Skin Disease in Organ Transplantation

Skin Disease in Organ Transplantation

Skin disease is a serious, long-term problem for the recipients of solid organ transplants. The potent systemic immunosuppression therapy necessary to sustain a life-saving solid organ transplant is associated with many adverse cutaneous effects, including significantly increased rates of cutaneous malignancies, difficult-to-treat cutaneous infections, and cutaneous adverse manifestations of multiple medications. Skin Disease in Organ Transplantation is the first scholarly compilation of the knowledge base surrounding the care of solid organ transplant recipients with dermatologic diseases. Supplemented with dozens of full-color photographs, this work brings together decades of knowledge into a cohesive format and establishes transplant dermatology as an important subspecialty within the field of dermatology and transplant medicine. Skin Disease in Organ Transplantation is an outstanding resource for transplant providers and dermatologists to determine the optimal diagnostic and therapeutic approach to the difficult problems of cutaneous disease in organ transplant recipients. Dr. Clark C. Otley is Chair of the Division of Dermatologic Surgery at Mayo Clinic and Professor of Dermatology at Mayo Clinic College of Medicine. He was the founding President of The International Transplant-Skin Cancer Collaborative, an organization dedicated to the advancement of clinical care and research for transplant patients with skin cancer and skin diseases. Dr. Otley attended medical school at Duke University School of Medicine and then received his specialty training in dermatology at Harvard University, serving as chief resident of the Department of Dermatology at Massachusetts General Hospital in 1995. He subsequently completed a fellowship in cutaneous oncology and Mohs micrographic surgery at Mayo Clinic, finishing in 1996. Dr. Otley has served on the Board of Directors of the American College of Mohs Micrographic Surgery and Cutaneous Oncology, as well as the Association of Academic Dermatologic Surgeons. He is a reviewer for the New England Journal of Medicine, the Archives of Dermatology, Dermatologic Surgery, and the Journal of the American Academy of Dermatology. He received the Young Leaders Award from the American Dermatologic Association prior to his induction to that organization. Dr. Otley has written more than 70 original research articles and lectures nationally and internationally. Dr. Thomas Stasko is Associate Professor of Medicine (Dermatology) at Vanderbilt University in Nashville, Tennessee. He received his medical degree from the University of Texas Health Science Center in San Antonio in 1977. After an internship at the U.S. Air Force Medical Center at Scott AFB, Illinois, he served as a General Medical Officer before completing a residency in dermatology at the University of Texas Health Science Center in 1983. His fellowship training in Mohs micrographic surgery was at Tufts/New England Medical Center in Boston. Dr. Stasko is the current President of the International Transplant-Skin Cancer Collaborative and also serves on the Board of Directors of the American College of Mohs Micrographic Surgery and Cutaneous Oncology. He has lectured and published widely on cutaneous oncology in solid organ transplant recipients.

Skin Disease in Organ Transplantation

EDITED BY

Clark C. Otley, MD

Thomas Stasko, MD

Professor of Dermatology Chair, Division of Dermatologic Surgery Department of Dermatology, Mayo Clinic Mayo Clinic College of Medicine Rochester, MN, USA

Associate Professor of Medicine (Dermatology) Vanderbilt University Medical Center Nashville, TN, USA

Matthew D. Griffin, MB, BCh Associate Professor of Medicine, Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, William J von Liebig Transplant Center, Rochester, MN, USA

Gillian M. Murphy, MD, FRCPI, FRCP, Edin Consultant Dermatologist, Senior Lecturer, Department of Dermatology, Beaumont and Mater Misericordiae Hospitals and Royal College of Surgeons in Ireland, Dublin, Ireland

Ryutaro Hirose, MD Associate Professor in Clinical Surgery, Division of Transplantation, Department of Surgery, University of California, San Francisco, CA, USA

Alvin H. Chong, FACD, MMed (Melb), MBBS Consultant Dermatologist and Lecturer in Dermatology, Department of Medicine (Dermatology), St. VincentÕs Hospital Melbourne, University of Melbourne, Melbourne, Victoria, Australia

CAMBRIDGE UNIVERSITY PRESS

Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo Cambridge University Press The Edinburgh Building, Cambridge CB2 8RU, UK Published in the United States of America by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/9780521870672 © Cambridge University Press 2008 This publication is in copyright. Subject to statutory exception and to the provision of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published in print format 2007 eBook (NetLibrary) ISBN-13 978-0-511-37132-5 ISBN-10 0-511-37132-2 eBook (NetLibrary) ISBN-13 ISBN-10

hardback 978-0-521-87067-2 hardback 0-521-87067-4

Cambridge University Press has no responsibility for the persistence or accuracy of urls for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. Every effort has been made in preparing this publication to provide accurate and up-todate information that is in accord with accepted standards and practice at the time of publication. Nevertheless, the authors, editors, and publisher can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors, and publisher therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

To our patients, whose suffering inspires this work and whose courage teaches us every day. To my wife, Jill, and our wonderful children, Taylor, Kendall, Grant, and Keller, who are my inspiration. And to Stu Salasche, MD, for his enthusiasm and steadfast support. – Clark C. Otley, MD To MaryAnn, my wife and partner in all things; my daughter Emily for encouragement and technical support; my son Roary and his wife Jenny for inspiring me to take on new adventures. To organ transplant patients, their families, my nurses, and staff, who together show how medicine can be so human. And to Stu. – Thomas Stasko, MD To our remarkable colleagues, patients, and their families. – Matthew D. Griffin, MB BCh To my husband, David, who inspires me, to my ever-cheerful children, Jenny and Simon, to my parents, Nuala and Michael, who always encourage me, and especially to my patients, whose courage and optimism motivate me to do my best for them. – Gillian M. Murphy, MD, FRCPI, FRCP, Edin To my patients, who have taught me the meaning of courage and grace. To my patient wife, Mivic, and our two beautiful children, Kentaro and Kyoko, who have taught me the meaning of love. – Ryutaro Hirose, MD To the memory of my father, Tong Chin. – Alvin H. Chong, FACD, MMed (Melb), MBBS

Contents

List of Contributors Foreword by Daniel R. Salomon Foreword by Robin Marks Foreword by Kathy Schwab Preface Acknowledgments

ix xiii xv xvii xix xxi

SECTION FOUR – CUTANEOUS EFFECTS OF IMMUNOSUPPRESSIVE MEDICATIONS

10. Cutaneous Effects of Immunosuppressive Medications Conway C. Huang

67

SECTION FIVE – INFECTIOUS DISEASES OF THE SKIN IN SECTION ONE – TRANSPLANT DERMATOLOGY: AN EVOLVING DYNAMIC FIELD

TRANSPLANT DERMATOLOGY

1. Introduction to Transplant Dermatology Thomas Stasko, Clark C. Otley

11. Bacterial Diseases in Organ Transplant Recipients Richard A. Johnson, Jennifer Y. Lin 12. Fungal Diseases in Organ Transplant Recipients Alexandra Geusau, Elisabeth Presterl 13. Viral Diseases in Organ Transplant Recipients Richard A. Johnson, Jennifer Y. Lin 14. Mycobacterial Diseases in Organ Transplant Recipients Alexandra Geusau, Elisabeth Presterl

3

SECTION TWO – TRANSPLANT MEDICINE AND DERMATOLOGY

2. The History of Organ Transplantation Henry W. Randle 3. The Development of Modern Immunosuppressive Medications Ryutaro Hirose, Matthew D. Griffin 4. Organ Transplantation: Current Status and Practice Matthew D. Griffin 5. The Immunology of Transplantation and Allograft Rejection Matthew D.Griffin, Ryutaro Hirose 6. Allograft-Specific Considerations in Transplant Dermatology Ryutaro Hirose, Clark C. Otley 7. Dermatologic Disease from the Transplant Perspective Matthew D. Griffin

9

13

88 98

106

SECTION SIX – BENIGN AND INFLAMMATORY SKIN DISEASES IN TRANSPLANT DERMATOLOGY

22

15. The Effects of Transplantation on Preexisting Dermatoses Namrata Sadanand Anavekar, Theresa R. Pacheco, Shawn E. Cowper 16. Porokeratosis in Organ Transplant Recipients Charlotte Proby, Catherine Harwood 17. Benign Cutaneous Neoplasms in Organ Transplant Recipients Catherine Harwood, Charlotte Proby 18. Anogenital Cutaneous Disease in Organ Transplant Recipients Karen L. Gibbon, Heena Patel, Charlotte Proby 19. Cutaneous Graft versus Host Disease after Solid Organ Transplantation Theresa R. Pacheco, Christina Rapp Prescott

29

39

46

SECTION THREE – PATHOGENIC FACTORS IN TRANSPLANT DERMATOLOGY

8. Basic Scientific Mechanisms of Accelerated Development of Squamous Cell Carcinoma in Organ Transplant Recipients John A. Carucci 9. Pathogenic Factors Involving Infections in Transplant Dermatology Jennifer Y. Lin, Richard A. Johnson

83

53

113

119

122

128

131

SECTION SEVEN – CUTANEOUS ONCOLOGY IN TRANSPLANT DERMATOLOGY

60

20. The Pathogenesis of Skin Cancer in Organ Transplant Recipients Gillian M. Murphy, Fergal Moloney vii

137

viii

21. The Epidemiology of Skin Cancer in Organ Transplant Recipients Bernt Lindelo¨f 22. The Clinical Presentation and Diagnosis of Skin Cancer in Organ Transplant Recipients Stephen D. Hess, Chrysalyne D. Schmults 23. Actinic Keratosis in Organ Transplant Recipients Cara Holmes, Alvin H. Chong 24. Basal Cell Carcinoma in Organ Transplant Recipients Jonathan Ng, Peter Foley 25. Squamous Cell Carcinoma in Organ Transplant Recipients Bradley T. Kovach, Thomas Stasko 26. Malignant Melanoma in Organ Transplant Recipients Leslie J. Christenson 27. Merkel Cell Carcinoma in Organ Transplant Recipients Paul Nghiem, Natalia Jaimes 28. Kaposi’s Sarcoma in Organ Transplant Recipients Sylvie Euvrard, Jean Kanitakis 29. Posttransplant Lymphoproliferative Disorder/ Lymphoma in Organ Transplant Recipients Leslie Robinson-Bostom, Kevan G. Lewis 30. Rare Cutaneous Neoplasms in Organ Transplant Recipients Marcy Neuburg 31. Histopathologic Features of Skin Cancer in Organ Transplant Recipients Kevan G. Lewis, Leslie Robinson-Bostom

CONTENTS

142

147 162

167

172

182

190 195

199

203

208

37. Transplant Hands: Severe Actinic Damage of the Hands in Organ Transplant Recipients Siegrid S. Yu, Rebecca S. Yu, Whitney D. Tope 38. Skin Cancer and Nevi in Pediatric Organ Transplant Recipients Fatemeh Jafarian, Julie Powell, Afshin Hatami 39. Dermatologic Surgery in Organ Transplant Recipients Clark C. Otley 40. Radiation Therapy in Organ Transplant Recipients Michael J. Veness 41. Reduction of Immunosuppression for TransplantAssociated Skin Cancer Clark C. Otley, Ryutaro Hirose 42. Systemic Retinoids for Prevention of Skin Cancer in Organ Transplant Recipients Jan Nico Bouwes Bavinck, J. W. de Fijter 43. Topical Treatment of Actinic Keratosis and Photodamage in Organ Transplant Recipients Warren Weightman 44. Imiquimod Use in Organ Transplant Recipients Summer R. Youker 45. Photodynamic Therapy in Organ Transplant Recipients Nathalie C. Zeitouni, Allan R. Oseroff 46. Skin Cancer Prevention and Photoprotection in Organ Transplant Recipients Sumaira Z. Aasi 47. Skin Cancer Prior to Organ Transplantation or Organ Donation Clark C. Otley, Ryutaro Hirose

242

246

249 254

262

272

277 286

291

295

302

SECTION EIGHT – SPECIAL SCENARIOS IN TRANSPLANT

SECTION NINE – EDUCATIONAL, ORGANIZATIONAL, AND

CUTANEOUS ONCOLOGY

RESEARCH EFFORTS IN TRANSPLANT DERMATOLOGY

32. Metastatic Squamous Cell Carcinoma in Organ Transplant Recipients 217 Randall K. Roenigk, David L. Appert, Kelly L. Brunner, Jerry D. Brewer 33. In-Transit Metastatic Squamous Cell Carcinoma in Organ Transplant Recipients 224 John A. Carucci 34. Metastatic Malignant Melanoma in Organ Transplant Recipients 228 Claas Ulrich, Charlotte Proby, Steve Nicholson, Catherine Harwood 35. Transplant Scalp: Severe Actinic Damage of the Scalp in Organ Transplant Recipients 234 Jennifer Z. Cooper, Marc D. Brown 36. Transplant Lip: Severe Actinic Damage of the Vermilion in Organ Transplant Recipients 238 Heather D. Rogers, Elbert H. Chen, De´sire´e Ratner

48. Quality of Life Associated with Dermatologic Disease in Organ Transplant Recipients Fiona O’Reilly Zwald 49. Patient Education in Transplant Dermatology: Pre- and Post Transplant Jeffrey C. H. Donovan, James C. Shaw 50. Transplant Dermatology Clinics Alvin H. Chong, Cara Holmes 51. Transplant Dermatology Organizations Henry W. Randle 52. Research Databases for Transplant Dermatology Jennifer Reichel 53. Resources for Transplant Dermatology Clark C. Otley Index

311

315 322 327 331 336

341

List of Contributors

Weill Medical College of Cornell University New York Presbyterian Hospital New York, NY USA Elbert H. Chen, MD Fellow in Mohs Micrographic Surgery Department of Dermatology Columbia University College of Physicians and Surgeons New York, NY USA Alvin H. Chong, FACD, MMed (Melb), MBBS Consultant Dermatologist and Lecturer in Dermatology Department of Medicine (Dermatology) St. VincentÕs Hospital Melbourne University of Melbourne Melbourne, Victoria AUSTRALIA Leslie J. Christenson, MD Assistant Professor, Mayo Medical School Department of Dermatology Mayo Clinic Rochester, MN USA Jennifer Z. Cooper, MD Assistant Professor of Dermatology Department of Dermatology University of Maryland Baltimore, MD USA Shawn E. Cowper, MD Assistant Professor of Dermatology and Pathology Department of Dermatology Yale University New Haven, CT USA J. W. de Fijter, MD, PhD Department of Nephrology Leiden University Medical Center Leiden The NETHERLANDS Jeffrey C. H. Donovan, MD, PhD Dermatology Resident Department of Medicine

Sumaira Z. Aasi, MD Assistant Professor Department of Dermatology Yale School of Medicine New Haven, CT USA Namrata Sadanand Anavekar MBBS (hons) Dermatology Resident Department of Dermatology St. VincentÕs Hospital Melbourne, Victoria AUSTRALIA David L. Appert, MD Mid Dakota Dermatologic Surgery, Cosmetics, & Laser Center Bismark, ND USA Jan Nico Bouwes Bavinck, MD, PhD Department of Dermatology Leiden University Medical Center Leiden The NETHERLANDS Jerry D. Brewer, MD Resident Department of Dermatology Mayo Graduate School of Graduate Medical Education Mayo Clinic College of Medicine Rochester, MN USA Marc D. Brown, MD Professor of Dermatology Department of Dermatology University of Rochester Rochester, NY USA Kelly L. Brunner, MD Resident Department of Dermatology Mayo Graduate School of Graduate Medical Education Mayo Clinic College of Medicine Rochester, MN USA John A. Carucci, MD, PhD Director, Mohs Micrographic and Dermatologic Surgery ix

x

LIST OF CONTRIBUTORS

University of Toronto Toronto, Ontario CANADA Sylvie Euvrard, MD Department of Dermatology Hoˆpital Edouard Herriot Lyon FRANCE Peter Foley, MBBS, BMedSc, MD, FACD Associate Professor Department of Medicine (Dermatology), St. VincentÕs Hospital Melbourne University of Melbourne Melbourne, Victoria AUSTRALIA Alexandra Geusau, MD Associate Professor Department of Dermatology Division of Immunology, Allergy, and Infectious Diseases Medical University of Vienna Vienna, AUSTRIA Karen L. Gibbon, MB, ChB, BSc (Hons), MRCP Consultant Dermatologist Whipps Cross University Hospital London UNITED KINGDOM Matthew D. Griffin, MB, BCh Associate Professor of Medicine, Mayo Clinic College of Medicine Department of Medicine, Division of Nephrology and Hypertension Mayo Clinic Rochester, MN USA Catherine Harwood, MA, MBBS, MRCP, PhD Clinical Senior Lecturer and Honorary Consultant in Dermatology Centre for Cutaneous Research Institute of Cell and Molecular Science Barts and the London Queen MaryÕs School of Medicine and Dentistry London UNITED KINGDOM Afshin Hatami, MD, FRCPC Assistant Professor Pediatric Dermatology Sainte Justine Hospital Montreal, Quebec CANADA Stephen D. Hess, MD, PhD Dermatology Resident Department of Dermatology University of Pennsylvania Philadelphia, PA USA

Ryutaro Hirose, MD Associate Professor in Clinical Surgery Division of Transplantation Department of Surgery University of California, San Francisco San Francisco, CA USA Cara Holmes, MBBS Research Fellow Department of Medicine (Dermatology) St. VincentÕs Hospital Melbourne University of Melbourne Melbourne, Victoria AUSTRALIA Conway C. Huang, MD Associate Professor and Director of Dermatologic Surgery Department of Dermatology University of Alabama at Birmingham Birmingham, AL USA Fatemeh Jafarian, MD Pediatric Dermatology Fellow Pediatric Dermatology Sainte Justine Hospital Montreal, Quebec CANADA Natalia Jaimes, MD Dermatology Resident Universidad Pontificia Bolivariana Medellı´n, Colombia SOUTH AMERICA Richard A. Johnson, MD Instructor of Dermatology Department of Dermatology Harvard Medical School Massachusetts General Hospital Boston, MA USA Jean Kanitakis, MD Department of Dermatology Hoˆpital Edouard Herriot Lyon, FRANCE Bradley T. Kovach, MD Clinical Instructor Center for Dermatologic and Cosmetic Surgery Washington University School of Medicine St. Louis, MO USA Kevan G. Lewis, MD Dermatology Resident Department of Dermatology Brown Medical School/Rhode Island Hospital Providence, RI USA

LIST OF CONTRIBUTORS

Jennifer Y. Lin, MD Harvard Dermatology Program Department of Dermatology Massachusetts General Hospital; Harvard Medical School Boston, MA, USA Bernt Lindelo¨f, MD, PhD Adjunct Professor of Dermatology Department of Dermatology and Venereology Karolinska University Hospital and Karolinska Institute Stockholm SWEDEN Fergal Moloney, MD, MRCPI Department of Dermatology Beaumont Hospital Dublin, IRELAND Gillian M. Murphy, MD, FRCPI, FRCP, Edin Consultant Dermatologist, Senior Lecturer Department of Dermatology Beaumont and Mater Misericordiae Hospitals and Royal College of Surgeons in Ireland Dublin, IRELAND Marcy Neuburg, MD Associate Professor Dermatology, Plastic Surgery, and Otolaryngology Medical College of Wisconsin Milwaukee, WI USA Jonathan Ng, MBBS, BMedSc Research Fellow Department of Medicine (Dermatology), St. VincentÕs Hospital Melbourne University of Melbourne Melbourne, Victoria AUSTRALIA Paul Nghiem, MD, PhD Assistant Professor University of Washington Dermatology/Medicine Fred Hutchinson Cancer Research Center Seattle, WA USA Steve Nicholson, MRCP, PhD Locum Consultant in Medical Oncology St. BartholomewÕs & The Royal London Hospitals London, UK Southend Hospital Southend, UK Fiona OÕReilly Zwald, MD Metropolitan Dermatologic Surgery, P.C. Atlanta, GA USA Allan R. Oseroff, MD, PhD Lawrence P. and Joan Castellani Family Endowed Chair in Dermatology Professor and Chair of Dermatology,

xi

Roswell Park Cancer Institute and State University of New York at Buffalo Roswell Park Cancer Institute Buffalo, NY USA Clark C. Otley, MD Professor of Dermatology, Mayo Clinic College of Medicine Chair, Division of Dermatologic Surgery Department of Dermatology Mayo Clinic Rochester, MN USA Theresa R. Pacheco, MD Assistant Professor of Dermatology Department of Dermatology University of Colorado at Denver and Health Sciences Center Aurora, CO USA Heena Patel, BSc, MBBS, MRCS Clinical Research Fellow Colorectal Cancer Unit St. MarkÕs Hospital London UNITED KINGDOM Julie Powell, MD, FRCPC Associate Professor Pediatric Dermatology Sainte Justine Hospital Montreal, Quebec CANADA Christina Rapp Prescott, PhD Medical Student Department of Dermatology University of Colorado at Denver and Health Sciences Center Aurora, CO USA Elisabeth Presterl, MD Associate Professor Department of Medicine Division of Infectious Diseases Medical University of Vienna Vienna, AUSTRIA Charlotte Proby, BA, MBBS, FRCP Clinical Senior Lecturer and Honorary Consultant in Dermatology Centre for Cutaneous Research Institute of Cell and Molecular Science Barts and the London Queen MaryÕs School of Medicine and Dentistry London UK Henry W. Randle, MD, PhD Professor of Dermatology

xii

LIST OF CONTRIBUTORS

Department of Dermatology Mayo Clinic Jacksonville, FL USA De´sire´e Ratner, MD George Henry Fox Associate Clinical Professor of Dermatology Department of Dermatology Columbia University Medical Center New York, NY USA Jennifer Reichel, MD Acting Assistant Professor Dermatologic Surgery University of Washington Seattle, WA USA Leslie Robinson-Bostom, MD Associate Professor of Dermatology Department of Dermatology Brown Medical School/Rhode Island Hospital Providence, RI USA Randall K. Roenigk, MD Professor & Chair Department of Dermatology Mayo Clinic College of Medicine Mayo Clinic/Foundation Rochester, MN USA Heather D. Rogers, MD Resident Department of Dermatology Columbia University Medical Center New York, NY USA Chrysalyne D. Schmults, MD Assistant Professor of Dermatology Director of Research, Division of Dermatologic Surgery University of Pennsylvania Philadelphia, PA USA James C. Shaw, MD, FRCPC Associate Professor Division of Dermatology, Department of Medicine University of Toronto Toronto, Ontario CANADA Thomas Stasko, MD Associate Professor of Medicine (Dermatology)

Vanderbilt University School of Medicine Nashville, TN USA Whitney D. Tope, MPhil, MD Metropolitan Dermatology & Cutaneous Surgery Wayzata, MO USA Claas Ulrich, MD Department of Dermatology, Charite´ Charite´ University Hospital Berlin, GERMANY Michael J. Veness, MBBS, MMed (Clin Epi), FRANZCR Clinical Senior Lecturer, Univeristy of Sydney Department of Radiation Oncology Westmead Hospital Sydney, New South Wales AUSTRALIA Warren Weightman, MBBS, FRACP, FACD Senior Lecturer, Univeristy of Adelaide Department of Dermatology Queen Elizabeth Hospital Woodville, South Australia AUSTRALIA Summer R. Youker, MD Assistant Professor Department of Dermatology St. Louis University St. Louis, MO USA Rebecca S. Yu, MD Clinical Instructor Department of Orthopaedics University of California, San Francisco San Francisco General Hospital San Francisco, CA USA Siegrid S. Yu, MD Clinical Instructor Department of Dermatology Dermatologic Surgery & Laser Center University of California, San Francisco San Francisco, CA USA Nathalie C. Zeitouni, MDCM, FRCPC Chief, Dermatologic Surgery Roswell Park Cancer Institute and Associate Professor of Clinical Dermatology State University of New York at Buffalo Buffalo, NY USA

Foreword – Transplant Dermatology: Skin Disease in Organ Transplant Recipients

Daniel R. Salomon, MD Co-Director, Scripps Center for Organ and Cell Transplantation, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA

In parallel with the etiological challenges, there is little standardization in the postcomplication management of these same patients. In general, when faced with a really serious posttransplant malignancy requiring surgical and medical therapy, we reduce the immunosuppression, but, in the absence of objective metrics for the level of immunosuppression, this is obviously based on best judgment and experience. However, of less certainty is the management of the many patients who are seen by dermatologists for uncomplicated, surgically treated skin malignancies. Although I might reduce immunosuppression slightly in these patients, an important open question is what the best approach is for the current immunosuppressive drug regimes or whether that is even appropriate given the potential impact of lowering immunosuppression on long-term graft survival and chronic rejection. For all these reasons and others detailed in this new textbook, it is critical to consider the importance of our partnership with experts in dermatology. It is important to encourage their participation in our regular clinical practice, to encourage our patients to see a dermatologist yearly after transplantation, to increase the understanding of transplant dermatology in all transplant physicians, and to participate actively in efforts underway and driven by the dermatology community to educate our patients to reduce sun exposure and use the latest generation of sun-blocking agents. Finally, as we continue forward in the constant evolution of transplantation, we need to include transplant dermatology outcome measures and ongoing analysis in our next generation of clinical trials. May 23, 2006

It is a singular honor to contribute a foreword to this new and comprehensive textbook on the science, art, and practice of transplant dermatology. As a transplant clinician with over 25 years of experience, I believe it is critical to admit right from the start that this is one area of our formal training that is significantly limited, which is counterintuitive, because among the most common late posttransplant complications are a variety of malignant and premalignant skin lesions. In addition, there are other classes of infection-related as well as nonmalignant, noninfectious skin changes that are less well understood and difficult to diagnose without expert dermatological assistance, and, in many instances, biopsy histology. A key point is that these lesions are caused by a complex mix of patient-specific history including sun exposure, lifestyle, environmental hazards, exogenous toxins, race and ethnicity, as well as the long-term impacts of our immunosuppressive drug regimes. This etiological complexity is greatly magnified, following a decade in which several new immunosuppressive drugs have been introduced and standard practice in dosing and target levels constantly changed. Azathioprine has given way to widespread use of formulations of mycophenolic acid. Induction therapies can include powerful panlymphocyte agents or more selective IL2 receptor blockers. Cyclosporine or FK506 is used in combinations now with rapamycin formulations, and more complicated regimes of initial use of calcineurin inhibitors (CNIs) with mycophenolic acid formulations followed by switching CNIs to rapamycin, are being studied. Thus, even for experienced clinicians, it is near impossible to determine the exact correlations of any specific component to the appearance of a dermatological complication, especially a malignancy.

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Foreword – ‘‘Life is a Matter of Balance’’

Robin Marks, MBBS, MPH, FRACP, FACD Professor of Dermatology, University of Melbourne, Melbourne, Australia

The book concentrates on the diseases consequent upon an organ transplantation, rather than diseases resulting in the need for it. There are many changes manifest on the skin in patients who have had organ transplantation, as can be seen in the variety of chapters in the book and the composition of each of them. The fact that there are so many changes, and so much effort is required to cope with the result, clearly reflects how important balance is in maintenance of the normal corpus. Although transplant immunologists may not agree, all these unwanted effects of organ transplantation are also a reflection of our relatively crude way of dealing with organ failure. But, having said that, there is no doubt that the ability to change the balance in favor of maintenance of the transplanted organ, and the provision of a satisfactory life that most people lead following organ transplantation, is a reflection that we have come a long way. Much can be done now. Much more remains to be done in the future. Organ transplantation offers a substantial improvement in outlook for those people with organ failure of various types. This textbook goes a long way to assisting those who are charged with the responsibility of dealing with the potential risks associated with our current solution to that problem.

The human body is a wonderful instrument. It has a huge number of complex integrated and interactive systems, all working together to comprise a fully functioning corpus. It is capable of surviving by adapting to change in the environmental circumstances in which it finds itself. Like most other complex instruments, its flexibility and ability to respond to demand, and hence survive, is dependent on a fine balance. Although the balance is generally between opposites, the outcome is seen as an overall steady state with fine changes occurring all the time to maintain the balance. All components of organ transplantation in humans reflect the general principles of life being a matter of balance. The various diseases that lead to the organ failure, and thus the need for organ transplantation, are a manifestation of either an acute or a chronic loss of balance that is life threatening. The process of replacing the failed organ requires a deliberate or medically-induced change in balance in the ability of the corpus to protect itself from an environmental challenge. This applies particularly to an immunological response to the organ transplanted. One could predict that a chronic imbalance, such as the immunosuppression required for organ transplantation, would inevitably lead to disease. Hence the need for this book.

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Foreword

Kathy Schwab, RN, BSN, CCTC President, International Transplant Nurses Society, Rochester, MN, USA

for many of our transplant patients who have achieved extended graft survival. Skin cancer has emerged as a significant and life-threatening issue. In Skin Disease in Organ Transplantation, world experts provide state-of-the-art information and practical management guidance for all physicians, nurses, and transplant coordinators involved in the care of transplant patients. The future of transplantation remains bright, as areas such as skin cancer are scrutinized and examined. Transplant nurses play an important role in collaborating with physicians to prevent and manage skin cancer. This text provides a valuable resource for transplant professionals in all roles to decrease the prevalence and significance of skin cancer for transplant patients in the future.

The International Transplant Nurses Society is committed to the promotion of excellence in transplant clinical nursing, through the provision of educational and professional growth opportunities, interdisciplinary networking, and collaborative activities, as well as transplant nursing research. Organ transplantation remains one of the more exciting and scientifically interesting success stories in medicine that has evolved during the 20th century. Transplantation has a short history dating back to 1954, when the first kidney transplant between identical twins was performed successfully. Remarkable understanding of the immunology of transplantation and the development of immunosuppressive drugs has allowed tremendous strides in solid organ transplantation. Although there is considerable optimism, problems exist

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Preface

Clark C. Otley, MD, and Thomas Stasko, MD

previously, we owe great appreciation. Skin Disease in Organ Transplantation represents the consolidation of an enormous body of important clinical experience and critical research that will guide the optimal care of these special patients. With the body of current knowledge coalesced in this work, we now embark upon the more difficult task of expanding the reach of our knowledge and the sophistication of our practice in the future. We hope that Skin Disease in Organ Transplantation will serve as an important resource for multiple constituents in the field of transplantation. Certainly, transplant dermatologists, general dermatologists, and dermatologic surgeons will benefit greatly from the information contained in this book. Transplant physicians and surgeons will likewise benefit from enhancing their knowledge of the important dermatologic manifestations they may be called upon to recognize in many of their patients. Prompt recognition of pathognomonic dermatologic findings, both neoplastic and infectious, can literally provide an opportunity to prevent a lethal outcome. Transplant coordinators and nurses are an incredibly important group of health care providers who are key partners in our goal to promote prevention, early recognition, and treatment of potentially life-altering cutaneous disease in chronically immunosuppressed patients through education and primary prevention strategies. Transplant dermatologists have greatly enjoyed interactions with our other non-organ-specific transplant physicians and colleagues, who we feel will benefit from increased knowledge of the cutaneous diseases they may encounter during their interactions with transplant patients. Our trainees and students can look to this resource as they attempt to master the complexities of the care of these complicated patients. Finally, there may be patients and family members who could benefit from this work, as they attempt to enhance their ability to manage the challenges they confront in conjunction with their life-saving gift. Welcome to the field of transplant dermatology. We hope you will have as much fun learning about the field as we have had in our journey to improve the lives of these most special patients. December 1, 2006

The miracle of successful solid organ transplantation is one of the most inspiring accomplishments of modern medicine and an impressive example of multidisciplinary collaboration. Due to the frequent involvement of the skin of transplant patients by infectious, neoplastic, and systemic diseases, dermatologists have always been an important part of the medical team caring for solid organ transplant recipients. As a by-product of the success in assuring prolonged survival for most organ transplant patients, the chronic and potent systemic immunosuppression has given rise to a new set of challenges for patients and providers alike, manifest by alarming increases in skin cancer and unusual manifestations of skin disease. Dermatologists are part of a larger community of what we refer to as ‘‘non-organ-specific transplant physicians,’’ composed of providers unbound by allograft-specific considerations. This non-organ-specific community includes infectious disease, endocrinology, bone, metabolism, hypertension, psychiatry, internal medicine, family medicine, and pediatric physicians, as well as general, plastic, head and neck, ophthalmologic, and orthopedic surgical colleagues. Additionally, this community includes nephrologists, cardiologists, hepatologists, and pulmonologists who care for patients with allografts transplanted by other allograft-specific specialists. Closely and critically allied are the transplant coordinators, nurses, dieticians, appointment coordinators, and social services providers who provide and coordinate the majority of care in these complex patients. The transplant patients themselves are a critical and inspiring part of the team, upon which the most critical responsibility rests. This is the family of transplantation, a family of which dermatology is proud to be part. With the publication of Skin Disease in Organ Transplantation, the emerging subspecialty of transplant dermatology has come of age. The emergence of this field was partially driven by necessity; our patients simply needed us to rise to their unique and compelling needs. But the field was also created through the enthusiastic innovation, collaboration, and hard work of many people, particularly the members of the International Transplant Skin Cancer Collaborative, many of whom have contributed their expertise to this book. To these individuals and all of our colleagues mentioned

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Acknowledgments

We wish to acknowledge and thank the following people for granting permission to reproduce figures:

CHAPTER 23

Figure 23.3 – Courtesy of Clark Otley, MD, Mayo Clinic CHAPTER 24

Figure 24.1, 24.2, 24.3, 24.4 – Courtesy of Clark Otley, MD, Mayo Clinic

CHAPTER 1

Figure 1.1 – Courtesy of the Israel Penn International Transplant Tumor Registry, Dr. Steven Woodle

CHAPTER 25

Figure 25.1, 25.2, 25.3, 25.4, 25.5, 25.6 – Courtesy of Clark Otley, MD, Mayo Clinic

CHAPTER 2

Figure 2.1 – Courtesy of the Minister of Works and Cultural Activities

CHAPTER 28

Figure 28.2, 28.3 – Courtesy of Clark Otley, MD, Mayo Clinic

CHAPTER 5

Figure 5.1 – Courtesy of Clark Otley, MD, Mayo Clinic CHAPTER 10

CHAPTER 30

Figure 10.1, 10.5, 10.7, 10.11 – Courtesy of Tom Stasko, MD Figure 10.2, 10.3, 10.4, 10.6, 10.8, 10.9, 10.10 – Courtesy of Clark Otley, MD

Figure 30.1, 30.2, 30.3, 30.4, 30.5, 30.6 – Courtesy of Clark Otley, MD, Mayo Clinic CHAPTER 34

Figure 34.2, 34.3 – Courtesy of Clark Otley, MD, Mayo Clinic

CHAPTER 12

Figure 12.8 – Courtesy of Professor Dr. Birgit Willinger, and Professor Dr. Stefan Winkler, Vienna Figure 12.10 – Courtesy of Professor Dr. Carlos Ferrandiz, Spain

CHAPTER 36

Figure 36.1 – Courtesy of Clark Otley, MD, Mayo Clinic CHAPTER 37

Figure 37.1, 37.2, 37.3, 37.4, 37.5 – Courtesy of Clark Otley, MD, Mayo Clinic

CHAPTER 14

Figure 14.1 – Courtesy of Clark Otley, MD, Mayo Clinic CHAPTER 16

CHAPTER 38

Figures 16.1 – Photomicrographs courtesy of Nneka Comfere, MD, Mayo Clinic

Figure 38.1 – Courtesy of Alfons Krol, Oregon Health Sciences University

CHAPTER 22

CHAPTER 43

Figures 22.1–3, 22.5, 22.8–10, 22.13–24, 22.28–34 – Courtesy of Clark Otley, MD, MayoClinic Figure 22.31 – Courtesy of Chris Miller, MD, University of Pennsylvania Figure 22.25 – Courtesy of James Shaw, MD, University of Toronto, Ontario, Canada Figure 22.26 – Courtesy of Dr. Nancy Samolitus, University of Utah

Figure 43.1, 43.2, 43.3 – Courtesy of Clark Otley, MD, Mayo Clinic CHAPTER 44

Figures 44.1, 44.2, 44.3 – Courtesy of Reinhard Dummer, MD, Leitender Arzt, Dermatologische Klinik, Universita¨tsspital, Zu¨rich, Switzerland. CHAPTER 46

Figure 46.1 – Courtesy of Clark Otley, MD, Mayo Clinic

xxi

Section One

TRANSPLANT DERMATOLOGY: AN EVOLVING DYNAMIC FIELD

1 Introduction to Transplant Dermatology

Thomas Stasko, MD and Clark C. Otley, MD

INT ROD UCTION TO T RANSPLANT DE RMAT OLOG Y

Recipient survival past the immediate transplant period allowed the observation of the consequences of transplantation and long-term immunosuppression. Aside from mortality from other causes, end-stage renal disease patients on hemodialysis were noted to have malignancy rates about twice the normal population. Transplant recipients were soon observed to have a much more significant increase. In 1969, Penn and Starzl reported lymphomas in five renal transplant patients and theorized that the malignancies were related to the use of immunosuppressants.[3] By 1971, Schneck and Penn reported a 6% chance of developing a malignancy within 4 to 8 years after transplantation.[4] The association between solid organ transplantation and an increased risk of skin cancers was first described by Walder and colleagues in 1971.[5] This relationship has now been confirmed by multiple centers with a documented 65-fold increased risk of SCC [6[, 10-fold increase in BCC [7], 3.6-fold increased risk of malignant melanoma [8], and 84fold increase in KaposiÕs sarcoma.[6] These tumors are also more aggressive in behavior when compared to those in the general population and demonstrate increased rates of metastasis.[9] Occasionally, patients will develop tremendous numbers of tumors, having 100 or more distinct skin cancers in a year.[10] Most of the early demographic data regarding the high incidence of skin cancer in organ transplant recipients came from transplant physicians collecting outcomes data on transplant survivors. Much of the awareness of the problem of increased malignancy in transplant recipients originated with Dr. Israel Penn. As noted in the preceding paragraph, Dr. Penn was the first to report on the increased incidence of malignancies following transplantation. He established the Cincinnati Transplant Tumor Registry, now the Israel Penn International Transplant Tumor Registry (www.ipittr.uc.edu/Home.cfm), which has tracked data on over 15,000 malignancies in transplant recipients. He also disseminated this information throughout the medical community via hundreds of publications. Dr. Penn is widely recognized as having laid the cornerstone of transplant oncology (Figure 1.1).

Forty years ago, the world marveled at the news of the first heart transplant and was saddened by the transplant recipientÕs not unexpected death 18 days later. Today it is not uncommon to see a cardiac transplant recipient living well 15 or more years after transplantation. Unfortunately, it is also common to see that patient plagued with multiple skin cancers. When solid organ transplantation was in its infancy in the 1960s and 1970s, surviving the immediate transplant period was the most pressing concern. Today, patients leave the hospital quickly after transplantation, and the challenges involve managing the complications of years of illness and immunosuppression: diabetes, hypertension, coronary artery disease, peripheral vascular disease, and skin cancer.

SOLID ORGAN TRANSPLANTATION AND SKIN CANCER Over many years, solid organ transplantation has evolved into a commonly practiced, successful life-saving medical intervention. An intersection of advances in physiology, immunology, pharmacology, surgical technique, and critical-care medicine has made solid organ transplantation the standard of care for many instances of kidney, heart, lung, and liver failure. Initial attempts at organ transplantation were disappointing in terms of both allograft and patient survival. Although there were widely publicized successes in living related kidney transplants in the 1950s, it was not until 1962 that a long-term successful cadaveric renal transplant was performed in the United States. Surviving a transplant for more than a brief time was accomplished with the use of potent immunosuppressive agents. By the end of the 1970s, azathioprine, in combination with prednisone, provided 1-year overall survival rates around 50% for cadaver kidney transplants and near 80% for living related transplants. Unfortunately, 5-year allograft survival rates for cadaver transplants hovered around 35%. With the widespread use of cyclosporine in the 1980s, 5-year cadaver allograft survival rates doubled.[1] This success led to a dramatic increase in transplantation, which was constrained only by donor organ availability. With increased transplantation and increased survival, the number of living transplant recipients in the United States more than doubled from 81,873 in 1995 to 168,761 in 2004.[2]

H IS TO RY OF T RANS PLANT DER MATO LOGY Dermatologists became involved in the field of transplant oncology as transplant patients presented for diagnosis and treatment of their cutaneous malignancies, as well as infectious and inflammatory skin diseases. As larger numbers of transplant 3

4

THOMAS STASKO AND CLARK C. OTLEY

Table 1.1 A timeline of transplant cutaneous oncology

1969 1971 1977 1982 1989 2000 2001 2002 2004 2006

Penn reports increased risk of lymphoma Walder reports increased risk of skin cancer Hoxtell reports increased risk of skin cancer in Archives of Dermatology Penn establishes the Cincinnati Transplant Tumor Registry Abel publishes CME article in JAAD on transplant dermatology SCOPE formed First ITSCC organizational meeting First joint ITSCC/SCOPE meeting Transplant Oncology supplement to Dermatologic Surgery AT-RISC Alliance formed

became clear that a more systematic approach was needed to care for this unique set of patients and that this approach would require a collaborative effort by physicians involved in transplant cutaneous oncology around the world. In addition, because cutaneous carcinogenesis in transplant patients is accelerated and accentuated, understanding the details of the disease process in transplant recipients might provide insight into the mechanisms that underlie the development of skin cancer in the general population. Figure 1.1. Israel Penn, M.D., 1930–1999, the father of transplant oncology. (Used with permission from Steven Woodle, MD, Israel Penn International Transplant Tumor Registry.)

patients presented with multiple, aggressive tumors and some succumbed to metastatic disease, dermatologists found it increasingly important to focus on defining the nature and magnitude of the problem and exploring its etiology. As early as 1977, the incidence of skin cancer in renal transplant recipients was being reported in the mainstream dermatologic literature when Hoxtell and colleagues detailed a 36-fold increase in cutaneous squamous cell carcinoma in a Minnesota renal transplant cohort.[11] Abel in 1989, provided a CME review of cutaneous problems in organ transplant recipients in the Journal of the American Academy of Dermatology solidifying the importance of transplant oncology in dermatology.[12] Berg and Otley updated the dermatologic community on transplant cutaneous oncology with another Journal of the American Academy of Dermatology CME article in 2002.[13] An issue of Dermatologic Surgery in April of 2004 was devoted to transplant oncology. A visible affirmation of the importance of transplant cutaneous oncology in dermatology can be seen in the March 2006 issue of the British Journal of Dermatology. The issue contains four original articles and an editorial pertaining to the field. The timeline of development of transplant dermatology is outlined in Table 1.1. Over the same period of time, transplant cutaneous oncology and transplant dermatology began to be discussed in presentations at regional and national meetings. Through the interaction between speakers and the audience, it gradually

OR G A NI Z AT I ON S I N T R A NS P L A NT DE RMAT OLOGY In attempting to define the course of metastatic SCC in transplant recipients, in 2000, Dr. Clark Otley and Juan Carlos Martinez recruited participation by interested dermatologists via email and internet invitations. This effort defined a multiinstitutional group of dermatologists with similar interests in better understanding skin cancer in transplant patients and improving patient care. Under the guidance of Dr. Otley and Dr. Stuart Salasche, a preliminary meeting of these physicians was held in October 2001, in conjunction with the American Society of Dermatologic Surgery and the American College of Mohs Micrographic Surgery and Cutaneous Oncology Combined Annual Meeting in Dallas, Texas. A collaborative organization was envisioned to improve the care and quality of life for transplant patients and the North American Transplant-Skin Cancer Collaborative was formed. After membership grew to include professionals from Central and South America and Australia, the name was changed to the International Transplant-Skin Cancer Collaborative (ITSCC). Meetings are held annually in conjunction with the annual meeting of the American Academy of Dermatology. The European counterpart to ITSCC, Skin Care in Organ Transplant Patients, Europe (SCOPE) was forming about the same time. Its initial goal was to establish an internet-based database of skin cancer in transplant patients. It rapidly expanded its vision to include not only epidemiology, but also basic research and patient care on transplant dermatology issues. SCOPE meets annually in the Spring. SCOPE includes

INTRODUCTION TO TRANSPLANT DERMATOLOGY

national organizations in its membership structure. One national organization, Skin Care in Organ Recipients, United Kingdom, has been particularly active with a separate yearly scientific meeting. Dr. Salasche was instrumental in bringing ITSCC and SCOPE together. Representatives of both organizations first met formally in Berlin in January 2002. With an agreement on the need for collaboration on major issues established, annual joint workshops were held in August from 2002 to 2005. These workshops resulted in the publication of guidelines for the treatment of skin cancer in organ transplant recipients [14] and numerous other publications addressing the use of retinoids and reduction of immunosuppression. This international cooperation continues with continued annual joint meetings planned beginning in 2007. Prevention of skin cancer was quickly established as a primary goal in the care of organ transplant patients at risk for skin cancer. Aggressive sun protection offers the best hope for prevention, and education is the key to sun protection. In addition, because most skin cancer is more easily treated when discovered early, education of transplant professionals and transplant patients is crucial. To this end, ITSCC teamed with the International Transplant Nurses Society and Transplant Recipients International, to form the After Transplant-Reduce the Incidence of Skin Cancer (AT-RISC) Alliance. The Alliance has developed educational materials to educate physicians, nurses, coordinators, and patients about the risks of skin cancer in transplant recipients. At the organizationÕs web site, www.at-risc.org, there are downloadable brochures, posters, fact sheets, and PowerPoint presentations targeted at the various constituencies. Through an aggressive outreach program, especially involving transplant nurses, the Alliance hopes to reach transplant patients with a sun protection and early skin cancer recognition program and improve outcomes.

T H E C H A LL E N G E Solid organ transplantation has overcome enormous hurdles and made incredible strides in the past 50 years, but the journey is not complete. Organ procurement, patient selection, surgical technique, and immunosuppression are still evolving with the goal of extending life in patients with organ failure. The challenge for transplant cutaneous oncology and transplant dermatology is to play an active role in this process to eliminate skin cancer as a significant cause of morbidity and mortality. Additionally, early diagnosis of cutaneous infectious diseases and management of the cutaneous compli-

5

cations after organ transplantation is a priority. Our goals, as this text will illustrate, include patient education, early skin cancer recognition, understanding the process of carcinogenesis, developing better treatment plans and chemopreventive strategies, and exploring the effects of alterations of immunosuppression. We know well the ravages of skin cancer in organ transplant patients. The challenge now is to lessen the burden of this preventable complication in this special patient population.

REFERENCES

1. Morrissey P, Madras P, Monaco A. History of Kidney and Pancreas Transplantation. In: Norman DJ, Turka LA, eds. Primer on Transplantation. Second ed. Mt. Laurel, NJ: American Society of Transplantation; 2001:411–13. 2. HHS/HRSA/HSB/DOT. 2005 OPTN/SRTR Annual Report 1995– 2004. Available at: http://www.hrsa.gov/. 3. Penn I, Hammond W, Brettschneider L, Starzl TE. Malignant lymphomas in transplantation patients. Transplant Proc. Mar 1969; 1(1):106–12. 4. Schneck SA, Penn I. De-novo brain tumours in renal-transplant recipients. Lancet. May 15 1971;1(7707):983–6. 5. Walder BK, Robertson MR, Jeremy D. Skin cancer and immunosuppression. Lancet. Dec 11 1971;2(7737):1282–3. 6. Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens [see comments]. J Am Acad Dermatol. 1999;40 (2 Pt 1):177–86. 7. Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation. 1990;49(3):506–09. 8. Hollenbeak CS, Todd MM, Billingsley EM, Harper G, Dyer AM, Lengerich EJ. Increased incidence of melanoma in renal transplantation recipients. Cancer. Nov 1 2005;104(9):1962–7. 9. Penn I. The changing pattern of posttransplant malignancies. Transplant Proc. 1991;23(1 Pt 2):1101–03. 10. Bouwes Bavinck JN, Hardie DR, Green A, et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia. A follow-up study. Transplantation. Mar 15 1996;61(5):715–21. 11. Hoxtell EO, Mandel JS, Murray SS, Schuman LM, Goltz RW. Incidence of skin carcinoma after renal transplantation. Arch Dermatol. Apr 1977;113(4):436–8. 12. Abel EA. Cutaneous manifestations of immunosuppression in organ transplant recipients [see comments]. J Am Acad Dermatol. 1989; 21(2 Pt 1):167–179. 13. Berg D, Otley CC. Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and management. J Am Acad Dermatol. Jul 2002;47(1):1–17;quiz 18–20. 14. Stasko T, Brown MD, Carucci JA, et al. Guidelines for the management of squamous cell carcinoma in organ transplant recipients. Dermatol Surg. Apr 2004;30(4 Pt 2):642–50.

Section Two

TRANSPLANT MEDICINE AND DERMATOLOGY

2 The History of Organ Transplantation

Henry W. Randle, MD, PhD

MD, Professor of Surgery in Lyon, connected the vessels of a sheep kidney to the vessels of one patient and the vessels of a pig kidney to the vessels of another patient, both of whom were dying of renal failure. Neither kidney worked. The first attempts to transplant cadaveric human kidneys were in the 1930s by a Ukrainian surgeon, Yu Yu Voronoy, MD, who transplanted six kidneys into human recipients; all the kidneys failed to function. This result brought an end to the first technical period of transplantation.[3] The first successful renal transplantation was between identical twins and was performed in 1954 in Boston. The recipient survived for 8 years before dying of heart complications but never had rejection of the kidney. This experience confirmed the benefit of organ replacement in the absence of an immune barrier. Organ transplantation became a reality for the first time. Allogeneic solid organ transplantation, however, began slowly and in only a few institutions. The early times were referred to as the ‘‘dark days’’ or the ‘‘black years’’ of transplantation because most patients died. These were frustrating and challenging times for the surgical pioneers and their patients. For example, Thomas Starzl, MD (the first to perform liver transplantations), reported that the initial patients receiving liver transplants survived for a maximum of 21 days.[4] In the 1960s, there were only six active kidney transplant programs in the United States. Other organs first transplanted in the 1960s were bones, intestines, and lungs. Dramatic attention was brought to the field of transplantation in 1967 when Christian Barnard, MD, in South Africa, transplanted the first human heart. The recipient survived for 18 days. The second heart transplant recipient survived for 6 hours, and the third for several years. This experience led to the frenetic transplantation of more than 100 hearts, but recipients had a 3-month survival rate of only 35%. Thus, cardiac transplantation was mostly abandoned until the 1980s. Why were these transplanted organs failing? It was clear from the studies in Vienna in the early 1900s that autografts were almost always successful and allografts were nearly always unsuccessful. Dr Alexis Carrel stated that these organs failed because of ‘‘biological’’ and not surgical factors. Subsequently, during World War II in the 1940s, the English zoologist Sir Peter Medawar and the plastic surgeon Thomas Gibson, MD, working with skin grafts in burn victims, referred to these biologic factors as a ‘‘second-set response.’’[5] The first time a patient received a skin graft it would be rejected in 7 days. When a second graft was performed on the same person, it would be rejected in 3 days. The body had developed a specific

Solid organ transplantation can yield cures for previously fatal diseases. The concept of transplantation is very old. According to legend, in the fourth century, Cosmas and Damian, twin brothers and physicians from Arabia, were credited with amputating the cancerous leg of the custodian of a Roman basilica and replacing it with the leg from a slain Ethiopian gladiator recently buried in the Church of St. Peter. As a result, the brothers were honored in artist Fra AngelicaÕs painting (Figures 2.1) and recognized as the patron saints of transplantation.[1,2] In modern times, physicians envisioned replacing diseased organs with healthy ones, but before organs could be transplanted successfully, several technical medical problems had to be overcome (Table 2.1). The solutions included general anesthesia, first used in 1842 by a country doctor, Crawford Long, MD, in Jefferson, Georgia. After this procedure was publicly demonstrated in 1846 by a dentist, William Morton, at Massachusetts General Hospital, the technique of general anesthesia disseminated around the world in months. Next, studies by the chemist Louis Pasteur in Paris defined the role of bacteria in fermentation and putrefaction in wine making. These findings convinced the great surgeon Joseph Lister, of Glasgow, that similar germs in the air were responsible for surgical infections, an idea that led him to develop antiseptic surgery in the 1860s. Finally, in the early 1900s, Alexis Carrel, MD, in Lyon, France, the father of vascular surgery, was the first to suture two blood vessels together (vascular anastomosis), a procedure that made solid organ transplantation possible. Carrel later moved to Chicago and worked with Charles Guthrie, MD, grafting many kidneys, hearts, and other organs, using his blood vessel anastomosis technique (Figure 2.2). Carrel was awarded the Nobel Prize for this work in 1912. More than fifteen Nobel prizes have been awarded to scientists in fields related to transplantation and immunology. Early experimentation with animal and human transplantation was performed in the early 1900s. Emerich Ullmann, MD, a surgeon born in Hungary, performed a famous demonstration before the Vienna Society of Physicians in the Bilroth-haus on March 7, 1902, removing a kidney of a dog and transplanting it into the neck of another dog. The end of the ureter was sutured to the skin and, in the presence of the audience, urine flowed from the ureter. Thus, Ullmann is credited with ushering in the era of solid organ transplantation. He later attempted to transplant the kidney of a pig into the elbow of a young woman with uremia, but the kidney failed to function and he ended his transplantation research.[3] A few years later, in 1906, Mathieu Jaboulay, 9

10

HENRY W. RANDLE

Figure 2.1. Cosmas and Damian, the patron saints of transplantation, replacing the cancerous leg of a man with the leg of a recently slain gladiator. (Used with permission of the Minister of Works and Cultural Activities.)

Table 2.1 Solid organ transplantation and skin cancer: a timeline Date th

4 century A.D. 1842 1900–1910 1902 1954 1959 1968 1971

Event Cosmas and Damian transplant leg 1st ether anesthesia for surgery Blood vessel anastomosis 1st public demonstration of solid organ transplantation 1st successful renal transplantation 1st use of immunosuppressants in organ transplant recipients 1st report of increased malignancies in transplant recipients 1st report of skin cancer in organ transplant recipients

response to the foreign tissue. This is now recognized as rejection, an immunologic event. The immunologic barrier was greater than the technical ability of the surgeons. The renowned heart surgeon Denton Cooley, MD, explained, ‘‘I have done all that I can do as a surgeon. It remains for the immunologists and biologists to unravel the mysteries that have limited our work.’’[6] Successful transplantation without immunosuppression was doomed to failure and would have to await an effective means of immunosuppression. Early attempts at immunosuppression to enhance survival of organ transplants began in 1959 with total body irradiation designed to cripple the immune system. The side effects from radiation included susceptibility to overwhelming infections and death. That same year, chemical immunosuppression with the anticancer drug 6-mercaptopurine was introduced to more selectively modify the immune response. In 1960,

azathioprine (the imidazole derivative of 6-mercaptopurine) was used with prednisone for immunosuppression. A combination of immunosuppressants (the cocktail approach), including prednisone, appeared to be more successful than the use of one drug alone. With the advent of effective multiagent immunosuppressive regimens, organ transplantation began to provide a realistic alternative to dialysis for kidney failure. In 1978, a calcineurin inhibitor, cyclosporine, a natural earth fungal by-product discovered by a Swiss microbiologist, led to marked improvement in liver transplant viability. By the late 1970s, the chance of survival was 18% in patients with liver transplants who did not receive cyclosporine and 68% in those who did. Unfortunately, with long-term immunosuppression using more potent medications, malignant disease was noted to be

THE HISTORY OF ORGAN TRANSPLANTATION

a hazard of organ transplantation and immunosuppressive therapy. This association was first reported in 1968 by Dr Thomas Starzl at the Swiss Society of Immunology and the American Surgical Association. In 1969, Israel Penn, MD, and other colleagues of Starzl at the University of Colorado published the first paper on the development of malignancy (lymphomas) in five recipients of renal transplants. The malignancies were thought to be an indirect complication of organ transplantation and the measures taken to prevent rejection.[7] It soon became clear that the frequency of tumors in transplant recipients could not be due to chance alone. Penn and colleagues determined that 11 (6%) malignancies developed in 184 recipients 4–8 years after transplantation. In order to learn about transplant-associated malignancies, Penn began an informal registry, the Denver Transplant Tumor Registry, subsequently known as the Cincinnati Transplant Tumor Registry. Over several decades, Penn recorded data on thousands of transplant-related malignancies. After PennÕs death in 1999, the registry was renamed the Israel Penn International Transplant Tumor Registry (http://www.ipittr. uc.edu/Main/main.cfm). The frequency of cancer in patients receiving dialysis is twice that in the general population; but in StarzlÕs first 483 patients who received transplants, the frequency was several times normal. It became clear that the frequency of tumors that were common in the general population (lung, prostate, breast, and colon) was not increased in transplant recipients but that the frequency of various uncommon tumors (lymphomas, squamous cell carcinomas of the lip, Kaposi sarcoma, and carcinoma of the vulva, kidney, and liver) was higher in transplant recipients. The average time to the first cancer was 61 months, and the increased incidence compared with the general population ranged from 4 to 65 times for skin cancer, 28 to 49 times for lymphoma, 100 times for vulvar carcinoma, and 20 times for liver cancer. Transplant-associated cancers could be classified as being of three origins: those inadvertently transmitted with the organ from the donor to the host (donor-derived), the relapse of previous cancer in recipients (recurrent), or development of new tumors, such as skin cancer and lymphoma (de novo), after transplantation. The cumulative risk for development of at least one malignancy (excluding nonmelanoma skin cancer) was approximately 30% after 20 years. Several common posttransplantation malignancies were thought to be virusrelated. Calcineurin inhibitors and azathioprine were linked with posttransplantation malignancy, whereas newer agents such as mycophenolate mofetil and sirolimus were not and were thought to have antitumor properties. By 1971, neoplasms of the lymphoreticular system were the only malignancies known to be associated with the use of immunosuppressive medications. That year, Brien Walder, MD, and colleagues from New South Wales, Australia, reported that 7 (14%) of 51 renal transplant recipients had a total of 20 malignant skin tumors 4 to 45 months after transplantation.[8] All patients had been treated with prednisone and azathioprine. In the investigatorsÕ regular dermatological

11

clinics, basal cell carcinomas were 11 times more common than squamous cell carcinomas, but in this series of transplant patients, the basal cell:squamous cell carcinoma ratio was reversed to 1:16. The seven patients had 16 squamous cell carcinomas, 1 basal cell carcinoma, and 3 keratoacanthomas. They were primarily found on sun-exposed skin (hands, arms, neck), in young patients (average age, 36 years), and in those who had not been previously treated for skin cancer. This report was the first to indicate a link among transplantation, immunosuppressive drugs, and an increased risk for the development of skin cancer. These findings have since been confirmed by numerous reports.[9–11] Compared with the general population, transplant recipients have an increased risk of skin cancer (squamous cell carcinomas, basal cell carcinomas, malignant melanomas, Merkel cell carcinomas, atypical fibroxanthomas, and KaposiÕs sarcoma) depending on a patientÕs history of sun exposure, duration since transplantation, and the number and dosages of immunosuppressive drugs. Skin cancers now represent one-third to one-half of de novo tumors in transplant recipients. Characteristic of transplant-associated skin cancers include a reversal of the basal cell:squamous cell carcinoma ratio, an increased incidence of skin cancer up to several hundredfold, and a worse prognosis compared to cancers in nonimmunosuppressed patients, including a greater tendency to recur after treatment and to metastasize.[12] In an excellent book on the history of transplantation by Nicholas Tilney, MD, published in 2003, a single sentence was devoted to skin cancer, referring to it as ‘‘an important epidemiological problem.’’[2] We now appreciate from numerous reports that skin cancer is one of several malignancies that may be a considerable hazard after organ transplantation as a result of long-term immunosuppressive therapy. The history of solid organ transplantation is fascinating and replete with lessons. As this book will demonstrate, the history of transplant dermatology is young, but holds a sense of excitement to tackle the challenges that transplant patients experience with cutaneous disease.

REFERENCES

1. Dewhurst J. Cosmas and Damian, patron saints of doctors. Lancet. 1988;2:1479–80. 2. Tilney NL. Transplant: from myth to reality. New Haven (CT): Yale University Press; 2003;7–9. 3. Druml W. The beginning of organ transplantation: Emerich Ullmann (1861–1937). Wien Klin Wochenschr. 2002;114:128–37. 4. Starzl TE. Organ transplantation: a practical triumph and epistemologic collapse. Proc Am Philos Soc. 2003;147:226–45. 5. Gibson T, Medawar PB. The fate of skin homografts in man. J Anat. 1943;77:299–310. 6. Frist WH. Transplant: a heart surgeonÕs account of the life-and-death dramas of the new medicine. New York: Atlantic Monthly Press; 1989;66. 7. Penn I, Hammond W, Brettschneider L, Starzl TE. Malignant lymphomas in transplantation patients. Transplant Proc. 1969;1: 106–12.

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HENRY W. RANDLE

8. Walder BK, Robertson MR, Jeremy D. Skin cancer and immunosuppression. Lancet. 1971;2:1282–3. 9. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348:1681–91. 10. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol. 2002;47:1–17.

11. Lindelof B, Dal H, Wolk K, Malmborg N. Cutaneous squamous cell carcinoma in organ transplant recipients: A study of the Swedish cohort with regard to tumor site. Arch Dermatol. 2005;141: 447–51. 12. Randle HW. The historical link between solid-organ transplantation, immunosuppression, and skin cancer. Dermatol Surg. 2004;30 (4 Pt 2):595–7.

3 The Development of Modern Immunosuppressive Medications

Ryutaro Hirose, MD and Matthew D. Griffin, MB, BCh

INT ROD UCTION

ticosteroid, an antiproliferative agent, and a calcineurin inhibitor (CNI). Because a high overall level of immunosuppression is generally required during the immediate posttransplant period, frequently the use of a biological agent to further inhibit or deplete functional lymphocytes is required. Table 3.1 summarizes the drugs and biological agents that are in common current use in the field of clinical transplantation. The corticosteroids most often administered to organ transplant recipients are methylprednisolone, dexamethasone, prednisone, and prednisolone. Typically, high doses of intravenous corticosteroids are prescribed during the first several days after a transplant, followed by a tapering oral schedule. The options for an antiproliferative agent include azathioprine, mycophenolate mofetil, and mycophenolate sodium. These medications are usually prescribed at fixed doses, which remain unchanged unless reductions are necessitated by toxicity or other immunosuppression-related adverse effects. The CNIs in current clinical use are cyclosporine and tacrolimus. More recently, a fourth class of immunosuppressant, inhibitors of the intracellular signaling protein mammalian target of rapamycin (mTOR), has entered the clinical arena in the form of the oral drug sirolimus (formerly referred to as rapamycin). For both CNIs and mTOR inhibitors, the doses are adjusted to achieve specific target trough levels in the blood with higher target levels prescribed during the initial months after the transplantation when rejection risk is highest. For long-term management, the preferred number of drugs and the overall level of immunosuppression required to prevent allograft rejection varies among the commonly transplant organs, being lowest for liver, intermediate for kidney, and highest for heart, lung, pancreas, and intestine. The currently available biological agents include polyclonal antibody preparations (rabbit and horse antilymphocyte antibodies), mouse monoclonal antibody preparations (anti-CD3 antibody (OKT3)) and human/mouse chimeric monoclonal antibody preparations (anti-CD25 antibodies (basiliximab and daclizumab), and anti-CD52 antibody (alemtuzumab)). These agents are typically used as courses of intravenous therapy during the first week after transplantation (induction therapy) or for intervention in the context of acute allograft rejection. Using this combinatorial approach, transplant physicians have sought out effective prophylaxis against acute allograft rejection while minimizing both the specific medication toxicities, as well as the major direct adverse effects of long-term immunosuppression such as cancer, accelerated cardiovascular disease, and infection.[1–9] It should also be noted that, in addition to the introduction of new antirejection

The advent of modern immunosuppressive therapy is arguably the single most important factor in allowing solid organ transplantation to progress from a dubious and dangerous venture to the treatment of choice for end-stage organ failure. During the past two decades, a broad array of immunosuppressants has emerged to expand the armamentarium used by transplant physicians and surgeons for prevention and treatment of organ allograft rejection. The availability of these drugs has resulted in steadily improved outcomes for kidney, kidney/ pancreas, liver, heart, lung, pancreas, and intestinal transplants. It has also allowed for the development of clinically feasible protocols for multiorgan transplantation, as well as transplantation of pancreatic islets, gonads, and compound tissues such as limbs. Despite these remarkable successes immunosuppressive drugs continue to lack specificity and are associated with many acute and chronic side effects. Although there has been significant progress in understanding the mechanistic basis of immunological tolerance, consistent clinical application of this knowledge to allow graft-specific tolerance, the ‘‘Holy Grail’’ of transplantation, remains elusive. Thus, the large majority of organ transplant recipients in the current era continue to require lifelong immunosuppression. Among the agents in common worldwide use for this purpose are corticosteroids, a select number of small-molecule drugs, and a growing panel of so-called biological agents that includes monoclonal and polyclonal antibodies. In addition to these established agents, a number of novel immunosuppressants have entered preclinical and clinical trials in organ transplant recipients in recent years and show promise for broader clinical use in the near future. In this chapter, the major, currently prescribed immunosuppressive medications, as well as the emerging panel of new agents targeting the immune response to organ allografts are summarized.

OVER ALL ST RATE GY F OR S OLID ORG AN T RANS PL A NT IM MU NO SU PPR ESS I ON For each of the commonly transplanted solid organs, the general strategy for prevention of graft rejection involves the use of a synergistic combination of immunosuppressive medications designed (usually through a process of trial and error) to maximize efficacy and minimize toxicity. Although the field has begun to change more rapidly in the past five years, these regimens have, most often, involved the combined use of a cor13

14

RYUTARO HIROSE AND MATTHEW D. GRIFFIN

Table 3.1 Summary of the currently employed classes of immunosuppressive medications in solid organ transplantation Nonproprietary drug name

Description

Administration

Typical prescription pattern

Methylprednisolone Dexamethasone

Corticosteroid

Intravenous

Thymoglobulin; Horse antithymocyte globulin; Rabbit antithymocyte globulin; Antilymphocyte globulin OKT3

Polyclonal antilymphocyte antibody

Intravenous

Mouse anti-CD3 monoclonal antibody

Intravenous

Daclizumab; Basiliximab

Chimeric/humanized anti-CD25 monoclonal antibody Humanized anti-CD52 monoclonal antibody Corticosteroid

Intravenous

Bolus doses during first posttransplant week or for treatment of mild acute rejection Bolus doses during first posttransplant week or for treatment of moderate to severe acute rejection Bolus doses during first posttransplant week or for treatment of moderate to severe acute rejection Two to five boluses during the first one to two weeks posttransplant

Alemtuzumab Prednisone; Prednisolone

Intravenous

Single bolus prior to or during transplantation

Oral

Tapering schedule from high dose early to low dose, continued indefinitely Stable dose administered indefinitely Stable dose administered indefinitely

Azathioprine Mycophenolate mofetil; Mycophenolate sodium Cyclosporine; ISA-247a

Antiproliferative Antiproliferative

Oral Oral

Calcineurin inhibitor

Oral

Tacrolimus

Calcineurin inhibitor

Oral

Sirolimus; Everolimusa

mTOR inhibitor

Oral

a

Dose adjusted to achieve a target trough or 2-h blood level; target level reduced over time, based on rejection risk Dose adjusted to achieve a target trough blood level; target level reduced over time, based on rejection risk Dose adjusted to achieve a target trough blood level; target level reduced over time, based on rejection risk

Currently in clinical trial development only.

medications, the past decade has been characterized by large-scale evaluation of alternative immunosuppression strategies using available agents. Examples include renewed interest in corticosteroid-free immunosuppression for kidney, liver, and heart recipients as well as carefully monitored stepwise minimization of immunosuppression in kidney and liver recipients.[10–16] Despite the extensive efforts of the transplant community to test and compare different drug combinations and prescription strategies for each of the commonly transplanted organs, toxicity due to immunosuppressive agents remains common and often constitutes the major limiting factor for the quality and quantity of life of the allograft recipient.[4,5,7,8,17] A major goal for the next generation of antirejection medications will be to provide short- and long-term graft protection comparable to current agents with reduced immunosuppression-related morbidity.[4]

TOD A Y – CURRE NT IM MUNOSUPPR ES SION

Corticosteroids After decades of successful organ transplantation, corticosteroids, the first effective class of antirejection drugs to be

employed, remain a mainstay of most immunosuppressive regimens and are still commonly used as first-line therapy to treat rejection.[14] The enduring paradox of corticosteroid therapy arises from the fact that these agents confer both a wide range of potentially beneficial immunosuppressive effects and an extensive number of nonimmunological adverse effects that, in many patients, progress over time. All corticosteroids are both lymphotoxic and alter the distribution of lymphocytes. Corticosteroids also directly inhibit antigen presentation and production of proinflammatory cytokines such as interleukin 1 by macrophages and dendritic cells. These broad mechanisms of immunosuppression tend to be synergistic with the more discrete mechanisms of action of other commonly used antirejection medications and may target profibrogenic inflammatory pathways that contribute to the chronic deterioration, which currently limits the functional life span of many organ allografts. Beneficially, high doses of corticosteroid administered at the time of transplantation, and during the first week thereafter, may serve to limit the potential for severe allergic reaction to biological induction agents, as well as to dampen intragraft inflammation occurring as a result of ischemia-reperfusion injury. An intravenous bolus of methylprednisolone is given at the time of most organ transplants with subsequent doses tapered

THE DEVELOPMENT OF MODERN IMMUNOSUPPRESSIVE MEDICATIONS

over days to months according to institutional protocol. In addition, the predominant first-line therapy for mild acute rejection episodes in recipients of most organ allografts consists of a pulse of high-dose corticosteroid followed by a slow taper toward the baseline oral dose. Based on these common paradigms, the majority of transplant patients have been exposed to a high cumulative dose of corticosteroid medication that results in significant and progressive risk for chronic toxicities such as Cushingoid features, weight gain, acne, hypertension, skin cancer, diabetes mellitus, osteonecrosis, and osteoporosis [7,15]. Brief pulses of high-dose corticosteroid therapy also produce heightened risk for acute complications, including opportunistic infection, psychosis, hyperglycemia, and, in the case of liver transplant recipients with hepatitis C, a rapid rise in circulating viral load that may herald a worse prognosis for recurrent hepatitis.[18] It is the common occurrence of these diverse side effects that has motivated many investigators to devise corticosteroid sparing regimens with the aid of more recently introduced immunosuppressive agents.

Antiproliferative Agents – Azathioprine and Mycophenolate The combination of azathioprine and corticosteroids was the mainstay of transplant immunosuppression until the introduction of cyclosporine in 1982. Azathioprine is a prodrug that is converted to 6-mercaptopurine, which by interfering with DNA replication inhibits both T-cell and B-cell proliferation.[5,6] Unfortunately, this antiproliferative action is not limited to immune cells and may result in adverse effects such as gastrointestinal ulceration and myelosuppression. Between the early 1960s and mid-1980s, azathioprine was the primary immunosuppressive agent responsible for successful transplantation. Surviving patients who underwent kidney, liver, or heart transplantation during this era are most likely to still be managed with azathioprine and corticosteroid alone. During the decade spanning the introduction of cyclosporine in the mid-1980s and the widespread adaptation of mycophenolate mofetil in the mid-1990s, azathioprine was most commonly employed as a secondary antirejection agent for recipients of kidney, liver, heart, pancreas, and lung transplants. As a result, large numbers of surviving graft recipients from the ‘‘cyclosporine era’’ also continue to take azathioprine as part of their baseline immunosuppressive regimen. In the past ten years, azathioprine has not been commonly prescribed for new transplants and has been largely replaced in this role by mycophenolate derivatives or by sirolimus. Nonetheless, it continues to represent a viable choice in patients who are intolerant of other agents or in circumstances where newer immunosuppressive drugs prove to be too costly. Mycophenolate is currently available in two orally administered forms: mycophenolate mofetil and enteric coated mycophenolate sodium. Mycophenolate inhibits inosine monophosphate dehydrogenase (IMPDH), which is an essential enzyme involved in the de novo pathway of purine syn-

15

thesis. Lymphocytes lack the purine salvage pathway enzymes and, as a result, are specifically inhibited by mycophenolate in their ability to proliferate following an activating signal. Mycophenolate is a highly effective immunosuppressant, inhibiting both T-cells and B-cells, and has now largely replaced azathioprine as the antiproliferative agent of choice in all forms of solid organ transplantation.[5,6,19] The success of mycophenolate derivatives in clinical practice derives from the proven superiority of mycophenolate mofetil in the prevention of acute rejection early posttransplantation when compared in large multicenter trials with immunosuppressive regimens containing either azathioprine or no antiproliferative agent.[6] The most common side effects are gastrointestinal (including gastroesophageal reflux, nausea/ vomiting, abdominal cramping, and diarrhea) and hematologic (leukopenia, thrombocytopenia, and anemia).[19] Notably, mycophenolate is not nephrotoxic and may be a useful immunosuppressive agent in the setting of renal insufficiency.

Calcineurin Inhibitors – Cyclosporine and Tacrolimus The introduction of the CNI immunosuppressants, cyclosporine (CYA), and subsequently tacrolimus (TAC), revolutionized solid organ transplantation. Following the widespread adaptation of CNI as primary antirejection therapy, one-year graft and patient survival approaching 90% for kidney and liver recipients and 80% for heart recipients became feasible. Currently, there is no question that both CYA and TAC are highly effective immunosuppressive drugs that act overwhelmingly on cellular (T-cell) immunity.[5,6] There remain conflicting data regarding whether TAC confers overall improved outcomes compared to CYA for any of the major solid organ transplants. Nonetheless, recent practice trends indicate that TAC has replaced CYA as the most commonly prescribed primary immunosuppressant for kidney, liver, pancreas, lung, and intestinal transplants in the United States and is now employed with equal frequency for heart transplantation.[14] Both CYA and TAC are usually administered twice daily in capsule or tablet form. Because the window between optimal immunosuppressive activity and potentially serious toxicity is relatively narrow for CNIs, and because of the potential for interaction with other pharmaceutical agents, it is essential to monitor CNI blood levels in organ transplant recipients.[6] The monitoring frequency typically varies from several days a week early posttransplant to once every one to four months at later times. Although CYA is often monitored using twelve-hour trough levels, C2 levels of CYA (drug levels at two hours post administration) more accurately represent CYA exposure (AUC, area under the curve). In contrast, TAC is adequately monitored using the twelvehour trough level. The metabolism on both CYA and TAC is dependent of cytochrome P450. Coadministration of drugs that induce or compete for this pathway can greatly affect drug levels and increase the risk for CNI toxicity due to

16

RYUTARO HIROSE AND MATTHEW D. GRIFFIN

elevated CNI exposure or the risk for acute rejection due to subtherapeutic CNI levels.[6] The mechanisms of action for CYA and TAC are very similar. Both function by entering T-lymphocytes and forming a complex with a specific intracellular protein (cyclophilin in the case of CYA and FK binding protein [FKBP] in the case of TAC). The corresponding drug–receptor complexes bind to and inhibit calcineurin, a calcium-dependent phosphatase that is normally responsible for dephosphorylation of key transcription factors such as NFAT following delivery of a T-cell activating signal.[6] Inhibition of calcineurin activity prevents activation-induced translocation of NFAT and other transcription factors to the nucleus and, by so doing, prevents the subsequent transcription of important cytokine-encoding genes such as interleukin 2 (IL-2). By administering either CYA or TAC, effective IL-2 production by activated T-cells is blocked. The most significant toxicities of CNIs include neurotoxicity, nephrotoxicity, gastrointestinal symptoms, hypertension, hyperglycemia, lipid abnormalities, and cutaneous side effects. There are well-recognized differences between CYA and TAC in regard to the relative frequency of these adverse effects. Tacrolimus is associated with higher frequency of hyperglycemia, neurotoxicity (especially, tremor and headache), gastrointestinal side effects, and alopecia, whereas CYA more commonly causes hypertension, hyperlipidemia, and cutaneous side effects (gingival hyperplasia, hypertrichosis, and coarsening of facial features). These differences may influence the initial choice of CNI for a given patient or may motivate a later conversion from one CNI to the other. Both CNIs are associated with acute, dose-related nephrotoxicity, as well as with the potential for chronic nephrotoxicity leading to chronic renal failure in recipients of kidney as well as nonkidney organ transplants.[17] Although the true contribution of CNI therapy itself to the burden of posttransplant chronic renal impairment remains unclear, evidence of progressive renal insufficiency in an allograft recipient may be an indication to reduce or discontinue CNI with or without addition of an antiproliferative agent or an mTOR inhibitor.[10] Although CNIs remain the dominant form of posttransplant immunosuppression due to their reliable potency against T-cell mediated antigraft immunity, it is likely that this dominance will be challenged during the next decade by antirejection agents with similar efficacy and less potential for nephrotoxicity. A synthetic analog of CYA, ISA247, is also currently undergoing clinical trials in kidney transplant recipients. Preclinical testing of this agent suggests that it may have better correlation between trough level and immunosuppressive activity than CYA as well as an improved side effect profile compared to CYA and TAC.[20]

mTOR Inhibitors – Sirolimus and Everolimus Sirolimus (formerly called rapamycin) is an immunosuppressive macrocyclic lactone produced by Streptomyces hygroscopicus that is now widely approved for clinical use in solid organ trans-

plantation.[21] A related derivative, everolimus, is currently undergoing evaluation in clinical trials and is likely to be more broadly available for use in transplant recipients in the near future. Both sirolimus and everolimus prevent activationinduced proliferation of T-cells by binding the same intracellular receptor as TAC (FKBP-12). Unlike TAC, these compounds do not inhibit calcineurin but, instead, interfere with the activity of a large molecule with kinase activity termed mTOR. This kinase is intricately involved in lymphocyte signal transduction pathways downstream to growth-factor receptors, including the IL-2 receptor. Specifically, mTOR is responsible for phosphorylation of signaling proteins such as p70S6 kinase and initiation factor 4E binding protein 1 that participate in growth-factor-induced transcriptional events. Functionally, the result of mTOR inhibition is an arrest in the cell cycle due to blockade of G1 to S phase transition. This cell cycle arrest has been well demonstrated in lymphocytes as well as in many tumor cells.[21] The efficacy of sirolimus as an immunosuppressive medication has been best demonstrated in randomized multicenter clinical trials of kidney transplantation. Overall, the experience with sirolimus in these trials demonstrated a reduction in acute rejection rates with the use of sirolimus, compared to placebo or azathioprine in combination with a CNI. The relative efficacy of sirolimus compared to mycophenolate in a CNI-based regimen for kidney transplantation is less clear at present.[22] Sirolimus has also been successfully employed in combination with mycophenolate mofetil in primary CNI-free regimens or as a later substitute for CNI in kidney transplant recipients.[22] Experience with sirolimus is more limited in other organ allografts such as heart and liver where it has primarily been reported to be effective as a replacement for CNI in individuals with stable graft function but worsening renal function.[3,10,14] Sirolimus is associated with a number of important adverse effects, the most common of which is a dose-dependent increase in serum cholesterol and triglycerides that frequently requires pharmacotherapy and sometimes necessitates discontinuation of the drug.[21] Sirolimus has also been linked in clinical studies with impaired wound healing, mouth ulcers, thrombocytopenia, leukopenia, peripheral edema, acneiform eruptions and, rarely, noninfectious pneumonitis. Although immunotherapy with sirolimus per se is not nephrotoxic, patients treated with full-dose CNI combined with sirolimus have lower renal function than those treated with CNI alone or CNI with azathioprine or mycophenolate mofetil.[22] The reduction in renal function in these patients appears to derive from accentuated CNI nephrotoxicity. As a result, current practice involves reduced target levels of CNI in transplant recipients managed with CNI/mTOR inhibitor combinations. In addition, more recent evidence suggests that sirolimus may also be associated with delayed recovery from acute tubular necrosis and with worsening proteinuria in some organ allograft recipients. The adverse effects of everolimus therapy are likely to be closely comparable to those of sirolimus.

THE DEVELOPMENT OF MODERN IMMUNOSUPPRESSIVE MEDICATIONS

Based on laboratory studies of cell lines and animal disease models, it has been proposed that the mTOR inhibitors may have additional important long-term benefits for organ transplant recipients. One such effect, that has been welldocumented experimentally, is the potential to prevent or retard the development of cancers, presumably as a result of cell-cycle inhibition in neoplastic cells. Similarly, there is evidence that mTOR inhibition may be antifibrotic and antiatherogenic in vivo properties that could be highly relevant to the increased risks of chronic allograft deterioration and accelerated cardiovascular disease that persist among most transplant populations.[21] The degree to which these theoretical benefits will be borne out in the clinical arena remains to be seen and clarification will require long-term follow-up studies of large randomized clinical trials.

Biological Agents Biological agents such as antilymphocyte antibodies have been in clinical use in organ transplantation for over three decades.[6] Both polyclonal and monoclonal antibody preparations continue to be widely employed to provide potent immunosuppression in the immediate posttransplant period (induction therapy) as well as to reverse moderate to severe acute allograft rejection. More recently, advances in molecular biology and protein engineering have resulted in the generation of new biological agents with enhanced specificity and selectivity. This progress has yielded therapeutic antibodies with reduced toxicity and prolonged biological activity in humans.[23–25] In the near future, it may also allow for biological agents to be administered chronically as a bona fide alternative to multidrug oral immunosuppressive regimens.[26] The range of biological agents currently in common use for organ transplant recipients is summarized here.

OKT3 OKT3 (muromonab-CD3) is a murine monoclonal antibody that is directed against the epsilon chain of the CD3 complex, a cluster of signaling proteins associated with the T-cell receptor. Binding of OKT3 to the CD3 complex results in internalization of the T-cell receptor and in depletion through activation-induced cell death of T-cells from the peripheral circulation and lymphoid organs. Its effects can be monitored by following numbers of T-cells in the peripheral blood. Although widely used in the past as an induction agent for all forms of solid organ transplantation, OKT3 is now used primarily in the setting steroid-resistant rejection. It is usually administered as a daily intravenous injection for between five and fourteen days. Typically, pretreatment with corticosteroids, diphenhydramine, and acetaminophen is used in anticipation of the sometimes severe side effects that occur as a result of the initial release of proinflammatory cytokines by activated T-cells. This cytokine release syndrome can include fevers, rigors, headache, dyspnea, gastrointestinal symptoms, and, particularly in patients with fluid overload, flash pulmonary edema. As with other lymphocyte-depleting

17

agents, OKT3 therapy may also be associated with increased subsequent risks for the development of posttransplant lymphoproliferative disease and of severe recurrent hepatitis C.

Thymoglobulin and Other Polyclonal Anti-Lymphocyte Antibodies Thymoglobulin is a polyclonal antibody derived from rabbits inoculated with human thymocytes. Administration of Thymoglobulin results in depletion of T-cells from the peripheral circulation and lymphoid organs. It is a highly effective induction and antirejection agent and has been used increasingly for these purposes during the past six years in recipients of kidney, liver, heart, pancreas, lung, and intestinal transplants. Thymoglobulin is usually administered daily or every other day for between five and fourteen days, depending on the clinical situation. A total dosage of 6 mg/ kg is often the target for induction purposes. As with OKT3, its use in acute rejection is typically reserved for treatment of steroid-resistant or histologically severe rejection. Because of its potency and prolonged action in depleting lymphocyte populations, Thymoglobulin has been specifically adopted in recent years as an effective induction agent for corticosteroidfree immunosuppressive regimens in kidney and liver transplantation.[11,13,14,16,27] Although its side effect profile is generally similar to that of OKT3, symptoms associated with cytokine release are typically milder and less frequent with Thymoglobulin. Reversible neutropenia and thrombocytopenia may also occur during therapy. Less commonly, serum sickness may appear days after a course of Thymoglobulin. A number of other polyclonal antilymphocyte antibody preparations are also clinically available for administration to organ allograft recipients although, in similar fashion to OKT3, their use has waned over the past six to ten years as a result of the frequency of adverse effects or lesser potency compared to Thymoglobulin.[14] These include antithymocyte and antilymphocyte polyclonal antibodies prepared in rabbit (ATG, NRATG) and horse (ATGAM). In general, the use of lymphocyte-depleting polyclonal antibodies is associated with reduced incidence of early acute rejection in most forms of solid organ transplantation but also with increased incidence of opportunistic infections and of posttransplant lymphoproliferative disorders. Alemtuzumab (Campath-1H) Alemtuzumab (also known as Campath-1H) is a humanized monoclonal antibody directed against the CD52 molecule, which is expressed broadly on bone-marrow-derived cell populations, including T-cells, B-cells, and natural killer (NK) cells. When administered as a single intravenous dose, it results in prolonged depletion of these populations both centrally and peripherally. Although initially developed and approved as a therapeutic intervention for autoimmune disease and lymphoma, it has been increasingly reported, in single-center clinical trials, to be a highly effective induction agent for recipients of kidney, pancreas, liver, lung, and

18

RYUTARO HIROSE AND MATTHEW D. GRIFFIN

intestinal transplants.[23,28] As with Thymoglobulin, much of the recent enthusiasm for the use of alemtuzumab as an induction agent stems from the growing interest in corticosteroid avoidance and early minimization of oral immunosuppressive drugs.[11,14,27,28] Results of these studies indicate that alemtuzumab induction effectively limits early acute rejection in combination with steroid-free, CNI-based immunosuppression with acceptable rates of infection and other complications. In contrast, the use of alemtuzumab without CNIs is associated with unacceptably high incidence of acute vascular rejection.[28] Long-term outcomes for such regimens are currently less well-understood and prolonged, randomized studies will likely be needed to determine whether alemtuzumab induction confers specific overall benefits in organ allograft recipients compared to other available agents.

Anti-Interleukin-2 Receptor (CD25) Antibodies – Basiliximab and Daclizumab The strategy of using antibodies against the receptor for IL-2 on T-cells has been known for some time to inhibit organ transplant rejection in animal models. The high-affinity IL-2 receptor is a heterotrimer made up of a, b, and c chains. The b and c chains are constitutively expressed by T-cells, whereas the a chain (CD25) is primarily expressed by activated T-cells. Blockade of CD25 may specifically prevent effective IL-2mediated stimulation of only those T-cells responding to an immunological challenge such as an allograft without inducing global T-cell suppression or depletion. Based on this strategy, chimeric and humanized anti-CD25 antibodies have been developed and successfully applied to the prevention of early acute rejection in human kidney, liver, heart, lung, and pancreas transplantation. The two such antibodies that are currently utilized as induction agents in clinical transplantation are basiliximab and daclizumab.[5,6,29,30] These agents are typically administered as single intravenous doses on the day of transplantation with one to four repeat doses administered between four and fourteen days later. Much of the clinical use of these anti-CD25 antibodies in transplantation has resulted from the publication of large randomized clinical trials of kidney transplantation in which significant reductions in acute rejection rates were observed with basiliximab or daclizumab therapy, compared to no induction in the context of CNIbased oral immunosuppression.[6,30] Importantly, in these studies, anti-CD25 therapy was not associated with increased rates of early infectious complications or malignancy. Two large series of liver transplant patients receiving basiliximab have also been recently reported. Both studies demonstrated acceptable rates of rejection, but with less benefit in patients with hepatitis C. Anti-CD25 antibody induction has also been reported to be effective in kidney transplant recipients managed by corticosteroid-free immunosuppression.[15] Adverse effects of anti-CD25 antibody therapy are generally mild and uncommon and do not include a cytokine release syndrome. Nonetheless, as with all biological agents, rare severe reactions have been reported.

TO MO RROW – THE PIPELINE The 1990s were extraordinary years in the clinical progress achieved with immunosuppressive agents as witnessed by the introduction of several novel agents described above such as mycophenolate derivatives, a microemulsion preparation of cyclosporine, a new CNI (tacrolimus), an mTOR inhibitor (sirolimus), and a highly effective polyclonal antibody preparation (Thymoglobulin). In contrast, between 2000 and 2005 no new drug was approved for organ transplantation. This apparent slowing of progress reflects the fact that such agents now face more hurdles than in the past on the path toward clinical acceptance for use in transplantation. In contrast to the medications introduced in the 1990s, for which the primary efficacy endpoint was the rate of acute rejection, the emphasis for emerging drugs must incorporate additional end points, such as success in eliminating corticosteroids and/or CNIs, the rate of chronic graft deterioration, the stability of renal function, the rate of cardiovascular morbidity and mortality, cancer development, and the frequency and severity of infectious diseases such as hepatitis C and polyomavirus. There are, nonetheless, a growing number of small molecules and biological agents that are currently in clinical development.[23] These include new members of existing classes of immunosuppressive agents (e.g., the CNI ISA-247 and the mTOR inhibitor everolimus – see Table 3.1), as well as entirely new classes of medication, some of which have been derived directly from recent basic insights into the immunology of allograft rejection and tolerance.[31] Important examples of these emerging novel agents are summarized in Table 3.2 and described briefly in the following text. Mechanistically, they can be viewed as targeting four specific aspects of immune function: 1. Biological Agents that Bind to Immune Cell Surface Receptors: A number of new monoclonal antibodies and fusion proteins with specificity for surface receptors on lymphocytes or antigen-presenting cells (APC) have undergone promising preclinical and clinical testing in solid organ transplantation in recent years. The humanized anti-CD20 antibody rituximab, which effectively depletes B-cells and is approved for treatment of B-cell lymphoma, has been used clinically to prevent or manage antibody-mediated rejection of solid organ allografts.[24] Humanized antibodies against CD40L, a surface receptor that mediates cross-talk between T-cells and APCs, showed high promise in primate organ transplant models but were associated with increased thromboembolism in human subjects and are no longer in clinical development.[32] Efalizumab, a humanized anti-LFA1 antibody, which is currently approved for therapy of psoriasis, may have important benefits for transplant recipients by reducing ischemia-reperfusion injury and inhibiting T-cell activation.[23,33] A phase II trial in kidney transplant recipients demonstrated efficacy in preventing acute rejection although a concerning number of cases of

THE DEVELOPMENT OF MODERN IMMUNOSUPPRESSIVE MEDICATIONS

19

Table 3.2 Examples of emerging immunosuppressive agents with novel mechanisms of action Name

Description

Mechanism

Stage of clinical development

Rituximab

Humanized anti-CD20 Monoclonal antibody

Binds to and depletes B-cells

Efalizumab

Inhibits lymphocyte adhesion and costimulation Prevents T-cell activation by blocking costimulation

CP-690,550

Humanized anti-LFA-1 Monoclonal antibody Recombinant Fusion Protein Specific to B7 Co-stimulatory ligands Recombinant fusion protein specific to IL-15 receptor JAK3 inhibitor

Approved for lymphoma; clinical use reported for prevention and treatment of antibody-mediated transplant rejection Approved for psoriasis; phase II for transplantation Phase III for kidney transplantation

FK778a

Malononitrilamide

Fingolomid (FTY720)a

S1P receptor agonist

Belatacept (LEA29Y) mIL-15/Fc

Inhibits proliferation of activated T-cells by blocking IL-15 stimulus

Preclinical testing in transplantation

Inhibits multiple cytokine effects in lymphocytes by blocking common c chain signaling Prevents lymphocyte proliferation by inhibiting de novo pyrimidine synthesis Prevents tissue infiltration by sequestering T-cells in lymphoid organs

Phase I/II in kidney transplantation

Phase III for kidney transplantation Phase III for kidney transplantation and autoimmune diseases

a

Clinical development has been recently halted at phase III stage.

lymphoproliferative disorder occurred at the highest dose. Low-dose efalizumab is being evaluated for islet cell and other solid organ transplants.[33] Among the most advanced new novel biological agents in clinical development is belatacept (also called LEA29Y), a soluble fusion protein derived from an experimental agent (CTLA4Ig) that was specifically designed to interfere with costimulatory signals to T-cells through the APC surface receptors B7-1 and B7-2.[26] Administration of CTLA4Ig in combination with other biological agents, or with an mTOR inhibitor, showed significant potential for inducing allograft-specific immune tolerance in animal transplant models.[32] A recently reported clinical trial, in which intermittent doses of belatacept were tested as an alternative to CNI therapy during the first year after kidney transplantation, indicated that this agent has equivalent efficacy to CYA in protecting against acute rejection, is associated with low toxicity, and may have the potential for reducing chronic graft fibrosis.[26] An additional novel biological agent in preclinical development is the anti-IL-15 fusion receptor protein mutant IL-15/Fc. This soluble fusion protein was designed specifically to block lymphocyte stimulation by the cytokine IL-15. In combination with IL-2 receptor blockade and mTOR inhibition, it can induce robust graft-specific tolerance in rodent models of transplantation through acceleration of activation-induced apoptosis of effector T-cells and preservation of regulatory (‘‘suppressor’’) T-cells.[34] It remains to be determined whether this approach can be duplicated in nonhuman primates and, subsequently, in humans. 2. Drugs that Target Intracellular Signaling Pathways: Inhibition of key intracellular signaling pathways in immune

cells is the primary mechanism of action of currently employed classes of immunosuppressive drugs such as CNIs and mTOR inhibitors. An example of a new class of signaling pathway inhibitors that are in the early stages of clinical development for transplantation are the Janus kinase 3 (JAK3) inhibitors.[35,36] JAK3 is an intracellular signaling enzyme that is highly expressed in lymphoid cells and is associated with a shared receptor (the common c chain) for several key cytokines including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.[36] Mutations of the common c chain or of JAK 3 are associated with severe combined immunodeficiency (SCID) in humans. One JAK3 inhibitor, CP-690,550 has been demonstrated to delay rejection and significantly prolong kidney allograft survival as monotherapy in both murine and nonhuman primate models [35] and is currently in a phase II trial in recipients of primary renal transplants in combination with mycophenolate mofetil and corticosteroids. 3. Emerging Antiproliferative Agents: New antiproliferative agents may offer improved side effect profiles or other clinical benefits compared to currently established drugs such as the mycophenolate derivatives. One such agent that has been recently developed for potential clinical use in organ transplant recipients is FK778, an analog of the drug leflunomide, which is currently approved for treatment of rheumatoid arthritis. FK778 and leflunomide belong to the malononitrilamide family of immunosuppressants that prevent both T-cell and B-cell proliferation through inhibition of dihydroorotate dehydrogenase, an important enzyme in the de novo synthesis of pyrimidines.[37] These drugs have also been shown to inhibit arterial smooth muscle cell proliferation and to

20

RYUTARO HIROSE AND MATTHEW D. GRIFFIN

have antiviral activity in vitro against CMV and BK polyomavirus. The efficacy of FK778 as an antirejection agent has been tested in several animal transplant models and in human kidney transplant recipients in combination with CNIs.[37] Results of clinical studies suggest that FK778 has acceptable immunosuppressive potency when combined with a CNI as long as therapeutic drug levels are achieved. The most frequently reported adverse event associated with FK778 treatment was dose-dependent anemia. 4. Drugs that Alter Lymphocyte Trafficking: The strategy of modifying trafficking of lymphocytes to prevent localized immunological injury represents an entirely new approach to the treatment of autoimmunity and organ allograft rejection. Only one such agent, fingolomid (also called FTY720) is currently in clinical development. Fingolomid is a synthetic structural analog of the fungal metabolite myriocin and shares structural and functional homology to sphingosine-1-phosphate (S1P) – the natural ligand to several G protein-coupled receptors. The active form of the drug acts as an S1P receptor agonist on lymphocytes and, by so doing, inhibits the egress of lymphocytes from lymph nodes and PeyerÕs patches into the circulation.[23,31,38] This sequestration reduces migration of effector T-cells to inflammatory tissues and has been shown to prevent acute cellular rejection of organ allografts in animal models as well as phase II human clinical trials. Unfortunately, clinical development of fingolomid in transplantation was recently halted during a phase III trial of kidney transplant recipients due to unexpected adverse effects. Nonetheless, cell-trafficking pathways will likely continue to be a target of novel therapies in the future.

S U MMARY A decade of innovation in the clinical application of immunosuppressive drugs has resulted in dramatic reductions in acute rejection and improvement in short- and long-term outcome in solid organ transplantation. Although, true immunological tolerance may not be broadly achieved in the near future, the reduction or elimination of certain classical immunosuppressants with their long-term toxicities is well within our grasp. Furthermore, it is likely that the novel interventional agents that are now emerging from basic insights into immune function will eventually result in more specific suppression of the immunological response to organ transplants while preserving protective immunity and, perhaps, providing added benefits for the graft such as ameliorating ischemiareperfusion injury and preventing chronic fibrosis.

REFERENCES

1. N. Singh, Infectious complications in organ transplant recipients with the use of calcineurin-inhibitor agent-based immunosuppressive regimens. Curr Opin Infect Dis. 18(4):342–5, 2005 Aug.

2. L. M. Russo, and S. A. Webber, Pediatric heart transplantation: immunosuppression and its complications. Curr Opin Cardiol. 19(2):104–9, 2004 Mar. 3. M. G. Massad, Current trends in heart transplantation. Cardiology. 101(1–3):79–92, 2004. 4. P. Keown, Improving quality of life – the new target for transplantation. Transplantation. 72(12 Suppl):S67–74, 2001 Dec 27. 5. J. C. Hong, and B. D. Kahan, Immunosuppressive agents in organ transplantation: past, present, and future. Semin Nephrol. 20(2): 108–25, 2000 Mar. 6. P. F. Halloran, Immunosuppressive drugs for kidney transplantation. New Engl J Med. 351(26):2715–29, 2004 Dec 23. 7. C. A. Galbraith, and D. Hathaway, Long-term effects of transplantation on quality of life. Transplantation. 77(9 Suppl):S84–7, 2004 May 15. 8. V. Q. Habwe, Posttransplantation quality of life: more than graft function. Am J Kidney Dis. 47(4 Suppl 2):S98–110, 2006 Apr. 9. A. Djamali, N. Premasathian, and J. D. Pirsch, Outcomes in kidney transplantation. Semin Nephrol. 23(3):306–16, 2003 May. 10. H. Yang, Maintenance immunosuppression regimens: conversion, minimization, withdrawal, and avoidance. Am J Kidney Dis. 47 (4 Suppl 2):S37–51, 2006 Apr. 11. F. Vincenti, Immunosuppression minimization: current and future trends in transplant immunosuppression. J Am Soc Nephrol. 14(7):1940–8, 2003 Jul. 12. F. Vincenti, E. Ramos, C. Brattstrom, S. Cho, H. Ekberg, J. Grinyo, R. Johnson, D. Kuypers, F. Stuart, A. Khanna, M. Navarro, and B. Nashan, Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation. Transplantation. 71(9):1282–7, 2001 May 15. 13. Y. Vanrenterghem, J. P. van Hooff, J. P. Squifflet, K. Salmela, P. Rigotti, R. M. Jindal, J. Pascual, H. Ekberg, L. S. Sicilia, J. N. Boletis, J. M. Grinyo, M. A. Rodriguez, and M. M. F. R. T. S. G. European Tacrolimus Minimization of immunosuppressive therapy after renal transplantation: results of a randomized controlled trial. Am J Transplant. 5(1):87–95, 2005 Jan. 14. H. U. Meier-Kriesche, S. Li, R. W. Gruessner, J. J. Fung, R. T. Bustami, M. L. Barr, and A. B. Leichtman, Immunosuppression: evolution in practice and trends, 1994–2004. Am J Transplant. 6(5 Pt 2):1111–31, 2006. 15. J. P. Lerut, Avoiding steroids in solid organ transplantation. Transpl Int. 16(4):213–24, 2003 Apr. 16. A. D. Kirk, R. B. Mannon, S. J. Swanson, and D. A. Hale, Strategies for minimizing immunosuppression in kidney transplantation. Transpl Int. 18(1):2–14, 2005 Jan. 17. A. O. Ojo, P. J. Held, F. K. Port, R. A. Wolfe, A. B. Leichtman, E. W. Young, J. Arndorfer, L. Christensen, and R. M. Merion, Chronic renal failure after transplantation of a nonrenal organ. New Engl J Med. 349(10):931–40, 2003 Sep 4. 18. R. S. Brown, Hepatitis C and liver transplantation. Nature. 436 (7053):973–8, 2005 Aug 18. 19. T. S. Mele, and P. F. Halloran, The use of mycophenolate mofetil in transplant recipients Immunopharmacology. 47(2–3):215–45, 2000 May. 20. T. Birsan, C. Dambrin, D. G. Freitag, R. W. Yatscoff, and R. E. Morris, The novel calcineurin inhibitor ISA247: a more potent immunosuppressant than cyclosporine in vitro. Transpl Int. 17(12):767–71, 2005 May. 21. B. D. Kahan, Sirolimus: a comprehensive review. Expert Opinion on Pharmacotherapy. 2(11):1903–17, 2001 Nov. 22. J. M. Grinyo, and J. M. Cruzado, Mycophenolate mofetil and sirolimus combination in renal transplantation. Am J Transplant. 6(9): 1991–9, 2006 Sep. 23. F. Vincenti, WhatÕs in the pipeline? New immunosuppressive drugs in transplantation Am J Transplant. 2(10):898–903, 2002 Nov.

THE DEVELOPMENT OF MODERN IMMUNOSUPPRESSIVE MEDICATIONS

24. M. D. Pescovitz, Rituximab, an anti-CD20 monoclonal antibody: history and mechanism of action. Am J Transplant. 6(5 Pt 1): 859–66, 2006 May. 25. P. J. Friend, Immunosuppression with monoclonal antibodies. Curr Opin Immunol. 2(6):859–63, 1989–1990. 26. F. Vincenti, C. Larsen, A. Durrbach, T. Wekerle, B. Nashan, G. Blancho, P. Lang, J. Grinyo, P. F. Halloran, K. Solez, D. Hagerty, E. Levy, W. Zhou, K. Natarajan, B. Charpentier, and G. Belatacept Study, Costimulation blockade with belatacept in renal transplantation. New Engl J Med. 353(8):770–81, 2005 Aug 25. 27. J. D. Eason, S. Nair, A. J. Cohen, J. L. Blazek, and G. E. Loss Jr., Steroidfree liver transplantation using rabbit antithymocyte globulin and early tacrolimus monotherapy. Transplantation. 75(8):1396–9, 2003 Apr 27. 28. J. F. Magliocca, and S. J. Knechtle, The evolving role of alemtuzumab (Campath-1H) for immunosuppressive therapy in organ transplantation. Transpl Int. 19(9):705–14, 2006 Sep. 29. F. Vincenti, A. de Andres, T. Becker, G. Choukroun, E. Cole, J. M. Gonzalez-Posada, M. A. Kumar, R. Moore, S. Nadalin, B. Nashan, L. Rostaing, K. Saito, and N. Yoshimura, Interleukin-2 receptor antagonist induction in modern immunosuppression regimens for renal transplant recipients. Transpl Int. 19(6):446–57, 2006 Jun. 30. T. Van Gelder, M. Warle, and R. G. Ter Meulen, Anti-interleukin-2 receptor antibodies in transplantation: what is the basis for choice? Drugs. 64(16):1737–41, 2004. 31. B. D. Kahan, Individuality: the barrier to optimal immunosuppression. Nature Reviews Immunology. 3(10):831–8, 2003 Oct.

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32. M. R. Clarkson, and M. H. Sayegh, T-cell costimulatory pathways in allograft rejection and tolerance. Transplantation. 80(5):555–63, 2005 Sep 15. 33. M. R. Nicolls, and R. G. Gill, LFA-1 (CD11a) as a therapeutic target. Am J Transplant. 6(1):27–36, 2006 Jan. 34. X. X. Zheng, W. Gao, E. Donskoy, M. Neuberg, M. Ruediger, T. B. Strom, and T. Moll, An antagonist mutant IL-15/Fc promotes transplant tolerance. Transplantation. 81(1):109–16, 2006 Jan 15. 35. D. C. Borie, P. S. Changelian, M. J. Larson, M. S. Si, R. Paniagua, J. P. Higgins, B. Holm, A. Campbell, M. Lau, S. Zhang, M. G. Flores, G. Rousvoal, J. Hawkins, D. A. Ball, E. M. Kudlacz, W. H. Brissette, E. A. Elliott, B. A. Reitz, and R. E. Morris, Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates. Transplantation. 79(7):791–801, 2005 Apr 15. 36. D. C. Borie, J. J. OÕShea, and P. S. Changelian, JAK3 inhibition, a viable new modality of immunosuppression for solid organ transplants. Trends in Molecular Medicine. 10(11):532–41, 2004 Nov. 37. J. Fawcett, and D. W. Johnson, FK778: a powerful immunosuppressive, but will it really be good for you? Transplantation. 78(1):7–8, 2004 Jul 15. 38. V. Brinkmann, J. G. Cyster, and T. Hla, FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am J Transplant. 4(7):1019–25, 2004 Jul.

4 Organ Transplantation: Current Status and Practice

Matthew D. Griffin, MB, BCh

O VE R V IE W O F T H E C U R R E NT ST AT U S OF S OL I D OR G AN TR A NS P L AN T A TI ON

database (1988), currently approach 300,000 for organs donated after death (deceased donor) and 80,000 for organs from living donors. Many additional recipients transplanted prior to 1988 are followed at transplant centers throughout the country. Although recipients of kidney, liver, and heart transplants constitute the three largest cohorts, it should be noted that cumulative recipient numbers of other organs and organ combinations are also substantial, estimated at between approximately 1,000 and 15,000 of each. Living donor transplantation is primarily utilized for kidney and liver recipients but small numbers of allografts have been successfully performed using portions of pancreas, lung, and intestine from living donors. Rarely, ‘‘domino’’ liver and heart transplants are carried out in which the excised organ from the recipient of a deceased donor transplant is considered to have sufficient function to sustain the life of a second recipient with lifethreatening disease. Annual data from the OPTN database indicate that the overall practice of organ transplantation has progressively expanded in the United States with total transplants increasing from approximately 19,000 to 28,000 per year between 1995 and 2005 (Figure 4.1B). The trend towards increased recipient numbers is evident for each major transplant subgroup with the exception of thoracic organ allografts (heart and/or lung), which have remained essentially stable. Significantly, despite the steady rise in allograft procedures, the number of patients added to waiting lists for transplantation each year consistently exceeds the number transplanted and, for kidney in particular, has risen at an accelerated rate over the past five years (Figure 4.1C). Thus limited availability of suitable organs for transplantation represents an important barrier to optimal application of this form of therapy. Transplant registry reports from Europe, Australia/New Zealand, and Japan[2–6], as well as published surveys from multiple other regions [7–9] reveal that the growth in transplantation has occurred, to varying degrees, on a worldwide basis. The achievement of excellent patient and graft survival rates has played a central role in dictating demand and utilization of organ transplantation. Adjusted one-, three-, and five-year graft survival rates for single- and combined-organ transplant types in the United States between 1995 and 2005 are summarized in Figure 4.2 and serve as an example for closely comparable graft survival rates reported from individual transplant centers and transplant data registries from other geographical regions.[2–6] As shown, the graft survival rates for individual organs and organ combinations vary considerably. These variations reflect a number of important factors,

Solid organ transplantation is a burgeoning field of medicine and biomedical science that has fulfilled and, perhaps, exceeded its envisaged potential to prolong and enhance the lives of individuals with irreversible organ failure. Although the history of transplantation is marked by individual bold innovations and discoveries, the consolidation of reproducible success and the persistent optimism for the future of this field now stem from collaboration, information sharing, and debate among the growing community of transplant-related professionals. Furthermore, as the process of overcoming barriers to successful treatment of organ failure has evolved worldwide, the field of solid organ transplantation has come to represent a unique nodal point for disciplines as diverse as medicine and surgery, immunology, pharmacology, biomedical industry, bioethics, sociology, jurisprudence, and politics. The purposes of this chapter are to encapsulate recent numerical trends in organ transplant practice worldwide, to highlight the complex medical and social drivers that underlie such trends, and to briefly discuss emerging factors that may shape its future.

RECENT TRENDS IN SOLID ORGAN TRANSPLANT NUMBERS AND SURVIVAL R AT ES Successful human transplantation protocols have been established for a range of individual solid organs and organ combinations over the past five decades. The single-organ grafts that are currently carried out routinely are kidney, pancreas, liver, small intestine, heart, and lung. Combined kidney/pancreas and heart/lung transplants have also emerged as established therapies for specific causes of double-organ failure. In addition, other multiorgan transplant procedures involving between two and four solid organs are performed when deemed appropriate for individual patients. Transplant data registries have been established in multiple geographic regions and now provide valuable records of numerical trends in organ donation and transplantation, in addition to allowing analyses of allograft survival rates.[1–7] Figure 4.1A illustrates cumulative transplant numbers within the United States, based on data submitted by organ procurement organizations and clinical transplant centers to the Organ Procurement and Transplantation Network (OPTN) (1). As shown, total transplant recipients in the United States, since establishment of the 22

ORGAN TRANSPLANTATION: CURRENT STATUS AND PRACTICE

Figure 4.1. A. Total numbers of each of the major types of solid organ transplants carried out in the United States between 1988 and 2005 are shown graphically and numerically for deceased donor source and living donor source. Transplant numbers are derived from publicly available OPTN data.[1] B. Annual numbers of the major organ transplant subgroups in the United States are shown graphically, based on OPTN data between 1995 and 2005. With the exception of thoracic organ transplantation (heart, lung, heart and lung) there has been a progressive increase in annual numbers of organ transplants. C. Annual numbers of individuals added to waiting lists in the United States for the major organ transplant subgroups are shown graphically, based on OPTN data between 1995 and 2005.

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Figure 4.2. A. One-, three-, and five-year graft survival rates are shown for kidney and liver transplants carried out in the Unites States between 1995 and 2005, based on OPTN data. Separate survival rates are shown for organs from deceased and living donors. Graft losses include those due transplant failure and to patient death with functioning graft. B. One-, three-, and five-year graft survival rates are shown for other major categories of single- and double-organ transplants carried out in the United States between 1995 and 2005, based on OPTN data. The data shown reflects results for deceased donor source only. Graft losses include those due transplant failure and to patient death with functioning graft.

including the complexity of the surgical procedure, the severity of underlying causes of organ failure and associated comorbidities among recipients, and the immunogenicity and propensity to chronic deterioration of the tissues being transplanted. For example, the notable fall-off in graft survival that occurs between one and five years following lung, heart/lung, and small intestine transplants compared to liver, kidney, and heart transplants (see Figure 4.2A and 4.2B) may be explained in part by the stimulation of persistent antidonor immune responses within immunologically active mucosal surfaces.[10] For kidney but not liver allografts, early and late graft survival rates are favorably impacted by transplantation from a living donor (see Figure 4.2A). In general, the past 2 decades have been characterized by striking improvements in early graft survival; however, there are continuing challenges in understanding and preventing chronic graft functional decline and late graft loss.[11,12] The basic numerical trends summarized here indicate that, regardless of all other future developments, there will clearly be a need for expansion of clinical expertise and research di-

rected toward primary and preventative care, as well as consultative specialty medical care for organ transplant recipients.

RECENT DEVELOPMENTS IN SOLID ORGAN TRANSPLANT PRACTICE More detailed review of worldwide organ transplant practice reveals a level of complexity that extends well beyond numerical increases in transplant numbers and success rates. A number of important recent trends are reviewed here and summarized in Table 4.1. One highly significant development has been the disproportionate increase in transplant recipients aged greater than fifty years compared to those of younger age. This is clearly illustrated in Figure 4.3A using OPTN data for recipients in the United States between 1995 and 2005. The trend toward aging of the transplant population carries multiple implications including higher levels of preexisting medical comorbidity, increased risk for cancers, infection and other immunosuppression-related toxicity, as well as altered

ORGAN TRANSPLANTATION: CURRENT STATUS AND PRACTICE

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Table 4.1 Trends that are shaping solid organ transplant practice

1. The total number of organ transplants carried out is increasing each year in most geographic regions. 2. One-year survival rates for all commonly transplanted organs and organ combinations have improved progressively but variable long-term patient and graft survival rates represent a persistent challenge. 3. Waiting list additions consistently exceed transplantations, creating a growing ‘‘organ availability’’ gap and driving the development of new criteria for acceptance and allocation of organs from deceased and living donors. 4. The transplant recipient population is aging and indications for organ transplantation are changing to reflect major worldwide trends in human health (e.g., increasing incidence of type 2 diabetes mellitus). 5. An increasing number of individuals are being retransplanted with the same organ or receiving additional organ transplants as a result of chronic immunosuppression-related morbidity. 6. Living donation for kidney and liver transplantation is progressively increasing, particularly from unrelated living donors. 7. Important ethical and political debates have arisen regarding the ‘‘commodification’’ of human organs for transplantation, the development of global living donor networks and the long-term health of living organ donors. 8. Success with solid organ allografts has stimulated clinical efforts to transplant other body parts such as pancreatic islets, limbs, and facial tissue, creating the potential for new populations of transplant recipients in the future. 9. Immunosuppression practice is rapidly diversifying, creating prospects for improved long-term outcomes, as well as uncertainty regarding future immunosuppression-related morbidity. 10. Major research endeavors in immunological tolerance, xenotransplantation, and stem cell technology have been initiated to specifically address current limitations in organ availability, long-term organ transplant survival, and immunosuppression-related toxicity.

expectations for longevity of graft function. In addition, the relative rise in older transplant recipients reflects important shifts in the etiology of organ failure to favor chronic progressive diseases of adulthood. The most dramatic examples of this are the worldwide increases that have occurred in ‘‘metabolic syndrome’’-related disease (obesity, hypertension, type 2 diabetes mellitus, steatohepatitis, and accelerated atherosclerosis) and in liver failure due to hepatitis C.[13,14] A related development that similarly augments the overall burden of comorbidity among recent transplant recipients is the increasing number that are retransplanted for functional deterioration of prior allografts or that receive kidney transplants for chronic renal failure occurring following nonkidney organ transplants.[1,14] The gap between organ demand and availability, which has caused transplant waiting lists to swell, has created some additional fascinating trends in organ donation and allocation. With the goal of maximizing the number and value of deceased organ donations, criteria for predicting the functional capacity of organs from such donors and for matching them with anticipated recipient requirements are being actively refined and tested. One result of this process has been the increase in ‘‘extended criteria’’ organ transplants that shorten waiting times for some recipients but also entail additional risk for short- and long-term complications.[15] Even more striking has been the rise in living donor kidney and liver transplantation during the past 10 years. As shown in

Figure 4.2B for kidney transplant numbers between the mid1990s and mid-2000s, a progressively greater proportion of recorded grafts have come from living donors in the United States, Europe, Australia/New Zealand, and Japan. These data also illustrate differences in overall acceptance of living donation among the geographical regions with low rates of living kidney donor transplantation (10–25%) in the United Kingdom and EuroTransplant countries; moderately high rates in the United States, Scandinavia, and Australia/New Zealand (30–40%); and a large predominance in Japan (80–90%). Reports from other Asian countries confirm that living organ donation is predominant and increasing rapidly across this continent.[7–9] Despite these geographic variations, increasing living donor transplantation represents a global phenomenon with additional emerging characteristics that reflect improvements in donor surgical technique, immunosuppression for poorlymatched allografts, and communications technology. For example, living organ donors are increasingly more likely to be genetically unrelated or even unknown to the recipient, to have developed a relationship with the recipient via internet correspondence, to live in another country, to be of older age, or to have preexisting medical conditions. All of these developments have heightened debate on the ethical and political oversight of living organ donation that focuses on multiple areas of concern, including the potential for illegal organ trafficking or coercion; donor payment; ‘‘medical

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Figure 4.3. A. Annual numbers of total recorded organ transplants in the United States between 1995 and 2005 are shown, based on age groupings at the time of transplantation. Increased annual numbers are most evident among recipients aged between fifty and sixty-four years and aged greater than sixtyfive years. B. Total numbers of deceased donor and living donor kidney transplants recorded in six different registries from North America, Europe, Australia/New Zealand (AUS/NZ), and Japan are shown for mid-1990s (1994 to 1997), for 2000 or 2001, and for 2004 or 2005. * = data not available. U.K. numbers are for England, Wales, Scotland, and Northern Ireland;[2] EuroTransplant numbers are for Austria, Belgium, Germany, Luxemburg, the Netherlands, and Slovenia;[3] ScandiaTransplant numbers are for Norway, Sweden, Denmark, Finland, and Iceland.[4]

tourism’’; long-term medical, psychological, and social outcomes of living organ donation; governmental regulation of living organ donation; and internet donor/recipient matching programs.[16,17]. The outcomes of these debates and the ability of the international transplant community to study and reach consensus on principles for living donor acceptance will, in fact, have a large influence on future organ transplant practice. In keeping with the innovative history of clinical transplantation, there have been a number of recent noteworthy

successes in expanding the range of human allografts that can be effectively performed. Such novel transplant procedures have included the long sought-after achievement of successful pancreatic islet transplantation for type I diabetes mellitus[18] as well as allogeneic transplantation of non-life-sustaining tissue such as limbs and face.[19,20] These exploratory programs, which have been the subject of both excitement and scrutiny, may produce new populations of transplant recipients with specific long-term care requirements in coming years.

ORGAN TRANSPLANTATION: CURRENT STATUS AND PRACTICE

A final ongoing trend in transplantation that merits consideration is the diversification of available immunosuppressive medications and immunosuppression strategies.[21] Several new developments in antirejection therapy, which are described in detail in Chapter 3, have entered preclinical and clinical practice in recent years, resulting in a large expansion of the permutations that can now be applied to multidrug immunosuppressive regimens. This expansion of potential drug combinations offers new hope for lowered overall toxicity and improved long-term graft survival but, additionally, introduces a level of uncertainly regarding the future medical needs of transplant recipients. Such uncertainty is heightened by the lack of long-term follow-up studies for many recently reported antirejection regimens. Thus, the experience that has accumulated with skin cancer and other complications among patients receiving calcineurin-inhibitor-based immunosuppression may not serve as an accurate template for subsequent generations of allograft recipients. As with the other trends reviewed in this section, the evolution of immunosuppression practice highlights the current dynamic nature of organ transplantation and the growing need for multidisciplinary management and long-term follow-up of transplanted patients.

T H E FU T U R E O F SO L I D O R G A N TRANSPLANTATION There is substantial hope that ongoing areas of research will eventually alter the field of organ replacement therapy to a stage where the need for lifelong immunosuppression or even the requirement to procure organs and tissues from other humans will be eliminated. Implicit in this future vision is the fact that removal of the barriers presented by limited organ availability or chronic medication toxicity will allow the field of transplantation to be broadened to include new indications, to address illnesses at earlier stages of morbidity, and to replace tissues that cannot currently be repaired. Three key research fields in this regard are: (1) the pursuit of clinical immunological tolerance strategies, (2) the development of successful xenotransplantation from genetically manipulated pigs to humans, and (3) the use of pluripotent human stem cells to generate functional organs, tissues, and cells. It is beyond the scope of this chapter to review the current states of advancement of these areas, which are described in more detail in Chapter 5 and elsewhere.[22–27] It is worth noting, however, that there have been both encouraging breakthroughs and previously unrecognized obstacles reported for each of them. For example, specific strategies for generation of immune tolerance have progressed from animal models to small-scale human trials including generation of mixed bone marrow chimerism prior to organ transplantation and blockade of T-cell costimulatory pathways. To date, however, the safety and efficacy of these strategies in humans has not achieved results comparable to those attained in the laboratory setting with animal models.[22–25] Similarly, for xenotransplanta-

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tion, striking advances in overcoming immediate antibodymediated rejection of pig organs in nonhuman primate recipients have revealed additional immunological and physiological barriers that prevent long-term established function of the transplanted organs.[26] Finally, remarkable scientific advancement has been achieved in the understanding of stem cell biology but the level of complexity that has been revealed along with the ethical implications of manipulating human embryonic cells indicate that successful harnessing of this technology to replace the function of whole organs remains, almost certainly, decades in the future.[26,27] Despite the uncertainty regarding eventual clinical success for these specific emerging innovations, the process of sequentially eliminating barriers to overall transplant success through focused research remains at the center of current and future organ transplantation practice.

REFERENCES

1. Organ Procurement and Transplant Network website: http:// www.OPTN.org 2. UK Transplant website: http://www.uktransplant.org.uk 3. Eurotransplant International Foundation website: http://www.eurotransplant.nl/ 4. Scandia Transplant website: http://www.scandiatransplant.org/ 5. Australia and New Zealand Dialysis and Transplant Registry website: http://www.anzdata.org.au/ 6. Japan Organ Transplant Network website: http://www.jotnw.or.jp/ english_top/englishtop.html 7. Kogan, A., Sahar, G., Orlov, B., Singer, P., Cohen, J., Godovic, G., Raanani, E., Berman, M., Vidne, B., and Aravot, D. Organ transplantation statistics in different countries: internet review. Transplant Proc.35(2):641–2, 2003 Mar. 8. Broumand, B. Transplantation activities in Iran. Experimental & Clinical Transplantation: Official Journal of the Middle East Society for Organ Transplantation.3(1):333–7, 2005 Jun. 9. Ota, K. Current status of organ transplants in Asian countries. Transplant Proc.36(9):2535–8, 2004 Nov. 10. Gourishankar, S., and Halloran, P.F. Late deterioration of organ transplants: a problem in injury and homeostasis. Curr Opin Immunol.14(5):576–83, 2002 Oct. 11. Sayegh, M.H., and Carpenter, C.B. Transplantation 50 years later– progress, challenges, and promises. New Engl J Med. 351(26):2761–6, 2004 Dec 23. 12. Zimmet, P., Alberti, K.G., and Shaw, J. Global and societal implications of the diabetes epidemic. Nature. 414(6865):782–7, 2001 Dec 13. 13. Shiffman, M.L., Saab, S., Feng, S., Abecassis, M.I., Tzakis, A.G., Goodrich, N.P., and Schaubel, D.E. 2006. Liver and Intestine Transplantation in the United States, 1995–2004. Am J Transplantation. 6:1170–87. 14. Ojo, A.O., Held, P.J., Port, F.K., Wolfe, R.A., Leichtman, A.B., Young, E.W., Arndorfer, J., Christensen, L., and Merion, R.M. Chronic renal failure after transplantation of a nonrenal organ. New Engl J Med. 349(10):931–40, 2003 Sep 4. 15. Lopez-Navidad, A., and Caballero, F. Extended criteria for organ acceptance. Strategies for achieving organ safety and for increasing organ pool. Clin Transplant. 17(4):308–24, 2003 Aug. 16. Wright, L., Faith, K., Richardson, R., Grant, D., and Joint Centre for Bioethics, U.o.T.T.O. Ethical guidelines for the evaluation of living organ donors. Can J Surg. 47(6):408–13, 2004 Dec.

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17. Delmonico, F. A Report of the Amsterdam Forum on the Care of the Live Kidney Donor: Data and Medical Guidelines. Transplantation. 79(6 Suppl):S53–66, 2005 Mar 27. 18. Shapiro, A.M., Lakey, J.R., Ryan, E.A., Korbutt, G.S., Toth, E., Warnock, G.L., Kneteman, N.M., and Rajotte, R.V. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. New Engl J Med. 343(4):230–8, 2000 Jul 27. 19. Okie, S. Facial transplantation: brave new face. New Engl J Med. 354(9):889–94, 2006 Mar 2. 20. Lanzetta, M., Petruzzo, P., Margreiter, R., Dubernard, J.M., Schuind, F., Breidenbach, W., Lucchina, S., Schneeberger, S., van Holder, C., Granger, D., et al. The International Registry on Hand and Composite Tissue Transplantation. Transplantation. 79(9):1210–4, 2005 May 15. 21. Halloran, P.F. Immunosuppressive drugs for kidney transplantation. New Engl J Med. 351(26):2715–29, 2004 Dec 23.

22. Newell, K.A., Larsen, C.P., and Kirk, A.D. Transplant tolerance: converging on a moving target. Transplantation. 81(1):1–6, 2006 Jan 15. 23. Vincenti, F., Larsen, C., Durrbach, A., Wekerle, T., Nashan, B., Blancho, G., Lang, P., Grinyo, J., Halloran, P.F., Solez, K., et al Costimulation blockade with belatacept in renal transplantation. New Engl J Med. 353(8):770–81, 2005 Aug 25. 24. Cosimi, A.B., and Sachs, D.H. Mixed chimerism and transplantation tolerance. Transplantation. 77(6):943–6, 2004 Mar 27. 25. Clarkson, M.R., and Sayegh, M.H. T-cell costimulatory pathways in allograft rejection and tolerance. Transplantation. 80(5):555–63, 2005 Sep 15. 26. Cascalho, M., and Platt, J.L. New technologies for organ replacement and augmentation. Mayo Clin Proc. 80(3):370–8, 2005 Mar. 27. Grove, J.E., Bruscia, E., and Krause, D.S. Plasticity of bone marrowderived stem cells. Stem Cells. 22(4):487–500, 2004.

5 The Immunology of Transplantation and Allograft Rejection

Matthew D. Griffin, MB, BCh and Ryutaro Hirose, MD

OVER VIEW OF THE D EVELOPM ENT AND CURRENT STATUS OF TRANSPLANT IM M UN OL OG Y

3. Transplantation of an organ between genetically nonidentical individuals has the potential to simultaneously activate many of the same immune effector mechanisms that exist to eliminate external pathogens but, in a manner that is magnified, prolonged, and stripped of much of its specificity by the structural differences between donor and host MHC proteins. 4. Long-term interactions between donor tissue and the host immune system, although less well understood, are equally complex and likely involve a balance between effector and regulatory mechanisms that may contribute both to chronic graft injury and to donor-specific tolerance in different transplant recipients.

Many of the historical and persistent barriers to successful transplantation derive from the complex immunological events that are set in motion once an organ or tissue from one individual is placed within the body of another. From a clinical standpoint, the immune interface between transplanted organs and their hosts dictates much of the need for pretransplant tissue typing and cross-match testing, lifelong posttransplant immunosuppressive therapy, regular monitoring of allograft function, and intermittent histological sampling of the graft. From a scientific perspective, the fields of immunology and transplantation have developed together in symbiotic fashion over the past century with experimentation and discovery in each influencing the other. Among the major immunological insights that have arisen partly or entirely from transplant-related experiments are the biology of natural and acquired antibodies, the significance of major histocompatibility complex (MHC) genetic diversity, the function of the thymus and other lymphoid organs, the nature of antigen presentation, the role of costimulation in T-Cell activation, and the mechanisms underlying self-tolerance. Recently, the parallel progress of the two fields has entered a new stage of productivity, the translation of mechanistic immunological discovery into novel targeted interventions, and treatment strategies for improving overall success in human transplantation. The purposes of this chapter are to succinctly describe our current understanding of the major elements of human protective immunity and to link these pathways with important aspects of the immune response to allogeneic organ transplants. Table 5.1 summarizes these elements and compares how they apply to natural protective immunity and to transplant-related immune responses. As a rule, it can be useful to consider four basic concepts when reviewing transplantation immunology:

T H E I N NA T E I MMU N E A XI S Innate immunity is generally considered to represent evolutionarily ancient systems of pattern recognition and response that act immediately against invading pathogens or other forms of injury. This axis includes specialized cells and soluble mediators but lacks the capacity for further adaptation through gene rearrangement and establishment of ‘‘memory.’’[1,2] Important aspects of innate immunity that are of direct relevance to understanding the response to allogeneic transplants are described as follows.

Localized Release of Proinflammatory Mediators For all organs and tissues, mechanical or toxic injury, acute ischemia, or invasion by a pathogenic microorganism elicit, within minutes to hours, a wide-ranging transcriptional program among the resident cells that results in the localized expression or secretion of many protective factors. These include antimicrobial peptides and reactive oxygen species, chemokines that recruit inflammatory cell populations, and cytokines that stimulate further protective mechanisms. Initiation of this genetic program for inflammation is stimulated by the binding of molecular products associated with injury and infection to pattern-recognition receptors (such as the toll-like receptors) on responding cells.[3] Thus, so-called endogenous and exogenous ‘‘danger signals’’ directly link a threat with the initiation of a protective response.

1. The human immune system has evolved to recognize specific external threats (e.g., harmful microorganisms) using a complex system of effector mechanisms to eliminate them and an equally sophisticated system of counterregulatory mechanisms to avoid self-destruction (autoimmunity) and prolonged immune activation. 2. The species itself is further protected by an extremely high rate of sequence polymorphism in genes encoding the MHC proteins that are primarily responsible for the specificity of immune responses against the universe of potential pathogens.

Transplant-Specific Considerations Transplanted organs are, almost invariably, subject to trauma and ischemia both before and after removal from the 29

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Table 5.1 Chapter summary: some of the major elements of immune function, their role in protection against infection and their importance for the immune response to organ transplants. Immunological axis

Characteristic

Role in protective immunity

Role in transplant immune response

Innate

Localized release of proinflammatory mediators Localized recruitment of leukocyte populations

1. Immediate antimicrobial mediators 2. Recruitment of inflammatory cells

1. Contributes to early graft dysfunction 2. Recruits host leukocytes to new transplant

1. Augmented antimicrobial activities 2. Specialized cellular killing functions

Uptake of antigen by and maturations of DCs

1. Acquisition of microbial proteins for antigen presentation 2. DC migration to lymphoid organs 3. Upregulation of MHC/peptide complexes and costimulatory ligands

Presentation of MHC/peptide complexes by DCs to T-cells

1. Interaction of antigen-bearing DCs with many T-cells in lymphoid organs 2. Activation of few microbe-specific T-cells for activation – ‘‘low precursor frequency’’ T-cell activation linked with upregulation of accessory ligands on DC by infection-related ‘‘danger signals’’ 1. CD8 ‘‘killer’’ and CD4 ‘‘helper’’ T-cells perform separate protective functions. 2. Different forms of CD4 differentiation (Th1, Th2, and Th3) allow individualized effector response to different infections. 3. Small proportion of infection-specific T-cells persists as memory cell. 1. Activation of few microbe-specific B-cells based on interaction of BCR with soluble or cell-bound whole microbial proteins. 2. Full B-cell activation linked to microbe-specific T-cell response through CD4 ‘‘helper’’ functions (CD40L, cytokines). 3. Isotype switching and somatic mutation in germinal centers further increase effectiveness of antibody response. 4. Small proportion of infection-specific B-cells persists as memory cells for potent secondary responses. 1. Antibodies arising in neonatal period against common microbial molecular patterns. 2. Lifelong ‘‘barrier’’ against bacterial invasion of blood stream and body cavities. 1. Marking of microbes for phagocytosis and killing by macrophages (opsonization). 2. Direct microbial killing through classical complement pathway.

1. Donor leukocytes present at transplantation 2. Host leukocytes enter graft rapidly 1. Donor DCs mature and carry transplant antigens to host lymphoid organs – ‘‘direct’’ alloantigen presentation. 2. Recipient DCs enter, take up donor antigens and mature – ‘‘indirect’’ alloantigen presentation. 1. Genetic polymorphisms of MHC result in ‘‘high precursor frequency’’ for donor-specific T-cells. 2. Basis for tissue typing and HLA matching. 3. Basis for anti-T-cell immunosuppression.

Cognate cellular

T-cell costimulation

T-cell effector functions and memory

Cognate humoral

B-cell activation and memory

Natural antibodies

Antibody effector functions

1. Costimulatory pathways upregulated early after transplantation 2. Basis for costimulatory blockade therapy 1. Infiltration of graft by CD8 and CD4 T-cells during acute cellular rejection. 2. Th1-type response predominates in most forms of cellular rejection. 3. Memory T-cells against donor HLA increase likelihood of acute and chronic rejection in some recipients. 1. Previous transplant, multiple blood transfusions or multiple pregnancies may result in preexisting B-cell response to donor HLA – ‘‘sensitized’’ recipient. 2. Basis for cross-match testing prior to transplantation. 3. Some recipients develop anti-HLA antibodies after transplantation – risk factor for chronic graft deterioration. 4. No very-effective treatments to suppress or eliminate anti-HLA antibodies. 1. Basis for hyperacute rejection of ABO blood group incompatible transplants 2. Basis for hyperacute rejection of organ xenotransplants 1. Basis for hyperacute and acute ‘‘humoral’’ rejection of transplants in recipients with preexisting anti-HLA antibodies 2. Basis for some forms of chronic rejection

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31

Immunological axis

Characteristic

Role in protective immunity

Role in transplant immune response

Immune tolerance

Central T-cell tolerance

Most T-cells bearing auto-reactive T-cells deleted in the thymus.

Peripheral T-cell tolerance

Autoimmunity prevented by multiple mechanisms for deleting, anergizing or actively suppressing auto-reactive T-cells in lymph nodes and spleen without preventing responses to infection.

B-cell Tolerance

1. Auto-reactive B-cells deleted in bone marrow. 2. Some auto-reactive B-cells anergized or deleted in lymph nodes and spleen.

Basis for myeloablative/non-myeloablative bone marrow transplant for donor-specific tolerance 1. Donor-specific regulatory T-cells develop in some recipients with long-term graft survival. 2. Basis for many experimental models and clinical concepts of donor-specific tolerance. B-cell tolerance desirable in sensitized recipients but no current interventions

donor as well as during and after the transplant surgery. An important result of this is that potent localized inflammatory responses are ongoing within the allograft in the peri-transplant period and may result in delayed or absent organ function. Key mediators in this regard include cytokines such as tumor necrosis factor (TNF), chemokines such as monocyte chemotactic peptide 1 (MCP-1), and adhesion proteins such as P-selectin. One role of corticosteroids in transplantation is to inhibit full expression of proinflammatory mediators within the newly transplanted organ. More specific inhibitors are also being tested for their ability to limit early graft dysfunction.

Recruitment of Inflammatory Cell Populations Localized inflammatory responses by resident cell populations of injured or infected tissues are followed, within hours, by the accumulation of bone-marrow-derived cell populations such as neutrophils, eosinophils, natural killer (NK) cells, and monocytes with the capacity to differentiate into macrophages or dendritic cells (DCs). This early cellular inflammation is orchestrated by localized upregulation of adhesion proteins, chemokines, and activating cytokines. The infiltrating cells fulfill a range of roles including secretion of additional antimicrobial products, phagocytosis of microorganisms and apoptotic cells, direct cytotoxicity of infected or damaged cells and, eventually, initiation of repair mechanisms.[2]

Transplant-Specific Considerations Transplanted organs, particularly from deceased donors, have typically undergone hours or days of injury response prior to procurement and thus may transmit many inflammatory cells (so-called ‘‘passenger leukocytes’’) from donor to recipient. Within hours of transplantation, the organ will become the site of a complex traffic involving these donor leukocytes and newly-recruited recipient inflammatory cells.[4] The implications of this process include the potential for ongoing intragraft inflammation and cell death and the immediate exposure of the host immune system to donor antigens in the form of migratory donor leukocytes. This latter may have the potential to activate subsequent donor-specific effector

responses as well as immune tolerance mechanisms, which will be described later.[5]

Uptake of Antigenic Material and Maturation of Antigen Presenting Cells Included among the resident cells of any tissue is a population of bone-marrow-derived leukocytes termed DCs that contribute to the localized innate response to injury and infection by rapidly secreting proinflammatory cytokines and chemokines.[6] In addition, resident DCs avidly ingest material from damaged cells and microorganisms during the early response phase. Having taken up the antigens associated with a given form of injury, DCs initiate a genetic program termed ‘‘maturation’’ by which they migrate out of the tissue to draining lymph nodes or spleen, display antigen on their surface in the form of peptide fragments bound to MHC proteins, and upregulate other surface receptors and cytokines that are necessary for the stimulation of antigen-specific cognate immunity.[6] During the phase of recruitment of additional inflammatory cells to a site of tissue injury, some of the recruited monocytes differentiate into DCs, which begin a second wave of antigen uptake, migration, and antigen presentation.

Transplant-Specific Considerations The passenger leukocytes of a transplanted organ include a population of DCs, which rapidly matures and migrates to host lymphoid organs. These donor DCs constitute the most potent initial source of donor antigen presentation to the host immune system.[4] The encounter between host T-cells and the MHC complexes expressed by mature donor DCs is often referred to as ‘‘direct’’ alloantigen presentation. Concurrent with this process, host monocytes enter the graft and differentiate into DCs, which also ingest donor antigenic material from damaged cells and process them for presentation as peptides on host MHC. Trafficking of these donor peptide-presenting host DCs to lymphoid organs constitutes the so-called ‘‘indirect’’ alloantigen presentation pathway and, in fact, more closely mimics the natural mechanism for activating cognate immune responses to ‘‘foreign’’ antigens.[7] For both direct

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and indirect alloantigen presentation, the DCs represent a conduit between the localized innate immune response (which is required to initiate antigen uptake, migration, and maturation of DCs) and the cognate immune response (which requires presentation of antigenic peptide on MHC in the context of a mature antigen presenting cell). At later time points after transplantation, these pathways of donor antigen presentation may be augmented by episodes of nonspecific graft injury or by localized or systemic infection, thus heightening the risk for host immune response. Over time, DC-mediated indirect alloantigen presentation also constitutes an ongoing immunological dialog between graft and host that, depending on its tempo and nature, may drive chronic forms of graft injury or may contribute to the emergence of a degree of donor-specific tolerance that favors graft longevity.[5]

C O G N AT E C E LL U L A R IM M U NI T Y – T H E D E N D R I T IC C E L L / T - C E L L A X IS T-Cells are lymphocytes that constitute one of the major mediators of cognate (sometimes called ‘‘adaptive’’) immunity. They are distinguished by expression of surface receptors (TCR) of highly variable sequence. Individual T-cell clones develop in the thymus through random rearrangement of the genes encoding the a and b chains that make up the complete TCR. Developing T-cells are selected for survival and released into the periphery, based on their ability to interact with peptides bound to MHC proteins on thymic antigen presenting cells (APCs). Individual new ‘‘naı¨ve’’ T-cells released from the thymus have the capability of responding only to a distinct MHC/peptide structure, a specificity that is dictated by the sequence of the TCR binding surface.[8] Productive binding of the TCR with its optimal MHC/peptide target, when combined with additional interactions between the T-cell and antigen APC, results in intracellular signaling events that induce the T-cell to proliferate, migrate, and activate effector mechanisms that eliminate or control an infecting microorganism.[8–10] A schematic representation of the molecular interface between mature DC and antigen-specific T-cell is presented in Figure 5.1. The diverse population of T-cells produced by a given individual is referred to as the ‘‘T-cell repertoire’’ and is responsible for that individualÕs potential to generate discrete cellular immune responses to tens of millions of different peptide antigens. Importantly, each individualÕs T-cell repertoire is selected to function effectively only in the context of his or her own panel of MHC proteins. In this section, details of some key concepts of T-cell-mediated (‘‘cellular’’) immunity are expanded upon and linked with some of the most important immunological events affecting allogeneic organ transplants.

The Major Histocompatibility Complex (MHC) and Antigen Presentation to T-cells The MHC consists of a family of cell surface proteins encoded by genes clustered together on individual chromosomes.[9] For

humans, these proteins are referred to as human leukocyte antigens (HLA) and are divided into Class I and Class II proteins. When fully assembled and expressed on a cell surface, both classes of HLA generate a binding groove on the extracellular portion of the molecule into which peptides of six to fourteen amino acid length are loaded. The combined structure of the peptide binding region of an HLA protein and the specific peptide that is loaded into it constitute the site of interaction with the TCR. The amino acid sequence of individual HLA binding-groove regions are highly polymorphic at a genomic level and represent the basis for high MHC variability within the human species. Class I HLA proteins consist of an a chain, which contains the entire peptide binding groove, and a nonpolymorphic stabilizing protein, – b2 microglobulin. Class I HLA proteins are expressed on all cell types and consist of three major types encoded by separate genes, – HLA A, B, and C. Class II HLA proteins consist of separate a and b chains which, together, form the peptide binding groove. Class II HLA proteins are expressed by specialized APCs (particularly DCs but also macrophages, B-cells, and activated endothelial cells) and include three major types encoded by separate genes, HLA DR, DP, and DQ. For both Class I and Class II HLA proteins, highly organized intracellular systems exist for loading peptides derived from endogenous or exogenous sources into their binding grooves before transport of the complexes to the cell surface. In the context of infection, the display of HLA-bound peptides derived from invading pathogens is essential for initiation of cognate cellular immune responses.[9,10] T-cells interact with HLA proteins through the TCR and additionally express one of two types of coreceptors that determine whether their specificity is for Class I or Class II HLA. Those expressing the coreceptor CD8 preferentially interact with Class I HLA and are often referred to as "CD8 positive,’’ ‘‘killer,’’ or ‘‘cytolytic’’ T-cells. Those which express the coreceptor CD4 preferentially interact with Class II MHC (see Figure 5.1) and are often referred to as ‘‘CD4 positive’’ or ‘‘helper’’ T-cells. Naı¨ve CD8 and CD4 T-cells are predominantly located within the T-cell zones of lymph nodes, spleens, and other specialized lymphoid structures such as PeyerÕs patches.[8] The classic mechanism for activation of cognate cellular immunity involves the interaction of mature DCs bearing MHC/peptide complexes derived from a site of infection with naı¨ve T-cells located in a lymph node.[6] Typically, only a minute fraction of the T-cells encountering DCborne antigens in this way will express TCRs capable of binding with optimal affinity to the presented MHC/peptide complexes. This ‘‘low precursor frequency’’ ensures that the resulting activation and proliferation of the responsive T-cell clones will be appropriately limited in its scope and specificity in order to avoid excessive tissue damage or initiation of autoimmunity.

Transplant-Specific Considerations Interindividual diversity of HLA gene sequences and, to a lesser extent, of the sequences of non-HLA genes means that allogeneic transplants create a unique interface between the host T-cell repertoire and the donor HLA/peptide library. Because of the disparities, this interaction is associated

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33

Figure 5.1. The interface between a CD4 positive T-cell and a mature antigen presenting cell (APC) is represented schematically to illustrate important features of T-cell antigen recognition and co-stimulation. Note: (a) The primary binding site involving the T-cell receptor (TCR) and an antigen peptide bound within the central groove form by two chains of a Class II major histocompatibility complex (MHC) protein. (b) The stabilizing interaction between the coreceptor CD4 expressed by the T-cell and one chain of the MHC protein expressed by the APC. (c) The non-covalently bound TCR-associated signaling complex (CD3). (c) The costimulatory interactions between specialized T-cell proteins (CD28 and CD154) and their binding partners (B7 and CD40) on the APC.

with a high precursor frequency of T-cells responding to donor-derived antigens presented by either the direct or indirect pathways described in the previous section.[7] Left unmodified, the T-cell response to a HLA-disparate organ transplant is intense, prolonged, and highly destructive, typically resulting in graft failure within days to weeks – a process termed acute cellular rejection.[11] Understanding this process has led to two of the major components of transplant clinical practice: 1. Cataloging of human HLA sequences and development of methods to rapidly test and compare the HLA types of potential organ donors and recipients. This practice, usually referred to as ‘‘tissue typing,’’ may allow rejection risk for organ transplants to be modified through a matching process that limits the number of genetically variable HLA genes involved.[12] Complete elimination of the risk of acute cellular rejection, however, cannot be achieved except for genetically identical donor/recipient pairs, as even non-HLA proteins (minor histocompatible antigens) can serve as a source of diversity between individuals when presented as peptides. 2. The development of immunosuppressive drugs and biological agents that specifically target T-cell activation and proliferation (described in detail in Chapter 3). It is a mea-

sure of the potency of the allogeneic T-cell immune response that acute cellular rejection may occur early in some transplant recipients despite adequate dosage of multiple immunosuppressive medications or may recur late after transplantation, following minor medication reductions. There is also evidence that uncontrolled activation of donor antigen-specific T-cells may underlie chronic vasculopathy and other forms of gradual graft deterioration in recipients of heart, kidney, and lung transplants.[5,11,13]

T-cell Costimulation An important breakthrough in the understanding of cognate cellular immunity came with the demonstration that binding of the TCR to its optimal MHC/peptide target is not, in and of itself, sufficient to induce full T-cell activation and may, in fact, result in a state of T-cell anergy. This concept led to the proposal that additional ‘‘costimulatory’’ interactions between T-cells and APC were necessary for initiation of productive cellular immune responses. Subsequently, the interaction between the CD28 receptor on T-cells and the B7 ligands on DCs and other APCs was identified as the archetypal costimulatory pathway.[14] After two more decades of intense study, it is now clear that many individual costimulatory ligand/receptor

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pairs exist, that these costimuli represent a complex array of signals that regulate many aspects of the cellular immune response, and that negative regulatory pathways operate in similar fashion during T-cell antigen encounters to prevent autodestruction and preserve self-tolerance. Important examples of these additional accessory pathways include CD40/ CD154(CD40L), CD152/B7, CD137(41BB)/41BBL, OX40/ OX40L, and ICOS/ICOSL.[14,15] Among the unique properties of DCs as APCs for T-cell activation is their capacity to express a broad range of costimulatory ligands in highly regulated fashion. Upregulation of B7 and other costimulatory ligands by DCs is strongly induced by innate immune stimuli, providing an additional example of the role of these cells in mediating cross-talk between innate and cognate immunity.[6]

Transplant-Specific Considerations It is now clear that transplant-related cellular immune responses are dependent upon costimulatory signals in similar fashion to T-cell responses against invading pathogens.[14] Corticosteroids inhibit upregulation of B7 and other costimulatory ligands by DCs. More discreet strategies for inhibition or blockade of costimulatory pathways following transplantation have been associated with prevention of acute cellular rejection in many animal models of transplantation and, in some models, have had the added effect of inducing donorspecific immune tolerance.[14,16] Examples include the soluble fusion protein CTLA4Ig, which blocks CD28/B7 interactions and anti-CD40L antibodies, which block the binding of CD40 on DCs to CD40L on activated T-cells. Although the tolerogenic potential of these agents has proven to be diminished in human transplantation, their ability to prevent rejection with limited toxicity is now the basis for recent and ongoing clinical trials.[14,16–18]

T-cell Differentiation, Effector Function and Memory CD8 and CD4 T-Cells follow the basic paradigm described earlier of being activated following specific binding of the TCR to MHC/peptide complex presented by a DC along with one or more costimulatory signals. For both T-cell subsets, the resulting intracellular signaling cascades induce cell proliferation, alteration of trafficking mechanisms to favor homing toward a site of tissue injury, and expression of effector mechanisms. Aside from this generic model of antigen-specific T-cell activation, a number of additional layers of complexity exist that greatly diversify the actual nature of a given cellular immune response. Some of the more important examples are briefly summarized here. 1. The effector functions of CD8 positive T-cells involve a number of cytolytic mechanisms that allow for the killing of individual cells within an infected tissue. These mechanisms include soluble lytic proteins (perforin and granzymes) as well as cell/cell interactions (Fas/FasL).

Specificity of this cell-killing function is ensured by the fact that infected cells must display the same Class I HLA/peptide complex, which the CD8 T-cell initially responded to on the presenting DC. In contrast, the effector functions of CD4-positive T-cells consist primarily of the activation-induced expression of soluble and cell surface-bound proteins that stimulate or augment the function of other immune effector cells. For this reason, CD4 T-cells are often referred as helper T-cells. Helper functions include secretion of cytokines such as IL-2, IL-4, and interferon c (IFNc) that enhance the activation of CD8 Tcells and B-cells and surface expression of costimulatory ligands such as CD40 that provide ‘‘reverse’’ costimulatory signals to DCs and B-cells. CD4 T-cells provide these forms of ‘‘help’’ both in lymphoid organs and at the site of tissue injury or infection.[8] 2. Following initial activation, the helper functions of CD4 Tcells may differentiate along various functional pathways that serve to orchestrate very different forms of immune response.[19] The most widely studied of these pathways have been termed T helper 1 (Th1) and T helper 2 (Th2). The first is characterized by predominant secretion of IL-2 and IFNc with resulting skewing of the overall response toward CD8 T-cell-mediated cytolysis (a ‘‘Th1-type response’’). The second is characterized by predominant secretion of IL-4, IL-5, and IL-13 with resulting skewing of the overall response toward production of antibodies and recruitment of eosinophils (a ‘‘Th2-type’’ response). More recently, additional forms of CD4 T-cell differentiation have been described, including a predominantly suppressive profile associated with production of IL-10 and TGFb1 (Th3) and a profile associated with chronic inflammation and secretion of IL-17 (Th17). The nature of CD4 T-cell differentiation is determined, at least in part, by the expression pattern of soluble and cell surface-accessory factors on the DC responsible for antigen presentation.[20] For example, IL-12 production by DCs strongly favors Th1-type responses.[21] Individuals may also be more or less genetically predisposed to certain CD4 differentiation pathways. In many immune responses, a mixture of CD4 T-cell differentiation responses may be present. 3. In the wake of an antigen-specific cellular immune response to a pathogenic microorganism, the large majority of activated CD8 and CD4 T-cells undergo apoptotic cell death. A smaller proportion persists in a permanently altered state in which subsequent encounter of the same antigen is followed by a secondary response that is more rapid and potent than the primary response. This basic concept, which applies similarly to humoral immunity describes immunologic ‘‘memory’’ and is best appreciated as the basis for vaccination against common pathogens.[22] More recently, many more details have been elucidated regarding the nature and mechanisms of T-cell memory. Most strikingly, specific cytokines (such as IL-7 and IL-15) are now known to provide ongoing survival signals to memory T-cell populations, and subpopulations of memory T-cells have been

THE IMMUNOLOGY OF TRANSPLANTATION AND ALLOGRAFT REJECTION

identified that differ in their migratory patterns, longevity, and responses to secondary antigen encounter.[23]

Transplant-Specific Considerations All of the concepts described in the preceding paragraphs have important relevance to the immune responses of transplant recipients to their grafts. Both CD8 and CD4 T-cell effector functions contribute to graft injury during acute cellular rejection, and both subsets are numerous among the infiltrating lymphocytes in diagnostic biopsies.[11] Direct killing of graft cell populations, such as tubulitis in a rejecting kidney transplant, is classically carried out by CD8 positive effectors. Destructive cellular immune responses against organ allografts tend to be skewed toward the Th1 differentiation pathway, and much research has been carried out to determine whether interventions designed to deviate such responses toward Th2 or other pathways can prolong graft survival or facilitate donorspecific tolerance. Currently, it appears likely that antidonor Th2 responses also arise and are not directly protective against acute or chronic rejection.[14] More immunosuppressive (Th3-like) CD4 T-Cell responses may additionally occur and the presence of IL-10/TGFb1-secreting lymphocytes has been demonstrated in some allografts with longstanding stable function on minimal or no immunosuppression[24] Finally, T-cell memory against donor HLA antigens, although rarely clinically tested, is likely to be present in organ recipients with a history of prior transplantation, frequent transfusions, or multiple pregnancies. In all these circumstances, the risk for acute cellular rejection, as well as chronic graft deterioration is heightened by the presence of preexisting immune responses to alloantigens.

C O G N A T E H U M O R A L I M M U N I T Y – TH E B-CE LL/ A NTIBOD Y/ COMPLE MENT A XIS B-cells are the second major category of lymphocytes. Like T-cells, they are distinguished by surface expression of receptors (BCR) of highly variable sequence and develop as clones with individual specificities through random rearrangement of the genes encoding the ‘‘heavy’’ and ‘‘light’’ chain components of the BCR.[25]

Primary B-Cell Responses and B-Cell Memory B-cells differ from T-cells in a number of important ways:[25] 1. They are selected in the bone marrow for survival and released to the peripheral lymphoid organs. 2. The BCR interacts with whole-molecule antigens rather than MHC-bound peptides. 3. Rather than migrate to the site of an infection, activated Bcells produce soluble versions of their BCRs called antibodies that circulate in the blood stream and tissue fluids. 4. Following initial activation, B-cells proliferate and undergo a second round of genetic rearrangement of the BCR/antibody-encoding genes (somatic hypermutation)

35

that further enhances the binding affinity of the antigenspecific variable region of the heavy and light chains. This process takes place in specialized structures called germinal centers in peripheral lymphoid organs. A second form of antibody maturation, termed ‘‘isotype switching,’’ occurs at the same time through additional gene rearrangements. Isotype switching typically involves the transition from expression of pentameric IgM antibodies to monomeric antibodies, bearing one of several IgG or IgA heavy chains. The nonvariable sequences of the different heavy chains convey different effector functions (e.g., complement binding, mucosal secretion) to the final mature antibody. 5. B-cells also possess APC function through expression of Class I and Class II MHC as well as costimulatory ligands. 6. In order to undergo antigen-induced proliferation and antibody production, naı¨ve B-cells are reliant on ‘‘help’’ from concurrently activated CD4 T-cells in the form of soluble growth factors (e.g., IL-4) and accessory signals (e.g., CD40/CD154 interactions).[15] In fact, T-cell/B-cell interactions provide mutual augmentation of cellular and humoral immunity through reciprocal antigen presentation and exchange of costimulatory signals. 7. Fully activated B-cells complete a differentiation program that transforms them into a cell type that is entirely specialized for continuous high-level production of mature antibody. This cell type, the plasma cell, may remain within peripheral organs or may migrate to the bone marrow. Long-lived plasma cells are likely to be responsible for the persistence of circulating antibodies against infectious microorganisms that can be detected for years following a primary infection or vaccination. In similar fashion to Tcells, B-cell responses also result in the persistence of a small population of memory cells capable of responding rapidly in the case of reexposure at a later time.[22]

Natural Antibodies A separate form of humoral immunity develops spontaneously in the neonatal period and involves the production, by a specialized population of B-cell termed B1 cells, of germlineencoded antibodies or ‘‘natural antibodies.’’[25] These antibodies, which do not require T-cell help or undergo further maturation, are most likely to represent the evolutionary development of a mobile ‘‘barrier’’ against invasion of the bloodstream or body cavities by microorganisms expressing common molecular patterns. The best examples of natural antibodies are those that arise against the carbohydrate moieties that constitute the ABO blood group antigens. These antibodies mediate severe transfusion reactions following administration of blood group-incompatible transfusions.

Antibody Effector Functions The specificity of a given antibody for its target antigen is determined by the amino acid sequence of the hyper variable

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regions of the heavy and light chains which, between them, form a binding surface. In contrast, the selection of a heavychain isotype is the key factor in determining actual effector function of the antibodies produced by an activated B-cell or plasma cell.[25] Although, binding of antibodies to the target antigen may have a range of specific functional effects, two major categories of antibody effector function typically occur. 1. Antibodies may coat the surface of a microorganism or infected cell and mark it for phagocytosis and/or direct killing by cellular mediators such as macrophages and cytolytic T-cells. This process is termed ‘‘opsonization’’ and involves binding of the nonvariable (Fc) portion of the antibody heavy chain to specialized receptors (FcR) on the responding leukocyte. 2. Antibodies bound to the surface of a microorganism or infected cell may serve as a nucleus for activation of the classical complement pathway, a cascade of enzymatic reactions among circulating proteins that culminates in the formation of cell-membrane pores (the membrane attack complex) in the target cell.

Transplant-Specific Considerations Humoral immunity has a number of important areas of relevance for human organ transplantation: 1. Natural antibodies against ABO blood group antigens (and occasionally, other blood group antigens) constitute a significant barrier to organ transplantation. Accidental performance of a transplant between ABO-incompatible individuals is usually associated with immediate (hyperacute) or early (acute) antibody-mediated rejection through binding of antiblood group antibody to graft endothelium and widespread activation of complement within the graft. In some circumstances, liver or kidney transplants can be carried out across an ABO blood group incompatibility if antibody levels are naturally low or reduced by plasmapheresis.[26,27] Natural antibodies against carbohydrate moieties are also responsible for hyperacute rejection of vascularized organ transplants from other species (xenotransplantation).[28] 2. Because of the very high level of genetic polymorphism among Class I and Class II HLA proteins, exposure of an immunocompetent person to cells or tissues of another is likely to result in the generation of antibodies to non-self HLA proteins. Such exposures, which include previous transplants, tissue grafts, pregnancies, and blood transfusions, are common among potential transplant recipients and may be associated with persistent circulating antiHLA antibodies. Patients with detectable anti-Class I or Class II HLA antibodies are often referred to as ‘‘sensitized’’ and are significantly less likely to be successfully transplanted.[14,29,30] Depending on the circulating level of anti-HLA antibody present, transplantation of a sensitized patient with an organ bearing HLA proteins to which he or she has preexisting antibodies may result in hyper-

acute or acute antibody-mediated (humoral) rejection. Histologically, these forms of rejection are characterized by vascular thrombosis, interstitial hemorrhage, and evidence of widespread complement deposition.[30] The need to avoid such devastating complications constitutes the basis for cross-match testing, which is carried out prior to most deceased donor and living donor organ allografts. Although a wide range of laboratory crossmatch tests are now in use, the basic principle of these assays is incubation of cells (or other particles) bearing donor HLA proteins with serum from the potential graft recipient followed by a detection technique to determine whether antibody binding has occurred. Cross-match testing may simply detect antibody-mediated killing of donor cells or may be used to quantify circulating antibodies against individual donor HLA proteins. Although the most common course of action is to avoid transplantation in the presence of a positive cross-match test, the alternative approach of reducing antidonor antibody with various combinations of plasmapheresis, intravenous immunoglobulin, splenectomy, and anti-CD20 antibody (rituximab) has been increasingly used to achieve successful transplantation in sensitized patients.[26] Unfortunately, there are currently no therapies capable of permanently suppressing or eliminating the long-lived plasma cells that are the likely primary source of anti-HLA antibodies in sensitized transplant candidates. 3. Although potent anti-T-cell immunosuppression serves also to prevent full-scale B-cell activation against donorderived antigens, there is growing evidence that some transplant recipients have persistent or newly-formed low-level antibodies against donor HLA. Detection of anti-HLA antibodies posttransplantation has been linked with increased risk of graft failure, with histological changes characterized by progressive arterial/arteriolar thickening and, in some cases, with evidence of vascular complement deposition.[14,26,29] As for patients with pretransplant sensitization, there are currently no therapies that are clearly effective at preventing the emergence of posttransplant anti-HLA antibodies, at inducing tolerance in donor-responsive B-cells, or at blocking the injurious effect of chronic intragraft antibody deposition. 4. Although blood group antigens and HLA proteins are the most common relevant targets for transplant-related antibodies, additional donor-specific or autoantibodies may contribute to episodes of transplant rejection. Examples include so-called ‘‘antiendothelial cell’’ antibodies and, as recently described for kidney transplants, antiangiotensin receptor antibodies. [31,32]

I M M U N O L O G IC A L T O L E R A NC E The concept of immunological tolerance arose from seminal experimental observations in transplantation by Owen, Medawar, Billingham, Brent et al.[33,34] To a large degree,

THE IMMUNOLOGY OF TRANSPLANTATION AND ALLOGRAFT REJECTION

scientific curiosity in this area continues to be driven by the possibility of harnessing immune tolerance pathways to allow permanent engraftment of organ transplants in the absence of immunosuppressive drugs and without compromising immunity to infection. In the past two decades, remarkable new progress has been made in characterizing the actual mechanisms underlying immunological tolerance. Three forms of immunological tolerance are of specific relevance to current progress in human transplantation.

Central T-Cell Tolerance As previously described, the thymus represents a specialized environment in which developing T-cells and their randomly generated TCRs are selected for release to the periphery. T-cells bearing receptors that bind strongly to MHC/selfpeptide complexes in the thymus are deleted as a means to avoid subsequent autoimmunity. The deletion of autoreactive lymphocytes is referred to as ‘‘central tolerance’’ and has given rise to the concept that the persistent presence of donor APCs in the host thymus would result in deletion of donor-specific T-cells and acceptance of transplanted tissues from this donor. In fact, this concept has been proven correct in multiple animal models as well as in humans through the strategy of donor bone marrow/hematopoietic stem cell transplantation preceded either by full myeloablation or by partial myeloablation resulting, if successful, in ‘‘mixed chimerism.’’[35,36] Widespread application of this robustly tolerogenic approach remains limited by the severe toxicity of full myeloablation and by the difficulty of achieving prolonged mixed chimerism in humans.

Peripheral T-Cell Tolerance It is now clear that some autoreactive T-cells do emanate from the thymus and that there is a need for active mechanisms of preventing autoimmunity during immunological activities occurring in lymph nodes, spleen, and other peripheral tissues. A number of distinct mechanisms of peripheral tolerance have now been definitively identified. These are often categorized as being associated with deletion, anergy or active negative regulation (‘‘suppression’’) of autoreactive T-cells.[37] A wide range of specialized molecular and cellular mediators of these basic peripheral tolerance mechanisms have been identified. It is apparent that peripheral mechanisms of T-cell tolerance to transplant antigens can be induced by a variety of interventional strategies in animal models and that similar mechanisms may arise spontaneously over time in some human allograft recipients.[16,18,24,37,38] In regard to donor-specific peripheral T-cell tolerance, two conceptual models rank among the most striking recent advances in this area. First, the combined use of costimulatory blockade (e.g., CD28/B7 blockade and/or CD40/CD40L blockade), donor antigen intravenous infusion (e.g., infusion of donor bone marrow cells) and proapoptotic immunosuppressive drugs (e.g., the mTOR inhibitor sirolimus) is associated with massive apoptotic de-

37

letion of donor-reactive T-cell clones that may lay the groundwork for emergence of prolonged tolerance to allografts from the same donor.[38] Second, under some circumstances, populations of donor antigen-specific regulatory (‘‘suppressor’’) T-cells can arise spontaneously following an organ allograft and serve to actively prevent activation of the effector T-cells that mediate cellular rejection. These cells, referred to as ‘‘T-regs,’’ are predominantly CD4 positive and function through a number of immunosuppressive pathways including secretion of IL-10 and TGFb1 and expression of cell surface inhibitory receptors such as CD152 (CTLA-4).[24] There is evidence that some of the currently used immunosuppressive drugs such as corticosteroids and calcineurin inhibitors may simultaneously inhibit both antidonor effector T-cells and T-regs, thus preventing both rejection and tolerance at the same time. Progress in applying peripheral immune tolerance mechanisms to human transplantation has been slower than might have been predicted from the rate of success in animal models. Reasons for this include true species differences in the immunology of tolerance, the more frequent presence of memory T-cells in humans requiring transplants, the role of infections and tissue injury in preventing or ‘‘breaking’’ immune tolerance, and the difficulty of designing human clinical trials involving multiple novel therapies.[16,17]

B-Cell Tolerance B-cells are clearly also regulated through central and peripheral tolerance mechanisms to prevent production of autoreactive antibodies. Central B-cell tolerance occurs in the bone marrow and involves deletion of B-cells expressing surface receptor that binds avidly to self-proteins. In similar fashion to T-cell central tolerance, there is evidence that bone marrow transplantation with partial myeloablation can produce donor-specific B-cell tolerance. Mechanisms of peripheral B-cell tolerance are less well understood although exposure of mature B-cells to antigen under some circumstances may result in anergy or deletion in the peripheral lymphoid organs. Although anti-CD20 antibody (rituximab) has been used as a B-cell depleting agent in some human transplant recipients with preexisting antidonor antibodies,[26] no clinically effective strategies for generating lasting B-cell tolerance to alloantigens currently exist. The reemergence of interest in the role of donor HLA-specific antibodies in chronic graft deterioration is likely to stimulate more experimentation in this area.

S U MMAR Y Advances in transplantation and immunology have been, and remain to this day, intimately linked.[34] New immunological concepts such as cross-talk between innate and cognate immunity, multiplicity of costimulatory signals, diversity of T-cell effector function and presence of antigen-specific regulatory T-cells can be applied directly to our understanding of

38

MATTHEW D. GRIFFIN AND RYUTARO HIROSE

why human organ allografts succeed and fail.[13] Furthermore, these conceptual advances identify targets for novel interventions to prevent acute and chronic transplant rejection and to induce or promote donor-specific immunological tolerance in the clinic.[14]

REFERENCES

1. C. A. Janeway, Jr., and R. Medzhitov, Innate immune recognition. Annu Rev Immunol. 20:197–216, 2002. 2. R. Medzhitov, and C. Janeway, Jr., Innate immunity. New Engl J Med. 343(5):338–44, 2000 Aug 3. 3. C. A. Janeway, Jr., How the immune system works to protect the host from infection: a personal view. Proc Natl Acad Sci U S A. 98(13):7461–8, 2001 Jun 19. 4. C. P. Larsen, J. M. Austyn, and P. J. Morris, The role of graft-derived dendritic leukocytes in the rejection of vascularized organ allografts. Recent findings on the migration and function of dendritic leukocytes after transplantation. Ann Surg. 212(3):308–15, 1990 Sep. 5. A. J. Demetris, N. Murase, A. S. Rao, J. J. Fung, and T. E. Starzl, The dichotomous functions of passenger leukocytes in solid-organ transplantation. Advances in Nephrology From the Necker Hospital. 24: 341–54, 1995. 6. J. Banchereau, and R. M. Steinman, Dendritic cells and the control of immunity. Nature. 392(6673):245–52, 1998 Mar 19. 7. P. Hornick, and R. Lechler, Direct and indirect pathways of alloantigen recognition: relevance to acute and chronic allograft rejection. Nephrol Dial Transplant. 12(9):1806–10, 1997 Sep. 8. U. H. von Andrian, and C. R. Mackay, T-cell function and migration. Two sides of the same coin. New Engl J Med. 343(14):1020–34, 2000 Oct 5. 9. J. Klein, and A. Sato, The HLA system. First of two parts. New Engl J Med. 343(10):702–9, 2000 Sep 7. 10. J. Klein, and A. Sato, The HLA system. Second of two parts. New Engl J Med. 343(11):782–6, 2000 Sep 14. 11. K. Solez, M. Afrouzian, N. Pakasa, K. Takeda, and K. Trpkov, Renal transplant biopsy: what does it tell? Curr Opin Nephrol Hypertens. 6(6):538–43, 1997 Nov. 12. M. Bunce, N. T. Young, and K. I. Welsh, Molecular HLA typing – the brave new world. Transplant. 64(11):1505–13, 1997 Dec 15. 13. B. D. Kahan, Individuality: the barrier to optimal immunosuppression. Nature Reviews Immunology. 1:233–239, 2001 Dec. 14. M. H. Sayegh, and C. B. Carpenter, Transplantation 50 years later – progress, challenges, and promises. New Engl J Med. 351(26):2761–6, 2004 Dec 23. 15. S. A. Quezada, L. Z. Jarvinen, E. F. Lind, and R. J. Noelle, CD40/ CD154 interactions at the interface of tolerance and immunity. Annu Rev Immunol. 22:307–28, 2004. 16. S. J. Knechtle, and W. J. Burlingham, Metastable tolerance in nonhuman primates and humans. Transplant. 77(6):936–9, 2004 Mar 27. 17. F. Vincenti, C. Larsen, A. Durrbach, T. Wekerle, B. Nashan, G. Blancho, P. Lang, J. Grinyo, P. F. Halloran, K. Solez, D. Hagerty, E. Levy, W. Zhou, K. Natarajan, B. Charpentier, and G. Belatacept Study, Costimulation blockade with belatacept in renal transplantation. New Engl J Med. 353(8):770–81, 2005 Aug 25. 18. T. E. Starzl, and R. M. Zinkernagel, Transplantation tolerance from a historical perspective. Nature Reviews Immunology. 3:831–838, 2003 Oct.

19. K. M. Murphy, and S. L. Reiner, The lineage decisions of helper T cells. Nature Reviews Immunology. 2:933–944, 2002 Dec. 20. M. L. Kapsenberg, Dendritic-cell control of pathogen-driven T-cell polarization. Nature Reviews Immunology. 3:984–993, 2003 Dec. 21. G. Trinchieri, Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Reviews Immunology. 3:133–146, 2003 Feb. 22. R. M. Welsh, L. K. Selin, and E. Szomolanyi-Tsuda, Immunological memory to viral infections. Annu Rev Immunol. 22:711–43, 2004. 23. F. Sallusto, J. Geginat, and A. Lanzavecchia, Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 22:745–63, 2004. 24. K. J. Wood, and S. Sakaguchi, Regulatory T cells in transplantation tolerance. Nature Reviews Immunology. 3:199–210, 2003 Mar. 25. M. D. Cooper, Current concepts. B lymphocytes. Normal development and function. New Engl J Med. 317(23):1452–6, 1987 Dec 3. 26. P. G. Dean, J. M. Gloor, and M. D. Stegall, Conquering absolute contraindications to transplantation: positive-crossmatch and ABO-incompatible kidney transplantation. Surgery. 137(3):269–73, 2005 Mar. 27. M. D. Stegall, P. G. Dean, and J. M. Gloor, ABO-incompatible kidney transplantation. Transplant. 78(5):635–40, 2004 Sep 15. 28. M. Cascalho, and J. L. Platt, Xenotransplantation and other means of organ replacement. Nature Reviews Immunology. 1:54–160, 2001 Nov. 29. P. I. Terasaki, Humoral theory of transplantation. Am J Transplant. 3(6):665–73, 2003 Jun. 30. S. K. Takemoto, A. Zeevi, S. Feng, R. B. Colvin, S. Jordan, J. Kobashigawa, J. Kupiec-Weglinski, A. Matas, R. A. Montgomery, P. Nickerson, J. L. Platt, H. Rabb, R. Thistlethwaite, D. Tyan, and F. L. Delmonico, National conference to assess antibody-mediated rejection in solid organ transplantation. Am J Transplant. 4(7): 1033–41, 2004 Jul. 31. D. Dragun, D. N. Muller, J. H. Brasen, L. Fritsche, M. NieminenKelha, R. Dechend, U. Kintscher, B. Rudolph, J. Hoebeke, D. Eckert, I. Mazak, R. Plehm, C. Schonemann, T. Unger, K. Budde, H. H. Neumayer, F. C. Luft, and G. Wallukat, Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection. New Engl J Med. 352(6):558–69, 2005 Feb 10. 32. S. Le Bas-Bernardet, M. Hourmant, S. Coupel, J. D. Bignon, J. P. Soulillou, and B. Charreau, Non-HLA-type endothelial cell reactive alloantibodies in pre-transplant sera of kidney recipients trigger apoptosis. Am J Transplant. 3(2):167–77, 2003 Feb. 33. L. Brent, The 50th anniversary of the discovery of immunologic tolerance. New Engl J Med. 349(14):1381–3, 2003 Oct 2. 34. C. G. Groth, L. B. Brent, R. Y. Calne, J. B. Dausset, R. A. Good, J. E. Murray, N. E. Shumway, R. S. Schwartz, T. E. Starzl, P. I. Terasaki, E. D. Thomas, and J. J. van Rood, Historic landmarks in clinical transplantation: conclusions from the consensus conference at the University of California, Los Angeles. World J Surg. 24(7):834–43, 2000 Jul. 35. T. Wekerle, and M. Sykes, Mixed chimerism and transplantation tolerance. Annu Rev Med. 52:353–70, 2001. 36. L. S. Kean, S. Gangappa, T. C. Pearson, and C. P. Larsen, Transplant tolerance in non-human primates: progress, current challenges and unmet needs. Am J Transplant. 6(5 Pt 1):884–93, 2006 May. 37. S. Sakaguchi, Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 22:531–62, 2004. 38. R. I. Lechler, O. A. Garden, and L. A. Turka, The complementary roles of deletion and regulation in transplantation tolerance. Nature Reviews Immunology. 3:591–597, 2003 Jul.

6 Allograft-Specific Considerations in Transplant Dermatology

Ryutaro Hirose, MD and Clark C. Otley, MD

performed, of which 229,000 were kidney transplants, based on data from the Organ Procurement and Transplantation Network (OPTN) (www.OPTN.org).[1] Therefore, by sheer volume, dermatologists are most likely to care for the skin diseases of renal transplant recipients. According to the Scientific Registry of Transplant Recipients (SRTR) (www. ustransplant.org) , the number of people living with a kidney transplant doubled from 1995 to 2004 from 50,000 to 100,000.[2] End-stage renal disease is increasing markedly in incidence, particularly in patients over age 55. As such, the waiting list for renal transplantation continues to grow in an inexorable fashion. The numbers of patients requiring a second kidney transplant is also increasing. According to the United Network for Organ Sharing (UNOS) (www.UNOS. org), renal transplants increased by 49% over the period from 1995–2005.[3]

Solid organ transplantation has evolved from a highly experimental and risky procedure to the standard of care and the treatment of choice of end-stage organ failure in the past four decades. For practical purposes, the first successful kidney transplant by Murray in the 1950s, followed by a successful heart transplant by Barnard heralded a new age of promise for patients with end-stage organ disease. The goals underlying all solid organ transplantation are unified: replacement of a dysfunctional host organ with a transplanted allograft that restores the function of the compromised organ. However, there are many subtle and profound differences between various aspects of organ transplantation specific to the type of allograft being transplanted, including the patient population, alternative therapies, donor population, immunogenicity of allografts, immunosuppressive regimens, risk of rejection, and the consequences of rejection/allograft loss. These considerations are relevant to transplant dermatology in important ways including the susceptibility of the patient population to specific skin diseases, particularly skin cancer, the relative carcinopermissiveness of the immunosuppressive regimen, the degree to which reduction or alteration of immunosuppression is possible, and the consequences if reduction of immunosuppression results in allograft rejection/loss. This chapter will consider these issues for each major allograft type, which are summarized in Table 6.1. Because the relative immunogenicity of various allografts is integral to the considerations of this chapter, we present a rough approximation of immunogenicity. As a generalization, immunogenicity is greatest for the thoracic organs (heart and lung) followed closely by small bowel, then pancreas, then kidney, with liver allografts being the least immunogenic. It is also important to recognize that tolerance, risk of rejection, and requisite levels of immunosuppression vary considerably on a patient-by-patient basis, due to patient- and donorspecific factors, including degree of sensitization. The complexity of these factors demands customization of medical care in order to obtain optimal outcomes.

Age Renal transplant recipients tend to be older than some other allograft recipients, but the age range of recipients is fairly broadly distributed.[3] Patients over the age of 65 account for 9.7% of renal transplant recipients, the greatest percent of all allograft types. However, recipients aged less than 1 year account for 2.6% of renal transplants, second only to heart allografts. Recipient Ethnicity According to UNOS data, the highest percentage of overall transplants received by black or Hispanic recipients was for kidneys, representing 24% and 13%, respectively.[3] Because skin cancer is uncommon in these ethnic groups, in some regions of the United States, a significant proportion of the kidney transplant population is less susceptible to skin cancer.[4] Regardless, the sheer size of the renal transplant population means that dermatologists will be managing skin disease predominantly in renal transplant recipients. Gender The majority of renal transplant patients are male, with men representing 60% of kidney transplant recipients.[3] This percentage is in the middle of the range of gender ratios among the major organ types, with heart transplants having the highest percentage of males and with pancreas transplants evenly divided by gender. Because male patients tend to be more susceptible to skin cancer, this gender inequity among renal transplant recipients makes skin cancer more likely.[5]

KIDNEY

Patient Demographics Population The kidney transplant recipient population is the largest, far outnumbering all other solid organ transplants by a substantial margin. In the United States, from January 1988 through August of 2006, 384,000 solid organ transplants were 39

40

RYUTARO HIROSE AND CLARK C. OTLEY

Table 6.1 Allograft-specific considerations Allograft Type

Alternative Therapy

Kidney

Dialysis

Donor Type

Live or deceased donor Heart None Deceased donor Lung None Deceased donor (rarely living) Liver None Live or deceased donor Pancreas Insulin Deceased donor (rarely living) Intestine Total Deceased parenteral donor nutrition (rarely living)

Immunogenicity Immunosuppressive Carcinopermissiveness Ability to reduce Consequences regimen immunosuppression of rejection Moderate

Moderate

Moderate

Moderate

High

High

High

Low

Loss of allograft; resumption of dialysis Death

High

High

High

Low

Death

Low

Low

Low

High

Death

Moderate–high

Moderate–high

Moderate–high

Moderate–low

Loss of allograft; resumption of insulin

High

High

High

Low

Loss of allograft; resumption of total parenteral nutrition

Effect of End Organ Disease on Skin Cancer Incidence Transplant recipients with specific pretransplant diseases, such as polycystic kidney disease, are at increased risk for skin cancer relative to patients with other causes of organ failure. Patients with diabetes mellitus had a lower incidence of skin cancer after renal transplantation.[6]

Overall Effect on Skin Cancer/Skin Disease The effects of the demographic characteristics of the renal transplant population outlined above on skin disease and skin cancer are complex and interrelated. Overall, the predominant factor is the huge number of renal transplant recipients overall, which makes this population the most likely to require dermatologic care. In terms of skin cancer development, the incidence of skin cancer for renal transplant recipients are intermediate between the high rates associated with cardiac transplantation and the low rates associated with liver transplantation. However, a recent study indicated the renal transplant recipients are more likely to develop greater numbers of skin cancers per patient than other allograft recipients.[7]

Alternative Therapies Unlike patients with end-stage heart, lung, and liver disease, patients with renal failure have a therapeutic alternative to transplantation in the form of dialysis. Having a viable alternative to transplantation, albeit one associated with significant

morbidity and mortality, inserts additional considerations in the clinical care of patients with end-stage renal failure, with a failing renal allograft, and with life-threatening skin cancer, which may prompt consideration of discontinuation of immunosuppressive therapy. Nephrologists may be more willing to consider aggressive modification of immunosuppressants when confronting serious skin cancer, knowing that, if irreversible rejection were to occur, dialysis remains a viable alternative therapy. Anecdotally, many patients are very reluctant to consider resuming dialysis, even when confronting a potentially serious cancer.

Donor Population In 2005, 40% of renal allografts were harvested from live donors. This is down slightly from the peak of 43% in 2003, but significantly above the 30% rate from 1995. Sixty-five percent of living donor transplants were from biologically related donors, associated with better match and potentially lower immunosuppression. This is reflected in the 15% higher survival rate at 3 years for recipients of living donor kidneys, compared to recipients of deceased donor allografts.[2] The popularity of living donor renal transplantation can also impact clinical decision making for renal transplant candidates or those needing retransplantation for a failing allograft. Because available allografts are allocated to potential recipients with the highest probable benefit, a patient with end-stage renal failure, but a history of severe prior skin cancer may not be considered a ‘‘good’’ candidate for a deceased donor allograft, because other patients are ‘‘better’’ candidates. However, with the presence of a willing living donor, allograft allocation

ALLOGRAFT-SPECIFIC CONSIDERATIONS IN TRANSPLANT DERMATOLOGY

41

decisions are less relevant because another candidate would not be deprived of a deceased donor allograft if the living donor allograft was utilized in a patient with a substantial skin cancer history.

the first year post renal transplant have been reduced to well below 20% in unsensitized patients.

Immunogenicity of Allografts

As time goes on in the life of a kidney transplant patient, the number of immunosuppressive agents and the respective doses are decreased, especially in those who do not have any rejection episodes. With the cumulative nephrotoxic effect of the calcineurin inhibitors, there is motivation to reduce the levels of these medications, balancing the risk of rejection. Although some patients enjoy excellent renal function for decades, many have a slow and steady decline of renal function as they approach 10–15 years post transplant. This has implications on how aggressive one has to be regarding immunosuppression. Especially considering that dialysis exists as a backup, one needs to consider the risks and benefits of continuing kidney transplant patients on moderate amounts of immunosuppression when, for example, an aggressive cutaneous malignancy occurs.[12]

Kidney allografts are considered intermediate between thoracic organs and liver in terms of immunogenicity. Correspondingly, the immunosuppressive levels necessary to prevent allograft rejection are intermediate, as outlined in the following text.

Immunosuppressive Regimens The usual immunosuppressive regimen for kidney transplant patients still involves a combinatorial approach, most commonly based on a calcineurin inhibitor, such as cyclosporine or tacrolimus.[8] An antiproliferative such as mycophenolate is also given, less frequently sirolimus or azathioprine. Although many centers have adopted a steroid-sparing approach to renal transplant immunosuppression, usually with the aid of an induction agent such as an anti IL-2 receptor antibody (e.g., daclizumab or basiliximab), others still use steroids as a mainstay. Finally, depending on the circumstances and whether the patient is sensitized or not, antibody induction with Thymoglobulin or an anti-IL2R antibody may be used selectively.

Carcinopermissiveness of Regimens The carcinopermissiveness of the immunosuppressive regimen largely reflects the overall intensity of immunosuppression rather than the effect of any one medication. Higher levels of overall immunosuppression are associated with higher levels of both skin cancer as well as infections.[9,10] Because kidney transplants have been performed for decades, there are more renal patients who remain on older azathioprine-based regimens, which, based on animal data, may be more carcinopermissive. Typical renal transplant recipients are now maintained on a moderately intense immunosuppressive regimen, which is associated with a moderate degree of carcinopermissiveness. Based on preliminary data, patients who are converted to sirolimus after stabilization of their allograft may be less likely to develop skin cancer.[11] Sirolimus is increasingly being utilized in renal transplant regimens.

Risk of Rejection Acute rejection episodes are avoided by maintaining relatively high immunosuppressive levels, particularly within the first year post transplant. Each episode of acute rejection in renal transplants clearly has an adverse effect on long-term renal allograft outcome and increases the risk of chronic rejection. With modern immunosuppressive regimens, rejection rates in

Ability to Reduce Immunosuppression

Consequences of Rejection/allograft Loss As mentioned previously, if reduction of immunosuppression is pushed too far and irreversible rejection were to occur, the potential to resume dialysis is an undesired but life-saving alternative. Additionally, with the potential for living donors, retransplantation is a distinct possibility. Allograft loss is almost always an undesirable consequence, but when confronted by life-threatening skin cancer, aggressive reduction of immunosuppression may be a consideration.

L I VE R

Patient Demographics Population In the United States, from January 1988 through August of 2006, 79,500 liver transplants were performed, making liver transplant recipients second in number to kidney recipients.[1] Liver transplants increased by 63% over the period from 1995–2005, the second highest percentage after pancreas.[1] Age Patients of all ages tend to be represented in the liver transplant population.[1] In combination with the fact that liver allograft recipients are the least heavily immunosuppressed, liver transplant patients are least affected by skin cancer. Recipient Ethnicity The ethnicity of liver transplant patients is diverse, with 72% white, 9% black, and 13% Hispanic, also contributing to a lower incidence of skin cancer in this population.[1]

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RYUTARO HIROSE AND CLARK C. OTLEY

Gender Liver transplant recipients are the second most likely to be male, after heart transplant recipients.[1] Sixty-six percent of liver recipients are male and thirty-four percent are female. Although the male predominance might be associated with more skin cancer, other factors are clearly more important, resulting in a low risk.

Effect of End Organ Disease on Skin Cancer Incidence Transplant recipients with specific pretransplant diseases, such as cholestatic liver disease, are at increased risk for skin cancer relative to other causes of liver failure, and may warrant closer surveillance.[6]

Overall Effect on Skin Cancer/Skin Disease Although liver transplant patients are diverse in terms of age, gender, and ethnicity, the predominant factor relevant to transplant dermatology is the lower immunogenicity of the allograft, which permits the lowest level of immunosuppression compared with other organs. This largely accounts for the lower levels of skin cancer as well as other complications among liver transplant recipients.

Donor Population In addition to living related kidney transplants, liver transplants are the other organs with living related donor potential. The peak of liver living related donation was in 2001, when 10% of allografts were from living donors.[1] For 2005, the rate was half that at 5%, which remains substantially above the rate of 1.4% from a decade earlier. Living donors were biologically related to the recipients in 71% of the cases, offering the possibility of improved match and lower need for immunosuppression. As with kidneys, living related donors afford a 10% better 3-year survival among liver transplant recipients.[2] As with living renal allografts, the availability of living related liver donors gives more options for securing an allograft for patients who are not considered ideal candidates due to a history of severe skin cancer.

Immunogenicity of Allografts The liver is a unique solid organ among transplanted organs. It is the least immunogenic of all allografts, and in some longterm liver transplant patients, minimal immunosuppression may be possible.

Immunosuppressive Regimens The goals of immunosuppression in liver transplantation differ slightly from those of other solid organs. In general, liver transplant recipients receive less overall immunosuppression than those of other organs.[13] Maintenance immunosup-

pression is usually steroid free and based on single-agent calcineurin inhibitor, usually tacrolimus. The doses are low and in long-term transplant recipients, minimal immunosuppressive levels can be attained after 10 years.

Carcinopermissiveness of Regimens Because of the low levels of single-agent immunosuppression, the relative carcinopermissiveness of the medications is least for liver transplant recipients.

Risk of Rejection Due to the low immunogenicity of liver allografts, the risk of rejection is also low. Additionally, the liver has impressive regenerative capacity and the ability to recover from episodes of rejection. Although acute rejection episodes are to be avoided, they do not portend as ominously as in other transplants. Unlike the scenario in renal transplantation, where every episode of acute cellular rejection has a significant negative impact on long-term allograft survival, acute rejection can have a minimal impact on long-term liver function and liver allograft survival.[1] Higher rejection rates are thus tolerated. On the other hand, rejection episodes for subsets of patients, such as those with hepatitis C, may have more severe negative implications. In addition, the very conditions that are considered contraindications for other organ transplants, such as malignancy (hepatocellular carcinoma) and chronic active infections (e.g., hepatitis B, hepatitis C), are, in fact, the most common indications for liver transplantation. The impact of immunosuppression on the potential recurrence of these diseases cannot be overemphasized.

Ability to Reduce Immunosuppression As liver transplant patients require less immunosuppression, one may become relatively aggressive about reduction of immunosuppression in those patients with no history of rejection.

Consequences of Rejection/Allograft Loss The consequences of acute cellular rejection in the organs also differ. In most solid organ transplants, any episode of acute rejection tends to decrease the overall graft survival and increases the risk of chronic rejection. However, liver transplants are an exception to that rule. It may be the unique capacity of the liver to regenerate, or the unique immunogenicity of the host hepatic dendritic cells, but it is clear that an episode of rejection in the first year post transplant does not necessarily bode poorly for the hepatic allograft survival. Obviously, the loss of a liver transplant will result in a need for retransplantation or death. However, rejection episodes may be relatively easier to reverse compared to other transplanted organs, which may also influence the strategy to alter, reduce,

ALLOGRAFT-SPECIFIC CONSIDERATIONS IN TRANSPLANT DERMATOLOGY

or withdraw immunosuppression in the face of cutaneous complications.

HEART/LUNG

Patient Demographics Population In the United States, from January 1988 through August of 2006, 40,000 heart transplants and 14,500 lung transplants were performed.[1] Whereas for kidney, pancreas, and liver transplants, the number of transplants and patients on the wait list is increasing steadily, with the significant advances in medical therapy for heart disease and heart failure as well as other factors, the number of cardiac transplants in the United States is declining as is the wait list of patients waiting for cardiac transplants.[2] Fortunately, death rates on the cardiac wait list have also declined.[2] Cardiac transplants declined by 10% over the period from 1995–2005.[1] Lung transplants increased by 61% during the same time period.[1] Age Based on UNOS data, heart transplant patients are fairly broadly distributed, based on age, with 14.8% aged less than 18 and 74% aged 35 or older.[1] Lung transplant recipients tend to be heavily concentrated in the 50- to 64-year age group, with 85% aged 35 or above.[1] However, the intense immunosuppression necessary for thoracic transplants is felt to be the predominant factor that incurs the high risk of skin cancer in this cohort. Recipient Ethnicity Whereas lung transplant recipients are the most likely to be white (87%), heart transplant recipients are an ethnically diverse group, 70% white, 18% black, and 8% Hispanic.[1] Gender Heart transplant recipients are the most likely to be male, at 72% of recipients, making them a particularly susceptible cohort of patients for skin cancer.[1] In contrast, there is only a minor predominance of males among lung transplant recipients, at 55%.

Effect of End Organ Disease on Skin Cancer Incidence There does not appear to be a subset of cardiac or lung transplant recipients that are more susceptible to skin cancer than others after multivariate analysis.[6]

Overall Effect on Skin Cancer/Skin Disease Although lung transplant recipients tend to be older and heavily immunosuppressed, the small number of these patients makes their dermatologic needs less predominant.

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Anecdotally, when lung transplant patients do develop skin problems, including skin cancer, they appear to be more severe. Heart transplant recipients are more common, tend to be male, and are also heavily immunosuppressed, resulting in the highest rate of skin cancer relative to other allograft types.[14,15] However, this finding is not consistent in all studies.[16,17] There is insufficient data on lung transplant patients to make meaningful statements about skin cancer risk, but it is assumed to be similar to that of heart transplant recipients.

Immunogenicitiy of Allografts Thoracic organs are considered the most immunogenic, requiring high levels of immunosuppression to prevent lifethreatening rejection.

Immunosuppressive Regimens Thoracic organ transplant recipients get a relatively high exposure to calcineurin inhibitors and other immunosuppression, based on the immunogenicity of the organs and because of the consequences of acute cellular rejection.[18,19] The great majority of thoracic organ transplants receive at least triple therapy which includes a calcineurin inhibitor, an antiproliferative agent, and corticosteroids. About 50% of cardiac recipients also receive induction antibodies, with the IL-2R antibodies coming more into favor. With the recent advances in immunosuppressive therapy, rejection rates in heart and lung transplants recipients are decreasing. However, chronic rejection, as manifested by allograft arteriopathy in heart transplants and bronchiolitis obliterans in lung transplants, still poses a significant challenge in the long run.

Carcinopermissiveness of Regimens Because of the high level of immunosuppression for thoracic allografts, these regimens are the most carcinopermissive, reflected by the highest incidence of skin cancer.

Risk of Rejection These patients remain challenging in terms of balancing the risk of rejection and untoward side effects from our conventional immunosuppressants. There is hope on the horizon that newer, more specific, less toxic immunomodulators may help alleviate the cutaneous and other side effects in this patient population.

Ability to Reduce Immunosuppression Reduction of immunosuppression is only undertaken for thoracic transplants with the understanding that provocation of acute rejection could have devastating consequences. Only with life-threatening cancer would a substantial reduction of immunosuppression be considered. However, conversion to

44

RYUTARO HIROSE AND CLARK C. OTLEY

sirolimus may be a reasonable strategy when faced with high risk or numerous skin cancers.

cutaneous malignancy, in terms of willingness to modify immunosuppression.

Consequences of Rejection/Allograft Loss

Immunogenicity of Allografts

Obviously, graft loss in this setting can be fatal, and is a major consideration when contemplating reduction of immunosuppression. As with most solid organ transplants, any episode of acute rejection tends to decrease the overall graft survival and increases the risk of chronic rejection.

Relative to liver and kidney transplants, the immunogenicity of pancreas allografts is considered relatively high.

PANCREAS

Patient Demographics Population In the United States, from January 1988 through August of 2006, 5,100 pancreas transplants were performed.[1] The number of pancreas transplants that are being performed is on the rise, but does not compare to the number of kidney transplants. Pancreas transplants increased by 396% over the period from 1995–2005, the highest percentage for any allograft type.[1] Age Pancreas transplant recipients are the youngest population of transplant patients, with only 18% aged 50 and over. Fiftysix percent of pancreas allograft recipients are between the ages of 35 to 49.[1] With pancreas transplants representing a small portion of overall transplants, dermatologists may be least likely to care for these patients. Recipient Ethnicity Eighty-five percent of recipients of pancreas transplants are white, whereas black and Hispanic patients are much less common recipients.[1] Gender Pancreas transplants are evenly divided between males and females, with a 51% to 49% representation, respectively.[1] This gender equality lends itself to lower skin cancer rates, given the lower tendency of females to skin cancer.

Immunosuppressive Regimens Pancreatic allografts are thought to be even more immunogenic than kidney transplants, and rejection can be somewhat more difficult to diagnose. Pancreatic transplants are most commonly performed in conjunction with a kidney transplant in type I diabetics with renal failure, either simultaneously (simultaneous pancreas kidney transplant=SPK), or following a living donor transplant (pancreas after kidney transplant= PAK). In selected cases, especially those with extremely brittle diabetics or those with severe hypoglycemic unawareness, patients without end-stage diabetic nephropathy may undergo isolated pancreatic transplantation (pancreas transplant alone=PTA). In all three cases, antibody induction is almost always used, due to the increased risk of rejection, and in general, the overall immunosuppression regimen is more intense than the average patient with an isolated kidney transplant.[20]

Carcinopermissiveness of Regimens Given the complexity of managing pancreatic allografts, immunosuppressive regimens tend toward the high side, with presumed increased risks of skin cancer. The population of pancreatic allograft patients is insufficient to provide robust epidemiologic data to confirm this impression.

Risk of Rejection The risk of rejection is moderate to high with pancreas allografts, thus allograft survival rates tend to be lower than with other organs.

Ability to Reduce Immunosuppression

Given the relative youth of many pancreas transplant patients, as well as the even distribution of males and females, pancreas transplant recipients may be less likely to develop skin caner and present for dermatologic care.

As with any high-risk organ, the ability to substantially reduce immunosuppression for pancreas patients is somewhat limited. However, when confronted by life-threatening skin cancer, the option of cessation of immunosuppression, with probable allograft rejection and resumption of insulin therapy, is available.

Alternative Therapies

Consequences of Rejection/Allograft Loss

As with kidney transplants, alternative therapy with insulin replacement is available should complete allograft loss occur. The availability of a therapeutic alternative clearly can influence the strategies employed when faced with a serious

The consequences of losing a pancreatic allograft completely results in a return to insulin therapy. Although loss of allograft viability and excision of the allograft are undesirable, the availability of alternative therapy ameliorates

Overall Effect on Skin Cancer/Skin Disease

ALLOGRAFT-SPECIFIC CONSIDERATIONS IN TRANSPLANT DERMATOLOGY

the impact of this complication relative to loss of other types of allografts.

SUM MARY Although all solid organ transplant recipients share the need for systemic immunosuppression, with inevitable toxicities, there are organ-specific considerations that affect clinical outcomes and decisions. Dermatologists are more likely to encounter kidney transplant recipients given the large size of the population, although individual thoracic organ transplant recipients may be the most severely affected by skin cancer. As attention is refocused on the importance of long-term quality-of-life measures after transplantation, customization of immunosuppressive regimens in order to reduce the risk of cutaneous and other complications is becoming more common. It is essential for clinicians to be aware of the allograftspecific considerations in order to individualize care and to maintain close communication with transplant physicians and surgeons regarding cutaneous complications.

REFERENCES

1. The Organ Procurement and Transplantation Network. www.OPTN. org. Accessed 11/29/06. 2. Scientific Registry of Organ Transplant Recipients. www.ustransplant. org. Accessed 11/29/06. 3. United Network for Organ Sharing. www.UNOS.org. Accessed 11/29/06. 4. Moosa MR, Gralla J. Skin cancer in renal allograft recipients – experience in different ethnic groups residing in the same geographic region. Clin Transplant 2005;19:735–741. 5. Lindelof B, Sigurgeirsson B, Gabel H, Stern RS. Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol 2000;143:513–19. 6. Otley CC, Cherikh WS, Salasche SJ, McBride MA, Christenson LJ, Kauffman HM. Skin cancer in organ transplant recipients: effect of

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pretransplant end-organ disease. J Am Acad Dermatol 2005;53: 783–90. 7. Euvrard S, Kanitakis J, Decullier E, et al. Subsequent skin cancers in kidney and heart transplant recipients after the first squamous cell carcinoma. Transplantation 2006;81:1093–100. 8. Gaston RS. Current and evolving immunosuppressive regimens in kidney transplantation. Am J Kid Dis 2006;47(Suppl 2):S3–21. 9. Fortina AB, Piaserico S, Caforio A, et al. Immunosuppressive level and other risk factors for basal cell carcinoma and squamous cell carcinoma in heart transplant recipients. Arch Dermatol 2004; 140:1079–1085. 10. Agueroo J, Almenar L, Martinez-Dolz L, et al. Variation in the frequency and type of infections in heart transplantation according to the immunosuppression regimen. Transplant Proc 2006;38: 2558–9. 11. Euvrard S, Ulrich C, Lefrancois N. Immunosuppressants and skin cancer in transplant patients: focus on rapamycin. Dermatol Surg 2004;30:628–33. 12. Otley CC, Berg D, Ulrich C, et al. Reduction of immunosuppression for transplant-associated skin cancer: expert consensus survey. Br J Dermatol 2006;154:395–400. 13. Said A, Lucey MR. Liver transplantation: an update. Curr Opin Gastroenterol 2006;22:272–8. 14. Jensen P, Hansen S, Moller B. et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 1999;40:177–186. 15. Gjersvik P, Hansen S, Moller B et al. Are heart transplant recipients more likely to develop skin cancer than kidney transplant recipients?. Transpl Int 2000;13(Suppl. 1)5380–1. 16. BelloniFortina A, Caforio AL, Piaserico S et al. Skin cancer in heart transplant recipients: Frequency and risk factor analysis. J Heart Lung Transplant 2000;19:249–255. 17. Naldi L, Fortina AB, Lovati S et al. Risk of nonmelanoma skin cancer in Italian organ transplant recipients. A registry-based study. Transplantation 2000;70:1479–84. 18. Meyer NJ, Bhorade SM. Evolving immunosuppressive regimens for lung transplant recipients. Semin Respir Crit Care Med 2006;27: 470–9. 19. Eisen H, Ross H. Optimizing the immunosuppressive regimen in heart transplantation. J Heart Lung Transplant 2004;23:S207–13. 20. Stratta RJ. Review of immunosuppressive usage in pancreas transplantation. Clin Transplant 1999;13:1–12.

7 Dermatologic Disease from the Transplant Perspective

Matthew D. Griffin, MB, BCh

M E D I C A L C A R E OF S O L I D O R G A N TR A N S P L A N T RE C I P I E N T S A N D T H E T I M E CO U R S E O F TRANSPLANT-RELATED COMPLICATIONS

AWARENES S OF DE RMATOLOG IC DISEASE DURING POSTTRANSPLANT M E D I C AL C A R E Skin health and dermatological disease have recognized significance for the primary-care team responsible for managing solid organ transplant recipients as summarized in the final column of Table 7.1. Most commonly encountered in the early time-period following transplantation are medication-related skin reactions (reflecting the initiation of multiple new medications at this time) and bacterial or candidal skin infections (to which the heavily immunosuppressed new graft recipient is highly susceptible). These common skin complications often respond to treatment alterations or first-line antimicrobial agents, and dermatological consultation is typically reserved for those that are initially severe or fail to resolve satisfactorily. Following the first posttransplant year, clinical evaluation for new skin cancers and precancerous lesions becomes progressively more significant during routine clinical visits, which usually occur one to three times a year. Transplant physicians are often comfortable dispensing advice regarding the avoidance of further skin damage as a means of reducing new skin cancers but rely heavily on dermatological consultation for diagnosis and management of these lesions. New, unexplained noncancerous skin lesions are also likely to result in prompt dermatological consultation, if reported by the patient or detected during routine examination. Unfortunately, during both early and long-term posttransplant care, the detection, treatment, and prevention of skin diseases often occupies a relatively low priority on the clinical agenda for the primary-care team. At various timepoints following transplantation, the recognized risks for graft rejection, infection, cardiovascular disease, systemic medication toxicity, lymphoma, and metabolic disease (see Table 7.1) are likely to dominate clinical evaluation and decisionmaking.[1,2] As a result of this pattern of clinical prioritization, the development of robust scientific literature, clinical outcomes analysis, and consensus formation regarding the prevention and treatment of skin disorders among organ transplant recipients has not occurred to the same degree as for other posttransplant complications. Figure 7.1 provides a summary of the total number of MEDLINEÒcited publications that can be linked with clinical organ

Clinical practice in solid organ transplantation has reached its current level of success primarily through the development of goal-oriented surgical and medical protocols. Patients typically progress through the stages of evaluation for transplant candidature, preparation for transplantation, management as a new graft recipient, and maintenance of mid- and long-term post-transplant care under the supervision of a highly specialized team of physicians and surgeons. In order to successfully steer solid organ transplant recipients through each of these processes, the primary management team characteristically prioritizes specific goals and focuses on detection and treatment of the most immediately threatening complications. Table 7.1 provides a generalized summary of important stages in this process and of the major complication risks for each. Although the details of individual management protocols vary significantly depending on both the organ transplanted and the transplant center, the central paradigms that have emerged from five decades of experience are quite similar. The approach of prioritized management, investigation, and decision-making by a specialized team has served to consolidate clinical experience in transplantation and to create benchmarks for success as a basis for achieving ongoing improvements. To some degree, however, it may also have inhibited the ability of other primary care and subspecialist practitioners to participate actively in the care of transplant recipients and to collaborate in clinical research protocols involving these patients. Specifically, concerns regarding the modification of immunosuppressive therapy or the potential for new interventions to destabilize graft function can result in a reluctance to aggressively manage important comorbidities that emerge during long-term follow-up. The latter consideration is highly pertinent to transplant-related dermatology. The primary purposes of this chapter are to review the current perspectives of transplant physicians and surgeons on dermatological disease and to highlight existing opportunities for enhancing the integration of transplant medicine and dermatology.

46

47

DERMATOLOGIC DISEASE FROM THE TRANSPLANT PERSPECTIVE

Table 7.1 Summary of major clinical goals, risks, and potential dermatological issues as typically recognized by solid organ transplant management teams at different time-points prior to and after transplantation Time period

Management priorities

Major complications and risks

Recognized skin conditions

Pre-Tx. Evaluation

1. Assessment of severity of organ failure. 2. Determination of eligibility for transplantation. 3. Detection and management of potential contraindications to transplantation. 1. Supportive care for organ failure. 2. Minimization of surgical risk. 3. Listing and continuous availability for transplantation.

1. Irreversible contraindication to transplantation. 2. Patient death or deterioration of organ failure during evaluation. 3. Immunological sensitization. 1. Patient death or deterioration of organ failure prior to transplantation. 2. Acute infection or cardiovascular event. 3. Organ shortage. 1. Primary organ failure or delayed function. 2. Acute cardiovascular or thromboembolic event. 3. Wound infection or dehiscence. 4. Hyperacute or acute vascular rejection. 5. Severe medication toxicity. 6. Systemic bacterial or fungal infection.

1. Prior history of melanoma or invasive nonmelanoma skin cancer.

1. Acute graft rejection. 2. Systemic or organ-specific CMV disease. 3. Other viral or fungal opportunistic infection. 4. Posttransplant diabetes mellitus. 5. Medication side-effects and interactions. 6. Posttransplant lymphoproliferative disease. 7. Recurrence of primary organ disease in the graft. 1. Early manifestations of chronic graft injury. 2. Noncompliance or loss to follow-up. 3. Chronic immunosuppression-related toxicities. 4. Acceleration of cardiovascular disease. 5. Posttransplant lymphoproliferative disease. 6. Fungal and other late opportunistic infections. 1. Established chronic graft injury and impending graft failure. 2. Malignancy. 3. Noncompliance or loss to follow-up. 4. Cardiovascular disease. 5. Bone fractures. 6. End-stage renal failure (nonkidney transplants).

1. Medication-related skin conditions. 2. Acute or chronic bacterial, viral, fungal skin infections.

Preparation for Tx.

0–30 days Post-Tx.

1–12 months Post-Tx.

1. Immediate intra- and postoperative care. 2. Initiation of high-level immunosuppression. 3. Early mobilization, wound care, and infection precautions. 4. Very frequent monitoring of graft function. 5. Rapid medical or surgical intervention for complications. 1. Return to the community with regular evaluations of graft function. 2. Detection and management of acute rejection. 3. Achievement and maintenance of optimal immunosuppression level. 4. Optimization of therapy for medical comorbidities. 5. Focused antimicrobial prophylaxis and surveillance for opportunistic infection.

1–5 years Post-Tx.

1. Intermittent evaluation of graft function. 2. Adjustment of immunosuppression to lowest effective level. 3. Detection and management of chronic graft injury. 4. Protocol-based management of medical comorbidities and cardiovascular risk factors.

>5 years Post-Tx.

1. Intermittent evaluation of graft function. 2. Detection and management of immunosuppression-related toxicities. 3. Maintenance of immunosuppression at lowest effective level. 4. Management of chronic graft injury and evaluation of need for retransplantation. 5. Cancer screening and management. 6. Ongoing management of medical comorbidities.

1. Bacterial skin infection. 2. Allergic skin reactions.

1. Acute bacterial or fungal skin infection. 2. Severe allergic skin reactions. 3. Corticosteroid-related acne.

1. New precancerous lesions and skin cancers. 2. KaposiÕs sarcoma. 3. Corticosteroid-related chronic skin changes. 4. Chronic bacterial, fungal, viral, or mycobacterial skin infections.

1. Numerous or invasive nonmelanoma skin cancers. 2. Cutaneous lymphoma. 3. Chronic bacterial, fungal, viral, or mycobacterial skin infections.

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MATTHEW D. GRIFFIN

transplantation or transplantation science during the past decade and the proportion of these publications that list keywords of relevance to skin physiology and skin diseases. This figure clearly shows that this proportion has remained relatively stable over time and represents approximately 6% of the total transplant-related literature. More significantly, when this search strategy is confined to journals directly related to organ transplantation (Figure 7.1), the proportion with relevance to dermatological disease is lower and demonstrates a trend towards decline (from 4.3% in 1995 to 3.3% in 2005). The direct exposure of transplant physicians to new studies related to skin health remains low and may even be diminishing. Additional insight to this issue can be obtained by further limiting the review of medical literature to those studies of human organ transplant recipients that are specifically categorized as ‘‘clinical trials’’ (Figure 7.2). Only 33 of over 6000 published transplant-related clinical trial reports can be identified as having relevance to skin diseases on the basis of keyword citations. To a large degree, this phenomenon reflects the predominant focus of clinical trials in transplantation on a very restricted set of outcomes including patient survival, graft survival, acute rejection rate, and lifethreatening early complications. In recent years, there have

Figure 7.1. A. The total annual number of MEDLINEÒ-cited publications related to transplantation, as well as the total number of these publications with keywords relevant to skin and skin diseases between 1995 and 2005 are shown graphically (column graph, left y-axis) along with the annual proportion of the total publications that were dermatology-related (line graph, right yaxis). B. The total annual number of original and review publications from 11 solid-organ transplant ‘‘core’’ journals, as well as the total number of these publications with keywords relevant to skin and skin diseases between 1995 and 2005 are shown graphically (column graph, left y-axis) along with the annual proportion of the total ‘‘core’’ journal publications that were dermatology-related (line graph, right y-axis). MEDLINEÒ SEARCH TERMS RELATED TO TRANSPLANTATION: Transplantation; transplant, heterologous; kidney transplantation; pancreas transplantation; liver transplantation; heart transplantation; lung transplantation; heart-lung transplantation; organ transplantation; transplant tolerance; transplant immunology. DERMATOLOGY-RELATED SEARCH TERMS: Dermatology; skin diseases; skin abnormalities; skin manifestations; skin physiology; skin ulcer; skin care; skin neoplasms. SOLID ORGAN TRANSPLANT ‘‘CORE’’ JOURNALS: American Journal of Transplantation; Clinical Transplantation; Clinical Transplants; Liver Transplantation; Journal of Heart and Lung Transplantation; Transplant Immunology; Transplant Infectious Diseases; Transplant International; Transplantation; Transplantation Proceedings; Transplantation Reviews.

Figure 7.2. The total number of MEDLINEÒ-cited publications related to solid organ transplant transplantation in humans that were designated as ‘‘Clinical Trials,’’ as well as the total number of these publications with keywords relevant to skin and skin diseases are shown graphically (column graph, left y-axis) along with the proportion of the total publications that were dermatology-related for each time-period (line graph, right y-axis). Results are shown for the entire MEDLINEÒ database up to December 31st, 2005, and for three time-periods – 1989 and earlier (< 1989), 1990–1999, and 2000–2005. MEDLINEÒ SEARCH TERMS RELATED TO SOLID ORGAN TRANSPLANTATION: Organ transplantation; kidney transplantation; pancreas transplantation; liver transplantation; heart transplantation; lung transplantation; heart-lung transplantation; islet of Langerhans transplantation; organ transplantation. DERMATOLOGY-RELATED SEARCH TERMS: Dermatology; skin diseases; skin abnormalities; skin manifestations; skin physiology; skin ulcer; skin care; skin neoplasms. SEARCH LIMITATIONS: 1. ‘‘Human.’’ 2. ‘‘Clinical Trial [Publication Type].’’

DERMATOLOGIC DISEASE FROM THE TRANSPLANT PERSPECTIVE

been distinct calls for a refocusing of outcome analyses from clinical transplant trials to include long-term complications, patient quality-of-life measures, overall disease burden, cardiovascular disease, and cancer incidence.[3,4] The increase in the proportion of transplant clinical trial reports with skin-related identifiers that has occurred between the 1990s and the current decade is possible evidence that recognition of these needs has impacted the study of dermatological outcomes (see Figure 7.2). Finally, it is worth noting that major clinical challenges in organ transplantation have often been methodically addressed through a process of consensus conferences and subsequent publication of evidence-based guidelines. In recent years, this has been exemplified in the publication of general consensus guidelines for long-term care of specific organ transplant recipients,[2] as well as guidelines for individual areas of care including posttransplant vaccination, lipid disorders, infection prophylaxis, diabetes mellitus, and long-term immunosuppression.[5–8] Such guidelines serve to highlight important underserved clinical needs of transplant patients, to consolidate existing knowledge at a given point in time, to disseminate ‘‘best practice’’ recommendations, and to generate new collaborative efforts aimed at furthering research in the area. It is encouraging, therefore, that recommendations for posttransplant skin cancer screening and treatment have been proposed by dermatological societies,[2] and that more comprehensive consensus guidelines are beginning to emerge regarding optimal prevention and management of skin diseases in organ transplant recipients.[9]

PROSPECTS FOR INCREASED COLLABO RATI ON BE TWE EN T RANS PL A NT PHYS ICI A NS AND DE RMAT OLOG IS TS As the number of organ transplant recipients continues to rise worldwide and early posttransplant outcomes progressively improve, there will be a growing need to study and reduce the long-term disease burden in this complex patient group.[3] Given the prevalence of skin cancers and other skin diseases among long-surviving transplant patients, it is important to consider how transplant physicians and dermatologists may work together in the future to better understand and manage transplant-related skin conditions. Four encouraging developments indicate that such collaborations have been initiated and are likely to gain momentum in the coming years: 1. Specialized transplant dermatology clinics have arisen in medical centers with large organ transplant practices.[10] 2. International societies have been formed to specifically foster clinical and research collaborations, data registries, and practice guidelines in transplant-related dermatology.[9,11]

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3. Clinical trials comparing different immunosuppressive regimens are beginning to yield data on skin cancer incidence.[12] 4. Basic science studies are now being executed to investigate the in vivo pathophysiology of skin cancer in immunosuppressed animals.[13] Each of these developments represents a vital step forward in improving the current level of understanding and of clinical practice in transplant dermatology.

REFERENCES

1. European Renal Association, and European Society for Organ Transplantation. European Best Practice Guidelines for Renal Transplantation (part 1). Nephrol Dial Transplant. 15 Suppl 7: 1–85, 2000. 2. Kasiske, B. L., M. A. Vazquez, W. E. Harmon, R. S. Brown, G. M. Danovitch, R. S. Gaston, D. Roth, J. D. Scandling, and G. G. Singer. Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation. J Am Soc Nephrol. 11 Suppl 15:S1–86, 2000 Oct. 3. Krakauer, H., R. C. Bailey, and M. J. Lin. Beyond survival: the burden of disease in decision making in organ transplantation. American Journal of Transplantation. 4(10):1555–61, 2004 Oct. 4. Keown, P. Improving quality of life–the new target for transplantation. Transplantation. 72(12 Suppl):S67–74, 2001 Dec 27. 5. Wilkinson, A., J. Davidson, F. Dotta, P. D. Home, P. Keown, B. Kiberd, A. Jardine, N. Levitt, P. Marchetti, M. Markell, S. Naicker, P. OÕConnell, M. Schnitzler, E. Standl, J. V. Torregosa, K. Uchida, H. Valantine, F. Villamil, F. Vincenti, and M. Wissing. Guidelines for the treatment and management of new-onset diabetes after transplantation. Clin Transplant. 19(3):291–8, 2005 Jun. 6. Kasiske, B., F. G. Cosio, J. Beto, K. Bolton, B. M. Chavers, R. Grimm, Jr., A. Levin, B. Masri, R. Parekh, C. Wanner, D. C. Wheeler, P. W. Wilson, and F. National Kidney. Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: a report from the Managing Dyslipidemias in Chronic Kidney Disease Work Group of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative. American Journal of Transplantation. 4 Suppl 7:13–53, 2004. 7. Jassal, S. V., J. M. Roscoe, J. S. Zaltzman, T. Mazzulli, M. Krajden, M. Gadawski, D. C. Cattran, C. J. Cardella, S. E. Albert, and E. H. Cole. Clinical practice guidelines: prevention of cytomegalovirus disease after renal transplantation. J Am Soc Nephrol. 9(9): 1697–708, 1998 Sep. 8. Fricker, J. New UK guidelines for use of immunosuppressive agents. Lancet Oncology. 5(11):643, 2004 Nov. 9. Stasko, T., M. D. Brown, J. A. Carucci, S. Euvrard, T. M. Johnson, R. D. Sengelmann, E. Stockfleth, W. D. Tope, C. International Transplant-Skin Cancer, and N. European Skin Care in Organ Transplant Patients. Guidelines for the management of squamous cell carcinoma in organ transplant recipients. Dermatol Surg. 30(4 Pt 2):642–50, 2004 Apr. 10. Christenson, L. J., A. Geusau, C. Ferrandiz, C. D. Brown, C. Ulrich, E. Stockfleth, D. Berg, I. Orengo, J. C. Shaw, J. A. Carucci, S. Euvrard, T. Pacheco, T. Stasko, and C. C. Otley. Specialty clinics for the dermatologic care of solid-organ transplant recipients. Dermatol Surg. 30(4 Pt 2):598–603, 2004 Apr. 11. Eedy, D. J. Summary of inaugural meeting of the Skin Care in Organ Recipients Group, UK, held at the Royal Society of Medicine, 7 October 2004. Br J Dermatol. 153(1):6–10, 2005 Jul.

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12. Mathew, T., H. Kreis, and P. Friend. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant. 18(4):446–9, 2004 Aug.

13. Vanbuskirk, A., T. M. Oberyszyn, and D. F. Kusewitt. Depletion of CD8+ or CD4+ lymphocytes enhances susceptibility to transplantable ultraviolet radiation-induced skin tumours. Anticancer Res. 25(3B):1963–7, 2005 May–Jun.

Section Three

PATHOGENIC FACTORS IN TRANSPLANT DERMATOLOGY

8 Basic Scientific Mechanisms of Accelerated Development of Squamous Cell Carcinoma in Organ Transplant Recipients

John A. Carucci, MD, PhD

INT ROD UCTION

not necessarily sufficient for cancer development. Tumor promotion, another necessary step in cutaneous carcinogenesis, is accomplished by interfering with tumor suppressor genes. In the presence of both tumor initiators and tumor promoters, the malignant clone is allowed to develop in an unchecked fashion.

More than 28,000 transplants were performed in 2006 and even more are expected in 2007.[1] As transplant recipients are living longer, the problem of managing their skin cancers becomes more challenging. This is especially true for squamous cell carcinoma (SCC), a significant cause of morbidity and mortality for this group.[2] This chapter will focus on some of the fundamental, molecular mechanisms responsible for accelerated development of SCC in transplant recipients. Chapter 20 will focus on pathogenesis from a more clinical, as opposed to a basic scientific, perspective. Tumorigenesis is a multistage process where multiple mutations are required to disrupt opposing forces of proliferation, apoptosis, and differentiation and result in the development of a hyperproliferative, invasive clone that does not undergo normal growth arrest. Proliferation and survival are mediated by proto-oncogenes, whereas tumor suppressor genes mediate programmed cell death. There is extensive interplay between genetic and environmental factors that contribute to the development of skin cancer. A simple example might involve an individual with ultraviolet radiation (UVR) overexposure in whom a malignant clone of keratinocytes develops and is allowed to proliferate due to corrupted tumor suppressor mechanisms. Add other potentially carcinogenic factors common in transplant recipients, including the presence of human papillomavirus (HPV) infection, direct proliferative effects attributable to specific immunosuppressive agents, and decreased tumor surveillance, and this represents a patient who is as at high risk for aggressive malignant cutaneous disease. A more detailed explanation of how these factors might interact to accelerate SCC development follows.

P 53 P53 has been called ‘‘the guardian of the genome.’’ It is commonly mutated in human cancers and its role in the development of human cutaneous SCC has been well characterized.[4] In normal skin, P53 acts as a cell cycle break, facilitating repair of damaged DNA (Figure 8.1). P53 gene product is expressed in response to UV-induced DNA strand breaks and induces p21cip1.[5] P21cip1 in turn inhibits cyclin-dependent kinases CDK2 and CDK4.[6,7] Inhibition of CDK2 and CDK4, in turn, blocks G1 cell cycle progression. With cell cycle progression halted, DNA repair may be performed prior to replication. If DNA damage is severe, BAX is induced, which binds BCL-2, inhibiting its antiapoptotic function.[7] This facilitates programmed death of cells harboring severely damaged DNA. Thus, the somewhat damaged DNA is repaired or rebuilt, whereas severely damaged DNA is not permitted to replicate. Studies have demonstrated that UV signature CC/TT or C/T mutations of p53 are present in 40–70% of SCC and 50–60% of actinic keratosis.[4] These studies support that interference with p53 is key in UV-induced carcinogenesis. Interestingly, mutations in p53 are responsible for the LiFraumeni syndrome, characterized by development of sarcomas and multiple cancers that do not include cutaneous squamous cell carcinoma.[8] This supports the involvement of additional factors in the development of SCC.

U L T R A V I O L E T R AD I AT I O N CDKN2A AND P16

UVR is key in cutaneous carcinogenesis as well as photoaging.[3,4] UVR acts as both tumor initiator and tumor promoter and thus, in laymanÕs terms, UV exposure can be described as ‘‘stepping on the accelerator while simultaneously disabling the break.’’ Tumor initiation occurs through creation of thymine dimers leading to transcription of mutated DNA. This accelerates tumorigenesis; however, initiation is

CDKN2a encodes the p16ink4a tumor suppressor.[9,10] Progression through G1 depends on a complex formed between Cyclin D1 and CDK4. The CDK4 component of this complex phosphorylates retinoblastoma product (Rb), which eventuates in release of elongation factor E2F (Figure 8.1). E2F

53

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Figure 8.1. UV light exerts far-reaching effects on tumor suppressor and cell cycle mediators.

mediates progression from G1 to S and thus facilitates proliferation. CDKN2a mutations have been reported in 10–40% of sporadic SCC. Tumor suppressor p16ink4a binds to CDK4 and inhibits its kinase activity. This, in turn, results in failure to release E2F and subsequent G1 arrest. Transcription factor E2F3 plays a key role in Rb-mediated regulation of proliferation [11] and was increased in human SCC compared with site-matched non-tumor-bearing skin.[12]

R AS ON C O G E NE AN D H U M A N CUTANEOUS SCC

hibitor IkBa in response to cytokine signaling, growth factors or DNA damage.[16] Loercher et al. [17] reported inactivation of NF-kB-inhibited malignant phenotypic features including proliferation and angiogenesis in murine SCC. Dajee et al. [18] report blockade of NF-kB and oncogenic RAS trigger invasive human epidermal neoplasia reminiscent of SCC. In the skin, NFKB1 was increased in psoriasis,[10] whereas NFKB2 and NFKBIA (IkBa) were decreased in SCC. It may be that downregulation of NFKB2 may be key in malignancy, with loss of proapoptotic function contributing to transformation in the skin as reported in lymphoma.[19]

W N T SI G N A L I N G A ND SC C RAS genes are families of proto-oncogenes that mediate proliferation [13,14] (Figure 8.2). Mutation of a single allele of ras can contribute to tumorigenesis. Of the three ras genes, H-Ras, K-ras, and N-ras, mutations in H-ras predominate in the general population with mutations at codons 12, 13, and 61 corresponding to UV-sensitive CC sites. Ras mutations are found in approximately 10–20% of SCC with a higher rate of ras mutation and N-ras predominance seen in SCC in patients with xeroderma pigmentosum. In a recent study, KRAS was increased in human SCC compared non-tumor-bearing skin. Enhanced expression of KRAS is consistent with the findings of Vitale-Cross et al. [15] who report that expression of KRAS in an epithelial compartment containing stem cell is sufficient for squamous cell carcinogenesis in mice.

NF-kB NF-kB is a transcription modulator expressed in most cells in an inactive form and is activated through degradation of in-

Wnt proteins are secreted signal molecules that act as local developmental mediators [20] (Figure 8.3). The cell surface receptors for Wnt belong to the Frizzled (Fzd) family of seven-pass transmembrane receptors that resemble G proteins. They signal primarily through a G-protein independent pathway requiring Disheveled (Dsh), a cytoplasmic signaling protein. Conventional Wnt signaling facilitates b-catenin interaction with transcription factor TCF-LEF with subsequent regulation of gene expression. In the absence of WNT signaling, b-catenin levels are kept low through degradation of cytoplasmic b-catenin. b-catenin is targeted for degradation by paired phosphorylation through the serine/threonine kinase casein kinase 1 (CK1) and glycogen synthase 3b (GSK3b) bound to a complex of axin and adenomatous polyposis coli (APC) protein. Wnt activation inhibits GSK-3b, which results in accumulation of cytoplasmic b-catenin, which, in turn, binds TCF/LEF to induce target gene expression. Wnt/b-catenin signaling inhibited death receptor mediated apoptosis in nude and promoted invasive growth of head

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55

Figure 8.2. The RAS pathway in cutaneous carcinogenesis.

and neck SCC in nude mice.[21] In another recent study, Wnt 5a was upregulated in both SCC and psoriasis in humans. This is consistent with the findings of Taki et al. [22] who showed upregulation of Wnt 5a by epithelial mesenchymal transition by human SCC cells in culture. Haider et al. showed that Wnt 5a was upregulated in both SCC and psoriasis suggesting that differential receptor expression may play a role in the ultimate determination of biological behavior.[12] In that study, Wnt receptor Fzd6 was increased in SCC compared to site-matched skin, and was not increased in psoriasis. Based on unique expression in SCC compared with site-matched skin and a lack of expression in benign hyperplasia, the authors suggested that Fzd6 might be involved in Wnt-mediated signaling in cutaneous SCC.

PTN AND SCC PTN encodes a 136 amino acid heparin-binding cytokine that accelerates tumor growth and angiogenesis.[23] PTN has been implicated in the pathogenesis of melanoma; [24] however, its potential role in the pathogenesis of SCC has been previously undefined. Wu et al. [24] demonstrated correlation of PTN expression with tumor progression and metastatic potential in melanoma. Haider et al. reported that PTN was more highly expressed in SCC than in psoriasis and even more highly expressed in non-tumor-bearing skin adjacent to SCC.[12] This might indicate that peritumoral skin acts to induce SCC through PTN.

HPV HPV is associated with common and genital warts, cervical carcinoma, and in some cases, cutaneous SCC. Warty lesions are extremely common in transplant recipients. HPV can be subtyped into broad classes, including alpha, beta, gamma, mu, and nu. An etiological relationship between HPV and epithelial cancer is best established for alpha types including HPV 16, which was initially described in the pathogenesis of SCCs involving the nail unit.[25] Beta HPVs, including types 5 and 8, are over-represented in SCCs from transplant recipients.[26] HPV-derived proteins E6 and E7 inhibit p53 and thus contribute to lack of tumor suppressor activity. In addition, E6 enhances proliferation in a p53 independent manner. Beta type HPV 8 associated E6 has been shown to inhibit DNA repair. Other beta HPV associated E6 have been shown to abrogate BAK, a protein involved in apoptosis signaling in skin in response to UV damage.[27] Interestingly, beta HPV8 associated E7 enhanced terminal differentiation and hyperproliferation in human keratinocytes in organotypic culture. Even more interesting, it caused these keratinocytes to acquire the ability to invade the underlying dermis. This was associated with increased expression of MMP-1, MMP-8, and MT1-MMP.

P R OT EA S ES A N D P R O TE AS E I NH I B IT OR S Invasion is a key defining feature of malignancy, separating SCC from benign processes including psoriasis and

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Figure 8.3. The WNT pathway in cutaneous carcinogenesis.

pseudoepitheliomatous hyperplasia. Matrix metalloproteinases (MMPs) are involved in extracellular matrix degradation, which is key to tumor invasion.[28] MMP1 degrades collagens I, II, and III, [29] and has been reported to mediate invasiveness and survival of keratinocytes.[30] MMP13 degrades type II collagen most efficiently and has also been implicated in malignant transformation of keratinocytes.[31] MMP10 degrades fibronectin and proteoglycans and has been implicated as a tumor promoter in lymphoma.[32] Haider et al. reported induction of proteases MMPs 1, 10, and 13 and cathepsin L2 and suppression of protease inhibitors TIMP 1 and TIMP3 in human SCC.[12] Interestingly, Cystatin M (CST6) was increased in SCC.[12] Cystatin M, an endogenous protease inhibitor, has been implicated as a potential tumor suppressor for breast cancer.[33]

S C C A N D T H E L O C A L I M M UN E M IC R O EN V IRO N MEN T Tumor regression is mediated by both innate and adaptive responses (Figure 8.4). Innate immunity refers to responses that are not antigen-specific. These are mediated through natural killer (NK) cells, NKT cells, and cdT cells.[34,35] Adaptive immunity refers to generation of antigen-specific responses mediated by specialized antigen processing cells (APCs) known as dendritic cells (DCs).[36] Cytokines, including IL-2, IL-12, IL-18, and IL-23 stimulate DCs to engulf and

process tumor antigens. These are presented to naı¨ve T cells in the context of the major histocompatibility complex (MHC). Antigens are presented to CD4+ (helper) T cells with MHC II and CD8+ (cytotoxic) T cells in the context of MHC I. Activation occurs when the T cell receptor interacts with the antigen-MHC complex. Costimulatory signals, including CD80, CD86, and CD40, determine whether the response is immunostimulatory or anergic.[36,37] Engagement of the T cell receptor, along with costimulation, results in immune response, whereas activation of the T cell receptor without costimulation results in anergy or tolerance. After activation, CD4+ cells differentiate into subpopulations of Th1 and Th2 cells. Th1 cells produce IL-2, IFN-c, TNF a, and GM-CSF. Interleukin-4, IL-5, and IL-10 are produced by TH2 cells and drive antibody production. CD8+ T cells mediate tumor cell destruction via perforins, granzymes, and Fas ligand with production of cytokines including IFN-c, TNF-a, and TNF-b. The local immune response may play a role in anticancer surveillance or potentially permissiveness in the skin. Little is known about the local immune microenvironment surrounding SCC. In one study, Terao et al. [38] found that T lymphocytes predominated and NK cells, B cells, and monocytes were rarely detected surrounding SCC. Smith et al. showed the presence of CD1a+ immature (DCs), and high numbers of CD3+ T cells with helper CD4 outnumbering CD8 (40% vs. 20%).[39] Low numbers of CD14+ macrophages were detected and CD56+ NK cells were absent. In a more

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57

Figure 8.4. Antitumor immunity is comprised of innate and adaptive components.

recent study of SCC in immune competent patients, immature DCs were detected but did not penetrate epithelial tumor nests. Mature DCs expressing CD80, CD86, or CD40 were not detected.[12] The authors reported low expression of granzyme B, key in tumor immunity,[40] consistent with a relatively dampened immune microenvironment associated with SCC. UV radiation has direct effects on the immune system and may dampen antitumor immunity. UV light results in local depletion of antigen processing Langerhans cells, inhibits antigen processing, induces production of immunosuppressive cytokines, and causes apoptosis of leukocytes.[41] Piskin et al. showed that neutrophils produce IL-10 following UVB exposure.[42] Yaron et al. demonstrated that UVB irradiation of human-derived peripheral blood lymphocytes induced apoptosis rather than T cell anergy.[43] This indicates a potential for additive effect when UVB-mediated immune suppression is combined with immunosuppressive medications following solid organ transplantation.

a 2-fold increase in keratinocyte growth factor attributable to cyclosporine. In contrast, Karashima [47] reported cell cycle blockade by cyclosporine in cultured human keratinocytes. They found that cyclosporine inhibited keratinocyte proliferation induced by EGF, TGF-alpha, or IL-6. The antiproliferative effects of cyclosporine directly correlated with blockade of the keratinocyte cell cycle at the G0/G1 phases. These findings might

D I R E C T E F F E C T S OF IM M U N O S U P P R E S S I V E AGENTS Calcineurin inhibitors, including cyclosporine, remain a mainstay of posttransplant immunosuppressive regimens and may contribute to accelerated development of skin cancer through nonimmune mediated mechansisms.[44] Yarosh et al. showed that cyclosporine inhibited removal of cyclobutane dimers and inhibited UV-mediated apoptosis.[45] Takahashi and Kamimura (2001) demonstrated that cyclosporine enhanced proliferation of murine epidermal keratinocytes over a wide range of doses.[46] Das et al. (2001) further demonstrated

Figure 8.5. Calcineurin inhibitors may decrease expression of tumor suppressor P21.

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indicate that the effects of tacrolimus and cyclosporine on proliferation of cultured normal human keratinocytes are probably related to direct effects on growth regulation of keratinocytes via EGF, TGF-alpha, or IL-6 stimulation. Santini et al. showed that treatment of primary mouse keratinocytes with cyclosporine suppressed the expression of terminal differentiation markers and of p21(WAF1/Cip1) and p27(KIP1), two cyclin-dependent kinase inhibitors that are usually induced with differentiation.[48] In parallel with downmodulation of the endogenous genes, suppression of calcineurin function blocks induction of the promoters for the p21 (WAF1/Cip1) and loricrin differentiation marker genes, whereas activity of these promoters is enhanced by calcineurin overexpression (Figure 8.5).

CONCLUSIONS Accelerated carcinogenesis in transplant recipients is a complex, multistep process involving the interplay between tumor suppressors, oncogenes, proteases and inhibitors, and the local immune microenvironment. Additional factors, including UV exposure, HPV infection and immunosuppressive medications, influence the classical pathways and exert novel effects to dramatically increase the risk for SCC in transplant recipients.

13. 14.

15.

16.

17.

18.

19.

20. 21.

22.

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23. 1. (UNOS) UNOS database www.UNOS.ORG 2. Berg D, Otley CC. Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and management. J Am Acad Dermatol. Jul 2002;47(1):1–17. 3. Brash DE, Ziegler A, Jonason AS, Simon JA, Kunala S, Leffell DJ. Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion. J Investig Dermatol Symp Proc. Apr 1996;1(2): 136–42. 4. Leffell DJ, Brash DE. Sunlight and skin cancer. Sci Am. Jul 1996;275(1):52–53, 56–59. 5. Fotedar R, Bendjennat M, Fotedar A. Role of p21WAF1 in the cellular response to UV. Cell Cycle. Feb 2004;3(2):134–7. 6. Samuel T, Weber HO, Funk JO. Linking DNA damage to cell cycle checkpoints. Cell Cycle. May-Jun 2002;1(3):162–8. 7. Basu A, Haldar S. The relationship between BcI2, Bax and p53: consequences for cell cycle progression and cell death. Mol Hum Reprod. Dec 1998;4(12):1099–1109. 8. Leversha MA, Fielding P, Watson S, Gosney JR, Field JK. Expression of p53, pRB, and p16 in lung tumours: a validation study on tissue microarrays. J Pathol. Aug 2003;200(5):610–619. 9. Nindl I, Meyer T, Schmook T, et al Human papillomavirus and overexpression of P16INK4a in nonmelanoma skin cancer. Dermatol Surg. Mar 2004;30(3):409–14. 10. Green CL, Khavari PA. Targets for molecular therapy of skin cancer. Semin Cancer Biol. Feb 2004;14(1):63–9. 11. Johnson DG, Schneider-Broussard R. Role of E2F in cell cycle control and cancer. Front Biosci. Apr 27 1998;3:d447–448. 12. Haider AS, Peters SB, Kaporis H, et al. Genomic analysis defines a cancer-specific gene expression signature for human squamous cell

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carcinoma and distinguishes malignant hyperproliferation from benign hyperplasia. J Invest Dermatol. Apr 2006;126(4):869–81. Mercurio AM. Invasive skin carcinoma – Ras and alpha6beta4 integrin lead the way. Cancer Cell. Mar 2003;3(3):201–2. Pierceall WE, Goldberg LH, Tainsky MA, Mukhopadhyay T, Ananthaswamy HN. Ras gene mutation and amplification in human nonmelanoma skin cancers. Mol Carcinog. 1991;4(3):196–202. Vitale-Cross L, Amornphimoltham P, Fisher G, Molinolo AA, Gutkind JS. Conditional expression of K-ras in an epithelial compartment that includes the stem cells is sufficient to promote squamous cell carcinogenesis. Cancer Res. Dec 15 2004;64(24):8804–07. Bell S, Degitz K, Quirling M, Jilg N, Page S, Brand K. Involvement of NF-kappaB signalling in skin physiology and disease. Cell Signal. Jan 2003;15(1):1–7. Loercher A, Lee TL, Ricker JL. et al. Nuclear factor-kappaB is an important modulator of the altered gene expression profile and malignant phenotype in squamous cell carcinoma. Cancer Res. Sep 15 2004;64(18):6511–23. Dajee M, Lazarov M, Zhang JY, et al. NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature. Feb 6 2003;421(6923):639–43. Neri A, Fracchiolla NS, Migliazza A, Trecca D, Lombardi L. The involvement of the candidate proto-oncogene NFKB2/lyt-10 in lymphoid malignancies. Leuk Lymphoma. Sep 1996;23(1–2): 43–8. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810. Yang F, Zeng Q, Yu G, Li S, Wang CY. Wnt/beta-catenin signaling inhibits death receptor-mediated apoptosis and promotes invasive growth of HNSCC. Cell Signal. 18(5):679–87, 2006 May. Taki M, Kamata N, Yokoyama K, Fujimoto R, Tsutsumi S, Nagayama M. Down-regulation of Wnt-4 and up-regulation of Wnt-5a expression by epithelial-mesenchymal transition in human squamous carcinoma cells. Cancer Sci. Jul 2003;94(7):593–97. Deuel TF, Zhang N, Yeh HJ, Silos-Santiago I, Wang ZY. Pleiotrophin: a cytokine with diverse functions and a novel signaling pathway. Arch Biochem Biophys. Jan 15 2002;397(2):162–71. Wu H, Barusevicius A, Babb J, et al. Pleiotrophin expression correlates with melanocytic tumor progression and metastatic potential. J Cutan Pathol. Feb 2005;32(2):125–30. Theunis A, Andre J, Noel JC. Evaluation of the role of genital human papillomavirus in the pathogenesis of ungual squamous cell carcinoma. Dermatology. 1999;198(2):206–8. Stockfleth E, Nindl I, Sterry W, Ulrich C, Schmook T, Meyer T. Human papillomaviruses in transplant-associated skin cancers. Dermatol Surg. Apr 2004;30(4 Pt 2):604–9. Talora C, Sgroi DC, Crum CP, Dotto GP. Specific down-modulation of Notch1 signaling in cervical cancer cells is required for sustained HPVE6/E7 expression and late steps of malignant transformation. Genes Dev. Sep 1 2002;16(17):2252–63. Kerkela E, Saarialho-Kere U. Matrix metalloproteinases in tumor progression: focus on basal and squamous cell skin cancer. Exp Dermatol. Apr 2003;12(2):109–25. Aznavoorian S, Moore BA, Alexander-Lister LD, Hallit SL, Windsor LJ, Engler JA. Membrane type I-matrix metalloproteinase-mediated degradation of type I collagen by oral squamous cell carcinoma cells. Cancer Res. Aug 15 2001;61(16):6264–75. Nagavarapu U, Relloma K, Herron GS. Membrane type 1 matrix metalloproteinase regulates cellular invasiveness and survival in cutaneous epidermal cells. J Invest Dermatol. Apr 2002;118(4): 573–81. Ala-aho R, Grenman R, Seth P, Kahari VM. Adenoviral delivery of p53 gene suppresses expression of collagenase-3 (MMP-13) in squamous carcinoma cells. Oncogene. Feb 14 2002;21(8):1187–95.

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32. Van Themsche C, Alain T, Kossakowska AE, Urbanski S, Potworowski EF, St-Pierre Y. Stromelysin-2 (matrix metalloproteinase 10) is inducible in lymphoma cells and accelerates the growth of lymphoid tumors in vivo. J Immunol. Sep 15 2004;173(6):3605–11. 33. Zhang J, Shridhar R, Dai Q, et al. Cystatin m: a novel candidate tumor suppressor gene for breast cancer. Cancer Res. Oct 1 2004; 64(19):6957–64. 34. Sinkovics JG, Horvath JC. Human natural killer cells: a comprehensive review. Int J Oncol. Jul 2005;27(1):5–47. 35. Munz C, Steinman RM, Fujii S. Dendritic cell maturation by innate lymphocytes: coordinated stimulation of innate and adaptive immunity. J Exp Med. Jul 18 2005;202(2):203–7. 36. Steinman RM. The control of immunity and tolerance by dendritic cell. Pathol Biol (Paris). Mar 2003;51(2):59–60. 37. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685–711. 38. Terao H, Nakayama J, Urabe A, Hori Y. Immunohistochemical characterization of cellular infiltrates in squamous cell carcinoma and BowenÕs disease occurring in one patient. J Dermatol. Jul 1992; 19(7):408–13. 39. Smith KJ, Hamza S, Skelton H. Topical imidazoquinoline therapy of cutaneous squamous cell carcinoma polarizes lymphoid and monocyte/macrophage populations to a Th1 and M1 cytokine pattern. Clin Exp Dermatol. Sep 2004;29(5):505–12. 40. Pardo J, Balkow S, Anel A, Simon MM. Granzymes are essential for natural killer cell-mediated and perf-facilitated tumor control. Eur J Immunol. Oct 2002;32(10):2881–87.

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41. Schwarz T. Mechanisms of UV-induced immunosuppression. Keio J Med. Dec 2005;54(4):165–71. 42. Piskin G, Bos JD, Teunissen MB. Neutrophils infiltrating ultraviolet B-irradiated normal human skin display high IL-10 expression. Arch Dermatol Res. Jan 2005;296(7):339–42. 43. Yaron I, Yaron R, Oluwole SF, Hardy MA. UVB irradiation of human-derived peripheral blood lymphocytes induces apoptosis but not T-cell anergy: additive effects with various immunosuppressive agents. Cell Immunol. Mar 15 1996;168(2):258–66. 44. Carucci JA. Cutaneous oncology in organ transplant recipients: meeting the challenge of squamous cell carcinoma. J Invest Dermatol. Nov 2004;123(5):809–16. 45. Yarosh DB, Pena AV, Nay SL, Canning MT, Brown DA. Calcineurin inhibitors decrease DNA repair and apoptosis in human keratinocytes following ultraviolet B irradiation. J Invest Dermatol. Nov 2005;125(5):1020–25. 46. Takahashi T, Kamimura A. Cyclosporin a promotes hair epithelial cell proliferation and modulates protein kinase C expression and translocation in hair epithelial cells. J Invest Dermatol. Sep 2001;117(3):605–11. 47. Karashima T, Hachisuka H, Sasai Y. FK506 and cyclosporin A inhibit growth factor-stimulated human keratinocyte proliferation by blocking cells in the G0/G1 phases of the cell cycle. J Dermatol Sci. Sep 1996;12(3):246–54. 48. Santini MP, Talora C, Seki T, Bolgan L, Dotto GP. Cross talk among calcineurin, Sp1/Sp3, and NFAT in control of p21(WAF1/CIP1) expression in keratinocyte differentiation. Proc Natl Acad Sci U S A. Aug 14 2001;98(17):9575–80.

9 Pathogenic Factors Involving Infections in Transplant Dermatology

Jennifer Y. Lin, MD and Richard A. Johnson, MD

INTR ODUCT IO N

commonly encountered pathogens. For this last topic we will focus on diagnostic and therapeutic considerations. Although severe cutaneous infections are more commonly seen in patients immunocompromised from hematological malignancies and secondary to chemotherapy or after bone marrow transplantation, these infections may present after solid organ transplantation as well, albeit less commonly.

Among the most formidable challenges to the clinician is the care of the patient with an impaired immune system – the compromised host. The growing number of organ transplant recipients has created a heightened need to characterize the infections of patients on chronic immunosuppression. For instance, in the United States, in the year 2005 alone, 28,000 transplants were performed. The success of the solid organ transplantation is incumbent on the success of our management of improved immunosuppressive therapies and our ability to recognize and control infections. Two characteristics of the compromised host, in particular, contribute to the complexity of management of infection in these patients: (1) the exceptionally broad variety of potential microbial pathogens and (2) the wide spectrum of clinical manifestations of disease resulting from the abnormal immune response. In the compromised patient, cutaneous and subcutaneous tissues may be expected to be an important focus of infection, for three reasons.[1] First, the skin, together with the mucosal surfaces, represents the first line of defense of the body against the external environment. These barriers assume an even greater importance when secondary defenses, such as phagocytosis, cell-mediated immunity, and antibody production, are impaired. Second, the rich blood supply of the skin provides a route of spread of infection, both from the skin to other body locations and to the skin from other sites of infection. In the latter case, a skin lesion may serve as an early warning system to alert the patient and the clinician to the existence of a systemic infection. These cutaneous lesions may be benign in appearance, presumably because of the diminished host immune response, and therefore be easily missed or dismissed as insignificant. Third, skin infections are common, occurring in about 75% of transplant patients.[2] The organ that is transplanted, the patientÕs level of immunosuppression, the intensity of the environmental exposure, and the timing of the infection in relation to transplantation determine the type and severity of infection. This chapter will give an overview of infection of the cutaneous and subcutaneous tissues in compromised hosts, specifically, recipients of solid organ transplants. Topics of discussion are the skin as a barrier to infection, a four-part classification of skin infection in compromised patients, the time course of infections post transplant, and an overview of

SKIN AS A BARRIER TO INFECTION The skin is usually quite resistant to infection. The mechanisms by which the resistance occurs are not well understood. Three important components that contribute to microbial resistance are nonspecific: (1) intact keratinized layers of the skin, which prevent penetration of microorganisms; (2) dryness of the skin, which retards the growth of certain organisms such as aerobic Gram-negative bacilli and Candida species; (3) the suppressant effect of the normal skin flora, which appears to reduce colonization of pathogens, a phenomenon known as bacterial interference. Within this framework, then, one might expect potentially serious skin infections to develop under the following circumstances: (1) destruction by trauma or bypass by introduction of intravascular catheters of the previously intact keratinized layer of skin; (2) moistening of the skin, such as under occlusive dressings; (3) alteration of the normal colonizing flora, such as after administration of antimicrobial agents. An example of these phenomena is the development of invasive fungal infection in compromised patients whose skin has been traumatized by tape holding intravascular lines in place. Infection with Rhizopus species has been associated with use of Elastoplast tape to secure intravascular catheters.[1] Skin infection with Aspergillus species has occurred at the site of boards to stabilize arms to protect intravenous lines.[2] Because of the occurrence of these types of infections, the following approach would seem warranted: occlusive dressings in immunocompromised patients should be avoided when possible, and skin covered by such dressings should be routinely inspected. Paper tape should be used in preference to cloth tape, and surgical dressings might be secured with girdles of elasticized netting rather than tape whenever possible. The effect of chronic administration of corticosteroids on the skin is another factor that may contribute to increased

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Table 9.1 Types of skin infection by pathophysiologic events Pathogen

Type of infection

Site of infection

Healthy host

Compromised host

S. aureus, Group A streptococcus

Primary skin infections with common pathogens Unusually widespread cutaneous infection

Epidermis, hair follicles, dermis, subcutaneous tissues

Impetigo, ecthyma, folliculitis, abscess, intertrigo

Epidermis, intertriginous sites, hair follicles, oropharynx, esophagus, genitalia

Dermatophytosis: epidermal (limited), folliculitis. Candidiasis: intertrigo, genital. Localized herpes; resolves spontaneously. Herpes zoster (mild). Molluscum contagiosum (localized, nonfacial) Common and mucosal warts

Opportunistic primary cutaneous infection Systemic infection metastatic to cutaneous and subcutaneous sites

Dermis, subcutaneous tissues

Swimming pool granuloma

Dermis, subcutaneous tissues

Soft-tissue infection 6necrosis Nodules

Soft tissue infection, necrotizing soft tissue infection, septicemia Dermatophytosis: epidermal (extensive), folliculitis. Candidiasis: intertrigo, folliculitis, mucosal. Chronic herpetic ulcers. Extensive herpes zoster 6hematogenous dissemination to skin Hairy leukoplakia. Widespread molluscum contagiosum, resistant to therapy. Widespread warts; squamous cell carcinoma (in situ and invasive) Soft-tissue infection 6necrosis; septicemia; bacillary angiomatosis Soft-tissue infection 6necrosis Nodules

Dermatophytes, Candida, Gram-negative rods, pseudomonas, herpes virus infections, molluscum virus infections, human papillomavirus infections.

Atypical mycobacteria, Nocardia, Bartonella henselae/quintana Bacteria

HSV: herpes simplex virus VZV: varicella-zoster virus Epstein–Barr virus (EBV) CMV: Cytomegalovirus MCV: molluscum contagiosum virus HPV: human papillomavirus

susceptibility of compromised patients to infection. Steroid therapy appears to inhibit proliferation of fibroblasts, synthesis of mucopolysaccharides, and deposition of collagen. The net effect is thin and atrophic skin that heals poorly. Minor trauma generates cutaneous impairments that tend to persist, providing potential portals of entry for pathogens.

T YP E S OF SK I N IN F E C T IO N Infection of the cutaneous and subcutaneous tissues in solid organ transplant recipients can be classified in a variety of ways: by pathogen, by underlying immunologic defect, or by source of infection. An additional categorization considers pathophysiological events and consists of four groups

Table 9.1: (1) True pathogens – infection originating in skin and being typical of that which occurs in immunocompetent persons, albeit with the potential for more serious illness; (2) sometime pathogens – extensive cutaneous involvement with pathogens that normally produce trivial or well-localized disease in immunocompetent patients; (3) opportunistic pathogens – infection originating from a cutaneous source and caused by opportunistic pathogens that rarely cause disease in immunocompetent patients but that may cause either localized or widespread disease in compromised patients; and (4) indicator of visceral pathogens – cutaneous or subcutaneous infection that represents metastatic or hematogenous spread from a noncutaneous site. Cutaneous and subcutaneous infections in immunocompromised patients are discussed in this section within the framework of these four groups.

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1. Primary Skin Infections with Common True Pathogens The incidence and severity of conventional forms of infections originating in the skin are often increased in the immunocompromised host. Gram-positive organisms, such as Staphylococcus aureus and group A streptococci, most commonly cause these infections. Patients with granulocytopenia are more susceptible to cellulitis caused by less virulent bacterial pathogens, such as Enterobacteriaceae and Pseudomonas species, and by anaerobic bacteria. Immunosuppressants that diminish cell-mediated immunity may be associated with erysipelas-like infection, caused by such organisms as Cryptococcus neoformans or Candida species, mimicking cellulitis caused by common Gram-positive bacteria. When evaluating cellulitis in an immunocompromised patient, common as well as uncommon/rare pathogens must be considered as potential pathogens. If a patient does not respond to conventional antimicrobial therapy, an aggressive approach to diagnosis is warranted, with biopsy of lesions for Gram and other stains, cultures, and dermatopathology, to correctly identify the pathogen.

2. Unusually Widespread Cutaneous Infection Nonvirulent skin fungi and viruses constitute the two major causes of infection in this category. These pathogens typically cause minor infections in immunocompetent persons, but in immunocompromised patients, tend to cause more extensive disease that may lead to more serious systemic illness. Viruses that cause exanthems (e.g., those caused by rubella, measles, or enterovirus) do occur in immunocompromised patients, but the more problematic pathogens include the family of herpes viruses and human papilloma viruses (HPV). Nonvirulent fungi include the dermatophytes (Trichophyton species, Microsporum species, and Epidermophyton), Candida species, Pityrosporum species, Fusarium solani, and Alternaria alternata. These fungi frequently colonize human skin and cause localized, superficial skin infection in immunocompetent persons, particularly when the skin has been traumatized. The incidence and severity of infections with these organisms may be increased in immunocompromised patients. Topical corticosteroid preparations prescribed mistakenly for epidermal dermatophytoses compromise local immunity, facilitating growth of the fungus, resulting in extensive local epidermal infection (so-called tinea incognito in that the diagnosis of dermatophytosis is missed). Dermatophytic folliculitis (MajocchiÕs granuloma) is commonly seen as an associated finding. Systemic corticosteroid therapy can also be associated with widespread epidermal dermatophytosis. These dermatomycoses are best treated with oral agents such as terbinafine, itraconazole, or fluconazole; secondary prophylaxis is often necessary. In chronically immunosuppressed patients, HPV-induced lesions, that is, verrucae and condylomata, either may be extremely numerous or may form large confluent lesions. Up to

40% of renal transplant recipients develop warts following transplantation, half have more than ten warts, and up to 1% have extensive disease. Skin infections with members of the herpesvirus family, particularly herpes simplex virus (HSV) and varicella-zoster virus (VZV) are very common in immunocompromised patients. For instance, immunocompromised patients may have more serious forms of HSV infection including chronic herpetic ulcers, esophageal or respiratory tract infection, or disseminated infection.

3. Opportunistic Primary Cutaneous Infection Following inoculation into the skin, organisms of low virulence can cause local or disseminated infections in patients with impaired immune defenses. Localized disease can be caused by Paecilomyces, atypical mycobacteria, and Prototheca. Localized disease with life-threatening systemic spread may be caused by Pseudomonas aeruginosa, Aspergillus species, Candida species, and Rhizopus species. Primary infection caused by Aspergillus, Rhizopus, or Candida species arises at localized cutaneous sites, but has the potential for disseminated disease in the compromised host. Primary cutaneous infection with these fungi has been associated with use of adhesive or Elastoplast tape, cardiac electrode leads, or extravasation of intravenous fluids. Aspergillus and Rhizopus species can invade blood vessels, resulting in infarction, hemorrhage, and hematogenous dissemination.

4. Systemic Infection Metastatic to Cutaneous and Subcutaneous Sites In a report of dermatologic manifestations of infection in immunocompromised patients, 8 of 31 patients (26%) had apparent spread of systemic infection to cutaneous and subcutaneous tissues.[2] In 6 of these 8 patients, cutaneous or subcutaneous lesions were the first clinical signs of disseminated infection. In immunocompromised hosts, cutaneous lesions resulting from hematogenous spread of infection are caused, in general, by three classes of pathogens: (1) Pseudomonas aeruginosa and other bacteria; (2) the endemic systemic mycoses Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, and Penicillium marneffei, reported primarily in Southeast Asia; and (3) the ubiquitous opportunistic organisms Aspergillus species, Cryptococcus neoformans, Candida species, Rhizopus species, and Nocardia species. Hematogenous dissemination of P. aeruginosa to the skin of a compromised patient can result in subcutaneous nodules, cellulitis, or necrotizing soft-tissue infection (ecthyma gangrenosum). The usual setting is profound granulocytopenia, often with acute leukemia. Ubiquitous opportunistic fungi and Nocardia species can cause asymptomatic pulmonary infections which, in the compromised host, disseminate hematogenously. Candida

PATHOGENIC FACTORS INVOLVING INFECTIONS IN TRANSPLANT DERMATOLOGY

usually disseminates from the GI tract or an infected intravascular line. Disseminated cryptococcosis often present with cutaneous lesions (molluscum contagiosum-like facial lesions), subcutaneous nodules, or cellulitis prior to the clinical presentation of meningitis. Disseminated histoplasmosis also presents on the skin with molluscum contagiosum-like facial lesions, guttate psoriasis-like lesions, as well as other morphologies. Nocardia disseminates from pulmonary infection, resulting in subcutaneous nodules.

CONSIDERATIONS OF TIME FRAME FOR I NF E C T I O N S IN TH E SO L I D O R G A N T R A NS P L A NT P A TI E N T As the protocols for managing immunosuppression have become sufficiently standardized in the solid organ transplant population, a time course of different infections can be delineated. This reflects the influence of immunosuppressants (type and duration) in determining infection susceptibility, as well as the environmental factors contributing to types of pathogens. Data on the timing of infections also helps guide prophylaxis schedules. In Figure 9.1, a timetable of infection after solid transplantation can be broken down into 3 parts:

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(1) first month posttransplant, (2) one to six months posttransplant, and (3) more than six months posttransplant. The first month posttransplant constitutes the highest state of immunosuppression. Latent infections in both the recipient and the donor organ may emerge during this time period. Latent viruses within the host such as herpes viruses typically reemerge during this time frame but do not always come to clinical attention. More recently, undiagnosed or asymptomatic infections, such as human immunodeficiency virus (HIV), rabies, and West Nile virus, have been transmitted from organ donor to recipient and present clinically during the early posttransplant period. This critical period also represents the timeframe for infections that may have been acquired during procurement of organ and the transplant operation itself. More than 95% of the infections are of the latter type and incidence may be dependent on the duration and conditions of surgery and the placement of devices that breach the skin barrier, such as vascular access devices and drainage catheters. Perioperative antibiotics aimed at preventing surgical site infection are often successful at managing these iatrogenic causes of infection. In the 1 to 6 months posttransplant period, three categories of infection may be present: (1) lingering infections acquired earlier; (2) viral infections manifest in the posttransplant period

Figure 9.1. Timeline of common skin infections after organ transplantation. Solid line indicates most common period for onset of infection. Dashed line indicates periods of continued risk or persistent infection. Bacterial infections are most commonly seen perioperatively including staphylococcus, streptococcus, and Gram-negative rods. Viral infections, especially herpesvirus family are more commonly reactivated although primary infections can be seen. Several cutaneous manifestations of viruses are seen many years later including infections from HPV. Fungal infections are more commonly seen as opportunistic infections in the 1- to 6-month period; however, transplant patients remain at risk as long as they are on sufficient immunosuppressive agents. (HSV, herpes simplex virus; VZV, varicella zoster virus; CMV, cytomegalovirus; EBV, Epstein–Barr virus; HPV, human papillomavirus; MCV, molluscum contagiosum virus) (Adapted from Rubin RH, Wolfson JS, Cosimi JS, Tolkoff-Rubin NE. Infection in the renal transplant recipient. Am J Med. 1981; 70: 405–411 and Snydman DR. Infection in solid organ transplantation. Transplant Infect Dis 1999; 1: 21–28. With permission.)

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such as with cytomegalovirus, Epstein–Barr virus, human herpesvirus-6, hepatitis B and C, and human immunodeficiency virus; and (3) the emergence of opportunistic infections such as Aspergillus fumigatus. As will be further discussed, several of the viral infections are immunomodulating. Sustained immunosuppression up to this point allows normally commensural flora to invade through breaks in the skin barrier function. Prevention of infections during this period requires noncontaminated air and potable water supply and control of CMV replication and invasion. After 6 months posttransplant, the causes of infection are much more heterogenous, depending on the degree of immunosuppression. Patients with good allograft function and lower immunosuppression levels may experience fewer opportunistic infections than patients in whom acute or chronic allograft rejection necessitates higher levels of immunosuppression. The degree of immunosuppression will also affect the ability of the body to ward off replicating latent viruses such as HPV and HHV-8. The oncogenic potential of these viruses has become a major cause of morbidity and an area where the dermatologist can offer a major contribution in the care of these patients.

D I A G N O S T I C C O N S I D E R A TI O N S O F S K I N I N FE C TI O N S I N T H E C O M P R O M IS E D PATIENT In the immunocompetent patient, the gross appearance of a skin lesion is an important aspect of diagnosis. By contrast, the clinical value of the gross appearance of a cutaneous lesion in a compromised host is more limited, because the lesions may appear atypical secondary to the altered immune response. It is essential to realize that the differential diagnosis of a particular skin lesion in an immunocompromised patient is extensive.

The approach to biopsy of a cutaneous lesion with a suspected infection should include two considerations: (1) The most rapid and most sensitive methods for detecting microbes both histologically and immunologically should be used and (2) appropriate cultures and stains should be obtained to optimize the chance of identifying the pathogen. Tissue sample is preferable to a swab or nonsterile aspirate. A 6- or 8-mm punch biopsy is usually adequate for a skin sample. Half the tissue is sent for histopathologic evaluation by routine methods and also by special stains for fungi, mycobacteria, and bacteria. The other half is sent to the microbiology laboratory to culture for aerobic and anaerobic bacteria, mycobacteria, and fungi (at 25°C and 37°C) and also for GramÕs stain, acid-fast, modified acidfast, and direct fungal stains of touch preparations or ground tissue.

SUM MARY Cutaneous infections in the compromised host, including solid organ transplant recipients, are an important cause of morbidity and may reflect underlying life-threatening systemic infections. The approach presented above highlights the need to maintain a heightened sensitivity to the atypical presentations of these infections. By following an orderly and careful evaluation process, the yield of dermatologic evaluation to the patient will be optimized.

REFERENCES

1. Wolfson, J.S., A.J. Sober, and R.H. Rubin, Dermatologic manifestations of infection in the compromised host. Annu Rev Med 1983;34: 205–17. 2. Bencini, P.L., et al., Cutaneous manifestations in renal transplant recipients. Nephron 1983;34(2):79–83.

Section Four

CUTANEOUS EFFECTS OF IMMUNOSUPPRESSIVE MEDICATIONS

10 Cutaneous Effects of Immunosuppressive Medications

Conway C. Huang, MD

organ transplant patientÕs antirejection regimen. Endogenous CushingÕs syndrome caused by various perturbations in the hypothalamic-pituitary axis (HPA) will not be covered.

LIST OF ABBREVIATIONS

AZA BCC CNI CYA ECS GCS HPA IF-c IL MMF SA SCC SCCis SRL TAC TGF-b TGF-b1 TNF-a VEGF

azathioprine basal cell carcinoma calcineurin inhibitor cyclosporine exogenous CushingÕs syndrome glucocorticosteroid hypothalamic-pituitary axis interferon gamma interleukin mycophenolate mofetil steroid acne squamous cell carcinoma squamous cell carcinoma in-situ sirolimus tacrolimus transforming growth factor beta transforming growth factor beta 1 tumor necrosis factor alpha vascular endothelial growth factor

Clinical Presentation The diagnosis of ECS is a generally straightforward process of observing typical physical stigmata including (in decreasing order of typical frequency) truncal obesity and weight gain, moon facies, striae, ecchymoses, skin atrophy, poor wound healing, hirsutism, acne, and superficial fungal infections (Figure 10.1). Confirmatory diagnostic biochemical tests are not usually performed.[1,2] Mechanism ECS is caused by chronic GCS excess, and its signs and symptoms are directly related to the specific glucocorticoid (peripheral catabolic and central lipogenic effects) effects of the GCS being taken. Although there is variability between individual patients, relevant properties of the steroids themselves include the formulation used, affinity for the GCS receptor, biologic potency, duration of action, dose, and duration of treatment. All available forms of GCS therapy (topical, intradermal, aerosolized, intra-articular, and systemic) have been associated with ECS.[3,4]

INT ROD UCTION The use of powerful immunosuppressive medications has allowed for long-term survival of transplanted solid organs. Unfortunately, as is the case with most pharmaceutical agents, effects other than those intended become manifest with use. These unwanted effects vary from mild nuisances to life-threatening adverse events, which may prevent the use of a needed agent. Although there is overlap between the effects of immunosuppressive drugs, each class of drug also presents distinct problems and challenges. As the prevalence of use of immunosuppressive agents changes, it becomes more important to be familiar with their side effects (Table 10.1).

Treatment PRIMARY TREATMENT

Discontinuation or minimization of GCS therapy is the primary treatment. As this can be complicated, treatment changes should occur under the guidance of qualified specialists. There are three primary complicating issues: (1) possible suppression of the HPA axis with secondary adrenal insufficiency, (2) organ rejection, and (3) steroid withdrawal syndrome.[1,2] P O S S I B L E S UP P R E S S I O N O F T H E HP A A X I S

Despite efforts to understand the effects of short- versus long-term and low- versus high-dose GCS treatment on the HPA axis, it is difficult to accurately predict as to which patient will have HPA suppression. Due to this individual variation in degrees of HPA suppression and rates of recovery from HPA suppression, there is not a predominant method of GCS reduction/withdrawal, and management by qualified specialists is indicated.

C O R T I C O ST E R O I D S

CushingÕs syndrome For the specialized purposes of this text, this discussion will focus on cutaneous findings of exogenous CushingÕs syndrome (ECS), that is, CushingÕs syndrome caused by the administration of glucocorticosteroids (GCS) as part of an

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Table 10.1 Change in Use of Agents for Maintenance Immunosuppression in Kidney Recipients during the First Posttransplant Year, 1994 to 2003 Drug

Common Nonneoplastic Adverse Effects

Use in 1994 (Percentage)

Use in 2003 (Percentage)

Corticosteroids

CushingÕs syndrome Acne Striae Fragile skin Hirsutism Sebaceous hyperplasia Gingival hyperplasia Gynecomastia Alopecia Hypersensitivity reactions Nonspecific rash Acne Impaired wound healing Acne/folliculitis Edema

99.6

85.2

93.2

26.9

9.8 85.2 0.6

72.4 2.8 81.7

0.3

20.9

Cyclosporine

Tacrolimus Azathioprine Mycophenolate Mofetil Sirolimus

HHS/HRSA/HSB/DOT. 2005 OPTN/SRTR Annual Report 1995–2004 (http://www.hrsa.gov/)

O R GA N RE J E C T I O N

Patients who experience organ rejection, should, in the short term, have their GCS dose increased to a level that nullifies rejection processes. Subsequently, the tapering process can best be summarized by reduction from supraphysiologic to physiologic doses, as allowed by symptoms of organ rejection, in combination with initiation of steroid-sparing agents as appropriate, while monitoring for and avoiding symptoms of adrenal insufficiency and allowing for adequate adrenal recovery. Reduction can occur over periods of 12 months or more.

vent rejection until the appropriate time to initiate a steroidsparing, long-term immunosuppressive regimen. Although it is important not to use an unnecessarily high dose, insufficient levels of GCS can also be detrimental, resulting in organ

S T E R O I D W I T H D RA W A L S Y N D RO M E

Steroid withdrawal syndrome is the least well-understood and rarest of the three. It is characterized by lethargy, malaise, anorexia, headaches, and even fever or desquamation of the skin. Upon testing, these patients have normal HPA axis function. It is felt that these patients are psychologically dependent on their steroids, and they do not appear to be in danger of collapse of the cardiovascular system or other extreme effects of adrenal insufficiency. SECONDARY TREATMENT

In instances where corticosteroid therapy cannot be reduced to accomplish resolution of symptoms of ECS, or when a steroid taper will require a lengthy period of time, treatment of individual symptoms as they occur should be undertaken. Examples of approaches include appropriate diet restriction for obesity, laser hair removal or antiandrogen therapy for hirsutism, appropriate treatment for acne or superficial fungal infections, and proper wound care for tissue trauma to atrophic skin.

Prevention Key for the prevention of ECS is optimal use of GCSs. Optimal use involves employing a dose just sufficient to pre-

Figure 10.1. Cushingoid facies in a renal transplant patient being tapered off of steroids.

CUTANEOUS EFFECTS OF IMMUNOSUPPRESSIVE MEDICATIONS

rejection. If organ rejection occurs, higher than normal doses of GCS may then be required.[1,2,3]

Steroid Acne Clinical Presentation Steroid acne (SA) may occur after administration of topical or systemic GCSs. Topical GCSs may produce erythematous papules and pustules (steroid rosacea), whereas systemic GCSs produce classic SA consisting of monomorphous, erythematous papules and pustules on the upper trunk, often sparing the face (Figure 10.2). Onset of lesions may occur weeks to months after initiation of GCS therapy. The relatively abrupt onset and monomorphous nature of multiple acneiform papules and pustules differs from acne vulgaris, which typically is of slower onset and is composed of acneiform lesions in different stages of development. Additionally, SA frequently involves the scalp and upper trunk while less frequently involving the face, opposite the typical distribution of acne vulgaris. Comedones, cysts, nodules, and scarring, all typical in acne vulgaris, are rarely seen in SA.[5]

tence of Pityrosporum folliculitis with SA, treatment with appropriate topical or systemic antifungals should be considered, especially if the patient is responding poorly to traditional acne-directed treatments.[5,6]

Prevention Given that the most common cofactor in the development of SA and Pityrosporum folliculitis is topical or systemic GCS, judicious administration of these agents is advised.

Striae Clinical Presentation Striae rubra distensae are linear bands of atrophic, wrinkled skin that are initially erythematosus and indurated, eventually becoming hypopigmented and atrophic (Figure 10.3). Typical locations are the thighs, buttocks, breasts, shoulders, and lower back. They can occur from weeks to months after topical or systemic corticosteroid use and can result from direct effects of corticosteroids on the skin or secondarily from weight gain.[7]

Mechanism Although there is information to suggest that, in a significant percentage of patients, what has traditionally been considered SA may, in fact, be due to Pityrosporum folliculitis, the exact pathophysiologic mechanism of SA is unknown. In one study, 26 out of 34 (76%) patients clinically diagnosed with SA had abundant Pityrosporum spore loads on potassium hydroxide examination.[6] Treatment Treatment for SA includes reduction or elimination of the suspected offending GCS, if possible. This change in medications is combined with traditional treatment for acne vulgaris, including topical retinoids, topical and systemic antibiotics, and benzoyl peroxide. Given the likely prevalence or coexis-

Figure 10.2. Steroid acne in a recently transplanted liver transplant recipient secondary to moderate dose steroids. Note small pustule size and monomorphic nature.

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Figure 10.3. Extensive striae after weight loss.

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Mechanism The mechanism of development of striae is unknown, although insights into mechanisms of cutaneous fragility (see section that follows) may also apply to striae. Treatment The only treatment that has shown to be effective, possibly aborting the development of permanent striae, is pulsed-dye laser given while striae are in their early erythematous stage. After striae have passed into the white, atrophic stage, there is no consistently effective treatment. Reported treatments for later stage striae include topical retinoids, topical over-thecounter scar preparations, chemical peels, pressure, cryotherapy, excision and grafting, CO2 laser, erbium laser, and Nd:YAG laser.[7]

important than the potency of the GCS. In producing epidermal thinning, corticosteroids have been shown to reduce the proliferative activity of keratinocytes. With regards to dermal thinning, GCS have been shown to reduce synthesis of type I and type III collagen, reduce the proliferative activity of dermal fibroblasts, reduce fibroblast protein synthesis, decrease tenascin-C gene expression (extracellular matrix protein), decrease production of hyaluronic acid and sulfated glycosaminoglycans, and downregulate synthesis of elastin. Numerous studies have shown that continuous or intermittent use of topical GCS results in a 90% or greater decrease in production of type I and type III collagen. This dramatic reduction in collagen synthesis directly correlates with thinning of the skin.[8,9,10]

Cutaneous fragility and ecchymosis

Treatment Mild atrophy of the skin can be reversible in its early stages if the offending GCS is reduced sufficiently, used on an intermittent basis, or eliminated. Once significant atrophy occurs, it is relatively permanent. There are no specific treatments for ecchymoses as they are usually self-limited. Local wound care is typically prescribed for incidental tearing and lacerations of the skin.

Clinical Presentation Cutaneous fragility presents as skin atrophy and bruising in which both the epidermis and dermis are thinned (Figure 10.4). Tearing and bruising of the skin after mild friction, bandaging, or incidental trauma are associated with this reduction in cutaneous thickness. This typically occurs weeks to months after the initiation of GCS therapy.

Prevention Prevention strategies begin with limiting GCS use. Avoidance of trauma, with special care being taken with bandages or adhesives, can reduce cutaneous tears and ecchymoses. Nonadhesive bandages should be employed whenever possible.

Prevention Minimization of systemic GCS use, avoiding weight gain, limiting use of topical GCS (the least potent effective topical GCS for the shortest duration possible), and the use of nonhalogenated GCS are primary strategies for preventing striae.

Mechanism Cutaneous fragility and ecchymosis can occur after the administration of topical, inhaled, or systemic GCS. In the case of topical administration, the length of use may be more

CALCINEURIN INHIBITORS CYCLOSPORINE

Hirsutism Clinical Presentation Hirsutism of face and body is a frequent, dose-related sideeffect of treatment with cyclosporine A (CYA) (Figure 10.5). In a case series of children, adolescents, and adults, 59% to 86% had CYA-associated hirsutism. Onset is usually measured

Figure 10.4. Cutaneous fragility and ecchymosis in a cardiac transplant recipient on steroids.

Figure 10.5. Hirsutism in a cardiac transplant patient on cyclosporine.

CUTANEOUS EFFECTS OF IMMUNOSUPPRESSIVE MEDICATIONS

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in months. CYA-associated hirsutism can significantly impact the transplant patient, causing depression and dissatisfaction with appearance significant enough to require switching to a different immunosuppressant.[11,12]

Mechanism Studies in mice have shown specific effects from CYA on follicular keratinocytes, giving insight into the mechanism of action in humans. In vivo effects observed include modulation of cytokine production (increased IL-1a and TGF-b, both catagen-associated cytokines), inhibition of the expression of keratinocyte terminal differentiation markers (p21waf/cip1, p27kip1) associated with catagen, inhibition of calcineurindependent nuclear factor of activated T cells (NFAT1), nuclear translocation in follicular keratinocytes (leading to delayed expression of terminal differentiation markers such as involucrin and loricrin), and inhibition of apoptosis-related gene products (Bax, p53) in hair epithelial cells. These effects translated into hair growth in nude mice and retardation of spontaneous catagen induction in depilated normal mice.[11] Prevention Other than minimizing dosage or using alternative immunosuppressive agents, there are no other specific preventative measures or agents currently available. Treatment Treatment options have centered on laser-assisted hair removal or changing to a different immunosuppressive medication. Multiple reports have documented improvement in hirsutism with a change from CYA immunosuppression to tacrolimus (TAC).[12]

Sebaceous hyperplasia Clinical Presentation In most cases, sebaceous hyperplasia presents within several years of the onset of CYA administration. Patients will usually develop multiple, globose, yellow papules primarily in the centrofacial region (Figure 10.6). Case series comparing heart transplant patients taking CYA who have sebaceous hyperplasia to those who do not have shown no significant differences in CYA dosage, interval since transplantation, or mean age. The only significant difference consistently noted was that all affected patients were male. Reported incidences of sebaceous hyperplasia range from 11–17% of organ transplant recipients compared to 1% of nonimmunosuppressed controls.[13] Mechanism The exact mechanism of the development of sebaceous hyperplasia is unknown, although several interesting observations have been made. Because CYA extends the anagen cycle of hair both in vivo and in vitro, it has been reasoned that the proliferative change in hair shaft production may be matched by changes in the associated sebaceous gland. As child solidorgan-transplant patients frequently experience CYA-associated

Figure 10.6. Extensive sebaceous hyperplasia in a renal transplant on cyclosporine.

hypertrichosis but only rarely experience CYA-associated sebaceous hyperplasia, CYA may exert its sebogenic effect on mature, postpubescent pilosebaceous units. Another theory posits that CYA-induced immunosuppression promotes benign neoplastic proliferations of which sebaceous hyperplasia is one.[14]

Prevention Other than reducing or eliminating exposure to CYA, methods of prevention are limited. Theoretically, use of topical retinoids, which have been shown to physically shrink sebaceous glands and reduce sebum output, will moderate or eliminate the development of CYA-associated sebaceous hyperplasia. Treatment Topical retinoids, as noted earlier, may help shrink sebaceous hyperplasia. Given their other side-effects, systemic retinoids are probably not indicated in most cases. Other treatment options include destruction with liquid nitrogen cryotherapy, superficial chemical peels, electrodessication and light curettage, shave removal, pulsed-dye laser, and near infrared laser therapy. Converting the patient from CYA to an equivalent antirejection medication such as TAC has been shown to improve or resolve this CYA-associated cutaneous side-effect without undue risk of rejection of the transplanted organ.[12,14]

Gingival Hyperplasia Clinical Presentation Gingival overgrowth in organ transplant recipients taking CYA became apparent soon after the drug entered widespread usage.[15] The reported incidence has ranged from 30 to 50% of patients taking CYA.[16] Gingival hyperplasia usually begins in the first 3 months after transplantation. It is similar in appearance to phenytoin-induced gingival overgrowth. Growth commonly begins with the anterior labial interproximal gingiva (Figure 10.7). The marginal gingival may become involved to such an extent that it covers portions of the clinical crowns of the teeth.[17]

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Figure 10.8. Diffuse alopecia in a renal transplant patient on tacrolimus. Figure 10.7. Gingival hyperplasia in a lung transplant patient on cyclosporine.

Mechanism Studies have been inconsistent in reporting the effect of dose and serum levels of CYA on the development of gingival hyperplasia in transplant recipients. In a similar manner, some reports have related the risk of gingival hyperplasia in patients taking CYA to the concomitant use of the calcium channel blocker nifedipine. In a study of 236 renal transplant recipients, 48% were found to have gingival hyperplasia, and CYA dose and serum level were the most significant indicators of risk of development. Nifedipine was not a significant factor.[18] CYA has been found to induce a number of growth factors, and, in tissue culture, there is evidence that CYA stimulates gingival keratinocyte growth.[19] Prevention Limiting or avoidance of CYA immunosuppression is the best strategy for prevention. Some studies have suggested that good oral hygiene, including the removal of plaque and treatment of gingivitis, prior to transplantation, might reduce the risk of gingival hyperplasia.[18] Treatment Improvement in gingival hyperplasia has been noted in patients converted from CYA to TAC immunosuppression.[20] The antibiotic azithromycin, both topically and systemically, has also produced marked improvement in cyclosporine-induced gingival hyperplasia.[21] Periodontal surgery may be useful in recalcitrant cases.

TACROLIMUS

Alopecia Clinical Presentation Widespread thinning of scalp hair, occurring at some time after initiation of TAC treatment, has been reported in differ-

ent case series occurring at a mean of 30–422 days (Figure 10.8). In a series of 58 consecutive kidney–pancreas transplants (27 females, 31 males) immunosuppressed with GCS/ CNI (CYA, n = 11, TAC, n = 40)/purine antimetabolite (AZA or MMF), the incidence of clinically significant alopecia in patients receiving TAC was 29% (n = 13). Other possible causes of alopecia were ruled out. Of these 13 patients, 11 were female. Other than female sex, there were no other significant risk factors noted for the development of alopecia. Other factors such as TAC dose, patient age, use of polyclonal or monoclonal antibodies, steroid dose, incidence of biopsy-proven graft rejection, kidney and pancreas allograft function, or development of diabetes mellitus were not found to be associated with alopecia. Although other case series have quoted incidences ranging from 3–10%, the true incidence is probably at least the 29% reported earlier due to the fact that transplant physicians typically will report cosmetic side-effects such as alopecia at a much lower incidence than transplant patients will selfreport.[22]

Mechanism The exact mechanism of TAC-related alopecia is unknown at this time, although the effect appears to specifically be specifically related to TAC. The rapid reversal, sometimes seen with topical minoxidil, indicates that the hair loss is not due to female sex hormones. The fact that most reported cases involve females may reflect the higher prevalence of preexisting androgenetic alopecia in men combined with a heightened sensitivity to alopecia in females. Prevention Other than one of the treatments listed below, there are no effective preventative measures. Treatment Primary treatment involves minimizing the TAC dose or conversion from TAC to CYA. Topical minoxidil has been reported to be effective within weeks.

CUTANEOUS EFFECTS OF IMMUNOSUPPRESSIVE MEDICATIONS

ANTI ME TAB OLIT ES AZATHIOPRINE In recent years, the use of azathioprine (AZA) has declined significantly. The North American Pediatric Renal Transplant Cooperative Study showed that in 1987, the standard tritherapy of prednisone, AZA, and CYA was used in 85% of patients. In 2000, 60% received CYA, 36% received TAC, 74% received mycophenolate mofetil (MMF), and 12% received AZA at day 30 post transplant. This change is largely attributed to the replacement of AZA by MMF in many transplant programs.[23] Short- to medium-term cutaneous side-effects of AZA are primarily limited to hypersensitivity reactions including urticarial, maculopapular, and vasculitic eruptions. Other less common reported side-effects are mucositis, photosensitive eruptions, and increased susceptibility to verrucae, herpes zoster, and Norwegian scabies. Although the increased incidence of skin cancer in transplant patients on immunosuppressive therapy, compared to the general population, is undisputed, the evidence that AZA has either a direct carcinogenic effect or that long-term immunosuppression from AZA monotherapy is a significant risk factor for the development of skin cancer in humans is not definitively quantified. It is believed that those patients who genetically have decreased thiopurine methyltransferase activity are more susceptible to skin cancer development. This was inferred from a study where renal transplant patients who had higher red blood cell levels of the active AZA metabolite 6-thioguanine nucleotide had a higher incidence of skin cancer compared to those who had normal levels and were taking the same dose.[24,25] Ultraviolet A and 6thioguaninine have been demonstrated to be synergistically mutagenic in a cultured cell model.[26] The relative carcinogenicity of AZA is discussed in the final section of this chapter.

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SIROLIMUS

Impaired wound healing Clinical Presentation Wound-healing problems (superficial or fascial wound dehiscence) and fluid collections (superficial or deep lymphoceles, seromas, or hematomas) have been observed to occur in higher frequency in patients taking sirolimus (SRL) when compared to patients on other immunosuppressive regimens (Figure 10.9). A retrospective study of 158 kidney transplant patients was performed to identify SRL-related risk factors associated with wound healing. Patients were divided into two groups: patients treated with MMF/TAC/prednisone (group 1) and patients treated with SRL/TAC/prednisone (group 2). Overall, there were 42 wound complications in 34 patients (22%). Complications comprised superficial and deep-wound dehiscence and superficial and deep-wound fluid collections. The incidence of wound complications was 2.4% for group 1 versus 43.2% for group 2 (p<0.0001). Multivariate, stepwise logistical regression analysis showed only SRL (p<0.001) and hypoalbuminemia (p=0.006) to independently correlate with complication occurrence.[29] In a retrospective study of 15 renal transplant patients receiving SRL/TAC or CYA/prednisone versus 15 matched patients receiving MMF/TAC/prednisone, surgical wound complication rate was 53% in the SRL group versus 7% in the non-SLR group (p=0.014). Complications consisted of hematoma, lymphoceles/seroma, delayed wound healing, or incisional hernia.[30] In a prospective study, investigators compared incidence of wound-healing complications in kidney transplant patients randomized to either SRL/MMF/prednisone or TAC/MMF/ prednisone. In the first phase, patients (n = 77) were included regardless of BMI. In the second phase, patients with a BMI > 32 kg/m2 (n = 46) were excluded and the target trough SRL level was lowered to 10–15ng/ml from 15–20ng/ml. Incidence

MYCOPHENOLATE MOFETIL As noted in the previous section, MMF is now widely used in replacement of AZA. Cutaneous side-effects of MMF have not been widely reported. ‘‘Rash’’ has been reported in 6–8% of renal and up to 22% of cardiac transplant patients taking MMF. Acne as well as peripheral edema and exacerbation of dyshidrotic eczema has been reported in 10% of patients. Well-known side-effects are primarily gastrointestinal, hematological (leucopenia, anemia), and infectious. Nonmelanoma skin cancer does occur in patients treated with MMF, but the frequency does not appear to be dose-dependent and is not greater than that seen with other immunosuppressive agents. From database registries from Australia and New Zealand, the incidence of skin and non-skin carcinomas were noted to be 4% of patients on MMF versus 4.2% in a cohort group on AZA. The relative carcinogenicity of MMF is discussed in the final section of this chapter.[27,28]

Figure 10.9. Impaired wound healing with superficial epidermal sloughing, dehiscence, and early infection after excision of squamous cell carcinoma on the hand of a renal transplant patient on sirolimus.

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of complications (perigraft fluid collections, superficial wound infections, and incisional hernias) was 8% (5/59) in the TAC group and 47% (30/64) in the SRL group (p<0.0001). Multivariate logistic regression analysis showed only SRL (p=0.0001) and BMI (p=0.0021) independently correlated with complications. In the first phase of the study, the SRLrelated wound complication rate was 55% (21/38). After excluding obese patients and lowering SRL trough levels, the wound complication rate in the SRL group dropped to 35% (9/26). There was no difference in 1-year graft survival between the 2 groups, and the 1-year patient survival rate was actually significantly higher in the SRL group (100%) compared to the TAC (95%) group (p=0.011).[31]

Mechanism The inhibitory effect of SRL on growth-factor-driven proliferation of various cell types involved in wound repair, particularly fibroblasts and endothelial cells, is thought to contribute heavily to wound-healing problems, especially when there are coexisting risk factors for impaired wound healing such as obesity, GCS use, diabetes, infection, reoperation, or older age.[32,33] Prevention Although surgical wound complications in patients receiving SRL do not generally affect graft or patient survival if managed aggressively, the options of delayed SRL use until wound healing is relatively complete, using the minimal dose possible or an alternative agent in obese patients, and avoidance of simultaneous perioperative GCS use, warrant serious consideration as preventative measures. A prospective study showed the beneficial effect of GCS avoidance (peri- and postoperative) on wound healing in transplant patients. Renal transplant patients (n = 109) received induction with antithymocyte globulin, SRL (target trough, 8–12 ng/ml), CYA (target trough, 100 ng/ml, discontinued between 3–6 months), and MMF (2 g/d). These were compared to a historical control group of 72 patients who received CYA/MMF/long-term maintenance with GCS (mean prednisone dose at 1 month was 13 mg; at 12 months, 8 mg). Although there was no significant difference between the groups in terms of wound hernia, wound dehiscence, wound abscess, or wound erythema, the GCS avoidance group had a significantly lower incidence of lymphocele (6% vs. 16%, p=0.02) and total wound-healing complications (14% vs. 28%, p=0.03).[34] Treatment Treatment of SRL-associated wound-healing complications is generally straightforward and complication-specific. Wound dehiscence is treated with either surgical intervention (debridement with or without closure) or granulation. Infection/cellulitis is treated initially with empiric antibiotic coverage followed by culture and sensitivity-directed antibiotic treatment. Wound fluid collections can be managed conservatively or be drained. In severe cases, the patient can be

switched to an immunosuppressive regimen that has a less detrimental effect on wound healing such as TAC.

Acne / folliculitis Clinical Presentation In a prospective review of 80 renal transplant patients taking SRL in combination with other immunosuppressive agents, the following pathologies of the pilosebaceous unit were observed: acnelike eruption (46%), scalp folliculitis (26%), hidradenitis suppurativa (12%), chronic skin folliculitis (14%), furuncles (11%), and stye or chalazion (5%) (Figure 10.10). This compares to retrospective studies that have estimated the frequency of acnelike lesions at 15–25%. The median time to development of acnelike lesions was 1 month. Interestingly, pilosebaceous pathologies were significantly sexdependent with 75% of the 48 men and 6% of the 32 women affected. Acnelike eruptions were mostly facial and truncal and were associated with scalp folliculitis in 53% of cases. Retentional components (comedones, cysts) were observed in only 21%, but inflammatory components (papules, pustules) were observed in 95% of cases. Hidradenitis suppurativa was not noted to be sex-dependent or associated with acnelike eruptions.[35] Mechanism The mechanism through which individuals receiving sirolimus develop this acnelike eruption is unknown. The fact that men are much more strikingly involved than women may give insight into the pathogenesis. Prevention There are no known effective preventative measures. Treatment Standard treatments for acne and hidradenitis, including topical antibiotics, benzoyl peroxide, and retinoids, and systemic antibiotics and retinoids are indicated as needed.

Figure 10.10. Acneiform eruption associated with sirolimus in a cardiac transplant patient.

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Edema Clinical Presentation In a retrospective review of 175 liver transplant patients, 62 (35%) had some type of edema (Figure 10.11). All patients had a GCS taper for 3 months with a subsequent CNI/SRL regimen. Twenty-four percent of patients were maintained on SRL monotherapy. SRL was started at an average of 732 days (range 1–1,647) after transplantation. The types of edema experienced were leg (57%), generalized (6%), upper extremity (3%), and facial (2%). Joint pain was significantly associated with leg edema in 25%. Leg edema, regardless of severity, was almost always asymmetric and painful enough to interfere with daily activities. Edema generally did not respond to diuretics or a decrease in SRL level. Discontinuation of SRL usually resulted in improvement within weeks to months. There was no significant association between edema and SRL dosage, TAC dosage, reason for or time from liver transplantation, time from starting SRL, patient age, or past medical history for MI or DVT. Of the 91 patients who experienced some type of SRL-related complication, 32 (35%) discontinued therapy with either resolution or improvement in their edema.[36] In a prospective review of 80 renal transplant patients taking SRL in combination with other immunosuppressive

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agents, edemas were noted in 65%. These consisted of chronic edemas (>1 month duration, resistant to diuretics, and without local, renal, or cardiac causes) in 55% of patients and angioedemas (acute SQ edema present >4 days) in 12% of patients. Chronic edemas involved the lower extremities in 98% and were observed to occur in 1 of 3 patterns: exacerbation of previous edema (18%), early-onset edema (development <1 month after SRL introduction) (38%), and late-onset edema (development >2 months after SRL introduction) (44%). Pattern 1 was 86% female (p=0.02), and edemas involved the lower extremities in 100% of patients and the upper extremities in 14% of patients. Pattern 2 had edema develop in a mean of 3 days, and edemas involved the lower extremities in 100% of patients and the upper extremities in 13% of patients. Pattern 3 had edema develop in a median of 16 (range 2–59) months of SRL treatment. In 65% of these cases, edema occurred after a leg trauma (45%), an inflammatory disease (36%), or local infection (18%). In 82% of these cases, the edema was asymmetric (p=0.04). This study also examined the incidence of angioedemas. The overall incidence was 15%, with 92% involving the face and 58% involving the oral cavity. In 92% of the patients, angioedema resolved without treatment whereas 8% required systemic GCS for treatment. In 83% of patients, the angioedema was recurrent, recurring from 2–25 times at the same location.[35]

Mechanism The exact mechanism of SRL-induced edema is unknown, but it is speculated that SRL may cause vasculitis, lymphatic obstruction, or even capillary leak syndrome. The SRLFKBP12 complex inhibits the growth of vascular smoothmuscle cells. This could involve the entire arterial network, thus altering local blood pressure and increasing edema formation. SRL reduces the production of VEGF which, in turn, might affect local vascular permeability and favor the occurrence of edemas. SRL promotes endothelial cell prostacyclin release, which may cause vasodilation and edema. It is noteworthy that angioedemas associated with angiotensin-converting enzyme inhibitors (ACEI) have also been reported in organ transplant patients. They have been observed to occur anywhere from hours to years after ACEI introduction. Their prevalences are estimated at 1% and 5% in renal and cardiac transplant patients respectively versus 0.1% to 0.5% of the general population.[35,36] Prevention From the preceding observations, the only seemingly controllable factors pertain to the late-onset edemas where avoidance of leg trauma and local infection seem prudent and to angioedemas where limitation or elimination of ACEI and/or angiotensin II receptor antagonists is recommended.[37,38]

Figure 10.11. Bilateral lower extremity edema in a renal transplant patient on sirolimus.

Treatment Medical optimization of extremity edema including dietary restrictions, normalization of blood pressure, and

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Table 10.2 Influence of immunosuppressive agents on skin cancer formation Agent

Direct Effect

General Effect

Overall Risk

Corticosteroids Cyclosporine A Tacrolimus Azathioprine

None known Increased TGF-b, IL-6, and VEGF Carcinogen; possible increased TGF-b Intercalation at the DNA level; synergy with UVA None known Antineoplastic

Immunosuppression Immunosuppression Immunosuppression Immunosuppression

+ ++++ +++ +++

Immunosuppression Immunosuppression

+++ +(Early, no long-term data)

Mycophenolate mofetil Sirolimus

compression therapy is indicated. Because diuretics are not often successful, discontinuation of SRL may be necessary. The management of angioedemas escalates from the avoidance of any known inciting factors, to systemic antihistamines and GCS, to epinephrine and airway support.

R E L A T I VE E F F E C T S OF V A R I O U S I MM U NO SU P P R E SS IV E A G E NT S I N T H E D E V E L O P M E N T O F SK I N C A N C E R There is strong evidence to support the assertion that the risk of skin cancer after transplantation closely correlates with the level of and the cumulative exposure to immunosuppression. Exposure to chronic immunosuppression severely depresses specific components of host immunity including both antitumor immune surveillance and antiviral activity. Put another way, immunosuppression from any source results in a general procarcinogenic effect. Additionally, there has been recent evidence that some immunosuppressant agents have direct procarcinogenic effects, whereas others may have anticarcinogenic effects. Therefore, the types of drugs used for induction and maintenance of immunosuppression and the duration of treatment with these agents influence both the incidence and types of cancer that develop. In general, these observations support immunosuppression minimization as a strategy to diminish the incidence of malignancy. This can be accomplished through diversification of immunosuppression regimens, potentially minimizing the toxicity of any individual agent. On the other hand, administering sufficient immunosuppression to avoid rejection is critical as well. Treatment of rejection often requires significantly higher levels of immunosuppression, thus potentially eliminating any benefit obtained by minimizing induction immunosuppression. Because opposing strategies are intimately linked, equilibrium between rejection and overimmunosuppression must be established. Determining the relative contribution of individual immunosuppressive drugs to the development of skin cancer has been difficult to quantify for several reasons. First, the latency period between initiation of immunosuppressive therapy and development of skin cancers is generally a minimum

of 5 years and can be much longer for patients grafted at a young age. Recently introduced immunosuppressant agents have not been in use long enough to have sufficient long-term data and follow-up that extends beyond the typical latency period. Second, there are coexisting and confounding carcinogenic influences such as UV-radiation exposure, skin type, and infection with oncogenic serotypes of human papilloma virus. Third, there are certain individual genetic factors including polymorphisms in p53 codon 72, glutathione S-transferases, and IL-10 promoter that are associated with the occurrence of skin cancer. Lastly, most immunosuppressive regimens are composed of multiple immunosuppressive agents making it difficult to discern the specific carcinogenic effects of an individual agent.[39,40] Given these limitations, a review of the most recent available information will be presented regarding the relative carcinogenicity of the following agents: GCS, AZA, CNI (CYA and TAC), MMF, and SRL (Table 10.2).

Corticosteroids GCS exert a carcinogenic effect through their general immunosuppressive effects. In exerting their immunosuppressive effects, GCS diffuse freely across cell membranes and bind to high-affinity cytoplasmic GCS receptors. This GCS receptor– steroid complex translocates to the nucleus, where it binds to the GCS response element within DNA. The GCS receptor– steroid complex may also bind to other regulatory elements, inhibiting their binding to DNA. Both actions cause transcriptional regulation, thereby altering the expression of genes involved in immune and inflammatory responses. GCS affect the number, distribution, and function of all type of leukocytes and endothelial cells. In nonlymphoid cells, steroids cause a decrease in the production of vasoactive and chemoattractant factors and lipolytic and proteolytic enzymes. In a population-based, case-control study of nontransplant patients taking systemic and/or inhaled GCS, patients having 592 BCCs and 281 SCCs were compared to 532 matched controls. Using unconditional logistic regression analysis to compute odds ratios associated with GCS use for 1 month or longer, while controlling for potential confounding factors, risk was increased for SCC (adjusted odds

CUTANEOUS EFFECTS OF IMMUNOSUPPRESSIVE MEDICATIONS

ratio=2.31, 95% CI 1.27–4.18) and modestly elevated for BCC (adjusted odds ratio=1.49, 95% CI 0.9–2.47) among users of systemic GCS. There was no effect detected with inhaled GCS. Although specific dosages and the concurrent ingestion of other immunosuppressive medications were not investigated, this study does give a unique look into the probable relative carcinogenic effect of systemic GCS.[41] In general, GCSs are felt to have a mild nonspecific carcinogenic effect resulting from their general immunosuppressive effects. This carcinogenic effect appears to be more potent for SCC, compared to BCC.

Azathioprine AZA exerts a carcinogenic effect through its general immunosuppressive effects and through a possible direct carcinogenic effect. As a purine analog, AZAÕs immunosuppressive effects are directly related to its ability to inhibit purine synthesis and metabolism. It is a prodrug of 6-mercaptopurine and acts by preventing gene replication and cell division, thus directly inhibiting the growth and differentiation of immune cells. In addition to blocking cell-mediated immunity, it inhibits primary antibody synthesis and decreases circulating monocytes and granulocytes. It is believed that those patients who genetically have decreased or inferior thiopurine methyltransferase activity are more susceptible to skin cancer development. This was found in a study where renal transplant patients who had a higher red blood cell level of the active AZA metabolite 6thioguanine nucleotide had a higher incidence of skin cancer compared to those who had normal levels and were taking the same dose.[25] AZA, via the accumulation of 6-thioguanine, is believed to exert a direct carcinogenic effect by intercalation at the DNA level, inhibiting repair splicing, and eliciting codon misreads.[24,42] It has been demonstrated that in cultured cells with 6-thioguanine substituted DNA, UVA exposure generates increased reactive oxygen species which have been implicated in the development of skin cancer.[26] In a retrospective study of 25,765 first-time kidney transplant patients from 1995–2001 using Medicare billing claims, use of AZA was associated with an increased relative risk of 1.17 (95% CI 1.01–1.37, p=0.0408) for nonmelanoma skin cancer.[43] As noted, AZA has a carcinogenic effect through its general immunosuppressive effects and may have a direct carcinogenic effect. Because AZA has such a long history of use as an immunosuppressant in organ transplantation and duration of immunosuppression is so highly associated with skin cancer development, AZA is strongly linked by many clinicians to the skin cancer risk after transplantation. This long-term use of AZA may exaggerate the impression of risk relative to other immunosuppressants.

Cyclosporine CYA exerts a carcinogenic effect both through its immunosuppressive effects and also through a direct carcinogenic effect. In exerting its immunosuppressive effects, CYA binds to

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cellular proteins called cyclophilins. This complex inhibits the movement of transcription factors into the nucleus, thus blocking IL-2 production and eventually leading to inhibition of T-cell proliferation and differentiation. CYA exerts a direct carcinogenic effect by increasing the production of growth factors (TGF-b, IL-6, and VEGF) that enhance angiogenesis, tumor growth, and metastasis. CYA has also been shown to transform phenotypically noninvasive adenocarcinoma cells (cuboidal epithelium) to an invasive phenotype (membrane ruffling, formation of multiple pseudopodia, and increased cell motility). These phenotypic changes were shown to be dose-dependent, reversible, and preventable with the addition of monoclonal antibodies against TGF-b. Documentation of these effects was performed in vitro to eliminate any confounding effects of CYA on in vivo immune surveillance mechanisms. In vivo, CYA has been shown to enhance tumor growth of several tumor cell lines in severe combined immune deficiency mice.[44] Evidence exists to demonstrate the dose-dependent carcinogenic effect of CYA. In a study of 231 kidney transplant patients where 50% each were randomized to a CYA dose adjusted for trough blood concentrations of either 75– 125ng/ml or 150–250ng/ml, the low-dose group developed fewer skin cancers (15 vs. 8 SCC, 2 vs. 5 SCCis, and 9 vs. 4 BCC, respectively, p=0.05) than the normal dose group. After a mean of 66 months of follow up, both groups had similar renal function and there was no difference in patient or graft survival.[45] CYA has been shown to be more carcinogenic than AZA. McGeown et al. showed in a follow-up study of 1,000 renal transplant recipients that patients on CYA regimens had a greater cumulative incidence of tumors after transplantation than those on AZA regimens.[46] Other large series have shown increases in skin cancer incidence with immunosuppressive triple drug therapy (CYA/ AZA/prednisolone) over two drug therapy (AZA/prednisolone). In a retrospective study involving 2,397 kidney transplant patients, the incidence of skin cancer was studied in patients treated with the following 3 different immunosuppressive regimens: AZA/prednisolone, CYA/prednisolone, or AZA/CYA/prednisolone. After adjusting for age, those taking CYA/AZA/prednisolone had a significantly higher relative risk (2.8, 95% CI 1.4–5.3) of cutaneous SCC than those receiving AZA/prednisolone. Those taking CYA/prednisolone had a higher risk (1.3, 95% CI: 0.44–3.8) of developing cutaneous SCC than those taking AZA/prednisolone.[40] In a similar historical cohort study comparing 180 renal transplant patients treated with CYA/AZA/prednisolone to 82 patients receiving AZA/prednisolone only, the increased relative risk to develop nonmelanoma skin cancer in the group taking CYA was 3.4 (95% CI 1.5–7.48, p=0.003). When analyzed for SCC only, the increased relative risk was 8.4 (95% CI 1.3–54.8, p=0.03).[47] In summary, CYA exerts a significant carcinogenic effect through both general immunosuppressive effects and direct carcinogenic effects (increasing production of growth factors

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(TGF-b, IL-6, and VEGF) that enhance angiogenesis, tumor growth, and metastasis).The risk of developing skin cancer is increased in patients treated with CYA/prednisolone versus AZA/prednisolone, and triple-drug therapy with AZA/CYA/ prednisolone presents a markedly greater risk.

Tacrolimus Much less data and long-term clinical experience is available for TAC compared to CYA. Available studies have shown conflicting results and in general, there is no clear difference in carcinogenic potential between the two. TAC is a macrolide antibiotic isolated from a soil actinomycete, Stretomyces tsukubaenis. Although it is a macrolide like CYA, it differs in its cytosolic binding site. It interacts with the FK binding protein and inhibits T-cell-derived lymphokines, including IL-2, 3, and 4, and IF-c, and inhibits clonal expansion of helper and cytotoxic T-cells. It also increases production of TGF-b. It blocks T-cell activation by a mechanism similar to that of CYA.[48,49] Other than increasing production of TGF-b, TAC does not having an obvious direct carcinogenic effect. Early in the use of TAC, there appears to be no significant difference in carcinogenic potential between TAC and CYA.

Mycophenolate mofetil MMF exerts a carcinogenic effect through its general immunosuppressive effects. MMF is the ethyl ester of the fungal antibiotic mycophenolic acid, a weak organic acid isolated from Penicillium stoloniferum, which inhibits the de novo purine biosynthesis pathway in B and T lymphocytes. In vivo, it is metabolized to mycophenolic acid, which noncompetitively inhibits eukaryotic inosine monophosphate dehydrogenase (IMP-DH) and blocks conversion of inosine-5-phosphate and xanthine-5-phosphate to guanine-5-phosphate, a necessary precursor for the synthesis of RNA and DNA. MMF thus preferentially affects those cell types that rely predominantly upon de novo purine biosynthesis rather than the salvage pathway for replication. The cell populations in the former category include T and B lymphocytes, which not only lack the salvage pathway, but also possess an IMP-DH isoform to which MMF has a particular affinity. Therein lies the selective advantage offered by MMF. MMF has been reported to inhibit antibody production, generation of cytotoxic T cells, and proliferation of fibroblasts, endothelial cells, and arterial smooth muscle cells. MMF may also inhibit recruitment of leukocytes into sites of inflammation and graft rejection, but it seems to have no effect on the release of cytokines associated with T-cell signal transduction, such as IL-1 and IL-2, and, therefore, to be ineffective in treating acute graft rejection. It is now widely used as a replacement for AZA. Although there is preliminary information showing that the risk of developing lymphoma is not elevated, there is no good information yet available on the relative increased risk of skin cancers. Nonmelanoma skin cancer does occur in patients treated with MMF, but the fre-

quency does not appear to be dose-dependent and is not beyond that seen with other immunosuppressive agents.[50] In a systematic review comparing the safety of MMF and AZA in renal transplantation, Medline, Embase, Cochrane library, and Chinese Biomedicine database were searched for randomized clinical trials. Twenty trials including 6,387 patients were identified. There were no significant differences between skin cancer incidences in the MMF (2 gm/d or 3 gm/ d) versus AZA groups. Interestingly, the skin malignancy incidence on MMF 3 gm/d was significantly lower than on 2 gm/ d (RR 0.54, p<0.05) at 3 years post transplantation.[51] There is no obvious explanation for this difference. Overall, MMF appears to have a general carcinogenic effect through its general immunosuppressive effects, somewhat equivalent to that of AZA.

Sirolimus In contrast to the previously discussed immunosuppressive agents, SRL seems to exert an anticarcinogenic effect through several mechanisms. SRL is a bacterial macrolide antibiotic produced by Streptomyces hygroscopicus, originally isolated from a soil sample from Easter Island (Rapa-Nui). Antineoplastic effects of SRL appear to be mediated by direct inhibition of cancer cell replication, induction of apoptosis, inhibition of IL-10 production, and inhibition of tumor angiogenesis through inhibition of vascular endothelial cell proliferation by both decreasing the expression of VEGF and inhibiting the mitogenesis of vascular endothelial cells in response to VEGF. SRL also inhibits secretion of TGF-b1. SRL has been shown to inhibit various UVB-induced cellular carcinogenic mechanisms such as the expression of matrixdegrading metalloproteinases (MMP1 and MMP3), TNF-a (SRL applied topically before UV exposure protected mice from TNF-a related contact hypersensitivity), and p53 (SRL reduced phosphorylation of p53 after UVB, maintaining the ability of p53 to inhibit TNF-a expression).[52,53] Clinical evidence of SRLÕs effect on cutaneous carcinogenesis concerns kidney transplant patients assessed at 2 years post graft in 5 multicenter studies. The first two studies compared SRL with AZA or placebo in 1,295 patients taking CYA. Two other studies (n = 161) compared SRL to CYA as a base therapy. In the fifth study, patients were randomly assigned at 3 months to either remain on SRL/CYA (n = 215) or to have CYA eliminated and to remain on SRL (n = 215). At 2 years posttransplantation, patients receiving SRL/CYA had a significantly lower incidence of skin cancer compared to traditional therapy. Patients receiving SRL as base therapy had no malignancies compared to 5% of those receiving CYA, and the incidence of malignancy was significantly lower in patients who were on SRL only (CYA elimination), compared to those who remained on SRL/CYA. In summary, SRL may be beneficial in protecting renal transplant patients from skin cancer even when given in combination with CYA.[54] Another study observed 1,008 renal transplant patients treated with a SRL/CYA regimen with or without prednisone

CUTANEOUS EFFECTS OF IMMUNOSUPPRESSIVE MEDICATIONS

over a mean of 62 months (range 27–131). This study found an incidence of skin cancer of 2.4%, significantly lower than the 7% incidence reported for similar renal transplant cohorts.[55] Most recently, clinical trials evaluating the conversion of patients at high risk of skin cancer to SRL have been initiated in the hope of minimizing skin cancer occurrence. Significant insights were obtained from the first 5,000 renal allograft patients treated with SRL when compared with a matched cohort from the Surveillance Epidemiology End Result (SEER) and Cincinnati Transplant Tumor Registry, recently renamed the Israel Penn International Transplant Tumor Registry (IPITTR), databases. The results demonstrated that SRLtreated patients displayed lower incidence of de novo malignancy when compared with a triple immunosuppressive regimen (CNI/antimetabolite/GCS) treated group, supporting the existence of the antineoplastic property of SRL.[52] Kahan et al. reported 10-year follow-up data of renal transplant recipients receiving a SRL/CYA showing an overall rate of skin cancer (1.9%) similar to the general U.S. population as described in the SEER database and lower than other immunosuppressive regimens.[56] In summary, SRL has anticarcinogenic effects through several mechanisms including: direct inhibition of cancer cell replication, induction of apoptosis, inhibition of IL-10 production, inhibition of tumor angiogenesis through VEGF-related mechanisms, inhibition of TGF-b1 secretion, and inhibition of various UVB-induced cellular carcinogenic mechanisms (decreased expression of matrix-degrading metalloproteinases, TNF-a, and p53). In the early years after transplantation, SRL appears to protect transplant patients from skin cancer even when given in combination with CYA. Optimal use of SRL probably calls for conversion from a CNI with or without GCS after initial wound healing from transplant surgery. The long-term effect of SLR on the development of skin cancer in transplant patients is encouraging, but yet to be determined.

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1. Hopkins, RL, Leinung, MC. Exogenous CushingÕs syndrome and glucocorticoid withdrawal. Endocrinol Metab Clin N Am. 2005; 34:371–84. 2. Arnaldi, G, Angeli, A, Atkinson, AB, et al. Diagnosis and complications of CushingÕs syndrome: A consensus statement. J Clin Endocrinol Metab. 2003;88:5593–602. 3. Joe, EK. Cushing syndrome secondary to topical glucocorticoids. Dermatol Online J. 2003;9:16–19. 4. Schacke, H, Docke, WD, Asadullah, K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Therapeutics. 2002;96:23–43. 5. Fung, MA, Berger, TG. A prospective study of acute-onset steroid acne associated with administration of intravenous corticosteroids. Dermatol. 2000;200:43–4. 6. Yu, HJ, Lee, SK, Son, SJ, Kim, YS, Yang, HY, Kim, JH. Steroid acne versus Pityrosporum folliculitis: the incidence of Pityrosporum ovale and the effect of antifungal drugs in steroid acne. Int J Dermatol. 1998;37:772–77. 7. Nuutinen, P, Autio, P, Hurskainen, T, Oikarinen, A. Glucocorticoid action on skin collagen: overview on clinical significance and consequences. J European Acad Dermatol Venereol. 2001;15:361–62.

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8. Oikarinen, A, Haapasaari, KM, Sutinen, M, Tasanen, K. The molecular basis of glucocorticoid-induced skin atrophy: topical glucocorticoid apparently decreases both collagen synthesis and the corresponding collagen mRNA level in human skin in vivo. Br J Dermatol. 1998;139:1106–10. 9. Nuutinen, P, Riekki, R, Parikka, M, Salo, T, Autio, P, Risteli, J, Oikarinen, A. Modulation of collagen synthesis and mRNA by continuous and intermittent use of topical hydrocortisone in human skin. Br J Dermatol. 2003;148:39–45. 10. Korting, HC, Unholzer, A, Shafer-Korting, M, Tausch, I, Gassmueller, J, Nietsch, KH. Different skin thinning potential of equipotent medium-strength glucocorticoids. Skin Pharmacol Appl Skin Physiol. 2002;15:85–91. 11. Gafter-Gvili, A, Sredni, B, Gal, R, et al. Cyclosporin A-induced hair growth in mice is associated with inhibition of calcineurin-dependent activation of NFAT in follicular keratinocytes. Am J Physiol Cell Physiol. 2003:284(6):C1593–1603. 12. Burrows, L, Knight, R, Genyk, Y, et al. Conversion to tacrolimus to ameliorate cyclosporine toxicity in kidney recipients. Transplantation Proc. 1998;30(5):2030–32. 13. de Berker, DA, Taylor, AE, Quinn, AG, et al. Sebaceous hyperplasia in organ transplant recipients: shared aspects of hyperplastic and dysplastic processes? J Am Acad Dermatol. 1996;35(5 Pt 1):696–699. 14. Boschnakow, A, May, T, Assaf, C, et al. Ciclosporin A-induced sebaceous gland hyperplasia. Br J Dermatol. 2003:149(1):198–200. 15. Macoviak JA, Oyer PE, Stinson EB, Jamieson SW, Baldwin JC, Shumway NE. Four-year experience with cyclosporine for heart and heart-lung transplantation. Transplant Proc. 1985;17(Suppl 2): 97–101. 16. Seymour RA, Thomason JM, Ellis JS. The pathogenesis of druginduced gingival overgrowth. J Clin Periodontol. 1996;23:165. 17. Meraw SJ, Sheridan PJ. Medically induced gingival hyperplasia. Mayo Clin Proc. Dec 1998;73(12):1196–99. 18. Thomas DW, Newcombe RG, Osborne GR. Risk factors in the development of cyclosporine-induced gingival overgrowth. Transplantation. Feb 27 2000;69(4):522–26. 19. Lauer G, Mai R, Pradel W, Proff P, Gedrange T, Beyer J. Influence of Cyclosporin A on human gingival keratinocytes in vitro. J Craniomaxillofac Surg. Sep 2006;34 Suppl 2:116–22. 20. Kohnle M, Lutkes P, Zimmermann U, Philipp T, Heemann U. Conversion from cyclosporine to tacrolimus in renal transplant recipients with gum hyperplasia. Transplant Proc. Nov 1999;31(7A): 44S–45S. 21. Argani H, Pourabbas R, Hassanzadeh D, Masri M, Rahravi H. Treatment of cyclosporine-induced gingival overgrowth with azithromycin-containing toothpaste. Exp Clin Transplant. Jun 2006; 4(1):420–24. 22. Tricot, L Lebbe, C, Pillebout, E, et al. Tacrolimus-induced alopecia in female kidney-pancreas transplant recipients. Transplantation. 2005;80(11):1546–49. 23. Smith, JM, Nemeth, TL, McDonald, RA. Current immunosuppressive agents: efficacy, side effects, and utilization. Pediatr Clin N Am. 2005;50:1283–300. 24. Anstey, AV, Wakelin, S, Reynolds, NJ. Guidelines for prescribing azathioprine in dermatology. Br J Dermatol. 2004;151:1123–32. 25. Lennard, L, Thomas, S, Harrington, CI, et al. Skin cancer in renal transplant recipients is associated with increased concentrations of 6-thioguanine nucleotide in red blood cells. Br J Dermatol. 1985;113:723–29. 26. OÕDonovan P. Perrett CM. Zhang X. Montaner B. Xu YZ. Harwood CA. McGregor JM. Walker SL. Hanaoka F. Karran P. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science. 309(5742):1871–4, 2005 Sep 16 27. Kulkarni, AA, Shah, B. Mycophenolate mofetil: A promising immunosuppressive agent. J Assoc Physicians India 2004;52:33–8.

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28. Lindenfeld, J, Miller, GG, Shakar, SF, et al. Drug therapy in the heart transplant recipient. Part II: Immunosuppressive drugs. Circulation. 2004;110:3858–3865. 29. Valente, JF, Hricik, D, Weigel, K, et al. Comparison of sirolimus versus mycophenolate mofetil on surgical complications and wound healing in adult kidney transplantation. Am J Transpl. 2003;3: 1128–34. 30. Troppmann, C, Pierce, JL, Gandhi, MM, et al. Higher surgical wound complication rates with sirolimus immunosuppression after kidney transplantation: A matched-pair pilot study. Transplantation. 2003;76(2):426–9. 31. Dean, PG, Lund, WJ, Larson, TS, et al. Wound-healing complications after kidney transplantation: A prospective, randomized comparison of sirolimus and tacrolimus. Transplantation. 2004;77: 1555–61. 32. Azzola, A, Havryk, A, Chhajed, P, et al. Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation. Transplantation. 2004;77:275–80. 33. Flechner, SM, Zhou, L, Derweesh, I, et al. The impact of sirolimus, mycophenolate mofetil, cyclosporine, azathioprine, and steroids on wound healing in 513 kidney-transplant recipients. Transplantation. 2003;76:1729–34. 34. Rogers, CC, Hanaway, M, Alloway, JW, et al. Corticosteroid avoidance ameliorates lymphocele formation and wound healing complications associated with sirolimus therapy. Transplant Proc. 2005;37: 795–7. 35. Mahe, E, Morelon, E, Lechaton, S, et al. Cutaneous adverse events in renal transplant recipients receiving sirolimus-based therapy. Transplantation. 2005;79:476–82. 36. Montalbano, M, Neff, GW, Yamashiki, N, et al. A retrospective review of liver transplant patients treated with sirolimus from a single center: An analysis of sirolimus-related complications. Transplantation. 2004;78:264–8. 37. Stallone, G, Infante, B, Di Paulo, S, et al. Sirolimus and angiotensinconverting enzyme inhibitors together induce tongue oedema in renal transplant patients. Nephrol Dial Transplant. 2004;19:2906–2908. 38. Kuypers, DRJ. Benefit-risk assessment of sirolimus in renal transplantation. Drug Safety. 2005;28:153–181. 39. Dantal, J, Soulillou, JP. Immunosuppressive drugs and the risk of cancer after organ transplantation. NEJM. 2005;352:1371–1373. 40. Jensen, P, Hansen, S, Moller, B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40:177–86. 41. Karagas, MR, Cushing, GL, Greenberg, ER, et al. Non-melanoma skin cancers and glucocorticoid therapy. Br J Cancer. 2001;85: 683–86.

42. Swann, PF, Waters, TR, Moulton, Dc, et al. Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science. 1996;273(5278):1109–11. 43. Kasicke, BL, Snyder, JJ, Gilbertson, DT, Wang, C. Cancer after kidney transplantation in the United States. Am J Tranplant. 2004;4:905–13. 44. Hojo, M, Morimoto, T, Maluccio, M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature. 1999; 397:530–34. 45. Dantal, J, Hourmant, M, Cantarovich, D, et al. Effect of long term immunosuppression in kidney-graft recipients on cancer incidence: randomized comparison of two cyclosporine regimens. Lancet. 1998;351:530–34. 46. McGeown, MF, Douglas, JF, Middleton, D. One thousand renal transplants at Belfast City Hospital: post-graft neoplasia 1969-1999, comparing azathioprine only with cyclosporine-based regimens in a single centre. In: Cecka JM, Terasaki, PI, eds. Clinical Transplants. 2000. Los Angeles, UCLA Tissue Typing Laboratory 2000: 193. 47. Glover, MT, Deeks, JJ, Raftery, MJ, et al. Immunosuppression and risk of non-melanoma skin cancer in renal transplant patients. Lancet. 1997;349:98. 48. Maluccio, M, Sharma, V, Lagman, M, et al. Tacrolimus enhances transforming growth factor-beta1 expression and promotes tumor progression. Transplantation. 2003;76(3):597–602. 49. Jonas, S, Rayes, N, Neumann, U, et al. De novo malignancies after liver transplantation using tacrolimus-based protocols or CsAbased quadruple immunosuppression with an interleukin-2 receptor antibody or antithymocyte globulin. Cancer. 1997;80:1141–50. 50. Kulkarni, AA, Shah, B. Mycophenolate mofetil: A promising immunosuppressive agent. J Assoc Physicians India. 2004;52:33–8. 51. Wang, K, Zhang, H, Li, Y, Wei, Q, Li, H, Yang, Y, Lu, Y. Safety of mycophenolate mofetil versus azathioprine in renal transplantation: A systemic review. Transplantation Proc. 2004;36:2068–70. 52. Buell, JF, Gross, TG, Woodle, ES. Malignancy after transplantation. Transplantation. 2005;80:S254–S264. 53. Yarosh, DB, Boumakis, S, Brown, AB, et al. Measurement of UVBinduced DNA damage and its consequences in models of immunosuppression. Methods. 2002;55–62. 54. Mathew, T, Kreis, H, Friend, P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplantation. 2004;18:446–9. 55. Kahan, BD, Yakuplogu, YK, Schoenberg, L, et al. Low incidence of malignancy among sirolimus/cyclosporine-treated renal transplant recipients. Transplantation. 2005;80:749–58. 56. Kahan, B, Knight, R, Schoenberg, L, et al. Ten years of sirolimus therapy for human transplantation: The University of Texas at Houston experience. Transplant Proc. 2003;35(Suppl 3A):25S–34S.

Section Five

INFECTIOUS DISEASES OF THE SKIN IN TRANSPLANT DERMATOLOGY

11 Bacterial Diseases in Organ Transplant Recipients

Richard A. Johnson, MD and Jennifer Y. Lin, MD

Ensconced in the nares, S. aureus is able to colonize and infect superficial skin breaks such as around hair follicles (Figure 11.1), skin disruptions from secondary dermatologic disorders (i.e., eczematous dermatitis, herpetic ulcer, molluscum contagiosum), or via vascular access lines or drainage tubes. The spectrum of pyodermas includes folliculitis, furuncles, carbuncles, abscess, impetigo, bullous impetigo, and ecthyma (Figure 11.2). Once established in the skin, S. aureus is able to invade more deeply into the soft tissue with resultant soft-tissue infection, such as cellulitis and necrotizing cellulitis (Figure 11.3). S. aureus can also reach the skin via dissemination from another source of infection. In this form of hematogenous seeding, the lesions can appear nonspecifically as petechiae, hemorrhages, subcutaneous nodules, soft-tissue infections, and pyomyositis. Systemic symptoms including fever may be masked if the patient is on steroids as part of their immunosuppression. S. aureus colonization has been associated with increased risk of soft-tissue infection, especially in the first two months after transplantation. This has been well characterized in the liver transplant patients where pretransplant colonization with methicillin-resistant S. aureus (MRSA) and methicillinsusceptible S. aureus (MSSA) was an independent risk factor for increased S. aureus infections (bacteremia, pneumonia, abscess, wound infection, sinusitis).[2] Treatment of S. aureus carriage with topical mupirocin has been successful in decreasing the rate of infections in postcardiothoracic surgery. It is still unclear whether the same effect will be achieved for OTRs for several reasons: (1) patients may be colonized in other areas on the skin other than nares, (2) there is an increased rate of mupirocin-resistant S. aureus, and (3) many patients subsequently become recolonized.[3] Various strains of S. aureus are capable of producing a variety of toxins, which cause the clinical syndromes of staphylococcal scalded skin syndrome (rare in patients greater than two years of age), staphylococcal scarlet fever, and toxic shock syndrome (TSS). TSS is a febrile, multiorgan disease caused by the elaboration of staphylococcal toxins, characterized by a generalized scarlatiniform eruption, hypotension, functional abnormalities of three or more organ systems, and desquamation after the evolution of the exanthem. Cellulitis caused by S. aureus that produce TSS toxins can be accompanied by the cutaneous and systemic findings of staphylococcal scarlet fever or TSS.[4]

Bacterial infections represent a major cause of morbidity in solid organ transplant recipients (OTRs). Soft-tissue infections from bacteria generally occur in the first month after transplantation when the skin is disrupted by the surgery itself or by indwelling catheters and lines. The incidence of wound infections in solid organ transplant patients ranges from 2 to 56% depending on surgical technique, host characteristics, and antibiotic prophylaxis.[1] The skin flora may also be a source of infection when introduced into normally sterile tissue, such as the transplanted organ itself. Surgical contamination of allografts can lead to pyelonephritis and cystitis in renal transplant recipients, cholangitis and intra-abdominal abscesses in liver transplants, and bronchitis and pneumonia in the lung transplant recipient. If infection is not promptly addressed, bacteremia may ensue and manifest itself to a dermatologist as subcutaneous abscesses from hematogenous spread. In this chapter, we will discuss bacterial infections in solid organ transplant patients. In the setting of immunosuppression, it is helpful to characterize pathogens by their pathophysiology: (1) true pathogens – infection originating in skin and being typical of that which occurs in immunocompetent persons, albeit with the potential for more serious illness in immunosuppressed transplant patients; (2) sometime pathogens – extensive cutaneous involvement with pathogens that normally produce trivial or localized disease in immunocompetent patients; (3) opportunistic pathogens – infection originating from a cutaneous source and caused by opportunistic pathogens that rarely cause disease in immunocompetent patients but that may cause either localized or widespread disease in immunosuppressed transplant patients; (4) indicator of visceral pathogens – cutaneous or subcutaneous infection that represents hematogenous spread from a noncutaneous site. With this framework, we will explore the common cutaneous bacterial pathogens (Table 11.1).

STAPHYLOCOCCUS AUREUS S. aureus causes the majority of all pyodermas and soft-tissue infections seen in solid organ transplant patients. Although not one of the cutaneous resident flora, it colonizes the anterior nares in up to 30% of healthy individuals at any one time, and in more than 50% of chronically ill individuals. The incidence of S. aureus nasal carriage is higher in OTRs, as it is in other immunologically compromised individuals, such as those with HIV disease, diabetes mellitus, or neutropenia. 83

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Table 11.1 Bacterial skin infections in solid organ transplant recipients Pathogen

Type of infection

Clinical presentation

Staphylococcus aureus

Common pathogen causing aggressive/extensive local infection

Group A streptococcus (streptococcus pyogenes)

Common pathogen causing aggressive/extensive local infection

Group B Streptococcus

Common pathogen causing aggressive/extensive local infection

Nocardia

Opportunistic pathogen causing aggressive/local infection +/hematogenous dissemination Opportunistic pathogen causing aggressive/local infection +/- hematogenous dissemination to skin

Primary infection (folliculitis, furuncles, carbuncles, abscess, impetigo, bullous impetigo, and ecthyma) Secondary infection of dermatoses/breaks in integrity of skin Soft-tissue infections (cellulitis) Toxin syndromes (Staphylococcal scalded skin syndrome, toxic shock syndrome, staphylococcal scarlet fever) Primary infection (impetigo, ecthyma) Secondary infection of dermatoses/breaks in integrity of skin Soft-tissue infections (erysipelas, cellulitis, necrotizing cellulitis) Toxin syndromes (Staphylococcal scalded skin syndrome, toxic shock syndrome, staphylococcal scarlet fever) Primary infection (intertrigo of anogenital region) Soft-tissue infection (anogenital region, lower extremities) Abscess, ulcers, granulomas, soft-tissue infection, mycetoma, lymphocutaneous infection; disseminate to lungs, CNS Soft-tissue infection 6 hemorrhagic bullae, 6 abscess, 6 necrosis, 6 ulceration

Gram-negative rods (E. coli, P. aeruginosa, K. pneumonia , P. mirabilis, A. hydrophila) Streptococcus pneumoniae (pneumococcus) Vibrio vulnificus

Bartonella henselae/quintana

Opportunistic/common pathogen with blood vessel invasion and hematogenous dissemination to skin Opportunistic/common pathogen with blood vessel invasion and hematogenous dissemination to skin Opportunistic/common pathogen with blood vessel invasion and hematogenous dissemination to skin

Standard perioperative antibiotics may be administered during transplantation to prevent potentially serious infections, with coverage aimed at skin flora. First-generation cephalosporins are most commonly used. Cultures must always be taken, however, in soft-tissue infections, because of increased prevalence of MRSA, and in order to detect atypical organisms, including fungus and mycobacterium. Vancomycin or linezolid may be employed where MRSA is of significant concern.

B E T A - H E M OL YT I C S TR E P TO C OC C U S Group A beta-hemolytic streptococci (Streptococcus pyogenes) (GAS) commonly colonizes the upper respiratory tract, and sec-

Soft-tissue infection

Soft-tissue infection 6necrosis

Localized or disseminated red-violaceous papules, nodules, plaques; subcutaneous nodules/tumors; disseminate to visceral organs

ondarily infects (impetiginizes) minor skin lesions, from which invasive infection can arise. Impetigo often appears as golden crusts with small vesicles and pustules (Figure 11.4). Certain strains of group A streptococci have a higher affinity for the skin than the respiratory tract and can colonize the skin, subsequently causing superficial pyodermas or soft-tissue infections. Other streptococci, such as Group B streptococci, commonly colonize the perineum and may cause soft-tissue infections at this site. Morbidity and mortality are relatively high for group B streptococcus infections, with a high incidence of bacteremia. Finally, necrotizing fasciitis is a severe form of soft-tissue infection extending into the subcutaneous fat and deep fascia. Immunosuppressed patients are particularly prone to this type

BACTERIAL DISEASES IN ORGAN TRANSPLANT RECIPIENTS

Figure 11.1. Folliculitis/furunculosis, axilla; Methicillin-resistant S. aureus (MRSA). Multiple erythematous nodules surrounding central hair follicles.

of infection. Causes can be monomicrobial (i.e., Beta-hemolytic streptococcus), or polymicrobial (non-group A streptococcus plus anaerobes). Pain out of proportion to physical findings in a patient with evidence of a systemically toxic condition should raise the clinical suspicion of necrotizing fasciitis. Treatment for S. pyogenes necrotizing fasciitis includes clindamycin and gamma globulin in addition to intensive care monitoring and surgical debridement as appropriate. S. pneumoniae can cause a range of infections including otitis media, sinusitis, and more rarely, cellulitis.[10–5] Clinically, affected skin is characterized by bullae formation, brawny erythema, and a violaceous hue. Approximately 50% of cases are the result of pneumococcal bacteremia, often from a pulmonary source, and are associated with a high morbidity. Transplant patients, especially pediatric patients who have the highest exposure risk, are also more likely to have recurrent disease with a mean time of 5.4 months between the first and second infections.[5–6] Studies have demonstrated decreased pneumococcal antibody titers 3 months after transplantation, secondary to the

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Figure 11.2. Large abscess; buttock: MRSA. Multiple MRSA infections had occurred previously; 6 ml of pus were drained from this large abscess. Once MRSA was identified on culture and sensitivities determined, linezolid 600 mg BID was effective in cure of the infection.

suppression of cell-mediated immunity. In the past, prophylaxis has been controversial but recent studies suggest that the polyvalent polysaccharide pneumococcal vaccine is safe and effective for patients with well-functioning allografts and the conjugate vaccine is similarly efficacious in generating a functional antibody response.[6–7,4]

G R A M - N E G AT I V E B A C I L L I Escherichia coli and other Gram-negative bacilli can rarely cause soft-tissue infection, notably in patients with hepatic cirrhosis, nephrotic syndrome and immunosuppression.[7–8] Spontaneous cellulitis secondary to Gram-negative bacilli has been reported posttransplantation, particularly in the setting of edema with no clear portal of entry (Figure 11.5). More than 80% of patients with Gram-negative cellulitis have associated secondary bacteremia from sources such as pneumonia (48.9%)

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Figure 11.3. Cellulitis with bullae formation; foot: S. aureus. Ill-defined brightly erythematous-to-violaceous edematous plaques with epidermal sloughing in renal transplant patient. Interdigital tinea pedis was the portal for bacterial entry into soft tissue.

and central line infections (22.2%).[8–9] Presentation of Gram-negative cellulitis can be characterized by bullous lesions, ulcers, abscesses, or extensive cutaneous necrosis with prominent vascular involvement on pathology. Isolates from the skin have included Klebsiellae pneumonia, E. coli, Pseudomonas aeruginosa[11–10], Proteus mirabilis, and Enterobacter. Initial empiric coverage with gentamicin is helpful until cultures from the blood and skin biopsy return. Mortality rate can be as high as 60% in the presence of bacteremia.[9–11] P. aeruginosa causes the necrotizing soft-tissue infection ecthyma gangrenosum (EG), which occurs as a primary skin infection or as a complication of pseudomonal bacteremia. EG occurs commonly as a nosocomial infection, especially in immunocompromised patients. P. aeruginosa gains entry into the dermis and subcutaneous tissues via adnexal epidermal structures or via areas with loss of epidermal integrity (pressure ulcers, thermal burns, and trauma). EG occurs most frequently in the axillae or anogenital regions but can arise at any cutaneous site. Clinically, EG presents initially as an erythematous, painful plaque that quickly undergoes necrosis. Established lesions show bulla formation, hemorrhage, necrosis, and surrounding erythema. If effective antibiotic therapy is not initiated promptly, the necrosis may often extend rapidly. Bacteremia occurs soon after the onset of EG, and may result in hematogenous spread of P. aeruginosa manifest as subcutaneous nodules and abscesses. Intravenous antibiotic treatment is typically required. Of note, in one institutionÕs study of resistant P. aeruginosa, ciprofloxacin susceptibility was inferior to imipenem, gentamicin, and tobramycin, emphasizing the need to obtain culture for sensitivities and to offer initial double coverage in this susceptible population.[9–11]

Vibrio Vulnificus V. vulnificus is a naturally occurring marine, Gram-negative rod, occasionally contaminating oysters and other shellfish. Either ingestion of raw seafood or exposure of open wounds

Figure 11.4. Impetigo; ankle: Group A streptococcus. Circular erythematous plaque with golden crusting and erosions on renal transplant patient.

to seawater can result in Vibrio bacteremia and soft-tissue infections. The cutaneous lesions begin as erythematous plaques, rapidly evolving to hemorrhagic bullae, and then to necrotic ulcers. Infection by the Vibrio species can lead to fulminant sepsis in immunocompromised hosts and these patients should be warned about eating uncooked seafood. Doxycycline 100 mg by mouth twice daily is the preferred treatment.

Bacillary Angiomatosis Bacillary angiomatosis (BA), characterized by angioproliferative lesions resembling pyogenic granulomas or KaposiÕs sarcoma, has been reported in cardiac transplant patients with high-dose immunosuppression. BA is caused by infection with fastidious Gram-negative bacilli of the genus Bartonella, B. henselae, and B. quintana. Clinically, the cutaneous lesions of BA are red-toviolaceous, dome-shaped papules or nodules, ranging in size from a few millimeters up to 2 to 3 centimeters in diameter.[12] B. henselae in the form of catch-scratch disease has also been reported in a transplant recipient. [13] The antibiotics of

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The most common causative organism is Nocardia asteroides. Although the primary entry point is typically respiratory, this Gram-positive, weakly acid fast bacterium can be directly introduced into the skin of immunocompromised patients or more commonly, the disease may represent hematogenous spread. Primary cutaneous infection can present as abscesses, ulcers, granulomas, soft-tissue infection, mycetoma, or sporotrichoid [lymphocutaneous] infection. In the majority of transplant patients, cutaneous nocardiosis results in disseminated disease with involvement of other organs.[14] Secondary cutaneous infection complicating hematogenous dissemination from the lungs can also present as pustules, abscesses, or nodules. Isolation of Nocardia by culture is preferable but may take a several days to become evident.[15] Trimethoprim-sulfamethoxazole (TMP-SMX) is the treatment of choice, but those on prophylactic antibiotic therapy for P. carinii can still acquire the disease. Long-term therapy is important to prevent reactivation of quiescent disease.

REFERENCES

Figure 11.5. Cellulitis arising in surgical wound infection with necrosis; R-inguinal: E. coli. Expanding, brightly erythematous plaques with necrosis at wound margins.

choice are erythromycin 250–500 mg PO four times daily or doxycycline 100 mg twice daily, continued for 3 months. Relapses are frequent if the duration of treatment is insufficient.

Nocardiosis Aerobic actinomycete can cause a localized or disseminated infection called nocardiosis in the immunocompromised host.

1. Hibberd, P.L. and R.H. Rubin, Renal transplantation and related infections. Semin Respir Infect, 1993;8(3):216–24. 2. Bert, F., et al., Risk factors for Staphylococcus aureus infection in liver transplant recipients. Liver Transpl, 2005;11(9):1093–9. 3. Paterson, D.L., et al., Lack of efficacy of mupirocin in the prevention of infections with Staphylococcus aureus in liver transplant recipients and candidates. Transplantation, 2003;75(2):194–8. 4. Kumar, D., et al., Randomized, double-blind, controlled trial of pneumococcal vaccination in renal transplant recipients. J Infect Dis, 2003;187(10):1639–45. 5. Imhof, A., et al., Fatal necrotizing fasciitis due to Streptococcus pneumoniae after renal transplantation. Nephrol Dial Transplant, 2003;18(1);195–7. 6. Schutze, G.E., et al., Pneumococcal infections in children after transplantation. Clin Infect Dis, 2001;33(1):16–21. 7. Kazancioglu, R., et al., Immunization of renal transplant recipients with pneumococcal polysaccharide vaccine. Clin Transplant, 2000; 14(1):61–5. 8. Yoon, T.Y., S.K. Jung, and S.H. Chang, Cellulitis due to Escherichia coli in three immunocompromised subjects. Br J Dermatol, 1998; 139(5):885–8. 9. Paterson, D.L., et al., Spontaneous gram-negative cellulitis in a liver transplant recipient. Infection, 2001;29(6):345–7. 10. Tsekouras, A.A., et al., Pseudomonas aeruginosa necrotizing fasciitis: a case report. J Infect, 1998;37(2);188–90. 11. Sligl, W., G. Taylor, and P.G. Brindley, Five years of nosocomial Gram-negative bacteremia in a general intensive care unit: epidemiology, antimicrobial susceptibility patterns, and outcomes. Int J Infect Dis., 2006 Jul; 10(4):320–5. 12. Koehler, J.E. and L.M. Duncan, Case records of the Massachusetts General Hospital. Case 30–2005. A 56-year-old man with fever and axillary lymphadenopathy. N Engl J Med, 2005;353(13):1387–94. 13. Dharnidharka, V.R., et al., Cat scratch disease and acute rejection after pediatric renal transplantation. Pediatr Transplant, 2002;6(4); 327–31. 14. Chapman, S.W. and J.P. Wilson, Nocardiosis in transplant recipients. Semin Respir Infect, 1990;5(1);74–9. 15. Wiesmayr, S., et al., Nocardiosis following solid organ transplantation: a single-centre experience. Transpl Int, 2005;18(9);1048–53.

12 Fungal Diseases in Organ Transplant Recipients

Alexandra Geusau, MD and Elisabeth Presterl, MD

F U N G A L S K I N I N FE C TI O N IN OR G AN TRANSPLANT RECIPIENTS – E P I D E M IO LO G Y , DI A G N O SI S , A ND T R E AT M E N T

Types of fungal infections Fungal skin infections in organ transplant recipients include classical dermatomycoses, opportunistic infections, and infections with rare fungal pathogens.

Introduction

Classical Fungal Skin Infections Classical fungal skin infections are typical primary infections also seen in immunocompetent patients, that is, infections with dermatophytes or nondermatophytes, such as Scopulariopsis spp. and Malassezia furfur. In transplant recipients, these infections may differ with regard to the clinical appearance, severity, or course of the disease. The prevalence of infections with dermatophytes in transplant recipients is high, occurring in up to 50% of patients. The most common clinical types observed are the epithelial surface infections tinea cruris and tinea corporis,[11] followed by tinea unguium and tinea pedis. Trichophyton rubrum is the most common pathogen isolated.[11] Transplant recipients may have widespread infection or scalp involvement, otherwise uncommon in adults (Figure 12.1).[12] Occasionally, dermatophytosis may become locally invasive into the dermis, as described for T. rubrum or Microsporum canis, presenting as inflammatory papules and nodules [13,14] (Figure 12.2A and Figure 12.2B). Systemic spread is not reported, because dermatophytes are considered exclusively keratinophilic.[15] Onychomycosis due to dermatophytes with involvement of multiple toe- or fingernails has been seen more commonly in immunocompromised patients than in other subjects. It may present as proximal subungual white onychomycosis, considered pathognomonic of immunosuppression [11,16] (Figure 12.3). Onychomycosis in transplant recipients may also be due to nondermatophyte Scopulariopsis spp. molds which, under immunosuppression, may also cause infection of subcutaneous tissue or fatal systemic infection.[17,18] The nondermatophyte yeast M. furfur is the etiological agent of pityriasis versicolor, clinically characterized by patches of fine scaling and hypo- and hyperpigmentation (Figure 12.4A and Figure 12.4B). It is commonly found in normal human skin, but may cause infection of the hair follicle in patients under immunosuppression.[19]

Organ transplant recipients are susceptible to bacterial, viral, and fungal skin infections. The rates and timing of fungal infections in transplant recipients vary by the type of transplant. Even though most of these infections occur within the first six months of transplantation, patients with rejection episodes who are maintained on higher doses of immunosuppressants remain at risk after this period.[1,2] T-cells and B-cells play a pivotal role in defending the body against invasive fungal infections, as supported by the spontaneous resolution of fungal lesions after discontinuation of immunosuppression.[3] Antifungal prophylaxis and preemptive antifungal therapy in the early posttransplantation period in patients with suspicion of fungal infection may lead to an increase in fungal infections in the later posttransplant phase [1,4] and to the emergence of unusual fungal pathogens that are less susceptible to standard antifungal agents.[5] Overall, organ transplantation and the accompanying use of immunosuppressive agents call for a high index of suspicion for skin infections, appropriate biopsy and culture, and early aggressive therapy, because skin and soft-tissue infections in transplant recipients may be a sign or cause of systemic infection. Despite the importance of skin and soft-tissue infection in transplant recipients, there is only limited data on the epidemiology and rate of fungal infections restricted to the skin in these patients.[6] One of the most common etiologic agents of fungal skin infections in transplant patients is Candida albicans, which causes infections predominantly during the first posttransplant year, and does not affect many new patients thereafter. In contrast, dermatomycoses also affect a substantial number of new patients after the first posttransplant year.[6,7] In a dermatological analysis of 157 kidney transplant recipients, cutaneous mycoses were the most frequent infective skin diseases (82.6%).[8] In a controlled study, the prevalence of infections with Malassezia furfur and C. albicans was higher among kidney recipients compared to a healthy control group, but there was no increased risk of infections with dermatophytes.[9]. This is in accordance with another report about kidney recipients, where the prevalence of onychomycosis was similar to that found in the immunocompetent population.[10]

Opportunistic Infections Opportunistic infections are caused by fungi occurring on the surface of skin and mucous membranes of the human body as saprophytes (e.g., Candida spp.) or ubiquitous in the

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Figure 12.1. Tinea corporis in an immunosuppressed patient: annular scaly lesion with active borders and typical Ôringworm-likeÕ configuration.

environment, such as water, soil, and vegetables, and generally without pathogenic potency for humans, such as Aspergillus, Cryptococcus, Zygomycetes, and Scedosporium spp. In a severely immunocompromised host, virtually any fungus occurring in the environment as saprophyte may lead to an infection with or without involvement of the skin. Forty-five percent of kidney recipients and eighty-four percent of liver recipients have colonization with Candida spp. at different sites of the body, primarily in the oropharyngeal region, without a clinical correlate.[7] Similar data (20– 50%) have been reported for healthy controls. In transplant recipients, colonization with Candida spp. may cause not only infection of the skin and mucous membranes but also rarely invasive disease with dissemination.[7] The localized form, candidiasis of the oral mucosa, or thrush, is the most common fungal infection in transplant recipients, affecting up to 64% of patients.[9,20] It is most prominent during the first posttransplant year [6] and is frequent in patients receiving antibacterial and corticosteroid therapy or wearing dentures.[7] The most frequent pathogen is C. albicans, but also non-albicans species have become increasingly important, among them C. tropicalis, C. krusei, C. glabrata, and C. parapsilosis.[21] The clinical spectrum of oral candidiasis includes glossitis, perle`che (Figure 12.5), and the pseudomembranous and erythematous form (Figure 12.6), the latter being frequently overlooked. The gastrointestinal tract may also be involved (e.g., Candida esophagitis), with gastrointestinal infection being considered invasive disease. Candida infection may also involve the skin folds, nails, and paronychial region; it may present as Candida folliculitis [20] or appear granulomatous, as seen in mucocutaneous candidiasis, a syndrome involving T-cell dysfunction. The incidence of Candida vulvovaginitis does not appear to be more frequent in transplant recipients; however data are scarce. Oral and vulvovaginal candidiasis are best treated with fluconazole or itraconazole. As for all skin manifestations, besides typical morphology, microscopy and culture of skin scraping, smears, or tissue sections are

Figure 12.2A. Locally invasive dermal (granulomatous) infection with T. rubrum in a liver transplant recipient receiving high-dose intravenous corticosteroids because of acute rejection: discrete scaling plaque with determined borders (arrows), inflammatory nodules (stitch after biopsy in situ). B. Dermatophyte infection: a wet mount preparation of skin scrapings with potassium hydroxide from the same patient demonstrates numerous hyphae. Fungal culture confirmed the diagnosis of T. rubrum infection.

necessary to speciate fungal species and even subspecies. Whether molecular methods contribute meaningfully to the diagnosis of Candida infections remains debatable. Invasive infections with Aspergillus spp., a ubiquitous dimorphic fungus, are the second most frequent opportunistic fungal infections in transplant recipients, [4] emerging particularly in the early period after transplantation. Primary cutaneous infections with Aspergillus spp. are uncommon, but have been reported in association with contaminated devices, such as catheters.[22] Skin lesions due to infection with Aspergillus spp. usually indicate systemic dissemination of the disease and may present as inflammatory infiltrates, plaques, and nodules.[23] Infection of the transplant wound with aspergillus manifest by necrosis and rapid spread has been described in a kidney recipient.[24] The diagnosis is usually made by biopsy demonstrating the invasive presence of hyphae of the Aspergillus type. A definitive diagnosis is made by

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Figure 12.3. Proximal subungual white onychomycosis of the toenails in a heart transplant recipient.

culture. In some cases, growth is inhibited and molecular methods, such as PCR, may be required to identify the pathogen. However, the results of PCR are variably sensitive.[25] An option to diagnose invasive aspergillosis is the detection of galactomannan by an enzyme immunoassay. However, reports on the value of this test are contradictory.[4,26] The role of serologic tests in solid organ recipients is even less clear.[4] Infection with Cryptococcus spp., most commonly C. neoformans, is usually associated with central nervous system infections in AIDS patients, but may also occur in transplant recipients.[27–29] Secondary cutaneous cryptococcosis occurs in up to 15% of patients with disseminated disease as described in renal, liver, and lung transplant recipients,[30] but the skin may also be the primary site of infection.[27,31] Clinically, cutaneous cryptococcosis presents as nonspecific papulopustular lesions, nonhealing ulcers, or cellulitis [30,31] (Figure 12.7A and Figure 12.7B). Infections caused by spores of Zygomycetes spp., whose most common representatives are Rhizopus, Absidia, and Mucor spp., are rare opportunistic fungal infections usually associated with hematologic diseases, tumors, and organ transplantation. Zygomycosis carries a high mortality rate. Spores are ubiquitous in the environment and can also be found in cultures of swabs from healthy subjects. Infection occurs usually via inhalation and presents in the nose and paranasal sinuses, frequently spreading into the orbit and brain by destruction of the bones.[32] Occasionally, direct skin inoculation or contamination of wounds may lead to localized primary skin disease, for example, at the site of laparotomy. A case of gangrenous cellulitis on the neck spreading from a jugular catheter has been described.[33] Belonging to a distinct division from most other medically important fungi, the management of zygomycosis is different. Amphotericin B is moderately active against Zygomycetes spp. and must be used in high doses. Although standard azoles, such as fluconazole, itraconazole, and voriconazole, are not active at all against Zygomycosis, data on the activity of the new azole posaconazole are promising.[30]

Figure 12.4A. Pityriasis versicolor in a heart transplant recipient: sharply marginated hypopigmented macules with fine scales on the upper extremity. B. A tape stripping of the skin surface to pick up scales from the lesion, mounted on a glass slide with methylene blue stains the organisms; spores and hyphae of Malassezia furfur appear as ‘‘noodles and meatballs.’’

Phaeohyphomycoses are a group of subcutaneous and deep-seated infections caused by darkly pigmented (dematiaceous) fungi adopting a septate mycelial form or yeastlike cells in tissue and irregular small chains in culture (Figure 12.8A and Figure 12.8B). More than 100 fungal species have been documented as etiological agents of phaeohyphomycosis, including Bipolaris, Exophiala, Cladosporium, and Alternaria spp.[34] Skin infections are mainly due to Curvularia and Alternaria spp.[34,35] They occur in the environment, and infections of the skin are either due to direct accidental inoculation into the skin after minor trauma or are a sign of a generalized infection in the severely immunocompromised patient. Dematiaceous fungi can produce three different types of infection, that is, phaeohyphomycosis, chromoblastomycosis, and mycetoma.[36] Clinically, phaeohyphomycosis appears as single cysts and nodes, evolving into abscesses. Alternaria spp. has been reported as the pathogen of cutaneous infection in transplant recipients, clinically presenting as nodules or crusted plaques [37–40] (Figure 12.9A–Figure 12.9C),

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Figure 12.5. Cheilitis angularis due to C. albicans (perle`che): because usually the mucous membranes of the cheeks are also involved, the oral cavity of affected patients should be inspected.

Figure 12.6. Erythematous Candida stomatitis: bright red, glossy appearing palate. Frequently seen in patients wearing dentures, as in this patient. Patients usually report oral discomfort.

Exophiala jeanselmei has been identified as the cause of ulcerating nodules on the legs of a heart transplant recipient.[36] In culture, identification of the various pathogens causing phaeohyphomycosis can be difficult. Treatment of phaeohyphomycosis should include complete surgical excision of accessible lesions combined with antifungal therapy. Itraconazole and amphotericin B have been found to be effective.[34] Hyalohyphomycosis refers to subcutaneous and systemic infections caused by nondematiaceous hyaline moulds or yeasts. The members of this group are heterogeneous and include Fusarium, Penicillium, Paecilomyces, Acremonium, and Scopulariopsis spp. Scedosporium apiospermum is a common etiological agent of this group. Infection by spores occurs through the respiratory tract, surgical wounds, and skin. In immunocompromised patients, infection can manifest with skin nodules, ulcerative nonhealing skin lesions, lymphocutaneous, subcutaneous (Figure 12.10), and systemic infection including pulmonary consolidation,[41] with better survival among patients with skin involvement. Infections due to

Figure 12.7A. Primary cutaneous cryptococcosis in lung transplant recipient. Infiltration of the subcutaneous tissue: erythematous subcutaneous plaque of the right lower leg. B. Histological examination of a hematoxylin-eosin stained biopsy from the erythematous area of the right lower leg showed a granulomatous inflammation, infiltrating histiocytes, and multinuclear giant cells. There were masses of spores; nonstaining capsules with an edematous, foamy, gelatinous appearance (arrows). (Reprinted from ‘‘Geusau A, Sandor N, Messeritsch E, Jaksch P, Tintelnot K, Presterl E. Cryptococcal cellulitis in a lung-transplant recipient. Br J Dermatol 2005;153: 1068–70.’’ With permission.)

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Figure 12.8. Disseminated Nattrassia mangiferae (dematiaceous fungus) with skin lesions in a kidney transplant recipient. A. Crusted lesions on the dorsum of the hands. B. Lactophenol blue stain of N.mangiferae, broad hyphae forming nonseptate or one-septate conidia (courtesy of Prof.Dr.Birgit Willinger, and Prof.Dr Stefan Winkler, Vienna).

pressed patients, and aggressive systemic antifungal therapy, for example, with amphotericin B, may be necessary over a prolonged period.[47] Trichosporon beigelii occurs in soil and in tropical areas. A superficial skin infection similar to tinea, called white piedra, may occur in immunocompetent individuals. In immunocompromised patients, papules, nodules, necrotic ulcers and invasive infection with fatal outcome have been reported.[48] Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatidis, and Paracoccidioides brasiliensis are dimorphic fungi endemic in certain parts of the United States and South America. In Europe, infections with these agents are rare and usually associated with a travel history to areas where these fungi are endemic. They can cause systemic infection in the normal host and in transplant recipients, and skin lesions usually represent disseminated disease.[42] Skin infection presents as subcutaneous tumors (Figure 12.11), for example, as nodules on the palate or as cellulitis, as reported in kidney recipients with histoplasmosis (see Table 12.1).[49–51] Primary skin infection without systemic involvement is described for coccidioidomycosis in immunocompetent patients.[52] Biopsy shows the invasive fungal elements. Although the histology is quite distinctive, culture confirms the identity of the pathogen. There is a possibility of serological proof of specific antibodies with variable sensitivity; however, little data exist on its performance in transplant recipients. The therapy of choice is azoles, foremost itraconazole or fluconazole, or amphotericin B in severe infection involving the central nervous system. The duration of therapy remains unclear; however, it is known that in the setting of immunosuppression, treatment must be maintained up to several months or even years.

Diagnosis S. apiospermum or S. prolificans have been studied in 80 transplant recipients and compared to 190 nontransplant patients: transplant patients frequently had disseminated disease and a high mortality of 58%.[42,43] Cutaneous infections usually manifest as pustules or subcutaneous nodules, but the infection may be generalized with pulmonary and cerebral abscesses.[41,44–46]

Rare Fungal Infections, Including Endemic Mycoses Skin infections in transplant recipients may also be caused by rare fungal pathogens, such as Sporothrix schenkii, and pathogens from the group of endemic mycoses (e.g., coccidioidomycosis, histoplasmosis, blastomycosis), systemic infections that may involve the skin. Sporothrix schenckii, a rare dimorphic fungus, occurs in the environment, particularly on plants, such as rose bushes. Sporotrichosis may also affect the immunocompetent host. It is rare, even in transplant recipients, but if inoculation occurs, the infection may spread from the skin to the joints and finally into the central nervous system.[47] Infection may be extremely difficult to eradicate in chronically immunosup-

For superficial mycoses, particularly dermatophytosis, wet mounts of skin scraping in 20% potassium hydroxide may be diagnostic, although a culture for identification of the fungus is preferred. However, for the proof of invasive disease due to Candida, Aspergillus, and other fungi, a skin or tissue biopsy for histopathology is required, showing invasion with hyphae. The diagnosis can also be established by positive cultures from a normally sterile site such as a needle biopsy or cerebrospinal fluid, although blood cultures are rarely positive. Fungal elements are easily seen with common fungal stains, such as GomoriÕs methenamine silver (GMS) or periodic acid-Schiff (PAS). Although the morphology, size, and branching of hyphae usually distinguish Aspergillus from agents of zygomycosis, they are not distinguishable from a number of other opportunistic moulds, such as Fusarium or Scedosporium, so that a positive culture is needed to confirm the diagnosis. Cultures should always be undertaken to identify the fungus. Culture also allows resistance testing, which, even though not required on a routine basis, may be helpful in recurrent disease.[53] The status of resistance to antifungals is not as closely related to clinical success or failure as it is the case for

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Figure 12.9. Alternaria infectoria infection of the skin: A. solitary papule on the dorsum of the hand and B. crusted infiltrated lesion involving the calf of a heart transplant recipient. C. PAS staining of one of the skin samples obtained from the same patient showed trichophytosis with masses of fungal elements in the hair follicle.

Figure 12.10. Scedosporium apiospermum infection in kidney recipient. Tender subcutaneous nodule on the right leg; histology showed acute panniculitis with abscess formation and fungal elements (courtesy of Prof. Dr. Carlos Ferrandiz, Spain).

bacterial infections and antibacterial agents.[54] Susceptibility tests of Candida and Aspergillus spp. for azoles and amphotericin B, as well as their clinical relevance and interpretation are standardized.[53] Hematogenous antigen detection of Aspergillus galactamannan may be a sign of invasive disease, but is rarely positive in solid transplant recipients,[55] whereas the Cryptococcus antigen detection in serum indicates invasive disease.[56] Radiographic findings, particularly computed tomography, may be useful for the diagnosis and management of invasive pulmonary aspergillosis, that is, the presence of a ‘‘halo’’ of low attenuation surrounding a nodular lesion is

Figure 12.11. Histoplasmosis of the oral cavity in a kidney transplant recipient, whose organ originated from South America. Foul smelling mass under the tongue without constitutional symptoms (courtesy of Prof. Dr. Carlos Ferrandiz, Spain).

an early finding that is used as a marker for on-time initiation of antifungal therapy in bone marrow recipients. Modern molecular biology methods, such as PCR and sequencing of fungal DNA extracted from tissue, may be routine methods in future, particularly with rare and uncultivable fungi. However, up to now, molecular tests are not commercially available and only offered by special mycology laboratories. In immunosuppressed patients, the diagnosis and identification of the fungal pathogens should be the domain of specialized and dedicated mycology laboratories.

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Table 12.1 Clinical criteria for the diagnosis of fungal skin lesions in transplant recipients

Classical dermatomycoses

Group

Fungal pathogens

Cutaneous symptoms

Dermatophytes

Anthropophilic species: Trichophyton rubrum, T. interdigitale, Epidermophyton floccosum, T. tonsurans Zoophilic species: Microsporum canis, T. mentagrophytes, T. verrucosum Scopulariopsis spp. Malassezia furfur

Tinea pedis, manum, corporis (widespread annular scaling plaques), tinea capitis, palmoplantar keratoderma, deep dermal (granulomatous) skin infection (papules and nodules), erythematous scaling papules, onychomycosis, proximal subungual white onychomycosis.

Moulds Yeasts Opportunistic fungal skin infections

Yeasts

Candida spp., mostly C. albicans, also C. tropicalis, C. krusei, C. glabrata, C. parapsilosis

Cryptococcus spp. (mostly C.neoformans)

Moulds

Aspergillus spp. (A. niger, A. fumigatus, A. flavus) Mucorales spp. (Rhizopus, Rhizomucor, Absidia, Mucor spp.)

Rare fungal infections

Dematiaceous fungi (moulds or yeasts)

Bipolaris, Exophilia jeanselmei, and Cladosporium, Alternaria, Curvularia spp.

Non dematiaceous fungi (moulds or yeasts)

Fusarium, Penicillium, Paecilomyces, Acremonium, Scopulariopsis, Scedosporium spp.

Dimorphic fungi

Sporothrix schenckii

Yeasts

Trichosporon spp.

Onychomycosis, subcutaneous infiltration. Pityriasis versicolor (superficial scaly lesions), folliculitis. Oropharyngeal infection (‘‘thrush’’), glossitis, pseudomembranous and erythematous stomatitis, perle`che, paronychial, nail and skin fold infection, Candida balanitis, vulvovaginal candidiasis, folliculitis, (erythematous, purpuric) papules, papulonodules (sometimes with central erosion or necrosis), pustules (single, multiple, localized, disseminated lesions), ‘‘Candida granuloma,’’ mucocutaneous candidiasis. Papulopustular lesions (sometimes with central necrosis), molluscum contagiosum-like, small umbilicated papules, pustules, non-healing (vegetative) ulcers, cellulites (resembling erythema nodosum), subcutaneous nodules. Inflammatory skin infiltrates, erythematous/purpuric papules, edematous plaques, nodules, bullae, ulcers, necrotic wound infection. Inflammatory infiltration of nasal mucous membranes and paranasal sinuses, rhinocerebral zygomycosis, wound infection, hemorrhagic subcutaneous nodules and cellulitis, pustules, plaques, ulcers. Clinically, three different types of infections, i.e., phaeohyphomycosis, chromoblastomycosis, and mycetoma, which are subcutaneous and deep-seated infections, single cysts and nodes evolving into abscesses with/without sinus tracts (sometimes without local or systemic signs of inflammation), plaques, ulcerating nodules, crusted/hemorrhagic lesions. Hyalohyphomycosis: Nodules, necrotic, ulcerating nonhealing skin lesions, purpuric papules, lymphocutaneous, subcutaneous infections, pustules, molluscum contagiosum-like central necrotic papules (Penicillium marneffei). Sporotrichosis: Nodules, papules, pustules, ulcerated plaques with erythematous borders, subcutaneous nodules, lymph node involvement, lymphocutaneous and mucocutaneous infection, bone or joint involvement. Tinea-like lesions, papules, nodules, necrotic ulcers.

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Endemic mycoses

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Group

Fungal pathogens

Cutaneous symptoms

Dimorphic fungi

Histoplasma capsulatum (South America, Mississippi, and Ohio river valleys) Coccidioides immitis (central, southwest, and south America, Mexico) Blastomyces dermatitidis (south-central, Midwestern United States, central Canada, Africa) Penicillium marneffei (South East Asia) Paracoccidioides brasiliensis (Latin America)

Usually sign of systemic disease. Inflammatory tumors, papules, nodules, erythematous macules, pustules, ulcers, cellulites, vegetative plaques, oral lesions (ulcers, nodules, mimicking squamous cell carcinoma). Usually sign of systemic disease. Verrucous, crusted papules and plaques, subcutaneous cold abscesses, ulcers, disseminated papules, lymphadenopathy, papulopustules, necrotizing cellulites. Usually sign of systemic disease. Disseminated papulopustules.

Therapy Generally, most of the cutaneous manifestations due to fungi or fungal opportunists have to be treated as systemic infections, that is, systemic involvement has to be ruled out in each case. Surgical excision, debridement, antifungal agents, and reduction of immunosuppression are the pillars of a successful treatment. Antifungal activity of the various agents largely depends on the extent of the hostÕs immunosuppression, on the underlying disease, and on the possibility of surgical removal of the infected tissue. Accurate diagnosis and close follow-up optimize the likelihood of cure in a transplant recipient.[57] The correct diagnosis and identification of the fungus are obligatory, because, for instance, Zygomycetes spp. are generally poorly susceptible to azoles, and Scedosporium is resistant to amphotericin B. For mucocutaneous Candida infections, fluconazole is still a good treatment option because it is orally available and virtually nontoxic. Fluconazole, though metabolized via the P-450 cytochrome pathway as are each of the azoles, carries a relatively low potential for interactions with cyclosporine A, tacrolimus, and sirolimus, which are metabolized by the same pathway, whereas itraconazole, and voriconazole in particular, strongly interfere with these drugs. Thus, the dosage of cyclosporine A or tacrolimus has to be adjusted, and close monitoring of the serum levels is mandatory. Sirolimus must not be used concomitantly with voriconazole, because of its long half-life. Treatment of dermatophyte infections with terbinafine is a good option in transplant recipients, because the potential for drug interactions with immunosuppressants is minimal and the dosage does not need to be adjusted. Amphotericin B still is the antifungal agent with the broadest spectrum and has – due to over 50 years of experience – the best documented effect against all types of rare fungi. The lipid

Usually sign of systemic (pulmonary) disease, umbilicated papules, nodules, ulcers Pulmonary form, mucocutaneous form (granulomas, ulcers, scarring), lymphatic form

formulation of amphotericin B is less nephrotoxic than the original formulation and is generally recommended in the critically ill transplant recipient. However, efficacy data with regard to fungi other than Candida spp. and Aspergillus spp. are scarce. A new class of antifungal compounds are echinocandins, including caspofungin, micafungin, and anidulafungin. They have successfully been used for the treatment of invasive candidiasis and serve as rescue therapy of invasive aspergillosis. However, data on the use of these compounds in fungal skin infections are few. The dosages and duration of antifungal therapy in rare fungal skin infections in transplant recipients are also not well documented. Antifungal therapy in transplant recipients should be maintained for weeks or even months. In view of the continuous suppression of the immune function necessary to avoid rejection of the allograft, certain subsets of patients may require lifelong antifungal treatment.

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patients with hematological malignancies. Clin Infect Dis 2005 Oct 15; 41(8):1143–9. Baumgarten KL, Valentine Garcia-Diaz JB. Primary cutaneous cryptococcosis in bacterial cellulitis in a liver transplant recipient: case report and review in a lung transplant recipient. South Med J 2004 Jul;97(7):692–5. Blackwell V, Ahmed K, OÕDocherty C, Hay RJ. Cutaneous hyalohyphomycosis caused by Paecilomyces lilacinus in a renal transplant patient. Br J Dermatol 2000 Oct;143(4):873–5. Singh N, Rihs JD, Gayowski T, Yu VL. Cutaneous cryptococcosis mimicking solid organ transplant recipients. Clin Transplant 1994 Aug;8(4):365–8. Herbrecht R. Posaconazole: a potent, extended-spectrum triazole anti-fungal for the treatment of serious fungal infections. Int J Clin Pract 2004 Jun;58(6):612–24. Geusau A, Sandor N, Messeritsch E, Jaksch P, Tintelnot K, Presterl E. Cryptococcal cellulitis in a lung-transplant recipient. Br J Dermatol 2005;153: 1068–70. Davari HR, Malekhossini SA, Salahi HA, Bahador A, Saberifirozi M, Geramizadeh B, et al. Outcome of mucormycosis in liver transplantation: four cases and a review of literature. Exp Clin Transplant 2003 Dec;1(2):147–52. Fisher J, Tuazon CU, Geelhoed GW. Mucormycosis in transplant patients. Am Surg 1980 May;46(5):315–22. Halaby T, Boots H, Vermeulen A, van der Ven A, Beguin H, van Hooff H, Jacobs J. Phaeohyphomycosis caused by Alternaria infectoria in a renal transplant recipient. J Clin Microbiol 2001;39:1952–55. Tessari G, Forni A, Ferretto R, Solbiati M, Faggian G, Mazzucco A, Barba A. Lethal systemic dissemination from a cutaneous infection due to Curvularia lunata in a heart transplant recipient. JEADV 2003;17:440–42. Silva MR, Fernandes OF, Costa CR, Chaul A, Morgado LF, FleuryJunior LF, Costa MB. Subcutaneoous phaeohyphomycosis by Exophiala jeanselmei in a cardiac transplant recipient. Rev Inst Med Trop Sao Paulo 2005 Jan;47(1):55–7. Torres-Rodriguez JM, Gonzalez MP, Corominas JM, Pujol RM. Successful thermotherapy for a subcutaneous infection due to Alternaria alternata in a renal transplant recipient. Arch Dermatol 2005 Sep;141(9):1171–3. Lo CG, Ligozzi M, Maccacaro L, Fontana R. Utility of molecular identification in opportunistic mycotic infections: a case of cutaneous Alternaria infectoria infection in a cardiac transplant recipient. J Clin Microbiol 2004 Nov;42(11):5334–6. Kazory A, Ducloux D, Reboux G, Blanc D, Faivre B, Chalopin JM, et al. Cutaneous Alternaria infection in renal transplant recipients: a report of two cases with an unusual mode of transmission. Transpl Infect Dis 2004 Mar;6(1):46–9. Merino E, Banuls J, Boix V, Franco A, Guijarro J, Portilla J, et al. Relapsing cutaneous alternariosis in a kidney transplant recipient cured with liposomal amphotericin B. Eur J Clin Microbiol Infect Dis 2003 Jan;22(1):51–3. Kusne S, Ariyanayagam-Baksh S, Strollo DC, Abernethy J. Invasive Scedosporium apiospermum infection in a heart transplant recipient presenting with multiple skin nodules and a pulmonary consolidation. Transpl Infect Dis 2000;2:194–96. Ahmed J, Ditmars DM, Sheppard T, del BR, Venkat KK, Parasuraman R. Recurrence of Scedosporium apiospermum infection following renal re-transplantation. Am J Transplant 2004 Oct;4(10):1720–4. Husain S, Munoz P, Forrest G, Alexander BD, Somani J, Brennan K, et al. Infections due to Scedosporium apiospermum and Scedosporium prolificans in transplant recipients: clinical characteristics and impact of antifungal agent therapy on outcome. Clin Infect Dis 2005 Jan 1;40(1):89–99.

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44. Campagnaro EL, Woodside KJ, Early MG, Gugliuzza KK, ColomeGrimmer MI, Lopez FA, et al. Disseminated Pseudallescheria boydii (Scedosporium apiospermum) infection in a renal transplant patient. Transpl Infect Dis 2002 Dec;4(4):207–11. 45. Montejo M, Muniz ML, Zarraga S, Aguirrebengoa K, Amenabar JJ, Lopez-Soria L, et al. Case Reports. Infection due to Scedosporium apiospermum in renal transplant recipients: a report of two cases and literature review of central nervous system and cutaneous infections by Pseudallescheria boydii/Sc. apiospermum. Mycoses 2002 Nov;45(9-10):418–27. 46. Ginter G, Petutschnig B, Pierer G, Soyer HP, Reischle S, Kern T, et al. Case report. Atypical cutaneous pseudallescheriosis refractory to antifungal agents. Mycoses 1999;42(7-8):507–11. 47. Gullberg RM, Quintanilla A, Levin ML, Williams J, Phair JP. Sporotrichosis: recurrent cutaneous, articular, and central nervous system infection in a renal transplant recipient. Rev Infect Dis 1987 Mar;9(2):369–75. 48. Viscomi SG, Mortele KJ, Cantisani V, Glickman J, Silverman SG. Fatal, complete splenic infarction and hepatic infection due to disseminated Trichosporon beigelii infection: CT findings. Abdom Imaging 2004;29:228–30. 49. Peterson PK, Dahl MV, Howard RJ, Simmons RL, Najarian JS. Mucormycosis and cutaneous histoplasmosis in a renal transplant recipient. Arch Dermatol 1982 Apr;118(4):275–7.

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50. Serody JS, Mill MR, Detterbeck FC, Harris DT, Cohen MS. Blastomycosis in transplant recipients: report of a case and review. Clin Infect Dis 1993 Jan;16(1):54–8. 51. Cooper PH, Walker AW, Beacham BE. Cellulitis caused by Histoplasma organisms in a renal transplant recipient. Arch Dermatol 1982;118:3–4. 52. Levan NE, Huntington RW Jr. Primary cutaneous coccidioidomycosis in agricultural workers. Arch Dermatol 1965;92:215–20. 53. Espinel IA, Barchiesi F, Hazen KC, Martinez-Suarez JV. Standardization of antifungal susceptibility testing and clinical relevance. Medical Mycology 1998;36 (Suppl 1):68–78. 54. Rex JH, Pfaller MA. Has antifungal susceptibility testing come of age? Clin Infect Dis 2002 Oct 15;35(8):982–9. 55. Husain S, Kwak EJ, Obman A, Wagener MM, Kusne S, Stout JE, et al. Prospective assessment of Platelia Aspergillus galactomannan antigen for the diagnosis of invasive aspergillosis in lung transplant recipients. Am J Transplant 2004 May;4(5):796–802. 56. Vilchez R, Shapiro R, McCurry K, Kormos R, bu-Elmagd K, Fung J, et al. Longitudinal study of cryptococcosis in adult solid-organ transplant recipients. Transpl Int 2003 May;16(5):336–40. 57. Miele PS, Levy CS, Smith MA, Dugan EM, Cooke RH, Light JA, et al. Primary cutaneous fungal infections in solid organ transplantation: a case series. Am J Transplant 2002 Aug;2(7): 678–83.

13 Viral Diseases in Organ Transplant Recipients

Richard A. Johnson, MD and Jennifer Y. Lin, MD

Reactivation of herpes simplex virus after transplantation is common; one study quotes 42% oral reactivation by PCR although only 1/12 had clinical manifestation.[2] Recurrent HSV is characterized by an itching or tingling sensation at the site, often prior to any visible alteration. Ulcerated, crusted lesions in perioral, anogenital, or digital locations are usually HSV in etiology, in addition to occasional atypical clinical appearances in organ transplant patients. With increasing immunosuppression, recurrent HSV infection may become persistent and progressive, forming large, deep lesions. For instance, herpetic infection of one or more fingers can form severely painful, large whitlows. HSV can then be inoculated into nearly any site including the ears and toes. Local spread can occur as well from the oropharynx onto esophageal mucosa, and from the anogenital area to the rectal tissue. Large atrophic scars may remain even after healing of deep herpetic ulcers. Primary HSV infection after organ transplantation is less common, but in the immunosuppressed background, can have a more fulminant presentation such as acute liver failure in the liver transplant recipient. Both primary and reactivated HSV can result in dissemination to visceral organs. Disseminated HSV infection can involve the skin only, or, of more concern, the viscera (lungs, liver, and brain), which has significant associated morbidity and mortality. Uncomplicated reactivation of HSV is not associated with patient or allograft compromise, unless it occurs in combination with CMV coinfection, which can be associated with reduced patient and allograft survival.[3,4] HSV infections can be diagnosed by isolation of the virus or identification of HSV antigen in lesional smears or biopsy specimens. If indicated, the isolate can be tested for sensitivity to various antiviral agents. Histology shows multinucleated giant epidermal cells indicative of HSV or VZV infection. The Tzanck test, which looks for giant epithelial or adnexal cells, preferably multinucleated, in smears of lesional exudate, is useful but is not always positive even in frank herpetic lesions; its reliability is dependent on the skill of the microscopist. Lesional biopsy is helpful when giant epidermal cells are detected, but cannot distinguish HSV from VZV infection. Viral culture of a lesion has a high yield in making the diagnosis. The polymerase chain reaction can detect VZV and HSV DNA sequences from a variety of sources, including formalin-fixed tissue specimens. Currently, three drugs are available for oral therapy of HSV infections: famciclovir, valaciclovir, and acyclvoir.

Viral pathogens have emerged as the most significant microbial agents causing deleterious effects in solid organ transplant recipients (OTRs). Cytomegalovirus (CMV) is the most common opportunistic organism encountered during the one- to six-month posttransplantation period, and prophylactic regimens have been carefully developed to counter its virulence. Several other viruses manifest on mucocutaneous sites, ranging from cosmetically disfiguring facial molluscum contagiosum virus (MCV) to extensive common or genital warts from human papillomavirus (HPV) to invasive or life-threatening HPV-induced squamous cell carcinoma. In the great majority of cases, viral opportunistic infection (OI) represents reactivation of latent viral infection, that is, herpes family of viruses, or proliferation of subclinical infection with HPV or MCV.

H E R P E TO VI R I D A E ( H U M A N H E R P E S V I R U SE S) Human herpesviruses (HHV), that is, herpes simplex virus (HSV) types 1 and 2; cytomegalovirus (CMV); varicella-zoster virus (VZV); Epstein–Barr virus (EBV); human herpesvirus-6, -7, -8 (HHV-6, HHV-7, HHV-8), share three characteristics in common that make them particularly effective pathogens in the immunocompromised host: (1) latency (once infected with the virus, the individual remains infected for life, with immunosuppression being the major factor responsible for reactivation of the virus from a latent state); (2) cell association (these viruses are highly cell-associated, rendering humoral immunity inefficient as a host defense and cellmediated immunity paramount in the control of these infections); and (3) oncogenicity (all herpes group viruses should be regarded as potentially oncogenic, with the clearest demonstration of this being EBV-related lymphoproliferative disease).[1] Of the herpes group viruses, those with the greatest impact on the mucocutaneous tissues of the immunocompromised transplant patients are HSV, VZV, CMV, HHV-8, and, to a lesser extent, EBV (Table 13.1).

HE RPE S SI MPLEX VI RUS (HSV ) - 1 A ND -2 The majority of HSV-1 and HSV-2 infections occurring in the immunocompromised host are reactivations of latent infections, typically occurring in the first three months posttransplantation.

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Table 13.1 Types of herpesvirus infections in immunocompromised patients Human Herpesvirus

Presentation in immunocompromised individuals

Management

HSV-1,2 (HHV-1,2)

Widespread local infection, eczema herpeticum Chronic, large ulcers (orofacial, anogenital, digital) Disseminated cutaneous infection Disseminated visceral infection (hepatitis, pneumonitis, encephalitis) Disseminated cutaneous infection Disseminated visceral infection Chronic herpes zoster Chronic ecthymatous VZV infection Posttransplant lymphoproliferative disorder (PTLD) Maculopapular rash (cutaneous involvement) Pneumonitis Colitis Retinitis KaposiÕs sarcoma

No immunization available yet;antiviral agents, including acyclovir, valacyclovir, famcyclovir, and foscarnet.

VZV (HHV-3)

EBV (HHV-4) CMV (HHV-5)

HHV-8

These agents can be given to treat primary or reactivated infection or to suppress reactivation. Intravenous acyclovir (5 mg/kg every 8 hours) may be given for severe infections. Improved bioavailability of famciclovir and valaciclovir makes their oral therapy preferable to oral acyclovir. Foscarnet, cidofovir, and trifluridine are administered intravenously for infections caused by acyclovir-resistant HSV. Cidofovir gel has been effective as a topical therapy of acyclovir-resistant HSV infections.[5] The use of chronic HSV suppression is controversial. In the management of chronic herpetic ulcers, immunosuppressive therapy should be reduced when possible. Fortunately, acyclovir resistance has not been as commonly seen in the transplant population as it has in the HIV population. In a study of acyclovir susceptibilities in 18 solid organ transplant patients after viral prophylaxis with either acyclovir or ganciclovir, all isolates were susceptible.[4]

V AR IC E LL A - Z O ST E R V I R U S ( VZ V) Primary VZV infection manifests as varicella (chickenpox); reactivation of VZV from a dorsal root ganglion or cranial nerve ganglion manifests as herpes zoster (HZ). In the compromised host, VZV infection can present as severe varicella, dermatomal HZ, disseminated HZ (sometimes without dermatomal HZ), and chronic or recurrent HZ. Disseminated HZ is defined as cutaneous involvement by greater than three contiguous dermatomes or >20 lesions scattered outside the initial dermatome, or systemic infection (hepatitis, pneumonitis, encephalitis). Rarely, the reactivation of VZV can produce pain without any cutaneous lesions (zoster sine zoster).

Immunization available; VZ IVIG; antiviral agents, including acyclovir, valacyclovir, famcyclovir, and foscarnet.

Antiviral agents including acyclovir and gancyclovir Immunization: vaccine promising; antiviral agents including ganciclovir, valaganciclovir, foscarnet, and cidofovir.

Improve immune status; chemotherapy

The immunocompromised host previously infected with VZV is still subject to exogenous reinfection with VZV. Zoster occurs in 5–15% of solid organ transplant patients, usually within the first year post transplantation (median onset of 9 months).[6] A more common problem in the immunocompromised host is reactivation of infection with HZ, where latent virus present in the dorsal nerve root ganglia becomes reactivated. The first manifestation of zoster is often pain in the dermatome that subsequently manifests the classical grouped vesicles on an erythematous base. Multidermatomal involvement, either contiguous or noncontiguous, may occur (Figure 13.1). Occasionally, in solid organ transplant patients, the dermatomal eruption may be bullous, hemorrhagic, necrotic, and be accompanied by severe pain. In this chronically immunosuppressed group, the risk of dissemination with HZ is as high as 40% (Figure 13.2). Despite antiviral therapy, mortality rates range from 4-34%.[7] The most common complications are cutaneous scarring (18.7%) or post herpetic neuralgia (PHN) (42.7%), which is defined as pain persisting more than six weeks after the development of cutaneous lesions. In transplant patients, complications from reactivated VZV tend to be more severe, including central nervous system complications in the form of progressive small-vessel encephalitis or myelitis.[8] Ophthalmic zoster has the highest incidence of serious complications, which include corneal ulceration, variable decrease of visual acuity, and retinal necrosis. Viscerally disseminated HZ in an immunocompromised host can be life threatening and organs involved include the lung and liver. In the immunocompromised patient, reactivated cutaneous VZV lesions can persist for months following either

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Figure 13.1. Varicella zoster virus (VZV) infection: multidermatomal herpes zoster. Dermatomal grouped hemorrhagic crusts on erythematous base in T5-6 distribution. Round erythematous plaque below represents patientÕs psoriasis.

Figure 13.2. VZV infection: cutaneous dissemination of herpes zoster. Dermatomal grouped vesicles on an erythematous base in T6-7 distribution with > 20 vesicles beyond dermatomal distribution. This eruption is indistinguishable from varicella and must be distinguished from disseminated HSV infection. Systemic dissemination did not occur; the patient felt well.

primary or reactivated VZV infection with a pattern of zoster[9] or disseminated infection,[10] referred to as chronic verrucous or ecthymatous VZV infection. Lesions may persist for months, either in the localized or disseminated form, appearing as hyperpigmented and/or hyperkeratotic painful nodules often with central crusting and/or ulceration with a border of vesicles. Verrucous/ecthymatous VZV was first appreciated in HIV patients, typically those with low CD4 counts (<100/mm3). There are now reports in the literature of verrucous VZV following kidney transplantation in patients taking tacrolimus and prenisolone.[11] Primary VZV after organ transplantation is rare and tends to present within 3 years or later, depending on exposure[12]. Primary VZV is more commonly seen in the pediatric transplant population. Varicella occurring in immunosuppressed children and adults can be severe, prolonged, and complicated by VZV dissemination (pneumonia, hepatitis, encephalitis, and pancreatitis), disseminated intravascular coagulation, bacterial superinfection, and death. The diagnosis of varicella and HZ can be made clinically, but as with HSV, the diagnosis can be confirmed by detection of viral antigen on a smear of the base of a vesicle or erosion or in a section of a lesional biopsy specimen. A positive Tzanck test confirms the diagnosis of either VZV or HSV. Isolation of VZV by culture is more difficult than isolation of HSV. Lesional biopsy is also helpful to establish a diagnosis, especially in unusual manifestations of VZV infection such as ecthymatous or chronic verrucous lesions; the diagnosis is confirmed by detection of VZV antigen. Serologies are now routinely screened prior to transplantation and there are reported rates of 1.6% VZV serology-negative patients. It is important to note that a negative VZV serology does not necessarily preclude prior infection, and that these patients can still manifest HZ. The same drugs approved for treatment of HSV are approved for treatment of VZV infection: famciclovir, valaciclovir, and acyclovir. Intravenous acyclovir (10 mg/kg every 8 hours) is given for severe infections. As with HSV infections, acyclovir-resistant strains can emerge following prolonged acyclovir treatment; most of these resistant strains respond to foscarnet therapy.[13] VZV-immunoglobuin (VZIG) is often given within 96 hours to VZV naı¨ve patients exposed to VZV to minimize the risk of infection. Administration of routine antiviral prophylaxis for prevention of CMV disease appears to reduce the mortality associated with zoster but does not affect the incidence of zoster. Prophylactic regimens for zoster are not practical because of late onset of disease and low proportion of affected individuals. It has been recommended that transplant recipients should receive VZIG after contact with either varicella or zoster. However, some retrospective studies question the effectiveness of this strategy. In one report, 17 of 31 cases of varicella infection occurred despite treatment with VZIG.[14] Varicella vaccination in the organ transplant population has slowly been emerging as more evidence indicates its safety. In the BMT population, seropositive BMT patients immunized with the vaccine had greater protection. Varicella vaccination

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is currently recommended prior to transplantation in children and adolescents.[15] Vaccination pretransplantation has been successful in inducing seroconversion.[16] The vaccination has been even used post renal transplantation with no adverse affects to the vaccine and a 66% rate of seroconversion.[17]

E P S TE I N– BA R R V I R U S ( E B V) EBV selectively infects cells of the B-lymphocyte lineage and certain types of squamous epithelium. The majority of adults have been infected with EBV and harbor the virus in a latent state. Primary cutaneous EBV-associated posttransplant lymphoproliferative disorder (PTLD) is the most common cutaneous manifestation of EBV in solid organ transplant patients, as discussed in detail in Chapter 29. PTLD can present in several ways including isolated or multiple lymphoid tumors, an infectious mononucleosis-like pattern, generalized lymphadenopathy, and rapidly progressive and widespread disease. PTLD can be seen in any organ site and the incidence ranges depending on organ type, from 1% of renal transplant patients to 5% of heart/lung transplant recipients.[18] Disease localized to the skin is even more rare and the appearance is polymorphic: single or multiple erythematous nodules, ulcers, or maculopapular eruptions.[19] PTLD is usually polyclonal at the onset and, with limited disease, patients often respond to reduction of immunosuppression. The disease can also become a rapidly progressive and ultimately fatal monoclonal disease. Predisposition to developing PTLD is intimately related to CMV infection and CMV D+/R- (donor positive, recipient negative) organ transplant patients are most susceptible.[20] Posttransplant cutaneous B-cell lymphoma, associated with EBV infection, is an uncommon complication of solid organ transplantation.[21] Findings are usually confined to the skin; systemic involvement is not common. Treatment is usually directed at the lesions, with surgery or radiotherapy.

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CMV disease occurs via: (1) primary CMV infection, (2) reactivation of latent CMV infection, or (3) reinfection with a new CMV subtype. As with the other members of the herpesvirus family, in most cases, CMV disease represents reactivation of latent virus. This typically occurs in the first 3 months post transplantation when immunosuppression is most intense. Reactivated cytomegalovirus (CMV) can cause hepatitis, pneumonitis, chorioretinitis, encephalitis, and colitis/esophagitis in transplant recipients; cutaneous CMV infections are rare. Cutaneous CMV infections are reported to present as nodules, ulcers, indurated plaques, vesicles, petechiae/purpura, or a maculopapular exanthem. Cutaneous ulcers and a morbilliform eruption are the most common presentation of cutaneous CMV involvement. Cutaneous manifestation may be seen in 10–20% of systemic CMV infections and has been associated with a poor prognosis.[22] This association has been postulated to be a marker of severe immune compromise as CMV generally does not replicate well in the dermis. Chronic CMV infection predisposes organ transplant patients to acute and chronic graft failure, as well as secondary immune deficiency and further risk of opportunistic infections. Detection of CMV can be obtained by biopsy specimens demonstrating the characteristic inclusion bodies, or by immunoperoxidase staining of tissue. Treatment of choice is intravenous ganciclovir for 2 to 3 weeks. For resistant virus strains, foscarnet 40 mg/kg IV every 8 hours is employed. Prophylactic regimens can be used and the most common is ganciclovir (15 mg/kg TID x 14–90 days), but newer drugs such as valganciclovir appear promising. Oral ganciclovir and valganciclovir prophylaxis are both effective at decreasing the incidence of infection in the CMV D+/R- solid organ transplant group. As a side benefit, the prophylactic regimen helps control other herpesvirus family members such as HSV, VZV, and even EBV.[23] More recently, late-onset CMV infections occurring a year after transplantation suggest the need to alter the length of prophylaxis regimen to extend for a longer time period.[24] This may, however, increase rates of viral resistance.

C YT O M E G A L O V I R U S ( C M V) H UM A N H E R P ES VI R U S- 8 ( H H V- 8 ) CMV is the major microbial pathogen of solid organ transplant patients. It accomplishes this by several mechanisms: (1) causes infectious disease syndromes, (2) augments iatrogenic immunosuppression and is thus commonly associated with opportunistic superinfection, and (3) contributes to graft failure. CMV infection occurs in 20–60% of all transplant recipients, the rate of infection being related to the serologic status of both the donor and recipient. The CMV-seronegative recipients of organs from seropositive donors (CMV D+/R- patients) represent the highest risk group for developing CMV disease. CMV is another member of the herpesvirus family, and seroprevalence studies of CMV infection indicate that 50% of the general population is infected by age 50 years. Following primary infection, CMV enters a latent phase of infection, during which asymptomatic viral shedding in saliva, semen, and/or urine is extremely common. In the immunocompromised host,

KaposiÕs sarcoma (KS) is a hemangioma-like proliferation of endothelial-derived cells, first reported by Moritz Kaposi in 1872 as ‘‘idiopathic pigmented sarcoma of the skin.’’ Classical KS occurs in men of Mediterranean or Eastern European descent and African KS was described in young patients from equatorial Africa. In the 1960s, a third variant of iatrogenic KS was described in patients on long-term immunosuppressive therapy but became most strongly associated with the HIV/ AIDS epidemic as a marker of end stage AIDS. The prevalence of KS in organ transplant recipients is anywhere from 0.1– 3.2% depending on the type of immunosuppression, HHV-8 status of donor and recipient, and country of origin. HHV-8 is a lymphotropic, oncogenic, herpesvirus that was first detected in KS in 1994. HHV-8 has also been detected in other neoplasms such as body cavity-based lymphoma and

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CastlemanÕs tumor. Reported cases of HHV-8 transfer from donor to recipient in heart and lung transplantations, with resulting KS, also strongly implicates this member of the herpesvirus family as the cause of transplantation-associated KS.[25] The clinical course of transplantation-associated KS may be quite variable with frequent occurrence of widespread cutaneous and visceral lesions, as described in detail in Chapter 28. Early lesions of KS present as slight discoloration of the skin, barely palpable papules, and, if very early, as macules. Over a period of weeks-to-months-to-years, these early lesions enlarge into nodules or frank tumors, and the color darkens to a violaceous, Concord grape color, often with a yellow-green halo. As lesions enlarge, epidermal changes may occur, demonstrating a shiny, atrophic appearance if stretched, or, at times, hyperkeratosis with scale formation (Figure 13.3). In late lesions, tumor necrosis may occur with erosion or ulceration of the surface. Oral lesions are common, and may be the first site of involvement, occurring typically on the hard palate as a violaceous stain of the mucosa.

The course of KS depends upon restitution of immune function. Few patients die from complications directly related to KS. An occasional patient will develop KS lesions involving internal organs in the absence of any visible mucocutaneous involvement. Although the diagnosis of KS can usually be suspected clinically, in most instances, histologic diagnosis on a lesional punch biopsy specimen should be accomplished. In the management of KS, the initial therapeutic focus is reduction in immune compromise by changing immunosuppressive drug therapies. In particular, the addition of rapamycin as a immunosuppressant in place of other drugs such as cyclosporine has been associated with regression of KS.[26] Localized cutaneous disease can be approached with application of an intralesional injection of vinblastine, cryotherapy, surgical excision, or radiation. Indolent, disseminated cutaneous KS is best treated with systemic immunotherapy or chemotherapy.

M O LL U S C U M C O NT A G I O S U M V I R U S ( M C V ) MCV commonly infects keratinized skin subclinically, and can cause lesions at sites of minor trauma and in the infundibular portion of the hair follicle. Transmission is usually via skinto-skin contact, occurring commonly in children and sexual partners. MCV infection is common in organ transplant patients with a reported 6.9% incidence in pediatric transplant patients.[27] Clinically, MCV infection presents as skin-colored papules or nodules, often with a characteristic central umbilicated keratotic plug. Lesions >1 cm in diameter (giant molluscum) may occur in the immunosuppressed population. In males, lesions are often confined to the beard area, the skin having been inoculated during the process of shaving (Figure 13.4). Therapeutically, the most efficacious approach toward MCV infection is correction of the underlying immunodeficiency. Otherwise, treatment is directed at controlling the

Figure 13.3. KaposiÕs sarcoma (KS), iatrogenic; plantar foot: HHV-8. A non-transplant patient had been treated with prednisone 100 mg daily and cyclosporine (CsA) 300 mg daily. With the occurrence of KS, prednisone was tapered to 30 mg daily, CsA discontinued and mycophenylate mofetil begun. (A) R-foot: violaceous plaques have resolved and only macular hemosiderin pigmentation remains. (B) L-foot: violaceous nodules of KS are present as well as regressed lesions with hemosiderin staining.

Figure 13.4. Molluscum contagiosum, buttocks; molluscum contagiosum virus (MCV). Skin-colored dome shaped papules with central umbilication in lung transplant patient. Several are flattened with hyperpigmentation after one treatment with podophyllin.

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Subclinical infection with human papillomavirus (HPV) is nearly universal in humans. With immunocompromise, cutaneous and/or mucosal HPV infection reemerges from latency, presenting clinically as verruca, condyloma acuminatum, squamous cell carcinoma in situ (SCCIS), or invasive squamous cell carcinoma (SCC). Human papillomavirus (HPV) colonizes keratinized skin of all humans producing common warts (verruca vulgaris, verruca plantaris, verruca plana) in many healthy individuals during the course of lifetime. The majority of sexually active individuals are subclinically infected with one or multiple HPV types. HPV-6 and -11 infect mucosal sites (genitalia, anus, perineum, oropharynx) and

cause genital warts (condyloma acuminatum); HPV-16 and -18 have greater malignant potential and can cause precancerous lesions, squamous intraepithelial lesion (SIL), SCCIS, and invasive SCC. In organ transplant recipients and other immunocompromised hosts, verrucae are not initially unusual in morphology, number, or response to treatment; however, with time, verrucae can enlarge, become confluent, and become unresponsive to therapy. The incidence and severity of warts are related to the degree of immunosuppression, with previously acquired latent virus reactivating with institution of immunosuppressive therapy. Warts are the most common cutaneous finding in the pediatric solid organ transplant population, affecting 53.8%. The prevalence in renal transplant patients increases with length of immunosuppression, from 11% in first year posttransplantation, to as high as 92% after >5 years of immunosuppression.[28] Verruca vulgaris and verruca plantaris appear as well-demarcated keratotic papules or nodules, usually with multiple tiny red-brown dots

Figure 13.5. Verruca vulgaris, extensive; plantar foot and toes. Numerous hyperkeratotic papules, coalescing and forming a mosaic, disrupting normal skin lines. Pinpoint red or brown dots represent thrombosed capillary loops.

Figure 13.6. Verruca plana, extensive; lower extremity. Flat-topped, pink papules with sharp margination and minimal hyperkeratosis on anterior lower extremities.

numbers and bulk of cosmetically disturbing lesions. Liquid nitrogen cryospray is the most convenient therapy, and usually must be repeated every 2 to 4 weeks.

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representing thrombosed capillaries; palmar and plantar warts characteristically interrupt the normal dermatoglyphics. They may be very numerous and confluent, giving the appearance of a mosaic (Figure 13.5). Verruca plana appears as a welldemarcated, flat-topped papule, which lacks the dots seen in other types of verrucae (Figure 13.6). When present in the beard area, hundreds of flat warts may be present. All types of verrucae may have a linear arrangement due to koebnerization or autoinoculation. Condylomata acuminata or genital warts are usually asymptomatic, although voluminous lesions may be painful and bleed. Lesions may be very numerous and become confluent. (Figure 13.7) Oropharyngeal HPV-induced lesions resemble anogenital condyloma, pink or white in color. Extensive intraoral condyloma acuminatum (oral florid papillomatosis) presents as multiple large plaques, analogous to anogenital giant condylomata acuminata of Buschke-Lo¨wenstein, and can also transform to verrucous carcinoma. In immunocompromised patients, HPV-induced lesions have the potential for malignant transformation, particularly on sun-exposed areas of the body. SCC arising in sites of chronic sun exposure occur 36 times more frequently in renal transplant recipients than in the general population, some clearly arising within warts; HPV DNA is demonstrable within

Figure 13.7. Condylomata acuminata; perianal. A cauliflower like tumor involving entire perianal region of liver transplant patient.

the tumors.[1] Rapidly enlarging hyperkeratotic verrucae should also be investigated for transformation to rule out SCC. HPV-induced anogenital in situ and invasive squamous cell carcinoma (SCC) is also ten times more common in transp lant recipients and HIV-infected individuals; these persons should be screened for in situ and invasive SCC with Pap test of the anus and cervix and lesional biopsy when indicated.[29] Acetowhitening, the appearance of white micropapules or macules after the application of 5% acetic acid (white vinegar) to the anogenital epithelium, can be helpful in defining the extent of HPV infection. Efficacy of treatment of verrucae vulgaris and condyloma acuminatum in organ transplant recipients varies with the degree of immunocompromise, and lesions can be very recalcitrant. In patients with early disease, these lesions should be managed as in the normal host. Cryotherapy remains a common choice but management in patients with extensive disease may include bleomycin injections, and application of topical salicylic acid and topical retinoids (Figure 13.8). More recently, imiquimod has been introduced for condyloma, and

Figure 13.8. Verruca vulgaris, extensive; periungual: (A) huge warts located periungually on the dorsum of fingers in a lung transplant recipient and (B) marked reduction after bleomycin injections as well as administration of acitretin.

VIRAL DISEASES IN ORGAN TRANSPLANT RECIPIENTS

small studies suggest safe usage in the organ transplant population although efficacy is still low at 36%.[30] For patients with HPV-induced skin cancer, chemoprevention with systemic retinoids appears effective, although the most effective and tolerable regimens remain to be determined. Management of patients with extensive warts should include avoidance of sun exposure, use of strong sunscreens, reduction in immunosuppressive therapy when possible, and careful observation for the development of malignant lesions.

REFERENCES

1. Stockfleth, E., et al., Human papillomaviruses in transplant-associated skin cancers. Dermatol Surg, 2004. 30(4 Pt 2): p. 604–9. 2. Griffiths, W.J., T.G. Wreghitt, and G.J. Alexander, Reactivation of herpes simplex virus after liver transplantation. Transplantation, 2005. 80(9): p. 1353–4. 3. Dunn, D.L., et al., Association of concurrent herpes simplex virus and cytomegalovirus with detrimental effects after renal transplantation. Arch Surg, 1984. 119(7): p. 812–7. 4. Boivin, G., et al., Acyclovir susceptibilities of herpes simplex virus strains isolated from solid organ transplant recipients after acyclovir or ganciclovir prophylaxis. Antimicrob Agents Chemother, 1993. 37(2): p. 357–9. 5. Lalezari, J., et al., A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. J Infect Dis, 1997. 176(4): p. 892–8. 6. Gourishankar, S., et al., Herpes zoster infection following solid organ transplantation: incidence, risk factors and outcomes in the current immunosuppressive era. Am J Transplant, 2004. 4(1): p. 108–15. 7. Fehr, T., et al., Disseminated varicella infection in adult renal allograft recipients: four cases and a review of the literature. Transplantation, 2002. 73(4): p. 608–11. 8. Gilden, D.H., et al., Neurologic complications of the reactivation of varicella-zoster virus. N Engl J Med, 2000. 342(9): p. 635–45. 9. Hoppenjans, W.B., et al., Prolonged cutaneous herpes zoster in acquired immunodeficiency syndrome. Arch Dermatol, 1990. 126(8): p. 1048–50. 10. Gilson, I.H., et al., Disseminated ecthymatous herpes varicella-zoster virus infection in patients with acquired immunodeficiency syndrome. J Am Acad Dermatol, 1989. 20(4): p. 637–42. 11. Jeyaratnam, D., et al., Concurrent verrucous and varicelliform rashes following renal transplantation. Am J Transplant, 2005. 5(7): p. 1777–80. 12. Pandya, A., et al., Varicella-zoster infection in pediatric solid-organ transplant recipients: a hospital-based study in the prevaricella vaccine era. Pediatr Transplant, 2001. 5(3): p. 153–9.

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13. Safrin, S., et al., Foscarnet therapy in five patients with AIDS and acyclovir-resistant varicella-zoster virus infection. Ann Intern Med, 1991. 115(1): p. 19–21. 14. Slifkin, M., S. Doron, and D.R. Snydman, Viral prophylaxis in organ transplant patients. Drugs, 2004. 64(24): p. 2763–92. 15. Ballout, A., et al., Vaccinations for adult solid organ transplant recipient: current recommendations. Transplant Proc, 2005. 37(6): p. 2826–7. 16. Geel, A., et al., Successful vaccination against varicella zoster virus prior to kidney transplantation. Transplant Proc, 2005. 37(2): p. 952–3. 17. Chaves Tdo, S., et al., Seroprevalence of antibodies against varicellazoster virus and response to the varicella vaccine in pediatric renal transplant patients. Pediatr Transplant, 2005. 9(2): p. 192–6. 18. Nalesnik, M.A., L. Makowka, and T.E. Starzl, The diagnosis and treatment of posttransplant lymphoproliferative disorders. Curr Probl Surg, 1988. 25(6): p. 367–472. 19. Capaldi, L., et al., Localized cutaneous posttransplant Epstein-Barr virus-associated lymphoproliferative disorder. J Am Acad Dermatol, 2004. 51(5): p. 778–80. 20. Walker, R.C., et al., Pretransplantation seronegative Epstein-Barr virus status is the primary risk factor for posttransplantation lymphoproliferative disorder in adult heart, lung, and other solid organ transplantations. J Heart Lung Transplant, 1995. 14(2): p. 214–21. 21. McGregor, J.M., et al., Posttransplant cutaneous lymphoma. J Am Acad Dermatol, 1993. 29(4): p. 549–54. 22. Pariser, R.J., Histologically specific skin lesions in disseminated cytomegalovirus infection. J Am Acad Dermatol, 1983. 9(6): p. 937–46. 23. Razonable, R.R., et al., Herpesvirus infections in solid organ transplant patients at high risk of primary cytomegalovirus disease. J Infect Dis, 2005. 192(8): p. 1331–9. 24. Razonable, R.R., Epidemiology of cytomegalovirus disease in solid organ and hematopoietic stem cell transplant recipients. Am J Health Syst Pharm, 2005. 62(8 Suppl 1): p. S7–13. 25. Collart, F., et al., Visceral KaposiÕs sarcoma associated with human herpesvirus 8 seroconversion in a heart transplant recipient. Transplant Proc, 2004. 36(10): p. 3173–4. 26. Stallone, G., et al., Sirolimus for KaposiÕs sarcoma in renal-transplant recipients. N Engl J Med, 2005. 352(13): p. 1317–23.g 27. Euvrard, S., et al., Skin diseases in children with organ transplants. J Am Acad Dermatol, 2001. 44(6): p. 932–9. 28. Barba, A., et al., Renal transplantation and skin diseases: review of the literature and results of a 5-year follow-up of 285 patients. Nephron, 1996. 73(2): p. 131–6. 29. Roka, S., et al., Prevalence of anal HPV infection in solid-organ transplant patients prior to immunosuppression Human papillomaviruses in transplant-associated skin cancers. Transpl Int, 2004. 17(7): p. 366–9. 30. Harwood, C.A., et al., Imiquimod cream 5% for recalcitrant cutaneous warts in immunosuppressed individuals Viral warts in organ transplant recipients: new aspects in therapy Topical imiquimod cream 5% for resistant perianal warts in a renal transplant patient. Br J Dermatol, 2005. 152(1): p. 122–9.

14 Mycobacterial Diseases in Organ Transplant Recipients

Alexandra Geusau, MD and Elisabeth Presterl, MD

MYC OBA C TE R I AL S K I N I N F E C T I O N I N O R G A N TR A N S P L A N T RE C I P I E N T S – E P I D E M IO LO G Y , DI A G N O SI S , A ND T R E AT M E N T

bacterial disease was 0.56% (0.36% M. tuberculosis infections, 0.20% NTM infections). Infections with M.tuberculosis mainly were systemic (67% pulmonary), whereas NTM infections were located in skin, tendons, and joints.[3] In a North American study involving 4000 kidney transplant recipients, the prevalence of mycobacterial infections was comparably low with 0.45% of the patients developing mycobacterial infection in the posttransplantation period. Among the pathogens isolated, 16.7% were M.tuberculosis, whereas the remainder comprised atypical mycobacteria, most frequently Mycobacterium avium complex (MAC), M. fortuitum and M. chelonae and other nontuberculous acid-fast bacilli. The most common clinical presentation was respiratory tract infection. Infections involving the skin and soft tissue were seen in 47% of the patients. Skin infections usually presented as a non-healing wound after accidental injury. The patients affected by mycobacterial infections had more often experienced a prior episode of acute rejection, suggesting a contributory role for high dose immunosuppression.[6] In 400 Saudi Arabian kidney transplant recipients, 14 cases of mycobacterial infection were identified during a nine-year period. Thus, the annual incidence of tuberculosis in this patient group was 50 times higher than in the general population. The majority of patients had disseminated or pulmonary infection; in one patient, M.tuberculosis infection was transmitted by the donorÕs kidney.[7] The major risk factor for acquiring any mycobacterial disease is immunosuppressive (IS) therapy. According to the Belgian analysis in kidney recipients, the major risk factor was the total dose of corticosteroids. With the introduction of cyclosporine and the newer immunosuppressive medications, more selective immunosuppressants, or tailored combination regimens, the incidence of mycobacterial infections was not higher after kidney transplantation than in the normal population. However, other risk factors were noted to include a history of previous mycobacterial infection, or radiological abnormalities suggestive of previous tuberculosis. Additional contributory factors that may influence the degree of overall systemic immunosuppression are viral infections, uremia, and malnutrition.[3]

Infections caused by mycobacteria occur not only in the early posttransplant period, during the time of the most intensive immunosuppression, but also in the late posttransplant period. They may be due to ‘‘typical’’ mycobacteria, M.tuberculosis, or atypical (or nontuberculous [NTM]) mycobacteria. Mycobacteria are acid-fast, nonmotile, weakly Gram-positive rods. NTM are ubiquitous environmental organisms with generally no attributable pathogenicity. Infection with M. tuberculosis, and in some cases with NTM, is not necessarily a sign of immunosuppression,[1] but, particularly for NTM, depends on individual susceptibility. M.tuberculosis is acquired primarily by inhalation of aerosolized droplets containing the organisms, leading to an infection of the respiratory tract, with subsequent dissemination via the lymphatic system and the bloodstream. NTM comprise slow- and rapidly growing organisms, including M.marinum, M.kansasii, M.avium-intracellulare complex, M.xenopi, M.ulcerans (which causes Buruli ulcer, a chronic progressive disease and important health problem in West African countries), M.fortuitum, M.chelonae, and M.abscessus.

Epidemiology There are very few epidemiological data on mycobacterial infections in solid organ transplant recipients. Infections with M.tuberculosis are uncommon in developed countries; however, these infections are increasing among foreign-born individuals in these countries.[2] Mycobacterial infections seem to be rare in transplant patients, particularly in populations with a low prevalence of the disease. In developed Western countries the reported prevalence of tuberculosis in renal transplant recipients ranges from 0.35 to 4%. In developing countries the reported prevalence is much higher,[3] occurring in up to 15% of transplant recipients in endemic areas.[4] The true incidence of NTM disease in the population of transplant recipients, because of the absence of mandatory reporting, can only be estimated and may range between 0.16 and 2.3%, depending on the type of allograft. The incidence of mycobacterial infection is higher in lung transplant patients compared to patients with renal allografts.[5] According to a retrospective study of the records of 2500 Belgian kidney transplant recipients, the prevalence of myco-

Clinical manifestations Mycobacterial infections of the skin may be primary, due to direct infectious inoculation of the skin by trauma and surgery, or endogenous, either with the spread of a tuberculous process from the underlying tissue (scrofuloderma) or due to 106

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hematogenous spread to the skin with no obvious portal of entry. In immunosuppressed individuals, a history of trauma is usually lacking. In transplant recipients with NTM infections, localized and disseminated cutaneous (approximately one-third of cases) and pleuropulmonary disease are most common, the latter particularly among lung transplant recipients (in 54% of reported cases). Disseminated NTM infection is reported to be the second most common presentation in kidney transplant recipients and the third most common in heart and lung recipients.[5] The spectrum of skin symptoms due to infection with M.tuberculosis and NTM can be quite diverse and mimic tumours or acute pyogenic bacterial infections. Disseminated infection with classical mycobacteria may present as cellulitis, as reported in a kidney transplant patient.[8] In another kidney recipient, subcutaneous swelling with abscess formation and purulent drainage was due to a localized infection with NTM.[9] A similar manifestation, subcutaneous nodules in a kidney transplant patient, has been reported with M. chelonae infection.[10] Another type of NTM, M.haemophilum, first identified in 1978 from ulcerating skin lesions, occurs mostly in immunosuppressed hosts such as AIDS patients and organ transplant recipients and may also present as cellulites.[11,12] An additional manifestation due to M. abscessus in transplant recipients, a sporotrichoid infection of the skin, is considered to be a very rare event.[13] Cases of cutaneous MAC infection have been reported in immunocompetent and immunosuppressed hosts, that is, as part of the spectrum of the nontuberculous mycobacterial immune reconstitution syndrome in HIV-infected individuals after initiation of a highly active antiretroviral therapy. The mycobacterial lesions may present as ulcers, nodules (Figure 14.1), or plaques, are indolent with or without lymph node reaction or systemic manifestations.[14] Accidental inoculation is an important mechanism of skin infection with NTM in the immunocompetent as well as immunsuppessed host. Infection with M.marinum usually occurs following exposure to fish-tank water, as reported for a lung transplant recipient. The clinical presentation was nodules on the hand and forearm, a condition which is called fish tank granuloma.[15] In immunosuppressed patients, dissemination of M.marinum infection may also occur.[16]

Diagnosis The diagnosis of a cutaneous mycobacterial infection is usually made by skin biopsy and special histologic stains demonstrating acid-fast bacilli in clusters. At times, the mycobacterial load is very low and nearly undetectable, but culture is an essential part of the work up. With recent technologic advances, it is now possible to identify mycobacterial infections by polymerase chain reaction (PCR) analysis. As mycobacterial culture may take up to 12 weeks for growth and even longer for identification, PCR can be helpful to detect and identify the mycobacteria in a shorter time. In case of positive cultures, susceptibility testing of mycobacterial isolates is an essential component and is helpful in the management of ther-

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Figure 14.1. Infection with Mycobacterium chelonei/abcessus in a renal transplant recipient, two years post transplant. He had recently been treated with systemic steroid for rejection. The infection resolved completely with antibiotics.

apy.[17–19] Theoretically, the diagnosis of mycobacterial infection is proved only when bacilli are present in biological samples, as the gold standard for diagnosis of tuberculosis is demonstration of mycobacteria from various body fluids. However, this is often not possible in the skin because of the pauci-bacillary nature of illness. Only 50% of cases in adults and 30% in infants have a positive bacteriological result.[20] Culture and staining methods utilized for M. tuberculosis may also detect NTM. Due to the slow growth of most species, the results of mycobacterial cultures may be delayed up to six weeks. Cultures of skin and soft tissue require incubation at low temperatures (28–30°C) and at 35°C because some species, such as M. marinum, M. chelonae, and M. haemophilum, grow only at low temperatures on primary isolation. M. ulcerans, M. genavense, or M. malmoense may require up to 12 weeks for growth. Newer molecular techniques detect mycobacteria even in a low amount, and are used increasingly for identification and detection of resistance. For screening purposes of M.tuberculosis infection, a Mandel– Mantoux test is usually performed before transplantation. The management of a transplant recipient who has a positive skin test is controversial. Generally, prophylactic administration of isoniazid is recommended. The risk of hepatotoxicity from isoniazid prophylaxis is low in transplant recipients without liver disease. In liver transplant candidates with severe liver disease, it is recommended to delay prophylaxis until after liver transplantation when the risk for tuberculosis is higher, and the patient is clinically stable.[21–23] Serological tests may also be of help for the identification of latent infection with typical mycobacteria, particularly using the interferon-gamma assay measuring the reactivity of lymphocytes to a specific antigen of M.tuberculosis.[24]

Treatment The therapy of cutaneous mycobacterial infections is complex and is dependent on the extent of the disease, the species, and

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the degree of immunosuppression. For tuberculosis, the therapeutic regimens follow the same guidelines as that of tuberculosis of other organs and comprise usually at least two different drugs, but most commonly a combination of three to four. The therapy and eradication of the organism in chronically immunosuppressed patient may be a challenge because of the interactions of antimycobacterial agents with drugs also metabolized via cytochrome P-450 enzymes, such as cyclosporine, tacrolimus, sirolimus, and particularly rifampicin and rifabutin. In addition, isoniazid, rifampicin, and pyrizinamide may enhance hepatotoxicity. For the treatment of infections with typical mycobacteria, a combination of at least three of the following agents is used: isoniazid, rifampicin, pyrizinamide and ethambutol if the susceptibility is known or the patient is from an area with low prevalence of multidrug-resistant M.tuberculosis. In case of multidrug resistance, a combination of the above agents with quinolones and clarithromycin has to be considered. Aminoglycosides, which are administered intravenously, are also active against M.tuberculosis, but may cause nephrotoxicity. The therapy of M. avium complex (MAC) is difficult because of the relative resistance of M. avium to common antimycobacterial drugs. The mainstay of MAC therapy is clarithromycin or azithromycin, in combination with the standard antimycobacterial agents; however, the failure rate may be up to 25–50%. For other NTM, including M. kansasii, M. genavense, M. haemophilum, M. simiae, M. celatum, M. marinum, and related pathogens, a combination of isoniazid, rifampicin, ethambutol or clarithromycin or rifampicin plus ethambutol is used. For cutaneous infections with M. marinum, ethambutol is combined with clarithromycin or minocycline or rifampicin. Skin infection due to M. abcessus requires therapy with clarithromycin for at least 6 weeks; however in disseminated infection, cefoxitin plus amikacin intravenously is added. Particularly for deep cutaneous infections, surgical excision may be an essential component of the treatment plan, in order to reduce large collections of mycobacterial infection. Besides surgical debridement or excision, the reduction of the immunosuppressive therapy to increase the immune function may be pivotal for a successful treatment of any mycobacterial disease in organ transplant recipients. The duration of the therapy is not well established in immunosuppressed patients, and is usually continued between six to eighteen months depending on the extent of the disease and immunosuppression. The duration may be extended depending on the clinical response.[21–23].

REFERENCES

1. Palenque E. Skin disease and nontuberculous atypical mycobacteria. Int J Dermatol 2000;39:659–66. 2. Smith KC, Armitige L, Wanger A. A review of tuberculosis: reflections on the past, present and future of a global epidemic disease. Expert Rev Anti Infect Ther 2003 Oct;1:483–91.

3. Vandermarliere A, Van Audenhove A, Peetermans WE, Vanrenterghem Y, Maes B. Mycobacterial infection after renal transplantation in a western population. Transpl Infect Dis 2003;5:9–15. 4. Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clin Infect Dis 1998;27:1266. 5. Doucette K, Fishman JA. Nontuberculous mycobacterial infection in hematopoietic stem cell and solid organ transplant recipients. Clin Infect Diseases 2004;38:1428–39. 6. Jie T, Matas AJ, Gillingham KJ, Sutherland DER, Dunn DL, Humar A. Mycobacterial Infections after Kidney transplant. Transpl Proceed 2005;37:937–39. 7. Qunibi WY, al-Sibai MB, Taher S, Harder EJ, de Vol E, al-Furayh O, Ginn HE. Mycobacterial infection after renal transplantation–report of 14 cases and review of the literature Q J Med. 1990 Oct;77(282):1039–60. 8. Seyahi N, Apaydin S, Kahveci A, Mert A, Sariyar M, Erek E. Cellulitis as a manifestation of miliary tuberculosis in a renal transplant recipient. Transpl Infect Dis 2005;7:80. 9. de Jong JJ, van Gelder T, Ijzermans JNM, Endtz HP, Weimar W. Atypical mycobacterium infection with dermatological manifestation in renal transplant recipient. Transpl Int 1999;12:71–3. 10. Endzweig CH, Strauss E, Murphy F, Rao BK. A case of cutaneous Mycobacterium chelonae abscessus infection in a renal transplant patient. J Cutan Med Surg 2001;5:28–32. 11. Lin JH, Chen W, Lee JYY, Yan JJ, Huang JJ. Disseminated cutaneous Mycobacterium haemophilum infection severe hypercalcaemia in a failed renal transplant recipient. Br J Dermatol 2003; 149:200–2. 12. Ledermann C, Spitz JL, Scully B, Schulman LL, Della-Latta P, Weitzman I, Grossman ME. Mycobacterium haemophilum cellulitis in a heart transplant recipient. J Am Acad Dermatol 1994;30: 804–6. 13. Prinz BM, Michaelis S, Kettelhack N, Mueller B, Burg G, Kempf W. Subcutaneous infection with Mycobacterium in a renal transplant recipient. Dermatology 2004;208:259–61. 14. Phillips P, Bonner S, Gataric N, Bai T, Wilcox P, Hogg R, OÕShaughnessy M, Montaner J. Nontuberculous mycobacterial immune reconstitution syndrome in HIV-infected patients: spectrum of disease and long-term follow-up. Clin Infect Dis 2005 Nov 15;41: 1483–97. 15. Torres F, Hodges T, Zamora MR. Mycobacterium marinum infection in a lung transplant recipient. J Heart Lung Transpl 2001;20: 486–9. 16. Streit M, Bohlen LM, Hunziker T, Zimmerli S, Tscharner GG, Nievergelt H, Bodmer T, Braathen LR. Disseminated Mycobacterium marinum infection with extensive cutaneous eruption and bacteremia in an immunocompromised patient. Eur J Dermatol 2006; 16:79–83. 17. Schluger NW. The diagnosis of tuberculosis: whatÕs old, whatÕs new. Semin Respir Infect 2003;18:241–8. 18. Cheng VC, Yew WW, Yuen KY. Molecular diagnostics in tuberculosis. Eur J Clin Microbiol Infect Dis 2005 Nov;24:711–20. 19. Clarridge JE3rd. Impact of 16S rRNA gene sequence analysis for identification of bacteria on clinical microbiology and infectious diseases. Clin Microbiol Rev. 2004 Oct;17(4):840–62. 20. Martinez V, Gicquel B. Laboratory diagnosis of mycobacterial infections. Arch Pediatr 2005;12(Suppl 2):S96–101. 21. Fitzgerald D, Haas DW. Mycobacterium tuberculosis, in Mandell G.L., Bennett J.E., Dolin R., eds: Principles and diagnosis of infectious diseases, 6th edition, Elsevier; Chapter 248, pp 2852–86. 22. Gordin FM, Horsburgh CR Jr. Mycobacterium avium Complex, in Mandell G.L., Bennett J.E., Dolin R., eds: Principles and diagnosis of infectious diseases, 6th edition, Elsevier; Chapter 250, pp. 2897–909.

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23. Brown-Elliott BA, Wallace RJ Jr. Infections Caused by Nontuberculous Mycobacteria, in Mandell G.L., Bennett J.E., Dolin R., eds: Principles and diagnosis of infectious diseases, 6th edition, Elsevier; Chapter 251, pp. 2909–16.

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24. Pai M. Alternatives to the tuberculin skin test: interferongamma assays in the diagnosis of mycobacterium tuberculosis infection. Indian J Med Microbiol. 2005 Jul;23(3): 151–8.

Section Six

BENIGN AND INFLAMMATORY SKIN DISEASES IN TRANSPLANT DERMATOLOGY

15 The Effects of Transplantation on Preexisting Dermatoses

Namrata Sadanand Anavekar, MBBS, Theresa R. Pacheco, MD, and Shawn E. Cowper, MD

I NF L A M M A T O R Y D E R M A T O S E S I N S O L ID O R G A N T R A N SP L A NT RE C I P I E N TS

medication rather than an association with an autoimmune form of alopecia. However, tacrolimus-related alopecia is not well understood and thus brief mention is made here, as well as in Chapter 10. A study by Tricot et al. found tacrolimus to be associated with higher incidences of generalized scalp alopecia among kidney-pancreas transplant recipients.[12] In this study, 13 of 58 kidney-pancreas transplant recipients had clinically significant alopecia. All were receiving tacrolimus. Of these 13 patients, 11 were female, suggesting that this tacrolimus-associated complication is seen more commonly in females. All patients, except for one, responded well to topical minoxidil. The remaining patient regrew hair after conversion to cyclosporine. There are also two case reports of renal transplant patients [13] (one female, one male) who experienced significant alopecia while receiving tacrolimus. Treatment for both included changing their immunosuppressive regimen to regime cyclosporine. It has been postulated that tacrolimus associated alopecia is a direct effect of the drug, rather than a manifestation of an autoimmune phenomena.[12] To summarize, AA is known to occur among solid organ transplant recipients, usually under cyclosporine immunosuppression. It is unclear how an autoimmune disease arises within an immunosuppressed population; however, it is a complication that physicians and patients should be aware of. Non-immunologically mediated alopecia may be associated with tacrolimus therapy. Both AA and drug-associated alopecia in transplant recipients can usually be managed using topical agents, such as minoxidil.

The advent of immunosuppressive medications has enabled organ transplantation between two genetically different individuals. Improved immunosuppressive regimens have resulted in a dramatic increase in the number of organ transplants worldwide, as well as increased survival rates among recipients. With the steady increase in the transplant population, multiple cutaneous complications of transplantation have been described and their recognition has become increasingly important. Infectious and malignant changes in transplant patients are well recognized, leading to an ongoing emphasis on regular dermatological surveillance of our transplant population. Inflammatory conditions, on the other hand, are less well documented, and may be an under-recognized aspect in the dermatologic care of transplant recipients. This chapter serves to further discuss inflammatory dermatoses and their significance in transplant recipients.

Alopecia Areata (AA) AA is generally regarded as an organ-specific autoimmune disease. This hypothesis has been supported by several findings: 1. Association with specific HLA genes [1] 2. Perifollicular T lymphocyte and antigen-presenting cell infiltrate [2] 3. Elevated levels of autoantibodies to follicular components [2] 4. Increased expression of class I and class II HLA antigens in the lower follicle [3] 5. Clinical response to immunosuppressive agents, including cyclosporine and topical tacrolimus [4]

Atopic Eczema (AE) AE is related to the intimate interplay between cellular and humoral immune mechanisms. When an IgE–antigen complex is presented to Langerhans cells, the irritant capacity of the allergen is magnified. This leads to the stimulation of epidermal T-helper lymphocytes, which then produce cytokines, and propagate allergen sensitization. Feedback then results in increased IgE production.[14] T-lymphocytes play a pivotal role in the pathogenesis of AE. A study of infants receiving heart transplants in the first year of life provides an intriguing and unexpected result. Niemeier et al. documented that the development of AE among immunosuppressed heart transplant recipients within the first year of life appeared to occur at a rate greater than that expected in immunocompetent infants.[15] Forty-one children were included in this study, all of whom received

Given the response of AA to immunosuppressive medications, it is surprising to find reports of AA among immunosuppressed transplant recipients. A literature review reveals nine documented reports of AA occurring among transplant patients receiving cyclosporine (Table 15.1). Two of these patients had type I diabetes, lending credence to an autoimmune mechanism being responsible for both diseases. It should also be remembered that the efficacy of cyclosporine is thought to be dose-dependent, and these cases of AA all appeared in the setting of dose reduction. The association of tacrolimus and alopecia noted in transplant patients is felt more to be a direct adverse effect of the

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Table 15.1 Alopecia Areata in transplant patients receiving cyclosporine[5] Reference 6

Roger, Charmes, and Bonnetblanc (1994) Dyall-Smith7 (1996) Cerottini, Panizzon, and de Virah8 (1999) Davies and Bowers9 (1995) Monti, Barbareschi, and Caputo10 (1995) Monti, Barbareschi, and Caputo10 (1995) Misciali et al.11 (1996) Phillips, Graves, and Nunley5 (2005) Phillips, Graves, and Nunley5 (2005)

Age (y) at onset/ gender

Type of transplant

Primary disease

46/F 30/F 5/M 27/M 23/F 6/F 22/F 28/F 44/F

Renal Renal Renal Heart Liver Liver Liver Kidney-pancreas Kidney-pancreas

Interstitial nephropathy Unknown Polycystic kidney disease Cardiomyopathy Hepatitis B Congenital biliary cirrhosis Hepatitis B Type 1 diabetes mellitus Type 1 diabetes mellitus

cyclosporine post-transplantation. Eleven of twenty-seven children who underwent transplantation within the first year of life developed AE. AE was not observed among any of the 7 children who received a heart transplant after one year of age or in 7 controls who had undergone heart surgery but not transplantation. The reasons why an immune-mediated inflammatory skin disease would be more common in infants who are receiving potent systemic immunosuppression remain open to conjecture. Given that T-lymphocyte maturation occurs in the first year of life, it is possible that the specific inhibitory effect of cyclosporine on these cells at this time promotes the development of AE. Thus far, there are no documented reports of atopy being transferred via solid organ transplantation. It is well known that this phenomenon does occur among bone marrow recipients; whether it is possible in other transplant patients can only be speculated. Atopic eczema has been reported in adult transplant patients, including the response to initiation of systemic immunosuppression. Euvrard et al. identified seven patients within their study population of organ transplant recipients who had AE.[16] Five patients had AE prior to transplantation, and their eczema cleared in the posttransplantation period. In two patients, AE developed following transplantation. The ages of these patients, and their immunosuppressive regime, was not cited. An example of an eczematous dermatitis in a transplant recipient is displayed in Figure 15.1. In clinical experience, adult patients with AE often experience dramatic improvement in their skin disease after renal transplantation, probably due to a combination of immunosuppressive medications and an improvement in renal function. Children, especially those transplanted before the age of one, may have an increased risk of AE, and the disease may be severe.

a role both in the initiation and propagation of psoriasis. The benefit of cyclosporine in psoriasis suggests T-cell activity is an effective target for immunotherapy. Additionally, the exacerbation of psoriasis by interferon-a also implies the involvement of autoreactive T-cells.

Psoriasis It is well recognized that the etiology of psoriasis is multifactorial, with interaction between hereditary and environmental factors. The exact pathogenic mechanisms are yet to be established; however, it is evident that immune mechanisms play

Figure 15.1. Eczematous dermatitis in a patient s/p liver transplant in 2002 maintained on tacrolimus and prednisone. The dermatitis began during treatment for hepatitis C with systemic interferon.

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Table 15.2 Psoriasis in organ transplant recipients Reference

Total number of patients

Number of patients with psoriasis

Response to transplantation

Euvrard et al.16 (2000) Alper et al.23 (2004) Formicone et al.24 (2005)

145 111 109

2 1 5

Complete resolution No comment No change

There are multiple reports of resolution of psoriasis following bone marrow transplantation.[17–19] In addition, there is also documentation of transmission of psoriasis,[20] and of psoriatic arthritis,[21] via bone marrow transplantation. This further supports autoimmune dysregulation as being the primary defect in the initiation of psoriasis. There is limited literature pertaining to psoriasis in the setting of solid organ transplant patients. The information that is available is derived from multiple studies, which have incidental findings of psoriasis within their patient population (Table 15.2). The study performed by Euvrard et al. involved children undergoing transplantation.[16] Whether the resolution of psoriasis is related to the susceptibility of a naı¨ve immune system to suppression can only be theorized. In addition to these studies, there has also been a case report of pustular psoriasis in a renal transplant patient failing to improve despite the use of cyclosporine.[22] Interpreting information from multiple studies is difficult as there is no indication as to which specific immunosuppressive agents were used, the dosing regime, or the type of transplant undertaken. In clinical practice, many patients with psoriasis tend to respond well to the immunosuppressive agents given for organ transplantation. Unfortunately, some organ transplant recipients may continue to experience refractory psoriasis despite potent immunosuppression. Further studies assessing the response of psoriasis to organ transplantation could provide multiple benefits. Studies of this response might provide a window into the immune mechanisms involved in the formation of a psoriatic plaque. This in turn could allow identification of specific immune targets for instituting therapies. Furthermore, with additional information, patients undergoing transplantation could be educated about the potential resolution or exacerbation of their chronic dermatological condition.

whom reported this to be a preexisting condition. In this study there was no comment relating to management difficulties. EuvrardÕs study of skin diseases in children post solid organ transplantation observed two patients with vitiligo.[16] One of these children developed the condition post transplantation. The management and outcome of the child was not outlined. The other patient had vitiligo pretransplant and demonstrated partial repigmentation following the reintroduction of azathioprine. Figure 15.2 depicts a transplant patient with partial repigmentation of vitiligo after transplantation. EuvrardÕs study also showed a progressive increase in melanocytic nevi after transplantation, reiterating the possible role of immune mechanisms in suppressing the development of nevi. Interestingly, this phenomenon always occurred after seven years of age, despite some patients undergoing transplant in infancy. There are a number of interesting case reports regarding other dermatoses in transplant recipients. In 1988, Polson et al. described the case of a 13-year-old boy with erythropoietic protoporphyria, who underwent liver transplantation.[26] Prior to transplantation, the boy experienced recurrent photosensitivity, which resolved completely following orthotopic transplantation. In contrast, a woman who had received a liver transplant following hepatic failure, secondary to primary biliary cirrhosis, developed discoid lupus erythematosus despite

Miscellaneous inflammatory conditions There is a paucity of literature pertaining to a wide range of inflammatory dermatoses in transplant patients. Information must be gathered from multiple sources and inferences may be difficult due to conflicting reports. For example, evaluation of Oxford renal transplant recipients [25] revealed seborrheic eczema to be a notably difficult condition to treat in transplant recipients compared to the normal population. In contrast, however, a study of 109 Italian renal transplant patients [24] only observed seborrheic dermatitis in three patients, all of

Figure 15.2. Repigmenting vitiligo in a patient s/p liver transplant in 1999 and renal transplant in 2005, while immuosuppressed with tacrolimus, mycophenolate mofetil, and prednisone. The vitiligo repigmented after increased immunosuppression with renal transplantation.

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treatment with cyclosporine.[27] This report speculates that a combination of a predisposition to autoimmune disorders (as evidenced by the patientÕs primary biliary cirrhosis) and cyclosporine can elicit autoimmune dysfunction via its selective activity on T-lymphocyte function. Unfortunately, despite reports of skin pathology within the transplant population such as lichen simplex chronicus and lichen planus,[28] the lack of commentary regarding response to transplantation and subsequent immunosuppression, prevents the synthesis of informed conclusions. It is even uncertain whether these conditions occur at a higher, lower, or similar incidence as that found within the normal population. Further investigations looking at inflammatory skin conditions in transplant recipients would be beneficial.

Nephrogenic Systemic Fibrosis (NSF) NSF is a condition that warrants detailed discussion. Originally discovered in 1997, a registry identifying these patients now contains approximately 215 documented cases of NSF.[29] It is a scleroderma-like disease of the skin, solely found in patients with renal insufficiency.[30] The onset of renal impairment may be acute, chronic, or transient, with a wide range of renal pathologies implicated in its presentation.

Epidemiology Thus far, all patients with NSF are consistently found to have associated renal failure. Although many of the patients have received dialysis or failed renal transplantation, this is not a constant feature, and should be recognized as merely a common finding within a population of patients with renal impairment. This disease affects males and females in a 1:1 ratio and has no racial predilection.[29] Although most commonly seen among the adult population, as most renal failure patients are adults, pediatric cases have been described.[31] The relatively recent emergence of NSF cases since 1997 has prompted a search for recent advances in medical practice, which may have triggered the onset of this systemic disorder. Although dialysis was once believed to be a possible culprit, given its strong association with NSF, there are several arguments against this possibility: 1. Ten percent of patients documented to have NSF have never been dialyzed.[29] 2. There is no specific dialysis regimen that has been implicated among NSF patients receiving dialysis.[29] 3. The vast majority of patients receiving dialysis have not developed NSF.[32] More recently, an association between MRI scanning and onset of NSF has been recognized. Recent reports from Europe, as well as epidemiological information from the NSF Registry [33] in the United States, strongly associate recent MRI imaging with the contrast agent gadolinium with disease onset.[34,35] Gadolinium deposits have recently been observed in tissue specimens from patients with documented

NSF who had undergone an MRI with gadolinium-based contrast material.[36,37] Unless a causal relationship is excluded, the use of gadolinium should be avoided in the setting of renal insufficiency.[38] Further studies assessing medical intervention and the onset of NSF will provide better insight into possible etiological agents.

Associated Features Numerous hypercoagulable states have been reported in association with NSF, including anticardiolipin antibodies, protein C and S deficiency.[39] There are also reports of thrombotic events such as deep venous thrombosis and pulmonary embolus among these patients. There is a common finding of surgical procedures prior to the onset of NSF.[30] These procedures include vascular reconstruction, hepatic, or renal transplant and fistula construction. Non-renal organ diseases, such as chronic liver disease and pulmonary fibrosis, have been seen in NSF patients.[30] In those patients with hepato-renal syndrome, reestablishment of renal function via liver transplantation may improve cutaneous manifestations of NSF.[40] Clinicopathologic Findings Typically, cutaneous lesions of NSF comprise fleshcolored to erythematous papules, which coalesce to form plaques with a peau dÕorange surface, often described as having a ‘‘woody’’ texture (Figure 15.3). There is usually a symmetrical distribution over the limbs and trunk. Occasionally, nodules and bullae have been described. Additionally, there have been reports of associated edema of hands and feet. There is often restricted mobility of hands and feet, with frequent involvement of major joints. It is not uncommon to observe rapid development of joint contractures and subsequent immobility. The differential diagnoses for NSF include scleromyxedema, systemic sclerosis/morphea, porphyria cutanea tarda, amyloidosis, calciphylaxis, and fibrosis induced by drugs, silica, or organic solvents. In the setting of an acute onset of symptoms, cellulitis is often a presumptive diagnosis. Histopathology offers diagnostic confirmation to a compatible clinical scenario. Features include infiltration and proliferation of dermal fibrocytes and dendritic cells with the relative absence of lymphocytes. There is thickening of collagen bundles, prominent areas of angiogenesis, increased elastic fibers, and occasionally increased dermal mucin. The dermal spindle cells (fibrocytes) are characteristically immunohistochemically positive for both CD34 and procollagen. This finding may imply that a process similar to wound healing is taking place in noninjured tissues, thus leading to the cutaneous manifestations observed. Management Given that prompt improvement is observed following normalization of renal function, currently the ideal therapy is

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REFERENCES

Figure 15.3. Eighty-year-old man with biopsy-proven cutaneous nephrogenic systemic fibrosis. The patient has ANCA-positive vasculitis isolated to the kidneys with end-stage renal disease on hemodialysis and had received gadolinium for an MRI.

renal transplantation.[30,41] As NSF appears most commonly among patients with chronic renal impairment requiring dialysis, these individuals are frequently awaiting transplantation. The onset of NSF should prompt expedience of transplantation. Several reports have highlighted the resolution of NSF post transplantation, warranting its place as first-line management. Two pediatric cases of NSF demonstrated prompt improvement of cutaneous disease following cadaveric kidney transplant.[31] Of these patients, one rejected the transplant and required recommencement of dialysis. Despite a return to dialysis, his skin lesions did not reappear. In all patients with NSF, a complete coagulation screen should be performed in order to detect and prevent thrombotic complications. Alternate therapies for NSF include extracorporeal photophoresis, which has been successful in three patients observed in Europe.[42] Multiple therapeutic options are undergoing further investigation, including oral and topical steroids, calcipotriene, cyclophosphamide, cyclosporine, PUVA, intravenous immunoglobulin, and interferon-a.[29]

1. de Andrade M, Jackow CM, Dahm N, Hordinsky M, Reveille JD, Duvic M. Alopecia areata in families: association with the HLA locus. J Invest Dermatol Symp Proc. 1999; 4: 220–3. 2. Tobin DJ, Orentreich N, Fenton DA, Bystryn J-C. Antibodies to hair follicles in alopecia areata. J Invest Dermatol. 1994; 102: 721–4. 3. Christoph T, Muller-Rover S, Audring H, et al. The human hair follicle immune system: cellular composition and immune privilege. Br J Dermatol. 2000; 142: 862–73. 4. Madani S, Shapiro J. Alopecia areata update. J Am Acad Dermatol. 2000; 42: 549–70. 5. Adapted from Phillips MA, Graves JE, Nunley JR. ;Alopecia areata presenting in 2 kidney-pancreas transplant recipients taking cyclosporine J Am Acad Dermatol. 2005; S252–5. 6. Roger D, Charmes JP, Bonnetblanc JM. Alopecia occurring in a patient receiving cyclosporin A [letter]. Acta Derm Venereol. 1994; 74: 154. 7. Dyall-Smith D. Alopecia areata in a renal transplant recipient on cyclosporine. Australas J Dermatol. 1996; 37: 226–7. 8. Cerottini JP, Panizzon RG, de Virah PA. Multifocal alopecia areata during systemic cyclosporine A therapy. Dermatology 1999; 198: 415–7. 9. Davies M, Bowers P. Alopecia areata arising in patients receiving cyclosporine immunosuppression. Br J Dermatol. 1995; 132:835–6. 10. Monti M, Barbareschi M, Caputo R. Alopecia universalis in liver transplant patients treated with cyclosporine. Br J Dermatol. 1995; 133: 663–4. 11. Misciali C, Peluso AM, Cameli N, Tosti A. Occurrence of alopecia areata in a patient receiving systemic cyclosporine A. Arch Dermatol. 1996; 32: 843–4. 12. Tricot L, Lebbe C, Pillebout E, Martinez F, Legendre C, Thervet E. Tacrolimus-induced alopecia in female kidney-pancreas transplant recipients. Transplantation 2005; 1546–9. 13. Talbot D, Rix D, Abusin K, Mirza D, Manus D. Alopecia as a consequence of tacrolimus therapy in renal transplantation? [letter] Transplantation 1997; 1631–2. 14. Wollenberg A, Bieber T. Antigen-presenting cells. In: Bieber T, Leung DYM eds. Atopic Dermatitis. New York: Marcel Dekker Inc, 2002:267–83. 15. Niemeier V, Passoth Pr, Kramer U, Bauer J, Oschmann P et al. Manifestation of atopic eczema in children after heart transplantation in the first year of life Pediatr Dermatol. 2005; 102–8. 16. Euvrard S, Kanitakis J, Cochat P, Cambazard F, Claudy A. Skin diseases in children with organ transplants. J Am Acad Dermatol. 2001; 932–9. 17. Windrum P, Jones FGC, McMullin MF. Adoptive immunotherapy after bone marrow transplantation in a patient with relapsed acte myeloid leukemia and severe psoriasis Bone Marrow Transplantation 2004; 281–2. 18. Kanamori H, Tanaka M, Kawaguchi H, Yamaji S, Fujimaki K et al. Resolution of psoriasis following allogenic bone marrow transplantation for chronic myelogenous leukemia: case report and review of the literature Am J Haematol. 2002; 41–4. 19. Adkins DR, Abidi MH, Brown RA, Khoury H, Goodnough LT et al. Resolution of psoriasis after allogenic bone marrow transplantation for chronic myelogenous leukemia: late complications of therapy Bone Marrow Tranplantation 2000; 1239–41. 20. Snowden JA, Heaton DC. Development of psoriasis after syngeneic bone marrow transplant from psoriatic donor: further evidence for adoptive autoimmunity Br J Dermatol. 1997; 130–2. 21. Daikeler T, Gunaydin I, Einsele H, Kanz L, Kotter I. Transmission of psoriatic arthritis by allogenic bone marrow transplantation for

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chronic myelogenous leukemia from an HLA-identical donor [letter] Rheumatology 1999; 89–90. Coulson IH, Evans CD, Holden CA. Generalized pustular psoriasis after renal transplantation–failure to suppress with cyclosporin A. Clin Exp Dermatol. 1988; 13(6): 416–7. Alper S, Kilinc I, Dunman S, Toz H, Ceylan C et al. Skin diseases in Turkish renal transplant recipients Int J Dermatol. 2005; 939–41. Formicone F, Fargnoli MC, Pisani M, Rascente A, Famulari A, Peris K. Cutaneous manifestations in Italian kidney transplant recipients Transplant Proc. 2005; 2527–8. Eedy DJ. Dermatology issues in solid organ transplant recipients [editorial]. Br J Dermatol. 2006; 154: 393–4. Polson RJ, Lim CK, Rolles K, Calne RY, Williams R. The effect of liver transplantation in a 13-year-old boy with erythropoietic protoporphyria. Transplantation. 1988; 46: 386–9. Obermoser G, Weber F, Sepp N. Discoid Lupus Erythematosus in a patient receiving cyclosporine for liver transplantation [letter to the editor]. Acta Derm Venereol. 2001: 81. Avermaete A, Altmeyer P, Bacharach-Buhles M. Non-malignant skin changes in transplant patients [editorial comments]. Nephrol Dial Transplant. 2002; 17: 1380–3. DeHoratius DM, Cowper SE. Nephrogenic systemic fibrosis: an emerging threat among renal patients [editorial]. Seminars in dialysis. 2006; 19: 191–4. Cowper SE. Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol. 15: 785–90. Jan F, Segal JM, Dyer J, LeBoit P, Siegfried E, Frieden IJ. Nephrogenic fibrosing dermopathy: two pediatric cases. J Pediatr. 2003; 143: 678–81. Cowper SE, Su L, Robin H, Bhawan J, LeBoit PE. Nephrogenic fibrosing dermopathy. Am J Dermatopathol. 2001; 23: 383–93.

33. Cowper SE: Nephrogenic fibrosing dermopathy [NFD/NSF Web site]. Available at http://www.icnfdr.org; accessed September 26, 2006 34. Grobner T. Gadolimium: a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006; 21: 1104–8. 35. Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, Thomsen HS. Nephrogenic Systemic Fibrosis: Suspected Causative Role of Gadodiamide Used for Contrast-Enhanced Magnetic Resonance Imaging. J Am Soc Nephrol 17: 2359–62, 2006. 36. High WA, Ayers RA, Chandler J, Zito G, Cowper SE. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol. 56(1):21–6, 2007 Jan. 37. Boyd AS, Zic JA, Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol. 56(1):27–30, 2007 Jan. 38. Public Health Advisory. United States Food and Drug Administration, Issued June 8, 2006. Available at: http://www.fda.gov/cder/drug/ advisory/gadolimium_agents.htm 39. Mackay-Wiggan JM, Cohen DJ, Hardy MA, Knobler EH, Grossman ME. Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease. J Am Acad Dermatol. 2003; 48: 55–60. 40. Cantos K, Hillebrand DJ, Hu KQ, Ojogho ON, Nehlsen-Cannarella S, Concepcion W. Nephrogenic fibrosing dermopathy after liver transplantation successfully treated with plasmapharesis. Am J Dermatopathol. 2003; 25: 204–9. 41. Cowper SE. Nephrogenic systemic fibrosis: the nosological and conceptual evolution of nephrogenic fibrosing dermopathy [editorial]. Am J Kidney Diseases. 2005; 46: 763–5. 42. Gilliet M, Cozzio A, Burg G, Nestle FO. Successful treatment of three cases of nephrogenic fibrosing dermopathy with extracorporeal photophoresis. Br J Dermatol. 2005; 152: 531–6.

16 Porokeratosis in Organ Transplant Recipients

Charlotte Proby, BA, MBBS, FRCP and Catherine Harwood, MA, MBBS, MRCP, PhD

INT ROD UCTION

is the most widely accepted. They postulated that a focal anomaly in keratinization is due to expansion of a clone of mutant keratinocytes underlying the parakeratotic column. The clinical, histological, and cytological features of PK support the theory.[5] UV light and immunosuppression, which together with genetic susceptibility play a major role in the pathogenesis of PK, are also consistent with the ‘‘mutant clone’’ theory.[2] With DSAP there is considerable clinico-epidemiological data to support UV light as an eliciting factor, including lesions located on sun-exposed sites, exacerbation in summer months, and experimental induction of lesions after artificial UV exposure. Although UV exposure would be expected to promote PK development through induction of local immunosuppression, the role of UV light in the genesis of other forms of PK is less clear. The profound iatrogenic immunosuppression required following organ transplantation is associated with a significantly increased incidence in PK.[1] PK has also been associated with immunodeficiency diseases and various inflammatory or autoimmune diseases requiring immunosuppressive drugs or chemotherapy. Genetic factors are paramount in familial cases of PK where an autosomal dominant mode of inheritance has been reported, but are not usually apparent in transplantassociated disease.

Porokeratosis (PK) is an uncommon disorder of epidermal differentiation with an increased incidence in organ transplant recipients (OTR).[1,2] There are different clinical manifestations of PK, but all share a distinct histopathology characterised by the ‘‘cornoid lamella,’’ a narrow dyskeratotic column, which interrupts the granular layer with associated parakeratosis and often hydropic degeneration of the corresponding basal layer (Figure 16.1).

C L I N I C AL F E A T UR E S Porokeratosis presents as a well-demarcated, irregular plaque that expands slowly in a centrifugal fashion with a prominent hyperkeratotic, ridged border corresponding to the cornoid lamella and some central atrophy. PK was first described by Mibelli in 1893,[3] and the classic Porokeratosis of Mibelli (PKM) is a form found commonly in OTR. PKM presents as one or more localized asymptomatic annular plaques. These may become large (up to 20 cm diameter) and are usually, but not exclusively, located on the limbs, commonly the lower legs (Figure 16.2). Other clinical presentations of PK include: 1. Disseminated superficial actinic porokeratosis (DSAP): Common in countries with high ultraviolet (UV) exposure and presenting with multiple small superficial, annular lesions symmetrically distributed on sun-exposed areas of skin. Individual lesions are less prominent than those of PKM and may be overlooked or ignored. Patients often describe symptomatic exacerbations following sun exposure. 2. Disseminated superficial porokeratosis (DSP): Similar to DSAP, but without UV light as a precipitating factor. 3. Linear porokeratosis (LPK): Linear systemized lesion reminiscent of an epidermal nevus. 4. Porokeratosis palmaris, plantaris et disseminata (PPPD): DSAP-like lesions initially limited to the palms and soles. 5. Punctate porokeratosis (PPK): Punctate keratotic spines on the palms and soles, which may mimic other punctuate palmar keratoses.

POROKERATOSIS ASSOCIATED WITH O R G A N TR A N S P LA N T AT I ON The reported incidence of PK following organ transplantation varies considerably between different series. In most retrospective studies, incidence is low,[2] probably because PK lesions are often asymptomatic and ignored by patients or over looked by physicians. Many OTR have numerous keratotic or warty skin lesions, and PK may be mistaken for seborrheic keratoses, solar keratoses, flat viral warts, or even plaques of BowenÕs disease. A prospective study of 103 renal transplant recipients (RTR) found 11 cases of PK (10.7%).[1] In a cohort of 799 RTR followed prospectively since 1995 and systematically examined for PK by the authors, we found an overall incidence for all types of porokeratosis of 8% (occurring in 64/799 RTR). These transplant-associated PK lesions were most commonly PKM type and often multiple. The incidence was significantly higher in patients with a history of skin cancer (34/248: 13.7%) compared to those without

P A T H OGE NE SI S Although the pathogenesis of PK is unknown, the ‘‘mutant clone’’ theory, first proposed by Reed and Leone in 1970,[4] 119

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CHARLOTTE PROBY AND CATHERINE HARWOOD

Figure 16.1. Photomicrograph of a transplant-associated porokeratosis demonstrating the characteristic parakeratotic column of dyskeratotic keratinocytes, or Ôcornoid lamellaÕ (Hematoxylin and eosin).

a history of skin cancer (30/551: 5.45%) [p < 0.001]. Transplant-associated PK usually presents as one or several PKM lesions, or as multiple DSP/DSAP lesions on the legs, or as a spectrum involving both types of PK. DSAP is usually associated with severe actinic damage and can predate organ transplantation. The relative paucity of DSAP in our transplant cohort may relate to latitude, strict sunavoidance, and use of high protection-factor sunscreens. PK lesions are notoriously resistant to treatment, but have been known to regress after discontinuation of immunosuppression.[2] The response to topical treatments such as 5-fluorouracil cream is often disappointing. Isolated lesions can be excised surgically or destroyed with cryotherapy, laser, or electrocautery.[2]

P O R O K E R A T O S I S AN D M A L I G N A N C Y In classical PK, malignant conversion is reported as a late event, occurring after an average of 33.5 years.[6] Until recently, however, SCC had not been reported with the common forms of transplant-associated PK, perhaps because few patients had been followed long enough. In a single report, an OTR with extensive actinic damage had preexisting multiple PK lesions and subsequently developed metastatic SCC.[7] Malignant conversion is more frequent in linear porokeratosis from which multiple tumors may develop, and there has been a report of metastatic SCC arising from perianal LPK in an RTR.[8] The rarity with which transplant-associated PK transforms to malignancy might suggest that it is a benign disease; however, our understanding of the pathogenesis together with the frequent association of PK with other posttransplant cutaneous malignancies, suggests that malignant conversion is likely in the long term. Mean follow-up for our 64 patients with transplant-associated PK, none of whom have developed

Figure 16.2. Transplant-associated porokeratosis on the lower leg of a renal transplant recipient.

malignancy, is 15.75 years (range 7 months to 31 years). Arguably, this is too short a time for the expected malignant conversion. Consequently, if the size, site, or number of PK lesions makes removal or destruction impractical, it is important for the patient to practice self-surveillance and to return promptly, should a proliferative lesion arise at the site of a porokeratosis.

REFERENCES

1. Herranz P, Pizarro A, de Lucas R, Robayana M, Rubio F, Sanz A, Contreras F, Casado M. High incidence of porokeratosis in renal transplant patients. Br J Dermatol 1997; 136: 176–9. 2. Kanitakis J, Euvrard S, Faure M, Claudy A. Porokeratosis and immunosuppression. Eur J Dermatol 1998; 8: 459–65. 3. Mibelli V. Contributo allo studio della ipercheratosi dei canali sudoriferi. Gior Ital Mal Ven 1893; 28: 313–55. 4. Reed R, Leone P. Porokeratosis – a mutant clonal keratosis of the epidermis. Arch Dermatol 1970; 101: 340–7. 5. Otsuka F, Someya T, Ishibashi Y. Porokeratosis and malignant skin tumors. J Cancer Res Clin Oncol 1991; 117: 55–60.

POROKERATOSIS IN ORGAN TRANSPLANT RECIPIENTS

6. Sasson M, Krain A. Porokeratosis and cutaneous malignancy. A review. Dermatol Surg 1996; 22: 339–42. 7. Silver S, Crawford R. Fatal squamous cell carcinoma arising from transplant-associated porokeratosis. J Am Acad Dermatol 2003; 49: 931–3.

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8. Anzai S, Takeo N, Yamaguchi T, Sato T, Takasaki S, Terashi H, Takayasu S, Takahashi S. Squamous cell carcinoma in a renal transplant recipient with linear porokeratosis. J Dermatol 1999; 26: 244–7.

17 Benign Cutaneous Neoplasms in Organ Transplant Recipients

Catherine Harwood, MA, MBBS, MRCP, PhD and Charlotte Proby, BA, MBBS, FRCP

INTR ODUCT IO N

ological presentations, or that management should differ in OTRs.

A wealth of information has been published in recent years concerning the incidence, clinicopathological spectrum, treatment, prognosis, and prevention of skin malignancies in organ transplant recipients (OTRs). However, relatively little has been reported in relation to benign skin tumors. This section will review the available published literature, together with unpublished data, relating to benign tumors observed in our own cohort of over 800 renal transplant recipients under long-term surveillance since 1989 at BartÕs and the London NHS Trust, London, U.K (BLT). It should be emphasised that accurate prevalence data are limited for almost all of these tumors, and most published and unpublished observations should therefore be regarded as essentially anecdotal until further data are available from larger cohort studies. Nonetheless, an appreciation of the spectrum of benign tumors in OTRs is important, as some of these tumors may simulate more aggressive malignancies; others represent a source of considerable morbidity, and a few may possess potential for malignant transformation. Relevant published data are summarized in Table 17.1, [1–26] and particular tumors are discussed in more detail in the following text.

Epidermoid cysts There are several anecdotal reports describing the occurrence of these keratin-containing cysts lined by epidermis in OTRs.[4–10] However, published data provide no indication of whether these lesions are significantly more common in OTRs. In our patient cohort at BLT, epidermoid cysts were routinely documented from 1995 to 2005. We identified 86/ 797 (10.8%) of patients with such cysts, not all of whom were receiving cyclosporine. Although in most cases epidermoid cysts were clinically typical and solitary, one individual had multiple, deforming, histologically-proven epidermoid cysts, which required repeated surgical intervention (Figure 17.2). This is a rare but recognized complication of epidermoid cysts, but has not previously been reported in OTRs. The pathogenesis of epidermoid cysts in OTRs has been particularly associated with cyclosporine therapy, but HPV and trauma, including an isotopic response to herpes zoster, have been proposed as causes.[4–7] Milia, small subepidermal keratin cysts arising from underdeveloped sebaceous glands or interrupted sweat ducts, are also described in OTRs and a relationship to cyclosporine postulated.[8,9]

K E R A T I NO C YT E TU M OR S APPENDAGEAL TUMORS

Squamous cell papillomas, verrucal keratoses Viral warts (HPV-induced squamous cell papillomas) are, undoubtedly, the most prevalent benign keratinocyte tumor in OTRs, and these are dealt with elsewhere in the volume. However, another group of squamous cell papillomas that lack typical HPV-associated histopathological features are also well recognised in OTRs.[1] Often referred to as verrucal keratoses, these lesions usually present as hyperkeratotic papules and nodules (Figure 17.1). Their pathogenesis is unclear. Cryotherapy and topical agents are often unsuccessful, and surgery (excision or curettage and cautery) may be required if these lesions become troublesome.

We have previously reported a greatly increased frequency of malignant appendageal tumors, particularly those of sebaceous origin, in OTRs compared with the immuncompetent population. Benign appendageal tumors also appear to be overrepresented.[11] As in the general population, the clinical appearances may be subtle (Figure 17.3), and diagnosis is often made only after excision and histological examination. The etiology of these tumors is unclear. Ultraviolet radiation and human papillomavirus may be involved in some tumors,[11] and immunosuppressive drugs may play a cofactor role, independent of their immunosuppressive effects. It is noteworthy, for example, that cyclosporine is implicated in causing hyperplasia and dysplasia of the pilar matrix,[28] and that azathioprine may have specific effects on sebaceous tumor development,[29] possibly enhanced by its interaction with UVA.[30] There is no evidence that treatment of these tumors in OTRs should differ from that in immunocompetent individuals.

Seborrheic Keratoses Although reported in OTRs,[2,3] there is no information available to suggest that these common lesions are more prevalent, that they have atypical clinical or histopath-

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123

Table 17.1 Benign cutaneous neoplasms reported in organ transplant recipients Cell of origina

Classification

Keratinocyte

Appendageal

Selected reports b

Apocrine and eccrine differentiation

Follicular

Sebaceous

Melanocytic

Nevi

Soft tissue

Vascular / pericytic tumors Adipocyte Smooth muscle Fibrohistiocytic Neural

Squamous cell papilloma (non-viral) Seborrheic keratosesb Epidermoid cysts and miliab Epidermolytic acanthoma Hidrocystoma Poroma Syringofibradenoma Spiradenoma Syringocystadenoma papilliferum Trichoblastoma (trichoepithelioma) Pilomatricoma Tumor of the follicular infundibulum Inverted follicular keratosis Sebaceous gland hyperplasia (SGH)b Sebaceous adenoma Steatosebocystadenoma Benign melanocytic nevib Dysplastic melanocytic nevib Hemangioma Tufted angiomas Glomus tumor Lipoma Angiolipoma Angioleiomyoma Dermatofibroma Neurofibroma

1 2,3 4–9 10 11 11 BLT BLT 11, 12 11 11 11 11 13–19 11 20 21–23 24 BLT 25 BLT BLT BLT BLT 26 BLT

a

As defined in the World Health Organisation Classification of Tumors: Skin Tumors (Edited by BeBoit PE, Burg G, Weedon D, Sarasin A; IARC Press, Lyon, 2006) and Tumors of Soft Tissue and Bone (Edited by Fletcher CDM, Unni KK, Mertens F; IARC Press, Lyon, 2002). b Specifically discussed in the text BLT, unpublished data relating to tumors observed and histologically confirmed at least once in a cohort of >800 organ transplant recipients attending BartÕs and the London NHS Trust, London, UK.

Sebaceous gland hyperplasia (SGH) SGH requires particular mention as a benign appendageal tumor, given its prevalence and associated cosmetic morbidity in OTRs. SGH was first confirmed to be significantly more common in OTRs in 1996. Cyclosporine has most frequently been implicated in its pathogenesis.[13] In our cohort, 187/ 815 (22%) individuals have at least one lesion of clinically typical SGH, similar to the 17% (30/173) reported in an Irish renal transplant cohort [28] and 17.4% in a French liver transplant cohort.[19] We have noted a possible association with skin cancer in that 56% (99/176) of patients with NMSC developed SGH compared with 14% (88/617) without NMSC. Similar findings have been previously reported.[31] It is noteworthy that 23 patients with SGH were Fitzpatrick skin phototypes V or VI, representing a prevalence of 13.5% (23/170) in non-Caucasian OTRs. 23 patients (2.8%) were not on cyclosporine. Severe SGH (defined as >20 individual lesions) occurred in 19% (36/187) of patients, of whom 9 were sufficiently concerned by the cosmetic appearance to actively seek treatment. In our experience, topical retinoids have been

unsuccessful, and those individuals on low-dose oral acitretin, as NMSC chemoprophylaxis, noticed no improvement in SGH. Cryotherapy was of significant benefit in only 1 of 7 patients and trichloroacetic acid in 1 of 3. Electrodessication helped in 2 of 4 patients but was associated with significant scarring. Photodynamic therapy with methylaminolaevulinic acid resulted in excellent response and cosmetic result in one individual with particularly severe SGH (Figure 17.4).[32] Carbon dioxide laser has also been reported as effective in one case.[17] In general, however, treatment of SGH in OTRs has not been systematically evaluated, and given the potential impact of SGH on quality of life,[18] this is an area particularly deserving of future clinical research efforts.

Melanocytic nevi There is substantial evidence that numbers of benign melanocytic nevi are significantly increased compared with age and sex-matched controls following organ transplantation. Such increased nevi numbers has been reported in both adult RTRs [21,22] as well as in childhood transplant recipients,[23,24]

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Figure 17.2. Multiple epidermoid cysts and milia.

Figure 17.1. Examples of verrucal keratoses on the hands.

with the back and acral sites being particularly involved in all age groups.[21,23] The onset of nevi may be eruptive post transplant,[24] although, at least in children, numbers tend to increase more gradually with the duration of immunosuppression.[23] Although sun exposure, genetic influence, and hormonal factors have been implicated in their pathogenesis, reduced immune surveillance per se is likely to be an important cofactor. Increased numbers of nevi have been reported in other models of immunosuppression such as human im-

munodeficiency virus infection.[21] Most descriptions are of clinically banal nevi, but dysplastic nevi have also been documented,[24] although it is not clear whether the number of dysplastic nevi is specifically increased in OTRs. It has been reported that the incidence of malignant melanoma is increased following organ transplantation, up to 8-fold in our cohort.[33] Melanoma is discussed in detail in Chapter 26. Given the association between increased benign melanocytic nevi and the risk of melanoma, together with a report that a significant proportion of transplant-related melanomas arise in dysplastic nevi,[34] careful surveillance of melanocytic nevi would seem mandatory in OTRs.

SO FT -T IS SUE T UMOR S A few isolated case reports have discussed soft-tissue tumors such as tufted angioma [26] and dermatofibromas [27] arising in OTRs. Table 17.1 documents the benign soft-tissue tumors of adipocyte, vascular, and pericyte origin that we have observed on at least one occasion in the BLT patient cohort.

BENIGN CUTANEOUS NEOPLASMS IN ORGAN TRANSPLANT RECIPIENTS

Figure 17.3. Appendageal tumors: (A) sebaceous adenoma, (B) large desmoplastic trichoepithelioma, (C) apocrine hidrocystoma, and (D) eccrine spiradenoma on the forearm.

Figure 17.4. Examples of sebaceous gland hyperplasia.

125

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CATHERINE HARWOOD AND CHARLOTTE PROBY

Figure 17.5. Soft-tissue tumors: (A) capillary haemangioma (diagnosed clinically as possible SCC); (B) angioleiomyoma; (C) glomus tumor on the forearm.

These limited data do not allow an assessment of the relative prevalence of these tumors in OTRs compared with the immunocompetent population (Figure 17.5).

REFERENCES

1. Blessing K, McLaren KM, Benton EC, Barr BB, Bunney MH, Smith IW, Beveridge GW. Histopathology of skin lesions in renal allograft recipients – an assessment of viral features and dysplasia. Histopathology. 1989 Feb;14(2):129–39. 2. Cohen EB, Komorowski RA, Clowry LJ. Cutaneous complications in renal transplant recipients. Am J Clin Pathol. 1987 Jun;88(1):32–7. 3. Hsu C, Abraham S, Campanelli A, Saurat JH, Piguet V. Sign of LeserTrelat in a heart transplant recipient. Br J Dermatol. 2005 Oct;153(4):861–2. 4. Schoendorff C, Lopez Redondo MJ, Roustan Gullon G, Hospital-Gil M, Requena L, Sanchez Yus E, Robledo Aguilar A. Multiple epidermoid cysts in a renal transplant recipient taking cyclosporine A. Cutis. 1992 Jul 50(1):36–8.

5. Richter A, Beideck S, Bender W, Frosch PJ. Epidermal cysts and folliculitis caused by cyclosporin A. Hautarzt. 1993 Aug;44(8): 521–3. 6. Gupta S, Radotra BD, Kumar B, Pandhi R, Rai R. Multiple, large, polypoid infundibular (epidermoid) cysts in a cyclosporin-treated renal transplant recipient. Dermatology. 2000;201(1):78. 7. Sandhu K, Saraswat A, Handa S. Multiple epidermoid cysts occurring at site of healed herpes zoster in a renal transplant recipient: an isotopic response? Clin Exp Dermatol. 2003 Sep;28(5):555–6. 8. Carrington PR, Nelson-Adesokan P, Smoller BR. Plaque-like erythema with milia: a noninfectious dermal mucinosis mimicking cryptococcal cellulitis in a renal transplant recipient. J Am Acad Dermatol. 1998 Aug;39(2 Pt 2):334. 9. Dogra S, Kaur I, Handa S. Milia en plaque in a renal transplant patient: a rare presentation. Int J Dermatol. 2002 Dec;41(12):897–8. 10. Chun SI, Lee JS, Kim NS, Park KD. Disseminated epidermolytic acanthoma with disseminated superficial porokeratosis and verruca vulgaris in an immunosuppressed patient. J Dermatol. 1995 Sep;22(9):690–2. 11. Harwood CA, McGregor JM, Swale VJ, Proby CM, Leigh IM, Newton R, Khorshid SM, Cerio R. High frequency and diversity of cutaneous

BENIGN CUTANEOUS NEOPLASMS IN ORGAN TRANSPLANT RECIPIENTS

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

appendageal tumors in organ transplant recipients. J Am Acad Dermatol. 2007;48(3):401–8. Ramsay HM, Fryer AA, Reece S, Smith AG, Harden PN. Clinical risk factors associated with nonmelanoma skin cancer in renal transplant recipients. Am J Kidney Dis. 2000 Jul;36(1):167–76. Bencini PL, Montagnino G, Sala F, De Vecchi A, Crosti C, Tarantino A. Cutaneous lesions in 67 cyclosporin-treated renal transplant recipients. Dermatologica. 1986;172(1):24–30. de Berker DA, Taylor AE, Quinn AG, Simpson NB. Sebaceous hyperplasia in organ transplant recipients: shared aspects of hyperplastic and dysplastic processes? J Am Acad Dermatol. 1996 Nov;35(5 Pt 1): 696–9. Walther T, Hohenleutner U, Landthaler M. Sebaceous gland hyperplasia as a side effect of cyclosporin A. Treatment with the CO2 laser. Dtsch Med Wochenschr. 1998 Jun 19;123(25-26):798–800. Perez-Espana L, Prats I, Sanz A, Mayor M. High prevalence of sebaceous hyperplasias in renal transplants. Nefrologia. 2003;23(2): 179–80. Pang SM, Chau YP. Cyclosporin-induced sebaceous hyperplasia in renal transplant patients. Ann Acad Med Singapore. 2005 Jun;34(5): 391–3. Moloney FJ, Keane S, OÕKelly P, Conlon PJ, Murphy GM. The impact of skin disease following renal transplantation on quality of life. Br J Dermatol. 2005 Sep;153(3):574–8. Salard D, Parriaux N, Derancourt C, Aubin F, Bresson-Hadni S, Miguet JP, Laurent R. Cutaneous complications following liver transplantation: epidemiologic and clinical study in 86 patients. Ann Dermatol Venereol. 2002 Oct;129(10 Pt 1):1134–8. Mudhar HS, Parsons MA, Farr R, Ford A, Gudgeon P, Collins C, Chang BY. Steatosebocystadenoma: a novel cystic sebaceous neoplasm in an immunosuppressed individual. Histopathology. 2005 Oct;47(4):429–3. Grob JJ, Bastuji-Garin S, Vaillant L, Roujeau JC, Bernard P, Sassolas B, Guillaume JC. Excess of nevi related to immunodeficiency: a study in HIV-infected patients and renal transplant recipients. J Invest Dermatol. 1996 Nov;107(5):694–7. Szepietowski J, Wasik F, Szepietowski T, Wlodarczyk M, SobczakRadwan K, Czyz W. Excess benign melanocytic naevi in renal transplant recipients. Dermatology. 1997;194(1):17–19.

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23. Smith CH, McGregor JM, Barker JN, Morris RW, Rigden SP, MacDonald DM. Excess melanocytic nevi in children with renal allografts. J Am Acad Dermatol. 1993 Jan;28(1):51–5. 24. Euvrard S, Kanitakis J, Cochat P, Cambazard F, Claudy A. Skin diseases in children with organ transplants. J Am Acad Dermatol. 2001 Jun;44(6):932–9. 25. Barker JN, MacDonald DM. Eruptive dysplastic naevi following renal transplantation. Clin Exp Dermatol. 1988 Mar;13(2):123–5. 26. Chu P, LeBoit PE. An eruptive vascular proliferation resembling acquired tufted angioma in the recipient of a liver transplant. J Am Acad Dermatol. 1992 Feb;26(2 Pt 2):322–5. 27. Viseux V, Chaby G, Agbalika F, Luong MS, Chatelain D, Westeel PF, Denoeux JP, Lok C. Multiple clustered dermatofibromas on a superficial venous thrombosis in a kidney-transplanted patient. Dermatology. 2004;209(2):156–7. 28. Chastain MA, Millikan LE. Pilomatrix dysplasia in an immunosuppressed patient. J Am Acad Dermatol. 2000;43:118–122. 29. Harwood CA, Swale VJ, Bataille VA, Quinn AG, Ghali L, Patel SV et al. An association between sebaceous carcinoma and microsatellite instability in immunosuppressed organ transplant recipients. J Invest Dermatol. 2001;116:246–253. 30. OÕDonovan P, Perrett CM, Zhang X, Montaner B, Xu YZ, Harwood CA, McGregor JM, Walker SL, Hanaoka F, Karran P. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science. 2005 Sep 16;309(5742):1871–4. 31. Salim A, Reece SM, Smith AG, Harrison D, Ramsay HM, Hardin PN, Fryer AA. Sebaceous hyperplasia and skin cancer in renal transplant patients. (abstract) Br J Dermatol. 2004;151(s68);28–9. 32. Perrett CM, McGregor JM, Warwick J, Karran P, Leigh IM, Proby CM, Harwood CA. Treatment of post-transplant pre-malignant skin disease: a randomized intra-patient comparative study of 5-fluorouracil cream and topical photodynamic therapy. Br J Dermatol. 2007;156(2):320–8. 33. Brown VL, Matin RN, Leedham-Green M, Cerio R, Proby CM, Harwood CA. Melanomas in renal transplant recipients: the London experience, and invitation to participate in a European study. Br J Dermatol. 2007;156(1):165–7. 34. Greene M, Young T, Clark WH Jr. Malignant melanoma in renal transplant patients Lancet. 1981; i:1196–9.

18 Anogenital Cutaneous Disease in Organ Transplant Recipients

Karen L. Gibbon, MB, ChB, BSc, MRCP, Heena Patel, BSc, MBBS, MRCS, and Charlotte Proby, BA, MBBS, FRCP

BACKGROUND

loma, and are usually associated with low-risk HPV types 6 and 11. In contrast to immunocompetent patients with genital warts, mixed HPV infections are frequent in OTR and may include oncogenic HPV types 16 or 18.[1] Shared management between dermatologists or genitourinary physicians and transplant physicians is recommended. Currently, firstline therapy is either topical podophyllotoxin on 3 consecutive days per week for 4 to 5 weeks or the immune response modifier (IRM), 5% imiquimod cream, applied overnight 3 times per week for up to 16 weeks.[3] If topical treatments fail, laser treatment may be successful. In addition, for limited numbers of warts, conventional ablative therapies such as cryotherapy, excision, or electrocautery are still widely used. A combination of surgical debridement followed by imiquimod may be appropriate for giant condyloma, together with a reduction in iatrogenic immunosuppression, if possible. Alternative approaches, including topical fluorouracil or intralesional interferon, may be tried in resistant cases, but attention must be paid to the possible deleterious effects of injected interferon on the grafted organ. Unfortunately, relapse is frequent in OTR and close follow-up is recommended.[3]

The anogenital skin of organ transplant recipients (OTR) is commonly affected by a variety of inflammatory, infective, and premalignant conditions. Inflammatory dermatoses including lichen sclerosus and lichen planus are not increased in incidence, but carry an increased risk of malignancy. As a result, nonspecific symptoms such as itching and soreness require careful examination of the skin, combined with appropriate samples for microscopy and culture. Biopsy of clinically suspicious lesions should be undertaken early and repeated if a definitive diagnosis cannot be made or if an appropriate response to therapy is not encountered. Female transplant recipients are at higher risk of developing anogenital carcinoma than male transplant recipients. Anogenital diseases seen more frequently or with increased clinical significance in OTR include those conditions listed in Table 18.1. All are associated with human papillomavirus (HPV) infection.

CONDYLOMATA ACUMINATA ( G E N I T A L V I R AL W A R T S )

A N AL A N D CE R V I C A L N E O P L A S I A

Genital warts are a common infection caused by HPV with an increased incidence in OTR.[1] Clinical and virological features of anogenital HPV-related lesions in transplant recipients suggest they may represent a marker for profound immunosuppression rather than the more common association with sexual partners and sexual practices.[1] A study of 1002 OTR revealed anogenital warts in 2.1% (21/1002) of patients. Ninety-five percent (20/21) had multifocal disease involving the vulva (8/10), anus (5/10), and cervix (3/10).[1] A cohort study of 816 renal transplant recipients (RTR) referred for skin surveillance over a 10-year period found that 49 (5.7%) had anogenital disease, of which 32 (3.7%) had nondysplastic viral warts (Proby and Harwood, unpublished data). Bone marrow transplant patients are also at risk, and 1.3% (3/238) developed anogenital lesions in a recent study.[2] The onset of anogenital warts occurs on an average of 4 years following transplantation in RTR,[1] but earlier, within two years of transplantation, in bone marrow recipients.[2] Clinical features of anogenital condylomata in OTR are similar to those seen in the general population, but disease is more likely to be multifocal throughout the genital region, extensive and refractory to therapy [1] (Figure 18.1). Condyloma may reach a considerable size, so-called ÔgiantÕ condy-

Intraepithelial neoplasia of the anal canal (AIN), cervix (CIN), vulva (VIN), and perianal region has been observed at higher frequency in OTR than in the general population.[4] In a casecontrol study, there was a higher prevalence of AIN, the precursor lesion to anal SCC, in RTR (20.3%, 27/133), than in age-matched controls (0.7%, 1/145).[5] However, the majority of these transplant-associated AIN cases (20/27) were low-grade AIN I, and only 10% (3/27) were in the highest grade AIN III. Surveillance of high grade AIN III over a 10-year period in 35 patients (3 RTR, 3 with HIV and 29 immunocompetent) documented malignant transformation only in the immunosuppressed group, but failed to detail whether this was HIV- or RTR-associated.[6] This study suggests a possible 50% risk of invasive disease in immunosuppressed patients with AIN III and highlights the need for long-term observation and appropriate management in this group. Anal cancer is a rare disease and studies on excess of risk in transplant patients have been performed using the Swedish Cancer Registry [4] (n = 5931 OTR). The relative risk for anal cancer in OTR was calculated to be 10 as compared to an age 128

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129

Table 18.1 HPV-associated anogenital diseases and their synonyms Anogenital disease

Synonyms

Condylomata acuminata Anogenital intraepithelial neoplasia (AGIN)

- Genital warts - Bowenoid Papulosis, - vulval (VIN), anal (AIN) and penile (PIN) - SCC

Squamous cell carcinoma

Note: Sites affected include vulva, cervix, anal and perianal regions. Note: VIN = vulval intraepithelial neoplasia; AIN = anal intraepithelial neoplasia; PIN = penile intraepithelial neoplasia.

and sex-matched population. Anal cancer, like cervical cancer, is HPV-associated, but the risk ratio for cervical cancer in OTR is only 2 – 4,[4,7] despite an increased risk ratio for CIN of 14. This situation is presumably because female OTR are screened more intensively for cervical disease, and therapeutic intervention prevents progression of CIN to invasive malignancy.

V UL V A L N E O P LA S IA The incidence of VIN and vulval SCC is increasing in both immunocompetent and immunosuppressed women and is occurring at an earlier age. A recent systematic review of series of VIN in the general population has shown the mean age of diagnosis of VIN to be 46 years and SCC to be 52 years, with the mean time to progression being 55 months (range 4–216 months).[8] In our experience, immunosuppressed women present younger with VIN and progress more quickly to highgrade disease and SCC. Oncogenic HPV 16 is the etiological agent in the majority of cases and is found consistently in higher grade VIN (VIN II-III). The term ‘‘Bowenoid Papulosis’’ is a clinical description of multifocal, pigmented papules and plaques where HPV infection is present with high-grade intraepithelial neoplasia histologically (Figure 18.2). There are two histological categories of high-grade VIN: undifferentiated (warty, basaloid, and mixed) defined by full-thickness cytological and architectural epithelial atypia, and differentiated VIN where cytological and architectural atypia are confined to the basal layers. Bowenoid papulosis is synonymous with HPV-associated VIN, and there is now a move to adopt this as the preferred terminology.[9] The overall risk of progression of untreated high-grade VIN into SCC in all women is around 9%,[8] but this figure is higher for any subset of specifically immunosuppressed patients including transplant recipients. Spontaneous regression of VIN II and III has been documented in immunocompetent women, but occurs extremely rarely, if ever, in immunosuppressed individuals. Lesions of AGIN are clinically diverse, and present as white, red, or brown warty papules or plaques, which are characteristically multifocal and itchy. AGIN may present as solitary, tender, eroded, or ulcerated plaques. Lesions may be found any-

Figure 18.1. Extensive genital viral warts (condyloma accuminata) in an organ transplant recipient.

where on the anogenital skin, but frequently occur around the lower vestibule, periclitoral area, perineum, and perianal skin. Treatment of AGIN in immunosuppressed women is complex and ideally should be undertaken in a multidisciplinary setting. In these patients, AGIN frequently persists, recurs, and extends to adjacent areas of the cervix, vagina, vulva, and anus in spite of conventional therapy. A reduction in iatrogenic immunosuppression is desirable and may be effective, particularly in cases of extensive or refractory disease.[1] Psychosexual morbidity is high and multiple surgical procedures are often disfiguring, contributing to sexual dysfunction. Surgical, destructive, or ablative treatment modalities for AGIN are frequently unsuccessful with a high rate of relapse due to the ‘‘field change’’ nature of AGIN. Furthermore, the documented occurrence of occult or microinvasive SCC occurring in VIN may exclude the use of laser treatment or cryotherapy, as no specimen is submitted for histological analysis. Alternative medical treatment with topical immune response modifiers such as imiquimod can produce clearance rates for VIN/AGIN of around 40–45% when used three times per week over a 16-week period in a mixed population of

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the majority (5/7) of women with mixed HPV infections were immunosuppressed. Furthermore, all but one patient had a previous history of high-grade CIN occurring 2 to 15 years earlier. This study also looked at histological and HPV clearance rates of VIN following topical imiquimod in 14 of these women. The majority (10/14) of biopsies remained positive for HPV, of which 90% contained HPV 16, and 40% (4/10) showed a mixed HPV infection.[10] It is essential that these women remain under long-term regular follow-up care with close surveillance and frequent screening tests of their entire anogenital area by appropriate specialists to optimize their care. Malignancy, or premalignancy, detected at one genital site should prompt a search for lesions throughout the genital region. Such screening tests should include the use of multiple field biopsies, combined with photography, to effectively monitor the anogenital skin.

REFERENCES

Figure 18.2. Multifocal, pigmented papules and plaques of Bowenoid Papulosis in the perianal region of a transplant patient with erosion due to imiquimod therapy.

immunocompetent and immunosuppressed patients.[10] A small prospective study of 12 consecutive cases of undifferentiated VIN, treated similarly for up to 7 months, found complete or >75% clearance in 3/12 and 4/12 patients, respectively.[11] Such medical therapy can be repeated as often as necessary, especially on anatomically important sites such as the clitoris. Medical therapy may be tissue conserving if used prior to surgery. With the advent of a highly sensitive nested and degenerate PCR technique using fresh frozen tissue, it has been possible to establish for the first time whether mixed HPV infection with mucosal and cutaneous types occurs on lower genital tract skin. A recent prospective uncontrolled study of 40 biopsies from 37 consecutively treated women (both immunosuppressed and immunocompetent) with high-grade, multifocal, AGIN confirmed mixed HPV infection with both mucosal and epidermodysplasia verruciformis (EV) types in 7/37 (19%) of patients. EV types identified included HPV 5, HPV 21, and HPV 37. HPV 16 was detected in 30/40 (75%) of biopsies, and

1. Euvrard S, Kanitakis J, Chardonnet Y, Noble CP, Touraine JL, Faure M, Thivolet J, Claudy A. (1997) External anogenital lesions in organ transplant recipients. Arch Dermatol. 133:175–78. 2. Daneshpouy M, Socie G, Clavel C, Devergie A, Rivet J, Cartier I, Brousse N, Birembaut P, Gluckman E, Janin A. (2001) Human papillomavirus infection and anogenital condyloma in bone marrow transplant recipients. Transplantation. 71(1):167–69. 3. Maw R, et al. National Guideline for the Management of Anogenital Warts. Clinical Effectiveness Group (HPV Special Interest Group of the Medical Society for the Study of Venereal Diseases). Revised January 2002. BASHH publication. U.K. 4. Adami J, Gabel H, Lindelof B, Ekstrom K, Rydh B, Glimelius B, Ekbom A, Adami H-O, Granath F. (2003) Cancer risk following organ transplantation: a nationwide cohort study in Sweden. Br J Cancer. 89:1221–7. 5. Ogunbiyi OA, Scholefield JH, Raftery AT, Smith JHF, Duffy S, Sharp F, Rogers K. (1994) Prevalence of anal human papillomavirus infection and intraepithelial neoplasia in renal allograft recipients. Brit J Surg. 81:365–7. 6. Scholefield JH, Castle MT, Watson NFS. (2005) Malignant transformation of high-grade anal intraepithelial neoplasia. Br J Surg. 92: 1133–6. 7. Alloub MI, Barr BBB, McLaren KM, Smith IW, Bunney MH, Smart GE. (1989) Human papillomavirus infection and cervical intraepithelial neoplasia in women with renal allografts. Br Med J. 298:153–6. 8. van Seters M, van Beurden M, de Craen AJ. (2005) Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients. Gynecol Oncol. 97(2):645–51. 9. Sideri M, Jones RW, Wilkinson EJ, Preti M, Heller DS, Scurry J, Haefner H, Neill S. (2005) Squamous vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology Subcommittee. J Reprod Med. 50(11):807–10. 10. Gibbon KL, Ran H, Purdie K, Leigh IM, Proby CM. Mixed Human Papillomavirus infection in vulvar disease and the response to imiquimod. J Reprod Med. 2007;52:120–21. 11. Wendling J, Saiag P, Berville-Levy S, Bourgault-Villada I, Clerici T, Moyal-Baracco M. Treatment of undifferentiated vulvar intraepithelial neoplasia with 5% imiquimod cream: a prospective study of 12 cases. Arch Dermatol. 2004;140:1220–4.

19 Cutaneous Graft versus Host Disease after Solid Organ Transplantation

Theresa R. Pacheco, MD and Christina Rapp Prescott, PhD

INT ROD UCTION

Since 1988, when Burdick et al. [9] first reported GVHD after liver transplantation, more than 50 cases of GVHD have been reported in association with liver transplantation. The onset of symptoms ranges from 2 days to 6 weeks post transplant, and patients present with an erythematous maculopapular skin rash, fever, pancytopenia, and diarrhea. The skin rash has a predilection for the palms and soles, and while initially maculopapular, can progress to bullae and desquamation.[1] Cutaneous GVHD is diagnosed by skin biopsy (Table 19.1). In approximately 15% of cases, GVHD is confined to the skin alone and this presentation is associated with a better prognosis. Most cases of GVHD rapidly progress to involve the gastrointestinal tract and hematopoietic tissues.[1] In some reported cases, the rash was initially misdiagnosed as either an infection or a drug allergy, resulting in delayed treatment. All but two reported cases of GVHD following liver transplant have been acute, although it has been reported as late as 8 months postoperatively.[1,10] The mortality rate of GVHD in liver transplant recipients is high: a review of published cases documents a fatal outcome in 38/51 patients.[1] Death is usually due to overwhelming sepsis. Patients who present with fever have a poor outcome, with 29 of 30 patients dying. Death occurred between 20 days and 10 months post transplant. Of patients who presented with cutaneous manifestations alone without systemic involvement, 100% were reported to survive (7 of 7 patients).[1] Two index case reports are summarized below:

Graft-versus-host disease (GVHD) is a complication usually associated with allogenic bone marrow transplantation, occurring in 40–80% of recipients. Rarely, GVHD can develop subsequent to solid organ transplantation, particularly after liver and small-bowel transplantation. It has been reported to occur in 1.2% (12/1082) to 1.5% (7/453) in two series of liver transplant recipients and 4.7% (6/128 adults) to 6.5% (8/122 children) of small-bowel transplant recipients.[1,2] GVHD is rare after cardiac, lung, and renal transplantation, having been reported in only 2 heart/lung transplant patients, 4 lung transplant patients, and 1 kidney transplant patient.[3–6] This chapter will focus on GVHD, which occurs in solid organ transplant recipients.

P A T H OGE NE SI S For GVHD to occur, donor tissue containing immunocompetent T cells must be placed into an immunocompromised recipient possessing tissue antigens otherwise absent from the donor. The pathogenesis of GVHD is initiated prior to transplantation with damage to host tissue caused by underlying illness, therapeutic intervention, infection, or pretransplant conditioning. These insults can lead to host antigen presenting cell activation and release of tumor necrosis factor alpha, interleukin-1, and interleukin-6. Once the transplant occurs, these factors facilitate activation of donor T cells transferred with the allograft, which differentiate into T-helper 1 cells that secrete interferon-gamma and interferon-2. The net result of these events is activation of cytotoxic T cell lymphocytes, natural killer cells, and macrophages that attack host cells, primarily in the skin.[7] Risk factors for developing GVHD in liver transplant recipients include age greater than 65, closely matched HLA recipients (1% incidence if 3–4 antigen mismatches and 7.5–12.5% incidence if 0–1 antigen mismatches), and a donor more than 40 years younger than the recipient.[8,1]

1. A 68-year-old man developed a generalized (70% of total body area, including palmoplantar involvement, without involvement of the mucus membranes) blanching maculopapular eruption and a fever of 102°F, 15 days after orthotopic liver transplantation. Skin biopsies revealed acute grade II GVHD, characterized by lymphocytic interface dermatitis with mild basal cell layer vacuolization, lymphocytic exocytosis, and characteristic satellite cell necrosis with multiple lymphocytes adjacent to scattered necrotic keratinocytes in the epidermis. Although blood and urine cultures were negative, the patient was initially treated with antibiotics (piperacillin/tazobactam, vancomycin, trimethoprim/sulfamethoxazole, and voriconazole). Four days later, the patient developed diarrhea and pancytopenia and was treated with tacrolimus, intravenous methylprednisolone, intravenous immunoglobulin, filgrastim, and multiple transfusions (platelet, granulocyte, and packed red cell). Despite treatment, the

C L I N I C AL P R E S E N T A T I O N GVHD may present acutely with dermatologic (in both stem cell and solid organ transplants), hepatic (in stem cell transplants), hematologic (in solid organ transplants), or gastrointestinal (in both stem cell and solid organ transplants) symptoms. 131

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patient developed acute renal and respiratory failure and died.[8] 2. A 52-year-old man presented with oral thrush 8 months after an uncomplicated liver transplant. He was initially treated with fluconazole but returned three days later with pharyngitis, oral ulcers, a diffuse rash, diarrhea, abdominal pain, fever, and pancytopenia. He was admitted and treated for a presumed drug reaction (to either valganciclovir or trimethoprim/sulfamethoxazole) with broad-spectrum antibiotics, erythropoietin and filgrastim, and was then discharged. The patient was readmitted 5 days later for rash and fever, at which time he was diagnosed with grade II GVHD (based on a skin biopsy performed during his previous admission and a chimerism analysis showing that 96% of the peripheral blood mononuclear cells were of donor origin.) He received OKT3, followed by an allogeneic peripheral blood hematopoietic progenitor cell transplantation, accompanied by antibiotic and antifungal therapy. Despite these measures, the patient developed a disseminated Candida kruseii infection five days after transplantation and died.[10]

D IA G NO SI S The clinical features of fever, rash, and diarrhea are suggestive for GVHD. Skin biopsies which show epidermal necrosis and dyskeratotic keratinocytes are also suggestive, but not pathognomonic. Macrochimerism, where donor cells account for more than 1% of the circulating nucleated cells in the peripheral blood, can be demonstrated by molecular techniques and is an important diagnostic tool.[11] Recently, Shrager et al. also described a method of using short tandem repeats for DNA fingerprinting to demonstrate the presence of donor DNA in both skin and rectal mucosa in a patient who developed acute GVHD post orthoptic liver transplantation.[12]

M A NAGE ME NT There is no standard therapeutic protocol for GVHD post solid organ transplantation. Current treatments include antilymphocyte regimens (OKT3, antithymocyte globulin, antilymphocyte globulin), increasing immunosuppression with calcineurin inhibitors, either increasing or decreasing steroid doses, granulocyte monocyte colony stimulating factor, and activated host lymphocyte infusions. However, the disease is usually refractory to these treatments and is fatal in 75 to 90% of cases.[8,13] Causes of mortality are variable and include sepsis, sometimes from unusual opportunistic organisms, gastrointestinal bleeding , pneumonia, and renal failure.[1] Immunosuppression usually mediates an initial improvement in symptoms, with an associated decrease in both host and donor T cells. However, the donor T cells preferentially recover, leading to recurrence. One promising experimental therapy is with activated host lymphocyte infusion, in which

Table 19.1 Histologic grading of cutaneous graft versus host disease Grade

Findings

I II III

Lymphocytic infiltrates in the upper dermis Vacuolization of the basal layer Subepidermal clefts through confluence of basal vacuolization Massive necrosis of keratinocytes, resembling toxic epidermal necrosis

IV

ex vivo activated alloreactive host T cells are repetitively retransferred into the host.[14] In addition, basiliximab, a chimeric (murine/human) IgG monoclonal antibody that specifically binds to the Interleukin-2 receptor alpha (CD25), is a promising new medication that selectively inhibits activated T cells. This agent has been successfully used to treat two cases of acute GVHD following liver transplantation.[13] There has also been a case of acute GVHD following liver transplantation, which resolved following withdrawal of immunosuppression.[15] Because GVHD is more likely to occur subsequent to stem cell transplantation than solid organ transplantation, current GVHD prevention is geared toward patients with leukemia. However, current standard immunosuppressive prophylaxis with tacrolimus and low-dose prednisolone is used to prevent transplant rejection and is similar to the GVHD prophylaxis used prior to stem cell transplantation (e.g., methotrexate plus cyclosporine or methotrexate plus tacrolimus).

SUM MARY GVHD is an uncommon complication of solid organ transplantation, occurring primarily after liver transplantation. A high index of suspicion in the immediate transplant period for GVHD in patients with fever, rash, gastrointestinal symptoms, and pancytopenia is necessary in order to initiate some of the novel treatment regimens that may have a chance of decreasing the high mortality rate associated with the disease.

REFERENCES

1. Taylor AL GP, Bradley JA. Acute Graft Versus Host Disease Following Liver Transplantation: The Enemy Within American Journal of Transplantation 2004; 4: 466–74. 2. Mazareigos GV A-EK, Jaffe R, Bond G, Sindhi R, Martin L, Macedo C, Peters J, Girnita A, Reyes J. Graft-versus-Host Disease in Intestinal Transplantation. American Journal of Transplantation 2004; 4: 1459–65. 3. Luckraz H ZM, McNeil K, Wallwork J. Graft-versus-Host Disease in Lung Transplantation: 4 Case Reports and Literature Review. J Heart Lung Transplant 2003; 22: 691–7. 4. M-Chau EM LK, Yew WW, Chiu CS, Wang EP. Mediastinal Irradiation for Graft-versus-Host Disease in a Heart-Lung Transplant Recipient. J Heart Lung Transplant 1997; 16(9): 974–9.

CUTANEOUS GRAFT VERSUS HOST DISEASE AFTER SOLID ORGAN TRANSPLANTATION

5. Pfitzmann R HM, Grauhan O, Waurick P, Ewerta R, Loebe M, Weng Y and Hetzer R. Acute Graft-versus-Host Disease after Human HeartLung Transplantation: A Case Report. J Thorac Cardiovasc Surg 1997; 114: 285–7. 6. Smith D AE, Netto G, Collins R, Levy M, Goldstein R, Christensen L, Baker J, Altrabulsi B, Osowski L, McCormack J, Fichtel L, Dawson DB, Domiati-Saad R, Stone M, Klintmalm G. Liver Transplant-Associated Graft-Versus-Host Disease. Transplantation 2003; 75: 118–26. 7. Iwasaki T. Recent Advances in the Treatment of Graft-versus-Host Disease. Clinical Medicine and Research 2004; 2: 243–52. 8. Whalen JG JD, English JC III. Rash and pancytopenia as initial manifestations of acute graft-versus-host disease after liver transplantation. J Am Acad Dermatol 2005; 52: 908–12. 9. Brudick JF VG, Smith WJ, Farmer ER, Bias WB, Kaufmann SH, Horn J, Colombani PM, Pitt HA, Perler BA. et al. Severe graft-versus-host disease in a liver-transplant recipient. New Engl J Med 1988; 318: 689–91. 10. Pollack MS SK, Callander VS, Freytes CO, Espinoza AA, Esterl RM, Abrahamian GA, Washburn WK, Hallf GA. Severe, late-onset graftversus-host disease in a liver transplant recipient documented by chimerism analysis. Hum Immunol 2005; 66: 28–31. 11. Taylor AL GP, Sudhindran S, Key T, Goodman RS, Morgan CH, Watson CJ, Delriviere L, Alexander GJ, Jamieson NV, Bradley JA,

12.

13.

14.

15.

133

Taylor CJ. Monitoring systemic donor lymphocyte macrochimerism to aid the diagnosis of graft-versus-host disease after liver transplantation. Transplantation 2004; 77: 441–6. Shrager JJ V-JC, Graber SE, Neff AT, Chari RS, Wright KJ, Pinson CW, Stewart JH, Gorden DL. Use of Short Tandem Repeats for DNA Fingerprinting to Rapidly Diagnose Graft-versus-Host Disease in Solid Organ Transplant Patients. Transplantation 2006; 81: 21–5. Sudhindran S TA, Delriviere L, Collins VP, Liu L, Taylor CJ, Alexander GJ, Gimson AE, Jamieson NV, Watson CJE, Gibbs P. Treatment of graft-versus-host disease after liver transplantation with Basiliximab followed by bowel resection. American Journal of Transplantation 2003; 3: 1024–9. Kuball J TM, Ferreira RA, Hess G, Burg J, Maccagno G, Barreiros AP, Luth S, Schimanski CC, Schuchmann M, Schwarting A, Neurath M, Otto G, Galle PR, Lohse AW. Control of Organ Transplant-Associated Graft-versus-Host Disease by Activated Lymphocyte Infusions. Transplantation 2004; 78: 1774–9. Lehner F BT, Sybrecht L, Luck R, Schwinzer R, Slateva K, Blasczyk R, Hertensstein B, Klempnauer J, Nashan B. Successful Outcome of acute graft-versus-host disease in a liver allograft recipient by withdrawal of immunosuppression. Transplantation 2002; 73: 307–10.

Section Seven

CUTANEOUS ONCOLOGY IN TRANSPLANT DERMATOLOGY

20 The Pathogenesis of Skin Cancer in Organ Transplant Recipients

Gillian M. Murphy, MD, FRCPI, FRCP, Edin and Fergal Moloney, MD, MRCPI

INT ROD UCTION

with greater multiplicity and with a more aggressive nature, including a higher rate of local recurrence and a greater propensity to invade locally and metastasize.[1,10] Finally, the preponderance of (SCC) with a ratio of 3:1 (SCC:BCC), represents a reversal of the usual ratio in the nontransplanted population.[1] This chapter will examine the various clinical contributors to accelerated carcinogenesis on OTR, whereas Chapter 8 focuses on the basic science aspects of cutaneous carcinogenesis.

Skin cancer is the most common malignancy in the western world. National Registries containing information on both malignant melanoma (MM) and nonmelanoma skin cancers (NMSCs), including basal cell carcinomas, demonstrate that malignancies of the skin account for over 1/3 of all malignancies.[1] Skin cancers occur more frequently in organ transplant recipients (OTR) relative to the general population. Although there is a documented increase in several solid organ malignancies following transplantation,[2] it is in the skin we see the most dramatic increase in cancer. Transplant recipients are at particularly high risk of squamous cell carcinoma (SCC), with up to a 100-fold increase in the relative risk when compared with the nontransplanted population.[1,3] This compares with a 10- to 16-fold increase in basal cell carcinoma (BCC) for renal transplant recipients.[1] Within 20 years of transplantation, approximately 40–50% of Caucasian patients in most western countries and 70–80% of Caucasian Australians will have developed at least one NMSC.[4–7] An increased incidence of melanoma in transplant patients has been reported [1,8,9] but other studies have failed to confirm these findings.[10,11] Small cohort size and failure to standardize data for age and sex may explain some of the nonsignificant studies. In many studies, almost all patients with melanoma are male, in part a consequence of the fact that two thirds of the population with renal transplants are male. Other types of skin cancer associated with immunosuppression in transplant patients include KaposiÕs sarcoma [3] and Merkel cell carcinoma.[12] Comparison of the risk and pattern of skin cancer in transplanted and nontransplanted populations offers some clues as to the pathogenesis of posttransplant skin cancer. The pattern of skin cancer observed in Caucasian OTR is consistent with the principal etiological role of ultraviolet radiation (UVR).[13] Skin cancers in OTR show the same age dependence and the same anatomical distribution by sex as in the general population.[1,13–17] However, differences in the rapidity of onset of skin cancers have been found in those who undergo transplantation over the age of 50 compared to those transplanted under the age of 50. The older group develops skin cancer much more quickly compared with the younger group. This situation may reflect the effects of immunosuppression unmasking previously initiated subclinical tumors, mainly SCCs.[1] Additionally, OTR develop skin cancers

PHOTOCARCINOGENICITY The most important risk factor for the development of melanoma and nonmelanoma skin cancer is intermittent intense or chronic UVR exposure.[18] UVR is subdivided into UVA and UVB. UVA (315–400 nm) is more prevalent in sunlight (100 times more than UVB) and penetrates more deeply into the skin than UVB (290–315 nm), but UVB is 1000-fold more biologically active. UVB is mainly absorbed by the epidermis with only 10% reaching the dermis. UVB is believed to be responsible for the majority of epidermal skin damage.[19] Mechanisms of photocarcinogenesis include the absorption of UV by cellular DNA leading to DNA damage and formation of photoproducts such as cyclobutane pyrimidine dimers (thymine dimers), 6Õ4Õpyrimidine pyridone photoproducts and the Dewar isomer. UVB leaves signature mutations, typically CC-TT and C-T mutations.[20,21] If DNA is too badly damaged, genetic controlled programmed cell death occurs through the caspase dependent pathway, termed ‘‘apoptosis.’’ This is an error-free mechanism for elimination of DNA damage. DNA enzymatic repair, on the other hand, is not 100% accurate. It is an intricate process, dependent on the DNA repair complex of enzymes working in concert. Repeated DNA damage leads to accumulation of DNA mutations.[21] UV-induced mutations may ultimately cause skin cancer by altering proto-oncogenes such as Ras and tumor suppressor genes such as p53. UVR is a complete carcinogen in that it may initiate, promote, and encourage progression of cancers. Initiation occurs by cumulative mutations in DNA. Promotion occurs in a variety of ways, including downregulation of tumour suppressor genes, upregulation of tumor promoting genes, and induction of immunosuppression.[22] UVR induced immunosuppression is complex.[23] UVR depletes epidermal Langerhans cells 137

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[24] (antigen-presenting cells). It also targets keratinocytes, which consequently produce and release immunosuppressive mediators such as Interleukin 1, 4, 6, and 10. In addition, UVR causes urocanic acid to be converted from the cis to trans– isomer, inducing a state of relative immunosuppression that prevents tumor rejection.[19,22,23] Essentially, all studies examining the relationship of UVR to skin cancer development in OTRs have postulated a prime role for sun exposure. What is yet to be resolved is the timing of such exposure. Does UVR prior to transplantation or UVR after transplantation play a more important role?

D R U G - I ND U C E D M A L I G N A NC Y Mutations and immunosuppression induced by UVR can be augmented by pharmaceutical agents. For example, humans have a dose-related risk of skin cancer from psoralen photochemotherapy (PUVA) used in psoriasis. Patients who have had over 200 PUVA treatments have a significant risk of developing skin cancer.[25] Looking at drugs commonly used in transplantation, in the hairless mouse exposed to UV irradiation, prednisolone had no effect on the development of skin cancers. Cyclosporine caused a moderate reduction in the tumor induction latent period. Azathioprine also decreased the tumor latent period, increased tumor yield per mouse and induced a larger proportion of carcinomas.[26] Unfortunately, little clinical information is available on the carcinogenic or photocarcinogenic risk of systemic corticosteroids. There appears to be an association between the longterm use of oral corticosteroids and NMSC.[27,28] In a group of non-OTR receiving oral corticosteroid therapy, the relative risk of SCC was 2.31, whereas the risk of BCC was 1.49.[28] There is an established association between the onset of cancer (most frequently skin cancer and non-Hodgkin lymphoma) and long-term systemic immunosuppression induced by a combination of different immunosuppressive drugs, including corticosteroids and oral calcineurin inhibitors, in transplant recipients.[4,5] In spite of this associated risk, it is generally felt that corticosteroids play a very modest role in the increase in NMSC in OTR. On a clinical basis, azathioprine has been implicated as a direct carcinogen in renal transplant recipients.[29] Azathioprine has also been proposed to exert a direct carcinogenic effect by intercalation at the DNA level. There it elicits codon misreads and inhibits repair splicing.[30] In addition, in cultured cells with 6-thioguanine substituted DNA, exposure to UVA appears to generate increased reactive oxygen species, which have been implicated in the development of skin cancer.[31] Cyclosporine increases the production of growth factors TGF-B, IL-6, and VEGF. As these factors enhance angiogenesis, tumor growth, and metastasis, cyclosporine may promote carcinogenesis independent of its immunosuppressive properties.[32,33] Cyclosporine has been shown, in vitro, to

transform noninvasive adenocarcinoma cells into cells with an invasive phenotype in a dose-dependent, reversible manner.[34] In spite of the differences in direct carcinogenic effect between immunosuppressive drugs, several studies have found no significant differences between the incidence of posttransplant skin cancer in patients treated with various immunosuppressive regimens. These studies suggest that the risk of skin cancer in organ transplant recipients may be related to the cumulative immunosuppressive load rather than to a specific immunosuppressive agent.[4,6,7] In addition to the immunosuppressive load, other factors that are associated with increased skin cancer include older age at transplantation, cumulative sunlight exposure, and Caucasian skin type.[11,35] These findings suggest that sun damage prior to transplantation may result in subclinical foci of atypical cells that become promoted to expression as full skin cancers by exposure to systemic immunosuppressants.[1,3,7,10,15] Mechanisms underlying this promotion are still being unravelled. Chronic immunosuppression severely depresses antitumor immune surveillance. The ability of immunosuppressants, especially calcineurin inhibitors, to block apoptosis,[36] may further allow DNA damage to accumulate, augmenting the effects induced by UVR.[35] An increased risk of skin cancer has been shown for psoriasis patients treated long-term with cyclosporine, which is further enhanced by additional PUVA therapy.[37,38] HLA mismatch may require higher levels of immunosuppression and lead to greater exposure to immunosuppressants.[39]

HPV AND POSTTRANSPLANT SKIN CARCINOGENESIS Viral warts are caused by human papilloma virus (HPV) infection. It is well recognized that certain high risk types of HPV, such as 16, 18, 31, and 32 are associated with cervical cancer and anogenital cancers. However, in immunocompetent individuals, even these high-risk HPV types are rarely linked to SCC on other cutaneous surfaces. In immunosuppressed individuals, HPV has been more closely linked to cutaneous SCC. Oncogenic types of HPV have long been associated with the condition epidermodyplasia verruciformis. These patients have a defect in natural killer cell activity. They develop extensive sheets of velvety warts often associated with HPV 5 and 7. Lesions are maximal in UV-exposed sites and SCC may develop in these growths, usually beginning in the second decade of life. Although this disease is a consequence of susceptibility to HPV, UV acts as a cocarcinogen leading to cancer development. In nonimmunosuppressed individuals, skin harbors multiple different HPV types. More HPV exists on sun-exposed sites, but HPV is also commonly found by PCR in normal appearing hair bulbs. HPV in skin is usually of the low-risk type. Transplant patients who are immunosuppressed harbor greater quantities of low- and medium-risk HPV types.[40] The high prevalence of HPV infection in nonlesional areas is remarkable. Harwood and colleagues detected

THE PATHOGENESIS OF SKIN CANCER IN ORGAN TRANSPLANT RECIPIENTS

HPV DNA in 58/67 (87%) samples of normal-appearing skin in renal transplant recipients and 20/57 (35%) samples from immunocompetent patients.[41] In another study, HPV DNA was detected in plucked hairs from 100% of renal transplant recipients and 45% of controls.[42] The mechanism for induction of cancers associated with HPV in skin is slowly being elucidated. In cervical cancer, the role of the HPV E proteins in blocking p53 is well understood. This does not appear to happen with nonmucosal HPV types, where active viral replication may lead to other mechanisms that interfere with tumor suppression. This active replication is clinically evident in the growth of viral warts of the planar type (HPV 10) and myriads of medium-risk HPV, as well as new types of HPV whose risk has not yet adequately been categorized. These viruses seem to interfere with apoptosis. There is emerging evidence of the role of oncogenic viruses acting as cofactors with UVR in the pathogenesis of skin cancers post transplantation.[43] The combination of systemic immunosuppressing drugs and the local immunosuppressive effect of UVR promotes HPV replication, which in turn leads to oncogenic effects in the skin. Recent work identifies an association specifically with the epidermodysplasia verruciformis HPV types and the development of SCCs of the skin in transplant patients.[40,43]

C A N C E R SU S C E P T I B I L I T Y GE N E S AN D S K I N C A N C E R PO S T TR A N S P L A N T Inherited and acquired genetic mutations also play a role in skin carcinogenesis. The effects of ultraviolet radiation on the skin are highly variable within normal populations. More deeply pigmented individuals are at a lower risk of skin cancer than fair-skinned individuals whether transplanted or not. In addition to inherited skin phototype, combinations of mutations in proto-oncogenes and tumor suppressor genes are known to confer an increased risk of skin cancer development. Mutations in the p53 gene, in particular those with signature mutations of exposure to UVB radiation,[44] have perhaps even greater implications for posttransplant skin carcinogenesis than for tumor development in normal individuals.[45] Loss of p53 function is known to occur early in skin carcinogenesis [46] with mutations seen in sun-exposed noncancerous epidermis. UV-induced p53 mutations are seen in nearly all SCCs, whereas sporadic basal cell carcinomas demonstrate p53 mutations in approximately 50% of cases.[47] A significant association was found between p53-72R homozygosity and NMSC in renal transplant recipients, which was not seen in immunocompetent individuals although further studies have failed to reproduce this finding.[48] The glutathione-S-transferase (GST) genes play a role in detoxification of carcinogens and mutagens, including some produced by UVR. Studies looking at gene polymorphisms for GST in RTR indicate that GST M1 conferred a significant increase in risk of NMSC development, particularly in the presence of high UV exposure.[49–51] It has been suggested

139

that oxidative stress generated by UVA exposure contributes to the genomic instability that promotes the development of SCCs.[7,51] Interpatient variability in the metabolism of immunosuppressant drugs may also contribute to variations in posttransplant skin cancer risk. Eleven percent of the population is heterozygous or homozygous for the thiopurine-s-methyl transferase (TPMT) gene resulting in low TPMT activity, which in turn increases the myelosuppressant effect of azathioprine.[52] Assessment of an Irish cohort showed that patients with heterozygosity for TPMT either had the drug stopped early post transplant due to leukopenia or required significant drug reduction because of adverse effects. Among those remaining on azathioprine, heterozygosity was more heavily associated with skin cancers than normal metabolizers. No homozygotes were detected.[53] Most recently we have described a polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene. Individuals carrying the MTHFR 677T allele had a marked increase in risk of SCC (adjusted OR=2.54, p=0.002, with adjustment for age, sex, skin type, sun exposure score, and immunosuppression duration; lower 95% confidence boundary OR of 1.41).[54] Studies are in progress to investigate the possible reversal of the resulting folate deficiency by folic acid supplementation. Such a simple therapy could benefit not only cancer prevention but also possibly cardiovascular risks as patients with renal transplants typically have homocysteine levels, which confer risk.

S K I N T Y P E A ND P OST T R A NS P L A NT C A R CI N O G E N E S I S The highest incidence of skin cancer is seen in areas of high ambient UVR such as Queensland, Australia,[35] in particular among fair skin types whose ancestors hailed from Northern Europe. Older patients are known to harbour more DNA photoproducts than younger individuals,[32] possibly a function of reduced DNA repair. Skin color is one of the major susceptibility factors predetermining risk of skin cancer. Melanocortin-1 receptor gene variants are also associated with both melanoma and nonmelanoma skin cancer. Certain variants of the MC1R gene are also strongly associated with the development of NMSC post renal transplantation. Asp84Glu and Arg151Cys variants contributed to increased NMSC risk post transplant, a finding that was independent of skin type and hair color.[55] Skin color is influenced by MC1R polymorphisms but the mechanism is more complex than originally thought.[56]

CONCLUSION Carcinogenesis of skin after organ transplantation is a highly complex event. No single mechanism entirely explains the increased risk in these patients. Numerous factors act under

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the influence of immunosuppressive drugs to produce skin cancers.

REFERENCES

1. Moloney FJ, Comber H, OÕLorcain P, OÕKelly P, Conlon PJ, Murphy GM. A population-based study of skin cancer incidence and prevalence in renal transplant recipients. Br J Dermatol. 2006 154(3): 498–504. 2. Sheil AG. Cancer in renal allograft recipients in Australia and New Zealand. Transplant Proc 1977; 9: 1133–6. 3. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003 Apr 24;348(17):1681–91. 4. Otley CC, Berg D, Ulrich C, Stasko T, Murphy GM, Salasche SJ, Christenson LJ, Sengelmann R, Loss GE Jr, Garces J; Reduction of immunosuppression task force of the international transplant skin cancer collaborative and the skin care in organ transplant patients europe. Reduction of immunosuppression for transplant-associated skin cancer: expert consensus survey. Br J Dermatol. 2006 Mar;154(3): 395–400. 5. Moloney FJ, de Freitas D, Conlon PJ, Murphy GM. Renal transplantation, immunosuppression and the skin: an update. Photodermatol Photoimmunol Photomed. 2005 Feb;21(1):1–8. 6. Webb MC, Compton F, Andrews PA, Koffman CG. Skin tumours posttransplantation: a retrospective analysis of 28 years’ experience at a single centre. Transplant Proc. 1997;29:828–30. 7. Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation. 1990;49:506–9. 8. Leveque L, Dalac S, Dompmartin A, Louvet S, Euvrard S, Catteau B et al. [Melanoma in organ transplant patients] [Article in French] Ann Dermatol Venereol.2000;127:160–5. 9. Laing ME, Moloney FJ, Kay EW, Conlon P, Murphy GM. Malignant melanoma in transplant patients: review of five cases. Clin Exp Dermatol. 2006;31(5):662–4. 10. Lindelof B, Sigurgeirsson B, Gabel H, Stern RS. Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol. 2000;143:513–9. 11. Jain AB, Yee LD, Nalesnik MA, Youk A, Marsh G, Reyes J et al. Comparative incidence of de novo nonlymphoid malignancies after liver transplantation under tacrolimus using surveillance epidemiologic end result data. Transplantation. 1998;66:1193–200. 12. Douds AC, Mellotte GJ, Morgan SH. Fatal Merkel-cell tumour (cutaneous neuroendocrine carcinoma) complicating renal transplantation. Nephrol Dial Transplant. 1995;10:2346–8. 13. Berg D, Otley CC. :Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and management. J Am Acad Dermatol. 2002;47:1–17. 14. Ferrandiz C, Fuente MJ, Ribera M, Bielsa I, Fernandez MT, Lauzurica R et al. Epidermal dysplasia and neoplasia in kidney transplant recipients. J Am Acad Dermatol. 1995;33:590–6. 15. Stockfleth E, Ulrich C, Meyer T, Christophers E. Epithelial malignancies in organ transplant patients: clinical presentation and new methods of treatment. Recent Results Cancer Res. 2002;160:251–8. 16. Caforio AL, Fortina AB, Piaserico S, Alaibac M, Tona F, Feltrin G et al. Skin cancer in heart transplant recipients: risk factor analysis and relevance of immunosuppressive therapy. Circulation. 2000; 102(19 Suppl 3):III222–7. 17. Espana A, Martinez-Gonzalez MA, Garcia-Granero M, Sanchez-Carpintero I, Rabago G, Herreros J. A prospective study of incident nonmelanoma skin cancer in heart transplant recipients. J Invest Dermatol. 2000;115:1158–60.

18. Grossman D, Leffell DJ. The molecular basis of nonmelanoma skin cancer: new understanding. Arch Dermatol. 1997;133:1263–70. 19. Matsumura Y, Ananthaswamy HN. Toxic effects of ultraviolet radiation on the skin. Toxicol Appl Pharmacol. 2004;195:298–308. 20. Ichihashi M, Ueda M, Budiyanto A, Bito T, Oka M, Fukunaga M et al. UV-induced skin damage. Toxicology. 2003;189:21–39. 21. Matsumura Y, Ananthaswamy HN. Short-term and long-term cellular and molecular events following UV irradiation of skin: implications for molecular medicine. Expert Rev Mol Med. 2002;2002:1–22. 22. Aubin F. Mechanisms involved in ultraviolet light-induced immunosuppression. Eur J Dermatol. 2003;13:515–23. 23. Murphy GM. Ultraviolet radiation and its effects on the immune system. Clin Exp Dermatol. 2000 Mar; 25(2):162–3. 24. Murphy GM, Norris PG, Young AR, Corbett MF, Hawk JL. Low-dose ultraviolet-B irradiation depletes human epidermal Langerhans cells. Br J Dermatol. 1993 Dec;129(6):674–7. 25. Stern RS. Photocarcinogenicity of drugs.. Toxicol Lett. 1998;102–103: 389–92. 26. Kelly GE, Meikle W, Sheil AG. Effects of immunosuppressive therapy on the induction of skin tumors by ultraviolet irradiation in hairless mice. Transplantation. Sep 1987;44(3):429–34. 27. Sorensen HT, Mellemkjaer L, Nielsen GL, Baron JA, Olsen JH, Karagas MR. Skin cancers and non-hodgkin lymphoma among users of systemic glucocorticoids: a population-based cohort study. J Natl Cancer Inst. 2004;96:709–11. 28. Karagas MR, Cushing GL Jr, Greenberg ER, Mott LA, Spencer SK, Nierenberg DW. Non-melanoma skin cancers and glucocorticoid therapy. Br J Cancer. 2001;85:683–6. 29. Taylor AE, Shuster S. Skin cancer after renal transplantation: the causal role of azathioprine. Acta Derm Venereol. 1992; 72(2):115–19. 30. Swann PF, Waters TR, Moulton DC, Xu YZ, Zheng Q, Edwards M, Mace R. Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science. Aug 23 1996;273(5278):1109–11. 31. OÕDonovan P. Perrett CM. Zhang X. Montaner B. Xu YZ. Harwood CA. McGregor JM. Walker SL. Hanaoka F. Karran P. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science. 309((5742)):1871–4, 2005 Sep 16. 32. Bertolino P, Deckers M, Lebrin F, ten Dijke P. Transforming growth factor-beta signal transduction in angiogenesis and vascular disorders. Diagn Mol Pathol. 2001 Sep;10(3):190–9. Chest. 2005 Dec;128(6 Suppl):585S–590S. 33. Baczkowska T, Perkowska-Ptasinska A, Sadowska A, Lewandowski Z, Nowacka-Cieciura E, Cieciura T, Pazik J, Lewandowska D, Mroz A, Urbanowicz A, Nazarewski S, Danielewicz R. Serum TGF-beta1 correlates with chronic histopathological lesions in protocol biopsies of kidney allograft recipients. Transplant Proc. 2005;37(2):773–5. 34. Hojo M, Morimoto T, Maluccio M, Asano T, Morimoto K, Lagman M, Shimbo T, Suthanthiran M. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature. Feb 11 1999; 397(6719):530–34. 35. Bouwes Bavinck JN, Hardie DR, Green A, Cutmore S, MacNaught A, OÕSullivan B et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia. A follow-up study. Transplantation. 1996;61:715–21. 36. Yarosh DB, Pena AV, Nay SL, Canning MT, Brown DA. Calcineurin inhibitors decrease DNA repair and apoptosis in human keratinocytes following ultraviolet B irradiation. J Invest Dermatol. 2005 Nov;125(5):1020–5. 37. Paul CF, Ho VC, McGeown C, Christophers E, Schmidtmann B, Guillaume JC. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study. J Invest Dermatol. 2003;120:211–6. 38. Marcil I, Stern RS. Squamous-cell cancer of the skin in patients given PUVA and ciclosporin: nested cohort crossover study. Lancet. 2001; 358:1042–5.

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39. Bouwes-Bavinck JN, Vermeer BJ, van der Woude FJ, Vandenbroucke JP, Schreuder GM, Thorogood J et al. Relation between skin cancer and HLA antigens in renal-transplant recipients. N Engl J Med. 1991;325:843–8. 40. Stockfleth E, Nindl I, Sterry W, Ulrich C, Schmook T, Meyer T. Human papilloma viruses in transplant-associated skin cancers. Dermatol Surg. 2004;30(4 Pt 2):604–9. 41. Harwood CA, Surentheran T, Sasieni P, Proby CM, Bordea C, Leigh IM, Wojnarowska F, Breuer J, McGregor JM. Increased risk of skin cancer associated with the presence of epidermodysplasia verruciformis human papillomavirus types in normal skin. Br J Dermatol. May 2004;150(5):949–57. 42. Boxman IL, Berkhout RJ, Mulder LH, Wolkers MC, Bouwes Bavinck JN, Vermeer BJ, ter Schegget J. Detection of human papillomavirus DNA in plucked hairs from renal transplant recipients and healthy volunteers. J Invest Dermatol. May 1997;108(5): 712–15. 43. OÕConnor DP, Kay EW, Leader M, Murphy GM, Atkins GJ, Mabruk MJ. Altered p53 expression in benign and malignant skin lesions from renal transplant recipients and immunocompetent patients with skin cancer: correlation with human papillomaviruses? Diagn Mol Pathol. Sep 2001;10(3):190–199. 44. Mukhtar H, Forbes PD, Ananthaswamy HN. Photocarcinogenesis – models and mechanisms. Photodermatol Photoimmunol 1999;15: 91–95. 45. Bennett MA, OÕGrady A, Kay EW, Leader M, Murphy GM. p53 mutations in squamous cell carcinomas from renal transplant recipients. Biochem Soc Trans. 1997 Feb;25(1):342–5. 46. Sarasin A, Giglia-Mari G. p53 gene mutations in human skin cancers. Exp Dermatol. 2002;11 Suppl 1:44–7. 47. Rubin AI, Chen EH, Ratner D. Basal-cell carcinoma. N Engl J Med. 2005 Nov 24;353(21):2262–9. Review.

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48. OÕConnor DP, Kay EW, Leader M, Atkins GJ, Murphy GM, Mabruk MJ. p53 codon 72 polymorphism and human papillomavirus associated skin cancer. J Clin Pathol. 2001 Jul;54(7):539–42. 49. Fryer AA, Ramsay HM, Lovatt TJ, Jones PW, Hawley CM, Nicol DL, Strange RC, Harden PN. Polymorphisms in glutathione S-transferases and non-melanoma skin cancer risk in Australian renal transplant recipients. Carcinogenesis. 2005 Jan;26(1):185–91. 50. Carless MA, Lea RA, Curran JE, Appleyard B, Gaffney P, Green A, Griffiths LR. The GSTM1 null genotype confers an increased risk for solar keratosis development in an Australian Caucasian population. J Invest Dermatol. 2002 Dec;119(6):1373–8. 51. Ramsay HM, Harden PN, Reece S, Smith AG, Jones PW, Strange RC, Fryer AA. Polymorphismsin glutathione S-transferases are associated with altered risk of nonmelanoma skin cancer in renal transplant recipients: a preliminary analysis. J Invest Dermatol. 2001 Aug;117(2): 251–5. 52. Lennard L, Van Loon JA, Weinshilboum RM. Pharmacogenetics of acute azathioprine toxicity relationship to thiopurine methylransferase genetic polymorphism. Clin Pharmacol Ther 1989; 46: 149–54. 53. Moloney F. MD Thesis 2005 University College Galway, National Universities of Ireland 54. Moloney FJ. Dicker P. Conlon PJ. Shields DC. Murphy GM. The frequency and significance of thiopurine S-methyltransferase gene polymorphisms in azathioprine-treated renal transplant recipients. Br J Dermatol. 2006 Jun;154(6):1199–200. 55. Box NF, Duffy DL, Irving RE, Russell A, Chen W, Griffyths LR, Parsons PG, Green AC, Sturm RA. Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma. J Invest Dermatol. 2001 Feb;116(2):224–9. 56. Healy E, Jordan SA, Budd PS, Suffolk R, Rees JL, Jackson IJ. Functional variation of MC1R alleles from red-haired individuals. Hum Mol Genet. 2001 Oct 1;10(21):2397–402.

21 The Epidemiology of Skin Cancer in Organ Transplant Recipients

Bernt Lindelo¨f, MD, PhD

INTR ODUCT IO N

of tumors was associated with birth in a hot climate, childhood sunburn, pretransplantation actinic keratoses, and smoking.[14] In a nested, population based, case-control study of possible causative factors of SCC, carried out on 95 renal OTR who had developed SCC after transplantation, compared to an accurately matched control population of 145 renal OTR without SCC, the differences between cases and controls were not significant for sun exposure before or after the transplantation, sun protective measures, number of sunburns, outdoor occupation, smoking habits, or use of sun beds. However, compared to patients with skin type IV, the SCC odds ratio was 3.0 (95% CI = 1.3–7.0) for skin types I and II. Patients with light blond or red hair color also had a higher odds ratio than those with dark hair, 3.2 (95% CI = 1.2–4.2) and patients with warts after the transplantation had a higher odds ratio than those without, 2.2 (95% CI = 1.2–4.2). The authors concluded that poor tanning ability rather than the amount of sun exposure was associated with the development of SCC in renal OTR.[15] The increased relative risk of SCC in OTR can be dramatic. It was reported to be 18-fold in an early report [3] and 65- to 109-fold in more recent Scandinavian studies.[4,6] In a Dutch study of renal OTR from a single center, the overall incidence of SCC was 250 times higher when compared with the general Dutch population.[5] Once an individual develops an SCC, the risk of developing a subsequent SCC is very high. One-quarter of OTR with SCC will develop another SCC within 13 months and one-half will develop an additional SCC within 3.5 years.[6] In a study of the Swedish OTR cohort of 5,931 patients, the head and neck were the predominant sites of SCC in men, and the trunk was the predominant site in female patients. The most common site in younger patients was the chest, and in older patients the face. The ear was a common site in male patients but in contrast, no tumors were located there in females.[12] The lip is a very common site of SCC in OTR and the reported excess risks have ranged from 14 to 378. [2–4,6] The highest figure is reported in females.[3] Multivariate analyses have not revealed any trend with regard to follow-up, but there are significant rates among patients younger than 50 years at transplantation, compared to those 50 years or older.[2] A number of case studies in OTR have found that the incidence rates of SCC have been reduced if the

Organ transplant recipients (OTR) are at increased risk of having both cutaneous and systemic cancer develop. In 1971, Walder et al. were the first to identify that a group of Australian OTR who had received immunosuppression were at increased risk of developing skin cancers.[1] Today, more than 1,000 papers concerning cancer in OTR, many of them including skin cancers, have been published, but very few of the observations have been population based. As a result, the figures on incidence and risks must be interpreted with caution. However, a few population-based studies based on national population-based cancer registries and calendarperiod-specific incidence rates in the general population [2–9] do exist, and they have yielded reliable insight into the magnitude of the problem (Table 21.1). Studies from different countries present a similar picture of increased cancer in OTR, but the type and incidence of tumors varies considerably in different populations depending on geographic and genetic factors as well as transplantation-related factors. The overall increased risk for any type of cancer in OTR has been estimated to be fourfold greater than that in the general population.[2] The most common posttransplantation cancers in Western populations include nonmelanoma skin cancer, lip cancer, non-HodgkinÕs lymphoma, cancer of the vulva, vagina, or oral cavity, and anal cancer. In contrast, some of the most common cancers in the general population, breast cancer and prostate cancer, have not been found to have increased incidences in OTR. For lung cancer and colon cancer there are only moderately increased risks with standardized incidence ratios (SIR) of 1.7 and 2.3, respectively.[2]

I N C I D E N C E OF SK I N CA N C E R B Y T Y P E

Squamous cell carcinoma (SCC) The most frequently encountered skin cancer in OTR is SCC and it may account for more than 90% of all cases.[10] SCC in OTR is also believed to be more aggressive than in the general population with a higher risk of metastasis.[11] Other differentiating features are the young age of the patients [11] and the high incidence of multiple tumors.[6,12,13] The risk of SCC in 361 renal OTR living in Australia, was strongly associated with blue or hazel eyes, time-resident in a hot climate, and pretransplantation SCC. The number 142

THE EPIDEMIOLOGY OF SKIN CANCER IN ORGAN TRANSPLANT RECIPIENTS

Table 21.1 Population-based standardized incidence ratios (SIR) of skin cancer in organ transplant recipients by type Skin cancer

SIR

References

SCC SCC of the lip BCC Malignant Melanoma Kaposi’s sarcoma

18–253 14–378 10 NS – 3.6 26.5–84

2–6, 9 2–4, 6 5 2–4, 6–9 4,8

Note: NS = not significant.

immunosuppressive load is reduced or removed. No single immunosuppressive agent seems to be responsible, but a clear correlation has been established with the overall degree of immunosuppression.[16]

Basal Cell Carcinoma (BCC) Approximately 30–50% of the OTR with SCC also have BCC,[10] making it the second most common skin cancer in OTR. The risk of BCC in 361 renal OTR living in Australia was strongly associated with acute or intermittent sun exposure during childhood, and pretransplantation BCC. Tumor numbers were associated with blue and hazel eyes, time spent living in a hot climate, and male gender.[14] Quantification of the increased risk of BCC in OTR is more difficult because of the paucity of population-based databases for BCC. Reported increased incidence figures for skin cancer in OTR have often been obtained by comparing rates to those found in tumor registries where BCC are not uniformly reported. In a Dutch single-center study of 764 renal OTR, the overall incidence of BCC was 10 times higher when compared with the general population.[5] Another aspect that merits consideration is the SCC/BCC ratio. The normal SCC/BCC ratio is 1:4 in the general population. This ratio has been reported to be reversed in renal OTR from the Netherlands.[5] In a prospective study from Spain of renal OTR, the incidence of BCC increased linearly from the time of transplantation, whereas the increase in SCC incidence was slower initially, but increased in an exponential fashion later. This finding may explain why different ratios of SCC to BCC in OTR are seen in different studies. The ratio may depend on the length of the follow-up period.[17] The authors in the cited study reported an almost normal SCC/BCC ratio of 1:3.1 the first three years post transplant, whereas at the end of the study, the ratio was 1:1.4. A similar result has also been reported from Italy.[18] A larger ratio of SCC/BCC of 3.2:1 was found in a study from United Kingdom.[19] In contrast, this reversed ratio has been reported to be less pronounced in renal OTR in Australia (1.5:1) [20] but of the same magnitude as in the Netherlands and United Kingdom in another Australian study of 455 heart OTR (3:1).[21] It is possible that higher levels of sun exposure contribute to a higher proportion of BCC in Australia, whereas

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in temperate climates, SCC will develop more often.[19] This could be the result of viral transformation of squamous epithelium facilitated both by iatrogenic suppressed immune responses and sun exposure, as reflected in the anatomical distribution of SCC and BCC.[12,5] Epidemiologic studies suggest that different patterns of UV exposure influence skin cancer risks in the general population; BCC is more associated with intermittent intense exposure, whereas SCC is more associated with cumulative UV exposure. This difference in pattern has also been suggested to be true in an OTR population.[14]

Malignant Melanoma (MM) Existing studies are not in full agreement over whether OTR have an increased risk of MM. Compared to SCC, the low incidence of MM has made prospective study in OTR populations difficult. Studying 89,786 renal OTR during the years 1988–1998 from the United States Renal Data System, it has been shown that these patients were nearly 3.6 times more likely to develop MM than the general population.[7] Similar results have been reported from Norway,[4] Australia, and New Zealand.[8] In contrast, a population-based cohort study from Sweden of 5,356 OTR found no significantly increased risk with 6 reported MM compared with the expected number of 5.4.[6] Separately, a higher number of melanocytic nevi, a documented risk factor for MM, has been found in kidney OTR compared with age- and sex-matched healthy controls,[10] supporting an increased risk for MM in OTR.

KaposiÕs sarcoma (KS) KS has been reported in excess among OTR, especially from patient populations in which the disease is endemic, such as patients of Mediterranean, black African, or Caribbean origin.[22] Unfortunately, there are few population-based studies to document this increase. The incidence has been reported to be increased 84-fold in OTR from Norway (4 cases of KS in 2,561 OTR)[4] and 28-fold in OTR from Australia and New Zealand (28 cases in 13,077 OTR).[8] Only 2 cases of KS were found in the Swedish OTR cohort of 5,356 patients.[6] Perhaps due to its relationship to Human Herpes Virus 8 infection, KS often appears early, at a mean interval of 13 months after transplantation.[23] The male predominance, well known in sporadic, endemic, and epidemic KS, also exists in posttransplant KS. The male/female ratio has ranged from 2–40/1.[24]

Other types of skin cancer The incidence of Merkel cell carcinomas in OTR appears to be increased. Fifty-five cases have been reported, largely in a report from the Cincinnati Tumor Registry by Penn.[25,10] Merkel cell carcinoma has a high mortality rate

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in immunocompetent patients, and lethal Merkel cell carcinomas have been reported in OTR.[19,10] Lymphomas are among the most common complications of transplantation, affecting up to 5% of all OTR, but purely cutaneous lymphomas are rare with fewer than 30 cases reported.[10] A number of cases of other types of skin cancer, such as atypical fibroxanthoma, malignant fibrous histiocytoma, and dermatofibrosarcoma protuberans, have been reported. Because these tumors are rare, any increased incidence in OTR has been difficult to quantify.[26]

I N C I D E N C E OF SK I N CA N C E R B Y A L L O G R A FT TY P E Much of the literature concerning skin cancer in OTR describes renal transplant recipients or cardiac transplant patients. There are few studies concerning skin cancer in liver, lung, and pancreas OTR. Cardiac OTR seem to have a higher incidence of nonmelanoma skin cancer in comparison to other OTR.[4,27] After adjustment for age and in comparison to the general population, the overall risk is appears notably greater for cardiac OTR than for kidney or liver OTR.[28] However, this finding has not been confirmed by all studies.[29,18] This increased risk has been attributed to the significantly higher doses of immunosuppressive agents used to prevent and treat allograft rejection in heart OTR compared to other solid OTR.[21] A second possible factor is that heart OTR are generally about 15 years older at transplantation than renal OTR and, therefore, at higher risk of skin cancer. The location of the skin cancers has also differed between different populations of OTR. A cephalic location occurred in 70% of heart OTR compared to 40% of kidney OTR.[30] Again, the difference in age at transplantation might account for this observation.[12] The time interval between transplantation and development of skin cancer was much shorter in heart OTR (3.9 years) compared to the renal OTR (8.6 years).[30] There is sparse literature concerning skin cancer in liver OTR, but it has been suggested that the incidence of nonmelanoma skin cancer is less in liver OTR than in other OTR, because the level of required immunosuppression is lower and the drug regimens utilized differ from those employed for other solid OTR.[31] A study supporting this hypothesis [32] still found an increased risk of nonmelanoma skin cancer of 20-fold.

I N C I D E N C E OF SK I N CA N C E R B Y A G E Older OTR are more likely to develop skin cancer, probably because they have had a greater cumulative sun exposure before transplantation.[6,9,26] Some studies have suggested that in renal OTR this skin cancer risk was largely established predialysis/transplantation as a significant change in sun behavior

post transplant was not readily related to a reduction in risk.[15] Little data is available on the long–term outcome of children who have undergone organ transplantation. The available data suggests that skin cancer is the most frequent malignancy following pediatric renal transplantation and the second most common, following lymphoproliferative disorders, in the overall group of transplanted children.[33] The increased risk for nonmelanoma skin cancer has been reported to be 222-fold higher in a Dutch population of pediatric renal OTR compared to the general population.[34] The reversal of SCC/BCC ratio compared to the general population was even more pronounced in children than in adult OTR (2.8:1 vs. 1.7:1).[35] The relative proportion of MM among skin cancers has been shown to be higher in pediatric than adult OTR, but the number of reported cases has been small, only 14 cases.[34,35] Twenty-five percent had a fatal outcome.[35]

I N C I D E N C E O F S K I N C A N C E R BY G E O G R A P H I C LO C A TI O N Most of the population-based studies concerning incidence of skin cancer in OTR pertain to populations of northern Europe, United States, and Australia [2–9], where the majority of people have a lighter skin type and different habits of sun exposure than the population of the Mediterranean areas, Asia, and Africa. The highest risks are reported from Australia.[20,14] Most of the studies from developing countries have not been population-based, and the number of patients and years of follow-up has been limited. The incidence of all types of cancer in renal OTR varies significantly between countries with developed market economies and those with developing economies. In developing countries, the crude overall incidence of cancer in general was much lower than in developed countries. In a review, 4,985 (13.6%) patients developed malignancies among 36,628 renal OTR from developed countries. In contrast, 753 (4.7%) of the patients from developing countries had malignancies in a total recipient pool of 15,825. Even comparing only non-skin malignancies the difference was still pronounced.[36] In developing countries, the most common cancer after renal transplantation was Kaposi’s sarcoma, as opposed to SCC in industrialized countries. In most regions, the pattern of cancers occurring after transplantation differs from that seen in the general population; however, in Japan, the pattern is similar to the general population;[36] In Japan, the overall pattern of tumors after renal transplantation is quite different from that in Western countries, with a lower frequency of skin cancer and an absence of Kaposi’s sarcoma.[37] Similar figures have been reported in 156 cardiac OTR from Taiwan. Again, there was no skin cancer or KS.[38] In a study from South Africa of 542 renal OTR, the incidence of cancer in general was comparable in white and

THE EPIDEMIOLOGY OF SKIN CANCER IN ORGAN TRANSPLANT RECIPIENTS

nonwhite patients. However, SCC and BCC (in that order) were the most common cancers in whites, whereas KS was the most common cancer in nonwhites and accounted for almost 80% of all cancers in that group.[36]

I N C I D E N C E O F S K I N C A N C E R B Y TI M E A F T E R TR A N S P L A N T A T I O N The cumulative incidence of nonmelanoma skin cancer parallels the prolonged survival of patients after organ transplantation and presents a particular challenge to dermatologists worldwide.[28] Many studies report the occurrence of cancer as a proportion of the transplant cohort. Unfortunately, this may be misleading because of discrepancies in age at transplantation, length of follow-up, and other differences between cohorts.[3,4] In a study of 1,098 renal OTR in Australia, the cumulative incidence of skin cancer, calculated by life-table analysis, increased progressively from 7% after one year of immunosuppression to 45% after 11 years and 70% after 20 years. Different combinations of immunosuppressive agents (cyclosporine, azathioprine, prednisolone) were also studied, but no differences were observed. The authors concluded that the increased risk of skin cancer associated with immunosuppression was independent of the agent used and was the result of the immunosuppression per se.[20] The incidence of skin cancer in Australia increased steeply in the first few years after transplantation and then tended to stabilize.[20] In a Dutch cohort of 764 renal OTR, the induction period for skin cancer was much longer, and the incidence did not start to rise significantly until about 6 years post transplantation [5] when the curve of the cumulative incidence started to parallel that of the Australian cohort.[20] In 455 heart OTR from Australia, the cumulative incidence of skin cancer was 31% at 5 years and 43% at 10 years.[21] In Italy, heart OTR had a 5-year cumulative incidence of nonmelanoma skin cancer of 15% and a 10-year rate of 33%.[39] For renal OTR, the corresponding figures were lower at 6% and 17%, respectively.[29] Not only cumulative incidences but also cumulative risks have been calculated and reported. In a study from the United Kingdom, the cumulative risk of skin cancer reached 9% at 5 years, 27% at 10 years, 43% at 15 years, and 61% at 20 years after renal transplantation.[19] In a Swedish study of 5,356 OTR, the relative risk of cancer was estimated for different time periods after the first transplantation. It was shown that even in a population with limited solar exposure and resultant lower innate risk of skin cancer, the relative risk of nonmelanoma skin cancer increased to about 40-fold during the first 5 years, increasing to about 100-fold by 10 years. The magnitude of increased relative risk was subsequently relatively stable. In contrast, the relative risks of cancer of all types were almost constant during the entire observation period up to 24 years.[6]

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M O R T A L I T Y O F SK I N C A N C E R IN OT R In spite of the large number of studies reporting skin cancer in OTR, few studies have reported figures on mortality.[11,21,40] In an Australian study of 455 heart OTR, 11 patients died of skin cancer, accounting for 27% of the deaths occurring after the fourth year post transplant.[21] Six died of SCC, four of melanoma, and one patient died of Merkel cell carcinoma. An Irish study of 1,553 renal OTR showed six patients dying from aggressive SCC. The patients with lethal SCC had 5–26 tumors.[40] Recently, figures on SCC mortality have been presented from the Swedish OTR cohort comprising 5,931 patients including 236 heart transplant recipients.[11] Seven patients, six males and one female, died from SCC. All were kidney transplant recipients. All tumors were located on the head, and four of the patients had only one SCC. The principal site of metastasis was the parotid gland. The mean time between date of transplantation and death was 10.4 years (range 6–17), and the mean age at death was 60.7 years (range 49–68). Mortality from SCC was compared with the general population. There was a highly increased risk with the standardized mortality ratio (SMR) being 52.2 (95% confidence interval, CI: 21.0– 107.6). The authors also attempted to compare the risk of death from SCC of a patient with SCC in the Swedish OTR cohort to a patient with SCC in the normal Swedish population. This risk could only be roughly estimated using data from the Swedish Cancer Registry. The expected number of deaths in the OTR cohort was estimated to be 0.078 compared with the 7 deaths observed, giving an SMR of 90. This indicates that the risk of death from SCC in OTR affected with SCC is much higher than that for normal patients afflicted with SCC, confirming the highly aggressive behavior of SCC in OTR. Although the risk of death was felt to be increased in each of the studies, the magnitude of the deaths caused by SCC in the Australian cohort – six lethal SCC in 455 OTR [21] and in the Irish cohort, six lethal SCC in 1,553 OTR [40] – was greater than that found in the Swedish cohort [11] of only seven lethal SCC in 5,931 OTR (including 236 heart transplant recipients). Further studies focusing on differences between these cohorts in order to explain the different mortality rates should be a priority.

REFERENCES

1. Walder B, Robertson M, Jeremy D. Skin cancer and immunosuppression. Lancet 1971;2:1282. 2. Adami J, Ga¨bel H, Lindelo¨f B, et al. Cancer risk following organ transplantation: a nation-wide cohort study in Sweden. Br J Cancer 2003;89:1221–7. 3. Birkeland SA, Storm HH, Lamm LU, et al. Cancer risk after renal transplantation in the Nordic countries 1964–1986. Int J Cancer 1995;60:183–9. 4. Jensen P, Hansen S, Moller B et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 1999;40:177–86.

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5. Harvelt M, Bouwes-Bavinck J, Koote J, et al. Incidence of skin cancer after renal transplantation in the Netherlands. Transplantation 1990; 49:506–09. 6. Lindelo¨f B, Sigurgeirsson B, Ga¨bel H, Stern RS. Incidence of skin cancer in 5356 patients following organ transplantation. Brit J Dermatol 2000;143:513–9. 7. Hollenbeak CS, Todd MM, Billingsley EM, et al. Increased incidence of melanoma in renal transplantation recipients. American Cancer Society 2005;104:1962–7. 8. Buell JF, Gross TG, Woodle ES. Malignancy after transplantation. Transplantation 2005;80:s254–s264. 9. Moloney FJ, Comber H, O’lorcain P et al. A population-based study of skin cancer incidence and prevalence in renal transplant recipients. Br J Dermatol 2006;154:498–504. 10. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003;348:1681–91 11. Lindelo¨f B, Jarnvik J, Ternesten-Bratel A et al. Mortality and clinicopathologic features of cutaneous squamous cell carcinoma in organ transplant recipients.: A study of the Swedish cohort. Acta Derm Venereol 2006;86(3):219–22, 2006. 12. Lindelo¨f B, Dal H, Wolk K, Malmborg N. Cutaneous cell carcinoma in organ transplant recipients: A study of the Swedish cohort with regard to tumor site. Arch Dermatol 2005;141:447–51. 13. Penn I. Cancers in renal transplant recipients. Adv Ren Replace Ther 2000;7:147–56. 14. Ramsay HM, Fryer AA, Hawley CM et al. Factors associated with nonmelanoma skin cancer following renal transplantation in Queensland, Australia. J Am Acad Dermatol 2003;49:397–406. 15. Lindelo¨f B, Granath F, Dal H et al. Sun habits in kidney transplant recipients with skin cancer: A case control study of possible causative factors. Acta Derm Venereol 2003;83:189–93. 16. Otley CC, Coldiron BM, Stasko T et al. Decreased skin cancer after cessation of the therapy with transplant-associated immunosuppressants. Arch Dermatol 2001;137:459–63. 17. Fuente MJ, Sabat M, Roca J, et al. A prospective study of the incidence of skin cancer and its risk factor in a Spanish Mediterranean population of kidney transplant recipients. Brit J Dermatol 2003;149: 1221–6. 18. Naldi L, Fortina AB, Lovati S et al. Risk of nonmelanoma skin cancer in Italian organ transplant recipients. A registry-based study. Transplantation 2000;70:1479–84. 19. Bordea C, Wojnarowska F, Millard PR et al. Skin cancer in renaltransplant recipients occur more frequently than previously recognized in a temperate climate. Transplantation 2004;77:574–79. 20. Bouwes-Bavinck J, Hardie D, Green A, et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia. Transplantation 1996;61:715–721. 21. Ong C, Keogh A, Kossard S et al. Skin cancer in Australian heart transplant recipients. J Am Acad Dermatol 1999;40:27–34. 22. Moosa MR. Kaposi’s sarcoma in kidney transplant recipients: a 23-year experience. Q J Med 2005;98:205–14.

23. Woodle E, Hanaway M, Buell J,et al. Kaposi’s sarcoma. An analysis of the US and international experiences from the Israel Penn international transplant tumor registry. Transplant Proc 2001;33: 3660–1. 24. Penn I. Sarcomas in organ allograft recipients. Transplantation 1995;60:1485–91. 25. Penn I, First MR. Merkel’s cell carcinoma in organ transplant recipients: report of 41 cases. Transplantation 1999;68:1717–21. 26. Berg D, Otley CC. Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002;47:1–17. 27. Gjersvik P, Hansen S, Moller B et al. Are heart transplant recipients more likely to develop skin cancer than kidney transplant recipients? Transpl Int 2000;13(Suppl. 1)5380–1. 28. Ulrich C, Schmook T, Sachse MM et al. Comparative epidemiology and pathogenic factors for nonmelanoma skin cancer in organ transplant patients. Dermatol Surg 2004;30:622–7. 29. Belloni Fortina A, Caforio AL, Piaserico S et al. Skin cancer in heart transplant recipients: Frequency and risk factor analysis. J Heart Lung Transplant 2000;19:249–55. 30. Euvrard S, Kanitakis J, Pouteil-Noble C et al. Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation. J Am Acad Dermatol 1995;33:222–9. 31. Otley CC, Pittelkow MR. Skin cancer in liver transplant recipients. Liver Transpl 2000;6:253–62. 32. Herrero JI, Espana A, Quiroga J et al. Nonmelanoma skin cancer after liver transplantation. Study of risk factors. Liver Transpl 2005;11: 1100–6. 33. Euvrard S, Kanitakis J, Cochat P, Claudy A. Skin cancers following pediatric organ transplantation. Dermatol Surg 2004;30:616–21. 34. Coutinho HM, Groothoff JW, Offringa M et al. De novo malignancy after pediatric renal replacement therapy. Arch Dis Child 2001;85:478–83. 35. Penn I. De novo malignancy in pediatric organ transplant recipients. Pediatr transplant 1998;2:56–63. 36. Moosa MR. Racial and ethnic variations in incidence and pattern of malignancies after kidney transplantation. Medicine 2005;84: 12–22. 37. Hoshida Y, Aozasa K. Malignancies in organ transplant recipients. Pathology International 2004;54:649–58. 38. Hsu R-B, Chen RJ, Chou N-K et al. Low incidence of malignancy after transplantation in Chinese heart allograft recipients. Transplant Int 2005;18:283–8. 39. Caforio AL, Fortina AB, Piaserico S et al. Skin cancer in heart transplant recipients: risk factor analysis and relevance of immunosuppressive therapy. Circulation 2000;103:III222–27. 40. Moloney FJ, Kelly PO, Kay EW, Conlon P, Murphy GM. Maintenance versus reduction of immunosuppression in renal transplant recipients with aggressive squamous cell carcinoma. Dermatol Surg 2004;30:674–8.

22 The Clinical Presentation and Diagnosis of Skin Cancer in Organ Transplant Recipients

Stephen D. Hess, MD, PhD and Chrysalyne D. Schmults, MD

AKs or in situ SCC.[4] In OTRs, AKs may develop at an earlier age, occur in greater numbers, and progress more rapidly to invasive SCC.[3,5] The development of eruptive AKs following heart transplantation has also been reported.[6] AKs may be difficult to distinguish clinically from other cutaneous neoplasms that are frequently present in OTRs, such as viral warts, seborrheic keratoses, stucco and lichenoid keratoses, and in situ SCC.[7] Actinic keratoses are often diagnosed by their clinical appearance. However, as noted above, they can often be indistinguishable from cancerous lesions. In such cases where the diagnosis is uncertain, a shave biopsy must be performed to confirm the diagnosis and rule out malignancy.

The clinical presentation and diagnosis of skin cancer in organ transplant recipients is generally similar to that in nonimmunosuppressed patients. However, as detailed elsewhere in this book, transplanted patients may have more numerous, severe, and life-threatening tumors. This chapter will discuss the clinical characteristics of the most common types of tumors seen in organ transplant recipients (OTRs) and will briefly highlight aspects that are unique to transplant patients where they exist. Each major tumor type will be discussed in greater detail, including treatment options, in subsequent chapters. Table 22.1 summarizes common terms used to describe the clinical appearance of dermatologic lesions. These terms will be used throughout this chapter and in other chapters of the book.

BASAL CELL CARCINOMA ( F I G U R E 2 2. 5 –F IG UR E 22 . 8)

AC TI N I C KE R A T O S I S ( F IGU R E 22 .1 –F I G U R E 2 2 .4 )

The incidence of basal cell carcinoma (BCC) is increased after organ transplantation, though not to the same degree as SCC. In the first several years after transplantation, BCC remains more common than SCC. However, the usual BCC to SCC ratio of 4:1 eventually becomes reversed in OTRs.[8] Although BCCs rarely metastasize, they can result in significant morbidity through locally destructive growth. BCCs can be subdivided into a number of distinct variants based on clinicopathologic criteria, including nodular BCC, superficial BCC, and morpheaform BCC. The classic nodular BCC is a small pink or red, well-circumscribed nodule with a ‘‘pearly’’ (i.e., translucent) appearance, a rolled border, and overlying telangiectasia. Progressive enlargement of the lesion may lead to central ulceration and crusting, which can obscure the typical clinical features. Superficial BCCs are pink or red, thin, slightly scaly plaques that may be associated with fine ‘‘threadlike’’ telangiectasia. Superficial BCCs occur more commonly on the trunk and extremities compared to nodular BCC, which tends to develop on the head and neck. Morpheaform BCC presents as an ill-defined, sclerotic, ivory-colored plaque, often with overlying telangiectasia. The designation ‘‘morpheaform’’ is derived from its resemblance to morphea, a localized form of scleroderma. These lesions are easily mistaken for scars. Melanin pigment may be present in variable amounts in all subtypes of BCC, though morpheaform BCCs are rarely pigmented. The presence of melanin pigment may lead the clinician to misclassify the tumor as a melanocytic lesion.[9]

Actinic keratosis (AK) is a proliferation of atypical keratinocytes confined to the epidermis, with the potential to progress to invasive squamous cell carcinoma (SCC). The vast majority of AKs are induced by UV radiation and their incidence increases with age, degree of UV exposure, and lighter skin pigmentation. There is some controversy with regard to whether AK should be considered a premalignant neoplasm or the earliest form of in situ SCC. Due to the risk of progression, AKs should be treated with curative intent.[1,2] Clinically, AKs present as rough, scaly papules on sunexposed skin. They are often difficult to appreciate by visual inspection and are more easily recognized by the identification of rough sandpaper-like patches on light palpation of the skin. Most lesions occur on the face, scalp, ears, neck, and the dorsal aspect of the hands and forearms. Individual lesions may be flesh-colored, tan, pink, erythematous (red), or darkly pigmented. Most AKs are between 3 and 6 mm in diameter, though pinpoint lesions and larger plaquelike lesions are not uncommon. Patients may present with a single AK, several scattered AKs, or innumerable and/or confluent AKs on sun-exposed sites.[1,2] The clinical presentation of AKs in OTRs is similar to that in nonimmunosuppressed individuals; however, the incidence of AKs is greater in the transplant population and increases with time post transplant.[3] Within the first 5 years of immunosuppression, 40% of OTRs may develop 147

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Table 22.1 Common terms used to describe skin lesions Term

Definition

Macule

Circumscribed, flat discoloration of the skin, up to 1 cm in diameter Circumscribed, flat discoloration of the skin, greater than 1 cm in diameter Elevated solid lesion, up to 1 cm in diameter, usually with surface textural change Circumscribed, broad, elevated lesion, greater than 1 cm in diameter Elevated solid lesion, between 0.5 cm to 2.0 cm in diameter, with minimal surface textural change Elevated solid lesion, greater than 2.0 cm in diameter Focal loss of epidermis only; heals without scar Focal loss of epidermis and dermis; heals with scar Excess dead epidermal cells produced by abnormal keratinization, usually white or yellow in color Collection of dried serum, pus, or blood; usually mixed with cellular debris Dilated superficial blood vessels that are visible through the skin

Patch Papule Plaque Nodule

Tumor Erosion Ulcer Scale

Crust Telangiectasia

Figure 22.2. Common presentation of multiple AKs in sun exposed areas: 2–8 mm erythematous patches and papules, rough to the touch due to hyperkeratosis.

Figure 22.1. Early AK in center of photo: A white patch with surrounding erythema with slight central hyperkeratosis (white scale of excess stratum corneum due to increased keratinocyte proliferation) making it rough to the touch.

Data on BCC in OTRs is surprisingly limited, most likely because BCCs are not as common or life-threatening as SCC in this population. The clinical presentation of BCC in OTRs is generally similar to that in non-OTRs though several differences have been established. For example, in the largest study to date, Kanitakis et al. found that BCCs in OTRs occurred at an earlier age (54.6 vs. 69.8 years), were more common in men (male to female ratio 4.8:1 vs. 1.3:1), and were more likely to arise in extracephalic locations (37.5% vs. 24.5%) compared to

Figure 22.3. Hypertrophic variant of AK in which hyperkeratosis (scale) is more prominent.

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Figure 22.4. Diffuse and extensive AKs, many of which are hypertrophic, likely admixed with SCCIS in a renal transplant patient.

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Figure 22.6. Superficial variant of BCC, an erythematous ill-defined patch, in this case with erosion.

Figure 22.7. Very extensive BCC, untreated for many years, with ulceration and tissue destruction centrally; periphery still has suggestion of pearly translucent appearance characteristic of BCC.

Figure 22.5. Classic BCC, an erythematous papule with a pearly, that is, slightly translucent appearance. This case has central erosion.

non-OTRs.[10] BCCs arising in such unusual locations as the auditory canal, axilla, hand, wrist, and genitalia were seen only in OTRs.[10] Similar results were obtained by Harwood et al., who also showed that multiple BCCs were more common in OTRs compared to immunocompetent patients.[11] Despite these differences, BCC appears to have a similar course and prognosis in OTRs compared to non-OTRs.[11]

Figure 22.8. Morpheaform variant of BCC with hypopigmented scarlike appearance, in this case with fine telangiectasias helping to establish diagnosis.

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Table 22.2 Summary of skin biopsy techniques Procedure

Applications

Shave biopsy

Removal of lesion with razor blade or #15 scalpel blade; may be superficial (including minimal dermis) or deep (including most or all of the dermis); hemostasis achieved without sutures

Punch biopsy

Round core of tissue removed with 2–10mm punch biopsy tool; incision is perpendicular to skin surface; samples epidermis, dermis, and part of subcutaneous fat; usually requires sutures for hemostasis Entire lesion removed using a scalpel incising perpendicular to the skin surface; tissue removed including superficial subcutaneous fat; final defect often elliptical to facilitate closure; sutures required for hemostasis (superficial +/ deep sutures) Similar to excisional biopsy, but only a portion of the lesion is sampled; rarely used (punch or excision is preferred)

Neoplasms arising from the epidermis in which sampling of epidermis confirms diagnosis and complete visualization of the dermal component is not critical (BCC, AK, SCCIS, low-risk SCC) Neoplasms in which the dermal or subcutaneous component is important for diagnosis or prognosis (e.g., high-risk SCC, PTLD, AFX)

Excisional biopsy

Incisional biopsy

A biopsy is needed to confirm the diagnosis of BCC. A shave biopsy is generally adequate and is the most common diagnostic approach. In cases where a benign diagnosis is highly unlikely and the lesion has well-defined borders, an excisional biopsy can efficiently provide diagnostic confirmation and definitive treatment simultaneously. If this option is used, the excision should be carried to the level of the subcutaneous tissue. All margins must be carefully evaluated histologically to ensure the tumor was completely removed. Because definitive diagnosis based solely on clinical exam is often impossible in dermatology, skin biopsies are utilized commonly. A skin biopsy is required for definitive diagnosis of all skin cancers. Table 22.2 summarizes the common biopsy techniques employed.

Technique of choice if melanoma or another lesion with high-risk of metastasis is suspected (e.g., metastasis, MCC, MM)

Large plaque or tumor that would be difficult to excise, is too deep for punch biopsy, or in which clinical diagnosis is uncertain

ized by solar elastosis, mottled dyspigmentation, telangiectasia, and multiple AKs is often noted. Most SCCs enlarge slowly and are not associated with symptoms; however, rapid tumor growth may result in pain, ulceration, weeping, and bleeding. Numbness, tingling, pain, or muscle weakness may reflect underlying perineural involvement [14] and a high risk of metastasis. Immunosuppressed patients, including those with organ transplants, are more likely to experience rapid growth of SCC.[15] In situ SCC (SCCIS) is a superficial early form of SCC confined to the epidermis without dermal invasion. If completely removed, SCCIS has no risk of metastasis. OTRs with diffuse AKs often have many SCCIS lesions as well. SCCIS tumors are often difficult to distinguish from AKs. However, they are often more erythematous and raised. In a Swedish retrospective cohort study of 179 OTRs with 475 cutaneous SCCs, anatomic location of SCC was evaluated

SQUAMOUS CELL CARCINOMA (FI G URE 2 2. 9– FIGUR E 22 .1 2 A ND F I G U R E 2 2. 3 0– FI G U R E 22 .3 2) Squamous cell carcinoma (SCC) is the most common malignancy in OTRs, occurring 65 to 250 times more frequently than in the general population. Multiple studies have demonstrated that SCC in OTRs develops at a younger age compared to non-OTRs. The risk of SCC appears to increase dramatically with time, following organ transplantation for those patients with light skin (Fitzpatrick skin types I and II) and a history of substantial sun or other UV exposure. SCC in OTRs is characterized by an increased risk of local recurrence, nodal and distant metastasis, and mortality.[7,8,11–13] The typical SCC appears as a scaly pink papule, nodule, or plaque on sun-exposed skin. Surface changes may include scaling, ulceration, crusting, of the presence of a cutaneous horn. A background of severely sun-damaged skin character-

Figure 22.9. SCC presenting as an erythematous papule with central erosion.

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Figure 22.11. High-risk SCC. This lesion demonstrates multiple high-risk features including large diameter, depth to subcutaneous tissues and likely beyond (periosteum and potentially bone), and recurrence after non-Mohs excision with clear margins and adjuvant radiotherapy. In addition, it is multifocal around the granulation scar of the original excision with a large (10 cm) ill-defined zone of elevation likely representing subcutaneous tumor. The graft scar at left is due to remote (>10 years) excision of a different primary SCC indicating another risk factor, a history of severe SCCs.

Figure 22.10. A more advanced SCC with greater tumor bulk (indicating increased tumor depth and dermal involvement) and central ulceration; such a tumor may often involve perichondrium and even cartilage.

with regard to age and sex. This study showed that SCC was more likely to develop on the head and neck in male OTRs and in those born before 1940. In contrast, both younger and female OTRs developed SCC predominately on the trunk and extremities.[13] Among patients who received an organ transplant before age 18, SCC of the lip accounts for 23% of all skin cancer.[8,16] Anogenital SCC is also more common in OTRs, especially among those who underwent transplantation in childhood. Lesions tend to be multiple and/or extensive, appearing as pigmented papules (i.e., bowenoid papulosis), which are often impossible to distinguish from warts without a biopsy.[7] A number of atypical presentations of SCC in OTRs have been reported in the literature, including 2 cases of primary SCC arising in porokeratosis, both of which subsequently metastasized.[17,18] SCCIS developed at the exit site of a tunneled hemodialysis catheter in a liver transplant patient with endstage renal disease.[19] Ibe et al. describe a patient who developed Bowen’s disease (a subtype of SCCIS) of the finger and perianal bowenoid papulosis after cardiac transplantation. In

Figure 22.12. These erythematous ill-defined plaques represent invasive SCC which appeared at surgical sites only 3 weeks after treatment of SCCIS in a transplant patient. This represents an unusual phenomenon of reactive SCC formation in response to surgical trauma. KAs have been reported in this context as well.

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this case, HPV type 16 was isolated from both lesions suggesting contact transmission.[20] Any lesion suspected of being SCC or SCCIS should be biopsied. A shave biopsy is used most commonly. Excisional biopsy may also be considered for small or well-circumscribed lesions (see discussion of excisional biopsy for BCC earlier). Though complete surgical removal is curative in most cases, further staging in the form of imaging or evaluation of lymph nodes may be considered in certain cases of SCC at high-risk for metastasis.[12] If lymph node disease is detected before distant organ metastasis has occurred, cure rates on the order of 70% can still be achieved with combined lymphadenectomy and adjuvant radiotherapy.

KERATOACANTHOMA ( F I G U R E 2 2. 13 –F I G U R E 2 2 .1 5) Keratoacanthoma (KA) is an epithelial neoplasm characterized by rapid growth and a high degree of cellular maturation. Although they may resolve spontaneously, they are generally treated as SCCs because it is difficult to distinguish them clinically and histologically from SCCs. The KA usually begins as a small papule that enlarges rapidly over a period of 2–4 weeks to form a firm, domeshaped nodule. During the maturation phase, a firmly embedded keratin plug develops within the center of the nodule and resembles a plug within the crater of a volcano. Spontaneous regression may occur, usually over a period of 2–6 months, leaving an atrophic scar. Because differentiation from SCC is difficult and because some KA will exhibit continued growth, most clinicians manage them like SCC. Most KAs present as solitary nodules with a diameter of 2 cm or less. Less common variants include the giant KA, multinodular KA, verrucous KA, and the subungual KA.[21] In OTRs, the clinical presentation of KA is similar to that in non-OTRs; however, the incidence of KAs is reportedly increased, and such lesions may be more locally aggres-

Figure 22.14. A larger KA in which central crater is more prominent but still contains keratin.

Figure 22.15. Multiple eruptive KAs.

sive.[22,23] There is no evidence to date that immunosuppression leads to an increased risk of metastasis, which is exceedingly rare in KA. The simultaneous development of multiple KAs (i.e., florid or eruptive keratoacanthomas) has been documented in renal transplant recipients, one of whom also developed a large plaque studded with numerous small nodules that were confirmed by histology to be KAs.[24,25] Eyelid involvement by KA has also been reported in OTRs.[26] Keratoacanthomas are best diagnosed by broad deep-shave biopsies or conservative excisional biopsies. The biopsy should be deep enough to remove the base of the lesion as evaluation of the tumor base is critical in differentiating KA from SCC.

MA L I G N A N T M EL A N O MA ( FI G U R E 22 .1 6 –F IG U R E 22 . 20 ) Figure 22.13. Classic KA: a well-circumscribed dome-shaped papule with central crater containing a keratin ‘‘plug.’’

Malignant melanoma (MM), although uncommon in OTRs, is potentially lethal. The incidence of MM in OTRs is increased

THE CLINICAL PRESENTATION AND DIAGNOSIS OF SKIN CANCER IN ORGAN TRANSPLANT RECIPIENTS

Figure 22.16. An early superficially invasive melanoma easily mistaken for a dysplastic (atypical but benign) nevus (mole). If the patient had multiple similar-looking lesions, this clinical appearance would be unlikely to represent melanoma. However, a history of recent growth or change of this lesion, coupled with the absence of similar lesions elsewhere arouses suspicion for malignancy. Additionally, the border of this lesion is slightly irregular.

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Figure 22.18. A still more advanced melanoma demonstrating all four ABCDs with the addition of a nodular component representing increased lesion depth. As depth of the primary lesion is the primary predictor of prognosis in melanoma, this lesion likely carries a relatively poor prognosis.

Figure 22.17. A more classic and also more advanced melanoma demonstrating the ABCDs of melanoma: asymmetry, border, color, and diameter. The lesion demonstrates asymmetry from one side to the other, irregular (noncircular or ovoid) border, color variation throughout the lesion with areas of red, white, and brown coloration, and diameter greater than a pencil eraser.

by a factor of 1.6 to 3.4 compared to the general population.[7,8] MM accounts for 6.2% of posttransplant skin cancer in adults and 15% in children.[27] MM usually presents as a pigmented (i.e., dark brown to black) macule or papule with lesional asymmetry, an irregular or indistinct border, and color variegation. The presence of multiple colors within a single lesion including brown, black, blue, white, and red is highly suspicious for MM. Amelanotic melanoma is a difficult-to-diagnose variant due to the lack of brown/black pigment. Amelanotic melanoma may appear

Figure 22.19. The lentigo maligna variant of melanoma (a form of melanoma in situ) can be difficult to distinguish from an ordinary lentigo (sun spot) as both are flat pigmented macules or patches. However, lentigo maligna is generally larger (>1cm) with irregular borders and coloration as seen in this case.

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KAPO SI’S SARCOM A ( FI G U R E 22 .2 1 –F IG U R E 22 . 24 )

Figure 22.20. Amelanotic variant of melanoma. This variant is often overlooked or mistaken for BCC or scar. The atrophic contracted appearance and small amount of pigmentation help to inform the clinical diagnosis. A punch biopsy should be performed whenever melanoma is in the differential diagnosis.

skin-colored, pink, or red. Any change in size, shape, color, or texture of a pigmented lesion may herald the development of MM. Similarly, symptoms such as itching, pain, bleeding, or crusting may be associated with malignant transformation of a pigmented lesion, although most MM are asymptomatic.[28] The clinical presentation of primary MM in OTRs is similar to that in nonimmunosuppressed individuals, although diagnosis may be more difficult due to the presence of numerous skin lesions. Patients with MM treated prior to organ transplantation are at greater risk for recurrence, even if the primary lesion occurred as long as 10 years before transplantation.[27] In addition, numerous reports documenting transmission of metastatic MM from donor to OTRs have been published.[27,29–31] Allogeneic melanoma can present with cutaneous and/or visceral metastasis, which are often fatal.[30,31] However, removal of the allograft and discontinuation of immunosuppressive therapy may be curative in some cases.[27] Biopsy is required in any pigmented lesion in which there is any suspicion of malignancy. When melanoma is suspected, a punch or excisional biopsy (not a shave biopsy) is needed. The most important factor in melanoma prognosis is depth of the primary lesion. Thus, a punch biopsy to the level of subcutaneous fat through the central or most advanced-appearing portion of the lesion will provide such valuable prognostic information. This information will influence treatment as excision margins are based on depth of the primary lesion. It will also influence staging decisions as the need for imaging, lymph node evaluation, and even possible adjuvant therapy will be informed by the prognosis based on the primary lesion’s depth. If the lesion is highly suspicious for melanoma, an excisional biopsy may be most appropriate in order to ensure that the deepest portion of the tumor is evaluated in making prognostic estimates.

The incidence of Kaposi’s sarcoma (KS) is increased by a factor of 84- to 500-fold in OTRs, compared to the general population. Most cases of KS occur in OTRs of Mediterranean, Jewish, Arabic, Caribbean, or African descent, and the maleto-female ratio is 3:1 or greater.[7] In Turkey, KS is the most frequent posttransplant malignancy, accounting for 80% of all transplant-related cancers.[32] Kaposi’s sarcoma in OTRs is less common in the United States, compared to Europe and the Middle East, and mostly occurs in recent immigrants. It appears that risk decreases in high-risk ethnic groups if individuals have not lived in endemic areas. KS frequently occurs at a younger age in OTRs compared to those with classic KS, with the mean age reported to be 38–43 years; rare cases have been reported in children with transplants.[7,32] Posttransplant KS is usually clinically similar to the classic form of the disease, which manifests as angiomatous lesions on the lower extremities associated with lymphedema. Skin lesions typically begin as violaceous macules that may evolve into infiltrative plaques, nodules, or even large fungiform tumors.[33] Ninety percent of OTRs with KS have cutaneous and/or mucosal lesions. Thus, routine examination of the oral mucosa is indicated for OTRs. Oral lesions are usually located on the hard palate and appear as flat reddish-blue or purple patches.[34] Oral KS may also mimic gingival hyperplasia, especially in patients receiving cyclosporine.[35] Although cyclosporine itself may produce a generalized, erythematous, fibrotic gingival hyperplasia, KS lesions manifest as a more localized red-purple enlargement.[34] Visceral involvement of KS is common in OTRs with 30–40% of patients having such involvement of internal organs.[7,32] Visceral KS in the absence of cutaneous lesions is rare in OTRs, occurring in approximately 10% of cases.[7,36] However, in a study of Taiwanese renal transplant recipients with KS, 3 of 4 patients initially presented with only peripheral lymphadenopathy.[37] In addition to lymph nodes, the

Figure 22.21. Patch (early flat) stage of Kaposi’s sarcoma (KS) appearing as a violaceous vascular-appearing macule.

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Figure 22.23. Diffuse cutaneous KS with multiple violaceous macules, papules, and plaques over the trunk. Figure 22.22. Plaque (raised) stage of KS with multiple raised violaceous plaques, coalescing in this case, and lymphedema.

gastrointestinal tract and lungs are the most common sites of visceral KS in OTRs.[7,36] Visceral KS is potentially lethal in OTRs and generally requires drastic reductions in immunosuppression, which can precipitate rejection. Diagnosis of oral or cutaneous KS is best accomplished by a broad, deep-shave biopsy or punch biopsy. If KS is confirmed by biopsy, CT of the chest and abdomen is indicated in OTRs to search for potential visceral involvement.

CUTANEO U S POS TT RANSPLANT L YM P HOPRO L IF ER ATI VE D IS OR DER ( F IG U R E 22 .2 5 –F IG U R E 2 2. 26 ) Posttransplant lymphoproliferative disorder (PTLD) is a common complication of both bone marrow and solid organ transplantation, affecting up to 5% of all transplant recipients.[7] Most cases of PTLD (~70%) are B-cell in origin and represent an Epstein–Barr virus (EBV)-driven proliferation. B-cell PTLD often presents at extra-nodal sites including the

Figure 22.24. Oral lesions of KS, showing an admixture of violaceous patch, plaque, and tumor-stage lesions.

lungs, gastrointestinal tract, central nervous system, and the transplanted organ.[7,38] Systemic symptoms such as fever, weight loss, fatigue, and malaise are commonly reported in such cases.

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Figure 22.25. PTLD presenting as shallow erythematous plaques with ill-defined borders and a small well-circumscribed erythematous dome-shaped nodule. Diagnosis would best be established with an excisional biopsy of the papule as it appears to have the greatest tumor bulk. (Photo courtesy of Dr. James Shaw, University of Toronto, Ontario, Canada.)

Cutaneous T-cell PTLD is much less common than its B-cell counterpart, and it is most often EBV-negative. Patients with T-cell PTLD usually present with skin lesions resembling classic mycosis fungoides (i.e., erythematous, scaling patches and plaques) or erythroderma associated with generalized lymphadenopathy.[7,39] Less commonly, cutaneous T-cell PTLD may present in a similar manner to B-cell PTLD with the development of multiple firm, tender, ulcerated, subcutaneous nodules. This presentation appears to be associated with the rare CD30+ anaplastic large-cell lymphoma (ALCL) variant of T-cell PTLD.[39–41] Diagnosis of PTLD is best accomplished by a punch or excisional biopsy. As most reported patients with cutaneous PTLD have gone on to succumb to generalized lymphoma, a thorough lymph node exam, staging by chest and abdominal CT, and referral to oncology is appropriate for any patient diagnosed with cutaneous PTLD.

MERKEL CELL CARCINOMA ( FI G U R E 22 .2 7 A N D F IG UR E 22 . 34 ) Merkel-cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy of neuroendocrine origin.[42] OTRs appear to be at greater risk for developing MCC than the general population,

Figure 22.26. PTLD presenting as multiple cutaneous nodules. (Photo courtesy of Dr. Nancy Samolitus, University of Utah.)

Cutaneous involvement by PTLD is rare, with fewer than 50 cases reported in the literature. In contrast to most cases of systemic PTLD, which occur within 1–2 years of transplantation, cutaneous PTLD is more likely to exhibit a later onset (>5 years posttransplant) and is less likely to be associated with systemic symptoms.[7,38] Cutaneous B-cell PTLD presents as solitary to multiple firm, subcutaneous or dermal nodules on the face, trunk, or extremities.[7] Asymmetric, erythematous, indurated plaques have also been reported.[38] Lesions often undergo rapid enlargement and may be associated with pain or tenderness, overlying erythema, and ulceration.

Figure 22.27. A classic presentation of Merkel cell carcinoma as an asymptomatic erythematous deep dermal nodule with overlying telangiectasia.

THE CLINICAL PRESENTATION AND DIAGNOSIS OF SKIN CANCER IN ORGAN TRANSPLANT RECIPIENTS

though fewer than 60 cases of MCC in OTRs have been reported in the literature.[7,43,44] Similar to other cutaneous malignancies, MCC in the posttransplant setting occurs at a younger age (mean age of 53 years in OTRs compared to 69 years in the general population) and is more aggressive.[44,45] In the largest cases series of OTRs with MCC, 36% of lesions presented on the head and neck, 32% on the upper extremities, and 16% on the trunk.[44] This distribution is similar to that seen in nonimmunosuppressed patients. MCC usually appears as a solitary, asymptomatic, red or violaceous nodule, sometimes with overlying telangiectasia.[7,45] In OTRs, MCC may be mistaken for other forms of skin cancer, which Penn and First noted in nearly half of their patients with MCC.[44] Skin biopsy for accurate diagnosis is of paramount importance in such cases, because MCC is probably the most aggressive of all skin cancers and its prognosis in OTRs is dismal with a 56% mortality rate at 2 years.[44] Diagnosis is best accomplished by punch biopsy or conservative excisional biopsy. Potential spread of tumor to adjacent tissues may be possible, and this should be kept in mind during biopsy if MCC is suspected. Closure with undermining should be avoided until clear surgical margins have been confirmed. Complete tumor removal with clear surgical margins is of paramount importance in preventing metastasis. Staging with magnetic resonance imaging, computed tomography, or positron emission tomography is sometimes used preoperatively, particularly if the lesion is near major nerve branches, lymph node basins, or is clinically advanced. Thorough clinical evaluation of nodal basins by palpation is also crucial. Any palpable nodes should be evaluated with excision or fineneedle aspiration preoperatively. At our institution, MCC is treated by Mohs or wide-margin excision with histological confirmation of all margins. All patients with normal lymph node exams also receive sentinel lymph node biopsy, lymphadenectomy if sentinel node is positive, and adjuvant radiotherapy, usually to both primary site and nodal basin.

Figure 22.28. Atypical fibroxanthoma presenting as an erythematous nodule with ill-defined borders and associated serosanguinous crust over an area of erosion.

ATYPICAL FIBROXANTHOMA ( F IGU R E 22 .2 8 –F IG U R E 2 2. 29 AN D F IG UR E 22 . 33 ) Atypical fibroxanthoma (AFX) is an uncommon spindle-cell neoplasm that typically arises on chronically sun-damaged skin of elderly patients. AFX is generally considered to be a more superficial and less aggressive variant of malignant fibrous histiocytoma (MFH).[46] Both AFX and MFH are rare in the transplant population, with only 5 cases of AFX and fewer than 10 cases of MFH reported in the literature; however, epidemiologic data suggest that the incidence of AFX and MFH are increased in OTRs.[6,47–50] Clinically, AFX appears as a solitary, pink to red, rapidly enlarging nodule that may become ulcerated.[46,49] All reported cases of AFX in OTRs have occurred on the head or neck.[6,47–50] The clinical appearance of AFX can mimic other cutaneous neoplasms including SCC, BCC, and pyogenic

157

Figure 22.29. Atypical fibroxanthoma as an exophytic well-circumscribed erythematous nodule with shallow hemorrhagic crusting.

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Figure 22.30. Metastatic SCC from a cutaneous primary presenting as multiple light pink small dermal nodules coalescing to form a plaque.

granuloma. AFX in the transplant setting is often associated with a history of multiple premalignant and malignant skin neoplasms.[7] By routine histology, AFX may resemble other spindle-cell tumors such as spindle-cell SCC, malignant melanoma, and dermatofibrosarcoma protuberans. Consequently, immunohistochemical and/or ultrastructural studies may be required for diagnosis.[49] AFX may be locally aggressive though it is usually cured with surgical excision and carries a low risk for recurrence or metastasis.[46] The course of AFX in OTRs has not been well characterized due to the rarity of this neoplasm. However, local recurrence occurred in 2 of the 5 reported cases. Metastasis of AFX has been documented in a patient with CLL suggesting that impaired cellular immunity may be associated with a worse prognosis.[50,51] In addition, Kovach et al. described a cardiac transplant recipient who developed a total of 3 AFXs over a period of 9 years.[50] Taken together, these data suggest that OTRs may be at greater risk for developing AFX and that such tumors may be more aggressive in this population. Diagnosis is ideally accomplished with a punch biopsy through the central portion of the lesion so that the depth of invasion can be assessed and MFH ruled out. However, since

Figure 22.31. A primary SCC with two nearby in-transit or satellite metastases (circled) presenting as small flesh-colored nodules. Such early metastases are easily overlooked without close inspection and a high index of clinical suspicion. They portend a worse prognosis but are still potentially curable with aggressive treatment (wide excision plus adjuvant radiation and careful lymph node staging and treatment). (Photo courtesy of Dr. Chris Miller, University of Pennsylvania, Philadelphia, Pennsylvania.)

most lesions are thought to be SCC or BCC clinically, shave biopsies are often submitted. If the shave biopsy is deep, encompassing the lower portion of the dermis, an accurate diagnosis can usually be made.

ME TAS TAS IS (FI G URE 2 2. 30 –FI G URE 2 2. 3 4) Primary cutaneous neoplasms account for the vast majority of skin cancer in OTRs. Metastasis to the skin is uncommon. Cutaneous SCC is responsible for most cases of cutaneous metastasis, though it is far more likely to spread to regional lymph nodes.[52] When SCC does spread to the skin, it usually appears as discrete, gray-white, flesh-colored, or pink dermal or subcutaneous papules that are distinct from, but in close proximity to the primary tumor site.[8,53] Berg and Otley described this presentation of metastatic SCC in OTRs as ‘‘in-transit metastasis,’’ a concept that is well recognized in melanoma.[8] These lesions can be very subtle yet carry a poor

THE CLINICAL PRESENTATION AND DIAGNOSIS OF SKIN CANCER IN ORGAN TRANSPLANT RECIPIENTS

159

Figure 22.32. Advanced metastatic SCC from a cutaneous primary tumor with multiple tumors coalescing. Such a patient will usually have distant organ metastasis. Thorough staging is required to make appropriate treatment decisions.

Figure 22.34. A case of metastatic Merkel cell carcinoma presenting as a subcutaneous palpable nodule at the inferior edge of the scar from previous surgery and radiation.

Figure 22.33. A rare case of metastatic AFX with ill-defined dermal and subcutaneous erythema and infiltration. Ulcerated areas are bordered by pink tumor nodules on close inspection. These nodules would be the best place to obtain punch or excisional biopsy for diagnosis.

prognosis. Therefore, close inspection of the 10-cm area around all primary SCC sites is warranted at regular followup intervals for OTRs with a history of SCC, particularly, highrisk SCC. In the largest study to date, Carucci et al. characterized 21 patients (15 OTRs and 6 non-OTRs) with in-transit metastasis. In this case series, 15 of 22 primary SCCs resulting in intransit metastasis were located on the head, and had a mean diameter of 1.7 cm. Other high-risk tumor factors including origin within a scar, deep invasion, and perineural involvement were associated with the development of in-transit metastasis. The metastatic tumor nodules themselves ranged in size from 0.2 to 1.1 cm in size and were located an average of 2.5 cm from the primary tumor. Diagnosis of in-transit metastasis was made an average of 10 weeks after treatment of the primary tumor (range 1–56 weeks), suggesting that this type of metastasis has a relatively short latency period. Furthermore, nearly half of the patients with in-transit metastasis presented with multiple metastatic lesions.[53]

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Table 22.3 Summary of cutaneous malignancies occurring in organ transplant recipients Actinic keratosis (AK) Squamous cell carcinoma (SCC) Basal cell carcinoma (BCC) Keratoacanthoma (KA) Malignant melanoma (MM) Kaposi’s sarcoma (KS) Cutaneous post-transplantation lymphoproliferative disorder (PTLD) Merkel cell carcinoma (MCC) Atypical fibroxanthoma (AFX) Malignant fibrous histiocytoma (MFH) Sebaceous carcinoma Dermatofibrosarcoma protuberans (DFSP) Angiosarcoma Leiomyosarcoma

Atypical presentations of metastatic SCC have been reported in OTRs. For example, Shafqat et al. describe a case of zosteriform metastasis occurring in a renal transplant recipient.[54] Perineural spread of SCC along the spinal accessory nerve presenting as a palpable cordlike mass has also been documented.[55]

CONCLUSION In this chapter, the clinical presentation of common cutaneous neoplasms has been highlighted. (Table 22.3) The clinical features of most skin cancers are similar in OTRs and nonimmunosuppressed patients. However, numerous tumors and more aggressive presentations are seen in OTRs. By becoming familiar with the clinical presentation of skin cancer in OTRs, clinicians of all related specialties may reach diagnostic and therapeutic decisions at the earliest possible time, enhancing the likelihood of favorable outcome.

REFERENCES

1. Callen, J. P., D. R. Brikers, and R. L. Moy. Actinic keratoses. J Am Acad Dermatol 1997; 36(4): 650–65. 2. Moy, R. L. Clinical presentation of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 2000; 42(1 Pt 2):8–10. 3. Ulrich C, Schmook T, Nindl I, Meyer T, Sterry W, Stockfleth E. Cutaneous precancers in organ transplant recipients: an old enemy in a new surrounding. Br J Dermatol 2003; 149 Suppl 66:40–42. 4. Stockfleth E, Ulrich C, Meyer T, Christophers E. Epithelial malignancies in organ transplant patients: clinical presentation and new methods of treatment. Recent Results Cancer Res 2002; 160:251–8. 5. Boyd AS, Stasko T, Cameron GS, Russell M, King LE Jr. Histologic features of actinic keratoses in solid organ transplant recipients and healthy controls. J Am Acad Dermatol 2001; 45:217–21. 6. Paquet, P., and G. E. Pierard. Invasive atypical fibroxanthoma and eruptive actinic keratoses in a heart transplant patient. Dermatology 1996; 192(4):411–3.

7. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003; 348:1681–91. 8. Berg, D, and Otley C. C. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002; 47:1–17. 9. Miller, S. J. Biology of basal cell carcinoma (Part I). J Am Acad Dermatol 1991; 24(1):1–13. 10. Kanitakis J, Alhaj-Ibrahim L, Euvrard S, Claudy A. Basal cell carcinomas developing in solid organ transplant recipients: clinicopathologic study of 176 cases. Arch Dermatol 2003; 139(9):1133–7. 11. Harwood CA, Proby CM, McGregor JM, Sheaff MT, Leigh IM, Cerio R. Clinicopathologic features of skin cancer in organ transplant recipients: a retrospective case-control series. J Am Acad Dermatol 2006; 54:290–300. 12. Schmults, C. D. High-risk cutaneous squamous cell carcinoma: identification and management. Adv Dermatol 2005; 21:133–52. 13. Lindelof B, Dal H, Wolk K, Malmborg N. Cutaneous squamous cell carcinoma in organ transplant recipients: a study of the Swedish cohort with regard to tumor site. Arch Dermatol 2005; 141:447–51. 14. Goldman, G. D. Squamous cell cancer: a practical approach. Semin Cutan Med Surg 1998; 17(2):80–95. 15. Billingsley EM, Davis N, Helm KF. Rapidly growing squamous cell carcinoma. J Cutan Med Surg 1999; 3(4):193–7. 16. Penn, I. Posttransplant malignancies in pediatric organ transplant recipients. Tranplant Proc 1994; 26:2763–5. 17. Anzai S, Takeo N, Yamaguchi T, et al. Squamous cell carcinoma in a renal transplant recipient with linear porokeratosis. J Dermatol 1999; 26(4):244–7. 18. Silver SG, Crawford RI. Fatal squamous cell carcinoma arising from transplant-associated porokeratosis. J. Am Acad Dermatol 2003; 49:931–3. 19. Hammes JS, Bestoso JT, Sharma A. Squamous cell carcinoma in situ arising at the exit site of a tunneled catheter. Am J Kidney Dis 2004; 44(3):e43–6. 20. Ibe M, Kawase M, Ishiji T, Kamide R, Niimura M. A cardiac allograft recipient with Bowen’s disease on a finger and concurrent perianal bowenoid papulosis. J Dermatol 2003; 30(5):389–94. 21. Schwartz, R. A. Keratoacanthoma. J Am Acad Dermatol 1994; 30(1): 1–19. 22. Bordea C, Wojnarowska F, Millard PR, Doll H, Welsh K, Morris PJ. Skin cancers in renal-transplant recipients occur more frequently than previously recognized in a temperate climate. Transplantation 2004; 77(4):574–9. 23. Sullivan, J. J. Keratoacanthoma: the Australian experience. Australas J Dermatol 1997; 38(suppl1):S36–9. 24. Jacobsson S, Linell F, Rausing A. Florid keratoacanthomas in a kidney transplant recipient Case report. Scand J Plast Reconstr Surg 1974; 8(3):243–6. 25. Washington, C. V., and G. R. Mikhail. Eruptive keratoacanthoma en plaque in an immunosuppressed patient. J Dermatol Surg Oncol 1987; 13(12):1357–60. 26. Stewart WB, Nicholson DH, Hamilton G, Tenzel RR, Spencer WH. Eyelid tumors and renal transplantation. Arch Ophthalmol 1980; 98(10):1771–2. 27. Penn, I. Malignant melanoma in organ allograft recipients. Transplantation 1996; 61(2):274–8. 28. Otley, C. C., and M. R. Pittelkow. Skin cancer in liver transplant recipients. Liver transplantation 2000; 6(3):253–62. 29. Stephens JK, Everson GT, Elliott CL et al. Fatal transfer of malignant melanoma from multiorgan donor to four allograft recipients. Transplantation 2000; 70(1):232–6. 30. Morris-Stiff G, Steel A, Savage P, et al. Transmission of donor melanoma to multiple organ transplant recipients. Am J Transplantation 2004; 4:444–6.

THE CLINICAL PRESENTATION AND DIAGNOSIS OF SKIN CANCER IN ORGAN TRANSPLANT RECIPIENTS

31. Zavos G, Papaconstantinou I, Chrisostomidis C, Kostakis A. Metastatic melanoma within a transplanted kidney: a case report. Transplant Proc 2004; 36:1411–12. 32. Duman S, Toz H, Asci G, et al. Successful treatment of posttransplant Kaposi’s sarcoma by reduction of immunosuppression. Nephrol Dial Transplant 2002; 17:892–96. 33. Costa Ferreira P, Miguel Pereira J, Oliveira I, et al. Unusual Kaposi’s sarcoma in a renal transplant recipient. Nephrol Dial Transplant 2005; 20:2830–31. 34. Darling M, Thompson I, Meer M. Oral Kaposi’s sarcoma in a renal transplant patient: case report and literature review. J Can Dent Assoc 2004; 70(9):617–20. 35. Qunibi WY, Akhtar M, Ginn E, Smith P. Kaposi’s sarcoma in cyclosporine-induced gingival hyperplasia. Am J Kidney Dis 1998; 11(4):349–52. 36. Penn, I. Kaposi’s sarcoma in transplant recipients. Transplantation 1997; 64:669–73. 37. Huang JY, Chiang YJ, Lai PC, et al. Post-transplant Kaposi’s sarcoma: report from a single center. Transplant Proceedings 2004; 36:2145–47. 38. Beynet DP, Wee SA, Horwitz SS, et al. Clinical and pathological features of posttransplant lymphoproliferative disorders presenting with skin involvement in 4 patients. Arch Dermatol 2004; 140:1140–46. 39. Coyne JD, Banerjee SS, Bromley M, Mills S, Diss TC, Harris M. Posttransplant T-cell lymphoproliferative disorder/T-cell lymphoma: a report of three cases of T-anaplastic large-cell lymphoma with cutaneous presentation and a review of the literature. Histopathology 2004; 44:387–93. 40. Yurtsever H, Kempf W, Laeng RH. Posttransplant CD30+ anaplastic large cell lymphoma with skin and lymph node involvement. Dermatology 2003; 207:107–10. 41. Salama, S. Primary ‘‘cutaneous’’ T-cell anaplastic large cell lymphoma, CD30+, neutrophil-rich variant with subcutaneous panniculitic lesions, in a post-renal transplant patient: report of unusual case and literature review. Am J Dermatopathol 2005; 27(3): 217–23. 42. Poulsen, M. Merkel-cell carcinoma of the skin. Lancet Oncol 2004; 5(10):593–9.

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43. Williams RH, Morgan MB, Mathieson IM, Rabb H. Merkel cell carcinoma in a renal transplant patient: increased incidence? Transplantation 1998; 65(10):1396–7. 44. Penn, I., and M. R. First. Merkel’s cell carcinoma in organ recipients: report of 41 cases. Transplantation 1999; 68(11):1717–21. 45. Esen BA, Pinarbasi B, Buyukbabani N, et al. Merkel-cell carcinoma arising after liver transplantation: a case report. Transplant Proc 2005; 37:4413–15. 46. Stadler FJ, Scott GA, Brown MD. Malignant fibrous tumors. Semin Cutan Med Surg 1998; 17(2):141–52. 47. Kanitakis J, Euvrard S, Montazeri A, Garnier JL, Faure M, Claudy A. Atypical fibroxanthoma in a renal graft recipient. J Am Acad Dermatol 1996; 35(2 Pt 1):262–4. 48. Hafner J, Kunzi W, Weinreich T. Malignant fibrous histiocytoma and atypical fibroxanthoma in renal transplant recipients. Dermatology 1999; 198:29–32. 49. Perrett CM, Cerio R, Proby CM, Harwood CA. Atypical fibroxanthoma in a renal transplant recipient. Histopathology 2005; 47(3):326–7. 50. Kovach BT, Sams HH, Stasko T. Multiple atypical fibroxanthomas in a cardiac transplant recipient. Dermatol Surg 2005; 31(4):467–70. 51. Kemp JD, Stenn KS, Arons M, Fischer J. Metastasizing atypical fibroxanthoma Coexistence with chronic lymphocytic leukemia. Arch Dermatol 1978; 114(10):1533–5. 52. Martinez JC, Otley CC, Stasko T, et al. Defining the clinical course of metastatic skin cancer in organ transplant recipients. Arch Dermatol 2003; 139:301–06. 53. Carucci JA, Martinez JC, Zeitouni NC, et al. In-transit metastasis from primary cutaneous squamous cell carcinoma in organ transplant recipients and nonimmunosuppressed patients: clinical characteristics, management, and outcome in a series of 21 patients. Dermatol Surg 2004; 30:651–55. 54. Shafqat A, Viehman GE, Myers SA. Cutaneous squamous cell carcinoma with zosteriform metastasis in a transplant patient. J Am Acad Dermatol 1997; 37(6):1008–9. 55. Streams BN, Eaton JS, Zelac DE. Perineural spread of squamous cell carcinoma involving the spinal accessory nerve in an immunocompromised organ transplant recipient. Dermatol Surg 2005; 31(5):599–601.

23 Actinic Keratosis in Organ Transplant Recipients

Cara Holmes, MBBS and Alvin H. Chong, FACD, MMed, MBBS

INTR ODUCT IO N

increased risk of skin malignancy remains the subject of debate.[8] Human papillomavirus (HPV) has also been implicated as a causal agent in the pathogenesis of AK and nonmelanoma skin cancer (NMSC), particularly in immunosuppressed individuals. In one study, HPV DNA was present in 88.2% of premalignant skin lesions (AK or SCC in situ) in immunosuppressed patients, compared to 54.4% of premalignant lesions in the immunocompetent group.[9] In the same study, HPV DNA was found in 75% of SCC lesions in the immunosuppressed group, but only 27.2% in the immunocompetent group. Although epidemiological HPV detection studies have shown associations with NMSC, further research is required before a causal association can be reliably confirmed. Epidemiological studies have recognised that a wide array of HPV types are potentially associated with skin cancer. It is thought that the contribution of HPV to the development of skin tumors is likely to be in cooperation with UV radiation. Possible mechanisms include the direct activation of viral genes by UV light, enhanced replication of HPV in the host due to UVinduced immunosuppression or inactivation of keratinocyte regulatory genes, such as p53.[10] The proapoptotic protein, Bak, which is induced by UV damage to keratinocytes has been shown to be degraded by cutaneous HPV E6 protein. It was shown that HPV-positive skin cancers had undetectable levels of Bak, whereas HPV-negative skin cancers expressed the Bak protein.[11] This, along with other antiapoptotic mechanisms may be the pathway by which diverse HPV types contribute to skin carcinogenesis.

Actinic keratoses (AK), also known as solar keratoses, are common cutaneous lesions resulting from a localized proliferation of atypical epidermal keratinocytes, which have been damaged by ultraviolet radiation. AK occur most frequently on sun-exposed sites, such as the upper limbs, face, ears and neck.[1] In immunocompetent patients, a small proportion of actinic keratoses are thought to undergo malignant transformation to squamous cell carcinoma (SCC). The transformation rate in organ transplant recipients is almost certainly higher, although there is no data on the exact rate. Actinic keratoses in organ transplant recipients can cause significant morbidity and also are a biomarker of prior excessive sun damage, thus acting as a clinically useful predictor for development of skin malignancy.

PATHOG ENES IS Cumulative ultraviolet (UV) radiation is the most significant etiological factor in the development of AK. Ultraviolet B radiation is absorbed by the germinal basal keratinocytes, and causes a signature mutation of the deoxyribonucleic acid (DNA), predominantly in the p53 tumor suppressor gene.[2] These mutations lead to defective DNA repair and a reduced initiation of apoptosis in damaged cells, thus allowing propagation and accumulation of further genetic damage.[3] The same genetic mutations are observed in both AK and squamous cell carcinoma (SCC), thus supporting similar pathogenesis.[4] Immunosuppressed solid organ transplant recipients are at high risk of AK and SCC. The pathogenesis is yet to be fully understood although UV-radiation-induced genetic damage remains a major etiological factor. It has been shown that p53 mutations are more prevalent in AK from transplant recipients than equivalent lesions from nontransplant controls[5] This is thought be the result of systemic immunosuppression. It has been speculated that tolerance to antigens associated with UV-induced genetic damage may allow tumor escape mechanisms, and therefore a reduction in the cell-mediated immunologic ‘‘rejection’’ of these tumors.[6] This hypothesis is supported by the increased risk of SCC in transplant recipients who receive higher doses of immunosuppression, such as in patients with a poorly matched allograft or history of allograft rejection.[6,7] Which specific immunosuppressive agent is most strongly associated with

I NC I D E NC E The incidence of actinic keratosis varies greatly depending on the demographics and geographical location of the population under review. Prevalence of AK in males is consistently higher than in females and incidence increases with age. Australia has the highest known rate of AK in the world, with a prevalence of 40–60% of the population aged 40 years or above.[12] As in immunocompetent individuals, the rate of AK in organ transplant recipients depends on a number of risk factors including skin type and history of UV exposure. Comparatively though, the prevalence appears to be significantly higher in organ transplant recipients, with lesions tending to occur at a younger age than in the general population. Most data on AK, however, has been obtained as part 162

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of larger studies on the risk factors for development of NMSC in organ transplant recipients and therefore is cross-sectional in nature. One study in southeast Scotland monitored 202 renal transplant recipients over three years. They found that 38% of patients with a surviving allograft for greater than five years had AK, compared to 17% of those with an allograft for less than five years.[13] Another U.K. study examining the risk factors for development of NMSC in renal transplant recipients found AK in 4.9%, 12.7%, and 29.3% of patients with a duration of transplantation of less than five years, five to ten years, and greater than ten years, respectively.[14] These rates are significantly lower than the rates seen in a cross-sectional study of 398 renal transplant patients in Queensland, Australia. In the Australian study, 56.5% of patients, who had a median time since first transplant of 7.1 years, were found to have AK. Of these patients, 14.2% had a history of AK before transplantation.[15]

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Figure 23.2. Confluent actinic keratoses on the chest of renal transplant patient.

C L I N I C AL P R E S E N T A T I O N Actinic keratoses most commonly occur on chronically sundamaged areas such as the face, bald scalp, and dorsum of the hands (Figure 23.1). A typical actinic keratosis lesion is discrete, variably erythematous, and irregular with a dry scaly surface. They may be flat or form a keratin horn and are often easier to identify by palpation than by visual inspection. The lesions may be asymptomatic but can be pruritic or painful. Most lesions are between 2 and 6 mm in diameter, although they may become confluent and form sheets or plaques (Figure 23.2). Actinic keratosis of the mucosal lip is called actinic cheilitis and is described in detail in Chapter 36 (Figure 23.3). The clinical differential diagnosis of AK may include all other lesions that present as small keratotic erythematous

Figure 23.3. Actinic cheilitis, with erosion.

macules and papules in sun-exposed areas. The most common of these include irritated seborrheic keratosis, viral warts, SCC in situ, actinic porokeratosis, and SCC. If lesions show rapid growth, thickening, bleeding, or tenderness, SCC should be excluded with biopsy prior to treatment.

M A NAG EME NT

Figure 23.1. Actinic keratoses on the dorsal hand of a renal transplant patient.

Given the large number of AK commonly seen in organ transplant recipients, and their potential for malignant transformation, early treatment of lesions is recommended. With a wide array of therapeutic options, the advantages and disadvantages of the various approaches must be considered. Most dermatologists utilize a variety of techniques to manage AK, depending on the specifics of the clinical scenario. There is no ideal treatment modality for AK, and dermatologists attempt to balance the advantages and disadvantages of the options in terms of cure rates, tissue reactions, cost, inconvenience,

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Table 23.1 Advantages and disadvantages of various treatment options for actinic keratoses in transplant recipients Treatment option

Method of use

Advantages

Disadvantages

Cryotherapy



Cryogun or cotton tipped applicator  Recommended freeze time 5–15 seconds  Apply cream twice daily for 3–6 weeks until endpoint of dusky red color, widespread crust, and pruritus  Application of photosensitising agent for 3 or more hours followed by illumination with red or blue light



Convenient Economical  Quick









Topical 5-Flurouracil cream Photodynamic Therapy

Topical Imiquimod cream



Application of cream on 3–5 days per week for 6 to 12 weeks

Systemic Retinoids



Daily dosage of oral retinoid (Acitretin 10–30mg/day) indefinitely

Pain Hypopigmentation  Interuser variability



Good for multiple lesions or field change





Excellent cosmetic result Similar efficacy to cryotherapy





Good for multiple lesions or field change  Similar efficacy to cryotherapy  Significant global decrease in dysplasia and epidermal proliferation

Severe skin irritation and inflammation

Limited availability Painful  Time consuming  Expensive  More expensive, particularly for large areas  Unpredictable local irritation  May be poorly tolerated due to mucocutaneous adverse effects, headache, musculoskeletal symptoms, and hyperlipidemia 

durability or response, and adverse effects. The various treatment options are summarized in Table 23.1.

treated for 4 weeks experienced moderate to severe irritation of the skin.

Liquid nitrogen cryotherapy

Photodynamic therapy

Liquid nitrogen cryotherapy is the most commonly used treatment option for management of AK as it is inexpensive, convenient, and effective. Although no randomized control trials have been performed, a prospective, multicenter study showed a ‘‘lesion complete response’’ rate ranging from 39% for a freeze time of less than five seconds, to 83% for longer than 20 seconds, three months after treatment.[16] Cryotherapy can, however, cause mild to moderate short term pain and may be complicated by hypopigmentation.

Photodynamic therapy has also been shown to be a successful modality to treat AK, but may be limited by availability and cost. Photodynamic therapy (PDT) involves the application of a photosensitising agent, either aminolevulinic acid (ALA) or methylaminolevulinate (MAL) and light of a specific wavelength to activate the phototoxic reaction, which produces controlled cell death via free oxygen radical generation. A number of randomized controlled trials have been completed in immunocompetent patients, and have shown that the AK lesion clearance rates are comparable to those using cryotherapy. Patient satisfaction and cosmetic outcome, however, tend to be superior with PDT. A number of studies have now examined the use of PDT in transplant recipients. One study looked at the cure rates of AK and squamous cell carcinoma in situ in transplant recipients compared to immunocompetent controls. The results showed that the cure rates in both patient groups were similar 4 weeks after completion of treatment but were significantly lower in the transplant recipients at 12 and 48 weeks, 68% and 48% respectively, versus 89% and 72% for controls.[19] Another study found that the AK lesions treated with MAL PDT were clinically cleared in 13 out of 17 transplant recipients 16 weeks post treatment.[20] The main adverse effects of PDT treatment are local burning, stinging, and pain during treatment.

Topical 5-fluorouracil cream Topical 5% 5-flurouracil (5-FU) cream is a particularly useful option for patients with actinic ‘‘field-change’’ or multiple lesions of or confluent AK, as commonly seen in organ transplant recipients. It does, however, usually result in significant skin irritation and inflammation, which should be discussed with the patient prior to use. 5-flurouracil cream should be applied sparingly once or twice daily for three to six weeks, depending on site and response. Generally the endpoint of treatment is signalled by change in colour from bright to dusky red, evidence of erosion and reepithelialization, widespread crust formation, and pruritis.[17] There are no data on efficacy of 5-FU in transplant recipients, but in an immunocompetent population, the clearance rate of AK lesions using 5-FU once daily has been shown to range from 26.3% of lesions after 1 week of treatment to 47.5% of lesions after 4 weeks of treatment.[18] However, 90% of patients

Imiquimod cream Imiquimod cream, the first in a new class of immune response modifiers, has been shown to be effective in the treatment of

ACTINIC KERATOSIS IN ORGAN TRANSPLANT RECIPIENTS

AK. Imiquimod has been shown to have an indirect antiviral effects, as well as significant antitumor activity.[21] Imiquimod stimulates the innate immune response through the induction, synthesis, and release of cytokines, predominantly interferon alpha (INF-alpha), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha).[22] Imiquimod has been used with caution in transplant recipients, because of a theoretical risk of excessive immunologic stimulation resulting in allograft rejection. However, although data in transplant recipients is still limited, systemic absorption of imiquimod appears to be minimal, without measurable effects on systemic immunity.[23] A number of large randomized, double-blinded, controlled trials have examined the effectiveness of imiquimod for the treatment of AK in immunocompetent populations. Complete clearance rates for AK have ranged from 48.3% [24] to 57.1% [25] for five or three times a week daily application, respectively, for 16 weeks. Common localised side effects are severe erythema, crusting, and ulceration. A recent randomized, blinded, placebo-controlled study examining the safety and efficacy of 5% imiquimod cream for the treatment of AK in renal transplant recipients compared areas of skin treated with the imiquimod to control areas of the same patientÕs skin. Seven of fourteen patients using imiquimod had reduced skin atypia after application of cream three times a week for 16 weeks.[26] Areas of up to 60 cm2 were treated, and no patients experienced any detrimental effect on their renal allograft, as determined by creatinine levels.

Systemic retinoids Studies have shown that the use of oral retinoids may be effective for the reduction of AK, as well as SCC, in organ transplant recipients. It has been demonstrated that following acitretin treatment, there is a significant reduction in epidermal thickness of AK lesions as well as an increase in normal differentiation.[27] It is thought that systemic acitretin reduces AK by alteration of the keratinization process, resulting in peeling of the hypertrophic stratum corneum and softening of the lesions. There appears to be no significant decrease in proliferation or dysplasia, which may explain the recurrence of AK upon cessation of acitretin treatment.[27] The major limitation to the use of acitretin is poor tolerance due to adverse effects including headache, xerosis, musculoskeletal symptoms, and hyperlipidemia. Monitoring for hyperlipidemia and abnormal liver function should be continued throughout treatment. A double-blind, placebo controlled study in renal transplant recipients looked at treatment with 30 mg per day of acitretin compared to a placebo, for a duration of 6 months. The relative decrease in AK lesions in the acitretin group was 13.4% compared with an increase in the placebo group of 28.2%. They also found a significant reduction in the development of SCC.[28] Most patients in the acitretin group experienced mucocutaneous side effects, but these were easily managed. No data are available regarding optimal long-term

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dosing. One study compared acitretin dosing of 0.4 mg/kg/day for three months followed by 0.2 mg/kg/day for nine months to 0.4 mg/kg/day for a year. It was found that the number of AK decreased by nearly 50% in both groups but that most patients in both groups required reduction of their dose due to mucocutaneous side effects, including cheilitis, excessive peeling of skin, and hair disorders.[29] Dryness of the skin was found to decrease significantly after the first two months of treatment.

Other treatments Topical retinoids and diclofenac gel are also used in the treatment of actinic keratosis with moderate results, although there are no data in transplant recipients. Topical retinoids have been shown to reduce the dysplasia in AK and promote new collagen formation. The exact mechanism of action of diclofenac in treating AK remains speculative, but a significant reduction in AK in comparison to placebo has been documented. Other less common therapies, generally used in patients with extensive damage include ablative lasers, chemical peels, and dermabrasion.

P RE V E N T I O N Organ transplant recipients often develop large numbers of AK lesions and treatment can be painful, time-consuming, and costly for the patient. Thus, ideally, focus on prevention should be emphasized. Because the most important risk factors for AK, immunosuppression, prior cumulative sun exposure, and HPV infection are relatively immutable, many patients will continue to develop AK and skin cancer despite judicious sun protection. Although no studies have been done in transplant recipients, the use of a high sun-protection factor (SPF) sunscreen and sun avoidance are considered of fundamental importance in the management and prevention of AK. In the general population, sunscreens have been shown to reduce the number of UV- induced p53 mutations [30] and decrease the immunosuppressive effects of sunlight.[31] It has been shown in immunocompetent patients that daily use of a high SPF sunscreen reduces the development of new AK and increases the rate of remission of existing lesions, when compared to a vehicle cream.[32,33]

CONCLUSION Actinic keratosis is a common cutaneous problem in organ transplant recipients. Given the potential for malignant transformation, early treatment of AK is recommended. Therapeutic options are diverse, and the ideal choice depends on the lesion, the physician and patient preference, cost, and availability. All organ transplant recipients should be educated in primary prevention, and those most severely affected should be considered for preventative treatment with multimodality treatment regimens.

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REFERENCES

1. Frost CA, Green AC. Epidemiology of solar keratoses. Br J Dermatol 1994; 131:455–64. 2. Hutchinson F. Induction of tandem base change mutations. Mutat Res 1994; 309:11–15. 3. Fu W, Cockrell C. The actinic (solar) keratosis. Arch Dermatol 2003; 139:66–70. 4. Ashton K, Weinstein M, Maguire D, Griffiths L. Chromosomal aberrations in squamous cell carcinoma and solar keratoses revealed by comparative genomic hybridization. Arch Dermatol 2003; 139:876–82. 5. Ferrandiz C, Fuente MJ, Fernandez-Figueras MT, Bielsa I, Just M. p53 immunohistochemical expression in early posttransplant-associated malignant and premalignant cutaneous lesions. Dermatol Surg 1999; 25:97–101. 6. Caforio ALP, Belloni Fortina A, Piaserico S, Alaibac M, Tona F, Feltrin G, Pompei E, Testolin L, Gambino A, Dalla Volta S, Thiene G, Casarotto D, Peserico A. Skin cancer in heart transplant recipients risk factor analysis and relevance of immunosuppressive therapy. Circulation 2000; 102[suppl III]:222–7. 7. Bouwes Bavinck JN, Vermeer BJ, van der Woude FJ, et al. Relations between skin cancer and HLA antigens in renal-transplant recipients. N Engl J Med 1991; 325:843–848. 8. Otley CC, Pittelkow R. Skin cancer in liver transplant recipients. Liver Transpl 2000; 6:253–62. 9. Harwood CA, Proby CM. Human papillomaviruses and nonmelanoma skin cancer. Curr Opin Infect Dis 2002; 15:101–14. 10. Harwood CA, Surentheran T, McGregor JM, Spink PJ, Leigh IM, Breuer J, Proby CM. Human papillomavirus infection and nonmelanoma skin cancer in immunosuppressed and immunocompetent individuals. J Med Virol 2000; 61(3):289–97. 11. Jackson S, Harwood C, Thomas M, Banks L, Storey A. Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev 2000; 14:3065–73. 12. Marks R, Ponsford MW, Selwood TS, Goodman G, Mason G. Nonmelanotic skin cancer and solar keratoses in Victoria. Med J Aust 1983; 24:619–22. 13. Barr BB, Benton EC, McLaren K, Bunney MH, Smith IW, Blessing K. Hunter JA. Human papilloma virus infection and skin cancer in renal allograft recipients. Lancet 1989; 1(8630):124–9. 14. Ramsay HM, Fryer AA, Reece S, Smith AG, Harden PN. Clinical risk factors associated with nonmelanoma skin cancer in renal transplant recipients. Am J Kidney Dis 2000; 36:167–76. 15. Ramsay HM, Fryer AA, Hawley CM, Smith AG, Nichol DL, Harden PN. Non-melanoma skin cancer in the Queensland transplant population. Br J Dermatol 2002; 147:950–6. 16. Thai K, Fergin P, Freeman M, Vinciullo C, Francis D, Spelman L, Murrell D, Anderson C, Weightman W, Reid C, Watson A, Foley P. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol 2004; 43:687–92. 17. Goette DK. Topical chemotherapy with 5-fluorouracil. J Am Acad Dermatol 1981; 4:633–47. 18. Weiss J, Menter A, Hevia O, Jones T, Ling M, Rist T, Roberts J, Shavin JS, Sklar J, Webster G, Connolly M, Furst K, Levy S. Effective treatment of actinic keratosis with 05% fluorouracil cream for 1, 2, or 4 weeks. Cutis 2002: 70:22–9.

19. Dragieva G, Hafner J, Dummer R, Schmid-Grendelmeier P, Roos M, Prinz BM, Burg G, Binswanger U, Kempf W. Topical photodynamic therapy in the treatment of actinic keratoses and BowenÕs disease in transplant recipients. Transplantation 2004; 77:115–21. 20. Dragieva G, Prinz BM, Hafner J, Dummer R, Burg G, Binswanger U, Kempf W, A randomized controlled clinical trial of topical photodynamic therapy with methyl aminolaevulinate in the treatment of actinic keratoses in transplant recipients. Br J Dermatol 2004; 151:196–200. 21. Tyring S, Conant M, Marini M, Vander Meijden, Washenik K. Imiquimod: An update on therapeutic uses in dermatology. Int J Dermatol 2002; 41:810–16. 22. Reiter MJ, Testerman TI, Miller RL, Weeks CE, Tomai MA. Cytokine induction in mice by the immunomodulator imiquimod. J Leukoc Biol 1994; 55:234–40. 23. Smith KJ, Germain M, Skelton H. Squamous cell carcinoma in situ (BowenÕs disease) in renal transplant patients treated with 5% imiquimod and 5% 5-fluorouracil therapy. Dermatol Surg 2001; 27:561–4. 24. Lebwhol M, Dinehart S, Whiting D, Lee PK, Tawfik N, Jorizzo J, Lee JH, Fox TL. Imiquimod 5% cream for the treatment of actinic keratosis: Results from two phase III, randomised, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol 2004; 50:714–21. 25. Szeimies R, Gerritsen MP, Gupta G, Ortonne JP, Serresi S, Bichel J, Lee JH, Fox TL, Alomar A. Imiquimod 5% cream for the treatment of actinic keratosis: Results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology. J Am Acad Dermatol 2004; 51:547–55. 26. Brown VL, Atkins CL, Ghali L, Cerio R, Harwood CA, Proby CM. Safety and efficacy of 5% imiquimod cream for the treatment of skin dysplasia in high-risk renal transplant recipients: randomized, double-blind, placebo-controlled trial. Arch Dermatol 2005; 141: 985–93. 27. Smit JV, de Sevaux RG, Blokx WA, van de Kerkhof PC, Hoitsma AJ, de Jong EM, Acitretin treatment in (pre)malignant skin disorders of renal transplant recipients: Histologic and immunohistochemical effects. J Am Acad Dermatol 2004; 50:189–96. 28. Bavinck JN, Tieben LM, Van der Woude FJ, Tegzess AM, Hermans J, ter Schegget J, Vermeer BJ. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol 1995; 13:1933–8. 29. de Sevaux RG, Smit JV, de Jong EM, van de Kerkhof PC, Hoitsma AJ. Acitretin treatment of premalignant and malignant skin disorders in renal transplant recipients: clinical effects of a randomized trial comparing two doses of acitretin. J Am Acad Dermatol 2003; 49:407–12. 30. Ananthaswamy HN, Loughlin SM, Ullrich SE, Kripke ML. Inhibition of UV-induced p53 mutations by sunscreens: Implications for skin cancer prevention. J Invest Dermatol Symp Proc 1998; 3:52–6. 31. Whitmore SE, Morison WL. Prevention of UVB-induced immunosuppression in humans by a high sun protection factor sunscreen. Arch Dermatol 1995; 131:1128–33. 32. Thompson SR, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Eng J Med 1993; 14:1147–51. 33. Naylor MF, Boyd A, Smith DW, Cameron GS, Hubbard D, Nelder KH. High sun protection factor sunscreens in the suppression of actinic neoplasia. Arch Dermatol 1995; 131:170–5.

24 Basal Cell Carcinoma in Organ Transplant Recipients

Jonathan Ng, MBBS, BMedSc and Peter Foley, MBBS, BMedSc, MD, FACD

INT ROD UCTION

BCCs, especially in countries with high levels of sun exposure.[2,8,9] In one report, pretransplant BCCs were associated with a 6-fold increased risk of BCC development, as well as increasing number of posttransplant BCCs.[2] Pretransplant SCCs and actinic keratoses also confer increased post transplant BCC risks, although their association with post transplant SCC is much stronger. The presence of BCC pre transplant, in the absence of metastasis, is not considered to be a contraindication to solid organ transplantation.[10]

Basal cell carcinoma (BCC) is the most common form of cancer in the Caucasian population. In Australia, for example, BCC is more common than all other cancers (excluding squamous cell carcinoma [SCC] of skin) combined. With a population of 20 million, Australia reports that an estimated 246,000 people have at least one BCC treated every year and, due to the occurrence of multiple BCC in many patients, the annual incidence of treated BCC is 884 per 100,000.[1] Fortunately, BCC is a relatively nonaggressive tumor that while locally invasive and destructive to local tissues, rarely metastasizes or is a cause of death.

Age of transplantation Older age at transplantation is a highly significant risk factor for BCC development.[5,7] In one study, individuals aged 59 or more at transplantation had an 8.5 times increased risk of BCC, compared to patients 43 years or younger.[5]

P A T H OGE NE SI S

UV exposure As with the general population, the development of posttransplant BCC and SCC is affected to varying extents by different patterns of ultraviolet (UV) exposure. Cumulative lifetime sun exposure has not been shown to increase the risk of posttransplant BCC.[2–3] However, the development of BCC is linked to increasing numbers of actinic keratoses, markers of solar damage, at or before transplantation.[2] Intermittent intense sun exposure, including number of sunburns in childhood, appears to be a much more significant risk for posttransplant BCCs.[2] Individuals with more sensitive skin phototypes are more likely to develop BCCs,[2] with rates as much as 5.7 times higher in one report.[5]

Human papillomavirus The role of human papillomavirus (HPV) in posttransplant NMSC carcinogenesis remains controversial. Although some evidence exists for HPV (especially HPV 5 and 8) in the pathogenesis of SCC, there are no definite correlations between HPV detection rate or viral load in the development of post transplant BCCs.[11] In the transplant population, smoking and arsenic exposure, although suggested for increased SCC risk, have not been shown to contribute to BCC development.[2]

I N C ID E N C E

Immunosuppression

Cumulative incidence

The duration and type of immunosuppression appear to bear a less direct relationship to BCC development, compared with that of SCC. The cumulative immunosuppressive drug dose did not affect BCC incidence in one study.[5] In another, when comparing the use of triple versus double immunosuppressive drugs in kidney transplant recipients, no increased incidence of BCC was found.[6] However, individuals on cyclosporine and prednisolone, compared with azathioprine, were more likely to develop BCCs.[2] Furthermore, an increased degree of HLA mismatch has not been found to lead to more BCCs.[3,7]

The incidence of BCC in a predominantly Caucasian transplant population in a subtropical area has been reported to be 21.5% at five years, 39.1% at 10 years, 56.2% at 20 years, and 64.3% at more than 20 years.[9] Comparable figures were seen in a Spanish population, with incidence of 14% at 5 years and 40.6% at 10 years.[12]

Risk Ratio The risk of developing posttransplant BCC has been described as about 10 times the baseline in a Dutch population.[13] More dramatic increases have been noted in an Irish study, whereby the risk was 16-fold relative to agedmatch controls, while in younger subjects, the risk was as much as 130-fold when matched for age.[14]

Pretransplant skin cancers The presence of pretransplant nonmelanoma skin cancers (NMSC) is a well-recognized risk factor for posttransplant 167

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Type of Transplant BCCs are disproportionately more common in heart transplant recipients than kidney transplant recipients,[15] although the fact that heart transplant recipients are generally older and receive higher doses of immunosuppressants may confound the issue.

SCC/BCC ratio In the general population the incidence of SCC is less than that of BCC, with an SCC/BCC ratio of about 1:4. It is well recognized that the SCC/BCC ratio is generally reversed in the transplant setting, as SCCs represent the predominant NMSC type. The incidence rate of SCCs may increase exponentially after transplant, whereas the rate of increase for BCCs is linear, resulting in a higher SCC/BCC ratio within three years posttransplant. The SCC/BCC ratio appears reversed to the largest extent in temperate regions, with a value of 2:1[9] to 3.2:1[7] in Britain. Similar ratios are found in the subtropical regions of Australia.[16] In the Mediterranean population, the SCC/BCC ratio reversal does not seem to occur. A Spanish study reported a ratio of 1:1.4,[12] whereas a similar figure of 1:1.1 was observed in an Italian cohort.[17] This discrepancy is likely due to genetics differences, skin phototypes, and sunexposure habits. It is worth mentioning that the true incidence of BCC in transplant recipients is likely to be underestimated, as many studies are based on cancer registries, which are prone to incomplete reporting, rather than prospective studies.

BCCs in nonimmunosuppressed patients, in whom they represent 0.37% of BCCs.[20] Other unusual locations, for example the genitalia and axillae, may also be involved.[18]

Morphology Similar histological subtypes of BCC occur in transplant recipients and the general population – namely superficial, nodular, and sclerosing/infiltrative or morpheaform BCCs (Figure 24.1– Figure 24.4). Superficial BCCs, the least aggressive form, appear to be the most common.[18] Clinical diagnosis of BCCs in the transplant setting has been reported to be accurate in only 40% of cases (sensitivity 66.6%, specificity 85.6%), with the lowest accuracy rate for lesions on the truncal regions.[21] This may be partly explained by changes in the BCCÕs typical morphology in the transplant setting, as well as physiciansÕ tendency to overdiagnose benign lesions as malignant.

Clinical behavior In contrast to SCCs, BCCs in transplant recipients do not seem to display increased aggression. To date there has been no

CLINICAL FEATURES

Demographics Compared to the general population, on average BCCs develop 15 years earlier in transplant recipients.[7,18] BCCs can occur as early as young adulthood, usually in the setting of childhood organ transplantation.[18,19] In male transplant recipients, BCCs are more common, and are more likely to be multiple.[7]

Latent period There tends to be a latent period after transplantation before BCCs start to develop. The reported mean latent period of post transplant BCCs ranges from 43 months[12] to 6.9 years.[9,16] This lag period is noted to be shorter in liver or heart transplant recipients, compared with kidney transplants.[18]

distribution/ distribution Although BCCs predominantly occur over the head and neck in both transplant recipients and the general population, the proportion occurring over extracephalic sites is higher post transplant.[18] As much as 20–25% of BCCs have been reported to arise on non-sun-exposed sites.[9] Up to 5% of BCCs may develop on the hands,[7] an uncommon site for

Figure 24.1. Superficial basal cell carcinoma, characterized by an erythematous slightly scaly patch.

BASAL CELL CARCINOMA IN ORGAN TRANSPLANT RECIPIENTS

Figure 24.2. Nodular basal cell carcinoma, characterized by a pearly translucent telangiectatic nodule.

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Figure 24.3. Morpheaform basal cell carcinoma, characterized by a shiny scarlike appearance of the skin. Extensive subclinical extension exists.

reported cases in the medical literature of metastases or death attributable to BCC in the transplant population, consistent with the similar extremely low rates in the general population. Of note, BCCs are found only very infrequently in the small subset of transplant recipients who display ‘‘catastrophic’’ carcinogenesis, in which more than 100 NMSCs (primarily SCCs) develop annually. The variety of clinical appearances of BCC is displayed in Figure 24.1 through Figure 24.4.

TREATMENT The treatment of BCC in organ transplant patients is very similar to that in nonimmunosuppressed patients, although techniques may need to be adapted to accommodate larger numbers of skin cancers in an individual patient. The advantages and disadvantages of various treatment modalities are summarized in Table 24.1.

Surgical excision, including Mohs micrographic surgery There are no known specific studies examining the efficacy of simple excision or excision margins for BCC in transplant recipients. Existing guidelines for the general population recommend simple excision, with at least 4-mm margin, for clinically favourable BCCs (small nodular or superficial BCCs), providing a 5-year cure rate of 90–98%. For clinically unfavourable BCCs (larger than 2 cm, multiple, or morpheaform types) specialist referral is recommended, particularly for Mohs micrographic surgery with associated 5-year cure rates of 97–99%.[22]

Cryotherapy Cryotherapy with single or multiple freeze–thaw cycles has been used to treat BCCs in the general population with great

Figure 24.4. Massive, neglected basal cell carcinoma forming an eroded friable mass.

efficacy, especially in small, well-defined BCCs away from the head and neck. A 3–5mm equivalent margin is advocated.[22] Again there are no specific studies exploring the efficacy of cryotherapy in post transplant BCCs.

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Table 24.1 Advantages and disadvantages of various treatments in BCCs in organ transplant recipients Technique

Pros

Cons

Surgical excision Mohs micrographic surgery

High rates of cure Highest cure rates; sparing of unaffected tissues Ease of treatment; rapid; cost-effective Ease of treatment; rapid; cost effective Ease of treatment; field effect; cosmetic outcome; patient controlled

Sacrifices margin of normal skin; scarring More expensive; requires advanced technical expertise; scarring Lower cure rates; scarring Lower cure rates; scarring Lowest cure rates; indicated only for superficial BCCs; local tissue reaction; theoretical immune activation in patients with allografts Lower cure rates; effective only for superficial BCCs

Cryotherapy Curettage Imiquimod

Photodynamic therapy

Ease of treatment; cosmetic outcome; physician controlled

Curettage Curettage, usually with electrocautery or desiccation, has been shown to be efficacious in the treatment of superficial and nodular BCC in the general population. No specific studies have examined this modality in the transplant setting, but it is a popular treatment option.

feasible, as well as in recurrent or incompletely excised BCCs. Radiotherapy is generally avoided in patients younger than 60 years of age due to the delayed risk of carcinogenesis. In transplant recipients, the tempo of carcinogenesis is further accelerated. Theoretically, radiotherapy-induced cutaneous malignancies could occur at a more rapid rate in a transplant recipient. Therefore, while no formal evidence exists, radiotherapy for treatment of posttransplant BCCs is not advised, if other options are feasible.

Topical immunomodulators Although the efficacy of imiquimod is proven in superficial BCCs in the immunocompetent population, little evidence is available in the transplant setting. An open label trial of imiquimod consisting of a 24-application regimen in five kidney transplant recipients, reported full clearance of four out of ten BCCs, with the efficacy being highest among the superficial BCCs.[23] The remission is reportedly maintained after eight monthsÕ follow-up. In other studies, imiquimod has been used to treat SCCs in immunosuppressed individuals, with no significant difference in side effects, including no graft-related problems, or any loss of efficacy.[24] Further trials are obviously needed to ascertain the safety and efficacy of imiquimod in larger numbers of transplant recipients, as the results above are suboptimal. A recent survey of dermatologists in the US reported that four out of 25 respondents were already using imiquimod in superficial BCCs in transplant recipients, despite the lack of FDA approval.[25]

Photodynamic therapy (PDT) PDT has been used with success in actinic keratoses and BowenÕs disease with no loss of efficacy in transplant recipients, but studies with BCCs are again lacking. There is no evidence to suggest any potential compromise of the transplanted organ. One case report has shown effectiveness of PDT with methylaminolevulinate (MAL) for treatment of a single nodular BCC on the nasal tip of a liver-transplant recipient, with clinical clearance maintained at 12 monthsÕ follow-up.[26]

Radiotherapy In the general population, radiotherapy is used in the minority of primary BCCs, where conventional surgery is difficult or non-

P R E VE NT I ON

Photoprotection Intensive photoprotection with the use of appropriate clothing, broad-spectrum sunscreens and sun avoidance is generally recommended for all organ transplant recipients. Given the predominant relationship of BCCs with childhood intermittent sun exposure rather than cumulative exposure, it is likely that basal cell carcinoma may have already been initiated, and adult photoprotection may primarily prevent SCCs. Lifelong photoprotection would be required to prevent BCCs.

Retinoids Oral retinoids, acitretin being the most studied drug, appear to be at least partially effective as chemoprophylaxis in SCCs and, to a lesser extent, BCCs in transplant recipients, as reviewed by a recent report.[27] Overall, the specific role of retinoids in preventing post transplant BCC is certainly not clearly established and requires further study.

SUM MARY Whereas SCC in solid organ transplant recipients is in many respect different than SCC in immunocompetent patients, BCC in OTRs is similar in its presentation, diagnosis, and management between the two groups. The primary differences in managing BCC in OTRs relates to the greater number of tumors, the presence of numerous SCC, warts, and AKs, and theoretical concerns regarding the use of topical immunomodulators in transplant patients.

BASAL CELL CARCINOMA IN ORGAN TRANSPLANT RECIPIENTS

REFERENCES

1. NCCI Non-melanoma Skin Cancer Working Group. The 2002 national non-melanoma skin cancer survey. National Cancer Control Initiative. Melbourne 2003. 2. Ramsay HM, Fryer AA, Hawley CM, Smith AG, Nicol DL, Harden PN. Factors associated with nonmelanoma skin cancer following renal transplantation in Queensland, Australia. J Am Acad Dermatol. 2003; 49:397–406. 3. Bouwes Bavinck JN, Vermeer BJ, van der Woude FJ, Vandenbroucke JP, Schreuder GM, Thorogood J, Persijn GG, Claas FH. Relations between skin cancer and HLA antigens in renal-transplant recipients. N Engl J Med. 1991; 325:843–8. 4. Espana A, Martinez-Gonzalez MA, Garcia-Granero M, SanchezCarpintero I, Rabago G, Herreros J. A prospective study of incident nonmelanoma skin cancer in heart transplant recipients. J Invest Dermatol. 2000; 115:1158–60. 5. Fortina AB, Piaserico S, Caforio AL, Abeni D, Alaibac M, Angelini A, Iliceto S, Peserico A. Immunosuppressive level and other risk factors for basal cell carcinoma and squamous cell carcinoma in heart transplant recipients. Arch Dermatol. 2004; 140:1079–85. 6. Glover MT, Deeks JJ, Raftery MJ, Cunningham J, Leigh IM. Immunosuppression and risk of non-melanoma skin cancers in renal transplant recipients. Lancet. 1997; 349:398. 7. Bordea C, Wojnarowska F, Millard PR, Doll H, Welsh K, Morris PJ. Skin cancers in renal-transplant recipients occur more frequently than previously recognized in a temperate climate. Transplantation. 2004; 77:574–9. 8. Bouwes Bavinck JN, Hardie DR, Green A, Cutmore S, MacNaught A, OÕSullivan B, Siskind V, Van Der Woude FJ, Hardie IR. The risk of skin cancer in renal transplant recipients in Queensland, Australia. Transplantation. 1996; 61:715–21. 9. Ramsay HM, Fryer AA, Hawley CM, Smith AG, Harden PN. Non-melanoma skin cancer risk in the Queensland renal transplant population. Br J Dermatol. 2002; 147:950–6. 10. Otley CC, Hirose R, Salasche SJ. Skin cancer as a contraindication to organ transplantation. Am J Transplant. 2005; 5:2079–84. 11. Stockfleth E, Nindl I, Sterry W, Ulrich C, Schmook T, Meyer T. Human papillomaviruses in transplant-associated skin cancers. Dermatol Surg. 2004; 30:604–9. 12. Fuente MJ, Sabat M, Roca J, Lauzurica R, Fernandez-Figueras MT, Ferrandiz C. A prospective study of the incidence of skin cancer and its risk factors in a Spanish Mediterranean population of kidney transplant recipients. Br J Dermatol 2003; 149:1221–1226. 13. Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP. Incidence of skin cancer after renal transplantation in the Netherlands. Transplantation 1990; 49:506–9.

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14. Moloney FJ, Comber H, OÕLorcain P, OÕKelly P, Conlon PJ, Murphy GM. A cohort study of cancer patterns in renal transplant recipients in Ireland. Br J Dermatol 2005; 153 (Suppl.1):3. 15. Fortina AB, Caforio AL, Piaserico S, Alaibac M, Tona F, Feltrin G, Livi U, Peserico A. Skin cancer in heart transplant recipients: frequency and risk factor advantages. J Heart Lung Transplant. 2000; 19: 249–55. 16. Ong CS, Keogh AM, Kossard S, Macdonald PS, Spratt PM. Skin cancer in Australian heart transplant recipients. J Am Acad Dermatol. 1999; 40:27–34. 17. Naldi L, Fortina AB, Lovati S, Barba A, Gotti E, Tessari G, Schena D, Diociaiuti A, Nanni G, La Parola IL, Masini C, Piaserico S, Peserico A, Cainelli T, Remuzzi G. Risk of nonmelanoma skin cancer in Italian organ transplant recipients. A registry based study. Transplantation. 2000; 70:1479–84. 18. Kanitakis J, Alhaj-Ibrahim L, Euvrard S, Claudy A. Basal cell carcinoma developing in solid organ transplant recipients: clinicopathologic study of 176 cases. Arch Dermatol. 2003; 139:1133–7. 19. Euvrard S, Kanitakis J, Cochat P, Claudy A. Skin cancers following paediatric organ transplantation. Dermatol Surg. 2004; 30: 616–621 20. van Zuuren EJ, Bastiaens MT, Posma AN, Bouwes Bavinck JN. Basal cell carcinoma on the dorsum of the hand: report of 11 cases. J Eur Acad Dermatol Venereol. 2000; 14:307–10. 21. Cooper SM, Wojnarowska F. The accuracy of clinical diagnosis of suspected premalignant and malignant skin lesions in renal transplant recipients. Clin Exp Dermatol. 2002; 27:436–8. 22. Non-melanoma skin cancer: Guidelines for treatment and management in Australia. Australian cancer network management of nonmelanoma skin cancer working party. Commonwealth of Australia 2002. 23. Vidal D, Alomar A. Efficacy of imiquimod 5% cream for basal cell carcinoma in transplant patients. Clin Exp Dermatol. 2004; 29: 237–9. 24. Eklind J, Tartler U, Maschke J, Lidbrink P, Hengge UR. Imiquimod to treat different cancers of the epidermis. Dermatol Surg. 2003; 29: 890–6. 25. Clayton A, Stasko T. Treatment of nonmelanoma skin cancer in organ transplant recipients: Review of responses to a survey. J Am Acad Dermatol. 2003; 49:413–16. 26. Perrett CM, Tan SK, Cerio R, Goldsmith PC, McGregor JM, Proby CM, Harwood CA. Treatment of basal cell carcinoma with methylaminolaevulinate photodynamic therapy in an organ-transplant recipient. Clin Exp Dermatol. 2005; 31:146–7. 27. Kovach BT, Sams HH, Stasko T. Systemic strategies for chemoprevention of skin cancers in transplant recipients. Clin Transplant. 2005; 19:726–34.

25 Squamous Cell Carcinoma in Organ Transplant Recipients

Bradley T. Kovach, MD and Thomas Stasko, MD

There are currently over 150,000 solid organ transplant recipients (OTRs) living in the United States. As more transplants are performed and postoperative survival improves, the complications of chronic immunosuppression, including development of cutaneous squamous cell carcinoma (SCC), have become more prevalent.

With a growing transplant population, practitioners will increasingly be faced with managing SCCs in this high-risk population, making an understanding of its pathogenesis, clinical presentation, and strategies for treatment and prevention important.

P A TH OGE NE SI S I N C ID E N C E SCC occurs in OTRs with an incidence approximately 65 to 100 times that in the general population.[1,2] In contrast to the nonimmunosuppressed population in which SCC is outnumbered by basal cell carcinoma at a 1:4 ratio, SCC occurs approximately 2 to 4 times more frequently than basal cell carcinoma in OTRs, making it the most common skin cancer in these patients. The incidence of SCC in OTRs is related to the patientÕs age at transplantation, gender, skin phototype, degree of pretransplant and posttransplant ultraviolet radiation (UVR) exposure, and duration and level of immunosuppression. Chronic immunosuppression contributes to increased cutaneous malignancies, with the prevalence of nonmelanoma skin cancer (NMSC) reaching 40–75% 20 years after transplantation. OTRs with lighter skin phototypes, corresponding to a tendency to burn rather than tan with sun exposure, develop SCC at a higher frequency than those with darker phototypes residing in the same geographic area.[3] Males experience a higher incidence of SCC than females,[4] as do patients receiving their transplants at a greater age.[5] Residence in a geographic location with a lower latitude, and therefore higher ambient UVR exposure, is also associated with increased rates of SCC following transplantation. Most studies from Western Europe have shown a 10–20% incidence of skin cancer in OTRs within 10 years of transplantation, [5–8] whereas approximately 50% of patients from Australia develop skin cancer during this same period.[9,10] These numbers are variable between different studies, however, with 13% of OTRs in a study from Spain developing an SCC or BCC within 3 years after transplantation, increasing to 27.5% at 6 years and 48% at 10 years.[11] A study from Australia revealed an incidence of NMSC of 29% within 5 years, 52% by 10 years, 72% by 20 years, and 82% at greater than 20 years after transplantation, further highlighting the influence of duration of immunosuppression on incidence of SCC.[10] Probably due to innate and external UVR protection, the incidence of posttransplant SCC in Japan and the Middle East is very low.[12]

The pathogenesis of SCC in OTRs is only partially understood. Some of the factors conferring susceptibility to skin cancer in OTRs are similar to those in nonimmunosuppressed patients and include: previous skin cancers or precancerous actinic keratoses (AKs), tendency towards sunburns, history of chronic sun exposure, and greater age.[13] Additional risk factors in OTRs include greater intensity and duration of immunosuppression, the presence of human papillomavirus (HPV) infection, and decreased CD4 T cell count.[13] Similar to SCC in the nonimmunosuppressed population, the primary mutagen in OTRs is thought to be UVR, which may serve as both a carcinogenic initiator and promoter. Specifically, UVR is thought to cause DNA mutations in keratinocytes affecting genes that regulate cell cycle control, such as the genes encoding the tumor suppressor p53. UVR also induces local and systemic immunosuppression, thereby altering a patientÕs ability to combat cutaneous malignancies and precancerous lesions. Antigen presentation by Langerhans cells, which plays a key role in the defense against carcinogenesis, is impaired by UVR, both directly via DNA damage within Langerhans cells and indirectly via soluble biological response modifiers and cytokines.[14,15] Additionally, UVR induces a switch from a TH1 cellular immune response to a TH2 pattern, most likely through induction of the release of IL-10 and other mediators.[16] Clinically, this pathogenic role for UVR manifests as the predominance of SCC on sun-exposed sites. Greater levels and duration of systemic immunosuppression result in a higher frequency of cutaneous malignancies, whereas cessation of immunosuppression leads to a reduction of tumor incidence.[17] Cardiac transplant recipients, who typically require higher levels of immunosuppression than renal transplant recipients, develop SCC at a higher frequency, whereas liver transplant recipients tend to receive lower levels of immunosuppression and appear to develop fewer cutaneous malignancies.[18,19] The primary mechanism behind the association of immunosuppression with skin cancer is probably the impairment of immune surveillance, thereby allowing 172

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UVR-induced DNA mutations within keratinocytes to go undetected. Some immunosuppressive medications, such as cyclosporine and azathioprine, may also be mutagenic in addition to immunosuppressive; cyclosporine has direct proliferative effects via induction of TGF-b.[20] Chronic immunosuppression is also associated with increased frequency of infection with HPV. Although not proven, a role for HPV in the development of SCC has been implicated, which may be particularly relevant in OTRs, in whom there is an increased prevalence of HPV in SCCs.[21] Specifically, oncogenic HPV types 5 and 8 are more often found in immunosuppressed transplant recipients.[21] In addition to inducing cellular proliferation, proteins elaborated by HPV may inhibit apoptosis through both p53-dependent and independent pathways, such as inhibition of Bak, a proapoptotic protein expressed by keratinocytes in response to ultraviolet B exposure.[22,23] AKs, porokeratosis, and perhaps viral warts are thought to represent precursors lesions to SCC in OTRs. Because SCCs in OTRs often appear rapidly and within a field of numerous keratotic lesions, it is difficult to determine if they arose de novo or from a preexisting lesion. Similarly, extensive areas of in-situ SCC, AKs and viral warts are often found histologically at the margins of invasive SCC in OTRs. In summary, UVR serves as a mutagen, inducing mutations in keratinocytes, including in the p53 tumor suppressor gene. Such mutations result in a loss of cell cycle control and subsequent unregulated keratinocyte proliferation. Mutations may also be induced by immunosuppressive medications. HPV virus, which is allowed to flourish under transplant immunosuppression, interferes with p53 product and perpetuates UVR-induced mutation. Immunosuppression, due to both the effects of UVR and systemic immunosuppressive medications, inhibits the ability to recognize and eliminate the mutated cells, thus allowing proliferation of atypical keratinocytes and the formation of SCC in OTRs.

C L I N I C AL P R E S E N T A T I O N SCC is the predominant skin cancer occurring in OTRs and may have a presentation and clinical course distinct from that in the nonimmunosuppressed population. Although SCCs may occur at any time following transplantation, they tend to present at a younger age than in nonimmunosuppressed patients, typically first appearing 3 to 8 years after transplantation. Although many OTRs will develop only a few SCCs during the years after transplantation, a substantial subset will develop numerous SCCs. This heavily affected subgroup may develop hundreds of distinct SCCs, which may follow an aggressive clinical course, accounting for significant morbidity and mortality. Approximately 6–9% of SCCs in OTRs metastasize, most often during the two years after excision, with a 50% 3-year disease-specific survival in those patients with metastases.[23–27] Local recurrence rates for SCC are also high, with approximately 14% of renal transplant recipients

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developing local recurrence after initial therapy.[24] An estimated 5% of OTRs ultimately die from skin cancer, with SCC accounting for a majority of these fatal malignancies.[25] In one study of a group of Australian heart transplant recipients, 27% of deaths occurring 4 or more years after transplantation were due to skin cancer.[9] SCCs in OTRs often present within a field of diffuse keratotic lesions that may include verrucae, AKs, porokeratosis, and SCC in all stages, all of which occur with increased frequency in the transplant population. It may be difficult to clinically distinguish malignant lesions from these benign and premalignant lesions. As in the nonimmunosuppressed population, SCCs in OTRs most frequently occur on chronically sun-exposed skin, particularly that of the head, neck, forearms, and dorsal hands (Figure 25.1–Figure 25.3) In males, the head and neck are the most common locations, whereas the trunk, particularly the chest, and the upper extremities predominate in females.[28] Satellite, or in-transit, metastases, thought to represent local cutaneous metastases via draining lymphatic channels, have been described in OTRs and are discussed more fully in chapter 33. In-transit metastases typically present as one or more dermal or subcutaneous nodules, distinct and discontiguous from the primary SCC, occurring en route to the draining lymph node basin. In-transit metastases usually present during the first several months after treatment of a primary aggressive SCC, most often on the forehead and scalp.[29] In one series, in-transit SCC metastasis in OTRs was associated with a 33% disease-specific mortality at 24 months, with an additional 33% of patients alive with the presence of nodal or distant metastases.[29] Lymph nodes are the most common site of metastasis for SCC in OTRs, and non-nodal sites can include the bones and lungs (Figure 25.4).[27] Clinical features suggesting increased risk for an aggressive clinical course include deeply invasive growth, or multiple SCC in the same patient, large size, rapid growth, ulceration, poorly-defined clinical margins, occurrence in high-risk sites, clinical satellite lesions, and recurrence after previous therapy (Table 25.1, Figure 25.1–Figure 25.6). High-risk histological features include poor cytologic differentiation, perineural invasion or dense perineural inflammation, perivascular or intravascular invasion, and extension of the carcinoma into the subcutaneous fat.[13]

M A NAG EME NT Although many SCCs in OTRs can be easily managed with the same modalities utilized in the nontransplant population, the management of OTRs who develop multiple or aggressive SCCs is challenging, requiring a multifaceted and multidisciplinary approach (Table 25.2). Cooperative management of these complex patients is best accomplished by the close interaction of dermatologists with transplant physicians and surgical, medical, and radiation oncologists. When available, multidisciplinary transplant clinics, in which several

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Figure 25.2. Multiple squamous cell carcinomas(SCCs) on the face of a heart transplant patient. Biopsy of the smaller lesions is helpful to determine the most appropriate treatment modality. The large SCC was treated with Mohs micrographic surgery.

Figure 25.1. Multiple eruptive squamous cell carcinomas(SCCs) on the arm of a cardiac and renal transplant patient. The SCC at left is well differentiated and minor and was treated with curettage and cryotherapy. The SCC at bottom was well differentiated but more invasive and was treated with excision. The SCC at right was keratoacanthoma-like and was treated with deep saucerization, curettage, and electrodesiccation.

surgical and medical specialties collaborate, can provide a convenient and efficient setting in which to care for these patients. The International Transplant-Skin Cancer Collaborative and the European Skin Care in Organ Transplant Patients Network, two multidisciplinary organizations of clinicians and researchers who care for and study skin cancer in OTRs, have published guidelines for the management of SCC in OTRs.[13] Selection of the most appropriate therapy for a SCC is influenced by its clinical and histological characteristics, the presence or absence of lymphadenopathy or metastatic disease, as well as the patientÕs co-morbidities, preferences, and degree of tolerance. (Figure 25.7) Classification of squamoproliferative lesions as benign or precancerous, lower-risk SCC, or high-risk SCC is fundamental for proper management. Management of verrucae and premalignant AKs and porokeratoses should be pursued aggressively in this population. In addition to decreasing the likelihood of such lesions progress-

ing to SCC, treatment also diminishes the field of keratotic lesions that often exists in OTRs, obstructing the ability to detect early SCC. Individual AK and verrucae may be treated with destructive methods such as cryosurgery with liquid nitrogen, curettage, and/or electrodessication. Larger fields of keratotic lesions may be treated topically with imiquimod, 5-flourouracil, diclofenac, or retinoid creams. Although there is a theoretical risk of systemic immune activation with the use of imiquimod, potentially affecting graft viability, there have not been reports of such adverse events in OTRs, however published experience is limited. Until more data is available, it may be prudent to limit the use of topical immunomodulators to one body site at a time. Due to the risk of systemic absorption, diclofenac should be used with caution in patients with renal impairment. Photodynamic therapy has also been reported to be useful in the treatment of keratotic lesions in OTRs.[30,31] Modalities with theoretical but less welldocumented utility in OTRs include chemical peels, laser resurfacing, and dermabrasion. There should be a low threshold for biopsy or excision of presumed AKs, porokeratoses, and warts that do not respond to traditional therapy or which have an atypical clinical presentation, as it can be very difficult to clinically distinguish such lesions from SCC in OTRs. Presumed SCCs with lower-risk clinical features (defined as a lack of high-risk clinical features listed in Table 25.1), should be biopsied. If there are no high-risk clinical or histological features, the lesion may be classified as a lower-risk SCC. Treatment of lower-risk SCC can include surgical

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Figure 25.3. (A) Large, infiltrative squamous cell carcinoma of the ear of a lung transplant patient, necessitating complete auriculectomy. (B) Postoperative defect after tumor clearance with Mohs micrographic surgery.

extirpation, either via Mohs micrographic surgery or standard excision with postoperative margin control with or without intraoperative evaluation of margins via frozen sections, or destructive techniques such as electrodesiccation and curettage (ED&C) or cryosurgery. In patients developing numerous lower-risk SCCs in areas other than the head and neck, a deep-shave biopsy encompassing the visible tumor followed by ED&C may be an efficient and useful modality. If histology confirms a lower-risk SCC, then this treatment can be considered adequate therapy and the site carefully observed, whereas if the lesion is histologically classified as a high-risk SCC, further treatment is necessary. In this setting, ED&C is convenient, rapid, and usually effective in OTRs; however, it does not allow histological evaluation of the margins. Similarly, deep-shave biopsy followed by curettage and cryosurgery may be appropriate for lowerrisk SCC in selected patients. It should also be used with caution due to its lack of margin evaluation. Mohs micrographic surgery offers the advantage of allowing examination of the entire excised margin, resulting in higher cure rates and maximal tissue conservation for any individual lesion. If standard excision with postoperative margin assessment is performed, margins of at least 4–6 mm of clinically uninvolved skin should be included in the excision to maximize cure rates.[13] There are often extensive areas of in-situ carcinoma contiguous with invasive SCC; thus, the goal of Mohs micrographic surgery or excision is often to clear the invasive and acanthotic component of the SCC, leaving the in-situ com-

ponent to be treated with an appropriate complimentary modality. Margin control is particularly important in OTRs due to the higher risk of subclinical extension, recurrence, and metastasis. Additionally, SCC recurrences in scars at prior sites of cryosurgery or ED&C can be difficult to detect clinically in their initial stages. If there is persistence or recurrence of an SCC after treatment with any of these modalities, it should be classified as a high-risk SCC and be managed as such. High-risk SCC confined to the skin and adjacent subcutaneous tissues without local or distant metastatic spread is usually managed with complete surgical extirpation. Mohs micrographic surgery is the excisional modality with the highest cure rate and should be strongly considered when available for the management of high-risk SCC in OTR. Other forms of excision such as standard excision with intraoperative frozen section analysis or postoperative margin assessment with at least 6-mm clinical margins may also be employed.[13] In selected patients, primary or adjuvant radiation therapy is appropriate. Primary treatment with radiation can be used for tumors considered inoperable either due to size and location, or due to the patientÕs inability to tolerate excision. Adjuvant radiation may be considered following excision in cases in which clear histological margins cannot be obtained, or if significant perineural invasion or perineural inflammation is observed. As discussed later, a reduction or modification in the level of immunosuppression and/or the addition of oral retinoids may also be considered as adjuvant therapy in the setting of high-risk SCC.

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Figure 25.4. Aggressive poorly differentiated squamous cell carcinoma in a renal transplant patient. Mohs surgery was used to treat the primary tumor. Bilateral sentinel lymph node biopsy revealed a single metastatic node in the right parotid gland, removed by parotidectomy.

Sentinel lymph node biopsy may provide some aid in the evaluation and management of high-risk SCC in OTRs, but there are no studies demonstrating a survival benefit or providing clinical guidance for patient selection. In patients with multiple tumors, the primary source of a metastasis can be difficult to determine. Additionally, in patients in whom dozens or hundreds of SCCs may develop, the decision to employ lymph node dissection is complicated. The morbidity associated with this procedure should be weighed carefully against the potential benefits, and should only be performed in centers with significant experience with the technique. All OTRs with SCC require careful examination of the surrounding skin for satellite lesions representing in-transit metastases, and of regional lymph nodes for evidence of lymphadenopathy. If in-transit or satellite metastases are discovered, patients should be further evaluated for more distant spread via lymph node examination, a complete skin exam, and imaging studies. Satellite lesions, like the primary SCC, should be excised with margin evaluation, and either primary or postoperative radiation therapy should be strongly considered because the tumor has become discontiguous and has a high risk of development of more in-transit metastases. The finding of clinically or radiographically enlarged lymph nodes should prompt histological evaluation either via fine needle biopsy or open lymph node biopsy. If lymph node involvement is confirmed histologically, prompt excision of the affected lymph node basin is essential. Adjuvant radiation is an important management strategy for both satellite and nodal metastases, as surgical margins are more likely to be inaccurate in metastatic disease. Following surgical excision or primary radiotherapy, reduction of immunosuppression with or without the addition of oral retinoids should also be entertained in patients with either satellite or nodal metastases. Identification of SCC metastases should prompt referral back to the patientÕs transplant physician, as well as medical and surgical oncologists for coordinated care, which may

Table 25.1 High-risk clinical and histological features of SCCs in OTRs High-risk clinical features

High-risk histological features

1. Large size Greater than 0.6cm on high-risk locations (nose, lips, ears, eyelids, etc. see following text) Greater than 1 cm on scalp, forehead, cheeks, neck Greater than 2 cm on extremities and trunk

1. 2. 3. 4. 5.

2. Multiple SCC in same patient 3. Ulceration 4. Poorly-defined margins 5. High-risk locations: genitalia, digits, eyelids, lips, eyebrows, periorbital, nose, chin, mandible, ear, temple, preauricular, postauricular 6. Satellite/in-transit lesions 7. Recurrence after initial therapy

Poor cytologic differentiation Perineural invasion Dense perineural inflammation Perivascular or intravascular invasion Extension into subcutaneous fat

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Figure 25.5. Renal transplant recipient who exhibits the ravages of multiple squamous cell carcinomas. The left ear has been partially removed due to squamous cell carcinoma, resulting in deformity. There have been metastases to the parotid lymph nodes and a parotidectomy and neck dissection have been performed. A metastatic atypical fibroxanthoma of the scalp necessitated extensive surgery and radiation, requiring free flap reconstruction.

include reduction of immunosuppression, oral retinoids, resection, radiation, and/or systemic chemotherapy. For advanced inoperable metastatic SCCs in OTRs, systemic chemotherapy is a consideration, although the data supporting its use is limited. Chemotherapeutic agents that have been reported to be of benefit, usually as components of multiagent regimens, have included cisplatin, 5-fluorouracil, bleomycin, interferon-alpha, and retinoic acid.[32–35]

P R E VE NT I ON Prevention of SCC in OTRs can be classified as either primary or secondary prevention. Primary preventative measures are those that are taken prior to onset of SCC, whereas secondary measures are those taken to prevent recurrent or de novo SCC after a patient has had a prior SCC. Prevention of SCC in OTRs should begin with pretransplant education regarding the risk of skin cancer following transplantation, common clinical presentations of SCC and its precursors (AK and porokeratosis), techniques for self-skin examination, and strategies for daily photoprotection including sun avoidance, sunscreen use, and use of protective clothing. This education should be repeated frequently and regularly following transplantation.

Figure 25.6. Lung transplant recipient with nodule of in-transit metastatic squamous cell carcinoma in the skin of the parietal scalp. The cancer also metastasized to the lung and bone.

An important component of prevention is regular followup visits, during which a history of new or changing skin lesions or lesions of concern to the patient should be elicited, current and past medications should be reviewed with a focus on immunosuppressants, a total skin examination should be performed including sites of prior skin cancers and their draining lymph node basins, and patients should be reeducated regarding photoprotection and self-examination of the skin and lymph nodes.[13] The intervals between follow-up will vary for individual patients based on their risk factors, with more frequent examination of patients with a history of prior skin cancer (Table 25.3). At these visits, identification and treatment of precursor lesions such as AKs and porokeratosis is also pursued to decrease the likelihood of such lesions progressing to SCC, and to make diagnosis of early SCCs easier. For patients with severe confluent carcinomas and keratinocytic stypia of the dorsal hands, prophylactic excision of the skin on the dorsal hands and forearms with split-thickness skin grafting has been described as a method of both removing multiple lesions and providing an extended absence of SCC

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Table 25.2 Treatment options for SCC, SCC in situ, and precancerous lesions in OTRs Treatment Topical 1. Imiquimod

Pros

Cons

Useful for premalignant and early thin SCC Field treatment Very effective

Theoretical risk of systemic immune activation Variably significant local inflammation and irritation Lack of histologic confirmation and margin control Not useful for invasive SCC Less effective Irritating Must be used chronically Not useful for in situ or invasive SCC Significant local inflammation and irritation Lack of histologic confirmation and margin control Not useful for invasive SCC Systemic absorption may be problem in impaired renal function (diclofenac) Less effective Not useful for in situ or invasive SCC

2. Retinoids

Field treatment Mild chronic irritation

3. 5-fluorouracil

Useful for premalignant and early thin SCC Field treatment Very effective

4. Diclofenac

Field treatment Minimal irritation

Destructive Lesion treatment 1. Cryosurgery

Convenient and rapid Treat multiple lesions at one session

2. Electrodessication and/or curettage or curettage and cryotherapy

Effective for selected lower risk lesions, including low-risk, minor invasive SCC

3. Ablative laser

Rapid for numerous lesions

Field treatment 1. Photodynamic therapy

Treat large areas of premalignant and thin SCC in situ

Lack of margin control Pain Scarring Blistering (cryosurgery) Useful only for in situ and minimally invasive SCC Lack of margin control Pain Scarring Not useful for high-risk SCC Lack of margin control Pain Most scarring Useful only for in situ and minimally invasive SCC Lack of histologic confirmation and margin control Not indicated for invasive SCC Less effective than 5-fluorouracil cream Less effective than 5-fluorouracil cream

2. Chemical peel 3. Dermabrasion Excisional 1. Excision with postoperative margin evaluation

Field treatment for AK Field treatment for AK

2. Excision with intraoperative margin evaluation

Ability to remove deeper tumors with immediate but incomplete margin evaluation Treatment of choice for higher risk tumors Evaluation of total surgical margin with maximal tissue preservation

Incomplete and delayed evaluation of surgical margin May require reexcision of + margins Significant recurrence rate Incomplete evaluation of surgical margin May be difficult for management of multiple tumors High use of time and resources May be difficult for management of multiple tumors

Possible improvement in advanced SCC, decreased development of new SCC

Risk of allograft rejection Not a primary treatment modality

3. Mohs micrographic surgery

Systemic 1. Reduction of immunosuppression

Ability to remove deeper tumors

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Treatment

Pros

Cons

2. Oral Retinoids

Possible improvement in advanced SCC, decreased incidence of new SCC Decreased precancerous keratoses

3. Chemotherapy

Possible improvement in inoperable SCC

Other 1. Radiotherapy

Mucocutaneous side effects Lipid and liver function abnormalities Rebound after discontinuation Not a primary treatment modality Significant adverse effects Limited efficacy Limited experience for cutaneous SCC Not a primary treatment modality

Useful for poor surgical candidates, inoperable tumors and some metastases Essential for in-transit metastases Noninvasive May help provide staging information Theoretical early detection of nodal metastases

2. Sentinel lymph node examination

in these locations. This technique is described in detail in Chapter 37. Oral and topical retinoids have been shown to have chemopreventative effects, and should be considered in selected OTRs. Systemic retinoids are often initiated in OTRs with a history of numerous SCCs, aggressive SCC, and when

Acute radiation dermatitis Lack of margin control Recurrences in radiation treatment sites may be difficult to treat Unproven survival benefit Lack of clear guidelines for use Morbidity associated with surgery (lymphedema, seroma, hematoma, etc.)

there are extensive concomitant AKs and warts. Acitretin is the most commonly used oral retinoid, with doses ranging from 10–50 mg daily. Oral retinoids are more beneficial for suppressing the development of new SCCs than for treating existing SCCs. Their chemosuppressive effects require chronic therapy, as there is frequently a rebound phenomenon with

Clinical Impression Benign/Premalignant

SCC Low-risk clinical features (see Table 25.1)

Treat: 1. Cryosurgery 2. Topical 5-FU 3. Imiquimod 4. PDT

High-risk clinical features (see Table 25.1)

Biopsy and ED&C

Biopsy to confirm SCC

Persists Resolves

179

No high-risk histologic features (see Table 24.1)

High-risk histologic features (see Table 25.1)

Mohs surgery +/- Oral retinoids or Reduced immunosuppression

Recurrence 1. Deep SCC in high-risk area (see Table 25.1) or 2. Perineural invasion

Regular follow-up visits for the life of patient (see Table 25.3)

Negative

+/- Sentinel lymph node dissection or radiation therapy Positive

Adjuvant radiation and/or chemotherapy

Figure 25.7. Management of squamoproliferative lesions in OTRs. 5-FU=5-fluorouracil, PDT=photodynamic therapy, ED&C=electrodessication and curettage.

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Table 25.3 Proposed intervals for follow-up visits for organ transplant recipients Presentation and risk factors

Initial intervention

Metastatic squamous cell carcinoma Multiple NMSC High-risk squamous cell carcinoma One squamous cell carcinoma One basal cell carcinoma Viral warts or Actinic keratoses Positive risk factors, but no prior malignant or precancerous lesions No additional risk factors

Clinical Clinical Clinical Clinical Clinical Clinical Clinical

examination examination examination examination examination examination examination

Clinical examination

Follow-up interval for clinical examinationsa(months) and and and and and and

treatment treatment treatment treatment treatment treatment

1–3 3 3 3–6 3–6 3–6 6–12 12–24

a

Clinical examinations should be continued indefinitely throughout the posttransplant period. Source: Stasko T, Brown MD, Carucci JA, Euvrard S, Johnson TM, Sengelmann RD, Stockfleth E, Tope WD. Guidelines for the management of squamous cell carcinoma in organ transplant recipients. Dermatol Surg. 2004;30(4):642-50.

a return to the development of SCCs at pretreatment levels within several months after their discontinuation. Intolerance of side effects prevents the use of retinoids in some patients. The use of retinoids is discussed in more detail in Chapter 42. Alterations in immunosuppressive regimens may decrease the incidence of SCC in OTRs, and reduced levels of immunosuppression may be appropriate in patients with a history of multiple high-risk SCC. Such alterations of immunosuppressive regimens should be undertaken by the transplant physicians after careful assessment of the potential benefit and risks. Dermatologists can help quantify the level of risk posed by the patientÕs SCCs, and therefore often play an important role in initiating the consideration of lowering the level of immunosuppression. Although the indications for reduction of immunosuppression in OTRs are not firmly established, factors to be considered are discussed in Chapter 41. The lowest level of immunosuppression, which is adequate to safely maintain graft function should be a goal in all OTRs with SCC. A more aggressive reduction is probably most appropriate in patients with life-threatening skin cancer and those with a tremendous tumor burden.

CONCLUSION Cutaneous SCC is the most common cancer in OTRs and causes significant morbidity and mortality. An understanding of its pathogenesis, clinical presentation, and available therapeutic and preventative strategies is essential for all physicians involved in the care of these patients. Skin cancer prevention, early diagnosis, and appropriate treatment can have a significant impact the posttransplant health of OTRs. REFERENCES

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2. B. Lindelo¨f, B. Sigurgeirsson, H. Ga¨bel, R.S. Stern. Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol. 2000;143(3):513–9. 3. Moosa MR, Gralla J. Skin cancer in renal allograft recipients– experience in different ethnic groups residing in the same geographical region. Clin Transplant. 2005;19(6):735–41. 4. Bordea C, Wojnarowska F, Millard PR, Doll H, Welsh K, Morris PJ. Skin cancers in renal-transplant recipients occur more frequently than previously recognized in a temperate climate. Transplantation. 2004;77(4):574–9. 5. Fortina AB, Peaserico S, Caforio AL, Abeni D, Alaibac M, Angelini A, Iliceto S, Perserico A. Immunosuppressive level and other risk factors for basal cell carcinoma and squamous cell carcinoma in heart transplant recipients. Arch Dermatol. 2004;140(9):1079–85. 6. Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation. 1990;49(3):506–9. 7. Naldi L, Fortina AB, Lovati S, Barba A, Gotti E, Tessari G, Schena D, Diociaiuti A, Nanni G, La Parola IL, Masini C, Piaserico S, Peserico A, Cainelli T, Remuzzi G. Risk of nonmelanoma skin cancer in Italian organ transplant recipients. A registry-based study. Transplantation. 2000;70(10):1479–84. 8. London NJ, Farmery SM, Will EJ, Davison AM, Lodge JP. Risk of neoplasia in renal transplant patients. Lancet. 1995;346(8972):403–6. 9. Ong CS, Keogh AM, Kossard S, Macdonald PS, Spratt PM. Skin cancer in Australian heart transplant recipients. J Am Acad Dermatol. 1999;40(1):27–34. 10. Ramsay HM, Fryer AA, Hawley CM, Smith AG, Harden PN. Nonmelanoma skin cancer risk in the Queensland renal transplant population. Br J Dermatol. 2002;147(5):950–6. 11. Fuente MJ, Sabat M, Roca J, Lauzurica R, Fernandez-Figueras MT, Ferrandiz C. A prospective study of the incidence of skin cancer and its risk factors in a Spanish Mediterranean population of kidney transplant recipients. Br J Dermatol. 2003;149(6):1221–6. 12. Samhan M, Al-Mousawi M, Donia F, Fathi T, Nasim J, Nampoory MR. Malignancy in renal recipients. Transplant Proc. 2005; 37(7): 3068–70. 13. Stasko T, Brown MD, Carucci JA, Euvrard S, Johnson TM, Sengelmann RD, Stockfleth E, Tope WD. Guidelines for the management of squamous cell carcinoma in organ transplant recipients. Dermatol Surg. 2004;30(4):642–50. 14. Vink AA, Strickland FM, Bucana C, Cox PA, Roza L, Yarosh DB, Kripke ML. Localization of DNA damage and its role in altered antigen-presenting cell function in ultraviolet-irradiated mice. J Exp Med. 1996;183(4):1491–500.

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15. Seiffert K, Granstein RD. Neuropeptides and neuroendocrine hormones in ultraviolet radiation-induced immunosuppression. Methods. 2002;28(1):97–103. 16. Rivas JM, Ullrich SE. Systemic suppression of delayed-type hypersensitivity by supernatants from UV-irradiated keratinocytes. An essential role for keratinocyte-derived IL-10. J Immunol. 1992; 149(12):3865–71. 17. Otley CC, Coldiron BM, Stasko T, Goldman GD. Decreased skin cancer after cessation of therapy with transplant-associated immunosuppressants. Arch Dermatol. 2001;137(4):459–63. 18. Euvrard S, Kanitakis J, Pouteil-Noble C, Dureau G, Touraine JL, Faure M, Claudy A, Thivolet J. Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation. J Am Acad Dermatol. 1995;33(2 Pt 1):222–9. 19. Frezza EE, Fung JJ, van Thiel DH. Non-lymphoid cancer after liver transplantation. Hepatogastroenterology. 1997;44(16):1172–81. 20. Hojo M, Morimoto T, Maluccio M, Asano T, Morimoto K, Lagman M, Shimbo T, Suthanthiran M. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature. 1999;397:530–4. 21. Stockfleth E, Nindl I, Sterry W, Ulrich C, Schmook T, Meyer T. Human papillomaviruses in transplant-associated skin cancers. Dermatol Surg. 2004;30(4 Pt 2):604–9. 22. Jackson S, Storey A. E6 proteins from diverse cutaneous HPV types inhibit apoptosis in response to UV damage. Oncogene. 2000;19(4):592–8. 23. Jackson S, Harwood C, Thomas M, Banks L, Storey A. Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev. 2000; 14(23):3065–73. 24. Winkelhorst JT, Brokelman WJ, Tiggeler RG, Wobbes T. Incidence and clinical course of de-novo malignancies in renal allograft recipients. Eur J Surg Oncol. 2001;27(4):409–13. 25. Penn I. Tumors after renal and cardiac transplantation. Hematol Oncol Clin North Am. 1993; 7(2):431–45. 26. Sheil AG, Disney AP, Mathew TH, Amiss N. De novo malignancy emerges as a major cause of morbidity and late failure in renal transplantation. Transplant Proc. 1993; 25(1 Pt 2):1383–4.

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27. Martinez JC, Otley CC, Stasko T, Euvrard S, Brown C, Schanbacher CF, Weaver AL; Transplant-Skin Cancer Collaborative. Defining the clinical course of metastatic skin cancer in organ transplant recipients: a multicenter collaborative study. Arch Dermatol. 2003;139(3): 301–6. 28. Lindelof B, Dal H, Wolk K, Malmborg N. Cutaneous squamous cell carcinoma in organ transplant recipients: a study of the Swedish cohort with regard to tumor site. Arch Dermatol. 2005;141(4): 447–51. 29. Carucci JA, Martinez JC, Zeitouni NC, Christenson L, Coldiron B, Zweibel S, Otley CC. In-transit metastasis from primary cutaneous squamous cell carcinoma in organ transplant recipients and nonimmunosuppressed patients: clinical characteristics, management, and outcome in a series of 21 patients. Dermatol Surg. 2004;30(4 Pt 2): 651–5. 30. Dragieva G, Prinz BM, Hafner J, Dummer R, Burg G, Binswanger U, Kempf W. A randomized controlled clinical trial of topical photodynamic therapy with methyl aminolaevulinate in the treatment of actinic keratoses in transplant recipients. Br J Dermatol. 2004;151(1):196–200. 31. Dragieva G, Hafner J, Dummer R, Schmid-Grendelmeier P, Roos M, Prinz BM, Burg G, Binswanger U, Kempf W. Topical photodynamic therapy in the treatment of actinic keratoses and BowenÕs disease in transplant recipients. Transplantation. 2004;77(1):115–21. 32. Shin D, Glisson B, Khuri F, et al. Phase II and biologic study of interferon alfa, retinoic acid, and cisplatin in advanced squamous skin cancer. J Clin Oncol. 2002;20: 364–70. 33. Guthrie TJ, Porubsky E, Luxenberg M, et al. Cisplatin-based chemotherapy in advanced basal and squamous cell carcinomas of the skin: results in 28 patients including 13 patients receiving multimodality therapy. J Clin Oncol. 1990;8: 342–6. 34. Khansur T, Kennedy A. Cisplatin and 5-fluorouracil for advanced locoregional and metastatic squamous cell carcinoma of the skin. Cancer. 1991;67: 2030–2. 35. Sadek H, Azli N, Wendling J, et al. Treatment of advanced squamous cell carcinoma of the skin with cisplatin, 5-fluorouracil, and bleomycin. Cancer. 1990;66: 1692–6.

26 Malignant Melanoma in Organ Transplant Recipients

Leslie J. Christenson, MD

INTR ODUCT IO N

though these are real considerations, they are still theoretical and not based on existing valid data.

Malignant melanoma (MM) is the most life-threatening form of skin cancer. It is considered an immunologic tumor and, therefore, raises concerns regarding its behavior and outcomes in the population of immunosuppressed solid organ transplant recipients. Three clinical scenarios are of concern for transplant patients with MM: (1) a history of MM before transplant, (2) development of MM as a result of transmission from the organ donor, and (3) de novo development of MM after transplantation. In making clinical decisions for patients within each scenario, a basic understanding of the pathogenesis of MM, prognostic variables, treatment outcomes, and survival in the general population and transplant population is required.

I NC I D E NC E From 1950 to 2000, the National Cancer InstituteÕs SEER (Surveillance, Epidemiology, and End Results) database documented increases of 619% in annual diagnoses of cutaneous MM and 165% in annual mortality related to MM.[8] In 2005, the American Cancer Society estimated that 59,580 persons in the United States received a diagnosis of MM. Transplant recipients with a history of MM before transplantation may have a high incidence of recurrence of MM after transplantation – a rate of 19% on the basis of 6 recurrences in a series of 31 reported cases.[5] No data exist regarding the incidence of a second primary MM in this patient population. MM is one of the most common donor-transmitted cancers in solid organ transplant recipients, accounting for 12 of 167 different types of donor-transmitted malignancies from 163 donors in one study.[9] Although primary brain neoplasms are the most common known donor-transmitted malignancy and carcinoma of the kidney is the most commonly transmitted tumor confined to the donated allograft, MM is the most commonly transmitted tumor causing distant metastasis (28%).[10] In one series of 13 donors with MM, the tumor was transferred to 21 of 28 organ recipients (75%).[9] Other case reports document a 50–100% transmission rate.[11,12] Only one study has reported no transmission of MM from four organ donors with a history of MM at a mean of five years before organ donation;[13] however, these authors still consider the risk of transmission high on the basis of prior reports and the limited number of cases in their study. The incidence of a de novo melanoma developing in transplant recipients is debated. Prior studies have shown variable incidence rates of MM in transplant recipients, ranging from no increase [14] to an 8-fold increase in incidence when compared with that in the general population.[7] The incidence is slightly higher in male transplant recipients than in female recipients.[15,16] It is of note that the incidence of MM in African American renal transplant recipients has been reported to be 17.2 times higher than that for African Americans in the general population.[15] MM is relatively more common in pediatric transplant

PATHOG ENES IS Cutaneous melanoma develops from melanocytes that reside in the bottom layer of the epidermis or in nevi extending down into the dermis. Sun exposure, genetic susceptibility with known familial susceptibility genes CDKN2A and CDK4,[1,2] BRAF gene mutations,[3] and immune response all can have a role in the development of melanoma. In one early study of MM in renal transplant recipients, a precursor nevus was detected at the margin of the majority of tumor. Additionally, a decreased tumor lymphocytic infiltrate response was present in 10 of 14 tumors. The authors concluded that ‘‘MM in renal transplant recipients appears to evolve from precursor nevi in a host unable to mount a tumor-specific cellular immune response.’’[4] Although simplistic, the mechanism of pathogenesis proposed on the basis of this studyÕs findings seemed to confirm intuitive ideas. Other studies found a similar absence of a lymphocytic infiltrate,[4–7] but failed to show nevi at the margin of the MM.[7] Crucial immune mechanisms of the host needed to prevent, contain, or overcome MM may be absent in transplant recipients. For example, interleukin-2, which enhances the immune response to MM vaccines, is inhibited by calcineurin inhibitors taken by transplant recipients as a part of their immunosuppressive drug regimen, which could affect outcomes. It follows that immunosuppression may indeed increase the incidence, recurrence rate, donor transmission rate, and metastatic rate of MM in transplant recipients. Al-

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recipients than in adult recipients, with 12% versus 5% of patients developing posttransplant skin cancers, respectively.[17]

C L I N I C AL P R E S E N T A T I O N A N D R I S K FACTORS Cutaneous melanoma most commonly presents as an atypical pigmented lesion. The ‘‘ABCDE’’ guidelines have been established to assist in the screening of pigmented lesions. A lesion with asymmetry, border irregularity, color variation, diameter greater than 6 mm, or a recent history of change (evolution) is of concern, and a biopsy should be performed for histologic examination (Figure 26.1). Cutaneous melanoma can present in many ways and, therefore, clinical suspicion should always remain high.

183

Patients most at risk for the development of MM include those with fair skin, red or blonde hair, blue eyes, history of sunburns, atypical nevi, numerous nevi, and a personal or family history of MM. Within the transplant population, MM has been most commonly reported in renal recipients.[5,6] However, comparison of risk on the basis of transplant type is not possible due to incomplete reporting and most reports being case studies only. MM in transplant recipients appears most commonly on the trunk, followed by the upper arm.[5,7] Mean age at the time of diagnosis of MM has ranged from 36.5 [6] to 52 years.[7] MM appeared at a mean of 61 months (range, 1–244 months) after transplantation in several analyzed studies;[5,6,18] however, one study showed a shorter mean time of 41.6 months in those receiving cardiac and/or lung transplants.[19] The mean latent period from transplant to

Figure 26.1. A, Classic appearance of malignant melanoma with asymmetry, border irregularity, color variation, and diameter >6 mm. B, Melanoma with asymmetry, border irregularity, color variation, and large diameter, but on non-sun-exposed skin. C, Amelanotic melanoma. D, Melanoma presenting with only slight variation in color.

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diagnosis of melanoma may be shorter if the MM develops within a dysplastic nevus – 22 months in one study, compared with 40 months for the entire group.[4] No particular immunosuppressive regimen has been shown to be associated with a higher risk of MM. Most transplant recipients with de novo MM have been on the commonly used regimens of azathioprine, cyclosporine, or combined azathioprine and cyclosporine.[5,6,14,19,20] As in the general population, a history of nonmelanoma skin cancer such as squamous cell carcinoma or basal cell carcinoma appears to be a risk factor for MM in the transplant population. A history of other skin cancers has been reported in 27% of transplant recipients with MM.[5] Another report showed all 8 renal transplant recipients with MM having a history of from 1 to 76 squamous cell carcinomas and 1 to 8 basal cell carcinomas.[21] The presence of multiple nevi is a known risk factor for MM in the general population. Children with renal allografts have been noted to have greater numbers of nevi than matched nontransplant controls, and the number of nevi increase with the duration of immunosuppression.[22] This increase in nevi also is seen in adult renal transplant recipients.[23] The increased number of nevi in the transplant population is of concern because it may contribute to the increased risk of MM. Cause of death in donors retrospectively found to have transmitted MM with the donated allograft has been commonly misattributed to cerebrovascular accident or primary brain tumor; thus, donor death from these causes may be viewed as having a potentially increased relative risk for the transmission of MM from an organ donor through false reporting.[10,11,24] Only one case in the literature documents transmission from a donor with a known MM. In that case, the Breslow depth was 2.6 mm.[24] There is no known report of a donor with malignant melanoma in situ (MMIS) transmitting MM to organ recipients.

Table 26.1 Melanoma TNM classification T classification T1: <1.0 mm a: Without ulceration and ClarkÕs level II/III b: With ulceration or Clarks level IV/V T2: 1.01–2.0 mm a: Without ulceration b: With ulceration T3: 2.01–4.0 mm a: Without ulceration b: With ulceration T4: >4.0 mm a: Without ulceration b: With ulceration N classification N1: 1 metastatic node a: Micrometastasisa b: Macrometastasisb N2: 2–3 metastatic nodes a: Micrometastasisa b: Macrometastasisb c: In transit mets/satellites without metastatic nodes N3: >4 metastatic nodes, or matted nodes, or in transit mets/ satellites with metastatic nodes M classification M1a: Distant skin, subcutaneous, or nodal mets; normal LDH level M1b: Lung mets; normal LDH level M1c: All other visceral mets; normal LDH level Any distant met; elevated LDH level Note: LDH = serum lactate dehydrogenase; met = metastasis. a Diagnosed after sentinel or elective lymphadenectomy. b Defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension. Source: Modified from Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001; 19:3635–48. Used with permission.

O U TC OM ES In the general population, which is considered immunocompetent, prognostic factors for MM have been extensively evaluated.[25] These prognostic factors have been used to establish the latest version of the American Joint Committee on Cancer staging system for cutaneous melanoma [26] (Table 26.1 and Table 26.2). Outcomes based on staging have been established (Table 26.3) (Figure 26.2–Figure 26.4). It is important to recognize that these prognostic factors are based on the general population; however, it is unknown whether the same factors have similar importance in the immunosuppressed transplant population. Transplant recipients with a history of MM before transplantation who have recurrence of MM after transplantation typically have poor outcomes.[5] In a cohort of 31 patients with MM resected at a median of 25 months before transplant, six patients (19%) had recurrence of MM after transplant, all of whom died of MM at a mean of 16 months after diagnosis.

No information was available on the thickness or stage in five cases. The remaining case was known to be ClarkÕs level IV, but with unknown Breslow depth. Transplant recipients with MM transmitted from an affected donor have high mortality rates.[5,9,11,12,27,28] In the largest reported series, 13 of 21 recipients (62%) in whom MM developed due to transmission from the donor died of the disease.[9] Smaller case reports record a 50% [12] to near 100% mortality from organ-donor-transmitted MM.[11,28,29] Definitive prognosis for de novo MM in transplant recipients is also unknown, with few studies reporting outcomes [4,6,7,19,20,30,31] and only four studies providing limited data regarding prognostic factors.[4–7] It is unclear if MM in transplant recipients presents at a more advanced stage of disease because few reports have documented the clinical stage at diagnosis. If transplant recipients present with de novo melanoma at more advanced stages they would inherently have worse outcomes.

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Table 26.2 Stage groupings for cutaneous melanoma Clinical staginga

0 IA IB IIA IIB IIC IIIc

Pathologic stagingb

T

N

M

T

N

M

Tis T1a T1b T2a T2b T3a T3b T4a T4b Any T

N0 N0 N0 N0 N0 N0 N0 N0 N0 N1 N2 N3

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0

Tis T1a T1b T2a T2b T3a T3b T4a T4b

N0 N0 N0 N0 N0 N0 N0 N0 N0

M0 M0 M0 M0 M0 M0 M0 M0 M0

IIIA

T1-4a T1-4a T1-4b T1-4b T1-4a T1-4a T1-4a/b T1-4b T1-4b Any T

IIIB

IIIC Clinical staginga

IV

T Any T

N Any N

M Any M1

T Any T

N1a N2a N1a N2a N1b N2b N2c N1b N2b N3 Pathologic stagingb N Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0

M Any M1

Note: Tis = tumor in situ. a Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases. b Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial or complete lymphadenectomy. Pathologic stage 0 or stage IA patients are the exception; they do not require pathologic evaluation of their lymph nodes. c There are no stage III subgroups for clinical staging. Source: From Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001; 19:3635–48.Used with permission.

In the study by Greene et al.,[4] 14 primary MMs developed in 13 patients: Breslow depth was <0.76 mm in four MMs, 0.76–1.50 mm in five (<1 mm in five MMs), 1.51–4.0 mm in two, >4.0 mm in one, and indeterminate depth in two. In one patient, the primary site of MM was never determined, but the diagnosis was verified as metastatic melanoma on tissue review. At the time of publication, six patients were alive and well, one was alive with metastatic disease, and seven were dead from metastatic melanoma. Another study showed a similar 50% mortality rate, but histologic prognostic information on the cases was not provided.[21] All patients in the Greene et al. [4] study with MM of Breslow depth less than 1 mm were alive and well. Leveque et al. indicated that prognosis is difficult to predict.[6] In that study, only four of 17 patients with MM (cutaneous MM in 14, mucosal MM in two, no data for one) died

of metastasis at a mean of 15 months: three had ulcerated nodular MM and one had rectal MM.[6] Prognostic data for this series of cases included two cases of MMIS, seven cases of superficial MM, and three cases of nodular MM. Eight of these patients had a ClarkÕs level of III or higher, and three of the 10 cases of superficial and nodular MM had a Breslow depth of 1.5 mm or greater. The mean duration of follow-up for 12 living patients was three years.[6] In one patient, lymph node metastasis developed twice but remission was achieved with interferon therapy. Le Mire et al. [7] reported 10 patients with 12 melanomas: 10 superficial spreading, one nodular, and one lentigo maligna. Seven were in the radial growth phase and five in the vertical growth phase. Breslow depth was less than 1 mm in all patients except one in whom the only death due to MM

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Table 26.3 Survival rates for melanoma TNM and staging categories Survival6SE, (%) Stage

TNM

2 Years

5 Years

IA IB

T1a T1b T2a T2b T3a T3b T4a T4b N1a N2a N1a N2a N1b N2b N1b N2b N3 M1a M1b M1c

99.060.2 98.760.3 97.360.3 92.960.9 94.360.6 84.861.0 88.661.5 70.761.6 88.062.3 82.763.8 75.063.2 81.064.1 78.563.7 65.665.0 54.265.2 44.164.9 49.862.7 36.763.6 23.163.2 23.661.5

95.360.4 90.961.0 89.060.7 77.461.7 78.761.2 63.061.5 67.462.4 45.161.9 69.563.7 63.365.6 52.864.1 49.665.7 59.064.8 46.365.5 29.065.1 24.064.4 26.762.5 18.863.0 6.762.0 9.561.1

IIA IIB IIC IIIA IIIB

IIIC

IV

Figure 26.3. Comparison of 5-year survival rates for patients with (N+) and without (N ) positive nodal disease for each T stage. Data are based on 5,346 patients with disease staged by regional lymph node dissection or sentinel lymphadenectomy. (Modified from Balch et al.[26] Used with permission.)

Source: Modified from Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19:3635–48. Used with permission.

occurred. This patient had a nodular melanoma, with a Breslow depth of 4.5 mm. In the largest reported series of transplant patients with de novo MM (177 patients; 164 with primary cutaneous MM, five with ocular MM, eight with unknown primary), 56 (32%) died of MM. Breslow depth was known in 42 cases: <0.76 mm in 13 (31%), 0.76–1.50 mm in 9 (21%), 1.51–4.00 mm in 15 (36%),

Figure 26.2. Curves illustrating survival to 10 years based on Breslow depth and ulceration of localized melanoma. , no ulceration; +, positive ulceration. (Modified from Balch et al. [26] Used with permission.)

Figure 26.4. Survival to 15 years based on overall tumor stage. (Modified from Balch et al. [26] Used with permission.)

and >4.00 mm in 5 (12%). Two of the thirteen with MM of Breslow depth <0.76 mm died of metastatic disease. Increasing Breslow depth was associated with increased mortality due to MM as 12 of 29 with Breslow depth >0.76 mm died of MM. There were a total of 11 cases of MMIS and superficial spreading MM. None of these tumors were associated with mortality due to MM. Lymph node metastasis occurred in 32 of 164 patients (20%) with de novo cutaneous melanoma, 24 (75%) of whom died of metastatic MM. Follow-up in this series was limited to a median of 25 months.[5] Statistically valid outcome predictions in the transplant population, based on American Joint Committee on Cancer staging criteria, remain unknown. However, in the small case series that have been reported, those with thin MM (Breslow depth less than 0.76 to 1 mm) appear to have a good outcome, similar to that of immunocompetent persons in the general population. Those with MM of greater Breslow depth or more advanced stage appear to have worse outcomes, but this is yet to be proven. Patients in the series discussed received varying treatments, from wide local excision of the MM [4] to

MALIGNANT MELANOMA IN ORGAN TRANSPLANT RECIPIENTS

therapeutic lymph node dissection [4] to some decrease in immunosuppression [7] to wide excision in combination with interferon.[6] This diversity of treatments also clouds any outcomes analysis.

MANAGEMENT Education is vital to preventing primary MM. Transplant patients must be educated on the damaging effects of the sun and their increased risk of skin cancer. They should be instructed on proper sun protection with sunscreen (SPF 30 or greater, blocking UVA and UVB rays), protective clothing, broad-brimmed hats, and avoidance of the noontime sun. They should have an initial-screening skin examination by a dermatologist, with follow-up examinations scheduled according to individual risk. Transplant recipients with numerous or dysplastic nevi deserve close observation, with follow-up at least every six months. Biopsies should be performed on suspicious lesions. Living donors should provide a thorough history to document prior history of MM or atypical pigmented lesions, including any histologic or staging information. A complete skin examination should be performed to detect any undiag-

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nosed MM before organ donation. In retrospect, cadaveric donors with a history of cerebrovascular accident or primary brain tumor have been responsible for most cases of transmitted MM; therefore, organ donors with such history should be considered cautiously. A biopsy at the time of transplant or posttransplant autopsy should be performed to rule out any possible MM. Patients with a history of MMIS are considered to be at an extremely minimal risk for recurrence and metastasis, therefore, no required waiting time for transplantation has been recommended.[5] Patients with a superficial spreading tumor or radial growth-phase tumor with a Breslow depth of less than 1 mm are recommended to have a 2-year waiting period from diagnosis of MM to transplant.[5] Approximately 95% of patients with MM and negative sentinel lymph nodes (SLN) in the general population reach the 5-year survival point.[26] No similar data is available showing the outcomes of immunosuppressed transplant recipients with MM and negative SLN. Knowing the good prognosis in the general population, however, patients with thin melanomas and negative SLN may be considered eligible for transplant after a 2-year waiting period or less. Patients with thicker MM and no evidence of lymph node involvement or distant metastasis require at least a 5-year waiting period. Patients with lymph node

Figure 26.5. Treatment algorithm for malignant melanoma. LND, lymph node dissection; SLN, sentinel lymph node.

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involvement or metastatic disease are not generally candidates for transplantation. Similar guidelines have been proposed for donors. After a recurrent or de novo MM develops in an immunosuppressed transplant recipient, it should be treated with wide local excision with the surgical margin dictated by the Breslow depth: 0.5-cm margins for MMIS, 1-cm margins for MM <1 mm, 2-cm margins for MM of 1–2 mm, and 2- to 3-cm margins for MM >2 mm. Complete staging with SLN examination for MM greater than 1 mm in Breslow depth is strongly recommended as such information may alter recommendations regarding a decrease in immunosuppression and other adjuvant treatment. Therapeutic lymph node dissection should be strongly considered if SLN are positive. In all clinical scenarios, a decrease in the level of immunosuppression should be discussed with the transplant team and patient. Risk of death from MM versus the risk of loss of the transplanted allograft or death due to rejection of the allograft must be considered. If the patient is on a standard immunosuppression protocol and a decrease in dosage would not put the transplanted allograft at risk, such a decrease should be strongly encouraged. If the patient has an advanced-stage MM with a poor prognosis, a more substantial decrease in immunosuppression must be considered, while considering the risk to the graft versus the possible benefit.[32] Renal transplant recipients can medically tolerate a greater risk of organ rejection with a decrease of immunosuppression because renal failure can be treated with dialysis. Rejection in cardiac and liver transplant recipients will result in death. In cases of advanced MM, a combination of all or several of the following treatment options may be considered in addition to surgical therapy: decrease or withdrawal of immunosuppression, removal of the allograft, interferon, chemotherapy, radiotherapy, and vaccine therapy (if immunosuppression has been withdrawn). Patients with donortransmitted MM have been reported to have improved outcomes if immunosuppression is decreased or withdrawn and the transplanted allograft is removed.[7,18,27] One report showed cure of a donor-derived metastatic MM in a renal transplant recipient after treatment with immunosuppression withdrawal and systemic interferon-a, followed by allograft removal, treatment with tumor vaccine of cultured melanoma cells, pooled allogeneic cell vaccination, and adoptive immunotherapy using lymphokine-activated killer T cells.[33] Cardiac and liver transplant recipients would require retransplantation if their allograft was removed. Although successful retransplantation has been reported,[33,34] this practice is incredibly controversial because it is unclear if removal of the allograft seeded with MM will provide a definitive cure. Current treatment recommendations are based on the guidelines established for the general population with alterations for existing data regarding MM in the transplant population (Figure 26.5). One transplant recipient stated that it was ‘‘difficult to balance the tremendous value of the kidney [he] received against [his] possible increased risk of recurrence of a malignancy which would be life-threatening.’’[35]

It must be remembered that treatment providing the best overall survival may not always equate with the best quality of life for the transplant recipient. Every case must be treated on an individual basis. Extreme caution should be taken with this aggressive cancer, but irrational fear cannot dictate care – such fear could keep a life-saving transplant from an appropriate recipient or keep an appropriate donor from giving the gift of life.

REFERENCES

1. Hussussian CJ, Struewing JP, Goldstein AM, Higgins PA, Ally DS, Sheahan MD, et al. Germline p16 mutations in familial melanoma. Nat Genet. 1994;8:15–21. 2. Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet. 1996;12:97–9. 3. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002 Jun 27;417:949–54. Epub 2002 Jun 9. 4. Greene MH, Young TI, Clark WH Jr. Malignant melanoma in renaltransplant recipients. Lancet. 1981;1:1196–9. 5. Penn I. Malignant melanoma in organ allograft recipients. Transplantation. 1996;61:274–8. 6. Leveque L, Dalac S, Dompmartin A, Louvet S, Euvrard S, Catteau B, et al. Melanoma in organ transplant patients [French]. Ann Dermatol Venereol. 2000;127:160–5. 7. Le Mire L, Hollowood K, Gray D, Bordea C, Wojnarowska F. Melanomas in renal transplant recipients. Br J Dermatol. 2006;154: 472–7. 8. National Cancer Institute [homepage on the Internet]. 51-Year trends in U.S. cancer death rates [cited 2006 Apr 10]. Available from: http://seer.cancer.gov/csr/1975_2000/results_merged/topic_inc_mor trends.pdf. 9. Penn I. Transmission of cancer from organ donors. Ann Transplant. 1997;2:7–12. 10. Penn I. Transmission of cancer from organ donors [short survey]. Nefrologia. 1995;15:205–13. 11. Stephens JK, Everson GT, Elliott CL, Kam I, Wachs M, Haney J, et al. Fatal transfer of malignant melanoma from multiorgan donor to four allograft recipients. Transplantation. 2000;70:232–6. 12. Birkeland SA, Storm HH. Risk for tumor and other disease transmission by transplantation: a population-based study of unrecognized malignancies and other diseases in organ donors. Transplantation. 2002;74:1409–13. 13. Kauffman HM, McBride MA, Delmonico FL. First report of the United Network for Organ Sharing Transplant Tumor Registry: donors with a history of cancer. Transplantation. 2000;70: 1747–51. 14. Lindelof B, Sigurgeirsson B, Gabel H, Stern RS. Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol. 2000;143:513–9. 15. Hollenbeak CS, Todd MM, Billingsley EM, Harper G, Dyer AM, Lengerich EJ. Increased incidence of melanoma in renal transplantation recipients. Cancer. 2005;104:1962–7. 16. Birkeland SA, Storm HH, Lamm LU, Barlow L, Blohme I, Forsberg B, et al. Cancer risk after renal transplantation in the Nordic countries, 1964–1986. Int J Cancer. 1995;60:183–9. 17. Penn I. De novo malignancies in pediatric organ transplant recipients. Pediatr Transplant. 1998;2:56–63. 18. Sheil AG. Donor-derived malignancy in organ transplant recipients. Transplant Proc. 2001;33:1827–9.

MALIGNANT MELANOMA IN ORGAN TRANSPLANT RECIPIENTS

19. Veness MJ, Quinn DI, Ong CS, Keogh AM, Macdonald PS, Cooper SG, et al. Aggressive cutaneous malignancies following cardiothoracic transplantation: the Australian experience. Cancer. 1999;85:1758–64. 20. Sheil AG, Flavel S, Disney AP, Mathew TH, Hall BM. Cancer incidence in renal transplant patients treated with azathioprine or cyclosporine. Transplant Proc. 1987;19:2214–6. 21. Bouwes Bavinck JN, Hardie DR, Green A, Cutmore S, MacNaught A, OÕSullivan B, et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia: a follow-up study. Transplantation. 1996;61:715–21. 22. Smith CH, McGregor JM, Barker JN, Morris RW, Rigden SP, MacDonald DM. Excess melanocytic nevi in children with renal allografts. J Am Acad Dermatol. 1993;28:51–5. 23. Szepietowski J, Wasik F, Szepietowski T, Wlodarczyk M, SobczakRadwan K, Czyz W. Excess benign melanocytic naevi in renal transplant recipients. Dermatology. 1997;194:17–9. 24. MacKie RM, Reid R, Junor B. Fatal melanoma transferred in a donated kidney 16 years after melanoma surgery. N Engl J Med. 2003;348:567–8. 25. Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19:3622–34. 26. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19: 3635–48. 27. Morris-Stiff G, Steel A, Savage P, Devlin J, Griffiths D, Portman B, et al, Welsh Transplantation Research Group. Transmission of donor

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melanoma to multiple organ transplant recipients. Am J Transplant. 2004;4:444–6. Elder GJ, Hersey P, Branley P. Remission of transplanted melanoma: clinical course and tumour cell characterisation. Clin Transplant. 1997;11:565–8. Buell JF, Trofe J, Hanaway MJ, Lo A, Rosengard B, Rilo H, et al. Transmission of donor cancer into cardiothoracic transplant recipients. Surgery. 2001;130:660–6. Ramsay HM, Fryer AA, Hawley CM, Smith AG, Harden PN. Nonmelanoma skin cancer risk in the Queensland renal transplant population. Br J Dermatol. 2002;147:950–6. Webb MC, Compton F, Andrews PA, Koffman CG. Skin tumours posttransplantation: a retrospective analysis of 28 yearsÕ experience at a single centre. Transplant Proc. 1997;29:828–30. Otley CC, Berg D, Ulrich C, Stasko T, Murphy GM, Salasche SJ, et al, Reduction of Immunosuppression Task Force of the International Transplant Skin Cancer Collaborative and the Skin Care in Organ Transplant Patients Europe. Reduction of immunosuppression for transplant-associated skin cancer: expert consensus survey. Br J Dermatol. 2006;154:395–400. Suranyi MG, Hogan PG, Falk MC, Axelsen RA, Rigby R, Hawley C, et al. Advanced donor-origin melanoma in a renal transplant recipient: immunotherapy, cure, and retransplantation. Transplantation. 1998;66:655–61. Loren AW, Desai S, Gorman RC, Schuchter LM. Retransplantation of a cardiac allograft inadvertently harvested from a donor with metastatic melanoma. Transplantation. 2003;76:741–3. Sorscher SM. Withdrawal of immunosuppressive therapy after developing melanoma. J Am Acad Dermatol. 2004;50:802.

27 Merkel Cell Carcinoma in Organ Transplant Recipients

Paul Nghiem, MD, PhD and Natalia Jaimes, MD

INTR ODUCT IO N

incidence of 0.44 per 100,000 or about a thousand cases per year in the United States.[4,5] The important risk factors for MCC are age greater than 65 years, fair skin, prolonged sun exposure and profound ongoing immunosuppression. Several studies have documented a roughly tenfold increase in MCC after solid organ transplantation.[6] 68% of organ transplant recipients develop lymph node metastases if they have an MCC versus approximately 20% of organ transplant patients if they are diagnosed with a melanoma.[7] Overall survival is also much poorer in this population after MCC than melanoma. There is a 60% MCCspecific death rate in the OTRs as compared to 29% in melanoma patients who have undergone transplantation.[7,3] As further evidence of the important role of the immune system in MCC, the ratio of MCC to melanomas in the general population is 1:65, and this is increased in the organ transplant population to 1 MCC for every 6 melanomas.[6] The age at presentation for MCC is markedly diminished among transplant patients compared with the general population. The median age in the general population for MCC diagnosis is 70 years of age with only 5% of cases presenting in patients less than 50 years of age. Among transplant patients, however, 29–49% of MCC presents in patients younger than 50 years of age.[7,3] The median delay from the start of iatrogenic immunosuppression until when MCC appears is roughly seven to eight years.[7,3]. Gender of patients, however, is not altered by immunosuppression with a 2:1 ratio of males to females in the general population and a 2.4:1 ratio of males to females in transplant recipients.[2,7] In other types of cancer there is a question as to whether the drugs themselves, such as cyclosporine, act directly on cancer cells to promote growth or if they work via immune suppression. In the case of MCC, it appears that the key effect is indeed immune suppression rather than a specific medication, given that MCC risk is also markedly increased among HIV-positive patients, who are not receiving iatrogenic immunosuppression with agents such as cyclosporine. Among HIV-positive patients, the relative risk of MCC is approximately 13-fold increased compared with the general population.[8] The fundamental biology of MCC is essentially not known. In general, though, there is no clear tumor suppressor gene or oncogene that has been conclusively implicated. Recurrent chromosomal abnormalities on chromosomes 1, 11, and 12 have been reported in one third of cases and also trisomies of 1, 6, 11, and 18 are associated. In particular, p53 mutations

Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma of the skin that has a higher mortality (approximately 33% at three years) than melanoma in the general population.[1,2] The fact that 8% of MCC cases have been encountered in solid organ transplant recipients (OTRs) indicates a greater than tenfold increased incidence among these patients.[3] This increased risk among transplant patients and a 60% disease-specific mortality of MCC in this population make it an important issue in transplant medicine. Further challenges surrounding MCC include a therapeutic approach that is very different than that employed for other skin cancers, is controversial within the literature, and that is in a state of evolution. Optimal care of MCC in OTRs requires coordination between dermatologists, surgeons, transplant physicians, and radiation and medical oncologists. Compared to most other malignant processes, MCC has a relatively recent history dating to only 1972 when Toker described five cases of ‘‘trabecular cell carcinoma of the skin.’’ The histologic diagnosis of this cancer was difficult until 1978 when Tang and Toker described ‘‘dense core granules’’ on electron microscopy in these tumors. In 1992, a major additional development was the description of antibodies that could detect cytokeratin 20, which is specific for MCC relative to other malignant processes. This new immunohistochemical technique made the diagnosis of MCC much more straightforward. Over the past fifteen years, there has been evidence of rapidly increasing incidence of MCC. A factor that likely contributes to this observed increase in incidence is more accurate recognition of this malignancy, which was sometimes confused with lymphoma or metastatic small cell lung cancer (SCLC) or otherwise undifferentiated carcinoma in the era prior to widespread use of cytokeratin 20 immunohistochemistry. In addition, many of these reported cases likely reflect the increased number of people at risk for this malignancy, particularly those over 65 years of age, with extensive sun exposure, fair skin, and prolonged immunosuppression.

ME R KE L C E LL C A RCI N O M A I N O RG AN TRANSPLANT RECIPIENTS Multiple lines of evidence indicate that the immune system plays an important role in preventing the initial development of MCC as well as in the bodyÕs ability to avoid fatal metastases from a primary MCC. In the general population, the incidence of MCC has tripled since 1986, based on several studies, to an

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were not found in MCC at an elevated rate and thus, direct mutation of p53 likely plays only a minor part in the development of this disease.[9]

C L I N I C AL P R E S E N T A T I O N Frustratingly, there are no unique clinical characteristics or features to identify an MCC in the general population or in transplant recipients. Clinically, these lesions appear as firm, red-to-purple or skin colored, typically non-tender papules or nodules (Figure 27.1 and Figure 27.2). It is rare for them to ulcerate until very late stages. Most patients report rapid growth within the prior one-to-three months and the majority of lesions present when they are less than 2 cm in diameter. Although they tend to present on sun-exposed locations, such as the head, neck, and upper distal arms, this is not a uniform feature and indeed this tumor is not as obviously linked to sun exposure, as for example basal cell carcinoma or squamous cell carcinoma, in terms of distribution. In our own series, 8% of patients presented with MCC on an entirely sun-protected area such as the buttock, vulva, or even subungually. Among solid OTRs, MCC has a similar site distribution to the general population with many noted on the head and neck followed by the upper extremities and trunk.[7,3] However, nodal metastasis at the time of disease presentation is much more common in OTRs, present in 46% of transplant recipients as compared to only about 10% in the general population.[7,3] The nonspecific clinical appearance of MCC is reflected in the initial presumed diagnosis given by the clinician at the time of biopsy. In our patient population, the majority of the presumed diagnoses were in fact benign, with ‘‘cyst/ folliculitis’’ being the single most common presumed diagnosis (36%) followed by nonmelanoma skin cancer (14%), lymphoma and numerous other individual entities such as dermatofibroma, lipoma, or adnexal tumor.

Figure 27.1. Multiple Merkel cell carcinoma metastases in a 70-year-old male renal transplant recipient .

Figure 27.2. Merkel cell carcinoma on the knee of a 70-year-old woman with CLL. Pen marks indicate satellite metastases that developed several months after the primary lesion.

P AT H OL O G Y OF ME R KE L C E LL C A R C IN OM A In general, the histologic differential diagnosis for MCC is that of the ‘‘small blue cell tumors’’ including melanoma, lymphoma, and small-cell carcinoma of the lung. In terms of pathology, there are three characteristic patterns for MCC that all share a similar prognosis. The ‘‘intermediate’’ type is the most common, presenting with uniform small cells, minimal cytoplasm, and pale nuclei. The ‘‘small cell’’ type has an Indian file distribution in a pattern similar to that of small-cell lung carcinoma. Without special stains this small-cell type cannot be histologically distinguished from a metastasis of small-cell carcinoma. The ‘‘trabecular’’ type was the first type to be described but it is, in fact, the least common. It has a netlike or latticelike pattern, and the differential includes metastatic carcinoid tumor. Given these relatively broad and variable presentation patterns, immunohistochemistry is absolutely essential in making this diagnosis. Cytokeratin 20, described in 1992, is a key study to rule in a diagnosis of MCC. This will be positive in a ‘‘perinuclear dot’’ pattern and is essentially sufficient for making a diagnosis of MCC. To distinguish MCC from small-cell lung carcinoma, Thyroid Transcription Factor-1 and cytokeratin-7 are very useful (Table 27.1). Leukocyte common antigen and S-100 can differentiate lymphoma and melanoma, respectively, from MCC (Table 27.1). Importantly, in terms of pathology, although the routine histological appearance can be nonspecific, if immunohistochemistry is done properly, the diagnosis is established without ambiguity. A hallmark of MCC in both the general population and organ transplant patients is its locally aggressive behavior, often with discontiguous lymphatic spread. On careful examination of histologic sections beyond a ‘‘clear’’ margin, it is often possible to demonstrate lymphatic vessels containing isolated MCC cells. This helps to explain the importance of

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Table 27.1 Immunohistochemistry diagnostic panel for Merkel cell carcinoma: CK20 Merkel cell carcinoma Small-cell lung carcinoma Lymphoma Melanoma

CK7 & TTF1

LCA

S100

+ + + +

Note: CK-20 = cytokeratin-20; CK7 = cytokeratin-7; LCA = leukocyte common antigen; TTF1 = thyroid transcription factor 1, is another marker that is increasingly used to distinguish MCC from small-cell lung cancer;its pattern of expression is the same as CK7 among this panel of tumors.

adjuvant radiation therapy (discussed in the following text) to the primary tumor site in securing high rates of local control.

S TA G I N G A ND P R OG N OS I S Presentation with MCC is traditionally divided into three stages. Stage one corresponds to local disease only, stage two is nodal disease, and stage three is extranodal metastatic disease. Similarly to melanoma, in the past few years, sentinel lymph node biopsy (SLNB) has been shown to be important in accurately staging patients with MCC. To date, there are no data about SLNB in transplant recipients. In the general population, however, roughly one third of patients who present clinically with local (Stage one) MCC indeed will be found to have micrometastases in the draining node bed if an SLNB is carried out. As with melanoma, however, there are no data to suggest that performing an SLNB will improve survival. Adjuvant therapy to an involved nodal bed, however, is very important in preventing subsequent recurrence, and several studies suggest that SLNB is a sensitive technique to determine which patients are likely to recur in that node bed. Among transplant recipients, disease-specific survival from MCC is 80% at one year, 49% at three years, and 46% at five years.[3] The prognosis among MCC patients in the general population is highly dependent on stage at presentation. Prognosis is excellent for stage one disease, which is pathologically negative by SLNB. Immunocompetent patients have disease-specific survival rates of over 90% for SLNBnegative disease. Survival falls to about 60% if the patient has microscopic or gross involvement of MCC in the draining lymph node bed.[10] Survival among patients who present with distant metastatic disease is very poor, under 10%.

T R E AT M E N T In general, there are no quality data to guide how immunosuppressed patients with MCC should be managed relative to the general population. The guidelines below are our best assessments from the literature for the general population

and our own experience with over 100 patients. As discussed earlier, the risks of recurrence and death among immunosuppressed patients are significantly higher than in the general population. Given the high risk of death from MCC in this population, it is considered reasonable to attempt to minimize immunosuppressive therapy. This is rational, in that it appears that the immune system plays a role in minimizing the likelihood of metastasis and of death from this cancer. Thus, optimization of the immune system is important in maximizing survival from MCC. Whenever possible, immunosuppressive drugs should be reduced to minimal tolerable doses. Once MCC already has metastasized, it is not clear that decreasing immunosuppressive regimens is beneficial. The goal of surgery for MCC is to obtain negative surgical margins whenever possible. Numerous studies demonstrate that surgery alone, even with wide margins (2–3 cm), has a significant recurrence rate of 15–40% that can be markedly reduced if the primary tumor site is treated with radiation therapy. Therefore, radiation therapy to the primary site should be added in almost all cases of wide local excision or Mohs surgical excision. Extensive wide margins or extremely aggressive surgeries, which may delay radiation therapy are not indicated because radiation is very effective at treating local discontiguous spread of this tumor. MCC has been established to be an extremely radiationsensitive tumor. Indeed, in our series of approximately a hundred patients, we essentially have never had a recurrence in an irradiated field, even in immunosuppressed patients. In contrast, there have been numerous recurrences within and adjacent to surgical fields. Given the fact that side effects of radiation therapy are quite minimal, with mild to moderate fatigue, acute and rapidly resolving erythema, and chronic radiation skin changes, such as alopecia and modest pigmentary changes, we favor treating the primary site with adjuvant radiation in most cases. Radiation is, of course, invaluable in cases where clear margins cannot be obtained or in patients who are not candidates for extensive surgery. Indeed, several reports from the literature as well as many of our own cases suggest that radiation as monotherapy can be effective in obtaining local control. For radiation monotherapy, the recommended dose would be approximately 60 Gray (6,000 cGy). In immunosuppressed patients, it would be prudent to obtain negative margins prior to beginning radiation therapy. Management of nodal MCC should involve surgery and/or radiation therapy to the involved nodal bed. SLNB offers the ability to accurately stage the nodal basin with a low risk of complications. In our practice, for nodal disease we routinely use radiation therapy rather than lymphadenectomy because the side effects typically are less, and we believe the efficacy is better. Chemotherapy can, of course, be used in an adjuvant or palliative manner in MCC. The most common regimen for MCC is that used in small-cell lung carcinoma, typically carboplatin and etoposide.[10] Although adjuvant chemotherapy

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at the time of presentation is administered by some practitioners, we no longer give adjuvant chemotherapy for MCC for the following reasons: 1. A recent study from Memorial Sloan Kettering Cancer Center showed a trend for worse survival among node positive MCC patients who received adjuvant chemotherapy (40% survival n = 23 patients) as compared to node positive patients who did not receive adjuvant chemotherapy (60% survival N = 53). Although this is not statistically significant and subject to referral bias, this finding does not suggest a major benefit for chemotherapy in this disease. 2. Chemotherapy suppresses the immune system (already a major issue in transplant recipients), which is known to be especially important in combating MCC. 3. There is a 4–16% toxic death rate directly due to adjuvant chemotherapy among MCC patients who are on average 70 years of age.[11,12] 4. Adjuvant chemotherapy causes significant morbidity with 60% of patients developing neutropenia and 40% developing fever and sepsis.[13]

5. Chemotherapy decreases quality of life with marked side effects including prolonged fatigue and hair loss. 6. MCC that is recurrent after adjuvant chemotherapy is less responsive to later palliative chemotherapy. For patients with metastatic MCC, we typically recommend radiation first for palliation whenever possible due to its favorable side effect profile and effectiveness at achieving local control. Surgery would be a second choice, with or without radiation. Chemotherapy can be quite useful for palliating MCC that otherwise is inoperable. One should keep in mind that typically MCC usually responds once to chemotherapy with significant shrinkage, but after recurrence, further clinical response is unlikely, even to different agents. A proposed treatment plan summary is shown in Figure 27.3.

S U MMAR Y MCC incidence is rising in the general population, having tripled in the past fifteen years. The fact that transplant recipients

Biopsy of Primary Lesion

Nodes Not Palpable

Nodes Palpable

Sentinel Lymph Node Biopsy excision with negative margin

Biopsy of Palpable Node

SLNB Negative

SLNB Positive

Radiotherapy* to Primary Draining Lymph Node Basin

Biopsy shows MCC

Biopsy does not show MCC

CT Scan of Chest, Abdomen

Excision with negative margin + Radiotherapy* to Primary Draining Lymph Node Basin

CT Scan Negative

CT Scan Positive

Excision with negative margin + Radiotherapy* to Primary Draining Lymph Node

Further Evaluation and Palliative Surgery, Radiotherapy &/or Chemotherapy

*Recommended Radiation Therapy dose (NCCN Guidelines for MCC 2006) 45–50 Gy for: Primary site with negative excision margins Node bed with no palpable disease 55–60 Gy for: Primary site with positive excision margins Node bed with palpable disease (XRT given in 2 Gy fractions, 5 times/week over 4–6 weeks) MCC: Merkel cell carcinoma; SLNB: Sentinel Lymph node biopsy; XRT: Radiation Therapy Figure 27.3. Recommended management algorithm for Merkel cell carcinoma

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have a 10- to 20-fold increase in MCC incidence means this will be a significant problem for patients with chronic immune dysfunction. Initial clinical recognition of this tumor is difficult due to its nonspecific appearance. Especially in an OTR, however, a rapidly growing, nontender nodule on a sun-exposed area should be of concern and should be promptly biopsied. The aggressive nature of MCC among transplant recipients in terms of stage at presentation as well as likelihood of metastasis makes this a vexing challenge that proves lethal for 60% of immunosuppressed patients who develop MCC. A multidisciplinary approach to the management of MCC in organ transplant recipients is optimal.

REFERENCES

1. Nghiem P, Mckee P, Haynes H: Merkel Cell (Cutaneous Neuroendocrine) Carcinoma. Chapter in: Skin Cancer, Atlas of Clinical Oncology, American Cancer Society, Eds A Sober and F Haluska 2001. 2. Agelli M, Clegg LX: Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 2003;49:832–41. 3. Buell JF, Trofe J, Hanaway MJ, Beebe TM, Gross TG, Alloway RR, First MR, Woodle ES: Immunosuppression and Merkel cell cancer. Transplant Proc 2002;34:1780–81. 4. Hodgson NC: Merkel cell carcinoma: changing incidence trends. J Surg Oncol 2005;89:1–4.

5. Pan D, Narayan D, Ariyan S: Merkel cell carcinoma: five case reports using sentinel lymph node biopsy and a review of 110 new cases. Plast Reconstr Surg 2002;110:1259–65. 6. Miller RW, Rabkin CS: Merkel cell carcinoma and melanoma: etiological similarities and differences. Cancer Epidemiol Biomarkers Prev 1999;8:153–8. 7. Penn I, First MR: MerkelÕs cell carcinoma in organ recipients: report of 41 cases.Transplantation 1999;68:1717–21. 8. Engels EA, Frisch M, Goedert JJ, Biggar RJ, Miller RW: Merkel cell carcinoma and HIV infection.Lancet 2002;359:497–8. 9. Schmid M, Janßen K, Dockhorn-Dworniczak B, Metze D, Zelger B, Luger T, Schmid K: p53 Abnormalities are rare events in neuroendocrine (Merkel cell) carcinoma of the skin An immunohistochemical and SSCP analysis. Virchows Archiv 1997;430:233–7. 10. Allen PJ, Bowne WB, Jaques DP, Brennan MF, Busam K, Coit DG: Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol 2005;23:2300–09. 11. Tai PT, Yu E, Winquist E, Hammond A, Stitt L, Tonita J, Gilchrist J: Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases. J Clin Oncol 2000;18:2493–99. 12. Voog EMD, Biron PMD, Martin JPD, Blay JMD, Ph.D.: Chemotherapy for Patients with Locally Advanced or Metastatic Merkel Cell Carcinoma.Cancer 1999;85:2589–95. 13. Poulsen M, Rischin D, Walpole E, Harvey J, Macintosh J, Ainslie J, Hamilton C, Keller J, Tripcony J: Analysis of toxicity of Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans-Tasman Radiation Oncology Group study. Int J of Radiat Oncol Biol Phys 2001;51:156–63.

28 KaposiÕs Sarcoma in Organ Transplant Recipients

Sylvie Euvrard, MD and Jean Kanitakis, MD

INT ROD UCTION

HHV8-seropositive kidney transplant recipients (KTR) have an estimated 23–28% risk of developing KS during the first three years after transplantation.[5] Viral transmission from the donor may also occur. Ten percent of KTR who were HHV8-seronegative before grafting and received their graft from HHV8-seropositive donors developed KS within 26 months of transplantation.[6] The development of KS in different recipients of each of two kidneys from the same donor also strongly supports this mode of transmission. A recent study has further suggested that KS originates from the seeding of donor-derived progenitors [7], Seroconversion occurs mainly within the first three months post transplant. Although HHV8 infection is generally asymptomatic, especially in KTR,[6] primary infection may induce severe pancytopenia and hemophagocytosis.[8] Preliminary results of a French study involving more than 5000 organ transplant recipients show that the risk of HHV8 infection transmitted via organ transplantation is <5% for KTR, but 33% for heart transplant recipients (HTR) and 40% for liver transplant recipients (LTR).[9] The manifestations of HHV8 infection also appear to be more severe after liver transplantation.[10] The fact that not all recipients who are HHV8-seropositive before transplantation, or who show seroconversion thereafter, develop KS, suggests that additional cofactors may be necessary. Several different infections have been found to be associated with KS, [5] but it is unclear if they simply reflect a deeper level of immunosuppression or function as true cofactors. Immunosuppressive treatments may contribute by decreasing immunosurveillance but may also have a direct oncogenic effect.[11] HLA antigen distribution in patients with KS is the same as that of control groups of the same ethnic background. Poor donor-recipient matching also does not seem to be a risk factor for the development of KS.

KaposiÕs Sarcoma (KS) is an angioproliferative condition, the precise nature of which has been long debated. It is still usually classified as a cancer, although with recent advances in virology, it can also be considered to be an opportunistic infection. Classical KS was first described in 1872 in elderly men of Mediterranean origin. An endemic form was subsequently reported in young men in Africa. The epidemic form, described during the early 1980Õs in AIDS patients, affects homosexual men more often than drug abusers (or hemophilic patients). The iatrogenic form, observed after organ transplantation, differs with respect to clinical presentation, demographics, therapeutic options based on considerations involving immunosuppressive drugs and the specific transplanted allograft.[1]

P A T H OGE NE SI S It has been clearly shown that all forms of KS are associated with a herpes virus discovered in 1994, called KS-associated herpesvirus or Human Herpes Virus 8 (HHV8). HHV8 is an oncogenic gamma2-herpesvirus (rhadinovirus) encoding cytokines and regulatory factors involved in malignant transformation of B-cells and endothelial cells, such as K1, vGPCR, kaposin (A, B, C), LANA, vIL-6, and vMIP/vCCLs. HHV8 DNA is present within nearly all KS tissues and occasionally in normal skin of KS patients; however, evidence of HHV8 DNA disappears from scar tissue remaining after the regression of KS lesions. Quantification of HHV8 load within peripheral blood mononuclear cells has been shown to be useful in following disease progression.[2] Persistent viremia may long precede the development of clinical disease. The ethnic distribution of KS, which was initially thought to be linked to genetic susceptibility, in fact reflects the seroprevalence of HHV8 infection in the general populations (<5% in Northern America and France, 4–18% in Italy, and over 50% in central and southern Africa).[3] In Mediterranean regions, the prevalence rate has been shown to increase with age, varying from 9.7% among subjects in the 0–14 year age group to 26.3% for subjects older than 59 years.[4] Several mechanisms may account for KS development after solid organ transplantation. Because most transplant patients who develop KS are HHV8-seropositive before grafting, the disease appears to result from virus reactivation.

E P I DEM IO L OG Y The incidence of posttransplant KS has decreased since 1996; however, transplant recipients continue to face up to a 128fold increased risk as compared with control groups.[1] As with other KS forms, a male predominance exists, men having a 2- to 3-fold higher risk as compared with women.[1,3] Incidence may also depend on the type of allograft. Several series report a higher incidence in LTR as compared with KTR. By contrast, HTR have exhibited a lower risk in comparison to KTR.[1,12] The incidence of KS in organ transplant recipients

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appears to be related to the HHV8 seroprevalence and varies from 0.4–0.5% in western countries to 1.5% in northern Italy, 3.0% in southern Italy, and 4.1% in the Middle East, where KS is the most common tumor in KTR.[3] A recent study in the United States found that the cumulative incidence of KS increased from 0.08% the first year after transplantation to 0.14% three years after transplantation.[13] Most cases of KS occur in patients of Mediterranean, Middle East or African origin, whereas no increased risk has been reported in Chinese and Japanese transplant recipients. The risk is about 5-fold higher in patients born in southern compared with northern Italy.[1] The close association of KS with place of birth (rather than area of living) suggests that HHV-8 acquisition occurs early in life. However, KS is 3-fold more frequent in persons aged 50 years or older at transplantation than those younger than 34, consistent with a continued risk of HHV-8 infection.[4] The mean age at KS development is lower in transplant patients than in the classic form of KS, and pediatric cases do exist. The timing of KS occurrence has changed over time, probably because of the changing pattern of immunosuppressive treatments. Although the disease appeared an average of 2 years post transplant when patients were treated with azathioprine and steroids, KS develops earlier now, usually in the first year post transplant. The risk of developing KS has been reported to be 5-fold higher in the first year than after 5 years;[1] however, late occurrences of KS have been reported (up to 18 years post transplant). Among cyclosporine-treated patients, those receiving the microemulsion formulation (Neoral) have a 4-fold higher KS incidence than patients receiving the initial formulation (Sandimmune).[14] This is probably because Neoral is associated with higher cyclosporine bioavailability and higher levels of immunosuppression. Converting transplant patients treated with Sandimmune for several years to Neoral could favor the development of KS. An HTR we reported developed KS after switching from Neoral to Sandimmune 5 years post transplant and died from extensive disease.[12] In contrast, the annual incidence rates are similar between patients given azathioprine or MMF.

ease in AIDS patients.[12] Skin lesions may be located in scars of various origins, especially in the transplantation scar. Mucosal lesions are associated with skin lesions in 25–30% of patients and may affect the nasal mucosa, palate (Figure 28.3), pharynx, larynx, and conjunctiva. Internal organs are involved in 25–30% of KTR with KS, and 50% of HTR and LTR, most commonly in those who have extensive cutaneous involvement. KS is found most frequently in the gastrointestinal tract, lungs, and lymph nodes, but any organ may be affected, including the allograft. The lesions may be found by thoracoabdominal computed tomography scanning or endoscopic examination. In 10% of cases, the disease is limited to the viscera.

D I A G N O S IS The clinical diagnosis of KS should be confirmed with histology. KS lesions, especially when single, may mimic other vascular proliferations seen in transplant patients, such as pyogenic granuloma, angiosarcoma or bacillary angiomatosis. Cutaneous and visceral lesions of KS show similar pathologic features. The typical histology is seen in fully-developed nodular lesions, and includes a proliferation of variously differentiated vessels admixed with a proliferation of characteristic, eosinophilic spindle cells (KS cells). An inflammatory infiltrate of lymphocytes, plasma cells, extravasated red blood cells and siderophages is usually present. Early lesions (patches/plaques) show a proliferation of vessels with jagged outlines, some degree of hemorrhage, and few spindle cells. Immunohistochemically, KS cells express several antigens of blood- and/or lymphatic endothelial cells: CD34, CD31, podoplanin, LYVE-1, and less

C L I NI C O P A T H O L O G IC F E A T UR E S More than 90% of transplant patients with KS present with skin and/or mucosal lesions. These lesions consist of redpurple, infiltrated, angiomatous plaques and nodules that take on a bluish tinge in black patients. The size and extent of lesions somewhat depends on the level of immunosuppression. Some patients (20% in our experience) may have only one or a few (<5) nodular lesions in a single area of the body; however, in most transplant recipients KS is similar to the classic form with multiple lesions, predominately on the lower limbs (Figure 28.1) and often associated with lymphedema. In more profoundly immunosuppressed patients, the lesions may spread to the trunk and face (Figure 28.2), similar to the dis-

Figure 28.1. Typical plaques of KaposiÕs sarcoma on the soles of a kidney transplant recipient.

KAPOSI’S SARCOMA IN ORGAN TRANSPLANT RECIPIENTS

Figure 28.2. Isolated patch of KaposiÕs sarcoma.

Figure 28.3. KaposiÕs sarcoma of the palate.

consistently von Willebrand factor. Confirmation of KS can be obtained by demonstrating HHV8 within the lesion, either by immunohistochemistry for the LNA-1 antigen (Figure 28.4) or in situ hybridization. HHV8 is absent in the histologic simulators of KS. In ambiguous cases, a negative HHV8 serology can rule out the diagnosis of KS. The course of KS is chronic and in most cases rather indolent, often relating to the level of immunosuppression. The disease may develop or spread with increased immunosuppression and disappear within months after reduction of immunosuppression. Prognosis generally depends on the extent of lesions. Patients with visceral involvement have a much higher mortality (57–78%) compared to those with purely cutaneous disease (11–23%). A fatal outcome appears to be more frequent in HTR as compared to KTR. Overall 5-year survival was found to be 69% [15] but appears lower among HTR.

MANAGEMENT Because immune surveillance appears to play a major role in post-transplant KS, the first therapeutic measure should be

197

Figure 28.4. In situ immunohistochemical detection of HHV-8 (LNA-1 antigen) in a KaposiÕs sarcoma lesion.

minimization of immunosuppression. Reduction of immunosuppression may be achieved by decreasing or withdrawing calcineurin inhibitors and/or antiproliferative agents. Although early publications reported that tapering of immunosuppression led to KS regression in only 17% of cases, more recent figures indicate regression in up to 46% of patients receiving Neoral.[14] The regression of lesions appears related to the extent of immunosuppression reduction and occurs within 3 to 6 months. In most cases, the graft remains functional with lower levels of immunosuppression; however, about 25% of KTR in whom immunosuppression is reduced will lose their graft and return to dialysis.[12,14] In addition to conventional reduction of immunosuppression as a therapeutic strategy for organ transplant recipients with KS, other options are now available. Several authors have observed KS regression after switch from cyclosporine to sirolimus.[11,12] The beneficial effect of this new immunosuppressant on KS may be linked to its antiangiogenic activity related to impaired VEGF production by inhibiting the Aktp70S6 kinase signaling pathway. Furthermore, sirolimus continues to maintain immunosuppression and usually maintains the function of the allograft. Sirolimus is not appropriate for all patients and is not always effective, and thus additional therapeutic strategies may be necessary. If KS becomes lifethreatening, complete discontinuation of the immunosuppressive treatment can be attempted with KTR and some LTR. If this extreme modification of immunosuppressive treatment is ineffective, chemotherapy can be considered with various agents, including vinca alkaloids (vincristine, vinblastine, vindesine), bleomycin or doxorubicin, singly or in various combinations.[3] Interferon (IFN), used in KS in immunocompetent patients, may induce allograft rejection and should be generally avoided. Exceptions may be made for some LTR. Isolated KS lesions can be treated by surgical excision, cryotherapy, or laser. Radiotherapy should be avoided due to the risk of additional cutaneous malignancies. Some antiviral drugs (foscarnet, ganciclovir, cidofovir) have proven in vitro activity against HHV8, but have no effect in vivo on KS. The aim of the treatment should not necessarily be a total

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disappearance of all lesions, because potent chemotherapy or complete weaning of immunosuppression can be overall more deleterious than beneficial.

PR EVENTION Routine HHV8 screening of recipients and donors is not performed because there is currently no rapid, standardized method appropriate to the transplant setting. When available, HHV8 screening should be considered for recipients originating from areas endemic for KS and for living donors from all settings. Preexisting HHV8 infection in recipients or donors does not preclude transplantation but requires close surveillance. Indeed, even retransplantation of patients with previous KS may induce a recurrence of the disease, but this is not always the case.[16] Rapamycin given as an initial immunosuppressant may have a protective effect against development of KS, but this observation needs confirmation. Recipients who are HHV8-seropositive prior to grafting should receive as low a level of immunosuppression as is practical to maintain allograft function. HHV8-seronegative recipients receiving a graft from a HHV8-seropositive donor should be closely monitored clinically and biologically including screening for HHV8 in the blood by PCR. In this setting, the use of preventive treatments, such as foscarnet, which has been reported to be effective in HHV8 primary infection, and/or rituximab, could be beneficial. Additional clinical studies are needed to define the role of such strategies.

REFERENCES

1. Serraino D, Angeletti C, Carrieri MP, et al. KaposiÕs sarcoma in transplant and HIV-infected patients: an epidemiologic study in Italy and France. Transplantation 2005;80:1699–1704.

2. Pellet C, Chevret S, France`s C, et al. Prognostic value of quantitative Kaposi sarcoma-associated herpesvirus load in posttransplantation Kaposi sarcoma. J Infect Dis 2002;186:110–3. 3. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl Med 2003;348:1681–91. 4. Cattani P, Cerimele F, Porta D et al. Age-specific seroprevalence of human herpesvirus 8 in Mediterranean regions. Clin Microbiol Infec 2003;4:274–9. 5. France`s C, Mouquet C, Marcellin AG, et al. Outcome of kidney transplant recipients with previous human herpevirus-8 infection. Transplantation 2000;69: 1776–9. 6. Regamey N, Tamm M, Wernli M, et al. Transmission of Human herpesvirus 8 infection from renal-transplant donors to recipients. N Engl J Med 1998;339:1358–63. 7. Barozzi P, Luppi M, Facchetti F, et al. Post-transplant KaposiÕs sarcoma originates from the seeding of donor-derived progenitors. Nature Medicine 2003;9:554–61. 8. Luppi M, Barozzi P, Rasini V, et al. Severe pancytopenia and hemophagocytosis after HHV-8 primary infection in a renal transplant successfully treated with foscarnet. Transplantation 2002;74:131–2. 9. France`s C, Lebbe C. Maladie de Kaposi du transplante´ dÕorgane: fautil pre´venir, stabiliser ou tenter de gue´rir? Ann Dermatol Venereol 2005;132:839–43. 10. Marcelin AG, Roque-Afonso AM, Hurtova M, et al. Fatal disseminated KaposiÕs sarcoma following human herpesvirus 8 primary infections liver transplant recipients. Liver Transpl 2004;10:295–300. 11. Stallone G, Schena A, Infante B, et al. Sirolimus for KaposiÕs sarcoma in renal-transplant recipients. N Engl J Med 2005;352:1317–23. 12. Becuwe C, Euvrard S, Bosshard et al. Maladie de Kaposi et transplantation dÕorganes: 22 cas. Ann Dermatol Venereol 2005;132:839–43. 13. Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancer after kidney transplantation in the United States. Am J Transplant 2004;4:905–13. 14. Cattaneo D, Gotti E, Perico N et al. Cyclosporine formulation and KaposiÕs sarcoma after renal transplantation. Transplantation 2005; 80:743–8. 15. Woodle ES, Hanaway M, Buell J, et al. Kaposi sarcoma: an analysis of the US and International experiences from the Israel Penn International Transplant Registry. Transplant Proc 2001;33:3660–1. 16. Euvrard S, Kanitakis J, Bosshard S, et al. No recurrence of posttransplantation KaposiÕs sarcoma three years after renal retransplantation. Transplantation 2002;73:297–9.

29 Posttransplant Lymphoproliferative Disorder/Lymphoma in Organ Transplant Recipients

Leslie Robinson-Bostom, MD and Kevan G. Lewis, MD

INT ROD UCTION

the virus disappears. In contrast, in T-cell PTLD, it has been proposed that EBV may infect a subset of T-cells that express the CD21 receptor, the entry point for EBV, which is more commonly found on the surface of B-cells.[2]

Posttransplant lymphoproliferative disorder (PTLD) is a wellknown, serious complication of solid organ transplant recipients (OTRs) or bone marrow (hematopoietic stem cell) transplant recipients. The clinicopathological spectrum ranges from a mononucleosis-like illness or benign lymphoid hyperplasia to an aggressive malignant lymphoma. Although the skin may be involved as a component of disease dissemination, primary localized cutaneous disease is rare.

E P I DEM IO L OG Y PTLD is a disorder of the immunosuppressed state, and the overall incidence has been rising with use of newer, more potent immunosuppressive agents.[2] The incidence of PTLD varies with the age of the allograft and of the recipient, the EBV-seropositivity status of the donor and the recipient, the type of organ transplanted, and the intensity of the immunosuppressive therapy. The risk of developing PTLD is highest during the first year after transplantation and decreases with time.[1] PTLD occurs in pediatric OTRs four times more frequently than in adult OTRs.[2] In pediatric patients, transplant from an EBV-seropositive donor into a seronegative recipient is the most important risk factor in the development of PTLD.[2] As most adults are EBV-seropositive at the time of transplantation, this is less of a problem in adults. PTLD is associated with up to 20% of small-bowel transplants, 4.2%–10% of lung transplants, 2.4– 5.8% of heart–lung transplants, 1%–6.3% of heart transplants, 2%–8% of liver transplants, and 1%–2.3% of kidney transplants.[2] Of note, incidence data are largely derived from small series that lack standardized diagnostic criteria for PTLD. Several studies have examined the effect of different immunosuppressive protocols on the development of PTLD. In one retrospective study of 1537 renal transplant recipients, the addition of cyclosporine to the immunosuppressive regimen resulted in a dramatic increase in the frequency of PTLD from a single documented case to 2.3%. Preliminary data suggested that the use of OKT3 during induction increased the risk of PTLD from 1.3 to 11.4%; however, more comprehensive studies with lower cumulative doses of OKT3 failed to confirm these findings.[1] Similarly, although the use of tacrolimus instead of cyclosporine has been associated with a 2- to 5-fold increase in the risk of developing PTLD, this finding has not been consistently demonstrated.[1,2] The impact of immunosuppressive agents in differing dosages is variable and suggests that the incidence of PTLD may be more closely related to the total level of immunosuppression rather than the specific types of medications used.

P A T H OGE NE SI S The etiology of PTLD is multifactorial. More than 95% of the worldÕs population is infected by Epstein–Barr Virus (EBV). With primary infection, EBV establishes latency in memory B-cells. Immunocompetent individuals mount a humoral immune response producing antibodies that bind to viral membrane proteins and neutralize viral infectivity. A cellular immune response, composed of cytotoxic T-lymphocytes (CTL), is necessary to control primary and latent EBV-infected cells. In the latent state, viral proteins, Epstein–Barr nuclear antigen (EBNA) and latent membrane proteins (LMP), are produced and protect the B-cell from apoptosis while allowing for continued viral replication.[1] In the setting of immunosuppression, the normal CTL response to EBV antigens is impaired, allowing viral replication to continue unabated and leading to cell cycle dysregulation in B-cells and an uncontrolled lymphoproliferative response. When unregulated replication proceeds, the virus can infect adjacent host cells. Viral proliferation leads to expression of EBV-derived oncogenes including synthesis of EBNA and LMP.[2] Persistent immunosuppression and additional mutations may result in transformation from an EBVmediated polyclonal lymphoproliferative disorder to a true, potentially aggressive, monoclonal lymphoma. Mutations in bcl-6 (found in 44% of OTRs), and sporadic mutations in the N-ras, p53, and c-myc genes have been associated with aggressive PTLD.[1] The pathogenesis of EBV-negative PTLD and T-cell PTLD are not clearly defined. In EBV-negative PTLD, a ‘‘hit and run’’ hypothesis for EBV has been suggested.[2] In these cases, EBV may produce preneoplastic cell injury (e.g., DNA mutations); however, after neoplastic cell division begins, 199

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CLINICAL PRESENTATION

mon. The second group, polymorphic PTLD, may manifest with variable B-cell maturation, nuclear atypia, tumor necrosis, and destruction of the tissue architecture (Figure 29.2 and Figure 29.3). Subtypes may be polyclonal, but are more commonly monoclonal. Lymph node or extranodal sites may become involved years after transplantation. Usually a single subtype of EBV is implicated; however, as in early PTLD, oncogene and tumor suppressor gene alterations are lacking.[5] A variable response to reduction of immunosuppression is seen; some patients respond completely, whereas others require treatment. The third group, monomorphic PTLD, corresponds to malignant lymphomas and includes B-cell lymphomas, T-cell lymphomas, Hodgkin lymphoma, Hodgkin lymphoma-like PTLD, and others. Patients present with widespread disease such as bone marrow involvement, have monoclonal disease, contain a single type of EBV, and have alterations of one or more oncogenes or tumor suppressor genes (c-myc, ras, p53, bcl-6).[3,5] Distinguishing polymorphic PTLD from monomorphic may be difficult histologically because features of both may be seen in the same biopsy.

The clinical presentation of PTLD is diverse and variable. Lymph nodes or extranodal tissue at any site may be involved. Early symptoms are often nonspecific, and include fever (50%), lymphadenopathy (30%), malaise, and weight loss.[1,3] In pediatric patients, EBV-associated infectious mononucleosis is the most common presentation and occurs within several weeks post transplant. Fulminant, disseminated multiorgan systemic disease that resembles septic shock has also been reported.[3] PTLD presenting greater than a year post transplant is more likely to be anatomically localized, and is associated with fewer systemic symptoms. Single or multiple lesions may be seen.[4] Common extranodal sites include the central nervous system, gastrointestinal tract, and the allograft.[1,2] Isolated cutaneous involvement is rare, and typically presents as single or multiple, red to violaceous patches, scaling or reticulated plaques, nodules (Figure 29.1), ulcers, or morbilliform eruptions at any site.[5,6,7] In the United States, approximately 85% of cases of PTLD are of B-cell lineage and greater than 80% are associated with EBV infection.[1] Approximately 10–15% are of T-cell lineage, of which only 30% are associated with EBV-infection. Natural killer cells and other hematopoietic cell lineages rarely give rise to PTLD. The World Health Organization categorizes PTLD into three distinct morphologic groups. The first group, early PTLD lesions, includes diffuse B-cell hyperplasias with preservation of the normal tissue architecture and an infectious mononucleosis-like presentation.[1,4,5] This type occurs within the first year after transplantation in younger patients, is nearly always polyclonal, and usually contains multiple EBV-infectious events. Notably, mutations in oncogenes and tumor suppressor genes do not occur. Regression after reduction of immunosuppression, or even spontaneously is com-

Management of PTLD in OTRs is based on case reports and small series. Therapy varies by clinical situation and is tailored to the individual patient. A biopsy is required for diagnosis, including routine hematoxylin and eosin staining, immunochemistry and molecular studies such as fluorescent in-situ hybridization for EBV early RNA and polymerase chain reaction (PCR) for the EBV-genome. Computed tomographic scans of the chest, abdomen, and pelvis, as well as endoscopy, lumbar puncture, pleurocentesis, and paracentesis may also be indicated.[2] Serial evaluation of the patientÕs clinical status, tumor size, clonality, graft function, and PCR to monitor viral

Figure 29.1. Nodules of cutaneous involvement with PTLD.

Figure 29.2. Diffuse dermal infiltrate composed of atypical lymphoid cells in polymorphous PTLD (H & E stain, original magnification 103).

MANAGEMENT

POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER/LYMPHOMA IN ORGAN TRANSPLANT RECIPIENTS

201

Histologic diagnosis of PTLD Staging and WHO classification Localized cutaneous disease EBV-negative

EBV-positive Early PTLD or polymorphic PTLD

Monomorphic PTLD

Reduction of immunosuppresion Surgical excision if practical +/- radiation Remission

Persistent disease

Continue reduced immunosuppression (monitor graft function)

Rituximab

Remission

Persistent disease Chemotherapy Remission

Figure 29.4. Suggested management of localized cutaneous PTLD (B-cell lineage).

Figure 29.3. Polymorphous PTLD with Reed Sternberg-like cells (H & E stain, original magnification 1003).

load are factored into the treatment strategy. To date, there are no universally accepted algorithms for the treatment of isolated localized cutaneous disease.(Figure 29.4) For all categories of PTLD in OTRs, first-line therapy is reduction of immunosuppression, which can lead to tumor regression of polyclonal and monoclonal lesions in 23–50% of patients.[4,8] A stepwise approach to dose reduction is employed by most transplant centers with close monitoring of graft function due to the increased risk of allograft rejection. The concomitant use of antiviral agents is controversial. Both acyclovir and ganciclovir inhibit the lytic phase of EBV replication in vitro; however, they have no effect during the latent period. Most EBV-infected cells within PTLD lesions are transformed B-cells that are not undergoing lytic infection. Therefore, antivirals may only modestly reduce transmission of EBV to previously uninfected cells.[9] Surgical resection is useful for localized lesions, tumor debulking, and management of local complications, with or without radiation. This approach is favored when PTLD is limited to a solitary accessible site such as in isolated localized cutaneous disease. There have been several anecdotal reports of long-lasting complete responses with INF-a, which exerts antiviral, proin-

flammatory, and antiproliferative effects.[9] Unfortunately, allograft rejection is a frequent complication, and may be related to upregulation of HLA-antigen expression in the allograft. Anti-CD20 (rituximab) may also be used as primary therapy. Rituximab aborts the lytic-replicative phase of EBVmediated lymphoproliferation. Currently, a multicenter trial is evaluating the efficacy of rituximab in pediatric and adult patients with PTLD that is refractory to reduction in immunosuppression.[8] Potential complications include secondary infections, tumor lysis syndrome, and impaired immunoglobulin synthesis.[2] Moreover, rituximab does not restore the cellular immune response to EBV, which may be critical for long-term control of EBV-mediated B-cell proliferation.[3] Studies involving newer radioconjugates of anti-B-cell antibodies are also ongoing.[9] Chemotherapy is used for patients with aggressive monoclonal disease or late PTLD. Anthracycline regimens including CHOP or ProMACE-CytaBOM are most commonly employed. In several small series, high rates of complete remission have been reported; however, these were associated with significant toxicity (up to 70%) and mortality.[3] Among hematologic stem cell transplant recipients with EBV-associated PTLD, treatment with in vitro-expanded CTL has been used successfully. In OTRs, use of donor lymphocytes is not possible. Autologous EBV-specific CTL therapy has been studied by several investigators in OTRs. This technique is not widely available.[10]

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For T-cell PTLD, with its globally poor prognosis, reduction of immunosuppressive therapy is insufficient to induce remission. For PTLD-associated mycosis fungoides, standard therapies for mycosis fungoides are employed. Patients with PTLD-associated primary cutaneous CD30-positive large Tcell lymphoma are treated with local radiation therapy or methotrexate. Combination chemotherapy is reserved for lymph node or systemic involvement.[10,11]

PR EVENTION In addition to minimizing levels of immunosuppression, a theoretical approach toward preventing PTLD is to immunize EBV-seronegative recipients prior to transplantation. Several EBV vaccine preparations are currently under development. Unfortunately, avoiding transplantation with an organ from an EBV-seropositive donor into a seronegative recipient is practically difficult because donor EBV serologies are not typically available when an organ is accepted and seropositivity is so prevalent in donor groups. Although many centers continue to use antivirals for three to six months posttransplant, there is little evidence demonstrating a benefit. An ongoing multicenter trial is investigating the use of arginine butyrate to induce latent EBV-thymidine kinase expression followed by treatment with ganciclovir.[11] The use of intravenous immunoglobulin for immunoprophylaxis is also under investigation in a multicenter, randomized, controlled trial.[9] Lastly, monitoring patients for increasing viral load and aggressively treating early disease may prevent progression to symptomatic disease and warrants further study.

REFERENCES

1. Taylor AT, Marcus R, Bradley A. Posttransplant lymphoproliferative disorders (PTLD) after solid organ transplantation. Crit Rev Oncol Hematol 2005;56:155–67. 2. Shroff R, Rees L. The posttransplant lymphoproliferative disordera literature review. Pediatr Nephrol 2004;19:369–77. 3. Gottschalk S, Rooney CM, Heslop HE. Posttransplant Lymphoproliferative Disorders. Annu Rev Med 2005;56:29–44. 4. Andreone P, Gramenzi A, Lorenzini S, Biselli M, Cursaro C, Pileri S, Bernard M. Posttransplantation Lymphoproliferative Disorders. Arch Intern Med 2003;163:1997–2004. 5. Biokx W A.M., Andriessen M P.M., Van Hamersvelt HW, Van Kriehen J H.J.M. Initial Spontaneous Remission of Posttransplantation Epstein-Barr virus related B-cell Lymphoproliferative Disorder of the Skin in a Renal Transplant Recipient, Case Report and Review of the Literature on Cutaneous B-cell Posttransplantation Lymphoproliferative Disease. Am J Dermatopathol 2002;24:414–22. 6. Capaldi L, Robinson-Bostom L, Kerr P, Gohh R. Localized cutaneous posttransplant Epstein-Barr virus-associated lymphoproliferative disorder. J Am Acad Dermatol 2004;51:778–80. 7. Beynet DP, Wee SA, Horwitz SS, Kohler S, Horning S, Hoppe R, Kim YH. Clinical and Pathological Features of Posttransplantation Lymphoproliferative Disorders presenting with skin involvement in 4 Patients. Arch Dermatol 2004;140:1140–46. 8. Paya CV, Fung JJ, Nalesnik MA, Gores G, Habermann TM, Wiesner RH, et al, for the ASTS/ASTP EBV-PTLD Task Force and the Mayo Clinic organized International Consensus Development meeting on Epstein-Barr virus-induced Posttransplant Lymphoproliferative Disorders (PTLD). Epstein-Barr virus-induced Posttransplant Lymphoproliferative Disorders. Transplantation 1999;68:1517–25. 9. Weber S, Green M. Posttransplantation lymphoproliferative disorders. Pediatr Clin N Am 2003;50;1471–91. 10. Lok C, Viseux V, Denoeux JP, Bagot M. Posttransplant T-cell lymphomas. Crit Rev Oncol Hematol 2005;56:137–145. 11. Loren AW, Porter DL, Stadtmauer EA, Tsai DE. Posttransplant lymphoproliferative disorder: a review. Bone Marrow Transplan 2003;31:145–55.

30 Rare Cutaneous Neoplasms in Organ Transplant Recipients

Marcy Neuburg, MD

surgical excision, particularly with Mohs micrographic surgery, and local recurrence following incomplete removal is common. In cases where there is deep extension into the subcutis and underlying fascia and/or muscle, the diagnosis of malignant fibrous histiocytoma should be considered. There are three case reports in the literature of AFX occurring in renal transplant recipients and a single case in a heart transplant patient.[1–4] All four cases describe tumors occurring in heavily sun-damaged skin in patients who had other ultraviolet radiation associated nonmelanoma skin cancers. Although this may be an instance of underreporting, there is no suggestion that the incidence of AFX is increased in transplant recipients or that the biologic behavior of AFX is more aggressive in the setting of chronic immunosuppression.

The previously discussed cutaneous neoplasms seen in solid organ transplant recipients are not only common in the setting of chronic immunosuppression, but also are relatively common in the nontransplant population. Therefore, populationbased studies of incidence and prevalence of these tumors associated with long-term antirejection regimens reveal statistically significant trends that are clinically meaningful in the care of transplant patients. In contrast, large, controlled, statistically significant studies of rare cutaneous neoplasms in both immunocompetent and organ transplant patients are lacking. Rare cutaneous neoplasms are, as the term implies, infrequent observations in immunocompromised as well as immunocompetent hosts. The literature pertaining to these rare tumors is characterized primarily by case reports and summaries of case reports. Table 30.1 lists the rare cutaneous neoplasms that have been reported in transplant recipients, as well as their corresponding biological behavior. Because of their rarity, the relationship between these tumors and the chronic immune suppression of transplantation is tenuous, at best. However, this group of neoplasms is mentioned here both for completeness, as well as the fact that these tumors represent important considerations in the clinical and histologic differential diagnosis of some of the more common neoplasms discussed in this text.

MALIGNANT FIBROUS HISTIOCYTOMA Malignant fibrous histiocytoma (MFH) is a highly malignant spindle-cell neoplasm that is histologically similar to AFX. However, the clinical presentation of MFH is quite different. Most MFHs originate in deeper tissues (skeletal muscle, abdominal cavity, retroperitoneum) with only 7% of tumors confined to the subcutis without fascial involvement.[5] Deep cutaneous MFH may present as an enlarging mass with skin involvement as a late event, occurring via direct extension from a subcutaneous location. Metastasis from MFH is common and is associated with increased tumor depth and size. The largest series of sarcomas in transplant recipients was described by Penn who reported 20 cases of MFH in 8191 organ allograft recipients.[6] Although not specified, these tumors, like most MFHs, were likely noncutaneous in origin. Hafner et al. reported two cases of cutaneous MFH in 642 renal transplant recipients.[2] Although these authors concluded that this observation represents an elevated incidence of cutaneous MFH in the setting of transplant-related immunosuppression, this conclusion is not supported by further examination of the literature. In a recent review, Stein et al. refer to the occurrence of both cutaneous MFH and AFX in transplant recipients as anecdotal.[7].

ATYPICAL FIBROXANTHOMA Atypical fibroxanthoma (AFX) is a tumor of presumed mesenchymal origin that presents as a rapidly growing, sometimes ulcerated nodule on actinically damaged skin of the head and neck region of older individuals (Figure 30.1). AFX is a low-grade malignancy associated with rare reports of metastases to local lymph nodes. Many dermatopathologists believe that AFX is most appropriately classified as a superficial variant of malignant fibrous histiocytoma. The diagnosis of AFX is rarely made on clinical grounds as its initial appearance is usually most suggestive of aggressive squamous cell carcinoma. The light microscopic features of AFX are that of an undifferentiated spindle cell neoplasm located in the papillary and mid-dermis. The important differential diagnoses are other spindle-cell neoplasms including spindle-cell squamous cell carcinoma, spindle-cell melanoma, malignant fibrous histiocytoma, and leiomyosarcoma. The diagnosis of AFX, while often suspected on the basis of clinical and light microscopic findings, must be confirmed with the use of immunohistochemical stains. The treatment of AFX involves

LE IO MYOSAR CO MA Leiomyosarcoma is a malignant spindle-cell neoplasm of smooth muscle origin. Like MFH, most leiomyosarcomas are not cutaneous in location. The most common sites for these 203

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Table 30.1 Rare Cutaneous Neoplasms in Transplant Recipients Rare Cutaneous Neoplasms in Transplant Recipients and associated biologic behavior Atypical Fibroxanthoma Malignant fibrous histiocytoma Leiomyosarcoma Sebaceous carcinoma Microcystic adnexal carcinoma Angiosarcoma Dermatofibrosarcoma protuberans

Risk of local recurrence Low with Mohs surgery Low with cutaneous type Low with cutaneous type Moderate Low High Moderate with excision Low with Mohs surgery

deeply located tumors are the gastrointestinal and uterine smooth muscle. Cutaneous leiomyosarcoma is a very rare neoplasm arising from the arrector pili muscle of the hair apparatus. Cutaneous leiomyosarcoma usually presents as a solitary, firm smooth nodule that is often painful (Figure 30.2). Superficial location (dermis) is associated with excellent prognosis,

Risk of metastasis Low High Low with cutaneous type Moderate Low High Low

although local recurrence following incomplete surgical excision is common. Tumors with deeper extension (subcutis) are prone to metastasis, primarily to the lung. Penn reported 15 leiomyosarcomas in his cohort of 8191 transplant patients in the Israel Penn International Transplant Tumor Registry (IP-ITTR).[6] Five of these occurred in pediatric patients and one in an area of previous irradiation. Reference to cutaneous location is absent in this report. Humphreys reported a single case of a subcutaneous leiomyosarcoma in an immunosuppressed renal transplant patient.[8] The tumor exhibited deep invasion into soft tissue, consistent with its subcutaneous origin. The patient experienced in-transit metastases and amputation of the involved limb resulted in no evidence of disease at three year follow-up. Based on these reports, there does not seem to be an association between long-term immunosuppression in organ transplant recipients and elevated incidence or more aggressive biology of cutaneous leiomyosarcoma.

SEBACEOUS CARCINOMA

Figure 30.1. Clinical appearance of atypical fibroxanthoma.

As the name implies, sebaceous carcinoma originates in the sebaceous glands of the skin. It can occur wherever sebaceous glands are located, most commonly in the periocular region, especially the upper eyelid (Figure 30.3). The specialized sebaceous glands of the tarsal plate (meibomian) and cilia (Zeis) are the primary progenitors of this highly malignant tumor. The so-called pagetoid variant of sebaceous carcinoma may share common histologic features with other entities including melanoma, extramammary PagetÕs disease, and BowenÕs Disease. Although the periocular location is highly characteristic, special stains may be required to distinguish between sebaceous carcinoma and other tumors. Furthermore, other tumors such as squamous cell carcinoma and basal cell carcinoma may display sebaceous differentiation. In nonocular locations, the distinction between these latter entities and sebaceous carcinoma may be challenging. Sebaceous carcinoma is one of the sebaceous neoplasms which may be associated with the autosomal dominantly transmitted Muir–Torre Syndrome (MTS). However, the vast majority of these tumors are sporadic rather than genetic

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Figure 30.3. A. Clinical appearance of sebaceous carcinoma of eyelid. B. Clinical appearance of extraocular sebaceous carcinoma. Figure 30.2. Clinical appearance of cutaneous leiomyosarcoma.

in nature. As part of a larger retrospective study looking at cutaneous appendageal tumors in organ transplant recipients and immunocompetent individuals, Harwood, et al. concluded that transplant recipients were more likely to have appendageal tumors that were both malignant and sebaceous in origin compared to immunocompetent hosts.[9] These authors speculate that ‘‘immunosuppressive drugs, UV radiation, genetic factors, and HPV infection are plausible contributory factors.’’ Interestingly, none of the sebaceous carcinomas in this study were periocular in location nor did the tumors in this study exhibit the aggressive biology and high metastatic rate associated with the periocular variant. Harwood et al. have also described the finding of an increased incidence of microsatellite instability of DNA taken from sebaceous neoplasms in transplant recipients, similar to that reported for MTS.[10] The exact clinical significance of this finding requires further investigation.

M I C R O C Y S T I C A D E N E X AL C A R C I N O M A Microcystic adnexal carcinoma (MAC) is a rare skin neoplasm of disputed etiology. Both eccrine and apocrine origins

have been proposed. This tumor presents most commonly on the upper lip or central face of mature, Caucasian women (Figure 30.4). It is slow growing and prone to extensive subclinical extension making complete removal quite challenging. There have been sporadic published cases of MAC in transplant recipients but no increase in prevalence has been documented.[9,11]

ANGIOSARCOMA Angiosarcoma is a rare malignant neoplasm of endothelial origin. There are two types of angiosarcoma. The most common type is noncutaneous and arises in areas of chronic lymphedema. The rare cutaneous form typically presents on the upper face or scalp of elderly males and is associated with a generally poor prognosis (Figure 30.5). The first case of angiosarcoma of the scalp in a transplant recipient was reported by Kibe et al. in 1997.[12] More recently, Ahmed and Hamacher reported 13 cases of angiosarcoma in renal transplant recipients based on literature review.[13] Of these 13 cases, only 4 showed cutaneous involvement. Additionally, in 5 of the cases, the noncutaneous tumor arose in

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MARCY NEUBURG

Figure 30.6. Clinical appearance of dermatofibrosarcoma protuberans.

D E R M A T O F I B R O S A R C O M A PR O T U B E R A N S

Figure 30.4. A. Clinical appearance of microcystic adnexal carcinoma. B. Postoperative defect after removal of clinically subtle microcystic adnexal carcinoma.

Dermatofibroma protuberans (DFSP) is a rare, low-grade sarcoma of fibrohistiocytic origin. It is frequently present for several years prior to diagnosis. Typical locations are head and neck, trunk, and proximal extremities. Biopsy usually follows the appearance of single or multiple nodules within or around a longstanding flat, firm scarlike plaque (Figure 30.6). In PennÕs review, which represents the largest series of sarcomas in transplant recipients, no DFSPs were reported. Picciotto et al. reported a case of DFSP occurring adjacent to an arteriovenous fistula five years after a renal transplant.[14] Two other reports describe single cases of classic DFSP (chin, shoulder) in renal transplant recipients.[15,16]

SUM MARY

Figure 30.5. Clinical appearance of very early cutaneous angiosarcoma.

association with an arteriovenous fistula site. Whether the latter observation is associated with the fistula microenvironment (akin to that of chronic lymphedema) or the direct result of prolonged immunosuppression is unclear. In sum, there does not seem to be an increased incidence of cutaneous angiosarcoma in transplant recipients.

In summary, rare tumors of the skin have been reported in transplant recipients. Most of these are single patient case reports of an anecdotal nature. Although Penn has demonstrated an increased incidence of non-KaposiÕs sarcomas in transplant patients, his data subdivides the tumors into internal and soft-tissue sites with no mention of cutaneous locations. Similarly, Husted et al. performed an updated (1985–2000) review of the IP-ITTR registry population.[17] Excluding KaposiÕs sarcoma, they found 27 de novo sarcomas (some of which were previously reported by Penn, 1968– 1995). Examining multiple factors, they found that compared to immunocompetent population statistics, the sarcomas in the transplant group were more likely to be of high-grade histology, metastatic at the time of diagnosis, located on the head and neck, and associated with diminished survival rates at five years. Again, the authors did not draw distinctions between sarcomas of the skin and those arising in deep soft tissues. HarwoodÕs data suggests the possibility that there is an overrepresentation of malignant appendageal tumors of sebaceous origin in transplant recipients. However, the patients in

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HarwoodÕs study suffered low morbidity and did not share patient demographics associated with sebaceous carcinoma in immunocompetent hosts such as periocular location, female gender, Asian phenotype, and high metastatic rate. Unlike the aggressive biologic behavior observed for more common nonmelanoma skin cancers in OTRs, there is no evidence to suggest that rare cutaneous neoplasms occur with increased frequency, follow a more aggressive course or occur at a younger age in patients on long-term immunosuppression for organ transplantation.

REFERENCES

1. Kanitakis J. Euvrard S. Montazeri A. Garnier JL. Faure M. Claudy A. Atypical fibroxanthoma in a renal graft recipient. J Am Acad Dermatol 1996;35:262–4. 2. Hafner J. Kunzi W. Weinreich T. Malignant fibrous histiocytoma and atypical fibroxanthoma in renal transplant recipients. Dermatology 1999;198:29–32. 3. Perrett CM. Cerio R. Proby CM. Harwood CA. Atypical fibroxanthoma in a renal transplant recipient. Histopathology 2005;47:326–7. 4. Paquet P. Pierard GE. Invasive atypical fibroxanthoma and eruptive actinic keratoses in a heart transplant patient. Dermatology 1996;192: 411–3. 5. Weiss SW. Enzinger FM. Malignant fibrous histiocytoma: an analysis of 200 cases. Cancer 1978;41:2250–66. 6. Penn I. Sarcomas in organ allograft recipients. Transplantation 1995; 60:1485–91. 7. Stein A. Hackert I. Sebastian G. Meurer M. Cutaneous malignant fibrous histiocytoma of the scalp in a renal transplant recipient. Br J Dermatol. 2006;154:183–5.

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8. Humphreys TR. Finkelstein DH. Lee JB. Superficial leiomyosarcoma treated with Mohs micrographic surgery. Dermatol Surg 2004;30: 108–12. 9. Harwood CA. McGregor JM. Swale VJ. Proby CM. Leigh IM. Newton R. Khorshid SM. Cerio R. High frequency and diversity of cutaneous appendageal tumors in organ transplant recipients. J Am Acad Dermatol 2003;48:401–8. 10. Harwood CA. Swale VJ. Bataille VA. Quinn AG. Ghali L. Patel SV. Dove-Edwin I. Cerio R. McGregor JM. An association between sebaceous carcinoma and microsatellite instability in immunosuppressed organ transplant recipients. J Invest Dermatol 2001;116: 246–53. 11. Snow S. Madjar DD. Hardy S. Bentz M. Lucarelli MJ. Bechard R. Aughenbaugh W. McFadden T. Sharata H. Dudley C. Landeck A. Microcystic adnexal carcinoma: report of 13 cases and review of the literature. Dermatol Surg 2001;27:401–8. 12. Kibe Y. Kishimoto S. Katoh N. Yasuno H. Yasumura T. Oka T. Angiosarcoma of the scalp associated with renal transplantation. Br J Dermatol 1997;136:752–6. 13. Ahmed I. Hamacher KL. Angiosarcoma in a chronically immunosuppressed renal transplant recipient: report of a case and review of the literature. Am J Dermatopathol 2002;24:330–5. 14. Picciotto F. Basolo B. Massara C. Caliendo V. Aloi F. Gaia S. Bayle F. Quarello F. Dermatofibrosarcoma protuberans at the site of arteriovenous fistula in a renal transplant recipient. Transplantation 1999; 68:1974–5. 15. Brown VL. Proby CM. Harwood CA. Cerio R. Dermatofibrosarcoma protruberans in a renal transplant recipient. Histopathology 2003; 42:198–200. 16. Lai KN. Lai FM. King WW. Li PK. Siu D. Leung CB. Lui SF. Dermatofibrosarcoma protuberans in a renal transplant patient. Aust N Z J Surg 1995;65:900–2 17. Husted TL. Buell JF. Hanaway MJ. Trofe J. Beebe T. Gross T. First MR. Woodle ES. De novo sarcomas in solid organ transplant recipients. Transplant Proc 2002;34:1786–7.

31 Histopathologic Features of Skin Cancer in Organ Transplant Recipients

Kevan G. Lewis, MD and Leslie Robinson-Bostom, MD

A C T I N I C K ER A T O S I S

ABBREVIATIONS

BCC HPV NMSC OTR SCC

basal cell carcinoma human papilloma virus nonmelanoma skin cancer organ transplant recipient squamous cell carcinoma

Investigation of premalignant lesions including actinic keratoses in the setting of organ transplantation has demonstrated distinctive histopathologic features. A retrospective histopathologic review of 80 biopsy specimens from OTRs and nonimmunosuppressed controls that were clinically suspicious for malignancy and diagnosed histopathologically as actinic keratoses was performed.[2] Actinic keratoses arising in OTRs were significantly more likely to exhibit bacterial colonization, confluent parakeratosis, and hyperkeratosis. Verrucous changes (including papillomatosis, vascular proliferation, streaming parakeratosis, and koilocytic changes) were also more frequent. (Figure 31.1 and Figure 31.2) A greater degree of mitotic activity was observed in the transplant group and may be a harbinger of evolution to SCC. Although many biopsy specimens showed features of acantholysis, cytologic atypia (including dyskeratotic keratinocytes, epidermal monster cells, pagetoid spread, and atypical mitoses), basal cell layer proliferation, adnexal involvement, Demodex mite and Pityrosporum colonization, and a dermal inflammatory infiltrate, the proportion of cases exhibiting these findings was similar between groups.[2]

INTR ODUCT IO N The histopathology of epidermal neoplasms arising in the solid organ transplant population is most remarkable for the diversity of features exhibited, much more so than adherence to a rigid set of microscopic criteria. Histologic evaluation is a critical step in the management of cutaneous neoplasms, as microscopic evidence of aggressive behavior impacts prognosis and guides therapeutic decisions. Unfortunately, it has been demonstrated that the diagnosis of neoplastic lesions based on clinical features may correlate poorly with that rendered after histopathologic examination, suggesting that histologic examination is an important step in rendering the most appropriate treatment for skin cancer.[1] In this brief overview of the histopathologic features of transplant skin disease, the most common epidermal neoplasms including actinic keratosis, SCC, BCC, and melanoma are explored in detail. Photomicrographic examples of these common neoplasms are displayed in Figure 31.1–Figure 31.8. A multitude of other benign and malignant neoplasms also have been reported in the transplant population including cases of Merkel cell carcinoma, KaposiÕs sarcoma, atypical fibroxanthoma, leiomyosarcoma, angiosarcoma, porokeratosis with malignant transformation, and sebaceous carcinoma. Histopathologic investigation of these entities has been limited or unremarkable, however, and they will not be discussed further. Although numerous reports describe a range of histopathologic features observed in epidermal tumors of organ transplant recipients (OTRs), large-scale prospective studies confirming the prognostic significance of these findings are lacking generally. In addition, the literature is frequently inconsistent and contradictory. As a result, transplant dermatopathology relies heavily on data derived from more substantial studies performed in nonimmunosuppressed patients. Therefore, seminal reports of skin cancer in nonimmunosuppressed patients are presented en face in order to contextualize the results from studies performed in OTRs.

SUM MARY Verrucous features occur frequently in actinic keratoses and other squamoproliferative lesions including SCC in the setting of organ transplantation. In addition, viral warts commonly have foci of atypia usually described in SCC and are consistent with early malignant transformation. The presence of HPV in premalignant and malignant keratinocyte neoplasms is well known and likely accounts for these findings.[1]

SQUAMOUS CELL CARCINOMA Squamous cell carcinoma is the most common cutaneous malignancy in the posttransplant setting. Histopathologic evaluation of SCC in OTRs frequently demonstrates evidence of aggressive behavior. An early retrospective case review of 29 OTRs with 54 biopsy specimens of keratotic lesions reported that premalignant and malignant squamous lesions were more pleomorphic than routinely observed.[1] In particular,

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HISTOPATHOLOGIC FEATURES OF SKIN CANCER IN ORGAN TRANSPLANT RECIPIENTS

Figure 31.1. Actinic keratosis with intracorneal septate hyphae indicative of fungal coinfection (H & E stain, original magnification 203).

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Figure 31.3. Squamous cell carcinoma, in situ, with Bowenoid features (H & E stain, original magnification 203).

Figure 31.2. Proliferative actinic keratosis with verrucous features and minimal cytologic atypia of the overlying epidermis (H & E stain, original magnification 103).

features of multinucleated keratinocytes, ‘‘monster cells’’ or large dyskeratotic keratinocytes with abundant eosinophilic cytoplasm, and large hyperchromatic keratinocyte nuclei with vesicular chromatin and prominent nucleoli were observed commonly, similar to the findings described in actinic keratoses. Although the number of mitotically active keratinocytes was increased, the degree of cytologic atypia did not appear to correlate with a specific regimen (drug or dosage) of immunosuppressive therapy. These findings were consistent and predictable; the investigators reported 80–90% accuracy in differentiating in situ SCCs arising in OTRs from a control group of otherwise healthy adults.[1] A larger prospective observational study (n = 291) of OTRs who underwent full-body skin examination by a dermatologist reported that 331 lesions appeared clinically suspicious for SCC and underwent biopsy.[3] Under histopathologic exam-

Figure 31.4. Squamous cell carcinoma demonstrating BowenÕs disease with invasion (H & E stain, original magnification 103)

ination, specimens from 17% of patients showed features of actinic keratosis, 12% showed in situ (Figure 31.3) or invasive SCC, 59% showed benign warty (verrucous) keratosis, and 12% showed viral warts. Additionally, nearly two thirds of patients with histopathologic evidence of actinic keratoses also

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Figure 31.7. Basal cell carcinoma, superficial multicentric type (H & E stain, original magnification 203).

Figure 31.5. Squamous cell carcinoma demonstrating perineural invasion (H & E stain, original magnification 203).

Figure 31.6. In-transit metastatic squamous cell carcinoma with acantholytic pattern (H & E stain, original magnification 103).

had in situ or invasive SCC in other locations.[3] These findings suggest that the positive predictive value of a clinical diagnosis of SCC may be lower in OTRs, perhaps attributable to the propensity to form exuberant viral warts and seborrheic keratoses with verrucous architecture, as well as the often observed ‘‘field effect’’ of diffuse areas of widespread keratotic lesions. In addition, the frequent coexistence of SCC in patients with actinic keratoses suggests that thorough and frequent surveillance with full-body skin examinations may be indicated once a histopathologic diagnosis of a premalignant lesion is made. A large prospective observational study catalogued the histopathologic features of SCC observed in 697 patients including 79 OTRs.[4] The proportion of tumors demonstrating acantholysis, BowenÕs disease with invasion, (Figure 31.4), and dermal invasion from the basilar layer despite evidence of minimal atypia in the overlying epidermis were all significantly more common in OTRs. An infiltrative pattern marked by

Figure 31.8. Basal cell carcinoma with nodular and infiltrative patterns (H & E stain, original magnification 103).

downward migration between collagen bundles or within the adventitia of blood vessels, adnexal structures, or nerves was also more frequent in the transplant group. Desmoplastic features, increased angiogenesis, and moderate to poor cellular differentiation (Broder grades 3–4) were common.[4] Tumors of intermediate thickness (2–5 mm depth) occurred more frequently in OTRs compared to nonimmunosuppressed patients, a finding that strongly supports the need for close follow-up and increased surveillance in the high-risk transplant population.

HISTOPATHOLOGIC FEATURES OF SKIN CANCER IN ORGAN TRANSPLANT RECIPIENTS

A recent report of 100 cases of SCC from OTRs and nonimmunosuppressed controls examined the histopathologic features thought to be associated with immunosuppression.[5] Spindle-cell morphology (diffuse or focal) with fascicles of elongated cells, prominent nuclear pleomorphism, atypical mitotic figures, and overlying ulceration were significantly more common in OTRs, occurring in nearly 20% of cases. The magnitude of inflammatory infiltrate was significantly less in OTRs. Features of concomitant HPV infection including architectural symmetry with papillomatosis and acanthosis, inwardly pointing rete ridges, hyperkeratosis with tiers of parakeratosis, dilated capillaries in the dermal papillae, hypergranulosis, and koilocytosis were more common among OTRs, although the trend did not reach statistical significance. Among transplant patients, the average depth of invasion (2.63 mm) and the frequency of tumors exhibiting poor differentiation (43%, BroderÕs classification grades 3–4), perineural invasion (3%) (Figure 31.5), ulceration (22%), acantholysis (42%), or single cell invasion (13%) was remarkable, but did not differ significantly between groups.[5] The propensity for SCC to recur locally and metastasize remotely during the posttransplant period is well documented. Histopathologic evidence to support this clinical observation is limited, however. A case series of OTRs who developed intransit metastasis (Figure 31.6) from cutaneous SCC reported that a similar proportion of metastatic lesions was well-differentiated (58%) compared to poorly-differentiated (42%).[6] This finding suggests that histopathologic features of cellular maturation are not predictive of biologic behavior. In addition, conventional wisdom suggests that subclinical extension of NMSC may be greater in OTRs and result in recurrence and metastasis more frequently, although a small study of eight OTRs failed to confirm this clinical observation.[7] Statistical testing of stratified subgroups was limited by sample size, however. Nevertheless, both groups demonstrated clinically meaningful subclinical extension of NMSC (4.1 mm in OTRs and 3.3 mm in controls). A comprehensive systematic review of the literature (1940–1992) and meta-analysis of histopathologic factors associated with recurrence and metastasis of SCC independent of immune status has been performed.[8] Deeply invasive (>4 mm) SCC was noted to recur locally in 17% of cases and metastasize in 46%, compared to superficially invasive (<4 mm) SCC which demonstrated local recurrences (5%) and metastases (7%) less frequently. Poorly differentiated SCC (Broders grade 3 and 4) was associated with local recurrence in 29% of cases and metastasis in 33% whereas well-differentiated tumors recurred locally in 14% of cases and metastasized in 9%. Subgroup analysis of immunosuppressed patients (including OTRs) estimated the overall rate of metastasis from SCC at 13%, attributable to the increased aggressive behavior of tumors observed in this population. Overall, the cure rate following Mohs surgery was substantially higher (97% for well-differentiated SCC, 67% for poorly differentiated SCC) compared to surgical excision (81% and 46%, respectively). The cure rates for SCC in OTRs treated with Mohs surgery

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have not been studied. Similarly, the rates of local recurrence (<1%) and metastasis (8.3%) of tumors with perineural invasion were markedly better following Mohs surgery compared to surgical excision (47% and 47%, respectively).[8] Although large studies of OTRs have yet to be reported, robust data on survival from SCC based on histopathologic criteria derive from a prospective observational cohort study of 210 nonimmunosuppressed patients.[9] Two hundred seventy-seven cases of SCC were diagnosed of which 14% showed perineural invasion, 11% showed lymphatic or vascular invasion, and 16% showed deep invasion beyond the subcutaneous tissues. Disease-specific survival at 3 years was significantly reduced in the presence of deep invasion beyond subcutaneous tissue (73% vs. 88%), perineural invasion (64% vs. 91%), lesion size (>4cm, 67% vs. <4 cm, 93%) and greater depth of invasion (>7mm, 78% vs. <7 mm, 85%).[9]

S U MMAR Y The histopathologic features of SCC in OTRs are variable. Epidermal hyperplasia and keratinocyte atypia are requisite findings that are commonly accompanied by architectural and cytologic evidence of HPV infection. There are several microscopic features that appear to correlate with an increased risk of metastasis including tumor depth (>4mm or invasion of the subcutaneous fat), perineural, vascular or lymphatic invasion, poor cytologic differentiation, infiltrative architecture, and location within a scar or area of chronic inflammation (Table 31.1).[10] Histopathologic findings suggestive of aggressive behavior are found frequently in SCC arising in OTRs. Pharmacologic immunosuppression may account for the sparse inflammatory infiltrate commonly observed.

BASAL CELL CARCINOMA BCC is the commonest malignant neoplasm arising in the nonimmunosuppressed population, and is second only to SCC in transplant patients. Primary BCC is considered generally to be low risk even among OTRs, although tumors with an aggressive growth pattern and tumor recurrences may be more frequent in this population. A recent report of 225 cases of BCC from OTRs and nonimmunosuppressed patients demonstrated that the nodular growth pattern was the commonest in both groups.[5] However, superficial BCC was significantly more common in OTRs (29%) compared to nonimmunosuppressed patients (14%) (Figure 31.7). The proportion of lesions arising in OTRs that demonstrated a predominantly micronodular pattern (12%) was significantly smaller than the control group (24%), as were tumors with mixed patterns (micronodular plus infiltrative/morpheaform features). A substantial proportion of tumors in OTRs had features of infiltrative BCC in OTRs (15%), although this was not significantly different from the control group (Figure 31.8). Of note, poor host inflammatory response, incidental actinic

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Table 31.1 Criteria for high-risk squamous cell carcinoma of the skin 1. 2. 3. 4. 5. 6.

Tumor depth (>4 mm or invasion of the subcutaneous fat) Perineural invasion Vascular or lymphatic invasion Poor cytologic differentiation Infiltrative architecture Location within a scar or area of chronic inflammation

Source: Schmults, C.D., High-risk cutaneous squamous cell carcinoma: identification and management. Adv Dermatol, 2005. 21: p. 133–52.

keratosis, and features of coexisting HPV infection were identified significantly more often in OTRs.[5] Additional characteristics were evaluated including: stromal features (including degree of compact/fibroblastic stroma and retraction artifact) and tumoral features (including ulceration, palisading, mitoses, pleomorphism, cyst formation, single-cell necrosis, amyloid, mucin, giant cells, melanization, lipidization, and the presence of granular/clear/signet cells); none were significantly different between groups. Although evidence-based histopathologic criteria for aggressive BCC are lacking, some authors have suggested that infiltrative, morpheaform, or micronodular growth patterns and squamous cytologic differentiation are associated with a higher rate of recurrence and greater morbidity. Of these criteria, only BCC with squamous differentiation was more common in OTRs in this study.[5] A large (n = 1039) prospective study of BCC in nonimmunosuppressed patients treated with standard excision showed through histopathologic examination that micronodular, infiltrative, and mixed tumors with infiltrative patterns were associated with significantly higher rates of positive margins compared to nodular and superficial patterns.[11] The nodular subtype was most common (21%), followed by superficial (17.4%), micronodular (15%), infiltrative (7%), and morpheic (1%). Comparatively, infiltrative (15%) and superficial (29%) types of BCC were substantially more frequent among OTRs,[5] although interstudy heterogeneity restricts direct comparisons.

S U MMARY Together these data suggest that OTRs may be at increased risk of developing BCC with histopathologic features of aggressive behavior. Infiltrative BCC demonstrates a greater propensity for local invasion into vital structures and occurs commonly in this population. Superficial BCC appears to be significantly more common in this population and has been associated with an increased rate of recurrence most likely due to subclinical involvement of perilesional skin and inadequate primary therapy. The biologic behavior of BCC with squamous differentiation is considered to approximate that of SCC and is therefore considered a higher risk tumor. Further histologic

investigation into the prognosis of these subtypes of BCC in OTRs is warranted.

ME LANOM A Although the incidence of melanoma is lower than that of keratinocyte carcinomas, the case fatality attributed to it is substantially higher. Relatively few cases of melanoma arising in OTRs have been published, which limits the generalizability of the available data. A retrospective review of transplant registries containing records on approximately 30,000 OTRs was performed, from which 14 patients with melanoma arising in the posttransplant period were identified.[12] Histopathologic examination revealed that more than two thirds of melanomas were associated with a decreased or absent inflammatory infiltrate in OTRs, similar to the findings reported in BCC. A precursor nevus was identified in a similar proportion of cases, of which most showed features of dysplastic (ClarkÕs) nevus. Melanomas with Breslow thickness <1 mm were associated predictably with a favorable prognosis, although thicker melanomas (>1 mm) were more common (64% of cases) in OTRs than would be expected in a nonimmunosuppressed population. Theoretically, these data could suggest that immunosuppressive therapy may impair or prevent the immune system from mounting a tumor-specific cellular immune response that results in decreased immune surveillance, increased risk of malignant transformation of atypical nevi, and accelerated progression from in situ to invasive melanoma. Whereas conservative management of clinically atypical but unchanging nevi may be appropriate for nonimmunosuppressed individuals, a lower threshold for biopsy of atypical nevi in the organ transplant population may be indicated. A retrospective review of 8191 records in the Cincinnati Transplant Tumor Registry from 1968 through 1995 identified 164 patients who developed primary cutaneous melanoma during the posttransplant period.[13] A substantial proportion (47%) of recorded cases demonstrated Breslow thickness >1.51 mm, suggesting that the risk of melanoma presenting clinically as an invasive cutaneous malignancy is markedly higher in the organ transplant population. More recently, a multicenter retrospective study of 12,477 in OTRs in France from 1971 through 1997 reported 14 cases of primary cutaneous melanoma occurring during the posttransplant period.[14] As in previous studies, a review of histopathologic features demonstrated that 30% of invasive melanomas (superficial spreading and nodular types) had a Breslow thickness of >1.5 mm, more than half arose in preexisting nevi, and in all cases analyzed (n = 7) the inflammatory reaction was absent or nonbrisk.

SUM MARY Despite a paucity of reported cases of melanoma in transplant patients, the available data suggest that iatrogenic

HISTOPATHOLOGIC FEATURES OF SKIN CANCER IN ORGAN TRANSPLANT RECIPIENTS

immunosuppression is associated with impaired local immune surveillance as evidenced by the absence or diminution of an antitumoral host inflammatory response. Although large scale prospective studies are required to confirm the biologic significance of depth of invasion and ulceration of melanoma in the transplant population, these factors are considered to be the primary determinants of prognosis for this disease. Further investigation of the potential significance of decreased peritumoral inflammation also is required.

SPE C IAL H IS T OL OGI C C O NS I DER A TI ONS I N T H E TR AN S P LA N T PO P U L AT I O N Systemic retinoids are used commonly for chemoprevention in OTRs who demonstrate a proclivity for developing highrisk skin cancer. The histopathologic influence of the most commonly prescribed chemopreventive retinoid, acitretin, is largely unknown. Preliminary data from an immunohistochemical study of actinic keratoses arising in OTRs receiving acitretin demonstrated that keratins 13 and 19 were increased compared to normal skin.[15] The interpretation of this finding is uncertain, however, as expression of low-molecular-weight keratins also has been associated with malignant transformation to SCC.[16] A similar study followed 9 OTRs who interrupted treatment with acitretin and subsequently underwent biopsies of actinic keratoses at 6- and 12-week intervals.[17] The aberrant expression of keratin 13 (normally expressed in nonkeratinizing stratified squamous epithelia) was noted to decrease substantially over time, whereas MIB-1, p53, and p16INK4A expressions did not change. These results suggest that acitretin may be chemoprotective against NMSC by inducing aberrant terminal differentiation rather than inducing tumor suppressor gene expression or by exerting a direct antiproliferative effect on keratinocytes.[17] Evidence that impaired immune surveillance may explain partially the pathogenesis of accelerated skin cancer in OTRs is derived from immunohistochemical studies demonstrating that CD4 and CD8 lymphocytes, natural killer cells, and Langerhans cells may be diminished in actinic keratoses, viral warts, BCC, and SCC arising in OTRs.[18] Langerhans cells are antigen-presenting cells that play a critical role in mediating the antitumoral immune response in the immunocompetent host. Loss of Langerhans cell staining is directly related to the magnitude of immunosuppression; patients receiving triple drug therapy and long-term treatment with azathioprine have demonstrated the lowest density of epidermal Langerhans cells.[19] In contrast to OTRs, Langerhans cells in nonimmunosuppressed patients may be increased in squamous epidermal neoplasms, possibly representing a host antitumoral response.[20] Long-term (greater than 12 months) therapy with acitretin appears to reverse Langerhans cell depletion, as the number of Langerhans cells and the prominence of dendritic processes among keratinocytes are increased significantly following treatment.[21] The numbers of CD4 and CD8 lymphocytes, and natural killer cells were not affected by acitretin, however.

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The number of Langerhans cells also was increased in SCC arising in OTRs who received etretinate, a retinoid closely related to acitretin.[18–22] There was no association, however, between Langerhans cell density and tumor grade (differentiation), features compatible with HPV infection, level of invasion, number of mitoses, patient age, or duration of immunosuppression.[18] The mechanism of action of systemic retinoids on epidermal Langerhans cells is poorly understood but has been postulated to derive from induction of monocytes to differentiate into Langerhans cells or from promotion of migration of Langerhans cells from a reservoir in the follicular epithelium.[23] The importance of aberrant Langerhans cells staining and of other immunohistochemical abnormalities in OTRs remains poorly delineated. Future investigation will likely reveal insights into the significance of Langerhans cells in the pathogenesis of cutaneous malignancy in the organ transplant population.

CONCLUSIONS Evidence-based guidelines that define the prognostic significance of histopathologic findings exhibited by epidermal neoplasms in OTRs generally are lacking in large part due to the paucity of population-based studies. Nevertheless, the necessity of managing this high-risk patient population requires that rational decisions be made with the best available data. We recommend that the dermatopathologist comment descriptively on the presence of unusual histopathologic features of benign and malignant neoplasms, and the transplant dermatologist keep abreast of the literature as future studies delineate further the clinical significance of the observed histopathologic findings and the changes in management dictated by them.

REFERENCES

1. Price, M.L., et al., Distinctive epidermal atypia in immunosuppression-associated cutaneous malignancy. Histopathology, 1988. 13(1): p. 89–94. 2. Boyd, A.S., et al., Histologic features of actinic keratoses in solid organ transplant recipients and healthy controls. J Am Acad Dermatol, 2001. 45(2): p. 217–21. 3. Glover, M., et al., Cutaneous squamoproliferative lesions in renal transplant recipients. Differentiation from lesions in immunocompetent patients. Am J Dermatopathol, 1995. 17(6): p. 551–4. 4. Smith, K.J., S. Hamza, and H. Skelton, Histologic features in primary cutaneous squamous cell carcinomas in immunocompromised patients focusing on organ transplant patients. Dermatol Surg, 2004. 30(4 Pt 2): p. 634–41. 5. Harwood, C.A., et al., Clinicopathologic features of skin cancer in organ transplant recipients: a retrospective case-control series. J Am Acad Dermatol, 2006. 54(2): p. 290–300. 6. Carucci, J.A., et al., In-transit metastasis from primary cutaneous squamous cell carcinoma in organ transplant recipients and nonimmunosuppressed patients: clinical characteristics, management, and outcome in a series of 21 patients. Dermatol Surg, 2004. 30(4 Pt 2): p. 651–5.

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7. Mehrany, K., et al., Lymphocytic infiltrates and subclinical epithelial tumor extension in patients with chronic leukemia and solid-organ transplantation. Dermatol Surg, 2003. 29(2): p. 129–34. 8. Rowe, D.E., R.J. Carroll, and C.L. Day, Jr., Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol, 1992. 26(6): p. 976–90. 9. Clayman, G.L., et al., Mortality risk from squamous cell skin cancer. J Clin Oncol, 2005. 23(4): p. 759–65. 10. Schmults, C.D., High-risk cutaneous squamous cell carcinoma: identification and management. Adv Dermatol, 2005. 21: p. 133–52. 11. Sexton, M., D.B. Jones, and M.E. Maloney, Histologic pattern analysis of basal cell carcinoma. Study of a series of 1039 consecutive neoplasms. J Am Acad Dermatol, 1990. 23(6 Pt 1): p. 1118–26. 12. Greene, M.H., T.I. Young, and W.H. Clark, Jr., Malignant melanoma in renal-transplant recipients. Lancet, 1981. 1(8231): p. 1196–9. 13. Penn, I., Malignant melanoma in organ allograft recipients. Transplantation, 1996. 61(2): p. 274–8. 14. Leveque, L., et al., [Melanoma in organ transplant patients]. Ann Dermatol Venereol, 2000. 127(2): p. 160–5. 15. Smit, J.V., et al., Acitretin treatment in (pre)malignant skin disorders of renal transplant recipients: Histologic and immunohistochemical effects. J Am Acad Dermatol, 2004. 50(2): p. 189–96. 16. Watanabe, S., et al., Changes of cytokeratin and involucrin expression in squamous cell carcinomas of the skin during progression to malignancy. Br J Dermatol, 1995. 132(5): p. 730–9.

17. Blokx, W.A., et al., Immunohistochemical effects of temporary cessation of long-term acitretin treatment in keratinocytic intraepidermal neoplasia of renal transplant recipients. Arch Dermatol, 2003. 139(5): p. 671–3. 18. Gibson, G.E., et al., Langerhans cells in benign, premalignant and malignant skin lesions of renal transplant recipients and the effect of retinoid therapy. J Eur Acad Dermatol Venereol, 1998. 10(2): p. 130–6. 19. Bergfelt, L., O. Larko, and I. Blohme, Skin disease in immunosuppressed patients in relation to epidermal Langerhans’ cells. Acta Derm Venereol, 1993. 73(5): p. 330–4. 20. McArdle, J.P., et al., Quantitative assessment of Langerhans cells in actinic keratosis, BowenÕs disease, keratoacanthoma, squamous cell carcinoma and basal cell carcinoma. Pathology, 1986. 18(2): p. 212–6. 21. Carneiro, R.V., et al., Acitretin and skin cancer in kidney transplanted patients. Clinical and histological evaluation and immunohistochemical analysis of lymphocytes, natural killer cells and Langerhans’ cells in sun exposed and sun protected skin. Clin Transplant, 2005. 19(1): p. 115–21. 22. Rook, A.H., et al., Beneficial effect of low-dose systemic retinoid in combination with topical tretinoin for the treatment and prophylaxis of premalignant and malignant skin lesions in renal transplant recipients. Transplantation, 1995. 59(5): p. 714–9. 23. Murphy, G.F., S. Katz, and A.M. Kligman, Topical tretinoin replenishes CD1a-positive epidermal Langerhans cells in chronically photodamaged human skin. J Cutan Pathol, 1998. 25(1): p. 30–4.

Section Eight

SPECIAL SCENARIOS IN TRANSPLANT CUTANEOUS ONCOLOGY

32 Metastatic Squamous Cell Carcinoma in Organ Transplant Recipients

Randall K. Roenigk, MD, David L. Appert, MD, Kelly L. Brunner, MD, and Jerry D. Brewer, MD

P A T H OGE NE SI S

receiving cyclosporine were shown to have an increased incidence of skin cancer independently of immunosuppression.[14] Antibodies targeting transforming growth factor b (TGF-b) decreased this association, leading some authors to believe that TGF-b upregulation is implicated in the proposed carcinogenesis of cyclosporine.[14] Controversy remains as to whether the risk of carcinogenesis is higher with cyclosporine than with azathioprine. Combination immunosuppressive regimens may be another important factor in the development and progression of skin cancer to metastatic disease. The use of cyclosporine with azathioprine is associated with an increased risk of SCC.[11,19] Newer immunosuppressants, such as tacrolimus, are also associated with a high risk of skin cancer.[20] The exact mechanisms of how a suppressed immune system allows for more aggressive skin cancer and for more frequently metastasizing SCCs have not been fully elucidated. More investigation is needed in this area. Ultraviolet radiation (UVR) is a primary pathogenic factor in the development of SCC in OTRs as well as in the general population.[21] The documented association between latitude and SCC development in OTRs supports the role of UVR in the transplant population.[22] The chance of skin cancer developing within 10 years after transplantation is 45% for patients with organ transplants in Australia and 10–15% for patients in England and Holland.[22–25] Patients in Japan with less sun exposure and natural protection from UVR have very little skin cancer after organ transplantation.[26,27] UVR is directly mutagenic and as well immunosuppressive to the cutaneous immune system.[28,29] The compromised immune surveillance system of OTRs is less likely to detect and eradicate precancers that develop after years of UVR exposure. Human papillomavirus (HPV) infection is thought to be an important cofactor in the development of SCC in OTRs.[30] HPV types 5 and 8 have been identified in 60–80% of SCCs in renal transplant patients.[31] Viral proteins E6 and E7 work to inhibit the tumor suppressor gene p53, which may have a role in SCC development in these patients.[32] Studies have demonstrated a high prevalence of HPV in cutaneous SCCs of both immunocompetent and immunosuppressed patients, with an association as high as 90% in OTRs.[33] However, the exact role of HPV in the development and metastasis of SCCs in OTRs remains unclear because HPV is also found frequently

Organ transplant recipients (OTRs) are a special group of patients with important characteristics and unique medical needs. Because squamous cell carcinomas (SCC) in OTRs tend to be common, with more aggressive local invasion, early recurrence, and higher rates of metastases,[1–6] the recognition and treatment of skin cancer, especially SCC, in these patients is becoming a more important aspect of their overall care. As OTRs live longer with better antirejection regimens, the incidence of metastatic SCC in these patients will most likely increase. The pathogenesis of malignancies, specifically SCC in OTRs, is multifactorial. The immunosuppression required in OTRs is a well-documented factor in the development of SCC and other malignancies.[7] In fact, cancer of any type is three to four times more likely to develop in OTRs than in the general population.[8] Immunosuppression not only predisposes OTRs to the development of SCC but also increases tumor aggressiveness, the chance of metastatic disease, and the possibility of death.[1,9] The level and duration of immunosuppression is the single most important factor influencing malignant transformation and metastasis in OTRs.[10–12] This is well illustrated by cardiac transplant patients, who generally receive higher levels of immunosuppression than recipients of other types of organ transplants and have the highest rate of SCC among OTRs. Moloney et al. postulated that immunosuppression can affect whether a local primary SCC transforms into a tumor with the potential to metastasize.[13] Immunosuppression may increase the incidence of SCC through at least two mechanisms. First, immunosuppressants may be carcinogenic; second, the associated immunosuppressed state may decrease immune surveillance and the associated ability to eliminate the development of precancer.[14–17] Azathioprine is an immunosuppressant known to have mutagenic and photosensitizing capabilities. A metabolite of azathioprine, 6-thioguanine, accumulates in DNA. One study [18] has demonstrated higher levels of reactive oxygen species, oxidative DNA damage, and photosensitivity in patients with 6-thioguanine-substituted DNA, which may contribute to the increased incidence of SCC in OTRs taking azathioprine. Similarly, cyclosporine may contribute to the development of malignancies independently of immunosuppression. Mice 217

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in benign lesions and in normal skin of both immunosuppressed and immunocompetent patients.[34] Factors such as lighter skin, older age, and skin cancer prior to organ transplantation are also important markers for the development of SCC in OTRs. These characteristics identify patients who are predisposed to the development of skin cancer, and therefore metastasis, independent of OTR due to increased cumulative sun exposure and decreased photoprotection provided by lighter skin.[35] Location of the primary tumor also appears to be a factor in the risk of metastasis. Tumors on the lip, ear, and external genitalia have an increased incidence of metastasis in the general population as well as in OTRs.[36] On a molecular level, certain mutations are prevalent in SCCs. Gene p53 mutations in SCC have been identified in 50% of cases in the general population and in 43% of patients with renal transplants.[37] Mutations in the CDKN2A locus of chromosome 9p21 (INK4a-ARF) are present in 24% of all SCCs.[38,39] Molecular analysis of p53 and INK4a-ARF mutations can associate the primary SCC with the subsequent metastatic spread.[40] The most important cellular processes in the pathogenesis of metastatic SCC seem to be disengagement, invasion, migration, and angiogenesis.[41] Disengagement is the breaking away of the malignant cell from its neighboring cells and the loss of cell–cell interaction, adhesion, and communication. Cadherins (especially E-cadherin) and integrins are intercellular molecules that are important in maintaining normal cellular structure and intercellular communication. These molecules are frequently abnormal in SCC. It is thought that abnormalities are present in cadherins and integrins when metastatic disease occurs.[41] E-cadherin is regulated by methylation and growth factors and it has been shown that epidermal growth factor receptors (EGFRs) are upregulated in SCC as well as in other tumors.[42] This has led to the investigation of therapeutic options directed at maintaining normal cellular structure and intercellular communication such as the use of monoclonal anti-EGFR antibodies.[43] Invasion occurs when tumor cells destroy surrounding tissue and the basement membrane by use of proteases (matrix metalloproteases, serine proteases, and aspartyl proteases). Certain proteases have been found to be upregulated in SCC and are also thought to be important in the process of metastasis.[44] Migration and angiogenesis occur when the primary tumor cells have entered the vascular or lymphatic circulation (or both), are carried to a different site in the body, and begin to proliferate at this new site.

I N C I D E N C E A ND P R O G N O S I S Skin cancer is by far the most common malignancy in OTRs. The most common skin cancer is SCC.[40] The ratio of basal cell carcinoma (BCC) to SCC in the general population is 5:1; however, this ratio in OTRs ranges from 1:1.8 to 1:15. The

magnitude of this reversal is notable.[31] Metastatic SCC occurs in up to 5% of general populations with SCC [45] and in 5–10% of OTRs with SCC.[9] The mean time to the development of metastatic SCC in OTRs is 10.7 years from transplantation, developing roughly 1.4 years after the diagnosis of the primary tumor.[9] Characteristics of SCCs, which predispose patients to a high risk of metastasis include multiple SCC, rapid recurrences; high-risk locations, especially the head and neck (although in OTRs, metastasis occurs at a higher rate at all locations); size larger than 2 cm; history of aggressive growth; high-grade histology; and invasion deeper than 4 to 6 mm, especially into fat, muscle, cartilage, bone, or nerve.[1] Lymphatic invasion and lymph node involvement are strong indicators of distant metastatic potential.[46] Spread of disease beyond the capsule of the lymph nodes is the best predictor of survival, local–regional recurrence, and distant metastasis.[47] In general, the presence of metastatic SCC, either nodal or at distant sites, is an ominous finding with a poor prognosis. In one study,[9] the relapse rate of metastatic SCC in OTRs was 29% at 1 year, with 5-year survival rates between 14% and 39% even with therapeutic intervention. The median 3-year disease-specific survival of these OTRs with metastatic SCC was only 56%.[9]

C L I N I CA L P R E S E N T A T I O N OTRs with metastatic SCC may have various clinical presentations, depending on the site of metastasis and the characteristics of the patient. Metastatic SCC may occur as dermal or in-transit metastasis, lymphatic metastasis, or metastasis at a site distant from the primary tumor. Dermal or in-transit metastasis typically occurs clinically as pink to gray papules located between the primary tumor and the primary draining lymph node basin. Most in-transit metastases occur on the face and are often best treated with adjuvant radiotherapy (1–5 cm in diameter from the tumor border). Clear surgical margins alone are frequently unreliable.[48] Decreasing the amount of immunosuppression is warranted if possible. In-transit metastases (Figure 32.1) develop in up to 26% of OTRs with metastatic SCC.[9] Dermal or in-transit metastases carry a very poor prognosis; in one study,[48] 33% of patients were deceased within 2 years. Metastatic spread of SCC in the general population and OTRs is primarily to the lymph nodes [9] (Figure 32.2). Aggressive primary SCCs have been shown to spread through the local lymphatic drainage and generally spread to the regional lymph nodes before metastasizing to more distant sites [49] (Figure 32.3). The most common sites for lymph node metastasis from head and neck SCC are the parotid and cervical nodes. Thirty-five and thirty percent of patients, respectively, have isolated involvement; 45% have involvement of both sites. Metastasis to these locations

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Figure 32.1. Two patients with in-transit metastasis of squamous cell carcinoma. (A) On the face. (B) On the trunk.

Figure 32.2. Squamous cell carcinoma and nodal metastasis to the supraclavicular lymph nodes.

Figure 32.3. Squamous cell carcinoma and subcuticular metastatic disease.

usually appears within 2 to 3 years after diagnosis of the primary tumor. Sentinel lymph node biopsy may be a valuable diagnostic tool. In one small study,[50] nearly half of the patients with high-risk SCC and clinically negative lymph nodes had a histologically positive sentinel node after preoperative lymphoscintigraphy. Two of the four patients with positive nodes had additional metastatic disease and died within 2 years.

Systemic metastases typically involve the lungs or bone and, less frequently, the liver, central nervous system, or skin.[9]

M A NAG EME NT Metastatic SCC in OTRs is generally associated with a poor prognosis. The overall 3-year survival for transplant patients

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Table 32.1 Treatment of metastatic squamous cell carcinoma in OTR Metastatic tumor involvement

Treatment

Recurrent cutaneous SCC

Reexcision using Mohs micrographic surgery Consider nodal dissection, especially in high-risk areas or if pathologic findings are worrisome [54] Consider adjuvant radiotherapy Lymphadenectomy Consider adjuvant radiotherapy Consider decreasing immunosuppressive medication dosages Lymphadenectomy + adjuvant radiotherapy to the affected nodal basin Consider decreasing immunosuppressive medication dosages Lymphadenectomy + adjuvant radiotherapy to the affected nodal basin Consider decreasing immunosuppressive medication dosages Palliative surgery Chemotherapy: cisplatin, fluorouracil, carboplatin, methotrexate, or paclitaxel Consider decreasing immunosuppressive medication dosages Chemotherapy: cisplatin, fluorouracil, carboplatin, methotrexate, or paclitaxel Consider decreasing immunosuppressive medication dosages

Single lymph node

Multiple lymph nodes Extracapsular spread Systemic metastasis

Recurrent nodal metastasis

Note: SCC = squamous cell carcinoma.

with metastasis is 48%. Although there is currently no standard of care for the management of metastatic SCC in OTRs, many therapeutic options, both surgical and medical, have been advocated. Treatment of a metastatic SCC depends on the extent of tumor involvement: single lymph node or nodal basin involvement versus systemic spread (Table 32.1). Potentially curative surgical options exist for localized metastasis. If tumor is noted in a single lymph node, lymphadenectomy is the surgical treatment of choice.[1] If more than one lymph node is involved or if extracapsular spread is detected, adjuvant radiotherapy may combined with lymph node removal. For systemic metastasis, which most commonly affects the bone and lung, surgical treatment becomes palliative.[9] Metastases to the cervical or parotid lymph nodes are typically treated by excision of the primary tumor if still present, nodal basin dissection (especially if invasion beyond the subcutaneous fat and lymphovascular invasion are noted on histologic examination of the primary lesion), and postoperative radiotherapy. Although this approach is aggressive, distant metastases still developed in up to 17% of patients in one study that used this regimen.[51] Medical management may be considered for any type of metastatic SCC. The goals of therapy should be individualized to attempt to prevent additional cancers, decrease the risk of recurrence, lessen the tumor burden, or provide palliation. Medical management may include decreasing or discontinuing immunosuppression, adjuvant radiotherapy, and topical or systemic chemotherapies. One of the mainstays of medical therapy is to decrease the level of immunosuppression. This requires a careful risk– benefit analysis and often a multidisciplinary approach involving the transplant physician, oncologist, and dermatologist. Decreasing the level of immunosuppression in OTRs with metastatic SCC usually leads to decreased aggressiveness of

the metastatic cancer but may also lead to an increased chance of rejecting the transplanted organ. Several studies have shown or suggested that decreasing immunosuppression did not significantly affect the overall function or survival of the transplanted organ; however, this is highly variable by individual and depends, in part, on the type of organ transplanted. Some authors advocate decreasing the dosage of azathioprine first because cyclosporine confers better graft survival.[1] Radiotherapy may also be used as an adjunctive treatment for any type of cutaneous metastatic lesion. Perineural spread of metastatic cancer to the brain has been treated using palliative external beam radiotherapy. For these patients, stereotactic radiotherapy has shown a trend toward prolonged survival when compared to standard palliative external beam radiotherapy.[52] Chemotherapy is another adjunctive treatment option for OTRs with metastatic SCC. Unfortunately, most drugs only work for a short time, with a median survival of 6 to 8 months after diagnosis.[53] The mainstay of chemotherapy for metastatic SCC includes the use of the platinum-based medications cisplatin (often combined with 5-fluorouracil) and carboplatin. Various other regimens have been tried as first- or second-line therapies but have yielded little increased survival benefit.[53] These regimens have included methotrexate, gemcitabine, bleomycin, nolatrexed dihydrochloride, tegafururacil, and combination treatments.[53] New chemotherapy regimens are being developed continuously. Newer agents included EGFR tyrosine kinase inhibitors such as gefitinib (Iressa) and erlotinib (Tarceva). Cetuximab (Erbitux) is an IgG1 monoclonal antibody directed at the extracellular ligand-binding domain of EGFR.[53] These medications have shown promise in phase 2 trials for patients who have progressed with use of first-line chemotherapy regimens. Many studies have demonstrated that combining treatment modalities improves survival benefit over single-modality

METASTATIC SQUAMOUS CELL CARCINOMA IN ORGAN TRANSPLANT RECIPIENTS

therapy. For metastases to locally draining lymph nodes, a combination of surgical therapy and radiotherapy has yielded superior results to single modality therapy.[51,54] In one study of patients with metastatic tumors not conducive to surgical therapy, a combination of radiotherapy and chemotherapy provided a longer mean survival (212 days) than either radiotherapy alone (188 days) or chemotherapy alone (107 days).[53] However, this data may have been skewed by patient selection bias. As with all skin cancers, close follow-up is necessary. For patients with metastatic SCC, follow-up should occur every 2 months for 2 to 3 years.[1] The follow-up visit should include a relevant history with a review of systems, skin examination, and palpation of lymph nodes, especially of the draining lymph node basin from the primary tumor.

P R E VE NT I ON The key to prevention of metastatic SCC in OTRs is early detection and timely treatment of the primary SCC. Prevention of SCCs and early detection of developing SCC in the transplant patient requires patient education and close follow-up. Sun avoidance, protective clothing, and proper sunscreen usage are critical elements. Transplant patients should also be taught to perform monthly skin self-examinations, and they should have at least annual full skin examinations by a physician. Because lymphatic spread is the most common form of metastasis, regional lymph nodes should be palpated on a regular basis, and the skin around the primary tumor site should be inspected and palpated as well. Treatment of metastatic SCC is most successful when the disease is confined to a single lymph node or nodal basin, making early detection critical. Chemoprevention before or during immunosuppression may decrease the probability of the development of new skin cancers. Systemic retinoids have been found to lessen background actinic keratosis and to decrease the number of new SCCs.[55,56] The mechanism of action of systemic retinoids is poorly understood but is thought to include immunomodulation and induction of apoptosis. Systemic retinoids may also affect cell cycle control, influence multiple transcription factors, inhibit ornithine decarboxylase, alter gap junction intercellular communication, and affect keratinocyte differentiation and expression. The transplant patients who seem to benefit most from these agents are those with multiple prior skin cancers.[56] Because the risk of metastasis is related to the number of SCCs, it is hoped that the decrease in new skin cancers seen during retinoid usage will lessen the incidence of metastasis. Large-scale studies will be necessary to confirm this impression. In a like manner, the use of retinoids after metastasis in OTR to prevent recurrence or progression has not been well studied. However, the use of retinoids is this situation is frequently advocated.[57] There is no consensus on the appropriate starting or maintenance dose of systemic retinoids. Owing to the mucocuta-

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neous side effects, the dosage of acitretin is usually started low, such as at 10 mg/d, and increased as tolerated and clinically necessary.[56] An average dosage of acitretin is 25 mg/d, with a range of 10 to 50 mg/d. Isotretinoin dosage is 10–70 mg/d. The occurrence of side effects typical with oral retinoids may prompt decreasing the dosage or discontinuing use of the medication. All patients receiving retinoids should have regular follow-up and appropriate laboratory monitoring to detect side effects. When use of retinoid is discontinued, a rebound effect occurs, with an increase, even from baseline, in the number of new actinic keratoses and SCCs.[56]

CONCLUSIONS OTRs are at increased risk for the development of cutaneous SCC and metastatic SCC. Primary prevention through the use of sun protection is of critical importance. Early detection of cutaneous SCC and aggressive treatment may prevent the development of metastatic SCC. OTRs with SCC should be frequently evaluated for lymph node spread as treatment of early, limited metastases has the best chance for success. The use of oral retinoids and the reduction of immunosuppression should be considered in patients with metastatic SCC or at high risk for metastasis.

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RANDALL K. ROENIGK, DAVID L. APPERT, KELLY L. BRUNNER, AND JERRY D. BREWER

regimens more likely to develop skin cancer than those on azathioprine and prednisolone? Transplant Proc. 1999;31:1120. Moloney FJ, Kelly PO, Kay EW, Conlon P, Murphy GM. Maintenance versus reduction of immunosuppression in renal transplant recipients with aggressive squamous cell carcinoma. Dermatol Surg. 2004;30:674–8. Hojo M, Morimoto T, Maluccio M, Asano T, Morimoto K, Lagman M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature. 1999;397:530–4. Kelly GE, Meikle W, Sheil AG. Effects of immunosuppressive therapy on the induction of skin tumors by ultraviolet irradiation in hairless mice. Transplantation. 1987;44:429–34. Boyle J, MacKie RM, Briggs JD, Junor BJ, Aitchison TC. Cancer, warts, and sunshine in renal transplant patients: a case-control study. Lancet. 1984;1:702–5. Servilla KS, Burnham DK, Daynes RA. Ability of cyclosporine to promote the growth of transplanted ultraviolet radiation-induced tumors in mice. Transplantation. 1987;44:291–5. OÕDonovan P, Perrett CM, Zhang X, Montaner B, Xu YZ, Harwood CA, et al. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science. 2005;309:1871–4. Glover MT, Deeks JJ, Raftery MJ, Cunningham J, Leigh IM. Immunosuppression and risk of non-melanoma skin cancer in renal transplant recipients. Lancet. 1997;349:398. Jain AB, Hamad I, Rakela J, Dodson F, Kramer D, Demetris J, et al. A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone, and mycophenolate mofetil in primary adult liver transplant recipients: an interim report. Transplantation. 1998;66:1395–8. Bavinck JN, De Boer A, Vermeer BJ, Hartevelt MM, van der Woude FJ, Claas FH, et al. Sunlight, keratotic skin lesions and skin cancer in renal transplant recipients. Br J Dermatol. 1993;129:242–9. Bouwes Bavinck JN, Robertson I, Wainwright RW, Green A. Excessive numbers of skin cancers and pre-malignant skin lesions in an Australian heart transplant recipient. Br Heart J. 1995; 74:468–70. Ong CS, Keogh AM, Kossard S, Macdonald PS, Spratt PM. Skin cancer in Australian heart transplant recipients. J Am Acad Dermatol. 1999;40:27–34. Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP. Incidence of skin cancer after renal transplantation in the Netherlands. Transplantation. 1990;49:506–9. Naldi L, Fortina AB, Lovati S, Barba A, Gotti E, Tessari G, et al. Risk of nonmelanoma skin cancer in Italian organ transplant recipients: a registry-based study. Transplantation. 2000;70:1479–84. Marubayashi S, Tashiro H, Watanabe H, Fudaba Y, Hayamizu K, Ohdan H, et al. Study on eight patients with malignant tumors after renal transplantation. Hiroshima J Med Sci. 2000;49:117–20. Kishikawa H, Ichikawa Y, Yazawa K, Hanafusa T, Fukunishi T, Ebisui C, et al. Malignant neoplasm in kidney transplantation. Int J Urol. 1998;5:521–5. Kripke ML. Ultraviolet radiation and immunology: something new under the sun: presidential address. Cancer Res. 1994;54:6102–5. Parrish JA. Ultraviolet radiation affects the immune system. Pediatrics. 1983;71:129–33. Soler C, Chardonnet Y, Allibert P, Euvrard S, Schmitt D, Mandrand B. Detection of mucosal human papillomavirus types 6/11 in cutaneous lesions from transplant recipients. J Invest Dermatol. 1993;101:286–91. Barr BB, Benton EC, McLaren K, Bunney MH, Smith IW, Blessing K, et al. Papillomavirus infection and skin cancer in renal allograft recipients. Lancet. 1989;2:224–5. Jackson S, Harwood C, Thomas M, Banks L, Storey A. Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev. 2000;14:3065–73.

33. de Villiers EM. Human papillomavirus infections in skin cancers. Biomed Pharmacother. 1998;52:26–33. 34. Boxman IL, Mulder LH, Russell A, Bouwes Bavinck JN, Green A, Ter Schegget J. Human papillomavirus type 5 is commonly present in immunosuppressed and immunocompetent individuals. Br J Dermatol. 1999;141:246–9. 35. Veness MJ, Quinn DI, Ong CS, Keogh AM, Macdonald PS, Cooper SG, et al. Aggressive cutaneous malignancies following cardiothoracic transplantation: the Australian experience. Cancer. 1999;85:1758–64. 36. Euvrard S, Kanitakis J, Pouteil-Noble C, Disant F, Dureau G, Finaz de Villaine J, et al. Aggressive squamous cell carcinomas in organ transplant recipients. Transplant Proc. 1995;27:1767–8. 37. McGregor JM, Berkhout RJ, Rozycka M, ter Schegget J, Bouwes Bavinck JN, Brooks L, et al. p53 mutations implicate sunlight in post-transplant skin cancer irrespective of human papillomavirus status. Oncogene. 1997;15:1737–40. 38. Kubo Y, Urano Y, Matsumoto K, Ahsan K, Arase S. Mutations of the INK4a locus in squamous cell carcinomas of human skin. Biochem Biophys Res Commun. 1997;232:38–41. 39. Soufir N, Moles JP, Vilmer C, Moch C, Verola O, Rivet J, et al. P16 UV mutations in human skin epithelial tumors. Oncogene. 1999; 18:5477–81. 40. Blokx WA, Ruiter DJ, Verdijk MA, de Wilde PC, Willems RW, de Jong EM, et al. INK4-ARF and p53 mutations in metastatic cutaneous squamous cell carcinoma: case report and archival study on the use of INK4a-ARF and p53 mutation analysis in identification of the corresponding primary tumor. Am J Surg Pathol. 2005;29:125–30. 41. Zender CA, Petruzzelli GJ. Why do patients with head and neck squamous cell carcinoma experience distant metastases: can they be prevented?Curr Opin Otolaryngol Head Neck Surg. 2005;13:101–4. 42. Lorch JH, Klessner J, Park JK, Getsios S, Wu YL, Stack MS, et al. Epidermal growth factor receptor inhibition promotes desmosome assembly and strengthens intercellular adhesion in squamous cell carcinoma cells. J Biol Chem. 2004;279:37191–200. 43. Kim ES, Kies M, Herbst RS. Novel therapeutics for head and neck cancer. Curr Opin Oncol. 2002;14:334–42. 44. Ghosh S, Munshi HG, Sen R, Linz-McGillem LA, Goldman RD, Lorch J, et al. Loss of adhesion-regulated proteinase production is correlated with invasive activity in oral squamous cell carcinoma. Cancer. 2002;95:2524–33. 45. Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med. 2001;344:975–83. 46. Sparano A, Lathers DM, Achille N, Petruzzelli GJ, Young MR. Modulation of Th1 and Th2 cytokine profiles and their association with advanced head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg. 2004;131:573–6. 47. Puri SK, Fan CY, Hanna E. Significance of extracapsular lymph node metastases in patients with head and neck squamous cell carcinoma. Curr Opin Otolaryngol Head Neck Surg. 2003;11:119–23. 48. Carucci JA. Cutaneous oncology in organ transplant recipients: meeting the challenge of squamous cell carcinoma. J Invest Dermatol. 2004;123:809–16. 49. Dinehart SM, Pollack SV. Metastases from squamous cell carcinoma of the skin and lip: an analysis of twenty-seven cases. J Am Acad Dermatol. 1989;21:241–8. 50. Carucci JA. Squamous cell carcinoma in organ transplant recipients: approach to management. Skin Therapy Lett. 2004;9:5–7. 51. Moore BA, Weber RS, Prieto V, El-Naggar A, Holsinger FC, Zhou X, et al. Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck. Laryngoscope. 2005;115:1561–7. 52. Fowler BZ, Crocker IR, Johnstone PA. Perineural spread of cutaneous malignancy to the brain: a review of the literature and five patients treated with stereotactic radiotherapy. Cancer. 2005;103:2143–53. 53. Leon X, Hitt R, Constenla M, Rocca A, Stupp R, Kovacs AF, et al. A retrospective analysis of the outcome of patients with recurrent

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and/or metastatic squamous cell carcinoma of the head and neck refractory to a platinum-based chemotherapy. Clin Oncol (R Coll Radiol). 2005;17:418–24. 54. Veness MJ. Treatment recommendations in patients diagnosed with high-risk cutaneous squamous cell carcinoma. Australas Radiol. 2005;49:365–76. 55. Martinez JC, Otley CC, Euvrard S, Arpey CJ, Stasko T. Complications of systemic retinoid therapy in organ transplant

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recipients with squamous cell carcinoma. Dermatol Surg. 2004; 30:662–6. 56. Kovach BT, Sams HH, Stasko T. Systemic strategies for chemoprevention of skin cancers in transplant recipients. Clin Transplant. 2005;19:726–34. 57. Otley CC, Stasko T, Tope WD, Lebwohl M. Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects. Dermatol Surg. 2006;32(4):562–8.

33 In-Transit Metastatic Squamous Cell Carcinoma in Organ Transplant Recipients

John A. Carucci, MD, PhD

INTR ODUCT IO N

to correlate with risk for in-transit disease. In one study,[4] risk factors for in-transit metastasis included location on the scalp, prior history of local recurrence, and presence of perineural invasion.

Squamous cell carcinoma of the skin is the second most common human cancer, occurring 300,000 times each year in the United States.[1] SCC may behave aggressively and may metastasize to local lymph nodes or distant organs.[2] The concept of in transit metastasis has been well described in melanoma but only recently described for primary cutaneous SCC.[3,4] In-transit metastases from primary cutaneous SCC are more common in transplant recipients and signify poor prognosis in this group. In-transit metastases from cutaneous SCC in transplant recipients were described by Berg and Otley[3] in 2002. Martinez, et al, expanded on this definition in an effort to describe the course of metastatic skin cancer in organ transplant recipients.[5] In-transit metastases from primary cutaneous SCC are best described as subcutaneous or dermal relapse discontiguous from the site of the primary or locally recurrent tumor that occurs between the original site and the local nodal basin. Key defining features of in-transit metastases include the following: (1) in-transit metastases are distinct from local recurrence; (2) in-transit metastases are associated with factors indicative of highrisk SCC including large size, recurrence, and location on the forehead and scalp; (3) in-transit metastases are associated with long-term immunosuppression following organ transplant; and (4) in-transit metastases are associated with increased morbidity and mortality in organ transplant recipients.

EPIDEMIOLOGY Although the true incidence of in-transit metastases remains undefined, the phenomenon appears to be more common in transplant recipients. In one series, 15/21 patients with intransit metastases were organ transplant recipients.[4] Most of the transplant recipients in that series were taking 2 or 3 immunosuppressant drugs and the average time after transplantation was over 10 years. Men were more likely to be at risk for in-transit metastases, with a mean age of 61 years. Patients were fair-skinned (skin types 1–3) with history of significant sun damage.

C L I N I CA L C H A R A C T E R I S T I C S O F I N- T R A N SI T M E TA S TA T IC SQ U A M O U S C E L L C A R CI N O M A The clinical attributes of in-transit metastases from cutaneous SCC were characterized in a recent series [4] and can be summarized as follows: (1) in-transit metastases from cutaneous SCC are typically subcutaneous or dermal papules without surface change (Figure 33.1), (2) lesions are usually less than 1 cm in size, (3) in-transit metastases are usually found within 2.5 cm of the primary site, (4) multiple intransit lesions are commonly found, (5) in-transit lesions are commonly discovered soon after treatment of the primary or recurrent cancer, and (6) histologic differentiation is variable with ~40% showing poor differentiation (Figure 33.2). The characteristics of in-transit metastatic SCC are summarized in Table 33.1. The presence of dermal papules surrounding the site of a previously treated high-risk SCC should raise suspicion for intransit metastasis. In one series, lesion size ranged from 0.3–1.2 cm; thus a keen clinical eye is necessary to diagnose small nondescript lesions. The need for close and frequent follow-up of high-risk patients is supported by the mean time of diagnosis of 10 weeks following treatment of the primary or recurrent cancer.

PATHOG ENES IS Cancer can spread via direct extension, hematogenously, or through lymphatics.[2] Local marginal recurrence is most often secondary to inadequate resection of tumor. This may be due to any number of factors including observation rather than retreatment of positive margins, false negative margins, or discontiguous spread (skipping) associated with invasion of nerves. Local marginal recurrence is diagnosed when tumor is present at the peripheral or deep margin of a previously treated site. In contrast, in-transit metastases represent an aggressive form of relapse likely secondary to tumor spreading through dermal or subcutaneous lymphatic ducts. Several risk factors for aggressive behavior in SCC have been found 224

IN-TRANSIT METASTATIC SQUAMOUS CELL CARCINOMA IN ORGAN TRANSPLANT RECIPIENTS

Figure 33.1. In-transit metastases from primary cutaneous SCC: (A) subcutaneous plaques appearing 8 months after surgery for SCC and (B) subcutaneous papule distal to site of locally recurrent SCC.

HIGH-RISK TUMORS In one series, cutaneous SCCs that resulted in in-transit metastasis had an average diameter of 1.7 cm.[4] Fifteen of 22 tumors that developed in-transit metastasis from that series were located on the head. Surprisingly, the tumor was histologically well differentiated in 13 of 16 cases. Other clinical characteristics of the primary SCC that were risk factors for in-transit metastases included perineural invasion, extension into subcutaneous fat, and formation within a scar (summarized in Table 33.2). Recurrent carcinoma eventuated in intransit metastasis in 9/13 cases from that series (Figure 33.3).

Figure 33.2. (A) In-transit metastatic SCC showing poor differentiation. (B) Cytokeratin staining supporting microscopic diagnosis of SCC in a poorly differentiated lesion.

is most often multidisciplinary and may involve a dermatologic surgeon, head and neck oncologic surgeon, radiation oncologist, and medical oncologist. If the patient is a transplant recipient, the primary transplant physician must be involved in all decision processes. In one series, management included varying combinations of excision (Mohs or standard) and radiotherapy.[4] Margins of excision ranged from 0.4 to 2.0 cm with an average of 1 cm. Intralesional or systemic chemotherapy has also been used.

Table 33.1 Characteristics of in-transit metastases from cutaneous SCC Clinical Description

MANAGEM ENT OF IN-TRANS IT METASTASE S Strict guidelines for treatment of in-transit metastases from primary cutaneous SCC remain to be defined and management is best approached on case-by-case basis. Management

225

Location Number Histologic Differentiation Time course

Subcutaneous or dermal papule, nodule, or plaque Discontiguous from primary tumor Single or multiple Variable Rapid onset, development and growth

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JOHN A. CARUCCI

Table 33.2 Characteristics of primary SCC eventuating in in-transit metastases Size Location Differentiation Neurotropism History of prior treatment

1.7 cm Forehead, scalp, ear, face 81% well differentiated 28% present 30% primary

19% poorly differentiated 72% absent 70% recurrent

Adapted from ref 4.

Agents included interferon-a (IFN-a), blebleomycin, 5Fluorouracil, cis-platinum, and methotrexate. Oral retinoids, particularly acitretin, may be useful in management of transplant recipients with numerous and aggressive skin cancers and have been used in transplant recipients with in-transit metastases from SCC.[6,7] Immunosuppression has been reduced or altered for transplant recipients with aggressive cancers and should be considered for transplant recipients with in-transit metastases from SCC.[8,9] Based on clinical experience, we suggest the following strategy: (1) complete history and physical examination for detection of nodal or distant metastases; (2) appropriate imaging studies as indicated including MRI, CT, or PET-CT; (3) excision (either standard or Mohs) to remove all clinically apparent disease; and (4) wide field postoperative XRT (Figure 33.4). Although there is a paucity of data from controlled studies evaluating the use of postoperative radiotherapy for aggressive SCC, it has become increasingly common in practice. McCord et al., showed the effectiveness of radiotherapy alone or in combination with surgery in the treatment of microscopic and clinical perineural invasion by SCC.[10,11] Because surgical margins are inherently compromised in a metastatic process, radiotherapy is likely key in eradicating residual discontiguous SCC beyond the clinically apparent foci. In general, we suggest that a radiation field extending 5 cm in all directions beyond the distance of the furthest clinical or histologic evidence of disease from the primary tumor site would

be reasonable, modified based on anatomic and functional considerations. The decision to perform sentinel lymph node biopsy or to administer radiation to the regional nodes must be made on a case-by-case basis. Lymphoscintigraphy may be utilized to define which nodal basins are at risk prior to design of the radiation field. After treatment of the metastatic focus is accomplished with surgery and radiation, adjunctive medical therapy should be considered. This may include systemic retinoids, particularly acitretin. For transplant recipients, reduction of immunosuppression would also be an important consideration. Any alteration of immunosuppressants must be done under the guidance of the primary transplant physician. Capecitabine, a 5-flurouracil prodrug, has been shown to be effective in locally aggressive and metastatic SCC and may have role in management of in-transit metastases from primary cutaneous SCC.[12]

OUT C OME In-transit metastases are a poor prognostic indicator in transplant recipients. In one series, control was achieved in 33% of transplant recipients at 24 months compared to 80% of nontransplant patients.[4] Remissions ranged from 1–38 months with an average of 14 months. Follow-up ranged from 1 to 108 months with a mean of 24 months. At 24 months, diseasespecific mortality was 33% in transplant recipients versus 0% in nontransplant recipients. Strikingly, an additional 33% of transplant patients progressed to nodal or distant metastatic disease at 24 months (Table 33.3).

Management of In-Transit Metastatic SCC in OTRs

In-transit Metastatic SCC

Figure 33.3. Multifocal locally recurrent and in-transit metastatic SCC in a transplant recipient. This patient is at high risk for subsequent proximate and distant in-transit relapse.

Evaluation to exclude distant metastases Assess LN Reduce immunosuppression Adjunctive medical management

Surgical Excision + XRT

Role for SLND is not yet defined for SCC

Figure 33.4. Approach to management of in-transit metastatic SCC.

IN-TRANSIT METASTATIC SQUAMOUS CELL CARCINOMA IN ORGAN TRANSPLANT RECIPIENTS

Table 33.3 Outcome following diagnosis of in-transit metastases from cutaneous SCC Outcome

Transplant recipients

Nontransplant recipient

No evidence of disease Alive with disease Dead from disease

33% 33% 33%

80% 20% 0%

Source: From Carucci JA, Martinez JC, Zeitouni NC, et al. In-transit metastasis from primary cutaneous squamous cell carcinoma in organ transplant recipients and nonimmunosuppressed patients: clinical characteristics, management, and outcome in a series of 21 patients. Dermatol Surg. Apr 2004;30(4 Pt 2):651–655. With permission.

C O N C L US I O N S In-transit metastases from primary cutaneous SCC represent a form of relapse that is distinct from local marginal recurrence. Although rare, this phenomenon is more common in transplant recipients than in immunocompetent patients. Transplant recipients with in-transit metastases from primary cutaneous SCC appear to be predisposed to nodal and distant metastases. Multidisciplinary strategies including surgery, radiotherapy, retinoids, and decreased or altered immunosuppression should be considered for treatment of in-transit metastases from cutaneous SCC.

REFERENCES

1. Goldman GD. Squamous cell cancer: a practical approach. Semin Cutan Med Surg. Jun 1998;17(2):80–95. 2. Nguyen TH. Mechanisms of metastasis. Clin Dermatol. May–Jun 2004;22(3):209–16.

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3. Berg D, Otley CC. Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and management. J Am Acad Dermatol. Jul 2002;47(1):1-17; quiz 18–20. 4. Carucci JA, Martinez JC, Zeitouni NC, et al. In-transit metastasis from primary cutaneous squamous cell carcinoma in organ transplant recipients and nonimmunosuppressed patients: clinical characteristics, management, and outcome in a series of 21 patients. Dermatol Surg. Apr 2004;30(4 Pt 2):651–5. 5. Martinez JC, Otley CC, Okuno SH, Foote RL, Kasperbauer JL. Chemotherapy in the management of advanced cutaneous squamous cell carcinoma in organ transplant recipients: theoretical and practical considerations. Dermatol Surg. Apr 2004;30(4 Pt 2):679–86. 6. Carneiro RV, Sotto MN, Azevedo LS, Ianhez LE, Rivitti EA. Acitretin and skin cancer in kidney transplanted patients. Clinical and histological evaluation and immunohistochemical analysis of lymphocytes, natural killer cells and Langerhans’ cells in sun exposed and sun protected skin. Clin Transplant. Feb 2005;19(1): 115–21. 7. Chen K, Craig JC, Shumack S. Oral retinoids for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomized controlled trials. Br J Dermatol. Mar 2005;152(3): 518–23. 8. Otley CC, Berg D, Ulrich C, et al. Reduction of immunosuppression for transplant-associated skin cancer: expert consensus survey. Br J Dermatol. Mar 2006;154(3):395–400. 9. Otley CC, Maragh SL. Reduction of immunosuppression for transplant-associated skin cancer: rationale and evidence of efficacy. Dermatol Surg. Feb 2005;31(2):163–8. 10. McCord MW, Mendenhall WM, Parsons JT, et al. Skin cancer of the head and neck with clinical perineural invasion. Int J Radiat Oncol Biol Phys. Apr 1 2000;47(1):89–93. 11. McCord MW, Mendenhall WM, Parsons JT, Flowers FP. Skin cancer of the head and neck with incidental microscopic perineural invasion. Int J Radiat Oncol Biol Phys. Feb 1 1999;43(3):591–95. 12. Wollina U, Hansel G, Koch A, Kostler E. Oral capecitabine plus subcutaneous interferon alpha in advanced squamous cell carcinoma of the skin. J Cancer Res Clin Oncol. May 2005;131(5):300–4.

34 Metastatic Malignant Melanoma in Organ Transplant Recipients

Claas Ulrich, MD, Charlotte Proby, BA, MBBS, FRCP, Steve Nicholson, MRCP, PhD, and Catherine Harwood, MA, MBBS, MRCP, PhD

INTR ODUCT IO N

reported from the nontransplant population,[6,7] although it is important to appreciate that this registry is not populationbased and so cannot provide accurate data on incidence or clinical course. Not all series have reported a greater mortality in the immunocompetent population, with one recent series indicating no excess mortality amongst OTR.[3] A critical unanswered question in this regard is whether the likelihood of metastasis based on AJCC-staging criteria [6] is greater for OTR compared with the general population, particularly, if matched according to Breslow thickness and sentinel lymph node status. No published studies have had sufficient power to provide this information, because melanoma is uncommon and individual transplant populations are small. Two population-based studies in the United Kingdom found a similar incidence of posttransplant MM (7- to 8-fold increase over the local population), but the reported outcome is different. Le Mire et al. found that outcome based on Breslow thickness is similar in OTR compared with the general population,[3] whereas our own experience suggests that this is not necessarily the case.[4] The BartÕs and the London NHS Trust study identified 7 cases of de novo melanoma in a cohort of renal transplant recipients (RTRs) with a follow-up period of 8,557 patient years between 1990–2005. Three of these seven patients died from metastatic melanoma. Two deaths occurred within 2 years of diagnosis in patients whose Breslow thickness exceeded 2 mm, whereas the third RTR developed metastases from a lentigo maligna melanoma with Breslow thickness of just 0.4 mm. Although intriguing, such a series is clearly too small to statistically confirm a poorer prognosis in RTRs. Comparative studies to evaluate the impact of type, degree, and duration of immunosuppressive therapy on risk of metastasis are also lacking. The populationbased studies necessary to provide these data are only likely to be feasible if undertaken as multicenter collaborations.

The incidence, clinical presentation, and outcome of transplantassociated malignant melanoma (MM) are discussed more fully in Chapter 26. Surveys on the incidence of transplant-associated MM are limited, but those available have described a range from no increased risk up to an 8-fold increase relative to the nontransplanted immunocompetent population.[1–4]. Donorderived MM accounts for 28% of cases of donor-derived transplanted tumors,[5] making this the most common type of transplanted metastatic disease in organ transplant recipients (OTR). Information on other forms of posttransplant MM is scarce, and data on the incidence, management, and course of metastatic MM in OTR are almost nonexistent (Figure 34.1). The staging of metastatic (stage IV) melanoma was revised in 2001,[6] and is now delineated as summarized in Table 34.1. Treatment of posttransplant metastatic MM is directed by our experience in immunocompetent individuals, with the crucial added consideration of whether graft-preserving immunosuppression should be withdrawn or altered. Management of this difficult clinical problem is unlikely ever to be strictly protocoldriven given the current lack of a robust evidence base, but rather requires a careful balancing of many complex allograftand tumor-related factors, which is possible only through a multidisciplinary approach.

I N C I D E N C E A ND P R O G N O S I S OF M ET A ST A TI C M EL A NO MA IN OT R Available literature suggests a very poor prognosis (62% mortality) for transplant recipients with a history of MM before transplantation who have a recurrence of MM after transplantation.[7] Similarly, OTR with donor-derived MM have high mortality rates with a 5-year survival of only 5%.[7–12] These specific clinical scenarios have been discussed in Chapter 26. Examples of the clinical presentation of patients with metastatic melanoma are shown in Figure 34.2 and Figure 34.3. The prognosis for de novo MM occurring in OTR is not clear; the few studies that report outcomes mostly indicate a mortality rate of up to 50%.[4,13–16]Data from the Israel Penn International Transplant Tumour Registry (former Cincinnati Transplant Tumour Registry CTTR) suggest a 32% mortality rate among 177 transplant patients with de novo MM posttransplantation, apparently higher than that

TH ERAPE UT I C S TR AT EG IE S F OR ME TAS TATIC ME LANOM A IN TRANSPLANT RECIPIENTS Published data reflect the limited therapeutic choices available for patients with metastatic melanoma, regardless of immune status. In general terms, little meaningful progress in therapy for metastatic MM has been achieved despite more than 20 years of intense efforts. The goal for stage IV therapy is therefore primarily palliative and focuses on regression of the 228

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229

Figure 34.1. Management options for transplant patients with metastatic melanoma

tumor masses and symptom-free survival time. Therapeutic approaches may vary considerably from country to country, but whichever approach is used, one of the most important decisions to be made by clinician and patient is whether to withdraw, reduce, or modify immunosuppression as an adjunctive therapeutic strategy in management of this extraordinarily difficult clinical situation.

R E D U C T I O N OR MO D I F I C A T I O N OF IMMUNOS U PPRES SION

Withdrawal or Reduction of Immunosuppression The degree to which transplant-associated immunosuppression may adversely affect prognosis has not been quantified but, in the absence of such data, it is reasonable to assume that increased levels of immunosuppression will be associated with increased melanoma aggression. A major management decision in OTR with high-risk or metastatic MM is whether or not to withdraw immunosuppression with potential sacrifice of the allograft. Even if immunosuppressive drugs are not completely withdrawn, ‘‘severe’’ dose reduction has been recommended in advanced melanoma based on expert consensus opinion.[17] Although the dermatologist may be important in initiating consideration of immunosuppression, ultimately, management of immunosuppression should be performed by transplant physicians. There is very little information available on the effect of withdrawal of immunosuppression on outcome in de novo or posttransplant recurrence of pretransplant MM, and the data that are available primarily relate to donor-derived MM. Stimulated rejection of the allograft does not seem automatically to trigger an immunological destruction of transplanted melanoma. The largest series of allogenic melanomas published

so far documented 11 donors, all with retrospectively diagnosed MM. Among the 20 organ recipients, 17 developed stage IV metastatic MM after a median interval to clinical presentation of 10 months, and only 3 remained disease free. Of these 17 affected patients, 11 died from melanoma, 5 went into complete remission after cessation of the immunosuppression, and 1 required additional IFN-alpha therapy.[11] The type of allograft is a major determinant of the degree to which immunosuppression may be reduced, a consequence of the important differences in immunogenicity, outcome associated with rejection, and potential for alternative therapy if allograft failure ensues. Further complicating factors are the unquantified risks of allograft rejection within and between individuals for a given level of reduction of immunosuppression and the lack of a reliable marker of an individualÕs absolute level of immunosuppression. Although successful withdrawal of immunosuppression with removal of the allograft has been reported in a renal transplant recipient,[18] such an approach requires retransplantation for heart and liver allograft recipients and is clearly very risky. Successful retransplantation has been reported,[18,19] but it is by no means certain that removal of an allograft seeded with metastatic MM will provide a definitive cure, especially since the increased immunosuppression required for retransplantation may allow any residual metastatic disease to escape immunological control. Finally, perhaps the most important consideration in the decision to withdraw or reduce immunosuppression is the patientÕs perception of the choices available. Ultimately, it is patient preference that most influences the treatment course followed and, in our experience, some OTR with obvious rapid progression towards metastatic MM will opt to die with a functioning graft rather than discontinue their immunosuppression. In view of the poor prognosis, this may be an appropriate decision for OTR with metastatic MM.

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CLAAS ULRICH, CHARLOTTE PROBY, STEVE NICHOLSON, AND CATHERINE HARWOOD

Table 34.1 American Joint Committee on Cancer staging for metastatic melanoma Stage

Disease sites

LDH

M1a

Distant skin, subcutaneous, or nodal metastases Lung metastases All other visceral metastases

Normal

M1b M1c

Normal Elevated

Source: Adapted for use from American Joint Committee on Cancer 2001. With permission.

Modification of Immunosuppression Another potential approach for metastatic MM in OTR is to switch from calcineurin inhibitor -based immunosuppression with cyclosporine or tacrolimus to the mammalian target of rapamycin (mTOR) inhibitor sirolimus (rapamycin). The phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway controls many cellular processes that are important for the formation and progression of cancer, including apoptosis, transcription, translation, metabolism, angiogenesis, and cell

Figure 34.3. In transit metastatic melanoma surrounding a primary melanoma. (Courtesy of Clark Otley, MD, Mayo Clinic.)

cycle progression. Sirolimus shows antiangiogenic activities linked to decreased production of vascular endothelial growth factor (VEGF), with inhibition of metastatic tumor growth and angiogenesis in in vivo mouse models of malignant melanoma.[20] Furthermore, sirolimus was able to control the growth of established tumors with normal immunosuppressive doses, potentially allowing allograft-preserving immunosuppression to be continued. Retrospective analyses of OTR treated with sirolimus show a significantly lower nonmelanoma skin cancer (NMSC) rate compared to patient groups treated with calcineurin inhibitors. There are no specific data reporting sirolimus-induced tumor control in OTR with metastatic MM. However, a recent phase II trial of the sirolimus analogue, Temsirolimus (CCI-779), administered in a nonimmunosuppressive dosing schedule for MM in immunocompetent individuals was disappointing.[21] The encouraging in vivo mouse-model data, the clinical data in NMSC, and insights into mechanism of action of mTOR inhibitors imply that such an approach might still be beneficial in OTR with metastatic MM.

CHEMOTHERAPY

Figure 34.2. Metastatic melanoma in the parotid lymph nodes. (Courtesy of Clark Otley, MD, Mayo Clinic.)

The reference drug by which all treatment for malignant melanoma is judged is dacarbazine, a tetrazine alkylating agent that is administered intravenously and that produces measurable reduction in melanoma burden in about 20% of the immunocompetent population. Many clinicians would probably elect to use temozolomide, which is metabolised to the same active moiety as dacarbazine, but which is an oral preparation that has the added advantage of crossing the blood–brain barrier.[22–24] There is no evidence base on which to recommend the use of these drugs in OTR, but personal experience suggests that they are safe in such patients. It is important to recognize that treatment is designed, first and foremost, to improve symptoms and that there is no overall survival benefit to the use of chemotherapy.

METASTATIC MALIGNANT MELANOMA IN ORGAN TRANSPLANT RECIPIENTS

IMMUNOLOGICAL THERAPY Immunological strategies in the management of melanoma can be divided into cytokine therapy (predominantly interferon and interleukin-2) and vaccine therapy. There is little evidence for the use of either in the immunocompromised patient. Interferon-a at standard doses (3–5 million units subcutaneously, thrice weekly) has a response rate of around 15% in immunocompetent patients with metastatic disease.[25] There are no case series of this treatment being used in OTR. Individual case reports suggest activity is seen, although at the expense of possible allograft rejection.[18] This schedule is distinct from high-dose interferon-a as given in the so-called ‘‘Kirkwood regimen’’, which is used in the adjuvant setting for patients with completely resected stage III (nodal) melanoma in some centers and which is licensed for this use in the United States. High-dose interferon is not licensed for the metastatic (stage IV) setting, and there is considerable debate about its value in stage III disease, as the improvement in overall survival reported from the ECOG 1684 trial has not been supported either by subsequent studies,[26] by independent review of the primary source data,[27] nor by prolonged follow-up of the original trial patient population.[28] Interleukin-2 (IL-2) has shown its greatest promise when used in high doses to treat patients with unresectable metastatic disease confined to skin, subcutaneous tissues, and lymph nodes (Stage M1a).[29] An overall response rate in excess of 50% is seen in this patient group, although the toxicity of the treatment means that patients must be carefully selected. The potential for immune-mediated toxicity and the requirement for adequate cardiac and renal function would probably preclude the use of high-dose IL-2 in many OTR. Vaccine therapy of all types relies on the ability of the recipient to mount a cellular immune response and consequently is not a logical treatment for OTR. There are no published reports of vaccine-based approaches in the organ transplant population.

B IO CH E M O TH E R A P Y The publication of several randomized phase III trials has shown that biochemotherapy (the combination of chemotherapy and cytokines) has no survival benefit when compared to chemotherapy alone.[30] That it has a higher response rate is undeniable (together with its greater toxicity), and there may be circumstances in the immune competent population when biochemotherapy is felt to have a role. There are no reports of its use in OTR, and unlikely to be any formal studies now, following the publication of these negative phase III trials.

NEW AGENTS The era of molecular drug development continues to generate new drugs whose role in melanoma have yet to be defined.

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There are some features of these agents, however, that enable a degree of cautious speculation. Humanised anti-CTLA4 monoclonal antibody (MDX010, Ticilimumab) has shown activity in phase II trials, but response seems to be strongly associated with autoimmune side effects (immune breakout events).[31] Such an approach would be undesirable in an OTR if retention of the graft were necessary. Where loss of the graft is not an issue, however, it would be of interest to establish whether anti-CTLA4 therapy combined with immunosuppressive withdrawal resulted in enhanced antitumor activity. Tyrosine kinase inhibitors acting on the B-RAF signaling pathway have produced disease stabilization in pretreated patients and one of these, Sorafenib, is currently being studied in combination with chemotherapy in two phase III trials.[32] Immunological problems do not seem to complicate the use of this drug and it may be safe to use in OTR. There is, as yet, no data on this subject. The mTOR inhibitors have the unusual feature of being studied as both antirejection and antimelanoma drugs. Their use in metastatic melanoma has identified disease stabilization as the best response,[21,33] but this is the same ‘‘signal’’ of potential activity that has led to the studies involving Sorafenib. It is possible, therefore, that combination of mTOR inhibitors with chemotherapy may be a useful pathway for the management of metastatic melanoma in OTR.

L O C AL I Z E D TR E A T M E N T Because response to systemic treatment is generally poor in stage IV melanoma, active management often focuses on localized treatment including surgery and radiotherapy.

Surgical Management There are several scenarios where metastatic disease may be amenable to surgical control. The data on these clinical indications is derived from the immunocompetent population, but there is good reason to assume that metastatectomy may have a role in OTR, particularly where immunosuppression is being altered concurrently. 1. Resectable CNS disease: There is good evidence that patients with solitary brain metastases should undergo resection (without postoperative radiotherapy) where possible.[34,35] This will usually apply to patients who have only CNS disease, but may occasionally include patients with extracranial metastases who have good performance status. 2. Resectable gastro-intestinal metastases: There is an apparent survival advantage for resection of GI disease (including hepatic metastases) where surgery leads to complete remission.[36–38] Median survival for this highly selected group of patients is approximately 12 months, with up to 35% surviving to 5 years. Referral to

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a surgeon with experience and an interest in metastatectomy is essential. 3. Resectable pulmonary metastases: A favourable outcome from pulmonary metastatectomy is associated with complete surgical resection, a longer disease-free interval and a tumor-doubling time of more than 60 days.[39]

Radiation Therapy Melanoma is often perceived to be a radio-resistant tumor. However, there is increasing evidence that radiation therapy has an important role to play in melanoma, particularly disseminated disease in immunocompetent individuals [40] and it is reasonable to assume that the same is the case for OTRs, although, once again, an evidence base is lacking. Short course and even single fractions may be appropriate, for example, in palliation of bleeding and fungating skin metastases, relief of pain from nodal involvement and bony deposits, and reduction in neurological compromise and spinal cord compression from vertebral metastases. In such situations, successful palliation is expected in approximately two thirds of cases.[41] Radiotherapy is also a useful adjunct to management of brain metastases. Stereotactic radiotherapy delivers high radiation dose to a limited target volume, may be used for single or multiple brain metastases, and may be an option for inoperable metastases. The role of whole-brain radiotherapy after stereotactic radiotherapy or surgical excision is controversial. However, its use in combination with high-dose steroids in the setting of multiple metastases is reasonable, and several strategies for enhancing its effectiveness, such as combination with temozolomide, are currently being investigated.[42]

CONCLUSION The complexity of the clinical considerations, which must be balanced in OTR-associated metastatic MM, highlights the crucial requirement for management in a multidisciplinary setting, with involvement of dermatologists, surgeons, medical and radiation oncologists, clinical nurse specialists, pathologists, and radiologists. The lack of a firm therapeutic evidence base means that treatment, of necessity, is very much individualized rather than protocol based. Nonetheless, a conceptual protocol incorporating the various aspects of management discussed in this section, based on relevant known and theoretical factors, is presented in Figure 34.1. There is now a need for evidence-based data on predictive factors, outcome, and treatment strategies for this aggressive and notoriously therapy-resistant malignancy in OTR, all of which will only be achieved in the setting of multicenter collaborative studies. Finally, given the lack of reliably effective therapeutic options and the poor prognosis for disseminated MM, early diagnosis prior to metastasis remains the best approach. Routine followup of high-risk patients in a dermatology clinic within the transplant unit provides an opportunity for patient education

and skin surveillance [43] and is therefore, arguably, the best investment we can make to prevent the almost universally dismal outcome of disseminated malignant melanoma in OTR.

REFERENCES

1. Lindelof B, Sigurgeirsson B, Gabel H, Stern RS. Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol. 2000;143:513–9. 2. Hollenbeak CS, Todd MM, Billingsley EM, Harper G, Dyer AM, Lengerich EJ. Increased incidence of melanoma in renal transplantation recipients. Cancer. 2005;104:1962–7. 3. Le Mire L, Hollowood K, Gray D, Bordea C, Wojnarowska F. Melanomas in renal transplant recipients. Br J Dermatol. 2006;154:472–7. 4. Brown VL, Matin RN, Cerio R, Leedham-Green ME, Proby CM, Harwood CA. Melanomas in renal transplant recipients: the London experience, and invitation to participate in a European study. Br J Dermatol 2006 (in press). 5. Penn I. Transmission of cancer from organ donors [short survey]. Nefrologia. 1995;15:205–13. 6. Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19:3622–34. 7. Penn I. Malignant melanoma in organ allograft recipients. Transplantation. 1996;61: 274–8. 8. Penn I. Transmission of cancer from organ donors. Ann Transplant. 1997;2:7–12. 9. Stephens JK, Everson GT, Elliott CL, Kam I, Wachs M, Haney J, et al. Fatal transfer of malignant melanoma from multiorgan donor to four allograft recipients. Transplantation. 2000;70:232–6. 10. Birkeland SA, Storm HH. Risk for tumor and other disease transmission by transplantation: a population-based study of unrecognized malignancies and other diseases in organ donors. Transplantation. 2002;74:1409–13. 11. Morris-Stiff G, Steel A, Savage P, Devlin J, Griffith D, Portman B, Mason M, Jurewicz WA. Welsh Transplantation Research Group. Transmission of donor melanoma to multiple organ transplant recipients. Am J Transplant. 2004;4:44–446. 12. Elder GJ, Hersey P, Branley P. Remission of transplanted melanoma: clinical course and tumour cell characterisation. Clin Transplant. 1997;11:565–8. 13. Greene MH, Young TI, Clark WH Jr. Malignant melanoma in renaltransplant recipients. Lancet. 1981;1:1196–9. 14. Bouwes Bavinck JN, Hardie DR, Green A, Cutmore S, MacNaught A, OÕSullivan B, et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia: a follow-up study. Transplantation. 1996;61:715–21. 15. Veness MJ, Quinn DI, Ong CS, Keogh AM, Macdonald PS, Cooper SG, et al. Aggressive cutaneous malignancies following cardiothoracic transplantation: the Australian experience. Cancer. 1999;85:1758–64. 16. Leveque L, Dalac S, Dompmartin A, Louvet S, Euvrard S, Catteau B, et al. Melanoma in organ transplant patients [French]. Ann Dermatol Venereol. 2000;127:160–5. 17. Otley C, Berg D, Ulrich C, Stasko T, Murphy GM, Salasche SJ, Christenson LJ, Sengelmann R, Loss GE, Garces J. Reduction of immunosuppression for transplant-associated skin cancer: expert consensus survey. Br J Dermatol. 2006;154:395–400. 18. Suranyi MG, Hogan PG, Falk MC, Axelsen RA, Rigby R, Hawley C, Petrie J. Advanced donor-origin melanoma in a renal transplant recipient: immunotherapy, cure, and retransplantation. Transplantation. 1998;15:655–61.

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19. Loren AW, Desai S, Gorman RC, Schuchter LM. Retransplantation of a cardiac allograft inadvertently harvested from a donor with metastatic melanoma. Transplantation. 2003;76:741–3. 20. Guba M, Von Breitenbuch P, Steinbauer M, Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002;8: 128–35. 21. Margolin K, Longmate J, Baratta T, Synold T, Christensen S, Weber J, Gajewski T, Quirt I, Doroshow JH. CCI-779 in Metastatic Melanoma. A phase II trial of the California Cancer Consortium. Cancer. 2005; 104:1045–8. 22. Agarwala SS, Kirkwood JM, Gore M, Dreno B, Thatcher N, Czarnetski B, Atkins M, Buzaid A, Skarlos D, Rankin EM. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol. 2004;22:2101–7. 23. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000; Jan;18(1):158–66. Erratum in: J Clin Oncol 2000;18:2351. 24. Kiebert GM, Jonas DL, Middleton MR. Health-related quality of life in patients with advanced metastatic melanoma: results of a randomized phase III study comparing temozolomide with dacarbazine. Cancer Invest. 2003;21:821–9. 25. Legha SS. The role of interferon alfa in the treatment of metastatic melanoma. Semin Oncol. 1997;24(1 Suppl 4):S24–31. 26. Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, Smith TJ, Rao U, Steele M, Blum RH. High- and lowdose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000;18:2444–58. 27. Lens MB, Dawes M. Interferon alfa therapy for malignant melanoma: a systematic review of randomized controlled trials. J Clin Oncol. 2002;20:1818–25. 28. Kirkwood JM, Ibrahim J, Manola J. High-Dose Interferon Versus GM2 Vaccine in High-Risk Malignant Melanoma. J Clin Onc 2001; 19:4350. 29. Phan GQ, Attia P, Steinberg SM, White DE, Rosenberg SA. Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol. 2001;19:3477–82. 30. Atkins MB, Lee S, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM. A prospective randomized phase III trial of concurrent biochemotherapy (BCT) with cisplatin, vinblastine, dacarbazine (CVD), IL-2 and interferon alpha-2b (IFN) versus CVD alone in patients with

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metastatic melanoma (E3695): An ECOG-coordinated intergroup trial. Proc ASCO 2003 abstract 2847. Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Restifo NP, Haworth LR, Levy C, Mavroukakis SA, Nichol G, Yellin MJ, Rosenberg SA. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23:6043–53. Ahmad T, Marais R, Pyle L et al. BAY 43-9006 in patients with advanced melanoma: The Royal Marsden experience. J Clin Oncol. 2004;22:7506. Rao RD, Windschitl HE, Allred JB, Lowe VJ, Maples WJ, Gornet MK, Suman VJ, Creagan ET, Pitot HC, Markovic SN. Phase II trial of the mTOR inhibitor everolimus (RAD-001) in metastatic melanoma. Proc ASCO 2006 Abstract No: 8043. Sampson J, Carter J, et al. Demographics, prognosis and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg. 1998;88: 11–20. Fife K., Colman M, et al. Determinants of Outcome in Melanoma Patients with Cerebral Metastases. J Clin Oncol. 2004;22:1293– 1300. Agrawal S, Yao T, et al. Surgery for melanoma metastatic to the gastrointestinal tract. Ann Surg Oncol. 1999;6:336–344. Gutman H, Hess K, et al. Surgery for abdominal metastases of cutaneous melanoma. World J Surg. 2001;25:750–758. Wood T, DiFronzo L, et al. Does complete resection of melanoma metastatic to solid intra-abdominal organs improve survival? Ann Surg Oncol. 2001;8:658–662. Ollila D, Stern S, et al. Tumor doubling time: a selection factor for pulmonary resection of metastatic melanoma. J Surg Oncol. 1998;69:206–211. Stevens G, McKay MJ. Dispelling the myths surrounding radiotherapy for treatment of cutaneous melanoma. Lancet Oncology. 2006; 7:575–583. Overgaard J, von der Maase H, Overgaard M. A randomized study comparing two high-dose per fraction radiation schedules in recurrent or metastatic malignant melanoma. Int J Radiat Oncol Biol Phys. 1985;11:1837–39. Mehta MP, Khuntia D. Current strategies in whole-brain Radiation therapy for brain metastases. Neurosurgery. 2005;57(suppl 5): S33–44. Ismail F, Mitchell L, Casabonne D, Gulati A, Newton R, Proby CM, Harwood CA. Specialist dermatology clinics for organ transplant recipients significantly improve with photoprotection and levels of skin cancer awareness. Br J Dermatol. 2006 (in press).

35 Transplant Scalp: Severe Actinic Damage of the Scalp in Organ Transplant Recipients

Jennifer Z. Cooper, MD, and Marc D. Brown, MD

INTR ODUCT IO N

tors may contribute to the diffuse and almost contiguous actinic change often observed in the transplant scalp (Figure 35.1). It is well accepted that actinic damage can extend down into the follicular epithelium. The density of follicular structures of the scalp may provide a safe harbor that protects actinically damaged keratinocytes from superficial destructive modalities such as cryotherapy, preserving a persistent source of atypical cells that can repopulate the skin during the healing phase. Secondly, the concept of field cancerization is applicable to the scalp and other areas of the OTRÕs skin surface with the tendency to develop contiguous disease. First introduced by Slaughter in the 1950s, in reference to distinct perilesional histologic changes in oral squamous cell cancer, the concept of field cancerization has since been found to be applicable to diffusely actinically damaged areas of skin that are susceptible to skin cancer. Field cancerization is defined as the presence of genetically altered cells of monoclonal origin that do not yet possess the hallmark behaviors of cancer, invasive growth, and metastatic potential. A field lesion is defined as preneoplastic; however, the abnormal cells in the field show a high proliferative capacity. The presence and proliferating state of these genetically altered cells are risk factors for cancer and a possible factor in the development of secondary and seemingly recurrent cancers within the field.[3]

The management of skin cancer in organ transplant recipients (OTRs) represents a significant challenge. One anatomic area that presents distinct management difficulties is the scalp of transplant recipients. Diffuse precancerous and cancerous changes over the entire field of the scalp, known as ‘‘transplant scalp,’’ is very difficult to manage. Likewise, isolated aggressive skin cancer occurring on the scalp can exhibit aggressive behavior, and presents a different challenge.

E P I DEM IO LO G Y The incidence of diffuse scalp disease in the OTR is not well described. In an analysis of 1,069 cardiothoracic transplant recipients, 11.2% of patients developed nonlymphoid malignancies. Half of these malignancies were tumors of the head and neck with 96% being of cutaneous origin and 80% of those being squamous cell carcinoma (SCC). The scalp was the most commonly involved site, accounting for over 15% of head and neck tumors.[1] One particular characteristic that may predispose patients to the development of field disease of the scalp is androgenetic alopecia, especially if the hair loss preceded organ transplantation. In an 8-year population-based study of skin cancer in 1,558 renal transplant patients in Ireland, 622 posttransplant cutaneous malignancies were identified. Seventy-eight of these tumors were found on the scalp or neck of males, whereas only three were identified on the scalp or neck of females. This finding indicates that hair density may be a major factor in the development of scalp neoplasms in the transplant recipient.[2] Although patients with hair loss or thinning are more susceptible to actinic changes of the scalp, OTRs with normal hair density may also develop actinic keratoses and cutaneous carcinomas of the scalp. A thorough scalp examination is a crucial component of routine surveillance in all OTR patients.

M A N A G E M EN T A N D TR EA T M E N T Treatment options specifically for the actinically damaged scalp in organ transplant patients have not been addressed in the literature with controlled trials. A systematic approach can be helpful in the setting of seemingly overwhelming disease (Figure 35.2).

Management of Clinically Distinct Lesions If a complete skin exam reveals clearly defined lesions of the scalp, it is necessary to determine whether these lesions represent actinic keratosis or invasive SCC. Frequently, it may be difficult to clinically distinguish between these developmental stages of actinic disease. If the lesions represent actinic keratoses, traditional destructive modalities such as cryotherapy, curettage, topical 5-fluorouracil, imiquimod, photodynamic therapy, or a medium-depth chemical peel can be employed, with clinical follow-up to ensure eradication of the lesions as

PATHOG ENES IS The pathogenesis of diffuse scalp disease in OTRs is most likely similar to the pathogenesis of all cutaneous malignancies and premalignancies on other anatomic sites. Two important fac234

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and postoperative margin assessment may be utilized. In the setting of a high-risk tumor, particularly if there is perineural involvement, adjuvant radiotherapy may be considered. Sentinel lymph node biopsy or elective lymph node dissection may also be considered, but the role of such procedures has not been defined in clinical trials. In-transit metastatic SCC has been described in the organ transplant population, and can occur on the forehead and scalp. In a study by Carucci et al., 9 of 22 in-transit metastatic SCCs were located on the forehead and scalp.[4] If in-transit metastatic disease is found, treatment considerations should include surgical excision and a wide field of radiotherapy to eliminate any subclinical discontiguous foci of in-transit metastatic skin cancer. Sentinel lymph node biopsy may also be considered. In all cases of aggressive or metastatic SCC, the patientÕs immunosuppressive regimen should also be discussed with the transplant team to determine if cessation or decrease in medications can be considered.[4]

Management of Ill-defined Disease

Figure 35.1. Diffuse actinic damage with multiple focal lesions suspicious for possible invasive SCC on the scalp of a male transplant recipient with androgenic alopecia.

well as to inspect for new lesions. If the diagnosis is uncertain or invasive disease is suspected, a biopsy should follow. Although traditional biopsy techniques such as punch biopsy may be used, many clinicians prefer a deep-shave excision or saucerization followed by a destructive procedure such as electrodessication and curettage, cryotherapy, trichloracetic acid, or a combination of these procedures. By performing a more aggressive sampling during biopsy, the clinician can be assured that the base of the lesion is visualized during histological evaluation, as well as providing a therapeutic debulking of the lesion. If actinic keratoses or in-situ squamous cell carcinoma (BowenÕs disease) is determined by histology with the deep margins free of disease, the lesion may be considered treated and close clinical follow-up can ensue. If invasive SCC is revealed by pathology, additional treatment may be necessary. If a small tumor is histologically low risk, superficial, and well differentiated, and an aggressive biopsy followed by additional destruction has been performed, close observation may still be appropriate. Otherwise, surgical excision with appropriate (6-mm margins) with postoperative margin assessment or Mohs micrographic surgery is warranted. Higher-risk lesions, as defined in Figure 35.2 should be excised either with Mohs micrographic surgery or surgical excision with margin control. If intraoperative histologic margin control is not possible, wide excision with 1-cm margins

In a patient with diffuse or ill-defined scalp disease, careful examination should determine if there are specific areas suspicious for invasive disease. If these areas exist, biopsies should be taken. The histopathology of the lesions should determine the treatment course followed. If actinic keratosis or in-situ SCC is revealed, treatment of the field disease as described in the next paragraph can follow. If invasive SCC is found, destruction or excision of all invasive disease is desired, with the limitation that all superficial field disease may not be eradicated with these modalities. In the situation of complete excision of invasive disease with persistent positive margins with in situ disease, termination of surgery followed by adjuvant treatment for field disease is a reasonable approach, as described in the following text. Once potentially more aggressive lesions are cleared, treatment of the field disease should follow. Medium depth chemical peel may be considered as well as topical chemotherapeutic agents such as 5-fluorouracil. The use of imiquimod remains under investigation. As an immune response modifier, theoretical concerns exist as to the effects of the drug on the transplanted organ and the ability of the drug to be effective in an immunosuppressed host. In a randomized controlled study, 15 renal transplant patients with premalignant skin change used imiquimod cream three times per week for 16 weeks on 20–60 sq cm of skin surface. None experienced any detrimental effects on their transplant. Fifty percent of these patients had a reduction in skin atypia and viral warts, but only thirty-five percent had a reduction in actinic keratoses, much lower than the response rate usually seen in non-OTRs. There was no statistically significant reduction in SCCs.[5]. Photodynamic therapy (PDT) with methyl aminolaevulinate has also shown promise for the transplant patient with diffuse scalp disease [6].

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JENNIFER Z. COOPER AND MARC D. BROWN

OTR with scalp lesion(s) Diffuse or ill-defined disease

Bx lesion(s) suspicious for invasive SCC

Rx of lesions based on path then rx of field disease

Distinct clinical lesions

Treat field disease

Medium depth chemical peel Imiquimod 5-fluorouracil PDT

AKs

? Invasive Disease

Destructive modalitiesCryotherapy Curettage PDT 5 Fluorouracil Imiquimod

Punch biopsy or Deep shave excision (saucerization) +/ED&C, cryotherapy, TCA or combination

AK

SCC in-situ (Bowen's)

Invasive SCC

Follow clinically

Low risk

High Risk

Well differentiated Smaller size (<1cm)

Poorly diff Depth ( into subcutaneous fat or below galea) Perineural Recurrent Rapid growth

Standard surgical excision or Mohs

In-transit metastasis

Excision + adjuvant radiotherapy IL 5-fluorouracil IL methotrexate XRT +/- capecitabine

Mohs or WLE Consider: Adjuvant XRT SLNB/ELND Reduction / alteration of immunosuppression

Figure 35.2. An algorithm for the evaluation and treatment of transplant scalp.

S U MMARY Diffuse actinic disease of the scalp in an OTR is a significant treatment problem. The high density of follicular structures as

well as field cancerization enhance the difficulties encountered in this clinical situation. Aggressive management of both isolated neoplasms and actinic field disease is necessary to eliminate local disease and prevent the development of metastatic disease.

TRANSPLANT SCALP: SEVERE ACTINIC DAMAGE OF THE SCALP IN ORGAN TRANSPLANT RECIPIENTS

REFERENCES

1. Pollard, J.D., et al., Head and neck cancer in cardiothoracic transplant recipients. Laryngoscope, 2000. 110(8): p. 1257–61. 2. Moloney, F.J., et al., A population-based study of skin cancer incidence and prevalence in renal transplant recipients. Br J Dermatol, 2006. 154(3): p. 498–504. 3. Braakhuis, B.J., et al., A genetic explanation of SlaughterÕs concept of field cancerization: evidence and clinical implications. Cancer Res, 2003. 63(8): p. 1727–30. 4. Carucci, J.A., et al., In-transit metastasis from primary cutaneous squamous cell carcinoma in organ transplant recipients and nonim-

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munosuppressed patients: clinical characteristics, management, and outcome in a series of 21 patients. Dermatol Surg, 2004. 30(4 Pt 2): p. 651–5. 5. Brown, V.L., et al., Safety and efficacy of 5% imiquimod cream for the treatment of skin dysplasia in high-risk renal transplant recipients: randomized, double-blind, placebo-controlled trial. Arch Dermatol, 2005. 141(8): p. 985–93. 6. Dragieva, G., et al., A randomized controlled clinical trial of topical photodynamic therapy with methyl aminolaevulinate in the treatment of actinic keratoses in transplant recipients. Br J Dermatol, 2004. 151(1): p. 196–200.

36 Transplant Lip: Severe Actinic Damage of the Vermilion in Organ Transplant Recipients

Heather D. Rogers, MD, Elbert H. Chen, MD, and De´sire´e Ratner, MD

8 years, 10.8% developed skin cancers, 80% of which were SCC and 12% of which were on the lip.[1] Because both in situ and invasive SCC of the lip are more aggressive than their glabrous skin counterparts, dermatologists must have a low threshold for lip biopsy to ensure that malignant disease is identified and treated early in this high-risk population.

The most common skin cancer of the cutaneous and mucosal lip is basal cell carcinoma, found most often on the glabrous surface of the upper cutaneous lip of women. However, organ transplant recipients (OTRs) are at increased risk of developing squamous cell carcinoma (SCC) of the lower lip, which is frequently preceded by severe actinic damage. This chapter focuses on the diagnosis and treatment of actinic cheilitis and SCC of the lower lip vermilion in this high-risk patient population.

M A N A G E M EN T A N D TR EA T M E N T

Actinic Cheilitis CLINICAL PRESENTATION

The management of actinic cheilitis and skin cancer of the lip in OTRs is difficult to standardize, as there are few published studies in this population and much must be inferred from studies performed in the general population (Table 36.1). Treatments for focal actinic cheilitis include cryosurgery or electrodesiccation. Lubritz reported a 96.2% cure rate with cryosurgery in 53 patients with focal actinic cheilitis of varying degrees of severity.[2] Electrodesiccation may be a cost-effective treatment for localized, superficial lesions but recurrence rates have not been reported. The effectiveness and cosmesis of both treatments is highly operator dependent. In OTRs, actinic cheilitis is frequently diffuse, requiring treatment of the entire lower vermilion. Historically, extensive actinic cheilitis was treated with surgical vermilionectomy. In this procedure, part or all of the vermilion is surgically excised and the labial mucosa is advanced to the outer lip. Vermilionectomy requires sound surgical technique to ensure that only the superficial labial mucosa is mobilized. If the lip is undermined too deeply, significant morbidity may result, including hematoma formation, hypesthesia, and restriction of oral competency and restricted movement from scarring. Although highly effective for the treatment of actinic cheilitis, vermilionectomy has become less common with the advent of effective, less invasive treatment modalities. Carbon dioxide (CO2) laser resurfacing is currently considered the gold standard for treatment of diffuse actinic cheilitis. It is generally well tolerated, although moderate burning has been reported for up to 12 hours post procedure. Reepithelialization occurs within 2–4 weeks, typically with excellent cosmetic results. Patients with a history of HSV should be treated prophylactically with antiviral agents. Dufresne reported a total of 3 (2.1%) recurrences in 140 patients treated with CO2 laser resurfacing.[3] Scarring was the most common complication, reported in 15 of the 140 patients.

Actinic cheilitis is a premalignant condition of the vermilion of the lower lip, which is analogous to actinic keratosis arising on glabrous skin (Figure 36.1). Major risk factors for actinic cheilitis and SCC of the lip include exposure to ultraviolet radiation, fair skin, smoking, male gender, age over 50, family history of skin cancer, and human papillomavirus (HPV) infection. Actinic cheilitis presents as scaling or dryness of the lower vermilion, within which more distinct erythematous, keratotic, or erosive lesions can develop. Malignant transformation of actinic cheilitis occurs in 10– 20% of the general population, with higher transformation rates expected in OTRs. SCC in situ and invasive SCC present clinically in a continuum from solitary, sharply demarcated, red, scaly plaques to ulcerated bleeding nodules (Figure 36.2). Verrucous carcinoma of the lip, or oral florid papillomatosis, is a slow-growing low-grade SCC that rarely metastasizes. Often resembling a wart, it may be soft with multiple sinuses opening to the skin surface. HPV plays a role in the induction of verrucous carcinoma, and immunosuppressed patients have a higher incidence of these HPV-related growths.

I N C ID E N C E Lip carcinomas are the most common malignancy of the oral cavity, representing 0.6% of all malignancies in the United States. OTRs have a 10-fold greater incidence of BCC, a 65fold greater incidence of SCC, and a 20-fold greater incidence of lip SCC than nonimmunosuppressed individuals. In 1069 cardiothoracic transplant recipients followed for an average of 238

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Figure 36.1. Diffuse actinic cheilitis of the lower vermilion in a transplant patient (Courtesy of Clark Otley, MD, Mayo Clinic.) Figure 36.2. Actinic cheilitis with invasive SCC arising on left lower lip.

Photodynamic therapy (PDT) is a newer treatment option for diffuse actinic cheilitis. In a small case series, two treatments of topical methylaminolevulinate activated by 634 nm red light for actinic cheilitis in 3 patients led to clinical clearance in all patients with excellent cosmetic outcomes and no recurrences one year post treatment.[4] Pulseddye–laser-activated PDT with topical 20% 5-aminolevulinic acid solution led to complete clearance of actinic cheilitis in 13/19 patients after three monthly treatments.[5] PDT has a shorter recovery time and less postprocedure discomfort than CO2 laser, but appears to have lower clearance rates than CO2 laser. As with the CO2 laser, patients with a history of HSV should be treated with antiviral agents before undergoing PDT. Adverse effects of PDT include burning, pain, and erosion. Nonsurgical therapies, including 5-fluorouracil (5-FU) and imiquimod cream, have been used to treat diffuse actinic cheilitis, but no data on the use of these agents in OTRs has been reported. Epstein treated 12 patients with 5% 5-FU 3 to 4 times daily for 9–15 days.[6] All patients had clinical clearance, but 2 of the 12 recurred after a mean follow-up of 22 months. Smith treated 15 actinic cheilitis patients with imiquimod three times a week for 4–6 weeks, with complete clinical clearing 4 weeks after stopping therapy.[7] Side effects of both therapies included mild to moderate inflammation, edema, localized pruritus, tenderness, and burning.[6,7] If actinic cheilitis is severe, erosion of the area is to be expected, with consequent morbidity. No studies with long-term follow-up of patients treated with these topical modalities are available, nor are there any published data regarding the effectiveness of serial treatments with 5-FU or imiquimod for actinic cheilitis. Because of the limited data available for most of these options, patient preference and physician experience will play an important role in final treatment choice. Regardless of which modality is used, regular follow-up is imperative to ensure that incompletely treated or recurrent disease is biop-

sied to exclude malignant transformation, and that the patient receives additional therapy.

Squamous Cell Carcinoma Surgery is the standard of care for lip SCCs given their potential for aggressive behavior. These lesions can be excised by Mohs micrographic surgery (MMS) or standard excision, although the former yields higher cure rates. The 5-year recurrence rate in 7022 primary lip SCCs treated with nonMohs modalities (surgical excision, curettage and electrodesiccation, cryosurgery, or radiation therapy) was 10.5%, compared with 2.3% for 952 primary and recurrent lip SCCs treated with MMS.[8] Because SCCs often arise within actinic cheilitis, OTRs often require treatment of the remaining actinically damaged vermilion with additional therapy after surgical removal of their tumors. MMS is also the treatment of choice for other lip tumors which may arise in OTRs, including BCC. SCCs with high-risk features, including size greater than 2 cm, perineural involvement, rapid growth, recurrent nature or unresectable margins, are at increased risk of recurrence and metastasis. Rowe reported a 5-year metastatic rate of 13.7% for primary lip SCCs and 31.5% for recurrent tumors, compared with 5.2% and 25.1%, respectively, for their glabrous counterparts.[8] The 5-year survival of 1496 patients with metastatic lip SCC was 37.2%.[8] Additional work-up for patient with these high-risk tumors includes regional lymph node examination and clinically appropriate imaging to identify possible nodal metastases. Sentinel lymph node biopsy may be considered as a staging modality in OTRs with very high-risk SCC of the lip. Adjuvant radiation therapy may be a reasonable consideration for high-risk SCC, particularly with perineural invasion.

H E A T H E R D . R O G E R S , E L B E R T H . C H E N , A N D D E´ S I R E´ E R A T N E R

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Table 36.1 Treatment options for premalignant and malignant neoplasms of the vermilion in transplant patients, with classification of supporting evidence

Suspicious lip lesion in setting of severe actinic damage

History and physical exam, total body skin and regional lymph node exam

Lip biopsy

Actinic Cheilitis

SCC (in situ or invasive) or BCC

Focal – Cryosurgery (III) – Electrodesiccation (IV)

– Mohs Micrographic Surgery (II) – Standard excision (II)

Diffuse – Carbon dioxide (CO2) laser (III) – Vermilionectomy (III) – PDT (IV) – 5-FU (IV) – Imiquimod (IV)

If unresectable margins, >2 cm, or perineural invasion consider metastatic work up including – Appropriate imaging (III) – SLNB (IV)

Follow up every 3 to 6 months for history, total body skin exam, lymph node exam, and patient education regarding self examination of skin and sun protection.

Level I II III IV V

Type of Evidence Evidence is obtained from meta-analysis of multiple, well-designed, controlled studies. Randomized trials with low false-positive and low false-negative errors (high power). Evidence is obtained from at least one well-designed experimental study. Randomized trials with high false-positive and/or negative errors (low power). Evidence is obtained from well-designed, quasi-experimental studies such as non-randomized, controlled single-group, pre-post, cohort, time, or matched case-control series. Evidence is from well-designed nonexperimental studies such as comparative and correlational descriptive and case studies. Evidence from case reports and clinical examples.

PR EVENTION Patient education and sun avoidance are the most important factors in preventing lip cancers in OTRs. OTRs should apply SPF 30 sunscreen several times daily to the lips and wear a broadbrimmed hat in direct sunlight. Topical retinoids are effective in reducing actinic keratoses and can be used on the lips for OTRs with actinic cheilitis. Chemoprophylaxis with systemic retinoids has been shown to effectively decrease the number of premalig-

nant and malignant lesions in OTRs and should be considered in patients with severe actinic damage of the vermilion. REFERENCES

1. Pollard, J.D., et al., Head and neck cancer in cardiothoracic transplant recipients. Laryngoscope, 2000. 110(8): p. 1257–61. 2. Lubritz, R.R. and S.A. Smolewski, Cryosurgery cure rate of premalignant leukoplakia of the lower lip. J Dermatol Surg Oncol, 1983. 9(3): p. 235–7.

TRANSPLANT LIP: SEVERE ACTINIC DAMAGE OF THE VERMILION IN ORGAN TRANSPLANT RECIPIENTS

3. Dufresne, R.G., Jr. and M.U. Curlin, Actinic cheilitis. A treatment review. Dermatol Surg, 1997. 23(1): p. 15–21. 4. Hauschild, A., et al., Treatment of actinic cheilitis using photodynamic therapy with methyl aminolevulinate: report of three cases. Dermatol Surg, 2005. 31(10): p. 1344–7, discussion 1348. 5. Alexiades-Armenakas, M.R. and R.G. Geronemus, Laser-mediated photodynamic therapy of actinic cheilitis. J Drugs Dermatol, 2004. 3(5): p. 548–51.

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6. Epstein, E., Treatment of lip keratoses (actinic cheilitis) with topical fluorouracil. Arch Dermatol, 1977. 113(7): p. 906–8. 7. Smith, K.J., et al., Topical 5% imiquimod for the therapy of actinic cheilitis. J Am Acad Dermatol, 2002. 47(4): p. 497–501. 8. Rowe, D.E., R.J. Carroll, and C.L. Day, Jr., Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip Implications for treatment modality selection. J Am Acad Dermatol, 1992. 26(6): p. 976–90.

37 Transplant Hands: Severe Actinic Damage of the Hands in Organ Transplant Recipients

Siegrid S. Yu, MD, Rebecca S. Yu, MD, and Whitney D. Tope, MPhil, MD

PATHOG ENES IS

MANAGEMENT

Cumulative ultraviolet radiation exposure, Fitzpatrick skin type, and cellular DNA repair capacity are key factors in the pathogenesis of cutaneous malignancies. In transplant recipients, long-term immunosuppression is clearly implicated in tumorigenesis. There is also evidence that certain immunosuppressive medications and human papillomavirus types are oncogenic.

As in immunocompetent patients, many small nonaggressive SCCs in transplant patients can be effectively managed with conventional treatment modalities, including superficial ablative techniques (electrodessication and curettage, or cryotherapy) and excisional surgery (excision, Mohs micrographic surgery). Topical medical therapy with 5-fluorouracil or imiquimod cream is less effective on the hands, particularly in heavily affected transplant patients. Compared with SCC in immunocompetent patients, SCCs are more invasive and aggressive in transplant recipients, with increased multiplicity, recurrence, and risk for metastasis. The aggressive clinical presentation of SCC in transplant patients can create significant therapeutic challenges on the dorsal hand where anatomic, functional, and aesthetic considerations all play important roles in management. Despite optimal medical and surgical management, a subset of transplant patients develops potentially life-threatening tumors on the dorsal hand after having exhausted conventional therapeutic options. These high-risk patients present with two or more simultaneous tumors, large tumors (>2 cm), or rapid tumor recurrence on a background of diffuse, severe actinic damage (Table 37.1). In these patients, the conventional technique of repeated excision with defect closure may not be feasible. Following surgical tumor extirpation of such tumors, second intention healing or primary closure may be suboptimal; limited hand flexion may result from wound contraction and hypertrophic scarring or wound tension and dehiscence, respectively. Local flaps are often not viable options due to poor quality of adjacent donor skin, which is often actinically damaged, thin, and fragile. For a carefully selected group of patients with severe field cancerization of the dorsal hands, complete excision of the skin of the dorsal hand followed by resurfacing with split-thickness skin grafts may be considered. The challenges to the dermatologic surgeon in hand resurfacing include assuring adequate excision of the affected skin, preservation of function, and maintenance of cosmesis.

INCID ENCE A ND PREVENTIO N Long-term transplant recipients have a markedly increased risk of developing squamous cell carcinoma (SCC). Because of extensive cumulative exposure to ultraviolet light, the dorsal hand is a common site for malignancies. Patients who are older and more than five years post transplant have a particular tendency to develop flat warts and keratotic lesions on the dorsal hands. SCC accounts for up to 90% of malignancies in this anatomic location.[1] Although most SCC of the hands and fingers are effectively cured with standard surgical techniques, aggressive SCC of the hands and fingers may result in phalangeal, digital, or ray amputations, with consequent functional compromise. BCC of the hands is much less common than SCC, particularly in transplant patients.

CLINICAL PRESENTATION Squamous cell carcinoma frequently presents as an indurated, inflamed, or painful keratotic nodule, often arising in photodamaged skin. SCC may clinically resemble hypertrophic actinic keratosis, verruca vulgaris, or stucco keratosis, though carcinoma is often distinguished by the presence of an indurated base, thickness, and pain. Basal cell carcinomas in transplant patients are clinically and histologically similar to those seen in immunocompetent patients.[2] In heavily sun-damaged transplant patients, the skin of the dorsal hands may become diffusely dysplastic, with scattered verruca, actinic keratoses, and numerous in situ and invasive SCC. This condition has become known as ‘‘transplant hand’’ (Figure 37.1).

P ER IO P ERA T I VE C O NS ID ER A T IO N S Careful patient selection is critical for dorsal hand resurfacing. Optimal results require a concerted effort on the part of the 242

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243

Table 37.1 Indications for resurfacing of the dorsal hand with skin grafts in transplant patients. Indications for dorsal hand resurfacing Two or more simultaneous tumors or Large tumors (>2 cm) or Rapid tumor recurrences and Background of diffuse, severe actinic damage and numerous keratotic skin lesions and warts and Failure to respond to conventional medical and surgical management Figure 37.1. Classic transplant hand with multiple keratotic lesions and tumors.

surgeon, the therapist, and most importantly, the patient. Strict compliance with a perioperative regimen is crucial. Patients must be counseled on the time to full recovery, which often approaches several months to a year. Those who smoke or have bleeding diatheses may be at higher risk for graft failure. Additional risks include micromotion at the graft site, infection, and seroma or hematoma formation. The selected donor skin should be harvested from a nonsun-exposed area of the body, such as the anterior thigh or buttock. Split-thickness skin grafts from the scalp are cosmetically advantageous, but typically do not provide enough skin to cover the entire dorsum of the hand. The affected dorsal hand skin is excised, typically from the level of the wrist to the fingers, but may extend to the elbow. The excision should begin at the juncture of glabrous and nonglabrous skin, along the midaxial line of each digit (Figure 37.2). Care should be taken to completely excise the skin around the proximal and lateral nailfolds. In previous reports, SCC developed postoperatively in two nail folds, immediately outside the border of the skingrafted area.[3] The level of dissection is subdermal, superficial to the dorsal veins, and leaves the vasculature and extensor paratendons intact. If tumor extension requires extensive excision of these deeper tissues, a free flap may be required for coverage, as donor skin will not engraft to avascular structures such as denuded tendon. Intraoperative hemostasis should be meticulous to minimize risk of hematoma and seroma formation. Medium-thickness (~0.012–0.016 in., ~0.30–0.46 mm) split-thickness skin grafts are recommended. The thinner the skin graft, the higher the probability of graft take; however, thinner grafts are at higher risk for developing contracture.[4] The harvested skin is fenestrated to allow for fluid drainage in the early stages of healing. After the graft is sutured into place, a compressive bolster is fashioned to assist graft conformation to the contour of the dorsum of the hand and to decrease risk for hematoma or seroma formation. In the absence of specific clinical risk factors, antibiotic prophylaxis is typically not prescribed. Discomfort is usually greater at the donor site than at the recipient site.

Figure 37.2. Extent of surgical resection marked preoperatively with purple lines.

The hand is then splinted for a period of 5–7 days, without disturbance, to prevent shearing forces on the graft. In older patients, splint removal is recommended in 3 days to limit loss of hand mobility.[1] Recommendations have been

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SIEGRID S. YU, REBECCA S. YU, WHITNEY D. TOPE

Figure 37.3. Four-week postoperative split-thickness skin graft appearance; significant edema and purplish erythema exist.

Figure 37.4. Seven-month postoperative split-thickness skin graft appearance; persistent edema impairs full range of motion.

made to splint the hand in the intrinsic plus position, the wrist in 30 degrees of extension, the metacarpophalangeal joints at 80–90 degrees of flexion, and the interphalangeal joints in full extension, to prevent ligamentous contracture. After the initial dressing change and graft check, the hand is splinted for an additional two weeks prior to beginning hand therapy. Physical therapy is important to limit joint contractures, skin webbing, and syndactyly. Therapy includes active, active-assisted, and passive range of motion exercises, along with modalities for edema control and scar management. Mean time to recovery is 8.0 months +/ 5.6 months.[5]

Van Zuuren et al. performed a retrospective review of eleven kidney transplant recipients undergoing dorsal hand resurfacing and noted no SCC recurrences in the 16 hands resurfaced over a mean follow-up period of 4.7 years (range 2–12 years).[5] In contrast, three of the six hands not resurfaced developed nine SCCs. This very low recurrence rate compares quite favorably to a recurrence rate of 23% in patients treated with conventional surgical techniques.[3] Four patients experienced slight flexion limitations of the wrist due to cutaneous contractures. A single patient had 10–20% limitation of the proximal and distal interphalangeal joints and 20% limitation of the metacarpophalangeal joints. In these patients, the dysfunction was perceptible with fine motor skills such as tying shoe laces and fastening buttons. We suggest further evaluation of functional outcome following this procedure with goniometric range of motion and dynamometric (grip strength) measurements, and use of the AMA guidelines in determining residual functional impairment of the grafted hands. The concerns with cosmesis include scar formation, pigment mismatch, and altered texture of the grafted skin. The

LONG-TER M OUTCO ME M EASUR ES The key outcome measures with regard to dorsal hand resurfacing include graft survival, disease-free survival, preservation of function, and cosmesis. Although long-term outcome data is limited, published results appear encouraging. Schlotens et al. reported skin graft take was between 90–100%.[3]

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the graft over 12 months. In the case series described above, two patients had slight hypopigmentation of the grafted skin and one developed hypertrophic scarring. Patients should be counseled to consider the postoperative cosmetic appearance in comparison to severely actinically damaged skin covered with numerous keratotic lesions. In summary, for most transplant patients, standard management techniques are appropriate for skin cancer of the hand. However, for severely affected patients, dorsal hand resurfacing is a viable option for control of numerous, aggressive, potentially life-threatening SCCs manifesting as ‘‘transplant hand.’’ Patients must be selected carefully and counseled regarding side effects including cutaneous contractures potentially interfering with fine motor coordination, possible pigment mismatch, and scarring. This treatment should be reserved for a subset of high-risk patients who have exhausted conventional medical and surgical management.

REFERENCES

Figure 37.5. Twelve-month postoperative split-thickness skin graft appearance; at this stage, the appearance and function are very good.

grafts take considerable time to mature and look normal. Figure 37.3–Figure 37.5 demonstrate the maturation process of

1. Gloster HM, Daoud MS, Roenigk RK. The use of full-thickness skin grafts for repair of defects on the dorsal hand and digits. Dermatol Surg 1995;21:953–9. 2. Glover MT, Niranjan N, Kwan JTC et al. Non-melanoma skin cancer in renal transplant recipients: the extent of the problem and strategy for management. Brit J Plas Surg 1994;47:86–9. 3. Schlotens REM, van Zuuren EJ, Posma AN. Treatment of recurrent squamous cell carcinoma of the hand in immunosuppressed patients. J Hand Surg 1995;20A:73–6. 4. Germann G, Blome-Eberwein SA. Skin Grafts and Tissue Expanders in Hand Surgery. Lippincott Williams & Wilkins. New York 2004. Edited by Berger RA, Weiss A-P. 1119–30. 5. van Zuuren EJ, Posma AN, Scholtens REM et al. Resurfacing the back of the hand as treatment and prevention of multiple skin cancers in kidney transplant recipients. J Am Acad Dermatol 1994;31: 760–4.

38 Skin Cancer and Nevi in Pediatric Organ Transplant Recipients

Fatemeh Jafarian, MD, Julie Powell, MD, FRCPC and Afshin Hatami, MD, FRCPC

INTR ODUCT IO N

the pathogenesis of these tumors. Human papilloma virus may also be involved in the pathogenesis of nonmelanoma skin cancer by its promoter effect, acting in conjunction with ultraviolet radiation. Although the risk increases steadily with the length of time since transplantation, the mean interval between transplantation and occurrence of the nonmelanoma skin cancer depends mainly on the age at the time of transplantation. Patients receiving transplants at approximately 40 years of age develop skin cancer approximately 8 years after transplantation.[5] In contrast the mean interval between transplant and appearance of a first nonmelanoma skin cancer is 3 years for patients transplanted after the age of 60.[6] It has been suggested that the extent of preceding UV-induced cumulative damage is responsible for this variation in latency periods. Therefore, it is not surprising that patients who have received allografts during childhood rarely develop nonmelanoma skin cancer before the age of 18. Low cumulative sun exposure probably accounts for the low incidence of skin carcinoma during the childhood period. Although pediatric transplant patients do not develop skin cancer as rapidly as adult transplant patients, with their longer life expectancy, skin cancer may eventually become a significant problem. In fact, the risk of skin cancer continuously increases with time after transplantation as most patients will be exposed to ongoing sun-induced skin damage. Cutinho et al. estimated a standardized risk of 222 for nonmelanoma skin cancer in pediatric transplant recipients after an average follow-up of 15.5 years after transplantation.[7] This estimate should invoke significant concern over future skin cancer prevalence in pediatric transplant recipients among providers and patients alike. The data on skin cancer in pediatric transplant patients is derived from one large international database, one series from France, and one case report. In the data reported by Penn from the Cincinnati transplant tumor registry, the largest series of posttransplant malignancies, a total of 572 tumors occurred in 512 pediatric transplant recipients.[3] Carcinoma of the skin and lip made up 19% of these neoplasms. As expected, the majority of these tumors developed in young adulthood, at an average age of 26 years. Only 10 patients had nonmelanoma skin cancer that presented during childhood. Four had squamous cell carcinoma of the lip, 4 had squamous cell carcinoma of the skin and 1 had both basal cell carcinoma and squamous cell carcinoma. In this study, the squamous cell carcinomas were found to be more aggressive in pediatric than in adult recipients. They more commonly metastasized to regional lymph nodes and subsequently caused a higher death rate

Organ transplantation has gained increasing acceptance as the treatment of choice for many end-stage organ diseases in pediatric patients. Organ transplantation in recipients younger than 18 years of age accounts for 4–7% of all transplantations.[1] The life-long immunosuppression required for graft survival predisposes these patients to various neoplastic disorders. Transplant patients have an overall 5–6% incidence of malignancies, which is 100 times greater than the general population.[2] Although skin cancers are the most common malignant condition in adult organ transplant recipients, posttransplant lymphoproliferative disorder (PTLD) constitutes the most prevalent posttransplantation malignancy in pediatric recipients.[3] Skin carcinoma is the second most frequent malignancy associated with pediatric transplantation.[3] Although there are multiple studies on skin cancers in adult organ transplant recipients, only a few studies have focused on skin malignancies in pediatric transplant patients. In addition, considering the retrospective design and lack of long-term follow-up in these studies, it seems that they can not provide a complete picture of the frequency, type, and outcome of skin malignancies in pediatric transplant recipients particularly as they transition into adulthood. Prospective studies of larger numbers of pediatric transplant recipients and longer follow-up periods are needed. This chapter is based on the available data regarding skin cancer in pediatric solid organ transplant recipients.

N O N M E L A N O M A SK I N CA N C E R Solid organ transplant recipients have an increased risk of skin cancer compared to the general population. Nonmelanoma skin cancer, including primarily squamous and basal cell carcinomas, account for more than 90% of all skin cancers in adult transplant recipients. Eventually they affect more than 50% of the Caucasian transplant recipients.[4] Long-term immunosuppressive therapy results in impaired immunosurveillance. In this context, ultraviolet radiation acts as the major environmental risk factor contributing to the development of nonmelanoma skin cancer in transplant recipients. Ultraviolet radiation induces additional local and systemic immunosuppression. The occurrence of nonmelanoma skin cancer mainly on sun-exposed areas and notably in fair-skinned organ transplant recipients with significant sun exposure emphasizes the importance of ultraviolet radiation in 246

SKIN CANCER AND NEVI IN PEDIATRIC ORGAN TRANSPLANT RECIPIENTS

compared to adults. Squamous cell carcinoma of the lip was also overrepresented in pediatric compared to the adult transplant recipients. There is only one other case of nonmelanoma skin cancer reported after pediatric organ transplantation, which occurred in childhood.[8] The patient was a 13-yearold boy who was transplanted as a result of adriamycin cardiomyopathy. He developed a squamous cell carcinoma of the lower lip diagnosed by excisional biopsy 2.5 years after transplantation at the age of 15 years. Euvrard et al, in a study of 225 pediatric transplant patients, did not observe any cutaneous carcinomas during childhood.[1] However 4 of their patients developed nonmelanoma skin cancer between 10 and 20 years after transplantation at a mean age of 28 years. In summary, as more than 80% of transplanted children will survive to become adults, the prolonged duration of immunosuppression and concomitant cumulative sun exposure results in an increased risk of nonmelanoma skin cancer. As our pediatric organ transplant recipients survive for thirty years or more post transplant, the incidence of skin cancer experienced will likely be very high. Furthermore, with prolonged immunosuppression, the rates of aggressive tumor growth, metastasis, and even mortality will likely present a substantial problem. Strict photoprotection and dermatologic surveillance will be critical to prevent catastrophic skin cancer in these patients.

ME LA N OM A A N D ME L A NO C YT IC N EV I Adult organ transplant recipients are 3.6 times more likely to develop melanoma compared with the general population.[9] This suggests that immunosurveillance is important in the development of melanoma. In the largest series of posttransplant malignancies in pediatric transplant recipients, 14% of skin cancers in patients who received transplants during childhood were malignant melanomas compared with 5% in those who received transplants in adult life.[3] Half of the melanomas in pediatric transplant recipients occurred during childhood and before 18 years of age. This high incidence of melanoma in pediatric transplant recipients is of considerable concern, considering that 36% of these children were bone marrow allograft recipients and not organ transplant recipients. This data suggests that a low threshold for biopsying suspicious pigmented lesions in pediatric transplant patients may be warranted. The rarity of melanoma in pediatric age group limits the power of this study to quantify the precise increased incidence of melanoma in pediatric organ transplant recipients. Nevertheless immunosuppression beginning at an early age may be a risk factor for melanoma. Long-term data and careful monitoring are needed to determine the incidence of melanoma in the emerging and aging cohort of pediatric transplant recipients. In addition to an increased risk of melanoma, children who have undergone renal transplantation tend to develop higher numbers of benign and dysplastic melanocytic nevi, particularly on non-sun-exposed areas.[10,11] Multiple nevi

247

may appear as an eruptive phenomenon as shown in Figure 38.1. However, not all the transplanted children develop an increased number of nevi, suggesting an essential role for genetic predisposition.[1] There is a significant positive correlation between total number of nevi and the duration of immunosuppressive therapy.[10] Immunosuppression may permit the rapid proliferation of melanocytes to be accentuated in pediatric patients in whom the melanocytic activity is normally at its peak. However, immunohistochemical analysis of proliferation associated markers that are usually overexpressed by nevocellular nevi with malignant potential does not show any evidence of greater proliferative activity in melanocytic nevi from organ transplanted children compared to nonimmunosuppressed subjects.[12] Although in the general population, increased number of melanocytic nevi appears to correlate with an increased risk for development of malignant melanoma, this association has not been verified in the pediatric transplant population. Nonetheless, with a known increased risk of skin cancer, and a possible relationship between multiple nevi and melanoma, it makes sense to follow-up transplanted children with multiple nevi on a regular basis.[13]

K A P OS I’ S SA R CO MA An increased incidence of Kaposi’s sarcoma is a well-recognized complication of organ transplantation and associated immunosuppressive therapy. Kaposi’s sarcoma accounts for 3.4% of the malignancies following organ transplantation with a frequency of up to 500 times greater than in the general population, depending on geographic origin of transplant recipients.[4] It mainly affects patients of Mediterranean, African, or Caribbean origin. Human herpes virus 8 (HHV8) has been accepted as the etiological agent for Kaposi’s sarcoma. The clinical disease usually arises from reactivation of the virus as a result of immunosuppressive therapy in a previously infected recipient. However, HHV 8 can also be transmitted from the allograft donor to the transplant recipient.[4] Kaposi’s sarcoma in adult organ transplant recipients usually appears within a mean interval of 13 months after transplantation. However, pediatric recipients have a shorter time interval for appearance of Kaposi’s sarcoma, with an average of 4 months. Therefore, approximately 80% of Kaposi’s sarcoma developing in the pediatric transplant population occurs during their childhood. Unlike adults in whom most cases of Kaposi’s sarcoma initially present with skin lesions, the predominant form of the disease in children involves lymph nodes and viscera. Like adults, Kaposi’s sarcoma occurs more frequently in children who received kidney transplantation compared to recipients of other solid organs. Usually adult cases of post transplantation Kaposi’s sarcoma show complete or partial regression after reduction of immunosuppression, although this approach can lead to graft rejection. In contrast, it seems that the prognosis of Kaposi’s sarcoma in children is very poor even if immunosuppressive therapy is discontinued. The worse prognosis of Kaposi’s sarcoma in pediatric

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ommended with dermatological input to reinforce compliance. In addition, regular dermatological visits will allow early detection of suspicious neoplasms. For pediatric transplant patients who develop skin cancer, the management is essentially the same as for adults, including surgical excision or other therapeutic modalities and consideration of reduction or modification of immunosuppression.[1] Timely diagnosis and treatment of warts may be important because human papillomavirus may act as a cofactor in pathogenesis of squamous cell carcinoma.

REFERENCES

Figure 38.1. Multiple eruptive melanocytic nevi in a 12-year-old boy with a renal transplant. (Courtesy of Alfons Krol, MD.)

transplant patients could be related to more frequent visceral involvement in children.[3,14] Recently it has been suggested that sirolimus, an immunosuppressive agent that also has antiangiogenic properties, inhibits the progression of dermal Kaposi’s sarcoma in kidney transplant recipients while maintaining an antirejection effect.[15] Although there are no studies on the potential effects of sirolimus in Kaposi’s sarcoma associated with pediatric organ transplantation, this approach may be promising.

M A NAGE ME NT Pediatric transplant recipients are a particularly vulnerable group. Although skin cancer usually does not appear during their childhood, pediatric transplant recipients will likely suffer enormously from skin cancer in coming decades. Cumulative UV-induced damage is the main cause of the increased occurrence of skin cancer in transplanted patients, accentuated by lifelong immunosuppression. Therefore, sun protection during childhood and adolescence is an essential strategy to decrease the mortality and morbidity that these children will face during young adulthood and later years.[1] Sun protection in pediatric transplant patients may be more effective in preventing skin cancer than in adults who already have suninduced skin damage at the time of transplant. The amount of sun damage received in childhood plays a large part in the development of skin cancer later in life. In addition, sun protection during the first 18 years of life decreases the risk of nonmelanoma skin cancer by 80%.[16] Therefore, the potential to prevent skin cancer could be greater in pediatric than adult organ transplant recipients. Consistent and effective sunprotection education for these patients and their parents should be started as soon as transplantation is considered and should be continued long term. Regular follow-up is rec-

1. Euvrard S, Kanitakis J, Cochat P, Claudy A. Skin cancers following pediatric organ transplantation. Dermatol Surg. 2004; 30: 616–21. 2. I. Occurrence of cancers in immunosuppressed organ transplant recipients. Clin Transpl. 1994; 99–109. 3. Penn I. De novo malignances in pediatric organ transplant recipients. Pediatr Transplant. 1998; 2:56–63. 4. A. Skin cancers after organ transplantation. N Engl J Med. 2003; 348: 1681–91. 5. Euvrard S, Kanitakis J, Pouteil-Noble C, Dureau G, Touraine JL, Faure M, Claudy A, Thivolet J. Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation. J Am Acad Dermatol. 1995; 33:222–9. 6. Webb MC, Compton F, Andrews PA, Koffman CG. Skin tumours posttransplantation: a retrospective analysis of 28 years’ experience at a single centre. Transplant Proc. 1997; 29:828–30. 7. Coutinho HM, Groothoff JW, Offringa M, Gruppen MP, Heymans HS. De novo malignancy after pediatric renal replacement therapy. Arch Dis Child. 2001; 85:478–83. 8. Bernstein D, Baum D, Berry G, Dahl G, Weiss L, Starnes VA, Gamberg P, Stinson EB. Neoplastic disorders after pediatric heart transplantation. Circulation. 1993; 88:II230–7. 9. Hollenbeak CS, Todd MM, Billingsley EM, Harper G, Dyer AM, Lengerich EJ. Increased incidence of melanoma in renal transplantation recipients. Cancer. 2005; 104:1962–7. 10. Smith CH, McGregor JM, Barker JN, Morris RW, Rigden SP, MacDonald DM. Excess melanocytic nevi in children with renal allografts. J Am Acad Dermatol. 1993; 28:51–5. 11. Barker JN, MacDonald DM. Eruptive dysplastic naevi following renal transplantation. Clin Exp Dermatol. 1988; 13:123–5. 12. Kanitakis J, Euvrard S, Faure M, Claudy A. Proliferative characteristics of nevus in children with organ transplants. Ann Dermatol Venereol. 1999; 126:687–90. 13. Baron J, Krol A. Management of nevi in transplant patients. Dermatol Ther. 2005; 18:34–43. 14. al-Sulaiman MH, Mousa DH, Rassoul Z, Abdalla AH, Abdur Rehman M, al-Khader AA. Transplant-related Kaposi sarcoma in children. Nephrol Dial Transplant. 1994; 9:443–5. 15. Stallone G, Schena A, Infante B, Di Paolo S, Loverre A, Maggio G, Ranieri E, Gesualdo L, Schena FP, Grandaliano G. Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med. 2005; 352:1317–23. 16. Stern RS, Weinstein MC, Baker SG. Risk reduction for nonmelanoma skin cancer with childhood sunscreen use. Arch Dermatol. 1986; 122:537–45.

39 Dermatologic Surgery in Organ Transplant Recipients

Clark C. Otley, MD

STANDARD PRO C ED UR ES FOR M A N A G E M E N T O F S K I N C A N C E R IN O R G A N T R A N SP L A NT RE C I P I E N TS

M EG A S ES SI ON : E XC I SI ON O F N U ME R OU S SKIN CANCERS IN A S INGLE S ESSION When numerous primary cutaneous malignancies develop simultaneously in organ transplant recipients, expeditious treatment may be necessary to render the patient free of tumors. New skin cancers may develop over the course of weeks, lending urgency to surgery. Additionally, patients frustrated with extensive surgical procedures may postpone seeking medical care and may ultimately present with numerous malignancies. This severely affected population of organ transplant recipients may be candidates for a ‘‘megasession.’’ Martinez and Otley [5] defined a megasession as the simultaneous excision of 5 or more skin lesions in 1 operative session. Figure 39.1 shows a typical candidate for a megasession.

As in nonimmunosuppressed patients,[1] common and nonaggressive nonmelanoma skin cancer in organ transplant recipients can be managed with various standard techniques. Therapeutic options for basal and squamous cell carcinoma include electrodesiccation and curettage, curettage and cryotherapy, cryotherapy, excision, Mohs micrographic surgery, radiation, and topical 5-fluorouracil cream or imiquimod cream.[1] The decision-making process for selecting the optimal therapeutic modality for individual skin cancers considers various factors, including histologic subtype, anatomic location, history of recurrence, depth of tumor infiltration, and patient considerations.[1] In general, the modalities used to treat nonimmunosuppressed patients can also be used to manage nonmelanoma skin cancer in immunosuppressed transplant patients, but increased vigilance is necessary because of a higher risk of recurrence and metastasis.[2] This chapter describes the management of organ transplant recipients severely affected by skin cancer and the technical treatment of patients with simultaneous presentation of multiple tumors.

Indications A megasession is the most expeditious method of removing numerous skin cancers to achieve a tumor-free state; it may be the best option for patients with numerous rapidly developing tumors. Tumors should be removed before initiating treatment with topical chemopreventive agents (such as imiquimod or 5-fluorouracil) or systemic agents (including the oral retinoids acitretin or isotretinoin). Indications for a megasession include multiple lifethreatening or high-risk skin cancers that cannot wait for multiple surgical sessions, or the presence of multiple skin cancers that are lower risk (a megasession may facilitate simultaneous healing and minimize cost). In addition, megasessions may be more practical than multiple smaller surgical sessions for patients who travel far for expert surgical management. As a rule, it is helpful to have patients undergo smaller surgical sessions and experience a less rigorous surgical intervention to understand the advantages, disadvantages, and healing requirements associated with a megasession. Smaller treatment sessions also help patients and their surgeons determine patient tolerance of multiple simultaneous excisions of skin cancers. Many patients appreciate the convenience and ability to preclude skin cancer progression with megasessions.

RADIOLOGIC IMAGING OF SKIN CANCER I N O R G A N T R A N SP L A NT RE C I P I E N TS For most localized cutaneous malignancies, including those in organ transplant recipients, radiologic imaging is unnecessary. However, radiologic imaging may provide useful staging information for high-risk neoplasms with potential for metastasis, including squamous cell carcinoma and melanoma. Computed tomography is the method of choice for evaluating head and neck lymphadenopathy for metastatic involvement from a cutaneous malignancy, whereas magnetic resonance imaging is preferred for defining soft-tissue infiltration from deeply invasive tumors.[3] Occasionally, imaging with both methods may provide optimal staging information when both lymph node involvement and deep soft-tissue infiltration are suspected clinically. Positron emission tomography has gained acceptance as a highly sensitive, albeit less specific, imaging method for staging the entire patient for metastatic disease, but sensitivity is low for patients with microscopic metastatic disease.[4] Consultation with a radiologist is recommended to select optimal imaging methods for patients with particularly high-risk neoplasms.

Preparation A megasession requires a dedicated team of experienced health care providers in order to accomplish the goals safely and effectively. Patients and their families must have realistic expectations; they should understand the duration of the 249

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concentration, 0.25%) with epinephrine (diluted 1:400,000) is usually necessary to avoid overdosage. In addition, intramuscular or intravenous administration of drugs for anxiolysis, or moderate sedation, can be an important adjuvant anesthetic technique to maximize patient comfort. We routinely administer an oral anxiolysis medication (midazolam, 5–20 mg) or a combination of intramuscular analgesic (meperidine, 50–125 mg) and hydroxyzine (50–75 mg). If benzodiazepines and narcotics are used in combination, moderate sedation protocols with dedicated cardiorespiratory monitoring by certified providers can provide considerable comfort.[6] Additionally, local or regional nerve blocks and use of tumescent anesthetic solutions may enhance patient tolerance.

Techniques

Figure 39.1. Numerous skin cancers (transplant patient required megasession treatment).

A dedicated team must prepare all supplies before the procedure. We use a numbering system with anatomic diagrams to facilitate accurate labeling of pathologic specimens (Figure 39.2 and Figure 39.3). To optimize efficiency, we simultaneously perform the same procedural step on multiple sites. For example, when repairing defects, we undermine multiple sites at the same time, achieve hemostasis on those sites at the same time, and then suture the sites. This process facilitates efficient management and decreases operative time. All the procedures on one body part are performed at the same time; afterward, patients are repositioned for treatment of other body regions. Our Mohs histologic technicians facilitate tissue processing by assisting with specimen sectioning and inking. Key elements of a successful megasession are shown in Table 39.1.

Minimizing Risks megasession, the extent of postoperative wound care, the need for assistance with dressing changes, and activity restrictions during the early healing phase. A team of 2 to 3 dermatologic surgery nurses, a Mohs surgeon, and a surgical fellow or resident works to process numerous excisional or Mohs micrographic surgery specimens expeditiously and accurately. We also allot sufficient time for a Mohs histologic technician to process multiple specimens. A dedicated room for surgery allows patients to remain in the same room throughout the megasession. Patients should be encouraged to change into a hospital gown, which facilitates efficient exposure of affected body parts and minimizes soiling of clothing. Large areas of sterile skin preparation facilitate removal of multiple cancers. Procedures may range from 60 to 600 minutes, depending on the extent of tumor removal. The importance of technically skilled and dedicated nurses cannot be overemphasized.

Anesthesia To make the excision procedure tolerable for patients, local anesthetic (lidocaine) is used. Dilution of lidocaine (final

Simultaneous excision of numerous skin cancers inherently increases the odds of complications. Attention to sterile procedure and administration of preoperative prophylactic antibiotics to prevent postoperative wound infection are important, particularly with immunosuppressed patients. Our usual regimen includes administration of 1–2 g of second-generation cephalosporin 30 minutes before the procedure.[7] Postoperative antibiotics are also administered in the majority of cases, particularly if reconstruction is performed. Careful attention to hemostasis and expert application of pressure dressings minimize the risk of hematoma formation. Risk of deep venous thrombosis is minimized by repositioning and moving patients multiple times during the procedure. With Mohs micrographic surgery, patients are not under general anesthesia; they maintain neuromuscular function, and they often have periods of sitting and standing while waiting for results of the pathologic examination. Finally, talking to patients about their previous surgical experiences and tailoring the extent of surgery to their level of tolerance is important.

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Figure 39.2. Anatomic cards used to facilitate tumor processing.

Table 39.1 Key elements of a successful megasession Careful selection of patients with strong family support Adjuvant anesthetic techniques to minimize pain Use of dilute local anesthetic agents Excellent nursing care Sufficient time for the histologic technician to process samples Organized system for accurate management of multiple tumors Postoperative analgesia and antibiotics

Figure 39.3. Anatomic Mohs surgery maps for documenting tumor clearance.

minutes. Nine patients reported excellent tolerance of the procedure. One patient had unacceptable pain because only limited moderate sedation could be administered due to hypoventilation. No patients had serious complications, and 9 felt that the megasession met their expectations. Patients appreciated the convenience of a megasession (in terms of logistics and healing time) compared to numerous small sessions with a longer healing course. The authors concluded that carefully selected patients with extensive skin cancer can tolerate excisional surgery of many neoplasms in 1 session, with few and readily managed complications. Nine of ten patients preferred megasession tumor removal to treatment over several sessions with removal of fewer tumors per session.

Complications Outcomes Martinez and Otley [5] described their experience with 10 patients undergoing megasessions (removal of 5 or more skin cancers in 1 operative session); this is currently the only paper about megasession skin cancer excision in the medical literature. All patients had a history of numerous surgically removed skin cancers. The median number of lesions excised per megasession was 8 (range, 5–21 lesions). All patients received a local anesthetic, 9 received a sedative, and none had general anesthesia. The median procedure duration was 480

Martinez and Otley [5] documented few complications, and none were life threatening. Two patients were admitted to the hospital for overnight observation. One had transient hypoxemia (described earlier) and finished the session without further complication. The other lived 150 miles from the hospital and had undergone subtotal auriculectomy. The patient was observed overnight for pain control and to minimize risk of bleeding during traveling. Both patients were hospitalized without event and dismissed the next day. One patient had a graft failure, and another had a hematoma, neither of which was surprising, given the extensive cancer removal.

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Advantages The primary advantages of a megasession were described by Martinez and Otley.[5] Patients cited ‘‘less overall pain,’’ ‘‘less hassle,’’ ‘‘more efficient,’’ ‘‘no way we can keep up with the skin cancers otherwise,’’ ‘‘decreased travel,’’ and ‘‘more convenience.’’ These advantages are substantial for patients with extensive nonmelanoma skin cancer; in fact, megasessions are absolutely necessary for patients with cancers that develop too rapidly for periodic removal with standard (smaller) sessions. From the surgeonÕs perspective, a megasession demands substantial commitment of staff, operative time, and resources. Additionally, the need for substantial anesthesia and the occasional overnight hospitalization may increase the cost of providing care. Because insurance companies often discount payment for multiple procedures performed on the same day, reimbursement may be lower for a megasession than for multiple smaller sessions. However, the advantages for patients in these uncommon but serious situations may outweigh the disadvantages.

Disadvantages The primary disadvantage of a megasession is the possibility of increased complications with numerous surgical sites. Additionally, patients may be very tired after the extensive excision session, although study patients did not find this to be a problem.[5] Increased risks of infection and bleeding necessitate administration of prophylactic antibiotics, careful hemostasis, and expert application of pressure dressing.

R E C O N S T R U C T I O N A F T E R SK I N CA N C E R R EMO VAL IN ORG AN TR ANS P LANT R EC I P IE NT S Reconstructive principles for organ transplant patients with skin cancer are generally the same as those for patients with normal immune systems.[8] If a patient has multiple defects in close proximity, reconstruction may require creativity (Figure 39.4). However, because additional skin cancer is likely to develop within months in organ transplant patients, surgeons may avoid unduly complicated reconstruction if a patient has increased likelihood of recurrence or new cancer development at a nearby anatomic site. Dermatologic surgeons are more likely to allow wounds to heal by second intention when patients have megasessions because the risk of complications increases with numerous complicated reconstructive procedures.

M U LT I D I SC I P LI N A R Y M AN A G E M E N T O F S K I N C A N C E R S I N O R G A N TR AN S P L A N T R EC I P IE NT S Management of high-risk skin cancers in organ transplant recipients ideally is performed by a skilled and experienced dermatologist or dermatologic surgeon who can refine

Figure 39.4. Complex flap closure of multiple close defects after removal of numerous skin cancers.

treatment on the basis of clinicopathologic correlation. Occasionally, a particularly high-risk skin cancer may warrant multidisciplinary management, with consultation and collaboration with physicians specializing in head and neck surgery, oculoplastic surgery, general surgery, plastic surgery, radiation oncology, and medical oncology. The decision to use sentinel lymph node biopsy or adjuvant radiotherapy for high-risk tumors is complicated and requires experience, knowledge of the disease and surgical procedures, and a collaborative approach. Additionally, transplant physicians should be informed of patient status and involved in decisions regarding patient care, particularly if considering adjuvant administration of systemic retinoids or alteration of immunosuppressive regimens.

C O N C L US I O N Organ transplant recipients affected by multiple synchronous skin cancers may require aggressive surgical intervention with excision of numerous tumors in a single session. Megasession removal of extensive skin cancer can be a challenge for patients and surgeons alike. With careful preparation and judicious

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selection of patients, megasessions can be performed safely and result in high levels of patient satisfaction. REFERENCES

1. Martinez JC, Otley CC. The management of melanoma and nonmelanoma skin cancer: a review for the primary care physician. Mayo Clin Proc. 2001;76:1253–65. 2. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol. 2002;47:1–17. 3. Lanka B, Turner M, Orton C, Carrington BM. Cross-sectional imaging in non-melanoma skin cancer of the head and neck. Clin Radiol. 2005;60:869–77.

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4. Cho SB, Chung WG, Yun M, Lee JD, Lee MG, Chung KY. Fluorodeoxyglucose positron emission tomography in cutaneous squamous cell carcinoma: retrospective analysis of 12 patients. Dermatol Surg. 2005;31:442–6. 5. Martinez JC, Otley CC. Megasession: excision of numerous skin cancers in a single session. Dermatol Surg. 2005;31:757–61. 6. Otley CC, Nguyen TH. Safe and effective conscious sedation administered by dermatologic surgeons. Arch Dermatol. 2000;136: 1333–5. 7. Maragh SL, Otley CC, Roenigk RK, Phillips PK. Antibiotic prophylaxis in dermatologic surgery: updated guidelines. Dermatol Surg. 2005;31:83–91. 8. Chen EH, Johnson TM, Ratner D. Introduction to flap movement: reconstruction of five similar nasal defects using different flaps. Dermatol Surg. 2005;31:982–5.

40 Radiation Therapy in Organ Transplant Recipients

Michael J. Veness, MBBS, MMed, FRANZCR

INTR ODUCT IO N

SQUAMOUS CELL CARCINOMA

Nonmelanoma skin cancer (NMSC) is the most common malignancy worldwide. Most lesions (80–90%) arise on the sunexposed head and neck in middle-aged to elderly fair-skinned people. In the nontransplant, or immunocompetent population, basal cell carcinoma (BCC) occurs more often than squamous cell carcinoma (SCC). However, organ transplant recipients (OTR) experience not only a markedly higher incidence of NMSC compared to the general population but also a much higher incidence of SCC compared to BCC. OTR developing NMSC are often younger (<50 years old) and may experience multiple primary NMSC. In addition to occurring on the head and neck, NMSC in OTR also arise on the sun-exposed extremities especially the arms and dorsal hands. A subset of OTR develop aggressive and potentially life threatening skin malignancies (usually SCC) secondary to immunosuppression.[1] Other less common, but also potentially aggressive cutaneous malignancies encountered in OTR are listed in Table 40.1. Radiotherapy (RTx) is an important modality in treating patients with cutaneous malignancies.[2] The general principles for recommending RTx apply equally to OTR and immunocompetent patients; however, an immunosuppressed state must be factored in to any management decision, particularly in the adjuvant (postoperative) setting, where recurrent (local or nodal) disease may be life threatening. The recommendation of definitive RTx, defined as primary RTx as a therapeutic modality instead of surgery, may be made when the outcome (cosmetic and/or functional) is considered better with RTx than with surgery, especially when a clinician is constrained by the site or size of the lesion.[3] However, in most cases a non–RTx approach is usually considered, as most lesions are small and amenable to surgical excision or other treatments. The aim of adjuvant RTx, defined as RTx administered postoperatively in conjunction with surgery, is to reduce the risk of recurrence in the setting of an high-risk tumor (i.e., SCC with a close/positive excision margin). Adjuvant RTx may also be administered as an elective treatment to regional nodes to minimize the chance of nodal metastasis. The role of palliative RTx is also important in patients with advanced and/or incurable disease. The aim of this chapter is to discuss the role of RTx in OTR. The emphasis will be on the treating patients with a high-risk NMSC (SCC, Merkel cell carcinoma) because this will reflect the most common clinical scenario in which a recommendation of RTx may be considered.

Patients diagnosed with SCC have the potential to develop lifethreatening disease arising from locally advanced SCC or, more ominously, nodal or distant metastatic disease. In the latter case, treatment is primarily palliative and in the case of advanced nodal metastases, treatment is complex and morbid and ultimately many patients will die despite treatment. The majority of patients that progress to metastatic disease will develop nodal disease as a first site of relapse. Distant metastatic disease is more often a consequence of failure to control nodal disease despite treatment (discussed in the following text). It is therefore imperative to treat SCC at an early stage and prevent the development of metastatic nodal disease.

High-risk SCC The approach to treating patients with SCC is influenced by the risk of metastatic spread to regional lymph nodes. The incidence of metastatic nodal SCC is low (2–3%) in immunocompetent patients with small (<2 cm), thin (2–3 mm) and nonrecurrent SCC. However, immunosuppression puts a patient at higher risk for developing nodal metastases (usually parotid +/ cervical nodes). This risk is further increased when other unfavorable high-risk features [4] are also present, as noted in Table 40.2. There is evidence to suggest that at the time of diagnosis many primary SCC in OTR exhibit histological features considered high risk. In one study comparing immunocompetent and OTR, a significant proportion of OTR had thick (>5 mm) tumors and exhibited early dermal invasion compared to immunocompetent patients.[5]

Definitive Radiotherapy for Primary Site SCC Definitive RTx, defined as primary RTx as a therapeutic modality instead of surgery, should not be considered a first option in most patients with SCC. Especially for high-risk SCC, patients should undergo surgery with the aim of achieving complete tumor removal, taking into consideration cosmesis and function. The surgical defect after removal of SCC is often more extensive than for a comparable-sized BCC, with wider excision margins (>6 mm) usually recommended. For high-risk cutaneous SCC, Mohs micrographic surgery is recommended as the optimal surgical approach or, alternatively, wide local excision with intraoperative frozen section control.[6] In a study of immunocompetent patients with 254

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Table 40.1 Aggressive, cutaneous malignancies in organ transplant recipients l

l l l l

Merkel cell carcinoma (primary cutaneous neuroendocrine carcinoma) KaposiÕs sarcoma Malignant melanoma Angiosarcoma Adnexal carcinoma

Table 40.2 High-risk features for cutaneous squamous cell carcinoma Thick/deeply invasive (>4–5 mm) Large size (>2 cm) l Recurrence after previous treatment l High-grade l Presence of perineural or lymphovascular invasion l Lesions located on or around the ear (parotid drainage), or lower lip. l l

cutaneous SCC <2 cm in diameter, the authors report that with a 4-mm excision margin 95% achieved negative excision margins. With lesions >2 cm a 6-mm margin achieved a 95% rate of negative excision margins.[7] Incompletely excised SCC should not be merely observed. Recurrent SCC is associated with a higher incidence of nodal metastases compared to the primary SCC, with spread in 25–45% of patients depending on the anatomic site.[8] In a study involving nonimmunosuppressed patients, recurrent SCC were larger (2.4 cm vs. 1.5 cm; P<0.0001), more likely to involve perineural invasion (24% vs. 10%), lymphovascular invasion (17% vs. 8%) and invade beyond subcutaneous tissues (30% vs. 10%) compared to primary SCC. These findings suggest recurrent SCC as biologically more aggressive.[9] Definitive RTx may be considered an acceptable primary treatment option if the alternative is extensive surgery in patients with multiple medical comorbidities that pose an anesthetic risk. Alternatively, if patients refuse surgery, RTx is a reasonable option. For specific scenarios, such as lower lip involvement with SCC, RTx achieves excellent maintenance of function (oral competency) and cure rates comparable to surgery (see following text).[10]

Lip SCC Many clinicians categorize lip SCC as a skin cancer rather than an oral cancer. Most SCC of the lip (90–95%) arise on the lower lip as a consequence of chronic occupational and recreational sun exposure. For small to moderate-sized SCC of the lip, the outcome with surgery or RTx is similar. Mohs micrographic surgery or excision with frozen section control followed by wedge reconstruction or other appropriate technique can offer excellent results. When >30–50% of the lip is

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involved, surgical excision may be more likely to cause functional (oral competency) deficits. Complex reconstruction is an option but insensate tissue may be result from reconstruction with concomitant impact on function. RTx is therefore an excellent option to preserve lip function. The lower lip lends itself very well to treatment with orthovoltage (low energy) photons following insertion of a 3-mm intraoral lead shield to protect the mandible and teeth. Doses are similar to equivalent-sized SCC on other sites, with a total dose of 50–55 Gy in 20–25 daily fractions recommended.[10,11] Patients will experience symptomatic confluent mucocutaneous reactions of the irradiated lip that may require strong analgesics to palliate. Patients should be assured that these reactions will resolve in 4–6 weeks. Elective treatment to first echelon nodes (level I) may be considered in deeply invasive, recurrent lip SCC.

Perineural Invasion Perineural invasion is an uncommon but serious consequence of SCC.[12] Approximately, 5% of excised SCC have incidental perineural invasion although only a minority of these (30–40%) are associated with neurological signs (motor deficit) or symptoms. Formication (sensation of ants crawling) may herald the diagnosis of perineural invasion. More often, dysesthesia, paresthesia, numbness, and pain suggest nerve involvement. Diagnosis is often delayed as perineural invasion is often not suspected. The reporting of a normal CT or MRI scan does not exclude the diagnosis of advanced perineural invasion. Ultimately, demonstration of perineural invasion (histologically) is necessary to establish the diagnosis. Patients with limited perineural invasion may undergo surgery alone or surgery with adjuvant RTx. RTx may be recommended in cases of advanced perineural invasion extending beyond the skull base. Prognosis, once signs (craniopathies) or symptoms develop, is poor, with 5-year survival reported at around 50%. The finding of perineural invasion following excision of a periorbital SCC, especially in the supraorbital area (trigeminal VI/VII distribution), should warrant the consideration of further treatment.[13] The retrograde spread of SCC along the first division of the trigeminal nerve towards the orbital apex portends to a poor prognosis. The second division of the trigeminal nerve and the facial nerve are also potential conduits for spread back to the central nervous system (CNS). In some circumstances, further surgery, often extensive, may be undertaken to explore and dissect out potentially involved nerves. Alternatively RTx, often requiring multifield megavoltage photons treating neural pathways to the brainstem and often treating first echelon lymph nodes, may be recommended.[12,13] RTx has the advantage of avoiding surgery but with the risk of late radiation damage to orbital and CNS structures. Patients with perineural invasion are reported to have a higher risk of subclinical metastases in first echelon nodes, thus adjuvant surgical or radiation treatment to at-risk nodal basins may be indicated.

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Adjuvant (Postoperative) Radiotherapy Following Surgical Excision Adjuvant local RTx, defined as RTx administered postoperatively in conjunction with surgery, is recommended when excision is incomplete and reexcision is not considered advisable. The aim of adjuvant RTx is to eradicate residual microscopic disease. Margin status is the most important pathological factor in deciding whether a patient requires adjuvant radiation. However other factors, particularly those that would classify a patient as high-risk, may also need to be considered. It is imperative that any pathology report document and quantify margin status. A patient with an incompletely excised (positive or close margin) SCC remains at risk of local recurrence. Patients with local recurrence are at risk of developing nodal metastases. However, there is no consensus with regards to the definition of an acceptable surgical margin. Published recommendations, in the setting of lip and other cutaneous SCC, range from 3–10 mm. Excision margins of 4–5 mm should be considered a minimum in OTR especially if high-risk features are present. Ideally, complete margin clearance with Mohs micrographic surgery can optimize tumor clearance[14]. Especially, high-risk SCC may warrant adjuvant radiotherapy despite histologic negative margins. It is well documented that SCC with multiple simultaneous high-risk features (deep, large, poorly differentiated, recurrent, perineural invasion) have an unacceptably high likelihood of local recurrence despite seemingly adequate surgical removal. For these SCC, adjuvant RTx may be a reasonable consideration. Adjuvant RTx is an effective option to reduce the risk of local relapse, with one study of immunocompetent patients with lower lip SCC documenting a 37% local recurrence rate in excised patients not receiving adjuvant RTx (27% close [<2 mm]/positive margins) versus a 6% local recurrence rate in patients treated with surgery and adjuvant RTx (94% close/ positive margins).[11] In some circumstances the adjuvant RTx field may also encompass the draining nodes, thereby achieving the elective treatment of at risk nodes (e.g., temple or preauricular SCC and parotid nodes).

scalp) are at greatest risk of developing nodal metastases. Therefore, those with recurrent, deeply invasive (>4–5 mm) SCC in the vicinity of the parotid are potential candidates for elective nodal treatment. The role of sentinel node biopsy for adjuvant staging of high-risk NMSC is evolving, with only limited evidence to support a role in OTR.

Therapeutic Radiotherapy for Metastatic Nodal SCC Metastatic SCC to regional lymph nodes (usually in the head and neck) carries a grave prognosis and necessitates urgent referral to a multidisciplinary cancer service. An obvious index lesion is not identified in ~20–30% of patients, although patients invariably have a previous history of NMSC. A very common site for metastatic spread is to the parotid nodes from a previously treated scalp, forehead or ear SCC (Figure 40.2 and Figure 40.3). With operable cases (not involving skull base or carotid artery), surgery (parotidectomy +/ neck dissection) should be recommended. The risk of subclinical disease in adjacent nodal levels in the setting of clinical metastatic nodal disease is high (20–40%), and surgical staging and treatment of the neck nodes must be considered in any management decision. Elective neck dissection or RTx are both viable options to

Elective, Adjuvant Nodal Radiotherapy Patients with SCC exhibiting high-risk features are at increased risk of both local relapse and spread to nodes. Despite this, there is little consensus and limited data as to which patients should receive elective nodal treatment (surgery or RTx) to first echelon nodes. In some circumstances, nodes are treated by default in conjunction with treatment of the primary (e.g., wide field adjuvant RTx) (Figure 40.1). Other than this scenario, clinicians must consider the toxicity of electively treating first echelon nodes weighed against the serious consequences of metastatic nodal SCC (see following text). Although potential candidates who may benefit from elective nodal radiotherapy have been highlighted, evidencebased guidelines are absent.[6] Patients with SCC in proximity to the parotid gland (ear, preauricular cheek, frontotemporal

Figure 40.1. A 78-year-old male with well-defined brisk erythema within an irradiated field encompassing both the excision site of a high-risk squamous cell carcinoma and electively treating the first echelon parotid nodes.

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Figure 40.2. A 65-year-old male with an advanced squamous cell carcinoma of the earlobe with concomitant metastatic nodal disease in the parotid tail.

manage a clinically node negative, high-risk neck. Patients deemed medically inoperable are still potentially curable with high-dose (60–70 Gy) RTx alone, although prognosis is very poor. Those with advanced and inoperable disease should be considered for RTx to palliate symptoms or delay the consequences (pain, bleeding, fungation) of uncontrolled nodal disease. Adjuvant RTx to any dissected nodal region (head and neck, axilla, groin) is considered best practice and nearly always recommended to improve locoregional control, because the risk of nodal relapse remains high with surgery alone.[15] In the scenario of very limited nodal involvement, such as a single positive node without extracapsular spread, it may be appropriate to forgo adjuvant nodal RTx. However, it should be remembered that recurrent nodal disease, especially in an OTR, is usually incurable. Patients with regional nodal relapse usually have multiple unfavorable features (multiple nodes, extranodal spread, close/positive margins). Following surgery and adjuvant RTx, non-OTR patients can expect a 5-year disease-free survival of 70–75%; however, OTR have a worse outcome. Martinez et al. reported the outcome of 60 OTR all with metastatic skin cancer (85% SCC) with 27% having an unknown cutaneous index lesion.[16] In this study, median primary SCC size was 12 mm and median depth of invasion was 3.2 mm. Three-year disease-specific

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Figure 40.3. A 65-year-old male with recurrent squamous cell carcinoma at the site of a previous excision 6 months following incomplete excision. The patient now presents with both local recurrence and advanced parotid nodal metastases.

survival was only 56%. Interestingly, this would suggest a lower lesion size and depth-of-invasion threshold for the development of metastatic cutaneous cancer compared with immunocompetent patients. Similarly, in another study comparing the outcome of immunocompetent patients and immunocompromised patients (OTR/leukemia/lymphoma) with metastatic cutaneous SCC to the parotid/neck, the outcome for those immunocompromised patients was worse. These patients had a significantly higher rate of local and/or regional relapse compared to immunocompetent patients (56% vs. 28%).[17] Despite the poor prognosis of metastatic nodal SCC, the benefit of adding chemotherapy to adjuvant RTx is unproven and currently awaiting the mature results of randomized data, at least in the setting of non-OTR.[18] For OTR with very high-risk or metastatic SCC, the decision to markedly reduce immunosuppression in this setting should be considered and may be life saving.[19]

MERKEL CELL CARCINOMA Merkel cell carcinoma (MCC) is a primary cutaneous neuroendocrine (small cell) carcinoma. It is uncommon, difficult to

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diagnose clinically, and most often seen on the head and neck. MCC are aggressive and have a high propensity for locoregional relapse and distant spread. Patients with MCC should undergo a thorough workup to exclude distant disease. In smokers, a diagnosis of metastatic small cell lung cancer should be excluded. In OTR the incidence of MCC is higher compared with the general population and the outcome is worse.[20] In a study of 41 OTR with MCC, many were younger (<50 yrs; 29%) and most (68%) had nodal disease at diagnosis. Consequently, almost 60% died of their disease, a much greater percentage compared with immunocompetent patients treated with MCC.[21] MCC is both a radiation and chemotherapy-responsive carcinoma. Current recommendations are for wide local excision of the primary lesion with appropriate excision margins (10–20 mm). MCC will often invade the intradermal lymphatics resulting in in-transit metastases. The regional lymph nodes must always be staged and/or treated. There is evidence that the requirement for extensive local surgery to achieve clear excision margins, necessitating advanced reconstruction, may not necessarily lead to a better outcome compared to surgery plus adjuvant locoregional RTx. There are proponents of surgery alone in selected cases of MCC, citing excellent outcome without the need for adjuvant treatment.[22] However, the weight of published evidence strongly suggests that adjuvant locoregional RTx should nearly always be recommended and be considered best practice.[23] Treatment should include the excision site, in-transit tissue, and regional lymph nodes. The aim is to reduce the risk of locoregional relapse that occurs in 40–50% of cases treated with surgery alone. A typical dose fractionation schedule would be 50 Gy in 20–25 daily fractions usually requiring megavoltage photons or moderate energy (9–12 MeV) electrons plus tissue equivalent bolus. An alternative to adjuvant nodal radiation therapy may involve sentinel lymph node biopsy. The role of adjuvant chemotherapy is currently unresolved, though recent trials may ultimately lead to the incorporation of adjuvant carboplatin-/etoposide-based chemotherapy in a multimodality regimen. In advanced or metastatic disease, both palliative RTx and chemotherapy can offer effective symptom improvement.

DERMAL (IN-TRANSIT) METASTASES Dermal-based metastases may arise in patients with lung and breast cancer and represent a manifestation of distant metastatic relapse. Less commonly, patients with cutaneous SCC, MCC, and malignant melanoma can also develop dermalbased in-transit (or satellite) metastasis. In-transit metastases arise as rapidly enlarging subcutaneous masses with intact overlying skin, often in close proximity to the site of a previously excised high-risk skin cancer.[24] The scalp and forehead are frequent sites of involvement. Dermal metastases, although uncommon, probably have a higher incidence in OTR (Figure 40.4). Treatment needs to be individualized,

Figure 40.4. A 47-year-old male with recurrent dermal-based squamous cell carcinoma at the site of a previous excision. The advanced nature of his disease precludes cure although palliative radiotherapy was recommended.

but patients with localized and operable disease should undergo surgery followed by adjuvant RTx. All patients with intransit metastases should be considered for wide field RTx because of the high risk of subclinical dermal metastases extending well beyond any operative field. Patients considered inoperable should be offered definitive RTx and are still potentially curable. One study of patients (OTR and immunocompetent) with in-transit metastases reported only a minority (33%) of OTR-disease-free at 2 years compared with 80% of immunocompetent patients. OTR patients had a high propensity to develop regional or distant relapse.[25]

BASAL CELL CARCINOMA

Definitive Radiotherapy for Primary Site Basal Cell Carcinoma BCC are rarely life threatening even in OTR. Unlike SCC, the risk of nodal and distant metastases developing from BCC is minimal, and therefore, any treatment is aimed at securing local control. Small (<20 mm) BCC can be adequately cured by various modalities. Local control rates (90–95%) for excision or RTx are similar, and management decisions are based on treatment, patient, and tumor-specific factors. RTx for BCC is an option when tumor and patient factors favour a nonsurgical, full-thickness treatment modality. An appropriate candidate for RTx might be an elderly patient with a small BCC located on the nose (ala nasi or nasal tip). In such sites, excision and primary closure is not always easily achievable and small skin grafts or flaps are often required. Larger lesions (>20 mm) can still be cured with definitive RTx, although with increasing size and depth of invasion local control decreases, and surgery (+/ adjuvant RTx) may result in better local control.

RADIATION THERAPY IN ORGAN TRANSPLANT RECIPIENTS

Sites such as the inner canthus or lower eyelid may at times lend themselves more suitable to a nonsurgical approach. Cases of superficial BCC involving large areas, particularly the face, may also be better approached with RTx, although alternatives such as destructive modalities, topical chemotherapy, and photodynamic therapy are also options. The decision on treatment options must be individualized, and RTx may be an excellent option in specific clinical scenarios.

Adjuvant (Postoperative) Radiotherapy Following Surgical Excision A recommendation for further treatment is often made in the setting of an incompletely excised BCC. Of particular concern is a positive deep margin, especially when a local flap has been used in reconstruction. In such cases, deep recurrence can be difficult to detect. Lesions located around the midface and periorbital area, sites where undetected deep recurrence may be associated with significant local morbidity, should be aggressively managed with either further definitive surgery, particularly Mohs surgery, or with adjuvant radiation therapy. It is accepted that at least 20–30% of incompletely excised BCC locally recur.[26] However, predicting an individualÕs risk of recurrence is difficult and immediate reexcision may offer the best chance to achieve a negative margin. However, in certain circumstances, the involved margin precludes reexcision, for example, the periosteum of the nose; in such cases, adjuvant RTx is an option. The aim of adjuvant RTx is to reduce the incidence of local recurrence by eradicating residual microscopic BCC. Though recurrences are not usually associated with serious consequences, extensive salvage surgery may be required. Patients with the more aggressive subtype of sclerosing (morpheaform) BCC are at a higher risk of local recurrence and are best managed with definitive treatment in the setting of inadequate excision.

M I S C E LL A N E O U S RTx may play a role in treating less commonly encountered malignancies such as melanoma, KaposiÕs sarcoma, angiosarcoma, or adnexal carcinomas. However, in most cases, a nonRTx approach will be the first option, with RTx limited to the adjuvant setting to reduce the risk of locoregional relapse. Inoperable disease may be well palliated with low dose RTx. Similarly, patients with advanced inoperable NMSC or metastatic disease (e.g., skeletal metastases) often benefit from a short course of palliative RTx to delay progression and control pain and symptoms.

RADIOT HE RAPY OVER VIEW

Advantages of Radiotherapy RTx offers the advantage of a nonsurgical approach to skin cancer, thereby avoiding surgical morbidity, scarring, and the

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Table 40.3 Critical anatomic sites amenable to radiation therapy for skin cancer l l l l l l

Periorbit (especially medial canthus) Lower eyelid Nose (especially ala nasi and nasal tip) Nasolabial fold Lip Chin

need for reconstruction. In situations where reconstruction with grafts or flaps is required, better cosmesis may at times be achieved with RTx. Also, RTx fields can be tailored with generous margins to encompass areas of subclinical risk that, if excised, may require complex surgery. It is also relevant to note that negative excision margins in certain anatomic sites may be difficult to achieve. Typical sites where radiation therapy offers advantages in terms of preserving critical anatomic structures are listed in Table 40.3.

Disadvantages of Radiotherapy RTx has disadvantages as well. In particular, patients require a protracted (10–30 fractions) course of daily outpatient treatment. Of note, a second course of RTx cannot be delivered to the same irradiated tissues secondary to the risk of serious late consequences such as severe fibrosis, ulceration, soft-tissue/ cartilage necrosis, and neural damage. This is an important point in OTR because many will develop multiple new NMSC, and previous RTx will limit this modality as a treatment option. Patients may develop new NMSC close to previous RTx fields. If RTx is necessary in a patient with prior exposure to radiotherapy, it is important that RTx fields (previous and proposed) do not overlap and that adequate field margins (5–10 mm) are still treated. Skin cancers that deeply invading cartilage or bone are often better excised (+/ adjuvant RTx), although definitive RTx still remains an option (local control 60–70%). RTx to lesions located on the foot, anterior lower leg or dorsum of the hand, although not contraindicated, are best treated with other modalities. RTx to poorly vascularized, edematous tissues is often associated with poor healing. Skin cancers arising in sites of chronic ulceration, trauma, or burns should not to be irradiated if at all possible. Such sites often have poor vascularity and consequently poor healing.

Acute Reactions to Radiotherapy Acute RTx morbidity following localized superficial treatment is minimal (infield cutaneous erythema and desquamation) and limited to the irradiated field. Most patients can expect local discomfort and moist desquamation by the end of RTx and the following 2–3 weeks. Scabbing/crusting occur following moist desquamation with reepithelialization occurring at around 3–4 weeks after completion of radiotherapy. However,

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irradiating larger volumes with multiple megavoltage photon beams such as regional nodes (e.g., parotid, neck, axilla, groin) may be associated with increased site-specific reactions (e.g., xerostomia, taste alteration). In general, OTR do not experience markedly worse reactions compared to immunocompetent patients.

Late Reactions to Radiotherapy The late cutaneous cosmetic effects (telangiectasia, epidermal atrophy, pigmentation change) of superficial localized RTx, arising years after treatment, may be suboptimal, associated with the following treatment characteristics: l l l l

Continued unprotected sun exposure Large doses per fraction (>3–4 Gy) High total RTx dose (>55 Gy) Treatment to large fields.

Patients are strongly advised to use sun protection to decrease the incidence of further NMSC (especially important in OTR) and thereby maintain the best in-field cosmetic result. Smaller treatment fields (2–3 cm) tolerate hypofractionation (doses <3–4 Gy) better, but even so, if cosmesis is important, larger fractions should still be avoided. Patients should also be warned of the small risk (<5%) of late soft-tissue and cartilage necrosis, which is related to large tumor size and larger doses per fraction. Radiation-induced malignancy is a rare (1 in many 1000) and late (10–15 years) in-field consequence of irradiating NMSC. In the setting of elderly OTR, this risk is unlikely to be a factor in any management decision, but should be considered in younger patients.

CONCLUSION RTx is an important modality in treating OTR with skin cancer. It remains an effective option for definitively treating primary NMSC, although in most cases should not be considered as a first option. An important consideration when recommending RTx is that reirradiation to previously treated tissues is not an option. Adjuvant RTx to an excision site, draining lymph nodes, nodal bed, or neural pathway may be life-saving in situations of presumed residual microscopic cancer, usually in the setting of SCC. Radiation oncologists experienced in treating patients with skin malignancy should be considered an important part of any multidisciplinary approach to OTR.

REFERENCES

1. Veness MJ, Quinn DI, Ong CS, Keogh AM, Macdonald PS, Cooper SG, Morgan GW. Aggressive cutaneous malignancies following cardiothoracic transplantation: The Australian experience. Cancer 1999;85: 1758–64. 2. Veness MJ, Richards S. Role of modern radiotherapy in treating skin cancer. Austral J Dermatol 2003;44:159–68.

3. Tsao MN, Tsang RW, Liu FF, Panzella T, Rotstein L. Radiotherapy management for squamous cell carcinoma of the nasal skin: The Princess Margaret Hospital experience. Int J Radiation Oncology Biol Phys 2002;52:973–9. 4. Veness MJ. Defining patients with high-risk cutaneous squamous cell carcinoma. Austral J Dermatol 2006;47:28–33. 5. Smith KJ, Hamza S, Skelton H. Histological features in primary cutaneous squamous cell carcinomas in immunocompromised patients focusing on organ transplant patients. Dermatol Surg 2004;30: 634–41. 6. Stasko T, Brown MD, Carucci JA, et al. Guidelines for the management of squamous cell carcinoma in organ transplant recipients. Dermatol Surg 2004;30:642–50. 7. Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol 1992;27: 241–8. 8. Rowe DE, Carroll RJ, Day CD. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear and lip. J Am Acad Dermatol 1992;26:976–90. 9. Clayman GL, Lee JJ, Holsinger C et al. Mortality risk from squamous cell skin cancer. J Clin Oncol 2005;23:759–65. 10. Veness MJ, Ong C, Cakir B, Morgan G. Squamous cell carcinoma of the lip. Patterns of relapse and outcome: Reporting the Westmead Hospital experience, 1980–1997. Australas Radiol 2001; 45:195–9. 11. Babington S, Veness MJ, Cakir B, Gebski VJ, Morgan GJ. Squamous cell carcinoma of the lip: Is there a role for adjuvant radiotherapy in improving local control following incomplete or inadequate excision? ANZ J Surg 2003;73:621–5. 12. Garcia-Serra A, Hinerman RW, Mendenhall WM, Amdur RJ, Morris CG, Williams LS, Mancuso AA. Carcinoma of the skin with perineural invasion. Head Neck 2003;25:1027–33. 13. Veness MJ, Biankin S. Perineural spread leading to orbital invasion from skin cancer. Australas Radiol 2000;44:296–302. 14. Berg D, Otley CC. Skin cancer in organ transplant recipients: Epidemiology, pathogenesis and management. J Am Acad Dermatol 2002;47:1–17. 15. Veness MJ, Morgan GJ, Palme CE, Gebski V. Surgery and adjuvant radiotherapy in patients with cutaneous head and neck squamous cell carcinoma metastatic to lymph nodes: Combined treatment should be considered best practice. Laryngoscope 2005;115:870–5. 16. Martinez JC, Clark CO, Stasko T, Euvard S, Brown C, Schanbacher CF, Weaver AL. Defining the clinical course of metatstatic skin cancer in organ transplant recipients. Arch Dermatol 2003;139: 301–6. 17. Southwell KE, Chaplin JM, Eisenberg RL, McIvor NP, Morton RP. Effect of immunocompromise on metastatic cutaneous squamous cell carcinoma of the parotid and neck. Head Neck 2006 [Epub] 18. Martinez JC, Otley CC, Okuno SH, Foote RL, Kasperbauer JL. Chemotherapy in the management of advanced cutaneous squamous cell carcinoma in organ transplant recipients: Theoretical and practical considerations. Dermatol Surg 2004;30:679–86. 19. Otley CC, Berg D, Ulrich C, et al. Reduction of immunosuppression for transplant-associated skin cancer: expert consensus survey. Br J Derm 2006;124:395–400. 20. Veness MJ. Aggressive skin cancers in a cardiac transplant recipient. Austral Radiol 1997;41:363–6. 21. Penn I, Roy FM. MerkelÕs cell carcinoma in organ recipients: Report of 41 cases. Transplantation 1999;68:1717–21. 22. Allen PJ, Bowne WB, Jaques DP, Brennan MF, Busam K, Coit DG. Merkel cell carcinoma: Prognosis and treatment of patients from a single institution. J Clin Oncol 2005;23:2300–9. 23. Veness MJ, Morgan GJ, Gebski V. Adjuvant locoregional radiotherapy should be considered best practice in Merkel cell carcinoma of the head and neck. Head Neck 2005;27:208–16.

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24. Veness MJ. Cardiac transplant-related cutaneous malignancies in an Australian recipient: Immunosuppression, friend or foe? Clin Oncol 1998;10:194–197. 25. Carucci JA, Martinez JC, Zeitouni NC, Christenson L, Coldiron B, Zweibel S, Otley CC. In-transit metastasis from primary cutaneous squamous cell carcinoma in organ transplant recipients and nonim-

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munosuppressed: Clinical characteristics, management, and outcome in a series of 21 Patients. Dermatol Surg 2004;30:651–5. 26. Wilson AW, Howsam G, Santhanam V, Macpherson D, Grant J, Pratt CA, Townend JV. Surgical management of incompletely excised basal cell carcinomas of the head and neck. British J Oral Maxillofacial Surg 2004; 42:311–4.

41 Reduction of Immunosuppression for Transplant-Associated Skin Cancer

Clark C. Otley, MD, and Ryutaro Hirose, MD

immunosuppression are highlighted, with an emphasis on coordination by the transplant physicians and coordinators and communication between the transplant team and dermatologists. For the sake of simplicity, the terms reduction of immunosuppression and modification of immunosuppression will be referred to as a reduction of immunosuppression.

ABBREVIATIONS

mTOR PI3 PRA

mammalian target of rapamycin phosphotidylinositol 3 panel reactive antibody

BACKGROUND RAT IO NALE F OR A RE DUCTION OF IMMUNOS U PPRES SION

The miracle of solid organ transplantation is made possible by the administration of potent systemic immunosuppressant medications that prevent allograft rejection.[1] As a byproduct of this immunosuppression, skin cancer is the most common malignancy after organ transplantation, and it can result in both substantial morbidity as well as occasional mortality.[2,3] Although most primary skin cancers are easily treatable, the multiplicity of tumors in heavily affected transplant patients can cause substantial morbidity, with some patients experiencing more than 100 skin cancers per year. In addition, individual high-risk skin cancers may be associated with a considerably increased risk of metastasis and death.[4,5] The risk of metastasis from squamous cell carcinoma in an organ transplant patient is about 7%, which is double that of the general population.[6] Furthermore, in high-risk transplant patients from Sydney, Australia, 27% of deaths after posttransplantation year 4 were due to metastatic skin cancer, indicating that skin cancer mortality can be substantial.[7] Standard treatments for skin cancer in solid organ transplant patients include topical chemotherapeutic, surgical, and radiotherapy methods. These treatments are highly effective in most cases; however, for patients who present with numerous or high-risk skin cancers, therapeutic options may not be as effective. Adjuvant treatment for patients with such skin cancers may include the administration of systemic chemoprophylaxis with oral retinoids, cyclooxygenase-2 inhibitors, capecitabine, or other agents. In conjunction with the administration of chemoprophylactic agents, the reduction or modification of immunosuppression is a possible therapeutic strategy for reducing the multiplicity of subsequent primary skin cancers and the risk of metastatic skin cancer.[8] This chapter outlines the rationale for, and the evidence of, the potential efficacy of a reduction or modification of immunosuppression for severe transplant-associated skin cancer.[9] Indications for the consideration of reduced immunosuppression are presented, as are the logistics of reducedimmunosuppression. The potential risks associated with a reduction of

Multiple conceptual reasons support the reduction of immunosuppression as an effective adjuvant strategy for reducing the multiplicity of new primary skin cancers or improving the prognosis for organ transplant recipients with high-risk skin cancers. The reduction of potent systemic immunosuppression may result in the partial restoration of an effective innate antitumor immunity, an effective antineoplastic immune surveillance mechanism, or an effective immunity against copathogenic viruses. In addition, the carcinogenic effects of immunosuppressive medications, such as cyclosporine, may be reduced by decreased doses of immunosuppressants or even discontinuation of them altogether.[10] Finally, reduced levels of photosensitizing metabolites of immunosuppressants such as azathioprine may lessen the risk of ultraviolet-induced cutaneous immunosuppression.[11]

EFFICACY O F A RE DUCTION OF IMMUNOS U PPRES SION Multiple lines of evidence suggest that the reduction or cessation of immunosuppression may result in a decreased likelihood of skin cancer in organ transplant recipients.[9] Although no single line of evidence is sufficient to prove the efficacy of this therapeutic strategy, the combined evidence from multiple lines of imperfect evidence suggests that it may be a reasonable therapeutic strategy, albeit with incompletely defined risks to allograft preservation.

Randomized Controlled Trials of a Reduction of Immunosuppression The most compelling evidence to support a reduction of immunosuppression as a therapeutic strategy to reduce the risk 262

REDUCTION OF IMMUNOSUPPRESSION FOR TRANSPLANT-ASSOCIATED SKIN CANCER

of skin cancer in transplant patients is a randomized controlled trial by Dantal et al. [12] In this study, 231 renal allograft recipients were randomized 12 months after transplantation either to maintenance immunosuppression with azathioprine and normal-dose cyclosporine or to a reduction of immunosuppression with azathioprine and low-dose cyclosporine at trough levels of 75–125 ng/ml. The authors studied impaired allograft function due to rejection as the primary endpoint and found no evidence of decreased actuarial graft or patient survival. It should be noted that patients on the lowdose cyclosporine regimen did experience more episodes of acute rejection that were medically manageable. These data offer reassurance that allograft function and patient survival are not affected substantially by a reduction of cyclosporine 1 year after transplantation. For a secondary endpoint of the study, Dantal et al.[12] determined the number of cancers. The low-dose cyclosporine patients experienced significantly fewer cancers than did the normal-dose cyclosporine group (P < .034) (Figure 41.1). Of note, viral-associated cancers (e.g., skin cancer, Kaposi sarcoma, posttransplantation lymphoproliferative disorder, and cervical cancer) were significantly less common in the lowdose cyclosporine group than in the standard treatment group (P = .05). Although the reduction in skin cancers, including Kaposi sarcoma, was insufficient to be statistically significant, there was a strong trend toward a reduced incidence in the low-dose group (P = .09). The multiplicity of skin cancers was also reduced in the low-dose cyclosporine group. This study provides the most direct evidence that a reduction of immunosuppression may result in a reduced risk of new primary skin cancers.

Figure 41.1. Kidney transplant recipients in one study who took low-dose cyclosporine had a reduced incidence of cancer. Skin cancer was the most common malignancy and the difference in the incidence of skin cancer showed a trend toward significance (P = .09). (From Dantal J, Hourmant M, Cantarovich D, Giral M, Blancho G, Dreno B, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet. 1998;351:623–8. Used with permission.)

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Cessation of Immunosuppression Occasionally, patients with truly life-threatening skin cancers require consideration of complete cessation of immunosuppressant medication, despite the high risk of allograft rejection. Evidence of the possible beneficial effect of a complete cessation of immunosuppression on the course of skin cancer is presented in a study of 6 transplant patients with a history of prior skin cancer whose immunosuppressant medication was completely withdrawn.[13] In 5 of these 6 patients, immunosuppression was withdrawn after the allograft had failed for causes unrelated to skin cancer, and in the sixth patient, lifethreatening skin cancers were the stimulus for cessation of immunosuppression and resumption of dialysis. Of the 6 patients, 4 experienced a marked reduction in the incidence of skin cancer after cessation, whereas 2 did not appear to benefit from a reduction. In one patient, the reintroduction of immunosuppression after retransplantation resulted in a subsequent increase in the development of skin cancer. Although complete cessation of all immunosuppressant medication, with its high risk of allograft rejection and failure, would be an uncommon therapeutic strategy, this study suggests the possibly beneficial effect of reduction on skin cancer multiplicity.

R ED UC T I ON O F I MM UN OS U P P R E SSI O N F O R AG G R E S S I V E A N D M E T A S T A T I C S K I N CANCER In solid organ transplant recipients, 7% of squamous cell carcinomas will metastasize,[14] for a 3-year survival rate of 54%.[15] In a recent report, 9 transplant recipients with squamous cell carcinomas deeply invasive to the subcutaneous fat or muscles or with metastasis to lymph nodes were managed either with the maintenance of immunosuppression or with a severe reduction or cessation of immunosuppression.[16] In the 4 patients who had a reduction of immunosuppression, survival was statistically longer than it was in the 5 patients whose immunosuppression was maintained (P = .02). Additionally, in 2 of the 3 patients who survived, acceptable allograft function continued despite the substantial reduction of immunosuppression; in 1 patient, rejection occurred and resumption of dialysis was necessary after 24 months. This study suggests that a reduction of immunosuppression may improve the prognosis of patients with severe life-threatening or metastatic skin cancer.

Incidence of Skin Cancer Parallels Intensity of Immunosuppression Numerous high-quality studies from Scandinavian countries with outstanding cancer and transplant registries have documented a direct relationship between the intensity of immunosuppressant medication and the incidence of skin cancer, suggesting that reduced levels of immunosuppression might result in fewer skin cancers. In a Norwegian cohort of transplant patients, those receiving triple immunosuppression with

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cyclosporine, azathioprine, and prednisolone had a 2.8-fold higher risk of cutaneous squamous cell carcinoma compared with patients who were receiving double immunosuppression with azathioprine and prednisolone alone.[17] Although a reduction of immunosuppression was not an actual therapeutic strategy, reduced levels of immunosuppression appeared to be associated with a decreased incidence of skin cancer (Figure 41.2). A similar study by Glover et al.[18] noted increased risks (hazard ratio, 8.43) of squamous cell carcinoma in patients who were taking triple versus double immunosuppressants.[18] Numerous other studies have corroborated this association[19–21] Similarly, numerous studies have noted that allograft recipients, who are the most heavily immunosuppressed (i.e., cardiac transplant recipients), experience the highest rates of skin cancer development, whereas liver allograft recipients, who are the least immunosuppressed, experience the least skin cancer.[17,22–24] Renal transplant patients who are taking immunosuppression regimens that are intermediate in intensity may also experience an intermediate level of skin cancer development.

Reduction of Immunosuppression for Other Cutaneous Cancers There is extensive experience with reduction of immunosuppression for Kaposi sarcoma and posttransplantation lymphoproliferative disorder in transplant patients. Reduction of immunosuppression has been a standard management strategy for these conditions for many years and can lead to effective regression or remission of tumors.[25–37] In addition, there is one published report of spontaneous regression of Merkel cell carcinoma after reduction of immunosuppression.[38]

Sirolimus as a Cancer-sparing Immunosuppressant With the introduction of the mammalian target of rapamycin (mTOR) inhibitor sirolimus (rapamycin) as an immunosuppressant with unique antiangiogenic and antiproliferative characteristics, studies have documented a decreased incidence of skin cancer in patients maintained on sirolimusbased immunosuppressant regimens. In a recent study by Kauffman et al.,[39] the incidence of cancer in the United Network for Organ Sharing Transplant Tumor Registry was significantly lower in matched patients maintained on rapamycin or sirolimus than in patients on other regimens based on calcineurin inhibitors (P < .01). Kahan et al.[40] noted a 1.9% incidence of skin cancer in rapamycin-treated patients during 5-year follow-up, which was substantially lower than the 7% historical incidence of skin cancer in transplant patients. In a pooled analysis of rapamycin studies with 2-year follow-up, Mathew et al.[41] documented a significantly lower rate of skin cancer development in low-dose (P < .01) and high-dose (P < .05) rapamycin regimens compared to cyclosporine-based regimens alone. With further elucidation of the molecular mechanisms that are altered in specific tumors occurring in specific patients, one may be able to predict which tumors might respond to mTOR inhibitions (e.g., those with increased phosphotidylinositol 3-kinase (PI3) kinase activity or aberrant Akt pathway activation). The use of sirolimus in patients who need further surgery is tempered by observations of, and concerns related to, delayed and impaired wound healing. If surgical intervention is planned, one might consider deferring a conversion to sirolimus until 6 weeks postoperative, although no major complications of cutaneous surgery have been noted in patients taking sirolimus (unpublished observation, C. Otley). The data by which the reduction of immunosuppression is supported are less than perfect. Only one randomized controlled trial has demonstrated the effectiveness of a reduction of immunosuppression on development of skin cancer.[12] More supportive data would strengthen the case for the reduction of immunosuppression and would assist clinicians in evaluating the risk–benefit ratio for this potential adjuvant therapeutic strategy.

I N D I C A T I O N S AN D T H R E S H O L D S FO R C O N S I D E R A T I O N OF A R E D U C T I O N O F IMMUNOS U PPRES SION

Figure 41.2. In another study, kidney transplant recipients taking only cyclosporine and prednisolone (CP) or azathioprine and prednisolone (AP) had a reduced incidence of skin cancer compared with patients taking cyclosporine, azathioprine, and prednisolone (CAP). (From Jensen P, Hansen S, Moller B, Leivestad T, Pfeffer P, Geiran O, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40:177–86. Used with permission.)

Recent studies have outlined the opinions of expert panels about the extent of skin cancer burden or metastatic risk that might warrant consideration of a reduction of immunosuppression (42, Otley CC, Griffin MD, Charlton MR, Edwards BS, Neuburg M, Stasko T, Unpublished data). Reduction of immunosuppression has been conceptualized in 4 ascending levels: none, mild, moderate, and severe. These levels correlate with 4 potential adverse allograft outcomes from the reduction

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265

Table 41.1 Levels of reduction of immunosuppression and associated risks to allograft Reduction level

Risk level

Potential risks

None Mild

None Mild

Moderate Severe

Moderate Severe

No allograft dysfunction Risk of reversible allograft rejection or dysfunction requiring medical treatment Risk of partial permanent allograft dysfunction from rejection Risk of allograft failure with potential for death (liver and heart); need to resume dialysis or undergo retransplantation; potential death (kidney)

Source: Modified from Otley CC, Berg D, Ulrich C, Stasko T, Murphy GM, Salasche SJ, et al, Reduction of Immunosuppression Task Force of the International Transplant Skin Cancer Collaborative and the Skin Care in Organ Transplant Patients Europe. Reduction of immunosuppression for transplantassociated skin cancer: expert consensus survey. Br J Dermatol. 2006;154:395–400. Used with permission.

of immunosuppression that have been categorized into corresponding levels (Table 41.1).[42] Table 41.2 outlines the consensus responses of participating dermatologic experts on the level of reduction of immunosuppression and the associated potential risk to the allograft that would be warranted when confronted by various skin cancers.[42] Table 41.3 outlines the responses of transplant physicians and surgeons (Otley CC, Griffin MD, Charlton MR, Edwards BS, Neuburg M, Stasko T, Unpublished data). Additionally, the transplant physicians were queried about the perceived risk of rejection associated with varying levels of a reduction of immunosuppression (Table 41.4–Table 41.6) (Otley CC, Griffin MD, Charlton MR, Edwards BS, Neuburg M, Stasko T, Unpublished data). The interpretation of these data is limited by the lack of randomized controlled studies on the efficacy of a reduction of immunosuppression after skin cancer developed in transplant patients. To date, there have been no published guidelines to assist clinicians in making this common decision. Expert consensus, albeit not based on rigorous research findings, is grounded in experience and thus should prove beneficial to clinicians who are trying to conceptualize the risks and benefits of a reduction of immunosuppression as an adjuvant therapeutic strategy. Our survey findings indicate that both dermatologists and transplant physicians believe that a reduction of immunosuppressant medication is a reasonable adjuvant therapeutic strategy. Both expert panels emphasized that transplant patients should have stable allograft function and should be reliably available for follow-up monitoring before any consideration of a reduction of immunosuppression. As expected, the experts concurred that the degree of reduction of immunosuppression that is warranted should increase concomitant with increases in the morbidity and mortality risks from skin cancer (42,Otley CC, Griffin MD, Charlton MR, Edwards BS, Neuburg M, Stasko T, Unpublished data). Additionally, a reduction of immunosuppression was believed to be more reasonable for kidney allograft recipients than for liver or heart allograft recipients, because of the availability of dialysis as a backup therapy should kidney rejection occur. However,

the liver is a relatively tolerogenic organ with regenerative potential, so liver transplant recipients may well be able to tolerate fairly aggressive weaning from immunosuppression.[9] The most controversial scenario for both expert panels involved metastatic skin cancer with a very poor prognosis; some respondents suggested that aggressive reduction offered the only hope for prolonged survival, whereas others noted that, in the face of the greater likelihood of death, continued allograft function would be associated with a better quality of life (42,Otley CC, Griffin MD, Charlton MR, Edwards BS, Neuburg M, Stasko T, Unpublished data). These respondents further emphasized that the risks of skin cancer and the risks of a reduction of immunosuppression will vary by patient and that this management decision should be individualized by weighing all the risks, benefits, and clinical factors specific to each patient.

L O GIS T ICS O F MO DI F ICAT IO N OF IMMUNOSUPPRESSION Four basic strategies can be used to modify immunosuppression for transplant-associated skin cancer (Table 41.7). First, a reduction of immunosuppression may be accomplished by reducing the dose of one or more immunosuppressant medications. Reduction can also be accomplished through the complete cessation of one agent from a multiagent immunosuppressant regimen. The third strategy would involve complete cessation of all immunosuppressant medications, which should be considered only when confronted by lifethreatening skin cancer. Rarely would a patient experience a skin cancer risk great enough to warrant complete cessation of immunosuppressant medications because of the substantially decreased quality of life resulting from an extremely large number of skin cancers or the increased likelihood of a lethal metastatic skin cancer. The final mechanism for the modification of immunosuppression would include the substitution of an immunosuppressant with an agent with less skin cancer potentiation. As discussed above, sirolimus may be associated

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Table 41.2 Survey responses of transplant dermatologists on reduction of immunosuppression for specific skin cancers Extent of reduction considered by type of allograftb Skin cancer scenarioa

Kidney

Heart

Liver

No history of actinic keratosis or skin cancer History of actinic keratosis (no risk or mortality; marker for increased skin cancer risk in future) History of <1 NMSC per year (negligible risk of mortality, with <1 minor surgical procedure per year; patients handle this with ease; warning sign of possible future skin cancers) History of 2 to 5 NMSCs per year (0.5% risk of mortality in 3 years, minor to moderate surgical procedure 2–5 times per year; patients can usually handle this, but it starts to bother them; likelihood of numerous future skin cancers) History of 6 to 10 NMSCs per year (1% risk of mortality in 3 years, minor to moderate surgical procedure 6–10 times per year; patients can usually handle this, but it bothers them; high likelihood of numerous future skin cancers) History of 11 to 25 NMSCs per year (2% risk of mortality in 3 years, minor to moderate surgical procedure 11–25 times per year; this level of morbidity causes moderate distress and moderate disfigurement; depression may begin; high likelihood of severe future skin cancers) History of >25 NMSCs per year (5% risk of mortality in 3 years, moderate to severe surgical procedure >25 times per year; this level of morbidity causes severe distress and disfigurement; patients question whether transplant was worth it; depression is common; high likelihood of severe and possibly life-threatening future skin cancers) Individual high-risk skin cancer (1% mortality in 3 years with average risk of SCC, cutaneous and oral KS, or stage IA melanomad) Individual high-risk skin cancer (5% mortality in 3 years with moderate risk of SCC or stage IB melanomad) Individual high-risk skin cancer (10% mortality in 3 years with high risk of SCC, early Merkel cell carcinoma or stage IIA melanomad) Individual high-risk skin cancer (25% mortality in 3 years with very high risk of SCC or stage IIB melanomad) Individual high-risk skin cancer (50% mortality in 3 years from metastatic SCC, stage IIC/III melanomad, aggressive Merkel cell carcinoma, or visceral KS) Individual high-risk skin cancer (90% mortality in 3 years from untreatable metastatic SCC, stage IV melanomad, or metastatic Merkel cell carcinoma)

Nonec None

Nonec Nonec

Nonec Nonec

Mild

None

Mildc

Mildc

Mild

Mild

Mildc

Mildc

Mild

Mildc

Mildc

Mild

Moderate

Mild

Moderate

Mildc

None

Mild

Mild

Mild

Mild

Moderate

Mild

Moderate

Moderate

Mild

Moderate

Severeb

Moderate

Moderate

Severeb

Severe

Severe

Note: KS = Kaposi sarcoma; NMSC = nonmelanoma skin cancer; SCC = squamous cell carcinoma. Estimates of mortality risk are derived from data in immunocompetent patients; risk may be higher in immunosuppressed patients. b Appropriate level of reduction of immunosuppression should be individualized on the basis of specific patient- and tumor-related data. c Unanimous opinion. d Melanoma staging derived from the American Joint Commission for Cancer. Source: Modified from Otley CC, Berg D, Ulrich C, Stasko T, Murphy GM, Salasche SJ, et al, Reduction of Immunosuppression Task Force of the International Transplant Skin Cancer Collaborative and the Skin Care in Organ Transplant Patients Europe. Reduction of immunosuppression for transplant-associated skin cancer: expert consensus survey. Br J Dermatol. 2006;154:395–400. Used with permission. a

with a decreased risk of skin cancer in organ transplant patients. Therefore, physicians may consider conversion from a cyclosporine-based regimen to a sirolimus-based regimen as an adjuvant therapeutic strategy. Any alteration of immunosuppression in a transplant patient may be associated with adverse risks of allograft rejection and compromise. Therefore, strict monitoring after immuno-

suppressant modification is required by biochemical testing or allograft biopsies or both. If acute rejection or acceleration of chronic rejection is detected and thought to be due to the reduction of immunosuppression, then a resumption of higher levels of immunosuppression or the administration of high-dose corticosteroids or immune blocking antibodies may be necessary.

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Table 41.3 Survey responses of transplant physicians on reduction of immunosuppression for specific skin cancers Extent of reduction considered by type of allograftb Skin cancer scenarioa

Kidney

Heart

Liver

No history of actinic keratosis or skin cancer History of actinic keratosis (no risk of mortality; marker for increased skin cancer risk in future) History of <1 NMSC per year (negligible risk of mortality, with <1 minor surgical procedure per year; patients handle this with ease; warning sign of possible future skin cancers) History of 2 to 5 NMSCs per year (0.5% risk of mortality in 3 years, minor to moderate surgical procedure 2–5 times per year; patients can usually handle this, but it starts to bother them; likelihood of numerous future skin cancers) History of 6 to 10 NMSCs per year (1% risk of mortality in 3 years, minor to moderate surgical procedure 6–10 times per year; patients can usually handle this, but it bothers them; high likelihood of numerous future skin cancers) History of 11 to 25 NMSCs per year (2% risk of mortality in 3 years, minor to moderate surgical procedure 11–25 times per year; this level of morbidity causes moderate distress and moderate disfigurement; depression may begin; high likelihood of severe future skin cancers) History of >25 NMSCs per year (5% risk of mortality in 3 years, moderate to severe surgical procedure >25 times per year; this level of morbidity causes severe distress and disfigurement; patients question whether transplant was worth it; depression is common; high likelihood of severe and possibly life-threatening future skin cancers) Individual high-risk skin cancer (1% mortality in 3 years with average risk of SCC, cutaneous and oral KS, or stage IA melanomaf) Individual high-risk skin cancer (5% mortality in 3 years with moderate risk of SCC, or stage IB melanomaf) Individual high-risk skin cancer (10% mortality in 3 years from high-risk SCC, early Merkel cell carcinoma, or stage IIA melanomaf) Individual high-risk skin cancer (25% mortality in 3 years from very high-risk SCC or stage IIB melanomaf) Individual high-risk skin cancer (50% mortality in 3 years from metastatic SCC, stage IIC/III melanomaf, aggressive Merkel cell carcinoma, or visceral KS) Individual high-risk skin cancer (90% mortality in 3 years from untreatable metastatic SCC, stage IV melanomaf, or metastatic Merkel cell carcinoma)

Nonec Nonec

Nonec None

Nonec Nonec

None

None to mildd

Mild

Mildc

Mildc

Mild

Moderate

Moderate

Moderate

Moderatec

Moderate

Moderate

Moderate

Moderate

Moderatee

Moderate

Moderatee

Mild

Moderatee

Moderatee

Moderatee

Severee

Moderate

Moderate

Severe

Moderatee

Severec

Moderate to severed Severec

Severec

Severec

Severe

Severe

Note: KS = Kaposi sarcoma; NMSC = nonmelanoma skin cancer; SCC = squamous cell carcinoma. Estimates of mortality risk are derived from data in immunocompetent patients; risk may be higher in immunosuppressed patients. b Appropriate degree of reduction of immunosuppression should be individualized on the basis of specific patient- and tumor-related data. c Indicated agreement of >75% of respondents (strong consensus). d In cases where opinions were evenly split, both answers are listed (split opinion). e Indicates no choice received majority (>50%) of votes (controversial). f Melanoma staging derived from the American Joint Commission for Cancer. Source: Modified from Otley CC, Grin MD, Charlton MR, Edwards BS, Neuburg M, Stasko T, Unpublished data. Used with permission. a

Individualization of a Reduction of Immunosuppression Considerations germane to the decision to reduce immunosuppression for skin cancer include patient-specific factors,

such as the quality of the allograft match, any prior history of allograft rejection, panel reactive antibody (PRA) activity, and other allograft concerns. In patients with evidence of potent antiallograft immunity, extreme caution must be exercised with the reduction of immunosuppression. The

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Table 41.4 Level of risk of renal allograft rejection or compromise with varying reductions of immunosuppression Reduction of immunosuppression scenario Reduction

Most likely riska

full dose; antiproliferative full dose;

None

Noneb

full dose; antiproliferative full dose;

Reduce antiproliferative 50%

None

full dose; antiproliferative full dose;

Reduce antiproliferative 100%

Mild

full dose; antiproliferative full dose;

Reduce antiproliferative 100%; reduce calcineurin inhibitor 25% Reduce antiproliferative 100%; reduce calcineurin inhibitor 75% Complete cessation of calcineurin inhibitor and antiproliferative; increase prednisone to 40 mgc Switch from calcineurin inhibitor to sirolimus

Mild

Baseline regimen Calcineurin inhibitor prednisone 5 mg Calcineurin inhibitor prednisone 5 mg Calcineurin inhibitor prednisone 5 mg Calcineurin inhibitor prednisone 5 mg Calcineurin inhibitor prednisone 5 mg Calcineurin inhibitor prednisone 5 mg Calcineurin inhibitor prednisone 5 mg

full dose; antiproliferative full dose; full dose; antiproliferative full dose; full dose; antiproliferative full dose;

Moderate Severeb Mild

a

Refer to Table 41.1 for examples of allograft risks. Indicates agreement of >75% of respondents (strong consensus). c Two respondents indicated that this was not a realistic scenario. Source: Modified from Otley CC, Griffin MD, Charlton MR, Edwards BS, Neuburg M, Stasko T, Unpublished data. Used with permission. b

Table 41.5 Level of risk of cardiac allograft rejection or compromise with varying reductions of immunosuppression Reduction of immunosuppression scenario Reduction

Most likely riska

full dose; antiproliferative full dose;

None

Noneb

full dose; antiproliferative full dose;

Reduce antiproliferative 50%

Mildb

full dose; antiproliferative full dose;

Reduce antiproliferative 100%

Mild

full dose; antiproliferative full dose;

Reduce antiproliferative 100%; reduce calcineurin inhibitor 25% Reduce antiproliferative 100%; reduce calcineurin inhibitor 50% Reduce antiproliferative 100%; reduce calcineurin inhibitor 75% Complete cessation of calcineurin inhibitor and antiproliferative; increase prednisone as indicated Switch from calcineurin inhibitor to sirolimus

Moderate

Baseline regimen Calcineurin inhibitor prednisone 5 mg Calcineurin inhibitor prednisone 5 mg Calcineurin inhibitor prednisone 5 mg Calcineurin inhibitor prednisone 5 mg Calcineurin inhibitor prednisone 5 mg Calcineurin inhibitor prednisone 5 mg Calcineurin inhibitor prednisone 5 mg Calcineurin inhibitor prednisone 5 mg

full dose; antiproliferative full dose; full dose; antiproliferative full dose; full dose; antiproliferative full dose; full dose; antiproliferative full dose;

Severe Severe Severeb Mild

a

Refer to Table 41.1 for examples of allograft risks. Indicates agreement of >75% of respondents (strong consensus). Source: Modified from Otley CC, Griffin MD, Charlton MR, Edwards BS, Neuburg M, Stasko T, Unpublished data. Used with permission.

b

availability of a living related donor, primarily in kidney and liver transplantation, to provide another organ if rejection were to occur may be a consideration as well.

Risks of a Modification of Immunosuppression Critical to considerations regarding any modification of immunosuppression because of skin cancer is the understanding

that potent immunosuppression is necessary for preservation of solid organ allograft function. The precipitation of acute or accelerated chronic rejection by modification of immunosuppression may cause allograft dysfunction or even death of the patient. Thus, modification of immunosuppression is a serious therapeutic intervention that should be undertaken only under the direct supervision of an experienced transplant physician. Unfortunately, the relative magnitude of the risk of inducing

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REDUCTION OF IMMUNOSUPPRESSION FOR TRANSPLANT-ASSOCIATED SKIN CANCER

Table 41.6 Level of risk of liver allograft rejection or compromise with varying reductions of immunosuppression Reduction of immunosuppression scenario Baseline regimen Calcineurin Calcineurin Calcineurin Calcineurin

inhibitor inhibitor inhibitor inhibitor

full full full full

dose dose dose dose

Calcineurin inhibitor full dose Calcineurin inhibitor full dose Calcineurin inhibitor full dose

Reduction

Most likely riska

None Reduce calcineurin inhibitor 25% Reduce calcineurin inhibitor 50% Reduce calcineurin inhibitor 75%; add low-dose antiproliferative or low-dose sirolimus Reduce calcineurin inhibitor 100%; add low-dose antiproliferative or low-dose sirolimus Complete withdrawal of immunosuppression Switch from calcineurin inhibitor to sirolimus

Noneb Mild Moderate Mild Mildc Severeb Mild

a

Refer to Table 41.1 for examples of allograft risks. Indicated agreement of >75% of respondents (strong consensus). c Indicated no choice received majority (>50%) of votes (controversial). Source: Modified from Otley CC, Griffin MD, Charlton MR, Edwards BS, Neuburg M, Stasko T, Unpublished data. Used with permission. b

Table 41.7 Strategies for reduction or modification of immunosuppression Strategy

Example

Reduction of 1 agent Cessation of 1 agent Cessation of all agents Switch to alternative agent

Dose reduction of azathioprine Discontinue azathioprine Discontinue all agents Switch from cyclosporine to sirolimus

allograft rejection or dysfunction at various levels of reduction of immunosuppression has not been well defined,[43–47] In a recent survey of transplant physicians, estimates of the risk of allograft compromise on the basis of various immunosuppressant reduction scenarios varied among providers (Otley CC, Griffin MD, Charlton MR, Edwards BS, Neuburg M, Stasko T, Unpublished data). Thus, there is some inherent imprecision in the ability to predict the likelihood of allograft rejection or compromise because of multiple individual patient factors. However, with careful monitoring for early signs of rejection, most cases of allograft rejection associated with a modification of immunosuppression can usually be safely managed. As a matter of course, the risks of any reduction of immunosuppression must be weighed against the potential benefits. The degree of risk to the allograft depends on multiple factors, including the type of allograft, the time since transplantation, the level of immunologic risk to the recipient, pretransplantation sensitization status, any previous history of rejection, and current allograft function. For patients with kidney allografts, more aggressive reduction of immunosuppression is possible because hemodialysis can provide a viable alternative in cases of rejection. However, any decision to reduce immunosuppression in heart transplant patients must be made judiciously, particularly for patients with a history of rejection.

In general, the risk of acute rejection is highest in the first postoperative year and tends to decline thereafter. Fortunately, the increased incidence of posttransplantation skin cancer tends to occur after the greatest risk of rejection has passed. Most transplant centers begin to reduce the number and dosage of immunosuppressive medications 6 months to 1 year after transplantation. For liver transplant patients, having an episode of acute rejection during the first year does not seem to affect long-term graft survival, and thus the reduction of immunosuppression can usually be more rapid and aggressive than it is for patients with other solid organ transplants. The immunosuppressive medications of kidney and heart recipients are reduced slowly over time, albeit more conservatively. With the institution of calcineurin inhibitor-sparing and steroid-free regimens, the risk of skin cancer in patients may decline.

Coordination by Transplant Physicians As mentioned earlier, any modification of an immunosuppressive regimen should be supervised and administered through the transplant physicians and the transplant team. Clear communication from the dermatologist to the transplant providers when patients begin to experience unacceptable levels of morbidity or a high risk of mortality from skin cancer is essential to stimulate consideration of a reduction of immunosuppression. Dermatologists are ideally suited to interpret the clinical and pathologic factors associated with skin cancer and to quantify these morbidity and mortality risks for transplant physicians. Dermatologists also fulfill a crucial role by monitoring the possible beneficial effects of a reduction of immunosuppression and by continuing to inform the transplant team about the ever-changing morbidity and mortality risks associated with transplant-associated skin cancer. The reduction of immunosuppression is a multidisciplinary decision, and patients should be active participants in this

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decision. When carefully coordinated and with all the individualized patient factors considered, reduction of immunosuppression appears to be a reasonable adjuvant therapeutic strategy for unacceptably high levels of morbidity or mortality risks from skin cancer in transplant patients.

REFERENCES

1. Morath C, Mueller M, Goldschmidt H, Schwenger V, Opelz G, Zeier M. Malignancy in renal transplantation. J Am Soc Nephrol. 2004;15:1582–8. 2. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol. 2002; 47:1–17. 3. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348:1681–91. 4. Martinez JC, Otley CC, Stasko T, Euvrard S, Brown C, Schanbacher CF, et al, Transplant-Skin Cancer Collaborative. Defining the clinical course of metastatic skin cancer in organ transplant recipients: a multicenter collaborative study. Arch Dermatol. 2003;139: 301–6. 5. Veness MJ, Quinn DI, Ong CS, Keogh AM, Macdonald PS, Cooper SG, et al. Aggressive cutaneous malignancies following cardiothoracic transplantation: the Australian experience. Cancer. 1999;85:1758–64. 6. Sheil AG, Disney AP, Mathew TH, Amiss N. De novo malignancy emerges as a major cause of morbidity and late failure in renal transplantation. Transplant Proc. 1993;25:1383–4. 7. Ong CS, Keogh AM, Kossard S, Macdonald PS, Spratt PM. Skin cancer in Australian heart transplant recipients. J Am Acad Dermatol. 1999;40:27–34. 8. Soulillou JP, Giral M. Controlling the incidence of infection and malignancy by modifying immunosuppression. Transplantation. 2001;72 Suppl 12:S89–93. 9. Otley CC, Maragh SL. Reduction of immunosuppression for transplant-associated skin cancer: rationale and evidence of efficacy. Dermatol Surg. 2005;31:163–8. 10. Hojo M, Morimoto T, Maluccio M, Asano T, Morimoto K, Lagman M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature. 1999;397:530–4. 11. Moore DE, Sik RH, Bilski P, Chignell CF, Reszka KJ. Photochemical sensitization by azathioprine and its metabolites III. A direct EPR and spin-trapping study of light-induced free radicals from 6-mercaptopurine and its oxidation products. Photochem Photobiol. 1994;60: 574–81. 12. Dantal J, Hourmant M, Cantarovich D, Giral M, Blancho G, Dreno B, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet. 1998;351:623–8. 13. Otley CC, Coldiron BM, Stasko T, Goldman GD. Decreased skin cancer after cessation of therapy with transplant-associated immunosuppressants. Arch Dermatol. 2001;137:459–63. 14. Sheil AG. Development of malignancy following renal transplantation in Australia and New Zealand. Transplant Proc. 1992;24: 1275–9. 15. Martinez JC, Otley CC, Stasko T, Euvrard S, Brown C, Schanbacher CF, et al, Transplant-Skin Cancer Collaborative. Defining the clinical course of metastatic skin cancer in organ transplant recipients: a multicenter collaborative study. Arch Dermatol. 2003;139:301–6. 16. Moloney FJ, Kelly PO, Kay EW, Conlon P, Murphy GM. Maintenance versus reduction of immunosuppression in renal transplant recipients with aggressive squamous cell carcinoma. Dermatol Surg. 2004;30:674–8.

17. Jensen P, Hansen S, Moller B, Leivestad T, Pfeffer P, Geiran O, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40:177–86. 18. Glover MT, Deeks JJ, Raftery MJ, Cunningham J, Leigh IM. Immunosuppression and risk of non-melanoma skin cancer in renal transplant recipients [letter]. Lancet. 1997;349:398. 19. Kehinde EO, Petermann A, Morgan JD, Butt ZA, Donnelly PK, Veitch PS, et al. Triple therapy and incidence of de novo cancer in renal transplant recipients. Br J Surg. 1994;81:985–6. 20. Shuttleworth D, Marks R, Griffin PJ, Salaman JR. Epidermal dysplasia and cyclosporine therapy in renal transplant patients: a comparison with azathioprine. Br J Dermatol. 1989;120:551–4. 21. Hiesse C, Rieu P, Kriaa F, Larue JR, Goupy C, Neyrat N, et al. Malignancy after renal transplantation: analysis of incidence and risk factors in 1700 patients followed during a 25-year period. Transplant Proc. 1997;29:831–3. 22. Ramsay HM, Fryer AA, Reece S, Smith AG, Harden PN. Clinical risk factors associated with nonmelanoma skin cancer in renal transplant recipients. Am J Kidney Dis. 2000;36:167–76. 23. Fortina AB, Caforio AL, Piaserico S, Alaibac M, Tona F, Feltrin G, et al. Skin cancer in heart transplant recipients: frequency and risk factor analysis. J Heart Lung Transplant. 2000;19:249–55. 24. Gjersvik P, Hansen S, Moller B, Leivestad T, Geiran O, Simonsen S, et al. Are heart transplant recipients more likely to develop skin cancer than kidney transplant recipients? Transpl Int. 2000;13 Suppl 1:S380–1. 25. Euvrard S, Kanitakis J, Bosshard S, Lebbe C, Garnier JL, Touraine JL, et al. No recurrence of posttransplantation KaposiÕs sarcoma three years after renal transplantation. Transplantation. 2002;73:297–9. 26. Penn I. KaposiÕs sarcoma in transplant recipients. Transplantation. 1997;64:669–73. 27. Penn I. Sarcomas in organ allograft recipients. Transplantation. 1995; 60:1485–91. 28. Woodle ES, Hanaway M, Buell J, Gross T, First MR, Trofe J, et al, Israel Penn International Transplant Tumor Registry. Kaposi sarcoma: an analysis of the US and international experiences from the Israel Penn International Transplant Tumor Registry. Transplant Proc. 2001;33:3660–1. 29. Besnard V, Euvrard S, Kanitakis J, Mion F, Boillot O, Frances C, et al. KaposiÕs sarcoma after liver transplantation. Dermatology. 1996;193: 100–4. 30. Duman S, Toz H, Asci G, Alper S, Ozkahya M, Unal I, et al. Successful treatment of post-transplant KaposiÕs sarcoma by reduction of immunosuppression. Nephrol Dial Transplant. 2002;17:892–6. 31. Green M. Management of Epstein-Barr virus-induced post-transplant lymphoproliferative disease in recipients of solid organ transplantation. Am J Transplant. 2001;1:103–8. 32. Starzl TE, Nalesnik MA, Porter KA, Ho M, Iwatsuki S, Griffith BP, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet. 1984; 1:583–7. 33. Mozzanica N, Cattaneo A, Fracchiolla N, Boneschi V, Berti E, Gronda E, et al. Posttransplantation cutaneous B-cell lymphoma with monoclonal Epstein-Barr virus infection, responding to acyclovir and reduction in immunosuppression. J Heart Lung Transplant. 1997;16:964–8. 34. Hanto DW, Frizzera G, Gajl-Peczalska KJ, Sakamoto K, Purtilo DT, Balfour HH Jr, et al. Epstein-Barr virus-induced B-cell lymphoma after renal transplantation: acyclovir therapy and transition from polyclonal to monoclonal B-cell proliferation. N Engl J Med. 1982; 306:913–8. 35. Armitage JM, Kormos RL, Stuart RS, Fricker FJ, Griffith BP, Nalesnik M, et al. Posttransplant lymphoproliferative disease in thoracic organ transplant patients: ten years of cyclosporine-based immunosuppression. J Heart Lung Transplant. 1991;10:877–86.

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36. Tsai DE, Hardy CL, Tomaszewski JE, Kotloff RM, Otloff KM, Somer BG, et al. Reduction in immunosuppression as initial therapy for posttransplant lymphoproliferative disorder: analysis of prognostic variables and long-term follow-up of 42 adult patients. Transplantation. 2001;71:1076–88. 37. Opelz G, Henderson R. Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet. 1993;342: 1514–6. 38. Friedlaender MM, Rubinger D, Rosembaum E, Amir G, Siguencia E. Temporary regression of Merkel cell carcinoma metastases after cessation of cyclosporine. Transplantation. 2002;73:1849–50. 39. Kauffman HM, Cherikh WS, Cheng Y, Hanto DW, Kahan BD. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation. 2005;80:883–9. 40. Kahan BD, Knight R, Schoenberg L, Pobielski J, Kerman RH, Mahalati K, et al. Ten years of sirolimus therapy for human renal transplantation: the University of Texas at Houston experience. Transplant Proc. 2003;35 Suppl 3:25S–34S. 41. Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant. 2004;18:446–9.

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42. Otley CC, Berg D, Ulrich C, Stasko T, Murphy GM, Salasche SJ, et al, Reduction of Immunosuppression Task Force of the International Transplant Skin Cancer Collaborative and the Skin Care in Organ Transplant Patients Europe. Reduction of immunosuppression for transplant-associated skin cancer: expert consensus survey. Br J Dermatol. 2006;154:395–400. 43. Aichberger C, Eberl T, Riedmann B, Pernthaler H, Ofner D, Konigsrainer A, et al. Long-term outcome after switch from cyclosporine-based triple-drug immunosuppression to double therapy at three months. Clin Transplant. 1996;10:209–12. 44. Matl I, Lacha J, Lodererova A, Simova M, Teplan V, Lanska V, et al. Withdrawal of steroids from triple-drug therapy in kidney transplant patients. Nephrol Dial Transplant. 2000;15:1041–5. 45. Mazariegos GV, Reyes J, Marino IR, Demetris AJ, Flynn B, Irish W, et al. Weaning of immunosuppression in liver transplant recipients. Transplantation. 1997;63:243–9. 46. Oike F, Yokoi A, Nishimura E, Ogura Y, Fujimoto Y, Kasahara M, et al. Complete withdrawal of immunosuppression in living donor liver transplantation. Transplant Proc. 2002;34:1521. 47. Mazariegos GV, Reyes J, Marino I, Flynn B, Fung JJ, Starzl TE. Risks and benefits of weaning immunosuppression in liver transplant recipients: long-term follow-up. Transplant Proc. 1997;29:1174–7.

42 Systemic Retinoids for Prevention of Skin Cancer in Organ Transplant Recipients

Jan Nico Bouwes Bavinck, MD, PhD, and J. W. de Fijter, MD, PhD

INTR ODUCT IO N A ND ME CHANISM S OF ACTION

than that of normal keratinocytes, probably by suppressing the early transcription of HPV genes. [13,14] These results provide a possible biochemical explanation for the role of retinoids in the chemoprevention of human papillomavirus-induced skin cancer in organ transplant recipients. Rooke et al. reported a marked increase of Langerhans cells within the epidermis in three patients after treatment with tretinoin and etretinate.[15] The increase was correlated with duration of therapy. [13,15] In addition, a trend was reported for an increase in Langerhans cell density in squamous cell carcinomas during etretinate therapy, although statistical significance was not reached.[13,16] Intracellularly, retinoids interact with cytosolic proteins and specific nuclear receptors, the retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which have been suggested to mediate retinoid activity at the molecular level.[17]

Vitamin A, its physiologic metabolites, and synthetic derivatives (retinoids) have been shown to have protective effects against the development of certain types of cancer.[1] Oral retinoids can be used to reduce and delay the development of skin cancer in organ transplant recipients.[3–4] Patients who may benefit most from retinoid chemoprevention are those who are actively developing large numbers of skin cancers or individual high-risk skin cancers.[3,3–7] Retinoids are a class of natural or synthetic compounds related to vitamin A that display a wide range of biological activity.[2,4,8] Retinoids play an important role in the inhibition of cell growth, epithelial cell differentiation, and the induction of cell death and have antiproliferative and cancerprotective properties.[9] Retinoids have also immunomodulating effects.[2] It is largely unknown how retinoids act beneficially in the prevention of skin cancer. The chemoprevention effect of retinoids is most likely exerted at the tumor-promotion phase of carcinogenesis.[1] Known effects of retinoids include reduction of proliferation and keratinization, induction of apoptosis, and immunomodulation.[2] In a study with 33 renal-transplant recipients, biopsies were taken before and after 3 months of treatment with acitretin in doses up to 0.4 mg/kg/day.[10] Histological and immunohistochemical parameters for dysplasia, epidermal thickness, proliferation, differentiation, apoptosis, and dermal inflammation were analyzed. Following acitretin treatment, a significant reduction in epidermal thickness and increase in normal differentiation parameter K10 was observed. Epidermal proliferation did not change, nor did apoptosis and inflammation.[10] Warts in renal-transplant recipients showed pronounced K13 and K19 expression in contrast to warts in the immunocompetent host. It has been suggested that by keeping keratinocytes in this esophageal-type differentiation, retinoids might act chemopreventively. [10,11] In another mechanistic study, six months of treatment with topical tretinoin resulted clinically in increased skin thickness. Histological and ultrastructural examination of ÔnormalÕ tretinoin treated skin of renal-transplant recipients revealed epidermal and dermal changes suggestive of increased cellular metabolism.[12] It has also been shown that retinoic acid is more effective at inhibiting the growth of HPV-infected human keratinocytes

E F F I CA C Y The efficacy of skin cancer chemoprevention with the help of systemic retinoids was first demonstrated in patients with xeroderma pigmentosum. [5,18] Clinically, isotretinoin (13-cis-retinoic acid) significantly reduced the appearance of new skin cancers in patients with xeroderma pigmentosum. [1,5,18] The first studies with retinoids to prevent skin cancer in organ transplant recipients were performed in the late 1980s with etretinate.[19,20] Although the use of systemic retinoids in organ transplant recipients is widespread, only very few studies with a limited number of patients have been performed to date. These studies have been reviewed by several authors.[19–4] One placebocontrolled trial has been performed with acitretin [7] and there are two additional randomized-controlled trials with acitretin.[21,22] The majority of the studies consist of small or some larger case series.[15,16,19,20,20–28] Definitive evidence for the efficacy of retinoids is, therefore, not yet available because of the lack of sufficient studies of good quality; the efficacy of these drugs is mainly based upon clinical experience. The clinical studies with retinoids in organ transplant recipients are summarized in Table 42.1. Initial studies were performed with etretinate.[15,16,19,20] Later etretinate was replaced by its active metabolite, acitretin,[7,7–28] There is only one study with one patient who was treated with isotretinoin.[29] 272

SYSTEMIC RETINOIDS FOR PREVENTION OF SKIN CANCER IN ORGAN TRANSPLANT RECIPIENTS

The four studies with etretinate were all without an explicit control group.[15,16,19,20] Etretinate was shown to have a beneficial effect in two studies with six and four renal transplant recipients, respectively.[19,20] A more recently performed study reported the chemoprophylactic effects of low-dose etretinate (0.3 mg/kg/day) in eleven renal transplant recipients.[16] A significant reduction in the number of skin cancers was shown during etretinate therapy of three and six months compared with an equally long pretreatment period.[16] Rooke et al. investigated the combination of lowdose systemic retinoid (etretinate 10 mg/day) with topical tretinoin for six months in renal transplant recipients with skin cancer. They also observed a beneficial effect. Three patients who were followed for 9 months and two who were followed for 12 months did not develop new squamous cell carcinomas, despite having 6–15 lesions per year in the 2-year pretreatment period.[15] For acitretin, only one placebo-controlled trial has been performed in The Netherlands.[7] This trial involved a randomized, double-blind, placebo-controlled trial in two groups of 19 renal transplant recipients at a dose of 30 mg/day. All patients had a minimum of 10 keratotic skin lesions on the hands and forearms and were treated for six months. The effect of acitretin on the prevention of skin cancer was assessed by the number of patients who developed new carcinomas within the first six months of the trial. During this period, 2 of 19 patients (11%) in the acitretin group reported a total of 2 new squamous cell carcinomas, compared with 9 of 19 patients (47%) in the placebo group who developed a total of 18 new carcinomas (p = 0.01).[7] Furthermore, the relative decrease of keratotic skin lesions was 13% in the acitretin group, as compared to a relative increase of 28% in the placebo group (p < 0.01). However, after the end of treatment and after discontinuation of acitretin therapy, skin cancers and keratotic skin lesions relapsed.[7] A prospective, open randomized crossover trial of acitretin for skin cancer prevention was conducted in Australia.[22] A dose of 25 mg acitretin per day was prescribed to 14 patients and 9 patients received no retinoid treatment, with crossover after one year. Eleven (47.8%) patients completed the 2-year trial. A significantly lower number of squamous cell carcinomas developed in patients while on acitretin compared to the drug-free period (p = 0.002).[22] A similar trend was observed in patients with basal cell carcinomas, but this was not significant and the numbers were small.[22] In contrast, de Se´vaux et al. reported, in a randomizedcontrolled open-label trial, no significant difference in numbers of skin cancers between 13 renal transplant recipients who were treated for one year with acitretin 0.4 mg/kg/day and 13 patients who were treated with acitretin 0.2 mg/kg/day and there was also no decrease of skin cancers compared to the pretreatment period.[21] Nevertheless, a decrease in actinic keratoses of 50% was reported in both groups.[21] Harwood et al. evaluated the long-term efficacy of systemic retinoids in reducing the incidence of squamous cell carcinomas in a retrospective before–after study of 32 organ transplant

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recipients who had received low-dose systemic retinoids (0.2 to 0.4 mg/kg/day) for 1 to 16 years to prevent squamous cell carcinomas.[23] The main outcome variable was the mean difference between the number of squamous cell carcinomas developing annually during retinoid treatment and the number during the 12-month pretreatment interval, showing a significantly reduced number of new squamous cell carcinomas during acitretin treatment.[23] Most remaining case series reported a beneficial effect of acitretin on the number of new skin cancers or actinic keratoses.[24,26,27] These studies were mainly performed with renal transplant recipients and are summarized in Table 42.1. One case series was performed in 5 heart transplant recipients showing a reduction in the number of nonmelanoma skin cancer in all patients after treatment with acitretin 10-25 mg/day compared with the pretreatment interval.[25] Only one patient was reported who was treated with isotretinoin (13-cis-retinoic acid) at a dose of 0.5 mg/kg/day has been reported.[29] There is some anecdotal evidence that acitretin is most effective in patients with one or more squamous cell carcinoma in their medical history.[7] McKenna et al. reported that patients with five or more squamous cell carcinomas prior to acitretin benefited most. [24] But Harwood et al. did not show a different benefit of retinoids in patients with fewer than 5 squamous cell carcinomas or 5 or more squamous cell carcinomas before treatment.[23]

A D V E R S E EF F E C T S The major limitation to the use of acitretin is poor tolerance due to adverse events.[2,4,7] Side effects of retinoids in organ transplant recipients are identical to those reported in the immunocompetent host. Frequently, acitretin dose has to be reduced because of the occurrence of mucocutaneous side effects, such as cheilitis, excessive peeling of the skin, and loss of scalp hair.[21] Headaches, rash, musculoskeletal symptoms and hyperlipidemia are the most important causes of withdrawal from treatment.[2,4,7] Hyperlipidemias are common after renal transplantation.[30] Most common are elevations in total and lowdensity lipoprotein cholesterol. Causes of dyslipidemia are usually multiple and can include immunosuppression (especially prednisone, cyclosporine, and sirolimus), graft dysfunction (reduced glomerular filtration rate and proteinuria), and genetic predisposition. There is a growing body of evidence suggesting that dyslipidemias contribute to the very high incidence of cardiovascular disease after transplantation; therefore, hypercholesterolemia, and especially increases in low-density lipoprotein cholesterol, should be treated using guidelines established for patients in the general population.[30] Osteoporosis is a particular problem for the posttransplant recipients, who are already at risk for osteoporosis from glucocorticoid exposure.[31] Retinoids may cause osseous

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Table 42.1 Details of studies with oral retinoids for chemoprevention of skin cancer in organ transplant recipients. Details of the study

Treatment results

Side effects

Etretinate Shuttleworth et al. 1988

No control group; n = 6,1 mg/kg/ day, 6 months.

Five patients had no new skin cancers; 1 patient had 2 new squamous cell carcinomas.

Kelly et al. 1991

No control group; n = 4, 50 mg/ day, 8–13 months.

Rook et al. 1995

No control group; n = 11, 10 mg/ day, 9 months. Also 0.025% topical tretinoin.

Gibson et al. 1998

No control group; n = 11, 0.3 mg/ kg/day, 17 months.

Acitretin Vandeghinste et al. 1992 Bouwes Bavinck et al. 1995

Case report, n = 1, 0.5 mg/kg/day, 2 months. Randomized- double-blind placebo-controlled trial, n = 38, 30 mg/day, 6 months of treatment, 1-year follow-up. No control group, n = 15, 10–50 mg/day, less than 6 to more than 12 months. No control group, n = 16, 0.3 kg/ mg/day, 5 years.

Four patients had considerable reduction of new squamous cell carcinomas. Three of 4 patients had no new squamous cell carcinomas (etretinate + tretinoin), 2 of 3 had no new squamous cell carcinomas after tretinoin only. Significant reduction of new skin cancer after 3 and 6 months compared to pretreatment interval. No new dysplastic skin lesions observed. Statistically significantly fewer patients with new skin cancer compared to placebo; reduction of keratotic lesions. Variable effect on skin cancer.

Cheilitis, increased triglycerides (n = 3), increased cholesterol (n = 2). No detoriation in renal function. Mild mucocutaneous side effects, thrombocytopenia (n = 1). Renal function unchanged. Mild mucocutaneous side effects.

Yuan et al. 1995

Mc Kenna et al. 1999

Mc Namara et al. 2002

No control group, n = 5, 10/25 mg/day, 10–24 months.

George et al. 2002

Randomized- controlled cross-over trial (compared to no treatment), n = 23, 25 mg/ day, 1-year treatment, 2 years of follow-up. Randomized- controlled trial (0.4 mg/kg/day vs. 0.2 mg/kg/day), n = 26, 1-year treatment.

de Se´vaux et al. 2003

Harwood et al. 2005

Retrospective before-after study, n = 28 0.2–0.4 mg/kg/day, 1 to 16 years.

Carneiro et al. 2005

No control group, n = 13, 20 mg/ day, 12 months.

Isotretinoin Bellman et al. 1996

Case report, n = 1, 0.5 mg/kg/day, 2 months.

Mild mucocutaneous side effects. Increased triglycerides (n = 3), increased cholesterol (n = 1). Mild mucocutaneous side effects. No effect on renal function. Mild mucocutaneous side effects, hair loss, increased cholesterol and triglycerides (n = 3). No deterioration in renal function. Mild mucocutaneous side effects.

Statistically significant reduction of new carcinomas after 4 years compared to pretreatment period. Three patients had significant decrease in new skin cancers compared to pretreatment period. Number of squamous cell carcinomas significantly lower on acitretin compared to drug free period.

Mild mucocutaneous side effects, increased cholesterol and triglycerides (n = 1).

Decrease of actinic keratoses by 50% in both groups, no effect on development of skin cancers in both groups compared to pretreatment period. Significantly reduced number of squamous cell carcinomas compared to pretreatment period.

Mild mucocutaneous side effects, mild hair loss.

Improvement of actinic keratoses compared to pretreatment period. Reduction by half of new lesions compared to pretreatment period.

Mild mucocutaneous side effects.

Cheilitis, headache, increase of musculoskeletal symptoms, gastritis, increased triglycerides.

Mild mucocutaneous side effects, palmoplantar desquamation, hair loss (n = 2), arthalgia (n = 2) increased cholesterol and triglycerides (n = 15).

No side effects were reported. No effect on renal function.

SYSTEMIC RETINOIDS FOR PREVENTION OF SKIN CANCER IN ORGAN TRANSPLANT RECIPIENTS

problems, but this potential side effect has not been systematically studied in organ transplant recipients. Oral retinoids have also been associated with excessive granulation tissue and hypertrophic scarring.[32] In a recent study, however, Tan et al. showed that systemic acitretin chemoprophylaxis did not appear to increase the risk of woundhealing complications in organ transplant recipients.[32] In organ transplant recipients there is a theoretical concern of immunostimulation caused by the systemic retinoids, which could lead to rejection of the transplanted organ. So far, no such clinically significant side effects have been reported. In addition, no alterations in renal or liver function have been reported during the periods of treatment or follow-up.[2] Increased numbers of squamous cell carcinomas occur following discontinuation of retinoids.[7,18,20,20–24] It therefore seems most appropriate to regard retinoid chemoprevention as a potentially lifelong treatment in organ transplant recipients.[23]

ADM INIST RATION AND M ONIT OR ING GUIDELINES Because the minimal effective dose varies greatly between patients and because of the theoretical risk of possible acute allograft rejection, it may be best to start acitretin at a low dose (10 mg per day), which can be increased depending on the side effects induced. If insufficient benefit is observed over subsequent months, then dosage may be increased up to a dose of 30 mg per day.[3,4,31] Because the benefit is present only while on acitretin, longterm treatment with oral retinoids is necessary. No optimal long-term dosing advice is available.[21] Temporary interruption of acitretin therapy may be necessary when encountering transient or treatable adverse effects.[21] Approximately one third of the patients are able to continue this regimen for at least 5 years without significant side effects [3,23] and some patients have been treated with oral retinoids up to 16 years.[23] Regular evaluation of efficacy with consideration of dose changes, for example at 3-month intervals, is appropriate throughout the course of treatment.[4] Symptoms of toxicity include dry skin, nausea, headache, fatigue, and irritability. Classically, three syndromes of toxicity have been recognized: acute, chronic, and teratogenic. Acute toxicity resembles the clinical picture of hypervitaminosis A and symptoms include nausea, vomiting, vertigo, and blurred vision. This is uncommon with current dosing regimens. Signs of chronic toxicity include ataxia, alopecia, hyperlipidemia, hepatotoxicity, bone and muscle pain, visual impairment, and a number of other nonspecific signs and symptoms. When acute and chronic symptoms occur, the dose of the retinoid can be reduced or the treatment can be discontinued. In the first trimester of pregnancy, retinoic acid has been associated with spontaneous abortions and fetal malformations, including microcephaly and cardiac anomalies. [33] This teratogenic effect precludes the use of retinoids in women

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of childbearing potential unless strict contraceptive practices are followed. Because of the prolonged half-life of acitretin, isotretinoin may be the agent of choice in women of childbearing potential. Of note, acitretin may diminish the therapeutic effect of contraceptive (Progestins). Contraceptive failure is possible. Adequate nonhormonal forms of contraception must be employed during retinoid therapy. In transplant recipients, retinoids are ideally part of a longterm plan for the management of skin lesions. Headaches, rash, musculosketetal symptoms, and hyperlipidaemia were the most common reported causes for withdrawal from treatment. Hepatotoxicity may, if undetected, eventually lead to cirrhosis, and has been associated with veno-occlusive disease.[34] Importantly, no changes in renal function have been reported. No significant interactions with the currently available immunosuppressive drugs have been reported. Although acitretin is considered to enhance the hepatotoxic effect of methotrexate, clinical studies have not been published. Concomitant use of acitretin and alcohol results in dose-related in vivo formation of etretinate, a retinoid with a much longer half-life than acitretin.[35] Periodical biochemical screening of liver function, lipid profile, and risks for osteoporotic fractures are standard in the follow-up of transplant recipients.[36]

CONCLUSIONS The available data from a small number of randomized controlled trials suggest that acitretin may have a role in the prevention of skin cancer in organ transplant recipients.[2–4] Tolerability of the drug, however, is a major factor limiting its use. Appropriate selection of patients may help improve the risk–benefit ratio.[2–4] Although optimal dosing and indications for initiation of systemic retinoid therapy are not conclusive from the data, retinoids appear most effective in patients with multiple previous squamous cell carcinomas.[4] Further investigation through randomized controlled trials is needed to further clarify the tolerability and efficacy of multiple dosing regimens on the incidence of premalignant and malignant lesions in transplant recipients and to further optimize their use as a chemopreventive strategy in high-risk organ transplant recipients.[23]

REFERENCES

1. Niles RM. Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer. Nutrition 2000 16(11–12):1084–9. 2. Chen K, Craig JC, Shumack S. Oral retinoids for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomized controlled trials. Br J Dermatol 2005 152(3):518–23. 3. De Graaf YG, Euvrard S, Bouwes Bavinck JN. Systemic and topical retinoids in the management of skin cancer in organ transplant recipients. Dermatol Surg 2004 30(4 Pt 2):656–61. 4. Kovach BT, Sams HH, Stasko T. Systemic strategies for chemoprevention of skin cancers in transplant recipients. Clin Transplant 2005 19(6):726–34.

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5. DiGiovanna JJ. Retinoid chemoprevention in patients at high risk for skin cancer. Med Pediatr Oncol 2001 36(5):564–7. 6. DiGiovanna JJ. Systemic retinoid therapy. Dermatol Clin 2001 19(1): 161–7. 7. Bouwes Bavinck JN, Tieben LM, Van der Woude FJ, Tegzess AM, Hermans J, ter Schegget J et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol 1995 13(8):1933–38. 8. Khera P, Koo JY. A review of the chemopreventive and chemotherapeutic effects of topical and oral retinoids for both cutaneous and internal neoplasms. J Drugs Dermatol 2005 4(4):432–46. 9. Altucci L, Gronemeyer H. The promise of retinoids to fight against cancer. Nat Rev Cancer 2001 1(3):181–93. 10. Smit JV, de Sevaux RG, Blokx WA, van de Kerkhof PC, Hoitsma AJ, de Jong EM. Acitretin treatment in (pre)malignant skin disorders of renal transplant recipients: Histologic and immunohistochemical effects. J Am Acad Dermatol 2004 50(2):189–96. 11. Blokx WA, Smit JV, de Wilde PC, van de Kerkhof PC, Ruiter DJ, de Jong EM. Immunohistochemical effects of temporary cessation of long-term acitretin treatment in keratinocytic intraepidermal neoplasia of renal transplant recipients. Arch Dermatol 2003 139(5): 671–73. 12. De Lacharriere O, Escoffier C, Gracia AM, Teillac D, Saint LD, Berrebi C et al. Reversal effects of topical retinoic acid on the skin of kidney transplant recipients under systemic corticotherapy. J Invest Dermatol 1990 95(5):516–22. 13. Bartsch D, Boye B, Baust C, zur HH, Schwarz E. Retinoic acid-mediated repression of human papillomavirus 18 transcription and different ligand regulation of the retinoic acid receptor beta gene in nontumorigenic and tumorigenic HeLa hybrid cells. EMBO J 1992 11(6): 2283–91. 14. Khan MA, Jenkins GR, Tolleson WH, Creek KE, Pirisi L. Retinoic acid inhibition of human papillomavirus type 16-mediated transformation of human keratinocytes. Cancer Res 1993 53(4):905–9. 15. Rook AH, Jaworsky C, Nguyen T, Grossman RA, Wolfe JT, Witmer WK et al. Beneficial effect of low-dose systemic retinoid in combination with topical tretinoin for the treatment and prophylaxis of premalignant and malignant skin lesions in renal transplant recipients. Transplantation 1995 59(5):714–9. 16. Gibson GE, OÕGrady A, Kay EW, Murphy GM. Low-dose retinoid therapy for chemoprophylaxis of skin cancer in renal transplant recipients. J Eur Acad Dermatol Venereol 1998 10(1):42–7. 17. Orfanos CE, Zouboulis CC, Almond-Roesler B, Geilen CC. Current use and future potential role of retinoids in dermatology. Drugs 1997 53(3):358–88. 18. Kraemer KH, DiGiovanna JJ, Moshell AN, Tarone RE, Peck GL. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 1988 318(25):1633–7. 19. Kelly JW, Sabto J, Gurr FW, Bruce F. Retinoids to prevent skin cancer in organ transplant recipients. Lancet 1991 338(8779):1407. 20. Shuttleworth D, Marks R, Griffin PJ, Salaman JR. Treatment of cutaneous neoplasia with etretinate in renal transplant recipients. Q J Med 1988 68(257):717–25.

21. de Sevaux RG, Smit JV, de Jong EM, van de Kerkhof PC, Hoitsma AJ. Acitretin treatment of premalignant and malignant skin disorders in renal transplant recipients: clinical effects of a randomized trial comparing two doses of acitretin. J Am Acad Dermatol 2003 49(3): 407–12. 22. George R, Weightman W, Russ GR, Bannister KM, Mathew TH. Acitretin for chemoprevention of non-melanoma skin cancers in renal transplant recipients. Australas J Dermatol 2002 43(4): 269–73. 23. Harwood CA, Leedham-Green M, Leigh IM, Proby CM. Low-dose retinoids in the prevention of cutaneous squamous cell carcinomas in organ transplant recipients: a 16-year retrospective study. Arch Dermatol 2005 141(4):456–64. 24. McKenna DB, Murphy GM. Skin cancer chemoprophylaxis in renal transplant recipients: 5 years of experience using low-dose acitretin. Br J Dermatol 1999 140(4):656–60. 25. McNamara IR, Muir J, Galbraith AJ. Acitretin for prophylaxis of cutaneous malignancies after cardiac transplantation. J Heart Lung Transplant 2002 21(11):1201–5. 26. Yuan ZF, Davis A, Macdonald K, Bailey RR. Use of acitretin for the skin complications in renal transplant recipients. N Z Med J 1995 108(1002):255–6. 27. Carneiro RV, Sotto MN, Azevedo LS, Ianhez LE, Rivitti EA. Acitretin and skin cancer in kidney transplanted patients. Clinical and histological evaluation and immunohistochemical analysis of lymphocytes, natural killer cells and Langerhans’ cells in sun exposed and sun protected skin. Clin Transplant 2005 19(1):115–21. 28. Vandeghinste N, De Bersaques J, Geerts ML, Kint A. Acitretin as cancer chemoprophylaxis in a renal transplant recipient. Dermatology 1992 185(4):307–8. 29. Bellman BA, Eaglstein WH, Miller J. Low dose isotretinoin in the prophylaxis of skin cancer in renal transplant patients. Transplantation 1996 61(1):173. 30. Andany MA, Kasiske BL. Dyslipidemia and its management after renal transplantation. J Nephrol 2001 14 Suppl 4:S81–S88. 31. DiGiovanna JJ. Posttransplantation skin cancer: scope of the problem, management, and role for systemic retinoid chemoprevention. Transplant Proc 1998 30(6):2771–5. 32. Tan SR, Tope WD. Effect of acitretin on wound healing in organ transplant recipients. Dermatol Surg 2004 30(4 Pt 2):667–73. 33. Soprano DR, Soprano KJ. Retinoids as teratogens. Annu Rev Nutr 1995 15:111–32. 34. Geubel AP, De Galocsy C, Alves N, Rahier J, Dive C. Liver damage caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases. Gastroenterology 1991 100(6): 1701–9. 35. Gronhoj LF, Steinkjer B, Jakobsen P, Hjorter A, Brockhoff PB, Nielsen-Kudsk F. Acitretin is converted to etretinate only during concomitant alcohol intake. Br J Dermatol 2000 143(6): 1164–9. 36. Otley CC, Stasko T, Tope WD, Lebwohl M. Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects. Dermatol Surg 2006 32: 562–8.

43 Topical Treatment of Actinic Keratosis and Photodamage in Organ Transplant Recipients

Warren Weightman, MBBS, FRACP, FACD

synthesis of DNA. 5-FU is taken up predominantly in proliferating keratinocytes. The subsequent lack of DNA synthesis, particularly in the rapidly growing dysplastic cells, prevents proliferation and acts selectively to cause cell death in actinic lesions but not in normal skin.[3] Topical 5-FU was approved by the US FDA in 1970 and is available in different formulations (creams, solutions, and lotions) and strengths (0.5%, 1%, 2%, and 5%). A new 0.5% fluorouracil cream (CaracTM) has been developed which incorporates 5-FU into a patented microsphere delivery system (MicrospongeR). The unique delivery system has several advantages such as once daily application, better drug retention at the application site,[4] and less systemic absorption.[5]

The incidence of actinic keratoses (AK) is increased in organ transplant recipients, occurring in 38% of patients after 5 years of immunosuppression.[1] AK in transplant recipients progress more rapidly to squamous cell carcinoma (SCC), which in turn are more aggressive and have an increased tendency to metastasize.[2] The most important risk factors for the development of AK are the degree and length of immunosuppression, human papilloma virus infection and sun exposure.[1] It is particularly important to treat AK early and aggressively in transplant recipients in order to minimize progression to invasive SCC. Traditionally, cryotherapy with liquid nitrogen has been the most frequent treatment for both individual and multiple AK. The other common treatments for AK include topical 5fluorouracil (5-FU), topical retinoids and topical diclofenac, which will be discussed in this chapter, and newer treatments including imiquimod cream and photodynamic therapy that have been discussed in chapters 44 and 45, respectively. Table 43.1 outlines the cure rates, advantages, and disadvantages of these medications. Compared with cryotherapy, all of these modalities are advantageous as field treatments of large areas of photodamage with multiple or confluent AK. A ‘‘field’’ treatment is one in which an entire area of photodamaged skin, including AK as well as intervening skin, is treated rather than only the clinically apparent AK. Because these treatments target both clinically evident AK as well as subclinical AK, they may reduce the potential for development of SCC on a broad area of photodamaged skin. Other advantages of field treatments include improvement in clinical appearance, less scarring, and a lower incidence of hypopigmentation, resulting in improved cosmetic results. Because these agents may offer the opportunity to substantially reverse photodamaged skin and reduce skin cancer development, it is important to start these treatments as early as possible and ideally before or soon after patients receive a transplant. These field treatments may need to be repeated at regular intervals or as AK return to keep the actinic load as low as possible. There have been no trials with topical 5-FU or diclofenac in transplant patients, so discussion on these latter modalities will be confined to the nontransplant population.

Indications 5-FU is indicated for the field treatment of mild to moderate actinic keratoses and is most effective on the face. It is less effective for thick or hyperkeratotic keratoses and those on the extremities. The aim of field treatment with 5-FU is to remove both clinical and subclinical AK and to reduce the risk of SCC. Organ transplant recipients with increased numbers of AK and SCC will particularly benefit from 5-FU treatment.

Administration The two main regimens for topical 5-FU are a short intensive course of treatment over weeks (standard therapy) or a prolonged and less intensive course over a period of months (pulse therapy). With either regimen, variations in frequency of application and length of treatment can be made during treatment depending on the patientÕs response and severity of side effects. Standard therapy for facial AK is 1–5% 5-FU twice daily or 0.5% 5-FU once daily for between 2 to 4 weeks. The complete clearance rates (14.9% [6] and 26% [7]) are lower for treatment periods of 1 week compared with 2 and 4 weeks although still a significant improvement when compared to placebo.[7] The length of treatment is usually determined by the treating physiciansÕ preference, although it is guided by the extent and severity of AK and actinic damage. Fair-skinned patients or those with severe actinic damage such as organ transplant patients will develop and inflammatory and erosive reaction more quickly than less photodamaged patients, but treatment duration is usually the same. Treatment is usually continued for a predetermined length of time, with the desired endpoint

5 - FL U O R O U R A C I L 5-FU is a pyrimidine analogue, which acts as a competitive inhibitor of thymidylate synthetase, a critical enzyme in the 277

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WARREN WEIGHTMAN

Table 43.1 Advantages and disadvantages of topical agents for actinic keratosis

Efficacy rates Standard regimen Pulse regimen Advantages

Disadvantages a b

5-Fluorouracil

Diclofenac

Retinoids

43–63%a 47–88%b 15–98%a Most effective Short treatment times Can vary regime to suit patient Most severe side effects

58–81%a Open label 29–39%a Double blind 39%b Double blind Well tolerated in majority

35–55%a 30–73%b

Long treatment times Less effective

Well tolerated in majority Most effective at reversing photoaging Effective combined with 5-FU Long treatment times Less effective

Complete clearance rates. Lesional response rates.

being inflammation and erosion of the keratotic AK. In order to determine the optimal duration of treatment, regular followup is necessary to assess response and severity of side effects. Many dermatologists will examine patients after two weeks of treatment to decide on the date of discontinuation. Side affects are invariable and may reduce compliance leading to early withdrawal. A detailed explanation and reassurance before and during treatment will help patients to finish the required course. Several different ways to minimize this reaction or to improve compliance without reducing efficacy have been developed. These include beginning once daily and increasing to twice daily if tolerated after one week, or starting at twice daily and reducing the frequency to once daily or less often if severe side effects develop. If side effects are severe, then breaks during treatment and reducing the length of treatment are other options. If there is a severe reaction, topical steroids can be used to settle the inflammation and reduce discomfort without reducing efficacy.[8] Treating one cosmetic area of the face at a time is useful although some patients prefer to treat the whole face at one time in order to achieve the most complete results. Pulse therapy reduces the frequency of 5-FU application but treatment continues for a longer time. Pearlman [9] studied 11 patients with more than 20 facial keratoses using once or twice weekly treatment with 5% 5-FU solution. The average length of treatment was 7.6 weeks (7–9) with a lesional response rate of 98%. The only side effect reported was erythema and patients found the treatment comfortable. Labandeira [10] studied 53 patients with 85 AK treated initially with four applications per week for the first week and, if intolerable irritation arose, applications were reduced to twice weekly for the rest of the treatment period. The lesional response rate was 88.6%. There was no or only mild irritation in 71% of cases when used at four times per week and no irritation in those who reduced to twice per week. Treatment times ranged from 7.4 to 10.2 weeks. Epstein [11] did not find a benefit with pulse therapy. He studied 13 patients using 5% 5-FU once or twice weekly with only 15% of patients showing a striking improvement and 23% showing some improvement. Treatment was continued

for a mean of 10.5 weeks (7–15 weeks). Over 60% had marked or severe reactions and there was a positive correlation between the reaction severity and the efficacy. Pulse treatment should be considered for those patients who have had a severe reaction with prior 5-FU treatment, those who are hesitant about using 5-FU because of the side effects, or those with severe actinic damage who are likely to react severely. Severely affected transplant patients may react vigorously to 5-FU, and consideration should be given to either using pulse therapy or using the standard regime but starting treatment with reduced frequency, reviewing at one week and then deciding on subsequent frequency depending on reaction. Many dermatologistsÕ clinical experience is that an increased severity of skin reaction with 5-FU correlates with increased efficacy and prefer the standard regimen in organ transplant patients but modified if there is a severe reaction.

Efficacy Studies on the efficacy of 5-FU display a surprising degree of variability in results, suggesting that the specific instructions for application and the patient population studied may be important variables. A meta-analysis by Gupta [12] of 6 papers and the data from the package insert for 0.5% 5-FU cream for treatment of facial AK showed a complete patient response of 62.5% and lesional response rate of 87.8%. This meta-analysis compared 5%, 1%, and 0.5% 5-FU creams using the standard treatment regimen of 2 to 4 weeks. A more recent paper [13] treating facial AK for 4 weeks showed a complete response rate of 43% for both the 0.5% and 5% 5-FU creams with a percentage reduction in facial AK from baseline of 67% and 47%, respectively. In two double-blind randomized, vehicle-controlled studies [6,7] using 0.5% 5FU cream (CaracTM) applied once daily to facial and anterior scalp AK for 4 weeks, the complete patient response rates were 48% and 53%. In studies involving direct comparisons there was no difference in treatment time or efficacy between 1% 5-FU cream (Fluoroplex) and 5% 5-FU cream (Efudex)[14] or between 0.5% 5-FU and 5% 5-FU creams when applied to facial AK.[13] Pulse treatment regimes showed lesional response

TOPICAL TREATMENT OF ACTINIC KERATOSIS AND PHOTODAMAGE IN ORGAN TRANSPLANT RECIPIENTS

rates of 87–98% in two studies [9,10] but in another showed striking improvement in only 15%.[11] Complete response rates were not reported in these studies. In summary, the efficacy rates in various studies were similar for all strengths of 5FU. When used in a standard regime of 1–5% 5-FU twice daily or 0.5% fluorouracil (CaracTM) once daily for 2–4 weeks, complete clearance rates between 43 and 62.5% are achieved for facial AK. Reductions in AK from baseline showed higher response rates ranging from 47% to 88%. The studies on pulse treatment with 5-FU demonstrate lesional response rates ranging from 15% to 98% and many clinicians feel this technique is less effective than continuous application. Significant methodological differences between these studies make direct comparison difficult and studies directly addressing AK in organ transplant patients are needed.

Comparison Studies When evaluating 5-FU in matched comparison studies with other agents, similar results are noted. Lawrence [15] used a bilateral paired comparison of medium-depth chemical peel involving JessnerÕs solution and 35% trichloroacetic acid versus 5% 5-FU twice daily for three weeks, after two weeks of pretreatment with 0.025% tretinoin cream. Equivalent reduction in AK was noted in both groups, with a decrease in the number of AK by 75%. In another study, a 3-week course of twice daily 5% 5-FU cream was compared with photodynamic therapy using 5-ALA on AK on dorsum of the hands with similar results showing a reduction in lesional area of 70% in both groups.[16]

Extremities 5-FU is most effective for treatment of AK on head and neck with less benefit on arms, hands and other areas. Disparate results have been noted in different studies, with Robinson [17] showing no significant clearance for AK on the forearms and dorsum of the hands, whereas Kurwa [16] treated AK on the dorsum of the hand with 5% 5FU and showed a reduction of lesional area of 70%. Measures to increase the success rates for treatment of extremity AK with 5-FU include longer treatment times (6–8 weeks), use of plastic occlusion, and combination treatments, which lead to greater efficacy. 5-FU is less effective for thick and hypertrophic AK, which may respond better to treatment with destructive measures such as cryotherapy, curettage, or electrodessication. Thicker AK remaining after 5-FU treatment may need to be treated with destructive modalities or biopsied to exclude SCC.

Combination Treatment Combination therapy utilizing 5-FU with topical and/or oral retinoids or cryotherapy has been used to enhance efficacy in treating AK of the extremities. Complete clearance rates for combination therapy range from 81–100% [17–20] and are similar to or higher than when 5-FU is used alone for treat-

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ment of facial AK. Bercovitch [18] compared 5% 5-FU twice daily to the arms and randomized patients to nightly application of tretinoin 0.05% cream to one arm and a control cream to the other arm for a period of two weeks. The arm receiving combination treatment with tretinoin had a significantly reduced number of AK compared to the control side. Another trial [19] combined 5% 5-FU twice daily and 20 mg of oral isotretinoin for treatment of hypertrophic, large AK located on hands, forearms, face, and scalp for a median treatment time of 21 days. Palpable AK regressed completely in 22 of the 27 (81%) subjects and almost completely in the remaining five with a median follow up of 12 months. This trial was the only one that delineated AK thickness. Robinson and Kligman [17] showed that neither twice daily 5% 5-FU cream or 0.05% retinoic acid were effective as single agents against AK on forearms and arms, but the combination of 5% 5-FU and 0.1% retinoic acid for 4–5 weeks was effective in complete removal of AK from the forearms of 20 of 20 patients and the hands of 18 of 20 patients. Finally, a double-blind, randomized, vehicle controlled study [20] investigated the efficacy of 0.5% 5-FU versus vehicle once daily for 7 days, followed by cryosurgery at four weeks post treatment for residual AK lesions. At 6 months, a significantly greater number of patients treated with 0.5% 5-FU/cryosurgery had complete clearance of AK (30%) compared with vehicle/cryosurgery (7.7%; p< 0.001). Thus, it appears that combination therapy using 5-FU and other agents can enhance efficacy on difficult to treat sites, such as extremities.

Photoaging After field treatment with 5-FU, there is usually a marked improvement in the clinical appearance of the skin with a smoother and more uniform appearance due to the clearance of AK. Quantification of this aesthetic improvement has not been specifically assessed in most articles. Lawrence [15] compared nine histologic features after treatment of facial AK with 5-FU, noting significant reductions in hyperkeratosis, parakeratosis, and inflammation, which lasted 12 months but no significant alteration of preexisting solar elastosis and telangiectasia. Epidermal atrophy developed after one month of fluorouracil treatment but this gradually returned to the baseline over 12 months. Patient questionnaires confirmed that considerable cosmetic improvement was achieved.

Adverse Effects The common adverse effects of 5-FU treatment include erythema, mild to severe irritation and inflammation, itching, pain, burning, crusting, and erosions. Those patients with more severe actinic damage such as organ transplant patients usually have a more severe response. Severe reactions can result in ulceration, necrosis, and are rarely scarring. When used around the eyes there may be periorbital edema. Photosensitivity during treatment is common, therefore treatment is best done during the cooler months. Allergic contact dermatitis has

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been reported and can be difficult to discern from the inflammatory reaction. The majority of patients experience side effects (98% at 4 weeks) [13] with the severity ranging from mild to moderate in the majority [6] or severe in approximately 50%.[7,13] Most pulse therapy regimes showed a lower incidence of side effects, reporting mild erythema or irritation but one study showed marked or severe reactions in the majority of patients despite pulse therapy. Many factors influence the degree of reaction including application frequency, amount of cream, degree of AK, and sensitivity of the skin. Optimal management requires attention to these details and individualization of treatment. The inflammatory reaction develops over the first week (median time 4–6 days) [6,13] and gradually worsens for the first 1 to 2 weeks. Photographic examples of a patient with multiple AK undergoing treatment with 5-FU are shown in Figure 43.1–Figure 43.3. Severely photodamaged patients may react more rapidly. The severity peaks during the third week [13] with a plateau at 4 weeks. There is usually rapid improvement in side effects 2 weeks after stopping and the reaction is usually resolved by 4 weeks. Most of the erythema usually resolves by 4 weeks but prolonged erythema may persist, especially in patients with severe actinic damage who react severely to treatment.

Summary Topical 5-FU is the most effective treatment for diffuse, mild to moderate AK compared with topical diclofenac or topical retinoids. It has the most severe and highest incidence of significant adverse effects in the form of a vigorous inflammatory reaction which is predictable, manageable by patient education and customized regimens. In addition to excellent therapeutic effects, treatment with 5-FU can result in improved skin health and may reduce the risk of subsequent nonmelanoma skin cancer. There is usually a good cosmetic improvement as well. For severely affected transplant patients, treatment may need to be repeated at one or two yearly intervals or if new AK develop. 5-FU is usually the initial topical treatment of choice for severe AK in transplant patients compared with topical diclofenac and topical retinoids, which are more often utilized in patients with very mild involvement. Imiquimod and photodynamic therapy are newer modalities which have similar efficacies to 5-FU and are also considered first-line treatment options for severe and widespread AK in transplant patients. These agents are discussed in Chapter 44 and Chapter 45.

DICLOFENAC Topical diclofenac was initially noticed to cause clinical regression of AK [21] when used as a topical antiinflammatory agent for arthritis. Further studies have shown that it can be an effective agent without serious side effects.[22–26] Diclofenac is a nonsteroidal antiinflammatory drug (NSAID), which

Figure 43.1. Transplant patient with diffuse actinic keratosis of scalp 10 days into treatment with 5% 5-fluorouracil cream. Beginning of early inflammatory reaction, highlighting extensive actinic keratoses.

works by inhibition of the cyclooxygenase enzymes COX-I and COX –II that decrease the products of arachidonic acid metabolism. These products have potent tumorigenic effects by inhibiting immunosurveillance and apoptosis, upregulating the invasive ability of tumour cells, mediating the conversion of procarcinogens to carcinogens and stimulating angiogenesis.[25] Hyaluronic acid (hyaluronan), a naturally occurring glycosaminoglycan, is a major component of the extracellular matrix of the skin, joints, and eye. It hydrates the stratum corneum and is widely used as a moisturizer. It is also useful for carriage of drugs into the skin as it accumulates in the surface layers of the skin and remains present for days, causing a depot effect. In addition, hyaluronic acid has been shown to be a modulator of the immune system with antiinflammatory effects.[27]

Indications Diclofenac 3% in 2.5% hyaluronic acid (DHA) is indicated for the treatment of both clinical and subclinical actinic keratoses.

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Figure 43.2. Excellent resolution of actinic keratoses 10 weeks after completing treatment.

Figure 43.3. Partial recurrence of actinic keratoses 2.5 years after completing therapy.

It is most commonly used as a field treatment for multiple AK rather than for solitary AK. The U.S. FDA approved its use in 2002 for twice daily treatment of AK for 60–90 days.

The first open label study [21] treated 29 patients using DHA twice daily to AK on the head, neck, or hands for up to 180 days with follow-up 30 days later. The AK were assessed as mild in 37%, moderate in 57%, and severe in 7% of cases. Twenty-two (81%) had a complete response and another 15% showed marked clinical improvement. Treatment periods were between 33 to 176 days (median 62 days). Another study by Nelson [22] treated 76 patients in an open-label format twice daily for 90 days with follow-up 30 days later. Patients had 5 or more AK on the forehead (58%), central face (30%), or scalp (32%). The AK were assessed as mild in 33%, moderate in 58%, and severe in 8% of cases. Results showed complete AK clearance in 41% at day 90 and 58% at day 120. McEwan and Smith [23] treated 130 patients in a double-blind controlled trial twice daily for 24 weeks. The AK in the DHA group were on the hand (43%), arm (12%), face and neck (38%,) or scalp (6%). Forty-two percent of AK were less than 2 mm and fifty-eight percent were greater than 2 mm. The complete response rates were 29% for the active gel and 17% for the control gel. Surprisingly, the difference was not statistically significant (P = 0.14). The other 3 double-blind

Administration DHA is applied twice daily for 60 to 90 days to the affected areas of skin. Treatment for 30 days has been shown not to offer significant benefit.[24] Sun avoidance is recommended during treatment to minimize photosensitivity, and patients with a known allergy to aspirin or other NSAIDs should not use this medication. Studies indicate that the therapeutic benefits continue to increase for more than 30 days after stopping.

Efficacy There have been 2 open label studies[21,22] and four doubleblind placebo controlled studies23–26 assessing the effectiveness of DHA. All trials used diclofenac 3.0% in 2.5% hyaluronic acid gel and none have involved organ transplant patients.

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vehicle-placebo-controlled studies[24–26] with a total of 364 patients have been analysed in a meta-analysis.[27] The intentto-treat analyses show that 42 out of 106 (39.6%) patients treated had complete resolution of all AK in the target area, 30 days after end of treatment with a mean treatment duration of 75 (+/ 21) days. There was resolution of the target and new AK in the treatment area in 70 out of 179(39.1%) patients in the treatment group, 30 days after end of treatment of mean duration 78 (+/ 16) days. The efficacy of DHA appears to depend on the dosage or amount of gel used which may explain the lower response rate with Gebauer [26] where 0.25g of DHA was used twice daily. This compares with 1g twice daily for Rivers Mclean,[21] which had the highest efficacy, and 0.5 g twice daily in two other studies,[24,25] which had slightly higher response rates. All but one of the studies [22] treated AK on both face and extremities. A review [28] combining results from two studies [24,25] and some unpublished data showed that DHA was more effective for AK on face and forehead. In the four studies [21–24] that mentioned AK thickness, three studies stated 91–96% were of mild to moderate thickness and one study had 42% of AK less than 2 mm thick. There was no mention of differences in response by AK of different thickness.

DHA is a useful modality but has lower response rates and longer treatment times than 5-FU. Although the side effects are generally less than 5-FU, the longer duration of therapy may be a disadvantage. For transplant patients with severe AK, 5-FU and imiquimod treatment may be much more effective. However, some patients cannot tolerate the significant adverse effects, and DHA may be helpful in these cases. For patients with mild AK, prolonged therapy with DHA may be a helpful off-label approach.

TO P I CA L RE TI NO ID S Retinoids have potent antiproliferative and prodifferentiation effects on a cellular level by altering gene expression via cytoplasmic binding proteins that transport retinoids to the nucleus. They activate intranuclear retinoic acid receptors (RAR) [29] and accomplish anticancer effects by inhibiting proliferation of some malignant cell lines, inducing benign differentiation, and interfering with tumour initiation.[30] Topical retinoids have been studied in both organ transplant patients and nonimmunosuppressed patients for treatment of AK as well as for the treatment of photodamage.

Indications Adverse Effects DHA causes much less inflammation and erosion than 5-FU, and is less associated with dryness and peeling than topical tretinoin. The most common adverse effects are pruritus, dry skin, application site reactions, erythema, edema, crusting, and irritant contact dermatitis. Less common adverse effects were paraesthesia and hyperaesthesia and acne localized to the treatment sites. Most of the side effects resolved within 1 to 2 weeks after stopping treatment, and there are no reports of significant differences in hematological or clinical biochemistry tests. The incidence of side effects ranged from 29–90% and were described as mild to moderate in the majority of patients.[21–26] Gebauer [26] reported that 20% of these skin-related side effects were severe, but in the other studies, severe side effects were very uncommon, ranging from 0–3%. Uniformly, the side effects from DHA are less severe and less frequent than with topical 5-fluorouracil.

Summary DHA had shown benefit in the treatment of diffuse, mild to moderate AK with complete clearance rates of approximately 40–50% in the double-blind placebo-controlled studies [23–26] and 58–81% in open label studies.[21,22] There is some evidence to suggest that it is more effective on the face but it is also somewhat effective on arms and hands, particularly if a greater amount of gel is used. Treatment times are on average 75 days with a range between 54 and 96 days with an improvement up to 30 days after the treatment is ceased.[27] There have been no studies to confirm long-term clearance with DHA.

Topical retinoids are used in an off-label indication for the field treatment of multiple AK in both nonimmunosuppressed patients and organ transplant patients. They are also beneficial in the treatment of photoaging. Relapses are observed several months after treatment is discontinued so either repeated courses or continuous therapy may be worthwhile.

Administration Topical retinoids are used once daily and require 4 to 15 months for a significant benefit to occur. Frequency of application may be limited by development of an irritant retinoid dermatitis, characterized by prolonged redness. Titration of frequency to avoid excessive irritation is necessary for successful long-term use. Multiple agents (tretinoin, adapalene, tazarotene), formulations (cream, gel, microgel, emollient cream) and strengths are available to customize treatment to patient needs. Facial AK respond best to retinoids, which can be used in combination with 5-FU to increase efficacy for AK of the extremities.

Efficacy Nonimmunosuppressed Patients As a gross generalization, adapalene is less irritating then tretinoin, which is less irritating than tazarotene, and efficacy may correlate crudely with irritant potential. Thus adapalene may be a good choice for a patient with sensitive skin, tretinoin may be appropriate for patients with normal skin, whereas tazarotene may be utilized for patients with very hyperkeratotic AK. Customization of retinoids choice for individual

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patients is critical. Studies of topical retinoids in nontransplant patients have shown lesional response rates of between 30.3 % and 73% [31–34] with treatment times between 4 and 15 months. One trial [35] had complete response rates of 35% and 55% in the treatment of facial AK with 0.1% and 0.3% tretinoin ointments for up to 8 weeks. Kligman and Thorne [31] performed a multicentre double-blind study on 1,120 patients who were treated twice daily for histologically confirmed AK with 0.05% tretinoin, 0.1% tretinoin, or vehicle for up to 15 months. The most effective treatment was 0.1% tretinoin with an excellent response in 73% of patients compared with 40% treated with vehicle. Misiewicz [32] performed a split face comparison of RO 1409796 (an aromatic methyl sulfone) for the treatment of facial AK versus 0.05% tretinoin cream applied twice daily for 16 weeks. The mean percentage decrease in the number of AK was 37.8% for Ro 14-9706 and 30.3% for areas treated with tretinoin. 50% of patients treated with tretinoin had severe erythema and 23% had severe scaling, whereas RO 14-9706 was better tolerated with only slight or absent inflammation. A double-blind trial of 100 patients studied the efficacy of twice daily application of 0.1% isotretinoin cream compared with vehicle applied for 24 weeks to face, scalp, and upper extremities. Patients who applied isotretinoin had a reduction in facial AK of >30% in 66% of patients compared with a >30% reduction in 45% with placebo. No significant benefit was seen for lesions on the scalp or upper extremities.[33] In another study, Kang [34] compared 0.1% and 0.3% adapalene gel with vehicle gel for facial AK once daily for 4 weeks and then twice daily for up to 9 months. The number of AK decreased significantly in the 0.1% and 0.3% adapalene groups. As mentioned previously, there have been good results with combination treatment with topical retinoids and topical 5-FU for hyperkeratotic AK, with up to 100% complete clearance rates.[17,18]

Organ Transplant Patients There are four studies,[36–39] exploring the use of topical retinoids in organ transplant patients. Euvrard [36] used 0.05% tretinoin once daily cream to treat AK on forearms and/or hands on one side and vehicle on the other for 3 months. There was a significant reduction of AK at 3 months (45% vs. 23%) and 6 months (29% vs. 19%). Euvrard and Kanitakis [37] compared 0.1% or 0.3% adapalene gel versus placebo gel applied daily for 6 months in a split face and arm study. The mean number of AK decreased significantly in the 0.3% adapalene group but not in the 0.1% group. Rook [38] studied 11 renal transplant patients, seven who were started on oral etretinate 10mg and 0.025% tretinoin cream and four who elected to use 0.025% tretinoin cream alone. After one month, the tretinoin concentration was increased to 0.05% as tolerance developed. Three of the four patients who used tretinoin alone were evaluable after 6 and 9 months of daily therapy. Two of three had improvement in AK and these two did not develop any new SCC. The third patient had modest improvement in size and number of AK

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but continued to develop new SCC. The addition of low dose etretinate did not appear to enhance efficacy. Smit [39] studied thirteen patients in a double-blind placebo-controlled study using calipitriol 50 lg/g cream once daily, tretinoin 0.02% cream twice daily, calipitriol 50 lg/g cream once daily, and tretinoin 0.02% cream once daily, and cremor cetomagrogol cream twice daily for 6 weeks to four comparable areas of AK on the extremities. There were no significant differences between the four treatment groups with regard to reduction in the number of AK or in desquamation.

Photoaging Among the clinical features of photoaging, surface roughness, dyspigmentation (brown spots and mottled pigmentation), and fine wrinkles demonstrate the most consistent and significant improvement with tretinoin therapy.[40] Kang [34] showed improvements in several parameters of cutaneous photoaging with 0.1% and 0.3% adapalene gel in comparison with vehicle. The most significant improvements were seen in mottled pigmentation and global appearance. Fine wrinkles and rosy glow (erythema) were also improved, but there was no reduction in the severity of coarse wrinkles. There was also lightening in the colour of solar lentigos. Kligman [41] showed that 0.05% tretinoin cream compared to vehicle on the face and forearms resulted in histological improvement in several areas including replacement of the atrophic epidermis by hyperplasia, elimination of dysplasia and atypia, eradication of microscopic AK, uniform dispersion of melanin granules, new collagen formation in the papillary dermis, new vessel formation, and exfoliation of retained horn in the follicles.

Adverse Effects The most common side effects of topical retinoids are erythema, peeling, scaling, dryness, burning, pruritus, irritant dermatitis, and inflammation. These are usually mild in severity. Topical adapalene is less irritating than tretinoin when used for acne and and the 0.3 and 0.1% adapalene formulations demonstrate similar adverse effect profiles.[34] Topical isotretinoin 0.1% showed mild to moderate irritation, which improved on reducing application to once daily, alternate daily, or with application of emollient.[33] New AK may become apparent after discontinuation of treatment. There have been no adverse systemic effects or changes in laboratory values reported with topical retinoids, although use in pregnancy is discouraged.[32]

Summary Topical retinoids are effective in treating diffuse mild to moderately thick facial AK but are overall less effective than DHA and 5-FU. Therefore, many dermatologists utilize topical retinoids as a continuous treatment in photodamaged patients with mild AK. Higher concentrations are more effective and tretinoin 0.1% and 0.3 % have given the best results. If side

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effects are significant, then a lower concentration of tretinoin or adapalene gel can be prescribed. The topical retinoids are also beneficial in photoaging, especially on the face. Topical retinoids are very effective when used in combination with 5-FU cream for treating AK of the extremities, and are used as monotherapy in patients with mild AK or who are intolerant of the more potent treatments. As with all these classes of medications discussed, topical retinoids have unique advantages and disadvantages which result in application for specific clinical indications, particularly long-term maintenance in photodamaged organ transplant patients with mild AK.

REFERENCES

1. Dreno B, Mansat E, Legoux B et al. Skin cancers in transplant patients. Nephrol Dial Transplant 1998; 13: 1681–91. 2. Boyd AS, Stasko T, Cameron GS, Russel M, King LE Jr. Histologic features of actinic keratoses in solid organ transplant recipients and healthy controls. J Am Acad Dermatol 2001; 45: 217–21. 3. Jorizzo JL. Current and novel treatment options for actinic keratosis. J Cutan Med Surg 2004; 8 (Suppl 3): 13–21. 4. Levy S. Furst K, Chem W. A comparison of the skin permeation of three topical 0.5% fluorouracil formulations with that of a 5% formulation. Clin Ther 2001; 23: 901–7. 5. Levy S. Furst K, Chem W. A pharmacokinetic evaluation of the 0.5% and 5% fluorouracil topical cream in patients with actinic keratosis. Clin Ther 2001; 23: 908–20. 6. Jorizzo J. Stewart D, Bucko a, Davis S. Randomized trial evaluating a new 0.5% fluorouracil formulation demonstrates efficacy after 1-,2-, or 4-week treatment in patients with actinic keratoses. Cutis 2002; 70: 6 335–40. 7. Weiss J, Menter A, Hevia O, et al. Effective treatment of actinic keratosis with 0.5% fluorouracil cream for 1,2 or 4 weeks. Cutis 2002; 70: 22–9. 8. Breza T, Taylor R. Eaglstein WH. Noninflammatory destruction of actinic keratoses by fluorouracil. Arch Dermatol 1976; 122: 1256–8. 9. Pearlman DL. Weekly pulse dosing: effective and comfortable topical 5-fluorouracil treatment of multiple actinic keratoses. J Am Acad Dermatol 1962; 25: 665–7. 10. Labandeira J, Pereiro M Jr, Valses F, Toribio J. Intermittent topical 5-fluorouracil is effective without significant irritation in the treatment of actinic keratoses but prolongs treatment duration Dermatol Surg 2004; 30: 4 517–20. 11. Epstein E: Does intermittent ‘‘pulse’’ topical 5-fluorouracil therapy allow destruction of actinic keratoses without significant inflammation. J Am Acad Dermatol 1995; 131: 176–81. 12. Gupta A.K. The management of actinic keratoses in the United States with topical fluorouracil: a pharmacoeconomic evaluation. Cutis 2002; 70(2 Supp): 30–6. 13. Loven K, Stein L, Furst K, Levy S. Evaluation of the efficacy and tolerability of 0.5% fluorouracil cream and 5% fluorouracil cream applied to each side of the face in patients with actinic keratosis. Clinical Therapeutics 2002; 24: 6 990–1000. 14. Simmons WL. Double-blind investigation comparing a 1%-vs-5% 5-fluorouracil topical cream in patients with multiple actinic keratoses. Cutis 1973; 12: 615–7. 15. Lawrence N. Cox SE, Cockerell CJ, Freeman RG, Cruz PD Jr. A comparison of the efficacy and safety of JessnerÕs solution and 35% trichloroacetic acid vs fluorouracil in the treatment of widespread facial keratoses Arch Dermatol 1995; 131: 176–81.

16. Kurwa HA, Yong-Gee SA, Sees PT, Markey AC, Barlow RJ. A randomized paired comparison of photodynamic therapy and topical 5-fluorouracil in the treatment of actinic keratoses. J Am Acad Dermatol 1999; 41: 414–8. 17. Robinson TA, Kligman AM. Treatment of solar keratoses of the extremities with retinoic acid and 5-fluorouracil. Br J Dermatol 1975; 92: 703–6. 18. Bercovitch L. Topical chemotherapy of actinic keratoses of the upper extremity with tretinoin and 5-fluorouracil: a double-blind controlled study. Br J Dermatol 1987; 116: 549–52. 19. Sander CA, Pfeiffer C, Kligman Am Plewig G. Chemotherapy for disseminated actinic keratoses with 5-fluorouracil and isotretinoin J Am Acad Dermatol 1997; 36: 236–8. 20. Jorizzo J, Weiss Furst K. et al. One-week treatment with topical 0.5% fluorouracil followed by adjunctive cryosurgery in treatment of actinic keratoses: six month follow-up. J Am Acad Dermatol 2004; 50: 128 (abstract p497). 21. Rivers JK, Mclean DI: An open study to assess the efficacy and safety of topical 3% diclofenac in a 2.5% hyaluronic acid gel for the treatment of actinic keratoses. Arch Dermatol 1997; 133: 1239–42. 22. Nelson C, Rigel D, Smith S, Swanson N, Wolf J. Phase IV, open-label assessment of the treatment of actinic keratosis with 3.0% diclofenac sodium topical gel (SolarazeTM) J of Drugs in Dermatol 2004; 3(4): 401–407. 23. McEwan L, Smith J.G: Topical diclofenac/hyaluronic acid gel in the treatment of solar keratoses. Aust J Dermatol 1997; 38: 187–9. 24. Rivers JK, Arlette J, Shear N, et al: Topical treatment of actinic keratoses with 2.5% diclofenac in 2.5% hyaluronic acid gel. Br J Dermatol 2002; 146: 94–100. 25. Wolf JE Jr, Taylor JR Tschen E, Kang S: Topical 3% diclofenac in 2.5% hyaluronic acid gel in the treatment of actinic keratoses. Int J Dermatol 2001; 40: 709–13. 26. Gebauer K, brown P, Varigos: Topical diclofenac in hyaluronan gel for the treatment of solar keratoses. Aust J Dermatol 2005; 44: 40–3. 27. Pirard D, Vereecken P, Me´lot C, Heenen M: three percent diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses: a metaanalysis of the recent studies. Arch Dermatol Res 2005; 297: 185–9. 28. Jarvis B, Figgit DP. Topical 3% diclofenac in a 2.5% hyaluronic acid gel. A review of its use in patients with actinic keratoses. Am J. Clin Dermatol 2003; 4(3): 203–13. 29. De Graaf YGL, Euvrard S, Bouwes Bavinck JN. Systemic and topical retinoids in the management of skin cancer in organ transplant recipients. Dermatol Surg 2004; 30: 656–61. 30. Peck GL, Topical tretinoin in actinic keratosis and basal cell carcinoma. J Am Acad Dermatol 1986; 15: 829–35. 31. Kligman AM, Thorne EG Topical therapy of actinic keratoses with tretinoin. In Retinoids in Cutaneous Malignancy (Marks R. ed.). Oxford: Blackwell Scientific publications. 1991; 66–73. 32. Misiewicz J, Sendagorta E, Golebiowska A, Lorenc B, Czarnetzki BM, Jablonska S. Topical treatment of multiple actinic keratoses of the face with arotinoid methyl sulfone (Ro 1409796) cream versus tretinoin cream: A double-blind comparative study. J Am Acad Dermatol 1991; 24: 448–51. 33. Alirezai M, Dupuy P, Amblard P, Kalis B, Souteyrand P, Frappaz A, Sendagorta E. Clinical evaluation of topical isotretinoin in the treatment of actinic keratoses. J Am Acad Dermatol 1994; 30: 447–51. 34. Kang S, Goldfarb MT, Weiss JS, Metz RD, Hamilton TA, Voorhees JJ, Griffiths CEM, Assessment of adapalene gel for the treatment of actinic keratoses and lentigines: A randomized trial. J Am Acad Dermatol 2003; 49: 83–90. 35. Bollag W, Ott F: Retinoic acid: Topical treatment of senile or actinic keratoses and basal cell carcinoma. Agent actions 1970; 1: 172–5. 36. Euvrard S, Verschoore M, Touraine JL, et al Topical retinoids for warts and keratoses in transplant recipients. Lancet 1992; 340: 48–9.

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37. Euvrard S, Kanitakis J, Claudy A. Topical retinoids of the management of dysplastic epithelial lesions. In: Skin Diseases after Organ Transplantation. Montrouge: John Libbey Eurotext; 1998; 175–82. 38. Rook AH, Jaworsky C, Nguyen T, Grossman RA, Wolfe JT, Witmer WK, Kligman AM. Beneficial effect of low-does systemic retinoid in combination with topical tretinoin for the treatment and prophylaxis of premalignant and malignant skin lesions in renal transplant recipients. Transplantation 1995; 59: 714–9.

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39. Smit JV, Cox S, Blokx WAM, Van de Kerkhof PCM, de Jongh GJ, de Jong EMGJ. Actinic keratoses in renal transplant recipients do not improve with calcipotriol cream and all-trans retinoic acid cream as monotherapies or in combination during a 6-week treatment period. Br J Dermatol 2002; 147: 816–8. 40. Kang S, Fisher GJ, Voorhees JJ. Photoaging and topical tretinoin Therapy, pathogenesis and Prevention. Arch Dermatol 1997; 133: 1280–4. 41. Kligman AM, Grove GL, Hirose R, Leyden JJ. Topical tretinoin for photoaged skin. J Am Acad Dermatol 1986; 15: 836–59.

44 Imiquimod Use in Organ Transplant Recipients

Summer R. Youker, MD

in concert with the TH-1 immune response to destroy tumor cells. Imiquimod is approved by the Food and Drug Administration (FDA) for the treatment of genital warts, actinic keratosis (AKs), and superficial basal cell carcinomas (sBCC). Successful use of imiquimod in immunocompetent patients for the treatment of squamous cell carcinoma (SCC), SCC in situ (SCCis), nodular and sclerosing BCC, lentigo maligna and lentigo maligna melanoma, and many other types of malignant, premalignant, and benign cutaneous neoplasms has been reported, although the reports are small and, in many cases, the results are less than optimal.[4]

Organ transplant recipients (OTRs) are disproportionately afflicted with premalignant and malignant skin lesions, with significant associated morbidity and mortality. Because of the intense immunosuppressive therapy necessary to sustain their grafts, the cutaneous malignancies they develop are more numerous and more dangerous than those of immunocompetent individuals. It is imperative that premalignant and localized malignant lesions are treated early in organ transplant recipients. Many modalities are utilized for this purpose, including surgical and nonsurgical approaches. The use of the topical immunomodulator imiquimod in OTRs is intriguing because it relies on the induction of a local immune response in patients with iatrogenically modified immune systems. However, it is important to consider whether this local immune induction poses a threat to the transplanted organ. Imiquimod is a topical chemotherapeutic agent of the imidazoquinoline family. It is an immune response modifier with antitumor and antiviral properties that induces migration and activation of dendritic (antigen-presenting) cells. Imiquimod binds to and stimulates cell surface receptors, such as Toll-like receptors 7 and 9, on macrophages and other dendritic cells. These cells then secrete proinflammatory cytokines that tip the balance of the immune response to a cell mediated, or TH-1, mode. The cytokines secreted by the activated dendritic cells include interferon a (IFN-a), tumor necrosis factor a (TNF-a), and interleukins (IL) 1 and 12. These cytokines stimulate activated T cells to secrete IL-2 and IFN-c which, in turn, induce more macrophage secretion of IL-12. A positive feedback mechanism is thus generated and is selfperpetuating.[1] Spontaneously regressing viral warts and basal cell carcinomas show a shift in immune response to a TH-1 profile.[1,2] Imiquimod and its ability to stimulate a TH-1 immune response is, therefore, an attractive possibility for treatment. Aside from its indirect effect on tumor cells via the TH-1 immune response, imiquimod also has a direct effect on tumor cells. Various tumors, including nonmelanoma skin cancer, are reported to evade immune surveillance through resistance to apoptosis.[2] These tumors often overexpress Bcl-2, an antiapoptotic member of the Bcl-2 gene family. After imiquimod treatment, these tumors show decreased Bcl-2 expression, indicating they are more susceptible to apoptosis. In keratinocyte-derived tumor cell lines, imiquimod has been shown to induce caspase-3 and mitochondrial release of cytochrome c resulting in tumor-cell specific apoptosis.[3] ImiquimodÕs ability to overcome the mechanisms of apoptosis resistance has a direct effect on tumor cells. These effects work

I M I Q U IM O D I N O TR s Although imiquimod has demonstrated its efficacy in immunocompetent patients, one must consider whether this agent will be effective in patients with iatrogenically modified immune systems. Although the results of imiquimod use in immunocompromised patients are not as dramatic as they are in the immunocompetent population, they are still encouraging. Perhaps the most important role for imiquimod in OTRs will be the treatment of AKs, histologic skin dysplasia, and human papillomavirus-related diseases (HPV). Its ability to treat a background of keratosis, thereby unmasking early malignancies, makes imiquimod an attractive adjunct in the care of these patients.

Actinic Keratosis In a randomized, double-blind, placebo-controlled trial of twenty-one renal transplant patients, Brown and colleagues studied the safety and efficacy of imiquimod for the treatment of skin dysplasia.[5] They applied imiquimod or placebo to one dorsal hand or forearm thrice weekly for 16 weeks with pre- and posttreatment biopsies. Because of the small number of participants, many of the studied variables were not statistically significant. Thirty-six percent of treated patients demonstrated a reduction in the number of AKs at the end of the study. This was significantly lower than the 84% total clearance achieved in a similar study involving immunocompetent patients.[6] The reduction in number of plane warts in the imiquimod-treated group versus the control group, however, was significant. The number of subsequent malignancies that developed in the treatment versus nontreatment area over the ensuing year was also significant. Interestingly, clinically 286

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Table 44.1 Dosing schedule for various indications in immunocompetent patients and OTRs Indication

Immunocompetent patienta

OTRs

Actinic keratosis sBCC Maintenance therapyc

2 3 qwk 3 16wks 5 3 qwk 3 6 wks

3 3 qwk 3 16 wks or 5 3 qwk 3 8 wksb 5 3 qwk 3 12 wks 3 3 qwk 3 12 wks every 6–12 months

Note: Each application is overnight (at least 8 hours) without occlusion with wash-off upon waking.[22] a per 3M pharmaceutical recommendations[22]; off-label use in OTRs b Dosing for treatment of AKs in OTRs varies depending upon patientÕs tolerance for local side effects. c Maintenance therapy indicates the use of imiquimod on a periodic basis to diminish the amount of warts, AKs, and histologic dysplasia in an effort to control the development of cutaneous malignancies.

apparent inflammation occurred in only 5 of the 21 patients (4 in treatment group, 1 in control group) and started late in the course (4, 6, 8, 12, and 16 weeks into therapy). This late, or complete lack of, clinical inflammation is seen in other studies involving the use of topical immunomodulators in transplant recipients. The authors point out, however, that there was no correlation between a positive clinical response and the degree of inflammation. This finding is in opposition to the direct correlation between the degree of inflammation and the histologic cure rate seen in imiquimodÕs phase III trials for the treatment of BCC in immunocompetent patients.[7] Although imiquimod appears promising, more data is needed to definitively characterize the efficacy of imiquimod in the treatment of skin dysplasia and AKs in OTRs. Various dosing regimens exist for immunocompromised patients (Table 44.1). A large, multicenter trial evaluating the safety and efficacy of imiquimod for the treatment of AKs in OTRs is currently underway in Europe.

HPV Infection OTRs cannot mount an adequate TH1 response to human papillomavirus infection and often develop numerous viral warts. Warts represent a significant quality of life issue for many OTRs, but there is a much more compelling reason to find an adequate treatment for this problem. Progression of warts to premalignant lesions and squamous cell carcinoma has been well-documented.[8] Using a PCR analysis to detect HPV, 148 nonmelanoma skin cancers from immunocompetent and immunosuppressed patients at a center in London were evaluated.[9] HPV DNA was detected in 84.1% of squamous cell carcinomas, 75% of basal cell carcinomas, and 88.2% of premalignant skin lesions from the immunosuppressed group compared with 27.2%, 36.7%, and 54.4%, respectively, in the immunocompetent group. The need to treat viral warts in OTRs is clear, but the best modality for treatment is uncertain. ImiquimodÕs ability to treat wide areas relatively painfree in a convenient, self-administered fashion makes it an attractive treatment alternative to the destructive modalities. In 2005, Harwood et al. studied the efficacy of imiquimod for the treatment of persistent cutaneous warts in immuno-

suppressed patients with an open label, prospective, nonrandomized right/left comparison study.[10] Twelve of the 15 immunosuppressed patients were OTRs. Imiquimod was initially applied thrice weekly overnight for 4 weeks, then daily for 8 weeks, if no response was noted. If the lesion still failed to respond, the patients applied the imiquimod daily with occlusion for 8 weeks. Five patients (36%) had a beneficial effect with imiquimod. The low response rate was likely due to hyperkeratosis and the persistent, treatment-resistant nature of these cutaneous warts. All warts had failed a minimum number of previous destructive modalities. Transient elevations in creatinine of 11–29% above baseline were seen in 3 renal transplant patients, although there was no evidence this was related to imiquimod use. In fact, 2 patients were rechallenged with no subsequent change in their creatinine level. A number of small series and case reports in the literature indicate that, in normal clinical practice and in combination with other therapies, imiquimod may be very promising. In one study, imiquimod was used under occlusion in combination with carbon dioxide laser to successfully treat resistant verrucae vulgaris in two cardiac transplant patients. The patients underwent carbon dioxide laser ablation of the verrucae, followed three days later with imiquimod. In one patient, it was used overnight under occlusion for 4 weeks, followed by thrice weekly for 10 weeks. In the second patient, it was used overnight under occlusion three times per week for 3 months.[11] Other case reports describe successful treatment of persistent warts on the lips of a lung transplant patient when used three times per week for 10 weeks[12] and condyloma accuminata in a renal transplant patient when used three times weekly for 16 weeks[13].

Basal Cell Carcinoma Imiquimod has also been used to successfully treat BCC as shown in an open-label, prospective trial in 2003.[14] Five OTRs with 10 BCC applied imiquimod either 4 times per week for 6 weeks or 5 times per week for 5 weeks without occlusion. Seven of 10 tumors achieved clinical and histologic clearance. The tumors that did not respond tended to be large (mean

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tumor area 104.7 mm2), located on the head, infiltrative, and had a lack of erosion in response to treatment.

Squamous Cell Carcinoma Another small, open-label, uncontrolled study evaluated the use of imiquimod for the treatment of SCC in situ (SCCis) in OTRs.[15] Four OTRs with 4 SCCis applied imiquimod thrice weekly for two weeks without occlusion, followed by daily application if there was no response for up to an additional 8 weeks. Three of the 4 lesions showed erythema, erosion, and crusting after 4 weeks. One of these showed an intense inflammatory reaction after only 8 days. Of the three lesions that had a clinical response, complete clinical clearance occurred after 6 weeks. Unfortunately, one of these lesions recurred after 10 months of follow-up. Another study looked at imiquimod thrice weekly in combination with topical 5fluorouracil applied four times per week over 9 weeks.[16] There was complete response in all 5 renal transplant patients with SCCis.

Figure 44.1. Left dorsal hand of an OTR with AKs before initiation of imiquimod therapy. (Photo courtesy of Reinhard Dummer, MD.)

S ID E EF F EC T S OF IM IQ U IM OD U SE In practice, the local side effect profile for imiquimod is clinically similar to that of other effective topical chemotherapeutic agents. Erythema, erosions, and crusting are commonly seen (Figure 44.1–Figure 44.3). Unlike other topical, selfadministered therapies for premalignant and malignant lesions, however, imiquimod is dosed less frequently, which may lead to improved patient compliance. Additionally, the idea of immunologic ‘‘memory’’ for the treated lesion is attractive. ImiquimodÕs induction of Langerhans cells to mature and increase their migration from the skin to the lymph nodes for antigen presentation and stimulation of T-cells is the mechanism by which some believe an immunologic ‘‘memory’’ for the imiquimod treated lesion is established.[17] The question exists: does the patient need to experience local side effects to get a clinical response? Urosevic et al. demonstrated that, in immunocompetent patients, the number of IFN-a producing dendritic cells in the treatment area corresponded directly to the degree of clinical inflammation.[18] However, they collected tumor samples 5 days after the start of imiquimod therapy, leading one to question whether these tumors would have eventually developed an appropriate immune response. Additionally, the investigators made no correlation between degree of inflammation and density of dendritic cells and clinical cure. Phase III trials of imiquimod for the treatment of superficial basal cell carcinomas in immunocompetent patients demonstrated that increasing severity of erythema, erosion, and crusting was associated with higher clearance rates.[7] It is documented that a considerable portion of OTRs require a longer period of time to develop an inflammatory response to imiquimod, and their local side effects are often milder.[5,13] Most studies of imiquimod use in immunosuppressed patients, including

Figure 44.2. Day 10 of 14 with daily application of imiquimod. (Photo courtesy of Reinhard Dummer, MD.)

Figure 44.3. Eight weeks post treatment with imiquimod. (Photo courtesy of Reinhard Dummer, MD.)

OTRs, extended treatment for 12 to 16 weeks to attempt to account for the slower response. Even more important than the question of whether an immunomodulator will be effective in an immunosuppressed

IMIQUIMOD USE IN ORGAN TRANSPLANT RECIPIENTS

host is the question of whether stimulation of the local immune system poses a threat to the engrafted organ. Although anecdotal, a case report of this potential effect exists in the literature. A young woman with severe spondyloarthropathy who was taking multiple immunosuppressive medications had a significant flare of her disease when imiquimod was used to treat genital warts.[19] Thousands of immunosuppressed patients, including OTRs, have used imiquimod without such potentially disastrous results, but the concern remains. A study in 2004 assessed the pharmacokinetics and safety of imiquimod in the treatment of AKs in 59 immunocompetent volunteers.[20] The patients applied imiquimod three times per week to face (12.5 mg, one sachet per application), bald scalp (25 mg, two sachets), or dorsal hands/arms (75 mg, 6 sachets) for 16 weeks. Minimally quantifiable serum levels of imiquimod or its metabolites were detected. The investigators estimated an extent of absorption of less than 0.6% in any individual, based on urinary excretion. All pharmacokinetic markers were highest in the dorsal hand/arm group and lowest in the face group. The patientsÕ serum IFN levels increased approximately 2- to 15-fold by the end of treatment, although this was judged to be systemic spillover from the local production of cytokines at the application site, rather than a systemic induction. This large variation in IFN levels reflects the diverse side effect profile seen clinically from patient to patient. In a large, phase III trial with 694 immunocompetent participants treating basal cell carcinomas with imiquimod, influenza-like symptoms such as headache, fatigue, fever, arthralgia, and myalgia were reported in <3% of participants.[7] These side effects are likely due to systemic spillover of local cytokine production. In the 2004 study with AKs, the serum drug concentrations were more than 200-fold less than the serum concentrations needed to induce systemic interferon production.[20] This suggests there is minimal systemic exposure during routine use of topical imiquimod. The question remains, however, whether this negligible exposure to imiquimod or to systemic spillover of cytokines could prove harmful to a grafted organ. Systemic IFNa is used routinely for the treatment of Hepatitis C infection in liver transplant recipients with a low rate of acute rejection. Numerous studies involving renal transplant recipients, however, report an increased risk of acute rejection after IFNa treatment for active hepatitis C infection.[21] As a result, systemic IFN is avoided in the renal transplant population. The risk of acute rejection secondary to topical imiquimod use in renal transplant recipients is likely to be very small given the low levels of percutaneous absorption. However, physicians should use caution in advocating imiquimod use on large body surface areas in these patients.

C O N C L US I O N Imiquimod is a promising therapy for management of skin disease in OTRs. Its use in the treatment of AKs, skin dysplasia, and viral warts is particularly exciting. The delayed clinical

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response commonly seen in OTRs may be overcome by extending the duration of treatment. Although preliminary studies indicate that imiquimod is safe in this population, patients should limit the body surface area exposed to the drug to minimize any systemic absorption. It is advisable to limit patients to one or two sachets per application. Many of our concerns regarding the use of imiquimod in OTRs will be answered with well-designed studies which assess the safety and efficacy of imiquimod in OTRs. Until more data is available, the safety of imiquimod in OTRs should be considered when advocating its use.

REFERENCES

1. Stanley, M.A., Imiquimod and the imidazoquinolones: mechanism of action and therapeutic potential. Clin Exp Dermatol, 2002. 27(7): p. 571–7. 2. Urosevic, M., et al., Mechanisms underlying imiquimod-induced regression of basal cell carcinoma in vivo. Arch Dermatol, 2003. 139(10): p. 1325–32. 3. Schon, M., et al., Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod. J Natl Cancer Inst, 2003. 95(15): p. 1138–49. 4. Kovach, B.T. and T. Stasko, Use of topical immunomodulators in organ transplant recipients. Dermatol Ther, 2005. 18(1): p. 19–27. 5. Brown, V.L., et al., Safety and efficacy of 5% imiquimod cream for the treatment of skin dysplasia in high-risk renal transplant recipients: randomized, double-blind, placebo-controlled trial. Arch Dermatol, 2005. 141(8): p. 985–93. 6. Stockfleth, E., et al., A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses. Arch Dermatol, 2002. 138(11): p. 1498–502. 7. Geisse, J., et al., Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol, 2004. 50(5): p. 722–33. 8. Harwood, C.A. and C.M. Proby, Human papillomaviruses and non-melanoma skin cancer. Curr Opin Infect Dis, 2002. 15(2): p. 101–14. 9. Harwood, C.A., et al., Human papillomavirus infection and nonmelanoma skin cancer in immunosuppressed and immunocompetent individuals. J Med Virol, 2000. 61(3): p. 289–97. 10. Harwood, C.A., et al., Imiquimod cream 5% for recalcitrant cutaneous warts in immunosuppressed individuals. Br J Dermatol, 2005. 152(1): p. 122–9. 11. Weisshaar, E. and H. Gollnick, Potentiating effect of imiquimod in the treatment of verrucae vulgares in immunocompromised patients. Acta Derm Venereol, 2000. 80(4): p. 306–7. 12. Schmook, T., et al., Viral warts in organ transplant recipients: new aspects in therapy. Br J Dermatol, 2003. 149 Suppl. 66: p. 20–4. 13. Gayed, S.L., Topical imiquimod cream 5% for resistant perianal warts in a renal transplant patient. Int J STD AIDS, 2002. 13(7): p. 501–3. 14. Vidal, D. and A. Alomar, Efficacy of imiquimod 5% cream for basal cell carcinoma in transplant patients. Clin Exp Dermatol, 2004. 29(3): p. 237–9. 15. Prinz, B.M., et al., Treatment of BowenÕs disease with imiquimod 5% cream in transplant recipients. Transplantation, 2004. 77(5): p. 790–1. 16. Smith, K.J., M. Germain, and H. Skelton, Squamous cell carcinoma in situ (BowenÕs disease) in renal transplant patients treated with 5% imiquimod and 5% 5-fluorouracil therapy. Dermatol Surg, 2001. 27(6): p. 561–4.

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17. Suzuki, H., et al., Imiquimod a topical immune response modifier, induces migration of Langerhans cells. J Invest Dermatol, 2000. 114(1): p. 135–41. 18. Urosevic, M., et al., Disease-independent skin recruitment and activation of plasmacytoid predendritic cells following imiquimod treatment. J Natl Cancer Inst, 2005. 97(15): p. 1143–53. 19. Benson, E., Imiquimod: potential risk of an immunostimulant. Australas J Dermatol, 2004. 45(2): p. 123–4.

20. Harrison, L.I., et al., Pharmacokinetics and safety of imiquimod 5% cream in the treatment of actinic keratoses of the face, scalp, or hands and arms. Arch Dermatol Res, 2004. 296(1): p. 6–11. 21. Cardarelli, F., et al., Interferon-alpha therapy in liver transplant recipients: lack of association with increased production of anti-HLA antibodies. Am J Transplant, 2004. 4(8): p. 1352–6. 22. Pharmaceuticals, M., Aldara (imiquimod): US prescribing information. 2004.

45 Photodynamic Therapy in Organ Transplant Recipients

Nathalie C. Zeitouni, MDCM, FRCPC and Allan R. Oseroff, MD, PhD

INT ROD UCTION

Diffuser fibers, which emit light in a cylindrical pattern, can be placed interstitially to enhance light penetration. Although lasers can efficiently couple to optical fibers, their relatively low total output power limits them to treating focal areas of skin. Nonlaser sources include filtered halogen or xenon arc lamps, blue or red fluorescent tubes, and light emitting diode (LED) arrays. In contrast to lasers, broadband lamps, fluorescent light sources and LED arrays are useful for treating extended areas of skin.[1]

Clinical applications of photodynamic therapy (PDT) have expanded over the last several years due to new light sources and FDA approved photosensitizers. Compared to surgery and radiation therapy for nonmelanoma skin cancers, PDT has many potential advantages. A single, noninvasive session can treat simultaneously multiple areas as well as extensive superficial lesions. Repeated sessions can be performed without total dose limitations. PDT is generally associated with good patient tolerance, relatively short healing time, and overall good cosmesis. It can be carried out in nonsurgical candidates and can occasionally be combined with other therapeutic modalities [1,2] (Table 45.1).

P H OT OSE N SITIZE RS Photosensitizers in PDT can be used either systemically or topically. Photofrin (porfimer sodium) is the most widely used systemic photosensitizer. It is currently administered off label for treating skin cancers. PhotofrinÕs use in dermatology is limited by a mild to moderate cutaneous photosensitivity that lasts up to six weeks, and a relatively high cost that make it feasible only for large or complex carcinomas, or for multiple lesions. 5-aminolevulinic acid (ALA) in a cream base or liquid formulation (Levulan Kerastick), or the methyl ester of ALA (Metvix) are topical formulations of photosensitizers that are more practical for use in dermatology. ALA is a precursor in the heme synthesis, and the endogenous photosensitive protoporphyrin IX (PpIX) is the penultimate step in this pathway. ALA bypasses the regulatory checkpoint in heme synthesis, leading to transient accumulation of PpIX as long as the rate of ALA / PpIX is greater than the rate of PpIX / heme.[5] Accumulation occurs in carcinomas, epidermally derived cells, mast cells, activated lymphocytes, dendritic cells, and monocytes, but not in connective tissue and muscle.[5] Thus, ALA-PDT can treat actinic keratoses and carcinomas without the dermal damage that leads to scarring, making it feasible to use over large body areas.[6] In 2001, the FDA approved the use of Levulan (20% ALA) with a blue light source for the treatment of multiple, nonhyperkeratotic AKs on the face and scalp. Metvix cream is approved in Europe for actinic keratosis (AK) and superficial skin cancers. In the United States, the FDA has approved Metvix for AKs, using a red light source and with curettage of the lesion prior to application of the cream.

M E C H A N I S M S O F A CT I O N PDT is a three-component process involving a photosensitizing drug, light, and molecular oxygen. Light absorption by the photosensitizer produces an excited triplet state, which transfers its energy to oxygen, forming highly reactive, cytotoxic singlet oxygen that can also generate other reactive oxygen species and free radicals.[3] The photosensitizer then can absorb another photon and repeat the process, generating multiple molecules of singlet oxygen until the photosensitizer is destroyed (photobleached) by autooxidation. The singlet oxygen and other free radicals produced by PDT directly kill cells through apoptosis and necrosis, and also activate both innate and adaptive host responses through the release of inflammatory and immune mediators. In addition, systemic PDT with exogenous photosensitizers can cause shutdown of tumor microvasculature with resulting oxygen and nutritional starvation of tumor and normal tissue cells fed by the vessels.

L IG H T Light sources available for PDT include laser and nonlaser sources. Lasers producing a red light at wavelengths longer than 600 nm are used to maximize penetration into the tissue. Among those lasers are the older argon or frequency-doubled (KTP) Nd:YAG pumped-dye lasers and the gold vapor laser. More recent models include compact, less expensive solidstate diode lasers. Laser sources can be efficiently coupled into multiple optical fibers. Light can be divided into up to 8 fibers, which allows simultaneous treatment of multiple lesions.[4]

CLINICAL APPLICATIONS PDT has been shown to be effective for precancerous actinic keratoses and superficial skin cancers in nonimmunocompromised 291

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Table 45.1 Advantages and disadvantages of photodynamic therapy Advantages l

l l l l

Treat multiple areas simultaneously Repeated sessions possible Good patient tolerance Good cosmesis May be used in nonsurgical patients

Disadvantages l l l l

Discomfort during treatment May need multiple sessions Local or systemic photosensitivity Occasional pigmentation changes or scarring

patients.[3] Clinical indications in these patients include actinic keratosis (AK), BowenÕs disease, and superficial basal cell carcinomas (BCC). In nonimmunocompromised patients, clinical response rates for AKs treated with ALA or methylALA range from 60–100% depending on the light source, body site, extent of skin preparation, and length of follow-up. For squamous cell carcinoma (SCC) in situ, topical ALA-PDT has about 90% clinical response with a 15 month average followup. With topical ALA-PDT, average complete response rate of 87% has been reported for superficial BCC. To date, there are few trials evaluating PDT for nonmelanoma skin cancers in organ transplant recipients. In 2004 Dragieva [7] published the first prospective study evaluating topical ALA-PDT for the treatment of AK and BowenÕs disease in transplant recipients. In this open, prospective trial, a total of 44 AK fields (average size of 3 3 4 cm) and four BowenÕs disease (average size 1.6 3 2 cm) were treated with a single or two consecutive treatments at one week apart. The authors used a 5-hour application time followed by the use of a red light source. Results were compared with a similar group of immunocompetent patients. All patients were evaluated at 4, 12, and 48 weeks. Initial clinical response rates in the two groups of patients at 4 weeks were similar (88% in transplant recipients vs. 94% in controls). However, at 12 weeks the response rate among transplant recipients had dropped to 68% and by 48 weeks they had only a 48% response rate, compared with 72% in the immunocompetent patients. The anatomic site treated correlated with response in transplant recipients. For AK on the scalp, face and neck, the respective 4 and 48 week complete response rates were 96% and 52%, whereas for AK treatment fields on the hands and arms, the 4- and 48-week complete response rates only were 55% and 9%. Thus, there was site-dependent benefit in immunosuppressed patients. In this study, lower long-term cure rates in the immunosuppressed transplant recipients may have been due to the large size of the treated areas, and it is likely that there was persistence of residual disease or recurrence of new lesions, relative to immunocompetent controls. The study also suggests the need for repeated treatments in transplant patients. A second trial by Dragieva (8) evaluated the use of MAL (Metvix) PDT for AK in organ transplant recipients. Seventeen patients with a total of 129 mild to moderate AK were treated

prospectively. Sixty-two areas were treated with MAL, while a placebo cream was applied to 67 areas. All patients were treated with two consecutive sessions at one week apart. The areas were studied at 4, 8, and 16 weeks after treatment. Clinical clearance was noted in 13 of the 17 MAL treated areas (76%) at 16 weeks, whereas there was no response at the placebo-treated sites. Recently Lee and colleagues studied cyclic PDT with topical Levulan and Blue U (417 nm) for the treatment of AK in organ transplant recipients. Participants had an average 14 years of immunosuppression. Twelve patients underwent treatment of truncal and extremities AK. These patients were treated at 6- and 8-week intervals for a total of 6 to 14 sessions. At one-year follow-up, the average number of lesions per patient was decreased from 18 to 4 and was further reduced to 1 lesion after two yearsÕ follow-up. Patients reported a mean pain score of 3.6 on a 0-10 point scale [9]. In another study,[10] 5 transplant patients with 32 nonmelanoma skin cancers of the face were treated with topical ALA PDT and a 635-nm diode laser. Complete remission was noted in 24 tumors (75%). Each area was evaluated at 2, 4, and 12 weeks. In six lesions, a second and third session was necessary for remission. Two invasive SCCs were refractory to PDT. Organ transplant recipients with aggressive epithelial tumors can be managed with a combination of therapies. Three patients with facial basal cell carcinoma and squamous cell carcinoma underwent combined therapy with surgical excision, antiviral medications and PDT. ALA-PDT with a 635-nm diode laser was used to treat successfully several recurrent tumors. Lesions less than 1 cm in diameter underwent remission after one PDT treatment, whereas larger tumors required repeated sessions.[2] A randomized control trial [11] assessing the effect of PDT on the development of new SCC in organ transplant recipients found no statistical difference between treated and untreated areas on the occurrence of SCC. PDT, however, tended to reduce the increase of keratotic lesions during the two-year follow-up period. Failure to find a preventative effect of PDT on new SCC may have been due to the types of photosensitizer and light used in this study. Both topical delta aminolevulinic acid and violet light (400–450 nm) used in the study would have reduced skin penetration compared to the use of ALA, Metvix, and the red light laser.

A D V E R S E EF F E C T S OF P D T Topical photodynamic therapy with ALA in cream base, the Levulan Kerastick or Metvix is generally well tolerated. Patients may describe mild to moderate, and sometimes significant burning and stinging discomfort during illumination of the skin. The pain associated with PDT increases with larger treatment areas, the amount of PpIX, and the intensity of the absorbed light.[8] Systemic analgesics given prior to the procedure, local anesthesia, and/or the use of a fan to cool the treated site can reduce pain during illumination. Most patients

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are able to complete the PDT session. For very large areas, conscious sedation may be helpful. Other side effects of topical PDT include site-specific swelling, crusting, and local photosensitivity. Depending on the size and thickness of the treated area, local skin reactions with erythema, swelling, and crust formation evolve over 1–2 weeks after treatment, with healing over a similar time period. Cosmetic results generally are excellent to very good, with few patients developing pigmentation changes or hypertrophic scarring.

OPT I M I ZI N G T R E A TM E N T Because PDT is broadly proinflammatory, it can act as a biological response modifier, and its induction of innate and adaptive immune responses plays an important role in short and long-term outcomes in immunocompetent patients. HSP70 released from oxidatively stressed cells can stimulate toll-like receptors 2 and 4,[12] which leads to production of TNF-a and IL-6. The injured and dying cells in the treatment field release chemokines, cytokines, and chaperoned immunogenic proteins, and endothelial cells express adhesion molecules facilitating an inflammatorily and immunologically active infiltrate.[13,14] The initial infiltrate is predominately neutrophils, followed by mast cells and macrophages [15] with NK cells also playing a role.[16] Because immunosuppressed organ transplant patients may be less likely to benefit from topical ALAPDT-mediated innate and adaptive immune responses, it is important to aggressively optimize direct cell killing with PDT. To ensure adequate ALA penetration, remove hyperkeratotic scale and crust from the lesions by physical means or with keratolytics, and apply the ALA long enough to allow adequate PpIX synthesis at the level of the skin appendages: 4 h probably is the minimum interval, and 5–6 h may be preferable.[17] The light dose should be at least 100 J/cm2 of red light (600–700 nm) or at least 10 J/cm2 of blue light, along with an optical coupling medium such as mineral oil or a transparent gel if any hyperkeratosis or scale remains; red wavelengths may be pref-

Figure 45.2. Complete response after one treatment with 20% ALA-PDT (24-hour application).

erable because they have decreased scattering and increased penetration compared to blue. In addition, because the PpIX may be photobleached before all target cells are directly killed, multiple treatment sessions every 7–10 days may be necessary to achieve clinical reduction in AK; resistant lesions need to be biopsied to rule out invasive SCC. The treatments may be repeated at 6–12 month intervals, as lesions recur or appear, while they are sparse, small, and more responsive. An example of PDT treatment is shown in Figure 45.1 and Figure 45.2.

CONCLUSION Organ transplant recipients are at high risk for transformation of AK to invasive SCC. PDT may reduce this risk by simultaneously treating many AK. It appears that aggressive approaches and repeated sessions are necessary to treat both AK and carcinomas in these patients. PDT may also play a role in the future in the prevention of precancerous or cancerous lesions.[5]

REFERENCES

Figure 45.1. Seventy-six-year-old renal transplant patient with two sites of biopsy-proven BowenÕs disease (squamous cell carcinoma in situ) of the right lower leg.

1. Zeitouni NC, Shieh S, Oseroff AR. Lasers and Photodynamic Therapy in the Management of Cutaneous Malignancies. Clin Dermatol 2001; 20:328–39. 2. Hyckel P, Schleier P, Meerbach A, et al. The therapy of virus-associated epithelial tumors of the face and the lips in organ transplant recipients. Med Microbiolo Immunol 2003; 192:171–6. 3. Dougherty TJ, Gomer CJ, Henderson BW, et al. Photodynamic therapy. J Natl Cancer Inst 1998; 90:889–905. 4. Wood LM, Bellnier DA, Oseroff AR, Potter WR. A Beam-splitting Device for Use with Fiber-coupled Laser Light Sources for Phtodynamic Therapy. Photochemo Photobiol 2002; 76:683–5. 5. Rittenhouse-Diakun K, Van Leengoed H, Morgan J, et al. The role of transferrin receptor (CD71) in photodynamic therapy of activated and malignant lymphocytes using the heme precursor delta-aminolevulinic acid (ALA). Photochemo Photobiol 1995; 61:523–8.

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6. Oseroff AR, Shieh S, Frawley NP, et al. Induction of immune cell infiltration into murine SCCVII tumour by photofrin-based photodynamic therapy. Arch Dermatol 2005; 141:60–7. 7. Dragieva G, Hafner J, Dummer R, et al. Topical photodynamic therapy in the treatment of actinic keratoses and BowenÕs disease in transplant recipients. Transplantation 2004; 77:115–21. 8. Dragieva G, Prinz BM, Hafner J, et al. A randomized controlled clinical trial of topical photodynamic therapy with methyl aminolaevulinate in the treatment of actinic keratoses in transplant recipients. Br J Dermatol 2004; 151:196–200. 9. Lee P. Squamous Cell Carcinomas in transplant recipients treated with Cyclic Topical Photodynamic Therapy with 20% 5-Aminolevulinic Acid. 2005. 10. Schleier P, Hyckel P, Berndt A, et al. Photodynamic therapy of virusassociated epithelial tumours of the face in organ transplant recipients. J Cancer Res Clin Oncol 2004; 130:279–84. 11. De Graaf YGL, Kennedy C, Wolterbeek R, et al. Photodynamic therapy does not prevent cutaneous squamous-cell carcinoma in organtransplant recipients: Results of a randomized-controlled trial. J Invest Dermatol 2006; 126:569–74.

12. Asea A, Rehli M, Kabingu E, et al. Novel Signal Transduction Pathway Utilized by Extracellular HSP70. Role of Toll-Like Receptor (TLR) 2 and TLR4. J Biol Chem 2002; 277:15028–34. 13. Gollnick SO, Vaughan L, Henderson BW. Generation of effective antitumor vaccines using photodynamic therapy. Cancer Res 2002; 6:1604–8. 14. Gollnick SO, Evans SS, Baumann H, et al. Role of Cytokines in photodynamic therapy-induced local and systemic inflammation. Br J Cancer 2003; 88:1772–9. 15. Krosl G, Korbelik M, Dougherty GJ. Induction of immune cell infiltration into murine SCCVII tumour by photofrin-based photodynamic therapy. Br J Cancer 1995; 71:549–55. 16. Korbelik M, Cecic I. Contribution of myeloid and lymphoid host cells to the curative outcome of mouse sarcoma treatment by photodynamic therapy. Cancer Lett 1999; 137:91–8. 17. Morton CA, MacKie RM, Whitehurst C, Moore JV, McColl JH. Photodynamic therapy for basal cell carcinoma: effect of tumor thickness and duration of photosensitizer application on response. Arch Dermatol 1998; 134:248–9.

46 Skin Cancer Prevention and Photoprotection in Organ Transplant Recipients

Sumaira Z. Aasi, MD

B AC K G R O UN D

DNA pyrimidine dimers form with exposure to UVR,[4] and these dimers impede the bodyÕs innate surveillance against dysplasia, allowing mutated cells to proliferate. UVR causes the formation of reactive oxygen species that lead to DNA strand breakage and structural anomalies of chromosomes.[5] UVR also activates inflammatory pathways generating vascular reactions that result in clinical erythema and eventually sunburn. These effects and their association with cutaneous malignancies have led to the official recognition of UVR as an environmental carcinogen.[6] The exact mechanism of UVR-induced cutaneous carcinogenesis has not been elucidated. It is a complex interplay between gene mutation, inflammation, and immunosuppression. Erythema is the clinically visible immediate effect on the skin from UVR. Evidence suggests that clinical erythema correlates with DNA damage. Wavelengths of UVR that are most efficient at producing erythema are also the most efficient at producing pyrimidine dimers.[4] However, many of the deleterious effects of UVR occur before the erythema threshold is reached. Such suberythemal effects of UVR include inflammation, photoaging, diminished antigen responsiveness and depletion of epidermal Langerhans cells.[7] The tumor suppressor, p53 protein, is also induced, which is a strong indication that DNA damage is occurring during suberythematous ultraviolet (UV) exposures.[8] Murine studies also clearly demonstrate that both suberythemal UVB and suberythemal UVA cause tumors.[9] Although much of the literature documents the effects of UVB on skin, many studies in recent years have highlighted the role UVA radiation plays in inducing damage to the skin by causing immunosuppression, DNA mutations, lipid and protein oxidative damage, and photoaging. As our knowledge of the role of UVA in photocarcinogenesis expands, it is critical to improve the capability of sun protection products so that they shield against UVA as well as UVB.

The prevention of skin cancer in organ transplant recipients (OTRs) through photoprotection is a multifaceted topic. This chapter will discuss ultraviolet radiation, photoprotection, concerns regarding vitamin D, and the educational and behavioral aspects of photoprotection. Skin cancer prevention and photoprotection practices, as outlined in Table 46.1, are essential strategies that may effectively reduce the risk of skin cancer in OTRs.

U L T R A V I O L E T R AD I AT I O N

The Physics of Ultraviolet radiation The electromagnetic spectrum spans a wavelength band of radiation with wavelengths ranging from 10 14 m (gamma radiation) to 104 m (radio waves). Ultraviolet radiation (UVR) refers to solar radiation with wavelengths in the 200 to 400 nm range. Radiation in the 400 to 700 nm length is referred to as visible light. In humans, skin is the organ with the highest surface area and is most at risk for damage from UVR exposure. UVR is further subdivided into UVC, UVB, and UVA based on different biological effects. The UVC band (200–290 nm) is known as the ‘‘germicidal’’ band and is almost entirely absorbed by the ozone layer. The UVB band (290–320 nm) is known as the ‘‘erythemal’’ band and is significantly attenuated by the atmosphere. UVA (320–400 nm) is known as ‘‘black light’’ and it is further subdivided into UVA I (340–400 nm) and UVA II (320–340 nm). The shorter wavelengths of UVA II are more erythmogenic than UVA I. Although UVA is more prevalent at the earthÕs surface, it is less effective than UVB in eliciting erythema in human skin.[1]

Biological Effects of Ultraviolet Radiation Skin cancer is the most prevalent cancer in humans. More importantly, however, skin cancer is not only curable if detected early but it is also preventable. Since the 1890s, even before the discovery of DNA and the concept of genetic mutations, sunlight exposure was implicated in the etiology of skin cancer.[2] Over time significant scientific evidence has been collected and has linked UVR with skin cancer formation. Skin cancers contain in their inactivated tumor suppressor genes mutations that are characteristic of UV-induced damage.[3]

Sun Exposure and Immunosuppression The importance of the immune system in controlling the development of sun-induced cutaneous malignancies is readily apparent by the particularly high incidence of skin cancer in immunosuppressed patients such as OTRs. Immunosurveillance is thought to be particularly important in preventing the early stages of skin cancer development. There are two mechanisms that account for the adverse effects of UVR on 295

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Table 46.1 Recommended sun protection practices for organ transplant recipients Daily use of broad-spectrum (UVA and UVB protection) with SPF > 30 Apply sunscreen daily as part of the morning hygiene routine, and then reapply as needed throughout the day Apply product 15–30 minutes before actual sun exposure Apply ‘‘2 coats’’ to cover all exposed areas adequately (One ounce or 30 ml of sunscreen is required to cover exposed areas of the body completely) Include areas often overlooked such as back of neck, ears, and lips, where lip balm with sunscreen is recommended Use waxy stick sunscreen in the periorbital area that will not melt or run when exposed to sweat Reapplication of sunscreen every 2–3 hours or after getting wet or with excessive perspiration Use sunscreen even on cloudy days Wear a wide-brimmed hat Wear UV-blocking sunglasses Wear protective clothing that has tight weave Minimize activity at peak sun exposure between 10 AM and 4 PM and seek shade

the immune system. Firstly, UVR exposure leads to immunosuppression through changes in cell populations involved in immune response. The Langerhans cells (LC), the principal antigen-presenting cells, are the major immune surveillance system of the skin. Exposure to UVB radiation has been shown to alter LC number, morphology, and antigenpresenting function. Within hours of UV exposure, there is loss of the LCÕs functional maturity to mount an immune response, failure to stimulate T-helper (Th)1 cells and preferential activation of Th2 cells resulting in an increased generation of suppressor T cells.[10,11] Second, UV-damaged keratinocytes release cytokines such as interleukin 1, interleukin 10, tumor necrosis factor a as well as prostaglandins.[12] Some of these immunologic responses are triggered by the cyclobutane dimers formed by UV exposure. Since sunscreens prevent pyrimidine dimer formation, they should theoretically also reduce or prevent some of the adverse immunologic effects of UVR.

P H O TO P R O TE CT I ON

Sunscreens Sunscreens function to protect the skin from UVR by absorbing, reflecting, or scattering sunlight. Sunscreens are a commonly used form of photoprotection. However, it is often human nature to disregard a preventative strategy, such as applying sunscreen to prevent future carcinogenesis. Furthermore, most photodamage is initially asymptomatic and signs of its occurrence do not appear until substantial time has elapsed. There is, then, often little incentive to perform a strategy where the benefits cannot be readily appreciated. This, along with societyÕs association of a tan with health and beauty, and the lack of the ‘‘perfect’’ sunscreen lead to unsafe attitudes and behaviors regarding sun exposure. The ideal sunscreen would protect against UVA and UVB radiation, would be nontoxic, photostable, nonallergenic, long-lasting, cosmetically elegant, waterproof, and inexpen-

sive. Although no ideal or perfect sunscreen exists at the moment, there has been a continuous improvement of these products (Table 46.2). In general sunscreens can be divided into two groups: chemical (or organic) and physical (or inorganic) sunscreens. Organic sunscreens are, in general, aromatic compounds that absorb UVR through chemical excitation and then dissipate this solar energy as longer wavelength energy that is less damaging to tissues. Inorganic sunscreen products attenuate UVR by reflection and scattering due to their large particle size. Of the chemical sunscreens, one the first products developed in the early 1970s used para-amino benzoic acid (PABA) as its active ingredient. PABA is effective in blocking the UVB radiation because of its ability to bind to epidermal cells and is therefore not easily removed by water/swimming, exercise, or abrasion. However, it can cause permanent staining of fabrics and is associated with photoallergic and irritant problems. With the addition of reports that PABA could decompose to produce a nitrosamine degradation product with a known carcinogenic potential,[13] it has been practically eliminated from sunscreens. Current organic sunscreen active ingredients that protect against UVB include cinnamates, salicylates, and esters of PABA that are less reactive, such as Padimate O. Chemical sunscreens that provide some UVA protection are the benzophenones (oxybenzone, dioxybenzone) and Avobenzone. Benzophenones are very stable molecules but their UVA absorption ability is still relatively poor. Often, sunscreen products contain a combination of active ingredients to improve their ability to filter UVR, to enhance stability, and to improve water resistance. The current globally-approved sunscreen active ingredients capable of attenuating long wavelength UVA are avobenzone, titanium dioxide, and zinc oxide. Avobenzone or Parsol 1789 (4-T-butyl-4-methoxydibenzoylmethane) was developed in the 1980s. It is broadly effective against the UVA spectrum and is usually marketed in combination with UVBblocking agents. However, there is concern that it becomes photoinstable in some formulations and loses its protective efficacy. The physical blockers, titanium dioxide and zinc

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Table 46.2 Summary of sunscreen ingredients Sunscreen active ingredient

Range of protection

Advantages

Disadvantages

PABA

UVB (260–315)

Binds to epidermal cells making it water/ perspiration resistant

PABA esters (padimate A, padimate O, glyceryl PABA) Cinnamates (Octyl methoxycinnamate, cinoxate) Salicylates (homosalicylate, octyl salicylate, triethanolamine salicylates) Benzophenones (oxybenzone, dioxybenzone, sulisobenzone)

UVB 290–315 290–315 260–313 UVB 280–310 270–328

Prone to staining. Most prone to allergic contact and photocontact allergy Rarely stain. Less contact and photocontact allergy Less water resistant

Nonstaining

UVB 290–315 260–310 269–320

Not as effective

UVB modest UVA 270–350 206–380 250–380

Do not stain

Dibenzoylmethanes Tertbutylmethoxydibenzoylmethane (Avobenzone, Parsol 1789) Titanium dioxide Zinc oxide

UVA 310-355

High degree of UV absorption

UVA and UVB

Terephtalylidene dicamphor sulfonic acid (Mexoryl SX) Bisethylhexyloxyphenol methoxyphenyl triazene (Tinosorb)

UVA

Broad spectrum. Chemically stable. No photoallergic or contact dermatitis Mid-range UVA protection

UVA and UVB 280–380

Photostable

oxide, provide excellent broad spectrum protection against UVR. Initially thick and opaque, with a tendency to melt in the sun and cause staining, they now are available in a finely ground (micronized) form that is much more cosmetically acceptable. These microfine variants of titanium dioxide and zinc oxide attenuate light through a combination of scattering, reflection, and absorption. Other advantages of the physical blockers are that they are chemically stable, do not cause any photoallergic or contact dermatitis, and because of their particle size, are not absorbed into the skin.

Newer Sunscreens Although there is a large choice of chemical UVB filters, effective chemical UVA absorbers are rare. The currently available UVA filters in the United States are either poor performing or not sufficiently photostable. Photoinstability occurs when UV exposure causes decomposition of the sunscreen agent, reduces its photoprotective power and promotes phototoxic or photoallergic contact dermatitis. Terephtalyidene dicamphor sulfonic acid (Mexoryl SX) is a newer product available in Europe and Canada but not yet in the United States. It has shown excellent photostability and is frequently formulated with avobenzone and UVB absorbers as a broad spectrum sunscreen.[14] In addition, another new development also available in Europe is bisethylhexyloxyphenol methoxyphenyl triazene (Tinosorb S). This broadband sunscreen filter also

Very stable products Nonsensitizing Water-insoluble Less water resistant. Often thicker and thus less cosmetically acceptable. Allergic reactions increasing Unstable, undergo photodegradation Opaque appearance to area applied, improved with the micronized forms Limited product availability in United States Not available in United States

provides more photostability to avobenzone-containing sunscreens.[15]

Measuring Efficacy of Sunscreens The effectiveness of sunscreens is rated by their sun protection factor or SPF. The SPF essentially measures prevention of ultraviolet-induced erythema. It is the ratio of the amount of time that a person exposed to the sun takes to sunburn while wearing a sunscreen compared with the time required to sunburn without protection. The SPF should not be viewed as a quantitative value but rather as a relative measure to compare products. It provides a clinically meaningful, comparative product index of protection against UV induced erythema and sunburn. The relationship between SPF and absorption of erythmogenic energy SPF is nonlinear. For instance, a product with an SPF 15 filters out greater than 93% of UVB radiation, whereas a product with an SPF 30 filters greater than 97% of UVB radiation. The SPF is assessed by a specific, detailed, universally-agreed protocol. It is determined by applying 2 mg/cm2 of the sunscreen product uniformly with a gloved finger on the lower back skin which is then exposed to simulated light. Erythema primarily arises from short wavelength radiation (UVB 290–320), although UVA (particularly UVA II) contributes to this as well. Because UVB is more erythmogenic than UVA, SPF is a more accurate measure of UVB protection.

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Clinical Efficacy of Sunscreens Although the precise mechanism of UV induced erythema is unknown, it seems to share an action spectrum with DNA damage and pyrimidine dimer formation.[16,17] Sunscreens with sufficient SPF can substantially limit or prevent this DNA damage and base pair mutation.[18] This effect has translated clinically in terms of precancerous lesions (or actinic keratoses) and nonmelanoma skin cancer with multiple studies showing a direct protective and preventative effect with sunscreen use. A study of 588 Australian individuals demonstrated that the daily use of sunscreen resulted in a significant reduction in the number of new actinic keratoses. In addition, among the sunscreen uses, the number of preexisting actinic keratoses decreased. This confirmed the importance of daily sun protection and the ability of human skin to undergo repair during sunscreen protection.[19] In another randomized, vehicle-controlled study, subjects who used sunscreen showed a 51% reduction in the number of new actinic keratoses compared to nonusers.[20] Finally, in a study looking at the incidence of squamous cell carcinomas in regular sunscreen users, there was a 46% decrease in the number of carcinomas that developed over a period of 4.5 years.[21] However, whether sunscreens can reduce the risk for melanoma has not yet been proven definitively. One ironic and controversial twist in the story of photoprotection is the concern of increased exposure to UVR, particularly UVA, with sunscreen usage. Because the overwhelming majority of sunscreen products currently available to consumers provide protection primarily against UVB and UVA II, the use of such products may paradoxically increase exposure to long-wavelength UVA I due to prolonged outdoor exposure. In addition, because chemical sunscreens reduce the occurrence of painful sunburns, they may prevent the formation of this warning sign, permitting people to extend the time spent in the sun and theoretically increasing the risk of developing skin cancer. Somewhat concerning is that such actions may be subconscious. In a recent study in which all participants were blinded to the SPF formulation that they received, participants who received high SPF sunscreen spent more time in the sun compared to those who received lower SPF sunscreen.[22] Despite these concerns, there is substantial evidence that sunscreen use protects against precancerous and cancerous growths. There is also indirect evidence supporting sunscreen use, such as a study which showed that melanoma rates are declining in white individuals in Hawaii, a group that has among the highest per capita use of sunscreen in the United States.[23]

Limitations of Sunscreens Human skin is exposed to all the ultraviolet bands from the sun and the division of these into UVA, UVB, and UVC is somewhat anthropomorphic and arbitrary. UVA exposure is clinically relevant for several reasons. It is well known that

exposure to UVA radiation can cause acute and chronic skin photodamage.[24] In addition, UVA exposure has been shown to induce skin tumors in animals.[25] UVA is not filtered by the stratospheric ozone layer and accounts for a greater proportion of the terrestrial UV radiation. In addition, because UVA has a longer wavelength, it penetrates deeper into the skin. Finally, UVA is not blocked by window glass. Although the United Kingdom, Germany, Australia, and Japan have adopted standards for testing and labeling products for UVA protect, the FDA and the European Union Commission have not adopted any method officially. The problem with in vivo evaluation of UVA protection is that the responses to UVA exposure are limited primarily to erythema and pigmentation. Both of these responses require relatively high exposure doses of UVA. On the other hand, although in vitro methods are safer to obtain, they may not be as accurate clinically. The current challenge with UVA protection is the ability to accurately measure clinical efficacy and to convey this information to the public in a simple and clear manner. Another dilemma arises from the fact that currently available chemical sunscreens are more effective at preventing sunburn than in protecting the immune response. A recent review of studies on sunscreens and UVA protection concluded that sunscreens provided only partial protection from UV-induced immune suppression. Some of the studies reviewed suggested, however, that sunscreens capable of absorbing UV over a broader spectrum (that is, both UVA and UVB) resulted in less immune suppression.[26] Other work corroborates that increasing the level of UVA protection in sunscreen products improves immune protection.[27,28] Another practical consideration is that the SPF of a sunscreen product is measured under ideal, controlled conditions. The true efficacy is a function of how the product is actually used and is affected by several factors. For instance, it takes on average 1 oz of sunscreen to cover the entire body. A number of studies indicate that sunscreen is inadequately applied and less is applied than what is used to establish the SPF on the bottle.[29] Hence, the actual SFP received may be only 20 to 50 % of that desired.[30] It has also been shown that the less cosmetically appealing a sunscreen, the less product individuals will apply.[31] Timing of application is relevant. The organic or chemical sunscreens take 15–20 minutes from the time of application before they become effective.[32] Reapplication of the sunscreen is also critical to compensate for initial underapplication and to replace product removed by water, friction, clothing, or sand. When sunscreen is applied prior to sun exposure and subsequently reapplied after a period of controlled exposure, a two- to three fold increase in production from sunburn can be expected.[33] Few studies have examined sunscreen reapplication and those that have show that less than two thirds of sunscreen users will reapply sunscreen when needed.[34] Taking into account factors such as cost, convenience, and human nature, it will be challenging to persuade users to reapply sunscreen regularly.

SKIN CANCER PREVENTION AND PHOTOPROTECTION IN ORGAN TRANSPLANT RECIPIENTS

Sun-protective Clothing Clothing such as long sleeve shirts and pants also provide significant skin coverage and protect the skin against photoaging, tanning, and wrinkling (Figure 46.1).[35] Several factors, however, must be taken into consideration when measuring the efficacy of UV protection with clothing. The most important factor in sun protection for clothing is the tightness of the weave; the tighter the weave, the more protection the fabric provides. Thicker fabric has higher UV-absorbing ability. Washing clothing also improves UV protection by depositing optical whitener and shrinking the fiber with each wash. Next in importance for UV protection is fabric type. Nylon and particularly polyester have high UV absorbance. However, unless these fabrics are made with vents, they do not allow diffusion of perspiration, allowing the skin to cool. Cotton and rayon fibers also have some UV protection but their UV absorbance is not as high and can be improved by finishing the fiber with optical whitener and UV-absorbing compounds. Optical whitening agents, also known as fluorescent whitening agents or brighteners are included in almost every heavy-duty detergent product sold in the United States and Europe because they whiten and brighten garments. These optical whitening agents also absorb UV, better in the UVA region than UVB region. UV-absorber compounds are available in select

Figure 46.1. Proper sun-protective attire.

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detergents and in a laundry product called Rit Sunguard manufactured by Phoenix Brands. They are also available in laundry detergents in Europe, Asia, and Australia. The color of fabric also contributes, with darker colors providing greater protection than lighter colors. When wet, fabrics lose significant sunprotective value. The SPF of a dry white cotton tee-shirt is approximately 6, reduced to 3 when wet.[36] A hat with an all-around wide brim can also provide significant UV protection. Marks et al. noted that the regular wearing of a hat with a 10-cm brim could lower lifetime skin cancer rates by 40%.[37] Sun-protective clothing is clothing, which makes a claim that it protects from UV light, reduces skin injury associated with sunlight, and uses a rating system that quantifies the amount of sun protection it provides. Garments with a UV protective claim are more costly but also more effective in their protection.

S U N P R O T E C T I O N A ND CO N CE R N S R EG A R DI NG V IT A MI N D There has recently been raised a concern that sun avoidance to prevent skin cancer may compromise vitamin D sufficiency. Vitamin D is important for calcium and bone homeostasis. It increases intestinal calcium absorption, enhances mobilization of calcium and phosphorus from bone, and suppresses parathyroid hormone secretion. One of the beneficial effects of UVB radiation is the production of vitamin D in the skin and conversion of provitamin D3 (7-dehydrocholestereol) to the active vitamin D3 metabolite (1,25 dihydroxyvitamin D3). Over time, deficiency in vitamin D can lead to osteomalacia, accelerated osteoporosis, and the potential increased incidence of bone fractures. However, studies correlating vitamin D status with bone fractures in the elderly have shown equivocal results. Sunscreens can decrease vitamin D synthesis [38] but they do not create a significant impact when dietary intake and absorption of vitamin D are adequate.[39,40] More importantly, UV-induced vitamin D synthesis is maximal at suberythemal UV doses, and further UV exposure does not increase pre-vitamin D3 levels but rather increases conversion of previtamin D3 to biologically inert compounds.[41] The rate of vitamin D photosynthesis varies inversely with skin phototype, at least in part because melanin pigment in the epidermis absorbs the UV photons otherwise responsible for photochemical reactions such as pre-vitamin D3 production. Thus, brief sun exposures often permit maximal vitamin D production in fair-skinned individuals but may allow only submaximal vitamin D production in dark-skinned individuals. Exposing 5% of the uncovered body surface twice a week in summer may be equivalent to an intake of 430 IU of vitamin D per day. Studies show that in most individuals incidental UV daily exposures appear to be greater than required to achieve adequate vitamin D level.[42] Finally, prospective, randomized controlled studies show that vitamin D deficiency does not result from regular sunscreen use.[43] Other sources of vitamin D, which do not carry an increased risk of photoaging

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and skin cancer, are vitamin D supplements or food sources supplemented with vitamin D, which should be encouraged over sun exposure.

S EL F S K I N E XA M IN A TI O N , E D U C A TI O N , A N D S UN P R O T E CT I O N C O M P L I AN C E Skin cancer prevention campaigns have increased awareness of the need for sun protection but knowledge does not always translate into a change in attitude or action. A phone survey of OTRs and the general population in the United States found that a higher percentage of OTRs viewed tanned skin to be healthy and attractive. Furthermore, they found that a majority of OTRs had hazardous sun-related attitudes and did not practice safe and risk-reducing sun behaviors compared to the general public.[44] In another study, organ transplant patients cited ‘‘hassle’’ and ‘‘lack of time’’ as the most common barriers that discouraged them from practicing sun protective behaviors and self-examinations.[45] Regardless, one cannot abandon public education and prevention as they can make a difference, albeit slowly. Compliance improves when rationale for use is given and is constantly rediscussed. Two decades of public health campaigns in Australia have led to a change in the beliefs, attitudes, and behavior regarding sun exposure and have affected the incidence of skin cancer.[46] For many OTRs, skin cancer is almost an inevitable reality. For this unique population, sunscreen use is axiomatic. Discussion of sun protection behavior in the pretransplant time period may be ideal. Pretransplant education may allow time for patients to try sun protective practices prior to experiencing the overwhelming information and medical responsibilities that occur at the time of actual transplantation. This education can be achieved via classes, support group sessions, mailed leaflets, and national web sites. In addition, individuals must understand that sunscreen use is just part of an overall sensible approach to avoiding photo damage. Unfortunately, using sun protection religiously is not a guarantee against the formation of skin cancer. Cancer formation is multifactorial and both primary and secondary prevention such as regular self-examination and complete skin examination by a physician are necessary. Such behavioral changes should ideally occur not just at the level of the individual but also in the community. A shift in the publicÕs perception of sun exposure is necessary and can be achieved through a coordinated, consistent effort that relies on primary prevention, education, long-term partnerships, and commitment between industry, media, and the medical community, eventually influencing cultural and social norms.

REFERENCES

1. Matts PJ. Solar ultraviolet radiation: definitions and terminology. Dermatol Clin 24 (2006):1–8. 2. Hyde JN. On the influence of light in the production of cancer of the skin. Am J Med Sci. 1906;131:1–22.

3. Ziegler A, Leffell DJ, Kunala S, Sharma HW, Gailani M, Simon JA et al. Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers. Proc Natl Acad Sci USA 1993;90:4216–20. 4. Hacham H, Freeman SE, Gange RW et al. Do pyrimidine dimer yields correlate with erythema induction in human skin irradiated in situ with ultraviolet light (275-365 nm)? Photochem Photobiol. 1991;53: 559–63. 5. Pentland AP. Active oxygen mechanisms of UV inflammation. Adv Exp Med Biol. 1994; 366:87–97. 6. Twombly R. New carcinogen list includes estrogen, UV radiation. J Natl Cancer Inst. 2003; 95(3):185–6. 7. Cooper K, Oberhelman L, Hamilton T et al. UV exposure reduces immunization rates and promotes tolerance to epicutaneous antigens in humans: relationship to dose, CD1a- DR + epidermal macrophage induction, and Langerhans cell depletion. Proc Natl Acad Sci USA. 1992; 89:8497–501. 8. Healy E, Reynolds NJ, Smith MD, et al. Dissociation of erythema and p53 protein expression in human skin following UVB irradiation, induction of p53 protein and mRNA following application of skin irritants. J Invest Dermatol 1994; 103:493–499. 9. Gallagher CH, Canfield PJ, Greenoak GE, Reeve VE. Characterization and histogenesis of tumors in the hairless mouse produced by lowdosage incremental ultraviolet radiation. J Invest Dermatol. 1984; 83: 169–174. 10. Simon JC, Tigelaar RE, Bergstresser PR, et al. Ultraviolet B radiation converts Langerhans cells from immunogenic to tolerogenic antigenpresenting cells. J Immunol. 1991; 146:485–91. 11. Ullrich SE. Mechanisms involved in the systemic suppression of antigen-presenting cell function by UV irradiation: keratinocytederived IL-10 modulate antigen-presenting cell function of splenic adherent cells. J Immunol. 1994; 152:3406–10. 12. Nishigori C, Yarosh DB, Donawho C, Kripke ML. The immune system in ultraviolet carcinogenesis. J Invest Dermatol Symp Proc. 1996; 1:143–146. 13. Pathak M, Robins P. A response to concerns about sunscreens: A report from the skin cancer foundation. J Dermatol Surg Oncol. 1989; 15:486–7. 14. Lowe NJ. An overview of ultraviolet radiation, sunscreens, and photo-induced dermatoses. Dermatol Clin 24 (2006):9–17. 15. Chatelain E, Gabard B. Photostabilization of Avobenzone and ethythexyl methoxycinnamate by ethythexyloxyphenol methoxyphenytriazine (Tinosorb S) a new broadband filter. Photoderm Photobiol 2001;74(3):401–6. 16. Hachmam H, Freeman SE, Gange RW, et al. Do pyrimidine dimmer yields correlate with erythema induction in human skin irradiated in situ with ultraviolet light (275-365 nm)? Photochem Photobiol 1991; 53:559–63. 17. Young AR, Chadwick CA, Harrison GI, et al. The similarity of action spectra for thymine dimers in human epidermis and erythema suggests that DNA is the chromophore for erythema. J Invest Dermatol 1998; 111:982–8. 18. Freeman SE, Ley RD, Ley KD. Sunscreen protection against UVinduced pyrimidine dimers in DNA of human skin in situ. Photodermatology. 19.88;5:243–247. 19. Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med. 1993; 329:1147–51. 20. Naylor MF, Boyd A, Smith DW, et al. High Sun protection factor (SPF) sunscreens in the suppression of actinic neoplasia. Arch Dermatol. 1995; 131:170–5. 21. Green A, Williams G, Neal R, et al. Daily sunscreen application and betacarotene supplementation in the prevention of basal-cell and squamous-cell carcinomas of the skin: a randomized controlled trial. Lancet. 1999:354;723–729. 22. Autier P, Dore J, Negrier S, et al. Sunscreen us and duration of sun exposure: A double-blind, randomized trial. J Natl Cancer Inst. 1999; 91:1304–9.

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23. Chaung TY, Charles J, Reizner GT, Elpern DJ, Farmer ER. Melanoma in Kauai, Hawaii, 1981–1990: the significance of an in situ melanoma and the incidence trend. Int J Dermatol. 1999:38:101–7. 24. Lowe NJ, Meyers DP, Wieder JM, et al. Low doses of repetitive ultraviolet A induced morphologic changes in human skin. J Invest Dermatol 1995;105:739–43. 25. Sterenborg HJCM, van der Leun JC. Tumorigenesis by a long wavelength UV-A source. Photochem Photobiol. 1990;51:325–30. 26. Ullrich S, Kim T, Ananthaswamy H, Kripke M. Sunscreen effects on UV-induced immune suppression. J Invest Dermatol Symp Proc. 1999;4:65–9. 27. Fourtanier A, Gueniche A, Compan D et al. Improved protection against solar-simulated radiation-induced immunosuppression by a sunscreen with enhanced ultraviolet A protection. J Invest Dermatol 2000;114:620–7. 28. Nghiem DX, Kazimi N, Clydesdale G, et al. Ultraviolet A radiation suppresses an established immune response: implications for sunscreen design. J Invest Dermatol 2001;117:1193–1199. 29. Bech-Thomsen WN, Wulf HC. SunbathersÕ application of sunscreen is probably inadequate to obtain the sun protection factor assigned to the preparation. Photodermatol Photoimmunol Photomed 9(1993): 242–244. 30. Stokes R, Diffey B. How well are sunscreen users protected? Photodermatol Photoimmunol Photomed. 1997:13(5–6):186–8. 31. Diffey BL, Grice J. The influence of sunscreen type on photoprotection. Br J Dermatol. 1997; 137:103–105. 32. Rigel DS. The effect of sunscreen on melanoma risk. Dermatol Clin 20 (2002):601–606. 33. Pruim B, Green A. Photobiological aspects of sunscreen re-application. Australasian J Dermatol. 40:14–18, 1999. 34. Pruim B, Wright L, Green A. Do people who apply sunscreen re-apply them? Australas J Dermatol. 199;40:79–82.

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35. Hatch KL, Osterwalder U. Garments as solar ultraviolet radiation screening materials. Dermatol Clin. 24:85–10, 2006. 36. Menter JM, Hollins TD, Sayre RM, Eternadi AA, Willis I, Hughes SN. Protection against UV photocarcinogenesis by fabric materials. J Am Acad Dermatol 1994;31(5, part1):711–6. 37. Marks R. Photoprotection and prevention of melanoma. Eur J Dermatol 1999:9(5):406–12. 38. Matsuoka LY, Ide L, Wortsman J, Mclaughlin JA, Holick MF. Sunscreens suppresses cutaneous vitamin D3 synthesis. J Clin Endocrinol Metab. 1987; 64:1165–1168. 39. Marks R, Foley PA, Jolley D, et al. The effect of regular sunscrren use on vitamin D levels in an Australian population: results of a randomized controlled trial. Arch Dermatol. 1995; 131:415–421. 40. Naylor MF, Farmer KC. The case for sunscreens: a review of their usage in preventing actinic damage and neoplasia. 41. Holick MF, MacLaughlin JA, Doppelt SH. Regulation of cutaneous previtamin D3 photosynthesis in man: skin pigment is not an essential regulator. Science. 1981; 211:590–3. 42. Lim HW, Gilcrest BA, Cooper KD et al. Sunlight, tanning booths, and vitamin D. J Amer Acad Dermatol. 52(5):868–876. 43. Marks R, Folley PA, Jolly D, Knight KR, Harrison J, Thompson SC. The effect of regular sunscreen use on vitamin D levels in an Australian population. Results of a randomized controlled trial. Arch Dermatol. 1995; 131:415–421. 44. Robinson JK, Rigel DS. Sun protection attitudes and behaviors of solid organ transplant recipients. Dermatol Surg. 2004:30(4 part 2):610–615. 45. Clowers-Webb HE, Christenson LJ, Phillips PK et al. Educational outcomes regarding skin cancer in organ transplant patients. Arch Dermatol. 2006; 142:712–718. 46. Staples M, Marks R, Giles G. Trends in the incidence of nonmelanocytic skin cancer (NMSC) treated in Australia 1985–1995: are primary prevention programs starting to have an effect? Int J Cancer. 1998; 78:144–8.

47 Skin Cancer Prior to Organ Transplantation or Organ Donation

Clark C. Otley, MD, and Ryutaro Hirose, MD

the data available to guide these decisions.[3] Much of the content of this chapter is modified from that review.

ABBREVIATIONS

BCC NMSC SCC

basal cell carcinoma nonmelanoma skin cancer squamous cell carcinoma

Evaluation of Transplant Candidates Who Have a History of Skin Cancer Given the increasing disparity between the supply of organs and the escalating demand of potential transplant recipients, available organs must be transplanted into patients with the greatest likelihood of benefit. As outlined in Table 47.1, estimating the risk of recurrence, metastasis, or occurrence of new primary skin cancers in candidates for solid organ transplantation who have a history of skin cancer involves a comprehensive review of their medical history, a complete physical examination, and critical assessment of the clinical and histologic details of any previous skin cancers. For patients with a history of skin cancer of indeterminate risk, transplant dermatologists, Mohs surgeons, and general dermatologists may be able to assess the clinical, surgical, and histologic details of the previous skin cancer and to provide an estimate of prognosis, taking into account the time that has elapsed since the occurrence of the primary skin cancer. Radiologic examination may be used to rule out occult residual disease, although there are limitations in the sensitivity and specificity of radiologic techniques for superficial cutaneous malignancies. Positron emission tomography is the most sensitive imaging technique to ascertain the presence of metastatic melanoma, high-risk squamous cell carcinoma (SCC), or Merkel cell carcinoma. Computed tomography provides more specificity in delineating the nature of hypermetabolic foci identified on positron emission tomograms.

BACKGROUND Many patients presenting for consideration of solid organ transplantation will have a history of skin cancer, the most common malignancy in humans. The avoidance of a recurrence of, or metastasis from, a previously treated skin cancer is paramount to allocating precious solid organ allografts to patients with the greatest likelihood of prolonged survival. For the vast majority of patients, the risk of recurrence or metastasis is minimal, and transplantation would be appropriate. Conversely, patients with active metastatic skin cancer would be considered inappropriate candidates for solid organ transplantation. Between these extremes are those patients with a history of high-risk skin cancer that has variable metastatic potential, who may harbor clinically and radiologically occult residual microscopic disease. In the worst-case scenario, occult metastatic skin cancer cells could grow under the influence of potent systemic immunosuppression, resulting in an increased risk of recurrence or metastasis.[1] Additionally, patients with a history of skin cancer are at high risk for development of de novo primary skin cancers at sites other than those of previous carcinomas. Patients with an extremely high number of prior skin cancers may develop life-altering skin cancers if transplanted, although most patients would still be appropriate candidates for transplantation. Finally, cadaveric or living-related organ donors may have a history of skin cancer that elicits concern about the transmissibility of occult metastatic cells within the donor allograft. Reports of donor-derived, lethal metastatic skin cancer indicate that this concern should be addressed before transplantation of any allograft.[2] A recent review in the transplantation literature that outlined the issues surrounding the evaluation of transplant candidates who have a history of skin cancer examined appropriate evaluation of these patients, prognostic factors associated with skin cancer that may assist in determining the appropriateness of transplantation, and the limitations of

Effect of Transplant-associated Immunosuppression on Prior Skin Cancer There are no prospective studies documenting the outcomes of previous skin cancers among patients who undergo solid organ transplantation and subsequent administration of potent systemic immunosuppression.[1] Although small case series have outlined the outcomes of previous skin cancers after transplantation, these data are too limited to allow definitive conclusions. Extensive validated prognostic data may help facilitate the estimation of prognosis in immunocompetent patients, although the effects of immunosuppression are not easily extrapolated. Despite these shortcomings, skin cancers that recur in patients after 302

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Table 47.1 Evaluation of solid organ transplant candidates who have a history of skin cancer 1. Obtain a complete history and perform a physical examination, paying specific attention to sites of prior skin cancers and palpating the regional nodal basin for high-risk skin cancers. 2. Review clinical and histologic details of prior skin cancers. Transplant dermatologists may be helpful in this regard. 3. Using prognostic data, estimate the risk of recurrence, metastasis, and development of new primary cancers. When estimating risk, consider the time elapsed since skin cancer was treated. 4. Consult Table 47.2 for general recommendations on the appropriateness of transplantation. 5. Assess risk of cancer recurrence, risk of end-organ disease, and risks of transplantation to determine transplant status. Consider the ethics of limited organ availability, which may differ depending on whether the donor is a living relative or deceased. 6. If the potential for occult micrometastasis exists, radiographic staging should be performed before considering the listing of the patient on the organ transplant waiting list. 7. Periodic examinations and imaging are appropriate for patients with prolonged waits for transplant organs. Source: From Otley CC, Hirose R, Salasche SJ. Skin cancer as a contraindication to organ transplantation. Am J Transplant. 2005;5:2079–84. Used with permission.

transplantation generally are associated with a worse prognosis than similar skin cancers in nonimmunosuppressed patients, although the precise degree of adverse effect has not been quantified. All available sources of prognostic data about previous skin cancer in transplant patients have substantial limitations. These limitations do not lessen the need for clinicians to make important clinical decisions on a regular basis about the best course of action for a patient with a history of skin cancer.

Prognostic Factors for Pretransplantation Skin Cancer The quality of the dermatologic literature about prognostic outcomes for different types of skin cancer varies considerably. For melanoma, reliable multivariate data can precisely predict the likelihood of disease-free and overall survival. Univariate data are available to assist in quantification of prognostic factors for SCC. Finally, with basal cell carcinoma (BCC), metastasis is extraordinarily rare; thus, prognosis is almost always favorable. For uncommon dermatologic tumors, univariate risk factors are less well defined and prognosis may best be estimated through consultation with an experienced transplant dermatologist or Mohs surgeon. Table 47.2 outlines the general recommendations for considering transplantation in patients with skin cancer and specifies the appropriate time frames for reevaluation after the occurrence of the primary tumor. Because metastasis of aggressive cutaneous malignancies usually occurs soon after primary occurrence, the relative risks of recurrence and metastasis lessen dramatically with the passage of time. After most of the risk has passed, reevaluation would therefore be appropriate to update the prognostic data for such patients. Caution is advisable for all cancers with metastatic potential because the available data has been derived from nonimmunosuppressed patients; thus, the risk of metastasis may be underestimated for immunosuppressed transplant recipients.

Allograft-specific Considerations In addition to the specific characteristics of the skin cancer, the type of allograft required by the patient may influence consider-

ations related to pretransplantation skin cancer. For patients with renal failure, hemodialysis is a viable option for maintaining survival while time elapses after skin cancer occurrence. For patients with hepatic or cardiac failure, however, a prolonged period off the organ transplant waiting list while allowing time to pass after the occurrence of a primary skin cancer may prove fatal due to end organ failure. The United Network for Organ Sharing and local organ procurement organizations allocate allografts to potential recipients by taking into account the severity of their need for transplantation and the potential benefit to the recipients, and they attempt to do so in a fair and just manner. With the improved performance of living-related kidney and liver allografts, the criteria for transplantation in a candidate with a history of cancer may be different than for a candidate with a cadaveric allograft donor, given that a living-related donor would not deprive another potential recipient of a cadaveric allograft.

BASAL CELL CARCINOMA

Risk of Recurrence and Death From Pretransplantation Basal Cell Carcinoma Because the risk for metastasis from BCC is exceedingly low, almost all patients with a history of BCC would still be appropriate candidates for solid organ transplantation. In rare instances of metastatic BCC, treatment is difficult and thus would represent an absolute contraindication to transplantation unless a disease-free interval of at least 5 years had passed since the last manifestation of disease, and complete restaging had shown no residual focus of tumor.

Risk of Multiple De Novo Nonmelanoma Skin Cancers After Transplantation Although a lethal outcome from nonmelanoma skin cancer (NMSC) is uncommon, pretransplantation BCC or SCC is a marker for an increased likelihood of multiple de novo NMSCs after transplantation. Among nonimmunosuppressed patients, 44% of patients with a history of BCC developed a new primary BCC within 3 years, and 6% developed a new primary SCC within 3 years.[4] Among nonimmunosuppressed

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Table 47.2 Pretransplantation skin cancer suggested assessment Cancer type

Basal cell carcinoma Primary Metastatic, in remission Metastatic, not in remission Squamous cell carcinoma Primary, low risk Primary, high risk Metastatic, in remission Metastatic, not in remission Melanoma In situ Stage I Stage II Stage III Stage IV Merkel cell carcinoma Primary Metastatic, in remission Metastatic, not in remission Kaposi sarcoma Atypical fibroxanthoma Dermatofibrosarcoma protuberans Sebaceous carcinoma Eccrine carcinoma Microcystic adnexal carcinoma Extramammary Paget disease

May receive transplant

Consult with transplant dermatologist

Should not receive transplant

Reevaluation interval after primary tumor diagnosis if denied transplant, in years

X X

5 NA

X X

3 3–5 NA

X X X

3–10 5–10 10 10

X

X X

X X

X

X X

2–3 3–5 NA NA 3

X X X X

3 3 3 3

X X

X

Note: NA = not applicable. Source: From Otley CC, Hirose R, Salasche SJ. Skin cancer as a contraindication to organ transplantation. Am J Transplant. 2005;5:2079–84. Used with permission.

patients with a history of SCC, new primary BCC occurred in 43% and new primary SCC developed in 18%.[4] In addition, among patients with a history of 3 or more NMSCs, the 3year risk of another skin cancer was 93%. Although rarely lethal, multiple NMSCs in transplant patients can decrease quality of life and may occasionally result in high-risk skin cancers that can be life threatening. Pretransplantation NMSC, however, is not a contraindication to transplantation unless the transplant candidate has an extremely high number of NMSCs or one or more individual high-risk NMSCs. A history of multiple NMSCs in an organ transplant candidate should be viewed as an opportunity to implement aggressive preventive treatment, including sun protection under the close supervision of an experienced dermatologist, before the patient can be listed for an organ transplant.

SQUAMOUS CELL CARCINOMA

Risk of Recurrence and Death From Pretransplantation Squamous Cell Carcinoma In nonimmunosuppressed patients, the risk of metastatic disease after cutaneous SCC is 3.6% at 3.8 years.[5] In contrast,

the rate of metastasis in immunosuppressed transplant recipients is nearly 7%.[6,7] Thus, systemic immunosuppression appears to almost double the risk for metastasis of cutaneous SCC. Table 47.3 outlines the multiple univariate factors associated with an increased risk of metastatic outcomes after SCC.[8] When assessing the likelihood of recurrence, metastasis, and death from a pretransplantation SCC, clinicians must weigh a complex group of factors, including histologic findings, clinical presentation, treatment history, and anatomical site. In general, truly high-risk SCC with a considerable risk of metastasis usually exhibits multiple simultaneous risk factors (Table 47.3). For a patient with truly high-risk SCC, delay of transplantation may be a reasonable consideration. However, the risk of metastatic disease with cutaneous SCC passes rapidly, with 90% of the risk occurring during the first 3 years. After 3 years, the likelihood of recurrence could be reevaluated and the presence of occult metastatic disease could be considered.[9] Patients with a history of metastatic skin cancer have a poor prognosis. Three-year survival of immunosuppressed patients with SCC is 56%, and 5-year survival is 34%.[10] Because of the high risk of recurrence from metastatic SCC, a waiting period of 3 to 5 years would be appropriate before conducting a comprehensive reevaluation for transplantation.

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Table 47.3 Risk factors for metastasis with cutaneous squamous cell carcinoma Recurrent Deep invasion Large diameter Poor differentiation Perineural invasion High-risk anatomical sites (temple, scalp, ear, and lip) Rapid growth Origin in scar Source: Data from Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip: implications for treatment modality selection. J Am Acad Dermatol. 1992;26:976–90. With permission.

ME LANOM A

Risk of Recurrence and Death From Pretransplantation Melanoma Most patients with cutaneous melanoma have prolonged survival, with an average 5-year disease-free survival of 80 to 85%. Thus, most patients with low-risk melanoma or a remote history of invasive melanoma may be reasonable candidates for solid organ transplantation. The most accurate method for quantification of the probability of survival of a patient with melanoma is staging with the 2001 staging system of the American Joint Committee on Cancer.[11,12] It is particularly important to recognize the terminology that describes melanomas with a negligible risk of metastatic disease. Melanoma in situ, which includes a disease called lentigo maligna, is categorized as stage Tis and has theoretical disease-specific survival of 100%. These tumors are localized above the basement membrane and thus have zero metastatic risk, as long as the histologic evaluation is accurate. Excluding patients with in situ melanoma from consideration for transplantation would be unwarranted on the basis of such negligible metastatic risk. With 45,000 patients in the United States each year developing melanoma in situ, all of them could be considered potential transplant recipients or donors. Clinical stage I or II melanoma, with the tumor localized to the primary tumor site, has an increasing risk of recurrence and death that correlates with increased tumor thickness and histologic evidence of ulceration. Patients who have melanoma that is less than 1 mm thick and without ulceration (stage I) have an outstanding prognosis, with 5-year survival of 95% or greater. Although metastatic potential always exists, this group of patients could be considered for transplantation after a few years. Patients with thick primary melanomas (>4 mm) have a high risk of micrometastasis and a poor prognosis, with 5-year survival of 45 to 67%. For patients with a history of stage II or stage III melanoma, organ transplantation should be delayed for 5 to 10 years. Any consideration of transplantation for patients with stage II or stage III melanoma should be performed with the knowledge that late recurrence may occur after 10 to 20 years. A history of metastatic melanoma

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would be an absolute contraindication to transplantation without an extended disease-free interval. Unfortunately, the potentially adverse influence of potent systemic transplant-related immunosuppression on melanoma has not been reliably quantified. The Israel Penn International Transplant Tumor Registry provided data for 30 patients that showed a 19% incidence of recurrence after transplantation.[13] This finding is within the expected range of recurrence. Further data from the tumor registry indicate a 30% mortality rate among patients in whom melanoma developed after transplantation, which is approximately 50% higher than the rate of mortality noted in the general nonimmunosuppressed population.[13] However, 69% of these patients had melanoma with a Breslow thickness greater than 0.75 mm, thus a 30% mortality rate may actually be in line with expectations. Penn recommended a waiting period of 5 years between a diagnosis of melanoma and consideration of transplantation. We believe that the patientÕs prognosis should be assessed individually with case-specific details, and then a risk–benefit analysis should be used to weigh potential outcomes – both positive and negative, with and without transplantation. These decisions can be difficult and are best accomplished through consultation with a multidisciplinary group of specialists.

UNCOMMON SKIN CANCERS AS A PRETRANSPLANTATION CONSIDERATION Rare cutaneous neoplasms vary considerably in their risk for recurrence and metastasis. To provide some guidance for transplant physicians who encounter patients with such rare tumors, we present a brief review of the biological behavior, risk of recurrence, metastasis, and death related to these uncommon cutaneous neoplasms. Ideally, consultation with a transplant dermatologist to review the specific characteristics of individual patients would be helpful to determine the appropriateness of transplantation in patients with a history of these neoplasms, for which prognostic factors are less well-defined.

Merkel Cell Carcinoma Although much less common than melanoma, Merkel cell carcinoma may be the most aggressive cutaneous neoplasm. These tumors appear to be more likely to occur after transplantation. Five-year survival rates in nonimmunosuppressed patients range from 50% to 68%.[14,15] In patients experiencing recurrence, the development is rapid, with a median time to nodal metastases of 7 to 8 months.[16] Patients with nodal metastasis have a poor outcome, with less than a 50% 5-year survival, in contrast to an 80% survival rate for patients without nodal disease.[14] In Penn and FirstÕs [14] series of 41 patients with Merkel cell carcinoma after transplantation, only 29% of patients were alive and without any evidence of disease after a mean follow-up of 13 months for deceased recipients and 18 months for living patients. In general, patients with

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a pretransplantation history of Merkel cell carcinoma should not be considered for organ transplantation for at least a 2- to 3-year period after occurrence of the primary tumor and even after such an interval they should receive comprehensive staging before being considered for transplantation.

Kaposi Sarcoma An infection-related neoplasm caused by human herpesvirus 8, Kaposi sarcoma is a low-grade vascular malignancy involving the skin and viscera. Because immunosuppression permits uncontrolled proliferation of viral-induced neoplasms, the prevalence of Kaposi sarcoma is increased up to 500 times in transplant patients compared with nonimmunosuppressed hosts.[17] Patients with pretransplantation Kaposi sarcoma have an extremely high probability of recurrence and exacerbation with immunosuppression. In the posttransplantation setting, therapy includes cessation of immunosuppressant medication with an attendant risk of allograft rejection and failure. In PennÕs [17] series of Kaposi sarcoma in organ transplant recipients, patients with cutaneous and oral Kaposi sarcoma had a 1% mortality at a median follow-up of 25 months, compared with a 41% disease-related mortality with visceral involvement at a median follow-up of 15 months in transplant recipients without Kaposi sarcoma. Effective antiviral regimens capable of eradicating human herpesvirus 8 may permit eradication of Kaposi sarcoma, although at the present time, solid organ transplantation in patients with preexisting Kaposi sarcoma is associated with a high risk of allograft compromise.

Atypical Fibroxanthoma Atypical fibroxanthoma is a soft-tissue malignancy found on sun-exposed areas of the head and neck in elderly patients.[18] These tumors appear to be more common after transplantation and may be associated with an increased risk of metastasis related to atypical fibroxanthoma in nonimmunosuppressed hosts.[19] However, with adequate local therapy, optimally with Mohs micrographic surgery, a patient with a history of atypical fibroxanthoma may be considered for transplantation.[20] A high-risk or large and complicated atypical fibroxanthoma may warrant a waiting period of several years before transplantation.

Dermatofibrosarcoma Protuberans Dermatofibrosarcoma protuberans is a low-grade, soft-tissue sarcoma that extensively invades the soft tissue with a high degree of subclinical extension. Due to its propensity for recurrence after standard excision, Mohs micrographic surgery provides optimal margin control and the highest cure rates.[21] The risk of metastasis from dermatofibrosarcoma is low, particularly with adequate surgical management. There is no evidence that immunosuppression worsens outcome for these patients, so a history of dermatofibrosarcoma in remission in a transplant candidate is not a contraindication to transplantation.

Sebaceous Carcinoma Sebaceous carcinoma occurs primarily in the periorbital region, where it arises from the meibomian glands of the eyelid. Although the rate of metastasis is low at 3%, the multifocality of tumor cells in sebaceous carcinoma may lead to a higher than acceptable risk of recurrence.[22] Sebaceous carcinoma arising in an extraocular location may metastasize in as many as 40% of patients.[23] Because of the possibility of metastasis, a history of sebaceous carcinoma may warrant a wait of 3 years and subsequent examination by an ophthalmologist and a dermatologist before organ transplantation. Metastatic disease is an absolute contraindication to organ transplantation.

Sweat Gland Carcinomas The sweat gland carcinomas are composed of multiple neoplasms arising from eccrine epithelium. They include porocarcinoma, syringomatous carcinoma, ductal carcinoma, adenocystic carcinoma, and mucinous eccrine carcinoma. The biologic behavior of these tumors is highly variable, with ductal carcinoma resulting in 50% mortality and mucinous eccrine carcinoma associated with minimal mortality.[24] Because of the rarity of sweat gland carcinomas, consultation with a Mohs surgeon or transplant dermatologist may optimize the clinicianÕs ability to prognosticate individual tumor outcomes.

Microcystic Adnexal Carcinoma A common subtype of eccrine carcinoma, microcystic adnexal carcinoma is associated with a low rate of metastasis (3%) and a very low rate of death (0.7%). This tumor should not be considered a contraindication to transplantation if review of the details of the case by an experienced transplant dermatologist finds no contraindications.[25]

Extramammary Paget Disease Extramammary Paget disease is an intraepithelial carcinoma with a 14% to 20% risk of associated internal gastrointestinal tract or genitourinary tract malignancy.[26,27] Careful evaluation for concurrent internal malignancies is critical before treatment of patients with extramammary Paget disease. In addition, locally advanced extramammary Paget disease may be associated with adenocarcinomatous extension that has the potential for metastasis. Therefore, a lapse of several years and a comprehensive gastrointestinal and genitourinary workup for underlying malignancy is recommended before transplantation.

MANAGEM ENT O F IMMUNOS U PPRES SION IN PATIENTS WITH PRIOR SKIN CANCER For patients with a history of skin cancer who are deemed to be candidates for transplantation, the immunosuppressive regimen should be tailored to minimize the risk of recurrent or de

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novo malignancies. Unfortunately, insufficient data exist to formulate specific recommendations, but several basic principles can be outlined. Observational studies have shown that cancer risk, and skin cancer risk in particular, correlates with the duration and intensity of immunosuppression. An underlying principle should be the use of adequate immunosuppression to avoid episodes of rejection with subsequent alterations as dictated by the presence or absence of rejection or other adverse effects of immunosuppressive medications. Because the risk of rejection decreases with the passage of time after transplantation and the risk of malignancy increases with time, it may be reasonable to consider gradually decreasing immunosuppression in patients who have prolonged rejection-free allograft function to lower the risk of malignancy while avoiding excessive risk of rejection. Regular review of transplant-associated immunosuppressive regimens may allow conscious optimization of the risks and benefits of the immunosuppressive regimen. Preliminary data suggesting that sirolimus may be associated with a decreased risk of skin cancer needs to be confirmed by larger long-term studies.[28–30]

Skin Cancer as a Contraindication to Organ Donation All potential living or cadaveric donors are screened for a prior history of malignancy to avoid unintended transmission of donor-derived malignancies. The mechanism for transmission of a donor-derived malignancy would include the presence of occult metastatic cells in the donated allograft that may proliferate in the recipient under the influence of potent systemic immunosuppression.[2] The same principles outlined above for evaluation of a transplant recipient for appropriateness of transplantation should apply to the evaluation of a potential transplant donor. If the specific characteristics of tumor prognosis and time frame since the occurrence of the primary tumor suggest an unacceptably elevated risk of metastatic cancer transmission, then organ donation should be refused. However, in the vast majority of patients with low-risk BCC, minor SCC, and in situ melanomas, organ donation is reasonable. It would be unreasonable to deprive a patient on a transplant waiting list of a viable allograft from a patient who had a prior skin cancer with metastatic risk approaching zero.

Limitations of Data and Future Research There are multiple limitations in the data guiding these important decisions about the appropriateness of transplantation and organ donation in patients with a history of skin cancer. Although the prognostic staging system for melanoma is accurate, the data are from nonimmunosuppressed patients and require interpretation as to the affect of immunosuppressant regimens on outcomes. The data for SCC are suboptimal given the lack of multivariate, proven risk factors that are easy to apply. Therefore, interpretation of prognostic factors by a knowledgeable transplant dermatologist may be optimal. The outstanding

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prognosis for BCC makes transplantation for these patients almost always appropriate. For patients with uncommon cutaneous neoplasms, however, clinicians must derive prognostic information from a review of case-specific materials and the expert opinion of an experienced dermatologist. A primary shortcoming of all available data is the lack of information on the effect of immunosuppressant medications on the course of prior skin cancer. Thus, extrapolation of survival data from nonimmunosuppressed patients may underestimate the risk of recurrence of metastasis in transplant recipients after they are immunosuppressed. Therefore, a cautious approach is advisable for skin cancer with metastatic potential. The International Transplant Skin Cancer Collaborative (www.itscc.org) is actively pursuing data accumulation in these areas of deficiency.

CONCLUSION Solid organ allografts are precious resources that need to be triaged to patients who will accrue the most benefit. Minimization of the potential for allograft loss or patient death from complications of cancer is in everyoneÕs best interest. Most patients with a history of skin cancer would qualify as reasonable candidates for transplantation because of the low morbidity of skin cancer and its highly successful treatment. For patients with metastatic skin cancer or extremely high-risk tumors, the decision not to list the patient on the organ transplant waiting list is straightforward. However, prior intermediate-risk skin cancer warrants a detailed review of the risks for recurrence, metastasis, and death before placement on, or deferral from, the transplant list. For patients who have an intermediate or uncertain risk of recurrence, metastasis, and death, consultation with a Mohs surgeon or a transplant dermatologist may be the optimal means to assess prognostic factors. Available prognostic data can inform the decision about the appropriateness of transplantation. Because of the unquantified effects of immunosuppression on preexisting malignancies, a conservative approach is advisable for patients who have had recent skin cancers with metastatic potential.

REFERENCES

1. Penn I. The effect of immunosuppression on pre-existing cancers. Transplantation. 1993;55:742–7. 2. Morris-Stiff G, Steel A, Savage P, Devlin J, Griffiths D, Portman B, et al, Welsh Transplantation Research Group. Transmission of donor melanoma to multiple organ transplant recipients. Am J Transplant. 2004;4:444–6. 3. Otley CC, Hirose R, Salasche SJ. Skin cancer as a contraindication to organ transplantation. Am J Transplant. 2005;5:2079–84. 4. Marcil I, Stern RS. Risk of developing a subsequent nonmelanoma skin cancer in patients with a history of nonmelanoma skin cancer: a critical review of the literature and meta-analysis. Arch Dermatol. 2000;136:1524–30.

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5. Chuang TY, Popescu NA, Su WP, Chute CG. Squamous cell carcinoma: a population-based incidence study in Rochester, Minn. Arch Dermatol. 1990;126:185–8. 6. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol. 2002;47:1–17. 7. Sheil AG, Disney AP, Mathew TH, Amiss N. De novo malignancy emerges as a major cause of morbidity and late failure in renal transplantation. Transplant Proc. 1993;25:1383–4. 8. Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip: implications for treatment modality selection. J Am Acad Dermatol. 1992;26:976–90. 9. Johnson TM, Rowe DE, Nelson BR, Swanson NA. Squamous cell carcinoma of the skin (excluding lip and oral mucosa). J Am Acad Dermatol. 1992;26:467–84. 10. Martinez JC, Otley CC, Stasko T, Euvrard S, Brown C, Schanbacher CF, et al, Transplant-Skin Cancer Collaborative. Defining the clinical course of metastatic skin cancer in organ transplant recipients: a multicenter collaborative study. Arch Dermatol. 2003;139:301–6. 11. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19:3635–48. 12. Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19:3622–34. 13. Penn I. Malignant melanoma in organ allograft recipients. Transplantation. 1996;61:274–8. 14. Penn I, First MR. MerkelÕs cell carcinoma in organ recipients: report of 41 cases. Transplantation. 1999;68:1717–21. 15. OÕConnor WJ, Brodland DG. Merkel cell carcinoma. Dermatol Surg. 1996;22:262–7. 16. Pitale M, Sessions RB, Husain S. An analysis of prognostic factors in cutaneous neuroendocrine carcinoma. Laryngoscope. 1992;102:244–9. 17. Penn I. Sarcomas in organ allograft recipients. Transplantation. 1995;60:1485–91. 18. Hafner J, Kunzi W, Weinreich T. Malignant fibrous histocytoma and atypical fibroxanthoma in renal transplant recipients. Dermatology. 1999;198:29–32.

19. Rizzardi C, Angiero F, Melato M. Atypical fibroxanthoma and malignant fibrous histiocytoma of the skin. Anticancer Res. 2003; 23:1847–51. 20. Davis JL, Randle HW, Zalla MJ, Roenigk RK, Brodland DG. A comparison of Mohs micrographic surgery and wide excision for the treatment of atypical fibroxanthoma. Dermatol Surg. 1997;23: 105–10. 21. Ratner D, Thomas CO, Johnson TM, Sondak VK, Hamilton TA, Nelson BR, et al. Mohs micrographic surgery for the treatment of dermatofibrosarcoma protuberans: results of a multiinstitutional series with an analysis of the extent of microscopic spread. J Am Acad Dermatol. 1997;37:600–13. 22. Muqit MM, Roberts F, Lee WR, Kemp E. Improved survival rates in sebaceous carcinoma of the eyelid. Eye. 2004;18:49–53. 23. Bassetto F, Baraziol R, Sottosanti MV, Scarpa C, Montesco M. Biological behavior of the sebaceous carcinoma of the head. Dermatol Surg. 2004;30:472–6. 24. Wick MR, Goellner JR, Wolfe JT III, Su WP. Adnexal carcinomas of the skin. I. Eccrine carcinomas. Cancer. 1985;56:1147–62. 25. Snow S, Madjar DD, Hardy S, Bentz M, Lucarelli MJ, Bechard R, et al. Microcystic adnexal carcinoma: report of 13 cases and review of the literature. Dermatol Surg. 2001;27:401–8. 26. OÕConnor WJ, Lim KK, Zalla MJ, Gagnot M, Otley CC, Nguyen TH, et al. Comparison of Mohs micrographic surgery and wide excision for extramammary PagetÕs disease. Dermatol Surg. 2003; 29:723–7. 27. Pierie JP, Choudry U, Muzikansky A, Finkelstein DM, Ott MJ. Prognosis and management of extramammary PagetÕs disease and the association with secondary malignancies. J Am Coll Surg. 2003; 196:45–50. 28. Kahan BD, Knight R, Schoenberg L, Pobielski J, Kerman RH, Mahalati K, et al. Ten years of sirolimus therapy for human renal transplantation: the University of Texas at Houston experience. Transplant Proc. 2003; 35 Suppl:25S–34S. 29. Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant. 2004;18:446–9. 30. Campistol JM, Gutierrez-Dalmau A, Torregrosa JV. Conversion to sirolimus: a successful treatment for posttransplantation KaposiÕs sarcoma. Transplantation. 2004;77:760–2.

Section Nine

EDUCATIONAL, ORGANIZATIONAL, AND RESEARCH EFFORTS IN TRANSPLANT DERMATOLOGY

48 Quality of Life Associated with Dermatologic Disease in Organ Transplant Recipients

Fiona O’Reilly Zwald, MD

I M P R O VI N G Q U A LI T Y O F L IF E – T H E N E W T AR G E T FO R TR A N S P LA N T AT I ON

naires (or instruments) is often related to the degree to which they emphasize objective as compared with subjective dimensions, the extent to which various domains are covered, and the format of the questions. Because many of the components of QOL cannot be observed directly, they are typically evaluated according to the classic principles of item measurement theory. This theory proposes that there is a true QOL value, Q, that cannot be measured directly, but that can be measured indirectly, by asking a series of questions known as ‘‘items,’’ each of which measures the same true concept.[2] The patients’ answers are converted to numerical scores, which are combined to yield ‘‘scale scores,’’ which may also be combined to yield ‘‘domain scores.’’ A good HRQOL instrument must be appropriate for the particular setting or purpose, be comprehensive in capturing the concept (measurement of QOL of transplant recipients with skin disease), be easy to understand and have reasonable respondent burden (time taken to complete). In selecting an instrument, it must be valid (evidence that the instrument measures what it is supposed to measure), be reliable (the extent to which an instrument yields the same results on independent repeated trials under the same conditions), and be responsive (the ability of the instrument to reflect real changes).

Organ transplantation has become the treatment of choice for many patients with end-stage disease. The goal of transplantation is to maximize both the length and the quality of life (QOL) while minimizing the effects of disease and costs of care. As short-term posttransplant survival is now excellent, attention has now been shifted to long-term graft function and patient quality of life. QOL is increasingly recognized as an important measure of outcome following solid organ transplantation.[1]

HEALTH-RELATED QUALITY OF LIFE (HRQOL) The terms Ôquality of life’ and more specifically Ôhealth-related quality of life’ refer to the physical, psychological, and social domains of health, seen as distinct areas that are influenced by a person’s experiences, beliefs, expectations, and perceptions.[2] Each of these domains can be measured in two dimensions: objective assessments of functioning or health status and subjective perceptions of health. Although the objective dimension is important in defining a patient’s degree of health, the patient’s subjective perceptions and expectations translate that objective assessment into the actual QOL experienced. Because expectations regarding health and the ability to cope with limitations and disability can greatly affect a person’s perception of health and satisfaction with life, two people with the same health status may have very different qualities of life. In summary, HRQOL is a multidimensional concept that includes physical, psychological, and social functioning and captures health-related outcomes from the patients’ perspective.

M E A S UR I N G H R Q O L I N T R A N S P L A N T A T I O N RESEARCH Three principle classes of measure are used to assess HRQOL, generic tools, disease-specific tools, and utilities/global indices. Generic tools are not limited to any specific age group, disease, or special situation. Examples include the Sickness Impact Profile (SIP), the 36-item short form of the Medical Outcomes Survey (SF-36), and the Nottingham Health Profile (NHP). Disease-specific instruments focus on the domains most relevant to the disease or condition under study and are most appropriate for clinical trials in which specific therapeutic interventions are being evaluated. Examples include the Kidney Transplant Questionnaire (KTQ), the Quality of Life Index-Liver Transplant Version, and Skindex-16 (a skin-diseasespecific questionnaire). The third major class of measurement tool is utilities/global indices, which summate the global assessment of functioning and well-being into a single index value. In order to define this value, the patient is asked to

M E A S U R I N G H E A L T H - R E L AT E D QU A LI T Y O F L IF E ( H R Q O L ) Translating the various domains and components of health into a quantitative value that indicates the HRQOL is a complex task. Most researchers measure each QOL domain separately, by asking specific questions pertaining to its most important components. Variation among HRQOL question311

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indicate his/her preference for a variety of specified health states. For comprehensive outcomes analysis it is recommended that investigators include both disease-specific and generic instruments. No single method of measuring HRQOL is ideal in all circumstances. Care must be taken to select the appropriate tool and in comparing HRQOL results from studies using different tools, as the results are critically dependent upon the tools used to record it. Quality of life outcomes after solid organ transplantation have been studied extensively during the last three decades. The earliest studies of HRQOL involved renal transplant recipients.[3] Recent studies examine HRQOL after heart [4] and lung transplantation.[5] HRQOL studies have since emerged following islet cell transplantation.[6] It is generally accepted that HRQOL improves dramatically after successful renal transplantation, compared to patients maintained on dialysis treatment but listed for transplant. Increasing yearly survival rates testify to the success of transplantation, but it remains unknown whether this objective success projects also in patients’ subjective appreciation and wellbeing.

AS SE SSM ENT O F PRE DI CTO RS OF H RQ OL – R OLE OF SK IN DISE AS E Investigators began to attempt to attempt to identify predictors of HRQOL post transplantation. Adverse effects of immunosuppression impact negatively on patients’ overall HRQOL both from the physical and dermatological standpoint. The End Stage Renal Disease Symptom Checklist Transplantation Module (ESRDSC-TM) was specifically developed to evaluate the effects of immunosuppressant medication on HRQOL.[7] Shield et al. were among the first authors to evaluate HRQOL in renal transplant recipients comparing different immunosuppressive regimens on outcome.[8] They found that tacrolimus treatment was associated with better appearance in the Bergner Physical Appearance Scale, designed to measure cosmetic effects of medical therapy such as gingival hyperplasia and hirsutism. Patient with tacrolimus-based immunosuppression reported significantly better global and disease-specific HRQOL than those receiving cyclosporine microemulsion.[9] In a randomized open-label trial in Europe, Australia, and Canada, Oberhauer and coworkers investigated HRQOL outcomes in patients after kidney transplantation.[10] In that trial 430 kidney transplant patients were randomly assigned three months after transplantation to continue cyclosporine and sirolimus therapy or to have cyclosporin withdrawn over a period of four weeks. HRQOL was measured at randomization, and at one and two years after transplantation using the disease-specific KTQ tool and the generic SF-36 tool. No differences in baseline HRQOL could be observed. In the two years follow-up investigation, the authors found a significant improvement in two domains of the KTQ, fatigue, and ap-

pearance, in the cyclosporine-free group. This may be explained by three common adverse effects of cyclosporine therapy – gingival hyperplasia, hair growth. and tremor. Vitality scores in the SF-36 questionnaire were higher in the cyclosporine-free sirolimus group at two years compared to baseline values, but decreased in the combination group. Questions remain relating to HQQOL associated with long-term survival. A recent multicenter study was the first to evaluate HRQOL of liver, kidney, and heart transplant recipients ten years post transplantation in a large sample of patients.[11] Each type of organ transplantation was compared to the general population using the National Institute of Diabetes and Digestive and Kidney Disease Questionnaire (NIDDK), a well-validated instrument representing five domains of HRQOL, measures of disease (physical symptoms), psychological status (emotional distress), personal function (working capacity and handicap), social and role function (social interaction), and general health perception. HRQOL beyond ten years after liver, heart, and kidney transplantation was found to be similar to that of the general population in social and role function. Kidney transplant recipients had the worst psychologic status and general health perception. Measure of disease and personal function scores were worse in each organ transplant group than the general population. Ten years after transplantation, HRQOL for kidney transplant recipients was found to be the lowest, heart transplant recipients intermediate, and liver transplant recipients, the highest. Patients included in this study received transplants before 1990, when cyclosporine was widely used both as maintenance and induction therapy. Major side effects were associated with all immunosuppressive drugs, particularly cyclosporine, tacrolimus, and corticosteroids. Side effects that have little or no direct effect on morbidity or mortality can be perceived by the patient as highly disturbing, which impacts negatively on their HRQOL. That could explain, in the measure of disease domain subscales, the particularly higher rates in kidney transplant recipients with altered facial appearance and skin conditions, for example, ecchymoses, fragile skin, tinea corporis, verrucae, and keratotic lesions. Kidney transplant recipients (60%) have a better ten-year survival rate than heart transplant recipients (45%), but the quality of the survival in the renal transplant group was found to be the worst. The challenge of maintaining the health and wellbeing of the long-term survivor has been achieved to a great extent in liver transplant recipients over other solid organ transplant recipients.

QUAL IT Y O F L I FE A S SO C IAT ED W I TH D E R M A T O L O G I C A L D I S E A S E IN OR G A N TRANSPLANT RECIPIENTS The purpose of HRQOL research in solid organ transplantation to date has been to describe HRQOL, to identify

QUALITY OF LIFE ASSOCIATED WITH DERMATOLOGIC DISEASE IN ORGAN TRANSPLANT RECIPIENTS

differences in HRQOL by age, sex, and race and to identify predictors of HRQOL long-term post transplantation. Few, if any, studies have discussed the impact of skin disease following solid organ transplantation and only in the context of immunosuppressive regimens, where it has been demonstrated that cutaneous adverse effects of immunosuppression impact negatively on patients’ HRQOL. Dermatological complications are myriad post transplantation and include acne, alopecia, gingival hyperplasia, skin fragility, bruising, sebaceous hyperplasia, and hirsutism. Eightyfive percent of renal transplant recipients have viral warts at five years post transplant and the incidence of skin cancer ranges from 5% to 25% at ten years post transplantation. Many skin diseases have been demonstrated to result in significant stress and impairment of QOL for patients.[12] This is related to a number of factors and not necessarily related to disease severity, for example, cosmetic disfigurement and social stigma are important in conditions such as verrucae and scarring from nonmelanoma skin cancer. A study by Murphy et al. is the first to evaluate the impact of cutaneous complications on HRQOL post transplantation.[13] In this study, a dermatological QOL questionnaire, the Dermatology Life Quality Index (DLQI), was used to assess the impact of skin disease following renal transplantation. The DLQI has been validated for over 100 dermatological problems including eczema, acne, and psoriasis. The study was designed to examine the effect of age, sex, duration since transplant, immunosuppressive regimens, and common posttransplant skin complications on the DLQI score of renal transplant recipients. Higher overall scores indicated increasing bother by skin condition and negative impact on HRQOL. Mean duration post transplant was 10.4 years. An increasing DLQI score was significantly associated with female sex, younger age, and increasing number of posttransplant skin diseases, for example, facial acne, sebaceous gland hyperplasia, and hypertrichosis. All patients who were most affected were receiving cyclosporine-based regimens. A more recent study concludes that tacrolimus has significantly better HRQOL outcomes than cyclosporine.[14] These cosmetic issues have altered the practice of prescribing cyclosporine-based immunosuppression for newly transplanted patients. Skin conditions that affect visible sites such as the hands or face cause greater distress than those that are socially invisible. HRQOL after transplantation may influence the patients’ motivation to comply with their medication. Post-renal transplant noncompliance is the third leading cause of renal graft loss, especially among the young transplant population. Chronic rejection may often result from multiple episodes of noncompliance.[15] HRQOL intervention studies may help to tailor the immunosuppressive regimen to the individual patient risk profile. Murphy et al. also examined the association between a history of skin cancer and the DLQI score and found it was not significant despite the preponderance of patients with posttransplant nonmelanoma skin cancer on sun-exposed sites.

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Alternatively, this may reflect limitations of the DLQI to assess the impact of skin cancer on HRQOL, and therefore artificially diminish the impact of these skin conditions. A new diseasespecific HRQOL instrument has been created for nonmelanoma skin cancer of the head and neck and will hopefully serve as an outcome measure in future intervention studies aimed at improving HRQOL in patients post transplantation.[16] A valid and skin-cancer-specific HRQOL instrument would also be useful for future studies assessing intervention to prevent skin cancer development post transplant and in comparing different skin cancer treatment modalities. Nonmelanoma skin cancer accounts for 90% of all skin cancers in transplant recipients. Squamous cell carcinoma is the most common skin cancer in transplant recipients occurring 65 times as commonly as the general population, and the incidence of squamous cell carcinoma increases with time after transplant. The most important element of preventive management of skin cancer in transplant recipients is patient education, frequent dermatological surveillance, and institution of prophylactic regimens against skin cancer. To implement such an intervention, dermatology clinics are established onsite, within the transplant center. To assess the impact of such an intervention, the author utilized both disease-specific and skin-specific QOL questionnaires as well as a general health questionnaire, to assess patients’ HRQOL and number of skin cancers at baseline, at six months and at one year after development of the multidisciplinary clinic. For renal transplant recipients, HRQOL as measured by the KTQ fear subscale improved with a great number of years since treatment and declined with increased skin cancer incidence. HRQOL as measured by the appearance subscale was influenced by treatment regimen. Skindex-16 function subscale score was negatively influenced by years since treatment and the mental function of the SF12 was influenced by skin cancer incidence.[17] Intervention studies designed to help identify prognostic factors for poor HRQOL and to further study the impact of skin disease and nonmelanoma skin cancer on HRQOL post solid organ transplantation are necessary. One intervention study, designed to improve HRQOL outcomes after heart transplantation has been described in the literature. This study examined the impact of an internet-based intervention, including patient education, workshops to improve coping skills and discussion groups versus usual care on physical and psychological outcomes. Patients in the intervention group demonstrated fewer symptoms of depression and anxiety, improved social functioning, and better compliance with taking medication than patients in the usual care group.[18] Skin cancer and dermatological disease contribute greatly to reduced HRQOL post transplantation. More intervention studies and HRQOL analysis are needed to reduce the morbidity associated with skin disease in transplant recipients and assist patients towards improved QOL post transplantation.

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REFERENCES

1. Keown P. Improving the quality of life-the new target for transplantation. Transplantation. 2001;72(12) S. 67–74. 2. Testa MA, Simonson D. Assessment of quality of life outcomes. N Eng J Med. 1996;334(13) 835–40. 3. Matas AJ, McHugh L, Payne WD. Long-term quality of life after kidney and simultaneous pancreas-kidney transplantation. Clin Transplant. 1998,12:233–42. 4. Heroux et al. Predictors of quality of life at 5 to 6 years after heart transplantation. J Heart Lung Transplant. 2005;24;1431–39. 5. Vasiliadis H, Collet J, Poirier C. Health-related quality of life determinants in lung transplantation. J Heart Lung Transplant. 2006;25: 226–33. 6. Alejandro R et al. Quality of life after islet transplantation. Am J Transplant. 2006;6:371–8. 7. Heemann U et al. Quality of life in end-stage renal disease patients after successful kidney transplantation: development of the ESRD symptom checklist-transplantation module. Nephron. 1999,83:31–9. 8. Shield CF, McGrath MM, Goss TF. Assessment of health-related quality of life in kidney transplant patients receiving tacrolimus (FK-506)-based versus cyclosporine-based immunosuppression. FK506 Kidney Transplant Study Group. Transplantation. 1997,64:1738–43. 9. Heemann U et al. Quality of life in kidney recipients; comparison of tacrolimus and cyclosporine-microemulsion. Clin Transplant. 2002, 16:48–54.

10. Oberbauer R et al. Health- related quality-of-life outcomes of sirolimus- treated kidney transplant patients after elimination of cyclosporine A: results of a two-year randomized clinical trial. Transplantation. 2003,75:1277–85. 11. Castaing D et al. Quality of life in adult survivors beyond 10 years after liver, kidney and heart transplantation. Transplantation 2003,76:1699–1704. 12. McGibbon D et al. Comparison of severity and quality of life in cutaneous disease. Clin Exp Dermatol. 2002;27:306–8. 13. Murphy et al. The impact of skin disease following renal transplantation on quality of life. Brit J Dermatol. 2005;153(3) 574–8. 14. Hilbrands LB et al. Conversion from cyclosporine to tacrolimus improves quality-of-life indices, renal graft function and cardiovascular risk profile. Am J Transplant. 2004;4:937–45. 15. Kahan BD et al. Patient noncompliance: a major cause of late graft failure in cyclosporine-treated renal transplants. Transplant Proc. 1988;20:63–9. 16. Rhee J et al. Creation of a quality of life instrument for nonmelanoma skin cancer. Laryngoscope. 2005;115:1178–85. 17. Gupta et al. Does participation in an integrated transplant dermatology clinic impact the quality of life and anxiety level of transplant recipients. JAAD 2006(54) 3: AB170 (abstract). 18. Dew et al. An internet-based intervention to improve mental health and medical compliance in heart transplant recipients. J Heart Lung Transplant. 2002,21:109.

49 Patient Education in Transplant Dermatology: Pre- and Post Transplant

Jeffrey C. H. Donovan, MD, PhD, and James C. Shaw, MD, FRCPC

INT ROD UCTION

types of high-risk skin cancers may present a contraindication to organ transplantation.[4] It is important to assess current sun-protection practices, as patients who use sun protection pretransplant may be more likely to be compliant with sun protection following transplantation.[5] Patients who smoke can be counseled on smoking cessation, both from the perspective of increased risk of skin cancer as well as risks to general health.[6]

Patient education, skin cancer screening, and early treatment intervention, comprise the essential components of patient care in transplant dermatology. Between 45 to 100% of transplant recipients are affected by skin disease.[1,2,3] Cosmetic, infectious, and neoplastic skin changes may provoke anxiety and concern from patients. Patient education, beginning pretransplant and continued posttransplant, may help to lessen patient anxiety and facilitate the early diagnosis and treatment of skin disease. The goals of patient education in transplant dermatology are listed in Table 49.1.

A N T I C I P A T O R Y G UI D A N C E F O R S K I N CHANGES FOLLOWING TRANSPLANTATION Many transplant recipients are not aware of the increased risk of developing skin cancer.[7] Prior to organ transplantation, potential recipients should be informed of the possibility of developing multiple skin cancers that may require multiple surgeries in the years following transplantation (Table 49.2).[8] Patients should be informed that while many of these skin cancers are treatable, they tend to behave more aggressively than skin cancers that develop in patients in the general population. In addition, these cancers have an increased likelihood to recur after treatment and in rare cases may prove fatal. In addition to skin cancer, patients should be informed of the possibility of developing other noncancerous changes, including skin infections and cosmetic changes related to use of immunosuppressive medications.[9] In one study, a history of dry skin, pruritus, hypertrichosis, sebaceous gland hyperplasia, acne, genital warts, and multiple herpes viral infections were each found to have significant impact on patient quality of life.[10] Notably, a history of skin cancer had less of an impact on quality of life than these infectious or cosmetic skin problems. With the goal of decreasing patient anxiety, patients may be advised that many treatment options are available for skin diseases occurring following organ transplantation. Good rapport between the physician and patient may also facilitate discussion of issues that might be considered sensitive to some patients, such as hair growth. The effect of pretransplantation counseling on patientsÕ level of patient anxiety or length of delay from first noticing a skin change to ultimately seeking dermatological evaluation remains to be studied. In theory, advising patients prior to transplant that all suspicious skin changes require prompt assessment by a dermatologist may decrease the delay in receiving treatment. For certain diseases, including various skin

PRETRANSPLANT EDUCATION An important goal of patient education prior to organ transplantation is to assist the transplant candidate in developing an understanding of the broad categories of skin disease that may develop following organ transplantation. These include skin cancer, infections, and the skin changes associated with immunosuppressive medications (Table 49.2). A significant portion of patient education in transplant dermatology is devoted to the subject of skin cancer. Although all transplant candidates may receive counseling regarding skin cancer and prevention, additional information may be provided on a patient-by-patient basis according to the individualÕs own risk for skin cancer (Table 49.3). A patientÕs overall risk for developing skin cancer can be ascertained efficiently through use of brief questionnaires. These may be completed by patients in the waiting room and responses then used as a reference for subsequent patient education. For example, information regarding place of birth, as well as childhood, current and occupational sun exposure will provide an estimate of cumulative sun exposure. Patients with significant previous sun exposure may be advised on the association between sun exposure and skin cancer and counseled on the importance of sun protection and close follow-up (see following text). Self-evaluation of Fitzpatrick skin type rating may be particularly useful as a launching point for subsequent sunprotection counseling, given that patients commonly underestimate their tendency to sunburn. Personal and family history of skin cancer should be noted. Pretransplantation squamous cell carcinoma (SCC) has been identified as an important risk factor for posttransplant SCC and transplant candidates with prior SCC will need careful evaluation and diligent follow-up. Certain 315

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Table 49.1 Goals of patient education in transplant dermatology l l l l l l

Fulfill patient need for information Skin cancer prevention Early recognition of skin disease including skin cancer Provide a system for prompt assessment of new skin changes Enhance rapport between patient and physician Minimize patient anxiety

infections and skin cancers, early assessment has the potential to reduce both morbidity and mortality.

S U N PR O T E C T I O N ED UC A T I O N I N O R G A N TRANSPLANT RECIPIENTS Ultraviolet radiation has a well-established role in the pathogenesis of skin cancer and skin cancers in organ transplant recipients are mainly located on chronically sun-exposed areas. Despite the increased risk of skin cancer, the sun-protection practices of transplant recipients are similar to those seen in the general population.[5,11] The pretransplant period is an ideal time to establish routines that will decrease sun exposure. Surveyed patients indicate they would like to receive more information about sun protection and the dermatologist can assist patients in developing effective sun protection practices.[12] Many organ transplantation centers provide patient education on the subject of skin cancer and skin cancer prevention. This education is more commonly given posttransplant than pretransplant.[13] In some centers, dermatologists provide the majority of patient education, whereas in other centers, this counseling is more often provided by transplant physicians and transplant nurses.[14] Dedicated transplant dermatology clinics are being established within academic transplant centers with increasing frequency which may shift the balance to a greater responsibility for dermatologists to provide patient education on issues related to transplant dermatology. With these increasing demands, it is likely that dermatology nurses may also share a prominent role in provision of patient education. Nurse led skin cancer education programs may be popular with patients.[15] The optimal method of delivering sun-protection education is not known. Patient learning abilities and learning styles differ, making it necessary to deliver material in a manner that best suits the individual. Information regarding skin cancer and prevention, skin infections, and the cosmetic changes associated with transplantation should be provided in both oral and written formats. Information can be provided orally in brief intervals, allowing time for patientÕs questions. Family members or hospital translators can help accurately relay information to patients with language barriers. Written advice in the form of pamphlets and brochures are important adjuncts but are unlikely to be superior to the face-to-face interaction between patient and physician. Useful brochures include those

produced by the International Transplant Skin Cancer Collaborative (ITSCC) and the AT-RISC Alliance (Table 49.2). Additional methods of relaying information include use of patient educational videos, which may be shown in the waiting room or in the patientÕs examination room. A free patient video on skin cancer in organ transplant patients is available at www.AT-RISC.org. These additional methods may enhance the retention of information and possibly improve patient satisfaction, although confirmatory studies are needed.

Counseling Regarding Sun Avoidance Many transplant patients do not take necessary precautions to limit sun exposure. Robinson et al. showed that organ transplant recipients wear less protective clothing and seek less shade when outdoors compared to individuals in the general public and report similar rates of sun burning.[7] Outdoor activities should be minimized between 10 a.m. and 4 p.m. when the intensity of ultraviolet radiation is strongest. [16] Patients should be encouraged to seek shade as another means of limiting sun exposure. Exploration of patient attitudes towards sun tanning is also an important component of helping the transplant patient ultimately develop effective sun protective behaviors. Nearly one-quarter of transplant recipients occasionally or frequently sun tan [11] and it has been suggested that many do so as a means to achieve a healthier appearance.[7] Information provided to transplant recipients must include specific instruction to avoid sun-tanning as well as the use of tanning beds (Table 49.4).

Sunscreen Sunscreen use has been shown to decrease the incidence of actinic keratoses and SCC in the general population and would be expected to have the same benefit in the transplant population.[17] It is encouraging that the proportion of patients using sunscreen increases following organ transplantation.[5] Nevertheless, a significant proportion of transplant recipients are not using sunscreen, including approximately 20% of light-skinned (Fitzpatrick type I-II) transplant patients.[11] Sunscreen with an SPF rating of 30 or greater should be applied 30 minutes before sun exposure and reapplied every 2–4 hours if exposure is continued. Alternatively, a second application of sunscreen approximately 20 minutes after the initial application may compensate for initial missed areas of application and may be preferred over reapplication every 2–4 hours.[18] Although transplant recipients should be encouraged to apply sunscreen daily, only a minority presently achieve this goal. In addition, sunscreen should not be used as a means to increase the length of time spent in the sun, a phenomenon which has been observed in some studies in the general population.[19] The remarkable variety of sunscreens available on the market may create confusion as to an appropriate brand for purchase. Patients are encouraged to seek a broad-spectrum

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Table 49.2 Educational topics and resources for transplant recipients ANTICIPATORY GUIDANCE Skin disease related to skin cancer l Elevated risk of skin cancer in transplant patients l Possibility of multiple skin cancers with multiple surgeries l Highly treatable nature of most skin cancer Skin disease other than skin cancer l Skin infections Fungal, bacteria, viral l Cosmetic changes Hair growth, acne, sebaceous hyperplasia, telangiectasia, purpura, delayed wound healing, dry skin, pruritus PREVENTION Sun protection beginning pretransplant l Regular examination by physician l Self-examination of skin l Smoking cessation l

SOURCES OF INFORMATION Pamphlets l ITSCC Organ Transplant Recipients – Skin Cancer Prevention l Take Cover Take Care (Roche) available at (www.tppp.net) l After Transplantation-Reduce Incidence of Skin Cancer (AT-RISC) Alliance materials (www.AT-RISC.org) Internet sites l ITSCC (www.itscc.org) l American Cancer Society (www.cancer.org) l Canadian Cancer Society (www.cancer.ca) l AT-RISC Alliance (www.AT-RISC.org) Others l Educational videos (www.AT-RISC.org)

sunscreen that contains compounds capable of scattering or absorbing radiation in both the UVA and UVB range. Sunscreens containing compounds that block both UVA (Avobenzene/Parsol 1789, Meroxyl SX, Tinosorb M or benzophenones) and UVB (PABA esters, salicylates, and cinnamates, or benzophenones) are likely to be more effective in preventing SCC than those that block only UVB.[16,20] Sunscreens with inorganic compounds, including titanium dioxide or zinc oxide, may offer improved protection from UVA. Patients may be encouraged to bring sunscreens to their dermatology appointments, as they would their prescription medications, in order to verify that the chosen sunscreen is appropriate. The sun protection factor (SPF) is a measure of the ability of a given sunscreen to protect against erythema.[16,20] An SPF of 15 can block 94% of the UVB radiation and an SPF 30 can block 97%. The majority of patients do not apply sufficient sunscreen to achieve the SPF value labeled on the package. Although a sunscreen concentration of 2 mg/cm2 is required to achieve the labeled SPF, most individuals apply only 25–60% of this concentration.[21] Certain sites such as the neck, temples, and ears are frequently missed.[22] These areas each require approximately one teaspoon of sunscreen, with slightly greater amounts required for larger areas such as the chest and back and legs. Lip balms may be used to protect

the lips. The use of sunscreen may be limited by cost and cosmetic acceptability. Oil-free and alcohol-based sunscreen may be preferred by transplant recipients due to their predilection for acne.

Sun-protective Clothing The use of sun-protective clothing includes the use of protective clothing, hats, and sunglasses (Table 49.4). Tightlywoven clothing should cover the arms and legs and wearing t-shirts and shorts should be discouraged. Broad-rimmed hats (4 inch brim), rather than baseball style hats are necessary to fully protect the ears. Sunglasses limit ultraviolet radiation exposure to the eye which in turn may help prevent cataracts, macular degeneration, and skin cancers around the eye. Sunglasses that block both UVA and UVB are necessary and can be identified with a label that reads ‘‘UV 400’’ or ‘‘100% UV protection.’’[23]

C H A L L E N G E S A N D B A R R I E R S TO PA T I E N T EDUCATION Studies of compliance with the use of immunosuppressive medications showed that nearly one-quarter of transplant

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Table 49.3 Essential information for planning individualized patient education Patient age, hair, and eye color, skin type (Fitzpatrick) Places of residence and duration l Previous sun exposure including childhood sunburn, occupational exposure l Previous actinic keratoses and skin cancers l Family history of skin cancer, especially melanoma l Current sun protection practices and patient attitudes towards sun protection l Previous and current smoking practices l l

Table 49.4 Sun protection counseling for the organ transplant recipient Sunscreen l Broad spectrum protection against UVA and UVB with SPF 30 or greater l Application thirty minutes before sun exposure and reapplication l Daily application Clothing cover l Long-sleeve shirts with high neck l Long pants with tight weave l Broad-rimmed hats (4 inches of rim) to cover the ears l Sunglasses with 100% UV protection Sun avoidance l Avoidance of sun between most intense hours of 10 am to 4 pm l Avoidance of sun–tanning and tanning beds l Seek shade where possible

recipients do not completely adhere to their medication regimen.[24] It is therefore important to set realistic expectations regarding adherence with sun-protection recommendations. The factors that influence compliance with sun protection are incompletely understood but relate to patient knowledge, patient attitudes, and several psychosocial variables. In addition, barriers to delivery and implementation of sun protection education include patient-related, physicianrelated, and factors related to the educational material [25] (Table 49.5). It is difficult to change sun-protection behaviors, even in high-risk patients. The ÔHealth Belief ModelÕ is a commonly-used psychosocial model to understand preventive behavior.[26] According to the model, how likely someone is to adopt a behavioral change is dependent on their perceived susceptibility. Patients are likely to make changes if they feel they are: (1) susceptible to the disease, (2) they feel their life will be affected were they to develop the disease, (3) they feel they can take steps to actively reduce their chances of getting the disease, and (4) the recommendations are easy to undertake. A given patient may limit the use of sun protection for reasons associated with one or more of these four areas. By assessing patient attitudes at each stage of the model, it might be possible to improve delivery of sun protection education. For example, only one-half of patients in one study were interested to participate in a skin cancer screening program,[12] suggesting that a proportion of transplant recipients may not appreci-

ate the increased susceptibility to develop skin cancer. Provision of patient education is a fundamental component of strategies to increase the use of sun protection by organ transplant recipients. In addition to increasing knowledge, an additional goal of sun-protection education is to promote development of healthier attitudes towards sun protection. Although a low level of knowledge does seem to be associated with a decreased use of sun protection, a high level of knowledge is not consistently associated with the increased use of sun protection.[27] The acquisition of a fundamental knowledge of the essentials of sun protection may be necessary but not sufficient to improve sun-protection use in transplant recipients. Further study of the relationship between patient knowledge, psychosocial variables, and the use of sun protection is needed.

I NS TR UC T I O N R E G A R D IN G SK IN SE LF-E XAM INATI ON Self-examination of the skin is recommended for transplant patients, and instruction on performing self-examination may begin prior to organ transplantation. There is currently no evidence to accept or refute the benefits of self-examination in reducing the incidence, morbidity, or mortality of skin cancer in organ transplant recipients. In the general population, the benefits of skin self-examination were realized in

PATIENT EDUCATION IN TRANSPLANT DERMATOLOGY: PRE- AND POST TRANSPLANT

terms of a lower incidence and mortality from melanoma.[28] Patients should be encouraged to examine the entire skin surface, including hair, nails, lips, and anogenital region in a brightly-lit room on a monthly basis. To examine the back, two mirrors can be used or a family member may assist. Most importantly, patients must be aware that all new skin changes require prompt evaluation by a dermatologist. Patients with a history of high-risk SCC or melanoma may also be provided with instruction on lymph node examination.

E D U C AT I O N R E G A R D IN G F O L L O W - U P IN T H E P OS T- T R A N SP L A NT P E R I O D Only a minority of transplant recipients receive regular followup by a dermatologist.[12] Patient education must convey the importance of routine screening examinations for skin cancer. Low-risk patients may be examined by the transplant physician and referred to the dermatologist if concerns arise. Highrisk patients may be assessed by a dermatologist with the frequency of appointments scheduled according to risk. Ideally, appointments should occur on the same day as the patientÕs regular transplant clinic appointment in order to reduce the burden of appointments already placed upon these patients. Patients with repeatedly missed appointments may be contacted directly by telephone or mail, as such patients may not appreciate the importance of surveillance in the posttransplant period. Each clinic appointment provides an opportunity to discuss strategies for skin cancer prevention and to review adherence with sun protection. Although this may begin prior to transplant, a delay in patient counseling may be appropriate immediately following transplant. The early posttransplant period is an emotionally stressful period, which can delay the learning and retention of information.[12] In general, most patient educational issues in transplant dermatology may be delayed until approximately four months following organ transplantation. Transplant recipients who develop skin changes should know the appropriate action necessary to be promptly seen by a dermatologist. Each dermatology center must establish a consistent policy on appointment scheduling for patients with new concerns. A method whereby the patient is able to telephone the dermatologistÕs office directly may be most efficient. Close communication is also essential between transplant physicians, transplant nurses, and the dermatology center in order to expedite consultation for patients with concerning skin lesions.

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Table 49.5 Barriers to successful delivery of sun protection education Patient-related factors l Perceived lack of benefits l Lack of motivation l Psychosocial factors including depression l Lack of family support l Advanced age l Low level of education l Low perceived susceptibility to disease l Low value placed on health l Feeling of helplessness Physician-related factors l Poor communication skills l Lack of time l Reduced frequency of follow-up visits Factors related to educational material/proposed plan l Complicated plan l Insufficient material given to patient l High cost of plan Source: Adapted from Chisholm MA. Enhancing transplant patientsÕ adherence to medication therapy. Clin Transplant 2002; 16:30–8. With permission.

from the patient, education regarding skin cancer risk and strategies for prevention can be offered to both patient and accompanying family members. It may be easier for patients to adopt healthy sun-protection practices if family members are also using sun protection. Families can encourage patients to apply sunscreen, to wear sun-protective clothing, and to limit sun exposure. Family members can play an important role in reminding patients to perform self-examination of the skin, and may themselves assist in monitoring skin changes in difficult to examine areas, such as the back.

P AT I E N T E D U C A T I O N I N SU B P O P U L A T I O N S A T H I G H R I S K F OR SK I N C A N C E R

Older Patients In general older patients use less sun protection than younger patients.[11,14] The mean interval between transplantation and diagnosis of skin cancer is eight years for patients who received their transplant at age 40 but only three years for those who received the transplant at age 60.[29] The older patient may benefit from frequent evaluation of sun-protection compliance.

Younger Patients E D U C AT I O N O F F A M I L IE S OF TR AN S P LA N T P A T IE NT S Families are an important source of support for patients and can benefit from understanding the dermatological issues that may occur following organ transplantation. With permission

The younger transplant recipient faces many years of continuous immunosuppression. Skin cancer in pediatric solid organ transplant recipients may be particularly aggressive.[30] Patient education regarding the importance of sun protection and the importance of self-examination is particularly important in this group.

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Patients with One or More Skin Cancers Post transplant Patients who develop skin cancer despite the use of sun protection may feel uncertain of the benefits of continued use. These patients require support to continue use of sun protection. For many patients, the surgical excision of a skin lesion is accompanied by a false belief that all concern regarding the cancer has been eliminated. Patients with high-risk SCC should be cognizant of the fact that local recurrence and lymph node metastases are possible and diligent self-examination may be beneficial to detect early recurrences.

Remotely Transplanted Patients Frequently, the most intensive education occurs in the first few years following organ transplantation. The most dramatic rise in skin cancer rates occurs 5 to 10 years following organ transplantation making it important that patient education be continued for many years after transplantation. Several groups have shown that remotely transplanted patients do not differ in the use of sun protection compared to new recipients.[5,11] This is especially concerning in light of the fact that remotely transplanted recipients have generally had more clinic visits and more opportunities for discussion of the importance of sun protection. It is important for physicians to be aware that remotely transplanted patients, like new recipients, may not be using adequate sun protection.

CONCLUSION Education is recognized to be an essential component of the care of the pre- and posttransplant patient. Information regarding the factors that influence sun protection use in the general population, and the transplant population continues to expand. Further study of various issues in patient education are needed including the effect of psychological variables on adherence with sun protection, as well as the potential role of the dermatology nurse to assist in the delivery of patient education. Anticipatory guidance of skin changes that can be expected following transplantation along with education regarding sun protection and the importance of self examination may reduce the burden of skin disease in organ transplant recipients.

REFERENCES

1. Koranda FC, Dehmel EM, Kahn G and Penn I. Cutaneous complications in immunosuppressed renal homograft recipients. JAMA 1974; 229:419–24. 2. Euvrard S, Kanitakis J, Pouteil-Noble C, Claudy A and Touraine JL. Skin cancers in organ transplant recipients. Ann Transplant 1997; 2: 28–32. 3. Strumia R, Perini L, Tarroni G, Fiocchi O and Gilli P. Skin lesions in transplant recipients. Nephron 1992; 62:137–41.

4. Otley CC, Hirose R and Salasche SJ. Skin cancer as a contraindication to organ transplantation. Am J Transplant 2005; 5:2079–84. 5. King GN, Healy CM, Glover MT, Kwan JT, Williams DM, Leigh IM, Worthington HV and Thornhill MH. Increased prevalence of dysplastic and malignant lip lesions in renal-transplant recipients. N Engl J Med 1995; 332: 1052–7. 6. Robinson JK and Rigel DS. Sun protection attitudes and behaviors of solid-organ transplant recipients. Dermatol Surg 2004; 30: 610–5. 7. Penn I. Tumors after renal and cardiac transplantation. Hematol Oncol Clin North Am. 1993; 7:431–45. 8. Moloney FJ, de Freitas D, Conlon PJ and Murphy GM. Renal transplantation, immunosuppression and the skin: an update. Photodermatol Photoimmunol Photome. 2005; 21:1–8. 9. Moloney FJ, Keane S, OÕKelly P, Conlon PJ and Murphy GM. The impact of skin disease following renal transplantation on quality of life. Br J Dermatol 2005; 153:574–8. 10. Moloney FJ, Almarzouqi E, OÕKelly P, Conlon P and Murphy GM. Sunscreen use before and after transplantation and assessment of risk factors associated with skin cancer development in renal transplant recipients. Arch Dermatol 2005; 141:978–82. 11. Donovan JC, Rosen CF and Shaw JC. Evaluation of sun-protective practices of organ transplant recipients. Am J Transplant 2004; 4:1852–8. 12. Cowen EW and Billingsley EM. Awareness of skin cancer by kidney transplant patients. J Am Acad Dermatol 1999; 40:697–701. 13. Harden PN, Reece SM, Fryer AA, Smith AG, Ramsay HM. Skin cancer surveillance in renal transplant recipients: questionnaire survey of current UK practice. BMJ 2001; 15;323:600–1. 14. Mahe E, Morelon E, Fermanian J, Lechaton S, Pruvost C, Ducasse MF, Mamzer-Brunell MF, Kreis H, Bodemer C and de Prost Y. Renaltransplant recipients and sun protection. Transplantation 2004; 78: 741–4. 15. Courtenay M and Carey N. Nurse-led care in dermatology: a review of the literature. Br J Dermatol 2006; 154:1–6. 16. Kullavanijaya P and Lim HW. Photoprotection. J Am Acad Dermatol 2005; 52:937–58. 17. Green A, Williams G, Neale R, Hart V, Leslie D, Parsons P, Marks GC, Gaffney P, Battistutta D, Frost C, Lang C, Russell A. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet 1999; 354:723–9. 18. Diffey BL. When should sunscreen be reapplied? J Am Acad Dermatol 2001; 45:882–5. 19. Autier P, Dore JF, Negrier S, Lienard D, Panizzon R, Lejeune FJ, Guggisberg D, Eggermont AM. Sunscreen use and duration of sun exposure: a double-blind, randomized trial. J Natl Cancer Inst 1999; 91:1304–9. 20. Rosen CF. Topical and systemic photoprotection. Dermatol Ther 2003; 16:8–15. 21. Stokes R and Diffey B. How well are sunscreen users protected? Photodermatol Photoimmunol Photomed 1997; 13:186–8. 22. Azurdia RM, Pagliaro JA, Diffey BL, Rhodes LE. Sunscreen application by photosensitive patients is inadequate for protection. Br J Dermatol 1999; 140:255–8. 23. Sliney DH. Photoprotection of the eye - UV radiation and sunglasses. J Photochem Photobiol B 2001; 64:166–75. 24. Greenstein S and Siegal B. Compliance and noncompliance in patients with a functioning renal transplant: a multicenter study. Transplantation 1998; 66:1718–26. 25. Chisholm MA. Enhancing transplant patientsÕ adherence to medication therapy. Clin Transplant 2002; 16:30–8. 26. Rosenstock I. The health belief model: explaining health behavior through expectancies. In Glanz K, Lewis F, Rimer B (eds). Health Behavior and Health Education: Theory, Research and Practice. Jossey-Bass, San Francisco, CA 1991: 39–62.

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27. Fleming C, Nicolson C, Toal F, MacKie R. Sun awareness in school teachers. Br J Dermatol 1998; 139:280–4. 28. Berwick M, Begg CB, Fine JA, Roush GC, Barnhill RL. Screening for cutaneous melanoma by skin self-examination. J Natl Cancer Inst 1996; 88:17–23.

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29. Webb MC, Compton F, Andrews PA, Koffman CG. Skin tumors post-transplantation: a retrospective analysis of 28 yearsÕ experience at a single center. Transplant Proc 1997; 29:828–30. 30. Euvrard S, Kanitakis J, Cochat P and Claudy A. Skin cancers following pediatric organ transplantation. Dermatol Surg 2004; 30:616–21.

50 Transplant Dermatology Clinics

Alvin H. Chong, FACD, MMed, MBBS and Cara Holmes, MBBS

INTR ODUCT IO N

l

As the number of living organ transplant recipients continues to rise with advances in immunosuppression, so do the long-term problems. Nonmelanoma skin cancers (NMSCs), particularly squamous cell carcinomas (SCCs) are the most common posttransplantation malignancy in countries with predominantly Caucasian populations. In subtropical Queensland, Australia, the cumulative incidence of NMSCs increased from 7% after one year of immunosuppression to 25% after 5 years, and 70% after 20 years.[1] The mean NMSC accrual in this same population was calculated as 1.85 +/ 3.84 tumors /person/year, increasing to 3.35 +/ 4.29 tumors/person/year after 20 years of immunosuppressive therapy,[2] representing a significant tumor load. Many of these patients can be described as having ‘‘catastrophic cutaneous carcinogenesis’’ with large numbers of premalignant and malignant lesions. Unfortunately, the dermatological care of transplant patients has long been reactive, rather than proactive. Patients are referred only when skin cancers develop, and often, the load of malignant and premalignant lesions can be overwhelming for any clinician. An improved model, or models, of care therefore needs to be developed for such patients.

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Some aspects of dermatological care for transplant patients are significantly different from that in an immunocompetent population. Important differences and similarities include: l

R OL E S O F T HE D E RM AT O L O G I S T I N T H E C A R E OF T R A N S P L A N T PA T I E N T S The roles of the dermatologist in the skin care of transplant recipients are essentially: l

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Screening of transplant recipients, ideally pretransplantation and regularly after transplantation. The frequency of screenings should be determined by the risk factors and past history of skin tumors for each individual patient. Treatment of other skin problems related to immunosuppression and medications. These commonly include opportunistic infections such as viral warts, which are more challenging to treat in transplant patients than in immunocompetent individuals. Close communication with transplant physicians and surgeons for effective multidisciplinary care. Education of patients, fellow physicians, and other health care providers on the diagnosis and prevention of NMSCs. This is a vital component of the dermatologistÕs role in the care of transplant recipients. All transplant recipients and their care providers should be aware of the increased risk of nonmelanoma skin cancer and be educated in risk-reduction behavior.

l

Treatment of established tumor load. This involves the diagnosis and management of skin malignancies existing at the time of initial consultation. Following diagnosis, the clinician may be able to treat the lesions, or need to liase with surgeons or other specialists to arrange treatment. Treatment of subsequent tumors. As new cancers develop, ongoing management will ideally remove them at the earliest possible time. Treatment of precancers to reduce subsequent tumor load. Given that the rate of malignant transformation of premalignant lesions is thought to be higher in immunocompromised patients, it is recommended that, when possible, all premalignant lesions be treated to reduce the eventual tumor load.

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Follow-up intervals which are appropriate for the patients. Patients with ‘‘catastrophic cutaneous carcinogenesis’’ may need to be seen every six weeks or less in order to adequately deal with their skin cancers and precancers. ‘‘Urgent’’ appointments must be available for patients who develop rapidly growing tumors. If possible, surgical appointments for immediate treatment are desirable. Many transplant recipients who have already developed a number of skin cancers, are accurate in self-diagnosis of new tumors. Given the relative ease of treating small tumors, and their tendency to grow rapidly, the accessibility of appointments is of vital importance. Easy and rapid access to cutaneous oncology specialists for rapid surgical, radiological or medical management of skin cancers when needed. Again, this enables tumors to be treated in earlier stages, which may save the need for more complicated procedures and reduce the potential for tumor spread. Close liaison and communication with transplant physicians particularly regarding reduction or modification of immunosuppression, or the use of additional pharmaceutical therapies such as acitretin or imiquimod.

TRANSPLANT DERMATOLOGY CLINICS

l

Access to the following modalities for the treatment skin cancers and precancers: s Cryotherapy. Cryotherapy remains the most common and easily used standard treatment for premalignant lesions, as well as early malignancies and other conditions such as viral warts. s Field treatment for premalignant and early malignancies. These treatments may be useful in certain clinical situations and include photodynamic therapy, 5-fluorouracil therapy, imiquimod therapy, and laser ablation. s Destructive skin surgery. For SCCs which are clinically less aggressive, superficially ablative treatment, such as shave excisions, curettage and electrocautery are accepted methods of treatment.[3] The latter method is particularly useful for the large numbers of well-differentiated, small SCCs that can occur on the forearms and dorsa of hands in transplant patients. The possibility of recurrence may be increased with destructive modalities. Such treatment should only be undertaken by experienced clinicians after careful assessment of the nature of skin lesions and with proper patient selection. Frequent follow-up is mandatory. s Excisional skin surgery. Surgical removal remains the treatment of choice for high-risk SCCs. When available, Mohs Micrographic Surgery or excision with immediate pathologic surgical margin evaluation is optimal. s Systemic retinoid treatment. This treatment modality has been shown in randomised-controlled trials to be able to reduce the numbers of pre-malignant skin lesions and nonmelanomas skin cancers.[4]

The manner in which such care can be delivered depends on many variables. These include the presence or absence of existing infrastructure, funding, staffing, and other logistic issues. There is usually already a system for the dermatologic care of the general population in place at most transplant centers. Simple adaptation and improvement of such existing systems may be appropriate. The following is a discussion of the various models of clinical care, including the advantages and disadvantages of each.

The main disadvantage is that the care of some transplant patients, especially those with a significant skin cancer load, is extremely labor intensive and may not fit well into the usual patient flow of the facility. It may also be inconvenient for the transplant patient, as procedures are often scheduled at different times than evaluation, necessitating multiple visits. Transplant recipients already spend a significant amount of time on the routine medical management of their organ graft. Most patients are required to see multiple doctors in a variety of specialist areas, as well as get regular blood tests and other investigations. Dermatology clinics are notoriously busy and long waiting times are the norm, which is an extra burden for patients. This is particularly the case if the patient has a large tumor load and needs to attend frequently. If seen in a general dermatology clinic, transplant patients are likely to need more frequent visits than they would in a specialist clinic, as time restraints often limit the assessment and management of their problems. Many general dermatology clinics also have waiting lists and therefore transplant recipients may not be able to be seen quickly when a problem arises. To reduce the delay between diagnosis and surgical excision, some centers automatically schedule transplant patients with a heavy skin cancer load directly into regular surgical slots.[5]

T RANSPLANT DE RMAT OLOG Y SUBSPECIALTY/DEDICATED D ER MA TO LO G Y C L I NI C The Mayo Transplant Dermatology Clinic[6] model has been well described and is an archetypal dedicated transplant dermatology clinic within a multispeciality transplant clinic (described below). Depending on staffing and resources, such clinics manage the majority of the transplant patients at their institution. The Mayo Transplant clinic runs twice a week and patients are seen by dermatological surgeons with special interest in transplant dermatology. The surgical facility is equipped to deal with patients with large tumor loads and education of transplant recipients is an integral part of the clinic. Examples of such clinics are detailed in Table 50.1 and Table 50.2. The advantages of such a clinic are these: l

T RANS PLANT PATI ENTS SEE N AS PAR T OF A N E XI ST I NG D ER M AT OL O G Y C L IN I C Skin care for the majority of transplant patients, worldwide, is provided in existing dermatology clinics. As noted, dermatology clinics are already present in most tertiary care settings in which organ transplantation is carried out. Transplant patients can be screened and regularly reviewed in such a setting along side other dermatology patients. There is often a dermatologist with a special interest in transplant recipients in a clinic who can provide expertise regarding the treatment of these patients. The advantage of this model is that it allows utilization of an existing infrastructure.

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Concentration of expertise in a facility. A specialist dermatology clinic for transplant recipients gives patients access to dermatologists, surgeons, and other staff who understand the unique care required in these patients. It is likely that these clinicians are more familiar with the latest research in prevention and management of carcinogenesis and other skin disorders in transplant recipients and subsequently more proactive in their care. Recognition of transplant dermatology as a clear subspecialty with increased profile amongst other disciplines. This promotes further research in the field of transplant dermatology, which increases knowledge of the discipline for both clinicians who specialize in the field and those that do not, resulting in superior patient care.

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Table 50.1 Examples of dedicated transplant dermatology clinics – Europe Locality

Comments

Charite´ University Hospital, Berlin, Germany (Ulrich & Stockfleth)

This clinic was established in 2002 following a previously established clinic at the University Hospital of Kiel,Germany. Charite´’s clinic cares for 2500 kidney +/ pancreas transplant patients, 3400 heart +/ lung transplant patients, and 3000 liver transplant patients. 1500 patients have been followed up for 3–4 years. Offers office-based procedures and noninvasive management of premalignant field change. Other therapies include: SLNB in high-risk invasive squamous cell carcinomas, ultrasound and confocal microscopy for diagnosis and follow-up.

Hoˆpital Edouard Herriot, Lyon, France (Euvrard)

Transplant dermatology clinic operates 5 mornings per week with a total of 40 patients. Two consultants are exclusively devoted to transplant patients and 4 others are often involved especially in skin surgery. Offers office-based procedures. This clinic was established in 1991 and has seen 2000 renal +/ pancreas transplant patients, 600 heart +/ lung transplant patients, and 200 liver transplant patients.

Medical University of Vienna, Austria (Geusau)

Transplant dermatology clinic runs one afternoon per week, 8 patients per clinic. Offers office-based procedures, skin surgery, ablative lasers and PDT.

Universitatsspital Zurich, Switzerland (Hofbauer)

Transplant dermatology clinic operates 3 mornings per week and sees 900 patients a year. Offers office-based procedures, skin surgery including Mohs, CO2 laser and PDT.

Barts and the London NHS Trust, London, United Kingdom (Proby & Harwood)

Clinic operates weekly with 30 patients, mainly renal transplant patients. Staffed by 2 consultants and 0.5 trainee registrar and a research nurse. Offers office-based procedures, including same day skin biopsy. PDT will soon be available. Weekly dermatopathology meetings to confirm diagnoses. High-risk tumors or those needing plastic surgical expertise are referred to a weekly multidisciplinary tumor clinic involving dermatologists, plastic surgeons, oncologists and radiotherapists. Offers surveillance for all RTR attending the regional transplantation unit. Currently has seen and is following prospectively 869 patients.

The Churchill, Oxford Radcliffe Hospital, Oxford, United Kingdom (Wojnarowska)

Clinic operates twice monthly, with 22 renal +/ pancreas patients. Staffed by 1 consultant dermatologist, and 1–2 dermatology trainees. Offers office-based procedures, Mohs surgery. Transplant surgeons run a dedicated minor surgery clinic on alternate weeks.

Royal Hallamshire Hospital, United Kingdom (Ramsay)

Transplant dermatology clinic runs monthly with up to 18 patients. Involves 1 consultant dermatologist, 2 dermatology trainees and 1 nurse practitioner. Offers office-based procedures. PDT not available on site. Nurse practitioner offers skin examination, patient education and can do diagnostic biopsies after consultation with medical staff. Supported by telephone ‘‘hot line’’ for patients who need advice or develop lesions between visits. All diagnoses of SCC, melanoma and rare/high-risk tumors discussed at monthly multidisciplinary skin cancer clinic involving dermatologists, plastic surgeons, oncologists, and dermatopathologists.

Manchester Royal Infirmary, United Kingdom (Lear)

Clinic operates once weekly, with 30 patients, all renal transplant recipients. Multidisciplinary clinic involving renal physician and specialist nurse. Offers office-based procedures, PDT, and Mohs surgery.

Beaumont Hospital Dublin, Ireland (Murphy)

National Renal transplant Centre. 2000 RTR. Renal transplant patients are seen twice weekly by a specific renal transplant research trainee dermatologist, in association with a consultant dermatologist. Patients may walk in with tumors as necessary, PDT, surgery, cryotherapy are performed during clinic or scheduled as appropriate. Plastic surgery review takes place the same day if appropriate. A new multidisciplinary tumor clinic has started jointly with radiotherapy on a monthly basis.

l

Clinic can be set up specially to deal with clinical problems occurring in population, for example, the need for multiple procedures per visit, and easy access to emergency visits. The main advantage of this arrangement is that it

reduces the time burden of skin care for transplant recipients. Because these patients often spend vast amounts of their time looking after their other medical requirements, they are more likely to neglect their skin problems if it is

TRANSPLANT DERMATOLOGY CLINICS

325

Table 50.2 Dedicated transplant clinics, North America and Australia Locality

Comments

Mayo Clinic, Rochester, United States (Otley)

1–2 half days per week, with 13–15 patients per half day. 1 Dermatologist and one specialty nurse per clinic. Offers office-based procedures. PDT and Mohs available. Rapid frozen biopsy results available in 60 minutes.

UCSF – High Risk Skin Cancer Clinic, San Francisco, United States (Tope)

Clinic runs twice monthly, with 15–20 patients per half day. Staffed by 2 dermatologists, 1 dermatology surgery fellow, 2 trainees. Offers office-based procedures, PDT, Mohs.

University of Colorado Health Sciences Centre – High Risk Skin Cancer Clinic, United States (Pacheco)

Clinic runs once weekly, with 15–20 patients per half day. Staffed by 1 dermatologist and 2 trainees. Offers office-based procedures.

University of Pennsylvania Hospital Service, United States (Schmults)

Clinic runs once a month with 2 consultants and 2 trainees. 40 patients seen per clinic. Offers office-based procedures and Mohs surgery.

University of Wisconson Hospital Service, United States (Vanness)

2–3 clinics per month with 12–15 transplant patient per clinic. Staffed by 1 consultant and 1 clinical assistant. Offers office-based procedures, Mohs cases referred on.

Brigham and WomenÕs Hospital, Massachusetts, United States (Miller)

Clinic runs once weekly, but there is an open door policy 5 days per week for patients who travel long distances. Offers office-based procedures with coordination with plastic surgery, Mohs, oncology input as required.

University of Toronto, Toronto, Canada. (Shaw)

Clinic runs once weekly, with 15 patients per half day. Offers office-based surgery. Mohs is referred.

Skin and Cancer Foundation Melbourne, Victoria, Australia. (Chong)

Clinic operates weekly with 5–8 patients. Mainly renal transplant patients. Staffed by 1 consultant and 2 trainees. Offers office-based procedures. PDT and Mohs available.

Mohs, ENT, radiation, and medical oncologists are available to come to clinic to consult on difficult cases.

Table 50.3 Nurse-led Clinics Locality

Comments

Derbyshire Royal Infirmary, United Kingdom (Shum and Jordan)

A dermatology specialist nurse sees 4 renal transplant patients per week in a nurse-led disease management clinic. All patients are seen and educated on sun avoidance and self-examination. Low-risk patients are seen annually for skin surveillance. Medium- and high-risk patients are followed up six to twelve monthly. Patients with skin cancers are referred onto dermatologists for treatment and further follow-up.

University Hospital of North Staffordshire, United Kingdom (AG Smith)

l

A nurse with a special interest in dermatology attends transplant clinics in nephrology. Patients with suspicious lesions are referred onto dermatologists for further treatment.

time-consuming or complicated, leading to delayed care and more difficult management. Research and teaching is facilitated. Specialized transplant dermatology clinics allow teaching of dermatology trainees in the discipline, which subsequently improves the management of all transplant recipients when they are attended to in the general dermatology arena. Research on the optimal ways to manage transplant patients with skin diseases can advance the care for future patients.

DE RMAT OLOG Y C LINICS INTE GRAT ED WI TH TR ANS PLANT CLI N ICS Such clinics run concurrently with transplant clinics and are true multidisciplinary clinics, attended by both derma-

tologists, transplant physicians and in some settings, such as at the Mayo Clinic, specialists dealing with other complications of transplantation. The advantages are essentially the same as dedicated transplant clinics, with the additional benefit of rapid input from transplant physicians regarding a variety of issues such as the reduction or alteration of immunosuppression in certain patients. This kind of setup also enables education and screening of patients before they develop skin malignancy or other problems. Without such a clinic, transplant recipients are rarely referred to dermatology before they develop cutaneous malignancies. The period prior to the development of skin lesions is optimal for beginning education regarding risk factors, prevention, and early detection of skin malignancy. Communication with specialists from other ‘‘non-allograft-specific’’ specialties, such as endocrinology, infectious diseases, psychiatry, and others, leads to

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ALVIN H. CHONG AND CARA HOLMES

mutual understanding and sharing of effective strategies for education and management.

M U LT I D I SC I P LI N A R Y T U M O R M A NAGE ME NT CLI N ICS Some centers offer multidisciplinary tumor clinics where difficult cases are managed by a multidisciplinary team including dermatologists, oncologic surgeons, radiation oncologists, and medical oncologists. These teams may be able to offer complicated surgical and other adjunctive treatments when required.

N U R S E PR A C T I T I O N E R C L I N I C S In the United Kingdom, nurse practitioners are responsible for the screening and triage of transplant recipients in some transplant centers [7] (Table 50.3). These nurse practitioners receive special training in the recognition of skin cancers, and are often able to perform simple procedures like cryotherapy and skin biopsies. Patients with a large tumor load can then be scheduled directly into surgical lists. Patients with specific problems can be referred to dermatologists for further management. The main advantage of this system is that it enables a rapid triage of problems. Early transplant patients may only require annual screening and education, easily managed by nurse practitioners, whereas others may require a more intensive approach, and can be referred to a dermatologist.

CONCLUSION The dermatological care of transplant recipients is challenging. The means of delivering such care to patients will depend on the availability and resources in particular institutions. There are many models of care that can be utilized, each with its own particular advantages and difficulties.

ACKNOWLEDGMENTS

The authors would like to thank the following for their input into the tables detailing the different transplant dermatology clinics: Dr Sylvie Euvrard, Dr Alexandra Geusau, Dr Catherine Harwood, Dr. Gu¨nther Hofbauer, Sister Sue Jordan, Dr John Lear, Dr Danielle Miller, Dr. Gillian Murphy, Dr Clark Otley, Dr Teresa Pacheco, Dr Charlotte Proby, Dr Helen Ramsay, Dr Chrysalyne Schmults, Dr James Shaw, Dr Kid Wan Shum, Dr AG Smith, Professor Eggert Stockfleth, Professor Whitney Tope, Dr Claas Ulrich, Dr Erin Vanness and Professor Fenella Wojnarowska. In particular, the authors thank Dr Charlotte Proby for her help in providing contact details of the transplant clinics in the United Kingdom.

REFERENCES

1. Bavinck JNB, Hardie DR, Green A, Cutmore S, MacNaught A, OÕSullivan B, Siskind V, van der Woude FJ, Hardie IR. The Risk of Skin Cancer in Renal Transplant Recipients in Queensland, Australia: A Follow-up Study. Transplantation 1996; 61: 715–21. 2. Carroll RP, Ramsay HM, Fryer AA, Hawley CM, Nicol DL, Harden PN. Incidence and Prediction of Non-melanoma Skin Cancer Post-Renal Transplantation: A Prospective Study in Queensland, Australia. Am J Kidney Dis 2003; 41: 676–83. 3. Stasko T, Brown MD, Carucci JA, Euvrard S, Johnson TM, Sengelmann RD, Stockfleth E, Tope W. for the International Transplant-Skin Cancer Collaborative and the European Skin Care in Organ Transplant Patients Network. Guidelines for the Management of Squamous Cell Carcinoma in Organ Transplant Recipients. Dermatol Surg 2004; 30: 642–50. 4. Chen K, Craig JC, Shumack S. Oral Retinoids for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomised controlled trials. Br J Dermatol 2005; 152: 518–23. 5. Christenson LJ, Geusau A, Ferrandiz C, Brown CD, Ulrich C, Stockfleth E, Berg D, Orengo I, Shwa JC, Carucci JA, Euvrard S, Pacheco T, Stasko T, Otley C. Specialty Clinics for the Dermatologic Care of Solid-Organ Transplant Recipients. Dermatol Surg 2004; 30: 598–603. 6. Otley CC. Organization of a specialty clinic to optimise the care of organ transplant recipients at risk for skin cancer. Dermatol Surg 2000; 26: 709–12. 7. Harden PN, Reece SM, Fryer AA, Smith AG, Ramsay HM. Skin Cancer Surveillance in Renal Transplant Recipients: Questionnaire Survey of Current UK Practice. BMJ 2001; 323: 600–1.

51 Transplant Dermatology Organizations

Henry W. Randle, MD, PhD

that increased patient longevity, 40 to 80% of patients eventually developed nonmelanoma skin cancer after 20 years of immunosuppression, with the number of squamous cell carcinomas being 65 times higher in transplant recipients than in the general population.[5,6] More than one third of de novo malignancies in this population were nonmelanoma skin cancers. The number and aggressiveness of these skin cancers presented another major challenge to the physicians treating these patients. During the early stages of recognition of the dermatologic problems of transplant patients, a few individuals took a special interest in these patients. One of them was Dr. Thomas Stasko at Vanderbilt University, where there was a large number of transplant recipients. Dr. Stasko began teaching a course at the American Academy of Dermatology in 1995 entitled ‘‘Non-Melanoma Skin Cancers – A Special Problem for Transplant Patients.’’ As more dermatologists became involved in treating transplant patients, some of whom had life-threatening skin cancers, a coalition of forces began to form, first in Europe, and shortly thereafter in the United States. ‘‘The SCOP-Network [skin care in organ transplant patients],’’ according to the organizationÕs web site (www. scopnetwork.org), ‘‘was founded in December 2000 (in Berlin by Drs. Eggert Stockfleth, Claas Ulrich, and others) as an interdisciplinary network of dermatologists, transplant physicians, patient support groups, and basic researchers to match the increasing needs of qualified dermatological aftercare.’’ This group collected epidemiological data on skin diseases in organ transplant recipients and began to develop prophylactic and therapeutic strategies. SCOP eventually assumed the name Skin Care in Organ Transplant Patients Europe, abbreviated as SCOPE. Parallel to establishment of this organization was formation of a collaborative group in the United States (initially called the Pan American Transplant – Skin Cancer Collaborative, then the North American Transplant Skin Cancer Collaborative), founded in 2001 to find better care for skin cancer in transplant patients.[7] As membership increased, the collaborative embraced members from Central America, South America, Australia, and other regions, and the name was changed to the International Transplant Skin Cancer Collaborative (ITSCC) (www.itscc.org). The group defines and creates guidelines for the management of skin cancer in organ transplant patients. The mission of ITSCC is twofold:

ABBREVIATIONS

ACMMSCO ASDS ITSCC SCOP SCOPE

American College of Mohs Micrographic Surgery and Cutaneous Oncology American Society for Dermatologic Surgery International Transplant Skin Cancer Collaborative Skin Care in Organ Transplant Patients Skin Care in Organ Transplant Patients Europe

Solid organ transplant recipients began receiving immunosuppressive drug regimens in the late 1950s and almost immediately began to manifest various dermatologic conditions. More than 90% of patients have dermatologic problems after transplantation.[1] The three most common in the early days of transplantation were herpes simplex, warts, and acne but dermatologic problems ranged from annoying minor infections with dermatophytes to life-threatening disseminated fungal infections.[2] Adverse effects were associated with specific medications: gingival hyperplasia, hirsutism, and gynecomastia from cyclosporine; CushingÕs syndrome, acne, striae, skin fragility, and ecchymoses from corticosteroids; alopecia from tacrolimus; edema, folliculitis, hidradenitis suppurativa, aphthous ulcers, vasculitis, and nail abnormalities from sirolimus; and bacterial, fungal, and mycobacterial infections from general immunosuppression. The initial response from the dermatologic community was to treat transplant patients like ‘‘regular’’ dermatology patients because their problems were in the realm of general dermatology. But these patients had problems of a different magnitude. From a therapeutic standpoint, one of the most difficult problems for dermatologists was the large number of recalcitrant warts that were common in these patients. A mixture of warts and cancers on the hands were referred to as the ‘‘transplant hand’’ and sometimes required resurfacing the backs of the hands.[3] The incidence of these warts, often associated with human papillomavirus infection, rose from 15 to 50% in the first 12 months to 50 to 90% after 5 years. As patients began to live longer and received allografts at older ages, the number of skin cancers increased substantially. Initially, the rate of cancer occurrence was modest, about 14%.[4] By the 1980s, the incidence of squamous cell carcinoma had increased 4- to 7-fold in regions of the world with limited sun exposure and more than 21-fold in regions with intense sun exposure. As a result of newer immunosuppressive agents (especially cyclosporine) and combinations of these drugs

1. To integrate and support basic scientific and clinical research to address the special needs of transplant recipients with skin cancer in order to improve quality of care. 327

328

HENRY W. RANDLE

Table 51.1 ITSCC meetings, 2001–2006 Date

Location

October 2001 January 2002 February 2002 August 2002 November 2002 March 2003 August 2003 October 2003 February 2004 August 2004 September 2004 November 2004 February 2005 August 2005 March 2006 July 2006

Dallas, Texas Berlin, Germany New Orleans, Louisiana Wonewok, Minnesota Chicago, Illinois San Francisco, California Wonewok, Minnesota New Orleans, Louisiana Washington, D.C. Wonewok, Minnesota San Diego, California Florence, Italy New Orleans, Louisiana Wonewok, Minnesota San Francisco, California Boston, Massachusetts

16 members at a satellite to ASDS/ACMMSCO to organize, plan, make bylaws Joint meeting with SCOP Satellite at AAD; elected officers; formed committees 30 members at ITSCC and SCOP retreat; scientific presentations and work groups Satellite at ASDS/ACMMSCO 44 members at satellite to AAD 30 members at ITSCC and SCOPE retreat Over 100 attendees at satellite of ASDS/ACMMSCO Satellite at AAD 30 members at ITSCC and SCOPE retreat Satellite at ASDS/ACMMSCO Satellite at EADV, SCOPE, and ITSCC Satellite at AAD 30 members at ITSCC and SCOPE retreat Satellite at AAD ITSCC half-day symposium at World Transplant Congress

Note: AAD = American Academy of Dermatology; ACMMSCO = American College of Mohs Micrographic Surgery and Cutaneous Oncology; ASDS = American Society for Dermatologic Surgery; EADV = European Academy of Dermatology and Venereology; SCOP/SCOPE = Skin Care in Organ Transplant Patients/Skin Care in Organ Transplant Patients Europe.

2. To educate patients, scientists, primary care doctors, and specialist physicians on the unique needs and clinical care issues in transplant patients. ITSCC was formed as an outgrowth of a research project by Dr. Clark Otley at Mayo Clinic in Rochester, Minnesota, and Juan Carlos Martinez, a student at the Mayo Medical School, with a goal to provide insight into the clinical course of metastatic skin cancer in organ transplant recipients. They were joined by Dr. Stuart Salasche of Tucson, Arizona, and undertook a multicenter investigation to collect additional patients. It soon became clear that multiple physicians were interested in these problems, and the collaborative organization began to solidify its focus on the needs of transplant patients with skin cancer. ITSCC held its first meeting in Dallas in October 2001 in association with the American College of Mohs Micrographic Surgery and Cutaneous Oncology (ACMMSCO) and the American Society for Dermatologic Surgery (ASDS) (Table 51.1). A joint meeting with the European sister organization SCOP was held in Berlin in January 2002. ITSCC was officially incorporated on June 6, 2002. Biannual meetings were held in conjunction with the joint meetings of the ASDS/ACMMSCO and the American Academy of Dermatology centered on sharing of clinical and research papers, and organizational efforts, including business meetings. Additionally, thirty members of ITSCC and SCOPE from 12 countries gathered for an annual retreat in Wonewok, Minnesota, each summer from 2002 through 2005 (Figure 51.1). These meetings have resulted in collaborations that led to guidelines for research and practice, guidelines for clinical approaches to treatment of various skin cancers in transplant patients, web site and patient education material development, committee meetings, updates on re-

search activities, identification of potential funding sources, and networking activities that permitted the members to interact extensively. Didactic reports were also presented, highlighting ongoing clinical and research work accomplished by members. The subjects at the scientific forums during ITSCC and SCOPE meetings ranged from descriptions of the quality of life in transplant patients with skin cancer to therapeutic strategies, including reducing and even eliminating the need for immunosuppressive drugs, to mining various databases, the use of retinoids to suppress development of skin cancer, and the human papillomavirus and its role in carcinogenesis in transplantassociated skin cancers in a cohort of patients with the human immunodeficiency virus. Attendance at the meetings has often been standing-room only. Three members of ITSCC attended and presented papers and posters at the American Society of Transplant Surgeons in January 2003 in Miami Beach, and 10 members presented a half-day satellite symposium on skin cancer in transplant patients at the World Transplant Congress in Boston in July 2006. A major professional and patient educational initiative, called the AT-RISC (After Transplantation – Reduce Incidence of Skin Cancer) Alliance and Initiative was begun by ITSCC in 2006, aimed at reducing the incidence of skin cancer after transplantation. AT-RISC is a collaborative effort of ITSCC, the International Transplant Nurses Society, and Transplant Recipients International Organization. Networking at ITSCC meetings has resulted in lasting friendships, visiting professorships, and collegial relationships that span the globe. New perspectives have been gained by those who work in dedicated transplant clinics and by Mohs surgeons in the United States who previously saw and treated only the most severe cases of skin cancer in transplant patients.

TRANSPLANT DERMATOLOGY ORGANIZATIONS

329

Figure 51.1. Joint meeting of ITSCC and SCOPE, Wonewok, Minnesota, August 2002. Row 1, left to right: Mariet Feltkamp, Netherlands, S; Alexandra Geusau, Austria, S; Evie Radel, 3M; Roberta Sengelmann, USA, BOD, I; Theresa Pacheco, USA, BOD, I; Kathleen Smith, USA, I; Leslie Christenson, USA, BOD, I; Sylvie Euvrard, France, S; Allison Vidimos, USA, I; June Robinson, USA, I. Row 2: Stephen Shumack, Australia, I; Nanda Gosala, 3M; Stuart Salasche, USA, founder, I; Marcy Neuberg, USA, I; Elizabeth Billingsley, USA, I; Gillian Murphy, Ireland, S; Whitney Tope, USA, I; James Shaw, Canada, I; Bert Slade, 3M. Row 3: Warren Weightman, Australia, I; Clark Otley, USA, founder, I; Henry Randle, USA, historian, BOD, I; Joe Gillis, 3M; Daniel Berg, USA, BOD, I; Stefano Piaserico, Italy, S; Carlos Fernandiz, Spain, S. Row 4: Carl Washington, USA, I; John Carucci, USA, BOD, I; Peter Schouten, 3M; Tom Stasko, USA, president, I; Enno Christophers, Germany, S; Eggert Stockfleth, Germany, founder, S; Bernt Lindelof, Sweden, S; Claas Ulrich, Germany, founder, S.I, International Transplant Skin Cancer Collaborative (ITSCC); BOD, board of directors; 3M, 3M Pharmaceuticals; S, Skin Care for Organ Transplant Patients Europe (SCOPE).

ITSCC has an open membership with no dues, which has encouraged rapid growth. By 2006, ITSCC had more than 260 members. Unrestricted grants from 3M Pharmaceuticals during the inception of ITSCC have permitted the organization to implement the summer retreats, offer outreach lectures, and development of a web site launched in 2003 (www.itscc.org), which features educational material for physicians and patients. A bibliography has been developed for the web site with more than 600 references. Many of these references have been compiled from the SCOPE/ITSCC membersÕ publications in journals ranging from The Lancet, New England Journal of Medicine, Archives of Dermatology, British Journal of Dermatology to a special issue of Dermatologic Surgery dedicated to skin cancer in transplant patients and published in April 2004. The web site also has PowerPoint presentations that can be downloaded to educate transplant physicians, colleagues, and patients and to use in grand rounds and patient support groups. The web site allows members to communicate

easily, and one of the most productive web-based tools has been a list serve, where members can discuss treatment and diagnostic issues. Within a few hours, diagnostic or therapeutic questions will have multiple responses from members in many countries. A patient brochure entitled ‘‘Organ Transplant Recipients – Skin Cancer Prevention’’ has been developed by ITSCC and distributed to the membership for use in educating patients. Various research projects have received support from ITSCC as well. Although problems related to transplant patients with skin disorders remain to be solved, the international multidisciplinary collaboration of interested physicians and scientists, aiming to find solutions in areas of clinical care, education, and research, has been of immeasurable help for the treatment of organ transplant recipients, as illustrated throughout this book. Future efforts of these transplant dermatology organizations will include research, clinical and translational initiatives

330

HENRY W. RANDLE

aimed at improving our understanding of and management of skin disease in solid organ transplant patients.

REFERENCES

1. Rafi A, Ghacha R, Sinha AK, Al-Khursany IAM, Al Kaltham MI. Spectrum of skin disease in renal transplant recipients. Dialysis Transplant. 2001;30:282–7. 2. Koranda FC, Dehmel EM, Kahn G, Penn I. Cutaneous complications in immunosuppressed renal homograft recipients. JAMA. 1974;229: 419–24.

3. van Zuuren EJ, Posma AN, Scholtens RE, Vermeer BJ, van der Woude FJ, Bouwes Bavinck JN. Resurfacing the back of the hand as treatment and prevention of multiple skin cancers in kidney transplant recipients. J Am Acad Dermatol. 1994;31:760–4. 4. Walder BK, Robertson MR, Jeremy D. Skin cancer and immunosuppression. Lancet. 1971;2:1282–3. 5. Berg D, Otley CC. Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and management. J Am Acad Dermatol. 2002;47:1–17. 6. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348:1681–91. 7. January 31, 2003. Editorial announcement of new organization: the International Transplant-Skin Cancer Collaborative. Dermatol Surg. 2003;29:795.

52 Research Databases for Transplant Dermatology

Jennifer Reichel, MD

in the UNOS cancer registry from 1997 to 2004 showed a cumulative incidence of 1.8% (nonpublished analysis by author). In comparison, similar studies in other countries demonstrate cumulative incidence of 2–25% at five years, and 7–33% at 10 years.[1–5] Increased education and awareness of the impact of NMSC in OTRs has and will continue to lead to improved reporting to current cancer registries. In 2005, UNOS made edits to their posttransplant malignancy data collection form (filled out by transplant coordinators, primary care providers, or specialists) to include specific variables regarding melanoma and NMSC occurrence. Establishment of new, multicenter transplant databases by clinicians and researchers in this field will further capture both organ specific and disease specific data. Also, as discussed later in this chapter, powerful analysis can also be done by linking current databases to each other, or to third party payor billing claims. This chapter will discuss general aspects of databases, specifically cancer registries, describe several established OTR related databases and review current articles that have used databases to derive information on OTRs and skin cancer.

In patients who have undergone organ transplantation, understanding causal links between exposures (risk factors), such as immunosuppression and outcomes (disease states), such as certain cancers, is vitally important for prevention, treatment, and optimization of transplantation. The fields of epidemiology and biostatistics utilize different study designs, including descriptive analyses and exposure/ outcome studies, (such as randomized trials, cohort studies, and case-control studies) for such analyses. All studies, regardless of design, rely on data. Although randomized trials involve prospective monitoring of two or more groups over time, most of our knowledge regarding disease causation comes from studies of retrospectively collected data. As such, one of the most powerful epidemiologic tools is found in the formation and continuation of well-designed databases. In 1971, the U.S. congress passed the National Cancer Act. This act mandated physicians and hospitals to collect and publish data for the treatment and prevention of cancer. Since that time, further laws have been established for mandatory reporting of cancer incidence and data to a centralized national registry through the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute (NCI). SEER currently collects and publishes cancer incidence and survival data from population-based cancer registries covering approximately 26% of the U.S. population. Specific to organ transplant recipients (OTRs), the United Network of Organ Sharing (UNOS) is the organization that administers the nationÕs Organ Procurement and Transplantation Network (OPTN) and maintains the largest database and cancer registry for solid OTRs in the United States. Unfortunately, it is difficult to perform large-scale comparative studies of skin cancer in OTRs and the general population in the United States. Melanoma is the only skin cancer with mandatory reporting to SEER. Data on melanoma is important for OTRs as melanoma incidence may be up to three times greater in OTRs than in the general population.[1] However, as discussed in previous chapters, nonmelanoma skin cancer (NMSC), particularly squamous cell carcinoma (SCC) causes significant morbidity and mortality for OTRs. Unlike in Sweden and Australia, where all NMSCs are reportable, the overall incidence of SCC and BCC in the United States is hard to establish because reporting is not mandatory. Most reports are from small, single-center studies. Even in the organ transplant population, skin cancer rates are vastly underreported. An analysis of 45,647 renal transplant patients

D A TA B A SE S IN GEN E R A L A database is an information storage system used to collect, manage, and analyze data for a specific population of people. In the design stage, the scope must be broad enough to answer questions that may come up in the future, but should also be directed toward answering a few key current questions. Most transplant databases, and particularly transplant cancer registries, include recipient demographic and medical history, donor characteristics, posttransplant immunosuppression, patient and graft survival, and other variables that track ongoing surveillance and possible confounding factors (i.e., tobacco use). Cancer specific registries also include information on pre- and posttransplant tumors such as primary site, cell type, extent of disease, and outcomes. Development of a good database should involve the primary researchers, persons with epidemiology and biostatistics background, and technical experts. For all clinical databases, the usefulness correlates directly with the quality of the collected data. Quality assurance depends on setting clear objectives, developing a user-friendly and error-free system for data collection and storage, and continuing input of complete, accurate, and reliable data.[6–9] 331

11,239

15,500

Prospective study, current enrollment not available

1969

1987

1995

Israel Penn International Transplant Tumor Registry

North American Pediatric Renal Transplant Cooperative Study of Pediatric Liver Transplantation

n/a

1.5 million living/ deceased, 400,000 living (2002)

n/a

Scientific Registry of Transplant Recipients

260,000 (2004)

Subject Number

United States Renal Data System

1986

Year Established

United Network of Organ Sharing

United States

DATABASE

Designs/carries out analysis of OPTN data End stage renal disease registry for US, mandated by Congress, NIH contracted to oversee access to care, cost, morbidity, mortality, quality of care and treatment. Reports to congress and NIH The registryÕs goal is to provide scientific data to allow optimal treatment and prevention of cancer in transplant patients Track all pediatric renal transplants (under 21) in US and Canada Track children s/p liver tx and those awaiting liver tx in US and Canada.

Track all Solid OTR

Main Objective

Table 52.1 Databases Relevant to Transplant Dermatology, General Information

All pediatric liver txs from participating centers

All consecutive pediatric renal txs

All tx patients with post-tx malignancies

All patients with ESRD (pre/post transplant) in US

All OPTN Solid OTRs

All Solid OTR/USA/ National

Patient Population/ Country/Center

No

No

Yes, thought to be most accurate and robust of all US databases. Not population-based.

Not in USRDS database Skin cancer data analysis done by link to Medicare claims data9

Yes, Melanoma and Non-Melanoma Skin Ca As above

Skin Specific Variables

web.emmes.com/study/ lvr/ 412-692-kids Dr Mazariegos

web.emmes.com/study/ ped/

www.ipittr.uc.edu

www.usrds.org

www.ustransplants.org

www.unos.org

Contact/Website

332 JENNIFER REICHEL

Australian/New Zealand ANZData

European Liver Transplant Registry Italian Group for Epidemiological Research in Dermatology (GISED)

Europe SCOPE

40,968

1400

1990

1977

57,665

?

>600

1985

2000

1997

4094

1986

Hepatitis C Recurrent Disease Registry

72,000

1968

International Registry for Heart and Lung Transplants Renal Allograft Disease Registry

1600 recipients and 2400 pregnancies

1991

National Transplantation Pregnancy Registry

Collect statistics related to outcome of treatment of ESRD in Australia and New Zealand

Collect comprehensive epidemiologic data on skin disease in OTRs Link Transplant Centers in Europe Track major cutaneous complications in renal and heart txs

Track heart, lung, heart+lung OTRs worldwide Track pre and post tx immunologic, metabolic disease and to establish a prototype for a comprehensive data base of recurrent disease Track pts with recurrent HCV after liver tx.

Track outcomes of pregnancies in female OTRs and those fathered by male OTRs

All consecutive renal tx/ Australia, New Zealand

113 European centers, 23 countries Kidney/heart tx pts/Italy/ multi-center

European tx pts/ specialized derm clinics

Liver tx pts reported on by 15 centers/USA, Mt Sinai Medical Center

14 States/USA/Headed by Medical College of Wisconsin

All female OTRs in US with pregnancy post tx. Infants of male OTRs/USA/Temple Univ

Yes, time to first skin cancer pre/post tx, incidence of mets/ death

Yes, all post-tx skin cancer

No

Yes

http://www.anzdata. org.au/ANZDATA/ anzdatawelcome.htm

www.gised.it

www.eltr.org

www.scopnetwork.org

www.centerspan.org/ registries/hepc.htm

www.centerspan.org/ registries/rardr.htm

No

No

www.ishlt.org/registries/ heartLungRegistry.asp

www.tju.edu/ntpr www.temple.edu/ NTPR

Yes

No

RESEARCH DATABASES FOR TRANSPLANT DERMATOLOGY

333

Renal transplant centers

Liver transplant centers

V

V

Australian/New Zealand ANZData

European Liver Transplant Registry Italian Group for Epidemiological Research in Dermatology (GISED)

Europe SCOPE

V

Renal Allograft Disease Registry Hepatitis C Recurrent Disease Registry

V, report 100%

All transplant centers Australia, New Zealand, data collected annually

Physicians, biologists

V

V

Specialized dermatology transplant clinics Transplant Centers

V

V

Data ‘‘entry personnel’’ sharing with UNOS, Eurotransplant, and UK transplant

V

International Registry for Heart and Lung Transplants

Specific centers, uncertain if still collecting data Specific centers, uncertain if still collecting data

Transplant centers, private physicians

V

V

C

V

Source of Data Entry

Transplant Coordinators at Transplant Centers, data collected at tx, 6 mo post-tx, yearly Arbor Research Collaborative of Health UNOS data and CMS Medicare claims collected yearly, dialysis treatment center information collected twice a year Transplantation centers, transplant physicians

C

Voluntary/ Compulsory

National Transplantation Pregnancy Registry

Israel Penn International Transplant Tumor Registry North American Pediatric Renal Transplant Cooperative Study of Pediatric Liver Transplantation

Scientific Registry of Transplant Recipients United States Renal Data System

United States United Network of Organ Sharing

DATABASE

Yes

Yes, reliability audit 2003 (see ref 8) Yes

?

Not found

Accuracy analysis with regular (annual) auditing of data submissions will began in 2004 Not found

?

Yes

Yes

Yes

OPTN semi-annual analysis, SRTR analysis checks all data so that it agrees amongst the multiple sources

OPTN semi-annual analysis, SRTR analysis

Internal Quality Monitor

Table 52.2 Databases Relevant to Transplant Dermatology: Data Validity and Availability

Novartis, Amgen, Janssen Cilag, Fresenius, Baxter, Roce, Wyeth

Novartis, Fujisawa, Roche No

Yes

Ortho Biotech

No

Astellas Pharma US Roche Pharmaceuticals MedImmune, Inc. Novartis Novartis, Fujisawa healthcare, Roche, Wyeth-Ayerst. No

?

Fujisawa, Roche, Novartis, Wyeth, MedImmune

Yes

Yes, must meet specific guidelines Yes

?

No

Yes, see website

Yes, see website Yes

Yes

No

Yes

Yes

Yes

No

Yes

Yes

No

No

Yes

Yes

Yes

Yes

Yes, see website

Access to Publications?

?

Yes

Yes

?

No

Yes, supplies statistics, data analysis, custom data sets Yes

Access to Data?

No

Industry Sponsorship

334 JENNIFER REICHEL

RESEARCH DATABASES FOR TRANSPLANT DERMATOLOGY

CURRENT DATABASES Table 52.1 and Table 52.2 contain information on many of the national and international databases. The information was collected by members of the International Transplant Skin Cancer Collaborative (ITSCC) Database Committee [10] through web site searches, article research, and direct contact with the individual organizations. Members of the database committee designed and administered a questionnaire to each organizational contact. The questionnaire addressed general information, database design, data availability, and data validity. The intent was to establish a working collaborative relationship with the organizations that maintain OTR related databases. Table 52.1 contains general information on the populations of each database, their main objectives, whether they contain skin-related variables, and contact information. Table 52.2 focuses on validity and access of each database. Although most U.S. databases were not designed with skin conditions in mind, several contain skin cancer variables. Many of the organizations are willing to share their data and some will formulate specifically requested data sets.

335

ciated with a 35% lower incidence of skin cancer, whereas azathioprine was associated with a 17% higher incidence (p = 0.04). These statistics were determined for each medication by comparing all patients on that particular medication at discharge to all patients not on that medication (private correspondence with author). Although the authors acknowledge that bias exists and that only a randomized trial could determine effects of immunosuppressive drugs on outcome, the linking of data from two robust sources enabled an analysis that would have been otherwise impossible. As organizations such as the International Transplant Skin Cancer Collaborative (ITSCC) and Skin Care in Organ Transplant Patients Europe (SCOPE) are working to increase awareness of skin disease in OTRs, national and international transplantation organizations continue to improve reporting of skin-related variables to their registries. Additionally, new dermatology-specific databases are forming. The use of these registries to report on risk factors, treatment outcomes, and disease statistics will continue to rise.

REFERENCES

A R T I C L E RE V I E W Multiple studies have used transplant and cancer registries to derive important statistics on skin cancer rates and risk factors in OTRs. In 2000, Naldi et al. used data from the Italian renal transplant registry and the Italian cancer registry to determine the overall incidence of NMSC in kidney OTRs (10 cases per 1000 post-transplant person years).[2] The overall risk of developing skin cancer increased from a cumulative incidence of 5.8% after 5 posttransplant years to an incidence of 10.8% after 10 years of graft survival. They analyzed data on NMSC in the general population to estimate the standard mortality ratio (SMR). This is the ratio of the number of events in the study group to the number that would be expected if the study population had the same specific rates as a standard reference population. An SMR of 1 indicates no difference between groups. The SMR for NMSC was 1392 for male kidney OTRs, indicating that NMSC is dramatically more prevalent in this population. In 2004, Kasiske et al. performed an analysis of renal transplant recipients in the United States, and demonstrated the power of linking database information. By examining rates of malignancies among kidney transplantations in 1995–2001 (n = 35,765) using Medicare billing claims linked to data from the USRDS,[9] they showed that NMSC rates were 20-fold that of the general population. Additionally, they looked at immunosuppressive medications at discharge from hospital posttransplant, and found that tacrolimus was asso-

1. Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40(2 Pt 1): 177–86. 2. Naldi L, Fortina AB, Lovati S, et al. Risk of nonmelanoma skin cancer in Italian organ transplant recipients. A registry-based study. Transplantation. 2000;70(10):1479–84. 3. Harden PN, Fryer AA, Reece S, et al. Annual incidence and predicted risk of nonmelanoma skin cancer in renal transplant recipients, Transplant Proc 2001;33:1302–4. 4. Carroll RP, Ramsey HM, Fryer A, et al. Incidence and prediction of nonmelanoma skin cancer post-renal transplantation: a prospective study in Queensland, Australia. Am J Kidney Dis 2003;41: 676–83. 5. Bouwes Bavinck JN, Hardie DR, Green A, et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia. A follow-up study. Transplantation. Mar 15 1996;61(5):715–21. 6. Van der Meulen JHP, Jacob M, Copley L. Assessing the Quality of the Data in a Transplant Registry: The European Liver Transplant Registry. Transplantation 2003;75(12):2164–7. 7. Hanto DW. Reliability of Voluntary and Compulsory Database and Registries in the United States. Transplantation. 2003;75:2162–64. 8. Karam V, Gunson B, Roggen R, et al. Quality Control of the European Liver Transplant Registry: Results of Audit Visits to the Contributing Centers, Transplantation 2003;75(12):2167–73. 9. Kasiske B, Snyder J, Gilbertson D et al. Cancer after Kidney Transplantation in the United States. Am J Transplant 2004;4: 905–13. 10. ITSCC Database Working group: OÕReilly F, Pacheco T, Christenson L, Randle H, Lindelof B, Shumack S, Leigeois-Kwon N, Munavalli G, Proby C, Nico J, Naldi L, Reichel J. Additional database collection by Weber, M.

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of ITSCC conduct substantial ongoing clinical, translational, and basic research on many topics in the field of transplant dermatology. Organizations interested in having an ITSCC member speak on the topic at a meeting are welcome to contact ITSCC for a list of possible speakers.

As the field of transplant dermatology grows, the number and sophistication of resources available for both patients and professionals continue to expand. Fortunately, many of these resources exist in publicly accessible digital format that allows for repeated and easy access for patients and providers alike. This chapter attempts to provide an annotated list of resources for patients and health professionals, focusing on sources that are from national and international societies and collaboratives rather than those from individual medical centers. This list is not intended to be exhaustive nor does inclusion imply that all information within these sites is current or accurate. Because medical decisions in transplant patients are often complex, consultation with specialists in transplant dermatology may optimize the customization of care for patients.

Skin Care in Organ Transplant Patients Europe (SCOPE) Web site: www.scopnetwork.org Contact via web site. Skin Care in Organ Transplant Patients Europe is an interdisciplinary network of transplant dermatologists, transplant physicians, and researchers that has as its mission: l

l

PR OFES SIONAL RE SO URCES

l

International Transplant Skin Cancer Collaborative (ITSCC) Web site: www.ITSCC.org Contact via web site. The International Transplant Skin Cancer Collaborative is a nonprofit collaborative of transplant dermatologists, transplant physicians and surgeons, transplant coordinators and nurses, basic, translational and clinical researchers, oncologists, surgeons, and other health care providers that has as its mission:

l

l

l

Standardize and collect epidemiological data on skin diseases in organ transplant patients Establish a consensus for prophylaxis and therapy of NMSC and skin infections in organ transplant recipients Define further fields of common research interests (i.e. novel therapeutic options) Extension of surveillance and knowledge on skin disease in organ transplanted patients.

SCOPE, in conjunction with its international sister organization, ITSCC, has been a leader in efforts to reduce the problem of skin cancer and skin disease in organ transplant patients. SCOPEÕs efforts have included collaborative epidemiological research efforts, basic science experimentation, and patient and professional education. The SCOPE web site lists the centers for transplant dermatology in Europe. The website provides extensive information for medical professionals and patients alike.

To integrate and support basic scientific and clinical research to address the special needs of transplant recipients with skin cancer in order to improve quality of care. To educate patients, scientists, primary care doctors and specialist physicians on the unique needs and clinical care issues in the transplant patients.

After Transplantation – Reduce Incidence of Skin Cancer Alliance (AT-RISC) Web site: www.AT-RISC.org Contact via web site. The After Transplantation-Reduce Incidence of Skin Cancer (AT-RISC) Alliance is a multidisciplinary collaborative comprising the International Transplant Skin Cancer Collaborative (ITSCC), the International Transplant Nurses Society (ITNS), and Transplant Recipients International Organization (TRIO) aimed at reducing the burden of skin cancer in transplant patients through an educational initiative targeted toward transplant providers and patients. The alliance is implementing a major educational campaign to enhance awareness of the problem and encourage preventative strategies to alleviate the difficulties in 2006. The alliance web site

ITSCC, along with its sister organization in Europe (SCOPE), has led efforts to lessen the burden of skin cancer and skin disease in solid organ transplant recipients. The ITSCC web site provides detailed information on skin cancer recognition, diagnosis, management, and prevention. The web site also provides a searchable database of scientific references on issues related to transplant dermatology. Additionally, ITSCC can provide the names of transplant dermatology specialists for consultation regarding clinical care. The members 336

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contains extensive educational material for providers and patients, all provided in downloadable form and free for use by all. Downloadable brochures, posters, lectures, and transplant manual inserts are available and as well as an online atlas of skin tumors. The alliance has created a unique AT-RISC Train the Trainer program for transplant coordinators and nurses who are interested in becoming Skin Cancer Experts.

International Transplant Nurses Society Web site: www.ITNS.org Contact via web site. The International Transplant Nurses Society is dedicated to advancing all aspects of nursing care for transplant patients and their families. As a key collaborator in the After Transplantation – Reduce Incidence of Skin Cancer (AT-RISC) Alliance, ITNS members serve as key educators in the educational efforts to prevent skin cancer in transplant patients. ITNS members have created transplant manual inserts on skin cancer and a select group of Skin Cancer Experts have participated in the AT-RISC Train the Trainer Skin Cancer Expert program, which aims to empower nurses to educate colleagues in their communities regard the problem of skin disease in organ transplant patients. United Network for Organ Sharing Web site: www.UNOS.org Contact via web site. The United Network for Organ Sharing (UNOS) is a nonprofit, scientific and educational organization that administers the Organ Procurement and Transplantation Network (OPTN) in the United States. The mission of UNOS is to advance organ availability and transplantation by uniting and supporting our communities for the benefit of patients through education, technology, and policy development. The UNOS community includes surgeons, physicians, nurses, technicians, and other professionals who specialize in donation and transplantation; transplant candidates and recipients; organ donors and their families. The UNOS database and the UNOS Transplant Tumor Database are publicly accessible databases with a wealth of information on transplantation as well as cancer in transplant patients. The UNOS web site provides searchable capabilities. American College of Mohs Micrographic Surgery and Cutaneous Oncology Web site: www.mohscollege.org Contact via web site. The American College of Mohs Micrographic Surgery and Cutaneous Oncology is the organization dedicated to advancing knowledge about and care of skin cancer through the use of Mohs Micrographic Surgery, the most advanced technique available for complete removal of high-risk skin cancers. The Mohs technique is practiced around the world and offers up to 99% cure rates for skin cancer while sparing normal uninvolved skin. Mohs surgeons are at the fore-

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front of caring for transplant patients with severe skin cancer. The Mohs College website can assist in locating Mohs surgeons who have the specialized credentials of having completed 1 to 2 years of formal approved fellowship training in Mohs surgery after completing a full residency in dermatology.

American Society of Transplantation Web site: www.a-s-t.org Contact via web site. The American Society of Transplantation is a resource for professionals involved in organ transplantation. The AST is a major leader in the field of transplantation and has collaborated with the ITSCC on skin cancer education. American Society of Transplant Surgeons Web site: www.asts.org Contact via web site. The American Society of Transplant Surgeons is a professional society focused on the advancement of surgical care of transplant patients. The ASTS has collaborated with the ITSCC on educational efforts. The Transplantation Society Web site: www.transplantation-soc.org Contact via web site. The Transplantation Society is an international forum for the worldwide advancement of organ transplantation. CenterSpan Web site: www.centerspan.org Contact via website. CenterSpan is an informational web site sponsored by the American Society of Transplant Surgeons with professional and patient information. American Cancer Society Web site: www.cancer.org Contact via web site. The American Cancer Society is an excellent resource for information on skin cancer, with dedicated skin cancer information available on their web site. The Cancer Council Australia Web site: www.cancer.org.au Contact via web site. The Cancer Council Australia has been a leader in developing preventative education programs and sun protection programs on a national basis in Australia. The Cancer Council also conducts research on skin cancer trends in Australia, the most heavily affected country in the world. American Academy of Dermatology Web site: www.aad.org Contact via web site. The American Academy of Dermatology is the largest professional organization of dermatologists in the world

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and conducts extensive skin cancer education and prevention programs, along with free skin cancer screenings. Patient brochures on skin cancer are available through the AAD.

British Association of Dermatologists Web site: www.bad.org.uk/public/leaflets/transplant Contact via web site. The British Association of Dermatologists web site has patient brochures for transplant patients to learn about early diagnosis, treatment, and prevention of skin cancer. The Skin Cancer Foundation Web site: www.skincancer.org Contact via web site. The Skin Cancer Foundation is a nonprofit foundation focused on public education about skin cancer as well as research and disease prevention. Center for Disease Control Web site: www.cdc.gov Contact via web site. The Centers for Disease Control collects health care information on all diseases in the United States. Educational material regarding skin cancer is available on their web site. National Cancer Institute Web site: www.cancer.gov Contact via web site. The National Cancer Institute is the branch of the National Institute of Health, the major public funding source for medical research in the United States. The NCI web site has skin cancer education materials. Post-transplant Skin Cancer Research Group at The Ohio State University Web site: http://digitalunion.osu.edu/r2rsummer05/ali.95 Contact via web site. Researchers at the Ohio State University are dedicated to basic scientific research on the topic of transplant related skin cancer. Using mouse models of accelerated carcinogenesis, they are trying to unravel the complex factors contributing to the problem. Collaboration is welcomed. Transplant Skin Cancer Database and Tissue Bank at University of California San Francisco Web site: www.dermatology.ucsf.edu/skincancer/transplant Contact via web site. Under the direction of Erv Epstein, MD, the University of California San Francisco transplant skin cancer database and tissue bank is a National Institute of Health-funded program project grant collecting biospecimens and data aimed at determining the scientific basis of accelerated skin cancer in subsets of transplant patients. Collaboration is welcomed.

PATIE NT RES OURCES After Transplantation – Reduce Incidence of Skin Cancer Alliance (AT-RISC) Web site: www.AT-RISC.org Contact via web site. The After Transplantation-Reduce Incidence of Skin Cancer (AT-RISC) Alliance is a multidisciplinary collaborative comprising the International Transplant Skin Cancer Collaborative (ITSCC), the International Transplant Nurses Society (ITNS), and Transplant Recipients International Organization (TRIO) aimed at reducing the burden of skin cancer in transplant patients through an educational initiative targeted toward transplant providers and patients. The alliance web site contains extensive educational material for providers and patients, all provided in downloadable form and free for use by all. Downloadable brochures, posters, lectures, and transplant manual inserts are available and as well as an online atlas of skin tumors. Transplant Recipients International Organization (TRIO) Website: www.trioweb.org Contact via website. TRIO is an independent, not-for-profit, international organization committed to improving the quality of life of transplant candidates, recipients, their families and the families of organ and tissue donors. Through the TRIO Headquarters and a network of chapters, TRIO serves its members in the areas of: awareness, support, education, and advocacy. TRIO is a primary collaborator in the AT-RISC Alliance and Initiative. International Transplant Skin Cancer Collaborative (ITSCC) Web site: www.ITSCC.org Contact via web site. The ITSCC is a nonprofit collaborative of transplant dermatologists, transplant physicians and surgeons, transplant coordinators and nurses, basic, translational and clinical researchers, oncologists, surgeons and other health care providers. The ITSCC web site provides detailed information on skin cancer recognition, diagnosis, management, and prevention. The ITSCC web site also provides a searchable database of scientific references on issues related to transplant dermatology. Organizations interested in having an ITSCC member speak on the topic at a meeting are welcome to contact ITSCC for a list of possible speakers. Skin Care in Organ Transplant Patients Europe (SCOPE) Web site: www.scopenetwork.org Contact via web site. SCOPE is an interdisciplinary network of transplant dermatologists, transplant physicians, and researchers. The SCOPE web site lists the centers for transplant dermatology in Europe. The web site provides extensive information for medical professionals and patients alike.

RESOURCES FOR TRANSPLANT DERMATOLOGY

International Transplant Nurses Society Web site: www.ITNS.org Contact via web site. The ITNS is dedicated to advancing all aspects of nursing care for transplant patients and their families. As a key collaborator in the After Transplantation – Reduce Incidence of Skin Cancer (AT-RISC) Alliance, ITNS members serve as key educators in the educational efforts to prevent skin can-

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cer in transplant patients. ITNS members have created a brochure about skin cancer in transplant recipients and transplant manual inserts on skin cancer. A select group of ITNS members have participated in the AT-RISC Train the Trainer Skin Cancer Expert program, which aims to empower nurses to educate colleagues and patients in their communities regard the problem of skin disease in organ transplant patients.

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Index

accelerated atherosclerosis, 25 accessory pathways, 34 acitretin, 123, 165, 272, 273, 275 for AK, 165 for BCC/SCC, 170, 226 dosage recommendations, 179, 221, 275 for in-transit metastases, 226 for NMSC, 213 in renal-transplant recipients, 272, 273 side effects, 273–275 acne folliculitis, 74 clinical presentation, 74 mechanism, 74 from sirolimus, 74 treatment, 74 Acremonium, 91–92 actinic cheilitis clinical presentation, 238 incidence of, 238 management of, 238–239 prevention of, 240 risk factors, 238 treatment of, 238–239 actinic keratosis (AK), 147 see also hypertrophic actinic keratosis; transplant scalp clinical presentation of, 163 dosing schedule, 287 due to heart transplantation, 147 histopathologic features, 208 incidence of, 162–163 management of, 163–165, 174 liquid nitrogen therapy, 164 photodynamic therapy, 164 systemic retinoids, 165 topical 5-fluorouracil cream, 164 pathogenesis of, 162 and PDT, 291–292 prevention of, 165 treatment options acitretin, 165 advantages/disadvantages, 164, 278 cryotherapy, 277 diclofenac, 280–282 imiquimod cream, 164–165, 286–287 topical 5-Fluorouracil, 277–280 topical retinoids, 282–283 acyclovir for HSV infections, 98 for PTLD, 201

for VZV, 100 adaptive immunity, 56 adhesion proteins cellular inflammation orchestration, 31 P-selectin, 31 adulthood, and disease rates, 25 aerobic actinomycete, and nocardiosis, 87 After Transplant-Reduce the Incidence of Skin Cancer (AT-RISC) Alliance, 5, 328, 336–337, 338 AFX. See atypical fibroxanthoma (AFX) AK. See actinic keratosis (AK) alemtuzumab (anti-CD52 antibody)(Campath-IH), 13, 17–18 allogenic solid organ transplantation, 9 allografts allograft-specific considerations, 40 immunogenicity of in end organ kidney disease, 41 in end organ liver disease, 42 alopecia, drug-induced, 72 from TAC clinical presentation, 72 mechanism, 72 prevention, 72 treatment, 72 alopecia areata (AA), 113 see also androgenetic alopecia and cyclosporine, 114 response to immunosuppressive medications, 113 risk factors, 72 Alternaria alternata species, 62 and fungal skin infections, 90 and phaeohyphomycosis, 90 alternative therapies for end organ kidney disease, 40 for end organ pancreas disease, 44 for NSF, 117 for VIN/AGIN, 129–130 American Academy of Dermatology, 4, 328, 337 American Cancer Society, 337 American College of Mohs Micrographic Surgery and Cutaneous Oncology (ACMMSCO), 4, 328, 337 American Society of Dermatologic Surgery (ASDS), 4, 328 American Society of Transplant Surgeons (ASTS), 328, 337

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American Society of Transplantation (AST), 337 aminoglycosides, for M. tuberculosis, 108 aminolevulinic acid (ALA), 164, 291, 292 amphotericin B for central nervous system infection, 92 for phaeohyphomycoses, 91 for Zygomycetes spp., 90 amyloidosis, and NSF, 116 anal canal intraepithelial neoplasia (AIN), 128 anal cancer, 128, 142 anal neoplasia, 128–129 androgenetic alopecia, 234 anesthesia, 9, 250, 252, 292 angioproliferative lesions, 86 angiosarcoma, 196, 205–206, 208, 259 anogenital cutaneous disease anal/cervical neoplasia, 128–129 condylomata acuminata, 128 vulval neoplasia, 128–129 anogenital intraepithelial neoplasia (AGIN) alternative therapies, 129–130 lesions of, 129 treatment of, 129 anogenital squamous cell carcinoma, 151 anti-CD52 antibody (alemtuzumab), 13 anti-CD3 antibody (OKT3), 13 anti-interleukin-2 Receptor (CD25) antibodies. See basiliximab; daclizumab antibiotics, perioperative, 63, 84 antibody effector functions, 35–36 antiendothelial cell antibodies, 36 antilymphocyte antibodies, 17 antimetabolites, 73–76 azathioprine, 10, 13, 15 mycophenolate mofetil, 73 sirolimus, 16–17, 73–76 antimicrobial agents, 46, 60 antiproliferative agents. See azathioprine (AZA); mycophenolate mofetil (MMF) antirejection therapy. See alemtuzumab; azathioprine; basiliximab; biological agents; corticosteroids; cyclosporine; daclizumab; mammalian target of rapamycin (mTOR) inhibitors; mycophenolate mofetil; OKT3;

342

sirolimus; tacrolimus; Thymoglobulin antithymocyte antibodies, 17 appendageal tumors, 122–124 sebaceous gland hyperplasia, 123 Aspergillus species, 62, 89–90 assessments of HRQOL, 312 of organ transplant candidates, 304 AST. See American Society of Transplantation (AST) ASTS. See American Society of Transplant Surgeons (ASTS) AT-RISC (After Transplantation-Reduce Incidence of Skin Cancer) Alliance Initiative, 328, 336–337 atherosclerosis, accelerated, 25 atopic eczema (AE), 113–114 in adults, 114 in infants, 113 atypical fibroxanthoma (AFX), 11, 144, 203 clinical presentation, 157–158 excisional biopsy for, 158 as pretransplantation consideration, 306 atypical mycobacteria, 62 Australia incidence of NMSCs, 137, 172 incidence of SCC, 142 living donor transplantation data, 25 azathioprine (AZA), 10, 13, 15 and BCC, 167 carcinogenic in renal transplants, 138 and prednisone combination, 3, 10, 73 skin cancer, relative effects, 77 and TPMT gene, 139 and UVR, 138 azithromycin, for MAC, 108 B-cell antigen receptors (BCR), 35 B-cells antibody/complement axis, 35–36 APC function, 35 differentiation from T-cells, 35 differentiation program, 35 proliferation/genetic rearrangement of BCR/antibody-encoding genes, 35 tolerance, 37 bacillary angiomatosis (BA), 86–87 bacterial skin infections, 84 bacillary angiomatosis, 86–87 beta-hemolytic streptococcus, 84–85 Group A, Streptococcus pyogenes, 84 Group B, 84 gram-negative bacilli, 85–86 B. henselae, 86 B. quintana, 86 Bartonella, 86 Enterobacter, 86 Escherichia coli, 85 Klebsielleae pneumonia, 86 Proteus mirabilis, 86 Pseudomonas aeruginosa, 86 nocardiosis, 87 Staphylococcus aureus, 62, 83–84

INDEX

Vibrio vulnificus, 86 Barnard, Christian, 9, 39 Bart’s and London NHS Trust, 122, 228 basal cell carcinoma (BCC), 3, 11, 137 biopsy confirmation of, 150 clinical features, 168–169 clinical behavior, 168–169 demographics, 168 latent period, 168 location/distribution, 168 morphology, 168 clinical presentation, 148–149 clinicopathological variants nodular BCC, 147 superficial BCC, 147 cumulative incidence, 167 due to AZA/CYA, 167 epidemiology of, 143 in heart transplant recipients, 168 histopathologic features, 211–212 pathogenesis, 167 age at transplantation, 167 HPV, 167 immunosuppression, 167 pretransplant skin cancers, 167 UV exposure, 167 posttransplantation, risk of multiple de novo NMSC, 303–304 pretransplantation, risk of recurrence/ death, 303 prevention photoprotection, 170 retinoids, 170 ratio to SCC, 143, 147, 168 risks factors/ratios, 167 treatment options, 169–170 acitretin, 170 analysis/advantages-disadvantages, 170 cryotherapy, 169 curettage, 170 imiquimod, 287–288 PDT, 170 radiotherapy, 170, 258–259 topical immunomodulators, 170 basiliximab, 13, 18 for renal transplant immunosuppression, 41 selective T cell activation, 132 BCC. See basal cell carcinoma (BCC) benign cutaneous neoplasms, 123 appendageal tumors, 122–124 sebaceous gland hyperplasia, 123 keratinocyte tumors epidermoid cysts, 122 seborrheic keratoses, 122 squamous cell papillomas/verrucal keratoses, 122 soft-tissue tumors, 124–126 Bergner Physical Appearance Scale, 312 beta-hemolytic streptococcus Group A, Streptococcus pyogenes, 84 Group B, 84 Billingham, R. E., 36

biochemotherapy, for metastatic MM, 231 biological agents, 17 monoclonal antibody preparations, 13 polyclonal antibody preparations, 13 biopsies. See also sentinel lymph node biopsy (SLNB); skin biopsy for keratoacanthomas, 152 for MM, 154 for SCC, 152, 174 techniques of, 150 for transplant scalp, 235 Bipolaris, and phaeohyphomycosis, 90 Blastomyces dermatitidis, 62 bleomycin for in-transit metastases, 225–226 injections for condyloma acuminatum, 104 for verruca vulgaris, 104 for KS, 197 for SCC, 177 blockades, costimulatory, 37 blood group antigens, 36 bone-marrow-derived cell populations, 31 bone marrow transplantation and genital viral warts, 128 and GVHD, 131 and psoriasis, 115 and PTLD, 155, 199 Bowenoid Papulosis, 129 Bowen’s disease, 119, 151, 204 and PDT, 170, 291–292 and SCC, 210 British Association of Dermatologists, 338 cadaver transplants, 3, 16 see also deceased donor tramsplants calcineurin inhibitors (CNI), 10, 13, 70–72 see also cyclosporine (CYA); tacrolimus (TAC) blocking of apoptosis, 138 immunosuppressive regimen basis, 41, 268, 269 inhibition antidonor effector T-cells/T-regs, 37 of IL-2, 182 for management of GVHD, 132 of post-transplant KS, 197–198 and metastatic MM, 230 monitoring of blood levels, 15 and mTOR combination, 16 and posttransplant malignancy, 11 side effects, 70–72 toxicities of, 16 calciphylaxis, differential diagnosis from NSF, 116 calcipotriene, for NSF, 117 Campath-IH. See alemtuzumab Cancer Council Australia, 337 cancer susceptibility genes, 139 Candida albicans, 88 Candida glabrata, 89 Candida infections, 46 esophagitis, 89

INDEX

folliculitis, 89 mucocutaneous, and fluconazole, 95 skin folds/nails/paronychial region, 89 vulvovaginitis, 89 Candida krusei, 89 Candida parapsilosis, 89 Candida species, 62 Candida tropicalis, 89 candidates, for organ transplants evaluation of, with skin cancer history, 302–303 liver transplantation, 107 renal transplantation, 40–41 suggested assessments, 304 carboplatin for MCC, 192, 258 for metastatic SCC, 220 carcinopermissiveness, of regimens, 43 in end organ heart/lung disease, 43 in end organ kidney disease, 41 in end organ liver disease, 42 Carrel, Alexis, 9 CD 4 positive T-cells, 32, 34, 37 apoptotic cell death, 34 helper functions of, 34 interface with mature APC, 33 CD 8 positive T-cells, 32, 34 apoptotic cell death, 34 helper functions of, 34 CD152/B7 accessory pathway, 34 CD28/B7 blockade, 37 CD40/CD154(CD40L) accessory pathway, 34 CD40/40L blockade, 37 CD137(41BB)/41BBL accessory pathway, 34 CDKN2a/P16, and SCC, 53–54 cellulitis/necrotizing cellulitis, 83, 85, 90 Gram-negative cellulitis, 85 and granulocytopenia, 62 and P. aeruginosa, 62 and S. aureus, 83–84 SRL treatment, 74 Center for Disease Control, 338 CenterSpan website, 337 central T-cell tolerance, 36 cervical cancer and CYA, 263 HPV association, 128, 139 cervical neoplasia, 128–129 cervix intraepithelial neoplasia (CIN), 128 chemical peel for AK, 165 for later stage striae, 70 for SCC/SCC in situ, 178 for sebaceous hyperplasia, 71 for transplant scalp, 234 chemokines cellular inflammation orchestration, 31 monocyte chemotactic peptide 1, 31 and PDT, 293 chemotherapy. See also biochemotherapy for in-transit metastatic SCC, 225 for Kaposi’s sarcoma, 99, 102, 197 for Merkel cell carcinoma, 192, 258 for metastatic malignant melanoma, 230

for metastatic SCC, 220 for PK, 119 for porokeratosis, 119 for PTLD, 202 for squamous cell carcinoma, 176–177 chorioretinitis, CMV causation, 101 chronic/recurrent HZ, 99, 100 cidofovir for acyclovir-resistant HSV, 99 for HHV8, 197 Cincinnati Transplant Tumor Registry, 79 see also Israel Penn International Transplant Tumor Registry cisplatin for metastatic SCC, 220 in multiagent regimens, 177 Cladosporium, 90, 94 clarithromycin, 108 clindamycin, for necrotizing fascitis, 85 clinical presentation of acne folliculitis, 74 of actinic cheilitis, 238 of AFX, 157–158 of AK, 163 of BCC, 148–149 of cutaneous fragility and ecchymosis, 70 of edema, from SRL, 75 of exogenous Cushing’s syndrome, 67 of gingival hyperplasia, from CYA, 71 of GVHD, 131–132 of hirsutism, from CYA, 70–71 of impaired wound healing, from SRL, 73–74 of in-transit metastatic SCC, 224 of MCC, 191 of metastatic SCC, 218–219 of MM, 183–184 of PDT, 291–292 of PTLD, 200 of SCC, 150, 173 of sebaceous hyperplasia, from CYA, 71 of steroid acne, 69 of striae, 69 of transplant hands, 242 clinics. See transplant dermatology, clinics Coccidioides immitis, 62 coccidioidomycosis, 92 cocktail approach, to immunosuppressive therapy, 10 cognate cellular immunity dendritic cell/T-cell axis, 32–35 MHC/antigen presentation to T-cells, 32–33 T-cell costimulation, 33–34 T-cell differentiation, effector function and memory, 34–35 cognate humoral immunity B-cell/antibody/complement axis, 35–36 antibody effector functions, 35–36 natural antibodies, 35 primary B-cell responses/B-cell memory, 35 colitis, CMV causation, 101 computed tomography

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for head/neck lymphadenopathy evaluation, 249 for Kaposi’s sarcoma, 196 condyloma acuminatum (genital warts), 55, 104, 128 from HPV, 98, 103, 128 and imiquimod, 286 quality of life impact, 317 consensus conferences, 49 Cooley, Denton, 10 corticosteroids, 13 see also prednisone beneficial/adverse effects, 14 dexamethasone, 13, 14 methylprednisolone, 13, 14, 131 and non-Hodgkin lymphoma, 138 oral, and NMSC, 138 prednisolone, 13, 14, 77, 132 Cosmas/Damian (patron saints of transplantation), 9 costimulatory blockade, 37 cryotherapy for actinic cheilitis, 238 for actinic keratosis, 277 for BCC, 169 for condyloma acuminatum, 104 keratinocyte damage from, 234 for primary lip SCCs, 239 for SCC, 175, 249 for transplant scalp, 234 for verruca vulgaris, 103, 104 Cryptococcus neoformans, 62, 90 curettage for BCC, 170 for keratinocyte tumors, 122 for SCC, 178, 249 for transplant scalp, 234 Curvularia, 90, 94 cutaneous carcinogenesis, 53 cutaneous fragility and ecchymosis, 70 clinical presentation, 70 mechanism, 70 prevention, 70 treatment, 70 cyclophosphamide, for NSF, 117 cyclosporine, ISA247 (synthetic analog), 16 cyclosporine (CYA), 13, 15–16, 57 and alopecia areata, 113, 114 antiproliferative effects of, 57 and BCC, 167 and epidermoid cysts, 122 and growth factor increases, 138 and HRQOL, 313 inhibition of cyclobutane dimer removal/ UV-mediated apoptosis, 57 interaction with fluconazole, 95 introduction of, 15 and liver transplantation, 10 for NSF, 117 side effects, 16, 68, 70–71, 71–72, 312 skin cancer, relative effects, 77–78 and survival rates, 3 and UVR, 138 and VEGF, 77 Cystatin M (CST6), and SCC, 56

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cytokines cellular inflammation orchestration, 31 and dendritic cells, 56, 286 IL-7/IL-15, 34 stimulation of DCs, 56 tumor necrosis factor, 31 cytomegalovirus (CMV), 63–64, 98, 101 daclizumab, 13, 18, 41 databases, for transplant dermatology research, 331–335, 332, 338 de novo NMSC, 303–304 deceased donor tramsplants, 3, 16 dendritic cells (DCs) and cognate cellular immunity, 32–35 and cytokines, 56, 286 differentiation to, 31 Denver Transplant Tumor Registry (Cincinnati Transplant Tumor Registry), 11 dermatofibrosarcoma protuberans (DFSP), 144, 158, 206, 306 dermatologic surgery, 249–253, 323–325 dermatologists. See also transplant dermatology, clinics collaboration with transplant physicians, 49 role of, 322–323 transplant dermatology subspecialty, 323– 325 Dermatology Life Quality Index (DLQI), 313 dermatomal HZ, 99 dermatophytic folliculitis (Majocchi’s granuloma), 62 dermatoses. See inflammatory dermatoses dexamethasone, 13, 14 DHA. See diclofenac in hyaluronic acid (DHA) diabetes (type 2) mellitus, 15, 25, 26, 40, 72 diclofenac in hyaluronic acid (DHA) for AK administration, 281 efficacy, 165, 281–282 indications, 280–281 side effects, 282 Disheveled (Dsh), cytoplasmic signaling protein, 54 disseminated histoplasmosis, 63 disseminated HZ, 99 disseminated superficial actinic porokeratosis (DSAP), 119 disseminated superficial porokeratosis (DSP), 119 donor populations, 25, 39, 40–41, 42 doxorubicin, for KS, 197 doxycycline, for Vibrio sepsis, 86 Dragieva studies of ALA-PDT, 292 of Metvix cream, 292 drugs. See antirejection therapy; individual drug listings ECS. See exogenous Cushing’s syndrome (ECS) ecthyma gangrenosum (EG), 62, 83–84

INDEX

eczematous dermatitis, 83 edema, from SRL, 75–76 clinical presentation, 75 mechanism, 75 prevention, 75 treatment, 75–76 education of families of transplant patients, 317, 319 of subpopulations older patients, 319 one/more post transplant skin cancers, 320 remotely transplanted patients, 320 younger patients, 319 of transplant patients barriers to, 317–318, 319 individualized education, 318 posttransplant knowledge, 319 pretransplant knowledge, 315–316 anticipatory skin change guidance, 315–316 Fitzpatrick skin type rating selfevaluation, 315 goals, 315, 316 sun protection guidance, 316–317, 318 electrodesiccation and curettage (ED&C) for actinic cheilitis, 238 for SCC, 175, 249 encephalitis, 99, 101 End Stage Renal Disease Symptom Checklist Transplantation Module (ESRDSCTM), 312 Enterobacteriaceae, 62, 86 eosinophils, 31, 34 epidemiology of in-transit metastatic SCC, 224 of Kaposi’s sarcoma, 143, 195–196 of malignant melanoma, 143 of mycobacterial skin infections, 106 of NSF, 116 of PTLD, 199 of SCC, 142–143 of skin cancer incidence by age, 144 incidence by allograft type, 144 incidence by geographic location, 144–145 incidence by time after transplantation, 145 incidence by type, 142–144 atypical fibroxanthoma, 144 BCC, 143 dermatofibrosarcoma protuberans, 144 lymphomas, 144 malignant fibrous histiocytoma, 144 Merkel cell carcinomas, 143 MM, 143 SCC, 142–143 mortality in OTR, 145 of transplant scalp, 234 epidermodysplasia verruciformis, 138

epidermoid cysts, 122 Epidermophyton, 62 Epstein-Barr virus (EBV), 98, 101 associated PTLD, 101, 155, 199 Escherichia coli, 85 esophagitis and candidal infections, 89 due to CMV, 101 ethambutol, 108 etoposide, 192, 258 etretinate, 213, 272–273, 275, 283 European Skin Care in Organ Transplant Patients Network, 174 everolimus, 16–17, 18 evidence-based guidelines, 49 excisional biopsies for AFX, 158 for BCC, 150 for KA, 152 for MCC, 157 for MM, 154 for PTLD, 156 for SCC, 152, 247 exogenous Cushing’s syndrome (ECS), 67– 69 clinical presentation, 67 mechanism, 67 prevention, 68–69 treatment, primary, 67–68 HPA axis, possible suppression, 67 organ rejection, 68 steroid withdrawal syndrome, 68 treatment, secondary, 68 Exophiala, 90 Exophiala jeanselmei, of heart transplant recipients, 90–91 extracorporeal photophoresis, for NSF, 117 extramammary Paget disease, 306 famciclovir for HSV infections, 98 for VZV, 100 family (of transplant patients) education, 317 field cancerization concept, 234 Fitzpatrick skin types I/II, 150, 315 fluconazole for Candida infections, 95 for dermatomycoses, 62 interactions with CYA/tacrolimus/ sirolimus, 95 for oral/vulvovaginal candidiasis, 89 folliculitis, 74 clinical presentation, 74 mechanism, 74 from sirolimus, 74 treatment, 74 foscarnet for acyclovir-resistant HSV, 99 for CMV, 101 for HHV8, 197 for VZV, 100 Frizzled (Fzd) family, of seven-pass transmembrane receptors, 54

345

INDEX

fulminant sepsis, 86 fungal skin infections deep fungal infections, 92 Blastomyces dermatidis, 92 Coccidioides immitis, 92 Histoplasma capsulatum, 92 Paracoccidioides brasiliensis, 92 Sporothrix schenckii, 92 Trichosporon beigelii, 92 diagnosis, 92–93 hyalohyphomycosis Acremonium, 91–92 Fusarium, 91–92 Penicillium, 91–92 Scedosporium apiospermum, 91 Scopulariopsis, 91–92 therapy, 95 types of classical Malassezia furfur, 88 Microsporum canis, 88 Scopulariopsis spp., 88 Trichophyton rubrum, 88 opportunistic Aspergillus, 89–90 Candida albicans, 88 Candida glabrata, 89 Candida krusei, 89 Candida parapsilosis, 89 Candida tropicalis, 89 Cryptococcus, 89, 90 Scedosporium, 89 Zygomycetes, 89, 90 phaeohyphomycoses, 90 fungi nonvirulent, 62 ubiquitous opportunistic, 62 Fusarium solani species, 62, 91–92 gamma globulin, for necrotizing fascitis, 85 ganciclovir for CMV, 101 for HHV8, 197 for PTLD, 201 gangrenous cellulitis, 90 gastrointestinal symptoms, 16, 17, 132 genes, for cancer susceptibility, 139 genetic polymorphism, 36 genital viral warts. See condyloma acuminatum gingival hyperplasia, 16 from CYA, 71–72, 312 clinical presentation, 71 mechanism, 72 treatment, 72 measurement of, 312 mimicked by oral KS, 154 glucocorticosteroids (GCS) and cutaneous fragility and ecchymosis, 70 and exogenous Cushing’s syndrome, 67–69 skin cancer, relative effects, 76–77 and steroid acne, 69 and striae, 69–70 glutathione-S-transferase (GST) genes, 139 graft-versus-host disease (GVHD)

clinical presentation, 131–132 diagnosis, 132 management, 132 pathogenesis, 131 gram-negative bacilli, 85–86 B. henselae, 86 B. quintana, 86 Bartonella, 86 Enterobacter, 86 Escherichia coli, 85 Klebsiellae pneumonia, 86 Proteus mirabilis, 86 Pseudomonas aeruginosa, 86 Gram-negative cellulitis, 85 granulocytopenia, 62 hands. See transplant hands health-related quality of life (HRQOL) assessment of predictors, 312 association with dermatological disease, 312–313 description, 311 measurement of, 311–312 heart/lungs, end organ disease carcinopermissiveness of regimens, 43 effect on skin cancer incidence, 43 immunogenicity of allografts, 43 immunosuppression reduction ability, 43–44 immunosuppressive regimens, 43 patient demographics, 43 rejection/allograft loss consequences, 44 rejection risks, 43 heart transplantation acitretin for, 273 by Barnard, 9 and BCC, 168 and eruptive AKs, 147 ethnicity of recipients, 43 and Exophiala jeanselmei, 90–91 first patient, 3 and gender, 39 and HHV8 infection, 195 in infants, 113 rejection risk with immunosuppression reduction, 268 hepatitis, 15, 63–64, 99 from CMV, 101 from OKT3 release, 17 and rejection risk, 42 treatment with systemic IFNa, 289 herpes simplex virus (HSV), 62 characteristics, 98 diagnosis, 98 HSV-1/HSV-2, 98–99 treatment, 98–99 types 1/2, 98 herpes zoster (HZ), 99, 100 herpetic ulcer, 83 Herpetoviridae (human herpes virus), 98 HHV8. under human herpesviruses high-risk squamous cell carcinoma (SCC), 179, 212, 254, 302

hirsutism from CYA clinical presentation, 70–71 mechanism, 71 prevention, 71 treatment, 71 from ECS, 67–69 measurement of, 312 Histoplasma capsulatum, 62 HLA proteins, Class 1 and II, 36 HPV infection. See human papillomavirus (HPV) infection human herpesviruses (HHV), 98 see also individual viruses in heart transplant recipients, 195 HHV-6, 98 HHV-7, 98 HHV-8, 98, 101–102, 195 (see also Kaposi’s sarcoma) types 1/2, 98, 99 human leukocyte antigens (HLA), 32 human/mouse chimerical monoclonal antibody preparations (anti-CD25 antibodies), 13 human papillomavirus (HPV) infection, 53, 62, 103–105 and actinic cheilitis, 238 and anal cancer, 128 associated anogenital diseases, 129 and genital warts, 98, 103 imiquimod for, 287 oncogenic types and epidermodysplasia verruciformis, 138 and posttransplant skin carcinogenesis, 138–139 subclasses of, 55 and viral warts, 138 humanized anti-CTLA4 monoclonal antibody, 231 hyalohyphomycosis, 91–92 hyperglycemia, 15, 16 hyperplasia. See gingival hyperplasia; sebaceous hyperplasia hypertension, 15, 16, 25 hypertrophic actinic keratosis, 242 hypothalamic-pituitary axis (HPA), 67 ICOS/ICOSL accessory pathway, 34 IgE-antigen complex, 113 imidazoquinoline family, of drugs, 286 imiquimod cream for actinic cheilitis, 239 for AK, 164–165, 286–287 for BCC, 287–288 for condyloma acuminatum, 104, 286 FDA treatment approvals, 286 for HPV, 287 for SCC, 249, 288 side effects, 288–289 TH-1 immune response stimulation, 286 for transplant scalp, 234 for verrucae vulgaris, 104

346

immune system effector mechanisms, 29 effects of UV radiation, 57, 217, 295–296 elements of function, 30 hyaluronic acid modulation, 280 iatrogenic modification of, 286 in MCC, 190, 192 and psoriasis, 115 in SCC, 217 total body irradiation of, 10 transplant specific considerations, 31–32 immunogenicity of allografts in end organ heart/lung disease, 43 in end organ kidney disease, 41 in end organ liver disease, 42 in end organ pancreas disease, 44 immunologic tolerance, 37 B-cell tolerance, 37 central T-cell tolerance, 37 peripheral T-cell tolerance, 37 immunosuppressive therapy. See also alemtuzumab; azathioprine; basiliximab; biological agents; corticosteroids; cyclosporine; daclizumab; mammalian target of rapamycin (mTOR) inhibitors; mycophenolate mofetil; OKT3; sirolimus; tacrolimus; Thymoglobulin acute/chronic side effects, 13 for BCC, 167 cessation of, 263 developments/current status, 29 direct effects on SCC, 57–58 in end organ heart/lung disease, 43 in end organ kidney disease, 41 in end organ liver disease, 42 in end organ pancreas disease, 44 intensity of in relationship to skin cancer, 263–264 management of prior skin cancer, 306–307 reduction of for aggressive/metastatic skin cancer, 263 associated allograft risks, 265 efficacy of, 262 indications/thresholds for, 264–265 individualization, 267–268 kidney transplantation risks, 268 for KS/PTLD/MCC, 264 logistics, 265–266 physician coordination, 269–270 physician survey, 266 randomized controlled trials, 262–263 rationale for, 262 risks, 268–269 successes of, 13 impaired wound healing, from SRL, 73–74 clinical presentation, 73–74 mechanism, 74 prevention, 74 treatment, 74 in-transit metastatic squamous cell carcinoma (SCC) clinical characteristics of, 224, 225, 226

INDEX

epidemiology of, 224 and high-risk tumors, 225 management of, 225–226 outcomes, 226, 227 pathogenesis, 224 radiotherapy for, 258 treatment options acitretin, 226 bleomycin injections, 225–226 chemotherapy, 225 radiotherapy, 258 incidence statistics of AK, 162–163 of BCC, 167 of metastatic MM, 228 of MM, 182–183 of NMSCs, 137, 172 of SCC, 142–143, 172 of skin cancer by age, 144 by allograft type, 144 by geographic location, 144–145 by time after transplantation, 145 by type, 142–144 atypical fibroxanthoma, 144 BCC, 143 dermatofibrosarcoma protuberans, 144 lymphomas, 144 malignant fibrous histiocytoma, 144 Merkel cell carcinomas, 143 MM, 143 SCC, 142–143 of transplant hands, 242 inflammatory cell population, recruitment, 31 inflammatory dermatoses alopecia areata, 113 atopic eczema, 113–114 miscellaneous conditions, 115–116 nephrogenic systemic fibrosis, 116–117 psoriasis, 114–115 innate immune axis, 29–32 inflammatory cell population, recruitment, 31 localized release of proinflammatory mediators, 29–31 uptake of antigenic material/maturation of antigen presenting cells, 31–32 interferon-a (IFN-a), 117, 286 exacerbation of psoriasis, 114 and in-transit metastases, 225–226 and metastatic MM, 188, 231 interleukin-2 (IL-2), 16, 18, 19, 34, 56, 77 and metastatic MM, 231 and MM, 182 International Transplant Nurses Society (ITNS), 5, 337, 339 International Transplant Skin Cancer Collaborative (ITSCC), 4, 174, 327– 328, 335, 338 invasive squamous cell carcinoma (SCC), 103

isoniazid, 108 isotretinoin (13-cis-retinoic acid), 272, 273 Israel Penn International Transplant Tumor Registry (IPITTR), 3, 11, 79, 204, 228, 305 ITNS. See International Transplant Nurses Society (ITNS) itraconazole for oral/vulvovaginal candidiasis, 89 for phaeohyphomycoses, 91 Jaboulay, Mathieu, 9 Japan, living donor transplantation data, 25 Kaposi’s sarcoma (KS), 11, 86 chemotherapy for, 102, 197 clinical course of, 102 clinicopathologic features of, 196 demographics, 154, 195 diagnosis of, 196–197 epidemiology of, 143, 195–196 and HHV-8, 98, 195 and immunosuppression reduction, 264 management of, 102, 197–198 origin of, 195 pathogenesis of, 195 in pediatric transplant recipients, 247–248 as pretransplantation consideration, 306 prevention of, 198 visceral involvement of, 154 keratinocyte tumors epidermoid cysts, 122 seborrheic keratoses, 122 squamous cell papillomas/verrucal keratoses, 122 keratoacanthoma (KA), 152 kidney disease, end organ alternative therapies, 40 carcinopermissiveness of regimens, 41 donor population, 40–41 effect on skin cancer incidence, 40 immunogenicity of allografts, 41 immunosuppression reduction ability, 41 immunosuppressive regimens, 41 patient demographics, 39 rejection/allograft loss consequences, 41 rejection risks, 41 kidney transplantation, 3 and alopecia areata, 113 and azathioprine, 138 of dog kidney, by Ulmann, 9 by living donors, 25 and lymphomas, 3 maintenance immunosuppression agents, 68 patient demographics, 39 of pigs/sheep, 9 and pustular psoriasis, 115 rejection risk with immunosuppression reduction, 268 and skin cancer, 4 of twins, 9 Kirkwood regimen, 231 Klebsiellae pneumonia, 86

INDEX

leiomyosarcoma, 203–204 lentigo maligna melanoma, 286 lesions. See also verrucal keratoses ABCDE screening guidelines, 183 from AC, 238 from actinic cheilitis, 238 from AK, 147, 162, 163, 177, 208 angioproliferative lesions, 86 anogenital lesions, 128 from BCC, 168 clinically distinct, in transplant scalp, 234– 235 from DSAP, 119 fungal skin lesions, 94 from GCS therapy, 69 from HPV infections, 103–104, 138, 217– 218 from in-transit SCC, 224 from KS, 102, 154, 196, 247 from MCC, 157, 191 from MCV, 102 megasession excision, 249 from metastasis, 159 from MM, 154 mycobacterial lesions, 107 neoplastic lesions, 208 from NSF, 116 from PK, 119, 177 precancerous treatment, 178 from PTLD, 156, 200 of scalp, 234–235 from SCC, 172, 173, 208, 242 warty lesions, 55 Levulan (20% ALA), 291 linear porokeratosis (LPK), 119 lip carcinomas. See actinic cheilitis lipid abnormalities, 16 liquid nitrogen therapy, 71, 103, 164, 277 Lister, Joseph, 9 liver disease, end organ carcinopermissiveness of regimens, 42 donor population, 42 effect on skin cancer incidence, 42 immunogenicity of allografts, 42 immunosuppression reduction ability, 42 immunosuppressive regimens, 42 patient demographics, 41–42 rejection/allograft loss consequences, 42–43 rejection risks, 42 liver transplantation and cyclosporine, 10 and GVHD, 131 and MRSA/MSSA, 83 risk of rejection with immunosuppression reduction, 269 living donor transplantation, 22 geographic variation, 25 issues of concern regarding, 25–26 for kidneys, 25 Long, Crawford, 9 lymphomas, 3, 11, 144, 200 lymphoreticular system, 11 M. abscessus, 106, 107

M. avium-intracellulare complex, 106 M. celatum, 108 M. chelonae, 106, 107 M. fortuitum, 106 M. genavense, 107, 108 M. haemophilum, 107, 108 M. kansasii, 106, 108 M. malmoense, 107 M. marinum, 106, 107, 108 M. simiae, 108 M. tuberculosis, 106, 107 M. ulcerans, 106, 107 M. xenopi, 106 magnetic resonance imaging (MRI), 116, 226, 255 major histocompatibility complex (MHC), 29, 32–33, 33, 56 Malassezia furfur, 88 malignant fibrous histiocytoma (MFH), 144, 157, 203 malignant melanoma (MM), 3, 11, 137 see also metastatic malignant melanoma (MM) biopsies for, 154 clinical presentation of, 183–184 epidemiology, 143 incidence of, 182–183 management of, 187–188 outcomes, 184–187 pathogenesis of, 182 risk factors, 183–184 stage groupings, 185 survival rates, 186 mammalian target of rapamycin (mTOR) inhibitors, 13 and CNI combination, 16 everolimus, 16–17, 18 and metastatic MM, 231 sirolimus, 16–17 management options for actinic cheilitis, 238–239 for AK, 163–165, 174 imiquimod cream, 164–165 liquid nitrogen therapy, 164 photodynamic therapy, 164 systemic retinoids, 165 topical 5-fluorouracil cream, 164 for GVHD, 132 for in-transit metastatic SCC, 225–226 for KS, 102 for metastatic MM, 229 for metastatic SCC, 219–221 for MM, 187–188 for NSF, 116–117 for PK, 174 for PLTD, 200–202 for SCC, 173–177, 239 for skin cancer, 248, 249, 252 for transplant hands, 242 for transplant scalp, 234–235, 235 for verrucae, 174 Mandel-Mantoux screening, 107 Martinez, Juan-Carlos, 4, 224, 328 matrix metalloproteinases (MMPs), 56, 78

347

Mayo Transplant Dermatology Clinic model, 323 MC1R gene, 139 Medawar, P. B., 36 MEDLINEÒ-cited publications, 48 megasession excisions, 249–252 advantages, 252 anesthesia, 250 complications, 251 disadvantages, 252 indications, 249–250 key elements, 251 outcomes, 251 preparation, 249–250 risk minimization, 250 techniques, 250 melanocytic nevi, 143 in adults, 123–124 in children, 115, 123–124, 247 melanoma histopathologic features, 212–213 in pediatric transplant recipients, 247 pretransplantation, risk of recurrence/ death, 305 and PTN, 55 TNM classification, 184 Memorial Sloan Kettering Cancer Center study, of MCC survival rates, 193 Merkel cell carcinomas (MCC), 11, 143 clinical presentation, 191 excisional biopsy for, 157 immunohistochemistry diagnostic panel, 192 and immunosuppression reduction, 264 neuroendocrine origins, 156 pathology of, 191–192 PET evaluation, 302 as pretransplantation consideration, 305–306 and SLNB biopsy, 192 and ‘‘small blue cell tumors,’’ 191 staging/prognosis, 192 survival rates, 193 treatment options, 192–193 carboplatin, 192, 258 chemotherapy, 192, 258 Mohs micrographic surgery, 157 radiotherapy for, 257–258 metabolic syndrome, related diseases, 25 metastatic malignant melanoma (MM) American Joint Committee on Cancer staging for, 230 and calcineurin inhibitors, 230 incidence/prognosis of, 228 and Interferon-a, 188, 231 and interleukin-2, 231 management options, 229 PET evaluation, 302 and sirolimus, 230 and temsirolimus (CCI-779), 230 therapeutic strategies, 228–229 biochemotherapy, 231 chemotherapy, 230

348

humanized anti-CTLA4 monoclonal antibody, 231 immunological therapy cytokine/vaccine therapy, 231 immunosuppression modification, 230 immunosuppression reduction, 229 mTOR inhibitors, 231 tyrosine kinase inhibitors, 231 treatment, localized, 231–232 radiation therapy, 232 surgical management, 231–232 metastatic nodal squamous cell carcinoma (SCC), 256–257 metastatic squamous cell carcinoma (SCC) chemotherapy for, 220 clinical presentation of, 218–219 management of, 219–221 pathogenesis of, 217–218 prevention of, 221 prognosis, 218 treatment options, 220 methicillin-resistant S. aureus (MRSA), 83 methicillin-susceptible S. aureus (MSSA), 83 methylaminolevulinate (MAL), in PDT, 164 methylene tetrahydrofolate reductase (MTHFR) gene, 139 methylprednisolone, 13, 14, 131 Metvix cream, 291, 292 MHC proteins, 29, 31, 32 microcystic adnexal carcinoma (MAC), 205, 306 Microsporum species, 62, 88 Mohs micrographic surgery, 4, 175 advantages of, 175 for BCC, 169 cure rates from, 175 for MCC, 157, 192 for SCC, 239, 249 for transplant scalp, 235 molluscum contagiosum virus (MCV), 83, 102–103 monitoring guidelines, 15 for adrenal insufficiency, 68 of allograft function, 29, 47, 201 of cardiorespiratory function, 250 CNI blood levels, 15, 95 for early rejection signs, 269 for hyperlipidemia, 165 of immunosuppression reduction effects, 269 for increasing viral load, 202 for liver dysfunction, 165 for systemic retinoids, 275 monoclonal antibodies, 13, 17–18 monocyte chemotactic peptide 1 (MCP-1), 31 monocytes, 31, 56, 77, 213, 291 mortality of skin cancer, in OTR, 145 Morton, William, 9 mouse monoclonal antibody preparations (anti-CD3 antibody), 13 MRSA. See methicillin-resistant S. aureus (MRSA)

INDEX

MSSA. See methicillin-susceptible S. aureus (MSSA) mTOR inhibitors. See mammalian target of rapamycin (mTOR) inhibitors Muir-Torre Syndrome (MTS), 204 multiagent immunosuppressive regimens, 10, 77, 177, 265 mupirocin. See topical mupirocin muromonab-CD3. See OKT3 (muromonabCD3) mutant clone theory, of PK, 119 mycobacterial infections, 62, 106, 107, 327 mycobacterial skin infections acquisition risks, 106 clinical manifestations, 106–107 diagnosis, 107 epidemiology, 106 treatment, 107–108 Mycobacterium avium complex (MAC), 106, 107, 108 mycophenolate mofetil (MMF), 13, 15, 73, 78 National Cancer Institute, 338 National Cancer Institute’s SEER (Surveillance, Epidemiology, and End Results) database, 182, 331 National Institute of Diabetes and Digestive and Kidney Disease Questionnaire (NDDK), 312 natural killer (NK) cells, 17, 31, 56, 131, 200 necrotizing cellulitis, 83 neoplasia, 54 anal/cervical, 128–129 vulval, 129–130 neoplasms of epithelium (see keratoacanthoma) of lymphoreticular system, 11 rare cutaneous neoplasms angiosarcoma, 205–206 associated biologic behavior, 204 atypical fibroxanthoma, 203 dermatofibrosarcoma protuberans, 206 leiomyosarcoma, 203–204 malignant fibrous histiocytoma, 203 microcystic adnexal carcinoma, 205 sebaceous carcinoma, 204–205 spindle-cell (see atypical fibroxanthoma) of vermillion, 240 nephrogenic systemic fibrosis (NSF), 116–117 alternate therapies, 117 associated features, 116 anticardiolipin antibodies, 116 deep venous thrombosis, 116 protein C and S deficiency, 116 pulmonary embolus, 116 clinicopathologic findings, 116 differential diagnosis, 116 epidemiology, 116 histopathology of, 116 management of, 116–117 nephrotoxicity, 16, 108

neurotoxicity, 16 nevi. See melanocytic nevi New Zealand, living donor transplantation data, 25 NF-kB, and SCC, 54 NMSCs. See nonmelanoma skin cancers (NMSCs) Nocardia asteroides, 87 Nocardia species, 62 nocardiosis and aerobic actinomycete, 87 and TMP-SMX, 87 nodular basal cell carcinoma, 147 non-Hodgkin lymphoma, 138 nonmelanoma skin cancers (NMSCs) among Caucasian/Caucasian Australians, 137 incidence of, 137, 172 multiple de novo, posttransplantation risks, 303–304 and oral corticosteroids, 138 in pediatric transplant recipients, 246–247 risk factors, 163, 167 treatment options acitretin, 213 oral corticosteroids, 138 nontuberculous NTM, 106, 107 nonvirulent fungi, 62 North American Transplant-Skin Cancer Collaborative, 4, 327 nurse practitioner clinics, 326 OKT3 (muromonab-CD3), 13, 17, 132, 199 onychomycosis, 88, 94–95 opportunistic infections. See also Kaposi’s sarcoma (KS) Aspergillus, 89–90 Candida albicans, 88 Candida glabrata, 89 Candida krusei, 89 Candida parapsilosis, 89 Candida tropicalis, 89 Cryptococcus, 89, 90 Scedosporium, 89 Zygomycetes, 89, 90 opportunistic pathogens, 61, 83 OPTN. See Organ Procurement and Transplantation Network (OPTN) oral candidiasis, 89 oral corticosteroids, and NMSCs, 138 oral florid papillomatosis, 104, 238 oral steroids, for NSF, 117 Organ Procurement and Transplantation Network (OPTN), 22, 24, 39, 331 ‘‘Organ Transplant Recipients-Skin Cancer Prevention’’ brochure (ITSCC), 329 organizations, for transplant dermatology, 327–330 organs, demand vs. availability, 25 osteoporosis, 15, 273, 299 otitis media, 85 Otley, Clark, 4, 328 OX40/OX40L accessory pathway, 34

349

INDEX

P16, and SCC, 53–54 P-selectin adhesion protein, 31 Paecilomyces, 62 Paget’s disease, 204, 306 Pan American Transplant-Skin Cancer Collaborative, 327 pancreas, end organ disease alternate therapies, 44 carcinopermissiveness of regimens, 44 effect on skin cancer/disease, 44 immunogenicity of allografts, 44 immunosuppression reduction ability, 44 immunosuppressive regimens, 44 patient demographics, 44 rejection/allograft loss consequences, 44–45 rejection risks, 44 pancreas transplants, 18, 26, 39, 44, 113 Pasteur, Louis, 9 pathogen physiology, 83 pathogenesis of AK, 162 of BCC, 167 age at transplantation, 167 HPV, 167 immunosuppression, 167 pretransplant skin cancers, 167 UV exposure, 167 of in-transit metastatic SCC, 224 of KS, 195 of metastatic SCC, 217–218 of MM, 182 of PFLD, 199 of SCC, 172–173 of transplant hands, 242 of transplant scalp, 234 patient demographics for end organ kidney disease, 39 for end organ pancreas disease, 44 for heart/lungs transplants, 43 for liver disease transplants, 41–42 pediatric transplant recipients. See skin cancer, in pediatric recipients Penicillium, 91–92 Penn, Israel, 3, 11 perineurial invasion, from SCC, 255 peripheral T-cell tolerance, 36 PET. See positron emission tomography (PET) phaeohyphomycoses, 90 photoaging, 53, 279, 283, 295 photocarcinogenicity, 137–138 photodynamic therapy (PDT) for actinic cheilitis, 239 advantages/disadvantages, 292 for AK, 164 for BCC, 170 for Bowen’s disease, 170, 291–292 clinical applications, 291–292 light sources, 291 mechanisms of action, 291 photosensitizing agents, 291 aminolevulinic acid, 164, 291 methylaminolevulinate, 164 side effects, 292–293

for transplant scalp, 234 treatment optimization, 293 physicians. See dermatologists transplant physicians pityriasis versicolor, 88 Pityrosporum folliculitis, 69 Pityrosporum species, 62 planar type (HPV 10) viral warts, 139 pleuropulmonary disease, 107 pneumonitis, 16, 99, 101 polyclonal antibody preparations (rabbit/ horse antilymphocyte antibodies), 13 antilymphocyte antibodies, 17 antithymocyte antibodies, 17 Thymoglobulin, 17 porokeratosis palmaris, plantaris et disseminata (PPPD), 119 porokeratosis (PK). See also disseminated superficial actinic porokeratosis (DSAP); disseminated superficial porokeratosis (DSP); linear porokeratosis (LPK); punctate porokeratosis (PPK) associated with organ transplantation, 119–120 chemotherapy for, 119 and malignancy, 120 management of, 174 mutant clone theory of, 119 pathogenesis, 119 porphyria cutanea tarda, 116 posaconazole, for zygomycosis, 90 positron emission tomography (PET), 157, 249, 302 Post-transplant Skin Cancer Research Group (Ohio State University), 338 posttransplant lymphoproliferative disorder (PTLD), 101, 155–156 associated EBV, 101, 155, 199 and bone marrow transplantation, 155, 199 clinical presentation of, 200 epidemiology of, 199 first-line therapy for, 201 and immunosuppression reduction, 264 management of, 200–202 pathogenesis of, 199 prevention of, 202 treatment options acyclovir/ganciclovir, 201 chemotherapy, 202 first-line therapy, 201 prednisolone, 13, 14, 77, 132 prednisone, 10, 13 and AZA combination, 3, 10, 73 for renal transplant patients, 73 pretransplantation skin cancer, 302–307 and AFX, 306 allograft-specific considerations, 303 and BCC, 303 and DFSP, 306 evaluation of candidates, 302–303, 303 and extramammary Paget disease, 306 immunosuppression management, 306–307

and KS, 306 and MAC, 306 and MCC, 305–306 and melanoma, 305 prognostic factors, 303 and SCC, 304 and sebaceous carcinoma, 306 suggested assessments, 304 and sweat gland carcinomas, 306 prevention strategies of acne folliculitis, 74 of actinic cheilitis, 74, 240 of AK, 165 of alopecia, from TAC, 72 of BCC, 170 of cutaneous fragility and ecchymosis, 70 of ECS, 68–69 of edema, from SRL, 75 of gingival hyperplasia, from CYA, 72 of hirsutism, from CYA, 71 of impaired wound healing, from SRL prevention, 74 of metastatic SCC, 221 of SA, 69 of SCC, 177–180 of sebaceous hyperplasia, from CYA, 71 of striae, 70 of transplant hands, 242 proinflammatory mediators, transplant considerations, 29–31 proteases/protease inhibitors, and SCC, 55– 56 Proteus mirabilis, 86 Prototheca, 62 Pseudomonas aeruginosa, 62, 86 Pseudomonas species, 62 psoralen photochemotherapy (PUVA) influence on skin cancer, 138 for NSF, 117 psoriasis, 114–115 from CYA, 138 and DLQI, 313 and PUVA, 138 PTN, and SCC, 55 pulmonary infections, 62 punctate porokeratosis (PPK), 119 PUVA. See psoralen photochemotherapy (PUVA) pyogenic granulomas, 86 pyrizinamide, 108 quality of life (QOL). See health-related quality of life (HRQOL) radiologic imaging, 249 radiotherapy (RTx) advantages of, 259 for BCC, 170, 258–259 disadvantages of, 259 for in-transit metastatic SCC, 258 for Merkel cell carcinoma, 257–258 for primary lip SCCs, 239 reactions to acute, 259–260

350

late, 260 for SCC, 249, 254–257 adjuvant nodal RTx, 256 adjuvant RTx, post surgical excision, 256 high-risk SCC, 254 lip SCC, 255 metastatic nodal SCC, 256–257 primary site SCC, 254–255 stereotactic/whole-brain, 232 for transplant scalp, 235 rapamycin. See sirolimus rare cutaneous neoplasms angiosarcoma, 205–206 associated biologic behavior, 204 atypical fibroxanthoma, 203 dermatofibrosarcoma protuberans, 206 leiomyosarcoma, 203–204 malignant fibrous histiocytoma, 203 microcystic adnexal carcinoma, 205 sebaceous carcinoma, 204–205 RAS oncogene, and human cutaneous SCC, 54 recipient, of solid organ transplants follow-up visit intervals, 179 patient demographics for end organ kidney disease, 39 for end organ pancreas disease, 44 for heart/lungs transplants, 43 for liver disease transplants, 41–42 time-course of transplant-related complications, 46 reduction, of immunosuppressive therapy for aggressive/metastatic skin cancer, 263 efficacy of, 262 indications/thresholds for, 264–265 individualization, 267–268 for KS/PTLD/MCC, 264 levels of, and associated allograft risks, 265 logistics, 265–266 physician coordination, 269–270 physician survey, 266 randomized controlled trials, 262–263 rationale for, 262 risks, 268–269 registries, of transplants, 22 IP-ITTR, 3, 11, 79, 204, 228, 305 Organ Procurement and Transplantation Network, 22, 39 Scientific Registry of Transplant Recipients, 39 Swedish Cancer Registry, 128, 145 Transplant Recipients International, 5, 328 United Network for Organ Sharing (UNOS), 39, 264, 331, 337 rejection, risk of. See also antirejection therapy; immunosuppressive therapy in end organ heart/lung disease, 43 in end organ kidney disease, 41 in end organ liver disease, 42 in end stage pancreas disease, 44 research databases, for transplant dermatology, 331–335, 332 retinoid acid receptors (RARs), 272

INDEX

retinoid X receptors (RXRs), 272 retinoids. See systemic retinoids; topical retinoids Rhizopus species, 62 rifampicin, for M. tuberculosis, 108 risk factors for AA, 72 for actinic cheilitis, 238 for AK, 162, 165 for BCC, 167 for GVHD in liver transplant patients, 131 for melanoma/nonmelanoma skin cancer, 137 for MM, 143, 183–184 for mycobacterial disease, 106 for NMSC, 163, 167 for rejection end organ heart/lung disease, 43 end organ kidney disease, 41 end organ liver disease, 42 end stage pancreas disease, 44 for SCC, 172, 305 of sirolimus, for wound healing, 73 Salasche, Stuart, 4, 5, 328 salicylic acid, topical for condyloma acuminatum, 104 for verruca vulgaris, 104 scalp. See transplant scalp Scandinavia, living donor transplantation data, 25 SCC. See squamous cell carcinoma (SCC) Scedosporium apiospermum, 89, 91 Scientific Registry of Transplant Recipients (SRTR), 39 scleroderma, 116, 147 sclerosing BCC, 286 Scopulariopsis, 88, 91–92 sebaceous carcinoma, 204–205, 208, 306 sebaceous gland hyperplasia (SGH), 123 from CYA, 71 clinical presentation, 71 mechanism, 71 prevention, 71 treatment, 71 seborrheic keratoses, 119, 122, 147, 210 SEER (Surveillance, Epidemiology, and End Results) database, National Cancer Institute, 182 self-examination of lymph nodes, 177 of skin, 177, 221, 300, 318–319 sentinel lymph node biopsy (SLNB), 176, 192, 219, 226, 235, 239, 252, 258 seven-pass transmembrane receptors, 54 side effects of acitretin, 273–275 of calcineurin inhibitors, 70–72 of cyclosporine, 16, 68, 70–71, 71–72, 72 of DHA, 282 of imiquimod cream, 288–289 of immunosuppressive therapy, 13 of PDT, 292–293 of sirolimus, 16, 73–74, 74, 75–76

of systemic retinoids, 273–275 of tacrolimus, 71, 72, 113 of topical retinoids, 283 sirolimus (SRL), 16–17, 73–76 see also temsirolimus (CCI-779) cancer-sparing effects of, 264 and decreased VEGF production, 75, 230 interaction with fluconazole, 95 and NMSC, 230 side effects, 16, 73–74, 74, 75–76 skin cancer, relative effects, 78–79 treatment of cellulitis, 74 6-mercaptopurine, 10, 15, 77 skin biopsy, 86, 107, 131, 150, 157 skin cancer as contraindication to organ transplantation, 307 described by Walder, 3 donor derived, 302 evaluation of transplant candidates, 302– 303 immunosuppressive agents, relative effects, 76–79 AZA, 77 CYA, 77–78 GCS, 76–77 MMF, 78 SRL, 78–79 TAC, 78 incidence of, 263–264 end organ kidney disease, 40 end organ liver disease, 42 management of, 249, 252 megasession excisions, 249–252 advantages, 252 anesthesia, 250 complications, 251 disadvantages, 252 indications, 249–250 outcomes, 251 preparation, 249–250 risk minimization, 250 techniques, 250 posttransplantation risk of multiple de novo NMSC, 303–304 prior, and transplant-associated immunosuppression, 302–303 radiologic imaging of, 249 reconstruction principles, 252 in renal transplant recipients, 4 and solid organ transplantation, 3 time from transplant to appearance, 11 skin cancer, clinical presentation/diagnosis actinic keratosis, 147 atypical fibroxanthoma, 157–158 basal cell carcinoma, 147–150 cutaneous PTLD, 155–156 Kaposi’s sarcoma, 154–155 keratoacanthomas, 152 malignant melanoma, 152–154 Merkel cell carcinoma, 156–157 metastasis, 158–160 squamous cell carcinoma, 150–152 skin cancer, epidemiology

INDEX

incidence by age, 144 incidence by allograft type, 144 incidence by geographic location, 144–145 incidence by time after transplantation, 145 incidence by type, 142–144 atypical fibroxanthoma, 144 BCC, 143 dermatofibrosarcoma protuberans, 144 KS, 143 lymphomas, 144 malignant fibrous histiocytoma, 144 Merkel cell carcinomas, 143 MM, 143 SCC, 142–143 standardized incidence ratios, 143 mortality in OTR, 145 skin cancer, histopathologic features of actinic keratoses, 208 of basal cell carcinoma, 211–212 of melanoma, 212–213 special considerations, 213 in squamous cell carcinoma (SCC), 208 skin cancer, in pediatric recipients, 246–248 Kaposi’s sarcoma, 247–248 management of, 248 melanoma/melanocytic nevi, 115, 247 nonmelanoma skin cancer, 246–247 skin cancer, pathogenesis drug-induced malignancy, 138 HPV/posttransplant, 138–139 photocarcinogenicity, 137–138 skin cancer, pretransplantation, 302–307 and AFX, 306 allograft-specific considerations, 303 and BCC, 303 and DFSP, 306 evaluation of candidates, 302–303, 303 and extramammary Paget disease, 306 immunosuppression management, 306– 307 and KS, 306 and MAC, 306 and MCC, 305–306 and melanoma, 305 prognostic factors, 303 and SCC, 304 and sebaceous carcinoma, 306 suggested assessments, 304 and sweat gland carcinomas, 306 skin cancer, prevention photoprotection, 170, 296–299 self-examination, 300 sun-protective clothing, 299 sunscreens, 296–297 clinical efficacy of, 298 limitations of, 298 summary of ingredients, 297 UVA/UVB with SPF >30, 296 ultraviolet radiation, 295–296 and Vitamin D, 299–300 Skin Cancer Foundation, 338 Skin Cancer in Organ Transplant Patients Europe (SCORE), 335

Skin Care in Organ Transplants, Europe (SCOPE), 4–5, 327, 338 skin grafts, 9, 177, 242, 243 skin infections diagnostic considerations, 64 time frame considerations, 63–64 first month, 63 one to six months, 63–64 six months+, 64 types of, 61–63 opportunistic primary cutaneous infection, 62 by pathophysiologic events, 61 primary, with common true systemic, metastatic to cutaneous/ subcutaneous sites, 62–63 unusually widespread cutaneous infection, 62 skin type and actinic cheilitis, 238 and carcinogenicity, 139 Fitzpatrick types I/II, 150 and MC1R polymorphisms, 139 and SCC, 142 small blue cell tumors, 191 small intestine transplantation, 24, 131 small-molecule drugs, 13 SNLB. See sentinel lymph node biopsy (SLNB) soft-tissue infections ecthyma gangrenosum, 62, 83–84 and Staphylococcus aureus, 83–84 and Vibrio vulnificus, 86 solid organ transplantation. See also allogenic solid organ transplantation; living donor transplantation autografts vs. allografts, 9 current status overview, 22 future of, 27 history of, 9–11 and increased uncommon tumors, 11 malignant disease hazard, 10–11 overall strategy for, 13–14 reason for failures, 9 recent developments, 24–27 and skin cancer, 3, 10 survival rates, 22–24 trends, 22–24, 25 spindle-cell tumors, 158 Sporothrix schenckii, 92 squamous cell carcinoma in situ (SCCIS). See also Bowen’s disease biopsies for, 152 and development of AK, 147 due to HPV, 103 and imiquimod, 286 ratio to BCC, 143, 168 treatment options, 178 imiquimod, 286 PDT, 291–292 tumors from, 150 squamous cell carcinoma (SCC), 3, 11 see also high-risk squamous cell carcinoma (SCC); in-transit

351

metastatic squamous cell carcinoma (SCC); metastatic nodal squamous cell carcinoma (SCC); metastatic squamous cell carcinoma (SCC); transplant hands; transplant scalp and AK, 147 atypical presentations, 151–152 biopsies for, 152 chemotherapy for, 176–177 clinical presentation, 150, 173 cryosurgery for, 175 direct effect of immunosuppressive agents, 57–58 ED&C for, 175, 249 epidemiology of, 142–143 high risk, criteria, 212 high-risk clinical/pathological features, 176 histopathologic features, 208 and imiquimod, 286 incidence of, 172 of lip, 11 and local immune microenvironment, 56– 57 management of, 173–177, 239 in men, 142 pathogenesis of, 172–173 perineurial invasion from, 255 pretransplantation, risk of recurrence/ death, 304 prevention of, 177–180 ratio to BCC, 143, 147 risk factors, 172, 305 scientific mechanisms of accelerated development, 53–58 CDKN2a and P16, 53–54 HPV, 55 increased KRAS, 54 P53 mutation, 53 proteases/protease inhibitors, 55–56 PTN, 55 RAS oncogene, 54 ultraviolet radiation, 53 WNT signaling, 54–55 treatment options, 178, 239 acitretin, 170, 226 chemotherapy, 176–177 curettage, 178, 249 imiquimod, 288 Mohs micrographic surgery for, 239 multiagent regimen, 177 radiotherapy, 249, 254–257 in women, 142 in younger patients, 142 squamous cell papillomas, 122 standardized incidence rations (SIR), population-based, 143 staphylococcal scalded skin syndrome, 83 staphylococcal scarlet fever, 83 Staphylococcus aureus, 62. See also methicillin-resistant S. aureus (MRSA); methicillin-susceptible S. aureus (MSSA) causative for pyodermas/soft-tissue infections, 83–84

352

toxins produced by, 83 treatment with topical mupirocin, 83 steatohepatitis, 25 stereotactic radiotherapy, 232 steroid acne (SA), 69 clinical presentation, 69 mechanism, 69 prevention, 69 treatment, 69 Streptococcus pneumonia, 85 Streptococcus pyogenes, 84 Streptomyces hygroscopicus, 16, 78 striae, 69–70 mechanism, 70 prevention, 70 treatment, 70 stucco keratosis, 242 sun protection issues patient education, 316–317, 318 sun-protective clothing, 299, 317 sunscreens, 296–297, 316–317 clinical efficacy of, 298 limitations of, 298 measuring efficacy of, 297 summary of ingredients, 297 UVA/UVB with SPF >30, 296 superficial basal cell carcinoma (sBCC), 147 dosing schedule, 287 treatment options imiquimod, 286 PDT, 291–292 surgical excision, for primary lip SCCs, 239 Surveillance Epidemiology End Result (SEER), 79, 331 survival rates, 22–24 and cyclosporine, 3 deceased donor vs. living transplants, 3 sweat gland carcinomas, 306 Swedish Cancer Registry, 128 systemic retinoids. See also acitretin; etretinate; isotretinoin (13-cisretinoic acid); topical tretinoin administration, 275 for AK, 165 efficacy of, 272–273 immunomodulating effects, 272 monitoring guidelines, 275 side effects, 273–275 study details, 274 systemic sclerosis/morphea, 116 T-cells. See also CD 4 positive T-cells; CD 8 positive T-cells axis, 32–35 central T-cell tolerance, 37 costimulation, 33–34 differentiation, effector function, and memory, 34–35 differentiation from B-cells, 35 peripheral T-cell tolerance, 37 tacrolimus (TAC), 13 and HRQOL, 313 interaction with fluconazole, 95 replacement for CYA, 15

INDEX

side effects alopecia, 72, 113 hirsutism, 71 temsirolimus (CCI-779), 230 thiopurine-s-methyl transferase (TPMT) gene, 139 Thymoglobulin, 17 time-course, of transplant-related complications, 46 topical 5-fluorouracil cream for actinic cheilitis, 239 for AK, 164, 277 administration, 277–278 in combinations, 279 comparison studies, 279 efficacy, 278–279 extremities, 279 indications, 277 photoaging, 279 side effects, 279–280 for SCC, 249 for transplant scalp, 234 topical diclofenac, 277 topical mupirocin, 83 topical retinoids, 277, 282–283 for AK, 165, 277, 282–283 for condyloma acuminatum, 104 for verruca vulgaris, 103 topical steroids, 117 topical tretinoin, 273, 283 toxic shock syndrome (TSS), 83 toxicities, of CNIs, 16 TPMT gene. See thiopurine-s-methyl transferase (TPMT) gene transplant cutaneous oncology divisions in field of, 3 timeline, 4 transplant dermatology history of, 3–4 introduction, 3 organizations in, 4–5 and skin cancer, 3 transplant dermatology, clinics. See also nurse practitioner clinics; tumor management clinics dedicated clinics, 323–325 Europe, 324 North America/Australia, 325 general/existing dermatology clinics, 323 integration with transplant clinics, 325–326 Mayo Clinic model, 323 role of dermatologist, 322–323 transplant dermatology, resources ACMMSCO, 4, 328, 337 American Academy of Dermatology, 4, 328, 337 American Cancer Society, 337 AST, 337 ASTS, 328, 337 AT-RISC, 5, 328, 336–337, 338 British Association of Dermatologists, 338 Cancer Council Australia, 337 Center for Disease Control, 338 CenterSpan website, 337

ITNS, 5, 337, 339 ITSCC, 174, 327–328, 335, 336, 338 National Cancer Institute, 338 Post-transplant Skin Cancer Research Group, 338 SCOPE, 4–5, 327, 336, 338 Skin Cancer Foundation, 338 Transplant Skin Cancer Database and Tissue Bank, 338 Transplantation Society, 337 TRIO, 5, 338 UNOS, 264, 331, 337 transplant dermatology organizations, 327–330 transplant hands clinical presentation of, 242 incidence/prevention of, 242 management of, 242 outcome measures, 244–245 pathogenesis of, 242 perioperative considerations, 242–244 and skin grafts, 243 transplant physicians, collaboration with dermatologists, 49 Transplant Recipients International Organization (TRIO), 5, 338 transplant scalp epidemiology of, 234 management/treatment of, 234–235 clinically distinct lesions, 234–235 ill-defined disease, 235 and Mohs micrographic surgery, 235 pathogenesis of, 234 Transplant Skin Cancer Database and Tissue Bank (UC San Francisco), 338 transplant-specific considerations antibody effector functions, 36 inflammatory cell population, recruitment, 31 MHC/antigen presentation to T-cells, 32– 33 proinflammatory mediators, localized release, 29–31 T-cell costimulation, 33–34 T-cell differentiation, effector function and memory, 35 uptake of antigenic material/maturation of antigen presenting cells, 31–32 Transplantation Society, 337 treatment options of AA, from TAC, 72 of acne folliculitis, 74 of AGIN, 129 of BCC, 169–170 cryotherapy, 169 curettage, 170 PDT, 170 radiotherapy, 170 topical immunomodulators, 170 of BCC analysis/advantages-disadvantages, 170 of cytomegalovirus, 101 of ECS, primary, 67–68 HPA axis, possible suppression, 67

353

INDEX

organ rejection, 68 steroid withdrawal syndrome, 68 of ECS, secondary, 68 of edema, from SRL, 75–76 of gingival hyperplasia, from CYA, 72 of hirsutism, from CYA, 71 of HSV, 98–99 of impaired wound healing, from SRL, 74 of M. celatum, 108 of M. genavense, 108 of M. haemophilum, 108 of M. kansasii, 108 of M. marinum, 108 of M. simiae, 108 of MCC, 157, 192–193, 257–258 of metastatic MM, 228–229 of metastatic SCC, 220 of mycobacterial skin infections, 107–108 of phaeohyphomycoses, 91 of SA, 69 of SCC, 178 of SCCIS, 178 of sebaceous hyperplasia, from CYA, 71 for Staphylococcus aureus, 83 for striae, 70 of transplant scalp clinically distinct lesions, 234–235 ill-defined disease, 235 Trichophyton species, 62, 88 trifluridine, intravenous, for acyclovirresistant HSV, 99 trimethoprim-sulfamethoxazole (TMPSMX), for nocardiosis, 87 TSS. See toxic shock syndrome (TSS) tumor management clinics, 326 tumor necrosis factor (TNF), 31, 78, 286 tumorigenesis, 53, 242 tumors appendageal tumors melanocyte nevi, 123–124 sebaceous gland hyperplasia, 123 high-risk, of in-transit metastatic SCC, 225 keratinocyte tumors epidermoid cysts, 122 seborrheic keratoses, 122

squamous cell papillomas/verrucal keratoses, 122 regression of, 56 for SCCIS, 150 small blue cell tumors, 191 soft-tissue tumors, 124–126 spindle-cell tumors, 158 uncommon, 11 tyrosine kinase inhibitors, 220, 231 ultraviolet radiation (UVR). See also sun protection issues biological effects, 295 physics of, 295 overexposure, 53 (see also photocarcinogenicity) and actinic cheilitis, 238 and BCC, 167 as complete carcinogen, 137 and cutaneous carcinogenesis/ photoaging, 53 dampening of antitumor immunity, 57 induction of mutations/ immunosuppression, 138 influence of PUVA, 138 subdivisions of, 137 sun exposure and immunosuppression, 295–296 and sun-protective clothing, 299 United Kingdom, living donor transplantation data, 25 United Network for Organ Sharing (UNOS), 39, 264, 331, 337 United States living donor transplantation data, 25 2005 transplant statistics, 60 valaciclovir for HSV infections, 98 for VZV, 100 varicella-zoster virus (VZV), 62, 98, 99–101 complications, 99 diagnosis, 100 vascular anastomosis, 9 vascular endothelial growth factor (VEGF), 75

and cyclosporine, 77–78 and sirolimus, 230 vermilionectomy, 238 verruca vulgaris, 242 verrucae and cryotherapy, 103 due to HPV, 103 management of, 174 verrucal keratoses, 122 Vibrio vulnificus, 86 vinca alkaloids, for KS, 197 viral load, increase of, 15 viral pathogens cytomegalovirus, 101 Epstein-Barr virus, 101 herpes simplex virus-1/-2, 98–99 Herpetoviridae (human herpes virus), 98 human herpes virus-8, 101 human papillomavirus infections, 103–105 molluscum contagiosum virus, 102–103 varicella-zoster virus, 99–101 viral warts (HPV-induced squamous cell papillomas), 122, 138 and imiquimod, 289 planar type (HPV 10), 139 visceral Kaposi’s sarcoma, 154 Vitamin A, 272 see also systemic retinoids; topical retinoids Vitamin D, 299–300 Voronoy, Yu Yu, 9 vulval intraepithelial neoplasia (VIN), 128, 129–130 alternative therapies, 129–130 differentiated/undifferentiated, 129 vulvar carcinoma, 11 warty lesions, 55 whole-brain radiotherapy, 232 WNT signaling, and SCC, 54–55 World Transplant Congress, 328 xeroderma pigmentosum, 272 Zygomycetes, 89, 90 zygomycosis, and posaconazole, 90