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ThoracicEndoscopy:Advances inInterventionalPulmonologyEDITED BY

Michael J. Simoff, MDDirector, Bronchoscopy & Interventional PulmonologyPulmonary and Critical Care MedicineHenry Ford Medical CenterDetroit, Michigan

Daniel H. Sterman, MDDirector, Interventional PulmonologyPulmonary, Allergy and Critical Care DivisionUniversity of Pennsylvania School of MedicinePhiladelphia, Pennsylvania

Armin Ernst, MDAssistant Professor in Medicine & PediatricsHarvard Medical SchoolBoston, Massachusetts

ThoracicEndoscopy:Advances inInterventionalPulmonology

This volume would not be complete if we did not thank our mentors, teachers, colleagues andfriends. The insight, support and guidance of these individuals have facilitated both the genesis andthe metamorphosis of this emerging discipline of interventional pulmonology. For those of us wholook toward the future it is wonderful to have support and experience to rely on for this journeyinto the future and company along the way. Thank you all.

— Editors

To my past, future and present: my past, my parents, James and Ilinka, who have given me thefoundation to achieve that which I strive toward. My future, my son Evan, who has reopened myeyes to the many whys around us. My present, my wife Evonne, whose love, support and guidanceI could not do without, each and every day of my life; with her at my side I will always be successful.

— Michael J. Simoff

To my wife, Jamine, for her patience and support,To my children, Drew, Grant and Caroline, for their love and spirit,And, to my parents, for their inspiration.Without all of you, none of this would have been accomplished.

— Daniel H. Sterman

I dedicate this work to my wife Dayna, whose never ending support is what makes efforts like thepublication of this book possible.

— Armin Ernst

ThoracicEndoscopy:Advances inInterventionalPulmonologyEDITED BY

Michael J. Simoff, MDDirector, Bronchoscopy & Interventional PulmonologyPulmonary and Critical Care MedicineHenry Ford Medical CenterDetroit, Michigan

Daniel H. Sterman, MDDirector, Interventional PulmonologyPulmonary, Allergy and Critical Care DivisionUniversity of Pennsylvania School of MedicinePhiladelphia, Pennsylvania

Armin Ernst, MDAssistant Professor in Medicine & PediatricsHarvard Medical SchoolBoston, Massachusetts

© 2006 by Blackwell Publishing

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First published 2006

1 2006

ISBN-13: 978-1-4051-2204-7

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Thoracic endoscopy : advances in interventional pulmonology / edited

by Michael J. Simoff, Daniel H. Sterman, Armin Ernst.

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ISBN-13: 978-1-4051-2204-7 (alk. paper)

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1. Chest–Endoscopic surgery. I. Simoff, Michael J. II. Sterman,

Daniel H. III. Ernst, Armin.

[DNLM: 1. Lung Diseases–surgery–Case Reports. 2. Bronchial

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Contents

Contributors, vii

Foreword, xi

Preface, xiii

Part I Advances in diagnosticbronchology

1 Autofluorescence in the detection of lungcancer, 3Michael J. Simoff

2 New technologies for the endobronchialassessment of the pulmonary tract, 21Mark E. Brezinski

3 Endobronchial ultrasound, 33Felix J.F. Herth & Heinrich D. Becker

4 Advances in diagnostic bronchoscopy:virtual bronchoscopy and advancedairway imaging, 44Rex C. Yung & Leo Patrick Lawler

5 Medical simulation: current uses andfuture applications, 76Joseph L. Tasto & Jonathan P. Balcombe

6 Bronchoscopy and computertechnology, 88Heinrich D. Becker

Part II Advances in therapeuticbronchology

7 Rigid bronchoscopy, 121Jed A. Gorden & Douglas E. Wood

8 Fire and ice: laser bronchoscopy,electrocautery and cryotherapy, 134Michael A. Jantz & Gerard A. Silvestri

9 Photodynamic therapy forendobronchial tumors: palliation anddefinitive therapy, 155David Ost

10 Stenting of the tracheobronchialtree, 167Armin Ernst

11 Transtracheal oxygen and percutaneoustracheotomy, 173David Feller-Kopman

12 Bronchoscopic lung volumereduction, 188Edward P. Ingenito & Larry W. Tsai

13 Endobronchial gene therapy, 198Robert J. Kruklitis & Daniel H. Sterman

Part III Interventional pleurology

14 Thoracentesis, percutaneous needlebiopsy of pleura, small-bore catheterdrainage: does size really matter? 213Luis Miguel Seijo

15 Medical thoracoscopy, 224Sjaak A. Burgers

16 Photodynamic therapy in the pleuralspace, 242Paul Baas

17 Intrapleural therapy: from BCG totherapeutic genes, 251Andrew R. Haas & Daniel H. Sterman

Part IV Case discussions

18 Management of patients at increased riskfor lung cancer, 271Boyd T. Hehn & Michael J. Simoff

v

vi Contents

19 Staging of bronchogenic carcinoma: aninterventional pulmonaryperspective, 279J. Francis Turner, Jr & Arthur D. del Rosario

20 Management of malignant pleuraleffusions, 298Michael S. Machuzak, Ali I. Musani &Daniel H. Sterman

21 Management of spontaneouspneumothorax, 310Michael H. Baumann

22 Obstruction of the central airways:evaluation and management, 323William Lunn

23 Management of massive hemoptysis, 330John Conforti

24 Management oftracheobronchomalacia, 344Kelly A. Carden & Armin Ernst

Index, 353

Contributors

Paul Baas, MD, PhD, FCCPThoracic OncologistThe Netherlands Cancer InstituteAmsterdam, The Netherlands

Jonathan P. Balcombe, PhDResearch ScientistPCRM (Physicians Committee for Responsible Medicine)Washington, DC, USA

Michael H. Baumann, MDProfessor of MedicineDivision of Pulmonary Critical Care and Sleep MedicineUniversity of Mississippi Medical CenterJackson, MS, USA

Heinrich D. Becker, MD, FCCPInternal Medicine, PulmonologyDirector, Department of Interdisciplinary EndoscopyThoraxklinik at Heidelberg UniversitySchool of MedicineHeidelberg, Germany

Mark E. Brezinski, MD, PhDAssociate ProfessorHarvard Medical SchoolBrigham & Women’s HospitalBoston, MA, USA

Sjaak A. Burgers, MD, PhDPulmonologistNetherlands Cancer InstituteAntoni van Leeuwenhoek HospitalDepartment of Thoracic OncologyAmsterdam, The Netherlands

Kelly A. Carden, MDInstructor in MedicinePulmonary and Critical Care MedicineBeth Israel Deaconess Medical CenterBoston, MA, USA

John Conforti, DOAssistant Professor of MedicineDirector of Interventional PulmonologyWake Forest UniversityDepartment of Pulmonary Critical Care andSleep Medicine Medical Center BLVDWinston-Salem, NC, USA

Arthur D. del Rosario, MD, FCAP, FASCPPathologistChartered/Quest Diagnostics, IncLas Vegas, NV, USA

Armin Ernst, MDDirector, Interventional PulmonologyBeth Israel Deaconess Medical CenterAssociate Professor of MedicineHarvard Medical SchoolBoston, MA, USA

David Feller-Kopman, MDDirector, Medical Procedure ServiceHarvard Medical SchoolInterventional PulmonologyBeth Israel Deaconess Medical CenterBoston, MA, USA

Jed A. Gorden, MDInterventional PulmonologyBeth Israel Deaconess Medical CenterBoston, MA, USA

Andrew R. Haas, MD, PhDThoracic Oncology/Interventional Pulmonary FellowHospital of the University of PennsylvaniaPulmonary, Allergy and Critical Care Division8th Floor Gates Building3400 Spruce StreetPhiladelphia, PA, USA

vii

viii Contributors

Boyd T. Hehn, MD, FCCPAssistant Professor of MedicineTufts University School of MedicineMedical Director Respiratory CareDirector, Interventional PulmonologyBaystate Medical CenterSpringfield, MA, USA

Felix J.F. Herth, MD, DSc, FCCPHead, Department of Pneumology & Critical Care MedicineThoraxklinik at the University HeidelbergHeidelberg, Germany

Edward P. Ingenito, MD, PhDAssistant Professor of MedicineBrigham and Women’s HospitalPulmonary & Critical Care MedicineBoston, MA, USA

Michael A. Jantz, MDDirector of Interventional PulmonologyUniversity of FloridaDivision of Pulmonary and Critical Care MedicineGainesville, FL, USA

Robert J. Kruklitis, MD, PhDDirector of Interventional Pulmonary MedicineLehigh Valley HospitalAssistant Professor of Clinical MedicinePenn State College of MedicineAllentown, PA, USA

Leo Patrick Lawler, MB, BCh, BAO, FRCRAssistant Professor of RadiologyInterventional and Body ImagingThe Russell H. Morgan Department ofRadiology and Radiological ScienceJohns Hopkins UniversityBaltimore, MD, USA

William Lunn, MDDirector, Interventional PulmonologyBaylor College of MedicineHouston, TX, USA

Michael S. Machuzak, MDInterventional Pulmonary Fellow830 West Gates Bldg3400 Spruce StPhiladelphia, PA, USA

Ali I. Musani, MD, FCCPAssistant Professor of MedicineInterventional Pulmonology ProgramHospital of the University of PennsylvaniaPhiladelphia, PA, USA

David Ost, MDDirector of Interventional PulmonologyNew York University Medical CenterAssociate Professor of MedicineNew York University School of MedicineNew York, NY, USA

Luis Miguel Seijo, MDAssociate Clinical ProfessorInterventional Bronchoscopy ProgrammePulmonary DivisionClínica Universitaria de NavarraUniversidad de NavarraPamplona, Spain

Gerard A. Silvestri, MD, MSAssociate Professor of MedicineMedical University of South CarolinaDivision of Pulmonary and Critical CareMedicine, Allergy & ImmunologyCharleston, SC, USA

Michael J. Simoff, MDAssistant Professor of MedicineDirector, Bronchoscopy & Interventional PulmonologyDivision of Pulmonary; Critical Care, Allergy, Immunologyand Sleep Medicine and ResearchHenry Ford Medical CenterDetroit, MI, USA

Daniel H. Sterman, MDDirector, Interventional PulmonologyPulmonary, Allergy and Critical Care DivisionUniversity of Pennsylvania School of MedicinePhiladelphia, PA, USA

Joseph L. Tasto, MD, MSPresident & CEOTasto Medical, LLCBrookeville, MD, USA

Larry W. Tsai, MDAttending PhysicianBrigham and Women’s HospitalBoston, MA, USA

Contributors ix

J. Francis Turner, Jr.,MD, FACP, FCCP, FCCMSection Head: Pulmonary & Critical CareMedicine, VASNHSDirector of Interventional PulmonologyDirector of Medical Intensive Care UnitMike O’Callaghan Federal HospitalLas Vegas, NV, USA

Douglas E. Wood, MDProfessor and Chief, General Thoracic SurgeryEndowed Chair in Lung Cancer ResearchUniversity of WashingtonSeattle, WA, USA

Rex C. Yung, MD, FCCPAssistant Professor of Medicine & Oncology

Director of Bronchoscopy

Director of Pulmonary Oncology

Johns Hopkins University

Baltimore, MD, USA

Foreword

The centennial anniversary of bronchoscopy is nowseveral years behind us. The modern era of inter-ventional pulmonology is more than two decadesold. However, many decades ago and before theadvent of the flexible bronchoscope, some phys-icians (usually surgeons) resected some tumorswith rigid bronchoscopes and forceps. Moreover,thoracoscopy was first performed in 1910 by aninternist who used a cystoscope to explore thepleural space [1]. It is tempting to consider myselfas an interventional pulmonologist who began hiswork at the advent of interventional pulmonology,but clearly this is not so. However, the progressof instrumentation and techniques since the 1980sforce me to reflect that what we did in the early1980s was very pedestrian. In the current era,new instruments have been developed and innovat-ive thinking has made interventional pulmonologymore widely available. There is crossover of prac-tice, such that many interventional pulmonologistshave expanded their practices to include forms ofcare that were once done almost exclusively bysurgeons.

This book is written by many of the pulmono-logists and surgeons who practice interventionalpulmonology as a major part of their professionalactivities. For it to be used and understood asan up-to-date and excellent reference, the readershould have solid foundations and an understand-ing of basic diagnostic bronchoscopy and simpleprocedures that are part of the practice of chestmedicine.

The editors have developed three complement-ary sections of the book, beginning with advanceddiagnostic bronchology. In the first chapter, amethod for detecting occult malignancies (auto-fluorescence bronchoscopy) is explained in detail.This was strictly a research method until very

recently. Another emerging field that has greatpromise for diagnosis and staging is endobronchialultrasound. The potential to improve patient care istruly impressive. Other advanced diagnostic tech-niques and use of simulators round out the firstsection of the book.

In the second section the editors have clusteredthe latest skills for interventional bronchoscopy.Rigid bronchoscopy, I am happy to see, occupies theleadoff position. I still believe that an interventionalpulmonology service is incomplete if the physiciandoes not acquire the requisite skills to use a rigidbronchoscope well. A variety of ablative instru-ments are described for use with bronchoscopes,and the costs and advantages of one or the otherinstrument are compared. Stents are now availablein many sizes, shapes and materials. None is perfect,but the choice among the many options is explainedto the reader. The future potential for endobron-chial lung reduction therapy and gene therapy withthe bronchoscope are discussed.

Next, the editors provide a window to the pleurawith a variety of topics that typically take additionaltraining beyond the years of standard residency andfellowship programs. Finally, a series of illustrativecases are presented with excellent photographs toenhance the application of these techniques in agiven practice.

Not all interventional pulmonologists willchoose to master each of the practice patterns thatare described, but this book provides a concentratedand cohesive orientation to all that is availableto such physicians at the moment. The editorsare among the most highly recognized names inthe field today, and they are continuing to provideadvances for the rest of us to incorporate into ourpractices. I extend my thanks to each of themand their contributing authors for a collection

xi

xii Foreword

that should serve as a ready reference for thestudent and the more experienced interventionalpulmonologist alike.

Paul A. Kvale, MDProfessor of Medicine

Division of Pulmonary, Critical Care, Allergy,Immunology, and Sleep Medicine and Research

Henry Ford Health SystemDetroit, MI, USA

Reference

1 Jacobaeus HC. Über die Möglichkeit die Zystöskopie bei

Untersuchung Seröser Höhlungen anzuwenden. Münch

Med Wochenschr 1910;57:2090–2092.

Preface

As the title of our textbook implies, the field ofinterventional pulmonology has expanded beyondjust managing malignant diseases of the trachea andmainstem bronchi to the diagnosis and manage-ment of diseases of the entire thorax. We felt that thetitle of the text, ‘Thoracic Endoscopy’ more com-pletely encompasses the expansiveness of the fieldof interventional pulmonology, which we continueto practice and hope to continue to expand.

From the inception of the practice of interven-tional pulmonology, there has been enthusiasm forthe practice of therapeutic procedures; from theinitial use of lasers and the ‘rediscovery’ of the rigidbronchoscope to electromagnetic guided broncho-scopy and endobronchial lung volume reduction.As the field grows, the breadth and depth ofour contribution to the diagnosis and manage-ment of diseases of the chest will also continueto grow.

In regard to chest malignancies, the furtheradvancements of endobronchial ultrasound, auto-fluorescence and optical coherence tomographyas well as external navigational techniques willprovide for a more comprehensive diagnostic arma-mentarium to identify and stage diseases. Withadvances in laser, electrosurgical and the evolu-tion of tracheobronchial stenting, interventional

pulmonology can treat endobronchial disease bet-ter than before. With advancements in medicalthoracoscopic procedures, we have expanded ourexpertise to diagnosis, monitoring and treatmentof the pleural space.

Benign tracheobronchial diseases are now a reg-ular part of the interventionalist’s realm, for bothdiagnosis as well as treatment. This not onlyincludes diseases of the large airways such astracheal stenosis or tracheobronchomalacia, butalso diseases of the small airways – emphysema andasthma. Advancements in percutaneous trache-ostomy and other related procedures have servedto expand the diversity of our contribution tomanagement of the critically ill patient.

Interventional pulmonology will only continueto grow as a specialty, particularly as the field incor-porates advances in nanotechnology and molecularmedicine. The technologies that exist on the hori-zon are exciting and awesome. This textbook ismerely an outline to the myriad of possibilitiesavailable to the inventive and far-reaching mind ofthe advanced chest endoscopist.

Michael J. Simoff, MDArmin Ernst, MD

Daniel Sterman, MD

xiii

I PART I

Advances indiagnosticbronchology

1 CHAPTER 1

Autofluorescence in the detectionof lung cancer

Michael J. Simoff, MD

Perception depends upon the detection technique. What we see is the result of the brilliantpossibilities of the human eye and human brain.

Martin Leonhard, “New Incoherent Autofluorescence/Fluorescence system forEarly Detection of Lung Cancer”

Lung cancer continues to be the leading killeramong all cancers. Despite recent advancements intreatment, the 5-year survival rate for lung can-cer remains at approximately 15%. In the 25% ofpatients diagnosed with lung cancer who are offeredsurgery for curative resection, only one half are ulti-mately cured of their disease. The greatest hope forpatients is the early detection of lung cancer allow-ing them the opportunity to attempt a treatmentcourse for a cure.

These poor statistics do not reflect on theaggressiveness of treatment, rather on the late dia-gnosis and frequent recurrence of lung cancer inpatients. Finding a solution to the dilemma ofhow to diagnose lung cancer early remains a goalof many researchers. Chest radiographs and com-puted tomography screening [1–3] have been andare being looked at to identify this disease earlier inits development.

With only 30% of early endobronchial cancerand/or premalignant lesions identified by whitelight bronchoscopy (WLB) [4], it would be anunderstatement to say that we are missing manyopportunities for the treatment of early synchron-ous and metachronous tumors. What is needed isa new modality to detect early forms of the disease,which then have the opportunity to be aggressivelytreated and potentially cured, some with endobron-chial techniques. One such technology for earlydetection is autofluorescence bronchoscopy (AF).

Autofluorescence is not the answer to thedilemma of the diagnosis of lung cancer, but it maygive us another tool for not only diagnosing, butalso guiding management decisions [5], thus betterallowing us treatment planning and option eval-uation for patients with lung cancer. The formatof this chapter will be to guide the reader throughthe whys and hows of AF bronchoscopy prior todiscussing the actual clinical use. Only by under-standing what information we gain by AF can thistool be effectively used.

The problem

Despite advancements in chemotherapeutic agents,radiation and surgical techniques, the recurrencerate of lung cancer is 3.6–4% per year. Secondprimaries occur in 17% of patients within 3 yearsof treatment of their primary disease [6,7]. With10–20% of patients having a second primary orrecurrence, it suggests a more complicated processthan a single tumor alone.

The presence of synchronous primary cancersis common. Of the patients who die of lungcancer, 15% have synchronous carcinoma in situ(CIS), with a prevalence of 3.4% among one–twopacks per day smokers, and 11.4% among patientssmoking greater than two packs per day [8]. Quet al. [9] looked at 225 subjects, including patientswith known or suspected lung cancer, patients post

3

4 PART I Advances in diagnostic bronchology

Table 1.1 Comparison of patients with known or sus-pected lung cancer. Status: post resection for lungcancer, with head and neck cancer and healthy volun-teers for the presence of precancerous and cancerouslesions [9].

Group n Moderate Severe CIS ≥2 focidysplasia dysplasia (%) (%)

(%) (%)

I 100 14 11 15 15

II 46 18 4 13 24

III 10 20 10 10 20

IV 67 36 15 5 13

n, number of patients.

I, known or suspected lung cancer.

II, stage I completely resected lung cancer.

III, head and neck cancer.

IV, volunteer smokers.

complete resection for lung cancer, those with headand neck cancer and in healthy volunteer smokers(Table 1.1). In the group suspected of cancer, 25%had moderate to severe dysplasia and 15% had CIS,with 15% of these patients having greater than twofoci. In the postoperative group 22% of patientswere identified to have dysplasia and 13% with CIS,24% of which had multiple foci. The patients withhead and neck cancer had a 30% prevalence of dys-plasia and 10% of CIS, 20% multifocal. And last,the volunteer smokers included 51% with dysplasiaand 5% with CIS, 13% of which had greater thantwo foci.

Carcinogenesis

The concept of carcinogenesis is a multi-step pro-cess, suggesting the possibility of blocking orreversing the progression and thus presents theopportunities for a more effective intervention.

Vogelstein et al.,“The Multistep Nature of Cancer”

The pattern of multifocal areas of dysplasia andCIS in many ways supports the theory of field can-cerization as it applies to cancer of the aerodigestivetract [10]. As they are inhaled, cigarette smokeand/or other irritants thought to be the primarycarcinogens for lung cancer, expose the entireaerodigestive tract to potential injury. This diffuseinjury to the mucosa of the lung should probably beexpected rather than be surprising to us. The initial

changes of genomic instability within a morpholo-gically normal epithelium begin the molecular stageof carcinogenesis [9]. These mutation-inducedchanges could therefore be expected to occurthroughout the respiratory epithelium.

The process of carcinogenesis begins with theinitial injury to the endobronchial epithelium.The genetic mutations that occur in response tothis injury bring about the morphologic findingsidentified as premalignant changes in the tissue.This process of mutagenesis, from normal tissuethrough metaplasia and subsequently dysplasia,takes 3–4 years to occur usually [11–14]. Onceidentified, endobronchial dysplasia is a difficultproblem in that it is unclear as to the evolutionof disease from this stage of change. There can bean apparent resolution of dysplasia to morpholo-gically normal tissue that has been identified andreported [15]. The gradation of mild and moder-ate to severe dysplasia have progressively strongerimplications of areas of true concern, regardingthe development of cancer. The pathologic evol-ution from severe dysplasia to CIS takes about6 months [11]. Therefore, from the time of a tissueinjury, which induces the pathologic changes thatallows the development of a cancer, multiple otherareas throughout the epithelium have sustainedsimilar injury and must be at similar risk for thedevelopment of cancer.

Several authors have studied the rate of pro-gression from CIS to microinvasive cancer; onegroup demonstrated a 23% progression rate of CISto microinvasive cancer, by performing follow-upbronchoscopies every 3 months [15]. Venmanset al. [16] followed pathologically confirmed CISin their patients every 3–4 months with broncho-scopy also. They eventually confirmed that all butone of their patients developed an invasive car-cinoma of the airways, which required therapy. Thesingle individual in whom CIS did not evolve intoa microinvasive cancer in the study had enoughmacroscopic changes by WLB alone; hence, ther-apy was begun despite incomplete evolution of thepathologic changes.

Overall, several authors have also begun to lookat the issue of progression of endobronchial patho-logy. It is suggested by review of data available that10% of moderate dysplasias, 19–46% of severe dys-plasias and 22–56% of CIS will eventually evolve

CHAPTER 1 Autofluorescence in the detection of lung cancer 5

from their current state to an invasive cancer[15–19].

As is suggested here, not all lesions progressto a more evolved state of disease; some actuallyspontaneously regress or demonstrate no histo-logic change over time. The studies available,which have used sequential surveillance broncho-scopy with AF, have all had limited numbersof patients [14,16,20,21]. In two of the studies,precancerous lesions that persisted for 3–6 monthswere treated with endobronchial modalities lim-iting the length of follow-up [16,20]. Lam et al.did follow endobronchial changes with AF in17 patients with pre-invasive disease for up to4 years. Of these patients 5 progressed to aninvasive squamous cell carcinoma. The lesions inthe remaining 12 patients, on the other hand,remained in a pre-invasive state throughout the4-year follow-up [21]. Unfortunately, despite theknowledge that some lesions improve with time,we are left in a situation where we do not know, nordo we have the capacity at this time to differentiate,which lesions will progress, stay the same or remissto normal mucosa. AF gives us new information onthe identification of these lesions, but also addedquestions as to what to do with them.

Microscopic anatomy ofthe airways

The airway is a multilayered structure, consistingof the ciliated epithelium (46 ± 3 microns) withthe underlying basement membrane. Immediatelybelow the basement membrane is the submucosa(680 ± 20 microns), which consists of mucousglands, collagen, elastin, nerves, lymphatics,and vascular structures. Smooth muscle separ-ates the submucosa from the cartilaginous layer(1.2 ± 0.1 mm) of the airway. The adventitia, a con-nective tissue sheath containing branches of bron-chial arteries and veins and nerve plexi, is the outermost layer of the airway [9,22].

The pathologic changes of dysplasia, CIS andmicroinvasive carcinoma are very superficial. Thesechanges occur initially in the epithelium, eventu-ally invading through the basement membrane andinto the upper submucosa (Figure 1.1). Pathologicevolution of microinvasive cancer usually involvesthe superficial 70–116 microns of the airway [9].

Figure 1.1 Depth of penetration of early cancerous lesionsin respect to microscopic anatomy of the bronchus wall.

It is important to understand the process of car-cinogenesis as well as the microscopic anatomy ofthe airway to effectively use the technique of AF.

WLB and the detection of earlydisease

Due to the intra-epithelial to superficial submu-cosal development of CIS and microinvasive can-cers, it is difficult to diagnose many of thesesites with conventional WLB techniques alone. CISand early cancers are only detected with WLBabout 29–40% of the time [4,7,23–25]. This isdue to the fact that these early pathologic lesionsare only a few cells thick (0.2–1 mm) leading toonly minimal mucosal changes. When visualized,these precancerous and early cancerous lesions aresuperficial, often flat lesions, which are usuallyless than 5 mm2 in surface area. Endobronchialchanges less than 10 mm2 are commonly invisibleto standard WLB observation. With WLB, many ofthese lesions present as nonspecific changes of theendothelium such as a pale or a more reddish dis-coloration of the mucosa. Other epithelial changesobserved by WLB examination include a lack ofluster or a rough/microgranular appearance of themucosa [23,25,26]. Mucosal folds and bronchialbifurcations can be swollen or thickened with nod-ular lesions becoming more evident after they havegrown greater than 2 mm in size [23,25].

Bronchoscopic evaluation of the airways can takeplace in bronchi of the fifth order with modern flex-ible WLB [27]. As the clarity of images continues toimprove with the advancement of bronchoscopic


optics, what will be the role for AF bronchoscopy?I was challenged on one occasion with this veryquestion. The questioner explained that with hisnewest generation bronchoscope, he could see thevascularity of the bronchial mucosa with great clar-ity; why then, with such advanced optics, do weneed a different tool to look for subtle endobron-chial changes when they should be clearly visible.My response was simply: “So do you look?” Thechanges we are trying to identify are subtle. Havingthe capability to examine the airway and actu-ally performing such a detailed examination in abreathing, coughing patient is very different. Thetechnology used for AF allows us an improved abil-ity to look for subtle changes throughout the air-ways of our patients in a relatively straightforward,safe and effective manner.

There have been multiple studies attempting touse conventional WLB to identify early stage lungcancer. One such study used WLB to evaluate theairways of patients with positive sputum cytologyfor lung cancer. They identified CIS or microinvas-ive cancer in 61% of patients who were examined,making the diagnosis of an early cancer in 88% ofthe patients (44 of 55 patients) [28]. Sato and col-leagues [29], looked at 180 patients who underwent527 bronchoscopies. Two hundred occult cancerswere identified during the time of the study. Toachieve this result though, it required a mean of29.2 months and an average of three bronchoscop-ies for each patient to attain a definitive diagnosis.Both groups of investigators identified early stagecancers; the limitations in time to diagnosis andthe number of bronchoscopies required make thisapproach of limited value and less practical forclinical application.

Light

Light is a form of electromagnetic radiation. Whitelight, as in sunlight or incandescent light, is apolychromatic blend of all wavelengths of thespectrum of visible light. White light can be sep-arated into individual wavelengths; each distinctcolor can be exposed by passing the white lightthrough a prism or as is similarly seen in a rainbow(Figure 1.2). We see in color due to the vari-ous light wavelengths and their interactions withobjects and/or tissue.

Figure 1.2 White light separated into various wavelengths(colors) through a prism. (Image courtesy of Karl Storz ofAmerica, Culver City, California, USA, with permission.)

Figure 1.3 Reflectance imaging: the four physicalproperties of light as it interacts with a surface:absorption, scattering, reflection and fluorescence.

When white light is shown onto a surface, andfor the purpose of this discussion, specifically atissue surface, the colors that we see are due to sev-eral of the physical properties of light: scattering,absorption, reflection and fluorescence. (Refer toFigure 1.3 for the following discussion.) As lightstrikes a surface, some of the light is scattered in dif-ferent directions still as white light. Our observationof this phenomenon is often referred to as glare. Asthe same light strikes a surface, some wavelengths oflight are absorbed into the tissue/structure. Thesewavelengths of light are absorbed into various


Figure 1.4 Florescence wavelengths ofthe major tissue fluorophores: FADH2,NADH, elastin and collagen 1. (Imagecourtesy of Karl Storz of America, CulverCity, California, USA, with permission.)

components of the structure (cells, molecules, etc.).This absorption leads to loss of these wavelengthsof light. The remaining light wavelengths that arereflected off the tissue/structure surface are blen-ded into the colors that we see objects in. Thiscombination of effects of reflection, back scat-tering and absorption are known as reflectanceimaging. We observe by reflectance imaging whenusing WLB.

Autofluorescence

As white light strikes a tissue surface, and reflect-ance imaging occurs, as mentioned earlier, someof the light is absorbed. Certain cells withinthe epithelium and upper submucosa, known asfluorophores, are stimulated by this influx ofenergy (Figure 1.1). The most commonly recog-nized fluorophores in the epithelium and submu-cosa are collagen I and II, elastin, NADH andFADH2 (Figure 1.4). Fluorophores absorb shortwavelengths of light, usually about 390–460 nm(blue light), stimulating electrons from theirground state energy level (E1) to an excited state(E2). Spontaneous decay from the excited stateleads to the emission of longer wavelengths of lightfrom the fluorophores that are eventually releasedfrom the surface of the tissue (Figure 1.5). Thesehigher wavelengths of light that are released are of520 nm, which is seen as green, and of 630 nm, seenas red (see Figure 1.6).

Fluorescence or AF is expressed by all tis-sue surfaces stimulated with white light, ormore specifically the shorter wavelength blue light

(390–460 nm) within white light. AF is alwayspresent, but as it is 10 000 times dimmer than reflec-ted light, it is not visualized with normal viewing.The tissue epithelium is not very biologically act-ive and is responsible for less than 5% of tissuereleased AF. On the other hand, due to their cellularmakeup, the submucosa and cartilage have strongAF potentials. Due to the shallow penetration ofblue light into the tissue surface, clinically observedAF is a characteristic of the upper submucosapredominantly (Figure 1.1) [30,31].

The tissue characteristic of AF was first discussedin the literature in 1933 [32]. Historically, AF waspharmacologically augmented by the use of photo-sensitizers like partially purified hematoporphyrin.With further advancements in 1961, hematopor-phyrin was found to have preferential retentionin cancer cells [33]. In 1979, hematoporphyrinwas used in work pertaining to the early detec-tion of lung cancer by Doiron et al. [34]. Asour knowledge of photobiology progressed, newpharmacologic agents were developed includinghematoporphyrin II in 1979 [35]. Low doses ofhematoporphyrin II were used by Palcic et al. toclinically identify early stage lung cancer [36].

The next leap in technology was in 1990with the development of a Lung Imaging Fluor-escence Endoscope (LIFE) (Xillix TechnologiesCorp., Richmond, British Columbia, Canada).LIFE bypassed the need of photosensitizers, ratherusing low energy monochromatic laser light tostimulate cellular AF. A series of filters and cameraswere then used to allow clear visualization of thegreen and red light generated by AF [37].


Figure 1.5 Certain wavelengths of light(390–460 nm) excite molecules influorophores to higher energy states(E2). Spontaneous decay producesfluorescence with emittance of green(520 nm) and red (630 nm) light. (Imagecourtesy of Karl Storz of America,Culver City, California USA, withpermission.)

Figure 1.6 Relative release of green andred wavelengths of normal tissue inresponse to excitation. (Image courtesyof Karl Storz of America, Culver City,California, USA, with permission.)

Autofluorescence bronchoscopy is performedby the stimulation of fluorophores by illumin-ating them with a monochromatic light source(helium–cadmium laser, filtered xenon or metalhalide light sources). Reflectance is then filteredout and with the assistance of filters and specificoptical camera systems images in green and red arevisualized. With AF normal bronchial epithelium isvisualized in green (520 nm), due to the predomin-ate formation of these wavelengths of green light bynormal stimulated fluorophores. Areas of the sub-mucosa or epithelial layers that have precancerouschanges or have evolved into microinvasive cancerswill have a diminishment in the green light releasedand subsequently increased visibility of red light(630 nm) produced.

The reduction of visualized green light is dueto the pathologic changes associated with thecellular evolution into a microinvasive cancer. Anearly change in the process is thickening of the

epithelium, which allows less of the delivered lightto pass into the submucosa, overall decreasingthe AF that is produced. Second, cancer-inducedangiogenesis occurs within the thickened epithe-lium and upper submucosa as the cancer con-tinues to grow locally. Blood is visualized by thenaked eye as red, due to the fact that bloodproducts have an increased absorption of col-ors other than red, in this case green, leavingred as the predominate color visualized. Therebythe localized angiogenesis of cancer formationincreases the red as seen with AF. The patholo-gic formation of a cancer also includes changesto the extracellular matrix in the epithelium andsubmucosa by secretion of mefalboproteinase byproliferating cancer cells. These structural changesin the submucosa also reduce the AF produced,but more significantly reduce the green pro-duced from affected areas (Figures 1.7a–c and 1.8)[29,38,39].


Figure 1.7 (a) Normal tissue: Normal tissue response tostimulation by blue (390–460 nm) light. Blue reflectanceas well as green (majority) and red fluorescence (Imagecourtesy of Karl Storz of America, Culver City, California,USA, with permission.) (b) Severe dysplasia: Precancerouschanges in tissue. Stimulation by blue (390–460 nm) lightalso has some blue reflectance, but due to changes in thesubmucosa there is a predominance of red lightfluorescence produced in these areas. (Image courtesy ofKarl Storz of America, Culver City, California, USA, withpermission.) (c) Microinvasive Cancer: There is a reductionin autofluorescence response to stimulation. In areas ofcancer, red is the primary color visualized. (Image courtesyof Karl Storz of America, Culver City, California, USA, withpermission.)

Figures 1.9–1.12 are examples of side-by-sideviews of the airway with WLB and AF in a normaltrachea, with epithelial changes of dysplasia, CISand a microinvasive carcinoma. (The AF imageswere created by the Storz D-Light system.)

The technology

The initially developed and still commonly usedtool for AF bronchoscopy is Laser Induced

Fluorescence Endoscopy or LIFE system (XillixTechnologies Corp., Richmond, British Columbia,Canada). The LIFE system uses a low-energyhelium–cadmium laser at a wavelength of 442nm for fluorophore stimulation. Two chargecoupled device (CCD) cameras connected througha fluorescence collection sensor and optical multi-channel analyzer are used via an optical broncho-scope. The image is then processed through animage board, which transforms the various light


Figure 1.8 Wavelength production byautofluorescence for both normaltissue and areas of the tumor. Therelative reduction in green wavelengthproduction is clearly identified. (Imagecourtesy of Karl Storz of America,Culver City, California, USA, withpermission.)

Figure 1.9 Normal Tissue: View of trachea with white light and AF light sources. (Image produced with D-Light system,courtesy of Karl Storz of America, Culver City, California, USA, with permission.)

intensities into a real time video image augmentingthe green of normal tissue and the red of abnormaltissue (Figure 1.13a,b).

The D-Light system (Karl Storz Endoscopy ofAmerica, Culver City, California, USA) uses axenon light source. The white light produced bythe xenon light source is transmitted to a dedic-ated optical bronchoscope through a liquid lightcable. A series of filters are fit into the eyepiece ofthe bronchoscope, which generates the monochro-matic light needed (380–460 nm) for fluorophorestimulation. Additional filters are used to reducereflectance of the blue light from the tissue allow-ing only red and green wavelengths to be visualized.The resulting image is seen in green (normal tissue)

and red (tissue with pathologic changes). Due tothe faint nature of tissue AF a reduced imagingspeed (16 images per second versus 60 images persecond in normal WLB) is currently used with theD-Light system to enhance light absorption andtherefore clarity of the image of the abnormal tis-sue. The system has a footswitch and switch on theattached camera to allow quick changes from whitelight to AF modes , thus permitting the operator tochoose which light source best fits his or her needsat any time during the examination (Figure 1.14;see Figures 1.9–1.12 for images).

The Diagnostic AutoFluorescence Endoscopy(DAFE) (Richard Wolf Endoskope, Knittlingen,Germany) is another technology using a filtered


Figure 1.10 Dysplasia: White light and autofluorescence localization of dysplastic tissue. Green identifies normal tissueand red identifies abnormal, precancerous tissue. (Image produced with D-Light system, courtesy of Karl Storz of America,Culver City, California, USA, with permission.)

Figure 1.11 Carcinoma in situ: White light and autofluorescence images of carcinoma in situ in a bronchus. (Imageproduced with D-Light system, courtesy of Karl Storz of America, Culver City, California, USA, with permission.)

xenon light source for cellular excitation. The xenonlamp uses an infrared blocking filter before light istransmitted via a liquid light guide. The image isthen generated via a photodetection system usingone black and white (B/W) CCD camera with a dualdetection range: 500–590 nm and 600–700 nm.This imaging system produces independent greenand red imaging, which is overlaid to producethe AF image. The DAFE system attempts tofurther improve upon AF technology by creating asimultaneous white light image via a color camera

driver that has the red and green AF imagingsuperimposed upon the white light view. Thisconcept allows simultaneous viewing of the airwayswith WLB and AF [40]. The DAFE system canbe used with rigid bronchoscopes or the Wolf,Olympus or Pentex flexible bronchoscope systems(Figure 1.15a,b) [41].

The Onco-LIFE system (Xillix TechnologiesCorp., Richmond, British Columbia, Canada)is currently not available for sale with onlypreliminary studies having been performed at


Figure 1.12 Microinvasive carcinoma: White light and autofluorescence visualization of a microinvasive cancer of thebronchus. (Image produced with D-Light system, courtesy of Karl Storz of America, Culver City, California, USA, withpermission.)

Figure 1.13 (a) The LIFE autofluorescence system. (b)White light and autofluorescence images produced withthe LIFE system. (Xillix Technologies Corp. Richmond,British Columbia, Canada, reproduced with permission.)

the British Columbia Cancer Agency. The Onco-LIFE system uses a filtered mercury arc lampfor fluorophore stimulation. It then uses a lowlight sensor (ICCD) for fluorescence imaging. Acolor CCD sensor is incorporated into the systemfor improved white light visualization as well asfor imaging of red in AF mode. These combinedsensor inputs are put together to create the imagevisualized. Operators can use a footswitch or switchon the camera. The Onco-LIFE system is developedfor use with any endoscope (both rigid and flex-ible) from Olympus, Pentax, Fujinon, Storz or Wolf(Figure 1.16) [42,43].

The System of Autofluorescence Endoscopy(SAFE) 1000 (Pentex Corporation, Asahi Optical,Tokyo, Japan) uses a xenon light source also,which is filtered to create a light with awavelength of 420–480 nm. Reflectance filtra-tion is used to improve visualization of AF. Animage intensifier is incorporated into the systemto improve distinction of the very low lightautofluorescent changes. This system createsthe distinctive green of typical background ofnormal mucosa with “cold spots” as areas ofabnormality [44].

The D-Light system is currently the only FDAapproved, commercially available system in the


Figure 1.14 The D-Light autofluorescence system. (KarlStorz Endoscopy of America, Culver City, California, USA,reproduced with permission.)

United States. It is also sold and used in the restof North America, Europe, Africa, South America,Asia and Australia [45]. The LIFE system is nolonger available for fresh purchase, but continuesto be used worldwide at those institutions that havethis equipment. The DAFE system is commerciallyavailable in Europe, Asia and Canada; the companyis considering further clinical trials [41]. Onco-LIFE is currently not commercially available. XillixTechnologies Corporation states that the first pub-lished data will likely be the study carried out aspart of the FDA regulatory approval process [42].No communications were received from PentexCorporation regarding the availability or plans ofclinical trials for the SAFE 1000 system despitemultiple attempts at contacting them.

Does it work?

One of the earlier clinical studies by Lam et al. [46]looked at 94 subjects, 53 with known or suspected

Figure 1.15 (a) The DAFE autofluorescence system. (Richard Wolf Endoscopy Gmbh, Knittlingen, Germany reproducedwith permission.) (b) Image produced with DAFE system. Note red area, identifying area of cancerous or precancerouslesion superimposed on a white light view (Richard Wolf Endoscopy Gmbh, Knittlingen, Germany reproduced withpermission.)


Figure 1.16 The Onco-LIFEautofluorescence system. (XillixTechnologies Corp. Richmond, B.C.,Canada, reproduced with permission.)

lung cancer and 41 volunteers (17 smokers, 16 ex-smokers, 8 nonsmokers). All patients had WLBand autofluorescence bronchoscopy with a LIFEsystem immediately following the white light exam-ination. All areas with changes consistent with earlylung cancer were biopsied when identified by whitelight or AF techniques. WLB and AF broncho-scopy identified normal tissue and was also biopsiedas a control. A total of 328 biopsy specimenswere obtained during the 94 performed proced-ures. Sixty-four invasive cancers, 29 CIS, 62 areas ofdysplasia and 173 normal biopsies were reviewed.The authors reported that for the detection of dys-plasia and CIS, they had sensitivities with whitelight versus AF bronchoscopies of 48.4 versus 72.5%and specificities of 94 versus 72.5% for white lightand AF bronchoscopies, respectively [46].

The pattern of improved sensitivity of AF bron-choscopy for the detection of early cancer andprecancerous lesions is repeated throughout the lit-erature. I compounded the information availablein 11 clinical studies [24,46–54]. Included inthese studies were 1084 patients who underwent1289 bronchoscopies with 3487 biopsies. Matchingdata as well as was possible, a combined analysisof sensitivity and specificity was performed. Thesensitivity of WLB versus AF was found to be 52.4to 84%, respectively. Specificities for WLB andAF bronchoscopy were 87 and 78%, respectively.The only limitation in these studies that shouldbe pointed out is that the sensitivity referenced insome cases is a relative sensitivity. The most recent

review of the use of the LIFE system by Lam et al.reports a twofold improvement in the detectionof precancerous lesions with AF versus WLB [55].Currently, there is no gold standard available toidentify all possible endobronchial lesions andtherefore the actual sensitivity of AF cannot bedetermined.

Several clinical studies have also been performedusing the D-Light system (Karl Storz Endoscopy,Tuttlingen, Germany) in Europe with encouragingstatistical results for the identification of precancer-ous and early cancerous lesions [56–58]. A clinicalstudy was recently completed in the United Stateswith the Storz D-Light system using a very sim-ilar research protocol as those performed with theoriginal LIFE studies. The six clinical sites involvedreported a white light sensitivity of 10.6% versusthe AF sensitivity of 61.2% for abnormal histology.The WLB versus AF specificities was 94.6 versus75.3%, similar to the specificity relationship seenin previous LIFE studies [59].

Published clinical studies using the DAFE sys-tem are currently limited. The study by Goujonet al. reports on 20 patients who had WLB andAF performed during the same session, withcomparison of identification of precancerous andcancerous lesions. They report a positive predictivevalue of 75% for AF versus 38% for WLB [40].These findings with the DAFE system echo those ofinvestigators using various AF systems. Other stud-ies have been performed using the DAFE system forAF evaluation and follow-up of patients, but data

thoracic endoscopy: advances in interventional pulmonology · 2013-07-23 · thoracic endoscopy:...

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