via subcostal drainage if secondarily infected. If the treatment is delayed, a decortication procedure may be unavoidable. The mortality rate of the pleural amebiasis varies from 14% to 40% depending on the nature of the disease and the general condition of the patient. Pulmonary Amebiasis Three types of pulmonary involvement may occur in pulmonary amebiasis. The first type is transdiaphragmatic extension into the lung. The second one is metastatic disease. A potentially hypothesized third form may be the aspiration of dust containing cysts and/or trophozoites of EH. When the pleural inflammatory reaction causes adhesion of parietal and visceral pleura, a complete obliteration of the pleural space may prevent the spread of infection into the pleural space. In such cases, amebic

infection may involve the lung parenchyma, directly causing a lung abscess and broncho-hepatic fistula without violating the pleural space. The common basal segments of the right lower lobe, middle lobe, and even lingula may be involved in the infection. Chest pain may occur with nonproductive cough, which may be followed by productive reddish brown, bile-stained expectoration in large quantities. The treatment of pulmonary disease consists of postural drainage, antibiotics to prevent the secondary infection, and antiamebic therapy.83 Pulmonary involvement has a better prognosis among the other amebiasis complications compared to pleural and peritoneal rupture. A bronchobiliary fistula may develop.83 Several authors perform the lung resection and closure of the fistulous tract while others recommend draining the liver abscess via a transabdominal route.83 Quite rarely bronchiectasis may develop and the treatment may consist of either resection or follow-up. A metastatic spread is infrequently seen. It is estimated that amebic lung disease without liver involvement occurs in 14.3% of all cases with lung involvement by amebiasis.85 The symptoms are the same as other lung abscesses. An unusual case of invasive lung amebiasis is presented with superior vena cava and brain without liver involvement.86 When the abscess ruptures into the pleura, an empyema develops and sepsis may follow. The diagnosis is difficult if the amebiasis is not demonstrated in the sputum or in the pleural drainage. Treatment is similar to any lung abscess with administration of antiamebic therapy. Antiamebic Therapy Oral or parenteral metronidazole is usually effective in treating extraintestinal amebiasis. Lactoferrin and lactoferricin have been found to kill EH, and it has been suggested that they may be coadministered with a low dose of metronidazole to reduce the toxicity of metronidazole.87 Older and more toxic drugs such as emetine or dehydroemetine may be recommended for more serious and complicated situations, such as peritoneal or pericardial involvement.88 Some physicians believe that both drugs provide a more rapid clinical response than metronidazole.89 Chloroquine may be preferred for pregnant patients with a mild form of disease. These medications are more effective in extraintestinal tissue forms of amebiasis. For the treatment of intestinal infections, a course of luminal amebicide such as iodoquinol may be followed with above-mentioned medications.

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Thoracic hydatid cyst: Clinical presentation, radiological features and surgical treatment. In: Firstenberg MS, ed. Principles and Practice of Cardiothoracic Surgery. Rijeka: Intech; 2013:195. 27. Garabedian GA. Evaluation of the reactivity of hydatid whole-scolex antigen in hydatid disease serology. Ann Trop Med Parasitol 1971;65:385–391. 28. Kagan IG. Diagnostic, epidemiologic, and experimental parasitology: Immunologic aspects. Am J Trop Med Hyg 1979;28:429–439. 29. Hira PR, Shweiki H. Counter immunoelectrophoresis using an Arc-5 antigen for the rapid diagnosis of hydatidosis and comparison with the IHA test. Am J Trop Med Hyg 1987;36:592–597. 30. Poretti D, Felleisen E, Grimm F, et al. Differential diagnosis between cystic hydatid disease and other cross-reactive pathologies. Am J Trop Med Hyg 1999;60:193–198. 31. Zhang W, Li J, Mc Manus DP. Concepts in immunology and diagnosis of hydatid disease. Clin Microbiol Rev 2003;16:18–36. 32. Zhang W, McManus DP. Recent advances in the immunology and diagnosis of the echinococcosis. FEMS Immunol Med Microbiol 2006;47:24–41. 33. Carmena D, Benito A, Eraso E. Antigens for immunodiagnosis of echinococcus granulosus infection: An update. Acta Trop 2006;98:74– 86. 34. Virgino VG, Hernandez A, Rott MB. et al. A set of recombinant antigens from echinococcus granulosus with potential for use in the immunodiagnosis of human cystic hydatid disease. Clin Exp Immunol 2003;132:309–315. 35. Gonzalez-Sapienza G, Lorenzo C, Nieto A. Improved immunodiagnosis of cystic hydatid disease by using a synthetic peptide with higher diagnostic value than that of its parent protein, Echinococcus AgB. J Clin Microbiol 2000;38:3979–3983. 36. Brunetti E, Kern P, Vuitton DA; Writing Panel for the WHO-IWGE. Writing Panel for WHO-IWGE. Expert consensus for diagnosis and treatment of cystic and alveolar echinococcosis in humans. Acta Tropica 2010;114:1–16. 37. Kern P. Medical treatment of echinococcosis under the guidance of good clinical practice (GCP/ICH). Parasitology International 2006;55:273–282. 38. Dakak M, Genc O, Gurkok S, et al. Surgical treatment for pulmonary hydatosis (a review of 422 cases). R Coll Edinb 2002;47:689– 692. 39. Morar R, Feldman C. Pulmonary echinococcosis. Eur Respir J 2003;21:1069–1077. 40. Athanasiadi K, Kalavrouziotis G, Loutsidis A, et al. Surgical treatment of echinococcosis by a transthoracic approach: A review of 85 cases. Eur J Cardiothorac Surg 1998;14:134–140. 41. Taha AM, Shab B, Nassar H. Surgical therapy for pulmonary hydatosis. Int Surg 1996;81:187–188. 42. De Groot M. The role of lung resection for hydatid cysts. J Thorac Cardiovasc Surg 1998;115:262–263.

43. Parelkar SV, Gupta RK, Shah H, et al. Experience with video assisted thoracoscopic removal of pulmonary hydatid cysts in children. J Pediatr Surg 2009;44:836–841. 44. Chowbey PK, Shah S, Khullar R, et al. Minimal access surgery for hydatid cyst disease: Laparoscopic, thoracoscopic and retroperitoneoscopic approach. J Laparoendosc Adv Surg Tech 2003;13:159–165. 45. Mehta KD, Gundappa R, Contractor R, et al. Comparative evaluation of thoracoscopy versus thoracotomy in the management of lung hydatid disease. World J Surg 2010;34:1828–1831. 46. Moore RD, Urschel JD, Fraser RA, et al. Cystic hydatid lung disease in Northwest Canada. Can J Surg 1994;37:20–22. 47. Qian ZX. Thoracic hydatid cysts: a report of 842 cases treated over a thirty year period. Ann Thorac Surg 1988;46:342–346. 48. Uchlkov AP, Shipkov CD, Prisadov G. Treatment of lung hydatosis by VATS: a preliminary report. Can J Surg 2004;47:380–381. 49. Symbas NP, Aletras H. Hydatid disease of the lung. In Shields TW, ed. General thoracic surgery, 5th ed. New York: Lippincott Williams & Wilkins; 2000:1113. 50. Dincer SI, Demir A, Sayar A, et al. Surgical treatment of pulmonary hydatid disease: a comparison of children and adults. J Pediatr Surg 2006;41:1230–1236. 51. Turna A, Yılmaz MA, Haciibrahimoglu G, et al. Surgical treatment of pulmonary hydatid cysts: Is capitonnage necessary? Ann Thorac Surg 2005;13:20–23. 52. Saidi F. Surgery for Hydatid Disease. 1st ed. Philadelphia. PA: WB Saunders; 1976:186. 53. Sonmez K, Turkyılmaz Z, Demirogulları B, et al. Hydatid cyst of the lung in childhood: Is capitonnage advantageous? Ann Thorac Cardiovasc Surg 2001;7:11–13. 54. Kosar A, Orki A, Haciibrahimoglu G, et al. Effect of capitonnage and cystotomy on outcome of childhood pulmonary hydatid cysts. J Thorac Cardiovasc Surg 2006;132:560–564. 55. Bilgin M, Oguzkaya F, Akcali Y. Is capitonnage unnecessary in the surgery of intact pulmonary hydatid cysts. ANZ J Surg 2005;75:992– 996. 56. Yaldiz S, Gursoy S, Ucvet A, et al. Capitonnage results in a low postoperative morbidity in the surgical treatment of pulmonary echinococcosis. Ann Thorac Surg 2012;93:962–967. 57. Sokouti M, Golzari SE, Aghdam BA. Surgery for uncomplicated hydatid cysts: capitonnage or uncapitonnage. Int J Surg 2011;9:221– 224. 58. Loinaz C, Hernández T, Mitjavila M, et al. Biliobronchial fistula after liver surgery for giant hydatid cyst. HPB Surg 2011;2011:347654. 59. Gugenheim J, Ciardullo M, Traynor O, et al. Bronchobiliary fistulas in adults. Ann Surg 1988;207:90–94. 60. Ong M, Moozar K, Cohen LB. Octreotide in bronchobiliary fistula management. Ann Thorac Surg 2004;78:1512–1513. 61. Uchiyama F, Morimoto Y, Nawa Y. Re-emergence of paragonimiasis in Kyushu, Japan. Southeast Asian J Trop Med Public Health 1999;30:686–691. 62. Nagayasu E, Yoshida A, Hombu A, et al. Paragonimiasis in Japan: a twelve-year retrospective case review (2001–2012). Intern Med 2015;54:179–186. 63. Nakamura-Uchiyama F, Mukae H, Nawa Y. Paragonimiasis: a Japanese perspective. Clin Chest Med 2002;23:409–420. 64. Vélez ID, Ortega JE, Velásquez LE. Paragonimiasis: a view from Columbia. Clin Chest Med 2002;23:421–431. 65. Obara A, Nakamura-Uchiyama F, Hiromatsu K, et al. Paragonimiasis cases recently found among immigrants in Japan. Intern Med 2004;43:388–392. 66. Oh IJ, Kim YI, Chi SY, et al. Can pleuropulmonary paragonimiasis be cured by only the 1st set of chemotherapy? Treatment outcome and clinical features of recently developed pleuropulmonary paragonimiasis. Intern Med 2011;50:1365–1370. 67. Burton K, Yogev R, London N, et al. Pulmonary paragonimiasis in Laotian refugee children. Pediatrics 1982;70:246–248. 68. Mukae H, Taniguchi H, Matsumoto N, et al. Clinicoradiologic features of pleuropulmonary Paragonimus westermani on Kyusyu Island, Japan. Chest 2001;120:514–520. 69. Johnson RJ, Johnson JR. Paragonimiasis in Indochinese refugees. Roentgenographic findings with clinical correlations. Am Rev Respir Dis 1983;128:534–538. 70. Im JG, Whang HY, Kim WS, et al. Pleuropulmonary paragonimiasis: radiologic findings in 71 patients. AJR Am J Roentgenol 1992;159:39–43. 71. Singh TN, Kananbala S, Devi KS. Pleuropulmonary paragonimiasis mimicking pulmonary tuberculosis—A report of three cases. Indian J Med Microbiol 2005;23:131–134. 72. Meehan AM, Virk A, Swanson K, et al. Severe pleuropulmonary paragonimiasis 8 years after emigration from a region of endemicity. Clin Infect Dis 2002;35:87–90. 73. Bartlett AH, Bonnell WF, Palamountain SE. Lung nodules in a thirteen-year-old male youth. Pediatr Infect Dis J 2005;24:746–753. 74. Hirayama S, Shiraishi T, Shirakusa T, et al. Pulmonary paragonimiasis report of two cases and a review of the Japanese literature. J Bronchol 2005;12:116–118. 75. Kim TY, Joo IJ, Kang SY, et al. Recombinant Paragonimus westermani yolk ferritin is a useful serodiagnostic antigen. J Infect Dis 2002;185:1373–1375. 76. Osaki T, Takama T, Nakagawa M, et al. Pulmonary Paragonimus westermani with false-positive fluorodeoxyglucose positron emission tomography mimicking primary lung cancer. Gen Thorac Cardiovasc Surg 2007;55:470–472. 77. Roy S, Herwaldt B. Prevention of specific infectious diseases: Amebiasis. In: Arguin PPM, Kozarsky PPE, Reed C, eds. CDC Health Information for Travel 2008. Atlanta: Centres for diseases and control; 2008. 78. Kean BH, William DC, Luminais SK. Epidemic of amebiasis and giardiasis in biased population. Br J Vener Dis 1979;55:375–378.

79. Shamsuzzaman SM, Hashiguchi Y. Thoracic amebiasis. Clin Chest Med 2002;23:479–492. 80. Acuna–Soto R, Maguire JH, Wirth DF. Gender distribution in asymptomatic and invasive amebiasis. Am J Gastroenterol 2000;95:1277– 1285. 81. Ravdin JL. Entaomeba histolytica: From adherence to enteropathy. J Infect Dis 1989;159:420–429. 82. Liu CJ, Hung CC, Chen MY, et al. Amebic liver abscess and human immunodeficiency virus infection. A report of three cases. J Clin Gastroenterol 2001;33:64–68. 83. Verghese M, Kapoor R, Eggleston FC. Pleuropulmonary amebiasis. In Shields TW, Locicero J, Ponn RB, Rusch VW, eds. General Thoracic Surgery, 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:1290. 84. Le Roux BT, Mohlala ML, Odell JA, et al. Suppurative diseases of the lung and pleural space: I. Empyema thoracis and lung abscess. Curr Probl Surg 1986;23:1–89. 85. Afsar S, Choudri AN, Ali J, et al. Primary pulmonary amebiasis: an unusual cause of pulmonary consolidation. J Pak Med Assoc 1992;42:245–246. 86. Lichenstein A, Kondo AT, Visvesvera GS, et al. Pulmonary amebiasis presenting as superior vena cava syndrome. Thorax 2005;60:350–352. 87. Leon-Sicairos N, Reyes-Lopez M, Ordaz-Pichardo C, et al. Microbicidal action of lactoferrin and lactoferricin and their synergistic effect with metronidazole in Entamoeba histolytica. Biochem Cell Biol 2006;84:327–336. 88. Lal C, Huggins JT, Sahn SA. Parasitic diseases of the pleura. Am J Med Sci 2013;345:385–389. 89. Roberts PP. Parasitic infections of the pleural space. Semin Respir Infect 1988;3:362–382.

88 Lung Transplantation Robin Vos ■ G. Alexander Patterson ■ Dirk Van Raemdonck

HISTORICAL REVIEW EARLY PHASE During the early 1950s, Metras1 in France and Hardin and Kittle2 in the United States reported successful canine lung transplantation. During that decade, many surgical techniques were developed that have proved useful in human lung transplantation. Hardy and colleagues3 reported the first human lung transplantation in 1963. Although their patient succumbed after 18 days, their brief success demonstrated the technical feasibility of the operation and stimulated worldwide interest in pulmonary transplantation. During the next 15 years, about 40 clinical lung transplant operations were performed in centers around the world.4 None of these procedures was successful. The only recipient actually discharged from the hospital was a 23-year-old patient of Derom and colleagues5 in Belgium. This patient left the hospital 8 months after transplantation and died 2 months later as a result of chronic rejection, sepsis, and bronchial stenosis. Most patients in this era died within 2 weeks of lung transplantation as a result of primary graft failure, sepsis, or acute rejection. The most frequent cause of death beyond the second week was bronchial anastomotic disruption. This problem of bronchial anastomotic dehiscence stimulated the interest of investigators in a number of surgical laboratories. Lima and colleagues6 in Toronto demonstrated that high doses of corticosteroids (2 mg/kg/day), necessary for immunosuppression in that era, had an adverse effect on bronchial anastomotic healing. The same group, as reported by Morgan and colleagues,7 also demonstrated that the ischemic donor bronchus could be revascularized within a few days by a pedicled flap of omentum. The omental pedicle provided new collateral circulation to the ischemic bronchus and the omentum itself also had a potential benefit in containing an anastomotic dehiscence in the event of partial disruption. During the same interval, the new drug cyclosporine demonstrated impressive immunosuppressive properties and eliminated the routine need for early high-dose corticosteroids. Furthermore, it was also demonstrated by the Toronto group, and reported by Goldberg and colleagues,8 that cyclosporine had no adverse effect on bronchial anastomotic healing. Reitz and colleagues9 of Stanford reported initial clinical experience with combined heart–lung transplantation in patients with pulmonary vascular disease. This experience demonstrated conclusively that the transplanted human lung could provide acceptable long-term function. Yet by 1983, successful isolated lung transplantation had not yet been achieved. Satisfactory patient selection remained the final obstacle to successful clinical lung transplantation. The Toronto group reasoned that end-stage respiratory failure from pulmonary fibrosis would provide the ideal physiologic conditions for single-lung transplantation. The increased resistance to both perfusion and ventilation resulting from high pulmonary

vascular resistance and decreased compliance of the native lung, respectively, would preferentially direct perfusion and ventilation to the pulmonary allograft. By careful recipient selection and strict adherence to rigid donor criteria, Cooper and colleagues achieved the first successful single-lung transplantation in 1983 in a 58-year-old man with idiopathic pulmonary fibrosis (IPF), as reported by the Toronto Lung Transplant Group.10 The subsequent development of an experimental and clinical en bloc bilateral-lung replacement technique by Dark11 and one of us (G.A.P.) and colleagues12 enabled application of bilateral-lung replacement in patients for whom single-lung transplantation was not appropriate. Although this procedure did have the definite attraction of preservation of the recipient heart, it was technically complex and full cardiopulmonary bypass (CPB) was mandatory. Double-lung transplantation with a tracheal anastomosis was associated with a high incidence of complications, notably donor airway ischemia, as the authors described,13 and cardiac denervation, as reported by Schaefers and colleagues.14 Both lungs remained connected by a left atrial cuff, main pulmonary artery, and trachea. Full CPB was needed to implant the double-lung bloc. After a few years, this original technique was abandoned by the pioneering group and replaced by a bilateral, sequential single-lung implant technique. To overcome the high incidence of lethal tracheal anastomotic disruption with en bloc double-lung transplantation, the group in Marseille15 developed a technique of bilateral bronchial anastomosis. Other groups in Bordeaux16 and Copenhagen17 described a technique whereby the tracheal anastomosis was revascularized by connecting a donor aortic patch including the orifices of bronchial arteries, with the recipient’s aorta thereby lengthening the operative procedure. Only one team worldwide has continued to prefer this en bloc technique over sequential, single-lung implantation.18

CURRENT STATUS As a treatment strategy for end-stage lung disease, transplantation has matured significantly in the past two decades. In 1988, there were only a handful of lung transplantation programs worldwide. Currently, there are experienced lung transplant programs in most western nations. In addition, eastern nations are beginning to develop an experience as well, most notably in Japan, China, and South Korea. The International Society for Heart and Lung Transplantation (ISHLT) Registry has evolved into a major repository of data for the international lung transplant community.19 Recent figures from the ISHLT registry reproduced in Figure 88.1A demonstrate that the annual number of isolated lung transplants is still increasing reaching nearly 4,000 procedures per year, mainly double-lung transplants while the number of single-lung transplants has plateaued around about 1,000 transplants per year. The number of registered heart–lung transplants, as shown in Figure 88.1B, reached a peak in the late eighties with >200 procedures annually and has come down since then to less than 100 procedures per year as of 2003. The distribution of isolated lung transplants and heart–lung transplants by center volume and by geographic location is shown in Figures 88.2A and 88.2B, respectively. Between January 2000 and June 2014, the majority of centers (n = 155) performed less than 30 lung transplants per year while the rest (n = 44) did about two-thirds of all registered transplants. Fourteen centers performed more than 50 procedures annually accounting for 33% of all transplantations worldwide in that time period.19 Heart–lung transplantation has become a rare procedure with the majority of centers doing only 1 to 2 cases per year.

FIGURE 88.1 A: Number of isolated lung transplantations. B: Heart–lung transplantations reported by year and by procedure type to the ISHLT Registry from the beginning in early eighties until 2013. This figure includes transplants submitted to the ISHLT registry from organ-exchange organizations in countries with a data-sharing agreement and transplants reported voluntarily from centers in countries without a specific data-sharing agreement between ISHLT and the national transplant organization. Therefore this figure may not represent the total number of procedures worldwide or the trend in activity. (Reprinted from Yusen R, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report—2015; focus theme: early graft failure. J Heart Lung Transplant 2015;34(10):1264–1277. doi: 10.1016/j.healun.2015.08.014. Copyright © 2015 International Society for the Heart and Lung Transplantation. With permission.)

RECIPIENT SELECTION

GENERAL CONSIDERATIONS Selection criteria were updated in 2014 in a consensus document by the ISHLT.20 Lung transplantation should be considered for adults with chronic, end-stage lung disease who meet all the following general criteria: (1) high (>50%) risk of death from lung disease within 2 years if lung transplantation is not performed; (2) high (>80%) likelihood of surviving at least 90 days after lung transplantation; (3) high (>80%) likelihood of 5-year posttransplant survival from a general medical perspective provided that there is adequate graft function. Because lung transplantation is a complex therapy with a significant risk of perioperative morbidity and mortality, it is important to consider the overall sum of contraindications and comorbidities. Patients who have coexisting dysfunction involving another organ system, are generally not eligible for transplantation unless combined organ transplantation or concurrent CABG is feasible, a limitation that especially affects patients in older age groups. In general, transplant centers do not accept patients >65 years of age, although the upper age limit in some centers is 75 years. The ISHLT Registry lists advanced recipient age as a specific predictor of increased medium- and long-term posttransplant mortality.19 In addition, patients with a history of malignant disease within the prior 2 to 5 years are generally not eligible for pulmonary transplantation, but should be evaluated individually taking into account tumor histology, staging, and adequate treatment received. A potential exception may be a patient with biopsy proven and properly staged multifocal pulmonary lepidic predominant adenocarcinoma in situ or minimally invasive adenocarcinoma of the lung (previously called bronchioloalveolar carcinoma). In a cumulative series of 29 patients, de Perrot and colleagues21 have reported a reasonable survival somewhat lower than noncancerous patients, but with a recurrence in 45% of the patients between 5 and 49 months after the transplant. The Leuven Lung Transplant Group has recently reported on a case series of combined or serial liver and lung transplantation for metastatic epithelioid hemangioendothelioma in lung with favorable long-term outcomes up to 8 years after lung transplantation.22 Patients with serious psychological dysfunction or persistent substance abuse (including smoking) should not be considered candidates for pulmonary transplantation. Few groups evaluate patients who continue to smoke. Serious contraindications for transplantation are listed in Table 88.1.

FIGURE 88.2 Distribution of isolated lung transplantations (A); and heart–lung transplantations (B) by center volume and by geographic location from January 2009 through June 2014. (Reprinted from Yusen R, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report— 2015; focus theme: early graft failure. J Heart Lung Transplant 2015;34(10):1264–1277. doi: 10.1016/j.healun.2015.08.014. Copyright © 2015 International Society for the Heart and Lung Transplantation. With permission.)

Previous thoracic surgery such as chest tube insertion for pneumothorax, pleurodesis, and lung resection including lung volume reduction surgery (LVRS) is no longer a specific contraindication to pulmonary transplantation, although resulting adhesions and anatomic distortion do complicate a subsequent transplant procedure.23,24 Patients receiving high-dose corticosteroid therapy (≥20 mg prednisone) are not eligible for lung transplantation, as a well-documented negative influence on bronchial healing and susceptibility to postoperative infection have been demonstrated. Therefore, corticosteroid therapy should preferably be tapered before lung transplantation. However, low- or moderate-dose steroid therapy does not result in an increased incidence of bronchial anastomotic

complications. Ventilator dependence is not an absolute contraindication to transplantation. Nevertheless, recent reports have demonstrated that outcome in these patients is inferior compared to patients not on ventilation, but still better than patients in whom transplantation was not performed on time.25,26 Also, the ISHLT Registry experience identifies recipient ventilator dependence as a risk factor for increased mortality.19 Even more controversial is transplantation in selected patients bridged on extracorporeal devices for severe hypoxemia, hypercarbia, or right heart failure. As reported by Hayanga and colleagues,27 extracorporeal life support (ECLS) with extracorporeal membrane oxygenation (ECMO) is increasingly being utilized in the United States with more successes over the years although survival after the transplant is still inferior compared to other recipients. Refinements in the technology and further development of ambulatory and simplified ECLS will bring these patients in better condition until the moment of a suitable donor offer. There has been an increasing trend to avoid mechanical ventilation in patients awaiting lung transplantation and to bridge these patients using awake extracorporeal support to transplant.28 Currently, about 4% to 5% of all lung transplants are performed following awake ECMO bridging.29 TABLE 88.1 Contraindications for Lung Transplantation20 Recent history of malignancy (88% saturation Partial carbon dioxide pressure Cardiac index prior to exercise Central venous pressure prior to exercise Age Creatinine Body mass index Diabetes Functional status 6-min walk distance Continuous mechanical ventilation Diagnosis From A Guide to calculating the lung allocation score from organ procurement and transplant network. https://www.unos.org/wpcontent/uploads/unos/lung_allocation_score.pdf. Accessed April 23, 2016.

TABLE 88.3 Factors That Predict Survival After Lung Transplantation Cardiac index prior to exercise Continuous mechanical ventilation Oxygen required to maintain oxygen saturation >88% Age at transplant Serum creatinine Functional status 6-min walk distance Diagnosis From Organ procurement and transplant network. https://www.unos.org/wp-content/uploads/unos/lung_allocation_score.pdf. Accessed April 23, 2016.

SPECIFIC CONSIDERATIONS BASED ON DIAGNOSIS Disease-specific guidelines for referral, as defined by the pulmonary council of the ISHLT, were updated and published in an expert consensus report in 2014.20 Detailed discussion of these criteria for each specific type of lung disease is beyond the scope of this chapter. It is of utmost importance to make referring lung physicians aware of these guidelines. Early referral for initial assessment at the transplant center should be encouraged even before the need for listing is anticipated in order to identify and address potential barriers to transplant, to initiate patient and family education, and to promote familiarity with the transplant team. Patients with progressive lung disorders like IPF, CF, and IPAH who continue to deteriorate despite optimal medical treatment should be screened early so that activation on the waiting list can be done with a realistic time perspective to find a suitable donor. We discuss below the most frequent indications for transplantation. Obstructive Lung Disease Obstructive lung disease, notably emphysema and alpha1-antitrypsin deficiency, is the most common indication for lung transplantation, accounting for 35.7% of the adult lung transplantations included in the 2015 Registry of the UNOS/ISHLT, as reported by Yusen and colleagues.19 Most patients have deteriorated to a point at which oxygen supplementation is required by the time of listing, typically slightly greater than 4 L/min of oxygen. A forced expiratory volume in 1 second (FEV1) of well under 1 L or 20% to 20% predicted, RV >200% predicted, PaCO2 70% of patients currently receiving bilateral-lung transplantation.19 Generally, for young patients, particularly those with alpha1-antitrypsin deficiency, bilateral-lung transplantation should be preferred. The bilateral option is also more attractive in larger recipients for whom an oversized single-lung donor would be difficult to obtain. For older or smaller recipients, single-lung transplantation offers a more attractive option, particularly when an oversized donor lung can be grafted. However, life-threatening complications such as pneumothorax, lung cancer, opportunistic infections, and hyperinflation with compression of the allograft may develop in the native lung in the years after successful single-lung transplantation.39 This decision of single- versus bilateral-lung transplantation for emphysema is controversial and requires consideration of benefit to an individual recipient versus global benefit from a limited supply of available donor lungs as discussed by the authors in a review of the topic.40 Septic Lung Disease Cystic fibrosis (CF) is the most frequently encountered disease in this category. It is a common inherited disorder resulting in diffuse bronchiectatic destruction of both lungs. Without transplantation, the overwhelming majority of patients die as a result of progressive respiratory failure in the second or third decade of life. As reported in the 2015 ISHLT Registry, CF is now the second most common indication for bilateral-lung transplantation and the third most common indication (16.2%) for lung transplant in general.19 The most reliable predictors of life expectancy in CF patients were published by Kerem and

colleagues.41 An FEV1 of less than 30% predicted, elevated PaCO2, requirement for supplemental oxygen, frequent admissions to the hospital for control of acute pulmonary infection, and failure to maintain weight are reliable predictors of early mortality in these patients. At this stage of disease, patients with CF usually have a rapidly progressive downhill course. Since the introduction of the LAS, median waiting time has decreased and waiting list mortality has dropped improving survival benefit for CF patients.42 Waiting list mortality for CF is on average 15%, but with increasing time on the waiting list.35 Nonadherence to medical therapy or chronic infection with highly virulent and/or resistant microbes (such as Burkholderia cenocepacia, Burkholderia gladioli, multidrug resistant Mycobacterium abscessus and Mycobacterium tuberculosis) are generally considered an absolute contraindication for lung transplantation in CF patients, whereas underweight generally is not and is rather considered a relative contraindication requiring nutritional optimalization. Fibrotic Lung Disease Pulmonary fibrosis or restrictive lung disease includes mostly patients with IPF and less commonly pulmonary fibrosis of other etiologies, end-stage sarcoidosis with elevated pulmonary artery pressures, and obliterative bronchiolitis (OB) (not retransplant cases). The 2015 ISHLT Registry report indicated that fibrotic lung disease was the second most common indication (38.9%) for single-lung transplantation and the third most common (22.3%) for bilateral-lung transplantation.19 Candidates for transplantation with pulmonary fibrosis have classic restrictive findings on spirometry, with a mean forced vital capacity (FVC) of 7 cm) lesions. In an analysis by Toffalorio et al. of 467 patients with stage IB lesions by sixth edition criteria, stage IB survival as currently classified by seventh edition criteria was 71% at 5 years as compared to 47.7% and 47.4% for reclassified stages IIA and IIB, respectively.106 In a retrospective study of 222 node-negative patients, Bergman et al. reported an overall 5-year survival rate of 51% in patients with a tumor size >3 cm. When stratified by size utilizing the seventh TNM edition criteria, the 5-year overall survival rates for stages IB, IIA, and IIB were 54%, 51%, and 35%, respectively.107 These studies highlight the importance of tumor size and the re-classification of the T descriptor emphasized in the seventh edition. TABLE 95.7 Survival After Surgical Resection for Stage IB NSCLC

Stage IB (T2N0)



Report

Year

N

5-Year Survival (%)

Williams et al.363

1981

236

62

Martini et al.30

1986

78

65

Roeslin et al.30

1987

121

43

Read et al.21

1990

327

57

Ichinose et al.281

1995

80

67

Mountain61

1997

549

57

Inoue et al.173

1998

271

65

Jassem et al.64

2000

220

53

van Rens et al.66

2000

797

46

Naruke et al.67

2001

506

60

Fang et al.274

2001

702

61

Rena et al.278

2002

292

55

Toffalorio et al.106

2012

349

71

Bergman et al.107

2013

142

54

Stage IB—Visceral Pleural Invasion The presence of visceral pleural invasion is associated with worse outcomes in patients with early-stage (3 cm) following sublobar resection,117–119 including anatomic segmentectomy.96,120,121 Stage IB status by visceral pleural invasion is associated with increased risk of locoregional recurrence and systemic metastases, including intralobar N1 nodal recurrences.122–124 This finding has raised concerns regarding the extent of resection performed for stage I NSCLC, and has led several authors to advocate lobectomy in all cases with suspected visceral pleural invasion. Schuchert et al. also found that visceral pleural invasion was a significant prognostic variable independently predictive of recurrence (HR: 1.86; 95% CI:1.11 to 3.10, p = 0.018), especially following segmentectomy. The reason for the worse prognosis following segmentectomy in the setting of stage IB disease is not entirely clear. It is conceivable that lobectomy permits better surgical margins compared to segmentectomy in relation to these typically larger tumors. It is also possible that increased tumor size is a marker of more aggressive tumor biology, both in terms of local invasiveness (visceral pleural invasion) and a resulting increased propensity for locoregional nodal involvement that is better addressed by lobectomy.124

FIGURE 95.5 Visceral Pleural Invasion—Adenocarcinoma with visceral pleural invasion. A: 14 mm pulmonary nodule contacting the pleura. B: 200× H&E stain. (Reprinted from Ebara K, Takashima S, Jiang B, et al. Pleural invasion by peripheral lung cancer: prediction with three-dimensional CT. Acad Radiol 2015;22(3):310–319. Copyright © 2015 Association of University Radiologists. With permission.)

In summary, visceral pleural invasion is an adverse pathologic variable associated with increased recurrence risk following segmentectomy. When larger tumors (3 to 5 cm) or visceral pleural invasion are encountered, lobectomy should be performed. Stage IB—Role of Adjuvant Chemotherapy The presence of aggressive pathologic tumor characteristics may provide an indicator for patients with resected stage I disease that might benefit from adjuvant therapy. CALGB 9633 evaluated the outcomes of 344 patients randomized to cisplatin-based chemotherapy following resection of T2N0 tumors versus surgery alone. In an unplanned subgroup analysis, the administration of adjuvant chemotherapy was found to be beneficial for tumors >4 cm in size.125 In a study evaluating patients from the National Cancer Database, the use of adjuvant chemotherapy in patients with tumors >3 cm was associated with improved median (101.6 vs. 68.2 months) and 5-year survival (67% vs. 55%).126 These studies suggest that there may be a marginal benefit for adjuvant chemotherapy in the setting of larger tumors >4 cm in size. Plans for adjuvant therapy in this setting are best reviewed in the setting of a multidisciplinary tumor board.

STAGE II NSCLC: N1 ADENOPATHY OR RESECTABLE LOCAL INVASION The seventh edition of the Lung Cancer Staging System separates stage II NSCLC into two groups: stage IIA, which includes T1N1, T2aN1, and T2bN0 subgroups and stage IIB, which includes T2bN1 and T3N0 designations. Together, the stage II group represents approximately 26% of patients with NSCLC, with IIA accounting for about 10% and IIB 16% of cases. Broadly speaking these groups are comprised of large >5 cm, node negative tumors, or T1-2 lesions with associated N1 disease. Within the stage II groups, T1N1, T2aN1, and T2bN1 represent 8% of the total patient population.103 Large series, including that of Naruke et al.,67 and the IASLC database show a 40% to 60% expected 5-year survival after resection. In Naruke’s retrospective analysis, 5-year survival after resection for pathologic T1N1, T2N1, and T3N0 were 57.5%, 43.8%, and 46.6%, respectively. After implementing changes to the staging

system and incorporating all subgroups, 5-year survival for stages IIA and IIB were found to be 46% and 36%, respectively.67 The recognition that larger node-negative tumors over 5 cm were associated with a worse prognosis provided the impetus for shifting these cases from stage IB to stage II (Fig. 95.6). Martini et al. found that tumors 5 cm.127 Furthermore, Carbone et al. showed that tumors 5 cm.128 Dai et al. analyzed 220 patients with stage II NSCLC. In their cohort, patients with ≤3 cm had a 55.7% 5-year survival rate, while patients with >3 cm had a 45.3% 5-year survival rate.129 Similar to trends seen in stage I disease, these studies highlight the importance of tumor size on survival in the stage II subgroups. Lobectomy is the treatment of choice for stage II disease with systematic lymph node sampling or formal lymph node dissection. Sublobar resection is generally not viewed as an appropriate option in these patients. Furthermore, larger IIB lesions tend to be more complicated, frequently requiring full thickness chest wall resections, sleeve resections, or even pneumonectomy.

FIGURE 95.6 7 cm mass involving right upper lobe.

Stage IIA—N1 Nodal Involvement Though stage II is commonly regarded as early stage NSCLC, the fact that it is associated with larger tumors and/or complicated by N1 nodal metastasis translates into lower survival and cure rates compared to stage I, regardless of surgical strategy employed. Survival for pT1N1 patients in the series of van Rens et al. is 52%.66 The Ludwig Lung Cancer Study Group reported a median survival time of 4.8 years for resected T1N1 patients (as compared with 2.3 years for T2N1).130 The number of involved lymph nodes may also have an impact on survival in this setting. Wisnivesky et al. showed with the Surveillance,

Epidemiology and End Results (SEER) database that a greater number of N1 LNs was associated with significantly worse lung cancer–specific and overall survival.131 Mean lung cancer–specific survival was 8.8 years, 8.2 years, 6.0 years, and 3.9 years for patients with one, two to three, four to eight, and more than eight positive lymph nodes, respectively. Though this study includes T1 to T3 cases, it highlights that the number of involved lymph nodes may be a potential prognosticator of survival in NSCLC.131 Similar results are seen in the study by Martini et al., showing that patients with a single malignant node had a 5year survival rate of 45% as opposed to 31% for those with multiple N1 metastases. Despite these findings, some groups do not show a significant difference in survival comparing single versus multiple N1 lymph node involvement.132 Wang et al. found that the 5-year survival with ≤1 and >1 lymph nodes involved was 61.0% and 46.9%, respectively, which did not achieve statistical significance in their study.133 In a similar retrospective study, Nakagawa et al. did not find a survival difference based on the number of involved lymph node stations. In their series, single versus multiple number of involved N1 lymph node stations yielded a 51.9% and 58.5% 5-year survival rate, respectively.134 Given the disparate findings in these studies, the number of involved N1 lymph nodes has not been found to be a reliable prognostic factor in current staging algorithims. Intralobar versus extralobar N1 nodal disease also has been suggested to be a prognostic factor in multiple studies. Yano et al. achieved a postresection survival rate of 65% in patients with “lobar” nodal disease (levels 12 and 13), as compared with only 40% when the “hilar” nodes (levels 10 and 11) contained metastatic cancer.135 Haney et al. retrospectively reviewed their database of stage II resections (n = 230 patients). In their study, extralobar was defined as including lymph nodes from levels 10 and 11 and intralobar included levels 12 to 14. The presence of extralobar (levels 10 and 11) positive lymph nodes was associated with a worse outcome compared to intralobar nodes (level 12 to 14). The median overall survival was 46.9 months for the intralobar cohort and 24.4 months for the extralobar cohort. Interestingly, 24 patients had both intra- and extralobar nodal disease. This cohort fared the same as patients with extralobar disease only.136 Li et al. showed similar results. Patients with hilar positive lymph nodes had a 35% 5-year survival rate compared to peripheral intralobar positive nodes, which had a 58% 5-year survival rate. In this study, patients with both had poorer outcomes with a 5-year survival of 23%.137 Likewise, Van Velsen and his group looked into the influences of lymph node involvement on survival rates in T1N1 and T2N1 NSCLC. For T1N1, the overall 5-year survival was 46% in their patient population.138 They discovered that, like Li et al., lobar N1 metastases had better outcomes than hilar N1 metastases (57% vs. 30%).139 In addition to this, lymph node involvement by direct extension carried better outcomes than noncontiguous metastases (69% vs. 30%).138 For their T2N1 group, overall postoperative survival rate at 5 years was 37.8%.139 Once again, lobar N1 metastases had better outcomes than hilar N1 metastases (65.3% vs. 21%). Patients with hilar metastases also had poorer 5year survival rates when compared to patients with lymph node involvement by direct extension (21% vs. 44.6%).139 Riquet et al. also reported improved survival rates for lobar versus hilar N1 (54% vs. 38%) disease. However, there was no difference in survival rates between direct extension versus separate metastasis.140 To further deduce the differences between nodal involvement, Tanaka et al. divided N1 disease into three groups. They reported postoperative survival for T1-2N1 to be 72% when levels 12 and 13 were affected, 62% for level 11, and 39% for level 10.141 With the re-emergence of sublobar resection techniques such as anatomic segmentectomy, the question of what to do with surprise N1 disease during the course of dissection has been raised. Recognizing the increased risk of locoregional recurrence associated with N1 disease,142 most authors would advocate converting the sublobar resection to lobectomy (assuming the patient’s physiological status permits) in

cases of surprise N1 nodal involvement detected by frozen section at the time of surgery. In a study by Nomori et al., 15 patients undergoing anatomic segmentectomy were found to have N1or N2 disease intraoperatively. Ten patients (67%) were converted to lobectomy, and five (33%) underwent completion of the segmentectomy only. None of the patients who went on to lobectomy developed a recurrence, whereas 2/5 (40%) of the patients treated by segmentectomy only developed recurrent disease. Interestingly, both of these recurrences were distant, raising the question of aggressive tumor biology as opposed to inadequate local control.143 In summary, stage II NSCLC associated with larger tumor sizes (>5 cm) and/or N1 nodal involvement is associated with 5-year survival rates ranging from 25% to 55% in most series, with an average survival of 40% to 45%. Given the larger tumors and nodal involvement inherent in this stage grouping, lobectomy is recommended as the procedure of choice. Central tumors might mandate sleeve resection or even pneumonectomy to achieve an R0 resection. Stage IIB—T3N0 Disease T3 tumors are lesions that are >7cm, or any size lesion that invades the chest wall, diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium. T3 now also includes tumors with ipsilateral intralobar nodules that involve the same lobe as the primary tumor (e.g., satellite nodules). Another subset of T3 tumors are those located within 2 cm of the carina without carinal involvement. Overall 5-year survival rates for T3N0 (stage IIB) involvement range from 22% to 48%, with an average survival between 30% and 35%. In a multi-institutional study, Choi et al. reported a 50% 4-year locoregional relapse-free survival following resection of T3N0 tumors.144 Naruke67 and van Rens66 reported 5-year survival rates of 22% and 33%, respectively. Wisnivesky et al., using the SEER database, reported that 5year survival rates for T1N1 and T3N0 were not significantly different at 46% and 48%, respectively. In fact, the long-term “cure rate” for T3N0 in their study was better, though not significant compared to T1N1, 33% versus 27%.145 Multiple Intralobar Nodules The seventh edition of the Lung Cancer Staging System has reclassified a second site within the same lobe from T4 to T3, and a second site within the ipsilateral lung from M1 to T4. Determining whether two lesions are separate primaries or if one is metastatic from the other, though not always easy, can often be elucidated by immunohistochemistry and molecular techniques. Deslauriers et al. found that the presence of “satellite nodules” (malignant foci close to the dominant tumor but separate from it) reduced long-term survival by approximately 50% after resection (Fig. 95.7).146 Nonetheless, the 5-year survival rate of 22% in patients with such nodules represented a much better prognosis than patients previously classified as T4 or M1. Fukuse et al. reported a similarly favorable 5-year survival rate of 26% in 41 cases of resected ipsilateral lesions.147 Yoshino et al. found a similar late survival in resected unilobar multifocal cases.148 Pennathur,149 Rosengart150 and Okada151 and their colleagues noted even more favorable results in this cohort of patients, with long-term survival rates of 26, 44%, and 70%, respectively. In the series by Pennathur et al., survival in the node-negative subset was found to be 40%. These positive findings have led the ACCP to issue clinical practice guidelines for satellite nodules acknowledging a good prognosis following surgery. The approach to evaluation and treatment requires no modification than what would be dictated by the primary tumor alone.152

FIGURE 95.7 Right lower lobe NSCLC with ipsilateral intralobar “satellite nodule.” (Borrowed from Alonso RC, ed. Non-small cell lung cancer (NSCLC): Review of the seventh edition of the TNM staging system and role of imaging in the staging and follow-up of NSCLC1970. European Congress of Radiology 2011.)

FIGURE 95.8 Right Upper Lobe NSCLC with pleural and potentially chest wall involvement.

Chest Wall Involvement By far the largest surgical experience with T3N0 tumors involves those invading the parietal pleura or chest wall (Fig. 95.8). It must be stressed that a high proportion of patients in many surgical reports were treated with preoperative or postoperative radiation therapy or both. Despite the chest wall involvement, these patients are surgical candidates for en bloc chest wall resection with reconstruction, as appropriate. The major correlatives of long-term survival are node negativity and complete resection. When both criteria are met, long-term survival can be achieved in 29% to 56% of surgical cases, averaging 42%. Efficacy of resection is markedly limited when malignant lymphadenopathy accompanies chest wall invasion (T3N1, stage IIIA). In a series of 334 patients undergoing attempted resection for parietal pleural or chest wall invasion, Downey et al. reported complete R0 resections in 52.4% of their patients. They noted a 5-year survival rate of 32% for a completely resected T3N0 lesion versus 4% in incompletely resected (R1 or R2) patients.153 Similarly, Burkhart et al. reported a 5-year survival rate of 39% after a complete resection.154 Lee et al. published their experience with T3 resections secondary to chest wall involvement, and noted a 5-year survival rate of 37.4%. A complete resection drastically affected survival compared to an incomplete resection in their series, 31.7% versus 7.5%. Prognostic factors for survival included extent of resection, tumor size, nodal status, and completeness of resection.155 The extent of invasion is divided pathologically into parietal pleural involvement versus extension into muscle and bone. This is often difficult to determine at the time of operation. Kawaguchi et al. examined resected specimens invading only to the parietal pleura versus soft tissue or ribs showing that preoperative CT findings of obvious tumor invasion and complaints of chest pain were independent

indicators of deep invasion into soft tissue or ribs. While some tumors may dissect easily off of the chest wall by extrapleural dissection, incomplete resection leads to a markedly reduced survival rate.156 In patients with T3N0 disease, McCaughan et al. achieved a 5-year survival rate of 62% for parietal pleural T3 as opposed to 35% for muscle and bone invasion, but the difference was not statistically significant.157 Likewise, Casillas,158 Elia,159 and Akay160 and their colleagues noted no significant difference between patients treated by extrapleural dissection versus full-thickness chest wall resection. Doddoli et al. strongly suggest that en bloc resection be the standard of care for chest wall invasion when technically possible.161 Albertucci et al. found a significant incidence of incomplete resection and lower survival for extrapleural dissection (33% vs. 50%). Despite this, there are multiple groups that have not noticed a statistically significant difference. Regardless of technique, a complete R0 resection is suggested. Therefore, if there is a lesion attached to parietal pleura by adhesions with superficial invasion, pulmonary resection with an extrapleural dissection can be appropriate in carefully selected cases. However, if there is any suspicion of formal chest wall involvement, an en bloc resection should be performed. Addition of radiotherapy in cases of R1 or R2 residual chest involvement has not been reliably shown to improve disease-free or overall survival.144 In summary, NSCLC involving a limited area of the parietal pleura and only superficial invasion may be treated adequately by pulmonary resection combined with extrapleural dissection, but any degree of deeper invasion requires full-thickness en bloc chest wall resection. The practical challenge is the definitive identification of the extent of invasion by preoperative and intraoperative assessment. When there is doubt, en bloc resection is appropriate. Superior Sulcus Tumors Superior sulcus tumors, or Pancoast tumors, are apical lesions that invade the chest wall and thoracic inlet (Fig. 95.9). Due to its location at the apex, frequently these tumors will invade the brachial plexus, subclavian vessels, and the spine. Because of this pattern of involvement, these are challenging tumors to completely resect because of the need to preserve or reconstruct the neurovascular structures. Patients with these lesions can present with Horner syndrome: miosis, ptosis, and anhidrosis. This indicates the invasion of the stellate ganglion and possibly the nerve root of T1. Preoperative workup with tissue biopsy is important as a small portion of these lesions are small cell carcinomas, which would warrant an alternative therapeutic approach. Careful pre-operative staging is essential in management, including PET-CT imaging and mediastinoscopy. N2 or N3 disease is an absolute contraindication for surgery given the associated poor prognosis.

FIGURE 95.9 Superior Sulcus Tumor. A and B: CT scan of superior sulcus tumor involving first through third ribs and approaching blood vessels anteriorly, C and D: Perivertebral and mediastinal encroachment. (Reproduced with permission from Heelan RT, Demas BE, Caravelli JF, et al. Superior sulcus tumors: CT and MR imaging. Radiology 1989;170(3 Pt 1):637–641.)

Shaw and Paulson demonstrated the feasibility of resecting superior sulcus tumors in 1961. They showed that preoperative irradiation followed by surgical resection improved 5-year survival rate to 30%. The extensive early experience of Paulson highlights the limitations of surgery, because only approximately 60% of patients presenting with Pancoast tumors were deemed suitable for treatment pathways including resection.162 Rusch et al. reported the largest series for resection of superior sulcus tumors (n = 225 patients). The majority of patients (55%) received preoperative radiation. Operative mortality was 4%. They noted that for T3N0 superior sulcus lesions, complete resection was achieved in 64% with an associated 5-year survival rate of 46%. However, once disease had progressed to stage III, 5-year survival was only 15%.163 Attar et al. compared the use of both radiotherapy and chemotherapy in patients with superior sulcus tumors, and evaluated whether preoperative or postoperative treatment mattered. They discovered that preoperative radiation followed by surgery was associated with improved median survival compared to other groups.164 Subsequently, the Southwest Oncology Group (SWOG) performed a prospective, multi-institutional trial of induction chemoradiotherapy in superior sulcus tumors including T3 and T4 lesions with N0 or N1 disease (Intergroup Trial 0160). Patients received trimodality therapy with two cycles of cisplatin and etoposide with concurrent 45 Gy of radiation. In this

study, 92% had a complete resection with 65% showing pathologic complete response or minimal microscopic disease. Two-year survival was 55% for all eligible patients, and 70% for patients who had a complete resection.165 Wright et al. compared induction chemoradiation versus radiation alone in patients diagnosed with superior sulcus tumors. Complete resection was possible in 80% of the radiation treatment patients versus 93% of the chemoradiation patients. The pathologic response was complete or near complete in 35% of the radiation patients and 87% of the chemoradiation patients. The 4-year survival rates were significantly different (49% for induction radiation and 84% for induction chemoradiation). Local recurrence was also improved in the preoperative induction chemoradiotherapy arm (0% vs. 30% for radiation alone).166 More recently, Antonoff et al. also showed preoperative chemoradiation frequently resulted in pathologic complete response (32%) supporting the use of neoadjuvant therapy and surgery for superior sulcus tumors.167 Induction therapy, including combined chemotherapy and radiation therapy, has thus become the standard of care for superior sulcus tumors. This approach offers a better chance at complete resection and improvements in overall survival. T3 Tumors Invading Structures Other Than Chest Wall There is limited data regarding stage II lesions that specifically invade other structures such as the mediastinum or those that are in close proximity to the carina. Mediastinal invasion limited to the mediastinal pleura is classified as T3. Pitz et al. found that patients undergoing a complete resection of tumors invading mediastinal pleura achieved a 25% 5-year survival rate.168 In a retrospective study, Burt et al. evaluated 225 patients with mediastinal T3 disease. In all patients studied, which also included some patients with mediastinal lymph node invasion (stage III disease), the survival rate was 9%. Among patients with T3N0 disease (n = 102), a 5-year survival rate of 19% was achieved. After an incomplete resection (R1 or R2), radiation therapy may improve local control in tumors with mediastinal pleural involvement.169 Wang et al. studied postoperative radiotherapy for stage II and III incompletely resected NSCLC and survival, including T3 tumors with mediastinal involvement. There was a statistically significant improvement in survival when these patients received postoperative radiation therapy.170 Recently, Rieber and his colleagues noted similar results.171 Diaphragmatic involvement with NSCLC also represents a potentially resectable T3 lesion. There is a paucity of reported surgical experience with this clinical situation. Weksler et al. found only eight cases in a review spanning two decades at Memorial-Sloan Kettering. All four patients with N2 disease died of their lung cancers, with a mean survival of only 92 weeks. Only a single N0 patient was alive at 70 weeks at the time of the report.172 Inoue et al. reported no 3-year survival in five operated patients with diaphragmatic invasion, despite complete resection and N0–1 status.173 For unclear reasons, more recent reports suggest an improved outcome. Rocco et al.174 and Riquet et al.175 achieved long-term survival in completely resected T3N0 cases with diaphragmatic involvement of 39% and 27%, respectively. Yokoi and colleagues performed combined lung and diaphragmatic resections in 26 cases with T3N0 and 29 cases with T3N1–2 lung cancer. Complete resection of N0 and of N1–2 cases yielded 5-year survival rates of 28% and 18%, respectively.176 In all of these series, long-term survival is not observed following incomplete resection. Central tumors within 2 cm from the carina without carinal involvement are also considered stage IIB. Mitchell et al. noted that overall 5-year survival was highest after isolated carinal resection at 51%, compared to 32% for N1 disease and 12% for N2/3 disease.177 Yamamoto et al. achieved a 28.3% survival rate after carinal resection. Their 5-year survival rate for N0 disease was 50%, and 0% for N1/2 disease.178 Similar results were shown by Rea et al. who observed a 5-year survival rate of 56% for N0

patients after resection. However, once again, N1 and N2 survival rates were dismal at 17% and 0%, respectively.179 Lastly, Pitz et al. reported their experience with tumors localized within 2 cm from the carina, and found a 40% 5-year survival rate.168 Liu et al. noted that 5-year survival becomes dismal if patients have locally advanced lung cancer infiltrating the carina. The 5-year survival rate of patients with primary tracheal and carinal tumors was 55% compared to 16.7% for those with locally advanced lung cancer directly infiltrating the carina.180 Patients with these lesions generally require either a sleeve resection with bronchoplastic reconstruction or a pneumonectomy to achieve adequate margins. A sleeve resection should always be considered when possible, given its favorable morbidity profile and preservation of pulmonary function when compared with pneumonectomy. Once again, thorough mediastinal staging is critical to optimize outcomes. Sleeve Resection Versus Pneumonectomy Hilar tumors present a challenging clinical scenario for thoracic surgeons given the inherent difficulties in attaining a complete (R0) resection with adequate margins. Generally, these patients will have central tumors that are commonly associated with hilar involvement of the mainstem bronchus or pulmonary artery (Fig. 95.10). Such lesions can be successfully managed by sleeve resection or pneumonectomy. Thomas first described the use of bronchial sleeve resection as a means of conserving lung parenchyma in 1947.14 Since that time, despite the technical complexities associated with sleeve resection, there has been a gradual increase in the use of this technique given its overall reduced morbidity and mortality profile (Table 95.8), preservation of pulmonary function, and comparable oncological outcomes in relation to pneumonectomy.

FIGURE 95.10 Hilar lesion requiring right upper lobe sleeve resection.

Deslauriers et al. analyzed their cohort of 1,230 patients in a single institution who underwent pneumonectomy (n = 1,046) or sleeve lobectomy (n = 184). The operative mortality was significantly higher in the pneumonectomy group compared to the sleeve lobectomy group, 5.3% versus 1.6%,

respectively. In addition to this, 5-year survival was significantly improved for sleeve lobectomy (52%) when compared to pneumonectomy (31%). However, Deslauriers noted that the rates for complete resection were higher for sleeve lobectomy than for pneumonectomy (58 vs. 33%, respectively). When stratifying outcomes by stage I and stage II NSCLC, there was a significant difference favoring sleeve lobectomy compared to pneumonectomy in each group. Finally, site of first recurrence was local in 22% of patients with sleeve lobectomy compared to 35% of patients with pneumonectomy, suggesting that there is no apparent oncological benefit in resecting more lung (e.g., pneumonectomy) as long as an R0 resection can be accomplished.181 Similar results were reported by Lee et al. In their series, 73 patients underwent sleeve lobectomy and 258 underwent pneumonectomy. Operative mortality was significantly different, 1.4% for sleeve lobectomy versus 10.1% for pneumonectomy. Major complications occurred in approximately 22% of patients in both groups. The 30-day mortality for sleeve lobectomy was 0% compared to 8.9% for pneumonectomy.182 Bagan et al. noted similar postoperative complication rates between sleeve resection and pneumonectomy, 28.8% versus 29.9%, respectively. Operative mortality was 12.6% for pneumonectomy versus 2.9% for sleeve lobectomy. Overall 5-year survival was 72.5% for sleeve resection and 53.2% for pneumonectomy.183 These results were further corroborated by a recent study from Schuchert et al. This was a retrospective review of 253 patients with stage IB-IIB NSCLC, with central disease confined to the inner half of the lung. Patients undergoing sleeve resection with bronchoplasty (n = 70) versus lobectomy (n = 123) had similar outcomes including overall morbidity (62.9% vs. 45.5%), 30-day mortality (1.4% vs. 0.8%), as well as recurrence-free (24.3% vs. 33.3%) and overall 5-year survival (41% and 45%).184 In a meta-analysis by Shi et al. of 19 studies comparing sleeve resection versus pneumonectomy, survival at 1, 3, and 5 years favored sleeve lobectomy. Postoperative complications and locoregional recurrences was not significantly different between the two surgical options.185 Ferguson et al. found that sleeve lobectomy offers a better quality of life and may be more cost effective than pneumonectomy.186 In summary, given the overall favorable outcomes associated with sleeve resection when compared to pneumonectomy, sleeve resection should be strongly considered in the surgical management of hilar lesions when technically feasible. Pneumonectomy should be reserved for those cases where an R0 resection can’t be accomplished by conventional lobectomy or sleeve lobectomy.

STAGE IIIA NSCLC Controversy exists regarding the optimal management of patients with stage IIIA NSCLC, which constitutes the “grey zone” between surgical (stage IA–IIB) and nonsurgical (stage IIIB–IV) patient populations. In the seventh edition of the AJCC Staging System for lung cancer, stage IIIA NSCLC is defined as T3N1M0, T1–3N2M0 or T4N0–1M0. Generally speaking, these are large (>7 cm), central tumors that may be associated with chest wall, mediastinal pleura, or parietal pericardium involvement. There may also be satellite tumor nodules within the same lobe or encroachment upon the mainstem bronchus within 2 cm of the main carina with associated nodal involvement (T3N1 or T3N2 lesions). This stage also encompasses patients with N2 mediastinal lymph node involvement (Fig. 95.11). The addition of the T4 descriptor to stage IIIA in the seventh edition of the AJCC Staging System includes those patients with tumor nodules in different lobes of the ipsilateral lung. As a result of these varying descriptors, there is significant heterogeneity in the underlying tumor characteristics and pattern of disease encountered among patients classified as having stage IIIA NSCLC.

TABLE 95.8 Periopertive Mortality Following Lobectomy, Sleeve Resection, and Pneumonectomy for NSCLC Author

Year

n

Lobectomy

Sleeve Resection

Pneumonectomy

Ginsberg et al.329

1983

2,220

2.9

—

6.2

Romano et al.330

1992

12,439

4.2

—

11.6

Suen et al.364

1999

7,099

—

5.2

4.9

Deslauriers et al.181

2004

1,230

—

1.6

5.3

Allen et al.334

2006

1,023

1.3

—

0

Schuchert et al.121

2012

253

0.8

1.4

6.7

FIGURE 95.11 PET-CT demonstrating a right upper lobe mass with hilar and subcarinal node involvement. (Reprinted from Lin WY, Hsu WH, Lin KH, et al. Role of preoperative PET-CT in assessing mediastinal and hilar lymph node status in early stage lung cancer. J Chin Med Assocn 2012;75(5):203–208. Copyright © 2012 Elsevier. With permission.)

While there are many treatment options for patients with stage IIIA NSCLC, the chances of cure remain quite low (7 cm) tumors with N1 nodal involvement, as well as patients with T4 tumors appear to benefit from the addition of adjuvant chemotherapy. Surgical resection following neoadjuvant therapy can be considered in patients with nonbulky, single-station lymph node involvement that can potentially undergo a complete resection. Lobectomy (with or without sleeve resection) is preferred over pneumonectomy following neoadjuvant therapy. When possible, patients with stage IIIA disease should be treated under the auspices of a multidisciplinary committee and/or clinical trial.

STAGE IIIB NSCLC Stage IIIB NSCLC constitutes approximately 10% to 15% of newly diagnosed NSCLC cases.131 In the seventh edition of the AJCC/UICC staging system for NSCLC, stage IIIB represents those patients with unresectable T4 tumors (T4N2) and those with contralateral (N3) mediastinal lymph node involvement. T4N0-1 neoplasms, which were historically classified as stage IIIB, are now included in the stage IIIA category. Malignant pleural effusions, also previously classified as stage IIIB, are now re-classified as stage IVA. Generally speaking, stage IIIB cases are not considered amenable to complete surgical resection, and correspondingly are most commonly treated with definitive concurrent chemoradiation in patients with minimal weight loss and a good performance status.239 The anticipated 5-year survival of patients falling in this category ranges from 3% to 7%.103,240 Previous studies have evaluated the role of surgery following induction chemoradiation in a highly selected groups of patients with stage IIIA and IIIB disease.241,242 In the SWOG 8805 trial, Albain et al. included selected patients with T4 (now stage IIIA) as well as patients with T4N2 and N3 disease (stage IIIB). A total of 34 of the 51 patients classified as IIIB in that study would currently qualify as stage IIIB in the current staging system (T4N2 = 7, N3 = 27). In subset analysis, the T4N0-1 group (now stage IIIA) had improved survival (median survival of 28 vs. 13 months, p = 0.07) compared with T4N2 or N3 subgroups. Among the 27 patients with contralateral N3 disease, the 2-year survival was 33% for patients with supraclavicular lymph node involvement versus 0% for those with N3 involvement. In multivariate analysis, the only subgroups associated with a positive prognosis were the T1N2 and T4N0-1 groups (currently stage IIIA). Overall 3-year survival for the stage IIIB cohort was 27%. Barlesi et al. evaluated 60 patients with stage IIIB disease undergoing surgery following neoadjuvant chemoradiation (classified as per the Sixth Edition of the AJCC/UICC Lung Cancer Staging System). The actuarial 5-year survival rate was 16.7% and was not significantly different than the stage IIIA group (17%). Completeness of resection, the presence of vascular invasion and visceral pleural invasion were all independent prognostic variables in multivariate analysis. Current consensus guidelines do not support routine surgical intervention for T4N2 or N3 disease.242 Salvage resection can be considered in patients suffering emergent complications (e.g., massive hemoptysis) as a life-saving measure. In addition, surgeons are occasionally consulted regarding patients who have undergone prior definitive chemoradiation for stage IIIB disease, who have demonstrated good response to therapy, and who are left with apparent localized disease on repeat staging. Yang et al. evaluated outcomes of patients undergoing salvage lobectomy after definitive chemoradiation in 31 patients.243 Of these, five patients were initially classified as stage IIIB disease. Pathological downstaging was noted in 68% of patients in the overall group, with a pathological nodal status of N0 in 90% of patients. The 5-year survival was 36% in this subgroup, compared to 0% in patients with residual nodal disease. This study demonstrates that salvage resection is technically possible in carefully selected patients. Surgical intervention in this setting should only be performed after detailed consideration by a multidisciplinary committee and/or under the auspices of a clinical trial.

STAGE IV NSCLC It is estimated that 40% of patients with newly diagnosed NSCLC have incurable stage IV disease, which is one of the key factors accounting for the overall poor survival associated with lung cancer.244 Stage IV lung cancer is divided into patients with malignant pleural effusion (stage IVA) and those with distant

metastases (stage IVB). Stage IV disease is generally not successfully treatable by surgical intervention, and systemic chemotherapy constitutes the standard of care in patients with reasonable functional status. Palliative interventions including endobronchial ablation and stenting and management of malignant pleural effusions represent important options in controlling symptoms and optimizing quality of life. These palliative surgical interventions are discussed in detail elsewhere in this text. Overall 5-year survival in patients with stage IV disease is 60 years of age had significantly lower survival at 1 year (42.5% vs. 67.3%, p = 0.023).276 The interactions associated with age are complex and include a multitude of factors including cardiopulmonary function, underlying medical comorbidities, prior surgery, and performance status. Increasing age is associated with an adverse impact on the above-mentioned variables, which ultimately translates to increased mortality risk with advancing age. Fernandez et al. showed that surgical treatment for NSCLC was associated with a 2.2% mortality rate in patients ≥65 years old. When further breaking this down by surgery type, mortality rates for wedge resection, segmentectomy, and lobectomy were all similar (3.5% vs. 3.5% vs. 4.3%).275 Berry et al. reported an operative mortality of 3.8% with a 47% morbidity rate in patients >70 years of age. LOS was increased in patients with at least one complication. Multivariate analysis found age (OR = 1.09, p = 0.01), and thoracotomy as surgical approach (OR = 2.21, p = 0.004) as independent predictors of

morbidity in patients >70 years old.277 These findings were corroborated by Cattaneo et al. who studied patients >70 years of age who underwent lobectomy for stage I NSCLC. Their results indicate that a VATS approach for lobectomy was associated with a lower rate of complications (28% vs. 45%, p = 0.04), LOS (5 days vs. 6 days, p < 0.001), and mortality (0% vs. 3%).50 Therefore, though the elderly population may experience more morbidity following lobectomy in general, proper patient selection and approach may minimize this risk. Because the elderly patient often presents with multiple comorbidities and can present as a clinically high-risk patient, surgical alternatives to lobectomy should be considered. Several studies have explored the use of sublobar resection for definitive management of stage I NSCLC in the elderly. Ikeda et al. focused on patients aged >80 years old and showed no significant difference in 5-year survival noted in patients with stage I NSCLC undergoing limited surgical resection (58.8%) vs. lobectomy (59.4%).278 Kilic et al. compared outcomes of patients >75 years of age that underwent either lobectomy (n = 106) or anatomic segmentectomy (n = 78) for stage I NSCLC. This study demonstrated a reduced morbidity (29.5% vs. 50%) and mortality (1.3 vs. 4.7%) when comparing the anatomical segmentectomy group with the lobectomy group. There was also no difference in locoregional recurrence (6% vs. 4%) or overall survival (49.8% vs. 45.5%) at a median follow-up of 21 and 18 months, respectively.279 These studies demonstrate that sublobar resection (including segmentectomy) can be effective and potentially beneficial in patients with NSCLC who are high risk due to advanced age. In 2012, Schuchert et al. compared outcomes following anatomic segmentectomy versus lobectomy for stage I NSCLC. Anatomic segmentectomy was associated with reduced complication (43.6% vs. 58.7%) as well as mortality (0% vs. 7.8%) in patients greater than 80 years old. More importantly, there was no reported difference in recurrence rate during a mean follow-up time of 37 months.121 Therefore, segmentectomy may be associated with lower mortality and complication rates with the similar recurrence and survival rates among the elderly population, particularly those over the age of 80. Histology Squamous cell carcinoma has historically been associated with lower recurrence and death rates per patient per year when compared with nonsquamous or mixed histologies.114 Read280 and Ichinose281 and their colleagues similarly observed an enhanced 5-year survival rate following resection of T1N0 squamous tumors relative to comparable adenocarcinomas. Several other studies, however, have failed to identify a significant difference between squamous and nonsquamous histology.282,283 As noted in the discussion on stage IIIA NSCLC, large-cell neuroendocrine carcinoma has been associated with a worse prognosis than other primary NSCLC histologies (adenocarcinoma, squamous cell carcinoma).284 Iyoda et al. reported a 5-year survival rate of 67% for resected stage I cases as compared to 88% for other stage I histologies.285 García-Yuste and colleagues noted 5-year survival in only 33% of resected stage I large cell neuroendocrine carcinoma patients.286 Battafarano et al. noted a significant reduction in freedom from recurrence and overall survival in patients with large cell neuroendocrine carcinomas.287 In cases of mixed histology containing 10% or more of cells of neuroendocrine differentiation, a lowered survival rate was observed in resected stage I adenocarcinoma patients.288 Along similar lines, the surgical prognosis for patients with node-negative mixed small cell and non-small cell lesions is also considerably worse than for pure NSCLC. Hage et al. reported 5-year survival rates of 50% and 26% for mixed small cell/non-small cell tumors of pathologic stage IA and IB, respectively, many of which were also treated with preoperative or postoperative chemotherapy.289

Ground Glass Opacities and Minimally Invasive Adenocarcinoma Screening of large populations of at-risk patients has generated a new conundrum. Many lesions discovered at screening are small, peripheral ground-glass lesions that turn out to be adenocarcinoma in situ, formerly known as bronchioloalveolar carcinoma (BAC), or minimally-invasive adenocarcinomas. A subset of adenocarcinoma of the lung can be classified as ground glass opacities, typically detected as isolated findings on CT imaging (Fig. 95.14). These lesions frequently are comprised of adenocarcinoma in situ/bronchioloalveolar cell carcinoma (BAC) or minimally invasive adenocarcinoma, which generally has a favorable prognosis. Although the 2004 World Health Organization definition of BAC has been narrowed to include only noninvasive lesions composed entirely of BAC, thoracic surgeons have long noted that patients with early-stage pure BAC, mixed BAC and adenocarcinoma, or adenocarcinoma with BAC features fare well with resection.290 Higashiyama et al. separated 206 resected peripheral adenocarcinomas 10 mm, it has a chance of 50% to become an AC.127 In summary, solitary cT1aN0M0 ground glass lesions can be managed with sublobar resection. Given the high incidence of multifocality in patients with GGOs, the value of a parenchymal preserving approach is evident. Although lymph node involvement is low in these cases, systematic N1 and N2 node sampling should be performed. Central Versus Peripheral Location The location of a tumor within the anatomical confines of a lobe has been shown to be associated with recurrence risk following surgical intervention in patients with stage I NSCLC. Utilizing sixth edition TMN Staging System criteria, Sagawa et al. found that tumor location negated the influence that tumor size had on outcomes. Specifically, in patients with peripheral tumors, 5-year survival was comparable between patients with tumors