Modern Thoracic Oncology 9789814725521, 9814725528

Table of contents :
About the pagination of this eBook
Volume 1
Contents
Foreword
List of Contributors
A. Anatomy and Embryology
Embryology and Anatomy of the Chest
Early Development — The First Two Weeks of Gestation
Embryonic Germ Layers — Week 3
Somites, Lateral Mesoderm, and the Neural Tube — Week 4
Heart and Cardiovascular System — Weeks 3 to 8
Gut, Esophagus, Trachea, and Lungs — Week 3 to 8 Years
Pharyngeal Arches and Thymus, Weeks 4 to 12
Thoracic Walls — Weeks 4 to 8
References
B. Medical Evaluation of Thoracic Oncology Patients
Pulmonary Evaluation of Thoracic Oncology Patients
References
Cardiac Evaluation of Thoracic Oncology Patients
Introduction
Cardiotoxicity of Cancer Therapies: Implications of Chemotherapy and Radiation
Cardiac Assessment Prior to Surgical Therapy
Pre-Operative Evaluation: Cardiac Risk Factors and Functional Status
Pre-operative Coronary Revascularization: Indications and Management
Perioperative Cardiac Medication Management
References
Evaluation of Elderly Patients
Introduction
Geriatric Assessment of Cancer Patients
Assessment of Older Patients Needing Surgery
References
C. Imaging of the Thorax
Standard Radiography
Computed Tomography
References
Positron Emission Tomography (and PET/CT)
References
Magnetic Resonance Imaging in Thoracic Malignancies
MRI Protocol for Thoracic Malignancies
Indications
Characterization and Staging of Mediastinal Tumors
Characterization and Staging of Pleural Tumors
Characterization and Staging of Chest Wall Tumors
Osseous, cartilaginous, and muscular tumors
Vascular tumors
Neurogenic tumors
Adipose tumors
Characterization and Staging of Superior Sulcus Tumors
Functional Assessment of Diaphragm
Assessment of Pulmonary Vasculature and Cardiac Function in Preparation for Surgery
MRI assessment of local tumor invasion
Cardiac MRI
References
Ultrasonography
Reference
Imaging’s Contribution to Staging Thoracic Tumors
Reference
D. Principles of Thoracic Surgical Oncology
Choosing Appropriate Resection for Operable Non-Small Cell Lung Cancer
References
Thoracic Surgical Lymphadenectomy
Defined Techniques of Complete Nodal Dissection
Video-Assisted and Robotically Assisted Node Dissection
Cervical Approaches: VAMLA/TEMLA
Data on Lymph Node Sampling versus Complete Lymphadenectomy
References
The Role of Minimally Invasive Surgery
Definition
Lung Cancer
Esophageal Cancer
Thymic Malignancies
Robotics
Summary
References
E. Principles of Thoracic Radiation Oncology
Radiation Treatment Planning and Delivery
Introduction
Simulation
Treatment Planning
Contouring
Treatment Planning Strategies
Target Dose and Normal Tissue Constraints
Conventionally Fractionated Radiotherapy
Stereotactic Body Radiotherapy
Motion Management Strategies
Quality Assurance and Patient Safety
Image Guided Treatment Delivery
Conclusion
References
Biological Basis of Clinical Radiation Oncology
Introduction to Fractionation Radiobiology
Biophysical Interpretation of Radiation Actions
Altered Fractionation Strategies
Dose Response Relationships
Tissue Organization
Heterogeneous Dose Distribution
Precision-Oriented Radiation Therapy
Special Considerations for Thoracic Irradiation
References
Radiation Toxicities and Management
Introduction
Acute versus late effects
Pathophysiology of Normal Tissue Injury
Lungs
Esophagus
Heart
Brachial plexus and spinal cord
Other normal tissue considerations
Consequences of Concurrent Chemotherapy
Mitigators of Normal Tissue Toxicity
Minimizing target volumes
Setting dose limits to normal structures
Radioprotectants
Amifostine
Angiotensin inhibitors
Concurrent smoking
Stereotactic Radiotherapy (SBRT/SABR)
Caution with central tumors
Other reports with modest hypofractionation
Managing Toxicities
Pulmonary
Esophageal
Cardiac
References
F. Principles of Thoracic Medical Oncology
Principles of Precision Medicine in Lung Cancer
Introduction
Driver Mutations in Lung Cancer
Targeted Therapies
Immunotherapy
Response Assessment — Traditional Outcomes and Advancing Technologies
Prevention
References
Commonly used Cytotoxic Agents in Thoracic Oncology
Platina Salts
Gemcitabine (dFdC) 2′, 2′-Difluorodeoxycytidine
Pemetrexed
Taxanes
Vinorelbine
Irinotecan
Topotecan
References
Targeted Biological Agents and Mechanisms
References
PD-1 Immunotherapy in Non-Small Cell Lung Cancer
Introduction
Mechanism of Action
Anti PD-1 and Anti PD-L1 Therapies in Advanced, Relapsed NSCLC
Anti PD-1 as Frontline Treatment in Advanced NSCLC
Toxicity of PD1/PDL-1 Blockade in NSCLC
Conclusion
References
Adverse Effects Induced by EGFR-TKIs: Rash and Diarrhea — Their Management
Effects of EGFR-TKI Inhibition on the Epidermis
Dermatological Adverse Events Induced by EGFR-TKIs
Acneiform Rash
Local Care Management Strategies
Pharmacologic Management Strategies
Paronychia
Local Care Management Strategies
Pharmacologic Management Strategies
Summary
Diarrhea Induced by EGFR-TKIs
Grading and Assessment of Diarrhea
Management of Diarrhea
Conclusion
References
G. Principles of Other Therapeutic Modalities
Percutaneous Image-Guided Ablative Therapy
Radiofrequency Ablation
Outcomes
Microwave Ablation
Outcomes
Cryoablation
Outcomes
Conclusion
References
Photodynamic Therapy
Introduction
History
Mechanism of Action
The Double-Edged Sword of Requiring Visible Light
FDA-Approved PDT Applications in Thoracic Oncology
Investigational Applications of PDT in Thoracic Oncology
Conclusion and Future Challenges
References
H. Principles of Supportive and Palliative Care
Nutrition
Prevalence and Significance of Malnutrition
Nutritional Screening and Assessment
Nutritional Support
Oral Nutrition
Enteral and Parenteral Nutrition
Palliative Surgery and Intraluminal Stents
Future Directions — Potential for Protein Anabolism
References
Chinese Herbal Medicine as Adjunct Therapy in Patients with Lung Cancer
Practice Guidelines
Data from Randomized Controlled Trials (RCTs)
Mechanisms of Therapeutic and Palliative Action
Clinical Reasoning
Diagnostic and Therapeutic Strategies
Study Quality
Summary
References
Integrative and Multidisciplinary Approaches to Pain Management in Lung Cancer
The Impact of Pain on Lung Cancer Survival and Quality of Life
Understanding the Multifactorial Nature of Pain
Surgical and Radiologic Interventions
Pharmacologic Interventions
Acupuncture
Manual Therapies
Summary
References
Acupuncture and the Needs of Patients with Lung Cancer
Mechanisms of Action — Acupuncture
Mechanisms of Action — Electroacupuncture
Clinical Evidence Relevant to Lung Cancer
Summary
References
End-of-Life Care
Advance Care Planning
Hemoptysis
Superior Vena Cava Syndrome
Malignant Airway Obstruction
References
Index
Volume 2
Contents
Foreword
List of Contributors
Part 1. Trachea and Lung Neoplasms
A. Tracheal Neoplasms
Epidemiology of Tracheal Neoplasms
References
Clinical Presentation and Diagnosis of Tracheal Neoplasms
References
Pathology and Staging of Tracheal Neoplasms
Epidemiology
Etiology — Premalignant Lesions
Prognosis
Histology — WHO Classification
Squamous Cell Carcinoma
Adenoid Cystic Carcinoma
Secondary Tumors
Staging — TNM Classification
References
Treatment of Tracheal Neoplasms by Surgery
Introduction
Primary and Metastatic Tumors
Histologic Types
Presentation
Evaluation
Treatment
Preparation
Approach
Resection
Post-Operative Care
Operative complications
Adjuvant Therapy
Results
Conclusion
References
Treatment of Tracheal Neoplasms by Radiation Therapy
References
Prognosis and Surveillance of Tracheal Neoplasms
References
B. Non-Small Cell Lung Neoplasms
Biological Basis of Non-Small Cell Lung Neoplasms
Molecular Epidemiology and Etiology
Genomic Classification of Lung Cancer
Oncogenes, Tumor Suppressor Genes, and Signaling Pathways in Lung Cancer
Hallmark: Sustaining Proliferative Signaling
EGFR/HER2/MET Signaling
RAS/RAF/MAPK Pathway
Pl3K/AKT/mTOR Pathway
Insulin Growth Factor (IGF) Pathway and ROS1
Other Fusion Proteins: EML4-ALK and RET
Hallmark: Resisting Cell Death and Evading Growth Suppressors
MYC
The 3p Tumor Suppressor Genes (TSGs) — Regulators of Apoptosis
The p53 Pathway
The p16INK4a-RB Pathway
Hallmark: Enabling Replicative Immortality
Hallmark: Inducing Angiogenesis
Hallmark: Activation Invasion and Metastasis
Hallmark: Avoiding Immune Destruction
Lineage-Dependent Oncogenes: SOX2 and NKX2-1 (TITF1)
Lung Cancer Stem Cells
Translation of Molecular Data to the Clinic
References
Epidemiology of Non-Small Cell Lung Neoplasms
References
Clinical Presentation and Diagnosis of Non-Small Cell Lung Neoplasms
Symptoms Related to Primary Tumor
Symptoms Related to Metastases
Constitutional Symptoms and Symptoms Related to Paraneoplastic Syndromes
Diagnosis and Staging of Lung Cancer
Radiology studies
Diagnostic biopsy
References
Imaging of Non-Small Cell Lung Neoplasms: Lung Cancer Screening
Background
Low dose chest computed tomography (CT)
Non-randomized control (observational) trials
Randomized control trials
DANTE
NLST
NELSON
Risks of Screening
False positive results in the NLST
Invasive diagnostic procedures and complications
Overdiagnosis
False negative results
Radiation exposure
Risk Assessment
Smoking Cessation
Recommendations and Coverage
Implementation and Cost Effectiveness
Conclusion
References
Imaging of Non-Small Cell Lung Neoplasms
Adenocarcinoma
Squamous Cell Carcinoma
Large Cell Carcinoma
Comparisons to Small Cell Carcinomas and Bronchopulmonary Carcinoid Tumors
Imaging and Cell Type
References
Treatment of Non-Small Cell Lung Neoplasms by Surgery
Introduction
Stage I (T1-2 N0)
Stage II (T1-2 N1, T3N0)
Stage IIIA (T1-3N2, T3N1)
Stage IIIB (T4/N3) Stage IV (M1)
Conclusion
References
Treatment of Non-Small Cell Lung Neoplasms by Radiation Therapy
Radiation Therapy for Early-Stage NSCLC
Radiation Therapy for Locally Advanced NSCLC
Consolidation/Palliative Radiation in Metastatic NSCLC
References
Treatment of Non-Small Cell Lung Neoplasms by Durg Therapy
Introduction
Staging
Stage I and Stage II NSCLC
Stage III NSCLC
Stage IV NSCLC
Histology
Targeted Therapy
Group A: Epidermal Growth Factor Receptor Mutation Positive
Group B: Anaplastic Lymphoma Kinase (ALK) Mutation Positive
Group C: Mutation Status Negative or Unknown
Anti-Angiogenic Agents
Squamous Histology
Immunotherapy
Conclusion
References
Prognosis and Surveillance of Non-Small Cell Lung Neoplasms
Introduction
Recurrence
Second Primary Lung Cancer
Surveillance Modalities
Clinical Follow-Up
Radiologic Surveillance
Low-Dose CT
Diagnostic CT versus CXR
PET
Biomarkers
Surveillance Team
Conclusions
References
C. Small Cell Lung Neoplasms
Biological Basis of Small Cell Lung Neoplasms
Introduction
Interplay between Loss of Retinoblastoma and TP53 and Neuroendocrine Signaling
The Role of Transcription Factors in SCLC Pathogenesis
Receptor Tyrosine Kinase Signaling
Apoptosis and Cell Cycle Control
DNA Repair Pathways
Conclusions
References
Epidemiology of Small Cell Lung Neoplasms
References
Clinical Presentation and Diagnosis of Small Cell Lung Neoplasms
References
Imaging of Small Cell Lung Neoplasms
References
Pathology and Staging of Small Cell Lung Neoplasms
Introduction
Gross/Microscopic Pathology
Differential Diagnosis
Low/Intermediate Grade Neuroendocrine Carcinoma (Typical/Atypical Carcinoid)
Large Cell Neuroendocrine Carcinoma (LCNEC)
Extrapulmonary Small Cell Carcinoma
Staging
References
Treatment of Small Cell Lung Neoplasms by Surgery
References
Treatment of Small Cell Lung Neoplasms by Radiation Oncology
Conflict of Interest
Acknowledgments
References
Treatment of Small Cell Lung Neoplasms by Drug Therapy
Limited Stage SCLC (T1-T2N0M0)
Limited Stage SCLC (T1-4N1-3M0, Except T3-4 Due to Additional Lung Nodules)
Extensive Stage SCLC (T1-4N1-3M1a-b)
References
Prognosis and Surveillance of Small Cell Lung Neoplasms
Limited-Stage Small Cell Lung Cancer
Extensive-Stage Small Cell Lung Cancer
Recurrent Small Cell Lung Cancer
Prognosis
References
Part 2. Pleural Neoplasms
A. Malignant Pleural Mesothelioma
Biological Basis of Malignant Pleural Mesothelioma
General Mechanisms of Tumorigenesis
Selected Molecular Pathways
Epigenetic Changes
Apoptotic Dysregulation
Other Oncogene and Tumor Suppressor Pathways
Recent Advances
Selected References
References
Epidemiology of Malignant Pleural Mesothelioma
References
Clinical Presentation and Diagnosis of Malignant Pleural Mesothelioma
Clinical Presentations
Diagnosis
Immunohistochemistry (IHC)
References
Imaging of Malignant Pleural Mesothelioma
Conventional Chest Radiograph
Computed Tomography
Positron Emission Tomography and PET/CT
Magnetic Resonance Imaging
Modified Response Evaluation Criteria in Solid Tumors (RECIST)
References
Pathology and Staging of Malignant Pleural Mesothelioma
Macroscopic Appearance
Cytologic Evaluation
Microscopic Evaluation
WHO Classification of Diffuse Malignant Pleural Mesothelioma
Epithelioid Mesothelioma
Sarcomatoid Mesothelioma
Desmoplastic Mesothelioma
Biphasic Mesothelioma
Immunohistochemistry
Staging of Malignant Pleural Mesothelioma
References
Treatment of Malignant Pleural Mesothelioma by Surgery
Introduction
Mesothelioma Characteristics Favoring Surgery
Mesothelioma Characteristics Against Surgery
Surgical Rationale
Types of Surgical Procedures
Thorascopic Pleurodesis
Pleurectomy and Decortication (P/D)
Extended Pleurectomy and Decortication (Extended P/D)
Partial Pleurectomy
Extrapleural Pneumonectomy (EPP)
Outcomes and Survival
Summary
References
Treatment of Malignant Pleural Mesothelioma by Radiation Therapy
Introduction
Radiotherapy After Extrapleural Pneumonectomy
Adjuvant Radiotherapy Following Pleurectomy with Decortication
Radiotherapy for Inoperable Patients
Prophylactic Irradiation of Chest Wall Incision Sites
Palliative Care
References
Treatment of Malignant Pleural Mesothelioma by Drug Therapy
Conclusion
References
Prognosis and Surveillance of Malignant Pleural Mesothelioma
References
Index
Volume 3
Contents
Foreword
List of Contributors
Part 1. Esophageal Neoplasms
A. Squamous Cell Carcinoma of the Esophagus
Biological Basis of Esophageal Squamous Cell Carcinoma
Genetic Alterations
Epigenetic Changes
References
Epidemiology of Esophageal Squamous Cell Carcinoma
Occupational Factors and ESCC
Tobacco Use and Alcohol Consumption As Main Risk Factors for ESCC
Risk of ESCC and Diet
Animal Contact, Oral Hygiene, Socioeconomic Status and Other Factors
Infection Factors
Genetic Susceptibility to ESCC
References
Clinical Presentation and Diagnosis of Esophageal Squamous Cell Carcinoma
Introduction
Clinical Presentation
Diagnosis
References
Imaging of Esophageal Squamous Cell Carcinoma
Pre-Treatment Tumor Staging
M Stage
N Stage
T Stage
References
Screening for Esophageal Squamous Cell Carcinoma
Identification of High-Risk Population
Endoscopic Screening
Chromoendoscopy
Image-Enhanced Endoscopy
Non-Endoscopic Screening
References
Pathology and Staging of Esophageal Squamous Cell Carcinoma
References
Treatment of Esophageal Squamous Cell Carcinoma by Surgery
Introduction
Surgical Approach
Lymphadenectomy
Reconstruction
Summary
References
Treatment of Esophageal Squamous Cell Carcinoma by Radiation Therapy
Introduction
Definitive Chemoradiotherapy
Pre-Operative Chemoradiotherapy
Pre-Operative Chemoradiotherapy versus Surgery Alone
Pre-Operative Chemoradiotherapy versus Definitive Chemoradiotherapy
Radiation Therapy Technique
References
Treatment of Esophageal Squamous Cell Carcinoma by Drug Therapy
Advanced Disease
Neoadjuvant Treatment
Adjuvant Treatment
References
Prognosis and Surveillance of Esophageal Squamous Cell Carcinoma
Prognosis
Response to Chemoradiation
Patterns of Failure
Surveillance
References
B. Adenocarcinoma of the Esophagus
Biological Basis of Esophageal Adenocarcinoma
Disease Progression
Targeted Therapy
References
Epidemiology of Esophageal Adenocarcinoma
Introduction
Descriptive Epidemiology
Risk Factors
Barrett’s Esophagus and Gastroesophageal Reflux Disease
Obesity and Body Size
Tobacco Smoking
Helicobacter pylori Infection
Non-Steroidal Anti-Inflammatory Drugs
Diet
Conclusions
References
Clinical Presentation and Diagnosis of Esophageal Adenocarcinoma
References
Imaging of Esophageal Adenocarcinoma
Pretreatment Imaging
Primary Tumor
Lymph node metastases
Distant Metastases
Posttreatment Imaging and Surveillance
Conclusions
References
Screening for Esophageal Adenocarcinoma
Introduction
Rationale for Screening
Challenges to Screening
Advances in Screening Techiniques
Minimally Invasive Screening Techniques
Imaging-Based Techniques
Identifying the Target Population for Screening
Stratification of Barrett’s Esophagus Cancer Risk
Demographic and Endoscopic Risk Factors
Histologic and Molecular Risk Factors
Summary
References
Pathology and Staging of Esophageal Adenocarcinoma
Pathology
Barrett’s Esophagus
Dysplasia
Adenocarcinoma
Screening
Staging
References
Treatment of Esophageal Adenocarcinoma by Endoscopic Therapies
Introduction to Endoscopic Eradication Therapy
Endoscopic Mucosal Resection (EMR)
Radiofrequency Ablation (RFA)
Cryotherapy and Photodynamic Therapy (PDT)
Summary
References
Treatment of Esophageal Adenocarcinoma by Surgery
Introduction
When is Surgery Necessary?
Type of Surgery
Pre-Operative Evaluation
Tumor Location
Brief Operative Details
Complications
Conclusion
References
Treatment of Esophageal Adenocarcinoma by Radiation Therapy
Radiation Therapy as a Single Modality
Dual-Modality Therapy: Adjuvant or Pre-Operative Radiation Therapy with Surgery
Dual-Modality Therapy: Chemoradiation
Tri-Modality Therapy: Surgery with Chemoradiation
Radiation Therapy Delivery Techniques
References
Treatment of Esophageal Adenocarcinoma by Drug Therapy
References
Prognosis and Surveillance of Esophageal Adenocarcinoma
Prognosis
Pathologic Response
Imaging Response
Surveillance
References
Stage-Specific Treatment of Esophageal Adenocarcinoma
Early-Stage Disease and Endoscopic Therapy
Early-Stage Disease and Primary Surgery
Locally Advanced Disease (Neoadjuvant Treatment)
Surgery
Adjuvant Treatment
Advanced Disease
Alternatives to Surgery
References
Part 2. Mediastinal Neoplasms
A. Thymic Neoplasms
Epidemiology of Thymic Neoplasms
References
Clinical Presentation and Diagnosis of Thymic Neoplasms
Clinical Presentation
Diagnosis
References
Imaging of Thymic Neoplasms
References
Pathology and Staging of Thymic Neoplasms
Introduction
Benign Conditions
Thymic Hyperplasia
Thymic Hyperplasia with Lymphoepithelial Sialadenitis-Like Features
Thymic Cysts
Thymolipoma/Thymofibrolipoma
Malignant Tumors
Thymoma
Thymic Carcinoma
Neuroendocrine Carcinomas of the Thymus
References
Treatment of Thymic Neoplasms by Surgery
Introduction
Principles of Surgery for Thymic Neoplasms
General Principles
Surgical Approach
Extent of Resection
Lymph Node Dissection
Cytoreductive Surgery
Summary
References
Treatment of Thymic Neoplasms by Radiation Therapy
Indications
Consensus Guidelines for PORT in Thymoma
Radiation Therapy Technique and Toxicity
Alternative Radiation Therapy Modalities — Hemithoracic Radiation Therapy
References
Treatment of Thymic Neoplasms by Drug Therapy
Introduction
Chemotherapy as Part of Curative Intent
Chemotherapy with Surgery
Chemotherapy with Radiation
Palliative Chemotherapy
Anthracyclines
Non-Anthracyclines
Amrubicin
Targeted Therapies
Octreotide
mTOR (Mammalian Target of Rapamycin)
c-KIT and Multi-Targeted TKIs
Epigenetic Modification
Insulin-Like Growth Factor 1 Receptor (IGF-1R)
Immune Checkpoint Inhibitors
EGFR Inhibitors, Src Inhibitors, and Cyclin-Dependent Kinase (CDK) Inhibitors
Conclusions
References
Prognosis and Surveillance of Thymic Neoplasms
References
B. Germ Cell Neoplasms
Epidemiology of Mediastinal Germ Cell Neoplasms
Introduction
Epidemiology of Mediastinal Germ Cell Tumors
References
Clinical Presentation and Diagnosis of Mediastinal Germ Cell Neoplasms
Clinical Presentation and Diagnosis
Rare Presentations of Primary Mediastinal Non-Seminomatous Germ Cell Tumors
Conclusion
References
Treatment of Mediastinal Germ Cell Tumors by Surgery
Mature Teratoma
Primary Mediastinal Seminoma
Primary Mediastinal Non-Seminoma
References
Treatment of Mediastinal Germ Cell Neoplasms by Radiation Therapy
Radiotherapy Alone for Mediastinal Seminoma: A Historical Perspective
The Emergence of Chemotherapy: Rationale and Evidence
Summary and Modern Role for Radiotherapy
Selected References
References
Prognosis and Surveillance of Mediastinal Germ Cell Tumors
Conclusions
References
Neurogenic Tumors
Radiological Indications in Neurogenic Tumors
Differential Diagnosis in Neurogenic Tumors
Neurogenic Tumors that Originate from Neural Sheath
Neurolemmoma
Melanotic schwannoma
Neurofibroma
Granular cell tumor
Neurosarcoma
Neurogenic Tumors that Originate from Sympathetic Ganglia
Ganglioneuroma
Neuroblastoma
Ganglioneuroblastoma
Neurogenic Tumors that Originate from Paraganglial Cells
Chemodectoma
Phaeochromocytoma
Tumors that Originate from Neuroectoderm
Melanotic progonoma
Askin tumor
Surgery of Neurogenic Tumors
References
Part 3. Chest Wall and Diaphragm Neoplasms
A. Bony and Soft Tissue Sarcomas
Treatment of Bony and Soft Tissue Sarcomas by Surgery
References
Treatment of Bony and Soft Tissue Sarcomas by Radiation Therapy
Tumor Location as a Risk Factor
The Impact of Surgical Margin and Tumor Size
Histological Grade as a Risk Factor
Unresectable Tumors: Is There a Role for Definitive Radiation Therapy?
The Sequencing of Radiation Delivery
Radiation Treatment Planning
Summary
References
Treatment of Bony and Soft Tissue Sarcomas by Drug Therapy
Overview
Etiology and Genetics
Clinical Presentation and Diagnosis
Imaging
Staging
Biopsy
Pathology
Histologic Classification
Prognosis
Treatment of Localized Disease
Surgery
Residual Disease
Radiation Therapy
Chemotherapy
Neoadjuvant
Adjuvant Chemotherapy
Metastatic Disease
Surgery for Metastatic Disease
Surveillance
References
Prognosis and Surveillance of Bony and Soft Tissue Sarcomas
References
Diaphragm Neoplasms
References
B. Cardiac Neoplasms
Primary Cardiac Tumors
Biological Basis of the Disease
Epidemiology
Clinical Presentation and Diagnosis
Imaging
Staging
Surgical Treatment
Chemotherapy
Prognosis
References
C. Metastatic Neoplasms of the Chest
Treatment of Thoracic Metastases by Surgery
Introduction
Common Criteria for Pulmonary Metastasectomy
International Registry of Lung Metastasis
Oliogoprogression
Surgical Techniques
Open versus Minimally Invasive Surgery
Unilateral versus Bilateral Exploration
Mediastinal Lymph Node Evaluation
Conclusion
References
Treatment of Thoracic Metastases by Radiation Therapy
References
Index

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About the pagination of this eBook This eBook contains a multi-volume set. To navigate this eBook by page number, you will need to use the volume number and the page number, separated by a hyphen. For example, to go to page 5 of volume 1, type “1:5” in the Go box at the bottom of the screen and click "Go." To go to page 5 of volume 2, type “2:5”… and so forth.

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Published by World Scientific Publishing Co. Pte. Ltd. 5 Toh Tuck Link, Singapore 596224 USA office: 27 Warren Street, Suite 401-402, Hackensack, NJ 07601 UK office: 57 Shelton Street, Covent Garden, London WC2H 9HE

Library of Congress Cataloging-in-Publication Data Names: Cameron, Robert B., editor. | Gage, Diana Lin, editor. | Olevsky, Olga, editor. Title: Modern thoracic oncology / editors, Robert B. Cameron, Diana Lin Gage, Olga Olevsky. Description: New Jersey : World Scientific, 2018. | Includes bibliographical references and index. Identifiers: LCCN 2017056795| ISBN 9789814725514 (hardcover (set) : alk. paper) | ISBN 9789813236288 (hardcover (volume 1) : alk. paper) | ISBN 9789813236295 (hardcover (volume 2) : alk. paper) | ISBN 9789813236301 (hardcover (volume 3) : alk. paper) Subjects: | MESH: Thoracic Neoplasms Classification: LCC RC280.C5 | NLM WF 970 | DDC 616.99/494--dc23 LC record available at https://lccn.loc.gov/2017056795

British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library.

Copyright © 2018 by World Scientific Publishing Co. Pte. Ltd. All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system now known or to be invented, without written permission from the publisher.

For photocopying of material in this volume, please pay a copying fee through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case permission to photocopy is not required from the publisher. For any available supplementary material, please visit http://www.worldscientific.com/worldscibooks/10.1142/9828#t=suppl Typeset by Stallion Press Email: [email protected] Printed in Singapore

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Foreword Thoracic oncology includes the treatment of cancers of the lung/trachea, pleura, esophagus, mediastinum, and chest wall. Over the past two decades, therapy for this group of malignancies has evolved into a highly complex oncologic subspecialty. Elaborate multimodality treatment regimens utilizing biologics, chemotherapy, radiation, and surgery are now the rule rather than the exception. Furthermore, many existing complex therapies recently have become even more complicated by the introduction of personalized care. As our knowledge of cancer genetics and biology grows, the elaborate therapy webs promises to become even more intricate and challenging to comprehend. The rapidity with which our field of thoracic oncology is evolving is truly staggering. The need for a comprehensive thoracic oncology book to keep clinicians, be it pulmonologists, pathologists, radiologists, surgeons, medical oncologists, radiation oncologists, or gastroenterologists, up to date is paramount. Yet such books recently have not been forthcoming. One major obstacle to the production of an up-to-date thoracic oncology book is the traditionally slow production timeline compared to the current rapid pace of change in the field. We have attempted to overcome this hurdle by recruiting world expert authors for each specific and concise topic in thoracic oncology, (many of which together comprise a traditional book “chapter”) so that the information contained in each section can be reviewed, published, and updated rapidly — thereby keeping this book, Modern Thoracic Oncology, relevant and current. Whether one desires information regarding lung cancer screening, esophageal cancer staging, mutational analysis, targeted therapies, stereotactic ablative radiation with real-time imaging, minimally-invasive and robotic surgery, combination immunotherapy, microwave/cryoablation, or methods of early cancer detection, we have endeavored to encompass all of the latest information in the field v

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Modern Thoracic Oncology: Volume 1

of thoracic oncology. With frequent future updates, we hope that this ambitious reference book will become your sourcebook for thoracic oncology. We are indebted to the many national and international contributors for their thoughtful efforts. We also wish to acknowledge the staff at World Scientific Publishing for their help in producing the first edition of Modern Thoracic Oncology. We are eternally grateful to our families, Betty, Cristina, Brian, Michael, and Angela Cameron; Will and Naomi Gage, Sam and Jennifer Lin; Emanuil and Leeza Olevsky, Roger Gillespie, Tony and Timmy Shar. Robert B. Cameron Diana Lin Gage Olga Olevsky January 2018

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Contents Forewordv List of Contributorsxi A. Anatomy and Embryology

1

Embryology and Anatomy of the Chest Robert Trelease

3

B. Medical Evaluation of Thoracic Oncology Patients

11

Pulmonary Evaluation of Thoracic Oncology Patients Rana Lee Adawi Awdish, Said Chaaban

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Cardiac Evaluation of Thoracic Oncology Patients Carla Holcomb, Mary T. Hawn

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Evaluation of Elderly Patients Patrizia Froesch, André Emanuel Dutly

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C. Imaging of the Thorax

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Standard Radiography David M. Naeger, W. Richard Webb

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Computed Tomography David M. Naeger, W. Richard Webb

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Positron Emission Tomography (and PET/CT) David M. Naeger, W. Richard Webb

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Magnetic Resonance Imaging in Thoracic Malignancies Fereidoun Abtin, Kathleen Ruchalski, Paul Finn

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Ultrasonography73 David M. Naeger, W. Richard Webb Imaging’s Contribution to Staging Thoracic Tumors David M. Naeger, W. Richard Webb

75

D. Principles of Thoracic Surgical Oncology

79

 hoosing Appropriate Resection for Operable Non-Small C   Cell Lung Cancer Rodney J. Landreneau

81

Thoracic Surgical Lymphadenectomy Joshua Sonett

93

The Role of Minimally Invasive Surgery Thomas A. D’Amico

101

E. Principles of Thoracic Radiation Oncology

111

Radiation Treatment Planning and Delivery Clayton B. Hess, Megan E. Daly, Stanley H. Benedict

113

Biological Basis of Clinical Radiation Oncology Steve P. Lee

135

Radiation Toxicities and Management Drew Moghanaki, Siddharth Saraiya, Joseph K. Salama

153

F. Principles of Thoracic Medical Oncology

181

Principles of Precision Medicine in Lung Cancer Kelly McCann, Amy Cummings, Mary Sehl

183

Commonly used Cytotoxic Agents in Thoracic Oncology Annelies Janssens, Jan P van Meerbeeck

197

Targeted Biological Agents and Mechanisms Xiuning Le, Daniel B. Costa

211

PD-1 Immunotherapy in Non-Small Cell Lung Cancer Aditya Shetty, Olga Olevsky, Deborah Wong

217

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Contents

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Adverse Effects Induced by EGFR-TKIs: Rash   and Diarrhea — Their Management Vera Hirsh

223

G. Principles of Other Therapeutic Modalities

233

Percutaneous Image-Guided Ablative Therapy Kelsey Pomykala, Robert Suh

235

Photodynamic Therapy Melissa Culligan, Joseph S. Friedberg

247

H. Principles of Supportive and Palliative Care

253

Nutrition255 Reinhard Imoberdorf, Peter E. Ballmer Chinese Herbal Medicine as Adjunct Therapy in Patients   with Lung Cancer Michael McCulloch, Anita Chen Marshall, Arian Nachat Integrative and Multidisciplinary Approaches to Pain   Management in Lung Cancer Michael McCulloch, Anita Chen Marshall, Darko Vodopich, Arian Nachat

261

269

Acupuncture and the Needs of Patients with Lung Cancer Melanie Keith, Michael McCulloch, Anita Chen Marshall, Arian Nachat

275

End-of-Life Care Anne M. Walling, Thanh H. Neville, Deborah Moran, Neil S. Wenger

279

Index287

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List of Contributors Fereidoun Abtin Department of Radiology, Thoracic Section David Geffen School of Medicine at UCLA Los Angeles, California, USA Rana Lee Adawi Awdish Henry Ford Hospital Detroit, MI, USA and Wayne State University School of Medicine Detroit, Michigan, USA Peter E. Ballmer Departement of Medicine Kantonsspital Winterthur Winterthur, Switzerland Stanley H. Benedict Department of Radiation Oncology University of California at Davis Comprehensive Cancer Center Sacramento, California, USA Said Chaaban Department of Internal Medicine Pulmonary and Critical Care Medicine University of Kentucky, Lexington, Kentucky, USA

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Daniel B. Costa Department of Medicine Division of Hematology/Oncology Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts, USA Melissa Culligan University of Maryland Marlene and Steward Greenebaum Comprehensive Cancer Center Baltimore, Maryland, USA Amy Cummings Division of Hematology/Oncology David Geffen School of Medicine at UCLA Los Angeles, California, USA Megan E. Daly Department of Radiation Oncology University of California at Davis Comprehensive Cancer Center Sacramento, California, USA Thomas A. D’Amico Duke University Medical Center Duke South, White Zone Durham, North Carolina, USA André Emanuel Dutly Thoracic Surgery EOC Unit San Giovanni Hospital Bellinzona, Switzerland Paul Finn Department of Radiological Sciences, Cardiovascular Section David Geffen School of Medicine at UCLA Los Angeles, California, USA

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List of Contributors

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Joseph S. Friedberg University of Maryland Marlene and Steward Greenebaum Comprehensive Cancer Center Baltimore, Maryland, USA Patrizia Froesch FMH Medicina Interna e Oncologia medica Caposervizio di Oncologia Medica IOSI - Istituto Oncologico della Svizzera Italiana Ospedale Distrettuale di Locarno Locarno, Switzerland Mary T. Hawn Department of Surgery School of Medicine Stanford University Stanford, California, USA Clayton B. Hess Department of Radiation Oncology University of California at Davis Comprehensive Cancer Center Sacramento, California, USA Vera Hirsh Department of Oncology McGill University Montreal, Canada Carla Holcomb Department of Surgery School of Medicine University of Alabama Birmingham, Alabama, USA

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Reinhard Imoberdorf Departement of Medicine Kantonsspital Winterthur Winterthur, Switzerland Annelies Janssens Department of Thoracic Oncology Antwerp University Hospital Edegem, Belgium Melanie Keith Integrative Medicine Service Kaiser Permanente Walnut Creek Hospital Walnut Creek, California, USA Rodney J. Landreneau Department of Cardiothoracic Surgery University of Pittsburgh Pittsburg, Pennslyvania, USA Xiuning Le Department of Medicine Division of Hematology/Oncology Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts, USA Steve P. Lee Department of Radiation Oncology David Geffen School of Medicine at UCLA Los Angeles, California, USA Anita Chen Marshall Integrative Medicine Service Kaiser Permanente Walnut Creek Hospital Walnut Creek, California, USA

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Kelly McCann Division of Hematology/Oncology David Geffen School of Medicine at UCLA Los Angeles, California, USA Michael McCulloch Integrative Medicine Service Kaiser Permanente Walnut Creek Hospital Walnut Creek, California, USA Jan P van Meerbeeck Department of Thoracic Oncology Antwerp University Hospital Edegem, Belgium Drew Moghanaki Department of Radiation Oncology Hunter Holmes McGuire Veterans Affairs Medical Center Richmond, Virginia, USA Deborah Moran Division of Palliative Care Greater Los Angeles Veterans Administration Health System Los Angeles, California, USA Arian Nachat Integrative Medicine Service Kaiser Permanente Walnut Creek Hospital Walnut Creek, California, USA David M. Naeger Department of Radiology and Biomedical Imaging University of California, San Francisco San Francisco, California, USA

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Thanh H. Neville Division of Pulmonary and Critical Care David Geffen School of Medicine at UCLA Los Angeles, California, USA Olga Olevsky Division of Hematology/Oncology David Geffen School of Medicine at UCLA Los Angeles, California, USA Kelsey Pomykala UCLA Department of Radiological Sciences David Geffen School of Medicine at UCLA Los Angeles, California, USA Kathleen Ruchalski Department of Radiological Sciences, Thoracic Section David Geffen School of Medicine at UCLA Los Angeles, California, USA Joseph K. Salama Department of Radiation Oncology Duke University Durham, North Carolina, USA Siddharth Saraiya Department of Radiation Oncology The University of Toledo Toledo, Ohio, USA Mary Sehl Division of Hematology/Oncology David Geffen School of Medicine at UCLA Los Angeles, California, USA

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Aditya Shetty Division of Hematology/Oncology David Geffen School of Medicine at UCLA Los Angeles, California, USA Joshua Sonett Section of Thoracic Surgery Columbia University Medical Center New York, NY, USA Robert Suh UCLA Department of Radiological Sciences David Geffen School of Medicine at UCLA Los Angeles, California, USA Robert Trelease Department of Pathology and Laboratory Medicine David Geffen School of Medicine at UCLA Los Angeles, California, USA Darko Vodopich Integrative Medicine Service Kaiser Permanente Walnut Creek Hospital Walnut Creek, California, USA Anne M. Walling Division of General Internal Medicine and Health Services Research David Geffen School of Medicine at UCLA and Division of Palliative Care Greater Los Angeles Veterans Administration Health System Los Angeles, California, USA Deborah Wang Department of Medicine David Geffen School of Medicine at UCLA Los Angeles, California, USA

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W. Richard Webb Department of Radiology and Biomedical Imaging University of California, San Francisco San Francisco, California, USA Neil S. Wenger Division of General Internal Medicine and Health Services Research David Geffen School of Medicine at UCLA Los Angeles, California, USA

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A.  Anatomy and Embryology

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b2344   Modern Thoracic Oncology: Volume 1

Embryology and Anatomy of the Chest Robert Trelease

Embryogenesis involves cellular transformations, differentiation of germ layer cell lineages with specialized genetic and molecular characteristics, and establishment of functional anatomical relationships, all of which are relevant to later neoplasia, tumorigenesis, metastasis, treatment, and prognosis. In this brief overview of the development of the thoracic ­viscera and walls, we will concentrate primarily on basic cellular and ­tissue morphogenesis.

Early Development — The First Two Weeks of Gestation Following fertilization of the ovum, rapid cleavage transforms the ­original large diploid cell into a ball of 16 smaller cells — a morula. The morula contains a compacted inner cell mass and a surrounding outer cell mass. This conceptus becomes an early blastocyst, when extracellular fluid penetrates between the inner and outer cell masses to create a b­ lastocele cavity. The inner cell mass is called the embryoblast, since it will give rise to all the tissues of the embryo proper. The outer cell mass forms the trophoblast, which progressively develops into the placenta. The b­ lastocyst normally attaches to the endometrial lining by trophoblast cells, with implantation beginning about six days after conception. As implantation progresses, the inner cell mass differentiates into two epithelial layers: epiblast and hypoblast. A new space develops in the superior epiblast, creating the primitive amniotic cavity. Cells of the hypoblast proliferate to form the initial lining of the early yolk sac. Viewed 3

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Figure 1.    Transverse section of late pre-somite embryo showing early folding, parietal and splanchnic mesoderm relationships, and paired endocardial tubes. Modified from Sadler (2014).

from above, the embryoblast appears as an oval embryonic disc, attached at its edges to the inside of the trophoblast sphere.

Embryonic Germ Layers — Week 3 Characteristic embryonic germ layers first develop in the embryoblast during week 3. First, a midline primitive streak appears in the caudal ­epiblast of the embryonic disc. Epiblast cells proliferate, and the streak grows cranially by adding new cells caudally. Cells of the primitive streak undergo an epithelial-mesenchymal ­transition, detaching and migrating internally (deep) to form a broad new mesoderm (mesoblast) layer between the epiblast and hypoblast. This early mesenchyme condenses initially at the midline to form the rod-like notochord, the axial mesoderm that serves as an organizing center ­inducing the further development of other tissues. Other mesenchymal cells from the epiblast migrate deeper to displace hypoblast cells, forming the embryonic endoderm that roofs the yolk sac. Remaining epiblast cells become the embryonic surface ectoderm.

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Somites, Lateral Mesoderm, and the Neural Tube — Week 4 In the fourth week, other mesenchyme condenses lateral to the notochord, forming right and left continuous masses of (1) paraxial, (2) intermediate, and (3) lateral (plate) mesoderm (from medial to lateral). The paraxial mesoderm condenses into a bilateral column of segmental somites, each having sclerotome, myotome, and dermatome subcomponents. Sclerotomes will differentiate into bony elements; myotomes will form associated segmental skeletal muscle; and dermatomes will produce related connective tissue, ligaments, and dermis. Sclerotomes further differentiate around the notochord, forming the vertebrae around the developing spinal cord. Cavitation separates the early lateral mesoderm into two layers — outer parietal mesoderm and inner splanchnic mesoderm — establishing the embryonic body cavity (coelom) (Figure 1). The inner surface of the parietal and the outer surface of the splanchnic layers become lined with a cuboidal mesothelium. The parietal layer of mesoderm develops into the main muscle and connective tissue masses of the thoraco-abdominal wall (somatopleure), surfaced by ectodermally derived skin. Splanchnic ­mesoderm condenses around early visceral epithelium, forming the smooth muscle and connective tissue walls (splanchnopleure) of viscera (e.g., the esophagus). Further development of the thoracic wall is covered below. The notochord also induces midline ectoderm to form the neural plate, which folds into the neural tube and ultimately develops into the central nervous system. Neural crest cells form between the rim of the neural plate and lateral surface ectoderm, then they transition to ­mesenchyme and migrate throughout the developing body to establish dorsal root and autonomic ganglia, adrenal medulla, meninges, Schwann cells, melanocytes, and bone, muscle, and connective tissues of the pharyngeal arches.

Heart and Cardiovascular System — Weeks 3 to 8 In the embryonic disc rostral to the neural plate (cardiogenic region), mesenchymal cells derived from the splanchnic mesoderm proliferate and form isolated angiogenic cell clusters (blood islands), which soon canalize

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into paired endocardial heart tubes. These tubes fuse to form the primordial heart tube, and other angiogenic clusters fuse to form the primitive major vessels. Additional splanchnic mesoderm condenses around the heart tube and differentiates into the primordial myocardium, which begins to contract at the beginning of the fourth week of development. Cavitation in the surrounding mesenchyme produces the early pericardial cavity, and this becomes continuous with the coelomic spaces of the lateral mesoderm. The primordium of the heart tube consists of four partial “chambers”: bulbus cordis, ventricle, atrium, and sinus venosus (in rostralcaudal order). Rostrally, the bulbus cordis is continuous with the truncus arteriosus (precursor of the ascending aorta and pulmonary trunk). The bulbus cordis becomes part of the ventricles. Three systems of paired veins drain into the sinus venosus of the ­primordial heart: the vitelline system (which becomes the portal system draining the gut), the cardinal veins (which form the caval and the azygos systems), and the umbilical system (which involutes after birth). As the heart tube grows, it folds and soon acquires the general e­ xternal configuration of the mature heart. The heart becomes partitioned into four chambers between the fourth and seventh weeks of development, beginning with the ingrowth of dorsal and ventral endocardial cushions. Fusion of the cushions creates right and left atrioventricular canals, around which the atrioventricular valves will develop. Atria are separated by the down-growing septum primum, followed by the septum secundum just to the right of the primum. The septum primum forms a flap valve over the foramen ovale in the septum secundum. During this same period, an apical interventricular septum grows toward the endocardial cushions and divides the ventricles. A portion of the endocardial cushion produces the membranous septum that closes off the interventricular canal. Right and left conotruncal ridges form the aorticopulmonary septum, partitioning the conus arteriosus into separate pulmonary and aortic channels.

Gut, Esophagus, Trachea, and Lungs — Week 3 to 8 Years The primitive gut is formed by infolding of portions of the endodermlined yolk sac. This endoderm gives rise to the epithelium of the

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digestive tract and the parenchyma of its derivatives: airways and lungs, tracheobronchial and GI glands. In general, the connective tissue, muscular, and intraperitoneal components of the gut derivatives originate from splanchnic mesoderm. The primitive gut is divided into four major portions. The pharyngeal gut or pharynx extends from the buccopharyngeal membrane (at the opening of the oral cavity) to the tracheobronchial diverticulum (site of the larynx and lung buds). The foregut, caudal to the pharyngeal tube, extends distally as far as the liver bud. The midgut extends from the liver bud to the junction of the second 2/3 of the mature transverse colon. The hindgut extends from the distal 1/3 of the transverse colon to the cloacal membrane. Around the middle of the fourth week of development, the lower ­respiratory system begins to develop from a median laryngotracheal groove in the floor of the caudal pharynx. The groove deepens to form the tracheobronchial diverticulum (respiratory primordium), which soon becomes separated from the foregut by mesenchymal tracheoesophageal folds that fuse to form a tracheoesophageal septum. This separates the proximal esophagus and the developing laryngotracheal tube. The esophagus lengthens rapidly with the growth of the heart, attaining final relative length by week 7. Striated muscle of the upper esophagus develops from pharyngeal arch mesenchyme. Lower esophageal smooth muscle differentiates from splanchnic mesoderm. During the fourth week, the tracheobronchial diverticulum develops a tracheal bud at its distal end: This bud subsequently bifurcates into two bronchial (lung) buds during the early part of the fifth week. Each ­bronchial bud soon enlarges to form a main bronchus, and then each bronchus give rise to two new bronchial buds, which develop into secondary bronchi. The right inferior secondary bronchus then divides into two bronchi. Within the thorax, these buds are surrounded by mesothelium, which will later become visceral pleurae. Airway and lung primordia also grow with intimate relationships to precursors of pulmonary artery branches, pulmonary veins, and bronchial branches of the thoracic aorta. The secondary bronchi supply the lobes of the developing lungs. Each bronchus undergoes progressive branching to form segmental bronchi. Each segmental bronchus, along with its surrounding mesenchyme, is the primordium of a bronchopulmonary segment. Branching continues until

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about 17 orders of branches have formed. Additional airways are formed after birth until about 24 orders of branches are present. Lung development is divided into four periods. During the pseudoglandular period (6–16 weeks), the bronchi and terminal bronchioles form. During the canalicular period (16–26 weeks), lumina of the bronchi and terminal bronchioles enlarge; the respiratory bronchioles and alveolar ducts develop; and lung tissue becomes highly vascular. During the ­terminal saccular period (26 weeks to birth), the alveolar ducts give rise to terminal saccules (primordial alveoli). Terminal saccules are initially lined with cuboidal epithelium that attenuates to squamous epithelium. The alveolar period, the final stage of lung development, extends from 32 weeks to about 8 years of age.

Pharyngeal Arches and Thymus, Weeks 4 to 12 The face and major structures of the head and neck develop from pharyngeal (or branchial) arch tissues. The process begins when neural crest cells migrate into the regions just lateral to the primitive pharynx, forming bilateral, ventrally extending bars of mesenchyme deep to the surface ectoderm. This mesenchyme produces characteristic muscle masses, ­cartilage, bone, and connective tissue for each arch, and each is supplied by its own specific cranial nerve and aortic arch artery. The first four of these early arches are separated by external, ectodermally lined clefts and by internal, endodermally lined pouches. In general, the endodermal lining of pouches 2, 3, and 4 gives rise to lymphoid or glandular ­ tissues. In the fifth week of development, the dorsal portion of pouch 3 differentiates into inferior parathyroid gland tissue and the ventral portion of pouch 3 gives rise bilaterally to primordia of the thymus. Both thymic primordia subsequently disconnect from the pharyngeal wall and migrate medially and caudally, along with the inferior parathyroid precursors. The main masses of thymic tissue migrate rapidly into the anterior ­thorax, where they fuse. Occasionally, tail portions of thymic tissue may persist as isolated cell nests along the cervico-thoracic migration path or embedded in the thyroid.

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Thoracic Walls — Weeks 4 to 8 With rapid growth in week 4, the embryo continues folding at its rostral, caudal, and lateral extents. The developing heart moves ventrally and caudal to the head fold and primitive brain, coming to lie ventral to cervical and thoracic foregut/esophagus. As the somites develop further, right and left lateral folds (ectoderm and parietal mesoderm) extend and curve ventrally toward the midline, enclosing the primitive heart and lung buds. The folds meet and fuse at the midline (Figure 2), enclosing the thoracic and abdominal contents, while leaving a gap through which the yolk stalk and sac protrude. Ribs are formed by ventral outgrowths from thoracic somite sclerotomes. The early “floor” of the thorax is formed by the septum transversum, the mesodermal plate lying between the pericardial sac and the yolk stalk. The diaphragm differentiates in parts from the septum transversum, lateral (parietal) mesoderm, ventral mesentery, and pleural folds. Its surfaces are lined by mesothelium. The superior mesothelial layer becomes the ­diaphragmatic parietal pleurae, the bases of the left and right pleural sacs,

Figure 2.    Transverse section of somite embryo showing completed folding of thoracic wall and neural tube, and fused heart tube relationship to the gut tube (esophagus). Modified from Sadler (2014).

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with the fibrous pericardium fused between them to the central tendon of the diaphragm. The mammary glands are modified sudoriferous glands formed by ectodermal epithelial-mesenchymal interactions. Epithelial mammary ridges (crests) are formed in the epidermis along a line running from the base of the upper limb to the lower limb root. Depressed thoracic ­remnants of ridge tissue persist and grow into the underlying mesenchyme. These epithelial pits sprout buds, which canalize and form lactiferous ducts. Shortly after birth the pits are transformed into nipples by (dermal) ­mesenchymal proliferation.

References 1. Moore KL, Persaud TVN. The Developing Human: Clinically Oriented Embryology, 9th ed. Philadelphia, PA: Saunders Elsevier, 2011. 2. Sadler TW. Langman’s Medical Embryology, 13th ed. Baltimore, MD: Lippincott Williams & Wilkins, 2014.

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B.  Medical Evaluation of Thoracic Oncology Patients

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Pulmonary Evaluation of Thoracic Oncology Patients Rana Lee Adawi Awdish, Said Chaaban

Identifying patients who are candidates for surgical resection is especially meaningful in localized lung cancer, as surgery confers the greatest opportunity for cure.1,2 Physicians tasked with pre-operative evaluation must include both a perioperative mortality risk assessment as well as a prediction of post-operative lung function in order to optimally counsel patients on anticipated outcomes.3 Due both to advanced stage of cancer at presentation and comorbid states, only one-third of patients are ultimately considered candidates for surgical resection.1 Despite modern surgical, anesthetic, and postoperative techniques, their still exists a perioperative mortality rate of 1–5%.1,3 Though the British Thoracic Society (BTS), The American College of Chest Physicians (ACCP), and the European Respiratory Society (ERS) vary in their recommendations for risk assessment, there are commonalities that can guide clinical decision making.3–5 Perhaps the most critical initial test is spirometric assessment of the FEV1 and the diffusing capacity (DLCO).3,6 Calculation of predicted postoperative (PPO) FEV1 and DLCO is integral in determining the risk of operative complications.3,7 Calculation of PPO values should be based on perfusion scan for patients undergoing pneumonectomy. For segmentectomy or lobectomy, equations based on the fraction of resected lung are suitable. The same equations are used for PPO DLCO, and both must be

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individually calculated as FEV1 DLCO represent different physiologic compartments and are not strongly correlated.

In pneumonectomy: PPO FEV1 = Pre-operative FEV1 X (1-fraction of the total perfusion for the resected lung) Lobectomy or segmentectomy: PPO FEV1 = Pre-operative FEV1 x (1-fraction of the resected lung) Fraction of the resected lung = Number of segments to be removed/ Total number of functional segments (19 segments)

As straightforward as this approach may seem, as lung cancer and COPD so often exist in concert, there are times when the resection of diseased parenchyma may actually result in an improvement in respiratory mechanics and elastic recoil. Indeed, some studies have shown an improvement in respiratory function three to six months after lobectomy in patients with moderate to severe emphysema.8 Also important to consider is that lung segment counting does not necessarily account for segment function. For functional assessment, analysis of the already available data from CT scan offers better quantitative assessment for the prediction of the post-operative lung function.7,9,10 If both the PPO FEV1 and PPO DLCO are more than 60% predicted, the patient is considered a suitable candidate for resection and no further testing is recommended.3,11 A PPO FEV1 that is less than 30% has been associated with an increase in morbidity and mortality as high as 43% and 12%, respectively.3,5 If either PPO FEV1 and/or PPO DLCO fall in the less than 30% range, then further testing with CPXT is warranted.3,12 Should the PPO FEV1 or the PPO DLCO fall between 30% and 60%, then additional testing with a shuttle walk test or stair climb test is recommended for risk stratification (Figure 1).3 The stair climb test is a surrogate for maximal oxygen consumption (VO2 max) and is easy, rapid, and inexpensive. A climb distance of 22 m correlates with a VO2 max greater than 15 ml/kg/min, and patients who can achieve this are considered at low risk for surgery.3,5,13 Despite the ease of the stair climb, there exists sufficient variability in administration, which may make it less reliable, so some centers favor the shuttle walk

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Figure 1    Adapted from Colice GL, Shafazand S, Griffin JP, Keenan R, Bolliger CT; American College of Chest Physicians. Chest. 2007 Sep;132(3 Suppl):161S-77S. ACCP Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidenced-based clinical practice guidelines (2nd edition).

test.3 This test involves walking back and forth between two 10-meter marks apart, a distance of 400 m, or 25 shuttles, before shortness of breath confers a positive predictive value of 90% for a VO2 max of more than 15 ml/kg.3 Patients who cannot meet either a 22 m stair climb or a 400 m shuttle distance require further evaluation with a cardiopulmonary exercise test (CPXT).3,14 Assessment of VO2 max is a well-validated surrogate marker for mortality and morbidity.12 If the VO2 max falls between 10–15 ml/kg/min (between 35% and 75% predicted), there is increased risk of perioperative mortality. A value greater than 20 ml/kg/min is not associated with increased risk of morbidity or mortality. If VO2 max is less than 10 ml/kg/ min (35% predicted), patients should generally be advised to pursue other non-surgical treatment modalities.3 If CPXT is not available, then a

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climbing test may qualify as a good screening test and patients achieving 22 m can undergo surgery with no further testing done.14 Simply not being able to perform exercise testing confers an increased risk of perioperative mortality following resection.8 Several scoring systems have been used to assess perioperative ­mortality. Unfortunately, none have proven to be sufficiently predictive.3–5 The European Society for Thoracic Surgery Mortality Score was more predictive of mortality than the European Society Objective Score but the discriminative ability was slightly worse.15 The Thoracoscore published by the French Society of Thoracic and Cardiovascular Surgery, though included in the BTS Guidelines, underestimates risk in low-risk cases and may overestimate risk in high-risk cases.3–5 If the patient requires neoadjuvant therapy, then a repeat spirometry with diffusion is warranted as some chemotherapeutic modalities decrease the diffusing capacity.16 The ERS guidelines share many similarities with the ACCP recommendations, but testing proceeds in a slightly different order. Baseline spirometry dictates whether patients should proceed to a CPXT (FEV1 or DLCO < 80%). IF VO2 max is prohibitively low ( 20 ml/kg/min) the testing is deemed conclusive. Patients in the intermediate range of 10–20 ml/kg/min VO2 max, require calculation of post-operative FEV1 and DLCO. If both the PPO FEV1 and PPO DLCO are greater than 30%, then the patient is considered a candidate for a limited resection. One value of less than 30%, however, requires a post-operative V02 max assessment. If the PPO VO2 is more than 35% or more than 10 ml/kg/min, then a limited resection could be performed. If PPO VO2 is less than 35%, it is not recommended to proceed with surgery.5 The BTS favors a PPO FEV1 and PPO DLCO cutoff value of 40%. Patients who do not meet this lower limit go on to a functional assessment of exercise capacity. If the distance walked on a shuttle walk test was more than 400 m or the VO2 max on the CPXT is more than 15 ml/kg/min, patients were classified into the moderate-risk group. This risk designation requires honest discussion of possible post-operative pulmonary disability as definition of a successful outcome is truly dependent on individual patient preferences. The BTS society did not include the stair

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climb test as part of the functional assessment. Patients who do not meet the above criteria are considered high-risk, and should be informed of the risks of severe post-operative dyspnea and possibly the need for oxygen, as individual patient preference will determine whether this is an acceptable outcome.4 The BTS and the Society for Cardiothoracic Surgery advocate for the utility of ventilation scintigraphy or perfusion scintigraphy for prediction of post-operative lung function if a ventilation perfusion mismatch is present. They also recommended the use of a CT or MRI for prediction of post-operative lung function, if the resources are available.4 Risk stratification and thorough assessment of surgical candidacy, though complex, is guided by discrete values and validated testing algorithms.17 Patients who meet the criteria should not be denied surgery irrespective of age.2,18,19 Patients who are deemed as non-surgical candidates are often still candidates for aggressive non-operative treatment.17 As many physiological variables including immune function, body weight and composition, insulin regulation, and metabolic syndrome are influenced by patients’ exercise tolerance, interventions focused upon improving exercise tolerance may improve prognosis.20 To this end, pulmonary rehabilitation should be prescribed in patients with poor exercise tolerance as it may increase VO2 max, which is not a static value, and improve surgical and non-surgical outcomes.21

References   1. Mazzone P. Preoperative evaluation of the lung resection candidate. Cleve Clin J Med May 2012; 79 Electronic Suppl 1: eS17–22.   2. Spyratos D, Zarogoulidis P, Porpodis K, et al. Preoperative evaluation for lung cancer resection. J Thorac Dis. Mar 2014; 6 Suppl 1: S162–166.   3. Brunelli A, Kim AW, Berger KI, Addrizzo-Harris DJ. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest May 2013; 143(5 Suppl): e166S–190S.   4. Lim E, Baldwin D, Beckles M, et al. Guidelines on the radical management of patients with lung cancer. Thorax Oct 2010; 65 Suppl 3: iii1–27.

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 5. Salati M, Brunelli A. Preoperative assessment of patients for lung cancer surgery. Curr Opin Pulm Med Jul 2012; 18(4): 289–294.  6. Ferguson MK, Dignam JJ, Siddique J, Vigneswaran WT, Celauro AD. Diffusing capacity predicts long-term survival after lung resection for cancer. Eur J Cardiothorac Surg May 2012; 41(5): e81–86.   7. Santini M, Fiorello A, Vicidomini G, Di Crescenzo VG, Laperuta P. Role of diffusing capacity in predicting complications after lung resection for cancer. Thorac Cardiovasc Surg Sep 2007; 55(6): 391–394.   8. Carretta A, Zannini P, Puglisi A, et al. Improvement of pulmonary function after lobectomy for non-small cell lung cancer in emphysematous patients. Eur J Cardiothorac Surg May 1999; 15(5): 602–607.   9. Wu MT, Pan HB, Chiang AA, et al. Prediction of postoperative lung function in patients with lung cancer: Comparison of quantitative CT with perfusion scintigraphy. Am J Roentgenol Mar 2002; 178(3): 667–672. 10. Papageorgiou CV, Kaltsakas G, Koulouris NG. Prediction of postoperative lung function in patients with lung cancer: The role of quantitative CT imaging. Chest Apr 2014; 145(4): 927–928. 11. Gaballo A, Corbo GM, Valente S, Ciappi G. Preoperative evaluation and risk factors of lung cancer. Rays Oct–Dec 2004; 29(4): 391–400. 12. Loewen GM, Watson D, Kohman L, et al. Preoperative exercise Vo2 measurement for lung resection candidates: Results of Cancer and Leukemia Group B Protocol 9238. J Thorac Oncol Jul 2007; 2(7): 619–625. 13. Brunelli A, Monteverde M, Al Refai M, Fianchini A. Stair climbing test as a predictor of cardiopulmonary complications after pulmonary lobectomy in the elderly. Ann Thorac Surg Jan 2004; 77(1): 266–270. 14. Brunelli A, Pompili C, Salati M. Low-technology exercise test in the preoperative evaluation of lung resection candidates. Monaldi Arch Chest Dis Jun 2010; 73(2): 72–78. 15. Bradley A, Marshall A, Abdelaziz M, et al. Thoracoscore fails to predict complications following elective lung resection. Eur Respir J Dec 2012; 40(6): 1496–1501. 16. Leo F, Solli P, Spaggiari L, et al. Respiratory function changes after chemotherapy: An additional risk for postoperative respiratory complications? Ann Thorac Surg Jan 2004; 77(1): 260–265. 17. Baser S, Shannon VR, Eapen GA, et al. Pulmonary dysfunction as a major cause of inoperability among patients with non-small-cell lung cancer. Clin Lung Cancer Mar 2006; 7(5): 344–349. 18. Damhuis RA, Schutte PR. Resection rates and postoperative mortality in 7,899 patients with lung cancer. Eur Respir J Jan 1996; 9(1): 7–10.

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19. Dillman RO, Zusman DR, McClure SE. Surgical resection and long-term survival for octogenarians who undergo surgery for non-small-cell lung cancer. Clin Lung Cancer Mar 2009; 10(2): 130–134. 20. Brunelli A, Pompili C, Berardi R, et al. Performance at preoperative stairclimbing test is associated with prognosis after pulmonary resection in stage I non-small cell lung cancer. Ann Thorac Surg Jun 2012; 93(6): 1796–1800. 21. Bobbio A, Chetta A, Ampollini L, et al. Preoperative pulmonary rehabilitation in patients undergoing lung resection for non-small cell lung cancer. Eur J Cardiothorac Surg Jan 2008; 33(1): 95–98.

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Cardiac Evaluation of Thoracic Oncology Patients Carla Holcomb, Mary T. Hawn

Introduction This section will review the cardiac considerations of the thoracic oncology patient. The purpose of this section is to provide a general overview regarding the identification and management of specific cardiac toxicities associated with chemotherapy and radiation treatments frequently encountered with thoracic malignancies. Additionally, we will discuss the pre-operative cardiac assessment of the oncology patient undergoing surgical treatment.

Cardiotoxicity of Cancer Therapies: Implications of Chemotherapy and Radiation The use of chemotherapeutic agents is a mainstay of thoracic oncologic treatment, especially in advanced stages of cancer. While chemotherapy can be effective in tumor regression, its use is often limited by systemic toxicity. Advancements in cancer treatments have prolonged patient survival and in effect uncovered the unintended and lasting side effects associated with chemotherapy. One of the most well-known examples of chemotherapy-induced cardiotoxicity is that of the anthracycline drug, Doxorubicin. Doxorubicin has efficacy for the treatment of breast cancer, Hodgkins and non-Hodgkins lymphoma.1 The toxicity of doxorubicin is dose-dependent and has been linked to cardiomyopathy, congestive heart failure, and left ventricular dysfunction.2,3 Retrospective studies have shown between 5% and 7% of patients develop doxorubicin-induced congestive heart failure, depending on dosage.4 Another frequently 21

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encountered chemotherapy agent linked to cardiac toxicity is the alkylating agent Cisplatin. This drug is used in the treatment of small cell lung cancer, non-small cell lung cancer, and esophageal cancer. Cardiotoxic side effects associated with cisplatin include hypertension, left ventricle hypertrophy, myocardial ischemia, and congestive heart failure.3,5 The risk for congestive heart failure with cisplatin is increased following chest irradiation or anthracycline treatment (citation). Other potentially cardiotoxic chemotherapy drugs include target therapies, such as the HER2-receptor blocker, Trastuzumab, used in the treatment of metastatic breast and gastroesophageal junction cancers. This drug has been linked to the development of myocardial dysfunction and heart failure, and can potentiate the cardiac effects associated with anthracyclines.6 In addition to chemotherapy, radiation treatment has been associated with cardiotoxic effects. External beam radiation can cause extensive damage to the pericardium leading to effusion, pericarditis,7 and myocardial fibrosis resulting in valvular heart disease.8 Additionally, radiation to the thorax can induce vascular injury leading to coronary artery disease.9 The proposed mechanism of radiation-induced coronary artery disease is through proliferation of fibrous tissue that leads to luminal narrowing10 but interestingly, thoracic external beam radiation has not been shown to affect coronary stent restenosis rates after percutaneous coronary intervention.11 Radiation is frequently used concomitantly with chemotherapeutic agents and it is important to be aware that radiation therapy can amplify the cardiotoxicity of the chemotherapy agents mentioned above.12 Understanding the potential cardiac effects of cancer therapies is essential in the prevention and treatment of these side effects. All patients being treated with potentially cardiotoxic chemotherapeutics or radiation therapy should undergo a full cardiac workup including an examination of the patient’s history, a physical, an electrocardiogram (EKG), and a transthoracic echocardiogram with special attention to the assessment of systolic and diastolic functions.13 During treatment, the use of cardiac biomarkers is gaining popularity as a means of detecting early cardiac toxicity from cancer therapy. Monitoring serum elevations in the levels of Troponin-I throughout treatment has allowed clinicians to identify at-risk patients and provide goal-directed therapies such as initiation of ACE-I to halt the progression of congestive heart failure.14,15 Patients

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should continue to be monitored for the development of potential cardiac side effects in the time following the completion of chemotherapy and radiation treatment. While there is no consensus on how often asymptomatic patients should be screened for the development of adverse cardiac effects ­post-treatment, expert opinion would suggest repeating a transthoracic echocardiogram every five to ten years. In the event that patients should develop any signs of heart failure, ACE-inhibitors and beta-blockers should be instituted accordingly, and standard treatment with stenting or coronary artery bypass grafting may be necessary for those that develop radiation-induced coronary artery disease.

Cardiac Assessment Prior to Surgical Therapy The oncologic patient undergoing surgical treatment is at risk for postoperative adverse events as a result of their disease state, the systemic effects of neoadjuvant therapy, the risk of the surgical intervention, and the underlying surgical risk factors that are also risk factors for cancers that result from activities such as smoking. Therefore, the identification of at-risk patients and targeted interventions are crucial in ensuring the best surgical outcomes. Post-operative myocardial infarction is an important source of morbidity and mortality, especially for those undergoing thoracic procedures.

Pre-Operative Evaluation: Cardiac Risk Factors and Functional Status Patients requiring surgical therapy for malignancy require a pre-operative evaluation commensurate with the invasiveness and extent of the ablative procedure. The presence of active cardiac conditions (unstable or severe angina, recent myocardial infarction, decompensated heart failure, arrhythmias, or valvular disease) should prompt a pre-operative cardiology referral prior to undergoing surgery. Risk factors for the development of adverse cardiac events include ischemic heart disease, congestive heart failure, insulin-dependent diabetes, kidney disease,

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cerebrovascular disease, and high-risk surgery.16 In addition to identifying cardiac risk factors, a pre-operative assessment is incomplete without quantifying a patient’s functional capacity. This can be achieved by the results of a formal stress test, measured in the units of metabolic equivalents (METs). One MET is defined as the basal oxygen consumption of a 40-year-old, 70-kg male, and ranges from 0 to 10. Poor functional capacity is generally defined as 4 METs. Asymptomatic patients able to perform activities >4 METs do not warrant further cardiac testing prior to surgery.18 For those patients with a functional capacity of 80%) for detecting patients with a geriatric risk profile on GA was observed with G-8 and fTRST.17,18

Assessment of Older Patients Needing Surgery In western countries, surgeons are regularly faced with octogenarians with resectable early stage lung cancer. The current literature on post-operative outcome in the older patients confirms the well-known correlations between pathologic stage, survival, lung function, and morbidity. There are recent studies that could not confirm the previous assumption of prohibitively high mortality and morbidity in elderly patients treated with lung resection for lung cancer,19,20,21 but no specific randomized controlled trial has yet been performed. As mentioned before, there is emerging evidence that in addition to a complete history and the cardiac and pulmonary pre-operative evaluation, GA is part of the decision process of geriatric surgical patients to establish their fitness and to predict post-operative complications. Therefore, diagnostic and therapeutic procedures of thoracic surgery on geriatric patients should be discussed in a specialized multidisciplinary team in order to offer a personalized approach and

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optimize care. In 2012 an expert panel from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) and the American Geriatrics Society (AGS) elaborated practice guidelines for optimal pre-operative assessment in the elderly. The authors selected evidence-based recommendations about following diagnosis: cognitive impairment and dementia, decision-making capacity, depression, risk factors for post-operative delirium, screening for alcohol and substance abuse, cardiac and pulmonary evaluation, functional status, mobility limitation, fall risk, frailty score, nutritional status, medication, family and social support, and diagnostic tests.22,23 The Preoperative Assessment of Cancer in the Elderly (PACE) was developed by the SIOG to determine the individualized risk for surgical intervention and includes ECOGperformance status, mini mental status, comorbidities, ADLs, IADL, depression, fatigue, the American Society of Anesthesiologists (ASA) grade and the Physiologic and Operative Severity Score for enUmeration of Mortality and Morbidity (POSSUM).24,25,26 PACE is also relevant in the pre-operative evaluation for elderly patients needing thoracic surgery.27 However, the appropriate pre-operative geriatric evaluation in this population should be validated in prospective trials.

References   1. Owonikoko TK, Ragin CC, Belani CP, Oton AB, Gooding WE, Taioli E, et al. Lung cancer in elderly patients: An analysis of the surveillance, epidemiology and end results database. J Clin Oncol 2007; 25(35): 5570–5577.   2. Sawhney R, Sehl M, Naeim A, et al. Physiologic aspects of aging: Impact on cancer management and decision making. Cancer J 2005; 11(6): 449–460.  3. Hutchins LF, Unger JM, Crowley JJ, Coltman Jr CA, Albain KS. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999; 341: 2061–2067.   4. Jatoi A, Hillman S, Stella P, Green E, et al. Should elderly non-small cell lung cancer patients be offered elderly-specific trials? Results of a pooled analysis from the North Central Cancer Treatment Group. J Clin Oncol 2005; 23(36): 9113–9119.  5. Davidoff AJ, Tang M, Seal B, Edelman MJ. Chemotherapy and survival benefit in elderly patients with advanced non-small cell lung cancer. J Clin Oncol 2010; 28(13): 2191–2197.

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  6. The National Comprehensive Cancer Network. NCCN Older Adult Oncology 2015. Available at: http://www.nccn.org  7. Extermann M, Aapro M, Bernabei R, Cohen HJ, Droz JP, Lichtman S, et al. Task Force on CGA of the International Society of Geriatric Oncology. Use of comprehensive geriatric assessment in older cancer patients: Recommendations from the task force on CGA of the International Society of Geriatric Oncology (SIOG). Crit Rev Oncol Hematol 2005; 55(3): 241–252.   8. The International Society of Geriatric Oncology (SIOG) Clinical Guidelines. Available at http://www.siog.org   9. Wildiers H, Heeren P, Puts M, Topinkova E, Janssen-Heijnen ML, Extermann M, et al. International Society of Geriatric Oncology Consensus on Geriatric Assessment in Older Patients with Cancer. J Clin Oncol 2014; 32(24): 2595–2603. 10. Ramjaun A, Nassif MO, Krotneva S, Huang AR, Meguerditchian AN. Improved targeting of cancer care for older patients: A systematic review of the utility of comprehensive geriatric assessment. J Geriatr Oncol 2013; 4(3): 271–281. 11. Versteeg KS, Konings IR, Lagaay AM, van de Loosdrecht AA, Verheul HM. Prediction of treatment-related toxicity and outcome with geriatric assessment in elderly patients with solid malignancies treated with chemotherapy: A systematic review. Ann Oncol 2014; 25(10): 1914–1918. 12. Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: The Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer 2012; 118: 3377–3386. 13. Aliamus V, Adam C, Druet-Cabanac M, et al. Geriatric assessment contribution to treatment decision making in thoracic oncology [in French]. Rev Mal Respir 2011; 28: 1124–1130. 14. Kenis C, Bron D, Libert Y, Decoster L, Van Puyvelde K, Scalliet P, Cornette P, et al. Relevance of a systematic geriatric screening and assessment in older patients with cancer: Results of a prospective multicentric study. Ann Oncol 2013; 24(5): 1306–1312. 15. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: A prospective multicenter study. J Clin Oncol 2011; 29: 3457–3465. 16. Hurria A, Cirrincione CT, Muss HB, Kornblith AB, Barry W, et al. Implementing a geriatric assessment in cooperative group clinical cancer trials: CALGB 360401. J Clin Oncol 2011; 29(10): 1290–1296.

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17. Decoster L, Van Puyvelde K, Mohile S, Wedding U, Basso U, Colloca G, et al. Screening tools for multidimensional health problems warranting a geriatric assessment in older cancer patients: An update on SIOG recommendations. Ann Oncol 2015; 26(2): 288–300. 18. Kenis C, Decoster L, Van Puyvelde K, De Grève J, et al. Performance of two geriatric screening tools in older patients with cancer. J Clin Oncol 2014; 32(1): 19–26. 19. Port JL, Kent M, Krost RJ, Lee PC, Levin MA, Flieder D, et al. Surgical resection for lung cancer in the octogenarian. Chest 2004; 126(3): 733–738. 20. Dominguez-Ventura A, Cassivi SD, Allen MS, Wigle DA, Nichols FC, Pairolero PC, et al. Lung cancer in octogenarians: Factors affecting longterm survival after resection. Eur J Cardiothorac Surg 2007; 32: 370–374. 21. Chambers A, Routledge T, Pilling J, Scarci M. In elderly patients with lung cancer is resection justified in terms of morbidity, mortality and residual quality of life? Interact Cardiovasc Thorac Surg 2010; 10: 1015–1021. 22. Chow WB, Rosenthal RA, Merkow RP, et al. Optimal preoperative assessment of the geriatric surgical patient: A best practices guideline from the American College of Surgeons National Surgical Quality Improvement Program and the American Geriatrics Society. J Am Coll Surg 2012; 215(4): 453–466. 23. The ACS NSQIP/AGS best practice guidelines: Optimal preoperative assessment of the geriatric surgical patient. Available at http://site.acsnsqip. org/wp-content/uploads/2011/12/ACS-NSQIP-AGS-Geriatric-2012Guidelines.pdf. 24. Audisio RA, Ramesh H, Longo WE, et al. Preoperative assessment of surgical risk in oncogeriatric patients. Oncologist 2005; 10: 262–268. 25. Pope D, Ramesh H, Gennari R, et al. Pre-operative assessment of cancer in the elderly (PACE): A comprehensive assessment of underlying characteristics of elderly cancer patients prior to elective surgery. Surg Oncol 2006; 15: 189–197. 26. Audisio RA, Pope D, Ramesh HS, et al. Shall we operate? Preoperative assessment in elderly cancer patients (PACE) can help. A SIOG surgical task force prospective study. Crit Rev Oncol Hematol 2008; 65(2): 156–163. 27. Jaklitsch M, Billmeier S. Preopertive Evaluation and Risk Assessment for Elderly thoracic Surgery Patients. Thorac Surg Clin 2009; 19(3): 301–312.

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C.  Imaging of the Thorax

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Standard Radiography David M. Naeger, W. Richard Webb

Chest radiographs are currently obtained using digital techniques and are typically interpreted on Picture Archiving and Communication Systems (PACS) capable of different types of image manipulation. Because of their low cost and wide availability, chest radiographs continue to have an important role in the practice of thoracic oncology, often in the initial assessment of a patient or in the evaluation of non-specific respiratory complaints, such as dyspnea, cough, or chest pain. Radiographs have only moderate sensitivity and specificity for the diagnosis of many important abnormalities associated with intrathoracic neoplasms. They are of limited value in the staging of patients with a known malignancy or in followup after treatment, though they have value in the immediate post-operative period. Radiographs may also be used in assessing the size of malignant pleural effusions, including after drainage. Chest radiographs may be the first study to suggest that a patient has a thoracic malignancy. Usually symptoms caused by the tumor itself lead to the examination, although many tumors are detected on radiographs ordered for other reasons. A negative chest radiograph in a patient with non-specific symptoms and a low clinical suspicion for malignancy may be sufficient for evaluation. However, a negative radiograph in a patient with a high clinical suspicion of malignancy or persistent and unexplained respiratory symptoms is often followed with a repeat radiograph or a computed topography (CT) scan. Of note, no study to date has convincingly demonstrated that chest radiographs should be used to screen asymptomatic patients who are at risk for developing lung cancer.

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Abnormal chest radiographs that have a finding suggestive of malignancy almost always lead to further assessment with chest CT; commonly seen abnormalities include lung nodules/masses, persistent atelectasis/ pneumonia, hilar masses, mediastinal abnormalities, and chest wall/pleural masses. Radiographs alone lack the accuracy to fully characterize these abnormalities or evaluate for disease spread.

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Computed Tomography David M. Naeger, W. Richard Webb

Computed tomography (CT) is the single most important imaging study in the evaluation of thoracic oncology patients. Current CT scanners allow for complete volumetric imaging of the chest during a single breath hold and with a low radiation dose. Chest CT is commonly ordered to further assess an abnormality detected on a chest radiograph. Chest CT is also commonly ordered without a preceding chest radiograph when a patient’s presenting symptoms are acute, severe, or confer a sufficiently high pretest probability for malignant or non-malignant disease. The National Lung Screening Trial (NLST) has demonstrated that low-dose Chest CT can be used to screen for lung cancer in high-risk patients resulting in a reduction in overall and lung cancer mortality.1 Lung cancer screening will be covered in a dedicated section later in this text. CT obtained for suspected or known thoracic malignancy should be acquired after intravenous contrast administration, provided there is no contraindication to administering iodinated contrast. Contrast enhancement allows for an improved evaluation of the mediastinum, hila, and chest wall.2 Reconstruction of the images with thin slices (1.25 mm) is optimal. Chest CT ordered for patients with a low probability of a malignancy, or when hematogenously-spread metastases are being sought, may be ordered without contrast. Low-dose screening CTs are almost always ordered without contrast. CT provides the most detailed morphologic assessment of lung, hilar, and mediastinal abnormalities of all the available imaging tests. CT findings can be used to differentiate pulmonary infection from malignancy with at least moderate accuracy,3 allows for the diagnosis of pericardial and pleural abnormalities, and can be used in the assessment of mediastinum, hilar, and chest wall structures. CT also allows for the 39

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tissue characterization of some mediastinal masses, including their enhancement characteristics, which may aid in the differential diagnosis. CT demonstrates moderate sensitivity in the detection of bone metastases. The radiologist’s interpretation of CTs of thoracic oncology patients improves when a complete history is provided, including current patient symptoms as well as prior and current treatments. CT can be used to guide biopsies of pulmonary nodules and masses, chest wall and pleural masses, and some mediastinal masses. Biopsy is generally reserved for nodules 8–10 mm in diameter or larger, although some smaller nodules can be biopsied if easily accessible. CT allows for the precise localization of the lesion to be biopsied and a safe path for the needle to traverse. CT guidance (compared to guidance with fluoroscopy) improves the biopsy yield particularly for smaller and more difficult-to-reach lesions.4 High success rates have been reported with relatively few complications categorized as severe (approximately 1%).5 Pneumothorax does result in a substantial minority of patients (~20–40%), though only a small portion of these patients require treatment with a chest tube.5,6 Biopsies of central lesions, lesions near emphysema or large vascular structures, and cavitary lesions carry a higher risk of complications.

References   1. National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med Aug 2011; 365(5): 395–409.   2. Cascade PN, Gross BH, Kazerooni EA, et al. Variability in the detection of enlarged mediastinal lymph nodes in staging lung cancer: A comparison of contrast-enhanced and unenhanced CT. Am J Roentgenol Apr 1998; 170(4): 927–931.  3. Erasmus JJ, Connolly JE, McAdams HP, Roggli VL. Solitary pulmonary nodules: Part I. Morphologic evaluation for differentiation of benign and malignant lesions. Radiographics Jan–Feb 2000; 20(1): 43–58.

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 4. van Sonnenberg E, Casola G, Ho M, et al. Difficult thoracic lesions: CT-guided biopsy experience in 150 cases. Radiology. May 1988; 167(2): 457–461.   5. Tomiyama N, Yasuhara Y, Nakajima Y, et al. CT-guided needle biopsy of lung lesions: A survey of severe complication based on 9783 biopsies in Japan. Eur J Radiol Jul 2006; 59(1): 60–64.  6. Laurent F, Michel P, Latrabe V, Tunon de Lara M, Marthan R. Pneumothoraces and chest tube placement after CT-guided transthoracic lung biopsy using a coaxial technique: Incidence and risk factors. Am J Roentgenol Apr 1999; 172(4): 1049–1053.

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Positron Emission Tomography (and PET/CT) David M. Naeger, W. Richard Webb

Positron emission tomography (PET) is a modality that images the radiation resulting from the decay of positron-emitting radiotracers. Emitted positrons collide with neighboring electrons, resulting in the annihilation of both, and the production of two high-energy photons that travel in opposite directions. The photons that escape the body can be detected by the scintillation crystals in PET cameras. The positron emitter most readily available and well-suited to imaging is Fluorine-18 (F-18). F-18 can be attached to a variety of compounds, though glucose is most commonly employed, resulting in the radiotracer 2‑[fluorine‑18]‑fluoro‑2‑­ deoxy‑D‑glucose (FDG). Approximately one hour after injection, PET images are acquired of the whole body or the whole body excluding the very top of the head and the legs. The images that result reveal the distribution of the labeled glucose in the body, including locations of physiologic metabolism (e.g., the brain), areas of FDG accumulation (e.g., the urine) and in abnormalities with high-level metabolism (e.g., tumors). PET images can be acquired alone or in sequence with a CT scan. The vast majority of PET scanners sold today are combined with a multi-slice CT scanner. The CT images serve multiple functions, though two are readily apparent. First, all PET images must be corrected for the attenuation caused by structures in the body and CT can be used to generate a map of this attenuation. Without this correction, the relative paucity of photons from deep structures results in photopenic defects on uncorrected images (which are often available for viewing) and the abundance of photons from superficial structures results in oversaturation. PET-only scanners generate a low-resolution attenuation map using an internal 43

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radiation source. The second main function of the CT images is to provide high-resolution morphologic imaging such that abnormalities detected by PET can be correlated to the CT images at the same location. Having anatomic correlation increases the sensitivity and specificity of PET. PET/CT readers will often interpret PET/CT studies on dedicated software that displays the PET and CT images separately as well as overlaid together; the review of each type of display, as well as a rotating whole-body maximum-intensity image, allows for the greatest interpretation accuracy. Though CT is commonly obtained as part of PET studies, the CT images of the chest are not generally of the same quality as a diagnostic chest CT, and may not be an adequate substitute. Most combined PET/ CTs are obtained without intravenous contrast, a choice that allows for the most accurate attenuation-correction of the PET images. Additionally, the CT scan from combined PET/CT studies is often acquired with a large field of view, thicker slice thickness, and free breathing, all of which result in lower special resolution. Some centers also use a very low-dose CT scanning protocol as part of their combined PET/CT protocols; such a technique is sufficient for attenuation correction purposes and can reduce the total radiation dose, but results in significant degradation of the CT image quality. One final caveat: the attention paid to interpreting the CT images varies by center. Some centers provide subspecialty CT interpretations as part of the combined PET/CT report, whereas others provide a very cursory review. One of the first accepted indications for PET imaging was for characterization of solitary pulmonary nodules (SPNs) less than or equal to 4 cm in size.1 The post-test probability of a nodule representing malignancy is substantially higher when metabolism is discernible on PET, though the degree to which the post-test probability increases is affected by the threshold used by the PET interpreter. In cases where a low threshold is used, the post-test probably of a nodule being cancer is moderately increased in PET positive cases, but substantially decreased in PET negative cases; the post-test risk of malignancy could potentially drop to a level in which a biopsy could be deferred and imaging follow-up selected. In modern practice, PET is usually reserved for troubleshooting difficult

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SPN cases, particularly when biopsying is considered risky or when the patient’s history and other test results seem discordant. In thoracic oncology, the most common indication for PET/CT is for the initial staging of a neoplasm. For non-small cell lung carcinoma, the most common thoracic malignancy, combined PET/CT has been shown to offer higher accuracy than PET or CT alone. Specifically, the metabolic information provided by PET improves sensitivity for lymph node metastases and distant metastases. PET/CT compared to CT alone identifies more patients who are surgically unresectable. Studies report an approximate 20% reduction in “futile” surgeries (surgeries on candidates ultimately found to have non-surgical disease) when PET/CT is used in the initial staging as opposed to staging without using PET.2 PET/CT has some use in small cell lung carcinoma. Most notably, it can slightly improve accuracy in assessing for limited versus extensive disease compared to CT alone (limited disease is confined to a single hemithorax, the mediastinum, and the supraclavicular space).3,4 The use of PET/CT for the initial staging of small cell carcinoma is less established than in the setting of non-small cell carcinomas, however. Combined PET/ CT is also generally indicated in the initial staging of esophageal cancer and many of the less common thoracic neoplasms. In thoracic oncology, PET/CT is generally not used for treatment monitoring (e.g., restaging) or for surveillance after a “curative” treatment. Detecting a difference in tumor metabolism appears to generally provide prognostic information beyond what can be gleaned by size changes alone,5 yet the clinical utility of follow up PET/CT studies after treatment has not been firmly established. Follow up PET/CT is commonly used in research studies and drug trials, however. For disease surveillance, some evidence points to improved accuracy with PET,6 though research has not convincingly demonstrated cost-effectiveness to the approach and it is not the current standard of care. PET/CT has notable limitations. Firstly, F-18 FDG PET can only demonstrate neoplasms with glucose utilization beyond the surrounding tissues. Some neoplasms simply are not hypermetabolic, including indolent tumors and tumors with little metabolically active tissue. For example, pulmonary adenocarcinoma in situ often does not appear

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hypermetabolic on PET/CT. Bronchopulmonary carcinoid tumors, nonaggressive thymic tumors, and cavitary pulmonary lesions also tend not to demonstrate significant hypermetabolism. Tumors with otherwise detectable metabolism may not be detected if they are adjacent to tissues with substantial physiologic uptake (e.g., the left ventricular myocardium). The second major limitation of PET/CT is the propensity for many non-neoplastic tissues/processes to demonstrate high-level FDG avidity, including lymph nodes affected by granulomatous infections or sarcoidosis. Such lymph nodes can be mildly to markedly hypermetabolic, often up to the levels seen in lymph nodes harboring tumor. Focal and diffuse pneumonias can also be hypermetabolic, though the CT appearance is often diagnostic for infection. Diffuse uptake in the esophagus and the thyroid gland can be physiologic or be the result of inflammation. Familiarity with the wide spectrum of physiologic/non-neoplastic causes of uptake is required to accurately interpret PET/CT. Often other tests or follow-up imaging is required to provide additional information in indeterminate cases. The latest advancement in PET technology is PET combined with magnetic resonance (MR) imaging. While some systems have been developed that use a common table that shuttles between adjacent separate scanners, most integrated systems currently sold today combine PET and MR components around a common bore forming a single scanner. Replacing CT with MR for oncologic imaging offers some benefits, including lower radiation doses, better soft tissue characterization, and the ability to obtained specialized sequences such as MR spectroscopy. The combined modality does present new difficulties; accurate attenuation correction is particularly difficult given MR images do not provide a direct measure of tissue attenuation. Creating attenuation maps from MR images, mostly by detecting tissues types and assigning tissuespecific values, is an area of intense research. PET/MR scanners are also very expensive and extensive training is required to operate the machinery. Once generated, the images produced generally require more time to interpret. Finally, even under the best of circumstances, MR imaging in the thorax is generally inferior to CT, particularly in evaluating the lungs.

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References  1. Bietendorf J. FDG PET reimbursement. J Nucl Med Technol Mar 2004; 32(1): 33–38.   2. Fischer B, Lassen U, Mortensen J, et al. Preoperative staging of lung cancer with combined PET-CT. N Engl J Med Jul 2009; 361(1): 32–39.   3. Fischer BM, Mortensen J, Langer SW, et al. A prospective study of PET/CT in initial staging of small-cell lung cancer: Comparison with CT, bone scintigraphy and bone marrow analysis. Ann Oncol Feb 2007; 18(2): 338–345.   4. Xanthopoulos EP, Corradetti MN, Mitra N, et al. Impact of PET staging in limited-stage small-cell lung cancer. J Thorac Oncol Jul 2013; 8(7): 899–905.   5. Ben-Haim S, Ell P. 18F-FDG PET and PET/CT in the evaluation of cancer treatment response. J Nucl Med Jan 2009; 50(1): 88–99.   6. Antoniou AJ, Marcus C, Tahari AK, Wahl RL, Subramaniam RM. Follow-up or Surveillance 18F-FDG PET/CT and Survival Outcome in Lung Cancer Patients. J Nucl Med Apr 2014; 55(7): 1062–1068.

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Magnetic Resonance Imaging in Thoracic Malignancies Fereidoun Abtin, Kathleen Ruchalski, Paul Finn

The role of magnetic resonant imaging (MRI) in the assessment of ­thoracic malignancies has become more established over the past decade. MRI benefits from excellent tissue contrast, multiplanar tissue acquisition, dynamic assessment of blood flow, differentiation of tumor from other abnormal tissue with diffusion imaging, and lack of ionizing radiation. However, the application of MRI in intrinsic lung disease has been limited by signal distortion induced from breathing, lack of protons in the lung parenchyma, and magnetic field inhomogeneity. These limitations are yet to be overcome by improved pulse sequences less sensitive to breathing and improved hardware.1 The current indications for use of MRI in thoracic malignancies include characterization and staging of mediastinal tumors, pleural tumors, chest wall tumors, and superior sulcus tumors; functional assessment of diaphragm; and assessment of pulmonary vasculature and cardiac function in preparation for surgery.

MRI Protocol for Thoracic Malignancies The MRI protocols used for assessment of thoracic malignancies are comprised of core sequences which are used to provide overall assessment of the thorax, followed by a special set of sequences to address the specific clinical question. An example is the use of chemical shift sequences for characterization of mediastinal masses. The core thoracic MRI sequences in our practice include coronal balanced steady-state free precession (TrueFISP on Siemens, FIESTA on GE), axial single-shot turbo spin-echo (HASTE on Siemens, single-shot FSE on 49

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GE), axial T2 and axial 3D GRE with fat-water separation (VIBE-DIXON on Siemens, IDEAL-SPGR on GE) with in and out of phase, water and fat sequences, followed by post-contrast axial 3D VIBE-DIXON water-only images and Coronal 3D VIBE sequences. Diffusion weighted imaging (DWI) and calculated apparent diffusion coefficient (ADC) are obtained in axial planes. DWI can be used to differentiate benign from malignant disease, and exploits the random motion of water molecules. The extent of tissue cellularity and the presence of intact cell membranes help determine the impedance of water molecule diffusion. This impedance of water molecule diffusion can be quantitatively assessed using the apparent diffusion coefficient (ADC) value. The higher cellular malignant tissue has the ability to restrict water molecule diffusion which appears as areas of higher signal intensity compared to muscle on DWI sequences. An ADC of a tissue is expressed in units of mm2/s. There is no unanimity regarding the boundaries of the range of normal diffusion, but ADC values less than 1.0–1.1 × 10–3 mm2/s (or 1,000–1,100 × 10–6 mm2/s) are generally acknowledged in adults as indicating restriction. The calculated ADC demonstrates areas with lower signal intensity compared to muscle corresponding to restricted diffusion. Dynamic diaphragmatic motion sequences using TrueFISP in coronal plane and one each side on sagittal planes are obtained with quiet breathing and maximum breathing effort. Pancoast tumors require additional post-contrast images with 3-mm slice thickness in sagittal and coronal planes, and fat-suppressed T1-weighted post-contrast images or MR angiography (MRA). For mesothelioma, pleural disease, and diseases of the diaphragm, dynamic diaphragmatic motion sequences are added to core sequences. Mediastinal tumors require special attention with in-phase and out-ofphase sequences, and thinner cuts at 3 mm in sagittal and coronal planes need to be obtained at mediastinal levels.

Indications Characterization and Staging of Mediastinal Tumors MRI ability for differentiating various tissues plays a major role in management and tissue characterization of mediastinal mass. These lesions are not as affected by breathing motion artifact but are subject to cardiac

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pulsatile motion signal degradation. MRI is especially useful for characterizing and staging the extent of mediastinal tumors in particular with involvement and patency of vessels. MRI is used to differentiate thymic hyperplasia from thymic gland tumors. This differentiation is especially useful in the management of patients with myasthenia gravis as the surgical approach and planning differs. MRI sequences take advantage of microscopic fat in thymic hyperplasia and the signal from chemical shifts using in-phase and out-of-phase sequences. Thymic hyperplasia reveals a relative signal loss on opposedphase chemical-shift MRI that is different from no significant signal change between in-phase and opposed-phase chemical-shift MR images in patients with malignancy. Inaoka et al. used the chemical shift ratio (CSR) to differentiate thymic hyperplasia from thymic tumors. CSR is determined by comparing the signal intensity of the thymus gland (tSI) with that of the paraspinal muscle (mSI) on both in-phase (in) and opposed-phase (op) images: CSR = (tSIop/mSIop)/(tSIin/mSIin). The mean CSR was 0.614 ± 0.130 in the hyperplasia group and 1.026 ± 0.039 in the tumor group (Figure 1).2 With MRI, thymomas manifest with low to intermediate signal intensity on T1-weighted images, and with high signal intensity on T2-weighted images that may approach the signal intensity of fat.3 Fat-suppression

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Figure 1.    MRI of thymoma: out-of-phase (A) and in-phase (B) imaging can be used to evaluate for microscopic fat and help differentiate between thymic hyperplasia and neoplasm. This anterior mediastinal lesion does not have significant loss of signal on opposedphase imaging, with CSR = 1.0, consistent with known thymoma. CSR = (tSIop/mSIop)/ (tSIin/mSIin) = (343/351)/(332/339) = 1.0.

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techniques may be useful in differentiating surrounding fat from thymoma. Heterogeneous signal intensity is present in tumors with necrosis, hemorrhage, or cystic change. Low signal intensity due to hemosiderin deposition may be seen on T1- and T2-weighted images. Although computed tomography (CT) is superior to MRI in the depiction of calcification within thymomas, MRI can occasionally reveal fibrous septa within the mass, as well as permit better evaluation of the tumor capsule. Visualization of the capsule and of septa within a tumor has been shown to be associated with a less aggressive histologic appearance.4 It is often difficult for mediastinal cysts to be characterized and differentiated from solid tumors with CT due to higher Hounsfield unit (HU) from internal blood or high protein. MRI has shown superiority in diagnosis of anterior mediastinal cysts, and accurately diagnosed thymic cysts in 71% of subjects compared to 46% on CT.5 MRI with T2-weighted sequences can help characterize fluid and soft tissue, with fluid having hyperintense signal. The extent of cyst wall enhancement on post-gadolinium-based contrast sequences can help differentiate benign from complex cysts. Lymphoma presentation as mediastinal mass is commonly Hodgkin’s lymphoma, representing approximately 50–70% of mediastinal lymphomas, while non-Hodgkin lymphoma comprises 15–25%.6 Non-Hodgkin disease (NHD) includes diffuse large B-cell lymphoma and T-cell lymphoblastic lymphoma. T-cell lymphoblastic lymphoma mainly occurs in children and adolescents. Differentiation from other tumors like invasive thymoma or germ cell tumor is essential to treatment. CT is still considered the diagnostic modality of choice with improved accuracy in combination with positron emission tomography (PET) scan. MRI alone is not superior to CT but when used in combination, it has shown to improve accuracy.5 MRI can also be used for follow-up of patients with treated lymphoma to avoid continued exposure to ionizing radiation which is of special concern in younger patients (Figure 2). Germ cell tumors (GCT) are uncommon tumors, with mediastinum being the most common extragonadal site. GCT accounts for 10–15% of anterior mediastinal masses in adults and 25% in children.7 On MRI, teratomas typically demonstrate heterogeneous signal intensity, representing various internal elements. Fat-fluid levels within the lesion are virtually diagnostic of teratoma.8

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Figure 2.    Incidentally detected large B cell lymphoma during pregnancy. (A) Initial chest MRI at time of diagnosis with anterior mediastinal soft tissue mass (*). (B) Surveillance MRI obtained during pregnancy demonstrating stable anterior mediastinal mass, allowing treatment to be withheld until after delivery.

Characterization and Staging of Pleural Tumors MRI can potentially characterize pleural effusions, and differentiate between exudates, transudates, and hemothoraces.9 However, CT remains advantageous for visualizing calcification within pleural lesions.10 Dynamic contrast-enhanced MRI (DCE-MRI) with sequential acquisition of images at short intervals for pharmacokinetic analysis including amplitude (Amp), redistribution rate constant (kep), and elimination rate constant (kel), has been used to differentiate benign from malignant pleural disease and also been used to monitor chemotherapeutic response and predict improved survival. In a study of 19 patients with malignant pleural mesothelioma (MPM) undergoing chemotherapy, clinical responders had a median kep value within the tumor of 2.6 minutes, while non-responders showed a higher value of 3.6 minutes, which coincided with longer survival (780 days versus 460 days).11 Magnetic resonance (MR) features of MPM include diffuse or nodular pleural thickening, pleural effusion, and local invasion of adjacent structures. Compared to adjacent chest wall musculature, MPM has intermediate or slightly high signal intensity on T1-weighted images (T1-WI) and moderately high signal intensity on T2-weighted images (T2-WI). On contrast-enhanced MR using Gd-based agents there is increased signal intensity in the MPM12 (Figure 3 A–C). DWI and ADC mapping are

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Figure 3.    83-year-old female patient with mesothelioma. (A) T1-weighted sequences demonstrate pleural mass isointense to surrounding muscles. (B) On Post-gadoliniumenhanced contrast sequence there is increase in signal intensity. (C) Post-contrast coronal image demonstrates extension of tumor beyond the left hemi-diaphragm (arrow) into the sub-diaphragmatic peritoneal space. (D) Diffusion weighted image (DWI) at b 1000 demonstrates restriction with areas of hyperintensity (arrows). (E) Corresponding apparent diffusion coefficient (ADC) demonstrates values averaging 1.3 × 10−3 mm2/s. On surgery this tumor was found to be 90% of epitheloid subtype.

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also used to differentiate the sarcomatoid from epitheloid MPM. The average ADC values were significantly higher between epithelioid MPM at 1.31 ± 0.15 (SD) × 10−3 mm2/s and sarcomatoid MPM at 0.99 ± 0.07 (SD) × 10−3 mm2/s (p < 0.05). Using the ADC value of 1.1 × 10−3 mm2/s the sensitivity and specificity for differentiating epithelioid from sarcomatoid MPM was 60% and 94%, respectively13 (Figure 3 D–E). The role of MRI in detection of drop metastasis from thymoma has not been described in literature. PET/CT scan may not be able to detect these areas of drop metastasis due to small size and inherent low level of activity. However, MRI, and in particular DWI sequences, can help in detecting drop metastasis. These lesions appear hyperintense on DWI sequences and hypointense to muscle on ADC (Figure 4).

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(D) Figure 4.  History of thymoma status post-resection. (A) On follow-up PET/CT scan there is evidence of hypermetabolic mass in deep anterior right costophrenic sulcus (arrow). The linear soft tissue thickening at the posterior paravertebral region (arrows) does not demonstrate metabolic activity. (B) Post-contrast MRI at the same level demonstrates enhancing tumors at anterior (arrow) and posterior (arrows) costophrenic sulcus. (C) DWI. (D) Corresponding calculated ADC demonstrates restricted diffusion presenting as areas of hyperintensity on DWI and hypointensity on ADC. The DWI and ADC mapping are especially of interest in differentiating between benign and neoplastic disease.

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Characterization and Staging of Chest Wall Tumors MRI is the preferred modality for the evaluation of chest wall tumors. The superior spatial resolution and tissue characterization offered by MR often enables accurate characterization of the tumor tissue and extent, including differentiation from adjacent areas of inflammation. Limiting breathing motion artifact can be achieved using prone positioning of the patient. Chest wall tumors are of various types and can have unique MR characteristics. Some of the more common tumors are described here. Osseous, cartilaginous, and muscular tumors The benign tumors include osteochondroma, fibrous dysplasia, aneurysmal bone cyst, ossifying fibromyxoid tumor, gian cell tumor, chondromyxoid fibroma, and osteoid osteoma. The malignant lesions include osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma, malignant fibrous histiocytoma, synovial sarcoma, and Ewing’s sarcoma. Hematologic malignancies involving the bone include lymphoma, plasmacytoma, and multiple myeloma. Osteochondromas are relatively common osseous lesions that originate from the aberrant growth of normal tissue. In the ribs these tumors favor the costochondral junction. The tumors are characteristically pedunculated osseous protuberances arising from the surface of the parent bone. MRI is particularly useful in detecting the medullary continuity and the cartilaginous tissues in the cap which appear high signal intensity on T2-weighted MR images. Malignant transformation occurs in approximately 1% of solitary lesions and 3–5% of patients with hereditary multiple exostosis (HME).14 Increased thickness of the cartilaginous cap is an ominous sign for malignant transformation, and the cartilaginous cap is measured for benign osteochondromas at 0.1–3.0 cm; average, 0.6–0.8 cm and those with secondary chondrosarcoma at 1.5–12 cm; average, 5.5–6.0 cm.15 Chondrosarcomas can also be primary and are the most common malignant primary tumors of the chest wall. These tumors commonly arise from the anterior rib cage and costochondral junction. CT is more sensitive than radiography and MR imaging for delineation of chondroid matrix calcifications, but MRI can better delineate the extent of the disease. MR T1-weighted images demonstrate lobulated masses with signal intensity

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similar to that of muscle, and on T2-weighted sequences the signal intensity is equal to or greater than that of fat. Enhancement after administration of intravenous contrast material typically is heterogeneous, especially at the periphery. Myxoid chondrosarcomas do not contain chondroid calcifications or bone formation and may have markedly high signal intensity on T2-weighted images.16 Fibrous dysplasia is a skeletal developmental anomaly in which mesenchymal osteoblasts fail to undergo normal morphologic differentiation and maturation. Most cases in the chest involve ribs, and 70–80% are monostotic while 20–30% are polyostotic. The finding is usually incidental except when complicated, commonly pathologic fractures result in pain. Amorphous or irregular calcification is often seen in the lesion on CT scans. MRI is useful in accurately defining the full extent of the lesion. The signal intensity varies from low to high on T2-weighted images but typically is low in areas of lesion involvement on T1-weighted images.17 Giant cell tumors are relatively common benign skeletal lesions and consist of vascular sinuses that are lined or filled with abundant giant cells and spindle cells. Giant cell tumors are typically solitary but can be multiple. Thoracic giant cell tumors are more common in females and often arise in subchondral regions of the flat and tubular bones of the chest wall, including the sternum, clavicle, and ribs. Tumors typically have a long relaxation time at T1- and T2-weighted MRI and appear as areas of low signal intensity on T1-weighted images and high signal intensity on T2-weighted images, and show septations. Fluid-fluid levels are less commonly seen in these tumors than in aneurysmal bone cysts.18 Primary malignant lymphomas in the chest wall are uncommon, being less than 2% of soft-tissue tumors, but secondary involvement of the musculoskeletal system is common. The osseous lymphoma manifestations include primary bone lymphoma and multifocal primary or disseminated lymphoma. MRI can help in characterization of primary masses which usually appear iso- or slightly lower than that of adjacent muscle on T1-weighted images and with high signal intensity on T2-weighted images.19 MRI plays a special role in detection of osseous lymphoma with subtle or normal appearance on other imaging. The replacement of fat and loss of marrow signal on T1-weighted images and restriction on DWI sequences are diagnostic (Figure 5).

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Figure 5.    72-year-old male with mediastinal mass and biopsy-proven T-cell lymphoma. (A) CT scan of the chest with contrast demonstrates a soft tissue mass in the anterior mediastinum, moderate right pleural effusion, and normal appearance of bone. The anterior soft tissue mass appears homogenous without significant enhancement. (B) Postgadolinium-enhanced MRI demonstrates heterogeneously enhancing soft tissue mass in anterior mediastinum. (C) DWI sequences demonstrate diffuse involvement of axial and appendicular skeleton with restriction which appears hyperintense (arrow). (D) Calculated ADC map confirms restricted diffusion with low signal in the bones (arrow). The ADC value was 0.5 and keeping with diffuse lymphoproliferative involvement of bone. This finding was evident only on the DWI and ADC and not on routine MRI and CT scans.

Vascular tumors These include cavernous hemangioma, glomus tumors, and angiosarcoma. Cavernous hemangiomas are among the least common benign chest wall masses and consist of dilated, tortuous, thin-walled vessels. They can be cutaneous and even less commonly non-cutaneous. T1- and T2-weighted MR images typically reveal areas of high signal intensity in the mass with streaks of high signal intensity from stagnant blood in cavernous or cystic

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spaces. On T1-weighted images, intramuscular cavernous hemangiomas manifest as poorly marginated masses with signal intensity similar to that of skeletal muscle. On T2-weighted images, these tumors are well marginated and have high signal intensity compared with that of subcutaneous fat. Signal intensity voids caused by rapidly flowing blood also can be seen.20 Neurogenic tumors These peripheral nerve tumors include schwannoma, neurofibroma, ganglioneuroma, and paraganglioma, with the malignant counterparts including neuroblastoma, ganglioneuroblastoma, and malignant peripheral nerve sheath tumors. Schwannomas are the most common (approximately 50%) mediastinal neurogenic tumors and frequently affect patients 20–30 years old. They can be solitary or multiple when associated with neurofibromatosis type 2. These tumors often extend into the neural canal and are encapsulated by a fibrous capsule. They are composed of Schwann cells within a background of loose reticular tissue and often undergo cystic and myxomatous degeneration, hemorrhage, lipidization, and calcifications. These changes are helpful to differentiate schwannomas from neurofibromas. Neurofibromas account for approximately 20% of mediastinal neurogenic tumors and present in patients 20–30 years old. These tumors are capsulated and homogenous. Schwannomas and neurofibromas show homogeneous or heterogeneous high signal intensity on T2-weighted images, which can vary depending on the ratio of myxomatous matrices, collagenous fibrous tissues, and tumor cells in the tumors. Cystic change, hemorrhage, and avid enhancement in the mass are more common in schwannomas than in neurofibromas (Figure 6).21 Ganglioneuroma, ganglioneuroblastoma, and neuroblastoma comprise 25% of mediastinal neurogenic tumors and arise from thoracic sympathetic trunks and their associated ganglia form the autonomic nervous system located on either side of the vertebral bodies. Sympathetic ganglion tumors show a vertically oriented mass along the anterolateral surface of several vertebrae, with a tapered appearance. Ganglioneuromas manifest as a well-defined mass with heterogeneous high signal intensity on T2-weighted images which can be heterogeneous or appear whorled.

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Figure 6.    32-year-old female with backache. MRI scans in sagittal plain demonstrate a hypointense mass on T1-weighted sequences (A) and hyperintense on T2-weighted sequences (B). There are internal areas of heterogeneous signal intensity from tumor inhomogeneity and hemorrhage. On post-contrast sequence there is heterogenous enhancement. (D) Resected specimen confirms schwannoma with internal bleeding.

The “whorled appearance” is due to curvilinear bands of low signal intensity that reflect collagenous fibrous tissue in the mass on T2-weighted images. Most ganglioneuromas show gradual and heterogeneous contrast enhancement. Neuroblastomas and ganglioneuroblastomas show a wellor ill-defined mass with typically more heterogeneous signal intensity and contrast enhancement on MRI due to tumor necrosis.22 Adipose tumors These include lipoma, spindle cell lipoma, and liposarcoma. The presence of fat in these tumors can be readily diagnosed with MRI which can help in narrowing the differential. These tumors are hyperintense on T1-weighted images and show signal drop-off on fat suppression. Differentiation of lipoma from liposarcoma is essential. Lipomas are more homogenous, capsulated, and well defined without local invasion. Distinguishing welldifferentiated liposarcoma from lipoma can be a diagnostic challenge with radiologic imaging. Although lesions composed entirely of adipose tissue can be reliably identified as lipomas, the presence of non-adipose components does not definitively indicate malignancy. Liposarcomas often present with heterogeneous signal intensity pattern with areas of high signal

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intensity on T2-weighted sequences and post-contrast suggestive of solid and myxoid components.23 Characterization and Staging of Superior Sulcus Tumors Thoracic MRI plays a significant role in the evaluation of the small subset of primary bronchogenic carcinomas termed superior sulcus tumors. A superior sulcus tumor consists of a non-small cell lung cancer residing within the lung apex and demonstrating direct soft tissue invasion. These tumors are often also referred to as Pancoast tumors. However, when originally described, Pancoast tumors referred to only those tumors presenting with the syndrome of shoulder pain and cervical sympathetic paralysis.24,25 With excellent delineation of soft tissue planes and multiplanar capabilities, MRI allows for optimal imaging of tumor staging of the superior sulcus at the thoracic outlet. Often used in adjunct with CT or PET/CT, MRI allows for better evaluation for local chest wall invasion as well as regional extension to and direct involvement of other vital structures, such as the brachial plexus, subclavian vasculature, esophagus, trachea, and vertebral bodies. While evaluation for chest wall invasion can be assessed with CT; multiplanar MRI has been shown to demonstrate higher specificity (1.0: MRI and 0.65: CT) and accuracy (0.94: MRI and 0.63: CT).26 MRI imaging of the thoracic outlet usually contains coronal and sagittal sequences to optimize depiction and contrast of the apical pleura (separated by a thin rim of adipose tissue) from those structures above the apex.26 Recommended superior sulcus MRI protocols include sagittal, coronal, and axial T1- and T2-weighted imaging of the involved thoracic inlet with or without post-contrast imaging.27 Thin section (3mm) sagittal T1-weighted imaging is recommended to be performed first, as this sequence provides the highest anatomic visualization of the tumor with respect to the brachial plexus and subclavian vasculature. However, given the horizontal course of the subclavian artery at the thoracic inlet, the coronal plane has been shown to be more specific in the evaluation for subclavian arterial involvement, which is often further aided by the acquisition of additional fat-suppressed T1-weighted post-contrast images or MR angiography (MRA)27,28,29 (Figure 7).

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Figure 7.    Squamous cell carcinoma superior pulmonary sulcus tumor. (A) Sagittal T1W image of a large lobulated right apical mass with extension to the thoracic outlet and involvement of the C8 and T1 nerve roots (arrows). (B) Sagittal CT image of same level also shows direct chest wall invasion; however, there is less clear delineation of brachial plexus involvement. (C) Post-contrast fat suppressed sagittal T1W image of the chest with a large superior sulcal tumor (*). The mass is in close proximity with the subclavian artery (arrow); however, a clear fat plane between the mass and artery suggests the artery is uninvolved.

Additionally, the extent of brachial plexus involvement alone can alter tumor staging. Involvement of only C8 and/or T1 nerve roots or lower trunk is considered T3; whereas more extensive involvement of the brachial plexus (C5–C7) is categorized as a T4 malignancy.27 Use of several MRI planar sequences optimizes visualization of different portions of the brachial plexus. For example, axial imaging is best for evaluating the proximal plexus (rami) and vertebral body involvement, and the sagittal plane optimizes visualization of the mid and distal branches30 (Figure 7). Functional Assessment of Diaphragm These sequences are obtained using dynamic true fast imaging with steadystate precession (TruFISP) sequences in the coronal plane and on both sides in sagittal planes with quiet breathing and maximum breathing effort. Dynamic diaphragmatic motion MRI is used to evaluate for diaphragmatic paralysis, restriction of diaphragmatic motion, and diaphragmatic herniation. Diaphragmatic paralysis can be from various causes. The most common cause in adults is tumoral involvement of the phrenic nerve. In children,

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birth trauma and cardiorespiratory surgery are the most common causes. Other etiologies for diaphragmatic paralysis include complication of neurologic disease, injury to the phrenic nerve from trauma to the thorax or cervical spine, and pressure on the phrenic nerve from a substernal thyroid or aortic aneurysm. Finally, diaphragmatic paralysis may be idiopathic. MRI can help in detecting the paralysis and investigate the possible etiologies in the same setup. Diaphragmatic restriction can be caused by bulky pleural disease, invasion of the diaphragm by the tumor, or both. The range of motion of the diaphragm gets limited with diaphragmatic infiltration and spread of tumor deep into the muscle. MRI enables easy recognition of the diaphragm and visceral herniation because it has the advantage of multiplanar imaging. MRI may be used in stable patients with an equivocal diagnosis based on other imaging results, in patients for whom laparotomy is not planned, and in some patients with penetrating injuries or late-appearing diaphragmatic ruptures. In one retrospective study, MRI was superior to other imaging modalities in detecting the site of diaphragmatic tears.31

Assessment of Pulmonary Vasculature and Cardiac Function in Preparation for Surgery MRI assessment of local tumor invasion Not infrequently, malignant diseases or processes which mimic them, involve the heart and thoracic blood vessels. In these cases, the techniques used to define the extent of disease differ from those used for purely parenchymal lung disease. Steady-state free precession (SSFP) techniques constitute a very powerful and versatile family for a rapid overview of cardiopulmonary anatomy and for more detailed imaging of the heart. SSFP is a gradient echo technique which differs from traditional spoiled gradient echo (SGE) techniques in that magnetization which persists following signal acquisition is recycled for subsequent iterations of the phase encoding gradient. The image contrast with SSFP looks predominantly T2-weighted (more correctly T2/T1 weighted) such that fluid such as blood, cerebrospinal fluid, and fat appear bright. With SSFP, a single-shot

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image can be acquired in less than a second, relaxing the requirement for breath holding and enabling very rapid multi-slice imaging of the thorax.32 When performance is pushed further, real-time images of diaphragmatic motion due to breathing can be performed routinely, such that asymmetry, tethering, paralysis, or paradoxical motion can be visualized. Contrast-enhanced MR angiography (CEMRA) is another powerful tool in the radiologist’s arsenal for diagnosis and staging of a variety of vascular and mass lesions. Typically, the first pass of a bolus of a gadolinium-based contrast agent (GBCA) is captured during a breath hold of 15–20 seconds and reconstructed into a high resolution three-dimensional angiogram. CEMRA can be used to diagnose disease involving any or all of the pulmonary arterial, pulmonary venous, systemic arterial, or systemic venous circulation of the thorax. Whereas the extracellular GBCAs are most commonly used for CEMRA, blood pool agents may have advantages for specific applications, for example venous imaging or when first-pass imaging is unsuccessful or problematic (Figure 8). The first-pass and steady-state images can be very similar and show multifocal tumor embolism and occlusion of segmental pulmonary arteries (Figure 9).

Figure 8.    Steady-state venous phase with 3D volume rendered CEMRA using gadofosveset (Ablavar, Lantheus Medical Systems) in a patient with occlusion of the bilateral subclavian, jugular, innominate veins, and SVC, demonstrates extensive right-sided intercostal and azygous collaterals (arrows).

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Figure 9.  Pulmonary tumor thrombo-embolism (arrows) in a 55-year-old patient on first-pass (A) and delayed phase (B) imaging with ferumoxytol (Feraheme, AMAG Pharmaceuticals).

Use of ECG-triggered MRA has been shown to decrease cardiac motion artifact and improve diagnostic accuracy for direct tumor invasion of the main pulmonary arteries or pulmonary veins. Ohno et al. demonstrated that cardiac synchronized MRI was able to better visualize tumor vascular encasement greater than 90 degrees, vascular distortion, and stenosis as well as vessel irregularity; when compared to contrastenhanced CT and conventional MRA.33 Localized pericardial invasion by tumor on MRI is visualized by focal loss of fat plane and interruption of the pericardium. Additionally pericardial metastases may be seen in up to 10% of cancer patients and may be detected on cardiac MRI by irregular pericardial thickening or nodularity.34 Pericardial involvement is also often associated with a disproportionately high volume of pericardial effusion.35 Although transthoracic echocardiography remains the standard for assessing pericardial effusion and cardiac tamponade, pericardial diseases are often well characterized on thoracic MRI, whether the imaging was obtained for more comprehensive pericardial evaluation or as part of initial tumor staging. MRI allows for a more extensive visualization of the pericardium and assessment for pericardial thickening and distribution of pericardial effusions. Effusion signal

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Ύ

Ύ Figure 10.    Metastatic Ewing sarcoma with pleural carcinomatosis and mediastinal invasion. Axial trufi image through the chest as part of cardiac MRI with several pleural-based soft tissue masses (*). A large paramediastinal soft tissue mass demonstrates mediastinal and pericardial invasion (arrow) with loss of intervening tissue between the pericardium and soft tissue mass. There are also small right greater than left pleural effusions (arrow head).

characteristics may also aid in assessment of fluid composition. Transudative fluid demonstrates high signal intensity on T2W and low signal intensity on T1W images; whereas an exudative effusion contains a higher concentration of proteinaceous contents, thus altering the T1 and T2W signal characteristics.36 Subacute hemopericardium will result in a heterogeneously higher T1- and T2-weighted signal intensity and may appear inhomogeneously low in signal intensity on cine (SSFP) imaging34,33 (Figure 10). Cardiac MRI Cardiac MRI may be performed alone or in conjunction with thoracic MRI techniques, and is often used to further delineate complex cardiac anatomy, ventricular function, myocardial ischemia, cardiomyopathies, and cardiac masses. MRI allows superior visualization of the heart structures through the use of multiplanar image acquisition obtained in body and cardiac planes as well as ECG-gating to minimize cardiac motion artifact.37 Cardiac planes routinely include four chamber (horizontal long axis), two chamber (vertical long axis), and short axis views; however, a customized axis may be performed if needed (Figure 11). Basic cardiac MRI protocols include a dark blood gradient echo sequence to evaluate cardiac anatomy. Additional bright blood sequence images are obtained to evaluate cardiac

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Zs Z

>s

> >s

(A)

>

(B)

>s Zs

(C)

Figure 11.  Common cardiac MRI planes with TruFisp sequence. (A) Two chamber (vertical long axis) image through the left ventricle (LV) and left atrium (LA). (B) Four chamber (horizontal long axis) also includes the right ventricle (RV) and right atrium (RA). (C) Short axis view through the right ventricle and left ventricle.

function, such as a T2-weighted TruFISP sequence. Use of cine technique with SSFP or TruFISP sequences allows visualization of valvular motility and function as well as assessment of ventricular motion.38 Phase contrast imaging is performed to quantify pulmonary arterial (Qp) and systemic (Qs) blood flow, with their ratio of flow used to evaluate extent of left to right shunts.36 Post-contrast images are commonly obtained for MRA, evaluation of cardiac masses, and to perform delayed inversion recovery imaging in the assessment of myocardial infarction and viability. Presence of delayed enhancement (10–15 minutes) is used to detect acute or chronic myocardial infarction with high sensitivity (acute MI 99% and chronic MI 94%) and results in accurate localization of the defect to the correct perfusion territory 97–100% of the time.39 More importantly, lack of delayed enhancement in hypokinetic myocardium differentiates hibernating myocardium from chronic infarction and suggests that this region of tissue and cardiac function is salvageable through coronary revascularization.40 Contrast-enhanced cardiac MRI is also routinely used in the evaluation of primary cardiac lesions and differentiation of primary malignancy from intracardiac thrombus. Although primary cardiac tumors are rare entities, they are associated with high morbidity and mortality and their clinical management vastly differs from bland thrombus.41,42 When disease affects the cardiac chambers or myocardium directly, it becomes necessary to perform cardiac gating in order to freeze cardiac

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motion. For this application, and for routine cardiac MR imaging, multishot or “segmented” SSFP cine imaging is the most widely used technique.43 Segmented SSFP cine differs from single-shot SSFP in that multiple sequential heartbeats are used to generate a multi-phase slice through the beating heart, which is viewed as a dynamic cine. In general, about ten heartbeats are required to produce a single cine slice, so breath holding is important for segmented SSFP cardiac cine. However, a breath hold of this duration (6–8 seconds) is well within the comfort zone of all but the most dyspneic patients (Figure 12).

Figure 12.    Several techniques can be used to define and characterize malignant involvement involving the heart and mediastinum, due in this case to metastatic osteosarcoma involving the right-sided pulmonary veins and left atrium (arrows). Included are images from SSFP cine (A), T1-weighted spin echo (B), and contrast-enhanced SGE (C) and CEMRA (D). All of these techniques provide complementary information about the extent and nature of the malignant mass.

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Dynamic perfusion imaging intends to visually depict tumor neovascularity and capillary network, which is often over-proliferated in malignant tumors and results in increased first-pass enhancement. Hoffman et al. demonstrated that use of post-contrast MR imaging aids in accurate differentiation of benign and malignant lesions, with dual readers accurately categorizing the lesions in 78% and 80% of the time (compared to 40% and 70% of cases without contrast).44 As expected, given their limited vascularity, intracardiac thrombi and fibroelastoma generally do not demonstrate enhancement on FFP.41,42 Cardiac myxomas also generally lack first-pass perfusion; however, they demonstrate multifocal heterogeneous delayed enhancement.45 Use of semi-quantitative analysis with graphical display of time intensity curves may further classify probability of malignancy and allow characterization of regional tumoral perfusion.46 Aside from enhancement characteristics, the presence of a pericardial effusion as well as morphologic features of intracardiac tumors such as paracardiac location, internal inhomogeneity, regional infiltration, and displacement of surrounding structures have also been shown to be malignant features.43

References  1. Hatabu H, Stock KW, Sher S, Edinburgh KJ, Levin DL, Garpestad E, Albert MS, Mai VM, Chen Q, Edelman RR. Magnetic resonance imaging of the thorax: Past, present, and future. Radiol Clin North Am 2000; 38(3): 593.  2. Inaoka T, Takahashi K, Mineta M, Yamada T, Shuke N, Okizaki A, Nagasawa K, Sugimori H, Aburano T. Thymic hyperplasia and thymus gland tumors: Differentiation with chemical shift MR imaging. Radiology 2007; 243(3): 869–876.   3. Maher MM, Shepard JA. Imaging of thymoma. Semin Thorac Cardiovasc Surg 2005; 17(1): 12–19.  4. Sadohara J, Fujimoto K, Müller NL, et al. Thymic epithelial tumors: Comparison of CT and MR imaging findings of low-risk thymomas, highrisk thymomas, and thymic carcinomas. Eur J Radiol 2006; 60(1): 70–79.  5. Tomiyama N, Honda O, Tsubamoto M, Inoue A, Sumikawa H, Kuriyama K, Kusumoto M, Johkoh T, Nakamura H. Anterior mediastinal tumors: Diagnostic accuracy of CT and MRI. Eur J Radiol 2009; 69(2): 280–288.

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 6. Duwe BV, Sterman DH, Musani AI. Tumors of the mediastinum. Chest 2005; 128: 2893–2909.  7. Takahashi K, Al-Janabi N. Computed tomography and magnetic resonance imaging of mediastinal tumors. J Magn Reson Imaging 2010; 32: 1325–1339.   8. Juanpere S, Cañete N, Ortuño P, Martínez S, Sanchez G, Bernado L. A diagnostic approach to the mediastinal masses. Insights Imaging 2013; 4(1): 29–52.  9. Davis SD, Henschke CI, Yankelevitz DF, et al. MR imaging of pleural effusions. J Comput Assist Tomogr 1990; 14: 192. 10. Hierholzer J, Luo L, Bittner RC, et al. MRI and CT in the differential diagnosis of pleural disease. Chest 2000; 118: 604. 11. Giesel F, Bischoff H, Tengg-Kobligk H, Weber M, Zechmann C, Kauczor H, Knopp M. Dynamic contrast-enhanced MRI of malignant pleural mesothelioma: A feasibility study of noninvasive assessment, therapeutic follow-up, and possible predictor of improved outcome. Chest 2006; 129(6): 1570–1576. 12. Lorenzo B, Feragalli B, Sacco R, Merlino B, Storto ML. Malignant pleural disease. Eur J Radiol 2000; 34(2): 98–118. 13. Gill R, Umeoka S, Mamata H, Tilleman T, Stanwell P, Woodhams R, Padera R, Sugarbaker D, Hatabu H. Diffusion-weighted MRI of malignant pleural mesothelioma: Preliminary assessment of apparent diffusion coefficient in histologic subtypes. Am J Roentgenol 2010; 195: W125–W130. 14. Bell RS. Musculoskeletal images: Malignant transformation in familial osteochondromatosis? Can J Surg 1999; 42: 8. 15. Hudson TM, Springfield DS, Spanier SS, Enneking WF, Hamlin DJ. Benign exostoses and exostotic chondrosarcomas: Evaluation of cartilage thickness by CT. Radiology 1984; 152: 595–599. 16. Varma DG, Ayala AG, Carrasco CH, Guo SQ, Kumar R, Edeiken J. Chondrosarcoma: MR imaging with pathologic correlation. RadioGraphics 1992; 12: 687–704. 17. Jee WH, Choi KH, Choe BY, Park JM, Shinn KS. Fibrous dysplasia: MR imaging. Characteristics with radiopathologic correlation. Am J Roentgenol 1996; 167: 1523–1527. 18. Lee MJ, Sallomi DF, Munk PL, et al. Pictorial review: Giant cell tumours of bone. Clin Radiol 1998; 53: 481–489. 19. Malloy PC, Fishman EK, Magid D. Lymphoma of bone, muscle, and skin: CT findings. Am J Roentgenol 1992; 159: 805–809. 20. Cohen EK, Kressel HY, Perosio T, et al. MR imaging of soft-tissue hemangiomas: Correlation with pathologic findings. Am J Roentgenol 1988; 150: 1079–1081.

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21. Murphey MD, Smith WS, Smith SE, Kransdorf MJ, Temple HT. From the archives of the AFIP. Imaging of musculoskeletal neurogenic tumors: Radiologic-pathologic correlation. RadioGraphics 1999; 19:1253–1280. 22. Lonergan GJ, Schwab CM, Suarez ES, Carlson CL. Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma: Radiologic-pathologic correlation. RadioGraphics 2002; 22: 911–934. 23. Kim T, Murakami T, Oi H, et al. CT and MR imaging of abdominal liposarcoma. Am J Roentgenol 1996; 166: 829–833. 24. Bruzzi JF, Komaki R, Walsh GL, et al. Imaging of non-small cell lung cancer of the superior sulcus. RadioGraphics 2008; 28(2): 551–560. 25. Pancoast HK. Importance of careful roentgen-ray investigations of apical chest tumors. J Am Med Assoc 1924; 83(18): 1407–1411. 26. Heelan RT, Demas BE, Caravelli JF, et al. Superior sulcus tumors: CT and MR imaging. Radiology 1989; 170(3): 637–641. 27. Bruzzi JF, Komaki R, Walsh GL, et al. Imaging of non-small cell lung cancer of the superior sulcus. RadioGraphics 2008; 28(2): 561–572. 28. Manenti G, Raguso M, D’Onofrio S, et al. Pancoast tumor: The role of magnetic resonance imaging. Case Rep Radiol 2013; 2013: 5. 29. Laissy JP, Soyer P, Sekkal SR, et al. Assessment of vascular involvement with magnetic resonance angiography (MRA) in pancoast syndrome. Magn Reson Imaging 1995; 13(4): 523–530. 30. Rapoport S, Blair DN, McCarthy SM, Desser TS, Hammers LW, Sostman HD. Brachial plexus: Correlation of MR imaging with CT and pathologic findings. Radiology 1988; 167(1): 161–165. 31. Shanmuganathan K, Mirvis SE, White CS, Pomerantz SM. MR imaging evaluation of hemidiaphragms in acute blunt trauma: Experience with 16 patients. Am J Roentgenol 1996; 167(2): 397–402. 32. Pereles FS, MC Carthy RM, Baskaran V, Carr JC, Kapoor V, Krupinski E, Finn JP. Unenhanced TrueFISP MR angiographic evaluation for thoracic aortic dissection and aneurysm in less than four minutes. Radiology 2002; 223: 270–274. 33. Ohno Y, Adachi S, Motoyama A, et al. Multiphase ECG-triggered 3D ­contrast-enhanced MR angiography: Utility for evaluation of hilar and mediastinal invasion of bronchogenic carcinoma. J Magn Reson Imaging 2001; 13(2): 215–224. 34. Rajiah P. Cardiac MRI: Part 2, pericardial diseases. Am J Roentgenol 2011; 197(4): W621–W634. 35. Bogaert J, Francone M. Pericardial disease: Value of CT and MR imaging. Radiology 2013; 267(2): 340–356.

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36. Bogaert J, Francone M. Cardiovascular magnetic resonance in pericardial diseases. J Cardiovasc Magn Reson 2009; 11(1): 14. 37. Ginat DT, Fong MW, Tuttle DJ, Hobbs SK, Vyas RC. Cardiac imaging: Part 1, MR pulse sequences, imaging planes, and basic anatomy. Am J Roentgenol 2011; 197(4): 808–815. 38. Pennell DJ. Cardiovascular magnetic resonance. Circulation 2010; 121(5): 692–705. 39. Kim RJ, Albert TSE, Wible JH, et al. Performance of delayed-enhancement magnetic resonance imaging with gadoversetamide contrast for the detection and assessment of myocardial infarction: An international, multicenter, double-blinded, randomized trial. Circulation 2008; 117(5): 629–637. 40. Vogel-Claussen J, Rochitte CE, Wu KC, et al. Delayed enhancement MR imaging: Utility in myocardial assessment. RadioGraphics 2006; 26(3): 795–810. 41. Butany J, Nair V, Naseemuddin A, Nair GM, Catton C, Yau T. Cardiac tumours: Diagnosis and management. Lancet Oncol 2005; 6(4): 219–228. 42. Pazos-López P, Pozo E, Siqueira ME, et al. Value of CMR for the differential diagnosis of cardiac masses. JACC Cardiovasc Imaging 2014; 7(9): 896–905. 43. Carr JC, Simonetti O, Bundy J, Li D, Pereles S, Finn JP. Cine MR angiography of the heart with segmented true FISP. Radiology 2001; 219: 828–834. 44. Hoffmann U, Globits S, Schima W, et al. Usefulness of magnetic resonance imaging of cardiac and paracardiac masses. Am J Cardiol 2003; 92(7): 890–895. 45. Hoey ETD, Shahid M, Ganeshan A, Baijal S, Simpson H, Watkin RW. MRI assessment of cardiac tumours: Part 1, multiparametric imaging protocols and spectrum of appearances of histologically benign lesions. Quant Imaging Med Surg 2014; 4(6): 478–488. 46. Libicher M, Kauffmann G, Hosch W. Dynamic contrast-enhanced MRI for evaluation of cardiac tumors. Eur Radiol 2006; 16(8): 1858–1859.

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Ultrasonography David M. Naeger, W. Richard Webb

Ultrasound is a commonly used imaging modality that relies on the reflection of sound waves in tissue to generate images. Hand-held surface ultrasound has few uses in thoracic oncology, however. The modality can be used to assess pleural and pericardial effusions, both malignant and benign, and can be used to guide procedures such as thoracentesis, pleural drainage catheter placements, and biopsies of chest wall and pleural masses. Axillary and supraclavicular lymph nodes can be evaluated by ultrasound, and ultrasound can be used to guide biopsies of lymph node in these regions, though CT is generally preferred to assess for lymphadenopathy given its ability to evaluate all of the thoracic lymph node stations. The most relevant application of ultrasound in thoracic oncology is endoscopic ultrasound (EUS), a technology whereby ultrasound images are generated from a small probe advanced through an endoscope. The esophageal application of this technology allows for a detailed assessment of the esophagus and periesophageal structures, including much of the posterior mediastinum. EUS is an essential tool in the workup of esophageal cancer patients. Endobronchial ultrasound (EBUS) works in a similar manner. Ultrasound images generated from a small probe advanced through a bronchoscope allows for detection of airway wall abnormalities as well as masses and lymph nodes around central airways. EBUS-guided biopsies allow for the pre-operative histologic assessment of some primary airway tumors and suspicious lymph nodes in the mediastinum. In the U.S. Medicare population in 2010, approximately 57% of all thoracic biopsies were performed using EBUS guidance (percutaneous biopsies comprised 36% of all thoracic biopsies and surgical biopsies comprised 7%).1 73

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Lastly, thoracic tumors in and around the heart can be evaluated by  echocardiography, ultrasound-based examinations of the heart using transthoracic (surface) or transesophageal (endoscopic) probes. Echocardiography is widely available and relatively inexpensive. Cardiac MRI generally provides a more detailed assessment, with excellent soft tissue characterization and the ability to image both deep and superficial structures, though the modality is generally more expensive and less available.

Reference 1. Sharpe RE, Jr, Levin DC, Parker L, Rao VM. The increasing role of ­radiologists in thoracic diagnosis: More thoracic biopsies are performed percutaneously. J Am Coll Radiol Oct 2013; 10(10): 770–773.

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Imaging’s Contribution to Staging Thoracic Tumors David M. Naeger, W. Richard Webb

The imaging, biopsies, and other examinations which comprise a “complete” initial staging vary by tumor type, and indeed, sometimes vary from patient to patient who have the same tumor type. The components of a “standard” initial staging for each individual tumor type will be discussed in subsequent chapters. Below are the general principles that guide the use of imaging in assessing tumor stage and determining when additional workup is needed. Imaging tests are appropriate for staging if (1) there is a reasonable chance of finding disease in the area being imaged, (2) finding the disease in the imaged area will change management, and (3) the detection of the disease by the imaging test is reliable. For example: • Non-small cell lung cancer. Radiographs alone are clearly insufficient. CT is reasonably accurate, although PET/CT is more so. The high frequency with which distant metastatic disease is detected, the important change in management that results from finding distant disease, and the overall accuracy of PET/CT, make whole body scanning with this modality a first line test for initial staging. The accuracy of PET/CT does suffer in a few targeted areas, one being the brain where there is high background physiologic uptake. For cases in which brain metastases are possible (usually more aggressive tumors) and where detecting them would change management, brain MRI is often included as part of the initial staging evaluation. • Other pulmonary tumors. In small cell lung cancer, PET/CT is less clearly indicated, largely because detecting additional disease does 75

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not often alter the management beyond what would be selected based on CT imaging alone. For indolent tumors, such as bronchopulmonary carcinoid, PET/CT is rarely indicated due to the low likelihood of metastatic disease and the poor sensitivity of PET in slowly growing tumors. • Esophageal, mediastinal, and chest wall tumors. Appropriate imaging varies by tumor type and the initial assessment of the disease extent. PET/CT is commonly ordered for esophageal cancer and for most moderate to large thoracic tumors. MR and other specialized tests may also be appropriate, depending on the situation. Additional workup is needed when parts of the imaging results are inconclusive or not sufficiently accurate to guide management. For example: • Tumor size and invasion. CT and PET/CT accurately reveal tumor size in aerated lung, the pleura, the chest wall, and the mediastinum. Tumor size is more difficult to measure in cases of smaller esophageal tumors and tumors in collapsed lung. Tumor invasion is generally well assessed by CT and PET/CT, though some cases require a more detailed evaluation with MR. • Nodal status. Massively enlarged, asymmetric, hypermetabolic lymph nodes along the lymphatic drainage pathway of a tumor are considered positive. Mildly FDG-avid normal-sized lymph nodes, particularly when symmetrically located in the mediastinum/hila, are often the result of granulomatous disease and are frequently reported as negative. The PET/CT evaluation of many patients’ lymph nodes, however, fall between these extremes. When imaging is not definitive for lymph node involvement, pre-operative mediastinoscopy or endoscopic biopsies may be attempted. Lymph nodes are also commonly sampled during “curative” resections to fully stage a patient and guide subsequent management. • Metastatic disease. For metabolically active tumors, PET/CT (with or without a brain MR) is often sufficiently accurate to initially stage a tumor for distant metastases. The diagnosis of widespread metastases suggested by PET/CT is rarely questioned, and a PET/CT negative for

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distant disease is usually trusted. Some equivocal findings seen in remote portions of the body occasionally need further workup, such as an indeterminate adrenal lesion or an isolated hypermetabolic bone focus. Many thoracic oncology programs have multidisciplinary teams who meet regularly to discuss the proper management of patients (e.g., thoracic tumor boards).1 It is essential that medical imaging experts be part of these discussions. Radiologists can provide input regarding imaging, as well as when percutaneous biopsies or imaging-guided ablations may be feasible.

Reference 1. Freeman RK, Van Woerkom JM, Vyverberg A, Ascioti AJ. The effect of a multidisciplinary thoracic malignancy conference on the treatment of patients with lung cancer. Eur J Cardiothorac Surg Jul 2010; 38(1): 1–5.

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Choosing Appropriate Resection for Operable Non-Small Cell Lung Cancer Rodney J. Landreneau

Choosing surgery for the patient with non-small cell lung cancer (NSCLC) and determining the extent of resection most appropriate for cure of the disease and preservation of the patient’s functionality have been important points of discussion over the years. The first intentional thoracotomy and resection of lung tissue was performed by the rural Georgia physician Milton Antony in 1821 to manage what was probably a necrotic lung cancer with extensive anterior chest wall invasion. Anesthesia for this event was accomplished with little more than alcohol intoxication; however, the patient survived the operative intervention and for several months after.1 From these rather primitive, yet remarkable beginnings, surgery to approach thoracic problems progressed in the late 19th and early 20th centuries, aided by improved anesthetic methods, the introduction of antiseptic techniques, and greater understanding of cardiopulmonary physiology. Lung cancer was considered a rarity at that time, with most surgery of the chest being performed to manage pulmonary tuberculosis and other intrathoracic infections.2 A common understanding with regard to cancer management, then and now, is that complete removal of all malignant tissue with a clear margin of normal and adequate sampling of the associated lymph nodes of the resected organ or affected portion of the organ is required.

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Pathologic confirmation of the success of this resection is considered an R0 resection. This should be the absolute and primary goal of all surgical resections aiming to cure the patient of regionally limited disease. Residual microscopic persistent disease (R1 resection) identified intraoperatively should be managed with attempts at more complete, R0 resection. This goal is one of the primary reasons for obtaining an intraoperative “quick/frozen section” pathologic review. Occasionally, delayed extended resection may be considered; however, if prolonged time to recognition of this “microscopic residual” disease is appreciated, supplemental local radiation therapy is often considered to salvage local control of the disease. Although persistent visibly gross tumor (R2 resection) following surgical resection should generally be considered a surgical strategic failure, there remains a minority of clinical circumstances where surgical de-bulking of the primary malignancy may have a therapeutic advantage for the patient. With these oncologic therapeutic concepts in mind, the next question folllows: What is the most appropriate excisional extent or approach for the resectable lung cancer? The resection possibilities range from simple parenchymal wedge resection to total pneumonectomy. The various advantages and limitations of these approaches are summarized in Table 1. I begin this discussion with a focus on pneumonectomy, as nearly a century ago, this was believed to be the most appropriate operation for any lung cancer — those tumors involving the hilum of the lung and small peripheral lung cancers.1–4 These sentiments followed the generally accepted surgical concepts evangelized by William Halsted. The primary principles were that cancer spreads contiguously like a “spilt can of paint” from the cancer tissue origin through the normal tissue of the affected organ and then directly to that organ’s regional lymph nodes and then beyond.5 Accordingly, the necessary surgical treatment to achieve any possibility of cure required the radical resection of the entire affected organ and draining lymph nodes. The early 1930s were memorable as pneumonectomy was accomplished by several surgical teams within months of each other. Alexander and Haight were the first to perform a successful pneumonectomy for

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Lobectomy

Pneumonectomy

Perioperative mortality Morbidity

Low (less than 1%) Usually low (10%)

Low (less than 1%) Moderate (20%)

Moderate (2–4%) Moderate (25%)

High (6–10%) Moderate to high (25–30%)

Local control of cancer

Least favorable (recurrence up to 25%)

Dependent on marginal status ( 5% with margin to tumor size ratio >1)

Low (5%)

Variable (5–15%) (dependent on hilar extent of disease)

Long-term survival

Variable (dependent on tumor stage and comorbidities)

Primarily dependent upon tumor pathologic stage

Primarily dependent upon tumor pathologic stage

Variable (dependent on tumor stage and comorbidities

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Anatomic Segmentectomy

Choosing Appropriate Resection for Operable Non-Small Cell Lung Cancer

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Table 1.   Characteristics of various R0 lung resections for NSCLC.

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tuberculosis (in two stages) and Nissen accomplished a similar feat shortly after.6,7 Graham performed the first successful single-stage pneumonectomy for carcinoma of the lung using a mass ligation of the pulmonary hilum and removal of the lung with extensive seven-rib thoracoplasty in 1933, and this was independently followed shortly after by Archibold with the assistance of Vineberg and Bethune, who accomplished the first pneumonectomy using indvidual ligation/division approach to the hilar vasculature and bronchus.8–10 This general belief of the superiority/necessity of pneumonectomy was strongly held by most thoracic surgeons of the middle part of the 20th century, although pulmonary lobectomy for benign and malignant disease had been performed since Hugh Morriston Davies’ first performance of lobectomy for lung cancer in 1912 using individual ligation and division of the lobar vasculature and bronchus.1,11–12 Unfortunately, Davies’ patient died several days after surgery from pulmonary insufficiency and pneumonia. The lack of “closed” drainage of the chest following thoracotomy certainly contributed to this fatal outcome. Howard Lilienthal accomplished the first successful lobectomy using a mass ligature technique to ligate and divide the lobar hilum and reported a series of 15 patients undergoing this approach with 42% perioperative mortality.13 As in Davies’ case, closed chest drainage was not used following resection. Outcomes following lobectomy would change for the better as a result of Graham’s 1919 post-World War I pneumonia commission report, which noted superior survival among soldiers managed with closed chest drainage of streptococcal empyemas following influenza pneumonia compared to those patients managed with open drainage of the empyema.14 Closed tube drainage has become accepted as standard therapy following tube thoracostomy and thoracotomy ever since. Significant reduction in surgical mortality following pulmonary resection or empyema drainage related to preservation of the patients’ “pulmonary vital capacity” was the positive consequence of this important investigation.14 Indeed, Brunn was the first to report a significant reduction in perioperative mortality following pulmonary lobectomy with the standard use of closed tube thoracostomy drainage following resection.15 The trend toward pulmonary lobectomy as the preferred resection approach for most lung cancers was established as a result of the study by

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Shimkin reported in 1962 comparing surgical outcomes for lung cancer between the Ochsner and Overholt Clinics.16 This investigation demonstrated equivalent survival among patients undergoing either lobectomy or pneumonectomy for “limited, completely resected” disease with reduced perioperative mortality overall among lobectomy patients (Figure 1). Since that time, anatomic lobectomy has been considered “the standard of care” for most lung cancers within the pulmonary parenchyma that does not involve the lung hilum. This concept has been extended to also suggest sleeve lobectomy with bronchoplasty reconstruction as an alternative to pneumonectomy for selected hilar tumors since Clement Price Thomas first performed this resection in 1951.12 The results with sleeve

Figure 1.    Comparison of survival between lobectomy and pneumonectomy peformed for limited lung cancer and advanced lung cancer at the Ochsner and Overholt clinics. From: Shimkin MB, Connelly RR , Marcus SC, Cutler SJ. Pneumonectomy and lobectomy in bronchogenic carcinoma. A comparison of end results of the Overholt and Ochsner clinics. Thorac Cardiovasc Surg. 1962; 44: 503–19.

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lobectomy appear to be equivalent to that of pneumonectomy when ­performed by experienced thoracic surgical teams.17–20 A confounding clinical issue for many patients with resectable lung cancer is the clinical presence of impaired pulmonary function which prohibits the significant loss of lung tissue associated with pneumonectomy or lobectomy. Sublobar pulmonary resection as a compromise operation for peripheral lung cancers was considered a reasonable option for such patients.21 Although overall survival for stage I NSCLC appears to be similar between patients undergoing either sublobar resection or lobectomy, local recurrence of cancer appears to be significantly increased among sublobar resection patients, particularly wedge resections with close surgical margins.22,23 Adjuvant external beam radiation therapy or intraoperative radiation brachytherapy has been suggested; however, current evidence suggests a limited role of adjuvant radiation therapy for completely resected peripheral lung cancers with adequate/clear surgical margins.24,25 Adding further fire to this discussion is the renewed enthusiasm with anatomic segmentectomy as a definitive, alternative resection to lobectomy for the small peripheral lung cancer (Figure 2). These considerations have been at play since Churchill and Belsey’s first segmental

Figure 2.    Subcentimeter lung carcinoma in the left upper lobe which could be considered for primary anatomic segmentectomy as definitive therapy along with mediastinal lymph node sampling/dissection.

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Table 2.   Pulmonary pathologic circumstances where anatomic segmentectomy may be a reasonable first resective consideration for cancer. Favorable Criteria for Anatomic Segmentectomy • Small Tumors: 1 cm (Margin/ Tumor ratio >1) • Elderly (Age >80) • Marginal pulmonary function (FEV1/DLCO