Rutherford\'s Vascular Surgery, 8th Edition

SAVE OFFLINE

IN MEMORIAM Robert B. Rutherford, MD, 1931-2013

Robert B. Rutherford, MD, the founding editor of this textbook, died on November 22, 2013, at the age of 82. The vascular surgery community is saddened by the loss of this extraordinary man, who created many opportunities for others and did so much to advance the care of patients with vascular disease. Dr. Rutherford was born in Edmonton, Alberta, Canada. He received his BA (Phi Beta Kappa) in 1952 and his MD (Alpha Omega Alpha) in 1956, both from Johns Hopkins University. After internship at Johns Hopkins, he completed his general surgery residency at the University of Colorado in 1963. During residency, he did a clinical fellowship year as a Fulbright Scholar at Lund University in Malmo, Sweden. After residency he served 2 years in the military at the Walter Reed Army Institute of Research. He was then appointed to the surgical faculty at Johns Hopkins in 1965 before returning to the University of Colorado in 1970 where he spent the remainder of his professional career as Professor of Surgery and Chief of the Vascular Surgery Section. In 1975, Dr. Rutherford was the first to recognize the need for a comprehensive textbook devoted exclusively to the new specialty of vascular surgery. He successfully recruited a group of peers to be associate editors, and in 1977 the first edition of Vascular Surgery was published. In the preface to the first edition, he stated in his usual humble manner that “our efforts will

ii

have been rewarded if the book proves helpful to any physician who has committed himself or herself to treating patients with vascular disease.” Over the next 30 years, Dr. Rutherford shepherded his textbook through six editions, constantly updating authors, content, and associate editors, before assigning editorship to the Society for Vascular Surgery to ensure publication in perpetuity. Known colloquially as “Rutherford,” this textbook, a reflection of his vision and commitment, has become the definitive source for all practitioners of vascular healthcare. It is his enduring contribution to our discipline for which he is owed a great debt of gratitude. Dr. Rutherford had broad interests in vascular surgery, a scholarly command of the literature, and an outstanding memory. This led to the publication during his career of more than 400 scientific articles and book chapters, on a wide range of topics. Dr. Rutherford also recognized the need for regular updates of topics for practicing vascular surgeons, which led to his development and editing of “Seminars in Vascular Surgery” from 1988 to 2012. Given his knowledge base and editorial expertise, he was selected as senior editor of the Journal of Vascular Surgery, a position he held from 1996 to 2003. He was a natural editor who provided critical, but fair and balanced reviews, and was always prepared to help less experienced authors. Dr. Rutherford was a member of many professional societies, and was president of four, most notably serving as the forty-third president of the International Society for Cardiovascular Surgery, North American Chapter (now the Society for Vascular Surgery). In his presidential address of 1995, he emphasized the importance of uniform disease-specific reporting standards for describing vascular interventions, their results, and complications. Dr. Rutherford organized the committees that developed the current reporting standards for the Society of Vascular Surgery (SVS), which was a major contribution to the advancement of our specialty. This initiative expanded globally when he co-chaired the first Transatlantic Consensus on Peripheral Arterial Occlusive Disease, in 2000. In 2005, the SVS honored Dr. Rutherford with its Lifetime Achievement Award. This is the highest honor that the SVS bestows on one of its members. It recognizes an individual’s outstanding and sustained contributions both to the profession of vascular surgery and to the Society, as well as exemplary professional practice and leadership. Throughout his career, Dr. Rutherford traveled widely as an invited speaker. Despite his many accomplishments, he remained a humble, friendly person, who would always listen to colleagues and provide unselfish help in developing their careers. This tall vascular surgeon with a sparkle in his eye was recognized around the world and appreciated by all. Bob Rutherford and his wife, Kay, enjoyed downhill and cross-country skiing in the Colorado mountains and sailing, windsurfing, tennis, and biking in Colorado and their summer home in Maine. In recent years, Bob enjoyed bird photography (especially in their winter home in North Padre Island), playing piano, fishing, and golf. His interest in new topics clearly extended to his recreational activities. He is survived by his wife of 58 years, their five children, and many grandchildren. Robert B. Rutherford was a surgeon-scholar who will be remembered most because he was a “teacher’s teacher” who conceived and edited the definitive vascular surgery textbook, lectured internationally, edited the Journal of Vascular Surgery, and stressed the importance of knowing outcomes through standard reporting. He made his scholarly mark on vascular surgery throughout the world through his enthusiastic work, friendships, mentoring of many colleagues, and tireless writing and editing. It was our distinct honor to have worked with Bob on many projects over the years, and to have become close personal friends. He is dearly missed by his many friends and colleagues in the global vascular community.

Jack L. Cronenwett, MD K. Wayne Johnston, MD, FRCS(C)

RUTHERFORD’S

VASCULAR SURGERY EIGHTH EDITION

Jack L. Cronenwett, MD PROFESSOR OF SURGERY GEISEL SCHOOL OF MEDICINE AT DARTMOUTH DARTMOUTH-HITCHCOCK MEDICAL CENTER LEBANON, NEW HAMPSHIRE

K. Wayne Johnston, MD, FRCS(C) PROFESSOR OF SURGERY UNIVERSITY OF TORONTO TORONTO GENERAL HOSPITAL TORONTO, ONTARIO CANADA

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

RUTHERFORD’S VASCULAR SURGERY, EIGHTH EDITION

ISBN: 978-1-4557-5304-8    Volume 1 Part Number: 9996096149    Volume 2 Part Number: 9996096084

Copyright © 2014, 2010, 2005, 2000, 1995, 1989, 1976 by Saunders, an imprint of Elsevier Inc. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the Publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data Rutherford’s vascular surgery / [edited by] Jack L. Cronenwett, K. Wayne Johnston.—Eighth edition.    p. ; cm.   Vascular surgery   Includes bibliographical references and index.   ISBN 978-1-4557-5304-8 (2 vol. set : hardcover : alk. paper)   I. Cronenwett, Jack L., editor of compilation.  II. Johnston, K. Wayne, editor of compilation.  III. Title: Vascular surgery.   [DNLM:  1. Vascular Surgical Procedures.  2. Vascular Diseases. WG 170]   RD598.5   617.4′13—dc23   2013038401 VP, Global Content: Judith Fletcher Content Development Specialist: Joanie Milnes Publishing Services Manager: Anne Altepeter Project Manager: Cindy Thoms Design Direction: Ellen Zanolle

Printed in China Last digit is the print number:  9  8  7  6  5  4  3  2  1

This edition is dedicated to all of the students, residents, and fellows who have enriched our academic careers by their desire for new knowledge. And to our early mentors, S. Martin Lindenauer, MD; James C. Stanley, MD; H. Edward Garrett, MD; Bernard Langer, MD; Ronald J. Baird, MD; and Donald R. Wilson, MD, who inspired and encouraged us to pursue an academic career. And to our wives, Debra Cronenwett and Jean Johnston, who have provided strong support for all our academic endeavors. And especially, to our founder, Robert B. Rutherford, MD, for his vision in creating this reference textbook for all providers of vascular healthcare. We miss our dear friend, whose name lives on in this important contribution—Rutherford’s Vascular Surgery.

ASSOCIATE EDITORS Ali F. AbuRahma, MD, RVT, RPVI Professor of Surgery Chief, Division of Vascular and Endovascular Surgery Director, Vascular Surgery Fellowship and Residency Programs Department of Surgery Robert C. Byrd Health Sciences Center West Virginia University Medical Director, Vascular Laboratory Co-Director, Vascular Center of Excellence Charleston Area Medical Center Charleston, West Virginia Section 3—Clinical and Vascular Laboratory Evaluation Jan D. Blankensteijn, MD, PhD Associate Professor of Vascular Surgery VU University Medical Center Amsterdam, The Netherlands Section 4—Vascular Imaging Richard P. Cambria, MD Chief, Division of Vascular and Endovascular Surgery Massachusetts General Hospital Robert R. Linton Professor of Vascular and Endovascular Surgery Harvard Medical School Boston, Massachusetts Section 17—Cerebrovascular Diseases W. Darrin Clouse, MD Professor of Surgery Uniformed Services University of Health Sciences Bethesda, Maryland University of California–Davis Sacramento, California Section 19—Upper Extremity Arterial Disease Anthony J. Comerota, MD Director Jobst Vascular Institute Toledo Hospital Toledo, Ohio Adjunct Professor of Surgery Department of Vascular Surgery University of Michigan Ann Arbor, Michigan Section 9—Venous Thromboembolic Disease Alan Dardik, MD-PhD, FACS Professor of Surgery (Vascular) Chief, Vascular Surgery VA Connecticut Healthcare Systems West Haven, Connecticut Section 1—Basic Science John F. Eidt, MD Professor of Surgery University of South Carolina School of Medicine—Greenville Greenville Health System Greenville, South Carolina Section 6—Perioperative Care

Ronald M. Fairman, MD Clyde F. Barker-William Maul Measey Professor in Surgery University of Pennsylvania School of Medicine Chief, Division of Vascular Surgery and Endovascular Therapy University of Pennsylvania Health System Philadelphia, Pennsylvania Section 21—Abdominal Aortic Aneurysms Alik Farber, MD Associate Professor of Surgery and Radiology Boston University School of Medicine; Chief, Division of Vascular and Endovascular Surgery Medical Director, Catheterization and Angiography Laboratories Co-Director of the Noninvasive Vascular Laboratory Boston Medical Center Boston, Massachusetts Section 16—Grafts and Devices Steven J. Fishman, MD Stuart and Jane Weitzman Family Chair in Surgery Boston Children’s Hospital Professor of Surgery Harvard Medical School Boston, Massachusetts Section 12—Vascular Malformations Thomas L. Forbes, MD, FRCSC, FACS Professor of Surgery Western University Chief, Division of Vascular Surgery London Health Sciences Centre London, Ontario, Canada Section 8—Complications Julie A. Freischlag, MD The William Stewart Halsted Professor Director, Department of Surgery Surgeon-in-Chief Johns Hopkins Medical Institutions Baltimore, Maryland Section 20—Thoracic Outlet Syndromes Randolph L. Geary, MD Professor Department of Vascular and Endovascular Surgery Department of Pathology Section on Comparative Medicine Wake Forest Institute for Regenerative Medicine Wake Forest University School of Medicine Winston-Salem, North Carolina Section 24—Renovascular Disease vii

viii

Associate Editors

Peter Gloviczki, MD Joe M. and Ruth Roberts Professor of Surgery Mayo Clinic College of Medicine Chairman Emeritus Division of Vascular and Endovascular Surgery Mayo Clinic Rochester, Minnesota Section 10—Venous Insufficiency and Occlusion Section 11—Lymphedema Heather L. Gornik, MD, MHS Assistant Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University Staff Physician and Medical Director Noninvasive Vascular Laboratory Cleveland Clinic Cleveland, Ohio Section 5—Atherosclerotic Risk Factors Thomas S. Huber, MD, PhD Professor and Chief Division of Vascular and Endovascular Surgery University of Florida College of Medicine Gainesville, Florida Section 13—Hemodialysis Access Lois A. Killewich, MD, PhD Leonard and Marie Louise Aronsfeld Rosoff Professor of Surgery Assistant Dean for Continuing Education University of Texas Medical Branch Galveston, Texas Section 14—Miscellaneous Joseph L. Mills, Sr., MD Professor and Chief Division of Vascular and Endovascular Surgery Co-Director, Southern Arizona Limb Salvage Alliance (SALSA) Department of Surgery University of Arizona Health Sciences Center Tucson, Arizona Section 18—Lower Extremity Arterial Disease J. Gregory Modrall, MD Professor of Surgery Division of Vascular and Endovascular Surgery University of Texas Southwestern Medical Center Dallas, Texas Section 27—Acute Ischemia Marc L. Schermerhorn, MD Chief, Division of Vascular and Endovascular Surgery Beth Israel Deaconess Medical Center Associate Professor of Surgery Harvard Medical School Boston, Massachusetts Section 25—Mesenteric Vascular Disease

Benjamin W. Starnes, MD Chief, Division of Vascular Surgery Department of Surgery University of Washington Seattle, Washington Section 26—Vascular Trauma W. Charles Sternbergh III, MD Professor of Surgery University of Queensland School of Medicine Chief, Division of Vascular and Endovascular Surgery Vice Chair for Research Department of Surgery Ochsner Clinic Foundation New Orleans, Louisiana Section 15—Technique Carlos H. Timaran, MD Chief, Endovascular Surgery G. Patrick Clagett Professor in Vascular Surgery Associate Professor of Surgery University of Texas Southwestern Medical Center Dallas, Texas Section 23—Peripheral and Visceral Aneurysm Gilbert R. Upchurch, Jr., MD Muller Professor of Surgery and Physiology Chief, Division of Vascular and Endovascular Surgery University of Virginia Charlottesville, Virginia Section 22—Thoracic Aortic Aneurysms and Dissection Fred A. Weaver, MD Professor of Surgery Chief, Division of Vascular Surgery and Endovascular Therapy Keck School of Medicine at University of Southern California Los Angeles, California Section 7—Bleeding and Clotting R. Eugene Zierler, MD Medical Director, D.E. Strandness, Jr. Vascular Laboratory University of Washington Medical Center Harborview Medical Center Professor of Surgery University of Washington Seattle, Washington Section 2—Pathophysiology

CONTRIBUTORS Ahmed M. Abou-Zamzam, Jr., MD Chief, Division of Vascular Surgery Associate Professor Department of Cardiovascular and Thoracic Surgery Loma Linda University Medical Center Loma Linda, California Lower Extremity Amputation: General Considerations Christopher J. Abularrage, MD Assistant Professor Division of Vascular Surgery and Endovascular Therapy The Johns Hopkins Hospital Baltimore, Maryland Takayasu’s Disease Ali F. AbuRahma, MD, RVT, RPVI Professor of Surgery Chief, Division of Vascular and Endovascular Surgery Director, Vascular Surgery Fellowship and Residency Programs Department of Surgery Robert C. Byrd Health Sciences Center West Virginia University Medical Director, Vascular Laboratory Co-Director, Vascular Center of Excellence Charleston Area Medical Center Charleston, West Virginia Complex Regional Pain Syndrome

Matthew J. Alef, MD Fellow in Vascular and Endovascular Surgery Beth Israel Deaconess Medical Center Boston, Massachusetts Upper Extremity Arterial Disease: General Considerations Yves S. Alimi, MD, PhD Professor of Vascular Surgery Chief, Department of Vascular Surgery Université de la Méditerranée University Hospital North Marseille, France Iliocaval Venous Obstruction: Surgical Treatment Ahmad Alomari, MD, MSc, FSIR Division of Vascular and Interventional Radiology Boston Children’s Hospital Harvard Medical School Boston, Massachusetts Endovascular Therapy of Vascular Malformations Juan I. Arcelus, MD, PhD Professor of Surgery Department of Surgery Hospital Universitario Virgen de las Nieves University of Granada Granada, Spain Acute Deep Venous Thrombosis: Prevention and Medical Management

Charles W. Acher, MD Professor of Surgery Division of Vascular Surgery University of Wisconsin Madison, Wisconsin Thoracic and Thoracoabdominal Aneurysms: Open Surgical Treatment

Frank R. Arko III, MD Director, Endovascular Surgery Co-Director, Aortic Institute Sanger Heart and Vascular Center Carolinas Medical Center Charlotte, North Carolina Intravascular Ultrasound

Stefan Acosta, MD, PhD Associate Professor and Specialist in Vascular Surgery Vascular Centre, Skåne University Hospital Malmö, Sweden Mesenteric Vascular Disease: Venous Thrombosis

David G. Armstrong, DPM, MD, PhD Southern Arizona Limb Salvage Alliance Department of Surgery University of Arizona College of Medicine Tucson, Arizona Diabetic Foot Ulcers

Nathan Airhart, MD Research Fellow in Vascular Surgery Washington University School of Medicine St. Louis, Missouri Arterial Aneurysms Ahmet Rüçhan Akar, MD, FRCS (C/Th) Professor of Cardiovascular Surgery Director, Ankara University Organ Transplantation Program Deputy Director, Ankara University Stem Cell Institute Heart Center, Ankara University School of Medicine Dikimevi, Ankara, Turkey Thromboangiitis Obliterans (Buerger’s Disease)

Maggie Arnold, MD Assistant Professor of Surgery The Johns Hopkins University School of Medicine Baltimore, Maryland Carotid Artery: Endarterectomy Zachary M. Arthurs, MD Assistant Professor of Surgery Uniformed Services University of Health Sciences Chief, Vascular Surgery San Antonio Military Medical Center San Antonio, Texas Vascular Trauma: Head and Neck ix

x

Contributors

Marvin D. Atkins, MD Assistant Professor of Surgery Division of Vascular Surgery Scott & White Hospital Texas A&M University Temple, Texas Carotid Artery: Aneurysms Robert Atnip, MD Professor of Surgery Penn State Heart and Vascular Institute Penn State Milton S. Hershey Medical Center Hershey, Pennsylvania Local Complications: Nerve Injury Faisal Aziz, MD Vascular Surgery Penn State Hershey Heart and Vascular Institute Hershey, Pennsylvania Acute Deep Venous Thrombosis: Surgical and Interventional Treatment Ali Azizzadeh, MD, FACS Associate Professor Department of Cardiothoracic and Vascular Surgery University of Texas Houston Medical School Director of Endovascular Surgery Memorial Hermann Heart and Vascular Institute Houston, Texas Vascular Trauma: Thoracic Martin R. Back, MD, MS, FACS, PVI Professor of Surgery Division of Vascular and Endovascular Surgery University of South Florida Morsani School of Medicine Tampa, Florida Local Complications: Graft Infection M. Shadman Baig, MD Assistant Professor Department of Surgery University of Texas Southwestern Medical Center Dallas, Texas Upper Extremity Aneurysms Jeffrey L. Ballard, MD Staff Vascular Surgeon St. Joseph Hospital Orange, California Operative Exposure for Spinal Reconstructive Surgery John R. Bartholomew, MD Section Head of Vascular Medicine Director, Thrombosis Center Sydell and Arnold Miller Family Heart and Vascular Institute Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University Cleveland, Ohio Atheromatous Embolization

Ruediger G.H. Baumeister, MD Doctor, Consultant in Lymphology Chirurgische Klinik Muenchen Bogenhausen Former Head Department of Surgery Division of Plastic, Hand, and Microsurgery, Lymphology University Hospital Grosshadern Muenchen, Bavaria, Germany Lymphedema: Surgical Treatment William Scott Beattie, MD, PhD R. Fraser Elliot Chairman in Cardiac Anesthesia Anesthesia and Pain Medicine University Health Network Professor Department of Anesthesia University of Toronto Toronto, Canada Systemic Complications: Cardiac Carlos F. Bechara, MD Division of Vascular and Endovascular Therapy Michael E. DeBakey Department of Surgery Baylor College of Medicine Michael E. DeBakey VA Medical Center Houston, Texas Superior Vena Cava Occlusion: Surgical Treatment Adam W. Beck, MD Assistant Professor of Surgery Division of Vascular Surgery and Endovascular Therapy University of Florida College of Medicine Gainesville, Florida Infected Aneurysms Joshua A. Beckman, MD, MS Associate Professor of Medicine Harvard Medical School Director, Cardiovascular Fellowship Program Cardiovascular Division Brigham and Women’s Hospital Boston, Massachusetts Atherosclerotic Risk Factors: Diabetes Michael Belkin, MD Chief, Division of Vascular and Endovascular Surgery Brigham and Women’s Hospital Boston, Massachusetts Aortoiliac: Direct Reconstruction Simona Ben-Haim, MD, DSc Department of Nuclear Medicine Chaim Sheba Medical Center Ramat-Gan, Israel Institute of Nuclear Medicine University College Hospitals NHS Trust London, United Kingdom Vascular PET/CT and SPECT/CT Kyla M. Bennett, MD Vascular Surgery Fellowship Duke University Durham, North Carolina Coagulopathy and Hemorrhage

Contributors



Scott A. Berceli, MD, PhD Professor of Surgery University of Florida College of Medicine Malcom Randall VA Medical Center Gainesville, Florida Autogenous Grafts Michael J. Bernas, MS Associate Scientific Investigator University of Arizona College of Medicine Tucson, Arizona Lymphatic Pathophysiology Boback M. Berookhim, MD, MBA Fellow Sexual and Reproductive Medicine Program Urology Service Memorial Sloan-Kettering Cancer Center New York, New York Erectile Dysfunction Christian Bianchi, MD, FACS Chief, Division of Vascular Surgery Loma Linda Veterans Affairs Healthcare System Associate Professor Cardiovascular Surgery Loma Linda University Loma Linda, California Lower Extremity Amputation: General Considerations Martin Björck, MD, PhD Professor of Vascular Surgery Uppsala University Uppsala, Sweden Mesenteric Vascular Disease: Venous Thrombosis James H. Black III, MD, FACS Bertram M. Bernheim MD Associate Professor of Surgery Johns Hopkins School of Medicine Baltimore, Maryland Aneurysms Caused by Connective Tissue Abnormalities Jan D. Blankensteijn, MD, PhD Associate Professor of Vascular Surgery VU University Medical Center Amsterdam, The Netherlands Computed Tomography

Ruth L. Bush, MD, MPH Professor of Surgery Interim Vice Dean, Bryan/College Station Texas A&M University Vascular Surgeon, Division of Vascular Surgery Central Texas Veterans Hospital Temple, Texas Carotid Artery: Aneurysms John Byrne, MD Chief, Division of Cardiac Surgery Professor, Harvard Medical School Brigham and Women’s Hospital Boston, Massachusetts Abdominal Aortic Aneurysms: Ruptured Xzabia A. Caliste, MD Vascular Surgery Residency Program University of Rochester Medical Center Rochester, New York Venography Keith D. Calligaro, MD Chief, Division of Vascular Surgery Pennsylvania Hospital Philadelphia, Pennsylvania Renovascular Disease: Aneurysms and Arteriovenous Fistulae Richard P. Cambria, MD Chief, Division of Vascular and Endovascular Surgery Massachusetts General Hospital Boston, Massachusetts Aortic Dissection Piergiorgio Cao, MD, FRCS Professor of Vascular Surgery University of Perugia, School of Medicine Chief, Division of Vascular Surgery S. Maria Misericordia Hospital Perugia, Italy Carotid Artery: Stenting

Thomas C. Bower, MD Professor of Surgery Mayo Clinic, College of Medicine Chair, Division of Vascular and Endovascular Surgery Mayo Clinic Rochester, Minnesota Venous Tumors

Joseph A. Caprini, MD, MS Louis Biegler Chair of Surgery Division of Vascular Surgery North Shore University Health System Evanston, Illinois Clinical Professor of Surgery Department of Surgery Pritzker School of Medicine University of Chicago Chicago, Illinois Acute Deep Venous Thrombosis: Prevention and Medical Management

Kathleen E. Brummel-Ziedins, PhD Associate Professor Department of Biochemistry University of Vermont Burlington, Vermont Normal Coagulation

Gregory D. Carlson, MD Staff Orthopedic Surgeon St. Joseph Hospital Orange, California Spinal Operative Exposure

xi

xii

Contributors

Teresa L. Carman, MD Director, Vascular Medicine Medical Director, Coumadin Clinic Medical Director, Center for Wound Care University Hospitals Case Medical Center Cleveland, Ohio Atherosclerotic Risk Factors: Hyperlipidemia Jeffrey P. Carpenter, MD Professor and Chairman Department of Surgery Cooper Medical School Rowan University Camden, New Jersey Magnetic Resonance Imaging George P. Casale, PhD Associate Professor of Surgery University of Nebraska Medical Center Omaha, Nebraska Ischemia-Reperfusion Neal S. Cayne, MD Associate Professor of Surgery Division of Vascular and Endovascular Surgery Director of Endovascular Surgery New York University Medical Center New York, New York Lower Extremity Aneurysms Rabih A. Chaer, MD, MSc Associate Professor of Surgery Division of Vascular Surgery The University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Carotid Artery: Dissection and Fibromuscular Dysplasia Elliot L. Chaikof, MD, PhD Johnson and Johnson Professor of Surgery Harvard Medical School Chairman Roberta and Stephen R. Weiner Department of Surgery Beth Israel Deaconess Medical Center Associate Faculty Wyss Institute of Biologically Inspired Engineering Faculty Harvard Stem Cell Institute Boston, Massachusetts Prosthetic Grafts

Jason Chin, MD Vascular Surgery Yale—New Haven Hospital New Haven, Connecticut Vessel Wall Biology Jayer Chung, MD Assistant Professor Division of Vascular and Endovascular Surgery Chief Division of Vascular and Endovascular Surgery Parkland Memorial Hospital University of Texas Southwestern Medical Center Dallas, Texas Thoracic Outlet Syndrome: Arterial Compartment Syndrome Daniel G. Clair, MD Professor of Surgery Cleveland Clinic Lerner College of Medicine Case Western Reserve University Chairman of Vascular Surgery Cleveland Clinic Cleveland, Ohio Brachiocephalic Artery: Endovascular Treatment Diseases W. Darrin Clouse, MD Professor of Surgery Uniformed Services University of Health Sciences Bethesda, Maryland University of California, Davis Sacramento, California Upper Extremity Arterial Disease: Amputation Anthony J. Comerota, MD Director Jobst Vascular Institute The Toledo Hospital Toledo, Ohio Adjunct Professor of Surgery Department of Vascular Surgery University of Michigan Ann Arbor, Michigan Acute Deep Venous Thrombosis: Surgical and Interventional Treatment Superficial Thrombophlebitis

Stephen W.K. Cheng, MBBS, MS, FRCS(E), FRCS Serena H.C. Yang Professor of Vascular Surgery Chief, Division of Vascular Surgery The University of Hong Kong Hong Kong Radiation Safety

Mark F. Conrad, MD Director of Clinical Research Assistant Program Director Division of Vascular and Endovascular Surgery Massachusetts General Hospital Institute for Heart, Vascular and Stroke Care Boston, Massachusetts Aortic Dissection

Andrea L. Cheville, MD, MDCE Associate Professor Physical Medicine and Rehabilitation Mayo Clinic Rochester, Minnesota Lymphedema: Nonoperative Treatment

Christopher J. Cooper, MD Chairman, Department of Medicine Professor of Medicine University of Toledo Toledo, Ohio Renovascular Disease: Endovascular Treatment

Contributors



Leslie T. Cooper, Jr., MD Director Gonda Vascular Center Professor of Medicine Mayo Clinic Rochester, Minnesota Vasculitis and Other Uncommon Arteriopathies

Demetrios Demetriades, MD, PhD, FACS Professor of Surgery Director, Acute Care Surgery Los Angeles County and University of Southern California Medical Center Los Angeles, California Vascular Trauma: Abdominal

Matthew A. Corriere, MD, MS Assistant Professor Department of Vascular and Endovascular Surgery Wake Forest University School of Medicine Winston Salem, North Carolina Renovascular Disease: Acute Ischemia

Sapan S. Desai, MD Department of Cardiothoracic and Vascular Surgery University of Texas Medical School at Houston Houston, Texas Brachiocephalic Artery: Surgical Treatment

David L. Cull, MD Professor of Surgery University of South Carolina School of Medicine-Greenville Vice-Chair of Academic Affairs Department of Surgery Greenville Health System University Medical Center Greenville, South Carolina Hemodialysis Access: Complex John A. Curci, MD Associate Professor of Vascular Surgery Washington University School of Medicine Chief Division of Vascular and Endovascular Surgery Veterans Affairs St. Louis Healthcare System St. Louis, Missouri Arterial Aneurysms Michael C. Dalsing, MD E. Dale and Susan E. Habegger Professor of Surgery Director of Vascular Surgery Indiana University School of Medicine Indianapolis, Indiana Chronic Venous Insufficiency: Deep Vein Valve Reconstruction Scott M. Damrauer, MD Instructor in Surgery University of Pennsylvania Fellow Division of Vascular Surgery and Endovascular Therapy University of Pennsylvania Health System Philadelphia, Pennsylvania Abdominal Aortic Aneurysms: Open Surgical Treatment Paola De Rango, MD, PhD Staff Vascular Surgery Vascular and Endovascular Surgery Unit S. Maria Misericordia Hospital University of Perugia Perugia, Italy Carotid Artery: Stenting David H. Deaton, MD Associate Professor of Surgery Georgetown University School of Medicine Chief, Division of Vascular and Endovascular Surgery Georgetown University Hospital Washington, District of Columbia Arterial Aneurysms: General Considerations

Paul J. DiMuzio, MD, FACS William M. Measey Professor of Surgery Director, Division of Vascular and Endovascular Surgery Program Director, Fellowship in Vascular Surgery Thomas Jefferson University Philadelphia, Pennsylvania Arteriogenesis and Angiogenesis Hasan H. Dosluoglu, MD, FACS Associate Professor of Surgery State University of New York at Buffalo School of Medicine and Biomedical Sciences Chief, Department of Surgery and Division of Vascular Surgery Veterans Affairs Western New York Healthcare System Buffalo, New York Lower Extremity Arterial Disease: General Considerations Matthew J. Dougherty, MD Associate Clinical Professor of Surgery Pennsylvania Hospital University of Pennsylvania Philadelphia, Pennsylvania Renovascular Disease: Aneurysms and Arteriovenous Fistulae Audra A. Duncan, MD Professor of Surgery Mayo Clinic College of Medicine Program Director Vascular Surgery Residency and Fellowship Division of Vascular and Endovascular Surgery Rochester, Minnesota Local Complications: Lymphatic Serkan Durdu, MD, PhD Associate Professor of Cardiovascular Surgery Heart Center, Ankara University School of Medicine Dikimevi, Ankara, Turkey Thromboangiitis Obliterans (Buerger’s Disease) Matthew J. Eagleton, MD Associate Professor Vascular Surgery Cleveland Clinic Lerner College of Medicine Case Western Reserve University Staff Vascular Surgery Cleveland Clinic Cleveland, Ohio Preoperative Management

xiii

xiv

Contributors

Jonothan J. Earnshaw, MBBS, DM, FRCS Consultant Vascular Surgeon Gloucestershire Royal Hospital Gloucester, United Kingdom Acute Ischemia: Evaluation and Decision Making Robert T. Eberhardt, MD Associate Professor of Medicine Boston University School of Medicine Director of Vascular Medicine Department of Cardiovascular Medicine Boston Medical Center Boston, Massachusetts Chronic Venous Disorders: General Considerations Matthew S. Edwards, MD, MS, RVT, FACS Associate Professor and Chairman Department of Vascular and Endovascular Surgery Wake Forest University Baptist Medical Center Winston-Salem, North Carolina Renovascular Disease: Endovascular Treatment John F. Eidt, MD Professor of Surgery University of South Carolina School of Medicine–Greenville Greenville Health System Greenville, South Carolina Lower Extremity Amputation: Techniques and Results Jonathan L. Eliason, MD Lindenauer Professor of Surgery University of Michigan Ann Arbor, Michigan Renovascular and Aortic Developmental Disorders Eric D. Endean, MD Professor of Surgery University of Kentucky Lexington, Kentucky Embryology Mark K. Eskandari, MD James S.T. Yao, MD, PhD, Professor of Education in Vascular Surgery Chief, Division of Vascular Surgery Northwestern University Feinberg School of Medicine Chicago, Illinois Occupational Vascular Problems Ronald M. Fairman, MD Clyde F. Barker-William Maul Measey Professor in Surgery University of Pennsylvania School of Medicine Chief Division of Vascular Surgery and Endovascular Therapy University of Pennsylvania Health System Philadelphia, Pennsylvania Abdominal Aortic Aneurysms: Endovascular Treatment Alik Farber, MD Associate Professor of Surgery and Radiology Boston University School of Medicine Chief, Division of Vascular and Endovascular Surgery Medical Director Catheterization and Angiography Laboratories Co-Director of the Noninvasive Vascular Laboratory Boston Medical Center Boston, Massachusetts Biologic Grafts

Peter L. Faries, MD Franz W. Sichel Professor of Surgery Mount Sinai School of Medicine Chief, Division of Vascular Surgery Mount Sinai Medical Center New York, New York Infrainguinal Disease: Endovascular Treatment Mark Fillinger, MD Professor of Vascular Surgery Dartmouth Medical School Program Director of Vascular Surgery Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire Technique: Managing Branches During Endovascular Aortic Aneurysm Repair Steven J. Fishman, MD Stuart and Jane Weitzman Family Chair in Surgery Boston Children’s Hospital Professor of Surgery Harvard Medical School Boston, Massachusetts Surgical Management of Vascular Malformations Thomas L. Forbes, MD, FRCSC, FACS Professor of Surgery Western University Chief, Division of Vascular Surgery London Health Sciences Centre London, Ontario, Canada Nonatheromatous Popliteal Artery Disease Charles J. Fox, MD Assistant Professor of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland Program Director of Vascular Surgery Attending Vascular Surgeon Walter Reed Army Medical Center Washington, District of Columbia Vascular Trauma: Military Julie A. Freischlag, MD The William Stewart Halsted Professor Chair, Department of Surgery Surgeon-in-Chief, The Johns Hopkins Hospital Baltimore, Maryland Thoracic Outlet Syndrome: General Considerations Gail L. Gamble, MD Cancer Rehabilitation Program Rehabilitation Institute of Chicago Department of PM&R Northwestern University Feinberg School of Medicine Chicago, Illinois Lymphedema: Nonoperative Treatment Randolph L. Geary, MD Professor of Vascular and Endovascular Surgery Wake Forest University School of Medicine Winston-Salem, North Carolina Renovascular Disease: General Considerations

Contributors



David L. Gillespie, MD Professor of Surgery Chief and Program Director, Division of Vascular Surgery University of Rochester School of Medicine and Dentistry Rochester, New York Venography

Arin K. Greene, MD, MMSc Associate Professor of Surgery Harvard Medical School Children’s Hospital Boston Boston, Massachusetts Vascular Tumors of Childhood

Natalia O. Glebova, MD, PhD Fellow Division of Vascular Surgery and Endovascular Therapy The Johns Hopkins Hospital Baltimore, Maryland Takayasu’s Disease

Carlos J. Guevara, MD Instructor, Radiology Washington University School of Medicine St. Louis, Missouri Endovascular Therapy of Vascular Malformations

Peter Gloviczki, MD Joe M. and Ruth Roberts Professor of Surgery Mayo Clinic College of Medicine Chairman Emeritus Division of Vascular and Endovascular Surgery Mayo Clinic Rochester, Minnesota Superior Vena Cava Obstruction: Surgical Treatment

Raul J. Guzman, MD Associate Professor of Surgery Vanderbilt University Medical Center Nashville, Tennessee Local Complications: Anastomotic Aneurysms

Philip P. Goodney, MD, MS Assistant Professor Section of Vascular Surgery Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire Patient Clinical Evaluation Kapil Gopal, MD Assistant Professor of Surgery University of Maryland Medical Center Baltimore, Maryland Intraoperative Management Heather L. Gornik, MD, MHS Assistant Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University Staff Physician and Medical Director Noninvasive Vascular Laboratory Cleveland Clinic Cleveland, Ohio Atherosclerotic Risk Factors: Smoking Anders Gottsäter, MD, PhD Associate Professor of Medicine Lund University/Skåne University Hospital Malmö, Sweden Renovascular Disease: Fibrodysplasia Roy K. Greenberg, MD† Director, Endovascular Research Department of Vascular Surgery Cleveland Clinic Associate Professor Department of Surgery Cleveland Clinic Learner College of Medicine Associate Professor Biomedical Engineering Case School of Engineering Case Western Reserve University Cleveland, Ohio Thoracic and Thoracoabdominal Aneurysms: Branched and Fenestrated Endograft Treatment †

Deceased

Allen Hamdan, MD Vice-Chairman Department of Surgery Associate Professor of Surgery Harvard Medical School Department of Surgery Beth Israel Deaconess Medical Center Boston, Massachusetts Upper Extremity Arterial Disease: General Considerations Kimberley J. Hansen, MD Professor of Surgery Department of Vascular and Endovascular Surgery Wake Forest University School of Medicine Winston-Salem, North Carolina Renovascular Disease: Open Surgical Treatment Linda M. Harris, MD Associate Professor of Surgery Chief, Division of Vascular Surgery Program Director Vascular Surgery Residency and Fellowship University at Buffalo, SUNY Buffalo, New York Hemodialysis Access: Nonthrombotic Complications Olivier Hartung, MD Vascular Surgeon Department of Vascular Surgery Université de la Méditerranée University Hospital North Marseille, France Iliocaval Venous Obstruction: Surgical Treatment Stephen M. Hass, MD, JD Assistant Professor of Surgery Division of Vascular and Endovascular Surgery West Virginia University Charleston, West Virginia Vascular Laboratory: Arterial Duplex Scanning Peter K. Henke, MD Leland Ira Doan Professor of Surgery University of Michigan Ann Arbor, Michigan Venous Pathology

xv

xvi

Contributors

Ariane L. Herrick, MD, FRCP Professor Centre for Musculoskeletal Research University of Manchester Manchester Academic Health Science Centre Salford Royal NHS Foundation Trust Salford, United Kingdom Raynaud’s Phenomenon Peter J. E. Holt, PhD, FRCS Senior Lecturer and Consultant Vascular Surgeon St. George’s Vascular Institute London, United Kingdom Abdominal Aortic Aneurysms: Evaluation and Decision Making Thomas S. Huber, MD, PhD Professor and Chief Division of Vascular and Endovascular Surgery University of Florida College of Medicine Gainesville, Florida Hemodialysis Access: General Considerations Justin B. Hurie, MD Assistant Professor of Surgery Department of Vascular and Endovascular Surgery Wake Forest University School of Medicine Winston-Salem, North Carolina Renovascular Disease: Open Surgical Treatment Mark D. Iafrati, MD Chief, Division of Vascular Surgery Tufts Medical Center Boston, Massachusetts Varicose Veins: Surgical Treatment Kenji Inaba, MD, FRCSC, FACS Program Director Surgical Critical Care Fellowship Medical Director-SICU Associate Professor Surgery and Emergency Medicine University of Southern California Keck School of Medicine Los Angeles, California Vascular Trauma: Abdominal

Iqbal H. Jaffer, BA (Hons), MBBS Division of Cardiac Surgery McMaster University Hamilton, Ontario, Canada Antithrombotic Therapy Zhihua Jiang, PhD Assistant Professor Department of Surgery University of Florida College of Medicine Gainesville, Florida Intimal Hyperplasia William Jordan, MD Professor of Surgery and Section Chief Division of Vascular Surgery and Endovascular Therapy University of Alabama School of Medicine at Birmingham Attending Surgeon University of Alabama Hospital Birmingham, Alabama Nonaortic Stents and Stent-Grafts Lowell S. Kabnick, MD, RPhS, FACS, FACPh Associate Professor of Surgery Division of Vascular Surgery Director, New York University Vein Center New York University Langone Medical Center New York, New York Attending Surgeon Morristown Hospital Center Morristown, New Jersey Varicose Veins: Endovenous Ablation and Sclerotherapy John Kakisis, MD, FEBVS Department of Vascular Surgery Attikon University Hospital Athens, Greece Atherosclerotic Risk Factors: General Considerations

Arsalla Islam, MD Assistant Professor of Surgery University of Texas Southwestern Medical Center Dallas, Texas Renovascular Disease: General Considerations

Venkat R. Kalapatapu, MD, FRCS (Edin), FACS Assistant Professor of Vascular Surgery University of Pennsylvania Chief, Division of Vascular Surgery Philadelphia Veterans Affairs Medical Center Philadelphia, Pennsylvania Lower Extremity Amputation: Techniques and Results

Ora Israel, MD Director, Department of Nuclear Medicine Rambam Health Care Campus Professor of Imaging Rappaport School of Medicine, Technion Haifa, Israel Vascular PET CT and SPECT CT

Jeffrey Kalish, MD Assistant Professor of Surgery and Radiology Boston University School of Medicine Director of Endovascular Surgery Boston Medical Center Boston, Massachusetts Biologic Grafts

Glenn Jacobowitz, MD Vice-Chief, Division of Vascular Surgery Associate Professor of Surgery, Division of Vascular Surgery New York University Langone Medical Center New York, New York Lower Extremity Aneurysms

Manju Kalra, MBBS Associate Professor of Surgery Vascular Surgery Mayo Clinic Rochester, Minnesota Superior Vena Cava Obstruction: Surgical Treatment

Contributors



Jeanwan Kang, MD Vascular Surgeon Department of Vascular Surgery Sydell and Arnold Miller Family Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio Preoperative Management Vikram S. Kashyap, MD Associate Professor Cleveland Clinic Lerner College of Medicine Case Western Reserve University Staff, Department of Vascular Surgery Cleveland Clinic Cleveland, Ohio Splanchnic Artery Aneurysms Paulo Kauffman, MD Professor of Vascular Surgery Department of Vascular Surgery University of Sao Paulo School of Medicine Sao Paulo, Brazil Upper Extremity Sympathectomy David S. Kauvar, MD Vascular Surgeon Department of Surgery Dwight D. Eisenhower Army Medical Center Fort Gordon, Georgia Associate Professor of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland Vascular Trauma: Extremity Lois A. Killewich, MD, PhD Leonard and Marie Louise Aronsfeld Rosoff Professor of Surgery Assistant Dean for Continuing Education University of Texas Medical Branch Galveston, Texas Venous Physiology Esther S. H. Kim, MD, MPH Staff Physician Sections of Vascular Medicine and Preventive Cardiology Cleveland Clinic Cleveland, Ohio Atherosclerotic Risk Factors: Smoking Melissa L. Kirkwood, MD Division of Vascular and Endovascular Surgery Department of Surgery University of Texas Southwestern Medical Center Dallas, Texa Thoracic Outlet Syndrome: Arterial Jordan P. Knepper, MD Integrated Vascular Surgery Resident Section of Vascular Surgery University of Michigan Ann Arbor, Michigan Acute Deep Venous Thrombosis: Pathophysiology and Natural History

Ted R. Kohler, MD Professor of Surgery University of Washington Chief, Division of Peripheral Vascular Surgery Veterans Affairs Puget Sound Healthcare System Seattle, Washington Vascular Laboratory: Arterial Physiologic Assessment Leo J. Schultze Kool, MD Professor of Interventional Radiology Radbound University Medical Centre Nijmegen, The Netherlands Computed Tomography Larry W. Kraiss, MD Professor and Chief Division of Vascular Surgery University of Utah Salt Lake City, Utah Vascular Trauma: Extremity Hari R. Kumar, MD Fellow Department of Vascular Surgery Northwestern University McGaw Medical Center Chicago, Illinois Occupational Vascular Problems Christopher J. Kwolek, MD Chief, Vascular and Endovascular Surgery Director Vascular and Endovascular Training Program Newton Wellesley Hospital Boston, Massachusetts Acute Ischemia: Treatment Nicos Labropoulos, PhD, DIC, RVT Professor of Surgery and Radiology Director, Vascular Laboratory Department of Surgery Stony Brook University Medical Center Stony Brook, New York Vascular Laboratory: Venous Duplex Scanning Ryan O. Lakin, MD General Surgery Lakewood, Ohio Splanchnic Artery Aneurysms Brajesh K. Lal, MD, FACS Professor Department of Surgery University of Maryland School of Medicine Associate Professor Department of Bioengineering University of Maryland Chief, Division of Vascular Surgery Veterans Affairs Medical Center Baltimore, Maryland Vascular Laboratory: Venous Physiologic Assessment

xvii

xviii

Contributors

Kathleen M. Lamb, MD Surgical Resident, Research Resident Department of Surgery Thomas Jefferson University Hospital Philadelphia, Pennsylvania Arteriogenesis and Angiogenesis

Michael P. Lilly, MD Professor of Surgery Division of Vascular Surgery University of Maryland School of Medicine Baltimore, Maryland Intraoperative Management

Glenn M. LaMuraglia, MD Visiting Surgeon Division of Vascular and Endovascular Surgery Massachusetts General Hospital Associate Professor of Surgery Harvard Medical School Boston, Massachusetts Carotid Artery: Carotid Body Tumors and Other Disorders

Peter H. Lin, MD Professor of Surgery Chief, Division of Vascular Surgery Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston, Texas Superior Vena Cava Occlusion: Endovascular Treatment

Giora Landesberg, MD, DSc Professor Department of Anesthesia and Critical Care Medicine Head of Cardiovascular Anesthesia Center Hadassah Medical Centre Hebrew University Jerusalem, Israel Systemic Complications: Cardiac Jeffrey H. Lawson, MD, PhD Associate Professor of Surgery Assistant Professor of Pathology Duke University School of Medicine Director of Vascular Surgery Research Laboratory and Clinical Trials for Vascular Surgery Duke University Medical Center Durham, North Carolina Coagulopathy and Hemorrhage Jason T. Lee, MD Associate Professor of Surgery Division of Vascular Surgery Stanford University Medical Center Stanford, California Thoracic Outlet Syndrome: Neurogenic Luis R. León, Jr., MD Agave Surgical Associates Tucson, Arizona Vascular Laboratory: Venous Duplex Scanning Wesley K. Lew, MD Vascular Surgeon Kaiser Sunset Los Angeles, California Thrombolytic Agents Christos Liapis, MD, FACS Professor of Vascular Surgery University of Athens Medical School Chairman of Department of Vascular Surgery Attikon Hospital Athens, Greece Atherosclerotic Risk Factors: General Considerations Howard A. Liebman, MD Professor of Medicine and Pathology Jane Anne Nohl Division of Hematology Keck School of Medicine University of Southern California Los Angeles, California Hypercoagulable States

Bengt Lindblad, MD, PhD Associate Professor of Vascular Surgery Lund University/Skåne University Hospital Malmö, Sweden Renovascular Disease: Fibrodysplasia Pamela A. Lipsett, MD, MHPE Warfield M. Firror Endowed Professorship in Surgery Professor Surgery, Anesthesiology, Critical Care, and Nursing Program Director General Surgery Residency Program Johns Hopkins University Schools of Medicine and Nursing Co-Director, Surgical Intensive Care Units Johns Hopkins Medical Institutions Baltimore, Maryland Systemic Complications: Respiratory Harold Litt, MD, PhD Associate Professor of Radiology and Medicine Chief, Cardiovascular Imaging Section Department of Radiology Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania Magnetic Resonance Imaging Ruby C. Lo, MD Research Fellow in Surgery Beth Israel Deaconess Medical Center Boston, Massachusetts Mesenteric Vascular Disease: General Considerations William B. Long, MD Trauma Medical Director Department of Surgery Legacy Emanuel Medical Center Professor of Surgery Oregon Health Sciences University Portland, Oregon Vascular Trauma: Epidemiology and Natural History Ying Wei Lum, MD Assistant Professor Division of Vascular Surgery and Endovascular Therapy The Johns Hopkins Hospital Baltimore, Maryland Section Director for Anatomy Perdana University Graduate School of Medicine Serdang, Selangor, Malaysia Thoracic Outlet Syndrome: General Considerations

Contributors



Fedor Lurie, MD, PhD, RPVI, RVT Associate Director Jobst Vascular Institute ProMedica Toledo, Ohio Acute Deep Venous Thrombosis: Clinical and Diagnostic Evaluation Chronic Venous Insufficiency: Treatment of Perforator Vein Incompetence Sean P. Lyden, MD Associate Professor Department of Vascular Surgery Cleveland Clinic Foundation Cleveland, Ohio Technique: Endovascular Diagnostic Michel S. Makaroun, MD Co-Director, UPMC Heart and Vascular Institute Professor and Chair, Division of Vascular Surgery University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Thoracic and Thoracoabdominal Aneurysms: Endovascular Treatment Thomas S. Maldonado, MD Associate Professor Service Chief at NYUHC New York University Langone Medical Center New York, New York Cerebrovascular Disease: General Considerations Bruce E. Maley, PhD Associate Professor Department of Anatomy and Neurobiology University of Kentucky Medical Center Lexington, Kentucky Embryology Kenneth G. Mann, PhD Emeritus Professor, Biochemistry and Medicine University of Vermont College of Medicine Colchester, Vermont Normal Coagulation George Markose, MD Assistant Professor, Radiology Juravinski Hospital and Cancer Centre McMaster University Hamilton, Ontario, Canada Cerebrovascular Disease: Diagnostic Evaluation William A. Marston, MD Professor and Chief, Division of Vascular Surgery University of North Carolina School of Medicine Chapel Hill, North Carolina Wound Care Matthew J. Martin, MD Trauma Medical Director Madigan Army Medical Center Tacoma, Washington Director of Trauma Informatics Department of Surgery Legacy Emanuel Medical Center Portland, Oregon Vascular Trauma: Epidemiology and Natural History

Michelle C. Martin, MD Fellow in Vascular and Endovascular Surgery Beth Israel Deaconess Medical Center Boston, Massachusetts Mesenteric Vascular Disease: Acute Ischemia Tara M. Mastracci, MD Department of Vascular Surgery Sydell and Arnold Miller Family Heart and Vascular Institute Assistant Professor of Surgery Cleveland Clinic Lerner College of Medicine Case Western Reserve University Cleveland, Ohio Thoracic and Thoracoabdominal Aneurysms: Branched and Fenestrated Endograft Treatment Jon S. Matsumura, MD Professor of Surgery and Chairman Division of Vascular Surgery University of Wisconsin School of Medicine and Public Health Madison, Wisconsin Aortic Stents and Stent-Grafts Kathleen O’Malley Maxfield, MD Neurology University of New Mexico Hospital Albuquerque, New Mexico Local Complications: Anastomotic Aneurysms James F. McKinsey, MD, FACS Associate Professor of Surgery Weill Medical College at Cornell University Ithaca, New York Site Chief, New York-Presbyterian Medical Center New York, New York Local Complications: Endovascular Robert B. McLafferty, MD Professor of Surgery Division of Vascular Surgery Southern Illinois University School of Medicine Springfield, Illinois Arteriography Manish Mehta, MD, MPH Professor of Surgery Albany Medical Center Albany, New York Abdominal Aortic Aneurysms: Ruptured George H. Meier, MD Professor, Chief, and Program Director, Vascular Division University of Cincinnati Cincinnati, Ohio Hemodialysis Access: Failing and Thrombosed Matthew T. Menard, MD Instructor in Surgery Harvard Medical School Associate Surgeon Brigham and Women’s Hospital Boston, Massachusetts Aortoiliac Disease: Direct Reconstruction

xix

xx

Contributors

Louis M. Messina, MD Professor and Chief Division of Vascular and Endovascular Surgery Vice Chair Department of Surgery University of Massachusetts Worcester, Massachusetts Thoracic Outlet Syndrome: Venous

John B. Mulliken, MD Co-director, Vascular Anomalies Center Department of Plastic and Oral Surgery Professor of Surgery Harvard Medical School Boston, Massachusetts Classification and Natural History of Vascular Anomalies

Joseph L. Mills, Sr., MD Professor and Chief Division of Vascular and Endovascular Surgery Co-Director, Southern Arizona Limb Salvage Alliance Department of Surgery University of Arizona Health Sciences Center Tucson, Arizona Infrainguinal Disease: Surgical Treatment

Daniel J. Myers, MD General Surgery Iola, Kansas Systemic Complications: Renal

Ross Milner, MD Associate Professor of Surgery Director, Center for Aortic Diseases Pritzker School of Medicine University of Chicago Chicago, Illinois Local Complications: Aortoenteric Fistula

A. Ross Naylor, MBChB, MD, FRCSEd, FRCSEng Professor of Vascular Surgery Leicester Royal Infirmary Leicester, United Kingdom Cerebrovascular Disease: Diagnostic Evaluation

Samantha Minc, MD Fellow Division of Vascular Surgery University of Chicago Medical Center Chicago, Illinois Local Complications: Aortoenteric Fistula J. Gregory Modrall, MD Professor of Surgery Division of Vascular and Endovascular Surgery University of Texas Southwestern Medical Center Dallas, Texas Compartment Syndrome Emile R. Mohler III, MD Professor of Medicine University of Pennsylvania Philadelphia, Pennsylvania Atherosclerotic Risk Factors: Hypertension Mark D. Morasch, MD, FACS Vascular Surgeon St. Vincent Healthcare Heart and Vascular Billings, Montana Vertebral Artery Disease Lindsay Muir, MB, MChOrth, FRCS(Orth) Consultant Hand Surgeon Salford Royal Hospital Salford, United Kingdom Raynaud’s Phenomenon John P. Mulhall, MD, MSc, FECSM, FACS Director Sexual and Reproductive Medicine Program Urology Service Memorial Sloan-Kettering Cancer Center New York, New York Erectile Dysfunction

Stuart I. Myers, MD, FACS Lincoln, Nebraska Systemic Complications: Renal

Matthew G. Nayor, MD Clinical Fellow in Medicine Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Atherosclerotic Risk Factors: Diabetes Peter Neglén, MD, PhD Vascular Surgeon SP Vascular Center Trimiklini, Cyprus Iliocaval Obstruction: Endovascular Treatment Richard F. Neville, MD, FACS Chief, Division of Vascular Surgery Professor of Surgery The George Washington University Washington, DC Technique: Open Surgical Louis L. Nguyen, MD, MBA, MPH Associate Professor of Surgery Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Epidemiology and Clinical Analysis Aksone Nouvong, DPM, FACFAS Assistant Professor College of Podatric Medicine Western University of Health Sciences Oakland, California Diabetic Foot Ulcers Thomas F. O’Donnell, Jr., MD Director Dedham Medical Associate’s Venous Center Atrius Health Norwood, Massachusetts Varicose Veins: Surgical Treatment



Contributors

Gustavo S. Oderich, MD Associate Professor of Surgery Division of Vascular and Endovascular Surgery Mayo Clinic College of Medicine Director of Endovascular Therapy Division of Vascular and Endovascular Surgery Mayo Clinic Rochester, Minnesota Mesenteric Vascular Disease: Chronic Ischemia

Giuseppe Papia, MD Assistant Professor of Surgery University of Toronto School of Medicine Physician Lead in Cardiovascular Intensive Care Unit Vascular and Endovascular Surgery Critical Care Medicine Sunnybrook Health Sciences Centre Toronto, Ontario, Canada Postoperative Management

W. Andrew Oldenburg, MD Associate Professor of Surgery Division of Vascular Surgery Mayo Clinic Florida Jacksonville, Florida Arterial Tumors

Luigi Pascarella, MD Clinical Assistant Professor of Surgery—Vascular Surgery University of Iowa Carver College of Medicine Iowa City, Iowa Chronic Venous Disorders: Nonoperative Treatment

Jeffrey W. Olin, DO Professor of Medicine (Cardiology) Director Vascular Medicine and Vascular Diagnostic Laboratory Zena and Michael A. Wiener Cardiovascular Institute Marie-Josée and Henry R. Kravis Center for Cardiovascular Health Ichan School of Medicine at Mount Sinai New York, New York Atheromatous Embolization

Marc A. Passman, MD Professor Section of Vascular Surgery and Endovascular Therapy University of Alabama at Birmingham Birmingham, Alabama Vena Cava Interruption and Pulmonary Embolism

Carl Orringer, MD Associate Professor, Medicine Case Western Reserve University School of Medicine Cleveland, Ohio Atherosclerotic Risk Factors: Hyperlipidemia Geoffrey O. Ouma, DO, MSc, RPVI Cardiovascular Medicine Nocturnist Division of Cardiovascular Medicine Penn Presbyterian Medical Center Philadelphia, Pennsylvania Atherosclerotic Risk Factors: Hypertension Christopher D. Owens, MD, MSc Associate Professor of Surgery Division of Vascular and Endovascular Surgery University of California San Francisco San Francisco, California Atherosclerosis

Virendra I. Patel, MD Associate Program Director General Surgery Vascular and Endovascular Surgery Massachusetts General Hospital Boston, Massachusetts Carotid Artery: Carotid Body Tumors and Other Disorders Philip Paty, MD Chief of Vascular Surgery St. Peters Hospital Albany Vascular Group Albany, New York Upper Extremity Arterial Disease: Revascularization Benjamin Pearce, MD Assistant Professor of Surgery Division of Vascular Surgery and Endovascular Therapy University of Alabama School of Medicine at Birmingham Attending Surgeon University of Alabama Hospital Birmingham, Alabama Nonaortic Stents and Stent-Grafts

C. Keith Ozaki, MD Associate Professor of Surgery Department of Surgery Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Intimal Hyperplasia

Bruce A. Perler, MD, MBA Julius H. Jacobson II Professor Department of Surgery The Johns Hopkins University School of Medicine Chief, Division of Vascular Surgery and Endovascular Therapy The Johns Hopkins Hospital Baltimore, Maryland Carotid Artery: Endarterectomy

David Paolini, MD Vascular Physician Jobst Vascular Institute ProMedica Toledo, Ohio Acute Deep Venous Thrombosis: Clinical and Diagnostic Evaluation

Iraklis I. Pipinos, MD, PhD Professor of Surgery University of Nebraska Medical Center Chief, Division of Vascular Surgery Veterans Affairs Nebraska and Western Iowa Medical Center Omaha, Nebraska Ischemia-Reperfusion

xxi

xxii

Contributors

Lori L. Pounds, MD Assistant Professor, Clinical University of Texas Health Science Center San Antonio, Texas Venous Physiology Richard J. Powell, MD Professor of Surgery and Radiology Geisel School of Medicine at Dartmouth Section Chief Vascular Surgery Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire Aortoiliac Disease: Endovascular Treatment Alessandra Puggioni, MD Vascular Surgery Scottsdale Vascular Services Scottsdale, Arizona Chronic Venous Insufficiency: Treatment of Perforator Vein Incompetence Zheng Qu, MD Harvard Medical School Department of Surgery Beth Israel Deaconess Medical Center Boston, Massachusetts Prosthetic Grafts Joseph D. Raffetto, MD, MS Associate Professor of Surgery Harvard Medical School Boston, Massachusetts Chief, Division of Vascular Surgery Veterans Affairs Boston Healthcare System West Roxbury, Massachusetts Brigham and Women’s Hospital Boston, Massachusetts Chronic Venous Disorders: General Considerations

Donald B. Reid, MD Wishaw General Hospital Wishaw, Scotland Intravascular Ultrasound Kristy L. Rialon, MD Surgeon Duke University Durham, North Carolina Surgical Management of Vascular Malformations John J. Ricotta, MD Harold H. Hawfield Chairman Department of Surgery Washington Hospital Center Professor of Surgery Georgetown University School of Medicine Washington, District of Columbia Carotid Artery Disease: Decision Making Including Medical Therapy Joseph J. Ricotta, MD, MS, FACS Chair Department of Vascular Surgery and Endovascular Therapy Director, Heart and Vascular Institute Northside Hospital Atlanta, Georgia Carotid Artery Disease: Decision Making Including Medical Therapy Addi Z. Rizvi, MD, FACS Vascular and Endovascular Surgery Minneapolis Heart Institute at Abbott Northwestern Hospital Clinical Assistant Professor of Surgery University of Minnesota Minneapolis, Minnesota Technique: Endovascular Therapeutic

Seshadri Raju, MD Emeritus Professor and Honorary Surgeon University of Mississippi Medical Center Jackson, Mississippi River Oaks Hospital Flowood, Mississippi Iliocaval Obstruction: Endovascular Treatment

Caron B. Rockman, MD, FACS, RVT Associate Professor of Surgery Director of Clinical Research Division of Vascular Surgery New York University Medical Center New York, New York Cerebrovascular Disease: General Considerations

Todd E. Rasmussen, MD Professor of Surgery Uniformed Services University Bethesda, Maryland Deputy Director US Combat Casualty Care Research Program Fort Detrick, Maryland Vascular Trauma: Military

Stanley G. Rockson, MD Allan and Tina Neill Professor of Lymphatic Research and Medicine Division of Cardiovascular Medicine Stanford University School of Medicine Stanford, California Lymphedema: Evaluation and Decision Making

Suman Rathbun, MD, MS, RVT Professor of Medicine University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma Superficial Thrombophlebitis Reid A. Ravin Resident in Vascular Surgery Mount Sinai School of Medicine New York, New York Infrainguinal Disease: Endovascular Treatment

Sean P. Roddy, MD Associate Professor of Surgery Albany Medical College Albany, New York Upper Extremity Arterial Disease: Revascularization Carolyn R. Rogers, MD Instructor in Surgery Department of Plastic and Oral Surgery Harvard Medical School Boston, Massachusetts Classification and Natural History of Vascular Anomalies

Contributors



Vincent L. Rowe, MD Associate Professor of Surgery Keck School of Medicine at University of Southern California Los Angeles, California Hemodialysis Access: Dialysis Catheters

Sharene Shalhub, MD, MPH Assistant Professor of Vascular Surgery University of Washington Spokane, Washington Vascular Trauma: Thoracic

Eva M. Rzucidlo, MD Associate Professor of Surgery Department of Vascular Surgery Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire Aortoiliac Disease: Endovascular Treatment

Cynthia Shortell, MD Professor and Chief of Vascular Surgery Department of Surgery Duke University Medical Center Durham, North Carolina Chronic Venous Disorders: Nonoperative Treatment

Mikel Sadek, MD Assistant Professor of Surgery Division of Vascular Surgery New York University Langone Medical Center New York, New York Varicose Veins: Endovenous Ablation and Sclerotherapy Hazim J. Safi, MD, FACS, FRCS Professor and Chairman Department of Cardiothoracic and Vascular Surgery The University of Texas Health Science Center at Houston Houston, Texas Brachiocephalic Artery: Surgical Treatment Elliot B. Sambol, MD Department of Surgery New York Presbyterian Hospital Weill Medical College of Cornell University Columbia University College of Physicians and Surgeons New York, New York Local Complications: Endovascular Andres Schanzer, MD Associate Professor of Surgery Division of Vascular and Endovascular Surgery University of Massachusetts Medical School Worcester, Massachusetts Lower Extremity Arterial Disease: Decision Making and Medical Treatment Marc L. Schermerhorn, MD Chief, Division of Vascular and Endovascular Surgery Beth Israel Deaconess Medical Center Associate Professor of Surgery Harvard Medical School Boston, Massachusetts Mesenteric Vascular Disease: General Considerations Joseph R. Schneider, MD, PhD Professor of Surgery Feinberg School of Medicine Northwestern University Chicago, Illinois Vascular Surgeon, Vascular and Interventional Program Cadence Physician Group and Cadence Health Winfield, Illinois Aortoiliac: Extra-Anatomic Bypass Peter A. Schneider, MD Chief, Division of Vascular Therapy Kaiser Foundation Hospital Honolulu, Hawaii Carotid Artery: Dissection and Fibromuscular Dysplasia

Fahad Shuja, MD Division of Vascular and Endovascular Surgery Massachusetts General Hospital Boston, Massachusetts Acute Ischemia: Treatment Anton N. Sidawy, MD, MPH Professor and Chairman Department of Surgery George Washington University Washington, District of Columbia Technique: Open Surgical Jessica P. Simons, MD, MPH Assistant Professor of Surgery Division of Vascular and Endovascular Surgery University of Massachusetts Medical School Worcester, Massachusetts Lower Extremity Arterial Disease: Decision Making and Medical Treatment Michael J. Singh, MD, FACS, RPVI Associate Professor of Surgery Division of Vascular Surgery University of Pittsburgh Medical Center Director of Aortic Center University of Pittsburgh Medical Center Heart and Vascular Institute Pittsburgh, Pennsylvania Thoracic and Thoracoabdominal Aneurysms: Endovascular Treatment Niten N. Singh, MD Associate Professor of Surgery Division of Vascular Surgery University of Washington Seattle, Washington Upper Extremity Arterial Disease: Amputation Leigh Ann Slater, MD Interim Visiting Assistant Professor of Surgery University of Maryland Baltimore, Maryland Systemic Complications: Respiratory Ann DeBord Smith, MD General Surgery Resident Brigham and Women’s Hospital Boston, Massachusetts Epidemiology and Clinical Analysis

xxiii

xxiv

Contributors

James C. Stanley, MD Handleman Professor of Surgery Director, Cardiovascular Center University of Michigan Ann Arbor, Michigan Renovascular and Aortic Developmental Disorders Benjamin W. Starnes, MD Chief, Division of Vascular Surgery Department of Surgery University of Washington Seattle, Washington Vascular Trauma: Head and Neck W. Charles Sternbergh III, MD Professor of Surgery University of Queensland School of Medicine Chief Division of Vascular and Endovascular Surgery Vice Chair for Research Department of Surgery Ochsner Clinic Foundation New Orleans, Louisiana Technique: Endovascular Aneurysm Repair David H. Stone, MD Assistant Professor of Surgery Section of Vascular Surgery Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire Local Complications: Graft Thrombosis Patrick A. Stone, MD Associate Professor of Surgery Division of Vascular and Endovascular Surgery West Virginia University Charleston, West Virginia Vascular Laboratory: Arterial Duplex Scanning Timothy M. Sullivan, MD Clinical Professor of Surgery University of Minnesota Chairman, Vascular and Endovascular Surgery Minneapolis Heart Institute Abbott Northwestern Hospital Minneapolis, Minnesota Technique: Endovascular Therapeutic David S. Sumner, MD† Distinguished Professor of Surgery, Emeritus Southern Illinois University School of Medicine Springfield, Illinois Arterial Physiology Vascular Laboratory: Arterial Physiologic Assessment Bauer Sumpio, MD, PhD Professor of Surgery and Radiology Yale University School of Medicine Chief, Division of Vascular Surgery Yale-New Haven Hospital Director, Vascular Center Program Director, Vascular Surgery Yale-New Haven Medical Center New Haven, Connecticut Vessel Wall Biology Deceased

†

Girma Tefera, MD Professor of Surgery University of Wisconsin School of Medicine and Public Health Vice Chair Division of Vascular Surgery Chief of Vascular William S. Middleton VA Hospital Madison, Wisconsin Aortic Stents and Stent-Grafts Matt M. Thompson, MD Professor University of London Professor of Vascular Surgery St. George’s Vascular Institute London, United Kingdom Abdominal Aortic Aneurysms: Evaluation and Decision Making Carlos H. Timaran, MD Associate Professor of Surgery The University of Texas Southwestern Medical School G. Patrick Clagett Professor in Vascular Surgery Chief, Division of Endovascular Surgery Dallas, Texas Upper Extremity Aneurysms Jessica M. Titus, MD Fellow Department of Vascular Surgery Cleveland Clinic Foundation Cleveland, Ohio Brachiocephalic Artery: Endovascular Treatment Diseases Cameron C. Trenor III, MD Dana Farber/Boston Children’s Cancer and Blood Disorders Boston Children’s Hospital Boston, Massachusetts Vascular Tumors of Childhood Eric J. Turney, MD Staff Surgeon Department of Vascular Surgery Mike O’Callaghan Federal Medical Center Las Vegas, Nevada Technique: Endovascular Diagnostic Gilbert R. Upchurch, Jr., MD Muller Professor of Surgery and Physiology Chief, Division of Vascular and Endovascular Surgery University of Virginia Charlottesville, Virginia Thoracic and Thoracoabdominal Aneurysms: Evaluation and Decision Making R. James Valentine, MD Professor and Chairman Division of Vascular Surgery Alvin Baldwin, Jr., Chair in Surgery University of Texas Southwestern Medical Center Dallas, Texas Thoracic Outlet Syndrome: Arterial

Contributors



Omaida Velazquez, MD Chief, Division of Vascular and Endovascular Surgery Executive Dean for Research and Research Training Director, Vascular Laboratory University of Miami Miller School of Medicine Professor of Surgery Vice Chairman for Research Department of Surgery University of Miami Jackson Memorial Medical Center Miami, Florida Cells of the Vascular System Gabriela Velazquez-Ramirez, MD Vascular Surgery Fellow Division of Vascular Surgery and Endovascular Therapy University of Florida College of Medicine Gainesville, Florida Infected Aneurysms Thomas W. Wakefield, MD Stanley Professor of Surgery Head, Section of Vascular Surgery University of Michigan Ann Arbor, Michigan Acute Deep Venous Thrombosis: Pathophysiology and Natural History Daniel B. Walsh, MD Professor of Surgery Dartmouth Medical School Hanover, New Hampshire Local Complications: Graft Thrombosis Bo Wang, MD Post-Doctoral Research Fellow Division of Vascular Surgery and Endovascular Surgery University of Miami Miller School of Medicine Miami, Florida Cells of the Vascular System Grace J. Wang, MD Assistant Professor of Surgery Division of Vascular Surgery and Endovascular Therapy University of Pennsylvania Philadelphia, Pennsylvania Abdominal Aortic Aneurysms: Endovascular Treatment Kenneth J. Warrington, MD Associate Professor of Medicine Gonda Vascular Center Mayo Clinic Rochester, Minnesota Vasculitis and Other Uncommon Arteriopathies Fred A. Weaver, MD Professor of Surgery Chief, Division of Vascular Surgery and Endovascular Therapy Keck School of Medicine at University of Southern California Los Angeles, California Thrombolytic Agents Ilene Ceil Weitz, MD Associate Professor of Clinical Medicine Jane Anne Nohl Division of Hematology Keck School of Medicine at University of Southern California Los Angeles, California Hypercoagulable States

Jeffrey I. Weitz, MD, FRCP(C), FACP Professor of Medicine and Biochemistry McMaster University Executive Director Thrombosis and Atherosclerosis Research Institute Hamilton General Hospital Campus Hamilton, Ontario, Canada Antithrombotic Therapy Marlys H. Witte, MD Professor of Surgery University of Arizona College of Medicine Attending Physician in Surgery University Medical Center Tucson, Arizona Lymphatic Pathophysiology Nelson Wolosker, MD, PhD Associate Professor Department of Vascular and Endovascular Surgery University of Sao Paulo Vice-President Albert Einstein Hospital Sao Paulo, Brazil Upper Extremity Sympathectomy Edward Y. Woo, MD Associate Professor of Surgery University of Pennsylvania Vice-Chief and Program Director Division of Vascular Surgery and Endovascular Therapy Director, Vascular Laboratory University of Pennsylvania Health System Philadelphia, Pennsylvania Abdominal Aortic Aneurysms: Open Surgical Treatment Karen Woo, MD Assistant Professor of Surgery Division of Vascular Surgery and Endovascular Therapy Keck School of Medicine University of Southern California Los Angeles, California Hemodialysis Access: Dialysis Catheters Mark C. Wyers, MD Assistant Professor of Surgery Harvard Medical School Division of Vascular and Endovascular Surgery Beth Israel Deaconess Medical Center Boston, Massachusetts Mesenteric Vascular Disease: Acute Ischemia Mimi Wynn, MD Associate Professor Department of Anesthesia University of Wisconsin Madison, Wisconsin Thoracic and Thoracoabdominal Aneurysms: Open Surgical Treatment

xxv

xxvi

Contributors

Wei Zhou, MD Professor of Surgery Stanford University Stanford, California Chief, Division of Vascular Surgery Veterans Affairs Palo Alto Health Care System Palo Alto, California Acquired Arteriovenous Fistulae

R. Eugene Zierler, MD Medical Director, D.E. Strandness, Jr. Vascular Laboratory University of Washington Medical Center Harborview Medical Center Professor of Surgery University of Washington Seattle, Washington Arterial Physiology

PREFACE As we complete our work as editors of the eighth edition of Rutherford’s Vascular Surgery, we are grateful on many levels. We appreciate the insight and hard work of the founding editor, Robert B. Rutherford, MD, who toiled through six editions of this textbook. Bob was a giant in many ways, but none more clearly than his enduring contribution of an encyclopedic reference that has elevated the quality of vascular health care since 1976. He was truly a “teacher’s teacher.” We have been honored to serve as editors of the seventh and eighth editions and appreciate the opportunity afforded to us by the Society of Vascular Surgery, which has assumed responsibility for continued publication of this textbook. This will be our last edition as editors, in part to establish a tradition that will provide opportunity for many skilled members of our specialty to participate as editors. We appreciate the great work done by our section editors Ali AbuRhama, Jan Blankensteijn, Richard Cambria, W. Darrin Clouse, Anthony Comerota, Alan Dardik, John Eidt, Ronald Fairman, Alik Farber, Steven Fishman, Tom Forbes, Julie Freischlag, Randy Geary, Peter Gloviczki, Heather Gornik, Thomas Huber, Lois Killewich, Joseph Mills, Greg Modrall, Marc Schermerhorn, Benjamin Starnes, Charles Sternbergh, Carlos Timaran, Gilbert Upchurch, Fred Weaver, and Eugene Zierler. In the eighth edition, we purposely expanded the number of section editors in order to distribute this large amount of work among more people. Each section editor participated in author selection and developed the content outline for his or her section. The most work, of course, was done by the individual authors, who were carefully selected for their expertise and scientific accomplishments. We recognize that they worked many hours without compensation to produce this educational material for the benefit of their colleagues and patients. We are especially grateful to each of them for this effort. Finally, we are grateful for having been part of the evolution and revolutions in vascular surgery over our careers.

Comparing the first and eighth editions of “Rutherford,” which span nearly 40 years, one is immediately struck by the tremendous changes that have occurred and continue to occur in vascular surgery. The predominant treatment of vascular disease has become interventional, rather than open surgery, and vascular surgeons have embraced and developed these techniques. The current vascular specialist has an increasingly diverse armamentarium of investigational techniques and management options, thus augmenting the complexity of decision making, as reflected in this textbook. We are especially excited that the eighth edition of Rutherford’s Vascular Surgery is available in an advanced electronic format both online and for e-readers. Accessible by computer, tablet, or smart phone, this format provides text, images, videos, web-linked references, self-study questions, and bloglike interaction with authors and other readers. Most importantly the electronic format allows continuous modification of the text over time, thus creating a “living” textbook. For example, articles published in the Journal of Vascular Surgery and the European Journal of Vascular and Endovascular Surgery will be added as new references to relevant chapters each month. As editors, we have found it very gratifying to participate in the development of these valuable features, which are now part of the most modern publishing standards. We hope that readers enjoy this textbook as much as we have enjoyed assembling it. In closing, we acknowledge the excellent work of the production team at Elsevier, who have worked especially hard to produce this edition in record time and to incorporate its many new features—Judy Fletcher, Vice President of Global Content; Joanie Milnes, Content Development Specialist; Stacy Matusik, Content Development Specialist; and Cindy Thoms, Project Manager. Jack L. Cronenwett, MD K. Wayne Johnston, MD, FRCS(C)

xxvii

VIDEO CONTENTS 1. Management of Infected Aortic Graft by Neo-Aortoilliac System (NAIS) Operation See Chapters 42 and 43 G. PATRICK CLAGETT, MD

2. Repair of Femoral Anastomotic Aneurysm See Chapter 44 CALVIN B. ERNST, MD  /  DANIEL J. REDDY, MD

3. Explant of an Intrarenal Aortic Endograft See Chapters 46 and 131 BART E. MUHS, MD  /  MARK A. ADELMAN, MD  /  GLENN JACOBOWITZ, MD

4. Endovenous Laser Treatment: Technique and Technology See Chapter 58 STEVEN M. ELIAS, MD

5. Correction of an A-V Fistula Induced Ischemia by Distal Arterial Ligation Bypass See Chapter 77 HARRY R. CHANZER, MD  /  MILAN SKLADANY, MD

6. The Transcervical Approach to Proximal Common Carotid Endarterectomy See Chapters 100 and 105 WESLEY S. MOORE, MD

7. Carotid Endarterectomy by Eversion Technique with and without the Use of a Shunt See Chapter 100 R. CLEMENT DARLING, III, MD

8. Carotid Endarterectomy: Standard Approach See Chapter 100 WESLEY S. MOORE, MD

9. Carotid Body Tumor Excision See Chapter 104 IAN GANLEY, MD  /  JATIN P. SHAH, MD

10. Surgical Resection of Carotid Body Tumors See Chapter 104 ALFIO CARROCCIO, MD  /  TIKVA S. JACOBS, MD  /  PETER L. FARIES, MD  /  PATRICK LENTO, MD  /  MICHAEL L. MARTIN, MD

11. Bypass of Occlusive Disease of the Aortic Arch Arteries See Chapter 105 K. WAYNE JOHNSTON, MD

12. Totally Laparoscopic Aortobifemoral Bypass—The “Apron Technique” See Chapter 110 YVES-MARIE DION, MD  /  CARLOS R. GRACIA, MD  /  YVES ALIMI, MD  /  CLAUDE JUHAN, MD  /  OLIVIER HARTUNG, MD

13. Reconstruction of the Entire Abdominal Aorta for Atherosclerotic Occlusive Disease See Chapter 110 RONALD J. STONEY, MD

14. Aortobifemoral Bypass for Hypoplastic Aorta See Chapter 110 K. WAYNE JOHNSTON, MD

15. Axillo-Bifemoral Bypass Graft See Chapter 111 LLOYD M. TAYLOR, JR., MD  /  JOHN M. PORTER, MD

16. Descending Thoracic Aorta to Femoral Bypass See Chapter 111 PETER G. KALMAN, MD

17. Intraoperative Angioscopy Endovascular Findings and Graft Failure See Chapter 113 ARNOLD MILLER, MD  /  DAVID CAMPBELL, MD  /  FRANK LOGERFO, MD  /  GARY GIBBONS, MD  /  MARK BOLDUC, MD  /  FRANK POMPESELLI, MD  /  JONATHAN ISAACSOHN, MD  /  DOROTHY FREEMAN, MD

18. Endoscopic Vein Harvest for Lower Extremity Distal Bypass See Chapter 113 ROBERT S. LEES, MD

19. Posterior Approach to the Popliteal Artery See Chapters 113, 115, and 139 W.H. PEARCE, MD  /  W.R. FLINN, MD  /  TIMOTHY BAXTER, MD

20. Subclavian Artery Reconstruction and Thoracic Outlet Decompression See Chapter 127 JON S. MATSUMURA, MD  /  JAMES S.T. YAO, MD

21. Retroperitoneal Approach to Abdominal Aortic Aneurysms See Chapter 131 R.P. LEATHER, MD  /  D.M. SHAH, MD  /  B.B. CHANG, MD

22. Surgical Treatment of Juxtarenal Abdominal Aortic Aneurysm See Chapter 131 JOSEPH S. COSELLI, MD

23. Abdominal Aortic Aneurysm Repair: Right Colon Approach See Chapter 131 FRANK W. LOGERFO, MD  /  BERNADETTE AULIVOLA, MD

24. Abdominal Aortic Aneurysm with Right Crossed Fused Renal Ectopia Repaired by the Left Thoracoabdominal Approach See Chapter 131 PATRICK O’HARA

25. Totally Percutaneous Aortic Aneurysm Repair See Chapter 132 BENJAMIN W. STARNES, MD  /  CHARLES A. ANDERSON, MD  /  JOSEPH RONSIVALLE, DO  /  JOHN STATLER, MD

26. Treatment of Ruptured Abdominal Aortic Aneurysm See Chapter 133 FRANK J. VEITH, MD  /  NEAL CAYNE, MD  /  MANISH MEHTA, MD  /  JACQUELINE BOTT, MD

27. Repair of Type II Thoracoabdominal Aortic Aneurysm Using Distal Aortic Perfusion, Cerebral Spinal Fluid Drainage, and Moderate Hypothermia See Chapter 135 HAZIM J. SAFI, MD, FACS, FRCS  /  KLAUS GRABITZ, MD  /  JOHN C. BALDWIN, MD

28. Surgical Management of Thoracoabdominal Aortic Aneurysm See Chapter 135 E. STANLEY CRAWFORD, MD

xxxvii

xxxviii

Video Contents

29. Thoracoabdominal Aortic Aneurysm Repair with Spinal Cord Cooling See Chapter 135 RICHARD P. CAMBRIA, MD

30. Fenestrated Endografts for Complex Aneurysms See Chapter 136 ROY K. GREENBERG, MD

31. Extra-Anatomic Renovascular Reconstruction See Chapter 145 DAVID C. BREWSTER, MD  /  RICHARD P. CAMBRIA, MD

32. Correction of Abdominal Aortic Coarctation with Visceral Artery Reconstruction See Chapter 150 W.C. MACKEY, MD  /  T.R. SULLIVAN, MD

33. Perioperative Management of the Patient with Symptomatic Chronic Mesenteric Arterial Insufficiency See Chapters 152 and 153 TIMOTHY R.S. HARWARD, MD  /  JAMES M. SEEGER, MD

34. Supraceliac Aortoceliac Superior Mesenteric Bypass for Chronic Mesenteric Ischemia See Chapter 152 GREGORIO A. SICARD, MD  /  LEONARDO I. VALENTIN, MD  /  CHARLES B. ANDERSON, MD  /  BRENT T. ALLEN, MD  /  VVJAY K. ANAND, MD

35. Vascular Diseases of the Intestine—Acute and Chronic See Chapters 152 and 153 JAMES S.T. YAO, MD

36.  Endovascular Repair of Traumatic Aortic Disruption See Chapter 157 DAVID G. NESCHIS, MD  /  THOMAS M. SCALEA, MD  /  BARTLEY P. GRIFFITH, MD

37.  Transesophageal Echocardiogram Demonstrating a Large Atheroma in the Aortic Arch See Chapter 164 JEFFREY W. OLIN, MD

CHAPTER 1 

Epidemiology and Clinical Analysis LOUIS L. NGUYEN  /  ANN DEBORD SMITH

The goal of this chapter is to introduce the vascular surgeon to the principles that underlie the design, conduct, and interpretation of clinical research. Disease-specific outcomes otherwise detailed in subsequent chapters will not be covered here. Rather, this chapter discusses the historical context, current methodology, and future developments in epidemiology, clinical research, and outcomes analysis. This chapter serves as a foundation for clinicians to better interpret clinical results and as a guide for researchers to further expand clinical analysis.

EPIDEMIOLOGY Epidemiology is derived from the Greek terms for “upon” (epi), “the people” (demos), and “study” (logos), and can be translated into “the study of what is upon the people.” It exists to answer the four major questions of medicine: diagnosis, etiology, treatment, and prognosis.

Brief History Hippocrates is considered to be among the earliest recorded epidemiologists because he treated disease as both a group event and an individual occurrence. His greatest contribution to epidemiology was the linkage of external factors (climate, diet, and living conditions) with explanations for disease. Before widespread adoption of the scientific method, early physicians inferred disease causality through careful observation. For example, they observed the geographic distribution of cases or common factors shared by diseased versus healthy persons. John Snow is recognized for ameliorating the cholera epidemic in the Soho district of London in 1854 by identifying the cause of the outbreak through mapping the location of known cases of cholera in the district. Based on the density and geographic distribution of cases, he concluded that the public water pump was the source and had the pump handle removed.1

Modern Developments Modern epidemiology and clinical analysis seek to establish causation through study design and statistical analysis. 2

Carefully designed studies and analyses can minimize the risk of false conclusions and maximize the opportunity to find causation when it is present. In other areas of biology, causation can be demonstrated by fulfilling criteria, such as Koch’s postulates for establishing the relationship between microbe and disease. In epidemiology, the study design that would offer ideal proof of causation would be comparison of people with themselves in both the exposed and the unexposed state. This impossible and unethical experiment would control for everything, except the exposure, and thus, establish the causality between exposure and disease. Because this condition cannot exist, it is referred to as counter­ factual. Because the ideal study is impossible to conduct, alternative study designs have developed with different risks and benefits. The crossover experimental design, for example, approaches the counterfactual ideal by exposing patients to both treatment groups in sequence. However, the influence of time and previous exposure to the other treatment assignment may still affect the outcome (also known as the carryover effect). Other study designs exist that include techniques such as randomization or prospective data gathering to minimize bias. Appropriate study design must be selected based upon a study’s objectives. After a study is complete, conclusions can be drawn from a carefully crafted statistical analysis. Modern epidemiology includes applied mathematical methods to quantify observations and draw inferences about their relationships. Evidence-based medicine is a relatively modern approach to the practice of medicine that aims to qualify and encourage the use of currently available clinical evidence to support a particular treatment paradigm. This practice encourages the integration of an individual practitioner’s clinical expertise with the best currently available recommendations from clinical research studies.2 Relying on personal experience alone could lead to biased decisions, whereas relying solely on results from clinical research studies could lead to inflexible policies. Evidence-based medicine stratifies the strength of the evidence from clinical research studies based on study design and statistical findings (Table 1-1). The criteria differ when the evidence is sufficient to support a specific therapeutic approach, prognosis, diagnosis, or other health services research. Criteria also differ among research institutions,

CHAPTER 1  Epidemiology and Clinical Analysis



Level 1a 1b 1c 2a 2b 2c 3a 3b 4 5

Levels of Evidence for Therapeutics

Evidence Systematic reviews of RCT studies with homogeneity Individual RCT with narrow confidence intervals “All or none” trials* Systematic reviews of cohort studies with homogeneity Individual cohort studies Clinical outcomes studies Systemic reviews of case-control studies with homogeneity Individual case-control studies Case-series studies Expert opinion without critical appraisal or based on bench research

Adapted from Oxford Centre for Evidence-based Medicine (2001). RCT, Randomized controlled trial. *In which all patients died before the therapeutic became available, but some now survive with it, or in which some patients survived before the therapeutic became available, but now none die with it.

including the U.S. Preventive Services Task Force and the U.K. National Health Service. However, common themes can be seen among the different fields. Systematic reviews with homogeneity are preferred over single reports, whereas randomized controlled trials (RCTs) are preferred over cohort and case-control studies. Even within similar study design groupings, the statistical strength of each study is evaluated, with preference for studies with large numbers, complete and thorough follow-up, and results with small confidence intervals. Clinical recommendations are then based on the available evidence and are further graded according to their strengths (Table 1-2).

CLINICAL RESEARCH METHODS Although measuring the incidence and prevalence of disease is useful in the initial understanding of a disease process, additional techniques must be used to identify risk factors and test treatments for disease. The choice of study design and

Table 1-2 Grade A B

C

D

Grades of Recommendation

Recommendation

Basis

Strong evidence to support practice Fair evidence to support practice

Consistent level 1 studies

Evidence too close to make a general recommendation Evidence insufficient or conflicting to make a general recommendation

Consistent level 2 or 3 studies or extrapolations from level 1 studies Level 4 studies or extrapolation from level 2 or 3 studies Level 5 evidence or inconsistent studies of any level

Adapted from U.S. Preventive Services Task Force Ratings (2003) and Oxford Centre for Evidence-based Medicine (2001).

statistical analysis technique depends on the available data, the hypothesis being tested, and patient safety and/or ethical concerns.

Study Design Clinical research can be broadly divided into observational studies and experimental studies. Observational studies are characterized by the absence of a study-directed intervention, whereas experimental studies involve testing a treatment, be it a drug, a device, or a clinical pathway. Observational studies can follow ongoing treatments but cannot influence choices made in the treatment of a patient. Observational studies can be executed in a prospective or retrospective fashion, whereas experimental studies can be performed only prospectively. Two factors that affect choice of study design include prevalence and incidence of disease. The prevalence of disease is the ratio of persons affected for the population at risk and reflects the frequency of the disease at the measured time point, regardless of the time of disease development. In contrast, the incidence is the ratio of persons in whom the disease develops within a specified period for the population at risk. For diseases with short duration or high mortality, prevalence may not accurately reflect the impact of disease because the single time point of measurement does not capture resolved disease or patients who died of the disease. Prevalence is a more useful parameter when discussing diseases of longer duration, whereas incidence is more useful for diseases of shorter duration.

Observational Studies There are two main types of observational studies: cohort and case-control studies. A cohort is a designated group of individuals that is followed over a period of time. Cohort studies seek to identify a population at risk for the disease of interest. After a period of observation, patients in whom the disease develops are compared with the population of patients who are free of the disease. Cohort studies are most often associated with epidemiology because they comprise many of the most prominent studies in the modern era. The classic example is the Framingham Heart Study (FHS), in which 5209 residents of Framingham, Massachusetts, were monitored prospectively, starting in 1948.3 Much of our epidemiologic knowledge regarding risk factors for heart disease comes from the FHS.4 Although the FHS was initially intended to last 20 years, the study has subsequently been extended and now involves the third generation of participants. Cohort studies also seek to identify potential risk factors for development of the disease of interest. For example, if cigarette smoking is suspected in the development of peripheral arterial disease (PAD), smokers are assessed for the development of PAD from the beginning of the observation period to the end of the observation period. Because PAD does not develop in all smokers, and conversely, not all PAD patients are smokers, a relative risk (RR) is calculated as the ratio of the incidence of PAD in smokers versus the incidence of PAD in nonsmokers.

SECTION 1 BASIC SCIENCE

Table 1-1

3

4

SECTION 1  Basic Science

For diseases with low frequency, it is not cost effective to use a cohort study design. Instead, a case series seeks to prospectively follow or to retrospectively report findings of patients known to have the disease. This method is also commonly used to identify patients with a yet unknown disease by linking common risk factors or disease manifestations. Most often, findings from a case series are compared with findings in patients without the disease (control group) in a case-control study. Case-control studies are less costly and time consuming because the existence of the disease is the starting point. Risk factors correlated with disease can be deduced by comparisons between the two groups. In this retrospective design, an odds ratio (OR) is calculated from the ratio of patients exposed to patients not exposed to the risk factor. This differs from RR, in that the starting cohort is estimated only in case-control studies. The use of ORs reflects Bayesian inference, in which observations are used to infer the likelihood of a hypothesis. Bayesians describe probabilities conditional on observations and with degrees of uncertainty. In contrast, the alternative probability theory of Frequentists relies only on actual observations gained from experimentation. The main challenge in case-control studies is to identify an appropriate control group with characteristics similar to those of the general population at risk for the disease. Inappropriate selection of the control group may lead to the introduction of additional confounding and bias. For example, matched case-control studies aim to identify a control group “matched” for factors found in the exposure group. Unfortunately, by matching even basic demographic factors, such as gender and the prevalence of comorbid conditions, unknown co-associated factors can also be included in the control group and may affect the relationship of the primary factor to the outcome. Appropriate selection of the control group can be achieved by using broad criteria, such as time, treatment at the same institution, age boundaries, and gender when the exposure group consists of only one gender.

Experimental Studies Experimental studies differ from observational studies in that the former expose patients to a treatment being tested. Many experimental trials involve randomization of patients to the treatment group or appropriate control group. Although randomization ensures that known factors are evenly distributed between the exposure and control groups, the importance of RCTs lies in the even distribution of unknown factors. Thus, a well-designed RCT will result in more simplified endpoint analyses because complex statistical models are not necessary to control for confounding factors. Randomization can be accomplished by complete randomization of the entire study population, by block randomization, or by adaptive randomization. For complete randomization, each new patient is randomized without prior influence on previously enrolled patients. The expected outcome at the completion of the trial is an equal distribution of patients within each treatment group, although unequal distribution may occur by chance, especially in small

trials. Block randomization creates repeated blocks of patients in which equal distribution between treatment groups is enforced within each block. Block randomization ensures better end randomization and periodic randomization during the trial. End randomization is important in studies with long enrollment times or in multi-institutional studies that may have different local populations. Because the assignment of early patients within each block influences the assignment of later patients, block randomization should occur in a blinded fashion to avoid bias. Intrablock correlation must also be tested in the final analysis of the data. Adaptive randomization seeks to achieve balance of assignment of randomization for a prespecified factor (e.g., gender or previous treatment) suspected of affecting the treatment outcome. In theory, randomization controls for these factors, but unique situations may require stricter balance. RCTs can be classified according to knowledge of the randomization assignment by the treating clinicians and their patients. In open trials, the clinician and patients know the full details of the treatment assignment. This leaves the potential for bias in interpretation of results and may also influence study patients to drop out if they are randomized to a treatment group that they perceive to be unfavorable. Open trials are often conducted for surgical patients, where it is not possible or ethical to conceal the treatment assignment from the patient or the provider. In single-blinded trials, the clinician is aware of the treatment assignment, but the patient is not. These studies have more effective controls, but are still subject to clinician bias. Double-blinded trials are conducted so that both clinicians and patients are unaware of the treatment assignment. Often, a separate research group is responsible for the randomization allocation and has minimal or no contact with the clinicians and patients. Experimental studies face stricter ethical and patient safety requirements than their observational counterparts. To expose patients to randomization of treatment, clinical equipoise must exist. The principle of equipoise relies on a situation in which clinical experts professionally disagree on the preferred treatment method.5 Thus, randomization of study patients to different treatments is justified to gain clinical information. Ideally, the patients being tested or their population counterparts would benefit from any medical knowledge gained from the study. It is worth noting that although the field may have equipoise, individual health care providers or patients may have bias for one treatment. In such a case, enrollment in an RCT may be difficult because the patients or their providers are not willing to be subject to randomization. Although RCTs represent the pinnacle in clinical design, there are many situations in which RCTs are impractical or impossible. Clinical equipoise may not exist, or common sense may prevent randomization of well-established practices, such as the use of parachutes.6 RCTs are also costly to conduct and must generate a new control group with each trial. For this reason, some studies are single-arm trials that use historical controls similar to the case-control design. In



Special Techniques: Meta-Analysis Meta-analysis is a statistical technique that combines the results of several related studies to address a common hypothesis. The first use of meta-analysis in medicine is attributed to Smith and Glass in their review of the efficacy of psychotherapy in 1977.7 By combining results from several smaller studies, researchers may decrease sampling error, increase statistical power, and thereby help clarify disparate results among different studies. The related studies must share a common dependent variable along with the effect size specific to each study. The effect sizes are not merely averaged among the studies, but are weighted to account for the variance in each study. Because studies may differ in patient selection and their associated independent variables, a test for heterogeneity should also be performed. Where no heterogeneity exists (P > .5), a fixed-effects meta-analysis model is used to incorporate the within-study variance for the studies included, whereas a random-effects model is used when concern for betweenstudy variance exists (.5 > P > .05). When heterogeneity among studies is found, the OR should not be pooled, and further investigation for the source of heterogeneity may then exclude outlying studies. The weighted composite dependent variable is visually displayed in a forest plot along with the results from each study included. Each result is displayed as a point estimate with a horizontal bar representing the 95% confidence interval for the effect. The symbol used to mark the point estimate is usually sized proportional to other studies to reflect the relative weight of the estimate as it contributes to the composite result (Fig. 1-1). Classically, meta-analyses have included only RCTs, but observational studies can also be used.8,9 Inclusion of observational studies can result in greater heterogeneity through uncontrolled studies or controlled studies with selection bias.

5

The strength of a meta-analysis comes from the strength of the studies that make up the composite variable. Furthermore, if available, the results of unpublished studies can also potentially influence the composite variable, because presumably many studies with nonsignificant results are not published. Therefore, an assessment of publication bias should be included with every meta-analysis. Publication bias can be assessed graphically by creating a funnel plot in which the effect size is compared with the sample size or other measure of variance. If no bias is present, the effect sizes should be balanced around the population mean effect size and decrease in variance with increasing sample size. If publication bias exists, part of the funnel plot will be sparse or empty of studies. Begg’s test for publication bias is a statistical test that represents the funnel plot’s graphic test.10 The variance of the effect estimate is divided by its standard error to give adjusted effect estimates with similar variance. Correlation is then tested between the adjusted effect size and the meta-analysis weight. An alternative method is Egger’s test, in which the study’s effect size divided by its standard error is regressed on 1/standard error.11 The intercept of this regression should equal zero, and testing for the statistical significance of nonzero intercepts should indicate publication bias.

Bias in Study Design Clinical analysis is an attempt to estimate the “true” effects of a disease or its potential treatments. Because the true effects cannot be known with certainty, analytic results carry potential for error. All studies can be affected by two broadly defined types of error: random error and systematic error. Random error in clinical analysis comes from natural variation and can be handled with the statistical techniques covered later in this chapter. Systematic error, also known as bias, affects the results in one unintended direction and can threaten the validity of the study. Bias can be further categorized into three main groupings: selection bias, information bias, and confounding. Selection bias occurs when the effect being tested differs among patients who participate in the study as opposed to those who do not. Because actual study participation involves a researcher’s determination of which patients are eligible for a study and then the patient’s agreement to participate in the study, the decision points can be affected by bias. One common form of selection bias is self-selection, in which patients who are healthier or sicker are more likely to participate in the study because of perceived self-benefit. Selection bias can also occur at the level of the researchers when they perceive potential study patients as being too sick and preferentially recruit healthy patients. Information bias exists when the information collected in the study is erroneous. One example is the categorization of variables into discrete bins, as in the case of cigarette smoking. If smoking is categorized as only a yes or no variable, former smokers and current smokers with varying amounts of consumption will not be accurately categorized. Recall bias is another form of information bias that can occur particularly

SECTION 1 BASIC SCIENCE

addition, patient enrollment for RCTs is more difficult than for other trial designs because some patients and clinicians are uneasy with the randomization of treatment. They may have preconceived notions of treatment efficacy or may have an inherent aversion to being randomized, even when they know that equipoise exists. This risk aversion may be greatest for more life-threatening conditions, although patients in whom conventional treatment has been unsuccessful may be accepting of greater risk to obtain access to novel treatments otherwise not available outside the clinical trial. RCTs can also have methodological and interpretative limitations. For example, study patients are analyzed by their assigned randomization grouping (intent to treat). Studies with asymmetric or numerous overall dropout and/or crossover rates will not reflect actual treatment effects. RCTs are often conducted in high-volume specialty centers; as a result, enrollment and treatment of study patients may not reflect the general population with the disease. Finally, RCTs are often designed and powered to test one hypothesis. A statistically nonsignificant result may be influenced by inaccurate assumptions made in the initial power calculations.

CHAPTER 1  Epidemiology and Clinical Analysis

6

SECTION 1  Basic Science Risk ratio (95% CI)

Study

% Weight

Naylor (1998)a

11.92 (0.73, 193.38)

0.5

Brooks (2001)b

0.32 (0.01, 7.70)

1.5

Wallstent

(2001)c

2.72 (1.00, 7.37)

4.9

CAVATAS (2001)d

1.01 (0.60, 1.71)

24.9

Maydoon (2002)e

0.70 (0.15, 3.20)

4.2

Sapphire (2004)f

0.89 (0.35, 2.25)

9.0

CaRESS (2005)g

0.59 (0.16, 2.15)

6.5

(2006)h

1.19 (0.79, 1.80)

38.4

EVA-3S (2006)i

2.47 (1.21, 5.04)

10.1

Brooks (2004)j

(Excluded)

Overall (95% CI)

1.30 (1.01, 1.67)

SPACE

.1

1

0.0

10

Risk ratio Favors CAS

Favors CEA

a

Naylor AR, et al: Randomized study of carotid angioplasty and stenting versus carotid endarterectomy: a stopped trial. J Vasc Surg 28:326-334, 1998. b Brooks WH, et al: Carotid angioplasty and stenting versus carotid endarterectomy: randomized trial in a community hospital. J Am Coll Cardiol 38:1589-1595, 2001. c Alberts MJ: Results of a multicenter prospective randomized trial of carotid artery stenting vs carotid endarterectomy. Stroke 32:325, 2001. d Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomised trial. Lancet 357:1729-1737, 2001. e

Madyoon H, et al: Unprotected carotid artery stenting compared to carotid endarterectomy in a community setting. J Endovasc Ther 9:803-809, 2002.

f

Yadav JS, et al: Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 351:1493-1501, 2004. g Carotid Revascularization Using Endarterectomy or Stenting Systems (CaRESS) phase I clinical trial: 1-year results. J Vasc Surg 42:213-219, 2005. h

SPACE Collaborative Group, et al: 30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial. Lancet 368:1239-1247, 2006.

i

Mas JL, et al: Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med 355:1660-1671, 2006.

j

Brooks WH, et al: Carotid angioplasty and stenting versus carotid endarterectomy for treatment of asymptomatic carotid stenosis a randomized trial in a community hospital. Neurosurgery 54:318-324, discussion 324-325, 2004.

in case-control studies. For example, patients with abdominal aortic aneurysms may seemingly recall possible environmental factors that put them at risk for the disease. However, patients without aneurysms may not have a comparable imperative to stimulate memory of the same exposure. Confounding is a significant factor in epidemiology and clinical analysis. Confounding exists when a second spurious variable (e.g., race/ethnicity) correlates with a primary independent variable (e.g., type 2 diabetes) and its associated dependent variable (e.g., critical limb ischemia). Researchers can conclude that patients in certain race/ethnicity groups are at greater risk for critical limb ischemia when diabetes is actually the stronger predictor. Confounding by indication is especially relevant in observational studies. This can occur when, without randomization, patients being treated with a

Figure 1-1  Example of a forest plot from a meta-analysis of carotid artery stenting (CAS) versus carotid endarterectomy (CEA) to determine 30-day risk for stroke and death. CI, Confidence interval. (Redrawn from Brahmanandam S, et al: Clinical results of carotid artery stenting compared with endarterectomy. J Vasc Surg 47:343-349, 2008.)

drug can show worse clinical results than untreated counterparts because treated patients were presumably sicker at baseline and required the drug a priori. Confounding can be addressed by several methods: assigning confounders equally to the treatment and control groups (for case-control studies); matching confounders equally (for cohort studies); stratifying the results according to confounding groups; and multivariate analysis.

OUTCOMES ANALYSIS As physicians, we can usually see the natural progression of disease or the clinical outcome of treatment. Although these observations can be made for individual patients, general inferences about causation and broad application to all

CHAPTER 1  Epidemiology and Clinical Analysis



Statistical Methods At the beginning of most clinical analyses, descriptive statistics are used to quantify the study sample and its relevant clinical variables. Continuous variables (such as weight or age) are expressed as means or medians; categorical variables (such as the Trans-Atlantic Society Consensus [TASC] Classification: A, B, C, or D) are expressed as numbers or percentages of the total. Study sample characteristics and their relative distribution of comorbid conditions help determine whether the sample is consistent with known population characteristics, and hence, addresses the issue of generalizability of the clinical results to the overall population. The next step in clinical analysis is hypothesis testing, in which the factor or treatment of interest is tested against a control group. The statistical methods used in hypothesis testing depend on the research question and characteristics of the data under comparison (Box 1-1). At its core, hypothesis testing asks whether the observable differences between groups represent a true difference or an apparent difference attributable to random error. A variety of statistical tests are available to accommodate the types of data being analyzed. One major distinguishing characteristic of data is whether it fits a normal (or Gaussian) distribution, where the distribution of continuous values is symmetric and has a mean of 0 and a variance of 1. Gaussian distributions are one example of parametric data in which the form of the distribution is known. In contrast, nonparametric data are not symmetric around a mean, and the distribution of the data is not well known. Nonparametric statistical methods are thus used because fewer assumptions about the shape of the distribution are made. In general, nonparametric methods can be used for parametric data to increase robustness, but at a cost of statistical power. However, the use of parametric methods for nonparametric data or data containing small samples can lead to misleading results.

Regression Analysis Among the statistical tests available, a few deserve special mention because of their common application to the clinical analysis of studies of vascular patients. Regression analysis is a mathematical technique in which the relationship between

BOX 1-1 

CHOOSING STATISTICAL TESTS BASED ON RESEARCH QUESTION AND DATA CHARACTERISTICS IS THERE A DIFFERENCE BETWEEN MEANS, MEDIANS, AND PROPORTIONS? One Group • Parametric data: one sample t-test • Nonparametric data: sign test, Wilcoxon signed rank test, transform data for t-test • Proportions: exact binomial test, z approximation to exact test Two Independent Groups • Parametric data: t-test • Nonparametric data: Wilcoxon rank-sum test • Proportions: χ2 or Fisher’s exact test Two Related Groups • Parametric data: paired t-test • Nonparametric data: sign test, Wilcoxon signed rank test • Proportions: McNemar test or κ statistic Three or More Independent Groups • Parametric data: analysis of variance (ANOVA) • Nonparametric data: Kruskal-Wallis test • Proportions: χ2 or Fisher’s exact test Three or More Related Groups • Parametric data: repeated-measures ANOVA • Nonparametric: ANOVA by ranks IS THERE AN ASSOCIATION? Two Comparable Variables • Nominal data: relative risk • Ordinal data: Spearman’s rank correlation test • Continuous data: linear regression One Dependent Variable and Two or More Independent Variables • Binary dependent variable: logistic regression • Categorical dependent variable: analysis of covariance (ANCOVA) • Continuous dependent variable: multiple linear regression • Censored observations: Cox proportional hazards (CPH) model • Clustered or hierarchic parametric data: linear mixed models • Clustered or hierarchic semi-parametric data: generalized estimating equations (GEE)

a dependent (or response) variable is modeled as a function of one or more independent variables, an intercept, and an error term. General linear models take the form Y = β0 + β1x1 + β2x2 + … + βnxn + e, although the model can take quadratic and higher functions of x and still be considered in the linear family. The coefficients (β1, β2, etc.) are model parameters calculated to “fit” the data, as commonly done with the least-squares method. They describe the magnitude of effect that each independent variable (x) has on the dependent variable (Y). The goodness of fit for the model is tested by using the R2 value and analysis of residuals. R2 is the proportion of variability that is accounted for by the model and has a range of 0 to 1. Although higher R2 values imply better fit, there is no defined threshold for goodness of fit, because R2 can be unintentionally increased by adding more variables to the model. For binary dependent variables, a logistic (logit) regression is used, whereas for continuous dependent variables, linear regression is used (Box 1-1).

SECTION 1 BASIC SCIENCE

patients cannot be made without further analysis. Clinical analysis attempts to answer these questions by either observing or testing patients and their treatments. Because clinical analysis can be performed only on a subset or sample of the relevant entire population, a level of uncertainty will always exist in clinical analysis. Statistical methods are an integral aspect of clinical analysis because they help the researcher understand and accommodate the inherent uncertainty in a sample in comparison to the ideal population. In the following sections, common clinical analytic methods are reviewed so that the reader can better interpret clinical analysis and also have foundations to initiate an analysis. Reference to biostatistical and econometric texts is recommended for detailed derivation of the methods discussed.

7

8

SECTION 1  Basic Science 100 6 mo SP 79.5 ± 5.6%

Patency (%)

75

>6 mo PP 56.8 ± 6.6%

50

endothelin Nitric oxide Thrombomodulin, tissue plasminogen activator, tissue factor pathway inhibitor

Anticoagulant mechanisms

Tissue factor– and fibrin-mediated, extrinsic pathway, cell adhesion molecules, von Willebrand factor –platelet Thrombosis; fibrosis Endothelin > adrenergic Nitric oxide Thrombomodulin, endothelial protein C receptor , urinary plasminogen activator

Varicose veins

Figure 12-1  Hypercoagulable, acquired, or inherited disorders as well as infection, inflammation, and stasis, in conjunction with the patient’s physiologic milieu and genetics, affect vein wall injury. This injury may lead to thrombosis, vein injury, or varicose veins. Of those patients in whom thrombosis develops, a pulmonary embolism may occur or thrombosis resolves with no sequela. More commonly however, chronic venous insufficiency (CVI) develops, which may potentiate varicosities as well as lead to postthrombotic vein injury and dermatitis with ulcers, pain, or swelling.

is stored in the venules and the systemic veins at any given time. The function of the blood capacitance system, via vasoregulation, is to maintain the filling pressure of the heart as well as to compensate for orthostatic changes. The physiology of venous blood flow in the limb related to the calf muscle pump and other actions is detailed in Chapter 11. Everyday activities and changes in body position cause large changes in venous pressure. The average venous pressure at the foot is approximately 100 mm Hg in a person 5 feet 10 inches tall and weighing 75 kg. This pressure drops significantly with ambulation and while the person is recumbent. The venous valves are endothelium-lined folds of tunica intima that allow directional flow and contribute to this pressure reduction as well as maintaining prograde blood flow. To accommodate pressure and volume changes, veins undergo complex alterations in shape, depending on the blood volume, resistance, and the amount of blood flow within the system. Less vascular resistance occurs with a circular shape than an elliptical shape, and thus as venous volume increases, resistance to flow lessens. Unlike arteries, large veins lack an extensive elastic lamella (composed of elastin) but exhibit marked distensibility. Veins have a much smaller ratio of wall thickness to radius and higher incremental distensibility in the low-pressure range then arteries do, thus indicating that the elastic modulus of veins can greatly exceed the stress modulus of arteries. As a result, veins have a high breaking pressure, nearly four atmospheres.8 Much of the stress-bearing function of the vein wall may depend on its smooth muscle cell and elastin content, in contrast to the abundance of collagen in the arterial wall. Indeed, vein wall compliance is decreased after experimental venous thrombosis (VT) injury, which correlates with its increased collagen content,9 and disrupted elastin, as measured histologically.10



CHAPTER 12  Venous Pathology

165

Venous Thrombosis Pathways

Whereas the elastic properties of the vein wall provide passive tone, active vasoregulation is provided by smooth muscle cells in the medial layer mediated through sympathetic nerves, as well as vasoactive circulating mediators, as in arteries. Central responses include changes in hormones, body temperature, blood volume, physiologic stress, and other conditions. Typical adrenergic agonists are noradrenalin and epinephrine, whereas acetylcholine causes both constriction and relaxation. Locally, vasodilation and vasoconstriction are mediated by endothelium-derived relaxing factor, namely, nitric oxide (NO) and the constricting agent endothelin-1. Stimulators for NO include muscarinic activation, thrombin, and α2-adrenergic agents. Interestingly, the venous endothelium synthesizes less NO and more endothelin-1 than the endothelium of arteries.11 However, the endothelium is a major regulator of venous tone, through similar mechanisms that regulate arterial tone.12 The vein wall also produces vasoactive prostanoids, both intraluminal and extraluminal, that alter tone. For example, prostacyclin synthesis in the vein wall is stimulated by numerous substances and by mechanical stretching and promotes venodilation. Other direct and indirect vasoregulators include angiotensin II, bradykinin, histamine, serotonin, and vasoactive intestinal peptide. The local physiologic environment also affects venous tone, particularly hypoxemia and the local pH. For example, decreased pH, elevated PCO2, and elevated lactate values correlate with decreased contractility in isolated vein ring experiments.13 Age-related declines in vasodilatory and vasoconstrictor responses occur and may contribute to the demographics of venous disease, which is much more common with advancing age.14 Blood flow rates can also affect venous tone independently of the pressure. Mechanically, vasoregulation occurs with pulsatile blood flow and increased endothelial shear stress,15 which induces synthesis of various substances. In a manner similar to that in arteries, the Na, K, and Ca pumps are also important at the cellular level of venous regulation. Interestingly, the local ionic environment of vein walls may contribute to development of essential hypertension, with greater amounts of sodium ions in juxtaposition with the vein walls in hypertensive patients than in nonhypertensive patients.16

Hemostasis is typically initiated by damage to the vessel wall and disruption of the endothelium, although it may be initiated in the absence of vessel wall damage, particularly in venous thrombosis.20 Vessel wall damage simultaneously results in release of tissue factor (TF), a cell membrane protein, from injured cells and the circulation, with subsequent activation of the extrinsic pathway of the coagulation cascade. These two events are critical to the activation and acceleration of thrombosis. Tissues also vary with regard to their susceptibility to thrombosis, and the local organ mechanisms may be somewhat different. For example, hemostasis in cardiac muscle may be more dependent on the extrinsic pathway for thrombosis, whereas skeletal muscle may be more dependent on the intrinsic pathway for thrombosis.21 Platelet activation and the formation of an effective hemostatic “platelet plug” is a primary thrombotic event. Two platelet activation routes are thought to exist physiologically.22 Without direct vessel damage, platelet activation may occur via TF de-encryption and activation by protein disulfide isomerase, with factor VIIa generation and activation of platelets. Alternatively, subendothelial collagen may directly bind to glycoprotein (GP) VI and von Willebrand factor (vWF), leading to platelet capture and activation. Platelet interactions and activation are mediated by vWF, whose receptor is GPIb, and via GPIIb/IIIa to fibrin.23Activation of platelets leads to the release of the prothrombotic contents of platelet granules, which contain receptors for coagulation factors Va and VIIIa. In addition, platelet activation also leads to the elaboration of arachidonic acid metabolites such as thromboxane A2, further promoting platelet aggregation (as well as vasoconstriction). Changes in platelet shape result in exposure of negatively charged procoagulant phospholipids normally located within the inner leaflet of the platelet membrane.24 Platelets also release microparticles (MPs), rich in TF and other procoagulants, which accelerate and concentrate the thrombus generation. Interestingly, circulating TF may be more important in venous thrombosis than in arterial thrombosis.20,25 The extrinsic pathway begins with activation of factor VII, by complexing TF with factor VII. The TF-VIIa complex then activates factors IX and X to IXa and Xa, respectively, in the presence of calcium. Feedback amplification occurs with factors VIIa, IXa, and Xa, all of which are capable of activating VII to VIIa, especially when bound to TF.26 Factor Xa is also capable of activating factor V to Va. Factors Xa, Va, and II (prothrombin) form on the platelet phospholipid surface in the presence of Ca2+ and initiate the prothrombinase complex, which catalyzes the formation of thrombin from prothrombin. Thrombin feedback amplifies the system by activating not only factor V to Va but also factors VIII (normally circulating bound to vWF) to VIIIa and XI to XIa. After activation, factor VIIIa dissociates from vWF and assembles with factors IXa and X on the platelet

ACUTE DEEP VENOUS THROMBOSIS Venous thromboembolism (VTE) is a significant health care problem in this country, with an estimated 900,000 cases of deep venous thrombosis (DVT) and pulmonary embolism (PE), causing approximately 300,000 deaths yearly.17 For the past 150 years, understanding the pathogenesis of VTE has centered on Virchow’s triad of stasis, changes in the vessel wall (now recognized as injury), and thrombogenic changes in the blood. Stasis is probably permissive, and not a direct cause, whereas systemic infection and systemic inflammation may be more causal than previously thought.18,19

SECTION 2 PATHOPHYSIOLOGY

Venous Vasoregulation

166

SECTION 2  Pathophysiology

surface in the presence of Ca2+ to form a complex called the Xase complex, which catalyzes the activation of factor X to Xa. Thrombin (factor II) is central to coagulation through its action of cleavage and release of fibrinopeptide A (FPA) from the α chain of fibrinogen and fibrinopeptide B (FPB) from the β chain of fibrinogen. This causes fibrin monomer poly­ merization and cross-linking, which stabilizes the thrombus and the initial platelet plug. Thrombin also activates factor XIII to XIIIa, which catalyzes the cross-linking of fibrin as well as that of other plasma proteins, such as fibronectin and α2-antitrypsin, resulting in their incorporation into the clot and increasing resistance to thrombolysis.27 In addition, factor XIIIa activates platelets as well as factors V and VIII, further amplifying thrombin production. Coagulation can be activated through the intrinsic pathway with activation of factor XI to XIa, which subsequently converts factor IX to IXa and promotes formation of the Xase complex and ultimately thrombin. Another mechanism by which this occurs in vitro is through the contact activation system, whereby factor XII (Hageman factor) is activated to XIIa when complexed to prekallikrein and high-molecular-weight kininogen (HMWK) on a negatively charged surface; factor XIIa then activates factor XI to XIa. Both thrombin and factor XIa are also capable of activating factor XI.28 The physiologic importance of the intrinsic pathway is not completely clear and is probably not as physiologically important in the venous system as in the arterial system.

Natural Anticoagulants Several interrelated processes localize thrombotic activity to sites of vascular injury. First, antithrombin (AT) is a central anticoagulant protein that binds to thrombin and interferes with coagulation by three major mechanisms: (1) inhibition of thrombin prevents removal of fibrinopeptides A and B from fibrinogen, limiting fibrin formation; (2) thrombin becomes unavailable for activation of factors V and VIII, thus slowing the coagulation cascade; and (3) thrombin-mediated platelet activation and aggregation are inhibited. In the presence of heparin, the accelerated inhibition of thrombin by antithrombin results in systemic anticoagulation. Antithrombin has been shown to directly inhibit factors VIIa, IXa, Xa, XIa, and XIIa. Thus, patients with a genetic deficiency of antithrombin are at much higher risk for development of VTE than the normal population is. A second natural anticoagulant is activated protein C (APC), which is produced on the surface of intact endothelium when thrombin binds to its receptor, thrombomodulin, and endothelial protein C receptor (EPCR). The thrombinthrombomodulin complex inhibits the actions of thrombin and also activates protein C to APC. APC, in the presence of its cofactor protein S, inactivates factors Va and VIIIa, therefore reducing Xase and prothrombinase activity.29 The third innate anticoagulant is tissue factor pathway inhibitor (TFPI). This protein binds the TF-VIIa complex,

thus inhibiting the activation of factor X to Xa and formation of the prothrombinase complex. Interestingly, factor IX activation is not inhibited. Finally, heparin cofactor II is another inhibitor of thrombin whose action is in the extravascular compartment. The activity of heparin cofactor II is augmented by glycosaminoglycans, including both heparin and dermatan sulfate, but its deficiency is not associated with increased VTE risk.30

Physiologic Thrombolysis Physiologic clot formation is balanced by controlled thrombolysis to prevent pathologic intravascular thrombosis. The central fibrinolytic enzyme is plasmin, a serine protease generated by the proteolytic cleavage of the proenzyme plasminogen. Its main substrates include fibrin, fibrinogen, and other coagulation factors. Plasmin also interferes with vWFmediated platelet adhesion by proteolysis of GPIb.31 Activation of plasminogen occurs by several mechanisms. In the presence of thrombin, vascular endothelial cells produce and release tissue plasminogen activator (tPA) as well as α2-antiplasmin, a natural inhibitor of excess fibrinbound plasmin. As clot is formed, plasminogen, tPA, and α2-antiplasmin become incorporated into it. In contrast to free circulating tPA, fibrin-bound tPA is an efficient activator of plasminogen. A second endogenous activator of plasminogen is through the urinary plasminogen activator (uPA), also produced by endothelial cells but with less affinity for fibrin. Activation of uPA in vivo is not completely understood. However, it is hypothesized that plasmin in small amounts (produced through tPA) activates uPA, leading to further plasminogen activation and amplification of fibrinolysis.32 The third mechanism of plasminogen activation involves factors of the contact activation system; activated forms of factor XII, kallikrein, and factor XI can each independently convert plasminogen to plasmin. These activated factors may also catalyze the release of bradykinin from high-molecularweight kininogen, which further augments tPA secretion. Finally, APC has been found to proteolytically inactivate plasminogen activator inhibitor type 1 (PAI-1), an inhibitor of plasmin activators that is released by endothelial cells in the presence of thrombin.33 The degradation of fibrin polymers by plasmin ultimately results in the creation of fragment E and two molecules of fragment D, which are released as a covalently linked dimer (D-dimer).34 Detection of D-dimer in the circulation is a marker for ongoing thrombus metabolism and has been shown to accurately predict ongoing risk of recurrent VTE.35 Interestingly, the resting state of the fibrinolytic system within the vein wall is lower in the area of the valvular cusps.36 In comparison with other anatomic locations, the deep veins of the lower limb have the lowest fibrinolytic activity in soleal sinuses as well as in the popliteal and femoral vein regions. This observation underlies a popular hypothesis as to why DVT most commonly originates in the lower limb.

However, no in vivo real-time imaging studies have ever shown how and where DVT forms.

ANTITHROMBOTIC

En do th

m liu he t o

Vasoconstriction PGI2 Vasodilatation NO

t-PA/u-PA Thrombolysis

TXA2 Endothelin-1 Inhibits thrombolysis

Anti-inflammatory

Resting state

PAI-1

Procoagulant proteins

EPCR APC TFPI Anticoag TM

IL-10

el iu

Initiate coagulation, modulate inflammation

vWF TF

P-selectin MPs

Systemic inflammation, local injury

Figure 12-2  The careful balance between an antithrombotic and a prothrombotic milieu exists primarily at the endothelial level. Antithrombotic mediators include prostacyclin (PGI2) and nitric oxide (NO). Local thrombolysis is conferred by tissue (tPA) and urinary (uPA) plasminogen activators. Endothelial receptor for protein-C (EPCR), tissue factor pathway inhibitor (TFPI), and thrombomodulin (TM) inhibit thrombosis. Lastly, interleukin-10 (IL-10) is an anti-inflammatory cytokine. On the prothrombotic side, thromboxane (TXA2) and endothelin-1 promote vasoconstriction. Plasminogen activator inhibitor-1 (PAI-1) inhibits thrombolysis, and von Willebrand factor (vWF) and tissue factor (TF) are both procoagulant proteins. Lastly, P-selectin and microparticles (MPs) initiate coagulation and also modulate inflammation.

CAM (ICAM), thereby promoting the adhesion and activation of leukocytes as well as platelets.7

Inflammation and Thrombosis The relationship between thrombosis and inflammation was first suggested in the early 1970s.48 Inflammation increases TF, membrane phospholipids, fibrinogen, and the reactivity of platelets while decreasing thrombomodulin and inhibiting fibrinolysis (Fig. 12-3).49 Microparticles are involved in the initiation and amplification of thrombosis. They are small (14 days). Thrombus neovascularity and cellularity of the thrombus are associated with resolution, which is a monocyte/macrophage-driven process. Within the vein wall, matrix turnover occurs with increased MMP-2 expression, as well as collagen I and collagen III production. IL-13 and transforming growth factor-β (TGF-β) are two profibrotic growth factors that may be involved with late vein wall remodeling.

170

SECTION 2  Pathophysiology

As the thrombus resolves, a number of proinflammatory factors are released into the local environment, including interleukin-1β (IL-1β) and tumor necrosis factor-α.77 The cellular sources of these different mediators have not been specifically defined but probably include leukocytes and smooth muscle–like cells within the resolving thrombus and adjacent vein wall. Leukocyte kinetics in the vein wall after DVT are similar to what is observed in the thrombus, with an early influx of PMNs followed by monocytes. On the basis of experimental studies, elastinolysis and collagenolysis seem to occur early, as measured by an increase in vein wall stiffness, persisting through 14 days, and are accompanied by elevated MMP-2 and MMP-9 activities.9,10 Data linking inflammation to fibrosis demonstrate that inhibition of the inflammatory response can decrease vein wall fibrosis. In a rat model of stasis DVT, treated with either low-molecular-weight heparin (LMWH) or an oral inhibitor to P-selectin 2 days after establishment of thrombosis, inhibition of P-selectin significantly decreased vein wall injury (independent of thrombus size), as measured by vein wall tensiometry (stiffness), intimal thickness score, IL-13 levels, MCP-1 levels, and platelet-derived growth factor-β (PDGFβ) levels.92 The mechanism accounting for this protective effect is not yet known but probably does not involve leukocyte blockade, because no differences in influx of monocytes into the vein wall were observed. Loss of venous endothelium likely also contributes to the vein wall fibrosis as well as the predisposition to recurrent thrombosis. An experimental model of DVT showed lower expression of homeostatic endothelial gene products, such as NO and thrombomodulin, than in controls, which correlated with loss of vWF positive cell luminal staining.93 Other investigators have found that prolonged venous stasis is associated with decreased plasminogen activators, probably related to loss of endothelium.94

Reflux Dermis

Vein

Associated with the early biomechanical injury from DVT is an elevation of profibrotic mediators, including TGF-β, IL-13, IL-6, and MCP-1.10,92,95 These mediators are present within the vein wall and thrombus and may drive the fibrotic response. Although exogenous MCP-1 may hasten DVT resolution, it promotes organ fibrosis in vivo. The profibrotic growth factor TGF-β is also present in the thrombus and is activated with normal thrombolysis.96 TGF-β may be a key mechanism promoting vein wall fibrosis. Late fibrosis has been observed in our mouse model of DVT, which demonstrated a significant increase in vein wall collagen after stasis thrombogenesis.9,97 Correlating with this increase in fibrosis is an increase in collagen I and III gene expression, as well as increases in MMP-2 and MMP-9 gene expression and activity. Genetic deletion of MMP-2 or MMP-2/9 is associated with decreased vein wall fibrosis, possibly by modulating vein wall elastin/collagen metabolism as well as monocyte influx.97a Moreover, the thrombus size itself does not drive the vein wall injury response; rather, the mechanism of thrombosis seems more important.10,98 Thus, early vein wall injury is associated with active matrix remodeling that seems to promote late fibrosis, not unlike many organ responses to inflammation “burnout.”6 Indeed, precedent exists in humans that the monocytic activation state may predict long-term DVT resolution.99 The specific mechanisms and strategies to reverse this process are being actively investigated.

CHRONIC VENOUS INSUFFICIENCY Limb manifestations of CVI are easy to recognize: variable swelling, varicosities, hyperpigmentation, stasis dermatitis, ulceration, and pain (Figure 12-5). The symptoms are widespread in the general population and are not always directly related to the magnitude of venous insufficiency (e.g.,

hydrostatic pressure (+)

Valvular insufficiency

Skin changes

Stasis, venous distention, endothelial activation Transudation of Fe+2, macromolecular proteins TGF-, PDGF

Leukocyte extravasation

Ulcer

Chronic dermal inflammation MMP, collagen alteration, ? apoptosis

Figure 12-5  The pathogenesis of chronic venous insufficiency (CVI) pathogenesis is complex. Primarily, CVI is caused by reflux, which increases hydrostatic pressure in the vein and is transmitted to the subcutaneous dermis and skin. This process occurs with both primary and secondary valvular insufficiency. Reflux also potentiates blood flow stasis, with vein distention and endothelial activation, followed by leukocyte extravasation and transudative macromolecules and iron. Chronic dermal inflammation occurs with increased matrix metalloproteinases (MMPs), collagen alteration, and possibly apoptosis. A venous ulcer is the most severe manifestation of CVI. FE+2, Ferrous iron; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor-β.

CHAPTER 12  Venous Pathology



Table 12-3

171

Characteristics of Venous Insufficiency

CEAP Class

Risk Factors

Histopathology

Mediators

Reflux

C2-3

Genetic, hormonal, occupation

Dilation with fragmentation

TGF-β, MMPs

Superficial > deep

C4-6

Genetics, venous obstruction, Fe+2 metabolism

Fibrin cuffs, matrix accumulation

TGF-β, bFGF, MMPs

Superficial ≤ deep

degree of reflux). However, the most severe CVI symptoms are related to venous reflux with an obstructed venous segment.100,101 The best way to categorize CVI is with the CEAP (clinical, etiologic, anatomic, pathologic) classification. This system is discussed in detail in Chapter 53; in brief, it is a standardized system to grade CVI on the basis of symptoms, etiology, anatomy, and pathophysiology.102 The higher the class, the more severe the symptoms and the patient’s disability.19 For clarity of discussion, this section separately focuses on the pathology of class 2 to 3 and class 4 to 6 CVI, although there are many common factors and the pathology clearly represents a spectrum. Mechanisms of chronic vein injury with primary and secondary valve damage have been reasonably well described (Table 12-3). The common mechanism is venous reflux between the superficial and deep systems, either at the site of perforators or through other deep and superficial system connections, which accounts for the increased venous hydrostatic pressure transmitted to the superficial veins and tissues. An obstructed vein segment worsens this process. Experimentally, venous hypertension activates leukocytes,103 although the activation is probably a local phenomenon.104 The process of vein wall fibrosis plays a contributing role in valvular damage, which then worsens the hydrostatic pressure regulation and consequently promotes greater venous hypertension with the upright position. The molecular and cellular events seem to point to adaptive responses to injury as well as abnormal healing.

et al109 also showed a positive correlation between the inability of the calf pump to reduce foot vein pressure during exercise and the number of capillaries in the skin.

Varicose Veins (CEAP Class 2 to 3 Disease) Varicose veins (VVs) have been described since before the Common Era and are obvious on the lower limbs of many people. The fact that varicose veins primarily affect the lower limb directly implicates the upright nature of humans— specifically, the effect of hydrostatic pressure on the pathophysiology of such veins. The relationship between body weight and extent of varicose veins and symptoms is variable. Limb symptoms are generally local and consist of pruritus and swelling. Occasionally, varicose veins can erode and bleed. Conversely, most such veins do not thrombose, despite relatively slow blood flow through these torturous structures, and this fact underlies the natural anticoagulant nature of venous endothelium, even in structurally abnormal vessels. The initial anatomic location of varicose veins is typically in the great and small saphenous distributions and their tributaries in the superficial system.110 Related risk factors are multiple, including primary etiologies associated with pregnancy, prolonged standing, female gender, and, rarely, congenital absence of valves.111 In addition, varicosities may develop as a result of prior DVT or trauma.

Historical Perspective and General Background Several important theories have been postulated regarding the etiology and pathophysiology of CVI. In 1917, John Homans105 produced a clinical treatise on the diagnosis and the management of patients with CVI and coined the term “post thrombotic syndrome.” Dr. Alfred Blalock106 put forth the hypothesis that local hypoxia precipitated CVI. Local tissue hypoxia and alterations in nutrient blood flow were proposed as an underlying etiology by Browse and Burnand.107 Their important study directly demonstrated the effect of venous hypertension on the venous microcirculation, and they observed histologically that in large capillaries, pericapillary fibrin deposition, which they called the “fibrin cuff,” occurred (Fig. 12-6). Dr. P.D. Coleridge Smith108 proposed that leukocyte trapping in slow-flow and distended venous segments may underlie much of CVI development. Burnand

Figure 12-6  Electron photomicrograph (×4300) of ulcer tissue in a patient with CEAP6 venous insufficiency. Note the perivascular fibrin cuff in close proximity to a fibroblast. Arrows point to macrophages that appear to be entering the lymphatic lumen.

SECTION 2 PATHOPHYSIOLOGY

bFGF, Basic fibroblast growth factor; MMP, matrix metalloproteinase; TGF-β, transforming growth factor-β.

172

SECTION 2  Pathophysiology

Studies support a genetic predisposition to varicose veins.112 In a prospective study of 402 subjects, the risk of development of varicose veins was 90% if both parents were affected, 25% for males and 62% for females if one parent was affected, and 20% if neither parent was affected.113 These data suggest an autosomal dominant with variable penetrance mode of genetic transmission. Studies are generally lacking in relation to early vein wall changes associated with varicose veins, because most histologic studies are limited to end-stage surgical specimens. In varicose veins, the orderly appearance of the medial layer is replaced by an intense and disorganized deposition of collagen that separates the closely apposed muscle cells. Smooth muscle cells appear elliptical and are likely a secretory phenotype, and both TGF-β and basic fibroblast growth factor (bFGF) have been documented to be significantly increased in hypertrophic segments of varicose veins.114 The underlying mechanism for these histologic changes is unknown, but the inciting event of increased hydrostatic pressure or an intrinsic genetic defect is probably primary. Active vein wall remodeling is consistently observed in specimens of varicose veins with abnormal matrix collagen metabolism.115 Quantitatively, higher collagen content and lower elastin content in varicose veins have been measured in human samples, suggesting an imbalance in connective tissue matrix regulation and turnover.116 Specific alteration in the type of collagen may also contribute to vessel weakening, with an observed increase in tissue water and collagen type I content in comparison with normal saphenous veins.117 Conversely, collagen types III and V levels were lower than in normal veins, and less type III collagen is associated with decreased elasticity. Similarly, in a separate study, varicose veins had increased type I and decreased type III collagen gene expression.118 Comparison of smooth muscle cells from varicose veins with controls has shown matrix dysregulation119 as well as regional differentiation as measured by antigen markers in the cells from varicose veins.120 Interestingly, a similar collagen dysregulation pattern has also been observed in patients with varicose veins after dermal biopsies,121 suggesting an intrinsic genetic abnormal response to injury. The observed pathology suggests a net effect of matrix deposition. One mechanism for these changes may be local upregulation of MMPs and fibrinolytic activity within the microenvironment.122 The upstream regulators of MMPs are in part, the plasmin system. Urinary PA levels are three to five times higher than in controls, as assessed from media of specimen organ culture from varicose veins.123 Interestingly, there is no difference in tPA activity or PAI-1 levels. Investigators have found that TIMP-1 and MMP-1 protein levels are higher at the saphenofemoral junction in patients with varicose veins and that MMP-2 activity is lower in normal controls.124 Similarly, high TIMP-1 activity and low MMP-2 activity have been observed in varicose vein segments, with a threefold significant difference in comparison with normal controls.125 Overall differences in MMP-9 protein have also been identified, and it is likely, with the inflammatory influx,

that MMP-9 is released primarily from PMNs but may be less important than MMP-2.126,127 This disordered vein structure also correlates with altered vasoreactivity. The contractual response of varicose and normal great saphenous rings to various alpha-adrenergic and non–alpha-adrenergic receptors has shown decreased contractility as compared with controls.128 This lower contractility may be due to repeated overdistention or impaired contractility related to persistent vein wall tension. However, it is a segmental response and likely adaptive.129 Receptor downregulation may also play a role. For example, feedback inhibition of ETA receptor secondary to increased endothelin-1 is also postulated to mediate the lower vasoreactivity content in the walls of varicose veins.130 The ratio of prostacyclin to thromboxane A2 is also lower, suggesting an increased basal contractile state.131 Finally, one investigation has suggested that MMP-2 may act to dilate the vein by direct hyperpolarization effects, via a Ca+2 channel mechanism.132

Pathophysiology of Stasis Dermatitis and Dermal Fibrosis (CEAP Class 4 to 6 Disease) Stasis venous dermatitis is a disease of chronic dermal inflammation due to persistent and sustained cutaneous and dermal injury secondary to venous hypertension. The primary injury may be extravasation of macromolecules and red blood cell products into the dermal interstitium, which creates a secondary inflammatory response, and multiple pathophysiologic hypotheses have been proposed.133 The clinical appearance is that of brawny induration, skin thickening, swelling, and tissue breakdown with ulceration in the gaiter regions. Alteration in extracellular matrix is clear on histologic assessment, with dermal space extracellular disorganized collagen deposition and perivascular tissue cuffs. The role of the common growth factor TGF-β1, which is secreted by activated endothelial cells, fibroblasts, and platelets and stimulates matrix protein production,134,135 has been studied in relation to venous ulcer development. TGF-β is an inducer of TIMP-1 and collagen production and inhibits MMP activity and gene expression.135 The local upregulation of TGF-β1 thus favors net collagen and matrix accumulation and is supported by histologic and clinical analysis, although gene upregulation may occur at an earlier stage than protein production.136 Whether TGF-β is acting directly or is associated with this process has not been substantiated in human studies to date. Several other growth factors are elevated in the dermis of patients with CVI, including platelet-derived growth factors α and β and VEGF.137 These various molecules are found within the capillaries surrounding fibroblasts and inflammatory cells in patients with venous skin changes. Further studies have suggested that endothelial activation results from venous hypertension.138 A significant rise in plasma levels of endothelial leukocyte adhesion molecule-1 (ELAM-1), ICAM-1, and vascular cell adhesion molecule-1 were observed in patients with venous hypertension, indirectly suggesting a role of these molecules in the pathogenesis.139 Similarly, increased endothelial expression of



173

proliferative responses of fibroblasts from patients with CVI to TGF-1β correlated with disease severity.148 Fibroblasts in patients with CEAP class 2 or 3 CVI retained agonist induce proliferative capacity, whereas those from patients with class 4 or 5 CVI showed diminished agonist-induced proliferation. Fibroblasts from patients with class 6 CVI and active ulcers did not proliferate with TGF-1β, suggesting that these ulcer fibroblasts are refractory to stimulation and may contribute to the inability to promote healing. Histologically, these fibroblasts appear morphologically similar to fibroblasts undergoing cellular senescence, and therefore may be proapoptotic from repeated injury. Another study showed similar impairment of dermal wound fibroblast proliferation response to both basic fibroblast growth factor and EGF.149 An interesting but unanswered question is which patients with similar degrees of reflux and hydrostatic pressures from CVI are more predisposed to development of venous ulcers. Data now suggest that iron metabolism and ulcer development are interrelated. Although commonly thought of as a consequence of all the other mechanisms of CVI, the iron deposition itself may cause tissue damage.150 More convincingly, the risk of ulcer development among patients with class 4 to 6 CVI was sevenfold higher in those with the C282Y genotype, a mutation related to iron processing.151 Taken together, venous insufficiency and secondary cutaneous manifestations suggest that active tissue remodeling occurs, likely via multiple mechanisms and in different stages. Whether the growth factors, cytokines, and proteinases are directly responsible or secondary to other factors of the disease has not been definitively answered. Regardless, the significant benefit of compression in ulcer healing suggests these factors may play a secondary role. In one study the benefit of compression therapy and how it may alter histologic and biochemical features was shown after 4 weeks.152 Complete epithelialization was frequent, the hemosiderin and red blood cell extravasation products had decreased, and fibrin cuffs were reversed. However, a single “silver bullet” approach to therapy is unlikely to be successful. Rather, identifying patients at risk for CVI with biomarkers (via genomics and proteomics) may be the best immediate translational approach.

VENOUS ANEURYSMS The etiology of venous aneurysms is poorly understood, and little clinical series data regarding their pathogenesis is available in the literature. Not surprisingly, no genetic studies related to any underlying connective tissue or matrix enzyme abnormalities have been performed. Venous aneurysms are more common in South America than in North America or Europe. The primary clinical risk associated with venous aneurysms is stasis, and VTE may develop in up to 71% of those with venous aneurysms.153 Few symptoms are associated with venous aneurysms, and the main indication for surgical management of such a lesion is the fact it may be a nidus for thrombus and contribute to VTE. Venous aneurysms are not really at risk for rupture per se.

SECTION 2 PATHOPHYSIOLOGY

ICAM-1, vascular cell adhesion molecule-1, and leukocyte function-associated antigen-1 (LFA-1) has been documented in patients with dermal disease.140 Several studies suggest conflicting data with regard to whether MMP-2, MMP-9, and TIMP-1 levels are higher or unaltered in patients with venous ulcers. This uncertainty may have to do with the measurement of MMP gene, protein, or activity expression as well as with the ulcer stage and patient characteristics that may not be controlled for. Another important proteinase is elastase, primarily derived from PMNs. Higher levels of plasma elastase were found in patients with venous ulceration than in those with uncomplicated varicose veins, perhaps reflecting active degranulation in those with ulcers.141 However, this evidence is only indirect, and whether proteinases are directly responsible for venous ulcer development is not known. Consistent with the tissue inflammation, leukocytes are markedly elevated in the gaiter region in association with the venous ulcers.142 This finding correlates with preceding elevation of IL-1α and ICAM-1 in the tissue of lipodermatosclerotic skin.143 The type and distribution of leukocytes in patients with CEAP class 5/6 CVI have been studied histologically.144 Numbers of mast cells and macrophages were two to four times greater around arterioles and postcapillary venules in patients with CEAP class 4/5 CVI than in controls. Similarly, increased macrophages are demonstrated around arterioles and postcapillary venules, although fibroblasts are the most common cell observed in both gaiter and thigh biopsy specimens. It is likely that these leukocytes regulate the tissue remodeling that results in dermal fibrosis. Sluggish venous blood flow related to increased hydrostatic pressure leads to hypoxia and PMN activation, with degranulation of mediators and proteinases that cause endothelial damage. Skin hypoxia also occurs on the gaiter areas of limbs with severe venous disease and is significantly different from controls, oxygen tension (tcPO2) differing by more than 20 mm.145 Although leukocyte trapping within the capillaries is probably not the sole cause, it is likely that leukocytes become activated, transmigrate into the vein walls, and mediate some of the observed damage. Consistently, findings in punch biopsy specimens of ulcers suggest that leukocytes play a role in the dermal manifestations of CVI.142 For example, leukocytes, macrophages, and mast cells have all been observed in immunohistochemical and electron microscopic examinations of affected tissue.144 The dermal fibroblast may also be dysfunctional and allow perpetuation of the disease. Decreased motility, in part mediated by the microenvironment, plays a role in the impaired healing process of ulcer tissue.146 Comparison of venous ulcer fibroblasts with control fibroblasts with stimulation with TGF-β suggested that there are differences in collagen production.147 With stimulation, collagen production was increased 60% in controls, whereas the venous ulcer fibroblasts were unresponsive. This finding may be related to an end-stage process, overstimulation of the ulcer fibroblast, or an intrinsically dysfunctional fibroblast. Consistently, the

CHAPTER 12  Venous Pathology

174

SECTION 2  Pathophysiology

There is no evidence of any link between venous aneurysms and arterial aneurysms. For example, patients with connective tissue disorders such as Ehlers-Danlos or Marfan’s syndrome do not manifest venous aneurysms. Of note, venous aneurysms are not just large varicosities, primarily because of the anatomic location differences. Venous aneurysms may be associated with either an acquired condition, such as an arteriovenous fistula or primary, or may be related to venous distention. Case reports have shown them to be present in jugular veins, the vena cava, axillary-subclavian veins, femoral veins, and popliteal veins.153,154 The overall primary pathologic etiology has not been determined. It is likely they are flow-related phenomena in one setting and a local degenerative process in other settings. In contrast to thrombotic injury, characterized as an occlusive fibrotic process, the flow dynamics in a venous aneurysm direct the vein in “outward” remodeling. Histologic analysis shows vein wall fragmentation with elastin degeneration.154 Pathologically the wall is thin, in which elastin fragmentation alternates with smooth muscle cell attenuation and fibrous tissue deposition, thus suggesting a typical response to vascular injury.155

THROMBOPHLEBITIS Thrombophlebitis may be sterile or associated with a bacterial infection, and may be a marker for DVT.156 Most often it involves the superficial venous system, such as the great saphenous or cephalic vein, and occurs after placement of an intravenous catheter or other superficial trauma. Symptoms include pain, redness, swelling, and tenderness to palpation, often with a cord present in the affected limb. A systemic febrile response is usually absent in noninfected cases, whereas bacterial thrombophlebitis may be a source of postoperative fever. Occasionally the latter may be associated with bacteremia and a septic picture. It is unclear whether there is a specific genetic predisposition to this disease, but clinical factors and environment likely play the biggest roles. A special case of thrombophlebitis is a migratory thrombophlebitis, which was described

Table 12-4

by Trousseau in the 1800s and is specifically linked to patients with pancreatic cancer. Mondor’s disease is superficial thrombophlebitis of the veins in the breast tissue, particularly in the upper outer quadrant. Sterile phlebitis may occur in varicosities, as well as after stripping or endovenous ablation. An experimental study of sterile thrombophlebitis showed a typical sequence of early PMN attachment followed by transmigration and inflammatory changes.157 Approximately 25% of the time, thrombosis occurs before symptoms. The histologic pathology is an acute vasculitis with marked thickening, inflammatory cells, and fibrin deposition.158 Later resolution involves fibrotic changes and recanalization of the venous segment at variable rates over weeks to months. One study has shown that anticoagulation for 45 days significantly decreased proximal venous thrombus propagation by approximately 85%.159 The role of bacterial infection in directly promoting thrombosis has been described in various clinical settings.160 The pathophysiology of infectious thrombophlebitis is similar to that of any closed-space infection, and bacterial antigens and proteins may directly stimulate venous thrombosis and the extrinsic pathway. Multiple organisms may be cultured from infectious thrombophlebitis, including both grampositive and gram-negative species.

INTERFACE OF ARTERIAL THROMBOSIS AND VENOUS THROMBOSIS Several interesting epidemiologic and basic science studies have suggested a common interface between risk for venous thrombosis and arterial vascular pathology (Table 12-4). Dysfunctional endothelium contributes to atherosclerosis and may also contribute to clinical VTE. Conversely, systemic vascular inflammation may affect both arteries and veins,161 and the differences are manifested as the typical clinical pathology of arterial and venous occlusions. Epidemiologic studies support risks common to these two vascular diseases. The concept that VTE and atherosclerosis may have common risk factors has been assessed by a

Comparison of Atherosclerosis and Venous Thrombosis Risk Factors

Effective Medications

Histopathology

Biomarkers

Atherosclerosis

Hypertension, smoking Hyperlipidemia Male inflammation

Medial artery injury with plaque rupture

High-sensitivity C-reactive protein Lipoprotein α CD40L

Venous thrombosis

Hypercoagulable states Stasis malignancy Systemic infection Diabetes mellitus Obesity Systemic inflammation

Antiplatelet agents Antihypertensive agents Diabetes mellitus control agents Warfarin

Thrombosis with post-lysis thickening

P-selectin, thrombin, cytokines, D-dimer microparticles

Statin, heparin, aspirin, factor II and Xa inhibitors

Leukocytes, fibrin, platelets

Cell adhesion molecules, urinary plasminogen/plasminogen activator inhibitor-1

Both

CHAPTER 12  Venous Pathology

Angiogenesis Vein wall

Immune modulation Endothelium

Clot MMP HIF1

TLR9 Proendothelial agents ? Statin G-CSF

Media

Pro-SMC differentiation

Figure 12-7  The potential future therapies for venous disease are speculative but promising, on the basis of experimental and epidemiologic studies. Proendothelial agents, such as statins, may decrease the risk of venous thrombosis or increase vein wall healing. Antiproliferative agents and pro–smooth muscle cell (SMC) differentiation agents may one day reverse the vein wall thickening and fibrosis that occur after deep venous thrombosis. Immune modulation with thrombus resolution—perhaps via an increase in local matrix metalloproteinase (MMP) activity, or through priming and driving thrombolysis mechanisms via Toll-like receptor 9 (TLR9)—is a potentially attractive mechanism by which to accelerate thrombus resolution without anticoagulant risk. G-CSF, Granulocyte colony stimulating factor; HIF1α, hypoxia-inducible factor 1α.

metaanalysis. Compared with control subjects, the risk of VTE was 2.33 for obesity, 1.5 for hypertension, 1.4 for diabetes, 1.2 for smoking, and 1.2 for hypercholesterolemia.162 Interestingly, mean high-density lipoprotein cholesterol levels were lower in patients with VTE than in controls. Conversely, patients with spontaneous VTE had a 1.6-fold measured incidence of symptomatic atherosclerosis.163 Clinical data also suggest that aspirin may decrease the rate of recurrent VTE164 as well as the number of arterial atheroembolic events in at-risk patients with VTE.165 Logically, any proendothelial agent will affect both arterial and venous systems. In addition to the endotheliumprotective effects of statins, these agents may increase thrombomodulin expression and enhance APC activity, thereby tipping the balance of endothelium toward a more antiinflammatory and anticoagulant state. Registry cohort patient data suggests a 22% lower rate in patients with symptomatic VTE undergoing statin therapy, than in those not receiving such therapy.166 Reports are forthcoming that 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may be associated with decreased DVT incidence. Glynn and colleagues,167 in a multicenter trial, showed that incident VTE was significantly reduced by the use of a statin agent over 3 years of follow-up. Experimentally, hyperlipidemic mice (in which the APOE gene has been deleted) have impaired thrombus resolution associated with significantly reduced plasmin activity, fewer monocytes, and reduced MCP-1 levels.97 Whether this finding directly translates to human pathophysiology is not clear. Statin treatment of mice with stasis DVT is associated with smaller venous thrombi, but the effect is time dependent.168 Statins also inhibit monocyte TF expression, possibly accounting for their antithrombotic effect.25 Much remains to be uncovered about the mechanisms and treatment of venous disease, but consideration of the similarities and differences between venous and arterial pathology will likely lead to novel therapies (Fig. 12-7).

SELECTED KEY REFERENCES Bergan JJ, Schmid-Schönbein GW, Smith PD, Nicolaides AN, Boisseau MR, Eklof B: Chronic venous disease. N Engl J Med 355:488–498, 2006. Comprehensive review of CVI by several of the world’s experts. Browse NL, Burnand KG: The cause of venous ulceration. Lancet 2(8292):243–245, 1982. A classic treatise on venous ulcer pathophysiology by two of the early investigators. Henke PK, Mitsuya M, Luke CE, Elfline MA, Baldwin JF, Deatrick KB, Diaz JA, Sood V, Upchurch GR, Wakefield TW, Hogaboam C, Kunkel SL: Toll-like receptor 9 signaling is critical for early experimental deep vein thrombosis resolution. Arterioscler Thromb Vasc Biol 31:43–49, 2011. An experimental study that suggests that immunomodulation of DVT is possible. Monos E, Bérczi V, Nádasy G: Local control of veins: biomechanical, metabolic, and humoral aspects. Physiol Rev 75:611–666, 1995. An extremely comprehensive review of venous physiology. Singh I, Burnand KG, Collins M, Luttun A, Collen D, Boelhouwer B, Smith A: Failure of thrombus to resolve in urokinase-type plasminogen activator gene-knockout mice: rescue by normal bone marrow-derived cells. Circulation 107:869–875, 2003. An elegant study that suggests the central role of uPA in mediating later DVT resolution. von Bruhl ML, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M, Khandoga A, Timiceriu A, Coletti R, Kollnberger M, Byrne RA, Laitinen I, Walch A, Brill A, Pfeiler S, Manukyan D, Braun S, Lange P, Riegger J, Ware J, Eckart A, Haidari S, Rudelius M, Schulz C, Echtler K, Brinkmann V, Schwaiger M, Preissner KT, Wagner DD, Mackman N, Engelmann B, Massberg S: Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 209:819–835, 2012. This comprehensive experimental study shows the critical early interactions of leukocytes, their functions and the coagulation system including the platelet in experimental venous thrombosis. It also confirms the role of innate immunity in venous thrombosis. Wakefield TW, Strieter RM, Wilke CA, Kadell AM, Wrobleski SK, Burdick MD, Schmidt R, Kunkel SL, Greenfield LJ: Venous thrombosis-associated inflammation and attenuation with neutralizing antibodies to cytokines and adhesion molecules. Arterioscler Thromb Vasc Biol 15:258–268, 1995. One of the first studies to follow up on the concept that venous thrombosis is an inflammatory disease. The reference list can be found on the companion Expert Consult website at www.expertconsult.com.

SECTION 2 PATHOPHYSIOLOGY

Antiproliferative agents

175

CHAPTER 12  Venous Pathology



REFERENCES

27. Davie EW, et al: The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 30:10363–10370, 1991. 28. Naito K, et al: Activation of human blood coagulation factor XI independent of factor XII. Factor XI is activated by thrombin and factor XIa in the presence of negatively charged surfaces. J Biol Chem 266:7353–7358, 1991. 29. Marlar RA, et al: Mechanism of action of human activated protein C, a thrombin-dependent anticoagulant enzyme. Blood 59:1067–1072, 1982. 30. Corral J, et al: Homozygous deficiency of heparin cofactor II: relevance of p17 glutamate residue in serpins, relationship with conformational diseases, and role in thrombosis. Circulation 110:1303–1307, 2004. 31. Adelman B, et al: Plasmin effect on platelet glycoprotein Ib-von Willebrand factor interactions. Blood 65:32–40, 1985. 32. Sidelmann JJ, et al: Fibrin clot formation and lysis: basic mechanisms. Semin Thromb Hemost 26:605–618, 2000. 33. Esmon CT: The regulation of natural anticoagulant pathways. Science 235:1348–1352, 1987. 34. Hassouna HI: Laboratory evaluation of hemostatic disorders. Hematol Oncol Clin North Am 7:1161–1249, 1993. 35. Palareti G, et al: D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 355:1780–1789, 2006. 36. Ljungner H, et al: Decreased fibrinolytic activity in the bottom of human vein valve pockets. Vasa 12:333–336, 1983. 37. Dano K, et al: Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res 44:139–266, 1985. 38. Vassalli JD, et al: The plasminogen activator/plasmin system. J Clin Invest 88:1067–1072, 1991. 39. Kohler HP, et al: Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med 342:1792–1801, 2000. 40. Booth NA, et al: Plasminogen activator inhibitor (PAI-1) in plasma and platelets. Br J Haematol 70:327–333, 1988. 41. Schulman S, et al: The significance of hypofibrinolysis for the risk of recurrence of venous thromboembolism. Duration of anticoagulation (DURAC) trial study group. Thromb Haemost 75:607–611, 1996. 42. Crowther MA, et al: Fibrinolytic variables in patients with recurrent venous thrombosis: a prospective cohort study. Thromb Haemost 85:390–394, 2001. 43. Segui R, et al: PAI-1 promoter 4g/5g genotype as an additional risk factor for venous thrombosis in subjects with genetic thrombophilic defects. Br J Haematol 111:122–128, 2000. 44. Zoller B, et al: A common 4g allele in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene as a risk factor for pulmonary embolism and arterial thrombosis in hereditary protein S deficiency. Thromb Haemost 79:802–807, 1998. 45. Becker MD, et al: Reduced leukocyte migration, but normal rolling and arrest, in interleukin-8 receptor homologue knockout mice. Invest Ophthalmol Vis Sci 41:1812–1817, 2000. 46. Yang Y, et al: Regulation of tissue factor expression in human microvascular endothelial cells by nitric oxide. Circulation 101:2144–2148, 2000. 47. Gross PL, et al: The endothelium and thrombosis. Semin Thromb Hemost 26:463–478, 2000. 48. Stewart GJ: Neutrophils and deep venous thrombosis. Haemostasis 23(Suppl 1):127–140, 1993. 49. Esmon CT: Inflammation and thrombosis. J Thromb Haemost 1:1343– 1348, 2003. 50. Gilbert GE, et al: Platelet-derived microparticles express high affinity receptors for factor VIII. J Biol Chem 266:17261–17268, 1991. 51. Mesri M, et al: Endothelial cell activation by leukocyte microparticles. J Immunol 161:4382–4387, 1998. 52. Sabatier F, et al: Interaction of endothelial microparticles with monocytic cells in vitro induces tissue factor-dependent procoagulant activity. Blood 99:3962–3970, 2002. 53. Falati S, et al: Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med 197:1585–1598, 2003.

SECTION 2 PATHOPHYSIOLOGY

1. Holderfield MT, et al: Crosstalk between vascular endothelial growth factor, notch, and transforming growth factor-β in vascular morphogenesis. Circ Res 102:637–652, 2008. 2. Aird WC: Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res 100:158–173, 2007. 3. You LR, et al: Suppression of notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature 435:98–104, 2005. 4. Delot EC, et al: Abnormal venous and arterial patterning in chordin mutants. Dev Dyn 236:2586–2593, 2007. 5. Davis GE, et al: Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circ Res 97:1093–1107, 2005. 6. Deroo S, et al: The vessel wall: a forgotten player in post thrombotic syndrome. Thromb Haemost 104:681–692, 2010. 7. Eriksson EE, et al: Powerful inflammatory properties of large vein endothelium in vivo. Arterioscler Thromb Vasc Biol 25:723–728, 2005. 8. Archie JP Jr, et al: Saphenous vein rupture pressure, rupture stress, and carotid endarterectomy vein patch reconstruction. Surgery 107:389– 396, 1990. 9. Deatrick KB, et al: Vein wall remodeling after deep vein thrombosis involves matrix metalloproteinases and late fibrosis in a mouse model. J Vasc Surg 42:140–148, 2005. 10. Henke PK, et al: Fibrotic injury after experimental deep vein thrombosis is determined by the mechanism of thrombogenesis. Thromb Haemost 98:1045–1055, 2007. 11. De Mey JG, et al: Heterogeneous behavior of the canine arterial and venous wall: importance of the endothelium. Circ Res 51:439–447, 1982. 12. Raffetto JD, et al: Endothelium-dependent nitric oxide and hyperpolarization-mediated venous relaxation pathways in rat inferior vena cava. J Vasc Surg 55:1716–1725, 2012. 13. Vanhoutte PM, et al: Endothelium-dependent contractions. Blood Vessels 28:74–83, 1991. 14. Hiremath AN, et al: Comparison of age-related changes in prostaglandin E1 and beta-adrenergic responsiveness of vascular smooth muscle in adult males. J Gerontol 44:M13–M17, 1989. 15. Bevan JA, et al: Comparable sensitivity of flow contraction and relaxation to Na reduction may reflect flow-sensor characteristics. Am J Physiol 263:H182–H187, 1992. 16. Simon G: Increased vascular wall sodium in hypertension: where is it, how does it get there and what does it do there? Clin Sci (Lond) 78:533–540, 1990. 17. Heit JA, et al: Estimated annual number of incident and recurrent, non-fatal venous thromboembolism (VTE) events in the US. Blood 106, 2005. 18. Gangireddy C, et al: Risk factors and clinical impact of postoperative symptomatic venous thromboembolism. J Vasc Surg 45:335–341; discussion 341–342, 2007. 19. Meissner MH, et al: Acute venous disease: venous thrombosis and venous trauma. J Vasc Surg 46(Suppl S):25S–53S, 2007. 20. Mackman N, et al: Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol 27:1687– 1693, 2007. 21. Mackman N: Tissue-specific hemostasis in mice. Arterioscler Thromb Vasc Biol 25:2273–2281, 2005. 22. Furie B, et al: Mechanisms of thrombus formation. N Engl J Med 359:938–949, 2008. 23. Savage B, et al: Selective recognition of adhesive sites in surface-bound fibrinogen by glycoprotein IIb-IIIa on nonactivated platelets. J Biol Chem 266:11227–11233, 1991. 24. Ferguson JJ, et al: Fundamentals of coagulation and glycoprotein IIb/ IIIa receptor inhibition. Eur Heart J 19(Suppl D):D3–D9, 1998. 25. Mackman N: New insights into the mechanisms of venous thrombosis. J Clin Invest 122:2331–2336, 2012. 26. Dahlback B: Blood coagulation. Lancet 355:1627–1632, 2000.

175.e1

175.e2 SECTION 2  Pathophysiology 54. Martinez MC, et al: Shed membrane microparticles from circulating and vascular cells in regulating vascular function. Am J Physiol Heart Circ Physiol 288:H1004–H1009, 2005. 55. Osterud B: The role of platelets in decrypting monocyte tissue factor. Semin Hematol 38:2–5, 2001. 56. Ahn ER, et al: Differences of soluble CD40l in sera and plasma: implications on CD40l assay as a marker of thrombotic risk. Thromb Res 114:143–148, 2004. 57. Hrachovinova I, et al: Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med 9:1020–1025, 2003. 58. Andre P, et al: Pro-coagulant state resulting from high levels of soluble P-selectin in blood. Proc Natl Acad Sci U S A 97:13835–13840, 2000. 59. Podor TJ, et al: Vimentin exposed on activated platelets and platelet microparticles localizes vitronectin and plasminogen activator inhibitor complexes on their surface. J Biol Chem 277:7529–7539, 2002. 60. Myers D Jr, et al: Selectins influence thrombosis in a mouse model of experimental deep venous thrombosis. J Surg Res 108:212–221, 2002. 61. Myers DD, et al: P-selectin and leukocyte microparticles are associated with venous thrombogenesis. J Vasc Surg 38:1075–1089, 2003. 62. Myers DD, et al: Inflammation-dependent thrombosis. Front Biosci 10:2750–2757, 2005. 63. Polgar J, et al: The P-selectin, tissue factor, coagulation triad. J Thromb Haemost 3:1590–1596, 2005. 64. Siddiqui FA, et al: The presence and release of tissue factor from human platelets. Platelets 13:247–253, 2002. 65. Giesen PL, et al: Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci U S A 96:2311–2315, 1999. 66. Celi A, et al: P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci U S A 91:8767–8771, 1994. 67. Jy W, et al: Platelet factor 3 in plasma fractions: its relation to microparticle size and thromboses. Thromb Res 80:471–482, 1995. 68. Reitsma PH, et al: Mechanistic view of risk factors for venous thromboembolism. Arterioscler Thromb Vasc Biol 32:563–568, 2012. 69. Brill A, et al: von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models. Blood 117:1400– 1407, 2011. 70. von Bruhl ML, et al: Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 209:819–835, 2012. 71. Day SM, et al: Macrovascular thrombosis is driven by tissue factor derived primarily from the blood vessel wall. Blood 105:192–198, 2005. 72. Henn V, et al: CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391:591–594, 1998. 73. Horrevoets AJ: Plasminogen activator inhibitor 1 (PAI-1): in vitro activities and clinical relevance. Br J Haematol 125:12–23, 2004. 74. Meissner MH, et al: Deep venous insufficiency: the relationship between lysis and subsequent reflux. J Vasc Surg 18:596–605; discussion 606–608, 1993. 75. Killewich LA, et al: Regression of proximal deep venous thrombosis is associated with fibrinolytic enhancement. J Vasc Surg 26:861–868, 1997. 76. Saha P, et al: Leukocytes and the natural history of deep vein thrombosis: current concepts and future directions. Arterioscler Thromb Vasc Biol 31:506–512, 2011. 77. Wakefield TW, et al: Venous thrombosis-associated inflammation and attenuation with neutralizing antibodies to cytokines and adhesion molecules. Arterioscler Thromb Vasc Biol 15:258–268, 1995. 78. Ripplinger CM, et al: Inflammation modulates murine venous thrombosis resolution in vivo: assessment by multimodal fluorescence molecular imaging. Arterioscler Thromb Vasc Biol 32:2616–2624, 2012. 79. Varma MR, et al: Neutropenia impairs venous thrombosis resolution in the rat. J Vasc Surg 38:1090–1098, 2003. 80. Fuchs TA, et al: Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 107:15880–15885, 2010.

81. Fuchs TA, et al: Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol 32:1777–1783, 2012. 82. Brill A, et al: Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 10:136–144, 2012. 83. Varma MR, et al: Neutropenia impairs venous thrombosis resolution in the rat. J Vasc Surg 38:1090–1098, 2003. 84. Henke PK, et al: Neutrophils modulate post-thrombotic vein wall remodeling but not thrombus neovascularization. Thromb Haemost 95:272–281, 2006. 85. Varma MR, et al: Deep vein thrombosis resolution is not accelerated with increased neovascularization. J Vasc Surg 40:536–542, 2004. 86. Hogaboam CM, et al: Novel roles for chemokines and fibroblasts in interstitial fibrosis. Kidney Int 54:2152–2159, 1998. 87. Humphries J, et al: Monocyte chemotactic protein-1 (MCP-1) accelerates the organization and resolution of venous thrombi. J Vasc Surg 30:894–899, 1999. 88. Henke PK, et al: Targeted deletion of CCR2 impairs deep vein thrombosis resolution in a mouse model. J Immunol 177:3388–3397, 2006. 89. Evans CE, et al: Upregulation of hypoxia-inducible factor 1 alpha in local vein wall is associated with enhanced venous thrombus resolution. Thromb Res 128:346–351, 2011. 90. Modarai B, et al: Adenovirus-mediated VEGF gene therapy enhances venous thrombus recanalization and resolution. Arterioscler Thromb Vasc Biol 28:1753–1759, 2008. 91. Lim CS, et al: Prolonged mechanical stretch is associated with upregulation of hypoxia-inducible factors and reduced contraction in rat inferior vena cava. J Vasc Surg 53:764–773, 2011. 92. Myers DD Jr, et al: Treatment with an oral small molecule inhibitor of P selectin (PSI-697) decreases vein wall injury in a rat stenosis model of venous thrombosis. J Vasc Surg 44:625–632, 2006. 93. Moaveni DK, et al: Vein wall re-endothelialization after deep vein thrombosis is improved with low-molecular-weight heparin. J Vasc Surg 47:616–624, 2008. 94. Stenberg B, et al: Effect of venous stasis on vessel wall fibrinolysis. Thromb Haemost 51:240–242, 1984. 95. Wojcik BM, et al: Interleukin-6: a potential target for post-thrombotic syndrome. Ann Vasc Surg 25:229–239, 2011. 96. Grainger DJ, et al: Release and activation of platelet latent TGFB in blood clots during dissolution with plasmin. Nature Med 1:932–937, 1995. 97. Diaz JA, et al: Impaired fibrinolytic system in APOE gene-deleted mice with hyperlipidemia augments deep vein thrombosis. J Vasc Surg 55:815–822, 2012. 97a.  Deatrick et al: JVS; In press. Deatrick KB, et al: The effect of matrix metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling. J Vasc Surg 2013 (in press), 98. Baldwin JF, et al: The role of urokinase plasminogen activator and plasmin activator inhibitor-1 on vein wall remodeling in experimental deep vein thrombosis. J Vasc Surg 56:1089–1097, 2012. 99. Deatrick KB, et al: Chronic venous insufficiency: current management of varicose vein disease. Am Surg 76:125–132, 2010. 100. Delis KT, et al: Venous claudication in iliofemoral thrombosis: longterm effects on venous hemodynamics, clinical status, and quality of life. Ann Surg 239:118–126, 2004. 101. Franzeck UK, et al: On the relationship between changes in the deep veins evaluated by duplex sonography and the postthrombotic syndrome 12 years after deep vein thrombosis. Thromb Haemost 77:1109– 1112, 1997. 102. Eklof B, et al: Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg 40:1248–1252, 2004. 103. Lalka SG, et al: Elevated cutaneous leukocyte concentration in a rodent model of acute venous hypertension. J Surg Res 74:59–63, 1998. 104. Pappas PJ, et al: Role of leukocyte activation in patients with venous stasis ulcers. J Surg Res 59:553–559, 1995. 105. Homans J: The etiology and treatment of varicose ulcer of the leg. Surg Gynecol Obstet 24:300–311, 1917.



175.e3

133. Cheatle TR, et al: The pathogenesis of skin damage in venous disease: a review. Eur J Vasc Surg 5:115–123, 1991. 134. O’Kane S, et al: Transforming growth factor beta S and wound healing. Int J Biochem Cell Biol 29:63–78, 1997. 135. Border WA, et al: Transforming growth factor beta in tissue fibrosis. N Engl J Med 331:1286–1292, 1994. 136. Pappas PJ, et al: Dermal tissue fibrosis in patients with chronic venous insufficiency is associated with increased transforming growth factorbeta1 gene expression and protein production. J Vasc Surg 30:1129– 1145, 1999. 137. Peschen M, et al: Increased expression of platelet-derived growth factor receptor alpha and beta and vascular endothelial growth factor in the skin of patients with chronic venous insufficiency. Arch Dermatol Res 290:291–297, 1998. 138. Nicolaides AN: Chronic venous disease and the leukocyte-endothelium interaction: from symptoms to ulceration. Angiology 56(Suppl 1):S11–S19, 2005. 139. Saharay M, et al: Endothelial activation in patients with chronic venous disease. Eur J Vasc Endovasc Surg 15:342–349, 1998. 140. Nicolaides AN: Investigation of chronic venous insufficiency: a consensus statement (France, March 5-9, 1997). Circulation 102:E126– E163, 2000. 141. Shields DA, et al: Plasma elastase in venous disease. Br J Surg 81:1496– 1499, 1994. 142. Scott HJ, et al: Histological study of white blood cells and their association with lipodermatosclerosis and venous ulceration. Br J Surg 78: 210–211, 1991. 143. Wilkinson LS, et al: Leukocytes: their role in the etiopathogenesis of skin damage in venous disease. J Vasc Surg 17:669–675, 1993. 144. Pappas PJ, et al: Morphometric assessment of the dermal microcirculation in patients with chronic venous insufficiency. J Vasc Surg 26: 784–795, 1997. 145. Clyne CA, et al: Oxygen tension on the skin of the gaiter area of limbs with venous disease. Br J Surg 72:644–647, 1985. 146. Raffetto JD, et al: Changes in cellular motility and cytoskeletal actin in fibroblasts from patients with chronic venous insufficiency and in neonatal fibroblasts in the presence of chronic wound fluid. J Vasc Surg 33:1233–1241, 2001. 147. Hasan A, et al: Dermal fibroblasts from venous ulcers are unresponsive to the action of transforming growth factor-beta1. J Dermatol Sci 16: 59–66, 1997. 148. Lal BK, et al: Altered proliferative responses of dermal fibroblasts to TGF-beta1 may contribute to chronic venous stasis ulcer. J Vasc Surg 37:1285–1293, 2003. 149. Stanley AC, et al: Reduced growth of dermal fibroblasts from chronic venous ulcers can be stimulated with growth factors. J Vasc Surg 26:994–999; discussion 999–1001, 1997. 150. Ackerman Z, et al: Overload of iron in the skin of patients with varicose ulcers: possible contributing role of iron accumulation in progression of the disease. Arch Dermatol 124:1376–1378, 1988. 151. Zamboni P, et al: Hemochromatosis C282Y gene mutation increases the risk of venous leg ulceration. J Vasc Surg 42:309–314, 2005. 152. Herrick SE, et al: Sequential changes in histologic pattern and extracellular matrix deposition during the healing of chronic venous ulcers. Am J Pathol 141:1085–1095, 1992. 153. Calligaro KD, et al: Venous aneurysms: surgical indications and review of the literature. Surgery 117:1–6, 1995. 154. Gillespie DL, et al: Presentation and management of venous aneurysms. J Vasc Surg 26:845–852, 1997. 155. Winchester D, et al: Popliteal venous aneurysms. Surgery 114:600–607, 1993. 156. Jorgensen JO, et al: The incidence of deep venous thrombosis in patients with superficial thrombophlebitis of the lower limbs. J Vasc Surg 18:70–73, 1993. 157. Woodhouse CR: Infusion thrombophlebitis: the histological and clinical features. Ann R Coll Surg Engl 62:364–368, 1980. 158. Luis Rodriguez-Peralto J, et al: Superficial thrombophlebitis. Semin Cutan Med Surg 26:71–76, 2007.

SECTION 2 PATHOPHYSIOLOGY

106. Blalock A: Oxygen content of blood in patients with varicose veins. Arch Surg 19:898–905, 1929. 107. Browse NL, et al: The cause of venous ulceration. Lancet 2:243–245, 1982. 108. Coleridge Smith PD, et al: Causes of venous ulceration: a new hypothesis. Br Med J (Clin Res Ed) 296:1726–1727, 1988. 109. Burnand KG, et al: The relationship between the number of capillaries in the skin of the venous ulcer-bearing area of the lower leg and the fall in foot vein pressure during exercise. Br J Surg 68:297–300, 1981. 110. Labropoulos N, et al: Where does venous reflux start? J Vasc Surg 26:736–742, 1997. 111. Sadick NS: Predisposing factors of varicose and telangiectatic leg veins. J Dermatol Surg Oncol 18:883–886, 1992. 112. Gundersen J, et al: Hereditary factors in venous insufficiency. Angiology 20:346–355, 1969. 113. Cornu-Thenard A, et al: Importance of the familial factor in varicose disease. Clinical study of 134 families. J Dermatol Surg Oncol 20:318– 326, 1994. 114. Badier-Commander C, et al: Smooth muscle cell modulation and cytokine overproduction in varicose veins: an in situ study. J Pathol 193: 398–407, 2001. 115. Niebes P: Vessel wall modification in venous pathology. Application to the study of phlebotonic drugs. Int Angiol 15:88–92, 1996. 116. Gandhi RH, et al: Analysis of the connective tissue matrix and proteolytic activity of primary varicose veins. J Vasc Surg 18:814–820, 1993. 117. Waksman Y, et al: Collagen subtype pattern in normal and varicose saphenous veins in humans. Isr J Med Sci 33:81–86, 1997. 118. Sansilvestri-Morel P, et al: Imbalance in the synthesis of collagen type I and collagen type III in smooth muscle cells derived from human varicose veins. J Vasc Res 38:560–568, 2001. 119. Sansilvestri-Morel P, et al: Abnormal deposition of extracellular matrix proteins by cultured smooth muscle cells from human varicose veins. J Vasc Res 35:115–123, 1998. 120. Porto LC, et al: Immunolabeling of type IV collagen, laminin, and alpha-smooth muscle actin cells in the intima of normal and varicose saphenous veins. Angiology 49:391–398, 1998. 121. Sansilvestri-Morel P, et al: Synthesis of collagen is dysregulated in cultured fibroblasts derived from skin of subjects with varicose veins as it is in venous smooth muscle cells. Circulation 106:479–483, 2002. 122. Somers P, et al: The histopathology of varicose vein disease. Angiology 57:546–555, 2006. 123. Shireman PK, et al: Plasminogen activator levels are influenced by location and varicosity in greater saphenous vein. J Vasc Surg 24:719– 724, 1996. 124. Parra JR, et al: Tissue inhibitor of metalloproteinase-1 is increased in the saphenofemoral junction of patients with varices in the leg. J Vasc Surg 28:669–675, 1998. 125. Badier-Commander C, et al: Increased TIMP/MMP ratio in varicose veins: a possible explanation for extracellular matrix accumulation. J Pathol 192:105–112, 2000. 126. Woodside KJ, et al: Morphologic characteristics of varicose veins: possible role of metalloproteinases. J Vasc Surg 38:162–169, 2003. 127. Kosugi I, et al: Matrix metalloproteinase-9 and urokinase-type plasminogen activator in varicose veins. Ann Vasc Surg 17:234–238, 2003. 128. Rizzi A, et al: Effects of vasoactive agents in healthy and diseased human saphenous veins. J Vasc Surg 28:855–861, 1998. 129. Raffetto JD, et al: Functional adaptation of venous smooth muscle response to vasoconstriction in proximal, distal, and varix segments of varicose veins. J Vasc Surg 51:962–971, 2010. 130. Barber DA, et al: Characterization of endothelin receptors in human varicose veins. J Vasc Surg 26:61–69, 1997. 131. Nemcova S, et al: Cyclic nucleotides and production of prostanoids in human varicose veins. J Vasc Surg 30:876–883, 1999. 132. Raffetto JD, et al: Matrix metalloproteinase 2-induced venous dilation via hyperpolarization and activation of K+ channels: relevance to varicose vein formation. J Vasc Surg 45:373–380, 2007.

CHAPTER 12  Venous Pathology

175.e4 SECTION 2  Pathophysiology 159. Decousus H, et al: Fondaparinux for the treatment of superficial-vein thrombosis in the legs. N Engl J Med 363:1222–1232, 2010. 160. Tapper H, et al: Modulation of hemostatic mechanisms in bacterial infectious diseases. Blood 96:2329–2337, 2000. 161. Shebuski RJ, et al: Role of inflammatory mediators in thrombogenesis. J Pharmacol Exp Ther 300:729–735, 2002. 162. Ageno W, et al: Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 117:93–102, 2008. 163. Prandoni P, et al: Venous thromboembolism and the risk of subsequent symptomatic atherosclerosis. J Thromb Haemost 4:1891–1896, 2006.

164. Becattini C, et al: Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 366:1959–1967, 2012. 165. Brighton TA, et al: Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 367:1979–1987, 2012. 166. Ray JG, et al: Use of statins and the subsequent development of deep vein thrombosis. Arch Intern Med 161:1405–1410, 2001. 167. Glynn RJ, et al: A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 360:1851–1861, 2009. 168. Diaz J: Unpublished data, 2011.

CHAPTER 13 

Lymphatic Pathophysiology MARLYS H. WITTE  /  MICHAEL J. BERNAS

Dedicated to the memory of Charles L. Witte, MD (1935-2003), beloved husband and father, and great teacher, researcher, and clinician. He was the primary author of the previous version of this chapter and an internationally recognized authority in the field of lymphology.

In a narrow sense, the lymph circulation is a unidirectional

vascular system that merely transports surplus tissue fluid back to the bloodstream. In a broader sense, however, this network stabilizes the mobile intercellular liquid and extracellular matrix microenvironment to ensure parenchymal cellular integrity and function. In its entirety, the lymphatic system is composed of vascular conduits: lymphoid organs, including the lymph nodes, spleen, Peyer’s patches, thymus, and nasopharyngeal tonsils; and cellular elements that circulate in the liquid lymph, such as lymphocytes and macrophages. These migrating cells cross the blood-capillary barrier along with a multitude of immunoglobulins, polypeptides, plasma protein complexes, and cytokines and enter the lymphatics to return to the bloodstream. Although body water circulates very rapidly as a plasma suspension of red blood cells within the blood vascular compartment, it percolates slowly outside the bloodstream as a tissue fluid-lymph suspension of lymphocytes through lymph vessels and lymph nodes. As a specialized subcompartment of the extracellular space, therefore, the lymphatic system completes a closed loop for the circulation by returning liquid, macromolecules, and other blood elements that “escape” or “leak” from blood capillaries (Fig. 13-1). Disruption of this blood-lymph loop promotes tissue swelling and is also responsible for a variety of syndromes characterized by scarring, wasting, immunodeficiency, and disordered angiogenesis. Rational therapeutic approaches, now and in the future, should be based on current and expanded understanding of these fundamental pathophysiologic principles.

ANATOMY Although, historically, identification of lymphatic vessels has long been hampered by the lack of readily identifiable structures, early physicians from Hippocrates (460-377 BC) to Aristotle (384-322 BC) and Erasistratus (310-250 BC) did describe vessels and nodes and on occasion noted visible intestinal lymphatic vessels in recently fed animals (see 176

Kanter1 for more details). After a period of little scientific advancement, the discovery of chylous mesenteric lacteals in a well-fed dog by Gasparo Asellius early in the 17th century set off a flurry of anatomic dissections in England and continental Europe that established the nearly ubiquitous presence of lymphatics throughout the body and their important role in the absorption of nutrients (Box 13-1).2 These lymphatic “absorbents” accompany venous trunks everywhere, except in the central nervous system and the cortical bony skeleton.

Macroscopic Anatomy In general, lymph from the lower part of the torso and viscera enters the bloodstream via the thoracic duct at the left subclavian-jugular venous junction (see Figs. 13-1 and 13-2). Lymphatics from the head and neck and from the upper extremities enter the central veins either independently or by a common supraclavicular cistern. Numerous interconnections exist within this rich vascular network, and subvariant anatomic pathways are plentiful. For example, the bulk of cardiac and pulmonary lymph, as well as intraperitoneal fluid, which drains through fenestrae of the diaphragm into substernal mediastinal collectors, unite as a common trunk to empty into the great veins in the right side of the neck. In contrast, intestinal lymph, which transports cholesterol, fatsoluble vitamins (vitamins A, D, K, and E), and long-chain triglycerides as chylomicra, courses retroperitoneally to the aortic hiatus, to form with other visceral and retroperitoneal lymphatics, the multichannel cisterna chyli and the thoracic duct, unlike intestinal blood, which flows directly into the liver. The bulk of the lymph formed in the liver flows retrograde or countercurrent to portal blood flow and joins intestinal lymph collectors just before the origin of the thoracic duct. Only a small amount of hepatic lymph drains anterograde along the major hepatic veins to the anterior mediastinum and right lymph duct. Although these topographic variants influence the development and progression of peripheral (lymph)edema only indirectly, they are nonetheless essential for a broad understanding of edema syndromes,

CHAPTER 13  Lymphatic Pathophysiology



P

Angiogenic syndromes (↑ angiostaticinhibitory agents)

including those accompanied by visceral lymphatic abnormalities, celomic effusions, and chylous reflux. Although the retina and brain do not technically have lymphatic apparatuses, they possess analogous circulations, such as the aqueous humor canal of Schlemm (the anterior chamber of the eye) or the cerebrospinal fluid/subarachnoid villus (pacchionian bodies) connections (the brain). Glial elements and non–endothelial-lined intracerebral BOX 13-1 

LANDMARKS IN LYMPHOLOGY 1. Discovery of chyliferous vessels and “imaging” of the lymphatic system—Gaspar Asellius, 1627 2. Lymph as the milieu intérieur (internal environment)—Claude Bernard, 1878 3. Transcapillary exchange of liquid, lymph formation, and edema—Ernest Starling, 1895 4. Embryology and phylogeny of lymphatic system—F. Sabin, O. Kampmeier, 1903 5. Transcapillary protein movement and lymph absorption—A. Krogh, C. Drinker, H, Mayerson, F. C. Courtice, 1925 6. Lymphangiogenesis in vivo, 1932, and in vitro, 1984 7. Lymphocyte migrant streams—J. Yoffey, B. Morris, J. Gowans, 1939 8. Lymphatic imaging/classification—J. Kinmonth, M. Servelle, F. Kaindl, 1950 9. Intrinsic contractility and distinctive ultrastructure of lymphatics—J. Hall, I. Roddie, J. Casley-Smith, L. Leak, 1962 10. Lymphostatic disorders and/or edematous states—I. Rusznyak, G. Szabo, M. E. Foldi, W. Olszewski, A. Dumont, M. C. Witte, 1960 11. Lymphoscintigraphy, including sentinel node mapping, 1970 12. Highly specific molecular and/or histochemical markers—LYVE-1, Prox-1, podoplanin, 5′-nucleotidase, VEGFR-3, 1990 13. Lymphatic growth factors and/or genetics—K. Alitalo, 1996; teams from the University of Pittsburgh and University of Connecticut/St George; University of Arizona and University of Michigan, 1998, 2000 VEGFR, Vascular endothelial growth factor receptor.

Interstitium

H2O

P

Node Edema

Blood capillary

Scarring diseases (↑ lymph absorption, mobilize scar)

(↓ lymph formation or ↑ absorption)

Lymphatic

P

Immunodeficiency (↓ lymph losses or immunorestoration) Nutritional depletion (↓ or replace lymph losses)

perivascular (Virchow-Robin) spaces probably also serve to transport interstitial fluid to nearby intracranial venous sinuses. Extensive interruption of the cervical lymphatic trunks (e.g., after bilateral radical neck dissection) therefore causes prominent facial suffusion and a transient neurologic syndrome resembling pseudotumor cerebri,3 whereas an infusion of crystalloid solution directly into the canine cisterna magna causes an elevation in intracranial pressure and increases lymph flow from draining neck lymphatics.4,5 Although abundant lymphatic pathways thus exist for surplus tissue fluid to return to the bloodstream, homeostasis of the internal environment nonetheless still depends on an unimpeded, intact, interstitial-lymph fluid circulatory system (see Figs. 13-1 and 13-2).

Embryonic Development Controversy has persisted since the early 1900s about the embryologic origin of lymphatics, that is, lymphovascu­ logenesis (endothelial precursors or stem cells, such as lymphangioblasts, differentiate and proliferate into a primitive tubular network) and subsequent lymphangiogenesis (sprouting from existing vessels) (Box 13-1).6 According to Sabin, lymphatics and veins derive from a common primordium in the venous system (Fig. 13-3).7 After injection of dye into pig skin, gradually extending lymphatic plexuses were observed, starting first at the base of the neck, which were in direct communication with the venous system. Sabin concluded that the primary lymphatic plexuses derive from central veins and that their growth progresses centrifugally by sprouting toward the periphery and ultimately forming the superficial lymphatic system. In contrast, Kampmeier,8 after a review of serial tissue sections, including Sabin’s original human embryo preparations, and phylogenetic considerations, proposed the centripetal theory that the lymphatic system arises independently from tissue mesenchyme in peripheral tissues and the surrounding primary lymph sacs and only later joins the central venous system to complete

SECTION 2 PATHOPHYSIOLOGY

Figure 13-1  Blood-lymph circulatory loop. Within the bloodstream, liquid flows rapidly as a plasma suspension of erythrocytes; outside the bloodstream, it flows slowly as a tissue fluidlymph suspension of immunocytes through the lymphatics and lymph nodes. Small and large molecules, including plasma protein, trafficking cells, particulates, and respiratory gases, cross the blood-capillary endothelial barrier, percolate through the tissues, enter the lymph stream, and return to the central venous system to complete the loop. Clinical disorders of the blood-lymph circulatory loop are manifested as swelling, scarring, immunodeficiency, nutritional depletion, and uncontrolled lymphangiogenesis and angiotumorigenesis. Current and potential future therapeutic approaches are in parentheses.

P

177

178

SECTION 2  Pathophysiology 4 5

22

7

1 6

8

3

2 10 13 12 9 11

Superficial lymphatics Jugular lymph sac Subclavian lymph sac Lymph node Deep lymphatics Thoracic duct

16

Retroperitoneal lymph sac 15b

14 15a

17 19

Cisterna chyli Posterior lymph sac

18

20 21

Figure 13-2  Macroscopic anatomy of the lymphatic system including major vessels, structures and nodes in relation to major arteries and veins. 1: left internal jugular vein; 2: left subclavian vein; 3: thoracic duct; 4: parotid lymph nodes; 5: submandibular lymph nodes; 6: accessory and comitant lymph nodes of the accessory nerve; 7: internal jugular lymph nodes with left jugular trunk; 8: supraclavicular lymph nodes with left supraclavicular trunk; 9: axillary lymph nodes with left subclavian trunk; 10: intercostal lymph nodes with left intercostals trunk; 11: parasternal lymph nodes with parasternal trunk; 12: anterior mediastinal lymph nodes with left anterior mediastinal trunk; 13: tracheobronchial lymph nodes with left tracheobronchial trunk; 14: cisterna chyli; 15a: left lumbar trunk; 15b: right lumbar trunk; 16: mesenteric lymph nodes; 17: lumbar lymph nodes; 18: left common iliac lymph nodes; 19: right external iliac lymph nodes; 20: internal iliac; 21: inguinal lymph nodes; 22: right lymphatic duct. (Modified from Kubik S: In Földi M, Földi E, editors: Foldi’s textbook of lymphology, ed 3, Munich, 2012, Urban & Fischer.)

the blood-lymph loop. Kampmeier reasoned further that as the developing blood capillaries begin to “leak clear fluid into tissues, lymph amasses in ever growing volume within the mesenchyme first collecting in separate pools or spaces, which then become confluent as the high pressure stream seeks an outlet…the current usurps the course of decadent and vanishing venules, expands and pours into the developing jugular lymph sac, which meanwhile has acquired continuity with the forming arch of the cardinal lymphatic. Thoracic and abdominal lymphatics form similarly: Discontinuous spaces spring up in the mesenchyme next to the intercardinal or periaortic venous plexus in the path of the potential lymphatic; and primordia quickly widen, lengthen and fuse into a continuous vessel.”8

Lymph node Superficial lymphatics

Figure 13-3  The developing lymphatic system showing the primary lymph sacs and the thoracic duct primordium, as well as several lymph nodes of a 2-month-old human embryo. (Modified from Sabin FR: On the origin and development of the lymphatic system from the veins and the development of the lymph hearts and the thoracic duct in the pig. Am J Anat 1:367, 1902; and Yoffey JM, et al: Lymphatics, lymph and the lymphomyeloid complex, New York, 1970, Academic Press.)

Although recent studies of the growth regulatory gene PROX19 and the receptor for lymphatic vascular endothelial growth factor (VEGFR-3)10 have tended to support the centrifugal theory (origin from venous spouting), other elegant work has demonstrated a substantial centripetal contribution from mesenchymal lymphangioblasts in the engrafted wing lymphatic system of chimeric quail chick embryos11 and early avian embryos through PROX1 staining.12 Both processes may contribute in various degrees to the ultimate link between the lymph and blood vasculature (e.g., the cervical thoracic duct/venous junction in humans). In addition, similar processes of lymphovasculogenesis and lymphangiogenesis are recapitulated after birth and probably involve the same complex expanding cascade of vascular growth factors (particularly the VEGF and angiopoietin families), endothelial receptors, and transcription factors already implicated in lymphatic growth and lymphedema-angiodysplasia syndromes (Table 13-1) (see the section on Lymphangiogenesis).

Light Microscopic Anatomy As an afferent vascular system, the lymphatics originate within the interstitium as specialized capillaries, although in certain organs, such as the liver, they seem to emanate from nonendothelialized precapillary channels (e.g., the spaces of

179

CHAPTER 13  Lymphatic Pathophysiology



Table 13-1

Vascular Growth Factors, Receptors, and Transcription Factors in Blood Vascular and Lymphatic Development VASCULAR GROWTH FACTOR LIGANDS

Receptors VEGFR-1/Flt-1

PIGF

VEGF-A

VEGF-B

+

+

+

Neuropilin-2

+ +

+

VEGF-E

+

VEGFR-3/Flt-4* Neuropilin-1

VEGF-D*

Ang-1*

Ang-2*

+

+

Ephrin B2

+ +

+

+

+

Tie-1 Tie-2*

+

EphB4 Transcription factors: Prox1*, FOXC2*, Net*, SOX18*. *Implicated specifically in lymphatic development.

Disse).13 Lymphatic capillaries are remarkably porous and readily permit the entry of even large macromolecules (molecular weight >1000 kD). In this respect, they resemble the uniquely “leaky” fenestrated sinusoidal blood capillaries of the liver, but are in distinct contrast to most other blood capillaries, which are relatively impervious to macromolecules even the size of albumin (molecular weight, 69 kD).14 Under light microscopy without pre–paraffin-embedded tracer or intravascular latex injection, it is difficult to distinguish between blood and lymph vessels, although the latter are usually thin walled and tortuous, have a wider, more irregular lumen, and are largely devoid of red blood cells. Many staining features have been advocated to differentiate between blood and lymph microvasculature, such as the endothelial marker factor VIII–related antigen : von Willebrand factor (vWF). Although staining characteristics vary in both normal and pathologic states and at different sites (perhaps related to endothelial cell de-differentiation), in general, lymphatic staining resembles but is less intense than its blood vessel counterpart. In other words, the staining differences have been more quantitative than qualitative.15-17 Most recently, several new markers have been proposed that appear to be more lymphatic specific, particularly antibodies to lymphatic endothelial hyaluronan receptor-1 (LYVE-1; a homologue of CD44 glycoprotein),18 podoplanin,19 PROX1,9 and to a lesser degree, VEGFR-3 (the endothelial receptor for VEGF-C, the so-called lymphatic growth factor),20,21 as well as 5′-nucleotidase (see under the next section, LymphaticSpecific Markers).22

Lymphatic-Specific Markers Lymphatic vessels can increasingly be distinguished from blood vessels in tissue sections by whole-mount staining with specific markers. Only 10 years ago, little histochemical specificity existed to distinguish lymphatic vessels from blood capillaries and veins, and identification was based primarily on

morphology, distinctive ultrastructure, or both. One of the most commonly used and most specific markers in use today is LYVE-1.19,23 It has been applied to tissues ranging from early mouse embryo to adult human and highlights collecting vessels and lymphatic capillaries (but not larger caliber vessels). Another strong marker localizing to the nucleus of lymphatic endothelial cells and adaptable to multiple tissues is the transcription factor PROX1.23 Podoplanin recognizes a transmembrane glycoprotein24 in lymphatics, but not blood vessel endothelial cells in the mouse, whereas its human analogue, D2-40,25 also sharply distinguishes lymphatic from blood vessel endothelium, but stains other distinguishable cells. This feature has been particularly useful in identifying preexisting and new lymphatics in tumor specimens and in generating quantitative differentials from blood vessels and indices of lymphatic invasiveness and tumor dissemination.26 5′-Nucleotidase staining is used by some research laboratories for its lymphatic specificity,22,27 and other common markers that show some cross reactivity to veins include VEGFR-310 and neuropilin-228 (reviewed elsewhere29,30). Thus, an array of lymphatic markers are now available to distinguish lymphatic from blood vessels, although there is some overlap of cell types in normal conditions and even more so in pathologic states.

Ultrastructure Ultrastructurally, lymph capillaries display both “open” and “closed (tight)” endothelial junctions, often with prominent convolutions.31 Depending on the extent of tissue “activity,” these capillaries can dramatically adjust their shape and lumen size. Unlike blood capillaries, a basal lamina (basement membrane) is tenuous or lacking altogether in lymph capillaries.31,32 Moreover, complex elastic fibrils, termed anchoring filaments, tether the outer portions of the endothelium to a fibrous gel matrix in the interstitium.33-35 These filaments allow the lymph microvessels to open wide, which

SECTION 2 PATHOPHYSIOLOGY

+

VEGFR-2/Flk-1*

VEGF-C*

180

SECTION 2  Pathophysiology

a Lumen

b

Anchoring filaments Collagen fibrils

Basal lamina

c Fibroblast

A

B

C

Figure 13-4  A, Lymphatic capillary reconstructed from collated electron micrographs. The lymphatic anchoring filaments originate from the abluminal surface of the endothelial cells and extend into adjacent collagen bundles, thereby forming a firm connection between the lymphatic capillary wall and the surrounding interstitium. B, Transmission electron micrograph demonstrating anchoring filaments (AF) that derive from the lymphatic endothelium (LE) and join nearby collagen bundles (CB). C, Response of lymphatic capillaries to an increase in interstitial fluid volume. As the tissue matrix expands, tension on the AF rises, and the lymph capillaries open widely to allow more rapid entry of liquid and solute (a to c). In contrast to stretching of the lymph capillaries, a rise in matrix pressure collapses the blood capillaries, thereby restricting further plasma filtration. (From Leak LV, et al: Ultrastructural studies on the lymphatic anchoring filaments. J Cell Biol 30:129-149, 1968; and Leak LV: Electron microscopic observation on lymphatic capillaries and the structural components of the connective tissue–lymph interface. Microvasc Res 2: 361-391, 1970.)

causes a sudden increase in tissue fluid load and pressure, in contrast to the simultaneous collapse of adjacent blood capillaries (Fig. 13-4). Just beyond the lymph capillaries are the terminal lymphatics. In contrast to more proximal and larger lymph collectors and trunks, the terminal lymphatics are devoid of smooth muscle, although the endothelial lining is rich in the contractile protein actin.15 Intraluminal bicuspid valves are also prominent features and serve to partition the lymphatic vessels into discrete contractile segments termed lymphangions.36 These specialized microscopic features of the lymphatic network support this delicate apparatus’ function of absorbing and transporting lymph node elements and the large protein moieties, cells, and foreign agents of the bloodstream (e.g., viruses, bacteria) that gain access to the interstitial space (Figs. 13-5 and 13-6).

Structural-Functional Imaging Early physicians were able to visualize the lymphatic system only by observing chyle-filled mesenteric lymphatics. Asellius’ initial publication37 included what has been reported as the first color anatomic plate in history (Fig. 13-7).1 This was followed by intralymphatic injection of mercury into cadavers by Nuck in 1692, which depicted fine channels,38 then the detailed and elegant work of Mascagni in 1787,39 and

subsequently, the classic images of both subcutaneous and deep vessels by Sappey in 1874.40 von Recklinghausen used silver nitrate, which allowed imaging to take place without removal of surrounding tissue and facilitated visualization of lymphatic vessels as distinct from blood capillaries.41 Gerota developed a technique in 1896 of injecting a mixture of Prussian blue and turpentine to highlight the vessels,42 and this was followed in 1933 by the intracutaneous injection of vital dyes that bind to tissue proteins by Hudack and McMaster,43 which is a technique still used today for investigation and in the clinic (Fig. 13-8). Modern imaging techniques also include direct (intralymphatic) injection of oily contrast agents, termed lymphangiography, as first described by Kinmonth in 1954,44 and whole-body lymphangioscintigraphy after subcutaneous or intradermal injection of protein-bound radiotracers (see Witte et al45 for an overview) (see Fig 13-8). Other agents used for indirect lymphography include a variety of fluorescent or magnetic particles,46,47 infrared particles and dyes,48-50 immunoglobulin conjugates,51 and microbubbles52 for detection with fluorescent microscopes, optical imaging systems, computed tomography (CT), magnetic resonance imaging (MRI) (with and without contrast),53 and ultrasound,54,55 with an expanding potential for highly specific molecular imaging. New contrast agents and techniques are continuing to be developed.56-58

CHAPTER 13  Lymphatic Pathophysiology

Lymph capillary network

E SP D

S

F

M

MS V MS

V

5 Lymphangion

RS Lymphatic node

SF

BK

CA SF

Figure 13-5  The lymphatic system consists of an initial superficial valveless network of endothelium-lined vessels connected to a deep valved collector system (lymphangion pumping segments defined by the valves). The deeper vessels run alongside major blood vessels and drain through lymph nodes to the main collectors; they ultimately empty into the thoracic duct or the right lymphatic duct. BK, Blood capillary network; C, cutis; CA, capsule; D, dermis; E, epidermis; F, fascia; M, musculature; MS, muscle layer; RS, marginal sinus; S, subcutis; SF, second follicle; SP, subcutaneous pseudofascia; V, lymphatic valves. (Modified with permission from BSN-Jobst Emmerich Conception, 2002.)

PHYSIOLOGY Any proteid which leaves these vessels…is lost for the time to the vascular system…it must be collected by lymphatics and restored to the vascular system by way of the thoracic or right lymphatic duct. PHYSIOLOGIST ERNEST STARLING, 1897

General Principles As a fine adjuster of the tissue microenvironment, the lymphatic system is often neglected in most treatises on vascular diseases. Yet this delicate system, so inconspicuous during life and collapsed after death, helps maintain the liquid, protein, and osmotic equilibrium around cells and aids in absorption and distribution of nutrients, disposal of wastes, and exchange of oxygen and carbon dioxide in the local milieu intérieur.

Interstitial (Lymph) Fluid Two thirds of the body is composed of water, and most of this liquid volume is contained within cells. It is the remainder that exists outside cells, however, that continuously

circulates. In a series of epochal experiments conducted more than a century ago, the English physiologist Ernest Starling outlined the pivotal factors that regulate partitioning of the extracellular fluid.59,60 In brief, the distribution of fluid between the blood vascular compartment and tissues and the net flux of plasma escaping from the bloodstream depends primarily on the transcapillary balance of hydrostatic and protein osmotic pressure gradients as modified by the character (i.e., hydraulic conductance) of the filtering microvascular surface (Fig. 13-9; also see Box 13-1). Normally, a small excess of tissue fluid forms continuously (net capillary filtration), and this surplus enters the lymphatic system and returns to the venous system. In contrast to blood, which flows in a circular pattern at several liters per minute, lymph flows entirely in one direction and at rest at a rate of only 1.5 to 2.5 L/24 hr. This limited volume derives from a slight hydrodynamic imbalance that favors movement of fluid, salt, and macromolecules from plasma into tissue spaces. Although blood capillary beds vary in hydraulic conductance, in general, disturbances in the transcapillary hydrostatic and protein osmotic pressure gradients (Starling forces) tend to promote edema that is low in protein content (1.5 g/dL [15 g/L]). Unlike blood flow, which is propelled by a powerful and highly specialized muscular pump (the heart), propulsion of lymph originates predominantly from spontaneous intrinsic segmental contractions of larger and probably also small lymph trunks (Fig. 13-10),61-63 and to a lesser extent, from extrinsic “haphazard forces” such as breathing, sighing, yawning, muscular squeezing (e.g., alimentary peristalsis), and transmitted arterial pulsations (Table 13-2).63,64 As noted, the contractions of lymphatic segments between intraluminal valves (i.e., the lymphangions) are highly responsive to lymph volume. Thus, an increase in lymph formation is accompanied by more frequent and more powerful lymphangion contractions (Fig. 13-11), a lymphodynamic response that resembles Starling’s other major physiologic principle, the law of the heart.36,65 Lymphatic truncal contraction, like venous and arterial vasomotion, is mediated by sympathomimetic agents (both α- and β-adrenergic agonists),66,67 by-products of arachidonic acid metabolism (thromboxanes and prostaglandins),68-71 and neurogenic, even pacemaker stimuli (Fig. 13-12).72,73 Oddly, in different regions of the body, lymphatic trunks seem to exhibit varying sensitivity to different vasoactive and neurogenic stimulants.67,74,75 Although the importance of truncal vasomotion as mediated by tunica smooth muscle is well established, it remains unclear whether terminal lymphatics or lymphatic capillaries are also capable of vasomotion or are simply passive channels. In some ways, this controversy parallels the prolonged dispute about whether blood capillary endothelial cells are capable of vasoactivity, an issue now clearly resolved in the affirmative. Because lymphatic endothelium, like blood endothelium, is rich in actin15 (a principal contractile protein), it is reasonable to assume that lymphatic microvessels also exhibit vasomotion.

SECTION 2 PATHOPHYSIOLOGY

C

181

182

SECTION 2  Pathophysiology Lymph

Tissue

Blood

RBC

Cytotoxicity

Edema, fibrosis fat

Endothelium

Fenestrae Parenchyma

Adhesion Inflammation

Lymphoid cell Fibroblast trafficking Adipocyte

Endothelium

RES

Lymph node +Ab

BM PMN ECM

Permeability Migration PMN

Coagulation cascade Platelet

Macro

Activation Lymphatic

Phagocytosis Proliferation, angiogenesis, vasculogenesis, tumor

Blood

Cytokine/chemokine signaling Vascular tone-flow

Figure 13-6  The postulated role of endothelial processes in microcirculatory events that have a bearing on angiogenesis in the blood-lymph loop. Such processes include macromolecular and liquid permeability, vasoreponsiveness, leukocyte adhesion and transmigration, coagulation cascading, particulate phagocytosis, antigen presentation and cytokine activation, lymphoid cell trafficking, and proliferative events leading to new vessel or tumor growth. Many mediators of these events have been identified by studying processes implicated at the blood vascular endothelial surface, which are likely to also occur at the lymphatic endothelial interface. The relative anatomic and dynamic relationships between blood and lymph vascular endothelium, parenchymal and extravascular connective tissue, and transmigrating leukocytes are shown. Black circle, exogenous particulates; black square, macromolecules; open circles, fluid (plasma, interstitial, or lymph). Ab, Antibody; BM, basement membrane; ECM, extracellular matrix; macro, macrophage; PMN, polymorphonuclear neutrophil; RBC, red blood cell; RES, reticuloendothelial system. (Modified from Witte MH, et al: Overlapping biomarkers, pathways, processes and syndromes in lymphatic development, growth, and neoplasa. Clin Exp Metastasis 29:707-727, 2012.) A H

Lymph Nodes

H A

In addition to their central immunologic role, lymph nodes are a potential site of impediment to the free flow of lymph. Unlike frogs, which lack lymph nodes but possess four or more strategically placed lymph hearts that propel large quantities of peripheral lymph back to the bloodstream,76,77 mammals possess immunoreactive lymph nodes, which when swollen, fibrotic, or atrophic, may act to initiate or perpetuate lymph stasis.78,79 Perhaps the intrinsic contraction of mammalian lymphatic trunks represents a phylogenetic vestige of amphibian lymph hearts (see the following section on FlowPressure Dynamics for more details).

B

B

K

H

C A

G B

A

C C A

B A B

B

A

L

C

B

H

C

B

B

Flow-Pressure Dynamics

A

H A

B

B G

T

I

Figure 13-7  Historical reproduction of Figure 1 from Gaspar Asellius (Gasparis Asellii) demonstrating chyle-filled lymphatic vessels of the mesentery. It is reported that this represents the first color anatomic figure ever published.1 (From a 1972 reproduction by Episteme Editrice, Milano, of the original text from Asellius G: De Lactibus sive Lacteis Venis Quarto Vasorum Mesaraicorum Genere Novo Inuento, Mediolani, 1627, JB Biddellium.)

Although lymphatic vessels, like veins, are thin-walled flexible conduits that return liquid to the heart, the flow-pressure relationships in the venous system and the lymphatic system are different. The energy to drive blood in the venous system derives primarily from the thrust of the heart. The cardiac propulsive boost maintains a pressure head through the arteries and blood capillaries into the veins. There is extensive neural regulation of venous tone that is essential for many activities, postural changes, and the negative pressure in the chest during inspiration. In addition, external compressive forces such as muscle can substantially alter venous pressure and gradients. Thus, muscular contractions such as walking

CHAPTER 13  Lymphatic Pathophysiology



SECTION 2 PATHOPHYSIOLOGY

Figure 13-8  Imaging techniques to delineate the structure and function of the lymphatic system. A, Evans blue dye injected intradermally in the tip of a mouse ear rapidly displays the draining lymphatic channels. A similar vital dye (lymphazurin blue or isosulfan blue) is used in the clinic. B, Classic lymphography image from Kinmonth clearly depicting the fine lymphatic vessels of the upper part of the thigh in an adult human.44 C, Radioisotope lymphangioscintigraphy displaying normal lymphatic tracer transport in the arms (upper panel) and the legs (lower panel). A single injection into each hand or foot is seen at the bottom of each image, with markers at the knees in the lower panel. (Modified from Witte CL, et al: Advances in imaging of lymph flow disorders. Radiographics 20:1697-1719, 2000.)

183

A

B

and running, in the presence of competent venous valves, supplement cardiac action in facilitating return of blood to the heart. In contrast, lymph vessels in tissues are not directly contiguous with the blood vasculature, and the chief source of energy for propulsion of lymph emanates from the intrinsic lymphatic truncal wall contractions (propulsor lymphaticum).61-77,80 Like amphibian lymph hearts (cor lymphaticum), mammalian lymphatic smooth muscle beats rhythmically, and in the presence of a well-developed intraluminal valve

C

system, facilitates transport of lymph.81 In a sense, the lymphatic structures function as micropumps that respond to fluid challenges with increases in both rate and stroke volume.36,68 Ordinarily, resistance to flow in the lymphatic vessels is relatively high in comparison to the low resistance in the venous system,82 but the pumping capacity of the lymphatics is able to overcome this impedance by generating intraluminal pressures of 30 to 50  mm  Hg (see Fig. 13-11) and sometimes even equaling or exceeding arterial pressure.61,82,83 This formidable lymphatic ejection force is Normal

Tissue Pc KF σ ηp Blood High-output failure

Blood

πt Lymph

Lymph formation = lymph absorption (KF [(Pc-Pt)-σ(πp -πt)] = QL

Low-output failure

Tissue

Tissue

Pc Pt KF σ πp

QL

Pc

(QL↑) πt

Blood Edema Lymph

Lymph formation↑↑ > Lymph absorption↑ (↑QL) (↑Pc, ↓Pt, ↓πp, ↑πt, ↑KF, ↓σ)

Pt KF σ πp πt

QL↓ Lymph Lymphedema

Lymph formation > Lymph absorption↓ (↓QL)

Figure 13-9  Primary forces regulating fluid flux into the interstitium and the importance of lymph flow in maintaining steady-state interstitial fluid volume, and hence, stable partitioning of extracellular fluid between the bloodstream and the interstitium (Starling’s equilibrium). Edema may occur as a result of high-output failure of lymph circulation (lymph overload with increased lymph flow) (lower left) or, less commonly, low-output failure (lymphedema) caused by interruption in lymph transport capacity (lower right).

SECTION 2  Pathophysiology

10

4

8

3

6

2

4

1

2

0

0

Figure 13-10  Lateral pressure (blue curve) and cumulative lymph flow (red curve) in a subcutaneous leg lymphatic of a healthy man lying supine during movement of the foot and at rest. Note that lymph flow occurs only during rhythmic contraction of the lymphatic collector and specifically not by voluntary contraction of calf muscles. (Redrawn from Olszewski WL, et al: Intrinsic contractility of prenodal lymph vessels and lymph flow in the human leg. Am J Physiol 239:H775-H783, 1980.)

modulated not only by filling pressure but also by temperature, sympathomimetics, neurogenic stimuli, circulating hormones, and locally released paracrine and autocrine cytokine secretions.84 It is often mistakenly thought that lymph return, like venous return, is directly enhanced by truncal compression

Primary propulsive unit Secondary propulsive force Distal (upright) pressure (mm Hg) Central pressure (mm Hg) Flow rate Vascular resistance Intraluminal valves Impediment to flow Conduit fluid column Conduit failure

Circulatory Dynamics of Vascular Conduits Lymphatic

Vein

Artery

Lymphangion

Heart

Heart

Haphazard*

Skeletal muscle

Vasomotion

2-3

90-100

20

6-10

0-2

100

Very low Relatively high

High Very low

High High

Innumerable

Several

None

Lymph nodes

None

None

Incomplete

Complete

Complete

Edema (>1.5 g/dL) with brawny induration and acanthosis

Edema (90%), it was not very sensitive (50%) causes at least a doubling of the peak systolic velocity. D, Beyond a significant narrowing, post-stenotic turbulence causes marked widening of the waveform. Fd, Frequency shift; SV, sample volume; T, time. (Courtesy Jean Primozich.)

similar methods to provide a full picture of the entire spectrum of frequencies present in each sampling interval. Frequency shifts are displayed on the vertical axis, and time is displayed on the horizontal axis. The amplitude of the reflected signal at each frequency is represented by a gray scale (see Fig. 15-2). The intensity of the gray scale is proportional to the number of red blood cells traveling at a particular velocity at each point in time. These devices, which are used in all duplex scanners, permit identification of features, such as uniformity of flow (narrow band of velocities) or nonuniformity (widening of the velocity waveform, known as spectral broadening). When the angle of insonation is known, the output can be displayed as velocity over time and various parameters can be measured, such as peak and end-diastolic velocity and ratios of various velocity components. As noted earlier, the normal velocity waveform from an artery supplying a resting extremity is triphasic. The short, reverse component in early diastole is caused by reflected waves from the periphery. When peripheral vascular resistance in the bed being supplied by an arterial segment is low, its velocity waveform does not have the reverse flow component and may become monophasic with forward flow throughout the cardiac cycle. This is true of waveforms from the renal, splenic, and internal carotid arteries. It is also true of waveforms from extremity arteries after exercise, hyperemia, or intra-arterial administration of vasodilating drugs. Conversely, high resistance results in a steep upstroke of the systolic waveform. These principles and the rapidity of the vasoregulatory mechanism at the arteriolar level are easily documented by handheld continuous-wave Doppler interrogation of the radial artery at the wrist. When the fist is clenched, the waveform is more abrupt with minimal diastolic flow. When the hand is relaxed, after as little as 10

CHAPTER 15  Vascular Laboratory: Arterial Physiologic Assessment



Pulsatility index =



Vmax − Vmin Vmean

[15.2]

where Vmax is the maximum velocity, Vmin is the minimum velocity, and Vmean is the mean velocity. The index is lower (1.30 1.00–1.29 0.91–0.99 0.41–0.90

Noncompressible Normal Borderline (equivocal) Mild to moderate peripheral arterial disease 0.00–0.40 Severe peripheral arterial disease

Right arm systolic pressure

Left arm systolic pressure

DP

DP

Right ankle systolic pressure

Left ankle systolic pressure PT

PT

Figure 15-6  Method for measurement of the ankle-brachial index (ABI). The higher of the two brachial pressures and the higher of the two ankle pressures are used for calculation of the index. The patient should be supine and resting for at least 5 minutes before the measurements are made. DP, Dorsalis pedis; PT, posterior tibial. (From Hiatt WR: Medical treatment of peripheral arterial disease and claudication. N Engl J Med 344:1608-1621, 2001.)

CHAPTER 15  Vascular Laboratory: Arterial Physiologic Assessment



were hypertensive. The goal is to detect occlusive disease by identifying pressure drops between the proximal aorta and ankle. The pressure waveform changes as it moves through the vasculature (Fig. 15-7). Peak systolic pressure is accentuated by the additive effect of reflected pressure waves from the periphery. Thus, although mean pressure decreases as the pressure wave travels distally, peak systolic pressure increases. As a result, ankle systolic pressure is normally about 10% higher than brachial pressure (ABI of 1.1). Significant PAD decreases this ratio. Consequently, because of the known variance of this test, ABIs in the range of 0.9 to 1.29 are considered normal.

160 140 120 100 80 60

160 140 120 100 80 60 0

200 400 600 800 1000

0

200 400 600 800 1000

0

200 400 600 800 1000

0

200 400 600 800 1000

0

200 400 600 800 1000

160 140 120 100 80 60

160 140 120 100 80 60 0

200 400 600 800 1000

160 140 120 100 80 60

160 140 120 100 80 60 0

200 400 600 800 1000

160 140 120 100 80 60

Figure 15-7  The pressure wave changes as it moves distally through the vasculature. Peak systolic pressure is accentuated, and mean arterial pressure decreases.

SECTION 3 CLINICAL AND VASCULAR LABORATORY EVALUATION

Normalizing ankle pressure to brachial pressure serves two purposes. First, it accounts for the normal variation in central pressure that occurs throughout the day and from day to day. This normalized value is less variable than ankle pressure alone. The standard deviation for ABI is approximately 0.07, so differences in measurement of twice this magnitude (0.15) or greater usually represent a significant difference.11 Second, the ratio gives a better appreciation of the extent of arterial occlusive disease. Without accounting for brachial pressure, it would not be possible to know whether a low ankle pressure was caused by systemic hypotension or PAD; conversely, an ankle pressure could be normal despite significant disease if the patient

219

220

SECTION 3  Clinical and Vascular Laboratory Evaluation

Ankle-brachial index

1.2 ±1 SEM

1.0 0.8 0.6 0.4 0.2 0 Normal

Popliteal– Superficial below knee femoral

Aortoiliac

Multilevel

Location of disease

Figure 15-8  Resting ankle-brachial index (ankle systolic/arm systolic) measured in normal limbs and in limbs with arterial obstruction localized to different anatomic levels. (Modified from Strandness DE, Jr, et al: Hemodynamics for surgeons, New York, 1975, Grune & Stratton. Data from Wolf EA, Jr, et al: Correlation between nutritive blood flow and pressure in limbs of patients with intermittent claudication. Surg Forum 23:238, 1972.)

ABI decreases as the severity and extent of PAD increase (Fig. 15-8). ABI tends to be greater than 0.5 with singlelevel disease and less than 0.5 with multilevel disease. Most patients with intermittent claudication have an ABI between 0.5 and 0.9, but it may be as high as 1.0 or as low as 0.2. Usually, patients with pain at rest have ABIs below 0.4, and those with impending gangrene have ABIs below 0.3 (Fig. 15-9). Normal

Intermittent claudication

Rest pain

Impending gangrene

Prognostic Value of Ankle Brachial Index

1.3 1.2 1.1 1.0 Ankle-brachial index

Noninvasive tests are useful for the diagnosis of entrapment syndrome. Anatomic entrapment syndrome can be diagnosed by noting changes in ankle plethysmography and ABI with stress maneuvers. The limb is examined with the knee extended and the foot in the neutral, forced plantarflexed, and forced dorsiflexed positions. The test is considered positive if the ABI decreases more than 0.5 or if there is flattening of the plethysmographic tracing with forced dorsiflexion or plantar flexion.12,13 ABI has been well validated against contrast-enhanced angiography for its ability to detect stenosis of greater than 50%.14 The sensitivity of this test depends on the lower limit of normal that is chosen, with higher limits detecting more disease than lower limits. Investigators have used values ranging from 0.8 to 0.91 as the lower limit of normal.15 Also, some investigators advocate measuring the ABI only at the posterior tibial artery. In contrast, using the lower of the two ankle pressures increases the sensitivity of the test.16 Using an average of the two measurements has been found to correlate better with walking distance than using either the lower or higher ankle pressure.17 The ABI should be interpreted with caution if there is a nonhealing wound. This index may be adequate based on the higher pedal pressure, and yet healing will not occur if the pedal arch is incomplete and the angiosome including the wound is supplied by the more diseased artery. In general, the sensitivity of ABI in detecting PAD ranges from 80% to 95%, and the specificity ranges from 95% to 100%, with positive and negative predictive values in excess of 90%.18 Duplex scanning is more sensitive than ABI in detecting subclinical PAD.19

.9 .8 .7 .6 .5 .4 .3 .2 .1

0 No. of limbs: 50 Mean: 1.11 SD: 0.10

213 0.59 0.15

77 0.26 0.13

36 0.05 0.08

Highly significant (better than 0.01%)

Figure 15-9  Relationship of the ankle-brachial index to functional impairment produced by the occlusive process. (Modified from Yao JST: Hemodynamic studies in peripheral arterial disease. Br J Surg 57:761, 1970.)

ABI has predictive value; measurements more than 0.5 are infrequently associated with progression to critical ischemia over the next 6 years.20 Decreased ABI and the presence of diabetes mellitus were the two factors associated with the development of chronic limb ischemia in a 15-year study of 1244 patients with claudication.21 Abnormal ABI (either 1.30) has been associated with increased overall mortality, as has decline in ABI over time.22-24 ABI is useful as an office screening tool for PAD in asymptomatic patients older than 65 years of age, for whom an ABI



brachial pressure, particularly when the relatively narrow, 10-cm standard thigh cuff is used. In this case, upper thigh pressure may be as high as or somewhat higher than brachial pressure, even in the presence of significant iliac disease. False negatives may also result from restriction of outflow into the thigh because of occlusion of vessels by the cuff. The resulting limitation of flow across a stenotic iliac segment can prevent a pressure drop across it. A decrease in pressure of 20 mm Hg or more at any one level in comparison to the level above indicates significant disease. Occasionally, well-developed collateral vessels can mask occlusive disease. For example, there may not be a significant pressure drop between the below-knee and ankle pressures if the anterior or posterior tibial artery is patent below the knee. In addition, because the most distal cuff is at the ankle, disease below this level is not detected. Toe pressure measurement may be necessary to detect lesions in the pedal arch or digital vessels. Segmental pressure measurements also do not detect disease in nonaxial vessels, such as the profunda femoris. Because of the difficulty in detecting stenoses when flow is restricted, multilevel disease can be difficult to identify when a proximal stenosis is causing a significant decrease in distal pressure and flow. Side-to-side comparisons should be made and are meaningful when there is a difference, but they may be misleading in patients with symmetric disease in the two extremities. An estimate of the extent of collateralization around the knee in patients with superficial femoral artery occlusion can be made using the profundapopliteal collateral index (PPCI).31 PPCI is calculated as the difference between the above-knee and below-knee blood pressure divided by the above-knee pressure. A low index indicates good collateral development (little pressure drop across the knee). In general, a PPCI of less than 0.25 predicts a good result from profundaplasty without infrainguinal bypass, whereas a PPCI of greater than 0.50 predicts no improvement with profundaplasty alone.32 Use of segmental pressure did not add to simple ABI in improving the accuracy of Doppler waveform analysis in the diagnosis of PAD.33 Although occasionally useful, segmental pressure measurement is an indirect method of locating disease, and like other indirect tests, is much less accurate and provides less anatomic detail than duplex scanning, which provides better anatomic information and categorization of degrees of stenosis.

Toe pressure (mm Hg)

222

Patients with rest pain

Figure 15-11  Toe blood pressure grouped according to symptoms and the presence of diabetes in patients with arterial disease. Mean and SDs for the nondiabetic and diabetic subgroups and for the two groups combined are indicated by vertical bars. (Modified from Ramsey DE, et al: Toe blood pressure: a valuable adjunct to ankle pressure measurement for assessing peripheral arterial disease. J Cardiovasc Surg 24:43, 1983.)

particularly in diabetic patients, in whom toe pressure is much less prone than ankle pressure to false-normal results. Toe pressure is sensitive to disease at the level of the pedal arch and digital vessels, which is not detectable by ankle pressure measurements.34 Occasionally, even digital arteries can be calcified and incompressible. Normal toe pressure is 20 to 40 mm Hg less than ankle pressure, possibly because of the measurement technique. Although the normal toe-ankle index is 0.6 ± 0.2, values less than 0.7 are considered abnormal.18 Pressure of 30 mm Hg or less is associated with ischemic symptoms. The range of toe pressure for patients with varying degrees of PAD is shown in Figure 15-11. Foot lesions usually heal when toe pressure is more than 30 to 40 mm Hg (or slightly higher in diabetics). Unfortunately, toe pressures often cannot be obtained in patients with forefoot and digital gangrene for whom transmetatarsal amputation is contemplated. For more detail on methods to predict amputation healing at various levels, see Chapter 117.

Stress Testing As noted earlier, the extent of the reduction in pressure across a stenosis depends on the rate of flow through it. A mild to

Exercise Testing

80

Normal Moderate disease

5:00

60 1:30

40

Severe disease

20 0 Resting

0

2

4

6

8

10

Time after exercise (min)

Figure 15-12  Examples of exercise test results in patients with various degrees of peripheral arterial occlusive disease. The resting ankle-brachial indices are noted, followed by similar measurements immediately after exercise and for several minutes thereafter.

effect of isolated occlusion of an infrainguinal vessel. Exercise testing is not effective for detection of disease below the level of the popliteal artery because the sural branches to the gastrocnemius muscle come off at or above this level. This is the same reason that revascularization of tibial arteries is not generally indicated for patients whose only complaint is claudication. Alternatives to Exercise Testing.  The treadmill exercise test is the ideal stress test for arterial claudication, but there are times when this test is not possible because of comorbid conditions. There is often a need to evaluate the effects of increased flow, particularly on inflow, in situations in which walking is not possible, for example, intraoperatively or during angiography. In these situations, flow may be increased 300 ±1 SEM

240 180 120 60 0 Normal

Popliteal– Superficial below knee femoral

Aortoiliac

Multilevel

Location of disease

Figure 15-13  Treadmill walking times in patients with occlusive arterial disease. Normal individuals can almost always exceed 5 minutes (300 seconds). The treadmill is set at 2 mph and a 12% grade. (Modified from Strandness DE, Jr, et al: Hemodynamics for surgeons, New York, 1975, Grune & Stratton.)

SECTION 3 CLINICAL AND VASCULAR LABORATORY EVALUATION

Because most patients with claudication and those with ischemic symptoms have decreased resting pressure, exercise testing is only rarely required to diagnose PAD. This test is most useful when it is difficult to distinguish between true arterial claudication and pseudoclaudication or when patients have both. This physiologic test helps determine the extent to which cardiopulmonary, orthopedic, and vascular disease contributes to the patient’s difficulty walking. It is also useful for measuring the effect of treatment, such as medications or interventional procedures. In a standard exercise test, the patient first rests supine for 20 minutes to ensure that systemic pressure and peripheral pressure are at baseline. Resting pressure is then measured. Blood pressure cuffs are left in position at both ankles and the upper extremities, and the patient is asked to walk at a set speed (2 mph) on a treadmill at a fixed inclination (12 degrees) for 5 minutes or until forced to stop because of symptoms. Note is taken of the time to the initial onset of symptoms, the nature of the symptoms, and the time until stopping, which may be influenced by many factors, such as shortness of breath, patient motivation, and muscular pain. The patient is then asked to lie down, and ankle and arm pressures are measured immediately after exercise and then serially every 2 minutes for 10 minutes or until the pressure returns to resting levels. Brachial pressure tends to increase with exercise. This increase is often more pronounced in patients with PAD, but the ABI always decreases in this group. Clinically significant lower extremity PAD can be reliably ruled out in patients who are able to walk the entire time without symptoms or development of a decrease in the ABI. The severity of disease is reflected in the extent of the postexercise drop in the ABI and the length of time required for return to baseline levels (Fig. 15-12). Patients with mild disease may have normal resting pressure, but they may also have a mild drop in pressure after exercise that returns within minutes to baseline levels. Those with moderate to severe disease have abnormal resting ABIs and further decreases after exercise that persist throughout the postexercise observation period of 10 to 15 minutes. Patients who have less than a 20 mm Hg pressure drop at the ankle in comparison to the upper extremity rarely benefit from vascular reconstruction. The treadmill test tends to be more positive with proximal disease than with distal disease (Fig. 15-13). The aortoiliac vessels supply all the musculature of the lower extremity, including the large muscular groups of the buttock and thighs, so the effect of lesions in these vessels is greater than the

Treadmill time (min) 5:00

100 Ankle-brachial index (%)

moderate stenosis may not cause a pressure drop at resting levels of flow. However, turbulence and pressure reduction may develop when flow increases following exercise, reactive hyperemia, or administration of vasodilators. This is the basis of exercise testing to detect stenoses that do not cause abnormalities at rest. It is a useful, practical method for quantitating the functional effect of arterial insufficiency.

223

CHAPTER 15  Vascular Laboratory: Arterial Physiologic Assessment

Time (sec)



224

SECTION 3  Clinical and Vascular Laboratory Evaluation

by reactive hyperemia or vasodilators. Reactive hyperemia is induced by occlusion of blood flow to the extremity by the tourniquet effect of a proximal blood pressure cuff inflated above the systolic pressure level for 3 to 5 minutes. When the cuff is released, peripheral vascular resistance is reduced and flow is increased. This test is used infrequently because it is uncomfortable and does not produce sustained increases in flow. Flow can also be augmented by injection of vasodilators. Typically, 20 to 30 mg of papaverine is injected directly into the artery, which will cause vasodilatation and a decrease in pressure, both systemically and locally. It is important to check systemic pressure to ensure that an adequate dose of vasodilator was given (i.e., there was a systemic effect) and to obtain the correct, simultaneous value for comparison with the more distal pressure response. A systolic pressure gradient of 10 mm Hg at rest or 20 mm Hg after maneuvers to increase flow is considered abnormal. Because this test requires an increase in flow of 50% or greater, pressure drops may not occur if outflow is extremely limited (for example, proximal occlusion of both the superficial and profunda femoral arteries without significant collateralization). A similar method may be used during angiography to detect clinically significant arterial stenoses in segments that do not have detectable narrowing on imaging. The angiography catheter is placed above the segment in question and pressure measurements are made as the catheter is withdrawn to below the segment. Systolic pressure above and below the segment is recorded. The same parameters described for intraoperative measurements are used with this method, which also includes the use of papaverine, hyperemia, or even exercise in rare instances to increase blood flow if resting pressure is normal. Again, there is a caveat regarding flow. The catheter may occlude a narrowed but otherwise patent segment,

which will reduce flow and thereby limit the drop in pressure.

Direct Pressure Measurement In some cases it is difficult to determine either by imaging or indirect testing whether a segment of artery has clinically significant narrowing. In such cases, the most definitive test is direct pressure measurement, which can be done intraoperatively or at the time of percutaneous angiography. Intraoperatively, one may want to ensure that an arterial segment is not causing a pressure gradient. For example, intraoperative measurement of pressure can be helpful before infrainguinal bypass if there is doubt about the adequacy of the supplying aortoiliac segment. Pressures should be measured after the bypass to insure adequate flow to detect insufficient inflow. Vasodilators can be used when results are equivocal. Measurement of pressure along the course of a bypass can be a useful, rapid means of locating technical problems. The technique is simple. The artery at the level of interest (generally the common femoral artery when the aortoiliac segment is being assessed) is punctured with a 19-gauge needle and connected to a standard strain gauge with stiff tubing. When comparing with a reference pressure, such as the radial artery, the same pressure transducer is used to make it easy to switch between the two pressure lines and to eliminate errors that may be caused by having the two transducers at different heights. The pressure measurement system must be set up properly to prevent overdamping or underdamping. Overdamping hinders transmission of the pressure wave within the measuring circuit. It results in blunting of the pressure waveform and a decrease in estimation of systolic pressure and an increase in estimation of diastolic pressure (Fig. 15-14). Overdamping occurs if the tubing used is too compliant (for example, use

OVERDAMPED WAVEFORMS Nature of Waveform

Widened and slurred pressure tracing

Effect on Measurements

Underestimates SBP Overestimates DBP MAP remains unchanged

Causes • Air bubbles • Overly compliant tubing • Catheter kinks • Blood clots/fibrin • Stopcocks • Injection ports • No fluid in flush bag • Low flush bag pressure

Optimally damped Underestimation of SBP Overdamped - Widened - Slurred

MAP unchanged Overestimation of DBP

Figure 15-14  Overdamping of the pressure measurement system causes the waveform to flatten with a lower systolic peak and higher diastolic value. The optimally damped wave is blue; the overdamped wave is green. DBP, Diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. (Courtesy Dr. Michael Cheatham.)

CHAPTER 15  Vascular Laboratory: Arterial Physiologic Assessment



225

UNDERDAMPED WAVEFORMS Effect on Measurements

Narrow, peaked tracing

Overestimates SBP Underestimates DBP MAP remains unchanged

Underdamped - Peaked - Narrow

Penile Pressure There are three paired penile arteries: the dorsal penile, the cavernosal (deep corporal), and the urethral (spongiosal) arteries (Fig. 15-16). All are terminal branches of the internal pudendal artery. The cavernosal artery is the most important for erectile function. Obstruction of any of the arteries leading to the corpora cavernosa, including the common iliac artery or terminal aorta, can be responsible for vasculogenic impotence. Measurement of penile blood pressure is performed by applying a pneumatic cuff 2.5 cm in width to the base of the penis. Return of blood flow when the cuff is deflated can be detected by a photoplethysmograph applied to the anterolateral aspect of the shaft or a Doppler flow probe. Although some investigators have positioned the probe over the dorsal penile arteries, others have emphasized the importance of detecting flow in the cavernosal artery. Penile pressure and brachial pressure are normally equivalent. Older men without symptoms of impotence tend to have lower indices. Penile-brachial indices greater than 0.75 to 0.80 are considered compatible with normal erectile function; an index of less than 0.60 is diagnostic of vasculogenic impotence, especially in patients with peripheral vascular disease. A brachial-penile pressure gradient of less than 20 to 40 mm Hg suggests adequate penile blood flow. Gradients more than 60 mm Hg suggest arterial insufficiency. For a more detailed discussion of the assessment of erectile dysfunction, including other diagnostic modalities, see Chapter 82.

• Long tubing • Increased vascular resistance

Overestimation of SBP

MAP unchanged

Optimally damped

of butterfly needles with soft tubing rather than connecting a needle directly to an arterial pressure line) or if there are kinks or air bubbles in the system. Underdamping (ringing) results from too little limitation on the transmission of reflected pressure waves within the system. It may cause false elevations of systolic pressure because of the additive effect of reflected pressure from the transducer at the end of the tubing (Fig. 15-15). Underdamping may occur if the pressure line is too long.

Causes

Underestimation of DBP

PERIPHERAL ARTERIAL DISEASE PLETHYSMOGRAPHY Plethysmography is based on measurement of change in volume of the extremity caused by the cyclic nature of arterial inflow. Early instruments used a mercury strain gauge placed around the extremity. Change in volume causes a change in circumference, and therefore, in the length and electrical resistance of the strain gauge. The resistance is easily measured and plotted on a strip chart, which results in a waveform that has the same basic contour as the pressure wave (Fig. 15-17).35 Impedance plethysmography works on similar principles; it monitors electrical impedance, which is inversely proportional to volume. Cavernosal arteries Dorsal penile arteries Corpora cavernosa

Urethra

Figure 15-16  The paired penile arteries (urethral arteries not shown).

SECTION 3 CLINICAL AND VASCULAR LABORATORY EVALUATION

Figure 15-15  Underdamping of the pressure measurement system causes the waveform to become peaked with a higher systolic value and underestimation of the diastolic value. The optimally damped wave is blue; the underdamped wave is green. DBP, Diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. (Courtesy Dr. Michael Cheatham.)

Nature of Waveform

226

SECTION 3  Clinical and Vascular Laboratory Evaluation 1.0

Table 15-2

Amplitude

0.8

Definition of Pulse Volume Recorder Categories

PVR tracing

DV (mm3)

CHART DEFLECTION (mm)

0.6 0.4 Intra-arterial measurement

0.2 0 0

0.2

0.4

0.6

0.8

1.0

Thigh and Ankle

Calf

1

>15*

>200*

>160

>213

>715

2

>15†

3 4

5-15

>20† 5-20

>160 54-160

>213 54-213

>715 240-715

8). PI values lower than 4 may reflect proximal inflow or occlusive disease, and change in PI or spectral waveform damping is diagnostic of multilevel occlusive disease. Division of distal artery PI by proximal artery PI calculates the “damping factor”; a normal value is 0.9 or higher, and a value of less than 0.9 is diagnostic of occlusive disease. The systolic acceleration time during systole can also be used to diagnose occlusive disease proximal to the pulsed Doppler recording site. A normal value is less than 133 milliseconds. As systolic acceleration time increases to longer than 200 milliseconds, the spectral waveform develops a rounded upslope configuration, termed tardus-parvus, because of the prolonged time to PSV. Diagnostic accuracy of the systolic acceleration time is influenced by cardiac conditions (cardiomyopathy, aortic valve disease), but downstream occlusive disease has minimal influence on diagnostic sensitivity.

Ultrasound Equation This is described in Chapter 15. Volume flow (Q; mL/ min) can also be measured by electronically extracting the spatial average velocity (Vsa; cm/s) as a function of time, measuring vessel diameter (d; cm), and expanding the sample volume size to encompass the entire flow lumen by the equation Q = Vsa π d 2 / 4(mL/ min)

Measurement of arterial volume flow has limited diagnostic accuracy in the classification of occlusive disease because of normal variation in peripheral resistance and the development of collateral flow, but it is clinically useful in the assessment of dialysis access function.

Artifacts and Errors Artifacts and errors in ultrasound measurement can limit the effectiveness of the evaluation and create inaccurate results. Various artifacts include mirror image artifacts, shadowing from overlying vessel calcification, inaccuracy due to refraction, and aliasing. Most errors can be attributed to the technologist because studies using flow models have found that adjustment of Doppler angle, sample volume placement, and Doppler gain were the most significant sources of error in PSV measurement. Spectral Doppler aliasing is the most common artifact and, similar to color Doppler aliasing, is recognized by a “characteristic” signal wraparound in the spectral display (see Fig. 16-5). Adjustment of the velocity scale (i.e., pulse repetition frequency) to above the Nyquist limit or a reduction in the baseline level can shift the spectrum downward and eliminate the artifact. Shadowing from overlying calcification impedes adequate visualization of underlying vessel anatomy with B-mode imaging and interferes with accurate velocity measurement. Mirror image artifacts, created when a tissue structure is reproduced at an incorrect location, occur when a strongly reflecting surface is further reflected by other strongly reflecting surfaces.3 Refraction can cause misregistration of the image and the Doppler sample volume and occurs when an ultrasound beam passes through mediums with different propagation speeds. Crosstalk, found only in Doppler evaluation, creates a mirror image where identical spectra appear above and below the baseline. It is usually caused by an excessive receiver gain setting or an incident angle near 90 degrees. Ghosting occurs when low-velocity motion from pulsating vessel walls produces small Doppler shifts that can cause color flashing into the surrounding anatomy; it can be fixed with wall filters. Variability of diagnostic criteria between laboratories stems from methods for defining the percentage of stenosis, different machines, and differences in technique.3 Factors such as gender and physiologic condition of the patient can also affect the outcomes of DUS evaluations. Studies have found that carotid PSV measurements in women average 10% higher than in men.4 Congestive heart failure, dysrhythmias, and artificial support measures (ventilators, intra-aortic balloon pumps, or pacemakers) can alter cardiac output, which in turn can affect PSV measurements. With regard to technologist error, the largest source is error in accurately aligning the cursor of the sample volume. Even small errors in angle measurement can result in significant errors in velocity measurement and severity of the stenosis.3 Sample volume assumes that flow is parallel to the walls; however, flow is not usually parallel in tortuous vessels or beyond an asymmetrical stenosis, and these situations can make correct sample volume positioning and true velocity readings difficult. Finally, the

SECTION 3 CLINICAL AND VASCULAR LABORATORY EVALUATION

Carotid duplex Transcranial Doppler Peripheral duplex Duplex draft surveillance Renal duplex Mesenteric duplex

Velocity Spectra Waveform Parameters Used for Interpretation of Duplex Tests

235

236

SECTION 3  Clinical and Vascular Laboratory Evaluation

turbulence with simultaneous forward and retrograde velocity spectra during systole). The ratio of PSV (Vr) across a stenosis is a useful parameter for grading the severity of a stenosis; a Vr value higher than 2 indicates a greater than 50% diameter reduction, and a value higher than 4 correlates with greater than 70% diameter reduction. Typically, a pressure-reducing (peak systolic pressure >20 to 30 mm Hg) and flow-reducing arterial ste­ nosis is associated with a Vr above 3.5, a PSV higher than 250 to 300 cm/s, and an elevation in EDV of 40 cm/s or more. Downstream of a “significant” pressure-reducing arterial stenosis, the spectral waveform should appear damped and monophasic with prolongation of the acceleration time and a decrease in PSV to below normal levels. As stenosis severity increases beyond greater than 90% diameter reduction, volume flow through the stenosis tends toward zero, which can produce PSV at the stenosis in a minimally elevated range (100 to 200 cm/s) and low-velocity (95%) diameter-reducing stenosis causes volume flow to decrease toward zero, whereas the velocity within the stenosis may be minimally elevated.



Patient Testing Arterial duplex scanning can be performed as a portable bedside or vascular laboratory examination. Scanning should be conducted on a height-adjustable table or stretcher with the patient in a supine position. The bed and room environment should provide a comfortable, quiet atmosphere for patient examination, a warm room temperature (75° F to 77° F) to avoid vasoconstriction of the extremities, and sufficient space to permit bilateral body access for ultrasound scanning. The typical examination time ranges from 30 to 60 minutes. Patients should refrain from tobacco use for at least 1 hour before the examination, and if abdominal scanning or visceral artery testing is planned, the patient should have fasted for 4 hours and the examination should be performed in the morning to minimize accumulation of intestinal gas. Assessment of visceral artery flow before and after a test meal may be required for the evaluation of patients with symptoms of mesenteric ischemia.

Equipment Safety DUS scanning is considered to be a safe and noninvasive diagnostic modality, but the potential for adverse bioeffects exists. The acoustic power output of the duplex scanner has the potential to produce tissue injury from both thermal (heating) and mechanical (cavitation) effects. Duplex testing should be conducted with the acoustic output or power setting as low as reasonably achievable (ALARA principle). Tissue temperature increases with exposure to diagnostic ultrasound and bioeffects are related to exposure time, pulse repetition frequency, power output, and sample volume size. The instrument displays a thermal index as a reference to the sonographer to monitor for potential adverse bioeffects. In theory, if the thermal index is 3 or less, the maximum increase in temperature with diagnostic ultrasound should be 3° C. Consensus guidelines on ultrasound exposure indicate that no significant bioeffects occur with increases in temperature of less than 2° C for less than 50 hours’ exposure, and thermal index–related bioeffects are a rare occurrence in clinical practice. Mechanical effects causing acoustic cavitation can be calculated by the mechanical index, which is normally

237

displayed together with the soft tissue index by the instrument. Values for the mechanical index in diagnostic imaging typically range from a maximum of 1.9 to 0.5. Echo cavitations cause soft tissue bubbles or air pockets to expand and contract rhythmically, thereby resulting in resonation, which can theoretically lead to tissue damage. The use of microbubble contrast agents to enhance Doppler signal strength increases tissue bioeffects.

CLINICAL APPLICATIONS AND TEST INTERPRETATION Carotid Artery Carotid DUS testing provides a noninvasive method of evaluation of the extracranial carotid and vertebral arteries in patients with suspected cerebrovascular disease.2,5-13 Because the carotid artery is superficially located and can reliably be assessed by duplex scanning, this has become the mainstay of imaging for many vascular surgeons before carotid surgery. Similarly, the vertebral and subclavian arteries are readily accessible to ultrasound imaging, so a wide spectrum of extracranial arterial disorders can be accurately diagnosed, such as the detection of aneurysmal changes and even indications of intracranial and intrathoracic disease (based on waveform analysis). The most common clinical application is for the detection of proximal ICA atherosclerotic plaque and estimation of stenosis severity. The extent of ICA bifurcation diameter reduction predicts the risk for stroke and thus assists clinicians in identifying patients who may benefit from carotid intervention on the basis of landmark clinical trials.5,6,11 Because of a wide variation in reporting by vascular laboratories across the country, consensus criteria were developed to standardize reporting.13 Carotid DUS is also widely used to assess the results of carotid interventions by continued surveillance for recurrent stenosis. TCD serves as a tool for evaluation of the intracranial circulation and collateral circulation during carotid interventions and assessment of spasm after intracranial hemorrhage. The association of coronary artery disease with increased intima-media thickness of the carotid artery has led some to suggest imaging of the carotid artery in asymptomatic patients as a screen for coronary or generalized atherosclerosis. However, a meta-analysis of 41 randomized controlled trials was unable to show a correlation in reduction of carotid intima-media thickness to a decrease in cardiovascular events. Although such screening is more often performed in Europe, restrictive insurance coverage has limited the utility of this assessment in the United States to clinical trials.14 Further, the use of duplex imaging for carotid disease surveillance was recently reviewed and found not to be cost-effective because only 7% of asymptomatic patients subsequently required carotid surgery.15 In the past decade, a better understanding of plaque morphology has provided further information on plaque echocardiographic morphology. Plaque morphology has been correlated with presenting symptoms16 (i.e., hemispheric,

SECTION 3 CLINICAL AND VASCULAR LABORATORY EVALUATION

different threshold PSVs for lesions with greater than 50% diameter reduction.5-10 PSV measurement variation is in the ±15% range, similar to other biologic measurements. This variation is related to the type of ultrasound system used and differences in Doppler angle assessment and sample volume positioning by the examiner. This limitation of duplex scanning can be minimized by reporting stenosis (i.e., diameter reduction) within a specified range (e.g., 0% to 49%, 50% to 75%, and 76% to 99%). In each clinical application, it is recommended that the vascular laboratory conduct ongoing quality assurance studies to confirm that the diagnostic accuracy of stenosis interpretation is greater than 80% relative to independent angiographic reports. It is not necessary to evaluate the diagnostic accuracy of individual DUS systems.

CHAPTER 16  Vascular Laboratory: Arterial Duplex Scanning

238

SECTION 3  Clinical and Vascular Laboratory Evaluation

amaurosis fugax, asymptomatic). Furthermore, plaque morphology has been shown to change after neurologic events, with the single longitudinal view–gray scale median (GSM) lowest within 30 days of a neurologic event and increasing to values similar to those of asymptomatic patients within 3 to 6 months.17 The ICAROS (Imaging in Carotid Angioplasty and Risk of Stroke) study demonstrated by multivariable analysis that the GSM was an independent predictor of stroke after carotid stenting, with 7.1% of patients with GSM of less than 25 and 1.5% of patients with GSM of more than 25 suffering a neurologic event in the perioperative period.18 Indications.  Results from two separate guidelines endorsed by the Society for Vascular Surgery support the use of DUS as the initial imaging modality for both asymptomatic and symptomatic patients.1,19 Initial carotid evaluation with DUS is acceptable for patients with a carotid bruit and to observe known asymptomatic stenosis. DUS is also frequently used for screening carotid evaluation in patients with known peripheral arterial disease, coronary artery disease, or abdominal aortic aneurysms. For symptomatic patients, initial carotid evaluation with DUS is appropriate for patients presenting with amaurosis fugax or hemispheric symptoms attributable to carotid territories. Secondary imaging, such as computed tomographic arteriography (CTA) or magnetic resonance arteriography (MRA), is necessary when sonography cannot be obtained, DUS results are equivocal in symptomatic patients, or confirmation of DUS findings is necessary for quality assurance. Technique.  A linear array transducer (5 to 10 MHz) is sufficient to image the arterial anatomy. Carotid artery imaging in gray scale is performed in transverse and sagittal planes to assess the intima-media thickness (normal, 1.5 mm), and to investigate the site or sites of more advanced plaque stenosis. The examination should include complete DUS imaging of the extracranial common carotid artery (CCA), ICA, and external carotid artery (ECA) as well as assessment of flow in the vertebral and subclavian arteries including bilateral brachial artery systolic pressure measurement. Accurate differentiation of the ICA from the ECA is paramount. The two can be differentiated on the basis of location (the ICA is posterior and lateral to the ECA), Doppler flow resistance (the ICA has lowresistance monophasic spectra, whereas the ECA has higher resistance multiphasic spectra), and the presence of branches (the ECA has branches) (see Fig. 16-8). Atherosclerotic plaque features, such as homogeneity or heterogeneity, are evaluated in gray scale by B-mode ultrasound imaging. GSM assessment of each plaque can provide additional information. Multiple images can be obtained in transverse views and a single longitudinal view. Two points of reference are used, with 0 designated for black and 255 for white. Excessive calcification can limit GSM assessment by blocking the ultrasound. Multiple points of assessment allow

a maximum and minimum GSM, with the difference in measurements determining the heterogeneity of the plaque. Notation of the carotid bifurcation relative to the angle of the mandible provides clinically important information in determining difficulty of surgical exposure for lesions at or above the angle of the mandible. Color Doppler imaging is useful to interrogate tortuous CCA or ICA segments and to assist in correct assignment of the Doppler angle for measurements of velocity spectra. The CCA is examined as far proximally as possible to detect flow turbulence caused by CCA origin stenosis. Velocity spectra are recorded (≤60-degree Doppler angle) at multiple sites in the CCA, ICA (proximal, mid, distal), and ECA. Color or power Doppler imaging is used to identify regions of maximal stenosis for pulsed Doppler interrogation. Interpretation Carotid Plaque Echomorphology.  The location and extent of atherosclerotic plaque, including features such as calcification, lumen irregularity, ulceration (>2-mm surface defect), and pattern of echogenicity (homogeneous versus heterogeneous), are determined by B-mode imaging. The extent of acoustic shadowing secondary to the extent of plaque calcification should be described. Lumen-reducing plaque with large echolucent regions may indicate plaque instability caused by intraplaque hemorrhage or degeneration. The more echogenic the plaque, the higher the GSM score. The GSM can determine B-mode plaque morphology more accurately than a single longitudinal assessment and provide scoring that can be standardized. Gross assessment of the carotid plaque should be categorized as less than 50% or more than 50% on the basis of plaque severity on transverse imaging. Severity of ICA Stenosis and Velocity Criteria (PSV/EDV Ratio).  A multispecialty panel developed a consensus for estimating the severity of ICA stenosis. Parameters used to determine the degree of stenosis include PSV and EDV measurements, with these values recorded from within the most stenotic ICA segment (Table 16-2).13 Testing data allow designation of ICA disease into categories of normal (no plaque or stenosis), less than 50% stenosis (plaque visualized, mild disease), 50% to 69% stenosis, greater than 70% diameter reduction (high-grade stenosis), and occlusion (no flow detected). The ICA/CCA ratio also assists in determining the severity of a stenosis. A PSV of 125 cm/s, recorded from a proximal diseased ICA segment, is the threshold for greater than or less than 50% stenosis. Extensive, bulky plaque may be imaged at the carotid bifurcation, but if PSV is in the range of 125 to 150 cm/s and the ICA/CCA ratio is less than 2, the appropriate estimation of ICA stenosis should be based primarily on the PSV value (i.e., hemodynamic classification of disease) (Fig. 16-11). Grading of ICA stenosis of more than 50% is determined by the PSV and EDV values. PSV values ranging from 230 to 280 cm/s are predictive of a greater than 70% stenosis by NASCET (North American Symptomatic Carotid Endarterectomy Trial) measurement criteria.6-8 However, interpretation of greater than 70% stenosis should not be

CHAPTER 16  Vascular Laboratory: Arterial Duplex Scanning



Table 16-2

239

Consensus Criteria for Interpretation of Carotid Duplex Imaging of Internal Carotid Artery Atherosclerotic Disease11

Disease Category (Diameter Reduction)

ICA PSV (cm/s)

ICA/CCA Ratio

ICA EDV (cm/s)

Plaque Imaging

Normal

60 degrees). Nearly total occlusions substantially decrease velocities by diminished flow. Severe calcification may

Figure 16-12  Vertebral artery waveform in patient with Left proximal subclavian artery occlusion. Note flow is reversed in the vertebral artery and is below the baseline.

SECTION 3 CLINICAL AND VASCULAR LABORATORY EVALUATION

CCA, Common carotid artery; DR, diameter reduction; EDV, end-diastolic velocity; ICA, internal carotid artery; IMT, intima-media thickness; PSV, peak systolic velocity.

240

SECTION 3  Clinical and Vascular Laboratory Evaluation

prevent accurate interrogation of the entire lesion, potentially missing the greatest point of stenosis.

Severe Stenosis of the Contralateral Carotid Artery In approximately 25% of patients, the presence of an occluded ICA is associated with increased compensatory collateral flow in the nonobstructed ICA with a resulting increase in PSV and EDV. This can result in overestimation of stenosis when plaque is present.24,25 When bilateral high-grade ICA stenosis or contralateral ICA occlusion is present, multiple diagnostic criteria (PSV, EDV, ICA/CCA ratio) are recommended to interpret greater than 50% or less than 70% diameter reduction ICA stenosis. Abou-Zamzam and colleagues documented that 20% of patients with bilateral severe stenosis greater than 60% were reclassified to less than 60% stenosis in the contralateral, untreated artery after treatment of the ipsilateral carotid disease.24 Likewise, increased PSVs in the ICA have been documented in patients with bilateral vertebral artery occlusive disease or subclavian artery steal syndrome with retrograde vertebral flow.25 The potential change of PSV criteria to higher requirements has been suggested by Fujitani et al.26 Sensitivity and specificity can be enhanced by use of a PSV higher than 140 cm/s and an EDV lower than 155 cm/s for defining a 50% to 79% stenosis and a PSV higher than 140 cm/s and an EDV higher than 155 cm/s for a stenosis of 80% or greater compared with classical Strandness criteria. With use of the Strandness criteria, the accuracy was approximately 70% in detecting a 16% to 79% stenosis. When these criteria were adjusted, the accuracy improved to more than 94% in all degrees of stenosis.

Internal Carotid Artery Occlusion The diagnosis of ICA occlusion requires several duplex findings to be present.27-29 Imaging should include B-mode plus color and pulsed Doppler as well as power Doppler to confirm absence of flow. Imaging should be adjusted for maximum flow sensitivity and minimum wall filter. The Doppler sample volume should be changed to sample the entire vessel. Interpretation.  No flow should be detected by color or power Doppler at the diseased carotid bulb and beyond in the distal ICA. Resistance to flow in the ipsilateral CCA should be increased, with flow at or approaching zero in early diastole. Low-resistance flow may be seen in the ECA because of the development of collateral flow. A characteristic flow “thump” may be recorded in the proximal ICA as flow abuts the occlusion. Accuracy.  The sensitivity, specificity, PPV, and NPV of DUS in detecting a carotid artery occlusion are 91%, 99%, 92% to 96%, and 98% compared with conventional arteriography.28,29

Intraoperative Carotid Duplex Testing DUS is a useful modality to assess carotid repairs for technical problems, including arterial clamp injury, shunt trauma,

suture line stenosis, and dissection of residual plaque in either the ICA or the CCA. The unpredictable occurrence of these residual lesions (documented in approximately 3% to 5% of procedures) can lead to repair site thrombosis or embolization of platelet thrombus and cause a stroke or transient ischemic attack after carotid surgery.30-32 Recurrent carotid stenosis has been postulated to have its origin in the “abnormal” repair site, with myointimal hyperplasia being more likely to develop in response to residual disturbed flow. Completion angiography, although an excellent method to verify a “technically adequate” repair (no lumen-filling defects, 300 cm/sec, EDV ≥40–100 cm/sec; Vr >4 >75% stenosis

PSV, Peak systolic velocity.

Figure 16-16 depicts the classic progression of deterioration of ankle-brachial index (ABI), decreasing PSV, and decreasing PI. Classification of peripheral arterial stenosis is based on duplex-derived criteria, similar to carotid duplex testing (e.g., PSV, EDV, and PSV ratio across a stenosis identified by color Doppler imaging) (Fig. 16-17; see Table 16-5). A doubling or step-up in PSV to more than 150 cm/s (Vr > 2) indicates 50% or greater diameter reduction stenosis. Duplex criteria for a critical flow-limiting stenosis include loss of the triphasic waveform, spectral broadening with an increase in velocity (PSV > 200 cm/s, EDV > 0 cm/s), and Vr greater than 3 across the stenosis. Higher degrees of stenosis (>75%) are associated with an EDV higher than 100 cm/s and a Vr above 4.62 Accuracy.  A prospective comparison of DUS to contrastenhanced MRA was performed with 152 patients, with conventional digital subtraction angiography as the “gold standard.” A PSV ratio of more than 2.5 was used to define

Posterior tibial artery velocity spectra

MV

MV

MV

ABI

PSV (cm/sec)

PI

1.09

58

8

0.72

45

2.5

0.40

36

1.4

Figure 16-16  Velocity spectra, ankle-brachial index (ABI), and pulsatility index (PI) recorded from the posterior tibial artery of limbs with normal (ABI > 0.9, PI > 4), moderate (ABI = 0.5 to 0.8), and severe (ABI < 0.5, PI < 1.5) limb ischemia. MV, Mean velocity; PSV, peak systolic velocity.

Figure 16-17  Duplex categories of peripheral artery stenosis based on velocity spectral waveform interpretation. EDV, End-diastolic velocity; PSV, peak systolic velocity.

a significant stenosis. Duplex had sensitivity, specificity, and overall accuracy of 76%, 93%, and 89%, respectively, whereas MRA had a sensitivity of 84%, a specificity of 97%, and an overall accuracy of 94%, with statistically significant improvements in MRA sensitivity (P = .002) and specificity (P = .03).63 Collins et al64 performed a systematic review of the literature comparing the three different imaging modalities. In detecting a greater than 50% stenosis, contrast-enhanced MRA demonstrated a median sensitivity and specificity of 95% and 97%; CTA showed a sensitivity and specificity of 91% and 91%; and DUS showed a sensitivity and specificity of 88% and 96%. For detection of occlusions, contrastenhanced MRA was more sensitive and specific than CTA or DUS.

Iliac Arteries The iliac arteries can be evaluated either by direct assessment via interrogation of the iliac artery or by indirect measures of common femoral artery waveform and velocity assessment. Direct assessment requires lower frequency abdominal probes and is limited by body habitus as well as by other factors (e.g., tortuosity, deep vessels) compared with indirect assessment of the femoral arteries. Interpretation Direct Imaging Criteria.  Direct imaging criteria for iliac artery stenosis include the following: for greater than 50% stenosis: PSV higher than 200 cm/s or PSV ratio of 2.5 or more; for greater than 75% stenosis: PSV ratio above 5.0 and EDV higher than 40 cm/s.65 PSV of 400 cm/s or more is suggestive of greater than 75% stenosis.65 Indirect Imaging Criteria.  Reduced velocities in the common femoral artery ( 200 cm/s): 95% sensitivity, 55% specificity, 68% PPV, 91% NPV, and 75% accuracy; for greater than 75% stenosis (EDV > 40 cm/s): 70% sensitivity, 90% specificity, 64% PPV, 92% NPV, and 86% accuracy; for greater than 75% (with Vr > 5.0): 65% sensitivity, 91% specificity, 65% PPV, 91% NPV, and 86% accuracy.65 Indirect Imaging.  An abnormal common femoral artery waveform contour (monophasic or biphasic) differentiated ipsilateral iliac artery stenosis of less than 50% from stenosis of greater than 50%, with 95% sensitivity, 89% specificity, 89% PPV, 95% NPV, and 92% accuracy. In differentiating between groups with greater than 50% stenosis and occlusion of the ipsilateral iliac artery, the specificity, PPV, and accuracy for PSV lower than 45 cm/s combined with a common femoral artery monophasic waveform are 97%, 92%, and 88%, respectively (Fig. 16-18).

Femoral-Popliteal and Tibial Arteries Studies, including a prospective blinded comparative study, have shown good agreement in the femoral-popliteal segment between DUS and digital subtraction angiography with use of a Vr of more than 2 for defining a greater than 50% stenosis by DUS. Agreement was better in the supragenicular than in the infragenicular segments.67 In a comparison of the agreement with digital subtraction angiography, specific areas had poor correlation: profunda femoral artery, tibioperoneal trunk, peroneal artery, and crural arteries. In addition, a report has recommended the combined use of a PSV higher than 200 cm/s and a Vr above 2 to predict a greater than 70% femoropopliteal stenosis.68

A

The sensitivity and specificity of DUS in the femoralpopliteal arteries depend on criteria used to determine the degree of stenosis. With use of a Vr above 2.4 in detecting a greater than 50% stenosis in the femoral artery, the sensitivity, specificity, PPV, and NPV were 81%, 93%, 84%, and 91%.66 A combined Vr above 2.0 and a PSV higher than 200 cm/s was associated with a sensitivity, specificity, PPV, and NPV of 79%, 99%, 99%, and 85% in detecting a greater than 70% stenosis.68 In the tibial arteries, the largest series reporting the accuracy of DUS in detecting 50% stenosis found a sensitivity of 88%, specificity of 75%, PPV of 83%, and NPV of 81% in 1690 infrageniculate segments correlated with conventional angiography69 (see Table 16-5). Limitations.  For the aortoiliac disease segment, body habitus is the main limitation. For infrainguinal stenosis, the major limitation of accuracy is the presence of a proximal stenosis, which can falsely decrease distal velocities. Consequently, the velocity ratio may more accurately identify focal areas of stenosis. DUS may signify a high-grade stenosis instead of occlusion if a collateral vessel is visualized therefore falsely demonstrating flow adjacent to an occluded vessel. Incomplete vessel imaging may occur as a result of poor patient cooperation or acoustic shadowing caused by plaque calcification. Arterial segments difficult to image include the proximal external iliac artery, internal iliac origin, and tibioperoneal trunk. Calcific changes in the tibial arteries can decrease the accuracy of velocities.

DUPLEX SURVEILLANCE Bypass Graft and Intervention Surveillance Vein Grafts A surveillance program after lower limb vein bypass grafting is recommended, but the extent of testing, including routine duplex testing, remains controversial.70 Current

B

Figure 16-18  Indirect imaging of iliac arteries. A, Common femoral artery (CFA) with damped low-velocity waveform. B, Common femoral artery triphasic waveform for comparison.

CHAPTER 16  Vascular Laboratory: Arterial Duplex Scanning



Technique.  Similar to native infrainguinal arterial examination, B-mode, color-flow, and pulsed Doppler imaging should be performed of the inflow, conduit, and outflow vessels. B-mode imaging can often identify early technical issues (i.e., retained valves or sclerotic vein segments). Pulsed Doppler with waveform analysis should be mapped of the lower limb with PSV, EDV, and Vr recorded. Specifics of the stenosis should also be recorded: diameter of the vein in transverse imaging above and below the stenosis, including length of stenosis in centimeters and anatomic location. Interpretation.  A combination of ABI, PSV, and Vr has been used to stratify patients into risk of subsequent vein graft failure. A PSV higher than 180 cm/s with associated Vr of 2.0 and no change in ABI correlates well with a 50% stenosis. A critical vein graft stenosis with impending failure has a PSV higher than 300 cm/s, a Vr of more than 3.5, and a decrease in ABI by 0.15 or more. Refer to Table 16-6 for risk stratification of failure. Vein graft lesions with the duplex-derived velocity spectra of a high-grade stenosis (PSV > 300 cm/s, EDV > 20 cm/s, Vr across the stenosis >3.5) correlate with a greater than 70% diameter reduction stenosis and should be repaired (see

Table 16-6

Fig. 16-6). In a prospective study, application of these threshold criteria identified all grafts at risk for thrombosis, and only one lesion with high-velocity criteria regressed. Multiple investigators have observed an approximately 25% incidence of graft thrombosis in stenotic bypasses when a policy of no intervention was followed.70-73 The risk for graft thrombosis is predicted by using the combination of high- and low-velocity duplex criteria and decreases in ABI (see Table 16-6). In the highest risk group (category I), the development of a pressure-reducing stenosis produces low flow in the graft, which will result in thrombosis if it is decreased below the “thrombotic threshold velocity.” Prompt repair of category I lesions is recommended, whereas category II lesions can be scheduled for elective repair within 1 to 2 weeks. A category III stenosis (PSV of 180 to 300 cm/s, Vr < 3.5) does not reduce pressure or flow in the resting limb. Serial scans at 4- to 6-week intervals are recommended to determine hemodynamic progression of these lesions. An important feature of a “graft-threatening” stenosis is its propensity to progress in severity, to reduce graft flow, and to form surface thrombus—events that can precipitate thrombosis. By use of serial duplex scans, a category III stenosis that does not progress can be distinguished from a progressive lesion that needs to be repaired. The majority (approximately 80%) of bypass grafts will have no stenosis identified (i.e., category I scan). For these patients, surveillance at 6-month intervals is recommended. In patients with category I scans, a graft flow velocity lower than 40 cm/s indicates a “low-flow” bypass that is at increased risk for thrombosis by the concept of the thrombotic threshold velocity, which is lower in autologous vein than in prosthetic bypasses. Prescribing an anticoagulation regimen of warfarin to maintain the prothrombin time at an international normalized ratio of 1.6 to 2 and antiplatelet therapy (aspirin, 81 mg/day, or clopidogrel bisulfate, 75 mg/day) may reduce the incidence of low-flow vein bypasses.70 Patients who are at high risk for development of vein graft stenosis70 include those with abnormal results on baseline testing (PSV, 180-300 cm/s; Vr, 2-3.5), multisegment venous conduit, repeated bypass grafting, and need for warfarin therapy (Fig. 16-19).

Risk Stratification for Vein Graft Occlusion by Duplex Criteria

Category

High-Velocity Criteria, Peak Systolic Velocity

Velocity Ratio (Vr)

Low-Velocity Criteria, Graft Flow Velocity

Change in ABI

I: Highest risk* (>70% stenosis with low graft flow)

>300 cm/s

>3.5

0.15

II: High risk* (>70% stenosis without change or normal graft flow)

>300 cm/s

>3.5

>45 cm/s

2.0

>45 cm/s

500 ms in the posterior tibial vein after removal of distal compression with the patient standing Reverse flow >500 ms in the popliteal vein during Valsalva

Labropoulos et al,41 2003

Jeanneret et al,42 1999

Lagattolla et al,43 1997

Markel et al,44 1994 Masuda et al,45 1994

Sarin et al,46 1994 Araki et al,47 1993

Time to valve closure using cuff inflation-deflation method is 0.5 s. Reverse flow after release of manual calf compression was >500 ms. Reverse flow measurement after release of manual calf compression is reproducible. Popliteal vein incompetence is optimally identified by the duration of reflux after distal compression with the patient standing. Adequate manual compression is sufficient to identify reflux. With proximal compression, difficulty producing normal valve closure may be misinterpreted as reflux. Testing should be performed to an observable endpoint in reflux or valve closure without emphasizing reflux velocity. Testing with the patient supine tends to lengthen flow reversal in normal limbs, which can be misinterpreted as reflux. Color-flow Doppler ultrasonography provides a rapid subjective evaluation of reflux but, in an objective measurement, may underestimate the duration of reflux. In normal limbs, mean tr from all maneuvers is 0.3 ± 0.03 s. In CVI limbs, mean tr is 2.5 ± 0.2 s. Among limbs, 0.5 s provided complete separation between the two groups, without overlap. Continued

SECTION 3 CLINICAL AND VASCULAR LABORATORY EVALUATION

Series

273.e2 SECTION 3  Clinical and Vascular Laboratory Evaluation Table e18-2

Published Criteria for Diagnosis of Reflux—cont’d

Series

Criteria

Van Bemmelen et al,48 1990

Venous valves close with reverse flow velocity >30 cm/s, which is not generated by manual limb compression. With Valsalva, this velocity is achieved only in the CFV (90% of cases). Velocities after Valsalva are progressively lower in more distal veins—the profunda femoris, the superficial femoral vein, and the popliteal vein. If velocities 45

Gadobenate

Normal dose (0.1-0.2 mmol/kg)

30-45

Gadobenate; consider a non–contrast-enhanced study Gadobenate; strongly consider non–contrastenhanced study Gadobenate, only if study is absolutely necessary

Half dose (0.05-0.1 mmol/kg)

15-30* 50%) in-stent recurrent stenosis rate was assessed in 464 limbs and remained low in

the long term, 5% at 72 months (Fig. 62-12).61 Factors associated with in-stent recurrent stenosis are similar to those associated with stent occlusion, except for age. The presence of thrombotic disease is the dominating factor. The cumulative rate of in-stent recurrent stenosis was higher in thrombotic limbs than in nonthrombotic limbs (10% and 1%, respectively). Despite this observation, it has not been conclusively proved that progressive in-stent recurrent stenosis results in occlusion.64 Stent occlusion appears to be caused by a recurrent thrombotic event rather than by slowly evolving narrowing of the stent. Hartung and colleagues reported a 13% restenosis rate, but these authors appear to have included stenosis at the lower stent-vein border area, which is not considered true in-stent recurrent stenosis.43 The nature and mechanism of development of in-stent recurrent stenosis are not yet known.

Rate of in-stent restenosis (%)

30

Figure 62-12  Cumulative rate of severe recurrent in-stent stenosis (>50%) in all stented limbs and in those stented for thrombotic and nonthrombotic obstruction. The lower numbers represent total limbs at risk for each time interval (SEM < 10%).

Thrombotic All limbs Nonthrombotic

20

10

0 0

12

24

36 Time (months)

48

60

72

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

Patency rates (%)

70

968

SECTION 10  Venous Insufficiency and Occlusion

Clinical Outcome Patients with chronic venous disease are younger, will live longer, and have a better prognosis compared with patients with arterial atherosclerotic disease. Chronic venous disease rarely threatens the survival of limb or patient, so the goal is to improve symptoms and the quality of life. The clinical results are gratifying, with substantial decrease in Venous Clinical Severity Score and Venous Disability Score, high cumulative ulcer healing rate, and improved quality of life. The median Venous Clinical Severity Score has been reported to markedly decrease in patients with obstruction of all etiology from 9 to 1 or 2 after iliofemoral stenting43,65,66 and in ulcerated limbs from 21 to 7.66 The median Venous Disability Score decreased from 2 to 1.43 Neglén and coworkers observed 918 of 982 patients (93%) for up to 8 3 4 years (mean, 24 months; range, 1-107 months).61 This study reported the degree of swelling assessed by physical examination (grade 0, none; grade 1, pitting, not obvious; grade 2, ankle edema; and grade 3, obvious swelling involving the limb) and level of pain measured by the visual analogue scale.67 The preoperative and postoperative mean pain and swelling scores improved substantially: 3.7 (range, 0-9) and 0.8 (range, 0-10), and 1.7 (range, 0-3) and 0.8 (range, 0-3), respectively (P < .0001). The rate of limbs with severe pain (≥5 on a visual analogue scale) fell from 41% to 11% after intervention; gross swelling (grade 3) in limbs decreased from 36% to 18%. After 5 years, overall 62% and 32%, respectively, remained completely free of pain and swelling. This analysis was based on complete relief of swelling and pain (grade 0 swelling and 0 level of pain) and does not reflect partial improvement (Fig. 62-13). The incidence of ulcer healing after stent placement in 148 limbs with active ulcer was 68%, and the cumulative ulcer recurrencefree rate at 5 years was 58% (Fig. 62-14). Ulcers recurred in only 8 limbs of 101 healed ulcers during the follow-up period. Thus, if healing of the ulcer was achieved after

stenting, ulcer recurrence was rare within the study period. These limbs frequently had remaining reflux, which was untreated during the observation period. Long-term ulcer healing was the same in limbs with primary (nonthrombotic iliac vein obstructive lesions) and thrombotic obstruction (62% and 55%, respectively; P = .2819). A recent report of 158 patients with stented ulcers of mixed etiology showed a greater cumulative ulcer-free rate at 5 years of 75% after iliofemoral stenting. In this study, healing was better in nonthrombotic limbs compared with postthrombotic limbs (87% vs 66% at 5 years, respectively; P < .02).68 The majority of patients with combined reflux and obstruction have sustained clinical improvement, including ulcer healing rate, after iliofemoral stenting alone despite the presence of reflux.2,3 Obstruction of the common femoral and iliocaval venous outflow is more likely to cause decreased quality of life than are femoropopliteal vein blockages, particularly after previous DVT.12,69-71 A validated health-related quality of life questionnaire (CIVIQ)72 assessing subjective leg pain, sleep disturbance due to leg problems, work-related leg problems, and effect of leg symptoms on morale and social activities was filled out by stented patients prospectively before and after intervention (mean follow-up, 5 months; range,1-79 months; n = 381).61 There was significant improvement in all five problem categories after stenting of both nonthrombotic iliac vein obstructive lesions and thrombotic outflow obstructions. Chronic venous disease regardless of etiology affects quality of life adversely, and stenting in patients with chronic venous outflow obstruction frequently markedly improved it.

Hemodynamic Outcome As previously discussed, there is no accurate hemodynamic test available to properly assess venous outflow obstruction and its improvement after stenting in individual limbs. It

Cumulative symptom relief (%)

100

80

60

40

Pain – Complete and partial relief (reduction 3 on VAS) Pain – Complete relief Swelling – Complete and partial relief (improvement 1 degree) Swelling – Complete relief

20

0 0

12

24

36

Time (months)

48

60

Figure 62-13  Cumulative complete relief and improvement of pain and swelling after iliofemoral venous stenting alone (with no subsequent reflux repair). The lower numbers represent total limbs at risk for each time interval (all SEM < 10%). VAS, Visual analogue scale.

CHAPTER 62  Iliocaval Obstruction: Endovascular Treatment



969

100

Figure 62-14  Cumulative ulcer recurrence-free rate after iliofemoral venous stenting alone (with no subsequent reflux repair). The steep fall at 3 months can be explained by the fact that limbs that failed to heal the ulcers during the observation period were considered not healed at 3 months. Leg ulcers that healed rarely recurred.

80 70 60 50 40 30 20 10 0

might, therefore, also be in vain to expect other hemodynamic parameters to significantly improve. The ultimate result of stenting is therefore better assessed by the clinical outcome as outlined before. Changes in the results of conventional tests, such as ambulatory venous pressure (percentage drop) with venous filling time, air plethysmography (venous filling index [VFI90], venous volume, and ejection fraction), and arm-foot pressure differential/hyperemiainduced pressure increase, have been found to be relatively minor compared with the clinical improvement.61 Significant decrease of the mean hand-foot pressure differential was found in stented limbs and occurred with and without remaining reflux and no adjunct procedures, and ambulatory venous pressure improved in most subsets of limbs in that study. Although numerically small, these changes were statistically significant and indicated that the outflow obstruction was alleviated and the global hemodynamics improved after stenting.73 After successful stenting of 23 selected limbs with iliofemoral postthrombotic obstruction and reflux, Delis and associates reported a significant increase in reflux matched by a greater venous filling time and decrease of residual volume fraction measured by strain-gauge plethysmography.12 It has been suggested that alleviation of proximal obstruction by stenting would increase distal reflux, a “protection” against reflux would be lost, and the clinical condition would perhaps be worsened. We found that better reflux-related parameters (venous filling time, VFI90, venous volume) after treatment were observed only when adjunct saphenous procedures were combined with the stenting.61 In no subset of patients was there observed a deterioration of venous reflux. The analysis of stented limbs with reflux and no adjunct procedure showed neither deterioration nor improvement of these parameters in this study. The presence of axial deep reflux before stenting did not worsen the global reflux measurably after stenting. Although increased retrograde flow measured by VFI90 may increase in individual patients, it was not found to be a

0

6

12

18

24

30

36

42

48

54

60

Time (months)

dominant or constant phenomenon in this larger stented group of limbs. Before stenting, limbs with thrombotic obstruction clearly had more extensive venous disease with more severe obstruction and reflux more frequently involving multiple systems and levels than did limbs with nonthrombotic iliac vein obstructive lesions.61 Despite this observation, stenting improved clinical symptoms and quality of life substantially and similarly in both groups of patients. The positive clinical outcome was achieved with an improvement of the calf muscle pump function in the limbs with nonthrombotic iliac vein obstructive lesions, whereas the thrombotic limbs had no measurable hemodynamic improvement in these parameters. The hemodynamic response in patients who became completely free of pain and swelling or in whom ulcers healed was no different from that in those with residual pain or swelling or nonhealing ulcers.

FOLLOW-UP Patients having had iliocaval stenting should be observed on a regular basis. Transfemoral venography, ascending venography, or iliocaval duplex ultrasound scanning should be performed before the patient is discharged, 6 weeks to 3 months later, 6 months after intervention, and then annually. Patients with high risk for development of early thrombosis, mainly limbs with recanalization of postthrombotic occlusion, may be seen more often. Adequate anticoagulation is vital for stent patency in this group of patients. When a recurrent in-stent stenosis of more than 50% is found on routine surveillance, balloon angioplasty should be performed to maintain stent patency whether or not the patient is symptomatic. On emergence of significant interval symptoms, even with normal venography or ultrasound findings, IVUS should be performed generously to ensure that an in-stent restenosis or extrastent de novo stenosis does not go undetected and untreated.

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

Limbs with healed ulcers (%)

90

970

SECTION 10  Venous Insufficiency and Occlusion

SELECTED KEY REFERENCES Neglén P, Hollis KC, Olivier J, Raju S: Stenting of the venous outflow in chronic venous disease: long-term stent-related outcome, clinical, and hemodynamic result. J Vasc Surg 46:979–990, 2007. A comprehensive long-term study of clinical and stent-related outcome after venous stenting. Neglén P, Raju S: Intravascular ultrasound scan evaluation of the obstructed vein. J Vasc Surg 35:694–700, 2002. The “gold standard” of IVUS to measure morphologic outflow obstruction is established. Neglén P, Thrasher TL, Raju S: Venous outflow obstruction: an underestimated contributor to chronic venous disease. J Vasc Surg 38:879–885, 2003. Study stressing that outflow obstruction, not only reflux, plays a major role in chronic venous disease.

Raju S, Neglén P: High prevalence of nonthrombotic iliac vein lesions in chronic venous disease: a permissive role in pathogenicity. J Vasc Surg 44:136–143; discussion 144, 2006. The importance of the previously overlooked nonthrombotic iliac vein lesions (external compression) is pointed out. Raju S, Darcey R, Neglén P: Unexpected major role for venous stenting in deep reflux disease. J Vasc Surg 51:401–408; discussion 408, 2010. Shows unexpected efficacy of stenting, even in patients with combined outflow obstruction and reflux. The reference list can be found on the companion Expert Consult website at www.expertconsult.com.



REFERENCES

970.e1

27. Rigas A, et al: Measurement of the femoral vein pressure in oedema of the lower extremities. Report of 50 cases. J Cardiovasc Surg (Torino) 12:411–416, 1971. 28. Raju S, et al: The clinical impact of iliac venous stents in the management of chronic venous insufficiency. J Vasc Surg 35:8–15, 2002. 29. Neglén P, et al: Endovascular surgery in the treatment of chronic primary and post-thrombotic iliac vein obstruction. Eur J Vasc Endovasc Surg 20:560–571, 2000. 30. Neglén P, et al: Intravascular ultrasound scan evaluation of the obstructed vein. J Vasc Surg 35:694–700, 2002. 31. Arnoldussen CW, et al: An imaging approach to deep vein thrombosis and the lower extremity thrombosis classification. Phlebology 27(Suppl 1):143–148, 2012. 32. Wolpert LM, et al: Magnetic resonance venography in the diagnosis and management of May-Thurner syndrome. Vasc Endovascular Surg 36:51– 57, 2002. 33. Sampson FC, et al: The accuracy of MRI in diagnosis of suspected deep vein thrombosis: systematic review and meta-analysis. Eur Radiol 17:175–181, 2007. 34. Thomas SM, et al: Diagnostic value of CT for deep vein thrombosis: results of a systematic review and meta-analysis. Clin Radiol 63:299–304, 2008. 35. Lindquist CM, et al: Utility of balanced steady-state free precession MR venography in the diagnosis of lower extremity deep venous thrombosis. AJR Am J Roentgenol 194:1357–1364, 2010. 36. Forauer AR, et al: Intravascular ultrasound in the diagnosis and treatment of iliac vein compression (May-Thurner) syndrome. J Vasc Interv Radiol 13:523–527, 2002. 37. Neglén P, et al: Balloon dilation and stenting of chronic iliac vein obstruction: technical aspects and early clinical outcome. J Endovasc Ther 7:79–91, 2000. 38. Ahmed HK, et al: Intravascular ultrasonographic findings in MayThurner syndrome (iliac vein compression syndrome). J Ultrasound Med 20:251–256, 2001. 39. Satokawa H, et al: Intravascular imaging methods for venous disorders. Int J Angiol 9:117–121, 2000. 40. Hingorani A, et al: Role of IVUS versus venograms in assessment of iliac-femoral vein stenosis. J Vasc Surg 52:804, 2011. 41. Alhalbouni S, et al: Iliac-femoral venous stenting for lower venous stasis symptoms. Ann Vasc Surg 26:185–189, 2012. 42. Neglén P, et al: Proximal lower extremity chronic venous outflow obstruction: recognition and treatment. Semin Vasc Surg 15:57–64, 2002. 43. Hartung O, et al: Mid-term results of endovascular treatment for symptomatic chronic nonmalignant iliocaval venous occlusive disease. J Vasc Surg 42:1138–1144; discussion 1144, 2005. 44. Raju S, et al: Percutaneous recanalization of total occlusions of the iliac vein. J Vasc Surg 50:360–368, 2009. 45. Marzo KP, et al: Early restenosis following percutaneous transluminal balloon angioplasty for the treatment of the superior vena caval syndrome due to pacemaker-induced stenosis. Cathet Cardiovasc Diagn 36: 128–131, 1995. 46. Neglén P, et al: Iliofemoral venous thrombectomy followed by percutaneous closure of the temporary arteriovenous fistula. Surgery 110:493– 499, 1991. 47. Wisselink W, et al: Comparison of operative reconstruction and percutaneous balloon dilatation for central venous obstruction. Am J Surg 166:200–204; discussion 204–205, 1993. 48. Walpole HT, Jr, et al: Superior vena cava syndrome treated by percutaneous transluminal balloon angioplasty. Am Heart J 115:1303–1304, 1988. 49. Murphy KD: Mechanical thrombectomy for DVT. Tech Vasc Interv Radiol 7:79–85, 2004. 50. Neglén P, et al: Venous stenting across the inguinal ligament. J Vasc Surg 48:1255–1261, 2008. 51. Rector WG, Jr, et al: Membranous obstruction of the inferior vena cava in the United States. Medicine (Baltimore) 64:134–143, 1985. 52. Lee BB, et al: Primary Budd-Chiari syndrome: outcome of endovascular management for suprahepatic venous obstruction. J Vasc Surg 43:101– 108, 2006.

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

1. Garg N, et al: Factors affecting outcome of open and hybrid reconstructions for nonmalignant obstruction of iliofemoral veins and inferior vena cava. J Vasc Surg 53:383–393, 2011. 2. Raju S, et al: High prevalence of nonthrombotic iliac vein lesions in chronic venous disease: a permissive role in pathogenicity. J Vasc Surg 44:136–143; discussion 144, 2006. 3. Raju S, et al: Unexpected major role for venous stenting in deep reflux disease. J Vasc Surg 51:401–408; discussion 408, 2010. 4. Neglén P, et al: Combined saphenous ablation and iliac stent placement for complex severe chronic venous disease. J Vasc Surg 44:828–833, 2006. 5. Neglén P, et al: Venous outflow obstruction: an underestimated contributor to chronic venous disease. J Vasc Surg 38:879–885, 2003. 6. Johnson BF, et al: Relationship between changes in the deep venous system and the development of the postthrombotic syndrome after an acute episode of lower limb deep vein thrombosis: a one- to six-year follow-up. J Vasc Surg 21:307–312; discussion 313, 1995. 7. Johnson BF, et al: The site of residual abnormalities in the leg veins in long-term follow-up after deep vein thrombosis and their relationship to the development of the post-thrombotic syndrome. Int Angiol 15:14– 19, 1996. 8. Nicolaides AN, et al: The relation of venous ulceration with ambulatory venous pressure measurements. J Vasc Surg 17:414–419, 1993. 9. Nicolaides AN, et al: Investigations of patients with deep vein thrombosis and chronic venous insufficiency, Los Angeles, Calif, 1991, Med-Orion Publishing Co. 10. Negus D, et al: Compression and band formation at the mouth of the left common iliac vein. Br J Surg 55:369–374, 1968. 11. Akesson H, et al: Venous function assessed during a 5 year period after acute ilio-femoral venous thrombosis treated with anticoagulation. Eur J Vasc Surg 4:43–48, 1990. 12. Delis KT, et al: Venous claudication in iliofemoral thrombosis: long-term effects on venous hemodynamics, clinical status, and quality of life. Ann Surg 239:118–126, 2004. 13. Plate G, et al: Long-term results of venous thrombectomy combined with a temporary arterio-venous fistula. Eur J Vasc Surg 4:483–489, 1990. 14. Rokitansky C, et al: A manual of pathological anatomy, vol 4, London, 1852, Sydenham Society, p 336. 15. May R, et al: The cause of the predominantly sinistral occurrence of thrombosis of the pelvic veins. Angiology 8:419–427, 1957. 16. Ehrich WE, et al: A frequent obstructive anomaly of the mouth of the left common iliac vein. Am Heart J 26:737–750, 1943. 17. McMurrich JP: The occurrence of congenital adhesions in the common iliac veins, and their relation to thrombosis of the femoral and iliac veins. Am J Med Sci 135:342–346, 1943. 18. Kibbe MR, et al: Iliac vein compression in an asymptomatic patient population. J Vasc Surg 39:937–943, 2004. 19. Cockett FB, et al: Iliac vein compression. Its relation to iliofemoral thrombosis and the post-thrombotic syndrome. Br Med J 2:14–19, 1967. 20. Cockett FB, et al: The iliac compression syndrome. Br J Surg 52:816– 821, 1965. 21. Strandness DE, Jr, et al: The effect of geometry on arterial blood flow. Hemodynamics for surgeons, New York, 1975, Grune & Stratton, pp 96–119. 22. Neglén P, et al: Detection of outflow obstruction in chronic venous insufficiency. J Vasc Surg 17:583–589, 1993. 23. Labropoulos N, et al: The role of venous outflow obstruction in patients with chronic venous dysfunction. Arch Surg 132:46–51, 1997. 24. Hurst DR, et al: Diagnosis and endovascular treatment of iliocaval compression syndrome. J Vasc Surg 34:106–113, 2001. 25. Albrechtsson U, et al: Femoral vein pressure measurements for evaluation of venous function in patients with postthrombotic iliac veins. Cardiovasc Intervent Radiol 4:43–50, 1981. 26. Negus D, et al: Femoral vein pressures in post-phlebitic iliac vein obstruction. Br J Surg 54:522–525, 1967.

CHAPTER 62  Iliocaval Obstruction: Endovascular Treatment

970.e2 SECTION 10  Venous Insufficiency and Occlusion 53. Raju S, et al: Venous obstruction: an analysis of one hundred thirtyseven cases with hemodynamic, venographic, and clinical correlations. J Vasc Surg 14:305–313, 1991. 54. van der Laan L, et al: [The central-venous compression syndrome: rare, but adequately treatable with endovascular stenting.] Ned Tijdschr Geneeskd 148:433–437, 2004. 55. Raju S, et al: Obstructive lesions of the inferior vena cava: clinical features and endovenous treatment. J Vasc Surg 44:820–827, 2006. 56. Neglén P, et al: Stenting of chronically obstructed inferior vena cava filters. J Vasc Surg 54:153–161, 2011. 57. Neglén P, et al: Bilateral stenting at the iliocaval confluence. J Vasc Surg 51:1457–1466, 2010. 58. Farrell T, et al: Sharp recanalization of central venous occlusions. J Vasc Interv Radiol 10:149–154, 1999. 59. Honnef D, et al: Sharp central venous recanalization by means of a TIPS needle. Cardiovasc Intervent Radiol 28:673–676, 2005. 60. Kölbel T, et al: Chronic iliac vein occlusion: midterm results of endovascular recanalization. J Endovasc Ther 16:483–491, 2009. 61. Neglén P, et al: Stenting of the venous outflow in chronic venous disease: long-term stent-related outcome, clinical, and hemodynamic result. J Vasc Surg 46:979–990, 2007. 62. Hartung O, et al: Endovascular management of chronic disabling iliocaval obstructive lesions: long-term results. Eur J Vasc Endovasc Surg 38:118–124, 2009. 63. Knipp BS, et al: Factors associated with outcome after interventional treatment of symptomatic iliac vein compression syndrome. J Vasc Surg 46:743–749, 2007. 64. Neglén P, et al: In-stent recurrent stenosis in stents placed in the lower extremity venous outflow tract. J Vasc Surg 39:181–187, 2004. 65. Rosales A, et al: Stenting for chronic post-thrombotic vena cava and iliofemoral venous occlusions: mid-term patency and clinical outcome. Eur J Vasc Endovasc Surg 40:234–240. 2010. 66. Wahlgren CM, et al: Endovascular treatment in postthrombotic syndrome. Vasc Endovascular Surg 44:356–360, 2010.

67. Scott J, et al: Accuracy of subjective measurements made with or without previous scores: an important source of error in serial measurement of subjective states. Ann Rheum Dis 38:558–559, 1979. 68. Raju S, et al: Endovenous management of venous leg ulcers. J Vasc Sug 1:165–172, 2013. 69. Comerota AJ: Quality-of-life improvement using thrombolytic therapy for iliofemoral deep venous thrombosis. Rev Cardiovasc Med 3(Suppl 2): S61–S67, 2002. 70. Mavor GE, et al: Collaterals of the deep venous circulation of the lower limb. Surg Gynecol Obstet 125:561–571, 1967. 71. Kahn SR, et al: Determinants of health-related quality of life during the 2 years following deep vein thrombosis. J Thromb Haemost 6:1105–1112, 2008. 72. Launois R, et al: Construction and validation of a quality of life questionnaire in chronic lower limb venous insufficiency (CIVIQ). Qual Life Res 5:539–554, 1996. 73. Raju S, et al: Recanalization of totally occluded iliac and adjacent venous segments. J Vasc Surg 36:903–911, 2002. 74. Hartung O, et al: Management of pregnancy in women with previous left ilio-caval stenting. J Vasc Surg 50:355–359, 2009. 75. Ye K, et al: Long-term outcomes of stent placement for symptomatic nonthrombotic iliac vein compression lesions in chronic venous disease. J Vasc Interv Radiol 23:497–502, 2012. 76. Kurklinsky AK, et al: Outcomes of venoplasty with stent placement for chronic thrombosis of the iliac and femoral veins: single-center experience. J Vasc Interv Radiol 23:1009–1015, 2012. 77. Oguzkurt L, et al: Iliac vein compression syndrome: outcome of endovascular treatment with long-term follow-up. Eur J Radiol 68:487–492, 2008. 78. Razavi MK, et al: Chronically occluded inferior venae cavae: endovascular treatment. Radiology 214:133–138, 2000.

CHAPTER 63 

Superior Vena Cava Obstruction: Surgical Treatment PETER GLOVICZKI  /  MANJU KALRA

S

ymptoms of venous congestion of the head and neck secondary to occlusion of the superior vena cava (SVC) or innominate veins develop in about 15,000 patients each year in the United States.1 SVC syndrome is caused by malignant tumors of the lung and mediastinum in 60% of cases.2 The most frequent nonmalignant causes include placement of intravenous catheters or pacemaker wires and mediastinal fibrosis. Surgical treatment of SVC syndrome in patients with advanced malignant disease is frequently palliative, but it is usually curative for those with benign disease. Few areas of venous disease provide a more satisfying experience for both the patient and the vascular specialist than reconstruction for SVC syndrome. Relief from severe, frequently incapacitating symptoms of venous congestion of the head and neck is almost instantaneous, and the benefit after reconstruction is generally long lasting. Endovascular treatment of both acute and chronic SVC occlusion has become the first line of treatment for most patients and is discussed in detail in Chapter 64. In this chapter, we review the etiology, clinical findings, and diagnostic evaluation of SVC syndrome and present techniques and results of open surgical treatment of SVC occlusion.

SVC syndrome in 40% of cases. Mediastinal fibrosis and granulomatous fungal disease, such as histoplasmosis, have been the most frequent benign causes of SVC and innominate vein obstruction.7,9-13 However, the rapid increase in the use of indwelling central venous catheters and cardiac pacemakers during the past 2 decades has resulted in greater numbers of patients with SVC obstruction of benign etiology. Millions of central venous catheters and 397,000 pacemakers are now implanted annually in the United States and are associated with upper extremity or central vein deep venous thrombosis in 7% to 33% of patients.14,15 SVC syndrome reportedly occurs in 1% to 3% of patients with central venous catheters and in 0.2% to 3.3% of patients with implanted pacemakers.2 Previous radiotherapy to the mediastinum, retrosternal goiter, and aortic dissection can also cause SVC syndrome. The risk for venous thrombosis is increased in patients with thrombophilia, such as the factor V Leiden mutation, and in those with deficiencies of circulating natural anticoagulants, such as antithrombin III, protein S, and protein C.

ETIOLOGY

Signs and symptoms of venous congestion of the head, neck, and upper extremities are determined by the duration and extent of the occlusive venous disease and by the amount of collateral venous circulation that develops. Patients with SVC syndrome have a feeling of fullness in the head and neck that is exacerbated when bending over or lying flat in bed. The severity of the disease can easily be graded by the number of pillows needed by the patient to sleep comfortably. Venous hypertension may cause dyspnea on exertion or orthopnea, headache, dizziness, syncope, or visual symptoms (Table 63-1).1,16-18 Patients may complain of mental confusion or coughing. Dilated neck veins and swelling of the face, neck, and eyelids are the characteristic physical signs most commonly seen (Fig. 63-1). Prominent chest wall collateral veins are frequently present, as are ecchymosis and cyanosis of the face. Although symptoms are usually localized to the head and neck, mild to moderate upper extremity swelling may also develop. Additional signs and symptoms of malignant SVC syndrome include hemoptysis, hoarseness, dysphagia,

The first case report of an SVC obstruction, described by William Hunter in 1757, was due to an aortic aneurysm.3 Aortic aneurysms remained the second most common cause of SVC syndrome after primary malignant thoracic tumors until the mid-1900s.2 The incidence of tuberculous and syphilitic mediastinitis decreased markedly early in the 20th century. Lung cancer with mediastinal lymphadenopathy and primary mediastinal malignant tumors have become the most frequent causes of malignant SVC syndrome in the past 3 decades.1-7 Primary mediastinal malignant tumors leading to SVC syndrome include mediastinal lymphoma, medullary or follicular carcinoma of the thyroid, thymoma, teratoma, angiosarcoma, and synovial cell carcinoma.1-8 Of malignant SVC syndromes, non–small cell lung cancer is the cause in 50%, followed by small cell lung cancer (22%), lymphoma (12%), metastatic cancer (9%), germ cell cancer (3%), and thymoma (2%).1 Benign disease is the cause of

CLINICAL FINDINGS

971

972

SECTION 10  Venous Insufficiency and Occlusion

Table 63-1

Signs and Symptoms of Superior Vena Cava Syndrome of Benign Etiology in 70 Patients

Signs and Symptoms

Number of Patients (%)

Feeling of fullness in the head or neck Dyspnea on exertion or orthopnea Headache Dizziness or syncope Visual problems Cough Nocturnal oxygen requirement Protein-losing enteropathy Head and neck swelling Large chest wall venous collaterals Facial cyanosis Arm swelling Pleural effusion

61 (87) 39 (56) 27 (39) 25 (36) 11 (16) 10 (14) 3 (4) 1 (1) 65 (93) 40 (57) 24 (34) 23 (33) 2 (3)

From Rizvi AZ, et al: Benign superior vena cava syndrome: stenting is now the first line of treatment. J Vasc Surg 47:372, 2008.

weight loss, lethargy, and palpable cervical tumor or lymph nodes. Patients with lymphoma may also complain of fever and night sweats.

DIAGNOSTIC EVALUATION The diagnosis of SVC obstruction is usually suggested from a detailed clinical history and physical examination. The

B

A

D

E

clinical diagnosis may be confirmed by a variety of tools, including plain film radiography, ultrasonography, computed tomography (CT), venography, and magnetic resonance imaging. The appropriate diagnostic study for an individual patient will demonstrate not only the underlying cause but also the site and extent of obstruction as well as the routes of collateral venous circulation.

Radiography Plain film radiographs of the chest are readily available and are often abnormal in patients with SVC obstruction. Findings most commonly include mediastinal widening, right hilar mass, pleural effusion, bilateral diffuse infiltrates, and upper lobe collapse; however, a normal radiograph of the chest does not preclude the diagnosis of SVC obstruction.1,5,16 On occasion, dilated collateral veins may be visible, especially enlargement of the azygos vein or superior intercostal vein (aortic nipple) draining the hemiazygos system. In more than 90% of patients, a diagnosis of SVC syndrome can be made on the basis of the clinical findings and plain chest radiograph.16

Ultrasonography Ultrasound evaluation with duplex scanning (see Chapter 18) is an effective, noninvasive screening technique for patients with suspected SVC obstruction. Although direct visualization of the SVC is not possible with transthoracic

C

Figure 63-1  A, Severe symptomatic superior vena cava (SVC) syndrome in a 69-year-old man. B, A bilateral upper extremity venogram confirms thrombosis of the SVC and both innominate veins after placement of pacemaker lines bilaterally. C, Right internal jugular vein/right atrial appendage spiral saphenous vein graft (SSVG). Arrows indicate anasto­ moses. D, Postoperative venogram confirming graft patency. E, Photograph of the patient 5 days after SSVG placement. The clinical result is excellent 8 years after the operation. (From Gloviczki P, et al: Superior vena cava syndrome: endovascular and direct surgical treatment. In Gloviczki P, Yao YST, editors: Handbook of venous disorders, London, 1996, Chapman & Hall, pp 580-599.)



973

Magnetic Resonance Venography Advantages of magnetic resonance venography (MRV) include the ability to demonstrate anatomic structures in multiple planes and to delineate the central venous chest circulation and collateral vessels. MRV is a relatively noninvasive modality and does not require the administration of iodinated contrast material. A disadvantage is its contraindication in patients with pacemakers and aneurysm clips. Recent problems with use of gadolinium in renal insufficiency have significantly decreased the utility of MRV in this group of patients.

Computed Tomographic Angiography

CONSERVATIVE THERAPY

CT accurately depicts the location and extent of the obstruction and also distinguishes various types of benign and malignant mediastinal disease.19-23 Any mass or tumor is easily identified, and central lines or pacemaker wires are well seen. Injection of intravenous contrast material delineates the central veins, and three-dimensional reconstruction helps map the venous occlusion. CT will also identify the collateral pathways, including (1) the azygos-hemiazygos pathway, (2) the internal mammary pathway, (3) the lateral thoracic–thoracoepigastric pathway, and (4) the vertebral pathway and small mediastinal veins. Less commonly, unusual shunts, including hepatic parenchyma as an intense focal enhancement in the medial segment of the left lobe of the liver, and pulmonary pathways are identified on CT.22,23 No definite relationship between the level of occlusion and the number of collateral pathways has been identified.

Conservative measures are used first in every patient to relieve symptoms of venous congestion and to decrease the progression of venous thrombosis. Such measures include elevation of the head on pillows during the night, modification of daily activities by avoiding bending over, and avoidance of wearing constricting garments or a tight collar. Patients frequently need diuretic agents to decrease, at least temporarily, excessive edema of the neck and head. Patients with acute SVC syndrome caused by malignant disease are generally treated with intravenous unfractionated or low-molecular-weight heparin, followed by warfarin, to prevent recurrence and to protect the venous collateral circulation. Thrombolytic treatment is considered in most patients with benign acute SVC syndrome, whereas those with metastatic malignant disease are candidates for treatment with endovascular stents, with or without thrombolytic therapy25,26 (see Chapter 64). Symptoms of SVC syndrome caused by mediastinal malignant tumors frequently improve after irradiation, chemotherapy, or combination chemoradiotherapy based on tumor histology.1 Symptoms resolve in 80% of patients within 4 weeks. In the past 2 decades, endovascular treatment with stents has become the first-line therapy for both malignant and benign SCV syndrome. For technique and results of endovenous therapy, readers are referred to Chapter 64.

Contrast-Enhanced Venography Venography has been considered the “gold standard” for accurate depiction of central venous obstruction and is used to provide an anatomic roadmap before reconstructive surgery. Venography also depicts the presence and direction of venous collateral flow. It is performed by simultaneous injection of contrast material in bilateral superficial arm veins. Stanford and Doty described four venographic patterns of SVC syndrome, each having a different venous collateral network, depending on the site and extent of SVC obstruction24 (Fig. 63-2 and Table 63-2). Type I is partial and type II is complete or nearly complete SVC obstruction, with flow in the azygos vein remaining antegrade. Type III is 90% to 100% obstruction of the SVC with reversed azygos blood flow (Fig. 63-3A), whereas type IV is extensive mediastinal central venous occlusion with venous return occurring through the inferior vena cava (see Fig. 63-1B). During upper extremity venography, only veins and collateral pathways between the injection site and the right atrium are visualized. The internal jugular veins, frequently used for inflow for surgical bypass, are not visualized.

SURGICAL TREATMENT Indications Patients with SVC syndrome can have severe, frequently incapacitating symptoms that cannot be alleviated by conservative measures. Patients with benign disease who have extensive chronic venous thrombosis (type III or IV) not anatomically suitable for endovascular treatment and those with less extensive disease (type I or II) who have failed to respond to endovascular therapy are candidates for open surgical reconstruction. There are multiple, frequently just small series in the literature reporting successful surgical reconstruction for a variety of benign causes of SVC syndrome, including granulomatous and idiopathic mediastinal fibrosis,

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

duplex ultrasound, valuable information can be obtained. The subclavian and internal jugular veins are accessible to sonographic evaluation and can provide indirect evidence of SVC patency or obstruction. In the presence of SVC obstruction, the normal variation in respiratory flow caused by changes in intrathoracic pressure seen in patent subclavian veins is lost. This can easily be demonstrated by reduced or no change in the diameter and blood flow through the subclavian veins in response to respiratory maneuvers, such as a sudden sniff or a Valsalva maneuver. Collateral vessels can be detected within the chest wall or in the mediastinum.

CHAPTER 63  Superior Vena Cava Obstruction: Surgical Treatment

974

SECTION 10  Venous Insufficiency and Occlusion Left brachiocephalic vein Accessory hemiazygos vein

Accessory hemiazygos vein Azygos vein

Azygos vein

Type I

Type II

Hemiazygos vein

B

A Right superior intercostal vein

Internal mammary veins

Accessory hemiazygos vein

Chest wall collaterals

Type III Superior epigastric veins

Hemiazygos vein

Type IV

C

D

Table 63-2

Inferior epigastric veins

Figure 63-2  Venographic classification of superior vena cava (SVC) syndrome according to Stanford and Doty.24 A, Type I: high-grade SVC stenosis but still normal direction of blood flow through the SVC and azygos vein. There is increased collateral circulation through the hemiazygos and accessory hemiazygos veins in type I. B, Type II: greater than 90% stenosis or occlusion of the SVC but a patent azygos vein with normal direction of blood flow. C, Type III: occlusion of the SVC with retrograde flow in both the azygos and hemiazygos veins. D, Type IV: extensive occlusion of the SVC and innominate and azygos veins with chest wall and epigastric venous collaterals. (Redrawn from Alimi YS, et al: Reconstruction of the superior vena cava: the benefits of postoperative surveillance and secondary endovascular interventions. J Vasc Surg 27:298-299, 1998.)

Venographic Classification* in 70 Patients Who Underwent Reconstruction for Benign Superior Vena Cava Syndrome

Type

Description

I II

>90% stenosis or occlusion of the SVC with patency and antegrade flow in the azygos–right atrial pathway

6 (9) 16 (23)

>90% stenosis or occlusion of the SVC with reversal of azygos blood flow Occlusion of the SVC and one or more of the major caval tributaries, including the azygos systems Total

20 (28) 70 (100)

III IV

Stenosis (up to 90%) of the SVC with patency and antegrade flow of the azygos–right atrial pathway

From Rizvi AZ, et al: Benign superior vena cava syndrome: stenting is now the first line of treatment. J Vasc Surg 47:372, 2008. SVC, Superior vena cava. *Classification of Stanford and Doty.24

Number of Patients (%)

28 (40)

CHAPTER 63  Superior Vena Cava Obstruction: Surgical Treatment



B

Figure 63-3  A, Bilateral upper extremity venogram documenting obstruction of the superior vena cava and retrograde flow through the azygos vein (arrow). B, Left innominate vein/right atrial appendage spiral saphenous vein graft. (From Gloviczki P, et al: Reconstruction of the vena cava and of its primary tributaries: a preliminary report. J Vasc Surg 11:373-381, 1990.)

central venous catheters, pacemaker electrodes, and ventriculoatrial shunts, as well as antithrombin III deficiency and idiopathic venous thrombosis.9-11,17,18,27-29 Surgical reconstruction of the SVC has also been performed in patients with different types and stages of malignant disease.30-41 Patients with a malignant tumor should undergo reconstruction through a median sternotomy only if their life expectancy is more than 1 year. Extra-anatomic subcutaneous bypass between the jugular vein and the femoral vein with a composite saphenous vein graft or polytetrafluoroethylene graft is an alternative if symptoms are severe and endovascular techniques fail or are not possible.42-45

Graft Materials Grafting of large veins has been difficult because largediameter autologous vein is not available to use as a conduit.

Great Saphenous Vein Graft The great saphenous vein is not usually suitable for direct reconstruction because of poor size match. Extra-anatomic reconstruction, however, in which the external or internal jugular vein is connected to the ipsilateral common femoral vein with both great saphenous veins sutured together in end-to-end fashion and tunneled subcutaneously, has been performed by several authors with good results.42,43 To prevent external compression, Panneton and colleagues placed the composite saphenous vein graft from the right internal jugular to the femoral vein inside an externally supported expanded polytetrafluoroethylene (ePTFE) graft.45

Femoral Vein Graft The femoral vein or the femoropopliteal vein is a good conduit to reconstruct the SVC. It has been used with success because of its excellent suitability in terms of size and length.17,18,46 However, if the patient has underlying thrombotic abnormalities, removal of a deep leg vein may result in at least moderate lower extremity edema and pain. Compartment syndrome and chronic venous insufficiency after harvesting of longer segments of the femoropopliteal veins have been reported.47,48 For this reason, in young patients who undergo SVC reconstruction for benign disease, we prefer use of a spiral saphenous vein graft (SSVG).

Spiral Saphenous Vein Graft An SSVG is autologous tissue with low thrombogenicity. Although its length is limited by the available saphenous vein segment, its diameter can easily be matched to that of the internal jugular or innominate vein49 (see Figs. 63-1 and 63-3B). Described in animal experiments first by Chiu and colleagues,50 this graft was first implanted in patients by Doty.9,10 Our technique for preparing the SSVG is illustrated in Figure 63-4.51 The saphenous vein is removed, distended with papaverinesaline solution, and opened longitudinally. The valves are excised, and the saphenous vein is wrapped around a 32F or 36F polyethylene chest tube. The edges of the vein are sutured together with running 6-0 or 7-0 monofilament nonabsorbable suture to form the SSVG conduit, with the suture line interrupted at every three-quarter turn (see Fig. 63-4). Alternatively, metal clips have the advantage of decreased

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

A

975

976

SECTION 10  Venous Insufficiency and Occlusion

Saphenous vein

time and less chance of purse-stringing the suture line (Fig. 63-5). The length of saphenous vein to be harvested to create a graft of sufficient length is determined according to an equation proposed by Chiu and coworkers50 in experiments (l = RL/r, with r and l being the radius and length of the saphenous vein and R and L being the radius and length of the SSVG). Harvesting of vein from the groin to the knee usually results in an SSVG approximately 10 cm long.

Expanded Polytetrafluoroethylene Graft

A

B

Of the available prosthetic materials, externally supported ePTFE is the one used for large-vein reconstruction almost exclusively.51-54 Short, large-diameter (10 to 14 mm) grafts have excellent long-term patency because flow through the innominate vein generally exceeds 1000 mL/min. If the peripheral anastomosis is performed with the subclavian vein, venous inflow is significantly less, and the addition of an arteriovenous fistula in the arm is usually required to ensure graft patency. For an internal jugular/atrial appendage bypass, a large-diameter (12 mm) ePTFE graft is a suitable alternative if use of the spiral saphenous vein is not possible. An arteriovenous fistula with direct flow into the graft has not been performed for jugular grafts. An externally supported prosthetic graft is a good choice in patients with a tight mediastinum and usually for all patients with malignant disease because recurrent tumor is more likely to compress and occlude a vein graft.55-59

Allograft/Cryopreserved Homograft A fresh iliocaval allograft can be considered in rare cases when immunosuppressive treatment is otherwise indicated for protection of a transplanted organ (Fig. 63-6).60 Homografts, cryopreserved femoral vein, and aortic arch grafts are other alternatives that have been used with success, as are grafts prepared from autogenous or bovine pericardium.61-69

Surgical Technique

C Figure 63-4  A, Technique for fashioning a spiral saphenous vein graft (SSVG). The saphenous vein is opened longitudinally, the valves are excised, the vein is wrapped around an argyle chest tube, and the vein edges are approximated with sutures. B, A 15-cm-long SSVG ready for implantation. C, Technique of left internal jugular/right atrial SSVG implantation. (From Gloviczki PG, et al: Venous reconstruction for obstruction and valvular incompetence. In Goldstone J, editor: Perspectives in vascular surgery, St. Louis, 1988, Quality Medical Publishing, pp 75-93.)

The operation is performed through a median sternotomy. If the internal jugular vein is used for inflow, the midline incision is extended obliquely into the neck along the anterior border of the sternocleidomastoid muscle on the appropriate side. The mediastinum is exposed, and biopsy of the mediastinal mass or resection of the tumor is performed before caval reconstruction. After biopsy or tumor resection is performed, the pericardial sac is opened to expose the right atrial appendage, which is used most frequently for the central anastomosis. A sidebiting Satinsky clamp is placed on the right atrial appendage, which is then opened longitudinally. Some trabecular muscle is excised to improve inflow, and an end-to-side anastomosis with the vein graft is performed with running 5-0 monofilament suture (see Fig. 63-4C). If it is not involved in the fibrosing process, a patent SVC central to the occlusion can also be used for this purpose. The peripheral anastomosis of the graft is performed with the internal jugular or innominate vein in an end-to-side or, preferably, an end-to-end fashion.

CHAPTER 63  Superior Vena Cava Obstruction: Surgical Treatment



A

Although we have placed bifurcated SSVGs (Fig. 63-7) or bifurcated prosthetic grafts in a few patients, a single straight graft from the internal jugular or innominate vein (Fig. 63-8; see Figs. 63-1 and 63-3) is our current operative choice for SVC reconstruction. Because collateral circulation in the head and neck is almost always adequate, unilateral reconstruction is sufficient to relieve symptoms in most patients. When only part of the circumference of the SVC is invaded by the tumor, resection plus caval patch angioplasty with a

A

B

prosthetic patch, bovine pericardium, or autogenous material such as saphenous vein or pericardium is also a viable option. Postoperative anticoagulation is started 24 hours later with heparin, and the patient is discharged on an oral anticoagulation regimen. Patients with SSVGs or femoral vein grafts who have no underlying coagulation abnormality are maintained on warfarin (Coumadin) for 3 months only. Those with underlying coagulation disorders and most

B

Figure 63-6  A, Venography in a 41-year-old woman with mediastinal fibrosis and liver failure demonstrates type III superior vena cava (SVC) occlusion with retrograde flow in the azygos vein (arrow). B, Left innominate vein/right atrial appendage bypass with an iliocaval allograft was performed concomitant with orthotopic liver transplantation. Arrows indicate the anastomoses. The graft is patent and the patient is asymptomatic from SVC syndrome 3 years after surgery. (From Rhee Y, et al: Superior vena cava reconstruction using an iliocaval allograft. Vasc Surg 30:77-83, 1996.)

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

Figure 63-5  A, Nonpenetrating vascular clips used for preparation of a spiral saphenous vein graft. B, Postoperative venogram demonstrating the patent left internal jugular/right atrial appendage bypass graft. The graft is patent and the patient is asymptomatic 3 years later.

977

978

A

SECTION 10  Venous Insufficiency and Occlusion

Figure 63-7  A, Bifurcated spiral saphenous vein graft in a 43-year-old woman. B, A venogram at 37 months reveals patent limbs of the bifurcated graft. (From Alimi YS, et al: Reconstruction of the superior vena cava: the benefits of postoperative surveillance and secondary endovascular interventions. J Vasc Surg 27:298-299, 1998.)

B

patients with ePTFE grafts continue lifelong anticoagulation therapy.

Results Open surgical treatment of SVC syndrome has excellent long-term results (Figs. 63-9 and 63-10). Outcome depends on the etiology, conduit, and length of the venous reconstruction. Of the autologous graft materials, experience with SSVGs and femoral vein grafts has been the largest. Doty and colleagues, reporting on the long-term results of 16 SSVGs used for benign SVC syndrome, achieved an 88% patency rate and excellent clinical results at a mean follow-up of 10.9 years.66 Our experience includes 22 SVC reconstructions

A

B

with SSVGs; the secondary patency rate was 86% at 5 years, 19 of the 22 grafts were patent at last follow-up, and clinical results were good to excellent in these patients.18 Increasing success with femoral vein as an arterial conduit has resurrected this autologous graft for large-vein reconstructions as well (Fig. 63-11).70 Recent reports of good early results indicate that when it is available, autologous femoropopliteal vein shows promise for replacement of large central veins. All six femoral vein grafts performed by us have remained patent.18 Still, the morbidity of harvesting a deep vein in patients with thrombotic potential and venous thrombosis elsewhere in the body is not well known. Two of our six patients who underwent SVC reconstruction with the femoral vein have mild but persistent swelling and venous

Figure 63-8  A, A venogram 10 months after placement of a left innominate vein/right atrial appendage spiral vein graft reveals severe stenosis at the proximal anastomosis (arrow). B, Successful reconstruction with placement of a Wallstent (arrow). (From Alimi YS, et al: Reconstruction of the superior vena cava: the benefits of postoperative surveillance and secondary endovascular interventions. J Vasc Surg 27:298-299, 1998.)

979

CHAPTER 63  Superior Vena Cava Obstruction: Surgical Treatment



85%

100

81%

75% 68%

75% 68%

58%

60

45%

Primary Assisted primary Secondary

20

Figure 63-9  Cumulative patency rates (primary, assisted-primary, and secondary) of 42 bypass grafts used for reconstruction of the superior vena cava. (From Rizvi AZ, et al: Benign superior vena cava syndrome: stenting is now the first line of treatment. J Vasc Surg 47:372, 2008.)

45%

40

0 0

1

2

3 Time (yr)

4

5

100 90%

Patency rate (%)

80

Figure 63-10  Cumulative secondary patency rates of 23 vein grafts and 6 expanded polytetrafluoroethylene (ePTFE) bypass grafts used for reconstruction of the superior vena cava. (From Kalra M, et al: Open surgical and endovascular treatment of superior vena cava syndrome caused by nonmalignant disease. J Vasc Surg 38:215-223, 2003.)

A

90%

90%

67%

60

50%

50%

40

20

Vein ePTFE

P = .02

0 0

B

1

2

3 Years

4

5

C

Figure 63-11  A, Left innominate vein/right atrial appendage bypass graft using femoral vein. B, Venogram 3 months after surgery confirms the graft to be widely patent. C, Illustration of a left innominate artery/right atrial appendage vein graft.

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

Patency rate (%)

80

980

SECTION 10  Venous Insufficiency and Occlusion

A

B

Figure 63-12  Venograms after placement of a left internal jugular vein/atrial appendage externally supported expanded polytetrafluoroethylene (ePTFE) graft. A, Widely patent graft 3 months after the operation. B, Patent ePTFE graft 13 months after intervention in another patient.

claudication. Nonetheless, it is a good conduit in patients with unavailable or inadequate saphenous vein. In several series, ePTFE grafts implanted into the mediastinum have resulted in excellent patency. In patients who have malignant disease, mortality and complications are frequently elevated because of the associated lung and mediastinal tumor resections.40,71-74 Dartevelle and associates observed continued patency in 20 of 22 ePTFE grafts at a mean follow-up of 23 months.33 Moore and Hollier observed no graft occlusion at a mean follow-up of 30 months in 10 patients who underwent large central vein reconstruction.28 In 8 of these 10 patients, an additional arteriovenous fistula at the arm was used to increase flow and to maintain patency. Magnan and coauthors reported on 10 patients who underwent reconstruction of the SVC with ePTFE grafts. Nine of the 10 patients had malignant disease. Although early mortality was high, with only two survivors during the follow-up period, in no patient did recurrent symptoms of SVC syndrome develop.34 Wisselink and colleagues reported a 100% patency rate at 1 year with ePTFE bypass grafts for central vein occlusion performed in six patients maintained on hemodialysis; however, a brachial arteriovenous fistula was concomitantly created in five of these six patients to augment graft blood flow.75 In a review by Picquet and coworkers of 24 patients by who underwent SVC reconstruction, no thrombosis was observed at a mean follow-up of 28 months.59 Two thirds of the patients, however, had underlying malignant tumors, and overall survival was only 53% at 1 year and 35% at 5 years. Reviewing other series from the literature as well, we have found that the patency rate of ePTFE grafts at 2 years is approximately 70%. In our experience, some thrombus formation occurs even in patent ePTFE grafts. Thrombosis occurs much more

frequently in patients in whom the distal anastomosis is performed with the internal jugular or the subclavian veins, and results appear to be much better in patients with innominate or SVC interposition grafts. Similar to our experience, Shintani and coworkers noted a greater incidence of occlusion in bifurcated versus straight grafts.76 Although a spiral vein graft continues to be our first choice for SVC replacement, short, large-diameter ePTFE is an excellent alternative for SVC replacement (Fig. 63-12). Rizvi and associates reported the results of open surgical treatment of SVC syndrome.18 Forty-two patients underwent placement of 22 SSVGs, 6 reversed femoral vein grafts, 13 ePTFE grafts, and 1 iliocaval allograft. Median sternotomy was performed in all. The grafts originated from the internal jugular vein in 15 patients, the subclavian vein in 1, and the innominate vein in 26; they were anastomosed centrally to the SVC in 12 patients and the right atrial appendage in 30. No early deaths or pulmonary thromboembolism occurred. Six patients underwent early reoperation for graft thrombosis: thrombectomy of four ePTFE grafts and thrombectomy and revision of side limbs of two bifurcated SSVG grafts. All grafts, except one limb of a bifurcated graft, were patent at the time of discharge. Thirty-day primary, assisted-primary, and secondary patency rates were 93%, 98%, and 100%, respectively. During a mean follow-up of 4.1 (0.1 to 17.5) years, the primary and secondary patency rates of all the grafts at 5 years were 45% and 75%, respectively. Of the different graft types, SSVGs performed well, with an 86% secondary patency rate at 5 years. The concomitant bilateral reconstructions attempted early in our experience resulted in complications. We have since shied away from bilateral reconstruction and have found that collateralization across the midline is



981

SELECTED KEY REFERENCES Rizvi AZ, Kalra M, Bjarnason H, Bower TC, Schleck C, Gloviczki P: Benign superior vena cava syndrome: stenting is now the first line of treatment. J Vasc Surg 47:372, 2008. A comparative review of the results of surgical and endovascular treatment of SVC syndrome of benign etiology in 70 patients. Sekine Y, Suzuki H, Saitoh Y, Wada H, Yoshida S: Prosthetic reconstruction of the superior vena cava for malignant disease: surgical techniques and outcomes. Ann Thorac Surg 90:223–228, 2010. A retrospective study of patients who underwent combined surgical resection of malignant tumors and SVC reconstruction by a ringed polytetrafluoroethylene graft. Stanford W, Doty DB: The role of venography and surgery in the management of patients with superior vena cava obstruction. Ann Thorac Surg 41:158, 1986. A classic paper on venographic classification of SVC syndrome. Wilson LD, Detterbeck FC, Yahalom J: Superior vena cava syndrome with malignant causes. N Engl J Med 356:1862, 2007. Excellent review of the etiology, anatomy, and medical and surgical treatment of SVC syndrome caused by malignant disease. Yildizeli B, Dartevelle PG, Fadel E, Mussot S, Chapelier A: Results of primary surgery with T4 non–small cell lung cancer during a 25-year period in a single center: the benefit is worth the risk. Ann Thorac Surg 86:1065–1075; discussion 74–75, 2008. A large retrospective analysis of 271 patients who underwent resection of a T4 non-small-cell lung carcinoma; 39 patients had concomitant SVC reconstructions. The reference list can be found on the companion Expert Consult website at www.exptertconsult.com.

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

adequate to decompress both sides with a single graft in most patients. Postoperative graft surveillance is important. Unfortunately, duplex ultrasound provides only indirect evidence of the patency of an intrathoracic graft. Therefore, contrastenhanced CT or MRV is recommended at 3 to 6 months after surgery and anytime afterward when symptoms recur. In our experience, all high-grade graft stenoses occurred within the first year postoperatively, and half of these patients had mild stenosis on the first postoperative surveillance venogram. Regardless of the treatment modality, discovery of stenosis was accompanied by recurrence of symptoms in all cases except one. A similar view has been expressed by Doty and associates.66 On the basis of these data, graft patency can be inferred from freedom from symptoms, and imaging after the first year needs to be performed only in symptomatic patients or in asymptomatic patients with known nonsignificant stenosis. Endovascular therapy is a useful adjunctive measure to treat graft stenosis and to improve long-term graft patency.17,18,27 Although endovascular treatment is the first line of therapy and it is less invasive than open surgery, the number of repeated interventions after stents is much higher than after open surgery, and long-term results of stenting are still not available. Open reconstructions are invasive procedures, but they are safe and durable and continue to have an important role in the treatment of patients with SVC syndrome.

CHAPTER 63  Superior Vena Cava Obstruction: Surgical Treatment



REFERENCES

981.e1

29. Kennedy DP, et al: Reconstruction of superior vena cava syndrome due to benign disease using superficial femoral vein. Ann Vasc Surg 24:555. e7–555.e12, 2010. 30. Bergeron P, et al: Our experience with surgery of the superior vena cava. Ann Chir 39:485, 1985. 31. Herreros J, et al: Superior vena cava compression syndrome. Our experience apropos of 26 cases. Ann Chir 39:495, 1985. 32. Ricci C, et al: Reconstruction of the superior vena cava: 15 years’ experience using various types of prosthetic material. Ann Chir 39:492, 1985. 33. Dartevelle PG, et al: Long-term follow-up after prosthetic replacement of the superior vena cava combined with resection of mediastinalpulmonary malignant tumors. J Thorac Cardiovasc Surg 102:259, 1991. 34. Magnan PE, et al: Surgical reconstruction of the superior vena cava. Cardiovasc Surg 2:598, 1994. 35. Kalra M, et al: Surgical and endovenous treatment of superior vena cava syndrome. In Gloviczki P, editor: Handbook of venous disorders, ed 3, London, Edward Arnold, 2009, p 553. 36. Chen KN, et al: Surgical treatment of complex malignant anterior mediastinal tumors invading the superior vena cava. World J Surg 30:162–170, 2006. 37. Inoue M, et al: Efficient clinical application of percutaneous cardiopulmonary support for perioperative management of a huge anterior mediastinal tumor. J Thorac Cardiovasc Surg 131:755, 2006. 38. Spaggiari L, et al: Superior vena cava resection for lung and mediastinal malignancies: a single-center experience with 70 cases. Ann Thorac Surg 83:223–229; discussion 229–230, 2007. 39. Gomez-Caro A, et al: Cryopreserved arterial allograft reconstruction after excision of thoracic malignancies. Ann Thorac Surg 86:1753–1761; discussion 1761, 2008. 40. Yildizeli B, et al: Results of primary surgery with T4 non–small cell lung cancer during a 25-year period in a single center: the benefit is worth the risk. Ann Thorac Surg 86:1065–1075; discussion 1074–1075, 2008. 41. Sekine Y, et al: Prosthetic reconstruction of the superior vena cava for malignant disease: surgical techniques and outcomes. Ann Thorac Surg 90:223–228, 2010. 42. Kuehnl A, et al: Resection of malignant tumors invading the vena cava: perioperative complications and long-term follow-up. J Vasc Surg 46:533, 2007. 43. Vincze K, et al: Saphenous-jugular bypass as palliative therapy of superior vena cava syndrome caused by bronchial carcinoma. J Thorac Cardiovasc Surg 83:272, 1982. 44. Graham A, et al: Subcutaneous jugulofemoral bypass: a simple surgical option for palliation of superior vena cava obstruction. J Cardiovasc Surg 36:615, 1995. 45. Panneton JM, et al: Superior vena cava syndrome relief with a modified sapheno-jugular bypass graft. J Vasc Surg 34:360, 2001. 46. Dhaliwal RS, et al: Management of superior vena cava syndrome by internal jugular to femoral vein bypass. Ann Thorac Surg 82:310, 2006. 47. Wells JK, et al: Venous morbidity after superficial femoral–popliteal vein harvest. J Vasc Surg 29:282–289; discussion 289, 1999. 48. Modrall JG, et al: Late incidence of chronic venous insufficiency after deep vein harvest. J Vasc Surg 46:520, 2007. 49. Gladstone DJ, et al: Relief of superior vena caval syndrome with autologous femoral vein used as a bypass graft. J Thorac Cardiovasc Surg 89:750, 1985. 50. Chiu CJ, et al: Replacement of superior vena cava with the spiral composite vein graft: a versatile technique. Ann Thorac Surg 17:555, 1974. 51. Gloviczki P, et al: Prosthetic replacement of large veins. In Bergan J, et al, editors: Atlas of venous surgery, Philadelphia, WB Saunders, 1992, p 191. 52. Meissner MH, et al: Secondary chronic venous disorders. J Vasc Surg 46:S68, 2007. 53. Bower TC, et al: Replacement of the inferior vena cava for malignancy: an update. J Vasc Surg 31:270, 2000. 54. Jost CJ, et al: Surgical reconstruction of iliofemoral veins and the inferior vena cava for nonmalignant occlusive disease. J Vasc Surg 33:320, 2001.

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

1. Wilson LD, et al: Superior vena cava syndrome with malignant causes. N Engl J Med 356:1862, 2007. 2. Rice TW, et al: The superior vena cava syndrome: clinical characteristics and evolving etiology. Medicine (Baltimore) 85:37, 2006. 3. Hunter W: The history of an aneurysm of the aorta with some remarks on aneurysms in general. Med Obs Inq (Lond) 1:323, 1757. 4. Ahmann F: A reassessment of the clinical implications of the superior vena cava syndrome. J Clin Oncol 2:961, 1984. 5. Parish JM, et al: Etiologic considerations in superior vena cava syndrome. Mayo Clin Proc 56:407, 1981. 6. Sculier JP, et al: Superior vena cava obstruction syndrome: recommendations for management. Cancer Treat Rev 12:209, 1985. 7. Chen J, et al: A contemporary perspective on superior vena cava syndrome. Am J Surg 160:207, 1990. 8. Yellin A, et al: Superior vena cava syndrome: the myth—the facts. Am Rev Respir Dis 141:1114, 1990. 9. Doty DB: Bypass of superior vena cava: six years’ experience with spiral vein graft for obstruction of superior vena cava due to benign and malignant disease. J Thorac Cardiovasc Surg 83:326, 1982. 10. Doty DB, et al: Bypass of superior vena cava: fifteen years’ experience with spiral vein graft for obstruction of superior vena cava caused by benign disease. J Thorac Cardiovasc Surg 99:889, 1990. 11. Gloviczki P, et al: Reconstruction of large veins for nonmalignant venous occlusive disease. J Vasc Surg 16:750, 1992. 12. Gupta D, et al: Cervical and mediastinal fibrosis presenting with superior vena cava syndrome. Indian Heart J 31:302, 1979. 13. Dodds GA, 3rd, et al: Relief of superior vena cava syndrome due to fibrosing mediastinitis using the Palmaz stent. Chest 106:315, 1994. 14. Roger VL, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee: Heart disease and stroke statistics—2012 update: a report from the American Heart Association [erratum appears in Circulation 125:e1002, 2012]. Circulation 125:e2–e220, 2012. 15. Korkeila P, et al: Venous obstruction after pacemaker implantation. Pacing Clin Electrophysiol 30:199, 2007. 16. Laguna Del Estal P, et al: Superior vena cava syndrome: a study based on 81 cases. An Med Interna 15:470, 1998. 17. Alimi YS, et al: Reconstruction of the superior vena cava: benefits of postoperative surveillance and secondary endovascular interventions. J Vasc Surg 27:287, 1998. 18. Rizvi AZ, et al: Benign superior vena cava syndrome: stenting is now the first line of treatment. J Vasc Surg 47:372, 2008. 19. Kim HJ, et al: CT diagnosis of superior vena cava syndrome: importance of collateral vessels. AJR Am J Roentgenol 161:539, 1993. 20. Yedlicka JW, et al: CT findings in superior vena cava obstruction. Semin Roentgenol 24:84, 1989. 21. Bashist B, et al: Abdominal CT findings when the superior vena cava, brachiocephalic vein, or subclavian vein is obstructed. AJR Am J Roentgenol 167:1457, 1996. 22. Yamada T, et al: Focal hepatic “hot spot” in superior vena cava obstruction: correlation between radiocolloid hepatic SPECT and contrastenhanced CT. Clin Nucl Med 24:533, 1999. 23. Cihangiroglu M, et al: Collateral pathways in superior vena caval obstruction as seen on CT. J Comput Assist Tomogr 25:1, 2001. 24. Stanford W, et al: The role of venography and surgery in the management of patients with superior vena cava obstruction. Ann Thorac Surg 41:158, 1986. 25. Gloviczki P, et al: Reconstruction of the vena cava and of its primary tributaries: a preliminary report. J Vasc Surg 11:373, 1990. 26. Schindler N, et al: Superior vena cava syndrome: experience with endovascular stents and surgical therapy. Surg Clin North Am 79:683, 1999. 27. Kalra M, et al: Open surgical and endovascular treatment of superior vena cava syndrome caused by nonmalignant disease. J Vasc Surg 38:215, 2003. 28. Moore W, et al: Reconstruction of the superior vena cava and central veins. In Bergan J, et al, editors: Venous disorders, Philadelphia, WB Saunders, 1991, p 517.

CHAPTER 63  Superior Vena Cava Obstruction: Surgical Treatment

981.e2 SECTION 10  Venous Insufficiency and Occlusion 55. Marshall W, et al: Management of recurrent superior vena caval syndrome with an externally supported femoral vein bypass graft. Ann Thorac Surg 46:239, 1988. 56. Durkovic S, et al: Prosthetic azygo-atrial bypass for palliation of superior vena cava syndrome. Eur J Cardiothorac Surg 41:e56–e58, 2012. 57. Okereke IC, et al: Results of superior vena cava reconstruction with externally stented–polytetrafluoroethylene vascular prostheses. Ann Thorac Surg 90:383–387, 2010. 58. Okereke IC, et al: Superior vena cava and innominate vein reconstruction in thoracic malignancies: single-vein reconstruction. Semin Thorac Cardiovasc Surg 23:323–325, 2011. 59. Picquet J, et al: Surgical reconstruction of the superior vena cava system: indications and results. Surgery 145:93–99, 2009. 60. Rhee R, et al: Superior vena cava reconstruction using an iliocaval allograft. Vasc Surg 30:77, 1996. 61. Billing JS, et al: Aortic arch homograft as a bypass conduit for superior vena cava obstruction. Ann Thorac Surg 76:1296, 2003. 62. Zembala M, et al: Pericardial tube for obstruction of superior vena cava by malignant teratoma. J Thorac Cardiovasc Surg 91:469, 1986. 63. Seelig MH, et al: Superior vena cava syndrome caused by chronic hemodialysis catheters: autologous reconstruction with a pericardial tube graft. J Vasc Surg 28:556, 1998. 64. Abdullah F, et al: Superior vena cava obstruction bypass—an alternative technique using bovine pericardial conduit: a case report. Heart Surg Forum 6:E50, 2003. 65. Singh S, et al: Reconstruction of the superior vena cava with the aid of an extraluminal venovenous jugulo-atrial shunt. Tex Heart Inst J 27:38, 2000. 66. Doty JR, et al: Superior vena cava obstruction: bypass using spiral vein graft. Ann Thorac Surg 67:1111, 1999.

67. Jaus M, et al: Superior vena cava and innominate vein reconstruction in thoracic malignancies: cryopreserved graft reconstruction. Semin Thorac Cardiovasc Surg 23:330–335, 2011. 68. Ciccone AM, et al: Long-term patency of the stapled bovine pericardial conduit for replacement of the superior vena cava. Eur J Cardiothorac Surg 40:1487–1491; discussion 1491, 2011. 69. Firstenberg MS, et al: Superior vena cava bypass with cryopreserved ascending aorta allograft. Ann Thorac Surg 91:905–907, 2011. 70. Hagino RT, et al: Venous reconstructions using the superficial femoralpopliteal vein. J Vasc Surg 26:829, 1997. 71. Spaggiari L, et al: Superior vena cava resection with prosthetic replacement for non–small cell lung cancer: long-term results of a multicentric study. Eur J Cardiothorac Surg 21:1080–1086, 2002. 72. Suzuki K, et al: Combined resection of superior vena cava for lung carcinoma: prognostic significance of patterns of superior vena cava invasion. Ann Thorac Surg 78:1184–1189; discussion 1189, 2004. 73. Shargall Y, et al: 15 years single center experience with surgical resection of the superior vena cava for non–small cell lung cancer. Lung Cancer 45:357–363, 2004. 74. Shen KR, et al: Special treatment issues in lung cancer: ACCP evidence-based clinical practice guidelines, ed 2. Chest 132(Suppl): 290S–305S, 2007. 75. Wisselink W, et al: Comparison of operative reconstruction and percutaneous balloon dilatation for central venous obstruction. Am J Surg 166:200, 1993. 76. Shintani Y, et al: Long-term graft patency after replacement of the brachiocephalic veins combined with resection of mediastinal tumors. J Thorac Cardiovasc Surg 129:809, 2005.

CHAPTER 64 

Superior Vena Cava Occlusion: Endovascular Treatment CARLOS F. BECHARA  /  PETER H. LIN

S

uperior vena cava (SVC) occlusion precludes normal blood venous return to the heart. This condition, also known as SVC syndrome, is an uncommon occurrence that affects approximately 15,000 patients each year in the United States. The SVC functions as the primary venous drainage system from the head, neck, upper extremities, and upper thorax; the occlusion can be due to an extraluminal compression or intraluminal obstruction in nature. In general, SVC is 6 to 8  cm long and extends from the junction of the right and left innominate veins to the right atrium. Located in the middle mediastinum, the SVC is surrounded by relatively rigid structures, such as the trachea, right bronchus, sternum, aorta, pulmonary artery, and paratracheal and perihilar lymph nodes. Because the SVC is a low-pressure and thin-walled venous structure, the venous wall of the SVC can be compressed easily as it traverses the right side of the mediastinum. SVC syndrome was first reported in 1757, when Dr. William Hunter described it in a patient with syphilitic aortic aneurysm.1 Historically, infections were the most common cause of SVC syndrome. In a study reported in 1954 by Schechter,2 who analyzed 274 confirmed cases of SVC syndrome, 40% were due to either syphilitic aneurysms or tuberculous mediastinitis. In the past 5 decades, there has been a gradual decline of these infectious etiologies as primary causes of SVC syndrome, owing in part to improved antimicrobial therapy. In later reports, carcinoma of the lung resulting in extraluminal SVC compression is the predominant cause of SVC obstruction. Patients with SVC obstruction require immediate diagnostic evaluation and therapeutic intervention, because it is common in patients with undiagnosed malignancy within the thorax.

PATHOPHYSIOLOGY The majority of cases of SVC syndrome are caused by neoplastic progression into the venous wall with resultant tumor mass compression against the relatively fixed, thin-walled SVC. Alternatively, SVC obstruction can also be due to intravascular thrombosis caused by neoplastic involvement. Postmortem studies have demonstrated that complete SVC obstruction is the result of extrinsic tumor compression in 982

conjunction with intravascular thrombosis. In contrast, incomplete SVC obstruction is more frequently caused by extrinsic compression without associated intravascular thrombosis.3,4 Figure 64-1 summarizes various causes of SVC syndrome. Because of the SVC’s location, primary carcinoma of the lung located in the right upper lung lobe has a higher likelihood of causing SVC obstruction than pulmonary carcinomas located elsewhere. Among various neoplastic etiologies of SVC syndrome, mediastinal malignancy is responsible for 80% of cases. Specifically, bronchogenic carcinomas account for 75% to 80% of all cases, with the majority being smallcell carcinomas. Non-Hodgkin lymphoma is responsible for the remaining 10% to 15% of cases of SVC syndrome of malignant etiology. Other malignant causes of SVC syndrome, albeit less common, are Hodgkin disease, metastatic cancers, primary leiomyosarcomas of the mediastinal vessels, and plasmocytomas. SVC obstruction can be caused by nonmalignant diseases, which account for less than 25% of all cases of SVC syndrome.3-5 Infectious conditions such as syphilis and tuberculosis accounted for the majority of cases of SVC syndrome around the turn of the twentieth century. The development of effective pharmacologic therapy in the past 4 decades has largely eradicated syphilitic and tuberculosis-related SVC syndrome. The most common nonmalignant cause of SVC syndrome is mediastinal fibrosis from an infectious or radiation-induced process.6 With an aging population on the rise, the frequency of placement of central venous devices, such as pacemakers, defibrillators, central venous infusion ports, and long-term hemodialysis catheters, is similarly increasing. As a result, data have shown that benign disease accounted for 35% to 40% of cases of SVC obstruction.7 These indwelling venous devices can cause SVC obstruction through mechanical trauma to the venous endothelium, which can result in intraluminal fibrosis.8-17

Collateral Venous Pathways Venous collateral network formation can occur from chronic SVC obstruction. There are several important venous collaterals that return venous circulation from the upper half

CHAPTER 64  Superior Vena Cava Occlusion: Endovascular Treatment



983

SVC syndrome

Intraluminal fibrosis

Malignant

Benign

Benign

Lung cancer Lymphoma Sarcoma Metastatic cancer Leiomyosarcoma Plasmocytomas

Tumors Mediastinitis Cardiovascular Pulmonary Trauma

Long-term indwelling catheters Pacemakers/defibrillators Hypercoagulable state Idiopathic Syphilis Tuberculosis

Figure 64-1  Causes of superior vena cava (SVC) syndrome.

of the torso to the right atrium. The first and most important pathway is the azygos venous system, which includes the azygos vein, the hemiazygos vein, and the connecting intercostal veins. The second pathway involves the internal mammary venous system as well as tributaries and secondary communications to the superior and inferior epigastric veins. The long thoracic venous system, which represents the third collateral venous network, is connected to the femoral veins and vertebral veins. The development of these collateral venous pathways is influenced by the chronicity of SVC obstruction as well as underlying causative factors (Table 64-1).

CLINICAL PRESENTATIONS AND DIAGNOSTIC EVALUATION Clinical manifestations of SVC syndrome and diagnostic evaluation of patients in whom it is suspected are described in detail in Chapter 63.

TREATMENT CONSIDERATIONS The traditional treatment for SVC syndrome associated with thoracic malignancy has been radiotherapy, chemotherapy, Table 64-1

Stanford Classification for Superior Vena Cava (SVC) Obstruction

Type

Description

I II

Up to 90% stenosis with patency of the azygos vein 90% stenosis to complete occlusion of SVC with patency of the azygos vein and antegrade flow through the azygos vein 90% stenosis to complete occlusion of SVC with patency of the azygos vein and retrograde flow through the azygos vein Complete occlusion of SVC and one or more of its branches including the azygos vein

III

IV

or both. The treatment response varies, depending on the invasiveness of thoracic malignancy, so typically resolution of symptoms may take several months. Although surgical construction of the SVC to bypass the venous obstruction along with removal of the underlying intrathoracic malignancy is an acceptable treatment option, this treatment approach requires a median sternotomy, which represents a major surgical challenge. The treatment benefits and operative morbidities must be weighed carefully against the patient’s life expectancy in those with malignant SVC syndrome. In patients with nonmalignant SVC syndrome, surgical reconstruction of the SVC creates a new venous conduit, which enables future dialysis access of pacemaker placement. In patients who have overt SVC syndrome or whose disease does not respond to medical therapy, additional catheter-based treatment such as balloon angioplasty or stenting is necessary in order to maintain SVC luminal patency. In contrast to chemotherapy and radiation treatment for malignant SVC syndrome, endovascular stenting of the SVC establishes immediate luminal patency and provides rapid symptomatic relief. Endovascular stenting has been used prior to chemotherapy in neoplastic SVC syndrome with success.18 Similarly, endovascular treatment options can be equally applied to patients with nonmalignant SVC syndrome. In patients whose SVC obstruction is caused by intraluminal thrombosis, thrombolytic therapy to dissolve the thrombus is effective. On the basis of an abundance of studies, endovascular therapy should be considered the first line of treatment in both malignant and nonmalignant SVC syndrome.19-22 The use of endovascular therapy to treat SVC syndrome has been extended to treat the pediatric and young adult populations.23 The only contraindication to endovascular therapy is inpatients with a contraindication to thrombolytic therapy or anticoagulation. Patients whose symptoms fail to respond or who are not candidates for endovascular therapy should be evaluated for surgical reconstruction.

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

External compression

984

SECTION 10  Venous Insufficiency and Occlusion

Techniques of Endovascular Intervention The endovascular procedure should be performed in either an interventional suite or operating room with a dedicated angiographic capability or a mobile C-arm fluoroscopic unit. Access for percutaneous stenting of the SVC is typically obtained via the femoral vein, but a brachial, basilic, or internal jugular vessel can also provide useful therapeutic access to the central veins. In the event of venous occlusion involving the SVC or brachiocephalic veins, bilateral upper extremity venous access via either a brachial or basilic vein should be considered because it facilitates the catheterization of the central vein occlusion. In addition to femoral access, additional upper extremity venous access is necessary in about 20% of the cases.22 This dual venous access not only enables antegrade and retrograde venograms but also facilitates crossing the SVC lesion. Femoral venous access is typically established with a 7F introducer sheath (Boston Scientific, Natick, Mass). A 260-cm Bentson guide wire (Boston Scientific) followed by a pigtail catheter is placed in the SVC. Venography of the SVC and brachiocephalic veins is performed via a femoral approach to visualize the SVC lesion. Whenever possible, a hydrophilic guide wire is used to traverse the SVC lesion. Once the lesion is successfully cannulated with the hydrophilic guide wire, the guide wire is exchanged for a stiff Amplatz wire (Boston Scientific) or a Lunderquist wire (Cook Medical, Inc., Bloomington, Ind) for balloon or stent delivery. If the wire is unable to cross an SVC occlusion or a high-grade lesion, a thrombolytic infusion catheter is placed for delivery of a thrombolytic drug either as a bolus or continuously for a certain period. Systemic anticoagulation with intravenous heparin (5000 U/kg) is given prior to any catheter-based intervention. We routinely perform an initial SVC balloon dilatation because this maneuver widens the lumen, facilitating subsequent stent deployment; other researchers have similarly supported this maneuver.24,25 In contrast, yet others have advocated avoiding this maneuver to reduce the risk of thrombus embolization.26 Treatment by means of balloon dilatation alone yields poor clinical results in the long term owing to a high rate of restenosis. Given the available clinical results, stenting of the SVC lesion is preferred over to SVC balloon angioplasty. Balloon angioplasty to dilate the SVC or brachiocephalic venous lesion is performed with either a 10 mm × 40 mm or 12 mm × 40 mm balloon angioplasty catheter. Following balloon dilatation of the SVC lesion, either a balloonexpandable stent or a self-expanding stent is deployed across the lesion. Infrequently a covered stent-graft is used to treat the SVC lesion. Occasionally, more than one stent is needed to treat the underlying pathology. Post-stenting balloon dilatation is routinely performed when a self-expanding stent or a stent-graft is deployed. In our series, if the segment of SVC adjacent to the stricture was greater than 16 mm in diameter, a bilateral brachiocephalic “kissing stent” technique using either a 12-mm- or a 14-mm-diameter stent is performed.22

A

B

C Figure 64-2  Images of a patient with symptomatic superior vena cava (SVC) syndrome. A, A high-grade SVC stenosis is depicted in the venogram (arrow). B, Luminal patency was established with the placement of a balloon-expandable Palmaz stent (arrow). C, Chest radiograph demonstrated the location of the Palmaz stent (arrow).

Completion venography is obtained to document treatment results (Fig. 64-2). Introducer sheaths and guide wires are next removed, and manual compression is applied to achieve hemostasis. In the event of chronic venous occlusion whereby conventional catheter and guide wire techniques are not successful in crossing the venous occlusion, radiofrequency guide wire technology has been shown to be beneficial in establishing access across the venous occlusion. The PowerWire Radiofrequency Guidewire (Baylis Medical Company Inc, Montreal) can be used to facilitate crossing vessels with thrombotic occlusion. This 0.035-inch wire has a hot tip and low-friction insulation but is not steerable. The device monitor displays delivered radiofrequency power, impedance, and elapsed time to allow for continuous monitoring. The utility of this technology was highlighted in a series of three patients with malignant SVC syndrome whose SVC occlusions were successfully crossed with use of a radiofrequency guide wire, followed by stent placement.27

Thrombolytic Therapy The first successful thrombolytic therapy in SVC syndrome caused by a pacemaker lead was described in 1974, in which streptokinase was delivered via catheter-directed infusion.28



CHAPTER 64  Superior Vena Cava Occlusion: Endovascular Treatment

administration of thrombolytic agents to exert the pharmacologic benefit of thrombus dissolution, followed by mechanical thrombectomy for thrombus extraction. The pharmacomechanical thrombectomy treatment strategy combines the advantages of pharmacologic thrombolysis and mechanical thrombectomy, in which the thrombolytic dosage can be reduced and the efficacy of mechanical thrombectomy is maximized. This treatment technique was adapted from our previously reported treatment strategy in DVT intervention.35 In our reported series, this pharmacome­ chanical thrombectomy with rheolytic thrombectomy and catheter-directed tissue plasminogen activator administration has yielded successful treatment outcome in patients with acute thrombosis of the SVC and brachiocephalic vein.22

Balloon Angioplasty and Stenting Vessel wall recoil following balloon angioplasty is a wellknown phenomenon that has diminished the attraction of this treatment modality for use in patients with SVC syndrome. In general, a short-segment venous disease may respond very well to plain balloon angioplasty. Because most patients with SVC syndrome have more extensive disease, additional interventions beyond balloon angioplasty are frequently necessary. Consequently, the role of balloon angioplasty has evolved from a primary intervention to an adjunctive procedure used prior to stenting.36 Advances in intraluminal stent placement in the past 2 decades have proven to be effective in treating venous outflow obstruction with low morbidity and mortality while maintaining a high treatment success rate. The therapeutic role of percutaneous stenting has been validated in both malignant and benign SVC syndrome.21-26 It establishes immediate luminal patency and provides rapid symptomatic relief with remarkable clinical success. The therapeutic objective of SVC stenting is similar to that of open surgery, which is to restore luminal patency and relieve obstructive symptoms. The choice of plain balloon angioplasty, balloon-expandable stent, self-expanding stent, or stent-graft depends on the venous lesion pattern, length of stenosis, and presence of venous branches or collaterals adjacent to the SVC lesions. Among these various therapeutic options, the intraluminal stent is the most commonly used endovascular strategy. Although the therapeutic efficacy of percutaneous stenting in intra-arterial lesions is well proven,37 comparable evidence in venous pathology remains scarce, particularly with regard to vena cava obstruction. Since the first use of stenting in SVC syndrome was described, the use of a variety of metallic stents has been described for the palliative treatment of SVC syndrome.38-43 Several metallic stents can be used in the treatment of SVC obstruction. The four most commonly used are the Gianturco-Z stent (Cook Medical, Inc.), the Palmaz stent (Cordis Corporation, Bridgewater, NJ), SMART stent (Cordis Corporation), and the Wallstent (Boston Scientific). The Gianturco Z-stent was one of the very first stents used in treating SVC obstruction and is described in the earlier

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

This treatment modality with or without angioplasty or stenting has been well validated.28-31 Thrombolytic therapy could lead to complete clot resolution or could partially recanalize the thrombus, allowing further endovascular management such as balloon angioplasty or stenting once the lesion is crossed with a wire. In general, chronic venous occlusions tend to be easier to cross with a wire than chronic arterial occlusions. Catheter-directed thrombolysis utilizes a smaller thrombolytic dose than systemic thrombolysis. The earlier the administration of thrombolytic therapy after the onset of symptoms, the better the response and the thrombus resolution. Most nonmalignant SVC syndromes respond to thrombolytic therapy, because the patients present with subacute or acute-on-chronic thrombosis. The process of thrombotic occlusion in malignant SVC syndrome is more insidious in nature. By the time symptoms occur, sufficient venous collaterals have usually developed. When thrombosis occurs and results in SVC occlusion, adjuvant thrombolytic therapy may be beneficial to dissolve the thrombus and unmask the underlying lesion prior to definitive endovascular treatment. Many physicians who performed endovascular stenting for SVC syndrome described the benefits of thrombolytic agents.32 Ariza et al24 administered urokinase in a 500,000 IU bolus followed by an infusion of 80,000 to 100,000 IU/hr for 24 to 48 hours after stent implantation. Gray et al33 described the safety and benefit of using streptokinase and urokinase for thrombolysis in SVC syndrome of both malignant and benign etiologies. They reported successful results when thrombolytic infusion was administered through an indwelling catheter within 5 days of the onset of symptoms. In SVC or brachiocephalic thrombotic occlusion, direct thrombolytic infusion via a catheter embedded in thrombus or through a preexisting indwelling catheter is an effective technique for treating SVC thrombosis. Rosenblum et al34 reported the utility of thrombolytic therapy in successfully treating patients with SVC syndrome due to long-term use of indwelling catheter. Sheikh et al25 reported the use of urokinase and recombinant tissue plasminogen activator (t-PA) prior to angioplasty and stent deployment in patients with SVC syndrome.25 Their study shows a high rate of treatment success and supports the use of adjuvant thrombolytic therapy in patients with SVC syndrome with underlying venous thrombosis and no con­ traindications to thrombolytic therapy. Heparin, oral anti­ coagulants, or antiplatelet therapy is typically given after IVC stenting, for a duration of at least 6 months and possibly indefinitely.24-26 Overall this anticoagulation is well tolerated and appears to decrease the risk of stent thrombosis, although fatal subdural hematoma was reported in one patient with nonmalignant SVC syndrome.25 Over the past decade, percutaneous mechanical thrombectomy has emerged as an effective treatment modality in patients with thrombotic venous occlusion.35 The clinical advantage of such a thrombectomy system is that it allows simultaneous catheter-directed infusion of thrombolytic agents, thereby creating a pharmacomechanical thrombectomy (PMT) strategy. It is accomplished with the initial

985

986

SECTION 10  Venous Insufficiency and Occlusion

clinical series.19 It is a rigid self-expanding stainless steel stent with the greatest radial force in its middle segment. It comes in diameters ranging from 15 to 35 mm and a length of 5 cm. Because the Z-stent provides the greatest radial force in its middle segment, placement of multiple overlapping Z-stents is necessary for treatment of long venous lesions. Several studies have shown the benefit of using Z-stents in recanalized SVC occlusions.44,45 Despite the high radial force of the stent, it did not gain wide acceptance in clinical practice owing to metal fatigue with the possibility of fracture in longterm study.46 Another type of stent that has been utilized in SVC lesions is the Palmaz stent, a balloon-expandable stent with a high radial force. This stent is ideally suited for lesions with extrinsic luminal compression. Available in a variety of diameters and lengths, it can be precisely deployed with limited foreshortening and can dilate to nearly 80% larger than its intended diameter. This over-dilatation can be accomplished with the use of using an oversized balloon catheter while strong radial force is maintained. The beneficial role of the Palmaz stent in treating SVC syndrome has been documented.22,29 Its disadvantage relates to its compressibility, which may lead to stent deformation or occlusion due to extrinsic compression from an adjacent extraluminal mass.33 The SMART stent is a self-expanding stent composed of nitinol, a nickel-titanium metallic alloy. This stent possesses shape memory, which enables it to assume its predetermined shape once deployed and at body temperature. Although the SMART stent comes in a variety of lengths and diameters, the most useful size for SVC intervention has a length of 60 mm and a diameter of 14 mm, which can accommodate large vessels such as the vena cava. The Wallstent is the most widely used stent for SVC syndrome treatment as reported in the literature.8,20-22 The device is a self-expanding stent with longitudinal flexibility, making it ideal for long tortuous lesions. The primary advantages of this stent are its flexibility and ease of deployment, which are ideally suited for long or tortuous lesions. However, a potential disadvantage is noteworthy; use of a large-diameter Wallstent in a patient with a critically stenotic SVC may result in low radial force owing to uneven stent conformability. Another disadvantage of the Wallstent relates to its considerable foreshortening during deployment, which can occur in up to 30% of the stent length. This foreshortening phenomenon can lead to migration of the stent if it is not deployed precisely. When this stent is used to treat a longsegment vascular lesion, significant stent foreshortening can occur which may lead to stent migration if the device is not centered on the stenosis.47,48 However, a beneficial feature of this device is that the stent can be re-sheathed and repositioned during the deployment process, minimizing potential stent misemployment. The Wallstent is available in a wide range of diameters (up to 18 mm) and lengths (up to 94 mm), making it versatile in treating the SVC or brachiocephalic veins. Although researchers have proposed the use of stent-grafts in venous pathology, we do not believe that it has a

significant advantage over the Wallstent because of potential coverage of important venous collaterals by a stent-graft in a patient with SVC syndrome, which might worsen the symptoms if the stent-graft becomes occluded. Clinical experience of the stent-graft in treating SVC syndrome remains scarce; there are only two reports of its use in patients in whom tumor ingrowth had developed in stents previously placed for malignant SVC syndrome.49,50 The stent-graft material prevents further tumor ingrowth, and in one case the stent-graft remained patent after 12 months.49 Stent-grafts are thought to have less predisposition to develop neointimal hyperplasia, but in-stent stenosis is a potential problem. Also, as previously mentioned, placing a stent-graft could potentially cover important venous collaterals in a patient with SVC syndrome, worsening the symptoms, especially when the stentgraft gets occluded. Whether stent-grafts should be used more in treating malignant SVC syndrome to prevent tumor or thrombus ingrowth warrants further study.

CLINICAL RESULTS OF SUPERIOR VENA CAVA STENTING The clinical efficacy of Wallstent in SVC obstruction has been reported by several studies, including our institutional experience.18,20-22,51 Dyet et al21 reported a primary patency rate of 90% and secondary patency rate of 100% in patients with symptomatic SVC syndrome.21 We and other researchers have reported 95% to 100% clinical success rates in the use of endovascular interventions to treat patients with malignant SVC syndrome.22,52 In our series, clinical success was achieved in 96% of cases. Primary patency rates in patients with malignant and benign causes of SVC syndrome were 64% and 76% at 1 year, respectively.22 Others have reported 95% technical success rates with primary and secondary clinical patency rates of 79% and 93%, respectively.29 Randomized studies comparing the different stents in treating SVC syndrome are lacking. Oudker et al53 reported the outcome of a comparative analysis between Wallstent and the Z-stent in palliative treatment of SVC syndrome. They reported early Wallstent thrombosis at 2 weeks and lower long-term patency (69%) in comparison with the Z-stent (100%). Because the majority of currently available self-expanding nitinol stents do not have a diameter greater than 12  mm, their role in the management of SVC syndrome remains limited. In contrast, the wide range of large-diameter (up to 18  mm) Wallstents provides versatile treatment options in structures such as the SVC and brachiocephalic vein. Patients with benign SVC syndrome have better survival than those with SVC syndrome of malignant causes (Fig. 64-3).22 Open surgery is considered a better option than endovascular therapy in maintaining luminal patency for future catheters or devices. Later reports have shown endovascular intervention with stenting to be an accepted first line of therapy for benign SVC syndrome.54 In our series, benign disease was responsible for SVC syndrome in 29% of

CHAPTER 64  Superior Vena Cava Occlusion: Endovascular Treatment

100

60 40 20 0 0

6

12

16

24

Time (months)

Figure 64-3  Kaplan-Meier survival curves of patients with malignant (lower line) and benign (upper line) superior vena cava syndrome. (From Barshes NR, et al: Percutaneous stenting of superior vena cava syndrome: treatment outcome in patients with benign and malignant etiology. Vascular 15:314-321, 2007.)

patients,22 a surprisingly greater proportion than in other contemporary series.* The clinical outcome of our series is comparable to that of a study by Ariza et al,24 whose clinical success rate was 85%. Petersen et al39 reported the long-term results of stenting in 19 patients with SVC syndrome caused by benign processes. With a mean follow-up period of 33 months, the primary patency rate was 83%, and the secondary patency was 100%. In a similar study, Sheikh et al25 performed SVC stenting in 19 patients with nonmalignant SVC syndrome. It is noteworthy that in 74% of them (16/19), SVC syndrome developed as a result of underlying indwelling intravascular catheters or devices. These patients had a remarkable clinical response after stenting, with a clinical success rate of 100%. Long-term primary and secondary patency rates of more than 70% and 100%, respectively, have been reported.22,24,25,54 As expected, patients with benign causes of SVC syndrome have a better long-term stent patency than those with malignant causes. SVC or brachiocephalic vein occlusion in patients requiring chronic hemodialysis poses a particular clinical challenge. Owing in part to the high turbulent flow created during episodic hemodialysis treatment, the central venous lesion tends to exhibit a higher incidence of restenosis following stent placement as well as shorter treatment patency. Kovalik et al56 reported their experience of treating 20 patients requiring hemodialysis in whom symptomatic central vein stenosis developed. In those patients who showed nonelastic central venous stenosis (defined as residual lumen greater than 50%), the recurrence rate was 81% during a follow-up period of 7.6 months. In contrast, in patients with elastic stenosis, the average time from treatment to recurrence was 2.9 months, and the recurrence rate was 100%. The investigators observed that the placement of Wallstent prostheses in nonelastic

*References 24, 31, 37, 40, 44, 55.

lesions had a lower recurrence rate than in elastic stenotic lesions. Consequently, Kovalik et al56 postulated that it may be necessary to place stents in nonelastic stenoses in patients subjected to hemodialysis, but not in patients with stenoses that are elastic or have minimal elasticity. A similar finding was noted in our series, in which all of the four patients with long-term indwelling hemodialysis catheters had in-stent stenosis following SVC intervention.22 Secondary intervention was necessary in all these patients undergoing hemodialysis to restore the luminal patency of their stents. A comparative study was reported in 73 patients with malignant SVC syndrome who were treated with either bare metal stents or covered stents. In this study, Gwon et al57 treated 37 patients with expanded polytetrafluoroethylene (ePTFE)–covered stents and retrospectively analyzed results in 36 patients treated with uncovered stents. There were no differences in technical success or complications between the two groups. Although the 1-year cumulative patency rate was significantly greater in the covered stent group (94% vs. 48%), there were no differences in overall clinical success or patient survival rate. Although the study noted a potential advantage of a high patency rate with covered stents, the investigators underscored two cautionary points with regard to the placement of covered stents in patients with malignant SVC syndrome. First, the risk of stent migration or dislodgement remains present whether the stent is covered or uncovered. To reduce the possibility of stent migration, they recommend oversizing the device by 10% to 20% in comparison with the SVC diameter. Second, placement of a covered stent across the confluence of brachiocephalic veins may occlude contralateral upper extremity venous drainage, resulting in contralateral upper extremity deep vein thrombosis. However, this study showed no evidence of contralateral upper extremity swelling or venous thrombosis in those patients in whom stents were placed in the SVC or brachiocephalic vein.57 This observation suggests that unilateral relief of obstruction using covered stents may allow contralateral venous return via mediastinal or cervical collateral venous circulation. In a Cochrane review of treatment for malignant SVC obstruction, Rowell and Gleeson5 reported that stent insertion provided more rapid symptom relief in a higher proportion of patients than did radiation therapy or chemotherapy.5 Other researchers have reported similar success rates, of 95% to 100%, in patients with malignancy-associated SVC syndrome after endovascular interventions.52 Kee et al29 reported a technical success rate of 95%, a primary clinical patency rate of 79%, and a secondary clinical patency rate of 93%. Their mortality and morbidity rates were 3% and 10%, respectively. Rosch et al19 reported one recurrence in a group of 20 patients during a follow-up period of 7 months (range 1 to 11 months). In one of the largest series, in which 76 patients with malignant SVC syndrome were treated with Wallstents with or without radiotherapy, stent therapy provided a faster symptom relief, and 90% of the patients remained symptom free until death.58 Only 12% in this study who underwent radiotherapy alone remained symptom free

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

Survival rate (%)

80

987

988

SECTION 10  Venous Insufficiency and Occlusion

until death, so the investigators recommended that stent insertion be the first line of therapy. Moreover, complete SVC obstruction should not be considered a contraindication to endovascular therapy. Multimodality therapy including thrombolysis, angioplasty, and stent insertion was successful in 85% of the cases.58 Dinkel et al26 hypothesized that bilateral stent placement is superior to unilateral stent placement in keeping tributaries to the SVC open and preventing recurrent occlusion. To their surprise, however, bilateral Wallstent placement had shorter patency with more complications.

TREATMENT COMPLICATIONS Although complications related to SVC stenting remain uncommon, they can have serious consequences. The complications include mediastinal hematoma, stent migration, infection, pulmonary embolus, stent thrombosis and SVC perforation, and pericardial puncture resulting in cardiac tamponade.25,59-61 The newer generation of stents with improved radiopacity, lower device profile, and accurate delivery system have reduced the likelihood of stent malposition or migration during deployment. Like other researchers, we advocate routine SVC balloon angioplasty prior to stent deployment to facilitate accurate stent placement and minimize stent migration.22,24,25 In the unusual event of stent infection or migration, multiple strategies for stent removal or salvage techniques for migrated stents have been described.61,62 These techniques include snaring the stent directly, crushing the stent followed by snaring and removing it and then deploying a migrated stent in a different venous system.61,62 Fatal hemorrhagic complications were typically attributed to administration of thrombolytic agents, including streptokinase, urokinase, and tissue plasminogen activator, to dissolve intracaval clot prior to insertion of a vascular prosthesis. Cerebral hemorrhage has also been reported in patients with intracranial metastases arising from SVC malignancy during thrombolytic therapy.63 Massive hemoptysis can also occur during thrombolytic therapy or during maintenance anticoagulation therapy.54,64 Malignancy-related hypercoagulable state combined with the presence of an intra-vascular stent can increase the risk of thrombosis after stent implantation. Researchers have postulated that this occurrence is due to the exposed stent metal

in a low-pressure venous circulation, which can exacerbate thrombus formation. Because the ideal anticoagulation regimen following SVC stent remains controversial, many patients are not given appropriate antithrombotic therapy following stent placement, undoubtedly contributing to the incidence of stent thrombosis. Nonetheless, ideal anticoagulation therapy following stent placement in patients with SVC malignancy remains to be determined. Some researchers recommended no antithrombotic therapy after stenting,65 but most advocate prolonged anticoagulation, including the use of heparin, warfarin, and antiplatelet agents.54,66,67 In the event of a stent thrombosis, immediate intervention with stent catheterization following by thrombolysis or thrombectomy can be effective in restoring lumen patency.

SELECTED KEY REFERENCES Barshes NR, Annambhotla S, El Sayed HF, Huynh TT, Kougias P, Dardik A, Lin PH: Percutaneous stenting of superior vena cava syndrome: treatment outcome in patients with benign and malignant etiology. Vascular 15:314, 2007. A comprehensive review of a large patient group with SVC syndrome with malignant and nonmalignant etiologies who underwent percutaneous endovascular treatment with long-term follow-up. Ganeshan A, Hon LQ, Warakaulle DR, Morgan R, Uberoi R: Superior vena caval stenting for SVC obstruction: current status. Eur J Radiol 71:343, 2009. An excellent article on the utility of stenting in patients with malignant SVC obstruction. Gwon DI, Ko GY, Kim JH, Shin JH, Yoon HK, Sung KB: Malignant superior vena cava syndrome: a comparative cohort study of treatment with covered stents versus uncovered stents. Radiology 266:979, 2013. A comparative study of 67 patients with malignant SVC syndrome who were treated with either bare metal stents or covered stents. The benefits and potential disadvantages of each treatment strategy are analyzed. Kim YI, Kim KS, Ko YC, Park CM, Lim SC, Kim YC, Park KO, Yoon W, Kim YH, Kim JK, Ahn SJ: Endovascular stenting as a first choice for the palliation of superior vena cava syndrome. J Korean Med Sci 19:519, 2004. Describes the beneficial role of endovascular stenting in patients with SVC syndrome and discusses various endovascular treatment strategies in the evaluation of these patients. Nguyen NP, Borok TL, Welsh J, Vinh-Hung V: Safety and effectiveness of vascular endoprosthesis for malignant superior vena cava syndrome. Thorax 64:174, 2009. A comprehensive discussion of the role of vascular stent implantation in treatment of obstruction of the SVC and brachiocephalic veins in patients with SVC syndrome. The reference list can be found on the companion Expert Consult website at www.expertconsult.com.



CHAPTER 64  Superior Vena Cava Occlusion: Endovascular Treatment

REFERENCES

28. Williams DR, et al: Thrombosis of superior vena cava caused by pacemaker wire and managed with streptokinase. J Thorac Cardiovasc Surg 68:134, 1974. 29. Kee ST, et al: Superior vena cava syndrome: treatment with catheterdirected thrombolysis and endovascular stent placement. Radiology 206:187, 1998. 30. Kalman PG, et al: Management of upper extremity central venous obstruction using interventional radiology. Ann Vasc Surg 12:202, 1998. 31. Blackburn T, et al: Pacemaker-induced superior vena cava syndrome: consideration of management. Am Heart J 116:893, 1988. 32. de Gregorio MA, et al: Interventional radiologic techniques in thoracic emergencies. Arch Bronconeumol 36:51, 2000. 33. Gray BH, et al: Safety and efficacy of thrombolytic therapy for superior vena cava syndrome. Chest 99:54, 1991. 34. Rosenblum J, et al: Intravascular stents in the management of acute superior vena cava obstruction of benign etiology. J Parenter Enteral Nutr 18:362, 1994. 35. Lin PH, et al: Catheter-direct thrombolysis versus pharmacomechanical thrombectomy for treatment of symptomatic lower extremity deep venous thrombosis. Am J Surg 192:782, 2006. 36. Courtheoux P, et al: Stent placement in superior vena cava syndrome. Ann Thorac Surg 75:158, 2003. 37. Singh KP, et al: Peripheral arterial disease: an overview of endovascular therapies and contemporary treatment strategies. Rev Cardiovasc Med 7:55, 2006. 38. Shah R, et al: Stenting in malignant obstruction of superior vena cava. J Thorac Cardiovasc Surg 112:335, 1996. 39. Petersen BD, et al: Long-term results of treatment of benign central venous obstructions unrelated to dialysis with expandable Z stents. J Vasc Interv Radiol 10:757, 1999. 40. Miller JH, et al: Malignant superior vena cava obstruction: stent placement via the subclavian route. Cardiovasc Interv Radiol 23:155, 2000. 41. Watkinson AF, et al: Expandable Wallstent for the treatment of obstruction of the superior vena cava. Thorax 48:915, 1993. 42. Nguyen NP, et al: Safety and effectiveness of vascular endoprosthesis for malignant superior vena cava syndrome. Thorax 64:174, 2009. 43. Ganeshan A, et al: Superior vena caval stenting for SVC obstruction: current status. Eur J Radiol 71:343, 2009. 44. Edwards RD, et al: Case report: superior vena cava obstruction complicated by central venous thrombosis—treatment with thrombolysis and Gianturco-Z stents. Clin Radiol 45:278, 1992. 45. Gaines PA, et al: Superior vena caval obstruction managed by the Gianturco Z stent. Clin Radiol 49:202, 1994. 46. Glanz S, et al: Axillary and subclavian vein stenosis: percutaneous angioplasty. Radiology 168:371, 1998. 47. Qanadli SD, et al: Subacute and chronic benign superior vena cava obstructions: endovascular treatment with self-expanding metallic stents. Am J Roentgenol 173:159, 1999. 48. Stock KW, et al: Treatment of malignant obstruction of the superior vena cava with the self-expanding Wallstent. Thorax 50:1151, 1995. 49. Gil lK, et al: Recurrent superior vena caval obstruction due to invasion by malignant thymoma: treatment using a stent-graft. Br J Radiol 73:414, 2001. 50. Chin DH, et al: Stent-graft in the management of superior vena cava syndrome. Cardiovasc Interv Radiol 19:302, 1996. 51. Hennequin LM, et al: Superior vena cava stent placement: results with the Wallstent endoprosthesis. Radiology 196:353, 1995. 52. Schindler N, et al: Superior vena cava syndrome: experience with endovascular stents and surgical therapy. Surg Clin North Am 79:683, 1999. 53. Oudker KM, et al: Self expanding metal stents for palliative treatment of superior vena caval syndrome. Cardiovasc Interv Radiol 19:146, 1996. 54. Rizvi AZ, et al: Benign superior vena cava syndrome: stenting is now the first line of treatment. J Vasc Surg 47:372, 2008. 55. Charnsangavej C, et al: Stenosis of the vena cava: preliminary assessment of treatment with expandable metallic stents. Radiology 161:295, 1986. 56. Kovalik EC, et al: Correction of central venous stenosis: use of angioplasty and vascular Wallstents. Kidney Int 45:1177, 1994.

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

1. Kamiya K, et al: Superior vena caval syndrome: review of the literature and a case report. Vasc Dis 4:59, 1967. 2. Schechter MM: The superior vena cava syndrome. Am J Med Sci 227:46, 1954. 3. Wilson LD, et al: Clinical practice: superior vena cava syndrome with malignant causes. N Engl J Med 356:1862, 2007. 4. Nieto AF, et al: Superior vena cava obstruction: clinical syndrome, etiology, and treatment. Curr Probl Cancer 10:441, 1986. 5. Rowell NP, et al: Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus: a systematic review. Clin Oncol (R Coll Radiol) 14:338, 2002. 6. Van Putten JW, et al: Superior vena cava obstruction caused by radiation induced venous fibrosis. Thorax 55:245, 2000. 7. Rice TW, et al: The superior vena cava syndrome: clinical characteristics and evolving etiology. Medicine (Baltimore) 85:37, 2006. 8. Slonim SM, et al: Placement of SVC stents over pacemaker wires for the treatment of SVC syndrome. J Vasc Interv Radiol 1:215, 2000. 9. Woodyard TC, et al: Acute superior vena cava syndrome after central venous catheter placement. Cancer 15:2621, 1993. 10. Laguna Del Estal P, et al: Superior vena cava syndrome: a study based on 81 cases. An Med Interna1 5:470, 1998. 11. Fa Qin LV, et al: Doppler superior vena cava flow evolution and respiratory variation in superior vena cava syndrome. Echocardiography 25:360, 2008. 12. Eren S, et al: The superior vena cava syndrome caused by malignant disease: imaging with multi-detector row CT. Eur J Radiol 59:93, 2006. 13. Cihangiroglu M, et al: Collateral pathways in superior vena caval obstruction as seen on CT. J Comput Assist Tomogr 25:1, 2001. 14. Thornton MJ, et al: A three-dimensional gadolinium-enhanced MR venography technique for imaging central veins. AJR Am J Roentgenol 173:999, 1999. 15. Marckmann P, et al: Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 17:2359, 2006. 16. Mahmud AM, et al: Follow-up of patients with superior vena cava syndrome by functional analysis of radionuclide venography. Nucl Med Commun 19:417, 1998. 17. Stanford W, et al: The role of venography and surgery in the management of patients with superior vena cava obstruction. Ann Thorac Surg 41:158, 1986. 18. Bierdrager E, et al: Endovascular stenting in neoplastic superior vena cava syndrome prior to chemotherapy or radiotherapy. Neth J Med 63:20, 2005. 19. Rosch J, et al: Gianturco-Rosch expandable Z-stents in the treatment of superior vena cava syndrome. Cardiovasc Interv Radiol 15:319, 1992. 20. Kim YI, et al: Endovascular stenting as a first choice for the palliation of superior vena cava syndrome. J Korean Med Sci 19:519, 2004. 21. Dyet JF, et al: Use of the Wallstent endovascular prosthesis in the treatment of malignant superior vena caval obstruction. J Vasc Interv Radiol 5:2, 1994. 22. Barshes NR, et al: Percutaneous stenting of superior vena cava syndrome: treatment outcome in patients with benign and malignant etiology. Vascular 15:314, 2007. 23. Tzifa A, et al: Endovascular treatment for superior vena cava occlusion or obstruction in a pediatric and young adult population. J Am Coll Cardiol 49:1003, 2007. 24. Ariza GA, et al: Percutaneous treatment of superior vena cava syndrome using metallic stents. Eur Radiol 13:853, 2003. 25. Sheikh MA, et al: Endovascular stenting of nonmalignant superior vena cava syndrome. Catheter Cardiovasc Interv 65:405, 2005. 26. Dinkel HP, et al: Endovascular treatment of malignant superior vena cava syndrome: is bilateral Wallstent placement superior to unilateral placement? J Endovasc Ther 10:788, 2003. 27. Iafrati M, et al: Radiofrequency thermal wire is a useful adjunct to treat chronic central venous occlusions. J Vasc Surg 55:603, 2012.

988.e1

988.e2 SECTION 10  Venous Insufficiency and Occlusion 57. Gwon DI, et al: Malignant superior vena cava syndrome: a comparative cohort study of treatment with covered stents versus uncovered stents. Radiology 266:979, 2013. 58. Nicholson AA, et al: Treatment of malignant superior vena cava obstruction: metal stents or radiation therapy. J Vasc Interv Radiol 8:781, 1997. 59. Brant J, et al: Hemopericardium after superior vena cava stenting for malignant SVC obstruction: the importance of contrast-enhanced CT in the assessment of postprocedural collapse. Cardiovasc Interv Radiol 24:353, 2001. 60. Martin M, et al: Fatal pericardial tamponade after Wallstent implantation for malignant superior vena cava syndrome. J Endovasc Ther 9:680, 2002. 61. Taylor JD, et al: Strategies for the management of SVC stent migration into the right atrium. Cardiovasc Interv Radiol 30:1003, 2007. 62. Srinathan S, et al: Radiological management of superior vena caval stent migration and infection. Cardiovasc Interv Radiol 28:127, 2005.

63. Nicholson AA, et al: Treatment of malignant superior vena cava obstruction: metal stents or radiation therapy. J Vasc Int Radiol 8:781, 1997. 64. Urruticoechea A, et al: Treatment of malignant superior vena cava syndrome by endovascular stent insertion: experience on 52 patients with lung cancer. Lung Cancer 43:209, 2004. 65. Bierdrager E, et al: Endovascular stenting in neoplastic superior vena cava prior to chemotherapy or radiotherapy. Neth J Med 63:20, 2005. 66. Lanciego C, et al: Stenting as first option for endovascular treatment of malignant superior vena cava syndrome. AJR Am J Roentgenol 177:585, 2001. 67. Lopez-Muniz JIC, et al: Treatment of superior and inferior vena cava syndrome of malignant cause with Wallstent catheter placed percutaneously. Am J Clin Oncol 20:293, 1997.

CHAPTER 65 

Venous Tumors THOMAS C. BOWER

Malignant venous tumors either originate primarily from

the vein wall, extrinsically compressing or invading the vein, or grow within it as tumor thrombus.1-5 Most patients with these tumors have such advanced disease that operation cannot be offered. Surgical resection remains the mainstay of treatment, but there is a growing literature on the role of preoperative or postoperative adjuvant therapy.6-9 Secondary tumors of the superior vena cava (SVC) are rarely operable, so SVC obstruction is usually treated with venous stenting.2 Peripheral vein tumors may require concomitant arterial, bone, or adjacent soft tissue resection, with or without axial venous replacement.10-12 Because malignant neoplasms that affect the inferior vena cava (IVC) are most common,13-43 much of this chapter focuses on the diagnosis and treatment of them. The selection of patients, the surgical principles of management, and the techniques used to replace major veins are reviewed.

DEFINITION AND TUMOR TYPES Tumors of the IVC are classified by whether they involve the infrarenal, suprarenal, or suprahepatic segment. The suprarenal IVC has a retrohepatic portion behind the liver and an infrahepatic portion that is located between the caudate lobe and the renal veins.2,3 Intracaval tumor thrombus is defined by level or extent of IVC involvement. Level I thrombus extends to within 2 cm of the renal vein; level II thrombus extends into the suprarenal IVC but below the hepatic veins; level III thrombus is to the hepatic veins but below the diaphragm; and level IV thrombus extends into the right side of the heart.2 The types of primary and secondary tumors are shown in Box 65-1. Primary venous leiomyosarcomas (PVLs) occur more often than arterial sarcomas but are much rarer than retroperitoneal leiomyosarcomas.2 The first venous leiomyosarcoma was described by Perl in 1871.44 Suprarenal involvement occurs in more than 40% of cases,4 and three fourths of these tumors involve retroperitoneal and abdominal veins. The great saphenous vein is the most frequent site of PVL of the lower extremity.5 Venous leiomyosarcomas are polypoid or nodular, are firmly attached to the vein wall, and exhibit less intratumor

hemorrhage or necrosis than other sarcomas.2,5 The most common growth pattern is intraluminal, but the tumor may grow through the vein wall and invade adjacent structures, which makes differentiation from other retroperitoneal sarcomas difficult.2,3 Distant metastases to the lung, liver, kidney, bone, pleura, or chest wall occur in half of the patients at the time of diagnosis,4,5 so survival is limited to months if surgery cannot be offered.4 Secondary cancers or sarcomas that involve the IVC are more common than PVL. Venous invasion, luminal obstruction by extrinsic compression, or intraluminal growth is the pathologic process (Fig. 65-1). Retroperitoneal sarcomas are the most common cause of malignant obstruction of the infrarenal segment but may affect higher levels.2,3 Sarcomas displace but rarely invade adjacent structures because of their pseudocapsule. However, the tissue planes between the tumor and IVC may be indistinct with large or irradiated tumors. Visceral or solid organ cancers affect the IVC in anatomic proximity to the site of origin of the neoplasm. For example, cancers of the liver, duodenum, pancreas, kidney, or adrenal glands involve the suprarenal IVC.2,3 A variety of cancers and sarcomas exhibit intraluminal tumor thrombus as part of their biologic behavior, with renal cell carcinoma (RCC) being most common (4%-15% of patients with this cancer).26-43 In fact, RCC is the most common cancer of the IVC that requires operative intervention.2 Tumor thrombus from RCC is found in the renal veins in 15% to 20% of cases21; the right kidney is affected more often than the left one, and tumors with thrombus tend to be larger than 4.5  cm in diameter.2,26,27 However, tumor thrombus can be seen with small renal cell or adrenocortical carcinomas (Fig. 65-2).2,3 In nearly half of patients with RCC and caval involvement, the tumor thrombus extends to within 2  cm of the renal vein–caval confluence (level I). Another 40% of patients have thrombus in the suprarenal IVC below the diaphragm (levels II and III), and in only 10% is thrombus in the right side of the heart (1% of all RCC patients).26,27 Similar to patients with PVL, survival of patients with secondary caval malignant neoplasms is measured in months without treatment.1-3,17 989

990

SECTION 10  Venous Insufficiency and Occlusion

BOX 65-1 

TUMORS OF THE VENA CAVA PRIMARY LEIOMYOSARCOMA SECONDARY SUPERIOR VENA CAVA TUMORS Lung cancer with mediastinal adenopathy Lymphoma Follicular or medullary thyroid cancer Teratoma Thymoma Angiosarcoma Synovial cell carcinoma SECONDARY INFERIOR VENA CAVA TUMORS Retroperitoneal soft tissue tumors Liposarcoma Leiomyosarcoma Malignant fibrous histiocytoma Hepatic tumors Cholangiocarcinoma Hepatocellular carcinoma Metastatic (e.g., colorectal) Pancreaticoduodenal cancers

Figure 65-1  Pathology specimen showing both extraluminal and intraluminal growth of a retroperitoneal sarcoma. Invasion of the lumen is shown by the arrow.

whereas PVL of the deep veins often invades the adjacent soft tissues.5

SECONDARY INFERIOR VENA CAVA TUMORS THAT MAY HAVE TUMOR THROMBUS Renal cell carcinoma Pheochromocytoma Adrenocortical carcinoma Sarcomas of uterine origin Leiomyomatosis Endometrial stromal cell Germ cell tumors Embryonal Teratocarcinoma

Most extremity venous tumors occur secondary to sarcomas of the bone, cartilage, muscle, or fatty tissues.10-12 Malignant melanoma and fibrohistiocytoma may also cause peripheral vein compression or invasion. PVL of the superficial lower extremity veins occurs as a nodular mobile mass,

A

B

CLINICAL PRESENTATION AND EVALUATION Primary leiomyosarcoma of the IVC is more common in women than in men, occurs over a wide age range, and has a mean patient age between 50 and 60 years.5,13-15 More than 80% of patients in the leiomyosarcoma registry compiled by Mingoli and colleagues were women.4 PVL of the peripheral veins affects men and women equally.5 Patients remain asymptomatic for a long time until symptoms or signs occur from metastatic disease or venous obstruction. Early detection is rare. Only 4 of 144 patients with IVC leiomyosarcoma in a review by Mingoli and colleagues had the tumor discovered incidentally.4 Abdominal pain is the most common presentation in 66% to 96% of patients.4,13 A palpable abdominal mass, lower limb edema, weight loss, Budd-Chiari syndrome, and vague symptoms (such as fever, weakness, anorexia, night sweats, and dyspnea) occur less often.4 Consumption coagulopathy is a rare but reported problem.2 Secondary caval tumors are detected in patients between the ages of 40 and 70 years.1-3,13-43 The mean age of patients

Figure 65-2  Axial (A) and coronal (B) images of a patient with a 3-cm adrenal tumor and associated inferior vena cava (IVC) tumor thrombus. The coronal image shows a 5-mm stalk of tumor thrombus extending from the left adrenal vein, through the left renal vein, and into the IVC (outlined by arrows).



991

system and IVC is hampered by bowel gas or when the tumor distorts the veins.2,3 Preoperative or intraoperative transesophageal echocardiography is sometimes used to corroborate the proximal extent of tumor thrombus if it is near the right atrium.26 If the tumor is localized and there are no metastases, a preoperative medical risk assessment is done, including a detailed cardiopulmonary evaluation. Of equal importance is an assessment of patient performance status.2 Patients in excellent physical condition with no or minimal limitation in daily activities (scores 0 and 1) have the best chance to maintain a similar quality of life after operation.1,17 Those who are either bedridden or need assistance in performing self-care (scores 3 and 4) are not offered operation at the author’s institution.

TREATMENT APPROACH AND TYPE OF RECONSTRUCTIONS At the time of diagnosis, most patients with IVC tumors have advanced disease, which precludes operation. Those with diffuse metastases, poor cardiopulmonary function, or physical debility should not undergo surgical resection, in my opinion. In contrast, patients with localized tumors, a good performance status, and few medical comorbidities are candidates for surgical resection.1-3,13-25 Operative treatment and approach depends on the tumor type and its extent, the segment of IVC involved by the tumor, the degree of caval obstruction, and the status of collateral veins. The choice of incision is based on the patient’s body habitus, the segment of IVC affected, and whether major liver resection or cardiopulmonary bypass is needed. A midline abdominal incision works well to approach the infrarenal or infrahepatic segment for patients with narrow costal margins and for patients with enlarged subcutaneous abdominal wall venous collaterals (Fig. 65-3). A bilateral subcostal incision is useful for patients with wide costal margins who need infrahepatic or retrohepatic IVC replacement and concomitant liver resection (Fig. 65-4). This incision can be extended by a median sternotomy in patients with large RCCs and level III or level IV tumor thrombus in whom cardiopulmonary bypass may be needed. Last, some patients who need major liver resection and retrohepatic IVC replacement are best approached by a right thoracoabdominal incision through the eighth or ninth interspace.2 Surgical treatment of secondary tumors of the iliac and peripheral veins is also dependent on the extent of tumor, but adjacent arterial and nerve involvement must be anticipated.10-12 Long-segment chronic occlusions of the iliac veins rarely require replacement unless collateral veins are sacrificed in the course of resection. Axial lower extremity autogenous venous reconstruction is needed when preoperative imaging shows a paucity of collateral veins draining into the ipsilateral saphenous, deep femoral, or iliac systems. Contralateral saphenous vein is the first choice as a conduit and

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

who underwent IVC resection and replacement for malignant disease in one Mayo Clinic report was 52 years but ranged from 16 to 88 years.1 The majority of patients have symptoms and signs related to the cancer, not to IVC obstruction.1-3,13-25 IVC obstruction is a late sign, so vena cava involvement is identified on imaging studies. Symptoms and signs vary by the segment of IVC obstructed and include pain, arrhythmia, syncope, Budd-Chiari or nephrotic syndrome, and motor or sensory neuropathies. Lower extremity edema and deep venous thrombosis are rare problems with IVC tumors but are seen with primary tumors of the iliac or peripheral veins.1-3,5 A multidisciplinary team is critical to the evaluation and treatment of patients with venous tumors. Medical and surgical oncologists and subspecialists (vascular, hepatobiliary, urologic, orthopedic, neurologic, and cardiothoracic surgeons) are needed to direct the evaluation and to determine treatment. The goals of evaluation include the identification of the type and extent of tumor, a search for metastases, an assessment of the degree of venous obstruction, and the determination of patient risk and performance status.2,3 Computed tomography (CT), magnetic resonance imag­ ing (MRI), ultrasonography, and rarely venography are used alone or in combination to accomplish these anatomic goals.1-3,7,17,18,45-50 CT and MRI are the most common tests used to define the location and extent of the tumor because the combination of axial, coronal, and sagittal images helps to plan the operation (Fig. 65-2). Venous phase imaging provides excellent views of the veins and collaterals. The role of venography is confined to the rare patient in whom histologic diagnosis by intraluminal fine-needle aspiration or true-cut needle biopsy would influence administration of preoperative adjuvant therapy2,3 or when computed tomographic venography or magnetic resonance venography inadequately defines venous occlusions and the collateral pathways. MRI is the study of choice to define the upper extent of intracaval tumor thrombus and to differentiate bland from tumor thrombus in the infrarenal cava.43 Because not every patient can tolerate MRI, improvements in multidetector CT imaging have been welcomed. Guzzo and associates50 studied 41 patients after operation who had multidetector CT imaging before surgery. CT findings concurred with the intraoperative pathologic findings in 84% of this group, and the level of tumor thrombus was accurately depicted in 96% of patients. Few studies have compared MRI and CT in these circumstances. Two small studies show accuracies between 75% and 100% for CT and between 75% and 88% for MRI.48,49 MRI has been used to predict IVC wall invasion in patients with tumor thrombus. Those with an abnormal signal on either side of the caval wall on gadolinium imaging, an IVC diameter of 40 mm or more, a level III or level IV thrombus, or an IVC diameter of 18 mm together with a renal vein ostium diameter of 14 mm are at high risk of tumor adherence to the vein wall (90% sensitivity).46 Ultrasonography provides an accurate assessment of peripheral vein obstruction, but its ability to image the iliac

CHAPTER 65  Venous Tumors

992

SECTION 10  Venous Insufficiency and Occlusion

that of autogenous reconstructions.11 The precept I use for treatment of patients with lower extremity malignant neoplasms is that in-line autogenous or prosthetic reconstruction should be done in those who have patent axial veins at the time of tumor resection. This is particularly important for the common femoral or popliteal vein.

Inferior Vena Cava Resection without Replacement

Figure 65-3  Tumors of the infrarenal segment can be approached through a midline abdominal incision. The infrarenal aorta and common iliac arteries often require partial mobilization to allow access to the lower vena cava and the proximal common iliac veins. Several lumbar veins may require division, and the surgeon must be wary of one to three small, middle, or lateral sacral veins that can cause troublesome bleeding if they are torn.

can be used as a straight, panel, or spiral graft. Venous reconstruction should follow arterial reconstruction when both vessels are resected. Anticipated patency rates of autogenous reconstructions in small clinical series have approached 80% at 2 and 5 years.12 A prosthetic graft has been used in the infrainguinal position but carries a lower patency rate than

A

The decision to replace the IVC during tumor resection is controversial but depends on whether the patient has problems from the caval obstruction, such as lower extremity edema or renal insufficiency.1-4,51 Patients with chronic IVC occlusion and well-developed venous collaterals that are not interrupted by operation can have the vena cava resected en bloc with the tumor with little venous morbidity.2 Patients with rapid occlusion of the IVC, few venous collaterals, and lower extremity edema are best treated with graft replacement.1-3 Although resection of the suprarenal IVC without replacement has been described, my preference always has been to reconstruct this segment because of the potential for acute kidney failure and lower extremity edema.1-3,18 The ability to predict which patients will tolerate resection without renal failure is difficult even if the paravertebral, lumbar, epigastric, adrenal, and gonadal venous pathways are patent.2,3 I reconstruct the remnant left or right renal vein if tumor resection involves a nephrectomy. Preservation of outflow through the remaining renal vein is necessary

B

Figure 65-4  The suprarenal segment can be approached through a midline abdominal, bilateral subcostal, or a right thoracoabdominal incision. The abdominal incision can be extended through the sternum if access is needed to the right heart, as in some patients with tumor thrombus. A right medial visceral rotation is used to expose either the retrohepatic (A) or infrahepatic (B) segment. Further mobilization of the infrahepatic segment requires ligation and division of between one and four caudate lobe veins.



if the patient develops intraoperative anuria or an acute reduction in urine flow.1,16

Renal Cell Carcinoma with Inferior Vena Cava Tumor Thrombus

993

to caval obstruction that are not decompressed with renal artery embolization. Early ligation of the renal artery, removal of the intracaval tumor thrombus, and restoration of normal IVC blood flow before the radical nephrectomy is completed helps decompress these veins. Intraoperative transesophageal echocardiography is used to guide the position of the upper caval clamp for those with level III tumor thrombus and to document clearance of tumor from the IVC.26 When thrombus clearly involves the right side of the heart, cardiopulmonary bypass, with or without circulatory arrest, may be needed.2,3,26 Concomitant deep hypothermia may be required in some patients, but this increases the risk of coagulopathy.2,3,26 The IVC is closed primarily unless tumor adherence or wall invasion requires partial or circumferential resection. Patch angioplasty or graft replacement is necessary in these circumstances.2,3,26 I patch the cava if 50% of the wall circumference requires resection (Fig. 65-6) and prefer this technique to interposition graft replacement, which becomes necessary in patients with extensive tumor remnants adherent to the IVC wall. Invasion of the renal vein ostium or the IVC by tumor thrombus significantly lessens survival unless these areas are resected. Zini and colleagues found a nearly sixfold increased risk of death from RCC on multivariable analysis controlled for tumor size, stage, and thrombus level in 32 patients who did not have complete removal of the tumor thrombus.46 Some patients need interruption of the infrarenal IVC because of chronic occlusive bland thrombus. Blute and colleagues reported 40 such caval interruptions among 160 cases treated for level II, III, or IV tumor thrombus during a 24-year period.41 The infrarenal IVC was either ligated or resected, or a Greenfield filter was placed inside of it. This group assessed postoperative disability according to the American Venous Forum International Consensus Committee. Of the 40 patients, 16 (40%) showed no disability, 12 had class I disability, 12 others had class II disability, and no one had class III disability. These authors recommend interruption of the infrarenal IVC in select patients with chronic occlusion or tumor involvement to minimize the chance of perioperative pulmonary embolism. The aforementioned operative techniques for the management of patients with RCC tumor thrombus also apply to other cancers that exhibit intracaval tumor extension.

Inferior Vena Cava Replacement At the Mayo Clinic, we believe that the vena cava at any level should be replaced if it is only partially obstructed and a majority of its circumference requires resection to provide clear tumor margins.1-3,17 We prefer large-diameter, externally supported polytetrafluoroethylene grafts (20 mm) and have found their patency rates to be greater than 95% in more than 90 patients now operated on at my institution. The UCLA group favors smaller diameter grafts because they believe that these generate higher blood flow velocities to maintain patency.16 Others use aortic or vena cava homografts with

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

The most common malignant neoplasm to involve the IVC with intraluminal tumor thrombus is RCC. In most cases, except with very large cancers and bulky thrombus extending well into the retrohepatic vena cava, the thrombus can be removed en bloc with the cancer by transection of the renal vein at its confluence with the IVC.2,3,26,27 Early ligation of the renal artery may shrink the thrombus and “simplify” operation when the proximal extent of tumor is near the hepatic veins or right atrium.26,32 Most patients have tumor thrombus confined to the infrahepatic IVC. The tumor can be removed by clamping this segment after the caudate lobe veins of the liver have been divided,26 which causes little hemodynamic change (Fig. 65-4A). Patients with thrombus in the retrohepatic IVC extending to the hepatic veins may benefit from total vascular isolation of the liver to remove the tumor and to minimize blood loss. Dilated lumbar veins may cause troublesome backbleeding, even with caval clamping and inflow occlusion to the liver. Mobilization of the retrohepatic IVC on its right lateral side allows ligation of these rare veins. Another cause of backbleeding with total vascular isolation is a replaced left hepatic artery. Some patients with level III thrombus require venovenous bypass during total vascular isolation to support hemodynamics (total vascular isolation and venovenous bypass techniques are discussed under retrohepatic IVC replacement with major liver resection).26 Resection of a large RCC that involves the liver and has retrohepatic IVC tumor thrombus is challenging (Fig. 65-5). Choice of incision and exposure are key first steps. Nesbitt and colleagues suggest nephrectomy first, followed by ligation and amputation of the renal vein rather than en bloc resection.27 This maneuver facilitates access to and exposure of the vena cava and simplifies removal of the tumor thrombus. Renal artery embolization has been used to reduce tumor vascularity with large cancers and to shrink the tumor thrombus. However, few data support its routine use. The Cleveland Clinic group compared the results of 135 patients who had preoperative embolization, radical nephrectomy, and IVC tumor thrombectomy with those of 90 patients who did not have embolization.40 There was no benefit from this treatment. In fact, the authors found a higher mortality rate in the embolized group (13% vs 3%) and a fivefold higher risk of perioperative death by multivariable analysis. Moreover, such treated individuals had greater transfusion requirements and a higher postoperative complication rate (43% vs 29%). The level of tumor thrombus was not significantly reduced with this therapy. At the Mayo Clinic, renal artery embolization is reserved for palliation of symptomatic and inoperable RCC. Most blood loss during radical nephrectomy comes from disruption of dilated perirenal and retroperitoneal venous collaterals due

CHAPTER 65  Venous Tumors

994

SECTION 10  Venous Insufficiency and Occlusion

A

B

C

D

E

Figure 65-5  Axial CT images of a patient with a large vascular renal cell cancer, right liver lobe hepatic metastasis, and vascular thrombus extending both from the right hepatic vein and from the renal vein into the IVC, which is obstructed (A-C, arrows). Note the large lumbar vein collateral in D. The renal cell cancer was resected, the right lobe of the liver was removed, and because of caval wall invasion, the IVC was replaced from the suprahepatic segment to the infrarenal vena cava with a short graft to reconstruct the left renal vein (E). Note that the rings of the graft are kept intact at the anastomoses to avoid compression.

CHAPTER 65  Venous Tumors

Dx3x% of caval wall to be replaced

D

Patch

Figure 65-6  If closure of a caval defect will narrow the vein, a bovine pericardial patch is used. The diameter of the patch is estimated from the percentage circumference resected from the normal vena cava. See diagram for calculation. In most cases, the patch assumes a wide elliptical or circular configuration.

good success.2,25 I used a femoral vein panel graft to reconstruct the IVC in one patient who had resection of a recurrent tumor during which intestinal resection was needed.1 A stenosis occurred at the upper caval anastomosis, which required balloon angioplasty. Perhaps a spiral vein or homograft would have provided better radial force to resist visceral compression. Whereas an arteriovenous fistula has been used to enhance patency of IVC reconstructions in some series, this adjunct is rarely used in our current practice.

Retrohepatic Inferior Vena Cava Replacement in Conjunction with Major Liver Resection Resection of liver cancers or sarcomas with perihepatic IVC involvement has been reported from a number of centers, including our own.1,13-25 These procedures may be done with in situ or ex situ techniques. It is our opinion that in situ resection with IVC replacement has broader applicability, versatility, and similar efficacy to those done ex situ.17 Our technique of combined liver resection and retrohepatic IVC replacement has evolved over the years (Fig. 65-7).17 Total vascular isolation, selective use of venovenous bypass to maintain hemodynamics, choice of a secure position for the upper caval cross-clamp, and ligation of the afferent and efferent lobar vasculature before parenchymal division are important steps. After exclusion of intraabdominal spread of tumor beyond the confines of safe resection, intraoperative ultrasonography is used to exclude occult intraparenchymal metastases and to determine the proximity of tumor to major vascular structures, including the planned remnant hepatic vein. The infrahepatic or pararenal IVC and the vessels in the gastrohepatic ligament are isolated before the liver is mobilized and the suprahepatic IVC is dissected free. Patients with large tumors that preclude complete mobilization with an abdominal incision may need extension of that incision into the right side of the chest or else an incision of the diaphragm. Hepatic resection is

performed with the CUSA device (Valleylab, Boulder, Colo) after a 5-minute period of inflow vascular occlusion to the liver. Additional ischemic preconditioning by inflow occlusion is used for patients at risk of abnormal parenchymal bleeding, as occurs in some repeated liver operations or with polycystic liver disease. Total vascular isolation is initiated when the surgeon is ready to transect the IVC to complete en bloc tumor resection. The sequence of IVC clamping with total vascular isolation is infrahepatic, hepatic artery and portal vein in the gastrohepatic ligament, and then suprahepatic. Extracorporeal venovenous bypass from the infrarenal IVC to the jugular vein is used if systolic blood pressure cannot be kept above 100  mm Hg with intravenous fluid. The need for venovenous bypass seems to be higher in patients with preexisting cardiopulmonary dysfunction or those older than 60 years.1 Low-dose intravenous heparin (1000-2000 units) is administered before the IVC is crossclamped, unless there has been significant blood loss during the liver resection from which the patient may be autoanticoagulated. The upper caval anastomosis is performed during total vascular isolation and often includes the remnant hepatic veins. The anastomosis is tested and flushed with the patient in head-down position and the lungs inflated to 30  mm Hg to avoid air embolism. This allows washout of acid metabolites from the liver before transfer of the suprahepatic caval clamp onto the graft. The lower anastomosis is fashioned end to end to the IVC. The position of the graft is marked and its length checked during maximum inspiration and expiration before the graft is cut to fit. This maneuver avoids torsion or buckling of the graft, which can obstruct the hepatic veins. The rings are kept close to the anastomosis to avoid graft compression (Fig. 65-8). The graft is circumferentially wrapped with omentum to keep it from contact with the bowel. The major limitation to in situ liver resection and caval reconstruction is warm hepatic ischemia time. Even though our mean liver ischemia time has been 18 minutes it can be unpredictable.17 In addition to the 5 to 10 minutes of hepatic vascular inflow occlusion for ischemic preconditioning, we have used perioperative allopurinol to potentially enhance ischemic tolerance in a few patients, but not as a routine.17 We have used cardiopulmonary bypass and hypothermic circulatory arrest to reconstruct one patient with PVL of the retrohepatic IVC (Fig. 65-9). Others prefer ex situ hepatic resection and autotransplantation of the hepatic remnant because of the unpredictability of hepatic ischemic time.23,24 An advantage of this technique is isolated hypothermic resection with the protective effects of liver perfusion, which allows time to perform difficult vascular reconstructions.17,23,24 However, ex situ resection increases operative time and the number of vascular anastomoses, carries higher perioperative mortality and liver failure rates, and has a real but low risk for salvage orthotopic liver transplantation.18,48,49 The accrued data from a number of centers have now firmly established the technical feasibility of these operations.1,5,13-25 The addition of other ischemic protective factors

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

L

995

996

SECTION 10  Venous Insufficiency and Occlusion

A

B

C

D

Figure 65-7  Operative technique for replacement of the retrohepatic inferior vena cava (IVC) in conjunction with major liver resection. A, Isolation of the IVC above and below the level of the tumor as well as isolation and division of the hepatic artery and portal vein branches. B, Hepatic vascular exclusion is used to complete resection of the liver, tumor, and retrohepatic IVC. If necessary, venovenous bypass via a cannula is performed. C, The upper caval anastomosis is performed first. D, The suprahepatic caval clamp is transferred across the graft after acid metabolites have been flushed from the liver. The lower caval anastomosis is completed. (From Bower TC, et al: Vena cava replacement for malignant disease: is there a role? Ann Vasc Surg 7:51-62, 1993, with permission.)

CHAPTER 65  Venous Tumors



997

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

B

A

Figure 65-8  Intraoperative photograph (A) and CT scan (B) of a patient who had suprarenal inferior vena cava (IVC) resection with reimplantation of the left renal vein. Note the stenosis at the upper graft–IVC anastomosis where the rings have been removed from the graft (arrow). This area was successfully stented (C).

C

998

SECTION 10  Venous Insufficiency and Occlusion

A

C

B

D

Figure 65-9  Patient with an infiltrative retrohepatic IVC leiomyosarcoma extending from the right renal vein to the cavoatrial junction. The tumor infiltrated the origin of the right hepatic vein (A, B). Reconstruction was accomplished with use of cardiopulmonary bypass and hypothermic circulatory arrest for organ protection. The IVC was replaced with a 20-mm externally supported PTFE graft from the atrium to the left renal vein–caval confluence. The hepatic orifices were recreated and reimplanted onto the graft as a patch. The right renal vein also was reimplanted (C, D).

to preserve hepatic function, detailed selection factors, and better neoadjuvant therapies may enhance the utility of these operations in the future.17 Most patients have elevation in their liver function test results and are mildly auto-anticoagulated during the first several days, depending on the length of warm ischemia time. Liver function test results return to baseline within 7 to 10 days.1-3,17 I obtain ultrasound or CT imaging of the IVC graft and the remnant hepatic and portal veins to assess patency if the liver function test results remain elevated more than what is expected for a particular operation. Subcutaneous heparin is begun once the surgeon thinks the risk of hemorrhage is low and as long as the platelet counts are in normal

range. Patients are started on oral warfarin before hospital dismissal, with a goal international normalized ratio of 2 to 3. Patients remain anticoagulated for at least 6 months, after which they are prescribed aspirin only, as long as imaging studies show the caval graft to be widely patent.1-3,17 Most patients with infrarenal grafts are anticoagulated lifelong.

Management of the Iliac Veins during Tumor Resection Management of the iliac veins during sacral resection or hemipelvectomies can be challenging. For patients undergoing sacral resection, the anterior stage of the operation often

CHAPTER 65  Venous Tumors



B

A

is done first. If the resection will extend to the L5 vertebral body, the lower aorta and IVC require mobilization. Patients may have between one and three small vein branches at the iliac vein–caval confluence that can be thin walled or broad based. Simple ligation of these branches is ineffective, and suture ligation is needed. Isolation of the common and external iliac arteries and veins is done before dissection of the internal iliac artery and vein branches. Individual ligation of as many internal iliac artery and vein branches as possible reduces blood loss during the bone resection. The internal iliac artery branches are first ligated, followed by those of the internal iliac veins. In some patients with high sacral resection, an effort is made to preserve the posterior division branches of the internal iliac artery. I prefer to control but not ligate the main internal iliac vein trunks; the more caudal and posterior branches are isolated and ligated. This prevents distention of the distal branches, many of which are thin walled and can cause troublesome bleeding if they are inadvertently injured. Several techniques can be used to control and to ligate or oversew short, broad-based internal iliac vein branches as shown in Figure 65-10. Patch angioplasty of the external or common iliac vein is preferred to graft replacement whenever possible. I use 12- or 14-mm-diameter PTFE grafts if segmental resection is done. However, replacement of both common iliac veins is rarely done if they are encased by tumors. If prosthetic graft is used, it is covered by omentum, adjacent soft tissue, or bovine pericardium.

OUTCOMES AND SURVIVAL Patient outcome is dictated by the same factors that affect operative risk, namely, tumor stage, segment and length of vein that requires resection or replacement, and patient performance status and comorbidities.1-3,13-43 Comparison of outcomes between studies is difficult because they include a variety of malignant neoplasms and

C

D

lump together patients who have circumferential IVC resection and graft replacement with those who have primary or patch closure of the IVC. These are important distinctions because the hemodynamic and physiologic stresses of partial resection of the IVC wall with patch angioplasty or removal of the infrarenal segment vary considerably in those who require retrohepatic IVC replacement in conjunction with major liver resection or need cardiopulmonary bypass and circulatory arrest to remove tumor thrombus. Table 65-1 lists the larger, more contemporary series as they relate to tumor type, complexity of the operation, segment of IVC treated, and tumor size. For example, in the series by Kieffer’s group, the mortality rate was 20%, but the tumors were very large, and 14 of the 20 patients had involvement of the suprarenal retrohepatic or suprahepatic IVC, of which 5 involved the hepatic veins or had cardiac extension. Thirteen of their patients had IVC graft replacement.13 In contrast, the Brigham and Women’s group had no mortality among 20 patients treated for PVL, but only 5 patients required prosthetic graft replacement of the IVC, one patient had tumor involvement above the hepatic vein, and another needed partial liver resection (one patient each required resection of a portion of the aorta or an iliac artery).14 The majority of the 11 patients in the Illuminati report from the University of Rome, Italy, had involvement of the infrarenal IVC.15 Mortality rates from resection of secondary IVC tumors, in which a majority of patients needed major liver resection, range from 0% to 6.9%. A recent report from Quinones-Baldrich and the UCLA group included 47 patients who underwent IVC resection and en bloc tumor excision between 1990 and 2011.16 The majority of tumors were sarcomas (77%), of which 30 originated primarily within the IVC. Of the 47 patients, 11 had primary repair of the IVC, 9 required patch angioplasty, but 27 had circumferential resection and cava replacement with a PTFE ringed graft. Of these 27 patients, 18 had replacement of

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

Figure 65-10  The internal iliac vein anatomy is variable, and some branches may be short and broad, which makes their control difficult (A). Methods of control are illustrated. The vein branches can be ligated or suture ligated as shown in B and C. The common and external iliac vein can be clamped, the distal branch suture ligated, and the internal iliac vein divided and oversewn as shown in D.

999

1000

SECTION 10  Venous Insufficiency and Occlusion

Table 65-1

Contemporary Series of Primary and Secondary Inferior Vena Cava Malignant Neoplasms Location N

Type

Illuminati 2006 Kieffer 2006 Ito 2007 Bower 2000

11 20 20 29

Sarmiento 2003

19

Kuehnl* 2007

35

Delis 2007

12

PVL PVL PVL PVL Secondary Cholangiocarcinoma Metastatic Sarcoma HCC Secondary PVL Colorectal HCC Cholangiocarcinoma PVL Secondary

Quinones-Baldrich 2012

IR

2 27 9 5 3 2 20 6 6 4 2 30 17

SR/RH

SH

Liver Resection

Tumor Size (cm)

Graft

Mortality, n (%)

8 3 6 10

3 13 13 19

0 4 1 0

— 4 1 13

15 21 10.7 —

11 13 5 29

0 4 (20) 0 2 (6.9)

0

19

0

19

—

18

1 (5)

5 (4)

7 (3)

—

—

—

2 (6)

0

12

12

—

12

0

9

18

NA

11.6

27†

0

14 (2) 0

HCC, Hepatocellular carcinoma; IR, infrarenal segment; PVL, primary venous leiomyosarcoma; SH, suprahepatic segment; SR/RH, suprarenal-retrohepatic segment. *Nine superior vena cava and 26 inferior vena cava tumors. The location of the nine patients with grafts is shown in parentheses. † The entire inferior vena cava was replaced with hepatic and renal vein reimplantation in eight patients; six patients had the suprarenal and pararenal inferior vena cava replaced, with seven renal vein reimplantations; and four patients had the infrarenal and pararenal inferior vena cava replaced, with four renal vein reimplantations.

more than one caval segment. Of these 18 patients, 8 had replacement of all caval segments with renal and hepatic vein reimplantation; 6 others had replacement of the pararenal and suprarenal IVC, with 7 renal veins reimplanted; and 4 had the infrarenal and pararenal segment replaced, which included reimplantation of 4 renal veins. The remaining 9 patients had infrarenal IVC grafts. Impressively, there was no mortality in this series. Major morbidity was 10.6% and included bowel obstruction, temporary acute renal failure, reoperation for bleeding, chylous ascites, and graft thrombosis in one each. Major morbidity with these operations ranges between 11% and 33%.1,13-19 Only one graft infection was reported among the series listed in Table 65-1.1 Prosthetic graft patency is excellent, ranging from 85% to 100% during a follow-up ranging from 18 months to nearly 4 years.1,13-19 One of my patients has a patent graft 18 years after combined infrarenal aorta and IVC replacement. We now have replaced the IVC in 91 patients, with 3 known graft occlusions, 2 of which occurred as a consequence of late sepsis after additional adjuvant therapies for recurrent disease. The UCLA group reported a graft thrombosis from similar problems.16 The operative mortality and morbidity rates for patients with RCC and intracaval tumor thrombus are the lowest at high-volume centers and have improved over time. A Mayo Clinic report by Blute and coworkers showed the mortality rate to be 8.1% for 86 patients with RCC and tumor thrombus operated on between1970 and 1989 but only 3.8% among

105 patients treated between 1990 and 2000.26 Complication rates were higher in those with level III and level IV thrombus. If venovenous bypass was used instead of cardiopulmonary bypass for these patients, the complication rate decreased from 31% to 17%. Survival for patients with IVC leiomyosarcoma seems to be best with curative resection. A study of 120 patients from the International Registry of Inferior Vena Cava Leiomyosarcomas by Mingoli and colleagues compared outcomes in 67 patients who had extensive tumor and IVC resection with those in 53 patients who had limited resection of the IVC wall.51 A variety of factors were analyzed, but multivariable analysis was unable to show a significant difference in survival or disease recurrence between the two groups. The other surgical series of IVC leiomyosarcoma show improved survival with curative resection. The report by Kieffer and associates had mean 3- and 5-year actuarial survival rates of 52% and 34.8%, respectively.13 The Ito paper showed a mean disease-free survival of 21 months but a median overall survival of 71 months for the 19 patients who had complete resection.14 The cumulative disease-free survival rate in the report from Illuminati and associates was 44% at 5 years.15 Meaningful impact of these operations on survival rates for patients with secondary IVC malignant neoplasms has improved during the past decade. Overall survival in the study from the Mayo Clinic was 89.3% at 1 year, 80.3% at 2 years, and 75% at 3 years.1 The mean survival among those who had infrarenal IVC resection and replacement was 3.1



VENOUS TUMORS IN THE CHEST Lung cancer with mediastinal adenopathy is the most common cause of SVC obstruction. Lymphoma, follicular or

1001

medullary thyroid cancer, teratoma, and thymoma are the most common primary mediastinal malignant neoplasms and together with lung cancer account for 60% to 85% of cases with malignant SVC obstruction.2 Angiosarcoma and synovial cell sarcoma less frequently cause this problem. Many patients with malignant SVC obstruction have unresectable disease, similar to secondary IVC malignant neoplasms, so the venous occlusion is treated with stenting. Surgical resection of the tumor is offered to patients with localized disease and without involvement of the aortic arch, great vessels, or heart. In our practice, SVC resection with replacement is rarely performed, and when it is, we use a prosthetic graft. Venous reconstruction of the innominate or subclavian veins is feasible and is done with a bovine patch or prosthetic or autogenous vein replacement. Kuehnl and associates described nine patients who underwent SVC resection and reconstruction for malignant disease.18 Four patients had non–small cell carcinoma of the lung; two had malignant thymoma; and leiomyosarcoma, germ cell metastases, and cancer of unknown origin accounted for the remaining three. Prosthetic grafts were used to replace the SVC in four patients, all of whom had lung cancer. The others had a wedge excision of the vein with primary closure. Primary vascular smooth muscle tumors are rare. A report by Butany and the Toronto, Ontario, Canada, group included 230 malignant smooth muscle neoplasms of vascular origin during the years 1987 through 2005.53 Pulmonary vein leiomyosarcoma was the most common in the chest, found in 18 patients. There was female predominance, and heart symptoms were most common, including palpitations, dizziness, syncope, dyspnea, and right-sided heart failure. Mean survival in the 18 patients was 26 months. Among all sites of vascular smooth muscle tumors during this time frame, the overwhelming majority involved the IVC, followed in order by the peripheral arteries, the pulmonary vein and artery, and the veins of retroperitoneal or uterine origin.

SELECTED KEY REFERENCES Bower TC, Nagorney DM, Cherry KJ Jr, Toomey BJ, Hallett JW, Panneton JM, Gloviczki P: Replacement of the inferior vena cava for malignancy: an update. J Vasc Surg 31:270–281, 2000. The paper provides an in-depth analysis of the types and locations of the IVC tumors, an analysis of outcomes, and detailed surgical techniques. Klatte T, Pantuck AJ, Riggs SB, Kleid MD, Shuch B, Zomorodian N, Kabbinavar FF, Belldegrun AS: Prognostic factors for renal cell carcinoma with tumor thrombus extension. J Urol 178:1189–1195, 2007. This paper identified prognostic factors for renal cell carcinoma with IVC tumor thrombus and concluded that positive nodes, distant metastases, sarcomatoid features, and performance status have a negative impact on survival. Mingoli A, Feldhaus RJ, Cavallaro A, Stipa S: Leiomyosarcoma of the inferior vena cava: analysis and search of world literature on 141 patients and report of the three new cases. J Vasc Surg 14:688–699, 1991. This is a large, collective review on IVC leiomyosarcomas. Pouliot F, Shuch B, LaRochelle JC, Pantuck A, Belldegrunt AS: Contemporary management of renal tumors with venous tumor thrombus. J Urol 184:833–841, 2010. This paper summarizes the contemporary management of patients with renal cell cancer and venous tumor thrombus. The authors provide comparative outcome data between the largest studies with regard to median survival, disease-specific survival, and impact of metastases or no metastases on disease-specific survival.

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

years, but it decreased to 2.88 years in those who had the entire IVC replaced and 2.26 years in those with suprarenal caval replacement. In another report from this group that analyzed retrohepatic IVC replacement with major liver resection, overall survival of patients who had partial or segmental liver resection and replacement of the retrohepatic IVC was 21% at 5 years; the median overall survival was 38 months, but the median recurrence-free survival was 11.5 months. Survival was best for patients with intrahepatic cholangiocarcinoma, which was 69% at 3 years.17 The 1-, 3-, and 5-year survival rates reported by the group from Munich, Germany, were 76%, 32%, and 21%, respectively, with a median survival of 29 months. This group found incomplete resection and cardiopulmonary risk to have a significant negative impact on survival.18 The median follow-up reported by the University of Miami group was 24 months, at which point 4 of the 12 patients in the surgical group had died of recurrent disease. The greatest survival benefit is for patients with RCC and IVC tumor thrombus.26,35,36,52 Five-year survival rates range from 40% to 65% for patients with venous involvement and no metastases but fall significantly to 6% to 28% in the presence of metastases.35 The report by Blute and coworkers had a 5-year cancer-specific survival rate of 59% in those who had no nodal or metastatic disease at the time of operation.26 Survival was found to be negatively affected by performance status, positive lymph nodes or distant metastases, and sarcomatoid features on the basis of multivariate analysis in the study by Klatte and associates.36 There is a growing literature on the role of adjuvant therapy, particularly for patients with retroperitoneal sarcomas or RCC. Local relapse is common if the sarcoma is large, high grade or an R0 resection is not achieved. Radiation therapy combined with wide local tumor excision has improved local rates of recurrence. Select individuals in whom an R0 resection is anticipated may benefit from a combination of external beam radiation therapy to a dose of 45 to 50 Gy in combination with an intraoperative boost of 10 to 20 Gy. Intraoperative focused radiation therapy, in which the bowel is retracted away from the field of treatment, seems to provide a more favorable therapeutic ratio between local control and complications to other tissues in the field, such as nerve, blood vessels, bone, and soft tissue.7 Targeted molecular therapies using tyrosine kinase inhibitors such as sunitinib may reduce RCC size to enhance resection but do not seem to reduce the extent of tumor thrombus.6 Few studies have assessed quality of life after operation. In the reports from the author’s group, careful patient selection has allowed more than 80% of patients operated on for malignant disease of the IVC to maintain an excellent status performance after operation, even if they later develop regional or distant metastases.1,17

CHAPTER 65  Venous Tumors

1002

SECTION 10  Venous Insufficiency and Occlusion

Quinones-Baldrich W, Alktaifi A, Eilber F: Inferior vena cava resection and reconstruction for retroperitoneal tumor excision. J Vasc Surg 55:1386– 1393, 2012. The UCLA group describes 47 patients treated with IVC resection and tumor excision between 1990 and 2011. The majority of tumors were sarcomas, of which 30 were primary to the IVC. Eleven patients had primary repair, 9 had patch angioplasty, and 27 had circumferential resection and IVC replacement with a PTFE graft. Eighteen of the reconstructions with grafts included more than one caval segment. There was no mortality and a 10.6% major morbidity rate. Sarmiento JM, Bower TC, Cherry KJ, Farnell MB, Nagorney DM: Is combined partial hepatectomy with segmental resection of the inferior vena cava justified for malignancy? Arch Surg 138:624–630, 2003. This paper analyzes outcomes of patients undergoing resection of the retrohepatic IVC in conjunction with major liver resection. There is a detailed outline of the surgical technique and an analysis of outcomes for various types of tumors. The paper by Delis and colleagues19 also provides an analysis of patients undergoing similar tumor and IVC resection. Subramanian VS, Stephenson AJ, Goldfarb DA, Fergany AF, Novick AC, Krishnamurthi V: Utility of preoperative renal artery embolization for

management of renal tumors with inferior vena caval thrombi. Urology 74:154–159, 2009. The Cleveland Clinic group compared outcomes between 135 patients who had renal artery embolization before renal cell cancer resection and 90 patients who did not have embolization. There was a higher mortality rate, greater transfusion requirements, and higher postoperative complication rate in the embolized group. Zini L, Destrieux-Garnier L, Leroy X, Villers A, Haulon S, Lemaitre L, Koussa M: Renal vein ostium wall invasion of renal cell carcinoma with inferior vena cava tumor thrombus: prediction by renal and vena caval vein diameters and prognostic significance. J Urol 179:450–454, 2008. There is a growing literature on radiologic factors that predict either renal vein ostium or inferior vena cava invasion by renal cancer and tumor thrombus. This is one of these papers. The group found a nearly sixfold increased risk of death from renal cell cancer in multivariable analysis controlled for tumor size, stage, and thrombus level in 32 patients who did not have complete removal of the tumor thrombus. The reference list can be found on the companion Expert Consult website at www.expertconsult.com.



REFERENCES

26. Blute ML, et al: The Mayo Clinic experience with surgical management, complications and outcome for patients with renal cell carcinoma and venous tumour thrombus. BJU Int 94:33–41, 2004. 27. Nesbitt JC, et al: Surgical management of renal cell carcinoma with inferior vena cava tumor thrombus. Ann Thorac Surg 63:1592–1600, 1997. 28. Gettman MT, et al: Charlson co-morbidity index as a predictor of outcome after surgery for renal cell carcinoma with renal vein, vena cava or right atrium extension. J Urol 169:1282–1286, 2003. 29. Frank I, et al: An outcome prediction model for patients with clear cell renal carcinoma treated with radical nephrectomy based on tumor stage, size, grade, and necrosis: the SSIGN score. J Urol 168:2395–2400, 2002. 30. Leibovich BC, et al: A scoring algorithm to predict survival for patients with metastatic clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. J Urol 174:1759–1763, 2005. 31. Haferkamp A, et al: Renal cell carcinoma with tumor thrombus extension into the vena cava: prospective long-term follow-up. J Urol 177:1703–1708, 2007. 32. Ciancio G, et al: Surgical management of renal cell carcinoma with tumor thrombus in the renal and inferior vena cava: the University of Miami experience in using liver transplantation techniques. Eur Urol 51:988–995, 2007. 33. Terakawa T, et al: Clinical outcome of surgical management for patients with renal cell carcinoma involving the inferior vena cava. Int J Urol 14:781–784, 2007. 34. Lambert EH, et al: Prognostic risk stratification and clinical outcomes in patients undergoing surgical treatment for renal cell carcinoma with vascular tumor thrombus. Urol 69:1054–1058, 2007. 35. Pouliot F, et al: Contemporary management of renal tumors with venous tumor thrombus. J Urol 184:833–841, 2010. 36. Klatte T, et al: Prognostic factors for renal cell carcinoma with tumor thrombus extension. J Urol 178:1189–1195, 2007. 37. Goetzel MA, et al: A contemporary evaluation of cytoreductive nephrectomy with tumor thrombus: morbidity and long-term survival. Urol Oncol 22:182, 2004. 38. Sweeney P, et al: Surgical management of renal cell carcinoma associated with complex inferior vena caval thrombi. Urol Oncol 21:327, 2003. 39. Karnes RJ, et al: Surgery insight: management of renal cell carcinoma with associated inferior vena cava thrombus. Nat Clin Pract Urol 5:329, 2008. 40. Subramanian VS, et al: Utility of preoperative renal artery embolization for management of renal tumors with inferior vena caval thrombi. Urology 74:154–159, 2009. 41. Blute ML, et al: Results of inferior vena caval interruption by Greenfield filter, ligation or resection during radical nephrectomy and tumor thrombectomy. J Urol 178:440–445, 2007. 42. Chiche L, et al: Adrenocortical carcinoma extending into the inferior vena cava: presentation of a 15-patient series and review of the literature. Surgery 139:15–27, 2006. 43. Boorjian SA, et al: Surgery for vena caval tumor extension in renal cancer. Curr Opin Urol 19:473–477, 2009. 44. Perl L: Ein Fall von Sarkom der Vena cava inferior. Virchows Arch Pathol Anat 53:378–383, 1871. 45. Padovan RS, et al: Venous spread of renal cell carcinoma: MDCT. Abdom Imaging 32:530–537, 2007. 46. Zini L, et al: Renal vein ostium wall invasion of renal cell carcinoma with inferior vena cava tumor thrombus: prediction by renal and vena caval vein diameters and prognostic significance. J Urol 179:450–454, 2008. 47. Laissey JP, et al: Renal carcinoma: diagnosis of venous invasion with GD-enhanced MR venography. Eur Radiol 10:1138, 2000. 48. Hallscheidt PJ, et al: Preoperative staging of renal cell carcinoma with inferior vena cava thrombus using multidetector CT and MRI: prospective study with histopathological correlation. J Comput Assist Tomogr 29:64–68, 2005.

SECTION 10 VENOUS INSUFFICIENCY AND OCCLUSION

1. Bower TC, et al: Replacement of the inferior vena cava for malignancy: an update. J Vasc Surg 31:270–281, 2000. 2. Bower TC: Evaluation and management of malignant tumors of the inferior vena cava. In Rutherford RB, editor: Rutherford’s vascular surgery, ed 7, Philadelphia, 2010, Elsevier Saunders, pp 983–995. 3. Bower TC: Primary and secondary tumors of the vena cava and iliac veins. In Gloviczki P, editor: Handbook of venous disorders, ed 3, London, 2009, Hodder Arnold, pp 574–582. 4. Mingoli A, et al: Leiomyosarcoma of the inferior vena cava: analysis and search of world literature on 141 patients and report of three new cases. J Vasc Surg 14:688–699, 1991. 5. Dzsinich C, et al: Primary venous leiomyosarcoma: a rare but lethal disease. J Vasc Surg 15:595–603, 1992. 6. Cost NG, et al: The impact of targeted molecular therapies on the level of renal cell carcinoma vena caval tumor thrombus. Eur Urol 59:912– 918, 2011. 7. Petersen IA, et al: Use of intraoperative electron beam radiotherapy in the management of retroperitoneal soft tissue sarcomas. Int J Radiat Oncol Biol Phys 52:469–475, 2002. 8. Bartlett E, et al: Current treatment for the local control of retroperitoneal sarcomas. J Am Coll Surg 213:436–446, 2011. 9. Zisman A, et al: Renal cell carcinoma with tumor thrombus extension. Biology, role of nephrectomy and response to immunotherapy. J Urol 169:909–916, 2003. 10. Matsushita M, et al: Sequelae after limb-sparing surgery with major vascular resection for tumor of the lower extremity. J Vasc Surg 33:694– 699, 2001. 11. Schwarzbach MHM, et al: Results of limb-sparing surgery with vascular replacement for soft tissue sarcoma in the lower extremity. J Vasc Surg 42:88–97, 2005. 12. Nishinari K, et al: Venous reconstructions in lower limbs associated with resection of malignancies. J Vasc Surg 44:1046–1050, 2006. 13. Kieffer E, et al: Leiomyosarcoma of the inferior vena cava: experience in 22 cases. Ann Surg 244:289–295, 2006. 14. Ito H, et al: Leiomyosarcoma of the inferior vena cava: survival after aggressive management. Ann Surg Oncol 14:3534–3542, 2007. 15. Illuminati G, et al: Prosthetic replacement of the infrahepatic inferior vena cava for leiomyosarcoma. Arch Surg 141:919–924, 2006. 16. Quinones-Baldrich W, et al: Inferior vena cava resection and reconstruction for retroperitoneal tumor excision. J Vasc Surg 55:1386–1393, 2012. 17. Sarmiento JM, et al: Is combined partial hepatectomy with segmental resection of the inferior vena cava justified for malignancy? Arch Surg 138:624–630, 2003. 18. Kuehnl A, et al: Resection of malignant tumors invading the vena cava: perioperative complications and long-term follow-up. J Vasc Surg 46:533–540, 2007. 19. Delis S, et al: Combined liver and inferior vena cava resection for hepatic malignancy. J Surg Oncol 96:258–264, 2007. 20. Arii S, et al: Significance of hepatic resection combined with inferior vena cava resection and its reconstruction with expanded polytetrafluoroethylene for treatment of liver tumors. J Am Coll Surg 239:712–721, 2004. 21. Hemming AW, et al: Combined resection of the liver and inferior vena cava for hepatic malignancy. Ann Surg 239:712–721, 2004. 22. Yoshidome H, et al: Should the inferior vena cava be reconstructed after resection for malignant tumors? Am J Surg 189:419–424, 2005. 23. Oldehafer KJ, et al: Long-term experience after ex situ liver surgery. J Surg 127:520–527, 2000. 24. Lodge JPA, et al: Ex vivo and in situ resection of inferior vena cava with hepatectomy for colorectal metastases. Ann Surg 231:471–479, 2000. 25. Praseedom RJ, et al: Leiomyosarcoma of the retrohepatic vena cava treated by excision and reconstruction with an aortic homograft: a case report and review of the literature. Surg Innov 14:287–291, 2007.

CHAPTER 65  Venous Tumors 1002.e1

1002.e2 SECTION 10  Venous Insufficiency and Occlusion 49. Lawrentschuk N, et al: Multi-detector computed tomography vs magnetic resonance imaging for defining the upper limit of tumour thrombus in renal cell carcinoma: a study and review. BJU Int 96:291, 2005. 50. Guzzo TJ, et al: The accuracy of multidetector computerized tomography for evaluating tumor thrombus in patients with renal cell carcinoma. J Urol 181:486–490, 2009.

51. Mingoli A, et al: The effect of extend of caval resection in the treatment of inferior vena cava leiomyosarcoma. Anticancer Res 17:3877–3882, 1997. 52. Wagner B, et al: Prognostic value of renal vein and inferior vena cava involvement in renal cell carcinoma. Eur Urol 55:452, 2009. 53. Butany J, et al: Vascular smooth muscle tumors: 13 cases and a review of the literature. Int J Angiol 15:43–50, 2006.

CHAPTER 66 

Lymphedema: Evaluation and Decision Making STANLEY G. ROCKSON

L

ymphedema is the clinical description of various disease states characterized by the progressive accumulation of protein-enriched interstitial fluid. These edematous states arise as a consequence of relative impairment of lymphatic drainage. Insufficient lymphatic function can result from either primary or acquired (secondary) anomalies of lymphatic outflow. Cryptogenic forms of lymphedema are often presumed to represent primary lymphatic dysfunction. Although impaired lymphatic function often is manifested as visceral involvement, particularly in the respiratory or gastrointestinal organs, upper or lower extremity edema, with or without visceral involvement, is the most common presentation of lymphatic impairment and is most predictive of the natural history of the condition.

PATHOPHYSIOLOGY Insufficient lymphatic outflow leads to the pathologic end result of lymphedema. In high-input failure, such as that which occurs in venous edema, increased capillary pressure leads to the accentuated production of interstitial fluid; if the production of lymph exceeds the maximal transport capacity of the lymphatic conduits, lymphedema will ensue, even if these structures are anatomically and functionally normal. By contrast, low-output failure ensues when some pathologic condition compromises lymphatic flow. Lymph stasis can accompany lymphatic hypoplasia or aplasia, functional insufficiency or anatomic absence of lymphatic valves, or, conceivably, blunted lymphatic contractility.1 Because the lymphatic circulation provides the normal conduit for the return of interstitial fluid and protein to the central circulation, abnormal lymph stasis creates an accumulation of protein and cellular metabolites in the extracellular space; with the ensuing increase in tissue colloid osmotic pressure, there is water accumulation and elevation of the interstitial hydraulic pressure (see Chapter 13). Insufficient lymphatic transport leads to the accumulation of hyaluronan and other glycoproteins within the extracellular space. This is followed by a secondary increase in the fibroblast, keratinocyte, and adipocyte content 1004

of the affected tissues along with the accumulation of mononuclear cells, including macrophages. Ultimately, an increase in collagen deposition occurs, typically accompanied by an overgrowth of connective tissue and adipose elements in the skin and subcutaneous tissue.2 Although the contributory mechanisms are still not well understood, there is a tendency for these processes to lead to progressive subcutaneous fibrosis.

CLASSIFICATION AND STAGING Standard clinical classifications distinguish lymphedema on the basis of cause (primary versus secondary). Primary lymphedema is further classified on the basis of genetics (familial versus sporadic) and time of onset (congenital, praecox, tarda) (Box 66-1).3-5 Although these systems are useful for categorizing lymphedema, they do not address the clinical severity of the disease and are usually not relevant to therapy. More recent classifications focus on the clinical stage of lymphedema or emphasize the underlying anatomic abnormality of the lymphatic system in an attempt to identify the best therapy.1,6,7

Primary Lymphedema Prevalence of the heritable causes of primary lymphedema is difficult to ascertain, and estimates vary substantially. Primary lymphedema is thought to occur in approximately 1 of every 6000 to 10,000 live births. On the basis of data collected by the Rochester group study, it affects 1.15 per 100,000 persons younger than 20 years.8 Females are affected 2- to 10-fold more commonly than males, and the incidence peaks between the ages of 12 and 16 years.6,9 Of 125 patients with primary lymphedema treated at the Mayo Clinic, 97 (78%) were female and 28 (22%) were male, yielding a female-to-male ratio of 3.5 : 1.10 The ratio of unilateral to bilateral lymphedema was 3 : 1. Congenital lymphedema occurred more frequently in males than in females. In these patients, the edema was usually bilateral and involved the entire lower extremity. In contrast, the typical patient with lymphedema praecox was female and had

CHAPTER 66  Lymphedema: Evaluation and Decision Making



BOX 66-1 

CLASSIFICATION OF LYMPHEDEMA BASED ON ETIOLOGY, AGE AT ONSET, AND INHERITANCE PRIMARY LYMPHEDEMA Congenital (onset before 1 year of age) Nonfamilial Familial (Milroy’s disease) Lymphedema praecox (onset from 1 to 35 years of age) Nonfamilial Familial (Meige’s disease) Lymphedema tarda (onset after 35 years of age)

marked gender imbalance, with an estimated 10 : 1 female-tomale prevalence.2 The edema is usually unilateral and is limited to the foot and calf in the majority of patients.10 Estrogenic hormones may play a role in the pathogenesis of this form of primary lymphedema.10 Lymphedema Tarda. Lymphedema tarda is relatively uncommon. Appearing after the age of 35 years, it typi­cally accounts for an estimated 10% of cases of primary lymphedema.

Classification by Morphology It has been suggested that a morphologic classification of primary lymphedema might provide more useful prognostic information than classification by age at onset (Fig. 66-1).2 This alternative classification scheme relies on an anatomic description of the lymphatic vasculature.3,11 Aplasia. In aplasia, no collecting vessels can be identified. Hypoplasia. In hypoplasia, a diminished number of vessels are seen.

unilateral involvement, with swelling usually extending up to the knee only. Primary lymphedema represents a heterogeneous group of disorders; therefore, its classification schemes are numerous. Affected individuals can be classified by age at onset, morphology, or clinical setting.

Classification by Age at Onset and Inheritance Lymphedema is termed congenital when it is apparent at birth or is recognized within the first year of life. Lymphedema praecox most commonly appears at the onset of puberty, but it may be delayed until the third decade of life. Lymphedema tarda typically begins after the age of 35 years (see Box 66-1). Congenital. Congenital lymphedema commonly occurs in a sporadic fashion; however, when clusters of cases occur in families, an autosomal dominant pattern of transmission is frequently observed.11 In addition to the genetic causes of isolated lymphedema, there is a strong association between intrauterine and congenital lymphatic dysfunction and heritable chromosomal abnormalities, including Turner’s syndrome, Klinefelter’s syndrome, and trisomy 21, among many others. In congenital lymphedema, the swelling can involve only a single lower extremity, but edema of multiple limbs, the genitalia, and even the face can be seen. Bilateral leg swelling and involvement of the entire lower extremity are more likely in congenital cases than in other forms of primary lymphedema.10 Lymphedema Praecox. Lymphedema praecox is the most common form of primary lymphedema, accounting for up to 94% of cases in large series. The name Meige’s disease has historically been reserved for a specific familial form of lymphedema with a recessive pattern of inheritance and typical onset at puberty. Lymphedema praecox displays a

Numerical Hyperplasia. In numerical hyperplasia (as defined by Kinmonth3), an increased number of vessels are seen. Hyperplasia. In addition to an increase in number, the vessels have valvular incompetence and display tortuosity and dilatation (megalymphatics, lymphangiectasia). Megalymphatics and lymphatic hyperplasia are less common than hypoplasia or aplasia. This pattern demonstrates a male predominance. These patients most often have unilateral edema involving the entire lower extremity. Cutaneous angiomas and chylous reflux can also be seen (Fig. 66-2). Megalymphatics are associated with a greater extent of involvement and a worse prognosis.

Classification by Anatomy Aplasia and hypoplasia have a different natural history, depending on whether they involve the distal or proximal portion of the leg. Distal Obstruction. Approximately one third of all cases are secondary to agenesis, hypoplasia, or obstruction of the distal lymphatic vessels, with relatively normal proximal vessels (see Fig. 66-1).11 In these cases, the swelling is usually bilateral and mild, and females are affected much more frequently than males. The prognosis is good. In general, after the first year of symptoms, there is little extension in the same limb or to uninvolved extremities. Although the maximal extent of involvement is established early in the disease in about 40% of patients, the girth of the limb continues to increase. Distal hypoplasia or aplasia of the lymphatics most often correlates with the presence of bilateral peripheral edema of the lower extremities. Familial occurrence, female predominance, and indolent progression characterize this pattern of lymphatic disturbance.

SECTION 11 LYMPHEDEMA

SECONDARY LYMPHEDEMA Filariasis Lymph node excision ± radiation Tumor invasion Infection Trauma Other

1005

1006

SECTION 11  Lymphedema

Normal

Obliteration (92% of patients)

Hyperplasia (8% of patients)

Iliac nodes Inguinal ligament Inguinal nodes

Distal obliteration

Distal and proximal obliteration

Pelvic obstruction

Bilateral hyperplasia (abnormal thoracic duct)

Megalymphatics

Figure 66-1  Lymphangiographic patterns of lymphatic morphology in a normal lower limb and in patients with different types of primary lymphedema. Obliteration of the lymphatic pathways may be due to aplasia, hypoplasia, or obstruction of the lymphatic channels and nodes.

Proximal Obstruction. In more than half the cases, the defect primarily involves obstruction of the proximal lymphatics or nodes, with an initial lack of involvement of distal lymphatic vessels. Pathologic studies reveal intranodal fibrosis.12 In these cases, the swelling tends to be unilateral and severe, and there may be a slight female predominance.11 In patients with proximal involvement, the extent and degree of the abnormality are likely to progress, requiring surgical intervention. Initially uninvolved distal lymphatic vessels may become obliterated over time. A minority of patients have a pattern of bilateral hyperplasia of the lymphatic channels. In these less common forms of primary lymphedema, there is a slight male predominance. When isolated proximal obstructive hypoplasia is observed, clinical involvement of the entire limb is more likely, with relentless worsening of edema. Alternatively, primary lymphedema can be classified by abnormal phenotype or associated clinical anomalies (see Box 66-1).13

form of inheritance with variable penetrance, was first described by Milroy in 1892.14 He reported “hereditary edema” affecting 22 individuals in 1 family over 6 generations. Although Milroy studied not only congenital lymphedema but also the praecox and tarda variants of the syndrome that bears his name, lymphedema praecox is better known as Meige’s disease.15 In general, congenital lymphedema with autosomal or sexlinked recessive forms of inheritance is less common than that with dominant forms of inheritance.11,16,17 Nevertheless, the list of heritable lymphedema-associated syndromes is long and growing.18 Primary lymphedema has been described in association with various forms of chromosomal aneuploidy, such as Turner’s and Klinefelter’s syndromes; with various dysmorphogenic genetic anomalies, such as Noonan’s syndrome and neurofibromatosis; and with a variety of as yet unrelated disorders, such as yellow nail syndrome, intestinal lymphangiectasia, lymphangiomyomatosis, and arteriovenous malformation.19-24 The association of lymphedema with vascular anomalies suggests a common developmental origin of the lymphatic and blood vasculature.

Inheritance. Although sporadic cases of primary lymph­ edema are more common,11 the tendency for congenital lymphedema to cluster in families is significant (Fig. 66-3). A familial predisposition for congenital lymphedema, which was ultimately determined to have an autosomal dominant

Associated Disorders. Numerous disorders are associated with heritable forms of lymphedema. Increasingly, these disorders have yielded to chromosomal mapping techniques. Lymphedema-cholestasis, or Aagenaes syndrome, has been mapped to chromosome 15q.25 In several family cohorts of

Classification by Clinical Setting



CHAPTER 66  Lymphedema: Evaluation and Decision Making

1007

further elucidation of the molecular pathogenesis of these diseases linked to FOXC2 and SOX18 mutations will lead to enhanced insights into the mechanisms of normal and abnormal lymphatic development.

Secondary Lymphedema

Cancer Of the various clinical settings that predispose patients to lymphedema, treatment of breast cancer is most commonly associated with acquired lymphatic insufficiency (of the upper extremity). Lymph node dissection and adjuvant

Figure 66-2  Primary lymphedema of the right leg caused by hyperplasia of the lymphatics and valvular incompetence. Midcalf skin vesicles contain a milky fluid because of lymphangiectasia and reflux of chyle.

Milroy’s disease, it has been determined that the disorder reflects missense inactivating mutations in the tyrosine kinase domain of vascular endothelial growth factor receptor 3 (VEGFR-3),26,27 thus underscoring the likelihood that this condition reflects an inherited defect in lymphatic vasculogenesis. Several additional lymphedema syndromes have recently lent themselves to successful genetic mapping.7 Lymphedema-distichiasis, an autosomal dominant dysmorphic syndrome in which lymphedema presents in association with a supplementary row of eyelashes arising from the meibomian glands, has been linked to truncating mutations in the forkhead-related transcription factor FOXC228; mutations in FOXC2 have subsequently been associated with a wide variety of primary lymphedema presentations.29 Similarly, a more unusual form of congenital lymphedema, hypotrichosis-lymphedema-telangiectasia, has been ascribed to both recessive and dominant inheritance of mutations in the transcription factor gene SOX18.30 It is plausible that

A

B Figure 66-3  A, Adult patient with congenital lymphedema. In addition to the bilateral arm lymphedema depicted, she has edema of both legs and the face. B, Upper extremities of this patient’s 18-year-old son, who has a similar distribution of lymphedema. This is an example of Milroy’s disease.

SECTION 11 LYMPHEDEMA

Acquired (secondary) lymphedema is the most commonly encountered form of lymphatic dysfunction (Fig. 66-4). In the United States, iatrogenic causes predominate among the acquired forms of lymphedema owing to the common occurrence of lymphatic trauma after surgery or radiotherapy for cancer.9

1008

SECTION 11  Lymphedema

A

C

B

Figure 66-4  Chronic acquired lymphedema of the lower extremities. Note severe skin changes (A) and swelling of the foot (B) associated with squaring of the toes (Stemmer’s sign) and the typical peau d’orange. C, Severe lymphedema with subcutaneous lymph cysts and chronic verrucous superinfection.

radiation therapy independently and synergistically predispose to lymphatic vascular insufficiency.20 According to the most recent estimates, 20% to 30% of breast cancer survivors experience clinically significant arm lymphedema after axillary intervention. Despite the benefits of recent surgical and radiotherapeutic enhancements, the problem of lymphedema has not been eradicated.18 Similar lymphatic sequelae are encountered in the lower extremities and pelvis after interventions for gynecologic or urologic malignant neoplasms. Malignant melanoma can cause either upper or lower extremity lymphedema when radical dissection is required in the axilla or groin, respectively.

Filarial lymphedema rapidly develops into grossly incapacitating elephantiasis that is extremely difficult to treat.

Filariasis

Clinical Staging

Filariasis, caused by infestation with parasites such as Wuchereria bancrofti, Brugia malayi, and Brugia timori, is by far the most frequent cause of secondary lymphedema in third-world countries. Of the estimated 90.2 million people in the world who are infected, more than 90% have bancroftian filariasis.31 The disease is most frequent in subtropical and tropical countries such as China, India, and Indonesia. It is transmitted by different types of mosquitoes, and transmission is closely related to poor urban sanitation.32 Perilymphatic inflammation, fibrosis, and sclerosis of the lymph nodes are caused by the indwelling adult worms. Lymph node fibrosis, reactive hyperplasia, and dilatation of the lymphatic collecting channels are caused by the worm products, by physical injury to the valves and vessel walls caused by the live worms, and by the immune response of the host.33 Eosinophilia is found in the peripheral blood smear, and microfilariae can be demonstrated in peripheral nocturnal blood, centrifuged urine sediment, or lymphatic fluid.34

Because none of the classification schemes addresses the clinical stage of the disease, the Working Group of the 10th International Congress of Lymphology in 1985 suggested staging chronic lymphedema, regardless of cause. A latent, subclinical stage and three clinical grades were established,35 and each grade was subclassified as mild, moderate, or severe: Latent phase: Excess fluid accumulates and fibrosis occurs around the lymphatics, but no edema is apparent clinically. Grade I: Edema pits on pressure and is reduced largely or completely by elevation; there is no clinical evidence of fibrosis. Grade II: Edema does not pit on pressure and is not reduced by elevation; moderate to severe fibrosis is evident on clinical examination. Grade III: Edema is irreversible and develops from repeated inflammatory attacks, fibrosis, and sclerosis of the skin

Other Causes Lymphedema can also be acquired from other types of lymphatic vascular trauma, including burns and large or circumferential wounds to the extremity. Additional causes of acquired lymphedema include pregnancy, bacterial and fungal infections, infections after snake or insect bites, contact dermatitis, and rheumatoid arthritis.9 Autoimmune destruction of the lymphatics has been hypothesized but not directly demonstrated.



and subcutaneous tissue. This is the stage of lymphostatic elephantiasis. The advantage of this classification is that it permits the evaluation of treatment effectiveness and the comparison of different treatment modalities. One drawback is that appropriate staging may be difficult in some cases without a biopsy of the subcutaneous tissue.

CLINICAL PRESENTATION History

excoriation of the skin may occur, but frank ulcerations are rare. Unlike the situation in venous stasis, the skin maintains a higher degree of hydration and elasticity for a long time in lymphedema, and ischemic changes due to high skin tension and disruption of the circulation to the skin and subcutaneous tissue are rare.37 Additional skin changes in chronic lymph stasis, primarily in patients with hyperplasia of the lymphatics and valvular incompetence, include verrucae or small vesicles, which frequently drain clear lymph (lymphorrhea). In patients with lymphangiectasia and reflux of chyle, drainage from the vesicles is milky (chylorrhea; see Fig. 66-2). Primary lymphedema may be associated with yellow discoloration of the nails.38-40 In the yellow nail syndrome, pleural effusion is also present. The pale yellow color of the nails is most likely caused by impaired lymphatic drainage. Severe clubbing, transverse ridging, friability, and decreased rate of nail growth are also observed.39,40

Pain Although some aching or heaviness of the limb is a frequent complaint, significant pain is rare. If a patient with lymphedema complains of marked pain, infection or neuritic pain in the area of scar tissue or radiation treatment should be suspected. Other possible causes of leg swelling, such as venous edema or reflex sympathetic dystrophy, should also be considered (see the later discussion of differential diagnosis).

Signs and Symptoms

Complications

The clinical signs and symptoms of lymphedema largely depend on the duration and severity of the disease.

Infection

Edema Initially, the interstitial space is expanded by an excess accumulation of relatively protein rich fluid. The swelling produced by the fluid collection is typically soft, is easily displaced with pressure (pitting edema), and may substantially decrease with elevation of the limb. In the lower extremities, the edema typically extends to the distal aspects of the feet, resulting in the characteristic “square toes” (Stemmer’s sign) seen in this condition. The dorsum of the forefoot is usually involved, resulting in the typical appearance of a “buffalo hump.” During a period of years, the limb may take on a woody texture as the surrounding tissue becomes indurated and fibrotic.

Skin Changes In the early stage of lymphedema, the skin usually has a pinkish red color and a mildly elevated temperature owing to the increased vascularity. In long-standing lymphedema, the skin becomes thick and shows areas of hyperkeratosis, lichenification, and development of peau d’orange. The term pigskin reflects the reactive changes of the dermis and epidermis in response to the chronic inflammation caused by lymphatic stasis.36 Recurrent chronic eczematous dermatitis or

1009

The propensity for recurrent soft tissue infection is one of the most troublesome aspects of long-standing lymphedema. Accumulated fluid and proteins provide a good substrate for bacterial growth. Lymphatic dysfunction impairs local immune responses, which plays a permissive role in the propagation of bacterial and fungal invasion. Furthermore, once it is established, soft tissue infection exacerbates the existing lymphatic dysfunction, sometimes irreversibly. With recurrent infection, there is progressive damage of lymphatic capillaries. In primary lymphedema, the reported infection rate is as high as 31%.10 The clinical presentation of soft tissue infection in lymphedema varies substantially—from the acute manifestation of rapidly progressive infection to only modest exacerbations of edema accompanied by subtle cutaneous erythema in the absence of fever. Recurrent attacks of cellulitis can damage the existing cutaneous lymphatics, exacerbate the skin disease, and further aggravate existing edema.

Malnutrition and Immunodeficiency Lymphangiectasia with protein-losing enteropathy or chylous ascites or chylothorax may result in severe loss of proteins, long-chain triglycerides, cholesterol, and calcium.41,42 Loss of lymphocytes, immunoglobulins, polypeptides, and cytokines

SECTION 11 LYMPHEDEMA

A careful history frequently reveals the cause of the swelling and suggests the diagnosis of lymphedema. A family history that is positive for leg swelling may indicate familial lymphedema. The development of painless leg swelling in a teenage girl without any identifiable cause strongly suggests primary (idiopathic) lymphedema. A history of diarrhea and weight loss is a clue to mesenteric lymphangiectasia, whereas intermittent drainage of milky fluid from skin vesicles indicates reflux of chyle. In patients with secondary lymphedema, the cause of limb swelling should be evident from the history, such as previous lymph node dissection, irradiation, tumor, trauma, or infection. In patients who have traveled in tropical countries, filariasis is suspected. Although the causes of primary and secondary lymphedema are different, the clinical presentation and characteristic physical findings are frequently similar.

CHAPTER 66  Lymphedema: Evaluation and Decision Making

1010

SECTION 11  Lymphedema

results in a state of immunodeficiency that decreases the patient’s ability to resist infections or malignant disease.

Malignant Tumors In rare cases, chronic lymphedema of any cause may be complicated by the development of malignant tumors in the involved limb. Lymphangiosarcoma after long-standing secondary lymphedema, originally described by Stewart and Treves,43 is a rare malignant disease that frequently results in limb loss or even death. Lymphangiosarcoma is manifested as multicentric lesions with bluish nodules, sclerotic plaques, or bullous changes. Other malignant tumors that appear with increased frequency in lymphedematous limbs include Kaposi’s sarcoma, squamous cell carcinoma, malignant lymphoma, and melanoma.

DIAGNOSIS In most cases of advanced, sustained lymphedema, the characteristic clinical presentation, history, and physical findings establish the diagnosis with near certainty.44 In more subtle presentations, it may be difficult to distinguish primary lymphedema from other edematous conditions. Additional objective data may be required to confirm the presence of impaired lymphatic flow or the typical pattern of abnormal fluid distribution within tissues. The diagnosis is more difficult to establish in the early stages of disease, particularly when edema is mild or intermittent.

Physical Examination The physical examination of a patient with lymphedema should include inspection for cutaneous and subcutaneous fibrosis and peau d’orange and attempts to elicit the pathognomonic Stemmer sign, in which the examiner is unable to tent the skin of the interdigital webs, based on the characteristic loss of cutaneous elasticity in lymphedema (see Fig. 66-4). In some cases, particularly early in the disease, the pitting edema of this condition may be indistinguishable from other local or systemic causes of edema.

Testing Objective documentation of lymphatic dysfunction is sometimes useful. Available tests include isotopic lympho­ scintigraphy, indirect and direct lymphography, lymphatic capillaroscopy, magnetic resonance imaging, axial tomography, and ultrasonography. Direct lymphography is rarely used today and should be restricted to those patients who are potential candidates for lymphatic surgery. Lymphatic capillaroscopy is available only in specialized centers.

Lymphoscintigraphy Isotopic lymphoscintigraphy is a reliable and reproducible method to confirm the diagnosis of lymphedema. A radiolabeled macromolecular tracer is injected intradermally or subdermally within one of the interdigital spaces of the affected

limb. The lymphatic transport of the radiolabeled macromolecule is tracked with a gamma camera. The biokinetic behavior of interstitially applied colloid particles depends on their surface charge and particle size. Particles with small diameters are absorbed into capillaries, whereas those in the 10-nm range, such as antimony trisulfide (Sb2S3), are absorbed into the lymphatic system. The time needed for activity to appear in the regional lymph nodes varies according to the physical characteristics of the imaging agent. For example, small particles such as technetium Tc 99m–labeled human serum albumin may appear in the pelvic nodes within 10 minutes,45 whereas relatively large agents, including rhenium and Sb2S3 colloid, should arrive within 30 minutes46 to 1 hour,47 respectively. In most centers, 99mTc-Sb2S3 or 99mTc-labeled human serum albumin is used for lymphoscintigraphy.45,47-49 Interpretation. Lymphoscintigraphy provides a semiquantifiable assessment of lymphatic function as well as visualization of major lymphatic trunks and lymph nodes. The data can be recorded in a standardized report format, which is helpful for creating reproducible reports when many physicians review these tracings. A sample report form, shown in Figure 66-5, is an adaptation of one proposed by Kleinhans and colleagues for the estimation of a transport index.50 In normal limbs, lymphoscintigraphy shows several lymph vessels as the tracer is visualized along the anteromedial aspect of the leg. The injection site, because of the relatively large tracer dose given, does not show details, and no information about lymph distribution in the feet is obtainable. Several lymph channels may be identified in the calf. In the thigh, however, the lymph vessels run close to each other, and separate activity in each larger channel is seldom seen on lymphoscintigrams (Fig. 66-6). Tracer activity is clear in the inguinal lymph nodes by 60 minutes (range, 15 to 60 minutes). A faint hepatic uptake, activity in the bladder, and faint traces in the para-abdominal nodes are visible at 1 hour. Three-hour images show intense uptake in the liver; symmetrical and good uptake in the lymph nodes of the groin, pelvis, and abdomen; and occasionally a tracer focus in the left supraclavicular area at the site of the distal thoracic duct. The qualitative interpretation of images has resulted in excellent sensitivity (92%) and specificity (100%) for the diagnosis of lymphedema.48 Quantitative lymphoscintigraphy, with measurement of lymphatic clearance, may improve the detection of early disease,45 but the results obtained in some studies have been equivocal.47,48 Neither the image pattern nor the quantitative parameters can reliably distinguish primary from secondary lymphedema.47-49 Lymphedema. Typical abnormalities observed in lymphedema include dermal backflow (Fig. 66-7), absent or delayed transport of tracer, crossover filling with retrograde backflow, and either absent or delayed visualization of lymph nodes. In primary lymphedema, channels are obliterated or absent; in a smaller percentage of cases, they become ectatic and incompetent. The asymmetry or delayed

1011

CHAPTER 66  Lymphedema: Evaluation and Decision Making



Patient’s Initials Clinic Number

Date

LYMPHOSCINTIGRAPHY DATA EVALUATION Arms

Legs

IMAGE

1 Hr R

3 Hr L

R

6 Hr L

R

24 Hr L

R

L

Lymph transport kinetics: SECTION 11 LYMPHEDEMA

0 = no delay, 1 = rapid, 3 = low-grade delay, 5 = extreme delay, 9 = no transport

Distribution pattern: 0 = normal, 2 = focal abnormal tracer, 3 = partial dermal, 5 = diffuse dermal, 9 = no transport

Lymph node appearance time: Minutes

Assessment of lymph nodes: 0 = clearly seen, 3 = faint, 5 = hardly seen, 9 = no visualization

Assessment of lymph vessels: 0 = clearly seen, 3 = faint, 5 = hardly seen, 9 = no visualization

Abnormal sites of tracer accumulation (describe)

Figure 66-5  Evaluation form for calculation of the lymphatic transport index. (Modified from Kleinhans E, et al: Evaluation of transport kinetics in lymphoscintigraphy: follow-up study in patients with transplanted lymphatic vessels. Eur J Nucl Med 10:349, 1985. Courtesy Springer-Verlag.)

A

B

Figure 66-6  Anterior and posterior images in two intensity settings from a total-body scan with a dual-headed gamma camera. A, Normal lymphoscintigram. B, Higher intensity settings in the same patient. A large area of high activity and scatter is seen at the feet, where the injection was made. The single well-outlined band in each leg represents the main lymphatic channels. The lymph nodes in the groin and liver, the pelvic and para-aortic nodes, and an area at the site of the upper thoracic duct are visualized.

1012

SECTION 11  Lymphedema

characteristic absence of muscle involvement produces distinctive changes that can be observed with computed tomography (CT) or magnetic resonance imaging (MRI). These typical imaging features facilitate the differentiation of lymphedema from other edematous entities. In lymphedema, the images reveal a characteristic honeycomb distribution of edema within the epifascial structures along with thickening of the skin. In venous edema, both the epifascial and subfascial compartments are affected, whereas in lipedema, there is fat accumulation without fluid. MRI is also helpful in the identification of lymph nodes and enlarged lymphatic trunks and in the differentiation of various potential causes of lymphatic obstruction in secondary lymphedema. The anatomic information derived from MRI can complement the functional assessment provided by lymphoscintigraphy. The greatest value of CT and MRI in the evaluation of a patient with a swollen leg is to exclude any obstructing mass that may result in decreased transport capacity of the lymphatic system.

Direct Contrast Lymphangiography Contrast lymphography is used primarily before reconstructive lymphatic surgery. Imaging is accomplished through the direct injection of iodine-based, lipid-soluble agents into the subcutaneous lymphatics, which are first identified by the Figure 66-7  Radionuclide lymphoscintigraphy in chronic bilateral lower limb lymphedema. The study demonstrates a dramatic degree of dermal backflow, suggesting the presence of lymphatic hypertension and valvular incompetence.

appearance of radiocontrast material in the proximal nodal tissue can be used as a semiquantitative measure of the severity of lymphatic vascular insufficiency. The density of subcutaneous accumulation of radiotracer (dermal backflow) can also be quantitated, as can the ratio of radioactivity in ipsilateral versus contralateral nodal tissues in the setting of unilateral limb edema. Quantitation has the greatest utility in predicting the likelihood of a beneficial response to therapeutic intervention. Lymphangiectasia. Scintigraphic findings in lymphangiec­ tasia consist of dilated lymph channels with only mild or no delay in lymph transport (Fig. 66-8). Colloid injected into the unaffected lower extremity may reflux into the affected lymphedematous leg because of lymphatic valvular incompetence. Similar reflux of the colloid may be seen in the dilated mesenteric lymphatics (Fig. 66-9) or in the retroperitoneum, perineum, or scrotum. Ruptured lymphatics cause extravasation of the colloid into the abdominal cavity or the chest in patients with chylous ascites or chylothorax. The images are generally not helpful in determining the exact site of the lymphatic leak.

Computed Tomography and Magnetic Resonance Imaging Lymphedema is typically confined to the epifascial space of the skin and subcutaneous tissue, sparing muscle. This

A

B

Figure 66-8  Bilateral leg scintigraphy with anterior (A) and posterior (B) views in a 24-year-old man outlines the swollen scrotum in the 6-hour image. Colloid reflux resulted from dilatation and valvular incompetence of the lymphatics.

CHAPTER 66  Lymphedema: Evaluation and Decision Making



1013

SECTION 11 LYMPHEDEMA

A

B

C

Figure 66-9  A-C, Lymphoscintigram of an 18-year-old man with lymphangiectasia, protein-losing enteropathy, and chylous ascites. Note the large leg lymphatics (A) and reflux of colloid into the mesenteric lymph vessels (B), filling almost the entire abdominal cavity. Note the large thoracic duct (C).

subcutaneous injection of dye (methylene blue) and then cannulated. Contrast lymphography poses distinct technical difficulties and may, in fact, exacerbate lymphatic malfunction through the accumulation and pooling of the oil-based contrast medium. For these reasons, its use should be limited to preoperative evaluation in specialized centers.

Differential Diagnosis The differential diagnosis (Box 66-2) frequently includes lipedema; a lipodystrophy that typically causes symmetrical enlargement of the lower extremities, particularly in obese females; and venous insufficiency, a hydrostatic cause of lower extremity edema. In lipedema, there may be a component of pitting edema; but in contradistinction to lymphedema, there is sparing of the feet despite pronounced enlargement of the calves and thighs. Venous stasis has relatively distinctive cutaneous attributes, including chronic deposits of hemosiderin in the skin. The patient’s history and the clinical setting often determine the degree to which chronic venous insufficiency plays a role in the differential diagnosis. However, even when the clinical setting and physical examination suggest the presence of venous stasis, the accompanying venous hypertension may chronically elevate the lymphatic load and thus predispose to the secondary development of lymphatic edema. In practice, therefore, such patients often have a mixed lymphatic-venous form of chronic edema.

Systemic Causes During the evaluation of patients with chronic limb swelling, a systemic cause should be excluded first. Underlying cardiac diseases, such as congestive heart failure, chronic constrictive pericarditis, and severe tricuspid regurgitation, are the most frequent systemic causes leading to pitting or bilateral leg swelling. Hepatic or renal failure, hypoproteinemia, malnutrition, and endocrine disorders (myxedema) are other possible causes of leg swelling. Allergic reactions, hereditary angioedema, and idiopathic cyclic edema are rare systemic causes that should be considered. Chronic use of diuretics may lead to generalized swelling that most frequently affects the extremities and the face. Other drugs that may cause swelling include corticosteroids, some antihypertensive drugs, and anti-inflammatory agents.

Venous Insufficiency Among the local or regional causes of limb swelling, chronic venous insufficiency is much more common than lymphedema. In some patients with chronic iliac or iliocaval obstruction, massive swelling of the entire extremity can develop (Fig. 66-10). The usual causes of proximal venous occlusion are deep venous thrombosis or external compression of the vein by tumor or retroperitoneal fibrosis. Whereas lymphedema is usually painless, venous hypertension results in marked pain and cramps after prolonged standing or at the

1014

SECTION 11  Lymphedema

BOX 66-2 

DIFFERENTIAL DIAGNOSIS OF CHRONIC LEG SWELLING SYSTEMIC CAUSES Cardiac failure Hepatic failure Renal failure Hypoproteinemia Hyperthyroidism (myxedema) Allergic disorders Idiopathic cyclic edema Hereditary angioedema Drugs Antihypertensives: methyldopa, nifedipine, hydralazine Hormones: estrogen, progesterone Anti-inflammatory drugs: phenylbutazone Monoamine oxidase inhibitors LOCAL OR REGIONAL CAUSES Chronic venous insufficiency Lymphedema Lipedema Congenital vascular malformation Arteriovenous fistula Trauma Snake or insect bite Infection, inflammation Hematoma Dependency Rheumatoid arthritis Post-revascularization edema Soft tissue tumor Hemihypertrophy

Figure 66-11  Left leg edema associated with a congenital vascular malformation (Klippel-Trénaunay syndrome).

end of the day. Patients with proximal venous obstruction may complain of typical claudication, which is manifested as throbbing pain in the thigh or calf after walking. The pain resolves with rest, although elevation of the extremity provides the fastest relief. The presence of varicosity, pigmentation, induration, or venous ulcers makes the diagnosis of venous insufficiency easier. Chronic inflammation in the subcutaneous tissue due to venous stasis may result in destruction of the collecting lymph channels; a mixed venous-lymphatic edema develops in these patients.

Vascular Malformation Patients with congenital vascular malformations frequently have a larger than normal extremity that may be difficult to distinguish from lymphedema (Fig. 66-11). An increase in the length of the affected extremity, the presence of atypical lateral varicosity, and a port-wine stain with underlying developmental abnormality of the deep venous system are characteristic of Klippel-Trénaunay syndrome.51 Although hypertrophy of the soft tissues and bones is caused by an abnormality in mesenchymal development, congenital lymphedema may also be present in these patients. In patients with high-shunt, high-flow arteriovenous malformations, the extremity is larger than normal and frequently longer as well.52 A bruit and thrill are present, the superficial veins are dilated and frequently pulsatile, and the distal arterial pulses may be diminished.

Lipedema Figure 66-10  Right leg swelling due to venous insufficiency, caused by chronic iliofemoral venous thrombosis.

Lipedema is characterized by deposition of a large amount of fatty tissue in the subcutaneous layers. Most of these patients

CHAPTER 66  Lymphedema: Evaluation and Decision Making



B

Figure 66-12  Lymphoscintigraphy in high-output lymphatic failure due to reflex sympathetic dystrophy of the right leg. A, Fast lymphatic transport in the affected right leg compared with the normal left leg is evident in the image of the inguinal nodes 20 minutes after injection. B, Total-body image at 3 hours shows a dermal pattern on the right but no evidence of proximal lymphatic obstruction.

have morbid obesity; some, mostly females, have fat deposition localized to the lower half of the body. Evaluation of the lymphatic system with lymphoscintigraphy or lymphangiography shows essentially normal findings.

Other Causes Trauma and subsequent reflex sympathetic dystrophy may result in painful swelling of the extremity. Because of disuse, a varying degree of osteoporosis can be observed, and increased sympathetic activity occurs in the limbs of these patients. The swelling is usually the result of high-output lymphatic failure, and increased lymphatic transport may be demonstrated on lymphoscintigraphy (Fig. 66-12). Baker’s cyst, soft tissue tumor, hematoma, and inflammation such as tenosynovitis or arthritis are additional local causes of limb swelling that should be considered in the differential diagnosis of lymphedema.

DECISION MAKING Clinical examination of the patient frequently reveals the correct cause of limb swelling. Initial laboratory examinations should include routine blood tests to look for signs of renal or hepatic failure, eosinophilia, or hypoproteinemia. Urinalysis may indicate proteinuria. Once a systemic cause of edema is excluded, the local or regional cause should be confirmed. Patients at risk for the development of secondary lymphedema (e.g., cancer survivors) pose a distinct challenge for

decision making because there is an imperative to recognize the evolving condition at its earliest stages. Within the last decade, there has been introduction of a new technology, bioimpedance spectroscopy, that provides the requisite sensitivity and specificity to detect stage 0 disease.53 Increasingly, this technique, which is rapidly and efficiently performed at the bedside, will have applicability to the serial monitoring of the patient’s treatment response as well.54 Venous duplex scanning confirms or excludes venous occlusion or valvular incompetence in the leg. CT has become routine for most adult patients with leg swelling to exclude underlying malignant disease. MRI provides the most accurate information in patients with clinical signs of congenital vascular malformation, soft tissue tumor, or retroperitoneal fibrosis. Lymphoscintigraphy is the test of choice for the confirmation of lymphedema, and a normal finding on lymphoscintigraphic examination essentially excludes the diagnosis of lymphedema. Patients with chronic venous insufficiency may have abnormal results on lymphoscintigraphic examination, with delayed transport because of mixed lymphatic and venous edema. As mentioned earlier, direct contrast lymphangiography should be performed selectively and should not be part of the routine evaluation of patients with chronic limb swelling. For all patients with chronic lymphedema, conservative management through physical means is the mainstay of therapy. Current indications and patient selection for conservative and surgical therapies of both primary and secondary lymphedema are discussed in detail in Chapters 67 and 68.

PROSPECTS FOR MOLECULAR THERAPY Although current therapeutic strategies for lymphedema effectively reduce excess volume, minimize complications, and optimize function, the disease currently lacks a cure. For these reasons, there has been an emphasis on the possible application of effective molecular therapies. Among these, one of the most exciting prospects is therapeutic lymphangiogenesis, a molecular approach based on growing insights into the mechanisms of lymphatic vascular development. Among the mitogenic substances that initiate and regulate the growth of vascular structures, the vascular endothelial growth factor (VEGF) family plays a central role.55,56 VEGF-C and VEGF-D direct the development and growth of the lymphatic vasculature in embryonic and postnatal life by binding to VEGFR-3, which is nearly exclusively expressed on lymphatic endothelia.57,58 In transgenic mice that overexpress VEGF-C, the lymphatic vessels demonstrate a hyperplastic, proliferative response, with secondary cutaneous changes.59 Exogenous administration of VEGF-C upregulates VEGFR-3, leading to a lymphangiogenic response.60,61 These molecular observations have helped elucidate the mechanisms that contribute to disease expression in the most common heritable form of lymphedema, the autosomal dominant condition known as Milroy’s disease. In many affected family cohorts, this disease has been linked to the flt4 locus,

SECTION 11 LYMPHEDEMA

A

1015

1016

SECTION 11  Lymphedema

encoding VEGFR-3.26 Disease-associated alleles contain missense mutations that inactivate the tyrosine kinase signaling mechanism, thereby preventing downstream cellular activation. It is believed that the mutant form of the receptor is not only functionally inactive but also excessively stable, serving as a potential “sink” for activating ligands. Thus, the normal signaling mechanism is blunted, leading to hypoplastic development of lymphatic vessels.62,63 The prospects for therapeutic lymphangiogenesis in human lymphedema have been underscored by the recent description of a mouse model of inherited limb edema that features a mutation in the VEGFR-3 signaling mechanism and a pathologic process that resembles human disease.63 In this model, therapeutic overexpression of VEGF-C with use of a viral vector induces the generation of new functional lymphatics and the amelioration of lymphedema. Similarly, in a rodent model of acquired postsurgical lymphatic insufficiency (resembling postmastectomy lymphedema), the exogenous administration of human recombinant VEGF-C restores lymphatic flow (as assessed by lymphoscintigraphy),64,65 increases lymphatic vascularity, and reverses the hypercellularity that characterizes the untreated lymphedematous condition. Intensive future investigation will be required to verify the therapeutic potential of such approaches and to establish dose-response relationships and the durability of the therapeutic response. As with other forms of angiogenic therapy, the relative virtues of growth factor therapy versus gene therapy must be established.66

SELECTED KEY REFERENCES Cambria RA, Gloviczki P, Naessens JM, Wahner HW: Noninvasive evaluation of the lymphatic system with lymphoscintigraphy: a prospective, semiquantitative analysis in 386 extremities. J Vasc Surg 18:773, 1993. Description of the techniques and interpretation of upper and lower extremity lymphoscintigraphic studies in normal patients and in those with various lymphatic disorders. Casley-Smith JR, Foldi M, Ryan TJ, et al: Lymphedema: summary of the 10th International Congress of Lymphology Working Group discussions and recommendations, Adelaide, Australia, August 10-17, 1985. Lymphology 18:175, 1985. Consensus document on the classification, evaluation, and treatment of chronic lymphedema. Cornish BH, Chapman M, Hirst C, Mirolo B, Bunce LH, Ward LC, Thomas BJ: Early diagnosis of lymphedema using multiple frequency bioimpedance. Lymphology 34:2–11, 2001. Prospective demonstration of the high positive predictive value of bioimpedance spectroscopy in the early diagnosis of lymphedema. Rockson SG: Diagnosis and management of lymphatic vascular disease. J Am Coll Cardiol 52:799–806, 2008. State-of-the-art review defining the clinical spectrum, etiology, evaluation, and treatment of primary and secondary lymphedema. Rockson SG, Miller LT, Senie R, Brennan MJ, Casley-Smith JR, Foldi E, Foldi M, Gamble GL, Kasseroller RG, Leduc A, Lerner R, Mortimer PS, Norman SA, Plotkin CL, Rinehart-Ayres ME, Walder AL: American Cancer Society Lymphedema Workshop. Workgroup III: diagnosis and management of lymphedema. Cancer 83(Suppl American):2882–2885, 1998. Position statement of the American Cancer Society on the diagnostic evaluation and management of upper extremity lymphedema secondary to the treatment of breast cancer. The reference list can be found on the companion Expert Consult website at www.expertconsult.com.



REFERENCES

31. Mak JW: Epidemiology of lymphatic filariasis. Ciba Found Symp 127:5, 1987. 32. Chernin E: The disappearance of bancroftian filariasis from Charleston, South Carolina. Am J Trop Med Hyg 37:111, 1987. 33. Case T, et al: Vascular abnormalities in experimental and human lymphatic filariasis. Lymphology 24:174, 1991. 34. Dandapat MC, et al: Management of chronic manifestations of filariasis. J Indian Med Assoc 84:210, 1986. 35. Casley-Smith JR, et al: Lymphedema: summary of the 10th International Congress of Lymphology Working Group discussions and recommendations, Adelaide, Australia, August 10-17:1985. Lymphology 18:175, 1985. 36. Schirger A: Lymphedema. Cardiovasc Clin 13:293, 1983. 37. Chant ADB: Hypothesis: why venous oedema causes ulcers and lymphoedema does not. Eur J Vasc Surg 6:427, 1992. 38. Samman PD, et al: The “yellow nail” syndrome. Br J Dermatol 76:153, 1964. 39. Taylor JS, et al: The swollen limb: cutaneous clues to diagnosis and treatment. Cutis 21:553, 1978. 40. Fields CL, et al: Yellow nail syndrome: a perspective. J Ky Med Assoc 89:563, 1991. 41. Servelle M: Congenital malformation of the lymphatics of the small intestine. J Cardiovasc Surg 32:159, 1991. 42. Kinmonth JB, et al: Protein-losing enteropathy in lymphoedema: surgical investigation and treatment. J Cardiovasc Surg 16:111, 1975. 43. Stewart FW, et al: Lymphangiosarcoma in postmastectomy lymphedema: a report of six cases in elephantiasis chirurgica. Cancer 1:64, 1948. 44. Rockson SG, et al: American Cancer Society Lymphedema Workshop. Workgroup III: diagnosis and management of lymphedema. Cancer 83:2882, 1998. 45. Weissleder H, et al: Lymphedema: evaluation of qualitative and quantitative lymphoscintigraphy in 238 patients. Radiology 167:729, 1988. 46. Stewart G, et al: Isotope lymphography: a new method of investigating the role of the lymphatics in chronic limb oedema. Br J Surg 72:906, 1985. 47. Vaqueiro M, et al: Lymphoscintigraphy in lymphedema: an aid to microsurgery. J Nucl Med 27:1125, 1986. 48. Gloviczki P, et al: Noninvasive evaluation of the swollen extremity: experiences with 190 lymphoscintigraphic examinations. J Vasc Surg 9:683, 1989. 49. Cambria RA, et al: Noninvasive evaluation of the lymphatic system with lymphoscintigraphy: a prospective, semiquantitative analysis in 386 extremities. J Vasc Surg 18:773, 1993. 50. Kleinhans E, et al: Evaluation of transport kinetics in lymphoscintigraphy: follow-up study in patients with transplanted lymphatic vessels. Eur J Nucl Med 10:349, 1985. 51. Gloviczki P, et al: Klippel-Trénaunay syndrome: the risks and benefits of vascular interventions. Surgery 110:469, 1991. 52. Gloviczki P, et al: Arteriovenous fistulas and vascular malformations. In Ascher E, editor: Haimovici’s vascular surgery, ed 5, Malden, Mass, 2004, Blackwell Publishing, p 991. 53. Cornish BH, et al: Early diagnosis of lymphedema using multiple frequency bioimpedance. Lymphology 34:2–11, 2001. 54. Cornish BH, et al: Bioelectrical impedance for monitoring the efficacy of lymphoedema treatment programmes. Breast Cancer Res Treat 38:169– 176, 1996. 55. Olofsson B, et al: Current biology of VEGF-B and VEGF-C. Curr Opin Biotechnol 10:528, 1999. 56. Veikkola T, et al: Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res 60:203, 2000. 57. Joukov V, et al: A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 15:1751, 1996. 58. Kaipainen A, 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 92:3566, 1995. 59. Jeltsch M, et al: Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276:1423, 1997.

SECTION 11 LYMPHEDEMA

1. Browse NL, et al: Lymphedema: pathophysiology and classification. J Cardiovasc Surg 26:91, 1985. 2. Schirger A, et al: Idiopathic lymphedema. Review of 131 cases. JAMA 182:124, 1962. 3. Kinmonth JB, et al: Primary lymphoedema: clinical and lymphangiographic studies of a series of 107 patients in which the lower limbs were affected. Br J Surg 45:1, 1957. 4. Kinmonth JB: The lymphoedemas: general considerations. In Kinmonth JB, editor: The lymphatics: surgery, lymphography and diseases of the chyle and lymph systems, London, 1982, Edward Arnold, p 83. 5. Allen EV: Lymphedema of the extremities: classification, etiology and differential diagnosis: a study of three hundred cases. Arch Intern Med 54:606, 1934. 6. Browse NL: The diagnosis and management of primary lymphedema. J Vasc Surg 3:181, 1986. 7. Browse NL: Primary lymphedema. In Ernst C, et al, editors: Current therapy in vascular surgery, Philadelphia, 1987, BC Decker, p 454. 8. Kurland LT, et al: The patient record in epidemiology. Sci Am 245:54, 1981. 9. Rockson SG: Lymphedema. Am J Med 110:288, 2001. 10. Smeltzer DM, et al: Primary lymphedema in children and adolescents: a follow-up study and review. Pediatrics 76:206, 1985. 11. Wolfe JHN, et al: The prognosis of primary lymphedema of the lower limbs. Arch Surg 116:1157, 1981. 12. Mendoza E, et al: A model for mechanics of primary lymphatic valves. J Biomech Eng 125:407, 2003. 13. Rockson S: Syndromic lymphedema: keys to the kingdom of lymphatic structure and function? Lymphatic Res Biol 1:181, 2003. 14. Milroy W: An undescribed variety of hereditary oedema. N Y Med J 56:505, 1892. 15. Milroy W: Chronic hereditary edema: Milroy’s disease. JAMA 91:1172, 1928. 16. Lewis JM, et al: Lymphedema praecox. J Pediatr 104:641, 1984. 17. Dahlberg PJ, et al: Autosomal or X-linked recessive syndrome of congenital lymphedema, hypoparathyroidism, nephropathy, prolapsing mitral valve, and brachytelephalangy. Am J Med Genet 16:99, 1983. 18. Radhakrishnan K, et al: The clinical spectrum of lymphatic disease. Ann N Y Acad Sci 1131:155, 2008. 19. Mucke J, et al: Early onset lymphoedema, recessive form—a new form of genetic lymphoedema syndrome. Eur J Pediatr 145:195, 1986. 20. Henriksen HM: Turners’s syndrome associated with lymphoedema, diagnosed in the newborns. Z Geburtshilfe Perinatol 184:313, 1980. 21. White SW: Lymphedema in Noonan’s syndrome. Int J Dermatol 23:656, 1984. 22. Venencie PY, et al: Yellow nail syndrome: report of five cases. J Am Acad Dermatol 10:187, 1984. 23. Wheeler ES, et al: Familial lymphedema praecox: Meige’s disease. Plast Reconstr Surg 67:362, 1981. 24. Abe R, et al: Retroperitoneal lymphangiomyomatosis with lymphedema of the legs. Lymphology 13:62, 1980. 25. Bull LN, et al: Mapping of the locus for cholestasis-lymphedema syndrome (Aagenaes syndrome) to a 6.6-cM interval on chromosome 15q. Am J Hum Genet 67:994, 2000. 26. Karkkainen MJ, et al: Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nat Genet 25:153, 2000. 27. Irrthum A, et al: Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet 67:295, 2000. 28. Fang J, et al: Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedemadistichiasis syndrome [in process citation]. Am J Hum Genet 67:1382, 2000. 29. Finegold DN, et al: Truncating mutations in FOXC2 cause multiple lymphedema syndromes. Hum Mol Genet 10:1185, 2001. 30. Irrthum A, et al: Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedematelangiectasia. Am J Hum Genet 72:1470, 2003.

CHAPTER 66  Lymphedema: Evaluation and Decision Making 1016.e1

1016.e2 SECTION 11  Lymphedema 60. Oh SJ, et al: VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Dev Biol 188:96, 1997. 61. Enholm B, et al: Adenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin. Circ Res 88:623, 2001. 62. Karkkainen MJ, et al: Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene 19:5598, 2000. 63. Karkkainen MJ, et al: A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci U S A 98:12677, 2001.

64. Szuba A, et al: Therapeutic lymphangiogenesis with human recombinant VEGF-C. FASEB J 16:U114, 2002. 65. Cheung L, et al: An experimental model for the study of lymphedema and its response to therapeutic lymphangiogenesis. BioDrugs 20:363, 2006. 66. Rockson SG: Experimental lymphedema: can cellular therapies augment the therapeutic potential for lymphangiogenesis? J Am Heart Assoc 1:e003400, 2012.

CHAPTER 67 

Lymphedema: Nonoperative Treatment ANDREA L. CHEVILLE  /  GAIL L. GAMBLE

Based on a chapter in the seventh edition by Gail L. Gamble

L

ymphedema remains a frustrating and complex management challenge for clinicians and patients alike. The pathophysiology and diagnosis of lymphedema are thoroughly reviewed in Chapter 13. Chronic lymphedema can engender functional morbidity and adverse symptoms that degrade patients’ quality of life (QoL).1 Despite remarkable advances in the molecular, genetic, and clinical understanding of this condition, lymphedema remains incurable.2,3 Fortunately, a majority of patients respond to conservative treatment, and their lymphedema can be indefinitely temporized. Nonsurgical management options fall into three categories: (1) preventive measures for at-risk patients; (2) risk reduction strategies for patients with established lymphedema; and (3) manual therapies to reduce and temporize established lymphedema. Pharmacologic treatments have little role in conventional lymphedema management. However, because they continue to be widely used, and because they may benefit patients with mixed etiology edema, they are outlined in this chapter. Lymphedema may engender profound dysmorphism, adversely affecting patients’ self-image, social roles, and QoL; therefore, approaches to address the psychosocial dimensions of lymphedema are also addressed.2-6

PREVENTIVE MEASURES FOR AT-RISK PATIENTS Primary Lymphedema A majority of patients who develop primary lymphedema have no family history of lymphedema or awareness of abnormal lymphatic development before the onset of swelling; thus, proactive measures cannot be used to prevent lymphedema. Recent advances in genetic mapping and the identification of mutations for primary disorders, such as the hereditary form of lymphedema (Milroy’s disease), or other disorders (lymphedema-distichiasis)6,7 now offer the possibility of genetic testing for potentially at-risk family members. Both genetic testing and counseling regarding early protective measures are available in a number of medical centers and may become more widespread in the future. Patients with unilateral primary lymphedema should be counseled to minimize risk factors that may trigger the

development of lymphedema in the contralateral limb or other areas of the body.

Secondary Lymphedema Secondary lymphedema develops from the traumatic, infectious, or iatrogenic compromise of an intact lymphatic system. In the developed world, secondary lymphedema occurs as a result of clinical efforts to stage or treat cancer, most commonly surgical lymphadenectomy and/or the radiation of lymph node beds. The extent of lymphatic damage can be quantified in the number of lymph nodes removed and the radiation dosage, allowing for risk stratification. Patients at higher risk can be instructed in preventive strategies. Recent efforts to modify cancer treatments to spare lymph nodes have proven extremely effective. For example, the shift from 2-3 level axillary lymph node dissection to sentinel lymph node biopsy, followed by completion dissection only if nodal metastases are detected as the standard of care, has reduced lymphedema incidence by approximately 80%.7-9 Similarly, the use of sentinel lymph node biopsy procedures to identify lymph nodes involved by metastatic melanoma has significantly reduced the requirement for extensive inguinal and pelvic lymphadenectomy, with a resultant decrease in lower extremity lymphedema.10 Novel techniques have also been developed to minimize the incidental, nontherapeutic radiation delivered to axillary lymph nodes critical for arm drainage, although these are not yet widely available in conventional practice.11 However, it is essential to bear in mind that, to date, no lymph node sparing technique eliminates the risk of lymphedema. Therefore, following lymph node removal or irradiation, early patient education regarding skin precautions and appropriate exercises may reduce the incidence of lymphedema.12 Worldwide, infestation by the parasite Wuchereria bancrofti is the most frequent cause of lymphedema. W. bancrofti is endemic in tropical climates.8 There has been much activity directed toward the control of filariasis in recent years.9,10 Programs have been developed to reduce vector transmission (decreased transmission of W. bancrofti and Brugia malayi parasites by mosquito bites) and to administer antifilarial drugs to at-risk populations.13 The mass administration of 1017

1018

SECTION 11  Lymphedema

diethylcarbamazine plus ivermectin significantly decreases lymphatic filariasis.9 Recognition that the endosymbiotic bacterial organism Wolbachia may also play a role in the development of filarial lymphedema has spurred investigation into the utility of other drugs for filariasis control.10,14 Clearly, management of this difficult issue must be aimed at public health measures. Other forms of chronic infection can cause sufficient inflammation to damage lymphatics, undermine the system’s functional capacity, and eventually, cause lymphedema. Recurrent cellulitic infections may cause permanent irreversible lymphatic compromise.14 However, because lymphedema is the strongest risk factor for cellulitis,15,16 it can, at times, be difficult to distinguish whether cellulitis simply reflects the initial presentation of previously subclinical lymphedema or independently causes lymphedema. The low-grade chronic inflammation produced by rosacea has been implicated in causing lymphedema of facial structures, particularly the eyelids.17

BOX 67-2 

PROPHYLACTIC SKIN MANAGEMENT SKIN HYGIENE • Wash daily • Apply moisturizer (non–alcohol based) to damp skin to trap moisture droplets and reduce cracks and fissures CLOTHING PRECAUTIONS • Wear clothing made of cotton or other cooling fabrics that wick moisture • Avoid synthetics • Wear loose-fitting clothing to avoid focal constriction TRAUMA AVOIDANCE • Wear protective clothing for heavy work • Treat cuts, scrapes, and puncture wounds immediately with cleansing and topical antibiotic cream • Prevent sunburn with sunscreen or clothing FUNGAL INFECTION CONTROL • Apply topical antifungal agents on a scheduled or intermittent basis as needed

Healthy Lifestyle: Activity and Diet Exercise, particularly walking and aerobic exercise, promotes lymph flow through a number of mechanisms, including an increase in sympathetic tone (Box 67-1). Historically, patients at risk for developing lymphedema have been advised against “overusing” their at-risk body parts for fear of triggering lymphedema. This recommendation is based on anecdotal associations of the initial onset of lymphedema with episodes of vigorous exercise or sustained, repetitive use of the at-risk extremity. Blanket recommendations against exercise have recently been tempered and re-framed based on the results of several adequately powered randomized controlled trials.18,19 These trials revealed that a gentle, incremental program of BOX 67-1 

PRACTICAL EDEMA PREVENTIVE MEASURES LIMB ELEVATION • Periodic daily elevation with the limb positioned above the heart • Elevated bed positioning (pillows or wedge) EXERCISE • Specific segmental muscle pump exercise to increase lymph flow in the limb • Range of motion • Gentle stretching • Mild resistance • Aerobic DIET • Adequate fluid intake • Weight management • Well-balanced meals • Low sodium PRESSURE AVOIDANCE • No blood pressure cuff applied to the affected limb • No tight jewelry or clothing in areas at risk • No chronic shoulder pressure (e.g., large purse, backpack)

full-body resistive training, begun at a low level and increased gradually, did not increase lymphedema incidence among breast cancer survivors at-risk of developing lymphedema, and might actually be protective. Similar trials have not yet shed light on the risk-benefit profile of exercise in lower extremity lymphedema. Various dietary restrictions have been advocated, but few have empirical support apart from avoidance of excessive salt intake. One study suggested that lowering triglyceride levels may offer benefit.20 Obesity unquestionably worsens lymphedema,21,22 and weight reduction augments the effects of other measures for edema reduction.23 Therefore, dietary moderation and weight management are integral to lymphedema prevention. Nutritional supplements, apart from protein supplementation in hypoalbuminemic patients, have not been subject to rigorous scrutiny; therefore, their use should not be endorsed as a credible lymphedema prevention strategy.

Skin Hygiene Attention to daily skin hygiene of the at-risk limb is imperative (Box 67-2), yet this is often challenging for patients who have medically complicated obesity17 and/or osteoarthritis, or who lack social support and resources. The limbs should be washed regularly with soap and water, and while still moist, lubricated with an alcohol-free emollient cream to trap moisture, thereby minimizing the risk of microfissures. Patients with a history of fungal infection, including candidiasis and tinea, should use topical antifungal medications. Routine use of topical clotrimazole cream (1%) or miconazole nitrate lotion or cream (2%) is sufficient for most patients. Oral fluconazole or itraconazole may be needed for recalcitrant or extensive infection. No studies have definitively addressed the efficacy of these treatments in terms of documenting a decreased incidence of lymphedema.

CHAPTER 67  Lymphedema: Nonoperative Treatment



1019

Prophylactic Compression

Table 67-1

The use of prophylactic compression has been endorsed as a preventive strategy for provocative situations that may theoretically trigger an increase in lymph production (e.g., air travel and exercise). Air travel, presumably due to reduced ambient pressure, has been anecdotally linked to the initial onset of lymphedema.24 The rationale for the use of prophylactic garments is their theoretical potential to minimize transient, situational increases in lymph production. Notably, no empirical data support their use, and poorly fit garments may actually increase patients’ risk of lymphedema by applying intense focal pressure and creating a tourniquet effect. Therefore, if a patient’s elevated risk of developing lymphedema seems to warrant use of a prophylactic garment, an experienced fitter should determine garment type and size, and compression should not exceed 15 to 20  mm Hg. The benefits of “prophylactic” compression may be substantially increased among patients who develop mild swelling or symptoms that suggest the presence of incipient lymphedema. For example, a report described the use of upper extremity compression sleeves among breast cancer survivors whose arm volumes increased by 3% over their preoperative baselines.26 Normalization of arm volumes was achieved for a majority of patients after 4 weeks of sleeve use and was maintained for an average follow-up of 4 months. At 1 year following diagnosis, lymphedema incidence was reduced relative to reported rates. The decision to use prophylactic compression is inevitably highly individual. The pros and cons must be carefully weighed, ideally by a patient in concert with their physician. Sometimes, if feasible, consultation with a lymphedema specialist may be of benefit. Educational materials to assist in decision making are available through patient advocacy groups, such as the National Lymphedema Network and the American Cancer Society in the United States.

Stage

Description

0 I

Preclinical: edema not evident on examination A history of one or more episodes of mild, transient resolved edema Early: pitting prevalent Edema reduces or reverses with elevation No fibrosis or skin thickening Chronic: often no pitting or pitting only with deep, prolonged pressure No reduction in edema with overnight elevation Skin thickened and fibrotic Irreversible: skin fibrosis and sclerosis in subcutaneous tissues Often secondary hyperkeratosis Verrucal hyperplasia

New evidence suggests that some patients may be predisposed to developing cellulitis by virtue of preexisting, subclinically impaired lymphatic drainage.27 A study that performed bilateral lymphoscintigraphies on 33 patients after limb cellulitis detected lymph flow impairment in the limb affected by cellulitis, as well as in the nonaffected limb. Prompt antibiotic control of even minor infection may therefore be effective in preventing clinical lymphedema.

PRACTICAL MANAGEMENT AND RISK REDUCTION STRATEGIES FOR ESTABLISHED LYMPHEDEMA The relative effectiveness of all management strategies hinges on a patient’s lymphedema stage. Lymphedema is divided into four stages (Table 67-1) based on the presence of intersitial fibrosis and dermal metaplasia.48 Consideration has led to the

III

recent addition of stage 0, a preclinical stage of lymphedema that may justify insurance coverage for treatments directed toward limbs at risk.28 A growing, although still tenuous, evidence base suggests the utility of addressing very early (preclinical) volume change.25,26,29 It should be noted that affected body parts generally have regions with different stages of lymphedema. For example, a patient with lower extremity lymphedema may have stage III lymphedema (distinguished by dermal keratinization and papilloma formation in the foot and ankle region), stage II lymphedema of the calf, and stage I lymphedema of the thigh. Generally, a body part is assigned the most advanced lymphedema stage among all its involved areas. Patients may be assigned a different stage for each affected body part. Lymphedema staging is integral to clinical decision making and communicates useful information regarding a patient’s likely treatment responsiveness, risk of progression, and propensity to develop complications. Any comprehensive lymphedema treatment program should include standardized measures of limb size and volume to monitor the response to treatment. Changes in limb size have been followed using objective measures, including circumferential measurements obtained at predetermined measurement intervals (e.g., 10  cm) from an anatomic landmark, or volumetric assessments using water-displacement or computed volumetric techniques.26 Newer methods using bioelectrical impedance analysis30 have been reported. Bioimpedance is growing in popularity as a means to monitor the limbs of breast cancer survivors at risk for lymphedema. Ultrasound is used in the research setting to measure dermal saturation that correlates with whole limb edema,31,32 and may become a more viable clinical tool in the future for measuring focal edema and edema effecting nonlimb body parts (e.g., breast, trunk, genitalia, etc.). Additionally, an infrared optoelectronic device for measuring both upper and lower extremity volumes has been validated and is in clinical use at larger lymphedema centers in the United States and Europe.33,34

SECTION 11 LYMPHEDEMA

Minimize Infections

II

Clinical Staging of Chronic Lymphedema

1020

SECTION 11  Lymphedema

Figure 67-1  Lymph wedge. This wedge can be used at several angles, provides firm support for elevation, and is portable.

may be needed for some patients with more severe lymphangitis and/or cellulitis. Antibiotic therapy should be continued for 7 to 14 days until all signs and symptoms of acute infection have clearly resolved. There is no consensus in the literature on the optimal treatment of recurrent cellulitis, with or without previous lymphedema. When spontaneous episodes occur more often (usually more than two to four times per year), a regular prophylactic program—penicillin VK (or an equivalent) 250 mg four times a day for 7 days of each month—can be considered. An alternative regimen of penicillin given intramuscularly once a month in patients at increased risk for cellulitis has not been effective in reducing infections.31 A definitive antibiotic prophylaxis regimen for patients who experience recurrent cellulitis has not yet been identified. For some patients, an intermittent prophylactic program may not be sufficient to prevent recurrent infections, and a daily antibiotic regimen may be needed.19 Manual decongestion with maintained volume reduction significantly reduces the incidence of lymphedema-related lymphangitis and/or cellulitis.

Elevation Elevation is the simplest way to reduce early, stage I lymphedema.35 The optimal degree of elevation has not been the subject of research. Thirty to 45 degrees is sufficient, although as little as 5 degrees of elevation, if maintained for a sufficient interval, offers meaningful benefit. Prolonged elevation was used for decades and is still used for early reversible lymphedema or for refractory cases as part of combined therapy. Lymphedema reduced through elevation must subsequently be managed with an adequate compression system; otherwise, all volume reduction will be lost. Today, in-patient treatment is a rare option, and patients often find elevation therapy outside the hospital impractical, and thus, ineffective. Also, growing appreciation of the importance of exercise and the preservation of muscle bulk and tone in lymphedema management has highlighted the downsides of the inevitable physical deconditioning that occurs with prolonged elevation. O’Donnell and Howrigan have suggested that 4- to 6-inch blocks be placed under the legs of the foot of the bed to provide adequate overnight elevation for patients with lower extremity edema.36 A foam wedge also offers an inexpensive and comfortable means of limb elevation (Fig. 67-1).

Antibiotics Prompt administration of appropriate antibiotic therapy to any patient with lymphangitis and/or cellulitis is essential.19,37 The pathogen responsible for limb cellulitis is usually a β-lactam–sensitive group A streptococcus. Staphylococcus species and other organisms are less commonly reported.19 At the first sign of cellulitis, antibiotic treatment, such as oral penicillin VK, 250 or 500 mg four times a day, should be initiated. Other β-lactam antibiotic therapy, a simple cephalosporin (e.g., cephalexin), or a macrolide (e.g., erythromycin, azithromycin) can be used. Intravenous antibiotic infusion, hospitalization, and bed rest with limb elevation

MECHANICAL REDUCTION OF LIMB SWELLING Complex Decongestive Therapy Complex decongestive therapy (CDT) is a comprehensive lymphedema reduction program that combines elevation, “remedial” exercise, manual lymphatic drainage massage, and compression wraps, and represents the current international standard of care.38,39 CDT, or highly related programs, popularized in Europe by Földi et al,40 Kasseroller,41 and Leduc et al,42 as well as Casley-Smith43 in Australia was introduced to the United States in the early 1990s and continues to be first-line therapy for stage II and III lymphedema. CDT’s success has been documented worldwide.44-47,48 The program involves two phases, each with four discrete components (Box 67-3). Although very successful, it is a resource-intensive treatment that requires a large investment of both the therapist’s and patient’s time. Therapists must be specially trained to perform standardized techniques of manual lymph drainage and complex multilayered wrapping. This treatment is currently offered in specialized practices, but these lymphedema BOX 67-3 

COMPLEX DECONGESTIVE THERAPY PROGRAM PHASE 1. INTENSIVE REDUCTION THERAPY • Manual lymph drainage massage • Multilayered low-stretch wrapping • Exercise techniques • Skin care and elevation principles PHASE 2. MAINTENANCE THERAPY • Daily wear of pressure garment • Continued nightly wrapping • Self-administered manual lymph drainage • Continued exercise and skin care

CHAPTER 67  Lymphedema: Nonoperative Treatment



B

C

D

Figure 67-2  A and B, Chronic untreated left lower extremity lymphedema after surgery and radiation treatment for cervical cancer. C and D, After 6 months of complex wrapping and exercise, largely through a home program, significant results (42% volume reduction) were achieved.

programs are becoming more widely available. In the United States, there is a voluntary certification process that involves the documentation of training and treatment hours, and a certifying examination to ensure competence. This effort was initiated and continues to be coordinated by the Lymphology Association of North America (LANA). Certified therapists are listed on LANA’s website (http://www.clt-lana.org), which can be searched by name, state, or zip code. Phase I CDT includes four components: manual lymph drainage, an exercise regimen, multilayered low-stretch wrapping, and skin care. It is the current “gold standard” of lymphedema management.38,39 CDT is aggressive and may not be appropriate for every patient.49 Extenuating factors such as co-morbidities (including severe obesity), local tumor recurrence, impaired cognitive status, patient noncompliance, and poor social support may undermine the effectiveness of CDT to the point that it is untenable. Although phase I CDT can achieve abrupt and dramatic reductions in limb volume, long-term success requires ongoing maintenance with a phase II home-based program. In the absence of consistent adherence, a patient’s lymphedema volume will inevitably

re-accumulate. The multi-week intensive treatment approach is also subject to limited insurance coverage in the United States, and modified programs, frequently with inferior outcomes, may be a patient’s sole option. An alternative program that involves home compression bandaging and exercise may achieve comparable results to conventional CDT in some patients with milder (e.g., stage II) lymphedema (Fig. 67-2).50

Manual Lymph Drainage Manual lymph drainage (MLD) is a specialized massage technique that uses gentle, sequential skin distention to stimulate the contractility of lymph-collecting vessels and enhance lymph sequestration and transport. The technique is light and superficial (in contrast to conventional techniques that target muscle spasm) and is applied to move lymph from stagnant regions to areas with intact drainage, thereby relieving lymphatic congestion. MLD also attempts to reduce subcutaneous fibrosis. MLD is performed sequentially in steps. The trunk is divided into six sections corresponding to the drainage

SECTION 11 LYMPHEDEMA

A

1021

1022

SECTION 11  Lymphedema

territories of the inguinal, axillary, and cervical lymph node beds. Treatment is initiated by massaging an intact section adjacent to the section that includes the affected limb or body part to prepare the area to receive congested lymph. MLD is then performed over the section adjacent to the affected area. Only after completely “clearing” the truncal areas, does the therapist gradually work into the affected territory, beginning at its most peripheral aspects. The therapist repeats the process in stages along the length of the limb, moving slowly from proximal to distal, by applying MLD strokes in a distal-to-proximal direction (Figs. 67-3 and 67-4). Practiced in this fashion, MLD has been shown to re-direct lymph toward functioning lymphatic territories.51 MLD techniques assume increased importance when treating body parts that are not conducive to sustained compression (e.g., face, breast, genitalia, and trunk).

Exercise Exercise is integral to lymphedema management, although it is often undervalued by patients and practitioners alike. A specific group of “remedial” exercises are unique to CDT. These exercises simply involve the repeated contraction and relaxation of muscles within a lymphedematous body part. When performed within compression bandages, the serial contractions and relaxations are believed to create an internal pumping mechanism that promotes lymph absorption and transport. Muscles are contracted and relaxed in specific sequences, depending on the location of the lymphatic congestion in an attempt to mobilize lymph from the distal to proximal areas of the affected body part. Aerobic exercise, also performed with external compression, is believed to stimulate central (i.e., truncal) lymph transport, thereby creating a gradient that promotes distal lymph flow. Patients who are unable to perform aerobic

Figure 67-4  Manual lymph drainage of the limb is performed after trunk drainage with sequential distal-to-proximal hand movements over short segments, beginning at the proximal portion of the limb.

exercise can still benefit because any movement is helpful. Simple range-of-motion exercises and gentle stretching promotes lymph flow, retards tissue fibrosis, and decreases the risk of contracture and stasis.

Compression Wrapping Elastic wrapping is the principal compression technique used in phase I CDT. Wrapping techniques are complex and favor the use of low-stretch, in lieu of the more traditional highstretch, bandages (Fig. 67-5). High-stretch wraps provide high pressure when the limb is still (high resting pressure), but yield when the limb moves. In contrast, the low-stretch wrap should be comfortable at rest (low resting pressure), but, with movement, should provide unyielding resistance that increases the pressure created by the muscle pump. In theory, this creates a pressure gradient that stimulates lymph flow. Frequently, foam padding is used to render the pressure applied by the bandages more even and tolerable (Fig. 67-6). During phase I CDT, low-stretch wraps are worn 24 hours a day (except when the patient is receiving a massage or bathing). In the maintenance phase, a compression garment is worn during the day and the wraps continue to be worn at night.

Compression Pumping Figure 67-3  Manual lymph drainage of the trunk involves light movements to stimulate and open proximal trunk lymph channels.

Intermittent pneumatic compression (Fig. 67-7) was used for decades before the introduction of CDT. The devices are

CHAPTER 67  Lymphedema: Nonoperative Treatment



B

Figure 67-5  A and B, Compression wrapping. The multilayered low-stretch wrap technique allows maximal pressure without causing patient discomfort.

diverse and may use either a single uniform-pressure sleeve or a sleeve with a series of overlapping chambers that are inflated sequentially in a distal-to-proximal direction.52-56 The relative benefits of the different devices have been limitedly researched. Bergan et al55 randomized 35 patients with lymphedema to a 2-hour-long treatment session with one of three types of compression pumps: (1) a unicompartmental pump using 50 mm Hg pressure; (2) a three-compartment pump with segmental pressures of 50 mm Hg in each cell; or (3) a multicompartmental gradient pressure pump with 10 cells ranging in pressure from 80 mm Hg distally to 30 mm Hg

A

B Figure 67-6  Low-stretch complex compression wrap with foam. The use of foam pads allows extra pressure to help contour focal hardened areas.

Figure 67-7  Sequential pneumatic pump used for intermittent compression treatment of (A) upper extremity or (B) lower extremity lymphedema. (Courtesy Camp International Inc., Jackson, Mississippi.)

SECTION 11 LYMPHEDEMA

A

1023

1024

SECTION 11  Lymphedema

proximally. Mean percentage volume change was +0.4% in the first group, +7.3% in the second, and –31.6% in the third. The authors concluded that multicompartment sequential compression achieved the best reduction of limb volume after a single treatment for chronic lymphedema. Pneumatic compression therapy is currently controversial. An increase in genital and truncal edema has been reported after pneumatic pumping.57 Another potential downside is that patients may develop a fibrosclerotic ring immediately proximal to the upper border of the pump. These adverse effects have led some lymphedema specialists to assert that pumps have no place in lymphedema management. Although many disagree, there is general consensus that conventional CDT achieves superior results to pumping alone. However, uncertainty persists as to the utility of pumps as an adjuvant treatment to augment the benefits of phase I and II CDT. Anecdotal results of combined treatment regimens have been positive (Fig. 67-8), and small pilot studies suggest potential efficacy. However, the results have yet to be replicated in

A

well-designed and adequately powered clinical trials. A newer generation of pneumatic devices have a greater number of small chambers and encompass the trunk and the limb in an effort to mimic the decongestive effects of MLD.58-60 Use of the device is well tolerated by patients, but its relative benefits compared with conventional pneumatic devices have not been rigorously characterized.

Compression Garments Strict adherence to the daily use of a properly fitting, appropriately graduated elastic compression garment is the key to maintaining limb size for most patients. Support garments come in a variety of sizes, compression strengths, and materials, and these features must be selected to meet the unique needs and dimensions of the individual. Although many limbs can be fitted with off-the-shelf prefabricated garments, those with significant swelling or an unusual shape may require custom stockings to obtain the best fit. It is better to

B

C

D

Figure 67-8  Severe primary lymphedema of the lower extremities. A, Limbs on presentation. B, Significant reduction of limb girth after 2 weeks of continuous leg elevation, elastic wrapping, and pneumatic compression treatment. C, After reduction, the maintenance program consisted of bilateral custom-made elastic stockings and a nonelastic wrap to reinforce the stocking on the left. D, Limbs 1 month after the initiation of therapy.



CHAPTER 67  Lymphedema: Nonoperative Treatment

1025

use a mechanical aid to don the stocking (e.g., rubber gloves, a metal frame) than to sacrifice needed pressure.

Pressure Garments are classified according to the amount of compression they deliver distally, and the compression they produce may be graduated or nongraduated. Graduated garments are made to provide the greatest compression in the distal portion of the limb, with progressively less pressure as the garment extends proximally. Over-the-counter support stockings usually provide 7 to 15  mm  Hg of compression and are not graduated. Antiembolism stockings provide 15 to 20  mm  Hg of compression and tend to be graduated. Therapeutic lower extremity elastic stockings designed for chronic venous insufficiency or lymphedema come in a variety of lengths and compression strengths (20-30, 30-40, 40-50, and 50-60  mm  Hg). Lower limbs with recalcitrant chronic lymphedema generally require 30 to 40  mm  Hg of compression at the ankle to control the swelling; however, for patients with comorbidities such as diabetes mellitus, arterial occlusive disease, arthritis, or other conditions that may limit the use of high-compression garments, stockings with pressures of 20 to 30  mm  Hg or less may be more appropriate. Upper extremity garments are typically fitted with 20 to 30  mm  Hg pressure; however, 15 to 20 or 30 to 40  mm Hg may be more appropriate depending on case specifics, such as lymphedema stage and tissue turgor.

Length Stocking length is frequently an issue for patients with lymphedema. As a rule, stockings should be long enough to cover the edematous portion of the limb, but patient preference and physical limitations must be taken into account. In general, knee-high or thigh-high compression garments with removable proximal pressure support (e.g., biking shorts, sport leotards) are better tolerated than full-length garments, which may be difficult to don. Patient input in selecting

among the wide range of options is key to promoting adherence. Good garment fit is critical. Garments should never be rolled at the top, creating the possibility of an obstructing tourniquet. Creases at the ankle or in the popliteal or cubital spaces can create enough pressure to cause skin breakdown. Skin should be carefully inspected for chafing or irritation after a new garment is worn.

Materials Stockings come in a variety of knits and materials; most are composed of some combination of latex, spandex, nylon, cotton, and silk (Fig. 67-9). Differences in construction and materials can significantly affect the “feel” and function of various brands and styles for a given patient. For this reason, a patient may need to try a variety of garments to find the one that works best. Although custom-fit garments are indicated for some patients, a widening array of material, color, and size options among prefabricated garments has reduced the need for costly custom fitting. With repeated washing, all brands exhibit fatigue; thus, garments should be replaced several times each year. Insurance coverage for garments is highly variable and may constrain patient options.

Nonelastic Compression Commercial nonelastic support devices are well received by patients as an alternative to nighttime wrapping. The Circ Aid (Shaw Therapeutics, Rumson, NJ) uses Velcro fastenings to adjust a series of nonelastic support bands around the leg and ankle. Another form of nonelastic support, the Reid sleeve (Peninsula Medical Inc., Scott Valley, Calif), is a tube of egg crate foam, surrounded by canvas, with multiple wide Velcro bands to apply compression. Nonelastic compression options are most helpful for patients who are unable to manage a program of complex wrapping by themselves (Fig. 67-10). The efficacy of nonelastic devices has not been prospectively tested.

SECTION 11 LYMPHEDEMA

Figure 67-9  Graduated compression garments. Many options exist in terms of fabric weave, color, and pattern. The fabric in these garments has a wicking property to enhance comfort during active exercise. (Courtesy Lymphediva Co., Philadelphia, Penn.)

1026

SECTION 11  Lymphedema

extremity may benefit from palliative diuretic therapy to alleviate symptoms.61

Benzopyrones

Figure 67-10  Rigid compressive devices, such as the Reid sleeve, provide nonelastic pressure yet require little effort to apply or remove. Many similar products are available when wrapping is not feasible. (Courtesy Peninsula Medical Inc., Scott Valley, Calif.)

Benzopyrones theoretically decrease lymphedema by stimulating tissue macrophages, thus altering the macrophagedependent balance between protein deposition and lysis.62-64 As a result of increased macrophage activity, the intercellular protein concentration is reduced, which promotes tissue softening and remodeling. Two randomized double-blinded studies examined the efficacy of 5,6-benzo-alpha-pyrone (coumarin) relative to placebo in reducing the volume of established lymphedema. One study enrolled patients with mixed upper and lower extremity lymphedema, whereas the other enrolled breast cancer survivors with upper extremity lymphedema.64,65 The former was a positive study, whereas the latter was not only negative but significant for a 6% incidence of elevated liver enzymes among the intervention group. Due to hepatotoxicity, coumarin has not been approved for use in the United States, and its approval has been revoked in Australia and several European countries.

Interventional and Alternative Treatments

PHARMACOLOGIC, INTERVENTIONAL, AND ALTERNATIVE THERAPIES Pharmacologic enhancement of lymph transport does not have a role in the current treatment of lymphedema. This can be frustrating to patients, who are often looking for a quick, effortless solution to a chronic disfiguring and debilitating condition.

Diuretics Treatment with diuretics is usually not appropriate for patients with chronic lymphedema because the primary pathophysiologic driver is inflammation and increased interstitial oncotic pressure secondary to the accumulation of macromolecular debris, not hydrostatic fluid retention. The diuretic effect is temporary, and secondary hemoconcentration and orthostasis can be unwanted side effects. In some circumstances, however, short-term diuretic therapy may be helpful. In patients hospitalized for massive multifactorial edema, there is often combined venous and lymphatic failure. When these patients are treated with bed rest, elevation, manual therapy techniques, and compression, their response to acute treatment can be augmented by temporarily administering a short-course diuretic. For women whose periodic exacerbations of edema correspond to the menstrual cycle, short-term oral diuretic therapy has been suggested, but this therapy remains controversial.40 Finally, patients in the terminal phase of a malignant disease who have painful swelling of the

Intralymphatic steroid injections have been used in an attempt to decrease fibrotic occlusion in lymph nodes and improve lymphatic transport. In a pilot study of 20 patients with primary lymphedema, 8 showed improvement for as long as 9 months after treatment.66 The effectiveness of steroid treatment remains unproved, however. Investigators in Japan attempted to treat secondary lymphedema by injecting autologous lymphocytes into the main artery of the affected limb, with 5 of 7 patients showing short-term improvement.67 These same authors reported the results of a larger series that used a combined approach of lymphocyte injection and compression therapy. Thirty-four of 46 patients experienced edema reduction.68 These studies have not been replicated to date. Low-level laser therapy has also been studied; edema reduction was noted after treatment and was sustained for several months.69 Results of hyperbaric oxygen therapy for breast cancer–related lymphedema have been mixed.70,71 Given the costly and time-consuming nature of the treatment, it cannot be currently endorsed.

OTHER TREATMENT CONSIDERATIONS Psychological and Functional Impairment, and Economic Issues The psychological and functional impairments associated with lymphedema are significant.21 The need to address the psychological impact of long-term disfigurement, especially in adolescents, cannot be overemphasized. Park et  al21 also discussed the functional impact of lymphedema on lifestyle. Twelve percent of patients reported that they



were limited to desk jobs or ones that allowed frequent sitting. Employees also reported the impression that job promotions had been withheld because of the edema. Some patients limited their participation in exercise or sports because of an uncomfortable or heavy sensation in the affected limb. Some third-party payers deem edema to be a cosmetic problem and deny reimbursement for both treatment and garments. This frustrating misperception often necessitates repeated communications between payers and physicians to justify appropriate treatment.72

Late-onset malignancies are a potentially devastating, but fortunately rare, complication of long-standing lymphedema. In most series, they develop in no more than 1% of patients with lymphedema. The most common are angiosarcomas73 and lymphangiosarcomas,2 which are thought to represent neoplastic transformation of blood vessels and lymphatics, respectively. Histologically and clinically, it is difficult to distinguish these two sarcomas from each other. The occurrence of angiosarcoma (or lymphangiosarcoma) in the setting of lymphedema is commonly called Stewart-Treves’ syndrome.73 Sarcomas can develop in patients with long-standing lymphedema of any cause—primary lymphedema or lymphedema secondary to filariasis,74 hysterectomy,75 trauma,75 or mastectomy.76 Other malignancies, including Hodgkin’s and non-Hodgkin’s lymphoma,77 Kaposi’s sarcoma,78 squamous cell carcinoma,79,80 and malignant melanoma,81 have been reported in association with chronic lymphedema, but a causal link has not been proposed. Limbs with edema must therefore be inspected frequently to permit the early detection and appropriate treatment of tumors.

1027

SELECTED KEY REFERENCES Baddour LM: Cellulitis syndromes: an update. Int J Antimicrob Agents 14:113–116, 2000. A key paper on the cause, recognition, and treatment of cellulitis associated with chronic lymphedema. Therapy is directed at the resolution of acute infection and the prevention of recurrent episodes of cellulitis. Bergan JJ, Stark S, Angle N: Lymphedema: a comparison of compression pumps in the treatment of lymphedema. Vasc Surg 32:455–462, 1998. A prospective, randomized study that showed the early benefit of multicompartmental sequential compression versus unicompartment and three-compartment pumps in the treatment of chronic lymphedema. Casley-Smith JR, Wang CT, Casley-Smith JR, Zi-hai C: Treatment of filarial lymphoedema and elephantiasis with 5,6-benzo-alpha-pyrone (coumarin). BMJ 307:1037–1041, 1993. A randomized, double-blind, placebo-controlled study that confirmed the efficacy of 5,6-benzo-alpha-pyrone in the slow volume reduction of chronic limb lymphedema. Földi E, Földi M, Clodius L: The lymphedema chaos: a lancet. Ann Plast Surg 22:505–515, 1989. An excellent review article from the authors who introduced decongestive physical therapy for lymphedema. They describe the cause, pathomechanism, diagnosis, and treatment of chronic lymphedema. Loprinzi CL, Kugler JW, Sloan JA, Rooke TW, Quella SK, Novotny P, Mowat RB, Michalak JC, Stella PJ, Levitt R, Tschetter LK, Windschitl H: Lack of effect of coumarin in women with lymphedema after treatment for breast cancer. N Engl J Med 340:346–350, 1999. A prospective, randomized, crossover study comparing the effects of a benzopyrone (coumarin) versus placebo in 140 patients with postmastectomy lymphedema. Upper extremity volumes were not significantly different between the two groups. Increased liver enzymes were reported in 6% of patients studied. Because of potential hepatotoxicity, coumarin has not been approved for lymphedema treatment in the United States. Pappas CJ, O’Donnell TF, Jr: Long-term results of compression treatment for lymphedema. J Vasc Surg 16:555–562, 1992. Treatment of patients with lymphedema using sequential compression pump and compression stockings was associated with long-term maintenance of reduced limb girth in 90% of patients. The reference list can be found on the companion Expert Consult website at www.expertconsult.com.

SECTION 11 LYMPHEDEMA

Lymphedema-Associated Malignancy

CHAPTER 67  Lymphedema: Nonoperative Treatment



REFERENCES

29. Soo JK, et al: Lymphatic abnormalities demonstrated by lymphoscintigraphy after lower limb cellulitis. Br J Dermatol 158:1350–1353, 2008. 30. Cornish BH, et al: Bioelectrical impedance for monitoring the efficacy of lymphoedema treatment programmes. Breast Cancer Res Treat 38:169– 176, 1996. 31. Wang JH, et al: Role of benzathine penicillin G in prophylaxis for recurrent streptococcal cellulitis of the lower legs. Clin Infect Dis 25:685–689, 1997. 32. Wrone DA, et al: Lymphedema after sentinel lymph node biopsy for cutaneous melanoma: a report of 5 cases. Arch Dermatol 136:511–514, 2000. 33. Stanton AW, et al: Validation of an optoelectronic limb volumeter (perometer). Lymphology 30:77–97, 1997. 34. Spillane AJ, et al: Defining lower limb lymphedema after inguinal or ilio-inguinal dissection in patients with melanoma using classification and regression tree analysis. Ann Surg 248:286–293, 2008. 35. Földi E, et al: Conservative treatment of lymphoedema of the limbs. Angiology 36:171–180, 1985. 36. O’Donnell TF, et al: The diagnosis and management of lymphedema. In Bell PRF, Jamieson CS, Ruckley CV, editors: Surgical management of vascular disease, Sussex, UK, 1992, Bailliere Tindall. 37. Sener SF, et al: Lymphedema after sentinel lymphadenectomy for breast carcinoma. Cancer 92:748–752, 2001. 38. Kissin MW, et al: Risk of lymphoedema following the treatment of breast cancer. Br J Surg 73:580–584, 1986. 39. Markby R, et al: Incidence of lymphoedema in women with breast cancer. Prof Nurse 6:502–508, 1991. 40. Földi M, et al: Textbook of lymphology for physicians and lymphedema therapists, San Francisco, 2003, Urban & Fischer. 41. Kasseroller RG: The Vodder School: the Vodder method. Cancer 83:(12 Suppl Amer):2840–2842, 1998. 42. Leduc O, et al: Bandages: scintigraphic demonstration of its efficacy on colloidal protein reabsorption during muscular activity. In Nishi M, Uchino S, Yabuki S, editors: Progress in lymphology XI, Amsterdam, 1990, Elsevier, pp 421–423. 43. Casley-Smith JR: Measuring and representing peripheral oedema and its alterations. Lymphology 27:56–70, 1994. 44. Boris M, et al: Lymphedema reduction by noninvasive complex lymphedema therapy. Oncology (Williston Park) 8:95–106; discussion 109–110, 1994. 45. Boris M, et al: Persistence of lymphedema reduction after noninvasive complex lymphedema therapy. Oncology (Williston Park) 11:99–109; discussion 110, 113–114, 1997. 46. Ko DS, et al: Effective treatment of lymphedema of the extremities. Arch Surg 133:452–458, 1998. 47. Daane S, et al: Postmastectomy lymphedema management: evolution of the complex decongestive therapy technique. Ann Plast Surg 40:128– 134, 1998. 48. Szuba A, et al: Decongestive lymphatic therapy for patients with cancerrelated or primary lymphedema. Am J Med 109:296–300, 2000. 49. Schunemann H, et al: Secondary lymphedema of the arm following primary therapy of breast carcinoma. Zentralbl Chir 117:220–225, 1992. 50. Johansson K, et al: A randomized study comparing manual lymph drainage with sequential pneumatic compression for treatment of postoperative arm lymphedema. Lymphology 31:56–64, 1998. 51. Williams AF, et al: A randomized controlled crossover study of manual lymphatic drainage therapy in women with breast cancer-related lymphoedema. Eur J Cancer Care (Engl) 11:254–261, 2002. 52. Richmand DM, et al: Sequential pneumatic compression for lymphedema. A controlled trial. Arch Surg 120:1116–1119, 1985. 53. Pappas CJ, et al: Long-term results of compression treatment for lymphedema. J Vasc Surg 16:555–562; discussion 562–564, 1992. 54. Klein MJ, et al: Treatment of adult lower extremity lymphedema with the Wright linear pump: statistical analysis of a clinical trial. Arch Phys Med Rehabil 69:202–206, 1988. 55. Bergan JJ, et al: Lymphedema: a comparison of compression pumps in the treatment of lymphedema. Vasc Surg 32:455–462, 1998.

SECTION 11 LYMPHEDEMA

1. Woods M, et al: The psychosocial morbidity of breast cancer patients with lymphoedema. Cancer Nurs 18:467–471, 1995. 2. Witte MH, et al: Lymphangiogenesis and lymphangiodysplasia: from molecular to clinical lymphology. Microsc Res Tech 55:122–145, 2001. 3. Karpanen T, et al: Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol 3:367–397, 2008. 4. Smeltzer DM, et al: Primary lymphedema in children and adolescents: a follow-up study and review. Pediatrics 76:206–218, 1985. 5. Mirolo BR, et al: Psychosocial benefits of postmastectomy lymphedema therapy. Cancer Nurs 18:197–205, 1995. 6. Ferrell RE, et al: Hereditary lymphedema: evidence for linkage and genetic heterogeneity. Hum Mol Genet 7:2073–2078, 1998. 7. Connell F, et al: Phenotypic characterization of primary lymphedema. Ann N Y Acad Sci 1131:140–146, 2008. 8. Hoerauf A: Control of filarial infections: not the beginning of the end, but more research is needed. Curr Opin Infect Dis 16:403–410, 2003. 9. Bockarie MJ, et al: Mass treatment to eliminate filariasis in Papua New Guinea. N Engl J Med 347:1841–1848, 2002. 10. Das PK, et al: Towards elimination of lymphatic filariasis in India. Trends Parasitol 17:457–460, 2001. 11. Ottesen EA, et al: Strategies and tools for the control/elimination of lymphatic filariasis. Bull World Health Organ 75:491–503, 1997. 12. Meyrowitsch DW, et al: Long-term effect of mass diethylcarbamazine chemotherapy on bancroftian filariasis. Results at four years after start of treatment. Trans R Soc Trop Med Hyg 92:98–103, 1998. 13. Ismail MM, et al: Efficacy of single dose combinations of albendazole, ivermectin and diethylcarbamazine for the treatment of bancroftian filariasis. Trans R Soc Trop Med Hyg 92:94–97, 1998. 14. Lammie PJ, et al: The pathogenesis of filarial lymphedema: is it the worm or is it the host? Ann N Y Acad Sci 979:131–142; discussion 188–196, 2002. 15. Vaqas B, et al: Lymphoedema: pathophysiology and management in resource-poor settings—relevance for lymphatic filariasis control programmes. Filaria J 2:4, 2003. 16. Semel JD, et al: Association of athlete’s foot with cellulitis of the lower extremities: diagnostic value of bacterial cultures of ipsilateral interdigital space samples. Clin Infect Dis 23:1162–1164, 1996. 17. Scheinfeld NS: Obesity and dermatology. Clin Dermatol 22:303–309, 2004. 18. Babb RR, et al: Prophylaxis of recurrent lymphangitis complicating lymphedema. JAMA 195:871–873, 1966. 19. Baddour LM: Cellulitis syndromes: an update. Int J Antimicrob Agents 14:113–116, 2000. 20. Soria P, et al: Dietary treatment of lymphedema by restriction of longchain tryglicerides. Angiology 45:703–707, 1994. 21. Park JH, et al: Incidence and risk factors of breast cancer lymphoedema. J Clin Nurs 17:1450–1459, 2008. 22. Petrek J, et al: Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer 92:1368–1377, 2001. 23. Shaw C, et al: Randomized controlled trial comparing a low-fat diet with a weight-reduction diet in breast cancer-related lymphedema. Cancer 109:1949–1956, 2007. 24. Casley-Smith JR, et al: Lymphedema initiated by aircraft flights. Aviat Space Environ Med 67:52–56, 1996. 25. Stout Gergich NL, et al: Preoperative assessment enables the early diagnosis and successful treatment of lymphedema. Cancer 112:2809– 2819, 2008. 26. Damstra RJ, et al: Erysipelas as a sign of subclinical primary lymph­ oedema: a prospective quantitative scintigraphic study of 40 patients with unilateral erysipelas of the leg. Br J Dermatol 158:1210–1215, 2008. 27. Kocak Z, et al: Risk factors for arm lymphedema in breast cancer patients. Acta Oncol 39:389–392, 2000. 28. Consensus Document of the International Society of Lymphology: In The diagnosis and treatment of peripheral lymphedema. Lymphology 36:84–91, 2003.

CHAPTER 67  Lymphedema: Nonoperative Treatment 1027.e1

1027.e2 SECTION 11  Lymphedema 56. Dini D, et al: The role of pneumatic compression in the treatment of postmastectomy lymphedema. A randomized phase III study. Ann Oncol 9:187–190, 1998. 57. Giuliano AE, et al: Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 220:391–398, discussion 398–401, 1994. 58. Wilburn O, et al: A pilot, prospective evaluation of a novel alternative for maintenance therapy of breast cancer-associated lymphedema [ISRCTN76522412]. BMC Cancer 6:84, 2006. 59. Ridner SH, et al: Self-reported comorbid conditions and medication usage in breast cancer survivors with and without lymphedema. Oncol Nurs Forum 35:57–63, 2008. 60. Mayrovitz HN: Interface pressures produced by two different types of lymphedema therapy devices. Phys Ther 87:1379–1388, 2007. 61. Mortimer PS: Therapy approaches for lymphedema. Angiology 48:87–91, 1997. 62. Casley-Smith JR: The pathophysiology of lymphedema and the action of benzo-pyrones in reducing it. Lymphology 21:190–194, 1988. 63. Piller NB: Macrophage and tissue changes in the developmental phases of secondary lymphoedema and during conservative therapy with benzopyrone. Arch Histol Cytol 53:209–218, 1990. 64. Casley-Smith JR, et al: Treatment of filarial lymphoedema and elephantiasis with 5,6-benzo-alpha-pyrone (coumarin). BMJ 307:1037–1041, 1993. 65. Loprinzi CL, et al: Lack of effect of coumarin in women with lymphedema after treatment for breast cancer. N Engl J Med 340:346–350, 1999. 66. Fyfe NC, et al: Intralymphatic steroid therapy for lymphoedema: preliminary studies. Lymphology 15:23–28, 1982. 67. Katoh I, et al: Intraarterial lymphocytes injection for treatment of lymphedema. Jpn J Surg 14:331–334, 1984. 68. Ogawa Y, et al: Investigation of the mechanism of lymphocyte injection therapy in treatment of lymphedema with special emphasis on cell adhesion molecule (L-sectin). Lymphology 32:151–156, 1999.

69. Carati CJ, et al: Treatment of postmastectomy lymphedema with lowlevel laser therapy: a double blind, placebo-controlled trial. Cancer 98:1114–1122, 2003. 70. Albertini JJ, et al: Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 276:1818–1822, 1996. 71. Veronesi U, et al: Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 349:1864– 1867, 1997. 72. Cheville AL: Current and future trends in lymphedema management: implications for women’s health. Phys Med Rehabil Clin N Am 18:539– 553, 2007. 73. Schmitz-Rixen T, et al: Angiosarcoma in primary lymphedema of the lower extremity—Stewart-Treves syndrome. Lymphology 17:50–53, 1984. 74. Muller R, et al: Lymphangiosarcoma associated with chronic filarial lymphedema. Cancer 59:179–183, 1987. 75. Alessi E, et al: Angiosarcomas in lymphedematous limbs. Am J Dermatopathol 8:371–378, 1986. 76. Benda JA, et al: Angiosarcoma of the breast following segmental mastectomy complicated by lymphedema. Am J Clin Pathol 87:651–655, 1987. 77. Tatnall FM, et al: Non-Hodgkin’s lymphoma of the skin associated with chronic limb lymphoedema. Br J Dermatol 113:751–756, 1985. 78. Ruocco V, et al: Kaposi’s sarcoma on a lymphedematous immunocompromised limb. Int J Dermatol 23:56–60, 1984. 79. Shelley WB, et al: Transformation of the common wart into squamous cell carcinoma in a patient with primary lymphedema. Cancer 48:820– 824, 1981. 80. Epstein JI, et al: Squamous carcinoma of the foot arising in association with long-standing verrucous hyperplasia in a patient with congenital lymphedema. Cancer 54:943–947, 1984. 81. Bartal AH, et al: Malignant melanoma appearing in a post-mastectomy lymphedematous arm: a novel association of double primary tumors. J Surg Oncol 30:16–18, 1985.

CHAPTER 68 

Lymphedema: Surgical Treatment RUEDIGER G.H. BAUMEISTER

The lymphatic system is the least understood part of the

vascular system. Lymphatic malformations such as chylous disorders, cystic hygromas, and lymphocysts are rare; acquired disorders such as lymphoceles and chylous effusions are also uncommon. However, local interruption and obstruction of the lymphatic vessels occur frequently from either congenital or acquired causes (see Chapter 66). In developed countries, most acquired lymphatic obstructions are iatrogenic, caused by medical procedures. In developing countries, the most frequent cause of lymphatic obstruction resulting in chronic lymphedema is filariasis. Vessel interruption is a common pathologic process in the vascular system, and surgical repair that involves bypassing an obstruction is a well-established method in vascular surgery. These principles of surgical treatment have also been applied successfully in the lymphatic system and are the topic of this chapter.

BASIS OF SURGICAL TREATMENT The development of lymphedema can be described as an imbalance between the lymphatic load—the amount of lymph that has to be cleared from a body part within a given time—and the lymphatic transport capacity—the amount of lymph that can be transported out of a body part within a given time, which is dependent on the number and function of lymphatic vessels and nodes (see Chapter 13).1 Reduced lymphatic flow due to obstruction leads to secondary tissue changes, a process that is not yet fully understood. Lymphatic outflow disorders are manifested mainly with advanced secondary changes and chronic lymphedema, a condition that can be difficult to treat unless the underlying problem of reduced lymphatic outflow is resolved. Historically, secondary tissue changes leading to excess fibrous and adipose tissue were treated solely by excisional procedures, without correcting the underlying cause. However, modern surgical concepts have been developed to attempt to correct the underlying pathophysiologic mechanism to the extent possible. Enhancing the number of functional lymphatic vessels through surgical reconstruction is the most natural way to address the problem and is especially beneficial when the 1028

reconstruction is performed before secondary tissue changes occur. Thus, it is not surprising that the surgical reconstruction of lymphatic vessels in selected patients has yielded excellent results. One obstacle is the small dimension of lymphatic vessels, which can be overcome only with advanced microsurgical approaches. Once secondary tissue changes have evolved, additional efforts may be required. One of the less invasive methods in current use is liposuction. Because conservative therapy consisting of limb elevation, compression garments, complex decongestive therapy, and compression pump therapy should be the first step (see Chapter 67), the question arises whether and at what time surgery is indicated. If the only purpose of surgery is resection, it is wise to reserve it as a last option. If, however, surgical reconstruction is possible, this procedure should be considered and offered to the patient early in the course of lymphedema.

HISTORICAL PERSPECTIVE Excisional Operations Surgical Excision The most radical excisional approach is the classic operation first described by Charles in 1912.2 It involves complete and circumferential resection of the skin, subcutaneous tissue, and deep fascia, followed by split-skin grafting. However, this procedure is associated with significant complications, and follow-up studies revealed hyperkeratosis, papillomatosis, and ulcerations in the grafted areas.3,4 Modifications of this technique, using the resected skin for grafting and performing the surgery in two stages,5-11 reduced the surgical trauma and the rate of complications. The techniques of resecting the fascia and subcutaneous tissue and creating skin flaps were based on the proposals of Auchincloss, Fontaine, Homans, and Servelle.12-15 In contrast to the Charles procedure, the flap procedure yields a better cosmetic result, but it requires sufficient healthy skin in the affected extremities. Limited resection of fascia, subcutaneous tissue, and skin was suggested by Sistrunk.16,17

CHAPTER 68  Lymphedema: Surgical Treatment



Liposuction A less invasive way to reduce the amount of subcutaneous tissue is liposuction. It was first described by Illouz as a method for treating lymphedema.18 More recently, Brorson and Svensson demonstrated lasting volume reduction if elastic compression garments are worn after the surgical procedure; this can result in an extremity that is even slimmer than the healthy limb.19

Functional Procedures The first attempts to divert lymph from the subcutaneous to the muscular compartment through partial or complete resection of the fascia were described by Lanz and Kondoleon.20-22 Redirection of lymph from the superficial to the deep compartment is also a component of the Thompson method. Thompson resected the fascia along with parts of the subcutaneous tissue, created a flap in two stages, and de-epithelialized the rim of the flap to allow the outflow of lymph. Subsequently, he buried the flap near the deep vessels to facilitate the creation of spontaneous lymphatic anastomoses.23-30 Facilitating spontaneous lympholymphatic anastomoses within the subcutaneous tissue has been the aim of several methods, and a variety of flaps have been created for transposition into the edematous area.31-35 Goldsmith and coworkers proposed the creation of a pedicle from the greater omentum,36,37 and Kinmonth and associates proposed the construction of an enteromesenteric bridge using a pedicle of

ileum (denuded of its mucosa) and its mesentery (rich in lymphatics) to drain lymph out of the edematous leg tissue.38 The use of veins for the reconstruction of an interrupted lymphatic system was investigated by Holle and Mandl experimentally and performed in two patients clinically.39,40 Campisi and colleagues reported on a larger series using this technique.41

Modern Techniques Currently, the most common way to drain lymph from edematous tissue is the construction of connections between the lymphatic (Fig. 68-1) and venous systems in the periphery. The first reports on lymphonodular and lymphovenous anastomoses were provided by Laine and Howard,42 Nielubowicz and Olszewski,43 Rivero and coworkers,44 and Allen and Taylor.45 Degni designed a special needle to facilitate the insertion of lymphatic vessels into veins.46,47 Further improvements were described by O’Brien and colleagues using microsurgical techniques.48,49 In some patients, excisional methods were combined with lymphovenous shunting. A large cohort of patients successfully treated with microsurgical lymphovenous anastomosis was reported by Campisi and associates.50 However, experimental studies revealed problems with thrombotic occlusion at the site of anastomosis, with a patency of 20% after 5 months of follow-up.51-53 Specific preparations that ensured an undisturbed connection to the venous valve led to an improved patency rate of 44% after 6 months.54,55 Gloviczki and colleagues reported on results of experimental microsurgical end-to-end anastomoses between

Supraclavicular nodes Deltoideopectoral node Inguinal lymph nodes

Infraclavicular nodes Axillary nodes

Lateral bundle

Superficial medial bundle

Medial upper arm bundle

Popliteal lymph nodes

Radial bundle Deep lymphatic system

Superficial lateral bundle

Ulnar bundle

Figure 68-1  A, Superficial lymphatic system of the lower extremity. B, Lymphatic system of the upper extremity. (Courtesy Mayo Foundation.)

Posterior tibial and peroneal lymphatics

A

B

SECTION 11 LYMPHEDEMA

Early Techniques

1029

1030

SECTION 11  Lymphedema

normal femoral lymph vessels and a tributary of the femoral vein in dogs and noted a 50% patency rate up to 8 months after the operation.56 Direct reconstruction of the lymphatic system became a possibility only after the development of microsurgery. Before that time, it was commonly thought to be impossible to anastomose lymphatic vessels because of their extremely small diameters. Hence, Danese approximated lymphatic vessels as close to each other as possible and waited for spontaneous regeneration. He was able to demonstrate transport of contrast medium (through the lymphatics) with this technique.57 In a patient with lymphedema of the arm, he mobilized two lymphatic channels proximally and distally, approximated them in the axilla, and achieved a reduction in edema.58 Subsequent approaches included interpositioning veins between lymphatic vessels,39-41 implanting microsurgical lymph node grafts,59,60 and implanting free flaps with lymphatic vessels.61,62 The question of optimal reconstruction material has been the subject of two experimental studies. In a series of 14 rats, 100% of the autologous lymphatic grafts were patent (observations made between days 7 and 119 postoperatively), whereas allogeneic lymphatic grafts were patent only until day 21 after transplantation. When lymphatics were replaced by small veins (n = 10), a patency of 70% was observed. Expanded polytetrafluoroethylene implants (n = 10) used as lymphovascular conduits were already thrombosed by day 7.63 In a comparison of lymphatic and venous interpositional autografts in 71 dogs, all 26 lymphatic autografts remained patent up to the end of the observation period at 24 weeks. Of 30 venous interpositional autografts, only 4 were patent after 1 week. None of the lympholymphatic anastomoses with silicone tubing showed patency at any time.64 Acland and Smith were the first to attempt to anastomose lymphatic vessels.65-67 The first successful therapeutic lympholymphatic graft was performed in 1980 by Baumeister in a patient with unilateral lymphedema of the lower extremity.68-71 This followed extensive animal experiments on thoracic duct transplants in rats72 and the treatment of experimental lymphedema in dogs using lymphatic autografts.67

PREOPERATIVE PLANNING Visualizing Lymphatic Vessels For vascular surgeons, direct visualization of a single lymphatic vessel would be the ideal technique for preoperative evaluation and planning.

lymphography, using a water-soluble contrast medium injected subepidermally, cannot visualize lymphatic vessels as well as direct lymphography and gained only limited use.74 In primary lymphedema, this technique might be used to evaluate whether there are any lymphatic vessels present in the periphery and, if so, whether they might be able to transport lymph toward a proximally performed anastomosis.

Magnetic Resonance Imaging Attempts to visualize lymphatic vessels with magnetic resonance imaging (MRI) and subdermally administered contrast medium have been promising. This technique may be useful in the future for preprocedure planning and postoperative assessment of the patency of lymphatic reconstructions.75 For the detection of vascular lymphatic malformations, MRI is extremely valuable both with and without contrast medium.

Lymphoscintigraphy The most important test to evaluate chronic lymphedema and to plan surgical treatment is lymphoscintigraphy. It can be repeated and used for treatment planning as well as for follow-up. It not only evaluates function but also visualizes routes of lymphatic transport. The lymphatic transport index summarizes the findings derived from lymphoscintigraphic studies and allows a semiquantitative evaluation of lymphatic flow without the need for standardized physical movements by the patient. The transport index ranges from 0 for an optimal lymphatic outflow to 45 for no visible transport; normal values are less than 10. It also provides a good basis for follow-up studies and can show lymphatic transport along the route of lymphatic grafts.76,77 In measuring lymph transport at regions of interest, it is critical to standardize the dose of radiopharmaceutical and the physical activity of the patient during the procedure.78

Dye Injection Another diagnostic tool that can be used to identify lymphatic channels is the subepidermal injection of a vital dye (patent blue dye in Europe; isosulfan blue [Lymphazurin] dye in the United States). Normally, lymphatic transport is visualized in the superficial lymphatic collecting system. In pathologic situations, dermal backflow leads to the pooling of contrast medium within the skin, resulting in a cloudlike appearance. Because allergic reactions have been reported, staining of lymphatic vessels with patent blue or isosulfan blue dye is generally performed during surgery under general anesthesia.

Lymphography

Lymphatic Donor Site Assessment

Direct contrast lymphography, using oily contrast medium and invasive administration through dissected lymphatic vessels, was introduced by Kinmonth and greatly advanced our knowledge of the lymphatic system.73 However, owing to the invasiveness of the procedure (and injury to the lymphatic vessels and lymph nodes), it was found to worsen lymphedema and is rarely used today. Indirect contrast

For lymphatic grafting, it is critical to choose and carefully evaluate the proper harvest site for lymphatic vessels to avoid the development of edema secondary to the procedure. Thus, the donor lower extremity must be evaluated by lymphoscintigraphy before harvesting. During the harvest, the narrowing lymphatic system at the medial aspect of the knee and the groin must be left untouched, and all stained lymphatic



vessels other than those used as grafts should be left in place. A study including 80 patients with arm edema showed that when this method was used, the harvest site and the untouched leg were not different in size.71

Patient Risk Assessment

SURGERY Autologous Lymphatic Grafting Indications Lymphatic vessel grafts can be attempted for the treatment of secondary lymphedema caused by localized obstruction or interruption of lymph vessels and lymph nodes, such as the lymphedema of the arm that develops after breast cancer surgery because of the excision of axillary lymph nodes and possible radiation treatment (see Fig. 68-1B). Patients with unilateral lower limb lymphedema due to the excision of inguinal or pelvic lymph nodes or pelvic irradiation for malignant disease are also potential candidates for such procedures. Transplantation of lymphatic vessels can be attempted in patients with primary lymphedema if it is caused by localized lymphatic obstruction or atresia, such as unilateral atresia of the pelvic or inguinal lymphatic system. Surgical intervention should be considered only after a trial of conservative therapy. Conservative treatment should be continued for at least 6 months because spontaneous regression has been reported. However, if conservative therapy is unsuccessful during this time frame, reconstruction should be attempted soon to avoid secondary tissue changes. Unfortunately, treatment is often delayed. In my experience, the mean time between the onset of edema and the patient’s presentation for surgery is more than 7 years.

1031

lymphatic vessels distal to the occlusion that are suitable for anastomosis. In all cases of lymphedema, malignant disease must be excluded before surgery.

Surgical Technique The lymphatic grafts are harvested from the patient’s thigh (Fig. 68-2). The ventromedial lymphatic bundle contains up to 16 lymphatic vessels.79 About one to four lymphatic collectors are dissected in the medial area of the thigh, and great care is taken to spare the lymphatic system where it narrows at the level of the knee and groin. Additional peripheral branches often exist, and these can be dissected as well to create a greater number of peripheral anastomoses. For free transfer of the graft, a ligature is placed on the lymphatic vessel selected as a graft beneath the inguinal lymph nodes with 6-0 polyglactin 910. One thread is left long to facilitate handling of the graft thereafter. Proximal to the ligature, the lymphatic vessel is transected. At the distal end of the proposed graft, the lymphatic vessel is transected proximal to the level of the knee. The lymphatic vessel beneath the transection site is occluded either by placing a suture or by using coagulation to avoid lymph leakage. If a transposition procedure is performed, the grafts are transected distally after double ligation and tunneled subcutaneously superior to the pubic symphysis to the contralateral side, where end-to-end lympholymphatic anastomoses are performed. In free transfers as well as in transposition procedures, the graft has to be pulled from one incision to the other (e.g., from the upper arm to the neck or between inguinal regions). To avoid any friction during tunneling, tubes

Preoperative Evaluation Bilateral isotope lymphoscintigraphy is performed in every patient. Both lower extremities are tested to determine a safe harvest site of lymph vessels for the transplant. Only limbs with normal lymphatic transport capacity are used as donors of lymphatic grafts. In primary lymphedema, indirect lymphography or MRI lymphography is performed in an attempt to visualize

Figure 68-2  Harvesting of lymphatic grafts from the patient’s thigh.

SECTION 11 LYMPHEDEMA

Because this type of surgery is performed in the subcutaneous tissue, the surgical risk is generally low, and the procedure is well tolerated. Peripheral lymphovenous shunting is often performed under local anesthesia and is unproblematic as long as the patient tolerates local anesthetics. Because the application of patent blue or isosulfan blue dye can lead to allergic reactions, it should be used only under general anesthesia. Excisional methods typically involve more surgical trauma and the possibility of greater blood loss. Therefore, it is sometimes advisable to perform large excisional operations in two stages. For surgical intervention within the abdomen and thorax, the usual preoperative risk assessment must be done (see Chapter 31).

CHAPTER 68  Lymphedema: Surgical Treatment

1032

SECTION 11  Lymphedema

between the incisions in the upper arm and neck. Subsequently, the grafts are pulled through the wet drain gently and without friction. After removal of the tube, the grafts remain in the subcutaneous tissue free of tension.

Figure 68-3  Lymphatic grafting in arm edema.

(suction catheters) are placed between the two incisions according to the proposed route of the grafts. Thereafter, the grafts themselves can be pulled through the tubes without tension. After removal of the tubes, the grafts remain undisturbed in place within the subcutaneous tissue. Arm and Neck.  For arm edema as a result of interventions in the axilla, the grafts are interposed between ascending lymphatic vessels in the upper arm and lymphatic vessels or lymph nodes in the neck (Fig. 68-3). In the upper arm, lymphatic vessels are usually epifascial (if not, they may be located subfascially in proximity to the vessels) and are best sought from an oblique incision made medially and superior to the route of the brachial vessels. The search is performed under the microscope with a medium (3× to 10×) magnification. In the early stages of lymphedema, the lymphatic vessels have a gray, shiny appearance, and the lumen can be seen clearly after transection. As the lymphatic vessels undergo fibrosis in later stages of lymphedema, it becomes more difficult to discriminate between small nerves and fibrous cords. In this case, the final decision about the potential use for grafting can be made only after transection of the structure. The walls of lymphatic vessels are thinner in the neck than in the arms and legs. Injection of a vital dye in the hairbearing parietal area above the ear facilitates the search for appropriate vessels. If the lymphatic vessels stain appropriately, recognition is easy. However, suturing in this area is often difficult because of the collapsing, thin-walled vessels. If this is the case, it is also possible to suture the grafts to lymph nodes. A superficial incision is made in the capsule of the node, and the graft is connected with approximately three single interrupted sutures. To position the grafts between the sites of anastomosis, tubing from a drain is placed in the subcutaneous tissue

Leg.  For unilateral edema of the lower extremity, the grafts remain attached to the inguinal lymph nodes, and the distal ends of the grafts are transposed to the opposite thigh with the help of tubing from a drain, which is temporarily interposed between the two incisions at the thigh (Figs. 68-4 to 68-6). The tension-free technique is used to anastomose the lymphatic vessels under the operating microscope with maximal magnification (Fig. 68-7). The suture opposite the surgeon should be performed first. Because of the fragility of the vessels, the vessels are not turned over. Only the back wall is lifted as far as necessary to place a dorsal stitch. One or two additional single stitches complete the anastomosis. In my experimental studies of suture material, absorbable polyglactin was superior to nonabsorbable material. Currently, 10-0 absorbable suture (polyglactin 910) is the thinnest material available, used on a BV-75-4 needle.

Postoperative Treatment After surgery, elastic bandages are applied, and an elastic compression garment is prescribed for 6 months, at which time discontinuation of the garment is considered. Antibiotics and erysipelas prophylaxis are given for 6 months because of the reduced immunologic resistance in patients with lymphedema. Low-molecular-weight dextran or 6%

Figure 68-4  Lymphatic grafting in unilateral edema of the lower extremity.

CHAPTER 68  Lymphedema: Surgical Treatment



1033

Figure 68-5  A, Exposure of lymph vessels for suprapubic transposition. Note that two major lymph vessels of the left thigh will be used for grafting (arrows). B, Two lymphatic grafts divided at the distal thigh are prepared for grafting. (Courtesy Mayo Foundation.)

reduced to 2273 cm3 from a mean preoperative volume of 3004 cm3 (P < .001). In 81 adult patients with unilateral edema of the lower extremities, the mean preoperative volume of 13,098 cm3 was reduced to a mean of 10,578 cm3 at the time of hospital discharge (P < .001). After a mean follow-up period of 1.7 years, the volume reduction was sustained, with a mean volume of 11,074 cm3 (P < .001). In a group of 12 patients observed for more than 4 years, the volume was reduced to 10,692 cm3 (P < .001).71 The following complications were observed: two cases of erysipelas in the initial group of patients, one lymphocyst at the harvesting site, and swelling of the lower leg after thrombosis in one patient. Lymphoscintigraphic studies were performed during a follow-up period of 8 years in 20 patients (12 upper extremities, 8 lower extremities). Of the 20 patients, 17 showed improved lymphatic outflow. In five patients, patent grafts could be demonstrated directly by visualizing the routes of activity.81 Figures 68-8 and 68-9 show lymphoscintigraphic studies along with the transport index for two patients with

hydroxyethyl starch infusions are given for 1 week postoperatively to improve lymph flow.

Results Results were evaluated by volume estimation based on circumferential measurements along the limb in increments of 4 cm. Further, lymphatic outflow was measured semiquantitatively by the lymphatic transport index based on lympho­ scintigraphic studies.76 Direct visualization of the grafts was difficult because, with lymphangiography using water-soluble contrast medium, the lymphatic vessels can generally be visualized only over short distances. However, in several patients, patent grafts could be demonstrated more than 10 years after grafting with this technique.80 In a series of 127 patients with arm edema, a significant volume reduction was achieved, from a mean of 3368 cm3 preoperatively to a mean of 2567cm3 after 8 to 10 days (P < .001). At a mean follow-up of 2.6 years, the mean volume was 2625 cm3 (P < .001). In a group of 8 patients with longterm follow-up of more than 10 years, the mean volume was

A

B

Figure 68-6  A, Completed suprapubic lymph graft with two lympholymphatic anastomoses in the right groin. Dashed line indicates the position of the suprapubic lymphatic grafts. B, Magnified photograph of two end-to-end lympholymphatic anastomoses (arrows) performed with 11-0 interrupted monofilament sutures. (Courtesy Mayo Foundation.)

SECTION 11 LYMPHEDEMA

B

A

1034

SECTION 11  Lymphedema

a follow-up period of 6 years. A quality of life study in 212 patients who had undergone lymphatic grafting showed a significant improvement in the physiologic and the psychologic conditions as well.82

Other Direct Reconstructive Methods Trevidic and Cormier described a method of directly bridging a lymphatic defect with a free flap.59 Li and colleagues isolated lymphatic vessels within the flap and created lympholymphatic anastomoses on both sides.62 Ho and coworkers used the greater saphenous vein to invaginate the lymphatic vessels and also performed lympholymphatic anastomoses at the peripheral and central ends of the interposition tissue.83 Another attempt to reconstruct a gap in the lymphatic system was described by Becker and associates, consisting of free lymph node grafting with the goal of spreading lymphatic connections peripherally and centrally.60 Another method of reconstructing an interrupted lymphatic system using veins was proposed by Mandl84 and described in a series by Campisi and colleagues41 (Fig. 68-10). The study included 64 patients, 59 with leg lymphedema and 5 with postmastectomy edema. Marked reduction was reported in 40 patients, moderate reduction in 18 patients, and mild reduction in 6 patients.

Conclusions A prerequisite for all reconstructive methods is a refined microsurgical approach. Lympholymphatic anastomosis appears to be more advantageous than lymphovenous anastomosis; adverse pressure gradients between lymphatic vessels and veins are avoided, and a lympholymphatic anastomosis is likely to heal faster because of the ability of lymphatic

Figure 68-7  Tension-free technique for lympholymphatic anastomoses.

Female patient, 55 yr. Breast cancer Secondary lymphedema 90 minutes after injection Transport index: 28

preoperative

15

12

15

postoperative 2 years

4 years

Figure 68-8  Lymphoscintigraphic long-term follow-up after lymphatic grafting in arm edema.

6 years

CHAPTER 68  Lymphedema: Surgical Treatment



1035

Male patient, 36 yr. Primary lymphedema Left leg 90 minutes after injection Transport index: 42

20

16

L preoperative

L postoperative 2 years

4 years

6 years

Figure 68-9  Lymphoscintigraphic long-term follow-up after lymphatic grafting in unilateral edema of the lower extremity.

A

B

C Figure 68-10  Techniques of lymphatic reconstruction with interposition vein graft (A) or lymphovenous anastomosis (B). Technique of invagination of multiple lymphatics into an interposition vein graft: lymphatic-venous-lymphatic anastomosis (C). (Courtesy Mayo Foundation.)

vessels to regenerate.85 Lymph’s lower coagulability than blood is another potential advantage of lympholymphatic anastomosis. In all patients who undergo surgical treatment, an attempt at conservative therapy should have failed. Two or three lymphatic channels seem to be sufficient to restore normal lymphatic transport; successful grafting results in a return of the lymphoscintigraphic transport index to the normal range. Whether reconstructive surgery can reverse secondary changes that have already occurred in the distal lymphatic channels, subcutaneous tissue, and skin of patients with chronic lymphedema is a challenging question that cannot be answered with generalities. In patients with mild secondary changes, the appearance of the extremity after lympholymphatic grafting can return to close to normal without additional treatment. In patients with more advanced secondary changes, the goal is often not to completely reduce excess volume but to improve the feeling of tension and heaviness; for some patients, reduction of swelling at the wrist and hand alone is a major success. Liposuction can be considered in addition to lymphatic reconstruction to reduce excess volume. Preliminary results show that volumes achievable in the affected extremity are slightly lower than those in the healthy one, without any additional therapy.

Lymphovenous Anastomosis Indications Patients with secondary lymphedema of recent onset without previous episodes of cellulitis or lymphangitis are potential

SECTION 11 LYMPHEDEMA

R

24

1036

SECTION 11  Lymphedema

candidates for surgical treatment unless they can be managed easily with conservative measures. In the late stage of lymphedema, fibrosis and valvular incompetence of the main lymph vessels develop, the intrinsic contractility of the vessel wall is lost, and interstitial pressure decreases owing to secondary changes in the subcutaneous tissue (see Chapter 13). The chance of successful lymphovenous anastomosis in such limbs is clearly diminished. Because venous hypertension impedes forward flow through the anastomosis, patients with chronic venous insufficiency are not candidates for this operation.

Preoperative Evaluation Isotope lymphoscintigraphy is usually sufficient for preoperative imaging of the lymphatic system. In ideal candidates, it confirms the presence of dilated infrainguinal lymph vessels with proximal pelvic lymphatic obstruction. Although it does not differentiate between primary and secondary lymphedema, and even though it is primarily a functional study rather than an anatomic one, semiquantitative lympho­ scintigraphy with technetium Tc 99m–antimony trisulfide colloid can reliably identify the pattern of lymphatic transport.86 In selected patients, direct contrast lymphangiography can be performed to show the fine details of the lymphatic circulation. Progress in visualizing superficial lymphatic vessels has been made with the use of indocyanine green fluorescence lymphography. Indocyanine green is injected intradermally. With the help of a near-infrared camera, the lymphatic vessels are detected as blurred linear images, whereas dermal backflow is seen as a spotty image. This facilitates the search for superficial lymphatic vessels appropriate for lymphovenous anastomoses.87 Other preoperative tests include noninvasive venous studies and duplex scanning of the deep veins. Computed tomography (CT) is used in most patients to exclude an underlying mass or malignant tumor. Once surgery has been decided on, the patient is hospitalized for 24 to 48 hours to elevate the extremity in a lymphedema sling and to allow the use of intermittent compression with a pump to decrease the volume of the extremity.

Surgical Technique Leg.  For lower extremity lymphedema, a transverse incision at the midthigh or a longitudinal incision close to the saphenofemoral junction is performed to allow dissection of the lymphatic of the superficial medial bundle. The greater saphenous vein and any tributaries are also dissected. An attempt is made to visualize the lymph vessels by injecting 5  mL of isosulfan blue dye subcutaneously; half this amount is directed toward the first interdigital space and half toward the area 10 to 15  cm distal to the incision site. Because of lymphatic obstruction, lymph flow even in patent lymphatics may be minimal, and the dye usually is not visible during dissection. With experience, the whitish fluid-filled lymphatics, frequently with vascularized adventitia, can be distinguished from small subcutaneous nerves or fibrotic bands.

If contrast lymphangiography is performed within 24 hours of the operation, the contrast-filled lymphatics are easily identifiable and can be located during the operation with an image intensifier and a C-arm. In some patients, contrast lymphangiography helps avoid many hours of unsuccessful searching for patent lymphatics in the groin. Once the lymphatic vessels and the veins are isolated, a standard microsurgical technique is used to perform an end-to-end anastomosis with six to eight interrupted 11-0 monofilament sutures. The operation is performed with a Zeiss operating microscope with 4× to 40× magnification. Arm.  For arm lymphedema, the lymphatics are dissected either through a transverse incision at the wrist or in the midcubital fossa or through a longitudinal incision at the medial aspect of the arm, a few centimeters proximal to the elbow. Lymphatics of the superficial medial lymphatic bundle are usually used for anastomoses, which are performed with the midcubital, basilic, or brachial veins or their tributaries in an end-to-side or end-to-end fashion.

Postoperative Treatment Postoperatively, the limb is wrapped with an elastic bandage and elevated 30 degrees. For the arm, this can be accomplished with two pillows; for the lower extremity, the foot of the bed can be elevated.

Results Objective evaluation of the long-term effectiveness of lymphovenous anastomosis has been difficult. Decrease in the circumference or volume of the extremity, patient satisfaction, decrease in episodes of cellulitis, and improvement in lymphatic clearance as measured by lymphoscintigraphy have been used as the criteria of success. In a review of 14 patients who underwent lymphovenous anastomosis at the Mayo Clinic, only 5 limbs remained improved at a mean follow-up of 46 months after surgery.88 Improvement was observed in four of seven patients with secondary lymphedema but in only one of seven with primary lymphedema. Improvement in lymphatic clearance from the injection site was the only indirect sign of shunt patency. Therefore, the investigators were unable to provide objective evidence of late patency of the lymphovenous anastomoses in these patients. A large experience with lymphovenous shunts was reported in Australia. O’Brien and colleagues published a welldocumented report with long-term follow-up of 90 patients who underwent lymphovenous anastomoses for chronic lymphedema.89 Although a significant number of patients underwent additional excisional operations, improvement was documented even in those with only lymphovenous anastomoses. Of the latter, 73% had subjective improvement, and 42% had objective long-term improvement. Seventy-four percent of all patients discontinued the use of elastic stockings. Because direct contrast lymphangiography occasionally results in progression of lymphedema owing to chemical lymphangitis or accumulation of contrast material in the lymph nodes due to poor lymphatic transport, this test was not used

CHAPTER 68  Lymphedema: Surgical Treatment



physical treatment before surgery, and continuous custommade pressure garments were used in 2 of 5 patients of stage 3 and in all patients of stage 4 lymphedema. There was no significant relationship between the number of microsurgical anastomoses or implantations and the mean reduction in volume.

Resection Resection involves the removal of the lymphedematous, fibrotic, and frequently sclerotic subcutaneous tissue of the limb. Liposuction is a more recent technique used to accomplish resection. Other open excisions are usually performed during staged procedures. If the skin is diseased and has to be resected, coverage with skin grafts may be necessary.

Liposuction Surgical Technique.  Brorson and Svensson advocate use of liposuction in patients with postmastectomy lymphedema to reduce the volume of the extremity.19 The rationale behind this treatment is that chronic lymphedema causes hypertrophy of the subcutaneous fat. Removal of the hypertrophied and edematous adipose tissue is performed through 20 to 30 3-mm-long incisions with vacuum aspiration. During the postoperative course, controlled compression therapy (CCT) is administered to decrease bleeding complications and to help reduce the volume of the limb. Results.  In a report by Brorson and Svensson, preoperative and postoperative arm edema volumes were measured by the water-displacement technique, and lymph transport was assessed by lymphoscintigraphy.99 Twenty-eight patients were prospectively matched and divided into two groups. One group received liposuction combined with CCT, and one group received CCT alone. Liposuction combined with CCT was more effective than CCT alone; the edema reduction figures after 1 year were 104% for liposuction with CCT and 47% for CCT alone (P < .0001). Continued use of compression garments is important to maintain the primary surgical outcome. Liposuction can be useful in patients with no functioning lymphatics, but in others, the destruction of functioning lymphatics and worsening of the edema are possible.

Staged Subcutaneous Excision beneath Flaps Surgical Technique.  The technique described by Miller and colleagues is most popular in the United States.100-103 The excision is performed in two or sometimes three stages, starting medially during the first operation. A bloodless field is obtained with a pneumatic tourniquet. An incision is made along the ankle beginning 1 cm posterior to the medial malleolus and extending proximally into the midthigh. Flaps approximately 1.5 cm thick are elevated anteriorly and posteriorly to the midsagittal plane in the calf, with less extensive dissection in the thigh and ankle. All subcutaneous tissue beneath the flaps is then removed, but the sural nerve is preserved. The deep fascia of the calf is incised over the tibia and resected, sparing the fascia at the knee and ankle

SECTION 11 LYMPHEDEMA

to document late patency of the anastomoses. Therefore, objective evidence that improvements were caused by patent and functioning lymphovenous anastomoses is still lacking. The largest experience to date comes from Campisi and colleagues in Italy.90,91 This group treated 665 patients with obstructive lymphedema using microsurgical lymphovenous anastomoses and achieved subjective improvement in 87% of their patients. In the 446 patients available for long-term follow-up, the authors observed volume reduction in 69% and discontinuation of conservative measures in 85%. This is a remarkable result that has not yet been duplicated elsewhere. The authors concluded that microsurgical reconstruction early in the course of lymphedema is more effective because the intrinsic contractility of the lymphatic vessel is maintained and the chance of normalizing the lymph circulation is better before significant chronic inflammatory changes develop in the subcutaneous tissue. Koshima and coworkers from Japan reported significant improvement of lymphedema at a mean of 3.3 years after lymphovenous anastomoses in 8 of 13 patients.92 However, Vignes and associates failed to confirm the therapeutic benefit of lymphovenous anastomoses in a group of 13 patients (10 with primary and 3 with secondary lymphedema).93 Global assessment of clinical outcome was very good or good in five patients and intermediate in another five, but the operation failed to improve the volume of lower limbs or to reduce the frequency of erysipelas. Variations in performing lymphovenous anastomoses have been described. Mihara and colleagues recommended anastomosis of both the proximal and the distal ends of a transected lymph vessel with a vein or with two tributaries of an adjacent vein, allowing both the anterograde and the retrograde flow of lymph.94 A follow-up study of 237 lymphaticovenous side-to-end anastomoses, performed in 57 patients with lymphedema, showed at least one patent anastomosis in 34 patients by use of indocyanine green fluorescence lymphography after a mean follow-up period of 14 months. In 23 patients, no patent anastomosis was seen. There was no significant difference in limb volume reduction between the two groups.95 In one surgical technique, the so-called lymphaticovenous implantation, the lymph vessel is inserted into the lumen of a bigger vein together with the surrounding fat, including the lymphatic capillaries.96 The same procedure is also used to improve lymphatic drainage of the dermal lymphatics.87 Large series of patients treated for secondary and primary lymphedema by the supermicrosurgical lymphovenous anastomosis and the lymphaticovenous implantation were published by Demirtas and colleagues.97,98 In 40 patients with unilateral primary lymphedema, a mean reduction of 56% of the surplus of volume was seen after a follow-up period of 13.3 months. Whereas only 17% of the patients had a complex physical therapy before surgery, all patients of stage 4 and most patients of stage 3 (according to Campisi’s classification) used custom-made pressure garments after surgery. In 20 patients with unilateral secondary lymphedema, a mean reduction of 60% was seen after a mean follow-up period of 12.8 months; 50% of the patients did not receive complex

1037

1038

SECTION 11  Lymphedema

to preserve joint integrity. Redundant skin, about 4 to 10 cm wide, is then resected; suction catheters are placed, and the wound is closed in a single layer with 4-0 nylon. In suturing around the ankle and knee, portions of the deep fascia are included in the suture to fix the skin flaps deeply and to ensure contour. The extremity is immobilized with a posterior splint and elevated. The patient is kept on bed rest for 9 days and mobilized afterward wearing tightly wrapped elastic bandages to prevent seroma formation and to promote optimal healing and contour. This regimen is continued for 3 weeks postoperatively. The second stage, consisting of lateral excision, is performed 3 months later in a similar fashion. During lateral excision, the sensory branches of the peroneal nerve are identified and carefully preserved. Results.  Staged excision underneath skin flaps offers the most reliable improvement of all debulking operations while minimizing the likelihood of postoperative complications. Miller and colleagues reported the long-term results in 38 patients with chronic lymphedema after staged subcutaneous excisions performed beneath skin flaps.103 Thirty patients had marked and durable reduction in extremity size with improved function. Episodes of cellulitis were reduced or eliminated. No difference in long-term results was seen in patients with primary versus secondary lymphedema. This series had a remarkably low rate of skin complications (four patients) and a low rate of late disease progression (six patients). The clinical benefit of excisional operations is directly related to the amount of subcutaneous tissue removed. Patients are susceptible to recurrences and should continue to wear elastic compression stockings. Although good volume reduction is achievable with most of these procedures, prolonged hospitalization, poor wound healing, long surgical scars, sensory nerve loss, and residual edema of the foot and ankle can be significant problems. Because of these potential complications, these procedures are generally offered only to patients with significant, disabling lymphedema that is not responding to medical measures. Staged skin and subcutaneous excision beneath skin flaps appears to provide the most durable result with the lowest rate of complications.

PRIMARY CHYLOUS DISORDERS Chylous disorders are characterized by an accumulation of chyle in abnormal areas of the body. Chylous ascites, chylothorax, and chylocutaneous fistula may be caused by a malignant tumor (most frequently lymphoma) or by trauma to the mesenteric lymphatics or the thoracic duct, which may also occur during vascular surgical procedures. Primary chylous disorders are usually caused by congenital lymphangiectasia or megalymphatics, which in some patients are associated with obstruction of the thoracic duct. In patients with lymphangiectasia and lymphatic valvular incompetence, chyle may reflux into the lower extremities, perineum, or genitalia.99-106 Depending on the site of the dilated lymphatics and the site of the chylous leak, these patients may also have

protein-losing enteropathy, chylous ascites, chylothorax, chylopericardium, or reflux of chyle into the lungs and tracheobronchial tree.99-116 The mean age of 35 patients (15 male, 20 female) treated surgically for primary chylous disorders at the Mayo Clinic was 29 years and ranged from 1 day to 81 years.108 The patients presented with lower limb edema (54%), dyspnea (49%), scrotal or labial edema (43%), and abdominal distention (37%). The cause was primary lymphangiectasia in 66%, yellow nail syndrome in 11%, lymphangioleiomyomatosis in 9%, and other disorders in 18%.108 Medical treatment is aimed at decreasing the production of chyle by means of a medium-chain triglyceride diet or occasionally by parenteral nutrition. Repletion of proteins and calcium lost with chyle is as important as strengthening of the body’s defense mechanism because lymphocytes and important immunoglobulins are also wasted in these patients. Only surgical treatment can provide long-term improvement and occasionally cure by ligation of the incompetent retroperitoneal lymph vessels and oversewing of the site of the lymph leak. Attempts to reconstruct the obstructed thoracic duct by the creation of thoracic duct–azygos vein or internal jugular vein anastomoses have been reported.106,117-119

Lower Extremity and Genitalia Many patients with lymphangiectasia and reflux of chyle have unilateral lower extremity lymphedema. The main discomfort for these patients, however, is the intermittent or continuous discharge of chyle from cutaneous vesicles in the lower extremity or the genitalia. The first five patients known to have suffered from this rare condition were described in 1949 by Servelle and Deysson.110 The preoperative evaluation of patients with chylous reflux into the lower extremity or genitalia should include lymphoscintigraphy (Fig. 68-11A). However, contrast lymphangiography is the definitive test to confirm the diagnosis and to localize the dilated retroperitoneal lymphatics and, frequently, the site of lymph leak. MRI with contrast enhancement may provide more precise information in the future.

Surgical Treatment The only effective technique to control the reflux of chyle and its drainage through skin vesicles in the perineum, labia, scrotum, or lower extremity is radical excision and ligation of the incompetent retroperitoneal lymph vessels. Gloviczki and coworkers used the technique of Servelle and performed the entire reflux operation in two stages through flank incisions by the retroperitoneal approach.108 Four hours before the procedure, the patient ingested 60 g of butter and 8 oz of whipped cream. The fatty meal allowed ready visualization of the retroperitoneal lymphatics during exploration (Fig. 68-11B to D). Ligation of the lymph vessels should be done with the utmost care to avoid tearing or avulsion of the lymphatics, resulting in residual leaks or rupture. In recent years, sclerotherapy of the dilated lymphatics has been added to ligation to increase the efficacy of the operation. Tetracycline solution, 500 to 1000 mg diluted in 20 mL of normal saline,

CHAPTER 68  Lymphedema: Surgical Treatment



SECTION 11 LYMPHEDEMA

A

1039

B

C

D

Figure 68-11  A, Right lower extremity lymphoscintigram in a 16-year-old girl with lymphangiectasia and severe reflux of chyle into the genitalia and left lower extremity. Injection of the isotope into the right foot reveals reflux into the pelvis at 3 hours and into the left lower extremity at 4 hours. B, Intraoperative photograph reveals dilated, incompetent retroperitoneal lymphatics in the left iliac fossa containing chyle. C, Radical excision and ligation of the lymph vessels were performed. In addition, two lymphovenous anastomoses were created between two dilated lymphatics and two lumbar veins. D, Postoperative lymphoscintigram reveals no evidence of reflux at 4 hours. The patient has no significant reflux 4 years after surgery. (From Gloviczki P, et al: Noninvasive evaluation of the swollen extremity: experiences with 190 lymphoscintigraphic examinations. J Vasc Surg 9:683, 1989.)

is injected directly into the dilated retroperitoneal lymph vessels to provoke obstructive lymphangitis. As reported by Molitch and associates, percutaneous CTor MRI-guided cannulation of these dilated lymphatics may be possible, and sclerotherapy to decrease reflux can be performed repeatedly if necessary.112 Lymphovenous anastomoses with the dilated lymphatics can also be performed. Reflux of blood into the dilated and incompetent lymphatics can occur, however. A competent valve on the venous side completely avoids reflux and increases the chance of successful lymphatic drainage.113,117

Results The largest group of patients studied was reported by Servelle, who operated on 55 patients with chylous reflux into the lower extremity or genitalia and reported a durable benefit in most patients.105 In Kinmonth and Cox’s series of 19 patients who underwent ligation of the retroperitoneal lymphatics

for chylous reflux to the limbs and genitalia, permanent cure was achieved in 5 patients, and alleviation of symptoms— frequently after several operations—occurred in 12 patients.106 No improvement or failure was noted in only two cases. Noel and coworkers reviewed the results of 35 patients with primary chylous disorders treated during a 24-year period.113 Twentyone patients (60%) underwent 27 surgical procedures. Nineteen procedures were performed for chylous ascites or reflux; 10 of these patients (53%) underwent resection of retroperitoneal lymphatics with or without sclerotherapy, 4 (21%) had lymphovenous anastomoses or saphenous vein interposition grafts, 4 (21%) had peritoneovenous shunts, and 1 (5%) had a hysterectomy for periuterine lymphangiectasia. All patients improved initially, but 29% had a recurrence of symptoms at a mean of 25 months (range, 1 to 43 months). Three patients with leg swelling had postoperative lymphoscintigraphy confirming improved lymphatic transport and diminished reflux.

1040

SECTION 11  Lymphedema

Chylous Ascites Chylous ascites usually results from intraperitoneal rupture of the mesenteric or retroperitoneal lymphatics or from exudation of chyle into the peritoneal cavity.113 The evaluation of such patients should include CT or MRI to exclude abdominal malignant disease. The diagnosis of lymphangiectasia is confirmed by bipedal contrast lymphangiography. Paracentesis is both diagnostic and therapeutic.

Surgical Treatment If conservative measures fail and ascites returns, abdominal exploration should be performed after a fatty meal, as described previously. If chylous ascites is due to primary lymphangiectasia, abdominal exploration may reveal ruptured lymphatics, which can be oversewn. Some patients develop large chylous cysts, which should be excised (see Fig. 68-11). If the condition is associated with protein-losing enteropathy and the disease is localized to a segment of the small bowel, the bowel segment should be resected. The outcome of the operation is usually good if a well-defined abdominal fistula is found. However, if the mesenteric lymphatic trunks are fibrosed, aplastic, or hypoplastic and exudation of chyle is the main source of the ascites, the prognosis is poor, and recurrence is frequent.

Results Browse and coworkers treated 45 patients with chylous ascites.107 The age at presentation ranged from 1 to 80 years (median, 12 years). Thirty-five patients had an abnormality of the lymphatics (primary chylous ascites); in the remaining 10, ascites was secondary to other conditions, principally non-Hodgkin’s lymphoma (6 patients). Surgery

A

B

(fistula closure, bowel resection, or insertion of a peritoneovenous shunt) was performed in 30 patients. Closure of a retroperitoneal or mesenteric fistula, when present, was the most successful operation, curing 7 of 12 patients. In those patients who develop chylous ascites from iatrogenic trauma, frequently after aortic reconstructions, a short period of conservative management is justified. If chylous ascites reaccumulates, reoperation with ligation of the fistula is the most effective treatment. Campisi et al reported on 12 patients with a mean follow-up of 5 years; there was 1 death after 1 year, 3 mild recurrences, and 1 major recurrence that was treated.120 Results with peritoneovenous shunts have been mixed; patency is usually judged by the recurrence of ascites. In Browse and coworkers’ experience with nine peritoneovenous shunt placements, all occluded within 3 to 6 months after insertion.107 Noel and colleagues used the LeVeen shunt with good results, although one of four patients developed symptomatic superior vena cava syndrome owing to thrombosis around the shunt.113

Chylothorax As with chylous ascites, the most frequent cause of chylothorax is trauma or malignant disease.118 Primary lymphatic disorders that cause chylothorax include lymphangiectasia with or without thoracic duct obstruction. However, chylothorax may also result from chylous ascites passing through the diaphragm. In these patients, the chylothorax is cured when the chylous ascites is controlled. Preoperative lymphangiography should be performed in these patients because it may localize the site of the chylous fistula or document occlusion of the thoracic duct (Fig. 68-12). Thoracentesis usually is not

Figure 68-12  A, Right chylothorax in a 63-year-old woman. B, Bipedal lymphangiography confirms thoracic duct obstruction at the base of the neck. Note contrast medium in the supraclavicular and left axillary lymphatics (arrows).

CHAPTER 68  Lymphedema: Surgical Treatment



1041

Carotid artery Vagus nerve Vertebral vein Left subclavian a. Thoracic

duct termination

Cisterna chyli

Left subclavian vein

Figure 68-13  Cervical and thoracoabdominal anatomy of the thoracic duct.

A

C

B

Figure 68-14  A and B, Thoracic duct–azygos vein anastomosis performed through a right posterolateral thoracotomy in an endto-end fashion with interrupted 8-0 polypropylene (Prolene) sutures. C, Chest radiograph 2 years later confirms the absence of chylothorax.

SECTION 11 LYMPHEDEMA

Thoracic duct

1042

SECTION 11  Lymphedema

effective in curing the disease, and chyle that leaks from the thoracic duct or one of the large intercostal, mediastinal, or diaphragmatic collaterals reaccumulates. Injection of tetracycline is frequently ineffective because it is diluted by the leaking chyle.

Surgical Treatment The best treatment of chylothorax is surgical pleurodesis with excision of the parietal pleura and prolonged pleural suction.114,118 After the patient has eaten a fatty meal, thoracotomy or video-assisted thoracoscopy is performed, and the leaking lymphatics are oversewn or clipped. This is followed by pleurodesis. In the Mayo Clinic series, eight procedures for chylothorax consisted of thoracotomy with decortication and pleurodesis (four patients), ligation of the thoracic duct (three patients), and resection of a thoracic duct cyst (one patient), with excellent early results in all patients.113

Thoracic Duct Reconstruction If occlusion of the cervical or upper thoracic duct (Fig. 68-13) is the cause of lymphangiectasia and reflux of chyle into the pleural or peritoneal cavity, thoracic duct–azygos vein anastomosis can be attempted to reconstruct the duct and to improve lymphatic transport. Preoperative imaging of the duct with contrast pedal lymphangiography is important because occlusion of the entire duct precludes anastomoses. The operation is performed through a right posterolateral thoracotomy, and the anastomosis between the lower thoracic duct and the azygos vein is performed in an end-to-end fashion with 8-0 or 10-0 nonabsorbable interrupted sutures and magnification with loupes or an operating microscope. Only a few patients undergoing this operation have been described.106,118 Both patients operated on by Gloviczki’s group121 had good immediate patency, and excellent flow of chyle was observed through the anastomosis intraoperatively (Fig. 68-14). Although neither had postoperative contrast lymphangiography, recurrent chylothorax (the main indication for the procedure) ultimately resolved in both. Browse et al reported two successes in three patients who underwent thoracic duct reconstruction.118 Kinmonth et al performed this procedure in two patients and concluded that the anastomosis alone is not effective for decompressing

the thoracic duct; ligation of the abnormal mediastinal lymphatics and oversewing of the sites of lymphatic leak are also necessary.106

Other Treatment Options A prospective study from Cope and colleagues described 11 patients with primary and secondary chylothorax treated with percutaneous catheterization and embolization of the thoracic duct; their 45% technical success rate suggests a role for percutaneous intervention.114 Silk and associates115 and, more recently, Engum and colleagues116 reported on the use of pleuroperitoneal shunts in children, with good results.

SELECTED KEY REFERENCES Baumeister RGH, Frick A: The microsurgical lymph vessel transplantation. Handchir Mikrochir Plast Chir 35:201, 2003. Survey of technique and results in lymphatic grafting. Brorson H: Liposuction of arm lymphoedema. Handchir Mikrochir Plast Chir 35:225, 2003. Survey of technique and results in liposuction treatment of lymphedema. Campisi C, Boccardo F, Tacchella M: Reconstructive microsurgery of lymph vessels: the personal method of lymphatic-venous-lymphatic (LVL) interpositioned grafted shunt. Microsurgery 16:161, 1995. Survey of lymphatic-venous-lymphatic shunts. Miller TA, Wyatt LE, Rudkin GH: Staged skin and subcutaneous excision for lymphedema: a favorable report of long-term results. Plast Reconstr Surg 102:1486; discussion 1499, 1998. Survey of technique and results in staged excisions for lymphedema. Noel AA, Gloviczki P, Bender CE, Whitley D, Stanson AW, Deschamps C: Treatment of symptomatic primary chylous disorders. J Vasc Surg 34:785, 2001. Survey of lymphedema in chylous disorders. O’Brien BM, Sykes PJ, Threlfall GN, Browning FC: Microlymphaticovenous anastomosis for obstructive lymphedema. Plast Reconstr Surg 60:197, 1977. Survey of technique and results in lymphovenous anastomosis. Weiss M, Baumeister RGH, Hahn K: Post-therapeutic lymphedema: scintigraphy before and after autologous lymph vessel transplantation—8 years of long-term follow-up. Clin Nucl Med 27:788, 2002. Long-term controlled study of lymphatic grafting. Weissleder H, Schuchhardt C: Lymphedema: diagnosis and therapy, Essen, 2008, Viavital. Concise information on lymphedema.

The reference list can be found on the companion Expert Consult website at www.expertconsult.com.

CHAPTER 68  Lymphedema: Surgical Treatment 1042.e1



REFERENCES

SECTION 11 LYMPHEDEMA

1. Foeldi M, et al: Foeldi’s textbook of lymphology, München, 2006, Elsevier Urban & Fischer. 2. Charles RH: Elephantiasis scroti. In Latham A, English TC, editors: A system of treatment, vol 3, London, 1912, Churchill, p 504. 3. Deutschmann W, et al: Long-term results in the surgical treatment of lymphedema. Chir Plast 5:109, 1980. 4. Pierer H: Die radikale Resektion beim chronischen Lymphödem. Langenbecks Arch Chir 325:113, 1969. 5. Barinka L: Our experience with the treatment of lymphedema of the lower limb. Acta Chir Plast 9:218, 1967. 6. Barinka L: Employment of dermatome-super in the treatment of lower limb lymphedema. Acta Chir Plast 10:223, 1968. 7. Barinka L: The technique of the excisional operation of the lower extremity using a new instrument. In Clodius L, editor: Lymphedema, Stuttgart, 1977, Thieme. 8. Cobbett J: Small vessel anastomoses. Br J Plast Surg 20:16, 1967. 9. Clodius L: Conservative management of postmastectomy lymphedema. Ther Ggw 118:229, 1979. 10. Mowlen R: The treatment of lymphedema. Br J Plast Surg 1:48, 1948. 11. Vediayev JP, et al: Simplified method for elaboration of tissues excised for replantation during radical operations of elephantiasis. Acta Chir Plast 20:4, 1978. 12. Auchincloss H: New operation for elephantiasis. Puerto Rico J Publ Health Trop Med 6:1949, 1930. 13. Fontaine R, et al: Die operative Therapie des Lymphödems. Langenbecks Arch Chir 325:89, 1969. 14. Homans J: The treatment of elephantiasis of the legs. N Engl J Med 215:1099, 1936. 15. Servelle M: Chirurgie der Elephantiasis. In Foeldi M, editor: Erkrankungen des Lymphsystems, Baden-Baden, 1971, Witzstrock. 16. Sistrunk WE: Further experiences with the Kondoleon operation for elephantiasis. JAMA 71:800, 1918. 17. Sistrunk WE: Certain modifications of the Kondoleon-operation for elephantiasis. Ann Surg 85:185, 1927. 18. Illouz YG: Body sculpturing by lipoplasty, Edinburgh, 1989, Churchill Livingstone. 19. Brorson H, et al: Complete reduction of lymphoedema of the arm by liposuction after breast cancer. Scand J Plast Reconstr Surg Hand Surg 31:137, 1997. 20. Lanz O: Eröffnung neuer Abflusswege bei Stauung im Bauch und unteren Extremitäten. Zentralbl Chir 38:153, 1911. 21. Kondoleon E: Die chirurgische Behandlung der elefantiastischen Ödeme durch eine neue Methode der Lymphableitung. Munch Med Wochenschr 59:2726, 1912. 22. Kondoleon E: Operative Behandlung der elefantiastischen Ödeme. Zentralbl Chir 30:1022, 1912. 23. Thompson N: Surgical treatment of chronic lymphedema in lower limb. BMJ 2:1566, 1962. 24. Thompson N: Surgical treatment of primary and secondary lymphoedema of the extremities by lymphatic transposition. Proc R Soc Med 38:1026, 1965. 25. Thompson N: Buried dermal flap operations for chronic lymphoedema of the extremities. Surg Clin North Am 47:245, 1967. 26. Thompson N: The late results of operative treatment of chronic lymphedema of the extremities using the buried dermis flap procedure. J Cardiovasc Surg 92:93, 1968. 27. Thompson N: Buried dermal flap operation for chronic lymphedema of the extremities. Plast Reconstr Surg 45:541, 1970. 28. Bohmert H, et al: Die operative Therapie des Armlymphödems. In Ergebnisse der Angiologie, Bd 6, Stuttgart, 1973, Thieme. 29. Bohmert H, et al: Zur Behandlung des Lymphödems mit einer modifizierten Methode nach Thompson. Ther Ggw 113:842, 1974. 30. Bunchmann HH, II, et al: Long term results with the use of the buried skin flap in lymphedemas. In Clodius L, editor: Lymphedema, Stuttgart, 1977, Thieme.

31. Grenzmann M, et al: Die lymphovenösen Anastomosen. Rofo 109:564, 1968. 32. Gillies HD, et al: Treatment of lymphoedema by plastic operation. BMJ 1:96, 1935. 33. Mukherji M: Surgical treatment of filarial elephantiasis of legs by the lymph-bearing flap. In Clodius L, editor: Lymphedema, Stuttgart, 1977, Thieme. 34. Smith JW, et al: Selection of appropriate surgical procedures in lymphedema. Introduction of the hinged pedicle. Plast Reconstr Surg 30:10, 1962. 35. Wynn SA: Surgical approach to postmastectomy lymphoedematous extremity. Arch Surg 70:418, 1955. 36. Goldsmith HS, et al: Relief of chronic lymphedema by omental transposition. Am Surg 166:573, 1967. 37. Goldsmith HS: Long term evaluation of omental transposition for chronic lymphedema. Ann Surg 180:847, 1974. 38. Kinmonth JB, et al: Relief of lymph obstruction by use of mesentery and ileum. Br J Surg 65:829, 1978. 39. Holle J, et al: Überbrückung eines Lymphgefäss­defektes mittels Veneninterposition—eine experimentelle Studie Vortr a.d. 2. Jahrestagung der deutschsprachigen Arbeitsgemeinschaft für Mikrochirurgie der peripheren Nerven und Gefaesse, Hamburg, 1979. 40. Mandl H, et al: Experimentelle Untersuchungen zur Mikrochirurgie der Lymphgefässe [Abstr XVIII]. Wissenschaftliche Tagung der GV-SOLAS, Lausanne, 1980, pp 28.5–30.5. 41. Campisi C, et al: Reconstructive microsurgery of lymph vessels: the personal method of lymphatic-venous-lymphatic (LVL) interpositional grafted shunt. Microsurgery 16:161, 1995. 42. Laine JB, et al: Experimental lymphatico-venous anastomosis. Surg Forum 14:111, 1963. 43. Nielubowicz J, et al: Surgical lymphovenous shunts for decompression of secondary lymphoedema. J Cardiovasc Surg 7(Suppl 2):262–267, 1966. 44. Rivero OR, et al: Experimental lympho-venous communications. Br J Plast Surg 20:124, 1976. 45. Allen PJ, et al: The use of free lymph-node grafts as a method of producing peripheral lymphovenous shunts. Br J Surg 55:385, 1968. 46. Degni M: New technique of lymphatic-venous anastomosis for the treatment of lymphedema. J Cardiovasc Surg (Turin) 19:577, 1978. 47. Fox U, et al: Surgical treatment of chronic oedema of the leg. Proc R Soc Med 43:1054, 1950. 48. O’Brien BM: Microlymphaticovenous surgery for obstructive lymphedema. Aust N Z J Surg 47:284, 1977. 49. O’Brien BM, et al: Role of microlymphaticovenous surgery in obstructive lymphedema. Clin Plast Surg 5:293, 1978. 50. Campisi C, et al: Microsurgery for treatment of peripheral lymphedema: long-term outcome and future perspectives. Microsurgery 27:333, 2007. 51. Calnan, JS, et al: The natural history of lymph node to vein anastomosis in the dog. Br J Plast Surg 20:134, 1967. 52. Calnan JS, et al: Attempts to create anastomoses between lymphatics and veins at peripheral sites. Br J Surg 55:385, 1968. 53. Calnan JS, et al: The late results of lymph node to vein anastomosis in the dog. J Cardiovasc Surg (spec issue), 1968. 54. Firica A, et al: Alleviation of experimental lymphedema by lymphovenous anastomosis in dogs. Am Surg 37:409, 1972. 55. Yamada Y: The study on lymphatic venous anastomosis in lymphoedema. Nagoya J Med Sci 32:1, 1969. 56. Gloviczki P, et al: The natural history of microsurgical lymphovenous anastomoses: an experimental study. J Vasc Surg 4:148, 1986. 57. Danese, G, et al: Postmastectomy lymphedema. Surg Gynecol Obstet 129:797, 1965. 58. Danese C, et al: A model of chronic postsurgical lymphedema in dog’s limbs. Surgery 64:814, 1968. 59. Trevidic P, et al: Free axillary lymph node transfer. In Cluzan RV, editor: Progress in lymphology, vol XIII, Paris, 1992, Excerpta Medica.

1042.e2 SECTION 11  Lymphedema 60. Becker C, et al: Postmastectomy lymphedema long-term results following microsurgical lymph node transplantation. Ann Surg 243:313, 2006. 61. Trevidic P, et al: Limb radionuclide lymphoscintigraphy prior and after a lymphatic bypass using an axillary flap. Lymphology 31(Suppl):605, 1998. 62. Li S, et al: Microvascular transfer of a “lymphatic-bearing” flap in the treatment of obstructive lymphedema. Plast Reconstr Surg 121:150e, 2008. 63. Saumweber DM, et al: Experiences in experimental reconstructive microsurgery of lymphatics. In Partsch H, editor: Progress in lymphology, vol XI, Amsterdam, 1988, Excerpta Medica. 64. Yuwono HS, et al: Comparison of lymphatic and venous interpositional autografts in experimental microsurgery of the canine lymphatics. Plast Reconstr Surg 85:752, 1990. 65. Acland RD, et al: Experimental lymphatico-lymphatic anastomoses, abstract book VII, Florence, 1979, International Congress of Lymphology. 66. Cordeiro AK, et al: Transplantations of lymphatic ducts, preliminary and experimental report, abstract book VII, Florence, 1979, International Congress of Lymphology. 67. Baumeister RGH, et al: Transplantation of lymph vessels on rats as well as first therapeutic application on the experimental lymphedema of the dog. Eur Surg Res 12(Suppl 21):7, 1980. 68. Baumeister RGH, et al: Experimental basis and first application of clinical lymph vessel transplantation of secondary lymphedema. World J Surg 5:401, 1981. 69. Baumeister RGH, et al: Treatment of lymphedema by microsurgical lymphatic grafting: what is proved? Plast Reconstr Surg 85:64, 1990. 70. Baumeister RGH, et al: 10 years experience with autogenous microsurgical lymph vessel transplantation. Eur J Lymphol 6:62, 1991. 71. Baumeister RGH, et al: The microsurgical lymph vessel transplantation. Handchir Mikrochir Plast Chir 35:202, 2003. 72. Baumeister RGH, et al: Homologous and autologous experimental lymph vessel transplantation: initial experience. Int J Microsurg 3:19, 1981. 73. Kinmonth JB: The lymphatics, London, 1972, Edward Arnold. 74. Partsch H: Practical aspects of indirect lymphography and lymphoscintigraphy. Lymphat Res Biol 1:71, 2003. 75. Lohrmann C, et al: High-resolution MR-lymphangiography in patients with primary and secondary lymphedema. AJR Am J Roentgenol 187:556, 2006. 76. Kleinhans E, et al: Evaluation of transport kinetics in lymphoscintigraphy: follow-up study in patients with transplanted lymphatic vessels. Eur J Nucl Med 10:349, 1985. 77. Weiss M, et al: Planning and monitoring of autologous lymph vessel transplantation by means of nuclear medicine lymphography. Handchir Mikrochir Plast Chir 35:210, 2003. 78. Weissleder H, et al: Examination methods in lymphedema, Essen, 2008, Viavital. 79. Kubik S: Zur klinischen Anatomie des Lymphsystems. Verh Anat Ges 69:109, 1975. 80. Baumeister RGH, et al: Microsurgical lymphatic grafting: first demonstration of patent grafts by indirect lymphography and long term follow-up studies. Lymphology 27(Suppl):787, 1994. 81. Weiss M, et al: Posttherapeutic lymphedema: scintigraphy before and after autologous lymph vessel transplantation—8 years long-term follow up. Clin Nucl Med 27:788, 2002. 82. Springer S, et al: Changes in quality of life of patients with lymphedema after lymphatic vessel transplantation. Lymphology 44:65–71, 2011. 83. Ho LCY, et al: Microlymphatic bypass in the treatment of obstructive lymphoedema of the arm: case report of a new technique. Br J Plast Surg 36:350, 1983. 84. Mandl H: Experimentelle Untersuchungen zur mikrochirurgischen Rekonstruktion von Lymphgefäßdefekten. Plast Chir 5:70, 1981. 85. Danese C, et al: Experimental anastomosis of lymphatics. Arch Surg 84:24, 1962.

86. Cambria RA, et al: Noninvasive evaluation of the lymphatic system with lymphoscintigraphy: a prospective, semiquantitative analysis in 386 extremities. J Vasc Surg 18:773, 1993. 87. Furukawa H, et al: Microsurgical lymphaticovenous implantation targeting dermal lymphatic backflow using indocyanine green fluorescence lymphography in the treatment of postmastectomy lymphedema. Plast Reconstr Surg 127:1804–1811, 2011. 88. Gloviczki P, et al: Microsurgical lymphovenous anastomosis for treatment of lymphedema: a critical review. J Vasc Surg 7:647, 1988. 89. O’Brien BM, et al: Long-term results after microlymphaticovenous anastomoses for the treatment of obstructive lymphedema. Plast Reconstr Surg 85:562, 1990. 90. Campisi C, et al: Long-term results after lymphatic-venous anastomoses for the treatment of obstructive lymphedema. Microsurgery 21:135, 2001. 91. Campisi C, et al: Lymphedema and microsurgery. Microsurgery 22:74, 2002. 92. Koshima I, et al: Long-term follow-up after lymphaticovenular anastomosis for lymphedema in the leg. J Reconstr Microsurg 19:209, 2003. 93. Vignes S, et al: Quantitative evaluation and qualitative results of surgical lymphovenous anastomosis in lower limb lymphedema [in French]. J Mal Vasc 28:30, 2003. 94. Mihara M, et al: Antegrade and retrograde lymphatico-venous anastomosis for cancer-related lymphedema with lymphatic valve dysfunction and lymphatic varix. Microsurgery 32:580–584, 2012. 95. Maegawa J, et al: Outcomes of lymphaticovenous side-to-end anastomosis in peripheral lymphedema. J Vasc Surg 55:753–760, 2012. 96. Yamamoto Y, et al: Microsurgical lymphaticovenous implantation for the treatment of chronic lymphedema. Plast Reconstr Surg 101:157– 161, 1998. 97. Demirtas Y, et al: Supermicrosurgical lymphaticovenular anastomosis and lymphaticovenous implantation for treatment of unilateral lower extremity lymphedema. Microsurgery 29:609–618, 2009. 98. Demirtas Y, et al: Comparison of primary and secondary lowerextremity lymphedema treated with supermicrosurgical lymphaticovenous anastomosis and lymphaticovenous implantation. J Reconstr Microsurg 26:137–143, 2010. 99. Brorson H, et al: Liposuction combined with controlled compression therapy reduces arm lymphedema more effectively than controlled compression therapy alone. Plast Reconstr Surg 102:1058, 1998. 100. Heffel DF, et al: Excisional operations for chronic lymphedema. In Rutherford RB, editor: Vascular surgery, ed 5, Philadelphia, 2000, WB Saunders, pp 2153–2159. 101. Miller TA: Surgical management of lymphedema of the extremity. Plast Reconstr Surg 56:633, 1975. 102. Miller TA: Surgical approach to lymphedema of the arm after mastectomy. Am J Surg 148:152, 1984. 103. Miller TA, et al: Staged skin and subcutaneous excision for lymphedema: a favorable report of long-term results. Plast Reconstr Surg 102:1486; discussion 1499, 1998. 104. Kinmonth JB: Chylous diseases and syndromes, including references to tropical elephantiasis. In Kinmonth JB, editor: The lymphatics: surgery, lymphography and diseases of the chyle and lymph systems, ed 2, London, 1982, Edward Arnold, pp 221–268. 105. Servelle M: Congenital malformation of the lymphatics of the small intestine. J Cardiovasc Surg 32:159, 1991. 106. Kinmonth JB, et al: Protein losing enteropathy in lymphedema: surgical investigation and treatment. J Cardiovasc Surg 16:111, 1975. 107. Browse NL, et al: Aetiology and treatment of chylous ascites. Br J Surg 79:1145, 1992. 108. Gloviczki P, et al: The surgical treatment of lymphedema caused by chylous reflux. In Bartos V, Davidson JW, editors: Advances in lymphology, Proceedings of the 8th International Congress of Lymphology, Montreal, 1981, Prague, 1982, Czechoslovak Medical Press, pp 502–507. 109. Sanders JS, et al: Chyloptysis (chylous sputum) due to thoracic lymphangiectasia with successful surgical correction. Arch Intern Med 148:1465, 1988.

110. Servelle M, et al: Reflux du chyle dans les lymphatiques jambiers. Arch Mal Coeur 12:1181, 1949. 111. Browse NL: The surgery of lymphedema. In Veith FJ, editor: Current critical problems in vascular surgery, St. Louis, 1989, Quality Medical Publishing, pp 408–409. 112. Molitch HI, et al: Percutaneous sclerotherapy of lymphangiomas. Radiology 194:343, 1995. 113. Noel AA, et al: Treatment of symptomatic primary chylous disorders. J Vasc Surg 34:785, 2001. 114. Cope C, et al: Management of chylothorax by percutaneous catheterization and embolization of the thoracic duct: prospective trial. J Vasc Interv Radiol 10:1248, 1999. 115. Silk YN, et al: Chylous ascites and lymphocyst management by peritoneovenous shunt. Surgery 110:561, 1991.

CHAPTER 68  Lymphedema: Surgical Treatment 1042.e3 116. Engum SA, et al: The use of pleuroperitoneal shunts in the management of persistent chylothorax in infants. J Pediatr Surg 34:286, 1999. 117. Burnand GK, et al: Principles of surgical treatment. In Browse N, Burnand GK, Mortimer PS, editors: Diseases of the lymphatics, London, 2003, Arnold, pp 179–204. 118. Browse NL, et al: Management of chylothorax. Br J Surg 84:1711, 1997. 119. Melduni RM, et al: Reconstruction of occluded thoracic duct for treatment of chylopericardium: a novel surgical therapy. J Vasc Surg 48:1600–1602, 2008. 120. Campisi C, et al: Diagnosis and management of primary chylous ascites. J Vasc Surg 43:1244, 2006. 121. Gloviczki P, et al: Surgical treatment of chronic lymphedema and primary chylous disorders. In Rutherford RB, editor: Vascular surgery, ed 6, 2005, pp 2428–2445. SECTION 11 LYMPHEDEMA

CHAPTER 69 

Classification and Natural History of Vascular Anomalies CAROLYN R. ROGERS  /  JOHN B. MULLIKEN

Based on a chapter in the seventh edition by Byung-Boong Lee and Leonel Villavicencio

V

ascular surgery matured as a specialty of general surgery during the twentieth century while the field of vascular anomalies remained obscured by a cloud of confusing nomenclature. This haze of bewildering nosology lifted during the last quarter of that century to reveal a truly interdisciplinary field that overlaps many specialties, including vascular surgery. Traditionally, vascular surgeons manage disorders of anatomically named arteries and veins. Only a few vascular surgeons, most of them European, have focused part of their practice on malformations distal to the main vascular trunks, particularly those in the extremities. Noteworthy in this regard are the names Malan, Schobinger, Servelle, Azzolini, Belov, Loose, and Matassi. In the mid-1970s, several of these vascular surgeons joined like-minded colleagues from other specialties to initiate a workshop for the study of vascular anomalies—this grew to become the International Society for the Study of Vascular Anomalies (ISSVA). The early gatherings of this organization were punctuated by heated discussions about terminology. Finally, there was a consensus at the 1996 meeting in Rome, and the ISSVA classification was accepted by the membership.1

radiography, and electron microscopy. This investigation delineated two major categories of vascular anomalies: tumors, which exhibit endothelial hyperplasia; and malformations, which have normal endothelial turnover unless disturbed. This binary “biologic” system became the foundation of the ISSVA classification (Table 69-1). Vascular malformations are structural anomalies, inborn errors of vascular morphogenesis. A single type of channel anomaly may predominate; however, often the malformed channels are combined forms. Vascular malformations are subcategorized on the basis of rheology and channel architecture as slow-flow (capillary, lymphatic, or venous), fast-flow (arterial), or combined. These malformations are more likely to be referred to vascular surgeons than are vascular tumors. The consultant must be wary because vascular tumors can masquerade as vascular malformations in various hues of pink, red, and blue. An estimated 54% of vascular malformations and 30% of vascular tumors in patients referred to one center between 1999 and 2010 were initially diagnosed incorrectly.3

NOSOLOGY

The spectrum of vascular tumors ranges from common infantile hemangiomas to uncommon lesions of borderline malignancy to rare malignant neoplasms (see Chapter 70). Unlike vascular malformations (and other vascular tumors), infantile hemangiomas are immune-positive for glucose transporter protein-1 (GLUT-1).4,5 Because most infantile hemangiomas arise in the head/neck region, vascular surgeons are unlikely to be asked for consultation. Vascular surgeons might be asked to opine on a rare variant of the common infantile tumor that has a predilection for the lower extremities called “reticular hemangioma.” This lesion is associated with intractable ulceration, anogenito-urinary-sacral anomalies, and sometimes cardiac overload. Reticular hemangioma of the lower limb can be confused with vascular malformations, such as capillary malformation, cutis marmorata telangiectatica congenita, and Parkes Weber syndrome.6 Congenital hemangiomas constitute a special category of vascular tumors

The earliest terminology for vascular anomalies was descriptive. Words such as “strawberry mark,” “port-wine stain,” and, “cherry angioma” referenced food because the mother was blamed for imprinting her unborn child. With the ascent of histopathology in the nineteenth century, all vascular anomalies were called “angiomas” or “lymphangiomas.” With increasing knowledge of cardiovascular embryology in the early twentieth century, vascular anomalies were envisioned as disorders of faulty development. Nevertheless, when put to the test of clinical usefulness, embryologic classifications failed to differentiate between vascular anomalies that regress and those that progress and, thus, offered little help in guiding management. A prospective study by Mulliken and Glowacki2 defined cellular features of vascular anomalies using histochemistry, 1044

VASCULAR TUMORS

CHAPTER 69  Classification and Natural History of Vascular Anomalies



Table 69-1

International Society for the Study of Vascular Anomalies (ISSVA) Classification of Vascular Anomalies

Vascular tumors

Vascular malformations

Infantile hemangioma Hemangioendotheliomas Angiosarcoma Miscellaneous Slow-flow: Capillary malformation (CM) Lymphatic malformation (LM) Venous malformation (VM) Fast-flow: Arterial malformation (AM) Combined

VASCULAR MALFORMATIONS Vascular malformations are, by definition, congenital, and most are obvious at birth (see Chapters 71 and 72). However, some vascular malformations are undetectable at birth and manifest in childhood, adolescence, or adulthood. Vascular malformations arise because of abnormal signaling processes regulating proliferation, differentiation, maturation, adhesion, and apoptosis of vascular cells, including endothelium, smooth muscle, and pericytes.11 Some are inherited in an autosomal dominant pattern, whereas others occur sporadically and are caused by somatic (postzygotic) mutations.

Slow-Flow Malformations Capillary Malformation Capillary malformation (CM) must be differentiated from the common fading macular stain naevus flammeus neonatorum (“angel’s kiss” or “stork bite”) frequently present in a newborn on the face and nuchal region. Capillary malformations (still often called “port-wine stains”) are red macular lesions seen at birth that persist throughout life. They are histopathologically characterized by thin-walled capillary- to venule-sized channels in the papillary and upper reticular dermis with deficient perivascular neural elements. Facial CM often darkens, thickens, and develops a cobblestone appearance in adulthood. In contrast, CM in the trunk and limbs deepens

in color with age but does not become nodular, although adjacent veins often become more prominent. Capillary malformations occur in association with several disorders; the best known is Sturge-Weber syndrome. Sturge-Weber Syndrome. Sturge-Weber syndrome is characterized by leptomeningeal vascular anomalies and facial CM, commonly manifesting as seizures and glaucoma. The clinical course is highly variable; some children have intractable seizures, behavioral issues, mental retardation, and recurrent stroke-like episodes. Soft tissue overgrowth in the area of facial CM occurs with age. More than half of patients with Sturge-Weber syndrome have noncontiguous, patchy CMs on the torso and extremities.12 Fifteen percent of patients with Sturge-Weber syndrome and extracranial staining have hypertrophy of an extremity.13 Varicose veins are seen in the stained areas in older patients with this disorder. Cutis Marmorata Telangiectatica Congenita. The vascular anomaly known as cutis marmorata telangiectatica congenita (CMTC) manifests in a neonate as serpiginous, reticulated bands of deep purple color with localized cutaneous atrophy and often ulceration. The lesions occur in a localized or regional pattern. The legs are most frequently involved; there may be subcutaneous hypoplasia or hypertrophy. The patient with leg involvement may be referred to a vascular surgeon because of concern about vascular occlusion in the limb. There have been rare case reports of hypoplasia of the iliac and femoral veins14 and of iliac arterial stenosis, including stenosis in the unaffected limb.15 Predictably, CMTC shows improvement during the first year of life that continues throughout childhood. Cutaneous atrophy and vascular staining persist, usually with venous ectasias in the involved limb. Macrocephaly–Capillary Malformation. Macrocephaly– capillary malformation (M-CM) is characterized by faint CM of the upper lip and scattered staining over much of the body in association with overgrowth, syndactyly or postaxial polydactyly, connective tissue dysplasia of the skin, subcutaneous tissue, and joints, and cortical brain malformations, typically polymicrogyria and megalencephaly/macrocephaly.16 This condition was initially mistakenly called “macrocephaly– cutis marmorata telangiectatica congenita.” Affected patients do not have CMTC; rather, they have diffuse, reticulate capillary staining that fades.17 Patients with M-CM may be referred to a vascular surgeon because their signs and symptoms are often confused with those of combined vascular malformation/overgrowth syndromes.

Venous Malformation For many years, vascular malformations (VMs) were called “cavernous hemangiomas;” this practice caused confusion with vascular tumors. Although present at birth, VMs may not be obvious and appears later as bluish, compressible swellings. They are histopathologically characterized by thinwalled interconnected vessels or pouches with abnormal

SECTION 12 VASCULAR MALFORMATIONS

that are fully grown at birth, behave differently from infantile hemangiomas, and are GLUT-1 negative. There is rare vascular tumors that are categorized as borderline malignant called hemangioendotheliomas and angiosarcomas. The doubly eponymic “Kasabach-Merritt” thrombocytopenia has been wrongly associated with infantile hemangioma. This disorder of platelet trapping occurs only with kaposiform hemangioendothelioma and tufted angioma, not with common infantile hemangiomas.7-9 Kasabach-Merritt phenomenon has also been used incorrectly to describe the localized intravascular coagulopathy that occurs with extensive venous malformations; this is an entirely different hematologic disorder.10

1045

1046

SECTION 12  Vascular Malformations

investing smooth muscle. VMs often develop thrombi and later phleboliths. Venous anomalies are typically painful, especially in the morning and when an affected limb is dependent. An extensive VM of the limb is known by the old eponym “genuine diffuse phlebectasia of Bockenheimer,”18 in which all soft tissues and long bones are affected. Leg length discrepancy may result, causing pelvic tilt, scoliosis, and gait disturbance. The blood contained in a large or extensive VM exhibits a localized intravascular coagulopathy—that is, slight decrease in platelets (100,000 to 150,000/mm3), normal PT and aPTT values, low fibrinogen content (150-200 mg/dL), and elevation of fibrin split products (D-dimer).9 Affected patients are at risk for development of a systemic coagulopathy following trauma or surgical intervention; the hematologic findings are similar to those in disseminated intravascular coagulopathy. If a patient presents with a lesion of uncertain vascular nature, elevation of D-dimer can be used as a diagnostic tool to differentiate large VM from another vascular lesion, such as glomuvenous malformation (normal D-dimer), arteriovenous malformation, or lymphatic malformation. D-dimer measurement can also differentiate a slow-flow disorder, such as Klippel-Trenaunay syndrome, from a fast-flow disorder, such as Parkes Weber syndrome.19 Low-molecular-weight heparin may be given to treat the pain caused by localized intravascular coagulopathy and to prevent decompensation to a systemic coagulopathy prior to an operation.10 Glomuvenous Malformation. A genetic diagnosis should be considered whenever there is a family history of VM, particularly multiple lesions. Glomuvenous malformation (GVM) is the most common heritable VM; it is autosomal dominant. Once known as “glomangiomas,” GVMs are clinically distinguished from common VMs because they have a cobblestone appearance and are painful on palpation.20 Also, unlike VMs, GVMs in limbs do not respond to elastic compressive garments and there is rarely deep extension. The lesions can be small or extensive and plaque-like, particularly on the trunk and extremities. They range from pink in infants to deep blue or purple in children and adults. Seventy-eight percent are located on the extremities.21 Histologically, GVMs have pathognomonic glomus cells within the walls of distended vein-like channels. Cutaneomucosal Venous Malformation. Patients with this hereditary disorder known as cutaneomucosal venous malformation (CMVM) typically have small, multifocal, soft, compressible cutaneous lesions appearing in various shades of blue. Unlike GVMs, these lesions are often present on mucosa, typically on the lips and tongue, and may occur in skeletal muscle. There may also be progressive venous ectasia in the neck and upper limb. Fifty percent of CMVMs are located in the cervicofacial area, and 37% on the extremities.21 Blue Rubber Bleb Nevus Syndrome. Soft, blue, nodularappearing cutaneous and gastrointestinal VMs characterize

blue rubber bleb nevus syndrome. Lesions increase in size and number with age. Gastrointestinal VMs can cause lifethreatening bleeding. The genetic cause of this disorder is most likely a postzygotic mutation.

Lymphatic Malformation Lymphatic malformations (LMs) are clinically and radiologically categorized as microcystic, macrocystic, or combined. These anomalies were previously described with terms such as “lymphangioma” (microcystic LM), “cystic hygroma” (macrocystic LM), and “lymphangiomatosis” (visceral LM). They are composed of anomalous channels or pockets of lymphatic fluid, often with overlying cutaneous lesions. The walls are of variable thickness with smooth and striated muscle components and nodular collections of lymphocytes. The spectrum of LMs is quite variable. Most LMs manifest in the infantile period. Deep LMs appear as generalized swellings to localized areas of overgrowth. Expansion is rapid if infection or intralesional bleeding occurs. Cutaneous LMs most often involve the chest and upper limbs, less often the lower limbs. They manifest as clear or dark red vesicles (due to intravesicular bleeding). Visceral LMs may go undetected until rapid expansion occurs. Congenital lymphedema is a type of LM that typically involves the lower limbs. Congenital Lymphedema. Primary (congenital) lymphedema is caused by anomalous lymphatic channels and must be differentiated from secondary (acquired) lymphedema due to injury to the lymph nodes or vessels (from operation, radiation, trauma, etc.) (see Chapter 66). Primary lymphedema is often nonfamilial, but it can be inherited in an autosomal dominant fashion, in which case it is also known as Milroy disease. This condition manifests shortly after birth in 49% of patients, during childhood in 10%, or during adolescence in 41%. Congenital lymphedema manifests as gradually progressive swelling of an extremity, most often the lower extremities (92%). Cellulitis affects 19% of patients and is often recurrent.22 Over time, soft tissue overgrowth develops because of fatty deposition and fibrosis. Compression is the mainstay of initial treatment; suction lipectomy has also been used.22-24 There are reports of success following microvascular lymphaticovenous anastomosis.25,26

Fast-Flow Malformations Arterial Malformations Arterial malformations are abnormally formed arteries such as aneurysms, fistulae, ectasias, and stenoses; the combined forms are arteriovenous malformation (AVM) and arteriovenous fistula (AVF).

Arteriovenous Fistula Congenital AVF occurs in isolation or as part of a complex AVM. It manifests as an enlarging, pulsatile lesion with palpable thrill and possibly signs and symptoms of shunting. The old name “congenital AVF” is often subsumed by the term AVM of which multiple AVFs are a component. Early

CHAPTER 69  Classification and Natural History of Vascular Anomalies



literature on “AVFs” of the lower extremity documented edema, hypertrophy causing leg length discrepancy, trophic changes, and even cardiovascular sequelae.27-29 Congenital AVFs in the upper limb typically manifest with the same signs and symptoms—pain, distal ischemia, and discoloration of the digits.30 Endovascular and operative techniques, alone or in combination, have been the mainstay of treatment for over 2 decades.31

Arteriovenous Malformations

V

A

Capillary-venous

L

Arteriovenous

V

C

Combined vascular malformations can involve any combination of capillary, lymphatic, venous, and arterial channels (Fig. 69-1). Like pure vascular malformations, combined malformations are classified as either slow-flow or fastflow. Often, these combined malformations constitute an overgrowth syndrome. Some of the well-known eponymous disorders involving combined malformations are described below.

L

Lymphatico-venous

Capillary-lymphatic

A

L

C

V

C

Capillary-arterial-venous - Parkes Weber - CM-AVM

V

Capillary-lymphatico-venous - Klippel-Trenaunay - Maffucci syndrome

A C

Combined Malformations and Overgrowth Syndromes

V

V L

Complex combined - PTEN hamartoma syndrome - CLOVES

Figure 69-1  Types of combined vascular malformations depicted in Venn diagrams. A, Artery/arterio; AVM, arteriovenous malformation; C, capillary; CLOVES, congenital, lipomatous, overgrowth, vascular malformations, epidermal nevi, and spinal/skeletal anomalies and/or scoliosis; CM, capillary malformation; L, lymphatic; PTEN, tumor suppressor gene; V, vein/venous.

Slow-Flow Klippel-Trenaunay Syndrome. Klippel-Trenaunay syndrome, also known as capillary-lymphaticovenous malformation (CLVM), is sporadic. The causative gene is not yet known; it is likely a regional somatic mutation. At birth, there are geographic large or small CMs over the extremity and buttock. Over time, the CMs usually become studded with lymphatic

Table 69-2

Schobinger Staging System for Arteriovenous Malformations

Stage I (Quiescence)

Stage II (Expansion) Stage III (Destruction) Stage IV (Decompensation)

Cutaneous blush, warmth (arteriovenous shunting documented by Doppler ultrasonography) Bruit, audible pulsations, expanding lesion Pain, ulceration, bleeding, infection Cardiac failure

vesicles. Lymphedema and/or microcystic and macrocystic LMs in the limb (often involving the pelvis or retroperitoneum) are present, along with splenic lymphatic cysts. Limb hypertrophy is present at birth and progressively worsens with growth. Complications of Klippel-Trenaunay syndrome include recurrent infections, pulmonary embolism, thrombophlebitis, gastrointestinal bleeding, constipation, bladder outlet obstruction, and hematuria.34-36 Young37 clearly differentiated slow-flow Klippel-Trenaunay syndrome from fast-flow Parkes Weber syndrome. There is ongoing controversy over the diagnostic criteria for Klippel-Trenaunay syndrome. The debate focuses on whether patients with capillary-venous malformation (CVM) or solely CM in a limb should be classified at the minor end of the Klippel-Trenaunay spectrum. Maffucci Syndrome. Maffucci syndrome is an extremely rare disorder characterized by cutaneous VMs, long bone enchondromas, and skeletal deformities.38 Enchondromas

SECTION 12 VASCULAR MALFORMATIONS

AVMs are present at birth and are usually quiescent during infancy and childhood. They initially are seen as telangiectasias or macular stains that may be mistaken for CMs or infantile hemangiomas. Histopathologically, AVMs are characterized by thick, fibromuscular walls with fragmented elastic lamina and fibrotic stroma. The epicenter of an AVM, called the nidus, is composed of arterial feeding vessels, micro- and macro-AVFs, and ectatic veins. The most common location for AVMs is intracranial, followed by limbs, trunk, and viscera. AVMs enlarge in response to triggers such as puberty and trauma. There is conflicting evidence about whether pregnancy causes expansion of AVMs.32 The clinical course is often slowly progressive and can be documented with the staging system proposed by Schobinger, a Swiss vascular surgeon and first president of ISSVA (Table 69-2).33

C

1047

1048

SECTION 12  Vascular Malformations

cause bony distortion and asymmetric growth; it is common for a patient to present with a pathologic fracture. Vascular malformations on the skin usually appear around age 4-to-5 years and are often progressive. These lesions begin as compressible, round, bluish spots; later they become firm, knotty, and warty, and they often contain phleboliths. A benign vascular tumor, spindle cell hemangioma, often arises in these malformed veins. Patients with Maffucci syndrome are at risk of developing chondrosarcoma and various other malignancies.39

Fast-Flow Parkes Weber Syndrome. Parkes Weber syndrome is characterized as a fast-flow combined capillary-arteriovenous malformation (CAVM) or capillary-lymphatico-arteriovenous malformation (CLAVM), usually involving the lower limb and proximal trunk. In many patients there is a mutation in the RASA1 gene, but not all patients with phenotypic Parkes Weber syndrome have this mutation.40 All patients with Parkes Weber syndrome and a mutation in RASA1 have the characteristic multiple CMs, as seen in capillary malformation–arteriovenous malformation (CM-AVM). The affected extremity exhibits a cutaneous flush/staining with underlying multiple micro-AVFs and generalized enlargement or overgrowth with or without lymphatic lesions or lymphedema. Capillary Malformation-Arteriovenous Malformation. A newly delineated familial disorder, capillary malformation– arteriovenous malformation (CM-AVM) is characterized by single or multiple small (1-2 cm in diameter) pink-to-red, round-to-oval CMs in association with AVM or AVF. Often the small lesions exhibit fast flow on hand-held Doppler ultrasonographic examination. Frequently there is a family history of one or more innocent-appearing capil­ lary stains. There is phenotypic overlap with Parkes Weber syndrome.40,41 Bannayan-Riley-Ruvalcaba Syndrome (PTEN Hamartoma Syndrome). Bannayan-Riley-Ruvalcaba syndrome, also known as PTEN hamartoma syndrome, is characterized by macrocephaly, multiple lipomas, hamartomatous polyps of distal ileum and colon, Hashimoto thyroiditis, pigmented penile macules, and vascular anomalies including CM, VM, and AVM.42 Affected patients have an increased risk of malignancy, particularly of the thyroid and breast. An estimated 31% of patients have some type of thyroid involvement, in the form of multinodular goiter, thyroid adenoma, or thyroid cancer.43 Bannayan-Riley-Ruvalcaba syndrome is an autosomal dominant condition known to be caused by a mutation in tumor suppressor gene PTEN; it is allelic with Cowden syndrome. The spectrum including both BannayanRiley-Ruvalcaba and Cowden syndromes is subsumed by the term PTEN hamartoma syndrome.

CLOVE(S) (Congenital, Lipomatous, Overgrowth, Vascular Malformations, and Epidermal Nevi) Syndrome. For many years, the disorder now known as CLOVE (congenital, lipomatous, overgrowth, vascular malformations, and epidermal nevi) syndrome was mistakenly designated “thoracic KlippelTrenaunay syndrome.” CLOVE syndrome is characterized by masses with fatty and lymphatic components in the trunk, retroperitoneum, pelvis, and extremities. Patients exhibit either nonprogressive or slightly progressive overgrowth.44 Capillary malformations are common on the trunk as well as the extremities. Lymphatic vesicles may appear on thorax and axilla, attesting to the underlying LM. Fast-flow lesions (AVMs) may be present in the fatty lesions on the trunk and paraspinal region, the latter of which can cause debilitating spinal myelopathy.45 The acronym was augmented with an “S” to CLOVES to include the frequently present scoliosis, spinal, and/or skeletal anomalies.46 Acral deformities are present, including symmetrically large, wide feet and hands, macrodactyly, and wide first web space (“sandal toe deformity”). Thoracic and central veins may be dilated; patients with this finding are at high risk for thromboembolism.47

INTERDISCIPLINARY CARE The field of vascular anomalies has emerged at the interface of many medical and surgical specialties. Patients with vascular anomalies were once medical nomads–they wandered from specialist to specialist because no one physician was able to address their many issues. Interdisciplinary teams for vascular anomalies have developed to care for these patients, and vascular surgeons are welcome members of such teams (Fig. 69-2). European vascular surgeons have been in the vanguard of this developing field, contributing endovascular and surgical techniques. The sharing of responsibility among specialties varies considerably from one institution to the next. Thankfully, there are usually no “turf battles,” given the difficulty in managing many patients with these anomalies.

TOWARD A MOLECULAR CLASSIFICATION Advances in molecular genetics are illuminating the field of vascular anomalies. Infantile hemangiomas have been shown to be clonal, likely arising by somatic mutation in an endothelial progenitor cell. There are also some families predisposed to development of hemangiomas, suggesting possible germ-line mutations. The causative genes for several vascular malformations have been identified (Table 69-3). The pathogenetics are being elucidated in vitro and in animal models. Once the basic mechanisms are understood, targeted pharmacologic therapies might be possible, and our classification system for vascular anomalies will be a molecular one.

Orthopedic Otolaryngology Pediatric surgery surgery Diagnostic/ Oral/maxillofacial Interventional surgery Radiology Plastic surgery

Vascular surgery

Neurology/ Neurosurgery

Cardiology

Vascular Anomalies Anesthesiology

Ophthalmology

Pathology

Endocrinology Pulmonology/ Critical care

Figure 69-2  Specialties involved in the interdisciplinary care of vascular anomalies.

Genetics Hematology/ Pediatrics Oncology

Molecular Genetics of Vascular Anomalies

Name

Mutation/Gene

Clinical Features

CAPILLARY MALFORMATION (CM) Sturge-Weber syndrome

Somatic/GNAQ48

Facial CM in V1/V2 dermatomes in association with ipsilateral leptomeningeal and ocular vascular anomalies, seizures, and glaucoma. CMs also occur on trunk and limbs. Patchy, reticular CMs, most commonly on nose, philtrum, limbs, and trunk. Hemi-hypertrophy of lower limb and/or syndactyly.

Macrocephaly–capillary malformation (M-CM) LYMPHATIC MALFORMATION Primary congenital lymphedema (“Milroy disease”) Lymphedema-distichiasis syndrome Meige syndrome VENOUS MALFORMATION (VM) Maffucci syndrome

Blue rubber bleb nevus syndrome Cutaneomucosal venous malformation Glomuvenous malformation COMBINED MALFORMATION Klippel-Trenaunay syndrome

Somatic/PIK3CA49,50

Germline/VEGFR351,52 Germline/FOXC253,54 Germline/FOXC2?55,56

Somatic/IDH1 or IDH238

Somatic/TIE257 Germline/TIE258,59

Neonatal lymphedema in lower extremities (usually bilateral). Males may have hydroceles and ureteral anomalies. Lymphedema usually in lower extremities in association with extra eyelashes. Late onset (after puberty) familial lymphedema; phenotypic overlap with lymphedema-distichiasis syndrome. Progressive exophytic venous anomalies of upper limbs, bony exostoses and enchondromas, and overgrowth. Malignant degeneration (usually chondrosarcoma) in 20%-40%. Soft, blue, nodular cutaneous (especially palmar and plantar) and visceral VMs; often severe gastrointestinal bleeding. Multiple tiny to several-centimeter dome-shaped VMs or ectatic major veins.

Germline/Glomulin60,61

Small or extensive plaque-like, cobble-stone lesions, firmer than typical VM, painful on palpation. Present at birth or arises in first 2 decades.

Somatic?

Capillary-lymphaticovenous malformation in association with soft tissue and skeletal overgrowth of lower limbs. Delayed motor and speech development, proximal myopathy, macrocephaly, penile macules, ileal and colonic hamartomas, subcutaneous lipomas, Hashimoto’s thyroiditis, and wide spectrum of vascular malformations. At risk for malignancy, especially breast or thyroid. Fast-flow capillary-arteriovenous malformation (AVM) of limbs and proximal trunk. Geographic macular staining, generalized enlargement/overgrowth, microscopic AVMs; sometimes lymphedema. Lipomas, vascular malformations (CM, VM, LM, AVM), large hands and feet, macrodactyly, sandal toes, renal, neurologic, or musculoskeletal anomalies, and epidermal nevi. Multiple tiny to circular CMs sometimes in association with AVM. Limbs have pale circles with central red dots (“polka-dot” appearance).

PTEN hamartoma syndrome (Bannayan-Riley-Ruvalcaba syndrome, Cowden syndrome)

Germline/PTEN62,63

Parkes Weber syndrome

Germline/RASA140

CLOVE(S) syndrome

Somatic/PIK3CA64

Capillary malformationarteriovenous malformation (CM-AVM)

Germline/RASA141

SECTION 12 VASCULAR MALFORMATIONS

Table 69-3

Dermatology

1050

SECTION 12  Vascular Malformations

SELECTED KEY REFERENCES Dompmartin A, Acher A, Thibon P, Tourbach S, Hermans C, Deneys V, Pocock B, Lequerrec A, Labbé D, Barrellier MT, Vanwijck R, Vikkula M, Boon LM: Association of localized intravascular coagulopathy with venous malformations. Arch Dermatol 144:873–977, 2008. Document features of localized coagulopathy associated with large VMs, particularly low D-dimer and palpable phleboliths, as well as potential for systemic coagulopathy with low fibrinogen levels. 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. Vascular anomalies are differentiated on the basis of endothelial cell characteristics; tumors have endothelial hyperplasia and malformations have normal endothelial cell turnover. This study is the basis for the ISSVA classification of vascular anomalies.

North PE, Waner M, Mizeracki A, Mihm MC, Jr: GLUT1: A newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol 31:11–22, 2000. Infantile hemangiomas were demonstrated to be positive for glucose transporter protein-1, a useful immunohistochemical marker for differentiating common infantile hemangiomas from uncommon vascular tumors. Sarkar M, Mulliken JB, Kozakewich HP, Robertson RL, Burrows PE: Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is associated with kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg 100:1377–1386, 1997. The histologic characteristics of vascular tumors associated with KasabachMerritt phenomenon are defined. The tumors are kaposiform hemangioendothelioma, not infantile hemangioma. The reference list can be found on the companion Expert Consult website at www.expertconsult.com.

CHAPTER 69  Classification and Natural History of Vascular Anomalies 1050.e1



REFERENCES

SECTION 12 VASCULAR MALFORMATIONS

1. Enjolras O, et al: Vascular tumors and vascular malformations (new issues). Adv Dermatol 13:375–423, 1997. 2. Mulliken JB, et al: Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 69:412–422, 1982. 3. Greene AK, et al: Vascular anomalies in 5,621 patients: guidelines for referral. J Pediatr Surg 46:1784–1789, 2011. 4. North PE, et al: GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol 31:11–22, 2000. 5. North PE, et al: A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol 137:559–570, 2001. 6. Mulliken JB, et al: Reticular infantile hemangioma of the limb can be associated with ventral-caudal anomalies, refractory ulceration, and cardiac overload. Pediatr Dermatol 24:356–362, 2007. 7. Sarkar M, et al: Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is associated with Kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg 100:1377–1386, 1997. 8. Enjolras O, et al: Infants with Kasabach-Merritt syndrome do not have “true” hemangiomas. J Pediatr 130:631–640, 1997. 9. Mulliken JB, et al: Case records of the Massachusetts General Hospital: weekly clinicopathological exercises: case 13-2004: a newborn girl with a large cutaneous lesion, thrombocytopenia, and anemia. N Engl J Med 350:1764–1775, 2004. 10. Dompmartin A, et al: Association of localized intravascular coagulopathy with venous malformations. Arch Dermatol 144:873–877, 2008. 11. Vikkula M, et al: Molecular genetics of vascular malformations. Matrix Biol 20:327–335, 2001. 12. Sujansky E, et al: Sturge-Weber syndrome: age of onset of seizures and glaucoma and the prognosis for affected children. J Child Neurol 10:49– 58, 1995. 13. Greene AK, et al: Sturge-Weber syndrome: soft-tissue and skeletal overgrowth. J Craniofac Surg 20:617–621, 2009. 14. Morgan JM, et al: Cutis marmorata telangiectatica congenita with hypoplasia of the right iliac and femoral veins. Br J Dermatol 137:119– 122, 1997. 15. Vogel AM, et al: Iliac artery stenosis in a child with cutis marmorata telangiectatica congenita. J Pediatr Surg 40:e9–e12, 2005. 16. Conway RL, et al: Neuroimaging findings in macrocephaly-capillary malformation: a longitudinal study of 17 patients. Am J Med Genet 43A:2981–3008, 2007. 17. Toriello HV, et al: Accurately renaming macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC) as macrocephaly-capillary malformation (M-CM) [letter]. Am J Med Genet 143A:3009, 2007. 18. Kubiena HF, et al: Genuine diffuse phlebectasia of Bockenheimer: dissection of an eponym. Pediatr Dermatol 23:294–297, 2006. 19. Dompmartin A, et al: Elevated D-dimer level in the differential diagnosis of venous malformations. Arch Dermatol 145:1239–1244, 2009. 20. Brouillard P, et al: Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations (“glomangiomas”). Am J Hum Genet 70:866–887, 2002. 21. Boon LM, et al: Glomuvenous malformation (glomangioma) and venous malformation: distinct clinicopathologic and genetic entities. Arch Dermatol 140:971–976, 2004. 22. Schook CC, et al: Primary lymphedema: clinical features and management in 138 pediatric patients. Plast Reconstr Surg 127:2419–2431, 2011. 23. Brorson H, et al: Complete reduction of lymphoedema of the arm by liposuction after breast cancer. Scand J Plast Reconstr Surg Hand Surg 3: 1137–1143, 1997. 24. Brorson H, et al: Controlled compression and liposuction treatment for lower extremity lymphedema. Lymphology 41:52–63, 2008. 25. Campisi C, et al: Microsurgery for lymphedema: clinical research and long-term results. Microsurgery 30:256–260, 2010.

26. Yamamoto T, 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. Callander CL: Study of arteriovenous fistula with an analysis of 447 cases. Ann Surg 71:428–459, 1920. 28. Leonard FC, et al: Congenital arteriovenous fistulation of the lower limb: report of a case successfully treated by total excision. N Engl J Med 245:885–888, 1951. 29. Malan E, et al: Congenital angiodysplasias of the extremities II: arterial, arterial and venous, and haemolymphatic dysplasias. J Cardiovasc Surg (Torino) 6:255–345, 1965. 30. Upton J, et al: Vascular malformations of the upper limb: a review of 270 patients. J Hand Surg Am 24:1019–1035, 1999. 31. Loose DA: Combined treatment of congenital vascular defects: indications and tactics. Semin Vasc Surg 6:260–265, 1993. 32. Liu AS, et al: Extracranial arteriovenous malformations: natural progression and recurrence after treatment. Plast Reconstr Surg 125:1185– 1194, 2010. 33. Kohout MP, et al: Arteriovenous malformations of the head and neck: natural history and management. Plast Reconstr Surg 102:643–654, 1998. 34. Baskerville PA, et al: The Klippel-Trenaunay syndrome: clinical, radiological and haemodynamic features and management. Br J Surg 72:232– 236, 1985. 35. Samuel M, et al: Klippel-Trenaunay syndrome: clinical features, complications and management in children. Br J Surg 82:757–761, 1995. 36. Jacob AG, et al: Klippel-Trenaunay syndrome: spectrum and management. Mayo Clin Proc 73:28–36, 1998. 37. Young AE: Combined vascular malformations. In Mulliken JB, et al Vascular birthmarks: hemangiomas and malformations, Philadelphia, 1988, WB Saunders, pp 246–274. 38. Pansuriya TC, et al: Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 43:1256–1261, 2011. 39. Verdegaal SH, et al: Incidence, predictive factors, and prognosis of chondrosarcoma in patients with Ollier disease and Maffucci syndrome: an international multicenter study of 161 patients. Oncologist 16:1771–1779, 2011. 40. Revencu N, et al: Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Hum Mutat 29:959–965, 2008. 41. Eerola I, et al: Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hu Genet 73:1240–1249, 2003. 42. Cohen MM, Jr: Bannayan-Riley-Ruvalcaba syndrome: renaming three formerly recognized syndromes as one etiologic entity. Am J Med Genet 35:291–292, 1990. 43. Tan WH, et al: The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management. J Med Genet 44:594–602, 2007. 44. Sapp JC, 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. 45. Alomari AI, et al: Complex spinal-paraspinal fast-flow lesions in CLOVES syndrome: analysis of clinical and imaging findings in 6 patients. AJNR Am J Neuroradiol 32:1812–1817, 2011. 46. Alomari AI: Characterization of a distinct syndrome that associates complex truncal overgrowth, vascular, and acral anomalies: a descriptive study of 18 cases of CLOVES syndrome. Clin Dysmorphol 18:1–7, 2009. 47. Alomari AI, et al: CLOVES syndrome with thoracic and central phlebectasia: increased risk of pulmonary embolism. J Thorac Cardiovasc Surg 140:459–463, 2010. 48. Shirley MD, et al: Sturge Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med 368:1971–1979, 2013.

1050.e2 SECTION 12  Vascular Malformations 49. Riviere J-B, et al: De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nature Genet 44:934–940, 2012. 50. Lee JH, et al: De novo somatic mutations in components of the PI3KAKT3-mTOR pathway cause hemimegalencephaly. Nature Genet 44: 941–945, 2012. 51. Ferrell RE, et al: Hereditary lymphedema: evidence for linkage and genetic heterogeneity. Hum Molec Genet 7:2073–2078, 1998. 52. Karkkainen MJ, et al: Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nature Genet 25:153–159, 2000. 53. Fang J, et al: Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedemadistichiasis syndrome. Am J Hum Genet 67:1382–1388, 2000. 54. Erickson RP, et al: Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutations. J Med Genet 38:761–766, 2001. 55. Finegold DN, et al: Truncating mutations in FOXC2 cause multiple lymphedema syndromes. Hum Molec Genet 10:1185–1189, 2001. 56. Rezaie T, et al: Primary non-syndromic lymphoedema (Meige disease) is not caused by mutations in FOXC2. Eur J Hum Genet 16:300–304, 2008.

57. Soblet J, et al: Variable somatic TIE2 mutations in half of sporadic venous malformations. Mol Syndromol 4:179, 2013. 58. Vikkula M, et al: Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 87:1181–1190, 1996. 59. Calvert JT, et al: Allelic and locus heterogeneity in inherited venous malformations. Hum Mol Genet 8:1279–1289, 1999. 60. Boon LM, et al: A gene for inherited cutaneous venous anomalies (“glomangiomas”) localizes to chromosome 1p21-22. Am J Hum Genet 65:125–133, 1999. 61. Brouillard P, et al: High-resolution physical and transcript map of the locus for venous malformations with glomus cells (VMGLOM) on chromosome 1p21-p22. Genomics 67:96–101, 2000. 62. Marsh DJ, et al: Germline mutations in PTEN are present in BannayanZonana syndrome [letter]. Nature Genet 16:333–334, 1997. 63. Longy M, et al: Mutations of PTEN in patients with Bannayan-RileyRuvalcaba phenotype. J Med Genet 35:886–889, 1998. 64. Kurek KC, et al: Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet 90:1108–1115, 2012.

CHAPTER 70 

Vascular Tumors of Childhood CAMERON C. TRENOR III  /  ARIN K. GREENE

Based on a chapter in the seventh edition by Glenn R. Jacobowitz

V

ascular tumors of childhood are usually benign and consist of four major types: infantile hemangioma, congenital hemangioma, kaposiform hemangioendothelioma, and pyogenic granuloma.1,2 They are manifested during infancy or childhood, may involve any location, and can cause local complications: bleeding, destruction of tissue, obstruction, and pain. Systemic sequelae may include thrombocytopenia, congestive heart failure, and death. Vascular tumors must be differentiated from vascular malformations of childhood. Vascular tumors usually are not present at birth, have proliferating endothelium, and exhibit postnatal growth. In contrast, vascular malformations arise from dysmorphogenesis, are present at birth, have quiescent endothelium, and grow proportionately with the child or slowly expand. Together, vascular tumors and malformations of childhood compose the field of vascular anomalies. The modern classification of vascular anomalies is based on cellular traits, correlated with physical findings and natural history3,4 (see Chapter 69). The subject of vascular tumors of childhood is confusing because many practitioners still refer to vascular lesions by their descriptive rather than by their biologic term (Table 70-1).5 Consequently, communication, diagnosis, and treatment of patients with these lesions remain difficult. The suffix –oma describes a lesion that formed by upregulated cellular growth.3 Thus, this suffix is used for vascular tumors. Terms such as cystic hygroma (macrocystic lymphatic malformation), lymphangioma (microcystic lymphatic malformation), and cavernous hemangioma (venous malformation), which describe nonproliferating malformations, are discouraged.3 This topic is also challenging because many vascular tumors and malformations look alike. Lesions may appear flat or raised and blue, red, or purple. Management often requires interdisciplinary cooperation between medical and surgical specialties. Significant progress in understanding and treatment of patients with vascular anomalies has been made during the past quarter century. For example, imaging instead of biopsy is now the standard for diagnostic confirmation, antiangiogenic drug treatment is available for problem tumors, sclerotherapy has replaced operative resection for most malformations, and techniques for excision have been

improved. Several multidisciplinary Vascular Anomalies Centers now serve as regional, national, or international referral centers for patients with these lesions.

INFANTILE HEMANGIOMA Clinical Features Infantile hemangioma, a benign tumor of the endothelium, is the most common neoplasm of infancy. It affects about 4% to 5% of white infants and is rare in dark-skinned individuals.6 It is more frequent in premature infants (the risk is increased 40% for every 500-g decrease in birth weight less than 2500 g) and girls (4 : 1).7 Most are single (80%) and involve the head and neck (60%), trunk (25%), or extremity (15%). Between 30% and 50% of lesions are visible at birth as a small pale spot, telangiectatic stain, or ecchymotic area. However, the median age at appearance is 2 weeks after birth. Infantile hemangioma has a unique growth pattern. During the first 9 months of life, the lesion grows rapidly, faster than the growth of the child (proliferating phase) (Fig. 70-1). Eighty percent of tumor growth is achieved by 3.2 (±1.7) months of age.8 If the tumor involves the superficial dermis, it appears red. If it occupies the deep dermis, the overlying skin may be bluish or have a normal appearance. By 10 to 12 months of age, growth plateaus and the tumor increases in size at the same rate of growth as the child. The involuting phase begins at approximately 1 year of age and is characterized by shrinkage of the tumor. The bright color fades, the skin pales at the center of the lesion, and the tumor becomes less tense. Involution is completed in most children by 3.5 years of age.9 Size, site, and previous treatment do not affect the rate of regression.9 The final involuted phase occurs after regression is complete. Fifty percent of patients have residually damaged skin, fibrofatty tissue, telangiectasias, discoloration, scarring, or redundant skin (Fig. 70-2).

Multiple Hemangiomas On occasion, children have multiple cutaneous hemangiomas (hemangiomatosis). The lesions usually are less than 5 mm in diameter and are domelike (Fig. 70-3). Individuals 1051

1052

SECTION 12  Vascular Malformations

Table 70-1

Common Types of Childhood Vascular Tumors

Correct Biologic Term

Incorrect Descriptive Name

Infantile hemangioma

Capillary hemangioma Strawberry hemangioma Cavernous hemangioma Infantile hemangioma Hemangioma Hemangioma Lobular capillary hemangioma

Congenital hemangioma Kaposiform hemangioendothelioma Pyogenic granuloma

with five or more cutaneous hemangiomas have a 16% chance of having visceral lesions that are almost always located in the liver.10 Patients are screened with ultrasonography to rule out hepatic hemangiomas.11 The brain, gut, and lung are rarely involved.

Hepatic Hemangiomas The liver is the most common site of extracutaneous hemangioma. Whereas most are small and discovered incidentally, children may present during the proliferating phase with congestive heart failure, hepatomegaly, anemia, or hypothyroidism. Differential diagnosis includes arteriovenous malformation and malignant neoplasm. However, 90% of

A

fast-flow lesions of the liver are hemangiomas; the remaining fast-flow lesions are arteriovenous malformations.11 Hepatoblastoma and metastatic neuroblastoma are less common and do not illustrate the shunting characteristics of hemangioma. Hepatic hemangiomas may be focal, multifocal, or diffuse.11 Focal lesions typically are asymptomatic and discovered incidentally on prenatal or antenatal ultrasonography. They usually are not associated with cutaneous hemangiomas. A focal lesion is a rapidly involuting congenital hemangioma and not an infantile hemangioma.11 Focal lesions undergo rapid involution postnatally and do not stain positive for GLUT1, a marker for infantile hemangioma.12 Rarely, macrovascular shunts from the hepatic artery or portal vein to the hepatic veins can cause congestive heart failure, possibly necessitating embolization of the shunts. Multifocal hepatic hemangiomas also are usually asymptomatic and discovered incidentally. Rarely, multifocal tumors can cause high-output cardiac failure by arteriovenous or portovenous shunting. Unlike focal lesions, multifocal hepatic hemangiomas are infantile hemangiomas and may be associated with multiple cutaneous lesions. These lesions stain for GLUT1 and begin involution after 12 months of age.11 A diffuse hemangioma can replace hepatic parenchyma and cause massive hepatomegaly, although high-output

B

Figure 70-1  Proliferating infantile hemangioma. A, A 2-month-old girl with a superficial tumor. B, A 9-month-old girl with a deep lesion of the chest.

A

B

C

Figure 70-2  Involuting infantile hemangioma. A, A 3-year-old girl with a residual fibrofatty lesion of the cheek. B, A 4.5-year-old girl with fibrofatty residuum and telangiectasias of the lower lip. C, A 4-year-old boy with redundant skin of the neck.



CHAPTER 70  Vascular Tumors of Childhood

1053

supraumbilical.15 Ninety percent of affected children are female, and the most commonly associated anomaly is a cerebrovascular malformation (72%).15 Less than one third of patients have more than one extracutaneous feature of the association. PHACES is estimated to represent 2.3% of all patients with infantile hemangioma, and 8% of patients with PHACES have infant stroke.15 MRI is obtained to evaluate the cerebrovasculature. If an anomaly is present, neurologic consultation is obtained. Ophthalmologic, endocrine, and cardiac evaluations are necessary to determine if associated anomalies are present.

LUMBAR Association

cardiac failure is rare. However, the inferior vena cava or thoracic cavity may be compressed, causing respiratory compromise or abdominal compartment syndrome. Virtually all infants will develop hypothyroidism because the hemangioma expresses a deiodinase that inactivates thyroid hormone.13 Patients with diffuse hepatic hemangioma must have thyroid-stimulating hormone monitoring. Massive intravenous thyroid hormone replacement may be necessary to prevent irreversible mental retardation until the hemangioma regresses. Liver transplantation may be indicated in a critical situation if the hemangioma fails to respond to pharmacotherapy.

Lumbosacral Location An infant with a large midline infantile hemangioma involving the lumbosacral area has an approximately 1 in 3 chance of having an underlying spinal anomaly (e.g., tethered cord, lipoma, intraspinal hemangioma).14 Magnetic resonance imaging (MRI) is performed between 3 and 6 months of age to rule out an occult spinal dysraphism.

PHACES Association PHACES association (posterior fossa brain malformations, hemangioma, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities, sternal clefting/ supraumbilical raphe) refers to a plaque-like infantile hemangioma of the face with one or more of the following anomalies: brain, cerebrovascular, cardiac, eye, and sternal/

Pathogenesis Evidence suggests that infantile hemangioma may arise from vasculogenesis (formation of blood vessels from progenitor cells).17 The precursor cell for infantile hemangioma may be a multipotent hemangioma-derived stem cell, which has been isolated.18 These cells produce human GLUT1-positive vessels in immunodeficient mice.18 Hemangioma-derived stem cells share similarities with placental endothelium, although genetic studies have shown that hemangiomaderived stem cells are derived from the child and not the mother.19,20 Several mechanisms might contribute to the enlargement of infantile hemangioma. Hypoxia may stimulate circulating hemangioma-derived endothelial progenitor cell recruitment to the tumor. Hemangioma-derived stem cells have defective activity of nuclear factor of activated T cells and decreased expression of vascular endothelial growth factor receptor (VEGFR)–1.21 Because VEGFR-1 is a decoy receptor, more vascular endothelial growth factor A becomes available to bind to VEGFR-2, which stimulates endothelial proliferation.21 A reduction in local antiangiogenic proteins also may potentiate tumor growth.22,23 The mechanism for infantile hemangioma involution is unknown. As endothelial proliferation slows, apoptosis increases, and the tumor is replaced by fibrofatty tissue. Apoptosis begins before 1 year of age and peaks at 24 months.24 Decreasing proangiogenic maternal estrogens or increasing

SECTION 12 VASCULAR MALFORMATIONS

Figure 70-3  A 2-month-old girl with hemangiomatosis. Ultrasonography showed hepatic hemangioma, which was asymptomatic.

Two thirds of infants with LUMBAR association (lower body infantile hemangioma, urogenital anomalies/ulceration, myelopathy, bone deformities, anorectal malformations/ arterial anomalies, and renal anomalies) are girls.16 The infantile hemangioma is large, superficial, and located in a regional distribution. The tumor has minimal postnatal growth and often ulcerates. The hemangioma affects the sacral area, lumbar region, perineum and genitalia, or lower extremity.16 Associated anomalies include spinal, cutaneous, anorectal, renal, urogenital, arterial, and bone. Infants younger than 3 months with suspected LUMBAR association undergo screening ultrasound of the spine, abdomen, and pelvis to determine whether a large anomaly or spinal dysraphism is present. Infants older than 3 months undergo screening MRI.16

1054

SECTION 12  Vascular Malformations

angiogenesis inhibitors in the epidermis overlying the hemangioma may promote involution.23 The source of adipocytes during involution is the hemangioma-derived stem cells, which also can differentiate into pericytes.18

Diagnosis History and Physical Examination

Management Observation Observation is the mainstay of management because 90% of infantile hemangiomas are small, are localized, and do not involve aesthetically or functionally important areas.1 Parents should be reassured by showing them photographs of the tumor in its proliferative, involuting, and involuted phases. Patients are observed closely through the proliferative phase of growth if the tumor is at risk for becoming a problem (e.g., obstruction or destruction of important areas).

Correct diagnosis of a vascular tumor of childhood can be made by history and physical examination in 90% of patients. When the diagnosis is unclear, radiographic imaging is usually diagnostic; biopsy is rarely necessary. Infantile hemangioma is not present at birth, although a light stain may be noted in 50% of infants. At an average age of 2 weeks, the lesion will grow rapidly larger. By 12 months of age, infantile hemangioma will begin to involute, becoming gray, soft, and smaller. A superficial infantile hemangioma appears red, whereas deeper lesions may not be noted until later as a blue mass visualized through the skin. A deep infantile hemangioma without significant cutaneous changes may be diagnosed with a handheld Doppler device; fast flow is consistent with infantile hemangioma.

During the proliferative phase, approximately 16% of lesions will have skin ulceration.29 Ulceration is more common on the lips, neck, and anogenital regions. To reduce the risk of ulceration, tumors can be covered with hydrated petroleum. Lesions in high-risk areas may be further protected with a petroleum gauze barrier.1 Ulcerated infantile hemangiomas are treated with soap and water irrigations twice daily. Small areas are covered with topical antibiotic. Deep wounds are managed with damp-to-dry dressing changes.

Imaging

Topical Pharmacotherapy

Less than 10% of infantile hemangiomas require imaging for a definitive diagnosis to be obtained. Ultrasound is the first-line confirmatory study and shows a well-circumscribed hypervascular mass.25 Low-resistance arterial waveforms are present with increased venous drainage. If ultrasound is equivocal, an MRI study is obtained. During the proliferative phase, an infantile hemangioma shows a parenchymal mass (unlike an arteriovenous malformation) with dilated vessels and signal voids. The lesion is isointense on T1 sequences, is hyperintense on T2 images, and enhances homogeneously after the administration of contrast material.25 An involuting infantile hemangioma has increased lobularity and adipose tissue. A reduced number of vessels, signal voids, and enhancement are noted.

Topical pharmacotherapy has minimal efficacy, especially when the infantile hemangioma is primarily in the deep dermis and subcutis.1 Although the lesion may lighten, if an underlying mass is present, it will not be affected. Topical ultrapotent corticosteroid (e.g., clobetasol) may be effective for small, superficial lesions, but hypopigmentation and skin atrophy can occur. The beta blocker timolol may have efficacy for small, superficial lesions. It is typically applied twice daily, but systemic absorption of the drug can occur.30

Histopathology Less than 1% of infantile hemangiomas require histopathologic evaluation for diagnosis. Biopsy is indicated if malignant disease is suspected or if the diagnosis remains unclear after the lesion is imaged. Rare lesions that may be confused with common vascular tumors of infancy include arteriovenous malformation, infantile myofibromatosis, infantile fibrosarcoma, Enzinger intramuscular hemangioma, pilomatrixoma, neuroblastoma, and lymphoma.26,27 A proliferating lesion shows tightly packed capillaries with plump endothelial cells and minimal intervascular stroma.28 During involution, infantile hemangioma exhibits reduced capillaries, enlargement of channels, and increased stroma. An involuted tumor is primarily fibrofatty with few residual capillaries.28 Infantile hemangioma uniquely expresses an erythrocyte-type glucose transporter (GLUT1) that can be used to differentiate the tumor immunohistochemically from other vascular tumors and malformations.12

Wound Care

Intralesional Corticosteroid Intralesional administration of corticosteroids is indicated for small, well-localized infantile hemangiomas that obstruct vision or the nasal airway or are at risk for damaging an aesthetically important area (eyelid, lip, nose).1 Triamcinolone stabilizes growth in 95% of infantile hemangiomas, and 75% will decrease in size.31 Injections are administered at 6-week intervals during the proliferative phase. Risks include subcutaneous fat atrophy and ulceration. Blindness has been reported with injection of periorbital hemangioma that may have been due to embolic occlusion of the retinal artery. If a localized infantile hemangioma fails to respond to corticosteroid injection, systemic pharmacotherapy is considered (Fig. 70-4).

Systemic Pharmacotherapy Systemic therapy is indicated for a problem hemangioma that is too large to be treated with a local injection.1 There are two primary drug options: prednisolone and propranolol. Prednisolone (3 mg/kg) is given once in the morning for 1 month).32 The dose is then tapered every 2 to 4 weeks until it is discontinued between 10 and 12 months of age.33 Nearly all infantile hemangiomas will stop growing and 88% will

CHAPTER 70  Vascular Tumors of Childhood



A

1055

B

become smaller.33 Twenty percent of patients develop a cushingoid appearance that resolves when the drug is discontinued. Twelve percent of infants have a temporary decrease in their gain in height but return to their pretreatment growth curve by 24 months of age.34 Gastric and antibiotic prophylaxis is not required. Complicated monitoring is unnecessary. The dose is rapidly tapered as the infant gains weight. Patients are observed monthly in the office, and the dose is lowered further. If rebound growth of the tumor occurs, the dose is elevated. Propranolol (2 mg/kg/day) is divided into two or three daily doses and then tapered until it is discontinued around 12 months of age. Cessation without tapering during the proliferative phase of infantile hemangioma can result in rebound growth. To improve tolerability, the drug is often started at 1.0 mg/kg/day and then slowly increased to 2 mg/ kg/day. Approximately 90% of tumors stop growing or regress.35 Risks (