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From Alibert’s Nosologie Naturelle, 1817
Mulliken & Young’s
Vascular Anomalies
Hemangiomas and Malformations

Second Edition

Edited by
John B. Mulliken, M.D.
Director Craniofacial Centre
Co-Director, Vascular Anomalies Center
Department of Plastic and Oral Surgery
Boston Children’s Hospital
Professor of Surgery, Harvard Medical School
Boston, MA

Patricia E. Burrows, M.D.

Professor of Radiology
Medical College of Wisconsin
Pediatric Interventional and Neurointerventional Radiology
Children’s Hospital of Wisconsin
Milwaukee, WI

Steven J. Fishman, M.D.

Co-Director, Vascular Anomalies Center
Stuart and Jane Weitzman Family Chair
Department of Surgery
Boston Children’s Hospital
Professor of Surgery, Harvard Medical School
Boston, MA

1
3
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Library of Congress Cataloging-in-Publication Data

Mulliken, John B.
Mulliken & Young’s Vascular Anomalies Hemangiomas and Malformations / John B. Mulliken, Patricia E. Burrows, Steven J. Fishman.—2nd ed.
p. ; cm.
Rev. ed. of: Vascular birthmarks / John B. Mulliken, Anthony E. Young. 1st ed. 1988.
Includes bibliographical references and index.
ISBN 978–0–19–514505–2 (alk. paper)—ISBN 978–0–19–972254–9 (alk. paper)—ISBN 978–0–19–998209–7 (alk. paper)
I. Burrows, Patricia E. II. Fishman, Steven J. III. Mulliken, John B. Vascular birthmarks. IV. Title. V. Title: Vascular anomalies.
[DNLM: 1. Vascular Malformations—etiology. 2. Hemangioma—etiology. 3. Hemangioma—therapy. 4. Vascular Malformations—
therapy. 5. Vascular Neoplasms. WG 220]
LC Classification not assigned
616.8′1—dc23
2012034144

ISBN 978–0–19–514505–2 (alk. paper)

ISBN 978–0–19–972254–9 (alk. paper)
ISBN 978–0–19–998209–7

This material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the conditions described in
this material is highly dependent on the individual circumstances. And, while this material is designed to offer accurate information with respect to the subject
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medications are being revised continually, with new side effects recognized and accounted for regularly. Readers must therefore always check the product information
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Dedication

Dr. Judah Folkman

(February 24, 1933–January 14, 2008)

Dr. Judah Folkman was the founding father of the field of angiogenesis. His laboratory was the first to purify
angiogenic molecules, discover angiogenic inhibitors, and propose therapy for angiogenesis-dependent dis-
eases. Less well-known are his inventive contributions to the first implantable cardiac pacemaker and the
development of sustained release drug-delivery systems.

Dr. Folkman was my Chief Resident when I was an intern at the Massachusetts General Hospital in 1964.
I worked under his guidance for the next 44 years. In 1974, he offered me space in his laboratory; Dr. Julie
Glowacki joined me. Judah suggested that we begin by answering the critical question “What cells are up-
regulated in vascular lesions?” This query to Mother Nature led to her revealing the biological classification
of vascular anomalies.

Dr. Folkman envisioned infantile hemangioma as an angiogenic disease. He personally cultured capillary
endothelium from specimens of proliferating hemangioma; this technique continues to be the initial step in
molecular and genetic studies of hemangioma-genesis. His laboratory first showed that mast cells potentiate
angiogenesis, but the role of elevated mast cells in infantile hemangiomas remains unclear.

Dr. Folkman was the scientific spiritual leader of our Vascular Anomalies Center (VAC). He was the first
to suggest interferon therapy for hemangioma. His “proof of principle” was shown in the successful treat-
ment of rare vascular tumors with anti-angiogenic agents. He envisioned pharmacologic therapy for vascular
malformations that would be based on increased levels of growth factors in the serum and urine. He was
fascinated by the deficiency of muscular layers in venous malformations. He proposed that molecules be
delivered by catheter to stimulate muscular growth to order to shrink the ectatic, malformed channels.

There is an empty chair at our VAC meetings, but Judah Folkman’s spirit lives on in all those he inspired. He
will always be remembered for his scientific passion, his humility, and his kindness.

J.B.M.
Boston, 2012
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Contents

Contributors xi
Foreword xiii
Preface xv
Preface from Mulliken and Young’s Vascular Birthmarks (1st Edition) xvii
Acknowledgments xix

Part One—Background

1. Vascular Birthmarks in Folklore, History, Art, and Literature 3

John B. Mulliken and Anthony E. Young

2. Classification of Vascular Anomalies 22

John B. Mulliken

Part Two—Infantile Hemangiomas and Other Vascular Tumors

3. Pathogenesis of Infantile Hemangioma 43

John B. Mulliken and Joyce Bischoff

4. Diagnosis and Natural History of Hemangiomas 68

John B. Mulliken

5. Radiological Imaging of Hemangiomas and Related Vascular Tumors 111

Patricia E. Burrows and Harriet J. Paltiel

6. Treatment of Cutaneous Hemangiomas 161

John B. Mulliken

7. Treatment of Visceral Vascular Tumors 239

Steven J. Fishman and Patricia E. Burrows

viii Contents

8. Vascular Tumors and Tumor-Like Lesions 259

Odile Enjolras, John B. Mulliken, and Harry P. W. Kozakewich

Part Three—Vascular Malformations

9. Molecular Genetics of Vascular Malformations 327

Laurence M. Boon and Miikka Vikkula

10. Clinical Assessment of Vascular Malformations 376

Steven J. Fishman and Anthony E. Young

11. Radiological Imaging of Vascular Malformations 392

Patricia E. Burrows and Harriet J. Paltiel

12. Histopathology of Vascular Malformations 480

Harry P. W. Kozakewich and John B. Mulliken

13. Capillary Malformations, Hyperkeratotic Stains, Telangiectasias,

and Miscellaneous Vascular Blots 508
John B. Mulliken

14. Slow-Flow Vascular Malformations 562

Steven J. Fishman and Anthony E. Young

15. Fast-Flow Vascular Malformations 595

Anthony E. Young and Steven J. Fishman

16. Vascular Malformations with Overgrowth 603

John B. Mulliken and Anthony E. Young

Part Four—Management of Vascular Malformations

17. Coagulopathy and Vascular Malformations 637

Denise M. Adams and Ellis J. Neufeld

18. Laser Therapy of Vascular Malformations 645

Marilyn G. Liang and Oon T. Tan

 Contents ix

19. Percutaneous Treatment of Slow-Flow Vascular Malformations 661

Patricia E. Burrows

20. Endovascular Treatment of Fast-Flow Vascular Anomalies 710

Patricia E. Burrows

21. Vascular Malformations of the Central Nervous System 765

Edward R. Smith, R. Michael Scott, and Patricia E. Burrows

22. Hereditary Hemorrhagic Telangiectasia 814

Jeffrey S. Pollak and Robert I. White, Jr.

23. Vascular Malformations of the Head and Neck 839

John B. Mulliken

24. Vascular Malformations of the Extremities 905

Joseph Upton, III

25. Truncal, Visceral, and Genital Vascular Malformations 966

Steven J. Fishman

26. Anomalies of the Aorta and Major Branches 1017

James A. O’Neill, Jr.

27. Combined Slow-Flow Vascular Malformation of the Lower Limb: Klippel- Trenaunay Syndrome 1027

David J. Driscoll and Peter Gloviczki with contributions by Steven J. Fishman

28. Orthopaedic Issues in Vascular Malformations 1041

James R. Kasser and Samantha A. Spencer

29. Primary Lymphedema 1056

Neil R. Feins and Arin K. Greene

30. The Emotional Impact of a Vascular Facial Birthmark 1077

Alexandra Murray Harrison

Glossary 1087
Index 1095
This page intentionally left blank
Contributors

Denise M. Adams, M.D. Arin K. Greene, M.D., MMSc

Medical Director, Hemangioma and Vascular Department of Plastic and Oral Surgery
Malformations Center Boston Children’s Hospital
Cincinnati Children’s Hospital Health Medical Associate Professor of Surgery
Center, Division of Hematology-Oncology Harvard Medical School
Professor of Pediatrics, University of Cincinnati Boston, Massachusetts
Cincinnati, Ohio
Alexandra Murray Harrison, M.D.
Joyce Bischoff, Ph.D. Training and Supervising Analyst in Adult, Child
Vascular Biology Program and Adolescent Psychoanalysis,
Department of Surgery Boston Psychoanalytic Society and
Boston Children’s Hospital Institute
Professor of Surgery, Harvard Medical School Assistant Clinical Professor in Psychiatry, Harvard
Boston, Massachusetts Medical School
Laurence M. Boon, M.D., Ph.D. Boston, Massachusetts
Director of Center for Vascular Anomalies
Division of Plastic Surgery, Cliniques universitaires James R. Kasser, M.D.
St. Luc Surgeon-in-Chief
Professor of Plastic Surgery, Université catholique Orthopaedic Surgeon-in-Chief
de Louvain Boston Children’s Hospital
Brussels, Belgium Catherine Ormandy Professor of
Orthopaedic Surgery, Harvard Medical
David J. Driscoll, M.D. School
Division of Pediatric Cardiology, Department of Boston, Massachusetts
Pediatrics
Professor of Pediatrics, Mayo Clinic College of Harry P. W. Kozakewich, M.D.
Medicine Department of Pathology
Rochester, Minnesota Boston Children’s Hospital
Associate Professor of Pathology, Harvard
Odile Enjolras, M.D.
Medical School
APHP, Consultations des Angiomes,
Boston, Massachusetts
Hôpital Lariboisière, Service de Neuroradiologie;
Hôpital d’Enfants Armand Trousseau, Service Marilyn G. Liang, M.D.
de Chirurgie Maxillofaciale et de Chirurgie Division of Dermatology
Plastique; Hôpital Tarnier Paris Boston Children’s Hospital
Neil R. Feins, M.D. Assistant Professor of Dermatology, Harvard
Department of Surgery Medical School
Boston Children’s Hospital Boston, Massachusetts
Clinical Professor of Surgery, Harvard Medical School
Ellis J. Neufeld, M.D., Ph.D.
Boston, Massachusetts
Director, Clinical Hematology, Division of
Peter Gloviczki, M.D. Hematology-Oncology
Chairman, Division of Vascular Surgery, Boston Children’s Hospital
Department of Surgery Professor of Medicine
Professor of Surgery, Mayo Clinic College of Medicine Harvard Medical School
Rochester, Minnesota Boston, Massachusetts
xii Contributors

James A. O’Neill, Jr., M.D. Oon Tian Tan, M.D., Ph.D.

J. C. Foshee Distinguished Professor and Chairman, Emeritus Director of Laser Center
Section of Surgical Sciences Massachusetts Eye and Ear Infirmary
Vanderbilt University School of Medicine Lecturer, Harvard Medical School
Nashville, Tennessee Boston, Massachusetts
Harriet J. Paltiel, M.D.
Joseph Upton, III, M.D.
Department of Radiology
Division of Plastic Surgery
Boston Children’s Hospital
Beth Israel-Deaconess Hospital and Boston Children’s
Associate Professor of Radiology, Harvard Medical School
Hospital
Boston, Massachusetts
Clinical Professor of Surgery, Harvard Medical School
Jeffrey S. Pollak, M.D. Boston, Massachusetts
Co-Section Chief, Vascular and Interventional Radiology
Robert I. White, Jr. Professor of Radiology Miikka Vikkula, M.D., Ph.D.
Yale University School of Medicine Director of Laboratory of Human Molecular Genetics
New Haven, Connecticut Co-director of de Duve Institute
WELBIO & de Duve Institute, Université catholique
R. Michael Scott, M.D. de Louvain
Neurosurgeon-in-Chief, Emeritus Professor of Human Genetics, Université catholique
Boston Children’s Hospital de Louvain
Professor of Surgery, Harvard Medical School Brussels, Belgium
Boston, Massachusetts
Edward R. Smith, M.D. Robert I. White, Jr., M.D.
Director, Pediatric Cerebrovascular Surgery Director of Yale Vascular Malformation Center
Department of Neurosurgery Section of Vascular and Interventional Radiology
Boston Children’s Hospital Professor Emeritus of Radiology, Yale University School of
Associate Professor of Surgery, Harvard Medical School Medicine
Boston, Massachusetts New Haven, Connecticut

Samantha A. Spencer, M.D. Anthony E. Young, M.A., M. Chir., F.R.C.S.

Department of Orthopaedic Surgery Emeritus Consultant Surgeon
Boston Children’s Hospital St. Thomas’ Hospital
Instructor in Orthopaedic Surgery, Harvard Medical School London
Boston, Massachusetts United Kingdom
Foreword

I started my clinical practice in plastic surgery in 1951. Twenty years later, my patient load and research had
increased to such a level that I decided it was time to recruit an associate. My mentor, Dr. Bradford Cannon,
highly recommended a former MGH resident, John Mulliken, as being “dependable” and “imaginative.”
Mulliken joined me in 1974 at the Peter Bent Brigham Hospital and Children’s Hospital.
I gave him an academic push by suggesting that he begin research on a common subject, such as heman-
gioma or skin cancer. Mulliken was much more attracted to pediatric than geriatric tumors. I talked to Dr.
Judah Folkman, and he agreed to have Mulliken work in the vascular biology laboratory. Dr. Julie Glowacki
joined the group shortly thereafter. At this same time, Tony Young was a fellow in vascular surgery at The
Brigham; he had written his Cambridge thesis (M. Chir.) on “Mixed Vascular Deformities of the Limbs.”
Mulliken and Young met in my office and immediately became friends based on their shared fascination
with vascular anomalies. With my encouragement, they initiated biennial local, then international, work-
shops for the Study of Vascular Anomalies.
That is how it all began. The landmark paper that defined the biological differences between vascular
tumors and malformations was published in 1982. Mulliken and Young’s volume Vascular Birthmarks:
Hemangiomas and Malformations (1988) is a classic. This updated version encompasses all that is currently
known by all involved medical and surgical specialists who care for patients with vascular anomalies. Mulliken
has enlisted two internationally recognized colleagues as co-authors: Patricia Burrows, interventional radi-
ologist, and Steven Fishman, pediatric surgeon. Contributing authors include other team members of the
Children’s Hospital Vascular Anomalies Center and well-known experts from other units.
I could never have imagined that mentoring a young colleague would lead to the emergence of a new,
truly interdisciplinary, field of medicine and surgery, with its own textbook now in second edition.

Joseph E
E. Murray
Murray, M D
M.D.
Nobel Laureate in Medicine or Physiology (1990)
Emeritus Professor of Surgery, Harvard Medical School
This page intentionally left blank
Preface

The First Edition of this book was conceived 25 years ago by two young surgeons. Their 1988 text was an
attempt to give structure and meaning to a diffuse and confusing group of disorders for which science had
made few inroads and clinical care was often haphazard or simply ignorant. The field of vascular anomalies
was once terra incognita, located beyond the major vessels and named tributaries and obscured by a cloud
of terminological confusion. Now this haze has largely lifted to reveal a wondrous realm. Most of the clini-
cal patterns and interrelations can be seen quite clearly. This emerging clarity also has stimulated ever more
basic scientific inquiry and has encouraged inter-specialty communication and new therapeutic strategies.
Patients with vascular anomalies and their families no longer wander as “medical nomads,” searching for
someone who understands their problems. Interdisciplinary teams and referral centers have been estab-
lished, providing patients access to optimal specialized care. The authors of the First Edition initiated bien-
nial international workshops in 1976; these were later formalized as meetings of the International Society
for the Study of Vascular Anomalies (ISSVA).
There were not quite six pages on pathogenesis of vascular malformations in the First Edition. The revo-
lution in molecular genetics has made possible the discovery of genes responsible for embryonic vascular
development, while the study of familial vascular anomalies has permitted the pursuit and exposure of
mutated genes. Basic research can now proceed from a structured knowledge and holds the promise of a
“molecular classification” of vascular anomalies, and more importantly, novel therapies.
There was only one magnetic resonance image in the First Edition. The technological advances in radiol-
ogy have revolutionized the field and necessitated radiologic subspecialists in vascular anomalies. Diagnostic
and interventional radiologists are first-line members of the vascular anomalies team. Ultrasonography and
magnetic resonance imaging (MRI) are routine. Ultrasonic prenatal diagnosis is common, and antenatal
MRI is available in specialized centers.
These advances have not shown any limits to this young and fascinating field; rather, they have revealed
that there is far more to learn. This new era has impelled the authors to muster their colleagues for a Second
Edition. Although much is new in this Second Edition, we have preserved the themes of the first volume: to
provide historical perspective, to choose our words precisely, to ground nomenclature in science as well as
clinical observation, and to acknowledge what we do not know.
Our subjects remain those often complex vascular disorders that occupy a common ground shared by der-
matologists, radiologists, surgical specialists (plastic, pediatric, maxillofacial, ophthalmologic, orthopedic,
otorhinolaryngologic), pathologists, pediatricians, geneticists, hematologists-oncologists, and vascular biol-
ogists. To acknowledge that this field extends beyond what was implied in the original Vascular Birthmarks,
the title has been enlarged to Vascular Anomalies so as to admit the other organ systems on an equal standing.
Although “hemangiomas” remains in the subtitle, other rare, and often more aggressive, vascular tumors are
included. The authors began writing this Second Edition over 10 years ago. We continually learned during
this decade of gestation. We believe that this textbook is worth the wait and hope our readers agree. Our
book is not the final word in a realm that is evolving so rapidly. Nevertheless, we hope that it presents a
comprehensive synthesis of current knowledge in the field—the well-known regions as well as the murky
backwaters that need further exploration.

John B. Mulliken
Patricia E. Burrows
Steven J. Fishman
This page intentionally left blank
Preface from Mulliken and Young’s
Vascular Birthmarks (1988)

Of every three children born, one will have a vascular birthmark, a red, blue, or purple blemish. The great
majority of these stains will fade or remain small and inconsequential. One child in a hundred will have a
vascular birthmark that requires an opinion from a doctor or referral to a specialist. Fortunately, gross and
disfiguring lesions are rare; however, many of these patients will become, in a sense, medical nomads, search-
ing for someone who understands their problems. The primary practitioner, whether a family physician,
pediatrician, or surgeon, will usually have little or no experience with diagnosis and management of the
uncommon vascular birthmarks. It is to these doctors, together with those familiar and fascinated, that this
book is directed.
Parents with blemished or malformed children put enormous pressures on medical advisors. The bur-
den of perinatal anxiety is such that early and accurate diagnosis and prognosis are essential. At the earliest
opportunity, parents should be given some indication of what the future may hold, including what kind
of treatment may be feasible or necessary. Our experience has been that both the referring physician and
the referral clinic may lack the expertise to give this advice, and months or even years can elapse before the
patient reaches someone familiar with these conditions. By this time, the family may be discouraged after
needless investigation and searching for a knowledgeable physician, or after unnecessary or even counterpro-
ductive procedures may have been performed.
This book is both medical and surgical. It is intended as a reference for both primary and secondary care
physicians and surgeons. Wherever possible, biological and physiological data are given. Our purpose is that
this text will help in the diagnosis and differential diagnosis, and allow rational investigation, correct prog-
nosis, and proper treatment. The journals are largely unhelpful for this task, as papers tend to be single case
reports or discuss small series. The general textbooks may be disappointingly brief or inaccurate. Of the two
specialist volumes, one is out of print and the other is not written in English.
A confusing nomenclature has been largely responsible for illogical thinking on the subject of vascu-
lar birthmarks. Edward Sapir, the American anthropologist and linguist, believed that “language structures
thought.” Mindful of this concept, we have made a concerted effort to free our subject from its old termino-
logical chamber of horrors. Based on clinical and cellular studies, vascular birthmarks are divided into two
major categories: hemangiomas and malformations. The chapters are organized under these headings. We
have used a consistent terminology throughout this book and have provided a glossary to relate our nosolog-
ical system to terms found elsewhere in the literature. This field is also replete with syndromic designations,
usually prefixed with personal names. All too often, eponymy lulls us into a false sense of knowledge. Hence,
we have tried whenever possible to define these syndromes in anatomical words. We hope that by present-
ing vascular birthmarks in clear and understandable terminology, our book will not only assist in improved
patient care but will also stimulate studies of pathogenesis.
The expression “vascular birthmark” used in the title is necessarily broad, and the intention was to signal
that in this book we hope to encompass the common hemangiomas of infancy as well as the developmental
aberrations of the vascular system—arterial, venous, capillary, and lymphatic—that show themselves in the
skin. We have, in addition, included chapters on vascular abnormalities affecting the central nervous system
and abdominal viscera, as they may be associated with cutaneous marks. We have not touched on anomalies
of the heart, great vessels, the eye, or the lung, as these are amply discussed elsewhere.
This book was written by two surgeons, one from Old England and one from New England, who share
a fascination with vascular birthmarks. In a desire for textual uniformity, the authors have taken great pains