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Lymphedema: Complete Medical and Surgical Management [1 ed.]
 9781626236714

Table of contents :
Dedications
Contributors
Preface
Acknowledgments
Contents
Part I: Current Concepts in Lymphedema
1 Lymphedema: Lack of Solutions to a Clinical Problem • Manish C. Champaneria, Peter C. Neligan
2 Lymphedema and Its Impact on Quality of Life • Jane M. Armer, Jennifer M. Hulett, Janice N. Cormier, Bob R. Stewart, Ausanee Wanchai, Kate D. Cromwell
3 Quality of Life Measurement Instruments • Vaughan Keeley
Part II: Anatomy, Physiology, and Lymphangiogenesis
4 Embryology • Sandro Michelini, Miguel Amore, Lucia Tapia, Gisela Romina Pattarone, Diego Mercado, Jeremy S. Torrisi, Ira L. Savetsky, Jason C. Gardenier, Babak J. Mehrara
5 Changing Concepts in Lymphatic Pathways • Wei-Ren Pan
6 Applied Anatomy • Miguel Amore, Lucia Tapia, Gisela Romina Pattarone, Diego Mercado
7 Lymphangiogenesis • Jeremy S. Torrisi, Ira L. Savetsky, Jason C. Gardenier, Babak J. Mehrara
8 Impact of Genetics on Lymphangiogenesis • Kristiana Gordon, Pia Ostergaard
9 Relationship Between Fat Tissue and Lymphangiogenesis • Mauro Andrade
10 Lymphatic Malformations • Sandro Michelini, Alessandro Fiorentino, Marco Cardone
11 Immune Regulation by the Peripheral Lymphatics • David G. Hancock
Part III: Pathophysiology and Clinical Presentation
12 Pathophysiology of Primary Lymphedema • Byung-Boong Lee, James Laredo
13 Pathophysiology of Secondary Lymphedema • Etelka Földi
14 Dermatologic Implications of Secondary Lymphedema of the Lower Leg • Terence Ryan, S.R. Narahari, B. Vijaya, Madhur Guruprasad Aggithaya
15 Filaria • Gurusamy Manokaran, Rajiv Agarwal, Devisha Agarwal
16 Lymphedema in Pediatric Patients • Cristobal Miguel Papendieck
17 Combined Lymphatic and Venous Failure: Phlebolymphedema • Audra A. Duncan
18 Lymphedema Risk Factors in Breast Cancer • Swetha Kambhampati, Stanley Rockson
19 Sentinel Lymph Node Biopsy Outcomes • Janice N. Cormier, Kate D. Cromwell, Jane M. Armer, Merrick I. Ross
Part IV: Diagnosis of Lymphedema
20 Causes and Classification of Lymphatic Disorders • Swetha Kambhampati, Stanley Rockson
21 Basic Approaches to the Diagnosis of Lymphedema: Clinicians’ Perspective • Yener Demirtas, Baris Yigit
22 Biomarkers • Kerstin Buttler, Jörg Wilting
23 Clinical Staging of Lymphedema • Sandro Michelini, Marco Cardone, Alessandro Fiorentino
24 Measuring Methods • Peter C. Neligan
25 Hydromechanics of Intercellular Fluid and Lymph • Waldemar Olszewski, Marzanna T. Zaleska
26 Radionuclide Lymphoscintigraphy • Byung-Boong Lee, James Laredo
27 Indocyanine Green Lymphography • Mitsunaga Narushima, Takumi Yamamoto, Isao Koshima
28 Magnetic Resonance Lymphangiography • Lee M. Mitsumori
Part V: Current Treatment of Lymphedema
29 Conservative Treatments for Lymphedema • Neil B. Piller
30 Pharmacologic Treatment of Lymphedema • Kathleen Wang
31 Excisional Approaches for the Treatment of Lymphedema • Manish C. Champaneria, Peter C. Neligan
32 Liposuction • Håkan Brorson
33 Multiple Lymphaticovenous Anastomoses and Multiple Lymphatic-Venous-Lymphatic Anastomoses • Corrado Cesare Campisi, Melissa Ryan, Corradino Campisi
34 Lymphatic Grafts • Rüdiger G.H. Baumeister
35 Lymphaticovenular Anastomosis • Isao Koshima, Mitsunobu Harima
36 Vascularized Lymph Node Transfer • Corinne Becker
37 Reverse Lymphatic Mapping • Joseph H. Dayan, Mark L. Smith
38 Local Flaps and Vascularized Lymph Node Transfer • Joshua Levine, Corinne Becker
39 Transverse Myocutaneous Gracilis With Vascularized Lymph Node Transfer • Sinikka Suominen, Maija Kolehmainen
40 Lymphatic Microsurgical Preventing Healing Approach Concept • Francesco Boccardo
41 Combined Surgical Treatment for Breast Cancer–Related Lymphedema • Jaume Masia
42 Interventional Timing • Peter C. Neligan, Jaume Masia
43 Lymphedema Complications and Their Treatment • Arin K. Greene, Reid A. Maclellan
44 Treatment of Lymphedema in India • Rajiv Agarwal, Devisha Agarwal
45 Surgical Treatment in China • Ningfei Liu
Part VI: Research and Future Directions
46 Animal Models of Lymphedema • Swapna Ghanta, Daniel A. Cuzzone, Babak J. Mehrara
47 Harnessing Stem Cell–Mediated Lymphangiogenesis for the Treatment of Lymphedema • Ramin Shayan, Geraldine Mitchell, Anthony Penington
48 Establishment of a Lymphedema Framework • Christine Moffatt, Susie Murray
Credits
Index

Citation preview

Lymphedema Complete Medical and Surgical Management

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Lymphedema Complete Medical and Surgical Management

Editors Peter C. Neligan, MB, FRCS(I), FRCSC, FACS Professor of Surgery, Division of Plastic Surgery, University of Washington, Seattle, Washington

Jaume Masia, MD, PhD

Chief, Plastic Surgery Department, Hospital de la Santa Creu i Sant Pau; Professor of Plastic Surgery, School of Medicine at Universitat Autònoma de Barcelona; Director, Microsurgery and Breast Reconstructive Unit, Clinica Planas, Barcelona, Spain

Neil B. Piller, BS, PhD, FACP

Professor and Director, Lymphoedema Research Unit, Department of Surgery, Flinders University School of Medicine, Bedford Park, Adelaide, South Australia, Australia

Illustrated by Cassio Lynm

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Director, Editorial Services: Mary Jo Casey International Production Director: Andreas Schabert International Marketing Director: Fiona Henderson International Sales Director: Louisa Turrell Director of Sales, North America: Mike Roseman Senior Vice President and Chief Operating Officer: Sarah Vanderbilt President: Brian D. Scanlan Library of Congress Cataloging-in-Publication Data is available from the publisher upon request.

Important note: Medicine is an ever-changing science undergoing continual development. Research and clinical experience are continually expanding our knowledge, in particular our knowledge of proper treatment and drug therapy. Insofar as this book mentions any dosage or application, readers may rest assured that the authors, editors, and publishers have made every effort to ensure that such references are in accordance with the state of knowledge at the time of production of the book. Nevertheless, this does not involve, imply, or express any guarantee or responsibility on the part of the publishers in respect to any dosage instructions and forms of applications stated in the book. Every user is requested to examine carefully the manufacturers’ leaflets accompanying each drug and to check, if necessary in consultation with a physician or specialist, whether the dosage schedules mentioned therein or the contraindications stated by the manufacturers differ from the statements made in the present book. Such examination is particularly important with drugs that are either rarely used or have been newly released on the market. Every dosage schedule or every form of application used is entirely at the user’s own risk and responsibility. The authors and publishers request every user to report to the publishers any discrepancies or inaccuracies noticed. If errors in this work are found after publication, errata will be posted at www.thieme.com on the product description page. Some of the product names, patents, and registered designs referred to in this book are in fact registered trademarks or proprietary names even though specific reference to this fact is not always made in the text. Therefore, the appearance of a name without designation as proprietary is not to be construed as a representation by the publisher that it is in the public domain.

© 2016 Thieme Medical Publishers, Inc. Thieme Publishers New York 333 Seventh Avenue, New York, NY 10001 USA +1 800 782 3488, [email protected] Thieme Publishers Stuttgart Rüdigerstrasse 14, 70469 Stuttgart, Germany +49 [0]711 8931 421, [email protected] Thieme Publishers Delhi A-12, Second Floor, Sector-2, Noida-201301 Uttar Pradesh, India +91 120 45 566 00, [email protected] Thieme Publishers Rio de Janeiro, Thieme Publicações Ltda. Edifício Rodolpho de Paoli, 25º andar Av. Nilo Peçanha, 50 – Sala 2508 Rio de Janeiro 20020-906, Brasil +55 21 3172 2297 eISBN 978-1-62623-753-7

This book, including all parts thereof, is legally protected by copyright. Any use, exploitation, or commercialization outside the narrow limits set by copyright legislation without the publisher’s consent is illegal and liable to prosecution. This applies in particular to photostat reproduction, copying, mimeographing or duplication of any kind, translating, preparation of microfilms, and electronic data processing and storage.

This book is dedicated to my wife, Gabrielle, who, as always, is my staunch supporter



P.C.N.

This book is dedicated to my family for their unconditional love and support, which allowed me to achieve my professional dreams



J.M.

To my fantastic wife, loving family, and caring friends for being there when I needed them, and for their enduring enthusiasm and support



N.B.P.

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EXECUTIVE EDITOR  Sue Hodgson SENIOR PROJECT EDITING MANAGER  Carolyn Reich SENIOR DEVELOPMENTAL EDITOR  Megan Fennell GRAPHICS MANAGER  Brett Stone DIRECTOR OF ILLUSTRATION AND DESIGN  Brenda Bunch MANAGING EDITOR  Suzanne Wakefield PROJECT MANAGER  Idelle Winer PRODUCTION  Chris Lane, Debra Clark, Susan Trail, Madonna Gauding PROOFREADER  Linda Maulin INDEXER  Matthew White

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C ontributors Devisha Agarwal, MBBS (Std) Medical Student, GSVM Medical College, Kanpur, Uttar Pradesh, India

Corinne Becker, MD Lecturer, Department of Thoracic Surgery, Hôpital Européen–Georges Pompidou; Surgeon, American Hospital of Paris, Paris, France

Rajiv Agarwal, MCh, FRCS Professor and Head, Department of Plastic Surgery and Burns, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow-Uttar Pradesh, India

Francesco Boccardo, MD, PhD Associate Professor of Surgery, Unit of Lymphatic Surgery, Department of Surgery; Director, Clinic for Medical Oncology, IRCCS University Hospital San Martino, National Institute for Cancer Research (IST), Genoa, Italy

Madhur Guruprasad Aggithaya, MD Institute of Applied Dermatology, Kasaragod, Kerala, India

Håkan Brorson, MD, PhD Associate Professor, Department of Clinical Sciences, Lund University; Department of Plastic and Reconstructive Surgery, Skåne University Hospital, Malmö, Sweden; Professor, Esculera de Graduados, Asociación Médica Argentina, Buenos Aires, Argentina

Miguel Amore, MD, PhD, FACS Director of Vascular Anatomy Laboratory; III Chair of Anatomy, Department of Anatomy, Buenos Aires University; Surgical Staff, Unit of Phlebology and Lymphology, Central Military Hospital, Buenos Aires, Argentina

Kerstin Buttler, MD Professor, Institute of Anatomy and Cell Biology, University Medical Center Göttingen, Göttingen, Germany

Mauro Andrade, MD, PhD Associate Professor of Surgery, Department of Surgery, University of São Paulo Medical School, São Paulo, Brazil

Corradino Campisi, MD, PhD, FACS University Department of Surgery (DISC), Section of Lymphology and Microsurgery, Operative Unit of Lymphatic Surgery, IRCCS University Hospital San Martino, National Institute for Cancer Research (IST), Genoa, Italy

Jane M. Armer, PhD, RN, CLT, FAAN Professor, Sinclair School of Nursing, University of Missouri; Director, Department of Nursing Research, Ellis Fischel Cancer Center; Director, American Lymphedema Framework Project, Columbia, Missouri

Corrado Cesare Campisi, MD, PhD, RAS-ACS Surgeon, Division of Plastic, Reconstructive and Aesthetic Surgery, Department of Surgery (DISC), IRCCS University Hospital San Martino (IST), Genoa; Surgeon, Division of Experimental and Microsurgery, Department of Surgery, IRCCS San Matteo University Hospital Foundation, Pavia, Italy

Rüdiger G.H. Baumeister, MD, PhD Professor, Former Head, Department of Surgery, Campus Grosshadern, Division of Plastic, Hand, and Micro-Surgery, Ludwig Maximilians University; Consultant in Lymphology, Department of Surgery, Chirurgische Klinik München-Bogenhausen, Munich, Germany vii

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viii

Contributors

Marco Cardone, MD Department of Rehabilitation Medicine, San Giovanni Battista Hospital, Rome, Italy

Etelka Földi, MD Professor, Center for Lymphology, Földiklinik, Hinterzarten-Baden-Württemberg, Germany

Manish C. Champaneria, MD Plastic and Reconstructive Surgeon, Department of Surgery, PeaceHealth Southwest Medical Center, Vancouver, Washington

Jason C. Gardenier, MD Research Fellow, Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York

Janice N. Cormier, MD, MPH, FACS Professor of Surgery, Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas Kate D. Cromwell, MS, MPH Clinical Studies Coordinator, Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas Daniel A. Cuzzone, MD Resident Research Fellow, Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center; Resident, Department of Plastic Surgery, Institute of Reconstructive Plastic Surgery, New York University Langone Medical Center, New York, New York Joseph H. Dayan, MD Assistant Professor, Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York Yener Demirtas, MD Associate Professor, Lymphest Plastic Surgery Clinic, Istanbul, Turkey Audra A. Duncan, MD Professor of Surgery, Mayo Clinic, Rochester, Minnesota Alessandro Fiorentino, MD Department of Vascular Surgery, Università Cattolica del Sacro Cuore, Policlinico Agostino Gemelli, Rome, Italy

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Swapna Ghanta, MD Research Fellow, Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York Kristiana Gordon, MBBS, MRCP, CLT, MD (Res) Honorary Senior Lecturer, Cardiovascular and Cell Sciences Research Institute, St. George’s University of London; Consultant, Department of Dermatology and Lymphovascular Medicine, St. George’s Hospital, London, United Kingdom Arin K. Greene, MD, MMSc Co-director, Lymphedema Program, Department of Plastic and Oral Surgery, Boston Children’s Hospital; Associate Professor of Surgery, Harvard Medical School, Boston, Massachusetts David G. Hancock, PhD Lymphoedema Research Unit, Department of Surgery, Flinders University School of Medicine, Bedford Park, Adelaide, South Australia, Australia Mitsunobu Harima, MD Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan Jennifer M. Hulett, PhD(c), APRN, FNP-BC Doctoral Candidate, Sinclair School of Nursing, University of Missouri, Columbia, Missouri Swetha Kambhampati, MD Resident in Internal Medicine, The Johns Hopkins Hospital, Baltimore, Maryland

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Contributors

Vaughan Keeley, PhD, FRCP Honorary Associate Professor, Department of Palliative Medicine, University of Nottingham School of Medicine, Nottingham; Consultant in Palliative Medicine/Lymphoedema, Derby Teaching Hospitals, NHS Foundation Trust, Derby, United Kingdom

Jaume Masia, MD, PhD Chief, Plastic Surgery Department, Hospital de la Santa Creu i Sant Pau; Professor of Plastic Surgery, School of Medicine at Universitat Autònoma de Barcelona; Director, Microsurgery and Breast Reconstructive Unit, Clinica Planas, Barcelona, Spain

Maija Kolehmainen, MD Department of Plastic Surgery, Helsinki University Central Hospital, Helsinki, Finland

Babak J. Mehrara, MD, FACS Director, Lymphatic Research Laboratory, Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center; Professor of Plastic Surgery, Weill Cornell University Medical Center, New York, New York

Isao Koshima, MD Professor and Chief, Department of Plastic, Reconstructive and Aesthetic Surgery, The University of Tokyo Hospital, Tokyo, Japan James Laredo, MD, PhD, FACS Associate Professor of Surgery, Department of Surgery, Division of Vascular Surgery, George Washington University Medical Center, Washington, DC Byung-Boong Lee, MD, PhD, FACS Professor of Surgery, Department of Surgery, George Washington University, Washington, DC Joshua Levine, MD Director of Surgical Services, Department of Plastic and Reconstructive Surgery, New York Eye and Ear Infirmary of Mount Sinai, New York, New York Ningfei Liu, MD, PhD Professor of Plastic Surgery, Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Reid A. Maclellan, MD, MMSc Instructor of Surgery, Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts Gurusamy Manokaran, MD Senior Consultant Plastic Surgeon and Lymphologist, Apollo Hospital, Chennai, India

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Diego Mercado, MD Institute for Immunological Research, University of Cartagena, Cartagena, Colombia Sandro Michelini, MD Chief of Vascular Rehabilitation, San Giovanni Battista Hospital; Past President, European Society of Lymphology; President, Italian Lymphoedema Framework; President-Elect, Italian Society of Phlebolymphology, Rome, Italy Geraldine Mitchell, PhD Faculty of Health Sciences, Australian Catholic University, Melbourne, Victoria, Australia Lee M. Mitsumori, MD, MSBE Affiliate Associate Professor, Department of Radiology, University of Washington, Seattle, Washington; Physician, Department of Radiology, Straub Clinic and Hospital, Honolulu, Hawaii Christine Moffatt, CBE, FRCN, PhD, MA, RGN, DN Professor of Clinical Nursing Research, School of Health Sciences, The University of Nottingham, Nottingham, United Kingdom Susie Murray MA, RGN, RHV (retired) Project Manager, International Lymphoedema Framework, London, United Kingdom S.R. Narahari, MD, DVD Chair and Director, Institute of Applied Dermatology, Kasaragod, Kerala, India

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Contributors

Mitsunaga Narushima, MD Assistant Professor, Department of Plastic and Reconstructive Surgery, University of Tokyo, Tokyo, Japan Peter C. Neligan, MB, FRCS(I), FRCSC, FACS Professor of Surgery, Division of Plastic Surgery, University of Washington, Seattle, Washington Waldemar Olszewski, MD, PhD Professor of Surgery, Medical Research Center, Polish Academy of Sciences, Central Clinical Hospital, Ministry of Internal Affairs, Warsaw, Poland Pia Ostergaard, PhD Senior Research Fellow, Lymphovascular Research Unit, Division of Cardiovascular and Cell Sciences, St. George’s University of London, London, United Kingdom Wei-Ren Pan, MD, PhD Professor, Department of Anatomy, Xuzhou Medical College, Xuzhou, Jiangsu, China Cristobal Miguel Papendieck, MD, FACS Department of Pediatric Surgery, Deutsches Hospital, Buenos Aires, Argentina Gisela Romina Pattarone, MD Department of Medicine, University of Buenos Aires School of Medicine, Buenos Aires, Argentina Anthony Penington, MB, BS, FRACS Jigsaw Professor of Pediatric and Maxillofacial Surgery, The Royal Children’s Hospital, Melbourne, Victoria, Australia Neil B. Piller, BS, PhD, FACP Professor and Director, Lymphoedema Research Unit, Department of Surgery, Flinders University School of Medicine, Bedford Park, Adelaide, South Australia, Australia

Stanley Rockson, MD, FACP, FACC Allan and Tina Neill Professor of Lymphatic Research and Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine; Director, Stanford Center for Lymphatic and Venous Disorders, Stanford University Hospital and Clinics, Stanford, California Merrick I. Ross, MD Chief, Melanoma Section, Charles C. McBride Distinguished Professorship in Surgical Oncology, Department of Surgical Oncology, Division of Surgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas Melissa Ryan, PhD, PgDips Clinical Psychologist, Department of Surgery, Section of Lymphology and Microsurgery, Operative Unit of Lymphatic Surgery, IRCCS University Hospital San Martino, Genoa, Italy Terence Ryan, DM, FRCP, KStJ Emeritus Professor, Department of Dermatology, Green Templeton College, Oxford University, Oxford, United Kingdom Ira L. Savetsky, MD Research Fellow, Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center; Resident, Department of Surgery, New York University Langone Medical Center, New York, New York Ramin Shayan, MB, BS, PhD, FRACS Jack Brockhoff Reconstructive Plastic Surgery Research Unit, Department of Anatomy and Cell Biology, The University of Melbourne, Parkville, Victoria, Australia Mark L. Smith, MD Division of Plastic and Reconstructive Surgery, Department of Surgery, Beth Israel Medical Center, New York, New York Bob R. Stewart, EdD Professor Emeritus, College of Education; Adjunct Professor, Sinclair School of Nursing, University of Missouri, Columbia, Missouri

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Contributors

Sinikka Suominen, MD, PhD Adjunct Professor and Department Chief, Clinic of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland

Kathleen Wang, B. Psych (Hon), MD candidate Research Officer, Lymphoedema Research Unit, Flinders University School of Medicine, Bedford Park, Adelaide, South Australia, Australia

Lucia Tapia, MD Department of Medicine, University of Buenos Aires School of Medicine, Buenos Aires, Argentina

Jörg Wilting, MD Professor, Institute of Anatomy and Cell Biology, Göttingen University Medical Center, Göttingen, Germany

Jeremy S. Torrisi, BA Research Assistant, Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York

Takumi Yamamoto, MD Department of Plastic and Reconstructive Surgery, University of Tokyo, Tokyo, Japan

B. Vijaya, MD Professor of Pathology, JSS Medical College of JSS University, Mysore, Karnataka, India Ausanee Wanchai, PhD, RN Nursing Instructor, Deputy Director for Academic Service and Research, Boromarajonani College of Nursing, Buddhachinaraj Hospital, Phitsanulok, Thailand

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Baris Yigit, MD Associate Professor, Düzce University, Department of Plastic Surgery, Düzce, Turkey Marzanna T. Zaleska, MD Medical Research Center, Polish Academy of Sciences, Department of Vascular and General Surgery and Radiology, Central Clinical Hospital, Ministry of Internal Affairs, Warsaw, Poland

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P reface Lymphedema is a significant global problem, and its incidence will increase with a population that is living longer. In addition, because of the interrelationship between the lymphatic system and adipose tissue, the obesity epidemic has led to a rapid rise in this complication. Lymphedema is unique in that it is the end result of myriad conditions affecting the blood, tissue, and lymphatic system, ranging from congenital anomalies to parasitic infestations to postcancer treatment sequelae and soft tissue trauma. Although we know a great deal about lymphedema in terms of its causes and consequences, we still know far too little to be able to propose a comprehensive targeted and sequenced treatment plan. So much work remains to be undertaken, and our knowledge base must be deepened and widened in this area. Lymphedema has been one of those conditions that most people do not want to acknowledge or treat. This is probably because we do not yet have a strong, standardized assessment regimen, an ability (and often willingness) to undertake an accurate differential diagnosis (separating lymphedema from other reasons for swelling), and a good objective knowledge of how best to sequence and target treatment. We still lack strong evidence as to which treatments are best, as well as an uncertainty about when to move from conservative to surgical strategies when conservative approaches fail, or even whether it is better to start with a surgical intervention (such as anastomoses) in the first place. Fortunately, there is a core group of practitioners who maintain their interest in this broad-based disorder, and in recent years, surgeons have joined them in recognition that surgical options after the failure of conservative treatment (or at times surgery may be added to conservative treatment early in the development of lymphedema) can offer improved management of the condition and thus improved quality of life for the at-risk group as well as those who already have lymphedema. In this book we highlight the surgical group, who have added a new dimension to our approach. We have tried to be rational, and where possible, evidence-based in our approach to lymphedema, although we acknowledge that at times the evidence is not strong or is based only on clinical judgments (the experience of experts). The fact that the symptoms and consequences of lymphedema often have a lifelong impact on the quality of survival of our patients must be dealt with in a balanced and holistic manner. For that reason, the book is divided into several parts. We have recruited the brightest minds and those with the greatest experience and expertise in the field, and put together a comprehensive, balanced, and considered approach to the condition. Lymphologists, therapists, and surgeons were asked to give their accurate (evidence-based and knowledge-based) appraisal of the problem. The result is a comprehensive catalog of where we are, what we know, and where we should go. xiii

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Preface

Part I outlines current concepts as a place to start. In Part II we discuss the anatomy and physiology of lymphedema and explore lymphangiogenesis. Embryology is also important to our understanding of the lymphatic system, particularly to our comprehension of lymphatic malformations. Furthermore, as our genetic knowledge deepens, additional genetic abnormalities are recognized. Here we examine their impact on these patients and their families. Finally, in this section the role of the lymphatics is addressed, as well as the general and specific aspects of immune system function, and the consequences when it fails. Part III examines in detail the pathophysiology of both primary and secondary lymphedema. Filariasis, the most common worldwide cause of lymphedema with over 1.4 billion at risk, is covered in a separate chapter. We also examine the impact of venous failure on lymphedema and how this and an often combined lymphatic failure affects adults as well as children. We tackle risk factors for lymphedema in patients with breast and other cancers and examine the role of sentinel node sampling in their management. Part IV emphasizes the fact that accurate diagnosis of lymphedema is vitally important; this is dealt with in its own section. Internationally accepted classification recommendations for lymphedema are discussed, because these systems offer a very useful tool to categorize clinical findings. The various assessment techniques, measurement options, imaging methods, and staging systems are reviewed, as well as lymph pressure and flow measurement using traditional and new techniques. We have tried to include all aspects of treatment. In Part V seventeen chapters have been assembled to cover every facet. These chapters not only include conservative approaches but also all of the surgical approaches currently being used around the world, together with recommendations for when and where they might be appropriate. One of the most important points emphasized in this section is how to recognize and treat the complications and comorbidities that are inevitable with this disease. In Part VI the book concludes with a review and critical appraisal of current research. This inevitably leads to a discussion of future directions. As mentioned at the outset, so much is unknown about lymphedema that there is a huge amount of work to be done. We explore several likely approaches that may be adopted. Lymphedema is presently of intense interest to investigators, and much research is being done in many areas, including genetics, conservative treatment and management, and surgical approaches, as well as the best strategies for early detection of lymphatic insufficiencies that can lead to lymphedema. Predictably, much of the information in this book will change in the coming years as we learn more and further understand the disease. However, it is our hope that this book will form the basis for new knowledge, enhance surgeons’ ability to explore innovative approaches, and lead all to provide better outcomes for patients at risk for and with lymphedema. Peter C. Neligan Seattle, Washington Jaume Masia Barcelona, Spain Neil B. Piller Bedford Park, Adelaide, South Australia, Australia

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A cknowledgments I would like first of all to acknowledge my two co-editors, Jaume and Neil, as well as the contributing authors who gave freely of their time and expertise to make this book possible. I am also indebted to my residents and fellows for always keeping me on my toes. My partners at the University of Washington are always supportive and encouraging, and I am grateful to them for that. It has been a pleasure working with the team at CRC Press led by Sue Hodgson, who, as always, keeps the project going and is constantly available to help and advise. Megan Fennell has done a stellar job, as has Idelle Winer. Brenda Brunch has directed the artwork, and Cassio Lynm has worked tirelessly with the contributing authors to make the illustrations not only look great but accurate. This book is a credit to all of them. P.C.N.

There are many people to whom I am indebted for making this publication possible. My heartfelt thanks to Peter and Neil for their expertise, enthusiasm, and honesty, which have been key factors in making this book a valuable resource for people wanting to learn more about lymphedema and to advance its treatment. I am sincerely grateful to the many colleagues and friends for their close collaboration and excellent contributions. Also to be thanked are the teams at Sant Pau University Hospital and at Clinica Planas, associates, residents, fellows, nurses, and secretaries, and in particular, my lymphedema nurse, Patricia Martinez, and my associate, Gemma Pons, for their constant concern and care for all our lymphedema patients. I want to take this opportunity to express my appreciation to the CRC Press team. Their professionalism has been essential to the quality of this book. Sue Hodgson deserves special mention, for without her experience and tenacity for excellence, the project would not have come together within the assigned time frame. And finally, I would like to extend a special thank you to everyone working in the field of lymphedema, for it is through the mutual sharing and exchange of knowledge that we will move forward in optimizing the quality of life for our patients. J.M.

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Acknowledgments

A plethora of people initiated and maintained my interest and enthusiasm for all things lymphologic, but there are four in particular to whom I am particularly indebted. These are Dr. John Casley-Smith, originally from the Electron Optics Unit in the School of Medicine at the University of Adelaide, who in the late 1960s introduced me to lymphedema and who taught me all I know about the importance of the ultrastructure of the microcirculation and of the blood-tissue-lymph system; Prof. Dr. Leo Clodius from the Plastische und Wiederherstellungs Chirurgie Department of the Kantonsspital in Zurich, with whom I worked in 1975, and who first drew my attention to the range of surgical treatments that could help lymphedema, taught me about surgical models for lymphedema, and who in my view was an unacknowledged early leader in microsurgical interventions for lymphedema; and Drs. Michael Földi and Etelka Földi, with whom I worked in 1977 and who made me aware of the deficits in our lymphatic and lymphedema knowledge, who led our awareness and knowledge of how conservative treatment can make a difference, and who made me think more critically about all we say and do regarding lymphedema. N.B.P.

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C ontents Part I  Current Concepts in Lymphedema

 1

Lymphedema: Lack of Solutions to a Clinical Problem 

 2

Lymphedema and Its Impact on Quality of Life 

 3

Quality of Life Measurement Instruments 

Manish C. Champaneria, Peter C. Neligan

3

25

Jane M. Armer, Jennifer M. Hulett, Janice N. Cormier, Bob R. Stewart, Ausanee Wanchai, Kate D. Cromwell

Vaughan Keeley

41

Part II Anatomy, Physiology, and Lymphangiogenesis

 4

Embryology 

 5

Changing Concepts in Lymphatic Pathways 

 6

Applied Anatomy 

 7

Lymphangiogenesis 

 8

Impact of Genetics on Lymphangiogenesis 

 9

Relationship Between Fat Tissue and Lymphangiogenesis 

10

Lymphatic Malformations 

11

Immune Regulation by the Peripheral Lymphatics 

53

Sandro Michelini, Miguel Amore, Lucia Tapia, Gisela Romina Pattarone, Diego Mercado, Jeremy S. Torrisi, Ira L. Savetsky, Jason C. Gardenier, Babak J. Mehrara

61

Wei-Ren Pan

97

Miguel Amore, Lucia Tapia, Gisela Romina Pattarone, Diego Mercado

113

Jeremy S. Torrisi, Ira L. Savetsky, Jason C. Gardenier, Babak J. Mehrara

Kristiana Gordon, Pia Ostergaard

121

Mauro Andrade

135

143

Sandro Michelini, Alessandro Fiorentino, Marco Cardone

David G. Hancock

163

xvii

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Contents

Part III  Pathophysiology and Clinical Presentation

12

Pathophysiology of Primary Lymphedema 

13

Pathophysiology of Secondary Lymphedema 

14

Dermatologic Implications of Secondary Lymphedema of the Lower Leg 

15

Filaria 

16

Lymphedema in Pediatric Patients 

17

Combined Lymphatic and Venous Failure: Phlebolymphedema 

18

Lymphedema Risk Factors in Breast Cancer 

19

Sentinel Lymph Node Biopsy Outcomes 

177

Byung-Boong Lee, James Laredo

Etelka Földi

189

Terence Ryan, S.R. Narahari, B. Vijaya, Madhur Guruprasad Aggithaya

195

215

Gurusamy Manokaran, Rajiv Agarwal, Devisha Agarwal

Cristobal Miguel Papendieck

235

Audra A. Duncan

Swetha Kambhampati, Stanley Rockson

247

255

263

Janice N. Cormier, Kate D. Cromwell, Jane M. Armer, Merrick I. Ross

Part IV Diagnosis of Lymphedema

20 21

Causes and Classification of Lymphatic Disorders  Swetha Kambhampati, Stanley Rockson

277

Basic Approaches to the Diagnosis of Lymphedema: Clinicians’ Perspective 

Yener Demirtas, Baris Yigit

22

Biomarkers 

23

Clinical Staging of Lymphedema 

24

Measuring Methods 

25

Hydromechanics of Intercellular Fluid and Lymph 

26

Radionuclide Lymphoscintigraphy 

291

299

Kerstin Buttler, Jörg Wilting

309

Sandro Michelini, Marco Cardone, Alessandro Fiorentino

Peter C. Neligan

315

Waldemar Olszewski, Marzanna T. Zaleska

Byung-Boong Lee, James Laredo

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Contents

27

Indocyanine Green Lymphography 

28

Magnetic Resonance Lymphangiography 

365

Mitsunaga Narushima, Takumi Yamamoto, Isao Koshima

Lee M. Mitsumori

379

Part V  Current Treatment of Lymphedema

29

Conservative Treatments for Lymphedema 

395

30

Pharmacologic Treatment of Lymphedema 

407

31

Excisional Approaches for the Treatment of Lymphedema 

Neil B. Piller

Kathleen Wang

Manish C. Champaneria, Peter C. Neligan

423



31-1  Severe Lymphedema—prepared by Peter C. Neligan

32 33

Liposuction  Håkan Brorson

437

 ultiple Lymphaticovenous Anastomoses and Multiple Lymphatic-VenousM Lymphatic Anastomoses  447 Corrado Cesare Campisi, Melissa Ryan, Corradino Campisi

34

Lymphatic Grafts 

Rüdiger G.H. Baumeister

463



34-1  Lymphatic Grafts—prepared by Rüdiger G.H. Baumeister

35

Lymphaticovenular Anastomosis  Isao Koshima, Mitsunobu Harima

473



35-1  Lymphaticovenular Anastomosis—prepared by Isao Koshima 35-2  Lymphaticovenular Anastomosis—prepared by Peter C. Neligan

36

Vascularized Lymph Node Transfer  Corinne Becker

487



36-1  Endoscopic Omentum—prepared by Peter C. Neligan 36-2  Vascularized Lymph Node Transfer—prepared by Jaume Masia

37

Reverse Lymphatic Mapping  Joseph H. Dayan, Mark L. Smith

503



37-1  Reverse Lymphatic Mapping—prepared by Joseph H. Dayan

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Contents

38

Local Flaps and Vascularized Lymph Node Transfer 

39

Transverse Myocutaneous Gracilis With Vascularized Lymph Node Transfer 

Joshua Levine, Corinne Becker

513

Sinikka Suominen, Maija Kolehmainen



519

39-1 Transverse Myocutaneous Gracilis With Vascularized Lymph Node Transfer—

40

prepared by Sinikka Suominen

Lymphatic Microsurgical Preventing Healing Approach Concept  Francesco Boccardo

527



40-1 Lymphatic Microsurgical Preventing Healing Approach (LYMPHA) Concept—prepared by Francesco Boccardo

41

Combined Surgical Treatment for Breast Cancer–Related Lymphedema  Jaume Masia

539



41-1  Combined Surgical Treatment—prepared by Jaume Masia

42

Interventional Timing 

Peter C. Neligan, Jaume Masia

553

43

Lymphedema Complications and Their Treatment 

44

Treatment of Lymphedema in India 

45

Surgical Treatment in China 

Arin K. Greene, Reid A. Maclellan

Rajiv Agarwal, Devisha Agarwal

Ningfei Liu

559

569

573

Part VI Research and Future Directions

46

Animal Models of Lymphedema 

47

 arnessing Stem Cell–Mediated Lymphangiogenesis for the Treatment of H Lymphedema  595

583

Swapna Ghanta, Daniel A. Cuzzone, Babak J. Mehrara

Ramin Shayan, Geraldine Mitchell, Anthony Penington

48

Establishment of a Lymphedema Framework 



Credits 

Christine Moffatt, Susie Murray

Index 

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Contents

xxi

DVD



31-1  Severe Lymphedema



34-1 Lymphatic Grafts



35-1 Lymphaticovenular Anastomosis



35-2 Lymphaticovenular Anastomosis



36-1 Endoscopic Omentum



36-2 Vascularized Lymph Node Transfer



37-1 Reverse Lymphatic Mapping



39-1 Transverse Myocutaneous Gracilis With Vascularized Lymph Node Transfer



40-1 Lymphatic Microsurgical Preventing Healing Approach (LYMPHA) Concept



41-1 Combined Surgical Treatment

prepared by Peter C. Neligan

prepared by Rüdiger G.H. Baumeister

prepared by Isao Koshima

prepared by Peter C. Neligan

prepared by Peter C. Neligan

prepared by Jaume Masia

prepared by Joseph H. Dayan

prepared by Sinikka Suominen

prepared by Francesco Boccardo

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Part I

Current Concepts in Lymphedema

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C hapter 1 Lymphedema: Lack of Solutions to a Clinical Problem Manish C. Champaneria, Peter C. Neligan

K ey P oints • There is no fully satisfactory treatment for lymphedema. • Current treatment is compressive or surgical. • Decongestant therapy is the benchmark of conservative treatment.

Lym

• Surgery has traditionally been excisional. • More recent surgery includes bypass operations (lymphaticovenular anastomoses) and vascularized lymph node transfer.

Lymphedema is a progressive, chronic condition that affects a significant number of people and can have deleterious effects on the physical and psychosocial health of the patient. Lymphedema, which is especially common after surgical treatment for malignancy, has traditionally been viewed as incurable or refractory. The precise cause of lymphedema is still not completely understood, and this has led to undertreatment and misdiagnosis. Even though lymphedema may be greatly ameliorated by appropriate management, many patients receive inadequate treatment, are unaware that treatment is available, or do not know where to seek help. Several recent systematic reviews have highlighted the distinct lack of evidence for the optimal management of lymphedema.1-3 There are nonsurgical options, also known as conservative treatment, that have remained unchanged for many years despite occasionally cumbersome regimens and average results. Surgical options, which include ablative operations, liposuction, and physiologic operations, have also been used, with mixed results. Despite advances in microsurgery, there is neither consensus on surgical or nonsurgical procedures nor a standardized protocol in the treatment of the patient with lymphedema. Given the lack of consensus on one particular avenue of treatment for lymphedema, the lymphedema practitioner must have multiple intervention options available. This book will present the 3

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Part I  Current Concepts in Lymphedema

latest information on the diagnosis, treatment, and management available in the field to allow the practitioner to best serve the patient. This chapter presents an overview of that information and the various solutions available to the lymphedema practitioner. The ultimate goal is to raise the profile of the condition and stimulate refined research and standardized treatment protocols to improve patient care.

Lymphedema: The Clinical Problem Lymphedema is a chronic, debilitating condition that results in the disruption of the lymphatic transport system, which leads to the accumulation of protein-rich fluid in the interstitial space because of an imbalance between interstitial fluid production and transport (usually low output failure). Outside of the United States, the most common cause of secondary lymphedema is infection with the nematode Wuchereria bancrofti. This condition is also known as filariasis (see Chapter 15 for more on filariasis). With obstructed or diseased lymphatic vessels, the accumulation of fluid gives rise to stasis of proteins and interstitial fluid. According to the Starling equation, increased protein concentration (Starling forces) results in increased colloid osmotic pressure in the tissue and a net gradient of fluid toward the interstitium. This physiologic phenomenon leads to edema, fat deposition of nontransported fat molecules, and fibrocyte activation as the result of an amplified inflammatory response. It is postulated that this triad of edema, fibrosis, and fat deposition is the supposed cause of lymphedema, although in reality this is more likely the effect than the cause. In patients with chronic lymphedema, large amounts of subcutaneous adipose tissue may form. Although incompletely understood, this adipocyte proliferation may explain why conservative treatment may not completely reduce the swelling and return the affected area to its usual dimensions (Fig. 1-1). Lymphedema manifests as soft and pitting edema early in the disease and progresses to chronic induration, overgrowth, and disfigurement later on (Fig. 1-2). Lymphedema may manifest as swelling of one or more limbs and may include the corresponding quadrant of the trunk, in addition to other areas, such as the head and neck, breast, or genitalia. It is congenital, infectious, or iatrogenic, although the exact cause is still not fully understood. Lymphedema is classified as either primary or secondary based on etiologic factors. Primary lymphedema is a congenital disease of the lymphatic system. It can present in infancy when it is known as Milroy disease. When it presents in adolescence, it is known as lymphedema praecox. Another manifestation presents when the patient is in his or her 30s and is known as lymphedema tarda. In primary lymphedema, lymphatic fluid collects in the subcutaneous tissues under the epidermis because of obstruction, malformation, or underdevelopment (hypoplasia) of various lymphatic vessels. Secondary lymphedema is an acquired disease of normal lymphatic vessels through either disruption or obstruction. At birth, about 1 in 6000 people will develop primary lymphedema. The overall prevalence of lymphedema has been estimated at 0.13% to 2%. In developed countries, the main cause of lymphedema is widely assumed to be treatment for cancer. The incidence of lymphedema after breast cancer treatment ranges from 24% to 49% after mastectomy4-8 and 4% to 28% after lumpectomy.9,10 Patients requiring more aggressive surgery and radiation have a greater risk of developing lymph-

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Chapter 1  Lymphedema: Lack of Solutions to a Clinical Problem

A

Interstitial fluid

Capillary

B

Increased interstitial fluid

Lymphatic capillary

Proteins and fat molecules

Interstitial fluid

Disrupted or damaged lymphatic system

Accumulation of proteins and fat molecules

Edema

Fibrosis (fibrocyte activation)

Amplified inflammatory response

Increased subcutaneous adipose tissue (adipocyte proliferation)

FIG. 1-1  A, Under normal circumstances, proteins and fat molecules are transported with the interstitial fluid in the lymphatic flow that drains the tissues. B, When this flow is blocked, proteins and fat molecules accumulate in the interstitial fluid. This increases the colloid osmotic pressure within the interstitium, increasing the gradient of fluid toward the interstitium.

FIG. 1-2  Patient with chronic lymphedema demonstrating extreme trophic skin changes, with multiple fissures and thickening of the skin. This is elephantiasis.

edema; however, the less invasive sentinel node biopsy is associated with only a 5% to 7% incidence of upper extremity lymphedema.11 In addition to breast cancer treatment, treatment for other malignancies is also associated with lymphedema: melanoma (16%), gynecologic cancers (20%), genitourinary cancers (10%), head and neck cancers (4%), and sarcomas (30%).12 However, it appears that about one quarter to one half of affected patients have other forms of lymphedema, including primary lymphedema and lymphedema associated with poor venous function, trauma, limb dependency, or cardiac disease.13

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TABLE 1-1  International Society of Lymphology Lymphedema Staging Stage*

Clinical Description

0

Latent or subclinical condition in which swelling is not yet evident despite impaired lymph transport with subtle changes in tissue fluid or changes in subjective symptoms. It may exist months or years before overt edema occurs.

I

Early accumulation of fluid relatively high in protein content, which subsides with limb elevation. Pitting may occur.

II

Limb elevation alone rarely reduces tissue swelling, and pitting is common.

III

Lymphostatic elephantiasis in which pitting can be absent and trophic skin changes, such as acanthosis, fat deposits, and warty overgrowths, develop.

*Other classifications/authors use arabic numerals for these stages: 0, 1, 2, 3.

The International Society of Lymphology has classified lymphedema into four stages based on certain clinical parameters14 (Table 1-1). Pain and discomfort are frequent symptoms, and increased susceptibility to cellulitis can result in frequent hospitalizations and long-term dependency on antibiotics.15 Lymphedema also causes hyperkeratosis, papillomatosis, erysipelas, lymphangitis, and the development of cutaneous tumors, such as Kaposi sarcoma, lymphoma, and even lymph­ angiosarcoma.16,17 Increased limb size can interfere with mobility and affect body image.18-20 In essence, lymphedema may produce significant physical and psychological morbidity. It is a chronic condition that presently is not curable but may be alleviated by appropriate management; if ignored, it can progress and become extremely difficult to manage.

Nonsurgical Management The treatment of lymphedema is divided into nonoperative and operative methods. With both approaches, meticulous skin hygiene and care (cleansing, low pH lotions, and emollients) are vital to the success of virtually all treatment approaches. Basic range-of-motion exercises of the extremities, limb compression, and limb elevation are also helpful. Some studies support vigorous exercises under the correct conditions. However, little substantive data exist in the form of well-designed, case-control studies that compare methodologies.14 It is clear that early treatment is optimal for the best outcome. The best practice management of lymphedema involves a multidisciplinary approach that includes the following: • Exercise and movement: to enhance lymphatic and venous flow • Swelling reduction and maintenance: to reduce limb size or volume and improve subcutaneous tissue consistency through compression and/or massage • Skin care: to optimize the condition of the skin, treat any complications caused by lymphedema, and minimize the risk of cellulitis or erysipelas • Risk reduction: to avoid factors that may exacerbate lymphedema • Pain and psychosocial management

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Swelling reduction is achieved through a combination of compression and exercise with or without lymphatic massage (manual lymphatic drainage [MLD] or intermittent pneumatic compression [IPC]). The precise regimen required will be determined by the site, stage, severity, and complexity of the lymphedema and the patient’s psychosocial status. Successful management of lymphedema relies on patients playing an active role in their care.

Manual Lymphatic Drainage MLD encourages fluid away from congested areas by increasing the activity of normal lymphatics and bypassing ineffective or obliterated lymph vessels. Although there is a wealth of clinical opinion advocating the benefits of MLD, massage alone does not appear to be beneficial.21-23 Based on current evidence from 10 randomized controlled trials, there is little evidence to support the use of massage alone.24 Furthermore, if performed overly vigorously, massage may damage lymphatic vessels. Deep, heavy-handed massage should be avoided, because it may damage tissues and exacerbate edema by increasing capillary filtration. The most appropriate techniques, optimal frequency, and indications for MLD, as well as the benefits of treatment, need clarification. MLD is a specialist skill that needs regular practice to maintain competence. (MLD is discussed in detail in Chapter 29.)

Combined Physical Therapy and Compression Combined physical therapy (CPT), also known as complete or complex decongestive therapy, is also a two-stage treatment protocol. In phase I, the main goals are size reduction of the affected limb and improvement of the skin. After phase I, the patient with lymphedema proceeds to phase II, an ongoing, individualized, self-management phase to maintain the gains of phase I.25 The goals of CPT are to: • Decrease swelling26,27
 • Increase lymph drainage from the congested areas28,29
 • Reduce skin fibrosis and improve the skin’s condition30
 • Enhance the patient’s functional status31
 • Relieve discomfort and improve quality of life26,27,32-36 • Reduce the risk of cellulitis and Stewart-Treves syndrome, a rare form of angiosarcoma17,37 CPT is more labor intensive than other modalities, but its efficacy in reducing lymphedema is supported by long-standing experience.38,39 It is considered the standard of treatment for several reasons. First, CPT uses skin care, manual lymph node drainage, range-of-motion exercises, and multilayer bandage wrapping. Multilayer bandage wrapping is the mainstay of conservative therapy.40 Second, phase II maintains the results of phase I with the use of a low-stretch elastic stocking or sleeve compression. Compression alone has shown some benefit. Both multilayer inelastic stockings and controlled compression therapy (the garment’s size is tailored after edema volume changes) reduce edema volume by 31%16 and 46%,41 respectively. With CPT, randomized, controlled studies have shown a mean decrease of between 40% and 60% in edema volume.21,42,43 Noncontrolled clinical trials demonstrate results similar to those of randomized trials.27,44-47

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Compliance is imperative for successful outcomes, and even with an actively participating patient, results vary.46 The prerequisites of successful CPT are the active participation of the patient, availability of physicians, nurses, and therapists specifically educated and experienced in this method, health insurance coverage of the cost of treatment, and industry willingness to provide highquality products. Compressive bandages, when applied incorrectly, can be harmful and should be placed by professionally trained personnel. Newer devices and garments are continuously being manufactured to reduce the bandage burden and improve compliance. However, the patient must understand that CPT is not a cure but only a risk-reduction strategy.

Thermal Therapy Although combinations of heat, skin care, and external compression have been successfully used by practitioners in Europe and Asia for thousands of patients, the role and value of thermotherapy alone without compression or MLD in the management of lymphedema remain unclear without further rigorous comparative studies.48-50

Medications Drug therapy to treat lymphedema has also been extensively studied. Diuretics have been tried, especially in the first stage of CPT. However, they are not routinely used, because they can cause fluid and electrolyte imbalance and have only a marginal benefit in reducing peripheral edema.51,52 Diuretics may also increase fibrosis because of worsening protein accumulation. Benzopyrones are not routinely used in lymphedema treatment because of poor outcomes and varied formulations and dose regimens.53 Once considered effective in the treatment of lymphedema by reducing edema fluid, softening limbs, and decreasing secondary infection, definitive conclusions about the efficacy of this medication are questionable with poor quality trials.54 Liver toxicity is linked to high dosages of this drug; therefore they are not licensed for use in the United States, United Kingdom, Australia, or France.55 Proponents claim that these drugs increase macrophage activity, encouraging the lysis of protein, which in turn reduces the formation of fibrotic tissue in the lymphedematous limb.56,57 Antimicrobials have no role in reducing lymphedema and are intended to treat cellulitis, lymphangitis, or erysipelas.40 To eradicate filaria from the bloodstream, diethylcarbamazine, albendazole, or ivermectin is recommended and may cause a variable inflammatory immune response by the host with aggravation of lymphatic blockage. There is limited evidence from rigorously designed studies on the use of natural supplements for lymphedema. American horse chestnut has been reported to reduce venous edema but not lymphedema.58 Selenium, a trace element nutrient that functions as a cofactor for a reduction of antioxidant enzymes, has been reported to improve lymphedema in head and neck cancer.59,60 Bromelain, a substance found in pineapple, has antiinflammatory, anticoagulant, enzymatic, and diuretic effects. Some have wondered if bromelain use may be beneficial for lymphedema, but it has not been studied specifically for lymphedema but rather in malignancy and other diseases.61-65

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9

Because of the potential interactions with prescription drugs and other negative side effects, patients should check with their physician or health care provider before taking any natural supplement.

Laser Therapy Recent reports with small numbers of patients have demonstrated the efficacy of low-level laser therapy in reducing lymphedema, particularly after breast cancer.66-69 A systematic review of 41 articles showed a reduction in limb volume in patients undergoing low-level laser therapy when compared with other treatments. However, because of a lack of comparison with complex physical therapy and other treatments, definitive conclusions about low-level laser therapy cannot be purported.70 Additional studies with larger numbers of patients in diverse settings are needed to confirm these findings.

Pneumomassage IPC, also known as pneumomassage, is a two-phase program in which external gradient compression is applied by a pump, followed by elastic stockings or sleeves, to maintain edema reduction. IPC reduces edema by decreasing capillary filtration, and therefore lymph formation, rather than by accelerating lymph return. Single-chamber pumps, which were used in the past, are no longer used for lymphedema. Single-chamber pumps can cause fluid to move in both directions, even toward the edematous areas. Also, the pressure in single-chamber pumps does not stimulate lymphatic flow as sequential pumps do.71 Acceptable pumps should have appliances (pump garments) with multiple chambers and sequential pressure delivery, with the chambers compressing in a specific pattern determined individually for the patient’s diagnosis and pattern of lymphedema.72 Compliance is a concern with this approach, especially with the proximal displacement of edema and development of a fibrosclerotic ring at the root of the extremity or genitalia. Obstruction of lymph may occur, causing significant genital edema. The pumps may not be suitable for use in patients with coexisting renal failure or congestive heart failure. Patients whose lymphedema is the result of cancer treatment should ideally also be free of metastasis in the limb to prevent the risk of spreading the malignancy.73 Studies of pneumomassage are conflicting; some illustrate immediate edema reduction and long-term success, whereas others show minimal improvement with use over time.73-78 One study demonstrated considerable differences in skin or device interface pressure patterns and magnitude, which may have had an impact on therapeutic outcomes.79 This is a significant concern because superficial structures may be harmed if the pressures applied in therapy are too high.80 In general, lower pressures are considered safer, but the pressure must be individualized to the patient’s diagnosis and skin condition. IPC is not a “stand-alone” treatment.

Exercise and Elevation Exercise is a common rehabilitative intervention used to reduce lymphedema. Presently there is little evidence to indicate which types, intensities, and frequencies of exercise may be safely used in the management of lymphedema. However, specific exercise is beneficial for all patients.81

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Exercise improves muscular strength, cardiovascular function, psychological well-being, and functional capacity. Gentle resistance exercise stimulates muscle pumps and increases lymph flow; aerobic exercise increases intraabdominal pressure, which facilitates pumping of the thoracic duct.82,83 Combinations of flexibility, resistance, and aerobic exercise may be beneficial in controlling lymphedema and should be tailored to the individual.84 Patient-appropriate exercise enables the person with lymphedema to resume activity while minimizing the risk of exacerbation of swelling.81,83-86 Physical therapy referral is required for patients who have difficulty with mobility, joint function, or joint movement. Elevation of the affected limb, ideally to just above the level of the heart, is often advised to reduce swelling. Elevation acts by maximizing venous drainage and decreasing capillary pressure and lymph production.

Diet and Weight Loss Lymphedema risk increases with obesity. Thus weight loss in overweight individuals and maintenance of optimal weight in normal-weight individuals should be integral aspects of lymphedema treatment.6,87-91 In one study, weight loss alone reduced arm volume in the lymphedema arm more than the uninvolved arm of obese women with postmastectomy lymphedema.92 However, weight loss alone does not cure lymphedema. No special diet has been proved to have therapeutic value for uncomplicated peripheral lymphedema. Restricted fluid intake has not demonstrated any benefit for peripheral lymphedema reduction. In chylous reflux syndromes (for example, intestinal lymphangiectasia), a diet as low as possible or even free of long-chain triglycerides (absorbed by intestinal lacteals) and high in shortand medium-chain triglycerides (absorbed by the portal vein) is beneficial in children. Specific vitamin supplements may be needed in very low–fat or no-fat diets.

Skin Care Skin problems are common in patients with lymphedema. Swelling may produce deep skin folds in which fungal and bacterial infections can develop, causing cellulitis or erysipelas; cracks and dry areas of the skin are entry points for bacteria and fungus.93,94 Maintenance of skin integrity, meticulous hygiene, and careful management of skin problems are important to decrease the amount of fungus or bacteria and minimize the long-term complications of skin damage. The general principles of skin care are to preserve skin barrier function through washing and the use of emollients. Ordinary soaps, which usually contain detergents and no glycerin, should be avoided because they tend to dry the skin. Natural or pH neutral soaps or soaps with glycerin should be used. The perfumes and preservatives in scented products may be irritants or allergenic. In high concentrations, mineral-based and petrolatum-based products may exacerbate dry skin conditions by occluding the skin pores and preventing the natural oils from surfacing.

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11

Low pH moisturizers should be applied to keep the skin from drying and cracking.95 Emollients reestablish the skin’s protective lipid layer, preventing further water loss and protecting the skin from bacteria and irritants. Emollients include bath oils, soap substitutes, or moisturizers (lotions, creams, and ointments). In general, ointments contain little or no water and are better skin hydrators than creams, which are better than lotions. Emollients may damage the elastic component of compression garments, and it is advisable to avoid application immediately before donning the garment. The best method of emollient application is unknown. Some practitioners recommend applying them with strokes in the direction of hair growth (toward the feet when applying to the legs) to prevent blockage of hair follicles and folliculitis. Others recommend applying emollients by stroking toward the trunk to encourage lymph drainage. There is little substantive evidence in the literature to support particular skin care products or regimens in the treatment of lymphedema except that skin care in general is important as a risk reduction strategy.

Surgical Management Traditional teaching held that if nonsurgical treatment has been tried and unsuccessful, surgical therapy should be considered, although that paradigm may be changing. Since 1912, when the first surgical procedure for lymphedema of the scrotum was described by Charles,96 newer, more advanced options have been developed. Surgical treatment of lymphedema can be classified into three categories: liposuction, ablative surgery, and physiologic surgery.

Liposuction Liposuction involves the removal of fat in the body part affected by chronic lymphedema. It is generally performed under general anesthesia and involves the creation of many small stab incisions, followed by the insertion of suction cannulas that break up, liquefy, and suction out the fat. Liposuction has been recommended as the first surgical choice in the treatment of lymphedema. Originally used for body contouring and cosmetic surgery, liposuction has shown promising results in reducing the volume of hypertrophic adipose tissue and is also an excellent option when no lymphatic vessel is found during a shunt operation. The largest case series of liposuction in women with lymphedema of the upper extremity caused by breast cancer therapy illustrated significant improvement in the appearance and symptoms, with a mean edema reduction of 106% at 4 years’ follow-up.41,97 Liposuction has also shown promising results in lower extremity lymphedema.98 The potential risk of damaging residual lymphatic vessels, and thereby worsening the lymphedema, is of concern with liposuction, in addition to a relapse of the lymphedema if compression therapy is not continued after liposuction.99 Compression therapy after liposuction is necessary for the life of the patient. The risks of liposuction include bleeding, infection, skin loss,

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Part I  Current Concepts in Lymphedema

asymmetry, abnormal sensation, and progression of lymphedema. However, with minimal complications and reduced invasiveness compared with other therapies, liposuction with compression therapy is a very viable option for patients. (For a full discussion of liposuction and its efficacy in treating lymphedema, see Chapter 32.)

Ablative Surgery Ablative operations involve the excision of subcutaneous tissue, with or without skin, from the lymphedematous body part. Several types of excisional procedures have been practiced and are still used today. These range from simple excision of the lymphedematous folds or festoons to more radical procedures, such as the Charles procedure. This procedure involves the radical excision of skin, subcutaneous tissue, and deep fascia en bloc and reconstruction with a primary or staged skin graft.96 Some surgeons prefer primary skin grafting with either the skin from the excised tissue or a nonaffected area; others favor a delayed approach to skin grafting. Both the onestage97 and two-stage98 procedures report good results in function, contour, and reduction in the incidence of secondary cellulitis. Major-General Sir Richard Henry Havelock Charles (1858-1934) was a noted physician and Sergeant Surgeon to King George V. He was also a member of the Indian Medical Service and was the medical advisor to the Secretary of State for India. While in India, Charles treated several patients with lymphedema and described its surgical treatment in the textbook, A System of Treatment. His most eponymous surgery was actually for elephantiasis of the scrotum, for which he devised a surgical garment, surgical plan, and postoperative regimen, some of which are still used today. Interestingly, Charles never performed the procedure that bears his name. He performed his technique for scrotal lymphedema, and the procedure was only later transferred to the extremities. However, the Charles procedure was cited by McIndoe and attributed to Charles. Although it is rarely performed today, there is still an occasional place for it, usually in extreme cases.100,101 The Charles procedure was refined in subsequent years. In 1927 the first surgical procedure for breast cancer–related lymphedema of the upper extremity was performed by Sistrunk,102 in which a large ellipse of skin and soft tissue, including the deep fascia, was excised along the ulnar aspect of the arm. In 1967 Thompson103,104 refined the technique by raising a hinge skin flap along the lateral aspect of the limb, excising the edematous tissue and deep fascia, and burying the skin flap over the neurovascular bundle. Both refinements created a bridge between the deep and superficial lymphatic channels, but there is no evidence to support this. Servelle described a technique in which the entire affected limb underwent a two-stage reduction (first the medial aspect and later the lateral aspect of the limb).105 This has been called total superficial lymphangiectomy and is probably a modification of the Homan procedure. This is in contrast to the Charles procedure, in which only the affected part of the limb is treated, and the cosmetic outcome is mediocre at best. These ablative operations are the simplest surgeries to perform, but they are generally no longer used because of morbidities, such as scarring, ulceration, cellulitis, lymphatic fistulas, and keloids. The main complications of this debulking procedure are infection and necrosis of the skin graft, which can lead to poor cosmetic and functional results. Nevertheless, for some extreme cases, the Charles procedure continues to be a reasonable option (Fig. 1-3).

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A

13

B

FIG. 1-3  A, Patient with filariasis of the right lower extremity. Chronic wound on the anterior shin. B, After the Charles procedure, the patient has an excellent functional outcome.

Microsurgery Physiologic operations reconstruct the lymphatic transport system by draining lymph into the lymphatic basins or venous system. Lymphatic vessel–containing tissues, such as the greater omentum, local skin, or musculocutaneous flaps, have been used to drain excess lymph fluid. Muscle flaps have been found to restore lymphatic function in obstructive lymphedema106 and regrow lymphatic vessels in microsurgical flap reconstructions.107 The greater omental flap, with its several lymphatic vessels, has been transferred to lymphedematous extremities in breast cancer patients after mastectomy.108,109 The greater omentum was raised from the abdomen with the ipsilateral gastroepiploic vessels and transferred through a subcutaneous tunnel in the chest to the limb. The omental flap has lost popularity because of surgical morbidity and a lack of objective evidence to support any benefit. In one study on the use of an omental flap in the lower extremity, the omental flap reduced leg circumference from 50% to 75%, with excellent functional improvement in walking, daily activity, and sports.110 However, this isolated study included only four patients. Other microsurgical techniques correct the underlying lymphatic pathology. These techniques include connections between lymphatic vessels and lymphatic vessels (lymphatic-lymphatic bypass), between lymphatic vessels and veins (lymphaticovenous bypass), and between lymph nodes and veins and arteries (microvascular lymph node transfer). Lymphatic-lymphatic bypass connects an obstructed lymphatic to a healthy lymphatic with another lymphatic as an interposition graft.111 One lymphatic-lymphatic approach involved harvesting a composite graft of healthy lymphatic vessels from the medial thigh and insetting under the skin of the shoulder with several lymphatic-lymphatic anastomoses in the neck. The goal was to create several bypass routes between the upper arm and supraclavicular region by microscopically identifying lymphatic vessels at each end of the graft. In addition, an anastomosis with recipient vessels in the neck and upper arm was performed according to lymphatic vessel flow. Results from this approach revealed newly created lymph pathways and faster clearance of the radioisotope, but long donor scars and donor leg lymphedema are possible risks.112

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FIG. 1-4  Lymphaticovenular anastomosis. Isosulfan blue dye is injected intradermally distal to the incision, which stains the lymphatics. A lymphatic channel is then anastomosed to an adjacent venule. The lymphatic vessel is on the right and the venule to which it has been anastomosed is on the left.

Another approach used a vein interposition graft between the proximal and distal lymphatic vessels to bypass the lymphedematous tissue.113 An anastomosis of the lymphatic vessels to the distal end of a vein graft and lymphatic vessels in the supraclavicular area to the other end of the graft is performed. Lymphatic-lymphatic bypass is technically demanding, time-consuming, and with such delicate, thin-walled structures, easily damaged. Lymphaticovenous bypass microsurgically connects obstructed lymphatic vessels to small, superficial veins to shunt lymph fluid into the venous system. This was first described in a rat model in 1963 by Laine and Howard114 and thereafter in dogs by Yamada,115 who then applied the technique to human patients with lymphedema. Several studies have since reported on the clinical benefit.116-120 Sedlácek121 described an end-to-side lymphaticovenous anastomosis between the saphenous vein and a lymphatic vessel. More recently, Campisi et al122 implanted several lymphatic vessels into a large vein. The lymphaticovenous anastomosis remains patent if the lymphatic pressure is higher than the venous pressure, and this is best ensured by anastomosing to low-pressure subdermal venules. Multiple small transverse incisions are made in the extremity. Subdermal venules of less than 1 mm are dissected and then anastomosed to lymphatic vessels with extra fine supermicrosurgery techniques and instruments (Fig. 1-4). Multiple anastomoses have been described, either end-to-end or end-to-side, all of which had some beneficial result.123-130 Most recently, in a study of 20 consecutive patients undergoing lymphaticovenous bypass for stage 2 or 3 lymphedema, 19 patients reported significant clinical improvement, with a mean reduction of 35% at 1 year.131 Table 1-2 outlines the published results from lymphaticovenous shunt operations. Outcomes for this type of procedure are very difficult to standardize and also to interpret, making definitive conclusions about this procedure nebulous.

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TABLE 1-2  Lymphaticovenous Bypass Surgery Authors

Procedure

Fox et al128

End-to-side implantation

Gloviczki et al129

Number of Limbs

Additional Treatment

Type of Measurement

Results

Follow-up

4

Volumetry

Improved: 2 Subjectively improved: 1 No change: 1

Unknown

Pneumopump, compression

End-to-side, end-to-end anastomoses

5

Circumference

Improved: 2 No change: 3

Unknown

Pneumopump, compression

O’Brien et al118

End-to-end anastomoses

46

Circumference, volumetry

34% average reduction

13.8 yr

Elevation, massage

Filippetti et al127

End-to-side anastomoses

25

Circumference, lymphoscintigraphy

Improved: 5 No change: 8

18 mo

Unknown

Yamamoto and Sugihara123

End-to-end implantation

6

Circumference

Improved: 6

25 mo

Unknown

Koshima et al130

End-to-end anastomoses

12

Circumference

47.3% average reduction

9 yr

Elevation, compression

Campisi et al122

Lymphatic shunts

194

Volumetry, lympho­ scintigraphy

.75% improved: 73% 50%-75% improved: 24% ,25% improved: 3%

15 yr

Unknown

Chang124

End-to-end anastomoses

20

Volumetry

35% average reduction

1 yr

Unknown

Lymph node transfer is another physiologic surgical treatment of lymphedema.132,133 With lymph node transfer, a recipient bed in the lymphedematous extremity is prepared with a scar excision, followed by a flap of tissue containing superficial lymph nodes. The flap is based on an artery and vein and anastomosed to an artery and vein in the recipient bed (Fig. 1-5). Lymph nodes can typically be obtained from three donor sites: inguinal, thoracic, and cervical. In this manner, upper extremity lymphedema has been treated by transplantation of inguinal lymph nodes to the axilla or elbow region in the lymphedematous limb and even to the wrist.134,135 Lymph node transfer can also be performed simultaneously during free flap breast reconstruction, such as a deep inferior epigastric perforator flap. It is believed that the transfer of healthy lymph nodes will produce vascular endothelial growth factor C,136 which promotes lymphangiogenesis and new connections between the proximal and distal lymphatic vessels.137,138 However, there are no data showing that lymphatic vessels actually regenerate from transferred nodes. In a sheep model of the transplantation of autologous lymph nodes into a nodal excision site, there was improved lymph transport, restored lymphatic transport function, and newly formed afferent and efferent lymphatic vessels.139 Lymph node transfer may further improve lymphedema when combined with the removal of any

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A

B

C

D

E

F

FIG. 1-5  Microvascular lymph node transfer in a breast cancer patient with lymphedema of the right upper extremity. A, Preoperative markings for the supraclavicular adipofascial flap with lymph nodes. B, Preoperative markings for node excision and exposure to recipient vessels in the right axilla. C, Dissection of the adipofascial flap with lymph nodes based on the supraclavicular artery. D, Dissection of the right axilla revealing the thoracodorsal artery as a recipient site for the flap. E, The adipofascial flap based on the supraclavicular artery. There are usually several veins to choose for outflow. F, The supraclavicular adipofascial flap with lymph nodes anastomosed to the thoracodorsal vessels in the right axilla.

scar tissue that blocks lymphatic flow,140 providing enhanced immunologic function that reduces the development of infection135 and serving as an interface between the lymphatic and venous systems without actually creating the anastomosis.141 Although physiologic operations for lymphedema are becoming more popular, the optimal technique is still under debate. There is significant discrepancy between the actual surgery and clini-

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cal results. This discrepancy exists because there is a lack of standardized objective assessment for lymphedema, difficulty in choosing functional lymphatics for reconstruction, and poorly defined indications for surgery. Also, lack of knowledge regarding the cause of lymphedema limits the development of definitive treatments. More research is required—in the form of both clinical and basic science—to improve the evaluation of lymphedema, understand its cause, and refine surgical procedures.

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65. Seligman B. Oral bromelains as adjuncts in the treatment of acute thrombophlebitis. Angiology 20:2226, 1969. 66. Ahmed Omar MT, Abd-El-Gayed Ebid A, El Morsy AM. Treatment of post-mastectomy lymphedema with laser therapy: double blind placebo control randomized study. J Surg Res 165:82-90, 2011. 67. Mahram M, Rajabi M. Treatment of lymphedema praecox through low level laser therapy (LLLT). J Res Med Sci 16:848-851, 2011. 68. Omar MT, Shaheen AA, Zafar H. A systematic review of the effect of low-level laser therapy in the management of breast cancer-related lymphedema. Support Care Cancer 20:2977-2984, 2012. 69. Ridner SH, Poage-Hooper E, Kanar C, et al. A pilot randomized trial evaluating low-level laser therapy as an alternative treatment to manual lymphatic drainage for breast cancer-related lymphedema. Oncol Nurs Forum 40:383-393, 2013. 70. E Lima MT, E Lima JG, de Andrade MF, et al. Low-level laser therapy in secondary lymphedema after breast cancer: systematic review. Lasers Med Sci 29:1289-1295, 2014. 71. Adams KE, Rasmussen JC, Darne C, et al. Direct evidence of lymphatic function improvement after advanced pneumatic compression device treatment of lymphedema. Biomed Opt Express 1:117-125, 2010. 72. Pilch U, Wozniewski M, Szuba A. Influence of compression cycle time and number of sleeve chambers on upper extremity lymphedema volume reduction during intermittent pneumatic compression. Lymphology 42:26-35, 2009. 73. Klein MJ, Alexander MA, Wright JM, et al. Treatment of adult lower extremity lymphedema with the Wright linear pump: statistical analysis of a clinical trial. Arch Phys Med Rehabil 69(3 Pt 1):202-206, 1988. 74. Johansson K, Lie E, Ekdahl C, et al. A randomized study comparing manual lymph drainage with sequential pneumatic compression for treatment of postoperative arm lymphedema. Lymphology 31:56-64, 1998. 75. Miranda F Jr, Perez MC, Castiglioni ML, et al. Effect of sequential intermittent pneumatic compression on both leg lymphedema volume and on lymph transport as semi-quantitatively evaluated by lymphoscintigraphy. Lymphology 34:135-141, 2001. 76. Richmand DM, O’Donnell TF Jr, Zelikovski A. Sequential pneumatic compression for lymphedema. A controlled trial. Arch Surg 120:1116-1169, 1985. 77. Szuba A, Achalu R, Rockson SG. Decongestive lymphatic therapy for patients with breast carcinomaassociated lymphedema. A randomized, prospective study of a role for adjunctive intermittent pneumatic compression. Cancer 95:2260-2267, 2002. 78. Zanolla R, Monzeglio C, Balzarini A, et al. Evaluation of the results of three different methods of postmastectomy lymphedema treatment. J Surg Oncol 26:210-213, 1984. 79. Mayrovitz HN. Interface pressures produced by two different types of lymphedema therapy devices. Phys Ther 87:1379-1388, 2007. 80. Segers P, Belgrado JP, Leduc A, et al. Excessive pressure in multichambered cuffs used for sequential compression therapy. Phys Ther 82:1000-1008, 2002. 81. Schmitz KH, Ahmed RL, Troxel A, et al. Weight lifting in women with breast-cancer-related lymphedema. N Engl J Med 361:664-673, 2009. 82. Cohen SR, Payne DK, Tunkel RS. Lymphedema: strategies for management. Cancer 92(4 Suppl): 980-987, 2001. 83. Johansson K, Tibe K, Weibull A, et al. Low intensity resistance exercise for breast cancer patients with arm lymphedema with or without compression sleeve. Lymphology 38:167-180, 2005. 84. Kwan ML, Cohn JC, Armer JM, et al. Exercise in patients with lymphedema: a systematic review of the contemporary literature. J Cancer Surviv 5:320-336, 2011. 85. McKenzie DC, Kalda AL. Effect of upper extremity exercise on secondary lymphedema in breast cancer patients: a pilot study. J Clin Oncol 21:463-466, 2003.

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86. Moseley AL, Piller NB, Carati CJ. The effect of gentle arm exercise and deep breathing on secondary arm lymphedema. Lymphology 38:136-145, 2005. 87. Fife C. Massive localized lymphedema, a disease unique to the morbidly obese: a case study. Ostomy Wound Manage 60:30-35, 2014. 88. Fife CE, Carter MJ. Lymphedema in the morbidly obese patient: unique challenges in a unique population. Ostomy Wound Manage 54:44-56, 2008. 89. Mahamaneerat WK, Shyu CR, Stewart BR, et al. Breast cancer treatment, BMI, post-op swelling/ lymphoedema. J Lymphoedema 3:38-44, 2008. 90. Modolin ML, Cintra W Jr, Paggiaro AO, et al. Massive localized lymphedema (MLL) in bariatric candidates. Obes Surg 16:1126-1130, 2006. 91. Soran A, D’Angelo G, Begovic M, et al. Breast cancer-related lymphedema—what are the significant predictors and how they affect the severity of lymphedema? Breast J 12:536-543, 2006. 92. Shaw C, Mortimer P, Judd PA. A randomized controlled trial of weight reduction as a treatment for breast cancer-related lymphedema. Cancer 110:1868-1874, 2007. 93. Macdonald JM. Wound healing and lymphedema: a new look at an old problem. Ostomy Wound Manage 47:52-57, 2001. 94. Mallon EC, Ryan TJ. Lymphedema and wound healing. Clin Dermatol 12:89-93, 1994. 95. Vaillant L, Gironet N. [Infectious complications of lymphedema] Rev Med Interne 23(Suppl 3):403S407S, 2002. 96. Charles RH. Elephantiasis Scroti. London: Churchill, 1912. 97. Brorson H. Liposuction in arm lymphedema treatment. Scand J Surg 92:287-295, 2003. 98. Greene AK, Slavin SA, Borud L. Treatment of lower extremity lymphedema with suction-assisted lipectomy. Plast Reconstr Surg 118:118e-121e, 2006. 99. Frick A, Hoffmann JN, Baumeister RG, et al. Liposuction technique and lymphatic lesions in lower legs: anatomic study to reduce risks. Plast Reconstr Surg 103:1868-1873; discussion 1874-1875, 1999. 100. Song R, Gao X, Li S, et al. Surgical treatment of lymphedema of the lower extremity. Clin Plast Surg 9:113-117, 1982. 101. Miller TA, Wyatt LE, Rudkin GH. Staged skin and subcutaneous excision for lymphedema: a favorable report of long-term results. Plast Reconstr Surg 10:1486-1498; discussion 1499-1501, 1998. 102. Sistrunk WE. Contribution to plastic surgery: removal of scars by stages; an open operation for extensive laceration of the anal sphincter; the Kondoleon operation for elephantiasis. Ann Surg 85:185193, 1927. 103. Thompson N. The surgical treatment of chronic lymphoedema of the extremities. Surg Clin North Am 47:445-503, 1967. 104. Thompson N. Buried dermal flap operation for chronic lymphedema of the extremities. Ten-year survey of results in 79 cases. Plast Reconstr Surg 45:541-548, 1970. 105. Servelle M. Surgical treatment of lymphedema: a report on 652 cases. Surgery 101:485-495, 1967. 106. Classen DA, Irvine L. Free muscle flap transfer as a lymphatic bridge for upper extremity lymphedema. J Reconstr Microsurg 21:93-99, 2005. 107. Slavin SA, Upton J, Kaplan WD, et al. An investigation of lymphatic function following free-tissue transfer. Plast Reconstr Surg 99:730-741; discussion 742-743, 1997. 108. Goldsmith HS. Long term evaluation of omental transposition for chronic lymphedema. Ann Surg 180:847-849, 1974. 109. Goldsmith HS, De los Santos R, Beattie EJ Jr. Relief of chronic lymphedema by omental transposition. Ann Surg 166:573-585, 1967. 110. Attash SM, Al-Sheikh MY. Omental flap for treatment of long standing lymphoedema of the lower limb: can it end the suffering? Report of four cases with review of literatures. BMJ Case Rep Feb 8;2013. 111. Springer S, Koller M, Baumeister RG, et al. Changes in quality of life of patients with lymphedema after lymphatic vessel transplantation. Lymphology 44:65-71, 2011.

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112. Baumeister RG, Siuda S. Treatment of lymphedemas by microsurgical lymphatic grafting: what is proved? Plast Reconstr Surg 85:64-74; discussion 75-76, 1990. 113. Campisi C. Use of autologous interposition vein graft in management of lymphedema: preliminary experimental and clinical observations. Lymphology 24:71-76, 1991. 114. Laine JB, Howard JM. Experimental lymphatico-venous anastomosis. Surg Forum 14:111-112, 1963. 115. Yamada Y. Studies on lymphatic venous anastomosis in lymphedema. Nagoya J Med Sci 32:1-21, 1969. 116. Demirtas Y, Ozturk N, Yapici O, et al. Supermicrosurgical lymphaticovenular anastomosis and lymphaticovenous implantation for treatment of unilateral lower extremity lymphedema. Microsurgery 29:609-618, 2009. 117. Mihara M, Murai N, Hayashi Y, et al. Using indocyanine green fluorescent lymphography and lymphatic-venous anastomosis for cancer-related lymphedema. Ann Vasc Surg 26:278.e1-e6, 2012. 118. O’Brien BM, Mellow CG, Khazanchi RK, et al. Long-term results after microlymphaticovenous anastomoses for the treatment of obstructive lymphedema. Plast Reconstr Surg 85:562-572, 1990. 119. O’Brien BM, Shafiroff BB. Microlymphaticovenous and resectional surgery in obstructive lymphedema. World J Surg 3:3-15, 121-123, 1979. 120. O’Brien BM, Sykes P, Threlfall GN, et al. Microlymphaticovenous anastomoses for obstructive lymphedema. Plast Reconstr Surg 60:197-211, 1977. 121. Sedlácek J. Lymphovenous shunt as supplementary treatment of elephantiasis of lower limbs. Acta Chir Plast 11:157-162, 1969. 122. Campisi C, Davini D, Bellini C, et al. Lymphatic microsurgery for the treatment of lymphedema. Microsurgery 26:65-69, 2006. 123. Yamamoto Y, Sugihara T. Microsurgical lymphaticovenous implantation for the treatment of chronic lymphedema. Plast Reconstr Surg 101:157-161, 1998. 124. Chang DW. Lymphaticovenular bypass for lymphedema management in breast cancer patients: a prospective study. Plast Reconstr Surg 126:752-758, 2010. 125. Yamamoto T, Koshima I, Yoshimatsu H, et al. Simultaneous multi-site lymphaticovenular anastomoses for primary lower extremity and genital lymphoedema complicated with severe lymphorrhea. J Plast Reconstr Aesthet Surg 64:812-815, 2011. 126. Yamamoto T, Narushima M, Kikuchi K, et al. Lambda-shaped anastomosis with intravascular stenting method for safe and effective lymphaticovenular anastomosis. Plast Reconstr Surg 127:1987-1992, 2011. 127. Filippetti M, Santoro E, Graziano F, et al. Modern therapeutic approaches to postmastectomy brachial lymphedema. Microsurgery 15:604-610, 1994. 128. Fox U, Montorsi M, Romagnoli G. Microsurgical treatment of lymphedemas of the limbs. Int Surg 66:53-56, 1981. 129. Gloviczki P, Fisher J, Hollier LH, et al. Microsurgical lymphovenous anastomosis for treatment of lymphedema: a critical review. J Vasc Surg 7:647-652, 1988. 130. Koshima I, Inagawa K, Urushibara K, et al. Supermicrosurgical lymphaticovenular anastomosis for the treatment of lymphedema in the upper extremities. J Reconstr Microsurg 16:437-442, 2000. 131. Suami H, Chang DW. Overview of surgical treatments for breast cancer-related lymphedema. Plast Reconstr Surg 126:1853-1863, 2010. 132. Assouad J, Becker C, Hidden G, et al. The cutaneo-lymph node flap of the superficial circumflex artery. Surg Radiol Anat 24:87-90, 2002. 133. Becker C, Hidden G. [Transfer of free lymphatic flaps. Microsurgery and anatomical study] J Mal Vasc 13:119-122, 1988. 134. Becker C, Assouad J, Riquet M, et al. Postmastectomy lymphedema: long-term results following microsurgical lymph node transplantation. Ann Surg 243:313-315, 2006. 135. Lin CH, Ali R, Chen SC, et al. Vascularized groin lymph node transfer using the wrist as a recipient site for management of postmastectomy upper extremity lymphedema. Plast Reconstr Surg 123:12651275, 2009.

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136. Saaristo AM, Niemi TS, Viitanen TP, et al. Microvascular breast reconstruction and lymph node transfer for postmastectomy lymphedema patients. Ann Surg 255:468-473, 2012. 137. Lähteenvuo M, Honkonen K, Tervala T, et al. Growth factor therapy and autologous lymph node transfer in lymphedema. Circulation 123:613-620, 2011. 138. Yan A, Avraham T, Zampell JC, et al. Mechanisms of lymphatic regeneration after tissue transfer. PLoS One 6:e17201, 2011. 139. Tobbia D, Semple J, Baker A, et al. Experimental assessment of autologous lymph node transplantation as treatment of postsurgical lymphedema. Plast Reconstr Surg 124:777-786, 2009. 140. Becker C, Vasile JV, Levine JL, et al. Microlymphatic surgery for the treatment of iatrogenic lymphedema. Clin Plast Surg 39:385-398, 2012. 141. Pegu A, Flynn JL, Reinhart TA. Afferent and efferent interfaces of lymph nodes are distinguished by expression of lymphatic endothelial markers and chemokines. Lymphat Res Biol 5:91-103, 2007.

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C hapter 2 Lymphedema and Its Impact on Quality of Life Jane M. Armer, Jennifer M. Hulett, Janice N. Cormier, Bob R. Stewart, Ausanee Wanchai, Kate D. Cromwell

Ly

K ey P oints • All patients undergoing lymph node dissection for any type of solid tumor are at a lifetime risk for the development of secondary lymphedema. These solid tumors include breast cancer, melanoma, gynecologic cancer, genitourinary cancer, and head/neck cancers. • Lymphedema results in negative psychosocial outcomes, poorer physical and mental well-being, social isolation, and higher economic burden. Psychological symptom clusters include emotional distress, decreased sleep, negative self-identity and decreased self-confidence, and psychological distress. • Health care providers have long believed that posttreatment late effects of cancer treatment such as lymphedema are to be expected and tolerated; this has led to survivors’ hesitation to share lymphedema concerns with their health care providers. • As cancer detection and treatment advance, a growing number of aging cancer survivors develop posttreatment multifactorial sequelae that require a multidisciplinary approach for rehabilitation and management. • Many survivors are aware of the risk for developing lymphedema after breast cancer treatment. They are hyperaware of engaging in physical activities that may trigger lymphedema or exacerbate existing lymphedema symptoms, which results in feelings of increased frustration and limitation of daily physical activities. This in turn leads to other deleterious survivorship outcomes. • Physical impairments, functional limitations, and symptoms associated with cancer-related lymphedema may be successfully treated using a multidisciplinary approach throughout the survivorship, a period that spans from the time of cancer diagnosis through all years of life. This includes a surveillance model that advocates early assessment and referral for exercise and rehabilitative therapies. Early physiotherapy intervention may reduce the risk of developing lymphedema and of progressive lymphedema. It may also be considered cost effective, because it reduces the economic burden associated with intensive rehabilitation measures and hospitalizations for infection. • Lymphedema teaching strategies should incorporate culturally specific, spiritually based interventions to promote positive worldviews and positive spiritual experiences to enhance perceptions of quality of life. Lymphedema education should focus on the promotion of positive self-efficacy strategies that reinforce a survivor’s ability to control lymphedema through early detection and early referral for rehabilitation.

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Lymphedema can arise as a consequence of the treatment of breast cancer and of many other solid tumors, such as melanoma, head and neck cancers, and gynecologic and genitourinary malignancies.1 A characteristic of all of these malignancies is that they spread to the regional lymph nodes before distant disease dissemination occurs. Treatment for many of these malignancies often includes complete dissection of the involved lymph node basin, which may include axillary, inguinofemoral, or pelvic (iliac/obturator) lymph nodes. Limited research has been dedicated to determining the incidence and impact of lymphedema among survivors of these malignancies.1 It is well established that symptoms of persistent cancer-related lymphedema result in negative psychosocial outcomes, poorer physical and mental well-being, social isolation, and higher economic burden.2-6 In addition, chronic lymphedema symptoms significantly affect the overall health-related quality of life (QOL) of older female survivors.7 As techniques for cancer detection and treatment improve, a growing population of aging cancer survivors report posttreatmentrelated difficulties that are unique and multifactorial and that therefore require a multidisciplinary approach for rehabilitation and management.8,9 Historically, health care providers have held the view that posttreatment late effects of cancer treatment such as lymphedema are expected and represent minor sequelae that are to be tolerated. Qualitative data suggest that this viewpoint has resulted in survivors’ perceptions that lymphedema symptoms should be disregarded, so these individuals therefore hesitate to share lymphedema concerns with their health care providers.10 These perceptions and interactions may be some of the reasons that few survivors receive early referrals to rehabilitation programs and consequently do not undergo baseline assessments for the early detection of physical and functional impairment.10 This chapter will explore the impact of lymphedema on QOL issues, including psychosocial outcomes, functional impairment, and economic burden experienced by cancer survivors with long-term lymphedema.

Incidence of Lymphedema In developed countries, secondary lymphedema is attributed to traumatic injury to the lymphatic channels associated with surgical interventions for the treatment of cancer.11 Determining the true prevalence and incidence rates of lymphedema is complicated, because they have been shown to vary according to the treatment received, the anatomic location affected, the methods of lymphedema assessment, the criteria applied, and the duration of follow-up.1 Moreover, methods for the global tracking and reporting of lymphedema occurrence are inconsistent, fragmented, and often disease based rather than population based.12 The diagnosis of lymphedema can be challenging given the multidisciplinary nature of treatment involving different clinicians from the time of diagnosis through the duration of long-term posttreatment follow-up care.13 Although few data are available regarding lymphedema prevalence rates in developed countries, an exception is a Brazilian study that reported a prevalence rate of 44.8% among breast cancer survivors.14 The reported incidence of lymphedema among breast cancer survivors in developed countries has been estimated as 28% in Australia, 21% in Jordan, 27% in Turkey, 30% in Great Britain, and 30% to 40% in the United States.15-22 With respect to the lifetime risk for the development of lymphedema, longitudinal data from American breast cancer survivors reveal a reported

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incidence that varies between 6% and 94% within 5 years after treatment, depending on the methods of measurement and the criteria applied.23,24 All patients who undergo lymph node dissection for any type of solid tumor evaluation are at a lifetime risk for lymphedema.1 Lymphedema affects survivors of various malignancies, including melanoma (16%), gynecologic cancer (20%), genitourinary cancer (10%), and head/neck cancers (4%).1 Risk factors for the development of lymphedema include poor general health, advanced breast cancer, and obesity, which are associated with breast cancer–related lymphedema.13 With respect to obesity, a body mass index (BMI) of more than 30 kg/m2 at the initiation of breast cancer treatment has been shown to be associated with a 3.6-fold increase in the likelihood of developing lymphedema at 6 months compared with survivors with BMIs of less than 30 kg/m2.13 However, weight gain after breast cancer treatment during the first 30 months of survivorship has not been shown to increase the risk of late-onset lymphedema.25 Advanced age (older than 80 years) has also been shown to be associated with a lower risk of lymphedema.7

Assessment of Quality of Life Health-related QOL is a multidimensional construct that encompasses physical, functional, emotional, and social and family well-being.26-29 Physical well-being in this context refers to symptoms related to disease (for example, pain, nausea, and fatigue) as well as side effects of treatment. The physical impact of lymphedema is very different among survivors of head/neck cancers. In this patient population, swelling of the head and neck region has significant functional implications, because it may have an impact on the patient’s ability to speak and swallow. In a study of 103 survivors of head/neck cancers, Deng et al26 reported that external and internal lymphedema also affected patients’ nutritional intake and resulted in weight loss. In addition, internal lymphedema was also linked to self-reported voice-related symptoms. Functional well-being includes an individual’s ability to perform activities of daily living such as walking, bathing, and dressing oneself in addition to societal role performance. Hull27 noted the effects of lymphedema on survivors’ daily lives, which included the following: • Difficulty sleeping because of positioning of the swollen limb • Difficulty carrying items, such as heavy pots and groceries • Challenges with many forms of exercise, even walking • Problematic fitting and comfort of clothing Overall, the physical problems associated with lymphedema affect a wide range of daily activities. Emotional well-being is a measure of coping ability, and it reflects the experience of feelings that range from enjoyment to distress, whereas social well-being reflects the quality of relationships with family and friends as well as wider social interaction.28 Health utilities are related to QOL, but they are distinctly different. Health utilities assess the value assigned by populations to specific health states with the use of standardized methods. One of the most commonly used health utilities instruments is the EuroQOL-5D, which uses preference weights from the general population and which can be used to calculate quality-adjusted life-years for cost-effectiveness analyses.30,31 In a study that examined the impact of lymphedema on utility

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measures, elevated BMI showed a strong association with decreasing utility scores for those with higher stages (stages 2 and 3) of lymphedema.30

Quality of Life Instruments A number of instruments have been used to measure QOL among breast cancer survivors. These include the validated Psychosocial Adjustment to Illness Scale (PAIS), which was used by one study to report a low to moderate relationship between lymphedema symptoms and poor function; however, the use of the PAIS did not demonstrate a correlation between lymphedema and physical, social, vocational, or sexual function measures.32,33 The EuroQOL-5D is a validated QOL tool widely used in Europe and the United States to measure five domains: self-care, mobility, usual activities, pain/discomfort, and anxiety/depression.30 In a study of 236 patients with lymphedema, many of whom were cancer survivors, lymphedema was found to be associated with lower utility values compared with the values of the general population; adjusted utility scores were lowest in patients with lower extremity lymphedema.30 The Lymphedema Quality of Life (LYMQOL) questionnaire is a self-report tool intended for use as a standard measure of QOL outcomes among patients with upper and lower limb lymphedema in clinical settings.34 The LYMQOL was adapted from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Questions (EORTC QLQ-C30),35 and it asks 38 questions of patients with upper limb lymphedema and 40 questions of patients with lower limb lymphedema to assess four domains: mood, function, body image/appearance, and symptoms. Although the LYMQOL has demonstrated validity and reliability for all domains (Cronbach’s alpha, .0.8), the tool’s responsiveness over time continues to be evaluated.36 In a systematic review of 17 QOL instruments, Pusic et al37 reported that only one study made use of a patient-reported outcome instrument, the Upper Limb Lymphedema 27 (ULL-27), which included lymphedema-specific items.38 The ULL-27 demonstrated strong psychometric properties and content validity for the purposes of lymphedema survivorship research. A study involving the ULL-27 demonstrated improvements in QOL—specifically in the social and emotional wellbeing domains—among survivors engaged in aqua therapy for lymphedema treatment.38 Generic QOL instruments such as the Medical Outcome Survey Short-Form 36 (SF-36) are not sensitive enough to detect or measure changes related to lymphedema-associated QOL.37-39 In a systematic review of the literature pertaining to QOL among patients with lower limb lymphedema, Cernal et al40 reported that a deficit exists with regard to the availability of high-quality studies. In this review, it was noted that the majority of studies also did not use validated patientreported outcome instruments specific to assessing lymphedema-associated conditions. Current expert opinion suggests that QOL instruments are inadequate for measuring the specific psychosocial factors associated with lymphedema; specifically, they do not assess the frustration associated with lymphedema management.37,40,41 Although a number of objective tools exist, data suggest that subjective tools may be more sensitive for assessing the functional and emotional impairment associated with lymphedema.42 Therefore QOL instruments specific to lymphedema and psychosocial impairment require further research and development.37,41

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In a retrospective trial that assessed the effect of complete decongestive therapy for patients with melanoma and lower extremity lymphedema, patients completed a questionnaire developed by the Italian Lymphedema Association.43 This instrument addressed the patient’s general medical status as well as patient-reported QOL, and it had been validated for patients with melanoma. With the use of this questionnaire, improved QOL was noted as a result of a complete decongestive therapy regimen and an active lifestyle. Preliminary data from a prospective trial of melanoma patients used the Functional Assessment of Cancer Therapy-Melanoma (FACT-M) questionnaire44 to evaluate changes in QOL over time in patients with melanoma with or without lymphedema. In this study, lower QOL was associated with lymphedema.45 In addition, patients with lower extremity melanoma, regardless of lymphedema status, reported lower QOL after surgical treatment compared with patients with upper extremity disease. The FACT is a validated 27-item cancer-specific instrument to which tumorspecific modules can be added for many different types of cancer, including breast, bladder, cervical, endometrial, nasopharyngeal, melanoma, prostate, vulvar, and other solid and nonsolid tumors.28,46,47 A study of survivors of head and neck cancers (N 5 103), which made use of the head and neck– specific module of the FACT, reported an inverse correlation between lymphedema and functional well-being. The investigators noted that the head and neck–specific subscale was sensitive to differences in QOL among those with and without lymphedema.26 The EORTC also developed and validated a tool to assess the QOL of patients with cancer.47,48 This tool has been used to evaluate survivors of gynecologic cancers, including uterine, ovarian, cervical, and breast. In a study of 263 patients who were stratified by age and evaluated using the disease-specific modules of the EORTC QLQ, women less than 45 years old were more affected by fatigue, lymphedema, poor body image, and impaired sexuality compared with women more than 45 years old.35,49 The EORTC questionnaire was also used in a study of patients with melanoma, which found no differences in overall QOL among patients with lymphedema compared with those without lymphedema.50 In a study of 63 patients who underwent ilioinguinal lymph node dissection for the treatment of various malignancies such as melanoma, squamous cell carcinoma, and vulvar cancer, the authors reported that QOL among these patients was similar to that of the general population and that lymphedema did not have an impact on overall scores or activities of daily living.51 These findings suggest that the EORTC questionnaire with diseasespecific modules may not be sensitive enough to detect lymphedema-specific issues. A systematic review of QOL and patient-reported outcomes among patients with cancer-related lower extremity lymphedema discussed five different tools used to capture patient-reported QOL.40 Among the instruments identified were those mentioned previously: PAIS, FACT, EORTC, ULL-27, and SF-36.* The SF-36 measures physical functioning as well as mental health constructs. It was also used in a pilot study of weight lifting among patients with lower extremity lymphedema

*References 28, 32, 35, 38, 39, 50.

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(n 5 10), but no significant differences in scores at the beginning of training compared with those obtained after the completion of training were found in this small sample.52 In another study that used the SF-36 to evaluate the effects of complex decongestive therapy on QOL among 57 survivors of gynecologic cancer, decreased limb volume was associated with statistically significant improvements in QOL.53

The Complex Effects of Lymphedema on Patients’ Well-Being Psychosocial Outcomes Lymphedema directly affects QOL through a combination of negative psychological and social factors that arise from coping with lymphedema symptoms and the complexities of lymphedema management.41 Both upper extremity and lower extremity lymphedema symptoms are associated with a psychological symptom cluster that includes emotional distress, decreased sleep, negative self-identity, decreased self-confidence, and psychological distress.4,41,54 Lymphedema in the affected hand and limb is associated with high levels of psychosocial distress, and those who have been identified as having lymphedema-associated pain have the highest levels of psychosocial distress.55 In a study that examined psychosocial distress among those with chronic lymphedema symptoms (stage 2 or 3 lymphedema) compared with those with early or transient lymphedema symptoms (stage 0 or 1 lymphedema), those with transient lymphedema reported greater levels of psychosocial distress.56 A systematic review of the psychosocial impact of lymphedema found no significant differences in emotional well-being and psychological distress among those with and without lymphedema.41 This suggests that patients accept their lymphedema over time and become better able to cope—or that the tools used are not sensitive to the differences. Qualitative findings from studies identified in the systematic review indicate that people with lymphedema feel negative social effects with respect to work, sexuality, and social engagement. Psychosocial impairment has been shown to affect breast cancer survivors with lymphedema to a greater extent than survivors without lymphedema with respect to body image, appearance, sexuality, and social isolation.41 Survivors with lymphedema experience increased feelings of frustration related to a lack of understanding from the public and a lack of consideration within the workplace, which perpetuates feelings of marginalization and social abandonment.57 Survivors’ perceptions of privacy may potentially be violated as a result of limb swelling, which is a visible indication of prior cancer treatment.58 Although studies have established that survivors of breast cancer with lymphedema rely on the social support of loved ones for physical assistance and emotional comfort, the culmination of many negative social factors may result in survivors with lymphedema limiting their social exposure, which results in further perceptions of marginalization, social abandonment, social isolation, and decreased sexuality.9,41,59

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Psychological Distress Recent reports note that cancer survivors experience psychological distress as early as the prediagnosis (biopsy) stage and that such distress may extend throughout the posttreatment period.60 Fear of breast cancer recurrence and of the development of posttreatment lymphedema are common causes of psychological distress during the early period of survivorship, whereas chronic symptom management and greater self-care burden contribute to ongoing psychological distress throughout survivorship.57,61,62 The emotional stress associated with cancer—particularly breast cancer—is unique with respect to recovery and rehabilitation as a result of the nonlinear and unpredictable nature of posttreatment late effects.63 A recent study reported that many survivors are aware of the risk for developing lymphedema after breast cancer treatment.59 Furthermore, survivors express a hyperawareness with regard to their decisions to engage in physical activities that may trigger lymphedema or exacerbate existing lymphedema symptoms; this in turn increases their frustration and limits their daily physical activities.64

Functional Impairment The most common sign of lymphedema is swelling of the affected limb in association with symptoms of altered limb sensation (for example, tightness, numbness, and heaviness) and limb pain; therefore many cancer survivors experience difficulty performing activities of daily living.65 Advancing age has been established as a risk factor for functional impairment in survivors who are living with lymphedema.7 With many chronic diseases, limited self-care practices have been shown to be predictive of disease progression and functional impairment.3 As functional impairment becomes chronic, lymphedema also negatively affects psychological well-being.7 Experts agree that the self-management of lymphedema symptoms after breast cancer treatment may improve survivors’ QOL.66 However, problems with treatment adherence arise in response to numerous self-care modalities that are time consuming and labor intensive but that are required for effective lymphedema symptom management.3,67 To control lymphedema symptoms, many patients must wear compression bandages and engage in ongoing bandage removal and rewrapping of the limb when participating in certain activities, particularly those that result in the wrapping getting wet, such as swimming and bathing.57 Patients may also wear compression sleeves; however, these are expensive, require hand washing, and need special care to avoid stains and other damage.68,69 Patients with lymphedema who are working have the additional burden of establishing and maintaining self-care routines with schedule constraints.70 Consequently, the burden of lymphedema self-management contributes significantly to these individuals’ overall perceptions of decreased QOL.3

Economic Impact Insurance coverage and rehabilitation costs also have a considerable impact on survivors of breast cancer with lymphedema to a greater extent than they do on survivors without lymphedema. The increased costs are primarily related to increased infections and associated rehabilitative treat-

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ments during the first 2 years after cancer treatment is initiated.2,8 For example, Shih et al2 found that American breast cancer survivors with lymphedema were twice as likely to have additional medical complications such as seromas, lymphangitis, or cellulitis that may be associated with costly diagnostic imaging studies and more frequent hospital admissions for treatment. Over a 2-year period after the initiation of breast cancer treatment, survivors with lymphedema had greater costs in medical claims compared with survivors without lymphedema, with costs ranging from $14,877 to $23,167, depending on whether cancer costs were included.2 In another cost-analysis model, Stout et al71 reported that the cost of treating patients during the early stages of lymphedema using an innovative prospective surveillance model was $636 per year, compared with $3125 per year for patients who were managed only during the late stages of lymphedema, which is representative of the traditional treatment model. These studies suggest that early physiotherapy intervention may reduce the risk of developing lymphedema and of progressive lymphedema; this type of intervention may also be cost effective, because it reduces the economic burden associated with intensive rehabilitation measures.30,71 The economic impact of lymphedema has additional implications for patients’ personal finances beyond medical and rehabilitation costs. In a study by Moffatt et al,16 it was found that 78% of cancer survivors with lymphedema reported lost work time and that 9% experienced a negative employment outcome. For many patients with lymphedema, major factors include a lack of family, social, and professional support; insufficient health insurance; and increased financial burden associated with treatment.6 Lymphedema imposes a direct negative impact on patients’ employability as a result of insufficient financial resources, unsupportive working environments, occupations that require physical labor, dealing with employers and coworkers who lack understanding, fearing the loss of one’s job or discrimination, and the accommodation of irregular work schedules.70

Family Our understanding of how spouses and family members of survivors of breast cancer cope with cancer survivorship and the late effects of cancer treatment, including lymphedema, remains minimal.57 Lymphedema symptoms are associated with self-consciousness and feelings of unattractiveness among survivors, and survivors who wear compression sleeves report a decreased sense of sexuality and sex appeal.41,64 In a recent systematic review, individuals with lymphedema reported decreased intimacy with significant others as a result of the inclusion of lymphedema into their body images.41 Survivors of breast cancer report challenges in the area of prioritizing self-care needs, particularly with respect to lymphedema risk reduction and management as well as balancing the needs of family members.57 In addition, survivors report feelings of frustration when family members hold a negative view of their required daily time commitment for lymphedema self-care and their view of lymphedema symptoms as trivial health issues.41 These reports suggest that family dynamics are affected by the physical impairment and psychosocial issues experienced by survivors of breast cancer with lymphedema, which necessitates the renegotiation of family roles.57 Families who demonstrate resilience and view the functional impairment associated with lymphedema

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symptoms as manageable tend to be successful when it comes to integrating lymphedema treatment as a normal part of daily family life.57

Cultural Considerations A comparison of survivors of breast cancer with lymphedema from South Africa and the United States found that both groups reported similar experiences with regard to the impact of lymphedema on activities of daily living. Both South African and American survivors expressed dissatisfaction with the education provided that pertained to lymphedema. Among South African survivors, feelings of inadequate preparation for lymphedema symptoms was expressed, whereas their American counterparts expressed a lack of guidance with regard to the management of lymphedema.72 Unique to American survivors were four common issues related to lymphedema: the management of public curiosity; the time burden associated with limb wrapping; experiences with wearing fitted clothing; and chronic lymphedema symptoms as a reminder of having had breast cancer. Survivors from both cultures reported an awareness of the importance of self-care practices for the reduction of lymphedema risk and exacerbation. Americans were more likely to wear compression sleeves on a daily basis as well as compression bandages at night, whereas South Africans reserved sleeve use primarily for traveling and gloves for specific activities such as gardening.72 Moreover, South African and American survivors both reported relying on faith to cope with lymphedema symptoms.59,72

Spirituality and Quality of Life Positive spiritual experiences have been reported to be associated with better physical outcomes and better coping with stress among individuals with chronic diseases; negative spiritual experiences have been reported to be associated with poorer mental health outcomes.73,74 Specifically, survivors of breast cancer rely on faith and social support to decrease stress and provide inner strength to cope with symptoms of lymphedema.75 In an 84-month qualitative study, many survivors of breast cancer, including those with lymphedema, attributed having positive spiritual beliefs and experiences, increased faith, compassion, gratitude, love, hope, and feelings of connectedness to God or a higher power as essential to breast cancer recovery and coping with lymphedema.59 Furthermore, perceptions of increased QOL have been shown to be influenced by positive spiritual beliefs and a positive worldview; some survivors of breast cancer have reported experiencing a degree of spiritual transcendence.59 These perceptions are common in Judeo-Christian cultures in which a higher power is believed to be essential for recovery.76 In an attempt to examine spirituality differences among different faith traditions, researchers have examined healthy individuals from five different faiths: Buddhism, Catholicism, Islam, Protestantism, and Reform Judaism. Data have demonstrated that individuals of differing faith traditions do express differing levels of spirituality and religiosity; however, all of the faith traditions were similar with respect to congregational (social) support. In addition, no differences were found with regard to physical or mental health based on faith tradition.77

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Interventions to Enhance Quality of Life Prevention and Education Data suggest that barriers to cancer survivors’ QOL stem from a lack of time management skills, deficits in symptom self-management knowledge, and an inability to cope with psychological distress. Therefore psychosocial interventions should be considered to address these issues.62 Individualized education programs should include information that pertains to factors that predispose individuals to the development of lymphedema, including high BMI; posttreatment complications, such as postoperative swelling, infection, and seromas; and a family history of lymphedema.9 Studies have demonstrated that exercise improves physical functioning and QOL among survivors of breast cancer.78 For example, a study of survivors with lymphedema who engaged in aqua lymphatic therapy reported greater improvements in social and emotional well-being, despite the absence of detectable limb volume changes; furthermore, survivors in the control group reported worsening QOL.38 Such findings suggest that perceptions of QOL can improve with lymphedema therapy independent of limb volume reduction.38 Furthermore, physical impairments and functional limitations associated with breast cancer treatment may be successfully treated with the use of a multidisciplinary approach throughout the survivorship period, including the incorporation of a surveillance model that advocates early assessment and referral for exercise and rehabilitative therapies.38,79,80 Lymphedema teaching strategies should also incorporate culturally specific, spiritually based interventions to promote positive worldviews and positive spiritual experiences to enhance perceptions of QOL.59

Early Intervention and Rehabilitation Intervention strategies should include planning for and assessing psychosocial problems that are commonly associated with lymphedema, including depression, poor coping, poor adherence to treatment recommendations, and social isolation.81 Symptoms of depression should be evaluated for the prompt referral of patients to mental health services; other identified psychosocial problems that are not resolved within 3 months should be referred to the appropriate specialist, such as a psychologist or social worker, for additional intervention.81 Strategies for improving QOL among cancer survivors with lymphedema should include goal setting, establishing daily care routines, regular exercise, positive self-talk, establishing support groups, and making resources for additional help available.6 Diet and exercise may be the most effective therapeutic interventions for the management of lymphedema.7 Studies have shown that reducing BMI through diet can also reduce lymphedema symptoms.82 Experts propose a prospective multidisciplinary breast cancer surveillance model that includes the following components: early and ongoing surveillance for the early identification of common physical and functional impairments; the provision of patient education to reduce lymphedema risk; prompt referral for rehabilitation and exercise interventions after physical impairments are

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identified; and the promotion of physical activity and weight-management strategies from diagnosis throughout the extended survivorship period.80,83,84 In a recent study, 60% of survivors were shown to have at least one posttreatment side effect that was potentially amenable to rehabilitative intervention.85 Slow and progressive resistance exercises, such as weight lifting, may reduce the onset and progression of lymphedema symptoms among cancer survivors.86,87 Aqua lymphatic therapy has been shown to be beneficial for the treatment of mild to moderate lymphedema among survivors of breast cancer.38

Integration of Complementary Alternative Medicine Practices Survivors of breast cancer tend to engage in complementary and alternative medicine (CAM) practices more than other cancer survivors do as a result of the high occurrence of side effects after treatment.88 Some survivors who were followed for 84 months reported using CAM therapies to manage these symptoms, although the success rate of symptom relief related to the use of these therapies remains largely unknown.59 Although large-scale studies of these methods are few, mindfulness-based stress reduction, acupuncture, yoga, and tai chi breathing exercises appear to be safe and may increase QOL while reducing psychological distress among survivors of breast cancer.89-91 Furthermore, preliminary studies have demonstrated a positive association between long-term yoga practice and improved QOL scores among survivors of breast cancer as well as a decrease in QOL scores among survivors who discontinue yoga practice.90 Lymphedema education should focus on the promotion of positive self-efficacy strategies that reinforce a cancer survivor’s ability to control lymphedema through early detection and early referral for rehabilitation.92 Previous research has consistently demonstrated that survivors of breast cancer with lymphedema across multiple cultural settings are open to CAM interventions.88,91

Conclusion In addition to the well-documented physical issues associated with lymphedema, there are a number of psychosocial issues that are also important to consider. Patients with lymphedema often report lower QOL, increased financial burden, and reduced social interaction. When assessing patients with lymphedema, it is crucial to evaluate all aspects of well-being. Although there are a few instruments available with lymphedema-specific items, there remains a need to develop and validate reliable and sensitive lymphedema-specific tools to assess social impact, emotional wellbeing, and functional impairment. Early studies indicate that the overall impact of lymphedema on QOL varies in accordance with the lymphedema’s anatomic location. Specifically, head and neck lymphedema is associated with a significant functional impact because it involves an impairment of the ability to swallow effectively and speak, whereas individuals with lower extremity lymphedema may be impaired in their ability to complete activities of daily living. Although the focus of lymphedema research has primarily been on lymphedema related to breast cancer, it is critical to identify the risk factors, natural histories, optimal treatment regimens, and impacts of lymphedema on survivors of cancer who had various other malignancies.

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C linical P earls • All patients with a history of lymph node dissection should receive baseline physical and functional assessments for impairment and lifetime monitoring for signs and symptoms of secondary lymphedema. • Health care providers should be aware of the common psychological symptoms associated with lymphedema, including psychological distress, decreased sleep, negative self-identity, and decreased self-confidence. • Health care providers need to regularly inquire about signs and symptoms of lymphedema to facilitate early and timely referrals to rehabilitation programs. • Early physiotherapy intervention may reduce the risk of developing lymphedema and of progressive lymphedema. • Lymphedema education should include positive self-efficacy strategies that reinforce survivors’ ability to control lymphedema through early detection and early referral for rehabilitation. • Lymphedema teaching strategies should incorporate culturally specific, spiritually sensitive interventions to promote positive worldviews and positive spiritual experiences to enhance perceptions of QOL.

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13. Ahmed R, Schmitz K, Prizment A, et al. Risk factors for lymphedema in breast cancer survivors, the Iowa Women’s Health Study. Breast Cancer Res Treat 130:981-991, 2011. 14. Paiva DM, Rodrigues VO, Cesca MG, et al. Prevalence of lymphedema in women undergoing treatment for breast cancer in a referral center in southeastern Brazil. BMC Womens Health 13:6, 2013. 15. American Cancer Society. Breast cancer: facts & figures 2013-2014, 2013. Available at www.cancer.org/ acs/groups/content/@research/documents/document/acspc-042725.pdf. 16. Moffatt CJ, Franks PJ, Doherty DC, et al. Lymphoedema: an underestimated health problem. QJM 96:731-738, 2003. 17. Bell RJ, Robinson PJ, Barallon R, et al. Lymphedema: experience of a cohort of women with breast cancer followed for 4 years after diagnosis in Victoria, Australia. Support Care Cancer 21:2017-2024, 2013. 18. Australian Government, Australian Institute of Health and Welfare. Australian Cancer Incidence and Mortality (ACIM) books. Breast cancer. Available at www.aihw.gov.au/acim-books/. 19. Morcos BB, Al Ahmad F, Anabtawi I, et al. Lymphedema. A significant health problem for women with breast cancer in Jordan. Saudi Med J 34:62-66, 2013. 20. Norman SA, Localio AR, Potashnik SL, et al. Lymphedema in breast cancer survivors: incidence, degree, time course, treatment, and symptoms. J Clin Oncol 27:390-397, 2009. 21. Paskett ED, Naughton MJ, McCoy TP, et al. The epidemiology of arm and hand swelling in premenopausal breast cancer survivors. Cancer Epidemiol Biomarkers Prev 16:775-782, 2007. 22. Ugur S, Arici C, Yaprak M, et al. Risk factors of breast cancer-related lymphedema. Lymphat Res Biol 11:72-75, 2013. 23. Armer JM, Stewart BR. Post-breast cancer lymphedema: incidence increases from 12 to 30 to 60 months. Lymphology 43:118-127, 2010. 24. Wilke LG, McCall LM, Posther KE, et al. Surgical complications associated with sentinel lymph node biopsy: results from a prospective international cooperative group study. Ann Surg Oncol 13:491-500, 2006. 25. Ridner SH, Dietrich MS, Stewart BR, et al. Body mass index and breast cancer treatment-related lymphedema. Support Care Cancer 19:853-857, 2011. 26. Deng J, Murphy BA, Dietrich MS, et al. Impact of secondary lymphedema after head and neck cancer treatment on symptoms, functional status, and quality of life. Head Neck 35:1026-1035, 2013. 27. Hull M. Functional and psychosocial aspects of lymphedema in women treated for breast cancer. Innov Breast Cancer Care 3:117-118, 1998. 28. Cella D, Nowinski CJ. Measuring quality of life in chronic illness: the functional assessment of chronic illness therapy measurement system. Arch Phys Med Rehabil 83(12 Suppl 2):S10-S17, 2002. 29. Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 11:570-579, 1993. 30. Cheville AL, Almoza M, Courmier JN, et al. A prospective cohort study defining utilities using time trade-offs and the Euroqol-5D to assess the impact of cancer-related lymphedema. Cancer 116:37223731, 2010. 31. Askew RL, Swartz RJ, Xing Y, et al. Mapping FACT-melanoma quality-of-life scores to EQ-5D health utility weights. Value Health 14:900-906, 2011. 32. Derogatis LR, Derogatis MF. The Psychosocial Adjustment to Illness Scale 21 (PAIS-SR) Administration, Scoring and Procedures Manual. Towson, MD: Clinical 22 Psychometric Research Inc, 1990. 33. Shigaki CL, Madsen R, Wanchai A, et al. Upper extremity lymphedema: presence and effect on functioning five years after breast cancer treatment. Rehabil Psychol 58:342-349, 2013. 34. Keeley VL, Veigas D, Crooks S, et al. The development of a condition-specific quality of life measure for lymphoedema (LYMQOL). Eur J Lymphol 12:36, 2004. 35. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993.

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36. Keeley V, Crooks S, Locke J, et al. A quality of life measure for limb lymphoedema (LYMQOL). J Lymphoedema 5:26-37, 2010. 37. Pusic AL, Cemal Y, Albornoz C, et al. Quality of life among breast cancer patients with lymphedema: a systematic review of patient-reported outcome instruments and outcomes. J Cancer Surviv 7:83-92, 2013. 38. Tidhar D, Katz-Leurer M. Aqua lymphatic therapy in women who suffer from breast cancer treatmentrelated lymphedema: a randomized controlled study. Support Care Cancer 18:383-392, 2010. 39. McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 31:247-263, 1993. 40. Cernal Y, Jewell S, Albornoz CR, et al. Systematic review of quality of life and patient reported outcomes in patients with oncologic related lower extremity lymphedema. Lymphat Res Biol 11:14-19, 2013. 41. Fu MR, Ridner SH, Hu SH, et al. Psychosocial impact of lymphedema: a systematic review of literature from 2004 to 2011. Psychooncology 22:1466-1484, 2013. 42. Bulley C, Gaal S, Coutts F, et al. Comparison of breast cancer-related lymphedema (upper limb swelling) prevalence estimated using objective and subjective criteria and relationship with quality of life. Biomed Res Int 2013:807569, 2013. 43. Carmeli E, Bartoletti R. Retrospective trial of complete decongestive physical therapy for lower extremity secondary lymphedema in melanoma patients. Support Care Cancer 19:141-147, 2011. 44. Cormier JN, Davidson L, Xing Y, et al. Measuring quality of life in patients with melanoma: development of the FACT-Melanoma subscale. J Support Oncol 3:139-145, 2005. 45. Hyngstrom JR, Chiang YJ, Cromwell KD, et al. Prospective assessment of lymphedema incidence and lymphedema-associated symptoms following lymph node surgery for melanoma. Melanoma Res 23:290-297, 2013. 46. Webster K, Cella D, Yost K. The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System: properties, applications, and interpretation. Health Qual Life Outcomes 1:79, 2003. 47. Fayers P, Bottomley A; EORTC Quality of Life Group; Quality of Life Unit. Quality of life research within the EORTC–the EORTC QLQ-C30. European Organisation for Research and Treatment of Cancer. Eur J Cancer 38(Suppl 4):S125-S133, 2002. 48. Groenvold M, Klee MC, Sprangers MA, et al. Validation of the EORTC QLQ-C30 quality of life questionnaire through combined qualitative and quantitative assessment of patient-observer agreement. J Clin Epidemiol 50:441-450, 1997. 49. Bifulco G, De Rosa N, Tornesello ML, et al. Quality of life, lifestyle behavior and employment experience: a comparison between young and midlife survivors of gynecology early stage cancers. Gynecol Oncol 124:444-451, 2012. 50. de Vries M, Hoekstra HJ, Hoekstra-Weebers JE. Quality of life after axillary or groin sentinel lymph node biopsy, with or without completion lymph node dissection, in patients with cutaneous melanoma. Ann Surg Oncol 16:2840-2847, 2009. 51. Brouns E, Donceel P, Stas M. Quality of life and disability after ilioinguinal lymphadenectomy. Acta Chir Belg 108:685-690, 2008. 52. Katz E, Dugan NL, Cohn JC, et al. Weight lifting in patients with lower-extremity lymphedema secondary to cancer: a pilot and feasibility study. Arch Phys Med Rehabil 91:1070-1076, 2010. 53. Kim SJ, Park YD. Effects of complex decongestive physiotherapy on the oedema and the quality of life of lower unilateral lymphoedema following treatment for gynecological cancer. Eur J Cancer Care (Engl) 17:463-468, 2008. 54. Dunberger G, Lindquist H, Waldenström AC, et al. Lower limb lymphedema in gynecological cancer survivors—effect on daily life functioning. Support Care Cancer 21:3063-3070, 2013. 55. Chachaj A, Malyszczak K, Pyszel K, et al. Physical and psychological impairments of women with upper limb lymphedema following breast cancer treatment. Psychooncology 19:299-305, 2010. 56. Olivieri JM, Day JM, Alfano CM, et al. Arm/hand swelling and perceived functioning among breast cancer survivors 12 years post-diagnosis: CALGB 79804. J Cancer Surviv 2:233-242, 2008.

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57. Radina ME, Armer JM, Stewart BR. Making self-care a priority for women at risk of breast cancerrelated lymphedema. J Fam Nurs 20:226-249, 2014. 58. Bernas M, Askew RL, Armer J, et al. Lymphedema: how do we diagnose and reduce the risk of this dreaded complication of breast cancer treatment? Curr Breast Cancer Rep 2:53-58, 2010. 59. Hulett JM, Armer JM, Stewart BR, et al. Navigating the extended survivorship continuum: breast cancer survivors’ perspectives from diagnosis through 84-months post-treatment. Presented at the Twentyfourth Congress of the International Society of Lymphology, Rome, Italy, Sept 2013. 60. Witek-Janusek L, Gabram S, Mathews HL. Psychologic stress, reduced NK cell activity, and cytokine dysregulation in women experiencing diagnostic breast biopsy. Psychoneuroendocrinology 32:22-35, 2007. 61. Disa JJ, Petrek J. Rehabilitation after treatment for cancer of the breast. In DeVita VT Jr, Hellman S, Rosenberg SA, eds. Principles and Practice of Oncology, ed 7. Philadelphia: Lippincott Williams & Wilkins, 2005. 62. Ridner SH, Dietrich MS, Kidd N. Breast cancer treatment-related lymphedema self-care: education, practices, symptoms, and quality of life. Support Care Cancer 19:631-637, 2011. 63. Battaglini C, Dennehy C, Groff D, et al. Complementary therapies in the management of cancer treatment-related symptoms: the individualized prescriptive exercise intervention approach. Medicina Sportiva 10:49-57, 2006. 64. Radina ME. Breast cancer‐related lymphedema: implications for family leisure participation. Fam Relat 58:445-459, 2009. 65. Ridner SH. Quality of life and a symptom cluster associated with breast cancer treatment-related lymphedema. Support Care Cancer 13:904-911, 2005. 66. Togawa K, Sullivan-Halley J, Ma H, et al. Symptoms of arm lymphedema and its effects on healthrelated quality of life among disease-free female breast cancer survivors. Ann Epidemiol 23:585, 2013. 67. Ridner SH, Fu MR, Wanchai A, et al. Self-management of lymphedema: a systematic review of the literature from 2004 to 2011. Nurs Res 61:291-299, 2012. 68. Casley-Smith JR, Casley-Smith JR. Modern treatment of lymphoedema. Mod Med Australia 35:70-83, 1992. 69. Rourke LL, Hunt KK, Cormier JN. Breast cancer and lymphedema: a current overview for the healthcare provider. Womens Health (Lond Engl) 6:399-406, 2010. 70. Fu MR. Cancer survivors’ views of lymphoedema management. J Lymphoedema 5:39-48, 2010. 71. Stout NL, Pfalzer LA, Springer B, et al. Breast cancer-related lymphedema: comparing direct costs of a prospective surveillance model and a traditional model of care. Phys Ther 92:152-163, 2012. 72. Wanchai A, Stewart BR, Armer JM. Experiences and management of breast cancer-related lymphoedema: a comparison between South Africa and the United States of America. Int Nurs Rev 59:117-124, 2012. 73. Johnstone B, Yoon DP. Relationships between the brief multidimensional measurement of religiousness/spirituality and health outcomes for a heterogeneous rehabilitation population. Rehabil Psychol 54:422-431, 2009. 74. Vespa A, Jacobsen PB, Spazzafumo L, et al. Evaluation of intrapsychic factors, coping styles, and spirituality of patients affected by tumors. Psychooncology 20:5-11, 2011. 75. Fu MR. Breast cancer survivors’ intentions of managing lymphedema. Cancer Nurs 28:446-457; quiz 458-459, 2005. 76. Levin J. How faith heals: a theoretical model. Explore (NY) 5:77-96, 2009. 77. Johnstone B, Yoon DP, Cohen D, et al. Relationships among spirituality, religious practices, personality factors, and health for five different faith traditions. J Relig Health 51:1017-1041, 2012. 78. McNeely ML, Peddle CJ, Yurick JL, et al. Conservative and dietary interventions for cancer-related lymphedema: a systematic review and meta-analysis. Cancer 117:1136-1148, 2011. 79. Schmitz KH, Stout NL, Andrews K, et al. Prospective evaluation of physical rehabilitation needs in breast cancer survivors: a call to action. Cancer 118(8 Suppl):2187-2190, 2012.

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80. Stout NL, Binkley JM, Schmitz KH, et al. A prospective surveillance model for rehabilitation for women with breast cancer. Cancer 118(8 Suppl):2191-2200, 2012. 81. Lymphoedema Framework. Best practice for the management of lymphoedema. International consensus, 2006. Available at www.woundsinternational.com/pdf/content_175.pdf. 82. Shaw C, Mortimer P, Judd P. A randomized controlled trial of weight reduction as a treatment for breast cancer-related lymphedema. Cancer 110:1868-1874, 2007. 83. Gerber LH, Stout NL, Schmitz KH, et al. Integrating a prospective surveillance model for rehabilitation into breast cancer survivorship care. Cancer 118(8 Suppl):2201-2206, 2012. 84. American College of Surgeons. National accreditation program for breast centers. Available at www. facs.org/quality-programs/napbc. 85. Schmitz KH, Stout NL, Andrews K, et al. Prospective evaluation of physical rehabilitation needs in breast cancer survivors: a call to action. Cancer 118(8 Suppl):2187-2190, 2012. 86. Schmitz KH, Ahmed RL, Troxel AB, et al. Weight lifting for women at risk for breast cancer-related lymphedema: a randomized trial. JAMA 304:2699-2705, 2010. 87. Kwan ML, Cohn JC, Armer JM, et al. Exercise in patients with lymphedema: a systematic review of the contemporary literature. J Cancer Surviv 5:320-336, 2011. 88. Wanchai A, Armer JM, Stewart BR. Performance care practices in complementary and alternative medicine by Thai breast cancer survivors: an ethnonursing study. Nurs Health Sci 14:339-344, 2012. 89. de Valois BA, Young TE, Melsome E. Assessing the feasibility of using acupuncture and moxibustion to improve quality of life for cancer survivors with upper body lymphoedema. Eur J Oncol Nurs 16:301309, 2012. 90. Douglass J, Immink M, Piller N, et al. Yoga for women with breast cancer-related lymphoedema: a preliminary 6-month study. J Lymphoedema 7:30-38, 2012. 91. Matchim Y, Armer JM, Stewart BR. Effects of mindfulness-based stress reduction (MBSR) on health among breast cancer survivors. West J Nurs Res 33:996-1016, 2011. 92. Sherman KA, Koelmeyer L. Psychosocial predictors of adherence to lymphedema risk minimization guidelines among women with breast cancer. Psychooncology 22:1120-1126, 2013.

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C hapter 3 Quality of Life Measurement Instruments Vaughan Keeley

Qu

K ey P oints • Quality of life assessment tools have emphasized the impact of lymphedema on people’s lives. • These tools have also shown the benefits of treatment. • Validated condition-specific tools for lymphedema are available. • It is recommended that these tools be used in clinical practice and research.

In many countries, lymphedema is an underrecognized condition that is not seen as a priority by health care providers. It is often believed that lymphedema is solely related to cancer treatment, that it is rare, that it causes little in the way of morbidity, that it does not reduce life expectancy, and that there is no successful treatment for it. During recent years, growing evidence has shown that these beliefs are false. There is a greater understanding of the breadth of the problem beyond its association with cancer. This understanding includes the idea that lymphedema is more common than previously thought and causes significant morbidity among a population with an increasing life expectancy. In addition, there are a growing number of treatments that may improve lymphedema symptoms. Fundamental to this improved understanding has been research into the impact of lymphedema on an individual’s quality of life (QOL) and the improvement of QOL with treatment. This chapter will look at the QOL assessment tools available for patients with lymphedema and some of the challenges associated with the use and interpretation of these tools.

Quality of Life: Definition and Measurement Tools Defining QOL can be challenging. Every individual will have his or her own view about what constitutes a “good” QOL, and this may vary over time. Cultural and social backgrounds, age, and expectations will all influence this view. However, in the context of health-related QOL, the following components are usually considered most important1: • Physical health (symptoms and signs of illness) • Physical functioning (the ability to carry out daily activities) 41

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• Social health (maintaining social relationships) • Social functioning (the ability to carry out social activities) • Psychological well-being (for example, the absence of psychological distress and anxiety) • Emotional well-being (for example, life satisfaction and coping skills) More information about these components and their relationship with lymphedema can be found in Chapter 2. The World Health Organization has developed an International Classification of Functioning, Disability and Health (ICF).2 This tool aims to describe and measure health and disability, and it is particularly relevant to individuals with chronic conditions such as lymphedema. A common international approach enables the comparison of the effects of lymphedema among affected individuals in different countries, and it also allows for comparison with other conditions. The impact of a condition on an individual’s QOL can be assessed in a number of ways. Qualitative methods such as structured interviews of individuals or focus groups can be used to derive common themes that affect people with particular conditions. For example, in a study of women with lower limb lymphedema after surgery for gynecologic cancers, such themes included impact on body image and mobility and shock related to the permanence and severity of the problem.3 Quantitative methods usually involve the use of a specific QOL measurement tool in the form of a questionnaire completed by a patient. Qualitative methods such as those described previously may be used in the development of such quantitative tools to ensure their validity. Quantitative methods have the advantage of producing scores that can then be combined to describe QOL in certain populations and to show changes in scores as a result of treatment. Most QOL tools have a number of response options that represent degrees of severity. These may be divided into categories by descriptive terms or scored numerically via a visual analog scale (for example, pain can be graded on a scale of “None” to “Severe” or 0 to 10). The process of the development and validation of QOL tools should ensure that they provide meaningful results, which are discussed later in this chapter. However, most QOL life tools do not incorporate a method of “weighting” individual items and therefore can be criticized for not always accurately reflecting what matters most to a particular patient. For example, for one person, the ability to function independently may be the most important factor; for another, it may be the impact of lymphedema on body image that is of most concern. Some QOL tools, such as the Schedule for the Evaluation of Individual Quality of Life (SEIQOLDW),4 have been specifically designed to allow patients to prioritize the QOL aspects that are most important to them. Patients then rate their level of satisfaction or functioning against each of the nominated areas and indicate the relative contribution of each to their overall QOL. Similarly, the Measure Yourself Medical Outcome Profile (MYMOP) is a tool that allows patients to designate their most important symptoms, which can then be scored and reassessed after treatment to measure the outcome of an intervention.5 MYMOP also incorporates measures of selfselected physical, social, and mental activities and a general feeling of well-being.

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Health-related QOL tools can be general (applicable to health in general and a variety of specific conditions) or condition specific (designed to measure the impact of a particular condition). Most QOL tools cover a number of domains; these are sections that encompass common themes, such as physical health, physical and social functioning, and emotional and psychological health. Usually these domains are scored separately, and then a combined score reflects overall QOL. For patients with lymphedema, general health-related QOL scores have been used in several studies, but these may not be as accurate or informative as condition-specific tools, which have been developed more recently.6

Use of Quality of Life Tools Health-related QOL tools, including those that assess the effects of lymphedema, can be used in both clinical practice and research settings. In clinical practice, a QOL tool may facilitate the initial assessment of an individual with lymphedema by demonstrating the impact of the condition on that individual. This can then aid in the planning of treatment. If repeated measures are used, they may be able to demonstrate the effect of treatment for the individual. The combining of such outcomes of treatment for individuals seen by a lymphedema service allows QOL tools to be used in a clinical audit to demonstrate service outcomes. However, it is important that these outcomes be combined with other measures such as limb volume, some understanding of the type and severity of the lymphedema or chronic edema, the comorbidities experienced by the patient, and other environmental factors so that a realistic appraisal can be made. For example, the outcomes of treating early lymphedema related to breast cancer in otherwise healthy individuals are likely to be better than those obtained when treating complex leg edema in immobile elderly patients who may have other comorbidities and who do not have access to caretakers who will help them to put on and take off compression garments. In research, QOL tools can be used to measure the impact of lymphedema in a population, and this can help to determine the health needs of that population. These tools can also be used to assess the impact of new treatments in clinical trials. In this type of setting, QOL tools are usually combined with other outcome measures (for example, a reduction in limb volume) to obtain a more detailed assessment. QOL tools can also be used to facilitate the making of economic decisions about investments in health care. For example, these tools are used by the National Institute for Clinical Excellence in the United Kingdom. The method of cost-utility analysis involves the use of measured outcomes to create a score of health that is derived from a combination of the duration of life and an index of the patient’s health state (in other words, the patient’s QOL). The EuroQOL-5D7 is a five-item score of an individual’s health state that can be expressed on a continuum from 0.0 (death) to 1.0 (perfect health). These values are called “utilities,” and they can be combined with the length of life to give a single index known as the quality-adjusted life year (QALY). For example, living 1 year with a utility of 1.0 (perfect health) would equate to 1 QALY; living 2 years with a health utility of 0.5 would also equate to 1 QALY. Cost-utility analysis involves the use of this concept but attaches a financial cost per QALY. Thus QALYs constitute a single outcome measure that can be costed, and comparisons can be made among different treatments for a particular condition

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and to assess the costs of treating different conditions. This enables decisions to be made about whether to invest in certain treatments.8

Quality of Life Tools: Validation Process QOL tools to be used in research and clinical practice should undergo a robust validation process. Although methodologies may vary to some extent in different publications, there are some standard themes that are usually addressed during this process: • Validity: Is the tool measuring what it was designed to measure? • Reliability: Does the tool produce similar results under different conditions? Are results repeatable? • Responsiveness: Does the tool detect significant changes after an intervention? The details of relevant methodologies can be found in the literature that describes the validation of individual tools.9-13 There are also consensus guidelines produced by the COSMIN initiative, which seeks to improve health measurement instruments.14

Quality of Life Measures Used in Lymphedema Studies The Short Form (36) Health Survey (SF-36) has been the most commonly used QOL assessment tool, and one study has suggested that it is the most appropriate tool to use for patients who have lower limb lymphedema.15 However, this study took place before the development of most of the lymphedema-specific tools, which are described later in this chapter. The SF-36 covers eight subscales: 1. Vitality 2. Physical functioning 3. Bodily pain 4. General health perceptions 5. Physical role functioning 6. Emotional role functioning 7. Social role functioning 8. Mental health A score of 0 on this scale represents the worst possible level of health, and a score of 100 represents the best possible health. Other general QOL tools that have been used in studies of lymphedema include the following: • SF-36 Medical Outcome Study-Short Form (36 items)16 • Nottingham Health Profile Part 1 (38 items)17 • The EuroQOL Group’s EuroQOL-5D (5 items)7 • The World Health Organization Disability Assessment Scale (WHODAS) based on the ICF described previously (12- and 36-item versions)18

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TABLE 3-1  Examples of Generic and Cancer-Related Quality of Life Tools Used in Lymphedema Studies Quality of Life Tool

Patient Group

Number

Results

SF-3620

Chronic edema (arm and leg)

228

Reduced QOL in patients with chronic edema compared with normative data

SF-3621

Breast cancer–related lymphedema

53

QOL improved as limb volume reduced with treatment

SF-36 and EuroQOL-5D15

Lower limb lymphedema

164

SF-36 was the most appropriate tool to use for patients with lymphedema

Nottingham Health Profile Part 117

Chronic edema (arm and leg)

34

Score improved after treatment

EORTC QLQ-C30, EORTC QLQ-BR23, and WHODAS2

Breast cancer­–related lymphedema and breast cancer

283

Patients with breast cancer–related lymphedema had higher overall disability

FACT-B 1 423

Breast cancer–related lymphedema

128 (64 with breast cancer–related lymphedema)

Poorer QOL found among patients with breast cancer–related lymphedema; also used the Upper Limb Lymph­edema 27 tool and the Wesley Clinic Lymphedema Scale to assess these patients

Cancer-Specific Quality of Life Tools Much research regarding lymphedema has focused specifically on lymphedema related to cancer and particularly to breast cancer. As a result, a number of cancer-specific QOL tools have been used in studies of lymphedema related to breast cancer treatment (Table 3-1). These tools can be used together to evaluate a specific aspect of treatment, as follows: • The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, with 30 core items (EORTC QLQ-C30), plus the breast cancer supplement, with 23 items (EORTC QLQ-BR23) (see Chapter 2) • The Functional Assessment of Cancer Therapy-Breast Cancer, with 36 items (FACT-B), plus the FACT-B 1 4, which includes an additional four items to address issues such as arm swelling19 • The Psychosocial Adjustment to Illness Scale (PAIS) (see Chapter 2)

Condition-Specific Quality of Life Tools for Lymphedema During recent years, a number of condition-specific QOL tools for patients with lymphedema have been developed (Table 3-2). Some have been fully validated, whereas others have been used without any formal published validation. Some are designed to be used with all types of lymphedema, whereas others are specific for arm, leg, or other types of lymphedema.

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TABLE 3-2  Condition-Specific Quality of Life Tools for Patients With Lymphedema Number of Items

Validation Published?

Language(s)

Breast cancer– related lymphedema

5

No

English

Arm lymphedema

27

2000

French and Dutch

Quality of Life Tool

Condition

Wesley Clinic Lymphedema Scale (WCLS)24 Upper Limb Lymphedema 27 (ULL-27)25

This is validated for the assessment of QOL in patients with arm lymphedema.

Unnamed26

Peripheral lymphedema

17

No

English

Freiburg Life Quality AssessmentLymphedema (FLQA-L)9

Lymphedema

92

2005

German

Lymphedema Quality of Life Study (LYMQOL)10

Lymphedema Quality of Life Inventory (LQOLI)11

This questionnaire covers both arm and leg lymphedema and has been validated in 392 patients with primary and secondary lymphedema. It covers a number of domains: physical status, everyday life, social life, emotional well-being, treatment satisfaction, and professional/household. A shortened version of this questionnaire (the FLQA-LK, with 33 items) has been used in published studies, but no specific details regarding its validation were found in the literature.27 Arm and leg lymphedema

Arm, 33; leg, 34

2010

English and Japanese

This consists of two separate questionnaires: one for patients with arm edema and one for patients with leg edema. It covers four domains: physical symptoms, functional aspects, mood, and body image. It also includes a general QOL question. Since the publication of its validation in English, it has been translated and validated in Japanese,28 and it has also been translated into other languages. It has been used in clinical settings as part of routine assessment, and it has also been used in audit and research settings as an outcome measure. There are a few published examples of its use.29,30 It has been used in 12 countries, including some within Europe, the United States, Australia, New Zealand, and Japan. Lymphedema, all types

58 (each with three subitems)

2010

Swedish and English

This tool was originally developed in Australia. It was later translated into Swedish, and its validation was published in Sweden. It covers four domains: physical, emotional, social, and practical. It also covers all types of lymphedema, not just that related to the extremities.

Lymphedema Functioning, Disability and Health Questionnaire (Lymph-ICF)12

Breast cancer– related lymphedema

29

2011

Dutch and English

Lymphedema Functioning, Disability and Health Questionnaire for Lower Limb Lymphedema (Lymph-ICF-LL)13

Lower limb lymphedema

28

2014

Dutch and English

These two tools are linked to the World Health Organization’s International Classification of Functioning, Disability and Health. They cover five domains: physical function, mental function, general tasks and household activities, mobility activities, and life domains and social life. There are separate questionnaires for breast cancer–related lymphedema and leg lymphedema. These tools were developed in Dutch then later translated into English.

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Issues to Consider When Using Quality of Life Tools Comorbidity Many lymphedema clinics are now seeing patients with more complex edema of mixed causes. Among elderly patients in particular there may be significant comorbidities, such as diabetes, neurologic problems, and respiratory and cardiac conditions. These can all affect QOL, and it is often quite difficult to separate the impact of edema from other factors. For example, if a patient with a neurologic condition and limb weakness develops edema in the affected limb, the limb weakness may not improve significantly even if the edema is completely resolved with treatment.

Midline Lymphedema Many of the condition-specific QOL tools have been developed for arm and leg lymphedema and have not addressed midline edema, such as that involving the genitals, the breasts, and the head and neck. Although some tools may be used in these settings (for example, the LQOLI), there are clear functional and body image issues that may differ from those related to limb lymphedema.

The Age of the Patient All of the condition-specific QOL tools described here have been validated for adults. There is no specific lymphedema QOL tool for children.

Minimum Clinically Important Difference When using QOL tools to assess the outcomes of treatment, particularly in clinical trials, the concept of a minimum clinically important difference needs to be considered. It is possible that consistent small changes in QOL after treatment may be statistically significant. However, the question arises as to whether these changes are large enough to be of clinical importance to the patient. Ways of developing minimum clinically important differences for QOL tools have been developed but have not yet been applied to the condition-specific QOL tools for lymphedema.31

Language Translation In an ideal situation, if a QOL tool is translated into another language, it should be revalidated in that language. However, this is not always easy, and it can be very time consuming. Methods do exist for rigorous translation to ensure that meaning is not altered.32 However, cultural differences may mean that some of the items used in a particular QOL tool will not be easily transferable to other languages and cultures.

Floor and Ceiling Effects If a patient starts with a higher QOL score, there may be little room for further improvement with treatment (ceiling effect). Conversely, if he or she starts with a low QOL score, treatment can result in a large change in score (floor effect). Therefore the range of pretreatment QOL scores needs to be taken into account when assessing the effect of an intervention.

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Length of Questionnaire and Frequency of Use A long questionnaire or a tool that needs to be used too frequently to monitor outcomes can deter patients from compliance. Consideration should be given to both of these aspects, particularly when administering a tool to elderly patients with significant comorbidities.

Conclusion During recent years, an increasing number of condition-specific QOL tools have become available for use by patients with lymphedema. It is important that these tools are used both clinically and in research studies to strengthen the evidence of the impact of lymphedema on patient QOL and the improvement of QOL with successful treatment.

C linical P earls • The following components are usually considered most important when assessing health-related QOL: physical health, physical functioning, social health, social functioning, psychological well-being, and emotional wellbeing. • Health-related QOL tools can be general (applicable to health in general and a variety of specific conditions) or condition specific (designed to measure the impact of a particular condition). • In clinical practice, a QOL tool may facilitate the initial assessment of an individual with lymphedema by demonstrating the impact of the condition on that individual. In research, QOL tools can be used to measure the impact of lymphedema in a population, and this can help to determine the health needs of that population. QOL tools can also be used to facilitate the making of economic decisions about investments in health care. • QOL tools to be used in research and clinical practice should undergo a robust validation process. • It is important that QOL tools be used both clinically and in research studies to strengthen the evidence of the impact of lymphedema on patient QOL and the improvement of QOL with successful treatment.

R EFERENCES 1. Bowling A. Research Methods in Health: Investigating Health and Health Services, ed 1. Philadelphia: Open University Press, 1997. 2. World Health Organization. International Classification of Functioning, Disability and Health (ICF), 2014. Available at www.who.int/classifications/icf/en/. 3. Ryan M, Stainton MC, Jaconelli C, et al. The experience of lower limb lymphedema for women after treatment for gynecologic cancer. Oncol Nurs Forum 30:417-423, 2003. 4. Hickey AM, Bury G, O’Boyle CA, et al. A new short form individual quality of life measure (SEIQOLDW): application in a cohort of individuals with HIV/AIDS. BMJ 313:29-33, 1996. 5. University of Bristol, Centre for Academic Primary Care. Welcome to MYMOP. Available at www. bristol.ac.uk/primaryhealthcare/resources/mymop.

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6. Morgan PA, Franks PJ, Moffatt CJ. Health-related quality of life with lymphoedema: a review of the literature. Int Wound J 2:47-62, 2005. 7. EuroQOL Group. EuroQOL—a new facility for the measurement of health-related quality of life. Health Policy 16:199-208, 1990. 8. Keeley V, Franks PJ. Evaluating a lymphoedema service. Lymphoedema Framework. Template for Management: Developing a Lymphoedema Service. London: MEP Ltd, 2007. 9. Augustin M, Bross F, Földi E, et al. Development, validation and clinical use of the FLQA-1, a diseasespecific quality of life questionnaire for patients with lymphedema. VASA 34:31-35, 2005. 10. Keeley V, Crooks S, Locke J, et al. Quality of life measure for limb lymphoedema (LYMQOL). J Lymphoedema 5:26-37, 2010. 11. Klernäs P, Kristjanson LJ, Johansson K. Assessment of quality of life in lymphedema patients: validity and reliability of the Swedish version of the Lymphedema Quality of Life Inventory (LQOLI). Lymphology 43:135-145, 2010. 12. Devoogdt N, Van Kampen M, Geraerts I, et al. Lymphoedema Functioning, Disability and Health questionnaire (Lymph-ICF): reliability and validity. Phys Ther 91:944-957, 2011. 13. Devoogdt N, De Groef A, Hendrickx AD, et al. Lymphedema Functioning, Disability and Health Questionnaire for Lower Limb Lymphoedema (Lymph-ICF-LL): reliability and validity. Phys Ther 94:705721, 2014. 14. COSMIN. The COSMIN checklist. Available at www.cosmin.nl/the-cosmin-checklist_8_5.html. 15. Franks PJ, Moffatt CJ, Doherty DC, et al. Assessment of health-related quality of life in patients with lymphedema of the lower limb. Wound Repair Regen 14:110-118, 2006. 16. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36) I. Conceptual framework and item selection. Med Care 30:473-483, 1992. 17. Sitzia J, Sobrido L. Measurement of health-related quality of life of patients receiving conservative treatment for limb lymphoedema using the Nottingham Health Profile. Qual Life Res 6:373-384, 1997. 18. World Health Organization. WHO Disability Assessment Schedule 2.0 (WHODAS 2.0), 2014. Available at www.who.int/classifications/icf/whodasii/en/. 19. Coster S, Poole K, Fallowfield LJ. The validation of a quality of life scale to assess the impact of arm morbidity in breast cancer patients post-operatively. Breast Cancer Res Treat 68:273-282, 2001. 20. Moffatt CJ, Franks PJ, Doherty DC, et al. Lymphoedema: an underestimated health problem. QJM 96:731-738, 2003. 21. Kim SJ, Yi CH, Kwon OY. Effect of complex decongestive therapy on edema and the quality of life in breast cancer patients with unilateral lymphedema. Lymphology 40:143-151, 2007. 22. Pyszel A, Malyszczak K, Pyszel K, et al. Disability, psychological distress and quality of life in breast cancer survivors with arm lymphedema. Lymphology 39:185-192, 2006. 23. Ridner SH. Quality of life and a symptom cluster associated with breast cancer treatment-related lymphedema. Support Care Cancer 13:904-911, 2005. 24. Mirolo BR, Bunce IH, Chapman M, et al. Psychological benefits of postmastectomy lymphedema therapy. Cancer Nurs 18:197-205, 1995. 25. Launois R, Alliott F. Quality of life scale in upper limb lymphoedema—a validation study. Lymphology 33:266-274, 2000. 26. Weiss JM, Spray BJ. The effect of complete decongestive therapy on the quality of life of patients with peripheral lymphedema. Lymphology 35:46-58, 2002. 27. Blome C, Augustin M, Heyer K, et al. Evaluation of patient-relevant outcomes of lymphedema and lip­ edema treatment: development and validation of a new benefit tool. Eur J Vasc Endovasc Surg 47:100107, 2014. 28. Takeuchi M. Development of a quality of life measure for limb lymphoedema (LYMQOL), Japanese version. Abstract from the International Lymphoedema Framework Conference, Montpellier, France, June 2012.

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2 9. Hardy D. Management of a patient with secondary lymphedema. Cancer Nurs Pract 11:21-26, 2012. 30. Jeffs E, Wiseman T. Randomised controlled trial to determine the benefit of daily home-based exercise in addition to self-care in the management of breast cancer-related lymphoedema: a feasibility study. Support Care Cancer 21:1013-1023, 2013. 31. Hays RD, Woolley JM. The concept of clinically meaningful difference in health-related quality of life research. How meaningful is it? Pharmacoeconomics 18:419-423, 2000. 32. Piault E, Doshi S, Brandt BA, et al. Linguistic validation of translation of the Self-Assessment Goal Achievement (SAGA) questionnaire from English. Health Qual Life Outcomes 10:40, 2012.

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Part II

Anatomy, Physiology, and Lymphangiogenesis

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C hapter 4 Embryology Sandro Michelini, Miguel Amore, Lucia Tapia, Gisela Romina Pattarone, Diego Mercado, Jeremy S. Torrisi, Ira L. Savetsky, Jason C. Gardenier, Babak J. Mehrara

K ey P oints • The lymphatic system has several critical roles, including transporting tissue fluids and plasma protein back to the bloodstream and providing major pathways for the spread of metastatic tumor cells. • The development of the lymphatic vasculature is a stepwise process requiring the specification of lymphatic endothelial cell progenitors from the embryonic veins. • The embryology of the vascular and lymphatic systems during gestation must be considered collectively because they are interconnected.

A

Em

The lymphatic system transports tissue fluids and extravasated plasma proteins back to the bloodstream and absorbs lipids from the intestinal tract. The lymphatic system also plays a crucial role in immune response and is one of the main routes for the metastatic spread of tumor cells. The developmental origin of the lymphatic system remained unclear until the first years of the twentieth century, when Sabine proposed (after extensive ink injection experiments in pig embryos) that the jugular sacs arose from the anterior cardinal vein. Recent analyses of targeted gene deletions and genetic lineage tracing studies in mice have confirmed Sabine’s models.1

Overview of the Lymphatic System The lymphatic system is the third vascular system. A major function of the lymphatic vasculature is to transport extracellular fluid back to the cardiovascular system. When blood enters a capillary bed, high hydrostatic pressure on the arterial side of the capillary causes plasma to leak into the interstitial space. On the venous side of the capillary bed, the inward pull of the blood’s high osmotic pressure exceeds the outward push of its hydrostatic pressure, causing the previously filtered fluid 53

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Right jugular trunk Right lymphatic duct Right subclavian trunk Right subclavian vein Right bronchomediastinal trunk

Left jugular trunk Left subclavian trunk Left subclavian vein Left bronchomediastinal trunk Thoracic duct

Cisterna chyli Lumbar trunks

Intestinal trunk

To right lymphatic duct To thoracic duct

FIG. 4-1  The lymphatic system of the upper extremity network of capillaries and collecting lymphatics. General pattern of lymph drainage to the right lymphatic and thoracic ducts.

to rush back into the capillary bed and reenter the systemic circulation. This system allows 90% of the filtered fluid to reenter the circulation; the remaining 10% is returned to the systemic circulation by the lymphatic system through a series of successively larger lymphatic vessels. Lymph is a fluid that is similar in composition to plasma but contains leukocytes and higher concentrations of macromolecules, such as proteins and lipids. Lymph enters the lymphatic system through lymphatic capillaries that are located near blood capillaries and is subsequently transferred to larger lymphatics, which are known as collecting lymphatic vessels (Figs. 4-1 and 4-2). These collecting lymphatic vessels then transfer the lymph unidirectionally toward the chest. Collecting lymphatics from the left side of the body, the abdomen, and from both legs drain lymph into the thoracic duct, which then drains the lymph into the left subclavian vein. Lymph from the right side of the body, head, and thorax drains into the right subclavian vein after it first drains into

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Chapter 4  Embryology

Lymphatic capillary plexus Skin

Epidermis Dermis

Lymphatic precollector vessel Superficial lymphatic collector vessel (afferent) Superficial lymph node

Subcutaneous tissue

Lymphatic collector vessel (efferent)

Deep fascia

Subfascial layer

To venous system and systemic circulation

Muscle

Perforating vessel

Deep lymphatic collector vessel

Deep lymph node

FIG. 4-2  Structure of the superficial and deep lymphatic system.

50 mm

FIG. 4-3  Capillary (red arrows) and collecting lymphatic (white arrow) vessels in a mouse hindlimb. Note the layer of smooth muscle cells on the collecting lymphatic vessel. (LYVE, Lymphatic vessel endothelial hyaluronan receptor; aSMA, alpha-smooth muscle actin; DAPI, 49, 6-diamidino-2 phenylindole.)

the right lymphatic duct. On entering the subclavian veins by way of lymphaticovenous anastomoses, the lymph is drained back into the venous system and returned to the systemic circulation. Lymphatic capillaries are thin-walled vessels that are composed of a single layer of lymphatic endothelial cells (LECs). These tiny vessels are only 30 to 80 mm in diameter, are not surrounded by pericytes or smooth muscles cells, and usually lack a basement membrane (Fig. 4-3). Lymphatic capillaries are discontinuous and contain gaps that make them highly permeable. This allows macromolecules and leukocytes to easily enter the vasculature. As lymph transits through the lymphatic capillaries, the fluid moves into precollector vessels. Unlike the capillaries, these vessels have some incomplete coverage by smooth muscle cells. The fluid then moves from precollector vessels to collecting lymphatics, which are larger vessels covered by smooth muscle cells that contain a basement membrane (see Fig. 4-3).

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FIG. 4-4  Collecting lymphatic vessel in a mouse hindlimb cut in a longitudinal section. Note the valve in the lymphatic vessel (black arrow).

Efferent vessels

Blood supply Hilum

Medullary sinus Marginal sinus Primary follicle

Valve

Secondary follicle with germinal center

Capsule

Trabecula

Afferent vessels

FIG. 4-5  Anatomy of a lymph node, showing afferent and efferent lymphatic vessels.

In addition, collecting lymphatics contain valves that maintain unidirectional flow (Fig. 4-4). Unlike the blood in the cardiovascular system, the lymph in the lymphatic system is not propelled forward by the heart. Instead, lymphatic fluid is moved by the relatively weak intrinsic pulsation of its smooth muscles cells in the lymphatic collectors. This force is greatly augmented by skeletal muscular contraction during periods of physical activity. As lymph travels from lymphatic capillaries back to the venous circulation, the lymph is filtered in the lymph nodes (Fig. 4-5). Lymphatic fluid enters the lymph node through afferent lymphatic vessels that drain into the subcapsular sinus and leaves the lymph node through efferent lymphatics located in the medulla. A typical adult human has 600 to 700 lymph nodes, which have various

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functions. For example, lymph nodes filter out waste products found in the lymph entering from the afferent lymphatic vessel. In addition, lymph nodes provide an environment for leukocytes to interact with activated antigen-presenting cells, allowing the creation of immune responses to pathogens (see Chapter 10). This interaction is dependent on lymph node resident cells and migrating leukocytes that enter the lymph node through the high endothelial venules.

Embryology The development of the lymphatic vasculature is a stepwise process that requires the specification of LEC progenitors from the embryonic veins. These veins will give rise to the primitive lymph sacs, from which the entire lymphatic system will be derived (Fig. 4-6).

Embryonic cardinal vein

Cell differentiation Lymphatic endothelial cell progenitors Sprouting and migration

Primary lymph sac

Separation

FIG. 4-6  Stepwise embryonic development of the lymphatic vasculature.

Sprouting Primitive lymphatic vessels Merging, remodeling, maturation, and vessel differentiation Lymphatic capillary plexus

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Lymphatic precollector vessel

Lymphatic collector vessel

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Embryology of the Vascular System The first channels of the vascular system can be seen after the third week of gestation. Vascular development is guided by receptors for growth factors. These first channels develop in three stages: • In stage 1, the undifferentiated stage, there is only a small network of capillaries. • In stage 2, the network-forming stage, plexiform structures are created that increase the system’s volume and extent. • In stage 3, the maturative stage—which occurs in the third week of gestation—the first large arteriosus, venous, and lymphatic ductus vessels stand and develop. Vessel formation—for both vasculogenesis and angiogenesis (the sprouting of blood vessels from preexisting angioblastic cords)—begins on the seventeenth day in the extraembryonic regions with the generation of blood islands in the mesoderm of the yolk sac, embryonic stalk, and chorionic villus. The vascular network expands throughout the embryonic disc, a process that gradually increases the network’s prevalence. By the twenty-fourth day, the yolk sac is connected to the embryo through two veins and three vitelline arteries (the celiac trunk, superior mesenteric artery, and inferior mesenteric artery). The red blood cells begin to circulate. The two allantoic veins and two allantoic arteries (which will become the umbilical cord) pass through the pedicle. A collection of veins, called the common cardinal veins, arise from the edge of the embryo: • Two anterior cardinal veins from the cephalic endpoint • Two posterior cardinal veins from the tail endpoint • Two common cardinal veins, left and right Initially the venous system is symmetrical, but in the second month of gestation, the right component takes over. The inferior vena cava develops from the right vitelline vein, left and right posterior cardinal veins, and superior and inferior cardinal veins. The common cardinal veins, the allantoic and vitelline veins, merge into the venous sinus, which, incorporated into the right atrium, will include the orifices of the superior and inferior vena cava. The superior vena cava develops from the common cardinal vein (right branch).

Embryology of the Lymphatic System The lymphatic system is derived in part from the mesoderm and in part from the mesenchyme, an undifferentiated tissue not yet specialized, which retains the ability to transform into another type of tissue even in adults. The mesenchymal origin of the lymphatic system is evident in the reticular cells, which constitute the frame of the immunocompetent organs, particularly the lymph nodes, which can transform into macrophages. Endothelial cells, which line the inside of the capillaries and lymph vessels, are also able to transform into macrophages. Animal model research has demonstrated that a subpopulation of blood endothelial cells, which sprout from cardinal and peripheral veins, will differentiate into LECs.2 Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) is the earliest known cell marker indicating that LEC competence has been acquired.3

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After most of the LEC progenitors bud off from the veins and migrate into the surrounding mesenchyme, lymph sacs are formed. Six primitive lymph sacs form: • Two jugular sacs, which are equal and symmetrical in cranial position, at the union of the jugular veins and anterior cardinal veins • Two iliac sacs, found at the union of the iliac and posterior cardinal veins • The retroperitoneal sac, which is located on the posterior abdominal wall, at the root of the mesentery • The cisterna chyli, positioned dorsally to the retroperitoneal bag The sacs are connected by lymphatic channels. Both main channels, born independent, are formed by primitive right and left thoracic ducts, and subsequently they join caudally with an anastomotic branch. They combine the jugular bags with the cisterna chyli. The thoracic duct of the adult grows caudally from the distal portions of the primitive thoracic ducts (right and left) and cranially from the left thoracic duct. The right lymphatic duct (large lymphatic right vein) derives from the cranial part of the right thoracic duct. The subclavian, jugular, and bronchomediastinal collector trunks derive from the jugular bags. After the primitive lymphatic vessels are formed, they will further differentiate into larger collecting vessels and smaller capillaries, which are the two predominant types of vessels of the lymphatic vasculature. In the collecting lymphatic vessels, valves form to prevent the backflow of the lymph and separate the lymphatic vessels into functional units called lymphangions. These are surrounded by smooth muscle and contract to actively transport lymph.1,4

Conclusion Clinicians must consider both the vascular and lymphatic systems as a whole and be aware of their interdependence, as seen in their clinical behavior in the adult organism. Remarkable vein malformations, such as the persistence of a marginal vein, can be associated with parallel lymphatic malformations, which must be considered in the clinical management. Lymphangiogenesis continues throughout life, influenced by growth factors and also by specific individual embryonic development of the vascular system.

R EFERENCES 1. Kiefer F, Schulte-Merker S, eds. Developmental Aspect of the Lymphatic Vascular System. Advances in Anatomy, Embryology and Cell Biology, vol 214. Heidelberg: Springer-Verlag Wien, 2014. 2. Okuda KS, Astin JW, Misa JP, et al. LYVE1 expression reveals novel lymphatic vessels and new mechanisms for lymphatic vessel development in zebrafish. Development 139:2381-2391, 2012. 3. Oliver G. Lymphatic vasculature development. Nat Rev Immunol 4:35-45, 2004. 4. Dieter R, Dieter R Jr, Dieter R III, eds. Venous and Lymphatic Diseases. New York: McGraw-Hill, 2011.

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C hapter 5 Changing Concepts in Lymphatic Pathways Wei-Ren Pan

K ey P oints • A rich avalvular lymph capillary network exists in the skin and galea of the scalp, which connects adjacent lymph territories in layers.

A

• The number and diameter of the lymph collectors differ from person to person. • Some lymph collectors drain upward toward the mandible in the anterior neck above the platysma. • The lymphatic drainage patterns of the head and neck are diverse among individuals, and even within each side of the same individual.

Cha

• Knowledge of the anatomy of the human lymphatic system and advances in imaging will help clinically when surgery of any type is anticipated as well as in follow-up scenarios for patients with lymphedema.

The lymphatic system is a vast network of tiny, colorless vessels that facilitate the removal of intracellular metabolic products from the body, provide protection from disease, and are the main route of cancer metastasis, yet remains the least described in the medical literature. Our current knowledge of the lymphatic system is mostly based on investigations that were done in the nineteenth century. However, this knowledge is often discordant with clinical experience. Further, it does not explain clinical anomalies seen with melanoma and breast cancer patients using technologic developments such as lymphoscintigraphy and sentinel node biopsy for early stage cancer treatment. Importantly, it is also well known that cancers can recur at distant sites in the absence of lymph node involvement, suggesting that disseminating cancer cells can access the circulation without traversing lymph nodes. Lymphatic malformations, such as those that occur in primary lymphedemas, and damage or destruction of them cause many pathologic states, including lymphedema. However, with the application of improved knowledge and awareness, as described in this chapter, we may be able to anticipate improved outcomes for our patients. The main leverage point is that of imaging the lymphatic system, perhaps only at first in anticipated high-risk patients, preoperatively and perioperatively, and using that knowledge to vary the process or procedure to minimize lymphatic damage but at the same time not increasing the risk of cancer recurrence. Once this becomes an 61

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established procedure, this imaging could be employed for all patients whose lymphatics are about to be damaged (such as individuals who are about to undergo a surgical or radiologic intervention) or for those who already have a lymphatic malformation or defect.

History of Lymphatic Discovery The accumulation of our knowledge of the lymphatic system was a gradual one, relating mainly to improvements in techniques to help visualize the delicate and mostly transparent lymphatic vessels. Originally, cadaveric dissection and observation were the major techniques. These were used for studies of the parietal and visceral tissues of the body after Aselli identified the lymphatics in a postprandial canine in 1622.1-3 In the following years, the discovery of mercury as an imaging aid, by Nuck in 1692,4 made it possible to map the lymphatics of the body.5-7 However, it was Sappey8 who published the definitive work using mercury injection to identify the fine lymphatic networks, long before the discovery of x-rays. His artistic drawings were based on studies of many subjects and resulted in the production of an overall map of the lymphatic network of the human body. Thereafter different types of injection materials, including dyes, iodine, milk, and radioactive isotopes were substituted for the toxic mercury, and it is these which formed the basic knowledge of the lymphatic system of the body.3,9-11 However, in many ways this was still inadequate; our knowledge of the lymphatic system needed to be updated to explain some of the unexpected findings frequently seen clinically.12-14 In the past decade a series of lymphatic studies in human cadavers have been published by using a new technique with radiopaque materials as the injection medium.15-28 These results might help to clarify some unexpected findings in the clinic. Recent clinical experience in melanoma and breast cancer and the most recent cadaveric results have led to a fundamental reevaluation of the “classic” theory, since the drainage varies from the traditional predictions of Sappey and others in many cases.12,13 Therefore a more precise and eventually an individualized map of the anatomic details of the lymphatic pathways of the human body, especially in the head and neck, can form an important basis for improved clinical management of trauma, infection, lymphedema, and cancer. In the past decade we studied a total of 62 specimens harvested from 27 unembalmed cadavers (12 male and 15 female cadavers), aged between 69 and 98 years (average 86 years).16-28 The investigation commenced at the distal end of each specimen; 0.5 ml of 6% hydrogen peroxide mixed with blue drawing ink (ratio 20:1), or 6% hydrogen peroxide only, was injected into the dermis. The epidermis and dermis were incised carefully and gently under a surgical microscope. The distended lymphatic vessel was identified in the subcutaneous tissue. A 30-gauge needle was then inserted into the vessel, and a radiopaque mixture (lead oxide or barium sulphate, milk powder, and water) was injected into the vessel. If the caliber of the vessel was smaller than 0.2 mm, a glass needle (premade using thin-walled G-100 glass tubes and the Puller PP-830) was used for injection. The specimen was radiographed using a Fuji FCR IP Cassette and a Fuji Computed Radiography Processor to locate the proximal extent of the injection for further cannulation and injection. All vessels were traced, photographed, and radiographed to demonstrate the lymphatic routes from the distal side to the proximal lymph nodes.16-28

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Head and Neck The drainage patterns of the head and neck were found to be different in individual specimens and even asymmetrical between the sides of the same body. The lymph-collecting vessels are dense in the scalp and lateral neck but sparse in the face and anterior and posterior neck areas. Imaging revealed a complete lymphatic map of the integument of the head and neck. The key outcome of these new observations is that the major lymphatic vessels may drain to different lymph nodes, even if they come from the same group. For example, the lymphatics of the parietal region may drain into preauricular, retroauricular, infraauricular, or even internal jugular lymph nodes. Therefore some lymph nodes could be first-tier nodes for one group of vessels but second-, third-, or even fourth-tier nodes for the other vessels. Furthermore, two layers of lymphatic vessels were found in the anterior superficial neck. Importantly, vessels in the head and neck did not always enter the closest lymph nodes but sometimes bypassed them (Figs. 5-1 and 5-2). Lymphatic vessels in the superficial tissue of the head and neck are distributed through the scalp (between the anterior hairline and occipital hairline), the face (between the anterior hairline and

Platysma Groups of lymphatic vessels: Frontal Parietal Occipital Eyelid

Nasal and oral Mental Internodal Anterior cervical (above the platysma)

FIG. 5-1  The lymphatic distribution of the superficial tissues in the head and neck (above the platysma) of one subject. Lymphatic vessels have been color coded to show each group entering their related first-tier lymph nodes.

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Groups of lymphatic vessels: Frontal Parietal Occipital Eyelid Nasal and oral Mental Internodal Anterior cervical Supraclavicular Supratrapezoid

FIG. 5-2  The lymphatic distribution of the superficial tissues in the head and neck (below the platysma). Vessels are color coded to highlight the different groups and lymph nodes.

the inferior board of the mandible), and the neck (below the inferior board of the mandible and occipital hairline) regions.

Scalp Region Our findings in the scalp showed rich avalvular lymph capillaries originating from both the dermis and the galeal layers (Fig. 5-3), where they converged to precollectors and directly drained to the collector. An alternative presentation occurred in which precollectors arose from the lymph capillaries of the dermis, crossed the subcutaneous tissue, and passed other collectors to join a precollector network in the galeal layer. Thus these were named indirect precollectors or bridge precollectors (Figs. 5-4 and 5-5). Measuring an average of 0.25 mm, the collecting lymphatic vessels are dense in the scalp region and run obliquely down to reach their first-tier lymph nodes (Figs. 5-4 and 5-6). Vessels diverged and converged along their course, like the branches of a river. Sometimes they crossed over each other and/or anastomosed with neighboring vessels. During their course, lymph collectors ran caudally in the deep aspect of the subcutaneous tissue, receiving precollectors on the way, and then drained toward their first-tier lymph nodes. The scalp lymphatic vessels include the frontal, parietal, and occipital groups, which are described next.

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A

B Capillary network

Precollecting vessels

Collecting vessel 1 mm

FIG. 5-3  A, Lymph capillary network in the dermis filled with an india ink mixture. B, Lymphatic vessels in the galeal layer filled with the india ink mixture.

Initial lymphatic capillary plexus in galeal layer

Subcutaneous tissue Dermis

Lymphatic precollector vessel

Galea aponeurotica

Lymphatic collector vessels

Ampulla structures

Initial lymphatic capillary plexus in dermis

Ampulla structures

First-tier lymph node

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FIG. 5-4  Basic lymphatic pathway in the scalp. The initial capillary lymphatic network originates from both the dermis and galeal layers to join a precollecting vessel that runs either directly or indirectly a short distance in both layers before forming a collecting vessel in the subcutaneous layer. Along its course, the collecting vessel divides and converges and may form different-shaped lymphatic ampullae before finally reaching the lymph node.

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A

FIG. 5-5  A, The lymph capillary network in the dermis of the scalp filled with a lead oxide mixture. B, The lymph capillary network of the skin is shown with an indirect precollecting lymph vessel that crosses the subcutaneous tissue and runs toward the galea, where it converges with the other precollectors that drain into the lymph-collecting vessel shown. C, The lymphatics are viewed from the galeal layer.

C

B

Indirect precollecting lymph vessel

Collecting lymph vessel

Skin Direct precollecting lymph vessel

Subcutaneous tissue Galeal layer (aponeurosis)

Precollecting lymph vessels

Precollecting vessel arises from the dermis piercing the subcutaneous tissue to the galeal layer

Frontal Group  Here, an average of 4 branches (range 3 to 6) of frontal collecting lymph vessels were found. These vessels course radially toward their first-tier lymph nodes in the deep aspect of the subcutaneous tissue between the superior verge of the eyebrow and the coronal suture. They drained to one or multiple lymph nodes in the preauricular, retroauricular, and deep parotid groups. Occasionally one vessel, arising from the midfrontal region, traveled anteriorly and passed over the forehead, inner canthus, and root of the nose before draining to either the nasolabial or buccinator lymph nodes. Parietal Group  Here an average of 6 branches (but with a wide range of 4 to 12) of parietal collecting lymph vessels were found in each specimen. These vessels traveled radially in the deep aspect of the subcutaneous tissue between the coronal suture and the lambdoid suture. They did not only drain to the retroauricular but also the preauricular lymph nodes, sometimes even the occipital and jugular lymph nodes. Occipital Group  Here an average of 6 (range 4 to 9) occipital collecting lymphatic vessels were found. Vessels traveled radially in the subcutaneous tissue between the lambdoid suture and the posterior hairline. They drained into the superficial, deep occipital, or jugular lymph nodes.

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es ch an r b tal on r F

es ch an r b tal on r F

Preauricular lymph node

Nasolabial lymph node

Retroauricular lymph node etal Pari

tal

n Fro

Parotid lymph nodes

Preauricular lymph nodes Parotid lymph nodes

ches

Buccinator lymph node

Preauricular lymph node

Pari e

es

tal b ranc h

anch al br t e i r Pa

bran

es

ch

n bra

es

Retroauricular lymph node Retroauricular lymph nodes

Lateral internal jugular lymph nodes

Retroauricular lymph nodes

cip ita lb ran c Oc

Occipita

ches al bran Occipit

he s

Preauricular lymph nodes

Deep occipital lymph nodes

es l branch

Deep occipital lymph nodes

Superficial occipital lymph nodes

Superficial occipital lymph nodes Lateral internal jugular lymph node

FIG. 5-6  Lymphangiograms of the head and neck after lymphatic contrast injection. The frontal lymph vessels (top), parietal lymph vessels (middle), occipital lymph vessels (bottom), and related lymph nodes (purple) are highlighted.

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A

B

C

FIG. 5-7  A, Image magnified from the purple boxed area. B, The site of lymphaticovenous anastomoses located in the occipital area (black arrows). It confirms the clinical findings of Wallace et al. C, Drawing of the same area. (Green, Lymphatic vessels; blue, vein.)

Lymphaticovenous Shunt  One lymphaticovenous shunt was found in the occipital region. The efferent lymph vessels of the superficial occipital lymph nodes formed a lymphatic network. From the network two vessels emerged to communicate with a superficial occipital vein in the subcutaneous tissues (Fig. 5-7). This confirmed the clinical findings described by Wallace et al.29

Facial Region Lymphatic vessels in the face were sparse. An average of 4 branches (range 3 to 5) was identified. The average diameter of vessels was 0.3 mm when distended with injectant, but this could be partly artifactual as a result of the vessels being abnormally stretched. Vessels traveled radially from medial to lateral in the deep aspect of the subcutaneous tissue between the eyebrow and the inferior border of the mandible toward their first-tier lymph nodes. Four groups of vessels are described according to their origin (Fig. 5-8): the eyelid group, nasal group, oral group, and mental group. Eyelid Group  The initial lymphatic capillaries arose in the upper and lower eyelids (Fig. 5-9). Outer Canthus Branch  At the outer canthus of the eyelid, one to three lymph-collecting vessels were identified that then merged into a main collector that ran obliquely in the subcutaneous tissue and drained to the submandibular, or parotid lymph nodes. Inner Canthus Branch  At the inner canthus of the eyelid a collector, formed by the initial lymphatic capillaries arising in the upper and lower eyelids, ran obliquely in the subcutaneous tissue and drained to the submandibular, parotid, or buccinator lymph nodes.

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Inner eyelid branch

Outer eyelid branches

Inferior eyelid branch

Outer eyelid branches

Inner eyelid branch

Inner eyelid branches Outer eyelid branches

Inferior eyelid branch

Parotid lymph nodes

Inferior eyelid branch Buccinator lymph node

Submandibular lymph node

Submandibular lymph nodes

Submandibular lymph nodes

Frontal branch

Nasal branches

Buccinator lymph nodes

Buccinator lymph node

Nasal branch

Nasal branch Oral branch

Oral branch

Submandibular lymph nodes Inner eyelid branch

Nasal branch

Nasal branch Nasolabial lymph node

Oral branch Submandibular lymph node

Oral branch Submandibular lymph node

FIG. 5-8  Lymphangiograms of the face after injection of a lymphatic contrast medium. The lymph vessels of the eyelids (top), nasal lymph vessels (middle), oral branch (bottom), and related lymph nodes (purple) are highlighted.

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Outer canthus lymphatic branch

Inferior eyelid lymphatic branch

Inner canthus lymphatic branch

Buccinator lymph node

Preauricular lymph node Parotid lymph node Submandibular lymph node

FIG. 5-9  Lymphatic drainage of the eyelids. Note that the inferior lymphatic branch of the lower eyelid can converge to either the outer or inner canthus lymphatic branches. Arrows indicate the direction of lymph flow.

Inferior Eyelid Branch  One vessel, arising from the middle-inferior aspect of the lower eyelid, ran obliquely down in the subcutaneous tissue. It merged either with the outer or inner canthus branches and drained to the submandibular or deep parotid lymph nodes. Occasionally an upper-inner canthus branch ran horizontally and laterally above the superior verge of the eyebrow and passed obliquely downward and posteriorly at the lateral edge of the eyebrow. Then it passed over the zygomatic process and descended anteriorly to converge with the main branch of the outer canthus draining to the submandibular lymph node. Nasal Group  The lymph vessel arising on the lateral side of the external nose traveled obliquely down from the median to the lateral side in the subcutaneous tissue of the cheek and drained into the nasolabial, buccinator, or submandibular lymph nodes. Oral Group  The initial lymphatic vessels arising in the perilabial tissue formed one or two collecting vessels near the corner of the mouth and drained to the buccinator, submandibular, or submental lymph nodes. Mental Group  The mental vessels ran in the deep aspect of the subcutaneous tissue and drained to the submental or submandibular lymph nodes (Fig. 5-10).

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A

Submandibular lymph node

Mental branch

Submental lymph node

Superficial anterior cervical lymphatic branches

B

Anterior cervical lymphatic branches

Submental lymph node

Mental branches

Submandibular lymph node

Superficial anterior cervical lymphatic branches

C Mental branches

Platysma

Thoracic duct

Supraclavicular node

FIG. 5-10  A, Superficial lymphatic drainage of the neck. B, Radiograph shows the pathways of the anterior cervical lymphatic branches (red) situated between the dermis and platysma in the anterior neck and their related lymph nodes (purple). Green arrows indicate the direction of lymph flow. C, Lymphangiogram of the face and neck after lymphatic contrast injection, showing the mental lymph vessels (aqua blue), the anterior cervical branches (red) below the platysma, and their related lymph nodes (purple).

Anterior cervical lymphatic branches

Supraclavicular node

Thoracic duct and ampulla

Cervical Region These vessels included the anterior, lateral, and posterior groups; these are discussed next.

Anterior Cervical Group Two layers of lymphatic vessels were found in the anterior superficial neck. Above the platysma vessels traveled upward, horizontally, or obliquely. The diameter of these vessels was small, 0.1 mm to 0.2 mm. Medially, they pierced the platysma near the midline, draining into the submental lymph node between the inferior border of the mandible and the laryngeal prominence and into the supraclavicular lymph nodes between the laryngeal prominence and jugular notch. Laterally, they turned over the lateral border of the platysma and drained to the submandibular lymph nodes. The vessels below the platysma were seen running above the deep fascia. They drained to the anterior jugular lymph node and/or supraclavicular lymph node.

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FIG. 5-11  Lymphangiogram of the head and neck following lymphatic contrast injection, showing the internodal lymph vessels (blue), supratrapezoid branches (green), supraclavicular branch (yellow), and related lymph nodes (purple).

Supratrapezoid branches

Left lymphatic duct with its ampulla

Supraclavicular lymph nodes

Supraclavicular branch

Lateral Cervical Group The vessels in the lateral cervical area were numerous and complex, located in the region between the inferior ear and root of the neck and running in different directions and in different layers: the subcutaneous (superficial), intermuscular (middle), and perivascular (deep) layers. Most of these vessels were situated between lymph nodes and are called the internodal lymph-collecting vessels (Fig. 5-11).

Posterior Group The vessels of the posterior group included the supraclavicular and supratrapezoid branches. Supraclavicular Branch  The diameter of these vessels was approximately 1 mm at least when distended with the injectant. The vessels ran anteromedially in the deep aspect of the subcutaneous tissue in the root of the neck, draining to the lateral internal jugular and/or supraclavicular lymph nodes. Supratrapezoid Branch  The diameter of these vessels also averaged 1 mm. They ran anteromedially in the deep aspect of the subcutaneous tissue in the root of the neck, draining to the supraclavicular lymph nodes.

External Ear Four groups of lymph-collecting vessels were found in the external ear: the anterior, superior, middle, and inferior (lobule) branches (Figs. 5-12 and 5-13).

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Superior branches

Superior branches

Middle branches

Middle branch Anterior branch

Point at which lymph vessel turns to back of ear

Anterior branch

Point at which vessel turns to back of ear

Preauricular lymph node Inferior (lobule) branches

Preauricular lymph node Infraauricular lymph node

Substernocleidomastoid lymph node

Inferior (lobule) branches

Infraauricular lymph node

FIG. 5-12  Lymphangiogram of two external auricles after injection of a lead oxide medium. The lymphatic pathways originating from different parts of the ear are highlighted with different colors.

Superior branch Middle branch Middle branch Anterior branch Preauricular lymph node Inferior branch

Substernocleidomastoid lymph node

Infraauricular lymph node

FIG. 5-13  Anterior and posterior diagrams show the lymphatic drainage of the external ear.

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Anterior Group  The initial lymphatic capillary network was distributed over most of the anterior aspect of the external ear. Medially, they converged to become one lymph-collecting vessel running under the skin of the crus of the helix and draining directly or indirectly (having merged with a vessel descending from the scalp) into the preauricular lymph node (see the green vessels in Figs. 5-12 and 5-13). Superior Group  Lymphatic vessels (here collectors are meant), arising in the superior part of the helix, traveled in the subcutaneous tissue of the back of the ear and merged together and then ran in the subcutaneous tissue of the upper lateral neck (sometimes they divided into branches) to reach the infraauricular and/or substernocleidomastoid lymph nodes (see the orange vessels in Figs. 5-12 and 5-13). Middle Group  These lymphatic vessels (here collectors are meant) arose from the scaphoid fossa near the auricular tubercle. They traveled down and passed over the cartilage at the middle of the rim and then ran obliquely in the subcutaneous tissue of the back of the ear. Continuing their course in the subcutaneous tissue of the upper lateral neck, they entered the infraauricular lymph node (see the yellow vessels in Figs. 5-12 and 5-13). Occasionally the vessel was divided before entering the infraauricular lymph node. One branch entered the node, and the other one bypassed the node and continued its course (see the large white arrow in Fig. 5-12). Inferior (Lobule) Group  Lymphatic vessels (here collectors are meant) arose in the lobule of the auricle, converged and ran obliquely down to reach the infraauricular lymph node (see the blue vessels in Figs. 5-12 and 5-13). Occasionally the vessel divided into two branches before entering the infraauricular lymph node. One entered the node while the other bypassed the node, continuing its course.

Clinical Applications of the Anatomy of the Head and Neck Rhytidectomy The postoperative incidence of prolonged edema following rhytidectomy procedures is very low but remains a frustrating complication for the surgeon and patient alike. Baker et al,30 after reviewing 1500 cases, reported that five patients had prolonged edema following rhytidectomy but did not mention any possible links between the lymphatic drainage and prolonged edema.31 Guy et al32 stated that postoperative persistent edema associated with rhytidectomy was unusual and presumably was related to lymphatic stasis, but they did not provide further discussion, and details of the lymphatic anatomy in this region were inadequate. Because the lymphatic drainage patterns of the superficial tissue in the head, face, and neck are different in each individual, the incision of the rhytidectomy might cross lymph-collecting vessels that gather in the preauricular area in some cases (Fig. 5-14) and cross those located in the subcutaneous tissue of the dissection area. Overdissection in this region might disrupt the major lymphatic vessels and result in the frustrating complication of edema. Lymphedema of the eyelid is an uncommon condition that presents in many cases as a chronic form related to acne, rosacea, irradiation, and ocular surgery.33 It has been mentioned that the degree of swelling is usually related to surgical factors such as excessive cauterization, extensive tissue manipulation or excision, and dissection in the lateral canthal area resulting in lymphatic interruption.34 Fig. 5-9 demonstrates that the avalvular initial lymphatic capillaries arose in the up-

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FIG. 5-14  The relationship of the facial lymphatics and the part of the preauricular incision in rhytidectomy.

per and lower eyelids where the lymph could flow to the outer-inner canthus or inferior branches. If one of those branches was damaged or blocked, the others could still perform the function. It is likely that severe edema would occur if all branches were damaged by a severe injury of the periocular soft tissue or by multiple surgical incisions on the eyelid.35

Sentinel Lymph Node Mapping and Biopsy Lymphoscintigraphy is an important diagnostic technique used to identify the sentinel lymph node.12,13 Sentinel lymph node biopsy has become an important procedure in the treatment of patients with melanomas in the head and neck.13 However, lymphoscintigraphy results13 have often been discordant with clinical predictions based on our “classic” knowledge of the lymphatic system. It was found that the false-negative result could be as high as 34% in patients with skin cancer of the head and neck area.13 This percentage suggests that the surgeon will fail to remove nodes potentially containing metastatic disease in one of three patients. The findings indicated in this section will help clinicians to reevaluate the often unexpected findings in lymphoscintigraphic results.16,19,22,23,25-27 Although the lymphatic anatomy of the head and neck, with the first-tier lymph nodes, have been described and demonstrated by photographs and radiographs, several important points still need to be emphasized: • A rich avalvular lymph capillary network exists in the skin and galea of the scalp, which connects adjacent lymph territories in layers. • Indirect precollector lymph vessels link up to the lymph capillaries of the skin and galea in the scalp. • The number and diameter of the lymph collectors differ from person to person.

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• Some lymph collectors drain upward toward the mandible in the anterior neck above the platysma. • The lymphatic drainage patterns of the head and neck are diverse among individuals, and even within each side of the same individual. • The lymphatic vessels of the head and neck do not always enter the first-tier (or the nearest) lymph nodes but sometimes bypass them. Some of the lymphatic characteristics listed above may be unique to the head and neck section, and some may be common features in other parts of the body, as will be described in the following sections.

Breast and Anterior Torso Two layers and three groups of lymphatic collectors of the female breasts and anterior torso were identified according to their origins. The superficial layer includes the subareola and superficial tissue groups; the deep layer contains the internal thoracic vascular group. Lymph collectors were found evenly spaced in the superficial layer of the anterior upper torso, draining radially into the axillary lymph nodes. The patterns of the drainage territories of the firsttier lymph nodes varied among specimens and even between the sides of the same subject (Fig. 5-15), as was similarly described for the head and neck areas. As vessels reached the breast, some passed over and some through the breast parenchyma. In one case, one lymph node in the axilla drained almost the entire breast. In the majority, however, more than one node was represented (Fig. 5-16).18 Sometimes one large axillary lymph node drained the anterior chest and breast as well as most of the medial surface of the upper limb (Fig. 5-17).17

LN1 LN1 LN2

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LN2

FIG. 5-15  The asymmetrical pattern of drainage is evident. White arrows indicate two lymphatic collectors arising from each side of the nipple-areola complex. The yellow arrow indicates the lymphatic plexus in the periareolar region. The green arrow indicates the vessel from the superficial to the internal mammary lymphatic system. Black arrows indicate the nipple-areola complex. The green lymphatic vessels drain to both lymph nodes 1 and 2; yellow vessels draining to lymph node 1 on the left and 2 on the right; the red vessels are the internal mammary lymphatic system. (LN, Lymph node.)

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A

B

C

D

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FIG. 5-16  Tracing distally of lymphatics of both hemi-upper torsos (A and C are male; B and D are female) from each firsttier lymph node color coded; pectoral node (green, orange, black, and yellow ), subclavicular node (light blue), and internal mammary node (red).

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Subclavian vein

Axillary vein

Axillary lymph node draining breast and medial upper limb

Thoracodorsal vein

FIG. 5-17  An axillary node can drain the entire breast and a large area of the upper limb.

Subareola Group On average, two precollecting lymph vessels arose from the subareola plexus of each breast (see the yellow vessels in Fig. 5-15). They converged with the superficial lymphatic vessels of the anterior upper torso and coursed radially toward the axillary lymph node (or nodes).

Superficial Tissue Group The superficial lymphatic vessels arose in the subcutaneous tissues around the costal margin and the lateral border of the sternum. They coursed radially toward their first-tier lymph nodes (axillary lymph nodes). Most vessels converged to form larger lymph collectors, and some diverged before entering their lymph nodes. The size and number of vessels varied between sides, demonstrating the asymmetrical drainage patterns between the two breasts. In both the left and right axillae, all the vessels drained into one or two different sized axillary lymph nodes (see the green vessels in Fig. 5-15).

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Internal Thoracic Vascular Group One or two precollecting lymph vessels arose in the inner costal margin behind rectus abdominis on each side of the chest. They converged with the superficial lymphatic vessels of the anterior upper torso and course upward to reach their first-tier lymph node and then pass through several lymph nodes in a row to emerge with the lymphatic vessel from the supraclavicular area (see the red vessels in Fig. 5-15).

Clinical Implications: Lymph Collectors of the Breast and Anterior Torso Sentinel Lymph Node Mapping and Biopsy The treatment of breast cancer has been one of the most rapidly changing fields in surgery. For example, developments in the sentinel lymph node biopsy concept are now widely applied for the treatment of patients with breast cancer, especially in its early stages. The information provided in this section is pertinent to breast cancer research and clinical applications. The findings highlight several key points regarding the use of sentinel lymph node mapping and biopsy: our finding of varying patterns of lymphatic drainage between contralateral sides indicates that an individualized approach to each breast is essential. Intraparenchymal lymphatics course superficially and thus are amenable to surgical approaches. Lymphatics do coalesce at the nipple; however, many lymphatic vessels bypass the nipple, and thus a periareolar injection (rather than peritumoral injection) of nuclear tracer or dye may not map the appropriate lymphatics. The anatomy of lymph collectors in the breasts, anterior upper torso, and the internal thoracic vascular bundles has been revealed. The drainage patterns of lymphatics into axillary lymph nodes has been demonstrated, with a predominance of superficial lymphatics, but with some parenchymal lymphatics identified. Once again, the patterns of lymphatic vessels found from origins to the first-tier lymph node in the region were asymmetrical between each side of the breasts even within an individual. Furthermore, sometimes one large axillary lymph node drained the anterior chest and breast as well as most of the medial surface of the upper limb.

Upper Limb Breast cancer–related lymphedema of the upper extremity is to date an unsolved complication that affects large numbers of patients after breast cancer surgery. The reported incidence of upper limb lymphedema in breast cancer survivors has ranged from 2% to 5% after sentinel lymph node biopsy,36,37 and 9% to 41% after axillary lymph node dissection.38 Detailed identification of lymphatic anatomy of the upper limb will help the clinician manage the lymphedema. Multiple lymph collectors were identified in the subcutaneous tissue of the upper limb, originating beneath the dermis in the midaxial lines of the fingers, wrist crease, and lateral side of the upper arm (Fig. 5-18).

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Digits Each digit contained two collecting lymphatic vessels, one lateral and the other medial. The diameters of the vessels varied from 0.2 to 0.5 mm (average 0.3 mm) and were larger on the proximal side and smaller on the distal end. They originated beneath the dermis alongside the distal phalanges and generally traveled tortuously along the midaxial lines in the subcutaneous tissue. Generally, the vessels of neighboring digits converged in the web spaces of the hand, the exception being those on the lateral border of the thumb and the medial border of the little finger. These then traveled radially to merge with lymphatic vessels in the dorsum of the hand (vessels colored blue and green in the fingers in Fig. 5-18). A transverse section of the finger showed that the digital lymphatic vessels traveled in the mid axial lines where they paralleled arteries, veins, and nerves (Fig. 5-19).

F

Axillary lymph nodes

Cubital lymph node

C

A

E

D

B

Palm

Thumb Little finger

FIG. 5-18  Superficial lymphatic distribution of the right upper limb. Left, Anteroposterior view; center, lateral view; right, lymphatic distribution of the integument. Each group of lymphatics was color coded. Vessels colored in green were divided by the incision. (A, Styloid process of the ulna; B, styloid process of the radius; C, medial epicondyle of the humerus; D, olecranon; E, lateral epicondyle of humerus; F, acromion of the scapula.)

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A

B B LV

A

LV

T N

A

T N

TD

V

2 mm

FIG. 5-19  A, Transverse section of digital lymphatic vessels (filled with lead oxide mixture) of the right index finger. B, Transverse section of the proximal joint of the right middle finger. (A, Digital arteries [inserted metal wires]; B, head of proximal phalanx of the middle finger; LV, digital lymphatic vessels [filled with a barium sulfate mixture]; N, digital nerves; T, flexor digitorum superficialis tendon; TD, flexor digitorum profundus tendon; V, digital veins.)

FIG. 5-20  The relationship of the superficial lymphatic vessels (filled with a barium sulfate and dye mixture) and veins on the dorsum of the right hand.

Hand An average of 16 lymph collectors as the continuation of lymph vessels arising from digits (range 14 to 18) were distributed in the subcutaneous tissue of the dorsum of the hand. The diameters of the vessels varied from 0.2 to 0.6 mm (average 0.4 mm). Vessels diverged and converged to each other, and crossed over or below the superficial veins when they met (Fig. 5-20). They formed two groups: dorsoradial and dorsoulnar.

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Dorsoradial Group  Lymph collectors arising from the three digits were distributed on the radial side of the dorsum (see the green vessels in Fig. 5-18). Dorsoulnar Group  Lymph collectors arising from the ulnar two digits distributed on the ulnar side of their dorsum (see the blue vessels in Fig. 5-18).

Forearm An average of 24 lymph collectors (range 17 to 30), distributed in the subcutaneous tissue of the forearm region with the diameters of the vessels varied from 0.3 to 0.6 mm (average 0.5 mm) were found. They were dense and paralleled the cephalic and basilic system of veins mostly on the surface of the forearm, except the dorsum of the elbow. Three groups of lymph collectors were identified: radial, ulnar, and volar. Radial Group  Arising from the dorsoradial group of the hand, these lymph collectors traveled in dorsoventral direction and crossed the radial forearm margin from the dorsoradial side of the wrist to the lateral part of the cubital fossa (see the green vessels in Fig. 5-18). Ulnar Group  Arising from the dorsoulnar group of the hand, these lymph collectors traveled dorsoventrally and crossed the ulnar forearm margin from the dorsoulnar side of the wrist to the medial part of the cubital fossa and the elbow (see the blue vessels in Fig. 5-18). Volar Group  Arising near the wrist crease, these lymphatic collectors traveled in the subcutaneous tissue of the volar of the forearm toward the cubital fossa (see the yellow vessels in Fig. 5-18). Clustering in the anteromedial aspect of the elbow, these three groups of collectors paralleled basilic veins and crossed over and below the median and basilic veins when meeting them. In

LN

V

N

E

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FIG. 5-21  The relationship of the superficial lymphatic vessels (filled with a barium sulfate mixture), veins, and nerve on the left cubital fossa. (E, Medial epicondyle of humerus; LN, lymph node; N, medial cutaneous nerve; V, basilic vein.)

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some cases, a cubital lymph node presented next to the basilic vein in the cubital fossa connected by a single afferent and efferent lymph collector, while the other vessels bypassed it (Fig. 5-21).

Upper Arm An average of 19 lymph collectors (range 17 to 21), were present in the upper arm. The diameters of these collectors varied from 0.3 to 1.2 mm (average 0.6 mm). Above the elbow, the collectors were dense on the medial side and sparse on the lateral side. They converged centrally to form larger vessels before entering the lymph nodes in the axilla. There was a definite tendency for postaxial clustering and increased vessel diameter in this region. Medial Group  Clustering above the elbow level in the medial side of the upper arm, three groups of the lymph collectors from the forearm converged to form larger diameter collectors before entering the lymph nodes in the axilla (see the vessels colored green, yellow, and blue in Fig. 5-18). Two or three vessels accompanied the basilic vein and medial cutaneous nerve (Fig. 5-22). Anterolateral Group  Lymph collectors originated from the lateral side of the upper arm and traveled obliquely and horizontally via the volar aspect of the upper arm to merge with the medial group of vessels before entering the axillary lymph node (see the brown vessels in Fig. 5-18). Posterolateral Group  Originated from the lateral side of the upper arm, vessels traveled obliquely and horizontally along the dorsal aspect to merge with the medial group of vessels before entering the axillary lymph node (see the brown vessels in Fig. 5-18).

LN3 LN2

N

V

FIG. 5-22  The relationship of the superficial lymphatic vessels (filled with a barium sulfate mixture), veins, and nerve on the medial aspect of the left upper arm. (E, Medial epicondyle of the humerus; LN1, cubital lymph node; LN2 and LN3, axillary lymph nodes; N, medial cutaneous nerve; V, basilic vein.)

LN1

E

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Clinical Implications of the Anatomy of the Upper Limb Secondary lymphedema of the upper limb is one possible sequela of breast cancer surgery. This unsolved iatrogenic complication is characterized by a progressive pathologic condition in which there is an interstitial accumulation of the protein-rich lymphatic fluid, recurrent cellulitis, hypertrophy of adipose tissue, and fibrosis, resulting in increased lymph volume and chronic edema in the affected region. Creation of a lymphaticovenous anastomosis is one of the contemporary options for surgical treatment of secondary lymphedema. Detailed lymphatic anatomy of the upper limb may help to locate the lymphatic collecting vessels for the proposed surgical procedure. In summary, the characteristic lymphatic distribution of the upper limb has been described as follows: • Lymph collectors were dense in the dorsum of the hand, forearm, and medial aspect of the upper arm. • Lymph collectors could be found surrounding the basilic and cephalic veins with their accessories. • The largest vessels were located in the medial aspect of the upper arm. Awareness of this information should emphasize to surgeons the importance of searching for the location of the best lymphatic collectors for potential lymphaticovenous anastomosis sites in the upper limb.

Lower Limb Multiple lymph collectors were identified in the subcutaneous tissue of the lower limb (Fig. 5-23). They originated beneath the dermis of each side of the toes, the foot, and the lateral side of the thigh. The diameters of the vessels varied from 0.2 to 2.2 mm. The vessels traveled in a tortuous fashion through the subcutaneous tissue toward the lymph nodes in the popliteal fossa, those adjacent to the superficial femoral vessels, and those in the inguinal region. During their course some vessels branched, diverged, or converged; sometimes they anastomosed with or crossed over neighboring vessels. As they approached the lymph node groups, most vessels converged to form larger collectors. Some of these larger collectors then split into small branches just before entering the lymph nodes. The drainage patterns were different in the individual specimens and even asymmetrical between each side of the same body. They traveled in a meandering fashion within the subcutaneous tissue and passed over and/or under the veins when they met them.

Toes Each toe contained two lymph collectors, one on each side, traveling in the subcutaneous tissue along the midaxial lines. The mean vessel diameter was 0.5 mm (range 0.2 to 0.8 mm). The vessels of neighboring toes converged in the web spaces of the foot, except for the vessels on the medial and lateral borders of the first and fifth toes. They then traveled radially to merge with lymphatic vessels in the dorsum of the foot.

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DILN E

SILN

G

F

FLN

SPLN

DPLN

D C

Posterior

Anterior

A

B

Sole

FIG. 5-23  Superficial lymphatic distribution of the left lower limb. Left, Anteroposterior view; center; lateral view; right, lymphatic distribution of the integument; far right, the parafemoral lymphatic vessels. Each group of lymphatics was colored differently. Black arrows indicate the cut points of vessels. (A, Lateral malleolus; B, medial malleolus; C, lateral epicondyle of femur; D, medial epicondyle of femur; E, anterior superior iliac spine; F, pubic tubercle; G, ischial tuberosity. DILN, Deep inguinal lymph nodes; DPLN, deep popliteal lymph nodes; FLN, femoral lymph nodes; SILN, superficial inguinal lymph nodes; SPLN, superficial popliteal lymph nodes.)

Foot An average of 14 lymph collectors (range 9 to 19) were found in the subcutaneous tissue of the dorsum of the foot. The mean vessel diameter was 0.6 mm (average 0.2 to 1.2 mm). They branched, diverged, converged, and anastomosed with or crossed over neighboring vessels, forming a large lymphatic network in three groups. Anterior Group  These arose from the toes, forming the front part of the lymphatic network on dorsum of the foot (see the light blue vessels in Fig. 5-23). Medial Group  These arose from the medial border of the foot, forming the medial part of the lymphatic network on the dorsum of the foot (see the yellow vessels in Fig. 5-23).

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G S V

FIG. 5-24  Lymphatic vessels (filled with a barium sulfate mixture) of the medial group in the middle of the left leg traveling with the great saphenous vein (GSV) and its branch. Green arrows indicate the direction of lymphatic flow.

Lateral Group  These arose from the lateral border of the foot, forming the lateral part of the network on the dorsum of the foot (see the green vessels in Fig. 5-23).

Ankle An average of 12 lymph-collecting vessels (range 9 to 17) were found in the subcutaneous tissue around the ankle. The mean vessel diameter was 1.0 mm (range 0.2 to 2.0 mm). Anterior Group  Most of these vessels (mean 10; range 8 to 13) were distributed in the anterior aspect of the ankle between the lateral and medial malleoli. They were continuous with vessels from the dorsum of the foot. Posterior Group  Only a few vessels (mean 2; range 1 to 4) were distributed in the posterior aspect of the ankle, arising from the sides of the Achilles tendon (tendocalcaneus) bilaterally in the subcutaneous tissue just above the heel.

Leg An average of 13 lymph-collecting vessels (range 12 to 16) were distributed in the subcutaneous tissue of the leg. The mean vessel diameter was 1.0 mm (range 0.2 to 1.8 mm).

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S S V

FIG. 5-25  Lymphatic vessels after injection of a lead oxide mixture traveling with the small saphenous vein (SSV) in the calf. Green arrows indicate the direction of lymphatic flow.

Anteromedial Group  They were denser with a straighter course, following the adjacent great saphenous vein (GSV) and its branches (see the yellow vessels in Fig. 5-23) (Fig. 5-24). Anterolateral Group  Vessels were relatively sparse, following a curving course and tending toward the anteromedial aspect of the proximal third of the leg (see the green vessels in Fig. 5-23). Posterior Group  There were only one or two large lymphatic vessels (mean diameter 1 mm; range 0.7 to 1.4 mm) in the posterior aspect of the leg accompanying the small saphenous vein (SSV) (see the orange vessels in Fig. 5-23) (Fig. 5-25).

Knee An average of 15 lymph collectors (range 11 to 17) were distributed in the subcutaneous tissue around the knee region. The mean vessel diameter was 0.8 mm (range 0.3 to 1.6 mm). Anterior Group  The anterior lymphatics were relatively sparse and traveled obliquely toward the anteromedial aspect of the thigh (see the green vessels in Fig. 5-23). Medial Group  The medial vessels were denser and were formed by the anteromedial and anterolateral groups from the leg region, following the adjacent GSV and its branches (see the yellow and green vessels in Fig. 5-23).

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DPLN

SPLN

SPLN

S S V

FIG. 5-26  Left, Posteroanterior view of an inverted radiograph showing the lymphatic distribution in the knee region. Posterior lymph vessels are represented in orange, internodal lymph vessels are yellow, and superficial femoral lymph vessels are blue. (DPLN, Deep popliteal lymph nodes.) Right, A magnified image from the circled area in the left radiograph. Lymphatic vessels after lead oxide mixture injection around the small saphenous vein (SSV) in the popliteal fossa entering the superficial popliteal lymph nodes (SPLN). Green arrows indicate the direction of lymphatic flow.

Posterior Group  There were only one or two larger lymphatic vessels in the popliteal fossa following the SSV entering the superficial popliteal and/or then the deep lymph node (or nodes) (see the orange vessels in Fig. 5-23) (Fig. 5-26).

Thigh An average of 29 lymph collectors (range 27 to 31) were found in the thigh. The mean vessel diameter was 0.8 mm (range 0.3 to 1.7 mm). Anterior Group  Vessels originated from the anterolateral aspect of the thigh, running obliquely in the subcutaneous tissue before entering the lateral group of the superficial inguinal lymph nodes (see the pink vessels in Fig. 5-23). Medial Group  The medial group consisted of the continuous vessels of the anteromedial and anterolateral groups from the leg, running in the subcutaneous tissue of the medial aspect of the

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SILN

G S V

G S V

FIG. 5-27  Lymphatic vessels after injection of a lead oxide mixture traveling with the great saphenous vein (GSV) in the calf. (SILN, Superficial inguinal lymph nodes.)

thigh. Vessels lay adjacent to the GSV and its branches and entered the center group of the superficial inguinal lymph nodes (see the yellow and green vessels in Fig. 5-23) (Fig. 5-27). Posterior Group  The posterior group originated from the posterolateral side of the thigh. Vessels ran obliquely in the subcutaneous tissue of the posterior aspect of the thigh toward the medial group of the superficial inguinal lymph nodes (see the blue vessels in Fig. 5-23).

Alternative Pathways From the Popliteal to Inguinal Lymph Nodes From the popliteal fossa to the inguinal lymph nodes, vessels traveled along three lymphatic pathways in the thigh region. Multiple pathways presented in the individual specimen (Figs. 5-28 and 5-29) include the superficial pathway, the parafemoral pathway, and the deep pathway. Other pathways were described by Viamonte and Rüttimann39: • The deep lymphatic vessels accompanying the obturator artery drained into the internal iliac lymph node. • Vessels accompanying the sciatic nerve drained into the inferior gluteal lymph node.

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DPLN V

SPLN

N MLV V

FIG. 5-28  Distribution of lymphatics in the left popliteal fossa. A vessel on the medial side (MLV) enters the superficial popliteal lymph node (SPLN); its efferent vessel continues in the subcutaneous tissue and then converges with the medial group of the thigh. A lateral lymph vessel (LLV) enters the deep popliteal lymph node (DPLN). (N, Tibial nerve in the popliteal fossa; V, branches of the small saphenous vein.)

LLV 5 mm

1 Superficial lymphatic pathway

Sciatic nerve

2 Parafemoral lymphatic pathway

3 Deep lymphatic pathway

External iliac lymph nodes (EILN) Superficial inguinal lymph nodes (SILN) Deep inguinal lymph nodes (DILN) Great saphenous vein Deep femoral vein Femoral vein Femoral lymph node (FLN) Deep popliteal lymph node (DPLN) To lumbar trunk DILN

EILN

Superficial popliteal lymph node (SPLN)

SILN

Deep popliteal vein and tibial nerve

1 2

Small saphenous vein

3

FLN DPLN SPLN From lateral heel

FIG. 5-29  Alternative pathways from the popliteal to inguinal lymph nodes.

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FIG. 5-30  Afferent lymph vessel from the superficial popliteal lymph node running in the subcutaneous tissue of the anteromedial side of the thigh and entering the superficial inguinal lymph node.

Popliteal fossa Patella

Superficial Pathway  The efferent lymph vessel, from the superficial popliteal lymph node, ascended in the subcutaneous tissue, turning toward the medial side at the distal part of the thigh and then the anteromedial side at the top of the thigh to join the medial group vessels of the thigh before entering the superficial inguinal lymph node (Fig. 5-30). Parafemoral Pathway  The efferent lymph vessel, from the deep popliteal lymph node, were coursing in variable relationship to the femoral vascular bundle (anteriorly, posteriorly, laterally, and medially between the femoral artery and vein) and sometimes winding around the bundle before entering the lymph nodes in the inguinal area (see the brown vessels in Figs. 5-23, 5-29, and 5-31, A). The vessels were single, dividing into multiple vessels before entering the inguinal lymph nodes. Deep Pathway  The efferent lymph vessel, from the deep popliteal lymph node, was running deep to the anterior side of the sciatic nerve near the superior margin of the popliteal fossa, and then between the sciatic nerve and the profunda femoral vessels and the common femoral vessels draining into an anterior external iliac lymph node (Fig. 5-31).

The Depth of Lymph Vessels in the Subcutaneous Tissue The depth of lymph collectors depends on the thickness of the surrounding subcutaneous tissue. On the dorsum of the foot, the vessels ran within a very thin layer of tissue, whereas in the groin, a great number of collectors were packed within the entire layer of tissue. Kubik and Manestar40 reported that the lymphatic vessels of the thigh formed three layers: the first layer lay immediately

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A

External iliac lymph nodes

B

Sciatic nerve

Lymphatics running between sciatic nerve and profunda vessels

Deep popliteal lymph nodes

Lymphatics running between sciatic nerve and profunda vessels Lymphatic running with femoral vascular bundle

Superficial popliteal lymph nodes

Deep popliteal lymph node Superficial popliteal lymph node

FIG. 5-31  A, Radiograph and B, photograph after lead oxide mixture injection showing the lymphatics in the lower limb. In the radiographic lateral view (left) and posteroanterior view (right) and photograph, note the two deep collecting lymph vessels in the thigh region.

below the surface of the subcutaneous fat, the second layer lay between the first and third layers, and the third layer lay on the deep fascia. However, Pan et al28 found that the lymph collectors were distributed in close association with the great and small saphenous vein, traveling tortuously in different depths of the subcutaneous tissue.

Clinical Implications: The Lower Limb Secondary lymphedema of the lower limb is a common occurrence after trauma, infection, and surgery, especially after a radical clearance of the inguinal lymph nodes. The reported incidence of lower limb lymphedema after groin dissection has ranged from 40% to 67%.41 Surgical treatment for secondary lymphedema requires accurate knowledge of the anatomy of lymphatic routes in the lower limb to assist in preoperative preparation and intraoperative management, ultimately affecting the postoperative outcome. As emphasized throughout this chapter, the entire lymphatic drainage pattern of the superficial tissues, including the femoral lymph vessels, has shown that quantitative (number of vessels) and qualitative (size of vessels) variations exist among individuals. These data provide an important baseline for clinical applications. Most lymphatic vessels have been found to drain into their first-

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tier lymph nodes in the groin (superficial inguinal lymph nodes). In contrast, there were one or two lymph collectors arising from the lateral side of the Achilles tendon in the subcutaneous tissue above the heel which traveled with the small saphenous vein. These vessels drained through popliteal and femoral lymph nodes before finally entering the deep inguinal, external iliac or inferior gluteal lymph node.24,39 Lymphaticovenous anastomoses have been performed to treat secondary lymphedema of the lower extremities.42-46 It has been mentioned that as many anastomoses as possible must be created to obtain the best result in this procedure.47 Figs. 5-23 through 5-31 provide a roadmap for surgeons when searching for potential lymphaticovenous anastomotic sites in the lower extremity where lymph vessels are situated close to veins, according to the following major scenarios: • The dorsum of the foot: rich lymphatic vessels were present in the same plane as the dorsal metatarsal veins (see Fig. 5-23). • The medial aspect of the lower extremity: abundant lymph vessels traveled with or crossed the great saphenous vein and its branches in the anterior tibial region adjacent to the medial malleolus, the medial leg, knee, and thigh (see Figs. 5-23, 5-24, and 5-27). • Posterior aspect of the leg: one or two large lymph vessels always accompanied the small saphenous vein (see Figs. 5-25 and 5-26). Lymphatic grafting procedures for treating secondary lymphedema have been reported.48 These procedures involve the harvest of single or multiple lymphatic vessels from the ventromedial bundle (medial group of the thigh) in the contralateral thigh (healthy limb). The distal end of these vessels in the donor side was anastomosed to vessels in the affected limb through a subcutaneous tunnel above the pubic symphysis. Alternatively, the vessels were harvested as free grafts for transfer to the upper limb.49 The results from this study have provided details of the lymphatic distribution in the thigh. If one or more vessels were harvested from the ventromedial bundle of the thigh, the remaining lymphatic vessels could probably still perform the required drainage function. Furthermore, vessels were constant and easily located, traveling on both sides of the small saphenous vein in the same depth of tissue in the posterior aspect of the leg. This could act as an additional donor site for harvesting lymphatic graft tissue for surgical treatment. The lower extremity (especially the medial thigh) is a common donor site for harvesting a flap. The details of the neurovascular supplies of these flaps have been well documented, but their lymphatic supply was not well understood.50-53 Fig. 5-23 identifies the afferent and efferent lymphatic pathways and the direction and quantitative distribution of lymph vessels within in the lower extremity to assist surgeons in designing soft tissue flaps (lymphatic bridging flaps) for surgical treatment of lymphedema patients.54-58 For example, a flap harvested from the medial aspect of the thigh would contain rich vertical lymphatic vessels, whereas a flap from lateral side of the thigh would contain fewer (obliquely oriented) vessels.

Sentinel Lymph Node Mapping and Biopsy Lymphoscintigraphy has been used to determine the sentinel lymph nodes for sentinel lymph node biopsy for the treatment of cancer patients.12-13 Reynolds et al59 created three-dimensional, colorcoded “heat maps” to show the lymphatic drainage patterns in patients with cutaneous melanoma. After analyzing lymphoscintigraphy data collected from more than 5000 patients, they found one patient with a melanoma on the right heel and lymphoscintigraphy results that showed lymphatic drainage to the ipsilateral popliteal lymph node fields, ipsilateral groin, and contralateral groin.

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This is a very surprising result, of course, but does indicate the variability in drainage pathways we are faced with when it comes to the lymphatic system. The results from this section have shown that the lymphatic drainage route from the lateral heel to the popliteal fossa passing through the subcutaneous tissue in the calf is constant. One or two collecting lymph vessels accompanying the small saphenous vein enter the popliteal lymph nodes. However, from the popliteal fossa to the groin area, there are three lymphatic pathways: through the superficial tissue of the medial side of the thigh, running with the superficial femoral blood vessels, or running between the sciatic nerve and the profunda femoral vessels. In addition to these three major routes, other pathways were described by Viamonte and Rüttimann,39 these being ones in which the deep lymphatic collectors accompanying the obturator artery drain into the internal iliac lymph node and one in which the lymph collectors accompanying the sciatic nerve drain into the inferior gluteal lymph node. These findings help explain the case reported by Reynolds et al59 (that is, drainage to the ipsilateral node fields and groin) and support their comments that lymphatic pathways from the popliteal fossa (efferent vessels of the lymph nodes) pass through different routes to reach different lymph node groups in the inguinal and pelvic areas.

Conclusion Actual and accurate lymphatic distribution and drainage patterns of the head and neck, anterior torso and breast, and extremities have been described and illustrated, as have the characteristics of the lymphatic anatomy in these regions. These empirical anatomic data provide the supplementary information to enrich our knowledge of the human lymphatic system, which may help clinically, especially when surgery of any type is anticipated, but also in follow-up scenarios when issues of lymphedema are being treated by therapists.

R EFERENCES 1. Aselli G. De Lactibus Sine Lacteis Venis. Milan, Italy, 1627. 2. Pecquet J. Experimenta Nova Anatomica. Paris, 1651. 3. Haagensen CD, Feind CR, Herter FP, et al, eds. The Lymphatics in Cancer. Philadelphia: WB Saunders, 1972. 4. Nuck A. Adenographia Curiosa et Uteri Foeminei Anastome Nova. Lugduni Betavorum, P vander Aa, 1692. 5. Cruikshank W. The Anatomy of the Absorbing Vessels of the Human Body. London: G Nicol, 1786. 6. Mascagni P. Vasorum Lymphaticorum Corporis Humani Historia et Ichonographia. Siena, Italy: P Carli, 1787. 7. Bonamy C, Broca P, Beau ME. Atlas d’Anatomie Descriptive du Corps Humain. Paris: Victor Masson, 1850. 8. Sappey PC. Anatomie, Physiologie, Pathologie des Vaisseaux Lymphatiques. Paris: Adrien Delahaye, 1874. 9. Gerota D. Zur Technik der Lymphgefassinjection. Eine neue Injections-masse für Lymphgefasse. Polychrom Injection. Anat Anzeiger 12:216-224, 1896.

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10. Bartels P. Das lymphgefassystem. In Bardeleben K, ed. Handbuch der Anatomie des Menschen (4th part). Jena: Gustav Fischer Verlag, 1909. 11. Rouvière H. Anatomy of the Human Lymphatic System. Michigan: Edwards Brothers, 1938. 12. Uren RF, Thompson JF, Howman-Giles RB. Lymphatic Drainage of the Skin and Breast. Sydney, Australia: Harwood Academic Publishers, 1999. 13. Thompson JF, Morton DL, Kroon BBR. Textbook of Melanoma. London: Martin Dunitz, 2004. 14. Liu NF, Lu Q, Jiang ZH, et al. Anatomic and functional evaluation of the lymphatics and lymph nodes in diagnosis of lymphatic circulation disorders with contrast magnetic resonance lymphangiography. J Vasc Surg 49:980-987, 2008. 15. Suami H, Taylor GI, Pan WR. A new radiographic cadaver injection technique for investigating the lymphatic system. Plast Reconstr Surg 115:2007-2013, 2005. 16. Pan WR, Suami H, Taylor GI. The lymphatic drainage of the superficial tissues of the head and neck: an anatomical study and clinical implications. Plast Reconstr Surg 121:1614-1624, 2008. 17. Suami H, O’Neill J, Pan WR, et al. Superficial lymphatic system of the upper torso: preliminary radiographic results in human cadavers. Plast Reconstr Surg 121:1231-1239, 2008. 18. Suami H, Pan WR, Mann GB, et al. The lymphatic anatomy of the breast and its implications for sentinel lymph node biopsy: a human cadaver study. Ann Surg Oncol 15:863-871, 2008. 19. Pan WR, Suami H, Corlett RJ, et al. Lymphatic drainage of the nasal fossae and nasopharynx: preliminary anatomical and radiological study with clinical implications. Head Neck 31:52-57, 2009. 20. Pan WR, Rozen WR, Stella D, et al. A three-dimensional analysis of the lymphatics of a bilateral breast specimen: a human cadaveric study. Clin Breast Cancer 9:86-91, 2009. 21. Pan WR, le Roux CM. Blood supply to the lymphatic vessels in the leg: an incidental finding. Clin Anat 23:451-454, 2010. 22. Pan WR, le Roux CM, Levy SM, et al. The morphology of the human lymphatic vessels in the head and neck. Clin Anat 23:654-661, 2010. 23. Pan WR, le Roux CM, Levy SM, et al. Lymphatic drainage of the tongue and the soft palate: anatomic study and clinical implications. Eur J Plast Surg 33:251-257, 2010. 24. Pan WR, le Roux CM, Levy SM. Alternative lymphatic drainage routes from the lateral heel to the inguinal lymph nodes: anatomic study and clinical implications. ANZ J Surg 81:431-435, 2010. 25. Pan WR, le Roux CM, Levy SM, et al. Lymphatic drainage of the external ear. Head Neck 33:60-64, 2011. 26. Pan WR, le Roux CM, Briggs CA. Variations in the lymphatic drainage pattern of the head and neck: further anatomic studies and clinical implications. Plast Reconstr Surg 127:611-620, 2011. 27. Pan WR, le Roux CM, Briggs CA. Reply: Acute lymphedema of the eyelid after major reconstruction of the medial canthus: the role of the lymphatic drainage pattern. Plast Reconstr Surg 128:372e, 2011. 28. Pan WR, Wang DG, Levy SM, et al. Superficial lymphatic drainage of the lower extremity: anatomic study and clinical implications. Plast Reconstr Surg 132:696-707, 2013. 29. Wallace S, Jackson L, Dodd GD, et al. Lymphatic dynamics in certain abnormal states. Am J Roentgenol Radium Ther Nuc Med 91:1199-1200, 1964. 30. Baker TJ, Gordon HL, Molienko P. Rhytidectomy. Plast Reconstr Surg 59:24-30, 1977. 31. Baker TJ, Gordon HL. Complications of rhytidectomy. Plast Reconstr Surg 40:31-39, 1967. 32. Guy CL, Converse JM, Morello DC. Aesthetic surgery for the aging face. In Converse JM, McCarthy JG, Littler JW, eds. Reconstructive Plastic Surgery, ed 2. Philadelphia: WB Saunders, 1977. 33. Chalasani R, McNab A. Chronic lymphedema of the eyelid: case series. Orbit 29:222-226, 2010. 34. Klapper SR, Patrinely JR. Management of cosmetic eyelid surgery complications. Semin Plast Surg 21:80-93, 2007. 35. Aveta A, Tenna S, Segreto F, et al. Acute lymphedema of the eyelid after major reconstruction of the medial canthus: the role of the lymphatic drainage pattern. Plast Reconstr Surg 128:370e-372e, 2011. 36. Langer I, Guller U, Berclaz G, et al. Morbidity of sentinel lymph node biopsy (SLN) alone versus SLN and completion axillary lymph node dissection after breast cancer surgery: a prospective Swiss multicenter study on 659 patients. Ann Surg 245:452-461, 2007.

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37. Lucci A, McCall LM, Beitsch PD, et al. Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group Trial Z0011. J Clin Oncol 25:3657-3663, 2007. 38. Suami H, Chang DW. Overview of surgical treatments for breast cancer-related lymphedema. Plastic Reconstr Surg 126:1853-1863, 2010. 39. Viamonte MJ, Rüttimann A. Atlas of Lymphography. New York: Thieme-Stuttgart, 1980. 40. Kubik S, Manestar M. Topographic relationship of the ventromedial lymphatic bundle and the superficial inguinal nodes to the subcutaneous veins. Clin Anat 8:25-28, 1995. 41. Williams AF, Franks PJ, Moffatt CJ. Lymphoedema: estimating the size of the problem. Palliat Med 19:300-313, 2005. 42. O’Brien BM, Mellow CG, Khazanchi RK, et al. Long-term results after microlymphaticovenous anastomoses for the treatment of obstructive lymphedema. Plast Reconstr Surg 85:562-572, 1990. 43. Koshima I, Nanba Y, Tsutsui T, et al. Long-term follow-up after lymphaticovenular anastomosis for lymphedema in the leg. J Reconstr Microsurg 19:209-215, 2003. 44. Takeishi M, Kojima M, Mori K, et al. Primary intrapelvic lymphaticovenular anastomosis following lymph node dissection. Ann Plast Surg 57:300-304, 2006. 45. Demirtas Y, Ozturk N, Yapici O, et al. Supermicrosurgical lymphaticovenular anastomosis and lymphaticovenous implantation for treatment of unilateral lower extremity lymphedema. Microsurgery 29:609-618, 2009. 46. Narushima M, Mihara M, Yamamoto Y, et al. The intravascular stenting method for treatment of extremity lymphedema with multiconfiguration lymphaticovenous anastomoses. Plast Reconstr Surg 125:935-943, 2010. 47. Huang GK, Hu RQ, Liu ZZ, et al. Microlymphaticovenous anastomosis in the treatment of lower limb obstructive lymphedema: analysis of 91 cases. Plast Reconstr Surg 76:671-685, 1985. 48. Baumeister RG, Siuda S. Treatment of lymphedemas by microsurgical lymphatic grafting: what is proved? Plast Reconstr Surg 85:64-74, 1990. 49. Weiss M, Baumeister RG, Hahn K. Dynamic lymph flow imaging in patients with oedema of the lower limb for evaluation of the functional outcome after autologous lymph vessel transplantation: an 8-year follow-up study. Eur Nucl Med Mol Imaging 30:202-206, 2003. 50. Taylor GI, Razaboni RM. Michel Salmon Anatomic Studies: Arteries of the Muscles of the Extremities and the Trunk—Arterial Anastomotic Pathways of the Extremities. St Louis: Quality Medical Publishing, 1994. 51. Pan WR, Taylor GI. The angiosomes of the thigh and buttock. Plast Reconstr Surg 123:236-249, 2009. 52. Mathes SJ, Nahai F. Reconstructive Surgery: Principles, Anatomy & Technique. St Louis: Quality Medical Publishing, 1997. 53. Strauch B, Yu HL. Atlas of Microvascular Surgery: Anatomy and Operative Approaches, ed 2. New York: Thieme Medical, 2006. 54. Becker C, Hidden G. [Transfer of free lymphatic flaps: Microsurgery and anatomical study] J Mal Vasc 13:119-122, 1988. 55. Gillies HD. Treatment of lymphoedema by plastic operation. Br Med J 1:96-98, 1935. 56. Thompson N. Buried dermal flap operation for chronic lymphoedema of the extremities: ten-year survey of results on 79 cases. Plast Reconstr Surg 45:541-548, 1970. 57. Salvin SA, Upton J, Kaplan WD, et al. An investigation of lymphatic function following free-tissue transfer. Plast Reconstr Surg 99:730-741; discussion 742-743, 1997. 58. Tanaka Y, Tajima S, Imai K, et al. Experience of a new surgical procedure for the treatment of unilateral obstructive lymphedema of the lower extremity: adipo-lymphatico venous transfer. Microsurgery 17:209-216, 1996. 59. Reynolds HM, Dunbar PR, Uren RF, et al. Three-dimensional visualisation of lymphatic drainage patterns in patients with cutaneous melanoma. Lancet Oncol 8:806-812, 2007.

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C hapter 6 Applied Anatomy Miguel Amore, Lucia Tapia, Gisela Romina Pattarone, Diego Mercado

K ey P oints • The lymphatic system plays an important role in transporting tissue fluids and extravasated plasma proteins back to the bloodstream and absorbing lipids from the intestines. • The lymphatic system is composed of collecting vesels and lymph nodes and comprises five distributions: superficial, deep, communicating, perforating, and visceral. • The superficial lymphatic system includes two subsystems: epifascial and interfascial.

App

Research into the anatomy of the lymphatic system and its links to functional status has been and continues to be a controversial subject, in part because of the great complexity of the methods for its visualization and the complexity and variability of the lymphatics between individuals. More than 30 years ago, Caplan and Ciucci of Buenos Aires University began working in the area of vascular anatomy, with a focus on the lymphatic anatomy, developing and adapting a range of techniques for visualization. Our research, the results of which are indicated in this chapter, is a continuation of their work and was carried out by our group in the Third Normal Anatomy Department of Buenos Aires University. In this chapter we will summarize our findings on the anatomy of the lymphatic system, focusing on the lymphatic drainage of the breasts and limbs, to increase understanding of the anatomic basis of lymphedema.

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Research Methods We began our anatomic study of the lymphatic system using a range of staining techniques (such as China ink, latex, Berlin blue, and others) that progressively improved over the years. We primarily used the Gerota method, which employs a mixture of turpentine essence, Prussian blue, and sulfur ether, as described by Dimitrie Gerota in 1896. We modified his method by replacing the sulfur ether with heat to dilate the lymph capillaries. To visualize the lymphatic vessels and the lymph nodes without risk of injuring them during dissection, and to enable our research into the morphology of the lymphatic system, its variant drainage, and the relationship with subfascial lymphatics, we added diaphonization by the Spalteholz technique. This technique is employed after fixation and clearing of the cadaveric material. First the specimen is dehydrated using alcohol, then it is immersed in xylol, thus changing the refractive index and making it possible to generate a three-dimensional image.1,2

General Considerations The lymphatic system plays an important role in transporting tissue fluids and extravasated plasma proteins back to the bloodstream as well as absorbing lipids from the intestinal tract. It is also important for the immune response and is one of the main routes for the metastatic spread of tumor cells. The system starts in the interstitial space with the initial lymphatic capillaries (Fig. 6-1). It drains the lymph through the collecting vessels, which is then filtered in the lymph nodes and finally cleared into the venous system. It is distributed throughout the body, except for the central nervous system, where the perivascular spaces have a prelymphatic or paralymphatic function.

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FIG. 6-1  Imaging of 1, the lymph capillaries and 2, blood vessels.

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Lymphatic System Distribution Topographically, the lymphatic system can be separated as follows: • Superficial system: Drains the cutis and subcutis. In terms of the lower-limb lymphatic drainage, in the superficial system there are two subsystems: ȤȤ The epifascial system, between the skin and the saphenous fascia ȤȤ The interfascial system, between the saphenous fascia and the muscle fascia • Deep system: Subaponeurotic/subfascial; drains the lymph from the muscles, joints, synovial sheaths, and nerves. It runs alongside the deep blood vessels. • Communicating system: Consists of a group of lymphatic vessels that interconnect a system (deep or superficial) on the same aponeurotic stratum. • Perforating system: Interconnects the two systems (superficial and deep). • Visceral system: Drains the lymph from different organs.

Lymph Trunks Classically and schematically, the thoracic duct is considered the main prevertebral collector that drains lymph from three body quadrants and discharges it into the left venous angle. It is formed by the union of the two lumbar trunks and the intestinal trunk, at the height of lumbar vertebrae L1 and L2 (abdominal origin) or behind the crus of the diaphragm and in front of thoracic vertebrae T11 and T12 (thoracic origin) (Fig. 6-2).

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FIG. 6-2  1, Lumbar trunks; 2, cisterna chyli; 3, azygos vein; 4, superior vena cava; 5, cervical portion of the thoracic duct; 6, esophagus.

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Occasionally a dilation of the origin can be observed, called the cisterna chyli. Anatomic variations are also frequently seen, such as the plexus shape in the origin and trunk (Fig. 6-3). The thoracic duct ascends between the azygos vein and the aorta and is covered by the pleura and esophagus. At the level of thoracic vertebrae T4 and T5, the duct crosses under the esophagus and aortic arch and ascends toward the thoracic inlet on the left margin of the vertebral column, between the esophagus and the left subclavian artery, reaching the left jugular subclavian angle (Fig. 6-4). Our research has shown that in the left carotid region there is a lymph collector that receives the lymph from the left fascial, cervical, carotid, and temporal regions. The right duct is the one that drains the remaining upper right quadrant to the right venous angle.3,4

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FIG. 6-3  A, 1, Thoracic duct; 2, trachea; 3, esophagus. B, 1, Thoracic duct formation; 2, azygos vein; 3, thoracic aorta artery.

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FIG. 6-4  1, Jugular-subclavian angle; 2, thoracic duct; 3, left common carotid artery; 4, brachiocephalic arterial trunk; 5, superior vena cava; 6, cervical trachea; 7, left vagus nerve; 8, lymph collector.

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Applied Anatomy of the Lymphatic System Lymphatic Drainage of the Breast Area The predominant lymphatic drainage pathway from the breast flows toward the axilla (Fig. 6-5). Axillary node dissection is a standard surgical treatment in patients with involved axillary lymph nodes. Unfortunately, arm lymphedema develops in 7% to 77% of patients with axillary lymph node dissections. Sentinel lymph node biopsy has become a frequently used and widely accepted method for surgical staging of axillary lymph nodes in breast cancer, although the incidence of arm lymphedema after sentinel lymph node biopsy varies from 0% to 13%.5 The reasons for this may be seen in the multiple interpretations of the term sentinel lymph node—variously identified as the first lymph node to which the tumor drains, the closest node to the tumor, or the node that is most seen with the probe (which answers only the first word of the term). Thus, under certain circumstances, when a biopsy of more than one node is performed, a minimally invasive surgery becomes a pseudoaxillary lymph node dissection procedure.6 In our anatomic research, we divided the lymphatic drainage of the mammary gland from that of the mammary skin and found it difficult to extrapolate our research to the clinical and surgical practice (Fig. 6-6). The most representative instance was the injection method in the sentinel

FIG. 6-5  1, Breast area; 2, axillary lymph nodes; 3, superficial lymphatic network.

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FIG. 6-6  1, Breast area; 2, cutaneous lymphatic network; 3, axillary lymph nodes.

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lymph node technique. The optimal sites of dye and/or colloid injection have not been defined: intradermic, subareolar, peritumoral, or intratumoral. There is no consensus on this topic. The problem is to consider the same lymphatic drainage of the mammary gland and the mammary skin as a unique functional unit based on the embryologic hypothesis. Under this concept, the subareolar plexus is considered the center of lymphatic drainage in the breast. This plexus was described by Sappey in 1874. Perhaps, as suggested by Turner Warwick, Sappey confused the milk ducts with lymph vessels. He emphasized the subareolar plexus considering that this technique is the mercury injection in cadaver and it dates from 1800.7,8 According to this concept, the exact tumor site is not as relevant at the moment of injection, because the tumor could be located in any of the breast quadrants. However, some investigators advocate injection in the subareolar area. The lymph produced in the mammary parenchyma goes through a perilobular lymphatic network and through the interlobular spaces that feed the lymph capillaries, which meet and lead to the secondary pedicles. These lymph vessels exit the mammary gland and make up the axillary, mediastinal, and retropectoral lymphatic pedicles.9-11

Axillary Pedicle The axillary pedicle is the largest of the three mammary lymphatic pedicles; it is formed by two to six lymphatic vessels. This pedicle may receive lymph vessels from any breast quadrant, either superficial or deep, from the nipple, areola, or the skin covering the breast. It emerges from the lateral region of the breast, following the border of the pectoralis major, passes to the base of the axilla, and then crosses the pectoroaxillary aponeurosis (Fig. 6-7). Four pedicles secondary to the axillary pedicle can be identified: 1. Lateral mammary: The lateral mammary pedicle follows the path taken by the lateral mammary vessels. It is formed by two to five lymphatic vessels and joins the nodes in the lateral mammary chain. This is the first node level of the axilla.

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FIG. 6-7  1, Breast area; 2, axillary lymph nodes; 3, axillary lymphatic pedicle. Inset: Closeup view.

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2. Subscapular: The subscapular pedicle is little developed. It passes toward the posterior surface of the axilla, where the subscapular vessels lie. It consists of one or two lymphatic vessels and joins the nodes in the subscapular chain. 3. Superior thoracic: The superior thoracic pedicle is formed by a single lymphatic vessel that crosses the aponeurotic base of the axilla, passes toward the apex of the axilla, and then slips in front of the anterior serratus and behind the pectoral muscles, to end in the superior thoracic chain. It is the second node level of the axilla. 4. Axillary-vein: The axillary-vein pedicle occurs least frequently. It is so named because it passes directly into the highest part of the axillary space and lies in direct contact with the axillary vein.

Mediastinal Pedicle The mediastinal pedicle emerges from the medial part of the mammary gland, either in the superficial plane or at a deeper level, and reaches the anterior surface of the fascia of the pectoralis major by following, in some cases, the perforating branches of the internal mammary vessels. During its passage, it is associated with two secondary pedicles that because of their relationship with the pectoralis major muscle, have been named the prepectoral pedicle and subpectoral pedicle (Fig. 6-8). Two pedicles secondary to the mediastinal pedicle have been identified: 1. Prepectoral: Some lymphatic vessels run across the anterior surface of the pectoralis major muscle before penetrating between the fibers of the costosternal part of this muscle, either in the middle of the muscle or close to its sternal border; others can cross the pectoralis major immediately and pass between it and the intercostal muscles toward the nodes of the internal mammary chain. 2. Subpectoral: As it leaves the mammary gland, the subpectoral pedicle passes downward toward the inferolateral border of the pectoralis major muscle and then rapidly insinuates itself between this muscle and the superior attachment of the rectus abdominis muscle.

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FIG. 6-8  Inner view of the thoracic wall. 1, Breast area; 2, internal mammary chain; 3, perforating lymph vessels.

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Retropectoral Pedicle The retropectoral pedicle emerges from the posterior surface of the mammary gland and passes toward the pectoralis major muscle, into which it enters together with the thoracoacromial (acromiothoracic) vessels. When it passes through the costosternal part of the pectoralis major muscle, it is possible to identify three secondary pedicles: transpectoral, interpectoral, and pectoroaxillary. Three pedicles secondary to the retropectoral pedicle have been identified: 1. Transpectoral: The transpectoral pedicle owes its name to the fact that the lymphatic vessels pass through both pectoral muscles. It is formed by a single lymphatic vessel that drains directly into the superior thoracic chain or into the axillary chain. 2. Interpectoral (Grosmann-Rotter): The interpectoral pedicle is the most frequently found of the posterior pedicles. It is formed by one or two lymphatic vessels that perforate the pectoralis major muscle, following the acromiothoracic vessels and draining in the interpectoral chain made up of two to six lymph nodes. 3. Pectoroaxillary: The pectoroaxillary pedicle is formed by a single lymphatic vessel that crosses the pectoralis major and emerges by its posterior surface. It drains in the external mammary chain. It is interesting to analyze the role of the perforating lymph vessels, which are able to communicate a superficial network with the deep lymphatic system. This is observed in some specimens, where there is evidence of the connection between the superficial systems by a perforating lymph vessel to the internal mammary chain.

Lymphatic Drainage of the Upper Limb Superficial Lymphatic System Pathways The superficial lymphatic drainage of the upper limb runs mainly on its anterior surface. At the level of the forearm and upper arm one can find different lymphatic pathways taking the axis of the superficial venous system.9-13 Pathways of the Forearm • Anterior radial: Runs obliquely following the superficial radial vein and it is formed by 3 to 10 lymph vessels. • Posterior radial: Formed between 5 and 15 lymph vessels and helps with the formation of the internal or bicipital and the external or cephalic pathways. • Anterior ulnar: Runs obliquely from the hypothenar region of the hand to the fold of the elbow, from inside to outside, accompanying the superficial ulnar vein. It is formed by 5 to 8 lymphatic vessels. • Posterior ulnar: Found in the posterior face of the wrist and the lower third of the forearm, where it meets with the anterior pathway, thus contributing to the formation of the anterior or bicipital and the internal or basilic terminal lymphatic pathway. It is made up of 5 to 15 lymphatic vessels.

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Pathways of the Arm • Bicipital: Formed by 9 to 17 lymphatic vessels. It runs obliquely from the elbow to the base of the axilla, where it goes through the superficial aponeurosis to reach the different node groups of the axilla. • Basilic: Accompanies the basilic vein and is formed by 2 or 3 lymphatic vessels, being the continuation of the anterior and posterior ulnar pathways. It penetrates the deep area of the arm, at different levels, and is continued by the humeral (deep) pathway, thus reaching the deep nodes of the axilla. • Cephalic: Formed by a single vessel, satellite of the cephalic vein, which goes through the external bicipital channel and goes on through the deltopectoral groove, thus ending in the axillar region, or passing over the clavicle and ending in the supraclavicular region. • Posterior: Runs through the posterior-external face of the arm, following the deltotricipital groove. It drains in the scapular circumflex nodes.

Deep Lymphatic System The deep lymphatic system is not described here because its anatomy is beyond the scope of this chapter.

Axillary Lymph Nodes The axillary nodes are the main center of the lymphatic drainage of the upper limb and of the anterolateral and posterolateral regions of the thoracic wall, including the mammary gland. We used the classification proposed by Caplan in 197414 concerning the venous drainage of the axilla. He described four main chains: • Lateral mammary chain: Located on the front of the axillary vessels, in the anterior wall of the axillary space, and runs along the lateral mammary vessels, between the second and seventh rib. This lymph node chain is the most important center of the lymphatic drainage of the upper limb as well as of the breast and skin from the anterior and posterior region of the thorax. Its efferent vessels head to the apex of the axilla to drain their lymph in the upper thoracic chain and the axillary chain, which make up the infraclavicular group described by earlier authors. • Upper thoracic chain: Located in the inner wall of the axilla, behind the pectoral muscles, following the upper thoracic vessels. The efferent lymphatic vessels of this chain drain its lymph in the lower chain of the axillary vein, called the infraclavicular chain by earlier authors. • Subscapular chain: A satellite of the subscapular vessels and a partial satellite of the nerve of the wide dorsal muscle. It receives the drainage of the posterior thoracic wall and, in a small percentage of cases, the lymphatic drainage of the anterior and internal thoracic wall. The efferent pathways of this chain lead to the external mammary gland or the apex of the axilla to drain its lymph in the axillary vein chain. • Axillary vein chain: Located in the upper region of the axillary space, running from the pectoral-axillary base to the apex. This chain is made up of 8 to 10 lymph nodes and four secondary chains: anterior, posterior, upper, and lower. This chain receives the lymphatic drainage from all the regions of the upper limb, from the anterior and posterior thoracic wall, and from the rest of the axillary chains. The efferent pathways generally follow on to the axillary vein to finally reach the venous jugular-subclavial angle or become part of the great lymphatic vein on the right side.

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2

3

1

FIG. 6-9  Upper limb superficial lymphatic network. 1, Axillary lymph nodes; 2, cephalic derivative pathway; 3, epitrochlear lymph nodes.

Derivative Lymphatic Pathways The derivative lymphatic pathways are lymphatic vessels that do not have a node station in the axilla. These are the cephalic pathway (Mascagni), deltotricipital pathway (Caplan), and the intraaxillary pathway (Ciucci) (Fig. 6-9). Knowledge of these derivative pathways represents one of the anatomic bases for rehabilitative therapy in patients who have upper limb lymphedema, because the pathways are stimulated by the physical therapist through manual lymphatic drainage.

Lymphatic Drainage of the Lower Limb In the lower limb, the lymphatic system can be divided into a superficial and a deep system, taking the muscle fascia–aponeurosis as the axis for this division. Within the superficial system is the epifascial system, between the skin and the saphenous fascia. It is the most developed subsystem in terms of collectors because of the origins of its network of skin sectors: it runs along the width of the subcutaneous cell tissue, accompanying the superficial veins, until it reaches the inguinal lymph nodes. The interfascial system, between the saphenous fascia and the muscle fascia, has few collectors. The deep system, which is smaller, starts in the osteo-articular-muscular region, and its lymphatic collectors accompany it all the way to the vascular packages, to drain themselves in the external iliac chain. Along the way they travel through different lymph node groups in the popliteal region and, less frequently, the nodes of the femoral chain in the thigh. Finally, there are the perforating lymphatic vessels that interconnect both systems.15-17

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Superficial Lymphatic System Pathways The superficial vessels start at the foot, where the plantar lymphatic vessels can be distinguished; these are distributed as a network along the foot and are related to the venous sole, as described by Quènu and Lejars. This lymphatic network presents different morphologic features regarding the plantar support points; adopting the plexus feature in the anterior and posterior region, these being the zones with the most pressure.18 This is in contrast to the middle sector, where there are transverse collectors that drain lymph to the posterior of the foot. This lymphatic distribution of the sole of the foot enables us to extrapolate the concept of the superficial venous pump described by Quènu and Lejars to the lymphatic system of this region, which is widely distributed and activated by minimal pressure, draining lymph to the posterior of the foot and contributing to form the pathways of the leg (Figs. 6-10 and 6-11).

2 1

FIG. 6-10  1, Superficial lymphatics; 2, venous network of the sole of the foot.

1

2

FIG. 6-11  Superficial lymphatic network of the lower limb. 1, Inguinal nodes; 2, femoral great saphenous current; 3, tibial great saphenous current. Inset: Closeup view of nodes.

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TABLE 6-1  Pathways of the Superficial Lymphatic System Pathway

Number of Vessels Involved

Location

Forearm Anterior radial

3-10

Runs obliquely following the superficial radial vein

Posterior radial

5-15

Helps with the formation of the internal or bicipital and the external or cephalic pathways

Anterior ulnar

5-8

Runs obliquely from the hypothenar region of the hand to the fold of the elbow, from inside to outside, accompanying the superficial ulnar vein

Posterior ulnar

5-15

Found in the posterior face of the wrist and the lower third of the forearm, where it meets with the anterior pathway, thus contributing to the formation of the anterior or bicipital and the internal or basilic terminal lymphatic pathway

Bicipital

9-17

Runs obliquely from the elbow to the base of the axilla, where it goes through the superficial aponeurosis to reach the different node groups of the axilla

Basilic

2 or 3

Accompanies the basilic vein; the basilic vessel is the continuation of the anterior and posterior ulnar pathways; it penetrates the deep area of the arm at different levels and is continued by the humeral (deep) pathway, thus reaching the deep nodes of the axilla

Arm

Cephalic

1

Posterior

Satellite of the cephalic vein, which goes through the external bicipital channel and on through the deltopectoral groove, thus ending in the axillary region, or passing over the clavicle and ending in the supraclavicular region Runs through the posterior external face of the arm, following the deltotricipital groove; it drains in the scapular circumflex nodes

At the level of the leg and thigh, with the great saphenous vein as the axis, different lymphatic paths can be identified (Table 6-1).

Deep Lymphatic System The few vessels of the deep lymphatic system are part of the deep vascular package and are not described here, because they are beyond the scope of this chapter.

Inguinal Nodes The inguinal nodes form the main center of lymphatic drainage for the lower limb. There are 7 to 17 nodes, all located at the superficial fascia. It is a mistake to include deep inguinal nodes in this classification. It is also inexact to include the classic Cloquet, Rosenmüller, or Pirogoff node within the crural ring or channel as a member of the upper deep inguinal group, because it belongs to the medial group of the external iliac chain.

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The nodes located in the internal face of the femoral vein, between the internal lower edge of the crural ring and the upper edge of the arch of the great saphenous vein, are not deep nodes, because at that level the superficial aponeurosis is bound to the pectineal aponeurosis. The nodes located in the medial region of the femoral vein, under the saphenous arch, should not be considered deep inguinal nodes, but nodes belonging to the femoral vessel chain. From the thirteenth century to date, a number of authors have described the inguinal nodes and have proposed different nomenclatures to classify the existing node groups,3,19-22 but the one that has stood the test of time is the one proposed by Quènu and Lejars,23 who classified the groups using two imaginary lines, one perpendicular and one vertical, in relation to the axis of the great saphenous vein. This classification allows these nodes to be grouped in four groups and a central one. In our research we were able to observe that there is a close relation between these nodes and the ones that branch from the great saphenous vein in the femoral saphenous junction. The lymph node vessels from this region drain in the various tributaries of the saphenous vein or in the vein itself. It is of utmost importance for anatomic repair of this vein and its tributaries to classify the inguinal nodes. Surgeons must take into account the random anatomic variations of the superficial venous system to avoid injuries to the lymphatic vessels. Optimal anatomic knowledge is essential to safe and successful surgery in this region. With these criteria, we can distinguish the following veins as tributary veins of the great saphenous vein: • Circumflex iliac vein • Superficial epigastric vein • Pudendal vein • Anterior accessory of the great saphenous vein Thus five very different groups can be defined: three upper groups and two lower ones (Figs. 6-12 and 6-13). • Circumflex iliac group: Located below the external third of the crural arch and closely related to the iliac circumflex vein. This group is constant and varies from 2 to 5 nodes. It has afferent vessels from the cutaneous area of the lumbar, gluteal, and external abdominal regions, the external genitals, the anal canal, and the lower limb. It has efferent vessels that are related to the superficial epigastric group and the external iliac chain. • Superficial epigastric group: Located below the middle third of the crural arch and related to the superficial epigastric vein. It is constant and varies from 2 to 3 nodes. It receives afferent vessels from the cutaneous area of the anterior abdominal and lumbar regions, the external genitals, and the anal canal. Its efferent vessels flow to the pudendal group and the iliac chain. • Pudendal group: Located below the internal third of the crural arch and above the pectineus muscle. This group has an intrinsic relation with the external pudendal veins, is constant, and has from 2 to 4 nodes. It receives afferent vessels from the external genital, anal, and abdominal regions, and a smaller proportion from the lower limb. Its efferent vessels flow to the crural ring to reach the external iliac chain, and it is the main receptor of the Cloquet, Rosemüller, or Pirogoff node, mistakenly considered a deep inguinal node.

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1

FIG. 6-12  1, Inguinal lymph nodes; 2, iliac lymph nodes. Inset: Closeup view of nodes.

3 2

FIG. 6-13  1, Deep lymph vessels; 2, inguinal lymph nodes; 3, iliac lymph nodes. 1

• Medial saphenous group: Located below the falciform ligament, inside the great saphenous vein. This group is constant and is made up of 1 to 3 nodes, of which 1 is frequently found. It receives afferent vessels from the lower limb, the external genitals, the anal canal, and the cutaneous area of the perineum. Its efferent vessels flow to the upper groups and the external iliac chain. • Lateral saphenous group: Located below the lower part of the falciform ligament and outside the anterior accessory vein. It is constant and frequently consists of 1 node. It mainly receives afferent vessels from the lower limb. Its efferent vessels flow to the upper groups, to the medial great saphenous vein, and to the external iliac chain. The difference in the afferent vessels between the upper groups in comparison with the lower groups means that it is of the utmost importance to preserve, to the degree possible, the lower groups—the ones that receive the greatest afferent vessels from the lower limb. Surgical injuries of

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the lymphatic system can occur during even a minimal intervention in this area, such as a simple biopsy, or as an unnoticed injury caused during venous surgery. This is the reason that in lymph node transfers, external upper inguinal nodes are frequently used to preserve the lower groups. Surgeons should not only be cautious of causing secondary injuries in the inguinal region, but also those that might occur in the trunk of the great saphenous vein, considering the relationship with the superficial lymphatic system in the internal leg. The distribution of the superficial lymphatic system in the lower limb is located mainly on the epifascial stratus and not on the interfascial one, together with the great saphenous vein. Saphenous stripping may have increased the likelihood of secondary injuries of the lymphatic system; today this is much less likely. Laser techniques and radiofrequency procedures are usually the best choice to completely avoid secondary injuries. However, if these technologies are used incorrectly, their thermal radiation may injure surrounding tissues.

Superficial Popliteal Node Several authors, such as Mascagni, Bardeleben, Haekel and Froshe, Poirier and Cuneo, Ehinger, Baum, and Jdanov, among others, who have observed this node. It is important to take this node into account when performing lymphoscintigraphy, because visualization of the nodes at the popliteal level is a marker of hypertension in the superficial system, referring to deep nodes and marking the difference with the superficial popliteal node, which is a simple node station belonging to the frequent solitaire nodes. It is located in the region of the popliteal fossa and is closely related to the small saphenous vein. It is represented by a single node and receives afferent vessels from the surrounding sectors and their efferent vessels drain to the deep popliteal nodes.

R EFERENCES 1. Houssay B. La Investigación Científica. Buenos Aires, Argentina: Ed Columba, 1960. 2. Pissas A. Dissertation à propos des téchniques d’injection cadaverique des vaisseaux lymphatiques et leur contribution à la connaissance du drainage lymphatique des viscères. Memoire. Presente a l’Univiersité Paris Nord, Paris, 1979. 3. Amore M, Verges J. Variación de la técnica de diafanización aplicada al sistema linfático. Presented at the Thirty-sixth Congreso Rioplatense de Anatomía, Mendoza, Argentina, 1999. 4. Bartels P. Das Lymphgefabsystem. In Bardeleben’s Handbuch der Anatomie des Menschen. Jena, Germany: G Fisher, 1909. 5. Poirier P, Cuneo B. Étude spéciale des lymphatiques des differentes parties du corp. In Poirier P, Charpy A. Traité de l’Anatomie Humaine. Part II, vol 4. Paris: Masson, 1902. 6. Rovuiere H. Anatomie des Lymphatiques de l’Homme. Paris: Masson, 1932. 7. Földi M, Földi E, Kubik S. Textbook of Lymphology. Munich: Elsevier, 2003. 8. Kiefer F, Schulte-Marker S. Developmental aspect of the lymphatic vascular system. Vienna: SpringerVerlag, 2014. 9. Dieter R, Dieter R Jr, Dieter R III. Venous and lymphatic diseases. New York: McGraw-Hill, 2011. 10. Campisi CC, Amore M. Lymphatic drainage of mammary gland: from anatomy to surgery to microsurgery. Progress in Lymphology XXIII. 45(Suppl):75-78, 2012. 11. Amore M. Review the lymphatic anatomy on the sentinel node era. Progress in Lymphology XXIII. 45(Suppl):99, 2012.

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12. Suami H, Pan WR, Mann GB, Taylor GI. The lymphatic anatomy of the breast and its implications for sentinel lymph node biopsy: a human cadaver study. Ann Surg Oncol 15:863-871, 2008. 13. Borgstein PJ, Meijer S, Pijpers RJ, et al. Functional lymphatic anatomy for sentinel node biopsy in breast cancer: echoes from the past and the periareolar blue method. Ann Surg 232:81-89, 2000. 14. Etude des Centres Lymphoganglionnaires superficiels et profonds du membre supérieur. 58 Congrès de l’Asociation des Anatomistes. Liège, 1974. 15. Caplan I. Lymphatic drainage of the mammary gland. Ann Clin 4:329-335, 1982. 16. Caplan I. Estudio e Investigación para una División de la Distribución Linfática Ganglionar de la Región Axilar dada por la Estrella Venosa de la Misma. Buenos Aires, Argentina: La Semana Medica, 1958. 17. Ciucci JL. Linfedema del Miembro Superior. Buenos Aires, Argentina: Nayarit, 2009. 18. Caplan I. Le système lymphatique du pouce. Mémoires du Laboratoire d’Anatomie de la Faculté de Médecine de Paris. 32:5-65, 1977 19. Ciucci JL. Doctoral thesis. Grandes corrientes linfáticas del miembro superior. Buenos Aires University, Buenos Aires, Argentina, 1987. 20. Caplan I. Sugestiones para una Nueva División Topográfica de la Distribución Linfática de la Región Inguinofemoral, dada por la Estrella Venosa de Scarpa. Buenos Aires, Argentina: La Prensa Medica, 1957. 21. Caplan I. Doctoral thesis. El sistema linfático ganglionar de la región poplítea. Buenos Aires University, Buenos Aires, Argentina, 1966. 22. Ciucci JL. Linfedema de los Miembros Inferiores. Buenos Aires, Argentina: Nayarit, 2009. 23. Quènu E, Lejars F. Les Veines de la Plante du Pied Chez l’Homme et le Grands Animaux. Ètudes sur le Système Circulatoire, vol I. Paris: G Steinheil, 1894.

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C hapter 7 Lymphangiogenesis Jeremy S. Torrisi, Ira L. Savetsky, Jason C. Gardenier, Babak J. Mehrara

K ey P oints • Lymphangiogenesis is the formation of new lymphatic vessels. • Lymphangiogenesis is regulated by both prolymphangiogenic and antilymphangiogenic mechanisms. • B cells and macrophages are key sources of prolymphangiogenic growth factors, such as vascular endothelial growth factors.

Lym

• T cells are a key source of antilymphangiogenic cytokines, such as interferon gamma.

Lymphangiogenesis is the formation of new lymphatic vessels. Specifically, lymphangiogenesis refers to the sprouting of lymphatic vessels from preexisting vessels with migration and differentiation of lymphatic endothelial cells (LECs). In contrast, lymphovasculogenesis refers to the de novo formation of lymphatic vessels from mesenchymal-derived sources. These processes are not mutually exclusive and contribute to varying degrees to lymphatic vessel development and proliferation. This process is regulated by a complex interaction between prolymphangiogenic and antilymphangiogenic forces, the balance of which modulates a wide variety of effects in LECs, including migration, differentiation, proliferation, and survival.

Prolymphangiogenic Mechanisms The discovery of lymphatic-specific markers such as Prox1, LYVE1, and podoplanin led to a significant increase in our understanding of the mechanisms that regulate lymphatic development and regeneration. These studies have identified several growth factors and cytokines that either directly or indirectly regulate LEC differentiation, proliferation, migration, and function. These molecules are expressed in various tissues and have overlapping functions. In general, the expression of lymphangiogenic factors leads to lymphatic vessel growth and regeneration, thereby increasing lymphatic function, although there are some tissue and temporal differences in the mechanisms of action. Although initial studies in this field focused on vascular endothelial growth 113

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factors, more recent studies have identified several crucial lymphatic regulators, which suggests that lymphatic homeostasis is a complex process in vivo.

Vascular Endothelial Growth Factors A crucial factor for LEC development is vascular endothelial growth factor C (VEGF-C). VEGF-C interacts with vascular endothelial growth factor receptor 2 (VEGFR-2) and vascular endothelial growth factor receptor 3 (VEGFR-3) and regulates a wide range of effects in LECs, including differentiation, survival, and migration. Vascular endothelial growth factor D (VEGF-D) is a closely related homolog that also activates VEGFR-2/VEGFR-3. VEGFR-3 expression is primarily limited to LECs in postnatal mice and is used as a specific marker to identify lymphatic vasculature.1 VEGF-C, and to a lesser extent VEGF-D, are highly expressed in the regions of the body in which the lymphatics develop in abundance.2 Gradients of VEGF-C regulate the migration of LECs during lymphatic repair after wound healing, and VEGF-C overexpression in the skin of transgenic mice results in lymphatic proliferation and vessel enlargement.3 Similarly, gene therapeutic or recombinant protein delivery of VEGF-C results in lymphangiogenesis caused by increased budding, migration, proliferation, and differentiation of LECs.4 The pioneering work of Karkkainen et al2 showed that VEGF-C is essential for lymphatic development, because VEGF-C–deficient mice do not develop lymphatic vasculature and die in utero. Mice heterozygous for VEGF-C have severely hypoplastic lymphatics with significant lymphatic defects, including lymphedema. Although VEGF-C and VEGF-D appear to have overlapping effects, the independent roles of these growth factors are not completely understood, because congenital VEGF-D deficiency is not lethal. However, exogenous delivery of VEGF-D can rescue VEGF-C knockout mice and restore lymphatic differentiation and development. The key roles for VEGF-C in the regulation of lymphatic development and function are also reflected in VEGFR-3– deficient mice and humans. Although homozygous deficiency of VEGFR-3 results in intrauterine death, mice with a heterozygous inactivating mutation of VEGFR-3 develop chylous ascites and primary lymphedema with severely hypoplastic cutaneous lymphatic vessels.4,5 Heterozygous inactivating mutations of VEGFR-3 have also been clinically identified and are the cause of Milroy disease, an autosomal dominant form of primary lymphedema. The exogenous administration of VEGF-C improves lymphatic function in many models of lymphatic insufficiency and dysfunction. For instance, local delivery of VEGF-C in various animal models of primary or secondary lymphedema, including the rabbit ear, rat hindlimb, and mouse tail models, significantly decreases edema, improves lymphangiogenesis, and decreases the pathologic changes associated with lymphedema.6-8 Similarly, the local delivery of VEGF-C in sheep, pig, and rat lymphadenectomy models enhances lymphatic transport and decreases lymphedema.9 Adenoviral VEGF-C delivery induced growth, remodeling, differentiation, and maturation of lymphatic capillaries after lymph node dissection in mouse and pig models.10-13 However, although these results are exciting, the clinical translation of these findings to patients with iatrogenic lymphedema resulting from cancer treatment has been hampered because VEGF-C is a major regulator of tumor growth and metastasis.14-16 In addition, in some preclinical models, the exogenous administration of even massive doses of VEGF-C has not led to an improvement in lymphedema, which suggests that additional mechanisms are involved.17 Therefore understanding these other pathways (see Antilymphangiogenic Mechanisms in this chapter) is critical if lymphangiogenesis and the restoration of lymphatic flow are the ultimate goals.

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VEGF-A (often simply referred to as VEGF) is a well-known regulator of angiogenesis and ac­ tivates VEGFR-2. However, recent work indicates that VEGF-A, which is also a regulator of lymphangiogenesis, plays a central role in this process in some circumstances. For example, inflammatory lymphangiogenesis in the lymph nodes is considered primarily regulated by in­ creased B-cell expression of VEGF-A. These effects are the result of activation of VEGFR-2 on LECs, which subsequently activate a diverse set of intracellular pathways with significant overlap with VEGF-C/VEGFR-3. Similarly, gene therapeutic approaches with VEGF-A promote lymphatic vessel enlargement and proliferation.18,19 However, in contrast to VEGF-C, VEGF-A administration is also associated with the proliferation of immature, leaky blood vessels. Macrophages are a key cellular source of VEGF-C and VEGF-A during wound repair. Indeed, these cells play a key role in the regulation of lymphangiogenesis in several physiologic settings, including inflammation, tumor-associated lymphangiogenesis, and during wound repair. Bone marrow–derived monocytes are recruited by various inflammatory stimuli and differentiate into macrophages that then secrete inflammatory cytokines and chemokines. In addition, macrophages produce large amounts of VEGF-C, thereby promoting LEC migration and differentiation. A few studies have also suggested that macrophages can transdifferentiate into LECs, thereby directly contributing to and incorporating into newly formed lymphatic vessels. Abnormalities in macrophage function and VEGF-C production have been linked to impaired lymphangiogenesis in diabetic mouse models, suggesting that this pathway plays an important physiologic role. Other sources of VEGF-C include B cells and mast cells. However, the relative contribution of these cell types to lymphangiogenesis during wound repair remains less well understood.20,21

Fibroblast Growth Factors Fibroblast growth factors (FGFs) are a family of growth factors that are involved in lymphangiogenesis, angiogenesis, endocrine signaling pathways, and wound healing.22 Although there are many isoforms of FGFs, the lymphangiogenic roles of FGF-1 and FGF-2 have been the most widely studied. These growth factors regulate lymphangiogenesis by direct (for example, direct effects on LECs) and indirect (by activation of VEGFs) mechanisms. However, the preponderance of evidence suggests that indirect mechanisms are more important in vivo. Several lines of evidence propose that these indirect mechanisms are related to increased expression of VEGF-C, VEGF-C independent activation of VEGFR-3, and upregulation of VEGFR-3 expression.23 Thus, although the exact mechanisms by which FGFs regulate lymphangiogenesis remain unknown, it is likely that these growth factors have key roles in vivo and that the effects of these pathways are dose, site, and situation dependent.24

Hepatocyte Growth Factor Hepatocyte growth factor (HGF) is a growth factor produced by various cells of mesenchymal origin. The growth factor is a heparin-binding glycoprotein whose expression is mediated by the binding of the HGF receptor, a large, membrane-spanning receptor kinase.25 HGF directly promotes the proliferation, migration, and tubule formation of LECs. Overexpression of HGF in transgenic mice significantly increases lymphatic vessel proliferation, and the delivery of exogenous HGF in mouse and rat models of lymphedema ameliorates lymphedema.26,27 Recent epidemiologic studies have also shown that HGF signaling plays a key role clinically in lymphan-

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giogenesis and lymphatic repair, because patients with HGF signaling defects had a significantly increased risk of developing secondary lymphedema.28,29

Insulin-Like Growth Factors Insulin-like growth factor1 (IGF-1) and IGF-2 directly regulate lymphangiogenesis by binding cell surface receptors and multiple IGF-binding proteins.30 In contrast to FGFs, the effects of IGFs on inflammatory lymphangiogenesis appear to be independent of VEGFR-3 activation or expression of VEGF-C, which suggests that IGFs have direct effects on LECs. This family causes promotion of lymphangiogenesis both in vivo and in vitro. With the corneal model of lymphangiogenesis, IGF-1 and IGF-2 induce lymphangiogenesis. Interestingly, this effect was not reduced after VEGFR-3 activity was inhibited, which suggests that IGF’s effect on lymphangiogenesis is not mediated by the VEGF-C/VEGFR-3 pathway. IGF-2 stimulates LEC proliferation and migration in vitro.31

Platelet-Derived Growth Factors Like the IGF family, the platelet-derived growth factor (PDGF) family is large and is composed of five different isoforms (PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD). These isoforms bind to three different tyrosine kinase receptors (PDGF alpha alpha, PDGF beta beta, and PDGF alpha beta).32 PDGFs have potent lymphangiogenic roles regulating LEC proliferation, survival, and migration as demonstrated by in vivo and in vitro studies. PDGF-induced lymphangiogenesis is not inhibited by VEGF-C antagonists or VEGFR-3 blockade, which suggests that the primary mode of action for PDGFs in lymphangiogenesis is a direct one.33 However, other studies have shown that although PDGF has direct effects on lymphangiogenesis, these effects are synergistic with VEGF-C/VEGFR-3 stimulation.34

Antilymphangiogenic Mechanisms The vast majority of studies in the literature have focused on mechanisms that promote lymphangiogenesis. However, recent studies indicate that this process is regulated on multiple levels and represents a balance between prolymphangiogenic and antilymphangiogenic forces. Thus, in some physiologic settings, even high doses of recombinant lymphangiogenic cytokines are overwhelmed by antilymphangiogenic forces, which result in impaired lymphatic function and defective lymphatic regeneration. Furthermore, the balance between prolymphangiogenic and antilymphangiogenic mechanisms is complex and context dependent such that temporal, spatial, or tissue-dependent factors can tip the balance between these opposing mechanisms. Nevertheless, it is clear that experimental approaches designed to improve lymphatic function must take both pathways into consideration and optimize their balance for best results.

Transforming Growth Factor Beta 1 Transforming growth factor beta 1 (TGF-beta 1) is a growth factor that plays a key regulator role in various cellular processes, including embryogenesis, immune responses, tissue and wound repair, and inflammation.35 TGF-beta 1 acts by signaling through transmembrane receptor serine and threonine kinases and regulates multiple intracellular pathways.36 Recent studies have shown that TGF-beta 1 is necessary for lymphatic development during embryogenesis, but serves as a

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negative regulator of lymphangiogenesis during wound repair and in tumor-associated lymph­ angiogenesis. In these circumstances, TGF-beta 1 directly decreases LEC proliferation and tu­ bule formation and negatively regulates genes necessary for lymphatic differentiation.37,38 TGFbeta 1 expression is potently increased in response to lymphatic injury and in lymphedematous tissues, and inhibition of TGF-beta 1 activity decreases fibrosis, increases lymphangiogenesis, and improves lymphatic function in preclinical mouse models.39 These effects of TGF-beta 1 appear to be independent of VEGF-C/VEGFR-3 signaling, because even high levels of VEGF-C do not overcome the negative effects of TGF-beta 1 on lymphatic function. Collectively, these findings suggest that manipulation of TGF-beta 1 function may be a novel way to improve lymphatic function and regeneration in the experimental treatment of lymphedema.

Interferon Gamma Interferon gamma (IFN-gamma) is a cytokine secreted by leukocytes with critical roles in innate and adaptive immune responses.40,41 More recent studies have shown that IFN-gamma, which is similar to TGF-beta 1, has direct antilymphangiogenic effects and plays an important role in the resolution of inflammatory lymphangiogenesis and in the regulation of lymphatics during wound healing. These results are related to various effects of IFN-gamma on LECs, including increased apoptosis, impaired proliferation, decreased migration, and inhibition of functional differentiation.42 In addition, similar to TGF-beta 1, IFN-gamma is bound by specific receptors expressed on the surface of LECs and directly regulates the expression of lymphatic-specific genes.43 Inhibition of IFN-gamma function markedly increases inflammatory lymphangiogenesis and delays its resolution after the inflammatory stimulus has been removed. A primary source of IFN-gamma in this process is T cells, a finding that has led some investigators to suggest that T cells are antilymphangiogenic. These findings are supported by previous studies showing that depletion of T cells markedly increases lymphatic repair after injury and suggests that inhibition of T-cell responses may represent a novel means by which lymphatic repair can be augmented.44

Endostatin Endostatin is a proteolytic fragment originating from collagen XVIII that inhibits endothelial cell proliferation, angiogenesis, and tumor growth.45 More recent studies have shown that endostatin is a potent physiologic inhibitor of lymphangiogenesis in tumor-associated lymphatics.46 In vitro studies have shown that endostatin markedly inhibits proliferation and tubule formation of LECs. These findings support in vivo studies in mice that have shown inhibition of lymphangiogenesis and lymph node metastases of human oral squamous cell carcinomas.47 These effects are related to the direct effects of endostatin on LECs and the indirect modulation of VEGF-C expression and disruption of LEC interaction with integrin alpha 9, a key extracellular matrix molecule regulating LEC proliferation and survival.48,49

Clinical Implications A clearer understanding of the cellular and molecular mechanisms that regulate lymphangiogenesis has important clinical implications. The most significant aspect of this research is the attempt to shift the balance between prolymphangiogenic and antilymphangiogenic forces to increase lymphangiogenesis. For example, blockade of antilymphangiogenic cytokines in combination with

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the delivery of VEGF-C may not only increase lymphatic regeneration potential but also decrease the dose of VEGF-C that is necessary to achieve this end result. This is important in patients with cancer-related lymphedema, because prolymphangiogenic growth factors such as VEGF-C and VEGF-A regulate tumor growth and metastasis. Thus decreasing the dose of these growth factors has important oncologic implications and may aid in clinical translation of preclinical studies. Alternatively, it may be possible to simply downregulate antilymphangiogenic mechanisms without the additional delivery of VEGF-C to achieve this end result. This approach has been reported in preclinical studies showing that blockade of TGF-beta 1 or inhibition of T-cell inflammatory responses can potently increase lymphangiogenesis independent of concomitant increases in VEGF-A or VEGF-C. A combination of these interventions with surgical treatment of lymphedema may lead to improved lymphangiogenesis and with more predictable outcomes, thereby increasing the efficacy of surgical interventions.

Conclusion Lymphangiogenesis is a complex process guided by various discrete but overlapping mechanisms. Understanding these pathways is critical for the development of novel methods designed to improve lymphangiogenesis and lymphatic function. In addition, understanding the balance between prolymphangiogenic and antilymphangiogenic pathways and the cellular sources of molecules that regulate these processes provides additional insight into viable treatment options that can be combined with surgery to augment lymphatic function.

C linical P earls • The treatment of lymphatic dysfunction may be improved by inducing lymphangiogenesis. • Lymphangiogenesis can be facilitated by the upregulation of prolymphangiogenic growth factors and the inhibition of antilymphangiogenic factors. • Augmentation of lymphangiogenesis along with other treatment modalities (for example, surgery and compression) may be necessary to stabilize the disease and improve patient outcomes.

R EFERENCES 1. Tammela T, Enholm B, Alitalo K, et al. The biology of vascular endothelial growth factors. Cardiovasc Res 65:550-563, 2005. 2. Karkkainen MJ, Haiko P, Sainio K, et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 5:74-80, 2004. 3. Jeltsch M, Kaipainen A, Joukov V, et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276:1423-1425, 1997 4. Karpanen T, Alitalo K. Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol 3:367-397, 2008.

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5. Alitalo K, Tammela T, Petrova TV. Lymphangiogenesis in development and human disease. Nature 438:946-953, 2005. 6. Szuba A, Skobe M, Karkkainen MJ, et al. Therapeutic lymphangiogenesis with human recombinant VEGF-C. FASEB J 16:1985-1987, 2002. 7. Yoon YS, Murayama T, Gravereaux E, et al. VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema. J Clin Invest 111:717-725, 2003. 8. Liu Y, Fang Y, Dong P, et al. Effect of vascular endothelial growth factor C (VEGF-C) gene transfer in rat model of secondary lymphedema. Vasc Pharmacol 49:44-50, 2008. 9. Baker A, Kim H, Semple JL, et al. Experimental assessment of pro-lymphangiogenic growth factors in the treatment of post-surgical lymphedema following lymphadenectomy. Breast Cancer Res 12:R70, 2010. 10. Tammela T, Saaristo A, Holopainen T, et al. Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Nat Med 13:1458-1466, 2007. 11. Lähteenvuo M, Honkonen K, Tervala T, et al. Growth factor therapy and autologous lymph node transfer in lymphedema. Circulation 123:613-620, 2011. 12. Honkonen KM, Visuri MT, Tervala TV, et al. Lymph node transfer and perinodal lymphatic growth factor treatment for lymphedema. Ann Surg 257:961-967, 2013. 13. Sommer T, Buettner M, Bruns F, et al. Improved regeneration of autologous transplanted lymph node fragments by VEGF-C treatment. Anat Rec (Hoboken) 295:786-791, 2012. 14. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011-1027, 2005. 15. Chen JC, Chang YW, Hong CC, et al. The Role of the VEGF-C/VEGFRs axis in tumor progression and therapy. Int J Mol Sci 14:88-107, 2012. 16. Skobe M, Hamberg LM, Hawighorst T, et al. Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. Am J Pathol 159:893-903, 2001. 17. Uzarski J, Drelles MB, Gibbs SE, et al. The resolution of lymphedema by interstitial flow in the mouse tail skin. Am J Physiol Heart Circ Physiol 294:H1326-H1334, 2008. 18. Nagy JA, Vasile E, Feng D, et al. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 196:1497-1506, 2002. 19. Kunstfeld R, Hirakawa S, Hong YK, et al. Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia. Blood 104:1048-1057, 2004. 20. Kim H, Kataru RP, Koh GY. Regulation and implications of inflammatory lymphangiogenesis. Trends Immunol 33:350-356, 2012. 21. Kataru RP, Lee YG, Koh GY. Interactions of immune cells and lymphatic vessels. Adv Anat Embryol Cell Biol 214:107-118, 2014. 22. Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 7:165-197, 2000. 23. Kubo H, Cao R, Brakenhielm E, et al. Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea. Proc Natl Acad Sci U S A 99:8868-8873, 2002. 24. Chang LK, Garcia-Cardeña G, Farnebo F, et al. Dose-dependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci USA 101:11658-11663, 2004. 25. Giordano S, Di Renzo MF, Narsimhan RP, et al. Biosynthesis of the protein encoded by the c-met protooncogene. Oncogene 4:1383-1388, 1989. 26. Kajiya K, Hirakawa S, Ma B, et al. Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J 24:2885-2895, 2005. 27. Saito Y, Nakagami H, Morishita R, et al. Transfection of human hepatocyte growth factor gene ameliorates secondary lymphedema via promotion of lymphangiogenesis. Circulation 114:1177-1184, 2006.

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28. Finegold DN, Schacht V, Kimak MA, et al. HGF and MET mutations in primary and secondary lymphedema. Lymphat Res Biol 6:65-68, 2008. 29. Miaskowski C, Dodd M, Paul SM, et al. Lymphatic and angiogenic candidate genes predict the development of secondary lymphedema following breast cancer surgery. PloS One 8:e60164, 2013. 30. Clemmons DR. Insulin-like growth factor binding proteins and their role in controlling IGF actions. Cytokine Growth Factor Rev 8:45-62, 1997. 31. BjÖrndahl M, Cao R, Nissen LJ, et al. Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc Natl Acad Sci USA 102:15593-15598, 2005. 32. Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22:1276-1312, 2008. 33. Cao R, Björndahl MA, Religa P, et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 6:333-345, 2004. 34. Onimaru M, Yonemitsu Y, Fujii T, et al. VEGF-C regulates lymphangiogenesis and capillary stability by regulation of PDGF-B. Am J Physiol Heart Circ Physiol 297:H1685-H1696, 2009. 35. Flanders KC, Major CD, Arabshahi A, et al. Interference with transforming growth factor-beta/Smad3 signaling results in accelerated healing of wounds in previously irradiated skin. Am J Pathol 163:22472257, 2003. 36. Massague J, Blain SW, Lo RS. TGF beta signaling in growth control, cancer, and heritable disorders. Cell 103:295-309, 2000. 37. Oka M, Iwata C, Suzuki HI, et al. Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis. Blood 111:4571-4579, 2008. 38. Clavin NW, Avraham T, Fernandez J, et al. TGF-beta1 is a negative regulator of lymphatic regeneration during wound repair. Am J Physiol Heart Circ Physiol 295:H2113-H2127, 2008. 39. Avraham T, Daluvoy S, Zampell J, et al. Blockade of transforming growth factor-beta1 accelerates lymphatic regeneration during wound repair. Am J Pathol 177:3202-3214, 2010. 40. Dalton DK, Pitts-Meek S, Keshav S, et al. Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science 259:1739-1742, 1993. 41. Schoenborn JR, Wilson CB. Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 96:41-101, 2007. 42. Shao X, Liu C. Influence of IFN-alpha and IFN-gamma on lymphangiogenesis. J Interferon Cytokine Res 26:568-574, 2006. 43. Kataru RP, Kim H, Jang C, et al. T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity 34:96-107, 2011. 44. Zampell JC, Yan A, Elhadad S, et al. CD4(1) cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis. PloS One 7:e49940, 2012. 45. O’Reilly MS, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277-285, 1997. 46. Dong X, Zhao X, Xiao T, et al. Endostar, a recombined humanized endostatin, inhibits lymphangiogenesis and lymphatic metastasis of Lewis lung carcinoma xenograft in mice. Thorac Cardiovasc Surg 59:133-136, 2011. 47. Fukumoto S, Morifuji M, Katakura Y, et al. Endostatin inhibits lymph node metastasis by a downregulation of the vascular endothelial growth factor C expression in tumor cells. Clin Exp Metastasis 22:31-38, 2005. 48. Brideau G, Mäkinen MJ, Elamaa H, et al. Endostatin overexpression inhibits lymphangiogenesis and lymph node metastasis in mice. Cancer Res 67:11528-11535, 2007. 49. Ou J, Li J, Pan F, et al. Endostatin suppresses colorectal tumor-induced lymphangiogenesis by inhibiting expression of fibronectin extra domain A and integrin alpha9. J Cell Biochem 112:2106-2114, 2011.

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C hapter 8 Impact of Genetics on Lymphangiogenesis Kristiana Gordon, Pia Ostergaard

K ey P oints • Primary lymphedema is the presenting symptom of numerous distinct conditions; it is genetically heterogeneous. • Several abnormalities within the genes involved in lymphangiogenesis have been reported to cause primary lymphedema.

Imp

• The identification of more pathogenic genes will advance our knowledge of the etiopathogenesis of lymphatic disease. In time, this may allow the development of therapeutic interventions. • Patients presenting with unexplained lymphedema, even in adulthood, are likely to have an underlying genetically determined primary lymphatic abnormality.

It has become clear that primary lymphedema is not one disease but a clinical sign of several distinct clinical entities. Most patients presenting with lymphedema in adulthood are diagnosed with secondary lymphedema, even without a clear underlying cause. It is likely that many of these patients will have an underlying genetically determined primary lymphatic abnormality that the clinician has not considered. The identification of the molecular abnormality for each subtype of primary lymphedema is crucial, because it advances the understanding of the underlying mechanism of the disease. This knowledge will assist with the identification of new therapeutic strategies in the future. Lymphangiogenesis is the term used to describe the growth of new lymphatic vessels. Developmental lymphangiogenesis occurs in the fetus as the lymphatic system develops. However, lymphangiogenesis may also occur postnatally (for example, in association with inflammatory disease or cancer). This chapter discusses the development of the lymphatic system. (Chapter 7 provides additional detail about the clinical consequences of abnormalities in this process.) 121

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Vein

Primary lymphatic plexus

VEGF-C

Master vasculature H2O Macromolecules cells Anchoring filaments

Buttonlike junctions

Lymph sac

Smooth muscle cells Luminal valve

LEC progenitors? Prox1 Sox18 COUP-TFII

VEGF-C/VEGFR-3 CCBE1

LEC differentiation

Lymphatic capillaries

Nrp2

FOXC2 Integrin-a9 Ephrin-B2

Sprouting

Zipperlike junctions Collecting vessels

Remodeling

FIG. 8-1  Developmental lymphangiogenesis. The main stages of lymphatic development and the characteristics of normal vessels are shown. The key regulators of different lymphangiogenic processes are indicated in blue. Blood and lymphatic vessels and endothelial cells are shown in red and blue, respectively. (CCBE1, Collagen and calcium-binding EGF domain 1; COUP-TFII, COUP transcription factor II; FOXC2, forkhead box C2; LEC, lymphatic endothelial cell; Nrp2, neuropilin 2; Prox1, prospero homeobox; Sox18, SRY (sex determining region Y)-Box18; VEGF-C, vascular endothelial growth factor C; VEGFR-3, vascular endothelial growth factor receptor 3.)

Martinez-Corral and Makinen1 have schematically summarized developmental lymphangiogenesis in Fig. 8-1. Until recently, the lymphatic system has remained largely ignored by the scientific and medical communities. An overview of the current theories and factors reported to be involved in lymphatic development is presented in this chapter. The literature is continuously updated with newly identified molecules thought to play a role1 (see Chapter 7). Research into lymphangiogenesis has recently identified several lymphatic endothelial cell–specific molecular markers and the genes involved in the process of lymphatic development (Fig. 8-2). Abnormalities within several of these genes are now known to cause different primary lymphedema phenotypes in both humans and animal models (see Chapter 46). However, these recent advances merely represent the “tip of the iceberg,” because there is much about lymphangiogenesis that must still be discovered.

The Origin of Lymphatic Endothelial Cells The first lymph sacs develop in human embryos at the age of 6 to 7 weeks’ gestation, almost 1 month after the blood vasculature system begins to develop.2 Animal model research (see Chapter 46) has demonstrated that a subpopulation of blood endothelial cells, which sprout from cardinal and peripheral veins, will differentiate into lymphatic endothelial cells (LECs).3 Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) is the earliest known cell marker indicating that LEC competence has been acquired.4 The LECs will then bud off to form primitive lymphatic structures called lymph sacs.5

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FIG. 8-2  The various molecular influences under development of the lymphatic system. (Ang1, 2, 3/4, Angiopoietin 1, 2, 3/4; CCBE1, collagen and calcium-binding EGF domain 1; ECM, endothelial cell membrane; FoxC2, forkhead box C2; IFN- g, interferon-gamma; LEC, lymphatic endothelial cell; LYVE-1, lymphatic vessel endothelial hyaluronan receptor 1; NFATct, nuclear factor of activated T cells, cytoplasmic 1; NP-2, NPK1-related protein kinase 2; Prox1, prospero homeobox; Sox18, SRY (sex determining region Y)-Box18; TGF-b, transforming growth factor beta; Tie1,2, tyrosine kinase with immunoglobulin-like and EGF-like domains 1 and 2; VEGF-C, vascular endothelial growth factor C; VEGF-D, vascular endothelial growth factor D; VEGFR-2/3, vascular endothelial growth factor receptor 2/3.)

The differentiation of LECs from blood vascular endothelial cells is controlled by transcription factors, such as prospero homeobox 1 (Prox1), Sox18, and COUP transcription factor 2 (COUPTFII). Prox1 is required for the differentiation of LECs during embryogenesis and for LEC maintenance during adult life.6 LECs that express Prox1 are then able to upregulate other lymphatic endothelial-specific molecules, such as vascular endothelial growth factor receptor 3 (VEGFR-3) and LYVE1.7 Sox18 is expressed in the cardinal vein and regulates Prox1 expression.8 However, the signal that induces Sox18-mediated Prox1 production has not yet been identified. COUP-TFII interacts with Prox1 and induces expression of LEC-specific genes, including Vegfr-3 and neuropilin 2 (Nrp2).9 It also establishes LEC specification by suppressing Notch signaling.10

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Venous Sprouting of Lymphatic Endothelial Cells In embryogenesis, individual LECs connect to each other by adherens junctions and will “sprout” into the primitive lymphatic structures, the lymph sacs.11 Animal studies have identified that the vascular endothelial growth factor C (VEGF-C)/VEGFR-3 and collagen and calcium-binding EGF domain 1 (CCBE1) signaling pathways regulate sprouting.12 The ligands vascular endothelial growth factor D (VEGF-C and VEGF-D) bind to and activate the tyrosine kinase receptors VEGFR-2 and VEGFR-3 and their coreceptor Nrp2 on LECs. VEGFR-3 is considered the main VEGF-C receptor for lymphangiogenesis.1 Both VEGF-C and VEGF-D promote migration and proliferation of LECs in vitro and lymphatic vessel hyperplasia in vivo. However, only VEGF-C is needed for embryonic lymphatic development.13,14 The other VEGF-C receptor, VEGFR-2, is thought to be involved in lymphangiogenesis, but this has not yet been proved. CCBE1 is expressed in tissues that are in close proximity to the budding venous-derived LECs. CCBE1 does not appear to have direct lymphangiogenic activity on its own but can enhance the lymphangiogenic effects of VEGF-C by upregulating the levels of it.15 It was recently discovered that CCBE1 promotes proteolytic cleavage of the poorly active 29/31-kDa form of VEGF-C by the ADAMTS3 protease, resulting in the mature 21/23-kDa form of VEGF-C, which subsequently induces increased VEGF-C receptor signaling.16

Lymphatic Sprouting Further development of the lymphatic system occurs by lymphatic vessel sprouting from the primitive lymph sacs mentioned previously. This process is controlled by the VEGF-C ligand and its receptor VEGFR-3. NRP2, Ephrin-B2, and Notch are also required for the regulation of late embryonic and postnatal lymphatic sprouting and remodeling.17 Notch will induce VEGFR-3 expression and thereby increase endothelial cell responsiveness to VEGF-C in early mouse embryos.18

Remodeling of a Lymphatic Vascular System The primitive lymphatic vessels are now required to mature into a functional vascular network with vessel-type features to serve their critical functions. Remodeling processes occur late in embryonic development and the early postnatal period. They lead to the formation of flap valves in lymphatic capillaries, the establishment of precollecting and collecting vessels by way of smooth muscle cell (SMC) recruitment, and the development of luminal valves. Flaplike openings (called primary valves) form between the LECs of lymphatic capillaries to create button-like intercellular junctions that facilitate the entry of interstitial fluid into initial lymphatic vessels.19 Molecular mechanisms controlling this process remain poorly understood, but vascular endothelial (VE)–cadherin is thought to promote junction stability.19 Intraluminal valves within developing collector vessels are formed by the expression of Prox1 and forkhead box (FoxC2) transcription factors by clusters of LECs. It has been proposed that mechanical forces resulting from the flow of lymph may play a role in establishing the locations

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of these valves.20 Valve-forming endothelial cells arrange themselves on the vessel wall to form a transverse ridge, which subsequently develops into mature valve leaflets.21 FOXC2 is a significant regulator of lymphatic valve formation. FOXC2 deficiency in humans and animal models results in lymphatic vessel valve dysplasia.22 However, it is apparent that other regulators are involved in lymphatic valve development, such as NFATC1, calcineurin, Ephrin-B2, Ang2, connexin, and integrin alpha9/fibronectin-EIIIA signaling pathways.21 The lymphatic precollectors and collecting lymphatic vessels are covered by SMCs except in the luminal valve areas to assist with the proximal propulsion of lymph.23 The number of perivascular SMCs increases progressively along the lymphatic vascular trunk. Several markers are involved in SMC recruitment, including platelet-derived growth factor B (PDGF-B).22

Clinical Consequences of Abnormalities Within the Lymphangiogenesis Pathway Until recently primary lymphedema received limited interest from both the clinical and academic communities. Until Connell et al24 published their 2010 paper on classification, phenotyping of patients was considered of little benefit. Their paper highlighted the importance of accurate indepth phenotyping and how it can lead to the identification of new causal genes. A revision of the classification pathway was published in 201325 (Fig. 8-3). It highlighted the spectrum of disorders that may present with primary lymphedema and suggested the underlying causal gene. The classification pathway was presented in the form of a color-coded algorithm to illustrate the five main categories of primary lymphedema and the individual subtypes within these categories. The main categories are as follows: 1. Syndromic disorders associated with lymphedema (but where lymphedema is not the predominant feature) (blue) 2. Localized or generalized lymphedema associated with systemic/visceral lymphatic abnormalities (pink) 3. Lymphedema in association with disturbed growth and/or cutaneous/vascular anomalies (yellow) 4. Congenital lymphedema (green) 5. Late-onset primary lymphedema (purple) There will be exceptions and outliers to this classification system, but it has proved a useful clinical and research tool that is still evolving. Rigorous phenotyping in combination with recent advances in genetic analysis, such as next-generation sequencing, will enhance the identification rate of new genes that cause primary lymphedema. Several abnormalities within genes involved in lymphangiogenesis have already been reported to cause primary lymphedema, and they will be discussed. Although we do not yet fully understand all mechanisms involved in lymphangiogenesis, the identification of mutations in VEGFR-3, VEGF-C, CCBE1, SOX18, and FOXC2 in humans with lymphatic insufficiency supports the critical role these genes play. Mendola et al26 recently screened 78 patients for mutations in known primary lymphedema genes and detected mutations in 36% of cases. This supports the hypothesis that other causal genes for primary lymphedema have yet to be identified. Certainly not all cases of primary lymphedema will have a monogenic cause.

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START Proteus syndrome AKT1

Unknown syndrome Syndromic

CLOVE/fibroadipose hyperplasia AKT/PIK3/mTOR pathway

Yes

Known syndrome e.g., Noonan and Turner

No

KT/KT-like

Systemic/visceral involvement prenatal or postnatal onset

Parkes-Weber syndrome RASA1

Some segments Yes All segments

No

Combined vascular malformation Yes

Lymphangioma

No

WILD syndrome

Congenital onset: Lymphedema within first year of life

Late onset: Lymphedema after age 1 yr No

Congenital unisegmental edema

Distichiasis

Lower limb 1 genital edema

Lymphedema-distichiasis syndrome FOXC2

Yes

Multiple segments One limb

Bilateral

Unilateral

No

Late-onset unilateral leg lymphedema

FH 2 ve

Unilateral

Lower limbs only

FH 2 ve Milroy disease FLT4(VEGFR-3) Milroy-like Consider KIF11, VEGF-C

Generalized lymphatic dysplasia (GLD)/ Hennekam syndrome Consider CCBE1

Disturbed growth/ cutaneous manifestations/ vascular anomalies

Lymphangiomatosis/ Gorham syndrome

Congenital multisegmental edema without systemic involvement

Multisegmental lymphatic dysplasia with systemic involvement (MLDSI)

Lower limb

FH 1 ve

Lower limb 1 genitalia

Yes

Bilateral FH 1 ve

No

Meige-like Meige Consider GJC2 Late-onset unisegmental lymphedema Late-onset multisegmental lymphedema Lower limbs 6 genitalia Consider GATA2 Four limb Consider GJC2, Turner

FIG. 8-3  Classification pathway for primary lymphedema. Red section indicates gene tests that are available and should be considered for each subgroup. (CCBE1, Collgen and calcium-binding EGF domain 1; FH, family history; 1ve, positive; 2ve, negative; FOXC2, forkhead box C2; GATA2, GATA binding protein 2; GJC2, gap junction protein, gamma 2; KT/KT-like, KlippelTrenaunay/Klippel-Trenaunay-like; VEGF-C, vascular endothelial growth factor C; VEGFR, vascular endothelial growth factor receptor.)

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TABLE 8-1  Pathway for Primary Lymphedema Cutaneous manifestations

Nevi/pigmentation variations (for example, epidermal nevi/vascular malformations)

Distichiasis

Presence of aberrant eyelashes arising from the meibomian glands

Disturbed growth

Hypertrophy (overgrowth) and hypotrophy of bone or soft tissue resulting in altered length of a limb or body part

KT/KT-like

Klippel-Trenaunay/Klippel-Trenaunay-like syndrome

Prenatal onset

Detection of lymphatic abnormality in the prenatal period; isolated pedal edema excluded from this definition, because this may be a presentation of Milroy disease

Segment

A region of the body affected by lymphedema (for example, the face, conjunctiva, genitalia, upper limbs, lower limbs—each constitutes one body part); multisegmental refers to more than one segment affected by lymphedema (bilateral lower limb swelling not considered multisegmental lymphedema)

Syndromic

A constellation of abnormalities, one of which is lymphedema

Systemic involvement

Systemic lymphatic problems persisting beyond the newborn period or manifesting at any age thereafter, including hydrops fetalis, chylous ascites, intestinal lymphangiectasia, pleural and pericardial effusions, and pulmonary lymphangiectasia

Vascular anomalies

Includes congenital vascular abnormalities

Primary Lymphedema From Genes Involved in Lymphangiogenesis VEGFR-3 Mutations Abnormalities within the gene that encodes VEGFR-3 on chromosome 5q35 cause Milroy disease.27,28 Mutations in VEGFR-3 (also known as FLT4) are found in 70% of patients with congenital onset primary lymphedema.29 Inheritance is autosomal dominant with 85% penetrance.27,30 De novo mutations may occur, and thus a family history is not mandatory. Animal models have confirmed the role of VEGFR-3 in lymphangiogenesis, and studies have demonstrated that mutant VEGFR-3 showed impaired kinase activity.31,32 To date all reported VEGFR-3 mutations have occurred within the tyrosine kinase domain, but the exact mechanism of disease is not yet fully understood. An investigation of patients with lymphoscintigraphy suggests the failure of initial lymphatic vessel absorption and demonstrates a characteristic picture of “functional aplasia of lymphatic vessels.”25 Unlike the mouse model (Chy-mouse),33 in humans the initial lymphatic vessels are present (confirmed on histologic examination) but presumably unable to absorb interstitial fluid.34 It is clear how VEGFR-3 mutations may cause lymphatic dysplasia given its key role in the lymphangiogenesis pathway. However, further information on the exact mechanism of disease is necessary to optimize future treatments.

VEGF-C Mutations VEGF-C is a ligand for VEGFR-3 and controls lymphatic sprouting during embryonic development.35,36 Two families with congenital lymphedema of the lower limb had frameshift mutations in the VEGF-C gene on chromosome 4q34.37,38 It seems logical that mutations in the ligand for

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VEGFR-3 will cause the same problems as a mutation in VEGFR-3 (for example, Milroy disease). In vivo overexpression assays in zebrafish confirm that VEGF-C frameshift mutations are causative for the Milroy-like phenotype seen.37 Therefore it is appropriate to consider VEGF-C screening in patients with Milroy-like lymphedema who have negative screening results for VEGFR-3 mutations.

CCBE1 Mutations Mutations in CCBE1 on chromosome 18q21 have been identified as causal for many patients with autosomal recessive, generalized lymphatic dysplasia (for example, Hennekam syndrome).39,40 Nearly all reported CCBE1 mutations have been missense, but one frameshift mutation has been reported.39,40 The phenotype composes lymphedema of all four limbs, lymphangiectasia (dysplasia of the lymphatic system of the intestines and/or lungs), variable degrees of learning difficulties, and characteristic facies (a flat face, flat and broad nasal bridge, and hypertelorism). Other associated problems may include hypothyroidism, glaucoma, seizures, hearing loss, and renal abnormalities. In severe cases it may present in the antenatal period with hydrops fetalis and/or cardiac abnormalities.41,42 Lymphoscintigraphy has rarely been undertaken in this condition. However, Bellini et al42 demonstrated abnormal drainage in the upper and lower limbs and the thoracic duct in one patient. Several affected individuals have a positive family history of lymphedema, which is usually suggestive of autosomal recessive inheritance inferring a higher risk of recurrence. CCBE1 mutations were present in only 23% of reported cases of Hennekam syndrome, which suggests genetic heterogeneity within this group.39 This is supported by the recent identification of homozygous or compound heterozygous mutations of the FAT4 gene (a member of the protocadherin family and not a recognized component of the lymphangiogenesis pathway) in 4 of 24 patients with CCBE1 mutation–negative Hennekam syndrome.43 CCBE1 plays a crucial role in lymphangiogenesis, including enhancing the effects of VEGF-C and subsequent receptor signaling. Therefore it is understandable that CCBE1 mutations cause widespread and severe abnormalities of lymphatic function.

SOX18 Mutations Three families with hypotrichosis-telangiectasia-lymphedema syndrome resulting from mutations in the SOX18 gene have been described.44 Two of the families were consanguineous with homozygous missense mutations in the SOX18 gene, which was located in 20q13. In the third family, the parents were nonconsanguineous, and both the affected child and his brother (who died in utero of hydrops fetalis) showed a heterozygous nonsense mutation that was not found in genomic DNA from either parent and constituted a de novo germline mutation. This rare form of primary lymphedema occurs as a result of either autosomal recessive or dominant SOX18 mutations negatively impacting on lymphatic development. The exact mechanism of disease remains unclear.

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FOXC2 Mutations Lymphedema-distichiasis syndrome is inherited in an autosomal dominant manner and occurs as a result of mutations in the FOXC2 gene on chromosome 16q24.45 Brice et al46 demonstrated that mutations can be identified in more than 95% of patients with typical lymphedema-distichiasis syndrome, such as late-onset lower limb lymphedema and distichiasis (aberrant eyelashes arising from the meibomian glands). Many cases result from small deletions or insertions.47 FOXC2 encodes a transcription factor necessary for the signal transduction pathway, which ensures normal development of the lymphatic collecting vessels and valves.48 Given the role of FOXC2, it is obvious how mutations in the FOXC2 gene will cause clinical signs of impaired lymphatic function. Lymphoscintigraphic findings of affected individuals demonstrated reflux of lymph within the lower limbs as a result of valve failure within the hyperplastic lymphatics.22 Similarly, abnormal venous valves led to early-onset venous reflux in all patients with FOXC2 mutations.49

Primary Lymphedema Resulting From Mutations in Genes Indirectly With Unknown Involvement in Lymphangiogenesis Several subtypes of primary lymphedema occur as a result of abnormalities within genes not known to be part of the lymphangiogenesis pathway. Some of these conditions will be discussed here. In time it may become evident how these genes impact on lymphatic development.

GATA2 Mutations Mutations in the GATA2 gene on chromosome 3q21 cause Emberger syndrome and are inherited in an autosomal dominant manner but with a high rate of new mutations.50 GATA2 is expressed in lymphatic, vascular, and endocardial endothelial cells.51 Mouse studies suggest the programming of lymphatic valve development may be affected as a result of loss of function of Gata2.52 GATA2 is also involved in the regulation of hematopoiesis, and mutations have been reported in heritable forms of immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia.53,54 This explains the phenotypic association of late-onset primary lymphedema, severe cutaneous warts, and myelodysplastic syndrome and/or acute myeloid leukemia.55 However, the association with high-frequency, progressive sensorineural deafness is harder to explain.

AKT1 Pathway Mutations Lymphedema may be seen in conjunction with vascular abnormalities, disorders of growth, and cutaneous abnormalities, including Proteus syndrome. This progressive overgrowth disorder is characterized by progressive, segmental overgrowth of skin, connective tissue, fat, skeletal, and central nervous systems. Lymphatic and capillary malformations are commonly observed vascular changes. Manifestations of Proteus syndrome may not be present at birth but develop and progress during infancy. The diagnosis can be established with diagnostic clinical criteria and/or molecular analysis.56 Most individuals with clinically confirmed typical Proteus syndrome are identified to have a common activating mutation in AKT1, c.49G.A (p.Glu17Lys), arising as a result of somatic mosaicism. It is hypothesized that germline AKT1 c.49G.A mutations would be lethal early in embryonic development.57 The exact mechanism of disease is unclear, but mouse models suggest that Akt1 is required for lymphatic network formation, remodeling, and valve development.58

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AKT acts within a molecular pathway that includes the mTOR and PIK3CA genes. This pathway is critical as a progrowth and antiapoptosis facilitator in cancer, but mutations in these genes have other implications. PIK3CA mutations have also been implicated in a range of disorders associated with somatic overgrowth, vascular malformations, fibroadipose overgrowth, pigmented cutaneous lesions, and megalencephaly.59-63 The identification of the PIK3/AKT/mTOR signaling pathway underpinning the disease processes gives rise to the potential for therapeutic targets through inhibition of this pathway.61

Syndromic Conditions Lymphedema is a recognized feature of many syndromes. In these conditions the lymphedema is not the primary problem but is an associated feature. The genetic causes of many of these syndromes are known and testing is available. A molecular result means that the mode of inheritance can be established, and where indicated, prenatal diagnosis can be offered. Turner and Noonan are the syndromes most frequently associated with lymphedema.25 Turner syndrome should always be considered as the cause of swelling in female infants presenting with congenital lymphedema of the hands and/or feet. Turner syndrome occurs as a result of a loss of one X chromosome. How this affects lymphangiogenesis remains unclear.

Microcephaly With or Without Chorioretinopathy, Lymphedema, and Intellectual Disability An autosomal dominant syndrome composing microcephaly, chorioretinopathy, and congenital lymphedema (mimicking Milroy disease both clinically and on investigation with lymphoscintigraphy) occurs as a result of mutations in the KIF11 gene on chromosome 10q24.64 The KIF11 protein product EG5 (a kinesin motor protein) is involved in spindle formation in mitosis but is not known to be directly involved in the lymphangiogenesis pathway. The mechanism by which KIF11/EG5 exerts its influence on the development of lymphatics remains a mystery.

Late-Onset Lower Limb or Four-Limb Lymphedema Mutations in the gap junction protein, gamma 2 (GJC2) gene have been implicated in the development of late-onset lymphedema of both lower limbs or all four limbs.65 The age of swelling onset varies considerably, ranging from childhood up to the sixth decade.66 GJC2 encodes the connexin-47 protein located on chromosome 1q42. The functional role of GJC2 within the lymphatic system is unclear. Lymphoscintigraphic findings performed in affected individuals showed lymphatic tracts that appear normal, but when quantification was done, there was significantly reduced absorption from tissues by the peripheral lymphatics in all four limbs.66 Therefore it can be hypothesized that normal GJC2 function is not required for lymphatic vessel development, but perhaps is necessary for maintenance of lymphatic function. This phenotype could explain the considerable number of patients presenting in adulthood with lymphedema without an obvious cause of their presumed “secondary lymphedema.” Clinicians should always consider a genetically determined primary lymphatic weakness in the absence of a clear underlying secondary cause. Imaging, such as with lymphoscintigraphy, may prove helpful in the investigation. For example, if the patient presents with unilateral lower limb swelling

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but lymphoscintigraphy shows bilateral impaired lower limb lymphatic drainage, then the likely cause of the lymphedema will be an intrinsic primary lymphatic abnormality rather than an external secondary cause.

Conclusion Numerous causal genes have now been identified in the pathogenesis of primary lymphedema, most within the past few years. Gene identification helps delineate the phenotype more specifically. The identification of the genetic causes of primary lymphedema provides a molecular diagnostic test for some of the subtypes. Patients and families benefit hugely from a molecular diagnosis, because it allows the clinician to confidently predict the clinical prognosis and offer screening for family members. It is clear how some primary lymphedema subtypes are caused by abnormal gene function (for example, VEGFR-3 mutations and Milroy disease; CCBE1 and Hennekam syndrome), because the causal genes play a significant role in the lymphangiogenic pathway. However, genes implicated in other forms of primary lymphedema are not known to play a role in lymphangiogenesis. For example, how does a mutation in KIF11 cause microcephaly with or without chorioretinopathy, lymphedema, and intellectual disability? It is clear that we have more to learn about lymphangiogenesis and the genes that regulate it. The identification of more pathogenic genes will advance our knowledge of the etiopathogenesis of lymphatic disease. In time this may allow the development of improved therapeutic interventions. For example, gene therapy may become a feasible treatment strategy for patients with primary lymphedema.

R EFERENCES 1. Martinez-Corral I, Makinen T. Regulation of lymphatic vascular morphogenesis: implications for pathological (tumor) lymphangiogenesis. Exp Cell Res 319:1618-1625, 2013. 2. Oliver G, Alitalo K. The lymphatic vasculature: recent progress and paradigms. Annu Rev Cell Dev Biol 21:457-483, 2005. 3. Okuda KS, Astin JW, Misa JP, et al. Iyve1 expression reveals novel lymphatic vessels and new mechanisms for lymphatic vessel development in zebrafish. Development 139:2381-2391, 2012. 4. Oliver G. Lymphatic vasculature development. Nat Rev Immunol 4:35-45, 2004. 5. Schulte-Merker S, Sabine A, Petrova TV. Lymphatic vascular morphogenesis in development, physiology, and disease. J Cell Biol 193:607-618, 2011. 6. Wigle JT, Harvey N, Detmar M, et al. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J 21:1505-1513, 2002. 7. Tammela T, Petrova TV, Alitalo K. Molecular lymphangiogenesis: new players. Trends Cell Biol 15:434441, 2005. 8. François M, Caprini A, Hosking B, et al. Sox18 induces development of the lymphatic vasculature in mice. Nature 456:643-647, 2008. 9. Lee S, Kang J, Yoo J, et al. Prox1 physically and functionally interacts with COUP-TFII to specify lymphatic endothelial cell fate. Blood 113:1856-1859, 2009.

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10. You LR, Lin FJ, Lee CT, et al. Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature 435:98-104, 2005. 11. Yang Y, García-Verdugo JM, Soriano-Navarro M, et al. Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos. Blood 120:2340-2348, 2012. 12. Hagerling R, Pollmann C, Andreas M, et al. A novel multistep mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy. EMBO J 32:629-644, 2013. 13. Veikkola T, Jussila L, Makinen T, et al. Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J 20:1223-1231, 2001. 14. Karkkainen MJ, Haiko P, Sainio K, et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 5:74-80, 2004. 15. Le Guen L, Karpanen T, Schulte D, et al. CCBE1 regulates VEGFC-mediated induction of VEGFR3 signaling during embryonic lymphangiogenesis. Development 141:1239-1249, 2014. 16. Jeltsch M, Jha SK, Tvorogov D, et al. CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation. Circulation 129:1962-1971, 2014. 17. Xu Y, Yuan L, Mak J, et al. Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3. J Cell Biol 188:115-130, 2010. 18. Shawber CJ, Funahashi Y, Francisco E, et al. Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression. J Clin Invest 117:3369-3382, 2007. 19. Baluk P, Fuxe J, Hashizume H, et al. Functionally specialized junctions between endothelial cells of lymphatic vessels. J Exp Med 204:2349-2362, 2007. 20. Sabine A, Agalarov Y, Maby-El Hajjami H, et al. Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation. Dev Cell 22:430-445, 2012. 21. Bazigou E, Makinen T. Flow control in our vessels: vascular valves make sure there is no way back. Cell Mol Life Sci 70:1055-1066, 2013. 22. Petrova TV, Karpanen T, Norrmén C, et al. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat Med 10:974-981, 2004. 23. Bridenbaugh EA, Gashev AA, Zawieja DC. Lymphatic muscle: a review of contractile function. Lymphat Res Biol 1:147-158, 2003. 24. Connell F, Kalidas K, Ostergaard P, et al. Linkage and sequence analysis indicate that CCBE1 is mutated in recessively inherited generalised lymphatic dysplasia. Hum Genet 127:231-241, 2010. 25. Connell FC, Gordon K, Brice G, et al. The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings. Clin Genet 84:303-314, 2013. 26. Mendola A, Schlögel MJ, Ghalamkarpour A, et al. Mutations in the VEGFR3 signaling pathway explain 36% of familial lymphedema. Mol Syndromol 4:257-266, 2013. 27. Ferrell RE, Levinson KL, Esman JH, et al. Hereditary lymphedema: evidence for linkage and genetic heterogeneity. Hum Mol Genet 7:2073-2078, 1998. 28. Gordon K, Spiden SL, Connell FC, et al. FLT4/VEGFR3 and Milroy disease: novel mutations, a review of published variants and database update. Hum Mutat 34:23-31, 2013. 29. Connell FC, Ostergaard P, Carver C, et al. Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas. Hum Genet 124:625-631, 2009. 30. Evans AL, Brice G, Sotirova V, et al. Mapping of primary congenital lymphedema to the 5q35.3 region. Am J Hum Genet 64:547-555, 1999. 31. Kaipainen A, Korhonen J, Mustonen T, et al. Expression of the FMS-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci U S A 92:35663570, 1995. 32. Karkkainen MJ, Ferrell RE, Lawrence EC, et al. Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nat Genet 25:153-159, 2000.

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33. Karkkainen MJ, Saaristo A, Jussila L, et al. A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci U S A 98:12677-12682, 2001. 34. Mellor RH, Hubert CE, Stanton AW, et al. Lymphatic dysfunction, not aplasia, underlies Milroy disease. Microcirculation 17:281-296, 2010. 35. Küchler AM, Gjini E, Peterson-Maduro J, et al. Development of the zebrafish lymphatic system requires VEGFC signaling. Curr Biol 16:1244-1248, 2006. 36. Hogan BM, Bos FL, Bussmann J, et al. CCBE1 is required for embryonic lymphangiogenesis and venous sprouting. Nat Genet 41:396-398, 2009. 37. Gordon K, Schulte D, Brice G, et al. Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema. Circ Res 112:956-960, 2013. 38. Balboa-Beltran E, Fernández-Seara MJ, Pérez-Muñuzuri A, et al. A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease. J Med Genet 51:475-478, 2014. 39. Alders M, Hogan BM, Gjini E, et al. Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nat Genet 41:1272-1274, 2009. 40. Connell FC, Kalidas K, Ostergaard P, et al. CCBE1 mutations can cause a mild, atypical form of generalized lymphatic dysplasia but are not a common cause of non-immune hydrops fetalis. Clin Genet 81:191-197, 2012. 41. Van Balkom ID, Alders M, Allanson J, et al. Lymphedema-lymphangiectasia-mental retardation (Hennekam) syndrome: a review. Am J Med Genet 112:412-421, 2002. 42. Bellini C, Mazzella M, Arioni C, et al. Hennekam syndrome presenting as nonimmune hydrops fetalis, congenital chylothorax, and congenital pulmonary lymphangiectasia. Am J Med Genet A 120A:92-96, 2003. 43. Alders M, Al-Gazali L, Cordeiro I, et al. Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome. Hum Genet 133:1161-1167, 2014. 44. Irrthum A, Devriendt K, Chitayat D, et al. Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am J Hum Genet 72:14701478, 2003. 45. Fang J, Dagenais SL, Erickson RP, et al. Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet 67:1382-1388, 2000. 46. Brice G, Mansour S, Bell R, et al. Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. J Med Genet 39:478-483, 2002. 47. Bell R, Brice G, Child AH, et al. Analysis of lymphoedema-distichiasis families for FOXC2 mutations reveals small insertions and deletions throughout the gene. Hum Genet 108:546-551, 2001. 48. Norrmén C, Ivanov KI, Cheng J, et al. FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. J Cell Biol 185:439-457, 2009. 49. Mellor RH, Brice G, Stanton AW, et al. Mutations in FOXC2 are strongly associated with primary valve failure in veins of the lower limb. Circulation 115:1912-1920, 2007. 50. Ostergaard P, Simpson MA, Brice G, et al. Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype. J Med Genet 48:251-255, 2011. 51. Khandekar M, Brandt W, Zhou Y, et al. A GATA2 intronic enhancer confers its pan-endothelia-specific regulation. Development 134:1703-1712, 2007. 52. Kazenwadel J, Secker GA, Liu YJ, et al. Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. Blood 119:1283-1291, 2012.

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53. Hahn CN, Chong CE, Carmichael CL, et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet 43:1012-1017, 2011. 54. Hsu AP, Sampaio EP, Khan J, et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 118:26532655, 2011. 55. Mansour S, Connell F, Steward C, et al. Emberger syndrome—primary lymphedema with myelodysplasia: report of seven new cases. Am J Med Genet A 152A:2287-2296, 2010. 56. Biesecker L. The challenges of Proteus syndrome: diagnosis and management. Eur J Hum Genet 14:151157, 2006. 57. Lindhurst MJ, Sapp JC, Teer JK, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 365:611-619, 2011. 58. Zhou F, Chang Z, Zhang L, et al. Akt/Protein kinase B is required for lymphatic network formation, remodeling, and valve development. Am J Pathol 177:2124-2133, 2010. 59. Kurek KC, Luks VL, Ayturk UM, et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet 90:1108-1115, 2012. 60. Lee JH, Huynh M, Silhavy JL, et al. De novo somatic mutations in components of the PI3K-AKT3mTOR pathway cause hemimegalencephaly. Nat Genet 44:941-945, 2012. 61. Lindhurst MJ, Parker VE, Payne F, et al. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet 44:928-933, 2012. 62. Rivière JB, Mirzaa GM, O’Roak BJ, et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet 44:934-940, 2012. 63. Emrick LT, Murphy L, Shamshirsaz AA, et al. Prenatal diagnosis of CLOVES syndrome confirmed by detection of a mosaic PIK3CA mutation in cultured amniocytes. Am J Med Genet A 164A:2633-2637, 2014. 64. Ostergaard P, Simpson MA, Mendola A, et al. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. Am J Hum Genet 90:356-362, 2012. 65. Ferrell RE, Baty CJ, Kimak MA, et al. GJC2 missense mutations cause human lymphedema. Am J Hum Genet 86:943-948, 2010. 66. Ostergaard P, Simpson MA, Brice G, et al. Rapid identification of mutations in GJC2 in primary lympho­edema using whole exome sequencing combined with linkage analysis with delineation of the phenotype. J Med Genet 48:251-255, 2011.

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C hapter 9 Relationship Between Fat Tissue and Lymphangiogenesis Mauro Andrade

K ey P oints • Adipose tissue overgrowth is a key clinical feature in chronic lymphedema. • Lymphangiogenesis may play a critical role in lymphedema-related adipogenesis. • It is still unclear how the intricate mechanisms of lymphangiogenesis, inflammation, and adipogenesis are interrelated.

A Fat deposition has long been recognized as one of the clinical features of elephantiasis. In a very elegant clinical description, Moritz Kaposi,1 in the nineteenth century, stated: “If an incision is made on a limb with advanced elephantiasis . . . the subcutaneous tissue is increased many fold . . .” In the twentieth century, debulking procedures to remove excess skin and fat became popular as the preferred surgical treatment for patients with lymphedema.

Rel

Until recently, much of our knowledge about the pathophysiology of lymph stasis focused on protein retention, altered immune cell trafficking, and inflammation. Little attention was directed to fat deposition, notwithstanding the fact that some authors considered it a subproduct of the inflammatory response.2 In the late 1990s, a great discussion ensued after Brorson and Svensson’s publication of a series of patients treated with liposuction.3 Soon after, advances in the comprehension of molecular mechanisms related to lymphangiogenesis and adipogenesis provided new insights into the relationship between lymph stasis and fat. This chapter discusses how these findings have influenced our current knowledge of the relationship between fat tissue and lymphangiogenesis and how this understanding can lead to future therapeutic approaches in patients with lymphedema. 135

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Adipogenesis For a long time, the known functions of subcutaneous fat were limited to energy storage and regulation of body temperature. Perhaps because of its relatively simple structure, adipose tissue was a victim of several decades of scientific neglect. It was not until the more recent recognition of the burden of obesity in modern society that further investigation into the nature of adipose tissue unveiled a whole complex and dynamic physiologic organ. Adipogenesis is the process of differentiation that turns preadipocytes or multipotent stem cells into mature adipocytes. This is regulated by several mechanisms (transcription factors, cofactors, and signaling) from as early as the embryonic period until adult life. The number of adipocytes does not vary after childhood and adolescence, even after weight changes.4 Thus most weight gain or loss depends on the size variation of the intracellular storage of triglycerides and cholesteryl esters in fat droplets. Because the total population of fat cells remains constant in adulthood, new adipocytes can be generated by two different pathways: preexisting undifferentiated progenitor cells or through dedifferentiation of mature adipocytes into preadipocytes, which can proliferate and differentiate into mature adipocytes.5 The annual turnover rate of fat cells is estimated to be 10%.4 The differentiation from a stem cell precursor to a mature adipocyte involves a complex sequence of gene expression and signaling and is subject to the environment in which it occurs, either in culture or in vivo. Multipotent stem cells are capable of differentiating into mesodermal cell types (adipocytes, chondrocytes, osteoblasts, and myocytes). Under stimulation by hormones, cytokines, and growth factors (insulin, insulin-like growth factor 1, glucocorticoids, mineralocorticoids, and thyroid hormone), some multipotent stem cells become committed to the adipogenic lineage (preadipocytes). Preadipocytes then differentiate into adipocytes by the action of transcription factors that activate specific genes responsible for the adipocyte phenotype. The most important transcription factors at this phase are CCAAT/enhancer-binding protein alpha (C/EBP-alpha) and peroxisome proliferator-activated receptor gamma (PPAR-gamma).6 Fig. 9-1 shows the normal relationship between the lymphatic system and fat in a limb.

Lymphangiogenesis Although lymphangiogenesis is discussed in greater detail elsewhere in Chapter 7, some brief aspects of lymphatic system development will illustrate the relationship between the lymphatics and fat. The lymphatic system appears during the sixth and seventh weeks of embryonic development,7 4 weeks after the primary components of the blood circulation arise. Two different theories about the origin of the lymphatics were proposed at the beginning of the twentieth century. Sabin’s anatomic studies8 suggested that sprouting from blood endothelial cells was the origin of the lymphatic system. This was in opposition to Huntington’s theory of the centripetal formation of the lymphatics from mesenchymal lymphangioblasts, which reached the venous system later in development.9 Some controversies still remain, and evidence seems to support both theories.10,11

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Healthy

Acute lymphedema Generalized protein and fluid accumulation Inflammation Some dilation and fibrosis of lymphatics

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Chronic lymphedema Sustained inflammatory response Increased and excessive adipose tissue Fibrosis and tissue architecture disruption Dilated and fibrosed lymphatics Lymphangiogenesis

FIG. 9-1  Left, Normal lymphatic circulation is demonstrated in a normal limb. Note the relationship between the lymphatics and the normal amount of fat in the limb. Center, A lymphedematous limb in acute lymphedema. Note the increased fat deposition compared with the healthy limb. Right, In a chronically lymphedematous limb there is increased fat deposition and increased fibrosis not only in the lymphatics, but also in the soft tissue of the limb.

The regulation and development of the lymphatic system depend on several signaling factors and cell receptors. The most important signaling factors are glycoproteins known as vascular endothelial growth factors (VEGFs). VEGFs are the primary regulators of endothelial proliferation, angiogenesis, vasculogenesis, and vascular permeability.12 There are six VEGF subtypes (A, B, C, D, and E) and placental growth factor (PlGF) that bind to specific membrane tyrosine kinase receptors. Three different VEGF tyrosine kinase receptors have been identified so far: • Vascular endothelial growth factor receptor 1 (VEGFR-1) (Flt-1) • VEGFR-2 (Flk-1 and KDR) • VEGFR-3 (Flt-4) VEGF-B and PlGF bind to VEGFR-1, whereas VEGF-A interacts with both VEGFR-1 and VEGFR-2. VEGF-E binds to VEGFR-2, and both VEGF-C and VEGF-D bind to VEGFR-3. VEGFR-1 and VEGFR-2 mediate angiogenesis, whereas VEGFR-3 is involved mainly in lymphangiogenesis. VEGFs and VEGFRs are essential for blood vessel development and angiogenesis. Unlike the other VEGFs, both VEGF-C and VEGF-D promote lymphangiogenesis through their specific lymphatic endothelial receptor VEGFR-3. Nevertheless, early experimental inactivation of Flt4, the gene responsible for encoding VEGFR-3, also results in defective blood vasculogenesis and

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angiogenesis,13 demonstrating that VEGF-C not only has a critical role in the development of the lymphatic system but is also essential in the development of the embryonic cardiovascular system. Lymphangiogenesis is a developmental process that occurs mainly in the embryonic phase and is uncommon in adult tissue. In adults new lymphatic tissue is formed in wound healing and is induced by some tumors. Thus the exact role of VEGF-C and VEGF-D in normal human physiology is unclear. Some VEGF actions have been described: stimulation of growth of lymphatic capillaries and recruitment of inflammatory cells,14 regulation of endothelial fatty acid, and control of salt-dependent interstitial volume and blood pressure.15 Interleukin-7 (IL-7) and interleukin-1 beta are cytokines involved in lymphoid tissue regulation and inflammation and can also participate in lymphangiogenesis. IL-7 increases the expression of lymphatic markers (lymphatic vessel endothelial hyaluronan receptor 1 [LYVE-1], podoplanin, and Prox1) in endothelial cells, and it induces the formation of lymphatic vessels in vivo. Interleukin-1 beta upregulates VEGF-C, and IL-7 upregulates VEGFR-3 and the expression of VEGF-D in endothelial cells.16

Where the Pathways of Lymphangiogenesis and Adipogenesis Cross The concept that lymphedema is restricted to tissue fluid accumulation is long gone. Advances in research on molecular mechanisms involved in cancer metastasis and obesity revealed intimate pathways of lymphangiogenesis, inflammation, and adipogenesis and opened a broad new field in the investigation of lymphatic disorders. Also, a lack of available experimental models for lymphedema has hindered specific evaluation of how lymph stasis influences tissue changes. Recently an experimental model of lymphedema17,18 provided new insights into the mechanisms responsible for many of the events resulting from impaired clearance of tissue lymph. The blockage of the lymphatic pathways in either clinical settings or experimental models affects lymph cell trafficking that leads to inflammation, fibrosis, and the disruption of normal tissue architecture. It is the result of the continuous production of growth factors, proteolytic enzymes, angiogenic factors, peroxisome proliferator-activated receptors, acute phase proteins (serum amyloid P), components of the renin-angiotensin-aldosterone system (Ang II), and cytokines, similar to other fibrotic disorders.19 In chronic lymphedema, the subcutaneous tissue displays a constant histologic pattern of inflammatory cell accumulation, increased amounts of ground substance, fibrosis, dilated lymphatic vessels, and proliferation of adipose tissue, whereas acute lymph stasis is accompanied by a marked increase in monocytes and macrophages.20 In fact, unlike chronic lymphedema, experimental acute lymph stasis resembles an inflammatory condition20 without the corresponding tissue damage (fibrosis and excessive fat) that is observed later in the development of the clinical disorder. A simple explanation may be that inflammation is the key trigger in the development of all histopathologic changes caused by chronic lymph stasis; fibrosis and fat deposition are a consequence of sustained inflammatory reaction in the tissue.

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It is well established that the lymphatics regulate the inflammatory response by transporting leukocytes and antigen-presenting cells from the site of inflammation to the lymph nodes. In lymph stasis, such regulation is impaired, suggesting that in this situation, the inflammatory reaction depends mostly on the local activity of monocytes and macrophages. Also, lymphangiogenesis is increased at the sites of tissue inflammation and wound repair, and VEGF-C and VEGF-D are overexpressed in macrophages.21 In addition, transforming growth factor beta, a cytokine that modulates local inflammation, acts as an inhibitor of lymphangiogenesis in inflammatory settings. Its inhibition decreases fibrosis and stimulates lymphangiogenesis, even without increases in VEGF-C expression.18,22 These findings support the hypothesis that there is a strong relationship and simultaneity between inflammation and lymphangiogenesis. On the other hand, experimental lymphedema in transgenic mice lacking VEGFR-3 does not induce fibrosis or an increase in lipid content and inflammation.23 This experimental model suggests that lymphangiogenesis and its regulators are essential to promote initial inflammation and late tissue changes, such as fibrosis and adipogenesis. However, is inflammation the first step in lymphangiogenesis and fat deposition? Are they independent features that converge in late-stage lymphedema? Is it lymphangiogenesis and lymph stasis that make lymphedema so different from other fibrotic diseases regarding fat deposition? Recent articles try to answer these intriguing questions. In patients undergoing axillary lymph node clearance, obesity is an established major risk factor for the development of lymphedema, but the underlying mechanism is unknown. Although the relationship between obesity and inflammatory response has elicited many publications, the correlation between lymphangiogenesis and obesity is still poorly understood and controversial. Increased circulating VEGF-C levels have been reported in obese individuals, and it has been suggested that such findings could explain the increased risk of metastasis that has been described in some cancers.24 On the other hand, two recent articles observed the opposite results. One study showed that adipose tissue played a protective role against prostate cancer dissemination.25 Conversely, another experiment that had mice consuming a high-fat diet demonstrated increased metastasis of the lymph nodes after enhanced lymphangiogenesis mediated by macrophage activation.26 Our group27 reported that fat cells in culture displayed marked expression of VEGFR-3 on the cell surface. Although fat cells must dedifferentiate to grow in culture media, the markers belong to undifferentiated mesenchymal cells. VEGF-C and VEGF-D may play a role in adipose cell replication as a response to lymph stasis. In fact, increased levels of circulating VEGF-D were found in the peripheral blood in patients with lymphedema. This suggests that a systemic response may try to increase lymphangiogenesis in the clinical setting of lymphatic stasis28 that could also influence adipogenesis and inflammation. In addition, lymph induced a more complete differentiation in preadipocytes in vitro.29 From these data it can be postulated that there is also a local action of lymph blockage, which favors a more important recruitment of mesenchymal cells into the adipose lineage. Experimental models of lymphedema are subjected to some criticism, because they hardly resemble the clinical evolution of lymphatic blockage where time is concerned; nevertheless, they seem to be useful, because they mimic the histopathologic picture that is observed in chronic human lymphedema. In a recently described model with mice tails,18 lymphatic blockage was obtained

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by resection of full-thickness skin, excising superficial lymphatics, and performing direct ligation of deep lymphatics. In this model, Zampell et al30 observed a significant change in the subcutaneous tissue caused by fat cell hypertrophy with the incremental size of fat droplets and also an increased number of adipocytes. However, there was a concomitant mononuclear cell inflammatory response, which made it difficult to ascertain whether fat deposition was a cause or a consequence of local inflammation. The same group31 demonstrated that CCAAT/C/EBP-alpha, PPAR-gamma, and adiponectin were highly expressed in the same experimental model of lymphedema. Again, C/EBP-alpha and PPAR-gamma are crucial for preadipocytes to turn into mature adipocytes.6 Adiponectin is a plasma protein secreted by adipose tissue,32,33 is downregulated in obesity states, and may influence lymphangiogenesis. In another recent study with the mouse tail model, adiponectin knockout mice had increased tail lymphedema and a lower number of lymphatics compared with wild-type mice.34 These findings could be reversed with the administration of adenoviral vectors encoding adiponectin. Furthermore, the same study demonstrated that adiponectin promoted the growth of human lymphatic endothelial cells in culture by the phosphorylation of AMP-activated protein kinase and endothelial nitric oxide synthesis.34 A possible mechanism of adiponectin control of lymphangiogenesis in vivo is the induction of VEGF-C expression in macrophages.35 However, in clinical lymphedema both adipogenesis and lymphangiogenesis coexist, and thus further studies are needed to verify whether lymphangiogenesis promoted by lymph stasis (or inflammation) interferes with adiponectin release by adipocytes.

Conclusion Recent advances in our knowledge of the intimate molecular mechanisms that may influence the development of chronic lymphedema and its accompanying tissue damage are the consequence of two major developments in medical research during the past years: (1) detailed information about the intimacy of lymphangiogenesis regulation obtained through studies of cancer biology and (2) the increasing interest in another important public health issue—obesity. It is still unclear how all the markers, signaling factors, and receptors that have been identified in tissues under the influence of lymph stasis orchestrate the evolution of the intricate events that follow the disruption of the lymphatic pathways. Another problem is to define how inflammation relates to and promotes lymphangiogenesis and adipose growth. Is inflammation the trigger, or are they intertwined players in the development of late tissue changes? A third and no less compelling issue is to identify the temporal sequence of events (if there is any) that may point to a targeted intervention to stop disease progression. However, most of our current and very recent knowledge is based on an experimental model that may not entirely translate into the clinical challenges faced by lymphedema patients and practitioners. Therefore, although this exciting subject still needs further investigation, its first steps promise to challenge how we currently address lymphedema and change our future approach to lymph stasis disorders.

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C linical P earls • Imaging and clinical evaluation of the fat content in limbs with lymphedema are essential to define the prognosis. • It is expected that control of adipogenesis and/or inflammation resulting from lymph stasis must be proved, as essential steps in lymphedema management.

R EFERENCES 1. Kaposi M. Leçons sur les Maladies de la Peau, vol 2. Paris: G Masson, 1881. 2. Földi E, Földi M. Lymphostatic diseases. In Földi M, Földi E, Kubik S, eds. Textbook of Lymphology for Physicians and Lymphedema Therapists. Munich: Urban & Fischer, 2003. 3. Brorson H, Svensson H. Complete reduction of lymphoedema of the arm by liposuction after breast cancer. Scand J Plast Reconstr Hand Surg 31:137-143, 1997. 4. Spalding KL, Arner E, Westermark PO, et al. Dynamics of fat cell turnover in humans. Nature 453:783787, 2008. 5. Moreno-Navarrete JM, Fernández-Real JM. Adipocyte differentiation. In Symonds ME, ed. Adipose Tissue Biology. New York: Springer-Verlag, 2012. 6. Mandrup S, Lane MD. Regulating adipogenesis. J Biol Chem 272:5367-5370, 1997. 7. Tille JC, Pepper MS. Hereditary vascular anomalies: new insights into their pathogenesis. Arterioscler Thromb Vasc Biol 24:1578-1590, 2004. 8. Sabin F. On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig. Am J Anat 1:367-391, 1902. 9. Huntington GS, McClure CFW. The anatomy and development of the jugular sacs in the domestic cat (Felis domestica). Am J Anat 10:177-311, 1910. 10. Wigle JT, Oliver G. Prox1 function is required for the development of the murine lymphatic system. Cell 98:769-778, 1999. 11. Schneider M, Othman-Hassan K, Christ B, et al. Lymphangioblasts in the avian wing bud. Dev Dyn 216:311-319, 1999. 12. Ferrara N, Alitalo K. Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 5:1359-1364, 1999. 13. Dumont DJ, Jussila L, Taipale J, et al. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282:946-949, 1998. 14. Wirzenius M, Tammela T, Uutela M, et al. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J Exp Med 204:1431-1440, 2007. 15. Hagberg CE, Falkevall A, Wang X, et al. Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464:917-921, 2010. 16. Al-Rawi MAA, Mansel RE, Jiang WG. Lymphangiogenesis and its role in cancer. Histol Histopathol 20:283-298, 2005. 17. Tabibiazar R, Cheung L, Han J, et al. Inflammatory manifestations of experimental lymphatic insufficiency. PLoS Med 3:e254, 2006. 18. Clavin NW, Avraham T, Fernandez J, et al. TGF-beta1 is a negative regulator of lymphatic regeneration during wound repair. Am J Physiol Heart Circ Physiol 295:H2113-H2127, 2008. 19. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol 214:199-210, 2008.

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20. Piller NB. Macrophage and tissue changes in the developmental phases of secondary lymphoedema and during conservative therapy with benzopyrone. Arch Histol Cytol 53 Suppl:209-218, 1990. 21. Cursiefen C, Chen L, Borges LP, et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 113:1040-1050, 2004. 22. Oka M, Iwata C, Suzuki HI, et al. Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis. Blood 111:4571-4579, 2008. 23. Markhus CE, Karlsen TV, Wagner M, et al. Increased interstitial protein because of impaired lymph drainage does not induce fibrosis and inflammation in lymphedema. Arterioscler Thromb Vasc Biol 33:266-274, 2013. 24. Silha JV, Krsek M, Sucharda P, et al. Angiogenic factors are elevated in overweight and obese individuals. Int J Obes (Lond) 29:1308-1314, 2005. 25. Moreira A, Pereira SS, Machado CL, et al. Obesity inhibits lymphangiogenesis in prostate tumors. Int J Clin Exp Pathol 7:348-352, 2013. 26. Jung JI, Cho HJ, Jung YJ, et al. High-fat diet-induced obesity increases lymphangiogenesis and lymph node metastasis in the B16F10 melanoma allograft model: roles of adipocytes and M2-macrophages. Int J Cancer 136:258-270, 2015. 27. Andrade M, Akamatsu F, Jacomo A. Adipocytes express specific lymphangiogenesis membrane receptors. FASEB J 25(Suppl):684.1, 2011. 28. Fink AM, Kaltenegger I, Schneider B, et al. Serum level of VEGF-D in patients with primary lymphedema. Lymphology 37:185-189, 2004. 29. Nougues J, Reyne Y, Dulor JP. Differentiation of rabbit adipocytes precursors in primary culture. Int J Obes 12:321-333, 1998. 30. Zampell JC, Aschen S, Weitman ES, et al. Regulation of adipogenesis by lymphatic fluid stasis: part I. Adipogenesis, fibrosis, and inflammation. Plast Reconstr Surg 129:825-834, 2012. 31. Aschen S, Zampell JC, Elhadad S, et al. Regulation of adipogenesis by lymphatic fluid stasis: part II. Expression of adipose differentiation genes. Plast Reconstr Surg 129:838-847, 2012. 32. Makki K, Froguel P, Wolowczuk I. Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm 2013:139239, 2013. 33. Piya MK, McTernan PG, Kumar S. Adipokine inflammation and insulin resistance: the role of glucose, lipids and endotoxin. J Endocrinol 216:T1-T15, 2013. 34. Shimizu Y, Shibata R, Ishii M, et al. Adiponectin-mediated modulation of lymphatic vessel formation and lymphedema. J Am Heart Assoc 2:e000438, 2013. 35. Hu D, Fukuhara A, Miyata Y, et al. Adiponectin regulates vascular endothelial growth factor-C expression in macrophages via Syk-ERK pathway. PLoS One 8:e56071, 2013.

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C hapter 10 Lymphatic Malformations Sandro Michelini, Alessandro Fiorentino, Marco Cardone

K ey P oints • Vascular malformations are mistakes in the development of the vascular system; hemangiomas are vascular tumors. • Endothelial hyperplasia is not a characteristic of vascular malformations. • Vascular malformations have multiple causes and complex clinical presentations; most vascular malformations are mixed. • Lymphoscintigraphy represents the highest standard in diagnostic tests for primary and secondary lymphedema (see Chapter 26).

A

• Arteriography and venography are needed for patients who require surgical or endovascular treatment. • Surgical treatment is reserved for more complex forms of vascular malformations, especially those with low flow.

Lym Lymphatic malformations are a type of morphostructural vascular disease. They have been described and classified in several ways because of their different clinical manifestations and types of onset. Simple malformations are usually named in Latin (for example, hemangioma simplex, angioma telangiectaticum, and hemangioma cavernosum), whereas complex or mixed malformations are named for the authors who first described them (for example, Klippel-Trenaunay syndrome [leg length discrepancy, varicose veins, or erythema without evidence of arteriovenous fistulas] and Parkes-Weber syndrome [Klippel-Trenaunay syndrome with the presence of arteriovenous fistulas]). The incidence of vascular malformations is 1.5% worldwide1; the prevalence of venous forms is 1 child in 5000 or 10,000, depending on the study.2 In his 1876 treatise on the pathology of tumors, Virchow3 discussed the first accurate medical description of a vascular malformation involving a cirsoid aneurysm, dating back to the sixteenth 143

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century. Nicoladoni4 and Branham5 nearly simultaneously described the occurrence of bradycardia after compression of a high-flow arteriovenous fistula. In 1964 Malan and Puglionisi6 published the first useful classification of angiodysplasia. Szilagyi et al7 further described clinical diagnosis and a therapeutic approach in 1976. In articles published in 1982, Mulliken and colleagues8,9 proposed a classification that distinguished between malformations or vascular abnormalities and vascular tumors (hemangiomas). This is currently the most widely used system. Vascular malformations are mistakes in the development of the vascular system; hemangiomas are vascular tumors. Mulliken et al9 described the characteristics of the endothelium and the biology of vascular malformations and hemangiomas. Approximately 30% of hemangiomas are present at birth, and 70% occur in the first 3 months of life. They grow during the proliferative phase (usually the first year of life) and regress in subsequent years. The female/male ratio of hemangiomas is 5:1. In a biologic study, hemangiomas had endothelial hyperplasia and an increase in mast cell inclusions; the cells grew if cultured, and they incorporated 3H-thymidine in their proliferative phase.10 Most hemangiomas regress spontaneously (95% are reduced by about 7 years of age) and require no therapy because any intervention (removal or reduction) would be aesthetically damaging due to healing of the tissues. In contrast, endothelial hyperplasia is not a characteristic of vascular malformations. These lesions do not have a proliferative phase (that is, they do not grow if placed in culture) and do not incorporate 3H-thymidine. They showed no mast cell inclusions in the biologic study.10 Their endothelium is surrounded by hyperplasia of the vascular wall. Approximately 90% of cases are present at birth, and the female/male ratio is 1:1. The growth of vascular malformations is related to the child’s growth and hemodynamic factors.

Embryology Vascular System The first channels of the vascular system can be seen beginning in the third week of gestation (see Chapter 4, Embryology). In 1922 Woollard11 sketched three stages of growth and differentiation: • Stage 1, the undifferentiated stage, is characterized by a small network of capillaries. • Stage 2, the retiform stage, involves the development of plexiform structures, increasing the vascular system’s volume and extent. • Stage 3, the maturation stage, occurs by the third week of gestation. The first large arteries, veins, and lymphatic ducts are seen. Vascular development is guided by receptors for growth factors. The blood vessels begin to form on the seventeenth day in the extraembryonic regions, with the generation of blood islands in the mesoderm of yolk sac, the embryonic stalk, and chorionic villus. Subsequently, throughout the embryonic disc the vascular network gradually expands for vasculogenesis (the formation of the circulatory system) and angiogenesis (the sprouting of blood vessels from preexisting angioblastic cords), a gradual process. By the twenty-fourth day, the yolk sac is connected to the embryo through the two veins and three vitelline arteries (celiac trunk,

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superior mesenteric artery, and inferior mesenteric artery), and the red blood cells begin to circulate. The two allantoic veins and the two allantoic arteries pass through the pedicle, which will become the umbilical cord. Various veins arise from the edge of the body of the embryo. These vessels are called common cardinal veins: • Two anterior cardinal veins from the cephalic endpoint • Two posterior cardinal veins from the tail endpoint • Two common cardinal veins, left and right Initially the venous system is symmetrical, but during the second month of gestation the right component takes over. The inferior vena cava derives from the right vitelline vein, the left and right posterior cardinal veins, and the superior and inferior cardinal veins. The common cardinal veins, the allantoic veins, and the vitelline veins merge into the venous sinus that, incorporated into the right atrium, will include the orifices of the superior and inferior vena cava. The superior vena cava develops from the common cardinal vein (right branch).

Lymphatic System The lymphatic system derives in part from the mesoderm and in part from the mesenchyme, an undifferentiated tissue that retains the ability to transform into another type of tissue, even in adults. The mesenchymal origin is evident in various cells. The reticular cells constitute the framework of the immunocompetent organs, particularly the lymph nodes, and can transform into macrophages. Endothelial cells, which line the inside of the capillaries and lymph vessels, are able to transform into macrophages. The origin of the lymphatic vessels is not entirely understood. They may develop directly from mesodermal protrusions or from endothelium evaginations of the veins in remodeling (lymphatic sacs). These structures are present in embryos measuring 2 cm (the fourth or fifth week of life or approximately 2 weeks after cardiovascular system development). Six primitive lymph sacs form: • Two equal and symmetrical sacs (jugular sacs) positioned cranially at the union of the jugular veins and the anterior cardinal veins • Two tail sacs (iliac sacs) at the union of the iliac veins and posterior cardinal veins • One median sac (retroperitoneal sac) on the posterior abdominal wall, at the root of the mesentery • One sac (cisterna chyli) dorsal to the retroperitoneal sac The sacs are connected by lymphatic channels. Both main channels develop independently and are formed by primitive right and left thoracic ducts. They join caudally with an anastomotic branch, combining the jugular sacs with the cisterna chyli. In adults, the thoracic duct grows caudally from the distal portions of the primitive thoracic ducts (right and left) and cranially from left thoracic duct. The right lymphatic duct (large lymphatic right vein) derives from the cranial part of the right thoracic duct. The subclavian, jugular, and bronchomediastinal collecting trunks derive from the jugular sacs.

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Classification of Vascular Malformations Vascular malformations have multiple causes and complex clinical presentations, making their classification challenging. Malan and Puglionisi6 tried to distinguish them by their anatomy and the presence or absence of arteriovenous fistulas. Szilagyi et al7 divided them into three stages according to the three main phases of embryologic life (segmentation, gastrulation, and organogenesis). According to this classification, capillary malformations (hemangiomatous malformations) occur when development is blocked during the first embryologic phase. (These should not be confused with hemangiomas, which are skin tumors.) Microarteriovenous or macroarteriovenous fistulas occur when development is interrupted during the second embryologic phase. Persistent embryonic veins indicate a developmental block in the third embryologic phase and involve mixed segmental vascular malformations. Jackson et al12 based their classification on hemodynamic and angiography findings. High- or lowflow lesions are distinguished by the amount of blood flow in arteriovenous fistulas. High-flow malformations correspond to the presence of arteriovenous macrofistulas, and low-flow malformations correspond to arteriovenous microfistulas, which carry a better prognosis. The most recent classification was published in Hamburg in 1990.13 Rutherford et al14 and Lee et al15 later revised this classification (Table 10-1). Malformations are classified based on the predominant basic defect as follows: • Arterial • Venous • Lymphatic • Mixed, either truncal or extratruncal forms according to the flow along the main axis or branches Predominantly arterial truncal malformations include congenital forms of sciatic artery or accessory subclavian artery persistence (which, passing behind the esophagus, is responsible for dysphagia lusoria); aortic arch anomalies; coarctation of the thoracic or abdominal aorta; and persistent embryonic vessels. Predominantly venous truncal malformations include forms of persistent embryonic veins, such as the outer marginal vein. These present with mixed forms of aplasia, ectasia, aneurysm, and thrombosis of various anatomic segments. The most frequent alteration is ectasia of the venous system, which occurs in patients with Klippel-Trenaunay syndrome and makes up approximately 40% of the malformations. Venous aneurysms or hypoplasia of the venous wall is much less common, accounting for less than 10% of malformations. Predominantly arteriovenous forms are most frequently extratruncal and may be localized or diffuse, especially on the skin or mucosa. They can be isolated or associated with more complex pathologic syndromes. Low-flow and high-flow shunt malformations can be distinguished. The predominantly arteriovenous malformations are more frequently seen in the lower limbs and pelvis, and the inherited forms usually occur in the lungs and sometimes in the brain. Hereditary hemorrhagic telangiectasia, for example, is characterized by the presence of spider veins in the dermis, mucosa, and viscera and is associated with arteriovenous fistulas in the lungs and brain.16

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TABLE 10-1  Hamburg Classification of Congenital Vascular Malformations (Modified) Affected Segment

Anatomic Form

Type

Arterial malformations

Truncal Extratruncal

Aplasia or obstruction Infiltrating Limited

Venous malformations

Truncal

Aplasia or obstruction Dilation Infiltrating Limited

Extratruncal Arteriovenous (arteriovenous shunt malformations)

Truncal Extratruncal

Lymphatic malformations

Truncal Extratruncal

Mixed vascular malformations

Truncal Extratruncal

Deep arteriovenous fistula Superficial arteriovenous fistula Infiltrating Limited Aplasia or obstruction Dilation Infiltrating Limited Arterial and venous Hemolymphatic Infiltrating hemolymphatic Limited hemolymphatic

These are manifested by recurrent nosebleeds, which occur in 90% of patients when they blow their nose or during a race or emotional stress. The mortality rate is 4%.

Capillary Malformations Capillary malformations are also known as hemangiomas. They are most often found on the head and limbs (upper and lower). The dimensions are extremely variable, from localized forms to giant forms with involvement of an entire side of the body. On clinical examination, capillary malformations appear as a red or rosy-purple skin rash with jagged or sharp margins. They are generally not raised, are highly variable in size and scope, and can be isolated or multiple and confluent. Within the patch, telangiectatic striae formed by largercaliber capillaries are evident. In capillary-venous mixed forms, abnormal reticular veins that drain from the malformation can be seen.17,18 Usually the skin lesion is sharply localized to the right or left of the midline, sometimes extending slightly beyond it. Another characteristic clinical aspect is metamerization (that is, the topography of the lesions usually follows the distribution of the head, trunk, or limb dermatomes). Facial locations typically respect the distribution of the sensory branches of the trigeminal nerve. In some patients, especially those with craniofacial lesions, hemangiomas tend to grow and produce a marked hyperplasia of the dermis and subcutaneous tissue. They are associated with a characteristic dilation of the subepidermal venous bed. These lesions are called hyperplastic birthmarks, commonly referred to as nevus flammeus or port-wine stains. On clinical examination, they pre­

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sent as patches of very dark purplish-red fibrotic tissue, often covered by vegetating plaques or polypoid formations.19

Lymphatic Malformations Congenital malformations of the lymphatic system are characterized by embryogenetic capillary abnormalities or by malformations of the major lymphatic collectors of the limbs, head, and torso.20 They are more common peripherally, especially in the legs, but can occur in the cervicofacial, thoracic, and pelvic regions.21 According to the Hamburg classification, congenital malformations of the lymphatic system can be distinguished by tissue forms (extratruncal) and cysts forms (truncal forms or lymphangiomas).22 Tissue lymphangiomas (or cystic hygromas) consist of a dense network of lymphatic microscopic vessels. Their dimensions are extremely variable, ranging from a small nodule to a voluminous mass. Lymphangiomas are characterized by an abnormal ectasia with saccular dilation of large lymph collectors or tanks. The locations correspond to the onset of major lymph node stations: submandibular, lateral cervical, axillary, inguinal, and mediastinal. The clinical development of lymphatic malformations is closely related to the type and severity of anatomic abnormalities and the body region affected. The tissue lymphangiomas manifest as skin rashes or subcutaneous swellings with a whitish, warty, and irregular surface, often covered by translucent microvesicles containing serous fluid. Cystic hygromas occur as massive swellings under the skin and have a soft and spongy texture. They float and expand with moderate antigravity maneuvers and are nonpulsating. The behavior of lymphatic malformations is extremely variable. They are usually present at birth and tend to gradually increase over the years, with remissions and relapses influenced by various factors (hormones, trauma, and infection). In some cases such as hemangiomas, progressive involution occurs after puberty.23,24 Lymphatic malformations may manifest clinically with lymphedema, an edema with a particularly high-protein concentration that can lead to permanent disability. Lymphedemas are truncal lymphatic malformations, because they appear after an interruption in the anatomy of a lymphatic region. Truncal lymphatic malformations can develop at birth or later. Lymphedemas are classified as primary or secondary. Primary lymphedema is connatal, early and late, and is often familial or inherited. Secondary lymphedema occurs after surgery, radiotherapy, trauma, and/or inflammation, or is functional (for example, postphlebitic). Secondary lymphedema is increasing in the average population because of the growing incidence of tumors. Treatments for tumors have improved; however, survival is associated with treatment sequelae, mainly secondary lymphedema. Lymphodynamic impairment results from agenesis or aplasia of lymph nodes or lymphatic trunks, impaired permeability of lymph capillaries, or lymphadenodysplasia. It can be familial or inherited (for “sporadic mutations” in only one member of the family) or caused by chromosomal abnormalities, amniotic bands, or other congenital diseases. Prevention is essential. Therefore if familial, it is important to know the genetic mutation in order to study the same mutation in subjects with a blood relation with the proband who has the mutation.

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The most frequent complications are usually local. Tissue forms can cause skin or mucosa necrosis, possibly associated with a lymphorrhage. Cystic forms can result in bleeding, infection, and compression of vital organs. More than 70% of vascular malformations are mixed.25 The most common forms seen clinically are listed in Table 10-2.

TABLE 10-2  Complex Vascular Malformations Syndrome

Genetic Description

Blue rubber bleb nevus

Type

Location

Characteristic Features

Autosomal dominant

Cavernous venous malformation

Skin, gastrointestinal tract, spleen, liver, central nervous system

Bluish, compressible rubbery lesions Gastrointestinal bleeding Anemia

Gorham Stout disease

Not hereditary

Angiomas Multiple lymphatic and venous malformations

Bones: shoulder, skull, pelvic girdle, jaw, ribs, and spine

Uncontrolled proliferation of thinwalled vascular or lymphatic vessels within bone, which leads to resorption and replacement of bone with angiomas and/or fibrosis

Hennekam syndrome

Autosomal recessive

Multiple lymphatic malformations

Viscera, bones, pulmonary system, face

Lymphedema Anomalies of the teeth, gingival hypertrophy Seizures Vascular anomalies Congenital pulmonary lymphangiec­ tasia Narrowness of the upper chest

Kasabach-Merritt syndrome

Autosomal dominant

Large cavernous venous malformation

Trunk, extremities

Thrombocytopenia Hemorrhage Anemia Ecchymosis Purpura

Klippel-Trenaunay syndrome

Somatic mutations

Few or low-flow arteriovenous shunt Venous or lymphatic trunk malformations Port-wine stains

Extremities, pelvis

Soft tissue and bone hypertrophy Varicosities (lateral lower limb to foot) Capillary or venous-lymphatic malformations

Maffucci syndrome (dyschondroplasia with vascular hamartoma)

Probably autosomal dominant

Arteriovenous malformations Cavernous lymphangioma

Fingers, toes, extremities, viscera

Enchondromas Spontaneous fractures Short extremity Vitiligo

Noonan syndrome

Autosomal dominant

Lymphatic or venouslymphatic malformations

Face, heart, skin, lower limbs, nervous system

Unusual facies (hypertelorism, downward-slanting eyes, and webbed neck) Congenital heart disease Short status Chest deformity Mental retardation Bleeding diathesis

Continued

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TABLE 10-2  Complex Vascular Malformations—cont’d Syndrome

Genetic Description

Parkes-Weber syndrome

Type

Location

Characteristic Features

Somatic mutations

Arteriovenous malformations (intraosseous or close to epiphyseal plate) Port-wine stain

Extremities, pelvis

Soft tissue and bone hypertrophy Atypical varicosity Capillary arteriovenous shunts High-flow arteriovenous shunts

Proteus syndrome

Somatic dominant gene mutation (lethal, except with mosaicism)

Multicutaneous and visceral arteriovenous, lymphatic, and venous malformations with muscle and skeletal diseases

Fingers, toes, extremities, viscera

Soft tissue abnormalities (lipomatosis, fatty hypertrophy, regional fatty atrophy, hyperpigmentation or cutaneous nevi, hyperkeratosis of the palms and soles, macrodactyly of the hands and feet, exostosis, bilateral genu valgum, kyphosis, and scoliosis secondary to vertebral dysplasia

Rendu-OslerWeber syndrome (h­ereditary hemorrhagic telangiectasia)

Autosomal dominant

Punctate angioma Telangiectasia Arteriovenous malformation of the gastrointestinal tract

Skin, mucous membranes, liver, lungs, kidneys, brain, spinal cord

Epistaxis Hematemesis, melena Hematuria Hepatomegaly Neurologic symptoms

Riley-Smith syndrome

Autosomal dominant

Multiple hemangiomas

Skin, brain, gastrointestinal tract, genitalia, thyroid

Symmetrical macrocephaly Pigmented maculae of the glans penis Mesodermal hamartomas (primarily subcutaneous and visceral lipomas, multiple hemangiomas, and intestinal polyps) Dysmorphy

Servelle-Martorell syndrome

Venous and rarely arterial malformations Cavernous hemangiomas

Limbs

Limb undergrowth, capillary stains, and varicose veins

Sturge-Weber syndrome (encephalotrigeminal angiomatosis)

Port-wine stains

Trigeminal area, leptomeninges, choroid oral mucosa

Convulsions Hemiplegia Ocular deformities Mental retardation Glaucoma Intracerebral calcifications

Hemangiomas

Retina, cerebellum

Cysts in cerebellum, pancreas, liver, adrenals, and kidneys

von HippelLindau (oculocerebellar hemangioblastomatosis)

Autosomal dominant

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Genetics of Vascular Receptors During embryonic development, vasculogenesis is mediated by growth factors (produced by the germ layers) and their receptor sites on the endothelial cells of the vascular system (see Chapter 4). In adults, growth factors are produced to a lesser extent. Their role in the regulation of angiogenesis is under study. Models that can help in understanding the mechanisms of suppression, control, and expression are the neoplastic cells, which, both in vitro and in vivo, reproduce the events that lead to the differentiation from mesodermal cells to the final cells. Among the growth regulators and their receptors, the most studied are vascular endothelial growth factor/vascular endothelial growth factor receptors (VEGF/VEGFR), forkhead box protein C2 (FOXC2), and SRY-related HMG box 18 (SOX18). Some genetic disorders currently under study in tumor development in animal models have shown a close relationship with vascular malformations. Some proteins are known growth factors such as hepatocyte growth factor (HGF); some genes encode junction proteins, which reshape cellular connections and can change the microvacular tissue unit function of absorption (see Table 10-3).

The Role of VEGF-3: Gene Map Locus 5q34.35 Vascular growth factors are important signaling proteins involved in vasculogenesis and angiogenesis. The activity of VEGF is mainly targeted to vascular endothelial cells, but also has effects on other types of cells (for example, monocytes and macrophages). In vitro VEGFs have proved capable of stimulating mitosis of endothelial cells and cell migration. VEGFs also increase microvascular permeability and are sometimes referred to as vascular permeability factors. All members of the VEGF family stimulate cellular responses by binding to receptor tyrosine kinases (VEGFR-X) on the surface of cells, causing their dimerization and activation through transphosphorylation. The receptors of VEGF have an extracellular portion composed of seven immunoglobulin domains, a single transmembrane region, and an intracellular portion containing tyrosine kinase. The most well-known growth factor, and the first to be isolated from the blood capillaries, is VEGF-A, which binds to two receptors: VEGFR-1 and VEGFR-2. Recently, a new receptor (VEGFR-3) was isolated. It does not bind VEGF-A. Instead, it binds two other growth factors, VEGF-C and VEGF-D, which are mainly expressed on lymphatic capillaries.26,27 He et al28 made an important contribution to this field by studying the behavior of cancer cells and identifying VEGF-C, a specific growth factor for lymphatic tissue that promotes lymphangiogenesis. VEGF-C is produced from a variety of human tumors, and its deregulation induces lymphangiogenesis and promotes tumor metastasis through lymphatics. Lymphangiogenesis induced by VEGF-C is primarily determined by the activation of tyrosine kinase bound to the receptor VEGFR-3. VEGFR-3 is expressed almost exclusively on lymphatic endothelium in normal adults. However, in studies with guinea pigs, VEGFR-3 is widely expressed on endothelial cells of the blood system, before lymphatic vessels appear in the fourth week of gestation.

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VEGF-D is another growth factor that activates VEGFR-3; its overexpression leads to accelerated lymphangiogenesis and the spread of cancer cells to lymph nodes. In turn, the inactivation of VEGF-C and VEGF-D inhibits tumor lymphangiogenesis. Unlike blood capillaries, lymphatic capillaries are lined by a single layer of nonfenestrated endothelial cells that lack pericytes, smooth muscle cells, and a basal membrane. VEGFR-3 is also expressed on the blood capillaries of normal breast tissue, on chronic wounds, and on neuroendocrine organs29,30; monocytes, macrophages, and some dendritic cells express this receptor. The receptor VEGFR-2, which is the main promoter of mitosis of endothelial cells in the blood and binds the factors VEGF-A, VEGF-C, and VEGF-D, is also expressed on lymphatic capillaries and mediates lymphangiogenesis. Lymphangiogenesis was prevented through the selective blockade of VEGFR-3, using an antibody (MF4-31C1) in a murine model for the study of regeneration lymphatics.31 Even in the presence of an overexpression of VEGF-C in breast cancer cells, the antibody MF4-31C1 reduced lymphangiogenesis and lymphatic metastases, confirming the essential role of this receptor. The preexisting lymphatic vessels did not appear morphologically or functionally altered by a prolonged blockade of VEGFR-3, and blood vessels, including those resulting from neovascularization, were only slightly reduced in number. Another potential target of a VEGFR-3 block may be the immune system, leading to disorders such as inflammatory bowel disease. In ulcerative colitis and Crohn disease, the number of lymphatic capillaries is substantially increased in the lamina propria and submucosa of the small and large intestine, which is thought to contribute to the morbidity of the disease.32 The preexisting lymphatic vessels did not appear to be substantially modified by the blockade of VEFGR-3. However, further in vitro studies have revealed the importance of VEGF-C/VEGFR-3 in the survival of lymphoid cells.33 The expression of VEGFR-3 increases in blood capillaries of chronic wounds, although the prolonged inhibition of VEGFR-3 only minimally influences the regeneration of capillaries. Mediation by interaction with VEFGR-2 probably plays an important role in vivo, along with the expression of VEGF-D, which binds to and activates VEGFR-3 and VEGFR-2.

The Role of FOXC2: Gene Map Locus 16q24.3 FOXC2 is a protein that in humans is encoded by the gene FOXC2, part of the family of transcription factors. FOXC2, similar to VEGF, is involved in the promotion of metastasis by lymph nodes. In particular, the expression of FOXC2 increases when the epithelial cells are subjected to a mesenchymalepithelial transition. The repression of FOXC2, using shRNA, reduces the metastatic ability of breast cancer cells.34 Mutations in the FOXC2 gene have been associated with multiple lymphedematous syndromes, including lymphedema-distichiasis syndrome, lymphedema–yellow nail syndrome, and

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lymphedema-ptosis, and they play an important role in the genesis of varicose veins. In addition, some FOXC2 mutations have been identified in patients with family obesity, diabetes mellitus, and adrenal insufficiency, especially in European families. FOXC2 is an essential transcription factor of the cardiovascular system and its diseases. However, the cellular and molecular functions of FOXC2 in vascular endothelial cells have not been fully understood. Some authors have identified targets of FOXC2, including molecules associated with cellular-extracellular matrix: integrin beta-3 (ITGB3), integrin beta-5 (ITGB5), and fibronectin. In particular, the expression of ITGB3 is directly regulated by FOXC2. In vitro, ITGB3 is a known regulator of angiogenesis. Overexpression of FOXC2 greatly improves the adhesion of endothelial cells, and this effect is strongly inhibited by neutralization, by antibodies of ITGB3. In addition, overexpression of FOXC2 enhances the tropism of the small vessels and intensifies angiogenesis.35 The normal lymphatic capillaries are devoid of smooth muscle cells, whereas the lymphatic manifolds are surrounded by a layer of smooth muscle cells, which allows the progression of the lymph in a centripetal direction, aided by the presence of one-way valves. The lymphatic capillaries of the lower limbs of patients who have mutations in FOXC2 are surrounded by smooth muscle cells abnormally organized, and lymphatic collectors are almost entirely lacking. In individuals without mutations in FOXC2, only the capillaries are surrounded by smooth muscle cells; however, in those with mutations in FOXC2, the lymphatic capillaries are surrounded by smooth, disorganized muscle cells.

The Role of SOX18: Gene Map Locus 20q13.33 The SOX18 transcription factor genes (sex determining region Y [SRY] and high mobility group [HMG] box) are a family of DNA-binding domain protein through the HMG. They play a key role in the embryonic development of eukaryotic organisms and in the regulation of gene expression required for cell differentiation. The transcription factor SOX18 is recognized as a specific switch in inducing the differentiation of endothelial cells of the blood vascular system to express prospero-related homeobox 1 (PROX1), a gene critical for the formation of lymphatic vessels from the cardinal veins. In experimental models, SOX proteins are transcription factors that regulate normal cell function through links on specific DNA sites that allow/inhibit the control of certain genes in the cells of the lungs, musculoskeletal system, cardiovascular system,36 brain, testes, liver, and leukocytes. Some studies, always on animal models, have demonstrated that the expression of SOX genes is present both during embryonic life and adult life.37 In experimental models of cancer progression, the selective blockade of the genes coding for the proteins of SOX18 transcription leads to 80% reduction of tumor angiogenesis. However, the selective blockade in experimental adult mice models leads to the development of cardiovascular diseases. Even in humans the transcriptional proteins family -SOX (SRY-related and HMG-box) are both involved in embryonic development and in the cellular regulation of adult life. The protein encoded by the gene, after forming a protein complex with other cytoplasmic proteins, regulates function in cells of blood vessels, lymphatic vessels, and hair. Mutations in this gene have been associated with recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia syndrome (Table 10-3).

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TABLE 10-3  Genetic Alterations Involved in Vascular Disorders Currently Under Study Gene

GeneCards Description

Hepatocyte growth factor (HGF)

HGF regulates cell growth, cell motility, and morphogenesis by activating a tyrosine kinase signaling cascade after binding to the protooncogenic c-Met receptor. Its ability to stimulate mitogenesis, cell motility, and matrix invasion confers a central role in angiogenesis, tumorogenesis, and tissue regeneration. Diseases associated with HGF include dfnb39 nonsyndromic hearing loss and deafness and autosomal recessive deafness.

Mesenchymal epithelial transition factor (MET)

MET, also known as hepatocyte growth factor receptor (HGFR), is a protooncogenic receptor tyrosine kinase. MET receptors are expressed on cells of epithelial origin. Aberrant activation of the HGF/MET pathway leads to a variety of cancers. MET mutation is associated with a poor prognosis, because it can trigger tumor growth, angiogenesis, and metastasis. Diseases associated with MET include papillary renal carcinoma and papillary carcinoma.

Gap junction protein gamma 2 (GJC2)

The GJC2 gene encodes a gap junction protein. Defects in this gene are the cause of autosomal recessive Pelizaeus-Merzbacher-like disease. Gap channels (also known as gap junctions) are specialized cell-cell contacts between almost all eukaryotic cells that provide direct intracellular communication. They are continuously synthesized and degraded, allowing tissues to rapidly adapt to changing environmental conditions. Connexins play a key role in many physiologic processes, including cardiac and smooth muscle contraction, regulation of neuronal excitability, epithelial electrolyte transport, and keratinocyte differentiation. Mutations in connexin genes are associated with human diseases, including sensorineural deafness, a variety of skin disorders, peripheral neuropathy, vascular abnormalities, and cardiac disease. Diseases associated with GJC2 include hereditary lymphedema 1C, and spastic paraplegia.

GATA binding protein (GATA-2)

GATA-2 encodes a member of the GATA family of zinc-finger transcription factors that are named for the consensus nucleotide sequence they bind in the promoter regions of target genes. The encoded protein plays an essential role in regulating the transcription of genes involved in the development and proliferation of hematopoietic and endocrine cell lineages. Diseases associated with GATA-2 include myelodysplastic syndromes and acute myeloid leukemia, susceptibility, gata2-related. Related superpathways are DREAM repression and dynorphin expression and platelet activation, signaling, and aggregation.

Vascular cell adhesion molecule (VCAM-1)

VCAM-1 is a member of the Ig superfamily and encodes a cell surface sialoglycoprotein expressed by cytokine-activated endothelium. This type I membrane protein mediates leukocyte–endothelial cell adhesion and signal transduction, and may play a role in the development of artherosclerosis and rheumatoid arthritis. Diseases associated with VCAM-1 include Mooren ulcer and vasculitis.

Fatty acid binding protein (FABP4)

FABP4 encodes the fatty acid binding protein found in adipocytes. Fatty acid binding proteins are a family of small, highly conserved, cytoplasmic proteins that bind long-chain fatty acids and other hydrophobic ligands. They bind long-chain fatty acids and retinoic acid and deliver long-chain fatty acids and retinoic acid to their cognate receptors in the nucleus. Diseases associated with FABP4 include back pain and bladder transitional cell carcinoma.

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Diagnosis Ultrasonography Doppler ultrasonography is an excellent tool for the initial assessment of patients with venous malformations. High- and low-flow forms are easily distinguished. High-flow malformations show waves with high speed and low resistance; in low-flow malformations, the volumes, arterial flow, and arterial resistance are normal in the arteries that supply the venous side. Flows with low resistance can be found in intramuscular malformations. Ultrasonography provides additional information on the morphology and evolution of venolymphatic lesions. The malformed veins are more or less compressible, depending on the parietal thickening that occurs with time. Patients can be assessed for venous thrombotic events. In those undergoing surgical or endovascular treatment, the incidence of deep venous thrombosis is high, beginning on postoperative day 1.38

Magnetic Resonance Imaging and Computed Tomography MRI provides information on only high- and low-flow forms, but also on the closer organs and surrounding tissues (muscles, bones, nerves, and adipose tissue). The venolymphatic malformations (low-flow) show a high signal intensity in the long TR/TE sequences, whereas the arterial malformations (high-flow) do not show an increase in the signal. Furthermore, the venous-lymphatic malformations give a signal intensity higher than that of muscle or skeleton in the T1- and T2-weighted images, probably because of the presence of a fibrous septum along the vascular endothelium. MRI, compared with arteriography or venography, allows better assessment of the extent of the malformation, especially in cases in which access to venous contrast fluid is difficult.39 Two-dimensional high-resolution CT with three-dimensional reconstructions provides good information on the extent of malformation, but does not distinguish between lesions that are predominantly arterial and mixed lesions. Because of the need for contrast, timing is important. (It is an operator-dependent examination.) Proper measurement of the lesion depends on the amount of blood that it contains.40 CT provides important information about the tissue characteristics of the suprafascial and subfascial compartments. It is helpful for developing a therapeutic approach and for monitoring the results of treatment.

Arteriography and Venography Arteriography is reserved for patients who will undergo embolization. Angiography is useful for measuring the size of the nurse artery and assessing the extent of the shunt. The flow volume is calculated from the size and proportion of the source artery opacification, whereas the shunt volume can be roughly calculated using the time of the appearance of contrast in the veins.41 Venography is reserved for patients who will undergo venous correction. The prevalence of venous malformations in the nurse artery is not increased, because the size of the capillary bed maintains a low resistance. Arteriography does not correctly show the extent of the malformation from the venous side. In these cases, injection of the contrast in the venous side reveals the complete vascular malformation.42

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Lymphoscintigraphy Lymphoscintigraphy is the benchmark of diagnostic imaging in patients with primary and secondary lymphedema. In the current guidelines, however, the method is not yet standardized, reducing the specificity of the examination. Lymphoscintigraphy had proved useful for identifying and defining lymphedemas; in directing preventive, physical, and surgical treatments; and in determining a prognosis. In patients with subclinical lymphedema, the appearance of lymph nodes along the limb (particularly after a lymphadenectomy) is interpreted as a sign of lymph transport failure. The examination provides morphologic and functional information about lymphatic circulation; a sterile technique is essential for accurate interpretation of data. Morphology demonstrated by lymphoscintigraphy includes the following: • Hypogenesis or agenesis of lymphatic stations or one-way lymphatic vessels or valves • The presence and extent of dermal backflow • The presence of lymph node obstructions in the middle of the limb (that is, the knee and the elbow) • The presence of alternative channels

Treatment There are absolute and relative indications for the treatment of vascular malformations. Absolute indications include the following: • Hemorrhage • Ischemia • Ulcers refractory to conventional treatments • Congestive heart failure Clinical manifestations for which treatment is absolutely indicated include the following: • Intramuscular or retroperitoneal hematoma • Hematuria • Rectal bleeding • Hematemesis • Hemoptysis • Unifocal/multifocal bleeding in the brain or spinal cord Relative indications for treatment are the following: • Pain • Intermittent claudication • Leg length discrepancy • Other aesthetic alterations A multidisciplinary approach to the evaluation and treatment of vascular malformation provides the best outcome, especially for young patients.

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Conservative treatment is recommended for most patients. Minimally invasive percutaneous techniques have evolved in recent years and include scleroembolization, a very complex procedure. Laser therapy has been used effectively for capillary malformations (port-wine stains and other imperfections). Surgical resection is reserved for patients who have superficial localized lesions or bulky varicose veins that developed when the patient was young and are debilitating. Compression is the most important element43 in the management of primary and secondary lymphedema.44,45 After the affected limb or limbs have undergone anatomic changes, bandages are placed to maintain constant external pressure.46 According to the Young-Laplace equation,47 compression, at constant tension, is directly dependent on the radius of the affected limb: Compression 5 Layers of bandages 3

Bandage tension Leg radius

A recent study showed that compression is most effective when patient compliance with the bandaging requirements is high.48 The bandage should be as comfortable as possible to ensure that it is kept in place and allows the most effective drainage.49 Lymphatic drainage depends on the level of injury of the lymphatic system and its residual function, which is influenced by the mobility of the limb. The patient’s lifestyle is a factor in the effectiveness of treatment. Good compliance with instructions for care of the bandage and the overlying elastic garment are essential. Venolymphatic malformations comprise a series of various-sized cysts covering the lymphatic vascular endothelium. Cysts in serum or whole blood may or may not communicate with each other and are immersed in a support matrix consisting of fibrous tissue, smooth muscle cells, and lymphocytic aggregates. It is possible to distinguish macrocystic lesions (cystic hygroma) from microcystic and mixed lesions. Surgical resection is considered the standard treatment, although the recurrence rate varies from 15% to 53%,50 and significant complications (nerve palsy) occur in up to a third of cases. Recurrence of cystic hygroma and serious surgical complications can be prevented with the use of interventional radiologic techniques. Minimally invasive radiotherapy50,51 is helpful for ablating selective vascular endothelial multicystic lesions52 through the use of different agents, including bleomycin, doxycycline, ethanol, Ethibloc, OK-432, and sodium tetradecyl sulfate. Therapeutic success is reported to vary from 20% to 64%. Macrocystic lesions (larger than 1 cm in diameter) are catheterized percutaneously under ultrasonographic guidance along different points of the malformation and then are injected with sclerosing agents. The best results, with a therapeutic success rate of 80% to 90%, are obtained with doxycyline, OK-432, and bleomycin.53-55 Minor complications such as hemolytic anemia, hypoglycemia, metabolic acidosis, transient hypotension, blisters, and hair loss develop in 10% to 14% of cases.56,57

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Microcystic malformations are treated with a single percutaneous injection under ultrasound guidance. Cysts are aspirated and sclerosing foam (usually doxycycline) is injected, changing the microbial environment of the treated areas. The therapeutic success rate is more than 90%.58 Surgical treatment is reserved for more complex forms of vascular malformations, especially those with low flow, and to compose venous flow in prevailing venous component. Surgery is preceded and/or followed by sclerotherapy of large areas of the lesion. The malformed component is usually excised in a bloodless field, and an Esmarch bandage is placed.59 In high-flow forms, the only necessary surgical treatment is amputation: amputation is often a life-saving medical treatment, because it corrects hemodynamic decompensation created by the shunt.60

Conclusion The approach to patients with vascular malformations is multidisciplinary, requiring a team that performs medical, radiologic, and surgical procedures and provides rehabilitation and psychological care. Correct assessment and the study of disease evolution are the first and most difficult steps in understanding and managing patients with vascular malformations. The diagnosis and therapy for patients with vascular malformations is extremely challenging. The clinical features are variable, from small cutaneous manifestations to complex deformity of organs and limbs. Initial assessments are performed to study the nature of the malformation, including its size and complexity, and to quantify the damage caused by hemodynamic alterations. The method chosen must be repeated over time to monitor the evolution of the lesion and the success of therapy. Ultrasonography is relatively inexpensive and clearly defines the hemodynamic profile of the malformation, especially in venolymphatic (low-flow) lesions. It is useful in the early stages of disease and can be a good corollary examination in more complex evaluations. Ultrasound examinations are operator dependent; diagnostic accuracy is strongly affected by experience. MRI (with or without a contrast medium) is perhaps the most comprehensive investigation for determining the morphofunctional damage. This mode is not strictly linked to the experience of the operator for diagnostic accuracy and is easily comparable and repeatable over time. Arteriography and phlebography are instrumental investigations carried out if contextual treatment is needed or if the vascular malformation is complex and the therapeutic choice difficult. Nonlethal vascular malformations can be disabling, affecting a patient’s a social life and self-image. They can influence quality of life by impairing the individual’s physical performance and through chronic clinical worsening. Complex surgical therapy is performed in a few specialized centers for patients with unfavorable results of hemodynamic assessment. Rehabilitation therapy, including medication and physical therapy, slows progression of the disease, allowing patients to be more autonomous in managing their activities of daily life, thus enhancing their quality of life. Furthermore, medical and physical therapy may be carried out more easily on the affected area, costs are lower, and optimal timing of surgery (corrective and demolitive) can be chosen.

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26. Saharinen P, Tammela T, Karkkainen MJ, et al. Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends Immunol 25:387-395, 2004. 27. Oliver G. Lymphatic vasculature development. Nat Rev Immunol 4:35-45, 2004. 28. He Y, Kozaki K, Karpanen T, et al. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst 94:819-825, 2002. 29. Valtola R, Salven P, Heikkila P, et al. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am J Pathol 154:1381-1390, 1999. 30. Paavonen K, Puolakkainen P, Jussila L, et al. Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing. Am J Pathol 156:1499-1504, 2000. 31. Pytowski B, Goldman J, Persaud K, et al. Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. J Natl Cancer Inst 97:14-21, 2005. 32. Geleff S, Schoppmann SF, Oberhuber G. Increase in podoplanin-expressing intestinal lymphatic vessels in inflammatory bowel disease. Virchows Arch 442:231-237, 2005. 33. Mäkinen T, Veikkola T, Mustjoki S, et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J 20:4762-4773, 2001. 34. Mani SA, Yang J, Brooks M, et al. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci U S A 104:10069-10074, 2007. 35. Hayashi H, Sano H. The FOXC2 transcription factor regulates angiogenesis via induction of integrin beta3 expression. J Biol Chem 283:23791-23800, 2008. 36. Downes M, Koopman P. SOX18 and the transcriptional regulation of blood vessel development. Trends Cardiovasc Med 11:318-324, 2011. 37. Matsui T, Kanai-Azuma M, Hara K, et al. Redundant roles of Sox17 and Sox18 in postnatal angiogenesis in mice. J Cell Sci 119(Pt 17):3513-3526, 2006. 38. Yakes WF, Ray RL, Stavros AT, et al. Diagnostic evaluation by different species of congenital vascular defects. In Balas P, ed. Progress in Angiology. Torino, Italy: Minerva Medica, 1990. 39. Rak KM, Yakes WF, Ray RL, et al. MR imaging of symptomatic peripheral vascular malformations. AJR Am J Roentgenol 159:107-112, 1992. 40. Mulligan PR, Prajapati HJ, Martin LG, et al. Vascular anomalies: classification, imaging characteristics and implications for interventional radiology treatment approaches. Br J Radiol 87(1035):20130392, 2014. 41. Natali J, Merland JJ. Superselective arteriography and therapeutic embolisation for vascular malformation. (Angiodysplasias). J Cardiovasc Surg (Torino) 17:465-472, 1976. 42. Yakes WF. Extremity venous malformation: diagnosis and management. Semin Intervent Radiol 11:332339, 1994. 43. Planinsek Rucigaj T, Tlaker Zunter V, Miljković J. [Compression therapy for lymphedema: our experience] Acta Med Croatica 64:167-173, 2010. 44. Compression therapy. Proceedings of a meeting organized by the International Compression Club. September 2008. Lucca, Italy. Int Angiol 29:391-470, 2010. 45. Linnitt N, Davies R. Fundamentals of compression in the management of lymphoedema. Br J Nurs 16:588-592, 2007. 46. Vaillant L, Müller C, Goussé P. [Treatment of limbs lymphedema] Presse Med 39:1315-1323, 2010. 47. Laplace PS. Essai Philosophique sur les Probabilités. Paris: Courcier, 1814. 48. Lee B, Andrade M, Bergan J, et al; International Union of Phlebology. Diagnosis and treatment of primary lymphedema. Consensus document of the International Union of Phlebology (IUP)-2009. Int Angiol 29:454-470, 2010. 49. Lay-Flurrie K. Use of compression hosiery in chronic oedema and lymphedema. Br J Nurs 20:418, 420, 422, 2011.

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50. Zhou Q, Zheng JW, Mai HM, et al. Treatment guidelines of lymphatic malformations of the head and neck. Oral Oncol 47:1105-1109, 2011. 51. Chaudry G, Burrows PE, Padua HM, et al. Sclerotherapy of abdominal lymphatic malformations with doxycycline. J Vasc Interv Radiol 22:1431-1435, 2011. 52. Lowe LH, Marchant TC, Rivard DC, et al. Vascular malformations: classification and terminology the radiologist needs to know. Semin Roentgenol 47:106-117, 2012. 53. Okazaki T, Iwatani S, Yanai T, et al. Treatment of lymphangioma in children: our experience of 128 cases. J Pediatr Surg 42:386-389, 2007. 54. Alomari AI, Karian VE, Lord DJ, et al. Percutaneous sclerotherapy for lymphatic malformations: a retrospective analysis of patient-evaluated improvement. J Vasc Interv Radiol 17:1639-1648, 2006. 55. Lee BB, Kim YW, Seo JM, et al. Current concepts in lymphatic malformation. Vasc Endovascular Surg 39:67-81, 2005. 56. Burrows PE, Mitri RK, Alomari A, et al. Percutaneous sclerotherapy of lymphatic malformations with doxycycline. Lymphat Biol Res 6:209-216, 2008. 57. Cahill AM, Njis E, Ballah D, et al. Percutaneous sclerotherapy in neonatal and infant head and neck lymphatic malformations: a single center experience. J Pediatr Surg 46:2083-2095, 2011. 58. Shiels WE, Dent CM, Murakami JW. Percutaneous treatment of microcystic lymphatic malformation. Presented at the Radiological Society of North America Scientific Assembly and Ninety-sixth Annual Meeting, Chicago, Sept 2010. 59. Villavicencio JL, Gillespie DL, Kreishman P. Controlled ischemia for complex venous surgery: the technique of choice. J Vasc Surg 34:947-951, 2001. 60. Trout HH III, McAllister HA Jr, Giordano JM, et al. Vascular malformations. Surgery 97:36-41, 1985.

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C hapter 11 Immune Regulation by the Peripheral Lymphatics David G. Hancock

K ey P oints • Lymphedema is characterized by numerous immune deficits, including altered wound healing and increased susceptibility to infection, which develop after an initial lymphatic insult. This connection between immune dysfunction and peripheral lymphatic dysfunction is also mirrored in most human inflammatory disorders, suggesting a crucial immune role for the lymphatics.

Imm

• The peripheral lymphatics are a highly integrated component of the immune system capable of mediating their effector function in response to pathogenic and immunogenic stimuli in the local immune microenvironment. • After activation by a diverse range of stimuli, the lymphatics upregulate a range of immune modulatory molecules capable of mediating cell migration and local immune function. Activation also induces lymphangiogenesis to facilitate cell migration and enhance antigen, cytokine, and fluid clearance from the affected site. • As a key immune organ, the lymphatics represent a promising target for future lymphatic-directed immunomodulatory therapies and a crucial area of interest for future research into human disease.

This chapter discusses the active roles of the lymphatics in an immune response. Active immune regulation by the peripheral lymphatics is essentially defined as the ability of the lymphatics to dynamically and specifically respond to immune mediators and subsequently modulate the function of peripheral immune cell populations in a stimulus-specific manner. Although these active immune roles remain poorly understood, they are critically important to the understanding of immune functioning as a whole. The peripheral lymphatic system plays several diverse roles in the human body, including the regulation of fluid balance and fatty acid transport from the gastrointestinal tract. Peripheral lymphatic dysfunction can lead to lymphedema, which is generally considered a circulatory condition characterized by abnormal fluid distribution (initially) and fat deposition (later stages). However, evidence of concurrent immune dysfunction in lymphedema suggests that lymphedema could also be classified as a functional immune disorder. The multiple immune deficits in lymphedema 163

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include excessive fibrosis and local inflammation, poor wound healing, increased susceptibility to infections, and increased risk for the development of malignancy in the affected area.1,2 The appearance of immune dysfunction resulting from lymphatic dysfunction in lymphedema strongly supports a relationship between the lymphatics and the rest of the immune system. This relationship is reciprocal rather than linear, because lymphatic dysfunction is also observed as a result of immune dysfunction in primary immune conditions. For example, chronic inflammation in patients with chronic obstructive pulmonary disease is characterized by multiple immune defects, including abnormalities in the phenotype and density of lymphatic vessels.3 Moreover, altered patterns of lymphangiogenesis (the formation of new lymphatic vessels) have been identified in most human inflammatory conditions, including psoriasis and chronic airway inflammation.4 Finally, peripheral lymphatic vessels also play key roles in transplant rejection and tumor metastases.5 Collectively, these observations highlight the complex and important interconnection between the lymphatic and immune systems. However, despite the identification of peripheral lymphatic involvement at a gross level in many diseases, the specific pathways and mechanisms underlying lymphatic-mediated regulation of immunity remain relatively poorly understood. The primary immune role for the lymphatics is the regulation of cell migration, which is mediated through both the expression of molecules involved in cellular trafficking and the formation of new lymphatic pathways by means of lymphangiogenesis. However, very few studies have directly investigated the immune role of the lymphatics in human disease, and thus the mechanisms of immune regulation remain poorly understood. In addition to this limited understanding, the lymphatics are also still often perceived as passive conduits for fluid, fatty acids, and immune cells. This perception inherently reduces the importance of the lymphatics as an immune organ, and this at least partially explains the omission of the lymphatics in most studies investigating immune function.

Lymphatic Activation by the Immune Microenvironment Compared with a passive component, the essential characteristic of an active component of the immune response is the ability to respond to diverse stimuli and change effector function in response to these diverse stimuli. For example, different activation signals induce different activation programs in macrophages and T cells, such as the classic M1/M2 macrophage responses or Th1/Th2 T-cell responses. This differential integration of signals allows functional specialization and active immune regulation. In contrast to their perceived role as a passive conduit for immune cells, the lymphatics can respond to a wide range of pathogenic stimuli (the so-called primary activation signals) and immune molecules (the so-called secondary activation signals), all of which induce different functional outcomes in immune cell activation/migration and lymphangiogenesis (Fig. 11-1).

Primary Activation Signals Lymphatic endothelial cells express functional toll-like receptors (TLRs) and thus can respond to pathogenic stimuli, including lipopolysaccharide (via TLR4) or lipoteichoic acid (via TLR2).6,7 As with other immune cell populations, stimulation via TLR4 (or any of the pathogen recogni-

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Induces mediators of immune function and cell migration

Promotes/inhibits lymphangiogenesis



Lymphatic endothelial cell Antigen presenting cell Immune molecules

Pathogenic signals Adhesion molecules Cytokines/chemokines/interleukins

FIG. 11-1  Mechanisms of active immune regulation by the lymphatics. The peripheral lymphatics can respond directly to pathogenic signals and secondary immune mediators produced by pathogen-activated antigen-presenting cells and other immune cell populations. This induces an activation-specific effector program, which involves the regulation of lymphangiogenesis, the expression of cytokines, chemokines, and adhesion molecules for the regulation of cell migration, and interleukins for the regulation of the local immune microenvironment.

tion receptors) induces the expression of a range of inflammatory mediators involved in effector function.6,7 In vitro stimulation of lymphatic endothelial cells with lipopolysaccharide induced the expression of a large number of molecules, including interleukin 6 (IL-6), IL-8, chemokine (CC motif) ligand 21 (CCL21), vascular cell adhesion molecule 1, and intercellular adhesion molecule 1 (ICAM-1).8 Although CCL21, vascular cell adhesion molecule 1, and ICAM-1 are related to the well-appreciated role of the lymphatics in cell migration, IL-6 and IL-8 are classic proinflammatory mediators involved in regulating the function of multiple immune populations,8 suggesting that the lymphatics may also regulate local immune homeostasis. In addition, lymphatic activation does not occur in isolation (as with an in vitro culture model) but instead in a complex, integrated immune milieu. This is perhaps best highlighted in TLRdeficient mouse models, which show concurrent deficiencies in lymphatic architecture/function and macrophage activation/migration. The macrophage deficits are at least partly caused by the reduced ability of the dysfunctional peripheral lymphatics to regulate macrophage recruitment, maturation, and function (and vice versa).9,10 The other crucial observation that highlights the integration of the lymphatics into the normal immune response to pathogens is the ability of lymphatic endothelial cells to uniquely respond to distinct pathogens (as is observed in all immune cell populations). This stimulus-dependent specificity is observed not only in simplified in vitro restimulation assays with various TLR agonists6-8 but also in more physiologic models of inflammation. For example, large differences in the transcriptional expression of key chemokines and integrins were observed in lymphatic endothelial cells isolated from models of oxazolone-induced contact hypersensitivity and complete Freund’s

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adjuvant-induced inflammation.11 These differences in immune mediator expression by lymphatic endothelial cells contributed to gross differences in inflammation, cell activation/migration, and edema formation between models.11 The large number of differentially expressed genes (.1000) in the inflammation-activated lymphatics also implies a far greater complexity than currently appreciated.11 Thus different pathogenic stimuli induce distinct functional programs in the lymphatics, allowing their active regulation of different immune responses (see Fig. 11-1).

Secondary Activation Signals Although external pathogenic signals may be responsible for the primary initiation of an immune response, a diverse range of interleukins, cytokines, and chemokines (secondary activation signals), produced by activated immune cells, serves to modulate the resulting response. As an integrated component of the immune response, the lymphatics are capable of responding to a wide range of chemokines, interleukins, and other immune mediators with a unique pattern of activation depending on the stimulus.4,12 The effector molecules induced by many of these immune mediators overlap with those induced by pathogenic stimulation,8,13 suggesting that changes in lymphatic phenotype/function in the context of in situ human disease are directed by an inseparable combination of primary and secondary activation signals (see Fig. 11-1). Indeed, it is becoming increasingly clear that activation of all immune populations (now including the lymphatics) in the immune microenvironment is complex and multifaceted and thus likely poorly reproduced in vitro. One of the important consequences of lymphatic activation by secondary immune mediators is the promotion or inhibition of lymphangiogenesis either directly or indirectly through the induction in the expression of lymphangiogenesis-promoting molecules in other immune populations.4,12 In inflammation, lymphangiogenesis increases the density and size of the lymphatic vessels to increase fluid drainage, cell migration, and antigen clearance from the affected site and is intrinsically linked to the resolution or progression of inflammation.14,15 Activated macrophages, T cells, mast cells, and dendritic cells can also directly produce vascular endothelial growth factors (VEGFs) A, C, and D, the canonical mediators of lymphangiogenesis.4,12 Given these strong links between multiple immune modulators and lymphangiogenesis, it is not surprising that altered patterns of lymphangiogenesis are commonly observed in human disease. Collectively, the ability of the lymphatics to regulate their effector function in response to secondary immune mediators emphasizes the lymphatics as an integrated component of the immune response (see Fig. 11-1).

Clinical Significance of Lymphatic Activation Although the ability of the peripheral lymphatics to respond to primary and secondary activation signals per se suggests an important integrated role for the lymphatics in the immune response, several more clinically relevant studies have highlighted a direct link between lymphatic function/ dysfunction and human disease pathogenesis. Lymphatic filariasis (also known as elephantiasis) is a tropical disease caused by the filarial parasites Wuchereria bancrofti (90% of cases), Brugia malayi, and Brugia timori.16 The direct and specific colonization of lymphatic vessels with the filarial parasites induces a clinical disease, which

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is remarkably similar to primary/secondary lymphedema, characterized by edema, altered lymphatic vessel distribution/phenotype, increased local fibrosis, and altered immune homeostasis in the affected area16 (see Chapter 15). Direct stimulation of lymphatic endothelial cells with B. malayi has been found to induce the differential expression of several key immunologic molecules related to lymphangiogenesis and immune cell migration and activation.16 This provides a strong link between altered lymphatic activation and the pathogenic characteristics of clinical disease, including the general immune deficits. Similar dysregulation of key immunologic molecules was also observed in lymphatic endothelial cells isolated from patients with lymphedema.17 As with lymphatic filariasis, this result further suggests that intrinsic defects in lymphatic activation are at least partially responsible for the immune dysfunction in patients with lymphedema and lymphatic disease. Thus lymphatic expression of key immune mediators in response to activation signals from the immune microenvironment appears essentially linked to overall immune function. In addition to the direct response to pathogenic signals (such as to filarial parasites), the responsiveness of the lymphatics to secondary immune mediators also appears critically related to lymphatic involvement in the pathogenesis of some human diseases. For example, transforming growth factor beta (TFG-beta) and IL-27 are primarily produced by antigen-producing cells (macrophages and dendritic cells) and have broad immunomodulatory properties, including a net inhibitory effect on lymphatic function and vessel growth.18,19 Altered wound healing is one of the most clinically relevant sequelae of lymphedema in disease morbidity.1 TGF-beta is commonly increased in altered wound healing and has a negative effect on lymphatic regeneration. Because the lymphatics play an important role in the wound healing process, the pathogenesis of altered wound healing in lymphedema may be partially dependent on the effects of altered TGF-beta signaling to the lymphatics, separate from the initial lymphatic insult.18 Similarly, IL-27 has an inhibitory effect on lymphangiogenesis, and circulating levels of IL-27 are commonly observed in many inflammatory disorders.19 Given that altered lymphatic vessel density is also a common characteristic of inflammatory disorders, altered IL-27 signaling to the lymphatics may be one mechanism underlying the lymphatic dysfunction in inflammatory conditions such as psoriasis.19 Thus the altered responses of the peripheral lymphatics to stimulation in human disease appear to be related to disease progression and immune-dependent pathogenesis.

Lymphatic Regulation of the Immune Response The definition of the lymphatics as an active component depends not only on their ability to respond to diverse stimuli but also on their ability to actively modulate the function of other immune cells (Box 11-1). As a conduit system connecting the peripheral to the lymphoid organs, the primary immune role of the lymphatics is the regulation of cell migration and migratory cell activation/function. However, the lymphatics also appear to play a role in regulating local immune responses, separate from immune cell migration. Moreover, the lymphatics have an important role in draining lo-

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BOX 11-1  Immune Processes With Peripheral Lymphatic Involvement • Drainage of local immune mediators from the tissue site • Immune cell activation/maturation • Immune cell migration • Immune tolerance induction • Regulation of local immune responses • Removal of cytokines and chemokines from circulation • Self- (tolerance) and foreign (immunity) antigen transport • Tissue fibrosis • Transplant rejection

cal immune molecules from the tissue site to maintain homeostasis of the local immune site and prevent damage from the accumulation of these immune mediators.20 The lymphatics are also involved in the direct removal of cytokines and chemokines from circulation by the expression of scavenger receptors such as D6 and the transport of antigens to lymphoid organs for immune tolerance (to peripheral self-antigens) or immune activation (to soluble foreign antigens).20 These additional roles for the lymphatics are critically linked to lymphangiogenesis and its regulation by the secondary immune mediators present in most immune responses as discussed previously.

Regulation of Cellular Migration and Activation The migration of dendritic cells from an infected tissue site to the draining lymph node is the essential first step in the initiation of peripheral adaptive immune responses. Despite the perception of the lymphatics as an inert conduit for cell migration, the lymphatics actively regulate dendritic cell migration and activation and thus can be considered an essential component of the adaptive immune system. Dendritic cell migration in the steady state and during inflammation involves different mechanisms that have largely been attributed to activation-induced expression of different chemokine receptors and integrins on dendritic cells.21 However, there is a concurrent, stimulus-specific upregulation of the chemokine and integrin partners on the peripheral lymphatics during inflammation.4,8,12,13 In addition, activation induces functional and spatial reorganization of peripheral lymphatic vessels (for example, the formation of ICAM-1–enriched microvilli structures) to actively promote cell migration.22 Thus lymphatic activation and functional reorganization are critical steps in the active regulation of dendritic cell immunity (Fig. 11-2). In addition to regulating migration into the lymph nodes, the lymphatics also contribute to migratory dendritic cell maturation/function (see Fig. 11-2). Signaling through chemokine receptors (for example, CCL21 through CCR7) and integrins (for example, ICAM-1 through lymphocyte function-associated antigen 1 [LFA-1]) induces both migration and maturation in dendritic cells and other immune cell subsets.23,24 Mice deficient for the agonists CCR7 through CCL21 show abnormal dendritic cell maturation, including altered proliferation, endocytosis, differentiation, and survival, which is separate from the defects in dendritic cell migration.23 In another example, steady-state dendritic cells receiving signals through lymphatic-expressed ICAM-1 show reduced CD86 expression, altered maturation, and a consequent reduction in their ability to activate T

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Lymphatic endothelial cell Dendritic cell Immune cell

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Immune molecules Pathogenic signals Adhesion molecules Cytokines/chemokines/interleukins

FIG. 11-2  An integrated model of immune cell activation. Concurrent activation of all local immune cell populations by pathogenic stimuli and pathogen-induced immune mediators allows coordinated immune cell activation and a fully functional immune response. Thus the peripheral lymphatics are one component of a tightly integrated immune system in which multiple immune populations coordinate their functional responses to pathogens and other immune insults, such as cancer and trauma.

cells.24,25 These results suggest that the interaction between the lymphatic endothelial cells and dendritic cells is critical for dendritic cell maturation and function, including downstream regulation of T-cell tolerance. Given that T cells also traffic through the lymphatics at various stages of the immune response, it is logical to suggest that the lymphatics play a similar active role in dendritic cell migration. Indeed, various T-cell subsets also express CCR7, and thus their maturation is also influenced by lymphatic expression of CCL21.26 Similarly, lymphatic-expressed molecules such as CCL21 can also induce local macrophage recruitment and maturation (without migration through the lymphatics).9 Finally, the lymphatic regulation of local immune function and immune cell maturation is not restricted to secondary cell activation in response to molecules primarily involved in migration. The lymphatics can also express a wide range of polyfunctional proinflammatory and antiinflammatory molecules, including IL-6/IL-8, which regulate neutrophil, macrophage, and dendritic cell function,8 and IL-7, which is involved in T-cell homeostasis.27 Although our understanding of the lymphatic-dependent regulation of immune function remains limited, these observations support a multifunctional, active role for the lymphatics in regulating the immune response both in cell migration and local immune function (see Fig. 11-2).

Clinical Significance of Lymphatic Regulation of Immune Responses Given the lack of definitive information about the active roles of the lymphatics in regulating immune responses, it remains difficult to determine the clinical significance of lymphatic dysfunction in disease. However, given the increasingly appreciable role for the lymphatics in normal dendritic

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cell, macrophage, and T-cell biology, it is extremely likely that the immune dysfunction observed in diseases showing altered lymphatic function is at least partially attributable to lymphatic intrinsic deficits in immune modulation. This also implies that lymphatic-targeted therapeutic approaches are a potential tool to address immune dysfunction in clinical practice. Several possible therapies have been proposed based on the ability of the lymphatic system to regulate immune function. One such approach is to alter T-cell responses by indirectly targeting dendritic cell maturation/migration through lymphatic promotion or inhibition.12,21 This approach might be useful in dendritic cell–delivered vaccinations in which enhanced migration/maturation is desired or in transplantation in which inhibiting migration might prevent graft rejection.12,21 Targeting the lymphatics in inflammatory disorders is another promising therapy for modulating other aspects of the immune regulatory functions of the lymphatics. Although these and other intervention strategies have, for the most part, not been introduced into clinical practice, they remain an area of increasing promise. As our understanding of lymphatic-based regulation of the immune response increases, the number of therapeutic targets and therapeutic options should also increase.

Linking Lymphatic Damage to the Immune Pathogenesis of Lymphedema Lymphedema is generally initiated by local lymphatic damage after radiation or surgery but results in several global immune deficits, including defects in immune surveillance (susceptibility to infection and malignancy) and local immune homeostasis (abnormal fibrosis, inflammation, and wound healing).1,2 Although these immune deficits are commonly observed in patients with lymphedema, the mechanisms of disease progression after an initial lymphatic insult are poorly understood. However, the active immune roles of the peripheral lymphatics may provide an insight into the pathogenesis of lymphedema. The primary result of lymphatic vessel damage after interventions such as surgery or radiation therapy is a gross reduction in drainage function.1,2 Given the responsiveness of the peripheral lymphatics to local immune mediators, local accumulation of fluid and immune mediators is likely to contribute to the gross transcriptional differences observed in lymphatic endothelial cells isolated from patients with lymphedema.17 Because the peripheral lymphatics appear to be critically involved in the regulation of local immune cell migration, maturation, and function, the altered lymphatic phenotype may contribute to the observed defects in immune surveillance (resulting from the dysfunctional lymphatic regulation of dendritic cell function and/or reduced antigen transport to the lymph nodes) and immune homeostasis (resulting from the altered immune mediator production by the lymphatics and/or deficient drainage of molecules from the local site). However, given the tightly integrated nature of the immune system (see Fig. 11-2), direct alterations in the function of other immune populations (resulting from abnormal immune mediator accumulation) also play an essential role in disease progression. Collectively, the reduction in the “passive” drainage function appears to be the initiating factor in the pathogenesis of lymphedema through local dysregulation of immune homeostasis. However, the subsequent alterations in the “active” immune regulatory functions of the lymphatics may also be critical for the progression of lymphedema.

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Conclusion The lymphatics are an active and integrated component of the immune response. Their active role in the immune response is initiated by the recognition of pathogenic and immunogenic stimuli by the peripheral lymphatics. These stimuli induce stimulus-specific activation programs in the lymphatics that allow the coordination of the immune functions of multiple additional immune populations. Alterations in these processes in lymphedema resulting from abnormal lymphatic vessel activation may be one contributing factor to the gross immune deficiencies that are characteristic of lymphedema. In general, the identification of the lymphatics as a critical immune organ has major consequences for our interpretation of immunity in health and disease in the following ways: • Although lymphatic dysfunction has been widely identified in a range of human immune conditions, the mechanisms, sequelae, and relative importance of this dysfunction remain poorly understood. • The peripheral lymphatics function as a core, integrated component of the peripheral immune system, and an improved understanding of their role is crucial for a complete appreciation of the immune processes involved in human disease. This necessitates a greater focus on lymphatic function in immunologic studies to clarify these roles, especially because the lymphatics are perhaps the least well-studied component of the immune system. • Lymphatics make up one component of a tightly coordinated immune system involving multiple immune cell populations. • The inherent implication of this observation is that multiple players are involved in any given aspect of an immune response, and scientific studies, where possible, must be designed and interpreted with this in mind. For example, a study of peripheral dendritic cell activation of T cells in inflammation is likely not complete without also considering the influence of lymphatic modulation on the dendritic cell’s function. • Overall, an increased understanding of the roles of the peripheral lymphatics is required to fully appreciate human disease and open up the possibilities for lymphatic-targeted interventions.

C linical P earls • A dysfunctional lymphatic system after surgery or radiation can lead to the development of lymphedema. • Later stages of lymphedema are characterized by an increased susceptibility to infection/malignancy and altered patterns of fibrosis, wound healing, and inflammation. • Dysfunctional lymphatic vessels have also been identified in a wide range of conditions, ranging from psoriasis to cancer, and may play a role in the altered immune homeostasis in these conditions. • A comprehensive clinical understanding of any human immune pathology may require consideration of the role of the lymphatic system. • As such, the lymphatic system may serve as a novel therapeutic target in human immune modulatory medicine.

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R EFERENCES 1. Rockson SG. The lymphatics and the inflammatory response: lessons learned from human lymphedema. Lymphat Res Biol 11:117-120, 2013. 2. Ruocco V, Schwartz RA, Ruocco E. Lymphedema: an immunologically vulnerable site for development of neoplasms. J Am Acad Dermatol 47:124-127, 2002. 3. Mori M, Andersson CK, Graham GJ, et al. Increased number and altered phenotype of lymphatic vessels in peripheral lung compartments of patients with COPD. Respir Res 14:65, 2013. 4. Aebischer D, Iolyeva M, Halin C. The inflammatory response of lymphatic endothelium. Angiogenesis 17:383-393, 2014. 5. Pegu A, Qin S, Fallert Junecko BA, et al. Human lymphatic endothelial cells express multiple functional TLRs. J Immunol 180:3399-3405, 2008. 6. Sawa Y, Tsuruga E. The expression of E-selectin and chemokines in the cultured human lymphatic endothelium with lipopolysaccharides. J Anat 212:654-663, 2008. 7. Sawa Y, Tsuruga E, Iwasawa K, et al. Leukocyte adhesion molecule and chemokine production through lipoteichoic acid recognition by toll-like receptor 2 in cultured human lymphatic endothelium. Cell Tissue Res 333:237-252, 2008. 8. Sawa Y, Ueki T, Hata M, et al. LPS-induced IL-6, IL-8, VCAM-1, and ICAM-1 expression in human lymphatic endothelium. J Histochem Cytochem 56:97-109, 2008. 9. Kang S, Lee SP, Kim KE, et al. Toll-like receptor 4 in lymphatic endothelial cells contributes to LPSinduced lymphangiogenesis by chemotactic recruitment of macrophages. Blood 113:2605-2613, 2009. 10. Zampell JC, Elhadad S, Avraham T, et al. Toll-like receptor deficiency worsens inflammation and lymphedema after lymphatic injury. Am J Physiol Cell Physiol 302:C709-C719, 2012. 11. Vigl B, Aebischer D, Nitschke M, et al. Tissue inflammation modulates gene expression of lymphatic endothelial cells and dendritic cell migration in a stimulus-dependent manner. Blood 118:205-215, 2011. 12. Dieterich LC, Seidel CD, Detmar M. Lymphatic vessels: new targets for the treatment of inflammatory diseases. Angiogenesis 17:359-371, 2014. 13. Chaitanya GV, Franks SE, Cromer W, et al. Differential cytokine responses in human and mouse lymphatic endothelial cells to cytokines in vitro. Lymphat Res Biol 8:155-164, 2010. 14. Huggenberger R, Siddiqui SS, Brander D, et al. An important role of lymphatic vessel activation in limiting acute inflammation. Blood 117:4667-4678, 2011. 15. Kataru RP, Jung K, Jang C, et al. Critical role of CD11b1 macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood 113:5650-5659, 2009. 16. Bennuru S, Nutman TB. Lymphangiogenesis and lymphatic remodeling induced by filarial parasites: implications for pathogenesis. PLoS Pathog 5:e1000688, 2009. 17. Ogunbiyi S, Chinien G, Field D, et al; London Lymphedema Consortium. Molecular characterization of dermal lymphatic endothelial cells from primary lymphedema skin. Lymphat Res Biol 9:19-30, 2011. 18. Clavin NW, Avraham T, Fernandez J, et al. TGF-beta 1 is a negative regulator of lymphatic regeneration during wound repair. Am J Physiol Heart Circ Physiol 295:H2113-H2127, 2008. 19. Nielsen SR, Hammer T, Gibson J, et al. IL-27 inhibits lymphatic endothelial cell proliferation by STAT1regulated gene expression. Microcirculation 20:555-564, 2013. 20. Santambrogio L, Stern LJ. Carrying yourself: self antigen composition of the lymphatic fluid. Lymphat Res Biol 11:149-154, 2013. 21. Teijeira A, Russo E, Halin C. Taking the lymphatic route: dendritic cell migration to draining lymph nodes. Semin Immunopathol 36:261-274, 2014. 22. Teijeira A, Garasa S, Peláez R, et al. Lymphatic endothelium forms integrin-engaging 3D structures during DC transit across inflamed lymphatic vessels. J Invest Dermatol 133:2276-2285, 2013.

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23. Marsland BJ, Bättig P, Bauer M, et al. CCL19 and CCL21 induce a potent proinflammatory differentiation program in licensed dendritic cells. Immunity 22:493-505, 2005. 24. Podgrabinska S, Kamalu O, Mayer L, et al. Inflamed lymphatic endothelium suppresses dendritic cell maturation and function via Mac-1/ICAM-1-dependent mechanism. J Immunol 183:1767-1779, 2009. 25. Wilson NS, Young LJ, Kupresanin F, et al. Normal proportion and expression of maturation markers in migratory dendritic cells in the absence of germs or Toll-like receptor signaling. Immunol Cell Biol 86:200-205, 2008. 26. Masopust D, Schenkel JM. The integration of T cell migration, differentiation and function. Nat Rev Immunol 13:309-320, 2013. 27. Miller CN, Hartigan-O’Connor DJ, Lee MS, et al. IL-7 production in murine lymphatic endothelial cells and induction in the setting of peripheral lymphopenia. Int Immunol 25:471-483, 2013.

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Part III

Pathophysiology and Clinical Presentation

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C hapter 12 Pathophysiology of Primary Lymphedema Byung-Boong Lee, James Laredo

K ey P oints • Primary lymphedema usually manifests as a truncular lymphatic malformation, the origin of which is a structural birth defect. • Although most primary lymphedemas are independent truncular lymphatic malformations, they can coexist with extratruncular lesions. • Occasionally, primary lymphedema and truncular lymphatic malformations develop along with congenital vascular malformations to form a hemolymphatic malformation.

Pat

• The defective development of the lymphatic system can occur at any stage of lymphangiogenesis, even as early as the eighth week of gestation. • In primary lymphedema the cause of reduced lymph transport is either an intrinsic defect or malfunction of the lymph conducting elements that result from a genetic abnormality in lymphatic function or anatomy.

Primary lymphedema mostly presents as the clinical manifestation of a truncular lymphatic malformation, with defective structural development of the lymphatic system observed as a birth defect.1-4 Most primary lymphedemas exist alone as an independent truncular lymphatic malformation lesion. However, because of the pathogenesis of congenital vascular malformations (CVMs), some of the primary lymphedemas and truncular lymphatic malformations exist with another form of lymphatic malformation, the extratruncular lesions, also known as cystic, cavernous, or capillary lymphangiomas.5-8 In addition, lymphatic malformations exist with other types of CVMs as part of complex birth defects affecting the entire circulation, including the arteries, veins, lymphatics, and capillary system.9-12 Therefore primary lymphedemas and truncular lymphatic malformations infrequently develop together with other CVMs to form a hemolymphatic malformation,13-16 consisting of a venous malformation,17-20 an arteriovenous malformation,21-24 and/or a capillary malformation.25,26 177

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For example, the lymphatic malformation coexists with venous and lymphatic malformations as the vascular malformation component of Klippel-Trenaunay syndrome.27,28 When they are further combined with an arteriovenous malformation, it is Parkes Weber syndrome. 29,30 The defective development of the lymphatic system can occur throughout any stage of lymphangiogenesis, resulting in various malformations of the lymphatic system, all of which have a basic outcome—lymphatic dysfunction.31-34 As early as the eighth week of gestation, the developing lymphatic sacs, which consist of two jugular and two iliac sacs, one of which is positioned at the base of the root of the mesentery and the other dorsal to the abdominal aorta/cisterna chyli, can show defective maturation. This results in sequestration of primitive lymphatic tissue; it remains as isolated clusters of amorphous lymphatic tissues (for example, lymphangioma).35,36 When these primitive lymphatic tissues do not develop normally and communicate with the remainder of the lymphatic networks and are consequently sequestered in various regions, they continue to dilate and become macrocystic and microcystic lesions, such as a cystic hygroma.37-40 This malformed lymphatic tissue has the unique characteristic of the mesenchymal cell when stimulated and appears as a residual embryonic tissue remnant originating from its early stage of lymphangiogenesis. These premature lymphatic tissues are classified as extratruncular lesions of the lymphatic malformation and are the outcome of defective development after the developmental arrest in the early stage of lymphangiogenesis.41-44 Extratruncular lymphatic malformation lesions, often called lymphangioma, continue to grow after birth through the unique characteristics of mesenchymal cells and lymphangioblasts (by way of comparison, truncular lymphatic malformation) whenever conditions are suitable. Some examples include menarche, pregnancy, female hormones, trauma, and surgery. After the ninth week of gestation, when disturbances in the lymph nodes and vessel formation processes associated with the main lymphatic trunk formation occur, various and often more significant structural variants of the lymph transporting system take place, including those of the thoracic duct.45,46 Such defective development during the later stage of lymphangiogenesis before the completion of fully mature normal lymphatic trunk formation is also grouped separately as truncular lymphatic malformations. These truncular lesions no longer have the ability to grow like extratruncular lesions (as previously described), but they can have a much more serious impact overall with respect to lymph transport function because of their direct structural impact on the lymph vessels.47,48 Therefore primary lymphedema mainly presents as a clinical manifestation of these defective formations of the lymphatic trunk, vessels, and nodes from the late stage of lymphangiogenesis. We see a range of defects, including lymphatic trunk hypoplasia, aplasia, numeric hyperplasia, or dilation (lymphangiectasia) with valvular incompetence. Regarding the lymph nodes, we often see selective lymph node dysplasia alone, which is also indicative of primary lymphedema, and is best known as lymphnododysplasia, although it is generally involved with lymphangiodysplasia as indicated previously.49,50

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To add complexity, not all primary lymphedemas are associated with such anatomic defects, or if present, they seemingly have little effect. Instead, some show only defective function, such as Milroy disease.51-54 Indeed, some primary lymphedemas have very little structural derangement and are limited to a functional defect that appears molecular in origin. For these reasons, some investigators believe that all lymphedemas caused by lymphatic malformations are genetically derived, and they define lymphedema as an abnormality of lymph drainage in which the predominant effect is on the tissue territory(ies) drained. Therefore a malformation may not necessarily have attributes that can be imaged, but may ultimately require detection or definition in molecular or other functional terms.3,4,55,56 Thus the cause of decreased lymphatic transport in primary lymphedema is either an intrinsic defect 5,8,57-60 or a malfunction of the lymph-conducting elements61-64 resulting from a genetically determined abnormality of lymphatic anatomy or function. When primary chronic lymphedema represents the clinical expression of heritable abnormal structural development, it clinically manifests as a macroscopic structural abnormality, which is defined as a truncular lymphatic malformation.8,65 Furthermore, primary lymphedema includes all the lymphedemas caused by the mutation of any of the genes involved in the development of the lymphatic system. Currently, representative genetic mutations identified in a familial distribution of primary lymphedema are FLT4,52,57,66 FoxC,54,57 and GJC2.67,68 The major clinical sign of all these forms of genetically determined lymphedema is lymphedema as the primary phenotype. For these families, an autosomal dominant pattern of inheritance has been reported. Various genes strongly associated with this pattern of inheritance have been demonstrated, with variable expression and variable age at onset.56,63,66 Milroy disease is one example of a familial lymphedema caused by an autosomal dominant, single gene disorder inherited as a germ line mutation at the locus 5q35.3. The gene mutated is FLT4, which encodes for the vascular endothelial growth factor receptor 3 (VEGFR-3).56,66,69 However, because of a somatic mutation, regionally limited genetic disorders will allow some tissue (for example, skin) to be unaffected, whereas the adjacent tissue (skin) carries the mutation (for example, mosaicism). Nevertheless, the hereditary type of primary lymphedema is quite rare, whereas the sporadic type represents the majority, although both have a genetic basis. What is important, however, is to acknowledge that all the malformations by definition are present at birth, although there is some concern regarding the current definition of primary lymphedema, because postnatal obliterations of lymph collectors and lymph nodes can mimic congenital and prenatal pathologies.

Overcoming the Problem Various cytokines70,71 are involved in the stimulation of lymphangiogenesis. For instance, vascular endothelial growth factor (VEGF)-C and -D are known to activate VEGFR-3 expressed on lymphatic endothelial cells.72 VEGF-C–deficient mice fail to develop a functional lymphatic system,73 attesting to its importance.

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Angiopoietin 1 also promotes lymphatic vessel formation through Tie2.74 Also, gene transfer of VEGF-C through its promotion of lymphangiogenesis reduces lymphedema, at least in an animal model.75 For these reasons, patients with lymphatic malformations with such risks for several congenital lymphatic disorders, including Down syndrome, Turner syndrome, and Noonan syndrome in particular, should receive genetic counseling for cytogenetic analysis for chromosomal aneuploidy before they consider becoming parents, because aneuploidic conditions can recur in subsequent pregnancies.76-79 As the previously mentioned case demonstrates, an accurate definition of the normal anatomophysiology of the lymphatic system is essential for a proper understanding of the pathophysiology of primary lymphedema and perhaps for better management of the condition.

Normal Role of the Lymphatics and Impact of Defects on the Cells, Tissue, and Body The circulatory function is the principal role of the lymphatic system, which maintains the drainage and transport of interstitial fluid to the main blood circulation. However, in addition to such an essential role for interstitial fluid homeostasis, the lymphatic system has multiple roles. It plays a crucial role for the immune systems, providing the immune traffic route to transport white blood cells and antigen-presenting cells to the lymphoid organs.80 It also has another unique function for the lipid absorption from the gastrointestinal tract. Absorption of fat from the intestine occurs through the lymphatic system, and subsequent transportation of the chyle to the liver depends on this system.81-83 Such crucial functions are directly affected by a defective development no matter what the reason. Many if not most of the structural malformations previously described lead to functional issues. The lymphatics are found throughout the body except in the central nervous system, and lymphatic vasculature and lymphoid tissue are more prevalent in tissues that are in close contact with the external environment (for example, the gastrointestinal tract and lungs).84 Such distribution seems to reflect the unique role of the lymphatics against infectious agents and foreign materials. Thus the location of the malformations may have an impact on any or all tissues. In the extremities the lymphatic system consists of superficial and deeper systems. A superficial system collects lymph from the epifascial tissue, such as skin and subcutaneous tissue, whereas a deeper system drains subfascial tissue, such as muscle, bone, and other deep structures like blood vessels. The two systems are mutually interdependent to provide the compensatory function, especially when one system fails because of a structural malformation or functional failure associated with it to maintain normal function and drainage. For example, the deep lymphatic system participates in lymph transport from the skin during lymphatic obstruction.85 The failure of adequate lymph transport promotes lymphedema and likely contributes to the pathologic presentation of a wide variety of lymphatic vascular diseases. In a normal state, the

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extravasation of fluids and proteins from blood vessels is adequately handled by lymphatic drainage and return into the bloodstream. However, if microvascular filtration in blood capillaries and venules exceeds the capacity of lymphatic drainage for long periods, an edema develops because of the accumulation of interstitial fluid in the interstitium (for example, advanced chronic venous disease).3 Lymph flow is established by the autonomous rhythmic contractions of the lymphangions, which propel the lymph.86-88 When interstitial fluid enters the initial lymphatics to flow into the lymphangions, the lymphatic wall is stretched by inflowing interstitial fluid. It stimulates the lymphatic wall muscles to evoke the contractions to generate the flow in a peristaltic fashion. The frequency of rhythmic contraction of the lymphatics depends on the volume of the interstitial fluid entering.88,89 Fluid transport into the initial lymphatics occurs against a pressure gradient. Such a phenomenon is explained based on the condition when episodic increases in interstitial fluid pressure by tissue movement combine with suction forces generated through the contraction of the collecting lymphatics.90 Under normal conditions, muscular activity, respiratory movements, passive movements, and arterial pulsation have little if no effect on lymph flow when the lymphangion-based peristaltic movement is sufficient for lymph transport and flow.87-89 Therefore the lymphatics of the limb are generally empty, with only a few microliters of lymph in some lymphangions. There is no hydrostatic pressure in the lymphatics of a normal leg in the upright position.88,89 The normal lymph transport mechanism is based on the autoregulated peristaltic flow led by the lymphangions; however, in lymphedema this mechanism fails. In addition, the unique lymphodynamics that would be applicable to normal conditions are no longer valid, and new fluid dynamics to compensate for the lymphedematous condition become identical to the venodynamics. Thus muscular contraction of the foot and calf may increase lymph pressure, and patent lymphatics are filled with lymph. Compression of the muscles could create a pressure gradient between the distal and proximal lymphatics.88,89 In normal limbs, the lymph flow occurs only during spontaneous contractions of lymphangions.89 However, in lymphedematous limbs, most of the lymph collectors are partially or totally obliterated as a consequence of the destruction of lymph vessel musculature and valves, and only some spontaneous flow may remain in patent vessel segments at different levels of the limb.91-93

Lymphostasis Various types of congenital abnormalities of lymphatic vessels and lymph nodes often lead to lymphatic hypertension, valvular insufficiency, and lymphostasis. An accumulation of interstitial and lymphatic fluid within the skin and subcutaneous tissue stimulates fibroblasts, keratinocytes, and adipocytes. Such a condition eventuates in the deposition of collagen and glycosaminoglycans within the skin and subcutaneous tissue to result in the destruction of elastic fibers and skin hypertrophy.94 The tissues deprived of proper lymph drainage become the site of a continuous inflammatory process.

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Lymphedema fluids accumulating in the skin and subcutaneous tissues contain cytokines, chemokines, activated immune cells, and most important, microorganisms. Lymph cytokines are lowmolecular-weight proteins, and thus they easily penetrate the capillary wall. However, they are also produced locally by keratinocytes, fibroblasts, dermal macrophages, dendritic cells, and lymphocytes in the skin and subcutaneous tissue. The local production increases the lymph cytokine levels to those above plasma (for example, lymphatic endothelial cell–produced VEGF- C).95,96 Under normal conditions, circulating immune cells are able to eliminate the microorganisms penetrating the epidermis, but in lymph stasis, for instance, they are unable to remove the microorganisms. Thus the microorganisms still proliferate to cause histologic changes, such as infiltrates and the formation of fibrous tissue, known as the clinical condition of dermatolymphangioadenitis.96 In lymphedema, the pathologic changes in the lymphatics resulting from infection can include a plethora of damage to the endothelial and muscular cells, which may subsequently lead to an obliteration of the lumen by the fibroblasts—the price the lymphatic system pays for its own function. The pathologic events in the skin and the reaction of the regional lymphatic system to them are the outcomes of the destructive effect of the inflammatory process to the healing of parenchymatous tissues caused by the system devoted to the elimination of microbes and clearance of damaged cells.97-99 There are all the other factors and influences, which in some ways may, despite the well-intentioned process, continue to worsen or compromise its function. The breathing space or reserve capacity of the lymphatics that have a primary deficiency or defect or dysfunction is less, and thus a patient with these circumstances who has an underlying primary lymphatic issue must be even more careful of these other issues, which may further compromise the lymphatic system and the range of critical roles it performs.

Conclusion The typical clinical presentation of primary lymphedema is a truncular lymphatic malformation with defective structural development of the lymphatic system that occurs during the later stage of lymphangiogenesis before fully mature normal lymphatic trunk formation is complete. Thus primary lymphedema usually results from a defect in the formation of the lymphatic trunk, vessels, and nodes and occurs in a wide range of defects, including lymphatic trunk hypoplasia, aplasia, numeric hyperplasia, or dilation (lymphangiectasia) with valvular incompetence. However, not all primary lymphedemas are associated with these anatomic defects. Some have only defective or limited function with very little structural derangement, such as Milroy disease. Therefore the cause of decreased lymphatic transport in primary lymphedema is either an intrinsic defect or a malfunction of the lymph-conducting elements resulting from a genetically determined abnormality of lymphatic anatomy or function. Most primary lymphedema and truncular lymphatic malformations exist alone as an independent lesion, but occasionally they are found with another form of lymphatic malformation—extratruncular lesions—also known as cystic, cavernous, or capillary lymphangiomas.

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Extratruncular lesions are residual embryonic tissue remnants that are the outcome of defective development from its early stage of lymphangiogenesis. Thus they have the unique characteristic of the mesenchymal cell; they grow steadily through the rest of life by various stimulations (by way of comparison, truncular lesions). In addition, lymphatic malformations exist with other types of CVMs as a part of complex birth defects that affect the entire circulation involving the arteries, veins, lymphatics, and capillary system.

C linical P earls • Most primary lymphedemas are truncular malformations. However, they can coexist with extratruncular lesions, also called cystic, cavernous, or capillary lymphangiomas. • Most primary lymphedemas are a defect of the lymphatic trunk, vessels, and nodes that occurs during late stage lymphangiogenesis. However, some primary lymphedemas have a molecular or genetic origin. • Patients at risk of severe congenital lymphatic disorders, such as Down syndrome, should undergo genetic counseling if they are considering becoming parents. • An inadequate lymph transport mechanism promotes lymphedema, contributes to various lymphatic vascular disorders, and causes edema. • Improper lymph drainage results in a continuous inflammatory process of tissue, including infection.

R EFERENCES 1. Lee BB, Villavicencio JL. Primary lymphedema and lymphatic malformation: are they the two sides of the same coin? Eur J Vasc Endovasc Surg 39:646-653, 2010. 2. Lee BB, Andrade M, Bergan J, et al; International Union of Phlebology. Diagnosis and treatment of primary lymphedema. Consensus Document of the International Union of Phlebology (IUP)-2009. Int Angiol 29:454-470, 2010. 3. Lee BB, Andrade M, Antignani PL, et al; International Union of Phlebology. Diagnosis and treatment of primary lymphedema. Consensus Document of the International Union of Phlebology (IUP)-2013. Int Angiol 32:541-574, 2013. 4. Lee BB, Antignani PL, Baroncelli TA, et al. IUA-ISVI consensus for diagnosis guideline of chronic lymphedema of the limbs. Int Angiol. 2014 Mar 19. [Epub ahead of print] 5. Lee BB. Lymphedema-angiodysplasia syndrome: a prodigal form of lymphatic malformation (LM). Phlebolymphology 47:324-332, 2005. 6. Lee BB, Laredo J, Lee TS, et al. Terminology and classification of congenital vascular malformations. Phlebology 22:249-252, 2007. 7. Lee BB, Laredo J, Lee SJ, et al. Congenital vascular malformations: general diagnostic principles. Phlebology 22:253-257, 2007. 8. Lee BB, Kim YW, Seo JM, et al. Current concepts in lymphatic malformation (LM). Vasc Endovasc Surg 39:67-81, 2005.

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9. Lee BB. Congenital venous malformation: changing concept on the current diagnosis and management. Asian J Surg 22:152-154, 1999. 10. Lee BB, Bergan JJ. Advanced management of congenital vascular malformations: a multidisciplinary approach. J Cardiovasc Surg 10:523-533, 2002. 11. Lee BB. Critical issues on the management of congenital vascular malformation. Ann Vasc Surg 18:380392, 2004. 12. Lee BB, Mattassi R, Loose D, et al. Consensus on controversial issues in contemporary diagnosis and management of congenital vascular malformation—Seoul communication. Int J Angiol 13:182-192, 2004. 13. Lee BB, Laredo J. Classification: venous-lymphatic vascular malformation. In Allegra C, Antignani PL, Kalodiki, eds. News in Phlebology. Turin, Italy: Edizioni Minerva Medica, 2013. 14. Lee BB, Bergan J, Gloviczki P, et al; International Union of Phlebology. Diagnosis and treatment of venous malformations. Consensus Document of the International Union of Phlebology (IUP)-2009. Int Angiol 28:434-451, 2009. 15. Lee BB, Baumgartner I, Berlien P, et al. Diagnosis and Treatment of Venous Malformations Consensus Document of the International Union of Phlebology (IUP): updated 2013. Int Angiol. 2014 Feb 25. [Epub ahead of print] 16. Lee BB, Antignani PL, Baraldini V, et al. ISVI-IUA consensus document. Diagnostic guidelines on vascular anomalies: vascular malformations and hemangiomas. Int Angiol. 2014 Oct 6. [Epub ahead of print] 17. Lee BB. Venous malformation and haemangioma: differential diagnosis, diagnosis, natural history and consequences. Phlebology 28 Suppl 1:176-187, 2013. 18. Lee BB, Laredo J. Venous malformation: treatment needs a bird’s eye view. Phlebology 28:62-63, 2013. 19. Lee BB, Baumgartner I. Contemporary diagnosis of venous malformation. J Vasc Diagn 1:25-34, 2013. 20. Lee BB. Current concept of venous malformation (VM). Phlebolymphology 43:197-203, 2003. 21. Lee BB, Lardeo J, Neville R. Arterio-venous malformation: how much do we know? Phlebology 24:193200, 2009. 22. Lee BB, Baumgartner I, Berlien HP, et al; International Union of Angiology. Consensus Document of the International Union of Angiology (IUA)-2013. Current concept on the management of arteriovenous management. Int Angiol 32:9-36, 2013. 23. Lee BB, Mattassi R, Kim BT, et al. Contemporary diagnosis and management of venous and AV shunting malformation by whole body blood pool scintigraphy (WBBPS). Int Angiol 23:355-367, 2004. 24. Lee BB, Mattassi R, Kim BT, et al. Advanced management of arteriovenous shunting malformation (AVM) with transarterial lung perfusion scintigraphy (TLPS) for follow-up assessment. Int Angiol 24:173-184, 2005. 25. Berwald C, Salazard B, Bardot J, et al. [Port wine stains or capillary malformations: surgical treatment] Ann Chir Plast Esthet 51:369-372, 2006. 26. Goldman MP, Fitzpatrick RE, Ruiz-Esparza J. Treatment of port-wine stains (capillary malformation) with the flashlamp-pumped pulsed dye laser. J Pediatr 122:71-77, 1993. 27. Lee BB. Klippel-Trenaunay syndrome: is this term still worthy to use? Acta Phlebologica 13:83-85, 2012. 28. Lee BB, Laredo J, Neville R, et al. Primary lymphedema and Klippel-Trenaunay syndrome. In Lee BB, Bergan J, Rockson S, ed. Lymphedema: A Concise Compendium of Theory and Practice. London: Springer Verlag, 2011. 29. Ziyeh S, Spreer J, Rossler J, et al. Parkes Weber or Klippel-Trenaunay syndrome? Noninvasive diagnosis with MR projection angiography. Eur Radiol 14:2025-2029, 2004. 30. Courivaud D, Delerue A, Delerue C, et al. Familial case of Parkes Weber syndrome. Ann Dermatol Venereol 133(5 Pt 1):445-447, 2006. 31. Schweigere L, Fotsis T. Angiogenesis and angiogenesis inhibitors in paediatric diseases. Eur J Pediatr 151:472-476, 1992.

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32. Enciso JM, Hirschi KK. Understanding abnormalities in vascular specification and remodeling. Pediatrics 116:228-230, 2005. 33. Leu HJ. Pathoanatomy of congenital vascular malformations. In Belov S, Loose DA, Weber J, eds. Vascular Malformations. Reinbek, Germany: Einhorn-Presse Verlag, 1989. 34. Bastide G, Lefebvre D. Anatomy and organogenesis and vascular malformations. In Belov S, Loose DA, Weber J, eds. Vascular Malformations. Reinbek, Germany: Einhorn-Presse Verlag, 1989. 35. Alitalo K, Tammela T, Petrova TV. Lymphangiogenesis in development and human disease. Nature 438:946-953, 2005. 36. Maby-El Hajjami H, Petrova TV. Developmental and pathological lymphangiogenesis: from models to human disease. Histochem Cell Biol 130:1063-1078, 2008. 37. Karpanen T, Mäkinen T. Regulation of lymphangiogenesis—from cell fate determination to vessel remodeling. Exp Cell Res 312:575-583, 2006. 38. Rutkowski JM, Moya M, Johannes J, et al. Secondary lymphedema in the mouse tail: lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9. Microvasc Res 72:161-171, 2006. 39. Rutkowski JM, Boardman KC, Swartz MA. Characterization of lymphangiogenesis in a model of adult skin regeneration. Am J Physiol Heart Circ Physiol 291:H1402-H1410, 2006. 40. Goldman J, Le TX, Skobe M, et al. Overexpression of VEGF-C causes transient lymphatic hyperplasia but not increased lymphangiogenesis in regenerating skin. Circ Res 96:1193-1199, 2005. 41. Leu HJ. Pathomorphology of vascular malformations: analysis of 310 cases. Int Angiol 9:147-155, 1990. 42. Woolard HH. The development of the principal arterial stems in the forelimb of the pig. Contrib Embryol 14:139-154, 1922. 43. Belov ST. Classification of congenital vascular defects. Int Angiol 9:141-146, 1990. 44. Belov ST. Anatomopathological classification of congenital vascular defects. Semin Vasc Surg 6:219224, 1993. 45. Borisov AV, Petrenko VM. The development of the thoracic duct lymphangions in the prenatal period of human ontogeny. Ontogenez 23:254-259, 1992. 46. Krutsiak VN, Polianskiĭ IIu. [Development of the thoracic duct in the prenatal period of human ontogeny] Arkh Anat Gistol Embriol 85:79-84, 1983. 47. Gloviczki P, Duncan AA, Kalra M, et al. Vascular malformations: an update. Perspect Vasc Surg Endovasc Ther 21:133-148, 2009. 48. Lee BB, Laredo J. Classification of congenital vascular malformations: the last challenge for congenital vascular malformations. Phlebology 27:267-269, 2012. 49. Lee BB, Laredo J, Neville R. Primary lymphedema as a truncular lymphatic malformation. In Lee BB, Bergan J, Rockson SG, eds. Lymphedema: A Concise Compendium of Theory and Practice. London: Springer Verlag, 2011. 50. Papendieck CM. Lymphangiomatosis and dermoepidermal disturbances of lymphangio-adenodysplasias. Lymphology 35:478-485, 2002. 51. Witte MH, Erickson R, Bernas M, et al. Phenotypic and genotypic heterogeneity in familial Milroy lymphedema. Lymphology 31:145-155, 1998. 52. Brice G, Child AH, Evans A, et al. Milroy disease and the VEGFR-3 mutation phenotype. J Med Genet 42:98-102, 2005. 53. Erickson RP. Lymphedema-distichiasis and FOXC2 gene mutations. Lymphology 34:1-5, 2001. 54. Brice G, Mansour S, Bell R, et al. Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. J Med Genet 39:478-483, 2002. 55. Burnand KG, Mortimer PS. Lymphangiogenesis and genetics of lymphoedema. In Browse N, Burnand KG, Mortimer PS, eds. Diseases of the Lymphatics. London: Arnold, 2003. 56. Witte MH, Erickson R, Reiser FA, et al. Genetic alterations in lymphedema. Phlebolymphology 16:1925, 1997. 57. Michelini S, Degiorgio D, Cestari M, et al. Clinical and genetic study of 46 Italian patients with primary lymphedema. Lymphology 45:3-12, 2012.

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58. Bernas MJ, Witte CL, Witte MH. The diagnosis and treatment of peripheral lymphedema. Lymphology 34:84-91, 2001. 59. Kinmonth JB, Wolfe JH. Fibrosis in the lymph nodes in primary lymphoedema. Histological and clinical studies in 74 patients with lower-limb oedema. Ann R Coll Surg Engl 62:344-354, 1980. 60. Vercellio, Baraldini V, Coletti M, et al. Strategies in early management of pure lymphatic malformations. Lymphology 35:472-477, 2002. 61. Rosbotham JL, Brice GW, Child AH, et al. Distichiasis-lymphoedema: clinical features, venous function and lymphoscintigraphy. Br J Dermatol 142:148-152, 2000. 62. Northrup KA, Witte MH, Witte CL. Syndromic classification of hereditary lymphedema. Lymphology 36:162-189, 2003. 63. Greenlee R, Hoyme H, Witte M, et al. Developmental disorders of the lymphatic system. Lymphology 26:156-168, 1993. 64. Aagenaes O, van der Hagen CB, Refsum S. Hereditary recurrent intrahepatic cholestasis from birth. Arch Dis Child 43:646-657, 1968. 65. Lee BB, Laredo J, Seo JM, et al. Treatment of lymphatic malformations. In Mattassi R, Loose DA, Vaghi M, eds. Hemangiomas and Vascular Malformations. Milan: Springer-Verlag Italia, 2009. 66. Ferrell RE, Levinson KL, Esman JH, et al. Hereditary lymphedema: evidence for linkage and genetic heterogeneity. Hum Mol Genet 7:2073-2078, 1998. 67. Ferrell RE, Baty CJ, Kimak MA, et al. GJC2 missense mutations cause human lymphedema. Am J Hum Genet 86:943-948, 2010. 68. Ostergaard P, Simpson MA, Connell FC, et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet 43:929-931, 2011. 69. Evans AL, Bell R, Brice G, et al. Identification of eight novel VEGFR-3 mutations in families with primary congenital lymphoedema. J Med Genet 40:697-703, 2003. 70. Oh SJ, Jeltsch MM, Birkenhäger R, et al. VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Dev Biol 188:96-109, 1997. 71. Leak LV, Jones M. Lymphangiogenesis in vitro: formation of lymphatic capillary-like channels from confluent monolayers of lymphatic endothelial cells. In Vitro Cell Dev Biol Anim 30:512-518, 1994. 72. Jussila L, Alitalo K. Vascular growth factors and lymphangiogenesis. Physiol Rev 82:673-700, 2002. 73. Karkkainen MJ, Haiko P, Sainio K, et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 5:74-80, 2004. 74. Morisada T, Oike Y, Yamada Y, et al. Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. Blood 105:4649-4656, 2005. 75. Yoon YS, Murayama T, Gravereaux E, et al. VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema. J Clin Invest 111:717-725, 2003. 76. Bernier-Buzzanga J, Su WP. Noonan’s syndrome with extensive verrucae. Cutis 46:242-246, 1990. 77. Wyre HW Jr. Cutaneous manifestations of Noonan’s syndrome. Arch Dermatol 114:929-930, 1978. 78. Lanning P, Simila S, Suramo I, et al. Lymphatic abnormalities in Noonan’s syndrome. Pediatr Radiol 7:106-109, 1978. 79. Perry HD, Cossari AJ. Chronic lymphangiectasis in Turner’s syndrome. Br J Ophthalmol 70:396-399, 1986. 80. Oliver G. Lymphatic vasculature development. Nat Rev Immunol 4:35-45, 2004. 81. Rockson RG. Physiology, pathophysiology, and lymphodynamics. General overview. In Lee BB, Bergan J, Rockson SG, eds. Lymphedema: A Concise Compendium of Theory and Practice. London: SpringerVerlag, 2011. 82. Smoke A, Delegge MH. Chyle leaks: consensus on management? Nutr Clin Pract 23:529-532, 2008. 83. Bibby AC, Maskell NA. Nutritional management in chyle leaks and chylous effusions. Br J Community Nurs 19(Suppl 10):S6-S8, 2014.

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84. Szuba A, Shin WS, Strauss HW, et al. The third circulation: radionuclide lymphoscintigraphy in the evaluation of lymphedema. J Nucl Med 44:43-57, 2003. 85. Brautigam P, Földi E, Schaiper I, et al. Analysis of lymphatic drainage in various forms of leg edema using two compartment lymphoscintigraphy. Lymphology 31:43-55, 1998. 86. Armenio S, Cetta F, Tanzini G, et al. Spontaneous contractility in the human lymph vessels. Lymphology 14:173-178, 1981. 87. Sjöberg T, Norgren L, Steen S. Contractility of human leg lymphatics during exercise before and after indomethacin. Lymphology 22:186-193, 1989. 88. Olszewski WL. Lymph vessel contractility. In Olszewski WL, ed. Lymph Stasis: Pathophysiology, Diagnosis and Therapy. Boca Raton, FL: CRC Press, 1991. 89. Olszewski WL, Engeset A. Intrinsic contractility of prenodal lymph vessels and lymph flow in human leg. Am J Physiol 239:775-783, 1980. 90. Reddy NP, Patel K. A mathematical model of flow through the terminal lymphatics. Med Eng Phys 17:134-140, 1995. 91. Olszewski WL. Contractility patterns of normal and pathologically changed human lymphatics. Ann NY Acad Sci 979:52-63, 2002. 92. Olszewski WL. Contractility patterns of human leg lymphatics in various stages of obstructive lymphedema. Ann NY Acad Sci 1131:110-118, 2008. 93. Olszewski WL. Physiology–lymph flow. In Lee BB, Bergan J, Rockson SG, eds. Lymphedema: A Concise Compendium of Theory and Practice. London: Springer-Verlag, 2011. 94. Szuba A, Rockson SG. Lymphedema: anatomy, physiology and pathogenesis. Vasc Med 2:321-326, 1997. 95. Olszewski WL. Physiology, biology, and lymph biochemistry. In Lee BB, Bergan J, Rockson SG, eds. Lymphedema: A Concise Compendium of Theory and Practice. London: Springer-Verlag, 2011. 96. Olszewski WL. Pathology and histochemistry. In Lee BB, Bergan J, Rockson SG, eds. Lymphedema: A Concise Compendium of Theory and Practice. London: Springer-Verlag, 2011. 97. Olszewski WL, Grzelak I, Engeset A. Cells in lymph draining normal human skin. Lymphology 15:168173, 1982. 98. Olszewski WL. Cells in lymph. In Olszewski WL, ed. Lymph Stasis: Pathophysiology, Diagnosis and Treatment. Boca Raton, FL: CRC Press, 1991. 99. Olszewski WL, Grzelak I, Ziolkowska A, et al. Immune cell traffic from blood through the normal human skin to lymphatics. Clin Dermatol 13:473-483, 1995.

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C hapter 13 Pathophysiology of Secondary Lymphedema Etelka Földi

P

K ey P oints • The transport capacity of the lymphatic drainage system may be reduced as a result of surgery and/or radiotherapy for malignant tumors or after severe accidents, subsequently leading to lymphedema. • The pathophysiology and pathomorphology of secondary lymphedema include the degree of damage, stage of the disease, and presence of comorbidities.

Path

• Recognition of the stage of lymphedema is crucial to early treatment, whether surgical or conservative, to normalize the disturbed homeostasis.

Secondary lymphedema occurs after damage to the lymphatic drainage system and is most commonly associated with oncologic treatment (for example, after diagnostic or therapeutic lymphadenectomies or radiotherapy). Secondary lymphedema may also be a sign of malignant disease. Extensive soft tissue trauma and chronic inflammatory processes are the next most common causes of secondary lymphedema. The most commonly affected areas are the limbs; the least common are the head, trunk, and/or genitals. The lymphatic drainage system comprises the lymph capillaries (initial lymph vessels), precollectors, prenodal and postnodal collectors, and lymph trunks.1 The main tasks of the lymphatic drainage systems are as follows2,3: • Regulation of interstitial fluid volume • Maintenance of the normal metabolism of cells and extracellular matrix (ECM) • Removal of waste products • Ensure the circulation of lymphocytes • Migration of tissue macrophages, dendritic cells, and so forth • Elimination of cellular debris, including chemical components, such as inflammatory mediators, from injured tissue 189

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When the physiologic function of the lymphatic drainage system is damaged, the homeostasis of the interstitium becomes disturbed both in the cellular and extracellular compartments. The disturbances of the complex relationships between the cellular compartment (fibroblasts, lymphocytes, macrophages, mast cells, and vascular and neurogenic structures) and ECM (collagen, glycoprotein, protein-glycan, glycosaminoglycans such as hyaluronan, chondroitin sulfate B, heparan, keratan sulfate, and other humoral substances and enzymes) lead to the remodeling of skin and subcutaneous tissues. Another important aspect is the influence on the immune system as a consequence of the impaired circulation of the lymphocytes.4

Pathophysiology and Pathomorphology The pathophysiology and pathomorphology of the secondary damaged lymphatic drainage system depend on several factors: • Degree of damage • Stage of the disease • Presence of comorbidities

Degree of Damage Acute Lymphedema Acute lymphedema is a rare condition that occurs most often after radical surgery (predominantly for pelvic malignancy) or severe accidents with soft tissue damage. The degree of damage to the lymphatic system can be so extensive that only a decreased number of functional lymph vessels remain. Their ability to regenerate is exceeded, and transport capacity in the lymphatic drainage system is dramatically reduced, with the consequence that lymphedema occurs and remains manifest.

Stage of the Disease Clinical Staging of Secondary Lymphedema In clinical practice, the stages of lymphedema are defined by a physical examination of the extremities and staged according to the parameters outlined in Box 13-1.

BOX 13-1  Staging of Lymphedema Latency: There is reduced transport capacity, with no clinical signs of swelling. Stage 1: Pitting edema subsides with limb elevation. Stage 2: Elevation of the limb is barely effective; in addition to pitting edema, there is hardening of the tissue resulting from fibrosis. Stage 3: Lymphostatic elephantiasis, or large volume of the limbs, appears in either column or lobular form. Attendant symptoms are congestive dermatitis, trophic skin changes, and fat deposition.

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Pathophysiologic Staging of Lymphedema Latency If the damage is less severe, sufficient numbers of functional lymph vessels remain and cope with the lymphatic load despite the reduced transport capacity. This condition refers to a latent or subclinical stage of lymphedema, in which swelling is not present despite the impaired lymph transport capacity. This stage of latency is characterized by increased lymph transport in the remaining functional lymph vessels, resulting from the activation of intrinsic factors. Stretching of the lymph vessel walls leads to increased lymphangion pulsation.5 Over time, these compensatory mechanisms become insufficient. Tissue fluid begins to accumulate, with pathologic changes to the lymph vessels themselves and the connective tissue. The transport capacity of the lymphatic drainage system is further compromised and lymphedema occurs. The latency stage can last for several months to years. Stage 1  In stage 1, the examination of tissue samples under a light microscope reveals indirect signs of raised fluid content. Tissue samples are transparent and can only be lightly stained with hematoxylin-eosin and Giemsa. The electron microscope image of stage 1 lymphedema is characterized by dislocation and compartmentalization of collagen fibers. Immunohistologic changes in stage 1 are rarely mentioned in the literature, but it must be assumed that the ECM reacts in a multitude of ways to the increased tissue fluid load. It can also be assumed that glycosaminoglycans (hyaluronic acids) play an important role in the deposition of lymph fluid.1,6 Stages 2 and 3  Pathomorphologic and pathophysiologic alterations in stages 2 and 3 of lymphedema are shown in Table 13-1. Examination of tissues under a light microscope reveals a high density of tissue through raised fiber content and increased cellular density, which surrounds the nerves, blood and lymph vessels, smooth muscle fibers, and fascia. Elastic fibers in particular remain in fragmented or granular forms. Furthermore, the inflammatory tissue changes lead to an increased deposition of adipose tissue. In chronic lymphedema of the skin, the dermis becomes

TABLE 13-1  Pathomorphologic and Pathophysiological Alterations in Stages 2 and 3 of Lymphedema Lymphedema Stages 2 and 3

Alteration

Collagen types I and III

Increased and altered

Fatty tissue

Increased

Dermoepithelial basal membrane

Discontinued

Cellular compartment of interstitium

CD4-lymphocytes ↑ Macrophages (M2 prominent) ↑ Mast cells ↑ Plasma cells ↑ Fibroblasts ↑ Dendritic cells ↑

Proinflammatory cytokine expression

Increased (TNF alpha; IL-1 beta; IL-6; VEGT-C; TGF beta)

IL-1 beta, Interleukin-1 beta; IL-6, interleukin-6; TGF beta, tumor growth factor beta; TNF alpha, tumor necrosis factor alpha; ↑, increased.

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thicker, extending cones of tissue in a wartlike manner not only toward the surface of the skin, but also into the subcutaneous adipose tissue structures. Collagen and lipid deposition lead, among others, to alterations in the hydraulic conductivity of the tissue.7-9 It is unknown which factors in secondary lymphedema determine whether collagen fibrils will increase and thus predominantly lead to epifascial tissue fibrosis, including the deep fascia, with hardening of the skin and subcutis, or whether the deposition of fatty tissue will dominate, leading to a more voluminous lymphedema remaining soft on palpation. Based on my own animal experiments on chronic lymphedema in rabbits and laboratory rats, I found that 28 to 30 days after surgery, midgrade epifascial fibrosis with consecutive hardening of the skin and subcutis occurred in 50% of the animals, extreme fibrotic processes with severe hardening of the fascia occurred in 17%, and fatty deposition in the tissue was present in 33% of the animals. I had similar findings in human patients with secondary lymphedema based on clinical and ultrasound examinations, particularly with computed tomography.10 I suspect that gender plays a role (and subsequent hormonal influences). The nutritional status of the patient also influences the pathophysiology of lymphedema.

Presence of Comorbidities The role of comorbidities in secondary lymphedema has not been extensively researched. Each year we treat more than 1500 patients with secondary lymphedema at the Földi Clinic, most commonly after treatment for cancer, but only 19% of these patients have no other comorbidities. Blood capillaries, lymph capillaries, and the interstitium form a functional unit. Diseases that lead to increased permeability of the blood capillaries also influence the pathophysiology of lymphedema,11-13 and inflammatory processes can also exacerbate the disease. They play a role in the length of the so-called stage of latency, according to the International Society of Lymphology classification, and influence the severity of the damage to the lymphatic drainage system and the progression of lymphedema. Hormonal imbalances, such as polycystic ovarian syndrome,14 autoimmune processes15 (various forms of vasculitis), metabolic diseases16 (insulin resistance in type 2 diabetes), and neuropathies,17 are the most common according to our observations. There is a considerable shortage in research results in the literature compared with clinical data on possible changes to the pathomorphology and pathophysiology of secondary lymphedema with comorbidities. However, comorbidities play an important role in the treatment of lymphedema and the medical indications for conservative and/or surgical treatment of secondary lymphedema. It is generally known, for example, that in the combination form of secondary lymphedema with diabetes mellitus type 2 and polyneuropathy, not only is the transport capacity of the lymphatic drainage system reduced, but also the lymphatic load is elevated because of the increased permeability of blood capillaries.

Conclusion The transport capacity of the lymphatic drainage system may be reduced as a result of surgery and/or radiotherapy for malignant tumors or after severe accidents, and subsequently lymphedema may occur. The manifestation and progression of the swelling depend on the degree of damage and presence of accompanying diseases. Clinicians treating lymphedema must recognize

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that lymphedema is more than the simple accumulation of fluid in tissue. Lymphostasis leads to inflammatory processes and structural tissue remodeling. Treatment, either conservative or surgical, must be started as early as possible to normalize the disturbed homeostasis. The treatment of lymphedema is multifactorial. The recognition of the stage of lymphedema is important, and the patient must be optimized nutritionally and physically to achieve the optimal outcome.

C linical P earls • The understanding of the pathophysiology of secondary lymphedema is essential for the optimal management of the disease in clinical practice. • The quantitative relationship between the degree of damage to the lymphatic system and the amount of lymphatic load can already be estimated with a detailed medical history and clinical examination, allowing the clinician to adequately determine subsequent therapeutic measures. • The degree of required therapy also increases with comorbidities. • Secondary lymphedema is a chronic disease, and therefore teaching of guidelines for suitable lifestyle adaptations and self-treatment is highly important to patients, in addition to conservative and/or surgical treatment.

R EFERENCES 1. Földi M, Földi E. Földi’s Textbook of Lymphology, ed 3. Munich, Germany: Elsevier, 2012. 2. Olszewski WL. The pathophysiology of lymphedema—2012. Handchir Mikrochir Plast Chir 44:322328, 2012. 3. Olszewski WL, Jain P, Ambujam G, et al. Topography of accumulation of stagnant lymph and tissue fluid in soft tissues of human lymphedematous lower limbs. Lymphat Res Biol 7:239-245, 2009. 4. Alitalo K. The lymphatic vasculature in disease. Nat Med 17:1371-1380, 2011. 5. Zawieja DC. Contractile physiology of lymphatics. Lymphat Res Biol 7:87-96, 2009. 6. Roberts MA, Mendez U, Gilbert RJ, et al. Increased hyaluronan expression at distinct time points in acute lymphedema. Lymphat Res Biol 10:122-128, 2012. 7. Rutkowski JM, Markhus CE, Gyenge CC, et al. Dermal collagen and lipid deposition correlate with tissue swelling and hydraulic conductivity in murine primary lymphedema. Am J Pathol 176:1122-1129, 2010. 8. Ji RC. Lymphatic endothelial cells, lymphedematous lymphangiogenesis, and molecular control of edema formation. Lymphat Res Biol 6:123-137, 2008. 9. Kim SH, Turnbull J, Guimond S. Extracellular matrix and cell signaling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor. J Endocrinol 209:139-151, 2011. 10. Földi E. Das Lymphödem: die Brücke vom Experiment zur klinik. Dokumenta Angiologorum, vol XXXI. Phlebologie 4:5-10, 2006. 11. Chappell D, Jacob M, Becker BF, et al. [Expedition glycocalyx: a newly discovered “Great Barrier Reef ”] Anaesthesist 57:959-969, 2008. 12. Cloutier N, Paré A, Farndale RW, et al. Platelets can enhance vascular permeability. Blood 120:13341343, 2012.

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13. Eskens BJ, Zuurbier CJ, van Haare J, et al. Effects of two weeks of metformin treatment on whole-body glycocalyx barrier properties in db/db mice. Cardiovasc Diabetol 12:175, 2013. 14. Gluszak O, Stopińska-Gluszak U, Glinicki P, et al. Phenotype and metabolic disorders in polycystic ovary syndrome. ISRN Endocrinology 2012:569862, 2012. 15. Kukolnikova EL, Lapina NV. [Etiology and pathogenesis of secondary edema of the lower extremities in patients with limited pretibial myxedema on the background of hyperthyroidism] Khirurgiia (Mosk) 9:67-70, 2011. 16. Woodcock TE, Woodcock TM. Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy. Br J Anaesth 108:384394, 2012. 17. Vignes S, Lebrun-Vignes B. Sclerodermiform aspect of arm lymphoedema after treatment with docetaxel for breast cancer. J Eur Acad Dermatol Venereol 21:1131-1133, 2007.

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C hapter 14 Dermatologic Implications of Secondary Lymphedema of the Lower Leg Terence Ryan, S.R. Narahari, B. Vijaya, Madhur Guruprasad Aggithaya

K ey P oints • Peau d’orange skin texture, a common presentation of lymphedema, results from swelling of the upper dermis limited by tethering of adnexal structures to the skin. • Most dermatologic manifestations of lymphedema occur in the lower extremity.

P

• Venous insufficiency should be estimated in all patients with lymphedema. • Lymphatic filariasis is the most common cause of lower extremity lymphedema. It is transmitted by mosquito and is endemic in 78 developing nations. • Podoconiosis (or mossy foot), which results from damage to the tissues and lymph nodes of individuals who walk barefoot in irritant soil, is commonly observed in Ethiopia.

Der the

• Recurrent secondary infection from bacteria and fungi worsen lymphedema. • Excess collagen and dilated thick-walled lymphatics and loss of elastin are the key histologic changes associated with worsening lymphedema.

Most of the changes seen with lymphedema occur in the lower extremity rather than in the upper extremity. For that reason, this chapter concentrates on changes of the lower leg. Primary lymphedema is caused by congenital hypoplasia of the lymphatics, failures of connection between the initial and connecting lymphatics, or impaired connections with the blood vascular system. Lymph is intercellular fluid formed by blood capillaries plus macromolecules and cells generated in the skin but not taken up by the venous system. The classic theory is that 90% of this fluid is absorbed by the venules, but this is no longer considered the case. The new perspective on fluid exchange postulates that there is dwindling filtration along the arterial and venous blood capillaries. Thus the lymphatic system is the only effective means of removing capillary filtrate from most tissues.1 The brain is the most studied exception.

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If the balance between filtration and resorption is disturbed, fluid accumulates in the intercellular space and edema develops. When this becomes chronic, the tissues react with the development of fibrosis and hyperplasia—features of lymphedema—and in its severest form elephantiasis. Many causes account for the failure of normal function, including cardiac failure, renal failure, gravitational overload of the venous system and immobility, inflammation, cancer and its treatment by surgery or radiotherapy2 and lymphatic filariasis3 (see Chapter 15).

Normal and Pathologic Tissue Fluids There is, of course, always some fluid in the interstitium provided by its blood supply and controlled by Starling’s law that describes the balance between intravascular and tissue hydrostatic and oncotic forces. It is currently believed that lymphedema results from a failure of lymphatic function. It rarely is a total failure; mostly it is a partial failure aggravated by overload from a failing venous system or inflammation causing transudation from the blood capillary bed. The richest capillary bed of the skin is found immediately deep to the epidermis, and the network of initial lymphatics lies immediately deep to the blood supply at the junction of the upper and middle dermis. When sectioned horizontally, the rete ridges of the epidermis provide a closely knit network. The capillary bed lies deep to this by less than 0.1 mm and has slightly wider mesh and hairpin-shaped capillary loops projecting into the papillae. Below that is the initial lymphatic network with a much wider mesh (up to 1.0 mm) lying at the junction of the upper and middermis normally without projections into the papillae. This layering was well illustrated by Kubik and Manestar4and can be reproduced and downloaded from Ikomi and Schmid-Schönbein.5 Ultrasonographic studies of the skin show very clearly the relative water content versus cellular and fibrous components of the skin. They reveal the relative density of the epidermis, the collagen fibers of the dermis, and the water-filled interstitium. Most of the water content is found in the upper dermis, where the capillary bed is the richest. Ultrasonographic findings also show an accumulation of water in the upper dermis after prolonged venous overload from the gravitational effects of dependency of the leg, and there is a reduction of water in the upper dermis after 2 hours of elevation.6 Ultrasound examination can show localized indentation of the upper dermis by the fingernail or with a matchstick to a depth of 0.3 mm to indent and disperse the upper dermal interstitial fluid. Light massage with circular movements has the same effect, whereas deeper kneading massage shifts deep dermal water often like a deep bruise, bringing it to the upper dermal lymphatics. A great increase in water content, such as when the lymphatic system fails and cannot cope with venous overload, results in the expansion of the upper dermis, but adnexal components, such as the hair follicle, prevent such expansion in their immediate vicinity. It gives the appearance of orange peel, known as peau d’orange (Fig. 14-1). When fluid accumulation increases, such as in cellulitis caused by streptococcal infections of the regions of lymphedema, the hair follicles are unable to prevent further expansion of the dermis. As a result, lymphedema becomes painful, warm, and swollen, and the superficial skin becomes red. As the edema increases because of active infection, the peau d’orange appearance can be seen at the expanding edges of cellulitis while more central tissues are destroyed (Fig. 14-2).

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The epidermis and upper dermis are subject to morphologic findings ranging from a flat epidermis—such as in atrophy—to extreme outward projection of the papilla and inward projection of the epidermis, giving the picture of acanthosis or hyperplasia (Fig. 14-3). The capillaries in the dermal papillae elongate and coil. Mostly the initial lymphatics maintain their position at the junction of the upper dermis with the mid-dermis. One of the features of lymphatic failure resulting from blockage of the collecting ducts into which they drain is that the initial lymphatics, which have only a single overlapping layer of endothelium

FIG. 14-1  Peau d’orange is swelling of the upper dermis, preventing expansion of the hair follicles and sweat glands.

FIG. 14-2  Further gross expansion of the upper dermis causing peau d’orange seen at the edge of the lesion with greater disruption in the center of the lesion.

FIG. 14-3  Hematoxylin-eosin–stained section of lymphedematous skin showing hypertrophy of the epidermis, dilated lymphatics, and patchy inflammatory infiltrate.

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FIG. 14-4  A, Hematoxylin-eosin stain. Dermis is showing dilated lymphatics with proteinaceous fluid. Lymphatic close to the overlying epidermis. Excess collagen in between dilated lymphatics (green arrow). Black arrow is pointing to a valve. Red arrow shows the smooth muscle in the wall filled with a few red cells. They are high in the upper dermal papillae in this patient with lymphedema. B, A severely hyperkeratotic leg (elephantiasis nostras verrucosa). The entire papillae, often lying deep to a severely hyperkeratotic epidermis. C, After removal of the excess keratin, the surface has the appearance of multiple polyps that appear similar to the villi of the small intestine.

in healthy individuals, develop smooth muscle, and the intralymphatic pressure rises as contractions become stronger (Fig. 14-4, A). One effect of this raised intralymphatic capillary pressure is to encourage the lymphatics undergoing lymphangiogenesis to penetrate higher in the upper dermis and into the widened papilla. As this becomes a dominant feature, the papilla extends closer to the surface, and the dilated lymphatic may reach the surface (Fig. 14-4, B). The entire papillae may resemble small intestinal villi (Fig. 14-4, C). Capillaries and lymphatics extend to the peak of each villus or present as vesicular fluid-filled lymphatics (see Fig. 14-6). Histologically there may be a smooth muscle–lined deep cyst into which the lymphatics drain and receive their lymph under high pressure.7 The variations in the dimensions of the polyplike protrusions can be observed in Fig. 14-5. The cobblestone-like nodules are often referred to as elephantiasis nostras verrucosa.8 Originally the Latin term for “ours,” nostras, referred to belonging to “our region,” indicating its typically tropical prevalence.

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B

A

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FIG. 14-5  A and B, As the tissues expand in lymphedema, the polypoid dimensions become larger. Individually they are frequently filled with compressible edema and dilated lymphatics, making them indentable and compressible, unlike the equally common hard nodules of fibrous tissue. C, A single large nodule composed of noncompressible whorls of collagen fibers. D, Scattered nodules of whorls of collagen. E, Numerous nodules of collagen, but at the same time the forefoot also shows much smaller surface changes, which are described as “mossy.”

The so-called mossy foot is now also used to describe podoconiosis, which is caused by damage to the tissues and lymph nodes by an alkaline colloid of silica from the soil penetrating the skin in individuals who walk barefoot; the condition is commonly observed in Ethiopia.9 Mossy foot, which is also described in Aboriginal Australians, usually begins around the toes. Gradually there is accompanying hypertrophy, and deep crevasses become entry points for bacteria and soil irritants. Lymph leaks and wets the surface of the skin, causing maceration, and secondary infection by bacteria and fungi occurs. The production of excess collagen gives rise to increasingly larger protuberances in which the lymphatics are sometimes hugely dilated. The condition is reported in all cases of lymphedema and occurs as a result of chronicity and repeated secondary infection of the area.

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FIG. 14-6  Lymphangioma circumscriptum. A, Dilated lymphatics close to the surface contain clear fluid. B, They also contain pink fluid resulting from a little blood contamination to deep red filled with blood. C, A milky white appearance occurs when the lymphatics are filled with lymph from the small intestine. D, A single leaking lymphatic is illustrated (arrow).

Lymphangioma Circumscriptum Dilated lymphatics often penetrate the papilla and epidermis to reach the surface of the skin. They develop contractile smooth muscle and loss of valves. Whimster7 found that these contractile lymphatics often drain into large high-pressure cystic dilations of the collecting lymphatics. The color of the superficial vesicular lymphatics depends on the number of red cells, or they can be milky white from chyle (Fig. 14-6). The term chylous reflux describes a backflow of chyle from its normal route from the bowel through the cisterna chyli and thoracic duct to reach the bloodstream in the great veins of the thorax. The clinical presentations include small blisters containing chyle-chylous vesicles, which may appear on the skin in the lower parts of the body and discharge milky fluid, thus forming one type of chylous fistula. Chylometrorrhagia causes vaginal discharge of chyle. Chyle may collect in the serous cavities of the body—producing chylothorax, chylous ascites, and chylocele.10

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FIG. 14-7  Examples of late-stage elephantiasis and great hypertrophy observed in lymphedema.

A

B

FIG. 14-8  A, Hematoxylin-eosin–stained section of lymphedema demonstrating excess collagen and dilated thick-walled lymphatics. B, NB, a lymphatic draining into a filled and dilated muscular lymphatic.

Tissue Hypertrophy As well demonstrated in studies of experimental lymphedema in dogs,11 there is huge enlargement of the tissues in elephantiasis in the later stage of lymphedema12,13 (Fig. 14-7). However, enlargement of the tissues is only partially the result of the accumulation of water. Such accumulation is supposedly enough to create tissue expansion and provide mechanical stress to tissue fibroblasts, which respond by a massive increase in collagen, some adipose tissue, lymphangiogenesis, and angiogenesis (Fig. 14-8).

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FIG. 14-9  A, Negative Stemmer sign in a patient with Ehlers-Danlos syndrome. The skin over the toes is easily picked up. B, Positive Stemmer sign showing measuring resistance to picking up a skin fold.

Stemmer Sign The chronic stimulus to the fibroblast-raised interstitial hydrostatic pressure is first identified in the toes of tall young adults from the standing and sitting positions. As shown by a physical therapist in the Földi Clinic (personal communication), about 20% of young adults will have some stiffness of the skin, and thus the skin over the dorsum of the toes cannot be easily picked up between the finger and thumb (Fig. 14-9).

Elastin As Unna14 demonstrated in his 1896 textbook, the normal lymphatic vessel is supported by elastin (Fig. 14-10), and he showed that edema leads to a loss of elastin. Most commonly elastases from neutrophils or activated mast cells and macrophages are responsible. The destruction of elastin has been found in granulomatous tissue in leprosy.15 Fibrosis is a cause of the nonpitting status of lymphedema, which is also termed brawny edema. The pitting of venous edema is seen in Fig. 14-11. Deep indentation over a wider area requires much greater pressure in lymphedema. Localized indentation to a depth of 0.3 mm by a fingernail or thumb can be achieved easily in all types of edema. The pattern of lymphedema that produces great expansion of the papilla filled with a dilated lymphatic will be softer and more compressible nodules than that produced by fibrosis (see Fig. 14-5, A). They will indent if pressure is applied to only one nodule. Often these nodules contain dilated dermal lymphatic vessels. Collagen is often found in collections of tightly bound fibers or whorls producing nodules, which may be few or many. They are firm and not compressible. They are usually observed in sites of surgical debridement of lymphedematous tissue (Fig. 14-12).

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B

A

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FIG. 14-10  Orcein stain. A and B, Normal lymphatic supported by elastin. A, The lymphatic lies at the junction of the upper and middle dermis and is longer than blood capillaries at this level in the skin. B, The elastin surrounding the lymphatic has tangential fibers extending to the epidermis. C, There is an absence of elastin, but there is expansion of the upper dermis by angiogenesis. The epidermis is thinned. The initial lymphatics (arrows) are now deep and dilated. D, Higher magnification showing angiogenesis.

A

B

FIG. 14-11  A, Pitting edema. B, Pressure with the thumb is resisted by brawny edema.

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FIG. 14-12  Surgical removal of excess tissue and grafts taken from the thigh has resulted in keloid development at both sites.

A

B

FIG. 14-13  Two examples of fissuring of the epidermis, common in individuals who do not wear shoes and are agricultural workers. A, Heels. B, Plantar surface of the forefoot.

Common Entry Points for Bacteria and Irritant Soils The recognition of easy access through the epidermis for bacteria and irritants has led to an emphasis on skin care. It is common for fissures to occur on the soles of the feet of individuals who do not wear footwear (Fig. 14-13). It is a feature of the shoeless agricultural worker and an important contribution to podoconiosis in the irritant soil of Ethiopia.9 It is also a feature of middle-aged overweight women and the forefoot of atopic children.16 One of the best recognized entry points is an intertrigo between the toes (Fig. 14-14). Here moisture may collect and cause maceration. If there is no secondary contamination from fungi and

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Candida, the maceration and scaling do not extend beyond the crevasse. Fungal contamination usually extends beyond the crevasse, and scaling is visible beyond the crevasse. If there is scale beyond the crevasse, then a candidal or fungal infection should probably be suspected, because they usually extend beyond the site of maceration. With the leg dependent, the depth of the crevasse may be difficult to examine, but it should be aerated by expanding with foam rubber (Fig. 14-15, A). After the edema is reduced by therapy, full examination of the depth of the crevasse is facilitated by elevation (Fig. 14-15, B). In advanced lymphedema in which volume becomes enormous, the crevasses are deep and multiple.

A

B

FIG. 14-14  A, Common entry point for bacteria or soil irritants is macerated skin. It is often confined deep in a crevasse, for example, between the toes. B, Another entry point is deep in a skinfold of hypertrophic skin.

B

A

FIG. 14-15  Two examples of opening up a deep crevasse for closer examination. A, By using pieces of foam. B, By elevation.

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Nail Changes Nail growth is disturbed by lymphedema. For unknown reasons, there is typically shortening and upward tilting of the nail, which is termed the ski jump nail (Fig. 14-16, A). In growing, the nail often shows hypertrophy of the tissue at the sides of the nail, and bandaging or tight-fitting shoes or bandages press the overgrown tissue into the nail (Fig. 14-16, B). There may also be gross onychogryphosis (Fig 14-16, C). Yellow nail syndrome (Fig. 14-17) is an unexplained condition in which nail growth ceases and the nail is thick and yellow. This syndrome is characterized by slowly growing, dystrophic, yellow nails, peripheral lymphedema, pleural effusions, rhinosinusitis, and bronchiectasis, with consecutive recurrent infections of the lower respiratory tract.17,18

A

FIG. 14-16  A, The elevated shape of the nail affected by lymphedema may resemble a ski jump. B, In growing, the nail shows hypertrophied skin lateral to the nail when compressed by shoes or bandages against the nail. C, The nail may be onychogryphotic.

B

C

FIG. 14-17  Rarely, nails stop growing and become uniformly discolored yellow. This is the yellow nail syndrome, which is associated with pleural effusions.

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Adipose Tissue Stimulation of overgrowth of adipose tissue is a feature of lymphedema,11,19,20 but there are normally small collections of adipose tissue around hair follicles and sweat glands (Fig. 14-18). In lymphedema adipose cells and tissue produce smooth, rubbery feeling masses of tissue (Fig. 14-19). They are mostly seen in late stage II of International Society of Lymphology grades. Lipedema characteristically involves localized primary adipose hypertrophy with a secondary collection of fluid, sparing the feet, with relatively less fibrosis and fewer other signs of tissue

FIG. 14-18  Hematoxylin-eosin stain of a full-thickness skin biopsy. Adipose tissue is normally subcutaneous, but it often protects adnexal tissue, such as hair follicles and sweat glands, from shearing forces and may provide essential fatty acids.

FIG. 14-19  Pathology of lymphedema also stimulates growth and inflammation of adipose tissue. It gives rise to local, often smooth-skinned, rubbery, consistent swellings.

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B

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D

FIG. 14-20  A, In lipedema. B, Hematoxylin-eosin–stained epidermis shows effacement of rete ridges. The dermis is expanded or thickened with dense collagen bundles. C, Dermis shows fragmented elastic fibers (in black Verhoeff–van Gieson stain). D, Subcutaneous tissue shows hypertrophic mature adipose cells.

component hypertrophy19-21 (Fig. 14-20, A). Some characteristics of this physical condition are deposition of excess fat on the legs (described classically as an Egyptian column shape) and arms with a negative Stemmer sign.22 The histopathologic findings of lipedema have not been extensively studied. In a few biopsied cases at the Institute of Applied Dermatology, Kasargod, India, the epidermis in lipedema was thin, elastic fibers were fragmented, and the dermis was thickened from collagen deposits (Fig. 14-20, B). Subcutaneous tissue showed hypertrophic adipose cells (Fig. 14-20, C). Others have emphasized inflammation, hypoxia, stem cells, and special features, such as an excess of CD68 macrophages and Ki671CD341cells (stem cells).23,24 It is difficult to manipulate by massage, because the forces applied are dissipated by adipocytes. It is easier to reshape the swollen adipose tissue than it is to reduce it (Fig. 14 -21).

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B

FIG. 14-21  A, Lymphedema, mostly comprised of adipose tissue, was located below the knee before bandaging. B, After 25 days of compression, it is reshaped and covers the knee.

Venous Reflux The three main contributors to lymphedema are: 1. Failure of lymph flow into and along the initial lymphatics 2. From the initial lymphatic system preferentially and by fast track into the collecting system 3. By a smooth muscle pump along the collecting lymphatics and through the lymph nodes and finally through the thoracic duct into the great veins assisted by deep breathing Such failure is often only partial, but it is greatly exacerbated by inflammation resulting from the entry of bacteria or irritants, and as emphasized previously, by venous overload caused by venous reflux.6 Dilated veins should be recorded on standing and managed by elevation, ankle movements, and support bandages or hosiery. Ulceration is more often the result of venous failure than lymphatic failure. It is common for persons with “heavy legs” to sit with their legs dependent and immobile. This results in gravitational overfilling of the veins. In lymphedema, venous incompetence must be recognized on the observation that dilated veins are the most obvious when standing (Fig. 14-22). Venous reflux is the retrograde flow in a vein in response to a stimulus such as a calf squeeze. It occurs in the standing position when valves are incompetent. Leakage of the distended venous capillaries results in characteristic pigmentation caused by hemosiderin (Fig. 14-23, A). In chronic venous insufficiency, increased matrix turnover results in a tendency for ulceration through lipodermatosclerosis. It should be expected if there is any ulceration at or above the ankle when minor trauma does not heal, especially when there are long-standing untreated varicose veins. Diabetes should be suspected when ulceration of the toes or sole of the foot is present (Fig. 14-24). In all patients the surgeon should always inquire about medication history, such as oral contraceptives and antipsychotic drugs.

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FIG. 14-22  Venous overload with dilated varicose veins is aggravated by lymphedema. Heavy legs and the tendency to sit immobile with the legs dependent may be observed in the clinic.

A

B

FIG. 14-23  A, One feature is leakage of blood from dilated capillary beds with resulting hemosiderin pigmentation. B, Retention of melanin pigment in some ichthyotic patterns of hyperkeratosis. Pigmentation resulting from hemosiderin is not a feature of lymphedema.

FIG. 14-24  Ulceration at pressure points on the foot should lead to a check for diabetes.

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Other Dermatologic Changes Folliculitis sometime occurs from bacteria but can also often be from irritants. One of these is the Ayurvedic oil used in massage, especially during the integrative treatment of lymphedema as practiced in India. Scarification marks are frequently from incisions made by traditional health practitioners to allow lymph to drain (Fig. 14-25). Ulcerated nodules resulting from malignancy (Fig. 14-26) are sometimes a consequence of lymphedema (for example, a lymphosarcoma named after Stewart and Treves) (Fig. 14-27). This sarcoma is a not too rare final consequence of lymphedema. It has been suggested that it is from impaired immunity, which is a feature of a failed lymphatic system. A squamous cell carcinoma of the foot reminds us that malignancies of every type may be more common when there is an impaired immune system.25-27

FIG. 14-25  Traditional healers cauterize lymphedema to drain the lymph. This harmful practice, which was observed until recently worldwide but now is mostly confined to rural Africa and India, results in acute inflammatory episodes resulting from secondary infection. Recurrent attacks worsen the lymphedema.

FIG. 14-26  Diffuse large B-cell type of non-Hodgkin lymphoma nodules and ulcerations developed over long-standing lower leg lymphedema of 13 years’ duration. Such nodules also occur from lymphangiosarcoma, a rare complication of lymphedema.

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FIG. 14-27  Erythematous and blood-stained nodules of lymphangiosarcoma developed over 7 years’ duration of lymphedema of the leg.

C linical P earls • In a patient with lymphedema, clinicians should look for features that contribute to disease progression, especially bacterial entry lesions. • When associated with nodules and ulcers, other causes and complications of lymphedema should be explored. • In all patients with lymphedema, the presence of reducible pitting edema and associated venous insufficiency should be estimated. • Lipedema is difficult to treat, and compression therapy helps to reshape the limb.

R EFERENCES 1. Levick JR, McHale N. The physiology of lymph production and propulsion. In Browse N, Burnand KG, Mortimer PS, eds. Diseases of the Lymphatics. London: Arnold, 2003. 2. Beesley V, Janda M, Eakin E, et al. Lymphedema after gynecological cancer treatment: prevalence, correlates, and supportive care needs. Cancer 109:2607-2614, 2007. 3. Michael E, Bundy DA, Grenfell BT. Re-assessing the global prevalence and distribution of lymphatic filariasis. Parasitology 112:409-428, 1996. 4. Kubik S, Manestar M. Anatomy of the lymph capillaries and pre-collectors of the skin. In Bollinger A, Partsch H, Wolfe JHN, eds. The Initial Lymphatics. New York: Thieme-Stratton, 1985. 5. Ikomi F, Schmid-Schönbein GW. Lymph transport in the skin. Clin Dermatol 13:419-427, 1995. 6. Hu D, Phan TT, Cherry GW, et al. Dermal edema assessed by high frequency ultrasound in venous leg ulcers. Br J Dermatol 138:815-820, 1998. 7. Whimster IM. The pathology of lymphangioma circumscriptum. Br J Dermatol 94:473-486, 1976. 8. Sha M. Images in clinical medicine: elephantiasis nostras verrucosa. N Engl J Med 370:2520, 2014.

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9. Davey G, Tekola F, Newport MJ. Podoconiosis: non-infectious geochemical elephantiasis. Trans Roy Soc Trop Med Hyg 101:1175-1180, 2007. 10. Kinmonth JB, Taylor GW. Chylous reflux. Br Med J 1:529-532, 1964. 11. Casley-Smith JR, Clodius L, Piller NB. Tissue changes in chronic experimental lymphedema in dogs. Lymphology 13:130-141, 1980. 12. International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema. 2009 Consensus Document of the International Society of Lymphology. Lymphology 42:51-60, 2009. 13. Bennuru S, Maldarelli G, Kumaraswami V, et al. Elevated levels of plasma angiogenic factors are associated with human lymphatic filarial infections. Am J Trop Med Hyg 83:884-890, 2010. 14. Unna PG. The Histopathology of the Diseases of the Skin. Edinburgh: Macmillan & Co, 1896. 15. Ryan TJ, Jones R, Mortimer PS, et al. Lymphatics in leprosy: relationship to elastic fibres and observations following intra-lesional injections of colloidal carbon. Lepr Rev 73:52-63, 2002. 16. Ashton RE, Griffiths WA. Juvenile plantar dermatosis—atopy or footwear? Clin Exp Dermatol 11:529534, 1986. 17. Norkild P, Kroman-Anderson H, Struve-Christensen E. Yellow nail syndrome—the triad of yellow nails, lymphedema and pleural effusion. A review of the literature and a case report. Acta Med Scand 219:221-227, 1986. 18. Hoque SR, Mansour S, Mortimer PS. Yellow nail syndrome: not a genetic disorder? Eleven new cases and a review of the literature. Br J Dermatol 156:1230-1234, 2007. 19. Ryan TJ. Lymphatics and adipose tissue. Clin Dermatol 13:493-498, 1995. 20. Földi M, Földi E, Kubic S. Textbook of Lymphology. Munich: Elsevier, 2007. 21. Reich-Schupke S, Altmeyer P, Stücker M. Thick legs— not always lipedema. J Dtsch Dermatol Ges 11:225-233, 2013. 22. Godoy GM, Barufi F, Godoy MF. Lipedema: is aesthetic cellulite an aggravating factor for limb perimeter? J Cutan Aesthet Surg 3:167-168, 2013. 23. Suga H, Araki J, Aoi N, et al. Adipose tissue remodeling in lipedema: adipocyte death and concurrent regeneration. J Cutan Pathol 36:1293-1298, 2009. 24. Szolnoky G, Kemény L. Lipoedema: from clinical presentation to therapy. Further aspects. Br J Dermatol 162:889, 2010. 25. Ruocco V, Astirata C, Guerera V, et al. Kaposi’s sarcoma on a lymphedematous immunocompromised limb. Int J Dermatol 23:56-60, 1984. 26. Mallon E, Powell SM, Mortimer PS. Contact sensitization and antigen recall in post-mastectomy lymphedema. Br J Dermatol 131(Suppl 44):14-29, 1994. 27. Ryan TJ, Mallon EC. Lymphatics and the processing of antigen. Clin Dermatol 13:485-492, 1995.

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C hapter 15 Filaria Gurusamy Manokaran, Rajiv Agarwal, Devisha Agarwal

K ey P oints • Adenolymphangitis is an important clinical manifestation of lymphatic filariasis; recurrence contributes to the progress of the disease. • Meticulous compliance with nonsurgical methods of treatment is essential to avoid surgery or prevent recurrence after surgery. • A combination of physiologic surgery, such as a nodovenous shunt or a lymphaticovenous shunt, with an immediate reduction or debulking procedure with skin grafting is a very effective treatment method. • Lymphatic filariasis has no cure.

Fila Approximately 120 million people worldwide are at risk of contracting filariasis, and 70 million people have established filariasis, of whom 40 million have lymphedema. Medical and paramedical professionals and health planners need to understand this disease and attempt to prevent and decrease morbidity by various means, including surgery. The World Health Organization is working toward elimination of lymphatic filariasis by 2020. In the meantime, patients with clinical manifestations require lifelong treatment. In the future, earlier detection and treatment may reduce the severity of the disease but will not eliminate the problem. Lymphatic filariasis is one of the most incapacitating of chronic diseases. Previously, no treatment was thought possible. Ancient sculptures and scriptures depicted lymphatic filariasis of the lower limb; these are currently seen in many temples in India. According to Manusmriti (300 BC) from Hindu mythology, the disease was considered a result of karma, a retribution for actions committed in a previous life. Some primitive treatments were performed. As science and technology progressed, the organism and its mode of transmission from mosquitoes to humans were identified. Initially many medical and surgical treatments were attempted, but invariably they were unsuccessful, and lymphatic filariasis became a neglected tropical disease.

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Pathogenesis of Lymphatic Filariasis Lymphatic filariasis is a vector-borne disease of tropical countries caused by infection with filarial worms transmitted from the Culex species of mosquitoes (Fig. 15-1). The breeding of these mosquitoes is associated with aquatic plants such as Pistia stratiotes (water lettuce) and Salvinia auriculata (butterfly fern). The infective mosquitoes harbor the larvae (microfilariae), which enter the human host through bite wounds and migrate into the lymphatic system, where they develop into adult male and female worms. These worms—most commonly Wuchereria bancrofti (Fig. 15-2, A), Brugia malayi (Fig. 15-2, B), and Brugia timori (Fig. 15-2, C)—invade the lymphatics, leading to pathologic changes culminating in filarial disease manifestations.1 In mainland India, the causative nematodes are mostly W. bancrofti (see Fig. 15-2) and B. malayi, which are transmitted by specific genera of mosquitoes that include Culex quinquefasciatus, Anopheles, and others. B. malayi infection is now reportedly restricted to rural areas of South India.

MOSQUITO STAGES

HUMAN STAGES

1 An infected mosquito takes a blood meal. Infective L3 larvae enter the human skin through the bite wound and migrate to the lymphatic system.

L4

7 Between days 11 and 13, L2 larvae develop and molt into infective L3 stage. L3 larvae migrate through the hemocoel to enter the mosquito’s mouthparts.

6 Between days 6 and 10 after entering the mosquito, L1 microfilariae develop within the thoracic muscles into L2 “sausage” stage.

2 Between days 9 and 14 after entering the human host, L3 larvae transform into L4 larvae. Within 6 to 12 months, L4 larvae grow into mature adult worms.

Adults

L3 3 Adult worms nest in the lymphatic system and mate. The female worm releases thousands of sheathed microfilariae into lymphatic circulation, where they migrate to the bloodstream.

L2

5 The ingested microfilariae move to the mosquito’s stomach and shed their sheaths. They migrate through the stomach wall, bore between wing muscle fibers, and enter thoracic flight muscles. 4 A mosquito takes a blood meal from an infected individual and ingests L1 microfilariae.

L1

FIG. 15-1  Life cycle of a lymphatic filarial parasite.

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A

B

C

FIG. 15-2  Worms known to cause lymphedema. A, W. bancrofti. B, B. malayi. C, B. timori.

FIG. 15-3  Characteristic histopathologic appearance of skin and subcutaneous tissues in chronic lymphatic filariasis. The tissue is lined by hyperkeratotic stratified squamous epithelium. The superficial dermis shows edema and sclerosis, along with proliferating small blood vessels and ill-defined epitheloid granulomas associated with lymphocytes, histiocytes, plasma cells, and occasional giant cells. Focal vasculitic lesions are also present.

The worms live in the lymph vessels and lymph nodes by making nests in the dilated lymphatics. The term worm nests refers to dilated lymphatic vessels with the characteristic movement pattern of worms, as evidenced on ultrasound examination. This early pathologic state predisposes the system to lymph dysfunction by causing incompetence of the unidirectional valves. Lymphatic filariasis is characterized by the presence of live adult parasites in the lymphatic system, with larvae (microfilariae) in the blood at certain times of the night (generally) in the early stage of the development of the lymphedema. The presence of microfilariae indicates an early stage in the life cycle in which the adult worms live in the lymph vessels and lymph nodes while they release microfilariae into the bloodstream of the host. The presence of microfilariae in the host bloodstream is called microfilaremia. This happens after the worms mate and the females produce millions of microfilariae, which migrate to the blood circulation. The sheathed microfilariae begin to appear in the blood circulation in 6 to 12 months after infection. They remain in the arterioles of the lungs during the day and emerge into the peripheral circulation at night. The periodicity of microfilariae coincides with the biting activity of the vector. They are taken up by blood-feeding vectors that spread the disease.

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Histopathologically, the filarial tissue shows hyperproliferation of keratinocytes, focal acantholysis, an accumulation of lymphocytes at the epidermodermal junction, and profuse pericapillary and perivenular mononuclear infiltrations (Fig. 15-3).

Manifestations of Lymphatic Filariasis The manifestations can be categorized as acute and chronic disease states (Table 15-1). Acute manifestations are comprised of adenolymphangitis, epididymoorchitis, and funiculitis, whereas chronic manifestations include lymphedema, hydrocele, elephantiasis, chyluria, chylothorax, chylascites, lymph scrotum, and tropical pulmonary eosinophilia. Advanced stages of lymphedema are characterized by increasing dilation and tortuosity of the lymphatics, endothelial proliferation, formation of new lymph channels, and obstructive changes with dermatosclerosis and warty lesions.2 Genital manifestations include filarial scrotum, ram’s horn penis, genital vesicles, and edema. Atypical lymphatic filariasis manifests as fleeting joint pains and lymphangitis (string sign). It can affect the breast, gluteal region, abdomen, and suprapubic region as isolated lesions. Manifestations are most commonly seen in the lower limb, more often in females.

TABLE 15-1  Clinical Presentation of Lymphatic Filariasis Clinical Stage

Clinical Feature

Pathogenesis

1  Asymptomatic parasite carrier state

Lymph vessel dilation Lymph vessel tortuosity

Subclinical infection

   a. Acute dermatoadenolymph­ angitis

Fever and chills Extremity warm and painful, swollen and tender Lymphangitis, cellulitis, abscess

Entry of bacteria and pathogens through the lesion

   b. Acute filarial lymphangitis

Tender lymph nodes Long tender cords underneath the skin

At site where adult worms die

   c. Acute epididymoorchitis and funiculitis

Pain, tenderness, and swelling of scrotum

Precipitated by secondary infection

  a. Lymphedema

Swelling of the extremity Three grades

Edema from lymphatic blockade

  b. Hydrocele

Swelling of scrotum

Accumulation of fluid in the tunica vaginalis

  c. Elephantiasis

Grade III lymphedema with dermatosclerosis and papillomatous lesions

Gross increase in edema

  d. Chyluria

Painless milky urine

Blockage of retroperitoneal nodes below cisterna chyli with reflux into renal lymphatics

   e. O  ccult filariasis and tropical pulmonary eosinophilia

Clinically asymptomatic High eosinophil count

Microfilariae in the tissues

2  Acute disease

3  Chronic disease

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FIG. 15-4  This 32-year-old patient from an endemic area has extensive involvement and deformity of the penis and scrotum.

Four grades of lymphedema have been described, depending on the severity of involvement and the quality of pitting.3 • Grade 1: Edema appears and disappears spontaneously and is pitting and uniform in size. • Grade 2: Edema is persistent, pitting, and uniform. • Grade 3: Edema is persistent, nonpitting, and uniform. • Grade 4: Giant lymphedema develops, with complications such as ulcers, warty growth, and loss of limb shape (elephantiasis). Any breach of skin integrity of the affected region (for example, from injury, fungal or bacterial infection, or even eczema) favors entry of pathogenic bacteria into the tissues, leading to acute attacks of adenolymphangitis, which is commonly seen in filarial limbs.4,5 Adenolymphangitis is one of the important clinical manifestations of lymphatic filariasis. Recurrence contributes to the progress of the disease and has important socioeconomic implications, because it affects a patient’s ability to work.6 Lymphedema of the extremities is a common chronic manifestation of lymphatic filariasis that results in elephantiasis as it progresses. Elephantiasis refers to massive swelling of the lower limbs caused by repeat attacks of filarial lymphangitis over several years. The limb becomes grossly enlarged, resembling the foot of an elephant. Repeated inflammatory reactions cause vessel dilation and thickening. In the advanced stages of lymphedema, the skin is thickened and thrown into folds, often with hypertrichosis, black pigmentation, nodules, warty growth, and intertrigo in the webs of the toes, with nonhealing ulcers. This usually involves the lower limbs, commonly unilaterally. The male genitalia are also commonly affected (Fig. 15-4). Vulval elephantiasis has been reported.7

Diagnosis Patient history is essential for diagnosing lymphatic filariasis, because it provides information about the causes. Careful clinical examination of the skin color, texture, and other changes is helpful for staging the disease. Circumferential measurements at fixed points of the upper and lower limbs are documented. The patient’s height and weight are recorded.

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Several diagnostic tools are available, including the following: • An immunochromatographic test can be conducted quickly and easily at the bedside to test for lymphatic filariasis. The test is highly sensitive for W. bancrofti. • Ultrasonography can be used as a screening test in endemic areas. It can reveal moving adult worms in the scrotum or breast. Patients with positive results may not have clinical signs and symptoms; removing the adult worms surgically from these patients will prevent the occurrence of lymphatic filariasis. • Lymphoscintigraphy is the single most useful tool in establishing the diagnosis, grading, and cause (see Chapter 26). It can show the outcome of treatment after chemotherapy or surgery. • MRI is useful in the presence of associated problems. MR lymphangiography is a very good assessment modality but very expensive in a country such as India, where health coverage by insurance or the government is not available (see Chapter 28).

Assessment Lymphedema can be objectively assessed by several methods, ranging from clinical evaluation to radiologic modalities. One clinical method involves measuring the limb circumference at various points. The upper limb is divided into four segments. The upper limit of measurement, known as the 65% point, is marked on the upper arm 65% of the distance from the olecranon to the acromion tip. The four segments are (1) the wrist at the level of ulnar styloid to the midforearm, (2) the midforearm to the elbow at the level of olecranon, (3) the elbow to the midarm, and (4) the midarm to the 65% point. These segments conform to the shape of a truncated cone. Measurements obtained using this method produce the least standard error of measurement. The volume of each segment can be calculated using the following formula: Segment volume 5 h(C12 1 C22 1 [C1 3 C2])/12p where h is the length of each segment and C1 and C2 are the circumference of each segment at both ends. The sum of the segment volumes is the volume of the limb.8 Another clinical method is water displacement volumetry. The patient’s upper limb is immersed in a graduated steel cylinder up to the 65% point. The volume of water displaced can be calculated using the following formula: Volume 5 pr2h where r is the radius of the cylinder and h is the height of the water displaced. Calculation of the volume of edema in unilateral cases is recommended. This is done by estimating the difference in the limb volume between the edematous limb and the normal limb. In lymphedema patients, high-frequency sonography is useful for assessing the thickness of the skin and the subcutaneous tissue. The patient can be sitting or lying down, with the limb extended to allow access to all aspects—anterior, posterior, medial, and lateral—to determine the average value. Compressibility of the regional veins can be assessed to rule out venous thrombosis.

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Lymphoscintigraphy using technetium sulphur colloid is a useful modality for studying the lymphatics preoperatively and postoperatively. It reliably allows visualization of the lymphatic vessels and lymph flow and is helpful in distinguishing between primary and secondary lymphedema.9 It is performed after intradermal injection of Tc99m (technetium) colloid in the web spaces of the lower limbs (see Chapter 26).

Medical Management The treatment options for patients with lymphedema are broadly divided into two categories: medical and surgical. Many methods used in the past, such as crepe bandaging and flap transfers, are now rarely used. The following recommendations apply to all four grades of lymphedema: • Foot care • Avoidance of injuries and injections to the affected limb • Elimination of the focus of sepsis • Complete decongestive therapy with bandaging, followed by placement of pressure garments Complete decongestive therapy is an important modality in the management of lymphedema. It consists of manual manipulation of the lymphatic ducts, short stretch compression bandaging, therapeutic exercises, and meticulous skin care. • Elevation of the affected part • Management of acute attacks • Cyclic chemotherapy (antibiotic and antifilarial) to prevent secondary infection

Maintenance of Limb Hygiene Filarial patients with damaged lymphatic vessels often have more bacteria on the skin than those without this disease; hence infections are very common. The large number of bacteria on the skin, multiple skin lesions, slow lymph fluid movement, and the reduced ability of the lymph nodes to filter bacteria cause inflammation characteristic of an acute attack. Washing the limb is essential to block this vicious cycle. Clean water at room temperature should be used. The least expensive soap without perfume is usually best. After the area is washed, it should be gently towel dried. This should be done twice daily, ideally in the morning and at night.

Prevention and Treatment of Entry Lesions Apart from the bite sites of the mosquitoes, other skin lesions are common in patients at risk of developing lymphedema and in those who already have it. These are most frequently found between the toes and deep skin folds and around the toenails. Dental caries are another source of secondary infection. The lesions allow bacteria or fungi to enter the body through the skin, and this can cause attacks of acute dermatoadenolymphangitis. Bacterial infections leak fluid that is watery and clear or viscous and colored at times. Fungal lesions are usually white or pink and do not leak fluid. Fluid leakage in bacterial infections is not chylous reflux, which essentially is white. Treatment involves the application of local antibacterial and antifungal creams at least twice daily. Prevention of secondary infection in the initial stages of lymphatic filariasis can reverse or minimize the damage done by the parasite10 (see Chapter 29).

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Elevation of the Limb Elevating the limb is important for patients with lymphedema, because it helps to prevent fluid from accumulating in the leg by improving lymph outflow. When the patient is sitting, the foot should be raised to a comfortable height, preferably as high as the hip.

Exercise and Footwear Exercise is useful for patients with lymphedema, because it helps to pump fluid and improve drainage. The more a patient exercises, the better the fluid drainage will be proximally. No exercise should be undertaken during acute attacks. While standing, the patient should perform heel-raising exercises five to ten times or as often as is comfortable. Patients should wear proper footwear and avoid tight-fitting shoes.

Management of Acute Attacks The onset of acute attacks in lymphatic filariasis indicates continuing destruction of the lymphatic system. Any reduction in the frequency of such attacks is an indication that the patient’s condition is improving. Patients should rest and elevate the limb comfortably as much as possible, as indicated previously. A cloth soaked in cool, clean water and placed around the limb can relieve pain. The limb should be gently and carefully washed with soap and clean water. After the skin is dry, an antiseptic should be applied, along with an antibiotic ointment. Patients should drink plenty of water. Paracetamol (acetaminophen) can be taken for fever every 6 hours until the fever lessens. Parenteral antibiotics are recommended during acute attacks, because they can shorten the duration of the attack.

Cyclic Chemotherapy Chemotherapeutic management involves diethylcarbamazine alone, diethylcarbamazine and albendazole, or diethylcarbamazine and ivermectin, along with periodic antibiotics such as penicillin, doxycyline, and sulphonamides. Doxycycline is very useful for treating symbiotic bacterial infections with Wolbachia, which reside inside the parasite and cause resistance to antifilarial drugs (Fig. 15-5) (see Chapter 30).

A

B l u

u

c

c h

u

h u

m

l

FIG. 15-5  Symbiotic infection with Wolbachia. A, Live organisms. B, Dead organisms after treatment with chemotherapy.

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Management of Grades III and IV Lymphedema In addition to the basic recommendations described previously, patients with grades III or IV lymphedema ideally should undergo surgical correction.

Surgical Management Various surgical procedures offer relief from lymphedema; however, there is no consensus on surgical intervention or the type and timing of procedures to be performed in a given case. The various surgical approaches to lymphedema treatment are covered in detail in other chapters. Our policy is to combine physiologic surgery such as a nodovenous shunt or a lymphaticovenous shunt with an immediate reduction or debulking procedure without skin grafting. After more than 25 years of experience, we have perfected the technique. The functional and aesthetic aspects of the limb are preserved through microvascular surgery, including free lymphatic channel transfer and lymph node transfer. Omental transfer and supermicrovascular surgery such as lymphaticlymphatic anastomosis are useful for treating congenital and postoperative lymphedema. These strategies have not traditionally played a strong role in the treatment of lymphatic filariasis.

Direct Excision Direct excision involves the removal of skin and subcutaneous tissues circumferentially to the level of the deep fascia; the resultant wound is then covered with a split-skin graft.11 In our experience, this procedure is the most common surgery performed for moderate to advanced stages of chronic lymphatic filariasis of an extremity (see Table 15-1). It results in satisfactory appearances and quick debulking of the lymphedematous tissues in one operation in India (Fig. 15-6) (see Chapter 31).

Scrotoplasty With Penile Debulking and Grafting Total subcutaneous excision followed by split- or full-thickness skin grafts is primarily indicated for primary lymphedema and for secondary lymphedema if the lymphatic trunks are sclerosed and unsuitable for microlymphatic anastomosis or if conservative measures were unsuccessful or not applicable.12 In cases of penile involvement (ram’s horn penis), penile debulking to the level of the tunica albuginea followed by skin grafting provides excellent cosmetic and functional results.13

Agarwal Surgical Technique of Direct Excision The Agarwal technique of direct excision is performed preferably with a regional block with tourniquet control. The involved area is excised down to the level of the deep fascia. The entire skin and subcutaneous tissue containing dilated vessels and lymphedematous tissue is excised. Once excision is complete, hemostasis is secured and confirmed. The wound is then covered by a splitthickness skin graft. In this technique, the deep fascia is preserved, which serves two purposes. First, the fascia facilitates better drainage of both venous blood and lymph, and second, it is a good bed for the split-skin graft.

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A

B

C

D

E

F

FIG. 15-6  This 25-year-old woman had chronic lymphatic filariasis (A-C). She is shown 1 year after direct excision and skin grafting on the foot region only. The cosmetic result is further enhanced by her functional ability to wear footwear, although the leg has not been debulked (D-F).

Excision with skin grafting gives immediate and satisfactory long-term results and is now becoming the treatment of choice for moderate to large chronic lymphatic filariasis of the leg and for chronic genital lymphedema.14 Postoperative Care Postoperatively the graft requires regular care and evaluations. The first dressing should be changed after 48 hours to make certain that no hematomas or seromas develop underneath the graft. Thereafter the dressings are changed every 2 to 3 days, because the wounds often produce a lot of exudate and discharge. The graft usually takes well. Patients are then advised to wear pressure garments to prevent hypertrophic scarring. These also help to control edema.

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Complications and Treatment Outcomes  The most common complications of this technique of direct excision are graft loss and infection from the high levels of bacteria residing on the skin of these patients. Minimal areas of graft loss are treated conservatively, and the wound is allowed to epithelialize. In patients with large, raw areas, repeat grafting may be needed to decrease the morbidity.

Manokaran Surgical Technique for Debulking The Manokaran surgical technique for debulking is the most useful protocol and provides the best acceptable results. The technique and time duration need to be modified for each patient. All patients are advised to follow the foot hygiene instructions provided, to eliminate the focus of sepsis, to prevent injury to the affected limb, and to preserve the limb shape with the use of pressure garments postoperatively. Stages 3 and 4 of lymphedema cannot be cured, only controlled. The debulking surgical procedure15 in lymphatic filariasis is performed for International Society of Lymphology stage III lymphedemas with nodules, warty growths, and ulcers. The basic principles of surgery are the following: • Augmentation of lymphatic drainage by a physiologic procedure • Reduction of the lymphatic load by debulking the lymphedematous, lymph-producing surface Our strategy involves a procedure to create temporary drainage, such as complete decongestive therapy for 1 week. A permanent drainage procedure is then performed, such as a nodovenous shunt, a lymphaticovenous shunt, a free omental transfer, or a supermicrovascular surgery, transplanting a myocutaneous flap with an arterial, venous, and lymphatic-lymphatic anastomosis. Once permanent lymphatic drainage is established, the grade 4 lymphedema with or without skin changes decreases, leaving only the subcutaneous fat, fibrous tissue, and the soft tissues above the muscle and fascia. We wait 10 to 14 days and then debulk the excess skin, fat, and subcutaneous tissue to the level of the deep fascia, under tourniquet control. This debulking surgery may have to be repeated periodically at a minimum interval of 6 weeks to 3 months, depending on the entire size of the limb, until the shape and size are near normal. We have tried to employ the same skin for resurfacing without using a split-thickness skin graft. The remaining skin with subcutaneous tissues containing the subdermal lymphatics drains the reshaped limb and maintains the contour for a long time. Assistance is provided with a pressure garment, leg elevation, elimination of the focus of sepsis, and prevention of secondary infection by periodic, cyclic antibiotics such as penicillin, doxycycline, and quinolones (ciprofloxacin, ofloxacin, and others), depending on patient sensitivity and the sensitivity pattern of the drug. The outcome of debulking surgery depends on rigidly sequenced preoperative preparation and postoperative follow-up, with the recommendations discussed previously.16 If a patient does not follow the postoperative instructions meticulously, secondary infection often develops. Secondary infection leading to lymphangitis and cellulitis is the main cause for the recurrence and progression of lymphedema. We have used this technique for 25 years with very good results, including maintenance of the shape and size of the limb in our long-term follow-ups. If a patient has recurrence or progression of lymphedema, a lymphoscintigram is performed to determine the status of the lymphatics, lymph nodes, and drainage. Most cases of recurrence are lymphangitis from

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noncompliance. We encourage these patients to meticulously follow the conservative, nonsurgical methods such as manual lymph drainage and complete decongestive therapy. Most patients improve with this therapy, and their original limb shape and size return. This is maintained with a pressure garment or bandages. Very few patients (5% to 6%) need a revision surgical procedure, for example, a repeat nodovenous shunt or a lymphaticovenous shunt. This debulking procedure is always done under tourniquet control to prevent blood loss, hematoma, and infection. The tourniquet can be used for up to 2 hours in the lower limb and 1 hour in the upper limb. Once the excision is completed, the tourniquet is released and hemostasis confirmed. The suction drain is left in place, and the wound is closed in layers.17 The incision is always made as a reverse hockey stick shape, on the medial side of the limb. The edges of the skin surface are confirmed to have good viability after excess skin is trimmed. We always try to use the same scar for subsequent reduction surgeries. The excision always stops short of the deep fascia. We never open the deep fascia, because it allows the muscle to bulge into the subcutaneous plane and complicates wound closure. It causes pain postoperatively and can block the suction drains. Complications  Very few complications occur with this surgery. They include the following: • Lymphorrhea • Lymphocele • Wound dehiscence • Hemorrhage Although several morbidities are possible, mortality has not been reported from these surgical procedures. A good preoperative assessment and preparation helps to prevent most unwanted complications postoperatively. In many of the centers where debulking surgery is performed for lymphedema, it is always undertaken as a secondary procedure, after a lymphatic drainage procedure is performed, as described previously.

Other Debulking Procedures Charles’s excision is another debulking procedure that has been performed for a long time (see Chapter 31). The lymphedematous tissue (skin and subcutaneous tissue, including the deep fascia) is excised circumferentially, and a split-thickness skin graft is used to cover the raw area. Because no subdermal plexus is available for drainage and the split-thickness skin graft adheres to the muscle, it produces much worse edema distal to the excision, usually in the foot. This procedure is not commonly performed today because of the bottleneck deformity and unaesthetic outcome. Kondolean’s excision is technically similar to the Charles procedure and is not often performed.16,18 Thompson’s procedure was claimed to be a physiologic procedure, because the deepithelialized dermal flap is buried under the opposite skin flap and sutured in two layers.19 The disadvantage of this procedure is that if the dermal flap is sutured as a deeper layer necroses, then the skin closure will not heal. Therefore the flaps need to be reopened and the necrosed skin flap salvaged. Skin coverage is then provided. This causes morbidity to the affected limb and prolongs healing time. Currently a multiple-stage process consisting of a microvascular lymphatic drainage procedure, a simple elliptical excision, and maintenance by conservative multimodality therapies such as periodic antibiotics, regular foot hygiene, complete decongestive therapy, and pressure garments

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provides the most acceptable long-term results. The newer techniques and microvascular surgery play a crucial role in management for more acceptable functional and cosmetic results.

Lymphosuction A number of studies have evaluated the use of liposuction for breast cancer–related upper extremity lymphedema. Brorson and Svensson20 prospectively followed patients and reported overall favorable results. The authors have, however, reported on the use of lymphosuction in the treatment of chronic lymphatic filariasis of long duration. Lymphosuction has been found to be a useful treatment modality for mild to moderate grade II lymphedema, with satisfactory results21 (see Chapter 32).

Flap Interposition In 1950 Gillies22 described the first flap interposition for treatment of lower extremity lymphedema through a two-stage operation in which a flap of skin and subcutaneous tissue was transferred from the arm to the affected groin. This provided a path for lymphatic fluid to bypass the damaged lymphatics in the groin. The procedure, however, was associated with a high incidence of complications when carried out by other surgical groups; therefore it is rarely performed today.

Free Muscle and Myocutaneous Flaps The free latissimus dorsi island myocutaneous flap has been used extensively for reconstruction after mastectomy. The bilateral transverse rectus abdominis myocutaneous flap is also used as free flap for the treatment of upper limb lymphedema. In this era of supermicrovascular surgery, surgeons in Spain and Belgium have tried anastomosing the artery, vein, and the lymphatics at the same time as the mastectomy, followed by reconstruction. They have proved that this can prevent postmastectomy lymphedema. Gracilis muscle and myocutaneous flaps have also been used in similar techniques to prevent lower limb lymphedema.23

Lymph Node Transfer In lymph node transfers, healthy lymph nodes are harvested and transplanted either to the original site of injury or to nonanatomic areas within the lymphedematous limb. The transplantation is performed by simply mincing the lymph nodes and delivering them to the site as an avascular graft or by transferring a vascularized tissue in which the lymph nodes and surrounding fat are intact, repairing their arterial and venous blood supply microsurgically.24 However, the risk of lymphedema in the donor extremity is a concern. Therefore such transfers have not been widely accepted (see Chapter 36)

Lymphaticovenous Bypass Procedures have been described to drain obstructed lymphatic vessels into the venous circulation by surgically creating lymphaticovenous shunts. Initially, these shunts were created using large superficial veins as the outlet vessels; however, venous hypertension with resultant decreased lymphatic outflow led to the use of subdermal venules.25 In India use of this technique is limited, because individuals with lymphatic filariasis typically present at a late stage.

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Nodovenous Shunt In 1963 Nielubowicz et al26 developed nodovenous anastomosis27-29 in lymphedema produced artificially in dogs. The procedure was carried out in various parts of world in humans with lymphedema, with positive outcomes. It has become a surgery of choice in early lymphedema in some centers and in patients with elephantiasis and is performed before cytoreduction or debulking procedures. Nodovenous anastomosis is a more physiologic procedure and is very useful in patients with a deformity or disease of the afferent lymphatics (for example, lymphatic filariasis, posttraumatic lymphedema, and postinflammatory lymphedema).30 However, it is not useful in the absence of lymphatics and lymph nodes (for example, after mastectomy or radiotherapy or for congenital lymphedema). Thus the procedure is not very popular in Europe, even though it was first developed there.

Indications Indications for a nodovenous shunt include the following: • Patients with a competent saphenofemoral junction • Patients without inguinal abscess or sepsis • All grades of lymphedema (according to the International Society of Lymphology stages) • A healthy and functioning lymph node or lymph nodes (determined with lymphoscintigraphy or ultrasonography)

Contraindications Contraindications to nodovenous shunt procedures include the following: • No visible lymph node on lymphoscintigraphy or ultrasonography • Associated varicose veins or saphenofemoral incompetence • No reduction of circumferential measurements of the leg at any given point, even after 6 days of manual lymph drainage • Acute adenolymphangitis • Elderly and debilitated patients • Associated medical comorbidities Two methods of anastomosis have been described: end-to-end and end-to-side.

End-to-End Anastomosis A nodovenous shunt for lower limb lymphedema is performed with the patient under general or regional anesthesia and placed in a supine position. A vertical 3 cm incision is made in the upper part of the thigh, just medial to the femoral pulsations, and the long saphenous vein (or another good-caliber vein) is exposed. The distal end is ligated with chromic catgut, and the upper end is opened in the shape of a fish mouth. The proximal segment should have no retrograde flow, confirming that saphenofemoral incompetence is not present. A vertical group of inguinal lymph nodes is identified. These nodes must be pink and at least 1 cm in diameter.31 No dissection is performed around the lymph nodes to preserve afferent and efferent lymphatics. The upper capsule of the lymph nodes is shaved. Lymph will ooze from the cut surface. Diathermy should not be used. Bipolar diathermy causes less damage and can be used if the area needs to be sealed.

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A

B

FIG. 15-7  Nodovenous bypass. A, Endto-end. B, End-to-side.

The proximal, cut end of the long saphenous vein is anastomosed to the cut surface of capsule of the node using 6-0 or 7-0 nylon continuous sutures (Fig. 15-7). Hemostasis is confirmed, and the wound is closed in layers. No drain is placed.

End-to-Side Anastomosis Alternatively, a nodovenous shunt can be performed in end-to-side fashion. Vascular clamps are applied to the vein both proximally and distally. A No. 11 blade is used to make a vertical stab incision of 0.5 to 1 cm, depending on the vein caliber, in the surface adjoining the lymph node. The cut surface of the node is anastomosed with the vertical stab incision of the vein using 8-0 nylon interrupted sutures.28,32-34 Clamps are released, and the vein is observed for filling. The anastomosis site is continuously irrigated with heparinized saline to prevent clot formation, which is common in this technique. If a healthy or adequate-sized lymph node cannot be identified in the inguinal region, multiple lymphatic channels can be buried along the length of the vein at three or four sites. Stab incisions are made in the vessel using an 18-gauge needle. The open end of the lymphatics are left to float in the venous lumen. The lymphatic vessels are anchored with 8-0 nylon single, interrupted sutures.

Complications Complications of nodovenous shunts include the following: • Seroma • Lymphorrhea • Lymphocele • Wound dehiscence

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Lymphatic-Lymphatic Anastomosis Lymphatic-lymphatic anastomosis is commonly performed to bridge the anatomic discontinuity in patients with congenital lymphedema. This method is useful for lymphedema that develops after a mastectomy. The lymphatics are harvested from the normal lower limb thigh segments. Multiple lymphatic channels are anastomosed with the upper and lower end of the normal lymphatics to bridge the absent lymphatics. An operating microscope with 123 to 143 magnification is used, as with other microsurgical procedures.35-39 We prefer to use 10-0 nylon suture.

Free Omental Transfer Free omental transfer is useful for lymphatic filariasis40 and posttraumatic and postoperative lymphedema. In lymphatic filariasis with lower limb lymphedema, a vertical upper thigh midline incision is made. The long saphenous vein, the superficial circumflex iliac artery, and the inguinal lymph nodes or lymphatics are exposed and prepared for microvascular anastomosis. The abdomen is opened with a lower transverse incision. The omentum is dissected with its artery, vein, and lymphatics, which can be anastomosed with the respective vessels. During the closure of the thigh incision, a small window is left open for assessing the viability of the omentum. The window can be closed secondarily. Hemostasis is confirmed, and the abdomen is closed in layers. The tunneling of omentum into the inguinal region (omentoplasty)41 was initially popular with Russian surgeons for management of various types of lymphedema. Because the continuity of the omentum was maintained, the incidence of lymphangitis of the leg increased, leading to peritonitis. The technique was subsequently abandoned. Surgery for lymphedema should not cause mortality. A certain percentage of morbidity is acceptable if patients’ overall condition improves.

Conclusion Intensive, well-planned, and sequenced conservative treatment of outpatients with all grades of lymphedema can produce significant reduction in the volume of the edema over a short time, even in the most advanced stages of the disease. The frequency of attacks of episodic adenolymphangitis is not related to the administration of specific antibiotics or diethylcarbamazine; for the most part, it is controlled by simple hygienic measures combined with good limb and foot care and the application of a local antibiotic or antifungal cream. If performed appropriately, these measures are effective in reducing the number of acute dermatoadenolymphangitis attacks. Surgical treatment comprising direct excision with skin grafting offers the best hope for patients who are refractory to conservative medical management. Secondary lymphedema is common in developing countries because of filarial worm infestations. Lymphatic filariasis, though not curable completely, can be treated. Morbidity can be managed and aesthetic results obtained. Future treatment in large part will depend on current and upcoming developments in surgical techniques.

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C linical P earls • Early, aggressive treatment in chronic lymphatic filariasis is essential for satisfactory results. • Lymphoscintigraphy is the most helpful modality for establishing a diagnosis and for assessing the effectiveness of treatments. • Cases of recurrence after debulking are typically lymphangitis from noncompliance, most of which are effectively treated with meticulous nonsurgical methods. • Deep fascia should not be opened in debulking procedures. • Surgical treatment comprising direct excision with skin grafting offers the best hope for patients who are refractory to conservative medical management. • Nodovenous shunt procedures are most useful in patients with diseases of the afferent lymphatics but are not effective in the absence of lymphatics and lymph nodes.

ACKNOWLEDGMENT Dr. Manokaran would like to thank all of his patients who made this study possible. He would also like to thank Drs. V. Rajmohan and K. Haripriya (research scholar), who have contributed to his work at various times. Drs. Agarwal would like to gratefully acknowledge the help of Professor Ramesh Chandra in proofreading the manuscript and Professor Padam K. Agarwal in helping with the histopathologic interpretation of the tissue specimens.

R EFERENCES 1. Shenoy RK. Clinical and pathological aspects of filarial lymphedema and its management. Korean J Parasitol 46:119-125, 2008. 2. Pani SP, Yuvaraj J, Vanamail P, et al. Episodic adenolymphangitis and lymphedema in patients with bancroftian filariasis. Trans Roy Soc Trop Med Hyg 89:72-74, 1995. 3. Kumaraswami V. The clinical manifestations of lymphatic filariasis. In Nutman TB, ed. Lymphatic Filariasis. London: Imperial College Press, 2000. 4. Shenoy RK, Kumaraswami V, Suma TK, et al. A double-blind, placebo-controlled study of the efficacy of oral penicillin, diethylcarbamazine or local treatment of the affected limb in preventing acute adenolymphangitis in lymphedema caused by brugian filariasis. Ann Trop Med Parasitol 93:367-377, 1999. 5. Suma TK, Shenoy RK, Varghese J, et al. Estimation of ASO titer as an indicator of streptococcal infection precipitating acute adenolymphangitis in brugian lymphatic filariasis. Southeast Asian J Trop Med Pub Health 28:826-830, 1997. 6. Shenoy RK, Sandhya K, Suma TK, et al. A preliminary study of filariasis related acute adenolymphangitis with special reference to precipitating factors and treatment modalities. Southeast Asian J Trop Med Public Health 26:301-305, 1995.

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7. Khanna NN, Joshi GK. Elephantiasis of female genitalia: case report. Plast Reconstr Surg 48:379-381, 1971. 8. Taylor R, Jayasinghe UW, Koelmeyer L, et al. Reliability and validity of arm volume measurements for assessment for lymphedema. Phys Ther 86:205-214, 2006. 9. Yuan Z, Chen L, Luo Q, et al. The role of radionuclide lymphoscintigraphy in extremity lymphedema. Ann Nucl Med 20:341-344, 2006. 10. Calnan JS. New concepts of the function of the lymphatic system in the swollen leg. Sci Basis Med Annu Rev 349-364, 1971. 11. Thompson N. The surgical treatment of chronic lymphoedema of the extremities. Surg Clin North Am 47:445-503, 1967. 12. Manokaran G. Management of genital manifestations of lymphatic filariasis. Ind J Urol 21:39-43, 2005. 13. Modolin M, Mitre AI, da Silva JC, et al. Surgical treatment of lymphedema of the penis and scrotum. Clinics (São Paulo) 61:289-294, 2006. 14. Morey AF, Meng MV, McAninch JW. Skin graft reconstruction of chronic genital lymphedema. Urology 50:423-426, 1997. 15. Handley WS. Hunterian lectures on the surgery of the lymphatic system. Br Med J 1:922-928, 1910. 16. Kondoleon E. Die operative Behandlung der elephantiastichen Oedeme. Zentralbl Chir 39:1022, 1912. 17. Larson DL, Coers CR, Doyle JE, et al. Lymphedema of the lower extremity. Plast Reconstr Surg 38:293301, 1966. 18. Servelle M. Surgical treatment of lymphoedema: a report on 652 cases. Surgery 101:485-495, 1987. 19. Sawhney CP. Evaluation of Thompson’s buried dermal flap operation for lymphoedema of the limbs: a clinical and radioisotopic study. Br J Plast Surg 27:278-283, 1974. 20. Brorson H, Svensson H. Liposuction combined with controlled compression therapy reduces arm lymphedema more effectively than controlled compression therapy alone. Plast Reconstr Surg 102:10581067; discussion 1068, 1998. 21. Agarwal R, Bhatnagar SK, Chandra R. Lymphosuction: a new treatment modality for chronic filarial lymphedema. Eur J Plast Surg 21:113-117, 1998. 22. Gillies H. The lymphatic wick. Proc R Soc Med 43:1054-1056, 1950. 23. Handley WS. Lymphangioplasty: a new method for the relief of the brawny edema of breast cancer and for similar conditions of lymphatic oedema: preliminary note. Lancet 1:783-785, 1908. 24. Lin CH, Ali R, Chen SC, et al. Vascularized groin lymph node transfer using the wrist as a recipient site for management of postmastectomy upper extremity lymphedema. Plast Reconstr Surg 123:12651275, 2009. 25. Huang GK, Hu RQ, Liu ZZ, et al. Microlymphaticovenous anastomosis in the treatment of lower limb obstructive lymphedema. Analysis of 91 cases. Plast Reconstr Surg 76:671-685, 1985. 26. Nielubowicz J, Olszewski W, Sokolowski J. Surgical lympho-venous shunts. J Cardiovasc Surg 9:262267, 1986. 27. Gloviczki PJ, Hollier LH, Nora FE, et al. The natural history of microsurgical lymphovenous anastomoses: an experimental study. J Vasc Surg 4:148-156, 1986. 28. Gloviczki PJ, Fisher J, Hollier LH, et al. Microsurgical lymphovenous anastomosis for treatment of lymphedema: a critical review. J Vasc Surg 7:647-652, 1988. 29. Olszewski WL. The treatment of lymphedema of the extremities with microsurgical lympho-venous anastomoses. Int Angiol 7:312-321, 1988. 30. Damstra RJ, Voesten HG, van Schelven WD, et al. Lymphatic venous anastomosis (LVA) for treatment of secondary arm lymphedema. A prospective study of 11 LVA procedures in 10 patients with breast cancer related lymphedema and a critical review of the literature. Breast Cancer Res Treat 113:199-206, 2009. 31. O’Brien BM, Mellow CG, Khazanchi RK, et al. Long-term results after microlymphaticovenous anastomoses for the treatment of obstructive lymphedema. Plast Reconstr Surg 85:562-572, 1990.

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32. Huang GK. [Results of microsurgical lymphovenous anastomoses in lymphedema: report of 110 cases] Langenbecks Arch Chir 374:194-199, 1989. 33. Yamamoto Y, Sugihara T. Microsurgical lymphaticovenous implantation for the treatment of chronic lymphedema. Plast Reconstr Surg 101:157-161, 1998. 34. Zolotorevskiĭ Vla, Savchenko TV, Chernysheva LM, et al. [Late results of lymphovenous anastomoses in lymphedema of the lower extremities] Khirurglia (Mosk) 5:96-101, 1990. 35. Campisi C, Boccardo F. Lymphedema and microsurgery. Microsurgery 22:74-80, 2002. 36. Campisi C, Boccardo F. Microsurgical techniques for lymphedema treatment: derivative lymphaticvenous microsurgery. World J Surg 28:609-613, 2004. 37. Campisi C, Davini D, Bellini C, et al. Lymphatic microsurgery for the treatment of lymphedema. Microsurgery 26:65-69, 2006. 38. Campisi C, Eretta C, Pertile D, et al. Microsurgery for treatment of peripheral lymphedema: long-term outcome and future perspectives. Microsurgery 27:333-338, 2007. 39. Clodius L, Piller NB, Casley-Smith JR. The problems of lymphatic microsurgery for lymphedema. Lymphology 14:69-76, 1981. 40. Goldsmith HS, De los Santos R, Beattie EJ Jr. Relief of chronic lymphedema by omental transposition. Ann Surg 166:572-585, 1967. 41. Silver D, Puckett CL. Lymphangioplasty: a ten year evaluation. Surgery 80:748-755, 1976.

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C hapter 16 Lymphedema in Pediatric Patients Cristobal Miguel Papendieck

K ey P oints • Pediatric lymphedema is a chronic, impairing, progressive disorder. • Each age group within the pediatric range has its specific and distinguishing issues and needs. • Comprehensive, multifaceted holistic treatment and management produce the best outcomes. • A constant in the treatment of primary and secondary lymphedemas in pediatric patients is appropriate and adequate vascular rehabilitation. • If a surgical option is considered, the most common one is lymphovenous anastomosis.

Lym Lymphedema, regardless of form and location, is a condition that has a low profile in the literature despite its prevalence; it is an orphan in the medical and pediatric world, even though one third of the lymphedema in the world affects pediatric populations (0 to 14 years).1-9 It is important to note that a primary lymphedema patient may have an expectation of 80-year survival, whereas survival for individuals with secondary lymphedema is estimated to be only approximately 20 years. This means a longer burden on the patient, the family, the health care system, and society if the lymphedema is not recognized, treated, and managed appropriately in the very early stages. Furthermore, serious life-threatening side effects of chronic lymphedema, such as Stewart-Treves syndrome,9 may occur more frequently in the primary lymphedema group because of its duration and severity, but there are no statistics regarding this. Primary lymphedema is expressed in pediatric patients as congenital, although it is not always known or identified at birth because of a lack of awareness of its possibility or a lack of screening for it.8 One or both lower limbs are the most frequently involved initially (Fig. 16-1), but the condition may present in any part of the body. It is thought to be the result of underdevelopment of the superficial lymphatic system, which results in the presence of abnormally high levels of proteins and tissue fluids in the interstitial space. Exploration of the underlying genetic causes of certain types of primary lymphedema is helping researchers identify and understand previously unrecognized syndromes. 235

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FIG. 16-1  Primary lymphedema in the foot of a newborn. The Stemmer sign in this infant was positive and the pitting test negative.

For primary lymphedemas (as well as secondary ones), distribution around the world is varied not only in terms of incidence and cause but also in the availability of the means for early and accurate diagnosis (sometimes lymphedema is not recognized until a vigilant therapist is consulted), the priority it is given, individual sociocultural status, and access to specialist treatment and management centers.

Diagnosis of Lymphedema in Pediatric Patients Lymphedema (a swelling of the affected area) in pediatric patients is a sign—not a symptom. It is a sign of a disorder or malformation of some section of the lymphatic system.10 It indicates the lymphatic system’s inability to evacuate and transport its specific fluid load (and its contents), which a healthy lymphatic system is supposed to return from the interstitial spaces to the truncal venous system. The interstitial space is where lymph is produced and where all solutes originate that will eventually drain into the venous system. Lymph is an indispensable necessity for vertebrate life.11 Any incompetence of the venous system for carrying its volume generates a potential overload in the lymphatic system, which is known as phlebolymphedema. The regulating mechanism of lymph formation is an activity that obviously never equals zero: lymph is “lymph” only when it enters the lymphatic system precapillaries; before that it is interstitial fluid with two pathways available for its removal, the lymphatics and the venous system. All lymphedemas have interstitial but not necessarily lymphatic hypertension. Lymphatic hypertension is common in secondary noninflammatory lymphedemas, but not in primary lymphedemas. This knowledge is very important when making therapeutic decisions, because a surgically created lymphovenous shunt works best if there is no pressure gradient between the venous and lymphatic systems. The part of the lymphatic system that is very important but which we do not talk about very often is that which transports chyle between the jejunum-ileum and the Pecquet cistern, and then as mixed lymph to the exit of the thoracic duct at the left shoulder (Fig. 16-2).

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FIG. 16-2  Chylous reflux (chyle and systemic lymph) seen during surgery on a primary lymphedema.

TABLE 16-1   Causes of Primary Lymphedema Cause

Description

Interstitial

Malfunctioning/dysplasia/hypoplasia of the interstitial lymphatic “endothelial” segment. As with all lymphedemas, this subgroup has only interstitial hypertension and no vessel hypertension or overload because lymph cannot be formed; substances normally transported in the lymph cannot enter the circuit. Essentially, this situation depends on the vascular endothelial growth factors and receptors related to this endothelial segment. Three well-known and identified mutations fall within this group: • VEGFR-3 Milroy disease14 OMIM 154100 • FOXC2 Lymphedema-distichiasis syndrome15,16 • SOX18 Hypotrichosis-lymphedema-telangiectasia syndrome OMIM 60782317

Canalicular (lymphatic vessel)

Lymphangiodysplasias (LAD I): dysplasia of the lymphatic vessels

Nodal

Lymphadenodysplasias (LAD II): dysplasia of the lymph nodes

Eventually both forms of lymphangiodysplasias above together lead to LAAD, lymphangioadenodysplasias.

Primary and Secondary Lymphedema in Pediatric Patients Primary Lymphedema Primary lymphedema is any lymphedema associated with an intrinsic or primary malfunction of the lymphatic system in all or one of the three hemicircuits, as described in Table 16-1. This may be because of interstitial issues such as fibrosis, malformations of the lymphatic vessels or nodes.12 Interestingly it now seems likely that many apparently secondary lymphedemas may have an underlying primary component.13 This is something we need to consider in the future in terms of early identification and anticipation of such problems (Fig. 16-3).

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FIG. 16-3  Primary lymphedema on the upper limb of a newborn. Stemmer sign positive, pitting test negative.

Hypoplasia of the lymphatic system, or hyperplasia or agenesis, either canalicular (lymph vessel) or of the lymph nodes (nodal), is not correctly called dysplasia unless it involves a short or regional system segment. In our experience, hypoplasias or hyperplasias occur more frequently than indicated in the literature about primary lymphedema. The same is true for hypotrophy. What is important to note is that the number and/or size of vessels or lymph nodes does not guarantee functionality or functional quality. Many agenesis-induced lymphedemas actually have hyperplasia of many lymph vessels. Not all dysplasias are enough to account for primary lymphedema. What is more, some dysplasias are never associated with lymphedema per se; for example, macrocystic lymphangiomas and cystic hygromas. Thus lymphedema in pediatric patients is a chronic, impairing, progressive disorder. This chronicity has, as also occurs in secondary lymphedemas, a regional lipogenic effect.18,19 We have much to learn and many problems to solve in terms of our knowledge of the underlying issues of the formation of the lymphatic system and of the treatment of it, especially in pediatric cases.

Syndromes Associated With Primary Lymphedema There are approximately 144 syndromes associated with primary lymphedema (Fig. 16-4).20 Among them, 22 are inherited with lymphatic malformations. Box 16-1 lists some of these conditions.21-44 In addition, primary lymphedemas can be caused by malformation (LAD I and II), with or without chylous reflux, and can occur in combined angiodysplastic syndromes, as follows: • Klippel-Trenaunay-Weber syndrome: Nevus, port-wine stain, varicose veins, osteohypertrophy, overgrowth, micro AV shunts45 • Klippel-Trenaunay-Servelle syndrome: Port-wine stain, varicose veins, osteohypertrophy, overgrowth, truncular venous malformation46,47 • F.P. Weber syndrome: Port-wine stain, macro AV shunt, osteohypertrophy, overgrowth48

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• Proteus syndrome: Tridermal and trisystemic vascular anomalies, overgrowth49,50 • CLOVES: Congenital lipomatous overgrowth, vascular malformation, epidermal nevi, primary or secondary scoliosis51 • N1 and N2 syndromes, including Von Recklinghausen syndrome: Neurofibromatosis, Gorrham-Stout-Haferkamp syndrome,52-54 intraosseous lymphangioma

A B

FIG. 16-4  Pediatric patients with primary lymphedema with A, Kasabach Merritt syndrome, and B, neurofibromatosis.

BOX 16-1  Syndromes That Can Occur With Primary Lymphedema Yellow nail syndrome Opitz syndrome Noonan syndrome Turner syndrome PEHO syndrome Aplasia cutis Bronspiegel syndrome Carbohydrate-deficient glycoprotein syndrome Cerebellar hypoplasia Lissencephaly Choanal atresia Cholestasis Aagenaes syndrome Lymphangiectasia Skeletal dysplasia Wässer syndrome Persistent Müllerian duct syndrome Polydactyly

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Cerebral AV malformations Avasthey syndrome Cleft palate Figueroa syndrome Hypoparathyroidism Dahlberg syndrome Leukemia-deafness Emberger syndrome Microencephaly Chorioretinopathy Microcephaly Cutis gyrata Mental retardation Müke syndrome Facial dysmorphia Aortic coarctation Nevo syndrome Hennekam syndrome

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Secondary Lymphedema Secondary lymphedema in pediatric patients can occur from a range of causes and situations, including the following: 1. Parasitic lymphedemas (filariasis). The most frequent and aggressive filaria that causes lymphedema is Wuchereria bancrofti. This worm may be as long as 11 cm and may block the lymph node system in any part of the body, but the nodes most affected are those draining the area related to the biting preferences of the mosquito. The host is human; the vector is the female Anopheles mosquito that inoculates microfilaria through its bite and capillary aspiration. Microfilaria larvae are deposited on the skin of the next carrier 24 to 96 hours after the parasite’s metamorphosis. The population at risk is about 1200 million inhabitants, mainly on the Equatorial belt, 30% of whom are children in the 0 to 14 age group. The infected population is more than 120 million, with an estimated 70 million with clinically manifest lymphedema.55 2. Podoconiosis.56,57 This is a regional disease in tropical volcanic farming areas at elevations lower than 1200 meters (because of the temperature and the conditions of work of the farmers who are most often limited to this area). The most affected country is Ethiopia.58 Podoconiosis involves the lower limbs as a result of the plantar absorption of volcanic minerals, which are often rich in silica. Most often it involves a nodal block at the groin.59 3. Phlebolymphedema. This lymphedema results from a truncular venous malformation60,61 with chronic venous hypertension. It is frequently associated with congenital lymphangioadenodyplasia. This is possibly the most frequent nonparasitic secondary lymphedema presentation in pediatric patients. It may be observed in big angiodysplastic syndromes (BAS)62 combined, such as Klippel-Trenaunay-Weber63,64 Servelle,65 Proteo,66,67 and CLOVES68 syndromes and others. 4. Trauma-induced lymphedemas. • Direct trauma, generally soft tissue related (but that later form scars) within and around the lymphatic/vascular systems. • Indirect trauma, inadequate vascular access, radiotherapy, surgery. • Infections, mainly specific and chronic infections such as tuberculosis (Koch bacillus), Calmette-Guerin bacillus, and brucellosis or Malta fever (Brucella melitensis). 5. “Puffy hand” caused by frequent vascular access associated with drug abuse and overuse, which most frequently occurs at the left elbow fold. 6. Side effects and the interaction of medications (chronic anticonvulsant therapy, hormonal medications). 7. Hair tourniquet syndrome.69 8. Amniotic band syndrome.70 9. Collagen disorders.

Treatment of Lymphedema in Pediatrics A constant in the treatment of primary and secondary lymphedemas in pediatrics is adequate vascular rehabilitation. To this end, we consider it essential to follow the clearly established guidelines of the international consensus documents of the International Society of Lymphology (ISL), the International Lymphedema Framework (ILF), and the Latin American Consensus about Lymphedema (LA). We use Vodder’s technique and follow Földi’s method. For bandaging, we use the

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multilayer system, with tailor-made soft compression nonelastic or low elastic supports. Skin care is an essential aspect of holistic care for these children. Sequential pumps are not generally used because of the small size of patients’ limbs and relatively large compartment size of the pumps, and because the pressures applied by these devices may be too high given the small circumference of the limbs in young patients.

General Considerations Care of pediatric patients is different and often more complex than that of adult patients. Newborns, infants, young children, and those approaching puberty each have their specific and distinguishing issues and needs.71,72 Unfortunately, relatively little attention has been focused in the literature on the specific care requirements of these children. Pediatric patients require more time, a dedicated health care space, specific psychophysical considerations, and a regard for the complex social aspects of lymphedema in a young person. We use the Porot test73 to determine the patient’s family inclusion, and the free drawing test to interpret psychosocial commitment. We take into consideration other relevant social aspects such as employment, schooling, distances from care facilities, the necessary parental commitment, costs, and the time factor associated with parental involvement. It is important to consider that the mother and father are often young when they suddenly face the diagnosis of such an unexpected and significant disorder in their child. The ongoing nature of treatment for these children can compromise the couple’s relationship and stability, leading to social and relationship issues. It may be useful to encourage involvement in pediatric patient group meetings through which patients and families are brought together who have a similar evolution and similar social and cultural status, the latter being particularly important. When secondary lymphedemas occur, they require specific medical and surgical therapies. For instance, to prevent erysipelas, we always prescribe antibiotics for 1 year with follow-up, to be repeated every 3 years. All patients with lymphedema with lymphatic vessel hypertension in some or all segments may benefit from shunt surgery. This is recommended for pediatric patients with primary lymphedema if their lymphatic hypertension is of the nature described earlier. Thus primary “interstitial” lymphedemas are excluded, but shunt surgery can be beneficial in secondary lymphedema. Similarly, all patients with lymphedema with chylous reflux74-76 to the lower limbs benefit from this technique. Generally, the greater the reflux, the better the outcome. In terms of their role in pediatric secondary lymphedemas, each of these proposed techniques can be considered when appropriate, but their application does not depend solely on one’s training. These are procedures for a lifetime, which means that the significance of the other adjuvant therapies and what they can achieve in remediation of the condition may provide a guide for when they might be used as a supplement to them. As an example, liposuction of fatty tissue in secondary lymphedema,77 which requires elastic support for life, is a questionable approach in pediatric patients. Similarly, the use of techniques requiring local and prolonged anesthesia is not possible, particularly in the younger pediatric group; VEGF-R is not approved for pediatric patients. Terminoterminal or terminolateral anastomosis between lymph vessels or lymphatic venous anastomosis between a normal sectioned vessel is not the same as between anarchic or malformed vessels. Moreover, the caliber of children’s vessels is different, often smaller, than that of adults. We may

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often consider some form of vascular rehabilitation, but this cannot be the sole indication or care plan for the projected 80 years of a young patient’s life.

Surgery in Pediatric Cases In our experience, the most frequent surgical technique used is that proposed by Olszewski.78 but we do not exclude other techniques, such as those proposed by Campisi and colleagues.79-81 We use lymph node venous anastomosis, similar to that of Olszewski, for several reasons: it is not microsurgery, an anastomosis means the involvement in one step of several vessels, and in general, multiplicity of this anastomosis is generally possible. Other issues that should be taken into account include the difficulty of identifying malformed lymph nodes, the significance of the risk of inadequate healing, and venous hypertension, which is a frequent factor in combined angiodysplastic syndromes. Surgery is useful only if lymph nodes are not mobilized, anastomosis is lateral (sagittal), and the vein is a nearby collateral vessel with pressure equal to zero, if the venous end is protected by a normal pair of valves (so that there is no venous hypertension). This type of anastomosis means a very small wound site and ensures that a very small biopsy can be performed involving all nodal planes at the time of preparation for the anastomosis. This offers adequate information on the status or involvement of lymph nodes in these primary lymphedemas. If there is venous hypertension in the vessels near the proposed level of anastomosis, we first plan an appropriate shunt using Palma’s technique,82 or we create new circuits, as for the Cockett or May-Thurner syndrome,83 and then create a vein lymph node anastomosis as a second step. If high local venous pressure means the procedure is likely to turn out unsatisfactorily, we make a Palma shunt for the anastomosis between a lymph node and the contralateral internal saphenous vein.84 The advantage is that this requires only one suture. In an upper limb, we translocate an external jugular vein and any of its collateral vessels for the lymph node–vein anastomosis at the axilla,84 and eventually the internal jugular vein to lessen venous hypertension in the limb, performing an end-to-end anastomosis with the subclavian vein. All patients undergoing such a surgical procedure also receive manual lymphatic drainage as necessary, and during the daytime, customized soft compression nonelastic support and taping are applied. We use this alternative technique occasionally in cancer patients who have undergone radical surgery, and in some patients with Klippel-Trenaunay-Servelle syndrome with agenesia or extreme segmental hypoplasia of the subclavian vein.

Conclusion It seems that the best outcomes are gained in the treatment of pediatric lymphedema when we consider and use the clearly established guidelines of the international consensus documents. These can provide core recommendations that are then augmented by information from a comprehensive patient and family assessment.

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In all cases of pediatric lymphedema it is important to realize that the parents are young when they are told about this significant and unexpected disorder in their child. Care of a child with primary lymphedema is an ongoing process involving significant parent cooperation and the stresses attendant on this care can have a deleterious effect on the couple’s relationship, and family stability can become compromised. Often treatment and management needs to extend to the whole family, requiring interaction with and assistance from a wide range of health care professionals. Lymphedema in pediatric patients requires a treatment plan that is quite different from a regimen designed for adults, in large measure because the reasons for the condition are generally different. The dominant concerns in pediatric patients—malformations and truncular venous hypertension and all considerations on the subject of growth and lymphedema—are typical of childhood, and these young patients are faced with living with the disorder for approximately eight decades. Given the need for different therapeutic approaches, it is necessary to identify and group the different disorders (diseases or syndromes). We have much to learn about the underlying reasons for and consequences of lymphatic malformation and thus how we should target treatment.

C linical P earls • To achieve the best outcomes, a comprehensive objective and subjective assessment of the patient is essential and must include a full family history as its basis. • Pediatric lymphedema requires more time from the physician, a dedicated health care space, specific psychophysical considerations, and a regard for the associated complex social aspects of the lymphedema on patient and family dynamics. • Hypoplasias and hyperplasias occur more frequently than indicated in the literature about primary lymphedemas, and health care providers should be knowledgeable and prepared to recognize and treat these.

R EFERENCES 1. Papendieck CM. Linfedema en pediatría. Clasificacion y etiopatogenia. Rev Hosp Niños BAires 45(201):14-22, 2003. 2. WHO Expert Committee on Lymphatic Filariasis. 1983 FIL7EC7WWP782.23 TDR. 3. Bancroft J. Cases of filarious disease. Trans Pathol Soc (London) 29:407-410, 1878. 4. Niño FL. Parasitologia. Puebla, Mexico: JM Cajica Publisher, 1958. 5. Chernin E, Manson P. The transmission of filariasis. Am J Trip Med Hyg 261:1065-1070, 1977. 6. Manson P. Elephantiasis arabum in the South Sea Islands. Br Med J 1(1744):1186-1187, 1894. 7. Romaña C, Wygodzinsky P. Acerca de la transmisíon de la Mansonella ozzardi (Filaria tucumana) Biglioeri y Araoz. An Inst Med Reg 3:29-34, 1950. 8. Papendieck CM. Lymphatic dysplasias in paediatrics. A new classification. Intern Angiol 18:6-9, 1999. 9. Földi M, Földi E, eds. Földi’s Textbook of Lymphology for Physicians and Lymphedema Therapists, ed 3. St Louis: Mosby Elsevier, 2012. 10. Papendieck CM. Lymphangioadenodysplasias in paediatrics. Lymphology 29:27-29, 1996. 11. Földi M, Földi E, Kubik S. Lehrbuch der Lymphologie, ed 6. Munich: Elsevier, 2005.

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12. Papendieck CM. Lymphangioadenodysplasias. Presented at the Twenty-fourth Meeting of the European Group of Lymphology (GEL), Fifth Meeting of the Latin Mediterranean Chapter of the International Society of Lymphology, San Marco di Castellabate, Salerno, 1998. 13. Nikitenko L, Shimosawa T, Henderson S, et al. Adrenomedullin haploinsufficiency predisposes to secondary lymphedema. J Invest Dermatol 133:1768-1776, 2013. 14. Witte MH, Dellinger MT, Bernas M, Jones KA, Witte CH. Molecular lymphology and genetics of lymphedema: angiodysplasia syndromes. In Földi M, ed. Földi’s Textbook of Lymphology for Physicians and Lymphedema Therapists, ed 2. St Louis: Mosby Elsevier, 2006. 15. Moffatt C. International Consensus Best Practice for the Management of Lymphoedema. LF. MEP2006. 6-8. 16. Temple K. Distichiasis-lymphedema. Clin Dysmorphol 3:139-142, 1994. 17. Witte MH, Dellinger MT, Bernas MJ, et al. Molecular lymphology and genetics of lymphedema-angiodysplasia syndromes. In Földi M, Földi E, eds. Földi’s Textbook of Lymphology, ed 2. St Louis: Mosby Elsevier, 2006. 18. Brorson H, Ohlin K, Olsson G, et al. Adipose tissue dominates chronic arm lymphedema following breast cancer: an analysis using volume rendered CT images. Lymphat Res Biol 4:199-210, 2006. 19. Ryan TJ. Lymphatics and adipose tissue. Clin Dermatol 13:493-498, 1995. 20. Hennekam RCM. Lymphatic syndromic maldevelopment. Presented at the Fourth National Lymphedema Network (NLN) International Conference, Orlando, FL, 2000. 21. Nordkild P, Kromann-Andersen H, Struve-Christensen E. Yellow nail syndrome—the triad of yellow nails, lymphedema and pleural effusions. A review of the literature and a case report. Acta Med Scand 219:221-227, 1986. 22. Papendieck CM, Bergada C, Gruñeiro L. Noonan syndrome with generalized lymphangiectasia. Rev Hosp Niños BAires 62:20-22, 1974. 23. Calzada LR. Identificacion y Nanejo del Niño con Talla Baja: Sindrome de Ullrich Turner. Mexico: Intersistema, 2007. 24. Allanson JE. Noonan syndrome. J Med Genet 24:9-13, 1987. 25. Somer M. Diagnostic criteria and genetics of the PEHO syndrome. J Med Genet 30:932-936, 1993. 26. Bronspiegel N, Zelnick N, Rabinowitz H, et al. Aplasia cutis congenita and intestinal lymphangiectasia. An unusual association. Am J Dis Child 139:509-513, 1985. 27. Carchon H, Van Schaftingen E, Matthijs G, et al. Carbohydrate-deficient glycoprotein syndrome type IA (phosphomannomutase-deficiency). Biochim Biophys Acta 1455:155-165, 1999. 28. Dobyns WB, Patton MA, Stratton RF, et al. Cobblestone lissencephaly with normal eyes and muscle. Neuropediatrics 27:70-75, 1996. 29. Har-El G, Borderon ML, Weiss MH. Choanal atresia and lymphedema. Ann Otol Rhinol Laryngol 100:661-664, 1991. 30. Aagenaes O. Hereditary cholestasis with lymphoedema (Aagenaes syndrome, cholestasis-lymphoedema syndrome). New cases and follow-up from infancy to adult age. Scand J Gastroenterol 33:335-345, 1998. 31. Wässer ST, Beyreiss K, Himmel D, et al. Exsudative Enteropathie bei kongenitaler intestinaler lymphangiektasie mit multipler Skelettveränderung. Acta Paediatr Acad Sci Hung 15:17-25, 1974. 32. Urioste M, Rodríguez JI, Barcia JM, et al. Persistence of müllerian derivatives, lymphangiectasis, hepatic failure, postaxial polydactyly, renal and craniofacial anomalies. Am J Med Genet 47:494-503, 1993. 33. Avasthey P, Roy SB. Primary pulmonary hypertension, cerebrovascular malformation, and lymphoedema feet in a family. Br Heart J 30:769-775, 1968. 34. Figueroa AA, Pruzansky S, Rollnick BR. Meige disease (familial lymphedema praecox) and cleft palate: report of a family and review of the literature. Cleft Palate J 20:151-157, 1983. 35. Dahlberg PJ, Borer WZ, Newcomer KL, et al. Autosomal or X-linked recessive syndrome of congenital lymphedema, hypoparathyroidism, nephropathy, prolapsing mitral valve, and brachytelephalangy. Am J Med Genet 16:99-104, 1983.

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36. Emberger JM, Navarro M, Dejean M, et al. [Deaf-mutism, lymphedema of the lower limbs and hematological abnormalities (acute leukemia, cytopenia) with autosomal dominant transmission] J Genet Hum 27:237-245, 1979. 37. Crowe CA, Dickerman LH. A genetic association between microcephaly and lymphedema. Am J Med Genet 24:131-135, 1986. 38. Limwongse C, Wyszynski RE, Dickerman LH, et al. Microcephaly-lymphedema-chorioretinal dysplasia: a unique genetic syndrome with variable expression and possible characteristic facial appearance. Am J Med Genet 86:215-218, 1999. 39. Opitz JM, Reynolds JF, FitzGerald JM. Mandibulofacial dysostosis or bilateral hemifacial microsomia with hearing loss, telecanthus, tetramelic postaxial hexadactyly, congenital hypotonia and lymphedema with joint hypermobility, and pigmentary dysplasia: a new syndrome? Am J Med Genet 33:433-435, 1989. 40. Alexander IE, Tauro GP, Bankier A. Fetal brain disruption sequence in sisters. Eur J Pediatr 154:654657, 1995. 41. Cormier-Daire V, Lyonnet S, Lehnert A, et al. Craniosynostosis and kidney malformation in a case of Hennekam syndrome. Am J Med Genet 57:66-68, 1995. 42. Mücke J, Hoepffner W, Scheerschmidt G, et al. Early onset lymphoedema, recessive form—a new form of genetic lymphoedema syndrome. Eur J Pediatr 145:195-198, 1986. 43. Dumić M, Vukelić D, Cviko A, et al. Nevo syndrome. Am J Med Genet 76:67-70, 1998. 44. Hennekam RC, Geerdink RA, Hamel BC, et al. Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation. Am J Med Genet 34:593-600, 1989. 45. Klippel M, Trenaunay P. Du naevus variquex osteohypertrophique. Arch Gen Med 3:641-672, 1900. 46. Papendieck CM. Sindrome de Klippel Trenaunay Servelle en pediatria. Rev Arg Cirugia 64:42-44, 1993. 47. Papendieck CM, Barbosa ML, Pozo P, et al. Klippel-Trenaunay-Servelle syndrome in pediatrics. Lymphat Res Biol 1:81-85, 2003. 48. Weber FP. Haemangiectasic Hypertrophy of the Foot and Lower Extremity, Congenital or Acquired. London: Presse Med, 1918. 49. Wiedemann HR. The proteus syndrome. Eur J Pediatr 140:5, 1983. 50. Papendieck CM. El sindrome proteo en pediatria. Prensa Med Arg 85:348-351, 1998. 51. Gucev ZS, Tasic V, Jansevska A, et al. Congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) syndrome: CNS malformations and seizures may be a component of this disorder. Am J Med Genet A 146A:2688-2690, 2008. 52. Gorham WL, Stout PH. Massive osteolysis (acute spontaneous absorption of bone, phantom bone disease, disappearing bone). J Bone Joint Surg Am 37:985-1004, 1955. 53. Mulliken JB, Young AE. Vascular Birthmarks: Hemangiomas and Malformations. Philadelphia: WB Saunders, 1988. 54. Papendieck CM. Sindrome de Gorham Stout Haferkamp con reflujo de quilo. Rev Arg Cirugia 79:710, 2000. 55. Aupali T, Ismid IS, Wibowo H, et al. Evaluation of the prevalence of lymphatic filariasis. Trans R Soc Trop Med Hyg 100:753-759, 2006. 56. Price EW. Podoconiosis: Non Filarial Elephantiasis. The Elephantiasis Story, 1-6. Oxford, UK: Oxford Medical Publications, 1990. 57. Dewa G, Tekola F, Newport MJ. Podoconiosis, non-infectious geochemical elephantiasis. Trans R Soc Trop Med Hyg 101:1175-1180, 2007. 58. Price EW. Podoconiosis: The Geographical Distribution of Endemic Podoconiosis, 15-19. Oxford, UK: Oxford Medical Publications, 1990. 59. Price EW. Podoconiosis: Pathogenesis and Pathology, 61-84. Oxford, UK: Oxford Medical Publications, 1990. 60. Kluken N. Documenta Angiologorum Vol XXIII. Curatorium Angiologiae Internationalis Ratschow Award 1993: Papendieck CM. Zur Bedeutung der Hypertension des Venen Systems im Kindesalter, 6-16, 1993.

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61. Servelle M. Pathologie Vasculaire. Les Affections Veineuses. Malformations Congenitales des Veines des Members. Paris: Mason et Cie, 1978. 62. Papendieck CM. The big angiodysplastic syndromes in pediatrics with the participation of the lymphatic system. Progress in Lymphology XVI. Lymphology 31(Suppl):390-392, 1998. 63. Berry SA, Pearson C, Mize W, et al. Klippel-Trenaunay syndrome. Am J Med Genet 79:319-326, 1998. 64. Papendieck CM. Angiodysplasias in Pediatrics: Klippel-Trenaunay Syndrome. Buenos Aires, Argentina: Médica Panamericana, 1988. 65. Papendieck CM. Pediatric Angiology: Klippel-Trenaunay-Servelle Syndrome. Buenos Aires, Argentina: Médica Panamericana, 1992. 66. Wiedemann HR, Burgio GR, Aldenhoff P, et al. The proteus syndrome. Partial gigantism of the hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anomalies and possible accelerated growth and visceral affections. Eur J Pediatr 140:5-12, 1983. 67. Papendieck CM. El syndrome proteo en pediatria. Prensa Med Arg 85:348-351, 1998. 68. Sapp J, Turner J, Van de Kamp JM, et al. Newly delineated syndrome of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome) in seven patients. Am J Med Genet A 143A:2944-2958, 2007. 69. Földi M, Földi E. The hair tourniquet syndrome in the newborn. In Földi M, ed. Földi’s Textbook of Lymphology for Physicians and Lymphedema Therapists, ed 2. St Louis: Mosby Elsevier, 2006. 70. Benson CD, Mustard WT, Ravitch MM, et al. Cirugía Infantil [Pediatric Surgery] 2:1267-1268, 1967. 71. Karlberg J, Engstrom I, Karlbeg P, et al. Analysis of linear growth using a mathematical model. I. From birth to three years. Acta Paediatr Scand Suppl 76:478-488, 1987. 72. Karlberg J, Fryer J, Engstrom I, et al. Analysis of linear growth using a mathematical model. II. From 3 to 21 years of age. Acta Pediatr Scand Suppl 337:12-29, 1987. 73. Laguado Acevedo D, Villanueva N, Gonzalez D, et al. Integracion psicosocial de sindromes angiodisplasicos combinados en pediatria. Presented at the Thirty-ninth Congress of the European Society of Lymphology, Valencia, Spain, June 2013. 74. Bellini C, Ergaz M, Radicioni I, et al. Congenital fetal and neonatal visceral chylous effusions: neonatal chylothorax, and chylous ascites revisited. A multicenter retrospective study. Lymphology 45:91-102, 2012. 75. Boccardo F, Campisi C, Molinari L, et al. Diagnosis and treatment of chylous disorders. EJLRP 65:1519, 2012. 76. Servelle M, Nogues C. The Chyliferous Vessels. Paris: Expansion Scientifique Francaise, 1981. 77. Brorson H. Liposuction gives complete reduction of chronic large arm lymphedema after breast cancer. Acta Oncol 39:407-420, 2000. 78. Olszewski WL. Microsurgical lymphovenous anastomosis after 45 years’ follow up and indications. Presented at the Thirty-eighth Congress of the European Society of Lymphology, Berlin, June 2012. 79. Campisi C, Bellini C, Campisi C, et al. Microsurgery for lymphedema: clinical research and long-term results. Microsurgery 30:256-260, 2010. 80. Campisi C, Boccardo F. Microsurgical techniques for lymphedema treatment: derivative lymphaticvenous microsurgery. World J Surg 28:609-613, 2004. 81. Campisi C, Da Rin E, Bellini C, et al. Pediatric lymphedema and correlated syndromes: role of microsurgery. Microsurgery 28:138-142, 2008. 82. Palma EC, Esperon R. Vein transplant and grafts in the surgical treatment of the postphlebitic syndrome. J Cardiovasc Surg 1:94-107, 1960. 83. Cockett FB, Thoma M. The iliac vein compression syndrome. Br J Surg 52:816, 1965. 84. Papendieck CM. Venous bridges as an alternative option for lymphovenous shunts. Presented at the Thirty-seventh Congress of the European Society of Lymphology, Warsaw, Poland, June 2011.

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C hapter 17 Combined Lymphatic and Venous Failure: Phlebolymphedema Audra A. Duncan

Com ede K ey P oints • Lymphedema resulting from venous failure is frequently misdiagnosed. • A high frequency of lymphatic dysfunction is found in chronic venous disease. • If diagnosed, the edema may be reduced with venous outflow stenting and adjunctive measures, such as compression and risk factor modification. • Intravascular ultrasound is an effective way to image venous outflow obstruction not visualized on contrast venography.

Lymphedema caused by chronic venous disease is often characterized as secondary lymphedema and is often difficult to differentiate from primary lymphedema. In reality, the condition is best referred to as phlebolymphedema,1 because it represents a combined central (or local) venous insufficiency combined with lymphatic insufficiency. Other causes of secondary lymphedema include filariasis (which is the most common cause in tropical countries), surgical intervention associated with cancer treatment, radiation, or recurrent infection.2 If secondary causes are eliminated with a comprehensive evaluation of the patient with a swollen limb, the assumption is that the lymphedema is primary. However, what is often overlooked is the high frequency (20% to 30%) of lymphatic dysfunction found in patients with chronic venous disease. The major causes of lymphatic damage develop from an elevated capillary and venous pressure (resulting from either right-sided heart failure, immobility, or venous obstruction) and chronic fluid overload on the tissues.3-5 Lymphedema resulting from venous failure may improve with interventions designed to decrease venous hypertension, but only if the correct diagnosis is made. Therefore a deep understanding of the cause of limb swelling is needed to ensure that patients with lymphedema are diagnosed 247

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with primary lymphedema only after a thorough evaluation. In this respect, it is essential that lymphologists and phlebologists work together in a team treatment capacity.6,7

Mechanism Primary or secondary lymphedema generally occurs as a result of the accumulation of interstitial (but not always) protein-rich fluid, whereas the edema noted in pure venous disease is generally low-protein. When venous insufficiency occurs, however, venous hypertension may overload the capacity of the lymphatics to drain from the limb, resulting in chronic lymphatic insufficiency. Thus a mixed lymphedema and venous edema results.

Diagnosis Limb swelling and/or cellulitis is the most common presentation of this combined failure, although lipodermatosclerosis, fibrosis and papillomatosis, and ulceration along the malleolus may also occur. However, in most patients in whom phlebolymphedema is unrecognized, the hallmark signs of venous hypertension, such as ankle hyperpigmentation and corona phlebectatica, although frequently seen, may not be obvious and sometimes lead to the misdiagnosis of primary lymphedema. In addition, clinical signs that are characteristic of lymphedema may be seen, such as pitting edema, squaring of the toes with swelling, and edema over the dorsum of the foot. In many patients, however, clinical findings are too nonspecific to make a definitive diagnosis without further imaging studies,8 although even the latter (MRI or CT) are often unable to provide a clear differentiation of the various forms of chronic edema.9

Noninvasive Studies Venous Plethysmography Venous plethysmography with air, strain-gauge, or photoplethysmography may be one of the early studies performed when evaluating the swollen limb. Typically findings are correlated with ultrasound for improved diagnostic sensitivity. Although studies have shown value in assessing venous functional changes and quantifying the results of surgical intervention,10,11 there is no clear role for venous plethysmography, in addition to duplex ultrasound.12

Imaging Duplex Imaging Although duplex imaging is often the primary imaging modality for both screening and the diagnosis of venous compression, it may not be sensitive enough to identify common iliac vein lesions. When performed in the upright and supine positions, duplex imaging may identify venous insufficiency or venous obstruction or reflux and quantify the degree of reflux. The criteria for valvular incompetence include a valve closure time greater than 1 second for femoral and popli-

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teal veins and 0.5 second for the great saphenous, small saphenous, tibial, deep femoral, and perforating veins.12 When ultrasound is used to identify outflow obstruction, however, the degree of iliac vein stenosis may be underestimated, and adjunctive imaging, such as CT, MR venography, or intravascular ultrasound (IVUS), may be necessary.8,13

Nucleotide Lymphangiography In both primary and secondary lymphedema, lymph node uptake may be delayed or absent, as demonstrated on nucleotide lymphangiography, even after prolonged observation periods.14,15 Lymphoscintigraphy may be more useful to assess improvement postoperatively, as will be discussed. When performed, an injection of technetium-99m sulfur colloid is given between the subcutaneous space of the first and second toes, and images are taken at scheduled intervals to assess movement of the colloid. The progress may be monitored for 2 hours or more, depending on the progress of the lymph drainage and the region of interest. The images are assessed for pooling of the tracer or reflux into the limb and the rate of movement up the limb (Fig. 17-1). Thus qualitative and quantitative information can be gained from the same imaging strategy. Typically, normal lymph drainage will allow movement of the colloid and visualization of the lymph nodes by 20 minutes.8 However, drainage is often affected by patient movement, facilitating lymph drainage (or not) during the observation period. Values still vary because of the lack of a standard protocol.9 Raju et al8 also recommend the use of triple-dose lymphangiography in which 1.8 mCi (compared with 0.6 mCi in standard lymphoscintigraphy) is injected to overcome the risk that a large fluid collection could dilute the isotope and interfere with lymphatic imaging. In their series, Raju et al8 report 71 limbs in all clinical, etiology, anatomy, pathophysiology (CEAP) classifications of chronic venous disease that had delayed or absent node visualization on standard lymphoscintigraphy. All 71 limbs underwent triple-dose lymphangiography. Of these 71 limbs, 10 were normal and 16 were abnormal in CEAP C3.8

Suspect mixed lymphedema/ venous failure Duplex scan

Equivocal

Venous reflux or obstruction

CTV or MRV

Lymphoscintigraphy Venogram 6 IVUS with iliac stent or ablation of reflux

FIG. 17-1  Algorithm for basic evaluation of a patient with suspected phleboedema. (CTV, CT venography; IVUS, intravascular ultrasound; MRV, MR venography.)

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Computed Tomography or Magnetic Resonance Venography CT venography and MR venography are primarily used to identify venous outflow lesions, such as iliofemoral or iliocaval stenosis or occlusion. CT venography should be done in the venous delayed phase but may also be performed with injection into a vein of the affected limb. MR imaging with a gadolinium injection with T1-weighted spin echo, T2-weighted turbo spin echo, and fat-suppressed T2 images has the additional advantage of identifying fluid in the subcutaneous tissues. In addition, subfascial fluid collections, dermal edema, or fibrosis may be seen on MR venography. A honeycomb pattern in the subcutaneous tissue, particularly on coronal T1 images, along with fluid accumulation on T2 images, may be diagnostic of lymphedema.1

Venography and Use of Intravascular Ultrasound Contrast venography with the potential for intervention may be the most useful study to combine both the diagnosis of venous outflow obstruction and treatment concomitantly. In the series of Raju et al8 of 72 patients with CEAP C3 with abnormal lymphangiographic findings and limb swelling, venography had only a 61% sensitivity in the diagnosis of venous obstruction. In 57 venograms, 61% had an iliac vein lesion; collaterals were noted in 26% as opposed to 68 patients with IVUS, 63 of whom had an obstructive lesion.8,16 However, IVUS may miss lesions that are adjacent to the hypogastric vein orifice, or focal and discrete.

Treatment and Results Because lymphedema as a consequence of chronic venous failure is a mixed etiologic disease, treatment modalities must address the underlying cause and its downstream effects.7 Although the treatment of venous hypertension may subsequently improve lymphatic drainage,13 it is often necessary to initiate nonsurgical treatment of lymphedema concomitantly. Venography with venous stenting can be used to treat iliac and caval outflow obstruction. If reflux is the main etiologic factor, endovenous treatment of reflux of the great saphenous vein with ablation (radiofrequency ablation or laser therapy) or foam sclerotherapy can be considered. Every effort should be made to use endovascular or endovenous means to treat phleboedema to minimize lymphatic dysfunction. If open surgical techniques are required (for example, venous outflow procedures such as the Palma procedure), further lymphatic complications may occur because of the disruption of already failing lymphatics.1 In a series by Szuba et al,17 in 17 patients with lymphedema of the upper and lower extremities, 15 of 17 cases of edema improved after interventional treatment of venous outflow obstruction. Neglen et al18,19 reported stent placement was typically done in their patients for all venous stenoses of the iliac veins, with stents ranging from 8 to 14 mm. Self-expanding, conformable stents are most commonly chosen for treating venous outflow obstruction.17-19

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To assess postoperative outcomes, patients are assessed by changes in CEAP classification, pain, sleep parameters, and objective swelling. Quality of life data with validated forms, such as the Chronic Venous Disease Quality of Life Questionnaire (CIVIQ), may provide insight into the success of the intervention. To quantify outcomes more accurately, Raju et al13 used preoperative and postoperative lymphoscintigraphy. In their series of 26 patients with lower limb swelling, preoperative technetium-99m sulfur colloid lymphoscintigraphy was abnormal (absent in 8 patients and reduced in 18). All patients had venous outflow stenosis based on duplex ultrasound and/or IVUS. After venoplasty and vein stenting in all 26 patients, follow-up lymphoscintigraphic findings were normal in 10 limbs, improved in 9, and remained the same in 7. At clinical follow-up at a mean of 1 year, 16 of 26 limbs were clinically improved, and 6 were completely asymptomatic for swelling. Correspondingly, many patients had improvement in pain symptoms, including nine who were completely pain free.13

Compression The use of compression may be critical, because many patients will not improve, even with the treatment of venous outflow obstruction resulting from long-standing lymphatic disease. Compression with low-stretch elastic wrapping, such as those used in lymphatic nonsurgical treatment, provides resistance when the limb moves, thereby mimicking a pressure gradient on the limb. Although high-stretch bandages (40 to 50 mm Hg for lymphatic disease and 30 to 40 mm Hg for venous disease) have been recommended in the past, the use of multilayered bandages has proved superior over single-layer compression in recent studies.20 Regardless of the type of compression, in the presence of venous ulcers, healing is improved with the use of compression compared with no compression therapy.12,21

Other Factors in the Management of Mixed Lymphedema and Venous Disease As with all patients with lymphedema, risk factor modification to minimize symptoms is an excellent adjunct to compression and venous interventions. Techniques include: • Exercising to improve calf muscle pump function, thereby increasing lymphatic limb flow • Performing range-of-motion and stretching exercises • Elevating the limb above the level of the heart both during the day and at night in bed • Maintaining a healthy weight • Avoiding pressure to the affected limb • Maintaining excellent skin hygiene Patients often ask about the role of medications in the treatment of edema. Diuretics are often tried in the early development of lymphedema or venous edema, but they do not provide a permanent solution.

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Conclusion Lymphedema caused by venous failure may occur in 20% to 30% of patients but is often misdiagnosed. When it is diagnosed, relief of edema may occur with venous outflow stenting or the management of venous reflux, along with adjunctive measures to control limb swelling. If venous failure is suspected but a cause is not readily identified, IVUS may help in imaging venous outflow obstruction that is not visualized on venography.

C linical P earls • The venous contribution to limb edema should be considered early in diagnosis and management. • IVUS can be used to uncover venous stenosis that is not imaged on contrast venography. • If venous outflow obstruction is diagnosed, both the venous disease and lymphedema should be treated concomitantly. • Adjuvant risk factor modification such as exercise and limb elevation are important keys to treatment.

R EFERENCES 1. Bunke N, Brown K, Bergan J. Phlebolymphedema: usually unrecognized, often poorly treated. Perspect Vasc Surg Endovasc Ther 21:65-68, 2009. 2. Földi M. Classification of lymphedema and elephantiasis. Presented at the Twelfth International WHO/ TDR/FIL Conference on Lymphatic Pathology and Immunopathology in Filariasis, Thanjavur, India. Lymphology 18:148-168, 1985. 3. Bull RH, Gane JN, Evans JE, et al. Abnormal lymph drainage in patients with chronic venous leg ulcers. J Am Acad Dermatol 28:585-590, 1993. 4. Keely V. The use of lymphoscintigraphy in the management of chronic lymphoedema. J Lymphoedema 1:42-57, 2008. 5. Gloviczki P, Calcagno D, Schirger A, et al. Noninvasive evaluation of the swollen extremity: experiences with 190 lymphoscintigraphic examinations. J Vasc Surg 9:683-689; discussion 690, 1989. 6. Partsch H, Lee BB. Phlebology and lymphology—a family affair. Phlebology 29:645-647, 2014. 7. Piller N. Phlebolymphoedema/chronic venous lymphatic insufficiency: an introduction to strategies for detection, differentiation and treatment. Phlebology 24:51-55, 2009. 8. Raju S, Furth JB IV, Neglen P. Diagnosis and treatment of venous lymphedema. J Vasc Surg 55:141-149, 2012. 9. Weissleder H. Diagnosis of lymphostatic oedema of the extremities. Fortschr Med 115:32-36, 1997. 10. Green S, Thorp R, Reeder EJ. Venous occlusion plethysmography versus Doppler ultrasound in the assessment of leg blood flow during calf exercise. Eur J Appl Physiol 111:1889-1900, 2011.

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11. Weingarten MS, Czeredarczuk M, Scovell S, et al. A correlation of air plethysmography and color flowassisted duplex scanning in the quantification of chronic venous insufficiency. J Vasc Surg 24:750-754, 1996. 12. O’Donnell TF Jr, Passman MA, Marston WA, et al; Society for Vascular Surgery; American Venous Forum. Management of venous leg ulcers: clinical practice guidelines of the Society for Vascular Surgery® and the American Venous Forum. J Vasc Surg 60(2 Suppl):3S-59S, 2014. 13. Raju S, Owen S Jr, Neglen P. Reversal of abnormal lymphoscintigraphy after placement of venous stents for correction of associated venous obstruction. J Vasc Surg 34:779-784, 2001. 14. Gloviczki P, Calcagno D, Schirger A, et al. Noninvasive evaluation of the swollen extremity: experiences with 190 lymphoscintigraphic examinations. J Vasc Surg 9:683-689; discussion 690, 1989. 15. Browse N, Burnand KG, Mortimer P. Diseases of the Lymphatics. London: Arnold, 2003. 16. Neglen P, Thrasher TL, Raju S. Venous outflow obstruction: an underestimated contributor to chronic venous disease. J Vasc Surg 38:879-885, 2003. 17. Szuba A, Razavi M, Rockson SG. Diagnosis and treatment of concomitant venous obstruction in patients with secondary lymphedema. J Vasc Interv Radiol 13:799-803, 2002. 18. Neglen P, Raju S. Balloon dilation and placement of venous stent of chronic iliac vein obstruction: technical aspects and early clinical outcome. J Endovasc Ther 7:79-91, 2000. 19. Neglen P, Berry MA, Raju S. Endovascular surgery in the treatment of chronic primary and postthrombotic iliac vein obstruction. Eur J Vasc Endovasc Surg 20:560-571, 2000. 20. O’Meara S, Tierney J, Cullum N, et al. Four layer bandage compared with short stretch bandage for venous leg ulcers: systematic review and meta-analysis of randomised controlled trials with data from individual patients. BMJ 338:b1344, 2009. 21. O’Meara S, Cullum N, Nelson EA, et al. Compression for venous leg ulcers. Cochrane Database Syst Rev 11:CD000265, 2012.

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C hapter 18 Lymphedema Risk Factors in Breast Cancer Swetha Kambhampati, Stanley Rockson

K ey P oints

P Lym

• Breast cancer treatment, one of the most common causes of lymphedema, affects more than one in five breast cancer survivors. • The presence of lymphedema has a substantial impact on a person’s physical, psychological, and social wellbeing. • Axillary surgery is one of the major risk factors for lymphedema. • The risk of lymphedema is not completely eliminated with sentinel node biopsy. • Postoperative radiation increases the risk of lymphedema by as much as 10-fold compared with surgery alone. • Exercise is beneficial. • Air travel, an elevated BMI, advanced age, and venous obstruction may contribute to the appearance or worsening of lymphedema.

Breast cancer treatment is one of the most common causes of lymphedema; more than one in five women who survive breast cancer will subsequently develop this chronic disease. Lymphedema after breast cancer treatment is characterized by regional swelling in the arm(s) ipsilateral to axillary staging and therapy; the acquired lymphatic vascular insufficiency leads to an accumulation of protein-rich interstitial fluid in the tissues distal to the obstructive lesion.1,2 This high incidence of lymphedema has been linked to treatment variables, along with a variety of other stressors that are still under active investigation. The cumulative incidence of arm lymphedema increases over time and is most pronounced during the initial 2 years after breast cancer intervention.3,4 Lymphedema has an extensive negative impact on the affected individual, including the physical symptoms of discomfort, pain, and limb tightness, accompanied by the loss of function in the limb. This functional deficit can compromise the individual’s work and social productivity and impact the ability to undertake self-care.5 The disease produces various pathologic sequelae, including an increased risk of infection6-9 and secondary malignancy.10-13 The negative impact on social 255

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relationships, emotional self-confidence, and psychological well-being cannot be overstated.14,15 The high incidence of lymphedema in breast cancer survivors, and its substantial impact on quality of life, suggest that the study of lymphedema and its associated risk factors is of high public health importance.

Treatment-Related Risk Factors for the Development of Lymphedema Patients who are in the early stages of breast cancer typically undergo primary surgery on the breast (lumpectomy or mastectomy) and regional nodes, with or without radiotherapy. After this local therapy, the patient may undergo systemic adjuvant therapy, depending on the tumor characteristics. Patients may choose to undergo either breast-conserving therapy (BCT), which consists of a lumpectomy plus radiotherapy, or a total mastectomy. A meta-analysis of 72 studies3 strongly supported an association between axillary lymph node dissection, the extent of lymph nodes dissected, and mastectomy and the development of lymphedema. There is moderate evidence to support an association between the risk of lymphedema after treatment and a higher number of lymph nodes with metastasis and the use of radiotherapy and chemotherapy. There is less robust support for a link between lymphedema development and the use of axillary radiotherapy.3 The diagnostic and treatment approaches to the management of breast cancer can have a significant impact on the risk of lymphedema after treatment, and an understanding of this can help physicians counsel patients appropriately.

Axillary Lymph Node Dissection Axillary surgery is one of the major risk factors for lymphedema. A desire to minimize the adverse outcomes associated with axillary lymph node dissection (ALND) led to the development of the sentinel lymph node biopsy (SLNB) technique. SLNB as a standard means of axillary nodal assessment significantly reduced the number of women undergoing axillary surgery and thus the prevalence of breast cancer treatment–induced lymphedema.16 A recent analysis suggests that the risk of lymphedema within 1 year of treatment is 2% after SLNB alone compared with 13% after SLNB combined with ALND.17 Another meta-analysis of lymphedema after breast cancer showed that the incidence of lymphedema in women who underwent ALND was almost four times higher than in those women who had SLNB.3 Because of the decreased adverse outcomes with SLNB, the American College of Surgeons Oncology Group initiated the Z0011 trial in 1999 to assess whether ALND improved outcomes in patients with sentinel node metastases who were undergoing BCT. The study demonstrated that SLNB alone did not result in inferior survival, a finding that has the potential to significantly change clinical practice.17 Based on this study, it is assumed that only patients with clinically suspicious axillary lymph nodes and a positive biopsy finding should undergo ALND at the time of BCT surgery. Other indications for ALND include patients with positive sentinel nodes undergoing mastectomy without postsurgical radiotherapy or patients with more than three positive sentinel nodes who are undergoing BCT. Patients with a negative biopsy result or clinically

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negative axillary examination with no suspicious palpable axillary nodes should only undergo SLNB at the time of BCT surgery. This will help the surgeon make decisions regarding adjuvant systemic therapy and radiotherapy while minimizing the potential for complications and adverse outcomes, such as lymphedema. However, even with the SLNB technique, the risk of lymphedema is not completely eliminated.18,19 It is not only axillary surgery but even more limited breast-conserving interventions (with or without local radiotherapy) that can increase the risk of developing lymphedema.20,21 A study comparing patients with ALND and radical mastectomy with patients with ALND and BCT followed by local radiotherapy revealed that the incidence of lymphedema with mastectomy was more than twice that of the other group.22

Radiotherapy Although surgical interventions significantly increase the risk that lymphedema will develop, the use of adjunctive radiotherapy in breast cancer treatment further increases this risk.23 Postoperative radiotherapy increases the risk by as much as 10 times compared with surgery alone. A possible explanation for this effect may reside in the impact of radiation on the residual lymphatic structures within the radiation port. Radiation may also promote tissue fibrosis, thereby suppressing lymphatic regeneration.24 The inclusion of the supraclavicular or posterior axillary regions within the target radiation field increases the risk of lymphedema twofold or threefold, respectively. To minimize the risk of lymphedema induced by radiotherapy used as an adjunct to surgical breast cancer treatment, radiation oncologists have adopted newer radiotherapy protocols and three-dimensional methods that minimize normal tissue exposure and conventional fractionation to the involved nodal regions.23,25,26 This allows collateral lymphatic drainage and reduces the risk of lymphedema.23

Chemotherapy Traditionally it was assumed that chemotherapy did not increase the risk of lymphedema.27 However, more recent studies have shown an increased risk of lymphedema after chemotherapy for breast cancer. This association between lymphedema and chemotherapy may exist because systemic chemotherapy is often used in more advanced stages of the disease requiring more extensive surgical treatment, which has a clear link to a higher incidence of lymphedema. The relationship between chemotherapy and lymphedema may also exist because more pharmacotherapy and chemotherapeutic agents are used today than in the past, resulting in an increase in adverse interactions between these agents and the lymphatic system, thereby leading to lymphedema.3,28,29

Nontreatment-Related Risk Factors for the Development of Lymphedema For many years there has been controversy regarding the impact of other risk factors on the incidence of lymphedema in breast cancer survivors, which resulted in much fear and frustration in the patient population.30 Physicians long discouraged physical exercise of the affected limb

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with lymphedema in breast cancer patients because they believed that exercise would precipitate lymphedema in these patients or exacerbate the already extant limb swelling.31 However, more recent studies and trials have challenged this belief and demonstrated that exercise does not worsen lymphedema.32-36 On the contrary, the available evidence supports the concept that exercise can help control and improve lymphedema in these patients.3,5,37-39 Airplane travel has also traditionally been thought to worsen lymphedema. A single-subject case study showed that interarm bioimpedance ratios (a measure of interstitial fluid volume disparities) worsened after flying.38 A larger study used questionnaires to assess the role of aircraft travel in precipitating lymphedema or worsening the existing condition in patients who were treated for breast cancer; the observed relationship led to the hypothesis that the lowered aircraft cabin pressure can compromise the lymphatic function in the limb, either through obstruction of veins and lymphatics or diminished lymphatic pumping, thus leading to an accumulation of fluid in the limb.40,41 However, given this mechanism, it can be conjectured that patients can reduce the flight-associated risk with the use of additional compression (for example, inflated splints or pressure bandages) during the flight.40 Some studies contradict this general notion that air travel may trigger lymphedema. For example, one study observed athletic breast cancer survivors who traveled from Canada to Australia for a dragon boat competition without a demonstrable adverse relationship between air travel and arm lymphedema.42 Air travel alone may not be enough to precipitate or worsen lymphedema in breast cancer patients after treatment but may be influenced by other factors such as exercise, which may confer a protective effect on the patients’ inherent predisposition to develop lymphedema. Certain stressors, such as air travel, may impose a significant load on an already stressed lymphatic system and thus may precipitate the lymphedema or induce an acute flare in the swelling.30 Obesity is also considered a risk factor for lymphedema. Many studies suggest that a BMI greater than 25 or a sedentary lifestyle can increase the likelihood of developing lymphedema in breast cancer survivors.43-47 Hypertension may also be an important comorbidity that predisposes patients with a history of breast cancer treatment to develop lymphedema. An infection of the affected arm can also increase the risk of lymphedema in this patient population.43,48,49 More recent observations indicate that venous disruption in patients after mastectomy and radiation can also play a role in the pathogenesis of lymphedema. In a study of 81 patients, more than half had venous outflow obstruction on Doppler imaging of the venous flow of the upper extremity.50 Our own case series suggests that venous outflow obstruction not only precipitates lymphedema, but also renders the swelling refractory to decongestive therapy.51 This conclusion is further substantiated by the therapeutic response seen in residual arm lymphedema after the venous obstruction is treated with percutaneous venoplasty, with or without stenting.51 Based on these findings, physicians have more opportunities to use nonsurgical techniques to help mitigate the swelling and enhance the responsiveness to conservative treatment of the lymphedema in patients with simultaneous venous flow abnormalities.

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Inconclusive evidence exists to support other risk factors for lymphedema, such as demographic characteristics, dominant versus nondominant limb involvement, postoperative infection, and certain lifestyle-associated factors (for example, self-care, use of the affected arm, and education about lymphedema).3 Also, a growing body of evidence suggests that inflammation plays a key role in the pathogenesis of lymphedema.52-54 Although our understanding of lymphedema and the risk factors for precipitating or worsening this condition in breast cancer patients has increased significantly, there is still much that must be learned about the pathogenesis of this disease. Physicians who are knowledgeable about the many risk factors will be able to better educate their patients with a history of breast cancer on ways to significantly reduce their risk of developing posttreatment lymphedema. As a result, physicians will also dispel the myths and fears of these patients.

Risk Factors for Lymphedema Progression The onset of lymphedema is insidious. It presents with aching pain and a sense of heaviness, discomfort, and fullness in the affected limb before the development of any visually perceptible changes.55 The limb subsequently starts to swell. At this early stage, the edema is characterized as soft and pitting. The pitting nature of the edema at this stage reflects the retention of excess interstitial fluid in the tissues.2,56,57 As lymphedema progresses, this pitting quality tends to disappear, reflecting the development of fibrosis and adipose tissue deposition. Over time the skin becomes not only resistant to deformity by palpation, but also dry and firm with dermal thickening, cutaneous fibrosis, and hyperkeratotic skin.30,58 The subcutaneous and subfascial adipose tissue deposition increases as the lymphedema progresses to such a degree that by the advanced, nonpitting stage, 73% of the excess volume in the affected limb is composed of adipose tissue.30,59,60 In these later stages of lymphedema, patients develop restricted range of motion in the affected limb. Studies have shown that, in individuals predestined to develop lymphedema, the problem is very likely to develop within the first 2 years after treatment. Often symptoms are mild, with little perceptible swelling and less than a 2 cm interlimb circumferential difference.30 More than half of these women do not progress beyond this stage in the subsequent several years, but the remaining cohort of these affected individuals manifest continuously progressing and worsening lymphedema beyond the initial mild stage.55,61 One factor that contributes to the likelihood of lymphedema progression is the temporal duration of the edematous state.62 Although patient age does not increase the risk of developing lymphedema, it has a negative impact on the likelihood of lymphedema progression. Older patients are more likely to progress beyond the mild, early manifestations of lymphedema. Thus the trend toward an increasingly aging population can be predicted to have an adverse effect on the observed natural history of lymphedema. Cardiovascular conditions other than hypertension also predispose to the development of subcutaneous fibrosis seen in the later stages of lymphedema.

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C linical P earls • The diagnostic and treatment approaches to the management of breast cancer can have a significant impact on the risk of lymphedema after treatment, and this understanding can help physicians counsel patients appropriately. • Exercise can help prevent, control, and treat lymphedema. • Inflammation plays an important role in disease pathogenesis. • Advancing age has a negative impact on the severity of lymphedema after it is present.

R EFERENCES 1. Rockson SG. Diagnosis and management of lymphatic vascular disease. J Am Coll Cardiol 52:799-806, 2008. 2. Cheville AL, McGarvey CL, Petrek JA, et al. The grading of lymphedema in oncology clinical trials. Semin Radiat Oncol 13:214-225, 2003. 3. DiSipio T, Rye S, Newman B, et al. Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis. Lancet Oncol 14:500-515, 2013. 4. Schünemann H, Willich N. [Secondary lymphedema of the arm following primary therapy of breast carcinoma] Zentralbl Chir 117:220-225, 1992. 5. Hayes SC, Johansson K, Stout NL, et al. Upper-body morbidity after breast cancer: incidence and evidence for evaluation, prevention, and management within a prospective surveillance model of care. Cancer 118:2237-2249, 2012. 6. Vaillant L, Gironet N. [Infectious complications of lymphedema] Rev Med Interne 23 Suppl 3:403s407s, 2002. 7. Dupuy A, Benchikhi H, Roujeau JC, et al. Risk factors for erysipelas of the leg (cellulitis): case-control study. Br Med J 318:1591-1594, 1999. 8. Herpertz U. [Erysipelas and lymphedema] Fortschr Med 116:36-40, 1998. 9. Masmoudi A, Maaloul I, Turki H, et al. Erysipelas after breast cancer treatment (26 cases). Dermatol Online J 11:12, 2005. 10. Woodward AH, Ivins JC, Soule EH. Lymphangiosarcoma arising in chronic lymphedematous extremities. Cancer 30:562-572, 1972. 11. Stewart FW, Treves N. Classics in oncology: lymphangiosarcoma in postmastectomy lymphedema: a report of six cases in elephantiasis chirurgica. CA Cancer J Clin 31:284-299, 1981. 12. Tomita K, Yokogawa A, Oda Y, et al. Lymphangiosarcoma in postmastectomy lymphedema (StewartTreves syndrome): ultrastructural and immunohistologic characteristics. J Surg Oncol 38:275-282, 1988. 13. Cozen W, Bernstein L, Wang F, et al. The risk of angiosarcoma following primary breast cancer. Br J Cancer 81:532-536, 1999. 14. Tobin MB, Lacey HJ, Meyer L, et al. The psychological morbidity of breast cancer-related arm swelling. Psychological morbidity of lymphoedema. Cancer 72:3248-3252, 1993. 15. McWayne J, Heiney SP. Psychologic and social sequelae of secondary lymphedema: a review. Cancer 104:457-466, 2005. 16. D’Angelo-Donovan DD, Dickson-Witmer D, Petrelli NJ. Sentinel lymph node biopsy in breast cancer: a history and current clinical recommendations. Surg Oncol 21:196-200, 2012.

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17. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 305:569-575, 2011. 18. Mansel RE, Fallowfield L, Kissin M, et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC Trial. J Natl Cancer Inst 98:599609, 2006. 19. Wilke LG, McCall LM, Posther KE, et al. Surgical complications associated with sentinel lymph node biopsy: results from a prospective international cooperative group trial. Ann Surg Oncol 13:491-500, 2006. 20. Stanisławek A, Kurylcio L, Janikiewicz A. Arm lymphoedema after surgical treatment for the cancer of the breast. Ann Univ Mariae Curie Sklodowska Med 55:155-160, 2000. 21. Kosir MA, Rymal C, Koppolu P, et al. Surgical outcomes after breast cancer surgery: measuring acute lymphedema. J Surg Res 95:147-151, 2001. 22. Nesvold IL, Dahl AA, Løkkevik E, et al. Arm and shoulder morbidity in breast cancer patients after breast-conserving therapy versus mastectomy. Acta Oncol 47:835-842, 2008. 23. Horst KC. Radiation complications. In Lee B, Bergan J, Rockson SG, eds. Lymphedema: A Concise Compendium of Theory and Practice. London: Springer, 2011. 24. Avraham T, Yan A, Zampell JC, et al. Radiation therapy causes loss of dermal lymphatic vessels and interferes with lymphatic function by TGF-beta1-mediated tissue fibrosis. Am J Physiol Cell Physiol 299:C589-C605, 2010. 25. Badiyan SN, Shah C, Arthur D, et al. Hypofractionated regional nodal irradiation for breast cancer: examining the data and potential for future studies. Radiother Oncol 110:39-44, 2014. 26. Graham P, Jagavkar R, Browne L, et al. Supraclavicular radiotherapy must be limited laterally by the coracoid to avoid significant adjuvant breast nodal radiotherapy lymphoedema risk. Australas Radiol 50:578-582, 2006. 27. Tsai RJ, Dennis LK, Lynch CF, et al. The risk of developing arm lymphedema among breast cancer survivors: a meta-analysis of treatment factors. Ann Surg Oncol 16:1959-1972, 2009. 28. Keser I, Basar S, Duzgun I, et al. Malpractice leading to secondary lymphedema after radical mastectomy: case report. Breast Care (Basel) 8:371-373, 2013. 29. Kilbreath SL, Lee MJ, Refshauge KM, et al. Transient swelling versus lymphoedema in the first year following surgery for breast cancer. Support Care Cancer 21:2207-2215, 2013. 30. Kilbreath SL. Breast cancer. In Lee B, Bergan J, Rockson SG, eds. Lymphedema: A Concise Compendium of Theory and Practice. London: Springer, 2011. 31. Lee TS, Kilbreath SL, Sullivan G, et al. Factors that affect intention to avoid strenuous arm activity after breast cancer surgery. Oncol Nurs Forum 36:454-462, 2009. 32. Harris SR, Niesen-Vertommen SL. Challenging the myth of exercise-induced lymphedema following breast cancer: a series of case reports. J Surg Oncol 74:95-98; discussion 98-99, 2000. 33. McKenzie DC, Kalda AL. Effect of upper extremity exercise on secondary lymphedema in breast cancer patients: a pilot study. J Clin Oncol 21:463-466, 2003. 34. Ahmed RL, Thomas W, Yee D, et al. Randomized controlled trial of weight training and lymphedema in breast cancer survivors. J Clin Oncol 24:2765-2772, 2006. 35. Turner J, Hayes S, Reul-Hirche H. Improving the physical status and quality of life of women treated for breast cancer: a pilot study of a structured exercise intervention. J Surg Oncol 86:141-146, 2004. 36. Bloomquist K, Karlsmark T, Christensen KB, et al. Heavy resistance training and lymphedema: prevalence of breast cancer-related lymphedema in participants of an exercise intervention utilizing heavy load resistance training. Acta Oncol 53:216-225, 2014. 37. Baumann FT, Bloch W, Weissen A, et al. Physical activity in breast cancer patients during medical treatment and in the aftercare—a review. Breast Care (Basel) 8:330-334, 2013. 38. Schmitz KH, Ahmed RL, Troxel A, et al. Weight lifting in women with breast-cancer-related lymphedema. N Engl J Med 361:664-673, 2009.

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39. Schmitz KH, Ahmed RL, Troxel AB, et al. Weight lifting for women at risk for breast cancer-related lymphedema: a randomized trial. JAMA 304:2699-2705, 2010. 40. Casley-Smith JR, Casley-Smith JR. Lymphedema initiated by aircraft flights. Aviat Space Environ Med 67:52-56, 1996. 41. Ward LC, Battersby KJ, Kilbreath SL. Airplane travel and lymphedema: a case study. Lymphology 42:139-145, 2009. 42. Kilbreath SL, Ward LC, Lane K, et al. Effect of air travel on lymphedema risk in women with history of breast cancer. Breast Cancer Res Treat 120:649-654, 2010. 43. Ugur S, Arici C, Yaprak M, et al. Risk factors of breast cancer-related lymphedema. Lymphat Res Biol 11:72-75, 2013. 44. Ahmed RL, Schmitz KH, Prizment AE, et al. Risk factors for lymphedema in breast cancer survivors, the Iowa Women’s Health Study. Breast Cancer Res Treat 130:981-991, 2011. 45. Kwan ML, Darbinian J, Schmitz KH, et al. Risk factors for lymphedema in a prospective breast cancer survivorship study: the Pathways Study. Arch Surg 145:1055-1063, 2010. 46. Helyer LK, Varnic M, Le LW, et al. Obesity is a risk factor for developing postoperative lymphedema in breast cancer patients. Breast J 16:48-54, 2010. 47. Hayes SC, Janda M, Cornish B, et al. Lymphedema after breast cancer: incidence, risk factors, and effect on upper body function. J Clin Oncol 26:3536-3542, 2008. 48. Shahpar H, Atieh A, Maryam A, et al. Risk factors of lymph edema in breast cancer patients. Int J Breast Cancer 2013:641818, 2013. 49. Ben Salah H, Bahri M, Jbali B, et al. [Upper limb lymphedema after breast cancer treatment] Cancer Radiother 16:123-127, 2012. 50. Svensson WE, Mortimer PS, Tohno E, et al. Colour Doppler demonstrates venous flow abnormalities in breast cancer patients with chronic arm swelling. Eur J Cancer 30A:657-660, 1994. 51. Szuba A, Razavi M, Rockson SG. Diagnosis and treatment of concomitant venous obstruction in patients with secondary lymphedema. J Vasc Interv Radiol 13:799-803, 2002. 52. Avraham T, Zampell JC, Yan A, et al. Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema. FASEB J 27:1114-1126, 2013. 53. Lin S, Kim J, Lee MJ, et al. Prospective transcriptomic pathway analysis of human lymphatic vascular insufficiency: identification and validation of a circulating biomarker panel. PloS One 7:e52021, 2012. 54. Leung G, Baggott C, West C, et al. Cytokine candidate genes predict the development of secondary lymphedema following breast cancer surgery. Lymphat Res Biol 12:10-22, 2014. 55. Norman SA, Localio AR, Potashnik SL, et al. Lymphedema in breast cancer survivors: incidence, degree, time course, treatment, and symptoms. J Clin Oncol 27:390-397, 2009. 56. Szuba A, Shin WS, Strauss HW, et al. The third circulation: radionuclide lymphoscintigraphy in the evaluation of lymphedema. J Nucl Med 44:43-57, 2003. 57. Stanton AW, Mellor RH, Cook GJ, et al. Impairment of lymph drainage in subfascial compartment of forearm in breast cancer-related lymphedema. Lymphat Res Biol 1:121-132, 2003. 58. Rockson SG. Lymphedema. Am J Med 110:288-295, 2001. 59. Brorson H, Ohlin K, Olsson G, et al. Breast cancer-related chronic arm lymphedema is associated with excess adipose and muscle tissue. Lymphat Res Biol 7:3-10, 2009. 60. Brorson H, Ohlin K, Olsson G, et al. Adipose tissue dominates chronic arm lymphedema following breast cancer: an analysis using volume rendered CT images. Lymphat Res Biol 4:199-210, 2006. 61. Bar Ad V, Cheville A, Solin LJ, et al. Time course of mild arm lymphedema after breast conservation treatment for early-stage breast cancer. Int J Radiat Oncol Biol Phys 76:85-90, 2010. 62. Casley-Smith JR. Alterations of untreated lymphedema and its grades over time. Lymphology 28:174185, 1995.

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C hapter 19 Sentinel Lymph Node Biopsy Outcomes Janice N. Cormier, Kate D. Cromwell, Jane M. Armer, Merrick I. Ross

K ey P oints • Sentinel lymph node biopsy (SLNB) is an oncologically safe procedure to identify the primary lymph node to which a solid tumor, such as a melanoma, breast cancer, or gynecologic cancer, is likely to drain. • Compared with nodal observation alone, SLNB increases overall and disease-free survival in patients with intermediate-thickness tumors. • The incidence of lymphedema has been reduced but not eliminated by the use of the SLNB technique. • The incidence of lymphedema after SLNB ranges from 4% to 9% in the three tumor types (melanoma, breast cancer, and gynecologic cancer) discussed in this chapter. • Patient-reported quality of life is affected less by SLNB than by total lymphadenectomy.

The use of the sentinel lymph node biopsy (SLNB) has changed the landscape for the surgical treatment of many types of solid tumors, including melanomas and breast cancer. This minimally invasive procedure identifies and resects sentinel lymph nodes (SLNs) for the pathologic staging of lymph node basins in patients at risk for nodal metastases and can be used to avoid the morbidity associated with a complete lymphadenectomy in patients with pathologically confirmed negative SLNs.

P

This chapter outlines the technique for performing a SLNB and highlights recent literature findings related to the efficacy of the procedure in different types of cancers. Finally, there is a discussion of the impact of SLNB on lymphedema and quality of life (QOL) outcomes related to the use of this technique.

Sen

Gould et al1 first described the concept of SLNB in 1960 after an incidental finding of a lymph node at the junction of the anterior and posterior facial veins during a total parotidectomy. After node removal and identification of metastatic tumor cells, a complete cervical lymph node dissection was performed. In 1977 Cabanas2 published an article on SLNB at the time of surgical resection for penile cancer in which lymphatic imaging was used to identify the SLN. The SLN was then 263

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A

B

C

Regional lymph nodes

Sentinel lymph nodes Tumor

Probe Tumor Sentinel lymph nodes

FIG. 19-1  SLN biopsy for the treatment of breast cancer. A, Radioactive isotope and/or blue dye is injected into the tissue surrounding the tumor. B, The injected material migrates to draining lymph nodes. Sentinel nodes are identified visually or with a gamma-detecting probe. C, The tumor and sentinel nodes are excised for pathologic assessment of the regional lymph nodes.

excised for immediate evaluation; on identification of tumor cells in the SLN, a total lymph node dissection was done. At about this time, Morton et al3 investigated the various techniques of SLN identification—first in a feline model and subsequently in patients—by the intraoperative injection of isosulfan blue dye adjacent to primary melanoma sites to identify SLNs in the regional nodal basin3 (Fig. 19-1). In the early 1990s, SLNB was adopted for the pathologic staging of regional lymph nodes in patients with breast cancer. In 1996 a prospective trial of patients with invasive breast cancer who underwent SLNB before a completion axillary lymph node dissection (ALND) and segmental mastectomy or mastectomy within a single surgical procedure was reported.4 In this trial the SLN was identified in 92% of patients, and a positive SLN was identified before ALND in all patients with positive nodal disease. Albertini et al4 reported that this technique reduced surgical morbidity. This technique also gave pathologists the opportunity for an in-depth evaluation of fewer lymph nodes to more accurately identify micrometastatic disease. SLNB has also been applied to gynecologic cancers. This procedure was initially piloted for the treatment of squamous cell carcinoma of the vulva.5 In a prospective study of women undergoing routine lymphadenectomy, surgeons identified and excised the SLNs with preoperative lympho­ scintigraphy and intraoperative blue dye and subsequently performed a completion inguinofemoral lymph node dissection (ILND). Metastatic nodal disease was pathologically confirmed in almost half of the patients, each of whom had a positive SLN.5 Breast and cervical cancers are the first and fourth most commonly diagnosed cancers in women worldwide; an estimated 1,676,633 new cases of breast cancer and 1,085,948 new cases of cervical

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cancer are diagnosed annually.6 Melanoma is one of only a handful of cancers with an increasing annual incidence worldwide; an estimated 232,130 cases were diagnosed worldwide in 2012.6 With an overall estimated incidence of lymphedema of 6% for breast cancer, 4% for melanoma, and 9% for gynecologic cancers after SLNB, we estimate that 207,617 people will be diagnosed annually worldwide with lymphedema after SLNB, and many more are at a significant lifetime risk.7

Surgical Technique The current standard technique for SLNB is as follows. To facilitate the accurate identification of SLNs, blue dye is injected at the site of the primary tumor, turning the SLNs blue. Radioisotopes can also be injected at the primary tumor to guide surgeons to SLNs harboring radioactivity, regardless of color uptake (Fig. 19-2). Current techniques for SLNB most commonly use technetium99m (99mTc)-sulfur colloid (in the United States), 99mTc-nanocolloid (widely used in Europe), or

A

Sentinel lymph node

Melanoma

Afferent lymphatic channels

Afferent lymphatic channels

2 cm margin around lesion

B

Melanoma

FIG. 19-2  A, SLN biopsy for the evaluation of melanoma. Radioactive isotope and blue dye are injected into the tissue surrounding the lesion. Sentinel nodes are identified, exposed, and excised for pathologic assessment. B, Wide local excision for the removal of the primary tumor.

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A

B

FIG. 19-3  A, SLNB with a positive gross tumor. B, Positive tumor cells on pathologic analysis.

99mTc-antimony

trisulfide colloid (used in Australia) as a radiopharmaceutical agent.8 After the blue dye and radioactive isotope are injected, the surgeon uses a gamma-detecting probe to help localize sites of high radioactivity in the lymph node basin (see Fig. 19-2). An incision is made at a regional nodal basin site that has significant radioactivity, and the nodal tissue is dissected to identify blue and/or radioactive lymph nodes. The SLN or SLNs are excised from the remaining contents of the nodal basin and undergo pathologic assessment (Fig. 19-3). The accuracy and sensitivity of SLNB have been shown in most cancer types in which the procedure is part of the current treatment recommendations. When SLNB was done according to the standard treatment guidelines, the accuracy was 97%, sensitivity was 91%, specificity was 100%, and negative-predictive value was 95% in breast cancer.9 Similar numbers have been found in melanoma studies. A systematic review and meta-analysis by Meads et al10 evaluating SLNB in vulvar cancer found that the accuracy of the procedure (when done with both a blue dye and radioactive tracer) was 98%, sensitivity was 95%, and negative-predictive value was 98%.

Impact on Outcomes Long-Term Survival Outcomes The first evaluation of the impact of SLNB on survival was conducted in a multiinstitutional, randomized, controlled trial, the Multicenter Selective Lymphadenectomy Trial (MSLT-1), led by Morton.11 In this trial patients with melanoma were randomly assigned to receive a wide local excision and either SLNB or nodal observation only. Ten-year follow-up data on more than 1500 patients were available for the final analysis, which was published in 2014.12 Statistically, the 10year melanoma-specific survival rates were significantly higher in patients who received SLNB (81.4% 6 1.5%) than in those who had nodal observation only (78.3% 6 2.0%). In light of these findings, the National Comprehensive Cancer Network guidelines have included recommendations for the pathologic staging of melanoma in patients with primary tumors that are thicker than 0.75 mm or a primary tumor of any thickness that is ulcerated or has at least one or more mitotic figures per high-power field.13

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Lymphedema Outcomes Lymphedema has long been recognized as a potential morbidity after a complete lymph node dissection for many solid tumors.7 In a systematic review of non–breast cancer lymphedema, Cormier et al7 identified 47 studies across five categories of malignancies (melanoma, gynecologic cancer, genitourinary cancer, head and neck cancer, and sarcoma) that reported incidences of lymphedema ranging from 4% to 40% after complete lymph node dissection. Recently SLNB has also been recognized as a risk factor for lymphedema; however, the risk is significantly less than that of complete lymph node dissection. Tables 19-1, 19-2, and 19-3 summarize the peer-reviewed publications (2000 to 2014) reporting the incidence of lymphedema after SLNB for breast cancer, melanoma, and gynecologic malignancies. There is significant heterogeneity in the measurement techniques used to quantify lymphedema, which included water displacement, perometry, and limb circumference measurement.

Melanoma Six studies that included patients with melanoma undergoing SLNB and reported data on lymphedema outcomes were identified. The weighted pooled incidence of lymphedema was 4% (range 0.6% to 15%) (Table 19-1). In a systematic review of lymphedema in non–breast cancer solid tumors, Cormier et al7 found that the pooled lymphedema incidence was 18% after ILND and 3% after ALND. In a prospective study designed to assess lymphedema after SLNB or complete lymph node dissection (axillary or inguinofemoral) for the pathologic assessment and treatment of cutaneous melanoma, Hyngstrom et al14 used perometry to measure the limb circumference of patients with lymphedema before and after surgical intervention (lymphedema was defined as a 10% increase in limb volume from baseline) and assessed subjective, patient-reported symptoms of lymphedema with a validated instrument, the 19-item Lymphedema and Melanoma Questionnaire. Twelve months after surgery, 15% of patients who underwent SLNB and 30% of those who

TABLE 19-1  Incidence of Lymphedema 12 Months After SLNB for the Treatment of Melanoma Author (yr)

Number of Patients

Hyngstrom et al14 (2013) 15

Murawa et al (2013) 16

Measurement Technique

Incidence of Lymphedema (%)

84

Perometry

15

47

Circumference

2

Palmer et al (2013)*

47

Not reported

2

de Vries et al17 (2006)

52

Circumference

6

de Vries et al18 (2005)

44

Water displacement

11

Roaten et al (2005)

339

Not reported

0.6

Total studies (N 5 6)

613

19

*Pediatric melanoma patient cohort. Mean: 6.1 (range 0.6-15); weighted pooled incidence: 4.1.

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TABLE 19-2  Incidence of Lymphedema 12 Months After SLNB for the Treatment of Breast Cancer Author (yr)

Number of Patients

Sackey et al21 (2014) 22

Sagen et al (2014) 23

Measurement Technique

Incidence of Lymphedema (%)

140

Water displacement

20

187

Water displacement

3

Velloso et al (2011)

45

Circumference

4

Goldberg et al24 (2010)

600

Circumference

5

Lucci et al25 (2007)*

446

Circumference

7

26

449

Circumference

3.5

27

Mansel et al (2006)

478

Circumference

5

Francis et al28 (2006)

26

Circumference

17

2904

Circumference

7

Not reported

4

Langer et al (2007)

Wilke et al20 (2006) 29

Leidenius et al (2004) 30

92

Ronka et al (2004)

57

Not reported

23

Langer et al31 (2004)

40

Not reported

0

683

Circumference

6

Haid et al (2002)

57

Circumference

4

Swenson et al34 (2002)

169

Subjective

9

35

303

Not reported

3

Schrenk et al (2000)

35

Not reported

0

Total studies (N 5 17)

6711

32

Blanchard et al (2003) 33

Sener et al (2001) 36

*Chosen from multiple papers with overlapping patients. Mean: 7 (range 0-23); weighted pooled incidence: 6.3.

underwent lymph node dissections had objectively measured lymphedema. The highest incidence of lymphedema was in patients who had an ILND, 46% of whom had objectively measured lymphedema 12 months after surgery.14

Breast Cancer In the breast cancer literature, 17 studies (6711 patients) reporting on the incidence of lymphedema after SLNB were identified (Table 19-2). In these studies the weighted pooled incidence of breast cancer–related lymphedema in patients who underwent SLNB as their most invasive regional nodal procedure was 6% (range 0% to 23%). Wilke et al20 were one of the first groups to examine surgical complications after SLNB in patients with breast cancer. In a multiinstitutional trial more than 5000 patients were evaluated for lymphedema 30 days and 6 months after surgery. Lymphedema was measured with the use of limb circumference; the threshold for lymphedema was defined as a 2 cm difference between the affected and unaffected limbs. Lymphedema was observed in 7% of patients 6 months after surgery, and a higher body mass index was identified as a statistically significant risk factor for the development of lymphedema.

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TABLE 19-3  Incidence of Lymphedema 12 Months After SLNB for the Treatment of Gynecologic Cancer Author (yr)

Number of Patients

Measurement Technique

Incidence of Lymphedema (%)

Robison et al39 (2014)

69

Not reported

8

Achouri et al38 (2013)

88

Subjective

11

Novackova et al40 (2012)

12

Circumference

25

37

23

Subjective

9

Moore et al (2008)

31

Not reported

0

Total (N 5 5)

223

Niikura et al (2012) 41

Mean: 10.6 (range 0-25); weighted pooled incidence: 9.0.

In another study, Lucci et al25 prospectively compared postoperative complications in almost 900 patients who underwent either ALND or SLNB. In this study lymphedema was defined objectively as a 2 cm difference in circumference between the affected and unaffected arms and subjectively with patient self-reports. Using objective measurements, the 12-month lymphedema incidences were 11% in the ALND group and 6% in the SLNB group. Because of the relatively small sample size of patients who agreed to participate in the lymphedema measurement part of the study, this difference was not statistically significant. However, according to the subjective outcomes, 19% of patients who had ALND and 6% of patients who had SLNB had lymphedema, and these differences were statistically significant.25 The cumulative incidence of lymphedema over time was not reported in this study, which may explain the lower incidence reported for the ALND group compared with the historical lymphedema incidences in patients who had this procedure. Another potential explanation for the lower than expected reported incidence in the ALND group is that the circumference was measured at only one point on the arm, a method that is less sensitive to changes in limb size than multiple measurements per limb.

Gynecologic Cancers For gynecologic malignancies, five studies (223 patients who underwent SLNB) had a weighted pooled incidence of lymphedema of 9% (range 0% to 25%) (Table 19-3). These studies included patients with cervical,37,38 vulvar,38-40 and endometrial cancer.38 All of these studies were conducted after biopsy and lacked baseline measurements, which may have impacted the outcomes. Only Novackova et al40 used objective measurements of lymphedema (circumference).

Quality of Life Outcomes Because of improved treatment outcomes and earlier detection, more people have survived cancer in recent years than previously. Thus it is essential to evaluate how cancer treatment impacts QOL. With the widespread use of SLNB for the nodal assessment of many malignancies, QOL after SLNB is an important consideration.

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Health-related QOL is a multidimensional construct that includes not only physical well-being but also functional, emotional, and social domains.42 Physical well-being includes domains related to symptoms (for example, pain, discomfort, and fatigue), and functional well-being is the ability to complete day-to-day tasks (for example, bathing, eating, sleeping, and dressing). Emotional well-being captures a person’s ability to cope with various situations and to manage feelings ranging from distress and anxiety to enjoyment and happiness. Social well-being includes measures of the quality of relationships with family and friends and interactions with others in a wider social context.43

Melanoma Only the study by de Vries et al44 reported on the QOL of patients after SLNB for the treatment of melanoma. This study used the European Organization for Research and Treatment of Cancer QOL generic instrument (EORTC QLQ-C30) and a pain and activity questionnaire to assess 116 patients undergoing an axillary or inguinal SLNB or total lymphadenectomy. The study’s findings reported that patients undergoing SNLB statistically had significantly more favorable scores in physical and role functioning in the EORTC domains than those who underwent total lymphadenectomy, but no other statistically significant differences were identified between the two groups.

Breast Cancer QOL after SLNB for the treatment of breast cancer has been evaluated primarily with the use of two instruments: the EORTC QLQ-C30 with the associated breast cancer module (EORTC QLQ-BR23)45-47 and the Functional Assessment of Cancer Therapy Breast Cancer module (FACTB14).48 In addition, functional well-being after SLNB has been assessed with the Disabilities of the Arm, Shoulder, and Hand (DASH) instrument.49 A prospective, longitudinal study that evaluated women undergoing surgery for breast cancer assessed QOL with the EORTC QLQ-BR23 and EORTC QLQ-C30 before surgery and three times after surgical intervention with 1 year of total follow-up.47 Before surgery, patients had similar QOL regardless of expected surgery. Global health status declined in the immediate postoperative period but returned to preoperative levels 12 months after surgery; similar findings were observed with the breast and arm disability scales.47 Dabakuyo et al47 reported that patients who underwent SLNB alone and those who underwent ALND with or without SLNB did not significantly differ in global QOL or symptom-specific scales at 12 months. However, a large amount of QOL data were missing because of patient attrition, which may have biased the results. A comparison of QOL outcomes between patients undergoing ALND and those undergoing SLNB is important, considering the reduced morbidity associated with SLNB. A prospective longitudinal comparison study of patients undergoing either ALND or SLNB evaluated patients preoperatively and at three time points in the 12 months after surgery with the FACT-B14 questionnaire.48 Patients in the SLNB group reported deterioration from baseline in arm disability at both 6 and 12 months, but this statistically significant deterioration was much less than that of the ALND group. In a study of the long-term impact of SLNB on the QOL of breast cancer patients, De Gournay et al45 prospectively assessed more than 500 patients preoperatively and for as long as 72 months

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after surgery with the EORTC QLQ-BR23 and EORTC QLQ-C30 questionnaires. At 72 months after surgery, patients undergoing SLNB statistically had significantly better arm symptom scores than those who received ALND. In a subset analysis, patients who had a positive SLN and subsequently underwent ALND and those who underwent ALND only did not significantly differ in arm symptoms, breast symptoms, or global QOL at any time point. Global QOL scores were similar between the ALND and SLNB groups at baseline, declined in the immediate postoperative period, and returned to baseline level 12 months after surgery. Scores declined again at 12 months, although these scores did not significantly differ when stratified by surgical group.

Gynecologic Cancers QOL after SLNB has not been assessed as much for patients with gynecologic cancers as it has been in patients with breast cancer. Oonk et al50 used the EORTC QLQ-C30 and a subscale specific to vulvar cancer in an assessment of the efficacy of SLNB in vulvar cancer at various points in the course of care.50 The differences were assessed between the general QOL and symptom scale within the EORTC QLQ-C30 and additional symptom subscale; the only significant difference between the SLNB and ILND groups was that patients undergoing ILND reported greater financial difficulties. For the vulva-specific subscale, the statistically significant differences between the two groups included higher levels of contentment and lower levels of edema than those treated with ILND.50 In this evaluation patients were asked whether they would undergo a SLNB given a certain false-negative rate or an ILND at the initiation of treatment; 82% of the entire cohort (97% of the SLNB group and 62% of the ILND group) responded that they preferred the SLNB if the false-negative rate was no more than 1%, considering the reduced morbidity of SLNB.

Conclusion The introduction of SLNB across multiple solid tumor cancers has helped increase 5-year survival and reduced the morbidity associated with total lymphadenectomy. In addition to the improved survival outcomes, SLNB is a less invasive surgical procedure, which means less time under general anesthesia, a reduced risk to develop postoperative infection, and a better cosmetic outcome. Although SLNB significantly reduces the risk of postoperative lymphedema compared with completion lymph node dissection, it does not eliminate the risk entirely. Therefore when obtaining operative consent for SLNB, the surgeon must inform the patient that lymphedema is a possible postoperative long-term morbidity.

C linical P earls • SNL procedures were developed and validated in the 1990s for melanoma and breast cancer. • The incidence of lymphedema after SNLB ranges from 4% to 9% and avoids the risk of completion lymph node dissection for patients who are node negative. • Patient-reported QOL is affected less by SLNB than by total lymphadenectomy.

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R EFERENCES 1. Gould EA, Winship T, Philbin PH, et al. Observations on a “sentinel node” in cancer of the parotid. Cancer 13:77-78, 1960. 2. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 39:456-466, 1977. 3. Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127:392-399, 1992. 4. Albertini JJ, Lyman GH, Cox C, et al. Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 276:1818-1822, 1996. 5. de Hullu JA, Hollema H, Piers DA, et al. Sentinel lymph node procedure is highly accurate in squamous cell carcinoma of the vulva. J Clin Oncol 18:2811-2816, 2000. 6. World Health Organization. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. Lyon, France: International Agency for Research on Cancer, 2012. 7. Cormier JN, Askew RL, Mungovan KS, et al. Lymphedema beyond breast cancer: a systematic review and meta-analysis of cancer-related secondary lymphedema. Cancer 116:5138-5149, 2010. 8. Thompson JF, Morton DL. Lymphatic mapping and sentinel lymph node biopsy: the concept. In Thompson JF, Morton DL, Kroon BBR, eds. Textbook of Melanoma. London: Taylor & Francis, 2004. 9. Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 349:546-553, 2003. 10. Meads C, Sutton AJ, Rosenthal AN, et al. Sentinel lymph node biopsy in vulval cancer: systematic review and meta-analysis. Br J Cancer 110:2837-2846, 2014. 11. Morton DL, Cochran AJ, Thompson JF, et al; Multicenter Selective Lymphadenectomy Trial Group. Sentinel node biopsy for early-stage melanoma. Accuracy and morbity in MSLT-1, an International Multicenter Trial. Ann Surg 242:302-313, 2005. 12. Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 370:599-609, 2014. 13. NCCN Guidelines for Physicians: Melanoma. Fort Washington, PA: National Comprehensive Cancer Network, 2014. 14. Hyngstrom JR, Chiang YJ, Cromwell KD, et al. Prospective assessment of lymphedema incidence and lymphedema-associated symptoms following lymph node surgery for melanoma. Melanoma Res 23:290-297, 2013. 15. Murawa D, Polom K, Murawa P. One-year postoperative morbidity associated with near-infraredguided indocyanine green (ICG) or ICG in conjugation with human serum albumin (ICG:HSA) sentinel lymph node biopsy. Surg Innov 21:240-243, 2013. 16. Palmer PE III, Warneke CL, Hayes-Jordan AA, et al. Complications in the surgical treatment of pediatric melanoma. J Pediatr Surg 48:1249-1253, 2013. 17. de Vries M, Vonkeman WG, van Ginkel RJ, et al. Morbidity after inguinal sentinel lymph node biopsy and completion lymph node dissection in patients with cutaneous melanoma. Eur J Surg Oncol 32:785789, 2006. 18. de Vries M, Vonkeman WG, van Ginkel RJ, et al. Morbidity after axillary sentinel lymph node biopsy in patients with cutaneous melanoma. Eur J Surg Oncol 31:778-783, 2005. 19. Roaten JB, Pearlman N, Gonzalez R, et al. Identifying risk factors for complications following sentinel lymph node biopsy for melanoma. Arch Surg 140:85-89, 2005. 20. Wilke LG, McCall LM, Posther KE, et al. Surgical complications associated with sentinel lymph node biopsy: results from a prospective international cooperative group trial. Ann Surg Oncol 13:491-500, 2006. 21. Sackey H, Magnuson A, Sandelin K, et al. Arm lymphoedema after axillary surgery in women with invasive breast cancer. Br J Surg 101:390-397, 2014. 22. Sagen A, Kaaresen R, Sandvik L, et al. Upper limb physical function and adverse effects after breast cancer surgery: a prospective 2.5-year follow-up study and preoperative measures. Arch Phys Med Rehabil 95:875-881, 2014.

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23. Velloso FS, Barra AA, Dias RC. Functional performance of upper limb and quality of life after sentinel lymph node biopsy of breast cancer. Rev Bras Fisioter 15:146-153, 2011. 24. Goldberg JI, Wiechmann LI, Riedel ER, et al. Morbidity of sentinel node biopsy in breast cancer: the relationship between the number of excised lymph nodes and lymphedema. Ann Surg Oncol 17:32783286, 2010. 25. Lucci A, McCall LM, Beitsch PD, et al. Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group Trial Z0011. J Clin Oncol 25:3657-3663, 2007. 26. Langer I, Guller U, Berclaz G, et al. Morbidity of sentinel lymph node biopsy (SLN) alone versus SLN and completion axillary lymph node dissection after breast cancer surgery: a prospective Swiss multicenter study on 659 patients. Ann Surg 245:452-461, 2007. 27. Mansel RE, Fallowfield L, Kissin M, et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC Trial. J Natl Cancer Inst 98:599609, 2006. 28. Francis WP, Abghari P, Du W, et al. Improving surgical outcomes: standardizing the reporting of incidence and severity of acute lymphedema after sentinel lymph node biopsy and axillary lymph node dissection. Am J Surg 192:636-639, 2006. 29. Leidenius M, Krogerus L, Tukiainen E, et al. Accuracy of axillary staging using sentinel node biopsy or diagnostic axillary lymph node dissection—a case-control study. APMIS 112:264-270, 2004. 30. Ronka R, Smitten K, Sintonen H, et al. The impact of sentinel node biopsy and axillary staging strategy on hospital costs. Ann Oncol 15:88-94, 2004. 31. Langer S, Guenther JM, Haigh PI, et al. Lymphatic mapping improves staging and reduces morbidity in women undergoing total mastectomy for breast carcinoma. Am Surg 70:881-885, 2004. 32. Blanchard E, Herman L, Larson L, et al. Understanding the role of sentinel lymph node biopsy in breast cancer and melanoma. JAAPA 16:49-50, 54, 2003. 33. Haid A, Koberle-Wuhrer R, Knauer M, et al. Morbidity of breast cancer patients following complete axillary dissection or sentinel node biopsy only: a comparative evaluation. Breast Cancer Res Treat 73:31-36, 2002. 34. Swenson KK, Nissen MJ, Ceronsky C, et al. Comparison of side effects between sentinel lymph node and axillary lymph node dissection for breast cancer. Ann Surg Oncol 9:745-753, 2002. 35. Sener SF, Winchester DJ, Martz CH, et al. Lymphedema after sentinel lymphadenectomy for breast carcinoma. Cancer 92:748-752, 2001. 36. Schrenk P, Rieger R, Shamiyeh A, et al. Morbidity following sentinel lymph node biopsy versus axillary lymph node dissection for patients with breast carcinoma. Cancer 88:608-614, 2000. 37. Niikura H, Okamoto S, Otsuki T, et al. Prospective study of sentinel lymph node biopsy without further pelvic lymphadenectomy in patients with sentinel lymph node-negative cervical cancer. Int J Gynecol Cancer 22:1244-1250, 2012. 38. Achouri A, Huchon C, Bats AS, et al. Complications of lymphadenectomy for gynecologic cancer. Eur J Surg Oncol 39:81-86, 2013. 39. Robison K, Roque D, McCourt C, et al. Long-term follow-up of vulvar cancer patients evaluated with sentinel lymph node biopsy alone. Gynecol Oncol 133:416-420, 2014. 40. Novackova M, Halaska MJ, Robova H, et al. A prospective study in detection of lower-limb lymphedema and evaluation of quality of life after vulvar cancer surgery. Int J Gynecol Cancer 22:1081-1088, 2012. 41. Moore RG, Robison K, Brown AK, et al. Isolated sentinel lymph node dissection with conservative management in patients with squamous cell carcinoma of the vulva: a prospective trial. Gynecol Oncol 109:65-70, 2008. 42. Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 11:570-579, 1993. 43. Cella D, Nowinski CJ. Measuring quality of life in chronic illness: the functional assessment of chronic illness therapy measurement system. Arch Phys Med Rehabil 83(12 Suppl 2):S10-S17, 2002.

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44. de Vries M, Hoekstra HJ, Hoekstra-Weebers JE. Quality of life after axillary or groin sentinel lymph node biopsy, with or without completion lymph node dissection, in patients with cutaneous melanoma. Ann Surg Oncol 16:2840-2847, 2009. 45. De Gournay E, Guyomard A, Coutant C, et al. Impact of sentinel node biopsy on long-term quality of life in breast cancer patients. Br J Cancer 109:2783-2791, 2013. 46. Boguševičius A, Čepulienė D. Quality of life after sentinel lymph node biopsy versus complete axillary lymph node dissection in early breast cancer: a 3-year follow-up study. Medicina (Kaunas) 49:111-117, 2013. 47. Dabakuyo TS, Fraisse J, Causeret S, et al. A multicenter cohort study to compare quality of life in breast cancer patients according to sentinel lymph node biopsy or axillary lymph node dissection. Ann Oncol 20:1352-1361, 2009. 48. Belmonte R, Garin O, Segura M, et al. Quality-of-life impact of sentinel lymph node biopsy versus axillary lymph node dissection in breast cancer patients. Value Health 15:907-915, 2012. 49. Hudak PL, Amadio PC, Bombardier C. Development of an upper extremity outcome measure: the DASH (disabilities of the arm, shoulder and hand) [corrected]. The Upper Extremity Collaborative Group (UECG). Am J Ind Med 29:602-608, 1996. 50. Oonk MH, van Os MA, de Bock GH, et al. A comparison of quality of life between vulvar cancer patients after sentinel lymph node procedure only and inguinofemoral lymphadenectomy. Gynecol Oncol 113:301-305, 2009.

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Part IV

Diagnosis of Lymphedema

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C hapter 20 Causes and Classification of Lymphatic Disorders Swetha Kambhampati, Stanley Rockson

K ey P oints • Primary lymphedema is generally categorized based on age of onset and is presumed to have a genetic basis. • Lymphedema is a hallmark feature of various syndromic disorders. • Secondary lymphedema arises as a consequence of other conditions or treatments. • Any surgical intervention can precipitate lymphedema. • Lymphangiomatosis can be isolated or systemic, superficial or visceral. It is generally characterized by the depth of the malformation within the tissue planes. • Lymphatic filariasis results from an infection and worldwide is the most common cause of lymphedema. • Abnormal development or damage to blood and lymphatic vascular systems can contribute to the appearance of complex vascular malformations.

Cau

• Protein-losing enteropathy and intestinal lymphangiectasia are associated with the loss of lymphatic fluid and plasma protein within the lumen of the gastrointestinal tract.

Lymphedema is a complex edematous state resulting from dysfunction of the lymphatic transport system that is essential to the maintenance of tissue homeostasis. Beyond lymphedema, however, there is a broad spectrum of diseases that directly or indirectly alter lymphatic structure and function. These lymphatic vascular diseases, which are characterized by a failure of adequate lymph transport, lead to a wide range of pathologic presentations.1 Given the central role of lymphatic function in circulatory homeostasis and a robust immune and metabolic contribution (based on suitable dietary absorption of gastrointestinal lipids), any lymphatic pathology will become clinically manifest as a regional or systemic immune impairment and/or significant metabolic derangement, often accompanied by chronic and often debilitating regional swelling and tissue edema.2-4

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Embryologic Development The lymphatic system arises from endothelial cells within the embryonic venous structures. Specific molecular markers determine the lymphatic endothelial cell specification and thus its unique phenotype. Additional lymphatic-specific markers are expressed, and blood vascular expression profiles are suppressed as the lymphatic endothelial cells continue to differentiate.5 Vascular endothelial growth factor C is necessary for the earliest steps of lymphatic endothelial cell differentiation.6 The differentiated lymphatic cell population migrates peripherally and establishes complete autonomy from the local venous environment. This developmental stage is characterized by primary budding. The primary lymph sacs form throughout the embryo, followed by secondary budding and migration. The latter requires endothelial sprouting into tissues to form local capillaries, thereby marking the final stages of lymphatic development.7,8

Lymphedema The International Society of Lymphology consensus document has identified four stages in the natural history of lymphedema.9 Stage 0 refers to a latent or subclinical condition in which swelling is not seen despite the presence of impairment in lymph transport. Stage 1 is seen as pitting edema. There is early accumulation of fluid that is relatively high in protein content and resolves with limb elevation. Stage 2 is characterized by the presence of pitting edema that does not resolve with limb elevation alone. Stage 3 is lymphostatic elephantiasis, in which pitting is no longer seen. The lymphedema is characterized by trophic skin changes, such as acanthosis, fat deposition, dermal cutaneous fibrosis, and verrucous overgrowth.10 Although lymphedema can be hereditary, its development can also be sporadic. Its cause is either primary or secondary: • Primary lymphedemas are congenital, developmental, or inherited disorders that arise from an inborn malformation or dysfunction of the lymphatic system. • Secondary lymphedema arises as a consequence of other conditions or treatments. Lymphedema is not a reversible condition. Its treatment is largely mechanical and requires physiotherapeutic interventions that reduce limb swelling through the stimulation of lymphatic contractility and that control reaccumulation of edema through limb compression. Complete decongestive therapy is a multicomponent treatment that reduces the degree of lymphedema and maintains skin health.11-13 At present there is no long-term pharmacologic therapy that is recommended for patients with lymphedema.

Primary Lymphedema Primary lymphedemas are congenital, developmental, or inherited disorders that arise from an inborn malformation or dysfunction of the lymphatic system. In general, these disorders do not shorten life expectancy but worsen quality of life.14 They are presumed to have a genetic basis; an

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autosomal dominant transmission pattern is most often described. Numerous distinct gene mutations associated with lymphedemas have thus far been noted and characterized.15,16 Primary lymphedemas are classified by the age of onset: • Congenital lymphedema presents at birth or by the age of 2 years • Lymphedema praecox presents before 35 years of age (most often in association with puberty). • Lymphedema tarda appears after 35 years of age. Congenital lymphedema can be syndromic in nature (for example, Noonan syndrome, Turner syndrome, or Klippel-Trenaunay syndrome)16,17 and can be organized by its pattern of inheritance. Chromosomal disorders, such as Klinefelter or Edwards syndrome, can result in multiple organ defects and a wide constellation of symptoms and complications, including a severe distortion of lymphatic function.3 Typically, congenital lymphedema of the hands and feet is seen in infants with Turner syndrome.18 Milroy disease, or hereditary autosomal dominant congenital lymphedema, presents as painless, nonprogressive edema of the lower extremity in infancy.19 It has been associated with mutations in the kinase domain of vascular endothelial growth factor receptor 3 (VEGFR-3), with incomplete penetrance.20 Despite the association of Milroy disease with a systemic mutation, lymphoscintigraphy often reveals normal, functional lymphatic anatomy in the upper limbs, but inadequate lymphatic functional integrity is present at the sites of swelling in the lower limbs.19 Lymphedema-distichiasis is a single-gene disorder caused by a mutation in the gene that encodes the nuclear transcription factor FOXC2. This is another common cause of primary lymphedema. Distichiasis (abnormal cilia arising from the meibomian glands along the lid margin) typically presents at birth, but the lymphedema generally presents at puberty (often earlier in males)21; it is an accompanying somatic anomaly that is found in 94% to 100% of patients with lymphedemadistichiasis. This feature can lead to recurrent corneal irritation and conjunctivitis.19 FOXC2 mutations can also be associated with the presence of cleft palate or congenital heart disease. Lymphoscintigraphy reveals reflux within the main collector lymphatics; in addition, deep vein reflux is seen on venous Doppler ultrasound examination.19,22 Lymphedema praecox (lymphedema presenting before the age of 35) is the most common form of primary lymphedema.23 The edema in this disease is often unilateral and commonly limited to the foot and calf.24 The disorder is characterized by an initial presentation at puberty and female preponderance, leading to the hypothesis that estrogen may play a role in the expression of the lymphedema.24 Meige disease is a term that has been applied to a familial form of lymphedema praecox with pubertal onset and an autosomal dominant pattern of inheritance.19

Secondary Lymphedema Secondary lymphedema arises as a consequence of other conditions or treatments. However, there is a growing conviction that genetic factors contribute to the susceptibility to the stressors that elicit an ostensibly pure acquired lymphedema. In other words, in many cases, there may be a primary predisposition to the development of secondary lymphedema.

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A common cause of acquired lymphedema is iatrogenic, as a result of treatment of malignancies. Furthermore, and less commonly, tumors can primarily obstruct lymphatic channels or infiltrate the lymphatic system, leading to lymphedema through obstruction of lymph flow. Treatment of a wide variety of cancers is associated with a significant incidence of lymphedema, including breast cancer, malignant melanoma, urogenital malignancies, lymphoma, and soft tissue sarcomas.25 Any surgery can result in lymphedema. The operative intervention can be for cancer (for example, a modified radical mastectomy or even a partial excision) or a non-cancer-related procedure, such as varicose vein ligation or saphenous vein harvesting for aortocoronary bypass.26,27 Trauma, infection, and burns can also lead to the development of lymphedema. Moreover, peripheral arterial disease can result in secondary lymphedema.26 Iatrogenic causes, such as intrathecal pump insertion or sirolimus administration, are common precipitators of lymphedema.28,29 Globally, infection is considered the leading cause of lymphedema. In tropical regions, endemic lymphatic filariasis predominates and is the most common worldwide cause of lymphedema.30

Acquired Conditions Infectious Diseases Lymphatic filariasis and lymphangitis are two conditions in which invading pathogens infect and infiltrate the lymphatic system, which leads to lymphatic dysfunction. The consequence of such events can often result in a chronic obstruction to lymph flow (acquired lymphedema), which is accompanied by the resulting impairment in regional immune function. More than 140 million people worldwide have been infected with filariasis. The prevalence and global burden of the disease lag only behind malaria and tuberculosis.31 Most of these infections are caused by Wuchereria bancrofti, whereas the remaining cases are caused by Brugia malayi.32 Patients are infected by the larvae of these filariae, or parasitic worms; after the larvae are delivered through the wound, they enter the draining lymphatic vessels. The larvae develop into mature adult worms that produce microfilariae, which then enter and circulate in the bloodstream. Lymphatic filariasis can be asymptomatic (subclinical) or can have acute or chronic clinical manifestations. Acute presentations include adenolymphangitis, which is characterized by fever and painful lymphadenopathy. Ultimately, there is fibrosis of the lymph nodes and impaired regeneration of lymphatic channels. Dermatolymphangioadenitis is another acute presentation that is characterized by inflammatory plaques and systemic symptoms as a consequence of superficial bacterial infection of damaged skin.33 Other acute presentations include filarial fevers and tropical pulmonary eosinophilia, which is caused by an immune response to filariae trapped in the lungs. Chronically, filariasis can lead to lymphedema, hydrocele, and renal involvement.34 Active infection can be diagnosed by the detection of the microfilariae in the blood; detection of localized, lymphatic obstruction by Doppler ultrasound is feasible.31 Serologic techniques can be substituted for the microscopic detection of microfilariae. The infection is treated with antibiotics and antiparasitic medications, such as albendazole, diethylcarbamazine, and ivermectin.35-37 Lymphangitis represents an inflammation of the lymphatic channels, most often seen in relation to infectious causes, including bacterial, mycobacterial, fungal, viral, and parasitic pathogens.38

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Lymphangitis often develops after cutaneous inoculation of microorganisms through a skin wound or as a complication of a distal infection that invades the lymphatic vessels and spreads toward regional lymph nodes. Lymphangitis can also reflect inflammation in the setting of malignancy (neoplastic lymphangitis or lymphangitis carcinomatosa) or a systemic inflammatory process, such as Crohn’s disease (granulomatous intestinal lymphangitis) or sclerosing lymphangitis of the penis.39-43 Recurrent episodes of bacterial lymphangitis lead to thrombosis and fibrosis of the lymphatic channels; this is one of the most common causes of lymphedema.44 The clinical presentation of this disease often encompasses the presence of painful erythematous cutaneous streaks and enlarged and tender lymph nodes.38 Patients also frequently have a history of minor trauma or skin infection and fever, chills, muscular pain, and headache.45 Imaging is rarely used for infectious causes, but lymphangiography and lymphoscintigraphy can be used to detect anatomic abnormalities, such as lymphatic obstruction or dilated, tortuous lymphatic vessels.46 Treatment most often involves the use of antimicrobial agents; some patients require surgical debridement.38,47

Congenital Conditions Lipedema Lipedema is a chronic disorder of adipose biology that results in symmetrical, bilateral, fatty subcutaneous tissue deposition in the lower extremities and buttocks. The condition is characterized by hyperplasia and hypertrophy of adipocytes. Lipedema can occur with lymphedema, although lipedema has distinctive features that allow it to be differentiated from the more common problem of lower extremity lymphedema. In lipedema, the skin is often sensitive to pressure. Affected individuals have both spontaneous pain and pressure-induced discomfort. The problem is also associated with easy bruising and hematoma development after even minimal trauma. In lipedema the Stemmer sign is absent, and the condition is described as foot sparing. Moreover, it is often characterized by a normal cutaneous architecture, with no demonstrable dermal fibrosis or cutaneous thickening. Lipedema almost exclusively affects females and is often associated with a familial distribution. Lipedema can ultimately cause secondary lymphedema (so-called lipolymphedema) by distorting the microlymphatic function.7,48-50 Therapies are mostly conservative and similar to those used in lymphedema, including complex decongestive therapy, pneumatic compression, manual lymphatic drainage, bandaging, and diet modifications.51,52

Lymphangiomatosis Lymphangiomatosis is a congenital lymphatic malformation that arises from abnormal embryologic development. When present, it is typically detected within the first 2 years of life. It is postulated to develop from abnormal grouping of lymph sacs during development or the failure of proper lymph vascular tissue anastomoses.53 There are three types of lymphangiomas, which are differentiated by the depth of the malformation54: 1. Lymphangioma circumscriptum (the most superficial of the three) 2. Cavernous lymphangiomas (characterized by deeper lesions) 3. Cystic hygromas (characterized by deeper lesions)

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However, this terminology is in transition. The most useful diagnostic approach to lymphangioma is to perform an MRI, which yields anatomic information within the various tissue strata. Lymphangioma circumscriptum is distinguished by superficial, 1 to 2 mm vesicles in the papillary dermis. These lesions, which are filled with clear, colorless fluid, connect by dilated lymphatic channels to the subcutaneous lymphatic sacs.55,56 Cavernous lymphangiomas are microcystic soft tissue masses with lymphatic dilation in various layers beneath the epidermis of the tissue, including the dermis, subcutaneous tissue, and intermuscular septa.53 The overlying skin may show some hyperpigmentation and hyperplasia but is otherwise generally unaffected. Cystic hygromas are fluid-filled lesions caused by an obstruction in the drainage of the lymphatic system into the jugular vein, thus leading to the local accumulation of lymphatic fluid.53 These macrocystic fluid-filled sacs, which are often encased in a fibrous capsule, enlarge and fill dilated lymphatic vessels and tissue, leading to lymphedema.57 Cystic hygromas are associated with chromosomal disorders, such as Turner and Klinefelter syndromes.53 Lymphangiomatosis can present either as isolated lesions or as a systemic, multifocal derangement in lymphatic development. In the latter instance, in which visceral involvement is present, there is often significant pathologic dysfunction of the affected respiratory, gastrointestinal, or other organs. The treatment of lymphangioma may include surgical excision or chemical sclerosis.

Conditions With Congenital or Acquired Etiologic Factors Complex Vascular Malformations Complex vascular malformations manifest as a consequence of abnormal development or damage to blood and lymphatic vascular systems.16,58 These diseases often present with dermal manifestations, such as nodules or lesions. Cystic angiomatosis is a rare congenital condition characterized by multifocal hemangiomatous and/or lymphangiomatous lesions of the skeleton with possible visceral organ development.59 These cystic skeletal lesions may be comprised of dilated blood vessels, lymphatic channels, or both, and appear round or oval with a wide variety in size.60,61 Patients present with soft tissue masses and pathologic fractures that cause pain and swelling.61-63 On radiographs they appear as areas of destroyed bone encircled by a sclerotic rim and are confirmed by biopsy.60,61 Chemotherapy and radiotherapy have been tried, but generally they are ineffective.60 Maffucci syndrome is another type of complex vascular formation that is characterized by multiple enchondromas and subcutaneous hemangiomas resulting from mesodermal dysplasia.64-66 These tumors present early in childhood and progressively worsen, leading to significant skeletal deformities.64,66 Most of these tumors are benign, but there is a 15% to 30% incidence of malignant

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transformation, the most common of which is chondrosarcoma.64,65 This syndrome can lead to infectious complications and lymphedema.67 Diffuse hemangiomatosis is characterized by benign, visceral hemangiomas that affect at least three organ systems. The vascular hamartomas are a congenital defect and lead to diffuse lesions of the skin, liver, brain, lungs, and gastrointestinal tract. These lesions have a favorable response to corticosteroids and interferon-alfa therapy. Gorham disease is a rare condition characterized by the uncontrolled growth of benign blood and lymphatic vascular channels and the progressive growth of lymphangiomatous tissue that leads to massive osteolysis and bone destruction.68,69 This condition is also associated with chylous pericardial and pleural effusions.69 Surgical intervention (both resection or bone reconstruction) and radiotherapy are the treatment methods of choice.69-72 Proteus syndrome is a rare congenital hamartomatous disease characterized by the overgrowth of numerous body tissues and cell lines.73,74 It presents as subcutaneous tumors, hyperostosis, hyperplastic connective tissue in the palms and soles, pigmented nevi, and partial gigantism of the hands or feet.74,75 Klippel-Trenaunay syndrome (KTS) is a complex vascular malformation that includes capillary anomalies (port-wine stain), venous malformation (varicose veins), lymphatic anomalies, and hypertrophy of bone and soft tissue that can affect one or multiple limbs.17,76 The histologic hallmark of this condition is dilated telangiectatic vessels in the upper dermis that do not spontaneously regress.77 Complications of KTS include deep vein thrombosis, pulmonary embolism, gastrointestinal bleeding, and vascular (often lymphatic) blebs within the capillary malformations.78 Doppler ultrasonography can distinguish a KTS lesion from a hemangioma, but MRI and MR venography are useful to evaluate the extent of venous and lymphatic malformation and soft tissue and bone hypertrophy. Lymphoscintigraphy is useful for assessing the extent of lymphatic involvement.79-82 Treatment is focused on symptomatic relief; elevation and compression stockings offer some relief from the edema.83,84 Blue rubber bleb nevus is a rare, congenital venous malformation that consists of vascular nevi on the skin and hemangiomas of the gastrointestinal tract and soft tissues.85 The condition is characterized by anemia, fatigue, gastrointestinal bleeding, and cutaneous lesions that are painless, compressible, deep blue, and rubbery; the blebs are distributed diffusely.86 Treatment includes supportive medical therapy, such as transfusions and iron replacement for any gastrointestinal blood loss.85 Pharmacologic therapy, such as corticosteroids or interferon-alfa, have not been found to be very effective.87 Endoscopic interventions, such as sclerotherapy, can also be used to help control gastrointestinal blood loss.

Protein-Losing Enteropathy and Intestinal Lymphangiectasia Protein-losing enteropathy and intestinal lymphangiectasia are two disorders characterized by edema and hypoproteinemia and associated with the loss of lymphatic fluid and plasma protein within the lumen of the gastrointestinal tract. Although patients with protein-losing enteropathy have local lymphatic obstruction and stasis, those with lymphangiectasia have dilated lymphatic vessels in the intestinal villi.88,89

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Protein-losing gastroenteropathies are characterized by an excessive loss of serum proteins into the gastrointestinal tract through the intestinal microvilli, resulting in hypoproteinemia, edema, and pleural and pericardial effusions. Protein-losing enteropathy is associated with various disorders, including inflammatory bowel disease, infection, rheumatic diseases, celiac disease, graft-versushost disease, cardiac disease, and primary intestinal lymphangiectasia.90 Protein loss in this type of disorder is nonselective, which is in contrast to the glomerular diseases.91 The clinical manifestations of protein-losing gastroenteropathies are highly variable and include edema, ascites, pleural and pericardial effusions, fat and carbohydrate malabsorption, and vitamin deficiencies. The diagnostic characteristics of this disorder include reduced serum concentrations of albumin, gamma globulins, fibrinogen, transferrin, and ceruloplasmin.90 The treatment of this condition largely depends on the underlying cause. Intravenous albumin replacement, small bowel resection, or high-dose steroid therapy may be beneficial.92-95 Severe reduction of dietary fat intake with supplementation of medium-chain triglycerides can be attempted. In patients with congenital cardiac disease, heparin administration is recommended.58,92 Primary intestinal lymphangiectasia is characterized by ectasia of enteral lymphatics, which are often located in the mucosa, submucosa, or subserosa. Clinical manifestations include severe edema, thickening of the small bowel wall, protein-losing enteropathy, chylothorax or chylous ascites, intermittent diarrhea, nausea, and vomiting. CT imaging can be used in the diagnosis of this condition and shows nodular thickening of the bowel wall with hypodense streaks in the small bowel, reflecting dilated lymphatics.96,97 Contrast lymphangiography, nuclear scintigraphy, and MR lymphangiography can also show abnormal intestinal lymphatics.98-100 Dietary fat restriction with medium-chain triglyceride supplementation has been found to be effective in this condition.101 Chylous ascites can be ameliorated through the administration of somatostatin or its analogs.102

Lymphangioleiomyomatosis Lymphangioleiomyomatosis is a disorder characterized by the cystic destruction of the lung and lymphatic wall thickening resulting from the migration of abnormal smooth muscle cells through the axillary lymphatics and pulmonary interstitium.103 Lymphangioleiomyomatosis is associated with pulmonary cysts and angiomyolipomas, tumors consisting of smooth muscle cells, adipose tissue, and underdeveloped blood vessels.104 The most common clinical presentation is pulmonary, with manifestations that include dyspnea, chylous pleural effusions, cough, hemoptysis, pulmonary hypertension, and pneumothorax.103 Chylous ascites is also frequently encountered. Nonpulmonary findings include lymphangioleiomyomas—benign neoplasms that present as cystic masses in the mediastinum, retroperitoneum, or pelvis.105,106 Renal angiomyolipomas and meningiomas are also associated with lymphangioleiomyomatosis.107-110 Tissue biopsy is the main diagnostic tool in lymphangioleimyomatosis.111 Treatment involves embolization and prevention of pneumothorax through pleurodesis and pleurectomy.58,112,113

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C linical P earls • In primary lymphedema, numerous distinct gene mutations have thus far been described and characterized. Clinical genetic testing is now available. • Trauma, infection, and iatrogenic factors predominate as the causes of acquired lymphedema. • Lipedema is a defect in the adipose biology that can be confused with lower extremity lymphedema. • Lymphatic and complex vascular malformations can be associated with the presence of superficial or visceral lymphedema. • Protein-losing enteropathy and intestinal lymphangiectasia are associated with the loss of lymphatic fluid and plasma protein within the lumen of the gastrointestinal tract. • Lymphangioleiomyomatosis is a rare, complex disorder that has a component of abnormal lymphatic biology and may encompass chylothorax or chylous ascites within its presentation.

R EFERENCES 1. Rockson SG. Physiology, pathophysiology, and lymphodynamics: general overview. In Lee BB, Bergan J, Rockson SG, eds. Lymphedema: A Concise Compendium of Theory and Practice. London: Springer-Verlag, 2011. 2. Ristevski B, Becker H, Cybulsky M, et al. Lymph, lymphocytes, and lymphatics. Immunol Res 35:5564, 2006. 3. Rockson SG. Lymphedema. Am J Med 110:288-295, 2001. 4. Harvey NL, Srinivasan RS, Dillard ME, et al. Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity. Nat Genet 37:1072-1081, 2005. 5. Wigle JT, Harvey N, Detmar M, et al. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J 21:1505-1513, 2002. 6. Karkkainen MJ, Haiko P, Sainio K, et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 5:74-80, 2004. 7. Rockson SG. Etiology and classification of lymphatic disorders. In Lee BB, Bergan J, Rockson SG, eds. Lymphedema: A Concise Compendium of Theory and Practice. London: Springer-Verlag, 2011. 8. Oliver G, Harvey N. A stepwise model of the development of lymphatic vasculature. Ann N Y Acad Sci 979:159-165; discussion 188-196, 2002. 9. Lu P. Staging and classification of lymphoma. Semin Nucl Med 35:160-164, 2005. 10. Michelini S, Cardone M, Failla A, et al. Clinical staging. In Lee BB, Bergan J, Rockson SG, eds. Lymphedema: A Concise Compendium of Theory and Practice. London: Springer-Verlag, 2011. 11. Lawenda BD, Mondry TE, Johnstone PA. Lymphedema: a primer on the identification and management of a chronic condition in oncologic treatment. CA Cancer J Clin 59:8-24, 2009. 12. Rockson SG. Diagnosis and management of lymphatic vascular disease. J Am Coll Cardiol 52:799806, 2008.

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13. Badger CM, Peacock JL, Mortimer PS. A randomized, controlled, parallel-group clinical trial comparing multilayer bandaging followed by hosiery versus hosiery alone in the treatment of patients with lymphedema of the limb. Cancer 88:2832-2837, 2000. 14. Camacho A, Jiménez F, De La Torre J, et al. Assembly of Bacillus subtilis phage phi29. 1. Mutants in the cistrons coding for the structural proteins. Eur J Biochem 73:39-55, 1977. 15. Ferrell RE, Kimak MA, Lawrence EC, et al. Candidate gene analysis in primary lymphedema. Lymphat Res Biol 6:69-76, 2008. 16. Mortimer PS, Rockson SG. New developments in clinical aspects of lymphatic disease. J Clin Invest 124:915-921, 2014. 17. Jacob AG, Driscoll DJ, Shaughnessy WJ, et al. Klippel-Trenaunay syndrome: spectrum and management. Mayo Clin Proc 73:28-36, 1998. 18. Denniston A. Turner’s syndrome. Lancet 358:2169-2170, 2001. 19. Connell F, Brice G, Mortimer P. Phenotypic characterization of primary lymphedema. Ann N Y Acad Sci 1131:140-146, 2008. 20. Evans AL, Brice G, Sotirova V, et al. Mapping of primary congenital lymphedema to the 5q35.3 region. Am J Hum Genet 64:547-555, 1999. 21. Brice G, Mansour S, Bell R, et al. Analysis of the phenotypic abnormalities in lymphoedema-​distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. J Med Genet 39:478-483, 2002. 22. Mellor RH, Brice G, Stanton AW, et al. Mutations in FOXC2 are strongly associated with primary valve failure in veins of the lower limb. Circulation 115:1912-1920, 2007. 23. Szuba A, Rockson SG. Lymphedema: classification, diagnosis and therapy. Vasc Med 3:145-156, 1998. 24. Smeltzer DM, Stickler GB, Schirger A. Primary lymphedema in children and adolescents: a follow-up study and review. Pediatrics 76:206-218, 1985. 25. Rockson SG, Rivera KK. Estimating the population burden of lymphedema. Ann N Y Acad Sci 1131:147-154, 2008. 26. Balzer K, Schonebeck I. [Edema after vascular surgery interventions and its therapy] Z Lymphol 17:4147, 1993. 27. Carrizo GJ, Livesay JJ, Luy L. Endoscopic harvesting of the greater saphenous vein for aortocoronary bypass grafting. Tex Heart Inst J 26:120-123, 1999. 28. Ibanez JP, Monteverde ML, Goldberg J, et al. Sirolimus in pediatric renal transplantation. Transplant Proc 37:682-684, 2005. 29. Aldrete JA, Couto da Silva JM. Leg edema from intrathecal opiate infusions. Eur J Pain 4:361-365, 2000. 30. Keiser PB, Nutman TB. Update on lymphatic filarial infections. Curr Infect Dis Rep 4:65-69, 2002. 31. Nutman TB. Lymphatic filariasis: new insights and prospects for control. Curr Opin Infect Diseases 14:539-546, 2001. 32. Global Programme to Eliminate Lymphatic Filariasis. Progress report on mass drug administration, 2010. Weekly Epidemiological Record/Health Section of the Secretariat of the League of Nations 86:377-388, 2011. 33. Dreyer G, Medeiros Z, Netto MJ, et al. Acute attacks in the extremities of persons living in an area endemic for bancroftian filariasis: differentiation of two syndromes. Trans R Soc Trop Med Hyg 93:413417, 1999. 34. Kumaraswami V. The clinical manifestations of lymphatic filariasis. In Nutman TB, ed. Lymphatic Filariasis Tropical Medicine: Science and Practice. London: Imperial College Press, 2000. 35. Shenoy RK, John A, Babu BS, et al. Two-year follow-up of the microfilaraemia of asymptomatic brugian filariasis, after treatment with two, annual, single doses of ivermectin, diethylcarbamazine and albendazole, in various combinations. Ann Trop Med Parasitol 94:607-614, 2000. 36. Dunyo SK, Nkrumah FK, Simonsen PE. A randomized double-blind placebo-controlled field trial of ivermectin and albendazole alone and in combination for the treatment of lymphatic filariasis in Ghana. Trans R Soc Trop Med Hyg 94:205-211, 2000.

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37. Hoerauf A, Volkmann L, Nissen-Paehle K, et al. Targeting of Wolbachia endobacteria in Litomosoides sigmodontis: comparison of tetracyclines with chloramphenicol, macrolides and ciprofloxacin. Trop Med Int Health 5:275-279, 2000. 38. Ryncarz RE, Heasley EC, Babinchak TJ. The clinical spectrum of nodular lymphangitis. Hosp Physician 35:63-66, 1999. 39. Wu JW, Chiles C. Lymphangitic carcinomatosis from prostate carcinoma. J Comput Assist Tomogr 23:761-763, 1999. 40. Kohmo S, Tachibana I, Osaki T, et al. Multiple organ mucosa-associated lymphoid tissue lymphoma presenting with lymphangitic pattern of spread in the lung. J Thoracic Oncol 2:1057-1059, 2007. 41. Murphy MJ, Kogan B, Carlson JA. Granulomatous lymphangitis of the scrotum and penis. Report of a case and review of the literature of genital swelling with sarcoidal granulomatous inflammation. J Cutan Pathol 28:419-424, 2001. 42. Van Kruiningen HJ, Colombel JF. The forgotten role of lymphangitis in Crohn’s disease. Gut 57:1-4, 2008. 43. Rosen T, Hwong H. Sclerosing lymphangitis of the penis. J Am Acad Dermatol 49:916-918, 2003. 44. Schirger A. Lymphedema. Cardiovasc Clin 13:293-305, 1983. 45. Kostman JR, DiNubile MJ. Nodular lymphangitis: a distinctive but often unrecognized syndrome. Ann Intern Med 118:883-888, 1993. 46. Lohrmann C, Foeldi E, Bartholomä JP, et al. Interstitial MR lymphangiography—a diagnostic imaging method for the evaluation of patients with clinically advanced stages of lymphedema. Acta Trop 104:8-15, 2007. 47. Garfein ES, Borud LJ, Warren AG, et al. Learning from a lymphedema clinic: an algorithm for the management of localized swelling. Plast Reconstr Surg 121:521-528, 2008. 48. Shin BW, Sim YJ, Jeong HJ, et al. Lipedema, a rare disease. Ann Rehabil Med 35:922-927, 2011. 49. Vignes S. [Lipedema: a misdiagnosed entity] J Mal Vasc 37:213-218, 2012. 50. Reich-Schupke S, Altmeyer P, Stucker M. Thick legs—not always lipedema. J Dtsch Dermatol Ges 11:225-233, 2013. 51. Szolnoky G, Varga E, Varga M, et al. Lymphedema treatment decreases pain intensity in lipedema. Lymphology 44:178-182, 2011. 52. Wagner S. Lymphedema and lipedema—an overview of conservative treatment. VASA 40:271-279, 2011. 53. Faul JL, Berry GJ, Colby TV, et al. Thoracic lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome. Am J Respir Crit Care Med 161:1037-1046, 2000. 54. Ganesh C, Sangeetha GS, Narayanan V, et al. Lymphangioma circumscriptum in an adult: an unusual oral presentation. J Clin Imaging Sci 3:44, 2013. 55. Mordehai J, Kurzbart E, Shinhar D, et al. Lymphangioma circumscriptum. Pediatr Surg Int 13:208210, 1998. 56. Whimster IW. The pathology of lymphangioma circumscriptum. Br J Dermatol 94:473-486, 1976. 57. Chervenak FA, Isaacson G, Blakemore KJ, et al. Fetal cystic hygroma. Cause and natural history. N Engl J Med 309:822-825, 1983. 58. Radhakrishnan K, Rockson SG. The clinical spectrum of lymphatic disease. Ann N Y Acad Sci 1131:155184, 2008. 59. Marcucci G, Masi L, Carossino AM, et al. Cystic bone angiomatosis: a case report treated with aminobisphosphonates and review of the literature. Calcif Tissue Int 93:462-471, 2013. 60. Schajowicz F, Aiello CL, Francone MV, et al. Cystic angiomatosis (hamartous haemolymphagiomatosis) of bone. A clinicopathological study of three cases. J Bone Joint Surgery Br 60:100-106, 1978. 61. Boyle WJ. Cystic angiomatosis of bone. A report of three cases and review of the literature. J Bone Joint Surg Br 54:626-636, 1972. 62. Seckler SG, Rubin H, Rabinowitz JG. Systemic cystic angiomatosis. Am J Med 37:976-986, 1964. 63. Brunzell JD, Shankle SW, Bethune JE. Congenital generalized lipodystrophy accompanied by cystic angiomatosis. Ann Intern Med 69:501-516, 1968.

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64. Albregts AE, Rapini RP. Malignancy in Maffucci’s syndrome. Dermatol Clin 13:73-78, 1995. 65. Kerr HD, Keep JC, Chiu S. Lymphangiosarcoma associated with lymphedema in a man with Maffucci’s syndrome. South Med J 84:1039-1041, 1991. 66. Jermann M, Eid K, Pfammatter T, et al. Maffucci’s syndrome. Circulation 104:1693, 2001. 67. Kinmonth JB. The Lymphatics: Surgery, Lymphography, and Diseases of the Chyle and Lymph Systems. London: Edward Arnold Publishers, 1982. 68. Manisali M, Ozaksoy D. Gorham disease: correlation of MR findings with histopathologic changes. Eur Radiol 8:1647-1650, 1998. 69. Patel DV. Gorham’s disease or massive osteolysis. Clin Med Res 3:65-74, 2005. 70. Mawk JR, Obukhov SK, Nichols WD, et al. Successful conservative management of Gorham disease of the skull base and cervical spine. Childs Nerv Syst 13:622-625, 1997. 71. Dunbar SF, Rosenberg A, Mankin H, et al. Gorham’s massive osteolysis: the role of radiation therapy and a review of the literature. Int J Radiat Oncol Biol Phys 26:491-497, 1993. 72. Heyd R, Micke O, Surholt C, et al. Radiation therapy for Gorham-Stout syndrome: results of a national patterns-of-care study and literature review. Int J Radiat Oncol Biol Phy 81:e179-e185, 2011. 73. Raboudi T, Bouchoucha S, Hamdi B, et al. Soft-tissue necrosis complicating tibial osteotomy in a child with Proteus syndrome. Orthop Traumatol Surg Res 100:247-250, 2014. 74. Biesecker L. The challenges of Proteus syndrome: diagnosis and management. Eur J Hum Genet 14:1151-1157, 2006. 75. Clark RD, Donnai D, Rogers J, et al. Proteus syndrome: an expanded phenotype. Am J Med Genet 27:99-117, 1987. 76. Kihiczak GG, Meine JG, Schwartz RA, et al. Klippel-Trenaunay syndrome: a multisystem disorder possibly resulting from a pathogenic gene for vascular and tissue overgrowth. Int J Dermatol 45:883890, 2006. 77. Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 69:412-422, 1982. 78. Huiras EE, Barnes CJ, Eichenfield LF, et al. Pulmonary thromboembolism associated with KlippelTrenaunay syndrome. Pediatrics 116:e596-e600, 2005. 79. Dubois J, Garel L, Grignon A, et al. Imaging of hemangiomas and vascular malformations in children. Acad Radiol 5:390-400, 1998. 80. Dubois J, Garel L. Imaging and therapeutic approach of hemangiomas and vascular malformations in the pediatric age group. Pediatr Radiol 29:879-893, 1999. 81. Kern S, Niemeyer C, Darge K, et al. Differentiation of vascular birthmarks by MR imaging. An investigation of hemangiomas, venous and lymphatic malformations. Acta Radiol 41:453-457, 2000. 82. Berry SA, Peterson C, Mize W, et al. Klippel-Trenaunay syndrome. Am J Med Genet 79:319-326, 1998. 83. Ring DS, Mallory SB. What syndrome is this? Klippel-Trenaunay syndrome. Pediatr Dermatol 9:8082, 1992. 84. Enjolras O, Mulliken JB. The current management of vascular birthmarks. Pediatr Dermatol 10:311313, 1993. 85. Rodrigues D, Bourroul ML, Ferrer AP, et al. Blue rubber bleb nevus syndrome. Rev Hosp Clin Fac Med Sao Paulo 55:29-34, 2000. 86. Ganesh R, Reddy M, Janakiraman L, et al. Blue rubber bleb nevus syndrome. Indian J Pediatr 81:317318, 2014. 87. Ertem D, Acar Y, Kotiloglu E, et al. Blue rubber bleb nevus syndrome. Pediatrics 107:418-420, 2001. 88. Chiu NT, Lee BF, Hwang SJ, et al. Protein-losing enteropathy: diagnosis with (99m)Tc-labeled human serum albumin scintigraphy. Radiology 219:86-90, 2001. 89. Hilliard RI, McKendry JB, Phillips MJ. Congenital abnormalities of the lymphatic system: a new clinical classification. Pediatrics 86:988-994, 1990. 90. Bhatnagar A, Kashyap R, Chauhan UP, et al. Diagnosing protein losing enteropathy. A new approach using Tc-99m human immunoglobulin. Clin Nucl Med 20:969-972, 1995.

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91. Strober W, Wochner RD, Carbone PP, et al. Intestinal lymphangiectasia: a protein-losing enteropathy with hypogammaglobulinemia, lymphocytopenia and impaired homograft rejection. J Clin Invest 46:1643-1656, 1967. 92. Donnelly JP, Rosenthal A, Castle VP, et al. Reversal of protein-losing enteropathy with heparin therapy in three patients with univentricular hearts and Fontan palliation. J Pediatr 130:474-478, 1997. 93. Warshaw AL, Waldmann TA, Laster L. Protein-losing enteropathy and malabsorption in regional enteritis: cure by limited ileal resection. Ann Surg 178:578-580, 1973. 94. Rychik J, Piccoli DA, Barber G. Usefulness of corticosteroid therapy for protein-losing enteropathy after the Fontan procedure. Am J Cardiol 68:819-821, 1991. 95. Rothman A, Snyder J. Protein-losing enteropathy following the Fontan operation: resolution with prednisone therapy. Am Heart J 121:618-619, 1991. 96. Fakhri A, Fishman EK, Jones B, et al. Primary intestinal lymphangiectasia: clinical and CT findings. J Comput Assist Tomogr 9:767-770, 1985. 97. Puri AS, Aggarwal R, Gupta RK, et al. Intestinal lymphangiectasia: evaluation by CT and scintigraphy. Gastrointest Radiol 17:119-121, 1992. 98. Laor T, Hoffer FA, Burrows PE, et al. MR lymphangiography in infants, children, and young adults. AJR Am J Roentgenol 171:1111-1117, 1998. 99. Yueh TC, Pui MH, Zeng SQ. Intestinal lymphangiectasia: value of Tc-99m dextran lymphoscintigraphy. Clin Nucl Med 22:695-696, 1997. 100. Bhatnagar A, Lahoti D, Singh AK, et al. Scintigraphic diagnosis of protein losing enteropathy using Tc-99m dextran. Clin Nucl Med 20:1070-1073, 1995. 101. Holt PR. Dietary treatment of protein loss in intestinal lymphangiectasia. The effect of eliminating dietary long chain triglycerides on albumin metabolism in this condition. Pediatrics 34:629-635, 1964. 102. Soto-Martinez M, Massie J. Chylothorax: diagnosis and management in children. Paediatr Respir Rev 10:199-207, 2009. 103. Johnson S. Rare diseases. 1. Lymphangioleiomyomatosis: clinical features, management and basic mechanisms. Thorax 54:254-264, 1999. 104. Travis WD, Usuki J, Horiba K, et al. Histopathological studies on lymphangioleiomyomatosis. In Moss J, ed. LAM and Other Diseases Characterized by Smooth Muscle Proliferation. Lung Biology in Health and Disease. New York: Marcel Dekker, 1999. 105. Johnson SR, Cordier JF, Lazor R, et al. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J 35:14-26, 2010. 106. Derweduwen AM, Verbeken E, Stas M, et al. Extrapulmonary lymphangioleiomyomatosis: a wolf in sheep’s clothing. Thorax 68:111-113, 2013. 107. Chu SC, Horiba K, Usuki J, et al. Comprehensive evaluation of 35 patients with lymphangioleiomyomatosis. Chest 115:1041-1052, 1999. 108. Bosniak MA, Megibow AJ, Hulnick DH, et al. CT diagnosis of renal angiomyolipoma: the importance of detecting small amounts of fat. AJR Am J Roentgenol 151:497-501, 1988. 109. Bernstein SM, Newell JD Jr, Adamczyk D, et al. How common are renal angiomyolipomas in patients with pulmonary lymphangiomyomatosis? Am J Respir Crit Care Med 152:2138-2143, 1995. 110. Moss J, DeCastro R, Patronas NJ, et al. Meningiomas in lymphangioleiomyomatosis. JAMA 286:18791881, 2001. 111. Johnson SR, Clelland CA, Ronan J, et al. The TSC-2 product tuberin is expressed in lymphangioleiomyomatosis and angiomyolipoma. Histopathology 40:458-463, 2002. 112. Bissler JJ, Kingswood JC. Renal angiomyolipomata. Kid Int 66:924-934, 2004. 113. Ferrans VJ, Yu ZX, Nelson WK, et al. Lymphangioleiomyomatosis (LAM): a review of clinical and morphological features. J Nippon Med Sch 67:311-329, 2000.

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C hapter 21 Basic Approaches to the Diagnosis of Lymphedema: Clinicians’ Perspective Yener Demirtas, Baris Yigit

K ey P oints • Lymphedema can be defined as the chronic accumulation of lymphatic fluid in the interstitial space between tissue cells.

Bas nici

• The differential diagnosis of edema requires a detailed medical history of the patient and a physical examination. Physician experience diagnosing lymphedema also plays a key role. • According to the 2013 Consensus Document of the International Society of Lymphology, lymphedema can be divided into four stages. • To establish an accurate diagnosis of lymphedema, the most important factors are the duration of the swelling, clinical findings, and whether the disease is unilateral or bilateral. Clinical tests, such as an MRI, CT, SPECT-CT, and isotopic lymphoscintigraphy, also play a crucial role.

Clinically, lymphedema can be described as chronic excessive fluid accumulation in the interstitial spaces between tissue cells. This deposition (which at least in the extremities is epifascial) swelling is a consequence of increased inflow or decreased outflow or both.1 The diagnosis of lymphedema is basically made by a familial and clinical history and physical examination. To do this well, the physician should have many prior assessments of clinically manifest lymphedema. The typical presentation of a patient with early to midstage lymphedema is with a combination of the following signs and symptoms: whole or partial limb swelling; tightness in the skin; pitting caused by rings, a watchband, tight socks, or underwear; and a history of recurrent infections or functional complaints, such as heaviness, fatigue, and difficulty moving joints.2,3 Most patients will also have a history of injury or damage (for example, from cancer treatment) to the lymphatic

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system, because secondary lymphedema is the most common form of lymphedema, at least in Western populations. However, we are now aware that for some of these patients, there may be an underlying primary component. Furthermore, obesity, infections, and a history of radiotherapy significantly increase the risk of lymphedema. Patients with primary lymphedema may have a family history; however, sporadic forms of primary lymphedema are more common. In these situations, the diagnosis of primary lymphedema is one of exclusion.3

Differential Diagnosis There are many reasons for a swollen limb, and an accurate and appropriate diagnosis is critical to ensure the appropriate treatment. The differential diagnosis of edema requires a detailed medical history of the patient, physical examination, and occasionally special laboratory tests, such as an MRI and ultrasonography. Although distinguishing, the duration and distribution of the edema and the presence of dermatologic changes depend on the reason for the edema.4,5 According to the 2013 Consensus Document of the International Society of Lymphology,6 lymphedema has four stages. Stage 0 refers to the latent or subclinical period. Stage I refers to the early phase of swelling. Stage II swelling is accurate, and limb elevation does not reduce the swelling alone, although it does in stage I. Stage III refers to lymphostatic elephantiasis. If the duration of the edema is less than 2 weeks and also unilateral with the presentation of pain, it may be related to an acute condition, such as deep vein thrombosis, cellulitis, or a ruptured Baker cyst.7 If the edema is gradual and progressive over a few months (suggesting chronicity) and is unilateral without pain, then a possible diagnosis may be chronic venous insufficiency, external venous compression caused by a tumor of the iliac region of the lower extremity, or tumors of the soft tissue or vascular structures.8 However, lymphedema (primary or secondary) cannot be easily excluded. If the beginning of the edema is gradual, progressive, and bilateral, possible causes include congestive heart failure, glomerulonephritis, cirrhosis, lipedema, chronic venous insufficiency, or a malignancy in the pelvis, abdomen, or retroperitoneal space.7,8 Of course, it could also be bilateral lymphedema. Table 21-1 defines the differential diagnosis. Rarely, patients with long-standing lymphedema will present with lymphangiosarcoma, an aggressive tumor with a 5-year survival rate of less than 10%. This complication was first reported by Stewart and Treves in 1948 in patients with postmastectomy lymphedema and is referred to as Stewart-Treves syndrome. In this case, patients present with red or purple nodules in the diseased tissues and are most commonly treated with amputation (Fig. 21-1).

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TABLE 21-1  Differential Diagnosis of Lymphedema Situation

History

Clinical Findings

Unilateral/Bilateral

Possible Diagnosis

Acute

Short history (less than 2 wk)

Pain

Unilateral

Deep vein thrombosis, cellulitis, or ruptured Baker cyst

Chronic

Gradual or progressive

No pain

Unilateral

Chronic venous insufficiency, lymphedema (primary or secondary), external venous compression, or soft tissue or vascular tumor

Chronic

Gradual and progressive

No pain

Bilateral

Congestive heart failure, glomerulonephritis, cirrhosis, lipedema, bilateral chronic venous insufficiency, bilateral lymphedema, or malignancy (pelvic, abdominal, or retroperitoneal)

FIG. 21-1  A patient with postmastectomy lymphedema with Stewart-Treves syndrome.

Diagnosis of Lymphedema Although it is not difficult to establish a diagnosis of lymphedema with clinical findings and questioning the medical history of patients with advanced lymphedema,9 it can be difficult to distinguish other reasons for the edema, especially in the early stages, when mild and/or intermittent swelling is present. Some physical findings make the discrimination easy, such as the peau d’orange appearance of the skin (cutaneous and subcutaneous fibrosis). The Stemmer sign (an inability to pick up a skin fold of the dorsum of the second toe between the thumb and forefinger) can help distinguish lymphedema from other causes of the swelling, particularly in the middle or later stages, although it can be positive in the normal population.10,11

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15 minutes

60 minutes

120 minutes

FIG. 21-2  Typical lymphoscintigraphic findings of a unilateral lower extremity lymphedema. The images were scanned 15, 60, and 120 minutes after injection of the tracer. Lymph drainage without pathologic findings and clearly visible inguinal lymph nodes in the left (normal) leg is seen. The right leg shows diffuse distribution of the radiopharmaceutical in the lower leg (dermal backflow). The lymphatic pathways are not visualized, and the inguinal nodes are only noticeable at 120 minutes.

Additional tests may be required to confirm the diagnosis of lymphedema, because the physical examination and medical history do not always provide the whole, accurate picture. The diagnosis of lymphedema can be strengthened by tests such as isotopic lymphoscintigraphy, indirect and direct lymphography, lymphatic capillaroscopy, MRI, axial tomography, ultrasonography, and more recently the use of indocyanine green (ICG). The mechanism of isotopic lymphoscintigraphy is monitoring the radio-labeled macromolecule with a gamma-camera after the intradermal injection of ICG contrast dye into the interdigital area of the toes or fingers. In a healthy lymphatic system, major lymphatic trunks and nodes will be rapidly seen. A common finding in lymphedema is an inability to visualize the trunks or delayed monitoring of tracer at the lymphatic trunks and lymph nodes. The presence of dermal backflow, which occurs from the escape of the radio-labeled molecule from the major lymphatic trunks to the skin, is another common finding in lymphedema12-15 (Fig. 21-2). Dermal backflow is frequently seen in secondary lymphedema, which is indicative of a proximal obstruction. Lymphangiography is another test that is generally not used much today because of technical difficulties, such as the detection and cannulation of the lymphatics. Another reason is that the contrast dye can injure the remaining lymphatic vessels and thus worsen the lymphedema. One

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of the new techniques, ICG fluorescence, is very valuable for diagnosis and is also used for lymphatic venous anastomosis. With this test the lymphatic pathways, obliteration level, and dermal backflow can easily be detected. The diagnosis and structural tissue changes of lymphedema and their quantification can also be performed with various noninvasive methods, including perometry,16,17 tissue tonometry,16 bioimpedance spectroscopy,18-20 tissue dielectric constants,20 and other radiologic imaging techniques. Perometry is a method for calculating limb volumes and relies on the use of infrared scanning technology to estimate limb cross-sectional diameters at multiple intervals. Bioimpedance measures the rate of electrical current transmission through tissues and can estimate fluid content in a lymphedematous limb when compared with the normal limb. This technique is particularly helpful in early stage lymphedema, because it can detect fluids long before they are often clinically discernible. To note and document the structural changes, MR and CT imaging and single photon emission computed tomography (SPECT)–CT imaging are the best evaluation tests.21 Radiographic discrimination of lymphedema involves the absence of the edema within the muscular compartment. Fluid collections within the subfascial compartment may also be seen, even if the swelling is presumably limited by the inelastic deep fascia investing the muscle.22 Another radiographic finding is the honeycomb distribution of the edema, which is characteristic of lymphedema (not seen in other edematous situations) within the epifascial plane, along with thickening of the skin. SPECT-CT images are obtained with overlapped images of the lymphoscintigraphic SPECT and anatomic CT data. Tissue tonometry and indurometry, bioimpedance analysis, and tissue dielectric constants are easy, noninvasive tests that are also useful to detect the response to treatment.16-20 Finally, ultrasound can be used to evaluate lymphedema by correlating the thickness of the subcutaneous tissue with the progression of lymphedema and fibrosis.3

Conclusion The diagnosis of a typical patient with lymphedema is often quite easy for a physician who is experienced in recognizing lymphedema when a thorough medical history is obtained and a physical examination performed. However, because of the lack of general awareness of the disease among surgeons, most patients, especially those with lymphedema of the lower extremity, may still visit many physicians before they are finally diagnosed with lymphedema. Clinically, lymphedema can be described as the chronic accumulation of lymphatic fluid in the interstitial space between tissue cells. For a diagnosis, an evaluation of the patient history and a physical examination are almost sufficient. Lymphedema has four stages, 0 through III, based on the consensus document of the International Society of Lymphology. A differential diagnosis should be performed carefully. The most important factors to establish an accurate diagnosis of lymphedema are the duration of the swelling, clinical findings, and whether the disease is unilateral or bilateral. Clinical tests such as an MRI, CT, SPECT-CT, and isotopic lymphoscintigraphy are also important to establish a diagnosis.

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C linical P earls • Twenty percent of patients with lymphedema referred to our clinic by other physicians have lipedema, not lymphedema. • During an examination of a patient with unilateral lymphedema of the lower extremity, the surgeon should remember that 25% of these unilateral cases are or will be bilateral. We have diagnosed many patients with bilateral disease who were unaware of the earlier stage lymphedema at the contralateral lower extremity. • The surgeon should always exclude a recurrence in patients with an oncologic history. • The severity or stage of the disease is not always related to the duration of the lymphedema.

R EFERENCES 1. Daroczy J. Pathology of chronic lymphedema. Lymphology 6:91-106, 1994. 2. Warren AG, Brorson H, Borud LJ, et al. Lymphedema: a comprehensive review. Ann Plast Surg 59:464472, 2007. 3. Levine ST, Chang DW, Mehrara BJ. Lymphedema: diagnosis and treatment. In Thorne CHM, ed. Grabb and Smith’s Plastic Surgery, ed 7. Philadelphia: Lippincott William & Wilkins, 2014. 4. Dreyer G, Addiss D, Dreyer P, et al. Basic Lymphoedema Management, Treatment and Prevention of Problems Associated with Lymphatic Filariasis. Hollis, NH: Hollis Publishing, 2002. 5. Herpertz U. Lymphödem und Erysipel. Fortschr Med 116:36-40, 1998. 6. International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: 2013 Consensus Document of the International Society of Lymphology. Lymphology 46:1-11, 2013. 7. Browse N, Burnand K, Mortimer P, eds. Diseases of the Lymphatics. London: Arnold, 2003. 8. Kim DI, Huh S, Lee SJ, et al. Excision of subcutaneous tissue and deep muscle fascia for advanced lymphedema. Lymphology 31:190-194, 1998. 9. Rockson SG, Miller LT, Senie R, et al. American Cancer Society lymphedema workshop. Workgroup III: diagnosis and management of lymphedema. Cancer 83(Suppl 12):2882-2885, 1998. 10. Stemmer R. [A clinical symptom for the early and differential diagnosis of lymphedema] Vasa 5:261262, 1976. 11. Pannier F, Hoffmann B, Stang A, et al. Prevalence of Stemmer’s sign in the general population. Results from the Bonn Vein Study. Phlebologie 6:289-292, 2007. 12. Cambria RA, Gloviczki P, Naessens JM, et al. Noninvasive evaluation of the lymphatic system with lymphoscintigraphy: a prospective, semiquantitative analysis in 386 extremities. J Vasc Surg 18:773782, 1993. 13. Ter SE, Alavi A, Kim CK, et al. Lymphoscintigraphy. A reliable test for the diagnosis of lymphedema. Clin Nucl Med 18:646-654, 1993. 14. Case TC, Witte CL, Witte MH, et al. Magnetic resonance imaging in human lymphedema: comparison with lymphangioscintigraphy. Magn Reson Imaging 10:549-558, 1992. 15. Stanton AW, Mellor RH, Cook GJ, et al. Impairment of lymph drainage in subfascial compartment of forearm in breast cancer-related lymphedema. Lymphat Res Biol 1:121-132, 2003. 16. Piller NB, Clodius L. The use of a tissue tonometer as a diagnostic aid in extremity lymphoedema: a determination of its conservative treatment with benzo-pyrones. Lymphology 9:127-132, 1976.

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17. Mikes DM, Cha BA, Dym CL, et al. Bioelectrical impedance analysis revisited. Lymphology 32:157-165, 1999. 18. Bunce IH, Mirolo BR, Hennessy JM, et al. Post-mastectomy lymphoedema treatment and measurement. Med J Aust 161:125-128, 1994. 19. Ward LC, Bunce IH, Cornish BH, et al. Multi-frequency bioelectrical impedance augments the diagnosis and management of lymphoedema in post-mastectomy patients. Eur J Clin Invest 22:751-754, 1992. 20. Mayrovitz HN, Davey S, Shapiro E. Localized tissue water changes accompanying one manual lymphatic drainage (MLD) therapy session assessed by changes in tissue dielectric constant in patients with lower extremity lymphedema. Lymphology 41:186-188, 2008. 21. Vaughan BF. CT of swollen legs. Clin Radiol 41:24-30, 1990. 22. Clodius L, Deak L, Piller NB. A new instrument for the evaluation of tissue tonicity in lymphoedema. Lymphology 9:1-5, 1976.

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C hapter 22 Biomarkers Kerstin Buttler, Jörg Wilting

K ey P oints • Although the ideal biomarker showing the complete lymphatic vascular system has not yet been discovered, a combination of markers can be used to reliably detect the lymphatics. • In comparison with the blood vascular tree, there is heterogeneity of lymphatic endothelial cells in the lymphatic vascular network.

Bio

• The most constant marker to detect lymphatic vessels in human tissues appears to be double staining with antibodies against CD31 and PROX1.

It is highly likely that the lymphatic vascular system was already known to Hippocrates of Kos (about 460 to 377 BC). The Alexandrian school (about 300 BC to 600 AD) called the lymphatic vessels ductus lactei.1 Gasparo Asellius2 began the “reinvestigation” of the lymphatics in dogs, and Jean Pecquet3 and Olof Rudbeck4 followed soon thereafter in humans. Three hundred years later, the invention of the electron microscope clarified the cellular nature of the delicate wall of the initial lymphatics.5 However, efficient biomedical and cellular studies on the development and function of the lymphatics were hampered by the lack of reliable biomarkers of lymphatic endothelial cells (LECs) in health and disease. The first molecular LEC markers were found more or less by chance. However, they were the prerequisite to distinguish between LECs and blood vascular endothelial cells (BECs), and they enabled the purification of LECs in vitro and their subsequent global characterization at RNA and protein levels. Recent studies show the heterogeneity of LECs in the lymphatic vascular tree (initial lymphatics, collectors, lymph nodes, and trunks) and the organ-specific behavior of lymphatics. Therefore the ideal marker showing the complete lymphatic vascular system and differentiating it from blood vessels has not yet been found. Nevertheless, a combination of markers can be used to reliably detect the lymphatics. In this chapter we describe the molecules that have been used most widely to characterize LECs.

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Ecto-59-Nucleotidase Enzyme histochemical staining for ecto-59-nucleotidase (NT5E, cluster of differentiation 73 [CD73]) was one of the first markers to identify the lymphatics, and staining for alkaline phosphatase activity was used in parallel to identify blood vessels.6 Ecto-59-nucleotidase is a glycosylphosphatidylinositol-anchored surface protein, which, in addition to other functions, catalyzes the hydrolysis of purine 59-nucleotide to nucleoside and orthophosphate in water. It is part of the cascade that completely hydrolyzes extracellular adenosine triphosphate to adenosine. It has anticoagulant activity and can be found in snake venom.7 However, NT5E and alkaline phosphatase are not specifically expressed in LECs or BECs, and the method relies on quantitative rather than qualitative differences. Immunostaining for NT5E confirms expression in both types of vessels, with more prominent signals in the lymphatics (Fig. 22-1). Nevertheless, in combination with other techniques, NT5E can be a useful marker of the lymphatics.

CD31 and PROX1 Double Staining Double immunostaining with antibodies against cluster of differentiation 31 (CD31) (platelet endothelial cell adhesion molecule 1 [PECAM1]) and PROX1 is the most reliable tool to detect lymphatic vessels in human tissues (Fig. 22-2). This method detects lymphatics in human fetuses and the tissues of healthy adults, including aged adults and patients with lymphedema. It also differentiates lymphangiomas from hemangiomas,8 although each single marker is not specifically expressed in LECs only. PECAM1 is an adhesion molecule of the immunoglobulin superfamily. It is located in the cell membrane of platelets, monocytes, neutrophils and the subsets of T cells.9 PECAM1 is highly enriched on the surface of BECs and to a lesser extent is expressed on LECs. It is a regulator of leukocyte diapedesis, but its functions are not completely understood, because it may have both proinflammatory and antiinflammatory functions.10 The homeobox-containing transcription factor Prox1 is the mammalian homolog of the Drosophila gene prospero. Prox1 is essential for the development of the lymphatic vascular system. In Prox1 knockout mice, the lymphatics do not develop, whereas the blood vessels are obviously normal.11 Because of multiple defects, the mice die during the early stages of development. In LECs, PROX1 is located in the nucleus and thereby facilitates the counting of LEC numbers in histologic sections. Costaining with CD31 must be performed, because PROX1 is not endothelial cell specific but is expressed in other cell types, including hepatocytes, pancreatic epithelium, cardiomyocytes, lens, retina, spinal, and vegetative ganglia.12,13 PROX1 is expressed in LECs but not in BECs. The only exception from this rule seems to be the valve-forming endothelial cells in the blood vascular system: the concave side of the cardiac valves and venous valves.12,14 Nevertheless, the combination of CD31 and PROX1 is an excellent marker for LECs in vivo both in the initial lymphatics and lymphatic collectors (see Fig. 22-2) and in vitro.

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L

L

100 mm

FIG. 22-1  Immunohistochemical staining for ecto-59-nucleotidase (NT5E) of the human colon. Note the strong expression in lymphatic vessels (L) and weak expression in other tissues.

A

L L L

L

L L L

L 100 mm

B

C

LC

LCy

50 mm

50 mm

FIG. 22-2  Immunofluorescence staining of human tissues with antibodies against CD31 (green) and PROX1 (red). Counterstaining of nuclei with DAPI (blue). A, Foreskin of a 2-year-old boy. Numerous initial lymphatics (L) are weakly positive for CD31 and show nuclear PROX1 expression. Blood vessels are CD31 positive (strong) and PROX1 negative. B, Lymphatic collector (LC) of an adult. LECs are positive for CD31 and PROX1. C, Lymphatic cyst (LCy) of an infant with multiple lymphangiomas. LECs are positive for CD31 and PROX1.

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Hyaluronan Receptor LYVE1 LYVE1 is a transmembrane glycoprotein and a homolog of the hyaluronan receptor CD44.15 It is highly expressed in the initial lymphatics of the skin and other organs (Fig. 22-3) but inconsistently expressed in lymphatic collectors and lymph node sinusoids.16,17 In our experience LYVE1 is an excellent marker of the lymphatics in the mouse, but in the human we have observed weak staining also in veins. Other BECs that express LYVE1 are the sinusoids of the liver and spleen, high endothelial venules, and the syncytiotrophoblast of the placenta.18,19 A large number of scattered mesenchymal cells, many of which are obviously macrophages, are positive for LYVE1.20 It has been suggested that the physiologic function of LYVE1 resides in the turnover of hyaluronan. Hyaluronan is an important component of the extracellular matrix and is abundantly expressed in the dermis. Its main degradation sites are the lymph nodes and liver, and its transport to these organs is obviously by the lymphatic vessels.18 However, no specific alterations of the hyaluronan content were found in Lyve1 knockout mice.21

Podoplanin Podoplanin (also known as OTS-8, T1-alpha, E11 antigen) is a 43-kDa surface glycoprotein. The name refers to its expression in kidney podocytes, but its highly restricted expression in LECs and not in BECs was soon recognized.22 In addition to LECs, podoplanin is found in basal cells of the epidermis, mesothelium, type I alveolar cells, choroid plexus, cholangiocytes, and osteoblasts. In some cases it is expressed in plasma cells, Schwann cells, and fibrocytes. Podoplanin is useful in the diagnosis of lymphangiomas but should be used in combination with other markers.16,18,23 In the initial lymphatics, podoplanin is coexpressed with LYVE1 (Fig. 22-4). The staining with anti-podoplanin antibodies is highly similar to that of the antibody D2-40 raised against the 40-kDa oncofetal antigen M2A.24 D2-40 marks the initial lymphatics intensely (Fig. 22-5), but not the lymphatic collectors in all cases and lymph node sinuses only weakly. Blood vessels, including those of the liver and spleen, are not detected by the antibody. However, D2-40

FIG. 22-3  Immunohistochemical staining of human foreskin with anti-LYVE1 antibodies. LYVE1 (black signal) marks the initial lymphatics.

60 mm

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A

B

DAPI

C

Podoplanin

D

70 mm LYVE1

Merged

FIG. 22-4  Immunofluorescence staining of human foreskin with antibodies against podoplanin (green) and LYVE1 (red). A, Counterstaining of nuclei with DAPI (blue). B, Anti-podoplanin. C, Anti-LYVE1. D, Merged picture. Note the double labeling of the initial lymphatics.

50 mm

FIG. 22-5  Immunofluorescence staining of human foreskin with D2-40 antibodies (magenta). The initial lymphatics are positive. In addition, we observed staining of the perineural sheath of the peripheral nerves (not shown).

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25 mm

FIG. 22-6  Immunofluorescence staining of lymphangioma tissue from an infant with antibodies against VEGFR-3 (green) and PROX1 (magenta). Lymphatic vessels are positive for the two markers.

also recognizes the mesothelium, follicular dendritic cells, and fibroblasts of scar tissue, basal cells of the epidermis and prostate, myoepithelial cells of the mammary gland, ependymal cells, and choroid plexus epithelium.16 In regard to neoplastic tissues, D2-40 marks gastrointestinal stroma tumors, seminomas, numerous brain tumors, and mesotheliomas.16

Vascular Endothelial Growth Factor Receptor 3 Vascular endothelial growth factor receptor 3 (VEGFR-3) is a receptor of the vascular endothelial growth factor (VEGF) family of endothelial growth factors. It is typically expressed on LECs and binds the lymphangiogenic growth factors VEGF-C and VEGF-D with high affinity.25 In addition to the transmembrane form of the receptor, an endogenous-secreted splice variant of VEGFR-3 was recently found, which acts as an inhibitor of lymphangiogenesis.26 VEGFR-3 is very important in the development of the lymphatics, and heterozygous mutations affecting the tyrosine kinase domain of the VEGFR-3 (FLT4) gene are the leading causes of the development of primary lymphedema.27 In early embryos, before the development of the lymphatics, VEGFR-3 is expressed in blood vessels. Its great importance in the development of early blood vessels is emphasized by cardiovascular failure and the early death of Flt4 knockout mice.28 Later in development, VEGFR-3 becomes restricted to the lymphatics and high endothelial venules. However, in pathologic tissues (solid tumors and hemangiomas), it becomes upregulated in subsets of blood vessels, reflecting the early embryonic status.29,30 Additional markers are then needed to unequivocally identify the lymphatics (Fig. 22-6).

Mannose Receptor, C Type 1 High expression of mannose receptor, C type 1 (MRC1) (also known as MRC1L1, CD206, CLEC13D) was found by gene microarray analyses in human LECs,31-33 although the detection of MRC1 at the protein level may be difficult in LECs. MRC1 is an endocytotic receptor for highmannose structures on the surface of pathogens (viruses, bacteria, and fungi). After non-selfrecognition, they can be neutralized by macrophages via phagocytic engulfment. Endogenous

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self-ligands include L-selectin, which is implicated in cell migration.34 The fact that Mrc1 knock­ out mice do not seem to have higher susceptibility for infection suggests that MRC1 functions can be compensated by other surface receptors.35 The highest levels of MRC1 are expressed during the resolution of inflammation.36 In addition, MRC1 has been implicated in antigen presentation.37 The expression of MRC1 on LECs, macrophages, and dendritic cells has led to the development of the clinical lymphatic tracer Lymphoseek, a radiolabeled (technetium-99m) macromolecule of multiple mannose units, which may be useful in the search for draining (sentinel) lymph nodes in cancer patients.38

Conclusion Studies on the lymphatic vascular system were characterized by great discontinuity during past centuries. After seminal documented studies on macroscopic aspects of the lymphatics in the seventeenth century,2,4 intense disputations on their development in the late nineteenth and early twentieth centuries,39,40 and clarification of their cellular composition in the 1960s,5 the era of molecular lymphology began in the 1990s with the detection of lymphangiogenic growth factors and their receptors.41-44 The identification of biomarkers of LECs facilitated their isolation and global characterization at RNA and protein levels and pointed to their distinction from BECs. Compared with the blood vascular tree, there is heterogeneity of LECs in the lymphatic vascular network. LECs of the initial lymphatics, collectors, and lymph node sinuses are molecularly distinct, and within the lymph nodes, even the parietal and visceral linings of the marginal sinuses are heterogeneous. The most constant marker for LECs seems to be double staining with the antibodies against CD31 and PROX1. We also learned that there is organ specificity of lymphatics; the visceral lymphatics show higher expression of the VEGF-C coreceptor neuropilin-2 compared with the dermal lymphatics,45 whereas the latter seems more dependent on signaling via Wnt5a.46 It is hoped that lymphedema and cancer patients will benefit from the translation of the data into the clinical realm.

R EFERENCES 1. Rusznyák I, Földi M, Szabó G. Lymphologie: Physiologie und Pathologie der Lymphgefässe und des Lymphkreislaufes. Stuttgart: Gustav Fischer, 1969. 2. Asellius G. De Lacteibus Sive Lacteis Venis Quarto Vasorum Mesaroicum Genere Novo Invente Gasp. Asellii Cremonesis Antomici Ticiensis Qua Sententiae Anatomicae multae, nel Perperam Receptae Illustrantur. Mediolani, apud Jo Baptistam Bidellium, 1627. 3. Pecquet J. Experimenta Nova Anatomica, Quibus Incognitum Chyli Receptaculum, et ab eo per Thoracem in Ramos Usque Subclavios Vasa Lactea Deteguntur. Montpellier, France, 1651. 4. Rudbeck O. Nova Exercitatio Anatomica Exhibens Ductus Hepaticos Aquosos et Vasa Glandularum Serosa, Nunc Primum Inventa, Aeneisque Figuris Delineata. Arosiae, Sweden, 1653. 5. Casley-Smith JR, Florey HW. The structure of normal small lymphatics. Q J Exp Physiol Cogn Med Sci 46:101-106, 1961. 6. Kato S, Miyauchi R. Enzyme-histochemical visualization of lymphatic capillaries in the mouse tongue: light and electron microscopic study. Okajimas Folia Anat Jpn 65:391-403, 1989. 7. Dhananjaya BL, Nataraju A, Rajesh R, et al. Anticoagulant effect of Naja naja venom 59nucleotidase: demonstration through the use of novel specific inhibitor, vanillic acid. Toxicon 48:411-421, 2006.

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8. Wilting J, Papoutsi M, Christ B, et al. The transcription factor Prox1 is a marker for lymphatic endothelial cells in normal and diseased human tissues. FASEB J 16:1271-1273, 2002. 9. Newman PJ, Berndt MC, Gorski J, et al. PECAM-1 (CD31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily. Science 247:1219-1222, 1990. 10. Privratsky JR, Newman DK, Newman PJ. PECAM-1: conflicts of interest in inflammation. Life Sci 87:69-82, 2010. 11. Wigle JT, Oliver G. Prox1 function is required for the development of the murine lymphatic system. Cell 98:769-778, 1999. 12. Rodriguez-Niedenführ M, Papoutsi M, Christ B, et al. Prox1 is a marker of ectodermal placodes, endodermal compartments, lymphatic endothelium and lymphangioblasts. Anat Embryol (Berl) 204:399406, 2001. 13. Tomarev SI, Zinovieva RD, Chang B, et al. Characterization of the mouse Prox1 gene. Biochem Biophys Res Commun 248:684-689, 1998. 14. Bazigou E, Makinen T. Flow control in our vessels: vascular valves make sure there is no way back. Cell Mol Life Sci 70:1055-1066, 2013. 15. Banerji S, Ni J, Wang SX, et al. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 144:789-801, 1999. 16. Kaiserling E. Morphologische und funktionelle Aspekte des normalen und pathologisch Veränderten lymphatischen Gewebes. In Földi M, Földi E, eds. Lehrbuch der Lymphologie. Munich: Elsevier, 2010. 17. Kasten P, Schnöink G, Bergmann A, et al. Similarities and differences of human and experimental mouse lymphangiomas. Dev Dyn 236:2952-2961, 2007. 18. Sleeman JP, Krishnan J, Kirkin V, et al. Markers for the lymphatic endothelium: in search of the holy grail? Microsc Res Tech 55:61-69, 2001. 19. Wrobel T, Dziegiel P, Mazur G, et al. LYVE-1 expression on high endothelial venules (HEVs) of lymph nodes. Lymphology 38:107-110, 2005. 20. Chen L, Cursiefen C, Barabino S, et al. Novel expression and characterization of lymphatic vessel endothelial hyaluronate receptor 1 (LYVE-1) by conjunctival cells. Invest Ophthalmol Vis Sci 46:45364540, 2005. 21. Gale NW, Prevo R, Espinosa J, et al. Normal lymphatic development and function in mice deficient for the lymphatic hyaluronan receptor LYVE-1. Mol Cell Biol 27:595-604, 2007. 22. Breiteneder-Geleff S, Soleiman A, Kowalski H, et al. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 154:385-394, 1999. 23. Schacht V, Ramirez MI, Hong YK, et al. T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J 22:3546-3556, 2003. 24. Marks A, Sutherland DR, Bailey D, et al. Characterization and distribution of an oncofetal antigen (M2A antigen) expressed on testicular germ cell tumours. Br J Cancer 80:569-578, 1999. 25. Tammela T, Alitalo K. Lymphangiogenesis: Molecular mechanisms and future promise. Cell 140:460476, 2010. 26. Singh N, Tiem M, Watkins R, et al. Soluble vascular endothelial growth factor receptor 3 is essential for corneal alymphaticity. Blood 121:4242-4249, 2013. 27. Evans AL, Bell R, Brice G, et al. Identification of eight novel VEGFR-3 mutations in families with primary congenital lymphoedema. J Med Genet 40:697-703, 2003. 28. Dumont DJ, Jussila L, Taipale J, et al. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282:946-949, 1998. 29. Partanen TA, Alitalo K, Miettinen M. Lack of lymphatic vascular specificity of vascular endothelial growth factor receptor 3 in 185 vascular tumors. Cancer 86:2406-2412, 1999. 30. Wilting J, Papoutsi M, Othman-Hassan K, et al. Development of the avian lymphatic system. Microsc Res Tech 55:81-91, 2001.

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31. Hirakawa S, Hong YK, Harvey N, et al. Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells. Am J Pathol 162:575-586, 2003. 32. Petrova TV, Mäkinen T, Mäkelä TP, et al. Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J 21:4593-4599, 2002. 33. Wilting J, Becker J, Buttler K, et al. Lymphatics and inflammation. Curr Med Chem 16:4581-4592, 2009. 34. Gordon S. Pattern recognition receptors: doubling up for the innate immune response. Cell 111:927930, 2002. 35. Gazi U, Martinez-Pomares L. Influence of the mannose receptor in host immune responses. Immunobiology 214:554-561, 2009. 36. Lee SJ, Evers S, Roeder D, et al. Mannose receptor-mediated regulation of serum glycoprotein homeostasis. Science 295:1898-1901, 2002. 37. Stahl PD, Ezekowitz RA. The mannose receptor is a pattern recognition receptor involved in host defense. Curr Opin Immunol 10:50-55, 1998. 38. Sondak VK, King DW, Zager JS, et al. Combined analysis of phase III trials evaluating [99mTc] tilmanocept and vital blue dye for identification of sentinel lymph nodes in clinically node-negative cutaneous melanoma. Ann Surg Oncol 20:680-688, 2013. 39. Kampmeier O. The value of the injection method in the study of lymphatic development. Anat Rec 6:223-233, 1912. 40. Sabin FR. On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig. Am J Anat 1:367-389, 1902. 41. Galland F, Karamysheva A, Pebusque MJ, et al. The FLT4 gene encodes a transmembrane tyrosine kinase related to the vascular endothelial growth factor receptor. Oncogene 8:1233-1240, 1993. 42. Jeltsch M, Kaipainen A, Joukov V, et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276:1423-1425, 1997. 43. Kaipainen A, Korhonen J, Pajusola K, et al. The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells. J Exp Med 178:2077-2088, 1993. 44. Oh SJ, Jeltsch MM, Birkenhager R, et al. VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Dev Biol 188:96-109, 1997. 45. Karkkainen MJ, Saaristo A, Jussila L, et al. A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci U S A 98:12677-12682, 2001. 46. Buttler K, Becker J, Pukrop T, et al. Maldevelopment of dermal lymphatics in Wnt5a-knockout-mice. Dev Biol 381:365-376, 2013.

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C hapter 23 Clinical Staging of Lymphedema Sandro Michelini, Marco Cardone, Alessandro Fiorentino

Clin

K ey P oints • There is no perfect staging system for lymphedema. • A staging system is essential to facilitate a scientific dialog and cohesive treatment planning. • In addition to staging the clinical disease, it is important to incorporate functional assessment. • Proper treatment planning can only occur with such a staging system.

There is no perfect staging system for lymphedema. This becomes patently obvious as we learn more about the condition. The present lack of a universally recognized staging system makes it difficult to compare not only diagnoses but also treatment options and outcomes in published reports. The staging of lymphedema is a long-standing question that has been discussed at consensus meetings at all national and international congresses of lymphology. To secure universal agreement about the definitions and framing of the pathology of lymphedema, a staging system characterized by simplicity, recognizability, and worldwide use is required. Four international proposals exist; they are based on different clinical aspects and instrumental measures of the pathology but have some characteristics in common. It is essential that these be synchronized and synthesized through the work of a special world commission to obtain a scientific tool with universally recognized and accepted parameters. A common tool to stage lymphedema is necessary for more precise scientific communication and medicolegal and social reasons. Particularly in its advanced stages, lymphedema is a socially significant disease with substantial cost implications for treatment and the loss of working capacity.

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International Society of Lymphology The present staging reported in the 2013 Consensus Document of the International Society of Lymphology (ISL)1 includes one preclinical and three clinical stages (Table 23-1). The initial staging of three clinical stages was revised by the International Society of Lymphology, Lymphology Association of North America, and German Society of Lymphology. This revision underscored the importance of including a preclinical stage for both primary and secondary lymphedema, which was defined as stage 0. The three clinical stages differ essentially in the presence of a pitting (stage I) or nonpitting (stages II and III) edema and in the association in the third stage of complications, often with a progressive evolution in the skin and subcutaneous tissues. The same stages are indicated in the Consensus Document of the International Union of Phlebology.2 Stage 0 is subclinical. Stage 1 represents an early accumulation of fluid with high-protein content that subsides with limb elevation (Fig. 23-1, A). Pitting edema is seen in this stage. In stage 2, limb elevation rarely reduces tissue swelling, and pitting is not a feature (Fig. 23-1, B). Stage 3 includes lymphostatic elephantiasis with absent pitting and trophic skin changes (acanthosis, fat deposits, and warty overgrowths) (Fig. 23-1, C). The severity of the stage is based on volume dif-

TABLE 23-1  Lymphedema Staging According to the 2013 Consensus Document of the International Society of Lymphology Stage

Evidence

0

Subclinical; absence of edema in “risk of development” patient

I

Presence of edema reduced by treatment (pitting edema)

II

Edema partially reduced by treatment (no pitting edema)

III

Elephantiasis with skin lesions and relapsing infections

B

C

A

FIG. 23-1  International Union of Phlebology stages. Stage 0 (is subclinical). A, Stage 1 (pitting edema); B, stage 2 (no pitting edema); C, stage 3 (complicated elephantiasis).

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ferences: minimal (less than 20% increase), moderate (20% to 40% increase), and severe (greater than 40% increase). At the Twentieth International Congress of Lymphology in Brazil, various groups offered different proposals on lymphedema staging. A special international commission gathered all these ideas to define the new official staging according to the ISL.2

German Staging The German Society of Lymphology, led by Etelka Földi, included for the first time four clinical stages of lymphedema. In addition to the four stages of the ISL Consensus Document, a stage 0 was included, representing all cases of subclinical lymphedema but with significant risk of the clinical appearance of edema (for example, lymphoscintigraphic findings of lymphatic impairment)3 (Table 23-2).

Italian Staging In 1995 the Italian Society of Lymphangiology proposed five stages4 (Table 23-3), in which preclinical cases with a risk of worsening edema are underscored (stage 1). However, this school also differed in the underlying cases of elephantiasis with severe chronic inflammatory and infective complications with the risk of tumor tissue degeneration (stage 5).4-7

TABLE 23-2  Lymphedema Staging According to the German Society of Lymphology Stage

Evidence

0

No edema but significant risk of its clinical appearance

1

Edema reduced with treatment (pitting edema)

2

Edema reduced with treatment only partially (no pitting edema)

3

Elephantiasis with skin lesions and relapsing infections

TABLE 23-3  Lymphedema Staging Proposed by the Italian Society of Lymphangiology Stage

Evidence

1

No edema in an at-risk patient (preclinical)

2

Edema that reduces spontaneously with antigravitational position and during the night

3

Edema that does not reduce spontaneously and only partially with treatment; appearance of recurrent lymphangitis

4

Fibrotic edema (disappearance of tendon and bone shapes)

5

Complicated elephantiasis with relapsing skin infections and involvement of deep layers (muscles and joints)

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Japanese Staging Ohkuma,8 a scientist with a particular interest in infective complications of the skin and subcutaneous tissues, proposed four stages based on clinical criteria and frequency of infections and inflammatory episodes, in which it is also possible to obtain prognostic information from this staging (Table 23-4).

South American Staging The staging system proposed by the Brazilian Society of Phlebology and Lymphology is led by the Brazilian group (Mauro Andrade). In addition to the preclinical aspects and risk of developing infectious and degenerative complications, this group stresses the functional data of the impairment resulting from the edema. According to this staging, only one major joint of the limb must be involved, although two or all three major joints can be affected. This aspect allows the establishment of a global therapeutic rehabilitative program to determine the necessity of assistance for the patient and the degree of reduction of activities of daily living9 (Table 23-5). Therefore this staging includes both clinical and functional criteria.9

TABLE 23-4  Lymphedema Staging Proposed by the Japanese School Characteristic of the Skin

Physical Examination

Lipodermatosclerosis With/Without Phlogosis

Prognosis

1

Normal

Pitting edema11

No

Temporary

2

Thin skin

Harder edema, pitting edema1

No

Permanent

3

Cutaneous lichenification

No pitting edema

Yes

Worsening edema

4

Cutaneous verrucosis

Fibrotic, no pitting edema

Very frequent

Worsening edema

Stage

1, Moderate; 11, remarkable.

TABLE 23-5  Lymphedema Staging Proposed by the Brazilian Society of Phlebology and Lymphology Stage

Evidence

0

No edema in an at-risk patient (preclinical)

1

Edema that reduces spontaneously with antigravitational position, pitting11, Stemmer sign1, and involvement of at least two joints

2

Edema that does not reduce spontaneously with antigravitational position but only by treatment, pitting1, Stemmer sign11, and involvement of at least two joints

3

Edema that reduces only partially with treatment, pitting1, Stemmer sign11, and involvement of at least three joints

4

Edema that reduces only partially with treatment, pitting1, Stemmer sign11, and involvement of at least three joints, with skin infections

1, Moderate; 11, remarkable.

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Conclusion The issue of lymphedema staging is important. With more precise, uniform definitions, each stage can be associated with specific levels of assistance parameters related to these pathologies, which are highly prevalent in the worldwide population. Staging is essential to guide physicians in developing an accurate diagnosis, selecting the appropriate treatment for each patient, monitoring the disease process, and determining the need for surgical intervention. In this way it is very important for primary prevention and early diagnosis to ensure the best management of this chronic illness. Early treatment and clinical management provide the best quality of life for the patient and less costs for both the individual and society. Currently, only the health care systems in some states and a few regions support lymphedema patients. Frequently the support available is inadequate, resources are poor, and patients are required to pay for their treatments and support systems. Therefore it is imperative to devise a common scientific tool for staging to facilitate a discussion of these problems at the regional, national, and international levels, as well as to promote epidemiologic studies on the serious disabilities caused by lymphedema. In recent years more centers around the world have started to apply the International Classification of Functioning, Disability and Health (ICIDH),10-12 because this organization provides a common framework for describing health conditions and outcome measurements. In addition to including the staging systems currently used, obtaining a disability quantification through an evaluation of specific core sets makes it possible to better describe the health condition in those patients, thereby providing a more complete tool for clinical evaluation and treatment planning.13-15

C linical P earls • Stemmer’s test results in either a positive or negative sign for primary lymphedema in all stages. • Pitting test is usually present in the early stages of lymphedema. • Fibrosis and elephantiasis are common in the advanced stages. • International Classification of Functioning, Disability and Health (ICF) is strongly recommended for describing disability and functional status.

R EFERENCES 1. International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: 2013 Consensus Document of the International Society of Lymphology. Lymphology 46:1-11, 2013. 2. Lee B, Andrade M, Bergan J, et al. Diagnosis and treatment of primary lymphedema. Consensus Document of the International Union of Phlebology (IUP)-2009. Int Angiol 29:454-470, 2010.

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3. Földi M, Földi E. Földi’s Textbook of Lymphology. New York: Elsevier, 2009. 4. Campisi C, Michelini S, Boccardo F, et al. Modern stadiation of lymphedema and corresponding preventive options. Eur J Lymphol 7:27-31, 1999. 5. Michelini S, Campisi C, Gasbarro V, et al. National guidelines on lymphedema. Lymphology 55:238242, 2007. 6. Michelini S, Failla A, Moneta G, et al. Clinical staging of lymphedema and therapeutical implications. Lymphology 35:168-176, 2002. 7. Michelini S, Failla A. Linfedemi: inquadramento diagnostico clinico e strumentale. Minerva Cardioangiol 45(Suppl 1):11-15, 1997. 8. Twentieth International Congress of International Society of Lymphology [abstract]. I Brasilian Congress of Lymphology—I Congreso del CAPAL (Latin American Charter of International Society of Lymphology), Salvadore, Brazil, 2005. 9. World Health Organization. International Classification of Functioning, Disability and Health (ICF). Geneva, Switzerland: WHO, 2002. 10. Michelini S, Failla A, Moneta G, et al. International classification of lymphedema functioning and disability evaluation. Eur J Lymphol 17:16-19, 2007. 11. International Lymph Framework: Best Practice for the Management of Lymphoedema, ed 2, 2012. Available at www.lympho.org. 12. Devoogdt N. The lymphoedema functioning disability and health questionnaire for lower limb lymphoedema (Lymph-ICF-LL): reliability and validity [abstract]. Twenty-fourth Congress of the International Society of Lymphology, Rome, Sept 2013. 13. Viehoff P. Developing of ICF core sets for lymphoedema: qualitative research [abstract]. Twenty-fourth Congress of the International Society of Lymphology, Rome, Sept 2013. 14. Hendrickx AA. The use of clinimetric instruments according to the International Classification of Functioning, Disability and Health in a multidisciplinary setting [abstract]. Twenty-fourth Congress of the International Society of Lymphology, Rome, Sept 2013. 15. Michelini S, Campisi C, Failla A, et al. Staging of lymphedema: comparing different proposals. Eur J Lymphol 16:7-10, 2006.

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C hapter 24 Measuring Methods Peter C. Neligan

Me

K ey P oints • No perfect measurement tool for lymphedema exists. • Limb circumference and volume are the most commonly performed measurements for lymphedema. • Volume is most frequently calculated using the truncated cone model. • Perometry is a reliable method of measuring limb volume, but it is not universally available. • Lymph flow measurement using lymphoscintigraphy is a reliable way to document lymphedema. • MRI provides excellent information but is not easily applicable for documenting ongoing changes. • Bioimpedance analysis is probably the most useful method for diagnosing preclinical lymphedema.

Making a diagnosis is one of the most important things that physicians do when they first see a patient with lymphedema. Evidence suggests that a subjective assessment through patient selfreporting is a more sensitive and less expensive means of diagnosing the development of lymphedema.1-3 Nevertheless, it is useful to maintain objective documentation. A combination of both approaches is probably best. The first step in diagnosing lymphedema is to determine the extent of the disease. This requires some sort of measurement. A means of comparative and quantitative assessment of the results of treatment is also required. The measurement technique needs to be standardized, quantitative, repeatable, and reproducible; it should also be easily available and inexpensive. The most often used quantitative assessment of lymphedema is assessment of size based on the measurement of circumference or volume. Other methods include measurements of lymph flow, tonometry (to evaluate compressibility), and bioimpedance.4-6 Each of these methods has advantages and disadvantages. No perfect measuring technique exists.

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Measurement of Limb Circumference and Limb Volume Limb circumference and limb volume are the most frequently obtained measurements in patients with lymphedema.

Measurement of Limb Circumference Limb circumference is measured from a fixed point such as the tip of the long finger or from anatomic landmarks such as the patella or the olecranon (Fig. 24-1). Identification of local landmarks can be problematic in lymphedematous patients, because they may not be readily palpable. Furthermore, landmark descriptions may have various interpretations, which can lead to confusion and inaccuracy. For example, the patella can be measured from the proximal end, the distal end, or the middle. This can make a significant difference, particularly when measurements are repeated and compared at different time points. Limb circumference as a means of measurement has been criticized because of inconsistencies in tape measure tension and placement from one measurement to the next. Although measurements at specified intervals from a fixed point may seem to be a more accurate technique, Taylor et al7 found excellent correlation between measurements taken in reference to fixed anatomic landmarks and plethysmography.

FIG. 24-1  A tape measure is used to document limb circumference measurements at 4 cm intervals from the tip of the second toe. Each point is marked, and limb circumference measurements are recorded at each point of measurement.

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FIG. 24-2  Water-displacement plethysmography is an accurate way of measuring limb volume. The arm (or leg) is immersed in a container of water. The volume of displaced water is equivalent to the volume of the limb.

Measurement of Limb Volume The most widely accepted measure of lymphedema is limb volume. The affected limb can be compared with the unaffected limb, or measurements of the affected limb can be compared before and after interventions or events that led to the lymphedema. Volumes are most accurately measured by plethysmography or water displacement8-10 (Fig. 24-2). However, defining and replicating the upper level for immersion can be difficult, and water displacement is not convenient for routine clinical use. Brorson and Höijer11 followed 10 women with unilateral upper extremity lymphedema after breast cancer treatment. They calculated volume indirectly by circumference measurements (CM), using the formula for a truncated cone. The authors developed two Excel-based formulas of the truncated cone: one for fixed 4 cm intervals, leading to 10 volume segments (VS) (CM-10-VS), and one for varying intervals, leading to four volume segments (CM-4-VS). Plethysmography yielded greater volumes, because the hand was included, but excellent correlation was observed between volumes measured by plethysmography and volumes measured by limb circumference from a fixed point. No difference was noted between CM-10-VS and CM-4-VS. In my practice I have adopted the CM-10-VS method, because in my experience, it is simple, reproducible, and repeatable, regardless of who obtains the measurements. For the upper limb, circumference is measured at 4 cm intervals from the tip of the long finger, and for the lower limb, similar measurements are taken at 4 cm intervals from the tip of the second toe. A Perometer (Pero-System) is an optoelectronic imaging device designed to measure the volume of an object. It is ideally suited for measuring limb volume. It consists of a square measuring frame that contains rows of infrared light–emitting diodes on two adjacent sides and rows

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FIG. 24-3  Inside a Perometer, two rows of measurement arrays are placed at a 90-degree angle to each other. Each determines an object diameter and its position inside the frame.

of corresponding sensors on the other two sides12 (Fig. 24-3). Two rows of measurement arrays are placed at a 90-degree angle to each other. Each of them determines an object diameter and its position inside the frame. The patient sits at one end of the Perometer, with the hand or foot resting centrally on an adjustable support or footplate. The frame is then moved along the length of the arm or leg, from the wrist to the axilla or from the ankle to the thigh. When the frame is moved manually, the diameters and positions are determined in short distances along the object. The collected data are not influenced by the position of the measured object within the frame. A computer produces a volume picture of the entire limb by using the cross-sectional information obtained from the biplanar shadow of the limb in the device. The collected data can be saved and analyzed. Data generated by a Perometer can be exported into other programs such as word processing programs, spreadsheets, or other standard software. Perometry has been rigorously assessed by comparison with other methods and is considered more accurate than tape measurements.12,13 In various studies it has proved highly reproducible, accurate, and reliable.14 This technology is safe and fulfills many of the criteria for an ideal measurement tool. However, it is not inexpensive or easily accessible.

Nuances of Circumference and Volume Measurements One of the biggest confounders of circumference and volume measurements is that causes of increased volume other than lymphedema are not taken into account. For example, breast cancer

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patients tend to gain weight after having chemotherapy.15 Measurement of changes in limb circumference or limb volume measurements alone is not helpful in distinguishing between increases from lymphedema and other causes. This confounder can be somewhat controlled in patients with unilateral lymphedema by comparing the affected side with the contralateral, normal limb. In patients with bilateral lymphedema, however, this method is not as useful.

Measurement of Lymph Flow One useful diagnostic criterion for diagnosing lymphedema is the documentation of evidence of slow, reduced, or completely absent lymphatic flow in the swollen tissue. Lymphoscintigraphy is generally considered to be the benchmark procedure for measuring flow. It involves the injection of technetium-99m–labeled, filtered sulfur colloid into the subcutis in the web spaces of the fingers or toes. The labeled colloid is taken up by the lymphatics and transported to the draining nodal basin (Fig. 24-4). The flow can be detected and visualized with scintigraphic scanning. A transport index (TI) score can be calculated to categorize the lymphatic flow as normal or pathologic. This takes several factors into account, including lymphatic transport kinetics, the distribution pattern, and the appearance time of lymph nodes, and provides assessment data of lymph nodes at two time-points (Table 24-1). A score of less than 10 signifies a normal transport index. Scores are reported bilaterally, even in cases of unilateral swelling.16

FIG. 24-4  Lymphoscintigram of a swollen right leg with impaired lymphatic clearance, indicated by the accumulation of isotope in the lower leg.

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TABLE 24-1  Components of Transport Index Score

0

3

5

9

Transport kinetics

No delay

Mild delay

Extreme delay

No flow

Distribution patterns

Normal

Partial dermal

Diffuse dermal

No flow

Time index

Time in minutes for appearance of regional lymph nodes, multiplied by 0.04

Lymph nodes

Normal

Visible, diminished

Barely visible

Not seen

Lymph vessels

Normal

Visible, diminished

Barely visible

Not seen

A normal transport index score is less than 10.

A

B

FIG. 24-5  MR lymphangiograms in two patients with lymphedema. A, Limited subdermal lymphatics. B, Abundant subdermal lymphatics (arrows).

The advantage of this index, with five different characteristics of the lymphatic system, is that it is helpful for identifying the varied disease processes that can be present within this system. In a prospective study of 386 extremities, Cambria et al17 identified patients in whom only the distribution pattern was abnormal; the transport kinetics were within normal limits. In other patients, the transport was delayed but the distribution pattern was normal. For this reason, the use of all five components of the transport index adds not only to its utility in diagnosing lymphedema, but also to its usefulness for defining specific anatomic details of the lymphatic system in each patient. More recently, MR lymphangiography (see Chapter 28) has been used to obtain good information about flow and therefore lymphatic function. It also provides high-definition images of the location and pattern of subdermal lymphatics (Fig. 24-5). This is invaluable information for plan-

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ning lymphatic surgery. Furthermore, information gathered from MR images can be used to very accurately measure limb volume. The amount and location of edema in the limb can be documented using this technology. However, this is an expensive, cumbersome, labor-intensive, and time-consuming method of limb volume measurement that is not universally available.

Tonometry Tissue tonometry is an easy-to-use, fast, accurate, and reproducible method of assessing pitting edema and fibrotic changes in edematous tissue. Pitting edema is present in stage I (International Society of Lymphology [ISL]) lymphedema and is the result of displacement of extracellular fluid (Fig. 24-6). With the progression of lymphedema, chronic inflammatory changes occur that result in progressive fibrotic induration. These are seen in patients with ISL stage II lymphedema. A tonometer is a mechanical device that pushes a plunger into the skin (Fig. 24-7). The depth of penetration of the plunger is recorded on a dial to a resolution of 0.01 mm. In early stage lymphedema, when pitting is present, the plunger can be pushed deeper into the skin. As the condition

FIG. 24-6  Finger pressure demonstrates pitting edema in this patient. The indentation remains after the finger is removed.

FIG. 24-7  A mechanical tonometer consists of a plunger that is pressed onto the skin and a scale for measuring the depth of penetration.

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progresses and fibrosis becomes more prominent, the degree of penetration decreases.18 Assessment of the rate of this change is useful for determining the impact of treatment and management of fibrosis in the patient, which is a major cause of poor lymph drainage and poor treatment outcomes.

Bioimpedance Spectroscopy Bioimpedance spectroscopy (BIS) analysis is a technology that uses resistance to electrical currents in comparing the composition of fluid compartments within the body. It is one of several techniques that directly measures lymph fluid volume. BIS is based on the theory that the amount of resistance to the flow of electrical current (impedance) through the body is inversely proportional to the volume of fluid in the tissue. In lymphedema, tissue impedance decreases with the accumulation of excess interstitial fluid. In BIS, an electrical current is passed through a body segment, and impedance to the flow of the current is measured. It operates on the premise that tissues such as fat and bone act as insulators, while electrolytic fluids conduct electricity. The properties unique to lymphatic fluid can be determined based on the measurements of the current flow. Low-frequency currents selectively pass through extracellular fluid compartments, whereas high-frequency currents pass through both intracellular and extracellular fluid. Although BIS can accurately measure extracellular accumulation of lymphatic fluid, it is not useful for quantifying other tissue elements that increase, such as fibrous and adipose tissue. Its utility in the measurement of chronic lymphedema characterized by increased fibrosis and fat deposition is therefore questionable. To determine the optimal frequency for bioimpedance measurement, Cornish et al19 measured limb impedance at 256 frequencies ranging from 3 kHz to 1000 kHz for a sample control population and in patients with arm lymphedema and leg lymphedema. They concluded that impedance measurements higher than 30 kHz decrease sensitivity to extracellular fluid and are not reliable for early detection of lymphedema. With the use of BIS, the affected limb and the contralateral unaffected limb can be compared. The measured impedance of both limbs can then be expressed as a ratio. Because impedance declines as extracellular fluid volume increases, the measured bioimpedance values are usually expressed as a ratio of the normal limb to the abnormal limb. In a person without lymphedema, this ratio should be 1. However, as the severity of lymphedema increases, the ratio rises proportionately. The presence of bilateral lymphedema poses particular challenges with regard to the use of BIS. As discussed previously, unilateral lymphedema can be monitored and quantitated through the use of the contralateral, normal limb as a reference with which to construct the bioimpedance ratio. For the assessment of bilateral lymphedema, the quantitation of intracellular fluid volume can serve as a suitable alternative reference.20 In theory, because intracellular fluid volume should be virtually unaffected by the onset or progression of lymphedema, an extracellular/intracellular fluid volume ratio can be constructed from the measured BIS.

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In prospective evaluations to date, patients and practitioners have found BIS to be rapid, accurate, and consistent. It is particularly useful for detecting preclinical lymphedema. In one study with BIS, lymphedema was detected 10 months before the condition could be clinically diagnosed.19 This may be the main strength of this technology; evidence shows that early treatment of lymphedema improves outcomes.21 Despite much evidence to support the efficacy of BIS, some authors have reported otherwise. Ward et al20 assessed the agreement between bioimpedance indices and interlimb volume differences. They used perometry to assess unilateral arm lymphedema. Despite a strong linear correlation between bioimpedance and perometric measurements (r 5 0.919), bioimpedance gave falsenegative results for 12 (27%) patients who had lymphedema. Box et al22 investigated the incidence of arm lymphedema after axillary dissection to determine the effect of prospective monitoring and early physiotherapy intervention. They used three measurements to detect arm lymphedema: arm circumferences (CIRC), arm volume (VOL), and multifrequency bioimpedance (MFBIA). An increase of at least 200 ml over the preoperative difference between the two arms indicated clinically significant lymphedema. The CIRC and MFBIA methods failed to detect lymphedema in up to 50% of women with an increased volume of at least 200 ml in the operated arm, compared with the unoperated arm. Fu et al23 examined the reliability, sensitivity, and specificity of BIS in the detection of lymphedema in 250 women. Some were healthy, some were breast cancer survivors with lymphedema, and others were at risk for developing lymphedema. They used circumferential tape measurements to validate the presence of lymphedema. Lymph fluid changes were measured with bioimpedance. The bioelectrical impedance analysis ratio, as indicated by an L-Dex ratio, was highly reliable in healthy women and survivors at risk for lymphedema. Reliability was acceptable for survivors with lymphedema. The bioelectrical impedance ratio correlated with limb volume assessed by sequential circumferential tape measurement. However, the L-Dex ratio had a diagnostic cutoff of greater than 17; it is thought that the 20% of lymphedema cases that are potentially missed is a problem related to this particular device and not necessarily to the technology. The authors noted the importance of integrating other assessment methods, such as self-reporting, clinical observation, or perometry, to ensure the accurate detection of lymphedema. The effectiveness of BIS is controversial in the literature. In the United States, most insurers consider it investigational.

C linical P earls • When limb circumference is consistently measured from a fixed point, it is a very effective means of determining limb volume. • MR lymphangiography provides accurate measurements of limb volume but is expensive, time consuming, and not readily available to many physicians. • Information obtained with a transport index is useful for defining unique anatomic details of the lymphatic system in each patient. • Lymphedema should be diagnosed and quantitated using a variety of assessment tools.

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R EFERENCES 1. Armer JM, Radina ME, Porock D, et al. Predicting breast cancer-related lymphedema using selfreported symptoms. Nurs Res 52:370-379, 2003. 2. Gartner R, Jensen MB, Kronborg L, et al. Self-reported arm-lymphedema and functional impairment after breast cancer treatment: a nationwide study of prevalence and associated factors. Breast 19:506515, 2010. 3. Armer JM, Stewart BR. A comparison of four diagnostic criteria for lymphedema in a post-breast cancer population. Lymphat Res Biol 3:208-217, 2005. 4. Armer JM. The problem of post-breast cancer lymphedema: impact and measurement issues. Cancer Invest 23:76-83, 2005. 5. Gerber LH. A review of measures of lymphedema. Cancer 83:2803-2804, 1998. 6. Ridner SH, Montgomery LD, Hepworth JT, et al. Comparison of upper limb volume measurement techniques and arm symptoms between healthy volunteers and individuals with known lymphedema. Lymphology 40:35-46, 2007. 7. Taylor R, Jayasinghe UW, Koelmeyer L, et al. Reliability and validity of arm volume measurements for assessment of lymphedema. Phys Ther 86:205-214, 2006. 8. Petrek JA, Pressman PI, Smith RA. Lymphedema: current issues in research and management. CA Cancer J Clin 50:292-307, 2000. 9. Megens AM, Harris SR, Kim-Sing C, et al. Measurement of upper extremity volume in women after axillary dissection for breast cancer. Arch Phys Med Rehab 82:1639-1644, 2001. 10. Kaulesar Sukul DM, den Hoed PT, Johannes EJ, et al. Direct and indirect methods for the quantification of leg volume: comparison between water displacement volumetry, the disk model method and the frustum sign model method, using the correlation coefficient and the limits of agreement. J Biomed Eng 15:477-480, 1993. 11. Brorson H, Höijer P. Standardised measurements used to order compression garments can be used to calculate arm volumes to evaluate lymphoedema treatment. J Plast Surg Hand Surg 46:410-415, 2012. 12. Stanton AW, Northfield JW, Holroyd B, et al. Validation of an optoelectronic limb volumeter (Perometer). Lymphology 30:77-97, 1997. 13. Tierney S, Aslam M, Rennie K, et al. Infrared optoelectronic volumetry, the ideal way to measure limb volume. Eur J Vasc Endovasc Surg 12:412-417, 1996. 14. Moseley A, Piller N, Carati C. Combined opto-electronic perometry and bioimpedance to measure objectively the effectiveness of a new treatment intervention for chronic secondary leg lymphedema. Lymphology 35:136-143, 2002. 15. Lankester KJ, Phillips JE, Lawton PA. Weight gain during adjuvant and neoadjuvant chemotherapy for breast cancer: an audit of 100 women receiving FEC or CMF chemotherapy. Clin Oncol 14:64-67, 2002. 16. Kleinhans E, Baumeister RG, Hahn D, et al. Evaluation of transport kinetics in lymphoscintigraphy: follow-up study in patients with transplanted lymphatic vessels. Eur J Nucl Med 10:349-352, 1985. 17. Cambria RA, Gloviczki P, Naessens JM, et al. Noninvasive evaluation of the lymphatic system with lymphoscintigraphy: a prospective, semiquantitative analysis in 386 extremities. J Vasc Surg 18:773782, 1993. 18. Piller NB, Clodius L. The use of a tissue tonometer as a diagnostic aid in extremity lymphoedema: a determination of its conservative treatment with benzo-pyrones. Lymphology 9:127-132, 1976.

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19. Cornish BH, Chapman M, Hirst C, et al. Early diagnosis of lymphedema using multiple frequency bioimpedance. Lymphology 34:2-11, 2001. 20. Ward LC, Essex T, Cornish BH. Determination of Cole parameters in multiple frequency bioelectrical impedance analysis using only the measurement of impedances. Physiol Meas 27:839-850, 2006. 21. Boccardo FM, Ansaldi F, Bellini C, et al. Prospective evaluation of a prevention protocol for lymphedema following surgery for breast cancer. Lymphology 42:1-9, 2009. 22. Box RC, Reul-Hirche HM, Bullock-Saxton JE, et al. Physiotherapy after breast cancer surgery: results of a randomised controlled study to minimise lymphoedema. Breast Cancer Res Treat 75:51-64, 2002. 23. Fu MR, Cleland CM, Guth AA, et al. L-Dex ratio in detecting breast cancer-related lymphedema: reliability, sensitivity, and specificity. Lymphology 46:85-96, 2013.

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C hapter 25 Hydromechanics of Intercellular Fluid and Lymph Waldemar Olszewski, Marzanna T. Zaleska

Hyd K ey P oints • In normal limbs, lymph flow occurs only during spontaneous contractions of lymphangions. • In obstructive lymphedema, the stagnant tissue fluid is primarily deep in the subcutaneous tissue. • In advanced stages of lymphedema, the hydraulic conductivity of the subcutis decreases. • Tissue fluid pressure is low in advanced stages of lymphedema because the interstitial spaces of the subcutis expand. • Compression pressures of 50 to 60 mm Hg are recommended in early stages of lymphedema, and pressures of up to 125 mm Hg are needed in advanced stages.

Human limb soft tissues are composed of skin; subcutaneous tissue containing loose connective tissue structures such as ground matrix, fibers, and adipocytes; nerve fibers; blood and lymphatic vessels; muscular fascia; and muscle fibers. All of these tissue elements bathe in the fluid filtered from blood exchange vessels, which is partly mobile and partly taken up by cells bound to the matrix. In cases of enhanced plasma filtration or obstruction of tissue fluid flow to the lymphatics, and further, to the blood circulation, the interstitial space becomes overloaded with fluid. This is clinically diagnosed as tissue edema. In the lower limbs, the estimated extravascular extracellular volume is 12% of the total tissue volume under normal conditions, whereas in lymphatic obstruction it may be 40% to 50%.1 Knowledge of the location of excess fluid and its pressure/flow mechanics is necessary to understand the role of tissue fluid in the metabolism of parenchymal cells under normal conditions and in patients with lymphedema from obstruction of lymph flow. Such information is indispensable for effective antiedema therapy.

327

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Various external forces in specific directions should be applied in compression therapy, depending on the mobile fluid topography at different limb levels; the fluid location in the deep layers of the subcutaneous tissue, around blood vessels and nerves, and above and under muscular fascia; and the hydraulic conductivity at various levels.

Accumulation of Tissue Fluid and Lymph Under Normal Conditions and in Obstructive Lymphedema Our understanding of the limb lymphatic network in physiologic conditions and in lymphedema is based on lymphographic or lymphoscintigraphic images of the superficial and deep systems and lymph nodes. This technique does not reveal minor lymphatic structures located under the epidermis. Direct lymphangiography with fluorescent tracers may be helpful in delineating minor dermal lymphatics but is rarely used, as it requires special equipment for visualization. Ultrasonography, CT, and MRI provide pictures of tissue spaces filled with stagnant tissue fluid; however, they do not show lymphatics. None of the listed methods provides sufficient imaging of the entire tissue fluid and lymph space—including the interstitial space and lymphatics—to know what these tissues look like in reality. It is difficult to imagine how tissue fluid in the areas with obstructed lymphatics finds its way to the normal, noncongested tissue regions and is absorbed. To date, it is only through anatomic dissection and histologic processing of biopsy material that one can visualize the tissue lymphatic network and the sites of accumulation of the excess mobile tissue fluid.1 Under normal conditions, the volume of mobile tissue fluid is negligible. Collecting lymphatics contain little lymph in the lymphangions (segments of lymphatic vessels bounded by valves). Some of them remain empty. The situation changes dramatically with the obstruction of lymph flow caused by damage to the lymph collectors: subepidermal lymphatics dilate and tissue fluid spaces form in the subcutaneous tissue around small veins and in the muscular fascia. The most superficial layer where fluid accumulates is the subepidermal lymphatic plexus, occupying a papillary and reticular dermis with a thickness of 200 to 300 microns (Fig. 25-1). However, the volume of fluid in this plexus is negligible, compared with the volume of the subcutaneous tissue fluid, and does not exceed 2% to 3% of the total tissue fluid retained in soft tissues. The bulk (95%) of mobile tissue fluid accumulates in the subcutaneous tissue, forming artificial, partly interconnected spaces (Fig. 25-2). These spaces are located between fat globules, fibrous bundles, and around small veins. The formation of large lakes of tissue fluid can be explained by the presence of lax connective tissue in these regions, its high compliance and subsequently low resistance to fluid flow. Tissue fluid channels form, which mostly are narrow longitudinal spaces between the normal fascial fibrous elements around and in the hypertrophic muscular fascia of the calf, sometimes reaching 2 cm in diameter. The hydraulic conductivity of these structures is high because of the linear positioning of fibers.2 The volume of fluid accumulating in the tissue spaces and calculated from the densitometric readings of the stained tissues can be as high as 40% to 50% of the total tissue volume1

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A

B

C

FIG. 25-1  Histologic image of skin and subcutaneous tissue in advanced lymphedema. A, The arrow points to multiple dilated (blue stained) subepidermal lymphatic vessels. B, Magnification of blue-stained subepidermal lymphatic vessels. C, The arrow points to dilated spaces between collagen bundles filled with excess tissue fluid (H&E, 2003).

A

B

FIG. 25-2  Histologic image of the subcutaneous tissue in advanced lymphedema. A, Collagen bundles are separated by tissue fluid. B, Tissue spaces are stained blue after intratissue injection with patent blue dye. The walls of the spaces are not lined by lymphatic endothelial cells. The area occupied by excess fluid is 40% to 50% of the total tissue (H&E, 6003).

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A

Epidermis Dermis Superficial lymphatic plexis

B

Subcutis No lymphatics Tissue spaces Fascia Perimuscular space

FIG. 25-3  A, Fluid distribution in the skin and subcutaneous tissue in lymphedema. Dilated subepidermal lymphatics (upper arrow) are evident below the epidermis. The subcutaneous tissue contains no lymphatics. The bulk of mobile fluid is in the subcutis, deep at the muscular fascia (center arrow), and sometimes in the muscular compartment (lower arrow). B, This skin and subcutaneous tissue specimen was removed during a debulking operation in a patient with stage IV lymphedema. The vertical arrow shows the thickness of the tissue with the most mobile tissue fluid, compared with the dermis. The horizontal arrow points to the level at which external compression should be applied to mobilize fluid.

(Fig. 25-3, A). Anatomic images of the skin and subcutis in lower and upper limb lymphedema show that the thickness of edematous tissues is 1 to 10 cm or more (Fig. 25-3, B). (The staging system referred to in this chapter is that of W.L. Olszewski.14) This information raises the following question: How much massaging force should be applied to affect the deepest edematous tissue layers? In this chapter, we attempt to answer this question.

Tissue Resistance to Flow and Dissipation of External Force Which tissue elements create tissue resistance to fluid flow, and where is most of the external force dissipated? The answers to these questions are presented in Fig. 25-4. Skin has inherent stiffness and becomes even harder in advanced stages of lymphedema because of continuing fibrosis. The subcutaneous tissue contains collagen, elastic fibers, and fat agglomerates. Its stiffness is lower than that of skin. However, in lymphedema, fibrogenesis makes it less elastic. These structures create resistance to flow. To move mobile tissue fluid, a pressure gradient should be generated between the collagen bundles and the ground matrix, perpendicular to the limb axis (middle horizontal arrow). The hydraulic conductivity of the subcutis thus steadily decreases. Higher external pressure will be needed to mobilize edema fluid in the deeper layers. The subcutaneous tissue becomes swollen and is relatively thicker than the skin.

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Subcutis Epidermis

331

Fascia Muscles

FIG. 25-4  Tissue sites where applied external force is dissipated. The horizontal arrows and the vertical arrow pointing upward represent the direction of applied force. The ground substance (white space in the subcutis), the pores between fibers (green dots), and the collagen bundles (brown lines) create resistance to flow, represented by the arrows pointing downward.

The amount of force lost during external compression can be estimated by measuring the pressure of the therapist’s hand on the skin, or measuring the undergarment pressure of a bandage or pneumatic device on the skin, and comparing that with tissue fluid pressure. The difference between applied and in-tissue, generated pressure will provide information on how much force was absorbed by the solid tissue and how much was used for generating the fluid pressure gradient necessary for propelling tissue fluid. Thus loss of force should always be taken into account when planning compression procedures. Compression-generated tissue fluid pressures are always lower than pressures applied at the compression device–skin interface.3

Measurement Techniques Intralymphatic Pressure and Flow To measure intralymphatic lymph pressure, a subcutaneous lymph vessel of the leg is cannulated against the direction of lymph flow, according to published techniques.4,5 The lymph vessel draining lymph from the skin, subcutaneous tissue, and perimuscular fascia of the foot and anterior aspect of the lower leg is cannulated. Pressures are recorded by an electronic micromanometer. To measure intralymphatic flow, we use a low-flow flowmeter that measures from 0.1 to 6 ml/min, with an accuracy of 0.1 ml.5

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Tissue Fluid Pressure and Flow To measure tissue fluid pressure, the wick-in-needle technique is routinely used. An 8-gauge injection needle with polyethylene tubing (outer diameter 1.34 mm) containing a glass-wool wick protruding 5 mm from the tubing tip is introduced under the skin. The outer part of the tubing is connected to the pressure transducer, and recordings are obtained using a three- or six-channel device. We use LabVIEW software.3 Tissue fluid flow is measured using strain-gauge plethysmography. The device measures circumference changes in the calf and thigh segments corresponding to the compressed limb region or sequentially inflated pneumatic sleeve chambers. The data are used for calculating volume changes of the limb caused by the proximally moved tissue fluid. The volume value obtained before compression is subtracted from that obtained during compression, providing data on the proximally transferred fluid volume.3

Characteristics of Lymph and Tissue Fluid Normal Tissues Lymph and tissue fluid hydraulics in human limb soft tissues, under normal conditions and in lymphedema, have been studied only in a few centers.6-11 The hydromechanics of lymph and mobile tissue fluid (normal and stagnant edema) differ considerably. Lymph is contained in the lumen of a rhythmically contracting vessel generating a pressure gradient, whereas tissue fluid is contained in the interstitial space, limited by cells and fibers. (Hydraulic conditions change dramatically with obstruction of the draining lymphatics.)

Extrinsic Factors Propelling Lymph Muscular activity, respiratory movements, passive movements, and arterial pulsation have no effect on lymph flow.6-8,10,11 Generally, limb lymphatics are empty, with only a few microliters of lymph in some lymphangions. In a normal leg positioned upright, the lymphatics have no hydrostatic pressure.8,11

Intrinsic Factors Propelling Lymph Lymph is propelled by autonomous rhythmic contractions of lymphangions.6-11 Tissue fluid enters the initial lymphatics to flow into the lymphangions. Stretching of lymphatic walls by inflowing tissue fluid causes contractions of the lymphatic wall muscles (according to Starling’s law for the heart muscle) and generates flow.

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Lymph Pressures Limb lymphatics contract rhythmically; the frequency depends on the volume of inflowing tissue fluid (Fig. 25-5). The frequency is high in regions with a high capillary filtration rate and tissue fluid formation. Table 25-1 outlines normal lymph pressures. Massaging of the foot or tapping of tissues containing lymphatics has no effect on lymph pressures. Heating of the foot significantly increases the pressure, amplitude, and frequency of lymphatic contractions.8,11

1 min

ml (1 ml 5 1 mm) 50 40 30 20 5 0

15

mm Hg

10

5 0 Patient supine: no movement

FIG. 25-5  Pressure (lateral) and flow recorded in a normal calf lymphatic vessel. Three pulse waves (red curves) are shown. Each has a different amplitude, and the time intervals vary between contractions. Each lymphangion contraction generates pressures, propelling flow (blue curve). The ascending fragment of each curve shows the stroke volume. Flow occurred only during lymphangion contractions.

TABLE 25-1  Lymph Hydraulics in Normal Leg Lymphatic Collectors

Free Proximal Flow (lateral pressure) Upright

Lying Down

Foot Flexing

Pressure (mm Hg)

7-30

7-30

10-30

Pulse amplitude (mm Hg)

5-17

Pulse frequency (pulses/min)

2-8

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Obstructed Flow in Normal Lymphatics (mimicking lymphatic obstruction in postsurgical lymphedema) (end pressure) Lying Down

Foot Flexing

15-55

15-50

3-20

3-35

3-14

0.6 to 6

2.5-10

3-12

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15

mm Hg

10

5

0 Patient 1 supine: no movement

Patient 1 supine: movement

Patient 2 supine: no movement

FIG. 25-6  Lymph pressure recorded in two patients with stage III lymphedema. Spontaneous pressure waves generated by damaged lymphangions are low (flat blue lines) and unable to create flow.

Lymphatic Obstruction In patients with postinflammatory, postoperative, posttraumatic, or idiopathic lymphedema, intralymphatic pressures and flow are abnormal because of (1) destruction of lymph vessel muscle cells, (2) destruction of valves, and (3) partial or total obstruction of the lumen. Tissue fluid flows to the nonswollen parts of the limb, along the hydraulically created tissue channels.

Lymph Pressures In obstructive lymphedema, only a few lymphatic collectors remain patent. However, the tissue space is filled with fluid, and the remaining patent lymphatics are filled with lymph. The recorded pressures during rest range from 5 to 45 mm Hg, depending on the remaining contractility force of the damaged lymphatic musculature.12,13 During calf muscle contractions, pressures are generally low, ranging from 10 to 25 mm Hg; tiptoeing in some cases generates end pressures of more than 200 mm Hg. Although the end pressure can be high, flow is absent, because the proximal vessels are obstructed (Fig. 25-6). Massaging the foot or tapping the tissues containing lymphatics has no effect on lymph pressures. However, heating the foot significantly increases the pressure, amplitude, and frequency of lymphatic contractions.8,11

Lymph Flow Because most collectors are partially or totally obliterated in obstructive lymphedema, only a small amount of spontaneous flow is in patent vessel segments at different levels of the limb.12,13 In most cases, a correlation of pressure and flow shows ineffective contractions of lymphangions (see Fig. 25-6).

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A

TISSUE FLUID PRESSURE: NORMAL LEG

mm Hg

4

2 0 Patient supine: no movement

Patient supine: movement

Patient supine: no movement

B

1 min

LYMPHEDEMA STAGE II

mm Hg

4

2

0 Patient supine: no movement

Patient supine: movement

Patient supine: no movement

Patient supine: after massage

FIG. 25-7  Tissue fluid pressures in normal and lymphedematous calf subcutaneous tissue in a horizontal position. A, In a normal leg, the pressure is approximately 0 mm Hg and is not affected by muscular contractions. B, In a lymphedematous limb, the pressure is approximately 2 mm Hg, with minor fluctuations during calf muscle contractions. Tissue fluid pressure, even in advanced stages of lymphedema, is low because of expansion of the interstitial space of the subcutis.

Subcutaneous Tissue Fluid Pressures Normal Tissue Under normal conditions, tissue fluid (intercellular fluid) pressure in the lower limb subcutaneous tissue measured at rest ranges between 23 and 11 mm Hg (Fig. 25-7). This is similar to findings from animal studies. Active calf movements may slightly decrease the pressure through emptying of the interstitial space; however, these differences are of no clinical importance.12

Lymphedema Tissue fluid pressure was measured under the skin in lymphedematous calf subcutis in a horizontal position12,13 (Fig. 25-8). Without movements, tissue fluid pressure ranged from 21.5 to 110 mm Hg (mean 2.5 6 3.0 mm Hg SD), and in controls, it ranged from 21.8 to 3.0 mm Hg (mean 0.8 6 1.2 mm Hg SD). No statistically significant differences were observed between them, although in some advanced cases pressures were slightly higher than the mean value. No significant changes in

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A

B

MIDCALF

ANKLE

10

8

mm Hg

6

4

2

0 Level 1 Patient supine: no movement

Level 1 Patient supine: movement

Level 1 Patient supine: no movement

Level 2 Level 2 Level 2 Patient supine: Patient supine: Patient supine: movement movement movement

FIG. 25-8  Tissue fluid pressures in lymphedema stage IV. A, Recorded at the level of the midcalf. B, Recorded at the level of the ankle. Minor differences were noted, depending on the level of measurement. Muscular contractions had no effect.

pressure occurred based on the change from the horizontal to upright position. The mechanism of low pressure could be explained by high skin compliance in the early stages of edema formation, leading to expansion of the subcutaneous space through absorption of excess capillary filtrate not drained by lymphatics. The protein-accumulating matrix osmotically absorbed water, expanded, and stretched the skin. A large subcutaneous space was created.

Subcutaneous Tissue Fluid Flow Normal Tissue In normal subcutaneous tissue, no flow is detectable (with contemporary means) at rest or during walking or massage.12

Minimum Tissue Fluid Pressure to Start Flow A water venous pressure manometer was attached to a needle placed in the subcutis. Fluid contained in the manometer tubing began to flow at pressures above 30 mm Hg (30 6 6 mm Hg).

Lymphedematous Tissue During muscular contractions in lymphedematous tissue, excess tissue fluid moves radially from the site of applied force but not unidirectionally toward the root of the extremity unless the distal portion of the limb is immediately bandaged.

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Effects of Various Compression Techniques Compression therapy requires awareness of which tissue structures should be compressed to move edema fluid. When lymphatic collectors are occluded, lymph nodes fibrose. Edema tissue fluid accumulates in the spontaneously formed tissue spaces. Limb compression cannot push fluid back into the occluded/obliterated collectors. Compression forces move fluid along tissue spaces2,14 (Fig. 25-9). They act on skin, subcutaneous tissue, veins, lymphatics, and solid elements of tissue, such as fibers and ground matrix (Fig. 25-10). Deformation of these elements by external force

Pathways of tissue fluid flow to hypogastrium

Tissue fluid enters femoral canal

FIG. 25-9  A lymphedematous limb with obstructed lymphatics, spontaneously formed tissue spaces, and pathways of edema fluid flow to the hypogastrium and femoral canal. Such limbs need intensive compression therapy to evacuate excess tissue fluid.

Tissue spontaneous channels Obliterated lymphatics

Artery

Lymphatic

Pressure on vein by muscles Pressure on lymphatics

Vein

Pressure on skin and subcutis Bandage IPC

x?

Pressure on veins

Pressure on tissue fluid Capillary filtration

FIG. 25-10  Anatomic structures and lymph and tissue fluid locations in the foot and calf, with forces acting on tissues during manual compression, bandaging or intermittent pneumatic compression (IPC). Plasma filtration processes takes place in the exchange capillary vessels (blue arrows). Filtered fluid accumulates in the intercellular space (long red arrow pointing to the green question mark). Lymphatic collectors are occluded (red X). Compression forces act on skin, subcutaneous tissue, veins, lymphatics and the solid elements of tissue as fibers and ground matrix (red horizontal arrows). Deformation of these elements transfers force to the tissue fluid (long red oblique arrow). A large part of externally applied force dissipates on the solid elements before it increases tissue fluid pressure and moves it. Compression force should be high enough to move fluid along tissue spaces (green arrow) but should not occlude arteries and veins. Calf tissue deformation during compression procedures is indicated by the dashed lines.

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50

20

0

100 50

40

mm Hg

0

100 60

50 0 100 50

80

0

50 100 0 Patient supine: no movement

Patient supine: movement

FIG. 25-11  The effect of bandaging on intralymphatic pressures in a patient with obstructive stage II or III lymphedema of the lower limb.

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transfers force to the mobile tissue fluid. A large portion of applied force is dissipated by the solid elements before it increases tissue fluid pressure and generates flow. Applied force should be high enough to move fluid without occluding arteries and veins. Effective tissue fluid pressures should exceed 30 mm Hg. This can be achieved by applying compression pressures of 50 to 60 mm Hg in early stages of lymphedema, and pressures of up to 125 mm Hg in advanced stages with stiff skin.

Manual Massage of the Foot The foot is the part of the lower limb where most tissue fluid and lymph are produced under normal conditions and accumulate in lymph flow obstruction. Manual massage of the foot in patients with early stages of lymphedema may propel lymph. However, discontinuation of massage is followed by an immediate cessation of lymph flow.

Bandaging of the Foot A gradual increase in bandage pressure raises lymph pressure to 50 mm Hg, with a series of lowamplitude pulses.13 Contractions of the calf muscle increase pressure to even higher levels (above 100 mm Hg). The most effective bandage pressures are 40 to 50 mm Hg. Higher pressures have no additional effect (Fig. 25-11). In the patient recorded in Fig. 25-11, a sphygmomanometer cuff had been placed around the foot and was wrapped by an elastic bandage. The intracuff pressures were gradually increased, and end pressures were simultaneously measured in a cannulated calf lymphatic vessel. Raising cuff pressures caused an increase of mean lymphatic pressure to 40 to 50 mm Hg. Intralymphatic pressures did not increase further, even with external pressures of 80 to 100 mm Hg. Contractions of calf muscles increased spontaneous pressures to 110 mm Hg at a cuff pressure of 40 mm Hg. Higher cuff pressures during calf muscle contractions had no additional effect on lymphatic pressure. The lymphangion’s contracting force reached peak values.

Manual Massage of the Calf Manual massage of lymphedematous calf soft tissues dissipates force radially. It may increase the tissue fluid pressure to higher than 100 mm Hg (Fig. 25-12). However, cessation leads to an immediate drop of pressure to 0 mm Hg. In advanced stages of lymphedema, high skin rigidity limits the force transferred to the subcutis, and thus limits lower pressures. To determine whether the manual force is transferred to proximal regions of the limb, we measured pressures at various distances from the massaging hand. Compression at a distance of 3 cm from the sensor did not raise pressure. This could be explained by low skin compliance and low hydraulic conductivity of the subcutis in lymphedema. Flow occurred only during hand pressure on the calf. Immediately after the hand was removed from the skin, flow stopped, with a backflow to the previously compressed area (Fig. 25-13).

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80

60 mm Hg

FIG. 25-12  Tissue fluid pressure during manual massage at three calf levels: above the ankle, in the midcalf, and under the knee. Sensors were inserted into the subcutaneous tissue. Massage was performed over the sensors. Each peak corresponded to one hand compression. Pressures reached different levels, as high as 100 mm Hg. The therapist was not informed of the level of pressure.

40

20

0 Massage above ankle Massage midcalf Massage under knee

FIG. 25-13  Plethysmographic recording of circumference changes with a strain gauge placed proximal and distal to hand compression (15 mm 5 5 mm limb circumference increase 5 10 to 15 ml tissue fluid flow). During compression, fluid moved proximally. Flow stopped after the hand was removed from the skin. Massage proximal to the strain gauge caused backflow (arrows).

Millimeters

15

10

5

0

Massage at ankle

Massage above ankle

Massage below knee

Massage above knee

Bandaging of the Calf One-layer bandaging with semistretch bandages raised tissue fluid pressures to 40 to 60 mm Hg. However, the generated pressures varied at different calf levels, depending on the mass of the soft tissue. They were usually lower under the knee and very low in the thigh (Fig. 25-14). Subsequent wrappings generated lower pressure, most likely because of the decrease of edema fluid volume. Pressure dropped slowly but significantly over time. This could partly be prevented by two-layer wrappings, because there is less elasticity with two layers than one. The level of tissue fluid pres-

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70 60

FIG. 25-14  Tissue fluid pressure in the subcutaneous tissue during bandaging (short stretch) at three calf levels: above the ankle, in the midcalf, and under the knee. The sensors were inserted under the skin. Pressure varied at different levels and was lowest below the knee. Foot movements generated pressure waves of 20 mm Hg (mid part of the yellow curve). The pressure decreased at all levels after 5 minutes.

50

mm Hg

40 30 20 10 0 210 Massage midcalf Massage under knee Massage above ankle

Sites of tissue fluid pressure and limb circumference recording

FIG. 25-15  Schematic presentation of the lower limb in a pneumatic sleeve with eight chambers, each 9 cm long. Tissue fluid pressure was measured at six points (red dots). The lowest point in the calf was at the level of chamber 3. In the thigh, pressures were measured at chamber levels 6, 7, and 8. The lines encircling the calf and thigh indicate the site of strain gauge placement for continuous measuring of circumference changes during compression.

3

4

5

6

7

8

Pressure sensor

1

2

3

4

5

6

Sleeve chamber numbers

7

8

Strain gauge

sure during bandaging did not correlate with bandage markers showing the bandage-skin interface pressure.

Intermittent Pneumatic Compression Pneumatic compression has become a generally used modality.15-17 We use a multichamber pneumatic compression device that provides sequential inflation with gradient inflation pressure and an inflation time sufficient for translocation of tissue fluid to the proximal region. The distal chambers are not inflated, preventing fluid backflow and venous stasis in the superficial limb system. The device is composed of eight segments, each 9 cm long. Inflation pressures are regulated from 50 to 125 mm Hg. Gradient pressures decrease proximally by 20%. The inflation time of each chamber is 50 seconds, with a total inflation time of 400 seconds. The distal chambers are not deflated. The deflation time of all chambers is 50 seconds at the end of each cycle (Fig. 25-15).

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The Foot and Lower Part of the Leg In stage II and early stage III lymphedema, the effect of pneumatic compression was similar to that of manual massage. In some cases it evoked spontaneous lymphatic pulse waves. In stage IV, cannulation of lymphatics was usually unsuccessful. In some cases lymphatic contractility was absent.

The Calf and Thigh Tissue fluid pressures were lower than those in the chambers during the first inflation of each sleeve chamber in normal subjects and those with lymphedema18 (Figs. 25-16 and 25-17). The high gradient across the skin was most likely caused by skin rigidity (fibrosis) and dispersion of the applied force to the proximal noncompressed regions. Unexpectedly, little tissue fluid pressure was transmitted from the compressed to the noncompressed proximal segments for a distance of 9 cm (width of the chamber) in normal and lymphedematous limbs. For example, inflation of chambers 1 and 2 in the calf did not increase pressure at level 3. In lymphedematous limbs the popliteal and upper thigh tissue fluid pressures reached lower levels than in other limb regions. These two regions contain loose connective tissue, are usually less swollen, and accumulate fluid translocated during sequential massage.

Effects of Various Sequential Inflation Times on Tissue Fluid Pressure and Flow Tissue Fluid Pressures During Pneumatic Compression for 5 Seconds/Chamber Inflation Time Using a sequential inflation time of 5 seconds, and based on the recorded pressure curves, we were not able to discriminate the tissue fluid head pressures that were generated by consecutive chambers, regardless of whether the inflation pressure was 50, 80, or 120 mm Hg18 (Fig. 25-18).

120 100

mm Hg

80 Massage below knee Massage above ankle Massage midcalf

60 40 20 0

Calf 3 4 5 6 7 8

FIG. 25-16  Tissue fluid pressure recordings in normal calf subcutaneous tissue during pneumatic compression of 120 mm Hg, 50 seconds/chamber. Pressures were recorded at level 3, above the ankle; at chamber level 4, at the midcalf; and at level 5, below the knee. Tissue flow pressures during the first inflation of chambers at levels 3, 4, and 5 were lower than those in the chambers (black dots). Inflation of chamber 3 increased tissue fluid pressure to 40 mm Hg at the corresponding level. This increased to 80 mm Hg during inflation of consecutive chambers. Inflation of chamber 4 increased tissue fluid pressure to 60 mm Hg at this level. This increased to 100 mm Hg during inflation of consecutive chambers. Tissue pressure below the knee (level 5) rose to 100 mm Hg.

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160 140 120

mm Hg

100 Massage midthigh Massage above knee Massage upper thigh

80 60 40 20 0 Thigh 3  4  5  6  7  8

FIG. 25-17  Tissue fluid pressure in the normal thigh subcutaneous tissue during pneumatic compression of 120 mm Hg for 50 seconds per chamber. Pressures were recorded in the chamber at level 6, above the knee; in the chamber at level 7, at the midthigh; and in the chamber at level 8, the upper thigh. Inflation of chamber 6 produced pressure of 110 mm Hg at level 6. Inflation of chamber 7 produced tissue fluid pressure of 110 mm Hg at level 7. The yellow curve shows a pressure of 25 mm Hg at level 8, close to the groin, usually with less edema and low flow resistance.

120 100

mm Hg

80 60 40 20

40 sec

0 220

50

80

120 mm Hg

FIG. 25-18  Tissue fluid pressures during 5 seconds of chamber pneumatic compression. Inflation of chambers 3, 4, and 5 generated tissue fluid head pressures under each chamber as low as 10 to 20 mm Hg, although the chamber pressures were much higher. Inflation pressures were 50, 80, and 120 mm Hg. Inflation of chambers 3, 4, and 5 generated tissue fluid head pressures as low as 10 to 20 mm Hg, although the chamber pressures were much higher. Inflation of the whole sleeve to 50 mm Hg, 80 mm Hg, and 120 mm Hg created final tissue fluid pressures of 25 to 40 mm Hg, 35 to 70 mm Hg, and 70 to 100 mm Hg, respectively. Inflation of the whole sleeve for 40 seconds did not generate and maintain tissue fluid pressure to a level as high as that in the sleeve. Moreover, a deflation period of 5 sec was not long enough to decrease pressure to 0 mm Hg. It remained at 20 to 30 mm Hg.

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Tissue Fluid Pressures During Pneumatic Compression for 20 Seconds/Chamber Inflation Time Using a sequential inflation time of 20 seconds, we were able to roughly discriminate between the tissue head pressures18 (Fig. 25-19).These pressures ranged from 10 to 20 mm Hg with chamber pressures of 50, 80, and 120 mm Hg. Tissue Fluid Pressures During Pneumatic Compression for 50 Seconds/Chamber Inflation Time In contrast to inflation times of 5 and 20 seconds, an inflation time of 50 seconds generated easily distinguishable tissue fluid head pressures at each level1 (Fig. 25-20). The mean head pressures under chamber 3 were 35, 45, and 60 mm Hg with inflation pressures of 50, 80, and 120 mm Hg, respectively. The respective pressures in the thigh were evidently lower, reaching 20 mm Hg in the groin. The head pressures at various limb levels depended on the shape of the limb dictated by the mass of soft tissues. They were high at the midcalf, lower below and above the knee, and higher at the midthigh, becoming low in the groin region. Inflation of the whole sleeve to 50 mm Hg created a pressure gradient between the calf and groin of 50 to 60 mm Hg to 20 mm Hg, respectively; inflation of the whole sleeve to 80 mm Hg created a pressure gradient of 85 to 30 mm Hg, respectively; and inflation of the whole sleeve to 120 mm Hg generated a pressure gradient of 130 to 40 mm Hg, respectively18 (Fig. 25-21). During deflation, the tissue fluid pressure dropped to 0 mm Hg, facilitating venous blood and tissue flow inflow into the distal limb segments to be compressed during the consecutive cycle.

120 120 mm Hg

100

mm Hg

80 60 40 20 0 220

160 sec

345678

FIG. 25-19  Tissue fluid pressures during 20 seconds per chamber of pneumatic compression. Inflation of the whole sleeve to 50 mm Hg generated tissue fluid pressures ranging from 50 mm Hg in the calf to 10 mm Hg in the groin. Inflation of the whole sleeve to 80 mm Hg generated tissue pressures ranging from 80 mm Hg in the calf to 20 mm Hg in the groin. Pressure generated by inflated chambers at various levels could not be discriminated because of short inflation times. Inflation of the whole sleeve to 120 mm Hg generated a tissue pressure of 40 mm Hg in the upper thigh. On deflation, tissue fluid pressure decreased to 20 to 30 mm Hg and did not reach the preinflation level of 0 to 5 mm Hg.

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100 80

mm Hg

60 40 20 0

50 12345678

120

80

220

FIG. 25-20  Tissue fluid pressure recording in a lymphedematous calf subcutaneous tissue at the level of sleeve chambers 3 (orange curve), 4 (red curve), and 5 (blue curve). Inflation pressures were 50, 80, and 120 mm Hg. Each chamber was inflated for 50 seconds. Distal chambers were not deflated. Tissue fluid pressures during the first inflation were lower than those in the chambers. Inflation of chamber 3 increased tissue fluid pressure at level 3 to 30 mm Hg but not at level 4. Inflation of chamber 4 produced tissue fluid pressure at level 4 to 40 mm Hg and at level 5 to 12 mm Hg. The pressure curves had a similar shape during inflation to 80 and 120 mm Hg. At level 5 (third ascending line) close to the knee with soft popliteal tissue, the tissue fluid pressures were much lower than in chamber 5. This could be explained by low resistance to flow in the popliteal fossa. However, the most important observation was the lack of transmission of pressure from the compressed level to the next proximal level.

50 sec 3

130

4

5

6

7

8

120 110 100 90 mm Hg

80 70 60 50

120 80 60

40 30 20 10 0

FIG. 25-21  Data from 20 measurements of tissue fluid pressure during intermittent pneumatic compression, 50 seconds per chamber. The first inflation of consecutive chambers 3 to 8 generated head pressures of 50, 80, and 120 mm Hg (mean 6 SD, n 5 15). Tissue fluid pressures were lower than those in the chambers, especially below and above the knee and under chamber 8 in the groin.

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30 25 20 Millimeters

15 10 5 0 25 220 3 Ankle

4

5 Leg

6

7

8

Knee

FIG. 25-22  Circumference changes in the lower limb during pneumatic compression for 50 seconds per chamber. The volume can be determined from the increase in circumference. Flow was different at various levels of the limb, depending on the volume of soft tissues and contained fluid. It was highest in the midcalf and lower in the midthigh. Pressure and flow curves are similar in Figs. 25-21 and 25-22.

Tissue Fluid Flow During Pneumatic Compression for 50 Seconds/Chamber Inflation Time Flow was different at various levels of the limb depending on the volume of soft tissues and contained fluid. It was highest in the midcalf and lower in the midthigh (Fig. 25-22). This might be explained by the movement of accumulated fluid from the calf to the popliteal fossa and to the upper thigh where fluid dissipated to the neighboring regions.18

Conclusion This study showed that in obstructive lymphedema, the bulk of the stagnant tissue fluid is located deep in the subcutaneous tissue but not in the subepidermal lymphatic plexus. The resting tissue fluid pressures were slightly above 0 mm Hg. The minimum transmural (through skin and subcutis) tissue fluid pressures necessary for propelling tissue fluid in the subcutaneous tissue were found to be 30 6 15 mm Hg. The tissue fluid pressures generated by routine manual massage ranged from 40 to above 100 mm Hg, depending on the level of the leg massaged, although apparently the same compression force was applied. Variations in tissue fluid pressures during massage could be explained by differences in calf skin and subcutaneous tissue tonicity and thickness at various levels. Our studies showed that pressures generated by manual compression were high enough to overcome tissue hydraulic resistance and propel tissue fluid. However, on release of the hand, pressures dropped to 0 mm Hg. The rapidly disappearing pressure gradient must have resulted in cessation of fluid flow and even its backflow. The obtained data indicate that manual compression–generated tissue fluid pressures could be effective in propelling fluid. However, to maintain the unidirectional proximal flow, compression should last longer than 15 seconds, and fluid return should be prevented by immediate and tight compression.

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Pneumatic compression of tissues with lymph stasis is beside manual massage a commonly used therapeutic modality in limb lymphedema. A number of pneumatic devices have been constructed. We tried to determine how high of a compression pressure should be applied, and for how long, to the limb soft tissues to reach tissue fluid head pressure above 30 mm Hg, necessary to initiate proximal flow. We found that (1) the tissue fluid head pressures were lower than those in inflated chambers, (2) inflation times of 5 and 20 seconds was too short to generate tissue fluid head pressures above 30 mm Hg, even if the compression pressures were as high as 120 mm Hg, (3) the 50-second timing achieved head pressures higher than 30 mm Hg. However, they consistently remained lower than in the compression chamber, (4) tissue fluid head pressures differed at various levels of the limb, depending on the soft tissue mass, (5) deflation of the inflated whole sleeve for 5 and 20 seconds was followed by high end pressures, whereas deflation of 50 seconds brought about a pressure drop to 0 mm Hg, facilitating refilling with tissue fluid of the distal parts of the massaged limb. Our observations point to the necessity of applying high pressures and compression times longer than 50 seconds to generate effective tissue fluid pressures and to provide enough time to facilitate flow.

C linical P earls • Lymph flow in limb lymphatics depends entirely on spontaneous rhythmic contractions of a segment between two unidirectional valves (lymphangions). • In lymphedema, there is no lymph flow in the collecting lymphatic vessels. • In lymphedema, tissue fluid accumulates in tissue spaces. • To move stagnant tissue fluid, compression in necessary. • Force (pressure/area) applied by compression materials and devices must be high enough to move fluid. • The effective compression pressure should be above 60 mm Hg in early stages of lymphedema and 125 mm Hg or higher in advanced stages. • Timing of compression is crucial for fluid movement because of tissue poroelastic resistance. Longer times are more effective. • High forces applied to tissues by bandages and devices are safe, because they have vertical direction and do not produce shear stress that damages microstructure.

R EFERENCES 1. Olszewski WL, Jain P, Ambujam G, Zaleska M, et al. Topography of accumulation of stagnant lymph and tissue fluid in soft tissues of human lymphedematous lower limbs. Lymphat Res Biol 7:239-245, 2009. 2. Zaleska M, Olszewski WL, Cakala M, et al. Intermittent pneumatic compression enhances formation of edema tissue fluid channels in lymphedema of lower limbs. Lymphat Res Biol. 2015 Mar 6. [Epub ahead of print]

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3. Olszewski WL, Jain P, Ambujam G, Zaleska M, et al. Tissue fluid pressure and flow during pneumatic compression in lymphedema of lower limbs. Lymphat Res Biol 9:77-83, 2011. 4. Engeset A, Harger B, Nesheim A, et al. Studies on human peripheral lymph. I. Sampling method. Lymphology 6:1-5, 1973. 5. Olszewski WL. Collection and physiological measurements of lymph and interstitial fluid in man. Lymphology 10:137-145, 1977. 6. Olszewski WL, Engeset A. Intrinsic contractility of leg lymphatics in man. Preliminary communication. Lymphology 12:81-84, 1979. 7. Olszewski WL, Engeset A. Lymphatic contractions. N Engl J Med 300:316, 1979. 8. Olszewski WL, Engeset A. Intrinsic contractility of prenodal lymph vessels and lymph flow in human leg. Am J Physiol 239:H775-H783, 1980. 9. Armenio S, Cetta F, Tanzini G, et al. Spontaneous contractility in the human lymph vessels. Lymphology 14:173-178, 1981. 10. Sjöberg T, Norgren L, Steen S. Contractility of human leg lymphatics during exercise before and after indomethacin. Lymphology 22:186-193, 1989. 11. Olszewski WL. Lymph vessel contractility. In Olszewski WL, ed. Lymph stasis: pathophysiology, diagnosis and therapy. Boca Raton, FL: CRC Press, 1991. 12. Olszewski WL. Contractility patterns of normal and pathologically changed human lymphatics. Ann N Y Acad Sci 979:52-63, 2002. 13. Olszewski WL. Contractility patterns of human leg lymphatics in various stages of obstructive lymphedema. Ann N Y Acad Sci 1131:110-118, 2008. 14. Olszewski WL, Cwikla J, Zaleska M, et al. Pathways of lymph and tissue fluid flow during intermittent pneumatic massage of lower limbs with obstructive lymphedema. Lymphology 44:54-64, 2011. 15. Rockson SG. Accruing evidence for a beneficial role of pneumatic biocompression in lymphedema. Lymphat Res Biol 8:v, 2010. 16. Pilch U, Wozniewski M, Szuba A. Influence of compression cycle time and number of sleeve chambers on upper extremity lymphedema volume reduction during intermittent pneumatic compression. Lymphology 42:26-35, 2009 17. Mayrovitz HN. Interface pressures produced by two different types of lymphedema therapy devices. Phys Ther 87:1379-1388, 2007. 18. Zaleska M, Olszewski WL, Jain P, et al. Pressures and timing of intermittent pneumatic compression devices for efficient tissue fluid and lymph flow in limbs with lymphedema. Lymphat Res Biol 11:227232, 2013.

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C hapter 26 Radionuclide Lymphoscintigraphy Byung-Boong Lee, James Laredo

K ey P oints • Radionuclide lymphoscintigraphy (LSG) is an essential, noninvasive test not only for the diagnosis of chronic lymphedema, but also for the follow-up assessment of functional changes in lymphatic dynamics. • LSG is easy to perform, repeatable with reliable results, and harmless to the lymphatic endothelial lining. • LSG has been the procedure of choice for the clinical evaluation of lymphatic functional status and provides clear images of lymph transport vessels and draining nodes.

Chronic lymphedema is no longer viewed as a simple condition of static swelling of an affected limb or region after blockage of the lymph transporting and collecting systems. Lymphedema is now considered a progressive condition involving the lymphatic system and the entire skin and soft tissue integument in which a chronic degenerative and inflammatory process occurs, resulting in fibrotic change. This condition involves tissues beyond the lymphatics and lymph nodes, characterized by recurring episodes of dermatolymphoadenitis.1-4 Such a steadily progressing condition that affects the entire soft tissue envelope will eventually result in a disabling and distressing condition associated with numerous complications, including bacterial and fungal infections, dermatolipofibrosis with chronic inflammation, immunodeficiency and a wasting phenomenon, and malignancy (for example, Kaposi sarcoma and lymphangiosarcoma)5-8 (Fig. 26-1). Therefore chronic lymphedema is no longer considered a simple phenomenon of fluid accumulation but the beginning of a complex systemic disease. This mandates correct diagnosis at the earliest possible stage for more effective treatment. Radionuclide lymphoscintigraphy (LSG) fulfills a critical role as a precise method of evaluation and repeated assessment of patients with lymphedema for advanced treatment and care.9-12 One of the main advantages of LSG is that it is readily available at most centers, compared with some of the newer techniques, such as MRI and indocyanine green lymphangiography. Although these latter techniques in some ways provide

Rad

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FIG. 26-1  These three clinical cases represent advanced stage (clinical stage III) lymphedema with increasing morbidity by dermatolipofibrosis with chronic inflammation and persistent bacterial and fungal infections. When lymphedema reaches this end stage, it often becomes a life-threatening condition, with recurrent sepsis.

even better information than LSG, their relatively restricted availability and evolving role mean that LSG is still the benchmark procedure. Many conditions cause swelling (edema) that mimics lymphedema. True lymphedema as the cause of limb swelling is less common than one would think. Most cases of limb swelling are caused by local (cellulitis and arthritis), regional (deep vein thrombosis and chronic venous disease), and systemic disorders (congestive cardiac failure, renal failure, hypoalbuminemia, and protein-losing nephropathy). Moreover, lymphedema is not necessarily an isolated condition and can coexist with other medical conditions.13-16 In this context, LSG is essential not only to sort out the differential diagnosis, but also to evaluate the various conditions that can be associated with lymphedema (either primary or secondary), although a careful history and physical examination are often sufficient to make the diagnosis of chronic lymphedema.1,4 LSG is performed particularly for the assessment of primary lymphedema, because this congenital condition is the clinical manifestation of a truncular lymphatic malformation (LM) (Fig. 26-2). Together with extratruncular LM lesions, known as lymphangiomas, truncular LM malformations can occur in combination with many other vascular malformations (for example, a venous malformation).17-20 Thus a detailed evaluation of primary lymphedema should be performed, including the use of LSG. Other vascular imaging studies should also be done throughout all potential areas of involvement, as well as the contralateral normal limb or body part for comparison, because various

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B 30 min

A

1 hr

Uptake (%):

4.65

9.97

5.87

6.25

6.63

7.26

Uptake (%):

2.13

7.60

2.27

5.51

1.76

4.73

Clearance (%):

16.7

C



2 hr

20.6

21.7

22.7

32.0

33.0

D

Anterior

Anterior 70%

Posterior

Posterior 70%

FIG. 26-2  A, Left lower extremity with primary lymphedema caused by a combination of truncular LM and venous malformation, resulting in a discrepancy in leg length. Primary lymphedema was confirmed with extensive dermal backflow/lymph stasis shown in LSG. B, An infiltrating extratruncular venous malformation was also confirmed along the left lower leg, seen here in whole-body blood pool scintigraphy. C. It was also confirmed by the MRI. D, Such a combination of various vascular malformations warrants precise assessment of the lymphatic system with LSG, not only for the initial diagnosis, but also for the follow-up assessment of treatment and its natural course and progression.

abnormal conditions of lymphatic leakage, lymphangiectasia, chylous ascites, and chylothorax are infrequently involved.1,4,21,22 The basic initial diagnostic procedures for both primary and secondary lymphedema, including volumetric measurements and symptom evaluation, should be performed to make the earliest possible diagnosis in patients at risk.23-26 An assessment of the clinical condition, including the clinical staging of lymphedema, requires the use of LSG, along with some other basic diagnostic tests. This is especially the case for primary lymphedema.27

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Definition LSG is an imaging technique developed for the assessment of lymphatic function. It is a radionuclide technique that uses radioisotope-tagged or radioisotope-labeled pharmaceutical particles as a tracer, which are injected intradermally or subcutaneously.28-31 LSG is a functional study to complement the anatomic information on the lymphatic system gleaned from other studies, such as phlebography or venography. It offers not only an anatomic study of the subaponeurotic lymphatic vessels but also a functional assessment. One of the criticisms of LSG is that the anatomic definition of the images is very poor, and this is true in the context of surgical planning. Both MRI (see Chapter 28) and ICG lymphangiography (see Chapter 27) provide much better information on detailed anatomy. However, neither of these studies is as widely available as LSG. With LSG, an evaluation can be done in both qualitative and quantitative assays, and the quantitative measurements in particular can give functional imaging of the lymphatic transport capacity30-33 (Fig. 26-3). LSG, which was first introduced in 1953, has become increasingly popular because of the benign nature of the technique. LSG is a minimally invasive test, easily performed and safe. This method has largely replaced the more invasive and technically demanding technique of lymphangiography, although in the future it will likely be replaced by other higher definition studies. Nevertheless, LSG is now considered an essential test not only to confirm clinically suspected lymphedema, but also to assess the progress and response to treatment. LSG has replaced the classic role of oil contrast–based lymphangiography.28,29 Before LSG became easily available for the management of lymphedema, the classic oil contrast– based lymphangiography, which was established by Kinmonth,34 was the only tool to visualize the lymphatics. For more than 40 years, it was the procedure of choice for definitive delineation of the lymphatic system. However, three major issues associated with lymphography limited its widespread use: (1) difficulty in the cannulation of large lymphatic draining collectors through tiny skin lymphatics; (2) the risk of damage to the lymphatic endothelial lining by the iodinated oil contrast; and (3) the risk of oil (fat) embolism.35 Because it is a difficult technique with potential side effects, lymphangiography has fallen out of favor and has largely been abandoned as a diagnostic tool. It is seldom used today.26 Although LSG is considered a “functional” imaging modality, it delivers comprehensive and consistent images, visualizing various structural and functional changes in lymphatic flow dynamics. LSG produces dynamic images of lymphatic transport and the peripheral and central lymphatic structures and function. Its transport index score36 allows semiquantification of peripheral lymphatic radiotracer transport. Delayed imaging shows lymph node uptake, albeit without the detailed structural information seen with conventional lymphography.

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A

Number of lymph nodes

Normal

Moderately decreased

Severely decreased

None

Normal

Hypoplastic

None

Collateral

Normal

Mild

Moderate

Severe

B

Lymphatic vessel

C

Dermal backflow

FIG. 26-3  Criteria for the qualitative analysis of LSG. A, The number of lymph nodes (normal, moderately decreased, severely decreased, or none visible). B, The condition of the lymphatic vessels (normal, hypoplastic, none, or collateral). C, The extent of dermal backflow (normal, mild, moderate, or severe).

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TABLE 26-1  Guideline Criteria for the Laboratory Staging System (Grades I-IV)* Lymph Node Uptake

Dermal Backflow

Collateral Lymphatics

Main Lymphatics

Clearance of Radioisotope From Injection Site

Grade I

Decreased (6)

None (2)

Good visualization (1)

Decreased visualization (6)

Decreased lymphatic transport (6)

Grade II

Decreased to none (2)

Visualization (1)

Decreased visualization (6)

Poor to no visualization (6)

More decreased (6)

IIA: Extent of dermal backflow does not exceed one half of each limb IIB: Extent of dermal backflow exceeds one half of each limb

Grade III

No uptake (2)

Visualization (1)

Poor visualization (2)

No visualization (2)

No clearance (2)

Grade IV

None (2)

Poor to no visualization (2)

No visualization (2)

No visualization (2)

No clearance (2)

*Minimum of two or more LSG findings for laboratory staging.

Periodic LSG findings provide proper clinical and laboratory staging, which is essential for proper clinical management37,38 (Table 26-1). LSG also has special merit in assessing the efficacy of medicines, surgery, and physical means to facilitate lymph movement or reduce lymph formation before and after treatment. Images of truncal lymph transport and draining nodes can be routinely obtained for follow-up studies to document functional changes in lymphatic dynamics (Fig. 26-4). However, LSG has never been fully appreciated for its ability to evaluate the lymphatic system as an independent test or adjunct to the patient’s history and physical examination. This is partly related to clinician unfamiliarity with LSG or a bias against LSG based on the old concept of chronic lymphedema. Thus the appropriate use of LSG requires a proper understanding of the new concept of chronic lymphedema.1,4 LSG has now been well proved to be a safe, noninvasive, easy to perform method of assessing the lymphatic system. Furthermore, it is harmless to the lymphatic endothelial lining. In addition, technetium-99m (99mTc) has a short half-life (6 hours) and is nearly completely decayed within 24 hours. The diagnostic value of LSG is further enhanced when combined with MRI and/or duplex ultrasonography as one of three essential noninvasive and minimally invasive tests for the evaluation of the lymphatic system. This combination of tests improves lymphatic functional assessment, allows the evaluation of the involvement of the arterial and venous systems, and provides a framework for subsequent therapy.1,4

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A

B

C

D

FIG. 26-4  A, Right lower extremity in grade I LSG stage of lymphedema with mildly decreased lymphatic transport function. Decreased lymph node uptake, localized/minimum lymphatic retention, and dermal backflow are seen on a 2-hour image, although the main vessel still appears normal. On the contrary, the left lower extremity shows no evidence of lymphedema—grade 0 LSG stage with normal lymph node uptake, no dermal backflow, and well-visualized main lymphatic vessels. B, Right lower extremity in grade II LSG stage of lymphedema with partial lymphatic obstruction. Image shows much decreased lymph node uptake, a significant amount of dermal backflow exceeding one half of the extremity (grade IIB), scanty collateral lymphatics, and almost no visualization of the main vessel. C, Right lower extremity in grade III LSG stage of lymphedema with severe lymphatic obstruction. Image shows no lymph node uptake, nonvisualization of the main lymphatic vessel, and a significant amount of dermal backflow. D, Left lower extremity in grade IV LSG stage of lymphedema with nearly nonfunctioning lymphatics. Image shows no lymph node uptake, nonvisualization of the main lymphatic vessel, and no dermal backflow.

In addition to its primary role in assessing chronic lymphedema, recent advances in the understanding of phlebolymphedema as a combination of chronic venous insufficiency and chronic lymphatic insufficiency mandate a new role for LSG in the assessment of its lymphatic component, along with MRI and duplex ultrasonography.39,40 Simultaneous assessment of the venous and lymphatic systems is essential for the proper identification of the delicate relationship between these two inseparable and mutually interdependent systems. Therefore a proper understanding of the unique relationship between these three tests is necessary, especially for primary lymphedema and phlebolymphedema management. Duplex ultrasonography should be the first test performed, even before LSG, in all forms of primary lymphedema to differentiate between lymphatic and venous etiologic factors. The ultrasonic features of lymphedema include volumetric changes, a change in the thickness of the dermis and subcutaneous layer, and structural changes, such as a hyperechogenic dermis and hypoechogenic subcutaneous layer. The suprafascial and subfascial thicknesses of the edematous tissue in high resolution are very useful measurements that allow the periodic assessment of the response to

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therapy, monitor a patient’s progress, and determine the prognosis.41-44 Ultrasonography has the distinct advantage of being noninvasive and easy to perform. However, it is very user dependent and demands a significant skill level on the part of the ultrasonographer. The features of MRI include circumferential edema with a typical honeycomb pattern, in addition to increased subcutaneous tissue volume with marked thickening of the dermis. MRI is also helpful to identify lymph nodes and enlarged lymphatic trunks and to differentiate the various causes of lymphatic obstruction in secondary lymphedema. The anatomic information from MRI provides a substantial complement to the functional assessment provided by LSG.45,46 A more detailed description of MR lymphangiography, including the most recent developments in this technology, is found in Chapter 28. Recently LSG and CT scans have been combined to improve diagnostic accuracy by retrieving functional (scintigraphy) and anatomic (CT) data together.47,48 The limb volume computation is accurate with this three-dimensional reconstruction of the limb by the volume rendering technique49 to characterize excess fluid limited to the skin and subcutaneous tissues.

Technical Aspects The imaging quality of LSG depends on the selection of an appropriate radiolabeled macromolecule or colloidal material, because particles greater than 10 nm in diameter are transported only by the lymphatics. 99mTc antimony colloid has been recognized as the most ideal small size colloid (3 to 30 nm) among the many different radiopharmaceutical particles used as a tracer. Unfortunately, it is no longer available in the United States because of the withdrawal of Food and Drug Administration approval. Therefore the next best available agent is 99mTc sulfur colloid (10 to 1000 nm), which is filtered to remove the larger particles, thereby creating a nearly uniform particle size (10 to 50 nm).28,29,50,51 However, 99mTc albumin colloid is another 99mTc-labeled colloid with a good reputation, because the albumin microcolloid has a reproducible colloid size distribution (95% is less than 80 nm), and there is ease of labeling. Its rapid clearance from the injection site makes it suitable for quantitative studies, and the injections are painless.28,29,51 Other available noncolloidal tracers include 99mTc human serum albumin, 99mTc dextran, and 99mTc human immunoglobulin. A dual mechanism clears the noncolloidal tracers from the injection site, with resorption into the capillaries and transport through the lymphatics, affecting diagnostic specificity in patients with lymphatic leakage. Therefore the noncolloidal tracers require different criteria for interpretation than those for colloidal tracers. However, 99mTc dextran is sufficient to diagnose ordinary lymphedema with no lymphatic leakage, whereas 99mTc sulfur colloid is a better tracer when the surgeon is looking for leakage sites. Furthermore, it takes more time with 99mTc dextran than with 99mTc sulfur colloid for dynamic acquisition and transport from the injection site. 99mTc phytate, which is another agent often used for scintigraphy, may have some advantages in sentinel LSG.4,28,29,50

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357

The injection technique will differ depending on the goal of the study and radiotracer used. The subcutaneous route is better than the intradermal route when looking for lymphatic leakage. On the other hand, a deeper injection may be preferable when looking for metastatic lymph nodes, which mostly involve deep lymph nodes. However, for routine studies of superficial lymphatics of the extremity, both subcutaneous and intradermal injections can be used with good outcomes.28,29 The radiopharmaceutical particles (for example, 99mTc dextran or 99mTc sulfur colloid) are first injected subcutaneously into the webs between the first, second, and third toes (or fingers), two sites per limb, and 37 MBq (1 mCi) per site. After the injection, patients complete a standardized exercise routine (for example, walk for more than 30 minutes) to facilitate the clearance. Generally whole-body and spot imaging are acquired with a gamma camera in a series starting 60 minutes after the injection.28,29,50,51 The routine imaging modality of LSG for lymphedema is based on a whole-body scan plus spot imaging. Although the information and findings from the whole-body scan are sufficient for a clinical diagnosis and assessment, spot imaging can give more detailed information. In addition to the whole-body scan and spot imaging, dynamic LSG is another excellent option for monitoring the time-activity curve of inguinal nodes. However, the protocol for LSG has not been standardized regarding the various radiotracers and radioactivity doses, different injection volumes, intracutaneous versus subcutaneous injection site, epifascial or subfascial injection, number of injections, different protocols of passive and active physical activity, varying imaging times, and static and/or dynamic acquisition techniques.28,29,52 In 2009 and 2013, the International Union of Phlebology recommended that LSG performed with a subcutaneous injection of 99mTc-labeled human serum albumin or 99mTc-labeled sulfur colloid into the first and second webspace of the toes or fingers was the test of choice to confirm or exclude lymphedema as the cause of chronic limb swelling.1,4 Movement of the colloid from the injection site, transition time to the knee, groin, or axilla, absence or presence of major lymphatic collectors, number and size of vessels and nodes, presence of collaterals and reflux, and symmetrical activity with the opposite side are recorded and used for interpretation (see Table 26-1). Semiquantitative assessment has been reported, and most recently the technique of quantitative assessment of transit time from the foot to the knee has also been validated1,4 (see Figs. 26-3 and 26-4).

Interpretation Criteria and Guidelines LSG shows the superficial lymph transport system—main, larger lymph vessels and nodes—as the basic architecture of the peripheral lymphatic system only. It does not show the deep lymph vessels carrying lymph from the nodes back to the blood circulation. LSG identifies abnormal lymphatic transport after lymphedema is fully established, and it shows slow or absent lymph flow and reflux (dermal backflow) areas. LSG also shows tracer uptake abnormalities in the lymph nodes, which detect abnormalities of the lymphatic system in the extremities quite accurately, regardless of the cause.28,29

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A

LT

LT Posterior RT

RT Anterior

B

FIG. 26-5  A, Normal clearance with normal main lymphatic vessels, but multiple collateral vessels on both lower extremities might suggest insufficient function of the main channel system alone to warrant the collaterals for the compensation, compatible with the clinical status. B, The clinical condition is in the early stage of lymphedema combined with lipedema, as shown, at the borderline of stage I and stage 0.

The first and most important finding to be verified is whether there is increased accumulation of radiotracer in the lymphatic system and surrounding soft tissue (for example, dermal backflow). Its positive findings indicate not only the existence of lymphedema but also the severity (for example, delayed clearance) and range or extension of the disease. For lower limb lymphedema, the appearance and uptake of the inguinal nodes are directly proportional to the severity of the condition. If the inguinal nodes are not seen on interval follow-up scanning, this often indicates a more advanced stage of the disease. Abnormal lymph nodes or an abnormal pattern of lymphatic drainage through the collaterals often indicate lymphatic dysfunction, especially in the primary lymphedema group, although they have limited significance as nonspecific signs28,29 (Fig. 26-5). Generally, the main criteria of scintigraphic diagnosis depend on whether the lymphatic channels are clearly visible and radiotracer is accumulated in the soft tissue and/or lymphatic vessels. There are many abnormal patterns of LSG. Normal LSG in a normal limb reveals the tracer at the injection site, but to a lesser degree than in the lymphedematous limb. Radiotracer is neither accumulated along the normal lymphatic drainage route in the soft tissue nor in the lymphatic vessels (Fig. 26-6).

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LT

LT Posterior RT

359

RT Anterior

3-hour delay

6-hour delay LT

LT Posterior RT

RT Anterior

15-minute delay

FIG. 26-6  Normal radiotracer (99mTc-filtered sulfur colloid) uptake in normal-appearing lymphatic channels is seen throughout the bilateral lower extremities. Bilateral groin and iliac chain lymph nodes are seen on 15-minute, 3-hour, and 6-hour delayed images. Radiotracer uptake in the liver and thoracic duct is seen at the 6-hour delay. No abnormal pooling of radiotracer and dermal backflow is seen in either leg.

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The test reveals various conditions of tracer clearance, including the presence of dermal backflow and asymmetry alteration in inguinoaxillary nodes (sensitivity 89%, specificity 96%).33 However, the accumulation of radioactivity in the soft tissues or lymphatic vessels is the most ominous and common pattern seen as a diagnostic criterion of lymphedema, in addition to the findings of abnormal lymph node images or poor or no groin nodal uptake in the diseased extremity.28,29,50,51 Although these findings are not directly related to the cause of the lymphedema, the presence of more of these findings indicates the severity of the disease.

Primary Lymphedema In addition to a clinical evaluation, LSG is now the most essential modality used in the diagnosis of primary lymphedema. LSG is extremely useful to identify the specific lymphatic abnormality and to visualize the lymphatic network. LSG can easily be repeated with minimal risk. Data and images obtained from the study identify lymphatic (dys)function, which is based on the visualization of the lymphatics, lymph nodes, dermal backflow, and semiquantitative data on radiotracer (lymph) transport.1,4 However, in primary lymphedema, there is poor definition of the lymphatic routes. There is also a delayed appearance of tracer in the regional lymph nodes and possible tracer dermal backflow in hypoplasia, whereas in aplasia there are no lymphatic routes and lymph nodes are not displayed. With quantification, a more precise uptake can be measured in the groin. This method needs a normal standard and protocol that includes “normal values of uptake” in the groin and “clearance values of the injection site.”28,29 Another method of investigating lymph transport is the use of a transport index, in which an index below 10 is normal. The index combines visual assessment of the following five criteria: the temporal and spatial distribution of the radionuclide, appearance time of the lymph nodes, and graded visualization of lymph nodes and vessels.53

Secondary Lymphedema Secondary lymphedema has various causes. The underlying abnormality is the obstruction or obliteration of lymph flow from an acquired source. In developed countries the most common cause is cancer treatment of the regional axillary, inguinal, or retroperitoneal lymph nodes, which are excised, irradiated, or otherwise destroyed along with surrounding lymphatic vessels, and occasionally the staging of breast cancer, melanoma, or gynecologic malignancies. Therefore the general finding is one of decreased or absent transport combined with various grades of dermal backflow. Sometimes collateral circulation, lymphocele, and lymphangioectases can also be seen (Fig. 26-7). Quantification is also useful, especially in comparison with the contralateral limb, to determine if a preexisting lymphatic impairment is already present. This is often the case in so-called postinfectious secondary lymphedema, which not infrequently proves to be a primary impairment.13,53-55

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Chapter 26  Radionuclide Lymphoscintigraphy

A

LT

LT Posterior RT

361

RT Anterior

B

15-minute delay

FIG. 26-7  A, Lymphoscintigraphy with 15-minute delay of 2.0 mCi of 99mTc sulfur colloid given intradermally. Severely tortuous main lymphatic vessels with the collaterals along the right lower extremity in a 56-year-old morbidly obese woman whose body weight was 280 pounds. B, Swelling in both legs rapidly became worse after recurrent bouts of cellulitis for the past few years and reached clinical stage III. Findings from her first LSG from 10 years ago were normal, which suggests that the infection and her lipedema were crucial precipitating factors for such rapid progression of the lymphedema.

Recommendation In the IUA-ISVI’s “Consensus for Diagnosis Guideline of Chronic Lymphedema of the Limbs,” the expert panel recommended LSG, from a morphofunctional viewpoint, for the pretreatment assessment of the lymphatic system.26 The panel also recommended LSG for follow-up assessment of therapy and natural disease progression for comparison with baseline values at the start. The strength of that recommendation is 1 (strong), and the quality of that evidence is A (high).56,57 Although the absolute majority of the panel gave a 1 (strong) and an A (high) recommendation to LSG as a noninvasive test for the basic evaluation of lymphedema, the current quality of LSG remains controversial because of poor image resolution. LSG is unable to detect edema in the lymphedematous limb and infrequently misidentifies dermal backflow. It is also known to yield false-positive findings (for example, erysipelas) in up to 10% of studies. However, LSG still has a leading role as a functional test in the initial diagnosis of an enlarged limb, although it hardly displays the anatomic abnormalities of a lymph vessel and lymph node compared with the old oil contrast lymphography.

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C linical P earls • Radionuclide lymphoscintigraphy (LSG) fulfills a critical role as a precise method of pretreatment evaluation and repeated assessment of patients with lymphedema. • The advantages of LSG are that it is minimally invasive, easily performed, safe, and widely available. Thus LSG remains the procedure of choice. • LSG is a radionuclide imaging technique for the assessment of lymphatic function that uses radioisotope-tagged or radioisotope-labeled pharmaceutical particles as a tracer. • Duplex ultrasonography should be the first test performed, even before LSG, in all forms of primary lymphedema to differentiate between lymphatic and venous etiologic factors. • LSG is used mostly in patients with primary lymphedema, although other vascular imaging studies should also be conducted in all areas of potential involvement and the contralateral normal limb for comparison.

R EFERENCES 1. Lee BB, Andrade M, Bergan J, et al; International Union of Phlebology. Diagnosis and treatment of primary lymphedema. Consensus document of the International Union of Phlebology (IUP)-2009. Int Angiol 29:454-470, 2010. 2. Lee BB. Chronic lymphedema, no more step child to modern medicine! Eur J Lymphol 14:6-12, 2004. 3. Lee BB. Contemporary issues in management of chronic lymphedema: personal reflection on an experience with 1065 patients. Lymphology 38:28-31, 2005. 4. Lee BB, Andrade M, Antignani PL, et al. Diagnosis and treatment of primary lymphedema. Consensus document of the International Union of Phlebology (IUP)-2013. Int Angiol 32:541-574, 2013. 5. International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema. 2009 Consensus document of the International Society of Lymphology. Lymphology 42:51-60, 2009. 6. International Lymphoedema Framework. Best Practice for the Management of Lymphoedema, ed 2, 2012. Available at www.lympho.org. 7. Lee BB. Classification and staging of lymphedema. In Tredbar LL, Morgan CL, Lee BB, eds. Lymphedema: Diagnosis and Treatment. London: Springer-Verlag, 2008. 8. Lee BB, Laredo J, Neville R, et al. Primary lymphedema and Klippel-Trenaunay syndrome. In Lee BB, Bergan J, Rockson S, eds. Lymphedema: A Concise Compendium of Theory and Practice. London: Springer-Verlag, 2011. 9. Lee BB, Kim DI, Whang JH, et al. Contemporary management of chronic lymphedema—personal experiences. Lymphology 35(Suppl):450-455, 2002. 10. Lee BB, Laredo J. Contemporary role of lymphoscintigraphy: we can no longer afford to ignore! [editorial] Phlebology 26:177-178, 2011. 11. Lee BB, Laredo J, Neville R. Combined clinical and laboratory (lymphoscintigraphic) staging. In Lee BB, Bergan J, Rockson S, eds. Lymphedema: A Concise Compendium of Theory and Practice. London: Springer-Verlag, 2011. 12. Michelini S, Campisi C, Gasbarro V, et al. National guidelines on lymphedema. Lymphology 55:238242, 2007. 13. Damstra RJ, van Steensel MA, Boomsma JH, et al. Erysipelas as a sign of subclinical primary lymphoedema: a prospective quantitative scintigraphic study of 40 patients with unilateral erysipelas of the leg. Br J Dermatol 158:1210-1215, 2008.

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14. Tiwari A, Cheng KS, Button M, et al. Differential diagnosis, investigation, and current treatment of lower limb lymphedema. Arch Surg 138:152-161, 2003. 15. Lee BB, Kim YW, Seo JM, et al. Current concepts in lymphatic malformation (LM). Vasc Endovasc Surg 39:67-81, 2005. 16. Szuba A, Razavi M, Rockson SG. Diagnosis and treatment of concomitant venous obstruction in patients with secondary lymphedema. J Vasc Intervent Radiol 13:799-803, 2002. 17. Lee BB, Laredo J. Classification: venous-lymphatic vascular malformation. In Allegra C, Antignani PL, Kalodiki E, eds. News in Phlebology. Turin, Italy: Edizioni Minerva Medica, 2013. 18. Lee BB, Villavicencio JL. Primary lymphoedema and lymphatic malformation: are they the two sides of the same coin? Eur J Vasc Endovasc Surg 39:646-653, 2010. 19. Lee BB, Laredo J, Seo JM, et al. Treatment of lymphatic malformations. In Mattassi R, Loose DA, Vaghi M, eds. Hemangiomas and Vascular Malformations. Milan: Springer-Verlag, 2009. 20. Lee BB. Lymphedema-angiodysplasia syndrome: a prodigal form of lymphatic malformation (LM). Phlebolymphology 47:324-332, 2005. 21. Pui MH, Yueh TC. Lymphoscintigraphy in chyluria, chyloperitoneum and chylothorax. J Nucl Med 39:1292-1296, 1998. 22. Cambria RA, Gloviczki P, Naessens JM, et al. Noninvasive evaluation of the lymphatic system with lymphoscintigraphy: a prospective, semiquantitative analysis in 386 extremities. J Vasc Surg 18:773782, 1993. 23. Bernas M, Witte M, Witte C, et al. Limb volume measurements in lymphedema: issues and standards. Lymphology 29(Suppl):199-202, 1996. 24. Sitzia J. Volume measurements in lymphoedema treatment: examination of formulae. Eur J Cancer Care (Engl) 4:11-16, 1995. 25. Casley-Smith JR. Measuring and representing peripheral oedema and its alterations. Lymphology 27:56-70, 1994. 26. Lee BB, Antignani PL, Baroncelli TA, et al. Iua-Isvi consensus for diagnosis of chronic lymphedema of the limbs. Int Angiol. 2014 Mar 19. [Epub ahead of print] 27. Gloviczki P, ed. Guidelines 6.2.0 on lymphoscintigraphy and lymphangiography. In Gloviczki P, ed. Handbook of Venous Disorders: Guidelines of the American Venous Forum, ed 3. London: Hodder Arnold, 2009. 28. Yuan Z, Chen L, Luo Q, et al. The role of radionuclide lymphoscintigraphy in extremity lymphedema. Ann Nucl Med 20:341-344, 2006. 29. Peller PJ, Bender CE, Gloviczki P. Lymphoscintigraphy and lymphangiography. In Gloviczki P, ed. Handbook of Venous Disorders: Guidelines of the American Venous Forum, ed 3. London: Hodder Arnold, 2009. 30. Szuba A, Shin WS, Strauss HW, et al. The third circulation: radionuclide lymphoscintigraphy in the evaluation of lymphedema. J Nucl Med 44:43-57, 2003. 31. Weissleder H, Weissleder R. Lymphedema: evaluation of qualitative and quantitative lymphoscintigraphy in 238 patients. Radiology 167:729-735, 1988. 32. Baulieu F, Lorette G, Baulieu JL, et al. [Lymphoscintigraphic exploration in the limbs lymphatic disease] Presse Med 39:1292-1304, 2010. 33. Infante JR, Garcia L, Laguna P, et al. Lymphoscintigraphy for differential diagnosis of peripheral edema: diagnostic yield of different scintigraphic patterns. Rev Esp Med Nucl Imagen Mol 31:237-242, 2012. 34. Kinmonth JB. Lymphangiography in man; a method of outlining lymphatic trunks at operation. Clin Sci (Lond) 11:13-20, 1952. 35. Steckei RJ, Furumanski S, Dunham R, et al. Radionuclide perfusion lymphangiography. An experimental technique to complement the standard ethiodol lymphangiogram. Am J Roentgenol Radium Ther Nucl Med 124:600-609, 1975. 36. Baumeister RG, Siuda S, Bull U, et al. Evaluation of transport kinetics in lymphoscintigraphy: followup study in patients with transplanted lymphatic vessels. Eur J Nucl Med 10:349-352, 1985.

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37. Lee BB, Bergan JJ. New clinical and laboratory staging systems to improve management of chronic lymphedema. Lymphology 38:122-129, 2005. 38. Michelini S, Failla A, Moneta G, et al. Clinical staging of lymphedema and therapeutical implications. Lymphology 35:168-176, 2002. 39. Lee BB, Laredo J, Neville R, et al. Diagnosis and management of primary phlebolymphedema. In Lee BB, Bergan J, Rockson S, eds. Lymphedema: A Concise Compendium of Theory and Practice. London: Springer-Verlag, 2011. 40. Lee BB, Bergan J, Gloviczki P, et al; International Union of Phlebology (IUP). Diagnosis and treatment of venous malformations. Consensus document of the International Union of Phlebology (IUP)-2009. Int Angiol 28:434-451, 2009. 41. Lim CY, Seo HG, Kim K, et al. Measurement of lymphedema using ultrasonography with the compression method. Lymphology 44:72-81, 2011. 42. Cavezzi A. Duplex ultrasonography. In Lee BB, Bergan J, Rockson S, eds. Lymphedema: A Concise Compendium of Theory and Practice. London: Springer-Verlag, 2011. 43. Antignani PL, Benedetti-Valentini F, Aluigi L, et al; Italian Society for Vascular Investigation. Diagnosis of vascular diseases. Ultrasound investigation—guidelines. Int Angiol 31(5 Suppl 1):1-77, 2012. 44. Garra BS. Imaging and estimation of tissue elasticity by ultrasound. Ultrasound Q 23:255-258, 2007. 45. Lu Q, Xu JR, Liu NF. Chronic lower extremity lymphedema: a comparative study of high-resolution interstitial MR lymphangiography and heavily T2-weighted MRI. Eur J Radiol 73:365-373, 2010. 46. Werner GT, Rodiek SO. Value of nuclear magnetic resonance tomography in leg edema of unknown origin. Preliminary report. Z Lymphol 17:2-5, 1993. 47. Buck AK, Nekolla S, Ziegler S, et al. SPECT/CT. J Nucl Med 49:1305-1319, 2008. 48. Kotani K, Kawabe J, Higashiyama S, et al. Lymphoscintigraphy with single-photon emission computed tomography/computed tomography is useful for determining the site of chyle leakage after esophagectomy. Indian J Nucl Med 27:208-209, 2012. 49. Uhl JF. 3D multislice CT to demonstrate the effects of compression therapy. Int Angiol 29:411-415, 2010. 50. Hung JC, Wiseman GA, Wahner HW, et al. Filtered technetium-99m-sulfur colloid for lymphoscintigraphy. J Nucl Med 36:1895-1901, 1995. 51. Inoue Y, Otake T, Nishikawa J, et al. Lymphoscintigraphy using Tc 99m human serum albumin in chylothorax. Clin Nucl Med 22:60, 1997. 52. Bellini C, Boccardo F, Campisi C, et al. Lymphatic dysplasias in newborns and children: the role of lymphoscintigraphy. J Pediatr 152:587-589, 2008. 53. Kleinhans E, Baumeister RG, Hahn D, et al. Evaluation of transport kinetics in lymphoscintigraphy: follow-up study in patients with transplanted lymphatic vessels. Eur J Nucl Med 10:349-352, 1985. 54. Mariani G, Campisi C, Taddei G, et al. The current role of lymphoscintigraphy in the diagnostic evaluation of patients with peripheral lymphedema. Lymphology 31(Suppl):316-319, 1998. 55. Bellini C, Di Battista E, Boccardo F, et al. The role of lymphoscintigraphy in the diagnosis of lymphedema in Turner syndrome. Lymphology 42:123-129, 2009. 56. Guyatt GH, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines. Chest 129:174-181, 2006. 57. Guyatt GH, Oxman AD, Vist GE, et al; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 336:924-926, 2008.

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C hapter 27 Indocyanine Green Lymphography Mitsunaga Narushima, Takumi Yamamoto, Isao Koshima

K ey P oints • Indocyanine green (ICG) lymphography, which can visualize superficial lymph flow in real time without radiation exposure, is a clinically useful evaluation method for lymphedema. • With progression of lymphedema, the ICG lymphographic pattern changes from the normal linear pattern to abnormal dermal backflow (DB) patterns (splash, stardust, and diffuse patterns).

Ind

• ICG velocity and lymph transportation capacity decrease as lymphedema progresses. • ICG lymphography is also useful for the preoperative assessment of lymphatic surgeries, because different ICG lymphographic findings represent different conditions of the lymphatic vessels; the more severe the DB pattern seen on ICG lymphography, the more sclerotic and smaller the lymphatic vessels are. • In dynamic ICG lymphography, one ICG injection is enough for pathophysiologic severity staging (DB stage), lymph pump function evaluation (ICG velocity), and preoperative assessment.

Several methods have been reported to visualize lymph flow and evaluate lymphedema, including MRI, CT, ultrasonography, and lymphoscintigraphy.1-4 Currently, lymphoscintigraphy is considered the benchmark for the evaluation of lymphedema. Lymphoscintigraphy can visualize deep lymphatic flow but its image is obscure, and it has a risk of radiation exposure.4,5 ICG was first reported in 2007 for the evaluation of lymphedema.6,7 ICG lymphography allows much clearer visualization of superficial lymph flow than lymphoscintigraphy. It is useful not only for lymphedema evaluation but also for the preoperative assessment of lymphatic surgeries.6-16 ICG lymphography is increasingly used in the clinical practice of lymphedema management.

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Material for Indocyanine Green Lymphography As an optical tracer agent, ICG is a medically useful green dye that was approved by the FDA in 1956. ICG is not only a green dye marker but also a fluorescent substance. Near-infrared fluorescent light penetrates tissue more deeply than does visible light.6,7 ICG lymphography, which is used to visualize superficial lymph flow after injection of ICG, is performed with a near-infrared camera device that is equipped with a charge-coupled device camera as a detector with a 760 nm light-emitting diode and a filter-cutting light below 820 nm.6-12 The fluorescent images are digitized for real-time display by using a standard personal computer. Several near-infrared camera devices are available. Some manufacturers include Hamamatsu Photonics, Mizuho, Novadaq Technologies, Olympus (microscope), Carl Zeiss (microscope), and Leica (microscope).13,14 Because ICG lymphography is used to visualize lymph flow in real time, ICG lymphography allows static evaluation of lymph circulation as well as dynamic lymph movement. With this property, dynamic ICG lymphography, or dual-phase ICG lymphography, was developed for comprehensive assessment of lymphedema.17,18

Procedures of Dynamic Indocyanine Green Lymphography Dynamic ICG lymphography is performed as follows. After a patient remains still for 15 minutes, 0.05 to 0.2 ml of ICG (Diagnogreen 0.25%, Daiichi Pharmaceutical, Tokyo, Japan) is injected subcutaneously (at the second web space for extremity and genital lymphedema and at the glabella and below the nose for facial lymphedema).8-12 Immediately after ICG injection (transient phase), fluorescent images of lymphatic flow are obtained with an infrared camera system.17,18 The observation is continued until lymph pump function is measured. Patients remain still in the supine position during lymph pump function measurement. Then patients are allowed to move freely. Twelve to 18 hours after ICG injection, ICG movement usually reaches the plateau phase. In this phase, lymph circulation is evaluated based on ICG lymphographic findings, which allow pathophysiologic severity staging and preoperative guidance for lymphatic surgeries.8-12 When patients move their extremity rigorously, ICG can reach a plateau 2 hours after ICG injection.17,18 The plateau phase usually continues until 72 hours after ICG injection. Thus it is possible to evaluate abnormal lymph circulation between 2 and 72 hours after ICG injection.15,16

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ICG injection 5 minutes Remain still Early transient phase 2-72 hours Move freely

IGC velocity (pump)

Late plateau phase Dermal backflow stage (circulation) Mapping (navigation)

FIG. 27-1  Dynamic ICG lymphography. At the early transient phase, lymph pump function is evaluated by ICG velocity. At the late plateau phase, pathophysiologic severity staging (dermal backflow stage) and lymphatic mapping are done based on ICG lymphographic patterns.

In dynamic ICG lymphography, lymphatic images are taken twice; at an early transient phase and at a late plateau phase.17,18 We usually inject ICG the day before lymphatic surgery; one ICG injection is enough for lymph pump function measurement, evaluation of abnormal lymph circulation, and preoperative mapping (Fig. 27-1).

Evaluation of the Lymphatics Lymph Vessels As ICG lymphographic patterns change according to the pathophysiologic changes of lymph flows, different ICG lymphographic findings indicate different conditions of the lymphatic vessels.9-16 As ICG lymphographic patterns change from linear to splash, stardust, and diffuse pattern, lymphatic vessels change to become more sclerotic with less lymph flow. Lymphatic vessels are almost intact in linear regions; on the other hand, they are very sclerotic with a pinhole-like lumen in diffuse regions9-14 (Fig. 27-2). According to a comparative study of ICG lymphographic findings and intraoperative conditions of 215 lymphatic vessels, the mean diameter of the lymphatic vessels was 0.45 mm in linear regions, 0.44 mm in splash and stardust regions, and 0.26 mm in diffuse regions.15 In planning lymphaticovenular anastomosis, diffuse regions should be avoided, because the detection rate of lymphatic vessels favorable for lymphaticovenular anastomosis is low.15,16

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Linear Normal

Splash

Stardust Abnormal (dermal backflow)

Diffuse

Progression of Lymphedema

FIG. 27-2  ICG lymphographic findings and conditions of lymphatic vessels. With progression of lymphedema, ICG lymphography patients change from linear to splash, stardust, and finally to a diffuse pattern.

Lymph Transportation Capacity Because ICG lymphography visualizes lymph flow in real time, lymph transportation capacity can be directly evaluated by measuring ICG movement at an early transient phase. There are several ways to evaluate lymph pump function, such as transit time, lymphatic pressure, and ICG velocity.17-20 Among the various lymph pump function evaluations, ICG velocity is the most practical one. ICG velocity can be measured within 5 minutes, whereas others sometimes require more than 1 hour in patients with severe lymphedema. The distance between the injection point and farthest proximal point at which the dye can be observed is measured 5 minutes after ICG injection; ICG velocity is calculated by dividing the distance by time. When ICG reaches the axilla and groin within 5 minutes after dye injection in patients with extremity lymphedema, ICG velocity is calculated by dividing the distance between the injection point and axilla and groin by the time required. ICG velocity decreases with the progression of lymphedema and increases after successful interventions. Because ICG velocity is a quantitative evaluation, it is easy to evaluate lymph pump function before and after therapeutic interventions.

Lymph Circulation ICG lymphography can detect lymphatic channels and nodes located up to 2 cm deep to the skin surface, assuming there is no fascia, muscle, or bone between the lymph channels and skin. Thus ICG lymphography dynamically shows superficial lymphatic channels (collectors, precollectors, and capillary channels) as a white line (linear pattern) on a screen. ICG lymphography can show lymphatic channels, lymphatic valves, and lymphatic flow immediately after the injection of ICG.

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The ICG lymphographic pattern changes from the normal linear pattern to abnormal dermal backflow (DB) patterns in obstructive lymphedema. With the progression of lymphedema, ICG lymphographic patterns change from the linear pattern to the splash, stardust, and finally to the diffuse pattern.8-12 Lymph flow obstruction leads to lymphatic hypertension, lymphangiectasis, lymphatic valve insufficiency, lymphosclerosis, and lymph backflow. ICG lymphography visualizes lymph backflow as the DB pattern. The splash pattern on ICG lymphography represents dilated superficial lymphatics, such as lymphatic precollectors and capillaries. Extravasation of lymph fluid occurs with the progression of lymphedema, which is represented as spots on ICG lymphography, the stardust pattern. Finally, the number of spots visualized on ICG lymphography increases to the point at which spots merge and cannot be distinguished from each other, the diffuse pattern. These DB patterns usually extend from proximal to distal regions in obstructive lymphedema, such as cancer-related lymphedema. The evaluation of abnormal lymph circulation with ICG lymphography allows pathophysiologic severity staging, which is a qualitative evaluation.

Dermal Backflow Stage for the Pathophysiologic Severity Staging System The DB stage, the pathophysiologic severity staging system, is determined based on ICG lymphographic findings (Table 27-1). There are four DB stages9-12,16: 1. Arm DB (ADB) (Fig. 27-3) 2. Leg DB (LDB)10 (Fig. 27-4) 3. Genital DB (GDB)12 (Fig. 27-5) 4. Facial DB (FDB) (Fig. 27-6)

TABLE 27-1  Dermal Backflow Pattern Staging Arm (ADB): Upper Extremity

Leg (LDB): Lower Extremity

Genital (GDB): Lower Abdominal and Genital Regions

Facial (FDB): Head and Neck Regions

0

No DB pattern seen

No DB pattern seen

No DB pattern seen

No DB pattern seen

I

Splash pattern seen around axilla

Splash pattern seen around groin

Splash pattern seen around groin and/or lower abdominal region

Splash pattern seen around neck

II

Stardust pattern limited proximally to olecranon

Stardust pattern limited proximally to superior border of patella

Stardust pattern around groin and/or lower abdominal region

Stardust pattern limited proximally to mandibular margin

III

Stardust pattern beyond olecranon

Stardust pattern extends distal to superior border of patella

Stardust pattern present in whole area between groin and genital regions

Stardust pattern extends proximal to mandibular margin

IV

Stardust pattern observed throughout limb

Stardust pattern observed throughout limb

Stardust pattern observed throughout groin and/or lower abdominal regions

Stardust pattern observed throughout head and neck region

V

Diffuse stardust pattern

Diffuse stardust pattern

Stage

Diffuse stardust pattern

ADB, Arm dermal backflow; LDB, leg dermal backflow; GDB, genital dermal backflow; FDB, facial dermal backflow.

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ADB Stage 0

ADB Stage III

Splash



Stardust



1 1

Splash Stardust Diffuse

Diffuse



1

1 1 1

ADB Stage IV

ADB Stage I

Splash



Splash Stardust Diffuse

Stardust Diffuse

1

ADB Stage II



1 1 1

1

ADB Stage V

Splash Stardust Diffuse

Splash Stardust Diffuse

FIG. 27-3  Arm dermal backflow (ADB) stage.

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LDB Stage III

LDB Stage 0

Splash



Stardust





Splash

Diffuse



1



11

Stardust Diffuse

111

LDB Stage IV

LDB Stage I

Splash Stardust Diffuse





Splash



1



Stardust Diffuse

1 1 1

1

LDB Stage V

LDB Stage II

Splash

Stardust Diffuse

Splash

Stardust Diffuse

FIG. 27-4  Leg dermal backflow (LDB) stage.

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GDB Stage 0

GDB Stage III

Splash



Stardust



1 1

Splash Stardust Diffuse

Diffuse



1

1 1 1

1

GDB Stage IV

GDB Stage I

Splash



Stardust Diffuse

Splash Stardust Diffuse

1

GDB Stage II

Splash Stardust Diffuse

FIG. 27-5  Genital dermal backflow (GDB) stage.

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FDB Stage 0

FDB Stage III

Splash



Stardust



1 1

Splash Stardust Diffuse

Diffuse



1

1 1 1

FDB Stage IV

FDB Stage I

Splash



Splash Stardust Diffuse

Stardust Diffuse

1

FDB Stage II



1 1 1

1

FDB Stage V

Splash Stardust Diffuse

Splash Stardust Diffuse

FIG. 27-6  Facial dermal backflow (FDB) stage.

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Linear

Splash

Stardust

Diffuse

Stage 0

Stage I

Stage II-IV

Stage V

Irreversible

Reversible Progression of Lymphedema

FIG. 27-7  Clinical significance of DB pattern differentiation. The splash pattern is a reversible lymph circulatory change, whereas the stardust pattern is an irreversible lymph circulatory change.

According to a prospective cohort study by Akita et al21 in which 100 consecutive patients with gynecologic cancer were followed for 2 years with ICG lymphography, the splash pattern was seen as a reversible lymph circulation change, whereas the stardust pattern was an irreversible change (Fig. 27-7). After pelvic lymph node dissection, 31 of 100 patients showed the splash pattern (LDB stage I), of which 5 improved to the linear pattern (LDB stage 0), 17 remained in the splash pattern (LDB stage I), and 9 progressed to the stardust pattern (LDB stage II). After observation on ICG lymphography, the stardust pattern never improved to the splash or linear pattern, even with conservative treatment. Because most patients are asymptomatic in DB stage I, asymptomatic patients should be followed carefully with ICG lymphography after cancer treatment to detect subclinical lymphedema.10,21,22

Intraoperative Navigation for Lymphaticovenular Anastomosis ICG lymphography can be used intraoperatively for navigation during lymphatic surgery. As mentioned previously, conventional ICG lymphography with a handheld camera system or microscopic ICG lymphography with a near-infrared camera-integrated microscope guides the surgeon

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to find lymphatic vessels suitable for lymphaticovenular anastomosis, to evaluate the patency or quality of lymphaticovenular anastomosis, and to harvest a vascularized lymph node flap.13,14,16,23-32 In severe DB regions, such as those with a diffuse pattern, lymphatic vessels are less likely to be enhanced intraoperatively. Thus intraoperative ICG lymphography is likely to help a lymphatic surgeon in mild lymphedema cases.13,14,27 When observed at a plateau phase, additional ICG injection is unnecessary or does not work for intraoperative navigation. When lymphatic vessels are not enhanced, the vessels are usually sclerotic, and additional ICG injection will not enhance them.13,14

Lymphedema Management With Indocyanine Green Lymphography When to start treatment and which treatments to perform are the most important issues to be solved in lymphedema management. ICG lymphography can be a useful evaluation method to guide decision-making in lymphedema management16,22 (Table 27-2). In DB stage 0 (no lymphedema), no treatment is indicated, because lymph circulation is intact. In DB stage I with a splash pattern (subclinical lymphedema), management is controversial. Although the splash pattern represents an abnormal lymph circulation pattern, it is a reversible change. Immediate therapeutic interventions are unnecessary and overtreatment should be avoided.10,16,22 Further studies are required to clarify the management of subclinical lymphedema: prophylactic treatment or careful follow-up with ICG lymphography. In DB stage II with the stardust pattern (early lymphedema), physiologic surgical treatments, such as LVA, are indicated, because there is an irreversible abnormal lymph circulation pattern that is refractory to conservative treatments. When treatment is indicated, conservative treatment should be initiated first not only as a definitive treatment, but also as a preoperative modality before lymphatic surgery. When lymphedema progresses despite conservative treatment, lymphatic surgery is indicated. For subclinical or early-stage lymphedema (DB stages I and II), lymphaticovenular anastomosis is the best treatment option because of its effectiveness and minimal invasiveness. Lymphaticovenular anastomosis can be performed under local anesthesia through a small incision.* For more advanced *References 10, 13, 14, 16, 22, 27.

TABLE 27-2  Dermal Backflow Stage and Lymphedema Management DB Stage

Clinical Phase

Management

Stage I

Subclinical

Follow-up or prophylaxis

Stage II

Early

Lymphaticovenular anastomosis

Stages III-V

Progressed

Lymphaticovenular anastomosis 1 Vascularized lymph node transfer 1 Liposuction

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lymphedema (DB stages III through V), lymphaticovenular anastomosis can work, but further surgical treatments are sometimes required when lymphaticovenular anastomosis is insufficient to improve the lymphedema. In particular, for DB stage V with a diffuse pattern, vascularized lymph node transfer is indicated, because there are few lymphatic vessels appropriate for lymphaticovenular anastomosis. Debulking surgeries, such as resection and liposuction, are required for volume reduction in patients with massive fat deposition.

C linical P earls • ICG lymphography follows cancer survivors’ prognosis regarding lymphedema. • The splash pattern (DB stage I) is a reversible lymph circulatory change; some patients improve to DB stage 0 spontaneously. • The stardust pattern (DB stage II) is an irreversible lymph circulatory change; no patients improve to DB stages 0 or I even with conservative treatment.

R EFERENCES 1. Case TC, Witte CL, Witte MH, et al. Magnetic resonance imaging in human lymphedema: comparison with lymphangioscintigraphy. Magn Reson Imaging 10:549-558, 1992. 2. Gamba JL, Silverman PM, Ling D, et al. Primary lower extremity lymphedema: CT diagnosis. Radiology 149:218, 1983. 3. Doldi SB, Lattuada E, Zappa MA, et al. Ultrasonography of extremity lymphedema. Lymphology 25:129133, 1992. 4. Henze E, Schelbert HR, Collins JD, et al. Lymphoscintigraphy with Tc-99m-labeled dextran. J Nucl Med 23:923-929, 1982. 5. International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema. 2009 Consensus Document of the International Society of Lymphology. Lymphology 42:51-60, 2009. 6. Ogata F, Azuma R, Kikuchi M, et al. Novel lymphography using indocyanine green dye for nearinfrared fluorescence labeling. Ann Plast Surg 58:652-655, 2007. 7. Unno N, Inuzuka K, Suzuki M, et al. Preliminary experience with a novel fluorescence lymphography using indocyanine green in patients with secondary lymphedema. J Vasc Surg 45:1016-1021, 2007. 8. Yamamoto T, Narushima M, Doi K, et al. Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns. Plast Reconstr Surg 127:1979-1986, 2011. 9. Yamamoto T, Yamamoto N, Ogata F, et al. Indocyanine green-enhanced lymphography for upper extremity lymphedema: a novel severity staging system using dermal backflow patterns. Plast Reconstr Surg 128:941-947, 2011. 10. Yamamoto T, Matsuda N, Doi K, et al. The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the mod­ ified dermal backflow stage and concept of subclinical lymphedema. Plast Reconstr Surg 128:314e321e, 2011. 11. Yamamoto T, Iida T, Matsuda N, et al. Indocyanine green (ICG)-enhanced lymphography for evaluation of facial lymphoedema. J Plast Reconstr Aesthet Surg 64:1541-1544, 2011.

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12. Yamamoto T, Yamamoto N, Yoshimatsu H, et al. Indocyanine green lymphography for evaluation of genital lymphedema in secondary lower extremity lymphedema patients. J Vasc Surg: Venous Lymph Dis. 2013 July 18. [Epub ahead of print] 13. Yamamoto T, Yamamoto N, Azuma S, et al. Near-infrared illumination system-integrated microscope for supermicrosurgical lymphaticovenular anastomosis. Microsurgery 34:23-27, 2014. 14. Yamamoto T, Yamamoto N, Numahata T, et al. Navigation lymphatic supermicrosurgery for the treatment of cancer-related peripheral lymphedema. Vasc Endovasc Surg 48:139-143, 2014. 15. Yamamoto T, Narushima M, Koshima I. Lymphedema evaluation using ICG fluorescent lymphography. In Koshima I, ed. Clinical Textbook of Lymphedema. Osaka: Nagai Shoten, 2011. 16. Yamamoto T, Yamamoto N, Narushima M, et al. Lymphaticovenular anastomosis with guidance of ICG lymphography. J Jpn Coll Angiol 52:327-331, 2012. 17. Yamamoto T, Narushima M, Yoshimatsu H, et al. Indocyanine green velocity: lymph transportation capacity deterioration with progression of lymphedema. Ann Plast Surg 71:591-594, 2013. 18. Yamamoto T, Narushima M, Yoshimatsu H, et al. Dynamic indocyanine green (ICG) lymphography for breast cancer-related arm lymphedema. Ann Plast Surg 73:706-709, 2014. 19. Unno N, Nishiyama M, Suzuki M, et al. Quantitative lymph imaging for assessment of lymph function using indocyanine green fluorescence lymphography. Eur J Endovasc Surg 36:230-236, 2008. 20. Unno N, Nishiyama M, Suzuki M, et al. A novel method of measuring human lymphatic pumping using indocyanine green fluorescence lymphography. J Vasc Surg 52:946-952, 2010. 21. Akita S, Mitsukawa N, Rikihisa N, et al. Early diagnosis and risk factors for lymphedema following lymph node dissection for gynecologic cancer. Plast Reconstr Surg 131:283-290, 2013. 22. Yamamoto T, Koshima I. Subclinical lymphedema: understanding is the clue to decision making. Plast Reconstr Surg 132:472e-473e, 2013. 23. Yamamoto T, Yoshimatsu H, Narushima M, et al. Split intravascular stents for side-to-end lymphaticovenular anastomosis. Ann Plast Surg 71:538-540, 2013. 24. Yamamoto T, Narushima M, Kikuchi K, et al. Lambda-shaped anastomosis with intravascular stenting method for safe and effective lymphaticovenular anastomosis. Plast Reconstr Surg 127:1987-1992, 2011. 25. Yamamoto T, Yoshimatsu H, Narushima M, et al. A modified side-to-end lymphaticovenular anastomosis. Microsurgery 33:130-133, 2013. 26. Yamamoto T, Koshima I, Yoshimatsu H, et al. Simultaneous multi-site lymphaticovenular anastomoses for primary lower extremity and genital lymphoedema complicated with severe lymphorrhea. J Plast Reconstr Aesthet Surg 64:812-815, 2011. 27. Yamamoto T, Narushima M, Yoshimatsu H, et al. Minimally invasive lymphatic supermicrosurgery (MILS): indocyanine green lymphography-guided simultaneous multisite lymphaticovenular anastomoses via millimeter skin incisions. Ann Plast Surg 72:67-70, 2014. 28. Yamamoto T, Yoshimatsu H, Narushima M, et al. Sequential anastomosis for lymphatic supermicrosurgery: multiple lymphaticovenular anastomoses on 1 venule. Ann Plast Surg 73:46-49, 2014. 29. Yamamoto T, Yoshimatsu H, Yamamoto N, et al. Side-to-end lymphaticovenular anastomosis through temporary lymphatic expansion. PLoS ONE 8:e59523, 2013. 30. Yamamoto T, Koshima I. Colourful indocyanine green lymphography. J Plast Reconstr Aesthet Surg 67:432-433, 2014. 31. Yamamoto T, Kikuchi K, Yoshimatsu H, et al. Ladder-shaped lymphaticovenular anastomosis using multiple side-to-side lymphatic anastomoses for a leg lymphedema patient. Microsurgery 34:404-408, 2014. 32. Narushima M, Mihara M, Yamamoto Y, et al. The intravascular stenting method for treatment of extremity lymphedema with multiconfiguration lymphaticovenous anastomoses. Plast Reconstr Surg 125:935-943, 2010.

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C hapter 28 Magnetic Resonance Lymphangiography Lee M. Mitsumori

K ey P oints • Three-dimensional heavily T2-weighted sequences are performed to assess the severity, extent, and distribution of lymphedema. • The number, size, and location of individual subdermal lymphatic channels and the areas of dermal backflow can be visualized with magnetic resonance lymphangiography (MRL). • MRL can be performed on 1.5 T or 3.0 T platforms with clinically available, high-resolution, three-dimensional volumetric sequences used for MR angiography. • MRL requires the intracutaneous injection of an extracellular gadolinium-based MR contrast agent. • Image postprocessing of three-dimensional volumetric MR datasets facilitates examination interpretation.

Ma

A number of microsurgical procedures for the long-term treatment of lymphedema have been developed, and the importance of individualizing the type of operative treatment based on the degree of lymphatic dysfunction and the state of the subcutaneous tissue is being recognized.1-5 One of the current challenges for lymphatic surgery is that there is no standardized method of imaging the structure and function of the lymphatic circulation to evaluate the quality and severity of lymphedema.6 Two lymphatic imaging methods that are clinically available are nuclear medicine lymphoscintigraphy and indocyanine green fluorescence lymphography (see Chapters 26 and 27). Although radionuclide lymphoscintigraphy has been considered the primary clinical imaging modality to diagnose lymphedema,7 the limited temporal and spatial resolution of the modality does not allow the identification and localization of individual lymphatic channels.8,9 Indocyanine green fluorescence lymphography is an imaging modality that is frequently used intraoperatively for microsurgical lymphatic procedures. Although indocyanine green fluorescence lymphography can provide a real-time map of the subdermal lymphatic channels, it has several disadvantages for the preoperative evaluation of lymphedema. These include a small field of view,

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lack of spatial information, limited skin penetration depth,6 and the inability to characterize soft tissues. Thus improved lymphatic imaging techniques are needed to determine whether suitable lymphatic channels are present for reconstruction, to depict the location of suitable lymphatic channels for preoperative planning, and to delineate the status of the subcutaneous soft tissues to facilitate the selection of the optimal treatment approach. Magnetic resonance lymphangiography (MRL) is a noninvasive technique that can image the subdermal lymphatic circulation in patients with lymphedema. MRL examinations provide the anatomic coverage to image an entire extremity with a high-resolution three-dimensional dataset and have sufficient temporal and spatial resolution to depict individual lymphatic channels and areas of dermal backflow. Imaging capabilities that are needed for the preoperative planning of lymphatic microsurgery.4,9 In addition, other MR pulse sequences can be included in the examination to evaluate the status of the subcutaneous soft tissues.8 With current 1.5 T and 3.0 T MR platforms, imaging data are acquired as three-dimensional volumetric datasets, which is important to enable the use of widely available image postprocessing algorithms that facilitate examination interpretation and microsurgical treatment planning.9,10 The main difference between MRL and other conventional contrast-enhanced MR examinations is the route of contrast administration. In MRL, a small volume of an extracellular gadoliniumbased MR contrast agent is injected intracutaneously in the interdigital webspaces of the hand or foot to promote contrast uptake by the lymphatic circulation. The low molecular weight of the extracellular MR contrast agents allows the lymphatic circulation to absorb the contrast agent in the interstitial space.11 Because of the off-label route of administration, the safety of the intracutaneous administration of extracellular gadolinium-based MR contrast agents was initially evaluated with animal experiments.12 Since the first few human clinical studies,13,14 several studies have been published that support the safety of the intracutaneous administration of different extracellular gadolinium-based MR contrast agents for MRL (gadopentetate dimeglumine,9 gadoterate meglumine,13 gadoteridol,4,15 gadodiamide,14,16 and gadobenate dimeglumine17,18). Although the intracutaneous contrast injection has been described as well tolerated by patients and no complications were reported by these studies, patients do describe mild to moderate pain during the injection, and some have transient swelling of the dorsum of the extremity around the injection site.11,13,14,16 To reduce the pain of the injection, a local anesthetic can be mixed with the contrast agent before intracutaneous administration, and a small-gauge needle should be used.11

MRL Imaging An MRL examination consists of two main components: a T2-weighted sequence to depict the severity and distribution of lymphedema and a fat-suppressed three-dimensional spoiled gradient recalled–echo (3D-SPGR) sequence after the intracutaneous injection of MR contrast to image lymphatic channels. Because the intracutaneously administered contrast agent is also absorbed by the venous circulation,1,9,11 the same high-resolution 3D-SPGR sequence can be repeated after a separate intravenous injection of contrast to obtain an MR venogram.19 Having the delayed MR

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venogram to compare with the MRL can be helpful to differentiate enhancing lymphatic channels from contrast-containing veins. MRL can be performed at 1.5 T or 3.0 T.9,15-17 Patient positioning, coil placement, and scan orientation will depend on whether the examination is of an upper or lower extremity and whether unilateral or bilateral imaging is performed. For unilateral imaging of the upper extremity, the patient is positioned supine and head first in the scanner gantry. The arm that will be scanned is placed at the patient’s side, and the patient is positioned as far laterally as possible with the arm propped with a pad to the level of the magnet isocenter. Surface coils are then positioned to image the target arm from the midhand to the shoulder. At 1.5 T we use a 16-channel torso phased array surface coil, whereas at 3.0 T a digital system with imbedded table coil elements is used, which allows coverage of the entire extremity with automatic coil element selection for each individual scan location. Headfirst patient positioning is helpful to allow access to the patient’s hand for the intracutaneous contrast injection that is performed midway through the examination. For the lower extremities, MRL is performed either as a unilateral or bilateral examination, depending on the clinical request. Patients are placed supine and feet first on the scanner table to allow access to the patient’s feet from the far side of the gan